Atherosclerosis.

Biochemical modifications in acute coronary syndrome

Atherosclerosis is the main cause of cardiac diseases witch includes acute myocardial
infarction (AMI), unstable angina (UA) and sudden death. Today all these events are known as
acute coronary syndrome (ACS). It can ultimately result in clinical presentations ranging from
entirely asymptomatic to unstable angina and to massive acute myocardial infarction. ACS is the
culmination of a series of events that begins with atherosclerosis, the narrowing of coronary arteries
by deposition of highly lipid-filled plaque.
Atherosclerosis involves many mechanisms which can be summarized:
1. deposition of lipoproteins in subendothelial space due to high LDL-cholesterol (LDL-C)
plasma level;
2. chemotaxis of inflammatory cells (particularly monocytes) with foam cell formation;
3. migration and proliferation of smooth muscle cells;
4. accumulation of extracellular matrix and fibrous cap formation;
5. endothelial dysfunction;
6. fibrous cap disruption and thrombus formation;

1. Deposition of lipoproteins in subendothelial space due to high LDL-cholesterol (LDL-

C) plasma level; It appears as disequilibrium between the number of LDL and HDL
particles. In the presence of a high LDL-C, the normal LDL-receptor (LDL-R) is repressed
and these particles could be taken only by monocytes (scavenges cells) because these type of
cells present a LDL-R which is not inhibit by intracellular cholesterol accumulation. These
monocytes will enter in the subendothelial space where they will become macrophages with
high amounts of cholesterol. These cells, secondary to phagocytosis, will activate the
membrane NADPH oxidase which will produce O2- (anion superoxide). O2- will oxidize
both circulating and intracellular LDL. They will also secrete chemotactic factors which will
attract new monocytes in the arterial vessel.
In the last decade evidence has accumulated that a crucial and causative role in the
pathogenesis of atherosclerosis is played by the free radical process known as lipid
peroxidation. Free radicals are responsible for the modifications of the LDL apoprotein (apo
B100). These particles are known as oxidized LDL (oxLDL) and they are taken only by
scavenger receptors of the monocytes. These oxLDL are responsible for many mechanisms
involved in atherogenesis such as: the chemotactic effects on other inflammatory cells,
endothelial dysfunction, the blockade of macrophage in subendothelial space, stimulation of
membrane phospholipase A2 with the releasing of arachidonic acid which is the precursor of
prostaglandins and leucotrienes, activation of monocytes/macrophages with cytokines
releasing.
2. Chemotaxis of inflammatory cells (particularly monocytes) with foam cell formation.
Due to macrophage accumulation in subendothelial space, new monocytes (which contain in
specially oxLDL) are attracted. Some of these cells will die and the lipids will abnormal
accumulate in the arterial space. They also will stimulate the entrance of new inflammatory
cells, in special monocytes and lymphocytes. The macrophages with high amounts of
cholesterol are known as foam cells.
3. Migration and proliferation of smooth muscle cells. The inflammatory cells from the
subendothelial space will secrete growth factors such PDGF (platelet derived growth factor),
MGF(monocyte growth factor ), EGF (epidermal growth factor), which will act on smooth
muscle cells from arterial vessel and will stimulate migration of these cells and the
proliferation of them in the subendothelial space.
4. Accumulation of extracellular matrix and fibrous cap formation; These smooth muscle
cells abnormal proliferate in intima and synthesize connective fibers (as collagen) and other
compounds of the extracellular matrix which will form the fibrous cap of the plaque. This
plaque will determine either the thickening of the mural and the reduction of the luminal
cross-sectional area.
5. Endothelial dysfunction Many authors consider that this mechanism is the first described
in the genesis of atherosclerotic plaque. A dysfunctional endothelium will have an increased
permeability and thus a higher number of monocytes will pass through the wall into intima.
Also these abnormal endothelium cells will secrete adhesion molecules such as VCAM1
which will act as chemotactic factors for other cells like monocytes and lymphocytes. So in
the intima of the arterial vessel an inflammatory process will occur.
6. Fibrous cap disruption and thrombus formation Shear stresses from diastolic blood
pressure can lead to plaque ruptures in vulnerable areas such as the edges or shoulders of
plaque lesions or bifurcations of the arterial tree. The exposure of the core contents of lipids,
cellular and extracellular elements (collectively termed “gruel”) results in thrombus
formation and platelet aggregation, and the development of chest pain. Incomplete occlusion
of the coronary artery leads to unstable angina, while total occlusion lead to acute
myocardial infarction (AMI).

