10.5
Cardiovasc Pathol Vol. 3, No. 2
Apri-June 1994:105-115
Pathobiology of Sudden Death: Coronary Causes James B. Atkinson, Departmmt
of Pathology, Vanderbilt UniversiQ, Nashville, Tennessee
Sudden cardiac death affects 300,000 to 400,000 annually (O.l%-0.2 % of tbe population), and coronary heart disease accounts for 80 % to 90 % of these cases (1,2). Of al1coronary heart disease deaths, 50% are “sudden.”This percentage has not changed despite recent declines in mortality from coronary heart disease in the United States. The incidence of sudden death attributable to coronary artery disease (CAD) increases with increasing age, but the proportion of deaths that are attributable to CAD and which are sudden decreases with advancing age (1-3). Risk factors for sudden death caused by CAD (sudden coronary death, SCD) include intraventricular conduction abnormalities, smoking, obesity, and psychosocial factors (1). Reichenbach et al. could find no relationship between SCD and age, severity of CAD, or frequency of remote myocardial intàrction in patients who died from SCD compared with those who were resuscitated and survived (4). Sudden death from CAD may be the first manifestation of heart disease in 20% to 25 % of patients (1). Depression of left ventricular ejection fraction is the strongest predictor of sudden deatb in patients with chronic ischemic heart disease. This review wil1 address predominantly the pathobiology of the most common etiology for SCD, atherosclerotic CAD. Mechanisms that may promote development of acute coronary lesions wil1 be summarized, and general approaches for the pathological assessment of SCD wil1 be reviewed. Before summarizing atherosclerotic causes of SCD, however, nonatherosclerotic causes of SCD wil1 be briefly reviewed.
Nonatherosclerotic Coronary Artery Disease A variety of nonatherosclerotic coronary artery abnormalities may be responsible for sudden death (Table 1). Abnormal
Manuscript received November 12,1993; accepted November 12,1993. Address for reprints: James B. Atkinson, MD, PhD, Department of Pathology, Vanderbilt University, Nashville, TN 37232; Telephone: (615) 322-2102, Fax: (615) 343-7023. 0 1994 by Elsevier Science Inc.
MD, PhD, FACC
distribution or origin of the coronary arteries has been associated with sudden death, particularly in young people who die during exercise (5-7). In a recent review of 242 patients who had isolated coronary artery anomalies, cardiac death occurred in 143 (59%); of these, 46 deaths occurred suddenly (8). Origin of the left coronary artery from the right sinus of Valsalva and anomalous origin of one major coronary artery from the pulmonary trunk are the most common anomalies found in this circumstance. It has been suggested that when the left coronary artery arises from the right sinus, the acute left angle passage between the aorta and pulmonary artery results in a slit-like lumen that is further compromised by distension of the aorta and puhnonary artery (5). In addition to abnormal coronary artery distribution, acute angle takeoff and valve-like ridges at the ostia may also be associated with sudden death (5-7). Ostial obstruction can also occur as a late sequela of inflammatory diseases of the aorta (e.g., Takayasu’s arteritis; Fig. 1). The consequences of coronary emboli vary, depending upon the size of the embolus (9). Large emboli may cause infarction or tätal arrhythmia, whereas intramyocardial emboli can be clinically silent. In one series, up to 80% of patients who died from coronary emboli died suddenly (10). Endocarditis (infective and nonbacterial thrombotic) is the major source of coronary emboli (Fig. 2)) although iatrogenic causes are becoming more common (Table 1). Cardiac tumors may occasionally embolize as wel1 (9). Coronary artery aneurysms and dissections, both spontaneous and iatrogenic, have been described as a cause of sudden and unexpected death (11). Spontaneous coronary artery dissection occurs most often in women, some of whom are peripartum, and as many as 80% may die suddenly (11). In many of these cases, significant inflammatory infiltrates, sometimes with a prominente of eosinophils, have been tbund, leading some to speculate that some cases may be a form of hypersensitivity (12). Coronary artery dissection may also occur with retrograde extension of a type A aortic dissection (Fig. 3) or as a complication of cardiac surgery. 1054-8807/94/$1.00
106
ATKINSON SUDDEN CORONARY DEATH
Table 1. Nonatherosclerotic
Coronary
Cardiovasc F’athol Vol. 3, No. 2 April-June 1994:105-115
Causes of Suddert Death
A. Congenital anomalies of coronary arteries 1. Anomalous origin of left coronary artery from right sinus of Valsalva 2. Origin of left main coronary artery from pulmonary trunk 3. Congenital hypoplasia B. Coronary emboli 1. Natural: Endocarditis (infective, nonbacterial thrombotic) Mural thrombus associated with arrhythmia, myocardial infarction, or cardiomyopathy Tumor Trauma (fat emboli) 2. Iatrogenic (platelet-fibrin, air, calcium, talc, suture, cholesterol): Cardiac catheterization Cardiac surgery Percutaneous transluminal coronary angioplasty C. Arteritis: Polyarteritis nodosa Kawasaki’s disease Thromboangiitis obliterans Rheumatic diseases Giant cel1 arteritis D. Aneurysms and dissections dysplasia E. Fibromuscular F. Coronary ostial obstruction: Acute angle take-off Vake-like ridges Prolapse of tumor (myxoma, papillary fibroelastoma) or valve Postinllammatory G. Metabolic diseases: Mucopolysaccharidosis Homocystinuria Fabry’s disease Amyloidosis H. Functional obstruction: Coronary artery spasm Myocardial bridge (tunnel) 1. Idiopathic arterial calcification of infancy
Figure 1. Right coronary artery from a 16-year-old female with Takayasu’s arteritis, showing marked fibrosis of the adventitia, disruption of the media, and near-occlusive intimal thickening (Movat pentachrome stain, x20).
Figure 2. Embolus (arrows) in lumen of eccentrically narrowed right coronary artery of a 7%year-old female. The source was a large, bulky vegetation on the aortic valve secondary to Candida endocarditis (hematoxylin-eosin stain, ~16).
In addition to congenital anomalies, coronary causes of sudden death in infants and children may include polyarteritis nodosa (13,14), Kawasaki disease (15,16), and idiopathic arterial calcification of infancy (17). James and colleagues have described thickening of the intramural coronary arteries (congenital dysplasia), particularly those supplying the sinoatrial and atrioventricular nodes, in young people who have died suddenly (18-20). Burke et al. (21) recently reported that dysplasia of the atrioventricular (AV) node artery was found in 12 of 27 young patients (mean age 25 years) who died suddenly, compared with only 1 of 17 control subjects who died traumatically. In 10 of the 12 subjects, the AV node artery was narrowed to a degree greater than two standard deviations over the control value; half of the subjects in this subgroup died during exercise, and one third had a family history of sudden unexplained cardiac death. A myocardial bridge (coronary artery “tunnel”) has been found in some cases of sudden death (22). It is thought that systolic compression of the left anterior descending coronary artery can reduce coronary flow during both systole and diastole, resulting in myocardial ischemia and possibly lethal arrhythmias (23,24).
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994:105-115
ATKINSON SUDDEN CORONARY DEATH
107
Figure 3. A 55year-old woman died from occlusion of the right coronary artery by retrograde extension of a type A aortic dissection (Movat pentachrome stain, ~55).
A variety of other nonatherosclerotic coronary artery discases have been described as potential causes of sudden death but wil1 not be discus& in this paper. These include arteritis, metabolic diseases that produce coronary arterial narrowing (mucopolysaccharidosis, amyloidosis), and functional obstruction (vasospasm).
Pathology of Atherosclerotic Coronary Artery Disease in Sudden Death It is difficult to compare data relating the extent of CAD obtained from various clinicopathologic studies of SCD because of nonuniformity in how the term “sudder? is defined. Sudden death has been variously designated as death occurring instantaneously or within 1, 2, 6, 12, or 24 hours after onset of symptoms. Although the World Health Organization has defined sudden death as that occurring within 24 hours of onset of symptoms, most would probably consider 6 hours
Figure 4. Right coronary artery from a 59-year-old man who had a history of unstable angina pectoris and died suddenly. (A) An eccentric, lipid-rich atherosclerotic plaque is covered by a thin fibrous cap. A focal intraplaque fissure extends into the media (arrowheads), although the fibrous tap is intact at this segment. Barium pigment is present within the arterial lumen (L); (Movat pentachrome stain, ~16). (B) Section showing site of plaque rupture. A near-occlusive luminal thrombus (T) is in direct continuity with hemorrhage in the plaque. The disrupted fibrous tap can be seen at the edge of this eccentric, lipid-rich lesion (arrowheads; Movat pentachrome stain, X20).
108
ATKINSON SUDDEN CORONARY DEATH
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994:105-115
Table 2. Summary of Extent of Atherosclerotic Coronary Artery Disease in Sudden Death Kuller et al. (25) Perper et al. (26) Davies (27) Wames & Roberts Lie (14) CA = coronary
(28)
artery;
77% 61% 61% 47% 46%
>90% narmwing >75% narrowing >75 96 narrowing 3-vessel CAD 3-vessel CAD
CAD = coronaq
in one CA in 3-4 CAS in 3 CAs
artery disease.
