Download CORONARY ARTERY DISEASE

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CORONARY ARTERY DISEASE
Ischemic
heart
disease
(which
includes
myocardial
infarction, angina pectoris and heart failure when preceded by myocardial
infarction) was the leading cause of death for both men and women
worldwide. Important risk factors are previous cardiovascular disease,
older age, tobacco smoking, high blood levels of certain lipids (lowdensity lipoprotein cholesterol, triglycerides) and low levels of high
density lipoprotein (HDL) cholesterol, diabetes, high blood pressure, lack
of physical activity and obesity, chronic kidney disease, excessive alcohol
consumption, the use of illicit drugs (such as cocaine and amphetamines),
and chronic high stress levels (Steptoe and Kivimäki, 2012).
Epidemiology:
Myocardial infarction is a common presentation of ischemic heart
disease/coronary
artery
disease.
The World
Health
Organization estimated that 12.2% of worldwide deaths were from
ischemic heart disease; with it being the leading cause of death in high or
middle income countries and second only to lower respiratory
infections in lower income countries. Worldwide more than 3 million
people have STEMIs and 4 million have NSTEMIs a year (White and
Chew, 2008).
Rates of death from ischemic heart disease have slowed or declined
in most high income countries, although cardiovascular disease still
accounted for 1 in 3 of all deaths in the USA in 2008. In contrast,
ischemic heart disease is becoming a more common cause of death in the
developing world. For example in India, ischemic heart disease had
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become the leading cause of death accounting for 1.46 million deaths
(14% of total deaths) and deaths due to ischemic heart disease were
expected to double during 1985–2015. Globally it is predicted
that disability adjusted life years (DALYs) lost to ischemic heart disease
will account for 5.5% of total DALYs in 2030, making it the second most
important cause of disability (after unipolar depressive disorder), as well
as the leading cause of death by this date (Roger et al., 2012).
Heart attack rates are higher in association with intense exertion,
(psychological stress or physical exertion), especially if the exertion is
more intense than the individual usually performs.The period of intense
exercise and subsequent recovery is associated with about a 6-fold higher
myocardial infarction rate (compared with other more relaxed time
frames) for people who are physically very fit for those in poor physical
condition, the rate differential is over 35-fold higher (Saikku et al.,
1992).
There is an association of an increased incidence of a heart attack
in the morning hours, more specifically around 9 a.m. Some investigators
have noticed that the ability of platelets to aggregate varies according to a
circadian rhythm, although they have not proven causation (Tofler et
al., 1987).
One observed mechanism for this phenomenon is increased pulse
pressure, which increases stretching of the arterial walls this stretching
results in significant shear stress on atheromas, which results in debris
breaking loose from these deposits, This debris floats through the blood
vessels, eventually clogging the major coronary arteries. Acute severe
infection, such as pneumonia, can trigger myocardial infarction (Saikku
et al., 1992).
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Myocardial infarction :
Myocardial infarction (MI) or acute myocardial infarction (AMI),
commonly known as a heart attack, results from the partial interruption
of blood supply to a part of the heart muscle, causing the heart cells to be
damaged or die. This is most commonly due to occlusion (blockage) of
a coronary artery following the rupture of a vulnerable atherosclerotic
plaque, which is an unstable collection of cholesterol and fatty
acids and white
blood
cells in
the
wall
of
an artery.
The
resulting ischemia (restriction in blood supply) and ensuring oxygen
shortage, if left untreated for a sufficient period of time, can cause
damage or death (infarction) of heart muscle tissue (myocardium)
(Mallinson, 2010).
Classification:
There are two basic types of acute myocardial infarction based on
pathology:
1-Transmural:
associated
with atherosclerosis involving
a
major
coronary artery. It can be subclassified into anterior, posterior, infe
rior, lateral or septal. Transmural infarcts extend through the whole
thickness of the heart muscle and are usually a result of complete
occlusion of the area's blood supply In addition, on ECG, ST elevation
and Q waves are seen.
2-Subendocardial: involving a small area in the subendocardial wall of
the left ventricle, ventricular septum, or papillary muscles. The
subendocardial area is particularly susceptible to ischemia (Reznik,
2010).
Myocardial infarction can be further subclassified clinically into :
1- ST elevation MI (STEMI)
2- non-ST elevation MI (non-STEMI)
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based on ECG changes. The phrase heart attack is sometimes used
incorrectly to describe sudden cardiac death which may or may not be the
result of acute myocardial infarction. A heart attack is different from, but
can be the cause of cardiac arrest, which is the stopping of the heartbeat,
and cardiac arrhythmia, an abnormal heartbeat. It is also distinct
from heart failure, in which the pumping action of the heart is impaired;
however severe myocardial infarction may lead to heart failure (Van de
Werf et al., 2008).
A 2007 consensus document classifies myocardial infarction into
five main types:
Type 1: Spontaneous myocardial infarction related to ischemia due to a
primary coronary event such as plaque erosion and/or rupture,
fissuring, or dissection
Type 2: Myocardial infarction secondary to ischemia due to either
increased oxygen demand or decreased supply, e.g. coronary
artery spasm, coronary embolism, anaemia, arrhythmias,
hypertension, or hypotension
Type 3 : Sudden unexpected cardiac death, including cardiac arrest, often
with
symptoms
suggestive
of
myocardial
ischaemia,
accompanied by new ST elevation, or new LBBB, or evidence
of fresh thrombus in a coronary artery by angiography and/or at
autopsy, but death occurring before blood samples could be
obtained, or at a time before the appearance of cardiac
biomarkers in the blood
Type 4 : Associated with coronary angioplasty or stents:
Type 4a – Myocardial infarction associated with PCI
Type 4b – Myocardial infarction associated with stent thrombosis
as documented by angiography or at autopsy
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Type 5 : Myocardial infarction associated with CABG (Thygesen et al.,
2007).
Signs and symptoms
A sizeable proportion of myocardial infarctions (22–64%) are
"silent", that is without chest pain or other symptoms (Roe et al., 2010 ).
The onset of symptoms in myocardial infarction (MI) is usually
gradual, over several minutes, and rarely instantaneous. Chest pain is the
most common symptom of acute myocardial infarction and is often
described as a sensation of tightness, pressure, or squeezing. Chest pain
due to ischemia (a lack of blood and hence oxygen supply) of the heart
muscle is termed angina pectoris (Van de Werf et al., 2008).
Pain radiates most often to the left arm, but may also radiate to the
lower jaw, neck,
right
arm, back,
and epigastrium, where
it
may
mimic heartburn. Levine's sign, in which the patient localizes the chest
pain by clenching their fist over the sternum, has classically been thought
to be predictive of cardiac chest pain, although a prospective
observational study showed that it had a poor positive predictive value
(Marcus et al., 2007).
Shortness of breath (dyspnea) occurs when the damage to the heart
limits the output of the left ventricle, causing left ventricular failureand
consequent pulmonary edema. Other symptoms include diaphoresis (an
excessive from of sweating), weakness, light-headehness, nausea,
vomiting, and palpitations. These symptoms are likely induced by a
massive
surge
of catecholamines from
thesympathetic
nervous
system which occurs in response to pain and the hemodynamic
abnormalities
that
result
from
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cardiac
dysfunction. Loss
of
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consciousness (due to inadequate cerebral perfusion and cardiogenic
shock) and sudden death (frequently due to the development of
ventricular fibrillation) can occur in myocardial infarctions (Van de
Werf et al., 2008).
Women and older patients report atypical symptoms more
frequently than their male and younger counterparts. Women also report
more numerous symptoms compared with men (2.6 on average vs 1.8
symptoms in men) (Canto et al., 2007).
The
most
common
symptoms
of
MI
in
women
include dyspnea (shortness of breath), weakness, and fatigue. Fatigue,
sleep disturbances, and dyspnea have been reported as frequently
occurring symptoms that may manifest as long as one month before. the
actual clinically manifested ischemic event. In women, chest pain may be
less predictive of coronary ischemia than in men (McSweeney et al.,
2003).
At least one-fourth of all myocardial infarctions are silent, without
chest pain or other symptoms. These cases can be discovered later on
electrocardiograms, using blood enzyme tests or at autopsy without a
prior history of related complaints. Estimates of the prevalence of silent
myocardial infarctions vary between 22 and 64% (Valensi et al., 2011).
A silent course is more common in the elderly, in patients
with diabetes mellitus and after heart transplantation, probably because
the donor heart is not fully innervated by the nervous system of the
recipient, In
people
with
diabetes,
differences
in pain
threshold, autonomic neuropathy, and psychological factors have been
cited as possible explanations for the lack of symptoms, any group of
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symptoms compatible with a sudden interruption of the blood flow to the
heart are called an acute coronary syndrome (Davis et al., 2004).
The differential diagnosis includes other catastrophic causes of
chest pain, such as pulmonary embolism, aortic dissection, pericardial
effusion causing cardiac
and esophageal
tamponade,
rupture.
Other
tension
non-catastrophic
pneumothorax,
differentials
includegastroesophageal reflux and Tietze's syndrome (Boie , 2005).
Risk factors for myocardial infarction :
Myocardial
infarction
results
from atherosclerosis. Smoking
appears to be the cause of about 36% of coronary artery disease and
obesity 20%. Lack of exercise has been linked to 7-12% of cases. Job
stress appear to play a minor role accounting for about 3% of
cases (Kivimäki et al., 2012).
1-Gender: men At any given age men are more at risk than women,
particularly before menopause. but because in general women live
longer than men ischemic heart disease causes slightly more total
deaths in women (Graham et al., 2007).
2-Diabetes mellitus (type 1 or 2).
3-High blood pressure
4-Dyslipidemia/hypercholesterolemia:
abnormal levels of lipoproteins in the blood, particularly high LDL-C,
low HDL-C and high triglycerides.
5-Tobacco smoking, including secondhand smoke (Smith et al., 2006).
6-Short term exposure to air pollution including:
carbon monoxide, nitrogen dioxide, and sulfur dioxide but not ozone.
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7-Family history of ischaemic heart disease or myocardial infarction
particularly if one has a first-degree relative (father, brother, mother,
sister) who suffered a 'premature' myocardial infarction (defined as
occurring at or younger than age 55 years (men) or 65 (women).
8-Obesity (defined by a body mass index of more than 30 kg/m², or
alternatively by waist circumference or waist-hip ratio).
9-Lack of physical activity (Graham et al., 2007).
10-Psychosocial factors including, low socio-economic status, social
isolation, negative emotions and stress increase the risk of myocardial
infarction and are associated with worse outcomes after myocardial
infarction. Socioeconomic factors such as a shorter education and
lower income (particularly in women), and unmarried cohabitation are
also correlated with a higher risk of MI (Nyboe et al., 1989)
11-Alcohol — Studies show that prolonged exposure to high quantities of
alcohol can increase the risk of heart attack.
12-Oral
contraceptive
pill –
women
who
use combined
oral
contraceptive pills have a modestly increased risk of myocardial
infarction, especially in the presence of other risk factors, such as
smoking.
13-Hyperhomocysteinemia (high homocysteine) in homocysteinuria is
associated
with
premature
atherosclerosis,
whether
elevated
homocysteine in the normal range is causal is contentious (Clarke et
al., 2011).
14-Calcium deposition is another part of atherosclerotic plaque
formation. Calcium deposits in the coronary arteries can be detected
with CT scans. Several studies have shown that coronary calcium can
provide predictive information beyond that of classical risk factors
(Detrano et al., 2008).
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Many of these risk factors are modifiable, so many heart attacks
can be prevented by maintaining a healthier lifestyle. Physical activity,
for example, is associated with a lower risk profile (Jensen ,et al. ,1991)
Non-modifiable risk factors include age, sex, and family history of
an early heart attack, which is thought of as reflecting a genetic
predisposition.To understand epidemiological study results, it is
important to note that many factors associated with MI mediate their risk
via other factors. For example, the effect of education is partially based
on its effect on income and marital status (Nyboe et al., 1989)
Pathophysiology
Acute myocardial infarction refers to two subtypes of acute
coronary syndrome, namely non-ST-elevated myocardial infarction and
ST-elevated myocardial infarction, which are most frequently (but not
always) a manifestation of coronary artery disease (Moe and Wong,
2010).
