The effects of cytoskeletal disruption and mechanical load on cardiac conduction

Myocardial disease is often associated with altered cardiac conduction and increased incidence of arrhythmia. Underlying mechanisms responsible for changes in conduction include altered calcium handling, myocardial remodeling, and mechanically induced changes in electrophysiology. The goal of this work was to utilize optical mapping experimental techniques and genetically modified mouse models to investigate two of these mechanisms: myocardial remodeling associated with disruption of the cytoskeleton, and increased mechanical load. Optical mapping was used to image electrical conduction in the isolated mouse heart. A multi-functional tandem lens optical setup was designed and built for use with a large chip, high-speed CMOS camera. Experimental and analytical techniques were developed to image conduction in the freely beating isolated mouse heart and in cardiomyocyte monolayers. Genetically modified mice provide useful experimental models of cardiac diseases. Four murine models with targeted ablation of cytoskeletal proteins each displayed altered myocardial remodeling and impaired cardiac conduction. Ablation of vinculin and desmoplakin in the heart each resulted in disruption of intercalated disc structure, disrupted myocardial conduction, and increased incidence of arrhythmias. Ablation of enigma homolog protein (ENH) and coxsackievirus and adenovirus receptor (CAR) each resulted in disruption of conduction through the specialized cardiac conduction system, without affecting myocardial conduction. An acute increase in ventricular load has previously been shown to slow conduction in the isolated rabbit heart. In the freely beating, isolated mouse heart, we observed a similar conduction slowing with pressure loading of the left ventricle. Preliminary experiments indicate that membrane unfolding, specifically caveolae opening, may play a role in this conduction slowing by altering passive membrane electrical propertie