Reduced intercellular coupling leads to paradoxical propagation across the Purkinje-ventricular junction and aberrant myocardial activation

Abstract

Ventricular tachycardia is a common heart rhythm disorder and a frequent cause of sudden cardiac death. Aberrant cell-cell coupling through gap junction channels, a process termed gap junction remodeling, is observed in many of the major forms of human heart disease and is associated with increased arrhythmic risk in both humans and in animal models. Genetically engineered mice with cardiac-restricted knockout of Connexin43, the major cardiac gap junctional protein, uniformly develop sudden cardiac death, although a detailed electrophysiological understanding of their profound arrhythmic propensity is unclear. Using voltage-sensitive dyes and high resolution optical mapping techniques, we found that uncoupling of the ventricular myocardium results in ectopic sites of ventricular activation. Our data indicate that this behavior reflects alterations in source-sink relationships and paradoxical conduction across normally quiescent Purkinje-ventricular muscle junctions. The aberrant activation profiles are associated with wavefront collisions, which in the setting of slow conduction may account for the highly arrhythmogenic behavior of Connexin43-deficient hearts. Thus, the extent of gap junction remodeling in diseased myocardium is a critical determinant of cardiac excitation patterns and arrhythmia susceptibility.

Fig. 1.

Diminished QRS amplitude in OCKO mice. Representative three lead surface ECG (leads I, II, and III) of control (A) and OCKO (B) mice are shown.

Fig. 2.

Analysis of isolated-perfused hearts. (A–C) Representative optical maps (Left), volume conducted ECGs in sinus rhythm (Center), and volume conducted ECGS during epicardial ventricular pacing (Right) in isolated-perfused control hearts (A), OCKO hearts (B), and control hearts treated with PA at doses that decreased CV_min by 50% (C). Shown are optical maps obtained during sinus rhythm in a series of control (D) and OCKO (E) hearts.

Fig. 3.

Normal patterning of the specialized conduction system in OCKO hearts. Shown is representative LacZ staining of a CCS-lacZ heart (A) and compound transgenic CCS-lacZ/OCKO hearts (B and C).

Fig. 4.

Optical maps during endocardial pacing and ventricular tachyarrhythmias. Shown are sequential optical maps obtained from an OCKO heart obtained during sinus rhythm (A) and then during pacing of the endocardial surface of the right ventricle (B). Paired images of the right (RV) and left (LV) ventricular free walls are shown. In each image, the apex is at the bottom left and the base is at the top right. (C and D) Maps showing reentry during sustained ventricular tachycardia in two OCKO hearts.