to be the upper limit. After 6 hours, pathology of the heart can change dramatically, and acute myocardial infarction, if present, can be identified. Despite discrepancies as to the definition of sudden death, there is universal agreement that extensive atherosclerosis is the most common postmortem finding. Several published studies that have quantitated the extent of CAD in victims of sudden death have documented at least 75 % reduction in cross-sectional luminal area in at least one major epicardial coronary artery (lhble 2). Kuller et al. (25) found that 77 % of hearts from patients who died from SCD had 290 % reduction in luminal area in at least one coronary artery. Perper et al. (26) reported 275 % reduction in three or four coronary arteries in 61% of hearts in SCD, and 15 % of hearts had at least 75 % lesions in two arteries. Davies (27) found a similar incidence of three-vessel disease in SCD subjects (61%); in contrast, only 27% of controls had two- or three-vessel disease, and the major@ of patients had one or more arteries with 285 % narrowing. In a study of 70 victims of SCD, Wames and Roberts (28) noted 275 % narrowing in 63 % of coronary arteries from patients with SCD; of these, 15 % of hearts had single-vessel disease, 27% had two-vessel disease, and 47% had three-vessel disease. Although there is some disagreement in the literature, the most severe narrowing in SCD tends to occur in the proximal coronary segments. Significant narrowing of the left main coronary artery appears to be infrequent (2%-13% of patients with SCD) (27-29). The prevalente of significant narrowing in the other three major epicardial coronary arteries (left anterior descending and left and right circumflex) is similar (14). Atherosclerotic ostial stenosis has been reported in up to 42% of sudden deaths (30). NO differences have been observed in the enlargement or extent of coronary collaterals in victims of SCD as compared with those with acute myocardial infarction or those who had similar grades of coronary artery disease but who died from noncardiac causes (31). Acute coronary lesions and sudden death. The incidence of coronary thrombosis in SCD varies more widely in the literature than that described for the frequency of fixed lesions. Different criteria for case selection, in addition to differences in how sudden death is defined, account for these discrepancies. For example, necropsy series that exclude patients with prior history of angina pectoris or acute myocardial infarction, or that select patients with a history of ischemic heart
disease or previous myocardial infarction, may report a lower frequency of acute coronary lesions than do prospective studies of al1 SCD victims (32). The likelihood of detecting acute lesions may also vary as the interval between onset of symptoms and death lengthens; the incidence of acute thrombosis is lowest in patients with instantaneous death and highest in those who survive up to 24 hours after onset of symptoms or those with acute myocardial infarction (33). Acute coronary artery lesions may consist of recent intraluminal thrombus (occlusive or mural), plaque fissures, or intraplaque hemorrhage (Fig. 4). A plaque fissure is defined as disruption of the fibrous tap overlying a lipid-rich core, usually found at the junction of the fibrous tap with the normal intima (the “shoulder” of the lesion). Intraplaque hemorrhage represents red cells within an atherosclerotic plaque and may be a common finding in SCD as wel1 as non-SCD victims (32). As a general rule, acute coronary lesions tend to occur in the proximal segments of the left anterior descending and left circumflex coronary arteries and in the middle to distal segments of the right coronary artery (34). Ruptured atherosclerotic plaques are more likely to be associated with lipid-rich lesions, which are often heavily infiltrated by foam cells at the shoulder region, than with collagenous, sclerotic plaques (35). An association between acute thrombosis and SCD has long been recognized (36). In a widely cited paper published by Davies and Thomas in 1984 (37), 100 subjects who died from ischemic heart disease within 6 hours after onset of symptoms were compared with 78 subjects who had suddenly died from noncardiac causes. Postmortem coronary angiography was performed in each case, and 3-mm sections of the three major epicardial coronary arteries were examined. Of the 100 SCD victims, 44 had major (>50% reduction in crosssectional luminal area) recent thrombi. Thirty hearts had minor occlusive thrombi, and 21 showed evidente of plaque fissuring. Only 5 of the 100 subjects had no acute arterial lesions (in contrast to 70 of the 78 control cases [89.8%]). In hearts with acute thrombi, 65 % of thrombi occurred at sites of pre-existing high-grade stenoses. Several recent studies have also examined the frequency of acute lesions in SCD. In a postmortem comparison of SCD subjects with those with unstable angina pectoris and acute myocardial infarction, Kragel et al. (38) found intraluminal thrombus in 29% of SCD patients, in 29% of patients with unstable angina, and in 69 % of subjects who died from acute myocardial infarction. Evidente of plaque hemorrhage was seen in 38 % of SCD patients, compared with 64 % in the unstable angina group and 90 % in the acute myocardial infarction group. Not al1series have noted a high incidence of coronary thrombosis in SCD, even when meticulous methods are used to examine the coronary arteries. Wames and Roberts (28) reported coronary thrombi in only 13 of 70 victims of SCD (19%). Baroldi et al. (29) found thrombi in 32 of 208 SCD cases (15.3%); of these subjects, 73% died within 10 minutes, 23% within 1 hour, and 5 % within 3 hours.
ATKINSON SUDDEN CORONARY DEATH
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994: 105-115
109
Figure 5. (A) and (B) A concentric atherosclerotic lesion that has a thin fibrous tap overlies a lipid-rich, necrotic core. A fissure is present at the margin of the necrotic core (arrow), and barium pigment has extended from the lumen (L) into the intima (Movat pentachrome stain: A, x20; B, x80). (C) Photomicrographshowinga very thin fibreus tap (arrcws) over a lipid-rich atherosclerotic lesion in which there has been intraplaque hemorrhage (L = arterial lumen; Movat pentachrome stain, X100). (D) Photomicrograph showing major plaque rupture, with intraplaque thrombus confined to the necrotic core and in direct continuity with an occlusive thrombus in the arterial lumen (L; Movat pentachrome stain, x50).
Pathology of the myocardium in sudden corouary death. For the reasons already cited for variations in coronary artery pathology, the frequency of various pathological findings in the myocardium may vary as wel1 (Table 3). The incidence of healed myocardial infarction in SCD ranges from 40% to 70% (33). Depending upon how sudden death is defined, the frequency of acute myocardial infarction varies from 0% to 46 % ; the average falls somewhere around 20 % , which correlates wel1 with out-of-hospital cardiac arrest survivors (4,33). A variety of histologie changes can be noted in the myocardium of victims of SCD (Table 3). In hearts from SCD victims, Baroldi and colleagues (29,39) found coagulation necrosis in 16.8% , contraction band necrosis in 71.6 % , and myocytolysis in 8 % . Armiger and Smeeton (40) found contraction band necrosis in 75 % of SCD hearts. Interpretation of contraction band necrosis at autopsy may be confounded
by effects from attempted resuscitation as wel1as changes secondary to pressors (“catecholamine effect”) (32,41,42). The role of resuscitation in production of contraction bands has been recently questioned, however (43). Intramyocardial platelet aggregates have been noted in 30 % of hearts from SCD victims (44), and multifocal myocardial
Table 3. Pathology of the Myocardium in Sudden Coronary Death Healed myocardial infarction Acute myocardial infarction Histopathology
Cardiomegaly
40-70% 0-4696 Normal Contraction band necrosis Hypereosinophilia Wavy fibers Coagulation necrosis Up to two tbirds
110
ATKINSON SUDDEN CORONARY DEATH
necrosis was associated with over half of these cases. This has led to the suggestion that ventricular fibrillation precipitated by myocardial necrosis caused by intramyocardial thromboemboli may be an underlying mechanism of sudden death in some cases. Left ventricular enlargement tends to be greater in hearts from SCD subjects than from those with chronic coronary artery disease (14,45).
Pathophysiology of Sudden Coronary Death In 1889, prior to the invention of the electrocardiograph, John McWilliam proposed that sudden death was caused by ventricular fibrillation (46). Up until that time, it was assumed that sudden death (“cardiac failure”) was caused by a sudden cessation of the heart in diastole. In his brief paper, McWilliam proposed that the anatomie substrate for sudden death was “diseased conditions (atheromatous, calcareous, or sclerotic) of the coronary arteries” and that the precipitating cause was ventricular fibrillation. Indeed, ventricular fibrillation is thought to be the agonal rhythm in at least 75 % of patients with SCD (23). Ventricular fibrillation in patients with coronary artery disease may be secondary to acute myocardial ischemia, myocardial fibrosis, or myocardial hypertrophy. Myocardial ischemia greatly reduces the fibrillation threshold of surviving myocardium (47). Release of catecholamines in response to myocardial ischemia may directly damage the myocardium and/or lower the threshold for ventricular fibrillation (14,48,49). A variety of factors may serve as “triggers” of SCD. The incidence of SCD has a circadian variation, with a threefold increased risk during the moming and a low incidence at night (50,5 1). The increased incidence of SCD in the morning may be related to a surge in sympathetic activity that is associated with moving from a supine to upright posture and with the initiation of activity (52,53). Psychological stress has also been implicated as a potential trigger for SCD (54-57). For example, the effect of mental stress on sudden death was shown by a marked increase in the number of sudden out-of-hospital deaths in Tel Aviv during the initial period of the Gulf War in 1991 (following the first missile attack on Israel), compared with one year earlier (58). In addition, certain conditions in the myocardium may provide a substrate for SCD. Patients with ventricular hypertrophy may be at higher risk for SCD (59), and myocardial fibrosis is associated with electrical instability (60). Sudden coronary death appears to be part of the spectrum of ischemic heart disease, which includes unstable angina and acute myocardial infàrction. What determines whether any given patient wil1 develop one of these three manifestations of coronary artery disease may relate to the suddenness of onset and completeness and duration of coronary artery obstruction . Based on premortem angiography and postmortem pathologie data, it is reasonable to propose that in a high percentage of SCD cases, the rapid evolution of a coronary artery lesion, with plaque rupture (fissuring) and intraluminal
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994:105-115
Table 4. Possible Mechanisms Underlying Coronary Artery Plaque Ruuhue A. Susceptibility of the plaque 1. Lipid-rich plaques 2. Thin fibrous tap over atherosclerotic plaque 3. Abundant foam cells at ‘shoulder” region of plaque 4. Site of plaque (tethering of coronary artery to myocardium) B. “Triggers” 1. Circadian inthtences Sympathetic activity: increase in heart rate, blood flow, myocardial contractility, coronary Row, coronary tone Low fibrinolytic activity High platelet aggregability 2. Exercise 3. Bloed pressure and circumferential tensile stress 4. Vasospasm 5. Shear stress associated with coronary artery narrowing 6. Psychological factors Adapted from Falk (35).
thrombosis, leads to myocardial ischemia and fatal electrical instability of the myocardium. It should be remembered, however, that evidente of plaque rupture may not be unique to SCD and can be found in subjects with unstable angina, acute myocardial intârction, and in subjects who died Erom noncoronary causes as wel1 (32). Falk (35) has divided potential factors that predispose to plaque rupture into those that make the plaque vulnerable to rupture and possible triggers (‘lhble4). Morphologic substrates for plaque rupture may include soft, lipid-rich plaques with thin fibrous taps and abundant foam cells at the shoulder region of the lesion (where the plaque may be the weakest and where circumferential tensile stress is greatest during systole; Fig. 5) (61-66). Although most plaque ruptures occur without any obvious precipitating cause, there may nonetheless be certain triggers that could promote instability of the plaque. These include increased sympathetic activity, which can lead to increases in heart rate, blood pressure, myocardial contractility, coronary blood flow, and coronary tone (66-68). The circadian predisposition for sudden death may relate to a similar temporal pattem of acute coronary even& as thrombosis may occur preferentially in the morning when fibrinolytic activity is low and platelet aggregability is high (69,70). Surges in intraluminal blood pressure could increase the tensile stress on the fibrous tap and trigger plaque rupture (65,71). Because coronary artery thrombi may occur preferentially at sites where the coronaries branch or change direction and are tethered to the myocardial surface, the constant beating and twisting of the heart may play a role (35,72,73). Although coronary vasospasm can be provoked in patients with atherosclerotic coronary artery disease without serious complications, the common association of spasm and unstable coronary artery lesions suggests a relationship (35). Vasoactive amines released from platelets and mast cells in areas of atherosclerotic narrowing could promote abnormal vasomotion and
Cardiovasc Apri-June
Pathol Vol. 3, No. 2 1994: 105-115
ATKINSON SUDDENCORONARYDEATH
111
Figure 6. Fbstmortem angiograms. (A) Normal coronary vasculature. (B) Multiple fixed lesions (arrowheads) in right, left anterior descending, and left circumflex coronary arteries in a 62-year-old man who died suddenly. (C) and (D) Remote occlusion in right coronary artery (arrowhead) resulted in enlargement of collateral anastomoses across the interventricular septum in a 67-year-old man who died within 3 hours of onset of chest pain.
112
ATKINSON SUDDEN CORONARY DEATH
plaque ruptum (74). It is also conceivable, however, that plaque rupture and thrombosis precede vasospasm (75). Cocaine and sudden cmonary death. Cocaine has now been established as being responsible for a number of adverse effects in the coronary arteries. Cocaine can produce coronary vasospasm, either by augmentation of the sympathetic nervous system or by direct effects on vascular smooth muscie (76). Cocaine may also promote thrombosis by increasing platelet aggregability and thromboxane production and by decreasing prostacyclin release by the endothelium (77). Cocaine use has recently been noted to be associated with accelerated atherosclerosis. Virmani and colleagues and others have noted an association between cocaine and atherosclerosis in experimental animals (78) and in autopsied subjects (79-82). Excessive numbers of inílammatory cells, including mast cells, may be associated with atherosclerotic lesions in cocaine users (81), and these cells could be potent sources of vasoconstrictive agents as well as substances that could accentuate platelet aggregation and thrombosis, leading to sudden death.
