Mechanisms and potential therapeutic targets for ventricular arrhythmias associated with impaired cardiac calcium cycling

The close relationship between life-threatening ventricular arrhythmias and contractile dysfunction in the heart implicates intracellular calcium cycling as an important underlying mechanism of arrhythmogenesis. Despite this close association, however, the mechanisms of arrhythmogenesis attributable to impaired calcium cycling are not fully appreciated or understood. In this report we review some of the current thinking regarding arrhythmia mechanisms associated with either abnormal impulse initiation (i.e. arrhythmia triggers) or impulse propagation (i.e. arrhythmia substrates). In all cases, the mechanisms are primarily related to dysfunction of calcium regulatory proteins associated with the sarcomere. These findings highlight the broad scope of arrhythmias associated with abnormal calcium cycling, and provide a basis for a causal relationship between cardiac electrical instability and contractile dysfunction. Moreover, calcium cycling proteins may provide much needed targets for novel antiarrhythmic therapies.