Atherosclerosis Detection Methods Biochemical Markers 2006

British Journal of Anaesthesia 97 (6): 75869 (2006)

doi:10.1093/bja/ael303 Advance Access publication October 30, 2006

REVIEW ARTICLE

Methods of detecting atherosclerosis in non-cardiacsurgical patients; the role of biochemical markers

G. M. Howard-Alpe*, J. W. Sear and P. Foex

Nuffield Department of Anaesthetics, John Radcliffe Hospital, Headley Way, Headington,

Oxford OX3 9DU, UK

*Corresponding author. E-mail: [email protected]

Atherosclerosis is a common condition in both the developed and developing world and is now

recognised to be an inflammatory condition leading to the development of ischaemic heart

disease, cerebrovascular disease and peripheral vascular disease. Ischaemic heart disease is a

major risk factor in the pathogenesis of perioperative adverse cardiovascular events which lead to

significant morbidity and mortality within the high risk surgical patient population. Current

methods of evaluating the likelihood of postoperative cardiovascular complications depend largely

on risk scoring systems, and the preoperative assessment of the functional status of the cardio-

vascular system. However, the possible role of inflammation in the generation of atherosclerosis

has led to the identification of several biochemical markers such as acute phase proteins, cellular

adhesion molecules and cytokines. An alternative approach therefore is the measurement of

preoperative levels of these biomarkers with the aim of assessing pre-existing disease activity.

This review summarises the pathophysiology of atherosclerosis and perioperative myocardial

infarction, and discusses the possible future role of biomarkers in the risk stratification of patients

undergoing non-cardiac surgery.

Br J Anaesth 2006; 97: 75869

Keywords: surgery, non cardiac cardiovascular system, effects; biomarkers; atherosclerosis;

C-reactive protein

Adverse cardiovascular events (including myocardial

ischaemia and infarction) are a significant cause of major

morbidity and mortality in the perioperative period and have

considerable economic consequences to the health service.

Data from the USA show that approximately 27 million

patients undergo surgery of which 8 million have known

coronary artery disease or risk factors for cardiovascular

disease. There are 1 million perioperative cardiac

complications, suggesting that the overall risk of a periop-

erative cardiovascular event is 1 in 27.47 Half a million

of these are perioperative myocardial infarctions (MI).

The rate of perioperative MI in males more than the age

of 50 years is 0.7%, but this incidence increases to 3.1%

after vascular surgery.4 Figures for the UK suggest a com-

parable incidence of approximately 8000 perioperative car-

diovascular deaths per year from roughly 5 million general

or regional anaesthetics performed.54 92 A major predispos-

ing factor in the development of a perioperative cardiovas-

cular event is the presence of ischaemic heart disease,

whether diagnosed or previously unknown. Atherosclerosis

is the main pathological disorder responsible for the devel-

opment of ischaemic heart disease. Therefore, identifying

patients at risk before operation is sensible, but only if the

clinician can use the information to modify perioperative

management and reduce complication rates. There are now

therapies that are of possible benefit in reducing the inci-

dence of cardiovascular events, and accurately predicting

those at risk would allow these therapies to be appropriately

targeted. These include beta-adrenoceptor blockade,18 62 78

a2-adrenoceptor agonists78 90 and statin therapy.20 58

Although regional anaesthetic techniques attenuate the sur-

gical stress response they do not completely abolish it,

and have not been shown to alter the incidence of periop-

erative cardiovascular events.53 69 72 96 Further factors that

may be affected by accurate risk stratification include

the most appropriate location of surgery, possible modifica-

tion of the original planned operation, sequenced or staged

surgery and the location and level of post-surgical care.

Atherosclerosis

Atherosclerosis affects the endothelial lining of arterial

blood vessels, resulting in atheromatous plaque formation.

The consequences of atherosclerosis include increased

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stiffness and a loss of elasticity in the blood vessel, stenosis

of the artery, plaque rupture and aneurysm formation.

Atherosclerosis is now recognized as an inflammatory

process,7 70 with many known risk factors (Fig. 1). There

is some evidence that infection may have a role in the aeti-

ology with herpes viruses (Cytomegalovirus, Epstein-Barr

virus and Herpes simplex-1 virus) and certain bacterial

(Chalmydia pneumoniae and Helicobacter pylori) DNA

having been detected in atherosclerotic plaques.

Within an affected blood vessel, characteristic alterations

of blood flow occur resulting in increased turbulence and

decreased shear stress leading to endothelial changes. These

early changes precede the formation of atherosclerotic

lesions and are responsible for endothelial cell dysfunction.

