Focal gap junction uncoupling and spontaneous ventricular ectopy

Abstract

Genetic studies in the mouse have demonstrated that conditional cardiac-restricted loss of connexin43 (Cx43), the major ventricular gap junction protein, is highly arrhythmogenic. However, whether more focal gap junction remodeling, as is commonly seen in acquired cardiomyopathies, influences the propensity for arrhythmogenesis is not known. We examined electrophysiological properties and the frequency of spontaneous and inducible arrhythmias in genetically engineered chimeric mice derived from injection of Cx43-deficient embryonic stem cells into wild-type recipient blastocysts. Chimeric mice had numerous well-circumscribed microscopic Cx43-negative foci in their hearts, comprising approximately 15% of the total surface area as determined by immunohistochemical analysis. Systolic function in the chimeric mice was significantly depressed as measured echocardiographically (19.0% decline in fractional shortening compared with controls, P < 0.05) and by invasive hemodynamics (17.6% reduction in change of pressure over time, P < 0.01). Chimeras had significantly more spontaneous arrhythmic events than controls (P < 0.01), including frequent runs of nonsustained ventricular tachycardia in some of the chimeric mice. However, in contrast to mice with conditional cardiac-resricted loss of Cx43 in the heart, no sustained ventricular tachyarrhythmias were observed. We conclude that focal areas of uncoupling in the myocardium increase the likelihood of arrhythmic triggers, but more widespread uncoupling is required to support sustained arrhythmias.

Abnormal Conduction and Morphology in the Atrioventricular Node of Mice With Atrioventricular Canal–Targeted Deletion of Alk3/Bmpr1a Receptor

“…16 The methods used to optically map the mouse heart have been described previously. 17 Briefly, hearts were isolated and perfused by the Langendorff method with warm (37°C), oxygenated (95% O 2 , 5% CO 2 ) Tyrode's solution.…”

Dysregulation of Cell Adhesion Proteins and Cardiac Arrhythmogenesis

“…Cellular uncoupling, as a result of the loss of Cx43 gap junction channels, can unmask ectopic foci or trigger arrhythmias by enhancing the generation of early after-depolarizations, which then likely initiate arrhythmias due to functional reentry. 28,31,32 The Role of N-cadherin in Stabilizing Gap Junctions in the Heart Cardiac myocytes are electrically coupled by exceptionally large gap junctions, 33 which have presumably evolved to ensure that adequate electrical conduction is always maintained within the myocardium. Gap junctions in the heart are invariably located in close proximity to points of cell-cell adhesion within intercalated discs, which is also likely an evolutionary adaptation that acts to protect the gap junction from mechanical stress.…”

GATA6 reporter gene reveals myocardial phenotypic heterogeneity that is related to variations in gap junction coupling

“…Gap junctions are dynamic structures, whose presence in the cell membrane is characterized by cycles of degradation and reassembly (5,57). Studies (12,26,62) have shown that a delicate balance between connexin synthesis and degradation must exist for proper heart function. This process may leave small numbers of myocytes unconnected to the larger myocardial tissue, and as a consequence, these Cx43-deficient myocytes would not contribute to the propagation of electrical signal in the heart.…”