Acta Astronautica Vol. 40. No. 10. pp. 719-722. 1997
©1998 Elscvier Science Ltd. All rights reserved
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(Received 2 May 1996)

Abstract—This hypothesis is that some crewmen on prolonged space flights may develop permanent myocardial injury despite the absence of coronary atherosclerosis and even without the hazards of radiation beyond orbit. This may result from atrophy of skeletal muscle and bone resulting in magnesium ion deficiency predisposing to a vicious cycle with catecholamine elevations, with the latter aggravated by stress, dehydration-provoked angiotensin elevations, unremitting endurance exercise, and in turn a second vicious cycle with severe ischemia. Toxic free radicals can develop complicating ischemia and potential high radiation, with magnesium ion deficiency and high vascular catecholamines playing contributing roles. These free radicals may lead to inactivation of endothelium-derived relaxing factor (EDRF) causing coronary endothelial injury by a third vicious cycle, increased peripheral resistance and coronary vasospasm intensifying ischemia. Local and systemic thrombogenesis could contribute ultimately to focal fibrosis of the myocardium. if the ischemia is not recognized. Sufficient magnesium and time for repair are vital. ©1998 Elsevier Science Ltd. All rights reserved

It appears logical to assume that man will not survive extended space travel without the benefits of unremitting endurance exercise to ward off complications related to disuse atrophy in a microgravity environment. An hypothesis has been put forth previously showing how extraordinary unremitting endurance exercise can injure permanently a normal heart [1], and it has been suggested that some of these concepts could be utilized in selecting crew-men for space missions [2]. There is an apparent dilemma regarding the necessity of exercise on space missions since too much may cause a magnesium ion deficit—often not suspected by routine blood studies [1-3]—and too little exercise may cause a negative magnesium balance secondary to bone and muscle tissue catabolism [4. 5]. Furthermore without sufficient magnesium ion, it is conceivable that cardiac tissue injured from space missions may not be adequately repaired [6]. In addition to an exercise-related factor, sleep deprivation [2] and emotional stress might contribute to catecholamine elevations in microgravity (4, 7, 8].

Although some studies have shown conflicting catecholamine concentrations [9], it is noteworthy that plasma norepinephrine is a poor indicator of changes in sympathetic nervous system activity [10] since plasma norepinephrine lacks sensitivity [11]. Beyond orbital range potentially serious radiation hazards may develop, adding further potential injuries to the normal heart [12]. These potential cardiac insults might conceivably all be caused by ischemic mechanisms [12-15] rather than necessarily postulating a direct myocardial injury [1].

Experimental animals after orbital flights of only several weeks, and without confounding factors related to exercise or significant radiation hazards, show impairment of coronary microcirculation with endothelial injuries and occlusions of small vessels which appear to be stress-related injuries and show as well "serious myocardium pathology". Experimental animals also show significant increases of cardiac tissue norepinephrine concentrations. In addition there is evidence of pronounced disuse atrophy of cardiac muscle, suppression of myocardial protein synthesis, and renewal of myocardial structure appears inhibited [7]; the latter suggests an adverse effect upon the repair mechanism [6].

A round trip to Mars is estimated to last about 600 days [16]. The present exercise program (Salyut scheduling) incorporates the use of treadmills and ergometers with exercise sessions up to 1 hour, twice per day. with 3 days of training and 1 day of active rest, with target heart rates up to 140-160 beats per minute [16. 17]. It has been postulated [7] that an increase in angiotensin levels shown among crewmen could be a result of a compensatory response to a reduction in intravascular volume [8] resulting in part from insufficient work loads reflected by skeletal muscle atrophy in space [5]. Raised angiotensin II could increase the release of catecholamines [18], increase vascular responsiveness to these hormones [19] and could thereby enhance the potential for clotting by accentuating caiecholamine-induced platelet aggregation [1].

These adverse angiotensin effects would compound the effects of catecholamines—demonstrated by high urinary excretions of catecholamines, for example following the second manned Skylab mission [8]. In addition significant microgravity-induced losses of body magnesium and skeletal muscle loss have been demonstrated "despite vigorous exercise regimens" [5].

Both high catecholamines and magnesium deficiencies are conducive to coronary vasospasm [1]. It has been postulated that both high catecholamines and magnesium deficiency-induced cardiac injury can occur at least partially as a result of a free radical-mediated mechanism [13-15]. Furthermore Seelig [15] has emphasized that focal necrosis of the myocardium can be induced in rats by a single dose of catecholamines—which could simulate exercise-induced levels [1]—with pathology of the myocardium under these circumstances similar to that in experimental animals with magnesium deficiency [14]. This same finding, i.e., small focal lesions "consistent with a remote ischemic insult", was found in the cardiac muscle of the case supporting the hypothesis of exercise-induced heart disease [20] precipitated by the same physiological vicious cycles described below.

