Cardiovascular space physiology has evolved through three major phases. Before human space flight became a reality, dire predictions were made. It was thought that exposure to microgravity would induce catastrophic regulatory failure. This phase ended abruptly with Gagarin's successful flight on April 12, 1961. The next three decades were the Gauer era. Gauer's concept(13) that the upright body position at 1G defines the normal operating conditions for the human cardiovascular system was incorporated-at least implicitly-in virtually all analyses of circulatory data from actual and simulated μG. Gauer's contributions will always be important, but new information is emerging that suggests that the adaptation to microgravity is more complex and less predictable than we had thought.
The flight data that form the base for this presentation were collected during three Spacelab flights, SLS-1 in 1991 and D-2 and SLS-2 in 1993. Ground-based simulations using the head-down tilt (HDT) model had a major role in the design of our first flight experiment, which had its beginnings in a 1978 NASA request for proposals. Our initial plans were supported by data from a series of bed rest studies and early head-down tilt experiments(2,20,21). Data from later simulation studies performed in our laboratory (12) and by Baisch et al. (1) also helped define the final protocols for the flight experiments.
An extensive general review of bed rest and HDT simulation studies has been published by Sandler and Vernikos (22). Our HDT studies demonstrated transient increases in cardiac filling beyond normal supine levels, documented by measurements of central venous pressure (CVP) and echocardiographic estimates of left ventricular end-diastolic dimensions. Stroke volume tended to increase early during tilt, but arterial pressure was kept unchanged by decreases in heart rate (young subjects) or by vasodilatation (middle-aged subjects). Within a few hours, a negative fluid balance had produced a decrease in intravascular volume. Supine cardiac filling pressures and stroke volumes after 24 h approached (but did not quite reach) pre-tilt upright levels, and as expected orthostatic tolerance was impaired.
The design of our flight experiments focused on the early cardiac effects of redistribution of intravascular volume. This made it mandatory to monitor cardiac filling pressures during the transition from 1G to actual μG. We had proposed central venous pressure measurements (CVP) in 1978 and were given an opportunity to obtain data in three crew members during the flights of SLS-1 and SLS-2 in 1991 and 1993. Foldager et al. (8) measured CVP in one crew member during the D-2 flight in 1993 using a different type of instrumentation. It would have been desirable to monitor actual left ventricular filling pressure, or at least pulmonary capillary wedge pressure, but CVP recorded with well-defined catheter tip and transducer locations closely reflects wedge pressures over a wide range of hemodynamic conditions in normal human subjects at rest (15), and, most importantly, CVP measurement is compatible with the space flight environment. The CVP instrumentation had to meet stringent requirements with respect to safety, accuracy, and precision, but a suitable unit was produced and performed as expected (4,5). The data from our three CVP subjects showed a characteristic pattern with only minor individual variations (see Fig. 1).
Mean CVP in the space shuttle before launch (measured with the crew members supine with elevated legs) was 11.0 mm Hg. CVP increased significantly during launch in direct proportion to front-to-back (+Gx forces) up to 3.5 G and then fell precipitously on main engine cutoff and arrival in μG to a mean of 1.8 mm Hg after 10 min in orbit. CVP remained at levels between 5 and 0 mm Hg for as long as measurements were made, i.e., for 4, 5, and 40 h in space in our three subjects. CVP catheter pull-out data were available for two crew members and verified normal function of the instrumentation with a return to a true 0 baseline (and also the presence of a significant central-peripheral pressure gradient at μG).
These results were unexpected and must be interpreted in the context of other hemodynamic measurements. Heart rates (and arterial blood pressure in one crew member) tended to be slightly elevated (80-115 beats·min-1), but only during the first 20-30 min in orbit. Cardiac output, estimated from heart rate and echo-cardiographic left ventricular dimensions, increased, but only from a pre-flight mean of 4.0 to 5.0 l·min-1 early at μG. Thus, the low CVP cannot be attributed simply to a greatly elevated cardiac output. Most importantly, early in-flight echocardiographic measurements in the three CVP subjects showed an increase in cardiac filling with a mean increase in left ventricular diastolic diameter from 4.6 cm supine pre-flight to 5.0 cm. There were no appreciable changes in end-systolic diameter, velocity of circumferential fiber shortening, or heart rate (5).
