CLINICAL CASE DISCUSSION

Biochemistry

ACUTE CORONARY SYNDROME

Cardiology case
A 45 year old male was admitted at the ICU of Fatima University Medical Center
because of severe progressive chest pain with cold sweating./ He is obese with
BMI of 32, BP 200/110, RR 30/min, HR 120 bpm. ECG was immediately done
with findings of ST segment elevation in I + AVL V3 V4 V5 V6 with reciprocal
changes in II, III, AVF his TROP T revealed 1, 200 ng/ml. Patient was
immediately given streptokinase 1,500 units by 1U and Nicardipine drip Isoket
were started.

1. Define obesity. How it is assessed? Why is it linked

to MI?
A.) define obesity
Obesity is an abnormal accumulation of body fat, usually 20% or more
over an individual's ideal body weight. Obesity isassociated with increa
sed risk of illness, disability, and death.
The branch of medicine that deals with the study and treatment of o
besity is known as bariatrics. As obesity has become amajor health pro
blem in the United States, bariatrics has become a separate medical a
nd surgical specialty.
B.) assessment
Assessment of weight and health risk involves using three key
measures:
Body mass index (BMI)
Waist circumference
Risk factors for diseases and conditions associated with
obesity
Body Mass Index (BMI)
BMI is a useful measure of overweight and
obesity. It is calculated from your height and
weight. BMI is an estimate of body fat and a
good gauge of your risk for diseases that can
occur with more body fat. The higher your BMI,

the higher your risk for certain diseases such

as heart disease, high blood pressure, type 2
diabetes, gallstones, breathing problems, and
certain cancers.
Although BMI can be used for most men and
women, it does have some limits:
It may overestimate body fat in athletes
and others who have a muscular build.
It may underestimate body fat in older
persons and others who have lost
muscle.
Use the BMI Calculator or BMI Tables to
estimate your body fat. The BMI score means
the following:
BMI
Underweight

Below 18.5

Normal

18.524.9

Overweight

25.029.9

Obesity

30.0 and Above

Waist Circumference
Measuring waist circumference helps screen
for possible health risks that come with
overweight and obesity. If most of your fat is
around your waist rather than at your hips,
youre at a higher risk for heart disease and
type 2 diabetes. This risk goes up with a waist
size that is greater than 35 inches for women
or greater than 40 inches for men. To correctly
measure your waist, stand and place a tape
measure around your middle, just above your
hipbones. Measure your waist just after you
breathe out.
The table Risks of Obesity-Associated
Diseases by BMI and Waist
Circumference provides you with an idea of
whether your BMI combined with your waist
circumference increases your risk for
developing obesity-associated diseases or
conditions.

Risk Factors for Health Topics Associated

With Obesity
Along with being overweight or obese, the
following conditions will put you at greater risk
for heart disease and other conditions:
Risk Factors
High blood pressure (hypertension)
High LDL cholesterol ("bad" cholesterol)
Low HDL cholesterol ("good"
cholesterol)
High triglycerides
High blood glucose (sugar)
Family history of premature heart
disease
Physical inactivity
Cigarette smoking
For people who are considered obese (BMI
greater than or equal to 30) or those who are
overweight (BMI of 25 to 29.9) and have two or
more risk factors, it is recommended that you
lose weight. Even a small weight loss (between
5 and 10 percent of your current weight) will
help lower your risk of developing diseases
associated with obesity. People who are
overweight, do not have a high waist
measurement, and have fewer than two risk
factors may need to prevent further weight gain
rather than lose weight.
Talk to your doctor to see whether you are at
an increased risk and whether you should lose
weight. Your doctor will evaluate your BMI,
waist measurement, and other risk factors for
heart disease.
The good news is even a small weight loss
(between 5 and 10 percent of your current
weight) will help lower your risk of developing
those diseases.
C.) why is it linked to MI