The most common triggering event is the disruption of
an atherosclerotic plaque in an epicardial coronary artery, which leads to
a clotting cascade, sometimes resulting in total occlusion of the artery
(Dohi and Daida, 2010)
Atherosclerosis is the gradual buildup of cholesterol and fibrous
tissue in plaques in the wall of arteries (in this case, the coronary
arteries), typically over decades. Blood stream column irregularities
visible on angiography reflect artery lumen narrowing as a result of
decades of advancing atherosclerosis (Spaan et al., 2008).
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Plaques can become unstable, rupture, and additionally promote
a thrombus (blood clot) that occludes the artery; this can occur in
minutes. When a severe enough plaque rupture occurs in the coronary
vasculature, it leads to myocardial infarction (necrosis of downstream
myocardium) (Dohi and Daida, 2010).
If impaired blood flow to the heart lasts long enough, it triggers a
process called the ischemic cascade; the heart cells in the territory of the
occluded coronary artery die (chiefly through necrosis) and do not grow
back. A collagen scar forms in its place. Recent studies indicate that
another form of cell death called apoptosis also plays a role in the process
of tissue damage subsequent to myocardial infarction (Krijnen et
al.,2002).
As a result, the patient's heart will be permanently damaged.
This myocardial scarring also puts the patient at risk for potentially life
threatening arrhythmias, and may result in the formation of a ventricular
aneurysm that can rupture with catastrophic consequences.
Injured heart tissue conducts electrical impulses more slowly than
normal heart tissue. The difference in conduction velocity between
injured and uninjured tissue can trigger re-entry or a feedback loop that is
believed to be the cause of many lethal arrhythmias. The most serious of
these arrhythmias is ventricular fibrillation (V-Fib/VF), an extremely fast
and chaotic heart rhythm that is the leading cause of sudden cardiac
death. Another life-threatening arrhythmia is ventricular tachycardia (VTach/VT), which may or may not cause sudden cardiac death. However,
ventricular tachycardia usually results in rapid heart rates that prevent the
heart
from pumping
blood
effectively. Cardiac
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pressure may fall to dangerous levels, which can lead to further coronary
ischemia and extension of the infarct (Dohi and Daida, 2010).
Myocardial infarction diagnosis
Medical societies recommend that the physician confirm that a
patient is at high risk for myocardial infarction before conducting
imaging tests to make a diagnosis. Patients who have a normal ECG and
who are able to exercise, for example, do not merit routine imaging.
Imaging tests such as stress radionuclide, myocardial, perfusion imaging
or stress echocardiography can confirm a diagnosis when a patient's
history, physical exam, ECG and cardiac biomarkers suggest the
likelihood of a problem (Taylor et al., 2010).
The diagnosis of myocardial infarction can be made after assessing
patient's
complaints
and
physical
status. ECG changes, coronary
angiogram and levels of cardiac markers help to confirm the diagnosis.
ECG gives valuable clues to identify the site of myocardialdamage
while coronary
angiogram allows
visualization
of
narrowing
or
obstructions in the heart vessels (Sudheer, 2011).
A pathologist can
diagnose
a
myocardial
infarction
based
on anatomopathological findings. A chest radiograph and routine blood
tests may indicate complications or precipitating causes and are often
performed upon arrival to an emergency department. New regional wall
motion abnormalities on an echocardiogram are also suggestive of a
myocardial infarction (Skoufis and McGhie, 1998).
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WHO criteria. formulated in 1979 have classically been used to
diagnose MI; a patient is diagnosed with myocardial infarction if two
(probable) or three (definite) of the following criteria are satisfied:
1-Clinical history of ischaemic type chest pain lasting for more than
20 minutes
2-Changes in serial ECG tracings (Anonymous ,March 1979).
3-Rise and fall of serum cardiac biomarkers such as creatine kinaseMB fraction and troponin.
The WHO criteria were refined in 2000 to give more prominence to
cardiac
biomarkers.
cardiac troponin rise
According
to
the
accompanied
by
either
new
guidelines,
typical
a
symptoms,
pathological Q waves, ST elevation or depression, or coronary
intervention is diagnostic of MI (Alpert et al., 2000).
A number of diagnostic tests are available to detect heart muscle
damage
including,
an electrocardiogram (ECG), echocardiography,
cardiac MRI and various blood tests. The most often used blood markers
are the creatine kinase-MB (CK-MB) fraction and the troponin levels
(Roe et al., 2010).
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Laboratory tests:
Types of cardiac markers include the following:
Table (1): cardiac markers.
Test
Approximate
Sensitivity and specificity
peak
Description
Troponin is released during MI
from the cytosolic pool of the
myocytes. Its subsequent release is
prolonged with degradation of actin
The most sensitive and
specific
and myosin filaments. Isoforms of
test
the protein, T and I, are specific to
for myocardial
myocardium. Differential diagnosis
damage. Because it has
Troponin test
increased
compared
MB,
specificity
with
troponin
superior
12 hours
CKis
marker
of troponin elevation includes acute
infarction,
severe
pulmonary
embolism causing acute right heart
a
overload, heart failure, myocarditis.
for
Troponins can also calculate infarct
myocardial injury.
size but the peak must be measured
in the 3rd day. After myocyte
injury, troponin is released in 2–4
hours and persists for up to 7 days.
CK-MB resides in the cytosol and
facilitates movement of high energy
Creatine
Kinase
MB) test
It is relatively specific
(CK- when skeletal muscle
damage is not present.
10–24
hours
phosphates
into
and
out
of
mitochondria. It is distributed in a
large number of tissues even in the
skeletal muscle. Since it has a short
duration, it cannot be used for late
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diagnosis of acute MI but can be
used to suggest infarct extension if
levels rise again. This is usually
back to normal within 2–3 days.
Lactate dehydrogenase catalyses
the
conversion
of pyruvate to lactate.
LDH-1
isozyme is normally found in the
heart muscle and LDH-2 is found
Lactate
dehydrogenase
(LDH)
LDH is not as specific
as troponin.
predominately in blood serum. A
72 hours high
LDH-1
level
to
LDH-2
suggest MI. LDH levels are also
high
in
tissue
breakdown
hemolysis.
It
or
can
mean cancer, meningitis, encephalit
is, or HIV. This is usually back to
normal 10–14 days.
Aspartate
This was the first used. It is not
transaminase(
specific for heart damage, and it is
AST)
also one of the liver function tests.
Myoglobin is used less than the
other markers. Myoglobin is the
Myoglobin (M
b)
low
specificity
for myocardial
primary oxygen-carrying pigment
2 hours of muscle tissue. It is high when
infarction
muscle tissue is damaged but it
lacks
specificity.
advantage
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of
It
has
responding
the
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rapidly, rising and falling earlier
than CK-MB or troponin. It also
has
been
used
in
assessing
reperfusion after thrombolysis.
IMA can be detected via the
albumin cobalt binding (ACB) test,
a limited available FDA approved
assay. Myocardial ischemia alters
the N-terminus of albumin reducing
the ability of cobalt to bind to
albumin. IMA measures ischemia
Ischemiamodified
in the blood vessels and thus
low specificity
returns results in minutes rather
albumin (IMA)
than traditional markers of necrosis
that take hours. ACB test has low
specificity
therefore
generating
high number of false positives and
must be used in conjunction with
typical acute approaches such as
ECG
and
physical
exam.
Additional studies are required.
This is increased in patients with
heart failure. It has been approved
Pro-brain
as a marker for acute congestive
natriuretic
heart failure. Pt with < 80 have a
peptide
much higher rate of symptom free
survival within a year. Generally, pt
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with CHF will have > 100.
Glycogen phosphorylase isoenzyme
BB (abbreviation: GPBB) is an
isoenzyme
of
phosphorylase.
glycogen
Glycogen
phosphorylase exists in 3 isoforms.
One of these Isoforms is GP-BB.
This isoform exists in heart and
brain tissue. Because of the blood–
brain barrier GP-BB can be seen as
heart muscle specific. During the
Glycogen
phosphorylase
process of ischemia, GP-BB is
0.854 and 0.767
7 hours converted into a soluble form and is
isoenzyme BB
released into the blood. This
isoform of the enzyme exists in
cardiac (heart) and brain tissue. GPBB is one of the "new cardiac
markers" which are discussed to
improve early diagnosis in acute
coronary syndrome. A rapid rise in
blood levels can be seen in
myocardial infarction and unstable
angina. GP-BB elevated 1–3 hours
after process of ischemia.
(Lewis et al ., 2008 and Lippi et al.,2013)
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Inflammation is known to be an important step in the process
of atherosclerotic
plaque formation. C-reactive
protein (CRP)
is
a
sensitive but non-specific marker forinflammation. Elevated CRP blood
levels, especially measured with high-sensitivity assays, can predict the
risk of MI, as well as stroke and development of diabetes. Moreover,
some drugs for MI might also reduce CRP levels (Wilson et al., 2006).
Prevention
The risk of a recurrent myocardial infarction decreases with strict
blood pressure management and lifestyle changes, chiefly smoking
cessation, regular exercise, a sensible diet for those with heart disease,
and limitation of alcohol intake. People are usually commenced on
several long-term medications post-MI, with the aim of preventing
secondary
cardiovascular
events
such
as
further
myocardial
infarctions, congestive heart failure or cerebrovascular accident (CVA)
(Rossi et al., 2006).
Unless contraindicated, such medications may include:
- Antiplatelet drug therapy such as aspirin and/or clopidogrel should
be continued to reduce the risk of plaque rupture and recurrent
myocardial infarction. Aspirin is first-line, owing to its low cost
and comparable efficacy, with clopidogrel reserved for patients
intolerant of aspirin. The combination of clopidogrel and aspirin
may further reduce risk of cardiovascular events, however the risk
of hemorrhage is increased (Peters et al., 2003).
- Beta blocker therapy such as metoprolol or carvedilol should be
commenced. These have been particularly beneficial in high-risk
patients such as those with left ventriculardysfunction and/or
continuing cardiac ischaemia. β-Blockers decrease mortality and
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morbidity. They also improve symptoms of cardiac ischemia in
NSTEMI (Dargie ,2001)
Treatment :
Immediate treatment for suspected acute myocardial infarction
includes oxygen, aspirin, and sublingualnitroglycerin, most cases of
myocardial infarction with ST elevation on ECG (STEMI) are treated
with
reperfusion
therapy,
such
as percutaneous
coronary
intervention (PCI) or thrombolysis (Roe et al.,2010).
Non-ST elevation myocardial infarction (NSTEMI) may be
managed with medication, although PCI may be required if the patient's
risk warrants it. People who have multiple blockages of their coronary
arteries, particularly if they also have diabetes mellitus, may benefit
from bypass surgery (CABG) (Hamm et al., 2011).
The European Society of Cardiology guidelines in 2011 proposed
treating the blockage causing the myocardial infarction by PCI and
performing CABG later when the patient is more stable. Rarely CABG
may be preferred in the acute phase of myocardial infarction, for example
when PCI has failed or is contraindicated (Van de Werf et al , 2008).
ACE inhibitor therapy should be commenced 24–48 hours post-MI
in hemodynamically stable patients, particularly in patients with a history
of MI, diabetes mellitus,hypertension, anterior location of infarct (as
assessed by ECG), and/or evidence of left ventricular dysfunction. ACE
inhibitors reduce mortality, the development of heart failure, and decrease
ventricular remodelling post-MI (Pfeffer et al.,1992).
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Statin therapy has been shown to reduce mortality and morbidity
post-MI. The effects of statins may be more than their LDL lowering
effects. The general consensus is that statins have plaque stabilization and
multiple other ("pleiotropic") effects that may prevent myocardial
infarction in addition to their effects on blood lipids (Ray and Cannon,
2005).
The aldosterone antagonist agent eplerenone has been shown to
further reduce risk of cardiovascular death post-MI in patients with heart
failure and left ventricular dysfunction, when used in conjunction with
standard therapies above. Spironolactone is another option that is
sometimes preferable to eplerenone due to cost. Evidence supports the
consumption of polyunsaturated fats instead of saturated fats as a measure
of decreasing coronary heart disease (Mozaffarian et al., 2010).
