Basic investigations on the role of connexin hemichannels as an arrhythmogenic substrate in ventricular arrhythmia

Ventricular arrhythmia is a frequent, high-mortality complication following myocardial infarction.

Current treatment options are limited and existing drugs are often ineffective, have considerable

side effects and may even be pro-arrhythmogenic, especially when coronary and/or structural heart

disease is present. Connexins form gap junctions that interconnect cardiomyocytes, and play a

crucial role in electrical conduction that coordinates myocardial contraction and cardiac pump

function. Connexins also form hemichannels, which are precursors of gap junctions with otherwise

no clearly defined physiological roles. Work of our group and others has demonstrated that

hemichannels can open in pathological conditions, including myocardial infarction. Because these

channels have little ionic selectivity and are endowed with a high single channel conductance, the

opening of a few of them may significantly alter electrical excitability and calcium ion signaling in

cardiomyocytes, thereby acting to destabilize the cardiac rhythm. As a result, hemichannels may be

a potential novel target for treating ventricular arrhythmia. The present project aims to collect

crucial experimental evidence, combined with computational modeling, to delineate the conditions

and consequences of a hemichannel contribution to arrhythmia and to determine its therapeutic

possibilities.