Many factors are involved in the atherogenic process

(Fig. 2). Increased permeability to lipoproteins and other

plasma constituents is mediated by increased concentrations

of nitric oxide, prostacyclin, platelet-derived growth factor,

angiotensin II and endothelin. A separate process (the attrac-

tion, rolling, adherence and migration of monocytes and

T-cells to the arterial wall) is mediated by factors including

the cell adhesion molecules, oxidized low-density lipopro-

tein (LDL), cytokines and chemokines. Migrated monocytes

are transformed into tissue macrophages and ingest lipid

deposits to form foam cells. The earliest visible evidence

of the atherosclerotic lesion is a fatty streak consisting of

foam cells and activated T lymphocytes. More advanced

atherosclerotic lesions contain smooth muscle cells which

form a fibrous cap walling the lesion off from the vessel

lumen. This is a protective response covering the inflam-

matory core of leukocytes, lipid and debris beneath, which

may be necrotic. Atherosclerotic lesions expand at their

shoulders by continued leukocyte adhesion and entry. Plate-

lets adhere to dysfunctional endothelium, exposed collagen

and macrophages becoming activated and releasing

cytokines and growth factors that together with thrombin

contribute to the migration and proliferation of monocytes

and smooth muscle cells. Erosion and rupture of the plaque

with consequent exposure of thrombogenic material can

lead to unstable coronary syndromes or MI. The different

stages in the development of an atherosclerotic plaque can

be seen in Figure 3.

The pathophysiology of perioperativemyocardial infarction

There are two mechanisms involved in the causation of

perioperative MI.40

(i) Coronary artery occlusion: Plaque erosion or rupture

leading to thrombogenesis and consequent occlusion or

thromboembolic occlusion of an already narrowed

coronary lumen.

SMOKINGLIPID PROFILE

HYPERTENSION

FAMILY HISTORY

LEPTINURIC ACID

HOMOCYSTEINE

DIABETESMELLITUS

METABOLICSYNDROME

RISK FACTORS

ATHEROSCLEROSIS

Fig 1 Risk factors for atherosclerosis.

INFLAMMATIONBLOOD FLOWCHANGES: TurbulenceShear stress

Inflammatory mediatorsCell adhesion moleculesCytokinesChemokinesAcute phase reactants

ATHEROGENESIS

ENDOTHELIAL DYSFUNCTION

LEUKOCYTES PLATELETS

Fig 2 The process of atherogenesis.

Initial lesionIsolated foam cells plus smooth muscle thickening

Fatty streakFoam cells and intracellular lipid accumulation

Pre-atheromaChanges of fatty streak lesion plus small extracellular

lipid pools

AtheromaChanges of fatty streak lesion plus a core of extracellular lipid

FibroatheromaLipid core and fibrotic layer, or multiple lipid cores and

fibrotic layers, or mainly calcific, or mainly fibrotic

Complicated lesionSurface defect (ulceration or rupture), haematoma-haemorrhage,

thrombus

Fig 3 The development of an atherosclerotic plaque.

Biochemical markers in detecting atherosclerosis

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(ii) Prolonged ischaemia (usually silent) secondary to an

imbalance between myocardial oxygen demand and supply.

The first type resembles acute MI in the non-surgical

setting and is related to the concept of the vulnerable pla-

que. These plaques tend to be the newer, less stable

coronary atherosclerotic lesions that have undergone

rapid progression and contain a substantial lipid core filled

with a large mass of thrombogenic lipids and macrophages

along with various cytokines covered by a relatively thin

fibrous cap. This protective cap undergoes constant inflam-

mation and repair, and the balance between these two pro-

cesses enables the plaque to expand in size but during this

process the plaque is liable to fissure and rupture. Figure 4

shows some of the histological features of a vulnerable

plaque. The older, more stable plaques have uniformly

dense protective fibrous caps with a small lipid core and

are therefore less likely to rupture. In the non-surgical

setting, there is evidence that small, non-occlusive plaques

rather than the large plaques contribute more to cardiovas-

cular morbidity and mortality.26 These vulnerable plaques

can be difficult to diagnose as they are not highly occlusive

with angiography being of limited value in identifying

them.17

The second type of perioperative MI occurs most

commonly in patients with severe but stable coronary artery

disease, and is usually associated with prolonged silent

postoperative ischaemia.40 This is thought to be the result

of an imbalance between a limited myocardial oxygen

supply and an increased perioperative oxygen demand.

As these patients may have severe coronary artery disease,

preoperative angiography can be useful in identifying those

with highly occlusive coronary stenosis. Unlike the plaque

rupture type of MI, the higher the grade of occlusion that a

coronary stenosis causes, the more likely a prolonged stress-

induced ischaemia type of MI is to occur. Therefore,

identification of patients with high grade coronary artery

stenosis is useful in allowing targeted interventions to

minimize individual risk.

