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-cardiac
surgical 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: georgina.howard-alpe@nda.ox.ac.uk

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 perioperative 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 comparable incidence of approximately 8000 perioperative cardiovascular deaths per year from roughly 5 million general
or regional anaesthetics performed.54 92 A major predisposing factor in the development of a perioperative cardiovascular event is the presence of ischaemic heart disease,
whether diagnosed or previously unknown. Atherosclerosis
is the main pathological disorder responsible for the development 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 incidence 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 surgical stress response they do not completely abolish it,
and have not been shown to alter the incidence of perioperative cardiovascular events.53 69 72 96 Further factors that
may be affected by accurate risk stratification include
the most appropriate location of surgery, possible modification 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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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 cardiovascular 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.

Biochemical markers in detecting atherosclerosis

SMOKING
LIPID PROFILE

ENDOTHELIAL DYSFUNCTION

FAMILY HISTORY

METABOLIC
SYNDROME

DIABETES
MELLITUS

HOMOCYSTEINE

BLOOD FLOW
CHANGES:
Turbulence
Shear stress

HYPERTENSION

URIC ACID

LEPTIN
RISK FACTORS

LEUKOCYTES

INFLAMMATION

Inflammatory mediators
Cell adhesion molecules
Cytokines
Chemokines
Acute phase reactants

PLATELETS

ATHEROSCLEROSIS
ATHEROGENESIS
Fig 2 The process of atherogenesis.

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 aetiology 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 attraction, 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 lipoprotein (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 inflammatory core of leukocytes, lipid and debris beneath, which
may be necrotic. Atherosclerotic lesions expand at their
shoulders by continued leukocyte adhesion and entry. Platelets 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

Initial lesion
Isolated foam cells plus smooth muscle thickening

Fatty streak
Foam cells and intracellular lipid accumulation

Pre-atheroma
Changes of fatty streak lesion plus small extracellular
lipid pools
Atheroma
Changes of fatty streak lesion plus a core of extracellular lipid

Fibroatheroma
Lipid core and fibrotic layer, or multiple lipid cores and
fibrotic layers, or mainly calcific, or mainly fibrotic

Complicated lesion
Surface defect (ulceration or rupture), haematoma-haemorrhage,
thrombus
Fig 3 The development of an atherosclerotic plaque.

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 perioperative

myocardial 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.

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Fig 1 Risk factors for atherosclerosis.

Howard-Alpe et al.

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 haemorrhage, 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 recommended 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 cardiovascular

disease
A more recent and alternative approach has been measurement 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

Necrotic lipid core

Haemorrhage

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

Fibrous thickening

Foam cells

Preoperative investigation

Smooth muscle
thickening
Plaque fissure and rupture
Vessel lumen
Thrombus

Fig 4 Drawing of blood vessel containing unstable, complicated

atheromatous plaque.

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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(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 plaque. 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 inflammation and repair, and the balance between these two processes 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 cardiovascular 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 stressinduced 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

Biochemical markers in detecting atherosclerosis

creatine kinase, aspartate aminotransferase and lactate dehydrogenase. However, these tests have been largely superseded by measurement of troponin I or T concentrations,
which are more specific for myocardial cell injury.

(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 and
oxaloacetate. 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 interconversion 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 consequently 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 cardiovascular events and is therefore a useful screening test in highrisk individuals perioperatively. Many studies have investigated the significance of early postoperative troponin
increases above the upper reference limit of the test

(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 perioperative 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-typespecific 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 a
trace constituent of normal plasma with the median level
being 0.8 mg litre 1 and the interquartile range 0.3
1.7 mg litre 1. Most apparently healthy subjects have
serum levels less than 3 mg litre 1 with levels greater
than this not considered normal.61 However, an individuals
baseline CRP level is fairly constant, substantially genetically 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 litre 1, within
2448 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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(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.

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

Howard-Alpe et al.

