Marc-Antoine Custaud

Spontaneous baroreflex sensitivity: toward an ideal index of cardiovascular risk in hypertension?

Objective Estimating the risk entailed by classical risk factors like blood pressure (BP) or serum cholesterol may be difficult because of their variability and the often unknown duration of exposure. Having variables integrating the impact of those classical risk factors on the cardiovascular system would probably aid the prediction of cardiovascular events. The present study aimed at determining whether cardiac baroreflex sensitivity (BRS), correlates with several risk factors and thus is a good candidate for being such an integrative variable. As a comparison, left ventricular mass (LVM), pulse wave velocity (PWV), and creatinine were also tested for association with risk factors. Design A total of 302 subjects referred for hypertension, were considered. They had a 24-h BP recording and a determination of BRS by two different methods (sequence and alpha coefficient), in two different positions (lying and standing). They were also tested for the presence of left ventricular hypertrophy (LVH) (by echocardiography and electrocardiogram) and had a PWV measurement. Biological testing included serum lipids, blood glucose, creatinine, proteinuria and urinary excretion of microalbumin. Results There was a strong correlation between the two methods of BRS measurement in each position (P < 0.001). BRS determined by the sequence method in the lying position was correlated significantly and independently with age, 24-h systolic BP, heart rate, and serum cholesterol with P values < 0.001, < 0.001, < 0.01, and < 0.05, respectively. In an univariate analysis, BRS was also correlated with echocardiographic LVM index (r =− 0.21, P < 0.05) and PWV (r =− 0.27, P < 0.001), which possibly reflects its dependence on both vascular and cardiac damages. Conclusion The present study supports the hypothesis that BRS could encompass the impact over time of several risk factors on the cardiovascular system . Thus, it may constitute a valuable parameter in assessing more precisely the risk of cardiovascular events.

Enforced physical inactivity increases endothelial microparticle levels in healthy volunteers

A sedentary lifestyle has adverse effects on the cardiovascular system, including impaired endothelial functions. Subjecting healthy men to 7 days of dry immersion (DI) presented a unique opportunity to analyze the specific effects of enhanced inactivity on the endothelium. We investigated endothelial properties before, during, and after 7 days of DI involving eight subjects. Microcirculatory functions were assessed with laser Doppler in the skin of the calf. We studied basal blood flow and endothelium-dependent and -independent vasodilation. We also measured plasma levels of microparticles, a sign of cellular dysfunction, and soluble endothelial factors, reflecting the endothelial state. Basal flow and endothelium-dependent vasodilation were reduced by DI (22 + or - 4 vs. 15 + or - 2 arbitrary units and 29 + or - 6% vs. 12 + or - 6%, respectively, P < 0.05), and this was accompanied by an increase in circulating endothelial microparticles (EMPs), which was significant on day 3 (42 + or - 8 vs. 65 + or - 10 EMPs/microl, P < 0.05), whereas microparticles from other cell origins remained unchanged. Plasma soluble VEGF decreased significantly during DI, whereas VEGF receptor 1 and soluble CD62E were unchanged, indicating that the increase in EMPs was associated with a change in antiapoptotic tone rather than endothelial activation. Our study showed that extreme physical inactivity in humans induced by 7 days of DI causes microvascular impairment with a disturbance of endothelial functions, associated with a selective increase in EMPs. Microcirculatory endothelial dysfunction might contribute to cardiovascular deconditioning as well as to hypodynamia-associated pathologies. In conclusion, the endothelium should be the focus of special care in situations of acute limitation of physical activity.

Orthostatic tolerance and spontaneous baroreflex sensitivity in men versus women after 7 days of head-down bed rest

Many factors are involved in the development of orthostatic intolerance after real or simulated weightlessness. The aim of our study was to compare the effects of 7-day head-down bed rest (HDBR) in eight women and eight men on the spontaneous baroreflex sensitivity (standard spectral method and new time-frequency algorithm) during lower body negative pressure (LBNP) tests. Results obtained before HDBR have shown in women, compared to men, higher heart rate, lower blood pressure, higher parasympathetic modulation at rest and greater decrease in baroreflex sensitivity with greater increase in sympathetic activity during LBNP. After HDBR, we observed in both men and women a dramatic decrease in orthostatic tolerance (7.0 min at R + 1 vs. 10.0 min, p<0.05, at BDC-1 in men; 5.4 vs. 9.0 min, p<0.05, in women) together with a decrease in plasma volume (-9.1 +/- 0.9% in men, -9.5 +/- 1.4% in women) and in spontaneous baroreflex sensitivity without gender effect. After HDBR, at the highest level of LBNP, diastolic blood pressure increased in men (+5.6 +/- 1.3 mm Hg) and decreased in women (-1.0 +/- 2.7 mm Hg) with a gender difference (p<0.05). This result suggests impaired vasoconstriction in women after HDBR. Neither endocrine response nor alterations to the cardiac baroreflex can explain gender differences in orthostatic tolerance after HDBR as reported by previous studies. Further studies need to be conducted in order to obtain a more precise analysis of gender difference in arteriolar vasoconstriction after HDBR. The time frequency method we developed to study changes in spontaneous baroreflex might be applied to the analysis of LBNP tests.

