A comparison between left ventricular ejection time measurement methods during physiological changes induced by simulated microgravity.

NEW FINDINGS: What is the central question of this study? First, we validated easy-to-use oscillometric left ventricular ejection time (LVET) against echocardiographic LVET. Second, we investigated progression of left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), total electromechanical systole index (QS2I) and PEP/LVET ratio during 60 days of head-down tilt (HDT). What is the main finding and its importance? The LVETosci and LVETecho showed good agreement in effect direction. Hence, LVETosci might be useful to evaluate cardiovascular responses during space flight. Moreover, the approach might be useful for individual follow-up of patients with altered ejection times. Furthermore, significant effects of 60 days of HDT were captured by measurements of LVETI, PEPI, QS2I and PEP/LVET ratio. ABSTRACT: Systolic time intervals that are easy to detect might be used as parameters reflecting cardiovascular deconditioning. We compared left ventricular ejection time (LVET) measured via ultrasound Doppler on the left ventricular outflow tract with oscillometrically measured LVET, measured at the brachialis. Furthermore, we assessed the progression of the left ventricular ejection time index (LVETI), the pre-ejection period index (PEPI), the Weissler index (PEP/LVET) and the total electromechanical systole index (QS2I) during prolonged strict head-down tilt (HDT) bed rest, including 16 male and eight female subjects. Simultaneous oscillometric and echocardiographic LVET measurements showed significant correlation (r = 0.53 with P = 0.0084 before bed rest and r = 0.73 with P < 0.05 on the last day of bed rest). The shortening of LVET during HDT bed rest measured with both approaches was highly concordant in their effect direction, with a concordance rate of 0.96. Our results also demonstrated a significant decrease of LVETI (P < 0.0001) and QS2I (P = 0.0992) and a prolongation of PEPI (P = 0.0049) and PEP/LVET (P = 0.0003) during HDT bed rest over 60 days. Four days after bed rest, LVETI recovered completely to its baseline value. Owing to the relationship between shortening of LVETI and heart failure progression, the easy-to-use oscillometric method might not only be a useful way to evaluate the cardiovascular system during space flights, but could also be of high value in a clinical setting.

Brain structure and neurocognitive function in two professional mountaineers during 35 days of severe normobaric hypoxia.

BACKGROUND AND PURPOSE: Animal studies suggest that exposure to severe ambient hypoxia for several days may have beneficial long-term effects on neurodegenerative diseases. Because, the acute risks of exposing human beings to prolonged severe hypoxia on brain structure and function are uncertain, we conducted a pilot study in healthy persons. METHODS: We included two professional mountaineers (participants A and B) in a 35-day study comprising an acclimatization period and 14 consecutive days with oxygen concentrations between 8% and 8.8%. They underwent cerebral magnetic resonance imaging at seven time points and a cognitive test battery covering a spectrum of cognitive domains at 27 time points. We analysed blood neuron specific enolase and neurofilament light chain levels before, during, and after hypoxia. RESULTS: In hypoxia, white matter volumes increased (maximum: A, 4.3% ± 0.9%; B, 4.5% ± 1.9%) whilst gray matter volumes (A, -1.5% ± 0.8%; B, -2.5% ± 0.9%) and cerebrospinal fluid volumes (A, -2.7% ± 2.4%; B, -5.9% ± 8.2%) decreased. Furthermore, the number (A, 11-17; B, 26-126) and volumes (A, 140%; B, 285%) of white matter hyperintensities increased in hypoxia but had returned to baseline after a 3.5-month recovery phase. Diffusion weighted imaging of the white matter indicated cytotoxic edema formation. We did not observe changes in cognitive performance or biochemical brain injury markers. DISCUSSION: In highly selected healthy individuals, severe sustained normobaric hypoxia over 2 weeks elicited reversible changes in brain morphology without clinically relevant changes in cognitive function or brain injury markers. The finding may pave the way for future translational studies assessing the therapeutic potential of hypoxia in neurodegenerative diseases.

Effects of short-term hypercaloric nutrition on orthostatic tolerance in healthy individuals: a randomized controlled crossover study.

Reduced-caloric intake lowers blood pressure through sympathetic inhibition, and worsens orthostatic tolerance within days. Conversely, hypercaloric nutrition augments sympathetic activity and blood pressure. Because dietary interventions could be applied in patients with syncope, we tested the hypothesis that short-term hypercaloric dieting improves orthostatic tolerance. In a randomized crossover trial, 20 healthy individuals (7 women, 26.7 ± 8 years, 22.6 ± 2 kg/m2) followed a 4-day hypercaloric (25% increase of energy intake by fat) or normocaloric nutritional plan, with a washout period of at least 23 days between interventions. We then performed head-up tilt table testing with incremental lower body negative pressure while recording beat-by-beat blood pressure and heart rate. The primary endpoint was orthostatic tolerance defined as time to presyncope. Time to presyncope during combined head-up tilt and lower body negative pressure did not differ between hypercaloric and normocaloric dieting (median 23.19 versus 23.04 min, ratio of median 1.01, 95% CI of ratio 0.5-1.9). Heart rate, blood pressure, heart rate variability, and blood pressure variability in the supine position and during orthostatic testing did not differ between interventions. We conclude that 4 days of moderate hypercaloric nutrition does not significantly improve orthostatic tolerance in healthy individuals. Nevertheless, given the important interaction between energy balance and cardiovascular autonomic control in the brain, caloric intake deserves more attention as a potential contributor and treatment target for orthostatic intolerance.

