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.

Functional uni-ventricular heart due to post-myocardial infarction ventricular septum rupture.

Ventricular septum defect (VSD) is an often lethal complication caused by myocardial infarction. We report a rare case of post-myocardial infarction ventricular septum rupture in a patient after extracorporeal cardiopulmonary resuscitation (eCPR). In the bedside echocardiography after VA ECMO cannulation, we noticed the circular, hypertrophied left ventricle with the disintegrated inter-ventricular septum (maximum dehiscence 3.3 cm), accompanied by decreased left-ventricular ejection fraction and the right ventricle being compressed by the left ventricle's free septal wall. There was no pressure-relevant inter-ventricular separation resulting in left-to-right-shunting and therefore resulting in a fully functional uni-ventricular heart.

Baroreflex activation therapy reduces frequency and duration of hypertension-related hospitalizations in patients with resistant hypertension.

PURPOSE: Baroreflex activation therapy (BAT) has been shown to lower blood pressure in patients with resistant hypertension. The purpose of this study was to analyze whether this translates into a reduction of more relevant clinical endpoints. METHODS: Patients with resistant hypertension were treated with the second-generation BAT system. Records on hospitalization (dates of admission and discharge, main diagnosis) were obtained from medical insurance companies. RESULTS: Records on hospitalization were available for a period of 1 year before BAT in two patients and 2 years in 22 patients. The total number of hospitalizations per patient was 3.3 ± 3.5/year before BAT and 2.2 ± 2.7/year after BAT (p = 0.03). Hospitalizations related to hypertension were significantly decreased from 1.5 ± 1.6/year before BAT to 0.5 ± 0.9/year after BAT (p < 0.01). The cumulative duration of hypertension-related hospital stays was significantly reduced from 8.0 ± 8.7 days/year before BAT to 1.8 ± 4.8 days/year after BAT (p < 0.01). Office cuff blood pressure was 183 ± 27 mmHg over 102 ± 17 mmHg under 6.6 ± 2.0 antihypertensive drugs before BAT and 157 ± 32 mmHg over 91 ± 20 mmHg (both p < 0.01) under 5.9 ± 1.9 antihypertensive drugs (p = 0.09 for number of drugs) at latest follow-up. Daytime ambulatory blood pressure was 164 ± 21 mmHg over 91 ± 14 mmHg before BAT and 153 ± 21 mmHg (p = 0.03) over 89 ± 15 mmHg (p = 0.56) at latest follow-up. Heart rate was 75 ± 16 bpm before BAT and 72 ± 12 bpm at latest follow-up (p = 0.35). CONCLUSIONS: Rate and duration of hypertension-related hospitalizations in patients with severe resistant hypertension were lowered after BAT. Whether the response is mediated through improvements in blood pressure control requires further studies.

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.

Improved Carotid Stenosis Quantification on Novel 4D/3D-Doppler Ultrasonography Indexing to the Common Carotid Artery.

PURPOSE: The accuracy of internal carotid artery stenosis (ICAS) quantification depends on the method of stenosis measurement, impacting therapeutic decisions and outcomes. The NASCET method references the stenotic to the distal ICAS lumen, the ECST method to the local outer and the common carotid artery (CC) method to the CC diameter. Direct morphometric stenosis measurement with four-dimensionally guided three-dimensional ultrasonography (4D/3DC-US) demonstrated good validity for the commonly used NASCET method. The NASCET definition has clinically relevant drawbacks. Our purpose was to investigate the validity of the ECST and CC methods. MATERIALS AND METHODS: 4D/3DC-US percent-stenosis measures of 103 stenoses (80 patients) were compared to quantitative catheter angiography and duplex ultrasonography (DUS) in a blinded fashion. RESULTS: The 4D/3DC-US versus angiography intermethod standard deviation of differences (SDD, n = 103) was lower for the CC method (5.7 %) compared to the NASCET (8.1 %, p < 0.001) and ECST methods (9.1 %, p < 0.001). Additionally, it was lower than the NASCET angiography interrater SDD of 52 stenoses (SDD 7.2 %, p = 0.047) and non-inferior for the ECST method (p = 0.065). Interobserver analysis of equivalent grading methods showed no differences for the SDDs between angiography and 4D/3DC-US observers (p > 0.076). Binary comparison to angiography showed equal Kappa values > 0.7 and an accuracy ≥ 85 % for the NASCET and CC methods, higher than for the ECST method. The binary accuracy of ICAS grading did not differ from DUS for all methods. CONCLUSION: The new 4D/3DC-US CC method is an accurate and well reproducible alternative to the NASCET and ECST methods and offers potential for clinical application.

