Solymar
74. 75. 76.
77. 78.
et al.
American
surgical treatment of aortic and mitral insufficiency. Angiology 1956;7:446-71. Ross DN. Homograft replacement of aortic valve. Lancet 1962;2:487. Barratt-Boyes BG. Homograft aortic valve replacement in aortic incompetence and stenosis. Thorax 1964;19:131-50. Merrill WH, deLeva1 MR, Ball C, Macartney FJ, Taylor FFN, Stark J. Homograft prosthetic heart valves. In: Dunn JM, ed. Cardiac valve disease in children, New York: Elsevier, 1988: 436-58. Stancel’ HC, Nude1 DB, Berman MA, Talner NS. Prosthetic valve renlacement in children. Arch Sum 1975:110:1397-400. Weinstein GS, Mavroudis C, Ebert PA.-Preliminary experi-
79. 80.
81.
82.
February 1991 Heart Journal
ence with aspirin for anticoagulation in children with prosthetic cardiac valves. Ann Thorac Surg 1982;33:549-53.Edmunds LH Jr. Thrombotic and bleeding complications of prosthetic heart valves. Ann Thorac Surg 1987;44:430-45. Bradley LM, Midgley FM, Watson DC, Getson PR, Scott LP III. Anticoagulation therapy in children with mechanical prosthetic cardiac valves. Am J Cardiol 1985;56:533-5. Stewart S, Cianciotta D, Alexson C, Manning J. The long-term risk of warfarin sodium therapy and the incidence of thromboembolism in children after prosthetic cardiac valve replacement. J Thorac Cardiovasc Sure: 1987:93:551-4. Woods A, Vargas J, Berri G, et al. Antithrombotic therapy in children and adolescents. Thromb Res 1986;42:289-301.
Sports-related and non-sports-related cardiac death in young adults
sudden
Allen P. Burke, Maj, USAF, Andrew Farb, MD, Renu Virmani, MD, Julia Goodin, MD, and John E. Smialek, MD. Baltimore, A4d.
As many as 50% of cardiovascular deaths in the United States are classified as sudden.l Because of the high prevalence of cardiovascular disease in this country, there is tremendous interest in the causes, epidemiology, and pathology of sudden cardiac death. The preoccupation with sports and exercise among large numbers of Americans has resulted in many reports of exercise-related sudden death.2-15 Most epidemiologic studies have shown that persistent exercise decreases the risk of sudden cardiac death in the long term16-2” but may increase this risk during and immediately after exertion.23 Autopsies performed on conditioned athletes who died during excercise have demonstrated a high prevalence of hypertrophic cardiomyopathy and
From the Department of Cardiovascular Pathology, Armed of Pathology, Washington, D.C., and the Office of the Chief iner, Baltimore, Maryland
Forces Institute Medical Exam-
The opinions or assertions contained herein are the private views of the authors and are not to he construed as official or reflecting the views of the Department of the Army, the Department of the Air Force, or the Department of Defense. Received Reprint thology, 6000.
4/l/25910 568
for publication requests: Armed
Allen Forces
June P. Burke, Institute
7, 1990;
accepted
July
23. 1990.
MD, Department of Cardiovascular of Pathology, Washington, D.C.
Pa20306.
anomalous coronary arteries in younger persons,* whereas most individuals over the age of 35 have severe coronary atherosclerosis.3* l”-15, 24 The relative frequencies of the pathologic findings in sportsrelated cardiac death are important to clinicians, who must prescribe exercise regimens for their patients who have underlying cardiac disease. In addition, these data may be helpful in designing screening programs to minimize the frequency of exerciseassociated cardiac mortality. The purpose of this study is to compare exercise and nonexercise-related sudden deaths in a defined population to demonstrate which conditions are preferentially seen in exercising inviduals. METHODOLOGY
The Office of the Chief Medical Examiner investigates all accidental, homicidal, suicidal, and unexplained or unexpected deaths in the state of Maryland. The files from the years 1981 through 1988, inclusive, were examined by two of us (Maj. Burke and Dr. Farb), and all cases of natural, unexpected cardiac death were retrospectively identified. The files contain a brief history recorded by site investigators as well as a cause of death determined at au*References
3-5, 15, 16, 24, 25.
Volume Number
121 2, Part
Sports
1
topsy. Cases were restricted to individuals between the ages of 14 and 40 years, because most exerciserelated deaths occurred in this age range and because complete autopsies were often not performed in cases of natural death of older individuals. Data on race, age, sex, and cause of death were recorded for all patients, in addition to cardiac findings. Unexpected cardiac death was defined as any case in which symptoms, if any were documented, lasted less than 24 hours and in which no other pathologic abnormality was found that could possibly lead to death. As part of an ongoing consultation service, the Armed Forces Institute of Pathology (AFIP) reviews the gross material on selected cardiac cases from the Office of the Chief Medical Examiner. These cases are maintained on file at the AFIP, and this material was available for restudy. Exercise-related sudden cardiac deaths were considered separately; these were defined as deaths with symptoms that occurred during a sport-related activity or within 1 hour of engaging in a sport-related activity with death occurring within 24 hours of onset of symptoms. Cardiac hypertrophy was defined with populationbased criteria for normal cardiac weights.26> 27 Cardiac hypertrophy, in the absence of other abnormalities (e.g., valvular, ischemic, or congenital heart disease) was divided into three main categories. (1) Hypertrophic cardiomyopathy was defined by the presence of assymmetric septal hypertrohpy that was more than 1.3 times the thickness of the left ventricular free wall, as well as by microscopic fibromuscular disarray that involved a significant portion of the interventricular septum. (2) Concentric idiopathic hypertrophy was defined by concentric left ventricular hypertrophy without ventricular dilatation, fibromuscular disarray, or a history of hypertension. (3) Concentric idiopathic hypertrophy with systemic hypertension required a clinical diagnosis of hypertension. Severe atherosclerosis was defined as one or more major coronary arteries narrowed by greater than 75% cross-sectional luminal area. The diagnosis of mitral valve prolapse was made on the basis of the elongation of the anterior or posterior leaflet with hooding and focal thickening of leaflets.28 Right ventricular dysplasia was diagnosed when there was either marked thinning, absence of right ventricular muscle, and/or fibrosis with fatty infiltration admixed with myocytes. 2g Myocarditis was diagnosed by the presence of lymphocytic infiltrate accompanied by myocyte necrosis as defined by the Dallas criteria.30 In cases of unexplained sudden death with negative toxicology and a lack of significant autopsy
Table
and
sudden
1. Causes of death, sports-versus Sportsrelated
n Age (yr, mean) Sex Male Female Race White Black Asian Cause of death Severe atherosclerosis (CHD) Hypertrophic cardiomyopathy Idiopathic LV hypertrophy Unknown (tunnel) Anomalous coronary artery Myocarditis Right ventricular dysplasia SH with LV hypertrophy Aortic dissection Cardiac sarcoidosis Aortic stenosis Floppy mitral valve Other
cardiac
death
569
non-sports-related Non-sportsrelated
34 (5%,) 26
656 (9tXro) 32
31 (91%) 3 (9%)
501 (76Y) 155 (24’-(7)
19 (56%) 15 (44%)
368 (56”;‘) 281 (43%) 7 (1%) n Percent 307 47t
n Percent 9 26 8
24*
20
3.0
3
9
42
6.4
6(2) 4
18 12
104(7) 8
16 1.2
2 1
6 3
31 0
4.5 0
0
0
31
4.7
0 0 0 0 1
0 0 0 0 3
17 13
2.6 2.0
12 11
1.8
60
1.7 9.1
CHD, Coronary heart disease; LV, left ventricular; SH, systemic hypertension. *Statistically significant increase wer total and age- and sex-matched control whites. tStatistically significant increase over total blacks, but not with age- and sex-matched controls. Other differences were not statistically significant.
findings, the cause of death was attributed to unknown cardiac factors; conduction systems were not routinely examined in these cases. Each exercise-related death was randomly matched with three nonexercise-related deaths, by age (within 2 years), sex, and race. The randomness of the distribution of cause of death in the exercise versus nonexercise groups was compared by the chi square statistic. The mean age of each group of exercise-related death was compared by the unpaired Student’s t test. OBSERVATIONS
There were 34 cases of exercise-related sudden cardiac death that were identified in the study period, and 656 cases of nonexercise-related sudden cardiac death, which represents a 5% incidence of sports activity (Tables I and II).
