University Hospital/Department of Anaesthesia, Hugstetter Str. 55, 79106 Freiburg, Germany. E-mail: priebe{at}ana1.ukl.uni-freiburg.de
Keywords: complications, myocardial ischaemia; complications, myocardial infarction; surgery, non-cardiac
![]() |
Introduction |
---|
![]() |
Incidence of perioperative myocardial ischaemia and infarction |
---|
Postoperative myocardial ischaemia seems to be the best predictor of in-hospital and long-term cardiac morbidity and mortality.11 26 46 5961 69 It increased the relative risk of experiencing an early postoperative cardiac event (e.g. myocardial infarction, unstable angina, congestive heart failure) by a factor between 959 and 21.46 Postoperative myocardial ischaemia also increased the odds for long-term (30 days to 2 years after surgery) cardiac events (unstable angina, non-fatal myocardial infarction, cardiac death, surgical coronary revascularization) 2.2-fold.61 In-hospital postoperative myocardial ischaemia preceded long-term adverse cardiac outcome in up to 70%.46 59
Incidence of perioperative myocardial infarction
The reported incidence of postoperative cardiac events (the combined incidence of non-fatal myocardial infarction, unstable angina, congestive heart failure, cardiac death) varies between 5.5 and 53%61 81 82 86 87 and that of postoperative myocardial infarction between 1.4 and 38%.27 44 46 48 51 61 69 8183 86 87 Postoperative myocardial infarction increased the odds for long-term cardiac events 20-fold.61 The various findings would suggest that postoperative cardiac outcome is more affected by postoperative factors that cause myocardial ischaemia than by the patients preoperative cardiac status.
![]() |
Definition and diagnosis of perioperative myocardial ischaemia and infarction |
---|
Perioperative myocardial ischaemia has predominantly been detected and defined by ECG. The reported incidence of perioperative myocardial ischaemia will, thus, greatly depend on choice and number of precordial leads, on the definition of ischaemic ST-segment change (extent and duration of ST-segment change), and on the mode of data acquisition (continuous vs intermittent).57 Holter monitor-detected myocardial ischaemia has a sensitivity of 3750% and a specificity of 8892%.88 101 Continuous 12-lead electrocardiography improves sensitivity to 6190%56 and 6697%.49
The reported incidence of ECG-defined myocardial ischaemia will also depend on the suitability of patients for reliable detection of ischaemia-specific ECG changes. Patients with left ventricular hypertrophy and those not in sinus rhythm are not suitable for ECG-derived diagnosis of myocardial ischaemia. In addition, perioperative changes in acidbase balance and electrolytes can affect the ECG in a way that interferes with ischaemia detection. Thus, apart from differences in the prevalence of underlying ischaemic heart disease and in the type of surgical risk, the high variability in the reported incidence of perioperative myocardial ischaemia is probably due to methodological problems.
Definition and diagnosis of perioperative myocardial infarction
Fundamental questions remain regarding the definition and diagnostic criteria of myocardial infarction in general2 and in the perioperative period in particular.64 According to the definition of the World Health Organization (WHO), at least two of three criteria must be fulfilled to diagnose myocardial infarction: typical ischaemic chest pain; increased serum concentration of creatine kinase-MB isoenzyme; and typical electrocardiographic findings, including development of pathological Q-waves.108 115 This definition provides adequate specificity but lacks high sensitivity.
The development of assays for the cardiac troponins T and I, which are highly specific and sensitive for myocardial injury, formed the basis of a revised definition of myocardial infarction proposed by the European Society of Cardiology and the American College of Cardiology.105 The following two criteria satisfy the diagnosis of an acute, evolving or recent myocardial infarction: (i) a typical increase and gradual decrease in troponin concentrations or more rapid increase and decrease in creatine kinase-MB concentration in combination with at least one of the following: (a) typical ischaemic symptoms, (b) development of pathological Q-waves in the ECG, (c) ECG changes indicative of myocardial ischaemia (ST-segment elevation or depression), and (d) coronary artery intervention; and (ii) pathological findings of an acute myocardial infarction.
Depending on whether myocardial infarction was defined by WHO criteria115 or by an increase in serum concentration of troponin I of >1.5 ng ml1 respectively, the incidence of postoperative myocardial infarction was 3 or 12%.44 Similarly, depending on whether myocardial infarction was defined by the typical creatine kinase-MB isoenzyme criteria or an increase in serum concentration of troponin T of >0.1 ng ml1, the incidence of postoperative myocardial infarction was 1.4 or 17%, respectively.51 Creatine kinase-MB is relatively inaccurate in detecting postoperative myocardial infarction.1 Other definitions of postoperative myocardial infarction include an increase in serum concentration of troponin I 3.1 ng ml1 accompanied by at least one of the following: typical ischaemic symptoms, ECG changes indicative of myocardial ischaemia (ST-segment depression or elevation) or new pathological Q-waves. By this definition, the incidence of postoperative myocardial infarction was 6.5%.48
The question remains whether a reported incidence of perioperative myocardial injury based on traditional definition underestimates the true incidence of clinically relevant myocardial injury or whether a reported incidence based on serum concentrations of troponins overestimates it. When using exclusively biochemical markers, specificity may be sacrificed for sensitivity. Another question is whether biochemical marker-defined myocardial injury carries the same predictive value as traditionally defined infarctions, and whether mechanisms and triggers are identical in both cases.
Characteristics of postoperative myocardial ischaemia
The majority of postoperative myocardial ischaemia in high-risk patients tends to develop on the day of or the day after surgery, most ischaemic episodes starting at the end of surgery and during emergence from anaesthesia.48 The vast majority (more than 90%) of postoperative episodes of myocardial ischaemia are silent.46 60 Postoperative ST-segment changes are almost exclusively episodes of ST-segment depression rather than elevation.27 48 56 59 60
The findings on the relationship between short-term changes in haemodynamics and the incidence of postoperative myocardial ischaemia are contradictory. Most studies did not find any association between changes in heart rate and postoperative ST-segment changes59 60 87 or troponin release.89 In one study, however, all episodes of ST-segment depression were preceded by increases in heart rate.48 Overall evidence would suggest that heart rate is not a reliable independent predictor of postoperative ST-segment depression and troponin release.