In high-risk people there is no clear-cut decrease in potentially fatal
arrhythmias due to omega-3 fatty acids. And they may increase risk in
some groups. Giving heparin to people with heart conditions like unstable
angina and some forms of heart attacks reduces the risk of having another
heart attack. However, heparin also increases the chance of minor
bleeding (Magee et al., 2008).
Angina pectoris : (Tobin., 2010).
Angina pectoris – commonly known as angina – is chest pain due
to ischemia of the heart muscle, generally due to obstruction or spasm of
the coronary arteries, the main cause of Angina pectoris is coronary
artery disease, due to atherosclerosis of the arteries feeding the heart. The
term derives from the Latin angina ("infection of the throat") from
the Greek ἀγχόνη ankhonē ("strangling"), and the Latin pectus ("chest"),
and can therefore be translated as "a strangling feeling in the chest".
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There is a weak relationship between severity of pain and degree of
oxygen deprivation in the heart muscle (i.e., there can be severe pain with
little or no risk of a Myocardial infarction (commonly known as a heart
attack), and a heart attack can occur without pain). In some cases Angina
can be extremely serious and has been known to cause death. People that
suffer from average to severe cases of Angina have an increased
percentage of death before the age of 55, usually around 60%.
Worsening ("crescendo") angina attacks, sudden-onset angina at
rest, and angina lasting more than 15 minutes are symptoms ofunstable
angina (usually grouped with similar conditions as the acute coronary
syndrome). As these may herald myocardial infarction (a heart attack),
they require urgent medical attention and are generally treated as a
presumed heart attack.
Classification of angina : (Tobin., 2010)
1- Stable angina
Also known as effort angina, this refers to the more common
understanding of angina related to myocardial ischemia. Typical
presentations of stable angina is that of chest discomfort and associated
symptoms
- Precipitated by some activity (running, walking, etc.)
- With minimal or non-existent symptoms at rest or with
administration of sublingual nitroglycerin.
- -Symptoms typically abate several minutes following cessation of
precipitating activities.
- Reoccur when activity resumes.
In this way, stable angina may be thought of as being similar
to intermittent claudication symptoms.
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2- Unstable angina
Unstable angina (UA) (also "crescendo angina;" this is a form of acute
coronary syndrome) is defined as angina pectoris that changes or
worsens (Simons and Michael, 2000). It has at least one of these three
features:
-It occurs at rest (or with minimal exertion), usually lasting >10 min;
-It is severe and of new onset (i.e., within the prior 4–6 weeks); and/or
-It occurs with a crescendo pattern (i.e., distinctly more severe,
prolonged, or frequent than before).
UA may occur unpredictably at rest which may be a serious
indicator of an impending heart attack. What differentiates stable angina
from unstable angina (other than symptoms) is the pathophysiology of the
atherosclerosis. The pathophysiology of unstable angina is the reduction
of coronary flow due to transient platelet aggregation on apparently
normal endothelium, coronary artery spasms or coronary thrombosis
(Mosca et al., 2011).
3- Microvascular angina
Microvascular Angina or Angina Syndrome X is characterized by
angina-like chest pain, but the cause is different. The cause of
Microvascular Angina is unknown, but it appears to be the result of
spasm in the tiny blood vessels of the heart, arms and legs. Since
microvascular angina isn't characterized by arterial blockages, it's harder
to recognize and diagnose, but its prognosis is excellent (Guyton and
Arthur, 2006).
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Major risk factors : (Moyer and Virginia .,2012).
1-Age (≥ 55 years for men, ≥ 65 for women)
2-Cigarette smoking
3-Diabetes mellitus (DM)
4-Dyslipidemia
5-Family history of premature cardiovascular disease (men <55 years,
female <65 years old)
6-Hypertension (HTN)
7-Kidney disease (microalbuminuria or GFR<60 mL/min)
8-Obesity (BMI ≥ 30 kg/m2)
9-Physical inactivity
10-Prolonged psychosocial stress.
Routine counselling of adults to advise them to improve their diet
and increase their physical activity has not been found to significantly
alter behaviour, and thus is recommended.
Pathophysiology
The process starts with atherosclerosis, and when inflamed leads to
an active plaque, which undergoes thrombosis and results in acute
ischemia, which finally results in cell necrosis after calcium entry.
Studies show that 64% of all unstable anginas occur between 10
PM and 8 AM when patients are at rest (Simons and Michael ,2000).
In stable angina, the developing atheroma is protected with a
fibrous cap. This cap (atherosclerotic plaque) may rupture in unstable
angina, allowing blood clots to precipitate and further decrease
the lumen of the coronary vessel. This explains why an unstable angina
appears to be independent of activity (Mosca et al., 2011).
26
Review of literature
Angina results when there is an imbalance between the heart's
oxygen demand and supply. This imbalance can result from an increase in
demand (e.g. during exercise) without a proportional increase in supply
(e.g. due to obstruction or atherosclerosis of the coronary arteries).
However, the pathophysiology of angina in females varies
significantly as compared to males. Non-obstructive coronary disease is
more common in females (Vaccarino, 2010).
Signs and symptoms : (Sun et al., 2002)
Angina pectoris can be quite painful, but many patients with angina
complain of chest discomfort rather than actual pain: the discomfort is
usually described as a pressure, heaviness, tightness, squeezing, burning,
or choking sensation. Apart from chest discomfort, anginal pains may
also be experienced in the epigastrium (upper central abdomen), back,
neck area, jaw, or shoulders.
This is explained by the concept of referred pain, and is due to the
spinal level that receives visceral sensation from the heart simultaneously
receiving cutaneous sensation from parts of the skin specified by that
spinal nerve's dermatome, without an ability to discriminate the two.
Typical locations for referred pain are arms (often inner left arm),
shoulders, and neck into the jaw. Angina is typically precipitated by
exertion or emotional stress.
It is exacerbated by having a full stomach and by cold
temperatures. Pain may be accompanied by breathlessness, sweating and
nausea in some cases. In this case, the pulse rate and the blood pressure
increases. Chest pain lasting only a few seconds is normally not angina
(such as Precordial catch syndrome).
27
Review of literature
Myocardial ischemia comes about when the myocardia (the heart
muscles) receive insufficient blood and oxygen to function normally
either because of increased oxygen demand by the myocardia or by
decreased supply to the myocardia. This inadequate perfusion of blood
and the resulting reduced delivery of oxygen and nutrients is directly
correlated to blocked or narrowed blood vessels.
Some experience "autonomic symptoms" (related to increased
activity
of
the autonomic
as nausea, vomiting and pallor.
include cigarette
pressure, sedentary
nervous
Major
risk
smoking, diabetes, high
lifestyle and family
system)
factors
such
for
angina
cholesterol, high
blood
history of
premature
heart
disease.
A variant form of angina (Prinzmetal's angina) occurs in patients
with normal coronary arteries or insignificant atherosclerosis. It is
thought to be caused by spasms of the artery. It occurs more in younger
women.
One study found that smokers with coronary artery disease had a
significantly
increased
level
of sympathetic
nerve activity
when
compared to those without. This is in addition to increases in blood
pressure, heart rate and peripheral vascular resistance associated with
nicotine which may lead to recurrent angina attacks. Additionally, CDC
reports that the risk of CHD (Coronary heart disease), stroke, and PVD
(Peripheral vascular disease) is reduced within 1–2 years of smoking
cessation. In another study, it was found that after one year, the
prevalence of angina in smoking men under 60 after an initial attack was
40% less in those who had quit smoking compared to those who
continued. Studies have found that there are short term and long term
benefits to smoking cessation. (Shinozaki et al., 2008).
28
Review of literature
Myocardial ischemia can result from: (Podrid, 2012)
A reduction of blood flow to the heart that can be caused
by stenosis, spasm, or acute occlusion (by an embolus) of the heart's
arteries.
Resistance of the blood vessels. This can be caused by narrowing
of the blood vessels; a decrease in radius. Blood flow is proportional to
the radius of the artery to the fourth power.
Reduced oxygen-carrying capacity of the blood, due to several
factors such as a decrease in oxygen tension and hemoglobin
concentration. This decreases the ability of hemoglobin to carry oxygen
to myocardial tissue.
Atherosclerosis is the most common cause of stenosis (narrowing
of the blood vessels) of the heart's arteries and, hence, angina pectoris.
Some people with chest pain have normal or minimal narrowing of heart
arteries; in these patients, vasospasm is a more likely cause for the pain,
sometimes in the context of Prinzmetal's angina and syndrome X.
Myocardial ischemia also can be the result of factors affecting blood
composition, such as reduced oxygen-carrying capacity of blood, as seen
with severe anemia (low number of red blood cells), or longterm smoking (Vaccarino, 2010).
Diagnosis : (Banks, et al., 2010)
Suspect angina in people presenting with tight, dull, or heavy chest
discomfort which is:
- Retrosternal or left-sided, radiating to the left arm, neck, jaw, or
back. Associated with exertion or emotional stress and relieved
29
Review of literature
within several minutes by rest. Precipitated by cold weather or a
meal.
- Some
people
present
with
atypical
symptoms,
including
breathlessness, nausea, or epigastric discomfort or burping. These
atypical symptoms are particularly likely in older people, women,
and those with diabetes.
- Angina pain is not usually sharp or stabbing or influenced by
respiration. Anti-acids and simple analgesia do not usually relieve
the pain. If chest discomfort (of whatever site) is precipitated by
exertion, relieved by rest, and relieved by glyceryl trinitrate, the
likelihood of angina is increased.
Laboratory tests : (Fox K, 2010)
Recommendations for laboratory investigation in initial assessment of
stable angina.
Class I (in all patients)
Fasting lipid profile, including TC, LDL, HDL, and triglycerides
(level of vidence B).
1. Fasting glucose (level of evidence B)
2. Full blood count including Hb and white cell count (level of
evidence B)
3. Creatinine (level of evidence C)
Class I (if specifically indicated on the basis of clinical evaluation)
1- markers of myocardial damage if evaluation suggests clinical
instability or ACS (level of evidence A).
2- Thyroid function if clinically indicated (level of evidence C).
30
Review of literature
Class IIa
(1) Oral glucose tolerance test (level of evidence B)
Class IIb
(1) Hs-C-reactive protein (level of evidence B)
(2) Lipoprotein(a), ApoA, and ApoB (level of evidence B)
(3) Homocysteine (level of evidence B)
(4) HbA1c (level of evidence B)
(5) NT-BNP (level of evidence B)
Recommendations for blood tests for routine reassessment in
patients with chronic stable angina.
Class IIa
(1) Fasting lipid profile and fasting glucose on an annual basis (level of
evidence C).
N.B
Class Level of symptoms
Class I ‘Ordinary activity does not cause angina’ Angina with strenuous
or rapid or prolonged exertion only
Class II ‘Slight limitation of ordinary activity’ Angina on walking or
climbing stairs rapidly, walking uphill or exertion after meals,
in cold weather, when under emotional stress, or only during the
first few hours after awakening.
Class III ‘Marked limitation of ordinary physical activity’ Angina on
walking one or two blocksa on the level or one flight of stairs at
a normal pace under normal conditions.
Class IV ‘Inability to carry out any physical activity without
discomfort’ or ‘angina at rest’.
31
Review of literature
In angina patients who are momentarily not feeling any one chest
pain, an electrocardiogram (ECG) is typically normal, unless there have
been other cardiac problems in the past. During periods of pain,
depression or elevation of the ST segment may be observed. To elicit
these changes, an exercise ECG test ("treadmill test") may be performed,
during which the patient exercises to their maximum ability before
fatigue, breathlessness or, importantly, pain intervenes; if characteristic
ECG changes are documented (typically more than 1 mm of flat or
downsloping ST depression), the test is considered diagnostic for angina.
Even constant monitoring of the blood pressure and the pulse rate can
lead us to some conclusion regarding the angina. The exercise test is also
useful in looking for other markers of myocardial ischaemia. (Podrid,
2012).
In patients in whom such noninvasive testing is diagnostic,
a coronary angiogram is typically performed to identify the nature of the
coronary
lesion,
and
whether
this
would
be
a
candidate
for angioplasty, coronary artery bypass graft (CABG), treatment only
with medication, or other treatments. There has been research which
concludes that a frequency is attained when there is increase in the blood
pressure and the pulse rate. This frequency varies normally but the range
is 45–50 kHz for the cardiac arrest or for the heart failure In patients who
are in hospital with unstable angina (or the newer term of "high risk acute
coronary syndromes"), those with resting ischaemic ECG changes or
those with raised cardiac enzymes such as troponin may undergo
coronary angiography directly. (Banks et al., 2010).
