Heart failure (HF) affects 5.7 million Americans, is associated with a 50% 5-year mortality, and disproportionately burdens African Americans (AAs), who have a 50% higher prevalence and ~80% higher incidence of HF compared to white Americans. HF with preserved LVEF (HFpEF) accounts for up to 70% of prevalent HF in AAs and has no efficacious therapy. A novel, promising, modifiable pathway underlying HFpEF involves inflammation, nitric oxide (NO) depletion, natriuretic peptides (NPs), and altered cGMP, and may be especially relevant in AAs who have greater systemic inflammation and an impaired NP response to LV wall stress compared to whites. The objective of this application is to define the contributions of comorbidity- driven inflammation with associated nitric oxide (NO) depletion, and of impaired NP response to LV wall stress, to the development of cardiac dysfunction, and the transition from asymptomatic cardiac dysfunction to overt HF in AAs. Our central hypothesis is that cardiovascular (especially hypertension, but also coronary disease, atrial fibrillation), non-cardiac (diabetes, obesity, renal dysfunction), and non-traditional (physical inactivity) HF risk factors activate inflammatory pathways which, combined with an impaired NP response to LV wall stress, exaggerate age-related progression in diastolic dysfunction and promote systolic dysfunction via depressed cGMP activity, ultimately resulting in HF. By leveraging the PI's ongoing funded project to perform echocardiography in ~800 AA participants in the Jackson Heart Study (JHS; R01HL135008), this proposal will obtain echos in the remaining ~2,000 JHS participants at the planned 4th study visit in a highly efficient manner that minimizes participant study burden. The project will also measure LV deformation on ~4,000 echos from JHS Visit 1 (20 years prior), and pathway biomarkers from Visits 1 and 4 to address the following specific aims: (1) Define the extent to which traditional and non-traditional clinical risk factors predict diastolic and systolic dysfunction in AAs; (2) Relate inflammatory pathways and NPs known to influence cGMP activity to key measures of diastolic and systolic dysfunction; (3) Determine the extent to which LV diastolic and systolic dysfunction predict incident HF in AAs. The contribution of the proposed research will be to define the temporal progression of LV dysfunction and its clinical predictors, establish the role of a novel and modifiable biologic pathway in this progression, and quantify its relation to incident HF. This contribution is significant in defining the importance of a promising biologic pathway targeted by several existing agents that could translate rapidly into preventative interventions. This proposal is fundamentally innovative in: (1) interrogating novel biological pathways and non-traditional HF risk factors as potentially underlying HFpEF; (2) focusing on an understudied population with excess burden of HF and risk factors; and (3)...