Cardiology 64 : 289 302 (1979)
Sudden Coronary Death and Coronary Artery Disease A Clinicopathologic Appraisal V. Rissanen Department of Medicine, University of Kuopio, Kuopio
Key Words. Sudden cardiac death • Postmortem studies • Epidemiology • Atherogenic factors • Triggering factors • Sensitizing factors ■Protecting factors Abstract. Clinicopathologic and epidemiological aspects of coronary artery disease (CAD) in relation to sudden death (SD) were studied in three postmortem series, two of sudden cardiac death and one of male violent death. There appears to be a critical level of severity of CAD which determines the risk of SD. The more severe the CAD within this range, the higher is the risk. Every annual cohort of SDs includes many patients with extremely severe, or ‘burned-out’, disease. CAD alone, however, is not a selective factor for sudden or not-sudden death. Epidemiological analysis (a) determines the age and frequency of persons reaching the critical risk level of CAD severity in the population (atherogenic factors); (b) influences the selection of the SD victims from the critical population (pre cipitating factors), and (c) determines the individual variation of CAD severity with which coronary heart disease and SD manifest themselves (sensitising and protecting factors).
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Coronary heart disease (CHD) is undoubtedly the main cause of sudden death (SD) in the population. Correlation between the extent of coronary artery stenosis and the risk of death has been demonstrated in clinical prospective studies in which coronary stenosis has been estimated by coronary angiography (3, 22). In post-mortem studies, extensive obstructive disease has also been revealed in the coronary arteries of patients who died suddenly (1, 14, 17). Clinical prospective studies based on coronary angiography have mainly involved those with symptomatic disease. Understanding of the role of coronary artery disease (CAD) as a cause of SD in the population is still imperfect. Similarly, it is not clear whether the risk factors for CHD are associated with increased risk of death due to premature, accelerated development of atherosclerosis or because
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of a different myocardial response to coronary stenosis. Little is known of factors related to individual tolerance of varying degrees of coronary stenosis. In the present study the above problems were investigated in three post mortem series; two series of sudden cardiac deaths and one of male violent deaths.
Materials and Methods
Violent Deaths. The series consisted of 214 men, aged 20 years or more, who met violent deaths by accident, suicide or homicide. The autopsies were performed at the Department of Forensic Medicine, University of Helsinki. The characteristics of the series have been described in detail in a previous report (11). Sudden Deaths I. The series comprised 140 men, aged 30-77 years, who Sied suddenly within 24 h of the onset of the fatal attack. The series was collected as an unselected sample of victims classified as coronary deaths at routine medico-legal autopsies performed during a period of 10 months at the Department of Forensic Medicine, University of Helsinki. The detailed characteristics of the series have been described previously (14).
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Sudden Deaths ll. This series was collected, 2 years after the first, during a period of 12 months as a part of a community study performed by the Ischemic Heart Disease Register of Helsinki. Altogether, 365 deaths from CHD outside hospital, were registered in Helsinki during the study period. A medico-legal autopsy using a special examination technique of the heart was performed in 213 cases. The study consisted of 151 in whom the fatal attack was witnessed and well documented, and in whom death occurred within 24 h of the onset of the attack (17). There were 114 men aged 31-83 years, and 37 women aged 44-90 years. The series of violent deaths and SD 1 were collected for the quantitative study of coronary atherosclerosis. The specimens of the opened and flattened coronary arteries were prepared according to the principles developed and used in extensive international studies on atherosclerosis (7, 21). The specifications set down by these studies were followed in the definition of atherosclerotic lesions (raised lesion). The absolute areas of raised lesions were assessed in arterial specimens using the point-counting technique (11). The presence of 50% stenosis and an occlusion was visually estimated in arterial specimens. The information concerning smoking habits was obtained from the next of kin in 84 cases of violent death and 94 SDs with the aid of questionnaires (12). In the series of SD II the data collection concerning the suddenness of the death, previous diseases and circumstances preceding the death was performed by the organization of the Ischemic Heart Disease Register of Helsinki (19). The methodological principles outlined by the WHO (20) were applied in the post-mortem examination of the hearts. The degree of coronary stenosis was estimated by double contrast coronary angiography (10). In the detection of recent myocardial infarctions, macroscopic histochemistry and conven tional histology were used. Infiltration of polymorphonuclear leucocytes within the area of
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the changed myofibres was used as a histological criterion of definite acute myocardial infarction (AMI), while a myocardial lesion without leucocyte infiltration was defined as an early AMI (17). Reliable data concerning stress producing events or feelings of stress expressed by the victim before death was obtained in 118 cases in the series of SD 11 (16).
