Review Article
Biomarkers of Atherosclerosis: Is the Evaluation Essential Preoperatively?
Minati Choudhury1* and Devagourou V2
1Department of Cardiac Anesthesia, Cardiothoracic Sciences Centre, AIIMS, New Delhi, India
2Department of Cardiothoracic Surgery, Cardiothoracic Sciences Centre, AIIMS, New Delhi, India
*Corresponding author: Minati Choudhury, Department of Cardiac Anesthesia, Room No 8,7th Floor Cardiothoracic Sciences Centre, AIIMS, New Delhi-110029, India
Published: 10 Oct, 2017
Cite this article as: Choudhury M, Devagourou V.
Biomarkers of Atherosclerosis: Is the
Evaluation Essential Preoperatively?.
Clin Surg. 2017; 2: 1657./p>
Abstract
Atherosclerosis is an inflammatory condition leading to various cardiovascular as well as
cerebrovascular events and Peripheral Vascular Disease (PVD). Presence of significant
atherosclerosis leads to perioperative adverse events, morbidity and mortality in the high risk
surgical population. The usual methods for evaluating the like hood of adverse cardiovascular or
cerebrovascular events postoperatively in these set of patients depends primarily on scoring system
and functional status of the cardiovascular system during preoperative assessment. The pre existing
disease activity and possible postoperative adverse Cardiovascular Event (CVE) can be estimated to
some degree from the preoperative levels of biomarkers associated with atherosclerosis. This minireview
summarizes the potential role of biomarkers related to the atherosclerosis process in the
cardiovascular risk stratification of patients undergoing non cardiac surgery. A Med Line search
of literature on atherosclerosis biomarkers in the perioperative period and adverse post operative
cardiovascular event was conducted; and thirty-three reports are added to this review.
Keywords: Atherosclerosis; Perioperative period; Biomarkers
Introduction
Atherosclerosis is an inflammatory process in the blood vessels that results in the formation of atheromatous plaque over the endothelial lining of blood vessels leading to stiffness and loss of elasticity of the vessel, stenosis of the artery, aneurysm formation, plaque rupture and dysfunction of endothelial cell lining [1]. Pre existing atherosclerosis may lead to acute unanticipated myocardial infarction during the perioperative period. Unanticipated arrhythmia, congestive cardiac failure, acute coronary syndrome and cerebrovascular accidents are some other perioperative adverse events which can cause major postoperative morbidity and mortality. Apart from the various non biochemical tests available for risk stratification, measurement of biomarkers in the blood during perioperative period can provide a clue for postoperative CVE [2-4].
Biomarkers of Atherosclerosis that Provide a Clue for Postoperative Cardiovascular Event
Traditional biomarkers: Lipoproteins, Creatinine kinase, Asparate aminotransferase, Lactate
Dehydrogenase and troponins.
Recent biomarkers:
A. Acute phase reactants
1. C-reactive protein
2. Serum amyloid A
3. Fibrinogen
4. Complement protein
B. Cell adhesion molecule
1. Intracellular Adhesion Molecule-1 (ICAM-1)
2. Vascular Cell Adhesion Molecule-1 (VCAM-1)
3. P-selectin
C. Cytokines and chemokines
1. Interleukins
2. Tumor necrosis factor-α
3. Endothelins
D. Miscellaneous
1. Brain natriuretic peptide<.br/>
2. Cystatin C
3. Matrix metalloproteinase
4. Leptin
Traditional Biomarkers
Lipoproteins
Low density lipoprotein and apolipoprotein (apo B) remains the
main target of atherosclerosis therapy and measure the atherogenesity
of plasma. Present studies primarily focused at the apo B: apo A-1
ratio. The consensus conference from American Diabetic Association,
stress the effectiveness of apo B level as a predictor of perioperative
CVE in patients in patients on statin therapy.5 According to the guide
lines the safe apo B targets are < 90 mg/dL for individuals with the
presence of diabetes or cardiovascular disease (CVD) risk factors and
< 80 mg/dL with known diabetes or CVD with an additional CVD
risk factor [5].
Creatine kinase (CK)
Creatine kinase is expressed in most of the body tissues and
organs, and has three iso-enzymes. The CK-MB iso-enzyme is found
in maximum concentrations in the myocardial tissue. In the patients
presenting with acute myocardial infarction, the level of CK-MB
begin to rise 4 h - 6 h after the onset of chest pain, peak level reaches at
12 h to 24 h and return to base line by 48 to 72 h. The ratio of plasma
CK-MB to total CK is a better indicator of myocardial cell damage
rather than the level of CK-MB alone.
