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Aims We recently showed that sildenafil did not improve pulmonary pressures and exercise capacity in a cohort of patients with heart failure and preserved ejection fraction (HFpEF) and predominantly postcapillary pulmonary hypertension. Here, we present the effects of sildenafil on cardiac structure and function, cardiopulmonary exercise testing, laboratory parameters and health-related quality of life measures. Methods and results Fifty-two HFpEF patients with pulmonary hypertension (mean pulmonary artery pressure >25 mmHg; pulmonary artery wedge pressure >15 mmHg) were randomized to sildenafil 60mg three times a day or placebo and treated for 12 weeks. Sildenafil neither changed cardiac structure nor function on echocardiography compared with placebo. Considering all patients irrespective of maximal effort, sildenafil reduced peak heart rate by 8 b.p.m. [95% confidence interval (CI) -14.97 to -1.03] and peak blood pressure by 13.8mmHg (95% CI -22.04 to -5.47)/7.3 mmHg (95% CI -13.60 to -1.07) (both P <0.05 vs. placebo). The minute ventilation/carbon dioxide production (VE/VCO2) slope remained unchanged in the sildenafil group (0.3, 95% CI -1.37-1.98), while it was reduced in the placebo group (-7.6, 95% CI -12.97 to -2.25, P =0.002). In both groups, renal function improved and N-terminal pro-brain natriuretic peptide concentration reduced equally. Haemoglobin and glycated haemoglobin levels slightly decreased in the sildenafil group (P <0.05 vs. placebo). All domains of the Kansas City Cardiomyopathy Questionnaire increased during treatment, but no differences between sildenafil and placebo were found. Conclusion Treatment with sildenafil for 12weeks in patients with HFpEF and predominantly isolated postcapillary pulmonary hypertension did not affect cardiac structure and function, integrative exercise responses, laboratory parameters, and/or quality of life. Clinicaltrials.gov number NCT01726049. [ABSTRACT FROM AUTHOR]

Background Heart failure with preserved ejection fraction (HFpEF), with associated pulmonary hypertension is an increasingly large medical problem. Phosphodiesterase (PDE)-5 inhibition may be of value in this population, but data are scarce and inconclusive. Methods and results In this single centre, randomized double-blind, placebo-controlled trial, we included 52 patients with pulmonary hypertension [mean pulmonary artery pressure (PAP) >25 mmHg; pulmonary artery wedge pressure (PAWP) >15 mmHg] due to HFpEF [left ventricular ejection fraction (LVEF) ≥45%]. Patients were randomized to the PDE-5 inhibitor sildenafil, titrated to 60 mg three times a day, or placebofor 12 weeks. The primary endpoint was change in mean PAP after 12 weeks. Secondary endpoints were change in mean PAWP, cardiac output, and peak oxygen consumption (peak VO2). Mean age was 74±10 years, 71% was female, LVEF was 58%, median NT-proBNP level was 1087 (535-1945) ng/L. After 12 weeks, change in mean PAP was 22.4 (95% CI 24.5 to 20.3) mmHg in patients who received sildenafil, vs. 24.7 (95% CI 27.1 to 22.3) mmHg in placebo patients (P = 0.14). Sildenafil did not have a favourable effect on PAWP, cardiac output, and peak VO2. Adverse events were overall comparable between groups. Conclusion Treatment with sildenafil did not reduce pulmonary artery pressures and did not improve other invasive haemodynamic or clinical parameters in our study population, characterized by HFpEF patients with predominantly isolated post-capillary pulmonary hypertension. (ClinicalTrials.gov, number NCT01726049). [ABSTRACT FROM AUTHOR]

Background: Impaired exercise capacity is one of the hallmarks of heart failure with preserved ejection fraction (HFpEF), but the clinical and hemodynamic correlates and prognostic value of exercise testing in patients with HFpEF is unknown., Methods: Patients with HFpEF (left ventricular ejection fraction [LVEF] ≥45%) and pulmonary hypertension underwent cardiopulmonary exercise test (CPX) to measure maximal (peak VO 2 ) and submaximal (ventilatory equivalent for carbon dioxide [VE/VCO 2 ] slope) exercise capacity. In addition, right heart catheterization was performed. Patients were grouped in tertiles based on the VE/VCO 2 slope. Univariate and multivariate regression analyses were performed. A Cox regression analysis was performed to determine the mortality during follow-up., Results: We studied 88 patients: mean age 73 ± 9 years, 67% female, mean LVEF 58%, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 840 (interquartile range 411-1938) ng/L. Patients in the highest VE/VCO 2 tertile had the most severe HF, as reflected in higher New York Heart Association functional class and higher NT-proBNP plasma levels (all P < .05 for trend), whereas LVEF was similar between the groups. Multivariable regression analysis with backward elimination on invasive hemodynamic measurements showed that VE/VCO 2 slope was independently associated with pulmonary vascular resistance (PVR). Cox regression analysis showed that increased VE/VCO 2 slope (but not peak VO 2 ) was independently associated with increased mortality., Conclusion: Increased VE/VCO 2 slope was associated with more severe disease and higher PVR and was independently associated with increased mortality in patients with HFpEF., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: This study sought to study the association of atrial fibrillation (AF) with exercise capacity, left ventricular filling pressure, natriuretic peptides, and