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Lecture Notes

Table of Contents: Cardiovascular Diseases

09/18/2013

Dana R. Abendschein, Ph.D.

Cardiovascular Diseases Table of Contents

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Welcome to Cardiovascular Disease

Remember Last Year? Fundamentals of ElectrocardiographyA Review
Systemic Hypertension and Antihypertensive Therapy
Ischemic Heart Disease and Acute Coronary Syndromes I and II
Hypertension Case Studies
Sinus Rhythm and Bradycardia
Ventricular Arrhythmias
Supraventricular Tachycardias
Ischemic Heart Disease Case Studies
Arrhythmia Therapy
Heart Failure and Cardiomyopathies
Arrhythmia Case Studies
Heart Failure Therapy
Valvular Heart Disease
Heart Failure Case Studies
Congenital Heart Disease
Valvular Heart Disease Case Studies
Congenital Heart Disease Case Studies

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Lecture Notes

Welcome to Cardiovascular Disease: 2013!

09/18/2013

Dana R. Abendschein, Ph.D.

Welcome to Cardiovascular Disease: 2013!

1. Faculty Contact
Dana R. Abendschein, Ph.D., Course Master, Associate Professor of Medicine, Cell Biology and
Physiology, dabendsc@dom.wustl.edu, or 362-8901 (Linda Lobos) to make an appointment.

Richard G. Bach, M.D., Associate Professor of Medicine, rbach@dom.wustl.edu, 362-1963.

Angela L. Brown, M.D., Associate Professor of Medicine, albrown@dom.wustl.edu, 747-3608.

Greg A. Ewald, M.D., Associate Professor of Medicine, gewald@dom.wustl.edu. 454-7011.

Brian R. Lindman, M.D., Assistant Professor of Medicine, blindman@dom.wustl.edu, 747-3617.

Keith Mankowitz, M.D., Associate Professor of Medicine, kmankowi@dom.wustl.edu, 362-1291.

Timothy W. Smith, M.D., Ph.D., Associate Professor of Medicine, tsmith@dom.wustl.edu, 454-

7982.

2. Course Philosophy/Introduction to the Course

CV Diseases is comprised of 12 lectures on six major topics in cardiac and vascular
pathophysiology. This is not meant to be an exhaustive overview of cardiology, but rather discussion of
the most important areas based on their prevalence in patients seen in the hospital or a cardiology
practice. The lectures will be presented by WUSM faculty members with considerable clinical experience
and expertise in the topic area. Four of the lectures will deal with therapies considered currently as the
standard-of-care for patients with the highlighted condition. When the therapy involves drugs, you will be
told how much detail you will be responsible for. In general, you will need to know the major actions
of a class of drugs and NOT the tradenames, doses, and side effects of specific drugs in the class.
You will find that the number of classes of drugs for cardio is actually pretty small and many of the
agents can be used for multiple problems.

A core aspect of the course that I believe is essential to learning both the pathophysiology
and treatment of CV problems is the Case Study Small Groups. There are six small group sessions
scheduled a few days after the associated lecture(s). Each small group of students will be led by a faculty
preceptor who has been briefed on the breadth and depth of the class understanding and the specific
learning objectives for the session. The preceptors will also have the answers to posed questions for
each of the cases and be given guidance by the lecture leader on what to cover. Not only is the case-
based approach used in small groups the primary type of question on the final exam for this course and
Step 1 of the USMLE, but I consider the discussion with faculty to be vital to your understanding of the
material. So much so that I will award a half point to your final grade for every small group you
attend!

In addition to lectures and small groups, the course will also add depth to two cardiology

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skills requiring practice: detecting heart sounds by auscultation and reading an ECG. An
Auscultation in CV Disease small group session is scheduled towards the end of the course to revisit
the heart sounds introduced in POM1 and Organ Systems Physiology now in the context of CV
pathophysiology. This session, while strongly encouraged, will not count towards your grade. Proficiency
reading ECGs takes a lot of practice, so you probably wont feel competent by the end of the course.
Nevertheless, we have provided some opportunities for self-study of ECG reading including ECGs of the
Week, posted each week in the database with some questions relevant to the interpretation. Answers will
be posted the following week. Dr. Smith and others are also working on ECG databases at WU and we
will direct you to these in class as well as several websites that have practice ECGs.

SOME WORDS OF ENCOURAGEMENT: The Course Masters know that the CPR block is a lot of
information, but the integration between major organ systems is probably best done at one time. We have
at least one CPC-like event that will emphasize these interconnections during the block. Plus, the
scheduling of pathophysiology in step with the same elements in the Pathology course was intentional
and should facilitate your process of integration. In the same way that first year was largely conceptual,
try to approach this course and the CPR block with a conceptual framework. Please let me know if you
have questions as you have them. I would also appreciate any feedback you have on the course as we
go along so I can make corrections and clarifications as needed. Have a great course!

3. Course Objectives
By the end of this course, students should:

a. Be able to identify the pathophysiologic mechanisms leading to ischemic heart disease, heart
failure, cardiomyopathies, and valvular heart disease.

b. Be able to interpret the most common arrhythmias and approximate location in the heart of
myocardial ischemia/infarction from looking at a 12-lead ECG.

c. Be able to use physical diagnostic indices and clinical and laboratory data to identify and treat
ischemic and cardiomyopathic conditions.

d. Know the treatment options for essential and secondary hypertension, brady and
tachyarrhythmias, forward and backward heart failure, valve stenosis and incompetence, and
congenital defects.

e. Understand the epidemiology and presentation of congenital heart defects in infants and children.

4. Course Materials
a. Texts. Many students try to get a copy of the Pathophysiology of Heart Disease, written with
the help of and for medical students. They are on the fifth edition, but if you get an earlier edition
from an upperclassman, it will be fine. For those who feel the need to review aspects of basic
physiology or delve more deeply into some aspects of pathophysiology, the following list of
textbooks are all highly recommended by the faculty.

(1) Pathophysiology of Heart Disease (5th ed); Lilly, 2011.

Lilly LS, editor, Harvard Medical School. Pathophysiology of heart disease: a collaborative
project of medical students and faculty. 5th ed. Baltimore: Wolters Kluwer, Lippincott Williams
& Wilkins; 2011.

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 (2) Basic and Clinical Pharmacology (11th ed); by Bertram Katzung, Susan Masters, Anthony
Trevor, 2009.

Katzung BG, Masters S, Trevor A. Basic and clinical pharmacology. 11th ed. New York:
Lange Medical Books/McGraw-Hill; 2009.

(3) Hypertension Primer (4th ed); by Joseph Izzo, Domenic Sica, Henry Black, 2007.

Izzo J, Sica D, Black H;, editors, and the Council for High Blood Pressure Research
(American Heart Association). Hypertension primer: the essentials of high blood pressure. 4th
ed. Dallas: Wolters Kluwer Lippincott Williams & Wilkins; 2007.

(4) Kaplan's Clinical Hypertension (10th ed.); by Norman Kaplan, Ronald Victor, 2009.

Kaplan NM, Victor RG. Kaplan's clinical hypertension. Wolters Kluwer Lippincott Williams &
Wilkins, 2009.

(5) The Only EKG Book You'll Ever Need (6th ed.); by Malcolm Thaler, 2009.

Thaler MS. The only EKG book you'll ever need. 6th ed. Philadelphia: Wolters Kluwer
Lippincott Williams & Wilkins; 2009.

(6) Rapid Interpretation of EKGs (6th ed.); by Dale Dubin, 2000.

Dubin D. Rapid interpretation of EKG's. A programmed course. 6th ed. Tampa: Cover Pub.
Co; 2000.

(7) Grossman's Cardiac Catheterization and Angiography (7th ed); Baim, 2005.

Baim DS, editor. Cardiac catheterization, angiography, and intervention. 7th ed. Philadelphia:
Lippincott Williams & Wilkins; 2005.

(8) Valvular Heart Disease (3rd ed.) by Catherine Otto and Robert Bonow, 2009.

Otto CM, Bonow RO. Valvular heart disease. 3rd ed. Philadelphia: Saunders Elsevier; 2009.

(9) Nadas' Pediatric Cardiology (2nd ed.); by John Keane, James Lock, and Douglas Fyler,
2006.

Keane JF, Lock JE, Fyler DC. Nadas' pediatric cardiology 2nd ed. Saunders-Elsevier, 2006.

(10) Braunwald's Heart DiseaseA Textbook of Cardiovascular Medicine (9th ed); Bonow,
Mann, Zipes, Libby, 2011.

Bonow R, Mann D, Zipes D, Libby P, editors. Braunwald's heart disease, a textbook of

cardiovascular medicine. 9th ed. Philadelphia: Saunders; 2011.

b. Additional Materials. A Glossary of Terms is provided in the reference section of the Med
Portal as a quick study guide. Additional material for self-study and self-assessment, including
"ECGs of the Week" and a previous exam for the course will be provided on the Med Portal.

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5. Policies
a. Grading.

(1) List of specific assessments with associated point values.

A final exam comprised of 50 multiple choice questions each worth 2 points will be the
primary assessment. The questions will, for the most part, will be in the vignette format
similar to those used in the Case Study Small Groups and USMLE Step 1 questions.

Half a point will be added to your final exam grade for each Small Group session
attended (with exception of Auscultation). A sign-in sheet will be available in the room
you are assigned to for the course.

(2) Describe grading system (e.g., points required for pass/fail/incomplete, exam retakes). The
grading system will be 100-88%Honors; 87-78%High Pass; and 77-60%Pass. A
representative exam from a previous year is posted on the Med Portal. Make-up exams will
be allowed only if arranged in advance with the Course Master or with prior consent from the
Dean of Students.

(3) Miscellaneous assessment information. Additional self-assessments are being developed

and may be provided at the end of lectures, but wont be graded.

(4) Note when and how graded assessments will be available for review. Exams will be graded
as quickly as possible and the answer key together with your exam packet will be available to
review in the Curriculum Office within five business days of the exam date. You will not be
allowed to take your exams from the Curriculum Office. Final grades will be posted on
Webstac within one week of the exam.

b. Attendance requirements (vs. expectations).

The faculty and I prefer a lecture hall filled with students than a half empty room. Theres a certain
synergy that occurs as students ask questions and the lecturer responds. This dynamic exchange
is quenched by low attendance. I would expect that students will attend as many lectures and
small group sessions as they possibly can, but attendance will only be taken at the small group
session since that can count towards your grade.

c. Participation (graded, if so how?).

Participation in all aspects of the course is encouraged. Please be respectful of your classmates
to seek out the lecturer after class if a simple question doesnt give you a clear or complete
answer.

6. Professional Expectations
Each Course Master has been asked to define professional behavior in relation to their course. In my
view, professionalism will be reflected by:

An acceptance of fellow students and faculty as professional colleagues deserving courtesy and
respect.

A focus on learning rather than simply studying for the exam.

An acceptance of uncertainty, ambiguity, and the inevitability of change in relation to medical

knowledge and practice.
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 A respect for alternative views or differing interpretations of scientific or clinical information, and a
respect for different teaching styles and practices.

The ability to assume personal responsibility for fulfilling course requirements, such as
attendance in lectures and small groups.

A willingness to help the faculty identify errors or deficiencies in course materials, and to provide
specific, thoughtful, and constructive feedback relating to lecture material or presentation style
and other course content through the liaisons to the Course Master and/or on the formal Course
Evaluations.

7. Concluding Notes/Suggestions for Success in the Course/Other

Uncategorized Material (including assignments to small groups/TBL,
information about academic prizes)
Unless noted, the lectures will take place in Connor auditorium, and the small group discussions on the
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4 floor of the Farrell Learning and Teaching Center. The class will be divided up for the group
discussions as follows:

Group A: Room 401 A & B Group B: Room 402 A & B

Abraamyan, Torgom Abreu, Damien
Benjamin, Lawrence Altenhofen, Brannon
Chen, Raymond Benzoni, Nicole
Dang, Na Bichanich, Miles
Fischer, Caroline Bollinger, Lucy
Fowle Grider, Ronald Chen, Simon
Gefen, Ashley Cheng, Tiffany
Grajales, Jose Deng, Francis
Hill, Kelly Garber, Charise
Lin, Jonathan Lalchandani, Gopal
Mah, Annelise Lohse, Austin
Meyerson, Cherise Madubata, Chinwe
Min, Jaspur Mishra, Shruti
Oetjen, Landon Moses, Lindsey
Rodriguez, Jocelyn Russler-Germain, Emilie
Russell, Aaron Sacks, Gina
Siller, Alejandro Smith, Sarah
Slade, Michael Thompson, Russell
Vachharajani, Punit Weese, Jonathan
Xiao, Daphne Yoshida, Mitsukuni
Zhao, Johnny Zhou, Daisy

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Group C: Room 403 A Group D: Room 403 B
Ahn, Ji Won Andersen, Britt
Baltazar Garcia, Moises Chu, Cheryl
Bern, Michael Connor, Emily
Blonski, Allison Dardas, Agnes
Cai, Alice Godbold, Tracey
Chionchio, Alicia Jacobi, Celina
Frisse, Ann Jalalizadeh, Bayan
Gluckstein, Jeffrey Kaufman, Johanna
Groves, Andrew Lindburg, Miranda
Kleckner, Vanessa Lorbeer, Karly
Lin, Kenneth Ma, Lisa
Ma, Yuntong Miller, Hannah
Mahlokozera, Tatenda Overschmidt, Bo
Mohapatra, Anand Patel, Keval
Orukari, Inema Ramsey, Kara
Ott, Katherine Rippberger, Gregory
Swor, Erin Skillington, Scott
Vandenberg, James Sun, Sam
Witt, Jacob Yu, Jenny
Xu, Wen Zhu Zhu, Tina

Group E: Room 404 A Group F: Room 404 B

Akhirome, Ehiole Agenor, Aouod
Berlin, Ari Bansal, Anchal
Chen, Ishita Bouchard, Brian
Fram, Brianna Chen, Andy (Yee-Shiuan)
Gallin, Hilary Chou, Chris
Greenstein, Daniel Essuman, Kow
Huverserian, Ari Fernandez, Estefania
Jalalizadeh, Rohan Gamble, Paul
Majidi, Shahriyar Huynh, Tien-Phat
McGilvray, Martha Leckie, Katherin
Morris, Marie Lee, Dong
Perry, Andrew Martin, Lauren
Qi, Owen Moon, Kelsey
Samen, Christelle Patel, Aalok
Shankar, Vikram Qualls, David
Thomas, Ariel Scheel, Paul
Vajapeyajula, Sravya Verbaro, Daniel
Varman, Rahul Vyhmeister, Ross
Wagner, Julia Wang , Pengcheng
Xiao, Qi Xu, Amy
Zubovic, Ema

For purposes of assessing attendance, please remain in your group throughout the course. The
purpose of the small groups is to permit informal discussion of representative clinical case(s) pertinent to
the lectures and to interact with the clinical faculty. You are responsible for the discussion of these cases
under the guidance of your faculty instructor. A suggested list of "answers" to the questions posted for
each case will be provided in the Case Study section of the course materials after the small group meets.

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Lecture Notes

Remember Last Year?A Brief Review

09/18/2013

Dana R. Abendschein, Ph.D.

Remember Last Year?A Brief Review

Objectives:
1. Review the origins and timing of cardiac activation, its manifestations on the body surface as
recorded by the 12-lead ECG, and the approach to reading ECGs by assessing the rate, rhythm, and
axis.

2. Describe the length-tension relationship for the heart, how factors such as preload, afterload, and
contractility affect cardiac output, and the important factors accounting for the majority of myocardial
oxygen consumption in the normal and pathophysiologic state.

Reference Text:

1. Lilly LS, ed. Harvard Medical School. Pathophysiology of Heart Disease: a collaborative project of
medical students and faculty. 5th ed. Baltimore: Wolters Kluwer, Lippincott Williams & Wilkins;
2011:1-43; 75-91; 216-225.

I. Origin of the Electrocardiogram (ECG)

The Body Surface Potential.

We know from cellular physiology that cardiac myocytes are electrically excitable due to an electrical
potential across the cell membrane (the sarcolemma) that is maintained by separating charge, in the form
of ions across the sarcolemma. Excitation produces an action potential, a series of openings and closings
of channels in the sarcolemma that allow ions (and current) to flow across the membrane. The action
potential is a self-limiting process, and the sarcolemma and the cell return to the baseline potential at the
completion of the action potential. The action potential is propagated to neighboring cells at specialized
junctions (intercalated discs) causing them to depolarize and reach the threshold for triggering their own
action potential. The action potential is therefore a signal that is propagated through the muscle. In the
heart, several sets of cells spontaneously depolarize (automaticity), initiating their own action potential,
which may then be propagated through the heart. Spontaneous depolarization is also called pacemaker
function. In the normal situation, the sino-atrial node (SA node or sinus node), has the most rapid cycle of
spontaneous depolarization and becomes the pacemaker for the rest of the heart. The normal rhythm
originated in the sinus node is called sinus rhythm. Its rate of firing is modulated by neurohumoral
influence and by drugs.

The ECG measured on the body surface with electrodes placed on the arms, legs, and across the
chest is not a transmembrane action potential, though. It is not even a sum of all the action potentials. It
is a sum of the measureable charge movement in the heart producing a potential difference that we can
measure between two points on the skin. The measureable movement of charge occurs on the surface of
the cell due to the change in charge across the membrane, but we actually detect a potential difference
with our recording electrodes. Figure 1A shows a schematic of two recording electrodes (one designated
positive and the other negative) placed on either side of a cardiac myocyte. At baseline, as you know, the
cell is normally polarized (positive outside, negative inside). The action potential is a depolarization of that
transmembrane potential. The recording electrodes "see" the development of a negative charge at one
end of the cell surface, while the other end remains positive (Figure 1B & C) registered as a potential
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difference or voltage between the recording electrodes. The potential difference produces a dipole (like a
battery that has one end positive and the other end negative) between the recording electrodes.
Changes/movement in the dipoles amplitude (number of cells), direction and polarity can be measured
by the voltmeter and recorded on a strip-chart recorder. As the action potential propagates through the
cells of the heart, the changes in the dipole are recorded.

Figure 1. Depolarization of a single myocyte. Figure 2. Repolarization of single myocyte.

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Similar to figures from Pathophysiology of Heart Disease, 5 edition, L. Lilly, 2011, pages 76 and 77.

Directionality.

A depolarizing wave with the positive end of the dipole travelling towards the positive recording electrode
will produce a positive (upright) deflection on the voltmeter/recorder. If the wave is travelling away from
the positive electrode, or the positive and negative recording electrodes are reversed (as in Figure 1E),
the deflection will be opposite or negative. If repolarization of the cell occurs in the same direction as
depolarization (i.e., from left to right towards the positive recording electrode in this example) a negative
deflection will be recorded (Figure 2). But, if the repolarization wave travels away from the positive
electrode, now the dipole is oriented the same way it was during depolarization and a positive deflection
will be recorded (Figure 2D). In fact, this is precisely what happens in the ventricles of the heart. Recall
that depolarization occurs from the endocardium to the epicardium inducing a dipole with the
positive aspect pointed towards positive measuring electrodes placed on the left side of the body.
However, because repolarization occurs in the opposite direction, that is, from the epicardium back
to the endocardium, the dipole is still oriented with the positive aspect pointed towards the positive
measuring electrodes on the left side! Thus, the T wave representing ventricular repolarization is normally
pointing in the same, upright direction as the QRS complex representing ventricular depolarization.

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Figure 3. Magnitude vs Direction in Lead I. From Pathophysiology of Heart Disease, 5th ed. L. Lilly, 2011.

So far, weve considered the wave of depolarization or repolarization propagating in line with the
electrode pair either directly toward or away from the positive electrode. This achieves the maximum
potential and maximum deflection of the recorded signal (Figure 3A). However, if a wave of
depolarization is proceeding at a right angle (orthogonal) to the axis of the recording electrode pair, the
wave is neither approaching nor receding from the positive electrode. No (or minimal) potential is
measured (Figure 3C). If the wave of depolarization is propagating at an oblique angle toward the
positive electrode, the positive deflection will reflect the vector portion that is proceeding directly towards
the positive electrode (and will thus be of lower amplitude than if the wave is propagating in the axis of the
two electrodes)(Figure 3B and D). Since we will ultimately explore several ECG leads recorded
simultaneously, we will be able to understand the course the wave takes through the heart.

Figure 3 is simplified in two important ways:

1. Figure 3 suggests a single wave moving uniformly through the heart in a single direction. In
reality, the waves of depolarization (and repolarization) change direction (and amplitude) as they
propagate through the atria and ventricles in three dimensions. (Figure 4.)

2. The heart has more than one single electrical component. The normal ECG shows a wave of
atrial depolarization, a wave of ventricular depolarization and a wave of ventricular repolarization.
Atrial repolarization is not seen due to the small mass of the atria and the predominance of
ventricular depolarization at the same time (Figure 5).

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Figure 4.

Einthoven named the waves seen on the normal ECG (Figure 5):

P-wave: atrial depolarization.

QRS: the waves showing ventricular depolarization. The QRS complex is the name now
given to the wave(s) of ventricular depolarization. The Q is any initial negative wave. The R is
any positive wave. The S is any negative deflection that follows an R wave of the QRS.

T-wave: ventricular repolarization.

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Figure 5.

The segments between the waves also have names: The PR segment (even if the next wave is a Q),
and the ST segment (even if the theres no S-wave). Commonly measured intervals have names and
usually include waves and segments.

PR interval: from the beginning of the P-wave to the beginning of the QRS complex.

QT interval: from the beginning of the QRS to the end of the T-wave.

The PR interval reflects the delay for the impulse to travel from the SA node, through the atrium and
then through the AV node into the ventricles. This delay is necessary to permit the atrial contraction to
occur before the ventricular contraction so the atria can provide a booster pump function for filling. The
QRS complex is normally narrow because of rapid conduction down the Bundle of His branches and out
over the Purkinje fibers (Figure 6).

Figure 6. His-Purkinje System Accounts for Narrow QRS Complexes

Einthovens Leads.

Einthoven envisioned the heart in the middle of an equilateral triangle so that leads along each side would
get a "view" of the heart from different angles.

Lead I: Positive electrode on the left arm (or wrist since the body is a volume conductor);
negative electrode on the right arm. Horizontal orientation, +0 to -180.

Lead II: Negative on the right arm, positive on the left leg. -120 to +60.

Lead III: Negative on the left arm, positive on the left leg. -60 to +120.
The connection to the right leg serves as a ground for the subject.

See Figure 4.14 in Lilly for more details on the Cartesian coordinates of the various leads.

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 The orientation of these lead axes in relation to the Einthoven triangle and the body are shown in
Figure 7 top. These axes all lie in the frontal anatomic plane so theyre called frontal leads, or just limb
leads.

Figure 7. ECG Leads.

To get additional angles for assessment of the average vector of depolarization, Emanuel
Goldberger, in 1942, combined two limb lead electrodes to be a new negative electrode, and then made
the third electrode positive. Leads with a central negative pole are often called unipolar leads (though its
a misnomer, since there must always be two poles) and have a V designation. These recordings require
some amplification to be represented on the same scale as the other limb leads. They are therefore
called augmented limb leads and have an a added to their names. There are three augmented limb leads
(Figure 7 middle) identified by the site of the positive electrode. Thus:

Lead aVR: Negative left arm and left leg; Positive right arm. +30 to -150. Dont get confused
here, the negative recording lead is oriented at +30. That usually makes the ECG in this lead
look upside down so the P, QRS, and T waves are all negative.

Lead aVL: Negative right arm and left leg: Positive left arm. +150 to -30.

Lead aVF: Negative left and right arms: Positive left leg. -90 to +90.

Have a look at Figure 4.14 in Lilly if any of this is still confusing you.
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The Precordial Leads.

Using the same idea of combining leads to obtain a new negative electrode, the precordial leads are
formed by combining all of the limb connections together as a negative lead and then using an exploring
positive lead at different points on the chest wall to obtain the electrical activity of the heart in the
horizontal anatomic plane. Six different positive electrode (unipolar) points are applied across the chest
forming V1 through V6 (Figures 7 bottom and 8). The QRS complexes change depending on the
contribution from the right ventricle (V1-V3) vs the left ventricle (V4-V6) (Figure 8).

Figure 8. Precordial leads.

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V1: 4 intercostal space, right of the sternum.

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V2: 4 intercostal space, left of the sternum.

V3: midway between V2 and V4.

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V4: Midclavicular line in the 5 intercostal space.

V5: Midway between V4 and V6.

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V6: Midaxillary line in the the 5 intercostal space.

Weve now reviewed the standard set of "perspectives" comprising the 12-lead ECG with which to
assess cardiac electrical activity. One standard way of representing the 12-Lead ECG is shown in Figure
9. The Einthoven leads (I, II, III) are in the first column. The augmented limb leads (aVR, aVL, aVF or "R,"
"L," and "F") are shown in the second column. The third column is the first three precordial ("chest") leads
(V1, V2, V3) and the fourth column is the other three chest leads (V4, V5, V6). It is very common to show
additional tracings of one or more leads all the way across the page to help analyze the rhythm (i.e.,
"rhythm strips") and the heart rate when it varies, such as during ventilation. Sometimes the choice of
rhythm leads is mysterious. Leads II and V1 are usually the best for observing P-waves and analyzing the
rhythm as well as the rate. The square wave at the beginning of each row is a 1 mV calibration pulse so
you can judge the significance of vertical changes such as ST segments, the R wave amplitude and ratios
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of V leads.

Figure 9. A 12-lead ECG with 3 rhythm strip leads. Example of a normal 12-lead ECG showing normal sinus rhythm.

II. Rate, Rhythm, and Axis (or as Dr. Smith prefers bRRAICEbasics, Rate,
Rhythm, Axis, Intervals, Conformations and Everything Else)
A. Basics have a look at Figure 5 again:

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 1. Verify that the ECG was recorded at the "standard settings" as shown in this segment
paper speed of 25 mm/sec, and vertical scale of 10 mm = 1 mV.

2. Look for excessive artifact or noise, which could mean loose electrodes or excessive muscle
tremor.

3. Make sure this is the patient you expected.

B. Rate.

1. Measure the ventricular rate from R-R intervals (Figure 10). You can also estimate the
ventricular rate by counting QRS complexes in 6 seconds and multiplying by 10 (Figure 11).
Alternatively, a standard one page of the 12-lead ECG is normally 10 sec, so you could count
across the page and multiply by 6. The 6 or 10 sec counts are best if the R-R interval is
variable (i.e., during ventilation). A third method is to remember the relation of heart rate to
the number of 0.2 sec intervals between successive R-waves (Figure 12).

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Figure 10. Measurement of ventricular rate from the R-R interval. R-R interval in sec is divided into 60 to get the heart rate.

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Figure 11. Measurement of the ventricular rate from the number of R waves in 6 sec. Count the number of R waves (excluding
ventricular premature depolarizations, a.k.a. premature ventricular contractions, which is an older term you may see in the literature.
Since its actually a premature depolarization, VPD is probably more correct) in 6 seconds and multiply by 10.

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Figure 12. Measurement of the ventricular rate from the box count. 1 box (between R waves) = 300/min, 2 boxes = 150/min, 3
boxes = 75/min, 4 boxes = 60/min, 5 boxes = 50/min.

2. The atrial rate should track the ventricular measurement and can be measured from the PP
intervals.

3. Ask Are the ventricles always activated from the atria? Is the rate normal? In adults, less
than 50 is bradycardia, and greater than 100 is tachycardia.

C. Rhythm.

1. Ask Is each P wave followed by a QRS complex? You can also ask Is the P wave upright
in LII and biphasic in V1 (consistent with a sinus origin). If the rhythm is sinus with 1:1 A-V
conduction, you can proceed with the next step in the algorithm.

2. If the rhythm is not obviously sinus or showing 1:1 conduction, then see if you can determine
the relationship between the P waves and the QRS complexes. Where to go with this will be
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 explained by Dr. Smith in his lectures.

D. Axis.

1. Using just the frontal limb leads, look for the leads with primarily positive QRS complexes. A
lead with a primarily positive QRS must be in the same half of the compass as the axis
vector. For example, if LI is positive, then the axis must be between -90 and +90. If LII is
positive, then the axis must be between -30 and +150. Normal vector axes are in this range.

2. Also look for the lead that has a nearly isoelectric QRS complex (same amount of positive as
negative deflection). The axis will be about perpendicular to the axis of the recording
electrodes for the isoelectric lead. Have a look again at Figure 4.14 in Lilly. If youre having
trouble with these angles, youll need to go back and memorize the leads.

3. The normal time-averaged vector axis of ventricular depolarization is between -30 and
+90. <-30 is left axis deviation consistent with left ventricular hypertrophy, and >+90 is right
axis deviation usually resulting from right ventricular hypertrophy.

Intervals, Conformations, and Everything else will be discussed by Dr. Smith in his lectures.

III. Ventricular Function

A. Recall the Wiggers Diagram showing the relationships of ventricular and aortic pressures, aortic
blood flow, ventricular volume, heart sounds and the ECG (Figure 13):

Figure 13. Wiggers Diagram for the left ventricle.

1. Systole is about 1/3 (300 msec) the total length of the cardiac cycle and diastole is 2/3 (600
24
 msec). When heart rate increases, diastole (filling) is shortened. After the peak of the R wave
in the ECG, ventricular contraction begins. The rise in ventricular pressure closes the mitral
st
and tricuspid valves causing the 1 heart sound, but the pressure is not yet high enough to
open the semilunar valves so the heart is contracting isovolumically during this time.
Eventually, the pressure exceeds the aortic and pulmonary artery pressures and the valves
open allowing ejection. Once ejection slows down and ventricular pressure drops below the
arterial pressure, the valves close causing the second heart sound. This is about at the end
of the T wave.

2. Systole duration is S1 to S2, or the peak of R to the end of T. Diastole is S2-S1.

th
3. A similar plot exists for the right ventricle, just operating at 1/5-1/6 the pressure of the left
ventricle and aorta. The lower pressures on the right side cause a slight difference in timing
of closure of the aortic and pulmonic valves and can produce an audible splitting of the
second heart sound when the timing of closure of the pulmonic valve is delayed during
inspiration.

B. Indices of Systolic Function.

Figure 14. Profiles of force development as heart muscle is stretched before it contracts with and without a change in
contractility resulting from increased or decreased calcium entry into cells. Resting tension as the muscle is stretched is also
increased and may increase more markedly as the muscle is made stiffer (less compliant) by disease.

1. Just as for the isolated heart muscle strip in Figure 14, the heart responds to increased
muscle length as it fills with blood by increasing the force development during contraction
leading to increased output. This is defined as Starlings Law where, up to a point, the more
blood the heart is filled with, the more blood it can pump out. If the heart is overstretched,
then also just like for isolated muscle, the usable force development is diminished and the
output of blood from the heart would decrease.

2. This first index of systolic function reflecting Starlings Law where increased filling leads to
increased output is known as the preload. It is the force/unit area or tension that is directly
proportional to the filling pressure (at end-diastole) and ventricular radius and inversely
proportional to twice the wall thickness as defined by Laplaces Law (Figure 14).

3. Contractility is the second index affecting systolic performance of the heart. Inotropes that

25
 can positively or negatively affect calcium movement across the sarcolemma or the reuptake
of calcium by the endoplasmic reticulum are responsible for this independent or extrinsic
effect on force development for any given amount of muscle stretch/ventricular filling. In other
words, this is a modifier of the Starling effect and muscle response to stretch. Examples of
positive inotropes are digitalis and norepinephrine, while negative inotropes are things like
hydrogen ions, -blockers, and verapamil (calcium channel blocker).

4. The last systolic index is afterload, but it has a negative influence on cardiac output. The
value of the afterload tension is derived from Laplaces Law where:

pressure x radius
Tension = 2 x wall thickness

Figure 14.
In other words, the force the heart has to overcome to eject blood into the arteries is
directly proportional to the diastolic pressure the heart sees when the valves open and the
amount of blood the heart is filled with. It is also inversely related to the thickness of the heart
wall, which is why weak hearts tend to get thicker walls to try to decrease this tension.

Not surprisingly, developing the afterload tension is what consumes the most oxygen
during the cardiac cycle. A quick estimation of afterload can be obtained by measuring
arterial pressure. The afterload is approximately equivalent to the aortic diastolic pressure,
which is related directly to the peripheral (or systemic) vascular resistance.

Figure 15 summarizes the systolic indices of ventricular function:

Figure 15. Factors Controlling Cardiac Output.

26
C. Indices of Diastolic Function.

1. Diastolic function, or how the heart relaxes is important because this is an active process
requiring ATP and it may be even more sensitive than systolic function to the onset of
disease.

2. It is defined by the resting tension profile on the ventricular function curve (Figure 14) or by
the diastolic pressure-volume curve on the P-V loop (Figure 16, and see Figure 9.7 in Lilly).

3. If the heart becomes less compliant (increased stiffness) from deposits of collagen scar after
an MI, for example, the slope of the resting tension profile may increase such that the
diastolic pressure increases for the same amount of filling with blood (Figure 16A).

4. Another possibility is that disease could affect a majority of the heart muscle so that the
myocytes dont relax completely during the isovolumetric phase of diastole. It would be like
taking a spring and deforming it by overstretching it. The ability to recoil and relax the spring
is affected. When this happens in the heart from amyloid or sarcoid deposits in the muscle,
then the whole resting tension profile may be displaced upwards (Figure 16B).

Figure 16 shows the difference in these two processes, both of which could change diastolic
function.

Figure 16. Diastolic dysfunction manifested as decreased ventricular compliance A, or decreased distensibility B.

27
Lecture Notes

Systemic Hypertension and Antihypertensive Therapy

09/20/2013

Angela L. Brown, M.D.

Systemic Hypertension and Antihypertensive Therapy

Objectives:
1. Review the basic pathophysiologic mechanisms of high blood pressure.

2. Describe the regulatory mechanisms of systemic blood pressure that form the basis for non-
pharmacologic and pharmacologic therapies.

3. Understand the natural history and overall prognosis of an individual with hypertension in relation to
cardiovascular morbidity, mortality, and target organ damage .

4. Describe how to evaluate a hypertensive individual in the clinical setting.

5. Describe how to treat an individual with hypertension: non-pharmacologic treatment, therapeutic

thresholds (when to treat), and therapeutic strategies involving classes of drugs.

Reference Text:

1. Lilly LS, editor, Harvard Medical School. Pathophysiology of heart disease: a collaborative project of
medical students and faculty. 4th ed. Baltimore: Williams & Wilkins; 2007. pp. 311-333.

2. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure: the JNC 7 report. Chobanian AV, Bakris GL, Black HR, Cushman
WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National
Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating
Committee. JAMA. 2003 May 21;289(19):2560-72.

3. Katzung BG, ed. Basic and clinical pharmacology. 10th ed. New York: Lange Medical
Books/McGraw-Hill; 2007. pp. 159-182.

I. Introduction
Systemic hypertension or high blood pressure is a major public health concern. It is the most common
chronic illness in the US and is the most common cardiovascular disease. Despite ease of identification
through screening and numerous available therapies for treatment, including lifestyle modifications,
control remains poor. The major goal of early identification and blood pressure control is to reduce
cardiovascular morbidity and mortality due to hypertension.

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II. Blood Pressure
Blood pressure is the force exerted by blood on the walls of blood vessels and provides the motive force
for circulation. Systemic arterial blood pressure is the force supplied by the left heart, and is primarily
determined by the cardiac output (CO, quantity of blood ejected from the heart per unit time) and the
systemic vascular resistance (SVR). The basic hemodynamic formula for blood pressure is: BP = CO x
SVR where CO = left ventricular stroke volume (SV) x heart rate (HR). Stroke volume is the quantity of
blood ejected from the heart in a single beat, and is primarily determined by cardiac myocyte contractile
force (contractility) and the extent to which the ventricles are stretched prior to ejection (preload). SVR is
mainly determined by arteriolar tone (the balance between vasoconstriction and vasorelaxation) and
arteriolar distensibility (arteriolar compliance). In hemodynamic formulas, blood pressure is expressed as
mean arterial pressure (MAP). In most clinical settings, blood pressure is estimated using indirect
measurement of the brachial artery pressure and reported as the systolic and diastolic blood pressures.

