The substrate may be structural remodeling secondary to an underlying disease process, and often includes a scar secondary to a prior MI or surgical repair, or patchy fibrosis in the setting of cardiomyopathy or hypertrophy. Changes in ion channel or transporter function and/or expression and cell to cell coupling secondary to the underlying pathology may alter the initiation or propagation of the cardiac action poten- tial. The electrophysiological substrate is dynamically influenced by a variety of factors including cardiac metabolism, electrolytes, signaling pathways and au- tonomic effects. Enhanced automaticity or abnormal automaticity causing VA may arise from subordinate pacemaker cells in the His-Purkinje system or ventricu- lar myocardium. Normal automaticity results from phase 4 spontane- ous depolarization of the transmembrane action po- tential arising from a normal resting potential, reach- ing threshold and initiating an action potential.S3.4-1,S3.4-3 An initiating current (If ) is responsible for spontaneous phase 4 depolarization in the sinus node. The rate is determined by the integration of the maximum dia- stolic potential at the end of repolarization, the slope of phase 4 depolarization, and the threshold potential. In contrast, abnormal automaticity arises from a par- tially depolarized membrane potential that is usually close to the activation potential for calcium channels in the cell membrane.S3.4-1,S3.4-3 In the acute phase of an MI or during transient ischemia, increased extracellular potassium causes partial depolarization of the resting membrane potential creating injury currents between the infarcted/ischemic tissue and healthy myocardium. These injury currents may initiate spontaneous activity. In ischemia, abnormal automaticity may occur in both CLINICAL STATEMENTS AND GUIDELINES ventricular myocytes and Purkinje fibers, and may also enhance normal automaticity in Purkinje fibers in the ischemic zone. 3.3. 