All ETDs from UAB

Advisory Committee Chair

Steven Pogwizd

Advisory Committee Members

Jack Rogers

Donald Bers

Rodolphe Katra

Suzanne Oparil

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) School of Engineering

Abstract

Stimulation of adrenergic receptors by catecholamines is the predominant regulatory mechanism for cardiovascular performance. Many cardiovascular diseases involve changes in ß-adrenergic signaling that often lead to decreased cardiac performance, cardiac arrhythmias, and/or sudden cardiac death. This has made ß-adrenergic receptors (ß-ARs) a significant therapeutic target in cardiovascular disease. Sex differences in ß-adrenergic responsiveness have been associated with cardioprotection in females, conferring a survival benefit in female patients with heart failure (HF). The heart contains three distinct ß-ARs: ß1-, ß2-, and ß3-AR. It is not known how each ß-AR subtype contributes to the sex differences in ß-responsiveness, let alone how this changes with disease. Therefore, the goals of this project were to assess the sex differences in ß-adrenergic responsiveness in healthy, adult rabbit hearts under physiologic conditions, and determine the distinct roles of the three ß-AR subtypes. It was hypothesized that female rabbits have a reduced responsiveness to ß-adrenergic stimulation compared to males, and that the degree and type of sex differences vary with selective activation of the ß1-, ß2-, and ß3-AR subtypes. To achieve these goals, an optical mapping system was developed to simultaneously record ventricular action potentials (AP) and intracellular calcium transients (CaT) in isolated adult rabbit hearts of either sex. ß-adrenergic responsiveness was assessed by treating the hearts with the nonselective ß-agonist isoproterenol (Iso) and ß-agonists selective for each receptor subtype. Female hearts demonstrated a reduced response to Iso, largely due to sex differences in the effects of ß1- and ß3-AR, but not ß2-AR activation. Furthermore, the Iso-induced changes in APs and CaTs were associated with arrhythmic activity in the form of spontaneous calcium release and ectopic beats (EBs) which were also lower in females. Additionally, there were sex differences in the contribution of the ß-AR receptor subtypes underlying this arrhythmic activity, and higher levels of ß-AR activation (e.g. activation of more than one receptor subtype) were required for the induction of EBs. The outcomes of these studies provide a better understanding of the mechanisms of reduced ß-responsiveness in females and its cardioprotective effects, and lay the foundation for future studies in animal models of HF.

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