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


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.[1] 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.[2] 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,[3] 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[4] in a runner nearing the end of a marathon was complicated since the athlete probably also had heat stroke.[5] 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[6] 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[7] that these findings were related to exercise induced high concentrations of catecholamines.[8]

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.[9] Coronary vasospasm secondary to frequent rises in catecholamine concentrations that result from very long endurance exercise, together with high shear stress[9] and turbulence,[9] could be responsible for endothelial injury. In dogs, submaximum exercise raises catecholamine concentration sufficiently to increase alpha-adrenergic coronary vasoconstrictor tone. [10]

This vasospasm in turn could be responsible for the focal necrosis that leads to the focal fibrosis of the myocardium.[11] A potential vicious cycle might be set up between coronary vasospasm, endothelial injury, and reduction or loss of endothelium-derived relaxing factor[12]" 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.[13] 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.[6]

With acute hypoxia during high-altitude marathons[7] run without acclimatisation[14] an imbalance betweeen myocardial oxygen supply and demand might be exacerbated by high concentrations of catecholamines[15] and by respiratory alkalosis,[14] both of which are conducive to coronary vasospasm.[10,16] Increased myocardial oxygen demand[13] occurs because of a high rate-pressure product resulting from hypoxia,[14] and exposure to cold. Both hypoxia and cold compound rises in catecholamine concentrations.[17]

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.[18] 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.[19] Exposure to heat also contributes to magnesium ion deficiency.[20] This deficiency increases release of catecholamines,[21] increases the potential for coronary vasospasm,[22] potentiates the vasoconstrictor action of catecholamines,[22] and—in combination with catecholamine infusions or stress—sensitises animals to myocardial necrosis.[23] Magnesium ion deficiency may precipitate a hypercoagulable state,[23] which may be aggravated by residual increased catecholamines (conducive to platelet aggregation and thrombin generation),[24] the increase in catecholamine concentration may persist until the second day after a marathon.[25] It is noteworthy that in a group of 20 patients with vasospastic (variant) angina Goto et al [26] 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[14] runner near the top of Pike's Peak,[7] 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[7] or of the myocardium.[11] An alternative mechanism for necrosis might be the cumulative effect of periods of less severe ischaemia (possibly totally silent[7]) secondary to unremitting endurance events.[27] 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.[13] 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.[28] Along with several other mechanisms,[11,13,29,30] formation of high concentrations of free fatty acids by catecholamine-induced lipolysis[19] can be very injurious.[30] However, emphasis has been placed on the ischaemic mechanism since the single case supporting this hypothesis showed evidence of exercise-induced ischaemia,[7] which could also explain the apparent recurrence of pulmonary oedema in the South African runners.[6] This mechanism also provides a teleological rationale[2] for ensuring adequate rest periods between endurance exercise for regression of ischaemia and endothelial repair. Furthermore, in the presence of an endothelial injury,[12] an ischaemic insult to the myocardium may occur at lower (ie, more plausible) catecholamine concentrations[10] than those possibly required for a direct myocardial injury.[29] 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.[31]

National registry
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[32] and in patients with vasospastic angina[33] suggest that the repair may take 2-6 months or longer. Some factors contributing to the severity of the injury would be exercise intensity[13] and duration,[8] and exposure to hypoxia,[14-16] cold,[17] and heat.[20] On the basis of these studies and the potential duration of residual magnesium deficiency,[18] 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.

Figure 1



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