Just as an ischemic mechanism could be responsible for injury of the myocardium from extraordinary unremitting endurance exercise [20], the lesions described in experimental animals in space [7] could be entirely on an ischemic basis rather than postulating a direct myocardial injury. In humans, vicious cycles could exist between high catecholamines—complicating exercise along with microgravity stress and angiotensin elevations—and reduced magnesium ion levels [3], and between severe ischemia and high catecholamines [1]. Both high radiation [7, 12] and ischemia (hypoxia) can cause an elevation of superoxide anion and other free radicals [21]; these can contribute to a reduction of EDRF [22. 23]. This in turn would be conducive to constriction of both coronary and peripheral vessels with the latter increasing oxygen demand by high peripheral resistance particularly with exercise.

Velocity gradients especially of the coronary circulation would be appreciably enhanced with high shear stress and turbulence increasing the potential for focal endothelial injuries [24] and the creation of a third potential vicious cycle [1] .

There would be in addition a predisposition for local thrombogenesis secondary to endothelial injury [24] as well as systemic thrombogenesis complicating high catecholamines [1], elevated angiotensin indirectly [19]. and reduced magnesium levels [3], in turn predisposing to irreversible cardiac injuries. There could be multiple occlusion-reperfusion cycles with stunning, complicating oxygen-derived free radicals contributing still further to inactivation of EDRF [22].

These complex mechanisms conceivably all related to ischemia provide a "second chance", since there is the potential for regression before irreversible cardiac injury occurs, by fine-tuning the frequency, intensity, and duration of exercise during a space mission, combined with the use of antioxidant supplements along with an antioxidant-rich diet [15]. It has been postulated [25] that cardiac tissue is selectively vulnerable to free radical injury since the heart has lower levels of protection by antioxidants such as Superoxide Dismutase. Regarding endothelial repair, even psychological stress may slow this process [26]. There must be adequate time allotted for repair [27] by individualizing [17] the frequency of exercise. Magnesium—required for DNA replication—is vitally important for endothelial repair and in the presence of a magnesium deficit, there may be inadequate angiogenesis [6]. Furthermore, Seelig [3] has emphasized that when magnesium and potassium deficiencies coexist—as might occur with prolonged hypokinesia [4, 5. 28]— repletion of magnesium is necessary for correction of a cellular potassium deficiency. In addition to the greater vulnerability of the heart to free radical injury [25], the heart is also particularly vulnerable to a magnesium deficiency, because of its dense mitochondrial structure and high enzyme content [3].

Based on an ischemic hypothesis, preliminary studies [29] suggest a rationale for screening prospective crewmen for an angiotensin converting enzyme (ACE) DD Genotype which may be associated with elevated levels of angiotensin II [2]. This would accentuate the vascular complications of potential space-related elevations of angiotensin as previously discussed (Fig. 1). Just as with potential marath-oners it seems reasonable to reject astronauts for interplanetary missions with high cholesterol levels and hypertension—even when both are corrected— since these conditions may predispose to both coronary and peripheral vascular constriction enhancing the likelihood of cardiac ischemia even in the absence of coronary atherosclerosis [2]. Moreover, recent studies suggest that individuals with an otherwise low risk for coronary artery disease may be more likely to have a genetic predisposition for vascular disease involving the renin-angiotensin system [29].

With an underlying ischemic mechanism, it appears appropriate to draw (for example at 2-week intervals) serial Tropinin I blood samples—which are highly sensitive and specific [30]—to determine approximately when myocardial necrosis might occur. These blood samples could possibly be preserved by freezing to -70" C. and determinations for Tropinin I delayed until return from a round-trip mission to Mars of about 600 days [16, personal communication A. Jaffe]. These studies could be performed in conjunction with non-invasive tests exemplified by Positron Emission Tomography (PET) scans and echocardiograms before and after a space mission. If permanent injury develops, characterized by acquired fibrosis, its degree possibly could be quantified; for example, impaired cardiac wall motion in conjunction with a "PET match pattern" has been shown to be correlated with extensive myocardial fibrosis [31].

Extrapolating from limited data derived from orbital flights, man's cardiac tolerance to interplanetary travel appears quite poor without the protective devices of genetic engineering [32]. This may be in the final analysis more practical from a financial standpoint than attempting to simulate gravity entirely (1 G)—avoiding the necessity of unremitting exercise—and attempting complete shielding from radiation. As we approach the next millennium these considerations are particularly pertinent.

Acknowledgements—I thank Nicholas Booth for his advice and triggering my interest in developing this hypothesis; Anders Hansson. Ph.D.. who shared some of his expertise in space technology with me; and similarly Prof. Kaare Rodahl, M.D., in exercise physiology; Allan Jaffe, M.D., for his critical review of this manuscript; and Jeff Kenkel for his construction of Fig. 1.

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Recent evidence has been published [33] indicating that the normal life span of an adult human endothelial cell has been estimated to be around 30 years. The regenerated cells, however are dysfunclional. predisposing to vasoconstriction [33]. Since young women retain magnesium better on marginal magnesium intakes than do young men [34]. and estrogens have been shown to have several cardio-vasular protective effects [35-37]. a case can be made for selecting an all-female astronaut crew to Mars with return prior to age 30.

†Delivered in part at the 11th IAA Man-in-Space Symposium, Toulouse. France, 28 March 1995.