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Nontraumatic death in joggers
Nontraumatic Death in Joggers A Series of 30 Patients at Autopsy
RENU MAX HUGH
VIRMANI, ROBINOWITZ, A.
M.D.,
MAJ,
MC,
USA
M.D.
MCALLISTER,
Jr.,
M.D.,
COL,
MC, USA Washington. D. C.
From the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, D.C. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Army or the Department of Defense. Reprint requests should be addressed to COL Hugh A. McAllister, Jr., MC. USA, Chairman, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC. 20306. Manuscript accepted December 1, 1981.
874
June 1992
Since few autopsy data are available on the cause of death in joggers, 30 joggers who underwent autopsy were studied. All were males 18 to 57 years of age (mean 38 years). Information on jogging habits was available in 18 patients who ran 7 to 105 miles per week (mean 33) for one to 28 years (mean 10). Three of the 30 patients were “marathon runners.” In 12 patients, the only available information was that they had been jogging for at lead six months, but information regarding the distance run was not available. Sixteen patients (53 percent) had clinical histories of systemic hypertension, hypercholesterolemla and/or family histories of coronary heart disease; eight patients had a previous history of coronary heart disease; two had transient ischemic attacks. Nineteen patients died suddenly while jogging; six died suddenly after jogging; three noted chest pains soon after jogging; two were found dead In bed. The heart weights were Increased in 18 (53 percent). Twenty-two patients (73 percent) had severe coronary artery atherosclerosis, six of whom had coronary artery thrombi; acute and/or healed myocardial infarction was present in 14 (47 percent). One patient had a floppy mitral valve. In seven patients, no cause of death could be established; three of these had cardiac hypertrophy and six had myocytolysis. Myocytolysis was also noted in 11 patients with severe coronary atherosclerosis. Severe coronary artery atherosclerosis was the major finding (73 percent) In the 30 joggers In this series. Jogging is the most popular exercise fad in the United States today. It was estimated in 1975 that there were 4 million American joggers of ages 20 to 59 years; there are probably many more today [ 11. As explained by Rennie and Hollenberg [2], “We run for fun and for reasons ranging from the transcendental through the esthetic to competitive.” Many of us have been led to believe that jogging increases longevity by reducing coronary heart disease. Joggers tend to be overzealous and heedless of the limitations of the human body, perhaps due to claims that “marathon runners are immune to fatal atherosclerosis” [3]. A few recent reports have described coronary atherosclerosis at autopsy in joggers [4-61, as well as in marathon runners [6-g], but the number of patients is small (Table I) [4,6-l 11. This study describes the cause of nontraumatic death in 30 joggers and/or marathon runners. MATERIALS AND METHODS The files of the Armed Forces Institute of Pathology, which include case material from military, Veterans Administration, and civilian sources, were searched from 1977 to 1980 for patients who had been described as
The American Journal of Medicine
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NONTRAUMATIC
TABLE I
ET AL.
Summary of Published Reports on Cause of Death in Joggers
AUthOf
Year
No. Pts.
Opie Opie Green Cantwell Noakes Noakes
1975 1975 1976 1978 1979 1979
1 1 1 1 1 5
5
Waller
DEATH IN JOGGERS-VIRMANI
1980
Age (yr)
Average
Duration
Run
Jogging
Heart
SCA
History
Weight
(no. vessels
Cause
Marathons
(Yr)
AMI
(ei
>75% narrowed)
Death
Completed
-
94~
(milwk)
46 44 28 41 44
M M M
48 50
-
M
25
-
M
-
M
41 36 27 38 40 40 46 49 53
M M M M M M M M M
40 21 50 30 60 42 108 14
8
-
+
0 0 0 0 + 0 0 0
350 -
0 0
460 357 344 360 350 -
0
0
385 460 380 480 425
0
0
0 0’ 0
-
?
+
(2)
+ + 0 0 + + + + +
(3) (1)
(3) (3) (3) (3) (3)
CHD ? ? HC CHD CHD AA AA AA CHD CHD CHD CHD CHD
several several 2 10 5 28 4 1 0 0 1 13 0
AA = automobile accident; AMI = acute myocardial infarction: CHD = coronary heart disease: SCA = severe coronary atherosclerosis; - = not available; ? = not determined; -I 2 present. Angina pectoris for two years. l
“joggers.” In all, 30 patients were included in the study. Details of the distance run per week or per day, and the length of time the patient had been running were sought from family members and medical records. Patient records were examined for risk factors and for the presence of symptomatic coronary or valvular heart disease. Only those cases in which the heart was available for examination (five), or in which adequate descriptions of the heart for the presence or absence of myocardial infarction and/or valvular heart disease, and of the coronary arteries for the severity of coronary atherosclerosis were included in the study. Of the 30 patients, 28 had adequate descriptions of the three major epicardial coronary arteries-right, left anterior descending and left circumflex. Only 10 had adequate descriptions of the left main coronary artery. In two patients, the presence of severe coronary atherosclerosis (greater than 75 percent crosssectional luminal narrowing) was noted without specification as to which artery was severely involved. The coronary arteries had been cut at 5 mm intervals, and the area of maximal narrowing was selected by gross examination and submitted for histologic examination. The paraffin blocks were available for further sectioning and staining with hematoxylin and eosin, and Movat’s pentachrome stain. The gross descriptions of the myocardium documented the presence or absence of macroscopic myocardiil fibrosis and/or necrosis, and at least three sections of the left ventricular myocardium were submitted for histologic examination. RESULTS
The 30 patients ranged in age from 18 to 57 years (mean 36); all were men. Seven were less than 30 years of age. In 27 patients (90 percent), the mode of presentation was sudden death (sudden death was defined as death occurring instantaneously, or within an hour of the onset of symptoms): 19 died suddenly during jogging; six died soon after jogging; two were found
dead in bed. Three patients had symptoms of chest pain lasting 2, 16 and 24 hours (Table II). Detailed jogging histories were available in 18 patients. They had run 7 to 105 miles per week (mean 33 miles). All had been running for one to 28 years (mean 10 years). Three had participated in marathons. The only history available in the other 12 patients was that all were “joggers” and had been participating in this sport for at least six months, but the information regarding the distance run was not available (Table II). Risk factors known to accelerate coronary atherosclerosis were present in 16 (53 percent) of the patients (Table II): nine had a strong family history of coronary heart disease; 11 had systemic hypertension; one had type IV hyperlipoproteinemia; seven others had cholesterol levels greater than 200 mg/dl wlithout a specified lipoprotein electrophoresis pattern abnormality. A history of smoking was not uniformly available, and when present the details about the numbers of cigarettes consumed per day and the duration in years usually were not mentioned. A history of coronary heart disease was present in eight (27 percent) patients: five had angina pectoris (of recent onset in four); three had histories of previous myocardial infarction (one year before death in two, and 20 months in the third). Two patients had a history of transient ischemic attacks (Table II). Nine patients had resting electrocardiograms two months to eight years before death: five had normal electrocardiograms; two had voltage criteria for left ventricular hypertrophy; one had right bundle branch block for eight years; one had multifocal premature ventricular contractions. One patient, a marathon runner, was known to have a floppy mitral valve. At autopsy, the heart weight was increased in 16 (53
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NONTRAUMATIC DEATH IN JOGGERS-VIRMANI
Cllnical and Morphologic Observations in Joggers
TABLE II
Age (yr)
ET AL.
