Factors contributing to arrhythmogenesis in hearts with heterogeneous sympathetic innervation. Myocardial injury (e.g., myocardial infarction) or chronic hypercholesterolemia (51) will cause a spatially uneven increase in sympathetic nerve density in the heart, resulting in regional variations in release and, consequently, variations in tissue levels of sympathetic neurotransmitters. Chronic, nonuniform elevations of neurotransmitters, through alterations in the expression of L-type Ca²⁺ channels and K⁺ channels, create spatial dispersion of action potential duration. Action potential prolongation and augmented Ca²⁺ influx through L-type Ca²⁺ channels combine to increase the susceptibility to EAD- and/or DAD-triggered activity in hyperinnervated regions. If the triggered beat propagates throughout the rest of the heart, the preexisting spatial dispersion of action potential duration and, thus, myocardial refractoriness facilitate the initiation of tachyarrhythmias. Locally elevated levels of neuropeptide Y and norepinephrine may increase coronary artery tone, thereby critically reducing the coronary perfusion reserve under conditions of increased oxygen demand (e.g., physical and/or emotional stress) and causing regional ischemia, which contributes to the development of an arrhythmia.