PDE5A inhibitor treatment of persistent pulmonary hypertension after mechanical circulatory support.

BACKGROUND: Pulmonary hypertension (PH) secondary to left heart failure portends a poor prognosis and is a relative contraindication to heart transplantation at many centers. We tested the hypothesis that when PH persists after adequate left ventricle unloading via recent left ventricular assist device (LVAD) therapy, phosphodiesterase type 5A inhibition would decrease PH in this population. METHODS AND RESULTS: We performed an open-label clinical trial using control patients not receiving therapy. Between 1999 and 2007, 138 consecutive patients undergoing cardiac transplantation evaluation with advanced left ventricular dysfunction, an elevated pulmonary capillary wedge pressure, and PH (defined by a pulmonary vascular resistance (PVR) >3 Woods Units), were treated with LVAD therapy. Fifty-eight of these patients reduced their pulmonary capillary wedge pressure to a value <15 mm Hg (11.8+/-2.0 mm Hg from baseline 23.2+/-6.2 mm Hg) 1 to 2 weeks after LVAD implantation, but despite this improvement, the PVR of these patients was only minimally affected (5.65+/-3.00 to 5.39+/-1.78 Wood Units). Twenty-six consecutive patients from this group with persistently elevated PVR were started on oral phosphodiesterase type 5A inhibition with sildenafil and titrated to an average of dose of 51.9 mg by mouth 3 times per day. The average PVR in the sildenafil-treated group fell from 5.87+/-1.93 to 2.96+/-0.92 Wood Units (P<0.001) and the mean pulmonary artery pressure fell from 36.5+/-8.6 to 24.3+/-3.6 mm Hg (P<0.0001) and was significantly lower when compared with the 32 LVAD recipients not receiving sildenafil at weeks 12 to 15 after the initial post-LVAD hemodynamic measurements (13 to 17 weeks post-LVAD implantation). In addition, hemodynamic measurements of right ventricular function in sildenafil-treated patients was also improved compared with patients not receiving sildenafil. CONCLUSIONS: In patients with persistent PH after recent LVAD placement, phosphodiesterase type 5A inhibition in this open-label trial resulted in a significant decrease in PVR when compared with control patients.

Right ventricular failure complicating heart failure: pathophysiology, significance, and management strategies.

Right heart failure most commonly results from the complication of left heart failure (systolic or nonsystolic dysfunction) or pulmonary hypertension. Over the past decade, greater attention has been paid to the role of right ventricular failure in the morbidity and mortality associated with cardiomyopathy and pulmonary hypertension. The right ventricle is distinct from the left ventricle not only in its spatial localization, but also in its response to increased afterload and signaling mechanisms. This article discusses the role of right ventricular failure in the setting of heart failure as well as the clinical diagnosis and management of right ventricular failure.

Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type natriuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart.

OBJECTIVES: The aim of this work was to test whether acute phosphodiesterase 5 (PDE5) inhibition via sildenafil (SIL) mimics and/or potentiates cardiorenal effects of exogenous natriuretic peptide (NP) infusion. BACKGROUND: Heart failure (HF) is often accompanied by elevated NP secretion yet blunted responsiveness. Such NP resistance may, in part, relate to increased cyclic guanosine monophosphate (cGMP) catabolism by PDE5. METHODS: Dogs (n = 7) were studied before and after tachypacing-induced HF. Animals received 30-min infusion of B-type natriuretic peptide (BNP) (2 mug/kg bolus, 0.02 mug/kg/min), and on a separate day SIL (1 mg/kg, intravenous), followed by BNP (SIL + BNP). Phosphodiesterase 5 activity was measured in lung, vasculature, and kidney. RESULTS: At baseline (non-failing), BNP lowered central venous, pulmonary capillary wedge, diastolic, mean pulmonary artery, and mean arterial pressure. Sildenafil had no effects, and SIL + BNP was similar to BNP alone. In contrast, SIL lowered these pressures similarly to BNP in dogs with HF, and SIL + BNP was additive in further reducing pulmonary pressures over BNP alone. Plasma cGMP/plasma BNP ratio was markedly reduced with HF, indicating NP resistance. Sildenafil plus BNP increased this ratio in HF, but had no effect in non-failing animals. Sildenafil had no independent diuretic/natriuretic effects nor did it enhance BNP effects under baseline or HF conditions. In HF, PDE5 activity was significantly increased in the systemic and pulmonary vasculature and in the kidney. CONCLUSIONS: The PDE5 activity in systemic and pulmonary vasculature increases in HF rendering hemodynamic responses to PDE5 inhibition identical to those from BNP infusion. Natriuretic peptide desensitization in HF relates, in part, to increased PDE5 activity, supporting a therapeutic role for PDE5 inhibition.