III. Blood Pressure Regulation

Blood pressure regulation is complex and involves many factors that alter CO and/or SVR. These factors
either directly or indirectly alter myocardial contractility, heart rate, arteriolar tone, and/or arteriolar
hypertrophy by directly affecting blood volume, neurohormonal responses, and cell membrane function. It
is unusual for elevated cardiac output to be the sole mechanism for increased blood pressure. For either
stroke volume or heart rate to be sufficiently elevated to cause a sustained increase in cardiac output,
there must be a defect in the normal autonomic and baroreceptor control mechanisms that would
otherwise reduce systemic vascular resistance by reflex corrective measures. This would therefore
indicate an abnormality of vascular responsiveness.

IV. Pathophysiologic Mechanisms

In over 97% of hypertensive patients, the cause of their hypertension cannot be identified, suggesting a
multifactorial etiology. This is called primary hypertension and there is no cure. A specific curable, or
treatable, cause can be identified in the remaining 3% or less of cases and is referred to as secondary
hypertension. Some of the causes of secondary hypertension include renovascular disease, renal
parenchymal disease, polycystic kidneys, aortic coarctation, pheochromocytoma, primary aldosteronism,
Cushings syndrome, hyperparathyroidism, and ingestion of exogenous substances. Exogenous
substances usually represent over-the-counter medicines, some prescription medications like
erythropoietin and oral contraceptives, or substances that either directly elevate the blood pressure or
interfere with anti-hypertensive therapy (sodium).

Certain pathophysiologic mechanisms deserve further discussion:

A. Age-Related Vascular Changes.

There is an age-related reduction in arterial elasticity. Increased arterial stiffness causes an increase
in pulse wave velocity and early reflected waves in the aorta, leading to late and augmented peaking
of the systolic blood pressure. This creates a widened pulse pressure (difference between systolic
and diastolic pressures) and is known as isolated systolic hypertension, the most common form of
hypertension in the elderly population.

29
B. Renin-Angiotensin-Aldosterone System.

The RAAS (or just RAS) system is an important regulatory system on BP control. Nevertheless, the
RAS system also mediates target-organ injury, thrombotic tendencies, and fibrinolysis. The RAS
system should be thought of as having two opposing functional arms. The first arm is the
vasodilatory, natriuretic, and growth-inhibiting side that is mediated by bradykinin, nitric oxide (NO),
prostacyclin, t-PA, etc. The second arm is the vasoconstrictive, anti-natriuretic, and growth promoting
side where the physiological effects are mediated by angiotensin II, aldosterone, and ang II-mediated
increases in sympathetic nervous system activity. The RAS system is an important regulatory system
that has been implicated as playing a pivotal role in hypertension, microvascular disease, left
ventricular hypertrophy, heart failure, kidney disease/proteinuria, atherosclerosis, and even the
development of diabetes mellitus.

C. Obesity-Related Hypertension.

Obesity-related hypertension can be characterized by three major factors.

1. Sympathetic nervous system activity is increased due to visceral adipocyte release of non-
esterified fatty acids that have been shown to increase alpha-1 adrenergic receptor tone and
degrade nitric oxide (NO, an important regulator of vascular tone and integrity).

2. The renin-angiotensin system is activated due to increased levels of angiotensinogen and

aldosterone seen in obese patients. Angiotensin II causes avid sodium reabsorption in the
proximal tubule. Aldosterone contributes to sodium reabsorption in the distal
nephron/collecting duct. Delivery of sodium to the macula densa in the distal nephron causes
NO generation and afferent arteriolar vasoconstriction via tubuloglomerular feedback;
however, decreased distal delivery of sodium to the distal nephron (as a consequence of avid
proximal tubular reabsorption of sodium) in obesity reduces NO generation and, alters
tubuloglomerular feedback (TGF) to the afferent glomerular arteriole resulting in inappropriate
dilation of the afferent arteriole for the level of systemic blood pressure. The dilation of the
afferent arteriole facilitates transmission of systemic arterial pressure into the glomerulus
leading to hemodynamically-mediated renal injury.

3. As outlined in the previous paragraph, obesity is associated with several alterations of

physiology that augment sodium retention. This leads to ECFV expansion, particularly
amongst persons who consume diets that are not restricted in sodium chloride. Angiotensin II
causes a shift in the pressure-natriuresis curve to the right. This means that higher levels of
BP are required to cause the kidney to excrete the sodium load presented to it. Thus, in the
setting of high sodium intake, steady-state in-out homeostasis is established at a higher level
of pressure and likely at a more expanded or higher ECFV. Obese persons, tend to manifest
salt sensitivity; that is, they experience a rise in BP when dietary sodium exposure is
increased and a fall in BP when dietary sodium intake is reduced.

D. Cerebral Blood Flow and Regulation.

Cerebral autoregulation maintains cerebral blood flow relatively constant across a broad range of
systemic perfusion pressures by dilation and constriction of cerebral resistance vessels to reductions
and elevations in systemic blood pressure, respectively. In chronic hypertension, the entire
autoregulatory curve is shifted to the right because of the pressure-related hypertrophy of the cerebral
resistance vessels that results in a diminished capacity for maximum dilation. In addition, the
hypertrophy of these same arterial resistance vessels allows the arteriole to withstand higher than
normal BP levels before its structural and functional integrity is compromised. Approximately 80% of
patients with acute stroke have elevated BP at the time of hospital admission. Blood pressure
30
reflexively rises during acute cerebral ischemia and brain trauma, and cerebral blood flow
autoregulation is disrupted in the ischemic areas of the brain surrounding the already infarcted area.
The disruption of autoregulation in the ischemic areas of the brain, which can last for weeks, leads to
a dependence on systemic perfusion pressure for blood flow and, therefore, oxygen delivery into
these areas.

E. Pressure-Mediated Renal Injury.

Transmission of systemic arterial pressure into the glomerulus is a major cause of renal injury. This
transmission is normally dampened through autoregulation of renal GFR and blood flow. In the setting
of chronic hypertension, the kidneys ability to autoregulate is impaired. The afferent arteriole
anatomically remodels and becomes functionally incapable of maximally dilating, and the number of
functional nephrons falls. GFR is maintained, at the expense of high intraglomerular pressure, by
local activation of the RAS system that causes angiotensin II-mediated efferent arteriolar constriction;
at the afferent arteriole, vasodilatory prostaglandins and nitric oxide mediate vasodilatation. These
changes in afferent and efferent arteriolar tone, in aggregate, lead to intraglomerular capillary
hypertension. There is also increased glomerular endothelial permeability resulting in excess filtration
of plasma proteins in direct relation to the increased glomerular pressure that is, in turn, elevated
because of transmission of systemic arterial pressure into a dilated afferent arteriole. A final common
pathway leading to further nephron destruction is glomerulosclerosis and tubulointerstitial fibrosis.

F. Renovascular Hypertension.

Critical renal artery stenosis (CRAS) is the most common cause of surgically curable hypertension.
Renovascular hypertension is attributable to atherosclerotic disease (usually involving the proximal
portions of the renal artery) as the cause of ~ 70% of CRAS. A large portion of the remaining CRAS
occurs as a consequence of fibromuscular dysplasia (FMD), a condition that usually involves the
middle portion of the renal artery and prototypically affects young to middle-aged women. The
stenosis must be severe enough (~60 - 70% reduction in luminal cross-section) to result in renal
hypoperfusion and therefore ischemia. When this occurs, renin activity increases leading to forward
activation of the RAS system. Renin secretion is typically suppressed in the contralateral kidney. In
unilateral CRAS, if the contralateral kidney is normal, or at least not severely diseased, the global
glomerular filtration rate is maintained, though usually because the GFR rises in the contralateral
kidney to offset the reduction in GFR in the stenotic kidney.

Bilateral CRAS has a much different pathophysiology than is observed in unilateral stenosis. The
circulating RAS system is not activated even though there is severe enough stenosis to cause chronic
ischemia of both kidneys. These patients often have expansion of their ECFV and can present with a
clinical presentation that is consistent with volume overload. Patients with bilateral CRAS also may
present with heart failure, pulmonary vascular congestion, and/or peripheral edema. Because the
stenosis involves both sides, the global GFR is much more likely to fall or be lower than in a patient
with unilateral CRAS. Hypertension is not an invariable consequence of either unilateral or bilateral
CRAS. Some patients, especially those with bilateral CRAS may present only with ischemic
nephropathy. The hypertension observed in bilateral CRAS is very, very difficult to control.

G. Pregnancy.

Hypertension occurs in ~ 5% of pregnancies. Plasma volume, ECFV, and cardiac output increase;
peripheral vascular resistance decreases during normal pregnancy. Vasodilatation occurs because of
increased endothelial cell synthesis of vasodilatory prostaglandins and nitric oxide, an arteriovenous
shunt in the placenta, and increased progesterone and estrogen levels. Pressor responses to
angiotensin II are diminished. Blood pressure decreases during the first and second trimesters, so
31
 that by mid-second trimester BP levels are ~ 10 mm Hg lower than pre-pregnancy levels. During the
third trimester BP rises to preconception levels. Chronic hypertension usually is diagnosed before the
th
20 week of pregnancy

V. Blood Pressure Variability

Blood pressure varies substantially during the day in response to activity, emotional state or temperature
(BP can rise when persons are cold). Blood pressure follows a circadian pattern and is approximately 10-
20% lower at night (2400 - 0599h) than between (0600 - 2200h). The rise in BP during the early morning
hours occurs in parallel with a rise in pulse rate, increase in blood viscosity, and increased platelet
aggregation. Most hypertensive patients maintain this pattern and are called "dippers." "Non-dippers" tend
to be those with an associated co-morbidity, like sleep apnea, left ventricular hypertrophy, or diabetes,
and carry an increased level of cardiovascular morbidity.

VI. Epidemiology of Systemic Hypertension

High blood pressure is a major health concern for the public. Systemic hypertension is the most common
chronic illness in the Unites States affecting approximately 33% of the adult American population (about
74.5 million people). This fact makes hypertension the most common cardiovascular disease. Data from
the National Health and Nutrition Examination Survey (NHANES) provide some important facts. About
76% of adults age 18-74 years old are aware that they have hypertension. Unfortunately, only 65% are
being treated, and only 66% of those on treatment are controlled. There are age, gender, and racial
differences in the prevalence of hypertension. Overall, blacks tend to have a higher incidence than age
and gender matched whites.

The level of blood pressure elevation is directly linked to cardiovascular morbidity and mortality. The
presence of hypertension increases the likelihood of developing coronary heart disease by 3-fold,
congestive heart failure by 6-fold, and having a stroke by 7-fold. Although deaths associated with stroke
and coronary heart disease increase as systolic and/or diastolic blood pressure rise, there is greater
incidence of death related to coronary heart disease with elevated systolic blood pressure for any given
level of diastolic blood pressure.

Blood pressure rises with age. Initially the rise is steeper in men than in women, but after menopause,
women show a greater rise and reach levels higher than those in men. In the younger years, the rise in
systolic and diastolic blood pressure is nearly parallel, but as one ages, the systolic blood pressure
continues to rise while the diastolic blood pressure falls.

VII. Measurement of Blood Pressure

There are two basic methods for determining arterial blood pressure. The gold standard for accuracy is
the invasive method where an intra-arterial measurement is performed using an intra-lumenal catheter.
The gold standard for practicality is the non-invasive method where an inflatable cuff is used to
temporarily occlude the artery and a stethoscope is used to listen for the presence or absence of sounds
that blood makes when flowing through a partially occluded artery. To obtain the most accurate
measurement, it is important that an appropriate cuff-size and calibrated equipment be used. The cuff-
bladder should encircle at least 80% of the circumference of the upper arm. The patient should be seated
with the arm bare and supported at or near the level of the heart. Measurements should be taken after at
least 5 minutes of rest, and the patient should refrain from smoking or ingesting caffeine for 30 minutes
32
prior. Both systolic and diastolic blood pressure should be determined using the Korotkoff sounds. The
first appearance of sounds is used as the SBP and the final disappearance of sounds indicates the DBP.
Two or more readings should be averaged, and the average then recorded as SBP/DBP (e.g., 130/80
mmHg). Pseudohypertension represents falsely elevated blood pressure readings in the setting of a rigid,
non-occludable brachial artery upon inflation of the cuff. "White coat" hypertension represents a
persistently elevated blood pressure in the clinic-type setting in combination with a normal ambulatory or
at-home blood pressure.

VIII. Classification and Diagnosis of High Blood Pressure

The designation of a threshold separating normal (normotension), abnormally low (hypotension), and
abnormally high blood pressure (hypertension) is somewhat arbitrary. The Joint National Commission on
Prevention, Detection, Evaluation and Treatment of High Blood Pressure 7 (JNC7) has issued
guidelines for adults who are not pregnant, acutely ill, or taking antihypertensive medications. BP is
considered normal when systolic BP is <120 mmHg and diastolic BP is <80 mmHg. Prehypertension
(120-139/80-89 mmHg) identifies people at risk for developing hypertension. Starting at 115/75 mmHg,
cardiovascular disease risk doubles with each incremental increase of 20/10 mmHg throughout the blood
pressure range. If a person is prehypertensive, they are at twice the risk of developing hypertension
compared to those with lower values. In persons with diabetes mellitus and/or chronic kidney disease, BP
is considered elevated and diagnostic of hypertension if the systolic BP is >130 and/or the diastolic BP is
>80 mmHg. In all other persons, hypertension is diagnosed if BP >140/90 mmHg on at least two different
days.

IX. Patient Evaluation

When evaluating a patient with HBP, it is important to (1) look for identifiable causes, (2) determine
whether target organ damage, cardiovascular disease or diabetes mellitus is present, and (3) identify
other cardiovascular risk factors, the management of which could improve clinical outcomes.

Risk factors are co-morbidities or lifestyles that when present significantly increase the chance of
developing cardiovascular disease, including stroke. Major risk factors include hyperlipidemia, diabetes,
smoking tobacco, physical inactivity, excess weight, increasing age, male gender and postmenopausal
women, and family history.

The evaluation consists of a medical history, physical examination, routine laboratory tests, and
optional testing should secondary hypertension be suspected. The medical history should determine the
JNC classification of HBP, duration of HBP, knowledge of the presence of cardiovascular disease or
TOD, a family history of systemic hypertension, presence of symptoms that might indicate the presence of
secondary hypertension, risk factors, lifestyle, and current and previous medications (both prescription
and over-the-counter). The minimal physical examination should include accurate BP readings and
recording, a check of BP in the contralateral arm (if the first visit), a check of BP in a lower extremity (if
coarctation of the aorta is suspected), measure of height and weight, fundoscopic examination,
examination of the neck, heart, lungs, abdomen, extremities and vasculature, and a neurological
examination.

Appropriate laboratory testing should be done in an effort to identify causes for HBP and the
presence of TOD or other risk factors. Prior to initiation of therapy, a urinalysis, complete blood count,
blood chemistries (sodium, potassium, creatinine, and fasting glucose), lipid profile, and 12-lead
electrocardiogram should be checked. If a secondary cause of HBP is suspected or certain risk factors
are indicated, additional laboratory testing may include: urinary creatinine clearance, 24-hour urinary
protein, serum calcium, serum uric acid, glycosylated hemoglobin (HgbA1C), thyroid stimulating hormone,
plasma renin level, plasma aldosterone, plasma metanephrines, urinary sodium, echocardiogram, renal
33
ultrasound and/or Doppler, or ankle/arm index.

X. Treatment of High Blood Pressure

There is no cure for primary hypertension but it is treatable and controllable. Some forms of secondary
hypertension are curable. The goals of treatment are to reduce the risk of stroke, heart disease, renal
failure, blindness, or death. There are two basic approaches to the treatment of HBP: (1) lifestyle
modification and (2) drug therapy.

Lifestyle modifications include weight loss, increasing physical activity, sodium restriction, limiting
alcohol consumption, and following the DASH diet (dietary approach to stop hypertension): high fiber,
calcium, and potassium; low fat and cholesterol. These measures are particularly important for people
with prehypertension.

Antihypertensive medications fall into three main classes: diuretics, vasodilators, and autonomic
nervous system agents. This classification mirrors our understanding of the three main organ systems
that regulate blood pressure: kidneys, arteries, and sympathetic nervous system. Logically, we should be
able to select drugs for treatment by determining the cause of the hypertension. Realistically, this is not
possible since 97% of hypertension is essential, and therefore multifactorial in nature. Logic would also
say when we look at the blood pressure equation (BP = CO x SVR) that we could use one drug to
decrease CO and another to decrease SVR. This approach is also somewhat impractical because few
drugs solely alter CO or SVR. [Diuretics come close in the early phase of therapy by lowering
intravascular volume, but in the long-term probably reduce SVR as well.] Although drugs have very
specific target enzymes or receptors, most tend to be "non-specific" in their overall hemodynamic effect.
Since the cause of essential hypertension is unknown, it is difficult to know what specific factors are
influencing CO and SVR (or both) to drive the blood pressure above normal. Blood pressure management
can be looked at as a column made of segments that can vary in height. The goal is to maintain a
normal total height of the column. Although one particular segment may be the culprit for the increase in
total height, we often decrease other segments, due to our lack of knowledge of the individual
components, in order to gain the overall effect of returning the column to normal height.

A. Diuretics.

Diuretics work by shifting the pressure-natriuresis curve to the left, or by simply making it easier for a
given pressure to push out a given amount of salt and water through the kidney. They also have
some other long-term effect, probably vasodilatory, that keeps the blood pressure down while
volumes return to baseline. Although patients with volume expansion tend to have a more robust
response to diuretic therapy, they work to some extent in the vast majority of patients, and have
therefore become the mainstay of antihypertensive therapy.

There are four classes available: thiazides (hydrochlorothiazide, metolazone), thiazide-like

(chlorthaladone, indapamide), loop (furosemide, ethacrynic acid, bumetanide, torsemide), and
potassium sparing agents (triamterene, amiloride, spironolactone, eplerenone). Thiazide and
thiazide-like diuretics decrease sodium and chloride reabsorption in the distal convoluted tubule by
inhibiting the Na/Cl co-transporter. Although their initial effect is ECFV reduction, blood volume and
cardiac output return to normal after a few days of therapy. The long-term effect is that of decreased
PVR, the mechanism of which is not completely known but likely involves alterations in vascular cell
ion transport. Loop diuretics inhibit the Na/K/2Cl co-transporter in the ascending loop of Henle to
prevent chloride and sodium reabsorption. This transporter is prostaglandin-sensitive; thus agents
that interfere with prostaglandin synthesis, like NSAIDS, can blunt the response of the loop diuretics.
The side effects of the diuretics are typically dose dependent and metabolic in nature. Common ones
include hypokalemia, hypomagnesemia, hyponatremia (mainly with thiazides), hypocalcemia (loop
diuretics), hypercalcemia (thiazides), hyperuricemia, hyperlipidemia, insulin resistance, and

34
impotence. All of the diuretics are indicated for first-line therapy except the loop diuretics which are
generally used in patients with reduced glomerular filtration rates and evidence of clinically significant
volume overload (renal failure, heart failure). Diuretics should be avoided in patients with prior
reactions to sulfa-type drugs.

Potassium-sparing agents block epithelial sodium transport channels in the distal tubule. This
action indirectly decreases aldosterone-sensitive sodium-potassium exchange. In the collecting duct,
the predominant mechanism of sodium reabsorption is the sodium transport channel. Because the
lumen potential becomes less negative, there is decreased potassium loss. (Several genetic studies
have identified families with inappropriate activation of their sodium channels who therefore have
hypertension due to excessive sodium reabsorption.) These drugs are particularly effective in low-
renin and salt-sensitive forms of hypertension. Spironolactone is a non-selective aldosterone
antagonist. Eplerenone is more selective and therefore reduces the progestational and
antiandrogenic effect seen with spironolactone like breast tenderness and breast enlargement.

B. Vasodilators.

1. Angiotensin Converting Enzyme Inhibitors (ACE-inhibitors).

The ACE-inhibitors (all end in pril: captopril, enalapril, lisinopril, trandolopril, etc.), as their
name suggests, block the activity of angiotensin converting enzyme in the conversion of
angiotensin I to angiotensin II (angII). This causes indirect arterial vasodilatation by
decreasing angII related vasoconstriction, inhibiting the degradation of bradykinin, and
reducing sympathetic nervous system activity (accompanied by blunted increases in
catecholamines and heart rate.) In addition, concentrations of aldosterone are lower and
there is decreased production of other vasoconstrictor substances such as endothelin.
Hemodynamically, there is a reduction of both preload and afterload. The ACE-inhibitors
(except captopril and lisinopril) are prodrugs, formulations that improve absorption but require
hydrolysis to an active diacid form in the liver or intestine. They are structurally
heterogeneous and have differences in absorption, protein and tissue binding, half-life, and
mode of metabolic disposition. These differences however rarely affect drug selection. The
antihypertensive effect of these agents correlates poorly with circulating ACE levels and/or
pretreatment renin levels. Side effects include dry, nonproductive cough (likely due to
increased levels of bradykinin metabolites), functional renal insufficiency (in states of
dehydration, heart failure, and microvascular renal disease where GFR is low; in patients with
either a solitary kidney and CRAS or bilateral CRAS), hyperkalemia, and angioneurotic
edema (unpredictable and potentially life-threatening). ACE-inhibitors have been shown to
reduce mortality post myocardial infarction and in high-risk coronary or peripheral arterial
disease patients. They also slow progression of target organ damage in heart failure and
various proteinuria prone nephropathies (diabetes, hypertension). These agents are
contraindicated in pregnancy because they can cause developmental defects in the second
and third trimester.

2. Angiotensin Receptor Blockers (ARBs).

There is a body of evidence suggesting an alternative pathway, catalyzed by chymase, by

which the body can produce angiotensin II bypassing angiotensin converting enzyme.
Angiotensin receptor blockers (ARBs) selectively bind to the angiotensin II type 1 receptor
(AT1) blocking the effects of angiotensin II. There is a resultant increase in plasma renin,
angiotensin I, and angiotensin II concentrations largely by inhibiting the negative feedback of
angiotensin II on renin release. There is variability within the class regarding bioavailability
and half-life. However, there is only minimal evidence that these pharmacokinetic differences
produce significant differences in BP lowering effects during the 24-hour treatment period.
35
 Agents in this class (all end in sartan) include losartan, irbesartan, telmesartan, candesartan,
valsartan, eprosartan, and olmesartan. The antihypertensive efficacy of the ARBs is
comparable to that of other classes of drugs, however, the dose-response effects are less
pronounced and the blood pressure-lowering efficacy between the starting dose and the
maximum dose is often only 4 to 8 mmHg. There is a virtual absence of dose-related side
effects, and these agents are often used in patients who are ACE-inhibitor intolerant. Clinical
trials with ARBs in hypertension, type 2 diabetes and nephropathy, and heart failure suggest
that the ARBs have clinical outcome benefits that go beyond their blood pressure lowering
effects. Like the ACE-inhibitors, they are contraindicated in pregnancy.

3. Calcium Antagonists.

Calcium plays a very important role in cellular communication, regulation, and function.
Calcium entry into cells causes stimulation of a number of cellular responses including
vascular smooth muscle cell contraction. The calcium antagonists, or calcium channel
blockers, reduce vascular resistance by blocking the L-type calcium channel, which directly
decreases cellular calcium entry and indirectly blunts angiotensin II and a-adrenergic
receptor-mediated vasoconstriction. The agents used fall into three subclasses:
phenylalkylamines (verapamil), benzothiazepines (diltiazem), and 1,4-dihydropyridines
(nifedipine, amlodipine). Each is distinct in that there is differential sensitivity and selectivity
for binding the pharmacologic receptors with the calcium channels in various tissues. As a
result, the calcium antagonists vary considerably in their effects on regional circulatory beds,
sinus and atrioventricular nodal functions, and myocardial contractility. This also results in
differences for clinical indications, contraindications, drug-drug interactions, and side-effect
profiles.

Calcium antagonists are very effective antihypertensive agents, and show efficacy across
all subgroups of patients. Side effects common to all include headaches, peripheral edema,
and gingival hyperplasia. Tachycardia is associated with the dihydropyridines, acute
myocardial infarction with short-acting dihydropyridines, heart block and congestive heart
failure with the non-dihydropyridines, and constipation with verapamil. The non-
dihydropyridines should be used cautiously with b-blockers.

4. Direct Vasodilators.

Hydralazine and minoxidil act directly on arterial smooth muscle cells to cause relaxation
and vasodilation. The mechanism of action of hydralazine and minoxidil is unknown, but is
felt to involve a change in the balance between vasoconstrictive and vasodilatory forces such
as cytosolic calcium and cyclic GMP. When used as monotherapy, blood pressure reduction
with these drugs is accompanied by a decrease in peripheral vascular resistance, but an
increase in cardiac output. There is reflex activation of the sympathetic nervous system, the
renin-angiotensin-aldosterone system, and accompanying salt and water retention. As a
result, activation of these blood pressure defense mechanisms leads to "pseudotolerance."
Minoxidil likely antagonizes the action of intracellular ATP on K+ channels causing them to
open. Hydralazine causes numerous side effects including a reversible lupus-like syndrome
at higher doses, flushing, headache, and edema. Its use is restricted to patients requiring
multi-drug therapy. However, it is the drug of choice in pregnancy-induced hypertension due
to its proven maternal and fetal safety. Minoxidil causes fluid retention (including pericardial
effusion and tamponade), flushing, and hypertrichosis. Minoxidil is indicated for cases of
resistant hypertension. These agents should be administered with a b-blocker (or central
sympatholytic drug) and a diuretic to combat the pseudotolerance and vasodilatory effects.

36
B. Autonomic Drugs.

1. -antagonists.

Selective 1-adrenoreceptor antagonists (-blockers) lower blood pressure by blocking the

postsynaptic vasoconstrictive effects of norepinephrine resulting in vascular smooth muscle
cell relaxation. Blood pressure reduction is achieved with little to no change in cardiac output
due to balanced arterial and venous dilation, and there is minimal effect on the renin-
angiotensin-aldosterone axis. The drugs tend to be more effective in the upright than the
supine position. They are indicated for use in patients requiring multi-drug therapy or in
hypertensive patients with benign prostatic hypertrophy (1-adrenoreceptors regulate the
degree of constriction of urinary tract sphincters). They also tend to have a modest beneficial
effect on metabolic abnormalities including insulin resistance and/or hypercholesterolemia.
Side effects include first dose orthostatic hypotension (50% of patients) and mild sodium and
water retention.

2. -agonists.

The central 2 sympathetic agonists reduce blood pressure by decreasing central

sympathetic outflow from the rostral ventrolateral medulla to the heart and blood vessels,
causing decreased heart rate and peripheral vascular resistance, and by causing feedback
inhibition of NE release on the sympathetic nerve terminal (prejunctional receptors). Plasma
renin activity is also lowered by central 2 receptor stimulation. These agents are particularly
useful in patients with hypertension-associated anxiety manifested by sympathetic
overactivity. Although effective antihypertensive agents, their use is limited by their side effect
profile which includes somnolence and dry mouth, and fluid retention and bradycardia at
higher doses. Methyldopa has been associated with autoimmune hemolytic anemia and
hepatitis. It is however very effective and widely used in pregnancy-induced hypertension.
Clonidine can cause rebound hypertension due to excessive sympathetic discharge if it is
suddenly discontinued and skin irritation can occur with transdermal clonidine. It is useful in
managing hypertensive urgencies due to its rapid onset of action (30-60 minutes); however, it
is relatively short-acting.

3. -blockers.

-blockers are very effective agents for lowering blood pressure. Their mechanism of action
is not totally clear, but most of the following actions are involved: reduction in heart rate and
cardiac output, inhibition of renin release, reduction in peripheral vascular resistance (ISA
drugs and /-blockers), reduction in vasomotor tone, resetting of baroreceptor function,
effects on prejunctional b-receptors leading to reduction in norepinephrine release, and
attenuation of pressor response to catecholamines (exercise and stress). Although the -
blockers as a group have similar therapeutic effects, there are structural differences that
confer many pharmacokinetic differences. In addition, differences in intrinsic chemical
properties confer significant clinical differences in effects.

a. 1-selectivity.

In low doses, 1 selective agents (acebutolol, betaxolol, bisoprolol, esmolol, atenolol,

metoprolol, and nebivolol) inhibit cardiac 1-receptors to a greater degree than the 2-
receptors on bronchial and smooth muscle cells. Leaving the 2-receptors unblocked may
render them more responsive to epinephrine and to 2-receptor mediated arteriolar
vasodilation.

37
 b. Intrinsic sympathomimetic activity.

These agents (propranolol, pindolol, acebutolol) are partial antagonists at 1-adrenergic

receptor sites, 2-adrenergic receptor sites, or both. This results in little change in heart
rate when the SNS is not activated and a blunted increase with stress. These agents still
are as efficacious in treating hypertension, angina, or arrhythmias as those without this
property.

c. Combined /-adrenergic blocking activity.

Labetalol and carvedilol are combined agents with direct vasodilator activity. Like other -
blockers, they are useful for treatment of hypertension and angina. However, unlike the
other agents, the additional -blocking property leads to a reduction in SVR that acts to
maintain higher levels of cardiac output.

In the approved prescribing dosages, the -blockers are equivalent in their

antihypertensive effects. Abrupt discontinuation of therapy may cause withdrawal
symptoms, including rebound hypertension; therefore, the dosage should be tapered
downward. Common side effects include fatigue, depression, bronchoconstriction and
bradycardia. They should be avoided in patients with asthma or COPD, decompensated
heart failure, heart block greater than first degree, and sick sinus syndrome. They should
be used cautiously in patients with insulin-dependent diabetes because they may mask
the symptoms of hypoglycemia. They should also be used cautiously with non-
dihydropyridine calcium antagonists (SA- and AV-nodal depression), and
pseudoephedrine, ephedrine, and epinephrine (increased blood pressure due to
unopposed alpha-receptor induced vasoconstriction).

4. Sympatholytics.

The peripheral sympatholytics (reserpine, guanethidine) lower blood pressure by depleting

nerve terminal norepinephrine from storage granules in the postganglionic sympathetic
nerves, thereby decreasing reflex peripheral arterial and venous constriction. This reflex
action is important during changes from lying down to standing up predisposing to orthostatic
hypotension. In addition, reserpine depletes other stores of norepinephrine and also reduces
serotonin levels. These agents are very effective in treatment of resistant hypertension, but
their utility is limited by numerous drug-drug interactions such as with monoamine oxidase
inhibitors (hypertensive crisis) and tricyclic antidepressants (decreased hypotensive effect);
and side effects including nasal stuffiness, increased gastric acidity, diarrhea, and retrograde
ejaculation.

D. Combination Therapy.

Most agents when used as monotherapy do not lower blood pressure to optimal levels. Combination
therapy not only improves efficacy, but also reduces side effects. There are benefits to using certain
drugs in combination due to their complementary mechanisms of action. For this reason, there are
several fixed-dose combination drugs available: a diuretic combined with ACE-I, ARB, or a beta-
blocker; and a calcium channel blocker combined with ACE-I, ARB and a diuretic.

38
Lecture Notes

Ischemic Heart Disease and Acute Coronary Syndromes I & II

09/24/2013

Richard G. Bach, M.D.

Ischemic Heart Disease and Acute Coronary

Syndromes I and II
Objectives:
1. Review the basic aspects of coronary physiology under normal and pathologic conditions.

2. Review myocardial oxygen consumption, and causes of an imbalance in myocardial oxygen supply
and demand.

3. Describe the current concepts regarding the pathophysiology of atherosclerotic vascular disease.

4. Define myocardial ischemia.

5. Describe principles governing diagnostic modalities useful in assessing patients for ischemic heart
disease.

6. Contrast alterations of myocardial function secondary to acute and chronic ischemia.

7. Describe the mechanism of action and basic principles underlying therapeutic modalities targeted for
ischemic heart disease.

Reference Text:

Lilly LS, editor, Harvard Medical School. Pathophysiology of heart disease: a collaborative project of
medical students and faculty. 5th ed. Baltimore: Lippincott Williams & Wilkins; 2011: 44-74; 97-102; 113-
189.

I. Introduction/Overview
The heart functions to pump an adequate supply of blood to the body over a wide range of pressure and
work demands. Over the course of an 80-year life span, the heart will pump over 200,000,000 liters of
blood. The anatomy and physiology of the coronary arteries, microcirculation, myocardium, coronary
endothelium, and coronary vascular smooth muscle are integrated and uniquely adapted to support the
mechanical energy necessary to drive the pump and maintain cardiac output, aortic pressure, and vital
organ perfusion. Disease states that impair normal coronary physiology and, in turn, impair normal
myocardial function, are unfortunately among the most common causes of morbidity and mortality in the
developed world today.

39
II. Anatomy and Physiology of the Coronary Circulation
A. Key Concepts:

Coronary autoregulation.

Phasic nature of coronary flow.

Coronary flow reserve.

Subendocardial vulnerability to ischemia.

Rate-pressure product.

Endothelial control of vasoreactivity.

The coronary arteries serve to provide oxygen and nutrients to the myocardium. Because of its
constant workload, the myocardiums resting oxygen needs are high compared to skeletal muscle.
Since the coronary arteries must constantly supply variable oxygen and nutrient requirements to the
myocardium, the coronary circulation is complex both structurally and functionally. The anatomy of
the coronary microcirculation is uniquely optimized for meeting the high myocardial oxygen demands.
The coronary arterial tree represents a system of frequently branching epicardial conduit vessels,
2
terminating in approximately 3500 capillaries/mm of myocardium (in comparison to 400
2
capillaries/mm for skeletal muscle). The oxygen and nutrient exchange rate for myocardium is 15
times that of skeletal muscle.

B. Regulation of Coronary Flow.

Due to its high energy requirements and dependence on oxidative metabolism, even in the resting
state myocardial oxygen extraction from blood is near maximal and coronary sinus oxygen
saturations are typically 30% or less, leaving little additional oxygen for the myocardium to extract if
demands increase. As a result, coronary blood flow must be tightly regulated to keep oxygen supply
in balance with myocardial demand; changes in myocardial oxygen demand can only be met by
proportionate changes in myocardial blood flow. The resultant maintenance of constant, steady-
state blood flow over a wide range of aortic driving pressures is known as coronary autoregulation
(Figure 1, Slide 6). As aortic pressure decreases, coronary blood flow is maintained at a constant
level by dilation of resistance vessels. The opposite compensatory response, that is constriction of
resistance vessels, autoregulates blood flow in reaction to increasing aortic driving pressure. Hence,
during normal resting conditions, coronary blood flow is essentially pressure-independent. The normal
epicardial coronary arteries serve primarily as conductance vessels, contributing only slightly to
coronary vascular resistance. The predominant resistance that modulates coronary flow arises from
small intramural arterioles beyond the resolution of coronary arteriography. Dynamic alterations in
coronary blood flow delivery are typically accomplished by changes in coronary arteriolar resistance.
The coronary circulation under resting conditions is typically a high resistance, low flow circuit. Basal
coronary resistance in normal vessels can be reduced, and coronary blood flow therefore increased,
2 to 5-fold by potent arteriolar vasodilators. This indicates a substantial reserve capacity within the
coronary circulation to deliver increased blood flow to the myocardium. The ability to increase flow in
response to appropriate stimuli has been termed the coronary vasodilator reserve or coronary
flow reserve (CFR), and is numerically expressed as the ratio of maximal hyperemic to basal flow
(Figure 2, Slides 8 and 9). When resistance vessels are dilated maximally, coronary blood flow
cannot be increased further without an increase in aortic pressure (and coronary blood flow and
pressure become linearly related).

40
Figure 1. Autoregulation demonstrated by acute (solid circles) and delayed (open circles) changes in coronary blood flow in
response to changes in coronary pressure (From Ann NY Acad Sci 1959;80:365).

Figure 2, see Slide 9. Schematic depiction of coronary flow reserve (From J Am Coll Cardiol 1990;16:763).]

There are clinically important physiologic consequences attributable to autoregulation and the
concept of CFR. In animal models where ligatures are used to mimic coronary obstructive lesions, as
a result of autoregulation, resting coronary artery blood flow does not decrease until the lumen is
narrowed by a diameter stenosis of approximately 80%. Maximal hyperemic coronary flow, however,
decreases when the percent diameter stenosis exceeds approximately 40-50%. The consequent
reduction of CFR shows an excellent correlation with the severity of an experimental stenosis (Figure
3, Slide 11).