Until recently the relation between obesity and coronary heart

disease was viewed as indirect, ie, through covariates related to
both obesity and coronary heart disease risk,12 including
hypertension; dyslipidemia, particularly reductions in HDL
cholesterol; and impaired glucose tolerance or noninsulindependent diabetes mellitus. Insulin resistance and accompanying
hyperinsulinemia are typically associated with these
comorbidities.13 Although most of the comorbidities relating obesity
to coronary artery disease increase as BMI increases, they also
relate to body fat distribution. Long-term longitudinal studies,
however, indicate that obesity as such not only relates to but
independently predicts coronary atherosclerosis.9 14 15 This relation
appears to exist for both men and women with minimal increases in
BMI. In a 14-year prospective study, middle-aged women with a
BMI >23 but <25 had a 50% increase in risk of nonfatal or fatal
coronary heart disease,9 and men aged 40 to 65 years with a BMI
>25 but <29 had a 72% increased risk.16 The overall relation
between obesity and coronary artery disease morbidity and
mortality is less clear for Hispanics,17 Pima Indians,18 and AfricanAmerican women.19

2. What is the metabolic syndrome? What are the

metabolic risk factors?
a. What Is Metabolic Syndrome?
Metabolic (met-ah-BOL-ik) syndrome is the name for a group
of risk factors that raises your risk for heart disease and
other health problems, such as diabetes andstroke. A
cluster of metabolic risk factor
The term "metabolic" refers to the biochemical processes
involved in the body's normal functioning. Risk factors are
traits, conditions, or habits that increase your chance of
developing a disease.
In this article, "heart disease" refers to coronary heart
disease (CHD). CHD is a condition in which a waxy
substance called plaque (plak) builds up inside the coronary
(heart) arteries.
Plaque hardens and narrows the arteries, reducing blood
flow to your heart muscle. This can lead to chest pain,
a heart attack, heart damage, or even death.
b.

Metabolic Risk Factors

The five conditions described below are metabolic risk

factors. You can have any one of these risk factors by itself,
but they tend to occur together. You must have at least three
metabolic risk factors to be diagnosed with metabolic
syndrome.

A large waistline. This also is called abdominal obesity or

"having an apple shape." Excess fat in the stomach area
is a greater risk factor for heart disease than excess fat in
other parts of the body, such as on the hips.

A high triglyceride level (or you're on medicine to treat

high triglycerides). Triglycerides are a type of fat found in
the blood.

A low HDL cholesterol level (or you're on medicine to

treat low HDL cholesterol). HDL sometimes is called
"good" cholesterol. This is because it helps remove
cholesterol from your arteries. A low HDL cholesterol
level raises your risk for heart disease.

High blood pressure (or you're on medicine to treat high

blood pressure). Blood pressure is the force of blood
pushing against the walls of your arteries as your heart
pumps blood. If this pressure rises and stays high over
time, it can damage your heart and lead to plaque
buildup.

High fasting blood sugar (or you're on medicine to treat

high blood

sugar). Mildly high blood sugar may be an early sign of

diabetes.

Large Waist Size

For men: 40 inches or larger

For women: 35 inches or larger

Either
Cholesterol: High Triglycerides

150 mg/dL or higher

or
Using a cholesterol medicine
Either

Cholesterol: Low Good Cholesterol

For men: Less than 40 mg/dL

For women: Less than 50 mg/dL

(HDL)

or
Using a cholesterol medicine
Either
Having blood pressure of 135/85mm Hg
or greater

High Blood Pressure

or
Using a high blood pressure medicine

Blood Sugar: High Fasting Glucose

Level

100 mg/dL or higher

3. Discuss the metabolic pathway of LDL and HDL

a. LDL
Cholesterol Transport and Utilization
Majority of cholesterol is transported as cholesterol ester.
The ester is synthesized in the plasma from cholesterol and the acyl
chain of the phosphatidylcholine (Lecithin)
Lecithin + Cholesterol

Lysolecithin + Cholesterolester
LCAT
LCAT(Lecithin:cholesterol acyltransferase)
The intracellular cholesterol is synthetized by ACAT. (AcylCoA:cholesterol acyltransferase)
Acyl-CoA + cholesterol

Cholesterolester + HS-CoA
ACAT

Low density lipoprotein (LDL) transport cholesterol to peripheral tissues,

and high-density lipoprotein (HDL) transport cholesterol from peripheral
tissues to the liver.