Characteristics of postoperative myocardial infarction
Clinical and electrophysiological characteristics
Most postoperative myocardial infarctions occur early after surgery and are asymptomatic,6 and most of them (60100%) are of the non-Q-wave type.6 27 46 49 The vast majority of perioperative myocardial infarctions are preceded by episodes of ST-segment depression.46 48 69 81 82 Long-duration (single duration >2030 min or cumulative duration >12 h) ST-segment change, rather than merely the presence of postoperative ST-segment depression, seems to be the important factor associated with adverse cardiac outcome.46 69 83 Short ischaemic episodes (<10 min) did not correlate with postoperative myocardial infarction and cardiac complications.46 48 However, seven patients with postoperative myocardial ischaemia lasting longer than 2 h did not sustain an ischaemic cardiac event.27
Pathological characteristics
In an autopsy study from the 1930s, fatal perioperative myocardial infarction was accompanied by thrombosis of the coronary artery supplying the infarcted area.68 Following fatal perioperative myocardial infarction, the vast majority (93%) of 42 autopsy heart specimens showed significant atherosclerotic coronary artery obstruction.20 There was evidence of plaque disruption in 55%, and evidence of plaque haemorrhage in 45% of 42 autopsy heart specimens. In more than half the patients, the site of infarction could not have been predicted from the severity of the underlying stenosis.
Such findings are similar to those in autopsies after acute myocardial infarction in the non-operative setting, suggesting that perioperative myocardial infarction has a coronary pathology similar to that of myocardial infarction in the non-operative setting with regard to coronary plaque haemorrhage, rupture and thrombus formation. Acute plaque disruption in the infarct-related coronary artery seems to be common, but the severity of underlying coronary artery stenosis does not predict the infarct territory. Such similarities would suggest that perioperative and non-perioperative myocardial infarctions occur by similar mechanisms.
Angiographic characteristics
When compared with a matched control group without perioperative death or myocardial infarction, patients who experienced perioperative myocardial infarctions had more angiographic evidence of extensive coronary artery disease (as reflected by a larger number of affected coronary arteries, high-grade stenoses and collateralized total occlusions).22 However, high-grade stenoses were an uncommon cause of complications. Inadequate collateralization of total occlusions seemed to have been the most common cause of infarction. In addition, in a third of the patients with perioperative cardiac events, a culprit site could not be identified (i.e. the coronary artery supplying the infarcted territory).22
In agreement with the latter finding, coronary angiography performed in three patients within 7 days of postoperative myocardial infarction revealed chronic, severe coronary artery disease but no angiographically visible thrombus or ruptured plaques.48 Such findings are consistent with the possibility that, in some patients with severe but stable coronary artery disease, postoperative myocardial infarction may develop because of prolonged myocardial ischaemia rather than because of acute plaque rupture and/or coronary thrombosis.
![]() |
Pathophysiology of myocardial ischaemia |
---|
Endothelial function is impaired in coronary artery disease, and is an important cause of myocardial ischaemia. Stimuli that are accompanied by activation of the sympathetic nervous system, by increases in circulating catecholamines and by increases in coronary blood flow secondary to an increase in myocardial oxygen demand (e.g. during exercise, mental stress or increase in heart rate) induce vasodilatation in normal coronary arteries. However, in atherosclerotic coronary arteries with endothelial dysfunction these stimuli can lead to paradoxical vasoconstriction.99 116 Acute myocardial ischaemia intensifies these paradoxical vascular responses. Such limitation of coronary flow as a result of paradoxical coronary vasoconstriction, and the inability of vessels to dilate near the site of an atherosclerotic plaque, may result in regional myocardial supply- or low-flow ischaemia.
The most common electrocardiographic finding during episodes of symptomatic or silent myocardial ischaemia in patients with chronic stable angina pectoris is ST-segment depression. When ischaemia is confined predominantly to the subendocardium, the overlying ECG leads show ST-segment depression.71 This subendocardial pattern is typical of spontaneous ischaemic episodes of angina pectoris or during symptomatic or asymptomatic (silent) ischaemia induced by exercise or by a stress test. Less obstructive thrombi and/or those that consist of less robust fibrin and more platelet aggregates usually produce ST-segment depression and/or T-wave inversion.
![]() |
Pathophysiology of myocardial infarction |
---|
Any attempt to define triggers of acute coronary syndromes (ACS) must take into account the extreme variations in clinical presentation. At one end of the spectrum are those patients who suffer a sudden cardiac death or a myocardial infarction without any preceding episode of angina, and not followed by recurrent instability. At the other end of the spectrum are those patients who develop a myocardial infarction after episodes of unstable angina over a period of days to weeks, and who often develop postinfarction angina and/or reinfarction. It is conceivable that the triggers of instability differ between such groups of patients.
Up to very recently, ulcerative, fissured and/or thrombotic coronary plaques that are characterized histologically by a central lipid core, inflammatory cell infiltrate and fibrous cap thinning have been termed vulnerable.73 The popular view that a vulnerable plaque constitutes the final common pathway that leads to the atherothrombotic events ignores not only the numerous, diverse triggers of acute coronary events but also the contributory role of blood rheology and coagulation (high-risk blood). A more dynamic and inclusive concept seems appropriate.16 43 67
Structural (central lipid core, thin cap) and functional (plaque thrombogenicity, intraplaque inflammatory cell infiltrate) factors interact in an unpredictable fashion. Exogenous factors (e.g. mechanical stress, vasomotor tone, infection, blood viscosity and coagulability) further modify such interaction, making the final outcome even less predictable. The transition from stable coronary artery disease to the ACS of non-Q-wave and Q-wave infarction and unstable angina is characterized by coronary plaque disruption and subsequent thrombosis, which constitute the major pathogenetic components of unstable or vulnerable plaques.67 However, at least in some cases and irrespective of the presence of unstable or stable plaques, a thrombogenic state or high-risk blood is likely to contribute to ACS.33
Comprehensive post-mortem studies no longer support the view that rupture of atheromatous (vulnerable) coronary plaques are the result of mostly localized mechanical shear stress forces, and that a single type of culprit coronary plaque is the only cause of instability.19 92 Inflammatory mechanisms and structural and functional plaque characteristics have received increasing attention.13 67 111
![]() |
Structural and functional characteristics of acute coronary syndromes |
---|
Structurally vulnerable plaques
Plaques with a central lipid core of >40% of the total lesion area and a cap thickness of 65150 mm are potentially vulnerable to mechanical stress and/or inflammatory weakening of their collagen structure, and they may rupture even if they cause a stenosis that is not visible on X-ray angiography.67 In the context of the perioperative period, it is important to remember that the prevalence of structurally vulnerable plaques is also high in patients with stable coronary artery disease13 and correlates with the total atherothrombotic burden.23 However, it is impossible to predict the time it will take the structurally vulnerable plaque to become unstable, or the trigger that causes the plaque to rupture (i.e. mechanical stress, coronary vasospasm, widespread acute inflammatory endothelial activation, or the chronic inflammatory component of atherosclerosis).