Intensive monitoring of myocardial damage by

biomarkers has added to the evidence that two distinct

pathophysiological mechanisms of perioperative MI exist.

The first type of infarction occurring in the postoperative

period is not preceded by ischaemic myocardial damage, is

associated with a sudden increase in the serum troponin

concentration to a level diagnostic of MI, and is probably

because of coronary occlusion secondary to plaque haem-

orrhage, rupture or thrombus formation. The later or delayed

type of perioperative MI is preceded by a long period, >24 h,of ischaemic myocardial damage observed as a moderate

increase in the troponin level, not initially in the range

diagnostic of MI but above the upper reference limit of

normal.42 Pathological studies examining the coronary

vessels at autopsy of patients who have suffered fatal

perioperative MI shows that the incidence of these two

types of MI is roughly equal.14 17

As the pathophysiological mechanisms involved in these

two types of perioperative MI are quite different, it follows

that the tests to identify high-risk patients and treatment

options available may also be different.

Predicting perioperative cardiovascular events

The adverse cardiovascular events that occur in the

perioperative period are not limited to MI; acute coronary

syndromes, congestive cardiac failure, arrhythmias and

cerebrovascular accidents can all cause major morbidity

and mortality. There are guidelines published on the recom-

mended preoperative risk stratification of patients,5 12 21 22

and there is extensive literature studying the various

different preoperative investigations that are available.

Table 1 lists these different preoperative tests.

Biochemical markers of cardiovasculardisease

A more recent and alternative approach has been measure-

ment of biomarkers of cardiovascular disease in the blood

before operation and after operation, and correlating the

levels with the incidence of cardiovascular adverse events.

(1) Traditional biomarkers

Traditionally biochemical markers of cardiovascular disease

risk have measured myocardial cell damage and include

Vessel lumen

Thrombus

Haemorrhage

Plaque fissure and rupture

Foam cells

Smooth muscle thickening

Fibrous thickening

Necrotic lipid core

Fig 4 Drawing of blood vessel containing unstable, complicated

atheromatous plaque.

Table 1 The different preoperative tests useful for predicting perioperative

cardiovascular events or the need for coronary revascularization before

non-cardiac surgery. *AECG, ambulatory electrocardiogram. MUGA, multiple

gated acquisition scan; LVEF, left ventricular ejection fraction

Preoperative investigation

At rest ECG

Holter (AECG)* monitoring

Exercise ECG

Radionucleotide ventriculography (MUGA)

Stress myocardial perfusion imaging

Resting echo LVEF

Pharmacological stress echo

Anaerobic threshold

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creatine kinase, aspartate aminotransferase and lactate dehy-

drogenase. However, these tests have been largely super-

seded by measurement of troponin I or T concentrations,

which are more specific for myocardial cell injury.

(a) Creatine kinase (CK)

This enzyme is expressed in many body tissues and

catalyses the conversion of creatine to phosphocreatine.

The enzyme has three different isoenzymes with different

tissue distributions. The CK-MB isoenzyme is present in the

highest concentrations within the myocardium, but it is not

completely specific for myocardial tissue, as it is also found

in skeletal muscle. To improve specificity, the ratio of

plasma CK-MB to total CK can be used to assess whether

the source is likely to be myocardial cell damage. In patients

presenting with MI, concentrations of the enzyme begin to

increase 46 h after the onset of chest pain, peak at 1224 h

and return to baseline within 4872 h.

(b) Aspartate aminotransferase (AST)

This enzyme is distributed widely in the body, being found

in red blood cells, liver, pancreas, myocardium, muscle and

kidney, catalysing the reversible transfer of an amino group

from aspartate to a-ketoglutarate to form glutamate andoxaloacetate. About 610 h after a MI, the serum

concentration begins to increase, peaking at 1248 h and

returning to normal after 34 days. It has low specificity for

cardiac disease and is therefore not used for this purpose.

(c) Lactate dehydrogenase (LDH)

This widely distributed enzyme catalyses the interconver-

sion of lactate and pyruvate. Five isoenzyme forms exist

including LDH-1, which is more common in heart muscle

and red blood cells. Plasma concentrations start to increase

1224 h after a MI, reaching a peak within 23 days, but

taking as long as 14 days to return to baseline. Under normal

conditions the concentration of isoezyme LDH-2 is greater

than that of LDH-1, but in MI this pattern is reversed.

