Lewis, Gregory D.

Background— Right 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 Results— In 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/VCO 2 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/CO 2 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/VCO 2 in patients with pulmonary hypertension and RVD. Conclusions— HFpEF 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 Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867.

Background— Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction. Methods and Results— A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (−0.29±0.28 mm Hg/mL versus +0.02±0.29, P =0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus −0.17±0.30, P =0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (ΔPWR/EDV −52±70 versus +0±40 mm Hg/s, P =0.006; ΔSW/EDV +0.3±5.8 versus −6.0±5.1 mm Hg, P =0.04). Sildenafil had no effect on pulmonary artery systolic pressure. Conclusions— In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00094302.

Background— Exercise 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 Results— Subjects 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. Conclusions— In 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— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867

Background— Atrial 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 V O 2 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 Results— RELAX 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 V O 2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and V E /V CO 2 was higher. Conclusions— AF 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 Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867.

Background— Hemodynamic assessment after volume challenge has been proposed as a way to identify heart failure with preserved ejection fraction. However, the normal hemodynamic response to a volume challenge and how age and sex affect this relationship remain unknown. Methods and Results— Sixty healthy subjects underwent right heart catheterization to measure age- and sex-related normative responses of pulmonary capillary wedge pressure and mean pulmonary arterial pressure to volume loading with rapid saline infusion (100–200 mL/min). Hemodynamic responses to saline infusion in heart failure with preserved ejection fraction (n=11) were then compared with those of healthy young (<50 years of age) and older (≥50 years of age) subjects. In healthy subjects, pulmonary capillary wedge pressure increased from 10±2 to 16±3 mm Hg after ~1 L and to 20±3 mm Hg after ~2 L of saline infusion. Older women displayed a steeper increase in pulmonary capillary wedge pressure relative to volume infused (16±4 mm Hg·L −1 ·m 2 ) than the other 3 groups ( P ≤0.019). Saline infusion resulted in a greater increase in mean pulmonary arterial pressure relative to cardiac output in women compared with men regardless of age. Subjects with heart failure with preserved ejection fraction exhibited a steeper increase in pulmonary capillary wedge pressure relative to infused volume (25±12 mm Hg·L −1 ·m 2 ) than healthy young and older subjects ( P ≤0.005). Conclusions— Filling pressures rise significantly with volume loading, even in healthy volunteers. Older women and patients with heart failure with preserved ejection fraction exhibit the largest increases in pulmonary capillary wedge pressure and mean pulmonary arterial pressure.