Fig 1. Plaque progression

The American Heart Association has subdivided the plaque progression into distinct phases.
Plaques formed in the early (I-III) are stable in that they have a thick fibrous cap, are not at the
risk for rupture, and the patient experiences no cardiac symptoms (fig1). However, for many
patients, the plaque progresses to phases IV and V which are lesions characterized by thinning
of the cap and are vulnerable to rupture. The fibrous cap can be thinned by inflammation and
 monocyte infiltration, activation of metalloproteinases, oxidation of LDL lipoproteins,
augmentation of growth factors, and other processes. Shear stress from diastolic blood pressure
can lead to plaque rupture in vulnerable areas such as the edges or shoulders of plaque lesions or
bifurcations of the arterial tree. The exposure of the core contents of lipids, cellular and
extracellular elements (collectively named “gruel”) result in thrombus formation and platelet
aggregation, and the development of chest pain. Incomplete occlusion of the coronary artery
leads to unstable angina, while total occlusion lead to AMI
Figure 2 summarizes the events and the potential markers for each event that takes place after
plaque rupture in ACS.

Plaque rupture

 inflammation markers (CRP (C-reactive protein), amyloid A)

Intracoronary thrombus

 increased coagulation factors and proteins (prothrombin fragments F1+2; II – ATIII

(thrombin – antithrombin III complex)
 increased soluble fibrin monomers
 increased P-selectin (a platelet membrane protein)

reduced blood coronary flow

 imaging changes
 fibrinolytic system activation (spontaneous / therapeutic)
 increased P-AP2 (plamin – antiplasmin 2) complexes, fibrin degradation products (D-
dimer)

Myocardial ischemia

 early ischemic indicators: glygogen phosphorylase BB

 ECG - ST depression

Myocardial necrosis
 biochemical markers: CKMB, cTnT, cTnI
 ECG - ST elevation

Fig 2 Pathophysiology of atherosclerotic plaque

 The main symptom in ACS is the chest pain. The common causes of chest pain are:
CARDIAC -ischemic syndromes- stable angina
- unstable angina
- variant angina
-AMI
-valvular disease –mitral valves prolapse
- aortic stenosis
- subaortic stenosis
-cardiomyopathy
-pericarditis

PULMONARY-bronchitis
-bronchospasm
-empyema
-pleural effusion
-pleuritis
-pneumonia
-pneumothorax
-pulmonary edema
-aortic dissection
-pulmonary embolism
-pulmonary hypertension

OTHERS- vascular -aortic dissection

-pulmonary embolism
-pulmonary hypertension
-gastrointestinal- esophageal spasm
- gastroesophageal reflux
- Mallory-Weiss tear
- esophagitis/ gastritis
- gastric/ duodenal ulcer
- biliary colic
-musculoskeletal – costochondritis
- muscle strain/ spasm
-cervical radiculopathy
- neurological – Herpes Zoster

The triage of patients with chest pain from the emergency department (ED) is one of the most
difficult challenges that face ED physicians today. The inappropriate discharge of ED patients who
have AMI has been estimated to occur in 2-13% of patients. That why there is a continuous
research for an ideal cardiac marker.