(d) Troponins

These proteins are involved in the calcium interaction

necessary for muscle contraction. Three subunits of the

troponin protein can be found; -I, -T and -C, and a variety

of tissue specific subtypes exist. However troponin-I and -T

are structural components of cardiac muscle and are conse-

quently highly specific for myocardial tissue. Elevated

plasma concentrations are detected 312 h after myocardial

cell damage (in a similar time frame as CK-MB) but the

concentrations remain elevated for longer (59 days for

troponin-I and up to 14 days for troponin-T).

An increase in cardiac troponin proteins perioperatively

has been found to be useful in the prediction of cardiovas-

cular events and is therefore a useful screening test in high-

risk individuals perioperatively. Many studies have inves-

tigated the significance of early postoperative troponin

increases above the upper reference limit of the test

assay. These are summarized in Table 2. A meta-analysis

of the 4910 patients included in the 18 studies listed show

increased troponins to have a high sensitivity, specificity and

negative predictive value. One problem in confirming

results has been the difficulties in determining the upper

reference limit of the normal range for different tests.82

(2) Other biomarkers

There is increasing interest in other plasma biomarkers,

especially those which are markers of inflammation and

the atherosclerotic process rather than myocardial cell

damage. Among these biomarkers, the majority of work

has focused on investigating C-reactive protein, but there

are several other plasma biomarkers that are postulated to

have a role in the pathogenesis of atherosclerosis, and are

discussed below.

In addition, some plasma biomarkers appear to be risk

factors for the atherosclerotic process (e.g. an unfavourable

lipid profile). Other less routinely measured risk factors

include uric acid, homocysteine and leptin. None of these

has been investigated for their ability to predict periopera-

tive cardiovascular events.

(a) Acute phase reactants

(i) C-reactive protein (CRP) CRP was discovered in the

1930s by Tillet and Francis83 who observed that a non-type-

specific polysaccharide fraction was precipitated from the

sera of acutely ill patients with pneumococcal pneumonia. It

was later discovered that, in the presence of calcium ions,

CRP binds a range of ligands most of which contain

phosphoryl choline.

CRP is produced by hepatocytes in response to some

pro-inflammatory cytokines, mainly interleukin-6 (IL-6),

but also IL-1b in the presence of IL-6. CRP is found as atrace constituent of normal plasma with the median level

being 0.8 mg litre1 and the interquartile range 0.31.7 mg litre1. Most apparently healthy subjects haveserum levels less than 3 mg litre1 with levels greaterthan this not considered normal.61 However, an individuals

baseline CRP level is fairly constant, substantially gene-

tically predetermined,91 and there is no gender or age

determined variation.

CRP was the first protein to be discovered that acted as a

positive acute phase reactant. With the onset of the acute

phase reaction, CRP levels increase rapidly and reach peak

levels, which may be as high as 300 mg litre1, within2448 h. The half time of CRP in the plasma is 19 h

and is constant in all conditions; hence levels decrease

rapidly on resolution of the inflammatory stimulus. It is

pro-inflammatory and pro-atherogenic, with the level

reflecting the extent and activity of the disease process.

Recent studies hypothesize that CRP is not only an

inflammatory marker of atherosclerosis, but also actively

participates in the process of atherogenesis, and is found


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within atherosclerotic plaques in both coronary and periph-

eral arterial vessels.84 86 In vitro, CRP binds to LDL and may

become trapped in the vessel intima attached to the

deposited lipids. It is well known that CRP can activate

the complement system, and identification of activated

complement system components along with CRP in early

atherosclerotic lesions has led to the concept of CRP being

involved in sustaining chronic inflammation within the arte-

rial wall. Foam cells also stain positively for CRP, and it is

hypothesized that CRP has a role in the formation of these

cells by opsonization of lipid particles.84 However, CRP

levels have not been shown to consistently correlate with

the extent or burden of atherosclerotic disease when

quantified by Doppler ultrasound of the carotid arteries24

and electron beam computerized tomography for coronary

calcium.33 63

The many inflammatory processes known to raise CRP

are shown in Table 3. In general, drugs or other treatments

do not affect CRP production unless they also affect the

disease process involved, while liver impairment will affect

production of CRP.

At present, most hospital biochemistry laboratories can

measure CRP concentrations, but will not quantify low

concentrations, reporting those under a certain threshold

limit as normal. However, the accurate measurement of

serum CRP concentrations up to 3 mg litre1 is now possiblewith the advent of new high sensitivity assays (hs-CRP).

Measurements at these low concentrations, which were

previously considered to be within the normal range,

have been shown to be a useful screening tool for the

risk of coronary artery disease providing prognostic

information in patients with known atherosclerotic disease.

