THE PICTURE AND REALITY OF HEART FAILURE

The picture represents what it represents, independently of its truth or falsehood,

through the form of representation.
What the picture represents is its sense.
In the agreement or disagreement of its sense with reality, its truth or falsity consists.
Ludwig Wittgenstein, Tractatus Logico-Philosophicus, 1922.
OVERVIEW: This case models the natural history of heart failure, highlighting pathophysiology, clinical
manifestations, prognosis, and therapy. Students should attempt to answer the questions relating to the numbered
paragraphs (italicized) before the conference. Answers provided in the "Guide for Instructors" will be available
after the conference.

OBJECTIVES:
1. Provide a description of the salient clinical features of heart failure
2. Provide a conceptual link between this clinical scenario and the underlying pathophysiological, biochemical
and molecular mechanisms.
3. Provide an historically based overview of new and emerging therapeutic strategies to improve symptoms and
quality of life, prolong survival, and minimize costs in managing the patient with heart failure.

CLINICAL DESCRIPTION
1.1: It is January, 1990. You receive a call from the Emergency Room of your local hospital informing you that
your patient, Mr. Gute Herz, was brought in by ambulance suffering from shortness of breath. You have cared for
Mr. Herz, a 54-year-old bookkeeper, for more than 15 years, during which time he had been in good health. He
normally walks briskly for about 2 miles several times each week, and has no risk factors for coronary disease. You
proceed to the Emergency Room and find Mr. Herz sitting up, wearing an oxygen mask, breathing with some
difficulty. The ER doctor tells you he had been more severely dyspneic when he arrived but that it was not
necessary to intubate him; however, because of the severity of his symptoms a Swan-Ganz catheter had been
passed into his pulmonary artery - we will review these data later.
What caused Mr. Herz dyspnea? Why is he sitting up? What is the value of oxygen?
Dyspnea:
Cardiac causes:
o Heart failure Fluid in lungs (see mechanism as MI)
o MI Left ventricle has Compliance = (Volume/Pressure)
Left ventricular end diastolic volume
Pulmonary capillary pressure
Fluid in air space
PO2
Pulmonary cause:
o Asthma
o Emphyzema
Mr. Herz dyspnea can be explained by fluid transudate in the pulmonary interstitium, which increases lung
stiffness and causes arterial hypoxia.
- The stiff lungs increase the work of breathing.
- Arterial hypoxia occurs because the low solubility of O 2 in aqueous solutions impairs oxygen
diffusion from the alveoli to the blood in the pulmonary capillaries.
Sitting up allows gravity to pool blood in the lower body, which reduces venous return to the right heart; according
to Starlings Law, this decreases the amount of blood pumped into Mr. Herz already engorged lungs. Increasing the
O2 content of the inspired air, by increasing alveolar pO2 can be expected to raise arterial pO2.

1.2: Mr. Herz gives you the following history: For the past 2-3 months he had noted the gradual onset of malaise
when he took long walks. About 4-6 weeks ago he noted fatigue and shortness of breath on exercise that gradually
worsened. For the past 7-10 days he had become dyspneic even during mild exertion. About 3 weeks ago he had
reduced his two-mile walks to one mile, then to a half mile, and a week ago stopped this all together. Two nights

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ago he felt a little short of breath when he lay down, and so put an extra pillow under his head. During the past
week he noticed that he had gained 10 pounds of weight, his ankles became slightly swollen, and 3 days ago he had
to let out his belt. The afternoon of the day of admission he noted shortness of breath while walking across his
living room, when this symptom persisted after he rested, he became frightened and called an ambulance. At no
time did he have chest pain or, except for the dyspnea, any unusual symptom during exercise - you questioned him
carefully on this matter, and he denied having had exertional arm pain, jaw pain, back pain or indigestion.
Is this history typical for heart failure? Are there features that suggest he has ischemic heart disease?

This history is typical for heart failure.

