Radiofrequency ablation using a novel insulated-tip ablation catheter can create uniform lesions comparable in size to conventional irrigated ablation catheters while using a fraction of the energy and irrigation.

INTRODUCTION: During radiofrequency ablation (RFA) using conventional RFA catheters (RFC), ~90% of the energy dissipates into the bloodstream/surrounding tissue. We hypothesized that a novel insulated-tip ablation catheter (SMT) capable of blocking the radiofrequency path may focus most of the energy into the targeted tissue while utilizing reduced power and irrigation. METHODS: This study evaluated the outcomes of RFA using SMT versus an RFC in silico, ex vivo, and in vivo. Radiofrequency applications were delivered over porcine myocardium (ex vivo) and porcine thigh muscle preparations superfused with heparinized blood (in vivo). Altogether, 274 radiofrequency applications were delivered using SMT (4-15 W, 2 or 20 ml/min) and 74 applications using RFC (30 W, 30 ml/min). RESULTS: RFA using SMT proved capable of directing 66.8% of the radiofrequency energy into the targeted tissue. Accordingly, low power-low irrigation RFA using SMT (8-12 W, 2 ml/min) yielded lesion sizes comparable with RFC, whereas high power-high irrigation (15 W, 20 ml/min) RFA with SMT yielded lesions larger than RFC (p < .05). Although SMT was associated with greater impedance drops ex vivo and in vivo, ablation using RFC was associated with increased charring/steam pop/tissue cavitation (p < .05). Lastly, lesions created with SMT were more homogeneous than RFC (p < .001). CONCLUSION: Low power-low irrigation (8-12 W, 2 ml/min) RFA using the novel SMT ablation catheter can create more uniform, but comparable-sized lesions as RFC with reduced charring/steam pop/tissue cavitation. High power-high irrigation (15 W, 20 ml/min) RFA with SMT yields lesions larger than RFC.

Use of the inverse solution guidance algorithm method for RF ablation catheter guidance.

INTRODUCTION: We previously introduced the inverse solution guidance algorithm (ISGA) methodology using a Single Equivalent Moving Dipole model of cardiac electrical activity to localize both the exit site of a re-entrant circuit and the tip of a radiofrequency (RF) ablation catheter. The purpose of this study was to investigate the use of ISGA for ablation catheter guidance in an animal model. METHODS: Ventricular tachycardia (VT) was simulated by rapid ventricular pacing at a target site in eleven Yorkshire swine. The ablation target was established using three different techniques: a pacing lead placed into the ventricular wall at the mid-myocardial level (Type-1), an intracardiac mapping catheter (Type-2), and an RF ablation catheter placed at a random position on the endocardial surface (Type-3). In each experiment, one operator placed the catheter/pacing lead at the target location, while another used the ISGA system to manipulate the RF ablation catheter starting from a random ventricular location to locate the target. RESULTS: The average localization error of the RF ablation catheter tip was 0.31 ± 0.08 cm. After analyzing approximately 35 cardiac cycles of simulated VT, the ISGA system's accuracy in locating the target was 0.4 cm after four catheter movements in the Type-1 experiment, 0.48 cm after six movements in the Type-2 experiment, and 0.67 cm after seven movements in the Type-3 experiment. CONCLUSION: We demonstrated the feasibility of using the ISGA method to guide an ablation catheter to the origin of a VT focus by analyzing a few beats of body surface potentials without electro-anatomic mapping.

Comparison of cardiovascular parameter estimation methods using swine data.