Troponins
Cardiac troponins (troponins T and I) are the regulatory proteins
that control the calcium interaction between actin and myosin
during heart muscle contraction. Troponins are needed to assess the
prognosis of Acute Coronary Syndrome (ACS), diagnosis of acute MI
and prediction of CVE perioperatively. Among the three subunits of
troponins, troponin-T (Tn-T) and I (Tn-I) are the tissue components
of cardiac muscle and are exceedingly specific for myocardial tissue.
The elevated plasma concentration are detected 3 h - 12 h after
myocardial damage and the concentration remain upraised for 5-9
days for Tn-I and up to 14 days for Tn-T. A raised level of Tn-T and
Tn-I has been found to be useful in the prediction of adverse CVE
and therefore considered to be a useful preoperative screening test
for high risk individuals. In one of the cohort study, using Tn-I value
0.02 ng/ml as a diagnostic cutoff point for the presence of coronary
artery disease (>70% stenosis), elevated Tn-I classified sixty five
percent of population as high risk. The authors concluded that Tn-I
value to have a similar predictive accuracy to that of stress testing
with imaging studies (70%) and better than ECG parameters during
stress testing (53%) [6]. Different studies show increased troponins in
various major surgery have a high sensitivity, specificity and negative
predictive value when perioperative CVE is the question [7-10].
Cardiac troponin value however have certain limitations; i) the value
does not necessarily equate to recent myocardial infarction or any
other CVE, ii) it is difficult for the clinician to distinguish whether a
raised level of troponins is the result of atherosclerotic plaque rupture
or due to some other reason, iii) there is difficulties in determining
the upper reference limit of the normal range for different tests.
Aspartate aminotransfrase (AST)
AST has ubicubitus distributions, its concentration increased
within 6-10 hr after acute MI, peaking at 12 h - 48 h and return to
normal level within 3-4 days. Because of low specificity it is been
hardly used to determine perioperative CVE.
Lactate dehydrogenase (LDH)
Among the five isoenzymes of LDH, LDH-I is common in heart
muscle. The plasma concentration of LDH-I start to rise 12 h - 24 h
after MI, reach a summit within 2-3 days and returns to base line by 14
days. The utility of this enzyme as a CVE marker in the perioperative
setting is gradually declining.
Acute phase reactants
The role of various Acute Phase Reactants (APRs) as a
predictor of postoperative outcome has been investigated by several
authors. Among these biomarkers the majority of work has been
focused on C-reactive protein (CRP). However, there are other
biomarkers which have a contribution towards the pathogenesis of
atherosclerotic disease and postoperative CVE in patients suffering
from atherosclerotic disease.
C-reactive protein (CRP)
C-reactive protein is produced primarily by the hepatic cells in
response to the release of interleukin -6 (IL-6) or tumor necrosis
factor-α (TNF-α), the pro inflammatory cytokines. CRP is found
within the atherosclerotic plaques in both coronary and peripheral
vessels [11-13]. The median CRP level in a normal healthy individual
is 0.8 mg/L with an inter percentile range 0.3-0.7 mg/L. During an
acute phase reaction the plasma level reaches to a peak of 300 mg/L
within 24 h -48 h and rapidly reverses within 19 h at the initiation
of inflammatory stimulus. This time of decline is constant for all the
cases. The high sensitivity assays (hs-CRP) measure the low CRP
concentration which cannot be measured by the routine biochemistry
laboratory. With this assay an accurate measurement of CRP
concentrations up to 3 mg/L are now possible. According to American
heart association and centre for disease control and prevention, a hs-
CRP level of >3 mg/L should considered as risk factor for perioperative
CVE in patients with asymptomatic atherosclerosis or stable ischemic
heart disease and levels > 10 mg/L have a greater prognostic value
in those suffering from acute coronary syndrome [14]. Vidula et al.
[15] evaluated the prognostic significance of CRP in patients with
peripheral vascular disease (PVD). In the authors study at four years
of follow up, each 50% elevation in CRP level was associated with
an increase risk of all causes of mortality (HR1.14,95% CI 1.05-1.24)
and cardiovascular disease related mortality (HR 1.17,95% CI 1.05-
1.30) A 2 year follow up suggesting that increased CRP level predicts
an increased in cardiovascular risk. Few of the previous authors
shown that a preoperative CRP level >2 mg/L was associated with
post operative complications in small group of patients undergoing
cardiac surgery and an uneventful recovery occurred in all patients
with a concentration of 2 mg/L [7,16]. Rossi E et al. [17] found a CRP
concentration >9 mg/L preoperatively as a predictor of adverse CVE
in patients undergoing non cardiac surgery.