Average Run (milwk)
27 33 37 38 41 41 50 57
70 -
18 22 22 26 27 29 31 31 33 38 38 39 40 40 42 42 42 42 44 45 45 46
-
Jogging History Duration
Jogging (yr) 5 1 l/1 ‘I* 12 28 4
42 14 -
21 14 84 -
72
3 23 18
28 105 12 7 7 21 50 21 7 -
3:; 3 3 31; 1 5 28 4
35 21 21
Marathon Runner
+ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 + 0 0 0 0 + 0 0 0 0 0 0
Family History CHD
CHD SH
(;dt)
Trpu
While running or Soon After SD CP
Patlents wlth Previous History of Coronary Heart Disease + nl AP + 0 + 0 275 AP + 0 0 + 214 AMI + 0 0 AP + 0 0 + AMI + 0 0 0 AMI + 0 0 + 274 AP + 0 0 + AP + 0 Patients wlthout Previous History of Coronary Heart Disease 0 + 0 +-0 +o 0 + 0 0 0 160 0 + 0 0 --o+o 0 + 0 0 + 0 0 0% ++ 0 + “IV” 0 + 0 + + 0 ++ 0 + 0 di + 0 + 0 240 0 + 0 0 0 0 0 + 0 0 -0 +o + 0 220 0 0 + + + 242 0 + 0 + 0 220 0 0 + 0 --o+o + + 0 +o 0 0 0 +o + + 0 ++ 0 0 0 0 + 0
Heart Welghl
No. CAs >75% Narrowed
(9)
AM
HMI
420 400 600 420 370 550 450 350
0 0 0 0 0 + 0 +
0 0 + + + + 0 +
0’ 2 2 1 2 2 “severe” 1
345 440 400 400 350 345 440 480 400 350 460 480 450 430 350 425 350 430 500 400 510 375
0 0 0 0 + 0 0 0 0 + 0 0 + + 0 + 0 0 0 0 + 0
0 0 0 0 0 0 0 0 0 0 0 + 0 0 0 0 0 0 + 0 + +
0 0 0 0 3 0 0 1 0 1 4 2 2 1 1 “severe” 1 1 2 2 1 2
AM = acute myocardial infarct; CA = coronary artery; CHD = coronary heart disease; CP = chest pain; HMI = healed myocardial SD = sudden death; SH = systemic hypertension: TC = total cholesterol. Floppy mitral valve. t Sudden death while sleeping. 3 History of transient ischemic attacks. l
TABLE III
Morphologic Observations in 30 Joggers Cause of Death Severe Coronary Alherosulurusis (22 patients)
Heart weight (g); range (avg) Heart weight increased Acute myocardial infarction Coagulation necrosis Contraction band necrosis MyOCytolysis Healed myocardial .infarction
350-699 (432) 12 (55%)
Acute and healed infarction
878
JUha 1982
The American Journal of Medicine
8 6 11 6 8
Volume 72
Floppy Mitral Valve (1 patient) 420 1 0 1 1 0 0
Unknown (7 patients) 345-450 (397) 3 (43%) 0 3 6 0 0
infarct;
NONTRAUMATIC
percent) patients (Table II and Table III). The cause of death was severe atherosclerosis in 22 patients, and floppy mitral valve in one; in seven patients, the cause of death was unknown. The one patient with a floppy mitral leaflet had hooding and bulging of the posterior mitral leaflet into the left atrium at autopsy; on histologic sectioning, the leaflet showed myxomatous degeneration (Figure 1). No other anatomic abnormalities were noted in the heart or elsewhere in this patient. In six of the 22 patients, only healed myocardial infarction was present; acute infarction with or without healed myocardial infarction was present in eight patients. Thus, a total of 14 (64 percent) of 22 patients who
DEATH IN JOGGERS-VIRMANI
ET AL.
died of severe coronary atherosclerosis had myocardial infarction. Myocytolysis (i.e., vacuolar degeneration) was present in the myocardium in 18 (60 percent), 10 (33 percent) had contraction band necrosis, irrespective of the presence or absence of severe coronary atherosclerosis (Table Ill and Figure 2). The amount and extent of coronary artery narrowing in the 22 patients who died of severe coronary atherosclerosis is summarized in Tables IV to VI and Flgures 3 to 6. Of the four major epicardial coronary arteries examined for severe atherosclerosis, only one artery was involved in nine patients (41 percent); two coronary arteries were involved in nine (41 percent): three and
Figure 1. Microscopic section of the posterior leaflet of the mitral valve of the patient with known floppy mitral valve. The leaflet is hoodedand shows increased acid mucopoiysaccharidematerial in the spongiosa (Masson trichrome; original magnification, A, X 15, B, X 50, both reduced by 35 percent).
Figure 2. A 29 year old “jogger” died suddenly while jogging. At autopsy his heart weighed 345 g and all four major epicardial coronary arteries were patent. The left ventricular myocardium showed extensive areas of contraction band necrosis. A, histologic section of the left anterior descending coronary showing mild fibrointimal proliferation; B and C, histologic sections of left ventricular myocardium showing contraction band necrosis (H&E; original magnification, A, X 25, B, X 160, C, X 360. all reducedby 25 percent).
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NONTRAUMATIC DEATH IN JOGGERS-VIRMANI ET AL.
