Deterioration of left ventricular chamber performance after bed rest : "cardiovascular deconditioning" or hypovolemia?

BACKGROUND: Orthostatic intolerance after bed rest is characterized by hypovolemia and an excessive reduction in stroke volume (SV) in the upright position. We studied whether the reduction in SV is due to a specific adaptation of the heart to head-down tilt bed rest (HDTBR) or acute hypovolemia alone. METHODS AND RESULTS: We constructed left ventricular (LV) pressure-volume curves from pulmonary capillary wedge pressure and LV end-diastolic volume and Starling curves from pulmonary capillary wedge pressure and SV during lower body negative pressure and saline loading in 7 men (25+/-2 years) before and after 2 weeks of -6 degrees HDTBR and after the acute administration of intravenous furosemide. Both HDTBR and hypovolemia led to a similar reduction in plasma volume. However, baseline LV end-diastolic volume decreased by 20+/-4% after HDTBR and by 7+/-2% after hypovolemia (interaction P<0.001). Moreover, SV was reduced more and the Starling curve was steeper during orthostatic stress after HDTBR than after hypovolemia. The pressure-volume curve showed a leftward shift and the equilibrium volume of the left ventricle was decreased after HDTBR; however, after hypovolemia alone, the curve was identical, with no change in equilibrium volume. Lower body negative pressure tolerance was reduced after both conditions; it decreased by 27+/-7% (P<0.05) after HDTBR and by 18+/-8% (P<0.05) after hypovolemia. CONCLUSIONS: Chronic HDTBR leads to ventricular remodeling, which is not seen with equivalent degrees of acute hypovolemia. This remodeling leads to a greater decrease in SV during orthostatic stress after bed rest than hypovolemia alone, potentially contributing to orthostatic intolerance.

Regulation of muscle sympathetic nerve activity after bed rest deconditioning.

Cardiovascular deconditioning reduces orthostatic tolerance. To determine whether changes in autonomic function might produce this effect, we developed stimulus-response curves relating limb vascular resistance, muscle sympathetic nerve activity (MSNA), and pulmonary capillary wedge pressure (PCWP) with seven subjects before and after 18 days of -6 degrees head-down bed rest. Both lower body negative pressure (LBNP; -15 and -30 mmHg) and rapid saline infusion (15 and 30 ml/kg body wt) were used to produce a wide variation in PCWP. Orthostatic tolerance was assessed with graded LBNP to presyncope. Bed rest reduced LBNP tolerance from 23.9 +/- 2.1 to 21.2 +/- 1.5 min, respectively (means +/- SE, P = 0.02). The MSNA-PCWP relationship was unchanged after bed rest, though at any stage of the LBNP protocol PCWP was lower, and MSNA was greater. Thus bed rest deconditioning produced hypovolemia, causing a shift in operating point on the stimulus-response curve. The relationship between limb vascular resistance and MSNA was not significantly altered after bed rest. We conclude that bed rest deconditioning does not alter reflex control of MSNA, but may produce orthostatic intolerance through a combination of hypovolemia and cardiac atrophy.

Dynamic regulation of heart rate during acute hypotension: new insight into baroreflex function.

UNLABELLED: To examine the dynamic properties of baroreflex function, we measured beat-to-beat changes in arterial blood pressure (ABP) and heart rate (HR) during acute hypotension induced by thigh cuff deflation in 10 healthy subjects under supine resting conditions and during progressive lower body negative pressure (LBNP). The quantitative, temporal relationship between ABP and HR was fitted by a second-order autoregressive (AR) model. The frequency response was evaluated by transfer function analysis. RESULTS: HR changes during acute hypotension appear to be controlled by an ABP error signal between baseline and induced hypotension. The quantitative relationship between changes in ABP and HR is characterized by a second-order AR model with a pure time delay of 0.75 s containing low-pass filter properties. During LBNP, the change in HR/change in ABP during induced hypotension significantly decreased, as did the numerator coefficients of the AR model and transfer function gain. CONCLUSIONS: 1) Beat-to-beat HR responses to dynamic changes in ABP may be controlled by an error signal rather than directional changes in pressure, suggesting a "set point" mechanism in short-term ABP control. 2) The quantitative relationship between dynamic changes in ABP and HR can be described by a second-order AR model with a pure time delay. 3) The ability of the baroreflex to evoke a HR response to transient changes in pressure was reduced during LBNP, which was due primarily to a reduction of the static gain of the baroreflex.