Sudden Coronary Death: General Approaches for the Pathologist Sudden death may occur in the setting of significant coronary artery disease either with or without myocardial scarring, and with or without evidente of acute myocardial ischemia or acute coronary artery lesions. Although these findings are well-recognized causes of sudden death, they should be interpreted only in light of the circumstances of the terminal event and the social and medical history (27,32,83). Because the majority of patients with SCD do not manifest acute myocardial infarction, and because the distinction between coronary artery disease as a cause of death and as an incidental finding may be difficult, a careful cardiac examination and exclusion of other potential causes of death are necessary. Coronary artery disease is common in the developed world. The degree of coronary artery narrowing generally regarded as significant is >75% reduction in cross-sectional luminal area (equivalent to 50% reduction in diameter by angiography) (32,84). Pitfalls to this cutoff include whether the coronary arteries were examined after perfusion fixation at physiologic pressure, lack of assessment of actual arterial diameters, and lack of allowance made by compensatory dilatation that may occur with atherosclerosis (3285). Although criteria have varied in the literature and wil1 continue to evolve as more is learned about the mechanisms of SCD, a reasonable rule of thumb based on pre- and postmortem data that currently allows one to attribute sudden death to coronary artery disease is the presence of at least one major epicardial coronary artery with >75% reduction in cross-sectional area and exclusion of other causes of death. Individual cases may be problematic. For example, how can one assume that an atherosclerotic plaque with recent plaque fissure and hemor-
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994:105-115
rhage but without associated intraluminal thrombosis accounts unequivocally for death (32)? The answer may lie in an understanding of the dynamic nature of coronary artery disease, in which intraltinal thrombi may undergo spontaneous lysis, or in which local coronary spasm may occur in response to plaque rupture. Approaches to examination of the heart to assess coronary artery disease have been well described (14,86). The ideal method to examine the coronary arteries is by injection of a barium-gelatin mixture at physiologic pressure, fbllowed by specimen radiography (Fig. 6). Badiographs of the intact heart (before and after coronary artery injection) can be made, as wel1 as radiographs of the epicardial arteries that have been removed from the heart. Pitfalls of this technique include difficulty in visualizing the ostia and proximal arterial segments - particularly the left main coronary artery (an artery that is usually neglected by pathologists) - and dissection of contrast medium into the media because of excessively high injection pressures or disruption of the artery by tight ligatures (87). Assessment of postmortem radiographs should address the location of lesions, with correlation to premortem angiograms if available, and note the characteristics of the narrowed segments (e.g., smooth stenoses vs. those with an irregular interface, suggestive of unstable lesions) (87,888).The presence, distribution, and quant@ of collateral channels should be noted, as should recanalized channels. Artifacts (bubbles) should also be recognized (88). Following radiography, the coronary arteries can be decalcified if necessary and then sectioned at 2- to 5mm intervals. Altematively, the coronary arteries may be left on the heart and sectioned if they are not calcifìed. Areas of maximal narrowing should be noted by indicating the degree of reduction in cross-sectional area of the lumen (e.g., 0%-25 % , 26%-50%, 51%-75%, 76%-90%, 91%-99%, 100%) (86). These gross observations should be confirmed by histologie examination. In some instances, it may be necessary to submit the entire artery for microscopic examination, and there are methods for the designation of segments in a proximalto-distal orientation (87,89). Sections of al1 coronary artery segments involved grossly by thrombi should be submitted for histology to determine the origin and course of thrombogenesis. The myocardium is best examined by making transverse slices through the ventricles, parallel to the atrioventricular groove, at 0.5- to l.O-cm intervals, extending up to but not through the valve chordae (86). Individual slices can be radiographed if the coronaries have been injected with barium. Grossly visible infarcts (acute and/or remote) should be described in terms of anatomie location, extent (circumference of ventricle involved and longitudinal extent [e.g., basal, medial, and apical thirds]), and distribution within the ventricular walls (transmural or subendocardial) . Full-thickness sections should be taken from infàrcted and normal zones. If myocardial lesions are not grossly visible, full-thickness
ATKINSON SUDDENCORONARYDEATH
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994:105-115
sections can be obtained in a spiral-stepwise marmer, and particular attention should be directed to myocardium in the distribution of narrowed coronary arteries (14). Techniques that identify acute infarcts of less than 24 hours’ duration (triphenyl tetrazolium chloride, nitroblue tetrazolium) may be useful(90). Although these techniques have been important in studying ischemia in experimental models, their utility may be limited in some cases when applied to humans. This may be because of the dynamic nature of the disease (i.e., occlusion of a coronary artery, followed by lysis of a thrombus and reperfusion) and by the multiplicity of preexisting disease, with variable contribution to myocardial blood flow by collateral supply.
Summary The single most common cause of sudden death in the western world is coronary artery disease. Sudden death from coronary causes occurs equally in asymptomatic patients, patients with angina, and patients with a known history of myocardial infarction. The mechanism of sudden coronary death in most patients is ventricular fibrillation secondary to ischemia. Microthrombi in intramyocardial coronary arteries may also play a role. Instability of atherosclerotic plaques, in terms of thrombosis and vasoreactivity, underlies the syndrome of unstable angina as wel1 as many cases of acute myocardial iníârction. Sudden coronary death falls within this spectrum of ischemic heart disease. Development of these syndromes depends on the abruptness of onset and the completeness and duration of coronary occlusion. Thus a rapidly evolving coronary artery lesion, with plaque fissure, rupture, and luminal thrombosis, can lead to myocardial ischemia, with fatal electrical instability of the myocardium as the first clinical manifestation. The diagnosis of sudden coronary death in the absente of myocardial infarction is determined by the degree of coronary artery narrowing and the exclusion of other causes of death . The presence of acute coronary artery lesions, which may be present in a significant number of sudden coronary death patients, lends support to the pathologie diagnosis. Thus the coronary arteries in victims of sudden coronary death may exhibit established atherosclerosis or acute lesions, whereas the myocardium may appear normal or show healed or acute infarction or hypertrophy. Although less common, nonatherosclerotic coronary artery diseases can account tbr sudden death as well, particularly in younger patients. Therefore, when sudden death occurs in children and young adults, coronary causes related to congenital anomalies, fibromuscular dysplasia, arteritis, or metabolic diseases should be considered.
References 1. Myerburg
RJ, Castellanos A. Cardiac arrest and suddert cardiac death. In: Braunwald E, ed. Heat? Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders Company, 1992:756-789.
113
2. Schatzkin A, Cupples LA, Heeren T, Morelock S, Mucatel M, Kennel WB. The epidemiology of sudden unexpected death: risk factors for men and women in the Framingham heart study. Am Heart J 1984;107:1300-1306. 3. Gillum RF. Sudden coronary Circulation 1989;79:756-765.
death in the United States, 1980-1985.
4. Reichenbach DD, Moss NS, Meyer E. Pathology of the heat? in sudden cardiac death. Am J Cardiol 1977;39:865-872. 5. Cheitlin MD, De Castro CM, McAllister HA. Sudden death as a complication of anomalous left coronary origin from the anterior sinus of Valsalva: a not-so-minor congenital anomaly. Circulation 1976;50: 780-787. 6. Barth CW, Rob& WC. Left main coronary artery originating from the right sinus of Valsalva and coursing between the aorta and pulmonary trunk. J Am Col1 Cardiol 1986;7:366-373. 7. Virmani R, Chun PKC, Goldstein RE, Robinowitz M, McAllister HA. Acute takeoffs of coronary arteries along the aortic wal1 and congenital coronary ostial valve-like ridges: association with suddert death. J Am Col1 Cardiol 1987;3:766-771. 8. Taylor AJ, Rogan KM, Virmani R. Sudden cardiac death associated with isolated congenital coronary artery anomalies. J Am Col1 Cardiol 1992;20:640-647. 9. Atkinson JB, Forman MB, Virmani R. Emboli and thrombi in coronary arteries. In: Virmani R, Forman MB, eds. Nonatherosclerotic Ischemic Heart Disease. New York: Raven Press, 1989:355-385. 10. Wenger NK, Bauer S. Coronary embolism: review of the literature and presentation of fifieen cases. Am J Med 1958;25:549-557. ll.
Virmani R, Forman MB. Coronary artery dissection. In: Virmani R, Forman MB, eds. Nonatherosclerotic Ischemic Heart Disease. New York: Raven Press, 1989:325-354.
12. Robinowitz M, Virmani R, McAllister HA. Spontaneous coronary artery dissection and eosinophilic inflammation: a cause and effect relationship? Am J Med 1982;72:923-928. 13. Ettinger RE, Nelson AM, Burke EC, Lie JT. Polyarteritis nodosa in childhood: a clinical-pathologie study. Arthritis Rheum 1979;22: 820-825. 14. Lie JT. Sudden death from diseases of the cardiovascular system. In: Silver MD, ed. Cardiovascular Patbology (2nd ed). New York: Churchill Livingstone, 1991:811-846. 15. Kegel SM, Dorsey TJ, Rowen M, Taylor WF. Cardiac death in mucocutaneous lymph node syndrome. Am J Cardiol1977;40:282-286. 16. Landing BH, Larson EJ. Are infantile periarteritis nodosa with coronary artery involvement and fatal mucocutaneous lymph node syndrome the same? Comparison of 20 patients from North America with patients from Hawaii and Japan. Pediatrics 1977;59:651-662. 17. Beuren AJ, Schulz R, Sinapius D, Stoermer J. Calcinosis of the arteries with coronary calcification in infancy. Am Heart J 1969;78:87-93. 18. James TN, Riddick L. Sudden death due to isolated acute infarction of the His bundle. J Am Col1 Cardiol 1990;15:1183-1187. 19. James TN. Morphologic characteristicsand tünctional significante of focal fibromuscular dysplasia of smal1 coronary arteries. Am J Cardiol 1990;65: 12G-22G. 20. James TN. The spectrum of disease of smal1 coronary arteries and their physiologic consequences. J Am Col1 Cardiol 1990;15:763-774. 21. Burke AP, Subramanian R, Smialek J, Virmani R. Nonatherosclerotic narrowing of the atrioventricular node artery and sudden death. J Am Col1 Cardiol 1993;21: 117-122. 22. Morales AR, Romanelli.R, Boucek IU. The mural left anterior descending coronary artery, strenuous exercise and sudden deatb. Circulation 1980;62:230-237. 23. Boucek RJ, Morales AR, Romanelli R, Judkins MP. Coronary Artery Disease: PathoIogic and Clinical Assessment. Baltimore, MD: Williams and Wilkins, 1984:201-223. 24. Ferreira
AG, Trotter SE, Konig B, Decourt LV, Fox K. Olsen EGJ.
114
ATKJNSON SUDDEN CORONARY DEATH
Myocardial bridges: J 1991;55:364-367.
morphological
Cardiovasc Pathol Vol. 3, No. 2 April-June
and functional
25. Kuller L, Cooper M, Perper J. Epidemiology Intern Med 1972;129:714-719.
aspects.
