Wave reflection, assessed by use of the ARCSolver Algorithm for pulse wave separation, is reduced under acute µg conditions in parabolic flight

Weightlessness during long-term space flight over 6-12 months leads to complex individual cardiovascular adaptation. The initial central blood volume expansion followed by a loss of plasma volume is accompanied by changes in vascular mechanoreceptor loads and responsive-ness, altered autonomic reflex control of heart rate and blood pressure, and hormonal changes in the long run. Hence, function and structure of the heart and blood vessels may change. Hemodynamic data obtained during short- and long-term space flight may indicate that the adaptation process resembles ageing of the cardiovascular system characterized by decreased diastolic blood pressure, increased central sympathetic nerve traffic and increased arterial pulse wave velocity. Experiments during parabolic flights in supine position suggest, that stroke volume does not change during transitions between µ-g and 1-g. We tested a novel method of pulse wave separation based on simple oscillometric brachial cuff waveform reading to investigate pulse wave reflection during acute weightlessness in healthy subjects. We hypothesized that the wave reflection magnitude (RM) remains unaltered during parabolic flights in supine position

Different associations between beta-blockers and other antihypertensive medication combinations with brachial blood pressure and aortic waveform parameters

BACKGROUND: Comparing the relationships of antihypertensive medications with brachial blood pressure (BP) and aortic waveform parameters may help clinicians to predict the effect on the latter in brachial BP-based antihypertensive therapy. We aimed to make such comparisons with new waveform measures and a wider range of antihypertensive regimens than examined previously. METHODS: Cross-sectional analysis of 2933 adults (61% male; aged 50–84 years): 1637 on antihypertensive treatment and 1296 untreated hypertensives. Sixteen medicine regimens of up to 4 combinations of drugs from 6 antihypertensive classes were analysed. Aortic systolic BP, augmentation index (AIx), excess pressure integral (EPI), backward pressure amplitude (Pb), reflection index (RI) and pulse wave velocity (PWV) were calculated from aortic pressure waveforms derived from suprasystolic brachial measurement. RESULTS: Forest plots of single-drug class comparisons across regimens with the same number of drugs (for between 1- and 3-drug regimens) revealed that AIx, Pb, RI and/or loge(EPI) were higher (maximum difference = 5.6%, 2.2 mm Hg, 0.0192 and 0.13 loge(mm Hg ⋅ s), respectively) with the use of a beta-blocker compared with vasodilators and diuretics, despite no brachial systolic and diastolic BP differences. These differences were reduced (by 34–57%) or eliminated after adjustment for heart rate, and similar effects occurred when controlling for systolic ejection period or diastolic duration. CONCLUSIONS: Beta-blocker effects on brachial BP may overestimate effects on aortic waveform parameters. Compared to other antihypertensives, beta-blockers have weaker associations with wave reflection measures and EPI; this is predominantly due to influences on heart rate

Effect of a reduction in glomerular filtration rate after nephrectomy on arterial stiffness and central hemodynamics: rationale and design of the EARNEST study

Background: There is strong evidence of an association between chronic kidney disease (CKD) and cardiovascular disease. To date, however, proof that a reduction in glomerular filtration rate (GFR) is a causative factor in cardiovascular disease is lacking. Kidney donors comprise a highly screened population without risk factors such as diabetes and inflammation, which invariably confound the association between CKD and cardiovascular disease. There is strong evidence that increased arterial stiffness and left ventricular hypertrophy and fibrosis, rather than atherosclerotic disease, mediate the adverse cardiovascular effects of CKD. The expanding practice of live kidney donation provides a unique opportunity to study the cardiovascular effects of an isolated reduction in GFR in a prospective fashion. At the same time, the proposed study will address ongoing safety concerns that persist because most longitudinal outcome studies have been undertaken at single centers and compared donor cohorts with an inappropriately selected control group.<p></p> Hypotheses: The reduction in GFR accompanying uninephrectomy causes (1) a pressure-independent increase in aortic stiffness (aortic pulse wave velocity) and (2) an increase in peripheral and central blood pressure.<p></p> Methods: This is a prospective, multicenter, longitudinal, parallel group study of 440 living kidney donors and 440 healthy controls. All controls will be eligible for living kidney donation using current UK transplant criteria. Investigations will be performed at baseline and repeated at 12 months in the first instance. These include measurement of arterial stiffness using applanation tonometry to determine pulse wave velocity and pulse wave analysis, office blood pressure, 24-hour ambulatory blood pressure monitoring, and a series of biomarkers for cardiovascular and bone mineral disease.<p></p> Conclusions: These data will prove valuable by characterizing the direction of causality between cardiovascular and renal disease. This should help inform whether targeting reduced GFR alongside more traditional cardiovascular risk factors is warranted. In addition, this study will contribute important safety data on living kidney donors by providing a longitudinal assessment of well-validated surrogate markers of cardiovascular disease, namely, blood pressure and arterial stiffness. If any adverse effects are detected, these may be potentially reversed with the early introduction of targeted therapy. This should ensure that kidney donors do not come to long-term harm and thereby preserve the ongoing expansion of the living donor transplant program.<p></p&gt