The echocardiographic data from SLS-1 and -2 were also analyzed using a technique (3) that produces a three-dimensional reconstruction of the left ventricle based on multiple two-dimensional images acquired over several cardiac cycles at a stable hemodynamic state.Figure 2 shows serial echocardiographic measurements before, during, and after flight in one of the CVP-instrumented crew members. This time course of adaptation (which was common to all crew members) conforms to the expected pattern with an initial increase in left ventricular size, followed within 48 h by a significant decrease relative to pre-flight supine dimensions. Contractile state (as defined by measurements of left ventricular ejection fraction and by endsystolic volume), did not change over the mission. Serial echocardiographic measurements in additional crew members and independent data on cardiac output and stroke volume based on the foreign gas rebreathing technique (19) are consistent with the echocardiographic data on left ventricular dimensions. Early data output were not available, but the stroke volume measurements made after 2 d in space approximated the 1G supine data. Measurements performed after 5 d or later approached, but did not quite reach, pre-flight upright levels. The cardiovascular conditions at μG after adaptation may thus be slightly different from Gauer's simple upright pattern and represent an intermediate hemodynamic state, accurately reflecting the normal human 24-h postural pattern, i.e., one 8-h part supine and two parts upright.
The combined data on cardiac filling pressure, left ventricular dimensions, and stroke volume early at μG make it evident that at least one significant aspect of the mechanical regulation of cardiac pump function has changed in a manner that was not predicted from ground-based simulations. There is an apparent discrepancy between measured and effective transmural ventricular filling pressures. The exact mechanism responsible for this is yet to be defined, but a large and sudden change in intrinsic myocardial properties is highly unlikely. Arrival in μG may alter the close ground-based relationship between CVP and left ventricular diastolic dimensions by affecting the physical interactions between the heart and the surrounding thoracic tissues. The tight correlation between CVP and the acceleration forces that compress the chest in front-to-back direction (+Gx) during launch is evident in Figure 1. The gravitational unloading of the ventricular wall on arrival in μG may produce a sudden change in ventricular diastolic pressure-volume relationship. A detailed modeling analysis of the transition from 1G to μG has been submitted for publication (White and Blomqvist).
The unexpected effects on left ventricular mechanics make it important to consider the impact of μG over a wider range of cardiovascular control mechanisms. Maximal exercise involving large muscle groups provides an effective means of probing integrated cardiovascular function (seeFig. 3). A prerequisite for maintaining maximal oxygen uptake at pre-flight levels is the integrity of both cardiac pump function and the multiple neurohumoral control mechanisms that mediate the hemodynamic responses to exercise. Measurements in 6 crew members during bicycle ergometer exercise before, during, and after space flight in collaboration with Farhi et al. (16) showed no change in maximal oxygen uptake or maximal heart rate after 7-8 d in space. A significant reduction in maximal oxygen uptake by 22% was present on landing day within hours after return to earth. Exercise capacity remained significantly reduced at 24-48 h after return but was restored to pre-flight levels at 6-9 d. The initial decrease was wholly attributable to a reduction in maximal stroke volume and cardiac output. Maximal heart rate, arterial blood pressure, and systemic arteriovenous oxygen difference were unchanged. Data on systemic oxygen transport at rest and during submaximal exercise in the six SLS-1 and -2 crew members who performed maximal exercise in space have also been published by Schykoff et al. (23).
Our in-flight data on maximal exercise at μG extend informal observations made during the flight of Skylab-4 (17). The results provide evidence against any defect that significantly affects cardiac pump function and/or cardiovascular regulation during heavy exercise. Essfeld and Baum (7) and Hoffman et al.(14) examined oxygen transport kinetics during exercise during the D-2 flight and found no demonstrable abnormalities at μG. However, significant changes were present during the early post-flight stage. The exact mechanisms underlying the change in maximal post-flight exercise performance are yet to de defined beyond the predictable hemodynamic effects of post-flight hypovolemia. Recent data from bed rest experiments by Levine et al. (16) indicate that changes in left ventricular pressure-volume characteristics may develop over a 2-wk period of bed rest in normal subjects and produce a stiffer ventricle with reduced end-diastolic volume over the normal physiological range of filling pressures.
