Modulating Arrhythmogenic Reentrant Circuits With Engineered Biomaterials
monophasic action potentials
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PublisherThe University of Arizona.
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EmbargoRelease after 01/12/2023
AbstractCardiovascular disease is one of the most common diseases in the world. Coronary artery disease increases the risk of an eventual heart failure diagnosis, and heart failure with reduced ejection fraction portends risk of reentrant arrhythmias such as monomorphic ventricular tachycardia. This tachyarrhythmia can be described as a single circuit composed of a depolarizing wavefront, an inactivated body, and a repolarizing tail that leaves an excitable gap. Though four mainstay therapies are used to treat monomorphic ventricular tachycardia and thereby decrease the risk of sudden cardiac death, an untapped opportunity lies in using an electrically insulating synthetic biomaterial to modulate the activity of the reentrant circuit without the shortcomings associated with drugs, ablation, implantable cardioverter defibrillators, and renal denervation procedures. First, the model used to recapitulate human heart failure and associated monomorphic ventricular tachycardia must undergo validation regarding the ability of the model to reproduce what is observed clinically, as well as characterization of the time-dependent remodeling process and arrhythmia incidence in the model. Second, a thorough evaluation of the infarcted myocardium in the model must be done, specifically by a novel electrophysiologic mapping parameter derived from an extremely narrow field-of-view. Third and finally, the biomaterial intervention can be evaluated in both in vitro and in vivo experiments to support or refute the hypothesized mechanism of action, the primary endpoint of ventricular repolarization prolongation, and the secondary endpoint of decreased arrhythmogenesis. The rodent model of heart failure with reduced ejection fraction was found to successfully recapitulate the prognostic factors associated with adverse ventricular remodeling, and also revealed a plateau in electrical instability and reentrant arrhythmogenesis after permanent left coronary artery ligation. Monophasic action potential amplitude was evaluated as a potential alternative to perform high resolution electroanatomic maps of the heart, but failed to produce as accurate quantification of scar burden as compared to the gold-standard bipolar voltage amplitude. Implantation of Polyglactin 910 on the epicardium of rats in heart failure produced a statistically significant increase in border region ventricular effective refractory period, and a physiologically relevant decrease in the incidence of inducible monomorphic ventricular tachycardia. These findings defend the utility of rodent models to study the electrophysiologic perturbations associated with heart failure with reduced ejection fraction. In addition, quantitative and qualitative data support the use of monophasic action potential amplitude to distinguish the three subtypes of tissue in an infarcted myocardium. Finally, a novel class of antiarrhythmic therapy may be achieved in prolonging local effective refractory period to quench the excitable gap of reentrant tachyarrhythmias.
Degree ProgramGraduate College