All individuals will have trace levels of CRP detectable on

hs-CRP testing, but certain patient characteristics have been

found to be associated with increased and decreased levels

as shown in Table 4. According to guidelines from the

American Heart Association and the Centers for Disease

Control and Prevention, a hs-CRP level of greater than

3 mg litre1 should be considered as a risk factor for futurecomplications in patients with stable coronary disease,

stroke and peripheral artery disease, while levels above

10 mg litre1 have greater prognostic value in thosesuffering from acute coronary syndromes.60

The current utility of CRP. The median level of hs-CRP,

within apparently healthy individuals, has been found to be

Table 2 The sensitivity, specificity, positive and negative predictive values for studies of perioperative cardiac troponin proteins in elective non-cardiac surgical

patients and short-term adverse outcome. Sens, sensitivity; Spec, specificity; PPV, positive predictive value; NPV, negative predictive value

Study Type of surgery Sens (%) Spec (%) PPV (%) NPV (%) No. of

subjects

Troponin

protein

Abnormal

level (ng ml1)

Adams and colleagues1 Elective vascular and spinal surgery 100 99 88.9 100 108 I >1.5Lee and colleagues 43 Elective or urgent major non-cardiac;

abdominal, orthopaedic,

thoracic, vascular and other surgery

76.5 84.9 13.2 99.2 1175 T >0.1

Munzer and colleagues52 Major non-cardiac; abdominal,

orthopaedic, thoracic

and vascular surgery

38.5 97.6 62.5 93.9 139 T >0.2

Metzler and colleagues49 Elective non-cardiac; abdominal,

orthopaedic and vascular surgery

100 91.5 61.5 100 67 T >0.2

Andrews and colleagues3 Major vascular surgery 86.7 94.1 72.2 97.6 100 I >0.1Haggart and colleagues27 Elective abdominal aortic

aneurysm repair

83.3 82.8 50 96 35 I >0.5

Jules-Elysee and

colleagues35Elective orthopaedic surgery 100 96.4 40 100 85 I >3.1

Mahla and colleagues46 Elective vascular surgery 50 91.5 33.3 95.6 51 T >0.1Filipovic and

colleagues23Major non-cardiac; intraperitoneal,

intrathoracic, orthopaedic

and vascular surgery

83.3 86.8 18.5 99.3 173 I >2

Higham and colleagues30 Major vascular surgery or

major joint arthroplasty

35 96 58.3 85.7 152 I >0.1

Landesberg and

colleagues41Elective major vascular surgery 100 79.4 13.8 100 501 I or T >0.6

0.03

Oscarsson and colleagues59 Non-cardiac; general, gynaecological,

orthopaedic, urological and

vascular surgery

100 68.8 7.5 100 161 T >0.02

Bursi and colleagues11 Elective major vascular surgery 76.2 84.8 37.6 96.7 391 I >0.1Hobbs and colleagues31 Major vascular surgery for critical

lower limb ischaemia

75 68 27.3 94.4 29 I >0.5

Le Manach and

colleagues42Infrarenal abdominal aortic

aneurysm surgery

100 90.2 35 100 1136 I >0.5

Martinez and colleagues48 Non-cardiac; vascular and

high-risk non-vascular

79.7 96.6 77 97 467 I >1.5

Motamed and colleagues51 Elective carotid endarterectomy 40 100 100 91.5 75 I >0.5Howell and colleagues32 Elective major vascular surgery 56.3 65.3 34.6 82.1 65 I >0.06Total Event rate=6.74% 76.4 87.5 30.7 98.1 4910

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significantly higher in those who later develop cardiovas-

cular events than in those who do not,16 64 66 and these

individuals risk of future cardiovascular disease can be

stratified according to their hs-CRP level.38 The Framing-

ham Risk Score was originally developed in 1991, and is a

widely used scoring system designed to estimate 10 yr future

risk of coronary heart disease in subjects without known

disease. Recent work has shown that inclusion of the hs-

CRP measurement can add additional prognostic informa-

tion to this risk score especially in intermediate-risk men

and high-risk women.15 CRP retains its independent asso-

ciation with incident coronary events even after adjusting

for many of the confounding factors known to affect levels

including age, total cholesterol, high-density lipoprotein

(HDL) cholesterol, cigarette smoking, BMI, history of dia-

betes mellitus, history of hypertension, exercise level and

family history of coronary heart disease.60

In patients with stable or unstable angina, CRP concentra-

tions can act as a predictor of the patients at high risk of

suffering a coronary event in the future.29 Similarly, CRP

concentrations are an independent predictor of ischaemic

stroke,95 and in patients with peripheral vascular disease

(PVD), the CRP concentration acts as a predictor of the sever-

ity PVD and the risk of subsequent cardiovascular events.6 86

CRP and outcome. A preoperative CRP value of greater

than 2 mg litre1 was shown to be associated with

postoperative complications in small group of patients

undergoing cardiac surgery, and an uneventful recovery

occurred in all patients with a concentration less than 2

mg litre1.10 In patients undergoing non-cardiac surgery,there are few studies investigating preoperative CRP con-

