All ETDs from UAB

Advisory Committee Chair

Louis J Dell'Italia

Advisory Committee Members

Robinna G Lorenz

Selvarangan Ponnazhagan

Meredith A Preuss

Chih-Chang Wei

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Mitral regurgitation (MR) is a common form of heart disease, but there are no approved medical therapies for MR or other cardiovascular conditions associated with hemodynamic volume overload (VO) and eccentric remodeling. We have previously shown that a standard heart failure treatment, ß-adrenergic system blockade (ß-RB), improves function in animal models of VO and in MR patients without attenuating the adverse eccentric hypertrophy that occurs in conjunction with VO. This paradox highlights how poorly we understand eccentric remodeling of the heart, and a better understanding of the molecular mechanisms at work in VO must be obtained before we can develop additional therapies. We have employed the aortocaval fistula (ACF) rat model of VO to elucidate how ß-RB provides functional benefit, and also to define the molecular mechanisms which underlie eccentric remodeling. We used the in vivo microdialysis technique to measure catecholamine levels in cardiac interstitial fluid of rats with ACF, and determined that the ß-blockers atenolol and propranolol attenuate further activation of the adrenergic nervous system. These medications directly protect the heart from norepinephrine toxicity, and provide an additional benefit by interrupting a feed-forward loop that would otherwise lead to additional catecholamine release. We then used whole-genome microarray profiling to categorize the changes in gene expression that occur in ACF rats at the sub-acute two week time point, and compared these animals to rats with the pressure overload of transaortic constriction (TAC), which has been more thoroughly studied. We found marked alterations in expression of extracellular matrix components, critical genes with functions in oxidative metabolism, signs of increased cell proliferation, and a downregulation of genes with key roles in cardiac function. These changes were much more extensive in ACF than TAC, suggesting that the eccentric remodeling driven by VO is a more complex process than the concentric hypertrophy of pressure overload. The combined results of our work suggest ß-RB has great potential as a medical therapy for patients with MR, and will also inform the ongoing search for additional medical therapies for cardiovascular conditions associated with VO.

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