In this study, new and existing methods of estimating stroke volume, cardiac output and total peripheral resistance from analysis of the arterial blood pressure waveform were tested over a wide range of conditions. These pulse contour analysis methods (PCMs) were applied to data obtained in six swine during infusion of volume, phenylephrine, dobutamine, isoproterenol, esmolol and nitroglycerine as well as during progressive hemorrhage. Performance of PCMs was compared using true end-ejection pressures as well as estimated end-ejection pressures. There was considerable overlap in the accuracies of the PCMs when using true end-ejection measures. However, for perhaps the most clinically relevant condition, where radial artery pressure is the input, only Wesseling's Corrected Impedance method and the Kouchoukos Correction method achieved statistically superior results. We introduced a method of estimating end-ejection by determining when the systolic pressure dropped to a value equal to the sum of the end-diastolic pressure plus a fraction of the pulse pressure. The most accurate estimation of end-ejection was obtained when that fraction was set to 60% for the central arterial pressure and to 50% for the femoral and radial arterial pressures. When the estimated end-ejection measures were used for the PCMs that depend on end-ejection measures and when radial artery pressure was used as the input, only Wesseling's Corrected Impedance method and the modified Herd's method achieved statistically superior results. This study provides a systematic comparison of multiple PCMs' ability to estimate stroke volume, cardiac output, and total peripheral resistance and introduces a new method of estimating end-systole.

Prospective Use of Microvolt T-Wave Alternans Testing to Guide Primary Prevention Implantable Cardioverter Defibrillator Therapy.

BACKGROUND: We hypothesized that a negative microvolt T-wave alternans (MTWA) test would identify patients unlikely to benefit from primary prevention implantable cardioverter defibrillator (ICD) therapy in a prospective cohort. METHODS AND RESULTS: Data were pooled from 8 centers where MTWA testing was performed specifically for the purpose of guiding primary prevention ICD implantation. Cohorts were included if the ratio of ICDs implanted in patients who were MTWA "non-negative" to patients who were MTWA negative was >2:1, indicating that MTWA testing had a significant impact on the decision to implant an ICD. The pooled cohort included 651 patients: 371 MTWA non-negative and 280 MTWA negative. Among non-negative patients, 62% underwent ICD implantation whereas only 13% of MTWA-negative patients received an ICD (P<0.01). Despite a substantially lower prevalence of ICDs, long-term survival (6.9 years) was significantly better among MTWA-negative patients (68.2% non-negative vs. 87.1% negative, P=0.026). CONCLUSIONS: MTWA-negative patients had significantly better survival than MTWA non-negative patients, the majority of whom had ICDs. Despite a very low prevalence of ICDs, long-term survival among patients with left ventricular ejection fraction ≤40% and a negative MTWA test was better than in the ICD arm of any study to date that has demonstrated a benefit of ICDs. This provides further evidence that MTWA-negative patients are unlikely to benefit from primary prevention ICD therapy.

Promiscuous binding of extracellular peptides to cell surface class I MHC protein.

Algorithms derived from measurements of short-peptide (8-10 mers) binding to class I MHC proteins suggest that the binding groove of a class I MHC protein, such as K(b), can bind well over 1 million different peptides with significant affinity (<500 nM), a level of ligand-binding promiscuity approaching the level of heat shock protein binding of unfolded proteins. MHC proteins can, nevertheless, discriminate between similar peptides and bind many of them with high (nanomolar) affinity. Some insights into this high-promiscuity/high-affinity behavior and its impact on immunodominant peptides in T-cell responses to some infections and vaccination are suggested by results obtained here from testing a model developed to predict the number of cell surface peptide-MHC complexes that form on cells exposed to extracellular (exogenous) peptides.

A method to noninvasively identify cardiac bioelectrical sources.