Results
Coronary Atherosclerosis in the Population and in Sudden Deaths As determined in the series of violent deaths, the first raised lesions in the coronary arteries of Finnish men appear around the age of 20. The mean extent of the coronary raised lesions in a population sample increased fairly rectilinearly in men between 30 and 50 years of age (fig. 1). As age advanced further the curve tended to form a plateau, though individual variation was very conspicious. There also seems to be an interesting plateau in the upper border of the range (about 12 cm2, fig. 1), above which there are only a few random cases.
Fig. 1. The extent of coronary raised lesions (cm1) in male violent deaths. The line connects the mean values of 10-year age groups.
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Age. years
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Age, years
Fig. 2. The extent of coronary raised lesions (cm2) in male sudden deaths (series 1). The lines indicate the mean values of 10-year age groups in sudden deaths (•------ • ) and in violent deaths (o------ o).
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The mean extent of the coronary raised lesions was significantly higher in the age groups of SDs (series I) than in the corresponding age groups of violent deaths (fig. 2). The mean areas of raised lesions in SDs tended to be the same irrespective of age. Individual variation in the extent of CAD in cases of SD was great. Marked overlapping between the SDs and violent deaths was characteristic. About half the violent deaths at the age of 50 or more overlapped with the SDs. In 9% of the violent deaths the extent of CAD exceeded the mean values of the SDs. On the other hand, in more than half of the SDs the extent of CAD fell within the range of the violent deaths. In 10% of the SDs the area of raised lesions was below the mean values of the violent deaths. In one third of the SDs the extent of CAD exceeded the upper border of the range (about 12 cm2,
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Age. years
Fig. 3. The mean extent of coronary raised lesions (cm2) in cigarette smokers (------ ) and non-smokers (------ ) in the series of violent deaths (10).
fig. 1) of the violent deaths. Triple vessel disease, i.e. at least 50% stenosis in three coronary arteries, was found in 67% of them, while the prevalence of the corresponding stenosis pattern was only 38% in SDs in whom the extent of CAD overlapped with that in the series of violent deaths (p 50%. 1 Heart weight >500 g in men, >450 g in women.
Discussion
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The basic process of CAD seems to develop in Finnish men fairly rectilinearly between 30 and 50 years of age. This phase of CAD development determines the age and frequency of persons reaching the critical risk level of CAD severity in the population. The plateau in advanced ages in the mean curve of the population sample is obviously caused by selection; individuals prone to develop the severe lesions are eliminated from the population. In this respect the plateau in the upper border of the range of raised lesion in violent deaths is interesting. It suggests the existence of a critical ‘level of vitality’ in the extent of coronary atherosclerosis. Persons whose developing atherosclerosis exceeds this level (about 12 cm2, fig. 1) tend to disappear from the population. SD is a major cause of this disappearance. It is obvious that every annual cohort o f SDs includes many patients with extremely severe CHD (‘burned-out’ disease). A quarter of the SD victims (series I) had severe triple vessel disease in their
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coronaries, i.e. an occlusion or multiple 50% stenoses in all three vessels. According to the clinical experience (9), these patients would have been suitable candidates for bypass surgery. The high mean extent of raised lesions in SDs, irrespective of age, and sex (14), or the presence or absence of a major risk factor, cigarette smoking (fig. 4), suggests that there is a critical threshold level o f severity of CAD which determines the risk of SD. This level has a fairly wide range with an overlap between the diseased and the asymptomatic population. The marked overlap in the extent of raised lesions between SDs and violent deaths suggests that there are many people in the Finnish population, perhaps even half of the men aged 50 or over, who are potential candidates for different manifestations of CHD, including SD. The occurrence of coronary stenosis in violent deaths supports this concept. Half of the men aged 55 or over and half of the women aged 65 or more had a stenosis of at least 50% in their coronaries (14). On the other hand, studies on SD have shown that SD seldom occurs truly unexpectedly. In the present series of SD II 78% had a history of CHD symptoms or previous myocardial infarction, 91% had either a history of CHD or premonitory symptoms preceding death, and 87% had either a history of CHD or of hyper tension, diabetes or claudication (16,17). There are, obviously, sensitising and protecting factors which determine the individual variation of CAD severity with which CHD and SD manifest them selves — and vice versa; the individual variation of CAD severity that is favourably tolerated. Although the mean severity of CAD is, in general, equal in male and female SDs (14), women were overrepresented in the group of SD with single vessel disease compared with the other two groups. It has been stated on the basis of clinical studies (8) that clinical symptoms and signs of CHD manifest themselves with less advanced stenosis in the coronary arteries of women than in men. Angina pectoris and myocardial ischemia or infarction with normal coro nary arteriogams have been equally often reported in both sexes (2). The lowest range of CAD severity in SDs thus seems to represent a special group of patients, in whom the factors contributing to SD may be different from those at work in the groups with more severe CAD. Correlation between clinical CHD and major risk factors, e.g. cigarette smoking, is well documented. The result from the group of violent deaths suggests that accelerated development of coronary atherosclerosis tends to be associated with cigarette smoking. This means that CAD at younger ages reaches the risk level of severity more frequently in cigarette smokers than in nonsmokers. Consequences of this hypothesis can be seen in cross-sectional popula