Functionally vulnerable plaques
In a substantial percentage of culprit lesions, thrombosed plaques without detectable fissures were observed.19 In such cases, plaque vulnerability is probably caused by thrombogenic or high-risk blood and/or local proinflammatory cytokines that trigger thrombosis, sometimes even in the absence of inflammatory cell infiltration and a lipid core.111
Complex coronary artery stenoses
Complex coronary artery stenoses, consisting of a variable combination of plaque fissuring and thrombosis, appear to be the hallmark morphological characteristic of ACS. However, the fate of these complex coronary stenoses is highly variable. They may remain complex but become functionally stable, or they may even become smooth after having undergone remodelling. This explains why a substantial fraction of patients with stable coronary artery disease demonstrate angiographically complex lesions. Thus, neither complex (as typically found in ACS) nor flow-limiting coronary stenoses (as typically found in stable angina) are isolated morphological substrates of instability. However, multiple angiographically complex lesions correlated with instability37 and elevated C-reactive protein (CRP) concentrations.117
Coronary endothelial erosions
Although fissure of the culprit lesion is the prominent finding in some patients with ACS, in 2040% of ACS cases coronary thrombi have been observed to overlie atherosclerotic plaques without disruption of the fibrous cap, but with endothelial lesions underneath or above stenotic or non-stenotic plaques of variable morphological characteristics (e.g. with or without inflammatory cell infiltrates, with or without a lipid core).14 24 28 100 109 111 The thrombi overlie plaques with only superficial endothelial erosion. These erosions are particularly common in young victims of sudden death, in smokers and in women. Under such conditions, thrombus formation may depend on hyperthrombogenicity-inducing systemic factors, such as hypercholesterolaemia, increased concentrations of catecholamines, diabetes, smoking, infection, a hypercoagulable state (with elevated serum concentrations of fibrinogen, von Willebrand factor, and factor VII) and a defective fibrinolytic state (with increased serum concentrations of plasminogen activator inhibitor 1 and decreased concentrations of tissue plasminogen activator and urokinase).18 Systemic factors, including elevated low-density lipoprotein cholesterol, cigarette smoking, hyperglycaemia and others, are associated with increased blood thrombogenicity.90 As erosion of plaques without the typical features of a vulnerable plaque (fissuring, thin fibrous cap, lipid-rich core) may result in ACS, the generic term high-risk plaque may be more appropriate than vulnerable plaque.67
Plaque inflammation
In ACS, 3040% of coronary thrombi overlie plaques that often contain inflammatory cell infiltrates, are denuded of endothelium, and often, if not mostly, have luminal inflammation.4 12 109 Activated T cells in the non-culprit arteries and systemic circulation15 104 were demonstrated in patients with unstable angina. These findings are consistent with recent evidence that the serum concentration of CRP better predicts the risk of myocardial infarction and stroke than total and low-density lipoprotein cholesterol concentrations.95 The incidence of elevated CRP serum concentrations is less than 50%, 70% and 100% in patients with very early myocardial infarction not preceded by unstable angina, severe unstable angina, and very early acute myocardial infarction preceded by unstable angina, respectively.54 55 In addition, the persistence of elevated markers of systemic inflammation predicts recurrence of instability.9 However, inflammatory cell infiltration is not uncommon in patients with stable coronary artery disease.100
In the event of plaque rupture, thrombus growth depends not only on the size and thrombogenicity of the fissured plaque, but also on the number and activation of exposed inflammatory cells.33 Inflammatory activation of the endothelium can turn its physiological vasodilatory and antithrombotic properties into pathological vasoconstrictor and prothrombotic properties. In addition, the inflammatory response of the circulating blood may activate coagulation.97
Plaque progression
Plaque progression is often abrupt and mostly unpredictable.16 Three facts are worthwhile recalling. First, plaque progression and clinical outcome are not always closely correlated, and each is poorly predicted by clinical and angiographic variables. Most plaques that underlie a fatal or nonfatal myocardial infarction stenose angiographically the respective coronary artery by less than 70%. Approximately 60% of those infarcts are caused by rupture of plaques which carry the characteristics of vulnerability (i.e. large thrombogenic core of lipid and necrotic debris, and a thin ruptured cap). Secondly, plaques often progress episodically in relation to episodes of thrombosis (which, in turn, are triggered by plaque rupture, erosion, endothelial activation or inflammation). In the absence of a hypercoagulable state, thrombi may remain mural rather than become occlusive, and may thus produce few if any symptoms (unless they embolize).66 If subsequent lysis is incomplete and is followed by re-endothelialization, the plaque will grow. Thirdly, plaques in a given patient often progress largely independently.36
These are all reasons for the unpredictability of individual patient outcome. Part of this unpredictability is probably related to fluctuations of risk factors and triggers (e.g. physical activity, mental stress, environmental temperature, smoking, infection, hydration and blood pressure). However, most of the independent plaque behaviour in a given patient is probably due to pronounced heterogeneity of plaque histology and to differences in the physical forces to which plaques are exposed.25 35
Pathogenesis of plaque rupture
The pathogenesis of plaque rupture involves both biochemical and physical factors. Rupture of the intimal surface is the result of a combination of cellular processes that promote plaque instability and physical (haemodynamic) processes that influence the magnitude and distribution of stress on the plaque. When intimal rupture occurs, the content of the plaque is important. Unstable plaques contain twice as much tissue factor and plasminogen activator inhibitor-1 than stable plaques.107
Passive plaque disruption is related to physical forces, and it occurs most frequently where the fibrous cap is weakest. Three main factors determine the vulnerability of the fibrous cap: (i) circumferential wall stress or cap fatigue; (ii) the location, size and consistency of the atheromatous core; and (iii) blood-flow characteristics, particularly the impact of flow on the proximal aspect of the plaque.23
The size of the thrombus that forms at the site of plaque rupture and the clinical consequences will depend on several key factors: the depth of injury, the composition of the plaque, the magnitude of the stenosis, and the extent of platelet activation and intrinsic fibrinolytic activity.28 The degree of plaque disruption (ulceration, fissure or erosion) and substrate exposure is a key factor in determining thrombogenicity at the local coronary artery site. Both plaque composition and its propensity to rupture are major determinants of future ischaemic events.18 These many variables explain why coronary lesions that are angiographically fairly small may progress acutely to severe stenosis or total occlusion, and may account for as many as two-thirds of the patients who develop unstable angina or other ACS.23
Physical factors in plaque rupture
ACS follow a circadian rhythm.73 74 This indicates that cardiac events do not occur entirely randomly and may be triggered by external activities. The likelihood of plaque rupture may be increased after awakening by the 2030 mm Hg increase in systolic blood pressure that occurs during the morning hours. The parallel increase in heart rate not only increases myocardial oxygen demand and decreases myocardial oxygen supply by decreasing diastolic filling time, but may also predispose to myocardial ischaemia by affecting the rheological properties at the site of a plaque and by predisposing the plaque to rupture. In the morning hours, increased vascular tone (placing additional haemodynamic stress on the plaque), platelet hyperreactivity, increased blood viscosity, a nadir of fibrinolytic activity, and reduced level of tissue plasminogen activator have been observed.106 Interestingly, and possibly relevant to the perioperative setting, the diurnal variation in plaque rupture is eliminated by ß-blockers and by aspirin.93
Consistent with the finding of a circadian rhythm of ACS, plaque rupture is more common during various kinds of strenuous physical activity, including exercise stress testing and emotional stress.72 In all of these situations, the sympathetic nervous system is activated. This leads to increased plasma concentrations of catecholamines, blood viscosity, and increases in blood pressure and heart rate, which are accompanied by detectable increases in platelet aggregation and decreases in fibrinolytic activity that both tend to favour thrombosis.38 This combination of increased prothrombotic and reduced fibrinolytic activity could initiate propagation and total occlusion of the coronary artery by a mural thrombus overlying a small plaque erosion that might otherwise have been harmless. Similar physiological processes may trigger ischaemic cardiac events in the perioperative period (a time that is characterized by comparable adrenergic stimulation) and increased prothrombotic and reduced fibrinolytic activity.
