Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction

Abstract

Background-The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil. Methods and Results-Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction Ն50%, and pulmonary artery systolic pressure Ͼ40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (Ϫ42.0Ϯ13.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (ϩ69.0Ϯ19.0%) and ejection rate (ϩ17.0Ϯ8.3%), and reduced right atrial pressure (Ϫ54.0Ϯ7.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, ϩ15.8Ϯ4.5%), the pulmonary vasculature (arteriolar resistance, Ϫ71.0Ϯ8.2%), and left-sided cardiac function (wedge pulmonary pressure, Ϫ15.7Ϯ3.1%; cardiac index, ϩ6.0Ϯ0.9%; deceleration time, Ϫ13.0Ϯ1.9%; isovolumic relaxation time, Ϫ14.0Ϯ1.7%; septal mitral annulus velocity, Ϫ76.4Ϯ9.2%). Results were similar at 12 months. Conclusions-The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156636.

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

“…Originally, work from Takimoto et al6 demonstrated the beneficial effects of PDE5 inhibition showing sildenafil attenuated hypertrophy, decreased fibrosis, and restored LV relaxation kinetics in aortic‐banded mice. Several preclinical and clinical studies followed investigating various methods of preserving cGMP levels, with beneficial results 5, 9, 10, 15, 44, 45, 46. However, the sole multicenter study targeting this signaling in HFpEF, the RELAX trial (Effect of Phosphodiesterase‐5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction), reported equivocal results after testing the PDE5 inhibitor sildenafil 47.…”

Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction

“…Outcomes are worse when PH complicates left heart disease and there are no specific treatments (1)(2)(3)(4). Further, in patients with left heart disease, therapies indicated for PAH, such as prostacyclins and endothelin receptor antagonists have been unsuccessful, while phosphodiesterase type 5 inhibitors have met with mixed results (5)(6)(7)(8)(9). Therefore, a great need exists to develop targeted therapies and to identify the patient population that can benefit.…”

Clinical Phenotypes in Heart Failure With Preserved Ejection Fraction

“…Recently, treatment with sildenafil failed to reduce PA pressure or hemodynamic parameters in a HFpEF cohort 183. In contrast, a single‐center, placebo‐controlled, randomized trial reported significant improvements in PA pressure, RV function, and LV relaxation with sildenafil in patients with HFpEF and PH 184. In the absence of evidence‐based data, PDE5‐I cannot be recommended for the treatment of PH in HFpEF 185, 186, 187.…”