570
Burke
et al.
Table
11. Cause
American
of death
by race: Nonexercise-related Mean
Cause
of death
Total Severe atherosclerosis Hypertrophic CM No diagnosis Dilated CM SH with LV hypertrophy Idio LV hypertrophy Myocarditis Chronic rheumatic disease Aortic stenosis Anomalous artery Tunnel artery Dissecting aorta Sarcoid CM, cardiomyopathy; *Indicates statistically
idio, idiopathic; other significant increased
White
sudden
cardiac
age
death n
Black
February 1991 Heart Journal
Percent
White
Black
White
Black
368 206* 11 50 12 I
281 100
57 56* 3 14 3 2
43 36 3 15 5 9*
p Value
32 35 32 26 33 33
31 34 29 29 31 31
28 26 34
30 27 29
19 14 1
23 16 7*
5 4 0.3
8 6 2
0.16 0.34 0.0137
35 35 34
28 21 24
7 5 2
5 3 4
2 0.5
2 1 1
0.86 0.98 0.22
29 30
30 32
12
5 12*
3 0.3
2 4*
0.36 0.0003
abbreviations likelihood
as in Table I. of this cause of death
9 43 14 24*
1
to complementary
group
(black
0.000001 0.9 0.6 0.36 0.00018
vs white)
Sports-related deaths. The average age of these 34 individuals was 26. Fifteen were black, and 19 were white; all but three were men. The hearts of 30 of these 34 cases were reviewed at the AFIP. They are grouped below by cause of death.
filtrates that accompanied myocyte necrosis. The heart weights ranged from 420 to 940 gm (mean 543 gm). There was no history of syncope or a known family history of cardiac problems in any of the eight individuals.
Severe atherosclerosis (nine cases, mean age 32).
Anomalous coronary artery (four cases, mean age 21). All four subjects were men; three died while
All hearts had one or more major coronary arteries with equal to or greater than 75% cross-sectional narrowing of the lumen by atherosclerotic plaque. Five individuals were runners; one each died while engaging in football, baseball, swimming, and aerobics. Four had healed infarcts, and one had an additional acute infarct. One had a clinical history of myocardial infarct. The race distribution was eight whites and one black. Five subjects had three-vessel disease (greater than 75 % narrowing of left anterior descending, left circumflex, and right coronary arteries), and four had single-vessel disease that involved the left coronary artery system (two patients) or right coronary artery (two patients). The average heart weight was 440 gm. Hypertrophic cardiomyopathy (eight cases, mean age 24). Seven men died while playing basketball; one
woman died while swimming. The racial distribution was six blacks and two whites. The septal thickness ranged from 2.1 to 2.9 cm, and the septal-free wall ratio ranged from 1.3 to 1.7 (mean 1.5). A prominent left ventricular outflow tract plaque was present in four cases, and a thickened anterior leaflet of the mitral valve was seen in four. Myofiber disarray was present as determined microscopically in all cases and was diffuse in two. One heart showed microscopic evidence of myocarditis as well, with lymphocytic in-
playing basketball, and one died while playing soccer. Two cases involved the right coronary artery arising in the left sinus of Valsalva; one case involved the left coronary artery arising in the right sinus; and one subject had hypoplastic coronary arteries, with absence of posterior descending artery and focal subendocardial fibrosis of the posterior left ventricular wall. One individual had a history of cocaine use, but postmortem toxicology was negative for cocaine. The hearts were enlarged for the age and weight of the patients and ranged in weight from 380 to 520 gm. Idiopathic concentric left ventricular hypertrophy (three cases, mean age 25). All three were men,
who engaged in basketball, running, and aerobics and who had heart weights of 480, 525, and 600 gm, respectively. In one case there was evidence of biventricular dilatation and microscopic myocyte hypertrophy. The others had left ventricular hypertrophy and a wall thickness up to 2 cm without asymmetry or myofiber disarray as determined microscopically. Two had muscular tunnels of the left anterior descending coronary artery, each 1 cm long and up to 3 mm deep. Myocarditis (two cases, ages 14 and 35). These were men who died while swimming and running, respectively. Heart weights and coronary arteries were
Volume Number
121 2, Part
Sports and sudden cardiac death
1
50
-
40
1 -
m i\l D
2 ;5 -s -6 z
30
2 z t CL
20
10
0 atherosclerosis
I,
hypertrophic cardiomyopathy
Fia. 1. Comnarison of snorts-related versus non-sports-related diomyopathy, and anomalous coronary arteries.
normal. myocyte filtrate. elicited
The only necrosis A history in either
abnormality was focal microscopic associated with a lymphocytic inof fever or flu-like illness was not case.
Right ventricular
dysplasia (one case, age 24).
This man died while playing baseball; his heart weighed 450 gm. The right ventricular walls were markedly thin, and the right ventricular cavity was dilated. Microscopic examination demonstrated both fibrous and fatty infiltration among muscle fibers and a focal lack myocardium between epicardium and endocardium. There was a family history of sudden death; the mother had died suddenly. Kawasaki disease (one case, age 17). This patient, a boy who was playing basketball, had a nondocumented history of a Kawasaki-like illness during childhood. The heart, at autopsy, weighed 400 gm and demonstrated an aneurysm in the proximal right coronary artery that measured 1.3 cm in diameter and 1 cm in length and an aneurysm in the left anterior descending artery that measured 1.5 cm in diameter and 2.3 cm in length. In addition, sectioning revealed a healed transmural posteroseptal infarction. Histologically, there was a mixed chronic inflammatory infiltrate in the wall of the affected vessels. Normal (six cases, mean age 24). All patients were male; sporting activities at the time of death were basketball (two), running (two), swimming (one), and football (one). Heart weights ranged from 340 to 480 gm; all were within normal limits for the total body weight. One heart had a 1.5 cm long, 3 mm deep muscular tunnel of the left anterior descending
57 1
exercise related non-exercise related non-exercise related age-sex-race matched controls
anomalous coronary
arteries
deaths (atherosclerosis,
hypertrophic
car-
artery; one had a 3 cm long, 2 mm deep tunnel of the left anterior descending artery; two hearts had histologic evidence of fibromuscular intimal proliferation of the artery to the conduction system; and one had an abnormal insertion of chordae tendineae of the mitral valve over a widened papillary muscle. Among sports-related deaths, the mean age of patients with severe atherosclerosis was higher than that of patients with hypertrophic cardiomyopathy (p = 0.03). The mean age of the group with severe atherosclerosis (32 years) was higher than that with anomalous coronary arteries (21 years); this difference was not statistically significant (p = 0.09), probably because of small number of cases. Non-sports-related sudden cardiac deaths. Of these 656 individuals, the mean age was 32; 501 were male, 155 female; 368 were white, 281 black, and 7 Oriental. Of the total 656 cases, 207 (32%) were reviewed at the AFIP. The cause of death was severe atherosclerosis in 307; 77 of these were subsequently reviewed and diagnosis was confirmed at the AFIP. In the remainder of cases, the causes of death were as follows (numbers in parentheses indicate the number of cases reviewed at the AFIP): anomalous coronary artery 8 (2); aortic valve stenosis 12 (5); congenital heart disease 10 (8); dilated cardiomyopathy 26 (11); aortic dissection 17 (12); endocarditis 10 (7); floppy mitral valve 11 (9) concentric left ventricular hypertrophy with a known history of systemic hypertension 31 (9); idiopathic concentric left ventricular hypertrophy 42 (12); hypertrophic cardiomyopathy with asymmetry 20 (8); myocarditis 30 (8); no pathologic abnormality 104 (19); chronic rheumatic heart
Burke et al.
