Cardiac pathology and sports medicine

Cardiac Pathology and Sports Medicine RENU VIRMANI, MD, AND MAX ROBINOWITZ, MD

Health is the vital principle of bliss And exercise, of health. James Thompson (1700-1748) flow t h r o u g h muscle undergoing static contraction may be increased markedly by compression of blood vessels in the muscle; however, in other areas o f the body that are nonexercising areas, t h e r e may be a decrease in resistance. T h e overall effect is an increase in peripheral resistance. In isotonic exercise, total peripheral resistance falls but heart rate and cardiac o u t p u t rise. T h e systolic blood pressure rises, but there is little change in diastolic pressure, resulting in an increase in mean arterial pressure. Most o f the muscle activities encountered in daily life involve a mixture o f isometric and isotonic effort; however, a rhythmic activity such as running is predominantly isotonic, and supporting heavy weights is largely an isometric effort. Intensity o f exercise is i m port ant and can be measured by the am ount of oxygen consumed. This reflects any change in cardiac output and the oxygen extraction by the tissues. Physiologists express exercise work as a percentage of the subject's maximum oxygen capacity (VO2ma• or m a x i m u m oxygen uptake) and consider light work the level below 25 per cent o f maximum; medium work, 25 to 50 per cent; heavy work, 51 to 75 per cent; and exhaustive work, 90 to 100 per cent of maximum. 11 T h e best m e a s u r e m e n t o f t r a i n i n g e f f e c t is VO2max. Many factors determine a person's VO2max; men have higher values than women (this may be dep e n d e n t on lean body mass); age and genetic factors are ot her variables. Beyond the age o f 20, the VO2m~ declines. When performing exhaustive work, the dem a n d f o r o x y g e n by the skeletal muscle may be higher than can be delivered, resulting in a shift to anaerobic metabolism and limiting a m o u n t of exercise that can be performed. This is the state that cardiologists describe as symptom-limited maximal oxygen uptake and may manifest itself as exhaustion. Patients in this condition also may stop exercising because o f chest pain, weakness, faintness, electrocardiographic changes, or fall in blood pressure because o f ventricular ischemia.

Participation in sports has been a major pastime for Americans in the last decade; however, it has now become an obsession. Obviously there are many possible causes for this craze or "craving" for exercise. At least in part this popularization and commercialization o f the beneficial effects of exercise are because o f perceived health benefits. 1 T o date no definitive study has shown that regular exercise prevents coronary heart disease. Nevertheless, there is a growing body o f evidence f r om epidemiologic studies suggesting that regular exercise may help to prevent coro n a r y h e a r t disease and r e d u c e the incidence o f s u d d e n death. 2-7 However, even the most faithful proponents o f exercise admit that there are still uncertainties about the effect o f exercise in altering the course o f the disease in patients with known coronary heart disease and that myocardial ischemia, cardiac arrhythmias, and sudden death have been reported to o c c u r m o r e f r e q u e n t l y d u r i n g vigorous exercise. l,s,9 Probably the overall effect o f habitual exercise is beneficial. PHYSIOLOGIC EFFECTS OF EXERCISE T h e effects o f exercise depend on the type of exercise, duration, frequency, and intensity o f the activity. 1~ T h e type o f exercise may be static or isometric, and dynamic or isotonic depending on the type o f muscle activity that may be involved. Examples o f isometric exercise are weightlifting, hand-grip exercises, and pushing or pulling against resistance; examples o f isotonic exercise are running, swimming, and bicycling. T h e hemodynamic effects o f the two types o f exercise are obviously quite different. Isometric exercise leads to an increase in total peripheral resistance with a subsequent rise in mean, systolic, a n d diastolic a r t e r i a l blood p r e s s u r e with virtually little increase in heart rate, cardiac output, or stroke volume. T h e increase in resistance to blood Received from the Deparnnent 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 viewsof the Department of the Army or the Department of Defense. Address correspondenceand reprint requests to Dr. Virmani: Department of Cardiovascular Pathology,Armed Forces Institute of Pathology, Washington, DC 20306-6000. 0046-8177/87 $0.00 + .25