Br Heart
of sudden death. Arch
26. Perper JA, Kuller LH, Cooper M. Arteriosclerosis of coronary arteries in sudden unexpected deaths. Circulation 1975; 52(Suppl BI): BI-27-111-33. 27. Davies MJ. Pathological 1981;45:88-96.
view of sudden cardiac
death. Br Heart J
28. Wames CA, Roberts WC. Sudden coronary death: comparison of patients with to those without coronary thrombus at necropsy.Am J Cardiol 1984;54:1206-1211. 29. Baroldi G, Falxi G, Mariani F. Sudden coronary death: a postmortem study in 208 selected cases compared to 97 “control” subjects. Am Heart J 1979;98:20-31. 30. Rissanen V. Gccurrence of coronary ostial stenosis in a necropsy series of myocanhal infarction, sudden death, and violent deatb. Br Heart J 1975;37:182-191. 31. Baroldi G, Scomaxxoni G. Coronary Circulation in the Normal and the Pathologie Heart. Washington, DC: American Registry of Pathology, Armed Forces Institute of Pathology, 1962. 32. Davies MJ. Anatomie features in victims of sudden coronary death: coronary artery patbology. Circulation 1992;85(Suppl I):I-19-1-24. 33. Virmani R, Roberts WC. Sudden cardiac deatb. In: Virmani R, Atkinson JB, Fenoglio JJ, eds. Cardiovascular Pathology. Philadelphia: WB Saunders Company, 1991:134-151. 34. Liberthson RR, Nagel EL, Hirschman JC, Nussenfeld SR, Blackbomne BD, Davis JH. Pathophysiologic observations in prehospital ventricular fibrillation and sudden cardiac death. Circulation 1974;49:790-798. 35. Falk E. Why do plaques BI-30-lII-42.
rupture?
Circulation
1992; 86(Suppl
111):
36. Crawford T, Dexter D, Teare RD. Coronary artery pathology in sudden death from myocardial ischemia. Lancet 1961;1:181-185. lesions 37. Davies MJ, Thomas A. Thrombosis and acute coronary-artery in sudden cardiac ischemic death. N Eng1 J Med 1984;310: 1137-1140. 38. Kragel AH, Gertz SD, Roberts WC. Morphologic comparison of frequency and types of acute lesions in tbe major epicardial coronary arteries in unstable angina pectoris, sudden coronary deatb and acute myocardial infarction. J Am Col1 Cardiol 1991;18:801-808. 39. Baroldi G. Pathology and mechanisms of sudden death. In: Hurst JW, ed. The Heart. New York: McGraw-Hill, 1982:589-599. necrosis: pattems of 40. Armiger LC, Smeeton WMI. Contraction-band distribution in the myocardium and their diagnostic usefulness in sudden cardiac death. Pathology 1986;18:289-295. 41. ROM G, Chappel CI, Balaxs T, Gaudry R. An infarct-like myocardial lesion and other toxic manifestations produced by isoporoterenol in the rat. Arch Pathol 1959;67:443-455. 42. ROM G. Catecholamine 17:291-306.
cardiotoxicity.
J Mol Cel1 Cardiol
1985;
43. Teraoka K, Kaneko N, Takeishi M. Clinical and pathologie studies on contraction band lesions: relation to acute myocardial infarction and unexplained sudden death. Mod Pathol 1991;4:6-12. 44. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986;73:418-427. 45. Haerem JW. Myocardial lesions in sudden unexpected coronary death. Am Heart J 1975;90:562-568. 46. McWilliam JA. Cardiac failure and sudden death. Br Med J 1889; 16-8. 47. Shumway NE, Johnson JA, Stish RJ. The study of ventricular fibrillation by threshold determinations. J Thorac Surg 1957;34:643-653. 48. McManus BM, Fleury TA, Roberts WC. Fatal catecholamine crisis in pheochromocytoma: curable cause of cardiac arrest. Am Heart J 1981;102:930-932. 49. Imperato-McGinley
J, Gautier T, Ehlers K, Zullo MA, Goldstein DS,
1994:105-115
Vaughan ED Jr. Reversibility of catecholamine-induced dilated cardiomyopathy in a child with a pheochromocytoma. N Eng1 J Med 1987;316:793-797. 50. Muller JE, Ludmer PL, Willich SN, et al. Circadian variation in the frequency of sudden cardiac death. Circulation 1987;75: 131-138. 51. Willich SN, Levy D, Rocco MB, Tofler GH, Stone PH, Muller JE. Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardioll987;60:801-806. 52. Brezinski DA, Tofler GH, Muller JE et al. Moming increase in platelet aggregability: association with assumption of the upright posture. Circulation 1988;78:35-40. 53. Willich SN, Maclure M, Mittleman M, Arntz HR, Muller JE. Sudden cardiac death: support for a role of triggering in causation. Circulation 1993;87:1442-1450. 54. Eliot RS, Buell JC. Role of emotions and stress in the genesis of sudden death. J Am Col1 Cardiol 1985;5(Suppl):95B_98B. 55. Wennerblom B, Holmberg S. Death outside hospital with special reference to heart disease. Eur Heart J 1984;5:266-274. 56. De Silva RA. Psychological stress and sudden cardiac death. In: Schmidt TH, Dembrowski TM, Blumchen G, eds. Biological and Psychological Factors in Cardiovascular Disease. Berlin: Springer-Verlag, 1986:155-183. 57. Cottington EM, Matthews KA, Talbott E, Kuller LH. Environmental events preceding sudden death in women. Psychosom Med 1980; 42~567-574. 58. Meisel SR, Kutx 1, Dayan KI, et al. Effect of Iraqi missile war on incidence on acute myoc&ial infarction and stalden de& in Israeli civilians. Lancet 1991;338:660-661. 59. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Eng1 J Med 1990;322: 1561-1566. 60. Myerburg RJ, Epstein K, Gaide MS, et al. Electrophysiologic consequences of experimental acute ischemia superimposed on healed myocardial infarction in Cats. Am J Cardiol 1982;49:323-330. 61. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardia1 infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985;53:363-373. 62. Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesbro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988;77: 1213-1220. 63. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The patbogenesis of coronary artery disease and the acute coronary syndromes: part 1 and 2. N Eng1 J Med 1992;326:242-250, 310-318. 64. Falk E. Morphologic features of unstable atherothrombotic plaque underlying acute coronary syndromes. Am J Cardioll989;63: 114E-120E. 65. Richardson PD, Davies MJ, Bom GVR. IntIuence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989;2:941-944. 66. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989;79:733-743. 67. Tofler GH, Stone PH, Maclure M, et al. Analysis of possible triggers of acute myocardial infarction (the MILIS Study). Am J Cardiol 1990;66:22-27. 68. Stone PH. Triggers of transient myocardial ischemia: circadian variation and relation to plaque rupture and coronary thrombosis in stable coronary artery disease. Am J Cardiol 1990;66:326-36G. 69. Andreotti F, Davies GJ, Hackett DR, et al. Major circadian fluctuations in fibrinolytic factors and possible relevante to time of onset of myocardial infarction, sudden cardiac death and stroke. Am J Cardiol 1988;62:635-637. 70. Rosing DR, Brakman P, Redwood DR. et al. Blood fibrinolytic activity in man: diurnal variation and the response to varying intensities of exercise. Circ Res 1970;27:171-184. 71. Davies MJ. A macro and micro view of coronary ischemic hcart disease. Circulation 1990;82(Suppl
vascular insult in II):II-38-11-46.
ATKINSON SUDDENCORONARYDEATH
Cardiovasc Pathol Vol. 3, No. 2 Apri-lune
19!34:105-115
12. Chapman 1. The initiating cause of coronaty artery thrombosis: tomic study. J Mt Sinai Hosp 1969;36:361-374.
an ana-
13. El Fawal MA, Berg GA, Wheatley DJ, Harland WA. Sudden coronary deatb in Glasgow: nature and frequency of acute coronary lesions. Br Heart J 1987;57:329-335. 14. Forman MB, Oates JA, Robertson D, Robertson RM, Roberts LJ, 11, Virmani R. Increased adventitial mast cells in a patient witb coronary spasm. N Eng1 J Med 1985;313:1138-1141. 75. Golino P, Ashton JH, Buja LM, et al. Local platelet activation causes vasoconstriction of large epicardial canine coronary arteries in vivo: thromboxane A2 and serotonin are possible mediators. Circulation 1989;79:154-166.
115
crease in atherosclerosis and adventitial mast cells in cocaine abusers: an altemative mechanism of cocaine-associated vasospasm and tbrombosis. J Am Col1 Cardiol 1991;17:1553-1560. 82. Kolodgie FD, Virmani R, Comhill JF, Herderick EE, Malcom GT, Mergner WJ. Cocaine: an independent risk factor of aortic sudanophilia. A preliminary report. Atherosclerosis 1992;97:53-62. 83. Davis JH, Wright RK. The very sudden cardiac deatb syndrome-a conceptual model for pathologists. Hum Pathol 1980; 11: 117- 12 1. 84. Arnett EN, Isner JM, Redwood DR, et al. Coronary artery narrowing in coronary heart disease: comparison of cineangiographic and necropsy findings. Ann Intern Med 1979;91:350-356.
76. Kloner RA, Hale S, Alker K, Rezkalla S. The effects of acute and chronic cocaine use on the heart. Circulation 1992;85:407-419.
85. Glagov S, Weisenberg E, Zaims CK, Stankunavicius Compensatory enlargement of human atherosclerotic ies. N Eng1 J Med 1987;316:1371-1375.
17. Togna G, Tempesta E, Togna AR, Dolci N, Cebo B, Caprino L. Platelet responsiveness and biosynthesis of thromboxane and protacyclin in response to in vitro cocaine treatment. Haemostasis 1985; 15: 100-107.
86. Virmani R, Ursell PC, Fenoglio JJ. Examination of the heart. In: Virmani R, Atkinson JB, Fenoglio JJ, eds. Cardiovascular Pathology. Philadelphia: WB Saunders Company, 1991: 1-20.
78. Kolodgie FD, Virmani R, Rite HE, Herderick EE, Mergner WJ. Intravenous cocaine accelerates atherosclerosis in cholesterol-fed New Zealand White rabbits (abstract). J Am Col1 Cardiol 1990;15:217A.
87. Thomas AC, Davies MJ. Post-mortem investigation and quantification of coronary artery disease. Histopathology 1985;9:959-976.
79. Virmani R, Robinowitz M, Smialek JE, Smyth DF. Cardiovascular effects of cocaine: an autopsy study of 40 patients. Am Heart J 1988; 115: 1068-1076. 80. Dressler FA, Malekzadeh S, Roberts WC. Quantitative analysis of amounts of coronary arterial narrowing in cocaine addicts. Am J Cardiol 1990;65:303-308. 81. Kolodgie FD, Virmani R, Comhill JH, Herderick
EE, Smialek J. In-
R, Kolettis GJ. coronary arter-
88. Thomas AC, Pazios S. The postmortem detection of coronary artery lesions using coronary arteriography. Pathology 1992;24:5-11. 89. Fulton WFM. The Coronary Arteries: Arteriography, Microanatomy, and Pathogenesis of Obliterative Coronary Artery Disease. Springfield, IL: Charles C. Thomas, 1965. 90. Schoen FJ. Interventional and Surgical Cardiovascular Philadelphia: WB Saunders Company, 1989;369-396.
Pathology.