![]() |
Factors and interventions affecting perioperative cardiac outcome |
---|
Factors associated with postoperative myocardial ischaemia
Postoperative myocardial ischaemia has been shown to be associated with postoperative anaemia,78 postoperative hypothermia29 30 and pain.7 62 Anaemia, hypothermia and pain will all activate sympathetic tone with the adverse effects on cardiovascular function and coagulation. The result will be an increase in myocardial oxygen consumption in the presence of a decrease in delivery.
Interventions associated with improved perioperative cardiac outcome
ß-Adrenoceptor antagonists
Perioperative ß-blocker therapy can provide a 6065% reduction in the likelihood of non-fatal myocardial infarction and cardiac death.5 63 84 The protective effect of perioperative ß-blocker therapy on perioperative cardiac outcome in patients with suspected or documented coronary artery disease may well be due to its ability to reduce the incidence and severity of perioperative myocardial ischaemia.112
The exact mechanism by which ß-adrenoceptor antagonists reduce postoperative myocardial ischaemia remains to be determined. In the heart, ß-adrenoceptor blockade improves myocardial oxygen balance by reductions in heart rate, blood pressure and contractility. A reduction in blood pressure and pulse rate at rest or with exercise with ß-blockers may reduce the propensity for plaque disruption by reducing circumferential stress on the fibrous caps of lipid-rich plaques. In addition to these possible benefits, ß-blockers also have anti-arrhythmic properties.
In the central nervous system, ß-blocker therapy leads to a reduction in peripheral sympathetic nerve discharge. The biochemical effects of ß-adrenoceptor blockade include anti-atherogenic effects (e.g. decreased endothelial injury), increased production of prostacyclins, inhibition of platelet accumulation, and decreased affinity of low-density lipoprotein to proteoglycans in the vessel wall.
2-Adrenoceptor agonists
2-Adrenoceptor agonists reduce perioperative mortality and myocardial ischaemia after non-cardiac surgery, and myocardial infarction after vascular surgery.70 79 80 113 The mechanism of their protective effect is likely to be manifold.
2-Adrenoceptor agonists attenuate perioperative haemodynamic instability,70 inhibit central sympathetic discharge,75 reduce peripheral norepinephrine release21 and dilate poststenotic coronary vessels.40
Aspirin
Early postoperative administration of aspirin improved outcome after coronary artery bypass surgery.65 Aspirin is known to reduce cardiac events in patients with acute coronary syndromes and in patients not known to have coronary heart disease.17 It eliminates the diurnal variation in plaque rupture.93 Compared with controls, patients with unstable angina have more than twice the blood concentrations of interleukin-6, CRP and macrophage colony-stimulating factor.41 These concentrations decreased after 6 weeks of aspirin treatment. Aspirin will, of course, reduce platelet aggregability, but its ability to reduce future myocardial infarction appears greatest in individuals with serological evidence of increased inflammation.94 Thus, the anti-inflammatory effect of aspirin may be additive to its antithrombotic effect in patients with plaque instability.
Statins
A retrospective casecontrol study provided evidence that the preoperative use of statins may be associated with reduced perioperative mortality in patients undergoing major vascular surgery.85 Patients on preoperative statin therapy had a more than 4-fold reduction in perioperative mortality. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A. Their direct effect on vascular function may result in coronary plaque stabilization.52 Statins possess anti-inflammatory action and reverse endothelial dysfunction.52 The beneficial effect of statins on perioperative outcome was comparable between users and non-users of ß-blockers.
Mechanisms and triggers of perioperative myocardial injury
All studies consistently found an association between perioperative myocardial ischaemia (defined by ST-segment changes) and perioperative cardiac morbidity. Furthermore, postoperative cardiac complications were preceded almost universally by long- rather than short-duration ST-segment changes, the ST-segment changes consisted almost exclusively of depression rather than elevation, and most postoperative myocardial infarctions were of the non-Q-wave rather than the Q-wave type. These characteristics of perioperative myocardial ischaemia may have several explanations: (i) prolonged perioperative myocardial ischaemia leads to myocardial infarction; (ii) repeated and prolonged ST-segment depression reflects the onset of a permanent cardiac event (e.g. myocardial infarction); and (iii) perioperative myocardial ischaemia and infarction are two separate events that both develop on the basis of underlying coronary artery disease.
There is pathological evidence that the pathogenesis and pathophysiology of perioperative myocardial infarction (i.e. acute plaque rupture and coronary thrombosis caused by acute increases in blood pressure, heart rate, coronary vasomotor tone and platelet aggregability and decreased fibrinolytic activity) resemble those in the non-surgical setting.20 On the other hand, the combination of consistent increases in heart rate preceding the ischaemic episodes, ST-segment depression rather than elevation during literally all ischaemic episodes, non-Q-wave rather than Q-wave myocardial infarctions in all cases of myocardial infarctions, the lack of angiographically visible thrombus or ruptured plaques in patients who underwent coronary angiography after postoperative myocardial infarction, and the complete reversal of ECG changes to baseline in all but one of the patients with ischaemia (including those with infarction)48 is highly suggestive that prolonged stress-induced myocardial ischaemia is the likely primary cause of postoperative myocardial infarction. Repeated brief ischaemic episodes may well have a cumulative effect and ultimately cause myocardial necrosis.34
Although ST-segment depression usually reflects subendocardial ischaemia and is often regarded as reversible injury, it is not inconsistent with a myocardial infarction. Especially elderly patients may present with myocardial infarction without ST-segment elevation.45 In most studies on perioperative cardiac ischaemic events, the study populations consisted largely of elderly patients. Thus, prolonged ST-segment depression may reflect either ongoing myocardial ischaemia (ultimately leading to myocardial infarction) or the beginning of an evolving myocardial infarction.