EFFECT OF DYNAMIC EXERCISE ON HEART AND CIRCULATION T h e heart and circulatory system are responsible for the transport o f oxygen from the atmosphere to the working tissues. At the beginning o f exercise, .heart rate increases within 0.5 second 12 because o f

493

HUMMq PATHOLOGY

Volume 18, No. 5 (May '1987]

decrease in vagal tone. 13 With m o d e r a t e work a steady-state h e a r t rate is r e a c h e d within 1 or 2 minutes, but if the exercise is severer, the rate continues to increase ~4 with a simultaneous increase in cardiac output. T h e maximum attainable heart rate is dependent on age and not on increased maximal oxygen uptake. Increased heart rate probably plays a major role in untrained subjects, although in trained subjects the stroke volume is considerably more important. As a rule a person's maximum heart rate can be estimated by subtracting his or her age from 220.1~ It is unusual for an adult to maintain a heart rate of more than 200 beats per minute over several minutes. T h e average "maximum" for a young man is about 195 beats per minute, and for women it is slightly higher at 198 beats per minute. The maximum heart rate is highest for children and preadolescents. 1~ Heart rates are higher for arm than for leg work. Physical conditioning decreases the heart rate at rest; heart rates of 40 to 50 beats per minute are common in highly trained endurance athletes. The mechanisms responsible are poorly understood but probably involve increased vagal tone, decreased sympathetic activity, and [3-adrenergic receptor density decrease in athletes as physical fitness increases. 15 Also, the m a x i m a l h e a r t rate achieved d u r i n g training is lower than that of the untrained person. Stroke volume also varies with the type o f activity. Values are greater on the treadmill than on the bicycle e r g o m e t e r 16 and are the greatest d u r i n g swimming? 7 Stroke volume can increase either as a restdt of greater ventricular filling during diastole or by more complete emptying during systole. Training improves the contractility of the heart and is dependent on length/tension (Starling's law). The increased contractility results in an increased ejection fraction. Animal experiments have shown that exercise produces an increase in myocardial capillary density and an increase in coronary flow and collateralization,18 but these have not been demonstrated in humans. 19 In patients with c o r o n a r y artery disease, recent studies suggest that global coronary blood flow may not increase with exercise. 2~ However, the main stimulus to an increase in coronary blood flow is probably a local reduction of oxygen tension that induces vasodilatation. T h e local accumulation of CO 2, adenosine, hydrogen ions, lactate, and other metabolites also contribute directly or indirectly to the vasodilatation. 22 Adrenaline and noradrenaline have a dilator action and both are liberated during sustained and vigorous exercise.

"ATHLETE HEART"

The clinical manifestations o f "athlete heart" as originally described include sinus bradycardia at rest, a soft systolic m u r m u r , audible third and f o u r t h heart sounds, and cardiomegaly on chest radiograph. 23-2s With the emergence o f echocardiography in the 1970s, it has been possible to assess non-

invasively cardiac dimensions in competitive athletes. 23 Long-term training produces "an increase in calculated left ventricular mass and is due to mild increase in either transverse end-diastolic dimension of left ventricle, increase in left ventricular wall thickness, or both. 23 T h e r e is an approximate 10 per cent increase in left ventricular end-diastolic dimension, a 15 to 20 per cent increase in left ventricular wall thickness, and about a 45 per cent increase in calculated left ventricular mass in athletes compared with matched control subjects. 23 T h e r e is evidence that modest increases in cardiac dimensions may develop rapidly (i.e., within weeks or months of initiation of vigorous exercise) and also may reverse in a similar time period after cessation of training. 29 The precise alterations in cardiac structure in athletes differ dep e n d i n g on the type of t r a i n i n g activity u n d e r taken. 27,3~Athletes participating in isotonic exercises are e x p o s e d p r i m a r i l y to conditions p r o d u c i n g volume overload and therefore will show increased left ventricular dimension without a significant increase in left ventricular wall thickness. 27,3~ Athletes participating primarily in isometric exercises, however, are exposed primarily to pressure overload and therefore will show increased left ventricular wall thickness with little or no increase in the cavity dimension.25.27, 30

