The maximal oxygen uptake (˙VO2max) is used to evaluate cardiovascular function in health and disease. It is reduced by bed rest(1-11,16,18-21,24-26,30-34,36-39,41-45), and the magnitude of its loss is dependent upon the duration of confinement(Fig. 1). The high correlation between duration of bed rest and reduction in ˙VO2max indicates a loss in aerobic capacity of 0.9% per day over 30 d of bed rest. Relative reduction (%Δ) in˙VO2max with bed rest is similar across and independent of gender and age (9,18,24). However, highly fit individuals who have greater ˙VO2max will sometimes demonstrate greater absolute reduction in their aerobic reserve compared with sedentary people (9,18,20,43), but not always(33,34). Therefore, duration of exposure and initial fitness and health are important for determining the magnitude of cardiovascular responses to bed rest.
Determination of the level and change in ˙VO2max provides a good measure of the cardiovascular consequences of bed rest because it represents the product of change in both central (cardiac output) and peripheral (oxygen delivery and utilization) factors. The purpose of this paper is to review data and discuss possible mechanisms that underlie the reduction in cardiovascular reserve associated with reduction of ˙VO2max in healthy subjects confined to prolonged bed rest.
The ˙VO2max decreased by 26% in five young male subjects after 21 d in bed (43), which was similar to the 26% reduction in maximal cardiac output from 20.0 l·min-1 before to 14.8 l·min-1 after bed rest. The slight compensatory increase in maximal heart rate from 193 beats·min-1 before to 197 beats·min-1 after bed rest did not compensate for the average reduction in stroke volume from 104 to 74 ml. The arteriovenous oxygen difference was unchanged, indicating that compromised stroke volume was the primary mechanism for reduction in ˙VO2max induced by bed rest.
Maximal heart rate. Both submaximal and maximal heart rate are increased during bed rest(8-11,16,18,19,23,24,26,31,46). Heart rate is higher for the same oxygen requirement (Fig. 2), and there is a 15% reduction in ˙VO2max despite an increase in maximal heart rate from 170 bpm before bed rest to 180 bpm following bed rest (36). The mechanism of the elevated exercise heart rate is unclear. Power spectral analysis of heart rate variability demonstrated that the resting tachycardia observed following bed rest developed as a result of reduced cardiac vagal tone with little alteration in baseline sympathetic tone (25). However, since maximal heart rate is controlled by sympathetic activation with complete withdrawal of vagal tone (27), it seems unlikely that reduced vagal tone is the primary mechanism underlying the elevated maximal heart rate during bed rest. Clearly, change in sympathetic response to exercise would provide a more reasonable explanation for bed rest-induced elevation in maximal heart rate. There is greater plasma norepinephrine during maximal exercise after bed rest (Fig. 3) and the heart rate response to a 0.02 μg/kg/min steady-state dose of isoproterenol is increased significantly (Fig. 4), suggesting thatβ-adrenergic receptor sensitivity is increased by bed rest. These data suggest that increased sympathetic secretion of norepinephrine and increased sensitivity of cardiac adrenergic receptors may cause the post-bed rest elevation in maximal heart rate to maintain maximal cardiac output.
Maximal stroke volume. Because maximal heart rate is elevated following bed rest, it is clear that the reduction in cardiac output and˙VO2max is the result of reduction in stroke volume. Echocardiographic measurements demonstrated lower resting heart volume in subjects after bed rest (43). The reduced stroke volume and lower cardiac volume in bed rest subjects, in supine as well as upright posture during exercise, may reflect decreased ventricular performance resulting from myocardial atrophy or other deterioration(43). Cardiac output and stroke volume were measured during submaximal and maximal exercise with radionuclide imaging in 12 middle-aged men before and after 10 d of bed rest(19,36). In confirmation of previous results(43), a 17% reduction in ˙VO2max resulted from a 23% reduction in cardiac output (19.7 l·min-1 before to 15.1 l·min-1 after bed rest) with little change in arteriovenous O2 difference. The reduction in cardiac output was solely a result of a 28% decrease in stroke volume (Fig. 5, lower panel) since maximal heart rate increased from 170 beats·min-1 before to 180 beats·min-1 after bed rest. Despite the significant reduction in exercise stroke volume after, compared with before, bed rest, the ejection fraction actually increased at rest and during exercise (Fig. 5, upper panel). The increased ejection fraction after bed rest suggests that ventricular performance was maintained and that myocardial deterioration was not evident.
A reduced cardiac output and increased ejection fraction and heart rate during exercise suggest that changes in venous return and cardiac filling may represent the primary mechanism by which maximal stroke volume is reduced during bed rest. Indeed, reduced stroke volume and cardiac output are associated with lower blood volume and cardiac filling (central venous) pressure during bed rest (13,43,44). If venous return and cardiac filling limit maximal stroke volume (Frank-Starling relationship), then the cardiac response to maximal exercise after bed rest would move to a lower stroke volume. However, despite a shift of the Frank-Starling relationship after bed rest, stroke volume is higher at any given filling pressure (Fig. 6). Maintenance of stroke volume at a lower filling pressure suggests increased cardiac compliance which may represent a mechanism to defend stroke volume in the presence of hypovolemia and reduced cardiac filling pressure.