- The absence of symptoms suggesting angina pectoris (cardiac pain) argues against ischemic heart
disease, although ischemia can sometimes cause effort dyspnea.
- A silent myocardial infarction must always be kept in mind when you see a patient with the
insidious onset of heart failure, but there is nothing in Mr. Herz history to support this diagnosis.

Why is the extra pillow helpful in relieving dypsnea in a individual with HF:
- Sitting up: Gravity helps prevent the tendency to distribute blood to the upper portion of the lungs
(this reduces the extravagation of fluid in the upper portion of the lung), allowing for improved oxygen
exchange
- Laying down: Blood is evenly distributed throughout the upper and lower portion of the lungs
(due to the lack of a gravitational gradient). This increases the extravagation of fluid in the upper portion
of the lung, reducing oxygen exchange.

PHYSICAL EXAMINATION

2.1: Mr. Herz is a 58, 170 pound white male sitting up and breathing heavily while wearing an oxygen mask. His,
his heart rate is regular at 140 beats per minute (bpm) with weak small pulses, and his respiratory rate is 24/min and
his blood pressure is 160/105 mm Hg. His core temperature is normal. He looks exhausted and very frightened.
Why is his blood pressure elevated? Why is his pulse small?

His blood pressure is elevated in part because he is terrified, which has caused sympathetic activation.
- The latter, which is also part of the neurohumoral response to impaired cardiac performance, causes
vasoconstriction and cardiac stimulation.
His pulse is small (low CO or dehydrated or in shock) because his stroke volume is low, which in turn can be
explained by impaired left ventricular function.
- Check pulse: Carotid (is best location) or brachial artery
o Volume
o Upstroke
Two types of heart failure
1. Systolic weak/floppy heart muscle, weak ejection fraction, ECG would reflect barely moving and
Q waves all over
2. Diastolic looks normal but the muscle is stiff (cant relax)

2.2: SKIN: Grayish-blue in color; cool and clammy to touch.

Explain the changes in his skin.

His skin is cool and blue because cutaneous blood flow is reduced by vasoconstriction, part of the 1-adrenergic
component of the neurohumoral response; the clamminess is due to sympathetic stimulation of his sweat glands.
- Blood flow to the brain and heart is preferentially preserved with low cardiac output
o Shunts blood away from the skin and intestines

2.3: NECK: His jugular veins are distended and you estimate his mean venous pressure to be 6 cm above the sternal
angle - about 11 cm above the mean right atrium; this is abnormally high.
Why is his venous pressure elevated?

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His venous pressure is elevated because his right ventricle cannot eject all of the systemic venous return into his
pulmonary artery; this has occurred because left ventricular failure has caused his lungs to be engorged. Right
ventricular ejection is also reduced when hypoxia-induced pulmonary arteriolar constriction increases right
ventricular afterload.

2.4: LUNGS: You hear fine inspiratory crackles (rles) that extend half way up to the apices bilaterally.
What is causing the sounds in his lungs? Why are they heard in the lower part of his chest?

The sounds are caused when air enters fluid-filled small bronchi; they are maximal in the lower chest because
gravity causes more fluid to accumulate in the lung bases (sign of left heart problems)

2.5: HEART: The precordium on inspection is unremarkable, but on palpation you feel his apical impulse at the
anterior axillary line; the left border of cardiac dullness percusses about 4 cm to the left of the mid-clavicular line.
On auscultation the second sound, which splits normally, is accentuated in the pulmonic area; as the loud sound is
the second component, you conclude this is a loud P2. There are no murmurs; at the apex you hear a grade 2-3 S 3.
Why is his left ventricular impulse displaced? Can you predict Mr. Herz left ventricular ejection fraction
(LVEF)? How do you calculate LVEF and what does this measure? What does the loud P2 mean? Why the
loud S3?