Physical science research needed to evaluate the viability and risks of marine cloud brightening.

Marine cloud brightening (MCB) is the deliberate injection of aerosol particles into shallow marine clouds to increase their reflection of solar radiation and reduce the amount of energy absorbed by the climate system. From the physical science perspective, the consensus of a broad international group of scientists is that the viability of MCB will ultimately depend on whether observations and models can robustly assess the scale-up of local-to-global brightening in today's climate and identify strategies that will ensure an equitable geographical distribution of the benefits and risks associated with projected regional changes in temperature and precipitation. To address the physical science knowledge gaps required to assess the societal implications of MCB, we propose a substantial and targeted program of research-field and laboratory experiments, monitoring, and numerical modeling across a range of scales.

Cerebral blood flow autoregulation assessment by correlation analysis between mean arterial blood pressure and transcranial doppler sonography or near infrared spectroscopy is different: A pilot study.

PURPOSE: Recently, cerebral autoregulation indices based on moving correlation indices between mean arterial pressure (MAP) and cerebral oximetry (NIRS, ORx) or transcranial Doppler (TCD)-derived middle cerebral artery flow velocity (Mx) have been introduced to clinical practice. In a pilot study, we aimed to evaluate the validity of these indices using incremental lower body negative pressure (LBNP) until presyncope representing beginning cerebral hypoperfusion as well as lower body positive pressure (LBPP) with added mild hypoxia to induce cerebral hyperperfusion in healthy subjects. METHODS: Five male subjects received continuous hemodynamic, TCD and NIRS monitoring. Decreasing levels of LBNP were applied in 5-minute steps until subjects reached presyncope. Increasing levels of LBPP were applied stepwise up to 20 or 25 mmHg. Normobaric hypoxia was added until an oxygen saturation of 84% was reached. This was continued for 10 minutes. ORx and Mx indices were calculated using previously described methods. RESULTS: Both Indices showed an increase > 0.3 indicating impaired cerebral autoregulation during presyncope. However, there was no significant difference in Mx at presyncope compared to baseline (p = 0.168). Mean arterial pressure and cardiac output decreased only in presyncope, while stroke volume was decreased at the last pressure level. Neither Mx nor ORx showed significant changes during LBPP or hypoxia. Agreement between Mx and ORx was poor during the LBNP and LBPP experiments (R2 = 0.001, p = 0.3339). CONCLUSION: Mx and ORx represent impaired cerebral autoregulation, but in Mx this may not be distinguished sufficiently from baseline. LBPP and hypoxia are insufficient to reach the upper limit of cerebral autoregulation as indicated by Mx and ORx.

Electrocardiographic changes during sustained normobaric hypoxia in patients after myocardial infarction.

The safety of prolonged high-altitude stays and exercise for physically fit post-myocardial infarction (MI) patients is unclear. Myocardial tissue hypoxia and pulmonary hypertension can affect cardiac function and electrophysiology, possibly contributing to arrhythmias. We included four non-professional male athletes, clinically stable after left ventricular MI (three with ST-segment elevation MI and one with non-ST-segment elevation MI) treated with drug-eluting stents for single-vessel coronary artery disease. Oxygen levels were reduced to a minimum of 11.8%, then restored to 20.9%. We conducted electrocardiography (ECG), ergometry, and echocardiography assessments in normoxic and hypoxic conditions. With an average age of 57.8 ± 3.3 years and MI history 37 to 104 months prior, participants experienced a significant increase in QTc intervals during hypoxia using Bazett's (from 402 ± 13 to 417 ± 25 ms), Fridericia's (from 409 ± 12 to 419 ± 19 ms), and Holzmann's formulas (from 103 ± 4 to 107 ± 6%) compared to normoxia. This effect partially reversed during recovery. Echocardiographic signs of pulmonary hypertension during normobaric hypoxia correlated significantly with altered QTc intervals (p < 0.001). Despite good health and complete revascularization following MI, susceptibility to hypoxia-induced QTc prolongation and ventricular ectopic beats persists, especially during physical activity. MI survivors planning high-altitude activities should consult cardiovascular specialists with high-altitude medicine expertise.

