Cellular pharmacology of cardiac automaticity and conduction: Implications in antiarrhythmic drug assessment

Abstract

Cardiac automaticity (the spontaneous or automatic generation of cardiac impulses) and conduction (propagation of cardiac impulses) are fundamental to the underlying periodicity and rhythmicity of heartbeats. Cardiac arrhythmias occur when the normal succession of impulse generation and/or its propagation becomes disrupted. Significant abnormalities in the cardiac conduction system, whether inherited or acquired structural/functional, if not successfully remedied will predispose to arrhythmias acutely (e.g., sudden cardiac death) and/or chronically (e.g., atrial fibrillation), the latter of which then predispose to various cardiovascular diseases. Advancements in pharmacogenomics have enabled considerable delineation of the molecular/cellular players underlying both normal and abnormal automaticity and conduction. This has, for example, in the sinoatrial node (SAN), led to the realization of intricate workings of the ensemble of ion channels, exchangers, and pumps constituting a coupled sarcolemmal membrane and calcium cycling clock that provide for a robust yet tunable normal intrinsic impulse generation and likewise has led to the realization of how myocardial injury, disease, and channelopathies affect such molecular/cellular ensembles and give rise to automaticity and conduction abnormalities responsible for life disparaging or life-threatening arrhythmias. Increased understanding via drug-target interaction mechanisms and multiple experimental animal models has enabled detailed investigations into the various cellular signaling systems involved in modulating automaticity, and conduction has vastly expanded drugable targets. Accordingly expanded is the potential for developing novel antiarrhythmic drugs that are more regionally specific, can effectively target ensembles rather than single players involved in aberrant automaticity/conduction by acting upstream, and can attenuate or possibly even reverse the remodeling processes that produce arrhythmogenic substrates. This chapter will detail how these recent advancements in cellular/molecular basis of cardiac automaticity and conduction as well as their physiological and pathophysiological modulation now lend itself to improved antiarrhythmic drug assessment and therapies.