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tion studies, e.g. in the study of the Ischemic Heart Disease Register of Helsinki. In this there was a total of 1,608 registered acute attacks of CHD during a period of 16 months. Below the age of 45, over 80% of the patients were current cigarette smokers, while in the age group 6 0 -6 5 the corresponding prevalence was 42% (13). The high mortality rate of smokers, cessation of smoking by diseased persons and an increasing number of non-smokers reaching the critical level of CAD severity explain the decreasing difference in the prevalence of acute CHD between cigarette smokers and non-smokers in the older age groups. Among those who died suddenly, cigarette smokers and non-smokers did not differ with regard to the severity of CAD. The threshold level of CAD severity is thus a major factor for SD risk in both smokers and non-smokers. This kind of postmortem study cannot supply an answer to the question of whether cigarette smoking causes an increased frequency of SD among those who have already reached the risk level of CAD. Follow-up studies of AMI patients suggest that in addition to the accelerated development of atherosclerosis this is another ex planation for the high frequency of SDs associated with cigarette smoking (23). Smoking seems to exert its harmful effect leading to SD via ischemia rather than through arrhythmia, but it may, however, favour the development of ar rhythmias at the early stage of ischemic myocardial injury (17). In addition to the factors which increase the risk of SD by enhancing the development of atherosclerosis, there are precipitating factors which trigger the acute events leading to SD. For example, stress factors may precipitate acute attacks by increasing the oxygen demand of the myocardium (4). One may ask whether stress factors can cause SD even without severe CAD. The present results show that even though the onset of an acute attack might be precipitated by stress factors, SD only seems to occur if the involvement of the coronary arteries has reached the risk level of severity. This, again, supports the signifi cance of the critical severity of CAD as a basic condition determining the risk of SD. CAD alone, however, is not a selective factor for sudden or non-sudden death among the critical population. In fact, patients with triple vessel disease seem to be overrepresented among both SDs outside hospitals and non-sudden AMI deaths in hospital (18) as compared with the survivors of AMI studied by clinical coronary arteriography (table II, IV). There is evidence suggesting that severe stenosis in the right coronary artery is a major finding in SDs, while in AMI deaths in hospital (15), a major Finding tends to be severe occlusion of the left anterior descending coronary artery. Left main stem disease, which is a generally accepted indication for surgery (9), seems, surprisingly, to occur with
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similar frequency (5%) in SDs (17) and clinical series of surviving AMI patients (5%) or those with angina (8%) (6). On the other hand, this stenosis pattern was clearly overrepresented in AMI deaths in hospital (20%) (18). Although the severity of CAD did not correlate with symptoms of the attack some selection during the acute attack seems to occur in relation to the acute ischemic event. When death occurred at the stage of definite infarction, CAD tended to be severe. In patients with less severe coronary stenosis patterns, the fatal arrhythmia was obviously released during the earlier stages of ischemic injury, the postmortem consequence being an early or no detectable recent lesion in the myocardium. It is possible that myocardial adaptation to chronic coronary obstruction influenced the course of the ischemic attack, the patients with severe coronary lesions being those who had longest avoided fatal arrhyth mias by the development of collaterals. Patients with triple vessel disease and an old myocardial infarction were clearly overrepresented in the series of SD. On the other hand, in patients without an old myocardial infarction the frequencies of triple, double and single vessel disease were very similar to those reported in the clinical series of coronary arteriography involving patients with angina pectoris and survivors of AMI (table IV). Furthermore, in the SD patients (series I), in whom the extent of CAD overlapped with that in the population sample (violent deaths), the prevalence of triple vessel disease was comparable with those reported in clinical arteriographic series, but the frequency was clearly higher in SDs if the extent of CAD exceeded the critical ‘level of vitality’ above which there were only random cases in the population sample. The latter SD patients were thus clearly excep tional in relation to the population while the former better represented a sample of the living patients. The difference in the severity of CAD between patients with and without an old myocardial infarction is interesting. Despite the more numerous occlusions, in even two or three coronaries, a more extensive coronary artery involvement by atherosclerosis also seems to be characteristic of patients with an old myocardial infarction compared with SDs with no old infarction (14). An important question remains; did a previous attack of infarction enhance the development of CAD in these patients? An infarction, even if the patient survives, causes deterioration both by myocardial damage and the thrombotic obstruction of the artery supplying the infarcted area (5, 6). Clinical arterio graphic studies have shown that AMI is almost invariably followed by progres sion of CAD (3). SD is in most cases a consequence of ventricular fibrillation released during the earliest stages of developing myocardial injury. The ischemic
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process would thus lead to a clinical AMI with its deteriorating effect even though the early arrhythmia could be prevented or cured. Hence, the aim should be to prevent the onset of acute ischemic events which lead to myocardial injury and acute infarction among people who have CAD of critical severity.