The displaced apical impulse implies a dilated left ventricle (high end-diastolic volume). Together with the small
pulse (which tells you his stroke volume is low), this suggests that he has a low left ventricular ejection fraction
(LVEF = SV/EDV).
- SV In Mr. Herz, the small pulse indicates that the numerator is small, while the displaced apical
impulse implies that the denominator is large.
A low LVEF does not correlate closely with the severity of symptoms, but is a reliable marker for a poor prognosis.
- The loud P2 tells you that his pulmonary artery pressure is high.
- The apical S3, which is caused by vibrations set up within the walls of the left ventricle during
ventricular relaxation, implies a stiff, non-compliant left ventricle.
S4 comes from the atrium

Backward Heart Failure

- LVEDP LAP Pulmonary vein pressure Pulmonary capillary
pressure Pulmonary artery pressure RVEDP RAP Carotid venous
pressure

2.6: ABDOMEN: Mildly distended with a slightly enlarged, mildly tender liver.
Why might his abdomen be distended? What has happened to his liver?

The abdominal distension may be due in part to ascites, which occurs when the high systemic venous pressure
causes fluid to be transudated into the peritoneal cavity. (This also explains why he let out his belt.) His liver is
large and tender because it is congested by the high venous pressure.

2.7: EXTREMITIES: Bilateral, symmetrical pitting edema of both ankles without redness or tenderness.
What has caused the edema?

Pitting edema is seen when the rate of fluid transudation from the capillaries into the tissues, which is determined
mainly by hydrostatic pressure, exceeds the rate of fluid resorbtion from the tissues into the capillaries, which is
determined mainly by plasma oncotic pressure. In Mr. Herz, fluid transudation is increased by the elevated systemic
venous pressure (backward failure of the right heart).

LABORATORY VALUES

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Systolic most common cause is coronary artery disease (MI) then non-ischemic cardiomyopathy (cardiomyopathy
that isnt from blocker arteries fancy word for not actually knowing anything but includes: anemia, hypertension,
sarcoidosis, viral, end-stage AIDS, Chagas bug)
Low ejection fraction

3.1: Mr. Herz hemoglobin, white blood count, electrolytes, serum iron and serum albumen are normal, but there are
mild abnormalities in his liver function tests. The blood urea nitrogen (BUN) and creatinine are slightly elevated at
18 mg/dl (normal 7-15) and 1.2 mg/dl (normal 0.8 - 1.1), respectively.
What conditions do the normal hemogram argue against? Can you explain the mild abnormalities of
hepatic and renal function?

The normal hemogram argues against anemia or infection, which can worsen heart failure. The abnormal liver
function can be explained by his congested liver.
Abnormal renal function, commonly seen in heart failure; is caused by reflex vasoconstriction in the kidneys, which
represents a very important consequence of the neurohumoral response to low cardiac output.

3.2: Arterial blood gases obtained shortly after admission showed him to be slightly hypoxic.
What mechanisms can cause arterial hypoxia in severe heart failure

Arterial hypoxia in severe heart failure can be explained by fluid accumulation in the pulmonary interstitium. As
noted above, because oxygen is poorly soluble in water this interferes with oxygen diffusion from the alveoli to the
blood in the pulmonary capillaries.

3.3: His electrocardiogram meets criteria for left ventricular hypertrophy. A chest x-ray obtained when he arrived in
the ER shows cardiomegaly and increased vascular markings consistent with pulmonary venous hypertension.
Explain the findings on the chest x-ray.

Pulmonary venous congestion is typical of impaired left ventricular function (backward failure of the left heart).
The cardiomegaly has already been explained.

3.4: An echocardiogram shows a dilated thin-walled left ventricle with globally depressed wall motion but no
regional abnormalities. The valves appear normal. Estimated LVEF is 20-25%.
Is the echocardiogram more typical of a dilated cardiomyopathy, hypertensive heart disease, or ischemic
heart disease? Explain your answer. Does the finding of a low LVEF fit with the bedside evaluation?

The low LVEF and thin-walled dilated left ventricle, which are characteristic of eccentric hypertrophy, rule out
concentric hypertrophy. Eccentric hypertrophy occur in ischemic and dilated cardiomyopathies, and volume
overload, whereas concentric hypertrophy is seen in pressure overload and hypertrophic cardiomyopathies. The
absence of a regional wall motion abnormality argues against ischemic heart disease. The low LVEF (SV/EDV) is
predicted by the bedside evaluation (see above).

