Sy Mah's Stress Test
THE LANCET VOL 340: SEPT 19, 1992, pp. 712-714
Extraordinary unremitting endurance exercise and permanent injury to normal heart
WILLIAM J. ROWE, MD
This hypothesis is that permanent cardiac injury could develop in some endurance athletes despite the absence of coronary atherosclerosis and ventricular hypertrophy. The proposed mechanism by which this injury could arise involves two physiological "vicious cycles". The first vicious cycle would occur between severe ischaemia and high catecholamines, the second would be between coronary vasospasm (induced by high catecholamines) and endothelial injury. The likelihood of the injury becoming permanent might increase if there is insufficient time between bouts of endurance exercise for regression of ischaemia and endotheliat repair. Furthermore, magnesium ion deficiency, which can be induced byexercise, could exacerbate these vicious cycles and also contribute to catecholamine-induced thrombogenesis. In addition to ischaemia, there are several mechanisms, including the effect of free fatty acids liberated by the lipolytic effect of high catecholamines, that could cause direct myocardial injury.
Early man's survival before the development of even the crudest of weapons probably depended on his capacity for great endurance. This capacity is exemplified today by the Tarahumara Indians of northern Mexico who can chase a deer for up to 2 days until the animal drops from exhaustion. Primitive hunting societies follow a "Palaeolithic rhythm" of 1 or 2 days of hunting, 6 to 8 hours a day, followed by 1 or 2 days of rest. Could some endurance athletes benefit by this restraint? In the past 2 decades there has been a sharp increase in the number of extremely challenging endurance events. Such events include the world's longest annual ultramarathon (over 1000 km) in Australia, and in the USA the most arduous yearly marathon, to Pike's Peak (4300 m). The cavalier attitude to the potential cardiac risk may result partly from the popular belief promulgated by Karvonen and cited in a widely circulated textbook of the heart, that there is no evidence that strenuous athletic activity in a trained individual with a normal heart increases the risk of early death or morbidity from cardiovascular disease.
Morbidity related to endurance exercise
The case of a fatal myocardial infarction in the absence of significant coronary atherosclerosis reported by Green et al in a runner nearing the end of a marathon was complicated since the athlete probably also had heat stroke. Acute pulmonary oedema developed in 2 apparently healthy participants near the end of the 90 km Comrades Ultramarathon in South Africa. Follow-up studies revealed that the athletes' coronary arteries were angiographically normal and that there were no other apparent confounding factors With regard to a permanent cardiac injury, Sy Mah, who set a world record of 524 marathons, was shown by stress tests to have probable exercise-induced coronary vasospasm with circadian variation 9 months before death from lymphoma at age 62 years. There was no history of heat stroke,[4,5] nor were any other confounding factors found at necropsy, which revealed focal fibrosis of the left ventricular papillary muscles. It was postulated that these findings were related to exercise induced high concentrations of catecholamines.
Two vicious cycles generating ischaemia and injury
The aetiology of coronary vasospasm is not fully understood. Only a 40-60% reduction in luminal diameter for 1 h is required to produce arterial endothelial damage and thrombosis. Coronary vasospasm secondary to frequent rises in catecholamine concentrations that result from very long endurance exercise, together with high shear stress and turbulence, could be responsible for endothelial injury. In dogs, submaximum exercise raises catecholamine concentration sufficiently to increase alpha-adrenergic coronary vasoconstrictor tone. 
This vasospasm in turn could be responsible for the focal necrosis that leads to the focal fibrosis of the myocardium. A potential vicious cycle might be set up between coronary vasospasm, endothelial injury, and reduction or loss of endothelium-derived relaxing factor" Since acute severe myocardial ischaemia caused by high concentrations of catecholamines induces release of catecholamines from the adrenal medulla and myocardial nerve endings, there is the potential for a second vicious cycle. By impairing left ventricular function, both cycles could have been responsible for the exercise-induced pulmonary oedema described above. Both runners had had similar symptoms while completing ultramarathons the previous year.
With acute hypoxia during high-altitude marathons run without acclimatisation an imbalance betweeen myocardial oxygen supply and demand might be exacerbated by high concentrations of catecholamines and by respiratory alkalosis, both of which are conducive to coronary vasospasm.[10,16] Increased myocardial oxygen demand occurs because of a high rate-pressure product resulting from hypoxia, and exposure to cold. Both hypoxia and cold compound rises in catecholamine concentrations.
