# Causes and consequences of myocardial purine dysregulation in heart failure

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $37,520

## Abstract

Project Summary
Cardiovascular diseases (CVDs) represent the number one cause of death worldwide. Therapeutic
advancements have improved cardiac mortality rates yet these treatments and/or interventions have ultimately
increased the incidence and prevalence of Heart Failure (HF). Conditions such as hypertension, aortic
stenosis, volume overload, and dilation often present in HF lead to chronically increased demand of adenosine
triphosphate (ATP) in myocardium. During ischemic conditions in HF the ability of oxidative phosphorylation to
meet the demand for ATP is impaired with negative implications in myocardial mechanical function. In
agreement with other studies in animal models of HF, a depletion of the Total Adenine nucleotide (TAN) has
been observed by our lab, and we have likewise observed a decrease in the TAN pool in ischemic and non-
ischemic Dilated Cardiomyopathy (DCM) HF patient samples compared to age matched controls. Strikingly,
enzymes involved in purine nucleotide synthesis, degradation, and salvage pathways have been implicated in
HF conditions, yet to this day neither the causes nor the consequences of the observed myocardial purine
dysregulation described are well understood.
We hypothesize that (1) Conditions of chronically elevated ATP demand and/or impair supply that occur in HF
conditions dispose the myocardium to an imbalance in purine nucleotide metabolism pathologically depleting
the myocardium of adenine nucleotides; and (2) Metabolic changes associated with adenine nucleotide
depletion have a direct impact on the mechanical function of the heart, contributing to the inability to meet the
blood-flow demands of the periphery in HF. In the two aims, we will characterize how purine metabolism alters
bioenergetics/mechanics in the left ventricular (LV) cardiomyocyte of the failing heart using biochemistry and
mechanic assessment approaches. Using computational modeling approaches, we will test if pathological
depletion of purine pools is a primary cause of metabolic/energetic dysfunction in HF (Hypothesis 1) and test if
metabolic/energetic dysfunction (due to purine metabolism dysregulation) contributes to the inability of failing
heart to meet the blood-flow demands of the periphery (Hypothesis 2). In sum, my proposed studies are
designed to yield new insights into the linked natural history, energetic and mechanical dysfunction of the
myocardium in cardiac decompensation and heart failure, which could potentially yield new therapeutic targets
associated with the mechanical/metabolic axis.

## Key facts

- **NIH application ID:** 10067369
- **Project number:** 5F31HL149214-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Edith Jones
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,520
- **Award type:** 5
- **Project period:** 2019-08-10 → 2022-08-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067369

## Citation

> US National Institutes of Health, RePORTER application 10067369, Causes and consequences of myocardial purine dysregulation in heart failure (5F31HL149214-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10067369. Licensed CC0.

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