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Background: Clinical studies demonstrated beneficial effects of sodium-glucose-transporter 2 inhibitors on the risk of cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes for cardioprotection remain unclear. The present study focused on the impact of empagliflozin (Empa) on myocardial function in a rat model with established HFpEF and analyzed underlying molecular mechanisms., Methods: Obese ZSF1 (Zucker fatty and spontaneously hypertensive) rats were randomized to standard care (HFpEF, n=18) or Empa (HFpEF/Empa, n=18). ZSF1 lean rats (con, n=18) served as healthy controls. Echocardiography was performed at baseline and after 4 and 8 weeks, respectively. After 8 weeks of treatment, hemodynamics were measured invasively, mitochondrial function was assessed and myocardial tissue was collected for either molecular and histological analyses or transmission electron microscopy., Results: In HFpEF Empa significantly improved diastolic function (E/é: con: 17.5±2.8; HFpEF: 24.4±4.6; P <0.001 versus con; HFpEF/Empa: 19.4±3.2; P <0.001 versus HFpEF). This was accompanied by improved hemodynamics and calcium handling and by reduced inflammation, hypertrophy, and fibrosis. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation. Cardiac mitochondrial respiration was significantly impaired in HFpEF but restored by Empa (V max complex IV: con: 0.18±0.07 mmol O 2 /s/mg; HFpEF: 0.13±0.05 mmol O 2 /s/mg; P <0.041 versus con; HFpEF/Empa: 0.21±0.05 mmol O 2 /s/mg; P =0.012 versus HFpEF) without alterations of mitochondrial content. The expression of cardiolipin, an essential stability/functionality-mediating phospholipid of the respiratory chain, was significantly decreased in HFpEF but reverted by Empa (con: 15.9±1.7 nmol/mg protein; HFpEF: 12.5±1.8 nmol/mg protein; P =0.002 versus con; HFpEF/Empa: 14.5±1.8 nmol/mg protein; P =0.03 versus HFpEF). Transmission electron microscopy revealed a reduced size of mitochondria in HFpEF, which was restored by Empa., Conclusions: The study demonstrates beneficial effects of Empa on diastolic function, hemodynamics, inflammation, and cardiac remodeling in a rat model of HFpEF. These effects were mediated by improved mitochondrial respiratory capacity due to modulated cardiolipin and improved calcium handling., Competing Interests: Disclosures Dr Winzer reports personal fees from Amarin, Amgen, AstraZeneca, Daiichi Sankyo, Bayer, Boehringer Ingelheim, CVRx, and Novartis for lectures and advisory board activities outside the submitted work. Dr Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, AstraZeneca, Novartis, Pfizer, Abiomed, Bayer, Boehringer, and other from Picardia, Transverse Medical, Claret Medical, outside the submitted work. The other authors report no conflicts.

Background: Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of all CS cases. Nevertheless, there is a lack of evidence on sex-related differences in HF-CS, especially regarding use of treatment and mortality risk in women vs. men. This study aimed to investigate potential differences in clinical presentation, use of treatments, and mortality between women and men with HF-CS., Methods: In this international observational study, patients with HF-CS (without acute myocardial infarction) from 16 tertiary-care centers in five countries were enrolled between 2010 and 2021. Logistic and Cox regression models were used to assess differences in clinical presentation, use of treatments, and 30-day mortality in women vs. men with HF-CS., Results: N = 1030 patients with HF-CS were analyzed, of whom 290 (28.2%) were women. Compared to men, women were more likely to be older, less likely to have a known history of heart failure or cardiovascular risk factors, and lower rates of highly depressed left ventricular ejection fraction and renal dysfunction. Nevertheless, CS severity as well as use of treatments were comparable, and female sex was not independently associated with 30-day mortality (53.0% vs. 50.8%; adjusted HR 0.94, 95% CI 0.75-1.19)., Conclusions: In this large HF-CS registry, sex disparities in risk factors and clinical presentation were observed. Despite these differences, the use of treatments was comparable, and both sexes exhibited similarly high mortality rates. Further research is necessary to evaluate if sex-tailored treatment, accounting for the differences in cardiovascular risk factors and clinical presentation, might improve outcomes in HF-CS., (© 2024. The Author(s).)

