OBJECTIVES: This study aims to explore whether defibrillation threshold elevation could be caused by sustained recruitment of stretch-activated channels (SACs) and, if so, what are the underlying mechanisms. BACKGROUND: Clinical studies have demonstrated that patients with dilated and overloaded ventricles have elevated defibrillation threshold. Prolonged ventricular stretch has been suggested as a possible factor in defibrillation threshold elevation; however, its role remains unclear. METHODS: A two-dimensional finite-element bidomain model of ventricular defibrillation was used in the study. Retaining the geometrical parameters in the model, defibrillation dose-response curves were constructed with and without SACs to isolate the effect of stretch on shock outcome. RESULTS: Simulations demonstrate that SAC activation leads to flattening of dose-response curve and increases in defibrillation threshold and effective dose for defibrillation by 31.4% and 18.8%, respectively. Examination of the electrophysiologic properties associated with sustained SAC recruitment pinpointed the main mechanisms responsible for the decrease in defibrillation efficacy. The lower conduction velocity of the shock-induced break excitations and the more positive transmembrane potential at the end of the effective refractory period in the tissue with SACs are proposed as main reasons for defibrillation threshold elevation. CONCLUSIONS: Demonstrating the contribution of SACs to defibrillation threshold elevation identifies SACs as an attractive pharmaceutical target to reduce defibrillation threshold in patients with dilated cardiomyopathy.
OBJECTIVES: This study aims to explore whether defibrillation threshold elevation could be caused by sustained recruitment of stretch-activated channels (SACs) and, if so, what are the underlying mechanisms. BACKGROUND: Clinical studies have demonstrated that patients with dilated and overloaded ventricles have elevated defibrillation threshold. Prolonged ventricular stretch has been suggested as a possible factor in defibrillation threshold elevation; however, its role remains unclear. METHODS: A two-dimensional finite-element bidomain model of ventricular defibrillation was used in the study. Retaining the geometrical parameters in the model, defibrillation dose-response curves were constructed with and without SACs to isolate the effect of stretch on shock outcome. RESULTS: Simulations demonstrate that SAC activation leads to flattening of dose-response curve and increases in defibrillation threshold and effective dose for defibrillation by 31.4% and 18.8%, respectively. Examination of the electrophysiologic properties associated with sustained SAC recruitment pinpointed the main mechanisms responsible for the decrease in defibrillation efficacy. The lower conduction velocity of the shock-induced break excitations and the more positive transmembrane potential at the end of the effective refractory period in the tissue with SACs are proposed as main reasons for defibrillation threshold elevation. CONCLUSIONS: Demonstrating the contribution of SACs to defibrillation threshold elevation identifies SACs as an attractive pharmaceutical target to reduce defibrillation threshold in patients with dilated cardiomyopathy.
Authors: Nathalie A Vikulova; Leonid B Katsnelson; Alexander G Kursanov; Olga Solovyova; Vladimir S Markhasin Journal: J Math Biol Date: 2015-12-19 Impact factor: 2.259