left atrial size in heart failure with preserved ejection fraction (HFpEF)., Background: The diagnosis of HFpEF in patients with AF remains a challenge because both contribute to impaired exercise capacity, and increased natriuretic peptides and left atrial volume., Methods: We studied 94 patients with symptomatic heart failure and left ventricular ejection fractions ≥45% using treadmill cardiopulmonary exercise testing and right- and/or left-sided cardiac catheterization with simultaneous echocardiography., Results: During catheterization, 62 patients were in sinus rhythm, and 32 patients had AF. There were no significant differences in age, sex, body size, comorbidities, or medications between groups; however, patients with AF had lower peak oxygen consumption (VO 2 ) compared with those with sinus rhythm (10.8 ± 3.1 ml/min/kg vs. 13.5 ± 3.8 ml/min/kg; p = 0.002). Median (25th to 75th percentile) N-terminal pro-B-type natriuretic peptide (NT-proBNP) was higher in AF versus sinus rhythm (1,689; 851 to 2,637 pg/ml vs. 490; 272 to 1,019 pg/ml; p < 0.0001). Left atrial volume index (LAVI) was higher in AF than sinus rhythm (57.8 ± 17.0 ml/m 2 vs. 42.5 ± 15.1 ml/m 2 ; p = 0.001). Invasive hemodynamics showed higher mean pulmonary capillary wedge pressure (PCWP) (19.9 ± 3.7 vs. 15.2 ± 6.8) in AF versus sinus rhythm (all p < 0.001), with a trend toward higher left ventricular end-diastolic pressure (17.7 ± 3.0 mm Hg vs. 15.7 ± 6.9 mm Hg; p = 0.06). After adjusting for clinical covariates and mean PCWP, AF remained associated with reduced peak VO 2 increased log NT-proBNP, and enlarged LAVI (all p ≤0.005)., Conclusions: AF is independently associated with greater exertional intolerance, natriuretic peptide elevation, and left atrial remodeling in HFpEF. These data support the application of different thresholds of NT-proBNP and LAVI for the diagnosis of HFpEF in the presence of AF versus the absence of AF., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The selective adenosine A1 receptor antagonist rolofylline showed a neutral overall result on clinical outcomes in the PROTECT trial. However, we hypothesized that response to rolofylline treatment could be influenced by underlying clinical risk., Methods: We performed a post-hoc analysis of the PROTECT trial - a large, double-blind, randomized, placebo-controlled trial that enrolled 2033 patients. Baseline risk of 180-day all-cause mortality was estimated using a previously published 8-item model. Evaluation of efficacy of rolofylline across subpopulations defined based on estimated risk of mortality was performed using subpopulation treatment effect pattern plot (STEPP) analysis. Findings were validated in an independent cohort of acute heart failure patients., Results: Median estimated risk of mortality was 13.0%, IQR [8.0%-23.0%] and was comparable between the rolofylline and placebo arms. In low to intermediate risk subgroups of patients, rolofylline was associated with a higher rate of 180-day all-cause mortality (11.9% in the rolofylline versus 8.4% in the placebo arms, p=0.050). In the high risk subgroup of patients, particularly those with estimated risk of mortality between 20% and 30%, 180-day all-cause mortality rate was markedly lower in the rolofylline arm (18.4% in the rolofylline versus 34.0% in the placebo arms, p=0.003). The trend towards potential harm with rolofylline treatment in the low to intermediate risk subpopulations and significant benefit in high risk patients was also observed in the validation cohort., Conclusion: Our findings suggest that selective adenosine A1 receptor antagonism could be harmful in low risk acute heart failure patients, while it might significantly benefit higher risk patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: Our aim was to identify circulating microRNAs (miRNAs) associated with acute heart failure (AHF)., Methods and Results: Plasma miRNA profiling included 137 patients with AHF from 3 different cohorts, 20 with chronic heart failure (CHF), 8 with acute exacerbation of COPD, and 41 healthy controls. Levels of circulating miRNAs were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Plasma levels of miRNAs in patients with AHF were decreased compared with CHF patients or healthy subjects, whereas no significant changes were observed between acute COPD patients and controls. Fifteen miRNAs found in the discovery phase to differ most significantly between healthy controls and patients with AHF were further investigated in an extended cohort of 100 AHF patients at admission and a separate cohort of 18 AHF patients at different time points. Out of these 15 miRNAs, 12 could be confirmed in an additional AHF validation cohort and 7 passed the Bonferroni correction threshold (miR-18a-5p, miR-26b-5p, miR-27a-3p, miR-30e-5p, miR-106a-5p, miR-199a-3p, and miR-652-3p, all P < 0.00005). A further drop in miRNA levels within 48 h after AHF admission was associated with an increased risk of 180-day mortality in a subset of the identified miRNAs., Conclusions: Declining levels of circulating miRNAs were associated with increasing acuity of heart failure. Early in-hospital decreasing miRNA levels were predictive for mortality in a subset of miRNAs in patients with AHF. The discovered miRNA panel may serve as a launch-pad for molecular pathway studies to identify new pharmacological targets and miRNA-based therapies., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Background: Increases in serum creatinine with