BACKGROUND: We have introduced a method to guide radiofrequency catheter ablation (RCA) procedures that estimates the location of a catheter tip used to pace the ventricles and the target site for ablation using the single equivalent moving dipole (SEMD). OBJECTIVE: To investigate the accuracy of this method in resolving epicardial and endocardial electrical sources. METHODS: Two electrode arrays, each of nine pacing electrodes at known distances from each other, sutured on the left- and right-ventricular (LV and RV) epicardial surfaces of swine, were used to pace the heart at multiple rates, while body surface potentials from 64 sites were recorded and used to estimate the SEMD location. A similar approach was followed for pacing from catheters in the LV and RV. RESULTS: The overall (RV & LV) error in estimating the interelectrode distance of adjacent epicardial electrodes was 0.38 ± 0.45 cm. The overall endocardial (RV & LV) interelectrode distance error, was 0.44 ± 0.26 cm. Heart rate did not significantly affect the error of the estimated SEMD location (P > 0.05). The guiding process error became progressively smaller as the SEMD approached an epicardial target site and close to the target, the overall absolute error was ∼ 0.28 cm. The estimated epicardial SEMD locations preserved their topology in image space with respect to their corresponding physical location of the epicardial electrodes. CONCLUSION: The proposed algorithm suggests one can efficiently and accurately resolve epicardial electrical sources without the need of an imaging modality. In addition, the error in resolving these sources is sufficient to guide RCA procedures.

Cardiac ablation catheter guidance by means of a single equivalent moving dipole inverse algorithm.

BACKGROUND: We developed and evaluated a novel system for guiding radiofrequency catheter ablation therapy of ventricular tachycardia. This guidance system employs an inverse solution guidance algorithm (ISGA) using a single equivalent moving dipole (SEMD) localization method. The method and system were evaluated in both a saline tank phantom model and in vivo animal (swine) experiments. METHODS: A catheter with two platinum electrodes spaced 3 mm apart was used as the dipole source in the phantom study. A 40-Hz sinusoidal signal was applied to the electrode pair. In the animal study, four to eight electrodes were sutured onto the right ventricle. These electrodes were connected to a stimulus generator delivering 1-ms duration pacing pulses. Signals were recorded from 64 electrodes, located either on the inner surface of the saline tank or on the body surface of the pig, and then processed by the ISGA to localize the physical or bioelectrical SEMD. RESULTS: In the phantom studies, the guidance algorithm was used to advance a catheter tip to the location of the source dipole. The distance from the final position of the catheter tip to the position of the target dipole was 2.22 ± 0.78 mm in real space and 1.38 ± 0.78 mm in image space (computational space). The ISGA successfully tracked the locations of electrodes sutured on the ventricular myocardium and the movement of an endocardial catheter placed in the animal's right ventricle. CONCLUSION: In conclusion, we successfully demonstrated the feasibility of using an SEMD inverse algorithm to guide a cardiac ablation catheter.

Sympathetic withdrawal is associated with hypotension after hepatic reperfusion.

OBJECTIVE: Post-reperfusion syndrome (PRS), severe hypotension after graft reperfusion during liver transplantation, is an adverse clinical event associated with poorer patient outcomes. The purpose of this study was to determine whether alterations in autonomic control in liver transplant recipients prior to graft reperfusion are associated with the subsequent development of PRS. METHODS: Heart rate variability (HRV), systolic arterial blood pressure (SBP) variability, and baroreflex sensitivity of 218 liver transplant recipients were evaluated using 5 min of ECG and arterial blood pressure signals 10 min before graft reperfusion along with other clinical parameters. Logistic regression analyses were performed to assess predictors of PRS occurrence. RESULTS: Seventy-seven patients (35 %) developed PRS while 141 did not. There were significant differences in SBP (110 ± 16 vs. 119 ± 16 mmHg, P < 0.001) and the ratio of low frequency power to high frequency power (LF/HF) of HRV (1.0 ± 1.4 vs. 2.1 ± 3.7, P = 0.003) between the PRS group and No-PRS group. In multivariate logistic regression analysis, predictors were LF/HF (odds ratio 0.817, P = 0.028) and SBP (odds ratio 0.966, P < 0.001). INTERPRETATION: Low LF/HF and SBP measured before hepatic graft reperfusion were significantly correlated with subsequent PRS occurrence, suggesting that sympathovagal imbalance and depressed SBP may be key factors predisposing to reperfusion-related severe hypotension in liver transplant recipients.

Accuracy of cardiac ablation catheter guidance by means of a single equivalent moving dipole inverse algorithm to identify sites of origin of cardiac electrical activation.