41
Figure 3, Slide 11. Relationship between stenosis severity (horizontal axis) and resting (dashed line) and maximal coronary
blood flow (solid line) expressed as a ratio of resting flow (on the vertical axis). (From: Gould and Lipscomb. Am J Cardiol
1974;34:50).

By positron emission tomography measurements of myocardial perfusion, recent studies have

confirmed in patients with coronary artery disease, in agreement with the animal models, that resting
regional myocardial blood flow remains unimpaired over a wide range of angiographic coronary
stenoses up to about 80% diameter narrowing, while hyperemic flow is increasingly impaired in direct
relation to stenosis severity above approximately 40%.

Coronary blood flow is affected by mechanical, neural, and metabolic factors. Mechanical factors
have an impact on coronary blood flow and account for its phasic pattern. Contraction of the
myocardium results in systolic compression of small vessels and a reduction of systolic blood flow. In
early diastole, coronary blood flow increases rapidly to an early diastolic peak and slowly falls during
the remainder of diastole in proportion to slowly falling diastolic aortic pressure. The result is a
predominant diastolic blood flow pattern (see Figure 2, Slide 8). Importantly, one effect of
tachycardia is shortening of diastolic perfusion time. Reducing the time available for coronary blood
flow to perfuse myocardium by limiting diastole may be one mechanism by which tachycardia
contributes to oxygen supply-demand imbalance and causes ischemia. From responses provoked by
sympathetic stimulation, cardiac neural adrenergic signals appear to participate in the regulation of
myocardial blood flow. Coronary arteries have both -adrenergic receptors, mediating
vasoconstriction, and 2-adrenergic receptors, which mediate vasodilation. The endothelium of
conduit and resistance vessels, by elaboration of specific endothelial-derived factors, including
endothelial-derived relaxation factor, or nitric oxide, and prostacyclin, both of which cause
vasodilation, and endothelin, which causes vasoconstriction, can have a profound effect on coronary
tone. Additional local metabolic factors can also strongly influence coronary blood flow. These include
oxygen, lactate, and adenosine. Endogenous release of adenosine appears to be one of the most
important events mediating increases in coronary blood flow during exercise and during ischemia.

There is important transmural heterogeneity of factors influencing the regulation of the coronary
microcirculation. The compressive effects of myocardial contraction during systole are more
pronounced in the subendocardial layers than in the subepicardial layers (Figure 4, Slide 12). This
predisposes to transmural blood flow maldistribution under conditions of stress, when flow may be
maintained to lower resistance subepicardial layers at the expense of the higher resistance
subendocardium. This factor makes the subendocardial layers more vulnerable to ischemia,
especially when epicardial stenoses add upstream resistance to the coronary circuit.

42
Figure 4. Transmural heterogeneity influencing coronary blood flow. (From Bell and Fox. Am J Med Sci 1974;268:2).

Myocardial oxygen consumption and thereby demand varies with a number of factors, including
(1) myocardial inotropic state (contractility), (2) heart rate, and (3) ventricular wall stress.
Contractility is increased by circulating catecholamines and inotropic drugs, and may be decreased
by certain agents, such as -adrenergic blocking drugs. Ventricular wall stress, expressed by
LaPlaces Law as

Wall stress = P x r
2h

is directly related to the pressure (P) in the ventricle and its radius (r), while inversely related to the
wall thickness (h). Thus wall stress and consequently myocardial oxygen consumption can be
substantially increased by higher ventricular pressures (e.g., accelerated hypertension or aortic
stenosis). Myocardial oxygen consumption is commonly approximated under clinical circumstances
by a simplified surrogate, the product of the heart rate and systolic blood pressure (called the "rate-
pressure product").

C. Coronary Endothelium.

The endothelium comprises a single layer of cells lining blood vessels situated between the vascular
smooth muscle of the media and the circulating blood. As such, normal endothelial cells serve
multifaceted roles in the interaction between the blood and the vascular wall. A normally functioning
endothelium is integral to maintaining normal coronary blood flow, and blood-endothelial interactions
cause the release of vasodilator or vasoconstrictor substances and inhibit platelet aggregation and
thrombosis in such ways as to maintain homeostasis in response to various stimuli. Substances
produced by the endothelium that modulate vascular tone include the vasodilators nitric oxide
(previously termed endothelium-derived relaxing factor or EDRF), prostacyclin, and endothelium-
derived contracting factors such as endothelin.

Endothelial nitric oxide is produced by metabolism of the amino acid L-arginine by the nitric oxide
synthase (NOS) family of enzymes. With an intact, normally functioning endothelium, nitric oxide
production is stimulated by several factors, including acetylcholine, histamine, bradykinin, and certain
platelet-derived substances. Nitric oxide may also be elicited in response to the mechanical
stimulation of flow in the form of fluid shear stress, resulting in an important phenomenon termed
flow-mediated vasodilation. Counterbalancing dilation, the endothelium also produces
vasoconstricting factors, such as endothelin, which can be stimulated by several factors, including
thrombin, transforming growth factor-beta, epinephrine, and angiotensin II. Recent evidence suggests
the balance of vasodilation vs. vasoconstriction mediated by the endothelium in coronaries of adult
humans may be influenced by certain extrinsic factors, such as the degree of adjacent intimal
43
thickening secondary to atherosclerosis and the level of serum cholesterol. Endothelial dysfunction,
indicated by abnormal responses to endothelium-dependent vasoactive agents, may be a factor that
precedes and may predispose to the development of atherosclerotic lesions.

D. Abnormal Coronary Physiology and Clinical Detection.

One of the most common etiologies of altered coronary artery physiology that becomes clinically
manifest is obstructive coronary artery disease due to coronary atherosclerosis (see below). As noted
above, as a result of autoregulation, under resting conditions, despite progressive narrowing,
coronary flow can remain normal until the coronary artery is very severely narrowed. As a result, in
general, atherosclerotic coronary obstructions develop gradually over decades, and patients may
remain asymptomatic until late in the course of the disease. However, maximum coronary blood flow
and the maximum potential increase in flow or coronary flow reserve begins to be impaired at more
moderate degrees of diameter narrowing. In essence, when a stenosis becomes sufficiently severe
so that its resistance is greater than that of the distal vascular bed, autoregulation will be exhausted
and flow will be determined predominantly by the stenosis resistance alone. The degree of maximal
flow limitation is one key factor among several factors that interact to determine the extent and
severity of rest and/or exercise-induced ischemia, and its typical symptomatic manifestation: angina
pectoris.

The concepts outlined above provide the basis for diagnostic testing for ischemic heart disease
commonly used in clinical practice. As a consequence of autoregulation, testing that measures
resting coronary flow or resting myocardial perfusion is insensitive to diagnosing the presence or
severity of coronary artery disease. However, because maximum coronary blood flow, and, in turn,
coronary flow reserve, become impaired in direct relation to the degree of coronary artery stenosis
above a threshold level, testing the capacity for peak coronary hyperemia can provide a sensitive
means for detecting the flow heterogeneity caused by coronary artery obstruction.

E. Diagnostic Modalities.

Diagnostic modalities in clinical use exploit aspects of the above concepts in order to allow detection
of altered coronary physiology and/or altered myocardial perfusion to diagnose coronary obstruction.

1. Exercise stress testing: An exercise stress test consists of having a patient perform a
controlled exercise protocol, typically by walking on a treadmill at increasing speeds and
degrees of slope, or pedaling a bicycle at stepwise increments of resistance, with continuous
assessment of symptoms, monitoring of a 12-lead electrocardiogram and intermittent
measurement of blood pressure. Given the relative vulnerability of the subendocardial
myocardial layers, the presence of epicardial coronary obstructions may limit maximal
achievable coronary blood flow sufficiently to cause subendocardial myocardial ischemia.
This results in a relative change of myocardial polarity from endocardial to epicardial layers,
manifest as depression of the ST segment on the electrocardiogram. The relative amount
of myocardial work (for example, as expressed by the rate-pressure product) required to elicit
anginal discomfort and/or ischemic changes on the electrocardiogram may be used as a
rough estimate of the severity of the coronary obstruction. Unfortunately, electrocardiographic
stress testing remains limited by imperfect sensitivity and specificity.

2. Nuclear Perfusion Imaging: More sensitive diagnostic tests for ischemic heart disease
incorporate adjunctive imaging modalities. The first of these is radionuclide myocardial
perfusion imaging. Used in combination with an exercise stress test, a radionuclide agent
with avidity for myocardial cells (thallium-201, technetium-99 sestamibi) is injected both at
rest and at peak exercise stress. Scans of the heart obtained with a scintillation camera at
rest and peak stress are then compared. Since during exercise maximal blood flow to the
44
 myocardium is restricted in areas with epicardial obstruction, but will increase normally in
non-obstructed areas, a disparity in radiotracer density can be detected that may be absent
at rest. Observation of stress-induced regional hypoperfusion provides a sensitive means
for identifying regional coronary artery obstruction. For patients who are unable to exercise
adequately, agents that induce vasodilation of coronary resistance vessels can be employed
in conjunction with myocardial radionuclide perfusion imaging. Because maximal coronary
flow and coronary flow reserve are limited in vessels with significant stenosis, vasodilation
with exogenous agents such as dipyridamole or adenosine can similarly promote regional
heterogeneity of myocardial perfusion detectable by scintigraphy.

3. Echocardiographic Imaging: Because regional ischemia due to limitation of maximal flow

and a resultant myocardial supply-demand imbalance results in alteration of contractile
function, adjunctive echocardiographic imaging during exercise stress testing can also be
used to diagnose the presence of obstructive coronary artery disease. The development of
localized hypokinesis with exercise is a reliable sign of regional ischemia. For patients
unable to exercise, dobutamine infusion, which causes tachycardia, increased contractility,
and increased myocardial oxygen demand, similarly may elicit regional ischemic contractile
dysfunction detectable by echocardiographic imaging.

III. Pathophysiology of Atherosclerotic Coronary Artery Disease

A. Key Concepts:

Stages of atherosclerotic plaque development.

Arterial remodeling/Glagov phenomenon.

Plaque vulnerability.

Plaque inflammation.

Plaque erosion or rupture.

Atherosclerosis is a progressive systemic disease of the arterial wall. Atherosclerotic lesions may
develop over variable intervals, but mature disease typically develops gradually over decades. In the
modified response-to-injury hypothesis, the process of atherogenesis is viewed as a stepwise
process initiated by injury to the vascular endothelium. Endothelial "injury" may be related to physical
disruption of endothelial cell integrity (shear stress, etc.), or to the toxic effects on the endothelium of
several factors, such as hyperlipidemia, hypertension, diabetes, or cigarette smoking. When the
endothelium becomes dysfunctional, a common manifestation includes altered release of vasoactive
substances, generally resulting in impaired vasorelaxation of inappropriate vasoconstriction to
stimulation. The injured endothelium may also lose its ability to serve as a permeability barrier and
antithrombotic surface.

45
Figure 5, Slide 19. Schematic depiction of atherosclerotic plaque development; the fibrous plaque shown is drawn with a thin
fibrous cap and large lipid core illustrating characteristics associated with vulnerability to rupture.

The earliest lesions of atherosclerosis have been identified as fatty streaks consisting of lipid-
laden monocytes and macrophages ("foam cells") that have been observed at autopsy in the arteries
of teenagers and young adults. These have been considered precursors to atherosclerotic lesions.
The atherosclerotic plaque gradually accumulates increasing amounts of intimal smooth muscle cells,
fibrous tissue, foam cells, and variable degrees of inflammation, progressing to the fibrous plaque
(Figure 5). Fibrous plaques are typically eccentric and most commonly develop in certain arteries,
such as, among others, the aorta, the coronary arteries, and the carotid arteries.

B. Arterial Remodeling.

Arterial remodeling has emerged as an important concept that describes the adaptive response of
the artery to the gradual development of atherosclerotic plaque, a process also known as the Glagov
phenomenon (Figure 6, Slide 20). Arterial remodeling helps account for why fairly extensive disease
of the arterial wall may be present even in the absence of severe obstruction of the coronary lumen or
of coronary bloodflow. As eccentric plaques develop within the coronary artery, there is a
compensatory enlargement of the entire vessel cross-sectional area such that the lumen of the artery
may be relatively preserved. This process can continue until a sufficient proportion of the artery
becomes involved, at which point additional plaque growth may outstrip the remodeling capabilities of
the artery and luminal encroachment and adverse consequences for coronary blood flow can
develop.

46
Figure 6. Schematic depicting arterial remodeling.

C. Vulnerable Plaque, Plaque Inflammation, and Plaque Rupture.

Important and relatively recent concepts regarding atherosclerosis relate to the vulnerability of
relatively mature plaquespresumably developing or present for yearsto spontaneous erosion or
disruption, with a resultant exposure of subendothelial plaque components and promotion of platelet
deposition and coronary thrombosis, the typical pathophysiologic basis for acute coronary syndromes
such as unstable angina and acute myocardial infarction. The morphology of a vulnerable plaque
(Figure 7, Slide 21) is felt to include a large lipid core and thin fibrous cap, suggesting a susceptibility
to rupture, possibly due in part to the influence of circumferential stress. Recent data also suggests
that plaque inflammation may also play an important role in the instability of plaques and their
tendency to rupture. Atherosclerotic plaques are characterized by variable amounts of inflammatory
macrophages and activated T-lymphocytes, especially localized to the "shoulder region"where the
lipid core is adjacent to more normal vessel wall. Vulnerable plaques appear to have larger numbers
of these inflammatory cells. It has been postulated that the degree of local inflammation and the local
production of enzymes such as metalloproteinases by inflammatory cells may account for thinning
and weakening of the fibrous cap, rendering the lesion more susceptible to rupture.

47
Figure 7, Slide 21. Schematic depicting characteristics of "vulnerable" and "stable" atherosclerotic plaques. The vulnerable plaque
has a large lipid core and thin fibrous cap, often with active inflammatory cells at the plaque "shoulder." The stable plaque has a
smaller lipid core and thick fibrous cap. The vulnerable vs. stable features cannot generally be differentiated by angiography. From
Libby P. Circulation 1995;91:2844-2850.

Plaque erosion or rupture exposes the subendothelial components of the plaque, especially the
highly thrombogenic lipid core with large amounts of tissue factor, to circulating blood, initiating
coagulation with a cascade of platelet adhesion, activation and aggregation, fibrin deposition and
intra-arterial thrombus formation. This accounts for the pathophysiologic basis for the majority of
cases of unstable angina (e.g., episodes of angina at rest or abruptly increased in frequency and
severity) and myocardial infarction. Of note, given that the coronary artery is capable of extensive
remodeling (reviewed above) and that lesion instability and vulnerability may be relatively
independent of stenosis severity within the artery, plaque rupture may commonly involve lesions that
were not obstructive and therefore not previously clinically manifest. This factor likely accounts for the
observation, made by comparing serial coronary angiograms in patients presenting with myocardial
infarction, that most clinically manifest ST-elevation acute myocardial infarctions are probably caused
by rapid progression to occlusion (by thrombus) of ruptured coronary lesions that were previously not
critically severe (i.e., less than 70% diameter stenosis) (see Figure 8). Developing methods to
identify vulnerable plaques before they rupture is an active area of current basic and clinical research.

48
Figure 8, Slide 22. Graph depicting stenosis severity of lesions at previous angiography for patients presenting with acute
myocardial infarction in multiple studies.

IV. Effects of Ischemic Heart Disease on Myocardial Metabolism

A. Key Concepts:

Myocardial energy normally from oxidative metabolism of FFA.

Hypoxia/ischemia result in shift to glycolysis.

PET scanning of metabolic analogues can provide clinically important data

regarding myocardial viability.

The primary source of energy for the working heart under normal conditions is oxidative metabolism
of free fatty acids (FFA). Metabolism of FFA provides 70 to 90% of the myocardial energy
requirements in the presence of an adequate supply of oxygen. The balance of energy requirements
is provided by aerobic metabolism of glucose, lactate, and pyruvate. With low flow ischemia or
hypoxia, myocardial free fatty acid metabolism is suppressed due to the absence of oxygen for their
oxidation; in turn, contractile function then becomes depressed.

49
 During hypoxia or low flow ischemia, the myocardium continues to take up glucose, and glycolytic
flux increases. The shift in energy substrate dependence to glucose and augmentation of glycolysis
may contribute to maintenance of viability of the myocardium during periods of reduced oxidative
phosphorylation by providing an alternative source of ATP. Based on this metabolic behavior, cardiac
positron emission tomography (PET) of positron radiolabeled metabolic analogues can be utilized
clinically to identify normal versus ischemic versus necrotic myocardium. For example, the relative
18
uptake of F-fluoro-2-deoxyglucose (FDG) closely parallels glucose extraction by myocardium. The
degree of myocardial FDG uptake may be used under specific conditions to distinguish between
necrotic (non-viable) and viable but underperfused myocardium. The determination of dysfunctional,
underperfused yet viable myocardium in the setting of ischemic heart disease suggests a potential for
recovery with revascularization (by angioplasty or bypass surgery), and represents an increasingly
important component of the diagnostic evaluation for many patients with ischemic heart disease.

V. Effects of Ischemic Heart Disease on Cardiac Function

A. Key Concepts:

Ischemia impairs both diastolic and systolic function.

Myocardial stunning and hibernation.

Both acute and chronic myocardial ischemia can have significant effects on cardiac function.
Although the impairment of systolic contractile function is relatively easily detected, ischemia may
also have a profound influence on both systolic and diastolic ventricular properties. Myocardial
ischemia is associated with an impairment of ventricular relaxation that is manifest by a decrease in
the rate of left ventricular pressure decline and prolonged isovolumic relaxation. In addition, ischemic
myocardium becomes less compliant than normal, and the sum effect is that ischemia induces
changes in diastolic ventricular properties that increase resistance to ventricular filling, contributing to
elevation of left ventricular diastolic pressure during ischemia (see Figure 9).

Figure 9. Left ventricular pressure-volume loop depicting changes typical for acute or chronic ischemia. The solid lines show a
normal ventricle pressure-volume relationship; the lower dotted line show how ischemia results in lower compliance (increased
stiffness) such that to distend the ventricle to the same preload requires increased pressure, in turn with an increased risk of
pulmonary congestion. The upper dotted line shows how ischemia causes reduced contractility, such that for any given afterload the
ventricle can eject less blood.

In addition to altering diastolic filling properties, myocardial ischemia results in a regional loss of
++
systolic contraction. This likely results from a reduced release of Ca by the sarcoplasmic reticulum,
++
making less Ca available to the contractile sites, and/or from cellular acidosis and its interference
++
with the interaction of Ca and contractile proteins. In turn, regional loss of myocardial contractile
50
 activity, if affecting a large enough portion of ventricular myocardium, can depress overall left
ventricular function, reducing stroke volume, stroke work, cardiac output, and ejection fraction. This
can also contribute to elevation of end diastolic volume and pressure.

Because diastolic left ventricular pressure correlates with pulmonary venous and pulmonary
capillary pressure, pulmonary congestion may be a consequence. Thus, the typical clinical
manifestations of such left ventricular failure are dyspnea, orthopnea and paroxysmal nocturnal
dyspnea. When a large proportion of myocardium is so affected, especially acutely, severe pump
failure may ensue resulting in inadequate cardiac output, inadequate systemic perfusion, and
cardiogenic shock.

Even transient episodes of myocardial ischemia can cause systolic and diastolic ventricular
dysfunction which may remain impaired for more prolonged periods. This prolonged impairment of
mechanical performance after transient myocardial ischemia is termed myocardial "stunning." Of
note, while the transient ischemia may reduce high-energy phosphate stores, the myocytes remain
viable. A similar but somewhat distinct entity where mechanical contractile function is impaired due to
chronic low flow ischemia in the absence of necrosis is called myocardial hibernation. However,
when blood flow to a region of myocardium abruptly ceases, as in the setting of acute coronary
thrombosis, myocardial infarction generally occurs, where the profound and sudden lack of oxygen
and nutrients results in frank myocardial necrosis.

VI. Therapeutic Maneuvers

A. Key Concepts:

Medical anti-ischemic therapy.

Myocardial revascularization.

With respect to medical interventions directed at treating chronic ischemic disease and improving the
myocardial oxygen supply-demand balance (reviewed elsewhere), nitrates, beta-adrenergic
blocking agents, and calcium channel antagonists are the most commonly employed agents.
Agents from each of these classes may provide symptomatic relief of angina pectoris, alone or in
combination. Nitrates appear to vasodilate diseased coronary vessels to augment coronary blood flow
to affected regions while also favorably affecting preload and afterload. Given their rapid onset of
action and excellent bioavailability, sublingual (or topical) nitrates may provide rapid relief of an acute
ischemic episode. Beta-adrenergic agents are negatively inotropic and typically slow the heart rate,
both of which may favorably affect myocardial oxygen supply-demand balance and relieve ischemia.
Beta-blockers also have membrane stabilizing and antiarrhythmic effects. They are among the most
important agents for reducing adverse clinical events and death in patients following myocardial
infarction and in those with severe ischemic heart disease. Calcium channel antagonists are
heterogeneous, with some acting as strong negative inotropes and others predominant vasodilators.
As a class they can be effective anti-anginal agents, but must be selected carefully with attention to
potential adverse effects and randomized trials suggesting worse outcomes when used in certain
patient populations. Many patients with severe obstructive coronary artery disease require
combination therapy with multiple agents for control of anginal symptoms.

Given the prominent role of platelets and intracoronary thrombus in the progression to clinically
manifest angina in the setting of chronic coronary artery disease, antiplatelet therapy with aspirin is a
mainstay of the treatment of atherosclerotic cardiovascular disease. Multiple clinical trials have
documented the efficacy of aspirin at doses as low as 81-325 mg/day in preventing future coronary
events in patients with established coronary atherosclerosis, unstable angina or myocardial infarction.
51
For patients with unstable coronary syndromes, the addition of an additional antiplatelet agent that
blocks the platelet ADP receptor (clopidogrel, prasugrel, or ticagrelor) further reduces adverse
ischemic events. Aspirin and an ADP receptor blocker (so called "dual antiplatelet therapy") in
combination with anticoagulation using unfractionated heparin or low molecular heparin represent
the current standard of care. A class of agents, the glycoprotein IIb/IIIa platelet fibrinogen
receptor antagonists that block the final common pathway of platelet aggregation, has also been
shown to reduce events even further in higher risk patients with acute coronary syndromes.

With respect to treatment options for patients with ischemic heart disease refractory to medical
management, in whom medical therapy is poorly tolerated, or in whom medical management may
provide insufficient protection from adverse sequelae, revascularization by endovascular techniques
or coronary artery bypass graft surgery (CABG) may effectively relieve ischemia. Endovascular
techniques of percutaneous coronary intervention (PCI) include balloon angioplasty, atherectomy,
and placement of stents. In each of these techniques, a specialized catheter is inserted via a
peripheral artery access point (usually femoral, brachial or radial) into the diseased coronary artery
under fluoroscopic guidance. For balloon angioplasty, a balloon sized for the coronary diameter is
inflated at the site of obstruction. For rotational atherectomy, a diamond-tipped olive-shaped burr is
spun at more than ~150,000 rpm to ablate plaque. For stent placement, a cylindrical metal device is
deployed at the site of plaque in the artery to act as a scaffold to optimize artery patency after
expansion. For CABG surgery, conduits composed of internal mammary or radial arteries, or
reversed saphenous vein, are anastomosed to segments of the coronary arteries distal to obstructive
lesions. Each of these techniques may be highly successful in select patients for relieving debilitating
anginal syndromes. In certain anatomic subsets of patients with atherosclerotic coronary artery
disease, such as patients with left main coronary obstruction, clinical trials have documented a
mortality benefit for CABG surgery. When a clinician considers the options of revascularization for a
patient, reference to clinical trials documenting the outcome of revascularization for patients with
specific anatomic or physiologic characteristics provide the actual evidence base from which clinical
decisions for each patient are appropriately made.

52
Case Study

Hypertension Case Studies

09/24/2013

Angela L. Brown, M.D.

Hypertension Case Studies

Case 1
40-year-old woman with no other medical problems presents for follow-up of hypertension. She was
started on a thiazide diuretic 2 months ago.

Her BP is well controlled at 128/76 mmHg. She complains of lower extremity cramping and is found to
have a decreased potassium level of 3.0 mmol/L.

What is the mechanism for her loss of potassium?

53
Case 2
62-year-old man with history of hypertension and atrial tachycardia presents for blood pressure control.
His BP is mildly elevated at 148/94 mmHg. Pulse varies from 100-110 bpm. He has been intolerant of
beta-blockers in the past due to extreme fatigue.

What would be the best alternative medication for this patient and why?

54
Case 3
A 76-year-old woman presents to the hypertension clinic for consultation. She was diagnosed with HTN
about 30 years ago, and had been treated and controlled with a thiazide diuretic since diagnosis. Over
the past 5 years, her blood pressure has slowly increased to consistently range from 158-180/72-80
mmHg. Although her PCP has told her not to be concerned because "this happens with age," she has
read otherwise on the internet.

How would you describe this womans hypertension and should she be concerned?

Describe 3 pathophysiologic changes that may contribute to her elevated blood pressure.

55
Case 4
A 58-year-old woman presents to establish care. Hypertension appeared transiently during her 3
pregnancies, but has persisted for the past 25 years. BP levels average 160/110 mmHg despite the use
of several medications that were taken only for short periods, with none taken over the past year. Type 2
diabetes was diagnosed 18 years ago and has been treated with oral agents. She denies tobacco,
alcohol, or illicit drug use. She eats out frequently and uses sea salt for seasoning. Exercise is through
her daily activities. Recent labs show HgbA1C of 8.8%, SCr of 1.9 mg/dl, and 24 hour urine protein of 1.3
g.

Based on JNC-7 guidelines, her target blood pressure is:

a. Less than 140/90.

b. Less than 120/80.

c. Less than 130/85.

d. Less than 130/80.

e. Less than 125/75.

Based on clinical trial evidence and JNC-7 recommendations, what would you recommend as
initial therapy to treat her hypertension and improve her overall clinical outcome?

How would you counsel her regarding lifestyle modifications that would improve her blood
pressure control?

56
Case 5
An 82-year-old man with history of hypertension for many years comes to clinic complaining that he has
had dizziness that has gradually worsened over the past 2 years. Symptoms are worse when he stands.
His PCP discontinued antihypertensive therapy, but symptoms have persisted. Vital signs reveal BP
149/84 mmHg supine, 134/68 mmHg seated, and 90/54 mmHg standing. The rest of his physical exam is
unremarkable.

Describe this mans hypertension and the possible mechanism.

57
Lecture Notes

Sinus Rhythm and Bradycardia

10/01/2013

Timothy W. Smith, M.D., D.Phil.

Sinus Rhythm and Bradycardia

Objectives:
1. Describe the pathophysiological basis of the abnormalities in impulse formation or impulse conduction
that can account for the bradyarrhythmias seen clinically.

2. Recognize the abnormalities detectable in the 12-lead electrocardiogram that are produced by
conduction delay or block in the AV node, His bundle, or bundle branches.

Reference Texts:

1. Lilly LS, ed. Harvard Medical School. Pathophysiology of Heart Disease: a collaborative project of
medical students and faculty. 5th ed. Baltimore: Wolters Kluwer, Lippincott Williams & Wilkins;
2011:261-293.
th
2. Dubin, Dale. Rapid Interpretation of EKGs. 6 ed. Fort Myers (FL): Cover Publishing; 2000.

Dont be put off by the "interactive" presentation. It is excellent for developing an understanding of the
priniciples of ECG reading. Many will find it best for reading through once to introduce concepts. May
be less useful as a lifetime reference.
th
3. Thaler MS. The Only EKG Book Youll Ever Need. 6 ed. Philadelphia: Wolters Kluwer Lippincott
Williams & Wilkins; 2009.

Excellent guide to ECGs and can serve you well as a reference throughout medical school and
beyond.

4. Smith TW. Tarascon ECG Pocketbook. Burlington, MA: Jones and Bartlett Learning, 2012. 134 pp.

Small pocket book intended as both learning tool and quick pocket reference. Has pretty much
everything the author knows about ECGs.

5. Smith TW and Pinto DS. Tarascon Pocket Cardiologica. Burlington, MA: Jones and Bartlett
Learning, 2012. 386 pp.

Another Tarascon small pocket book intended as useful, ready resource for the clinical
student/physician of cardiology.

58
I. Bradyarrhythmias
A. Mechanisms.

1. Altered impulse formationsinus node dysfunction.

2. Altered impulse conduction/propagationslow or blocked conduction between atria and

ventricles or block in the ventricular conduction system.

II. Sinus Node

A. Sinus Bradycardia.

1. ECG characteristics: the P wave, PR interval, and QRS complex are normal, but the rate is
<60 bpm (Figure 12-1 Lilly, Figure 1).

Figure 1. Sinus bradycardia. The P wave and QRS complexes are normal, but the rate is < 60 bpm.

2. Clinical conditions that could result in sinus bradycardia:

a. Increased parasympathetic (Vagus, CNX) activityoccurs during sleep; athletes tend to

have increased vagal tone and slower heart rates; elderly often have slower sinus node
rates.

b. Pharmacological actions of certain drugs such as beta-blockers and calcium-channel

antagonists can slow sinus rates.

c. Pathological states including hypothyroidism and sinus node disease (sick sinus
syndrome) can slow the rate.

B. Treatment of Sinus Node Dysfunction.

The American College of Cardiology (ACC) and the American Heart Association (AHA) have
published guidelines (J. Am. Coll. Cardiol.) that you can refer to on-line, but basically a pacemaker is
implanted whenever sinus node dysfunction becomes symptomatic.

III. Escape Rhythms

In addition to sinus node cells, two other areas of the heart's electrical system normally exhibit
spontaneous Phase 4 depolarization. These areas are cells within the AV node/His bundle and Purkinje
cells in the ventricles. Cells in the AV node/His bundle typically exhibit spontaneous Phase 4

59
depolarizations at rates between 40-60 bpm. Purkinje cells typically have Phase 4 depolarizations at rates
of 20-40 bpm. Under normal conditions, sinus node discharge rates >60 bpm suppress spontaneous
depolarizations from the AV/His bundle and Purkinje cells. Under physiologic or pathologic conditions that
suppress sinus node depolarizations, junctional or ventricular escape rhythms can emerge. An
example of a junctional escape rhythm is shown in Figure 2. Junctional escape rhythms are
characterized by a rate of 40-60 bpm, a narrow QRS complex because the distal conduction system is
still activated and used, and the absence of P-waves preceding each QRS complex. Ventricular escape
rhythms are "lower" still in the conduction system or result from spontaneous depolarization of ventricular
myocytes. This makes the rate less reliable. Typical features of ventricular escape rhythms are rates
between 20-40 bpm and a prolonged (wide) QRS complex because of slow cell to cell myocardial
propagation, rather than conduction using the His-Purkinje system.

Figure 2. Junctional escape rhythm. Normal-width QRS complexes at a slow, constant rate not preceded by P waves.

IV. AV Conduction Abnormalities.

A. Abnormalities in the Sequence of Activation.

1. Right bundle branch block (RBBB, Figures 3 and 4).

In RBBB, the left ventricle activates normally. Activation of the right ventricle is abnormal and
depends on cell to cell activation from the depolarized left ventricle. Accordingly, activation of
the right ventricle is delayed and haphazard. As a result, the QRS complex is abnormally
wide and the terminal portion of the QRS complex reflects the delayed and haphazard
activation of the right ventricle, with much of it occurring after normal activation of the left
ventricle. Because the right ventricle is both rightward and anterior to the left ventricle, ECG
leads that are most sensitive to right ventricular activation (V1 and V2) typically show a small
R' and a delayed and prolonged secondary R"-wave. ECG leads that are most sensitive to
left ventricular activation (leads I and V5 and V6) typically show a delayed and prolonged S-
wave.

60
Figure 3. Right Bundle Branch Block. From Netter FH. CIBA collection of medical illustrations. Volume 5 (Heart) CIBA; 1978. The
LV is activated first and quickly. The RV is activated slowly (through the myocardium rather than through the rapid Purkinje fibers of
the right bundle) and late. Late RV activation (after the LV depolarization is essentially finished) can be seen in the latter part of the
wide QRS, and the rightward vector in the later part of depolarization.

Clinical conditions causing RBBB include: coronary and hypertensive disease; cardiac
tumors; cardiomyopathy and myocarditis; congenital heart disease; idiopathic degenerative
disease of the electrical system (Lenegre's and Lev's diseases); and aberrant conduction.

61
Figure 4. Typical RBBB. From Corr PB, Cain ME. Electrophysiology. In: Ahumada GG, editor. Cardiovascular Pathophysiology.
New York: Oxford University Press; 1987. p. 34-73. Note R' in V1 & S wave in V4-V6.

2. Left bundle branch block (LBBB, Figures 5 and 6).

In LBBB, initial activation of the ventricles is altered with the right ventricular apex activated
first. Left ventricular activation is delayed and occurs haphazardly because of cell to cell
spread of electrical current from the right ventricle to the left ventricle. QRS duration is
abnormally prolonged and the QRS configuration reflects slowed and haphazard activation of
the otherwise dominant left ventricle.

62
Figure 5. LBBB. From Netter FH. CIBA Collection of medical illustrations. Volume 5 (Heart) CIBA; 1978. LBBB causes slow
conduction through the mass of the LV myocardium shifting the activation vector toward the left. Note the rabbit ear configurations
in LI and V5 that are characteristic.

Clinical conditions causing LBBB are the same as those causing RBBB including:
hypertensive and coronary artery disease; cardiomyopathy and myocarditis; congenital heart
disease; cardiac tumors; idiopathic degenerative disease of the electrical system (Lenegre's
and Lev's diseases); and aberrant conduction.

63
Figure 6. LBBB. From Corr PB, Cain ME. Electrophysiology. In: Ahumada GG, editor. Cardiovascular pathophysiology. New York:
Oxford University Press; 1987. p. 34-73. LBBB with a wide QRS, deep S wave in V1, broad R wave in V6. Note rabbit ears in V5 and
V6.

B. Abnormalities in the Timing of Activation (Figure 7).

A-V BLOCK TYPES

st
1 Degree: Prolonged time to conduct through AV node.
nd
2 Degree: Intermittent (or interrupted) conduction through AV node.
Mobitz Type I(Wenckebach) progressive conduction delay, followed by failure to conduct
activation through the AV node for one beat.
Mobitz Type IIFixed, normal conduction rate, with sudden failure to conduct a beat.
rd
3 Degree: No conduction through AV node. Also called atrial-ventricular dissociation.
Figure 7. AV Block Nomenclature.

1. Components of the conduction system that contribute to the PR interval are observed in the
electrophysiology lab with use of intracardiac electrode catheters (Figure 8).

64
Figure 8. Signals from an electrode catheter compared to same event by surface ECG leads. Diagram at top gives orientation.

Electrode catheters can be positioned in the heart to directly record components of the
heart's electrical system. This invasive approach provides more detailed information
concerning the heart's electrical system than can be obtained from analysis of the body
surface ECG. For example, the PR interval (between the start of the P-wave and the start of
the QRS complex) in the ECG actually includes sinus node electrical activity, activation of the
right and left atria, conduction through the AV node and His-bundle, conduction through the
right and left bundle branches and distal Purkinje network. With the use of an intracardiac
catheter, the health of each of these electrical components can be assessed. For example,
placing the electrode catheter in the area of the sinus node allows analysis of regional atrial
activation from the high right atrium (HRA, Figure 8). Placement of the catheter adjacent to
the AV node and His-bundle allows analysis of the conduction time through the AV node and
from the His-bundle to ventricular muscle. Intracardiac electrograms from this region of the
heart are shown in Figure 8 and labeled HBE. The letter A in the HBE recording denotes the
electrical activation of atrial tissue immediately adjacent to the AV node. The letter H
denotes the electrical signal generated when the His-bundle is activated. The letter V
denotes activation of ventricular muscle. The AH interval is a measure of conduction time
through the AV node. The HV interval is a measure of the conduction time from the His-
bundle to ventricular muscle. Abnormalities in AV conduction can occur at either or both of
these zones.