32
Review of literature
Therefore, there is need for identifying new biomarkers, which
alone or in combination with other risk markers are useful in monitoring
treatment and as prognostic markers for future cardiovascular events in
patients with ischemic heart disease. (Camilla and Henrik, 2009).
33
Review of literature
YKL-40
The inflammatory biomarker YKL-40: (Camilla and Henrik, 2009).
It has been found elevated in patients with both acute and stable
chronic cardiovascular diseases. Therefore, YKL-40 could potentially be
a new useful biomarker of disease severity, prognosis and survival in
patients with ischemic heart disease .
YKL-40 is an inflammatory glycoprotein involved in endothelial
dysfunction by promoting chemotaxis, cell attachment and migration, and
tissue remodelling as a response to endothelial damage. YKL-40 protein
expression is seen in macrophages and smooth muscle cells in
atherosclerotic plaques with the highest expression seen in macrophages
in the early lesion of atherosclerosis. Several studies demonstrate, that
elevated serum YKL-levels are independently associated with the
presence and extent of coronary artery disease and even higher YKL-40
levels are documented in patients with myocardial infarction. Moreover,
elevated serum YKL-40 levels have also been found to be associated with
all-cause as well as cardiovascular mortality .
YKL-40 levels are elevated both in patients with type 1 and type 2
diabetes, known to be at high risk for the development of cardiovascular
diseases, when compared to non-diabetic persons. A positive association
between elevated circulating YKL-40 levels and increasing levels of
albuminuria have been described in patients with type 1 diabetes
indicating a role of YKL-40 in the progressing vascular damage resulting
in microvascular disease. There is a relatin between YKL-40 and
34
Review of literature
endothelial dysfunction, atherosclerosis, cardiovascular disease and
diabetes and look ahead on future perspectives of YKL-40 research.
YKL-40 - biology and physiology:
YKL-40 is a 40 kDa heparin- and chitin-binding glycoprotein also
known as human cartilage glycoprotein 39 (HC-gp39) 38-kDa heparinbinding glycoprotein or chitinase-3-like protein 1 (CHI3L1) The
abbreviation YKL-40 is based on the one letter code for the first three Nterminal amino acids, tyrosine (Y), lysine (K) and leucine (L) and the
apparent molecular weight of YKL-40 (Camilla and Henrik 2009).
The CHI3L1 gene for human YKL-40 is localized in a highly
conserved area on chromosome 1q31-q32 and the crystal structure of
YKL-40 has been described . YKL-40 belongs to the family 18 of
glycosyl hydrolases comprising chitinases from various species, but
YKL-40 is without any enzymatic properties (Johansen, 2006).
YKL-40 is secreted by various cell-types including macrophages,
chondrocytes
and
some
types
of cancer
cells.
YKL-40
lacks chitinase activity due to mutations within the active site (conserved
sequence: DXXDXDXE ; YKL-40 sequence: DGLDLAWL). The exact
physiological role of YKL-40 is not known, but it has been implicated in
development,
inflammatory
disease
(such
as asthma, and
cancer
progression) (Ober, et al., 2008).
Function
Chitinases catalyze the hydrolysis of chitin, which is an abundant
glycopolymer found in insect exoskeletons and fungal cell walls. The
glycoside hydrolase 18 family of chitinases includes eight human family
members. This gene encodes a glycoprotein member of the glycosyl
35
Review of literature
hydrolase 18 family. The protein lacks chitinase activity and is secreted
by activated macrophages, chondrocytes, neutrophils and synovial cells.
The protein is thought to play a role in the process of inflammation and
tissue remodeling (Francescone et al., 2011).
YKL-40 is secreted in vitro by a variety of cells and seems
especially involved in activation of the innate immune system and in cell
processes in relation to extracellular matrix remodelling .YKL-40 induce
the maturation of monocytes to macrophages, and is secreted by
macrophages during late stages of differentiation and by activated
macrophages (Rehli ,et al 2003).
Studies show that the differentiation and maturation of CD14+
monocytes to CD14-, CD16+ macrophages are attended by an expression
of YKL-40 from CD16+ macrophages .YKL-40 has also been shown to
be an adhesion and migration factor for vascular cells and is secreted by
differentiated vascular smooth muscle cells (VSMCs) (Nishikawa and
Millis 2003).
The knowledge about the physiological function and the
mechanisms by which YKL-40 mediates its effects is still scarce.
Immunohistochemical studies of different types of normal human tissues
show, that cells with a high cellular activity, e.g. a high level of metabolic
activity and/or proliferation, have especially high YKL-40 expression
(Johansen et al., 2007).
In vivo YKL-40 protein expression is found in human VSMCs in
adventitial vessels and in subpopulations of macrophages and VSMCs in
different tissues with inflammation and extracellular matrix remodelling
as in atherosclerotic plaques (Nishikawa and Millis, 2003).
36
Review of literature
YKL-40 mRNA and protein expression are found in tissues from
all germ layers and are present during the early development of the
human musculoskeletal system where they seem associated with cell
proliferation, differentiation and tissue morphogenesis (Johansen et al.,
2007).
Other studies show, that YKL-40 stimulates the proliferation of
human connective tissue cells (fibroblasts, chondrocytes, synovial cells)
in a dose-dependent manner in a functional concentration range similar to
that of insulin-like growth factor (IGF-1). When present in suboptimal
concentrations, YKL-40 and IGF-1 work in a synergistic fashion
(Recklies et al., 2002).
In mouse studies, YKL-40 stimulates the antigen-induced T-helper
2-response and seems to induce tissue inflammation and fibrosis
mediated by IL-13. In this sense, YKL-40 plays an essential role in
antigen sensitization and IgE induction as well as in activation of innate
immune cells (Lee et al., 2009).
In fibroblasts and synovial cells YKL-40 mediates a mitogenic
effect through initiation of mitogen-activated protein kinase (MAPK) and
phosphoinoside-3 kinase (PI3K) signalling pathways by phosphorylation
of the extracellular signal-regulated kinase-1 and 2 (ERK1/ERK2) and
protein kinase B (AKT), respectively. Both pathways are required for the
cells to complete mitosis and the activation of these pathways stimulates
the growth of connective tissue cells (Recklies et al., 2002).
In fibroblasts and chondrocytes YKL-40 reduces the activation of
p38 and SAPK/JNK MAPKs which counteracts the inflammatory
responses to TNFα and IL-1. This leads to reduced concentrations of
37
Review of literature
matrix metalloproteinases (MMPs) and IL-8. The modulation of p38 and
SAPK/JNK by YKL-40 is mediated through the PI3K and the induction
and continued secretion of YKL-40 require sustained activation of NfκB. (Ling et al., 2005).
YKL-40 has no effect on the signalling pathways p38 and
SAPK/JNK MAPKs when present without the presence of TNFα and IL1 and similar do not affect the MMP or IL-8 production. This suggests
that YKL-40 expression is an anti-inflammatory counteract of the
inflammatory response mediated by TNFα and IL-1 beside its apparent
function as a growth factor (Recklies et al., 2002).
The activation of cytoplasmatic signal-transduction pathways
suggests, that YKL-40 interacts with one or several signalling
components on the plasma membrane. However, specific cell surface
receptors or potential YKL-40 ligands remain to be determined. No
difference in serum or plasma YKL-40 levels has been found between
genders (Johansen 2006).
YKL-40 in endothelial dysfunction and atherosclerosis:
(Malinda et
al., 2009).
The participation of YKL-40 in inflammatory states and vascular
processes implies that YKL-40 may play a role in endothelial dysfunction
and atherosclerosis. In endothelial dysfunction, elevated YKL-40 levels
seem to be involved in relation to cell migration, reorganization and
tissue remodelling as a response to endothelial damage.
In vitro VSMCs from explants of swine thoracic aorta syntesize
YKL-40 during the time of transition from monolayer culture to a nonproliferating differentiated multilayer culture .The YKL-40 secretion
38
Review of literature
continues during the reorganisation of the cells where multicellular
nodules are formed. In these nodules the cells re-express markers of
differentiated VSMCs.
This in vitronodule forming process mimics some of the
characteristics of the in vivo changes that occur in VSMCs following
injury, where media smooth muscle cells differentiate, migrate and
contribute to the process of restenosis and neointima formation.
In vitro studies also show that YKL-40 promotes chemotaxis, cell
attachment, spreading and migration of vascular endothelial cells which
suggest a role of YKL-40 in the atherosclerotic plaque formation, where
smooth muscle cells are induced to migrate through the intima in
response to exogenous signals.
YKL-40 also modulates vascular endothelial cell morphology by
promoting the formation of branching tubules, indicating that YKL-40
has a role in angiogenesis by stimulating the migration and reorganization
of VSMCs .These in vitro studies are supported by immunohistochemical
analysis which has shown in vivo protein expression of YKL-40 in human
smooth muscle cells in atherosclerotic plaques .
YKL-40 mRNA expression is highly up-regulated in distinct
subsets of macrophages in the atherosclerotic plaque, a plaque that is
characterized by the infiltration of monocytes into the subendothelial
space of the vessel wall and a subsequent lipid accumulation in the
activated macrophages. Particularly macrophages that infiltrate deeper in
the lesion show high YKL-40 mRNA expression and the highest
expression is seen in macrophages in the early lesion of atherosclerosis
(Boot et al., 1999).
39
Review of literature
An in vitro study with emphasis on biomarker discovery for
atherosclerosis by proteomics, show elevated YKL-40 levels in the
supernatant of macrophages following treatment with oxidized lowdensity lipoprotein, a process that mimics the formation of "foam cells
(Fach et al., 2004).
This also suggests a role of YKL-40 in the differentiation of
monocytes to lipid-laden macrophages during formation of the
atherosclerotic plaque.
YKL-40 in cardiovascular disease: (Kastrup et al., 2009).
In the last few years, several clinical studies have described
elevated YKL-40 levels in several cardiovascular conditions as well as
described an association between YKL-40 and mortality. Studies show,
that elevated YKL-levels are independently associated with the presence
of CAD.
One study even found, that YKL-40 levels increase with the extent
of CAD defined by the number of stenosed vessels as assessed by
coronary angiography .This findings indicate, that plasma YKL-40 levels
could be a quantitative indicator of disease progression as well as of
disease presence. In patients suffering myocardial infarction (MI) even
higher YKL-levels have been documented, and YKL-levels remain
higher in patients with prior MI compaired to individuals without
previous MI.
There seems to be no difference in YKL-40 levels between MI
patients with or without ST elevations, but higher YKL-40 levels were
seen in thrombolyzed patients compared with non-thrombolyzed patients
during the first 24 hours after the event, indicating that YKL-40 is
40
Review of literature
released from the dissolved thrombosis. Elevated YKL-40 levels have
also been documented in individuals with atrial fibrillation (AF) where
the highest YKL-40 levels were found in patients with permanent AF
compared to patients with persistent AF suggesting an association
between the chronicity of AF and the inflammatory burden (Nojgaard et
al., 2008).
Elevated YKL-40 levels have also been found to be associated with
all-cause as well as cardiovascular mortality in patients with stable
CAD .Furthermore, increasing mortality rates with increasing YKL-40
levels at baseline are also seen over a 5 year period in the general
population above 50 years of age without known diabetes or CVD in
which YKL-40 were also found to be an independent predictor of overall
as well as of cardiovascular mortality (Kastrup et al., 2009).
YKL-40 and diabetes
It has been demonstrated, that patients with type 1 diabetes as well
as patients with type 2 diabetes have elevated plasma YKL-40 levels . In
type 2 diabetes patients YKL-40 levels are correlated with insulin
resistance ,and in a single study also with the diabetic lipid profile . Some
studies have also shown a correlation between YKL-40 and glycemic
parameters such as hemoglobin A1c and fasting glucose whereas others
have not (Rathcke et al., 2006).
Individuals with diabetes have in general a 2- to 4-fold increased
risk of subsequent CVD .Persistent microalbuminuria is associated with
an increased risk of CVD in both patients with type 1 and type 2
diabetes . Patients with type 1 diabetes have up to a 9-fold increased
mortality risk from ischemic heart disease, excessively higher in patients
under 30 years of age (Rossing et al., 2005).