TABLE IV
Number of Four Major Coronary Arteries Narrowed >75% in Cross-Sectional Area by Atherosclerotic Plaque in 22 Joggers
TABLE V
Type and Combination of Four Major Coronary Arteries Narrowed >75% in Cross-Sectional Area by Atherosclerotic Plaque in 20 Joggers*
No.Patients No.
No. arteries 1 2
9 (41%) 9 (41%) 1(5%) 1(5%) 2 (9%) 6 (27%)
3 4 Severe coronary atherosclerosis’ Thrombi l
Coronary Artery R LAD LC LM R+LAD LAD + LC R + LC R + LM LM+LC LAD + LC + R LM+LAD+LC+R Total
Site not specified.
four coronary arteries in one patient each (Table IV). Thrombi were noted in six (27 percent) patients. The most frequent isolated artery of involvement was the left anterior descending, and the most frequent combination was the left anterior descending and right (Table V). Of a total of 70 coronary arteries examined in 20 joggers, 34 (49 percent) were severely narrowed, and six (8 percent) contained thrombi (Table VI). COMMENTS
Since Bassler’s statement [3] that “marathon runners are immune to fatal atherosclerosis,” few reports have appeared describing severe and fatal atherosclerosis in the coronary arteries of marathon runners. Of a total of 10 marathon runners described in the literature [4,6-g], five died of severe coronary atherosclerosis [4,6,9]. In our series of 30 joggers, three were marathon runners, and two of the three died of severe coronary atherosclerosis. One marathon runner with severe four-vessel disease was a 38 year old man who ran 105 miles per week and had been running for 23 years of his life. The only known risk factor was a family history of coronary artery disease. One year before his death, he had symptoms of syncope. His electrocardiograms demonstrated left ventricular hypertrophy and an echocardiogram showed no abnormalities. The second marathon runner was a 42 year old man who ran 50
TABLE VI
Patients 3 6 0 0 4 2 1 1 1 1 1 20
l
876
June 1982
No.>75 %
Examined
Narrowed (%) 11 3 15 5 34
ContaInlag Thrombl (%)
(55%) (30%) (75%) (25%) (49%)
In two joggers, the only information available was “severe atherosclerosis.”
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miles per week for the last three years of his life. He died while running the 23rd mile in a marathon. His risk factors included systemic hypertension and a serum cholesterol level of 242 mg/dl. Marathon running, at least in these patients, did not prevent the development of coronary atherosclerosis or lead to its regression. Of the 18 joggers described by Thompson et al. [5], five had been “exercising regularly” for at least one year, and nine had exercised for 3 years or more. Two with coronary heart disease had exercised for three years or more. Two with coronary heart disease had exercised less than a month-one for only nine days. A detailed jogging history was unavailable in the remaining two. Fifteen of the 18 died while running. Coronary heart disease was the cause of death in 13; one had myocarditis; one died of heat stroke; in three, the cause of death was unknown. Waller and Roberts [6] described five runners, 40 to 53 years of age (mean 46) who ran 14 to 108 miles a
No. 20 10 20 20 70
1 1
l
No. Coronary Artery
2 2
LAD = left anterior descending; LC = left circumflex; LM = left main; R = right. In two joggers, the only information available was “severe atherosclerosis.”
Number and Percentage of Right, Left Main, Left Anterior Descending, and Lefl Circumflex Coronary Arteries Narrowed >75% in Cross-Sectlonal Area by Atherosclerotic Plaque in 20 Joggers* Who Died of Coronary Artery Disease
Right Left main Left anterior descending Left circumflex Total
NO.with Thrombus
3 (15%) 0 3 (15%) 0 6 (8%)
NONTRAUMATIC
DEATH IN JOGGERS-VIRMANI
ET AL.
Figure 3. Histologic sections of the three major coronary arteries at the sites of maximal narrowing in a 45 year old man who ran 35 miles per week for several years and died soon after jogging. LAD = left anterior descending;LC = left circumflex; R = right (Movat; original magnification X 25, reduced by 45 percent).
Figure 4. A 27yearoMman whojogged 14 miles a week for the last two years died suddenly while jogging. At autopsy, the heart weight was normal. There was an acute subendocardial myocardial infarction and the left anterior descending (LAD), left circumflex (LC) and right (R) coronary arteries were severe& narrowed by atherosclerotic plaque (Movat; original *magnificationX 25, reduced by 35 percent).
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NDNTRAUMATIC
DEATH IN JOOGERS-VIRMANI
ET AL.
Figure 5. A 31 year old man who had jogged 84 miles a week for 14 years of his life. He had a history of transient ischemic attacks two months before death. He fractured his patella while jogging, at was which time his electrocardiogram normal. Twenty days later, he died in his sleep. At autopsy, his heart weighed 480 g and the left anterior coronary artery (LAD) was severely narrowed by atherosclerotic plaque (f&vat; original magnification X 25, reduced by 40 percent).
Figure 6. A 38 year old marathoner died while running. He had been jogging 705 miles per week for 23 years of his life. The only known risk factor was a family history of coronary heart disease. At autopsy, the heart weighed 460 g and all four major epicardial coronary arteries were narrowed greater than 75 percent in cross-sectional area by atherosclerotic plaque. LM = left main; LAD = left anterior descending; LC = left circumflex; R = right (f&vat; original magnification X 25, reduced by 40 percent).