Effect of head-down-tilt bed rest and hypovolemia on dynamic regulation of heart rate and blood pressure.

Adaptation to head-down-tilt bed rest leads to an apparent abnormality of baroreflex regulation of cardiac period. We hypothesized that this "deconditioning response" could primarily be a result of hypovolemia, rather than a unique adaptation of the autonomic nervous system to bed rest. To test this hypothesis, nine healthy subjects underwent 2 wk of -6 degrees head-down bed rest. One year later, five of these same subjects underwent acute hypovolemia with furosemide to produce the same reductions in plasma volume observed after bed rest. We took advantage of power spectral and transfer function analysis to examine the dynamic relationship between blood pressure (BP) and R-R interval. We found that 1) there were no significant differences between these two interventions with respect to changes in numerous cardiovascular indices, including cardiac filling pressures, arterial pressure, cardiac output, or stroke volume; 2) normalized high-frequency (0.15-0.25 Hz) power of R-R interval variability decreased significantly after both conditions, consistent with similar degrees of vagal withdrawal; 3) transfer function gain (BP to R-R interval), used as an index of arterial-cardiac baroreflex sensitivity, decreased significantly to a similar extent after both conditions in the high-frequency range; the gain also decreased similarly when expressed as BP to heart rate x stroke volume, which provides an index of the ability of the baroreflex to alter BP by modifying systemic flow; and 4) however, the low-frequency (0.05-0.15 Hz) power of systolic BP variability decreased after bed rest (-22%) compared with an increase (+155%) after acute hypovolemia, suggesting a differential response for the regulation of vascular resistance (interaction, P < 0.05). The similarity of changes in the reflex control of the circulation under both conditions is consistent with the hypothesis that reductions in plasma volume may be largely responsible for the observed changes in cardiac baroreflex control after bed rest. However, changes in vasomotor function associated with these two conditions may be different and may suggest a cardiovascular remodeling after bed rest.

Spontaneous fluctuations in cerebral blood flow: insights from extended-duration recordings in humans.

To determine the dependence of cerebral blood flow (CBF) on arterial pressure over prolonged time periods, we measured beat-to-beat changes in mean CBF velocity in the middle cerebral artery (transcranial Doppler) and mean arterial pressure (Finapres) continuously for 2 h in six healthy subjects (5 men and 1 woman, 18-40 yr old) during supine rest. Fluctuations in velocity and pressure were quantified by the range [(peak - trough)/mean] and coefficients of variation (SD/mean) in the time domain and by spectral analysis in the frequency domain. Mean velocity and pressure over the 2-h recordings were 60 +/- 7 cm/s and 83 +/- 8 mmHg, associated with ranges of 77 +/- 8 and 89 +/- 10% and coefficients of variation of 9.3 +/- 2.2 and 7.9 +/- 2.3%, respectively. Spectral power of the velocity and pressure was predominantly distributed in the frequency range of 0.00014-0.1 Hz and increased inversely with frequency, indicating characteristics of an inverse power law (1/f(alpha)). However, linear regression on a log-log scale revealed that the slope of spectral power of pressure and velocity was steeper in the high-frequency (0.02-0.5 Hz) than in the low-frequency range (0.002-0.02 Hz), suggesting different regulatory mechanisms in these two frequency ranges. Furthermore, the spectral slope of pressure was significantly steeper than that of velocity in the low-frequency range, consistent with the low transfer function gain and low coherence estimated at these frequencies. We conclude that 1) long-term fluctuations in CBF velocity are prominent and similar to those observed in arterial pressure, 2) spectral power of CBF velocity reveals characteristics of 1/f(alpha), and 3) cerebral attenuation of oscillations in CBF velocity in response to changes in pressure may be more effective at low than that at high frequencies, emphasizing the frequency dependence of cerebral autoregulation.

