Proceedings of the 8th. World Congress On Heart Failure Mechanisms and Management, Washington DC July 13-16,2002 (Advances in Heart Failure,91-94,CD ROM, Monduzzi Editore International Proceedings Division)

SPACE FLIGHT-RELATED ENDOTHELIAL DYSFUNCTION

WITH POTENTIAL CONGESTIVE HEART FAILURE

William J. Rowe, M.D.

Former Assistant Clinical Professor of Medicine

Medical University of Ohio at Toledo

Web Site:  www.femsinspace.com

Summary

            Despite invariable dehydration on space flights, there is the potential for congestive heart failure, resulting from endothelial dysfunction.  There is decreased thirst, inappropriate diuresis, atrophy of water storage sites in muscle, and reduced plasma volume.  This triggers angiotensin and catecholamine elevations and vicious cycles with magnesium (Mg.) ion deficits.  This leads in turn to oxidative stress, endothelial dysfunction/injuries, and insulin resistance.  Contributing to endothelial dysfunction and potential congestive failure is space flight-related thrombocytopenia, precipitating reduced vascular endothelial growth factor (VEGF).  Elevations of inflammatory cytokines and endothelin secondary to Mg. ion deficiencies also are likely contributing factors.

Introduction

            Space flight-related studies are limited since only about 500 humans have been in space.  There is hypokinesia, with loss of storage sites for Mg. in skeletal muscles and bone.  Contributing factors to a Mg. deficit are malabsorption and vicious cycles with catecholamine and angiotensin effects.1,2  Microgravity causes a shift of fluid to the upper body, conducive to decreased thirst and inappropriate diuresis, compounding a loss of water storage sites in skeletal muscle.  There is an early loss of extracellular fluid and on longer missions possible loss of intracellular fluid, triggering angiotensin elevations and a decrease of water's antioxidant effect.3,4  Even without the adverse effects of radiation, space missions are conducive to oxidative stress, resulting in endothelial dysfunction/injuries to the normal heart.1-3

In Vitro, Animal, Human Studies

            Cultured cells of human vascular endothelium are sensitive to simulated microgravity, resulting in a significant decrease in cell proliferative activity.  With longer durations there are further changes of the cell cytoskeleton, manifested by microfilament thinning with alterations in their distribution within the cell.5 

            Experimental animals show significantly increased norepinephrine concentrations in heart tissue, destructive changes of the mitochondria with serious myocardial pathology, atrophy, endothelial injuries with narrowing and occlusions of the microcirculation and impairment of repair mechanisms with suppression of synthesis of myocardial proteins.4

            Regarding humans, a unique example is provided by an unusual sequence of events preceding and during the 12 day Apollo 15 mission.  Both Irwin and Scott experienced severe pain and edema of the fingertips, which I postulated to be a result of endothelial injuries, secondary to peripheral vasospasm and fluid trapped distally.  This could serve as a warning that coronary vasospasm, with silent ischemia might exist as well (The Apollo 15 Space Syndrome).  Contributing to oxidative stress might have been heat-related Mg. deficits in training, followed by the use of 100% oxygen6 for 3 hours before lift-off to prevent decompression sickness.  In addition severe dehydration was encountered while working on the lunar surface because the in-suit water devices did not function properly.  Irwin had an episode of syncope complicating a bigeminal rhythm while transferring to the command module.  During reentry at 7G's he had typical symptoms of angina with severe dyspnea consistent with left heart failure.  Twenty-one months later he had an acute myocardial infarction.3

 Mechanisms and Space-Related Studies

             Mg. deficits are conducive to insulin resistance, which can be precipitated by microvascular injuries.  Space mission studies have demonstrated Mg. deficits, insulin resistance shown by excess C-peptide excretion and reduced cyclic-GMP (a second messenger of nitric oxide [NO]).2 

             Space flights are complicated by loss of body protein, one of which is transferrin, requiring both magnesium7 and insulin8 to sequester iron.  A transferrin deficiency is conducive to increased "free" iron, thereby contributing to oxidative stress.9 

             With a magnesium deficit there is the potential for congestive heart failure10 secondary to elevations of both inflammatory cytokines and endothelin.11,12  On the first day of a space flight, studies by Stein et. al13 showed significant elevations of interleukin 6 excretion.14

             Finally both VEGF and platelets4 are reduced in space.15  It has been shown by Gunsilius et al.16 that platelets are the major source of VEGF in the serum.  Since insulin resistance may also lead to decreased VEGF expression,17 these conditions could play a major role in contributing to endothelial dysfunction and in turn congestive failure.  The etiology of the thrombocytopenia is unknown, but conceivably it may be at least partially caused by reductions in NO.1,2,18  (Figure)

 Conclusions

             Congestive heart failure secondary to both coronary and peripheral endothelial dysfunction, can occur on space missions, despite invariable dehydration.  A Mg. ion deficit is the centerpiece of several vicious cycles, primarily with angiotensin and catecholamines, even on relatively short missions under the right circumstances.  The space-related mechanisms described, are consistent with the self-sustaining vascular inflammation mechanisms, now well established as a process conducive to atherosclerosis.

 

References

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 2.   ROWE WJ.  Potential myocardial injuries to normal heart with prolonged space mission: The hypothetical key role of magnesium, Mag Bull 22; 15-19: 2000

 3.  ROWE WJ.  The Apollo 15 space syndrome.  Circulation 97; 119-120: 1998

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12.  WEGLICKI WB, PHILLIPS TM.  Pathobiology of magnesium deficiency:  A cytokine/neurogenic inflammation hypothesis.  Am J Physiol 263; R734-R737: 1992

13.  STEIN TP, SCHLUTER MD.  Excretion of IL-6 by astronauts during spaceflight.  Am J Physiol 266; E448-E452: 1994

14.  BRASIER AR, RECINOS A, ELEDRISI, MS.  Vascular inflammation and the renin-angiotensin system.  Arterioscler Thromb Vasc Biol 22; 1257-1266: 2002

15.  GUNSILIUS E, PETZER AL, GASTI G.  Space flight and growth factors (letter).  Lancet 353; 1529: 1999

16.  GUNSILIUS E, PETZER AL, STOCKHAMMER G et al.  Thrombocytes are the major source for soluble vascular endothelial growth factor in peripheral blood.  Oncology 58; 169-174: 2000

17.  CHOU E, SUZUMA I, WAY KJ et al., Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states.  Circulation 105; 373-379: 2002

18.  BATTINELLI E, WILLOUGHBY SR, FOXALL, T et al.  Induction of platelet formation from megakaryocytoid cells by nitric oxide.  Proc Nat Acad Sci 98; 14458-14463: 2001