week (mean 53) for one to 10 years (mean five). Two were marathon runners. All died of severe coronary atherosclerosis, with three coronary arteries narrowed more than 75 percent in cross-sectional area. Of the five patients, four had one or more risk factors. In our series of 30 joggers, 18 had been running 7 to 105 miles per week (mean 33) for one to 28 years (mean lo), and the rest had jogged for at least six months. The cause of death was secondary to severe coronary atherosclerosis in 22; one, a marathon runner, died with floppy mitral valve: in seven, the cause of death was unknown. The majority of our patients (82
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June 1982 The American Journal of Medicine Volume 72
percent) had either one- or two-vessel disease. Threeand four-vessel disease was rare, a finding contrary to that in Waller and Roberts’ patients [6]. However, our patients were younger, with a mean age of 36 years. To our knowledge, ours is the first report of a marathon runner whose sudden death was probably secondary to a floppy mitral valve. The mechanism of death may have been either an arrhythmia [ 121 or coronary artery spasm [ 131, both of which have been well documented in patients with the floppy mitral valve syndrome. Recently, Morales et al. [ 141 reported intramyocardial
NONTRAUMATIC DEATH IN JOGGERS-VIRMANI
left anterior descending coronary artery as a cause of death in two joggers. Both had autopsy evidence of ischemic necrosis. They postulated that systolic constriction of the left anterior descending coronary artery may precipitate death. None of our patients had intramyocardial coronary arteries, but the cause of death in seven patients is unknown. Six of the seven had myocytolysis, which may indicate inadequate oxygen supply for the increased demand. Three of the seven patients also had contraction band necrosis, the significance of which, in humans, is not well understood. although it occurs in a variety of acute myocardial injuries [ 151, including sudden death [ 161 and early infarction [ 171. In canine experiments, it also signifies reperfusion of an ischemic area [ 181. Strenuous exercise has been shown to increase adrenergic reiease [ 19,201, and the circulating catecholamines may precipitate coronary artery spasm [21]. Perhaps, the contraction band necrosis in our three patients without severe coronary atherosclerosis was due to myocardial ischemia secondary to coronary artery spasm with or without reperfusion. In 1979 Noakes et al. [8] reported hypertrophic cardiomyopathy in a 42 year old marathoner who had been known to have cardiac murmur since the age of seven and had taken up longdistance running only three years before death. To our knowledge, this is the only report of sudden death in a jogger due to hypertrophic cardiomyopathy. Maron et al. [22] found that hypertrophic cardiomyopathy was the leading cause of sudden death in a series of 29 young competitive athletes (mean age 19 years), and only 10 percent had severe coronary atherosclerosis. That the leading cause of
ET AL.
death in our study of 30 joggers was severe coronary atherosclerosis (73 percent) might be explained by the older population studied (mean age 36 years). None had hypertrophic cardiomyopathy. While our study was designed to report on the various causes of death in joggers, the incidence of severe coronary atherosclerosis in this series raises the issue of possible prospective identification of joggers who may be at high risk for sudden death. Sedentary persons, especially those with a known risk factor for atherosclerosis, as well as patients with known or suspected cardiovascular, respiratory, metabolic, orthopedic or neurologic disorders, should obtain advice from their personal physician regarding their exercise plans, and exercise testing may be included to provide a basis for an appropriate exercise prescription. We cannot conclude from this study that running prolongs a jogger’s life by decreasing the progression of coronary atherosclerosis. Nor can we conclude that running shortens a jogger’s life span by precipitating an untimely cardiac event. We do believe, however, that prodromal symptoms of vague or definite chest pain (two of our patients in retrospect, had symptoms of angina a week before death) and transient ischemic attacks should not be ignored by the examining physician or the patient. Not only should an extensive cardiovascular examination be carried out, but the patient should be alerted to the nature of the prodromal symptoms. Exercise in moderation is probably healthy, but we should like to point out that ambitious exercise programs must be recommended with caution as to their benefit in preventing the occurrence or progression of coronary atherosclerosis.
REFERENCES 1. 2. 3. 4. 5.
6.
8. 9.
KoplanJP: Cardiovascular death while running. JAMA 1979; 242: 2576-2579. Rennie D, Hoftenberg NK: Cardiomythoiogy and marathoners. N Engl J Med 1979; 301: 103-104. Bassler TJ: Marathon running and immunity to atherosclerosis. Ann NY Acad Sci 1977; 301: 579-592. Opie LH: Long distance running and sudden death. N Engl J Med 1975; 293: 941-942 Thompson PD. Stern MP, Williams P, Duncan K. Haskell WL. Wood PD: Death during jogging or running. A study of 18 cases. JAMA 1979: 242: 1265-1267. Wailer BF, Roberts WC: Sudden death while running in conditioned runners aged 40 years or over. Am J Cardiol 1980; 45: 1292- 1300. Green LH, Cohen SI, Kurfand G Fatal myocardial infarction in marathon racing. Ann Intern Med 1976; 84: 704-706. Noakes TD, Rose AG, Opie LH: Hypertrophic cardiomyopathy associated with sudden death during marathon racing. Br Heart J 1979; 41: 624-627. Noakes TO, Opie LH, Rose AG, Kleynhaus PHT: Autopsy proved coronary atherosclerosis in marathon runners N Engl J Med 1979; 301: 66-89.
10. 11. 12.
13.
14.
15.
16.
17.
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Gpie LH: Sudden death and sport. Lancet 1975; I: 263266. Caniwefi JD, Fletcher GF: Sudden death and jogging. Phys Sports Med 1978; 94-98. DeMaria AN, Amsterdam EA, Vismara LA, Neumann A, Mason DT: Arrhythmias in the mitral valve prolapse syndrome: prevalence, nature and frequency. Ann Intern Med 1975; 84: 656-660 Buda AJ, Levene DL, Meyers MG. Chisholm AW. Shane SJ: Coronary artery spasm and mitral valve prolapse. Am Heart J 1978; 95: 457-462. Morales AR, Romanelli R, Boucek RJ: The mural left anterior descending coronary artery, strenuous exercise and sudden death. Circulation 1980; 62: 230-237. Riecherbach DD, Benditt EP: Catecholamines and cardiomyopathy: the pathogenesis and potential importance of myofibrillar degeneration. Hum Pathol 1970; 1: 125 150. Baroldi G: Different types of myocardial necrosis in coronary heart disease: a pathophysiologic review of their functional significance. Am Heart J 1975; 89: 742-752. Rose AG. Opie LH. Brocknell OL: Early experimental myo-
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18.
19.
882
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cardial infarction: evaluation of histologic criteria and comparison with biochemical and electrocardiographic measurements. Arch Pathol Lab Med 1976; 100: 516. Kloner RA, Ganote CE, Whalen DA Jr, Jennings RB: Effect of a transient period of ischemia on myocardial cells. II. Fine structure during the first few minutes of reflow. Am J Pathol 1974; 74: 399-414. Griggs DM Jr, Tchovoev VV, deClue JW: Effect of beta-adrenergic receptor stimulation of regional myocardial metabolism: importance of coronary vessel patency. Am Heart J 1971; 82: 492.
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20.
21.
22.