Cardiovascular deconditioning: From autonomic nervous system to microvascular dysfunctions

Weightlessness induces an acute syndrome called the cardiovascular deconditioning, associating orthostatic intolerance with syncope, increase in resting heart rate and decrease in physical capability. Orthostatic intolerance occurs after short term and long term head down bed rest and after long term space flight. Both head down bed rest and space flight induce a significant decrease of the spontaneous baroreflex sensitivity. However, spontaneous baroreflex sensitivity only characterizes the cardiac baroreflex loop. To go further with the analysis of cardiovascular deconditioning we were interested in the microcirculation. As the endothelium plays a crucial role in the regulation of vascular homeostasis and local blood flow, we hypothesized that endothelial dysfunction is associated with bed rest induced changes. We investigated endothelial properties before and after 56 days of bed rest in 8 women of control group and in 8 women who regularly performed physical exercise as countermeasure. Our study shows that prolonged bed rest causes impairment of endothelium-dependent functions at the microcirculation level, along with an increase in circulating endothelial cells. Endothelium should be a target for countermeasures during periods of prolonged bed rest or exposure to weightlessness.

Smoothed pseudo Wigner–Ville distribution as an alternative to Fourier transform in rats

Techniques for examining signals in the time and frequency domains are well-established tools. These tools have their limitations; they tell us in a broad sense where the signal component exists in the frequency domain, but they do not tell us how its frequency characteristics change over time. The time-frequency has become a powerful alternative for the analysis of signals. Among various time-frequency distribution methods, one of the most studied is the Wigner-Ville distribution. The aim of this study was to evaluate in conscious rats smoothed pseudo Wigner--Ville distribution (SPWVD) as an alternative to the fast Fourier transform (FFT) in RR intervals and in systolic blood pressure (SBP), before and after adrenergic and cholinergic receptor blockade. Fourteen Wistar rats equipped with telemetry probe were evaluated: (1) under control conditions; (2) after injection of saline (100 microl kg(-1) i.v.); (3) after atenolol (1 mg kg(-1) i.v.); (4) after atropine methyl nitrate (0.5 mg kg(-1) i.v.); and (5) after phentolamine (5 mg kg(-1) i.v.). FFT and SPWVD were applied to RR intervals and SBP time series. Six-minute time series of RR intervals, systolic and diastolic pressures were analysed. The bias and distribution of differences between FFT and SPWVD methods in RR intervals under base conditions were 1.4+/-0.4% (r2=0.94; P<0.01) in LF/LF+HF: 1.5+/-0.5% ( r2=0.92; P<0.01) in HF/LF+HF and 4.8+/-1.9% (r2=0.92; P<0.01) in LF/HF. In SBP the bias and distribution were 1.5+/-0.8% (r2=0.90) P<0.05) in LF/LF+HF and 1.7+/-0.6% (r2=-0.92; P<0.01) in HF/LF+HF. In the frequency domain analysis of RR intervals and SBP there was no difference between FFT and SPWVD. The agreement between the methods demonstrates that in stationary signals both methods can be used interchangeably. SPWVD may be an interesting tool to analyse biomedical signals; it provides a good resolution at high frequency and a good frequency resolution at low frequencies independently if signals remain stationary.

Adaptations to a 7-day head-down bed rest with thigh cuffs

PURPOSE Thigh cuffs were two elastic strips fixed at the upper part of each thigh, which limits the shift of fluid from the legs into the cardio-thoracic region. The purpose of this study was to examine the effects of thigh cuffs on hormonal and plasma volume responses and orthostatic tolerance during a 7-day head-down bed rest (HDBR). METHODS Orthostatic tolerance, plasma volume, total body water, blood volume-regulating hormones, and hydro-electrolyte responses were measured in eight healthy men (age range, 25-40 yr), using thigh cuffs 10 h daily during 7 d of -6 degrees HDBR. RESULTS Thigh cuffs worn during HDBR attenuated the decrease in plasma volume observed after HDBR (thigh cuffs: -5.85 +/- 0.95% vs control: -9.09 +/- 0.82%, P < or = 0.05). During this experiment, there was no significant change in total body water. Thus, the hypovolemia did not result from a loss of water but from a fluid shift from the blood compartment into the interstitial and/or intracellular compartment. Hormonal responses during HDBR and stand test were not modified by the thigh cuffs. Thigh cuffs had no significant effect on the clinical symptoms of orthostatic intolerance after HDBR. CONCLUSIONS Thigh cuffs worn during HDBR blunted the decrease in plasma volume but did not reduce orthostatic intolerance; thus, they are not a completely effective countermeasure. Furthermore, hypovolemia seems to be necessary but not sufficient to induce orthostatic intolerance after HDBR.

Platelet inhibition by low-dose aspirin but not by clopidogrel reduces the axon-reflex current-induced vasodilation in humans.