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6
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8 9 10 11 12
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Baroldi, G.; Radice, F.; Schmid, G., and Leone. A.: Morphology of acute myocardial infarction in relation to coronary thrombosis. Am. Heart J. 87: 65-75 (1974). Bemiller, C.R.; Pepine, C.J., and Rogers, A.K.: Long-term observations in patients with angina and normal coronary arteriograms. Circulation 47: 36-41 (1973). Bemis, C.E.; Gorlin, R.; Kemp, H.G., and Herman, M.W.: Progression of coronary artery disease. A clinical artériographie study. Circulation 47: 455-464 (1973). Cannom, D.A.; Harrison, D.C., and Schroeder, J.S.: Haemodynamic observations in patients with unstable angina pectoris. Am. J. Cardiol. 33: 17-21 (1974). Davies, M.J.; Woolf, N., and Robertson, W.B.: Pathology of acute myocardial infarc tion with particular reference to occlusive coronary thrombi. Br. Heart J. 38: 659-664 (1976). Fuster, V.; Frye, R.L.; Conolly, D.C.; Danielson, M.A.; Elvebach, L.R., and Kurland, L.T.: Artériographie patterns early in the onset of the coronary syndromes. Br. Heart J. 37: 1250-1255 (1975). Guzman, M.A.; McMahan, C.A.; McGill, H.C., jr.; Strong, J.P.; Tejada, C.; Rcstrepo, C ; Eggen, D.A.; Robertson, W.B., and Solberg, L.A.: Selected méthodologie aspects of the International Atherosclerosis Project. Lab. Invest. 18: 479-497 (1968). Hekali, P.: Coronary angiography and clinical symptomatology. Acta radiol., suppl., 254 (1976). Julian, D.G.: Aorta-to-coronary bypass surgery for angina; in Oliver, Modern trends in cardiology, vol. 3, pp. 439-464 (Butterworths, London 1975). Rissanen, V.T.; Double contrast technique for postmortem coronary angiography. Lab. Invest. 23: 517-520(1970). Rissanen, V.: Aortic and coronary atherosclerosis in a Finnish autopsy series of violent deaths. Suomal. Ticdcakat. Toim. 155 (1972). Rissanen, V.; Pyôrâlà, K., and Heinonen, O.P.: Cigarette smoking in relation to coronary and aortic atherosclerosis. Acta path, microbiol. scand. sect. A. 80: 491-500 (1972). Rissanen, V.: Smoke of cigarette and arteriosclerosis. 9th Int. Congr. Angiology, Florence 1974. Minerva cardioangiol. 22: 274 (1974). Rissanen, V.: Coronary atherosclerosis in cases of coronary death as compared with that occurring in the population. A study of a medico-legal autopsy series of coronary deaths and violent deaths. Ann. clin. Res. 7: 412-425 (1975). Rissanen, V.; Romo, M.; Sarna, S., and Siltanen, P.: Deaths from ischemic heart disease in persons aged 65 or younger in Helsinki in 1970. With special reference to pathoanatomic findings in hearts. Acta med. scand. 197: 51-60 (1975).
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References
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16
Rissanen, V.; Romo, M., and Siltanen, P.: Premonitory symptoms and stress factors preceding sudden death from ischemic heart disease. Acta med. scand. 204: 389 -396 (1978). 17 Rissanen, V.; Romo, M., and Siltanen, P.: Prehospital sudden death from ischemic heart disease. A postmortem study. Br. Heart J. 40: 1025-1033 (1978). 18 Rissanen, V.; Raunio, H., and Romppanen, T.: Autopsy findings in patients dying of acute myocardial infarction. (In preparation.) 19 Romo, M.: Factors related to sudden death in acute ischemic heart disease. A community study in Helsinki. Acta med. scand., suppl. 547 (1973). 20 World Health Organization: The pathological diagnosis of acute myocardial infarction. Preliminary results of a WHO cooperative study. Bull. Wld Hlth Org. 48: 23-25 (1973). 21 Uemura, K.; Sternby, N.; Vanecek, R.; Vihert, A., and Kagan, A.: Grading athero sclerosis in aorta and coronary arteries obtained at autopsy. Application of a tested method. Bull. Wld Hlth Org. 31: 297-312 (1964). 22 Webster, J.S.; Mobcrg, C., and Rincon, G.: Natural history of severe proximal coronary artery disease as documented by coronary cineangiography. Am. J. Cardiol. 33: 195-201 (1974). 23 Wilhelmsson, C.; Vedin, J.A.; Elmfeldt, D.; Tibblin, G., and Wilhelmssen, L.: Smoking and myocardial infarction. Lancet i: 415-422 (1975).