Cardiovasc Pathol Vol. 3, No. 2
Apri-June 1994:105-115
Pathobiology of Sudden Death: Coronary Causes James B. Atkinson, Departmmt
of Pathology, Vanderbilt UniversiQ, Nashville, Tennessee
Sudden cardiac death affects 300,000 to 400,000 annually (O.l%-0.2 % of tbe population), and coronary heart disease accounts for 80 % to 90 % of these cases (1,2). Of al1coronary heart disease deaths, 50% are “sudden.”This percentage has not changed despite recent declines in mortality from coronary heart disease in the United States. The incidence of sudden death attributable to coronary artery disease (CAD) increases with increasing age, but the proportion of deaths that are attributable to CAD and which are sudden decreases with advancing age (1-3). Risk factors for sudden death caused by CAD (sudden coronary death, SCD) include intraventricular conduction abnormalities, smoking, obesity, and psychosocial factors (1). Reichenbach et al. could find no relationship between SCD and age, severity of CAD, or frequency of remote myocardial intàrction in patients who died from SCD compared with those who were resuscitated and survived (4). Sudden death from CAD may be the first manifestation of heart disease in 20% to 25 % of patients (1). Depression of left ventricular ejection fraction is the strongest predictor of sudden deatb in patients with chronic ischemic heart disease. This review wil1 address predominantly the pathobiology of the most common etiology for SCD, atherosclerotic CAD. Mechanisms that may promote development of acute coronary lesions wil1 be summarized, and general approaches for the pathological assessment of SCD wil1 be reviewed. Before summarizing atherosclerotic causes of SCD, however, nonatherosclerotic causes of SCD wil1 be briefly reviewed.
Nonatherosclerotic Coronary Artery Disease A variety of nonatherosclerotic coronary artery abnormalities may be responsible for sudden death (Table 1). Abnormal
Manuscript received November 12,1993; accepted November 12,1993. Address for reprints: James B. Atkinson, MD, PhD, Department of Pathology, Vanderbilt University, Nashville, TN 37232; Telephone: (615) 322-2102, Fax: (615) 343-7023. 0 1994 by Elsevier Science Inc.
MD, PhD, FACC
distribution or origin of the coronary arteries has been associated with sudden death, particularly in young people who die during exercise (5-7). In a recent review of 242 patients who had isolated coronary artery anomalies, cardiac death occurred in 143 (59%); of these, 46 deaths occurred suddenly (8). Origin of the left coronary artery from the right sinus of Valsalva and anomalous origin of one major coronary artery from the pulmonary trunk are the most common anomalies found in this circumstance. It has been suggested that when the left coronary artery arises from the right sinus, the acute left angle passage between the aorta and pulmonary artery results in a slit-like lumen that is further compromised by distension of the aorta and puhnonary artery (5). In addition to abnormal coronary artery distribution, acute angle takeoff and valve-like ridges at the ostia may also be associated with sudden death (5-7). Ostial obstruction can also occur as a late sequela of inflammatory diseases of the aorta (e.g., Takayasu’s arteritis; Fig. 1). The consequences of coronary emboli vary, depending upon the size of the embolus (9). Large emboli may cause infarction or tätal arrhythmia, whereas intramyocardial emboli can be clinically silent. In one series, up to 80% of patients who died from coronary emboli died suddenly (10). Endocarditis (infective and nonbacterial thrombotic) is the major source of coronary emboli (Fig. 2)) although iatrogenic causes are becoming more common (Table 1). Cardiac tumors may occasionally embolize as wel1 (9). Coronary artery aneurysms and dissections, both spontaneous and iatrogenic, have been described as a cause of sudden and unexpected death (11). Spontaneous coronary artery dissection occurs most often in women, some of whom are peripartum, and as many as 80% may die suddenly (11). In many of these cases, significant inflammatory infiltrates, sometimes with a prominente of eosinophils, have been tbund, leading some to speculate that some cases may be a form of hypersensitivity (12). Coronary artery dissection may also occur with retrograde extension of a type A aortic dissection (Fig. 3) or as a complication of cardiac surgery. 1054-8807/94/$1.00
106
ATKINSON SUDDEN CORONARY DEATH
Table 1. Nonatherosclerotic
Coronary
Cardiovasc F’athol Vol. 3, No. 2 April-June 1994:105-115
Causes of Suddert Death
A. Congenital anomalies of coronary arteries 1. Anomalous origin of left coronary artery from right sinus of Valsalva 2. Origin of left main coronary artery from pulmonary trunk 3. Congenital hypoplasia B. Coronary emboli 1. Natural: Endocarditis (infective, nonbacterial thrombotic) Mural thrombus associated with arrhythmia, myocardial infarction, or cardiomyopathy Tumor Trauma (fat emboli) 2. Iatrogenic (platelet-fibrin, air, calcium, talc, suture, cholesterol): Cardiac catheterization Cardiac surgery Percutaneous transluminal coronary angioplasty C. Arteritis: Polyarteritis nodosa Kawasaki’s disease Thromboangiitis obliterans Rheumatic diseases Giant cel1 arteritis D. Aneurysms and dissections dysplasia E. Fibromuscular F. Coronary ostial obstruction: Acute angle take-off Vake-like ridges Prolapse of tumor (myxoma, papillary fibroelastoma) or valve Postinllammatory G. Metabolic diseases: Mucopolysaccharidosis Homocystinuria Fabry’s disease Amyloidosis H. Functional obstruction: Coronary artery spasm Myocardial bridge (tunnel) 1. Idiopathic arterial calcification of infancy
Figure 1. Right coronary artery from a 16-year-old female with Takayasu’s arteritis, showing marked fibrosis of the adventitia, disruption of the media, and near-occlusive intimal thickening (Movat pentachrome stain, x20).
Figure 2. Embolus (arrows) in lumen of eccentrically narrowed right coronary artery of a 7%year-old female. The source was a large, bulky vegetation on the aortic valve secondary to Candida endocarditis (hematoxylin-eosin stain, ~16).
In addition to congenital anomalies, coronary causes of sudden death in infants and children may include polyarteritis nodosa (13,14), Kawasaki disease (15,16), and idiopathic arterial calcification of infancy (17). James and colleagues have described thickening of the intramural coronary arteries (congenital dysplasia), particularly those supplying the sinoatrial and atrioventricular nodes, in young people who have died suddenly (18-20). Burke et al. (21) recently reported that dysplasia of the atrioventricular (AV) node artery was found in 12 of 27 young patients (mean age 25 years) who died suddenly, compared with only 1 of 17 control subjects who died traumatically. In 10 of the 12 subjects, the AV node artery was narrowed to a degree greater than two standard deviations over the control value; half of the subjects in this subgroup died during exercise, and one third had a family history of sudden unexplained cardiac death. A myocardial bridge (coronary artery “tunnel”) has been found in some cases of sudden death (22). It is thought that systolic compression of the left anterior descending coronary artery can reduce coronary flow during both systole and diastole, resulting in myocardial ischemia and possibly lethal arrhythmias (23,24).
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994:105-115
ATKINSON SUDDEN CORONARY DEATH
107
Figure 3. A 55year-old woman died from occlusion of the right coronary artery by retrograde extension of a type A aortic dissection (Movat pentachrome stain, ~55).
A variety of other nonatherosclerotic coronary artery discases have been described as potential causes of sudden death but wil1 not be discus& in this paper. These include arteritis, metabolic diseases that produce coronary arterial narrowing (mucopolysaccharidosis, amyloidosis), and functional obstruction (vasospasm).
Pathology of Atherosclerotic Coronary Artery Disease in Sudden Death It is difficult to compare data relating the extent of CAD obtained from various clinicopathologic studies of SCD because of nonuniformity in how the term “sudder? is defined. Sudden death has been variously designated as death occurring instantaneously or within 1, 2, 6, 12, or 24 hours after onset of symptoms. Although the World Health Organization has defined sudden death as that occurring within 24 hours of onset of symptoms, most would probably consider 6 hours
Figure 4. Right coronary artery from a 59-year-old man who had a history of unstable angina pectoris and died suddenly. (A) An eccentric, lipid-rich atherosclerotic plaque is covered by a thin fibrous cap. A focal intraplaque fissure extends into the media (arrowheads), although the fibrous tap is intact at this segment. Barium pigment is present within the arterial lumen (L); (Movat pentachrome stain, ~16). (B) Section showing site of plaque rupture. A near-occlusive luminal thrombus (T) is in direct continuity with hemorrhage in the plaque. The disrupted fibrous tap can be seen at the edge of this eccentric, lipid-rich lesion (arrowheads; Movat pentachrome stain, X20).
108
ATKINSON SUDDEN CORONARY DEATH
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994:105-115
Table 2. Summary of Extent of Atherosclerotic Coronary Artery Disease in Sudden Death Kuller et al. (25) Perper et al. (26) Davies (27) Wames & Roberts Lie (14) CA = coronary
(28)
artery;
77% 61% 61% 47% 46%
>90% narmwing >75% narrowing >75 96 narrowing 3-vessel CAD 3-vessel CAD
CAD = coronaq
in one CA in 3-4 CAS in 3 CAs
artery disease.