41
Review of literature
In patients with type 1 diabetes a positive association between
elevated plasma YKL-40 levels and increasing levels of albuminuria has
been described .This finding indicates a role of YKL-40 in the
progressing vascular damage in the kidneys resulting in complicating
microvascular disease. This hypothesis is supported by the finding that
YKL-40 and urinary albumin/creatinine ratio (UACR) are independent
markers with only weak intercorrelation that seem to predict overall as
well as cardiovascular mortality in a synergistic way in the general
population above 50 years of age without known diabetes or CVD over a
5 year period (Rathcke et al., 2009).
YKL-40 in other clinical conditions
The exact biological function of YKL-40 in cancer is unknown, but
YKL-40 seems to play an important role in tumor invasion. The
signalling pathways MAPK/ERK1/2 and PI3K/AKT which YKL-40 has
been demonstrated to mediate its effects through in other conditions ,are
critical in the malignant phenotype of glioblastoma and have been shown
to govern proliferation and survival, invasiveness and radiation
resistance .Furthermore, activation
of the PI3K/AKT-pathway is
correlated with increased tumor grade, lesser likelihood of apoptosis and
decreased overall survival . However, the functional ligand for the chitinbinding site in YKL-40 in relation to cancer is not presently known
(Pelloski et al., 2006).
Serum YKL-40 levels have been found to be elevated in other
clinical conditions not directly related to atherosclerosis or cardiovascular
disease. Several studies describe elevated YKL-40 levels in patients with
different types of cancer .YKL-40 levels seem to be related to tumor
grade and burden, short recurrence-free interval and short disease-free
and overall survival (Johansen, 2006).
42
Review of literature
An in vitro study has shown, that ectopic expression of YKL-40 in
breast and colon cancer cells respectively led to tumor formation with an
extensive angiogenic phenotype and that recombinant YKL-40 protein
promoted vascular endothelial cell angiogenesis whereas blockade of
YKL-40
suppressed
tumor
angiogenesis
both in
vitro and in
vivo Furthermore, immunohistochemical analysis of human breast cancer
showed a correlation between YKL-40 expression and blood vessel
density (Pelloski et al., 2006).
Therefore, the occurrence of high YKL-40 levels in highly
differentiated and advanced cancers and recurrent cancer states could be
explained by the role of YKL-40 in both angiogenesis and fibrogenesis,
since highly differentiated tumours are characterized by high
vascularization and a high turnover of extracellular matrix. YKL-40 is not
tumor specific and the studies of YKL-40 as a screening marker for
cancer and as a marker useful for monitoring therapeutic results differ.
Furthermore, YKL-40 seems not suited as a tumor marker due to low
specificity and sensitivity (Johansen et al., 2006).
Role in cancer
YKL-40
is
cytokine that
the tumor micro-environment
is
and
present
in
the
at
high
serum
levels
of
in
cancer
patients. Elevated levels of YKL-40 correlate strongly with stage and
outcome of various types of cancer, which establish YKL-40 as a
biomarker of disease severity. Targeting YKL-40 with neutralizing
antibodies has been proven effective as a treatment in animal models
of glioblastoma multiforme. YKL-40 is able to promote angiogenesis
through VEGF-dependent and independent pathways.
43
Review of literature
YKL-40 also enhances tumor survival in response to gammairradiation (Francescone et al., 2011).
Methods for determination of YKL-40 in tissues and body fluids:
(Johansen, 2006).
 Microarray cDNA analysis.
 In situ hybridization.
 Immunohistochemical analysis.
 Radio-and enzyme-linked immunoassays for the determination
of YKL-40.
44
Review of literature
Myeloperoxidase
Myeloperoxidase (MPO) is an enzyme stored in azurophilic
granules of polymorphonuclear neutrophils and macrophages and
released into extracellular fluid in the setting of inflammatory process.
The observation that myeloperoxidase is involved in oxidative stress and
inflammation has been a leading factor to study myeloperoxidase as a
possible marker of plaque instability and a useful clinical tool in the
evaluation of patients with coronaryheart disease. Myeloperoxidase
(MPO) is a well-known enzyme, mainly released by activated
neutrophils,
characterised
by
powerful
pro-oxidative
and
proinflammatory properties. Myeloperoxidase has been proposed as a
useful risk marker and diagnostic tool in acute coronary syndromes and in
patients admitted to emergency room for chest pain (Valentina et al.,
2008).
Pathophysiological Role of Myeloperoxidase in Ischemic Heart
Disease:
Myeloperoxidase (MPO) was traditionally considered to be a
bactericidal agent. Recent investigations revealed a crucial role of MPO
in
chronic,
nonmicrobial
inflammatory
processes
such
as
neurodegenerative diseases and atherosclerosis. MPO, a glycosylated,
arginine-rich, extremely basic protein (isoelectric point >10) is comprised
of two subunits, encoded within a single mRNA. Two of each subunits
are assembled with heme molecules to produce the functional enzyme
(donor:
hydrogen
peroxide,
oxidoreductase,
(Madlusudhana, et al., 20l1).
45
EC
1.11.1.7)
Review of literature
Oxidative stress and inflammation play important roles in the
destabilization of coronary artery disease (CAD) leading pathogenesis of
to acute coronary syndromes (ACS). Infiltrating macrophages and
neutrophils participate in the transformation of stable coronary artery
plaques to unstable lesions . There has been a renewed interest in MPO, a
proinflammatory enzyme that is abundant in ruptured plaque and can be
measured in peripheral blood (Takahiko et al., 2002).
MPO is stored in primary azurophilic granules of leukocytes and
the enzyme accounts for up to 5 and 1% of total cell protein content, in
neutrophilic polymorphonuclear leukocytes (neutrophils) and monocytes,
respectively.The
ability
of
MPO
to
generate
hypochlorous
acid/hypochlorite (HOCl/OCl−) from hydrogen peroxide in the presence
of chloride ions is a unique and defining activity for this enzyme. The
importance of MPO-catalyzed oxidative reactions and formation of a
variety of chlorinated protein and lipid adducts (with hypochlorous acid
as the major oxidant in causing tissue injury by phagocytic cells) has been
emphasized. (Madlusudhana, et al., 20l1).
MPO catalyzes the conversion of chloride and hydrogen peroxide
to hypochlorite and is secreted during inflammatory condition. It has been
implicated in the oxidation of lipids contained within LDL cholesterol. In
addition, MPO consumes endothelial-derived NO, thereby reducing NO
bioavailability and impairing its vasodilating and anti-inflammatory
properties. Major evidence for MPO as enzymatic catalyst for oxidative
modification of lipoproteins in the artery wall has been suggested in a
number of studies performed with low-density lipoprotein (Holvoet,
1998).
46
Review of literature
Furthermore, high levels of MPO-mediated endothelial dysfunction
may be an important mechanistic link between oxidation, inflammation,
and cardiovascular disease (CVD) .An elevated level of plasma MPO
served as independent predictor of increased risk of myocardial infarction
. However, the role of MPO in chronic kidney disease (CKD) is poorly
understood, and not much data is available regarding the variations of this
enzyme in these patients. It was speculated that raised levels of this
enzyme might be one of the factors responsible for the increased risk that
these patients have for developing CVD (Madlusudhana, et al., 20l1).
In contrast to low-density lipoprotein, plasma levels of highdensity
lipoprotein
(HDL)-cholesterol
and
apoAI,
the
major
apolipoprotein of HDL, inversely correlate with the risk of developing
coronary artery disease. There is now strong evidence that HDL is a
selective in vivo target for MPO-catalyzed oxidation, that may represent a
specific molecular mechanism for converting the cardioprotective
lipoprotein into a dysfunctional form, raising the possibility that the
enzyme represents a potential therapeutic target for preventing vascular
disease in humans (Shao et al., 2006).
MPO activity can be measured in blood and tissues by
spectrophotometric assays using hydrogen peroxide and o-dianisidine
dihydrochloride as substrates. In addition, MPO content can be measured
in neutrophils as an index of degranulation with the Coulter counter and
flow cytometry and circulating MPO by ELISA. Commercial methods
allowing low-cost and high-volume measurements have been proposed.
The introduction of these methods of measurement might make MPO a
new and useful cardiac biomarker (Valentina et al., 2008).
47
Review of literature
Furthermore, high levels of MPO-mediated endothelial dysfunction
may be an important mechanistic link between oxidation, inflammation,
and cardiovascular disease (CVD) .An elevated level of plasma MPO
served as independent predictor of increased risk of myocardial infarction
. However, the role of MPO in chronic kidney disease (CKD) is poorly
understood, and not much data is available regarding the variations of this
enzyme in these patients. It was speculated that raised levels of this
enzyme might be one of the factors responsible for the increased risk that
these patients have for developing CVD (Madlusudhana, et al., 20l1).
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is
encoded by the MPO gene. Myeloperoxidase is most abundantly
expressed in neutrophil granulocytes . It is a lysosomal protein stored
in azurophilic granules of the neutrophil. MPO has a heme pigment,
which causes its green color in secretions rich in neutrophils, such
as pus and some forms of mucus )Klebanoff., 2005).
Structure:
The 150-kDa MPO protein is a dimer consisting of two 15-kDa
light chains and two variable-weight glycosylated heavy chains bound to
a prosthetic heme group. Three isoforms have been identified, differing
only in the size of the heavy chains. It contains a calcium binding site
with seven ligands, forming a pentagonal pyramid conformation. One of
the ligands is thecarbonyl group of Asp 96. Calcium-binding is important
for structure of the active site because of Asp 96's close proximity to the
catalytic His95 side chain (Mathy-Hartert et al., 1998).
Function:
MPO
produces hypochlorous
acid (HOCl)
from hydrogen
peroxide (H2O2) and chloride anion (Cl-) (or the equivalent from a non48
Review of literature
chlorine halide) during the neutrophil's respiratory burst. It requires heme
as a cofactor. Furthermore, it oxidizes tyrosine to tyrosyl radical
using hydrogen peroxide as an oxidizing agent. Hypochlorous acid and
tyrosyl radical are cytotoxic, so they are used by the neutrophil to
kill bacteria and other pathogens (Kettle et al., 1997).
Myeloperoxidase deficiency is a hereditary deficiency of the
enzyme, which predisposes to immune deficiency. Antibodies against
MPO have been implicated in various types of vasculitis,most
rominently crescentic glomerulonephritisand Churg-Strauss
syndrome.
They are detected as perinuclear ANCAs (p-ANCAs), as opposed to the
cytoplasmic ANCAs (c-ANCAs) against proteinase-3 (PR3), which are
strongly associated with Wegener's granulomatosis. Recent studies have
reported an association between myeloperoxidase levels and the severity
of coronary artery disease. It has been suggested that myeloperoxidase
plays a significant role in the development of the atherosclerotic lesion
and rendering plaques unstable (Lau and Baldus ; 2006).
Medical uses:
An initial 2003 study suggested that MPO could serve as a
sensitive predictor for myocardial infarction in patients presenting
with chest pain. Since then, there have been over 100 published studies
documenting the utility of MPO testing. Heslop et al. 2010 reported that
elevated MPO levels doubled the risk for cardiovascular mortality over a
13-year period, and measuring both MPO and CRP (C-reactive protein; a
general and cardiac-related marker of inflammation) provided added
benefit for risk prediction than just measuring CRP alone. (Heslop et al.,
2010).
49
Review of literature
Upon neutrophil activation and degranulation these enzymes are
released into the plasma. MPO has been considered a surrogate marker of
neutrophil activation and plasma levels of the enzyme found to be
elevated in patients with coronary heart disease (CHD) and acute
coronary syndromes (ACS) (Marshall and Catriona, 2011).
Immunohistochemical staining for myeloperoxidase used
to
diagnose acute myeloid leukemia to demonstrate that the leukemic cells
were
derived
from
the myeloid lineage.
However,
the
use
of
myeloperoxidase staining in this setting has been supplanted by the
widespread use of flow cytometry. Myeloperoxidase staining is still
important in the diagnosis of myeloid sarcoma, contrasting with the
negative staining of lymphomas, which can otherwise have a similar
appearance (Kagan et al., 2010).