Although postoperative cardiac complications were mostly associated with only long-duration ST-segment depression, not all investigations found such an association.27 In addition, most studies did not find a correlation between acute increases in heart rate and myocardial ischaemia and infarction. This lack of a consistent association between heart rate and the length of postoperative ST-segment depression on the one hand and an adverse cardiac outcome on the other would argue for non-ischaemic causes of ST-segment depression in the perioperative period (e.g. hyperventilation, electrolyte changes, drug effects, positional changes), for compensatory mechanisms to myocardial ischaemia (e.g. preconditioning as a result of multiple brief episodes of myocardial ischaemia and coronary reperfusion,91 or for functional collateral perfusion).96
The preponderance of non-Q-wave infarctions is clearly different from what is found in the non-surgical setting. This, again, would indicate that perioperative myocardial infarctions are more often the result of prolonged ischaemia than of thrombotic occlusion, similar to the presumed pathophysiology of silent ischaemia.102 In contrast to the usual coronary thrombotic occlusion after an acute plaque disruption, in the presence of severe but stable coronary artery disease coronary thrombosis may result from a decrease in coronary blood flow and stasis.31 32 Some patients with stenotic atherosclerotic lesions may develop acute myocardial infarction without evidence for plaque rupture and superimposed thrombus formation. This may happen if there is a marked decrease in myocardial oxygen supply (e.g. prolonged severe coronary vasospasm) or a marked increase in myocardial oxygen demand. These infarcts are located along the least well-perfused inner portions of the ventricular wall and often extend beyond the territory of just one coronary artery.3 Such decrease in coronary blood flow in the presence of severe coronary artery disease may occur during tachycardia, which considerably shortens diastolic and, thus, coronary filling time42 and which can narrow atherosclerotic coronary arteries.76 Myocardial ischaemia-induced coronary vasoconstriction may further decrease coronary blood flow.98
It is thus conceivable that coronary thrombosis in the postoperative setting is the consequence rather than the cause of prolonged myocardial ischaemia and postoperative myocardial infarction. This possibility is consistent with the finding that both diabetes mellitus and left ventricular hypertrophy are independent predictors of postoperative myocardial ischaemia.48 Both conditions are accompanied by limited coronary flow reserve and microvascular dysfunction.77 103
Most ischaemic episodes tend to start at the end of surgery and during emergence from anaesthesia.48 This period is characterized by increases in heart rate, blood pressure, sympathetic tone and procoagulant activity.10 Increased sympathetic tone can result in increases in blood pressure, heart rate, contractility, coronary vasomotor tone and coronary vascular shear stress. This, in turn, may trigger coronary vasospam, plaque disruption and coronary thrombosis. However, if this were the primary mechanism of postoperative myocardial ischaemia and infarction, ST-segment elevations and more frequent Q-wave infarctions would be expected.
Increases in blood pressure, heart rate and cardiac contractility lead to subendocardial ischaemia by increasing myocardial oxygen demand in the presence of limited or absent coronary vasodilator reserve due to underlying coronary artery disease. In the experimental animal, prolonged (14 h) tachycardia-induced ischaemia in the presence of a fixed critical coronary artery stenosis led to a progressive decline in subendocardial blood flow and diffuse subendocardial necrosis.47
Surgery induces a state of hypercoagulability on the basis of increased number and reactivity of platelets, increased concentration of fibrinogen and other proteins of the coagulation cascade (factor VIII, von Willebrand factor, 1-antitrypsin), impaired deformability of erythrocytes, and a decrease in the concentration of proteins that are active in the fibrinolytic system (protein C, antithrombin III,
2-macroglobulin). Such simultaneous procoagulant and antifibrinolytic activity may trigger coronary artery thrombosis during low-flow conditions in the presence of underlying stable coronary artery disease even in the absence of acute plaque disruption. The ultimate fate of the thrombus and, thus, the extent of jeopardized myocardium will depend on the duration and degree of coronary occlusion, which in turn will depend on the balance between thrombosis and lysis, and on flow conditions (affected by coronary vasomotor tone, perfusion pressure, and the rheological properties of the blood).
![]() |
Conclusions |
---|
In many patients with unstable coronary artery disease, numerous mechanisms are responsible for the unstable nature of the disease. These include coronary artery thrombosis, platelet aggregation and emboli, progression of coronary artery disease, coronary artery vasospasm and vasoconstriction, systemic and local inflammation and infection, and increased myocardial oxygen demand in the presence of a fixed stenosis.
In the perioperative period, patients with coronary artery disease may develop a (temporary?) biochemical milieu that predisposes them to widespread plaque degeneration and/or accelerated subsequent thrombus formation. Sudden rupture of a vulnerable plaque may occur spontaneously without apparent reason, or it may follow a particular event, such as extreme cardiovascular demand, exposure to cold, or acute infection.73 114
Myocardial infarctions usually occur at sites that previously caused only angiographically determined mild to moderate luminal stenosis.23 53 This indicates that plaque transformation from the stable to the vulnerable state can be acute and helps to explain the observation that chronic, stable coronary atherosclerosis can transform into acute, potentially life-threatening coronary events at any time. Widespread waxing and waning of coronary inflammation and/or of systemic blood thrombogenicity may contribute to the development of plaque vulnerability, in the absence or presence of underlying structurally vulnerable plaques. Some patients may remain vulnerable for a period of weeks to months. In such (chronically) inflamed patients it is possible that plaques will suddenly flare up and become unstable, even in the absence of inflammatory cell infiltration and a central lipid core. Plaque rupture may occur without clinical manifestations (silent plaque rupture).
The symptoms associated with unstable coronary syndromes result from myocardial ischaemia that is principally caused by two factors: platelet and thrombus formation and subsequent intense vasoconstriction that results from the local accumulation of thromboxane 2 and serotonin and the reduction in local concentrations of endothelium-derived relaxing factor and inhibitors of platelet aggregation. These events are usually preceded by rupture or erosion of a vulnerable plaque. The thrombotic response to a plaque rupture is probably regulated by the thrombogenicity of the exposed plaque constituents, the local haemorheology (determined by the severity of the underlying stenosis), shear-induced platelet activation, and by systemic thrombogenicity and fibrinolytic activity.23
If the plaque disruption is major, with extensive exposure of thrombogenic core material to the blood stream, acute total coronary occlusion with subsequent myocardial infarction or sudden death may develop. If the disruption is minor, the forming thrombus can be non-occlusive and the patient may stay asymptomatic or develop unstable angina or a non-Q-wave infarction. A concomitant increase in coagulability and coronary vasoconstriction (as is common in the perioperative setting) may, however, transform a non-occlusive thrombus to an occlusive thrombus. Ultimately, the balance of thrombosis vs thrombolysis is the decisive factor in determining whether the clinical outcome will be myocardial ischaemia or myocardial infarction.
