All ETDs from UAB

Advisory Committee Chair

Steven M Pogwizd

Advisory Committee Members

Xun Ai

Andrew E Pollard

Raymond E Ideker

Document Type

Thesis

Date of Award

2012

Degree Name by School

Master of Science in Biomedical Engineering (MSBME) School of Engineering

Abstract

Heart failure is associated with a high mortality due to ventricular tachycardia leading to ventricular fibrillation that could arise from impaired conduction velocity. Myocardial conduction relies on intercellular coupling maintained primarily by the gap junction protein connexin43. The objective of this research is to assess the correlation between connexin43 remodeling and altered conduction in our novel irreversible and arrhythmogenic HF large animal model that mimics human heart failure. A novel heart failure canine model was established with combined strategy of creating aortic insufficiency and aortic constriction. We measured conduction velocity in heart failure and control left ventricular epicardium (n=5, 5) with high-density grid mapping (224 sites, inter-electrode distance of 350 µm). The mapped LV tissues were formalin-fixed for immunohistochemistry and histology studies. HF dogs exhibited reduced left ventricular fractional shortening from baseline (27.2 ± 1.9% vs. 40.1 ± 4.8%, p<0.001). Holter monitoring of spontaneous rhythm showed non-sustained ventricular tachycardia up to 15 beats long. Heart failure left ventricle exhibited slowed longitudinal conduction (48.6 ± 1.0 vs. 65.4 ± 1.5 cm/s in control; p<0.01) with baseline pacing (cycle length = 300ms) and with premature stimuli the cycle length of which progressively shortened. Quantitative immunohistochemistry showed a 33% reduction in junctional connexin43 (p<0.05) in HF. Longitudinal conduction velocity was positively correlated with level of junctional connexin43 expression (p<0.05). There were no changes in transverse CV (21.3 ± 1.5 vs. 24.1 ± 1.4 cm/s, heart failure vs. control, p=NS, drive train stimuli), lateralization of connexin43, or the extent of interstitial fibrosis (2.4 ± 0.2 % vs. 1.7 ± 0.3 %,n=4,5, heart failure vs. control, p=0.82). Our novel arrhythmogenic and irreversible canine heart failure model represents a powerful tool for investigating the mechanisms and treatments of heart failure. Heart failure left ventricle exhibit reduced junctional connexin43 that contribute to slowed longitudinal conduction; these findings, suggest that modulation of connexin43 expression could be potential therapeutic approaches to improve conduction in heart failure.

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