The ideal biochemical marker:

- would be one that has high clinical sensitivity and specificity,
- appears early after AMI to facilitate early diagnosis,
- remains abnormal for several days after AMI,
- can be assayed with a rapid turnaround time.
 Because there currently is no single marker that meets all of these criteria, a multianalyte
approach has the most merit.
The biochemical events that occur following the total occlusion of a coronary artery were
summarized by Hearse in 1979 and are still accurate today. The initial events occur within the few
seconds or minutes after total coronary artery occlusion and are associated with reversible changes.
This is characterized by the lack of oxygen delivery, and a reduced production of energy stores
(ATP molecules), as the myocyte shifts from the aerobic to anaerobic glycolysis and increased
glycogenolysis. Enzymes that participate in the breakdown of glycogen such as the phosphorylases
are putatively released during this time. In order to conserve energy, there is impairment of failure
of the ATP-dependent ion membrane pumps resulting in the release of intracellular electrolytes
such as potassium and phosphate. Concomitant to energy deficit is the inability of the heart to
remove waste products. This leads to accumulation and release of metabolites such as lactate and
adenosine. Low molecular weight proteins may be able to pass through reversibly injured but
repairably membranes.
If the affected artery becomes patent during the early time intervals either spontaneously or
by pharmacological (thrombolytic therapy) or surgical (angioplasty or bypass) means, the
jeopardized myocytes can fully recover. Prolonged or permanent occlusion, however, leads to the
onset of irreversible damage. The hallmark of irreversible damage is disruption of cellular
membranes and the release of macromolecules such as enzymes and large molecular weight
proteins. The release of the mitochondrial proteins in particular, is indicative of cell death and tissue
necrosis. Once the marker is released from the myocyte, it must pass through the interstitial space
before it can appear in the general circulation. Ions and low molecular weight metabolites readily
pass through the interstitial space directly into the vascular space (fig.4). Their appearance into
blood (fig5) is rapid. Unfortunately, these ions and metabolites are not specific to myocardial
injury, and are not indicative for irreversible damage. Cardiac enzymes and proteins have the
advantage of organ specificity, and essentially are only released during the irreversible damage.
However, they cannot directly pass to the vasculature, and must travel through slow lymphatic
drainage. Therefore there is a delay before they appear in blood. The size of the protein and its
distribution within the cell dictates the appearance rate. Small intracellular proteins (e.g. myoglobin
and fatty acid binding protein-FABP) appear first, while large proteins (e.g. CK and LDH) and
those that are part of the contractile apparatus (e.g. troponin) have a delayed appearance. Strategies
for development of early AMI markers should be focused on proteins that are specific to the heart.
In addition proteins with low molecular weight will appear in blood sooner than large proteins and
enzymes.
Fig. 4 Posssible routes for release of markers from tissue to blood

Fig 5. Release pattern of markers vs. time after onset of infarction

WHO has defined the diagnosis of AMI as a triad. Two of which must be present for
diagnosis:
- the history is typical if severe and prolonged chest pain is present and it is resistant
to nitro derivates;
- unequivocal ECG changes that are the development of abnormal, persistent Q or QS
waves, and evolving injury lasting longer than 1 day;
- unequivocal change consisting of serial enzyme changes, or initial rise and
subsequent fall. The changes must be properly related to the particular enzyme and
to the delay time between the onset of symptoms and blood sampling.

With the development of biochemical markers that are not themselves enzymes, such as
cTnT (cardiac troponin T), cTnI (cardiac troponin I), and myoglobin, the third criterion of
the WHO triad should be revised. More, 30% of AMI are not recognized due to the absence
of chest pain (“silent infarction”). Silent infarctions are especially common in diabetic
persons; females are affected more often than males. With advancing age in particular the
course of AMI is frequently atypical. Until now the laboratory diagnosis acute myocardial
damage was based on the detection of elevated serum enzyme activities of AST (GOT), CK,
LDH, and their isoenzymes. Determining the activities of these enzymes is neither very
sensitive nor very specific for the myocardium so an accurate diagnosis is difficult
especially in cases of non-Q wave myocardial infarctions, unstable angina pectoris,
myocarditis or toxic myocardial damage as well as in the presence of renal failure, multiple
organ failure or concomitant skeletal muscle injuries, e.g. after resuscitation efforts. Clearly
is it advantageous if a marker increases in blood exclusively after myocardial damage.

