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Aims Reduced physical activity increases the risk of heart failure; however, non‐invasive methodologies detecting subclinical changes in myocardial function are not available. We hypothesized that myocardial, left ventricular, systolic strain measurements could capture subtle abnormalities in myocardial function secondary to physical inactivity. Methods and results In the AGBRESA study, which assessed artificial gravity through centrifugation as potential countermeasure for space travel, 24 healthy persons (eight women) were submitted to 60 day strict −6° head‐down‐tilt bed rest. Participants were assigned to three groups of eight subjects: a control group, continuous artificial gravity training on a short‐arm centrifuge (30 min/day), or intermittent centrifugation (6 × 5 min/day). We assessed cardiac morphology, function, strain, and haemodynamics by cardiac magnetic resonance imaging (MRI) and echocardiography. We observed no differences between groups and, therefore, conducted a pooled analysis. Consistent with deconditioning, resting heart rate (∆8.3 ± 6.3 b.p.m., P

There is controversy whether a lifetime of heavy resistance training, providing pressure-overload, is harmful for left ventricular function. We compared left ventricular dimensions and function in elite Masters athletes involved in throwing events (requiring strength; n = 21, seven females, 60 ± 14 years) to those involved in endurance events (n = 65, 25 females, 59 ± 10 years) and sprinting (n = 68, 21 females, 57 ± 13 years) at the 2018 World Masters Athletic Championships. Left ventricular dimensions and function were assessed with B-mode ultrasound and Doppler. The ratio of left ventricular early diastolic peak filling velocity to peak velocity during atrial contraction (E/A) across the mitral valve and the ratio of E to velocity of the E-wave (E’) across the lateral and septal mitral annulus (E/E’) were used as indexes of left ventricular diastolic function. Intra-ventricular septal wall thickness was greater in throwers compared to sprinters (11.9 ± 2.2 vs. 10.3 ± 2.3 mm; p = 0.01). Left ventricular end diastolic diameter/body surface area was higher in endurance athletes and sprinters vs. throwers (25.2 ± 3.0, 24.3 ± 3.1, and 22.0 ± 3.1 mm/m2, respectively, p < 0.01). The E/A was higher in endurance athletes and sprinters vs. throwers (1.35 ± 0.40, 1.37 ± 0.43, and 1.05 ± 0.41, respectively; p < 0.01). The E/E’ was lower in endurance athletes and sprinters vs. throwers (6.9 ± 1.8, 6.6 ± 1.9, and 8.1 ± 1.9, respectively, p < 0.05). Compared to age-matched historical controls (n > 1,000; E/A = 1.06; E/E’ = 7.5), left ventricular diastolic function was not different in throwers, but superior in endurance athletes and sprinters (p < 0.01). Masters throwers have altered left ventricular dimensions and function vs. other athletes, but a lifetime of heavy resistance training does not appear to alter left ventricular function compared to age-matched controls.

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 p p = 0.182). Of the nine subjects, six had significantly lower BRS in hypoxia (p p p 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.

Supplemental Digital Content is available in the text., Sacubitril/valsartan (LCZ696), a novel angiotensin receptor-neprilysin inhibitor, was recently approved for the treatment of heart failure with reduced ejection fraction. Neprilysin degrades several peptides that modulate lipid metabolism, including natriuretic peptides. In this study, we investigated the effects of 8 weeks’ treatment with sacubitril/valsartan on whole-body and adipose tissue lipolysis and lipid oxidation during defined physical exercise compared with the metabolically neutral comparator amlodipine. This was a multicenter, randomized, double-blind, active-controlled, parallel-group study enrolling subjects with abdominal obesity and moderate hypertension (mean sitting systolic blood pressure ≥130–180 mm Hg). Lipolysis during rest and exercise was assessed by microdialysis and [1,1,2,3,3-2H]-glycerol tracer kinetics. Energy expenditure and substrate oxidation were measured simultaneously using indirect calorimetry. Plasma nonesterified fatty acids, glycerol, insulin, glucose, adrenaline and noradrenaline concentrations, blood pressure, and heart rate were also determined. Exercise elevated plasma glycerol, free fatty acids, and interstitial glycerol concentrations and increased the rate of glycerol appearance. However, exercise-induced stimulation of lipolysis was not augmented on sacubitril/valsartan treatment compared with amlodipine treatment. Furthermore, sacubitril/valsartan did not alter energy expenditure and substrate oxidation during exercise compared with amlodipine treatment. In conclusion, sacubitril/valsartan treatment for 8 weeks did not elicit clinically relevant changes in exercise-induced lipolysis or substrate oxidation in obese patients with hypertension, implying that its beneficial cardiovascular effects cannot be explained by changes in lipid metabolism during exercise. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT01631864.

