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Principal Investigator: Ravi Bharat Patel
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $671,254
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Actin Filaments><Active Follow-up><Aging><Atherosclerosis Risk in Communities><Atrial><Atrial Fibrillation><Auricular Fibrillation><Automobile Driving><Bio-Informatics><Biochemical Pathway><Bioinformatics><Biology><Blood><Blood Reticuloendothelial System><Cardiac><Cardiac Atrium><Cardiopulmonary><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell-Extracellular Matrix><Clinical><Communities><Coronary Artery Risk Development in Young Adults><Coronary Artery Risk Development in Young Adults Study><Data><Diabetes Mellitus><Dysfunction><ECM><EFRAC><Echocardiogram><Echocardiography><Ejection Fraction><Exercise Test><Extracellular Matrix><Fatty Acids><Framingham Heart Study><Functional disorder><Genetic><Genetic Diversity><Genetic Variation><Goals><Heart><Heart Atrium><Heart Vascular><Heart failure><Hospital Admission><Hospitalization><Human><Human Genetics><Hypertension><Individual><Inflammation><Intermediary Metabolism><Investigation><Joints><Left><Left Atrial Function><Left Atrium><Left atrial structure><Leg><Link><Measures><Mechanics><Metabolic><Metabolic Networks><Metabolic Pathway><Metabolic Processes><Metabolism><Methods><Microfilaments><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Multi-Ethnic Study of Atherosclerosis><Myocardium><Myofilaments><NHLBI><National Heart, Lung, and Blood Institute><Nuclear RNA><Obesity><Outcome><Participant><Pathogenesis><Pathway interactions><Patients><Pattern><Phenotype><Physiopathology><Population Heterogeneity><Predisposition><Prevention><Proteins><Proteome><Proteomics><Public Health><RNA Seq><RNA sequencing><RNAseq><Reaction><Regulation><Research Design><Rest><Risk><Risk Factors><Specific qualifier value><Specified><Study Type><Susceptibility><Syndrome><Time><Transthoracic Echocardiography><Validation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Veins><Work><active followup><adiposity><adjudication><adjudicative process and procedure><atrium><bio-informatics network><bioinformatics network><cardiac MRI><cardiac failure><cardiac magnetic resonance imaging><cardiac muscle><cardiometabolic risk><cardiovascular health><circulatory system><clinical risk><co-morbid><co-morbidity><cohort><comorbidity><corpulence><diabetes><diverse populations><driving><ethnic diversity><ethnically diverse><exercise capacity><follow up><follow-up><followed up><followup><heart muscle><heart sonography><hemodynamics><heterogeneous population><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><innovate><innovation><innovative><insight><mechanic><mechanical><metabolism measurement><metabolome><metabolomics><metabonome><metabonomics><molecular biomarker><molecular marker><molecular profile><molecular signature><mortality><multi-ethnic><multi-modality><multi-racial><multiethnic><multimodality><multiracial><pathophysiology><pathway><population diversity><preservation><prevent><preventing><proteomic signature><public health relevance><study design><therapeutic target><transcriptome sequencing><transcriptomic sequencing><validations>