572
American
Table III. Exercise-related sports Cause of death (n)
deaths:
of race/
Black
White
Sport
1
9
6
2
2
2
6
7
Running (5) Other (4) Basketball (7) Swimming (1) Basketball (2) Baseball (1) Soccer (1) Basketball (5) Running (4) Other (4)
Severe atherosclerosis (9) Hypertrophic cardiomyopathy (8) Anomalous coronary arteries (4) Others
Distribution
(13)
disease 8 (6); cardiac sarcoidosis 13 (8); amyloidosis 1 (1) spontaneous coronary artery dissection 2 (2); chronic constrictive fibrous pericarditis 1 (1); congenital coronary artery aneurysms 1 (1); and lipomatous hypertrophy of the atria1 septum 1 (1). In seven of the 104 hearts without abnormality, a tunnel of the left anterior descending artery was present and measured at least 1 cm in length for a depth of at least 1 mm. The large percentage of normal hearts (16 % ) may, in part, be due to occult abnormalities of the conduction system, for which tests were not routinely performed. In addition, all cases of unexplained sudden death, in the absence of cardiac, toxicologic, and other anatomic abnormalities, were attributed to cardiac events, which perhaps further inflated this percentage. Comparison deaths (Fig.
of
sports
versus
non-sports-related
1) Hypertrophic cardiomyopathy was more likely found in sports-related (8 of 34) than in non-sports-related deaths (20 of 656), p = 0.000019. This trend was also significant with age-, sex-, and race-matched controls (3 of 102, p = 0.0007). Anomalous coronary arteries were more often seen in sports-related deaths: 4 of 34 versus 8 of 656 (total non-sports-related deaths, p = 0.002); however, the difference was only of borderline statistical significance with age-, sex-, and race-matched controls (3 of 102, p = 0.06). Severe atherosclerosis was more likely found in total non-sports-related deaths (307 of 656 vs 9 of 34), but with age-, sex-, and race-matched controls, the ratios were similar (30 of 102, or 29 % , vs 9 of 34, or 26 % , p = 0.46). There were no statistically significant differences in the ratios of other causes of death, for total or age-, sex-, and racerelated deaths. Among individuals with no other cardiac abnormality, tunnels were more likely to be found in exercise-related deaths (2 of 6), compared with total non-exercise-related deaths (7 of 97); but the difference did not reach statistical significance (p = 0.07).
February 1991 Heart Journal
Racial and sex differences (Table III). Amongsportsrelated deaths, blacks were more likely to die of hypertrophic cardiomyopathy 0, = 0.05), and whites were more likely to die of severe atherosclerosis (p = 0.02). The mean age of blacks was 23.5 years, compared with 27.2 years for whites. Among non-sports-related deaths, blacks were less likely to die of severe atherosclerosis than whites (p = O.OOOOOl), in spite of a nearly identical mean age. Blacks were more likely to die of cardiac sarcoidosis (p = 0.0003) and systemic hypertension with left ventricular hypertrophy (p = 0.0002). The black/ white difference was greatest for sarcoidosis (13:1), followed by systemic hypertension with concentric left ventricular hypertrophy (2.6:1), and severe atherosclerosis (1.6:l). There was no statistically significant difference for other causes of death. Women were less likely to die of severe atherosclerosis 03 = 0.000004) than men (female/male ratio 057:l). COMMENTS
Our 5% rate of sudden cardiac death related to sports activity is similar to that of data from other U.S. populations.3 It is important to note that differing definitions of sudden cardiac death1 will greatly influence incidence statistics. Although it is well established that hypertrophic cardiomyopathy is a common cause of sudden cardiac death in athletes under the age of 30,3-5 it has been difficult to prove that this condition predisposes individuals to sudden cardiac death during excercise. We have studied all sudden cardiac deaths in a defined population and compared those that occurred during excercise to other deaths that were matched for sex, age, and race. Because a significantly higher proportion of sudden cardiac deaths occurred in patients with hypertrophic cardiomyopathy in the exercise group, we conclude that there is indeed an increased likelihood for patients with hypertrophic cardiomyopathy to experience sudden cardiac death during exercise. Our findings support and augment those of Sugishita et a1.31 who reported a far higher incidence of sudden cardiac death during exercise in patients with hypertrophic cardiomyopathy compared with a group of non-exercising patients who experienced sudden cardiac death who were not age-matched. Interestingly, in our study, blacks who died during exercise had a greater incidence of hypertrophic cardiomyopathy than whites and were younger, whereas the incidence of hypertrophic cardiomyopathy was similar in sedentary blacks and whites. Our site investigations did not reveal a family history of premature sudden cardiac death or of dyspnea, syncope, or angina in any of the eight patients in
Volume Number
121 2, Part
1
our study who died during exercise. Sudden cardiac death may be the first manifestations of hypertrophic cardiomyopathy,32 even though previous symptoms increase the likelihood of sudden cardiac death.33 Because the total number of individuals who participate in sport-related activities is large, comprehensive screening programs are not likely to be cost-effective. However, screening of athletes who undergo extensive training may be a reasonable alternative, although the definition of “competitive athlete” varies.4, 5 Long-term exercise itself may result in left ventricular hypertrophy, especially in athletes who engage in weight lifting. 34-37Therefore it is possible that in previously normal individuals, hypertrophic cardiomyopathy may be induced by exercise itself. A screening examination performed before the initiation of an exercise program would thus fail to identify athletes who subsequently develop cardiac hypertrophy. However, those with asymmetric hypertrophy would likely comprise an extremely small group of persons, since the few published autopsy studies,38 as well as short-term echocardiographic studies on living athletes,34 do not demonstrate a propensity for asymmetric hypertrophy among athletes. In addition, up to 60 % of casesof hypertrophic cardiomyopathy3” are familial, which indicates that most cases are not acquired. Idiopathic concentric left ventricular hypertrophy was present in nearly 10% of all cases of sudden death in our study; there were no significant differences between the exercise-related and non-exerciserelated groups. Whether left ventricular hypertrophy in athletes predisposes them to cardiac arrhythmias and sudden cardiac death remains controversial.3g, 4o It does not appear from our data that idiopathic concentric hypertrophy predisposes individuals to exercise-related death. Because aerobic exercise itself results in left ventricular dilatation and mild cardiac hypertrophy, it is likely that the cause of sudden cardiac death in some of the our casesof idiopathic concentric left ventricular hypertrophy was occult and may not be related to hypertrophy alone. Anomalous coronary arteries are a well known cause of sudden cardiac death41-44and are found relatively more frequently in young individuals who die during exercise.3, E Because of the small number of cases with these anomalies (4 of 36 sudden cardiac deaths with exercise, vs 8 of 656 sudden cardiac deaths at rest), we were unable to show a statistically significant increase in the proportion of our patients with anomalous coronary arteries who died during exercise over age-, race-, and sex-matched controls who died at rest, inspite of a trend. Although right ventricular dysplasia has been
Sports and sudden cardiac death
573
stated to be a major cause of exercise-related death,45 we demonstrated this abnormality in only one of our cases of sudden cardiac death that occurred doing exercise. Since fat accumulation is common in the anterior portion of the right ventricle in normal hearts, we were rigorous in our definition of right ventricular dysplasia, to include only those casesthat demonstrated apposition of endocardium and epicardium with a lack of intervening myocytes in the presence or absence of fibrosis. The prevalence of severe atherosclerosis was higher in the non-exercising group as a whole, which was most likely explained by the higher average age of non-exercisers versus exercisers. When age-, sex-, and race-matched individuals were compared, the proportions were almost identical. Although it is tempting to speculate that this is evidence for the lack of protective effects of exercise against severe atherosclerosis, we did not document a lifetime lack of exercise in individuals who died sedentary cardiac death or a persistent long-term record of exercise regimens of the individuals who died during sports. It does support the fact, however, that exercise does not have a protective effect in the short term against sudden cardiac death that is secondary to severe atherosclerosis, as has been suggested by other studies that have shown primarily a long-term benefit 2~23 Among sports-related deaths, the mean age of the patients with severe atherosclerosis was statistically significantly higher than those who died of hypertrophic cardiomyopathy, which supports the findings of other investigators. 3,I5 These same investigators have shown that the mean age of patients with anomalous coronary arteries who died suddenly is also lessthan that of the severe atherosclerotis group; this difference was not significant in our data, probably because of small sample size and age limitation of 40 years. The debate concerning the significance of tunnel coronary arteries (intramural arteries, myocardial bridges) in patients who experienced sudden cardiac death during exercises remains unresolved because of the high prevalence of this finding in normal individuals and the varied degrees of severity. Our data demonstrate a trend that tunnels may be more prevalent in persons who die during exercise than in those who die at rest, but this needs further investigation. The mechanism of sudden cardiac death in patients with this abnormality is attributed to systolic contraction of the left anterior descending artery with resultant myocardial ischemia.8 We did not find any evidence of tunnel arteries in our cases of exerciserelated sudden cardiac death with hypertrophic cardiomyopathy, although two casesof concentric idio-
574
Burke et al.