We have developed a system that could potentially be used to identify the site of origin of ventricular tachycardia (VT) and to guide a catheter to that site to deliver radio-frequency ablation therapy. This system employs the Inverse Solution Guidance Algorithm based upon Single Equivalent Moving Dipole (SEMD) localization method. The system was evaluated in in vivo swine experiments. Arrays consisting of 9 or 16 bipolar epicardial electrodes and an additional mid-myocardial pacing lead were sutured to each ventricle. Focal tachycardia was simulated by applying pacing pulses to each epicardial electrode at multiple pacing rates during breath hold at the end-expiration phase. Surface potentials were recorded from 64 surface electrodes and then analyzed using the SEMD method to localize the position of the pacing electrodes. We found a close correlation between the locations of the pacing electrodes as measured in computational and real spaces. The reproducibility error of the SEMD estimation of electrode location was 0.21 ± 0.07 cm. The vectors between every pair of bipolar electrodes were computed in computational and real spaces. At 120 bpm, the lengths of the vectors in the computational and real space had a 95% correlation. Computational space vectors were used in catheter guidance simulations which showed that this method could reduce the distance between the real space locations of the emulated catheter tip and the emulated arrhythmia origin site by approximately 72% with each movement. We have demonstrated the feasibility of using our system to guide a catheter to the site of the emulated VT origin.

Techniques for epicardial mapping and ablation with a miniature robotic walker.

BACKGROUND: Present treatments for ventricular tachycardia have significant drawbacks. To ameliorate these drawbacks, it may be advantageous to employ an epicardial robotic walker that performs mapping and ablation with precise control of needle insertion depth. This paper examines the feasibility of such a system. METHODS: This paper describes techniques for epicardial mapping and depth-controlled ablation with the robotic walker. The mapping technique developed for the current form of the system uses a single equivalent moving dipole model combined with the navigation capability of the walker. The intervention technique provides saline-enhanced radio frequency ablation, with sensing of needle penetration depth. The mapping technique was demonstrated in an artificial heart model with a simulated arrhythmia focus, followed by preliminary testing in the porcine model in vivo. The ablation technique was demonstrated in an artificial tissue model, and then in chicken breast tissue ex vivo. RESULTS: The walker located targets to within 2 mm using the SEMDM technique. No epicardial damage was found subsequent to the porcine trial in vivo. Needle insertion for ablation was controlled to within 2 mm of the target depth. Lesion size was repeatable, with diameter varying consistently in proportion to volume of saline injected. CONCLUSIONS: The experiments demonstrated the general feasibility of the techniques for mapping and depth-controlled ablation with the robotic walker.

Why is orthostatic tolerance lower in women than in men? Renal and cardiovascular responses to simulated microgravity and the role of midodrine.

BACKGROUND: Exposure to microgravity induces cardiovascular deconditioning, manifested by orthostatic intolerance (OI). We assessed the renal, cardioendocrine, and cardiovascular responses of women and men to simulated microgravity to examine the impact of gender on OI. METHODS: Fifteen healthy female and 14 healthy male subjects were given a constant diet for 3 to 5 days, after which they underwent a tilt-stand test (pre-TST) and began 14 to 16 days of head-down tilt bed rest (HDTB), followed by a repeat tilt-stand test (post-TST). Female subjects began HDTB so that the post-TST was at the same time in their menstrual cycle as their pre-TST. Twenty-four-hour urine collections (daily), hormonal measurements, plethysmography, and cardiovascular system identification were performed. RESULTS: The times to presyncope were significantly different for men and women before (p= .005) and after HDTB (p= .001), with all of the women but only 50% of the men experiencing presyncope during the pre-TST (p= .002) and all of the women but only 64% of the men experiencing presyncope during the post-TST. At baseline, the following differences between women and men were observed: women had higher serum aldosterone levels (p = .02), higher parasympathetic responsiveness (p = .01), lower sympathetic responsiveness (p = .05), and lower venous compliance (p = .05). Several parameters changed with HDTB in both men and women. In a double-blinded randomized trial, midodrine (5 mg orally) or placebo given to female subjects 1 hour before post-TST was ineffective in preventing 01. CONCLUSION: In conclusion, the frequency of OI is higher in women than in men and is not modified by midodrine at the dose used. This increased susceptibility is likely secondary to intrinsic basal differences in the activity of volume-mediated parasympathetic and adrenergic systems and in venous tone. Thus, approaches to reduce OI in women are likely to differ from those effective in men.