Fibrinogen
This acute phase protein is a key molecule in the process involved in the genesis of atherosclerosis. An elevated concentration of
fibrinogen has been found to be an independent predictor of fatal
cardiovascular complications in high risk patients with PVD [18].
Complement proteins
The complements proteins primarily synthesized in liver. It is
also produced by macrophages and monocytes. The activation of
complement system occurs during the initiation of biochemical
cascade involved in inflammation. An elevated level of C5a found
in plasma and atheromatous plaque can predict an increased
cardiovascular risk [19]. Serum Amyloid A Serum Amyloid A (SAA)
protein is synthesized in liver, involved in acute phase reaction and
maintains the reverse cholesterol transport system. Several studies
have shown its’ association in atherogenesis process and it is present
in atherosclerotic lesions. The Women’s’ Ischemic Syndrome
(WISE) study evaluated women referred for coronary angiography
for suspected myocardial ischemia and showed that SAA levels are
independently associated with CAD and highly predictive of one year
adverse CVE [20].
Cytokines
Interleukins (ILs): IL-6 is mainly important among all pro
inflammatory ILs. It has been shown that base line IL-6 is predictive
of peripheral arthrosclerosis disease progression within five years of
its detection [12].
Tumor Necrosis Factor –α: This multifunctional pro
inflammatory cytokine is associated with increased and recurrent
coronary events according to CARE trial [21].
Endothelins
These powerful vasoconstrictors are expressed by endothelial
cells. The plasma concentration of endothelin is raised in patients
having atherosclerotic risk factors and those with atherosclerosis. The
level increases with the severity of atherosclerosis or onset of coronary
artery disease or any other CVE [22]. Endothelins also behaves as
chemo attractants for the monocytes and macrophages and thought
to have a role in neovascularization. The angiogenesis role of ET has
been proved from the presence of ET receptors on the neo vessels
within the atherosclerotic plaque. Van Beneden et al. [22] have
shown that ET-1 concentration in plasma is a prognostic indicator in
patients with atherosclerosis and congestive cardiac failure. However,
in the authors view plasma Brain Natriuretic Peptide (BNP) is a better
prognostic indicator than ET-1 during perioperative period.
Cell adhesion molecules (CAM)
P-Selectin: This adhesion molecule is produced primarily by
platelets that mediate monocytes rolling before they adhere to the
endothelium in the initial stage of atherosclerotic plaque formation.
The critical role of P-selectin in both leukocyte recruitment and
atherosclerosis progression has been confirmed in various animal
models. Blann AD and colleague demonstrated that a deficiency
of P-selectin have a protective effect against atherosclerosis and an
increase level is associated with progression of atherosclerosis, CAD
and atrial fibrillation [23].
Vascular adhesion molecule-1 (VAM-1): VAM-1 is a strong
predictor of atherosclerotic risk; however its role in adverse CVE is
not proven [24].
Intercellular adhesion molecule-1 (ICAM-1): The ICAM-1
contributes to the adhesion of leukocytes to the activated endothelium
and mediates the adhesion of monocytes, lymphocytes and
neutrophils to the endothelial cells. There is evidence of expression of
ICAM-1 on smooth muscle cells in human aorta and coronary vessels
[25]. Elevated levels of ICAM-1 have been found in patients with
atherosclerosis. Witte DR and colleague demonstrated that ICAM-1 is
related to advanced atherosclerotic lesions and estimated risk of CAD
in otherwise healthy individual. Heim and colleague demonstrated
that an increased baseline plasma concentration of ICAM-1 was
associated with a greater incidence of future cardiovascular events in
patients with known CAD [26].
Miscellaneous
Brain natriuretic peptide (BNP): Plasma Brain Natriuretic
Peptide (p-BNP) and N-terminal pro BNP (P-NT-BNP) released
in response to myocardial stress an increased level of this peptide
has also been demonstrated in patients with atherosclerosis and it
correlates well with the severity of disease [27]. The role of BNP and
N-terminal pro BNP (NT-pro BNP) has been well proved to have
an association with increased short and long term mortality in 2656
randomly selected individuals from a cohort among whom only 5%
had a prior stroke or MI [28]. After a median follow up of 4.5 years,
the investigators found an increase in log-pro BNP to be a major
predictor of composite end point of non-fatal MI or non fatal stroke
and major cardiovascular death.