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V. Rissanen, Department of Medicine, University of Kuopio, Kuopio (Finland)
Sudden Coronary Death and Coronary Artery Disease A Clinicopathologic Appraisal V. Rissanen Department of Medicine, University of Kuopio, Kuopio
Key Words. Sudden cardiac death • Postmortem studies • Epidemiology • Atherogenic factors • Triggering factors • Sensitizing factors ■Protecting factors Abstract. Clinicopathologic and epidemiological aspects of coronary artery disease (CAD) in relation to sudden death (SD) were studied in three postmortem series, two of sudden cardiac death and one of male violent death. There appears to be a critical level of severity of CAD which determines the risk of SD. The more severe the CAD within this range, the higher is the risk. Every annual cohort of SDs includes many patients with extremely severe, or ‘burned-out’, disease. CAD alone, however, is not a selective factor for sudden or not-sudden death. Epidemiological analysis (a) determines the age and frequency of persons reaching the critical risk level of CAD severity in the population (atherogenic factors); (b) influences the selection of the SD victims from the critical population (pre cipitating factors), and (c) determines the individual variation of CAD severity with which coronary heart disease and SD manifest themselves (sensitising and protecting factors).
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Coronary heart disease (CHD) is undoubtedly the main cause of sudden death (SD) in the population. Correlation between the extent of coronary artery stenosis and the risk of death has been demonstrated in clinical prospective studies in which coronary stenosis has been estimated by coronary angiography (3, 22). In post-mortem studies, extensive obstructive disease has also been revealed in the coronary arteries of patients who died suddenly (1, 14, 17). Clinical prospective studies based on coronary angiography have mainly involved those with symptomatic disease. Understanding of the role of coronary artery disease (CAD) as a cause of SD in the population is still imperfect. Similarly, it is not clear whether the risk factors for CHD are associated with increased risk of death due to premature, accelerated development of atherosclerosis or because
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of a different myocardial response to coronary stenosis. Little is known of factors related to individual tolerance of varying degrees of coronary stenosis. In the present study the above problems were investigated in three post mortem series; two series of sudden cardiac deaths and one of male violent deaths.
Materials and Methods
Violent Deaths. The series consisted of 214 men, aged 20 years or more, who met violent deaths by accident, suicide or homicide. The autopsies were performed at the Department of Forensic Medicine, University of Helsinki. The characteristics of the series have been described in detail in a previous report (11). Sudden Deaths I. The series comprised 140 men, aged 30-77 years, who Sied suddenly within 24 h of the onset of the fatal attack. The series was collected as an unselected sample of victims classified as coronary deaths at routine medico-legal autopsies performed during a period of 10 months at the Department of Forensic Medicine, University of Helsinki. The detailed characteristics of the series have been described previously (14).
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Sudden Deaths ll. This series was collected, 2 years after the first, during a period of 12 months as a part of a community study performed by the Ischemic Heart Disease Register of Helsinki. Altogether, 365 deaths from CHD outside hospital, were registered in Helsinki during the study period. A medico-legal autopsy using a special examination technique of the heart was performed in 213 cases. The study consisted of 151 in whom the fatal attack was witnessed and well documented, and in whom death occurred within 24 h of the onset of the attack (17). There were 114 men aged 31-83 years, and 37 women aged 44-90 years. The series of violent deaths and SD 1 were collected for the quantitative study of coronary atherosclerosis. The specimens of the opened and flattened coronary arteries were prepared according to the principles developed and used in extensive international studies on atherosclerosis (7, 21). The specifications set down by these studies were followed in the definition of atherosclerotic lesions (raised lesion). The absolute areas of raised lesions were assessed in arterial specimens using the point-counting technique (11). The presence of 50% stenosis and an occlusion was visually estimated in arterial specimens. The information concerning smoking habits was obtained from the next of kin in 84 cases of violent death and 94 SDs with the aid of questionnaires (12). In the series of SD II the data collection concerning the suddenness of the death, previous diseases and circumstances preceding the death was performed by the organization of the Ischemic Heart Disease Register of Helsinki (19). The methodological principles outlined by the WHO (20) were applied in the post-mortem examination of the hearts. The degree of coronary stenosis was estimated by double contrast coronary angiography (10). In the detection of recent myocardial infarctions, macroscopic histochemistry and conven tional histology were used. Infiltration of polymorphonuclear leucocytes within the area of
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the changed myofibres was used as a histological criterion of definite acute myocardial infarction (AMI), while a myocardial lesion without leucocyte infiltration was defined as an early AMI (17). Reliable data concerning stress producing events or feelings of stress expressed by the victim before death was obtained in 118 cases in the series of SD 11 (16).
