# Mechanism and Modulation of Sex Differences in Myocardial Steatosis Induced Left Ventricular Dysfunction

> **NIH NIH R01** · UNIVERSITY OF TEXAS ARLINGTON · 2020 · $684,167

## Abstract

Mechanism and Modulation of Sex Differences in Myocardial Steatosis Induced Left Ventricular
Dysfunction
Obesity has reached epidemic proportions world-wide, and has led to a parallel rise in the prevalence of type 2
diabetes mellitus (T2D), together with an associated risk of cardiovascular disease and death. The risk for heart
failure in obesity is greater than can be accounted for by traditional risk factors such as hypertension and
coronary artery disease. Altered substrate metabolism is thought to contribute importantly to dysfunction of the
obese and diabetic heart; however, the exact mechanism leading to dysfunction remains incompletely
understood. One increasingly popular theory involves lipid overstorage (termed steatosis) and lipotoxic injury to
cardiomyocytes. These data have been derived almost entirely using pre-clinical rodent models however, with
translational human research being far less developed. Attempts to translate this work to human subjects have
been limited to correlations in patient groups with various underlying co-morbidities. To address this major
limitation, we propose a novel and innovative food restriction model, which reproducibly causes a transient,
physiological increase in myocardial triglyceride content in young healthy individuals. This experimental
approach will provide the most controlled environment to test if myocardial steatosis is directly related to cardiac
dysfunction—independent of underlying co-morbidities. Our preliminary data suggest that when exposed to
acute lipid overstorage, men—but not premenopausal women— develop LV diastolic dysfunction. Based on this
observation we will: 1) Test the hypothesis that cardiac steatosis induced left ventricular dysfunction is sexually
dimorphic, by comparing age-matched men and premenopausal women before and after an acute fasting
intervention. 2) Test the hypothesis that estrogen is protective against cardiac steatosis-induced dysfunction, by
suppressing ovarian sex hormones with a GnRH antagonist and repeating the fasting studies with and without
estrogen add-back. 3) Test whether plasma and myocardial fatty acid composition is sexually dimorphic, by
performing comprehensive plasma and myocardial lipidomics assessment. The results will provide new and
important mechanistic insight into the independent role of myocardial steatosis and its influence on cardiac
function in otherwise healthy young human subjects. The results also promise to address the NIH mandate
focusing on the influence of sex on disease risk. Taken together, these novel and innovative studies will facilitate
paradigm-changing diagnosis and treatment approaches to reduce the burden of heart disease in obesity and
diabetes.

## Key facts

- **NIH application ID:** 9859448
- **Project number:** 5R01HL136601-03
- **Recipient organization:** UNIVERSITY OF TEXAS ARLINGTON
- **Principal Investigator:** Michael Douglas Nelson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $684,167
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859448

## Citation

> US National Institutes of Health, RePORTER application 9859448, Mechanism and Modulation of Sex Differences in Myocardial Steatosis Induced Left Ventricular Dysfunction (5R01HL136601-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859448. Licensed CC0.

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