A. “Classical enzymes”
1. CK and isoenzymes
2. AST
3. LDH

B. Other parameters
1. Myoglobin
2. Troponin T
3. Troponin C
4. H-FABP
5. NT-proANP., BNP.
6. Galectin-3
7. CRP

Creatin kinase (CK)

CK, also incorrectly called creatine phosphokinase, catalyses the reversible phosphorilation
of creatine by ATP. CK activity is greatest in striated muscle, brain and heart tissue, which
contain some 2500, 550, and 470U/g protein, respectively. Other tissues, such as kidneys
and the diaphragm, contain significant less activity (< 30U/g protein), and the liver and
erythrocytes are essentially devoid of activity.
CK is a dimmer composed of two subunits, so the enzyme presents 3 isoenzymes: BB
(CK-1), MB (CK-2), MM (CK-3). The distribution of these isoenzymes is different: CK-
BB predominates in brain, prostate, gut, lung, bladder, uterus, placenta and thyroid. CK-MB
is present, to various degrees, in heart muscle (25% - 46% of CK activity) and also to a
minor degree in skeletal muscle (≈1- 5%). CK-MM predominates in skeletal and cardiac
muscle.
Both M and B subunits have a C-terminal lysine residue wchich can be hydrolyzed in blood
by different carboxypeptidases leading isoforms: for CK-MB there are 2 isoforms:CK-MB1
and CK-MB2. For CK-MM there are 3 isoforms: CK-MM1 and CK-MM2 and CK-MM3.
Isoforms CK-MB2 and CK-MM3 are cardiac specific markers.

Aspartate aminotransferase (AST or GOT)

AST and ALT (alanin aminotransferase) constitute a group of enzymes that catalyze the
interconversion of amino acids and α-oxo-acids by transfer of amino groups.
Transaminases are widely distributed in animal tissues. Both AST and ALT are normally
present in human plasma, bile, cerebrospinal fluid and saliva, but none is present in urine
unless a kidney lesion is present. The distribution of these enzymes is presented in table 1

Table 1. Transaminase activities in human tissues, relative to serum as unity

Tissue AST ALT
Heart 7800 450
Liver 7100 2850
Skeletal muscle 5000 300
Kidneys 4500 1200
Pancreas 1400 130
Spleen 700 80
Lungs 500 45
Erythrocytes 15 7
Serum 1 1

After MI, increased activity of AST appears in serum, as might be expected from relatively
high AST concentration in heart muscle (table 1). On average, serum levels do not become
abnormal, however, until 6 -8 h has elapsed after the onset of chest pain. Abnormal AST
levels are observed in more than 97% of cases of myocardial infarction when correctly
blood specimens are analyzed. Peak values of AST activity are reached after 18 to 24 h, and
the activity values fall to within the normal range by the 4th to 5th day, provided ni new
infarction has occurred. The peak values of AST activity are roughly proportional to the
extend of cardiac damage. Average increases are of order of 4 to5 times the upper limit of
normal. However, small elevations in serum levels do not necessarily indicate a favorable
prognosis.
ALT levels are within normal limits or are only marginally increased in uncomplicated MI,
because the concentration of this enzyme in heart muscle is only a fraction of that of AST
activity.
Lactate dehydrogenase (LDH)
LDH is a hydrogen transfer enzyme that catalyzes the oxidation of lactate to pyruvate with
the mediation of NAD+ as hydrogen acceptor. The enzyme is composed of 4 peptide chains
of 2 types: M and H leading to 5 isoenzymes: LDH1 (H4), LDH2 (H3M), LDH3 (H2M2),
LDH4 (HM3), and LDH5 (M4). LDH activity is present in all cells of the body and is
invariably found only in the cytoplasm of the cell. In the heart muscle predominate LDH1
and LDH2. In liver predominate LDH4 and LDH5.
Measurements of plasma enzymes have long been used to assist in the diagnosis of AMI.
The first enzyme to increase is CK-MB, followed by total CK, AST and LDH. (Fig 6). CK-
MB has long been regarded as a gold standard. As was described early, cardiac muscle
contains about 30% of its CK as CK-MB; the proportion in healthy skeletal muscle is about
1%.Thus even if total plasma CK is elevated (for example as a result of trauma or vigorous
exercise), the presence of more than about 5% of total as CK-MB suggests cardiac muscle
damage.