Aims: Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of CS cases. Whether patients with de novo HF and those with acute-on-chronic HF in CS differ in clinical characteristics and outcome remains unclear. The aim of this study was to evaluate differences in clinical presentation and mortality between patients with de novo and acute-on-chronic HF-CS., Methods and Results: In this international observational study, patients with HF-CS from 16 tertiary care centres in five countries were enrolled between 2010 and 2021. To investigate differences in clinical presentation and 30-day mortality, adjusted logistic/Cox regression models were fitted. Patients (n = 1030) with HF-CS were analysed, of whom 486 (47.2%) presented with de novo HF-CS and 544 (52.8%) with acute-on-chronic HF-CS. Traditional markers of CS severity (e.g. blood pressure, heart rate and lactate) as well as use of treatments were comparable between groups. However, patients with acute-on-chronic HF-CS were more likely to have a higher CS severity and also a higher mortality risk, after adjusting for relevant confounders (de novo HF 45.5%, acute-on-chronic HF 55.9%, adjusted hazard ratio 1.38, 95% confidence interval 1.10-1.72, p = 0.005)., Conclusion: In this large HF-CS cohort, acute-on-chronic HF-CS was associated with more severe CS and higher mortality risk compared to de novo HF-CS, although traditional markers of CS severity and use of treatments were comparable. These findings highlight the vast heterogeneity of patients with HF-CS, emphasize that HF chronicity is a relevant disease modifier in CS, and indicate that future clinical trials should account for this., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Heart failure with reduced ejection fraction (HFrEF) is associated with excessive sympathetic and impaired parasympathetic activity. The Barostim Neo™ device is used for electronical baroreflex activation therapy (BAT) to counteract autonomic nervous system dysbalance. Randomized trials have shown that BAT improves walking distance and reduces N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels at least in patients with only moderate elevation at baseline. Its impact on the risk of heart failure hospitalization (HFH) and death is not yet established, and experience in clinical routine is limited., Methods and Results: We report on patient characteristics and clinical outcome in a retrospective, non-randomized single-centre registry of BAT in HFrEF. Patients in the New York Heart Association (NYHA) Classes III and IV with a left ventricular ejection fraction (LVEF) <35% despite guideline-directed medical therapy were eligible. Symptom burden, echocardiography, and laboratory testing were assessed at baseline and after 12 months. Clinical events of HFH and death were recorded at routine clinical follow-up. Data are shown as number (%) or median (inter-quartile range). Between 2014 and 2020, 30 patients were treated with BAT. Median age was 67 (63-77) years, and 27 patients (90%) were male. Most patients (83%) had previous HFH. Device implantation was successful in all patients. At 12 months, six patients had died and three were alive but did not attend follow-up. NYHA class was III/IV in 26 (87%)/4 (13%) patients at baseline, improved in 19 patients, and remained unchanged in 5 patients (P < 0.001). LVEF improved from 25.5 (20.0-30.5) % at baseline to 30.0 (25.0-36.0) % at 12 months (P = 0.014). Left ventricular end-diastolic diameter remained unchanged. A numerical decrease in NT-proBNP [3165 (880-8085) vs. 1001 (599-3820) pg/mL] was not significant (P = 0.526). Median follow-up for clinical events was 16 (10-33) months. Mortality at 1 (n = 6, 20%) and 3 years (n = 10, 33%) was as expected by the Meta-Analysis Global Group in Chronic Heart Failure risk score. Despite BAT, event rate was high in patients with NYHA Class IV, NT-proBNP levels >1600 pg/mL, or estimated glomerular filtration rate (eGFR) <30 mL/min at baseline. NYHA class and eGFR were independent predictors of mortality., Conclusions: Patients with HFrEF who are selected for BAT are in a stage of worsening or even advanced heart failure. BAT appears to be safe and improves clinical symptoms and-to a modest degree-left ventricular function. The risk of death remains high in advanced disease stages. Patient selection seems to be crucial, and the impact of BAT in earlier disease stages needs to be established., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: PARADISE-MI examined the efficacy of sacubitril/valsartan in acute myocardial infarction (AMI) complicated by reduced left ventricular ejection fraction (LVEF), pulmonary congestion, or both. We sought to assess the trajectory of pulmonary congestion using lung ultrasound (LUS) and its association with cardiac structure and function in a pre-specified substudy., Methods and Results: Patients without prior heart failure (HF) underwent eight-zone LUS and echocardiography at baseline (±2 days of randomization) and after 8 months. B-lines were quantified offline, blinded to treatment, clinical findings, time point, and outcomes. Among 152 patients (median age 