pathic hypertrophy had this finding. The possible role of intramural coronary arteries has been questioned in casesof idiopathic cardiac hypertrophy and sudden cardiac death46; our data seem to indicate that it is not important in at least hypertrophy with asymmetry. The fibromuscular intimal and medial proliferation (dysplasia) of the atrioventricular nodal artery in two otherwise normal hearts from persons who died during exercise in our study is of uncertain significance. It has been described in traumatic deaths and presumed to be of no clinical significance47 but has also been described in athletes who died suddenly.2, 4RFurther studies that compare hearts from sudden cardiac deaths with hearts from noncardiac deaths are required before the significance of dysplastic intracoronary arteries can be established. To our knowledge, ours is the first report of a patient with probable Kawasaki diseaseto die suddenly during exercise. Because a firm clinical history was lacking in this patient, the clinical criteria for diagnosis could not be fulfilled.4g However, the lack of vasculitis elsewhere and the multiplicity of coronary aneurysms is strongly suggestive of Kawasaki disease. The percentage of patients with Kawasaki disease who present later in adulthood with occult coronary arterial aneurysms is unknown,4g but it is not surprising that exercise-related ischemic events may occur in these individuals. Our study is limited because it is retrospective, and we do not know the percentage of individuals who exercise in our population. We also lack a detailed history of the extent and duration of our exercising individuals, as well as a lack of controls to determine the cardiovascular effects of exercise in individuals who died a noncardiac death. Nevertheless, we compared the causesof sudden cardiac death in individuals who were exercising at or immediately before death, with all other cases of sudden cardiac death, which has not previously been attempted in a defined population. Our data therefore provide insight into the potential adverse effects of exercise in patients with underlying heart disease. In conclusion, hypertrophic cardiomyopathy was strongly associated with sudden cardiac death during exercise in young adults. In our population which ranged in age from 14 to 40, younger exercising individuals who died during exercise were most often black and died of hypertrophic cardiomyopathy, and older individuals were usually white and died of severe atherosclerosis. These data may be useful to counsel athletes and to initiate cost-effective screening to prevent exercise-related sudden cardiac death.
American
February 1991 Heart Journal
SUMMARY
Sports-related sudden cardiac deaths were compared with non-sports-related sudden cardiac death in individuals (14 to 40 years old) who were autopsied from 1981 to 1988 at the Maryland Medical Examiner’s Office. Thirty-four of 690 total cases of sudden cardiac death were sports-related, which represents 5 % of sudden cardiac death in this age group. Causes of death were severe atherosclerosis (nine), hypertrophic cardiomyopathy with asymmetry (eight), coronary artery anomalies (four), idiopathic concentric left ventricular hypertrophy (three), myocarditis (two), arrhythmogenic right ventricle (one), Kawasaki disease (one), and unknown (six); two of the cases with unknown causes had tunnel arteries. Exercise-related deaths were more likely due to hypertrophic cardiomyopathy (p = 0.0007) compared with 102 age-, sex-, and race-matched controls in the nonexercise group; there was no difference in the incidence of severe atherosclerosis (p = 0.4). The mean age of individuals with hypertrophic cardiomyopathy with asymmetry was less than that of those with severe atherosclerosis (24 vs 32 years, p = 0.03). Thus exercise precipitates sudden cardiac death in younger individuals with hypertrophic cardiomyopathy.
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9. 10.
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Myerburg RJ, Castellanos AC. Cardiac arrest and sudden cardiac death. In: Braunwald E, ed. Heart disease. Philadelphia: Saunders, 1988:742. James TN, Froggart P, Marshall TK. Sudden death in young athletes. Ann Intern Med 1967;67:1013. Kennedy HL, Whitlock JA. Sports related sudden death in young persons. J Am Co11 Car&o1 1984;3:622. Maron BJ. Roberts WC. McAllister HA. Rosins DR. Epstein SE. Sudden death in young athletes. Circulation 1980;62:218. Maron BJ, Epstein SE, Roberts WC. Causes of sudden death in competitive athletes. J Am Co11 Cardiol 1986;7:204. McClellan JT, Jokl E. Congenital anomalies of coronary arteries as a cause of sudden death associated with physical exertion. Medicine and Sport 1971;5:91. Moades TD, Rose AG. Opie LH. Hypertrophic cardiomyopathy associated with sudden death during marathon racing. Br Heart J 1979;41:624. Morales AR. Romanelli R. Boucek RJ. The mural left anterior descending coronary artery, strenuous exercise and sudden death. Circulation 1980;62:230. Northcote RJ, Ballantyne D. Sudden cardiac death in sport. Br Med J 1983;287:1357. Thompson PD, Stern MP, Williams P, Duncan K, Kaskell WL, Wood PD. Death during jogging or running; a study of 18 cases. JAMA 1979;242:1265. Thompson PD, Funk EJ, Carleton RA, Sturner WQ. Incidence of death during jogging in Rhode Island from 1975 through 1980. JAMA 1980;247:2535. Virmani R, Robinowitz M, McAllister HA. Nontraumatic death in joggers. Am J Med 1982;72:874. Virmani R, Robinowitz M. Cardiac pathology and sports medicine. Human Path01 1987;18:493. Waller BF, Roberts WC. Sudden death while running in con-
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1
ditioned runners aged 40 years or over. Am J Cardiol 1980;45:1292. Waller BF, Newhouse P, Pless J, Foster L, Wills E. Exerciserelated sudden death in 27 conditioned subjects aged < 30 and > 30 years: coronary artery abnormalities are the culprit. J Am Co11 Cardiol 1984;3:621. Coplan N, Gleim G, Nicholas JA. Exercise and sudden cardiac death. AM HEART J 1988:115:207. Hinkle LE, Thaler HT, Merke DP, Renier-Berg D, Morton NE. The risk factors for arrhythmic death in a sample of men followed for 20 years. Am J Epidemiol 1988;127:500. Kannel W, Belanger A, D’Agostino R, Israel I. Physical activity and physical demand on the job and risk of cardiovascular disease and death: the Framingham Study. AM HEART J 1986;112:802. Paffenberger RS, Hyde RT. Physical activity, all-cause mortality, and longevity of college alumni. N Engl J Med 1986;314:605. Salonen JT, Slater JS, Tuomilehto J, Rauramaa R. Leisure time and occupational physical activity: risk of death from ischemic heart disease. Am J Enidemiol 1988:127:87. Siscovick DS, Ekelund LG, Hyde JS, Johnson JL, Gordon DJ, LaRose JC. Physical activity and coronary heart disease among asymptomatic hypercholesterolemic men (the Lipid Research Clinics Coronary Primary Prevention Trial). Am J Publich Health 1988;78:1428. Slattery ML, Jacobs DR, Nichaman MZ. Leizure time physical activity and coronary heart disease death. The US Railroad Study. Circulation 1989;79:304. Siscovick DS, Weiss NS, Fletcher RH, Lasky T. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med 1984;311:874. Froehlicher VF, Roberts WC. Myocardial, valvular, and metabolic factors in exercise-related sudden death. Curr Prob Cardiol 1982;6:6. Kramer MR, Drori Y, Lev B. Sudden death in young soldiers. Chest 1988;93:345. Kitzman DW, Scholz DG, Hagen PT, Ilstrup DM, Edwards WD. Age-related changes in normal human hearts during the first 10 decades of life. Part II (Maturity). A quantitative anatomic study of 765 specimens from subjects 20 to 99 years old. Mayo Clin Proc 1988;63:137. Scholz DG, Kitzman DW, Hagen PT, Ilstrup DM, Edwards WD. Age-related changes in normal human hearts during the first 10 decades of life. Part I (growth). A quantitative anatomic study of 200 specimens from subjects from birth to 19 years old. Mayo Clin Proc 1988;63:126. Virmani R, Atkinson JB, Robinowitz M, Forman MB. Floppy mitral valve: the most common valvular heart disease. Human Path01 1987;18:596. Virmani R. Robinowitz M. Clark MA. McAllister HA. Sudden death and congenital partial absence of the right ventricular myocardium: a report of three patients and a review of the literature. Arch Path01 Lab Med 1982;106:163. Aretz HT, Billingham ME, Edwards WD, Factor SM, Fallon JT, Fenoglio JJ Jr, Olsen EG, Schoen JF. Myocarditis. A histopathologic definition and classification. Am J Cardiovasc Path01 1986;1:3.