Results
Coronary Atherosclerosis in the Population and in Sudden Deaths As determined in the series of violent deaths, the first raised lesions in the coronary arteries of Finnish men appear around the age of 20. The mean extent of the coronary raised lesions in a population sample increased fairly rectilinearly in men between 30 and 50 years of age (fig. 1). As age advanced further the curve tended to form a plateau, though individual variation was very conspicious. There also seems to be an interesting plateau in the upper border of the range (about 12 cm2, fig. 1), above which there are only a few random cases.
Fig. 1. The extent of coronary raised lesions (cm1) in male violent deaths. The line connects the mean values of 10-year age groups.
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Age. years
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Age, years
Fig. 2. The extent of coronary raised lesions (cm2) in male sudden deaths (series 1). The lines indicate the mean values of 10-year age groups in sudden deaths (•------ • ) and in violent deaths (o------ o).
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The mean extent of the coronary raised lesions was significantly higher in the age groups of SDs (series I) than in the corresponding age groups of violent deaths (fig. 2). The mean areas of raised lesions in SDs tended to be the same irrespective of age. Individual variation in the extent of CAD in cases of SD was great. Marked overlapping between the SDs and violent deaths was characteristic. About half the violent deaths at the age of 50 or more overlapped with the SDs. In 9% of the violent deaths the extent of CAD exceeded the mean values of the SDs. On the other hand, in more than half of the SDs the extent of CAD fell within the range of the violent deaths. In 10% of the SDs the area of raised lesions was below the mean values of the violent deaths. In one third of the SDs the extent of CAD exceeded the upper border of the range (about 12 cm2,
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Age. years
Fig. 3. The mean extent of coronary raised lesions (cm2) in cigarette smokers (------ ) and non-smokers (------ ) in the series of violent deaths (10).
fig. 1) of the violent deaths. Triple vessel disease, i.e. at least 50% stenosis in three coronary arteries, was found in 67% of them, while the prevalence of the corresponding stenosis pattern was only 38% in SDs in whom the extent of CAD overlapped with that in the series of violent deaths (p 50%. 1 Heart weight >500 g in men, >450 g in women.
Discussion
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The basic process of CAD seems to develop in Finnish men fairly rectilinearly between 30 and 50 years of age. This phase of CAD development determines the age and frequency of persons reaching the critical risk level of CAD severity in the population. The plateau in advanced ages in the mean curve of the population sample is obviously caused by selection; individuals prone to develop the severe lesions are eliminated from the population. In this respect the plateau in the upper border of the range of raised lesion in violent deaths is interesting. It suggests the existence of a critical ‘level of vitality’ in the extent of coronary atherosclerosis. Persons whose developing atherosclerosis exceeds this level (about 12 cm2, fig. 1) tend to disappear from the population. SD is a major cause of this disappearance. It is obvious that every annual cohort o f SDs includes many patients with extremely severe CHD (‘burned-out’ disease). A quarter of the SD victims (series I) had severe triple vessel disease in their
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coronaries, i.e. an occlusion or multiple 50% stenoses in all three vessels. According to the clinical experience (9), these patients would have been suitable candidates for bypass surgery. The high mean extent of raised lesions in SDs, irrespective of age, and sex (14), or the presence or absence of a major risk factor, cigarette smoking (fig. 4), suggests that there is a critical threshold level o f severity of CAD which determines the risk of SD. This level has a fairly wide range with an overlap between the diseased and the asymptomatic population. The marked overlap in the extent of raised lesions between SDs and violent deaths suggests that there are many people in the Finnish population, perhaps even half of the men aged 50 or over, who are potential candidates for different manifestations of CHD, including SD. The occurrence of coronary stenosis in violent deaths supports this concept. Half of the men aged 55 or over and half of the women aged 65 or more had a stenosis of at least 50% in their coronaries (14). On the other hand, studies on SD have shown that SD seldom occurs truly unexpectedly. In the present series of SD II 78% had a history of CHD symptoms or previous myocardial infarction, 91% had either a history of CHD or premonitory symptoms preceding death, and 87% had either a history of CHD or of hyper tension, diabetes or claudication (16,17). There are, obviously, sensitising and protecting factors which determine the individual variation of CAD severity with which CHD and SD manifest them selves — and vice versa; the individual variation of CAD severity that is favourably tolerated. Although the mean severity of CAD is, in general, equal in male and female SDs (14), women were overrepresented in the group of SD with single vessel disease compared with the other two groups. It has been stated on the basis of clinical studies (8) that clinical symptoms and signs of CHD manifest themselves with less advanced stenosis in the coronary arteries of women than in men. Angina pectoris and myocardial ischemia or infarction with normal coro nary arteriogams have been equally often reported in both sexes (2). The lowest range of CAD severity in SDs thus seems to represent a special group of patients, in whom the factors contributing to SD may be different from those at work in the groups with more severe CAD. Correlation between clinical CHD and major risk factors, e.g. cigarette smoking, is well documented. The result from the group of violent deaths suggests that accelerated development of coronary atherosclerosis tends to be associated with cigarette smoking. This means that CAD at younger ages reaches the risk level of severity more frequently in cigarette smokers than in nonsmokers. Consequences of this hypothesis can be seen in cross-sectional popula