Case Report: Muscle Wasting during Severe Sustained Hypoxia in Two Professional Mountaineers.

PURPOSE: Chronic exposure to hypoxia can induce muscle wasting in unaccustomed individuals. Detailed assessment of the effects of hypoxia on muscle tissue adaptation in elite mountaineers has not been performed. This study aims to assess muscle volume after exposure to normobaric hypoxia. METHODS: Two professional mountaineers (A and B) participated in a 35-d intervention of graded normobaric hypoxia with the aim of 14 d exposure to 8% oxygen corresponding to 7112-m altitude. Volume of the shank, thigh, and hip muscles was assessed by magnetic resonance imaging pre- and postintervention. Dietary intake and physical activity were monitored throughout the study from food images and accelerometry analysis, together with blood analysis and anthropometric measurements. RESULTS: Hypoxia reduced total leg muscle volume by 3.3% ± 6.0% in A and by 9.4% ± 7.3% in B. A lost 288 g and B 642 g of muscle mass, whereas dietary intake only declined by ~23% in the last intervention week. Arterial oxygen saturation declined from 95% and 86% to 77% and 72% in A and B, respectively. In hypoxia, participants could not maintain their physical activity levels. Notably, muscle loss varied substantially across muscle groups amounting to 5.4% ± 3.0%, 8.3% ± 5.2%, and 4.1% ± 8.6% for hip, thigh, and shank muscles, respectively. CONCLUSIONS: Our results indicate that hypoxia and resultant reductions in physical activity and caloric intake lead to substantial loss of muscle mass that was accentuated in proximal muscle as opposed to distal muscles. Surprisingly, thigh muscle wasting during this intervention is comparable with that observed during strict 56-d bed rest.

The Hypertension Paradox: Survival Benefit After ST-Elevation Myocardial Infarction in Patients With History of Hypertension. A Prospective Cohort- and Risk-Analysis.

Background: Mortality after ST-elevation myocardial infarction (STEMI) is dependent from best-medical treatment after initial event. Objectives: Determining the impact of prescription of guideline-recommended therapy after STEMI in two cohorts, patients with and without history of arterial hypertension, on survival. Methods: 1,025 patients of the Cologne Infarction Model registry with invasively adjudicated STEMI were dichotomized according to their history of arterial hypertension. We recorded prescription rates and dosing of RAS-inhibitors, ß-blockers and statins in all patients. The primary outcome was all-cause death. Mean follow-up was 2.5 years. Results: Mean age was 64 ± 13 years, 246 (25%) were women. 749 (76%) patients had a history of hypertension. All-cause mortality was 24.2%, 30-day and 1-year mortality was 11.3% and 16.6%, respectively. History of hypertension correlated with lower mortality (hazard ratio [HR], @30 days: 0.41 [0.27-0.62], @1 year: 0.37 [0.26-0.53]). After adjusting for age, sex, Killip-class, diabetes mellitus, body-mass index, kidney function and statin prescription at discharge 1-year mortality HR was 0.24 (0.12-0.48). At discharge, prescription rates for RAS-inhibitors, ß-blockers and statins, as well as individual dosing and long-term persistence of RAS-inhibitors were higher in patients with history of hypertension. On the same lines, prescription rates for RAS-inhibitors, ß-blockers and statins at discharge correlated significantly with lower mortality regardless of history of hypertension. Conclusion: Patients with history of hypertension show higher penetration of guideline recommended drug therapy after STEMI, which may contribute to better survival. Better tolerance of ß-blockers and RAS-inhibitors in patients with history of hypertension, not hypertension itself, likely explains these differences in prescription and dosing.