The role of the right ventricle during hypobaric hypoxic exercise: insights from patients after the Fontan operation.

OBJECTIVES: The principal objective of this study was to examine the importance of the right ventricle for maximal systemic oxygen transport during exercise at high altitude by studying patients after the Fontan operation. BACKGROUND: High-altitude-induced hypoxia causes a reduction in maximal oxygen uptake. Normal right ventricular pump function may be critical to sustain cardiac output in the face of hypoxic pulmonary vasoconstriction. We hypothesized that patients after the Fontan operation, who lack a functional subpulmonary ventricle, would have a limited exercise capacity at altitude, with an inability to increase cardiac output. METHODS: We measured oxygen uptake (VO2, Douglas bag), cardiac output (Qc, C2H2 rebreathing), heart rate (HR) (ECG), blood pressure (BP) (cuff), and O2 Sat (pulse oximetry) in 11 patients aged 14.5+/-5.2 yr (mean +/- SD) at 4.7+/-1.6 yr after surgery. Data were obtained at rest, at three submaximal steady state workrates, and at peak exercise on a cycle ergometer. All tests were performed at sea level (SL) and at simulated altitude (ALT) of 3048 m (10,000 ft, 522 torr) in a hypobaric chamber. RESULTS: At SL, resting O2 sat was 92.6+/-4%. At ALT, O2 sat decreased to 88.2+/-4.6% (P < 0.05) at rest and decreased further to 80+/-6.3% (P < 0.05) with peak exercise. At SL, VO2 increased from 5.1+/-0.9 mL x kg(-1) x min(-1) at rest to 23.5+/-5.3 mL x kg(-1) x min(-1) at peak exercise and CI (Qc x m(-2)) increased from 3.3+/-0.7 L x m(-2) to 6.2+/-1.2 L x m(-2). VO2 peak, 17.8+/-4 mL x kg(-1) x min(-1) (P < 0.05), and CI peak, 5.0+/-1.5 L x m(-2) (P < 0.05), were both decreased at ALT. Remarkably, the relationship between Qc and VO2 was normal during submaximal exercise at both SL and ALT. However at ALT, stroke volume index (SVI, SV x m(-2)) decreased from 37.7+/-8.6 mL x min(-1) x m2 at rest, to 31.3+/-8.6 mL x min(-1) x m2 at peak exercise (P < 0.05), whereas it did not fall during sea level exercise. CONCLUSIONS: During submaximal exercise at altitude, right ventricular contractile function is not necessary to increase cardiac output appropriately for oxygen uptake. However, normal right ventricular pump function may be necessary to achieve maximal cardiac output during exercise with acute high altitude exposure.

Fractal fluctuations in cardiac time series.

Human heart rate, controlled by complex feedback mechanisms, is a vital index of systematic circulation. However, it has been shown that beat-to-beat values of heart rate fluctuate continually over a wide range of time scales. Herein we use the relative dispersion, the ratio of the standard deviation to the mean, to show, by systematically aggregating the data, that the correlation in the beat-to-beat cardiac time series is a modulated inverse power law. This scaling property indicates the existence of long-time memory in the underlying cardiac control process and supports the conclusion that heart rate variability is a temporal fractal. We argue that the cardiac control system has allometric properties that enable it to respond to a dynamical environment through scaling.

Deterioration of cerebral autoregulation during orthostatic stress: insights from the frequency domain.