A vast variety of factors and interventions with vastly different mechanisms of action that are known to affect the occurrence of myocardial ischaemia and infarction in the non-operative setting (e.g. temperature, haematocrit, pain, ß-blocker, aspirin, statins) have been shown to do the same in the perioperative period. Thus, although the characteristics of coronary artery disease and the perioperative period make it likely that the trigger(s) of perioperative myocardial ischaemia and infarction will vary within and between patients, it is equally likely that the perioperative mechanisms and triggers (biochemical, physical) of myocardial ischaemia and ACS are comparable to those in the non-operative setting. In patients with an old myocardial infarction, stable angina or occult coronary artery disease, the development of postoperative myocardial ischaemia, as reflected by ST-segment depression, can be seen as a positive stress test result. In this case, the non-cardiac surgery is the stress. Taking the analogy of stopping an exercise or pharmacological stress test when signs of myocardial ischaemia develop, it is essential to manage aggressively the various factors that contribute to postoperative stress.
![]() |
References |
---|
2 Alpert JS. Defining myocardial infarction: Will the real myocardial infarction please stand up? [Editorial]. Am Heart J 2003; 146: 3779[CrossRef][ISI][Medline]
3 Antman EM, Braunwald E. Acute myocardial infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease, 6th edn. Philadelphia: W. B. Saunders, 2001; 1119
4 Arbustini E, Dal Bello B, Morbini P, et al. Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction. Heart 1999; 82: 26972
5 Auerbach A, Goldman L. ß-blockers and reduction of cardiac events in noncardiac surgery. JAMA 2002; 287: 143544
6 Badner NH, Knill RL, Brown JE, et al. Myocardial infarction after noncardiac surgery. Anesthesiology 1998; 88: 5728[ISI][Medline]
7 Beattie WS, Buckley DN, Forrest JB. Epidural morphine reduces the risk of postoperative myocardial ischaemia in patients with cardiac risk factors. Can J Anaesth 1993; 40: 53241[Abstract]
8 Boersma E, Mercado N, Poldermans D, Gardien M, Vos J, Simoons ML. Acute myocardial infarction. Lancet 2003; 361: 84758[CrossRef][ISI][Medline]
9 Bogaty P, Poirier P, Simard S, et al. Biological profiles in subjects with recurrent acute coronary events compared with subjects with long-standing stable angina. Circulation 2001; 103: 30628
10 Breslow MJ, Parker SD, Frank SM, et al. Determinants of catecholamine and cortisol responses to lower extremity revascularization: the PIRAT study group. Anesthesiology 1993; 79: 12029[ISI][Medline]
11 Browner WS, Li J, Mangano DT, for the Study of Perioperative Ischemia Research Group. In-hospital and long-term mortality in male veterans following noncardiac surgery. JAMA 1992; 268: 22832[Abstract]
12 Buffon A, Biasucci LM, Liuzzo G, et al. Widespread coronary inflammation in unstable angina. N Engl J Med 2002; 347: 512
13 Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation 1994; 89: 5035[ISI][Medline]
14 Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who die suddenly. N Engl J Med 1997; 336: 127682
15 Caligiuri G, Paulsson G, Nicoletti A, et al. Evidence for antigen-driven T-cell response in unstable angina. Circulation 2000; 102: 11149
16 Casscells W, Naghavi M, Willerson JT. Vulnerable atherosclerotic plaque. A multifocal disease. Circulation 2003; 107: 20725
17 Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet 2001; 357: 8995[CrossRef][ISI][Medline]
18 Corti R, Fuster V, Badimon JJ. Pathogenic concepts of acute coronary syndromes. J Am Coll Cardiol 2003; 41: 7S14S[CrossRef][ISI][Medline]
19 Davies MJ. Stability and instability: two faces of coronary atherosclerosis. Circulation 1996; 94: 201320
20 Dawood MA, Gutpa DK, Southern J, et al. Pathology of fatal perioperative myocardial infarction: implications regarding pathophysiology and prevention. Int J Cardiol 1996; 57: 3744[CrossRef][ISI][Medline]
21 Ellis JE, Drijvers G, Pedlow S, et al. Premedication with oral and transdermal clonidine provides safe and efficacious postoperative sympatholysis. Anesth Analg 1994; 79: 113340[Abstract]
22 Ellis SG, Hertzer NR, Young JR, Brener S. Angiographic correlates of cardiac death and myocardial infarction complicating major nonthoracic vascular surgery. Am J Cardiol 1996; 77: 11268[CrossRef][ISI][Medline]
23 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 65771
24 Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996; 93: 135463
25 Feldman CL, Stone PH. Intravascular hemodynamic factors responsible for progression of coronary atherosclerosis and development of vulnerable plaque. Curr Opin Cardiol 2000; 15: 43040[CrossRef][ISI][Medline]
26 Fleisher LA, Rosenbaum SH, Nelson AH, Barash PG. The predictive value for postoperative ischemic cardiac events in vascular and nonvascular surgery patients. Am Heart J 1991; 122: 9806[ISI][Medline]
27 Fleisher LA, Nelson AH, Rosenbaum SH. Postoperative myocardial ischemia: aetiology of cardiac morbidity or manifestation of underlying disease? J Clin Anesth 1995; 7: 16[CrossRef][ISI][Medline]
28 Forrester JS. Role of plaque rupture in acute coronary syndromes. Am J Cardiol 2000; 86 (Suppl.): J1523[ISI][Medline]
29 Frank S, Beattie C, Christopherson R, et al. Unintentional hypothermia is associated with postoperative myocardial ischemia. The Perioperative Ischemia Randomized Anesthesia Trial Study Group. Anesthesiology 1993; 78: 46876[ISI][Medline]
30 Frank S, Fleisher L, Breslow M, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial. JAMA 1997; 277: 112734[Abstract]
31 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathophysiology of coronary artery disease and the acute syndromes (I). N Engl J Med 1992; 326: 24250[ISI][Medline]
32 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathophysiology of coronary artery disease and the acute syndromes (II). N Engl J Med 1992; 326: 3108[ISI][Medline]
33 Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: biology. Lancet 1999; 353 (Suppl. 2): S1159
34 Geft IL, Fishbein MC, Ninomyia K, et al. Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circulation 1982; 66: 11503[Abstract]
35 Gertz SD, Roberts WC. Hemodynamic shear force in rupture of coronary arterial atherosclerotic plaques. Am J Cardiol 1990; 66: 136872[ISI][Medline]
36 Gibson CM, Sandor T, Stone PH, et al. Quantitative angiographic and statistical methods to assess serial changes in coronary luminal diameter and implications for atherosclerotic regression trials. Am J Cardiol 1992; 69: 128690[ISI][Medline]
