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.
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 placebo for 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 -2.4 (95% CI -4.5 to -0.3) mmHg in patients who received sildenafil, vs. -4.7 (95% CI -7.1 to -2.3) 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.
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).
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 m2. The eGFR declined less in the LCZ696 group than in the valsartan group (–1.5 vs. –5.2 mL/min per 1.73 m2; 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.
Current available inotropic agents increase cardiac contractility, but are associated with myocardial ischemia, arrhythmias, and mortality. A novel selective cardiac myosin activator, omecamtiv ...mecarbil (CK-1827452/ AMG-423) is a small molecule that activates the sarcomere proteins directly, resulting in prolonged systolic ejection time and increased cardiac contractility.
This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of omecamtiv mecarbil. Omecamtiv mecarbil represents a novel therapeutic approach to directly improve cardiac function and is therefore proposed as a potential new treatment of patients with systolic heart failure. The authors review results of previous studies investigating the effect of omecamtiv mecarbil in heart failure animal models, healthy volunteers, and patients with acute and chronic systolic heart failure.
Results of phase I and phase II studies demonstrate that omecamtiv mecarbil is safe and well tolerated both as an intravenous and oral formulation. In healthy volunteers and chronic systolic heart failure patients, administration of omecamtiv mecarbil resulted in a concentration-dependent increase of left ventricular ejection time, ejection fraction, fractional shortening, and stroke volume. The first results of a double-blind, randomized, placebo-controlled phase IIb dose-finding study with the oral formulation of omecamtiv mecarbil demonstrated beneficial effects on cardiac function and N-terminal pro-brain natriuretic peptide levels. This study will provide essential dosing information for the requisite phase III trials which will investigate whether the beneficial effects of omecamtiv mecarbil translate into improved clinical outcomes.
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.
This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of finerenone.
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.
Aims
Although echocardiography is generally used for the diagnosis of heart failure with preserved ejection fraction (HFpEF), invasive measurements of filling pressures are the gold standard. Studies ...simultaneously performing echocardiography and invasive measurements in HFpEF are sparse.
Methods and results
Invasive haemodynamic and echocardiographic measurements were simultaneously performed in 98 patients with heart failure New York Heart Association class ≥II, left ventricular ejection fraction (LVEF) ≥45%, and suspected pulmonary hypertension on a previous echocardiogram. Multivariable linear regression analyses were used to establish echocardiographic predictors of pulmonary artery wedge pressure (PAWP), left ventricular end‐diastolic pressure (LVEDP), and mean pulmonary arterial pressure (mPAP). Mean age of the study patients was 74 ± 9 years, 68% were female, mean LVEF was 57 ± 5%, and 30% had atrial fibrillation at the time of measurement. Mean PAWP, LVEDP and mPAP were 17.2 ± 6.2, 16.7 ± 5.8 and 30.9 ± 10.2 mmHg, respectively. Isovolumetric relaxation time (IVRT) and left atrial reservoir strain could moderately estimate PAWP (r = 0.656; P < 0.001). LVEDP was only modestly predicted by IVRT and right ventricular wall thickness (r = 0.548; P < 0.001). Surprisingly, a low correlation was found between E/e'mean and PAWP (r = 0.240; P = 0.019), E/e'mean and LVEDP (r = 0.081; P = 0.453). Correlation coefficients were similar in patients with and without atrial fibrillation.
Conclusion
In patients with HFpEF, echocardiographic measurements, including the E/e' ratio, have a poor to moderate predictive value for the estimation of invasively acquired LVEDP and PAWP. This limitation should be taken into account for the diagnosis and evaluation of patients with HFpEF.
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.
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).
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.
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.
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
) 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
vs. 42.5 ± 15.1 ml/m
; 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
increased log NT-proBNP, and enlarged LAVI (all p ≤0.005).
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.
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 60 mg 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 13.8 mmHg (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 12 weeks 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.
•The VE/VCO2 slope is of prognostic value in HFpEF patients.•Peak VO2 is often not reached in HFpEF patients with multiple comorbidities.•The VE/VCO2 slope can be used as a diagnostic tool in HFpEF ...patients.•Increased pulmonary pressures are associated with a worse VE/VCO2 slope.
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.
Patients with HFpEF (left ventricular ejection fraction LVEF ≥45%) and pulmonary hypertension underwent cardiopulmonary exercise test (CPX) to measure maximal (peak VO2) and submaximal (ventilatory equivalent for carbon dioxide VE/VCO2 slope) exercise capacity. In addition, right heart catheterization was performed. Patients were grouped in tertiles based on the VE/VCO2 slope. Univariate and multivariate regression analyses were performed. A Cox regression analysis was performed to determine the mortality during follow-up.
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/VCO2 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/VCO2 slope was independently associated with pulmonary vascular resistance (PVR). Cox regression analysis showed that increased VE/VCO2 slope (but not peak VO2) was independently associated with increased mortality.
Increased VE/VCO2 slope was associated with more severe disease and higher PVR and was independently associated with increased mortality in patients with HFpEF.
Background
Serelaxin showed beneficial effects on clinical outcome and trajectories of renal markers in patients with acute heart failure. We aimed to study the interaction between renal function and ...the treatment effect of serelaxin.
Methods
In the current post hoc analysis of the RELAX-AHF trial, we included all patients with available estimated glomerular filtration rate (eGFR) at baseline (
n
= 1132). Renal impairment was defined as an eGFR <60 ml/min/1.73 m
2
estimated by creatinine.
Results
817 (72.2 %) patients had a baseline eGFR <60 ml/min/1.73 m
2
. In placebo-treated patients, baseline renal impairment was related to a higher 180 day cardiovascular (HR 3.12, 95 % CI 1.33–7.30) and all-cause mortality (HR 2.81, 95 % CI 1.34–5.89). However, in serelaxin-treated patients, the risk of cardiovascular and all-cause mortality was less pronounced (HR 1.19, 95 % CI 0.54 –2.64;
p
for interaction = 0.106, and HR 1.15 95 % CI 0.56–2.34 respectively;
p
for interaction = 0.088). In patients with renal impairment, treatment with serelaxin resulted in a more pronounced all-cause mortality reduction (HR 0.53, 95 % CI 0.34–0.83), compared with patients without renal impairment (HR 1.30, 95 % CI 0.51–3.29).
Conclusion
Renal dysfunction was associated with higher cardiovascular and all-cause mortality in placebo-treated patients, but not in serelaxin-treated patients. The observed reduction in (cardiovascular) mortality in RELAX-AHF was more pronounced in patients with renal dysfunction. These observations need to be confirmed in the ongoing RELAX-AHF-2 trial.
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