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31. Sugishita Y, Iida K, Matsuda M, Ajisaka R, Ito I, Konishaga J, Ueno M. Sudden death in hypertrophic cardiomyopathy: a guideline to prevention in daily life. Acta Cardiol1988;43:677. 32. Maron BJ, Roberts WC, Epstein SE. Sudden death in hypertrophic cardiomyopathy: a profile of 78 patients. Circulation 1982;65:1388. 33. Maron BJ, Lipson LC, Roberts WC, Savage DD, Epstein SE. Malignant hypertrophic cardiomyopathy: identification of a subgroup of families with unusually frequent premature deaths. Am J Cardiol 1978;41:1133. 34. Allen HD, Goldberg SJ, Sahn DJ, Schy N, Wojcik R. A quantitative echocardiographic study of champion childhood swimmers. Circulation 1977;55:142. 35. Maron BJ. Structural features of the athlete’s heart as defined by echocardiography. J Am Co11 Cardiol 1986;7:190. 36. Morganroth J, Maron BJ, Henry WL, Epstein SE. Comparative left ventricular dimension in trained athletes. Ann Intern Med 1975;82:521. 37. Roeske WR, O’Rourke RA, Klein A, Leopold G, Karliner JS. Noninvasive evaluation of ventricular hypertrophy in professional athletes. Circulation 1976;53:286. 38. Noakes TD, Opie HL, Rose AG, Kleynhans PHT. Autopsyproved coronary atherosclerosis in marathon runners. New Engl J Med 1979;310:86. 39. Grossman W. Cardiac hypertrophy: useful adaptation or pathologic process? Am J Med 1980;69:576. 40. Pantano JA, Oriel RJ. Prevalence and nature of cardiac arrhythmias in apparently normal well-trained runners. AM HEART J 1982;104:762. 41. Cheitlin MD, DeCastro 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 1975;50:780. 42. Roberts WC. Major anomalies of coronary arterial origin seen in adulthood. AM HEART J 1986:111:941. 43. Roberts WC, Siegel RJ, Zipes DP. Origin of the right coronary artery from the left sinus of Valsalva and its functional consequences: analysis of 10 necropsy patients. Am J Cardiol 1982;49:863. 44. Virmani R, Rogan K, Cheitlin MD. Congenital coronary artery anomalies: pathologic aspects. In: Virmani R, Forman MB, eds. Nonatherosclerotic ischemic heart disease. New York: Raven Press, 1989153. 45. Thiene G, Nava A, Corrado D, Rossi L, Penelli N. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 1988;318:129. 46. Cheitlin MD. Editorial: the intramural coronary artery: another cause for sudden death with exercise? Circulation 1980;62:238. 47. Rossi L. Histopathology of cardiac arrhythmias. Milan, Italy: Case Eidtrice Ambrosiana Milano. 1978:16. 48. Rossi L, Thiene G. Arrhythmologic pathology of sudden cardiac death. Milan, Italy: Casa Editrice Ambrosiana Milano, 1983:26. 49. Robinowitz M, Forman MB, Virmani R. Nonatherosclerotic coronary aneurysms. In: Virmani R, Forman MB, eds. Nonatherosclerotic ischemic heart disease. New York: Raven Press, 1989277.
74. 75. 76.
77. 78.
et al.
American
surgical treatment of aortic and mitral insufficiency. Angiology 1956;7:446-71. Ross DN. Homograft replacement of aortic valve. Lancet 1962;2:487. Barratt-Boyes BG. Homograft aortic valve replacement in aortic incompetence and stenosis. Thorax 1964;19:131-50. Merrill WH, deLeva1 MR, Ball C, Macartney FJ, Taylor FFN, Stark J. Homograft prosthetic heart valves. In: Dunn JM, ed. Cardiac valve disease in children, New York: Elsevier, 1988: 436-58. Stancel’ HC, Nude1 DB, Berman MA, Talner NS. Prosthetic valve renlacement in children. Arch Sum 1975:110:1397-400. Weinstein GS, Mavroudis C, Ebert PA.-Preliminary experi-
79. 80.
81.
82.
February 1991 Heart Journal
ence with aspirin for anticoagulation in children with prosthetic cardiac valves. Ann Thorac Surg 1982;33:549-53.Edmunds LH Jr. Thrombotic and bleeding complications of prosthetic heart valves. Ann Thorac Surg 1987;44:430-45. Bradley LM, Midgley FM, Watson DC, Getson PR, Scott LP III. Anticoagulation therapy in children with mechanical prosthetic cardiac valves. Am J Cardiol 1985;56:533-5. Stewart S, Cianciotta D, Alexson C, Manning J. The long-term risk of warfarin sodium therapy and the incidence of thromboembolism in children after prosthetic cardiac valve replacement. J Thorac Cardiovasc Sure: 1987:93:551-4. Woods A, Vargas J, Berri G, et al. Antithrombotic therapy in children and adolescents. Thromb Res 1986;42:289-301.
Sports-related and non-sports-related cardiac death in young adults
sudden
Allen P. Burke, Maj, USAF, Andrew Farb, MD, Renu Virmani, MD, Julia Goodin, MD, and John E. Smialek, MD. Baltimore, A4d.
As many as 50% of cardiovascular deaths in the United States are classified as sudden.l Because of the high prevalence of cardiovascular disease in this country, there is tremendous interest in the causes, epidemiology, and pathology of sudden cardiac death. The preoccupation with sports and exercise among large numbers of Americans has resulted in many reports of exercise-related sudden death.2-15 Most epidemiologic studies have shown that persistent exercise decreases the risk of sudden cardiac death in the long term16-2” but may increase this risk during and immediately after exertion.23 Autopsies performed on conditioned athletes who died during excercise have demonstrated a high prevalence of hypertrophic cardiomyopathy and
From the Department of Cardiovascular Pathology, Armed of Pathology, Washington, D.C., and the Office of the Chief iner, Baltimore, Maryland
Forces Institute Medical Exam-
The opinions or assertions contained herein are the private views of the authors and are not to he construed as official or reflecting the views of the Department of the Army, the Department of the Air Force, or the Department of Defense. Received Reprint thology, 6000.
4/l/25910 568
for publication requests: Armed
Allen Forces
June P. Burke, Institute
7, 1990;
accepted
July
23. 1990.
MD, Department of Cardiovascular of Pathology, Washington, D.C.
Pa20306.
anomalous coronary arteries in younger persons,* whereas most individuals over the age of 35 have severe coronary atherosclerosis.3* l”-15, 24 The relative frequencies of the pathologic findings in sportsrelated cardiac death are important to clinicians, who must prescribe exercise regimens for their patients who have underlying cardiac disease. In addition, these data may be helpful in designing screening programs to minimize the frequency of exerciseassociated cardiac mortality. The purpose of this study is to compare exercise and nonexercise-related sudden deaths in a defined population to demonstrate which conditions are preferentially seen in exercising inviduals. METHODOLOGY
The Office of the Chief Medical Examiner investigates all accidental, homicidal, suicidal, and unexplained or unexpected deaths in the state of Maryland. The files from the years 1981 through 1988, inclusive, were examined by two of us (Maj. Burke and Dr. Farb), and all cases of natural, unexpected cardiac death were retrospectively identified. The files contain a brief history recorded by site investigators as well as a cause of death determined at au*References
3-5, 15, 16, 24, 25.