In patients with a typical history and ECG changes of MI, enzymes measurements do
not contribute to the initial management. Thrombolytic therapy is usually given unless
specifically contraindicated; this should be done as soon as possible, yet an increase in
CK-MB in plasma may not be seen until 4 -8 h after the onset of chest pain. When the
diagnosis is not obvious, an elevated CK-MB or increases in CK-MB of more than 15%
over 4-h period, even if both values are within the reference range, are suggestive for MI. As
so often with biochemical measurements, if feasible, may provide more information than
 single measurements. If CK does not increase in a patient with chest pain, MI is unlikely; a
failure of an elevated CK to fall suggests that the extension of the infarct has occurred.
AST and LDH measurements are rarely of practical value in the management of
patients with suspected MI. Exceptionally, when a patient with chest pain presents late,
measurement of LDH may be helpful as this enzyme remains elevated in the plasma for
several days following MI. However plasma troponin also remains elevated for up to a
week.
The lack of specificity and sensitivity of CK-MB measurements for MI, particularly
in the first few hours after the onset of the chest pain, has prompted the investigation of
many other potential cardiac markers, including myoglobin (Mb) and troponins.
Troponin I and troponin T are component proteins of the contractile apparatus in
muscle cells. Cardiac-specific isoforms of both have been identified. Neither increases in
plasma sufficiently early after the onset of the chest pain to inform to use of thrombolysis,
but both are highly specific and sensitive for myocardial damage. cTnT (and to lesser extend
cTnI) can also increase in unstable angina. Their greatest use is to exclude cardiac damage
in patients with chest pain: MI is highly unlikely is there is no increase in troponins. Finally,
troponin’s cardiac specificity helps eliminate the diagnostic uncertainty caused by increased
CK-MB following skeletal muscle injury.
It must be emphasized that the use of troponins for MI diagnosis requires a setting of
cardiac ischemia. Clinical interpretation of elevated cardiac troponin levels that are common
in heart failure, end-stage renal disease, and other conditions is uncertain at this time.
However, as a biomarker of adverse events, the presence of cardiac troponins suggests that
these patients are at grater risk for adverse cardiac events. It should be noted that even
though troponin measurements are based on immunoassays, false-positive results may be
associated with a variety of factors unrelated to heart disease.
cTnI
Although cTnI has a lower molecular weight (27kDa) than cTnT (37kDa) and CK-
MB (85kDa), its release kinetics and use as an early indicator of MI are similar to those of
cTnT and CK-MB. cTnI is similar to cTnT in most clinical applications, and its
measurements offers the same advantages over CK-MB. cTnI remains elevated 3 to7 days
after acute MI. Thus cTnI and Ck-MB have comparable diagnostic sensitivity for Mi during
the initial 48 to 72 hours after MI, with improved cTnI sensitivities 72 to 96 hours after MI.
In contrast to CK-MB and total CK, cTnI is not elevated in patients with extreme
skeletal muscle injury, including (1) acute skeletal muscle injury following marathon racing,
(2) chronic myopathy of Duchene’s muscular dystrophy, or (3) chronic renal failure
requiring dialysis.
cTnT
Once a Mi has occurred, cTnT increases in serum after 4 hours, achieving an initial
peak or plateau at 1 to 6 days.
According to the traditional WHO definition of Mi, the clinical sensitivity of cTnt is similar
to that of Ck-MB during the first 48 hours after onset of chest pain. Thus cTnT is not an early
marker of MI; it shows clinical sensitivity of 50% to 65% from 0 to 6 h after chest pain onset.
Because of the extended lifetime of cTnT in serum, levels may provide important diagnostic
information about the recent history of myocardial dysfunction. cTnT is important for risk
stratification of patients with ACS and is advocated in clinical guidelines for coronary
intervention and for targeting therapy with low-molecular-weight heparin and platelets inhibitors
in high-risk patients.

