Redefining catecholaminergic polymorphic ventricular tachycardia (CPVT) as a neurocardiac condition

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterised by adrenergic activity-induced sudden cardiac death. It is most often caused by mutations in the RYR2 gene encoding ryanodine receptor 2 (RyR2), which is essential for intracellular calcium handling. Research has traditionally focused on the consequences of mutations at the cardiomyocyte level. However, RyR2 is also expressed in neuronal tissue, and patients often present with clinical signs of autonomic dysfunction. Here, we assessed if there is a neuronal phenotype in this classically cardiac condition. Using the established CPVT mouse model Ryr2-R2474S, we found that RyR2 is abundantly expressed in stellate ganglia neurons (SGNs) - the adrenergic neurons that project directly to the myocardium and modulate heart function. We revealed that in isolated Ryr2-R2474S SGNs there is altered calcium homeostasis suggestive of intracellular calcium leakage, and increased neurite projections when maintained in culture. We furthermore showed that hearts of Ryr2-R2474S mice are sympathetically hyper-innervated, with an increased heterogeneity in innervation within the myocardium. This led to changes in the quantities of neurotransmitters and their metabolites within the heart, indicating increased norepinephrine turnover. CPVT may therefore be redefined as a neurocardiac disorder, with neuronal dysregulation being a prominent component of the disease. In addition to cardiomyocytes, RYR2 mutations also affect stellate ganglia neuron function and cardiac innervation, with potential implications for arrhythmogenesis, risk stratification and therapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/635037v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1494446org.highwire.dtl.DTLVardef@1218190org.highwire.dtl.DTLVardef@c11db9org.highwire.dtl.DTLVardef@8674aa_HPS_FORMAT_FIGEXP M_FIG C_FIG In wildtype hearts, activation of sympathetic neurons leads to their release of norepinephrine (NE), which binds to beta adrenergic receptors ({beta}-ARs) on the cardiomyocyte membrane. The resultant initiation of intracellular signalling cascades involving cyclic AMP (cAMP) leads to reduced inhibition of the sarcoendoplasmic reticulum (SR) calcium ATPase (SERCA) pump and consequent calcium overload in the SR. This triggers the opening of ryanodine receptor 2 (RyR2), causing SR calcium to be released into the cytoplasmic space resulting in a calcium wave which triggers contraction. In CPVT hearts, there is increased sympathetic neuron innervation of the ventricular myocardium. When cardiac sympathetic nerves are activated, there is an enhanced release of NE. This excess NE causes increased activation of {beta}-ARs and an augmented intracellular cAMP response, which in turn leads to a greater reduction of the inhibition of SERCA, augmented SR calcium overload, and a heightened propensity for spontaneous calcium leakage to trigger a calcium wave, delayed afterdepolarisations, and arrhythmias. Figure created with BioRender.com.