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Sports
1
topsy. Cases were restricted to individuals between the ages of 14 and 40 years, because most exerciserelated deaths occurred in this age range and because complete autopsies were often not performed in cases of natural death of older individuals. Data on race, age, sex, and cause of death were recorded for all patients, in addition to cardiac findings. Unexpected cardiac death was defined as any case in which symptoms, if any were documented, lasted less than 24 hours and in which no other pathologic abnormality was found that could possibly lead to death. As part of an ongoing consultation service, the Armed Forces Institute of Pathology (AFIP) reviews the gross material on selected cardiac cases from the Office of the Chief Medical Examiner. These cases are maintained on file at the AFIP, and this material was available for restudy. Exercise-related sudden cardiac deaths were considered separately; these were defined as deaths with symptoms that occurred during a sport-related activity or within 1 hour of engaging in a sport-related activity with death occurring within 24 hours of onset of symptoms. Cardiac hypertrophy was defined with populationbased criteria for normal cardiac weights.26> 27 Cardiac hypertrophy, in the absence of other abnormalities (e.g., valvular, ischemic, or congenital heart disease) was divided into three main categories. (1) Hypertrophic cardiomyopathy was defined by the presence of assymmetric septal hypertrohpy that was more than 1.3 times the thickness of the left ventricular free wall, as well as by microscopic fibromuscular disarray that involved a significant portion of the interventricular septum. (2) Concentric idiopathic hypertrophy was defined by concentric left ventricular hypertrophy without ventricular dilatation, fibromuscular disarray, or a history of hypertension. (3) Concentric idiopathic hypertrophy with systemic hypertension required a clinical diagnosis of hypertension. Severe atherosclerosis was defined as one or more major coronary arteries narrowed by greater than 75% cross-sectional luminal area. The diagnosis of mitral valve prolapse was made on the basis of the elongation of the anterior or posterior leaflet with hooding and focal thickening of leaflets.28 Right ventricular dysplasia was diagnosed when there was either marked thinning, absence of right ventricular muscle, and/or fibrosis with fatty infiltration admixed with myocytes. 2g Myocarditis was diagnosed by the presence of lymphocytic infiltrate accompanied by myocyte necrosis as defined by the Dallas criteria.30 In cases of unexplained sudden death with negative toxicology and a lack of significant autopsy
Table
and
sudden
1. Causes of death, sports-versus Sportsrelated
n Age (yr, mean) Sex Male Female Race White Black Asian Cause of death Severe atherosclerosis (CHD) Hypertrophic cardiomyopathy Idiopathic LV hypertrophy Unknown (tunnel) Anomalous coronary artery Myocarditis Right ventricular dysplasia SH with LV hypertrophy Aortic dissection Cardiac sarcoidosis Aortic stenosis Floppy mitral valve Other
cardiac
death
569
non-sports-related Non-sportsrelated
34 (5%,) 26
656 (9tXro) 32
31 (91%) 3 (9%)
501 (76Y) 155 (24’-(7)
19 (56%) 15 (44%)
368 (56”;‘) 281 (43%) 7 (1%) n Percent 307 47t
n Percent 9 26 8
24*
20
3.0
3
9
42
6.4
6(2) 4
18 12
104(7) 8
16 1.2
2 1
6 3
31 0
4.5 0
0
0
31
4.7
0 0 0 0 1
0 0 0 0 3
17 13
2.6 2.0
12 11
1.8
60
1.7 9.1
CHD, Coronary heart disease; LV, left ventricular; SH, systemic hypertension. *Statistically significant increase wer total and age- and sex-matched control whites. tStatistically significant increase over total blacks, but not with age- and sex-matched controls. Other differences were not statistically significant.
findings, the cause of death was attributed to unknown cardiac factors; conduction systems were not routinely examined in these cases. Each exercise-related death was randomly matched with three nonexercise-related deaths, by age (within 2 years), sex, and race. The randomness of the distribution of cause of death in the exercise versus nonexercise groups was compared by the chi square statistic. The mean age of each group of exercise-related death was compared by the unpaired Student’s t test. OBSERVATIONS
There were 34 cases of exercise-related sudden cardiac death that were identified in the study period, and 656 cases of nonexercise-related sudden cardiac death, which represents a 5% incidence of sports activity (Tables I and II).
570
Burke
et al.
Table
11. Cause
American
of death
by race: Nonexercise-related Mean
Cause
of death
Total Severe atherosclerosis Hypertrophic CM No diagnosis Dilated CM SH with LV hypertrophy Idio LV hypertrophy Myocarditis Chronic rheumatic disease Aortic stenosis Anomalous artery Tunnel artery Dissecting aorta Sarcoid CM, cardiomyopathy; *Indicates statistically
idio, idiopathic; other significant increased
White
sudden
cardiac
age
death n
Black
February 1991 Heart Journal
Percent
White
Black
White
Black
368 206* 11 50 12 I
281 100
57 56* 3 14 3 2
43 36 3 15 5 9*
p Value
32 35 32 26 33 33
31 34 29 29 31 31
28 26 34
30 27 29
19 14 1
23 16 7*
5 4 0.3
8 6 2
0.16 0.34 0.0137
35 35 34
28 21 24
7 5 2
5 3 4
2 0.5
2 1 1
0.86 0.98 0.22
29 30
30 32
12
5 12*
3 0.3
2 4*
0.36 0.0003
abbreviations likelihood
as in Table I. of this cause of death
9 43 14 24*
1
to complementary
group
(black
0.000001 0.9 0.6 0.36 0.00018
vs white)
Sports-related deaths. The average age of these 34 individuals was 26. Fifteen were black, and 19 were white; all but three were men. The hearts of 30 of these 34 cases were reviewed at the AFIP. They are grouped below by cause of death.
filtrates that accompanied myocyte necrosis. The heart weights ranged from 420 to 940 gm (mean 543 gm). There was no history of syncope or a known family history of cardiac problems in any of the eight individuals.
Severe atherosclerosis (nine cases, mean age 32).
Anomalous coronary artery (four cases, mean age 21). All four subjects were men; three died while
All hearts had one or more major coronary arteries with equal to or greater than 75% cross-sectional narrowing of the lumen by atherosclerotic plaque. Five individuals were runners; one each died while engaging in football, baseball, swimming, and aerobics. Four had healed infarcts, and one had an additional acute infarct. One had a clinical history of myocardial infarct. The race distribution was eight whites and one black. Five subjects had three-vessel disease (greater than 75 % narrowing of left anterior descending, left circumflex, and right coronary arteries), and four had single-vessel disease that involved the left coronary artery system (two patients) or right coronary artery (two patients). The average heart weight was 440 gm. Hypertrophic cardiomyopathy (eight cases, mean age 24). Seven men died while playing basketball; one
woman died while swimming. The racial distribution was six blacks and two whites. The septal thickness ranged from 2.1 to 2.9 cm, and the septal-free wall ratio ranged from 1.3 to 1.7 (mean 1.5). A prominent left ventricular outflow tract plaque was present in four cases, and a thickened anterior leaflet of the mitral valve was seen in four. Myofiber disarray was present as determined microscopically in all cases and was diffuse in two. One heart showed microscopic evidence of myocarditis as well, with lymphocytic in-
playing basketball, and one died while playing soccer. Two cases involved the right coronary artery arising in the left sinus of Valsalva; one case involved the left coronary artery arising in the right sinus; and one subject had hypoplastic coronary arteries, with absence of posterior descending artery and focal subendocardial fibrosis of the posterior left ventricular wall. One individual had a history of cocaine use, but postmortem toxicology was negative for cocaine. The hearts were enlarged for the age and weight of the patients and ranged in weight from 380 to 520 gm. Idiopathic concentric left ventricular hypertrophy (three cases, mean age 25). All three were men,
who engaged in basketball, running, and aerobics and who had heart weights of 480, 525, and 600 gm, respectively. In one case there was evidence of biventricular dilatation and microscopic myocyte hypertrophy. The others had left ventricular hypertrophy and a wall thickness up to 2 cm without asymmetry or myofiber disarray as determined microscopically. Two had muscular tunnels of the left anterior descending coronary artery, each 1 cm long and up to 3 mm deep. Myocarditis (two cases, ages 14 and 35). These were men who died while swimming and running, respectively. Heart weights and coronary arteries were
Volume Number
121 2, Part
Sports and sudden cardiac death
1
50
-
40
1 -
m i\l D
2 ;5 -s -6 z
30
2 z t CL
20
10
0 atherosclerosis
I,
hypertrophic cardiomyopathy
Fia. 1. Comnarison of snorts-related versus non-sports-related diomyopathy, and anomalous coronary arteries.
normal. myocyte filtrate. elicited
The only necrosis A history in either
abnormality was focal microscopic associated with a lymphocytic inof fever or flu-like illness was not case.