centration and cardiovascular outcome. One study of 51

surgical patients undergoing revascularization procedures

for PVD found that a CRP concentration greater than 9

mg litre1 was predictive of perioperative MI (it shouldbe noted that all patients with an ejection fraction of

plaques by facilitating the adherence of monocytes to the

vascular endothelium and deficiency of ICAM-1 has been

shown to be associated with protection against atheroscler-

osis in mice. The soluble form of ICAM-1 (sICAM-1) can

be measured in the plasma. The Bezafibrate Infarction Pre-

vention study showed that an increased baseline serum con-

centration of sICAM-I was associated with a higher

incidence of future coronary events in patients with chronic

coronary heart disease.28 The same study also showed that

concentrations of sICAM-1 were significantly associated

with the risk of ischaemic stroke.81 Another study showed

that the concentration of sICAM-1 is related to the estimated

risk of coronary heart disease in apparently healthy indi-

viduals. Concentrations in the upper quintile were associ-

ated with a 4.15% risk of coronary heart disease in the next

10 yr compared with 1.5% for those with a concentration in

the lowest quintile.93 The Physicans Health Study also

measured sICAM-1 concentrations for a proportion of

case-controlled subjects who developed MI and found a

significant association between baseline sICAM-1 concen-

trations and the risk of future MI independent of other risk

factors.65

(ii) Vascular cell adhesion molecule-1 (VCAM-1) VCAM-1

is a cell adhesion molecule which is not expressed under

baseline conditions, but is rapidly induced by proatheroscle-

rotic conditions. There is highly suggestive, but not conclu-

sive, evidence of a pathogenic role for VCAM-1 in the

development of atherosclerotic plaques. The soluble form

of VCAM-1 (sVCAM-1) can be measured in the plasma and

is increased in patients with hyperglycaemia. It has been

postulated to have a role in the excessive atherosclerotic

plaque formation seen in these patients.39 A study looking

at patients with previously documented coronary artery

disease, found that sVCAM-1 was a stronger predictor of

risk than sICAM-1,8 but both the Physicians Health study

and the Atherosclerosis Risk in Communities study did not

find that sVCAM-1 levels were predictive of future

cardiovascular risk.

(iii) Selectins P-selectin is an adhesion molecule produced

mainly by platelets that mediates initial monocyte rolling

before adherence to the endothelium in the early stages of

atherosclerotic plaque formation. Deficiency of P-selectin

has been shown to be protective against atherosclerosis in

mice and increased levels of P-selectin have been demon-

strated in a variety of cardiovascular disorders including

coronary artery disease, hypertension and atrial fibrillation.9

The concentration of a different selectin, E-selectin, has

been shown to be raised in the plasma of hyperglycaemic

men and is postulated to have a role in atherogenesis.39

(c) Cytokines and chemokines

(i) Interleukins The interleukins (IL) make up a group

of cytokines produced by a wide variety of cells. Certain

pro-inflammatory IL are involved in the acute phase reac-

tion, mainly IL-1, -6 and -8, and are termed acute phase

proteins. In response to these cytokines the liver produces a

number of acute phase reactants including CRP, SAA, com-

plement and fibrinogen. IL-6 appears particularly important.

It is secreted by T-lymphocytes and macrophages, and

receptors for IL-6 are found on the surface of many cells.

The Physicians Health study showed that baseline IL-6

concentrations can predict future cardiovascular events,68

and a further study showed that baseline IL-6 is predictive

of peripheral atherosclerotic disease progression within 5 yr

independent of other risk factors.85

(ii) Tumour necrosis factor-a (TNF-a) TNF-a is a multi-functional, pro-inflammatory cytokine with effects on many

different tissues including the endothelium. It is involved in

the acute phase reaction along with some of the IL. In the

Cholesterol and Recurrent Events (CARE) trial, elevations

of TNF-a in patients after MI were associated with anincreased risk of recurrent coronary events.67

