Heart failure (HF) disproportionately affects the elderly who predominantly develop HF with preserved left ventricular ejection fraction (HFpEF). Neurohormonal blockade has not proven efficacious for HFpEF, and no disease-specific therapy currently exists. There is an urgent need for novel targetable pathways, and basic/translational data implicate systemic inflammation as a potential unexploited therapeutic target, although human data is limited. The objective of this application is to define the contributions of inflammatory pathways to, and identify novel causal pathways for, the development of cardiac dysfunction and overt HF in the elderly. The central hypothesis is that specific inflammatory and neurohormonal pathways will differentially predict progressive LV dysfunction and incident HF phenotype (HFpEF vs HFrEF) in late life, and that detailed longitudinal proteomic and phenotypic data will allow for discovery of novel biologic pathways and prognostic risk markers for HF. Aptamer-based proteomics provide precise quantification of 4,931 circulating proteins and unprecedented profiling of relevant inflammatory and non-inflammatory pathways. Employing rigorous epidemiologic approaches, we will combine large-scale proteomics with detailed longitudinal cardiovascular phenotyping (echo, pulse wave velocity) and prospective HF adjudication in the largely biracial Atherosclerosis Risk in Communities (ARIC) cohort to address the following specific aims: 1) To identify individual circulating proteins and protein networks that predict incident HF and HF phenotype (HFpEF vs HFrEF); 2) To determine proteins and protein networks associated with longitudinal worsening of LV diastolic and systolic function; 3) To identify candidate proteins and protein networks most likely to be mediators of progressive LV dysfunction and HF using genomic data. The contributions of the proposed research will be to clarify the role of inflammatory ? relative to neurohormonal ? pathways for HF development and to discover novel mediators of HF in late life. These contributions will be significant because by determining the importance of pathways targeted by several existing agents, our findings could rapidly translate into novel preventative interventions for HF ? an essential step to decrease HF-associated morbidity and mortality. This research proposal is fundamentally innovative in: (1) focusing on large-scale circulating proteomics to understand HFpEF pathobiology, with simultaneous assessment of inflammatory, neurohormonal, and novel pathways in a cohort at risk for HFpEF to prevent HF development; (2) integrating proteomic and genomic data to identify candidate proteins and pathways that are HF risk mediators as opposed to risk markers; and (3) assessing novel antecedents to HFpEF beyond hypertrophy and diastolic dysfunction, including impaired LV strain, pulmonary vascular dysfunction, and RV dysfunction. This project is expected to provide an original, integrated understanding of the biologic pathways promoting HFpEF, providing a conceptual framework for future mechanistic and translational studies of HFpEF pathobiology.