PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial: rationale and design.
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ABSTRACT:
SUBMITTER: Redfield MM
PROVIDER: S-EPMC3530955 | biostudies-literature | 2012 Sep
REPOSITORIES: biostudies-literature
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PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial: rationale and design.
Redfield Margaret M MM Borlaug Barry A BA Lewis Greg D GD Mohammed Selma F SF Semigran Marc J MJ Lewinter Martin M MM Deswal Anita A Hernandez Adrian F AF Lee Kerry L KL Braunwald Eugene E
Circulation. Heart failure 20120901 5
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Project description:Heart Failure Network - Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (HFN RELAX-BioLINCC)
| PRJNA1079432 | ENA
Project description:Heart Failure Network - Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (HFN RELAX-BioLINCC)
| PRJNA1079431 | ENA
Project description:Approximately half of patients with heart failure have preserved ejection fraction. There is no proven treatment that improves outcome. The pathophysiology of heart failure with preserved ejection fraction is complex and includes left ventricular systolic and diastolic dysfunction, pulmonary vascular disease, endothelial dysfunction, and peripheral abnormalities. Multiple lines of evidence point to impaired nitric oxide (NO)-cGMP bioavailability as playing a central role in each of these abnormalities. In contrast to traditional organic nitrate therapies, an alternative strategy to restore NO-cGMP signaling is via inorganic nitrite. Inorganic nitrite, previously considered to be an inert byproduct of NO metabolism, functions as an important in vivo reservoir for NO generation, particularly under hypoxic and acidosis conditions. As such, inorganic nitrite becomes most active at times of greater need for NO signaling, as during exercise when left ventricular filling pressures and pulmonary artery pressures increase. Herein, we present the rationale and design for the INDIE-HFpEF trial (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction), which is a multicenter, randomized, double-blind, placebo-controlled cross-over study assessing the effect of inhaled inorganic nitrite on peak exercise capacity, conducted in the National Heart, Lung, and Blood Institute-sponsored Heart Failure Clinical Research Network. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02742129.
| S-EPMC5484533 | biostudies-literature
Project description:BackgroundRight ventricular (RV) dysfunction (RVD) is a poor prognostic factor in heart failure with preserved ejection fraction (HFpEF). The physiological perturbations associated with RVD or RV function indexed to load (RV-pulmonary arterial [PA] coupling) in HFpEF have not been defined. HFpEF patients with marked impairment in RV-PA coupling may be uniquely sensitive to sildenafil.Methods and resultsIn a subset of HFpEF patients enrolled in the Phosphodiesteas-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial, physiological variables and therapeutic effect of sildenafil were examined relative to the severity of RVD (tricuspid annular plane systolic excursion [TAPSE]) and according to impairment in RV-PA coupling (TAPSE/pulmonary artery systolic pressure) ratio. The prevalence of atrial fibrillation and diuretic use, n-terminal probrain natriuretic peptide levels, renal dysfunction, neurohumoral activation, myocardial necrosis and fibrosis biomarkers, and the severity of diastolic dysfunction all increased with severity of RVD. Peak oxygen consumption decreased and ventilatory inefficiency (VE/VCO2 slope) increased with increasing severity of RVD. Many but not all physiological derangements were more closely associated with the TAPSE/pulmonary artery systolic pressure ratio. Compared with placebo, at 24 weeks, TAPSE decreased, and peak oxygen consumption and VE/CO2 slope were unchanged with sildenafil. There was no interaction between RV-PA coupling and treatment effect, and sildenafil did not improve TAPSE, peak oxygen consumption, or VE/VCO2 in patients with pulmonary hypertension and RVD.ConclusionsHFpEF patients with RVD and impaired RV-PA coupling have more advanced heart failure. In RELAX patients with RVD and impaired RV-PA coupling, sildenafil did not improve RV function, exercise capacity, or ventilatory efficiency.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.