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
Type of surgery

Sens (%)

Adams and colleagues1

Lee and colleagues 43

Elective vascular and spinal surgery

Elective or urgent major non-cardiac;
abdominal, orthopaedic,
thoracic, vascular and other surgery
Major non-cardiac; abdominal,
orthopaedic, thoracic
and vascular surgery
Elective non-cardiac; abdominal,
orthopaedic and vascular surgery
Major vascular surgery
Elective abdominal aortic
aneurysm repair
Elective orthopaedic surgery

100
76.5

99
84.9

38.5

Munzer and colleagues52

Metzler and colleagues49
Andrews and colleagues3
Haggart and colleagues27
Jules-Elysee and
colleagues35
Mahla and colleagues46
Filipovic and
colleagues23
Higham and colleagues30
Landesberg and
colleagues41
Oscarsson and colleagues59
Bursi and colleagues11
Hobbs and colleagues31
Le Manach and
colleagues42
Martinez and colleagues48
51

Motamed and colleagues

Howell and colleagues32
Total

Elective vascular surgery

Major non-cardiac; intraperitoneal,
intrathoracic, orthopaedic
and vascular surgery
Major vascular surgery or
major joint arthroplasty
Elective major vascular surgery
Non-cardiac; general, gynaecological,
orthopaedic, urological and
vascular surgery
Elective major vascular surgery
Major vascular surgery for critical
lower limb ischaemia
Infrarenal abdominal aortic
aneurysm surgery
Non-cardiac; vascular and
high-risk non-vascular
Elective carotid endarterectomy
Elective major vascular surgery
Event rate=6.74%

Spec (%)

NPV (%)

No. of
subjects

Troponin
protein

Abnormal
level (ng ml 1)

88.9
13.2

100
99.2

108
1175

I
T

>1.5
>0.1

97.6

62.5

93.9

139

>0.2

91.5

61.5

67

>0.2

94.1
82.8

72.2
50

100
35

I
I

>0.1
>0.5

96.4

40

85

>3.1

50
83.3

91.5
86.8

33.3
18.5

95.6
99.3

51
173

T
I

>0.1
>2

35

96

58.3

85.7

152

>0.1

100

79.4

13.8

100

501

I or T

100

68.8

7.5

100

161

>0.6
0.03
>0.02

84.8
68

37.6
27.3

391
29

I
I

>0.1
>0.5

90.2

35

100

1136

>0.5

79.7

96.6

77

97

467

>1.5

40
56.3
76.4

100
65.3
87.5

100
34.6
30.7

75
65
4910

I
I

>0.5
>0.06

100
86.7
83.3
100

76.2
75
100

within atherosclerotic plaques in both coronary and peripheral 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 arterial 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

PPV (%)

100
97.6
96
100

96.7
94.4

91.5
82.1
98.1

concentrations, reporting those under a certain threshold

limit as normal. However, the accurate measurement of
serum CRP concentrations up to 3 mg litre 1 is now possible
with 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 litre 1 should be considered as a risk factor for future
complications in patients with stable coronary disease,
stroke and peripheral artery disease, while levels above
10 mg litre 1 have greater prognostic value in those
suffering 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

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Study

Biochemical markers in detecting atherosclerosis

Table 3 Conditions known to significantly raise CRP

Infections
Allergic complications of infection
Inflammatory disease

Trauma

Necrosis

Table 4 Patient characteristics known to alter hsCRP levels

Increased levels

Decreased levels

Raised BMI
Cigarette smoking
Metabolic syndrome and diabetes mellitus
Low HDL and high triglyceride
Oestrogen/progesterone hormone use
Moderate alcohol consumption
Increased activity or endurance exercise
Weight loss

significantly higher in those who later develop cardiovascular 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 Framingham 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 hsCRP measurement can add additional prognostic information to this risk score especially in intermediate-risk men
and high-risk women.15 CRP retains its independent association 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 diabetes mellitus, history of hypertension, exercise level and
family history of coronary heart disease.60
In patients with stable or unstable angina, CRP concentrations 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 severity PVD and the risk of subsequent cardiovascular events.6 86
CRP and outcome. A preoperative CRP value of greater
than 2 mg litre 1 was shown to be associated with

