Fig. 2
Schematic representation of the electrical effects of sympathetic stimulation under health conditions and in the setting of sympathoexcitation. Healthy: The binding of norepinephrine (NE) or epinephrine to the β-receptor results in cAMP-mediated activation of protein kinase A (PKA). Next, PKA phosphorylates the L-type calcium channel (LTCC), promoting the influx of calcium. Simultaneously, the calcium-induced calcium release from the sarcoplasmic reticulum (SR) is also enhanced by the phosphorylation of the ryanodine receptor (RYR). Simultaneously, phospholamban is also phosphorylated, which enhances the calcium re-uptake through the sarco/endoplasmic reticulum calcium ATPase (SERCA). Lastly, PKA also phosphorylates INa and IK,s, which accommodate the faster heart rate by increasing conduction velocity and shortening repolarization, respectively. Sympathoexcitation: At the cellular level, sympathetic excitation results in the same effects as under healthy conditions. However, the increased calcium influx through the LTCC and the increased SR calcium release (due to increased calcium loading) improve contractile force, but also predispose to the development of early (EAD) or delayed afterdepolarization (DAD; an EAD is shown, a normal action potential is depicted under “healthy” for reference). These afterdepolarizations are caused by the reactivation of the LTCC during the prolonged plateau phase of the action potential or by sodium-calcium exchanger (NCX)-medicated depolarization due to spontaneous calcium release. This predisposition to the development of an early afterdepolarization is further enhanced by the stimulation of INa, and by the slower effect of sympathetic stimulation on IK,s activation, both of which cause a prolongation in action potential duration