The observation that the reduced stroke volume following bed rest has been associated with change in plasma volume is further supported by the close relationship between the magnitude of change in blood volume and˙VO2max. The time course of reduction in ˙VO2max during bed rest (Fig. 7) shows a steeper decline within the first few days of bed rest followed by a more gradual reduction thereafter(31,32), which is similar to the time course of hypovolemia (12,32). Cross-sectional comparison of data from 12 studies demonstrates the high correlation between percent change in plasma volume and ˙VO2max(Fig. 8). The square of the correlation coefficient of these data suggests that about 70% of the variability in ˙VO2max can be explained by change in plasma volume. Relative changes in plasma volume and ˙VO2max following 10 d of bed rest were assessed in 10 sedentary (˙VO2max = 38 ml·kg-1min-1) and 10 moderately fit subjects(˙VO2max = 49 ml·kg-1·min-1) in a longitudinal study (20). The 16% reduction in˙VO2max of the fit subjects was nearly three times that of the 6% decrease in the unfit group. These relative losses in aerobic capacity were matched by 16% and 6% reductions in blood volume in the fit and unfit groups, respectively. These findings reinforce the observation that larger cardiovascular reserve associated with fitness is usually associated with greater absolute reduction in that reserve after bed rest deconditioning. The correlation coefficient of 0.79 between the percent changes in plasma volume and ˙VO2max using individual data of all 20 subjects was similar to that of 0.84 in Figure 8, which suggests that reduction in plasma volume contributes significantly to the limitation of maximal stroke volume, cardiac output, and ˙VO2 during bed rest. This proposed cause-effect relationship is supported by the observation that plasma volume retention by daily exposure to orthostatic pressure gradients or intense exercise training during bed rest minimizes or eliminates the reduction in˙VO2max(23,32).
In addition to the confounding effects of hypovolemia, increased venous pooling in the lower extremities when a patient assumes the upright posture during reambulation could contribute to lowered cardiac filling pressure and stroke volume during bed rest. Several observations support this notion. Despite maximal muscle pumping action on peripheral veins, increased leg venous pooling from application of lower body negative pressure caused lower central venous pressure, stroke volume, and cardiac output during exercise(40). Reduced cardiac filling and stroke volume during exercise induced by bed rest could be accentuated by increased venous pooling in the lower extremities since venous compliance of the legs increases by 20-25% with bed rest (14,15). In addition, reduction in ˙VO2max after 10 d of bed rest in the upright posture(≈17%) was more than twice in the supine posture (≈7%) in spite of the same elevation in heart rate (19) and ˙VO2 kinetics were significantly slowed in the upright compared with the supine posture (17). Taken together, these results provide evidence that orthostatic factors such as increased venous and leg compliance can contribute significantly to the reduction in post-bed rest˙VO2max. These factors must reduce cardiac filling and output since the reduction in post-bed rest maximal stroke volume was greater in the upright posture (36), whereas heart rate elevation in the upright posture was similar to that in the supine posture(16). The reduction in supine ˙VO2max supports the hypothesis that peripheral factors other than orthostatic pooling must contribute to reduced functional cardiovascular capacity following bed rest.
Oxygen delivery. In addition to their effect on cardiac output, change in peripheral mechanisms that control arteriovenous O2 difference, i.e., oxygen delivery and utilization, may contribute to reduction in ˙VO2max following bed rest. Although maximal oxygen utilization by exercising muscle may be compromised by reduction in oxidative enzyme function (35) and greater accumulation of lactate(21,43,49), this discussion will focus on the capacity of the cardiovascular system to deliver oxygen to skeletal muscle. Besides the direct effect of reduced blood volume on cardiac filling and output, prolonged bed rest deconditioning can decrease red blood cell mass by 5 to 25%(11,17,19,39,41,48) which may contribute to reduced ˙VO2max by compromising blood oxygen-carrying capacity. However, the correlation between changes in red cell mass and the ˙VO2max is low and the reduction in ˙VO2max with bed rest can occur without change in red cell mass(21). In general, hematocrit remains constant or increases during bed rest, suggesting that oxygen-carrying capacity per unit of blood should not change. It is therefore unclear if decreased red cell mass induced by bed rest represents a reduction in the maximal capacity to deliver oxygen to the active muscle.
Muscle blood flow. In addition to the reduction in red cell mass, a 36% lower resting blood flow in leg muscles during bed rest(14) was associated with a similar 38% reduction in capillarization in the muscular bed (34). These changes are consistent with reductions in maximal conductance and fatigability in calf muscles after 16 d of bed rest that were correlated to the magnitude of decrease in ˙VO2max(29). Although changes in peripheral mechanisms associated with restricted delivery to and utilization of oxygen by skeletal muscle could contribute to lower ˙VO2max after bed rest by promoting local fatigue, this possibility has not been apparent when based on calculation of maximal arteriovenous O2 difference (36,43). However, when blood volume and cardiac filling are not limiting, the influence of peripheral mechanisms for limiting ˙VO2max may become more apparent.
The cardiovascular consequences of bed rest can be divided into central(cardiac) and peripheral mechanisms that contribute to maintenance of˙VO2max(Fig. 9). An elevated maximal heart rate is associated with elevations in norepinephrine release at maximal exercise and increased cardiac β-adrenergic response in addition to lower vagal tone. These adrenergic changes could also increase cardiac contractility which would be consistent with the reported increase in ejection fraction during exercise following bed rest despite reductions in stroke volume and cardiac filling. Despite the increase in maximal heart rate and probably cardiac contractility, maximal cardiac output is dramatically reduced by an overwhelming decrease in stroke volume. Since cardiac contractility appears enhanced, the lowered stroke volume must be a result of reduced cardiac filling associated with less blood volume and lower central venous pressure. Increased compliance of the veins in the leg muscles may also contribute to the limited venous return, especially after return to the upright posture. Although arteriovenous O2 difference appears to remain constant during bed rest, reductions in capillarization and maximal blood flow in the muscle could limit oxygen delivery and utilization. The ultimate consequence of these alterations in cardiac and vascular functions resulting from bed rest confinement is the reduction in ˙VO2max.
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