Examination Date

Spring 4-3-2025

Degree

Dissertation

Degree Program

Physiology

Examination Committee

Dr. Jason Gardner

Abstract

Alcohol use is a significant global health concern, ranking as the seventh

leading risk factor for mortality worldwide. Chronic, excessive alcohol

consumption contributes to over 200 diseases, including alcohol-associated

cardiomyopathy (ACM), a severe and often fatal form of heart failure. ACM is the

most common cause of nonischemic dilated cardiomyopathy and accounts for a

significant proportion of heart failure cases. Despite its clinical relevance, ACM

remains poorly understood, with limited treatment options beyond alcohol

cessation.

This dissertation investigates the pathophysiology of ACM in a preclinical,

murine model. Chronic alcohol exposure decreases myocardial contractility, drives

cardiac inflammation and fibrosis, and disrupts mitochondrial function,

accelerating heart failure progression. ACM follows a trajectory from subclinical

dysfunction to overt heart failure but remains underdiagnosed, since it is a

diagnosis of exclusion and patients often present at the end stage of the disease.

Given the limited understanding of disease reversibility, we examined

whether abstinence could restore cardiac function using a chronic+binge alcohol

exposure model. Our findings provide highly sensitive pressure-volume data that

show that abstinence can lead to substantial recovery of cardiac function following

significant alcohol-induced dysfunction. This suggests that, contrary to the traditional

view of ACM as a largely irreversible condition, alcohol cessation may

allow for functional restoration before advanced myocardial remodeling occurs.

Sex differences in ACM were also evaluated, as men are diagnosed with

ACM at disproportionately higher rates, yet women appear more susceptible to

alcohol-induced cardiac dysfunction at lower levels of exposure. Our data indicate

that female hearts exhibit distinct physiological adaptations, potentially explaining

these disparities. Additionally, we investigated the role of mitochondrial

dysfunction in ACM, assessing its contribution to impaired cardiac bioenergetics,

sex differences, and disease progression.

This work provides insights into the potential for cardiac recovery following

abstinence, the sex-specific differences in disease susceptibility, and the

mechanisms underlying ACM. Our findings highlight the need for further research

into targeted therapeutic strategies beyond alcohol cessation to mitigate, treat, and

potentially reverse ACM.

Comments

None.

Additional Files
Edavettal, Josh - Dissertation Report Form.pdf (117 kB)
Dissertation Report Form
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