65
 st
2. 1 Degree AV blockprolonged conduction (Figure 9) with a PR interval greater than 200-
210 msec.
st
a. Clinical conditions that might prolong conduction leading to 1 Degree block include:
acute inferior or right ventricular infarction (because coronary branches feeding these
areas also provide blood to the AV node); ischemic heart disease/advanced plaque
buildup in these same vessels; excessive vagal tone; digitalis toxicity; beta-blockers and
calcium channel blockers; and electrolyte imbalance (e.g., hyperkalemia).
st
b. 1 Degree AV nodal block (Figure 9).
st
c. 1 Degree Infranodal block (Figure 10).

Figure 9. Sinus rhythm with 1st Degree AV Block (PR >200 ms). Arrows point to P waves.

st
d. 1 Degree AV block may occur because of abnormally prolonged conduction in the AV
node (Figure 10), His-bundle region (Figure 11), or both.

Figure 10. Intracardiac electrograms compared with surface ECG leads in 1st degree AV block. From Josephson ME. Clinical
cardiac electrophysiology. 2nd ed. Philadelphia: Lea and Fibiger; 1993. HBE (His bundle electrogram) reveals 250 ms delay in the
AV node (time between the atrial electrogram, A and the His electrogram, H).

66
Figure 11. PR prolongation (280 ms) due to infra-His (HV) delay. Normal HV interval is 35-55 ms. This delay represents
pathology in the His-Purkinje system (corroborated by the LBBB pattern in LI and V1)

nd
3. 2 Degree AV blockintermittent conduction.

a. Mobitz Type I (or Wenckebach)progressive prolongation in AV conduction precedes

complete AV block resulting in a dropped ventricular depolarization (Figures 12 and 13).

Figure 12. Mobitz Type I 2nd Degree AV Block. Surface ECG LII from a patient during acute inferior myocardial infarction shows
gradually prolonging PR intervals until a non-conducted (blocked) P occurs (top tracing only). The PR after the block is shorter
again. The QRS complexes tend to occur in groups (in this case a group of 3 is seen).

67
Figure 13. Intracardiac electrogram showing the mechanism of Mobitz Type I AV block. Progressive prolongation of the AH
interval leads to the complete block. Note that the HV interval is normal. This indicates that the delay is localized in the AV node.
nd
b. Clinical conditions that could result in Mobitz Type I 2 degree AV block include: acute
inferior or right ventricular infarction; ischemic heart disease; excessive vagal tone;
digitalis toxicity; beta-blockers and calcium channel-blockers; and electrolyte imbalance
(hyperkalemia).
nd
c. Mobitz Type II 2 Degree AV Blockdiffers from Type I by causing a sudden failure
of conduction (Figures 14 and 15).

Figure 14.Type II 2nd degree AV block in the surface ECG. The conducted PRs are of the same length, but there are occasional
non-conducted P waves. One trick to discern the type II 2 AV block is to identify the P waves and then look at sequential PR
intervals. In Type II, the PR interval of the beat before and after the blocked beat
will be the same.

68
Figure 15. Intracardiac recording showing the mechanism of Type II 2nd degree AV block. In this example, AV nodal
conduction (AH interval) is normal. The problem area is conduction disease in the His-bundle as shown by a prolonged HV interval
of 70 msec (first and third beats) and conduction block below the His-bundle (second beat).
nd
d. Clinical conditions that could induce Type II 2 degree AV block include: acute inferior or
right ventricular infarction; ischemic heart disease; Digitalis toxicity; beta-blockers and
calcium channel-blockers; Class I and III antiarrhythmic drugs; and electrolyte imbalance
(hyperkalemia).

4. Third degree AV blockno AV conduction. The atria and ventricles are dissociated
electrically. None of the sinus P-waves are conducting to the ventricles (Figures 16 and 17).
The ventricles are activated (generally at a slower rate than normal sinus rhythm) because of
a junctional or slower ventricular escape rhythm.

Figure 16. 3rd Degree AV Block seen on the surface ECG. The P-waves are faster than the QRS complexes and they are
dissociated. The junctional escape rate is about 36 bpm.

69
Figure 17. Intracardiac recording of third degree AV block with a junctional escape rhythm. From Josephson ME. Clinical
cardiac electrophysiology. 2nd ed. Philadelphia: Lea and Febiger; 1993. Atrial electrograms (HRA) are dissociated from the QRS
complexes.

rd
Clinical conditions that might induce 3 degree total AV block include: acute inferior or
right ventricular infarction and also acute anterior infarction; ischemic heart disease;
excessive vagal tone; Digitalis toxicity; beta-blockers and calcium channel-blockers; class I
and III antiarrhythmic drugs; and electrolyte imbalance (hyperkalemia).

C. Treatment.

Insert a single or dual-chamber permanent pacemaker (Figure 18).

Figure 18. Dual chamber pacing in a patient with acquired AV block. Note the biphasic stimulus artifacts before each QRS
complex.

70
Lecture Notes

Ventricular Arrhythmias
10/04/2013

Timothy W. Smith, M.D., D.Phil.

Ventricular Arrhythmias
Objectives:
Distinguish the electrocardiographic features of common ventricular arrhythmias including ventricular
tachycardia, ventricular fibrillation, and Torsade de pointes.

Reference Texts:

1. Lilly LS. Pathophysiology of Heart Disease: a collaborative project of medical students and faculty.
5th ed. Baltimore: Wolters Kluwer, Lippincott Williams & Wilkins; 2011: 294-300.

2. Smith TW. Tarascon ECG Pocketbook. Burlington, MA: Jones and Bartlett Learning, 2012.

3. Smith TW and Pinto DS. Tarascon Pocket Cardiologica. Burlington, MA: Jones and Bartlett
Learning, 2012.

I. DefinitionsVentricular arrhythmias include ventricular premature depolarizations, ventricular

tachycardia, and ventricular fibrillation.

A. Ventricular premature depolarizations (Figures 1 and 2). A ventricular premature

depolarization (VPD, a.k.a. PVC = premature ventricular contraction) is an electrical complex that
initiates in the ventricle independent of the sinus node or any supraventricular rhythm. During a
VPD, the ventricles are activated haphazardly and sequentially depending on the origin of the
VPD. As a result, the QRS complex is wide and has a bizarre configuration. Figure 1 shows two
ECG leads (lead I and VI) and intracardiac recordings during a normal sinus beat (left) and a VPD
(right). Compared to the sinus beat, the VPD (second beat) initiates in the ventricle as a wide and
bizarre QRS complex, and then conducts retrogradely through the His-bundle/AV node to the
atria resulting in a retrograde (reverse order) atrial activation sequence. Depending on
circumstances, VPDs may or may not conduct retrograde to the atria.

Figure 1. Ventricular Premature Depolarization. From Josephson ME. Clinical cardiac electrophysiology: techniques and
interpretation. 2nd ed. Philadelphia: Lea and Febiger; 1993. A ventricular premature complex follows a normal sinus beat. This VPD
conducts retrograde to the atrium. HRA = high right atrium, LRA = low right atrium, HBE = His-bundle electrogram, CS = coronary

71
sinus. The letter "A" denotes local atrial electrograms, the letter "H" the His-bundle electrogram, and V local ventricular electrograms

The ECG rhythm strips in Figure 2 show other examples of VPD.

Figure 2. VPDs

B. Ventricular tachycardia (VT) is defined as > 3 ventricular beats at a rate > 100 bpm. Usually,
the rate is 140-200 bpm.

1. Sustained VT is defined as lasting > 30 seconds or associated with hemodynamic collapse

(loss of blood pressure). Sustained VT may be monomorphic (Figure 3A) indicating that the
configuration of the QRS complex is the same during each beat of the tachycardia. Several
variants of VT exist.

2. Nonsustained VT (Figure 3B) is defined as lasting < 30 sec and not associated with
hemodynamic collapse (pressure developed after the ventricular activation is insufficient to
open the aortic valve so blood pressure drops precipitously).

Figure 3. Sustained and Non-sustained VT. 12-lead ECG of a 66 yo man after an acute inferior MI. A. Sustained VT at a rate of
170 beats/min and left bundle branch block. B. Episodes of nonsustained VT with the same BBB morphology interrupted by
72
conducted sinus impulses (arrows). From Electrocardiography in Clinical Practice, 6th ed. By B. Surawicz and T Knilans, Saunders,
2008, fig17-14, page 420.

3. Polymorphic VT and Torsade de pointes (Figure 4). VT may be monomorphic (QRS

complexes have the same or almost the same size, shape, and direction) or it may be
polymorphic where the QRS complexes differ markedly in shape, size, and direction from
beat to beat (Figure 4 left). A variant of polymorphic VT is Torsade de pointes, French for
twisting around a point, so-called because the QRS complexes change back and forth from
one shape, size, and direction to another over a series of beats. This type of VT is associated
with genetic or drug-induced prolongation of the QT interval. Quinidine, which prolongs the
QT interval, can induce this rhythm.

Figure 4. Polymorphic VT and Torsade de Pointes. From Basic Dysrhythmias, 3rd ed. R Huszar, Mosby 2002.

C. Ventricular flutter and fibrillation (Figure 5 and 6).

Figure 5. Ventricular Flutter. Monomorphic VT at rates over 200/min is called ventricular flutter. This patient has a ventricular rate
of about 250/min. The sawtooth appearance of the QRS complexes is characteristic.

73
Figure 6. Ventricular Fibrillation. Although fast ventricular rates with VT or flutter are dangerous, ventricular fibrillation is
immediately life-threatening. The QRS complexes are of variable size, shape and direction resulting in a disorganized, rapid
activation of the ventricles that does not produce enough ventricular contraction to open the semi-lunar valves. Cardiac output goes
to zero and death ensues unless the rhythm is reversed by electric shock.

II. Etiology of Ventricular Arrhythmias.

A. Ischemic and nonischemic cardiomyopathy are the most common causes.

B. Other causes include:

1. Arrhythmogenic right ventricular dysplasia.

2. Idiopathic VT.

III. Pathophysiology
A. Reentry (Figure 7). Reentry is the most common mechanism underlying VT, particularly among
patients with ventricular muscle disease produced by myocardial infarction. In this instance, scar
tissue forming at the border zone between the core infarct and adjacent viable tissue establishes
convoluted pathways of living myocytes separated by fibrosis. This anatomical matrix facilitates
parallel activation pathways having different electrophysiologic properties. The principles of
reentry in the Wolff-Parkinson-White syndrome apply to reentrant VT. In Figure 7, a diagram of
the left and right ventricles sectioned from base to apex is shown with the core infarct as the
blackened area. Histologic examples of the surrounding epicardium and endocardium are shown
in the different panels. The extensive and variable layers of viable myocytes and fibrosis are best
seen in panel D.

74
Figure 7. Reentrant and focal mechanisms underlying ventricular tachycardia in the human heart. Pogwizd SM, Hoyt RH,
Saffitz JE, Corr BP, Cox JL, Cain ME. Circulation 1992;86:1872-1887. Surviving myocardium in the border zone of an infarct may
create a protected isthmus that can serve as part of a reentrant circuit.

B. Triggered activity. A second mechanism responsible for VT is triggered activity. Triggered

activity is due to abnormal ion movement, especially calcium, which can initiate single or
repetitive ventricular complexes. Triggered activity that occurs during phase 2 and phase 3 of the
action potential is termed an early afterdepolarization (Figure 8); and triggered activity that
occurs after completion of phase 3 repolarization is termed a delayed afterdepolarizations
(Figure 9). Antiarrhythmic agents and other drugs that prolong the repolarization phase of the
action potential and induce Torsade de pointes do so by inducing EADs. Ventricular
arrhythmias associated with digitalis poisoning are most often mediated by DADs.

75
 1. Early afterdepolarizations.

Figure 8. Early afterdepolarizations. Triggered activity (arrow) occurs before the triggering action potential (AP) has fully
repolarized. Repetitive afterdepolarizations (dashed curve) may produce a rapid sequence of triggered action potentials,
and hence a tachyarrhythmia. From Pathophysiology of Heart Disease, 5th ed., Lilly LS, 2011. fig. 11.7.

2. Delayed afterdepolarizations.

Figure 9. Delayed afterdepolarizations. Triggered activity (arrow) arises after the triggering action potential (AP) has
fully repolarized. If the delayed afterdepolarization reaches the threshold voltage, a propagated action potential is fired
(dashed curve).

C. Automaticity. The least common mechanism initiating ventricular arrhythmias is normal

automaticity. Under certain circumstances, the normal spontaneous phase 4 depolarization
characteristics of Purkinje fibers can lead to rapid and repetitive ventricular beats.

76
Lecture Notes

Supraventricular Tachycardias
10/04/2013

Timothy W. Smith, M.D., D.Phil.

Supraventricular Tachycardias
Objectives:
1. Describe the pathophysiologic basis of re-entrant supraventricular arrhythmias using Wolff-Parkinson-
White syndrome as an example.

2. Understand the principles of pharmacologic and nonpharmacologic therapies for supraventricular

arrhythmias using Wolff-Parkinson-White syndrome as an example.

Reference Texts:

1. Lilly LS. Pathophysiology of Heart Disease: a collaborative project of medical students and faculty.
5th ed. Baltimore: Wolters Kluwer, Lippincott Williams & Wilkins; 2011:92-112; 261-278.

Very good guide to ECGs and can serve you well as a reference throughout medical school and
beyond.

2. Smith TW. Tarascon ECG Pocketbook. Burlington, MA: Jones and Bartlett Learning, 2012.

Small pocket book intended as both learning tool and quick pocket reference. Has pretty much
everything the author knows about ECGs.

3. Smith TW and Pinto DS. Tarascon Pocket Cardiologica. Burlington, MA: Jones and Bartlett
Learning, 2012.

Another Tarascon small pocket book intended as useful, ready resource for the clinical
student/physician of cardiology.

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I. Types of Supraventricular Arrhythmias

Figure 1. Incidence of SVTs.

Supraventricular tachycardias (SVTs) are those that the mechanism, or at least part of the mechanism
requires the atria or the AV node, which are "above" or supra to the ventricles.

A. Incidence of different types of SVTs (Figure 1).

1. Paroxysmal supraventricular tachycardia25%.

2. Atrial fibrillation45%.

3. Atrial flutter25%.

4. Other5%.

B. SVTs generally fall into one of two groups based on the location(s) of the mechanism:

1. The mechanism is completely contained in the atria. Note that, while they are called
"tachycardias" and they all involve rapid atrial rates, whether the heart rate is tachycardic or
not depends on the response of the AV node and ventricles. This group of SVT includes:

Trial fibrillation.

Trial flutter.

Atrial tachycardia.

2. Both the atria and the AV node are involved in a reentry mechanism. The ventricles may
also be part of the reentrant circuit. These are frequently called "Paroxysmal Supraventricular
Tachycardias"PSVTs because they have a sudden onset and termination. In the past,
theyve been called paroxysmal atrial tachycardias (PATs), but this is a misnomer. This group
of SVT includes:

AV nodal reentrant tachycardia (AVNRT, Figure 2).

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 AVNRT utilizing an accessory pathway.

Ectopic atrial tachycardia is included in PSVTs, but it often has a similar presentation,
and it is in the differential diagnosis of a regular narrow complex tachycardia that is
not atrial fibrillation or atrial flutter.

II. Types of Paroxysmal Supraventricular Tachycardias

Figure 2. AV Nodal Reentrant Tachycardia. A rapid, narrow complex tachycardia that is the most common presentation of a
PSVT.

A. Reentrant tachycardia may have several causes.

1. Accessory pathway mediated (WPW syndrome)35% of patients have this type.

2. AV nodal reentry50% of patients, the most common cause.

3. Intraatrial reentry5% of patients.

4. Other5% of patients the cause is unknown.

B. Automatic atrial tachycardia5% of patients have non-reentrant SVTs

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III. Wolff-Parkinson-White Syndromean example of an SVT using an accessory
pathway

Figure 3. Diagrammatic representation of accessory pathway conduction. From Cain ME, Lindsay BD. Pre-excitation
syndromes: diagnostic and management strategies. In: Horowitz LN, editor. Current management of arrhythmias. Philadelphia: B.C.
Decker; 1991. pp. 91-103. Left: A manifest accessory pathway (AP) allowing antegrade conduction and preexcitation of the
ventricle (delta wave before QRS). Right: A concealed AP that does not conduct antegrade; there is no preexcitation.

A. Definitions (Figure 3).

1. Accessory AV pathway abnormal AV conduction pathways (also known as bundles of Kent)

that bridge the fibrous layer insulating the atria from the ventricles bypassing the AV junction
and AV node.

2. Manifest accessory pathway (AP).

a. Activation conducts antegrade during normal sinus rhythm.

b. Results in delta waves or preexcitation of the ventricles (a slow, slurred initial part of the
QRS complex).

3. Concealed AP.

a. Activation conducts retrograde but not antegrade.

b. QRS narrow during normal sinus rhythm.

B. Pathophysiology.

1. To understand the pathophysiology of the WPW syndrome lets review the normal physiology of
atrial-ventricular conduction for the right ventricle (Figure 4). This figure relates activation times
measured in the heart to the surface ECG during a single sinus rhythm beat. Activation begins at
the SA node at time zero, and an event that coincides with the start of the P-wave is inscribed on
the surface ECG. In this example, it requires 60 msec for the atrial activation wavefront to reach
the AV node located in the intraatrial septum. Activation time through the AV node requires an
additional 100 msec. Accordingly, the activation wavefront reaches the His-bundle 160 msec after
it left the SA node. The conduction time through the His-bundle and through the right bundle
branch to reach the right ventricular apex is 40 msec. Accordingly, the right ventricular apex is
activated 200 msec after SA node discharge. The time required to activate the right ventricular
free wall and right ventricular base is 60 msec. This entire sequence requires 260 msec and is
related to the P-wave, the interval from the onset of the P-wave to the onset of the QRS complex,
and the QRS complex.

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Figure 4. Timing (ms) of electrical activation of the right ventricle in the presence of normal conduction. From Corr PB,
Cain ME. Electrophysiology. In: Ahumada GG, editor. Cardiovascular pathophysiology. New York: Oxford University Press;
1987. pp. 34-73.

2. In WPW, the sequence and timing of right ventricular activation is altered in the presence of
the accessory pathway (Kent Bundle) that conducts antegrade (Figure 5). Initiation of
depolarization in the SA node and conduction through the right and left atria proceeds
normally. However, spread of activation to the ventricles occurs over two different
pathways. The first is the normal AV node/His-bundle pathway as in Figure 4. Ventricular
activation can also occur through the accessory pathway, in this example located on the
lateral free wall of the right atrium/right ventricle. The accessory pathway electrically connects
the right atrium to the base of the right ventricle. Unlike the AV node, which demonstrates a
normal conduction delay, the accessory pathway transmits electricity to the right ventricular
base with minimal delay activating the base of the right ventricle only 120 msec following
initiation of the sinus node beat.

This premature or preexcitation of the right ventricle shortens the PR interval and slurs the initial
upstroke of the QRS complex because a portion of the right ventricle is being activated eccentrically
with the base activating before the right ventricular apex. The shortened PR interval and slurred
upstroke, termed a delta wave, of the QRS complex are the hallmarks for the ECG diagnosis of WPW
syndrome (Figure 5).

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Figure 5. Timing (msec) of electrical activation in the presence of ventricular preexcitation over a manifest accessory
pathway (K). From Corr PB, Cain ME. Electrophysiology. In: Ahumada GG, editor. Cardiovascular Pathophysiology. New
York: Oxford University Press; 1987. pp. 34-73. Note that activation of the basal RV (120) precedes the His bundle activation
(160). The delta wave () is a hallmark for preexcitation and the WPW syndrome.

3. ECG of manifest ventricular preexcitation. A 12-lead ECG acquired from a patient with WPW
syndrome is shown during normal sinus rhythm (Figure 6). A delta wave is apparent in many
of the leads and the QRS complex configuration is abnormal because the ventricles are being
activated eccentrically via both the accessory pathway and through the normal AV conduction
system.

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Figure 6. 12-lead ECG from a patient with WPW in sinus rhythm. Note the waves in the majority of the leads.

4. The presence of an accessory pathway not only alters the ECG during sinus rhythm, but can
also participate directly or passively in supraventricular arrhythmias. The schematic of
reentrant circuits in Figure 7 illustrates these mechanisms: sinus rhythm with an AP (WPW),
orthodromic SVT, antidromic SVT, and atrial fibrillation.

Figure 7. Pre-excitation mechanisms during sinus rhythm and causing pathologic SVT. From Cain ME, Lindsay BD. Pre-
excitation syndromes: diagnostic and management strategies. In: Horowitz LN, editor. Current management of arrhythmias.
Philadelphia: B.C. Decker; 1990. pp. 91-103.

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C. Orthodromic SVT.

The presence of two parallel pathways (accessory pathway and normal AV node/His-bundle)
having different electrophysiologic properties sets the stage for a reentrant rhythm (Figure 8).
Establishment of a reentrant rhythm requires an initiating event (usually an atrial premature
depolarization) that is blocked in one pathway, conducts slowly through the second, and reexcites
the initially blocked pathway to complete the circuit. To initiate orthodromic supraventricular
tachycardia, the antegrade refractory period of the accessory pathway is longer than the
refractory period of the AV node. In a typical example, the antegrade refractory period of the
accessory pathway is 350 msec. The antegrade refractory period of the AV node is 300 msec. An
atrial premature depolarization at 325 msec would block in the accessory pathway, conducting
exclusively to the ventricles using the AV node/His-bundle. The time required to conduct through
the AV node/His-bundle/right bundle branch/right ventricle is > 25 msec. Accordingly, the
ventricular wavefront can activate the accessory pathway from the ventricular side, reenter the
atrium and then reenter the AV node/His-bundle to complete the circuit and initiate orthodromic
SVT. During orthodromic SVT, the ventricles are activated normally, the QRS complex is
narrow and a retrograde P-wave is sometimes detectable immediately after the QRS
complex because the atria activate through the accessory pathway after ventricular
activation. Sometimes the retrograde P wave is also partially or completely hidden by the end of
the QRS complex and cant be distinguished.

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Figure 8.

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Figure 9. 12-lead ECG of orthodromic atrio-ventricular reentrant tachycardia (orthodromic AVRT, or just ORT). From Cain
ME, Lindsay BD. Pre-excitation syndrome: diagnostic and management strategies. In: Horowitz LN, editor. Current management of
arrhythmias. Philadelphia: B. C. Decker;1990:91-103. There is NO preexcitaton during tachycardia, because ventricular activation
occurs via the normal AV nodal pathway. The accessory pathway is the retrograde limb of the reentry, and therefore does not
conduct antegrade (i.e. no preexcitation). Note the inverted P waves after the QRS complexes in V1-V6. The T wave actually
looks like it should be the P wave before the QRS complex.

4. ECG features (Figure 9).

a. Narrow QRS (when bundle branch block is absent).

b. Retrograde P-wave may be seen immediately after QRS.

c. Short RP-long PR pattern.

d. 1:1 AV and 1:1 VA association must exist.

e. Rate: typically 160-220 bpm.

D. Antidromic SVT. (Note: "anti" in antidromic means backwards; "ante" in antegrade means
forward.)

1. Accounts for about 6% of AP mediated tachycardias.

2. Occurs only with manifest preexcitation.

3. Macroreentrant circuit. During antidromic supraventricular tachycardia, the macroreentrant

circuit spins in the opposite direction with antegrade conduction exclusively through the
accessory pathway and retrograde activation of the atria through the normal His-
bundle/AV node. The circumstances that initiate antidromic supraventricular tachycardia are
similar to orthodromic supraventricular tachycardia except that the AV node has a longer
antegrade refractory period than the accessory pathway. For example, if the antegrade
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 refractory period of the AV node is 350 msec and the antegrade refractory period of the
accessory pathway is 300 msec, an atrial premature depolarization arriving at 325 msec will
block in the AV node, conduct exclusively to the ventricles through the accessory pathway
and then reenter the normal His-bundle/AV node conduction system in a reverse direction
reexciting the atria which then conduct electricity back to the ventricle through the accessory
pathway completing the macroreentrant circuit. In this arrhythmia, the QRS complex is wide
and bizarre because the ventricles are activated eccentrically and exclusively through the
accessory pathway. Retrograde P-waves follow the QRS complex because the atria are
activated after the ventricles have activated.

a. Antegrade limb: Accessory pathway (AP).

nd
b. Retrograde limb: AVN/His bundle or 2 AP.

c. Atria and ventricles are part of the circuit.

Figure 10. Antidromic AVRT. Ventricular activation is entirely via the accessory pathway, so preexcitation is said to be maximal.
The AV node is now the retrograde limb of the reentry.

4. ECG features (Figure 10). From the ECG alone, antidromic tachycardia is difficult to
distinguish from ventricular tachycardia

a. A wider than normal QRS complex because the ventricles are activated entirely from
anterograde conduction over the accessory pathway. However, the QRS is still narrower
than that with ventricular tachycardia or bundle branch block.

b. Retrograde P-waves may be seen immediately after the QRS.

c. Short RP-long PR pattern.

d. 1:1 AV and 1:1 VA association must exist.

e. Rate: typically 160-220 bpm.

5. See Figure 12.17 in Lilly for a great diagram showing the differences between pre-
excitation (WPW), orthodromic and antidromic reentrant tachycardias.

E. Atrial flutter. Characterized by rapid atrial rates up to 350/min. Activations blocked in the AV node

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 during the refractory period so only a fraction are conducted to the ventricles, usually in a regular
fraction. An atrial rate of 300/min with 3:1 block would yield a ventricular rate of 100/min.

Atrial flutter is often recognized on the ECG by a saw-tooth pattern between the QRS
complexes.

F. Atrial fibrillation. Atrial fibrillation is a common supraventricular arrhythmia that can occur in a
variety of conditions including in patients with Wolff-Parkinson-White syndrome. During atrial
fibrillation, the atria activate at rates often exceeding 300-400 bpm because of numerous
simultaneous microreentrant circuits. When atrial fibrillation occurs in a patient without Wolff-
Parkinson-White syndrome, the inherent conduction delay properties of the AV node protect the
ventricles from these dangerous rates. The AV node prevents most of the atrial activation
wavefronts from conducting to the ventricles. In patients with Wolff-Parkinson-White syndrome,
especially those whose accessory pathway has a short antegrade refractory period, a greater
number of atrial activation wavefronts conduct to the ventricles resulting in left-threatening
ventricular rates. The configuration of the QRS complex is variable because during the course of
atrial fibrillation, the ventricles can be activated exclusively through the AV node/His-bundle,
exclusively through the accessory pathway, or through both the normal and accessory conduction
systems.

1. Occur with manifest or concealed AP.

2. May be primary or secondary to SVT.

3. About 17% of patients (manifest AP) at risk for life-threatening ventricular rhythms
(v.tachycardia or fibrillation).

4. ECG features (Figure 11).

a. Manifest AP: QRS preexcited, fused, or narrow.

b. Concealed AP: QRS narrow (in absence of BBB).

Figure 11. "FBI," Fast Broad and Irregular. Atrial fibrillation with preexcitation. Cain ME, Lindsay BD. Pre-excitation
syndromes: diagnostic and management strategies. In: Horowitz LN, editor.Current Management of Arrhythmias. Philadelphia: B. C.
Decker; 1990. pp. 91-103. Note the variable QRS widths (varying degrees of preexcitation) as well as the varying ventricular rate.
There poses a risk for inducing ventricular fibrillation.
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IV. Management Strategies for Treating Supraventricular Tachycardias
A. Treatment options: Pharmacologic and Non-pharmacologic.

B. Pharmacologic.

1. Key factors in selecting agents:

a. Frequency of SVT episodes.

b. Severity of symptoms/hemodynamic stability.

c. Patient age.

d. Efficacy/adverse effects of agents.

2. Sites of action of antiarrhythmic drugs (Table 1).

a. Primary action is at the AV node.

(1) Beta-blockers.

(2) Calcium-channel blockers.

(3) Digoxin.

(4) Adenosine.

b. Primary action is on the accessory pathway.

(1) Lidocaine.

(2) Class IA drugs: Procainamide, quinidine, disopryamide.

c. Both AV node and AP.

(1) IC drugs: Flecainide, propafenone.

(2) III drugs: Amiodarone, Sotalol.

Table 1. Sites of Action of Antiarrhythmic Drugs.

Decrease AV
Drug IV Prep Reentry Increase ERP AP
Class IA
Procainamide Yes ++ ++
Quinidine No ++ ++
Disopyramide No ++ ++
Class IC
Flecainide No +++ +++
Propafenone No +++ +++
Class III
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Amiodarone Yes ++++ +++
Sotalol No +++ ++
AV Nodal
Digoxin Yes + -
Verapamil/Diltiazem Yes ++ -
Beta-blocker Yes + -
Adenosine Yes ++++ -
IV Prep = available for parenteral use
AV = atrioventricular node.
ERP AP = effective refractory period of the accessory pathway.

C. Nonpharmacologic therapy.

1. Vagal maneuvers such as unilateral (right) carotid sinus massage (only in patients without
known carotid artery disease), Valsalva (exhale against a closed glottis), cough.

2. Catheter ablation.

a. Radiofrequency energy. Success rates >95%, morbidity/mortality <1%.

b. Indications for catheter ablation.

(1) Life-threatening ventricular rate during AF.

(2) AV reentry refractory to medical therapy.

(3) Intolerance to medical therapy.

3. Electrical cardioversionused to treat SVTs in hemodynamically unstable patients.

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Case Study

Ischemic Heart Disease Case Studies

10/04/2013

Richard G. Bach, M.D.

Ischemic Heart Disease Case Studies

Case 1
A 65-year-old man presents to the emergency room complaining of crushing chest pain radiating to the
left arm and jaw that developed while sitting at work 1 hour before. He is anxious and sweaty. The ECG
done at Triage is shown below:

Figure 1. Emergency Room ECG.

Past History:

No previous cardiac history.

History of cigarette smoker 1ppd; no HTN, DM.
On no meds.
Adopted, does not know family history.

Physical Examination:

VS - BP 170/95 mmHg, Pulse 110/min, Resp 20/min.

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 Obese, otherwise unremarkable.

Case Study Questions

A. What is the most likely diagnosis? Describe the typical pathophysiology for this diagnosis.

B. Where is the disease most likely located in the coronary arterial tree?

C. Your hisoty should include whether the patient has any of the five cardinal risk factors for
athersclerotic heart disease. Name them.

D. What primary treatments should you consider at this time? What medications would you
administer? Discuss the rationale for each of these therapies.

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ED Course:

Aspirin 81 mg x 4 given orally; a bolus of 4000 units of unfractionated heparin is given

intravenously.

Nitroglycerin under the tongue given. There is no improvement in pain.

Intravenous metoprolol 5 mg x 3 doses given.

Cardiac Cath Lab rapidly activatedthe patient is referred for primary percutaneous coronary
intervention

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E. What is the rationale for the use of primary PCI to open the occluded artery in this patient? If the
cath lab were not available or the patient refused cardiac cath, what alternative treatments would
you consider? What details about the history and physical examination would be important to
consider prior to the decision to administer such alternative pharmacologic therapy?

94
F. Based on the ECG and the findings of coronary angiography, what abnormalities of left
ventricular function would you predict? What tests would be useful to evaluate left ventricular
function in this patient?

95
96
G. What do the left ventriculogram and echocardiogram show? What does the concept of "stunned
myocarium" mean?

H. What immediate on longer-term pharmacologic therapy would you prescribe this patient? Explain
the rationale for each medication chosen.

Hospital Course:

Chest pain resolved after PCI.

Medical therapy initiated and dosages titrated.

Monitored in CCU x 24 hours.

Exam without signs of heart failure.

LDL cholesterol 148 mg/dl, HDL 35 mg/dl.

Day 4, ambulatory with no complaints.

Discharged home.
97
I. What additional therapeutic interventions, pharmacologic or otherwise, would be indicated for this
patient?

J. True or False:

1. The patient's cholesterol is low enough to justify a trial of diet alone.

2. Due to its higher potency, if clopidogrel is prescribed, aspirin use becomes optional.

3. Long-term nitrate therapy is indicated to reduce preload and reduce recurrent ischemia.

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Case 2
A 55-year-old man with a history of hypertension requests an office visit because of episodic chest
discomfort. He describes a substernal heavy feeling when he is jogging or bicycling uphill that is
associated with shortness of breath and that is relieved within 4-5 minutes by stopping and resting. He
denies any episodes at rest.

PMHx: HTN

Medications: HCTZ

FamHx: F under age 60 MI; M A+W age 76.

Physical Exam: BP 145/90 mmHg, P 72 reg, otherwise unremarkable.

A. What is the most likely diagnosis? Describe the typical pathophysiology for this diagnosis.

B. What are the options for "diagnostic" testing for this patient?

He is referred for an exercise stress test with myocardial perfusion imaging. He exercises for 5 minutes of
a standard treadmill protocol, to a maximal heart rate of 140 bpm and BP of 190/95 mmHg. The peak
stress ECG and select rest and stress tomographic perfusion scans are shown below:

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The test reports abnormal stress ECG results consistent with ischemia. Myocardial perfusion scans show
reversible hypoperfusion of the inferior segments (arrowheads). You inform the patient of the abnormal
stress test results. He wishes to avoid invasive procedures and requests medical management.

C. What abnormality is seen on the stress ECG? What is the patient's rate-pressure product?
Assuming the resting ECG and scans are normal, what are the implications of this patient's
history and abnormal test for his 1) coronary autoregulations, 2) coronary flow reserve, and 3)
myocardial oxygen supply/demand balance?

D. What pharmacologic agents would you prescribe for this patient and why? Describe the
mechanism of action of each class of medication you prescribe.

The patient returns in 3 months complaining of persistent chest heaviness and dyspnea with exertion
despite medical therapy. His exercise tolerance and quality of life are significantly limited by his
symptoms. He wants to know what else can be done.

E. What further testing would you recommend? What are your goals when recommending such
testing? What risks of that testing would you inform him of?

The patient undergoes evaluation by cardiac catheterization with selective coronary angiography. Images
from the test are shown below.

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The coronary angiography is reported to show moderate 60% stenosis of the left anterior descending and
diagonal arteries, 60% stenosis of the left circumflex artery, and severe 80% stenosis of the mid dominant
right coronary artery (with diffuse moderate proximal to mid disease).

F. Given the symptoms refractory to medical management, the positive stress perfusion imaging
study showing reversible hypoperfusion of the inferior wall, and the results of coronary
angiography, what would you recommend? What are the options for further management?

The patient is referred for coronary revascularization by percutaneous coronary intervention (PCI) with
drug-eluting stent implantation. The procedure is shown in the accompanying PowerPoint.

The patient returns to your office 1 week later and reports marked improvement in his anginal symptoms
and exercise tolerance.

G. What is you recommendation regarding continued medical therapy?

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Lecture Notes

Arrhythmia Therapy
10/07/2013

Timothy W. Smith, M.D., D.Phil.

Arrhythmia Therapy
Objectives:
1. Contrast the use of pharmacologic vs non-pharmacologic therapeutic approaches to treat
arrhythmias.

2. Describe how changes in impulse formation or impulse propagation that form the basis for many
arrhythmias define the type of therapy needed.

3. Describe the action of the key classes of pharmacologic agents on the movement of ions across cell
membranes and the action potential of the cell.

4. Review the pharmacology (kinetics, metabolism, etc.) of anti-arrhythmic drugs as needed to

understand those features identified as important in lecture.

Reference Texts:

1. Lilly LS. Pathophysiology of heart disease: a collaborative project of medical students and faculty.
5th ed. Baltimore: Wolters Kluwer, Lippincott Williams & Wilkins; 2011: 261-278; 408-418.

Has a nice summary of the anti-arrhythmic drugs.

2. Smith TW. Tarascon ECG Pocketbook. Burlington, MA: Jones and Bartlett Learning, 2012. 134 pp.

Small pocket book intended as both learning tool and quick pocket reference. Has pretty much
everything the author knows about ECGs.

3. Smith TW and Pinto DS. Tarascon Pocket Cardiologica. Burlington, MA: Jones and Bartlett
Learning, 2012. 386 pp.

Another Tarascon small pocket book intended as useful, ready resource for the clinical
student/physician of cardiology.

I. Pharmacologic vs Non-Pharmacologic Therapy

Some of the tachycardias weve discussed may cause hemodynamic collapse. In this instance, treatment
must be immediate, and typically centers on electrical defibrillation or cardioversion. Defibrillation applies
a high energy electrical field across the entire heart. The intention is to simultaneously depolarize the
entire myocardium (or as much as possible) to extinguish any existing propagating waves of
depolarization. This applies for both SVTs and VTs.