A weighted-principal component regression method for the identification of physiologic systems.

We introduce a system identification method based on weighted-principal component regression (WPCR). This approach aims to identify the dynamics in a linear time-invariant (LTI) model which may represent a resting physiologic system. It tackles the time-domain system identification problem by considering, asymptotically, frequency information inherent in the given data. By including in the model only dominant frequency components of the input signal(s), this method enables construction of candidate models that are specific to the data and facilitates a reduction in parameter estimation error when the signals are colored (as are most physiologic signals). Additionally, this method allows incorporation of preknowledge about the system through a weighting scheme. We present the method in the context of single-input and multi-input single-output systems operating in open-loop and closed-loop. In each scenario, we compare the WPCR method with conventional approaches and approaches that also build data-specific candidate models. Through both simulated and experimental data, we show that the WPCR method enables more accurate identification of the system impulse response function than the other methods when the input signal(s) is colored.

Continuous cardiac output monitoring by peripheral blood pressure waveform analysis.

A clinical method for monitoring cardiac output (CO) should be continuous, minimally invasive, and accurate. However, none of the conventional CO measurement methods possess all of these characteristics. On the other hand, peripheral arterial blood pressure (ABP) may be measured reliably and continuously with little or no invasiveness. We have developed a novel technique for continuously monitoring changes in CO by mathematical analysis of a peripheral ABP waveform. In contrast to the previous techniques, our technique analyzes the ABP waveform over time scales greater than a cardiac cycle in which the confounding effects of complex wave reflections are attenuated. The technique specifically analyzes 6-min intervals of ABP to estimate the pure exponential pressure decay that would eventually result if pulsatile activity abruptly ceased (i.e., after the high frequency wave reflections vanish). The technique then determines the time constant of this exponential decay, which equals the product of the total peripheral resistance and the nearly constant arterial compliance, and computes proportional CO via Ohm's law. To validate the technique, we performed six acute swine experiments in which peripheral ABP waveforms and aortic flow probe CO were simultaneously measured over a wide physiologic range. We report an overall CO error of 14.6%.

Usefulness of microvolt T-wave alternans for prediction of ventricular tachyarrhythmic events in patients with dilated cardiomyopathy: results from a prospective observational study.

OBJECTIVES: This study was designed to evaluate the ability of microvolt-level T-wave alternans (MTWA) to identify prospectively patients with idiopathic dilated cardiomyopathy (DCM) at risk of ventricular tachyarrhythmic events and to compare its predictive accuracy with that of conventional risk stratifiers. BACKGROUND: Patients with DCM are at increased risk of sudden death from ventricular tachyarrhythmias. At present, there are no established methods of assessing this risk. METHODS: A total of 137 patients with DCM underwent risk stratification through assessment of MTWA, left ventricular ejection fraction, baroreflex sensitivity (BRS), heart rate variability, presence of nonsustained ventricular tachycardia (VT), signal-averaged electrocardiogram, and presence of intraventricular conduction defect. The study end point was either sudden death, resuscitated ventricular fibrillation, or documented hemodynamically unstable VT. RESULTS: During an average follow-up of 14 +/- 6 months, MTWA and BRS were significant univariate predictors of ventricular tachyarrhythmic events (p < 0.035 and p < 0.015, respectively). Multivariate Cox regression analysis revealed that only MTWA was a significant predictor. CONCLUSIONS: Microvolt-level T-wave alternans is a powerful independent predictor of ventricular tachyarrhythmic events in patients with DCM.

Can microvolt T-wave alternans testing reduce unnecessary defibrillator implantation?

The Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) have established that patients with a reduced ejection fraction gain an overall mortality benefit from prophylactic implantable cardioverter-defibrillator therapy. Only a small proportion of the patients in these studies, however, have received life-saving therapy from the defibrillator. Because defibrillator therapy is invasive and expensive, patients with a low ejection fraction would benefit from effective risk stratification so that defibrillator therapy was used only in those at significant risk. In this review, we analyze prospective clinical trials that have evaluated microvolt T-wave alternans (MTWA) testing as a predictor of ventricular tachyarrhythmic events in populations of patients similar to those studied in MADIT II or SCD-HeFT; that is, patients with a reduced ejection fraction who were not selected on the basis of a history of ventricular tachyarrhythmias. In these studies, the average annual rate of fatal and nonfatal ventricular tachyarrhythmic events among the patients who tested negative for MTWA was around 1%. This rate is so low that it is unlikely that such patients would benefit from implantable cardioverter-defibrillator therapy. The mortality, moreover, was lower among MTWA-negative patients who did not receive implantable defibrillators than that observed in the MADIT II and SCD-HeFT patients who received implantable cardioverter-defibrillators. In response, patients with a low ejection fraction who are being considered for implantable cardioverter-defibrillator therapy should undergo MTWA testing as part of their evaluation.

Readaptation from simulated microgravity as a stimulus for improved orthostatic tolerance: role of the renal, cardioendocrine, and cardiovascular systems.

BACKGROUND: Microgravity and simulated microgravity (SM) lead to important changes in orthostatic tolerance (OT), the autonomic nervous system (ANS), and the volume-regulating systems. After one is exposed to microgravity or SM, a period of readaptation to gravity is known to take place, but it is not certain if orthostatic function returns to baseline within the initial recovery and what mechanisms are involved. We hypothesized that after a period of recovery, OT, ANS, and volume-regulating systems would return to pre-SM levels. METHODS: To test this hypothesis, 24 healthy men were placed on a constant diet for 3 to 5 days, after which a tilt-stand test (pre-TST) was performed. The TST was repeated after 14 to 16 days of head-down tilt bed rest (HDTB) (post-TST) and a 3-day period of recovery (rec-TST), at which times measurements of renal, cardioendocrine, and cardiovascular systems were conducted. RESULTS: Presyncope occurred in 46% of subjects pre-TST, in 72% post-TST, and in 23% during rec-TST. OT was significantly better during the recovery period than at baseline (p = .03). There was a significant decrease in urinary sodium and potassium excretion, along with a decrease in plasma renin activity and serum and urine aldosterone compared with baseline. Serum norepinephrine and sympathetic responsiveness remained below baseline values. CONCLUSION: In summary, OT improved compared with baseline after a period of readaptation. Retention of electrolytes (sodium, potassium) could be involved. These findings indicate that recovery after SM is not simply a gradual return to baseline values but is instead a dynamic process reflecting interaction of multiple regulatory systems.

Bed rest effects on human calf hemodynamics and orthostatic intolerance: a model-based analysis.

INTRODUCTION: Microgravity-induced orthostatic intolerance continues to be a primary problem after space missions. Its etiology remains uncertain despite significant research efforts over the past years. We hypothesized that calf hemodynamic parameters (compliance and resistance) are significantly affected by 14 to 16-d head-down bed rest (simulated microgravity), and their alterations play a role in the pathogenesis of orthostatic intolerance (OI) following bed rest. METHODS: To estimate these parameters, we developed a model-based approach to quantitatively simulate calf vascular response to venous occlusion, which only necessitates measurement of plethysmography data. In this study, plethysmography data were obtained from 29 subjects before and after 14-16 d of head-down bed rest. The subjects also underwent a tilt/stand test before and after bed rest. RESULTS: Statistical analyses demonstrated an increase in calf compliance (1.87 +/- 0.08, mean +/- SE, pre-bed rest; 2.16 +/- 0.10, end-bed rest) but no significant change in vascular resistance following bed rest. Compared with the tilt-intolerant subjects, those who were tilt-tolerant before bed rest had significantly higher calf compliance [2.00 +/- 0.09 (tolerant); 1.58 +/- 0.09 (intolerant)] and higher vascular resistance [7.79 +/- 0.18 (tolerant); 6.91 +/- 0.40 (intolerant)]. After bed rest, no such difference was detected. DISCUSSION: Based on these results, we validated the hypothesis that, instead of causing orthostatic intolerance, higher calf compliance before bed rest leads to recruitment of compensatory mechanisms (validated by the enhanced vascular resistance during venous occlusion) for a better toleration of orthostatic stress. With the absence of orthostatic challenge during bed rest, the difference in calf hemodynamic parameters is attenuated between the tilt-tolerant and tilt-intolerant groups.