| S-EPMC4831074 | biostudies-literature
Project description:Patients admitted for acute heart failure (AHF) experience high rates of in-hospital and post-discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin-2, a hormone with vasodilatory and end-organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX-AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all-cause and cardiovascular mortality by 37% through day 180. RELAX-AHF-2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX-AHF-2 is a multicentre, randomized, double-blind, placebo-controlled, event-driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild-to-moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all-cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in-hospital length of stay during index AHF. The results from RELAX-AHF-2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.
| S-EPMC5488179 | biostudies-literature
Project description:BackgroundExercise intolerance is a hallmark of heart failure, but factors associated with impaired exercise capacity in heart failure with preserved ejection fraction are unclear. We hypothesized that in heart failure with preserved ejection fraction, the severity of resting ventricular and vascular dysfunction are associated with impairment in exercise tolerance as assessed by peak oxygen consumption.Methods and resultsSubjects with heart failure with preserved ejection fraction enrolled in the PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX) clinical trial (n=216) underwent baseline Doppler echocardiography, cardiopulmonary exercise testing, and cardiac MRI. RELAX participants were elderly (median age 69 years) and 48% were women. Ejection fraction (60%) and stroke volume (77 mL) were normal, while diastolic dysfunction (medial E/e', 16; deceleration time, 185 ms; left atrial volume, 44 mL/m(2)) and increased arterial load (arterial elastance, 1.51 mm Hg/mL) were evident. Peak oxygen consumption was reduced (11.7 mLkg(-1)min(-1), 1141 mL/min) and age, sex, body mass index, hemoglobin, and chronotropic response collectively explained 64% of the variance in raw peak oxygen consumption (mL/min). After adjustment for these variables, left ventricular structure (diastolic dimension [1.5%, P=0.008] and left ventricular mass [1.6%, P=0.008]), resting stroke volume (2.0%, P=0.002), left ventricular diastolic dysfunction (deceleration time [0.9%, P=0.03] and E/e' [1.4%, P=0.009]), and arterial function (arterial elastance [2.1%, P=0.002] and systemic arterial compliance [1.5%, P=0.007]), each explained only a small additional portion of the variance in peak oxygen consumption.ConclusionsIn heart failure with preserved ejection fraction, potentially modifiable factors (obesity, anemia, and chronotropic incompetence) are strongly associated with exercise capacity, whereas resting measures of ventricular and vascular structure and function are not.Clinical trial registration urlhttp://www.clinicaltrials.gov. Unique identifier: NCT00763867.
| S-EPMC4119596 | biostudies-literature
Project description:BackgroundAtrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak VO2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF.Methods and resultsRELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. β-blocker use and chronotropic indices were also similar. Despite comparable left ventricular size and mass, AF was associated with worse systolic (lower EF, stroke volume, and cardiac index) and diastolic (shorter deceleration time and larger left atria) function compared with SR. Pulmonary artery systolic pressure was higher in AF. Patients with AF had higher N-terminal pro-B-type natriuretic peptide, aldosterone, endothelin-1, troponin I, and C-telopeptide for type I collagen levels, suggesting more severe neurohumoral activation, myocyte necrosis, and fibrosis. Peak VO2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and VE/VCO2 was higher.ConclusionsAF identifies an HFpEF cohort with more advanced disease and significantly reduced exercise capacity. These data suggest that evaluation of the impact of different rate or rhythm control strategies on exercise tolerance in patients with HFpEF and AF is warranted.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.