renin-angiotensin-aldosterone system (RAAS) inhibitors can lead to unnecessary discontinuation of these agents. The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection fraction, and pilot data suggest potential benefit in heart failure with preserved ejection fraction (HFpEF). The effects of LCZ696 on renal function have not been assessed., Methods and Results: A total of 301 HFpEF patients were randomly assigned to LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function [creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and urinary albumin to creatinine ratio (UACR)] at baseline, 12 weeks, and after 36 weeks of treatment. Worsening renal function (WRF) was determined as an serum creatinine increase of >0.3 mg/dL and/or >25% between two time-points. Mean eGFR at baseline was 65.4 ± 20.4 mL/min per 1.73 m(2) . The eGFR declined less in the LCZ696 group than in the valsartan group (-1.5 vs. -5.2 mL/min per 1.73 m(2) ; P = 0.002). The incidence of WRF was lower in the LCZ696 group (12%) than in the valsartan group (18%) at any time-point, but this difference was not statistically significant (P = 0.18). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group (2.4-2.9 mg/mmol), whereas it remained stable in the valsartan group (2.1-2.0 mg/mmol; P for difference between groups = 0.016)., Conclusion: In patients with HFpEF, therapy with LCZ696 for 36 weeks was associated with preservation of eGFR compared with valsartan therapy, but an increase in UACR., (© 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.)

Introduction: The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone reduce the risk of hospitalizations and mortality in patients with heart failure (HF) with reduced ejection fraction (HFrEF), and attenuate progression of diabetic kidney disease. However, their use is limited by the fear of inducing hyperkalemia, especially in patients with renal dysfunction. Finerenone is a novel nonsteroidal MRA, with higher selectivity toward the mineralocorticoid receptor (MR) compared to spironolactone and stronger MR-binding affinity than eplerenone., Areas Covered: This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of finerenone., Expert Opinion: The selectivity and greater binding affinity of finerenone to the MR may reduce the risk of hyperkalemia and renal dysfunction and thereby overcome the reluctance to start and uptitrate MRAs in patients with HF and diabetic kidney disease. Studies conducted in patients with HFrEF and moderate chronic kidney disease and diabetic kidney disease, showed promising results. Phase III trials will have to show whether finerenone might become the third-generation MRA for the treatment of HF and diabetic kidney disease.

Evidence-based treatment has succeeded in improving clinical outcomes in heart failure. Nevertheless, morbidity, mortality, and the economic burden associated with the syndrome remain unsatisfactorily high. Most landmark heart failure studies included broad study populations, and thus current recommendations dictate standardized, universal therapy. While most patients included in recent trials benefit from this background treatment, exceeding this already significant gain has proven to be a challenge. The early identification of responders and nonresponders to treatment could result in improved therapeutic effectiveness, while reduction of unnecessary exposure may limit harmful and unpleasant side effects. In this review, we examine the potential value of currently available information on differential responses to heart failure therapy-a first step toward personalized medicine in the management of heart failure., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: Vitamin D status has been implicated in the pathophysiology of heart failure (HF). The aims of this study were to determine whether a low vitamin D status is associated with prognosis in HF and whether activation of the renin-angiotensin system (RAS) and inflammatory markers could explain this potential association., Methods and Results: We measured 25-hydroxy-vitamin D (25(OH)D), plasma renin activity (PRA), interleukin-6 (IL-6), C-reactive protein (CRP), and the incidence of death or HF rehospitalization in 548 patients with HF. Median age was 74 (64-80) years, left ventricular ejection fraction was 30% (23-42), and mean follow-up was 18 months. Low 25(OH)D levels were associated with female gender (P< 0.001), higher age (P= 0.002), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P< 0.001). Multivariable linear regression analysis showed that PRA (P= 0.048), and CRP levels (P= 0.006) were independent predictors of 25(OH)D levels. During follow-up, 155 patients died and 142 patients were rehospitalized. Kaplan-Meier analysis showed that lower 25(OH)D concentration was associated with an increased risk for the combined endpoint (all-cause mortality and HF rehospitalization; log rank test P= 0.045) and increased risk for all-cause mortality (log rank test P= 0.014). After adjustment in a multivariable Cox regression analysis, low 25(OH)D concentration remained independently associated with an increased risk for the combined endpoint [hazard ratio (HR) 1.09 per 10 nmol/L decrease; 95% confidence interval (CI) 1.00-1.16; P= 0.040] and all-cause mortality (HR 1.10 per 10 nmol/L decrease; 95% CI 1.00-1.22; P= 0.049)., Conclusion: A low 25(OH)D concentration is associated with a poor prognosis in HF patients. Activation of the RAS and inflammation may confer the adverse effects of low vitamin D levels.