Distinct mechanisms mediate pacemaker dysfunction associated with catecholaminergic polymorphic ventricular tachycardia mutations: Insights from computational modeling

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced ventricular arrhythmia associated with rhythm disturbance and impaired sinoatrial node cell (SANC) automaticity (pauses). Mutations associated with dysfunction of Ca²⁺-related mechanisms have been shown to be present in CPVT. These dysfunctions include impaired Ca²⁺ release from the ryanodine receptor (i.e., RyR2^R4496C mutation) or binding to calsequestrin 2 (CASQ2). In SANC, Ca²⁺ signaling directly and indirectly mediates pacemaker function. We address here the following research questions: (i) what coupled-clock mechanisms and pathways mediate pacemaker mutations associated with CPVT in basal and in response to β-adrenergic stimulation? (ii) Can different mechanisms lead to the same CPVT-related pacemaker pauses? (iii) Can the mutation-induced deteriorations in SANC function be reversed by drug intervention or gene manipulation? We used a numerical model of mice SANC that includes membrane and intracellular mechanisms and their interconnected signaling pathways. In the basal state of RyR2^R4496C SANC, the model predicted that the Na⁺-Ca²⁺ exchanger current (I_NCX) and T-type Ca²⁺ current (I_CaT) mediate between changes in Ca²⁺ signaling and SANC dysfunction. Under β-adrenergic stimulation, changes in cAMP-PKA signaling and the sodium currents (I_Na), in addition to I_NCX and I_CaT, mediate between changes in Ca²⁺ signaling and SANC automaticity pauses. Under basal conditions in Casq2^−/−, the same mechanisms drove changes in Ca²⁺ signaling and subsequent pacemaker dysfunction. However, SANC automaticity pauses in response to β–AR stimulation were mediated by I_CaT and I_Na. Taken together, distinct mechanisms can lead to CPVT-associated SANC automaticity pauses. In addition, we predict that specifically increasing SANC cAMP-PKA activity by either a pharmacological agent (IBMX, a phosphodiesterase (PDE) inhibitor), gene manipulation (overexpression of adenylyl cyclase 1/8) or direct manipulation of the SERCA phosphorylation target through changes in gene expression, compensate for the impairment in SANC automaticity. These findings suggest new insights for understanding CPVT and its therapeutic approach.