| S-EPMC3972021 | biostudies-literature
Project description:BackgroundLeft ventricular diastolic dyssynchrony is common in patients with heart failure with reduced ejection fraction (HFREF). Little is known however, about its pathophysiology and clinical effects. Herein is hypothesized that presence of diastolic dyssynchrony at rest or at exercise may importantly contribute to HF symptoms. The aim was to investigate the influence of diastolic dyssynchrony and its exercise-induced changes on exercise capacity in HFREF patients.MethodsPatients with stable, chronic HF, left ventricular ejection fraction < 35%, sinus rhythm and QRS ≥ 120 ms were eligible for the study. Rest and cyclo-ergometer exercise echocardiography were performed. Diastolic dyssynchrony was defined as opposing-wall-diastolic-delay ≥ 55 ms measured in tissue-Doppler imaging. Exercise capacity was assessed by peak oxygen consumption (VO2peak). Association between diastolic dyssynchrony and VO2peak was assessed in univariate regression analysis and further adjusted for possible confounders.ResultsFourty eight patients were included (aged 63.7 ± 12.2). Twenty-seven (56.25%) had diastolic dyssynchrony at rest and 13 (27%) at exercise. Twenty-two (46%) experienced a change in diastolic dyssynchrony status during exercise. In univariate models diastolic dyssynchrony at rest or at exercise were associated with lower VO2peak (beta coefficient = -3.8, p = 0.004; beta coefficient = -3.6, p = 0.02, respectively). However, the ability to restore diastolic synchronicity during exercise was associated with higher VO2peak (beta coefficient = 3.4, p = 0.04) and remained an important predictor of exercise capacity after adjustment for age and HF etiology.ConclusionsThe ability to restore diastolic synchronicity at exercise predicts exercise capacity in patients with HFREF.
| S-EPMC8747811 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of confirmed HF cases in the United States. However, there are no highly effective evidence-based treatments currently available for these patients. Inflammation correlates positively with adverse outcomes in HF patients. Interleukin (IL)-1, a prototypical inflammatory cytokine, has been implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clinical trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2) is a phase 2, 2:1 randomized, double-blind, placebo-controlled clinical trial that will test the hypothesis that IL-1 blockade with anakinra (recombinant human IL-1 receptor antagonist) improves (1) cardiorespiratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation in patients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co-primary endpoints will be placebo-corrected interval changes in peak oxygen consumption and ventilatory efficiency at week 12. In addition, secondary and exploratory analyses will investigate the effects of IL-1 blockade on cardiac structure and function, systemic inflammation, endothelial function, quality of life, body composition, nutritional status, and clinical outcomes. The D-HART2 clinical trial will add to the growing body of evidence on the role of inflammation in cardiovascular disease, specifically focusing on patients with HFpEF.
| S-EPMC5744484 | biostudies-literature
Project description:Background Exercise-induced high heart rate may impair exercise tolerance by reducing diastolic filling time and ventricular filling in heart failure with preserved ejection fraction (HFpEF). Given the importance of chronotropic response, we hypothesized that reduction in diastolic filling time because of exercise-induced increased heart rate would not impair cardiac output reserve and exercise capacity. We sought to determine the association between heart rate, diastolic filling time, hemodynamics, and exercise capacity in HFpEF. Methods and Results Patients with HFpEF (n=66) and controls without HF (n=107) underwent bicycle exercise echocardiography with simultaneous expired gas analysis to measure oxygen consumption. Diastolic filling time was assessed by the overlap time between mitral E- and A-waves (longer overlap time indicates shorter diastolic filling duration). Overlap time increased (ie, diastolic filling time shortened) in HFpEF and controls as heart rate increased with exercise, and the relationship was similar between the groups. Greater heart rate response correlated with higher cardiac output (r=0.51, P<0.0001) and oxygen consumption (r=0.50, P<0.0001) during peak exercise. Shorter diastolic filling time, as assessed by longer overlap time, was correlated with higher cardiac output (r=0.47, P<0.0001) and peak oxygen consumption (r=0.38, P=0.007), not with E/e' or right ventricular-pulmonary artery uncoupling. Longer overlap time was associated with mitral A velocity (r=0.53, P<0.0001) and left atrial booster pump strain (r=0.42, P<0.0001). Conclusions Shortening of diastolic filling interval in tandem with increased heart rate during exercise does not limit cardiac output reserve or exercise capacity in HFpEF.
| S-EPMC9333393 | biostudies-literature