CAUSE OF DEATH IN JOGGERS AND MARATHON RUNNERS

It is estimated that there are 25 million Americans who engage in running on a regular basis. Most of them are 20 to 59 years old and belong to middle and upper socioeconomic groups. Few smoke or are overweight, and nearly all claim to "feel better" when engaging in r e g u l a r exercise. T h e most f r e q u e n t mode of death is sudden, with sudden death defined as death occurring within six hours after the onset of symptoms. T h e incidence o f sudden death in the general population is high (15 to 20 per cent), with the majority (80 to 95 per cent) dying because of cardiovascular causes. Interest in causes of death in joggers and marathon runners was stimulated when claims were made that marathon running provided immunity against coronary heart disease. 31 Opie 32 in 1975 reported the first case o f sudden death secondary to coronary heart disease in a long-distance runner. Since that first publication, a n o t h e r 114 cases o f d e a t h in joggers have been reported (tables 1 and 2). Analysis of the 114 published reports shows that by far the most common cause o f death in joggers and marathon runners has been coronary atherosclerosis (73 per cent) (fig. 1).33-46 T h e other causes o f death have been automobile accidents, amyloidosis, congenital hypoplastic c o r o n a r y arteries, myocarditis, heat stroke, floppy mitral valve, and gastrointestinal hemorrhage. In 14 per cent of cases, the cause o f death was unknown.

494

CARDIAC PATHOLOGYAND SPORTSMEDICINE[Virmani & Robinowitz) I".AJBLE1. Published Reports of Causes of Death in Joggers and Marathon Runners Author, Reference, and Year Opie a2 (1975)

N u m b e r of Patients

Age M M

48

44

M

50

1

28

M

25

1

41

M

5

2 7 - 4 4 (37)

5 M

18

--

5

4 0 - 5 3 (46)

5 M

14-108 (51)

2 2

34, 54 51, 17

2 M 1 M, 1 F

9, 29

2 1

46, 54 47

1 M, 1 F *1

9, 10 70

Virnmni et al. 43 (1982)

30

18-57

30 M

Thompson et al. 44 (1982) Waller et al. 45 (1984) Virmani et al. 46 (1984) Virmani (1986)

12

2 8 - 7 4 (47)

10 11 11

TOTAL (up to 1986)

114

Green et al. sa (1976) Cantwell and Fletcher a4 (1978) Noakes et al. 35 (1979) Noakes et al. 36 (1979) T h o m p s o n et al. 37 (1979) Waller and Roberts 38 (1980) Morales et al. 39 (1982) Waller and Roberts 4~ (1982) Siegel et al. 41 (1982) CPC 4~ (1984)

1 1

46

1

Sex

Miles Run/Week (mean)

--

Duration in Years (mean) ---

Cause of Death

N u m b e r of Marathon Runners

1 CHD

1

?

1

"Many"

1 HC

1

1.2-7 (3.4)

2 CHD* 3 AA 13 CHD 1 Myocarditis 1 Heart stroke 3 Unknown

5

-8

---

2 1 - 5 0 (37) --

--

9-13t

14-108 (4.8)

5 CHD-~

-3 - 5 (4)

2 TCA 1 CHD 1 Hypo CA 2 Am)'loidosis I CHD

7 - 1 0 5 (33)w

2 "Several )ears'" 1 - 2 8 (10)w

12 M

3 - 2 5 (10) ~

1 - 1 0 (3.5) 1

3 7 - 6 4 (48) 1 9 - 5 9 (41)