Mioglobin (Mb) is present both in cardiac and skeletal muscle, limiting its diagnostic
specificity. The value of Mb assay its is early appearance in serum after MI. Currently, Mb most
 effectively fits the role of an early marker. A rise in Mb is detectable in 1 to 2 hours after
symptom onset and is highly sensitive foe MI diagnosis and effective for rule-out in 2-to6 hour
time frame after onset of symptoms.
Mb is not cardiac specific, and patients with renal failure, or injury, trauma, or diseases
involving the skeletal muscle, can have abnormal Mb values in absence of MI.
Heart Fatty-Acid Binding Protein (H-FABP)
Heart-type fatty acid-binding protein is a low molecular weight (14.5 kDa) protein, which contains
132 amino acid residues. Fatty acid-binding proteins bind the long-chained fatty acids reversibly
and noncovalently, facilitating the intracellular cytoplasmic transport of the fatty acids, and are
highly expressed in tissues with active fatty acid metabolism such as the heart muscle. Heart-type
fatty acid-binding protein is abundant in the cytoplasm of myocardial cells and is also found in
skeletal muscle, in distal tubule cells of the kidney, and some parts of the brain. Following cell
damage by acute myocardial ischemia, H-FABP is released rapidly into the circulation and can be
detected at high concentrations in blood samples within 1h of myocardial necrosis. Its concentration
in blood reaches the maximum within 6–8h and generally decreases within 24–36 h. The release
and plasma kinetics of H-FABP closely resemble those of myoglobin. Recent studies showed that
H-FABP might be used as an early biochemical marker to detect myocardial necrosis in patients
admitted with acute chest pain. In patients with acute coronary syndrome, the serum markers of
myocardial necrosis indicate high risk. In particular, patients with atypical chest pain and
nondiagnostic ECG findings but suspected as having high-risk acute coronary syndrome can be
diagnosed and treated with the guidance of biochemical markers of myocardial necrosis in the early
period of chest pain.
In absence of renal insufficiency, H-FABP also provides a reliable estimate of infarct size
associated with ST segment elevation. When myocardial injury occurs after cardiac surgery, the
second peak in H-FABP concentration precedes that of myoglobin, CK-MB or troponins. In
addition, H-FABP peaks earlier and is more sensitive than troponins in the detection of subtle
myocardial injury in patients presenting with acute coronary syndrome without ST segment
elevation, and in patients with severe heart failure, thus offering early prognostic information.
Limitations of H-FABP include a limited cardio-specificity, a narrow diagnostic window (20 to
30 h), and a nearly exclusive renal elimination.
B-type Natriuretic Peptide or Brain Natriuretic Peptide (BNP)
Natriuretic peptides are a family of peptides which include atrial natriuretic peptide (ANP), brain
natriuretic peptide (BNP), C-type- natriuretic peptide (CNP) and urodilatin. Each is tissue specific
and independently regulated. Increased secretion of these natriuretic peptides in response to
intravascular volume expansion reduces blood pressure and plasma volume through coordinated
actions on the brain, vasculature, adrenal glands, and kidneys.
ANP is a hormone produced in the cardiac atria; it is released in response to stretching of the
atrial cavity. It relaxes venous capacitance of blood vessels by suppressing sympthatetic nervous
system activity. This reduces the increase in venous pressure that occurs with a given increase in
blood volume. ANP also increase vascular permeability and promotes natriuresis (renal loss of
sodium) and diuresis. The latter results from direct effects of ANP on renal hemodynamics (which
increase glomerular filtration rate), suppression of the rennin-angiotensin-aldrosterone system
(which inhibits tubular sodium reabsorption), and antagonization of the effect of ADH in the
collecting ducts (which inhibits water reabsorption). In the brain, ANP inhibits salt appetite, water
intake, and secretion of ADH and corticotrophin.
BNP is a hormone that is produce primarily in the left cardiac ventricles in response to left
ventricular pressure overload (it was first isolated in brain). It has cardiovascular, natriuretic, and
diuretic effects similar to ANP.
Release of both is increased in heart failure, although it would appear that BNP is better for
assessing ventricular function as a prognostic indicator. It is synthesized a prohormone, which is