Purpose 23Na MRI demonstrated increased tissue sodium concentrations in a number of pathologies. Acute atrophy results in muscle fibre volume shrinking that may result in a relative increase of extracellular volume and might affect sodium concentration. Thus, we hypothesized that local unloading of the calf muscles would lead to a decrease in muscle volume and an increase in muscle tissue sodium concentration. Method One lower leg of 12 healthy male subjects was submitted to a 60 day long period of unloading using the Hephaistos orthosis, while the other leg served as control. 23Na MRI and 2D PD-weighted Dixon turbo spin echo were obtained from the control and orthosis leg using a 3T scanner. For quantification, a sodium reference phantom was used with 10, 20, 30, and 40 mmol/L NaCl solution. Result Tissue sodium concentration (TSC) increased as an effect of unloading in the orthosis leg. Relative increases were 17.4 ± 16.8% (P = 0.005) in gastrocnemius medialis muscle, 11.1 ± 12.5 (P = 0.037) in gastrocnemius lateralis muscle, 16.2 ± 4.7% (P < 0.001) in soleus muscle, 10.0 ± 10.5% (P = 0.009) in the ventral muscle group, and 10.7 ± 10.0% (P = 0.003) in the central muscle group, respectively. TSC in the control leg did not significantly change. In the orthosis leg, muscle volume decreased as follows: medial gastrocnemius muscle: −5.4 ± 8.3% (P = 0.043) and soleus muscle: −7.8 ± 15.0% (P = 0.043). Conclusion Unloading atrophy is associated with an increase in muscle sodium concentration. 23Na MRI is capable of detecting these rather small changes.

We hypothesized that sympathetic baroreflex mediated uncoupling between neural sympathetic discharge pattern and arterial pressure (AP) fluctuations at 0.1 Hz during baroreceptor unloading might promote orthostatic pre-syncope. Ten volunteers (32 &plusmn, 6 years) underwent electrocardiogram, beat-to-beat AP, respiratory activity and muscle sympathetic nerve activity (MSNA) recordings while supine (REST) and during 80&deg, head-up tilt (HUT) followed by &minus, 10 mmHg stepwise increase of lower body negative pressure until pre-syncope. Cardiac and sympathetic baroreflex sensitivity were quantified. Spectrum analysis of systolic and diastolic AP (SAP and DAP) and calibrated MSNA (cMSNA) variability assessed the low frequency fluctuations (LF, ~0.1 Hz) of SAP, DAP and cMSNA variability. The squared coherence function (K2) quantified the coupling between cMSNA and DAP in the LF band. Analyses were performed while supine, during asymptomatic HUT (T1) and at pre-syncope onset (T2). During T2 we found that: (1) sympathetic baroreceptor modulation was virtually abolished compared to T1, (2) a progressive decrease in AP was accompanied by a persistent but chaotic sympathetic firing, (3) coupling between cMSNA and AP series at 0.1 Hz was reduced compared to T1. A negligible sympathetic baroreceptor modulation during pre-syncope might disrupt sympathetic discharge pattern impairing the capability of vessels to constrict and promote pre-syncope.