The exercise data from the flight experiments are conceptually important, but maximal exercise certainly does not test the full range of cardiovascular regulatory mechanisms. Post-flight orthostatic intolerance remains a highly significant clinical problem. Evidence is growing that this condition is not simply a consequence of post-flight hypovolemia, supporting the concept thatμG may induce fundamental changes in cardiovascular regulation. Studies by Mulvagh et al. (18), based on echocardiography, suggest that inadequate vasoconstrictor responses is an important factor in post-flight orthostatic intolerance. Fritsch et al.(9,10) have examined the characteristics of the human carotid-cardiac baroreflex over a wide range of conditions, including actual and simulated μG. They have used a neck collar to produce computer-controlled beat-to-beat changes in carotid artery transmural pressures. Data from the SLS-1 and D-2 flights(9,10), collected pre-flight and after 8 days on orbit demonstrated a significantly attenuated change in cardiac cycle length interval for a given change in carotid transmural pressure.
We have examined a wide range of cardiovascular regulatory mechanisms by comparing pre- and post-flight responses to a stand test. Detailed hemodynamic measurements were obtained within 4 h of return from space in 14 crew members after flights of 9-14 d. In the analyses of the stand test data, we(6) viewed arterial blood pressure as the triple product of heart rate, stroke volume, and peripheral resistance.
Previous analyses of the post-flight hemodynamic state have provided conflicting results. Mulvagh et al. (18) analyzed information derived from echocardiographic data and concluded that vasoconstrictor responses were attenuated early post-flight, whereas Gabrielsen et al. (11) reported enhanced post-flight cutaneous vasoconstrictor responses during LBNP. Whitson et al.(24) suggested that a blunted post-flight hemodynamic response should be attributed to endogenous catecholamines. However, separate data for finishers and nonfinishers were not available.
A comparison of responses in finishers and nonfinishers in our series clearly identified an inadequate vasoconstrictor response in nonfinishers as the critical difference. There were equally significant post-flight increases in upright heart rates and decreases in stroke volumes in both subgroups. The orthostatic heart rate response was actually greater in nonfinishers. The amount of venous pooling and the decrease in stroke volume were similar in both groups. In absolute terms, the vasoconstrictor response was greater than pre-flight in both subgroups, but only the finishers had a vasomotor response that had been enhanced to the extent necessary to maintain an adequate arterial pressure. The site(s) of this regulatory defect is unknown. The cardiovascular responses to graded intravenous infusions of alpha- and beta-adrenergic agonists were unchanged post-flight in SLS 1-2 crew members(Buckey et al., unpublished data) but negative results are inconclusive since the test could not be performed until 24-28 h after return to 1G.
Thus, the μG-induced hypovolemia is a likely prerequisite for the development of post-flight orthostatic intolerance, but the outcome in a given individual may depend to a great extent on the magnitude of the systemic vasoconstrictor response. The mechanisms underlying the inadequate post-flight vasoconstrictor response remain to be identified. Two principal alternatives should be considered: 1) Adaptation to μG has caused a degradation of neurohumoral cardiovascular control mechanisms that are essential at 1G, or 2) the dynamic range of the mechanisms that produce appropriate orthostatic vasoconstriction is an inborn characteristic of the individual. A limited range that is adequate for ordinary 1G conditions becomes inadequate in the hypovolemic condition early after return from space.
A degradation of the neurohumoral vasoconstrictor mechanisms may occur at one or more levels, i.e., afferent input, central integration, efferent output, and/or endorgan responsiveness. Currently available information provides no conclusive answers. The last currently scheduled Spacelab flight, Neurolab in 1998, includes a series of studies that should provide more accurate and specific mechanistic information. Plans include use of multiple well-defined cardiovascular stimuli (cold pressor test, isometric exercise, controlled respiration, lower body negative pressure) and detailed monitoring of cardiovascular and regulatory responses, including recording of muscle sympathetic nerve traffic and evaluation of norepineprine metabolism using spill-over techniques. Alternative 2 derives some support from our own series. The crew members who increased their post-flight orthostatic vasoconstrictor responses well beyond pre-flight levels and passed the post-flight stand test also had slightly (but significantly) greater increases in total peripheral resistance also pre-flight.
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