Noble J. Bourassa MG, Petitclerc R. Dyrda I: Myocardial bridging and milking effect of the left anterior descending coronary artery: normal variant or obstruction? Am J Cardiol 1976; 37: 993. Yasu H, Omote S, Takazawa A, Nagao M. Miwa K, Tanka S: Exertional angina pectoris caused by coronary arterial spasm: effects of various drugs. Am J Cardiol 1979; 43: 647. Maron BJ, Roberts WC, McAllister HA Jr, Rosing DR, Epstein SE: Sudden death in young athletes. Circulation 1980; 62: 218-229.
RENU MAX HUGH
VIRMANI, ROBINOWITZ, A.
M.D.,
MAJ,
MC,
USA
M.D.
MCALLISTER,
Jr.,
M.D.,
COL,
MC, USA Washington. D. C.
From the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, D.C. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Army or the Department of Defense. Reprint requests should be addressed to COL Hugh A. McAllister, Jr., MC. USA, Chairman, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC. 20306. Manuscript accepted December 1, 1981.
874
June 1992
Since few autopsy data are available on the cause of death in joggers, 30 joggers who underwent autopsy were studied. All were males 18 to 57 years of age (mean 38 years). Information on jogging habits was available in 18 patients who ran 7 to 105 miles per week (mean 33) for one to 28 years (mean 10). Three of the 30 patients were “marathon runners.” In 12 patients, the only available information was that they had been jogging for at lead six months, but information regarding the distance run was not available. Sixteen patients (53 percent) had clinical histories of systemic hypertension, hypercholesterolemla and/or family histories of coronary heart disease; eight patients had a previous history of coronary heart disease; two had transient ischemic attacks. Nineteen patients died suddenly while jogging; six died suddenly after jogging; three noted chest pains soon after jogging; two were found dead In bed. The heart weights were Increased in 18 (53 percent). Twenty-two patients (73 percent) had severe coronary artery atherosclerosis, six of whom had coronary artery thrombi; acute and/or healed myocardial infarction was present in 14 (47 percent). One patient had a floppy mitral valve. In seven patients, no cause of death could be established; three of these had cardiac hypertrophy and six had myocytolysis. Myocytolysis was also noted in 11 patients with severe coronary atherosclerosis. Severe coronary artery atherosclerosis was the major finding (73 percent) In the 30 joggers In this series. Jogging is the most popular exercise fad in the United States today. It was estimated in 1975 that there were 4 million American joggers of ages 20 to 59 years; there are probably many more today [ 11. As explained by Rennie and Hollenberg [2], “We run for fun and for reasons ranging from the transcendental through the esthetic to competitive.” Many of us have been led to believe that jogging increases longevity by reducing coronary heart disease. Joggers tend to be overzealous and heedless of the limitations of the human body, perhaps due to claims that “marathon runners are immune to fatal atherosclerosis” [3]. A few recent reports have described coronary atherosclerosis at autopsy in joggers [4-61, as well as in marathon runners [6-g], but the number of patients is small (Table I) [4,6-l 11. This study describes the cause of nontraumatic death in 30 joggers and/or marathon runners. MATERIALS AND METHODS The files of the Armed Forces Institute of Pathology, which include case material from military, Veterans Administration, and civilian sources, were searched from 1977 to 1980 for patients who had been described as
The American Journal of Medicine
Volume 72
NONTRAUMATIC
TABLE I
ET AL.
Summary of Published Reports on Cause of Death in Joggers
AUthOf
Year
No. Pts.
Opie Opie Green Cantwell Noakes Noakes
1975 1975 1976 1978 1979 1979
1 1 1 1 1 5
5
Waller
DEATH IN JOGGERS-VIRMANI
1980
Age (yr)
Average
Duration
Run
Jogging
Heart
SCA
History
Weight
(no. vessels
Cause
Marathons
(Yr)
AMI
(ei
>75% narrowed)
Death
Completed
-
94~
(milwk)
46 44 28 41 44
M M M
48 50
-
M
25
-
M
-
M
41 36 27 38 40 40 46 49 53
M M M M M M M M M
40 21 50 30 60 42 108 14
8
-
+
0 0 0 0 + 0 0 0
350 -
0 0
460 357 344 360 350 -
0
0
385 460 380 480 425
0
0
0 0’ 0
-
?
+
(2)
+ + 0 0 + + + + +
(3) (1)
(3) (3) (3) (3) (3)
CHD ? ? HC CHD CHD AA AA AA CHD CHD CHD CHD CHD
several several 2 10 5 28 4 1 0 0 1 13 0
AA = automobile accident; AMI = acute myocardial infarction: CHD = coronary heart disease: SCA = severe coronary atherosclerosis; - = not available; ? = not determined; -I 2 present. Angina pectoris for two years. l
“joggers.” In all, 30 patients were included in the study. Details of the distance run per week or per day, and the length of time the patient had been running were sought from family members and medical records. Patient records were examined for risk factors and for the presence of symptomatic coronary or valvular heart disease. Only those cases in which the heart was available for examination (five), or in which adequate descriptions of the heart for the presence or absence of myocardial infarction and/or valvular heart disease, and of the coronary arteries for the severity of coronary atherosclerosis were included in the study. Of the 30 patients, 28 had adequate descriptions of the three major epicardial coronary arteries-right, left anterior descending and left circumflex. Only 10 had adequate descriptions of the left main coronary artery. In two patients, the presence of severe coronary atherosclerosis (greater than 75 percent crosssectional luminal narrowing) was noted without specification as to which artery was severely involved. The coronary arteries had been cut at 5 mm intervals, and the area of maximal narrowing was selected by gross examination and submitted for histologic examination. The paraffin blocks were available for further sectioning and staining with hematoxylin and eosin, and Movat’s pentachrome stain. The gross descriptions of the myocardium documented the presence or absence of macroscopic myocardiil fibrosis and/or necrosis, and at least three sections of the left ventricular myocardium were submitted for histologic examination. RESULTS
The 30 patients ranged in age from 18 to 57 years (mean 36); all were men. Seven were less than 30 years of age. In 27 patients (90 percent), the mode of presentation was sudden death (sudden death was defined as death occurring instantaneously, or within an hour of the onset of symptoms): 19 died suddenly during jogging; six died soon after jogging; two were found
dead in bed. Three patients had symptoms of chest pain lasting 2, 16 and 24 hours (Table II). Detailed jogging histories were available in 18 patients. They had run 7 to 105 miles per week (mean 33 miles). All had been running for one to 28 years (mean 10 years). Three had participated in marathons. The only history available in the other 12 patients was that all were “joggers” and had been participating in this sport for at least six months, but the information regarding the distance run was not available (Table II). Risk factors known to accelerate coronary atherosclerosis were present in 16 (53 percent) of the patients (Table II): nine had a strong family history of coronary heart disease; 11 had systemic hypertension; one had type IV hyperlipoproteinemia; seven others had cholesterol levels greater than 200 mg/dl wlithout a specified lipoprotein electrophoresis pattern abnormality. A history of smoking was not uniformly available, and when present the details about the numbers of cigarettes consumed per day and the duration in years usually were not mentioned. A history of coronary heart disease was present in eight (27 percent) patients: five had angina pectoris (of recent onset in four); three had histories of previous myocardial infarction (one year before death in two, and 20 months in the third). Two patients had a history of transient ischemic attacks (Table II). Nine patients had resting electrocardiograms two months to eight years before death: five had normal electrocardiograms; two had voltage criteria for left ventricular hypertrophy; one had right bundle branch block for eight years; one had multifocal premature ventricular contractions. One patient, a marathon runner, was known to have a floppy mitral valve. At autopsy, the heart weight was increased in 16 (53
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Cllnical and Morphologic Observations in Joggers
TABLE II
Age (yr)
ET AL.