10 M 11 *I

1-55

1-22

2 1 - 4 7 (37)

10 M, 1 F

18--74

I 11 M, 3 F

--

--

--

--

--

1

22 CHD 1 MVP 7 Unknown 11 CHD 1 GI h e m o r r h a g e 10 CHD 10 CHD 1 HC 7 CHD 2 Unknown 1 HC 1 AVS** 83 CHD 3 HC 3 AA 2 TCA 2 Amyloidosis 1 MVP 1 *lyocarditis 1 Heart Stroke 1 AVS 1 GI h e m o r r h a g e 1 Hypo CA 15 Unknown

ABBREVIATIONS: AA, atttomobile accident; AVS, aortic valve stenosis; CHD, coronary heart disease; GI, gastrointestinal; HC, hypertrophic cardiomyopathy; Hypo CA, congenital hypoplastic coronary arteries; MVP, mitral valve prolapse; TCA, tunnel coronary artery; - - , not available; ?, not determined. * History of acute myocardial infarction in one patient. t 14jogged > one year, and of these nine jogged > three )'ears; two had history of coronar)" heart disease. History of angina pectoris for two )'ears in one patient. w Detailed jogging histories were available in 18 patients; three had had acute myocardial infarction, a n d five had history of angina pectoris. 1 Exercise history available for five. ** Congenitally bicuspid calcified stenotic aortic valve.

C o r o n a r y Atherosclerosis In reported series and individual cases of death i n j o g g e r s a n d m a r a t h o n r u n n e r s ( t a b l e 1) b y f a r t i l e most frequent cause of death was coronary athero-

s c l e r o s i s ( 8 3 o f 1 14). T h e n u m b e r of coronary arteries severely narrowed (/>75 per cent cross-sectional area luminal narrowing) usually has been at least two vessels. We have reported our findings in 30 joggers or

495

HUMAN PATHOLOGY

Volume 18, No. 5 (May 1987) TABLE 2.

Published Reports of Causes of Death a m o n g Type o f Sport

Author, Reference, and Year Buddington et al. 4s (1974)

Number o f Patients 109

Age (Range)

Ball Games

Military Training

Running

Swimming

22

28

31

28

6

9

0

0

0

19 (13-20) -(10-49) 20 (17-29) 28 (14-60) 30 (8-47)

21

0

4

0

7

0

2

0

10--60

91 (36%)

(9-39) Opie 49 (1975)

21

Maron et al.47

29

Kennedy and Whitlock5~ (1984)

11

Waller et al. 45 (1984)

17

Virmani et al) 6 (1984)

32

Virmani (1986)

33

TOTAL

252

>30

.

.

.

.

13

6

8

2

13

9

6

1

46 (18%)

48 (19%)

9 (4%)

ABBREVIATIONS; CAA, coronary artery anomalies; CAs, coronary arteries; Cong, congenital; CHD, coronary heart disease; HC, hypertrophic cardiomyopathy; ICH, idiopathic cardiac hypertrophy; MVP, mitral valve prolapse. * Other causes of death included: sarcoidosis, one; subacute bacterial endocarditis, one; congenital heart disease, four; bronchopneumonia, one; unknown, 16. l" Type of sport: seven of nine ball players were rugby players; golf, one; mountaineering, one; jogging, one; yachting, one. Each sport was tabulated for athletes participating in more than one: swimming, one; boxing, one; hockey, one; soccer, one; tennis, one; gymnastics, one. w Other causes of death were ruptured aorta, two; one had hypoplasticas; and in one patient there was no evidence o f cardiovascular disease.

