(Administrative Supplement) Cardiac Perfusion, Structure, and Function across the Primary Aldosteronism Spectrum

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. In fact, the recently published FINEARTS-HF trial, a new MR antagonist Finerenone
significantly reduced the composite outcome of worsening heart failure and cardiovascular death in patients
with 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.

Grant Number: 3K23HL159279-04S1
NIH Institute/Center: NIH
Principal Investigator: Jenifer Brown