Integrated Proteomic and Metabolomic Determinants of Left Atrial Dysfunction

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are prevalent cardiovascular syndromes of aging that frequently co-exist. Unfortunately, clinical outcomes are worse among individuals with comorbid HFpEF and AF compared with either syndrome in isolation. Although AF and HFpEF share several

common clinical risk factors, such risk factors lack the pathway-specific granularity that is essential toward identifying therapeutic targets for prevention and treatment. Over the last 6-years, our group has identified reduced left atrial (LA) mechanics as a shared upstream phenotype that predates both AF and HFpEF. Recently,

we have demonstrated that LA functional reserve (i.e., change in LA function after intravascular volume challenge) is uniquely linked to subclinical HFpEF syndromes. Despite consistent associations between LA dysfunction and cardiometabolic risk factors, how these risk factors promote LA dysfunction remains elusive.

The advent of high-throughput circulating metabolite profiling and protein quantification has presented a unique opportunity to define metabolic pathways driving LA dysfunction to illuminate its pathobiology. We have previously defined a distinct proteomic signature of LA dysfunction in prevalent HFpEF. Similarly, select

metabolites have been associated with LA dysfunction, AF, and HFpEF. Despite these early findings, several questions remain: 1) are these molecular biomarkers of LA dysfunction simply a consequence of prevalent AF/HFpEF?; 2) what is the proteomic and metabolomic signature of sensitive measures of LA function at rest

and after hemodynamic provocation?; and 3) do these associations exist in ethnically diverse populations at high joint AF and HFpEF risk? The overall goal of the proposal is to elucidate key metabolic pathways linked to LA dysfunction to determine the shared biology of AF and HFpEF among individuals at risk. Our study will leverage

multimodality measures of LA function at rest and after hemodynamic provocation in participants of the Multi- Ethnic Study of Atherosclerosis (MESA). In Aim 1, we will determine proteomic associations of LA dysfunction, incident AF, and incident HFpEF using targeted and untargeted approaches. We will validate our findings in the

Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities (ARIC) study, Coronary Artery Risk Development in Young Adults Study (CARDIA), and the HeartShare study. In Aim 2, we will determine the metabolomic signature of LA dysfunction and its association with incident AF and HFpEF in MESA, and validate

findings in CARDIA, Framingham Heart Study (FHS), a cohort of hospitalized patients who have undergone cardiopulmonary exercise testing, and the HeartShare study. In Aim 3, we will perform integrative analyses of the metabolome and proteome and its relationship with LA dysfunction, incident AF, and HFpEF. We will

determine associations of genetic variation of the most highly loaded proteins and metabolites within each network with LA dysfunction, AF, and HFpEF. Upon completion, this proposal will provide foundational insights into the pathogenesis of LA dysfunction, an upstream phenotype of the AF-HFpEF syndrome.