Plasma MPO levels have also been investigated in patients
presenting with troponin negative ACS and found to be higher than
controls suggesting the early activation of neutrophils. MPO has several
potentially deletrious effects including the ability to catalyse the
production of several reactive oxidant species such as hypochlorus acid
which can chlorinate both proteins and lipids. It also consumes nitric
oxide affecting endothelial function leading to vasoconstriction
(Marshall and Catriona., 2011).
In recent times MPO is being implicated in diseases associated
with chronic non-microbial pathological processes, which have no direct
link with infection, and, in which oxidative stress and inflammation play
dominant roles. This article seeks to provide a bird’s eye view of these
two aspects of the action of MPO, namely its protective action against
50
Review of literature
micro-organisms and its role in chronic diseases associated with
inflammation. MPO is an oxidoreductase (EC No. 1.11.1.7) which is
stored in the azurophilic granules of polymorphonuclear neutrophils
(Usha et al., 2012).
The enzyme myeloperoxidase (MPO) was almost exclusively
associated with the phenomenon of innate immunity. For almost a
century, most of the studies that were carried out on this enzyme were
directed towards elucidating the intricate biochemical mechanisms
involved in bacterial killing (Iyer et al. 1961).
It is a strongly cationic hemoprotein with a molecular mass of 114
kDa. It consists of two identical 72 kDa monomers linked by a disulphide
bridge. Each monomer is composed of a light chain and a heavy chain
which is glycosylated and also contains the heme lodged in a deep cleft
(Usha et al., 2012).
Hypochlorous acid further reacts with H2O2 and nitrates to form
reactive oxygen and nitrogen species. The highly reactive nature of these
products ensures destruction of the invading pathogen and is almost
invariably associated with a certain degree of damage to the host tissue.
While these reactions are primarily meant to take place within the
confines of the phagosomes, not infrequently they are discharged outside
the cell and this could bring about destruction of biomolecules in the
surrounding tissue. Although MPO is crucial for the protection against
invading pathogens, inappropriate activity of this enzyme could lead to
host tissue damage. Increased activity of this enzyme is now being
implicated in a wide variety of pathological conditions such as
51
Review of literature
cardiovascular disease, cancer, renal disease, lung injury and Alzheimer’s
disease (Klebenoff , 2005).
MPO and Cardiovascular Disease:
In recent years several epidemiologic studies have shown that
higher levels of MPO are associated with increased risk of cardiovascular disease and also that this was independent of the hitherto
established classical risk factors MPO levels were found to be higher in
patients angiographically proven coronary artery disease (Usha et al.,
2012).
MPO in patients presenting with acute chest pain provided
clinically useful information of prognostic significance. In patients
presenting with acute chest pain, it has been proved that, a single initial
measurement of plasma myeloperoxidase independently predicts the early
risk of myocardial infarction, as well as the risk of major adverse cardiac
events in the ensuing 30-day and six-month periods (Brennan et al.,
2003).
MPO serves not only as a marker of acute coronary syndromes but
is also intimately involved in the process of atherosclerosis; it potentially
acts as a mechanistic bridge between inflammation and cardio-vascular
disease. MPO dependant processes are involved in the etiopathogenesis
of atherosclerosis through multiple mechanisms which include, foam cell
formation, endothelial dysfunction, development of vulnerable plaque
and ventricular remodeling following acute myocardial infarction (Usha
et al .,2012).
The oxidative stress created by the down-stream products of
increased MPO activity can bring about conversion of native LDL into
52
Review of literature
the oxidized LDL, rendering it more atherogenic (Stefanescu et al.,
2008).
Nitric oxide, a biomolecule which brings about vasodilatation, is
rapidly inactivated by products of the MPO reaction causing endothelial
dysfunction. MPO also has a role in destabilization of stable coronary
plaques by promoting the degradation of the collagen layer which
prevents abrupt rupture. Plaque destabilization and rupture are thought to
be essential processes in inducing acute cardiovascular events (Usha et
al., 2012).
MPO and Lung Injury:
Studies carried out in experimental animals and humans have
shown that MPO has a role to play in the induction of lung injury. Severe
acute lung injury has been produced in rats by the simultaneous
intratracheal infusion of glucose oxidase which served as a source of
H2O2 and MPO Patients with idiopathic pulmonary fibrosis have
increased levels of MPO in the alveolar epithelial lining fluid .Tracheal
aspirates of premature infants who developed chronic lung disease had
elevated levels of 3-chlorotyrosine, which is considered to be a marker of
protein damage by the MPO system I (Usha et al., 2012).
Filtration of lungs by neutrophils, a condition referred to as
neutrophilia, is a common feature in a variety of lung diseases such as
acute respiratory distress syndrome, idiopathic pulmonary fibrosis,
asbestosis and chronic obstructive pulmonary disease (Haegens, et al
2009).
MPO promotes the development of lung neutrophilia and indirectly
influences subsequent chemokine and cytokine production in the lung.
53
Review of literature
Increased levels of MPO, a marker of active neutrophilia, have been
found in the broncho-alveolar lavage of patients with COPD and MPO
(Barczyk et al., 2004).
MPO and Alzheimer’s Disease:
MPO has been detected in microglia adjacent to senile clots in the
cerebral cortex of patients with Alzheimer’s disease Apo-E which is also
found in senile clots of these patients is highly susceptible to oxidation by
MPO (Reynolds et al., 1999).
MPO and Kidney Disease
MPO has been shown to be an important pathogenic factor in
glomerular and tubulo-interstitial diseases. Several studies have shown
the presence of MPO-containing cells MPO activity triggers the
production of several highly reactive and deleterious products as well as
MPO activity in a variety of renal disorders (Usha et al .,2012).
When neutrophils adhere to glomeruli, they generate oxidants
through MPO-catalysed reactions, causing degradation of the glomerular
basement membrane. Renal perfusion experiments with MPO followed
by its substrates, namely, H2O2 and chloride ions, resulted in glomerular
morphologic changes, endothelial and mesangial cell injury, activation of
platelets, and subsequent proliferative responses mimicking inflammatory
and proliferative glomerular nephritis in humans. MPO has been
implicated in the pathogenesis of various types of renal diseases (Malle
et al., 2003).
54
Review of literature
Lipoprotien (a)
Lipoprotein(a) [Lp(a)] has been considered a cardiovascular risk
factor for many years. Owing to incomplete scientific evidence, screening
for and treatment of high Lp(a) levels have to date been performed
principally by lipid specialists. However, during the last few years, major
advances have been achieved in understanding the causal role of elevated
Lp(a) in premature cardiovascular disease (CVD) (Kamstrup et al.,
2009).
Lipoprotein (a) is a plasma lipoprotein consisting of a cholesterolrich LDL particle with one molecule of apolipoprotein B100 and an
additional protein, apolipoprotein (a), attached via a disulfide
bond. Elevated Lp(a) levels can potentially increase the risk of CVD (i)
via prothrombotic/anti-fibrinolytic effects as apolipoprotein(a) possesses
structural homology with plasminogen and plasmin but has no
fibrinolytic activity and (ii) via accelerated atherogenesis as a result of
intimal deposition of Lp(a) cholesterol, or both (Clarke et al., 2009).
Genetics:
Plasma levels of Lp(a) are to a large extent genetically determined via
variation in the apolipoprotein(a) gene This makes the apolipoprotein(a)
gene ideal for use in a Mendelian randomization study, examining whether
lifelong, genetically elevated levels of plasma Lp(a) cause CVD. By
analogy, familial hypercholesterolaemia with mutations in the LDL receptor
or apolipoprotein B genes have lifelong, genetically elevated LDL
cholesterol levels and premature CVD, a fact that has helped establish that
elevated LDL cholesterol levels constitute a direct cause of atherosclerosis
and CVD (Borge et al., 2010).
55
Review of literature
A Mendelian randomization study needs three pieces of data to
help provide evidence for a causal link between elevated plasma Lp(a)
levels and CVD. First, elevated plasma Lp(a) levels is associated with
increased CVD risk. Secondly, genetic variation should exist in human
populations that can explain a large fraction of the variation in plasma
Lp(a) levels: such genetic variation has been known for many years, most
importantly the kringle IV type 2 size polymorphism ,resulting in a
variable number from 2 to >40 number of a 5.6 kb repeat associated
inversely with plasma Lp(a) levels. Thus, the fewer the repeats in the
apolipoprotein(a) gene, the higher the plasma levels of Lp(a), which has
also been demonstrated in the past. Thirdly, such genetic variation should
be linked directly with CVD risk (Kamstrup et al., 2009).
Metabolism:
It is believed that plasma concentrations of Lp(a) are determined
chiefly by rates of hepatic synthesis of apolipoprotein(a): although the
site of formation of Lp(a) has not been definitively identified, evidence
suggests that apolipoprotein(a) adducts extracellularly and covalently to
apolipoprotein
B100-containing
lipoproteins,
predominantly
LDL, Apolipoprotein(a) genotype, which determines both the synthetic
rate and size of the apolipoprotein(a) moiety of Lp(a), alone accounts for
90% of plasma concentrations of Lp(a) (Borge et al., 2010).
As hepatic secretion rates are lower for large apolipoprotein(a)
isoforms, and as most individuals are heterozygous for two different
isoforms, the smallest isoform typically predominates in plasma.
Lipoprotein(a) is thought to be catabolized primarily by hepatic and renal
pathways, but these metabolic routes do not appear to govern plasma
Lp(a) levels (Ballantyne et al., 2009).
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Review of literature
Pathophysiological Mechanisms Underlying the Atherothrombotic
Potential of Lipoprotein (a):
After transfer from plasma into the arterial intima, Lp(a) may be
more avidly retained than LDL as it binds to the extracellular matrix not
only through apolipoprotein(a), but also via its apolipoprotein B
component, thereby
contributing
cholesterol
to
the
expanding
atherosclerotic plaque. In vitro, Lp(a) binds to several extracellular matrix
proteins including fibrin and defensins, a family of 29–35 amino acid
peptides that are released by neutrophils during inflammation and severe
infection. It is likely that defensins, like lipoprotein lipase, provide a
bridge between Lp(a) and the extracellular matrix (Nielsen, 1999).
Lp(a) also interacts with the β2-integrin Mac-1, thereby promoting
the adhesion of monocytes and their transendothelial migration. [25] In
atherosclerotic coronary arteries, Lp(a) was found to localize in close
proximity to Mac-1 on infiltrating mononuclear cells (Sotiriou et al.,
2006).
Lipoprotein(a) has also been shown to bind pro-inflammatoryoxidized phospholipids and is a preferential carrier of oxidized
phospholipids in human plasma. Lipoprotein(a) also contains lipoproteinassociated phospholipase A2 (equally referred to as Paf-acetylhydrolase),
which may cleave oxidized fatty acids at the sn-2 position in oxidized
phospholipids to yield short chain fatty acids and lysolecithin (Tsimikas
et al., 2007).]
Apolipoprotein(a), a homologue of the fibrinolytic proenzyme
plasminogen, impairs fibrinolysis. Indeed, Lp(a)/apolipoprotein(a) can
competitively
inhibit
tissue-type
plasminogen
activator-mediated
plasminogen activation on fibrin surfaces, although the mechanism of
inhibition by apolipoprotein(a) remains controversial. Essential to fibrin
57
Review of literature
clot lysis are a number of plasmin-dependent, positive feedback reactions
that enhance the efficiency of plasminogen activation, including the
plasmin-mediated conversion of Glu-plasminogen to Lys-plasminogen. It
has been observed that the apolipoprotein(a) component of Lp(a) inhibits
the key positive feedback step involving conversion of plasmin-mediated
Glu-plasminogen to Lys-plasminogen. Lipoprotein(a) may also enhance
coagulation by inhibiting the function of tissue factor pathway inhibitor
(Feric et al., 2008).
Small isoforms of apolipoprotein(a) have been observed to possess
elevated potency in inhibiting fibrinolysis and thereby promoting
thrombosis. Indeed, a recent meta-analysis demonstrated a two-fold
increase in the risk of CHD and ischaemic stroke in subjects with small
apolipoprotein(a) phenotypes. Furthermore, prospective findings in the
Bruneck study have revealed a significant association specifically
between small apolipoprotein(a) phenotypes and advanced atherosclerotic
disease involving a component of plaque thrombosis. These data suggest
that the determination of apolipoprotein(a) phenotype/genotype may
provide clinicians with additional information by which to evaluate
Lp(a)/apolipoprotein(a)-associated atherothrombotic risk (Børge et
al., 2010).