Control of Cholesterol Biosynthesis

1) HMG-CoA reductase

The enzyme synthesis inhibited

Hydroxy cholesterols
Phosphorylation
dephosphorylation (active)

2) Hormonal regulation:

insulin
cortisol, glucagon

3) Dietary cholesterol intake "feedback inhibitory"

4) LDL (Low-density Lipoprotein) receptor regulation
5) n-3 polyunsaturated fatty acids
6) Drug action on HMG-CoA reductase (statins)

The LDL receptor pathway

The LDL receptor pathway (cont.)

Plasma LDL is taken up by cells via LDL receptors in clathrincoaated pits.
LDL are separated from their receptor in endosomes (pH 5 to 6)
then undergo digestion in lysosomes (pH ~3).
The LDL receptors recycle back to the cell surface making <100
trips in their lifetime.
Lysosomal enzymes breakdown apoB100 in LDL to amino acids
and liberate cholesterol for cellular needs.
The cellular level of cholesterol is self-regulating.
An oversupply of cholesterol has three metabolism effects:
1. inhibition of HMG-CoA reductase - The rate limiting step in
cholesterol synthesis.
2. activation of ACAT, which esterifies cholesterol for storage
3. inhibition of LDL receptor synthesis

Hereditary Hyperlipoproteinamias
Dysbetalipoproteinemia: Accumulation of IDL, VLDL and
chylomicron remnant. Elevated level of total cholesterol and
triglycerides. The disorder caused by Apo-E or Apo-E receptor.
Diabetes, hypothyroidism are associated with type III disorders.

Abetalipoproteinemia: Genetic defect in the synthesis of Apo-B.

Both chylomicron and VLDL are affected. Fat malabsorbtion
occurs because chylomicron can not be formed by intestine.

Multiple type hyperlipoproteinemia Increased level of VLDL

and LDL which is resulted from the overproduction of VLDL. The
biochemical defect is unknown.

Familial hypecholesterolemias: LDL receptor downregulation or

receptor defects. Homozygotes do not have functioning LDL
receptor. The gene defect is caused by mutation, deletions,
insertions.

Cholesterol Homeostasis in FH
FH: Familial Hypercholesterolemia
LDL receptor failed to migrate from endoplasmic reticulum to Golgi

Homozygous form (rare)

cholesterol level above 650 mg/ 100 ml
They die before age 20.

Heterozygous form (one defective allele)

cholesterol level 250 - 500 mg/ 100 ml
high risk to have heart attack

Involvement of the LDL receptor in cholesterol uptake and metabolism

Regulatory actions of cholesterol

After the synthesis in the endoplasmic reticulum, the LDL receptor
matures in the Golgi complex
then migrates to the cell cell surface, where it clusters in coated pits.
After internalization of LDL, multiple vesicles fuse to form endosome.
Proton pumping in the endosome membrane causes the pH to drop, which
in turn cause LDL to dissociate from the receptor.
The LDL apolipoprotein is degraded in lysosomes.
The LDL receptor remains in a vesicle, which returns to the plasma
membrane to start the cycle anew.

Structure of the LDL receptor

The structure is divided into five domains.

The first domain contains the LDL binding site.

This is followed by a large domain that contains homology with the
epidermal growth factor (EGF) precursor.
Next, is a small segment that contains a large number of O-linked
carbohydrate residues.
The fourth domain spans the plasma membrane.
The last domain is a short segment that projects into the

cytoplasm but does not have any kinase activity.

B. HDL
The hypertriglyceridemia that frequently accompanies diabetes mellitus and
persons with
the metabolic syndrome has important metabolic effects on HDL content, particle
size
and hence affecting its protective function. The increase in visceral fat in case of
abdominal obesity leads to increase free fatty acids in the plasma. In the liver,
the
increased fatty acids, is incorporated into triglycerids and secreted as VLDL
particles,
which are further remodeled through hydrolysis in the plasma component to free
fatty
acids that in-turn are incorporated into adipose tissue. Fig.1 demonstrates the
metabolic
effect of the VLDL particles with high triglyceride content on HDL and LDL
particles.
As shown in the figure, this triglyceride- loaded VLDL will activate a protein
specialized
in transfer of cholesterol ester between the different lipoprotein particles. This
cholesterol
ester transfer protein (CETP), will exchange cholesterol esters in HDL and LDL
particles
with the triglyceride content of the VLDL particles, a lipid shuttle activity that will
end in
increasing the triglyceride content of both HDL and LDL particles and decreasing
their
cholesterol ester content, an effect that is enhanced by the activity of the lipase
enzyme.
The resultant HDL particles are dysfunctional and less effective in cholesterol
removal
from the periphery to the liver, with more small LDL particles and progressive
atherosclerosis. This metabolic profile with high triglycerides, low HDL and small
LDL
particles is the atherogenic profile in many cases of diabetes, abdominal obesity
and
metabolic syndrome.