Average Run (milwk)
27 33 37 38 41 41 50 57
70 -
18 22 22 26 27 29 31 31 33 38 38 39 40 40 42 42 42 42 44 45 45 46
-
Jogging History Duration
Jogging (yr) 5 1 l/1 ‘I* 12 28 4
42 14 -
21 14 84 -
72
3 23 18
28 105 12 7 7 21 50 21 7 -
3:; 3 3 31; 1 5 28 4
35 21 21
Marathon Runner
+ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 + 0 0 0 0 + 0 0 0 0 0 0
Family History CHD
CHD SH
(;dt)
Trpu
While running or Soon After SD CP
Patlents wlth Previous History of Coronary Heart Disease + nl AP + 0 + 0 275 AP + 0 0 + 214 AMI + 0 0 AP + 0 0 + AMI + 0 0 0 AMI + 0 0 + 274 AP + 0 0 + AP + 0 Patients wlthout Previous History of Coronary Heart Disease 0 + 0 +-0 +o 0 + 0 0 0 160 0 + 0 0 --o+o 0 + 0 0 + 0 0 0% ++ 0 + “IV” 0 + 0 + + 0 ++ 0 + 0 di + 0 + 0 240 0 + 0 0 0 0 0 + 0 0 -0 +o + 0 220 0 0 + + + 242 0 + 0 + 0 220 0 0 + 0 --o+o + + 0 +o 0 0 0 +o + + 0 ++ 0 0 0 0 + 0
Heart Welghl
No. CAs >75% Narrowed
(9)
AM
HMI
420 400 600 420 370 550 450 350
0 0 0 0 0 + 0 +
0 0 + + + + 0 +
0’ 2 2 1 2 2 “severe” 1
345 440 400 400 350 345 440 480 400 350 460 480 450 430 350 425 350 430 500 400 510 375
0 0 0 0 + 0 0 0 0 + 0 0 + + 0 + 0 0 0 0 + 0
0 0 0 0 0 0 0 0 0 0 0 + 0 0 0 0 0 0 + 0 + +
0 0 0 0 3 0 0 1 0 1 4 2 2 1 1 “severe” 1 1 2 2 1 2
AM = acute myocardial infarct; CA = coronary artery; CHD = coronary heart disease; CP = chest pain; HMI = healed myocardial SD = sudden death; SH = systemic hypertension: TC = total cholesterol. Floppy mitral valve. t Sudden death while sleeping. 3 History of transient ischemic attacks. l
TABLE III
Morphologic Observations in 30 Joggers Cause of Death Severe Coronary Alherosulurusis (22 patients)
Heart weight (g); range (avg) Heart weight increased Acute myocardial infarction Coagulation necrosis Contraction band necrosis MyOCytolysis Healed myocardial .infarction
350-699 (432) 12 (55%)
Acute and healed infarction
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Floppy Mitral Valve (1 patient) 420 1 0 1 1 0 0
Unknown (7 patients) 345-450 (397) 3 (43%) 0 3 6 0 0
infarct;
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percent) patients (Table II and Table III). The cause of death was severe atherosclerosis in 22 patients, and floppy mitral valve in one; in seven patients, the cause of death was unknown. The one patient with a floppy mitral leaflet had hooding and bulging of the posterior mitral leaflet into the left atrium at autopsy; on histologic sectioning, the leaflet showed myxomatous degeneration (Figure 1). No other anatomic abnormalities were noted in the heart or elsewhere in this patient. In six of the 22 patients, only healed myocardial infarction was present; acute infarction with or without healed myocardial infarction was present in eight patients. Thus, a total of 14 (64 percent) of 22 patients who
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ET AL.
died of severe coronary atherosclerosis had myocardial infarction. Myocytolysis (i.e., vacuolar degeneration) was present in the myocardium in 18 (60 percent), 10 (33 percent) had contraction band necrosis, irrespective of the presence or absence of severe coronary atherosclerosis (Table Ill and Figure 2). The amount and extent of coronary artery narrowing in the 22 patients who died of severe coronary atherosclerosis is summarized in Tables IV to VI and Flgures 3 to 6. Of the four major epicardial coronary arteries examined for severe atherosclerosis, only one artery was involved in nine patients (41 percent); two coronary arteries were involved in nine (41 percent): three and
Figure 1. Microscopic section of the posterior leaflet of the mitral valve of the patient with known floppy mitral valve. The leaflet is hoodedand shows increased acid mucopoiysaccharidematerial in the spongiosa (Masson trichrome; original magnification, A, X 15, B, X 50, both reduced by 35 percent).
Figure 2. A 29 year old “jogger” died suddenly while jogging. At autopsy his heart weighed 345 g and all four major epicardial coronary arteries were patent. The left ventricular myocardium showed extensive areas of contraction band necrosis. A, histologic section of the left anterior descending coronary showing mild fibrointimal proliferation; B and C, histologic sections of left ventricular myocardium showing contraction band necrosis (H&E; original magnification, A, X 25, B, X 160, C, X 360. all reducedby 25 percent).