SVTs and VTs that do not cause hemodynamic collapse may also be treated electively with
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cardioversion/defibrillation, preferably with at least moderate anesthesia. However, this treatment has no
lasting influence on the rhythm. It may successfully return the rhythm to normal, but does not prevent
recurrence of the arrhythmia.

We will primarily discuss pharmacologic therapy. Drugs may be used to cardiovert some rhythms, but
most of their utility is in maintaining sinus rhythm. (Ibutilide is a notable exception).

We focus on pharmacologic therapy for tachyarrhythmias because there is little successful

pharmacologic therapy for bradyarrhythmias. A non-pharmacologic approach, the implantable
pacemaker, monopolizes bradycardia therapy.

There is also implantable device-based therapy for deadly tachyarrhythmias, such as VT an VF. The
implantable cardioverter-defibrillator (ICD) will be considered briefly. ICD therapy is very painful, so ICD
firing is usually reserved for the most deadly of arrhythmias. (ICDs are almost never used for SVTs, since
they are less likely to be deadly). Like defibrillation and cardioversion discussed above, an ICD shock is
intended to terminate the arrhythmia as quickly as possible and to prevent sudden death. It does not,
however, prevent the occurrence or recurrence of the arrhythmia. Despite progress in device therapy,
prevention of arrhythmias is still best left to pharmacologic therapy.

II. Bradycardia Therapy

Recall that bradycardias result either from slow impulse formation in the sinus node (a condition called
Sick Sinus Syndrome) or from conduction block, primary in the AV junction.

A. Pharmacologic Therapy.

1. Since the sinus node and the AV node are highly sensitive to autonomic nervous system
activity, drugs that inhibit parasympathetic input (anticholinergic drugs) may speed the
heart rate. In general, these drugs are only used in the "acute" (emergency) setting, since
they are only available in intravenous (IV) form.

a. Atropine.

b. Glycopyrrolate (available in oral form, but used for other anticholinergic effects).

2. Drugs that augment sympathetic input (beta-adrenergic agonists, sympathomimetic

drugs) can raise the heart rate. In general these drugs are only used in the "acute"
(emergency) setting, since they are only available in intravenous (IV) form.

a. Isoproterenol.

b. Epinephrine.

c. Dobutamine.

3. Methylxanthines may increase the heart rate, but have rarely been effective in treatment of
sinus node or AV node dysfunction.

a. Caffeine.

b. Theophylline (Used for bronchospasm in asthma).

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 B. Non-pharmacologic Therapy.

The implanted pacemaker is the mainstay of therapy for bradycardia. Modern pacemakers are very
sophisticated and can provide appropriate atrioventricular synchrony as well as mimic autonomic
control of the heart rate.

Temporary pacing can be achieved with a pacing catheter placed through a vein into the heart or
by applying a potential via two electrodes across the chest. The latter is very painful and can only be
used for the short term and if the patient is unconscious.

III. Tachyarrhythmia Therapy

A. Non-pharmacologic Therapy.

1. Cardioversion/Defibrillation is the application of a large potential difference across the

heart causing the simultaneous depolarization (then repolarization) of the majority of the
myocytes, allowing the normal rhythm to take over. It can be used on all types of
tachycardias. Its used in an emergency if the rhythm strongly affects hemodynamic status
and/or appears deadly. Cardioversion is also performed electively in non-lifethreatening
situations (with anesthesia, as it is painful).

The implantable cardioverter defibrillator (ICD) is designed to detect life-threatening

tachycardias and respond with a high energy (painful) shock. ICDs are highly effective and
can deliver therapy automatically, seconds after the arrhythmia is initiated. ICDs may also
terminate tachyarrhythmias by overdrive pacing (anti-tachycardia pacing; ATP) which
is painless. The device paces at some rate faster than the tachycardia to suppress the
mechanism of the tachycardia. When pacing is stopped, the rate can return to normal.

2. Ablation Therapy has become the therapy of choice for SVTs mediated by an accessory
pathway, as it is usually curative. It is also quite effective for focal tachycardias. The success
rate is lower in less straightforward substrates (MI scar, atrial fibrillation, cardiomyopathy), but
techniques are making catheter ablation more useful in these settings as well.

B. Pharmacologic Therapy of Tachyarrhythmias.

1. Potential Antiarrhythmic Drug Strategies: What can be modified to decrease tendency

toward tachycardia?

a. Membrane responsiveness (Figure 1). The membrane response relationship defines

the interaction between the resting membrane potential of a cardiac cell and the velocity
of upstroke of phase 0 depolarization. In general, the more negative the resting
membrane potential, the more rapid the phase 0 upstroke velocity that when applied to a
series of cells correlates with activation time. One way that antiarrhythmic drugs can
modify the electrophysiologic properties of a tissue is to suppress this relationship.
Antiarrhythmic drugs can slow tissue conduction, and move the curve to the right. Drugs
that primarily affect the sodium channel most often mediate this action.

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Figure 1. Membrane response relationship. The magnitude of Vmax is directly related to the resting membrane potential (a). A shift
to curve (c) indicates a decrease in membrane responsiveness of a particular cell. From Corr PB, Cain ME. Electrophysiology. In:
Ahumada GG, editor. Cardiovascular pathophysiology. New York: Oxford University Press; 1987. p. 34-73.

b. Refractoriness (Figure 2). A second mechanism of how antiarrhythmic drugs exert

changes in the electrophysiologic properties of cells and tissue is to alter refractoriness.
The refractory period of a cell or tissue defines the interval of time necessary for the cell
to recover from a previous depolarization. A stimulus attempting to re-excite a cell before
it has completely recovered may result in conduction block or conduction slowing.
Antiarrhythmic drugs, particularly those that block potassium channels, prolong the
refractory period of cardiac cells and cardiac tissue.

Figure 2. Refractory periods of a cardiac myocyte. From Corr PB, Cain ME. Electrophysiology. In Ahumada GG,
editor.Cardiovascular pathophysiology. New York: Oxford University Press; 1987. pp. 34-73.

105
 c. Automaticity (resting membrane potential, threshold, slope of phase 4Figure 3). The
third mechanism of how antiarrhythmic drugs alter the electrophysiologic properties of
cells and tissue is through changes in automaticity. Antiarrhythmic drugs that change the
slope of phase IV, change the threshold for depolarization, or change the resting
membrane potential alter the spontaneous firing rate.

Figure 3. Determinants of automaticity. The rate of an automatic pacemaker can be altered by a change in the slope of
depolarization (a) by a change of threshold (b) or by a change in resting membrane potential (c). From: Corr PB and Cain ME.
Electrophysiology. In: Ahumada GG, ed. Cardiovascular pathophysiology. New York: Oxford University Press; 1987. p. 34-73.

2. Actual Clinical Strategies for Antiarrhythmic Drugs.

a. Decrease Excitability.

Calcium Channel Blockers and Beta-adrenergic blockers will tend to

decrease cellular Ca loading, decreasing tendency for focal (triggered and
automatic) tachyarrhythmias.

Sodium Channel Blockers decrease excitability by inhibiting Phase 0 of the

myocardial action potential.

b. Prolong Refractoriness: primarily suppress reentry.

Potassium Channel Blockers prolong the action potential plateau, which

prolongs the refractory period.

o Note that prolonging the ventricular action potential plateau is equivalent

to prolonging the QT interval on the ECG, which may lead to Torsade de
pointes, a potentially dangerous triggered rhythm that may degenerate
to ventricular fibrillation.

Mechanism of antiarrhythmic effect. The wavelength of depolarized myocardium

is directly related to the refractory period (Figure 4a and 4b). If the wavelength is
extended by extending the refractory period (Figure 4c), then the wavelength
may not be able to exist in the physical circuit. If the head of the wavelength
collides with the refractory tail, the reentry cannot be sustained (Figure 4d).
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 d

Figure 4. The antiarrhythmic effect of prolongation of the refractory period. (a) The wavelength circulates in the circuit with an
excitable gap. (b) The wavelength is the product of the conduction velocity (v) and the refractory period (r). (c) If an antiarrhythmic
agent prolongs refractoriness by 1.3, the wavelength will also be prolonged. (d) The wavelength will not exist in the circuit if the head
meets the refractory tail.

C. Summary of antiarrhythmic agents. Classification of antiarrhythmic drugs is imperfect.

Several classification schemes are currently used in an effort to identify specific drug class
actions.

Though some have tried to improve on it, the Vaughan-Williams Classification of

antiarrhythmic agents is the most widely used (Table 1). It divides the antiarrhythmic agents into
four classes. Classes I and III may be thought of as the "potent" antiarrhythmic agents that have
strong effects on the action potential. The Classification is as follows:

1. Class I: Sodium channel blockers. There are three subclasses:

a. Moderately slow conduction (Na channel blockade) and potently prolong the action
potential/refractory period (K channel blockade).

b. Minimal slowing of conduction (Na channel blockade) with shortening of the action
potential. Most effective in ischemic/injured myocardium and have little effect on atrial
myocytes.

c. Potent to slow conduction (Na channel blockade) with minimal prolongation of the action
potential/refractory period.

2. Class II: Beta-adrenergic blockers (propranolol, metoprolol, atenolol).

3. Class III: Potasium channel blockers prolong action potential/refractoriness/QT interval.

Potential toxicity is Torsade de pointes.

4. Class IV: Calcium channel blockers (diltiazem, verapamil). Slow the AV node and sinus
node and may suppress focal arrhythmias (e.g., ectopic atrial tachycardia)

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Vaughan-
Williams Class Drugs Comments Toxicities
+
Quinidine Na channel blockers, with All: QT prolongation and
I-A Procainamide
+
important K channel
blocking (and QT
Torsade de pointes.
Quinidine: cinchonism
Disopyramide
prolonging) effects. (headache, tinnitus)
Disopyramide is a potent Procainamide: Lupus-like
negative inotrope. syndrome
Disopyramide: Potent
anticholinergic (dry mouth,
constipation, urinary
hesitancy).
+
Lidocaine (IV) Na channel blockers. Little Lidocaine: CNS side effects
I-B Mexiletine (oral) effect on the atria. Used
primarily for ventricular
(headache, hallucination);
cardiovascular depression
(Tocainide)
arrhythmias associated with Mexiletine: GI upset.
ischemia and infarction.
+
Flecainide Potent Na channel High risk for proarrhythmia in
I-C Propafenone blockers. presence of MI scar.
(Moricizine)
(Encainide)
+
Sotalol Marked K channel blocking All: QT prolongation and
III Ibutilide (IV only; v. short
half life)
(and QT prolonging) effects
with risk of torsade de
torsades de pointes.
Amiodarone: Side
Dofetilide pointes. Amiodarone has effects/toxicities may occur
features of each Vaughan- in any organ system except
Amiodarone Williams class, and seems to the kidney.
New!: Dronedarone have less tendency to
proarrhythmia than other
Class III agents.
Dronedarone is hoped to be
similar in efficacy to
amiodarone without the non-
cardiac toxicity.
Table 1. The Vaughan-Williams Classification of the more potent antiarrhythmic drugs. Class II (Beta blockers) and Class IV
(Ca2 channel blockers) are omitted for simplicity. Drugs in gray are little used or unavailable. Amiodarone and Dronedarone are
highlighted because, though usually listed in Class III, they have features of each class.

108
 A more comprehensive classification of antiarrhythmic drugs, but one that isnt as descriptive of
the function is the Sicillian Gambit (Figure 5).

Figure 5. "The Sicilian Gambit", a proposal for a more complete and accurate classification of antiarrhythmic drugs. It is both more
complete and more accurate, but it turns out to be more of a list than a classification.
Circulation, Vol 84, 1831-1851.

109
 D. Proarrhythmia (Figure 6). Initially, it may seem absurd that proarrhythmia is one of the feared
risks of antiarrhythmic drug therapy. Nevertheless, antiarrhythmic properties may be
proarrhythmic. There are 2 main mechanisms.

1. Prolongation of the refractory period/action potential- (which also prolongs the QT on the
surface ECG) increases the risks of early after depolarizations (EADs), which are associated
with torsade de pointes.

Figure 6. Proarrhythmia. Top: Marked QT prolongation. Bottom: Polymorphic VT in the setting of QT prolongation, consistent with
torsade de pointes.

110
 2. Slowed conduction/suppressed excitability- (like the Class I-C agents, flecainide and
propafenone) will decrease the wavelength. If the wavelength becomes short enough to exist
and circulate within a circuit that previously would not accommodate it, reentry can occur
(Figure 7). These drugs are contraindicated in patients with scar from previous myocardial
infarction.

Figure 7. Figure 4, running in the opposite direction. If an antiarrhythmic agent shortens the wavelength by 0.8, the wave can now
circulate in a circuit into which it did not previously fit. Such a circuit might be present within an MI scar.

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IV. Pharmacology of Antiarrhythmic Drugsfor reference only (not testing)
Administration of antiarrhythmic drugs to patients is complex. In addition to their profound
electrophysiologic actions, the ultimate impact on the care of a patient also depends on the drugs
pharmacokinetic, pharmacodynamic, and pharmacogenetic properties. The tables that follow summarize
many of these key factors that impact on usage and dosage.

A. Pharmacology Definitions.

Pharmacokinetics.

o The relationship of the magnitude of a drug dose and the plasma/tissue

concentration achieved by that dose.

Pharmacodynamics.

o The relationship between plasma-tissue concentration and a measurable response at

the active pharmacologic site.

Pharmacogenetics.

o Genetically determined patterns of drug-metabolizing enzymes.

B. Pharmacokinetic determinants of plasma drug concentration.

Bioavailability.

o The amount of drug that reaches the systemic circulation following oral administration
compared with intravenous administration (100%).

o Function of absorption and first-pass clearance through the liver.

o oAffected by: Formulation, absorption, first-pass clearance (liver health/disease).

Distribution.

o Affected by: Body size, disease states, protein binding, drug interactions.

Biotransformation.

o Affected by: Disease states, age, drug interactions, genetics.

Elimination/Metabolism.

o Affected by: Disease states, hepatic and renal function, age, drug-interactions.

112
C. Protein binding of antiarrhythmic drugs.

High protein binding (>90%).

o Propafenone, Amiodarone, Verapamil.

Medium protein binding (50-80%).

o Quinidine, Disopyramide, Lidocaine, Mexiletine, Sotalol, Diltiazem.

Low protein binding (10-40%).

o Procainamide, Flecainide, Ibutilide.

D. Metabolism of antiarrhythmic drugs.

Hepatic. Hepatic metabolism is largely by the cytochrome P450 system, which has
multiple subtypes, including the 3A4 and 2D6 systems.

o Quinidine, Lidocaine, Mexiletine, Propafenone, Propranolol, Esmolol, Amiodarone,

Ibutilide, Verapamil, Diltiazem.

Renal.

o Sotalol, Dofetilide, Digoxin.

Hepatic and Renal.

o Procainamide, Disopyramide, Flecainide.

Cellular.

o Adenosine, ibutilide.

E. Antiarrhythmic drugs: active metabolites.

Parent Compound Metabolite

Quinidine 3-Hydroxyquinidine
Procainamide NAPA
Disopyramide 1,5 N-monodealkyl disopyramide
Lidocaine MEG-GX
Propafenone 5-OHG propafenone
Amiodarone Desethylamiodarone

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F. Cytochrome P450 3A4 System.

Substrates: diltiazem, verapamil, amiodarone, dofetilide, digoxin.

Several antiarrhythmic drugs undergo biotransformation by hepatic oxidative metabolism

through the cytochrome P450 system.

Inhibiitors (may result in taxic accumulation of antiarrhythmic drugs): verapamil, grapefruit

juice, cimetidine, and amiodarone.

Inducers (may result in increased metabolism and decreased activity of the

antiarrhythmic drug): rifampin (antibiotic), St. Johns wort.

G. Cytochrome P450 2D6 System.

P450D6 is the major enzyme for biotransformation of propafenone, flecainide, metoprolol,

propranolol, timolol.

"Poor metabolizers" (5-10% of Caucasian and Black population) have reduced amounts
of P450D6.

Low doses of quinidine can inhibit P450D6 thus increasing the peak and steady-state
plasma concentrations and prolonging the half-life of parent compounds such as
propafenone.

H. Antiarrhythmic Drug Half-Lives.

Quinidine 6 hrs Propranolol 3-6 hrs

Procainamide 3 hrs Bretylium 8 hrs
Disopyramide 7 hrs Amiodarone 53 days
Lidocaine 1.7 hrs Sotalol 12 hrs
Mexiletine 11 hrs Ibutilide 3-6 hrs
Flecainide 20 hrs Dofetilide 10 hrs
Propafenone 4-6 hrs

I. Altered pharmacokinetics of CHF.

Reduced volume of distribution causes increased plasma drug concentrations at any

given dose.

Decreaed renal and hepatic blood flow: decreaesd metabolism/excretion and increased
plasma levels.

Passive hepatic congestion can reduce hepatic enzyme activity resulting in a longer half-
life of the drug.

Toxic/therapeutic ratio is narrowed.

Efficacy may be limited by dose related drug toxicity.

114
J. Noncardiovascular adverse effects of antiarrhythmic drugs.

Drug Most Common Long-Term

Procainamide GI Lupus erythematosus
Dermatologic Granulocytopenia
Quinidine GI Hemolytic anemia
Chinchonism Thrombocytopenia
Disopyramide Anticholinergic Cholestatic jaundice
GI
Mexiletine GI
CNS
Flecainide CNS
Propafenone CNS
GI
Sotalol Beta-blockade
Amiodarone Dermatologic Pulmonary fibrosis
CNS Thyroid dysfunction
Ocular Skin discoloration
Myopathy/neuropathy

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Lecture Notes

Heart Failure and Cardiomyopathies I and II

10/08/2013

Keith Mankowitz, M.D.

Heart Failure and Cardiomyopathies

Objectives:
1. Review the effects of alterations in preload, afterload, and contractility on systolic function of the
normal heart and understand how these indices are altered in the failing heart.

2. Describe the causes and precipitating factors leading to heart failure and the adaptive physiologic
compensations that become maladaptive.

3. Contrast systolic (forward) and diastolic (backward) heart failure.

4. Contrast the pathophysiology of heart failure caused by dilated, restrictive, and hypertrophic
cardiomyopathies with that caused by constrictive pericarditis.

5. Describe important clinical signs and symptoms, and distinguishing features of heart failure caused
by dilated, restrictive, and hypertrophic cardiomyopathies, and constrictive pericarditis.

Reference Text:

Lilly LS, ed. Harvard Medical School. Pathophysiology of Heart Disease: a collaborative project of
th
medical students and faculty. 5 ed. Baltimore: Wolters Kluwer, Lippincott, Williams & Wilkins; 2011: 216-
260; 324-338.

I. Pathophysiology of Heart Failure

A. Definition: The heart is unable to supply the metabolic needs of the tissues or it can only do so at
the expense of high filling pressures. Heart failure can be caused by pathology in any component
of the heart or the circulatory system. Examples include:

1. Cardiac valvesA severe valvular stenosis or leak (e.g., aortic stenosis or mitral
regurgitation) can cause heart failure.

2. Cardiac muscleA weak, poorly squeezing heart muscle (systolic dysfunction) or a stiff, thick
heart muscle that doesnt relax properly (diastolic dysfunction) can cause heart failure.

3. PericardiumA thickened pericardium can squeeze the heart preventing adequate filling and
heart failure.

4. Abnormalities of components of the blood vessel or bloodSuch as arterio-venous fistulas or

severe anemia can cause heart failure.

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II. Determinants of Cardiac Output

Figure 1. Key mediators of cardiac output. Determinants of the stroke volume include contractility, preload, and afterload.
Cardiac output = Heart rate x Stroke volume. From: Lilly LS, editor, Harvard Medical School. Pathophysiology of Heart Disease: a
collaborative project of medical students and faculty. 5th ed. Baltimore: Williams & Wilkins; 2011, Figure 9.2, p. 219.

Recall from Organ Systems Physiology that cardiac contractility and preload increase the stroke
volume whereas afterload reduces the stroke volume (Figure 1). The product of heart rate and stroke
volume equals cardiac output.

A. Definitions of Key Mediators of Cardiac Output.

1. Preload is the initial stretch of the heart before contraction. It is estimated by end-diastolic
volume (EDV) and end-diastolic pressure (EDP), and represents the abscissa on the LV
function curve (Figure 2). The greater the end-diastolic blood volume, the greater is the
stretch (preload) on the myocytes. As preload increases (up to a point), the stretched muscle
fibers develop greater shortening during systole that ejects more blood increasing the stroke
volume and cardiac output. This is the Frank-Starling principle and it explains how the
normal heart increases its stroke volume during physiologic stresses such as exercise.

However, in the failing heart, as a result of muscle weakness (e.g., loss of contractility)
and compensating increases in the retention of sodium and water by the kidney, the heart
can become overfilled and overstretched such that stroke volume increases only slightly for a
greater volume increase (b to c in Figure 2). The high end-diastolic pressures cause fluid to
"back up" into the venous system resulting in pulmonary congestion or edema (fluid in the
lungs).

117
Figure 2. Left ventricular (LV) performance (Frank-Starling) curves relate preload, measured as LV end-diastolic volume
(EDV) or pressure (EDP), to cardiac performance, measured as ventricular stroke volume or cardiac output. From Lilly . . .
2011, Figure 9.3, p 220.

2. Contractility is the intrinsic contractile force of the heart. In patients with systolic dysfunction
(e.g., dilated cardiomyopathy), the heart muscle is very weak and has poor contractility. The
body attempts to improve the contractility by secreting catecholamines (e.g., norepinephrine).
This initially improves the contractility, but with time causes more harm by accelerating the
muscle fatigue and promoting the death of muscle cells (apoptosis).

3. Afterload is the resistance against which the heart contracts. In clinical practice, the mean
arterial blood pressure and peripheral arterial resistance are considered synonymous with the
afterload. As the heart fails, the body causes an increase in the afterload by generating
angiotensin II, endothelin and norepinephrine. Increased afterload reduces the cardiac
output. One of the most effective treatments for heart failure is to give an angiotensin
converting enzyme inhibitor (ACE-I). These drugs significantly reduce the afterload and
thereby improve the cardiac output. ACE-I not only improves the patients symptoms (how
they feel), but also improves their survival.

4. Wall Stress or tension describes what the heart muscle "experiences" as it fills and empties.
It is directly proportional to the pressure developed by the ventricle and the size of the
ventricle, and inversely proportional to the thickness of the ventricular wall. This relationship
is defined by Laplaces law:

Wall stress = p x r
2h
In dilated cardiomyopathy, for example, the heart radius (r) increases, which increases the
wall stress. The heart attempts to counteract wall stress by thickening of the ventricular wall
(h). Eventually, however, as the heart continues to dilate, this compensatory mechanism fails
and the wall tension/stress of the myocardium increases despite hypertrophy.
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III. Adaptive and Maladaptive Mechanisms
Initially, as heart failure develops, the body attempts to maintain cardiac output by modifying the key
mediators reviewed above. However, these physiologic mechanisms used to maintain cardiac output
can quickly become maladaptive and make heart failure worse:

A. Frank-Starling Mechanism. This adaptive mechanism normally causes very little change in
pressure or volume of the heart. In patients with systolic heart failure, however, this
compensatory mechanism to increase output when filling increases has a detrimental effect
because it worsens elevations of pressure and volume of the ventricle, which have already
reached their maximum capacities. As a result, blood leaks into the lungs causing pulmonary
edema.

B. Neurohumoral System. The reduction in cardiac output leads to elevations of atrial pressures
that cause a series of neurohumoral changes (described below) to occur. Initially, these changes
help improve the delivery of blood to vital tissues. However as heart failure progresses, these
compensatory mechanisms accelerate the circulatory systems decompensation and contribute to
premature death by causing more cardiac strain and increasing the chance of fatal arrhythmias.

1. Autonomic Nervous SystemActivity of the sympathetic nervous system increases in heart

failure (to compensate for low CO). Elevations in plasma norepinephrine (NE) correlate with
the severity of heart failure. Increased NE stimulates myocardial contraction, increases heart
rate, increases renin release, and promotes systemic vasoconstriction. This is beneficial over
the short term, but increased adrenergic activity is harmful in the long term as it increases
afterload and it may trigger fatal arrhythmias. NE may also directly promote the death of
myocytes (a process called apoptosis).

As opposed to plasma NE levels, cardiac NE levels are markedly reduced. This may be due
to exhaustion from prolonged adrenergic activation. There is also down regulation of Beta1-
adrenergic receptors. These two events severely limit the capacity of the myocardium to
produce cyclic AMP (which enhances myocardial contractility by stimulating calcium influx
into the myocyte). From a therapeutic standpoint, this will result in a poor response to an
inotropic agent such as dobutamine. In contrast, the use of a Beta1 receptor antagonist (e.g.,
Metoprolol) can increase the amount of beta-receptors and restore the contractile response
to dobutamine.

2. Renin-Angiotensin System (RAS, Figure 3). Reduction of renal blood flow activates renal
baroreceptors, stimulates Beta1-receptors in the juxtaglomerular apparatus of the kidneys and
reduces sodium presented to the macula densa of the kidney, which all stimulate the release
of renin from the kidney. [Renin is also produced by other organs].

119
Figure 3. The systemic and tissue components of the renin-angiotensin system. Several tissues, including myocardium,
vasculature, kidney, and brain, have the capacity to generate angiotensin II independent of the circulating renin-angiotensin system.
Angiotensin II produced at the tissue level may play an important role in the pathophysiology of heart failure. (Modified from
Timmermans PB, Wong PC, Chiu AT, et. al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev
1993;45:205) From Braunwald E. Heart disease: a textbook of cardiovascular medicine. 5th ed. Philadelphia: Saunders; 1997.
Figure 13-24, p. 413.

Renin converts angiotensinogen into Angiotensin I. Angiotensin converting enzyme (90-

99% of which is found in tissues) converts Angiotensin I to Angiotensin II.The production of
Angiotensin II may also occur via the chymase pathway. Angiotensin II stimulates angiotensin
receptors: Angiotensin I (AT1) and Angiotensin II (AT2). AT1 predominates in the vasculature
and myocardium. All the necessary components of the renin-angiotensin system are present
in several organs including the blood vessels, heart and kidneys.

Angiotensin II is a potent vasoconstrictor and contributes to elevated systemic vascular

resistance produced by the adrenergic system. Angiotensin II enhances the release of NE
and stimulates the release of aldosterone from the adrenal gland. Aldosterone increases
tubular sodium reabsorption and causes remodeling of cardiac myocytes.

3. Antidiuretic Hormone (ADH, a.k.a. arginine vasopressin). A posterior pituitary hormone

that plays a role in regulating free water clearance and plasma osmolality. Circulating ADH,
which is increased in heart failure, contributes to increased vascular volume by promoting
water retention in the distal nephron. This may contribute to the inability to excrete free water
resulting in hyponatremia. ADH may also increase systemic vascular resistance.

4. Endothelin. A potent vasoconstrictor released by endothelial cells throughout the circulation.

There are three endothelin peptides:1, 2, and 3 and two types of endothelin receptors: A and
B. Endothelin 1 is increased in heart failure and it contributes to the elevation in pulmonary
and systemic vascular resistance. Antagonists of the endothelin receptor improve
hemodynamic function.

120
 5. Natriuretic Peptides. There are three natriuretic peptides:

a. ANPAtrial natriuretic peptide: stored mainly in the right atrium and released during atrial
distension. It causes vasodilation and natriuresis (plus elimination of water) to counteract
increases blood volume.

b. BNPBrain natriuretic peptide: stored mainly in cardiac ventricular myocardium and may
be responsive to ventricular pressures. It causes vasodilation and natriuresis also to
control blood volume.

c. CNPC-natriuretic peptide: located primarily in the vasculature. It may interact with the
renin system.

Circulating levels of ANP and BNP are elevated in heart failure. All three peptides are
markedly elevated in the myocardium during heart failure. These peptides function to
promote vasodilation, increase fluid excretion and reduce filling pressures. In addition they
may suppress NE, vasopressin, aldosterone and renin levels. There is also evidence to
suggest that they may inhibit cardiac myocyte and vascular smooth muscle cell hypertrophy
and inhibit interstitial fibrosis.

6. Cytokines. Inflammatory cytokines including TNF (tumor necrosis factor) and IL-1B
(interleukin1B) may play a role in the pathogenesis of heart failure. Inflammatory cytokines
can regulate growth and gene expression in cardiac myocytes. TNF can induce immediate
myocardial dysfunction. Circulatory levels of TNF- and IL-6 (interleukin-6) are increased in
patients with heart failure.

C. Myocardial Remodeling. The heart muscle thickens (hypertrophies) to reduce wall tension (by
Laplaces Law) as end-systolic volume and venous return increase to compensate for low CO.
Note that ventricular volume increases cause both preload tension and afterload tension to
increase. The ventricle responds to pressure overload (e.g., high peripheral resistance and high
arterial pressure) by replicating myofibrils in parallel, thickening individual myocytes and
concentric hypertrophy. In response to volume overload such as severe aortic insufficiency,
sarcomeres replicate in series, myocytes become elongated and the ventricle dilates.

Myocardial hypertrophy develops in a manner that maintains systolic wall stress at the lowest
level possible. If myocardial remodeling is insufficient or if the overload increases, an exhaustion
phase begins, resulting in the loss of myofibrils and the development of replacement fibrosis.
Mechanical strain, neurohormones (NE, angiotensin II), inflammatory cytokines (TNF),
endothelin and reactive oxygen species (e.g., superoxide) are responsible for the abnormal
remodeling process. Myocyte loss can occur either by necrosis or apoptosis. Necrosis occurs
when the myocyte is deprived of oxygen or energy.

Hypertrophy of the ventricular myocardium also causes a mismatch in the blood supply.
Capillary density is reduced in hypertrophied myocardium and may result in ischemia, which is
most severe in the subendocardium. This may also lead to ischemic necrosis and replacement
fibrosis.

Apoptosis (programmed cell death) is an energy dependent process by which a specific

genetic program activates a molecular cascade that causes degradation of nuclear DNA.
Catecholamines, angiotensin II, reactive oxygen species, nitric oxide, inflammatory cytokines and
mechanical strain can all induce apoptosis.

121
IV. Cardiomyopathies
As discussed in the definition of heart failure, an abnormality of the heart valves, myocardium,
pericardium, blood vessels or blood components can cause heart failure. The adaptive/compensatory
mechanisms are similar. The cardiomyopathies constitute a group of diseases in which there is direct
involvement of the heart muscle itself. There are three basic types of cardiomyopathies (Figure 4):

A. Dilated CardiomyopathyThe most common: characterized by ventricular dilatation, contractile

dysfunction (systolic dysfunction) and congestive (backward) heart failure.

In the strictest definition, dilated cardiomyopathy is a primary myocardial abnormality and is

not due to hypertension, congenital heart disease, valvular heart disease, ischemic diseases or
any other known cause. As a subclassification, there are several specific cardiomyopathies due
to known causes. These include: Ischemic cardiomyopathysevere coronary artery disease
can lead to infarction, fibrosis, and severe ischemia resulting in myocardial dysfunction that leads
to left ventricular dilatation and dysfunction. Other examples include: valvular cardiomyopathy,
hypertensive cardiomyopathy, inflammatory cardiomyopathy, metabolic cardiomyopathy
and peri partum cardiomyopathy.

Figure 4. Anatomic appearance of the cardiomyopathies (CMP). (A) Normal heart demonstrating left ventricle (LV) and left
atrium (LA). (B) Dilated CMP is characterized by ventricular dilatation with only mild hypertrophy. (C) Hypertrophic CMP
demonstrates marked ventricular hypertrophy, often predominantly involving the intraventricular septum. (D) Restrictive CMP is due
to infiltration or fibrosis of the ventricles, usually without enlargement of the cavities. Note that LA enlargement is common to all
three types of CMP. From: Lilly LS, editor, Harvard Medical School. Pathophysiology of Heart Disease: a collaborative project of
medical students and faculty. 4th ed. Baltimore: Williams & Wilkins; 2011, Figure 10.1, p. 245.

B. Hypertrophic CardiomyopathyCharacterized by inappropriate left ventricular hypertrophy.

The systolic function is normal. Because of the increased muscle mass, many of these patients
have diastolic dysfunction (impairment of diastolic filling).

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 C. Restrictive CardiomyopathyLeast common: characterized by excessively rigid ventricular
walls that impede ventricular filling. (diastolic dysfunction). The systolic function is normal.

Two other cardiomyopathies are recognized: Arrhythmogenic right ventricular

cardiomyopathy (ARVD) and unclassified. Unclassified includes: fibroelastosis, systolic
dysfunction with minimal dilatation and mitochondrial involvement. ARVD is due to fatty or fibro
fatty infiltration mainly of the right ventricle. It is an important cause of ventricular arrhythmias in
children and young adults.

V. Systolic Versus Diastolic Dysfunction

A. Systolic DysfunctionThe dilated cardiomyopathies are characterized by ventricular
enlargement and systolic dysfunction. The intrinsic myocardial contractility is severely impaired.
The principal effect is a decreased stroke volume impairing the hearts ability to supply blood to
the tissues (Forward failure).

B. Diastolic DysfunctionThere is a defect in ventricular relaxation/filling resulting in failure of the

ventricles to accommodate normal blood volume. The principal manifestation of diastolic
dysfunction relates to the elevation of ventricular filling pressures, which causes pulmonary
and/or systemic congestion (Backward failure). Hypertensive heart disease is an example of
diastolic dysfunction. In hypertension, the walls of the ventricle thicken and stiffen thus impairing
filling. Other conditions associated with diastolic dysfunction include restrictive cardiomyopathy,
hypertrophic cardiomyopathy and pericardial constriction. The treatment of choice for conditions
associated with pure diastolic dysfunction is a diuretic.

In many patients, systolic and diastolic dysfunction co-exist. An example of this is

ischemic cardiomyopathy where systolic failure is caused by loss of myocardium from prior
myocardial infarction and diastolic dysfunction is caused by reduced compliance of the ventricle
caused by stiff fibrous scar tissue replacing the myocardium and by reduced myocardial
relaxation caused by the ischemic myocardiums inability to relax (relaxation is an energy
requiring process).

C. Pressure Volume Loops can help conceptualize systolic and diastolic dysfunction.

Figure 5. Pressure volume loops of systolic and diastolic dysfunction. (A) The normal pressure-volume loop (solid line) is
compared with one demonstrating systolic dysfunction (dashed line). In systolic dysfunction due to decreased cardiac contractility,
the end-systolic pressure-volume relation is shifted downward and rightward (from line 1 to line 2). As a result, the end-systolic
volume (ESV) is increased (arrow). As normal venous return is added to the greater than normal ESV remaining in the ventricle,
there is an obligatory increase in the end-diastolic volume (EDV) and pressure (preload), which serves a compensatory function by
partially elevating stroke volume towards normal via the Frank-Starling mechanisms. (B) The pressure-volume loop of diastolic
dysfunction due to increased stiffness (decreased compliance) of the ventricle (dashed line). The passive diastolic pressure-volume
curve is shifted upward (from line 1 to line 2) such that at any diastolic volume, the ventricular pressure is greater than normal. The
result is a decreased EDV (arrow) because of reduced filling of the stiffened ventricle, at a higher than normal end-diastolic
123
pressure. From: Lilly LS, editor, Harvard Medical School. Pathophysiology of Heart Disease: a collaborative project of medical
students and faculty. 4th ed. Baltimore: Williams & Wilkins; 2011, Figure 9.7, p. 225.

D. Etiology of Systolic Dysfunction.

1. Coronary Artery Disease ~ 50%.

2. Idiopathic ~ 18%.

3. Valvular ~ 4%.

4. Hypertension ~ 3.8%.

5. Alcohol ~ 1.0%.

6. Viral ~ 0.4%.

7. Post Partum ~ 0.4%.

8. Amyloidosis ~ 0.1%.

Other causes include: endocrine, rheumatic, nutritional, toxic, metabolic, inherited, and
tachycardia induced.