Eccentric Sarcomeres are added in series;

whole chamber is dilated

Concentric Sarcomeres are add in

parallel; walls thick, chamber size normal

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COURSE IN THE EMERGENCY ROOM

4.1: Mr. Herz had been given oxygen by mask and received intravenous furosemide, a loop diuretic, shortly after he
arrived. About an hour later he began to pass large amounts of urine and felt better; his breathing became easier and
after you told him he did not appear to have had a heart attack, he became much less frightened.
How did the furosemide contribute to his improvement? What did you do as a physician to help?

The improvement following intravenous furosemide is due in part to a vasodilator effect that reduces left
ventricular afterload; more important is the ability of this drug to cause a diuresis that reduces the preload on both
ventricles.

Reassurance, which reduces the neurohumoral response and so decreases the work of the failing left ventricle, is
also important in the management of acute pulmonary edema.

HEMODYNAMIC DATA:

5.1: Pressures (mm Hg):

Chamber Mr. Herz Values Normal Values
RA mean: 12 <5

RV 60/12 <30/5

PA 60/30 <30/12
mean: 50 <20

*
PCW mean: 30 <12

Radial Artery 180/90 125/75

*
PCW = Pulmonary capillary wedge, an index of LA pressure.
Key for whether or not there is left sided failure
If all the values were normal except PCW then would think hypertension
High values means there is too much fluid

Are these pressures consistent with backward failure of the right, left, or both ventricles?

The high filling pressures (RA and PCW) are typical of backward right and left ventricular failure respectively.

RA Indicates right sided HF (backward failure sign for RV)

PCW Indicates left sided HF (backward failure sign for LV)

5.2: Cardiac Output: 4 L/min (Cardiac Index = 2.2 l/min/m2) Normal Cardiac Index = 2.5 - 3.5 l/min/m2
Is his cardiac index consistent with a diagnosis of forward failure.

The low cardiac index is diagnostic of forward failure systolic heart failure
(backward failure would lead to fluid accumulation ex. Edema)

5.3: Pulmonary Vascular Resistance: ~400 dynes/cm5 (5 Wood Units) Normal = <200 dynes/cm5 (2.5 Wood Units).
Define vascular resistance. Why is the pulmonary resistance high?

Resistance is pressure gradient divided by flow; for pulmonary vascular resistance this is [(PA mean pressure -
PCW mean pressure) divided by cardiac output]. The high pulmonary resistance is most likely due to hypoxia.

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5.4: Systemic Vascular Resistance: ~2160 dynes/cm5 Normal = 700 -1600 dynes/cm5.
What caused the elevated systemic vascular resistance? What are the mediators of this response? Does this
give you a clue as why he had impaired renal function?

Systemic vascular resistance [(mean aortic pressure - RA mean pressure) divided by cardiac output] is increased
largely by sympathetic (1-adrenergic) stimulation, part of the neurohumoral response to his low cardiac output.
- Other mediators of this vasoconstrictor response in heart failure include angiotensin II, endothelin
and vasopressin.
- Renal vasoconstriction can impair renal function and contributes to fluid retention patients with
heart failure.

HOSPITAL COURSE

6.1: You admit Mr. Herz to the hospital and switch him to oral furosemide. His blood pressure soon falls to its
normal level. Following the usual practice in 1990, you begin digoxin.
What is the role of cardiac glycosides in chronic heart failure?

