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.arrhythmia ͉ connexin43 ͉ Purkinje fiber ͉ transgenic ͉ optical mapping E lectrical uncoupling of the murine heart by cardiac-restricted inactivation of the Connexin43 (Cx43) gap junction channel gene results in slowing of ventricular conduction velocity (CV), spontaneous ventricular arrhythmias, and sudden cardiac death (1). However, the early mortality in these conditional knockout (CKO) mice complicated mechanistic studies of arrhythmia initiation and maintenance. Therefore, by selectively breeding longer-term survivors, we recently established a subline of conditional knockout mice, termed OCKO mice, in which the Cre-dependent inactivation of Cx43 in the myocardium was temporally delayed and death from ventricular arrhythmias, although still inevitable, was correspondingly delayed on average by about a month (2). ECGs in OCKO mice during the weeks preceding their demise demonstrated that all were in normal sinus rhythm (NSR), but, surprisingly, unlike control mice, they displayed a progressive reduction in the amplitude of the QRS complex, a time-and voltage-dependent signal indicative of myocardial depolarization (2). The aim of the current study was to investigate the mechanisms through which reductions in cell-cell coupling influence cardiac electrophysiological behavior and ultimately lead to the development of ventricular tachyarrhythmias. MethodsMice. Cardiac-restricted Cx43-mutant mice have been described, as have the derivative OCKO subline, obtained by selectively breeding longer-term survivors. The OCKO mice have progressive loss of Cx43 in the ventricular myocardium without compensatory changes in the abundance of either Cx45 or Cx40 (1, 2). Control mice did not carry the Cre recombinase tr...

The Role of the Purkinje System in Defibrillation

“…to reveal its transmural course (Ono et al, 2009). Furthermore, while the endocardial network appears dense, the number of functional PMJs is far less (Morley et al, 2005). The one-dimensional cubic Hermite finite elements are only electrically connected to the myocardium at end points through gap junctions.…”

“…Currently, the number of functional PMJs is not well characterized. Although the density of the PS on the endocardium appears high, the number of penetrating segments is unknown, as is the number of PMJs that successfully transmit pulses (Morley et al, 2005). There are significant species differences in the degree of transmural penetration of terminal PS fibres.…”

Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias

“…To overcome the mismatch, there must be a reduced sink via uncoupling or an increased source via DAD synchronization between adjacent cells. Both mechanisms have been suggested to appear under conditions of gap-junctional remodeling (Morley et al, 2005) or adrenergic stimulation (Myles et al, 2012), respectively. Following this argumentation, enhanced coupling should increase the sink and may reduce the risk of arrhythmia.…”

Modelling conduction through the Purkinje ventricular junction and the short-QT syndrome associated with HERG mutation in the rabbit ventricles

“…However, remarkable differences in action potential (AP) properties between the PF and ventricular cells [1,2] may lead to abnormalities in excitation conduction through the Purkinje-ventricular junction (PVJ) and arrhythmogenic behaviour [3][4][5]. Primarily, as action potentials (APs) from PF cells are typically longer than ventricular APs, it has been suggested that dispersion of the action potential duration (APD) at the PVJ can result in unidirectional conduction block [3], triggered activity [4] and reentry [5] under both physiological and pathological conditions.…”

“…However, remarkable differences in action potential (AP) properties between the PF and ventricular cells [1,2] may lead to abnormalities in excitation conduction through the Purkinje-ventricular junction (PVJ) and arrhythmogenic behaviour [3][4][5]. Primarily, as action potentials (APs) from PF cells are typically longer than ventricular APs, it has been suggested that dispersion of the action potential duration (APD) at the PVJ can result in unidirectional conduction block [3], triggered activity [4] and reentry [5] under both physiological and pathological conditions.Computer simulations have been used previously in order to reconstruct APs in a single PF cell [6] and AP conduction in the whole fibre [7], as well as characterize electrotonic modulation of the APD dispersion at the PVJ [8]. However, the DiFrancesco-Noble model for a single rabbit PF cell [6] used in the latter simulations has been based on limited experimental data, whereas APs in ventricular cells were simulated using the Luo-Rudy model for a guinea-pig ventricular myocyte [9].…”