to be the upper limit. After 6 hours, pathology of the heart can change dramatically, and acute myocardial infarction, if present, can be identified. Despite discrepancies as to the definition of sudden death, there is universal agreement that extensive atherosclerosis is the most common postmortem finding. Several published studies that have quantitated the extent of CAD in victims of sudden death have documented at least 75 % reduction in cross-sectional luminal area in at least one major epicardial coronary artery (lhble 2). Kuller et al. (25) found that 77 % of hearts from patients who died from SCD had 290 % reduction in luminal area in at least one coronary artery. Perper et al. (26) reported 275 % reduction in three or four coronary arteries in 61% of hearts in SCD, and 15 % of hearts had at least 75 % lesions in two arteries. Davies (27) found a similar incidence of three-vessel disease in SCD subjects (61%); in contrast, only 27% of controls had two- or three-vessel disease, and the major@ of patients had one or more arteries with 285 % narrowing. In a study of 70 victims of SCD, Wames and Roberts (28) noted 275 % narrowing in 63 % of coronary arteries from patients with SCD; of these, 15 % of hearts had single-vessel disease, 27% had two-vessel disease, and 47% had three-vessel disease. Although there is some disagreement in the literature, the most severe narrowing in SCD tends to occur in the proximal coronary segments. Significant narrowing of the left main coronary artery appears to be infrequent (2%-13% of patients with SCD) (27-29). The prevalente of significant narrowing in the other three major epicardial coronary arteries (left anterior descending and left and right circumflex) is similar (14). Atherosclerotic ostial stenosis has been reported in up to 42% of sudden deaths (30). NO differences have been observed in the enlargement or extent of coronary collaterals in victims of SCD as compared with those with acute myocardial infarction or those who had similar grades of coronary artery disease but who died from noncardiac causes (31). Acute coronary lesions and sudden death. The incidence of coronary thrombosis in SCD varies more widely in the literature than that described for the frequency of fixed lesions. Different criteria for case selection, in addition to differences in how sudden death is defined, account for these discrepancies. For example, necropsy series that exclude patients with prior history of angina pectoris or acute myocardial infarction, or that select patients with a history of ischemic heart
disease or previous myocardial infarction, may report a lower frequency of acute coronary lesions than do prospective studies of al1 SCD victims (32). The likelihood of detecting acute lesions may also vary as the interval between onset of symptoms and death lengthens; the incidence of acute thrombosis is lowest in patients with instantaneous death and highest in those who survive up to 24 hours after onset of symptoms or those with acute myocardial infarction (33). Acute coronary artery lesions may consist of recent intraluminal thrombus (occlusive or mural), plaque fissures, or intraplaque hemorrhage (Fig. 4). A plaque fissure is defined as disruption of the fibrous tap overlying a lipid-rich core, usually found at the junction of the fibrous tap with the normal intima (the “shoulder” of the lesion). Intraplaque hemorrhage represents red cells within an atherosclerotic plaque and may be a common finding in SCD as wel1 as non-SCD victims (32). As a general rule, acute coronary lesions tend to occur in the proximal segments of the left anterior descending and left circumflex coronary arteries and in the middle to distal segments of the right coronary artery (34). Ruptured atherosclerotic plaques are more likely to be associated with lipid-rich lesions, which are often heavily infiltrated by foam cells at the shoulder region, than with collagenous, sclerotic plaques (35). An association between acute thrombosis and SCD has long been recognized (36). In a widely cited paper published by Davies and Thomas in 1984 (37), 100 subjects who died from ischemic heart disease within 6 hours after onset of symptoms were compared with 78 subjects who had suddenly died from noncardiac causes. Postmortem coronary angiography was performed in each case, and 3-mm sections of the three major epicardial coronary arteries were examined. Of the 100 SCD victims, 44 had major (>50% reduction in crosssectional luminal area) recent thrombi. Thirty hearts had minor occlusive thrombi, and 21 showed evidente of plaque fissuring. Only 5 of the 100 subjects had no acute arterial lesions (in contrast to 70 of the 78 control cases [89.8%]). In hearts with acute thrombi, 65 % of thrombi occurred at sites of pre-existing high-grade stenoses. Several recent studies have also examined the frequency of acute lesions in SCD. In a postmortem comparison of SCD subjects with those with unstable angina pectoris and acute myocardial infarction, Kragel et al. (38) found intraluminal thrombus in 29% of SCD patients, in 29% of patients with unstable angina, and in 69 % of subjects who died from acute myocardial infarction. Evidente of plaque hemorrhage was seen in 38 % of SCD patients, compared with 64 % in the unstable angina group and 90 % in the acute myocardial infarction group. Not al1series have noted a high incidence of coronary thrombosis in SCD, even when meticulous methods are used to examine the coronary arteries. Wames and Roberts (28) reported coronary thrombi in only 13 of 70 victims of SCD (19%). Baroldi et al. (29) found thrombi in 32 of 208 SCD cases (15.3%); of these subjects, 73% died within 10 minutes, 23% within 1 hour, and 5 % within 3 hours.
ATKINSON SUDDEN CORONARY DEATH
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994: 105-115
109
Figure 5. (A) and (B) A concentric atherosclerotic lesion that has a thin fibrous tap overlies a lipid-rich, necrotic core. A fissure is present at the margin of the necrotic core (arrow), and barium pigment has extended from the lumen (L) into the intima (Movat pentachrome stain: A, x20; B, x80). (C) Photomicrographshowinga very thin fibreus tap (arrcws) over a lipid-rich atherosclerotic lesion in which there has been intraplaque hemorrhage (L = arterial lumen; Movat pentachrome stain, X100). (D) Photomicrograph showing major plaque rupture, with intraplaque thrombus confined to the necrotic core and in direct continuity with an occlusive thrombus in the arterial lumen (L; Movat pentachrome stain, x50).
Pathology of the myocardium in sudden corouary death. For the reasons already cited for variations in coronary artery pathology, the frequency of various pathological findings in the myocardium may vary as wel1 (Table 3). The incidence of healed myocardial infarction in SCD ranges from 40% to 70% (33). Depending upon how sudden death is defined, the frequency of acute myocardial infarction varies from 0% to 46 % ; the average falls somewhere around 20 % , which correlates wel1 with out-of-hospital cardiac arrest survivors (4,33). A variety of histologie changes can be noted in the myocardium of victims of SCD (Table 3). In hearts from SCD victims, Baroldi and colleagues (29,39) found coagulation necrosis in 16.8% , contraction band necrosis in 71.6 % , and myocytolysis in 8 % . Armiger and Smeeton (40) found contraction band necrosis in 75 % of SCD hearts. Interpretation of contraction band necrosis at autopsy may be confounded
by effects from attempted resuscitation as wel1as changes secondary to pressors (“catecholamine effect”) (32,41,42). The role of resuscitation in production of contraction bands has been recently questioned, however (43). Intramyocardial platelet aggregates have been noted in 30 % of hearts from SCD victims (44), and multifocal myocardial
Table 3. Pathology of the Myocardium in Sudden Coronary Death Healed myocardial infarction Acute myocardial infarction Histopathology
Cardiomegaly
40-70% 0-4696 Normal Contraction band necrosis Hypereosinophilia Wavy fibers Coagulation necrosis Up to two tbirds
110
ATKINSON SUDDEN CORONARY DEATH
necrosis was associated with over half of these cases. This has led to the suggestion that ventricular fibrillation precipitated by myocardial necrosis caused by intramyocardial thromboemboli may be an underlying mechanism of sudden death in some cases. Left ventricular enlargement tends to be greater in hearts from SCD subjects than from those with chronic coronary artery disease (14,45).
Pathophysiology of Sudden Coronary Death In 1889, prior to the invention of the electrocardiograph, John McWilliam proposed that sudden death was caused by ventricular fibrillation (46). Up until that time, it was assumed that sudden death (“cardiac failure”) was caused by a sudden cessation of the heart in diastole. In his brief paper, McWilliam proposed that the anatomie substrate for sudden death was “diseased conditions (atheromatous, calcareous, or sclerotic) of the coronary arteries” and that the precipitating cause was ventricular fibrillation. Indeed, ventricular fibrillation is thought to be the agonal rhythm in at least 75 % of patients with SCD (23). Ventricular fibrillation in patients with coronary artery disease may be secondary to acute myocardial ischemia, myocardial fibrosis, or myocardial hypertrophy. Myocardial ischemia greatly reduces the fibrillation threshold of surviving myocardium (47). Release of catecholamines in response to myocardial ischemia may directly damage the myocardium and/or lower the threshold for ventricular fibrillation (14,48,49). A variety of factors may serve as “triggers” of SCD. The incidence of SCD has a circadian variation, with a threefold increased risk during the moming and a low incidence at night (50,5 1). The increased incidence of SCD in the morning may be related to a surge in sympathetic activity that is associated with moving from a supine to upright posture and with the initiation of activity (52,53). Psychological stress has also been implicated as a potential trigger for SCD (54-57). For example, the effect of mental stress on sudden death was shown by a marked increase in the number of sudden out-of-hospital deaths in Tel Aviv during the initial period of the Gulf War in 1991 (following the first missile attack on Israel), compared with one year earlier (58). In addition, certain conditions in the myocardium may provide a substrate for SCD. Patients with ventricular hypertrophy may be at higher risk for SCD (59), and myocardial fibrosis is associated with electrical instability (60). Sudden coronary death appears to be part of the spectrum of ischemic heart disease, which includes unstable angina and acute myocardial infàrction. What determines whether any given patient wil1 develop one of these three manifestations of coronary artery disease may relate to the suddenness of onset and completeness and duration of coronary artery obstruction . Based on premortem angiography and postmortem pathologie data, it is reasonable to propose that in a high percentage of SCD cases, the rapid evolution of a coronary artery lesion, with plaque rupture (fissuring) and intraluminal
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994:105-115
Table 4. Possible Mechanisms Underlying Coronary Artery Plaque Ruuhue A. Susceptibility of the plaque 1. Lipid-rich plaques 2. Thin fibrous tap over atherosclerotic plaque 3. Abundant foam cells at ‘shoulder” region of plaque 4. Site of plaque (tethering of coronary artery to myocardium) B. “Triggers” 1. Circadian inthtences Sympathetic activity: increase in heart rate, blood flow, myocardial contractility, coronary Row, coronary tone Low fibrinolytic activity High platelet aggregability 2. Exercise 3. Bloed pressure and circumferential tensile stress 4. Vasospasm 5. Shear stress associated with coronary artery narrowing 6. Psychological factors Adapted from Falk (35).
thrombosis, leads to myocardial ischemia and fatal electrical instability of the myocardium. It should be remembered, however, that evidente of plaque rupture may not be unique to SCD and can be found in subjects with unstable angina, acute myocardial intârction, and in subjects who died Erom noncoronary causes as wel1 (32). Falk (35) has divided potential factors that predispose to plaque rupture into those that make the plaque vulnerable to rupture and possible triggers (‘lhble4). Morphologic substrates for plaque rupture may include soft, lipid-rich plaques with thin fibrous taps and abundant foam cells at the shoulder region of the lesion (where the plaque may be the weakest and where circumferential tensile stress is greatest during systole; Fig. 5) (61-66). Although most plaque ruptures occur without any obvious precipitating cause, there may nonetheless be certain triggers that could promote instability of the plaque. These include increased sympathetic activity, which can lead to increases in heart rate, blood pressure, myocardial contractility, coronary blood flow, and coronary tone (66-68). The circadian predisposition for sudden death may relate to a similar temporal pattem of acute coronary even& as thrombosis may occur preferentially in the morning when fibrinolytic activity is low and platelet aggregability is high (69,70). Surges in intraluminal blood pressure could increase the tensile stress on the fibrous tap and trigger plaque rupture (65,71). Because coronary artery thrombi may occur preferentially at sites where the coronaries branch or change direction and are tethered to the myocardial surface, the constant beating and twisting of the heart may play a role (35,72,73). Although coronary vasospasm can be provoked in patients with atherosclerotic coronary artery disease without serious complications, the common association of spasm and unstable coronary artery lesions suggests a relationship (35). Vasoactive amines released from platelets and mast cells in areas of atherosclerotic narrowing could promote abnormal vasomotion and
Cardiovasc Apri-June
Pathol Vol. 3, No. 2 1994: 105-115
ATKINSON SUDDENCORONARYDEATH
111
Figure 6. Fbstmortem angiograms. (A) Normal coronary vasculature. (B) Multiple fixed lesions (arrowheads) in right, left anterior descending, and left circumflex coronary arteries in a 62-year-old man who died suddenly. (C) and (D) Remote occlusion in right coronary artery (arrowhead) resulted in enlargement of collateral anastomoses across the interventricular septum in a 67-year-old man who died within 3 hours of onset of chest pain.
112
ATKINSON SUDDEN CORONARY DEATH
plaque ruptum (74). It is also conceivable, however, that plaque rupture and thrombosis precede vasospasm (75). Cocaine and sudden cmonary death. Cocaine has now been established as being responsible for a number of adverse effects in the coronary arteries. Cocaine can produce coronary vasospasm, either by augmentation of the sympathetic nervous system or by direct effects on vascular smooth muscie (76). Cocaine may also promote thrombosis by increasing platelet aggregability and thromboxane production and by decreasing prostacyclin release by the endothelium (77). Cocaine use has recently been noted to be associated with accelerated atherosclerosis. Virmani and colleagues and others have noted an association between cocaine and atherosclerosis in experimental animals (78) and in autopsied subjects (79-82). Excessive numbers of inílammatory cells, including mast cells, may be associated with atherosclerotic lesions in cocaine users (81), and these cells could be potent sources of vasoconstrictive agents as well as substances that could accentuate platelet aggregation and thrombosis, leading to sudden death.
