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 for the pathological calcium release, regarding the tissue origin of the arrhythmic beats that initiate ventricular tachycardia, and regarding optimal therapeutic approaches. At present, mutations in six genes involved in SR calcium release have been identified as the genetic cause of CPVT: RYR2 (encoding ryanodine receptor calcium release channel), CASQ2 (encoding cardiac calsequestrin), TRDN (encoding triadin), CALM1, CALM2 and CALM3 (encoding identical calmodulin protein). Here, we review each CPVT subtype and how CPVT mutations alter protein function, RyR2 calcium release channel regulation, and cellular calcium handling. We then discuss research and hypotheses surrounding the tissue mechanisms underlying CPVT, such as the pathophysiological role of sinus node dysfunction in CPVT, and whether the arrhythmogenic beats originate from the conduction system or the ventricular working myocardium. Finally, we review the treatments that are available for patients with CPVT, their efficacy, and how therapy could be improved in the future.

Keywords: arrhythmia; calcium; heart excitation.

Figure 1.. The sarcoplasmic reticulum (SR) calcium release complex in cardiac muscle

Pictured above are the proteins that are involved in the regulation of calcium release from the SR during excitation-contraction coupling. The ryanodine receptor type 2 (RyR2) is a large conductance calcium channel located in the junctional SR membrane that is gated by calcium influx via the L-type calcium channels (LTCC) in the cell membrane. RyR2 open probability is regulated by post-translational modifications (e.g. phosphorylation by calcium-calmodulin kinase II, CaMKII, protein kinase A, PKA), by cytosolic RyR2 binding proteins (calmodulin [CaM], immunophillins such as FK506 binding protein [FKBP]) and SR luminal proteins (calsequestrin [Casq2], triadin, junction). Casq2 forms polymers that are anchored to RyR2 and the junctional SR by triadin and junctin. CaM bound to LTCC mediates calcium-dependent inactivation of LTCC.

Figure 2.. Cellular pathogenesis of catecholaminergic polymorphic ventricular tachycardia (CPVT)

The cartoon illustrates cellular mechanisms underlying CPVT caused by the loss of calsequetrin. 1, catecholamines released during stress or exercise activates β-adrenergic receptor signalling, leading to cardiomyocyte calcium loading and enhanced sarcoplasmic reticulum (SR) Ca uptake. 2, the increased SR calcium load is a physiological response necessary for increasing cardiac output during the physiological fight or flight response (Bers, 2001). Normally, ventricular myocytes can handle the increased SR calcium load. 3, if a CPVT mutation is present, RyR2 SR calcium release channels open spontaneously during late diastole, causing unregulated ‘pathological’ SR calcium release termed ‘spontaneous calcium release events’ (SCR). 4, the rise in cytosolic calcium during the SCR activates the electrogenic sodium calcium exchanger, which generates an arrhythmogenic transient inward current. 5, this induces a cell membrane depolarization termed ‘delayed afterdepolarizations’ (DADs). 6, DADs are a well-established cellular mechanism that can then cause triggered beats that lead to ventricular arrhythmias (Priori & Corr, 1990).

Figure 3.. Summary of current hypotheses for how RyR2 mutations could lead to catecholaminergic polymorphic ventricular tachycardia

The first theory states that mutations prevent FKBP binding to RyR2. The second theory states that a mutation can lower the intra-sarcoplasmic reticulum (SR) calcium threshold needed RyR2 to open during diastole, termed ‘store overload-induced calcium release’ (SOICR). Finally, the ‘unzipping’ theory stems from the observation that the N-terminal and central domain of RyR2 interact with one another forming a tight seal. Mutations in RYR2 can affect the interaction and lead to an unzipping of the protein, making RyR2 more prone to open spontaneously.

Figure 4.. The new cardiac calsequestrin filament (Titus et al. 2019, with permission)

Pictured above is the putative structure of the cardiac calsequestrin filament. a, putative calsequestrin filament including its dimeric and tetrameric assembly. b, the filament exhibits a helical structure at the domain level. For simplicity, calsequestrin monomers are coloured by thioredoxin domain (domain I, purple; domain II, yellow; domain III, cyan). The filament is formed by an inner thioredoxin double helix (domains II and III) with an outer thioredoxin single helix (domain I) wrapped around the double helical core. Right side: The monomers are translated but remain in their dimer-forming orientation.

Figure 5.. Cardiac conduction system (CSS) targeted CASQ2 gene deletion or rescue

Cartoon showing the heart rate and ventricular arrhythmia phenotype of mice with conditional deletion or rescue of calsequestrin in the CCS. Red colour indicates functional CASQ2.