(iii) Endothelins Endothelins are powerful vasoconstrictor

peptides that are produced by a variety of tissues including

the endothelial lining of blood vessels. Endothelin-1 is

expressed by endothelial cells, macrophages and smooth

muscle cells. It is produced as an inactive precursor called

big endothelin-1. Plasma endothelin concentrations are

elevated in patients with traditional atherosclerotic risk

factors and in those with early atherosclerosis and coronary

endothelial dysfunction. In advanced atherosclerotic

disease, plasma and tissue endothelin concentrations have

been found to be raised in proportion to the extent of ath-

erosclerosis. Endothelin is known to be a chemo-attractant

for monocytes and macrophages and is also thought to have

a role in neovascularization. The presence of receptors for

endothelin on neovessels within the atherosclerotic plaque

implies an angiogenic role of endothelin-1 in atheroscler-

osis.73 Levels of endothelin-1 and big endothelin-1 have

been shown to be significant prognostic factors in patients

with congestive cardiac failure and there is some evidence

that endothelin concentrations are better at predicting

survival than brain natriuretic peptide levels, but this has

not been applied to the perioperative period.87

(d) Other

(i) Matrix metalloproteinases (MMPs) The MMPs are

endopeptidases with the capacity to cleave components of

the extracellular matrix, such as collagen and elastin. They

are secreted as a pro-form and require activation for prote-

olytic activity. The activity of MMPs is normally low in

healthy tissue, but it is postulated that they may play a role in

the pathophysiology and progression of cardiovascular

disease. Depletion of matrix components from the fibrous

cap of atherosclerotic plaques causes an imbalance between

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synthesis and breakdown that leads to cap thinning,

predisposing the fibrous cap to rupture. This enhanced

matrix breakdown has been attributed to MMPs which

are expressed in atherosclerotic plaques by inflammatory

cells and may also be activated by thrombin in the athero-

sclerotic plaque. The MMPs are inhibited by tissue inhibitor

of metalloproteinases (TIMPs), but the activity of MMPs

requires the co-secretion of TIMPs. MMP-2 concentrations

have been shown to be increased in patients with unstable

angina or acute MI when compared with healthy controls.36

The Atherogene study showed that the mean baseline

value of TIMP-1 was higher in those who suffered a fatal

cardiovascular event than those who did not and this finding

was independent of other risk factors.45 CRP has been

shown to induce MMP-1 and MMP-10 in human endothelial

cells.50

(e) Risk factors

(i) Uric acid Serum uric acid is the major product of purine

metabolism and is formed from xanthine. Epidemiological

studies have shown that elevated uric acid levels predict an

increased risk of cardiovascular events with a recent

population-based study of initially healthy men showing

that serum uric acid concentrations are a strong predictor

of cardiovascular disease mortality independent of other

variables.55 However, the Framingham Heart study did

not find a causal role for uric acid and concluded that any

apparent association was probably because of the associa-

tion between uric acid concentration and other risk factors.

(ii) Homocysteine Homocysteine is an amino acid that is

known to be a risk factor for cardiovascular disease. Patients

suffering from homocysteinuria develop premature vascular

disease, and there are many studies showing a correlation

between plasma homocysteine concentration and coronary

artery disease, peripheral arterial disease, stroke and venous

thrombosis. Homocysteine is thought to affect coagulation

by acting as a prothrombotic factor, and reduce the resis-

tance of the endothelium to thrombosis.57 Elevated homo-

cysteine concentrations on admission to hospital in patients

with acute coronary syndrome are predictive of late but not

early (within 28 days) cardiac events,79 and elevated

concentrations before coronary angioplasty are predictive

of late mortality and adverse outcome.74 However, a

meta-analysis performed in 2002 found that an elevated

homocysteine concentration is at best a modest predictor

of ischaemic heart disease and stroke risk in the healthy

population.13

(iii) Leptin This peptide hormone is produced by white

adipose tissue. Plasma leptin concentrations are propor-

tional to body adiposity, and are markedly increased

in obese individuals. Leptin exhibits potentially athero-

genic effects such as endothelial dysfunction, stimulation

of inflammatory reaction, oxidative stress, decrease in

paraoxonase activity, platelet aggregation, migration,

hypertrophy and proliferation of vascular smooth muscle

cells. Leptin deficient and leptin-receptor deficient mice

are protected from arterial thrombosis and neointimal hyper-

plasia in response to arterial wall injury. Epidemiological

studies show that a raised plasma concentration of leptin is

predictive of acute cardiovascular events even after adjust-

ment for BMI, plasma lipids, glucose and CRP.89 In patients

with known coronary atherosclerosis, the plasma leptin level

has been found to be predictive of future cardiovascular

events over a 4 yr follow-up period.94

A future role for plasma biomarkers?

There are still a number of patients who suffer perioperative

cardiovascular events in whom the traditional preoperative

tests for stress-induced myocardial ischaemia do not identify

a highly increased risk. We postulate that this is because the

traditional preoperative tests do not identify patients at risk

of the plaque rupture type of perioperative MI. None of the

preoperative tests we currently use can identify vulnerable

plaques, and consequently identifying patients at risk of

plaque rupture and haemorrhage, is not possible.

