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Emerging novel molecular targets in anti-arrhythmic therapy - Title: Emerging novel molecular targets in anti-arrhythmic therapy

Investigators GF Tomaselli (Baltimore, USA), KR Sipido ( Leuven, BE), AW Trafford (Manchester,GB), and LS Maier (Göttingen, DE) reviewed the role of ionic channels, sarcoplasmic reticulum (SR), ryanodine receptors (RyR), Na + / Ca 2+ exchanger, and Ca 2+ /calmodulin-dependent protein kinase (CaMK) on ventricular arrhythmias linked to abnormal intracellular calcium handling and therefore, to abnormal membrane afterdepolarizations.



The regulatory intracellular calcium handling system as an emerging target for anti-arrhythmic drug development.

A micro-array expression profile in a dog model of rapid pacing-induced heart failure is feasible and allows to correlate the temporal gene expression with the evolving electrophysiological derangements (prolongation of action potential duration and slowing of conduction velocity).

Heart failure is associated with abnormal SR calcium release, hyperphosphorylation of ryanodine receptors, activation of the Na + / Ca 2+ exchanger in the reverse mode, and overexpression and function of Ca MKII. Drugs that modulate the function of this calcium handling protein system may have the potential to exert antiarrhythmic effects. However, like CaMK (see figure), most of the calcium handling modulators exert their effects at various intracellular sites and cellular structures. Thus a better knowledge of these interactions is needed to develop drugs with a resultant net beneficial action. Moreover, most of our knowledge on the relationship between intracellular calcium and arrhythmogenesis linked to afterdepolarizations is based on experimental models of ventricular arrhythmias.




Since atrial arrhythmias such as atrial fibrillation are associated with abnormal SR calcium release and these can in turn be elicited by afterdepoplarizations, drugs that modulate intracellular calcium handling may have antiarrhythmic potential properties at both atrial and ventricular levels.




Emerging novel molecular targets in anti-arrhythmic therapy - Basic Science Track

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.