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Principal Investigator: Gregory Dyer Lewis
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $1,396,877
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
Heart failure (HF) with preserved ejection fraction (HFpEF) represents ≈50% of HF, with limited methods for
prevention and treatment. Current approaches to detect/treat HFpEF rely on cardiac phenotypes obtained at
rest, missing reserve capacity impairments in multiple organ systems central to HFpEF that are uniquely revealed
through exercise. In the first R01 period, we performed 3117 cardiopulmonary exercise tests (CPETs) in the
Framingham Heart Study (FHS) to quantify cardiorespiratory fitness, individual exercise responses, and their
metabolomic signatures. We defined a “normal” metabolic response to exercise and reported novel measures of
impaired fitness and HF risk. Strikingly, ≈1 in 4 asymptomatic community-dwelling FHS participants displayed
fitness impairment that overlapped with individuals with hemodynamically confirmed HFpEF studied in our
clinical referral lab. Metabolites related to HFpEF physiology were also associated with exercise responses in
FHS. These results underscore a critical molecular and phenotypic overlap between clinical HFpEF and the early
stages of its development, providing a unique opportunity to define the origins of HFpEF and reveal new targets
for its screening/prevention. Proteins are potentially targetable biomarkers that provide a readout of specific
pathways relevant to multiple organs, have direct correlation with genetics, and have a well-defined process for
assay development. The hypothesis of this renewal is that molecular pathways related to precise HFpEF
phenotypes captured during exercise will specify mechanisms underlying HFpEF susceptibility long before its
usual clinical detection. We leverage 2 unique samples developed in the first period: (1) deeply-phenotyped
HFpEF patients with hemodynamic measures during CPET (MGH-ExS, N=500) and (2) FHS participants with
CPET and plasma samples at rest/peak exercise (N=1500). We will study a broad circulating proteome (>3000
proteins at rest/peak exercise) in relation to precise exercise phenotypes, in silico bioinformatics, and human
genetics to specify proteomic signatures of exercise response in 3 aims. In Aim 1, we identify pathways of organ-
specific responses to exercise in HFpEF (using the rest proteome) and their relation to subclinical phenotypes
central to HFpEF susceptibility in the community. In Aim 2, we will quantify changes in the circulating proteome
with acute exercise and evaluate how exercise-induced changes differ in the presence of HFpEF (MGH-ExS vs.
FHS) and HFpEF risk factors. In Aim 3, we measure association of proteomic signatures of HFpEF phenotypes
with incident HF and cardiovascular disease (CVD) in racially diverse primary prevention cohorts. We also
construct genetic instruments of implicated proteins (pQTLs) for association with HF/CVD in large biobanks using
Mendelian randomization. This application unites profiling of broad pathways with relevance to HFpEF with
unique, precise exercise phenotypes collected during the first grant period to resolve clinical heterogeneity in
HFpEF and to prioritize novel targets for earlier and more precise prevention. This project will provide a unique
resource for the scientific community, with all data made publicly available immediately upon completion.
Terms: <Acute><BMI><BMI percentile><BMI z-score><Bio-Informatics><Biochemical><Bioinformatics><Biological><Biological Markers><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Sample><Blood Vessels><Blood specimen><Body System><Body Tissues><Body mass index><Cardia><Cardiac><Cardiopulmonary><Cardiovascular Diseases><Cell Body><Cells><Clinical><Collection><Communities><Data><Data Bases><Databases><Detection><Development><Diagnosis><Disease><Disorder><Dysfunction><EFRAC><Ejection Fraction><Epidemiology><Exercise><Exercise Test><Exposure to><Fibrosis><Framingham Heart Study><Functional disorder><Genetic><Grant><Heart failure><Heterogeneity><Human Genetics><Impairment><Individual><Innate Immunity><Kinetics><Link><Lung><Lung Respiratory System><Measures><Mendelian randomization><Metabolic><Methods><Molecular><NIH><National Institutes of Health><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><O element><O2 element><Obesity><Organ><Organ System><Oxygen><Participant><Pathogenesis><Pathway interactions><Patients><Pattern><Persons><Phenotype><Physical activity><Physiologic><Physiological><Physiology><Physiopathology><Plasma><Plasma Serum><Predisposition><Preparation><Prevention><Primary Prevention><Process><Production><Prognosis><Proteins><Proteome><Proteomics><Pump><Quetelet index><Reporting><Research Resources><Resources><Rest><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Sampling><Site><Skeletal Muscle><Specific qualifier value><Specified><Stress><Susceptibility><Symptoms><Time><Tissues><United States National Institutes of Health><Validation><Voluntary Muscle><Work><adiposity><assay development><bio-markers><biobank><biologic><biologic marker><biomarker><biorepository><cardiac failure><cardiac preservation><cardiometabolic><cardiometabolism><cardiorespiratory fitness><cardiorespiratory health><cardiovascular disorder><clinical development><clinical heterogeneity><cohort><corpulence><cost><cost effective><data base><developmental><epidemiologic><epidemiological><fitness><gastric cardia><heart preservation><hemodynamics><impaired capacity><improved><in silico><innovate><innovation><innovative><instrument><life-style factor><lifestyle factors><metabolism measurement><metabolomics><metabonomics><novel><pathophysiology><pathway><preparations><preservation><prevent><preventing><prospective><proteomic signature><pulmonary><racial diversity><racially diverse><response><screening><screenings><sedentary><stomach cardia><tool><uptake><validations><vascular>