Of the tests described above, CRP appears the most

promising for measurement in the perioperative period.

CRP does not correlate with atherosclerotic burden, but

may act as a marker of other atherosclerotic characteristics,

possibly the activity of lymphocyte and macrophage

populations within the plaque or the degree of plaque desta-

bilization and ongoing ulceration or thrombosis.2 We ques-

tion whether CRP could be useful in identifying patients

with vulnerable plaques. If used as a preoperative test for

unstable atherosclerotic plaques, the result would only be

interpretable in those patients without other co-existing

inflammatory conditions. This might limit its use. However,

vascular surgical patients have the highest incidence of

perioperative cardiovascular events and this test would be

applicable in the majority of these patients.

Possible perioperative medical treatment forvulnerable plaques

It would be extremely useful to identify patients with

vulnerable plaques before operation if an intervention

could then be initiated with the aim of reducing the risk

of perioperative plaque rupture.

Possible drugs of importance include the 3-hydroxy-3-

methylglutaryl coenzyme A (HMG-CoA) reductase

inhibitors (statins), which modify lipid levels; lowering

LDL and total cholesterol levels, whilst increasing HDL

levels. They have been shown to be highly effective

drugs in reducing the risk of cardiovascular events in the

setting of both primary and secondary prevention. The

magnitude of this risk reduction is much greater than can

be predicted on the basis of lowering LDL cholesterol alone,


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and it is postulated that some of this risk reduction is because

of pleiotrophic, non-lipid properties including the improve-

ment of endothelial function, plaque stabilization and

the reduction of oxidative stress in vascular inflammation.80

The anti-inflammatory effects appear to be mediated via

interference with the synthesis of isoprenoid intermediates

(mevalonate metabolites) and limitation of the nuclear

factor-kB dependent transcriptional regulation in responseto an inflammatory stimulus.77

The question of whether or not inflammatory markers

such as CRP are clinically useful in selecting patients

who may benefit from statin therapy despite having normal

LDL cholesterol levels has yet to be answered, and the

JUPITER trial has been set up to address this question.

Although statins lower CRP levels, it has yet to be proven

that this represents a true reduction in inflammation.

A recent study showed that CRP expression in human hepa-

tocytes after statin therapy was blocked even in the presence

of cytokines known to induce CRP,88 suggesting that statins

block CRP expression at the level of transcription. Work has

shown that CRP in itself may be a cardiovascular risk factor,

by quenching the production of nitric oxide which in turn

inhibits angiogenesis, an important compensatory mecha-

nism in chronic ischaemia.

Statin therapy has been shown to reduce the incidence

of perioperative cardiovascular complications in patients

undergoing major non-cardiac surgery in a large retro-

spective cohort study,44 and a prospective double-blind

randomized controlled trial.20 After abdominal aortic aneur-

ysm repair, long-term statin therapy has been shown to be

associated with a 3-fold reduction in cardiovascular

mortality.37 Concerns about an increased incidence of

statin-associated myopathy within the surgical population

are unfounded.75

Studies have shown that improvements in endothelial

function, and reductions in serum inflammatory markers

occur within 216 weeks after beginning statin therapy

but the minimum period of preoperative and postoperative

therapy has not yet been determined. The most efficacious

dose of statin therapy in the perioperative period is another

area lacking research. In acute coronary syndromes, high

dose statin therapy is now advocated showing a reduction

in future events over placebo or a standard dose regimen.56

The question of whether patients at increased risk of peri-

operative cardiovascular events with raised inflammatory

markers would benefit from this sort of high dose statin

regimen during the perioperative period has yet to be

answered.

Another class of drug known to reduce the concentrations

of inflammatory mediators including CRP is the thiazo-

lidinedione group,25 which are used in the treatment of

diabetes mellitus type 2. These drugs have been found to

have a beneficial effect on the cardiovascular system

independent of their anti-diabetic effect but any potential

protective role of these drugs in the perioperative period has

not been studied.

Conclusion

Most work to date has focused on the identification of a

subgroup of surgical patients at high risk of PMI. Whilst

traditional preoperative tests of myocardial reserve and

coronary stenosis can be helpful in predicting those at

risk of ischaemia-induced PMI, there is no currently

available test that can reliably identify surgical patients

with vulnerable plaques.

Of those molecules and mediators of the atherosclerotic

process that can be measured in the plasma, CRP has been

investigated more extensively than others with regard to

prognostic significance. However, its role in identifying

surgical patients at risk of perioperative plaque rupture

and haemorrhage has yet to be studied. Future studies are

needed to evaluate the perioperative potential of this and

other biochemical markers.

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