All ETDs from UAB

Advisory Committee Chair

Louis J Dell'Italia

Advisory Committee Members

Scott W Ballinger

Mark O Bevensee

Amit Gaggar

Lufang Zhou

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Mechanisms of left ventricular dysfunction in cardiac volume overload (VO) are not well understood and currently, no medical therapy exists to treat this condition. Cardiac VO is marked by eccentric remodeling and contractile dysfunction ultimately resulting in cardiac failure. Oxidative stress is implicated in the pathophysiology of heart failure and recent evidence suggests mitochondrially- produced reactive oxygen species play a role in VO. To study VO, we used a rat model of aortocaval fistula (ACF). ACF results in early diastolic stress on the left ventricle (LV) and recapitulates the progressive nature of heart failure with contractile function being initially maintained and then depressed by 6 weeks. To determine the role of mitochondrially-produced reactive oxygen species in the setting of VO, we utilized an established mitochondrially-targeted antioxidant, mitoubiquinone (MitoQ), in the ACF animal model. The following questions have been addressed in this dissertation: 1) What are the early events in VO that set forth a cycle of progressive remodeling and dysfunction? 2) Do mitochondrially-produced reactive oxygen species play a role in these events? 3) Are mitochondrially-produced reactive oxygen species a valid therapeutic target in cardiac VO both in a chronic setting? In testing these concepts, we have used a combined in vivo and in vitro approach to determine the cardiac response to VO with end points including cardiac function, cardiac remodeling, and cardiac efficiency. Our data support a causative role for mitochondrially-produced reactive oxygen species in both the acute phase of VO and in the transition to cardiac failure. These findings establish interplay between ROS production and cytoskeletal degradation that may provide a new therapeutic target to prevent progression to heart failure in VO.



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