Diurnal variation of aldosterone and plasma renin activity: timing relation to melatonin and cortisol and consistency after prolonged bed rest.

Exposure to prolonged bed rest is known to induce changes in the renin-angiotensin-aldosterone system (RAAS) by way of posture, sodium and potassium balance, and stress, which may have serious consequences for patients. We focused on the diurnal variation of the RAAS by investigating changes in the levels of plasma renin activity (PRA) and aldosterone; for comparison to markers of the intrinsic pacemaker and to stress, we measured melatonin and cortisol. PRA, aldosterone, melatonin, and cortisol were measured hourly in 10 normal subjects with standardized sleep patterns, posture, and diet at baseline and after 11 days of prolonged bed rest conducted under a light-dark cycle. Circadian characteristics of hormone secretion patterns were estimated by multiple harmonic regression with excellent goodness-of-fit measures. Variability in the melatonin and cortisol patterns across subjects was minimal. Even for pulsatile hormones, this technique successfully estimated the acrophase, which was the salient feature. Baseline hormone peak times started with melatonin near the middle of the sleep period, followed by PRA, then aldosterone, and then cortisol around wake time. Prolonged bed rest did not induce significant changes in any timing characteristic of the secretion patterns. Baseline and prolonged bed rest peak times for melatonin and cortisol and amplitude characteristics for all hormones were highly correlated, indicating consistency within individuals. These data provide strong evidence that prolonged bed rest of 11 days' duration does not disrupt either the timing characteristics of the RAAS or the intrinsic pacemaker.

Sleep restriction does not affect orthostatic tolerance in the simulated microgravity environment.

Orthostatic intolerance (OI) is a major problem following spaceflight, and, during flight, astronauts also experience sleep restriction. We hypothesized that sleep restriction will compound the risk and severity of OI following simulated microgravity and exaggerate the renal, cardioendocrine, and cardiovascular adaptive responses to it. Nineteen healthy men were equilibrated on a constant diet, after which they underwent a tilt-stand test. They then completed 14-16 days of simulated microgravity [head-down tilt bed rest (HDTB)], followed by repeat tilt-stand test. During HDTB, 11 subjects were assigned to an 8-h sleep protocol (non-sleep restricted), and 8 were assigned to a sleep-restricted protocol with 6 h of sleep per night. During various phases, the following were performed: 24-h urine collections, hormonal measurements, and cardiovascular system identification. Development of presyncope or syncope defined OI. There was a significant decrease in time free of OI (P = 0.02) and an increase in OI occurrence (P = 0.06) after HDTB among all subjects. However, the increase in OI occurrence did not differ significantly between the two groups (P = 0.60). The two groups also experienced similar physiological changes with HDTB (initial increase in sodium excretion; increased excretion of potassium at the end of HDTB; increase in plasma renin activity secretion without a change in serum or urine aldosterone). No significant change in autonomic function or catecholamines was noted. Simulated microgravity leads to increased OI, and sleep restriction does not additively worsen OI in simulated microgravity. Furthermore, conditions of sleep restriction and nonsleep restriction are similar with respect to renal, cardioendocrine, and cardiovascular responses to simulated microgravity.