Sudden Coronary Death: General Approaches for the Pathologist Sudden death may occur in the setting of significant coronary artery disease either with or without myocardial scarring, and with or without evidente of acute myocardial ischemia or acute coronary artery lesions. Although these findings are well-recognized causes of sudden death, they should be interpreted only in light of the circumstances of the terminal event and the social and medical history (27,32,83). Because the majority of patients with SCD do not manifest acute myocardial infarction, and because the distinction between coronary artery disease as a cause of death and as an incidental finding may be difficult, a careful cardiac examination and exclusion of other potential causes of death are necessary. Coronary artery disease is common in the developed world. The degree of coronary artery narrowing generally regarded as significant is >75% reduction in cross-sectional luminal area (equivalent to 50% reduction in diameter by angiography) (32,84). Pitfalls to this cutoff include whether the coronary arteries were examined after perfusion fixation at physiologic pressure, lack of assessment of actual arterial diameters, and lack of allowance made by compensatory dilatation that may occur with atherosclerosis (3285). Although criteria have varied in the literature and wil1 continue to evolve as more is learned about the mechanisms of SCD, a reasonable rule of thumb based on pre- and postmortem data that currently allows one to attribute sudden death to coronary artery disease is the presence of at least one major epicardial coronary artery with >75% reduction in cross-sectional area and exclusion of other causes of death. Individual cases may be problematic. For example, how can one assume that an atherosclerotic plaque with recent plaque fissure and hemor-
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994:105-115
rhage but without associated intraluminal thrombosis accounts unequivocally for death (32)? The answer may lie in an understanding of the dynamic nature of coronary artery disease, in which intraltinal thrombi may undergo spontaneous lysis, or in which local coronary spasm may occur in response to plaque rupture. Approaches to examination of the heart to assess coronary artery disease have been well described (14,86). The ideal method to examine the coronary arteries is by injection of a barium-gelatin mixture at physiologic pressure, fbllowed by specimen radiography (Fig. 6). Badiographs of the intact heart (before and after coronary artery injection) can be made, as wel1 as radiographs of the epicardial arteries that have been removed from the heart. Pitfalls of this technique include difficulty in visualizing the ostia and proximal arterial segments - particularly the left main coronary artery (an artery that is usually neglected by pathologists) - and dissection of contrast medium into the media because of excessively high injection pressures or disruption of the artery by tight ligatures (87). Assessment of postmortem radiographs should address the location of lesions, with correlation to premortem angiograms if available, and note the characteristics of the narrowed segments (e.g., smooth stenoses vs. those with an irregular interface, suggestive of unstable lesions) (87,888).The presence, distribution, and quant@ of collateral channels should be noted, as should recanalized channels. Artifacts (bubbles) should also be recognized (88). Following radiography, the coronary arteries can be decalcified if necessary and then sectioned at 2- to 5mm intervals. Altematively, the coronary arteries may be left on the heart and sectioned if they are not calcifìed. Areas of maximal narrowing should be noted by indicating the degree of reduction in cross-sectional area of the lumen (e.g., 0%-25 % , 26%-50%, 51%-75%, 76%-90%, 91%-99%, 100%) (86). These gross observations should be confirmed by histologie examination. In some instances, it may be necessary to submit the entire artery for microscopic examination, and there are methods for the designation of segments in a proximalto-distal orientation (87,89). Sections of al1 coronary artery segments involved grossly by thrombi should be submitted for histology to determine the origin and course of thrombogenesis. The myocardium is best examined by making transverse slices through the ventricles, parallel to the atrioventricular groove, at 0.5- to l.O-cm intervals, extending up to but not through the valve chordae (86). Individual slices can be radiographed if the coronaries have been injected with barium. Grossly visible infarcts (acute and/or remote) should be described in terms of anatomie location, extent (circumference of ventricle involved and longitudinal extent [e.g., basal, medial, and apical thirds]), and distribution within the ventricular walls (transmural or subendocardial) . Full-thickness sections should be taken from infàrcted and normal zones. If myocardial lesions are not grossly visible, full-thickness
ATKINSON SUDDENCORONARYDEATH
Cardiovasc Pathol Vol. 3, No. 2 April-June 1994:105-115
sections can be obtained in a spiral-stepwise marmer, and particular attention should be directed to myocardium in the distribution of narrowed coronary arteries (14). Techniques that identify acute infarcts of less than 24 hours’ duration (triphenyl tetrazolium chloride, nitroblue tetrazolium) may be useful(90). Although these techniques have been important in studying ischemia in experimental models, their utility may be limited in some cases when applied to humans. This may be because of the dynamic nature of the disease (i.e., occlusion of a coronary artery, followed by lysis of a thrombus and reperfusion) and by the multiplicity of preexisting disease, with variable contribution to myocardial blood flow by collateral supply.
Summary The single most common cause of sudden death in the western world is coronary artery disease. Sudden death from coronary causes occurs equally in asymptomatic patients, patients with angina, and patients with a known history of myocardial infarction. The mechanism of sudden coronary death in most patients is ventricular fibrillation secondary to ischemia. Microthrombi in intramyocardial coronary arteries may also play a role. Instability of atherosclerotic plaques, in terms of thrombosis and vasoreactivity, underlies the syndrome of unstable angina as wel1 as many cases of acute myocardial iníârction. Sudden coronary death falls within this spectrum of ischemic heart disease. Development of these syndromes depends on the abruptness of onset and the completeness and duration of coronary occlusion. Thus a rapidly evolving coronary artery lesion, with plaque fissure, rupture, and luminal thrombosis, can lead to myocardial ischemia, with fatal electrical instability of the myocardium as the first clinical manifestation. The diagnosis of sudden coronary death in the absente of myocardial infarction is determined by the degree of coronary artery narrowing and the exclusion of other causes of death . The presence of acute coronary artery lesions, which may be present in a significant number of sudden coronary death patients, lends support to the pathologie diagnosis. Thus the coronary arteries in victims of sudden coronary death may exhibit established atherosclerosis or acute lesions, whereas the myocardium may appear normal or show healed or acute infarction or hypertrophy. Although less common, nonatherosclerotic coronary artery diseases can account tbr sudden death as well, particularly in younger patients. Therefore, when sudden death occurs in children and young adults, coronary causes related to congenital anomalies, fibromuscular dysplasia, arteritis, or metabolic diseases should be considered.
References 1. Myerburg
RJ, Castellanos A. Cardiac arrest and suddert cardiac death. In: Braunwald E, ed. Heat? Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders Company, 1992:756-789.
113
2. Schatzkin A, Cupples LA, Heeren T, Morelock S, Mucatel M, Kennel WB. The epidemiology of sudden unexpected death: risk factors for men and women in the Framingham heart study. Am Heart J 1984;107:1300-1306. 3. Gillum RF. Sudden coronary Circulation 1989;79:756-765.
death in the United States, 1980-1985.
4. Reichenbach DD, Moss NS, Meyer E. Pathology of the heat? in sudden cardiac death. Am J Cardiol 1977;39:865-872. 5. Cheitlin MD, De Castro CM, McAllister HA. Sudden death as a complication of anomalous left coronary origin from the anterior sinus of Valsalva: a not-so-minor congenital anomaly. Circulation 1976;50: 780-787. 6. Barth CW, Rob& WC. Left main coronary artery originating from the right sinus of Valsalva and coursing between the aorta and pulmonary trunk. J Am Col1 Cardiol 1986;7:366-373. 7. Virmani R, Chun PKC, Goldstein RE, Robinowitz M, McAllister HA. Acute takeoffs of coronary arteries along the aortic wal1 and congenital coronary ostial valve-like ridges: association with suddert death. J Am Col1 Cardiol 1987;3:766-771. 8. Taylor AJ, Rogan KM, Virmani R. Sudden cardiac death associated with isolated congenital coronary artery anomalies. J Am Col1 Cardiol 1992;20:640-647. 9. Atkinson JB, Forman MB, Virmani R. Emboli and thrombi in coronary arteries. In: Virmani R, Forman MB, eds. Nonatherosclerotic Ischemic Heart Disease. New York: Raven Press, 1989:355-385. 10. Wenger NK, Bauer S. Coronary embolism: review of the literature and presentation of fifieen cases. Am J Med 1958;25:549-557. ll.
Virmani R, Forman MB. Coronary artery dissection. In: Virmani R, Forman MB, eds. Nonatherosclerotic Ischemic Heart Disease. New York: Raven Press, 1989:325-354.
12. Robinowitz M, Virmani R, McAllister HA. Spontaneous coronary artery dissection and eosinophilic inflammation: a cause and effect relationship? Am J Med 1982;72:923-928. 13. Ettinger RE, Nelson AM, Burke EC, Lie JT. Polyarteritis nodosa in childhood: a clinical-pathologie study. Arthritis Rheum 1979;22: 820-825. 14. Lie JT. Sudden death from diseases of the cardiovascular system. In: Silver MD, ed. Cardiovascular Patbology (2nd ed). New York: Churchill Livingstone, 1991:811-846. 15. Kegel SM, Dorsey TJ, Rowen M, Taylor WF. Cardiac death in mucocutaneous lymph node syndrome. Am J Cardiol1977;40:282-286. 16. Landing BH, Larson EJ. Are infantile periarteritis nodosa with coronary artery involvement and fatal mucocutaneous lymph node syndrome the same? Comparison of 20 patients from North America with patients from Hawaii and Japan. Pediatrics 1977;59:651-662. 17. Beuren AJ, Schulz R, Sinapius D, Stoermer J. Calcinosis of the arteries with coronary calcification in infancy. Am Heart J 1969;78:87-93. 18. James TN, Riddick L. Sudden death due to isolated acute infarction of the His bundle. J Am Col1 Cardiol 1990;15:1183-1187. 19. James TN. Morphologic characteristicsand tünctional significante of focal fibromuscular dysplasia of smal1 coronary arteries. Am J Cardiol 1990;65: 12G-22G. 20. James TN. The spectrum of disease of smal1 coronary arteries and their physiologic consequences. J Am Col1 Cardiol 1990;15:763-774. 21. Burke AP, Subramanian R, Smialek J, Virmani R. Nonatherosclerotic narrowing of the atrioventricular node artery and sudden death. J Am Col1 Cardiol 1993;21: 117-122. 22. Morales AR, Romanelli.R, Boucek IU. The mural left anterior descending coronary artery, strenuous exercise and sudden deatb. Circulation 1980;62:230-237. 23. Boucek RJ, Morales AR, Romanelli R, Judkins MP. Coronary Artery Disease: PathoIogic and Clinical Assessment. Baltimore, MD: Williams and Wilkins, 1984:201-223. 24. Ferreira
AG, Trotter SE, Konig B, Decourt LV, Fox K. Olsen EGJ.
114
ATKJNSON SUDDEN CORONARY DEATH
Myocardial bridges: J 1991;55:364-367.
morphological
Cardiovasc Pathol Vol. 3, No. 2 April-June
and functional
25. Kuller L, Cooper M, Perper J. Epidemiology Intern Med 1972;129:714-719.
aspects.