E. Etiology of Diastolic Dysfunction.

1. Coronary Artery Disease.

2. Hypertension.

3. Diabetes Mellitus.

4. Aortic Stenosis.

5. Restrictive Cardiomyopathy.

6. Hypertrophic Cardiomyopathy.

7. Pericardial Constriction.

8. Obesity.

F. Precipitating Causes of Heart Failure. The most common cause is dietary excess of sodium
and fluids and/or a reduction or discontinuation of diuretics, angiotensin converting enzyme
inhibitor or digoxin use in a patient with confirmed heart failure. Other precipitants include: chronic
arrhythmias, myocardial ischemia or infarction, infections, pulmonary embolism, physical stress
(prolonged exertion), environmental stress (hot, humid), renal insufficiency, alcohol, cocaine, and
cardiac depressant medications.

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G. Clinical Symptoms and Signs of Heart Failure.

1. Symptoms.

a. Backward.

(1) Left-sided.

(a) Dyspneadifficulty getting enough breath.

(b) Orthopneadyspnea that develops in the recumbent position.

(c) Paroxysmal nocturnal dyspnea (PND)Attacks of dyspnea at night causing the

patient to awaken suddenly with feelings of anxiety and suffocation.

(2) Right-sided.

(a) Right upper quadrant (RUQ) tenderness (from venous congestion in the liver).

(b) Reduced appetite (from venous congestion in the bowel).

(c) Edema (generally extremities from venous pooling).

b. Forward.

(1) Fatigue.

(2) Weakness.

2. Signs.

a. Backward.

(1) Left-sided.

(a) Tachypnearapid breathing

(b) Lung cracklesrales during breathing

(2) Right-sided.

(a) Jugular vein distension (JVD)jugular vein may pulsate even when patient is
sitting.

(b) Hepatomegalyenlargement because of chronic engorgement with blood

(c) Edematypically in the lower extremities ("pitting"push in with fingertip and

indentation stays for a few minutes).

b. Forward.

(1) Left-sided.

(a) Decreased mental statusfrom decreased perfusion of the brain.

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 (b) Cool extremitiesdecreased perfusion of the periphery.

(c) Pulsus alternansstrong followed by a weak pulse.

(d) Cheyne Stokes respirationresults from decrease perfusion of the medulla.

3. Signs revealed by cardiac auscultation.

a. Loud pulmonary valve closure (P2) (pulmonary hypertension).

b. S3 (Abn early LV filling sound).

c. S4 (atria contracts against noncompliant ventricle).

d. Murmurs (turbulence produced by leaking or stenotic valves).

VI. Dilated Cardiomyopathy

Dilated cardiomyopathy is a syndrome characterized by cardiac enlargement and impaired systolic
function of one or both ventricles. The left ventricle is primarily affected in the majority of cases.

A. Etiology. Dilated cardiomyopathy represents a final common pathway that is the end result of
myocardial damage by a variety of insults (see section on etiology of systolic dysfunction).
Approximately 25% of cases are idiopathic, meaning the cause is unclear. There are three
possible mechanisms:

1. Familial and genetic.

2. Viral myocarditis and other cytoxic insults.

3. Immunological abnormalities.

(See section on Etiology of systolic dysfunction for the other causes of Dilated Cardiomyopathy)

B. Natural History. In symptomatic patients there is usually progressive deterioration with 25% of
patients dying within one year and 50% dying within five years. One-fourth of patients diagnosed
with recent onset dilated cardiomyopathy improve spontaneously.

In patients with an identifiable cause of heart failure such as coronary artery disease,
hypertension or alcohol abuse, treatment of the primary etiology can significantly improve the
heart function and even return it to normal.

The degree of ventricular enlargement and the severity of left ventricular dysfunction
correlate with prognosis. Marked limitation of exercise capacity manifested by reduced maximal
systemic oxygen uptake (especially when below 10-12 ml/kg/min) is a reliable predictor of
mortality and is used as an indicator for consideration of cardiac transplantation.

C. Clinical Manifestations. Signs and symptoms of congestive heart failure usually develop
gradually. See section G. above for clinical signs and symptoms of heart failure.

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 D. Diagnosis.

1. Echocardiographyshould be performed in any patient suspected of having heart failure.

Echo accurately identifies the size and function of both ventricles as well as the size of the
atria and the function of the valves. Once the diagnosis has been confirmed, an intense
search for possible causes should be done. A stress test or a cardiac catheterization should
be done to rule out coronary artery disease. Obtain a history of ingestion of toxic medications
such as Adriamycin or toxins (alcohol or cocaine). Blood tests should also be done to
evaluate thyroid functions, calcium, phosphorous, iron and HIV.

2. Chest x-rayusually reveals an enlarged heart with or without fluid in the lungs.

3. ECGThere are no specific signs of a cardiomyopathy on the ECG. If there is significant

coronary artery disease, there may be abnormal Q waves signifying an old myocardial
infarction. Poor R wave progression and conduction abnormalities especially left bundle
branch block are common in dilated cardiomyopathies.

E. Therapy.

Specific therapy is not possible. Treating the underlying cause (e.g., coronary artery disease) can
result in normalization of cardiac function. The basic medical treatment includes diuretics, angiotensin
converting enzyme inhibitors, digoxin and beta-blockers (the topic of another lecture).

VII. Hypertrophic Cardiomyopathy

A. Definition. This condition is characterized by inappropriate hypertrophy of some or all myocardial
walls. In the majority of cases, all left ventricular walls are thickened, but the ventricular septum
is usually much thicker than the other walls. This is termed asymmetrical septal
hypertrophy (ASH).

The systolic function is usually supra-normal with an ejection fraction greater than 80%
(normal is 60-70%). The reason for this hypercontractile state is unclear.

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Figure 6. Pathophysiology of left ventricular (LV) outflow obstruction and mitral regurgitation in hypertrophic
cardiomyopathy (HCM). Left panel. The LV outflow tract is abnormally narrowed between the hypertrophied interventricular
septum and the anterior leaflet of the mitral valve (AML). It is thought that the rapid ejection velocity along the narrowed tract in early
systole draws the AML toward the septum (small arrow). Right panel. As the mitral valve abnormally moves anteriorly and contracts
the septum, outflow into the aorta is transiently obstructed. Because the mitral leaflets do not coapt normally in systole, mitral
regurgitation (MR) also results. From: Wein MN, Dec GW, Lilly LS. The cardiomyopathies. In: Pathophysiology of Heart Disease.
A collaborative project of medical students and faculty. Lilly LS, ed. 4th ed. Philadelphia: Wolters Kluwer/Lippincott Williams &
Wilkins; 2011: Figure 10.7, p. 253.

B. Pathophysiology. The ventricle is characterized by abnormal stiffness with resultant impaired

ventricular filling. This may result in congestive heart failure from diastolic dysfunction. In ~ 25%
of patients, there is dynamic obstruction of blood as it moves out of the left ventricle into the
aorta. The obstruction occurs because of the combination of the thickened ventricular septum and
the anterior mitral leaflet (AML) moving towards the septum as the ventricle ejects its blood
volume (Figure 6). The asymmetrically septal hypertrophy (ASH) together with the
hyperdynamic left ventricular contractility produce a Venturi effect just below the aortic valve in
the region of the left ventricular outflow tract (LVOT) (Figure 6). This Venturi effect causes the
anterior leaflet of the mitral valve to move anteriorly towards the ventricular septum. The systolic
anterior movement (SAM) of the mitral valve in combination with ASH causes variable degrees
of left ventricular outflow tract obstruction.

Because of the outflow obstruction, the pressure within the left ventricle is much higher than
the pressure in the aorta. This pressure gradient is an attempt by the ventricle to move blood out
of the ventricle. The pressure gradient can vary from patient to patient and it can also vary
significantly in the same individual at different times. The LVOT gradient may be responsible for
some of the symptoms such as dyspnea and syncope. The gradient can be accurately assessed
by Doppler echocardiography and by cardiac catheterization. Patients may also have mitral
regurgitation (MR), the mechanism of which may be related to either SAM or to a functionally
abnormal mitral valve. Severe MR may cause significant dyspnea. Myocardial ischemia is
common and multifactorial and may be caused by: inadequate capillary density for the increased
muscle mass; abnormally hypertrophied coronary arteries that cannot dilate appropriately;
increased myocardial oxygen demand; and compression of the coronary arteries when the
myocardium contracts.

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 Myocardial hypertrophy, LVOT obstruction, diastolic dysfunction, ischemia and mitral
regurgitation are responsible for many of the symptoms. However, the interaction is very complex
and variable.

C. Prevalence. 1 in 500.

D. Genetics. HCM is an autosomal dominant condition with variable penetrance. It is also caused by
spontaneous mutations.

The disease loci are found on at least eight different chromosomes encoding sarcomeric peptides
including: Beta Myosin heavy chain gene, Troponin T, Myosin binding protein C and Alpha
Tropomyosin, myosin light chain, actin and Troponin I. There are also other as yet unidentified
genes. There is a wide variation in the phenotypic expression of a specific mutation of a given
gene. Certain mutations are associated with a high risk of sudden death.

E. Histology. There is myocardial hypertrophy and gross disorganization of the muscle bundles
resulting in a whorled appearance. There is cell fiber disarray with abnormalities of cell to cell
arrangement and disorganization of myofibrillar architecture of a given cell. Fibrosis is usually
prominent and necrosis may be present. Almost all HCM patients have some degree of disarray
and in general one-fourth or more of the myocardium demonstrates disarray. The intramural
coronary arteries have thickening of the vessel wall, resulting in a smaller lumen.

F. Clinical Manifestations. Most patients with hypertrophic cardiomyopathy are asymptomatic or

minimally symptomatic. The first manifestation of this disease can be sudden death. HCM is the
most common cause of sudden death in athletes under 35 years. Patients symptoms are
variable, and a general, but not absolute relationship exists between symptoms and the degree of
hypertrophy.

The most common symptom is dyspnea. Other symptoms include angina, fatigue,
presyncope, syncope and palpitations. Syncope may result from obstruction of the LVOT, from
arrhythmias or from peripheral vasodilation. The physical exam may be normal in patients with no
LVOT obstruction and minimal hypertrophy. Often there is a forceful apical impulse (due to the
powerful squeeze of the ventricle). The carotid pulse rises briskly. There may be a fourth heart
sound (S4) (resulting from contraction of the atrium against a stiff non-compliant ventricle). If there
is LVOT obstruction, a loud ejection systolic murmur is heard between the apex and the left
sternal border. This murmur gets louder with any condition that reduces the left ventricular cavity
size promoting more LVOT obstruction. As the ventricular volume gets smaller, there is more
abnormal contact between the AML and the septum. If the patient performs the Valsalva
maneuver (forceful expiration against a closed glottis) or the patient stands up (blood pools in the
legs), this will result in a decreased filling of the left ventricle and a more significant degree of
LVOT obstruction. Conversely, by increasing the left ventricular volume, the gradient will lessen.
Squatting and raising the legs will both increase the left ventricular volume and thus reduce the
LVOT gradient. The loudness of the murmur correlates with the severity of the LVOT gradient.
Mitral regurgitation may be heard if there is leakage across the mitral valve.

G. Diagnostic Tests.

1. ECGThe ECG is usually abnormal with significantly increased voltages as well as ST and T
wave changes. Q waves reflecting an alteration in electrical forces may be present.

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 2. EchocardiographyThe left ventricle can be accurately assessed for thickness, size and
function. Typically the ventricular septum is > 15mm and the range varies from 13mm to
50mm (normal is < 11mm). If the ventricular septum is 1.3 to 1.5 times the thickness of the
posterior wall, it is referred to as Asymmetrical Septal Hypertrophy (ASH). Doppler echo can
accurately measure the gradient across the LVOT as well as assess any other valvular
abnormalities. Doppler can also assess abnormalities of diastolic function.

3. Cardiac CatheterizationCardiac catheterization is reserved for situations where coronary

artery disease needs to be ruled out. Cardiac catheterization can accurately measure the
pressure in all cardiac chambers as well as the LVOT gradient.

H. Prognosis. The annual mortality is about 3% in adults seen at large referral centers, but is
probably closer to 1% in the general population.

Progression of HCM to a dilated cardiomyopathy occurs in 10-15% of patients. Risk factors

for sudden death include young age (<30) at diagnosis, a family history of sudden death or a
genetic mutation associated with an increased prevalence of sudden death, an abnormal blood
pressure response to exercise, syncope and marked hypertrophy.

I. Management. Strenuous exertion should be avoided. The vast majority of patients require
only medical management.

1. DiureticsCautious use of diuretics often helps reduce symptoms of pulmonary congestion.

2. Beta-blockersThese drugs are the mainstay of medical therapy and 1/3 to 2/3 of patients
experience symptomatic improvement. Beta-blockers improve angina, dyspnea and reduce
the increase in LVOT gradient that occurs with exertion.

3. Calcium AntagonistsVerapamil is often effective in improving symptoms in patients who

have not benefited from beta-blockers. Verapamil improves diastolic filling, can reduce the
LVOT gradient (by its negative inotropic effect) and improves angina. Verapamil should not
be used in patients with symptoms of heart failure (e.g., PND or orthopnea) or if there are
high filling pressures (raised jugular venous pressure, edema, pulmonary crackles) since it
may cause worsening of pulmonary edema and a fatal outcome.

4. DisopyramideThis is a class I antiarrhythmic drug and it can produce symptomatic

improvement and reduction of the LVOT gradient by depressing the left ventricular
contractility.

J. Invasive Procedures. 5-10% of patients fail to respond to medical management and may be
candidates for the following:

1. Dual chamber pacemakerThe pacemaker depolarizes the ventricle in such a way that the
ventricular septum moves outward. This can reduce the LVOT gradient and improve
dyspnea. This is more effective in the elderly.

2. Implantable cardioverter defibrillator (ICD)This is reserved for high-risk patients

especially those with sustained ventricular arrhythmias or aborted sudden death. Patients
with syncope and risk factors for sudden death may also be candidates for an ICD.

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 3. Alcohol Septal AblationSeveral small trials have shown symptomatic improvement in
patients with severe LVOT obstruction who have undergone this procedure. A chemical
infarction is induced in a small area of the ventricular septum by injecting alcohol into a small
septal blood vessel.

4. SurgeryThere are a number of surgical procedures aimed at reducing the LVOT gradient:

a. Myomectomy: Excision of a portion of the ventricular septum. The mortality is 3-5%, but
surgery results in long-term improvement in symptoms and exercise capacity in most
patients.

b. Mitral Valve Surgery: Either repair or replacement of the mitral valve can reduce the
LVOT obstruction by abolishing SAM. Mitral valve surgery is also used to treat severe
mitral regurgitation.

VIII. Restrictive and Infiltrative Cardiomyopathies

Restrictive Cardiomyopathy is the least common cardiomyopathy. The ventricular walls are excessively
rigid and impede ventricular filling causing severe diastolic dysfunction. Systolic function is normal until
the ventricle burns out and dilates, which may occur in the end stages.

A. Classification of Restrictive and Infiltrative Cardiomyopathies.

Infiltrative: Storage Diseases

* - Amyloidosis Hemochromatosis
* - Sarcoidosis Fabry Disease
- Gauchers Disease Glycogen storage disease
- Fatty Infiltration
Endomyocardial Myocardial (non infiltrative)
* - Endomyocardial fibrosis * - Idiopathic
Carcinoid Familial
Hypereosinophilic syndrome Scleroderma
* - Radiation Diabetic cardiomyopathy
* - Toxic effect of anthracycline
Drugs that can cause fibrosis or endocarditis (serotonin, methysergide, ergotamine, mercurial agents, busulphan). * denotes
most common.

B. Clinical Manifestations. Patients initially present with weakness and dyspnea on exertion. As
the condition progresses, patients develop edema, hepatomegaly, ascites and eventually severe
edema termed anasarca.

The disease presents in a very similar manner to and needs to be differentiated from
pericardial constriction.

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C. Echocardiogram. The echocardiogram reveals normal systolic function and the Doppler reveals
evidence of diastolic dysfunction. In patients with an infiltrative process, the left ventricle walls
may be thickened.

D. ECG. The ECG usually shows diffusely diminished voltage in all leads.

E. Hemodynamics. There is a marked elevation of pressure in all four cardiac chambers. The
pulmonary pressure is usually >50 mmHg (normal<25). In the atrial pressure tracing, there is a
characteristic M or W waveform. The left ventricular filling pressures usually exceed the right by
at least 5mmHg. In most patients there is a characteristic "Square Root Sign" in the left
ventricular pressure tracing. This hemodynamic feature (dip and plateau) is shared by pericardial
constriction and is characterized by a deep dip and rapid early increase in ventricular pressure at
the onset of diastolic followed by a rapid rise to a plateau in early diastole (Figure 7).

Figure 7. Schematic tracings of left (LV) and right (RV) ventricular pressure in constrictive pericarditis. Early diastolic
ventricular filling abruptly halts as the volume in the ventricles quickly reaches the limits imposed by the constricting
pericardium (the "plateau"). Throughout most of diastole, the LV and RV pressures are normally elevated and equal. From: Lilly
LS, editor, Harvard Medical School. Pathophysiology of Heart Disease: a collaborative project of medical students and
faculty. 4th ed. Baltimore: Williams & Wilkins; 2011, Figure 14.6, p. 336.

F. Management. Look for an etiology: An abdominal fat pad aspirate is the best procedure to
assess for amyloidosis. Iron studies to evaluate for hemachromatosis. An endomyocardial biopsy
can assess for other causes.

G. Treatment. Diuretics are the mainstay of treatment for restrictive cardiomyopathy. In amyloidosis
due to AL (amyloid protein composed of portions of immunoglobulin light chains), there is
improved survival and reduced symptoms with use of alkylating chemotherapeutic agents. For
hemachromatosis, phlebotomies or the use of chelating agents (desferrioxamine) may be helpful.

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IX. Constrictive Pericarditis
Constrictive pericarditis "imprisons" the heart and impairs the filling of all four chambers. It presents in a
similar way and needs to be differentiated from restrictive cardiomyopathy. Constrictive pericarditis can
be cured by the removal of the pericardium.

A. Causes.

1. Idiopathicaccounts for the majority of cases.

2. Infectionsviral, bacterial, TB.

3. Traumatic or post surgical.

4. Radiation.

5. Neoplastic.

6. Uremia.

7. Connective tissue.

8. Drug relatedProcainamide, hydralazine.

B. Clinical Features. Patients with pericardial constriction present with signs and symptoms of
congestive heart failure. There is evidence of biventricular failure although it is not the ventricles
that have failed. Jugular vein distension is easily detected and the Kussmaul sign (inspiratory
increase in JVD) is common. This is the opposite of normal physiology, in which inspiration
results in a decrease in jugular venous pressure. A sharp diastolic thrust is common in chronic
constrictionpericardial knock. This sound may follow the second heart sound (so, during early
filling) in patients with severe calcific constriction. It represents the sudden cessation of
ventricular filling imposed by the rigid pericardial sac.

C. Chest X-ray. Pleural effusions are common. Calcification of the pericardium may be seen
especially in the lateral view.

D. Cardiac Catheterization. Hemodynamics closely resemble these of restrictive cardiomyopathy.

There is elevated and near equalization (< 5 mmHg) of pressures in all chambers. The square
root sign is seen in both ventricular tracings. Typically the pulmonary artery systolic pressure is
30 to 45 mmHg. (See hemodynamics of square root sign under restrictive cardiomyopathy.)

E. Echocardiography. There is normal systolic function with dilated atria, which is similar to
restrictive cardiomyopathy. The thickened pericardium usually cannot be visualized on echo.
There is often subtle abnormal systolic and diastolic wall motion.

F. CT and MRI. Both these techniques can accurately measure pericardial thickness, which is
significantly increased.

G. Management. Treat the underlying cause if one is found. Use diuretics to relieve elevated filling
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 pressure. Pericardial stripping is the definitive treatment.

Differences Between Pericardial Constriction and Restrictive Cardiomyopathy

Pericard. Constriction Restrictive Cardiomyopathy

A. Physical Exam
S3 Absent Present
Pericardial knock Present Absent
Kussmaul's sign Present Maybe present
Heart failure Present Present
B. Echocardiogram
Thickened ventricular walls Absent Maybe present
Valvular regurgitation Absent Present
Atrial enlargement Present Present
C. Hemodynamic
Atrial pressures Elevated Elevated
Ventricular pressure (square root sign) (square root sign)
Pulmonary pressure 35-40 mm Hg > 50 mm Hg
D. Imaging of Pericardium
CT scan or MRI Thickened Normal
E. Biopsy
Normal Infiltrative process

X. Approach to the Patient Presenting with Heart Failure.

A systematic and thorough evaluation using the following five modalities will enable one to make the
diagnosis of congestive heart failure, establish the mechanism and etiology of heart failure and develop a
treatment plan.

A. Thorough history and physical examination.

B. ECG.

C. Chest x-ray.

D. Echocardiogram.

E. CT or MRI (when indicated).

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XI. Pericardial Tamponade
The pericardial sac consists of 2 layers, the parietal and visceral pericardium between which is usually 15
to 30 ml of fluid.

A. Pathophysiology. Accumulation of fluid in the pericardial space is unnoticed until it begins to

exert pressure on the chambers of the heart. Initially, the intra-pericardial pressure rises and this
causes the right atrial, pulmonary artery diastolic pressure, and left atrial pressures to be elevated
and equal. As the pressure rises further, the elevated chamber pressure reduces the ability of the
heart to fill during diastole. The end-diastolic volume falls causing a reduction in the cardiac
output. The cardiac output is initially maintained by an increase in the heart rate. The blood
pressure is initially maintained by an increase in heart rate, contractility and peripheral
vasoconstriction. As the cardiac chambers become more compressed, this compensatory
mechanism cannot be maintained and the blood pressure falls.

If pericardial fluid accumulates slowly over months, the pericardium is able to stretch and
accommodate a large amount of fluid (~1000ml) before compromising cardiac filling and cardiac
output. If a pericardial effusion accumulates rapidly, the pericardium does not have time to stretch
resulting in acute hemodynamic compromise.

B. Etiology of Pericardial Effusion.

1. Idiopathic.

2. Iatrogenic.

3. Malignancy.

4. Myocardial Infarction.

5. End Stage Renal Disease.

6. Congestive Heart Failure.

7. Infections such as Tuberculosis.

C. Symptoms.

1. Shortness of breath.

2. Chest pain.

3. Nausea.

4. Abdominal paindue to liver and visceral congestion.

D. Signs.

1. Vital Signs: tachycardia, hypotension, tachypnea.

2. Pulsus Paradoxus. Not really paradoxical, but an exaggeration of the normal inspiratory
decrease in blood pressure. During inspiration there is an increase in filling of the right heart
chambers as the intra-pleural pressure is negative. The increased right heart filling pushes

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 the ventricular septum to the left and reduces its filling and thus cardiac output. During
expiration, filling of the right heart is reduced (due to reduced venous return) and filling of the
left heart is increased (due to blood being pushed out of the lungs from the positive lung
pressure into the left atrium). This increases the left-sided filling and thus the cardiac output
and blood pressure. In cardiac tamponade, this filling pattern is exaggerated because the
high intra-pericardial pressures compress the cardiac chambers adding to the reduced left-
sided filling during inspiration and reduced right-sided filling during expiration.

Pulsus paradoxus is measured by listening for the Korotkoff sounds (sounds of the pulse
with a stethoscope on the brachial artery). The cuff is inflated above 200 mmHg and slowly
deflated. Initially a sound will be heard only during expiration, corresponding to the cardiac
output which is increased during expiration and reduced during inspiration). With further cuff
deflation, the sound of the blood pressure will be heard both during inspiration and expiration.

The systolic pressure at which the Korotkoff sound is first heard is recorded and then
subtracted from the systolic pressure at which the Korotkoff sound is heard during inspiration
and expiration. This difference is called the pulsus paradoxus and is usually less than
10mmHg. Pericardial tamponade is one cause of a pulsus paradoxus and may decrease
systolic pressure more than 10 mmHg during inspiration. Other causes include severe
asthma, emphysema and massive pulmonary embolism.

3. Elevated jugular venous pressure (JVP).

4. Reduced heart sounds, the so-called "quiet precordium" because of the insulating effect of
the effusion.

5. Pericardial Rubat times. A scratchy pericardial friction rub is common in acute pericarditis.
It is believed to be caused by the movement of the inflamed pericardial layers against one
another.

6. Electrocardiogram:

a. Low QRS Voltage.

b. Electrical alternans (changes in the amplitude or shape of the P, QRS and/or ST-T waves
from one beat to the next. This is due to the heart swinging in the pericardial sac).

c. Atrial arrhythmias such as atrial flutter and fibrillation.

d. ST segment elevation.

7. Chest X-Ray.

Large globular heart.

8. Echocardiogramcan detect the amount of fluid present and shows compression of the heart
chambers indicating the degree of hemodynamic compromise.

E. Treatment.

1. PericardiocentesisRemoval of fluid with a needle.

2. Pericardial Window: If a pericardiocentesis cannot be performed, a surgeon can make a cut

below the sternum visualizing the pericardium directly and draining the fluid. A residual hole
(pericardial window) is left to allow fluid to drain into the chest cavity.

3. The cause of the pericardial effusion should be evaluated and treated.

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Case Study

Arrhythmia Case Studies

10/08/2013

Timothy W. Smith, M.D., D.Phil.

Arrhythmia Case Studies

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Lecture Notes

Heart Failure Therapy

10/11/2013

Keith Mankowitz, M.D.

Heart Failure Therapy

Objectives:
1. Appreciate the importance of heart failure in the context of its prevalence, morbidity, and mortality.

2. Review the etiologies of heart failure resulting from systolic dysfunction.

3. Describe the progression of heart failure in the context of dysregulation of neurohormones and
cytokines.

4. Describe the deleterious effects of the renin-angiotensin-aldosterone system in patients with heart
failure as well as the strategies for inhibiting this pathway.

5. Describe the importance of upregulation of the adrenergic nervous system in heart failure and its
biologic consequences as well as the role of beta-adrenergic blockade in the management of patients
with heart failure.

6. Understand the mechanism of action of digoxin and its role in the symptomatic management of heart
failure.

7. Review the mechanisms of action of diuretic therapy including the potassium sparing diuretics and
describe their role in the management of heart failure.

8. Contrast the role of inotropic agents in the management of heart failure as therapeutics that may
improve hemodynamics and symptoms, but have an adverse impact on mortality.

9. Understand the role of device therapy including implantable defibrillators and left ventricular assist
devices in the management of patients with heart failure.

Reference Text:

Lilly LS, ed. Harvard Medical School. Pathophysiology of Heart Disease: a collaborative project of
th
medical students and faculty. 5 ed. Baltimore: Wolters Kluwer, Lippincott, Williams & Wilkins; 2011: 244-
260; 386-408; 418-422.

th
Katzung BG, ed. Basic and Clinical Pharmacology. 10 ed. New York: Lange Medical Books/McGraw-
Hill; 2007: 198-210, 236-253.

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I. Introduction
Heart failure has been called a contemporary crisis in American medicine. It is estimated that nearly five
million Americans have a diagnosis of heart failure, and this number is expected to increase as the
population ages. The prevalence also is affected by evolving technologies and therapies that are
prolonging life in individuals with other cardiovascular diseases, particularly acute ischemic heart disease.
Heart failure will account for 2.6 million hospitalizations this year and is the most common reason to
hospitalize a patient age 65 years and older. It is also a very mortal disease causing or contributing to
300,000 deaths each year.

Several models have been developed to explain the progression of heart failure. Initially, we
considered heart failure in terms of the cardiorenal model in which myocardial injury resulted in
decreased renal blood flow that led to retention of sodium and water. Our thinking evolved in the late
1900s into the cardiocirculatory model, which suggested that much of the pathophysiology of heart failure
was related to both arterial and venous vasoconstriction. Our thinking evolved again in the 1990s into the
neurohormonal model. In this model, an index cardiac event is followed by dilatation of the left ventricular
chamber with hypertrophy of the viable myocytes and progressive cell loss through apoptotic pathways.
This leads to left ventricular systolic dysfunction and results in activation of a variety of neurohormonal
pathways that lead to salt and water retention, vasoconstriction, and poor peripheral blood flow.
Therefore, the neurohormonal model actually embodies both the cardiorenal model and the
cardiocirculatory model, but explains them in the context of dysregulation of neurohormonal pathways. As
it is understood in the 2000s, the effects of the sympathetic nervous system and the renin-
angiotensin-aldosterone system are the most deleterious in the pathogenesis of heart failure. We
have specific pharmacologic agents that block these pathways. Many of the dysregulated neurohormones
and cytokines can also be used as markers that predict disease severity and mortality. Most recently a
brain natriuretic peptide has become a commercially available assay that directly correlates with an
individuals symptoms and with their risks for mortality.

II. Treatment of Systolic Heart Failure

A general approach to the management of patients with systolic heart failure includes risk factor
modification and altering disease processes and lifestyles that increase an individuals risk for new
cardiac injury. Patients should be counseled to stop smoking, maintain a normal body weight, and to limit
their sodium intake to 2 gm daily and weigh themselves daily. It is now appreciated that physical activity is
an important component of the management of these individuals and daily aerobic activity prevents
peripheral deconditioning.

A. Inhibition of Angiotensin II. Upregulation of the renin-angiotensin-aldosterone system has

deleterious effects in heart failure. The biologically active form of this pathway is angiotensin II.
This molecule interacts with the angiotensin II type 1 receptor resulting in peripheral
vasoconstriction, secretion of antidiuretic hormone, cell hypertrophy, salt and water retention,
stimulation of the thirst center in the brain, and activation of the sympathetic nervous system.
Angiotensin converting enzyme (ACE) inhibitors block the effects of this pathway by inhibiting the
enzyme that catalyzes the conversion of angiotensin I to angiotensin II, the biologically active
form of the pathway. There are compelling data from large, well-done, multicenter, randomized,
placebo-controlled trials demonstrating the benefits of ACE inhibition. ACE inhibitors have
consistently been shown to improve cardiac function, limit heart failure symptoms, and reduce
hospitalizations and mortality. The ACE inhibitor drugs vary with regards to their pharmacologic
properties, but their beneficial effects in heart failure are largely considered to be a class effect.
The ACE inhibitors have been tested across the symptomatic spectrum of heart failure and
have been demonstrated to reduce patients risks for morbidity and mortality. They have
also been shown to decrease the remodeling that occurs following cardiac injury and decrease an

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 individuals likelihood of progressing to more symptomatic stages of heart failure.

There are other pathways by which the body can make angiotensin II that are capable of
bypassing the ACE inhibitor drugs. This is the rationale for the use of angiotensin II receptor
blockers (ARBs). Several trials of the angiotensin II receptor blockers have failed to demonstrate
significant mortality benefits beyond those seen with ACE inhibition and this class of drugs should
still be considered a second-line therapy for individuals who fail to show benefit from ACE
inhibitors. Angiotensin receptor blockers should be considered as primary therapy in patients that
cannot tolerate ACE inhibitors primarily due to ACE inhibitor induced cough or previous
angioedema. Trials using a combination of ACE inhibitor and angiotensin receptor blocker have
not demonstrated additional benefit to warrant the risk of progression of renal insufficiency and
hyperkalemia.

B. Inhibition of Aldosterone. In addition to the effects of angiotensin II, aldosterone appears to be

an important neurohormone elaborated by upregulation of the renin-angiotensin-aldosterone
system. In patients with congestive heart failure and a normal dietary sodium intake, the
aldosterone secretion rate may be 4-5 times that of a normal individual. Decreased metabolic
clearance of aldosterone contributes to a further increase in plasma concentrations in these
patients. Aldosterone acts at the cells of the distal cortical collecting duct promoting reabsorption
of sodium as well as hypokalemia and hypomagnesemia. It also produces effects at the tissue
level including myocyte hypertrophy, interstitial fibrosis, endothelial cell dysfunction, and vascular
remodeling. These tissue effects and electrolyte abnormalities contribute to increased propensity
to cardiac arrhythmias and sudden cardiac death in the heart failure population.

The aldosterone antagonist spironolactone has been demonstrated to reduce mortality

significantly in the RALES Trial. Administration of spironolactone in addition to usual medical
therapy for left ventricular dysfunction in patients with New York Heart Association class III and IV
heart failure resulted in a 30% reduction in mortality over a 3-year follow-up period. More recently,
the selective aldosterone blocker eplerenone was evaluated in a randomized, placebo-controlled
trial of over 6,000 patients with acute myocardial infarction, left ventricular dysfunction (EF <
40%), and clinical evidence of heart failure. Eplerenone was used in addition to standard
therapies for left ventricular dysfunction such as ACE inhibitors and beta-blocker therapy. There
was a 15% reduction in all cause mortality over a 30-month time period. In both of these clinical
trials of aldosterone blockade, much of the reduction in mortality was due to a reduction in
sudden cardiac death. Further trials are in progress to examine the role of aldosterone blockade
in less severe forms of heart failure, as well as assess the role of aldosterone in ventricular
remodeling.

C. Inhibition of the Adrenergic Receptors. The next pathway that has been identified as having a
significant role in the pathogenesis of heart failure is the sympathetic nervous system (SNS). The
effects of SNS upregulation are mediated through both the beta- and alpha-receptors. The beta-
receptors are widely distributed throughout the heart as well as the peripheral vasculature and
lungs. Chronic stimulation of these receptors can result in a hypertrophic cardiac phenotype.
Stimulation also results in a positive inotropic and chronotropic response. Further, direct
stimulation of the beta-receptors is toxic to myocytes and stimulation of the beta-I receptor is pro-
apoptotic. These issues really provide the rationale for the use of beta-adrenergic blocking drugs
in heart failure. There have now been more patients randomized in beta-blocker trials than in
ACE inhibitor trials in the heart failure population. Beta-blockers have consistently been
shown to improve cardiac function and symptoms and reduce both morbidity and
mortality. As opposed to the ACE inhibitors, it is not at all clear that the beneficial effects of the
different beta-blocking agents are a class effect. The earliest beta-blockers blocked both the beta-
I and beta-II receptors. The prototype nonselective beta-blocker is Propranolol. In the early
1980s, several pharmaceutical companies attempted to develop cardioselective beta-blockers
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 that only block the beta-I receptors. The prototypes of these drugs are Metoprolol, Atenolol, and
Bisoprolol. More recently, new hybrid agents have been formulated that block both beta-receptors
as well as alpha-receptors. The prototype of these drugs are Carvedilol and Bucindolol.

There are several consistencies that have been demonstrated in the heart failure beta-
blocker trials. Beta-blockers improve some patients' symptoms, improve ejection fraction, result in
reverse remodeling of the ventricle, reduce hospitalizations, reduce mortality, and are well
tolerated when started at low doses and titrated slowly. The average mortality reduction in the
beta-blocker trials is approximately 35%.

D. Digoxin. Digoxin is the oldest heart failure therapy and has been used for hundreds of years. It
was initially extracted from the foxglove plant. This agent inhibits the sodium/potassium ATPase
resulting in increased cytosolic calcium concentrations. The physiologic effects of digoxin are
increased contractile velocity and extent of sarcomere shortening. Digoxin is particularly useful in
symptomatic heart failure patients with dilated left ventricles and significantly depressed systolic
function. However, this agent has many significant disadvantages including a very narrow
therapeutic window, synergistic toxicity with serum potassium abnormalities and multiple
drug interactions. Digitalis has been demonstrated to improve the symptoms of heart failure, but
has no impact on mortality. The use of digoxin has decreased in the heart failure population,
and one needs to be cautious about the potential side effects. Drug dose is based on lean body
mass and renal function. Toxicity of this agent includes headaches, irritability, fatigue, confusion,
and GI upset. Digoxin can also cause visual disturbances typically characterized as the
observation of halos around lights. This agent is also arrhythmogenic with the most common
rhythm abnormality being paroxysmal atrial tachycardia with block. However, we need to be
aware that digitalis can cause any rhythm abnormality. Digitalis toxicity can be lethal. Initially,
discontinuation of the agent is indicated. Non life-threatening arrhythmias can be treated with
either lidocaine or dilantin. Life-threatening arrhythmias should be treated with the dig-specific
monoclonal antibody, Digibind. Following the administration of Digibind, the measurement of
serum digoxin levels is not useful.

E. Diuretics. Loop diuretics are an important component of the management of systolic heart
failure. The patients major complaints tend to be dyspnea and edema. The loop diuretics
(Furosemide, Torsemide, Bumetanide) are potent agents that are very effective at removing large
volumes of fluid. The addition of Metolazone, which blocks sodium reabsorption in the proximal
tubule, in combination with the loop diuretic can promote profound diuresis. Caution should be
utilized when aggressively diuresing patients to ensure that they dont become volume depleted
and that they don't develop significant electrolyte abnormalities including hyponatremia and
hypokalemia. These diuretics have not been demonstrated to impact mortality in the heart failure
population.

