Research Project
10485467
Project Summary/Abstract This Kirschstein NRSA Predoctoral Fellowship proposal aims to train the candidate to develop an independent research career in public health genomics, using epidemiological methods to identify clinical and genetic predictors of spironolactone response in patients with heart failure with preserved ejection fraction (HFpEF). Public health genomics is an emerging field of study that uses genomic sciences, in addition to the traditional correlates of disease, to improve population health and prevent disease. The training goals in this application include: 1) enhancing genomic and epidemiological data analysis skills, 2) training in public health, and 3) professional development; all preparing the candidate for a career on the translational front of preventive and precision medicine. Given the increasing prevalence of HFpEF, together with limited evidence-based treatments, treatment of HFpEF is considered one of the current, greatest unmet needs in cardiology. Studies show spironolactone, an aldosterone receptor antagonist (ARA), has beneficial effects on cardiac fibrosis, blood pressure, and cardiac remodeling, which contribute to HFpEF pathophysiology; however, its use in HFpEF management remains underutilized because of mixed results observed in clinical trials. These mixed results have been attributable to the significant heterogeneity seen in HFpEF etiology and pathophysiology and inter-patient differences in drug response. Thus, the objective of this proposal is to identify factors and subgroups of patients most likely to respond to ARA therapy or, conversely, at the greatest risk for toxicity with ARA therapy, thus informing personalized therapy and potentially improving effectiveness and safety with spironolactone use in patients with HFpEF. To achieve the objective of this proposal, the first aim is to identify genetic variants associated with spironolactone response, both efficacy and safety, in patients with HFpEF. Data from a genome-wide association study in the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial will be used to identify these variants. The second aim is to identify clinical factors associated with spironolactone response, both effectiveness and safety, in patients with HFpEF in a real-world setting. This analysis will be done using data from the large health system?s electronic health records at the candidate?s institution, with predictors identified using LASSO penalized regression models. The results of these studies could have an impact on the management of patients with HFpEF, potentially providing new data to inform more personalized therapeutic strategies. This proposal is in line with NHLBI?s objectives: 1) to optimize treatment of HFpEF and 2) to identify phenotypic, biomarker, and molecular characteristics which predict differential responses to therapy in individuals and in different populations with cardiovascular diseases.
