Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced cardiac channelopathy that has a high mortality in untreated patients. Our understanding has grown tremendously since CPVT was first described as a clinical syndrome in 1995. It is now established that the deadly arrhythmias are caused by unregulated 'pathological' calcium release from the sarcoplasmic reticulum (SR), the major calcium storage organelle in striated muscle. Important questions remain regarding the molecular mechanisms that are responsible Matthew Wleklinski is an MD/PhD student interested in studying how mutations in calcium handling proteins lead to cardiac arrhythmias and sudden death. His current work focuses on the protein calsequestrin and its role in catecholaminergic polymorphic ventricular tachycardia. Dr

The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes

“…Major changes become obvious under β-adrenergic stimulation, including diminished Ca 2+ transient amplitude and, importantly, the incidence of spontaneous diastolic Ca 2+ waves that drive EADs and DADs [15,41]. More direct treatment strategies targeting the RyR2 macromolecular complex that have been successfully tested using animal models include (1) pharmacological inhibition of RyR2 (dantrolene [44], flecainide [81], JTV-519 [48,83]); (2) overexpression of WT form of accessory protein (i.e., CASQ) to reduce impact Calm2; CALM2 gene, mutations underlie LQT15 and phenotype overlaps with CPVT. Calm3; CALM3 gene, mutations underlie LQT16 and CPVT6.…”

“…Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant arrhythmogenic disorder, manifesting as polymorphic or bidirectional VT after emotional stress or exercise in patients with structurally normal hearts [ 15 , 82 ]. Mutations linked to CPVT are typically associated with gain of function of RyR2 SR Ca 2+ release complex that promotes arrhythmogenic spontaneous SR Ca 2+ release (Fig.…”

“…CPVT types 2 and 5 are caused by mutations in SR luminal proteins calsequestrin (CASQ2) and triadin (TRDN) respectively [ 15 ], and characterized by loss of control of RyR2 complex activity by luminal Ca 2+ . Mutations in calmodulin (Calm) 1 and 3 (underlying CPVT types 4 and 6, respectively) and more recently Calm2, which tether to RyR2 at the cytosolic side, interfere with the complex responsiveness to activation by cytosolic Ca 2+ [ 82 ]. CPVT type 3 has been linked to mutations in trans-2,3-enoyl-CoA reductase-like (TECRL) [ 24 , 59 ], an enzyme residing primarily in the SR, but the mechanism of action is yet to be defined.…”

Genetic Variants as Sudden-Death Risk Markers in Inherited Arrhythmogenic Syndromes: Personalized Genetic Interpretation

“…Nine genes are associated with CPVT ( Figure 1 ), and genetic alteration (noncommon variants and CNV) is a potential cause in almost 65% of cases, although 60% of cases are attributed to rare nonsynonymous variants in the cardiac ryanodine receptor ( RYR2 ) [ 20 ]. Current guidelines recommend analysis of RYR2 in CPVT diagnosis [ 10 ].…”

Cardiac regulatory mechanisms: from cardiac mechanisms to novel therapeutic approaches

“…signalling as an arrhythmia mechanism. The authors discuss the molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia, a genetic arrhythmia disorder in which ventricular tachycardia is caused by aberrant calcium signalling (Wleklinski et al 2020). Christopher Johnson then reviews how the cardiac Na + channels are regulated by calcium, and what can go wrong in heart disease (Johnson, 2020).…”