The potassium sparing diuretic Spironolactone has been demonstrated to reduce mortality in
the RALES trial. In fact, over a 36-month follow-up, the use of Spironolactone resulted in a 30%
reduction in mortality. The apparent disparity between the effects of Spironolactone and the loop
diuretics on mortality is explained by the observation that Spironolactone is an aldosterone
antagonist, and aldosterone is another of the dysregulated neurohormones in heart failure.

F. Hydralazine and Nitrates. The combination of hydralazine and nitrates was tested in an early
heart failure trial (V-HeFT-I). This regimen does not have beneficial effects on neurohormones,
but is a regimen that principally dilates both the arterial and venous systems. Hydralazine and
nitrates are superior to placebo, but are inferior to the use of ACE inhibitors with regards to
improving mortality. The A-HeFT Trial examined the benefit of a combination of hydralazine and
nitrates in African-American patients with Class III-IV heart failure. This randomized trial
155
 examined the addition of hydralazine and nitrates to standard therapy of an ACE inhibitor or
angiotensin receptor blocker and a beta blocker. The trial was stopped early due to a significant
impact on survival in the hydralazine-nitrate treated patients. The primary role of this combination
of drugs at the present time is in people with significant renal insufficiency and African-American
patients.

G. Nondigitalis Inotropic Agents. Finally, the nondigitalis inotropic agents have been used in heart
failure. These agents have two mechanisms of action: direct stimulation of the beta-receptors or
blockade of phosphodiesterase resulting in high levels of cyclic AMP. The net result of both of
these classes of inotropic drugs is increased intracellular calcium levels. The inotropic agents do
have hemodynamically beneficial effects improving the cardiac output and reducing peripheral
resistance to blood flow. However, every trial of nondigitalis inotropic agents has demonstrated
excess mortality in the treatment arm compared to the placebo arm. Therefore, these agents
should be used very selectively as a bridge to other kinds of heart failure treatment such as
transplantation or ventricular assist devices or as end of life therapy. It also should be utilized with
disclosure to the patient that these agents have been demonstrated to increase mortality.

H. Other Neurohormonal Therapies. Brain type natriuretic peptide (BNP) is released by the
ventricles in response to increased wall stress and filling pressures. BNP is a balanced
vasodilator and promotes natriuresis in the kidney. Recombinant BNP (nesiritide) has been
shown to decrease intracardiac filling pressure and improve symptoms in patients with
decompensated HF. A large scale multicenter trial did not demonstrate a survival benefit or
reduction in HF hospitalizations with an acceptable safety profile. Antagonists of vasopressin are
also being evaluated in clinical trials in patients with heart failure.

III. Device and Transplant Therapy in Heart Failure

Sudden death due to ventricular arrhythmias is a common cause of death in patients with heart failure
due to left ventricular systolic dysfunction. Clinical trials have shown that placement of implantable
cardioverter defibrillators decrease the risk of sudden death in this patient population. They should
be considered in patients with an ejection fraction less than 30-35% despite optimal medical therapy. In
patients with LBBB and a QRS duration of greater than 130 ms, placement of a LV pacing lead
(biventricular pacing) may improve symptoms and survival in patients with NYHA class III HF. Mechanical
circulatory support with left ventricular assist devices (LVAD) is a useful tool in patients with advanced HF
as a bridge to cardiac transplantation (BTT) as well as selected non-transplant candidates as long-term
therapy (destination therapy, DT). Heart transplantation continues to be the ideal therapy in a selected
population of patients with advanced heart failure and the absence of comorbid conditions.
Transplantation is limited by the availability of suitable donors.

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Lecture Notes

Valvular Heart Disease

10/18/2013

Alan Zajarias, M.D.

Brian Lindman, M.D.

Valvular Heart Disease

Objectives:
1. Understand the etiology, pathophysiology, natural history, clinical history and physical exam,
diagnostic testing and treatment for valvular heart diseases with a focus on aortic and mitral valve
disease.

Reference Texts:

1. Lindman B. Valvular Heart Disease. In: Cuculich PS, Kates AM, eds. The Washington Manual:
nd
Cardiology Subspecialty Consult, 2 ed. 2008. Lippincott Williams & Wilkins, 186-218.

2. Lilly LS, ed. Pathophysiology of Heart Disease a collaborative project of medical students an
th
faculty, 5 ed. Wolters Kluwer, Lippincott Williams & Wilkins. 2011:, 190-215..

These notes are adapted from:

Lindman B. Valvular Heart Disease. In: Cuculich PS, Kates AM, eds. The Washington Manual:
nd
Cardiology Subspecialty Consult, 2 ed. 2008. Lippincott Williams & Wilkins, 186-218.

I. Introduction
Valvular heart disease encompasses those diseases characterized by abnormal mobility or closure of the
heart valves, causing obstruction or regurgitation of (forward) flow through the valve. The atrioventricular
valves (tricuspid and mitral) are between the atria and ventricles; the semilunar valves (pulmonic and
aortic) are between the ventricles and the great vessels as blood exits the heart. Valvular diseases can
be acquired or congenital and may affect any of the four valves. Because the proper functioning of heart
valves reflects a dynamic interplay of the valve, annulus, ventricular shape/size/function, and subvalvular
apparatus, an abnormality in any of these can lead to valvular heart disease. Valve disease causes
adverse consequences in the heart mostly via pressure overload or volume overload effects that impact
heart muscle structure and function.

Although disease prevalence is not known precisely, valve disease is common. It is estimated that >5
million people in the U.S. have moderate to severe regurgitant valvular lesions. Aortic stenosis is present
in 2% of people >65 and 4% of those >85 years of age. Although worldwide rheumatic valve disease is
quite common, in the developed world antibiotic usage and the aging of the population has led to
degenerative valve lesions being the most common etiology. Although sometimes underappreciated,
valvular disease is not benign: numerous studies have shown that various valve lesions are associated
with excess morbidity and mortality, even when asymptomatic.

Forthcoming studies may show a role for medical therapies in slowing the progression of particular
valve lesions, but because valve disease is largely a mechanical problem the role for mechanical
157
therapies will likely remain prominent. A growing understanding of the adverse consequences of valve
disease combined with significant improvements in surgical technique and expanding percutaneous
therapies will hopefully lead to expanded options and more appropriate timing in our efforts to treat
valvular heart disease.

II. Aortic Valve DiseaseAortic Stenosis

The aortic valve is a trileaflet valve that permits unidirectional flow from the left ventricle (LV) into the
aorta. Aortic stenosis (AS) is characterized by incomplete opening of the valve during systole which limits
antegrade flow, yielding a systolic pressure gradient between the LV and ascending aorta. Aortic
regurgitation (AR) is caused by incompetence of the valve, allowing backward flow of blood from the aorta
into the LV during diastole.

Lesions of the aortic valve are the most common cause for obstruction of flow from the LV into the
aorta. Other causes of obstruction and the consequent pressure gradient between the LV and aorta
include obstruction above the valve (supravalvular) and below the valve (subvalvular), both fixed (i.e.,
subaortic membrane) and dynamic (i.e., hypertrophic cardiomyopathy with obstruction). The focus here
will be on obstruction at the level of the valve. Aortic sclerosis is thickening of the AV leaflets that causes
turbulent flow through the valve and a murmur but no gradient and, therefore, no stenosis.

A. Aortic StenosisEtiology.

Calcific/Degenerative Most common cause in U.S.

th th
Trileaflet calcific AS usually presents in the 7 -9 decades (mean age
mid-70s).
Risk factors similar to CAD, exacerbated by abnormal Ca
metabolism.
Active biological process with bone formation in the valve.
Calcification leading to stenosis affects both trileaflet and bicuspid
valves.
Bicuspid Occurs in 1-2% of population (congenital lesion).
th th
Usually presents in the 6 -8 decades (mean age mid-late 60s).
~50% of patients needing AVR for AS have a bicuspid valve.
More prone to endocarditis than trileaflet valves.
Associated with aortopathies (i.e., dissection, aneurysm) in a
significant proportion of patients.
Rheumatic More common cause worldwide, much less common in U.S.
rd th
Usually presents 3 -5 decades.
Almost always accompanied by mitral valve disease.

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 B. Aortic StenosisPathophysiology.

The pathophysiology for calcific AS involves both the valve and the ventricular adaptation to the
stenosis. Within the valve, there is growing evidence for an active biological process that begins
much like the formation of an atherosclerotic plaque and eventually leads to calcified bone formation.

Valvular obstruction Intraventricular pressure to maintain CO

Ventricular walls hypertrophy to reduce wall stress
(Laplaces Law: Wall stress = pressure x radius / 2 x thickness)

LVH (1) Compliance, impaired passive filling, preload dependence on atrial contraction;
(2) LVEDP Subendocardial ischemia ( myocardial perfusion pressure) & pulmonary congestion

Progressive valvular obstruction, hypertrophy, fibrosis, and increasing wall stress

Ischemia, arrhythmia, filling pressure, ventricular dilation, contractile dysfunction, & EF

Angina, Syncope, and Dyspnea

Pathophysiology of Aortic Stenosis: CO, cardiac output; LVH, left ventricular hypertrophy; LVEDP, left ventricular end diastolic
pressure; EF, ejection fraction.

C. Aortic StenosisNatural History.

AS is a progressive disease typically characterized by an asymptomatic phase until the valve area
2
reaches a minimum threshold, generally <1 cm . In the absence of symptoms, patients with AS have
an overall good prognosis with a risk of sudden death estimated to be <1%/year. Predictors of
decreased event-free survival (free of AVR or death) include: higher peak aortic jet velocity, extent of
valve calcification, and coexistent CAD. Once patients experience symptoms, their average survival is
2-3 years with a high risk of sudden death.

D. Aortic StenosisHistory and Physical Exam.

The classic symptoms include of aortic stenosis include: (1) angina; (2) syncope; and (3) shortness of
breath (heart failure). Frequently patients will gradually limit themselves in ways that mask the
presence of symptoms, but indicate a progressive and premature decline in functional capacity. In the
setting of severe AS, these patients should be viewed as symptomatic.

The physical exam is characterized by a harsh systolic crescendo-decrescendo murmur usually

heard best at the right upper sternal border with radiation to the carotids. Often the murmur also
radiates to the apex (or may be best heard there); this may cause it to be misinterpreted as mitral
regurgitation. The time to peak intensity of the murmur correlates with severity of the stenosis (later
peak more severe), however between the extremes of stenosis (very mild or very severe) it is often
difficult to assess AS severity by exam.

E. Aortic StenosisDiagnostic Testing.

A standard evaluation for a patient with aortic stenosis includes a CXR, EKG, and transthoracic echo.
The echo provides an evaluation of the severity of the stenosis, the leaflet number, and the structure
and function of the left ventricle. Further testing may include a transesophageal echo, exercise stress
159
test, dobutamine echo, and/or cardiac cath.

F. Aortic StenosisTreatment.

Surgery: Therapeutic decisions are primarily based on the presence or absence of symptoms. The
treatment of severe AS is almost exclusively surgical aortic valve replacement. Symptomatic severe
AS is a deadly disease and deserves prompt surgical intervention. Certain associated high risk
features or the need for another cardiac surgical intervention may lead to the recommendation for a
valve replacement even when the patient is asymptomatic or has less than severe stenosis.
Operative mortality varies significantly depending on age, comorbidities, and concurrent surgical
procedures to be performed.

Medical Therapy: Severe symptomatic AS is a surgical disease. There are no medical

treatments proven to decrease mortality or delay surgery. Nevertheless, there are some
guidelines for medical therapy in nonsurgical candidates, asymptomatic patients, or those with less
severe stenosis.

HTN: treat with appropriate antihypertensive agents cautiously to avoid hypotension.

ACE-I: some data suggests that ACE inhibition may advantageously interfere with the
valvular biology that leads to valve calcification.

Statins: some clinical evidence suggests statins may slow progression of AS.

Avoid over-diuresis and loss of preload, which may precipitate hypotension.

Use vasodilators, particularly nitroglycerin, very cautiously so as to avoid hypotension.

Percutaneous / Transcatheter: Recent advances have introduced a new way of implanting an

aortic valve that avoids the need for open-heart surgery. Using catheters and balloons, an aortic valve
can now be implanted via a transfemoral (femoral artery) or transapical (small incision made
between the ribs at the apex of the heart) approach. This field is rapidly evolving, but offers an
alternative to surgical valve replacement. Currently, these techniques are not FDA-approved and are
only used in high-risk valve replacement candidates, but ongoing trials will provide results soon which
may lead to approval and expanded use of these techniques.

160
III. Aortic Valve DiseaseAortic Regurgitation
A. Aortic RegurgitationEtiology.

Aortic regurgitation results from pathology of the aortic valve with or without involvement of the aortic
root. Several potential causes for AR variably affect the valve and aortic root. AR usually develops
insidiously, but may be acute.

More common Bicuspid aortic valve.

Rheumatic disease.
Calcific degeneration.
Infective endocarditis.
Idiopathic dilatation of the aorta.
Myxomatous degeneration.
Systemic HTN.
Dissection of the ascending aorta.
Marfans syndrome.
Less common Traumatic injury to the aortic valve.
Collagen vascular diseases (ankylosing spondylitis, rheumatoid arthritis,
Reiters syndrome, giant-cell aortitis, and Whipples disease).
Syphilitic aortitis.
Osteogenesis imperfecta.
Ehlers-Danlos syndrome.
Discrete subaortic stenosis.
VSD with prolapse of an aortic cusp.
Anorectic drugs.
Acute Infective endocarditis.
Dissection of the ascending aorta.
Trauma.

B. Aortic RegurgitationPathophysiology.

Acute Aortic Regurgitation.

Pathophysiology of Acute Aortic Regurgitation: LV, left ventricle; LVEDP, left ventricular end diastolic pressure; LAP, left atrial
pressure; CO, cardiac output; HR, heart rate; SV, stroke volume.

Chronic Aortic Regurgitation.

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Pathophysiology of Chronic Aortic Regurgitation: LV, left ventricle; LVED, left ventricular end diastolic; LVEDP, left ventricular
end diastolic pressure; EF, ejection fraction; SV, stroke volume; CO, cardiac output; CHF, congestive heart failure.

C. Aortic RegurgitationNatural History.

Natural History of Aortic Regurgitation.

Asymptomatic patients with normal LV systolic function:
Progression to symptoms and/or LV Less than 6% per year
dysfunction
Progression to asymptomatic LV Less than 3.5% per year
dysfunction
Sudden death Less than 0.2% per year
Asymptomatic patients with LV
dysfunction:
Progression to cardiac symptoms Greater than 25% per year
Symptomatic patients:
Mortality rate Greater than 10% per year
From Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr., Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, OGara
PT, ORourke RA, Otto CM, Shah PM, Shanewise JS. ACC/AHA 2006 guidelines for the management of patients with valvular heart
disease. JACC 2006; 48(3):e1-148.

D. Aortic RegurgitationHistory and Physical Exam.

Patients with acute AR typically present with pulmonary edema manifested by severe dyspnea.
Other presenting symptoms may be related to the causes of acute AR. The presentation of patients
with chronic AR depends on the presence of LV dysfunction and whether the patient is in the
compensated vs. decompensated stage. Compensated patients are typically asymptomatic,
whereas those in the decompensated stage may note decreased exercise tolerance, dyspnea,
fatigue, and/or angina.

162
Physical Exam.
Acute Wide pulse pressure may be present, but often is not because forward stroke volume (and
therefore systolic BP) is reduced.
rd
Brief soft diastolic murmur heard best at 3 L intercostal space (often not heard).
Systolic flow murmur (due to volume overload and hyperdynamic LV).

Chronic LV heave.
PMI is laterally displaced.
Diastolic decrescendo murmur heard best at LSB leaning forward at end-expiration (severity of AR
correlates with duration, not intensity, of the murmur).
Systolic flow murmur (due mostly to volume overload; concomitant AS may also be present).
Austin Flint murmurlow-pitched diastolic murmur heard best at the apex caused by antegrade
flow through a mitral orifice narrowed by severe AR restricting the motion of the anterior MV leaflet.
S3 is often heard as a manifestation of the volume overload and is not necessarily a sign of CHF.
Widened pulse pressure (often >100 mmHg) with a low diastolic pressure.
Characteristic signs related to wide pulse pressure:
o Mussets sign: head bobbing with each cardiac cycle.
o Corrigans pulse: rapid carotid upstroke followed by arterial collapse.
o Mllers sign: pulsation of the uvula.
o Traubes sign: pistol-shot murmur heard on the femoral artery.
o Duroziezs sign: to-and-fro murmur over the femoral artery when partially compressed.
o Quinckes pulse: visible capillary pulsation in the nail bed after holding the tip of the nail.

E. Aortic RegurgitationDiagnostic Testing.

A standard evaluation for a patient with aortic regurgitation includes a CXR, EKG, and transthoracic
echo. The echo provides an evaluation of the severity of the regurgitation, the leaflet number, and the
size and function of the left ventricle. Transesophageal echo can provide further assessment of the
severity of regurgitation, dimension of the aorta, and facilitate an evaluation of endocarditis or aortic
dissection. MRI or CT can also be helpful to assess aortic dimensions and severity of aortic
regurgitation.

F. Aortic RegurgitationTreatment.

Surgery is indicated for any symptomatic patient with severe AR regardless of LV systolic
function. Acute severe AR is almost universally symptomatic and is treated surgically. Valve repair
may be feasible in a small subset of patients. If the aortic root is dilated, it may be repaired or
replaced at the time of valve replacement. Although worse NYHA functional class, LV dysfunction,
and the chronicity of these abnormalities are predictors of higher operative and post-operative
mortality, valve replacement is usually a better alternative than medical therapy in improving overall
mortality and morbidity. If a patient is in decompensated heart failure, short-term treatment with
vasodilator therapy (i.e., nitroprusside) is reasonable to improve their hemodynamics prior to surgery.

Medical Therapy: The role of medical therapy in patients with AR is limited. There are no
randomized, placebo-controlled data showing that vasodilator therapy delays the development of
symptoms or LV dysfunction warranting surgery. Vasodilator therapy (i.e., nifedipine, ACE-I,
hydralazine) has a potential role in three situations:

1. Chronic therapy in patients with severe AR who have symptoms or LV dysfunction but are
not surgical candidates.

2. Short-term therapy to improve hemodynamics in patients with severe heart failure and severe
LV dysfunction prior to surgery.

163
 3. May be considered for long-term therapy in asymptomatic patients with severe AR who have
some LV dilatation but normal LV systolic function.

In general, vasodilator therapy is indicated to reduce systolic blood pressure in hypertensive

patients with AR. In the absence of hypertension, it is not indicated for those who are asymptomatic,
with mild or moderate AR, normal LV function, and normal LV cavity size.

IV. Mitral Valve DiseaseMitral Stenosis

The mitral valve permits unidirectional flow from the left atrium (LA) to the LV. The mitral apparatus is
composed of an annulus, two leaflets, posteromedial and anterolateral papillary muscles, and chordae
tendineae. The latter two are considered the mitral subvalvular apparatus. Together with the LV, the
proper interaction between these various parts is necessary for the adequate function of the mitral valve.

Mitral stenosis (MS) is characterized by incomplete opening of the mitral valve during diastole, which
limits anterograde flow and yields a sustained diastolic pressure gradient between the LA and LV. Mitral
regurgitation (MR) is caused by inadequate coaptation of the valve leaflets, allowing blood to flow
backward from the LV into the LA during systole.

A. Mitral StenosisEtiology.

Rheumatic Predominant cause of MS.

2/3 are female.
May be associated with MR.
Stenotic orifice often shaped like a fish mouth.
Rheumatic fever can cause fibrosis, thickening, and calcification leading to fusion of
the commissures, cusps, chordae, or some combination.
Other causes Congenital.
(fairly rare) Mucopolysaccharidoses.
Malignant carcinoid.
SLE.
Rheumatoid arthritis.
Mitral annular calcification (MAC).
Functional MS may occur with obstruction of left atrial outflow due to:
o Tumor, particularly myxoma.
o LA thrombus.
o Endocarditis with a large vegetation.
o Congenital membrane of the LA (i.e., cor triatriatum).
o MV prosthesis dysfunction.
o Oversewn mitral annuloplasty ring.

164
 B. Mitral StenosisPathophysiology.

Pathophysiology of Mitral Stenosis: LA, left atrium; LV, left ventricle; CO, cardiac output; HR, heart rate; LAP, left atrial pressure;
LAE, left atrial enlargement; PVR, pulmonary vascular resistance; RV, right ventricle; RVH, right ventricular hypertrophy; CO,
cardiac output.

Physiologic states that either increase the transvalvular flow (enhance cardiac output) or
decrease diastolic filling time (via tachycardia) can increase symptoms at any given valve area.
Pregnancy, exercise, hyperthyroidism, atrial fibrillation with rapid ventricular response, and fever are
examples in which either or both of these occur. Symptoms are often first noticed at these times.

C. Mitral StenosisNatural History.

MS usually progresses slowly with a long latent period (several decades) between rheumatic fever
2
and the development of stenosis significant enough to cause symptoms (usually <2-2.5 cm with
2
exercise or <1.5 cm at rest). Ten-year survival of untreated patients presenting with MS depends on
the severity of symptoms at presentation: asymptomatic or minimally symptomatic patients have an
80% 10-year survival, whereas those with significant limiting symptoms have a 0-15% 10-year
survival. Once severe pulmonary HTN develops, mean survival is 3 years. The mortality of untreated
patients is due mostly to progressive pulmonary and systemic congestion, systemic embolism,
pulmonary embolism, and infection (in order of frequency).

165
D. Mitral StenosisHistory and Physical Exam.

After a prolonged asymptomatic period, depending on when they present, patients may report any of
the following: dyspnea, decreased functional capacity, orthopnea and/or PND, fatigue, palpitations
(often due to atrial fibrillation), systemic embolism, hemoptysis, chest pain, and signs and symptoms
of infective endocarditis.

Findings on physical exam will depend on the severity of valve obstruction and the associated
adaptations that have had time to develop in response to it. They may include:

Accentuation of S1 may occur when the leaflets are flexible.

Opening snap (OS)caused by sudden tensing of the valve leaflets after they have
completed their opening excursion; the A2-OS interval varies inversely with the severity of
stenosis (shorter interval ~ more severe stenosis).

Mid-diastolic rumblelow-pitched murmur heard best at the apex with the bell of the
stethoscope; the severity of stenosis is related to the duration of the murmur, not intensity
(more severe ~ longer duration).

Irregularly irregular pulse due to atrial fibrillation.

MR murmur may be present.

Loud P2, TR murmur, PA tap, and/or RV heave can indicated pulmonary HTN.

JVP, hepatic congestion, and peripheral edema can indicate varying degrees of right heart
failure.

E. Mitral StenosisDiagnostic Testing.

A standard evaluation for a patient with mitral stenosis includes a CXR, EKG, and transthoracic echo.
The echo provides an evaluation of the severity of the stenosis and any associated pulmonary
hypertension or right heart failure. Transesophageal echo (TEE) helps assess the etiology of the MS,
severity of any associated MR, and presence of any left atrial clot; this is helpful in determining
whether balloon valvuloplasty is a treatment option. Cardiac cath can be helpful if invasive
hemodynamics are needed to clarify the severity of MS and any associated pulmonary HTN.

F. Mitral StenosisTreatment.

Treatment of MS depends on patient symptoms, the severity of stenosis, the presence and severity of
associated pulmonary HTN, presence of an associated arrhythmia, and the risk of thromboembolism.

Medical therapy is aimed at slowing progression of pulmonary HTN, preventing

endocarditis, reducing the risk of thromboembolism, and reducing heart failure symptoms. For
heart failure, intermittent diuretics and a low-salt diet are often adequate if there is evidence of
pulmonary congestion. For patients who develop symptoms only with exercise (likely associated with
tachycardia), negative chronotropic agents such as -blockers or non-dihydropyridine CCBs which
blunt tachycardia may be of benefit. Since almost all MS is rheumatic in origin, prophylaxis against
rheumatic fever is appropriate.

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 Atrial Fibrillation: Patients with MS are particularly prone to develop atrial fibrillation and/or
flutter (30-40% of patients with MS). AF can exacerbate and worsen symptoms (particularly in the
setting of a rapid ventricular response) due to a shortened diastolic filling period and loss of atrial kick
increased LA pressure increased pulmonary congestion. Therapy is mostly aimed at rate control
and prevention of thromboembolism. For rate control, -blockers or non-dihydropyridine CCBs tend to
more effective than digoxin for tachycardia associated with exertion. Efforts to maintain sinus rhythm
(through DCCV, ablation, or with drugs) are focused on those patients with symptoms from their AF,
but can be particularly challenging in patients with MS. Anticoagulation is indicated to prevent
thromboembolism.

Percutaneous Mitral Balloon Valvotomy (PMBV): PMBV is generally performed via a

transseptal approach (after a transseptal puncture of the interatrial septum, a catheter with a balloon
is passed across the interatrial septum until the balloon is positioned across the mitral valve) with one
or two balloons. Balloon inflation separates the commissures and fractures some of the nodular
calcium in the leaflets, yielding an increased valve area. Usually the transmitral pressure gradient
decreases by 50-60%, cardiac output increases 10-20%, and valve area increases from 1.0 to 2.0
2
cm . Contraindications to PMBV include: LA thrombus, moderate-severe MR (>2+), and unfavorable
valve/subvalvular anatomy related to calcification and fibrosis. When done in those with favorable
mitral valve morphology, event-free survival is quite good. It compares favorably with surgical mitral
commissurotomy (open or closed) and is the valvotomy procedure of choice in experienced centers in
patients without contraindications.

Surgery: Surgical treatment is usually reserved for those who are not candidates for PMBV
because of the presence of one or more contraindications to PMBV or because the percutaneous
option is unavailable. Surgical valvotomy can be done either closed (bypass unnecessary) or open
(done under direct visualization on bypass). Open valvotomy yields better outcomes and is the
preferred approach in developed countries; closed valvotomy continues to be used in some
developing countries without access to open-heart surgery or percutaneous approaches. When the
valve cannot be repaired, valve replacement is required.

V. Mitral Valve DiseaseMitral Regurgitation

Prevention of MR is dependent on the integrated and proper function of the mitral valve (annulus and
leaflets), subvalvular apparatus (chordae tendineae and papillary muscles), left atrium, and the ventricle.
Abnormal function of any one of these components can lead to MR. Given the complexity of this
interaction, the terminology to describe MR (the final common pathway of all abnormalities of the valve
apparatus or ventricle that lead to MR) is often confusing. Organic MR refers to MR caused primarily by
lesions to the valve leaflets and/or chordae tendinae (i.e., myxomatous degeneration, endocarditis, and
rheumatic). Functional MR refers to MR caused primarily by ventricular dysfunction usually with
accompanying annular dilatation (i.e., cardiomyopathy and ischemic MR).

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 A. Mitral RegurgitationEtiology.

Degenerative Usually occurs as a primary condition but has also been associated with
(Essentially analogous heritable diseases affecting the connective tissue.
to Mitral Valve Prolapse May be familial or non-familial.
Syndrome)
Occurs in 1-2.5% of the population (based on stricter echo criteria).
Female to male 2:1
Either or both leaflets may prolapsed.
Most common reason for MV surgery.
Myxomatous proliferation and cartilage formation can occur in the leaflets,
chordate tendineae, and/or annulus.
Dilated Cardiomyopathy Mechanism of MR due to both:
o Annular dilatation from ventricular enlargement.
o Papillary muscle displacement due to ventricular enlargement and
remodeling prevents adequate leaflet coaptation.
May occur in the setting of non-ischemic DCM or ischemic DCM (there is
often on overlap of mechanism for MR is the setting of previous
infarction).
Ischemic Ischemic MR is usually due to a prior infarction that has caused thinning
and dilation of the ventricle displaces the papillary muscle prevents
adequate coaptation of the leaflets.
Rarely, MR may develop acutely from papillary muscle rupture in the
setting of an MI (more commonly of the posteromedial papillary muscle).
Rheumatic May be pure MR or combined MR/MS.
Caused by thickening and/or calcification of the leaflets and chords.
Infective Endocarditis Usually caused by destruction of the leaflet tissue (i.e. perforation).
Acute causes Ruptured papillary muscle.
Ruptured chordae tendineae.
Infective endocarditis.

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 B. Mitral RegurgitationPathophysiology.

Acute Mitral Regurgitation.

Pathophysiology of Acute Mitral Regurgitation: LA, left atrium; LV, left ventricle; LVEDP, left ventricular end diastolic pressure;
LAP, left atrial pressure; SV, stroke volume; CO, cardiac output; EF, ejection fraction.

Chronic Mitral Regurgitation.

Pathophysiology of Chronic Mitral Regurgitation: LA, left atrium; LV, left ventricle; LVEDP, left ventricular end diastolic
pressure; LAP, left atrial pressure; SV, stroke volume; CO, cardiac output; EF, ejection fraction; pHTN, pulmonary hypertension.

C. Mitral RegurgitationNatural History.

The natural history and progression of MR depends significantly on the etiology, associated LV
dysfunction, and severity of MR at the time of diagnosis. Mitral valve prolapse (MVP) with little or no
MR most often has a benign prognosis and normal life expectancy; a minority of these patients will go
on to develop severe MR (10-15% of patients). The compensated asymptomatic phase of patients
with severe organic MR (mostly degenerative, but also rheumatic and endocarditis) with normal LV
function is variable but may last several years.

The natural history for ischemic MR and MR due to dilated cardiomyopathy (DCM) (these
populations overlap) is generally worse than for degenerative MR because of the associated
comorbidities in these patients, namely CAD and LV dysfunction with or without CHF. In both
ischemic MR and MR due to DCM, because MR begets MR the ventricles of these patients dilate
further and their CHF symptoms worsen.

D. Mitral RegurgitationHistory and Physical Exam.

Acute MR: The most prominent symptom is relatively rapid onset of significant SOB which may lead
quickly to respiratory failure. Symptoms of reduced forward flow may also be present depending on
the patients ability to compensate for the regurgitant volume.
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 Chronic MR: The etiology of the MR and the time at which the patient presents will influence the
symptoms reported. In degenerative MR that has gradually progressed, the patient may be
asymptomatic even when the MR is severe. As compensatory mechanisms begin to fail, patients may
note: dyspnea on exertion (may be due to pulmonary HTN and/or pulmonary edema perhaps
exacerbated by increased regurgitant volume during exercise), palpitations (from AF), fatigue, volume
overload and other symptoms of CHF. Patients with ischemic MR and MR due to DCM may report
similar symptoms; in general, these patients will tend to be more symptomatic because almost all of
them have associated LV dysfunction.

Physical Exam.
Acute MR Tachypnea with respiratory distress.
Tachycardia.
Systolic murmur, usually at the apexmay not be holosystolic and may be
absent.
S3 and/or early diastolic flow rumble may be present due to rapid early filling of LV
during diastole because of large regurgitant volume load in LA.
Apical impulse may be hyperdynamic.
Crackles on lung exam.
Relative hypotension (even shock).
Chronic MR Apical holosystolic murmur that radiates to the axilla.
The murmur may radiate to the anterior chest wall if the posterior leaflet is
prolapsed or toward the back if the anterior leaflet is prolapsed.
In MVP, there is a midsystolic click heard before the murmur.
May have irregularly irregular rhythm (AF).
Other signs of CHF (LE edema, CVP, crackles, etc.).

E. Mitral RegurgitationDiagnostic Testing.

A standard evaluation for a patient with mitral regurgitation includes a CXR, EKG, and transthoracic
echo. The echo provides an evaluation of the severity of the regurgitation, mechanism/etiology of the
MR, LA and/or LV enlargement, and LV function. Transesophageal echo (including 3D imaging) can
clarify the severity and mechanism of the MR. An exercise echo can assess whether there is
inducible pulmonary hypertension with exercise, which may indicate the need for surgery. Cardiac
cath can provide invasive hemodynamics and allows for a ventriculogram as another way to assess
MR severity, but this is usually not necessary.

F. Mitral RegurgitationTreatment.

Surgery: Mitral valve surgery for MR is most commonly performed in patients with degenerative
mitral valve disease. With advances in surgical technique (including more frequent and better repairs
instead of replacements) and lower operative mortality, there is a push in some centers to operate
earlier on patients with severe MR, even when they are still asymptomatic. Repair of the valve
(particularly for degenerative MR) is preferred over replacement. Operative mortality is ~2%, even
<1% in some centers for the best operative candidates. Pre-operative factors that increase operative
and/or post-operative mortality include worse NYHA functional class, LV dysfunction (EF<60%), age,
associated CAD, and atrial fibrillation.

Surgery for patients with ischemic MR and MR due to DCM is more controversial and potentially

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 more complex. In many clinical scenarios, it is not yet clear whether surgery improves functional
capacity or survival for these patients. Since the MR is largely due to a ventricular problem (a dilated
ventricle with displaced papillary muscles preventing coaptation of the mitral leaflets), an isolated
annuloplasty (tightening of the annulus) likely will not solve the problem. Various approaches are
currently under investigation and trials are underway to clarify the role for surgery in these patients.

Medical.

Acute: In the setting of severe acute MR, surgical treatment is indicated, often urgently or
emergently. While awaiting surgery, aggressive afterload reduction with IV nitroprusside or a balloon
pump can diminish the amount of MR and stabilize the patient by promoting forward flow and
reducing pulmonary edema. These patients are usually tachycardic, but attempts to slow their heart
rate should be avoided as they are often heart rate dependent for an adequate forward cardiac
output.

Chronic: Given that chronic MR may have different etiologies, the role of medical therapy may differ
in each setting. In the asymptomatic patient with normal LV function and chronic severe MR due to
leaflet prolapse, there is no generally accepted medical therapy. In the absence of systemic
hypertension there is no known indication for vasodilating drugs. Whether ACE inhibitors or -
blockers delay ventricular remodeling and the need for surgery is being investigated in prospective
studies. In contrast, patients with functional MR (ischemic MR and MR due to DCM) should be treated
as other patients with LV dysfunction. ACE inhibitors and -blockers are indicated and have been
shown to reduce mortality and the severity of MR. Some patients may also qualify for cardiac
resynchronization therapy, which has also been shown to reduce the severity of MR.

Percutaneous: An ever-expanding list of percutaneous approaches are being considered for the
treatment of MR, some of which are quite complex. Various approaches target each of the
interrelated components that can contribute to MR: annular dilatation, lack of leaflet coaptation, and
ventricular remodeling causing papillary muscle displacement. Currently, the most developed device
may be the placement of a mitral clip, which pinches the leaflets together in an attempt to enhance
coaptation. The clip is placed under TEE guidance by a catheter using a transseptal approach.

VI. Tricuspid Valve DiseaseTricuspid Stenosis

The tricuspid valve lies between the right atrium and ventricle. It has three cusps: anterior, posterior, and
septal. Primary tricuspid valve disease is relatively uncommon.

A. Tricuspid StenosisEtiology.

Rheumatic heart disease (most common cause).

Other causes include: carcinoid, congenital abnormalities, infective endocarditis (with bulky
vegetations), and right atrial mass causing functional obstruction.

B. Tricuspid StenosisHistory and Physical Exam.

Patients typically note symptoms consistent with right heart failure, including peripheral edema,
increased abdominal girth, fatigue, and palpitations (if there are associated arrhythmias). Physical
Exam may show: elevated JVP with a giant a wave and diminished rate of y descent, hepatomegaly
with a pulsatile liver, middiastolic murmur (low pitched) that increases with inspiration, opening snap,
or edema in lower extremities (often anasarca).
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 C. Tricuspid StenosisDiagnostic Testing.

Evaluation includes an EKG, CXR, and transthoracic echo. Additional testing may include
transesophageal echo (for a different look at the valve) and cardiac cath (for invasive
hemodynamics).

D. Tricuspid StenosisTreatment.

Medical treatment consists mostly of diuretic therapy for volume overload. Further medical
management depends on other comorbidities. The most common cause of tricuspid stenosis is
rheumatic valve disease, which inevitably will involve the mitral +/- aortic valves. Timing of surgical
intervention is usually driven by the severity of the left-sided valvular lesions. Tricuspid valvuloplasty
or TV replacement (preferably bioprosthetic) is indicated for severe TS. For congenital tricuspid
stenosis, there may be other associated abnormalities that influence management and therapeutic
decisions.