Br Heart
of sudden death. Arch
26. Perper JA, Kuller LH, Cooper M. Arteriosclerosis of coronary arteries in sudden unexpected deaths. Circulation 1975; 52(Suppl BI): BI-27-111-33. 27. Davies MJ. Pathological 1981;45:88-96.
view of sudden cardiac
death. Br Heart J
28. Wames CA, Roberts WC. Sudden coronary death: comparison of patients with to those without coronary thrombus at necropsy.Am J Cardiol 1984;54:1206-1211. 29. Baroldi G, Falxi G, Mariani F. Sudden coronary death: a postmortem study in 208 selected cases compared to 97 “control” subjects. Am Heart J 1979;98:20-31. 30. Rissanen V. Gccurrence of coronary ostial stenosis in a necropsy series of myocanhal infarction, sudden death, and violent deatb. Br Heart J 1975;37:182-191. 31. Baroldi G, Scomaxxoni G. Coronary Circulation in the Normal and the Pathologie Heart. Washington, DC: American Registry of Pathology, Armed Forces Institute of Pathology, 1962. 32. Davies MJ. Anatomie features in victims of sudden coronary death: coronary artery patbology. Circulation 1992;85(Suppl I):I-19-1-24. 33. Virmani R, Roberts WC. Sudden cardiac deatb. In: Virmani R, Atkinson JB, Fenoglio JJ, eds. Cardiovascular Pathology. Philadelphia: WB Saunders Company, 1991:134-151. 34. Liberthson RR, Nagel EL, Hirschman JC, Nussenfeld SR, Blackbomne BD, Davis JH. Pathophysiologic observations in prehospital ventricular fibrillation and sudden cardiac death. Circulation 1974;49:790-798. 35. Falk E. Why do plaques BI-30-lII-42.
rupture?
Circulation
1992; 86(Suppl
111):
36. Crawford T, Dexter D, Teare RD. Coronary artery pathology in sudden death from myocardial ischemia. Lancet 1961;1:181-185. lesions 37. Davies MJ, Thomas A. Thrombosis and acute coronary-artery in sudden cardiac ischemic death. N Eng1 J Med 1984;310: 1137-1140. 38. Kragel AH, Gertz SD, Roberts WC. Morphologic comparison of frequency and types of acute lesions in tbe major epicardial coronary arteries in unstable angina pectoris, sudden coronary deatb and acute myocardial infarction. J Am Col1 Cardiol 1991;18:801-808. 39. Baroldi G. Pathology and mechanisms of sudden death. In: Hurst JW, ed. The Heart. New York: McGraw-Hill, 1982:589-599. necrosis: pattems of 40. Armiger LC, Smeeton WMI. Contraction-band distribution in the myocardium and their diagnostic usefulness in sudden cardiac death. Pathology 1986;18:289-295. 41. ROM G, Chappel CI, Balaxs T, Gaudry R. An infarct-like myocardial lesion and other toxic manifestations produced by isoporoterenol in the rat. Arch Pathol 1959;67:443-455. 42. ROM G. Catecholamine 17:291-306.
cardiotoxicity.
J Mol Cel1 Cardiol
1985;
43. Teraoka K, Kaneko N, Takeishi M. Clinical and pathologie studies on contraction band lesions: relation to acute myocardial infarction and unexplained sudden death. Mod Pathol 1991;4:6-12. 44. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986;73:418-427. 45. Haerem JW. Myocardial lesions in sudden unexpected coronary death. Am Heart J 1975;90:562-568. 46. McWilliam JA. Cardiac failure and sudden death. Br Med J 1889; 16-8. 47. Shumway NE, Johnson JA, Stish RJ. The study of ventricular fibrillation by threshold determinations. J Thorac Surg 1957;34:643-653. 48. McManus BM, Fleury TA, Roberts WC. Fatal catecholamine crisis in pheochromocytoma: curable cause of cardiac arrest. Am Heart J 1981;102:930-932. 49. Imperato-McGinley
J, Gautier T, Ehlers K, Zullo MA, Goldstein DS,
1994:105-115
Vaughan ED Jr. Reversibility of catecholamine-induced dilated cardiomyopathy in a child with a pheochromocytoma. N Eng1 J Med 1987;316:793-797. 50. Muller JE, Ludmer PL, Willich SN, et al. Circadian variation in the frequency of sudden cardiac death. Circulation 1987;75: 131-138. 51. Willich SN, Levy D, Rocco MB, Tofler GH, Stone PH, Muller JE. Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardioll987;60:801-806. 52. Brezinski DA, Tofler GH, Muller JE et al. Moming increase in platelet aggregability: association with assumption of the upright posture. Circulation 1988;78:35-40. 53. Willich SN, Maclure M, Mittleman M, Arntz HR, Muller JE. Sudden cardiac death: support for a role of triggering in causation. Circulation 1993;87:1442-1450. 54. Eliot RS, Buell JC. Role of emotions and stress in the genesis of sudden death. J Am Col1 Cardiol 1985;5(Suppl):95B_98B. 55. Wennerblom B, Holmberg S. Death outside hospital with special reference to heart disease. Eur Heart J 1984;5:266-274. 56. De Silva RA. Psychological stress and sudden cardiac death. In: Schmidt TH, Dembrowski TM, Blumchen G, eds. Biological and Psychological Factors in Cardiovascular Disease. Berlin: Springer-Verlag, 1986:155-183. 57. Cottington EM, Matthews KA, Talbott E, Kuller LH. Environmental events preceding sudden death in women. Psychosom Med 1980; 42~567-574. 58. Meisel SR, Kutx 1, Dayan KI, et al. Effect of Iraqi missile war on incidence on acute myoc&ial infarction and stalden de& in Israeli civilians. Lancet 1991;338:660-661. 59. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Eng1 J Med 1990;322: 1561-1566. 60. Myerburg RJ, Epstein K, Gaide MS, et al. Electrophysiologic consequences of experimental acute ischemia superimposed on healed myocardial infarction in Cats. Am J Cardiol 1982;49:323-330. 61. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardia1 infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985;53:363-373. 62. Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesbro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988;77: 1213-1220. 63. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The patbogenesis of coronary artery disease and the acute coronary syndromes: part 1 and 2. N Eng1 J Med 1992;326:242-250, 310-318. 64. Falk E. Morphologic features of unstable atherothrombotic plaque underlying acute coronary syndromes. Am J Cardioll989;63: 114E-120E. 65. Richardson PD, Davies MJ, Bom GVR. IntIuence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989;2:941-944. 66. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989;79:733-743. 67. Tofler GH, Stone PH, Maclure M, et al. Analysis of possible triggers of acute myocardial infarction (the MILIS Study). Am J Cardiol 1990;66:22-27. 68. Stone PH. Triggers of transient myocardial ischemia: circadian variation and relation to plaque rupture and coronary thrombosis in stable coronary artery disease. Am J Cardiol 1990;66:326-36G. 69. Andreotti F, Davies GJ, Hackett DR, et al. Major circadian fluctuations in fibrinolytic factors and possible relevante to time of onset of myocardial infarction, sudden cardiac death and stroke. Am J Cardiol 1988;62:635-637. 70. Rosing DR, Brakman P, Redwood DR. et al. Blood fibrinolytic activity in man: diurnal variation and the response to varying intensities of exercise. Circ Res 1970;27:171-184. 71. Davies MJ. A macro and micro view of coronary ischemic hcart disease. Circulation 1990;82(Suppl
vascular insult in II):II-38-11-46.
ATKINSON SUDDENCORONARYDEATH
Cardiovasc Pathol Vol. 3, No. 2 Apri-lune
19!34:105-115
12. Chapman 1. The initiating cause of coronaty artery thrombosis: tomic study. J Mt Sinai Hosp 1969;36:361-374.
an ana-
13. El Fawal MA, Berg GA, Wheatley DJ, Harland WA. Sudden coronary deatb in Glasgow: nature and frequency of acute coronary lesions. Br Heart J 1987;57:329-335. 14. Forman MB, Oates JA, Robertson D, Robertson RM, Roberts LJ, 11, Virmani R. Increased adventitial mast cells in a patient witb coronary spasm. N Eng1 J Med 1985;313:1138-1141. 75. Golino P, Ashton JH, Buja LM, et al. Local platelet activation causes vasoconstriction of large epicardial canine coronary arteries in vivo: thromboxane A2 and serotonin are possible mediators. Circulation 1989;79:154-166.
115
crease in atherosclerosis and adventitial mast cells in cocaine abusers: an altemative mechanism of cocaine-associated vasospasm and tbrombosis. J Am Col1 Cardiol 1991;17:1553-1560. 82. Kolodgie FD, Virmani R, Comhill JF, Herderick EE, Malcom GT, Mergner WJ. Cocaine: an independent risk factor of aortic sudanophilia. A preliminary report. Atherosclerosis 1992;97:53-62. 83. Davis JH, Wright RK. The very sudden cardiac deatb syndrome-a conceptual model for pathologists. Hum Pathol 1980; 11: 117- 12 1. 84. Arnett EN, Isner JM, Redwood DR, et al. Coronary artery narrowing in coronary heart disease: comparison of cineangiographic and necropsy findings. Ann Intern Med 1979;91:350-356.
76. Kloner RA, Hale S, Alker K, Rezkalla S. The effects of acute and chronic cocaine use on the heart. Circulation 1992;85:407-419.
85. Glagov S, Weisenberg E, Zaims CK, Stankunavicius Compensatory enlargement of human atherosclerotic ies. N Eng1 J Med 1987;316:1371-1375.
17. Togna G, Tempesta E, Togna AR, Dolci N, Cebo B, Caprino L. Platelet responsiveness and biosynthesis of thromboxane and protacyclin in response to in vitro cocaine treatment. Haemostasis 1985; 15: 100-107.
86. Virmani R, Ursell PC, Fenoglio JJ. Examination of the heart. In: Virmani R, Atkinson JB, Fenoglio JJ, eds. Cardiovascular Pathology. Philadelphia: WB Saunders Company, 1991: 1-20.
78. Kolodgie FD, Virmani R, Rite HE, Herderick EE, Mergner WJ. Intravenous cocaine accelerates atherosclerosis in cholesterol-fed New Zealand White rabbits (abstract). J Am Col1 Cardiol 1990;15:217A.
87. Thomas AC, Davies MJ. Post-mortem investigation and quantification of coronary artery disease. Histopathology 1985;9:959-976.
79. Virmani R, Robinowitz M, Smialek JE, Smyth DF. Cardiovascular effects of cocaine: an autopsy study of 40 patients. Am Heart J 1988; 115: 1068-1076. 80. Dressler FA, Malekzadeh S, Roberts WC. Quantitative analysis of amounts of coronary arterial narrowing in cocaine addicts. Am J Cardiol 1990;65:303-308. 81. Kolodgie FD, Virmani R, Comhill JH, Herderick
EE, Smialek J. In-
R, Kolettis GJ. coronary arter-
88. Thomas AC, Pazios S. The postmortem detection of coronary artery lesions using coronary arteriography. Pathology 1992;24:5-11. 89. Fulton WFM. The Coronary Arteries: Arteriography, Microanatomy, and Pathogenesis of Obliterative Coronary Artery Disease. Springfield, IL: Charles C. Thomas, 1965. 90. Schoen FJ. Interventional and Surgical Cardiovascular Philadelphia: WB Saunders Company, 1989;369-396.
Pathology.
