Background-Arrhythmogenic ventricular remodeling is hallmarked by both reduced gap junction expression and increased collagen deposition. We hypothesized that reduced connexin43 (Cx43) expression is responsible for enhanced fibrosis in the remodeled heart, resulting in an arrhythmogenic substrate. Therefore, we investigated the effect of normal or reduced Cx43 expression on the formation of fibrosis in a physiological (aging) and pathophysiological (transverse aortic constriction [TAC]) mouse model. Methods and Results-The Cx43fl/fl and Cx43 CreER(T)/fl mice were aged 18 to 21 months or, at the age of 3 months, either TAC or sham operated and euthanized after 16 weeks. Epicardial activation mapping of the right and left ventricles was performed on Langendorff perfused hearts. Sustained ventricular arrhythmias were induced in 0 of 11 aged Cx43 fl/fl and 10 of 15 Cx43Cre-ER(T)/fl mice (PϽ0.01). Cx43 expression was reduced by half in aged Cx43 CreER(T)/fl compared with aged Cx43 fl/fl mice, whereas collagen deposition was significantly increased from 1.1Ϯ0.2% to 7.4Ϯ1.3%. Aged Cx43CreER(T)/fl mice with arrhythmias had significantly higher levels of fibrosis and conduction heterogeneity than aged Cx43CreER(T)/fl mice without arrhythmias. The TAC operation significantly increased fibrosis in control compared with sham (4.0Ϯ1.2% versus 0.4Ϯ0.06%), but this increase was significantly higher in Cx43CreER(T)/fl mice (10.8Ϯ1.4%). Discoidin domain receptor 2 expression was unchanged, but procollagen peptide I and III expression and collagen type 1␣2 mRNA levels were higher in TAC-operated Cx43HZ mice. Conclusions-Reduced cellular coupling results in more excessive collagen deposition during aging or pressure overload in mice due to enhanced fibroblast activity, leading to increased conduction in homogeneity and proarrhythmia. (Circ Arrhythm Electrophysiol. 2012;5:380-390.)Key Words: arrhythmia Ⅲ collagen Ⅲ electrophysiology mapping Ⅲ connexin43 Ⅲ fibroblast I n the heart, the highly orchestrated propagation of the electric impulse balances on the delicate interplay between excitability, cell-to-cell coupling, and architecture of myocardial tissue. An important aspect of the myocardial architecture is interstitial collagen (fibrosis), which, together with connexin43 (Cx43), determines cell-to-cell coupling in ventricular myocardium. Under normal physiological conditions, the amount of collagen between the cardiomyocytes is low (Ͻ1% of total tissue volume) but contributes to the structural organization of the heart and the anisotropic character of impulse propagation. We recently showed that, in senescent mouse hearts, collagen content was increased (200%) and Cx43 expression was decreased (50%), changes that were associated with increased inducibility of ventricular tachycardias. 1 On the other hand, when the excessive deposition of fibrosis was prevented through long-term inhibition of the renin-angiotensin-aldosterone system, the normal pattern of Cx43 expression was preserved and arrhythmia vulnerability was strongly red...

Both acute and chronic CaM/CaMKII inhibition improves conduction characteristics and enhances localization of Cx43 in the intercalated disc. In the absence of fibrosis, this reduced the susceptibility for arrhythmias.

Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca2+/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (INa-Late), all related to intracellular calcium (Ca2+) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

Whereas SkM1 gene transfer reduces the incidence of inducible VT/VF, Cx32 therapy to improve gap junctional conductance results in larger infarct size, a different VT morphology, and no antiarrhythmic efficacy.