Drugs 42 (Suppl. 2): 1-7, 1991 00 12-6667/91/0200-0001/$3.50/0 © Adis International Limited. All rights reserved. DRSUP2125

The Pathophysiology and Epidemiology of Myocardial Infarction A Review

John Gill Adis Drug Information Services, Chester, Cheshire, England

Summary

Myocardial infarction continues to represent a major cause of death in the Western world, and although there have been significant reductions in its incidence in recent years, some countries such as Scotland and Finland still have high mortality rates. Thrombotic occlusion, in association with varying degrees of plaque disruption and coronary artery spasm, represents the major cause of acute myocardial infarction (AMI). At the cellular level, this results in a shift towards anaerobic metabolism, depletion of energy stores, disrupted membrane integrity, alterations in ionic gradients, myocyte oedema, inhibition of contraction and a proarrhythmic potential. Reperfusion can exacerbate the damage, producing calcium ion accumulation and free radical generation. Infarct expansion and ventricular remodelling can often follow AMI as can additional necrosis, in the form of infarct extension/reinfarction. Rational and optimal treatment of AMI should be based on an understanding of the epidemiological influences and the pathophysiological processes involved. This review considers some of the important features in the pre-, peri- and postinfarction periods.

Necrosis of myocardial tissue secondary to a loss of blood supply (and therefore oxygen) constitutes an acute myocardial infarction (AMI); this occurs primarily in patients with substantial luminal diameter narrowing (equal to or greater than 70%) of 1 or more of the major coronary arteries (Zeller & Bauman 1986), thus emphasising the fact that some form of coronary artery stenosis is generally a prerequisite for AMI. Clinically, the diagnosis is based upon past medical history, presenting symptoms, ECG and enzyme analysis, particularly the MB isoenzyme of creatine kinase (CK). AMI is frequently accompanied by a characteristic crushing chest pain. Interestingly, some patients whose initial ECGs are normal or nonspecific have significantly lower mean peak CK levels and a lower short term mor-

ta1ity (Rouan et al. 1989), confirming the role of the ECG as both a prognostic and diagnostic indicator (Bell et al. 1990; Timmis 1990). AMI is associated with a series of well documented risk factors (Berenson et al. 1990; Stokes 1990). Less well characterised risk factors include decreased selenium levels (Kok et al. 1989a), haemorrheological changes (Toth et al. 1989), pyridoxine status (Kok et al. 1989b), and dental caries (Gilmour & Northridge 1989; Mattila et al. 1989), the roles of which are uncertain. One other pathogenic factor worthy of note is the effect of the sympathetic nervous system, which may be responsible for circadian variations and triggers (such as emotional upset), in AMI (Hammill & Khandheria 1990; Muller et al. 1985; Tofler et al. 1990; Willich et al. 1989).

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This review provides a general introduction to the epidemiology of AMI and examines some of the important considerations in the pre-, peri- and postinfarction periods (fig. 1).

1. Epidemiology The World Health Organization (WHO) continues to emphasise the importance of cardiovascular disease as a major cause of death in the Western world, with 30 to 50% of patients dying within a few hours of the onset of symptoms of AMI (Misinski 1988). There are approximately 11 million deaths per annum in the developed countries, 2.4

million of which are due to ischaemic heart disease (lHO). Interestingly, in Europe there appears to be a decreasing gradient of IHO in a northeast/southwest direction (WHO 1989). Mortality rates from IHO and AMI, however, vary considerably between males and females and also between countries (table I). Studies in the USA have suggested that the declining mortality from coronary heart disease observed in recent years is due, at least in part, to a decline in the incidence of myocardial infarction (MI) [Goldberg et al. 1989; Pell & Fayerweather 1985]. In New Orleans, autopsy studies have shown that the prevalence of raised atherosclerotic lesions Myocardial infarction

Before

After

Medical history _ _ _ _ _ _ _ _ _ _ _ _....._ _ _ _ _ _ _ _ _ _ _ _ _• Atherosclerosis

-------------t--------------.

Coronary vasculature - - - - - - - - - -......- - - - - - - - - - - - -... Coronary artery spasm ThrolJlbosis/occlusion Myocardial oxygen demand - - - - - - - -......- - - - - - - - - - - - -.. Coronary blood flow

- - - - - - - - - - - - - t l - - - - - - - - - - - - -... Cellular changes/irreversible damage Expansion/remodelling Extension/reinfarction Cardiac output Arrhythmias Heart failure/shock

Diagnosis Type/extent

Fig. 1. Schematic representation of some of the important features to be considered in the pre-, peri- and postinfarction periods. Some features need to be considered at all stages.

Pathophysiology and Epidemiology of Myocardial Infarction

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Table I. Mortality rates (per 100000 of the population) reported in various countries for ischaemic heart disease (IHO) and acute myocardial infarction (AMI) [from WHO 1989] AMla

IHoa

Scotland Finland USA Japan

male

female

year

male

female

year

336 317 197 29

103 51 61 9

1984-86 1984-86 1984-86 1984-86

298.7 230.0 118.3 29.7

239.3 184.0 90.7 22.3

1988 1987 1987 1988

a Subjects with IHO were aged between 35 and 64 years; those with AMI were from ali age groups.

in White males was substantially lower in the years 1968 to 1972 than in the years 1960 to 1964 (Strong & Guzman 1980). Risk factor reduction is undoubtedly responsible for changes of this nature. Conversely, Maru (1989) noted a rise in the incidence of coronary heart disease in an indigenous African population.