Elevated Lp(a) levels may promote atherosclerosis via Lp(a)derived cholesterol entrapment in the intima, via inflammatory cell
recruitment, and/or via the binding of pro-inflammatory-oxidized
phospholipids.
The
prothrombotic,
anti-fibrinolytic
actions
of
apolipoprotein(a) are expressed on the one hand as inhibition of
fibrinolysis with enhancement of clot stabilization and on the other as
enhanced coagulation via the inhibition of tissue factor pathway inhibitor
(Erqou et al., 2010).
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Review of literature
Measurement:
Several types of Lp(a) assays are currently available, some
commercially; prominent among them are sandwich enzyme-linked
immunosorbent
assays
(ELISA),
non-competitive
ELISA,
latex
immunoassays, immunonephelometric assays, and immunoturbidometric
and fluorescence assays. In order for clinical laboratories to provide
clinicians with Lp(a) values which allow correct cardiovascular risk
evaluation when Lp(a) is included in the estimate, the following elements
in standardization between Lp(a) assays are critical (Børge et al., 2010).
Compared with LDL, Lp(a) is relatively refractory to both lifestyle
and drug intervention. The data on the effects of statins and fibrates on
Lp(a) are limited and highly variable. Overall, statins have, however,
been shown to consistently and modestly decrease elevated Lp(a) in
patients with heterozygous familial hypercholesterolaemia. Other agents
reported to decrease Lp(a) to a minor degree (<10%) include aspirin, Lcarnitine, ascorbic acid combined with L-lysine, calcium antagonists,
angiotensin-converting enzyme inhibitors, androgens, oestrogen, and its
replacements (e.g. tibolone), anti-estrogens (e.g. tamoxifen), and
thyroxine replacement in hypothyroid subjects (Ballantyne ,et al., 2009).
In the absence of a defined physiological role of Lp(a), its
pathophysiological role is undoubtedly that of a prominent risk factor for
the development of CVD. Circulating levels of Lp(a) are not significantly
modified by traditional lipid-lowering therapies, and so alternative
approaches to target its adverse functions specifically are necessary and
may be of therapeutic value. This paper will focus on the detrimental
effects of Lp(a) in the cardiovascular system including the coagulation
cascade, inflammatory pathways and modulation of smooth muscle
59
Review of literature
(SMC), and endothelial cell (EC) behaviour within blood vessel walls
(Lippi and Targher, 2012).
Following injury to the vessel wall, platelets become activated and
trigger thrombus formation. Fibrin cross-links and stabilises the clot;
during resolution it is broken down by plasmin to minimise vessel
occlusion. Lp(a) has been demonstrated to act as a prothrombotic factor,
interfering with clot biology at multiple levels, as follows:
Evidence of Lp(a) influencing the initial activation of platelets is
scarce, although both Lp(a) and apo(a) alone have been demonstrated to
promote activation via thrombin-receptor-activated hexapeptide (TRAP).
However, the ability of Lp(a) to directly affect platelet aggregation is
much more contentious. Studies have shown that both Lp(a) and apo(a)
alone enhanced aggregation in response to arachidonic acid and TRAP
had no effect on aggregation induced by collagen or thrombin (Riches
and Porter,2012).
Lp(a) had previously been demonstrated to inhibit aggregation
induced by low concentrations of collagen (4 mg/mL) ,however, in that
case the inhibitory effect was not observed when collagen concentrations
were increased to 10 mg/mL . Aggregation in response to platelet
activating factor (PAF) has also been reported to be inhibited by Lp(a)
( Tsironis et al., 2004).
The antiaggregatory effects of Lp(a) may be mediated via its
interaction with integrin I I b3. Integrin I I b3 is normally bound by
fibrinogen to promote platelet aggregation, yet apo(a) can displace
fibrinogen from the receptor thus inhibiting this process. In addition,
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Review of literature
functional effects of Lp(a) can be dependent on modifications of the
Lp(a) molecule—platelet granule secretion was altered when Lp(a) was
modified by lipid peroxidation products or acetylation . It is clear that the
interaction of Lp(a) with platelets is complex and involves a balance
between Lp(a) subunit binding, protein modifications, and the factor
stimulating platelet aggregation (Riches and Porter,2012)
Transportation of Oxidised Phospholipids:
Lp(a) is claimed to be an acute phase reactant, with increased
circulating levels being observed following myocardial infarction and
percutaneous coronary intervention. It is speculated that this may point to
a physiological anti-inflammatory role for Lp(a) in patients with low
plasma levels, whereby Lp(a) could bind to and remove oxidised
phospholipids from the circulation, preventing further damage. Oxidised
phospholipids are proinflammatory in nature and are bound by Lp(a).
Although they are often found associated with apoB-100 , studies have
shown that within the Lp(a) molecule the association was dependent on
KV of the apo(a) moiety (Edelstein et al., 2003).
The amount of oxidised phospholipid bound to apo(a) remained
constant and was unaffected by apo(a) size suggesting that it was bound
to apo(a) during synthesis in the hepatocyte and was not derived from
plasma LDL. Whilst this may be beneficial in low concentrations, in
patients with high plasma levels of Lp(a) preferential binding of oxidised
phospholipids may lead to their deposition within the vessel wall, hence
promoting atherogenesis (Edelstein et al., 2009).
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Review of literature
Induction of Inflammatory Cytokines
Lipoprotein(a) (Lp(a)) is an LDL-like molecule consisting of an
apolipoprotein B-100 (apo(B-100)) particle attached by a disulphide
bridge to apo(a). Many observations have pointed out that Lp(a) levels
may be a risk factor for cardiovascular diseases. Lp(a) inhibits the
activation of transforming growth factor (TGF) and contributes to the
growth of arterial atherosclerotic lesions by promoting the proliferation of
vascular smooth muscle cells and the migration of smooth muscle cells to
endothelial cells (Malaguarnera et al, 2013).
Lp(a) has been shown to induce inflammatory cytokine expression
in a cell-type-specific manner. For example, apo(a) induced IL-8
expression in macrophages, but not monocytes. Detailed analysis
revealed that Lp(a) induced a 12-fold increase in IL-8 mRNA, whereas
apo(a) alone was almost three times more potent in inducing
transcription. This was mirrored at the protein level and was dependent
on KV and interaction with Gs protein receptors. IL-8 induction was not
observed by exposure to LDL or Lp(a) moieties without the apo(a)
fragment confirming the essential role of the apo(a) moiety in this
process. In addition, Lp(a) also induced expression of IL-1β, tumour
necrosis factor alpha (TNF-α), and monocyte chemoattractant protein
(MCP-1) in macrophages (Nakagami et al., 2010).
Moreover Lp(a) inhibits plasminogen binding to the surfaces of
endothelial cells and decreases the activity of fibrin-dependent tissue-type
plasminogen activator. Lp(a) may act as a proinflammatory mediator that
augments the lesion formation in atherosclerotic plaques. Elevated serum
Lp(a) is an independent predictor of coronary artery disease and
myocardial infarction (Malaguarnera et al, 2013).
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Review of literature
Cardiovascular diseases cause 3% of all deaths in North America
being the most common cause of death in European men under 65 years
of age and the second most common cause in women. These facts
suggested us to consider new strategies for prediction, prevention, and
treatment of cardiovascular disease (Klingenberg and Hansson et al.,
2009).
Furthermore, Lp(a) levels should be a marker of restenosis after
percutaneous transluminal coronary angioplasty, saphenous vein bypass
graft atherosclerosis, and accelerated coronary atherosclerosis of cardiac
transplantation. Finally, the possibility that Lp(a) may be a risk factor for
ischemic stroke has been assessed in several studies. Recent findings
suggest that Lp(a)-lowering therapy might be beneficial in patients with
high Lp(a) levels. A future therapeutic approach could include apheresis
in high-risk patients in order to reduce major coronary events
(Malaguarnera et al, 2013).
Inflammatory mechanisms play a central role in the pathogenesis
of atherosclerosis and its complications .It has been demonstrated that
atherogenic lipoproteins such as apo(B-100), oxidized low-density
lipoprotein (LDL), remnant lipoprotein (beta-VLDL), and lipoprotein(a)
play a critical role in the proinflammatory reaction. High-density
lipoprotein (HDL) is antiatherogenic lipoproteins that exert antiinflammatory functions (Motta et al., 2009).
Plasma LDL cholesterol is a well-established predictor of coronary
artery disease (CAD), and many observations have pointed out that Lp(a)
and apolipoprotein(a) (apo(a)) levels may be risk factors for
cardiovascular diseases (CVD) (Walldius and Jungner, 2004).
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Review of literature
Animal experiments showed that apo(a) serves as a distinctive
marker of Lp(a) and represents an atherogenic component of Lp(a)
.Furthermore, apo(a) has also been reported to be correlated to coronary
artery disease as well as renal disease. Dissociation of apo(a) may lead to
the exposure of an additional lysine-binding site, increasing the affinity of
free apo(a) for plasmin modified fibrin, thus impeding fibrinolysis
.Apo(a) is a member of a family of “kringle" containing proteins, such as
plasminogen, tissue plasminogen activator (tPA), prothrombin, factor
XII, and macrophage stimulating factor (MSF). Lp(a) shares a high
degree of sequence identity with plasminogen. These similarities could
explain the role of Lp(a) in thrombogenesis and as a proinflammatory
factor .Native Lp(a) has been shown to enhance the expression of
adhesion molecules (Galvano et al., 2010).
Because of the structural homology with plasminogen, Lp(a) might
have important antithrombolytic properties, which could contribute to the
pathogenesis of atherothrombotic disease. For example, Lp(a) binding to
immobilised fibrinogen and fibrin results in the inhibition of plasminogen
binding to these substrates .In addition, Lp(a) competes with plasminogen
for its receptors on endothelial cells, leading to diminished plasmin
formation, thereby delaying clot lysis and favouring thrombosis. The high
affinity of Lp(a) for fibrin provides a mechanistic basis for their frequent
colocalization in atherosclerotic plaques .Moreover Lp(a) induces the
monocyte chemoattractant (CC chemokine I-309), which leads to the
recruitment of mononuclear phagocytes to the vascular wall (Haque et
al., 2000).
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Review of literature
Oxidized Lp(a):
Lp(a) particles can suffer oxidative modification and scavenger
receptor uptake, with cholesterol accumulation and foam cell formation
,leading to atherogenesis. Oxidation of LDL and Lp(a) affects the
catabolism of the lipoproteins, including changes in receptor recognition,
catabolic rate, retention in the vessel wall, and propensity to accelerate
atherosclerosis. Oxidative modification of apo(a) may have an influence
on Lp(a) recognition by scavenger receptors of macrophages. Some
studies showed that Lp(a) particles are prone to oxidation and that the
increased risk of coronary artery disease associated with elevated Lp(a)
levels may be related in part to their oxidative modification and uptake by
macrophages, resulting in the formation of macrophage-derived foam
cells (Malaguarnera et al, 2013).
The oxidative form of Lp(a) (ox-Lp(a)) might attenuate fibrinolytic
activity through the reduction of plasminogen activation, might enhance
PAI-1 production in vascular endothelial cells, and might impair
endothelium-dependent vasodilation. Particularly, the role of ox-Lp(a) is
linked to macrophages that take up ox-Lp(a) via scavenger receptor as
well as oxidized LDL. Lp(a) particles are susceptible to oxidative
modification and scavenger receptor uptake, leading to intracellular
cholesterol accumulation and foam cell formation, which contributes
further to atherogenesis .Morishita et al. demonstrated increased values of
ox-Lp(a) in patients with coronary artery disease (Morishita et al., 2009).
A study of autopsy findings demonstrated a deposition of ox-Lp(a)
in the vessel margin inside the calcified areas .Probably it was related to
the promotion of an antifibrinolytic environment, foam cell formation,
generation of a fatty streak, and an increase in smooth muscle cells.
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Review of literature
Moreover ox-Lp(a) is a potent stimulus of monocyte adhesion to
endothelial cells, thus contributing to atherogenic changes in human
blood vessels. (Malaguarnera et al, 2013).
