# Mechanism of impaired conducted vasodilation in HFpEF

> **NIH NIH F31** · AUGUSTA UNIVERSITY · 2020 · $50,520

## Abstract

PROJECT SUMMARY
 Heart Failure (HF) in the United States alone affects approximately 5.7 million individuals. It is a costly,
debilitating and deadly disease with nearly 50% mortality rate within 5 years of diagnosis. More than one-half
of all HF patients are diagnosed with HF with preserved ejection fraction (HFpEF, also known as diastolic heart
failure) for which there is no effective treatment. Our goal is to investigate the unique role of coronary
microvascular dysfunction (CMD) in the development of HFpEF, and to identify novel targets in coronary
microvessels for pharmacological prevention of left ventricle (LV) diastolic dysfunction. Our preliminary data
reveals a novel mechanistic link between CMD and LV diastolic dysfunction in HFpEF. In patients with HFpEF
and multiple rodent models of HFpEF (obese ZSF1 rats and obese db/db mice) we identify a critical deficit in
conducted vasodilation, which normally coordinates upstream coronary arteriole dilator signaling to efficiently
couple myocardial perfusion with metabolic demand. We further identify a greater expression of adenosine
kinase (ADK) in the vascular endothelial cells (EC) in both patients and animals with HFpEF. We hypothesize
that ADK inhibition augments endogenous adenosine (ADO) levels to amplify conducted vasodilation and
thereby improve LV diastolic function in HFpEF. We will test our hypothesis through pursuing the following
Specific Aims: Aim 1: Define the mechanisms of impaired conducted vasodilation in HFpEF. Using ex
vivo coronary arteriole preparations from a rat HFpEF model, the obese ZSF-1 vs. lean control rats, we will
measure conducted vasodilation and test if impaired gap junction coupling and EC Ca2+-induced
hyperpolarization spread is mediated by TNF-induced upregulation of ADK, which diminishes ADO effects in
coronary arterioles in HFpEF. Aim 2: Determine the mechanisms by which inhibition of ADK improves LV
diastolic dysfunction in HFpEF. Using non-invasive echocardiography and invasive pressure-volume
relationship measurements, as well as ex vivo Langendorff-perfused hearts and in vitro EC culture we will
determine if pharmacological ADK inhibition in the ZSF-1 rats or EC-specific genetic deletion of ADK in the
obese, db/db mice improves LV perfusion and LV diastolic function. We will test if ADK inhibition augments
conducted vasodilation and activates eNOS, which increases endogenous NO production to improve LV
perfusion and LV diastolic dysfunction in HFpEF. Proposed studies outline a novel therapeutic approach to
augment vascular ADO levels by ADK inhibition and thereby stimulate endogenous NO production at the right
place and time to ameliorate LV diastolic dysfunction in HFpEF.

## Key facts

- **NIH application ID:** 9998011
- **Project number:** 5F31HL142183-03
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Alec Christopher Davila
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-09-30 → 2021-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998011

## Citation

> US National Institutes of Health, RePORTER application 9998011, Mechanism of impaired conducted vasodilation in HFpEF (5F31HL142183-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9998011. Licensed CC0.

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