65, 32% women, mean LVEF 41%), B-lines were detectable in 87% at baseline [median B-line count: 4 (interquartile range 2-8)]. Among 115 patients with LUS data at baseline and follow-up, B-lines decreased significantly from baseline (mean ± standard deviation: -1.6 ± 7.3; P = 0.018). The proportion of patients without pulmonary congestion at follow-up was significantly higher in those with fewer B-lines at baseline. Adjusted for baseline, B-lines at follow-up were on average 6 (95% confidence interval: 3-9) higher in patients who experienced an intercurrent HF event vs. those who did not (P = 0.001). A greater number of B-lines at baseline was associated with larger left atrial size, higher E/e' and E/A ratios, greater degree of mitral regurgitation, worse right ventricular systolic function, and higher tricuspid regurgitation velocity (P-trend <0.05 for all)., Conclusion: In this AMI cohort, B-lines, indicating pulmonary congestion, were common at baseline and, on average, decreased significantly from baseline to follow-up. Worse pulmonary congestion was associated with prognostically important echocardiographic markers., Competing Interests: Conflict of interest: E.P.’s employer has received support from Novartis for consulting work, and she has consulted for scPharmaceuticals outside of the submitted work. She has received research support from NHLBI and NIDDK. B.C. reports consultancy fees from Novartis, Amgen, Boehringer Ingelheim, Cardurion, Corvia, and Myokardia. A.K. reports personal fees from Argus Cognitive, Inc., outside the submitted work and research grant from GE Healthcare, outside the submitted work. M.C. reports Institutional Research Grants from Abbott, Novartis, Pfizer; Institutional Trial Funding from Novartis, Corvia; travel grants, speaker and advisory board honoraria from Abbott, Abiomed, Amicus, AstraZeneca, Bayer, Boehringer Ingelheim, GE Healthcare, Krka Pharma, LivaNova, Medtronic, Novartis, Orion Corporation, Pfizer, Sanofi, Swixx, Teva Pharmaceutical Industries. E.B.W. reported receiving personal fees from Amarin (lectures), Bayer (lectures and advisory board activities), Boehringer Ingelheim (lectures and advisory board activities), Daiichi-Sankyo (lectures), CVRX (lectures), and Novartis (lectures and advisory board activities) outside the submitted work. M.P.L. and J.G. are employees of Novartis. L.K. reports speaker’s honorarium from Nova, Novartis, AstraZeneca, Bayer and Boehringer. J.J.V.M.’s employer, Glasgow University, has received payments from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, DalCor, GSK, KBP Biosciences, Novartis, Pfizer, and Theracos for his work on clinical trials, consulting, and other activities and he has received personal payments from Abbott, Hikma, Ionis, Sun Pharmaceuticals, and Servier. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, Puretech Health. M.A.P. reports research grant support through Brigham and Women’s Hospital from Novartis; and consulting fees from Alnylam, AstraZeneca, Boehringer Ingelheim, and Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, National Heart, Lung, and Blood Institute (NHLBI) CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, and Sanofi; and has equity in DalCor. A.S. has received research support from Novartis and Philips Ultrasound through Brigham and Women’s Hospital, and consulting fees from Philips Ultrasound and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇O 2 ) in patients with heart failure with preserved ejection fraction (HFpEF); however, inter-individual responses vary significantly. Because it is unlikely that ET-induced improvements in peak V̇O 2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O 2 -pulse (V̇O 2  × HR -1 , reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak V̇O 2 , is inversely associated with the change in peak V̇O 2 (adjusted by body weight) following ET versus guideline control (CON) in patients with HFpEF., Methods and Results: This was a secondary analysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure, NCT02078947) trial, including all 158 patients with complete baseline and 3 month cardiopulmonary exercise testing measurements (106 ET, 52 CON). Change in peak V̇O 2 (%) was analysed as a function of baseline peak V̇O 2 and its determinants (absolute peak V̇O 2 , peak O 2 -pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak V̇O 2 through changes in peak O 2 -pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (V̇O 2 at the ventilatory threshold, VT1) was analysed as a secondary endpoint. Among 158 patients with HFpEF (66% female; mean age, 70 ± 8 years), changes in peak O 2 -pulse explained approximately 72% of the difference in changes in peak V̇O 2 between ET and CON [10.0% (95% CI, 4.1 to 15.9), P = 0.001]. There was a significant interaction between the groups for the influence of baseline peak O 2 -pulse on change in peak V̇O 2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O 2 -pulse was associated with a decreased mean change in peak V̇O 2 of -1.45% (95% CI, -2.30 to -0.60, P = 0.001) compared with a mean change of -0.08% (95% CI, -1.11 to 0.96, P = 0.88) following