2. Principal Types of AA-fl 2.1 Regional AMI

This is the most common type of AMI; It IS usually described as anteroseptal, lateral, or posterior and can be further subdivided into transmural and subendocardial. In general, the area of necrosis is directly related to occlusion of the particular artery subtending the region of supply (Davies 1987; Jackson 1988). Electrocardiographic differences between Q-wave and non-Q-wave MI should not be confused with transmural and nontransmural (subendocardial) infarction, as there is little anatomical evidence to substantiate the distinction (Andre-Fouet et al. 1989; Bashour et al. 1988; Freifeld et al. 1983; O'Brien & Ross 1989). 2.2 Nonregional AMI Also known as a diffuse or circumferential infarct, nonregional AMI involves the subendocardial myocardium throughout the left ventricle, the necrosis generally reflecting a global reduction in coronary blood flow. Patients in whom there is an extension of the atherosclerotic process into small arteries, such as in those with diabetes, seem par-

ticularly prone to this type of infarction (Davies 1987; Jackson 1988). 2.3 'Silent' AMI A number of MIs are referred to as 'silent'; these are not immediately or retrospectively recognised by either the patient or the physician (Hammill & Khandheria 1990; Kannel & Abbott 1984). Diagnosis requires unequivocal electrocardiographic evidence of a previous infarction without either the patient or physician being aware that an infarct has occurred (Margolis et al. 1973).

3. Causes of AMI Current concepts regarding the cause(s) of AMI revolve, in general, around the following areas: • plaque rupture or fissure together with thrombotic occlusion; • platelet activation and aggregation (possibly induced by intimal injury); • coronary artery spasm; • chronic severe coronary stenosis; • intermittent coronary artery occlusion; • a combination of some or all of these factors. 3.1 Thrombotic Occlusion In the majority of regional transmural infarcts (in some reports over 90%), the causative agent has been a thrombus overlying a lipid-rich atheromatous plaque that has undergone fissuring or rupturing of the fibrous cap (Davies 1987; Davies &

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Thomas 1981; Horie et al. 1978). This process of fissuring or rupturing involves contact being established between blood and potent platelet activators such as fatty acids and collagen. Smooth muscle hyper-reactivity, however, may also be required in the progression toward an occlusive episode (Maseri et al. 1986). The important consideration is that infarction implies thrombosis, even if only temporarily (Alpert 1989; Carroll et al. 1990; DeWood et al. 1980). The relationship of subendocardial AMI to coronary thrombosis is not as definite as that for regional transmural infarction. Blood flow in the subendocardial regions occurs primarily during diastole as the intramyocardial pressure gradient during systole impedes the flow in this area. Davies (1987) suggests 3 hypotheses: 1. occlusive thrombosis with collateral vasculature protecting the epicardial regions; 2. relief of occlusion before the infarct evolves transmurally; 3. intramyocardial 'steal' related to a high-grade stenosis. In AMI, ischaemia develops initially in the subendocardial regions and moves transmurally to the subepicardial areas (Alpert 1989; Misinski 1988), emphasising subendocardial vulnerability during periods of reduced flow. 3.2 Intimal Injury

Intimal damage, whether mechanical or atherosclerotic in origin, can adversely alter the thrombotic-thrombolytic balance between vasoconstrictor/platelet-activating factors and vasodilator/ antiaggregant factors. The resultant build-up of platelets, leucocytes, monocytes and macrophages can become self-perpetuating, enhance vasoconstriction and lead to AMI (Feldman 1987; Pepine 1989), althought the mechanism by which this happens has not been fully delineated (Maseri et al. 1986). Future studies will no doubt continue to concentrate on thrombogenic factors such as thromboxane A2, leukotrienes, serotonin, histamine, platelet glycoproteins and von Willebrand factor, and thrombolytic factors such as prosta-

cyclin, plasminogen activator and endothelialderived relaxing factor. 3.3 Coronary Artery Spasm Coronary artery occlusion with little thrombotic involvement is also recognised as a cause of AMI. The development of a nonfunctional myocardium due to poor coronary perfusion leads to increased oxygen requirements of surrounding tissue and blood flow 'steal'. The vicious cycle continues and infarction ensues (Guyton 1976). The thromboischaemic re-entry mechanism (TRM) theory (Gasser & Dienst! 1986; Gasser et al. 1986) suggests that necrosis results from repeating cycles of coronary spasm followed by compensatory dilatation, with platelets responsible for the alternating activity. This confirms that platelet activation is a major pathogenic factor in coronary spasm (Ogasawara et al. 1985). Moreover, the results of Hackett et al. (1987) demonstrate that coronary occlusion in the early phase of MI is frequently intermittent; although these authors did not suggest a causative factor, Bashour et al. (1988) state that spasm with or without platelet aggregation can lead to MI. Overall, the precise role of coronary artery spasm in AMI remains unknown (Conti & Mehta 1987).