(ii) Serum amyloid A (SAA) SAA belongs to a family of

proteins that form a major component of the acute-phase
inflammatory response. It is synthesized in the liver in
response to a pro-inflammatory stimulus. It is thought to
alter HDL-cholesterol delivery to cells, which is how it
may be involved in the pathogenesis of atherosclerosis.
The WISE study showed a strong independent relationship
between SAA concentrations and future cardiovascular
events in women referred for angiography.34
(iii) Fibrinogen Fibrinogen has many functionsplaying
an essential part in thrombogenesis, acting as an acute phase
reactant, and as a mediator of both inflammation and coagulation. It is therefore a key molecule in the processes
involved in atherogenesis. Epidemiological studies have
shown that patients with peripheral arterial disease have
an increased plasma fibrinogen concentration. It has also
been shown that in high-risk patients with PVD an elevated
fibrinogen concentration is predictive of fatal cardiovascular
complications over a 10 yr follow-up period.19
(iv) Complement proteins The complement proteins form
a biochemical cascade involved in inflammation. There are
three pathways by which the cascade can be activated; the
classical pathway (by antigenantibody complexes and
CRP), the alternative pathway (by microbial surfaces)
and the lectin-binding pathway (by acute phase proteins).
Complement proteins are synthesized mainly by the liver,
but other cells including monocytes and macrophages can
produce them. Increased plasma concentrations of complement proteins indicate that an acute phase reaction or
inflammatory process is occurring. Studies have shown
that patients with atherosclerosis have elevated plasma complement concentrations and within atheromatous plaqueactivated complement components have been found.
Complement activation, as indicated by a raised C5a, in
patients with advanced peripheral artery disease has been
shown to predict an increased cardiovascular risk.76
(b) Cell adhesion molecules
(i) Intercellular adhesion molecule-1 (ICAM-1) ICAM-1
plays a critical role in the formation of early atherosclerotic

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Malignant neoplasia

Rheumatic fever
Erythema nodosum leprosum
Rheumatoid arthritis
Juvenile chronic arthritis
Ankylosing spondilitis
Psoriatic arthritis
Systemic vasculitis
Polymyalgia rheumatica
Reiters disease
Crohns disease
Familial Mediterranean fever
Surgery
Burns
Fractures
Myocardial infarction
umour embolization
Acute pancreatitis
Lymphoma
Hodgkins disease
Carcinoma
Sarcoma

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 litre 1.10 In patients undergoing non-cardiac surgery,
there are few studies investigating preoperative CRP concentration and cardiovascular outcome. One study of 51
surgical patients undergoing revascularization procedures
for PVD found that a CRP concentration greater than 9
mg litre 1 was predictive of perioperative MI (it should
be noted that all patients with an ejection fraction of
<40% were excluded).71

Howard-Alpe et al.

(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 proatherosclerotic conditions. There is highly suggestive, but not conclusive, 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 demonstrated 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 reaction, 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, complement 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 multifunctional, 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 an
increased 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 atherosclerosis. 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 atherosclerosis.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 proteolytic 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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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 atherosclerosis in mice. The soluble form of ICAM-1 (sICAM-1) can
be measured in the plasma. The Bezafibrate Infarction Prevention study showed that an increased baseline serum concentration 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 individuals. Concentrations in the upper quintile were associated 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 concentrations and the risk of future MI independent of other risk
factors.65

Biochemical markers in detecting atherosclerosis

(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 association 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 resistance of the endothelium to thrombosis.57 Elevated homocysteine 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 proportional to body adiposity, and are markedly increased
in obese individuals. Leptin exhibits potentially atherogenic 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 hyperplasia in response to arterial wall injury. Epidemiological
studies show that a raised plasma concentration of leptin is
predictive of acute cardiovascular events even after adjustment 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 destabilization and ongoing ulceration or thrombosis.2 We question 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 for

vulnerable 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-3methylglutaryl 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,

765

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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 atherosclerotic 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

Howard-Alpe et al.

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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