Orthostatic intolerance commonly occurs after prolonged bed rest, thus increasing the risk of syncope and falls. Baroreflex-mediated adjustments of heart rate and sympathetic vasomotor activity (muscle sympathetic nerve activity – MSNA) are crucial for orthostatic tolerance. We hypothesized that prolonged bed rest deconditioning alters overall baroreceptor functioning, thereby reducing orthostatic tolerance in healthy volunteers. As part of the European Space Agency Medium-term Bed Rest protocol, 10 volunteers were studied before and after 21 days of −6° head down bed rest (HDBR). In both conditions, subjects underwent ECG, beat-by-beat blood pressure, respiratory activity, and MSNA recordings while supine (REST) and during a 15-min 80° head-up tilt (TILT) followed by a 3-min −10 mmHg stepwise increase of lower body negative pressure to pre-syncope. Cardiac baroreflex sensitivity (cBRS) was obtained in the time (sequence method) and frequency domain (spectrum and cross-spectrum analyses of RR interval and systolic arterial pressure – SAP, variability). Baroreceptor modulation of sympathetic discharge activity to the vessels (sBRS) was estimated by the slope of the regression line between the percentage of MSNA burst occurrence and diastolic arterial pressure. Orthostatic tolerance significantly decreased after HDBR (12 ± 0.6 min) compared to before (21 ± 0.6 min). While supine, heart rate, SAP, and cBRS were unchanged before and after HDBR, sBRS gain was slightly depressed after than before HDBR (sBRS: −6.0 ± 1.1 versus −2.9 ± 1.5 burst% × mmHg−1, respectively). During TILT, HR was higher after than before HDBR (116 ± 4 b/min versus 100 ± 4 b/min, respectively), SAP was unmodified in both conditions, and cBRS indexes were lower after HDBR (α index: 3.4 ± 0.7 ms/mmHg; BRSSEQ 4.0 ± 1.0) than before (α index: 6.4 ± 1.0 ms/mmHg; BRSSEQ 6.8 ± 1.2). sBRS gain was significantly more depressed after HDBR than before (sBRS: −2.3 ± 0.7 versus −4.4 ± 0.4 burst% × mmHg−1, respectively). Our findings suggest that baroreflex-mediated adjustments in heart rate and MSNA are impaired after prolonged bed rest. The mechanism likely contributes to the decrease in orthostatic tolerance.

BACKGROUND: Essential arterial hypertension is one of the main treatable cardiovascular risk factors. In Germany, approximately 13% of women and 18% of men have uncontrolled high blood pressure (≥ 140/90 mmHg). METHODS: This review is based on pertinent publications retrieved by a selective literature search in PubMed. RESULTS: Arterial hypertension is diagnosed when repeated measurements in a doctor's office yield values of 140/90 mmHg or higher. The diagnosis should be confirmed by 24-hour ambulatory blood pressure monitoring or by home measurement. Further risk factors and end-organ damage should be considered as well. According to the current European guidelines, the target blood pressure for all patients, including those with diabetes mellitus or renal failure, is

Natriuretic peptides are commonly considered cardiovascular and renal hormones. Indeed, genetic natriuretic peptide deletion promotes arterial hypertension and associated organ damage.1 Conversely, pharmacological natriuretic peptide augmentation lowers blood pressure. Less recognized is the fact that natriuretic peptides potently affect lipid and glucose metabolism. Through these metabolic actions, natriuretic peptides may provide a pathophysiological link between cardiovascular and metabolic disease. Indeed, arterial hypertension and insulin resistance or overt type 2 diabetes mellitus commonly occur in the same patients. Similarly, heart failure is associated with impaired skeletal, muscular oxidative function and insulin resistance.2,3 The review focusses on recent epidemiological, genetic, physiological, and pharmacological evidence linking the natriuretic peptide system with metabolic disease. Moreover, we discuss clinical trials evidence suggesting that natriuretic peptide modulation could be pursued further in metabolic disease prevention and treatment. ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) are released from cardiac atria and ventricles, respectively. Both peptides are produced as preprohormones and are stored as prohormones in intracellular granules. The native peptides are released in equimolar amounts with N-terminal peptide fragments, which are more stable than the native hormones and can serve as natriuretic peptide release markers. Stretch of atrial or ventricular cardiomyocytes which can be secondary to increased sodium intake, physical exercise, or diseases associated with volume overload triggers natriuretic peptide release. Both natriuretic peptide and their N-terminal peptide fragments are clinically established heart failure biomarkers. Once released, natriuretic peptides raise renal sodium excretion, elicit vasodilation, and are the physiological antagonists of the renin-angiotensin system.4 Natriuretic peptides also attenuate sympathetic nervous system activity at least in part through interaction with central vasopressin pathways.5 ANP and BNP responses are primarily mediated by the GCA (guanylyl cyclase-coupled natriuretic peptide receptor; also known as NPR-A [natriuretic peptide receptor A]). NPR-C, which is sometimes …