marathon runners who died nontraumatic deaths. 43 Twenty-two died with severe coronary atherosclerosis; their ages ranged from 27 to 57 years (mean, 41 years); all were men; and all had been jogging for more than six months. T h e history of jogging was 9well documented in 18 patients who ran seven to 105 miles per week (mean, 33) and had been running for one to 28 years (mean, 10 years). Three were marathon runners. The other 12 patients had been jogging for at least six m o n t h s . Review o f medical records of these patients revealed family history of heart disease in nine patients, systemic hypertension in nine patients, and a total cholesterol count of 200 mg/dl in seven patients. None were diabetic. Smoking history was not consistently recorded, and when present the details were not mentioned. A history of coronary heart disease was present in eight (27 per cent). Nineteen died suddenly (death occurred instantaneously or within an h o u r o f the onset o f symptoms), and three had a history of chest pain lasting two, 16, and 24 hours. In six patients, deaths occurred soon after jogging, and two were found dead in bed. At autopsy, the heart weights ranged from 345 to 600 g (mean, 432 g). In 16 patients the heart weights were increased beyond the normal range. Patients with a history of coronary heart disease had similar extent o f coronary atherosclerosis as those without such histories (1.7 versus 1.6 coronary arteries narrowed per patient). The majority of our pa496

tients had either one- or two-vessel disease. Three- or four-vessel disease was rare, a finding contrary to that in patients described by Waller and Roberts. 47 This may reflect the relative youth of our patients. Since the publications o f our article on nontraumatic death in 30 joggers, we have studied another 22 male patients. Their mean age was 39 years (range, 19 to 59 years) (table 1). Sudden death occurred while 20 o f 22 patients were jogging. T h r e e o f 22 had history of hypercholesterolemia, two had systemic hypertension, and one had a family history o f premature coronary heart disease. Only two of the 22 had a history of prior cardiac disease. One had angina pectoris, and one had a history o f myocardial infarction and had undergone left ventricular aneurysmectomy with coronary bypass surgery. Details of jogging history were only available in two. One was a 43-year-old man who had been jogging 50 miles per week for five to six years and had even participated in several marathons. His heart weighed 600 g; he had an acute myocardial infarction and had t>75 per cent cross-sectional area luminal narrowing of right, left anterior descending, and left circumflex coronary arteries by atherosclerotic plaques with a superimposed thrombus in the left circumflex (fig. 2). The second p a t i e n t , a 40-year-old female m a r a t h o n runner, died while jogging. Her heart weighed 350 g at autopsy, and there was a 70 per cent cross-sectional area luminal narrowing o f left anterior descending artery, and the right coronary artery had an

CARDIAC PATHOLOGYAND SPORTSMEDICINE(Virmani & Robinowitz] Competitive and Noncompetitive Athletes Cause o f Death CHD

IIC

Cong CAA

.MVP

lCtl

Myocarditis

SickleCell Trait

Tennis, 2; other, 14

43*

5

7

2

18

4

9

Referees, 4; tennis, 2;t other, 3 Wrestling, 3~t

18

0

0

0

0

0

0

3w

14

3

0

5

0

0

Soccer, 1; golf, I

71

2

1

0

0

0

0

**

0

4tt

2

2

6

0

0

Tennis, 2

8~t~:

2

3

2

4

4

3

Hiking 1; gymnastics, 1; athletic contest, 1; weightlifting, 1

14w167

2

2

3

2

2 ~1

1

36 (14%)

93w167 (37%)

30 (12%)

18 (18%)

9 (4%)

35 (14%)

Other

lO (4%)

13 (5%)

$ Unknown, one. ** Ten were competitive athletes at high school, college, or professional level. t t Other causes o f death included: Epstein tricuspid valve, one; and in two the hearts were normal. ~ Other causes o f death included: tunnel coronary artery, two; intramural coronary' artery" thickening, two; rhenmatic heart disease, one; aortic dissection, one. w167 Other causes o f death: tunnel coronary artery, one; intramyocardial coronary" thickening, two; multiple intramyocardial coronary artery emboli, one; status after surgical removal of cardiac myoxma, one; etiology unknown, two. ~I One had sarcoidosis, and the other had idiopathic lymphocytic myocarditis.

