R01HL160761

Mechanisms of Clinical and Hemodynamic Response to Pulmonary Vasodilator Therapy in Fontan Physiology - Project Summary/Abstract

Congenital heart disease (CHD) is the leading cause of cardiovascular death in people less than 50 years of age, and most of the premature cardiovascular deaths occur in people with complex CHD. Although the Fontan operation is an effective palliation for complex CHD, it creates a unique physiology characterized by systemic venous congestion and end-organ dysfunction, which leads to premature death from circulatory failure (median survival ~40 years).

One of the mechanisms leading to this suboptimal outcome begins with impaired nitric oxide signaling, leading to endothelial dysfunction and pulmonary vascular disease (PVD), and in turn, end-organ dysfunction and death. The therapeutic benefits of chronic pulmonary vasodilator therapy for PVD in people with Fontan palliation have not been consistent across trials, and this may be related to the lack of well-defined criteria for PVD diagnosis in Fontan physiology, and lack of understanding regarding the underlying mechanisms.

Recent data show that assessment of pulmonary vascular reserve during exercise improves detection of PVD, and that impairment in pulmonary vascular reserve correlates with severity of endothelial dysfunction and end-organ dysfunction. However, it remains unclear whether pulmonary vasodilators can improve pulmonary vascular reserve in these patients, or what the mechanisms might be. Such data will be critical for the development of novel therapies for prevention and treatment of end-organ dysfunction due to PVD, an important risk factor for mortality in the Fontan population.

The long-term goal is to delay the onset of end-organ dysfunction and mortality from systemic venous congestion, through early diagnosis and treatment of hemodynamic derangements in Fontan physiology. The overall objective for this application is to determine the mechanisms by which enhancement in nitric oxide signaling might improve pulmonary vascular reserve and end-organ function in Fontan physiology.

The central hypothesis is that enhancement in nitric oxide signaling through treatment with phosphodiesterase-5 inhibition (PDE5I) will improve pulmonary vascular reserve, and endothelial and end-organ function. This hypothesis will be tested by pursuing two specific aims: (1) determine the mechanism of response to pulmonary vasodilator therapy in Fontan physiology; (2) determine the mechanism of improvement in end-organ function, aerobic capacity, and quality of life (QOL) outcomes after pulmonary vasodilator therapy.

For the first aim, 80 subjects will be randomized 1:1 to PDE5I or placebo, and invasive exercise test and peripheral artery tonometry will be performed before and after 52 weeks of therapy. For the second aim, multi-domain outcome assessment (liver, kidney, gut, aerobic capacity, and QOL metrics) will be assessed before and after therapy.

This proposal is innovative and significant as it will delineate the mechanism of response to pulmonary vasodilators, and in turn, enable targeting of these mechanisms with current and novel therapies to delay the onset of end-organ dysfunction and circulatory failure.

Mayo Clinic

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Rochester, Minnesota 559050001 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the total obligations have increased 388% from $632,301 to $3,083,947.