37 Goldstein JA, Demetriou D, Grines CL, et al. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000; 343: 91522
38 Grignani G, Soffiantino F, Zuchella M, et al. Platelet activation by emotional stress in patients with coronary artery disease. Circulation 1991; 83 (Suppl. II): 12836[ISI]
39 Häggmark S, Hohner P, Östman M, et al. Comparison of hemodynamic, electrocardiographic, mechanical, and metabolic indicators of intraoperative myocardial ischemia in vascular surgical patients with coronary artery disease. Anesthesiology 1989; 70: 1925[ISI][Medline]
40 Heusch G, Schipke J, Thamer V. Clonidine prevents the sympathetic initiation and aggravation of poststenotic myocardial ischemia. J Cardiovasc Pharmacol 1985; 7: 117682[ISI][Medline]
41 Ikonomidis I, Andreotti F, Economou E, et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999; 100: 7938
42 Indolfi C, Ross J Jr, The role of heart rate in myocardial ischemia and infarction: implications of myocardial perfusion-contraction matching. Prog Cardiovasc Dis 1993; 36: 6174[CrossRef][ISI][Medline]
43 Kereiakes DJ. The emperors clothes. In search of the vulnerable plaque. Circulation 2003; 107: 20767
44 Kim LJ, Martinez EA, Faraday N, et al. Cardiac troponin I predicts short-term mortality in vascular surgery patients. Circulation 2002; 106: 236671
45 Krumholz HM, Friesinger GC, Cook EF, et al. Relationship of age with eligibility for thrombolytic therapy and mortality among patients with suspected acute myocardial infarction. J Am Geriatr Soc 1994; 42: 12731[ISI][Medline]
46 Landesberg G, Luria MH, Cotev S, et al. Importance of long-duration postoperative ST-segment depression in cardiac morbidity after vascular surgery. Lancet 1993; 341: 7159[ISI][Medline]
47 Landesberg G, Zhou W, Aversano T. Tachycardia-induced subendocardial necrosis in acutely instrumented dogs with fixed coronary stenosis. Anesth Analg 1999; 88: 9739
48 Landesberg G, Mosseri M, Zahger D, et al. Myocardial infarction after vascular surgery: the role of prolonged stress-induced, ST depression-type ischemia. J Am Coll Cardiol 2001; 37: 183945[CrossRef][ISI][Medline]
49 Landesberg G, Mosseri M, Wolf Y, et al. Perioperative myocardial ischemia and infarction. Identification by continuous 12-lead electrocardiogram with online ST-segment monitoring. Anesthesiology 2002; 96: 26270
50 Landesberg G. The pathophysiology of perioperative myocardial infarction: facts and perspectives. J Cardiothorac Vasc Anesth 2003; 17: 90100[CrossRef][ISI][Medline]
51 Lee TH, Thomas EJ, Ludwig LE, et al. Troponin T as a marker for myocardial ischemia in patients undergoing major noncardiac surgery. Am J Cardiol 1996; 77: 10316[CrossRef][ISI][Medline]
52 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 113543
53 Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988; 78: 115766[Abstract]
54 Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med 1994; 331: 41724
55 Liuzzo G, Biasucci LM, Gallimore JR, et al. Enhanced inflammatory response in patients with preinfarction unstable angina. J Am Coll Cardiol 1999; 34: 1696703[CrossRef][ISI][Medline]
56 London MJ, Hollenberg M, Wong MG, et al. Intraoperative myocardial ischemia: Localization by continuous 12-lead electrocardiography. Anesthesiology 1988; 69: 23241[ISI][Medline]
57 London MJ. Multilead precordial ST-segment monitoring. The next generation? [Editorial views]. Anesthesiology 2002; 96: 25961[ISI][Medline]
58 Mangano DT. Perioperative cardiac morbidity. Anesthesiology 1990; 72: 15384[ISI][Medline]
59 Mangano DT, Browner WS, Hollenberg M, et al. Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. N Engl J Med 1990; 323: 17818[Abstract]
60 Mangano DT, Hollenberg M, Fegert G, et al. Perioperative myocardial ischaemia in patients undergoing noncardiac surgery I: incidence and severity during the 4 day perioperative period. J Am Coll Cardiol 1991; 17: 84350[ISI][Medline]
61 Mangano DT, Browner W, Hollenberg M, et al. for the Study of Perioperative Ischemia Research Group. Long-term cardiac prognosis following noncardiac surgery. JAMA 1992; 268: 2339[Abstract]
62 Mangano DT, Siliciano D, Hollenberg M, et al. Postoperative myocardial ischemia therapeutic trials using intensive analgesia following surgery. Anesthesiology 1992; 76: 34353
63 Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery: Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996; 335: 171320
64 Mangano DT. Adverse outcomes after surgery in the year 2001 a continuing odyssey. [Editorial]. Anesthesiology 1998; 88: 5614[ISI][Medline]
65 Mangano DT, for the Multicenter Study of Perioperative Ischemia Research Group. Aspirin and mortality from coronary bypass surgery. N Engl J Med 2002; 347: 130917
66 Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart 1999; 82: 2658
67 Maseri A, Fuster V. Is there a vulnerable plaque? Circulation 2003; 107: 206871
68 Master AM, Dack S, Jaffe H. Perioperative coronary artery occlusion. JAMA 1938; 110: 14158
69 McCann RL, Clements FM. Silent myocardial ischemia in patients undergoing peripheral vascular surgery: incidence and association with perioperative cardiac morbidity and mortality. J Vasc Surg 1989; 9: 5837[CrossRef][ISI][Medline]
70 McSPI-Europe Research Group. Perioperative sympatholysis: beneficial effects of the 2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia. Anesthesiology 1997; 86: 34663[ISI][Medline]
71 Mirvis DM, Goldberger AL. Electrocardiography. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease, 6th edn. Philadelphia: W. B. Saunders, 2001; 1078
72 Mittleman MA, Maclure M, Tofler GH, et al. Triggering of acute myocardial infarction by heavy physical exertion: protection against triggering by regular exercise. N Engl J Med 1993; 329: 167783
73 Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989; 79: 73343[Abstract]
74 Muller JE, Abela GS, Nestro RW, Tofler GH. Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol 1994; 23: 80813
75 Muzi M, Goff DR, Kampine JP, et al. Clonidine reduces sympathetic activity but maintains baroreflex responses in normotensive humans. Anesthesiology 1992; 77: 86471[ISI][Medline]
76 Nabel GE, Selwyn AP, Ganz P. Paradoxical narrowing of atherosclerotic coronary arteries induced by increases in heart rate. Circulation 1990; 81: 8509[Abstract]
77 Nahser PJ Jr, Brown RE, Oskarsson H, et al. Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation 1995; 91: 63540