acute angle take-off. However, no acute necrosis or fibrosis was noted in the myocardium. Eleven of 22 patients had at least two-vessel disease, severely narrowed by atherosclerotic plaques. T h r e e had onevessel disease, and the others had been described as having severe c o r o n a r y atherosclerosis. Acute or healed myocardial infarcts were present in 10 of 17 patients. Two had hypertrophied hearts without coronary atherosclerosis, one had asymmetric septal hypertrophy, and the other had symmetric hypertrophy with history o f systemic hypertension. One had a congenitally bicuspid stenotic aortic valve, and two had normal hearts with mild left ventricular hypertrophy in one. T h e other reports of large series of joggers who died suddenly have been reported by Thompson et al. 37 and by Waller et al. 45 The series by Thompson et al. 37 described 18 joggers, with five "exercising regularly" for at least one year, and nine exercising regularly for three or more years. Details of jogging history were not available in the others. Fifteen of 18 died while j o g g i n g and o f these, 13 had coronary heart disease. Waller et al. 4s described 10 patients over 30 years o f age who ran one to 55 miles per week for one to 12 years. All had at least one coronary artery severely narrowed by an atherosclerotic plaque, and six had myocardial infarcts. It is apparent, therefore, that coronary atherosclerosis has been well described in joggers, but whether rtmning prolongs a jogger's life by decreasing the progression of coronary atherosclerosis remains unknown. 497

CAUSE OF DEATH IN COMPETITIVE ATHLETES Maron et al. 47 have described causes of sudden death in competitive athletes whom they define as "individuals who participate in an organized team or individual sport in which regular competition is a component, a high priority is placed on excellence and achievement and virgorous training in systematic manner is required." The age ranged from 13 to 30 years (mean, 19 years). Structural cardiovascular abnormalities were present in 28 (97 per cent), and in 22 (76 per cent) these were certainly a cause of death. The most common cause of sudden death was hypertrophic cardiomyopathy (HC), occurring in more than one half of the patients (14 patients). T h e mechanism by which sudden death occurs in patients with HC is unknown but probably structural-functional abnormalities predispose these individuals to malignant ventricular arrhythmias. Other cardiovascular a b n o r m a l i t i e s n o t e d were congenital a n o m a l o u s orgin of the left coronary artery from the right sinus of Valsalva in four, including one patient With HC, three with atherosclerotic coronary artery disease, and two with ruptured aorta secondary to Marfan's syndrome. In five patients, the exact cause of death was not certain; however, four had idiopathic concentric left ventricular hypertrophy, and one had mitral valve prolapse. One 17-year-old distance runner had a normal heart weight (280 g) but the coronary artery distribution was abnormal. The left main and left a n t e r i o r d e s c e n d i n g c o r o n a r y arteries were

HUMAN PATHOLOGY

Volume 18, No. 5 [May 1987]

Unknown 11% Coronary Heart 73%

Automobile Accidents

3%

Hypertrophic Cardiomyopathy

FIGURE t . C a u s e of death in 114 joggers and marathon runners.

Tunnel Coronary Arteries Amyloidosis

1% GI Hemorrhage

Hypoplastic Coronary Arteries Heat Stroke Myocarditis Aortic Valve Stenosis

normal, but the left circumflex gave rise to two small posterior descending branches and the right coronary artery was small in caliber and gave rise to two small branches to the lateral and posterior wall of right ventricle. No artery supplied the posterior wall o f left ventricle. O t h e r published reports 47-s~ of death in competitive and noncompetitive athletes describe a higher per cent with coronary heart disease and a lower incidence of hypertrophic cardiomyopathy (table 2). This difference may be a function of an athlete's age: the younger the athlete, the less the likelihood of dying from coronary heart disease; or the more highly trained an athlete, the greater the likelihood of developing hypertrophic cardiomyopathy. 47 Also, the precise prevalence of cardiovascular

