A rat model of complete atrioventricular block recapitulates clinical indices of bradycardia and provides a platform to test disease-modifying therapies

Nam Kyun Kim,David Wolfson,Natasha Fernandez,Minji Shin,Hee Cheol Cho

doi:10.1038/s41598-019-43300-9

Abstract

Complete atrioventricular block (CAVB) is a life-threatening arrhythmia. A small animal model of chronic CAVB that properly reflects clinical indices of bradycardia would accelerate the understanding of disease progression and pathophysiology, and the development of therapeutic strategies. We sought to develop a surgical model of CAVB in adult rats, which could recapitulate structural remodeling and arrhythmogenicity expected in chronic CAVB. Upon right thoracotomy, we delivered electrosurgical energy subepicardially via a thin needle into the atrioventricular node (AVN) region of adult rats to create complete AV block. The chronic CAVB animals developed dilated and hypertrophied ventricles with preserved systolic functions due to compensatory hemodynamic remodeling. Ventricular tachyarrhythmias, which are difficult to induce in the healthy rodent heart, could be induced upon programmed electrical stimulation in chronic CAVB rats and worsened when combined with β-adrenergic stimulation. Focal somatic gene transfer of TBX18 to the left ventricular apex in the CAVB rats resulted in ectopic ventricular beats within days, achieving a de novo ventricular rate faster than the slow atrioventricular (AV) junctional escape rhythm observed in control CAVB animals. The model offers new opportunities to test therapeutic approaches to treat chronic and severe CAVB which have previously only been testable in large animal models.

Highlights

Complete atrioventricular block (CAVB) is a major cardiac conduction disorder, in which the transmission of an electrical impulse from the atria to the ventricles is completely inhibited[1,2,3]
We sought to develop a rodent model of CAVB that requires only a routine set of surgical instrumentation, yields a high success rate in 6-month old female rats, persists long-term (4 weeks), and recapitulates ventricular arrhythmias that are often manifested in CAVB patients[25]
We sought to reverse the severe CAVB-induced ventricular bradycardia by focal somatic gene transfer of TBX18-injected animals (TBX18), a concept we have previously demonstrated for converting chamber cardiomyocytes to induced pacemaker cells[12,26,27]

Summary

Introduction

Complete atrioventricular block (CAVB) is a major cardiac conduction disorder, in which the transmission of an electrical impulse from the atria to the ventricles is completely inhibited[1,2,3]. Direct intramyocardial delivery of TBX18 into the left ventricular apex of chronic CAVB rats revealed emergence of ectopic ventricular beats at a rate higher than the slow AV junctional rhythm of the control animals.

Results

Conclusion