Cardiac glycosides inhibit the sodium pump (Na-K ATPase) which in the heart increases contractility (because
the increased intracellular sodium reduces calcium efflux via the Na/Ca exchanger) and cause arrhythmias (because
reduced potassium uptake decreases the potassium gradient across the plasma membrane) can slow conduction
through AV node
- These drugs also have an important central effect that increases parasympathetic outflow and
inhibits sympathetic activity.
Introduced in the 18th Century, when most patients with heart failure had atrial fibrillation secondary to mitral valve
disease, the benefit of cardiac glycosides was due largely to inhibition of atrioventricular conduction.
- The role of these drugs today, when most patients with heart failure are in sinus rhythm, remains
controversial.
- A large clinical trial has shown that digoxin reduces hospitalization and death from heart failure,
but does not modify survival because of increased myocardial infarction and sudden death.
Toxicity is a concern (Low threshold)
Drug treatments ACE inhibitors, beta blockers, spironolactone (a diuretic) reduce preload but will decrease
hospitalization and mortality

6.2: Serial measurements of serum creatine phosphokinase and cardiac troponins T and I show no significant
elevations. Serial ECGs remain unchanged.
What do the persistently normal levels of creatine phosphokinase and cardiac troponins T and I tell you
about the possibility that he had myocardial necrosis? Does the stable ECG confirm this impression?

The normal creatine phosphokinase and cardiac troponins and the stable ECG agree with other data indicating that
Mr. Herz heart failure was not caused by a recent myocardial infarction. (Small elevations in troponin levels are
sometimes seen in patients with heart failure who have not had a myocardial infarction.)

6.3: On the second hospital day he undergoes left heart catheterization and coronary angiography. The latter shows
no significant narrowing of the coronary artery lumina. His left ventricular angiogram shows globally depressed left
ventricular function with an estimated LVEF of about 30%.
Obstructive coronary atherosclerotic disease is now ruled out, so what is your diagnosis? What are some of
the causes of this syndrome.

Mr. Herz findings meet criteria for dilated cardiomyopathy (DCM), of which approximately 25-35% appear to
be familial. Several cytoskeletal mutations have been found to cause DCM, while most familial hypertrophic
cardiomyopathies are caused by myofibrillar protein abnormalities.

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 - Mr. Herz gives no history of toxic exposure and his normal serum iron rules out hemochromatosis.
(Alcoholism)
- The role of viral infection as a cause for DCM is less clear than was once believed as patients with
viral myocarditis (which is rare) can recover.

6.4: After 3 days of steady improvement you elect to send Mr. Herz home on digoxin and oral furosemide. You
advise him to avoid foods that are high in sodium and not to add salt to his foods.
Can you comment on the dietary advice given Mr. Herz? What foods are most likely to contain large amounts
of sodium?

The dietary advice given Mr. Herz is reasonable because powerful diuretics make it possible to avoid the extremely
low sodium diets that patients find unpalatable.
- It is still essential, however, for these patients to avoid foods that contain large amounts of sodium
and not to use added table salt; the former include most prepared foods, such as fast foods, canned soups
and frozen dinners.
- Specific low salt foods are needed for more severe heart failure. It is a good idea to instruct Mrs.
Herz, who cooks most of the meals, about ways to minimize his sodium intake.

6.5: This treatment plan, although accepted practice through the 1980s, is not in accord with todays standard of
care. Incorporation of new information, much of which became available during the 1990s, is described below.
Today, we know that patients like Mr. Herz suffer from problems other than the hemodynamic disorder. What
is going on in his heart besides the pump abnormality?

Mr. Herz myocardium is deteriorating, and in 1990 he could be expected to die of progressive left ventricular
dysfunction within 4-5 years.
- This reflects the many harmful consequences of the neurohumoral response to low cardiac output
and the hearts proliferative response to chronic overload, notably progressive dilatation (remodeling).
o Catecholamines/Angiotensin II causes increase myocyte hypertrophy and
apoptosis
- Using today's optimal therapy survival is probably about twice as long, but to achieve this
improvement requires close monitoring of the patients, who must adhere to a complex medical regimen as
described below.

LONG-TERM FOLLOW-UP
7.1: Mr. Herz is much improved and resumes his sedentary work as a bookkeeper. His girth returns to normal, his
ankles are no longer edematous, his venous pressure is no longer elevated and his blood pressure remains in the
normal range. He still notes mild dyspnea when he hurries uphill, and he is troubled by fatigue. You follow him
carefully, having alerted him to the importance of worsening symptoms or weight gain. A follow-up
echocardiogram 6 months later, in July 1990, shows a LVEF of 25-30%.
While Mr. Herz therapy led to clinical improvement, he is not a well man. What evidence is there for
persistent heart failure? What concerns are raised by the persistently low LVEF? Why did you warn him
about the hazard of weight gain?