Cystatin C
Cystatin C is primarily a novel biomarker for renal dysfunction
has more importance than serum creatinine when perioperative renal
failure is concern. An increase level of cystatin is also found to be
associated with adverse CVE by several authors [29,30]. An increase
level of cystatin C was related to atherosclerosis risk and increase
incidence of coronary artery calcium deposition in one of the study
[30].
Matrix metalloproteinases (MMPs)
MMPs are zinc dependent proteases produced by several cell
types. They are classified into different subgroups based upon
their structure and substrate specificity. MMPs are responsible
for degradation of collagen and other extracellular matrix (ECM)
components. MMPs particularly MMP-2 is involved in all stages
of atherosclerosis process. They promote the migration of smooth
muscle cell and early plaque development. In the subsequent stage
of atherosclerosis, there is breakdown of ECM by MMP, which leads
to rupture of atherosclerotic plaque and erosion of endothelium.
MMPs also influence intraplaque angiogenesis through interaction
between integreins and protenases. The aneurysm formation during
atherosclerosis process is also due to the arterial remodeling and
increased ECM breakdown by MMPs. Studies also shown that there is
an increase concentration of MMPs in patients with unstable angina
or acute MI when compared with healthy controls [31]. The role of
these proteins in post operative CVE in patients with atherosclerosis
is again unknown.
Leptin
Leptin, a 167 amino acid peptide produced mainly by adipose
tissue, although the leptin receptors are expressed in several tissues
of the body. Recent studies suggested that leptin is involved in
various process of atherogenesis including endothelial dysfunction,
platelet aggregation, oxidative stress, hypertrophy and proliferation
of vascular smooth muscle cells. Several epidemiological studies
have demonstrated that increase leptin level can predict acute CVE,
restenosis of coronary vessels after angioplasty even after correction of body weight, plasma glucose, CRP and lipid levels [32].
What is the Role for Plasma Biomarkers in Patient with Known Atherosclerosis? Present Scenario
In spite of a battery of available preoperative tests for stress
induced myocardial ischemia; it is difficult to identify who are really
the patients at risk for perioperative CVE. It might be due to the fact
that vulnerable plaques cannot be identified by the available tests and
thereby it is not possible to identify the population at risk of plaque
rupture to give rise symptoms. Among all the biomarkers, CRP
appears to be the most promising biomarker for prediction of CVE
during perioperative period. Though CRP does not correlate with
the entire atherosclerotic burden, it may indicate other atherogenesis
event eg. Vascular cell activation, expression of inflammatory
mediators, grade of plaque destabilization, ongoing thrombosis or
plaque rupture.
One should not forget that CRP act as a protective adverse event
protein and maintain some balance between ongoing inflammatory
process and stability of atherosclerotic disease. This can be use for
interpretation of unstable atherosclerotic plaque only in patients who
does not have any other coexisting inflammatory conditions. On
the other hand, most of the patients who undergo a major surgical
procedure have a greater incidence of CVE. Therefore CRP level
estimation should be done in majority of such patients.
Use of multiple biomarkers simultaneously to predict the
cardiovascular risk has been tried by few authors. The main conclusion
of these studies is that use of multi biomarker score can reclassify the
risk in 30% of the individuals and predict CVE in future [33].
Atherosclerotic Biomarkers, how Important are they in Perioperative Setting?
To be clinically useful biomarkers must change the management and thus improves the outcome. Targeting the therapy for a reduction of biomarker level in plasma those thought to be a risk factor or direct contributor towards atherosclerosis should reduce the risk of CVE. However, the reports on the role of atherosclerotic biomarkers in perioperative CVE prediction is limited, with no existing researches supporting the fact that, “ treatment plans can be changed according to the atherosclerosis biomarker level or a reduction of perioperative CVE can be done with targeting the therapy to decrease the biomarker level”.
Summary and Conclusion
There is growing interest in biomarkers of inflammation and atherosclerosis rather than myocardial cell death. Some biomarkers seem to be risk factors (eg. elevated LDL levels) for atherogenesis, where as others are inconclusive (eg. leptin). Few of the recent studies elaborated the association of several atherosclerotic biomarkers with increased cardiovascular risk. However till date there are no randomized trials exists to demonstrate that intensifying or modifying the treatment in response to elevated biomarker levels leads to reduction of CVE. This limits the clinical utility of atherosclerotic biomarkers in perioperative setting.
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