Sildenafil to Reduce Vascular Remodeling during Left Ventricular Assist Device Support

Project Summary Over 6.5 million individuals in the United States suffer from heart failure (HF), with the burden of this disease expected to grow over the next decade. Approximately 300,000 of these patients have advanced HF and may benefit from durable left ventricular assist device (LVAD) therapy, which can improve outcomes during advanced HF. However, despite advancements in device design that have increased survival rates, large registries of real- world cases reveal that nearly half of patients experience severe vascular adverse events, including stroke and bleeding, during prolonged contemporary LVAD support. This elevated adverse-event rate remains a major barrier to safely expanding the use and durability of LVAD therapy. Vascular remodeling or aging of the large and small blood vessels is known to promote stroke and bleeding within the general population. Critically, such remodeling is rapidly accelerated under conditions of reduced pulsatility produced by LVADs, evidenced by large vessel stiffening and fibrosis, small vessel angiodysplasia, and endothelial dysfunction. Phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, are prescribed to select LVAD patients with pulmonary hypertension and right heart failure. However, given that these agents enhance nitric oxide–cGMP signaling in platelets and vascular smooth muscle cells, leading to anti-thrombotic and anti-fibrotic effects, they may also reduce vascular remodeling and related adverse events. Consistently, we and others have noted that PDE5i are associated with reduced ischemic stroke and death during contemporary LVAD support. Moreover, our preliminary data show that sildenafil is associated with lower platelet activation, lower arterial stiffness and reduced levels of mediators of vascular remodeling and fibrosis, including angiopoietin-2 and endothelin-1. Here, based on our preliminary findings, we propose to conduct a double-blind, randomized, placebo-controlled trial to determine the effects of chronic sildenafil administration on vascular remodeling during LVAD support. After LVAD placement, patients (n=75) meeting eligibility criteria will be randomized to receive sildenafil or placebo for at least 6 months and up to 2 years. We will determine between-group differences in aortic stiffness and carotid distensibility by vascular ultrasound, angiodysplasia formation via video capsule endoscopy, and endothelial dysfunction by finger thermal recovery. Markers of pulsatility will be assessed to determine their association with vascular remodeling, and aortic wall fibrosis and differential mRNA expression will be measured in a subset of patients that undergo heart transplantation. If we determine that sildenafil can reduce vascular remodeling during LVAD, our findings will prompt its use to avert serious vasculogenic adverse events, including stroke and bleeding, thereby benefiting HF patients. Moreover, these data would provide rationale to assess other at-risk populations, such as those with hypertension and diabetes mellitus. Irrespective of the effect of sildenafil, our study will comprehensively delineate longitudinal changes in large and small vessels during contemporary LVAD support and provide proof of concept for a method to assess the effect of anti-fibrotic pharmacotherapeutics on human vascular tissue.