PDE5 INHIBITION AS ADJUNCTIVE MEDICAL THERAPY IN AORTIC STENOSIS

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DESCRIPTION (provided by applicant): This proposal describes a 3-year research and training program that will allow Dr. Brian Lindman to develop into an independent clinical translational investigator with a focus on calcific aortic stenosis (AS). The unmet scientific and clinical needs for AS were what ignited Dr. Lindman's desire to pursue an investigator path. The emphasis of the award application is Dr. Lindman's development as an investigator who will be able to advance our understanding of the pathophysiology of AS, identify novel and promising targets for medical therapy, and design and execute proof of concept clinical trials with surrogate endpoints that pave the way for larger trials with clinical endpoints. The research aims, career development activities, and mentorship team have been designed to fill particular educational and experiential gaps in Dr. Lindman's training. Career Goals: * To become a productive, independent clinical translational investigator who makes a significant contribution to our understanding of AS, with the intent of changing our clinical practice in ways that improve patient outcomes. * To elucidate the adverse impact of and mechanisms contributing to ventricular and vascular remodeling in patients with AS. * To identify and test novel medical therapies for AS Environment and Career Development Plan. At an institutional level and specifically within the cardiovascular division, Washington University provides an incredibly rich and supportive intellectual and collaborative research environment with ample resources and opportunities available for Dr. Lindman to successfully accomplish his research and career development goals. The mentorship team represents a multidisciplinary group of individuals specifically chosen to complement one another with the PI's particular scientific and career development goals carefully considered. The primary mentor is Douglas Mann, MD, an internationally recognized expert in heart failure, who has a long track record of translating basic science discoveries into clinical trials and identifying novel targets for therapy. The Institute for Clinial and Translational Sciences (CTSA funded) provides extensive opportunities for collaboration, has energized clinical and translation research at Washington University, and provides numerous core facilities to streamline research activity. The career development plan includes coursework, conferences, and several tailored practical learning experiences combined with specific activities to apply the knowledge gained. Collectively, these should complement the research aims to address gaps in the PI's training and knowledge to enable him to pursue his research studies independently. Research plan. The focus of the management and treatment of AS has traditionally been limited to the valve, causing us to often treat the valve rather than the patient. However, it is nw clear that maladaptive remodeling in the ventricle and vasculature contribute substantially to the morbidity and mortality of the disease. Emerging preclinical and clinical data suggest that phosphodiesterase type 5 (PDE5) inhibition may help in this regard. During the recent period of KL2 support, the PI made the novel observation that a single dose of a PDE5 inhibitor is safe and well-tolerated in patients with severe AS and is associated with acute improvements in pulmonary and systemic hemodynamics, resulting in biventricular unloading. This finding raises the interesting possibility that PDE5 inhibitors may be useful as adjunctive medical therapy in AS by unloading the left and right ventricles, improving abnormal hemodynamics, and stabilizing heart failure symptoms prior to more definitive therapies for AS. In this application, the PI proposes to build upon the findings of the single-dose study by conducting two longer term clinical studies that are intended to explore the possibility that adjunctive medical therapy with PDE5 inhibition will improve clinical outcomes in patients with AS. The proposed studies will test the role of PDE5 inhibition in patients with AS using surrogate endpoints, laying the foundation for future studies evaluating patient-centered, clinical endpoints. Aim 1 will evaluate short-term (2 weeks) PDE5 inhibition in patients with symptomatic AS to see whether it can provide sustained hemodynamic benefits, which could serve as a stabilizing bridge to definitive therapy with valve replacement. Aim 2 will evaluate chronic (6 months) PDE5 inhibition in patients with asymptomatic AS to see whether this therapy could decrease hypertrophic cardiac remodeling and improve ventricular function, which may delay symptom onset and prepare the ventricle better for surgery. Aim 3 will evaluate a novel MRI sequence to assess cardiac fibrosis, which may improve our risk stratification of patients with AS and provide a non- invasive tool for assessing the response to anti-fibrotic therapies. The proposed studies combined with the planned career development activities will prepare the PI to pursue future clinical studies evaluating adjunctive medical therapy in the treatment of AS independently, employing PDE5 inhibitors and other emerging therapies.