CON. None of the other factors showed significant interactions with study groups for the change in peak V̇O 2 (P > 0.05). Change in V̇O 2 at VT1 was not associated with any of the investigated factors (P > 0.05)., Conclusions: In patients with HFpEF, the easily measurable peak O 2 -pulse seems to be a good indicator of the potential for improving peak V̇O 2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O 2 -pulse, patients with high O 2 -pulse may need to use additional therapies to significantly increase peak V̇O 2 ., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: In heart failure with preserved ejection fraction (HFpEF), the reduction of nitric oxide (NO)-bioavailability and consequently endothelial dysfunction leads to LV stiffness and diastolic dysfunction of the heart. Besides shear stress, high-density lipoprotein (HDL) stimulates endothelial cells to increased production of NO via phosphorylation of endothelial nitric oxide synthase (eNOS). For patients with heart failure with reduced ejection fraction, earlier studies demonstrated a positive impact of exercise training (ET) on HDL-mediated eNOS activation. The study aims to investigate the influence of ET on HDL-mediated phosphorylation of eNOS in HFpEF patients., Methods and Results: The present study is a substudy of the OptimEx-Clin trial. The patients were randomized to three groups: (i) HIIT (high-intensity interval training; (ii) MCT (moderate-intensity continuous training); and (iii) CG (control group). Supervised training at study centres was offered for the first 3 months. From months 4-12, training sessions were continued at home with the same exercise protocol as performed during the in-hospital phase. Blood was collected at baseline, after 3, and 12 months, and HDL was isolated by ultracentrifugation. Human aortic endothelial cells were incubated with isolated HDL, and HDL-induced eNOS phosphorylation at Ser 1177 and Thr 495 was assessed. Subsequently, the antioxidative function of HDL was evaluated by measuring the activity of HDL-associated paraoxonase-1 (Pon1) and the concentration of thiobarbituric acid-reactive substances (TBARS). After 3 months of supervised ET, HIIT resulted in increased HDL-mediated eNOS-Ser 1177 phosphorylation. This effect diminished after 12 months of ET. No effect of HIIT was observed on HDL-mediated eNOS-Thr 495 phosphorylation. MCT had no effect on HDL-mediated eNOS phosphorylation at Ser 1177 and Thr 495 . HIIT also increased Pon1 activity after 12 months of ET and reduced the concentration of TBARS in the serum after 3 and 12 months of ET. A negative correlation was observed between TBARS concentration and HDL-associated Pon1 activity in the HIIT group (r = -0.61, P < 0.05), and a trend was evident for the correlation between the change in HDL-mediated eNOS-Ser 1177 phosphorylation and the change in peak V̇O 2 after 3 months in the HIIT group (r = 0.635, P = 0.07)., Conclusions: The present study documented that HIIT but not MCT exerts beneficial effects on HDL-mediated eNOS phosphorylation and HDL-associated Pon1 activity in HFpEF patients. These beneficial effects of HIIT were reduced as soon as the patients switched to home-based ET., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Exercise intolerance is a cardinal feature of heart failure with preserved ejection fraction and so far exercise training (ET) is the most effective treatment. Since the improvement in exercise capacity is only weakly associated with changes in diastolic function other mechanisms, like changes in the skeletal muscle, contribute to improvement in peak oxygen consumption. The aim of the present study was to analyze molecular changes in skeletal muscle of patients with heart failure with preserved ejection fraction performing different ET modalities., Methods: Skeletal muscle biopsies were taken at study begin and after 3 and 12 months from patients with heart failure with preserved ejection fraction randomized either into a control group (guideline based advice for ET), a high-intensity interval training group (HIIT) or a moderate continuous training group. The first 3 months of ET were supervised in-hospital followed by 9 months home-based ET. Protein and mRNA expression of atrophy-related proteins, enzyme activities of enzymes linked to energy metabolism and satellite cells (SCs) were quantified., Results: Exercise capacity improved 3 months after moderate continuous exercise training and HIIT. This beneficial effect was lost after 12 months. HIIT mainly improved markers of energy metabolism and the amount and function of SC, with minor changes in markers for muscle atrophy. Only slight changes were observed after moderate continuous exercise training. The molecular changes were no longer detectable after 12 months., Conclusions: Despite similar improvements in exercise capacity by HIIT and moderate continuous exercise training after 3 months, only HIIT altered proteins related to energy metabolism and amount/function of SC. These effects were lost after switching from in-hospital to at-home-based ET., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02078947.

