# Characterization of Molecular and Physiologic Signatures of Impaired Multi-Organ System Reserve Capacity During Exercise in Heart Failure with Preserved Ejection Fraction

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $671,616

## Abstract

Project Summary/Abstract
Heart failure with preserved ejection fraction (HFpEF) comprises half of all HF, has high morbidity and is
growing in prevalence. Traditional HF therapy does not improve outcomes in HFpEF, potentially owing to
heterogeneous definitions of HFpEF itself. Societal and clinical trial definitions of HFpEF lack consensus,
relying largely on resting cardio-centric measures (e.g., hypertrophy, diastolic filling, filling pressure) and
natriuretic peptide levels. Furthermore, the cardinal manifestation of HFpEF is exertional intolerance (with or
without overt congestion), the etiology of which is frequently not captured by resting characterization. Our
group has used comprehensive cardiopulmonary exercise testing (CPET) as a quantitative probe of global
metabolic capacity (peak VO2) alongside measures of multi-organ reserve in HF. Through simultaneous
quantitation of invasive hemodynamics, blood gases, cardiac function, arterial tonometry and gas exchange
patterns during exercise in individuals with conventionally defined HFpEF, we have started to delineate
contributions of impaired cardiac, pulmonary, vascular, and peripheral musculoskeletal reserve capacity that
are not evident at rest. We further hypothesized that distinct metabolic defects underlie these findings,
identifying selected circulating metabolites associated with HF-defining phenotypes in humans and animal
models. While these preliminary studies suggest that mapping metabolic responses during exercise may
resolve phenotypic heterogeneity within HFpEF, studies addressing this approach in large populations with
well-characterized phenotypes during exercise are lacking. Here, we address this gap by characterizing
suspected HFpEF via measures of sympathetic nervous system, cardiac, vascular, and musculoskeletal
metabolic function during exercise in 1312 individuals via CPET and metabolite profiling. We hypothesize that
exercise will unmask predominant organ-specific reserve deficits representing distinct HFpEF
“pathophenotypes.” We further hypothesize that metabolic patterns associated with these pathophenotypes will
be dysregulated early in HFpEF progression, identifying targetable pathways central to HFpEF. In Aim 1, we
identify predominant organ-specific pathophenotypes in 1312 individuals with suspected HFpEF in a
prospective cohort study at our center (MGH-ExS study). In Aim 2, we identify metabolic correlates of HFpEF
pathophenotypes via targeted metabolite profiling in MGH-ExS and evaluate these metabolite-pathophenotype
associations in the community (Framingham Heart Study [FHS] 3rd Generation). In Aim 3, we test association
of metabolite- and CPET-based HFpEF pathophenotypes with long-term HF in the MGH-ExS and in the
community (Health ABC study; FHS). Our team has extensive experience in exercise physiology, HF,
metabolite profiling, and bioinformatics uniquely suited to this application. Successful completion will enhance
precision-definitions of HFpEF and wil...

## Key facts

- **NIH application ID:** 10134428
- **Project number:** 5R01HL151841-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Gregory Dyer Lewis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $671,616
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134428

## Citation

> US National Institutes of Health, RePORTER application 10134428, Characterization of Molecular and Physiologic Signatures of Impaired Multi-Organ System Reserve Capacity During Exercise in Heart Failure with Preserved Ejection Fraction (5R01HL151841-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10134428. Licensed CC0.

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