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tion studies, e.g. in the study of the Ischemic Heart Disease Register of Helsinki. In this there was a total of 1,608 registered acute attacks of CHD during a period of 16 months. Below the age of 45, over 80% of the patients were current cigarette smokers, while in the age group 6 0 -6 5 the corresponding prevalence was 42% (13). The high mortality rate of smokers, cessation of smoking by diseased persons and an increasing number of non-smokers reaching the critical level of CAD severity explain the decreasing difference in the prevalence of acute CHD between cigarette smokers and non-smokers in the older age groups. Among those who died suddenly, cigarette smokers and non-smokers did not differ with regard to the severity of CAD. The threshold level of CAD severity is thus a major factor for SD risk in both smokers and non-smokers. This kind of postmortem study cannot supply an answer to the question of whether cigarette smoking causes an increased frequency of SD among those who have already reached the risk level of CAD. Follow-up studies of AMI patients suggest that in addition to the accelerated development of atherosclerosis this is another ex planation for the high frequency of SDs associated with cigarette smoking (23). Smoking seems to exert its harmful effect leading to SD via ischemia rather than through arrhythmia, but it may, however, favour the development of ar rhythmias at the early stage of ischemic myocardial injury (17). In addition to the factors which increase the risk of SD by enhancing the development of atherosclerosis, there are precipitating factors which trigger the acute events leading to SD. For example, stress factors may precipitate acute attacks by increasing the oxygen demand of the myocardium (4). One may ask whether stress factors can cause SD even without severe CAD. The present results show that even though the onset of an acute attack might be precipitated by stress factors, SD only seems to occur if the involvement of the coronary arteries has reached the risk level of severity. This, again, supports the signifi cance of the critical severity of CAD as a basic condition determining the risk of SD. CAD alone, however, is not a selective factor for sudden or non-sudden death among the critical population. In fact, patients with triple vessel disease seem to be overrepresented among both SDs outside hospitals and non-sudden AMI deaths in hospital (18) as compared with the survivors of AMI studied by clinical coronary arteriography (table II, IV). There is evidence suggesting that severe stenosis in the right coronary artery is a major finding in SDs, while in AMI deaths in hospital (15), a major Finding tends to be severe occlusion of the left anterior descending coronary artery. Left main stem disease, which is a generally accepted indication for surgery (9), seems, surprisingly, to occur with
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similar frequency (5%) in SDs (17) and clinical series of surviving AMI patients (5%) or those with angina (8%) (6). On the other hand, this stenosis pattern was clearly overrepresented in AMI deaths in hospital (20%) (18). Although the severity of CAD did not correlate with symptoms of the attack some selection during the acute attack seems to occur in relation to the acute ischemic event. When death occurred at the stage of definite infarction, CAD tended to be severe. In patients with less severe coronary stenosis patterns, the fatal arrhythmia was obviously released during the earlier stages of ischemic injury, the postmortem consequence being an early or no detectable recent lesion in the myocardium. It is possible that myocardial adaptation to chronic coronary obstruction influenced the course of the ischemic attack, the patients with severe coronary lesions being those who had longest avoided fatal arrhyth mias by the development of collaterals. Patients with triple vessel disease and an old myocardial infarction were clearly overrepresented in the series of SD. On the other hand, in patients without an old myocardial infarction the frequencies of triple, double and single vessel disease were very similar to those reported in the clinical series of coronary arteriography involving patients with angina pectoris and survivors of AMI (table IV). Furthermore, in the SD patients (series I), in whom the extent of CAD overlapped with that in the population sample (violent deaths), the prevalence of triple vessel disease was comparable with those reported in clinical arteriographic series, but the frequency was clearly higher in SDs if the extent of CAD exceeded the critical ‘level of vitality’ above which there were only random cases in the population sample. The latter SD patients were thus clearly excep tional in relation to the population while the former better represented a sample of the living patients. The difference in the severity of CAD between patients with and without an old myocardial infarction is interesting. Despite the more numerous occlusions, in even two or three coronaries, a more extensive coronary artery involvement by atherosclerosis also seems to be characteristic of patients with an old myocardial infarction compared with SDs with no old infarction (14). An important question remains; did a previous attack of infarction enhance the development of CAD in these patients? An infarction, even if the patient survives, causes deterioration both by myocardial damage and the thrombotic obstruction of the artery supplying the infarcted area (5, 6). Clinical arterio graphic studies have shown that AMI is almost invariably followed by progres sion of CAD (3). SD is in most cases a consequence of ventricular fibrillation released during the earliest stages of developing myocardial injury. The ischemic
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process would thus lead to a clinical AMI with its deteriorating effect even though the early arrhythmia could be prevented or cured. Hence, the aim should be to prevent the onset of acute ischemic events which lead to myocardial injury and acute infarction among people who have CAD of critical severity.