Cardiovascular autonomic nervous system responses and orthostatic intolerance in astronauts and their relevance in daily medicine.

BACKGROUND: The harsh environmental conditions during space travel, particularly weightlessness, impose a major burden on the human body including the cardiovascular system. Given its importance in adjusting the cardiovascular system to environmental challenges, the autonomic nervous system has been in the focus of scientists and clinicians involved in human space flight. This review provides an overview on human autonomic research under real and simulated space conditions with a focus on orthostatic intolerance. METHODS: The authors conducted a targeted literature search using Pubmed. RESULTS: Overall, 120 articles were identified and included in the review. CONCLUSIONS: Postflight orthostatic intolerance is commonly observed in astronauts and could pose major risks when landing on another celestial body. The phenomenon likely results from changes in volume status and adaptation of the autonomic nervous system to weightlessness. Over the years, various non-pharmacological and pharmacological countermeasures have been investigated. In addition to enabling safe human space flight, this research may have implications for patients with disorders affecting cardiovascular autonomic control on Earth.

The thrombotic risk of spaceflight: has a serious problem been overlooked for more than half of a century?

The first ever venous thrombotic condition associated with spaceflight, an internal jugular vein thrombus requiring anticoagulation, has recently been reported. Systematic investigation of space travel-associated thrombotic risk has not been conducted. Cellular, animal, and human studies performed in ground-based models and in actual weightlessness revealed influences of weightlessness and gravity on the blood coagulation system. However, human study populations were small and limited to highly selected participants. Evidence in individuals with medical conditions and older persons is lacking. Evidence for thrombotic risk in spaceflight is unsatisfactory. This issue deserves further study in heterogeneous, high risk populations to find prevention strategies and to enable safe governmental and touristic human spaceflight.

Testing individual baroreflex responses to hypoxia-induced peripheral chemoreflex stimulation.

INTRODUCTION: Baroreflexes and peripheral chemoreflexes control efferent autonomic activity making these reflexes treatment targets for arterial hypertension. The literature on their interaction is controversial, with suggestions that their individual and collective influence on blood pressure and heart rate regulation is variable. Therefore, we applied a study design that allows the elucidation of individual baroreflex-chemoreflex interactions. METHODS: We studied nine healthy young men who breathed either normal air (normoxia) or an air-nitrogen-carbon dioxide mixture with decreased oxygen content (hypoxia) for 90 min, with randomization to condition, followed by a 30-min recovery period and then exposure to the other condition for 90 min. Multiple intravenous phenylephrine bolus doses were applied per condition to determine phenylephrine pressor sensitivity as an estimate of baroreflex blood pressure buffering and cardiovagal baroreflex sensitivity (BRS). RESULTS: Hypoxia reduced arterial oxygen saturation from 98.1 ± 0.4 to 81.0 ± 0.4% (p < 0.001), raised heart rate from 62.9 ± 2.1 to 76.0 ± 3.6 bpm (p < 0.001), but did not change systolic blood pressure (p = 0.182). Of the nine subjects, six had significantly lower BRS in hypoxia (p < 0.05), two showed a significantly decreased pressor response, and three showed a significantly increased pressor response to phenylephrine in hypoxia, likely through reduced baroreflex buffering (p < 0.05). On average, hypoxia decreased BRS by 6.4 ± 0.9 ms/mmHg (19.9 ± 2.0 vs. 14.12 ± 1.6 ms/mmHg; p < 0.001) but did not change the phenylephrine pressor response (p = 0.878). CONCLUSION: We applied an approach to assess individual baroreflex-chemoreflex interactions in human subjects. A subgroup exhibited significant impairments in baroreflex blood pressure buffering and BRS with peripheral chemoreflex activation. The methodology may have utility in elucidating individual pathophysiology and in targeting treatments modulating baroreflex or chemoreflex function.

What do we really know about supine hypertension in patients with orthostatic hypotension.