Besides structural alterations in the myocardium, heart failure with preserved ejection fraction (HFpEF) is also associated with molecular and physiological alterations of the peripheral skeletal muscles (SKM) contributing to exercise intolerance often seen in HFpEF patients. Recently, the use of Sodium-Glucose-Transporter 2 inhibitors (SGLT2i) in clinical studies provided evidence for a significant reduction in the combined risk of cardiovascular death or hospitalization for HFpEF. The present study aimed to further elucidate the impact of Empagliflozin (Empa) on: (1) SKM function and metabolism and (2) mitochondrial function in an established HFpEF rat model. At the age of 24 weeks, obese ZSF1 rats were randomized either receiving standard care or Empa in the drinking water. ZSF1 lean animals served as healthy controls. After 8 weeks of treatment, echocardiography and SKM contractility were performed. Mitochondrial function was assessed in saponin skinned fibers and SKM tissue was snap frozen for molecular analyses. HFpEF was evident in the obese animals when compared to lean-increased E/é and preserved left ventricular ejection fraction. Empa treatment significantly improved E/é and resulted in improved SKM contractility with reduced intramuscular lipid content. Better mitochondrial function (mainly in complex IV) with only minor modulation of atrophy-related proteins was seen after Empa treatment. The results clearly documented a beneficial effect of Empa on SKM function in the present HFpEF model. These effects were accompanied by positive effects on mitochondrial function possibly modulating SKM function.

Background: About half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so-called HFpEF). No specific therapeutics are available for HFpEF in contrast to HF where reduced ejection fractions (HFrEF) can be treated pharmacologically. Myocardial titin filament stiffening, endothelial dysfunction, and skeletal muscle (SKM) myopathy are suspected to contribute to HFpEF genesis. We previously described small molecules interfering with MuRF1 target recognition thereby attenuating SKM myopathy and dysfunction in HFrEF animal models. The aim of the present study was to test the efficacy of one small molecule (MyoMed-205) in HFpEF and to describe molecular changes elicited by MyoMed-205., Methods: Twenty-week-old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed-205 for 12 weeks; a comparison was made to age-matched untreated ZSF1-lean (healthy) and obese rats as controls. LV (left ventricle) function was assessed by echocardiography and by invasive haemodynamic measurements until week 32. At week 32, SKM and endothelial functions were measured and tissues collected for molecular analyses. Proteome-wide analysis followed by WBs and RT-PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1-KO) SKM tissues were included to validate MuRF1-specificity., Results: By week 32, untreated obese rats had normal LV ejection fraction but augmented E/e' ratios and increased end diastolic pressure and myocardial fibrosis, all typical features of HFpEF. Furthermore, SKM myopathy (both atrophy and force loss) and endothelial dysfunction were detected. In contrast, MyoMed-205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed-205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed-205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed-205 target, the synthesis of mitochondrial respiratory chain complexes I + II was increased in treated rats. MuRF1-KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1., Conclusions: MyoMed-205 improved myocardial diastolic function and prevented SKM atrophy/function in the ZSF1 animal model of HFpEF. Mechanistically, SKM benefited from an attenuated ubiquitin proteasome system and augmented synthesis/activity of proteins of the mitochondrial respiratory chain while the myocardium seemed to benefit from reduced titin modifications