Magnesium deficiency and thrombogenesis
Magnesium ion deficiency is a further possible complication of long exercise,[18-20] some deficiency may still be present 3 months later. The mechanism is not clear, but may be partly due to removal of free magnesium ions from the circulation by chelation with catecholamine-induced free fatty acids. Exposure to heat also contributes to magnesium ion deficiency. This deficiency increases release of catecholamines, increases the potential for coronary vasospasm, potentiates the vasoconstrictor action of catecholamines, and—in combination with catecholamine infusions or stress—sensitises animals to myocardial necrosis. Magnesium ion deficiency may precipitate a hypercoagulable state, which may be aggravated by residual increased catecholamines (conducive to platelet aggregation and thrombin generation), the increase in catecholamine concentration may persist until the second day after a marathon. It is noteworthy that in a group of 20 patients with vasospastic (variant) angina Goto et al  showed that almost half had magnesium ion deficiency that is often unrecognised.[19,21,26]
Ischaemic mechanism for necrosis
It is conceivable that with a near-maximum brief effort by an unacclimatised runner near the top of Pike's Peak, spasm[10,15-17,22] of one or more coronary vessels together with profound increase in myocardial oxygen demand[13-15,17] might precipitate focal necrosis of a papillary muscle or of the myocardium. An alternative mechanism for necrosis might be the cumulative effect of periods of less severe ischaemia (possibly totally silent) secondary to unremitting endurance events. This concept may be applicable to the hypothesis proposed even in the absence of coronary atherosclerosis, provided there is sufficient increase in myocardial oxygen demand. Contributing factors would be potential local[9,24] and systemic[23-25] hypercoagulability.
Direct myocardial injury
The mechanism for catecholamine-induced myocardial scarring[11-13] is not limited to ischaemia. Along with several other mechanisms,[11,13,29,30] formation of high concentrations of free fatty acids by catecholamine-induced lipolysis can be very injurious. However, emphasis has been placed on the ischaemic mechanism since the single case supporting this hypothesis showed evidence of exercise-induced ischaemia, which could also explain the apparent recurrence of pulmonary oedema in the South African runners. This mechanism also provides a teleological rationale for ensuring adequate rest periods between endurance exercise for regression of ischaemia and endothelial repair. Furthermore, in the presence of an endothelial injury, an ischaemic insult to the myocardium may occur at lower (ie, more plausible) catecholamine concentrations than those possibly required for a direct myocardial injury. Epidemiological studies to confirm this hypothesis would require necropsy examinations to establish the presence of focal fibrosis and to exclude confounding factors. One factor would be pathological ventricular hypertrophy since this process may itself cause myocardial necrosis.
It is conceivable that an injury to the coronary endothelium resulting from endurance exercise might be perpetuated by unrelenting scheduling of events without sufficient time for endothelial repair. Studies in an animal model and in patients with vasospastic angina suggest that the repair may take 2-6 months or longer. Some factors contributing to the severity of the injury would be exercise intensity and duration, and exposure to hypoxia,[14-16] cold, and heat. On the basis of these studies and the potential duration of residual magnesium deficiency, it seems appropriate to consider a national computer registry of entrants in very arduous endurance events such as ultramarathons and high-altitude marathons. The requirement of a minimum interval of 3 months between these events seems reasonable.
I thank Dr James T. Willerson for reviewing the manuscript and for his encouragement, and to Mr Jeffrey Kenkel for construction of the figure.
1. Bennett WC, Zingg RM. The Tarahumara: an Indian tribe of northern Mexico. Chicago: University of Chicago Press, 1935: 113.
2. Eaton SB, Shostak M, Konner M. The Paleolithic prescription. A program of diet & exercise and a design for living. New York: Harper and Row, 1988:32.
3. Wenger NK, Gilbert CA. The athlete's heart. In: Hurst JW, Logue RB, Schlant RC, Wenger NK, eds. The heart arteries and veins, 3rd ed. New York: McGraw-Hill, 1974: 1546.
4. Green LH, Cohen SI, Kurland G. Fatal myocardial infarction in marathon racing. Ann Intern Med 1976; 84: 704-06.
5. Knochel JP, Beisel WR, Herndon EG, Gerard ES, Barry KG. The renal, cardiovascular, hematologic and serum electrolyte abnormalities of heat stroke. Am 3 Med 1961; 30; 299-309.
6. McKechnie JK, Leary WP, Noakes TD, Kallmeyer JC, MacSerraigh ETM, Olivier LR. Acute pulmonary oedema in two athletes during a 90-km running race. 5 Afr MedJ 1979; 56: 261-65.
7. Rowe WJ. A world record marathon runner with silent ischemia without coronary atheroslerosis. Chest 1991; 99: 1306-08. 8. Dearman J, Francis KT. Plasma levels of catecholamines, cortisol and beta-endorphins in male athletes after running 26-2, 6, and 2 miles. J Sports Med Phys Fitness 1983; 23: 30-38.
9.Gert2 SD, Uretsky G, Wajnberg RS, Navot N, Gotsman MS. Endothelial cell damage and thrombus formation after partial arterial constriction: relevance to the role of coronary artery spasm in the pathogenesis of myocardial infarction. Circulation 1981; 63: 476-86.