Clinical evidence for backward failure of the right heart is gone, but he still has effort dyspnea that is probably
caused by backward failure of his left ventricle, which increases lung stiffness and the work of breathing. His
LVEF, although higher than when he was hospitalized, remains low due in part to low stroke volume (the
numerator) and - more importantly - to a persistently high end-diastolic volume (the denominator).
He has been appropriately warned about the hazard of weight gain, which generally indicates fluid retention (acute
edema), because a significant weight gain requires prompt attention and probably an increase in his medications to
avoid hospitalization and prevent pulmonary edema.

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7.2: After 2 years, in 1992, Mr. Herz again notes that his dyspnea is increasing. His blood pressure has remained
stable and his ECG has not changed, but an echocardiogram shows his LVEF has fallen to 15-20%. You increase
the dose of the diuretic with gratifying relief of his dyspnea. However, he remains fatigued.
This patients condition is clearly worsening, which unfortunately is the natural history of this syndrome.
Why is this happening? What is the value of the increased dose of diuretic? In what way does his current
therapy fail to address one of Mr. Herz major clinical problems?

Here we see the deficiency of the once traditional approach to therapy, which addresses only the hemodynamic
disorder but fails to deal with Mr. Herz worsening heart failure, which is the natural history of this condition. The
diuretic, while alleviating fluid retention and relieving symptoms, does not prevent deterioration of his failing heart.
The latter is manifest as progressive dilatation (remodeling) that is characteristic of heart failure with low LVEF.

7.3: A year later, in 1993, you attend a post-graduate course that includes a session on the management of heart
failure. This leads you to start an angiotensin converting enzyme inhibitor (ACE inhibitor) and add a long-acting
nitrate to his regimen. His blood pressure stabilizes in the 115/75 range.
Compared to direct acting arteriolar vasodilators, what are the special benefits of the ACE inhibitor and
nitrates in Mr. Herz?

Vasodilators were initially used to reduce the work of the failing left ventricle by lowering afterload. Although of
immediate benefit, short-acting arteriolar vasodilators can cause a rapid drop in blood pressure that increases the
harmful neurohumoral response. Among the vasodilators, ACE inhibitors, and to a lesser extent nitrates, slow
clinical deterioration and prolong survival in patients with heart failure in part because these agents attenuate the
neurohumoral response.
- The beneficial effects of ACE inhibitors, which inhibit angiotensin II production, can be explained
by their ability to prevent apoptotic and other maladaptive proliferative effects (hypertrophy) of this
signaling peptide. Nitrates generate nitric oxide (NO), which also has antiproliferative effects.

7.4: On this new therapy, Mr. Herz feels somewhat better. You repeat his echocardiogram, which shows that his
LVEF has risen slightly to 20-25%. For the next four years, although his exercise capacity remains limited, mainly
by fatigue, he is able to go to his job every day.
A small increase in LVEF is commonly seen with ACE inhibitors; can you explain the mechanism. Why has
fatigue emerged as a major cause of disability? What is its cause?

ACE inhibitors, by reducing afterload, increase stroke volume, the numerator in the equation for EF.
- These drugs can also reduce left ventricular mass and volume, due most likely to an
antiproliferative effect.
- This reduces the denominator in the equation for EF. The emergence of fatigue as a major cause of
disability in heart failure is typical.
Diuretics; although relieving the symptoms of congestion, do not modify a skeletal muscle myopathy whose
causes include mitochondrial damage and loss of oxidative enzymes. This myopathy is likely to be due in part to
disuse (heart failure patients are not very active) and poor nutrition (these patients generally have a poor appetite).
Elevated cytokine levels, commonly seen in severe heart failure, can damage both the heart and skeletal muscle.
However, clinical trials have shown that at lest two types of cytokine inhibitor worsen prognosis in these patients.