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

AORTIC VESSEL WALL PROPERTIES DURING 60 DAYS STRICT HEAD DOWN TILT BEDREST - PRELIMINARY RESULTS OF AGBRESA

Background Changes in large artery properties including increased arterial compliance and increased carotid artery stiffness have been described after space flight. Altered vascular structure, which heralds cardiovascular risk, and reversible changes in vascular function could contribute to the response. Compared with previous studies, which did not reproduce these findings, AGBRESA applied strict -6° head-down bedrest (HDT) mimicking chronic cephalad fluid shifts in space. In this study, we assessed aortic vessel wall properties using state-of-the art imaging methods and pulse wave analysis and tested for possible protective effects of artificial gravity training. Material and Methods We present preliminary data from 12 healthy subjects (8 men, 4 women) obtained during baseline data collection 9-6 days before bedrest (BDC, supine position) and towards the end of two months head down tilt bedrest (MRI on day 56 and echocardiography on day 60 of HDT). Subjects were assigned to 30 minutes per day continuous short arm centrifugation (cAG), 6 times for 5 minutes interval short arm centrifugation, iAG), or a control group (ctr). We assessed aortic pulse wave velocity using oscillometric upper arm and thigh cuffs (PWV-2C, CardioCube, AIT, Vienna, Austria) and 4D-flow cardiac velocity encoded phase contrast magnetic resonance imaging (PWV-4D-MRI). We also measured area, area changes, and distensibility (AoD) of the ascending aorta by 2D-phase contrast cardiac MRI and arterial compliance (Ca) using transthoracic echocardiography. Results Mean aortic area increased in all subjects after 60 days head down tilt bedrest (5.3±0.7 vs. 5.8±0.7 cm², p<0.05). Stroke volume decreased from 94±13 to 84±10 ml (p<0.05) and pulse pressure from 56±11 to 46±9 mmHg (p<0.05) in part through reductions in stroke volume. The figure illustrates individual data on aortic properties (red diamonds = women). In contrast to the more consistent changes in aortic area, stroke volume, and pulse pressure, aortic distensibility, compliance, and pulse wave velocity responses show substantial inter-individual variability. Conclusion The important finding of our study is that 60 days strict head down bedrest elicit consistent changes in ascending aortic area, pulse pressure, and stroke volume. The resulting changes in vascular loading conditions likely confound vascular function measurements, both, in head down bedrest studies and in space

Hepatic gene expression involved in glucose and lipid metabolism in transition cows: effects of fat mobilization during early lactation in relation to milk performance and metabolic changes.