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Baroldi, G.; Radice, F.; Schmid, G., and Leone. A.: Morphology of acute myocardial infarction in relation to coronary thrombosis. Am. Heart J. 87: 65-75 (1974). Bemiller, C.R.; Pepine, C.J., and Rogers, A.K.: Long-term observations in patients with angina and normal coronary arteriograms. Circulation 47: 36-41 (1973). Bemis, C.E.; Gorlin, R.; Kemp, H.G., and Herman, M.W.: Progression of coronary artery disease. A clinical artériographie study. Circulation 47: 455-464 (1973). Cannom, D.A.; Harrison, D.C., and Schroeder, J.S.: Haemodynamic observations in patients with unstable angina pectoris. Am. J. Cardiol. 33: 17-21 (1974). Davies, M.J.; Woolf, N., and Robertson, W.B.: Pathology of acute myocardial infarc tion with particular reference to occlusive coronary thrombi. Br. Heart J. 38: 659-664 (1976). Fuster, V.; Frye, R.L.; Conolly, D.C.; Danielson, M.A.; Elvebach, L.R., and Kurland, L.T.: Artériographie patterns early in the onset of the coronary syndromes. Br. Heart J. 37: 1250-1255 (1975). Guzman, M.A.; McMahan, C.A.; McGill, H.C., jr.; Strong, J.P.; Tejada, C.; Rcstrepo, C ; Eggen, D.A.; Robertson, W.B., and Solberg, L.A.: Selected méthodologie aspects of the International Atherosclerosis Project. Lab. Invest. 18: 479-497 (1968). Hekali, P.: Coronary angiography and clinical symptomatology. Acta radiol., suppl., 254 (1976). Julian, D.G.: Aorta-to-coronary bypass surgery for angina; in Oliver, Modern trends in cardiology, vol. 3, pp. 439-464 (Butterworths, London 1975). Rissanen, V.T.; Double contrast technique for postmortem coronary angiography. Lab. Invest. 23: 517-520(1970). Rissanen, V.: Aortic and coronary atherosclerosis in a Finnish autopsy series of violent deaths. Suomal. Ticdcakat. Toim. 155 (1972). Rissanen, V.; Pyôrâlà, K., and Heinonen, O.P.: Cigarette smoking in relation to coronary and aortic atherosclerosis. Acta path, microbiol. scand. sect. A. 80: 491-500 (1972). Rissanen, V.: Smoke of cigarette and arteriosclerosis. 9th Int. Congr. Angiology, Florence 1974. Minerva cardioangiol. 22: 274 (1974). Rissanen, V.: Coronary atherosclerosis in cases of coronary death as compared with that occurring in the population. A study of a medico-legal autopsy series of coronary deaths and violent deaths. Ann. clin. Res. 7: 412-425 (1975). Rissanen, V.; Romo, M.; Sarna, S., and Siltanen, P.: Deaths from ischemic heart disease in persons aged 65 or younger in Helsinki in 1970. With special reference to pathoanatomic findings in hearts. Acta med. scand. 197: 51-60 (1975).
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References
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Rissanen, V.; Romo, M., and Siltanen, P.: Premonitory symptoms and stress factors preceding sudden death from ischemic heart disease. Acta med. scand. 204: 389 -396 (1978). 17 Rissanen, V.; Romo, M., and Siltanen, P.: Prehospital sudden death from ischemic heart disease. A postmortem study. Br. Heart J. 40: 1025-1033 (1978). 18 Rissanen, V.; Raunio, H., and Romppanen, T.: Autopsy findings in patients dying of acute myocardial infarction. (In preparation.) 19 Romo, M.: Factors related to sudden death in acute ischemic heart disease. A community study in Helsinki. Acta med. scand., suppl. 547 (1973). 20 World Health Organization: The pathological diagnosis of acute myocardial infarction. Preliminary results of a WHO cooperative study. Bull. Wld Hlth Org. 48: 23-25 (1973). 21 Uemura, K.; Sternby, N.; Vanecek, R.; Vihert, A., and Kagan, A.: Grading athero sclerosis in aorta and coronary arteries obtained at autopsy. Application of a tested method. Bull. Wld Hlth Org. 31: 297-312 (1964). 22 Webster, J.S.; Mobcrg, C., and Rincon, G.: Natural history of severe proximal coronary artery disease as documented by coronary cineangiography. Am. J. Cardiol. 33: 195-201 (1974). 23 Wilhelmsson, C.; Vedin, J.A.; Elmfeldt, D.; Tibblin, G., and Wilhelmssen, L.: Smoking and myocardial infarction. Lancet i: 415-422 (1975).
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V. Rissanen, Department of Medicine, University of Kuopio, Kuopio (Finland)
