# Metabolic Signatures of Impaired Cardiorespiratory Fitness: Correlates, Prognostic Significance and Modulation with Exercise Training

> **NIH NIH K23** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $199,800

## Abstract

Current methods to evaluate cardiovascular disease (CVD) risk are primarily based on assessments made in
the resting state, but human circulation and metabolism evolved to respond to physiologic stress. The systemic
response to exercise-induced perturbations may carry key prognostic information regarding cardiovascular
health and reserve capacity. In particular, impaired cardiorespiratory fitness, representing low peak oxygen
uptake, is a potent predictor of CVD outcomes across strata of risk. However, the extent to which impaired
cardiorespiratory fitness reciprocally influences derangements in distinct metabolic pathways remains unclear.
This application will combine two state-of-the-art techniques – advanced cardiopulmonary exercise testing
(CPET) with comprehensive gas exchange measures and high-throughput profiling of ~290 circulating
metabolites (measured at rest and peak exercise) – to deeply phenotype the metabolic responses to
incremental exercise. We postulate that impaired cardiorespiratory fitness associates with discrete metabolite
signatures, that these metabolite signatures relate to prevalent subclinical CVD traits and incident CVD
outcomes, and that these signatures are modified by aerobic exercise training. In Aim 1, we will evaluate the
metabolite signatures of impaired cardiorespiratory fitness in 3040 participants enrolled in the community-
based Framingham Heart Study. We will also analyze the relations of these metabolite signatures to clinical
risk factors, novel risk markers, subclinical disease measures, and exercise-related excursions in select
pathway biomarkers. In Aim 2, we will examine the relations of these metabolite signatures to incident CVD
and metabolic syndrome in the Framingham Heart Study, and to CVD hospitalization and death in 1040
patients in a hospital-based referral cohort. In Aim 3, we will investigate the effect of aerobic exercise training
on longitudinal changes in metabolite signatures of impaired cardiorespiratory fitness and CPET gas exchange
variables in three distinct and clinically relevant hospital-based samples (total N=60). The overarching goal of
this proposal is to evaluate the premise that the metabolic responses to exercise provide incremental
information regarding the transition from cardiometabolic risk factors to overt CVD. This research will be
accomplished in the setting of a comprehensive career development program designed to provide Dr. Nayor,
an early career investigator and cardiologist, with the skills needed to become an independent physician-
scientist in cardiovascular medicine. His long-term career goal is to use in-depth characterization of physiologic
exercise responses to identify early CVD phenotypes that will further our understanding of disease
pathogenesis and enable discovery of novel targets for prevention. An outstanding mentoring team and an
advisory committee of established scientists in the fields of exercise physiology, metabolite profiling, and
advanced ep...

## Key facts

- **NIH application ID:** 10459683
- **Project number:** 7K23HL138260-07
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Matthew G. Nayor
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $199,800
- **Award type:** 7
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459683

## Citation

> US National Institutes of Health, RePORTER application 10459683, Metabolic Signatures of Impaired Cardiorespiratory Fitness: Correlates, Prognostic Significance and Modulation with Exercise Training (7K23HL138260-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10459683. Licensed CC0.

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