4. Discuss the pathogenesis of atherosclerosis

Pathogenesis of Atherosclerosis
Marchand introduced the term atherosclerosis describing the association of
fatty degeneration and vessel stiffening.1 This process affects medium and largesized arteries and is characterized by patchy intramural thickening of the
subintima that encroaches on the arterial lumen. Each vascular bed may be
affected by this process; the etiology, treatment and clinical impact of
atherosclerosis varies from one vascular bed to another.2 The earliest visible
lesion of atherosclerosis is the fatty streak, which is due to an accumulation of
lipid-laden foam cells in the intimal layer of the artery. With time, the fatty streak
evolves into a fibrous plaque, the hallmark of established atherosclerosis.
Ultimately the lesion may evolve to contain large amounts of lipid; if it becomes
unstable, denudation of overlying endothelium, or plaque rupture, may result in
thrombotic occlusion of the overlying artery.
Atherosclerotic lesions are composed of three major components. The first is the
cellular component comprised predominately of smooth muscle cells and
macrophages. The second component is the connective tissue matrix and
extracellular lipid. The third component is intracellular lipid that accumulates
within macrophages, thereby converting them into foam cells. Atherosclerotic
lesions develop as a result of inflammatory stimuli, subsequent release of various
cytokines, proliferation of smooth muscle cells, synthesis of connective tissue
matrix, and accumulation of macrophages and lipid.

5. discuss and illustrate the schematic structure

of myofilament showing relationship between
troponin, tropomyosin and myosin

6. Discuss the rise and fall of troponin T together with

other markers for MI. why is it the preferred marker?

7. what is the molecular mechanism of action of

streptokinase.
Plasminogen is an inactive molecule that becomes activated to plasmin when the
Arg/Val bond is cleaved. Plasmin breaks down fibrin clots created by the blood
clotting cascade. Streptokinase forms a highly specific 1:1 enzymatic complex
with plasminogen which converts inactive plasminogen molecules into active
plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma
proteins. This in turn leads to the degradation of blood clots.

8. what is the mechanism of action of nicardipine

Nicardipine is a calcium entry blocker (slow channel blocker or calcium ion
antagonist) which inhibits the transmembrane influx of calcium ions into cardiac
muscle and smooth muscle without changing serum calcium concentrations. The
contractile processes of cardiac muscle and vascular smooth muscle are
dependent upon the movement of extracellular calcium ions into these cells
through specific ion channels. The effects of Nicardipine are more selective to
vascular smooth muscle than cardiac muscle. In animal models, Nicardipine
produces relaxation of coronary vascular smooth muscle at drug levels which
cause little or no negative inotropic effect.
By deforming the channel, inhibiting ion-control gating mechanisms, and/or
interfering with the release of calcium from the sarcoplasmic reticulum,
nicardipine inhibits the influx of extracellular calcium across the myocardial and
vascular smooth muscle cell membranes The decrease in intracellular calcium
inhibits the contractile processes of the myocardial smooth muscle cells, causing
dilation of the coronary and systemic arteries, increased oxygen delivery to the
myocardial tissue, decreased total peripheral resistance, decreased systemic
blood pressure, and decreased afterload.

9. what is reperfusion injury

Reperfusion injury is the tissue damage caused when blood supply returns to
the tissue after a period of ischemia or lack of oxygen. The absence
of oxygen and nutrients from blood during the ischemic period creates a
condition in which the restoration of circulation results
in inflammation and oxidative damage through the induction of oxidative
stress rather than restoration of normal function.