7.5: In 1997 you attend another post-graduate course, which encourages you to add a -adrenergic receptor blocker.
You begin this drug cautiously, and Mr. Herz successfully reaches the full dose of the -blocker several months
later. Six months after starting the -blocker he feels much better. You repeat the echocardiogram and find that his
LVEF has increased to 30-35%.
The addition of the -blocker brings this plan of therapy in line with 1998 standard of care. Why must these
drugs be given carefully, at slowly increasing dose? What benefit do you expect and when might this appear?
What is the role of a trained nurse in managing heart failure? What cellular and molecular changes could
explain the ability of -blockers to increase his LVEF?

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-Blockers have been shown to improve survival and prevent hospitalization in patients with heart failure and low
LVEF (ischemic cardiomyopathy and idiopathic dilated cardiomyopathy). Because of their negative inotropic
effect, -blockers must be started carefully at slowly increasing dose to avoid worsening the hemodynamic
abnormalities before the more gradual improvement of left ventricular function begins to appear. This requires
close supervision and frequent communication with the patient, which can be facilitated by a trained "heart failure"
nurse. Increased LVEF generally seen after -blocker therapy appears to be due in part to reversal of proliferative
responses to norepinephrine that cause apoptosis and progressive dilatation (remodeling). The latter, caused by
cardiac myocyte elongation, increases wall stress (The Law of Laplace) and so worsens energy starvation in the
failing heart. -blockers also slow heart rate and reduce contractility, which have energy-sparing effects that benefit
the energy-starved failing heart. -Blockers can also prevent arrhythmias in these patients, an effect that probably
reflects their ability to reduce calcium influx across the plasma membrane - which by reducing the amount of
calcium that must be moved out of the cell, reduces the inward current associated with calcium efflux via the Na/Ca
exchanger.

7.6: The development of an inexpensive test for measuring brain natriuretic peptide (BNP) allows you to follow this
measurement as well.
What is the meaning of an increase in BNP levels? What should be done if he suddenly gains weight?

Patients with severe heart failure are susceptible to thromboembolic disease because their low cardiac output causes
stasis of blood flow, notably in their legs. There is substantial, but not conclusive evidence that anticoagulation
improves prognosis. BNP, which is secreted when walls of the heart become stretched, causes both vasodilatation
and natriuresis, so that this peptide is the bodys natural defense against fluid retention. Recent data show that short-
term administration of a synthetic brain natriuretic peptide is beneficial in acute heart failure; however, when given
for long periods these effects become blunted. Rapid weight gain implies fluid retention, and indicates a need for
increased diuretic therapy to eliminate fluid and/or vasodilator therapy to unload a failing left ventricle.
BNP is useful to see if they dont have heart failure if shortness of breath but if low BNP then not heart failure

7.7: He remains quite stable for another year, now more than 8 years after he was first hospitalized. You increase
the doses of his diuretics when he gains weight, which allows him to avoid hospitalization. In the spring of 1999,
based on the results of a widely publicized clinical trial, you add spironolactone, an aldosterone antagonist.
Once again, in spite of optimal therapy, he continues to deteriorate, albeit at a slowed rate.
Neurohumoral blockade (-blockers, ACE inhibitor or angiotensin receptor blockers, aldosterone
antagonists) has been shown to improve prognosis, allow patients with heart failure to function and feel
reasonably well, and reduce the need for hospitalization. But still he is getting worse. What sorts of
processes might be occurring in his ventricle to explain the progressive decrease in his ejection fraction?

