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Advisory Committee Chair

Louis Dell'Italia

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Mechanisms of left ventricular dysfunction in cardiac volume overload (VO) are not well understood and there is no medical therapy. 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 xanthine oxidase (XO) plays 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 XO in the setting of VO, we utilized an established XO inhibitor, allopurinol, 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) Does XO play a role in these events? 3) Is XO a valid therapeutic target in cardiac VO both in the acute and 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, bioenergetics, and cardiac efficiency. Our data support a causative role for XO in both the acute phase of VO and in the transition to cardiac failure. These findings establish an interplay between XO activation and bioenergetic dysfunction that may provide a new therapeutic target to prevent progression to heart failure in VO.

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