and fibrosis., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Aims: ACTIVITY-HF was a randomized, double-blind, active-controlled study, which assessed the short-term effect of sacubitril/valsartan compared with the active comparator enalapril on improving maximal exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF)., Methods and Results: A total of 201 ambulatory patients with HFrEF (left ventricular ejection fraction ≤ 40%, New York Heart Association class III) across 34 centres in Germany were randomized (1:1) to receive sacubitril/valsartan 97/103 mg bid (n = 103) or enalapril 10 mg bid (n = 98). The primary endpoint of the study was the change from baseline in peak oxygen consumption (VO 2 ; adjusted to body weight) after 12 weeks, and the key secondary endpoint was change from baseline in peak VO 2 after 6 weeks. The study population was predominantly male (81.1%) with a mean age of 66.9 years and a body mass index of 29.4 kg/m 2 . Change in peak VO 2 from baseline to Week 12 was similar between sacubitril/valsartan and enalapril groups [least squares mean difference: 0.32 mL/min/kg; 95% confidence interval (CI) -0.21, 0.85; P = 0.2327]. Similarly, no significant differences were observed between the two treatment groups in minute ventilation to carbon dioxide production slope, exercise capacity at first ventilatory threshold or Borg scale at either Week 6 or Week 12. Change in heart rate at first ventilatory threshold was lower in the sacubitril/valsartan group compared with the enalapril group at Week 12 (mean -3.75 bpm; 95% CI -7.03, -0.48; P = 0.0248). The safety of sacubitril/valsartan was comparable to enalapril., Conclusion: In patients with HFrEF, short-term treatment with sacubitril/valsartan for 12 weeks did not result in significant benefits on peak VO 2 when compared with enalapril., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Skeletal muscle (SM) alterations contribute to exercise intolerance in heart failure patients with preserved (HFpEF) or reduced (HFrEF) left ventricular ejection fraction (LVEF). Protein degradation via the ubiquitin-proteasome-system (UPS), nuclear apoptosis, and reduced mitochondrial energy supply is associated with SM weakness in HFrEF. These mechanisms are incompletely studied in HFpEF, and a direct comparison between these groups is missing., Methods and Results: Patients with HFpEF (LVEF ≥ 50%, septal E/e' > 15 or >8 and NT-proBNP > 220 pg/mL, n = 20), HFrEF (LVEF ≤ 35%, n = 20) and sedentary control subjects (Con, n = 12) were studied. Inflammatory markers were measured in serum, and markers of the UPS, nuclear apoptosis, and energy metabolism were determined in percutaneous SM biopsies. Both HFpEF and HFrEF showed increased proteolysis (MuRF-1 protein expression, ubiquitination, and proteasome activity) with proteasome activity significantly related to interleukin-6. Proteolysis was more pronounced in patients with lower exercise capacity as indicated by peak oxygen uptake in per cent predicted below the median. Markers of apoptosis did not differ between groups. Mitochondrial energy supply was reduced in HFpEF and HFrEF (complex-I activity: -31% and -53%; malate dehydrogenase activity: -20% and -29%; both P < 0.05 vs. Con). In contrast, short-term energy supply via creatine kinase was increased in HFpEF but decreased in HFrEF (47% and -45%; P < 0.05 vs. Con)., Conclusions: Similarly to HFrEF, skeletal muscle in HFpEF is characterized by increased proteolysis linked to systemic inflammation and reduced exercise capacity. Energy metabolism is disturbed in both groups; however, its regulation seems to be severity-dependent., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The angiotensin receptor/neprilysin inhibitor Sacubitril/Valsartan (Sac/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac/Val treatment reduced E/é ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.

[Figure: see text].