We previously showed a prolonged inhibition of current-induced vasodilation (CIV) after a single oral high dose of aspirin. In this study, we tested the hypothesis of platelet involvement in CIV. Nine healthy volunteers took 75 mg aspirin/day, 98 mg of clopidogrel bisulfate/day, or placebo for 4 days. CIV was induced by two consecutive 1-min anodal current applications (0.08 mA/cm(2)) through deionized water with a 10-min interval. CIV was measured with laser Doppler flowmetry and expressed as a percentage of baseline cutaneous vascular conductance: %C(b). In a second experiment in 10 volunteers, aspirin and placebo were given as in experiment 1, but a 26-h delay from the last aspirin intake elapsed before ACh iontophoresis and postocclusive hyperemia were studied in parallel to CIV. In experiment 1, the means +/- SE amplitude of CIV was 822 +/- 314, 313 +/- 144, and 746 +/- 397%C(b) with placebo, aspirin (P < 0.05 from placebo and clopidogrel), and clopidogrel (NS from placebo), respectively. In experiment 2, CIV impairment with aspirin was confirmed: CIV amplitudes were 300 +/- 99, and 916 +/- 528%C(b) under aspirin and placebo, respectively (P < 0.05), whereas vasodilation to ACh iontophoresis (322 +/- 74 and 365 +/- 104%C(b)) and peak postocclusive hyperemia (491 +/- 137 and 661 +/- 248%C(b)) were not different between aspirin and placebo, respectively. Low-dose aspirin, even 26 h after oral administration, impairs CIV, while ACh-mediated vasodilation and postocclusive hyperemia are preserved. If platelets are involved in the neurovascular mechanism triggered by galvanic current application in humans, it is likely to occur through the cyclooxygenase but not the ADP pathway.

Craniomandibular System and Postural Balance after 3-Day Dry Immersion

The objective of the study was to determine the influence of simulated microgravity by exposure to dry immersion on the craniomandibular system. Twelve healthy male volunteers participated in a 3-day dry immersion study. Before and immediately after exposure we measured maximal bite force using piezoresistive sensors. The mechanical properties of the jaw and cervical muscles were evaluated before, during, and after dry immersion using MyotonPRO. Because recent studies reported the effects of jaw motor activity on the postural stability of humans, stabilometric measurements of center of pressure were performed before and after dry immersion in two mandibular positions: rest position without jaw clenching, and intercuspidal position during voluntary teeth clenching. Results revealed no significant changes of maximal bite force after dry immersion. All postural parameters were significantly altered by dry immersion. There were however no significant differences in stabilometric data according to mandibular position. Moreover the masseter tonicity increased immediately after the end of dry immersion period. Dry immersion could be used as a valid model for studying the effects of microgravity on human subjects. However, 3 days appear insufficient in duration to evaluate the effects of weightlessness on maximal bite force. Our research suggests a link between postural disturbance after dry immersion and masseter tonicity.

Clinical effects of thigh cuffs during a 7-day 6° head-down bed rest

Thigh cuffs are used by Russian cosmonauts to limit the fluid shift induced by space flight. A ground simulation using the head-down bed rest (HDBR) model was performed to assess the effects of thigh cuffs on clinical tolerance and orthostatic adaptation. 8 male healthy volunteers (32.4 +/- 1.9 years) participated twice in a 7-day HDBR--one time with thigh cuffs (worn daily from 9 am to 7 pm) (TC) and one time without (WTC). Orthostatic tolerance was assessed by a 10 minute stand test and by a LBNP test (5 min at -15, -30, -45 mmHg) before (BDC-1) and at the end of the HDBR period (R+1). Plasma volume was measured before and at the end of HDBR by the Evans blue dye dilution technique. Thigh cuffs limits headache due to fluid shift, as well as the loss in plasma volume (TC: -5.85 +/- 0.95%; WTC: -9.09 +/- 0.82%, p<0.05). The mean duration of the stand test (R+1) did not differ in the two group (TC 7.1 +/- 1.3 min; WTC 7.0 +/- 1.0 min). The increase in HR and decrease in diastolic blood pressure were slightly but significantly larger without thigh cuffs. Duration of the LBNP tests did not differ with thigh cuffs. Thigh cuffs limit the symptoms due to fluid shift and the loss in plasma volume. They partly reduced the increase in HR during orthostatic stress but had no effect on duration of orthostatic stress tests.

Permanent proteins in the urine of healthy humans during the Mars-500 experiment

Urinary proteins serve as indicators of various conditions in human normal physiology and disease pathology. Using mass spectrometry proteome analysis, the permanent constituent of the urine was examined in the Mars-500 experiment (520 days isolation of healthy volunteers in a terrestrial complex with an autonomous life support system). Seven permanent proteins with predominant distribution in the liver and blood plasma as well as extracellular localization were identified. Analysis of the overrepresentation of the molecular functions and biological processes based on Gene Ontology revealed that the functional association among these proteins was low. The results showed that the identified proteins may be independent markers of the various conditions and processes in healthy humans and that they can be used as standards in determination of the concentration of other proteins in the urine.