Increased activation of the renin-angiotensin system is involved in the onset and progression of cardiometabolic diseases, while natriuretic peptides (NP) may exert protective effects. We have recently demonstrated that sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, which blocks the angiotensin II type-1 receptor and augments natriuretic peptide levels, improved peripheral insulin sensitivity in obese hypertensive patients. Here, we investigated the effects of sacubitril/valsartan (400 mg QD) treatment for 8 weeks on the abdominal subcutaneous adipose tissue (AT) phenotype compared to the metabolically neutral comparator amlodipine (10 mg QD) in 70 obese hypertensive patients. Abdominal subcutaneous AT biopsies were collected before and after intervention to determine the AT transcriptome and expression of proteins involved in lipolysis, NP signaling and mitochondrial oxidative metabolism. Both sacubitril/valsartan and amlodipine treatment did not significantly induce AT transcriptional changes in pathways related to lipolysis, NP signaling and oxidative metabolism. Furthermore, protein expression of adipose triglyceride lipase (ATGL) (Ptime*group = 0.195), hormone-sensitive lipase (HSL) (Ptime*group = 0.458), HSL-ser660 phosphorylation (Ptime*group = 0.340), NP receptor-A (NPRA) (Ptime*group = 0.829) and OXPHOS complexes (Ptime*group = 0.964) remained unchanged. In conclusion, sacubitril/valsartan treatment for 8 weeks did not alter the abdominal subcutaneous AT transcriptome and expression of proteins involved in lipolysis, NP signaling and oxidative metabolism in obese hypertensive patients.

Background/Introduction: Endovascular baroreflex amplification (EBA) is a novel device­based therapy that has been shown to lower blood pressure (BP) in patients with resistant hypertension (RHTN) in an uncontrolled first­in­human study. It is postulated that EBA lowers BP, at least in part, by inhibiting sympathetic nerve activity (SNA). However, this has never been studied. Purpose: The aim of this study was to determine the effect of EBA on SNA and sympathetic cardiovascular reactivity. Methods: In a single­center sub­study of the CALM­DIEM study (Controlling And Lowering blood pressure with the MobiusHD – Defining Efficacy Markers), the endovascular MobiusHD device was unilaterally implanted into the carotid sinus of patients with RHTN (24­hour mean ambulatory systolic BP >130 mmHg on ≥3 antihypertensive medications, including a diuretic) without atherosclerotic carotid disease. Microneurography at the right peroneal nerve and non­invasive continuous BP measurements were performed at baseline and 3 months, after a 2­week washout of antihypertensive medications affecting sympathetic regulation. Changes in resting muscle SNA and cardiovascular responses to cold pressor testing (CPT) were determined. Results: 10 patients, mean age 52 (±8 years), 6 males, have been included in the study thus far. Of these, 8 patients had a paired measurement at baseline and 3 months. One patient has not yet reached the third month endpoint and one patient was unable to visit our clinic for measurements at 3 months. Two of the 8 paired measurements were excluded from analysis because of poor quality of muscle SNA recording and one was excluded because of frequent premature ventricular complexes. 24­hour mean ambulatory BP (n=8) decreased from 156/98 (±22/17) mmHg to 145/88 (±19/17) mmHg (p=0.028 for systolic and p=0.048 diastolic BP). Analysis of the first 5 patients to complete the study with paired data, suggests a decrease in resting muscle SNA from 38.6 (range 15.7–70.6) to 30.3 (range 5.0–65.9) bursts/min, and from 48.3 (range 21.2–81.2) to 37.9 (range 7.3–75.2) bursts/100 heartbeats, 3 months after EBA. In contrast, cardiovascular reactivity appears unaffected because MAP and HR responses to CPT did not change. Conclusion: In patients with RHTN we observed a decrease in BP and muscle SNA 3 months after EBA. The finding is consistent with attenuated central sympathetic drive and may suggest that EBA, indeed, improves sympathetic baroreflex restraint. Furthermore, the MAP and HR responses to CPT did not change, indicating that BP reactivity remains intact after EBA.