Importance: Endurance exercise is effective in improving peak oxygen consumption (peak V̇o2) in patients with heart failure with preserved ejection fraction (HFpEF). However, it remains unknown whether differing modes of exercise have different effects., Objective: To determine whether high-intensity interval training, moderate continuous training, and guideline-based advice on physical activity have different effects on change in peak V̇o2 in patients with HFpEF., Design, Setting, and Participants: Randomized clinical trial at 5 sites (Berlin, Leipzig, and Munich, Germany; Antwerp, Belgium; and Trondheim, Norway) from July 2014 to September 2018. From 532 screened patients, 180 sedentary patients with chronic, stable HFpEF were enrolled. Outcomes were analyzed by core laboratories blinded to treatment groups; however, the patients and staff conducting the evaluations were not blinded., Interventions: Patients were randomly assigned (1:1:1; n = 60 per group) to high-intensity interval training (3 × 38 minutes/week), moderate continuous training (5 × 40 minutes/week), or guideline control (1-time advice on physical activity according to guidelines) for 12 months (3 months in clinic followed by 9 months telemedically supervised home-based exercise)., Main Outcomes and Measures: Primary end point was change in peak V̇o2 after 3 months, with the minimal clinically important difference set at 2.5 mL/kg/min. Secondary end points included changes in metrics of cardiorespiratory fitness, diastolic function, and natriuretic peptides after 3 and 12 months., Results: Among 180 patients who were randomized (mean age, 70 years; 120 women [67%]), 166 (92%) and 154 (86%) completed evaluation at 3 and 12 months, respectively. Change in peak V̇o2 over 3 months for high-intensity interval training vs guideline control was 1.1 vs -0.6 mL/kg/min (difference, 1.5 [95% CI, 0.4 to 2.7]); for moderate continuous training vs guideline control, 1.6 vs -0.6 mL/kg/min (difference, 2.0 [95% CI, 0.9 to 3.1]); and for high-intensity interval training vs moderate continuous training, 1.1 vs 1.6 mL/kg/min (difference, -0.4 [95% CI, -1.4 to 0.6]). No comparisons were statistically significant after 12 months. There were no significant changes in diastolic function or natriuretic peptides. Acute coronary syndrome was recorded in 4 high-intensity interval training patients (7%), 3 moderate continuous training patients (5%), and 5 guideline control patients (8%)., Conclusions and Relevance: Among patients with HFpEF, there was no statistically significant difference in change in peak V̇o2 at 3 months between those assigned to high-intensity interval vs moderate continuous training, and neither group met the prespecified minimal clinically important difference compared with the guideline control. These findings do not support either high-intensity interval training or moderate continuous training compared with guideline-based physical activity for patients with HFpEF., Trial Registration: ClinicalTrials.gov Identifier: NCT02078947.

Aims: Heart failure with preserved ejection fraction (HFpEF) is associated with reduced exercise capacity elicited by skeletal muscle (SM) alterations. Up to now, no clear medical treatment advice for HFpEF is available. Identification of the ideal animal model mimicking the human condition is a critical step in developing and testing treatment strategies. Several HFpEF animals have been described, but the most suitable in terms of comparability with SM alterations in HFpEF patients is unclear. The aim of the present study was to investigate molecular changes in SM of three different animal models and to compare them with alterations of muscle biopsies obtained from human HFpEF patients., Methods and Results: Skeletal muscle tissue was obtained from HFpEF and control patients and from three different animal models including the respective controls-ZSF1 rat, Dahl salt-sensitive rat, and transverse aortic constriction surgery/deoxycorticosterone mouse. The development of HFpEF was verified by echocardiography. Protein expression and enzyme activity of selected markers were assessed in SM tissue homogenates. Protein expression between SM tissue obtained from HFpEF patients and the ZSF1 rats revealed similarities for protein markers involved in muscle atrophy (MuRF1 expression, protein ubiquitinylation, and LC3) and mitochondrial metabolism (succinate dehydrogenase and malate dehydrogenase activity, porin expression). The other two animal models exhibited far less similarities to the human samples., Conclusions: None of the three tested animal models mimics the condition in HFpEF patients completely, but among the animal models tested, the ZSF1 rat (ZSF1-lean vs. ZSF1-obese) shows the highest overlap to the human condition. Therefore, when studying therapeutic interventions to treat HFpEF and especially alterations in the SM, we suggest that the ZSF1 rat is a suitable model., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose: This study aimed to investigate baseline, exercise testing, and exercise training-mediated predictors of change in peak oxygen uptake (V˙O2peak) from baseline to 12-wk follow-up (ΔV˙O2peak) in a post hoc analysis from the SMARTEX Heart Failure trial., Methods: We studied 215 patients with heart failure with left ventricular ejection fraction (LVEF) ≤35%, and New York Heart Association (NYHA) classes II-III who were randomized to either supervised high-intensity interval training with exercise target intensity of 90%-95% of peak heart rate (HRpeak) or supervised moderate continuous training (MCT) with target intensity of 60%-70% of HRpeak, or who received a recommendation of regular exercise on their own. Predictors of ΔV˙O2peak were assessed in two models: a logistic regression model comparing highest and lowest tertiles (baseline parameters) and a multivariate linear regression model (test/training/clinical parameters)., Results: The change in V˙O2peak in response to the interventions (ΔV˙O2peak) varied substantially, from -8.50 to +11.30 mL·kg·min. Baseline NYHA (class II gave higher odds vs III; odds ratio (OR), 7.1 (2.0-24.9); P = 0.002), LVEF (OR per percent, 1.1 (1.0-1.2); P = 0.005), and age (OR per 10 yr, 0.5 (0.3-0.8); P = 0.003) were associated with ΔV˙O2peak.In the multivariate linear regression, 34% of the variability in ΔV˙O2peak was explained by the increase in exercise training workload, ΔHRpeak between baseline and 12-wk posttesting, age, and ever having smoked., Conclusion: Exercise training response (ΔV˙O2peak) correlated negatively with age, LVEF, and NYHA class. The ability to increase workload during the training period and increased ΔHRpeak between baseline and the 12-wk test were associated with a positive outcome.