PURPOSE OF REVIEW: Patients with severe orthostatic hypotension due to autonomic failure may be hypertensive in the supine position. Until recently, there were no internationally recognized diagnostic criteria for supine hypertension. This review covers diagnostic criteria, mechanisms, and management of supine hypertension in autonomic failure patients. RECENT FINDINGS: Recently, an international consensus group defined supine hypertension in patients with neurogenic orthostatic hypotension as brachial SBP at least 140 mmHg and/or DBP at least 90 mmHg while supine. Using these criteria, a large proportion of patients with orthostatic hypotension is diagnosed with supine hypertension. Recent research supports the concept that the hypertension can be mediated through residual sympathetic nervous system function and independently from sympathetic activity, for example via mineralocorticoid receptor activation. SUMMARY: The clear definition of supine hypertension is an important step that will hopefully foster clinical research in this area. Supine hypertension promotes renal sodium excretion, thus, worsening orthostatic hypotension the next morning. Supine hypertension may promote cardiovascular and renal disease. Yet, long-term benefits of treating supine hypertension be it through non pharmacological or pharmacological means have not been proven by sufficiently large clinical trials.

Modeling human orthostatic responses on the Moon and on Mars.

PURPOSE: Since manned missions to the Moon and Mars are planned, we conducted active standing tests with lunar, Martian, terrestrial, and 1.8 loads of inertial resistance (+Gz) modeled through defined parabolic flight maneuvers. We hypothesized that the cardiovascular response to active standing is proportional to the +Gz load. METHODS: During partial-+Gz parabolic flights, 14 healthy test subjects performed active stand-up maneuvers under 1 +Gz, lunar (0.16 +Gz), Martian (0.38 +Gz), and hyper inertial resistance (1.8 +Gz) while heart rate and finger blood pressure were continuously monitored. We quantified amplitudes and timing of orthostatic response immediately following standing up. RESULTS: The maximum early heart rate increase was 21 (SD ± 10) bpm with lunar, 23 (± 11) bpm with Martian, 34 (± 17) bpm with terrestrial +Gz, and 40 (± 11) bpm hyper +Gz. The time to maximum heart rate increased gradually with increasing loads of inertial resistance. The transient blood pressure reduction was most pronounced with hyper +Gz but did not differ significantly between lunar and Martian +Gz. The mean arterial pressure nadir was reached significantly later with Martian and lunar compared to 1 +Gz. Paradoxically, the time for blood pressure to recover was shortest with terrestrial +Gz. CONCLUSION: While load of inertial resistance directly affects the magnitude of the transient blood pressure reduction and heart rate response to active standing, blood pressure stabilization is most rapidly attained during terrestrial +Gz. The observation might suggest that the human cardiovascular system is tuned to cope with orthostatic stress on earth.

Airway and systemic inflammatory responses to ultrafine carbon black particles and ozone in older healthy subjects.

Increased adverse health effects in older subjects due to exposure to ambient air pollutants may be related to the inflammatory response induced by these contaminants. The aim of this study was to assess airway and systemic inflammatory responses in older healthy subjects to a controlled experimental exposure with spark-generated elemental carbon black ultrafine particles (cbUFPs) and ozone (O3). Twenty healthy subjects, age 52-75 years, were exposed on three occasions separated by at least 8 weeks. The exposures to filtered air (FA), to cbUFP (50 µg/m3), or to cbUFP in combination with 250 ppb ozone (cbUFP + O3) for 3 h with intermittent exercise were performed double blind, and in random order. Sputum and blood samples were collected 3.5 h after each exposure. Exposure to cbUFP + O3 significantly increased plasma club cell protein 16 (CC16), the number of sputum cells, the number and percent of sputum neutrophils, and sputum interleukin 6 and matrix metalloproteinase 9. Exposure to cbUFP alone exerted no marked effect, except for an elevation in sputum neutrophils in a subgroup of 13 subjects that displayed less than 65% sputum neutrophils after FA exposure. None of the inflammatory markers was correlated with age, and serum cardiovascular risk markers were not markedly affected by cbUFP or cbUFP + O3. Exposure to cbUFP+O3 induced a significant airway and systemic inflammatory response in older healthy volunteer subjects. The effects induced by cbUFP alone suggest that the inflammation was predominantly mediated by O3, although one cannot rule out that the interaction of cbUFP and O3 played a role.

A genetic basis for mechanosensory traits in humans.