10. Chilian WM, Harrison DG, Haws CW, Snyder WD, Marcus ML. Adrenergic coronary tone during submaximal exercise in the dog is produced by circulating catecholamines: evidence for adrenergic denervation supersensitivity in the myocardium but not in coronary vessels. Circ Res 1986; 58: 68-82.
11. Factor SM, Sonnenblick EH. The pathogenesis of clinical and experimental congestive cardiomyopathies: recent concepts. Prog Cardiovasc Dis 1985; 27:395-420.
12. Furchgott RF. Role of endothelium in responses of vascular smooth muscle. Circ Res 1983; 53; 557-73.
13. Rona G. Catecholamine cardiotoxicity. J Mol Cell Cardiol 1985; 17: 291-306.
14. Astrand P-O, Rodahl K. Textbook of work physiology physiological bases of exercise, 3rd ed. New York: McGraw-Hill, 1986: 685-706.
15. Escourrou P, Johnson DG, Rowell LB. Hypoxemia increases plasma catecholamine concentrations in exercising humans, J Appl Physiol 1984; 57:1507-11.
16. Yasue H, Nagao M, Ornote S, Takizawa A, Miwa K, Tanaka S. Coronary arterial spasm and Prinzmetal's variant form of angina induced by hyperventilation and tris-buffer infusion. Circulation 1978; 58: 56-62.
17. Hiramatsu K, Yamada T, Katakura M. Acute effects of cold on blood pressure, renin-angiotensin-aldosterone system, catecholamines and adrenal steroids in man. Clin Exp Pharmacol Physiol 1984; II: 171-79.
18. Stendig-Lindberg G, Shapiro Y, Epstein Y, et al. Changes in serum magnesium concentrations after strenuous exercise. J Am Coll Nutr 1987; 6:35-40.
19. Ryzen E, Servis KL, Rude RK. Effect of intravenous epinephrine on serum magnesium and free intracellular red blood cell magnesium concentrations measured by nuclear magnetic resonance, J Am Coll Nutr 1990; 9; 114-19.
20. Beller GA, Maher JT, Hartely LH, Bass DE, Wacker WEC. Changes in serum and sweat magnesium levels during work in the heat. Aviat Space Environ Med 1975; 46: 709-12.
21. EbelH,GuntherT. Magnesium metabolism: a review. J Clin Chem Clin Biochem 1980; 18:257-70.
22. Prasad DM, Turlapaty V, Altura BM. Magnesium deficiency produces spasms of coronary arteries: relationship to etiology of sudden death ischemic heart disease. Science 1980; 208: 198-200.
23. Seelig MS, Heggtveit HA. Magnesium interrelationships in ischemic heart disease: a review. Am J Clin Nutr 1974; 27; 59-79.
24. Badimon L, Badimon JJ, Fuster V. Pathogenesis of thrombosis. In: Fuster V, Verstraete M, eds. Thrombosis in cardiovascular disorders. Philadelphia: Saunders, 1992:17-39.
25. Maron MB, Horvath SM, Wilkerson JE. Blood biochemical alterations during recovery from competitive marathon running. Eur J Appl Physiol 1977; 36:231-38.
26. Goto K, Yasue H, Okumura K, et al. Magnesium deficiency detected by intravenous loading test in variant angina pectoris. Am J Cardiol 1990; 65:709-12.
27. Geft IL, Fishbein MC, Ninomiya K, et al. Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circulation 1982; 66:1150-53.
28. Todd GL, Baroldi G, Pieper GM, Clayton FC, Eliot RS. Experimental catecholamine-induced myocardial necrosis. II. Temporal development of isoproterenol-induced contraction band lesions correlated with ECG, hemodynamic and biochemical changes. J Mol Cell Cardiol 1985; 17: 647-56.
29. Kondo T, Ogawa Y, Sugiyama S, lto T, Sarake T, Ozawa T. Mechanism of isoproterenol induced myocardial damage. Cardicwasc Res 1987; 21: 248-54.
30. Majumder S, Singal PK, Ganguly PK. Catecholamines and heart disease: possible metabolic interventions. In: Ganguly PK, ed. Catecholamines and heart disease. Boca Raton, Florida: CRC Press, 1991: 267-75.
31. Laks MM. Functional status of the sympathetic nervous system in cardiovascular disease—the role of norepinephrine in the production of physiologic and pathologica hypertrophy. In: Ganguly PK, ed. Catecholamines and heart disease. Boca Raton, Florida: CRC Press, 1991:103-22.
32. Schwartz SM, Stemerman MB, Benditt EP. The aortic intima II. Repair of the aortic lining after mechanical denudation. Am J Pathol 1975; 81: 15-31.
33. Previtali M, Panciroli C, DePonti R, Chimienti M, Montemartini C, Salerno JA. Time-related decrease in sensitivity to ergonovine in patients with variant angina. Am Heart J 1989; 117: 92-99.