Combined effects of reduced connexin 43, depressed active generator properties and energetic stress on conduction disturbances in canine failing myocardium

Abstract

To show that reductions in connexin43 (Cx43) can contribute, in association with electrophysiological alterations identified from unipolar recordings, to conduction disturbances in a realistic model of heart failure, canines were subjected to chronic rapid pacing (240/min for 4 weeks) and progressive occlusion of the left coronary circumflex artery (LCx) by an ameroid constrictor. Alterations identified from 191 epicardial recordings included abrupt activation delay, functional block, ST segment potential elevation, and reduced maximum negative slope (-dV/dt (max)). The LCx territory was divided into apical areas with depressed conduction velocity (LCx1: 0.06 +/- 0.04 m/s, mean +/- SD) and basal areas with relatively preserved conduction (LCx2: 0.28 +/- 0.01 m/s). Subepicardial Cx43 immunoblot measurements (percent of corresponding healthy heart measurements) were reduced in LCx1 ( approximately 40%) and LCx2 ( approximately 60%). In addition, -dV/dt (max) was significantly depressed (-3.8 +/- 3.3 mV/ms) and ST segment potential elevated (23.3 +/- 14.6 mV) in LCx1 compared to LCx2 (-9.5 +/- 3.4 mV/ms and 0.3 +/- 1.4 mV). Anisotropic conduction, Cx43 and ST segment potential measurements from the left anterior descending coronary artery territory, and interstitial collagen from all regions were similar to the healthy. Thus, moderate Cx43 reduction to "clinically relevant" levels can, in conjunction with regional energetic stress and depression of sarcolemmal active generator properties, provide a substrate for conduction disturbances.

Avaliação da expressão da conexina 43 no miocárdio de cães indenes submetidos ou não à técnica de circulação extracorpórea

“…Peracchia (2003) Como mencionamos anteriormente, as arritmias podem ser observadas entre os animais submetidos à CEC (KOMTEBEDDE, 1993), sendo que tais distúrbios podem ser decorrentes da diminuição da expressão da conexina 43. Tal teoria pode ser comprovada em estudos realizados em humanos portadores de insuficiência cardíaca, nos quais foi reportado uma redução na expressão da Cx43 de 50% em relação ao valor normal (DUPONT et al, 2001;KITAMURA et al, 2002;KOSTIN et al, 2003;KOSTIN et al, 2004;FALCAO et al, 2007 Através deste estudo verificamos a importância da conexina 43 no miocárdio dos cães e pudemos perceber que a referida proteína encontra-se intimamente relacionado aos processos fisiológicos e fisiopatológicos no coração saudável ou doente. Novas pesquisas deverão ser conduzidas no intuito de se estudar melhor as alterações, tanto da conexina 43, quanto das conexinas 40 e 45 presentes no miocárdio de cães, quando da instituição da circulação extracorpórea.…”