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TABLE IV
Number of Four Major Coronary Arteries Narrowed >75% in Cross-Sectional Area by Atherosclerotic Plaque in 22 Joggers
TABLE V
Type and Combination of Four Major Coronary Arteries Narrowed >75% in Cross-Sectional Area by Atherosclerotic Plaque in 20 Joggers*
No.Patients No.
No. arteries 1 2
9 (41%) 9 (41%) 1(5%) 1(5%) 2 (9%) 6 (27%)
3 4 Severe coronary atherosclerosis’ Thrombi l
Coronary Artery R LAD LC LM R+LAD LAD + LC R + LC R + LM LM+LC LAD + LC + R LM+LAD+LC+R Total
Site not specified.
four coronary arteries in one patient each (Table IV). Thrombi were noted in six (27 percent) patients. The most frequent isolated artery of involvement was the left anterior descending, and the most frequent combination was the left anterior descending and right (Table V). Of a total of 70 coronary arteries examined in 20 joggers, 34 (49 percent) were severely narrowed, and six (8 percent) contained thrombi (Table VI). COMMENTS
Since Bassler’s statement [3] that “marathon runners are immune to fatal atherosclerosis,” few reports have appeared describing severe and fatal atherosclerosis in the coronary arteries of marathon runners. Of a total of 10 marathon runners described in the literature [4,6-g], five died of severe coronary atherosclerosis [4,6,9]. In our series of 30 joggers, three were marathon runners, and two of the three died of severe coronary atherosclerosis. One marathon runner with severe four-vessel disease was a 38 year old man who ran 105 miles per week and had been running for 23 years of his life. The only known risk factor was a family history of coronary artery disease. One year before his death, he had symptoms of syncope. His electrocardiograms demonstrated left ventricular hypertrophy and an echocardiogram showed no abnormalities. The second marathon runner was a 42 year old man who ran 50
TABLE VI
Patients 3 6 0 0 4 2 1 1 1 1 1 20
l
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No.>75 %
Examined
Narrowed (%) 11 3 15 5 34
ContaInlag Thrombl (%)
(55%) (30%) (75%) (25%) (49%)
In two joggers, the only information available was “severe atherosclerosis.”
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miles per week for the last three years of his life. He died while running the 23rd mile in a marathon. His risk factors included systemic hypertension and a serum cholesterol level of 242 mg/dl. Marathon running, at least in these patients, did not prevent the development of coronary atherosclerosis or lead to its regression. Of the 18 joggers described by Thompson et al. [5], five had been “exercising regularly” for at least one year, and nine had exercised for 3 years or more. Two with coronary heart disease had exercised for three years or more. Two with coronary heart disease had exercised less than a month-one for only nine days. A detailed jogging history was unavailable in the remaining two. Fifteen of the 18 died while running. Coronary heart disease was the cause of death in 13; one had myocarditis; one died of heat stroke; in three, the cause of death was unknown. Waller and Roberts [6] described five runners, 40 to 53 years of age (mean 46) who ran 14 to 108 miles a
No. 20 10 20 20 70
1 1
l
No. Coronary Artery
2 2
LAD = left anterior descending; LC = left circumflex; LM = left main; R = right. In two joggers, the only information available was “severe atherosclerosis.”
Number and Percentage of Right, Left Main, Left Anterior Descending, and Lefl Circumflex Coronary Arteries Narrowed >75% in Cross-Sectlonal Area by Atherosclerotic Plaque in 20 Joggers* Who Died of Coronary Artery Disease
Right Left main Left anterior descending Left circumflex Total
NO.with Thrombus
3 (15%) 0 3 (15%) 0 6 (8%)
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Figure 3. Histologic sections of the three major coronary arteries at the sites of maximal narrowing in a 45 year old man who ran 35 miles per week for several years and died soon after jogging. LAD = left anterior descending;LC = left circumflex; R = right (Movat; original magnification X 25, reduced by 45 percent).
Figure 4. A 27yearoMman whojogged 14 miles a week for the last two years died suddenly while jogging. At autopsy, the heart weight was normal. There was an acute subendocardial myocardial infarction and the left anterior descending (LAD), left circumflex (LC) and right (R) coronary arteries were severe& narrowed by atherosclerotic plaque (Movat; original *magnificationX 25, reduced by 35 percent).
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Figure 5. A 31 year old man who had jogged 84 miles a week for 14 years of his life. He had a history of transient ischemic attacks two months before death. He fractured his patella while jogging, at was which time his electrocardiogram normal. Twenty days later, he died in his sleep. At autopsy, his heart weighed 480 g and the left anterior coronary artery (LAD) was severely narrowed by atherosclerotic plaque (f&vat; original magnification X 25, reduced by 40 percent).
Figure 6. A 38 year old marathoner died while running. He had been jogging 705 miles per week for 23 years of his life. The only known risk factor was a family history of coronary heart disease. At autopsy, the heart weighed 460 g and all four major epicardial coronary arteries were narrowed greater than 75 percent in cross-sectional area by atherosclerotic plaque. LM = left main; LAD = left anterior descending; LC = left circumflex; R = right (f&vat; original magnification X 25, reduced by 40 percent).