In all vertebrates hearing and touch represent two distinct sensory systems that both rely on the transformation of mechanical force into electrical signals. There is an extensive literature describing single gene mutations in humans that cause hearing impairment, but there are essentially none for touch. Here we first asked if touch sensitivity is a heritable trait and second whether there are common genes that influence different mechanosensory senses like hearing and touch in humans. Using a classical twin study design we demonstrate that touch sensitivity and touch acuity are highly heritable traits. Quantitative phenotypic measures of different mechanosensory systems revealed significant correlations between touch and hearing acuity in a healthy human population. Thus mutations in genes causing deafness genes could conceivably negatively influence touch sensitivity. In agreement with this hypothesis we found that a proportion of a cohort of congenitally deaf young adults display significantly impaired measures of touch sensitivity compared to controls. In contrast, blind individuals showed enhanced, not diminished touch acuity. Finally, by examining a cohort of patients with Usher syndrome, a genetically well-characterized deaf-blindness syndrome, we could show that recessive pathogenic mutations in the USH2A gene influence touch acuity. Control Usher syndrome cohorts lacking demonstrable pathogenic USH2A mutations showed no impairment in touch acuity. Our study thus provides comprehensive evidence that there are common genetic elements that contribute to touch and hearing and has identified one of these genes as USH2A.

What do we know about the role of menopause in cardiovascular autonomic regulation in hypertensive women?

OBJECTIVE: We investigated the systemic arterial hypertension effects on cardiovascular autonomic modulation and baroreflex sensitivity (BRS) in women with or without preserved ovarian function. METHODS: A total of 120 women were allocated into two groups: middle-aged premenopausal women (42 ± 3 y old; n = 60) and postmenopausal women (57 ± 4 y old; n = 60). Each group was also divided into two smaller groups (n = 30): normotensive and hypertensive. We evaluated hemodynamic and anthropometric parameters, cardiorespiratory fitness, BRS, heart rate variability (HRV), and blood pressure variability. The effects of hypertension and menopause were assessed using a two-way analysis of variance. Post hoc comparisons were performed using the Student-Newman-Keuls test. RESULTS: Comparing premenopausal groups, women with systemic arterial hypertension showed lower BRS (9.1 ± 4.4 vs 13.4 ± 4.2 ms/mm Hg, P < 0.001 ) and HRV total variance (1,451 ± 955 vs 2,483 ± 1,959 ms 2 , P = 0.005) values than normotensive; however, the vagal predominance still remained. On the other hand, both postmenopausal groups showed an expressive reduction in BRS (8.3 ± 4.2 vs 11.3 ± 4.8 ms/mm Hg, P < 0.001) and HRV characterized by sympathetic modulation predominance (low-frequency oscillations; 56% ± 17 vs 44% ± 17, P < 0.001), in addition to a significant increase in blood pressure variability variance (28.4 ± 14.9 vs 22.4 ± 12.5 mm Hg 2 , P = 0.015) compared with premenopausal groups. Comparing both postmenopausal groups, the hypertensive group had significantly lower values ​​of HRV total variance (635 ± 449 vs 2,053 ± 1,720 ms 2 , P < 0.001) and BRS (5.3 ± 2.8 vs 11.3 ± 3.2 ms/mm Hg) than the normotensive. CONCLUSIONS: Hypertensive middle-aged premenopausal women present HRV autonomic modulation impairment, but they still maintain a vagal predominance. After menopause, even normotensive women show sympathetic autonomic predominance, which may also be associated with aging. Furthermore, postmenopausal women with hypertension present even worse cardiac autonomic modulation.

Physical exercise is essential for increasing ventricular contractility in hypertensive rats treated with losartan.

The treatment of hypertensive patients with losartan is very common. Despite the reduction in blood pressure, its effects on cardiac contractility and sympathetic autonomic drive are still controversial. In turn, aerobic physical training (APT) also presents an important therapeutic option, providing significant improvements in cardiovascular autonomic control, however little is known about its effects on cardiac contractility, especially when associated with losartan. Therefore, we investigated in spontaneously hypertensive rats (SHR) the effects of losartan and APT on cardiac hemodynamics and functionality, with emphasis on autonomic tonic balance and cardiac contractility. Sixty-four SHR (18 weeks old) were divided into four groups (N = 16): vehicle; vehicle submitted to APT through swimming for 12 weeks; treated with losartan (5 mg·kg-1·d-1) for 12 weeks; and treated with losartan associated with APT. The groups were submitted to cardiac morphological and functional analysis by echocardiography; double blockade of cardiac autonomic receptors with atropine and propranolol; and coronary bed reactivity and left ventricular contractility analyses by the Langendorff technique. APT improved functional parameters and autonomic balance by reducing sympathetic drive and/or increasing vagal drive. In contrast, it promoted a concentric remodeling of the left ventricle (LV). Treatment with losartan reduced sympathetic autonomic drive and cardiac morphological parameters, but there were no significant gains in cardiac functionality and contractility. When combined, the concentric remodeling of the LV to APT was abolished and gains in cardiac functionality and contractility were observed. Our findings suggest that the effects of losartan and APT are complementary and should be applied together in the treatment of hypertension. In spontaneously hypertensive rats, the combination of aerobic physical training with losartan treatment was crucial to greater blood pressure reductions and an increase in left ventricular contractility. Furthermore, losartan treatment prevented the concentric left ventricular remodeling caused by aerobic physical training.