Sex-dependent cardiac cyclic-AMP signaling and arrhythmias in the failing heart

PROJECT SUMMARY
Heart failure (HF) with reduced ejection fraction is a leading cause of death in the US. HF is associated with
autonomic dysregulation and significant remodeling of calcium handling, excitation-contraction coupling, and
electrophysiology, which collectively lead to contractile dysfunction and increased risk of ventricular arrhythmia.
HF incidence and outcomes are strongly sex-dependent; men have a higher incidence of HF, and in patients
with non-ischemic cardiomyopathy, women display a lower arrhythmia propensity than men. The precise
mechanisms underlying these sex differences and the protection in female hearts remain unclear.
Our initial studies discovered regional- and sex-dependent differences in b-adrenergic receptor (b-AR)- cyclic
AMP (cAMP) signaling that lead to previously unrecognized functional electrophysiological differences in male
and female mice, and could act as a potential anti-arrhythmic mechanism in female hearts. By combining whole-
heart, cellular, and subcellular approaches, this project aims to uncover novel mechanisms that underlie sex
differences in b-AR-cAMP signaling, which may play a role in sex-dependent outcomes in HF. A multi-level
experimental approach will be employed, investigating at the nanoscale, cellular, and whole heart level, to
examine: 1) the structural and functional mechanisms underlying sex differences in b-AR-cAMP signaling in the
intact heart, and 2) how sex- and region-dependent sympathetic remodeling in HF impacts b-AR-cAMP signaling
and arrhythmias. We propose to collaborate with a multidisciplinary advisory team to use novel whole-heart
FRET + optical mapping, isolated myocyte experiments, biochemical approaches, and super resolution
microscopy to assess cellular and subcellular mechanisms underlying regional- and sex-differences in b-AR-
cAMP signaling. How these signaling cascades and functional outputs are remodeled in a rodent model of HF
will also be tested. Completion of this proposal will significantly advance our understanding of sex differences in
cardiac patho-physiology and may provide insight into new gender-specific therapeutic approaches.
UC Davis offers an exceptional training environment for the mentored phase of the award to achieve these
goals. Moreover, the proposed research and training plan will significantly contribute to the applicant's personal
and professional growth. The mentored phase of this award will provide an invaluable training opportunity to
develop a unique scientific and professional skillset necessary to address the goals of this proposal, as well as
prepare for independence and make the applicant a competitive candidate for faculty positions. The independent
phase of this award will provide time, and funds, to create an independent research program in cardiovascular
physiology.

Grant Number: 5K99HL171836-02
NIH Institute/Center: NIH
Principal Investigator: Jessica Caldwell