diseases in a group of athletes dying suddenly probably cannot be derived from any of the published series because of limitations concerning patient selection. 5~ O f 252 competitive and noncompetitive athletes who died, idiopathic concentric h y p e r t r o p h y was seen as frequently as hypertrophic cardiomyopathy (fig. 3). Most of the athletes with concentric left ventricular hypertrophy had nondilated left ventricles with a heart weight between 450 to 500 g and a left ventricular wall thickness of 15 to 22 ram. T h e r e was only minimal or absent fibromnscular disorganization and no intramyocardial coronary thickening. It is possible that these patients had a variant of hypertrophic cardiomyopathy that is not genetically trans-

FIGURE 2. A 43-year-old man who jogged 50 miles per week for at least five years and had participated in several marathons died suddenly while running. His heart weighed 600 g, and there was a transmural acute myocardial infarction of the posterolateral wall of the left ventricle; however, no healed infarcts were seen. He had 75 per cent cross-sectional area luminal narrowing of left anterior descending (LAD], left diagnal (LD], left circumflex (LC), left obtuse marginal [LOM], and right [R) coronary arteries. The left main [LM] was the only artery not severely involved.

498

CARDIAC PATHOLOGYAND SPORTSMEDICINE[Virmani & Robinowitz)

Idiopathic Cardiac Hypertrophy Cornona~ Heart Disease 37%

14o~

Tunnel Coronal',/Artery - - ' ' 12%

Intra Mural Coronary Artery Thickenin,

yopathy

Bacterial Endocarditis Congenital Heart Disease , ~ Hypoplastic Coronary Arteries Sarcoidosis Coronary Emboli Aortic Dissection Rheumatic Heart Disease Myocarditis Epstein Tricuspid Valve Mitcal Valve Prolapse

10%

/

Sickle Cell Trait

"Normal" Heart

Congenital Coronary Artew Anornolies

FIGURE 3. Cause of death in 252 competitive and noncompetitive athletes who died suddenly.

mitted, or these patients may have had tmdetected systemic hypertension.

T h e r e f o r e , the role of sickle cell trait in causing sudden death remains unclear. Heat Stroke

Sickle Cell Trait a n d S u d d e n Deaths

We have observed the coexistence of sickle cell trait and sudden death during exercise. Among our 65 patients whose deaths were related to exercise, four had sickle cell trait (table 2). All had sickled red cells in various organs, and one also had rhabdomyolysis, diffuse intravascular coagulation, and acute tubular necrosis. Jones et al. 52 reported sudden death in four military recruits with sickle cell trait during basic training at an altitude of 4,000 feet. At autopsy, intravascular sickling was evident in most o f the organs. They suggested that red cell sickling resulted from hypoxia, metabolic acidosis, and dehydration during strenuous exercise. Koppes et al. 53 treated four men with sickle cell trait who collapsed during basic training and had intravascular coagulation, myoglobinuria, rhabdomyolysis, and acute renal failure. One of the four died with hyperkalemia and bleeding. However, others have shown that during treadmill exercise, patients with sickle cell trait do not demonstrate increased myocardial ischemia, cardiac arrhythmias, or ventricular dysfunction when comp a r e d with patients with normal h e m o g l o b i n . 54 499

By far the most important factor in s u d d e n death among athletes and joggers is the climate in which exercise is being performed. Serious thermal injuries are preventable and the American College of Sport Medicine recommends that long-distance races should not be conducted in temperatures that exceed 28~ (82.4~ 55 T h e r e are several reports of thermal injuries occurring during running in Australia, Canada, and the United States."~6 - 58 T h e physiologic response to exercise is hyperthermia. T h e amount of heat generated is related directly to the intensity of exercise. T h e body is only 25 per cent efficient in converting calories generated into external work, and the remaining 75 per cent of energy is c o n v e r t e d into heat. T h e r e f o r e a large amount of heat must be lost by the body to prevent raising the core temperature. If no heat were being lost by the body, then the core temperature of athletes would increase by I~ every 5 minutes. ~9 It is the efficient mechanisms o f thermoregulation of the body that prevent hyperthermia. T h e main mechanisms are sweating and heat loss by radiation and convection. The factors that may prevent