VII. Tricuspid Valve DiseaseTricuspid Regurgitation

Mild TR is found in up to 70% of normal patients; it is clinically unremarkable in most.

A. Tricuspid RegurgitationEtiology.

Secondary TR is caused by RV and annular dilatation and RV failure, most commonly secondary to
(1) LV failure +/- valvular disease, which causes pulmonary HTN, or (2) pulmonary HTN independent
of left-sided cardiac disease. Abnormalities of the tricuspid valve itself leading to TR can be caused
by:

Infective endocarditis, the most common anomaly and frequently associated with IV drug
abuse.

Carcinoid heart disease, commonly presenting as TR but also associated with tricuspid
stenosis.

Right-sided MI, causing papillary muscle dysfunction.

Trauma (i.e., from pacemaker/ICD lead or repeated RV biopsy after transplant).

Rheumatoid arthritis.

Rheumatic heart disease, indicating severe aortic or mitral valve disease.

Marfan syndrome.

Radiation-induced valvulitis.

B. Tricuspid RegurgitationHistory and Physical Exam.

Generally, TR is clinically insignificant and well tolerated. Patients may complain of fatigue, lower
extremity edema, increased abdominal girth, early satiety, or loss of appetite depending on the

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 degree of hepatic congestion, bowel wall edema, and ascites. Physical Exam may show: prominent
v waves in the JVP; systolic murmur (usually holosystolic) heard best at the left lower sternal border
that increases with inspiration (Carvallos sign); right-sided S3 or increased P2 intensity may be
present; pulsatile liver, hepatomegaly, lower extremity edema, and ascites may be present.

C. Tricuspid RegurgitationDiagnostic Testing,

Evaluation includes an EKG, CXR, and transthoracic echo. Additional testing may include
transesophageal echo (for a different look at the valve) and cardiac cath (for invasive
hemodynamics). Assessment of pulmonary pressures is an important part of the evaluation.

D. Tricuspid RegurgitationTreatment.

Medical therapy is limited to diuretics and afterload reduction to decrease the severity of right-
heart failure. Usually TR is secondary to some other processpHTN, left-sided heart failure or
valvular abnormalitythat is the primary focus of treatment. When surgery is indicated for TR, repair
with annuloplasty ring is preferred to replacement. If replacement is necessary, bioprosthetic valves
are preferred to mechanical valves due to the risk of thrombosis (lower pressure on the right side of
the heart predisposes to thrombosis of mechanical valves). Increasingly evidence is suggesting the
value of a TV annuloplasty for secondary TR (particularly with a dilated annulus) at the time of mitral
valve surgery, even if the TR is not severe.

VIII. Pulmonic Valve Disease

Clinically significant pulmonic valve disease is usually congenital in etiology. Pulmonary regurgitation due
to pHTN is common, but usually not more than mild and rarely clinically significant.

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Case Study

Heart Failure Case Studies

10/18/2013

Keith Mankowitz, M.D.

Heart Failure Case Studies

Case 1
A 55-year-old businessman presents to the office complaining of increasing fatigue and shortness of
breath that have evolved over the last two years. He has noted increasing symptoms recently and he is
more comfortable sleeping on three pillows. Several times a week he awakens at 1am with shortness of
breath. He denies any chest pain or pleuritic pain. His only medications are a diuretic and a beta-blocker
for hypertension of 10 years duration. He smokes two packs of cigarettes per day. He drinks whiskey
socially and admits to three martinis at lunch every day. There is no family history of heart disease.

On examination his heart rate is 105/min, respirations 20/min, and BP 150/90 mmHg. There are
grade II hypertensive retinopathy changes present; his JVP is 12cm; his lungs reveal bilateral basal
crackles; his carotid upstrokes are normal. The apical impulse is laterally displaced and sustained. S1 and
S2 are normal. There are a loud S4 and a moderately loud S3. There is a grade 2/6 holosystolic murmur
that radiates to the axilla. There is bilateral ankle pitting edema. The echocardiogram demonstrates
biventricular dilatation, left ventricular hypertrophy and left atrial enlargement of moderate severity with a
moderate degree of global ventricular dysfunction (ejection fraction estimated at 30%); the
electrocardiogram demonstrates left ventricular hypertrophy.

Based on this information:

1. Discuss at least three possible etiologies responsible for the clinical picture of congestive heart
failure. Discuss the possible evolution of symptoms on the interrelationship between hypertrophy,
diastolic function and systolic function of the left ventricle.

2. How would you characterize the systemic vascular resistance in this patient at this time? What
are the neurohormonal interactions mediating this response and what are the implications for
pharmacologic intervention?

3. How do patients with dilated hearts maintain their cardiac output at near normal levels? Using the
Frank-Starling concept, describe the potential effects of diuretics, vasodilators and positive
inotropic agents in this patient.

4. What is the level of norepinephrine likely to be in the serum and in myocardium (if measured by
biopsy, only for research purposes) in patients like this?

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Case 2
A 58-year-old African American was in his usual state of health until six weeks ago when he began to
develop dyspnea on exertion. Over the ensuing four weeks, he noted progressive fatigue, swelling of his
lower extremities and increasing abdominal girth. His exercise tolerance decreased until he could no
longer walk a block. He denied chest pain and palpitations. He reported orthopnea, paroxysmal nocturnal
dyspnea and nocturia. He denied fever and weight loss.

Physical exam revealed a man in mild respiratory distress. The heart rate was 80/min and regular,
and his BP was 120/70. Carotid upstroke was normal. Jugular venous pressure was 14-cm water and
there was a Kussmauls sign. Lungs revealed dullness to percussion with no air entry at both bases.
Cardiac exam showed a nondisplaced point of maximal intensity with a normal S1 and S2. There was a
soft S3 and a murmur of mitral and tricuspid regurgitation. There was no rub. The abdomen was distended
with shifting dullness and an enlarged liver (18-cm). There was extensive pitting edema from the ankles to
the mid thighs. ECG showed sinus rhythm with low voltage. Chest x-ray showed mild cardiomegaly and
bilateral pleural effusions. Admission labs were normal except for abnormal liver function tests.

An echocardiogram revealed normal LV systolic function, thickened LV walls and moderate tricuspid
and mitral regurgitation.

Cardiac catheterization revealed a pulmonary artery pressure of 60/20, right ventricular pressure of
60/22. LV pressure of 123/32 and mean right atrial pressure of 22mmHg. The left and right ventricular
diastolic pressures exhibited a square root (dip and plateau) pattern. The coronary arteries were normal.

1. Discuss the possible explanations for the clinical picture of congestive heart failure.

2. Discuss the differences between constrictive pericarditis and restrictive cardiomyopathy.

3. Discuss the echocardiographic and hemodynamic findings.

4. What is the most likely diagnosis and how do you confirm this?

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Lecture Notes

Congenital Heart Disease

10/28/2013

Caroline Kim Lee, M.D.

Congenital Heart Disease

Objectives:
1. Describe the changes in the circulatory system that occur with the transition from fetal to extrauterine
life (transitional circulation).

2. Understand the factors that determine the pathophysiology of congenital heart defects.

3. Understand the effects of age and anatomy on the pathophysiology of left-to-right (systemic-to-
pulmonary) shunts, and the pulmonary vascular disease that can develop with a large unrepaired left-
to-right heart defect.

4. Understand the pathophysiology of obstructive heart lesions.

5. Understand the different pathophysiologic mechanisms associated with cyanosis and types of
cyanotic congenital heart disease.

6. Describe extracardiac manifestations of cyanotic congenital heart disease.

7. Understand long-term palliation for single ventricle lesions"Fontan physiology"and complications

that may develop.

Reference Text:

Lilly LS, Pathophysiology of Heart Disease: a collaborative project of medical students and faculty. 5th
ed. Baltimore: Wolters Kluwer, Lippincott, Williams & Wilkins; 2011:361-385.

I. Overview
Congenital heart defects are the most common birth defect, occurring in ~8/1000 live births. Defects
range from minor ones that are not clinically or hemodynamically significant, to severe life-threatening
abnormalities that require immediate intervention after birth. The diagnosis and treatment of congenital
heart disease represent some of the major advances in medicine and surgery in the last 50 years. Prior to
1950, most children with major congenital heart anomalies died in infancy or childhood. Currently, survival
into adulthood is possible with virtually every type of congenital heart defect. Many of the major advances
in cardiovascular medicine, such as cardiopulmonary bypass and pacemakers were initially developed for
the treatment of congenital heart defects. This success is reflected in the development of a "new" cardiac
patientthe adult with congenital heart disease. Currently, there are more adults in the United States
carrying a diagnosis of congenital heart disease than children.

Congenital malformations of the heart cause most of their morbidity from connections between the
pulmonary and systemic circulations, or shunts. In the normal heart, the amount of blood flow to the
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lungs is equal to the amount of blood flow to the body (systemic flow). With shunts, the systemic blood
flow is different than the pulmonary blood flow. Blood flow may be from the systemic to pulmonary
circulation, left-to-right shunts, or from the pulmonary to systemic circulation, right-to-left shunts
(cyanotic heart defects). Quantification of shunt flow is accomplished through the measurement of oxygen
(O2) saturations in the different cardiac chambers and great vessels during cardiac catheterization. The
magnitude of shunting is expressed as the ratio of pulmonary blood flow to systemic blood flow, or a
Qp/Qs ratio. In normal hearts the Qp/Qs ratio = 1. Left-to-right shunt lesions have Qp/Qs ratios > 1.
Right-to-left shunt lesions often (but not always) have Qp/Qs ratios < 1.

Additionally, other congenital cardiac malformations include obstructive lesions to right or left
ventricular inflow or outflow, abnormal drainage or connections of vessels, hypoplasia of one ventricle
producing single ventricle lesions, and complex lesions which combine several or all these
abnormalities.

For the purposes of this lecture, we will discuss congenital heart defects using four main
pathophysiologic categories: left-to-right shunts; obstructive lesions; cyanotic lesions (right-to-
left shunts); and single ventricle lesions. (Refer to Fig. 1-3 at end of text)

II. Fetal and Transitional Circulation

There are several important differences between the fetal and post-natal circulations. In utero, the ductus
venosus, foramen ovale, and ductus arteriosus are important shunts that are not needed after birth
and typically close within hours to days after birth (see Figure 16.10 in Lilly text). In utero pulmonary
vascular resistance is high, pulmonary blood flow is extremely limited, and the fetus receives oxygenation
from the placenta. This oxygenated blood from the placenta enters the fetus via the umblicial vein, and
then approximately half of this blood is shunted through the ductus venosus into the IVC. This blood is
then shunted from the right atrium to the left atrium across the foramen ovale. This oxygen-rich blood
enters the left heart and will supply the coronary arteries and fetal brain. Meanwhile, SVC blood and the
remainder of the IVC blood enter the right atrium and right ventricle, and because of the high resistance in
the fetal lungs, most of the blood is shunted from the right ventricle through the ductus arteriosus to the
descending aorta. Importantly, fetuses with significant congenital heart defects can survive and grow in
utero while the foramen ovale and ductus arteriosus are patent, but after birth these babies can develop
severe cardiovascular compromise once these structures close. The neonatal ductus can be
pharmacologically manipulated to stay open by intravenous infusion of prostaglandin E1 and thereby
palliate lesions that are associated with severe obstruction to systemic or pulmonary blood flow until
surgery can be undertaken.

Transitional circulation refers to the physiologic changes that occur in the heart and lungs once a
baby is born. Separation from the placenta results in an increase in systemic vascular resistance and
expansion of the lungs at birth leads to immediate pulmonary vasodilation and increases in pulmonary
blood flow. The increase in pulmonary flow is associated with a rapid (days) decrease in pulmonary
vascular resistance. As a result, mean pulmonary artery pressure is approximately 60 mmHg
immediately after birth and drops to a mean of 15-20 mmHg in a few days. This decrease in pulmonary
vascular resistance is associated with the development of symptoms related to many congenital heart
defects.

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III. Determinants of Pathophysiology in Congenital Heart Defects
There are many factors that determine the pathophysiology and thus the signs and symptoms of a
particular heart defect. These include:

Size of the septal defect or arterial shunt.

o E.g., large ventricular septal defect; small patent ductus arteriosus.

Severity of the valve or vessel abnormality.

o E.g., mild aortic stenosis; severe mitral regurgitation; pulmonary atresia.

Abnormal connections between chambers and/or vessels.

o E.g., transposition of the great arteries; anomalous pulmonary venous return to the right
atrium.

Hypoplasia of a ventricle with only one adequately functioning ventricle.

o E.g., tricuspid atresia with hypoplastic right ventricle; hypoplastic left heart syndrome.

Age of the patient.

Systemic and pulmonary vascular resistances.

Systemic vascular resistance (SVR) is an index of arteriolar compliance throughout the body,
excluding the lungs:

Mean arterial pressure Right atrial pressure

Cardiac output

Pulmonary vascular resistance (PVR) is an index of arteriolar compliance throughout the lungs:

Pulmonary artery pressure Left atrial pressure

Cardiac output

As discussed previously, PVR in utero is high and then after birth decreases substantially. PVR is
usually 5-6x lower than SVR.

IV. Pathophysiology of Left-to-Right Shunts (Figure 1)

A. Overview. Left-to-right shunt lesions are characterized by a communication between the left
(systemic) and right (pulmonary) sided heart chambers. These include atrial septal defects,
ventricular septal defects, patent ductus arteriosus, and complete atrioventricular canal.
As a group, they comprise about half of all heart defects. Oxygenated blood from the left side of
the heart mixes with dexoygenated blood in the right side of the heart and circulates through the
lungs again, resulting in increased myocardial work, volume overload on the heart, and increased
pulmonary vascular congestion. Thus, chest x-rays with large left-to-right shunt lesions typically
show cardiomegaly with increased pulmonary vascularity.

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 B. Size of the Communication. Very small left-to-right shunts may be associated with loud
murmurs, but no cardiac symptoms. Some lesions that are large in infancy and associated with
large left-to-right shunts have the potential to decrease in size with age and even close
altogether. Thus, one of the reasons that not all large communications are closed at the time of
diagnosis is that some of them may spontaneously close or decrease in size to the point surgical
closure is not required.

C. Pulmonary-Systemic Resistance Ratio. The magnitude of the left-to-right shunt also depends
on the ratio of pulmonary-to-systemic vascular resistance. As PVR is usually lower than SVR,
large, unrestrictive lesions will flood the lungs with blood and create large cardiac volume
overloads. Cardiac dilatation and hypertrophy occur, ultimately leading to congestive heart failure
in the face of a normal cardiac output (high output heart failure). Increased pulmonary blood flow
leads to increased pulmonary artery pressures (pulmonary hypertension), and increased
pulmonary congestion may evolve into pulmonary edema.

D. Age of the Patient. At birth, the PVR is relatively high and the normal rapid drop in the first days
after birth is delayed for weeks in patients with large left-to-right shunts. Thus, in the first days
after birth there is little left-to-right blood flow across a large lesion. There may be no murmur and
no symptoms. As the PVR drops over the next 2-12 weeks, the amount of left-to-right flow will
increase, a murmur may appear, and signs and symptoms of pulmonary overcirculation will
develop (tachypnea, poor feeding, poor weight gain).

With time, the marked increase in pulmonary blood flow from large left-to-right shunts will
lead to irreversible structural damage to the pulmonary microvasculature and the large pulmonary
branch vessels. This results in a progressive rise in PVR which will lead to a decrease in
pulmonary blood flow, decreased left ventricular volume overload and less symptoms of
congestive heart failure. Eventually, the PVR may increase to the point where left-to-right
(systemic-to-pulmonary) shunts reverse to right-to-left (pulmonary-to-systemic) shunts and the
patient will become cyanotic, a condition termed Eisenmenger syndrome. By this time, the
increase in PVR cannot be reversed by repair of the defect, and fatal right heart failure will
eventually occur which may only be palliated by heart-lung transplantation.

E. Location of the Shunt. Congenital cardiac defects of the same size that are associated with left-
to-right shunts will differ in their pathophysiology depending on their location within the
cardiovascular system.

Risk of
Cardiac volume Intensity of the Appearance of pulmonary
Location overload murmur symptoms vascular disease
Pre-Tricuspid valve Right-sided Soft, easily missed In adulthood Low
(Atrial Septal
Defect)
Post-Tricuspid Left-sided Loud, can be soft In infancy High
valve (Ventricular with high PVR
Septal Defect or
Patent Ductus
Arteriosus)

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V. Pathophysiology of Obstructive Lesions (Figure 2)
Obstruction to ventricular outflow may occur at the subvalvular, valvular, and supravalvular levels.
Valvular stenosis has previously been discussed in a lecture in this course. Pulmonary stenosis may
occur in isolation, or as one component of a heart defect such as in Tetralogy of Fallot. Aortic stenosis
occurs most commonly in the setting of a bicuspid aortic valve. Valvular stenosis results from thickened,
abnormal valve leaflets that do not open completely, causing some degree of obstruction to flow. This
results in pressure overload on the respective ventricle, ventricular hypertrophy, and ultimately
ventricular failure. Valvular stenoses are typically first addressed by balloon dilation in the cardiac
catheterization laboratory, whereas subvalvular and supravalvular lesions require surgical repair.

Coarctation of the aorta is a narrowing of the descending aorta just distal to the left subclavian artery,
the last head/neck vessel off the aorta. Because of the narrowing, there is upper extremity hypertension
(proximal to obstruction), and there is lower blood pressure in the legs and decreased or absent lower
extremity pulses due to obstruction to descending aorta blood flow. Depending on the age of the patient
and severity of the coarctation, symptoms and exam findings may range from minimal in an older child
with mild coarctation, to cardiogenic shock in a neonate with severe coarctation that manifests once the
ductus arteriosus closes (in this setting, the ductus arteriosus allowed blood flow to get to the descending
aorta and bypass the coarctation).

Less commonly, congenital stenosis may occur at the tricuspid or mitral valve, often with resultant
hypoplasia of the associated ventricle, due to decreased inflow into that ventricle during development.
Obstruction may also rarely occur at the level of the pulmonary veins, either individually or in the setting
of total anomalous drainage of the pulmonary veins.

VI. Pathophysiology of Cyanotic (Right-to-Left) Shunts (Figure 3)

Cyanosis is a physical exam finding that occurs when there is a bluish color/tinge to the skin or mucous
membranes. Cyanosis generally occurs when there is decreased arterial O2 saturation of Hgb < 95%.
Arterial oxygen desaturation leads to the clinical recognition of cyanosis: > 5 gm/dl of blood of reduced
hemoglobin in adults and > 3 gm/dl of reduced hemoglobin in infants. Therefore, clinical detection of
cyanosis is dependent on both the magnitude of arterial blood desaturation and the blood hemoglobin
level. For example, when the Hgb is 20 gm/dl, cyanosis is detectable at an arterial O2 saturation of 85%,
but with a Hgb of 9 gm/dl it is detected with an arterial O2 saturation of 67%. Cyanosis occurs with
pulmonary disorders, hemoglobinopathies, and congenital heart disease with right-to-left shunts.

Cyanotic congenital heart defects have right-to-left shunting at the level of the atria, ventricles,
and/or great vessels. With a right-to-left shunt, desaturated ("blue") blood from the systemic venous side
bypasses the lungs and does not get oxygenated, gets mixed with oxygenated ("red") blood returning
from the lungs to the pulmonary venous side, and this mixed ("purple") blood is then sent to the body.

Cyanosis from right-to-left shunts, unlike cyanosis due to pulmonary disorders, is only minimally
improved by breathing 100% oxygen instead of room air (21% oxygen). This is because hemoglobin in
the shunted blood flow does not cross the pulmonary bed so it is not exposed to atmospheric oxygen, and
thus remains desaturated when it is mixed with the oxygenated pulmonary venous effluent and ejected
into the aorta. The blood exposed to the pulmonary vascular bed equilibrated with room air is already
100% saturated. Thus, increasing atmospheric oxygen will only increase the amount of O2 dissolved in
the blood. Dissolved oxygen is what is measured when one obtains a blood partial pressure of oxygen,
the "pO2" measure on an arterial blood gas. Thus, after equilibration with room air, there is 0.3 cc of
dissolved O2/100 cc of blood leading to a pO2 of 100 torr. With breathing 100% O2, the pO2 increases to
600 torr as dissolved O2 increases to 1.8 cc/100 cc of blood. However, the volume of blood being shunted
right-to-left is not exposed to the enriched O2 atmosphere, thus its hemoglobin does not increase its
saturation and the amount of oxygen dissolved in that blood volume remains the same, diminishing the
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benefits of supplemental oxygen.

The degree of tissue hypoxia is dependent on the oxygen delivery to the tissues. Tissue oxygen
delivery is dependent upon three factors: arterial oxygen saturation; systemic cardiac output; and level of
hemoglobin in the blood.

There are numerous anatomical congenital malformations that are associated with right-to-left shunts
and cyanosis. However, these anatomically complex malformations can be organized into three distinct
pathophysiological groups: (1) anatomic obstruction to pulmonary blood flow with a right-to-left
shunt; (2) complete intracardiac mixing of systemic and pulmonary circulations; and (3) parallel
systemic and pulmonary circulations.

Pulmonary
Cyanosis dependent vascular
Pathophysiological Group Presenting symptoms upon disease
Obstruction to pulmonary blood Cyanosis Degree of anatomic Low risk
flow with right-to-left shunt pulmonary obstruction
(e.g.,Tetralogy of Fallot)
Complete intracardiac mixing of Congestive Heart Failure Pulmonary vascular High risk
systemic and pulmonary resistance
circulations (e.g.,Truncus
Arteriosus)
Parallel systemic and pulmonary Cyanosis Degree of arterial- High risk
circulations (e.g., Transposition of venous mixing
the Great Vessels)

A. Chronic cyanosis caused by right-to-left shunting is associated with a number of non-cardiac

manifestations. These include:

1. Hematologic: Polycythemia will compensate for decreased arterial oxygen saturations

and/or decreased cardiac output to try to normalize tissue oxygen delivery. Thus, patients
with cyanotic congenital heart disease who exhibit "normal" blood hemoglobin/hematocrit
may actually be anemic for that particular lesion and are more sensitive to iron deficiency
anemia than non-cyanotic patients. Polycythemia is associated with blood hyperviscosity.
Thrombocytopenia and coagulopathies may also occur.

2. Central nervous system: Cyanotic congenital heart disease is one of the most common
causes of strokes in children. Strokes may occur from embolic phenomena and the right-to-
left shunt, but more often occur in the region of the brain at most risk for hypoxia in
association with anemia. An increased risk for brain abscess also is associated with
cyanotic heart disease.

3. Orthopedic: As in chronic lung disease, cyanotic heart disease is associated with

osteoarthropathy, or clubbing, of the fingertips and toes.

VI. Long-term Palliation of Hearts with One Functional Ventricle (Fontan

Physiology)
Congenital heart defects resulting in a functional single ventricle include those with hypoplasia of the right
or left ventricle, severe stenosis or atresia of an atrioventricular or semilunar valve (e.g., tricuspid atresia,
hypoplastic left heart syndrome with mitral and aortic atresia). In this situation, the pulmonary and
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systemic circulations are not in their normal series connection, but are in a parallel circuit; i.e., the single
ventricle pumps both to the systemic and pulmonary circulations. Blood from both the systemic veins and
pulmonary veins then return to the single ventricle, and these patients are cyanotic because of this
intracardiac mixing. This results in ventricular volume overload of the one pump. Average ventricular
volumes of single ventricles range from 110-140% of a normal left or right ventricle.

Initial surgical or cardiac catheterization-based palliation of the infant with a functional single ventricle
involves ensuring unobstructed systemic blood flow to the aorta and providing sufficient
pulmonary blood flow (augmenting or reducing as necessary) to achieve a balanced circulation.

In the early 1970s, cardiovascular surgeons applied a new concept of placing the pulmonary and
systemic circulation back in a series connection in the single ventricle patient. The series connection was
accomplished by connecting the systemic venous return (superior and inferior vena cavae) directly
to the pulmonary arteries without a ventricular pump. With what has been ultimately termed "Fontan
physiology," named after the French surgeon who pioneered the procedure, systemic venous pressure
becomes markedly elevated and drives the pulmonary flow. This circulatory system can only succeed if
(1) the pulmonary vascular resistance is low to accept the passive systemic venous flow; and (2) the left
atrial ("downstream") pressure is low, which requires good function of the systemic ventricular system of
atrioventricular and semilunar valves, ventricular pump, and aortic arch. If successful, Fontan physiology
leads to resolution of systemic hypoxemia and ventricular volume overload. Presently, achieving a Fontan
circulation is done in stages, with a bidirectional Glenn procedure (SVC to right pulmonary artery
anastamosis) performed at age 4-6 months, and then a Fontan procedure (baffling of IVC to pulmonary
arteries) at around age 3 years.

As flow from the vena cavae through the lungs to the ventricle is entirely passive, any obstruction to
flow, which can potentially occur at a number of levels, can lead to diminished cardiovascular
performance. A number of alterations in cardiovascular function can also be detected at rest in single
ventricle patients after the Fontan procedure including: (1) abnormalities of diastolic function;
(2) decreased ejection fraction and other measures of systolic funciton; (3) elevations of ventricular
afterload as the one ventricle pumps to both the systemic and pulmonary circulations sequentially; (4) a
limited preload reserve; and (5) chronotropic deficiencies frequently occur with sinus node dysfunction
and an abnormal heart rate response to exercise.

While some patients after the Fontan procedure have normal exercise tolerance, most patients have
mild-moderate exercise impairment. Predicted maximal oxygen consumption on average is only 55-65%
of normal. Cardiac arrhythmias requiring anti-arrhythmic medications and/or a pacemaker occur in as
many as 20% of the patients 5 years after operation. Other serious complications, such as systemic and
pulmonary thromboembolism and protein-losing enteropathy (loss of protein through the gut leading
to hypoalbuminemia, hypogammaglobulinemia, and fluid retention), occur in approximately 10% of long-
term Fontan survivors. Heart failure of the single ventricle may occur requiring consideration for heart
transplantation. These relatively disappointing long-term results in the single ventricle patient have led to
the Fontan procedure being considered more of a palliation for the single ventricle patient as opposed to
a reparative or curative procedure.

While the long-term morbidity of single ventricle patients is sobering, the progress made in the
surgical palliation of these patients should not be understated. The relative success in combining initial
stabilizing surgical procedures for infants with eventual Fontan palliation has dramatically improved the
short-term outlook for infants born with a single ventricle. As long-term survival can now be reasonably
anticipated for single ventricle patients to adulthood, ongoing efforts are focusing on modification and
revision of treatment strategies to optimize and extend survival of these patients into adulthood with the
best possible functional status and to attempt to decrease the risk of disability and heart failure with
increasing age.

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 Acyanotic (LR) Shunts

Figure 1. Congenital Defects Causing Left-to-Right Shunting of Blood.

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 Obstructive Lesions

Interrupted Aortic Arch,

type A

Figure 2. Congenital Heart Defects Causing Obstruction to Blood Flow.

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 Cyanotic Congenital Heart Disease

Lesions with obstructive Lesions with abnormal

Parallel Circulation
pulmonary blood flow with an intracardiac mixing
intracardiac communication Transposition of the
Total anomalous Great Arteries
Tetralogyof Fallot pulmonary venous
PulmonaryAtresia(+/- VSD) connection

TricuspidAtresia TruncusArteriosus

EbsteinsAnomaly HypoplasticLeft Heart

Syndrome

Figure 3. Congenital Heart Defects Causing Cyanosis.

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Case Study

Valvular Heart Disease Case Studies

10/28/2013

Alan Zajarias, M.D.

Brian Lindman, M.D.

Valvular Heart Disease Case Studies

Patient 1
Having been previously fairly healthy with only mild asthma, he presented on 7/6/06 complaining of 6
days of increasing wheezing and dyspnea. He had no chest pain and was a non-smoker. He refilled an
old prescription for albuterol (an inhaler to dilate the bronchioles useful in asthma) and it improved his
breathing somewhat. On exam at that time he had no wheezes and seemed comfortable. Pulmonary
function tests showed FEV1 (amount of air expired in one second, a measure of airway obstruction) of
50% predicted. After using a bronchodilator, his FEV1 improved to 60% predicted. He was placed on
prednisone (to further relieve the inflammation in the bronchioles and improve expiratory flow).

One week later, he was seen in clinic and still complained of mild dyspnea.

ER Visit-3 weeks after initial presentation:

Complained of increased dyspnea not improving with antibiotics (given because an outpatient
CXR suggested pneumonia), Albuterol, and Prednisone.

Chest X-Ray (CXR) Diffuse interstitial edema in both lungs suggestive of fluid overload.

Chest CT (computed tomography) Non-specific scattered ground glass opacities (mild

pulmonary edema).

o Possible Right Lower Lobe Pulmonary Embolus (later interpreted as artifact).

Physical exam in hospital:

Vitals: HR 60 BP 140/86 RR 16 O2 sat 97%.

Physical exam was notable for:

o Poor dentition.

o 3/6 holosystolic blowing murmur at the apex axilla-new-.

o Few bibasilar crackles.

o No peripheral edema.

EKG: Normal Sinus Rhythm, non-specific ST/T changes

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The patient comes to ER with diagnosis of asthma to explain the shortness of breath:

1. How does the Chest x-ray confirm or rule out this diagnosis.

2. How does the physical exam help you?

3. What does the murmur suggest?

4. What other questions would you ask the examiner about the cardiac exam

5. What does the murmur suggest?

6. What is the natural history of this situation?

6 month follow-up:

Recurrent dyspnea with exercise.

1. Why does the pulmonary pressure rise with exercise?

2. Why is he so short of breath with exertion?

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Patient 2
She is from Micronesia and immigrated to the U.S. 7 years ago. Now 6 months pregnant, she presents
with worsening SOB over the last 3 months. During the early part of her pregnancy, she noted no
exercise limitations. Currently she gets SOB when walking across the room. She is sleeping on 2 pillows
and sometimes is awakened suddenly with SOB requiring her to sit up on the side of the bed to catch her
breath (paroxysmal nocturnal dyspnea).

1. What is happening that makes it difficult to breathe lying down but better sitting up?

Physical exam:

Vitals: HR 66 BP 105/52 RR 20 O2 sat 95%.

o Cardiac: Regular rhythm.

Loud P2, early opening snap, 1/6 low-pitched diastolic murmur at apex, no systolic murmur.

Lungs: Bibasilar crackles.

Ext: No peripheral edema.

2. If the examiner had commented on the first sound, what might he have said?

3. What is the significance of no peripheral edema?"

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Patient 3
41 yo male with known bicuspid AV and strep viridans endocarditis treated successfully at age 32 feels
well and is quite active. He runs 15 miles per week.

The endocarditis led to significant aortic regurgitation (AR).

As his physician, your job is to follow him over time and recommend valve surgery at the right time if it
becomes necessary.

1. How will the heart remodel over time and adapt to aortic regurgitation? What other abnormalities
might be associated with a bicuspid aortic valve?

2. What do you want to avoid by waiting too long for valve replacement?

3. What do you lose operating too early?

4. How would you follow this patient to determine the right timing of valve surgery?

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Patient 4
78-year-old female with aortic stenosis.

In 1999, she underwent Coronary Artery Bypass Grafting (CABG) to the four major vessels which
was complicated post-operatively by mediastinitis requiring resection of most of her sternum.

At the time, her aortic valve was sclerotic but not stenotic.

Question: Why didnt the surgeon do something about the aortic valve when he performed the coronary
artery bypass?

Follow up 7 years later:

She develops worsening dyspnea.

Echo 11/06.

o EF 55%.

o Severe AS.

AVA 0.7 cm2 Mean AV gradient 50, Peak gradient 80.

Question: What are the options for management?

Not an operative candidate offered palliative balloon aortic valvuloplasty.

o Aortic Valve Area reduced from 0.8 cm2 1.0 cm2 (normal is >1.5 cm2).

o Aortic Valve pressure gradient reduced from 70mmHg 42mmHg.

She felt better for several months and was able to walk on a treadmill for 10 minutes at a time.

10 months after valvuloplasty, she presented to clinic SOB and fatigued after walking a few steps.
She had mild chest discomfort with exertion that was relieved with rest.

10 months after valvoplasty: exam:

Vitals: HR 80 BP 97/63 RR 16.

Delayed carotid upstrokes bilaterally.

Cardiac: normal rate, regular rhythm, 4/6 harsh crescendo-decrescendo late peaking systolic
murmur at the USB with radiation to both carotids and a musical systolic murmur in the apex, S2
inaudible.

Lungs: clear.

Extremities: 1+ edema bilaterally.

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ECHO EXAM:

Severe calcific Aortic Stenosis.

o Aortic Valve Area = 0.6cm2.

o Mean gradient 43mmHg.

o Peak gradient 71mmHg.

Moderate LV systolic dysfunction: EF 35%.

Diastolic dysfunction.

LVH (Left ventricular hypertrophy).

(PARTNERS STUDY basically a study of the use of percutaneously inserted cardiac valve on a stent)

No complications from the procedure.

6 months later, she is feeling much better.

o Walking 10 minutes on a treadmill 3 times a week.

o NYHA class II.

Echo shows:

o Mean gradient 10mmHg (minimal).

o No Aortic Regurgitation.

o Normal LV systolic function.

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Case Study

Congenital Heart Disease Case Studies

10/29/2013

Caroline Kim Lee, M.D.

Congenital Heart Disease Case Studies

Case 1
A heart murmur is heard in a two-week-old term baby boy that was not heard at his newborn examination.
A chest x-ray shows an enlarged heart and prominence of the pulmonary vessels. An echocardiogram is
performed.

A. What is the most likely cause of the murmur? Why was it not heard at his initial exam?

B. What is the significance of the chest x-ray findings?

C. What are the management options at this time?

The infant is hospitalized four weeks later with tachypnea and poor feeding. The infant is started upon
diuretics with improvement in symptoms. The infant seems to be stable and the echocardiogram is
repeated at six months of age.

A. Why did the baby's symptoms develop at six weeks or age?

Surgery is recommended, but the parents refuse as they feel the child has improved. They move out
of the area, but return when the child is five years of age because a chest x-ray done at an emergency
room visit still shows an enlarged heart. The parents tells you they stopped the child's medicines around 9
months of age and the child has not had a recurrence of the tachypnea. You note the murmur on
examination as well as a prominent, single second heart sound, and mild clubbing of the fingers.

A. What is the most likely explanation for the present clinical picture? Describe the hemodynamic
findings of the present state in terms of ventricular and pulmonary artery pressures; pulmonary
and systemic flow; and vascular resistance.

B. What is the natural history of this problem?

C. What diagnostic and therapeutic procedures would you recommend at this time?

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Case 2
You are examining a baby in the newborn nursery that was born last night. Mother had limited prenatal
care, but no concerns were noted. Delivery was at full term, vaginal and without complications. An
attempt at feeding by bottle earlier that morning had gone reasonably well. On exam, you notice the baby
appears pink, active and alert. His breathing, while comfortable, appears fast, ~70-80 breaths per minute.
Lungs are clear to auscultation. On cardiac exam, he has a regular rate and rhythm. S2 is perhaps slightly
accentuated and difficult to determine whether normally split given the rapid respiratory rate. You note no
hepatomegaly and good peripheral pulses. Concerned about the rapid breathing, you order a complete
blood count and chest x-ray. The complete blood count is unremarkable. Chest x-ray shows a normal
heart size and clear lung fields. You ask for a pulse oximetry reading. On room air, on the foot, and
pulse oximeter reads 91%.

A. Is the pulse oximeter reading significant?

B. Is there anything wrong with the baby? If so, what are the diagnostic possibilities?

C. Are there any other tests that could be performed?

An echocardiogram is performed and demonstrates hypoplastic left heart syndrome shown

schematically below:

A. What is the most immediate problem with this anatomy?

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 B. What are the therapeutic options in this situation?

The parents select you for their pediatrician. You follow the child at regular intervals. At his 5-year-old
check up, the parents ask you what the future holds.

A. Has the childs heart lesion been repaired?

B. What are the potential medical problems the child will face in the future?

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