To determine whether dynamic cerebral autoregulation is impaired during orthostatic stress, cerebral blood flow (CBF) velocity in the middle cerebral artery (transcranial Doppler) and mean arterial pressure (MAP; Finapres) were measured continuously in 12 healthy subjects during ramped maximal lower body negative pressure (LBNP) to presyncope. Velocity and pressure were averaged over 6-min periods of stable data at rest and during LBNP to examine steady-state cerebral hemodynamics. Beat-to-beat variability of velocity and pressure were quantified by a "variation index" (oscillatory amplitude/steady-state mean value) and by power spectral analysis. The dynamic relationship between changes in pressure and velocity was evaluated by the estimates of transfer and coherence function. The results of the study were as follows. Steady-state MAP remained relatively constant during LBNP, whereas CBF velocity decreased progressively by 6, 15, and 21% at -30, -40, and -50 mmHg LBNP, respectively (P < 0.05 compared with baseline). At the maximal level of LBNP (30 s before presyncope) MAP decreased by 9.4% in association with a prominent reduction in velocity by 24% (P < 0.05 compared with baseline). The variation index of pressure increased significantly from 3.8 +/- 0.3% at baseline to 4.5 +/- 0. 6% at -50 mmHg LBNP in association with an increase in the variation index of velocity from 6.0 +/- 0.6 to 8.4 +/- 0.7% (P < 0.05). Consistently, the low- (0.07-0.20 Hz) and high-frequency (0.20-0.30 Hz) power of variations in pressure and velocity increased significantly at high levels of LBNP (P < 0.05) in association with an increase in transfer function gain (24% at -50 mmHg, P < 0.05). We conclude that the damping effects of autoregulation on variations in CBF velocity are diminished during orthostatic stress in association with substantial falls in steady-state CBF velocity. We suggest that these changes may contribute in part to the development of presyncope.

Transfer function analysis of dynamic cerebral autoregulation in humans.

To test the hypothesis that spontaneous changes in cerebral blood flow are primarily induced by changes in arterial pressure and that cerebral autoregulation is a frequency-dependent phenomenon, we measured mean arterial pressure in the finger and mean blood flow velocity in the middle cerebral artery (VMCA) during supine rest and acute hypotension induced by thigh cuff deflation in 10 healthy subjects. Transfer function gain, phase, and coherence function between changes in arterial pressure and VMCA were estimated using the Welch method. The impulse response function, calculated as the inverse Fourier transform of this transfer function, enabled the calculation of transient changes in VMCA during acute hypotension, which was compared with the directly measured change in VMCA during thigh cuff deflation. Beat-to-beat changes in VMCA occurred simultaneously with changes in arterial pressure, and the autospectrum of VMCA showed characteristics similar to arterial pressure. Transfer gain increased substantially with increasing frequency from 0.07 to 0.20 Hz in association with a gradual decrease in phase. The coherence function was > 0.5 in the frequency range of 0.07-0.30 Hz and < 0.5 at < 0.07 Hz. Furthermore, the predicted change in VMCA was similar to the measured VMCA during thigh cuff deflation. These data suggest that spontaneous changes in VMCA that occur at the frequency range of 0.07-0.30 Hz are related strongly to changes in arterial pressure and, furthermore, that short-term regulation of cerebral blood flow in response to changes in arterial pressure can be modeled by a transfer function with the quality of a high-pass filter in the frequency range of 0.07-0.30 Hz.

Effect of high-altitude exposure in the elderly: the Tenth Mountain Division study.

BACKGROUND: More than 5 million people/year over age 60 visit high altitude, which may exacerbate underlying cardiac or pulmonary disease. We hypothesized that the elderly would exhibit an impaired functional capacity at altitude, with increased myocardial ischemia compared with sea level (SL). METHODS AND RESULTS: Twenty veterans (68+/-3 years) were studied at (1) SL, (2) acute simulated altitude to 2500 m, and (3) after 5 days of acclimatization to 2500 m. With acute altitude, PaO2 and oxyhemoglobin saturation decreased and pulmonary artery pressure increased 43%, associated with sympathetic activation. VO2peak decreased 12% acutely but normalized after acclimatization. The best predictor of VO2peak with acute altitude was VO2peak at SL (r=.94). The double product that induced 1-mm ST depression during exercise with acute altitude was 5% less than SL but normalized after acclimatization. One patient with severe coronary disease sustained a myocardial infarction after an exercise test. CONCLUSIONS: Moderate altitude exposure in the elderly is associated with hypoxemia, sympathetic activation, and pulmonary hypertension resulting in a reduced exercise capacity that is predictable based on exercise performance at SL. Patients with coronary artery disease who are well compensated at SL do well at moderate altitude, although acutely ischemia may be provoked at modestly lower myocardial and systemic work rates. The elderly acclimatize well with normalization of SL performance after 5 days. A prudent policy would be for elderly individuals, particularly those with coronary artery disease, to limit their activity during the first few days at altitude to allow this acclimatization process to occur.