HUMAN PATHOLOGY

Volume 18, No. 5 (May '1987]

heat loss are high ambient temperatures, high humidity, dehydration (which prevents cutaneous vasodilatation), e x t r e m e s o f age, debility, excessive clothing, and drugs that may impair thermoregulationJ ~ The spectrum of heat injury includes three well-recognized syndromes: 1) heat cramps; 2) heat exhaustion; and 3) heat stroke. Heat cramps are painful spasms in the muscles in use. While heat exhaustion progresses to fatigue, hyperventilation, h e a d a c h e , l i g h t h e a d e d n e s s , nausea, and muscle cramps develop. Patients with heat exhaustion sweat but also have chills despite high core temperature. Heat stroke is by far the most serious of thermal injuries and is characterized by an altered state o f consciousness, which may progress rapidly to unconsciousness and seizure activity. The heat stroke patient is usually h o t a n d f l u s h e d , has d r y skin, tachycardia, and dehydration; circulatory collapse soon follows. Body temperature is usually above 4 I~ (106~ and the laboratory tests show hemoconcentration, leukocytosis, azotemia, acidosis, and abnormal liver function tests and muscle enzymes. Disseminated intravascular coagulation may occur. At autopsy, the findings are usually nonspecific and normally consist of petechial hemorrhages in the skin, mucous membranes, brain, lung, and heart. 6~ T h e hemorrhages in the heart are most pronounced in the epicardial and endocardial region--especially on the left side of the ventricular septum. 6~ Nonspecific vacuolation and hyaline changes may be seen in the myocardial fibers along with foci of contraction band necrosis. 6~ Damage to myocardial filaments and to intercalated discs have been described by electron microscopy in patients with malignant hyperthermia induced by anesthetic agents. 62 Other autopsy findings include cerebral and pulmonary edema and swelling of the liver, spleen, and kidneys. Factors that predispose runners to heat stroke include insufficient acclimatization, lack of conditioning, dehydration, age extremes, obesity, and a previous heat stroke. 6s ROLE OF EXERCISE IN PRECIPITATING SUDDEN DEATH

There are only a few studies that have assessed prospectively the role of exercise in precipitating sudden death, t In patients treated by paramedics in Seattle, 64 36 (11 per cent) o f 316 victims had collapsed during or immediately after exertion, and a similar number (17 per cent) has been reported in Miami. 65 Most of the autopsy studies on exertion-related sudden death have their limitations because they do not provide the total numbers of hours devoted to exercise by the victims. ~ Thompson et al. 44 in the state of Rhode Island reported 12 deaths related to jogging over a six-year period (i.e., a rate of 13 deaths per 100,000joggers per year, or one death per 396,000 hours of jogging). In contrast, the total death rate for sedentary individuals (i.e., expected and unexpected) was one death per three million 500

p e r s o n - h o u r s - - a 10-fold difference. Although these are derived numbers, they do point toward a casual relationship between physical exertion and sudden death. In a five-year survey by Hinkle, 66 42 per cent o f sudden deaths occurred in persons without previously known coronary heart disease. In another study on exercise-related deaths, 67 one cardiac arrest occurred in 375,000 person-hours of exercise. In the F r a m i n g h a m study, 6s-69 the incidence o f s u d d e n death was inversely related to the amount of physical activity. In the recent report from Seattle, 7~ the incidence o f cardiac arrest is five- to 56-fold greater during high-intensity exercise. Therefore, based on these studies, one can say that physical exertion may precipitate cardiac arrest in the normal population. However, no cost-effective screening programs are yet available to identify life-threatening cardiac problems in asymptomatic subjects who wish to participate in vigorous exercise programs. 71

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