78 Nelson AH, Fleisher LA, Rosenbaum SH. Relationship between postoperative anaemia and cardiac morbidity in high-risk vascular patients in the intensive care unit. Crit Care Med 1993; 21: 8606[ISI][Medline]
79 Nishina K, Mikawa K, Uesugi T, et al. Efficacy of clonidine for prevention of perioperative myocardial ischemia: a critical appraisal and meta-analysis of the literature. Anesthesiology 2002; 96: 3239[CrossRef][ISI][Medline]
80 Oliver MF, Goldman L, Julian DG, Holme I. Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease: the European Mivazerol Trial (EMIT). Anesthesiology 1999; 91: 95161[ISI][Medline]
81 Ouyang P, Gerstenblith G, Furman WR, et al. Frequency and significance of early postoperative silent myocardial ischemia in patients having peripheral vascular surgery. Am J Cardiol 1989; 64: 11136[ISI][Medline]
82 Pasternak PF, Grossi EA, Baumann G, et al. The value of silent myocardial ischemia monitoring in the prediction of perioperative myocardial infarction in patients undergoing peripheral vascular surgery. J Vasc Surg 1989; 10: 61725[CrossRef][ISI][Medline]
83 Pasternak PF, Grossi EA, Baumann G, et al. Silent myocardial ischemia monitoring predicts late as well as perioperative cardiac events in patients undergoing vascular surgery. J Vasc Surg 1992; 16: 17180[CrossRef][ISI][Medline]
84 Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 1999; 341: 178994
85 Poldermans D, Bax JJ, Kertai MD, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003; 107: 184851
86 Raby KE, Goldman L, Creager MA, et al. Correlation between preoperative ischemia and major cardiac events after peripheral vascular surgery. N Engl J Med 1989; 321: 1296300[Abstract]
87 Raby KE, Barry J, Creager MA, et al. Detection and significance of intraoperative and postoperative myocardial ischemia in peripheral vascular surgery. JAMA 1992; 268: 2227[Abstract]
88 Raby KE, Barry J, Treasure CB, et al. Usefulness of Holter monitoring for detecting myocardial ischemia in patients with nondiagnostic exercise treadmill test. Am J Cardiol 1993; 72: 88993[CrossRef][ISI][Medline]
89 Rapp H-J, Rabethge S, Luiz T, Haux P. Perioperative ST-segment depression and troponin T release. Acta Anaesthesiol Scand 1999; 43: 1249[CrossRef][ISI][Medline]
90 Rauch U, Osende JI, Fuster V, et al. Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med 2001; 134: 2248
91 Reimer KA, Murray CE, Jennings RB. Cardiac adaptation to ischemia. Ischemic preconditioning increases myocardial tolerance to subsequent ischemic episodes. Circulation 1990; 82: 22668[ISI][Medline]
92 Richardson P, Davies M, Born G. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989; 2: 9414[ISI][Medline]
93 Ridker PM, Manson JE, Buring JE, et al. Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation 1990; 82: 897902[Abstract]
94 Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 9739
95 Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347: 155765
96 Sabia PJ, Powers ER, Ragosta M, et al. An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction. N Engl J Med 1992; 327: 182531[Abstract]
97 Sambola A, Osende J, Hathcock J, et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation 2003; 107: 9737
98 Sambuceti G, Marzilli M, Marraccini P, et al. Coronary vasoconstriction during myocardial ischemia induced by rises in metabolic demand in patients with coronary artery disease. Circulation 1997; 95: 26529
99 Selwyn AP, Kinlay S, Creager M, et al. Cell dysfunction in atherosclerosis and the ischemic manifestations of coronary artery disease. Am J Cardiol 1997; 79: 1723[ISI][Medline]
100 Shah PK. Plaque disruption and thrombosis: potential role of inflammation and infection. Cardiol Rev 2000; 8: 319[CrossRef][Medline]
101 Sharp SD, Mason JW, Bray B. Comparison of ST segment depression recorded by Holter monitors and 12-lead ECGs during coronary angiography and exercise testing. J Electrocardiol 1992; 25: 32331[CrossRef][ISI][Medline]
102 Singh N, Langer A. Current status of silent myocardial ischemia. Can J Cardiol 1995; 11: 2869[ISI][Medline]
103 Sobue T, Yokota M, Iwase M, Ishihara H. Influence of left ventricular hypertrophy on left ventricular function during dynamic exercise in the presence and absence of coronary artery disease. J Am Coll Cardiol 1995; 25: 918[CrossRef][ISI][Medline]
104 Spagnoli LG, Bonanno E, Mauriello A, et al. Multicentric inflammation in epicardial coronary arteries of patients dying of acute myocardial infarction. J Am Coll Cardiol 2002; 40: 157988[CrossRef][ISI][Medline]
105 Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined: a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J 2000; 21: 150213
106 Tofler GH. Triggering and the pathophysiology of acute coronary syndromes. Am Heart J 1997; 134: S5561[ISI][Medline]
107 Toschi V, Gallo R, Lettino M, et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 5949
108 Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, et al. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 1994; 90: 583612[Abstract]
109 van der Wal AC, Becker AE, van der Loos CM, et al. Site of intimal rupture of erosion of thrombosed coronary atherosclerotic plaques is characterised by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994; 89: 3644[Abstract]
110 van der Wal AC, Becker AE, Koch KT, et al. Clinically stable angina pectoris is not necessarily associated with histologically stable atherosclerotic plaques. Heart 1996; 76: 3126[Abstract]
111 Virmani R, Kolodgie FD, Burke AP, et al. Lesson from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20: 126275
112 Wallace A, Layug B, Tateo I, et al., for the McSPI Research Group. Prophylactic atenolol reduces postoperative myocardial ischemia. Anesthesiology 1998; 88: 717[ISI][Medline]
113 Wijeysundera DN, Naik JS, Beattie S. Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications: a meta-analysis. Am J Med 2003; 114: 74252[CrossRef][ISI][Medline]
114 Willich SN, Maclure M, Mittleman M, et al. Sudden cardiac death. Support for a role of triggering in causation. Circulation 1993; 87: 144250[Abstract]
115 World Health Organization. MONICA Project (Monitoring Trends and Determinants in Cardiovascular Disease): a major international collaboration. WHO MONICA Project Principal Investigators. J Clin Epidemiol 1988; 41: 10511[ISI][Medline]
116 Yeung AC, Vekshtein VI, Krantz DS, et al. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N Engl J Med 1991; 325: 155156[Abstract]
117 Zairis M, Papadaki O, Manousakis S, et al. C-reactive protein and multiple complex coronary artery plaques in patients with primary unstable angina. Atherosclerosis 2000; 164: 3559