Komai et al., 2002 compared the effects of oxidized lipoproteins
and no oxidized lipoprotein on the progression of atherosclerosis. It was
investigated the mitogenic actions of Lp(a) and ox-Lp(a) on human
vascular smooth muscle cells (VSMC). The results were that Lp(a)
significantly stimulated the growth of human VSMC in a dose-dependent
manner, whereas ox-Lp(a) showed a stronger stimulatory action on
VSMC growth than native Lp(a). This study demonstrated that ox-Lp(a)
has a more potent effect than native Lp(a) in developing atherosclerosis
diseases.
Glycated Lp(a):
Nonenzymatic glycation of lipoprotein may contribute to the
premature atherogenesis in patients with diabetes mellitus by diverting
lipoprotein catabolism from nonatherogenic to atherogenic pathways. It
has been observed that the proportion of apo (B-100) in glycated form
was significantly higher in diabetic patients than in nondiabetic controls,
and equally that plasma Lp(a) levels might be increased in diabetic
patients .Anyway, glycation does not appear to significantly enhance the
atherogenic potential of unmodified Lp(a) ( Libby, 2002).
The formation of advanced glycation end-products (AGEs) and
EC-mediated oxidative modification may contribute to the alterations of
the generation of PAI-1 and t-PA induced by glycated Lp(a) . The
combination of hyperglyaemia and hyperlipoprotein(a) may reduce ECderived fibrinolytic activity, which may promote the development of
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Review of literature
thrombosis and atherosclerosis in subjects with diabetes (Malaguarnera
et al., 2013).
A task force for emerging risk factor assessed the relationship
between Lp(a) concentration and risk of major vascular and nonvascular
outcomes. In this long-term prospective study, Lp(a) plasma levels and
subsequent major vascular morbidity and/or cause-specific mortality were
recorded. Lp(a) was weakly correlated with several conventional vascular
risk factors, and it was highly consistent within individuals over several
years (Erqou et al., 2009).
Several epidemiologic studies have assessed the association
between Lp(a) and atherosclerotic disease .Many population-based
prospective studies had reported a controversial association between
Lp(a) levels and CHD risk. Few studies, however, have adequately
examined important aspects of the association, such as the size of relative
risks in clinically relevant subgroups (such as in men and women or at
different levels of established risk factors) (Malaguarnera et al., 2013).
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Review of literature
Highly sensitive c-reactive protien
C-reactive protein (CRP) is a protein found in the blood, the levels
of which rise in response to inflammation (i.e. C-reactive protein is
an acute-phase
protein).
Its
physiological
role
is
to
bind
to phosphocholine expressed on the surface of dead or dying cells (and
some types of bacteria) in order to activate the complement system . CRP
is
synthesized
by
by macrophages and
the liver in
fat
cells
response
(adipocytes). It
to
factors
is
a
released
member
of
the pentraxin family of proteins. It is not related to C-peptide or protein
C. C-reactive protein was the first pattern recognition receptor (PRR) to
be identified. (Mantovani et al., 2008).
History and nomenclature
C- reactive protein (CRP) was so named because it was first
discovered as a substance in the serum of patients with acute
inflammation that reacted with the C- (capsular ( polysaccharide of
pneumococcus ,Discovered by Tillett and Francis in 1930, it was initially
thought that CRP might be a pathogenic secretion as it was elevated in
people with a variety of illnesses including cancer ,however, the
discovery of hepatic synthesis demonstrated that it is a native protein .
(Peter et al., 2009).
Genetics and biochemistry:
The CRP gene is located on the first chromosome (1q21-q23). CRP
is a 224-residue protein with a monomer molecular mass of 25106 Da.
The protein is an annular pentameric disc in shape and a member of the
small pentraxins family (Kennelly et al., 2009).
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Review of literature
Function: (Pepys and Hirschfield, 2003).
The acute phase response develops in a wide range of acute and
chronic inflammatory conditions like bacterial, viral, or fungal infections;
rheumatic and other inflammatory diseases; malignancy; and tissue injury
or necrosis. These conditions cause release of interleukin-6 and other
cytokines that trigger the synthesis of CRP and fibrinogen by the liver.
During the acute phase response, levels of CRP rapidly increase within 2
hours of acute insult, reaching a peak at 48 hours. With resolution of the
acute phase response, CRP declines with a relatively short half-life of 18
hours.
Measuring CRP level is a screen for infectious and inflammatory
diseases. Rapid, marked increases in CRP occur with inflammation,
infection, trauma and tissue necrosis, malignancies, and autoimmune
disorders. Because there are a large number of disparate conditions that
can increase CRP production, an elevated CRP level does not diagnose a
specific disease. An elevated CRP level can provide support for the
presence of an inflammatory disease, such as rheumatoid arthritis,
polymyalgia rheumatica or giant-cell arteritis.
CRP binds to phosphocholine on microbes. It is thought to assist
in complementbinding to foreign and damaged cells and enhances
phagocytosis by macrophages (opsonin mediated phagocytosis), which
express a receptor for CRP. It is also believed to play another important
role in innate immunity, as an early defense system against infections.
CRP rises up to 50,000-fold in acute inflammation, such as
infection. It rises above normal limits within 6 hours, and peaks at 48
hours. Its half-life is constant, and therefore its level is mainly determined
by the rate of production (and hence the severity of the precipitating
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Review of literature
cause). Serum amyloid A is a related acute-phase marker that responds
rapidly in similar circumstances.
The physiological role of CRP is to bind to phosphocholine
expressed on the surface of dead or dying cells (and some types of
bacteria) in order to activate the complement system. CRP binds to
phosphocholine on microbes and damaged cells and enhances
phagocytosis by macrophages. Thus, CRP participates in the clearance of
necrotic and apoptotic cells. CRP is a member of the class of acute-phase
reactants, as its levels rise dramatically during inflammatory processes
occurring in the body. This increment is due to a rise in the plasma
concentration
of IL-6,
which
is
produced
predominantly
bymacrophages as well as adipocytes (Lau et al., 2005).
Clinical significance:
Scleroderma, polymyositis, and dermatomyositis often elicit little
or no CRP response. CRP levels also tend not to be elevated
in SLE unless serositis or synovitis is present. Elevations of CRP in the
absence of clinically significant inflammation can occur in renal failure.
CRP level is an independent risk factor for atherosclerotic disease.
Patients with high CRP concentrations are more likely to develop stroke,
myocardial infarction, and severe peripheral vascular disease (LopezGarcia et al., 2005).
Role in cardiovascular disease:
Research suggests that patients with elevated basal levels of CRP
are at an increased risk of diabetes, hypertension and cardiovascular
disease. A study of over 700 nurses
showed
that those in the
highest quartile of trans fat consumption had blood levels of CRP that
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Review of literature
were 73% higher than those in the lowest quartile (Lopez-Garcia et al.,
2005).
Although one group of researchers indicated that CRP may be only
a moderate risk factor for cardiovascular disease, this study (known as the
Reykjavik Study) was found to have some problems for this type of
analysis related to the characteristics of the population studied, and there
was an extremely long follow-up time, which may have attenuated the
association between CRP and future outcomes. Others have shown that
CRP
can
exacerbate ischemic necrosis in
a complement-dependent
fashion and that CRP inhibition can be a safe and effective therapy
for myocardial and cerebral infarcts; so far, this has been demonstrated in
animal models only (Pepys et al., 2006).
It has been hypothesized that a high CRP levels might reflect a
large benefit from statins. This is based on the JUPITER trial that found
that elevated CRP levels without hyperlipidemia benefited. Statins were
selected because they have been proven to reduce levels of CRP . Studies
comparing effect of various statins in hs-CRP revealed similar effects of
different statins. A subsequent trial however failed to find that CRP was
useful for determining statin benefit (Emberson et al., 2011).
Role in cancer:
The role of inflammation in cancer is not well understood. Some
organs of the body show greater risk of cancer when they are chronically
inflamed. Blood samples of persons with colon cancer have an average
CRP concentration of 2.69 milligrams per liter. Persons without colon
cancer average 1.97 milligrams per liter. The difference was statistically
significant. These findings concur with previous studies that indicate
that anti-inflammatory drugs could lower colon cancer risk (Erlinger et
al., 2004).
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Review of literature
Diagnostic use:
Measuring and charting CRP values can prove useful in
determining disease progress or the effectiveness of treatments. Normal
concentration in healthy human serum is usually lower than 10 mg/L,
slightly
increasing
late pregnant women,
with aging.
Higher
levels
mild inflammation and viral
are
found
in
infections(10–
40 mg/L), active inflammation, bacterial infection (40–200 mg/L),
severe bacterial infectionsand burns (>200 mg/L) (Clyne and Olshaker,
1999).
CRP is used mainly as a marker of inflammation. Apart from liver
failure, there are few known factors that interfere with CRP production.
Various analytic methods are available for CRP determination, such as
enzyme-linked immunosorbent assay (ELISA), immunoturbidimetry,
rapid immunodiffusion, and visual agglutination. In general, both the
CRP test and another test, called the erythrocyte sedimentation rate
(ESR), measure the increase in inflammatory generated proteins. The
CRP test is a direct measurement of C-reactive protein, while ESR
indirectly measures many proteins associated with inflammation
(Saljoughian, 2008)
CRP is a more sensitive and accurate reflection of the acute phase
response than the ESR (Erythrocyte Sedimentation Rate). The half-life of
CRP is constant. Therefore, CRP level is mainly determined by the rate of
production (and hence the severity of the precipitating cause). In the first
24 h, ESR may be normal and CRP elevated. CRP returns to normal more
quickly than ESR in response to therapy (Clyne and Olshaker, 1999).
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Review of literature
Cardiology diagnostic test:
Arterial
damage
results
from white
blood
cell invasion
and inflammation within the wall. CRP is a general marker for
inflammation and infection, so it can be used as a very rough proxy for
heart disease risk. Since many things can cause elevated CRP, this is not
a very specific prognostic indicator (Goldman, 2011).
The American Heart Association and U.S. Centers for Disease
Control and Prevention have defined risk groups as follows:
- Low Risk: less than 1.0 mg/L.
- Average risk: 1.0 to 3.0 mg/L.
- High risk: above 3.0 mg/L
But hs-CRP is not to be used alone and should be combined with
elevated levels of cholesterol, LDL-C, triglycerides, and glucose level.
Smoking, hypertension and diabetes also increase the risk level of
cardiovascular disease (Swardfager et al., 2012).
Nevertheless, a level above 2.4 mg/L has been associated with a
doubled risk of a coronary event compared to levels below
1 mg/L; however, the study group in this case consisted of patients who
had been diagnosed with unstable angina pectoris; whether elevated CRP
has any predictive value of acute coronary events in the general
population of all age ranges remains unclear. Currently, C-reactive
protein is not recommended as a cardiovascular disease screening test for
average-risk adults without symptoms (Goldman, 2011).
The level of this protein in plasma increases greatly during acute
phase response to tissue injury ,infection, or other inflammatory stimuli.
It is induced by interleukin-1 and interleukin-6 (Faraj and Salem, 2012).
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Review of literature
There are two different tests for CRP. The standard test measures a
much wider range of CRP levels but is less sensitive in the lower ranges.
The high-sensitivity CRP (hs-CRP) test can more accurately detect lower
concentrations of the protein (it is more sensitive), which makes it more
useful than the CRP test in predicting a healthy person's risk for
cardiovascular disease (Clyne and Olshaker, 1999).
CRP is one of several proteins that are often referred to as acute
phase reactants and is used to monitor changes in inflammation
associated with many infectious and autoimmune diseases (Faraj and
Salem, 2012).
C-reactive protein (CRP) is a substance that is released into the
blood in response to inflammation, the process by which the body
responds to injury. Elevated levels of CRP in the blood mean that there is
inflammation somewhere in the body, but other tests are needed to
determine the cause and location of the inflammation. Physicians now
believe that atherosclerosis, or hardening of the arteries, is an
inflammatory process. Atherosclerosis causes only a small amount of
CRP to be released into the blood. Therefore, a very sensitive test called a
high-sensitivity CRP test (hs-CRP) is used to measure CRP levels
(Ridker et al., 2007).
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