Gap junctions and clinical cardiology: from molecular biology to molecular medicine

Intercellular connections, and their remodelling in diseased myocardium, are determinants of the form and function of the heart on both microscopic and macroscopic scales. Altered coupling at the cellular level has effects on myocardium and the heart as a whole that are of clinical relevance, and provides a good example of how growing knowledge of molecular and cellular biology is giving insight and answers to important clinical challenges. Advances in the treatment of cardiovascular disease generally result from better understanding of pathogenesis. Although currently the subject of intense investigation, the pathological mechanisms underlying many cardiac arrhythmias remain poorly understood. This is reflected in part by the disappointing effects of conventional pharmacological agents in controlling arrhythmias, and also by the need to treat recurrent episodes of lethal ventricular tachyarrhythmias by implantation of cardioverterdefibrillators because attempts at treating the underlying mechanism have proven disappointing. It has long been known that fibrotic scarring of the myocardium plays a role in arrhythmogenesis. However, in the search for better therapeutic strategies it is becoming increasingly apparent that more subtle structural derangements of the myocardium are a key component of the arrhythmogenic substrate. This observation is supported by such clinical findings as the widely recognized association between the degree of left ventricular dysfunction and the risk of sudden arrhythmic death, and the antiarrhythmic and prognostic benefits associated with modifying post-infarction ventricular remodelling by treatment with angiotensin converting enzyme inhibitors. With changes in the architecture of the intercellular connections that must accompany the remodelling of diseased myocardium, be it in the form of hypertrophy, fibrotic scarring or dilatation (all of which are arrhythmogenic), alterations in the topology of the interactions between myocytes would be expected to affect patterns of electrical propagation.