Right ventricular
dysplasia (one case, age 24).
This man died while playing baseball; his heart weighed 450 gm. The right ventricular walls were markedly thin, and the right ventricular cavity was dilated. Microscopic examination demonstrated both fibrous and fatty infiltration among muscle fibers and a focal lack myocardium between epicardium and endocardium. There was a family history of sudden death; the mother had died suddenly. Kawasaki disease (one case, age 17). This patient, a boy who was playing basketball, had a nondocumented history of a Kawasaki-like illness during childhood. The heart, at autopsy, weighed 400 gm and demonstrated an aneurysm in the proximal right coronary artery that measured 1.3 cm in diameter and 1 cm in length and an aneurysm in the left anterior descending artery that measured 1.5 cm in diameter and 2.3 cm in length. In addition, sectioning revealed a healed transmural posteroseptal infarction. Histologically, there was a mixed chronic inflammatory infiltrate in the wall of the affected vessels. Normal (six cases, mean age 24). All patients were male; sporting activities at the time of death were basketball (two), running (two), swimming (one), and football (one). Heart weights ranged from 340 to 480 gm; all were within normal limits for the total body weight. One heart had a 1.5 cm long, 3 mm deep muscular tunnel of the left anterior descending
57 1
exercise related non-exercise related non-exercise related age-sex-race matched controls
anomalous coronary
arteries
deaths (atherosclerosis,
hypertrophic
car-
artery; one had a 3 cm long, 2 mm deep tunnel of the left anterior descending artery; two hearts had histologic evidence of fibromuscular intimal proliferation of the artery to the conduction system; and one had an abnormal insertion of chordae tendineae of the mitral valve over a widened papillary muscle. Among sports-related deaths, the mean age of patients with severe atherosclerosis was higher than that of patients with hypertrophic cardiomyopathy (p = 0.03). The mean age of the group with severe atherosclerosis (32 years) was higher than that with anomalous coronary arteries (21 years); this difference was not statistically significant (p = 0.09), probably because of small number of cases. Non-sports-related sudden cardiac deaths. Of these 656 individuals, the mean age was 32; 501 were male, 155 female; 368 were white, 281 black, and 7 Oriental. Of the total 656 cases, 207 (32%) were reviewed at the AFIP. The cause of death was severe atherosclerosis in 307; 77 of these were subsequently reviewed and diagnosis was confirmed at the AFIP. In the remainder of cases, the causes of death were as follows (numbers in parentheses indicate the number of cases reviewed at the AFIP): anomalous coronary artery 8 (2); aortic valve stenosis 12 (5); congenital heart disease 10 (8); dilated cardiomyopathy 26 (11); aortic dissection 17 (12); endocarditis 10 (7); floppy mitral valve 11 (9) concentric left ventricular hypertrophy with a known history of systemic hypertension 31 (9); idiopathic concentric left ventricular hypertrophy 42 (12); hypertrophic cardiomyopathy with asymmetry 20 (8); myocarditis 30 (8); no pathologic abnormality 104 (19); chronic rheumatic heart
Burke et al.
572
American
Table III. Exercise-related sports Cause of death (n)
deaths:
of race/
Black
White
Sport
1
9
6
2
2
2
6
7
Running (5) Other (4) Basketball (7) Swimming (1) Basketball (2) Baseball (1) Soccer (1) Basketball (5) Running (4) Other (4)
Severe atherosclerosis (9) Hypertrophic cardiomyopathy (8) Anomalous coronary arteries (4) Others
Distribution
(13)
disease 8 (6); cardiac sarcoidosis 13 (8); amyloidosis 1 (1) spontaneous coronary artery dissection 2 (2); chronic constrictive fibrous pericarditis 1 (1); congenital coronary artery aneurysms 1 (1); and lipomatous hypertrophy of the atria1 septum 1 (1). In seven of the 104 hearts without abnormality, a tunnel of the left anterior descending artery was present and measured at least 1 cm in length for a depth of at least 1 mm. The large percentage of normal hearts (16 % ) may, in part, be due to occult abnormalities of the conduction system, for which tests were not routinely performed. In addition, all cases of unexplained sudden death, in the absence of cardiac, toxicologic, and other anatomic abnormalities, were attributed to cardiac events, which perhaps further inflated this percentage. Comparison deaths (Fig.
of
sports
versus
non-sports-related
1) Hypertrophic cardiomyopathy was more likely found in sports-related (8 of 34) than in non-sports-related deaths (20 of 656), p = 0.000019. This trend was also significant with age-, sex-, and race-matched controls (3 of 102, p = 0.0007). Anomalous coronary arteries were more often seen in sports-related deaths: 4 of 34 versus 8 of 656 (total non-sports-related deaths, p = 0.002); however, the difference was only of borderline statistical significance with age-, sex-, and race-matched controls (3 of 102, p = 0.06). Severe atherosclerosis was more likely found in total non-sports-related deaths (307 of 656 vs 9 of 34), but with age-, sex-, and race-matched controls, the ratios were similar (30 of 102, or 29 % , vs 9 of 34, or 26 % , p = 0.46). There were no statistically significant differences in the ratios of other causes of death, for total or age-, sex-, and racerelated deaths. Among individuals with no other cardiac abnormality, tunnels were more likely to be found in exercise-related deaths (2 of 6), compared with total non-exercise-related deaths (7 of 97); but the difference did not reach statistical significance (p = 0.07).