Cardiac atrophy after bed-rest deconditioning: a nonneural mechanism for orthostatic intolerance.

BACKGROUND: The cardiovascular adaptation to bed rest leads to orthostatic intolerance, characterized by an excessive fall in stroke volume (SV) in the upright position. We hypothesized that this large fall in SV is due to a change in cardiac mechanics. METHODS AND RESULTS: We measured pulmonary capillary wedge pressure (PCWP), SV, left ventricular end-diastolic volume (LVEDV), and left ventricular mass (by echocardiography) at rest, during lower-body negative pressure, and after saline infusion before and after 2 weeks of bed rest with -6 degrees head-down tilt (n=12 subjects aged 24+/-5 years). Pressure (P)-volume (V) curves were modeled exponentially by P=ae(kV)+b and logarithmically by P=-Sln[(Vm-V)/(Vm-V0)], where V0 indicates volume at P=0, and the constants k and S were used as indices of normalized chamber stiffness. Dynamic stiffness (dP/dV) was calculated at baseline LVEDV. The slope of the line relating SV to PCWP during lower-body negative pressure characterized the steepness of the Starling curve. We also measured plasma volume (with Evans blue dye) and maximal orthostatic tolerance. Bed rest led to a reduction in plasma volume (17%), baseline PCWP (18%), SV (12%), LVEDV (16%), V0 (33%), and orthostatic tolerance (24%) (all P<.05). The slope of the SV/PCWP curve increased from 4.6+/-0.4 to 8.8+/-0.9 mL/mm Hg (P<.01) owing to a parallel leftward shift in the P-V curve. Normalized chamber stiffness was unchanged, but dP/dV was reduced by 50% at baseline LVEDV, and cardiac mass tended to be reduced by 5% (P<.10). CONCLUSIONS: Two weeks of head-down-tilt bed rest leads to a smaller, less distensible left ventricle but a shift to a more compliant portion of the P-V curve. This results in a steeper Starling relationship, which contributes to orthostatic intolerance by causing an excessive reduction in SV during orthostasis.

Effects of head-down-tilt bed rest on cerebral hemodynamics during orthostatic stress.

Our aim was to determine whether the adaptation to simulated microgravity (microG) impairs regulation of cerebral blood flow (CBF) during orthostatic stress and contributes to orthostatic intolerance. Twelve healthy subjects (aged 24 +/- 5 yr) underwent 2 wk of -6 degrees head-down-tilt (HDT) bed rest to simulate hemodynamic changes that occur when humans are exposed to microG. CBF velocity in the middle cerebral artery (transcranial Doppler), blood pressure, cardiac output (acetylene rebreathing), and forearm blood flow were measured at each level of a ramped protocol of lower body negative pressure (LBNP; -15, -30, and -40 mmHg x 5 min, -50 mmHg x 3 min, then -10 mmHg every 3 min to presyncope) before and after bed rest. Orthostatic tolerance was assessed by using the cumulative stress index (CSI; mmHg x minutes) for the LBNP protocol. After bed rest, each individual's orthostatic tolerance was reduced, with the group CSI decreased by 24% associated with greater decreases in cardiac output and greater increases in systemic vascular resistance at each level of LBNP. Before bed rest, mean CBF velocity decreased by 14, 10, and 45% at -40 mmHg, -50 mmHg, and maximal LBNP, respectively. After bed rest, mean velocity decreased by 16% at -30 mmHg and by 21, 35, and 39% at -40 mmHg, -50 mmHg, and maximal LBNP, respectively. Compared with pre-bed rest, post-bed-rest mean velocity was less by 11, 10, and 21% at -30, -40, and -50 mmHg, respectively. However, there was no significant difference at maximal LBNP. We conclude that cerebral autoregulation during orthostatic stress is impaired by adaptation to simulated microG as evidenced by an earlier and greater fall in CBF velocity during LBNP. We speculate that impairment of cerebral autoregulation may contribute to the reduced orthostatic tolerance after bed rest.