Purpose: In moderately impaired, stable chronic heart failure (CHF) patients, exercise training (ET) enhances exercise capacity. In contrast, the therapeutic benefits of regular ET in patients with advanced CHF, especially in the long-term, are limited or conflicting. Therefore, the aim of the present investigation was to elucidate whether ET performed over 12 months would improve left ventricular performance and exercise capacity in patients with advanced CHF., Methods: Thirty-seven patients with CHF and New York Heart Association (NYHA) class IIIb were randomized to a sedentary lifestyle or daily ET on a cycle ergometer (in-hospital and home-based at 50%-60% of maximal exercise capacity). Cardiopulmonary exercise testing and echocardiography were performed at baseline, 3, 6, and 12 months., Results: Exercise training resulted in continuous decreases in left ventricular end-diastolic diameter at 3, 6, and 12 months versus baseline (all P < .05). This was accompanied by a significant increase in resting left ventricular ejection fraction from 24.1% ± 1.2% at baseline to 38.4% ± 2.0% at 12-month followup (P < .05). Moreover, ET patients increased exercise capacity measured by maximal oxygen uptake (Equation is included in full-text article.)O2max at 3, 6, and 12 months compared with baseline: 15.3 ± 0.8 mL/min/kg, 17.8 ± 0.8 mL/min/kg, 19.0 ± 0.7 mL/min/kg, and 19.5 ± 0.9 mL/min/kg, respectively (all P < .05 vs baseline). This was associated with a reduced NYHA classification., Conclusions: Exercise training over 12 months resulted in an improvement in exercise capacity and reversing of left ventricular remodeling in patients with advanced CHF (NYHA IIIb). These beneficial adaptations continued to improve up to 6 months and remained stable thereafter.

Rationale: High-density lipoprotein (HDL) exerts endothelial-protective effects via stimulation of endothelial cell (EC) nitric oxide (NO) production. This function is impaired in patients with cardiovascular disease. Protective effects of exercise training (ET) on endothelial function have been demonstrated., Objective: This study was performed to evaluate the impact of ET on HDL-mediated protective effects and the respective molecular pathways in patients with chronic heart failure (CHF)., Methods and Results: HDL was isolated from 16 healthy controls (HDL(healthy)) and 16 patients with CHF-NYHA-III (HDL(NYHA-IIIb)) before and after ET, as well as from 8 patients with CHF-NYHA-II (HDL(NYHA-II)). ECs were incubated with HDL, and phosphorylation of eNOS-Ser(1177), eNOS-Thr(495), PKC-βII-Ser(660), and p70S6K-Ser(411) was evaluated. HDL-bound malondialdehyde and HDL-induced NO production by EC were quantified. Endothelial function was assessed by flow-mediated dilatation. The proteome of HDL particles was profiled by shotgun LC-MS/MS. Incubation of EC with HDL(NYHA-IIIb) triggered a lower stimulation of phosphorylation at eNOS-Ser(1177) and a higher phosphorylation at eNOS-Thr(495) when compared with HDL(healthy). This was associated with lower NO production of EC. In addition, an elevated activation of p70S6K, PKC-βII by HDL(NYHA-IIIb), and a higher amount of malondialdehyde bound to HDL(NYHA-IIIb) compared with HDL(healthy) was measured. In healthy individuals, ET had no effect on HDL function, whereas ET of CHF-NYHA-IIIb significantly improved HDL function. A correlation between changes in HDL-induced NO production and flow-mediated dilatation improvement by ET was evident., Conclusions: These results demonstrate that HDL function is impaired in CHF and that ET improved the HDL-mediated vascular effects. This may be one mechanism how ET exerts beneficial effects in CHF.