February 1991 Heart Journal
Racial and sex differences (Table III). Amongsportsrelated deaths, blacks were more likely to die of hypertrophic cardiomyopathy 0, = 0.05), and whites were more likely to die of severe atherosclerosis (p = 0.02). The mean age of blacks was 23.5 years, compared with 27.2 years for whites. Among non-sports-related deaths, blacks were less likely to die of severe atherosclerosis than whites (p = O.OOOOOl), in spite of a nearly identical mean age. Blacks were more likely to die of cardiac sarcoidosis (p = 0.0003) and systemic hypertension with left ventricular hypertrophy (p = 0.0002). The black/ white difference was greatest for sarcoidosis (13:1), followed by systemic hypertension with concentric left ventricular hypertrophy (2.6:1), and severe atherosclerosis (1.6:l). There was no statistically significant difference for other causes of death. Women were less likely to die of severe atherosclerosis 03 = 0.000004) than men (female/male ratio 057:l). COMMENTS
Our 5% rate of sudden cardiac death related to sports activity is similar to that of data from other U.S. populations.3 It is important to note that differing definitions of sudden cardiac death1 will greatly influence incidence statistics. Although it is well established that hypertrophic cardiomyopathy is a common cause of sudden cardiac death in athletes under the age of 30,3-5 it has been difficult to prove that this condition predisposes individuals to sudden cardiac death during excercise. We have studied all sudden cardiac deaths in a defined population and compared those that occurred during excercise to other deaths that were matched for sex, age, and race. Because a significantly higher proportion of sudden cardiac deaths occurred in patients with hypertrophic cardiomyopathy in the exercise group, we conclude that there is indeed an increased likelihood for patients with hypertrophic cardiomyopathy to experience sudden cardiac death during exercise. Our findings support and augment those of Sugishita et a1.31 who reported a far higher incidence of sudden cardiac death during exercise in patients with hypertrophic cardiomyopathy compared with a group of non-exercising patients who experienced sudden cardiac death who were not age-matched. Interestingly, in our study, blacks who died during exercise had a greater incidence of hypertrophic cardiomyopathy than whites and were younger, whereas the incidence of hypertrophic cardiomyopathy was similar in sedentary blacks and whites. Our site investigations did not reveal a family history of premature sudden cardiac death or of dyspnea, syncope, or angina in any of the eight patients in
Volume Number
121 2, Part
1
our study who died during exercise. Sudden cardiac death may be the first manifestations of hypertrophic cardiomyopathy,32 even though previous symptoms increase the likelihood of sudden cardiac death.33 Because the total number of individuals who participate in sport-related activities is large, comprehensive screening programs are not likely to be cost-effective. However, screening of athletes who undergo extensive training may be a reasonable alternative, although the definition of “competitive athlete” varies.4, 5 Long-term exercise itself may result in left ventricular hypertrophy, especially in athletes who engage in weight lifting. 34-37Therefore it is possible that in previously normal individuals, hypertrophic cardiomyopathy may be induced by exercise itself. A screening examination performed before the initiation of an exercise program would thus fail to identify athletes who subsequently develop cardiac hypertrophy. However, those with asymmetric hypertrophy would likely comprise an extremely small group of persons, since the few published autopsy studies,38 as well as short-term echocardiographic studies on living athletes,34 do not demonstrate a propensity for asymmetric hypertrophy among athletes. In addition, up to 60 % of casesof hypertrophic cardiomyopathy3” are familial, which indicates that most cases are not acquired. Idiopathic concentric left ventricular hypertrophy was present in nearly 10% of all cases of sudden death in our study; there were no significant differences between the exercise-related and non-exerciserelated groups. Whether left ventricular hypertrophy in athletes predisposes them to cardiac arrhythmias and sudden cardiac death remains controversial.3g, 4o It does not appear from our data that idiopathic concentric hypertrophy predisposes individuals to exercise-related death. Because aerobic exercise itself results in left ventricular dilatation and mild cardiac hypertrophy, it is likely that the cause of sudden cardiac death in some of the our casesof idiopathic concentric left ventricular hypertrophy was occult and may not be related to hypertrophy alone. Anomalous coronary arteries are a well known cause of sudden cardiac death41-44and are found relatively more frequently in young individuals who die during exercise.3, E Because of the small number of cases with these anomalies (4 of 36 sudden cardiac deaths with exercise, vs 8 of 656 sudden cardiac deaths at rest), we were unable to show a statistically significant increase in the proportion of our patients with anomalous coronary arteries who died during exercise over age-, race-, and sex-matched controls who died at rest, inspite of a trend. Although right ventricular dysplasia has been
Sports and sudden cardiac death
573
stated to be a major cause of exercise-related death,45 we demonstrated this abnormality in only one of our cases of sudden cardiac death that occurred doing exercise. Since fat accumulation is common in the anterior portion of the right ventricle in normal hearts, we were rigorous in our definition of right ventricular dysplasia, to include only those casesthat demonstrated apposition of endocardium and epicardium with a lack of intervening myocytes in the presence or absence of fibrosis. The prevalence of severe atherosclerosis was higher in the non-exercising group as a whole, which was most likely explained by the higher average age of non-exercisers versus exercisers. When age-, sex-, and race-matched individuals were compared, the proportions were almost identical. Although it is tempting to speculate that this is evidence for the lack of protective effects of exercise against severe atherosclerosis, we did not document a lifetime lack of exercise in individuals who died sedentary cardiac death or a persistent long-term record of exercise regimens of the individuals who died during sports. It does support the fact, however, that exercise does not have a protective effect in the short term against sudden cardiac death that is secondary to severe atherosclerosis, as has been suggested by other studies that have shown primarily a long-term benefit 2~23 Among sports-related deaths, the mean age of the patients with severe atherosclerosis was statistically significantly higher than those who died of hypertrophic cardiomyopathy, which supports the findings of other investigators. 3,I5 These same investigators have shown that the mean age of patients with anomalous coronary arteries who died suddenly is also lessthan that of the severe atherosclerotis group; this difference was not significant in our data, probably because of small sample size and age limitation of 40 years. The debate concerning the significance of tunnel coronary arteries (intramural arteries, myocardial bridges) in patients who experienced sudden cardiac death during exercises remains unresolved because of the high prevalence of this finding in normal individuals and the varied degrees of severity. Our data demonstrate a trend that tunnels may be more prevalent in persons who die during exercise than in those who die at rest, but this needs further investigation. The mechanism of sudden cardiac death in patients with this abnormality is attributed to systolic contraction of the left anterior descending artery with resultant myocardial ischemia.8 We did not find any evidence of tunnel arteries in our cases of exerciserelated sudden cardiac death with hypertrophic cardiomyopathy, although two casesof concentric idio-
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pathic hypertrophy had this finding. The possible role of intramural coronary arteries has been questioned in casesof idiopathic cardiac hypertrophy and sudden cardiac death46; our data seem to indicate that it is not important in at least hypertrophy with asymmetry. The fibromuscular intimal and medial proliferation (dysplasia) of the atrioventricular nodal artery in two otherwise normal hearts from persons who died during exercise in our study is of uncertain significance. It has been described in traumatic deaths and presumed to be of no clinical significance47 but has also been described in athletes who died suddenly.2, 4RFurther studies that compare hearts from sudden cardiac deaths with hearts from noncardiac deaths are required before the significance of dysplastic intracoronary arteries can be established. To our knowledge, ours is the first report of a patient with probable Kawasaki diseaseto die suddenly during exercise. Because a firm clinical history was lacking in this patient, the clinical criteria for diagnosis could not be fulfilled.4g However, the lack of vasculitis elsewhere and the multiplicity of coronary aneurysms is strongly suggestive of Kawasaki disease. The percentage of patients with Kawasaki disease who present later in adulthood with occult coronary arterial aneurysms is unknown,4g but it is not surprising that exercise-related ischemic events may occur in these individuals. Our study is limited because it is retrospective, and we do not know the percentage of individuals who exercise in our population. We also lack a detailed history of the extent and duration of our exercising individuals, as well as a lack of controls to determine the cardiovascular effects of exercise in individuals who died a noncardiac death. Nevertheless, we compared the causesof sudden cardiac death in individuals who were exercising at or immediately before death, with all other cases of sudden cardiac death, which has not previously been attempted in a defined population. Our data therefore provide insight into the potential adverse effects of exercise in patients with underlying heart disease. In conclusion, hypertrophic cardiomyopathy was strongly associated with sudden cardiac death during exercise in young adults. In our population which ranged in age from 14 to 40, younger exercising individuals who died during exercise were most often black and died of hypertrophic cardiomyopathy, and older individuals were usually white and died of severe atherosclerosis. These data may be useful to counsel athletes and to initiate cost-effective screening to prevent exercise-related sudden cardiac death.
American
February 1991 Heart Journal
SUMMARY
Sports-related sudden cardiac deaths were compared with non-sports-related sudden cardiac death in individuals (14 to 40 years old) who were autopsied from 1981 to 1988 at the Maryland Medical Examiner’s Office. Thirty-four of 690 total cases of sudden cardiac death were sports-related, which represents 5 % of sudden cardiac death in this age group. Causes of death were severe atherosclerosis (nine), hypertrophic cardiomyopathy with asymmetry (eight), coronary artery anomalies (four), idiopathic concentric left ventricular hypertrophy (three), myocarditis (two), arrhythmogenic right ventricle (one), Kawasaki disease (one), and unknown (six); two of the cases with unknown causes had tunnel arteries. Exercise-related deaths were more likely due to hypertrophic cardiomyopathy (p = 0.0007) compared with 102 age-, sex-, and race-matched controls in the nonexercise group; there was no difference in the incidence of severe atherosclerosis (p = 0.4). The mean age of individuals with hypertrophic cardiomyopathy with asymmetry was less than that of those with severe atherosclerosis (24 vs 32 years, p = 0.03). Thus exercise precipitates sudden cardiac death in younger individuals with hypertrophic cardiomyopathy.
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