week (mean 53) for one to 10 years (mean five). Two were marathon runners. All died of severe coronary atherosclerosis, with three coronary arteries narrowed more than 75 percent in cross-sectional area. Of the five patients, four had one or more risk factors. In our series of 30 joggers, 18 had been running 7 to 105 miles per week (mean 33) for one to 28 years (mean lo), and the rest had jogged for at least six months. The cause of death was secondary to severe coronary atherosclerosis in 22; one, a marathon runner, died with floppy mitral valve: in seven, the cause of death was unknown. The majority of our patients (82
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percent) had either one- or two-vessel disease. Threeand four-vessel disease was rare, a finding contrary to that in Waller and Roberts’ patients [6]. However, our patients were younger, with a mean age of 36 years. To our knowledge, ours is the first report of a marathon runner whose sudden death was probably secondary to a floppy mitral valve. The mechanism of death may have been either an arrhythmia [ 121 or coronary artery spasm [ 131, both of which have been well documented in patients with the floppy mitral valve syndrome. Recently, Morales et al. [ 141 reported intramyocardial
NONTRAUMATIC DEATH IN JOGGERS-VIRMANI
left anterior descending coronary artery as a cause of death in two joggers. Both had autopsy evidence of ischemic necrosis. They postulated that systolic constriction of the left anterior descending coronary artery may precipitate death. None of our patients had intramyocardial coronary arteries, but the cause of death in seven patients is unknown. Six of the seven had myocytolysis, which may indicate inadequate oxygen supply for the increased demand. Three of the seven patients also had contraction band necrosis, the significance of which, in humans, is not well understood. although it occurs in a variety of acute myocardial injuries [ 151, including sudden death [ 161 and early infarction [ 171. In canine experiments, it also signifies reperfusion of an ischemic area [ 181. Strenuous exercise has been shown to increase adrenergic reiease [ 19,201, and the circulating catecholamines may precipitate coronary artery spasm [21]. Perhaps, the contraction band necrosis in our three patients without severe coronary atherosclerosis was due to myocardial ischemia secondary to coronary artery spasm with or without reperfusion. In 1979 Noakes et al. [8] reported hypertrophic cardiomyopathy in a 42 year old marathoner who had been known to have cardiac murmur since the age of seven and had taken up longdistance running only three years before death. To our knowledge, this is the only report of sudden death in a jogger due to hypertrophic cardiomyopathy. Maron et al. [22] found that hypertrophic cardiomyopathy was the leading cause of sudden death in a series of 29 young competitive athletes (mean age 19 years), and only 10 percent had severe coronary atherosclerosis. That the leading cause of
ET AL.
death in our study of 30 joggers was severe coronary atherosclerosis (73 percent) might be explained by the older population studied (mean age 36 years). None had hypertrophic cardiomyopathy. While our study was designed to report on the various causes of death in joggers, the incidence of severe coronary atherosclerosis in this series raises the issue of possible prospective identification of joggers who may be at high risk for sudden death. Sedentary persons, especially those with a known risk factor for atherosclerosis, as well as patients with known or suspected cardiovascular, respiratory, metabolic, orthopedic or neurologic disorders, should obtain advice from their personal physician regarding their exercise plans, and exercise testing may be included to provide a basis for an appropriate exercise prescription. We cannot conclude from this study that running prolongs a jogger’s life by decreasing the progression of coronary atherosclerosis. Nor can we conclude that running shortens a jogger’s life span by precipitating an untimely cardiac event. We do believe, however, that prodromal symptoms of vague or definite chest pain (two of our patients in retrospect, had symptoms of angina a week before death) and transient ischemic attacks should not be ignored by the examining physician or the patient. Not only should an extensive cardiovascular examination be carried out, but the patient should be alerted to the nature of the prodromal symptoms. Exercise in moderation is probably healthy, but we should like to point out that ambitious exercise programs must be recommended with caution as to their benefit in preventing the occurrence or progression of coronary atherosclerosis.
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KoplanJP: Cardiovascular death while running. JAMA 1979; 242: 2576-2579. Rennie D, Hoftenberg NK: Cardiomythoiogy and marathoners. N Engl J Med 1979; 301: 103-104. Bassler TJ: Marathon running and immunity to atherosclerosis. Ann NY Acad Sci 1977; 301: 579-592. Opie LH: Long distance running and sudden death. N Engl J Med 1975; 293: 941-942 Thompson PD. Stern MP, Williams P, Duncan K. Haskell WL. Wood PD: Death during jogging or running. A study of 18 cases. JAMA 1979: 242: 1265-1267. Wailer BF, Roberts WC: Sudden death while running in conditioned runners aged 40 years or over. Am J Cardiol 1980; 45: 1292- 1300. Green LH, Cohen SI, Kurfand G Fatal myocardial infarction in marathon racing. Ann Intern Med 1976; 84: 704-706. Noakes TD, Rose AG, Opie LH: Hypertrophic cardiomyopathy associated with sudden death during marathon racing. Br Heart J 1979; 41: 624-627. Noakes TO, Opie LH, Rose AG, Kleynhaus PHT: Autopsy proved coronary atherosclerosis in marathon runners N Engl J Med 1979; 301: 66-89.
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Gpie LH: Sudden death and sport. Lancet 1975; I: 263266. Caniwefi JD, Fletcher GF: Sudden death and jogging. Phys Sports Med 1978; 94-98. DeMaria AN, Amsterdam EA, Vismara LA, Neumann A, Mason DT: Arrhythmias in the mitral valve prolapse syndrome: prevalence, nature and frequency. Ann Intern Med 1975; 84: 656-660 Buda AJ, Levene DL, Meyers MG. Chisholm AW. Shane SJ: Coronary artery spasm and mitral valve prolapse. Am Heart J 1978; 95: 457-462. Morales AR, Romanelli R, Boucek RJ: The mural left anterior descending coronary artery, strenuous exercise and sudden death. Circulation 1980; 62: 230-237. Riecherbach DD, Benditt EP: Catecholamines and cardiomyopathy: the pathogenesis and potential importance of myofibrillar degeneration. Hum Pathol 1970; 1: 125 150. Baroldi G: Different types of myocardial necrosis in coronary heart disease: a pathophysiologic review of their functional significance. Am Heart J 1975; 89: 742-752. Rose AG. Opie LH. Brocknell OL: Early experimental myo-
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cardial infarction: evaluation of histologic criteria and comparison with biochemical and electrocardiographic measurements. Arch Pathol Lab Med 1976; 100: 516. Kloner RA, Ganote CE, Whalen DA Jr, Jennings RB: Effect of a transient period of ischemia on myocardial cells. II. Fine structure during the first few minutes of reflow. Am J Pathol 1974; 74: 399-414. Griggs DM Jr, Tchovoev VV, deClue JW: Effect of beta-adrenergic receptor stimulation of regional myocardial metabolism: importance of coronary vessel patency. Am Heart J 1971; 82: 492.
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Noble J. Bourassa MG, Petitclerc R. Dyrda I: Myocardial bridging and milking effect of the left anterior descending coronary artery: normal variant or obstruction? Am J Cardiol 1976; 37: 993. Yasu H, Omote S, Takazawa A, Nagao M. Miwa K, Tanka S: Exertional angina pectoris caused by coronary arterial spasm: effects of various drugs. Am J Cardiol 1979; 43: 647. Maron BJ, Roberts WC, McAllister HA Jr, Rosing DR, Epstein SE: Sudden death in young athletes. Circulation 1980; 62: 218-229.