Constitutive Intracellular Na ⁺ Excess in Purkinje Cells Promotes Arrhythmogenesis at Lower Levels of Stress Than Ventricular Myocytes From Mice With Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

Background In catecholaminergic polymorphic ventricular tachycardia (CPVT) cardiac Purkinje cells (PCs) appear more susceptible to Ca2+ dysfunction than ventricular myocytes (VMs). The underlying mechanisms remain unknown. Using a CPVT mouse (RyR2R4496C+/Cx40eGFP), we tested whether PC intracellular Ca2+ ([Ca2+]i) dysregulation results from a constitutive [Na+]i surplus relative to VMs. Methods and Results Simultaneous optical mapping of voltage and [Ca2+]i in CPVT hearts showed that spontaneous Ca2+ release (SCR) preceded pacing-induced triggered activity at subendocardial PCs. On simultaneous current-clamp and Ca2+ imaging early (EADs) and delayed (DADs) afterdepolarizations trailed SCR and were more frequent in CPVT PCs than CPVT VMs. As a result of increased activity of mutant RyR2 channels, sarcoplasmic reticulum (SR) Ca2+ load, measured by caffeine-induced Ca2+ transients, was lower in CPVT VM and PCs than respective controls (Ctrls) and SR fractional release was greater in both CPVT PCs and VMs than respective Ctrls. [Na+]i was higher in both Ctrl and CPVT PCs than VMs, whereas the density of the Na+-Ca2+ exchanger (NCX) current was not different between PCs and VMs. Computer simulations using a PC model predicted that the elevated [Na+]i of PCs promoted DADs, which were always preceded by SCR events from hyperactive RyR2 channels. Increasing [Na+]i monotonically increased DAD frequency. Confocal imaging experiments showed that post-pacing Ca2+ spark frequency was highest in intact CPVT PCs, but such differences were reversed upon saponin-induced membrane permeabilization, indicating that differences in [Na+]i played a central role. Conclusions In CPVT mice, the constitutive [Na+]i excess of PCs promotes triggered activity and arrhythmogenesis at lower levels of stress than VMs.

Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

“…In line with these results, Zmpste24 deficiency did not affect the transcript level of RyR2 (Fig. 5C), which is responsible for calcium release from the SR (12 5 C and D). We also analyzed the expression of during relaxation in each contraction-relaxation cycle.…”

The transient receptor potential melastatin 4 channel inhibitor 9‐phenanthrol modulates cardiac sodium channel

“…Cardiac Purkinje fibres play an important role in maintaining rapid impulse propagation from atrioventricular node to ventricle and in the genesis of various arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (Willis et al, ), idiopathic ventricular tachycardia (Xiao et al, ). Our previous studies indicated that I NaL in PCs displayed larger rate‐dependent property, slower decay and recovery kinetics compared with VMs (Li et al, ), and I NaL inhibition ameliorated rate‐dependent adaption of APD and effectively terminated related arrhythmias in PCs (Hou et al, ; Li et al, ).…”

Delayed afterdepolarization‐induced triggered activity in cardiac purkinje cells mediated through cytosolic calcium diffusion waves

“…To simulate the effects of isoproterenol, the maximum conductance of six channels was altered (Faber & Rudy, 2007;Gaur, Rudy, & Hool, 2009;Zhang, Wang, & Nattel, 2002). Conductance through the T-type Ca channel (I CaT ) was increased conservatively by 115% since prior studies have reported the effects of isoproterenol to increase its maximum conductance by approximately 100%-130% (Willis et al, 2016;Zhang et al, 2002). Similarly, conductance through the L-type Ca channel (I CaL ) was conservatively increased by 100% based on the reported range of 40%-180% (Faber & Rudy, 2007;Gaur et al, 2009;Willis et al, 2016).…”

“…The heterogeneous electrotonic transmission properties at Purkinjemyocardium junctions may readily facilitate propagation of triggered action potentials in PCs due to stochastic SCR events (Ben Caref, Boutjdir, Himel, & El-Sherif, 2008;Deo, Boyle, Kim, & Vigmond, 2010;Schafferhofer-Steltzer, Hofer, Huelsing, Bishop, & Pollard, 2005). Recent experimental studies in transgenic mice carrying ryanodine receptor (RyR2) mutations, typically found in catecholaminergic polymorphic ventricular tachycardia (CPVT) patients, have demonstrated that the Ca-dependent triggers of arrhythmia may originate in the Purkinje system (Cerrone et al, 2007;Kang et al, 2010;Willis et al, 2016).…”