Insufficient feed intake during early lactation results in elevated body fat mobilization to meet energy demands for milk production. Hepatic energy metabolism is involved by increasing endogenous glucose production and hepatic glucose output for milk synthesis and by adaptation of postcalving fuel oxidation. Given that cows differ in their degree of fat mobilization around parturition, indicated by variable total liver fat concentration (LFC), the study investigated the influence of peripartum fat mobilization on hepatic gene expression involved in gluconeogenesis, fatty acid oxidation, ketogenesis, and cholesterol synthesis, as well as transcriptional factors referring to energy metabolism. German Holstein cows were grouped according to mean total LFC on d 1, 14, and 28 after parturition as low [300 mg of total fat/g of DM; n=7), indicating fat mobilization during early lactation. Cows were fed total mixed rations ad libitum and held under equal conditions. Liver biopsies were taken at d 56 and 15 before and d 1, 14, 28, and 49 after parturition to measure mRNA abundances of pyruvate carboxylase (PC); phosphoenolpyruvate carboxykinase; glucose-6-phosphatase; propionyl-coenzyme A (CoA) carboxylase α; carnitine palmitoyl-transferase 1A (CPT1A); acyl-CoA synthetase, long chain 1 (ASCL1); acyl-CoA dehydrogenase, very long chain; 3-hydroxy-3-methylglutaryl-CoA synthase 1 and 2; sterol regulatory element-binding factor 1; and peroxisome proliferator-activated factor α. Total LFC postpartum differed greatly among cows, and the mRNA abundance of most enzymes and transcription factors changed with time during the experimental period. Abundance of PC mRNA increased at parturition to a greater extent in high- and medium-LFC groups than in the low-LFC group. Significant LFC × time interactions for ACSL1 and CPT1A during the experimental period indicated variable gene expression depending on LFC after parturition. Correlations between hepatic gene expression and performance data and plasma concentrations of metabolites and hormones showed time-specific relations during the transition period. Elevated body fat mobilization during early lactation affected gene expression involved in gluconeogenesis to a greater extent than gene expression involved in lipid metabolism, indicating the dependence of hepatic glucose metabolism on hepatic lipid status and fat mobilization during early lactation

HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease

Background&Aims: Hepatocellular carcinoma (HCC) is a main cause of morbidity and mortality in patients with advanced chronic liver disease (ACLD) due to chronic hepatitis C and who have achieved sustained virologic response (SVR). We elaborated risk stratification algorithms for de-novo-HCC-development after SVR and validated them in an independent cohort. Methods: Derivation cohort: 527 patients with pre-treatment ACLD and SVR to interferon-free therapy were evaluated for de-novo-HCC-development. Among others, alpha-fetoprotein (AFP) and non-invasive surrogates of portal hypertension including liver stiffness measurement (LSM) were assessed pre-/post-treatment. Validation cohort: 1500 patients with compensated ACLD (cACLD) from other European centers. Results: During a median follow-up (FU) of 41 months, 22/475 cACLD (4.6%) (1.45/100patient-years)vs.12/52 decompensated patients (23.1%, 7.00/100patient-years, p<0.001) developed de-novo-HCC. Since decompensated patients were at substantial HCC-risk, we focused on cACLD for all further analyses. In cACLD, post-treatment-values showed a higher discriminative ability for patients with/without de-novo-HCC-development during FU than pre-treatment-values or absolute/relative changes. Models based on post-treatment AFP≥4.6ngxmL-1-3points, alcohol consumption (males:>30g/d/females:>20g/d)-2points (optional), age≥59year-2points, LSM≥19.0kPa-1point, and albumin<42gxL-1-1point, accurately predicted de-novo-HCC-development (bootstrapped Harrel’s C with and without considering alcohol:0.893 and 0.836). Importantly, these parameters also provided independent prognostic information in competing risk analysis and accurately stratified patients into low-(0-3points; ≈2/3 of patients) and high-risk (≥4points; ≈1/3) groups in the derivation (algorithm with alcohol consumption; 4-year HCC-risk:0%vs.16.5%) and validation (3.3%/17.5%) cohorts. An alternative approach based on age/alcohol (optional)/FU-LSM/FU-albumin (i.e., without FU-AFP) also showed a robust performance. Conclusions: Simple algorithms based on post-treatment age/albumin/LSM, and optionally, AFP and alcohol, accurately stratified de-novo-HCC-risk in cACLD patients with SVR. Approximately 2/3 were identified as having an HCC-risk <1%/y in both the derivation and validation cohort, thereby clearly falling below the cost-effectiveness threshold for HCC-surveillance. LAY SUMMARY: Simple algorithms based on age, alcohol consumption, results of blood tests (albumin and α-fetoprotein), as well as liver stiffness measurement after the end of hepatitis C treatment identify a large proportion (approximately 2/3) of patients with advanced but still asymptomatic liver disease who are at very low risk (<1%/year) of liver cancer development, and thus, might not need to undergo 6-monthly liver ultrasound