# Metabolic regulation of myocardial perfusion in the aging heart

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2024 · $508,368

## Abstract

PROJECT SUMMARY
Advanced age is the leading risk factor for all chronic diseases. It is associated with a host of genetic,
immunologic, and physiologic changes that contribute to progressive tissue dysfunction and an increased risk of
mortality. Although many hallmarks of aging have been identified, a key physiological feature of aging is
decreased tissue perfusion and an inability to match perfusion to the metabolic requirements of organ function.
The impacts of such deficits in perfusion are more pronounced in tissues with high oxygen demand; hence, due
to its high energy demand, the heart is particularly vulnerable to perfusion deficits. Acute increases in myocardial
demand, such as those due to increased physical activity, are met by an increase in perfusion (i.e., hyperemia).
This increase in myocardial perfusion is triggered by metabolic signals that evoke coronary vasodilation. Our
recent work shows that increases in O2 demand in cardiomyocytes modify the pyridine nucleotide redox potential
(i.e. elevates NADH:NAD) in coronary arterial smooth muscle cells, which stimulates voltage-gated K+ (Kv)
channel activity to promote vasodilation. Inhibition of this heterocellular signaling results in hypoperfusion and
acute pump failure during stress. We propose that disruption to this signaling is the key mechanism underlying
the progressive age-dependent loss of coupling between myocardial metabolism and coronary vascular tone.
Moreover, because cardiac output is essential for adequate perfusion and function of all peripheral tissues,
diminished cardiac function at high workloads (e.g., during exercise) likely contributes to widespread dysfunction
and could explain the pervasive deleterious effects of aging. Our preliminary data show that aged mice have
reduced myocardial perfusion, impaired diastolic and systolic function, and lower exercise capacity compared
with sex-matched young mice. Consistent with cardiac metabolic remodeling as an underlying cause of these
changes, recapitulating the metabolic profile of the aged significantly blunts work-dependent paracrine redox
signals to the vasculature, and suppresses the hyperemic response, consistent with a loss of redox-dependent
Kv channel stimulation. Furthermore, acute interventions that decrease cardiomyocyte carbohydrate metabolism
(ketone body infusion) rescue myocardial perfusion in aged mice. Based on these preliminary data, we
hypothesize that age-dependent changes in myocardial metabolism suppress pyridine nucleotide redox-
dependent K+ efflux in vascular smooth muscle, leading to progressive uncoupling of coronary perfusion from
myocardial workload. Accordingly, our specific aims are to: (1) delineate age-dependent changes in cardiac
metabolism, myocardial perfusion, and left ventricular function; (2) assess the impact of changes in myocardial
glucose metabolism on redox-dependent myocardial hyperemia; and (3) determine the efficacy of myocardial
metabolic interventions to prevent age-dep...

## Key facts

- **NIH application ID:** 10979015
- **Project number:** 1R01AG084688-01A1
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Bradford Guy Hill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $508,368
- **Award type:** 1
- **Project period:** 2024-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979015

## Citation

> US National Institutes of Health, RePORTER application 10979015, Metabolic regulation of myocardial perfusion in the aging heart (1R01AG084688-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979015. Licensed CC0.

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