Utility of estimated pulse wave velocity for assessing vascular stiffness: comparison of methods.

Background: Pulse wave velocity (PWV) independently predicts cardiovascular risk. Easy to use single-cuff oscillometric methods are utilized in clinical practice to estimate PWV. We applied the approach in master athletes to assess possible beneficial effects of lifelong exercise on vascular health. Furthermore, we compared single-cuff measurements with a two-cuff method in another cohort. Methods: We obtained single-cuff upper arm oscillometric measurements thrice in 129 master athletes aged 35-86 years and estimated PWV using the ArcSolver algorithm. We applied the same method in 24 healthy persons aged 24-55 years participating in a head down tilt bedrest study. In the latter group, we also obtained direct PWV measurements using a thigh cuff. Results: Estimated pulse velocity very highly correlated with age (R2 = 0.90) in master athletes. Estimated PWV values were located on the same regression line like values obtained in participants of the head down tilt bed rest study. The modest correlation between estimated and measured PWV (R² 0.40; p<0.05) was attenuated after adjusting for age; the mean difference between PWV measurements was 1 m/s. Conclusions: Estimated PWV mainly reflects the entered age rather than true vascular properties and, therefore, failed detecting beneficial effects of lifelong exercise. Funding: The AGBRESA-Study was funded by the German Aerospace Center (DLR), the European Space Agency (ESA, contract number 4000113871/15/NL/PG), and the National Aeronautics and Space Administration (NASA, contract number 80JSC018P0078). FH received funding by the DLR and the German Federal Ministry of Economy and Technology, BMWi (50WB1816). SM, JT and JJ were supported by the Austrian Federal Ministry for Climate Action, Environment, Energy, Mobility, Innovation, and Technology, BMK (SPACE4ALL Project, FFG No. 866761).

Cardiovascular deconditioning and impact of artificial gravity during 60-day head-down bed rest-Insights from 4D flow cardiac MRI.

Microgravity has deleterious effects on the cardiovascular system. We evaluated some parameters of blood flow and vascular stiffness during 60 days of simulated microgravity in head-down tilt (HDT) bed rest. We also tested the hypothesis that daily exposure to 30 min of artificial gravity (1 g) would mitigate these adaptations. 24 healthy subjects (8 women) were evenly distributed in three groups: continuous artificial gravity, intermittent artificial gravity, or control. 4D flow cardiac MRI was acquired in horizontal position before (-9 days), during (5, 21, and 56 days), and after (+4 days) the HDT period. The false discovery rate was set at 0.05. The results are presented as median (first quartile; third quartile). No group or group × time differences were observed so the groups were combined. At the end of the HDT phase, we reported a decrease in the stroke volume allocated to the lower body (-30% [-35%; -22%]) and the upper body (-20% [-30%; +11%]), but in different proportions, reflected by an increased share of blood flow towards the upper body. The aortic pulse wave velocity increased (+16% [+9%; +25%]), and so did other markers of arterial stiffness ( C A V I ; C A V I 0 ). In males, the time-averaged wall shear stress decreased (-13% [-17%; -5%]) and the relative residence time increased (+14% [+5%; +21%]), while these changes were not observed among females. Most of these parameters tended to or returned to baseline after 4 days of recovery. The effects of the artificial gravity countermeasure were not visible. We recommend increasing the load factor, the time of exposure, or combining it with physical exercise. The changes in blood flow confirmed the different adaptations occurring in the upper and lower body, with a larger share of blood volume dedicated to the upper body during (simulated) microgravity. The aorta appeared stiffer during the HDT phase, however all the changes remained subclinical and probably the sole consequence of reversible functional changes caused by reduced blood flow. Interestingly, some wall shear stress markers were more stable in females than in males. No permanent cardiovascular adaptations following 60 days of HDT bed rest were observed.