Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43

Abstract

Abstract-Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribute to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice with cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactivation of this gap junction channel gene and uncovered an essential role for Cx43 in the maintenance of electrical stability. Mice with cardiac-specific loss of Cx43 have normal heart structure and contractile function, and yet they uniformly (28 of 28 conditional Cx43 knockout mice observed) develop sudden cardiac death from spontaneous ventricular arrhythmias by 2 months of age. Optical mapping of the epicardial electrical activation pattern in Cx43 conditional knockout mice revealed that ventricular conduction velocity was significantly slowed by up to 55% in the transverse direction and 42% in the longitudinal direction, resulting in an increase in anisotropic ratio compared with control littermates (2.1Ϯ0.

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

“…Germline deletion of the Cx43 gene in mice leads to perinatal lethality due to developmental cardiac malformation 30 . In contrast, mice with cardiac-restricted inactivation of Cx43 are viable; however, they develop ventricular tachyarrhythmias leading to sudden cardiac death within 2 months 50,51 . Several mutations in Cx43 have previously demonstrated serious conduction abnormalities both in mouse models and in human patients 47,[52][53][54][55] .…”

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

“…In addition, Cx43, which contributes to intercellular communication and electrical coupling, is the principal component of ventricular gap‐junction proteins. Genetically engineered Cx43‐deficient (Cx43 +/− or Cx43 −/− ) mice have been reported to be markedly susceptible to ischemia‐induced ventricular tachycardia 36, 37, 38. Ando et al39 reported that increased vagal tone could prevent the loss of Cx43 during acute MI and thus exert antiarrhythmogenic effects.…”

Myocardial Morphological Characteristics and Proarrhythmic Substrate in the Rat Model of Heart Failure Due to Chronic Volume Overload

“…They found decrease in connexin43 levels in acute state of volume overload HF but when compensatory hypertrophy developed, the amount of connexin43 seemed to normalize (Goldfine et al, 1999). In any case, the absolute levels of connexin43 have to be decreased over 50% to induce significant physiological phenotype per se, as indicated by apparent normality of connexin43 heterozygous mice as well as ventricular arrhythmias leading to sudden cardiac death observed in myocardium-restricted null animals (Gutstein et al, 2001). In this respect, the 60% decreased in total amount of connexin43 found in our Western blot seems biologically sufficiently significant to form (together with changes in cell shape) a proarrhythmogenic substrate, as ventricular arrhythmias were recorded in $10% of our HF animals.…”