Heart Failure with Preserved EF: Female sex-hormones and cyclic GMP-PKG Modulation of Cardiac Disease and Metabolism
Description: Heart failure (HF) affects 5-6 million American adults, with half having preserved ventricular ejection fraction (HFpEF). The prevalence of HFpEF is rising, and associated with high morbidity, hospitalization rates, and mortality. HFpEF is now recognized to engage multiple extra-cardiac defects, including vascular dysfunction and stiffening, depressed skeletal muscle metabolism, pulmonary hypertension, and renal disease. This heterogeneity has stymied efforts at treatment, and better biological-based phenotyping is needed. HFpEF is more common in elderly, predominantly female, patients, and particularly female African-Americans (73% in ARIC cohort), a population also well represented in Baltimore. The cause for this sex-bias is unknown. The Hopkins Go Red for Women Center tests the hypothesis that the sex-bias results from depressed cyclic-GMP signaling post-menopause due to loss of sex hormones. Estrogen couples to NO-cGMP and phosphodieserase (PDE)-5 regulation, so this defect can explain prior difficulties in enhancing cGMP and its effecter protein kinase G (PKG) in this population. PKG signaling can blunt maladaptive cardiac remodeling, fibrosis, improve metabolism and skeletal muscle efficiency, counter obesity and reduce inflammatory stimuli ' all components of the HFpEF syndrome. The Population Science Core leverages CARDIA, MESA and ARIC cohorts to test associations of sex-hormones and NO/NP-cGMP-signaling with cardiac structure and function changes over time and incidence of HFpEF. The Clinical Science Core extensively phenotypes HFpEF patients using sex, sex hormone status, cardiac structure and function, and biomarkers of cGMP/PKG signaling as well as metabolic parameters. Whether postmenopausal estrogen therapy alters the cGMP response to PDE5 inhibition will be tested. We will assess cGMP stimulation by natriuretic peptide. The Basic Science Core dissects key pathways regulating cGMP/PKG signaling between the sexes, focusing on novel PDEs and their engagement of the NP pathway, and role of estrogen status on cardiac and metabolic protection. Human skeletal and cardiac muscle tissue samples from Clinical Core studies are assessed to determine a biological phenotype based on cGMP-dependent molecular profiling and broad-based non-biased protein and transcript profiling. Our work will identify novel options for enhancing the cGMP/PKG cascade and determine how to best leverage these in the female population.
Funder: American Heart Association
Amount: $682,000
Funding type: research
Funder scheme: Strategically Focused Research Network
Start date: 2016-04-01
End date: 2020-03-31
Investigators: Wendy Post, Wendy Post
Institution: Johns Hopkins University School of Medicine
Funded outputs count: 18
Funder award ID: 16SFRN27870000
OpenAlex ID: G3840465623