4. Cellular Alterations Cardiac muscle normally metabolises fatty acids to produce adenosine triphosphate (ATP) molecules for energy. During ischaemic conditions, however, metabolism shifts mainly to anaerobic glycolysis, utilising blood glucose, but producing lactic acid. The cellular alterations taking place in the initial stages are reversible ifreperfusion occurs quickly (Carroll et al. 1990; Lamer & Conway 1989), but continued ischaemia results in progression to irreversible cell damage and necrosis. The exact mechanisms of cell dysfunction are not fully understood and involve a complex cascade of events.

Pathophysiology and Epidemiology of Myocardial Infarction

4.1 Early Events In the early stages, ATP is degraded, via adenosine diphosphate (ADP) and adenosine monophosphate (AMP), to adenosine, which rapidly diffuses through the cell membranes. In fact, ischaemic injury appears reversible with ATP levels above 70% of control levels (Alpert 1989). The rate of resynthesis of adenosine, a requirement for normal cell function, is approximately 2% per hour. Prolonged ischaemia, therefore, produces cell death (Guyton 1976). Moreover, neutrophil-endothelial cell interaction may produce endothelial cell damage and disrupt membrane integrity, leaving the cell vulnerable to further damage from free radicals (Forman et al. 1989). 4.2 Subsequent Events Alterations in ion gradients, presumably related to a disrupted membrane structure, precipitate a redistribution of calcium ions. This, via a breakdown of adenosine to hypoxanthine, can catalyse a series of reactions leading to the production of superoxide free radicals (Lamer & Conway 1989; McCord 1985), which produce tissue damage (Granger et al. 1981). Calcium ion displacement from the contractile proteins and sarcoplasmic reticulum, linked with effluxes of magnesium, sodium and potassium ions, produces conditions of altered cell distensibility, oedema, inhibition of contraction and proarrhythmic potential (Dubey & Solomon 1989; Pepine 1989; Reimer & Jennings 1985). In fact, increases of up to 78% in the mean cell volume of myocytes have been recorded after large infarctions in experimental models (Anversa et al. 1985). Reperfusion of ischaemic tissue can, on its own, produce deleterious effects. Large accumulations of calcium have been detected, particularly in the mitochondria (Reimer & Jennings 1985; Shen & Jennings 1972), which may be related to myocardial 'stunning' (Bolli et al. 1989). The time at which reversible cell damage becomes irreversible is around 15 to 20 minutes after the onset of ischaemia; after this a 'wave' of ne-

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crosis spreads from the subendocardial regions (Alpert 1989; Reimer et al. 1977; Willerson & Buja 1988). Over a longer period, there is reactive hypertrophy, proliferation of fibroblasts and collagen deposition, producing scar tissue and a revised cardiac structure (Alpert 1989; Anversa & Sonnenblick 1990; Pfeffer & Braunwald 1990).

5. Postinfarction Events After AMI, the following series of events, which can involve noninfarcted areas and adversely affect mortality, may take place: infarct expansion, ventricular remodelling, infarct extension and reinfarction. 5.1 Infarct Expansion/Ventricular Remodelling Infarct expansion and ventricular remodelling are frequently used synonymously. Hutchins and Bulkley (1978) defined infarct expansion as 'acute dilatation and thinning of the area of infarction not explained by additional myocardial necrosis'. Moreover, it does not occur uniformly after all infarcts but is seen most frequently in large transmural infarcts. The process of expansion takes place in the first few hours after an AMI, before extensive fibroblast and collagen deposition have produced scar tissue (Hochman & Bulkley 1982; Kass et al. 1988; White 1989), and results in complex alterations in ventricular architecture involving both infarcted and noninfarcted regions (Pfeffer & Braunwald 1990; Weisman & Healy 1987). 5.2 Infarct Extension/Reinfarction Infarct extension and reinfarction are similar processes in the postinfarction period, and represent additional myocardial necrosis (Pepine 1989; Weisman & Healy 1987). With extension, new foci of necrosis are found on the borders of the original, older infarct and histological findings have revealed contraction-band necrosis (Forman et al. 1983; Hutchins & Bulkley 1978). With reinfarction, the most important factor de-

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termining the outcome is haemodynamically significant coronary artery disease (Weisman & Healy 1987).

6. Conclusion AMI will undoubtedly remain a major killer in the Western world for the rest of the decade, although primary prevention strategies aimed at cardiovascular disease in general and AMI in particular should reduce its incidence. Throughout the world, however, large numbers of people will ignore medical advice, make lifestyle changes too late or have a predisposing history, making it necessary for optimum diagnostic and treatment methods for AMI to be constantly available. Therefore, an understanding of the epidemiology and pathophysiology of AMI is necessary to provide a basis for rational therapeutic approaches, both in the short and longer term.

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Pathophysiology and Epidemiology of Myocardial Infarction

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Correspondence and reprints: J. Gill. Adis International Limited, The Old Palace, Little St John Street, Chester, Cheshire CHI IRE, England.