 cleaved on the release from cardiac muscle cell to produce BNP and an N-terminal fragment
called NT-proBNP. Both can be measured in plasma, and a normal value virtually excludes heart
failure, although a raised concentration may occur in other conditions. NT-proBNP has a longer
half-life and is less sensitive to short-term stimuli for secretion than BNP, so may prove more
useful as a rule-out test for heart failure, and reduce the need of echocardiography for definitive
diagnosis.
CNP is produced and secreted by vascular endothelial cells. Little, if any is found circulation in
plasma. Thus it seems to act at local level. BNP and, to a much lesser extend ANP stimulate CNP
secretion. Secretion is also stimulated by local growth factors and cytokines. It is the most potent
venous dilator of the four natriuretic peptides, but it has no natriuretic effects. The venodilatation
of CNP is mediated via receptors in vascular smooth muscle cells.
Urodilatin is similar to structure to ANP but is formed directly in the kidney from the same
precursor protein as ANP is in the atria. Its regulation is unclear, and its diuretic and natriuretic
effects are more potent than those of ANP.
Measurement of circulating natriuretic peptides concentrations to classify and predict
mortality in patients with congestive heart failure might reduce the need for more expensive
evaluations.
In clinical practice, plasma natriuretic peptides levels have been used as quantitative
biomarkers of heart failure and proved to be highly effective for the diagnosis of heart failure, for
risk-stratification of patients and guided therapy, as well as for screening for subclinical cardiac
stress. Emerging studies are revealing the cardioprotective attributes of these peptides and may
offer new therapeutic venues for myocardial infarction and heart failure. Clinical trials have
documented the benefits and risks of the use of synthetic ANP (Anaritide) and BNP (Nesiritide)
for treating heart failure, renal failure, and hypertension.
Galectin-3
Galectin-3 is a member of the galectin family, which consists of animal lectins that bind beta-
galactosides. Recently, a role for galectin-3 in the pathophysiology of heart failure has been
suggested. It was observed that galectin-3 is specifically up regulated in decompensated heart
failure compared with compensated heart failure in animal models of heart failure. This has been
associated with activation of fibroblasts and macrophages, which are a hallmark of cardiac
remodeling. Therefore, galectin-3 may be a culprit biomarker in heart failure. Initial clinical
observations indicate that galectin-3 may be a useful biomarker for decompensated heart failure,
with incremental value over well-used "pressure-dependent" biomarkers, such as B-type natriuretic
peptide. Future studies should focus on galectin-3 biology to better address the usefulness of
galectin-3 as a biomarker and probe the usefulness of anti-galectin-3 therapy in treating heart
failure.
C Reactive Protein (CRP) is a classic acute phase protein, historically one of the first to be
recognized. CRP is rapidly synthesized in liver following induction by IL-6 family. The biological
half life of CRP is about 19h but it may be cleared more rapidly once it is bound to ligands.
MI is usually associated with an increased CRP concentration, often occurring within a few
hours of the onset of pain and typically reaching a peak on the third or fourth day and reaching
normal value at 7 -10 days after CKMB have usually returned to normal. A raised level in the
presence of suggestive symptoms is a sensitive indicator of this condition, being present in 49 of 50
patients with AMI and in all of 100 patients with significant Q-wave ECG changes. High levels
after 10 days suggest the presence of complications and bode a poor prognosis. Recent studies show
that raised circulating levels of CRP predict coronary events in patients with stable or unstable
angina. A relative risk of 3 was found in patients with CRP> 3.6mg/L. The Physicians Health Study
has provided evidence that baseline CRP concentrations predict the risk of future myocardial
infarction and stroke. People with concentrations of CRP< 0.55mg/L had a relative risk of 1.0, in
those with levels between 1.15 and 2.10 mg/L it was 2.6 while at levels .2.11mg/l it was 2.9.
Lipid metabolism
In adults the screening for hyperlipidimia is part of the routine check-up program for
cardiovascular risk factors. The procedure is shown in fig 7.

Fig.7 Flow diagram for identifying patients at risk of coronary heart disease.