Mechanisms that explain the ability of neurohumoral blockade to improve prognosis in heart failure include
reduced cardiac energy demands caused by vasodilatation, slowed heart rate, and reduced contractility, all of which
are beneficial for an energy-starved failing heart. Other benefits of neurohumoral blockade reflect the fact that
mediators of the neurohumoral response, such as nor-epinephrine, angiotensin II, and aldosterone, stimulate
maladaptive proliferative responses. Proliferative signaling can damage the failing heart by activating transcription
factors that cause elongation of cardiac myocytes, a major cause of progressive dilatation, and by stimulating
apoptosis (programmed cell death). The relentless fall in LVEF seen in patients like Mr. Herz is due mainly to
increasing end-diastolic volume and, to a lesser extent, falling stroke volume. Death of cardiac myocytes is
especially deleterious because these terminally differentiated cells have little or no capacity to divide, so that when
lost few - if any - are replaced.

Although both ACE inhibitors and ARBs inhibit actions of angiotensin II that are mediated by AT1 receptor
activation, there are two fundamental differences. The first is that ACE inhibitors inhibit the enzyme that forms
angiotensin II, while ARBs inhibit the binding of this signaling peptide to the AT1 receptor. The second is that ACE
inhibitors, but not ARBs, inhibit the breakdown of bradykinin. The latter, a vasodilator peptide with
antiproliferative actions, can cause significant side effects, most commonly a dry cough; more dangerous, but rare,
is angioneurotic edema that may be fatal. The advantage of replacing an ACE inhibitor with an ARB is that the

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latter have fewer side effects; a theoretical disadvantage is that ARBs, which do not increase bradykinin levels, may
be slightly less effective in slowing progression. However, clinical trials have not shown ACE inhibitors to be more
effective than ARBs in preventing hospitalization and death in these patients. As Mr. Herz has tolerated his ACE
inhibitor for years, these is no advantage in making this shift.

7.8: The QRS complex in Mr. Herz electrocardiogram, which initially showed left ventricular hypertrophy,
becomes prolonged and he develops a left bundle branch block pattern. As the QRS complex becomes
progressively wider, you consider a resynchronization device to reduce the temporal dispersion of left ventricular
activation. However, you decide not to recommend this device.
What is the rationale for implanting a resynchronizing device?

A left bundle branch block pattern with a very wide QRS complex in a patient with advanced heart failure tells us
that left ventricular depolarization has become prolonged, which causes heterogeneous activation in which some
regions to begin to contract while other parts of the ventricle are still relaxed.
- This leads to inefficiency because the regions of the left ventricle that are activated first stretch
other regions that have not yet been activated; the resulting energy wastage is detrimental because the
failing heart is energy-starved.
- Normal wave of contraction is lost Want to pace LV in order to bypass block
Electrical devices that increase the homogeneity of left ventricular activation (resynchronization therapy) have
been shown both to reduce symptoms and improve prognosis in selected heart failure patients.
- These devices also include an internal defibrillator and so help prevent the sudden death commonly
seen in end-stage heart failure.
Defibrillator (= resynchronization) in systolic and LBB

7.9: His dyspnea, although still a problem when he exerts himself, has worsened only slightly when, one morning,
you receive a call from Mrs. Herz telling you that her husband died during the night.
There are two major causes of death in patients with heart failure: about half die of progressive heart failure,
most of the remainder die suddenly, presumably because of an arrhythmia. What is the current status of
arrhythmia management in heart failure patients? Are the Class I antiarrhythmic drugs, which reduce the
incidence of non-lethal, warning arrhythmias, beneficial in these patients? What other antiarrhythmic drug
might have been used? What is the role of the implantable defibrillator?

Most documented sudden deaths in heart failure patients are due to tachyarrhythmias (ventricular tachycardia and
fibrillation), but some can be caused by bradyarrhythmias (sinus slowing and A-V block). Class I antiarrhythmic
drugs such as quinidine, procaine amide reduce the frequency of non-lethal arrhythmias that are harbingers of
sudden cardiac death, but increase mortality in patients with heart failure. Amiodarone, a Class III drug with some
-blocking effect can be used in heart failure patients. Implantable defibrillators, which are expensive, have been
shown both to prevent sudden death and improve overall survival. Repeated shocks in end-stage heart failure can
prolong a life of misery, so that some patients with end-stage heart failure ask that these devices be turned off.

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