Cardiac Perfusion, Structure, and Function across the Primary Aldosteronism Spectrum

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PROJECT SUMMARY/ABSTRACT Heart failure with preserved ejection fraction (HFpEF) is a growing epidemic associated with multiple comorbidities, including hypertension. In part because of its heterogeneity, clinical trials in HFpEF have been largely disappointing to date, though the NHLBI-funded TOPCAT trial of spironolactone, a mineralocorticoid receptor (MR) antagonist, had promising results. This has prompted several ongoing NIH and industry trials of MR antagonists in HFpEF. However, the mechanisms through which MR antagonists may treat HFpEF remain poorly understood. The MR is expressed in cardiomyocytes and vascular endothelial and smooth muscle cells. Activation of the MR at these sites causes inflammation, oxidative stress, endothelial dysfunction, and fibrosis – all pathways implicated in HFpEF. Primary aldosteronism (PA) is a cause of both hypertension and disproportionate cardiovascular risk that is treated with MR antagonists, which target the underlying pathophysiology: renin-independent production of aldosterone that chronically activates the MR. Though considered rare, PA has recently been identified in up to 15-20% of apparently “essential” hypertension, with a continuum of severity ranging from subclinical to overt, paralleling blood pressure and responsiveness to MR antagonists: termed ‘subclinical PA.’ These data suggest an expanded role for MR antagonists as precision therapy in the appropriate patients. Given its prevalence in hypertension, subclinical PA may be an unrecognized mechanism of HFpEF pathogenesis and identify a patient subgroup best treated with MR antagonists. The current proposal aims to evaluate the relationship between subclinical PA and HFpEF risk and to probe the mechanism of risk using physiologic imaging techniques. Specific Aim 1 is to evaluate both the cross-sectional relationship with cardiac structure and function and the longitudinal relationship between subclinical PA and incident HFpEF in the NHLBI Atherosclerosis Risk in Communities (ARIC) cohort. Specific Aim 2 leverages the mentors’ established Adrenal and Cardiac PET registries to investigate the relationship between PA and myocardial flow reserve, a marker of vascular dysfunction and cardiovascular risk, by evaluating the effect of an MR antagonist. This research will be accomplished within a comprehensive career development plan designed to provide Dr. Brown with the skills to become an independent physician-scientist. Her long-term career goal is be an independent, R01-funded physician-scientist focused on understanding the underlying biological and hormonal mechanisms of heart failure risk, using physiologic imaging tools to identify and characterize subclinical phenotypes that can be leveraged to enrich for responsive patient populations in clinical trials, and ultimately to identify targets for heart failure prevention. An outstanding mentoring team and advisory committee of established scientists in the fields of aldosterone and vascular biology, HFpEF, state-of- the-art cardiovascular imaging, cardiovascular clinical trials, and epidemiological and biostatistical methods will guide the candidate’s transition to scientific independence over the course of the award period.