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 Table of Contents  
Year : 2021  |  Volume : 33  |  Issue : 4  |  Page : 323-331

The link between abnormalities of calcium handling proteins and catecholaminergic polymorphic ventricular tachycardia

1 School of Medicine, Tzu Chi University, Hualien, Taiwan
2 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
3 Master Program in Medical Physiology, School of Medicine; Department of Physiology, School of Medicine, Tzu Chi University, Hualien, Taiwan

Date of Submission03-Dec-2020
Date of Decision09-Feb-2021
Date of Acceptance03-Mar-2021
Date of Web Publication14-May-2021

Correspondence Address:
Kun-Ta Yang
Department of Physiology, School of Medicine, Tzu Chi University, 701, Zhongyang Road, Section 3, Hualien
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tcmj.tcmj_288_20

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Catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare autosomal dominant or recessive disease, usually results in syncope or sudden cardiac death. Most CPVT patients do not show abnormal cardiac structure and electrocardiogram features and symptoms, usually onset during adrenergically mediated physiological conditions. CPVT tends to occur at a younger age and is not easy to be diagnosed and managed. The main cause of CPVT is associated with mishandling Ca2+ in cardiomyocytes. Intracellular Ca2+ is strictly controlled by a protein located in the sarcoplasm reticulum (SR), such as ryanodine receptor, histidine-rich Ca2+-binding protein, triadin, and junctin. Mutation in these proteins results in misfolding or malfunction of these proteins, thereby affecting their Ca2+-binding affinity, and subsequently disturbs Ca2+ homeostasis during excitation–contraction coupling (E-C coupling). Furthermore, transient disturbance of Ca2+ homeostasis increases membrane potential and causes Ca2+ store overload-induced Ca2+ release, which in turn leads to delayed after depolarization and arrhythmia. Previous studies have focused on the interaction between ryanodine receptors and protein kinase or phosphatase in the cytosol. However, recent studies showed the regulation signaling for ryanodine receptor not only from the cytosol but also within the SR. The changing of Ca2+ concentration is critical for protein interaction inside the SR which changes protein conformation to regulate the open probability of ryanodine receptors. Thus, it influences the threshold of Ca2+ released from the SR, making it easier to release Ca2+ during E-C coupling. In this review, we briefly discuss how Ca2+ handling protein variations affect the Ca2+ handling in CPVT.

Keywords: Ca2+ mishandling, Calsequestrin 2, Catecholaminergic polymorphic ventricular tachycardia, Ryanodine receptors 2, Triadin

How to cite this article:
Lin DJ, Lee WS, Chien YC, Chen TY, Yang KT. The link between abnormalities of calcium handling proteins and catecholaminergic polymorphic ventricular tachycardia. Tzu Chi Med J 2021;33:323-31

How to cite this URL:
Lin DJ, Lee WS, Chien YC, Chen TY, Yang KT. The link between abnormalities of calcium handling proteins and catecholaminergic polymorphic ventricular tachycardia. Tzu Chi Med J [serial online] 2021 [cited 2022 Aug 8];33:323-31. Available from: https://www.tcmjmed.com/text.asp?2021/33/4/323/316088

  Introduction Top

Catecholaminergic polymorphic ventricular tachycardia (CPVT), which is known as an electrical disorder, is characterized as the normal cardiac structure with normal rest electrocardiography (EKG), but drastic changes in EKG during exercise or emotion, or increases of stress. CPVT can lead to episodic syncope and sudden cardiac death[1],[2]. It has been estimated that approximately 1/10,000 people has CPVT, which is usually diagnosed in the early stage of life with an average between 2 and 21 years (usually present between 7 and 11 years)[3],[4]. The incidence of inheriting CPVT is around 30% of total patients, and it is in favor of female inheritance[3]. The majority of them are autosomal dominant (RyR2, CALM), and few of them are autosomal recessive (CASQ2, TECRL, and TRDN)[3],[4]. The severity of symptoms in CPVT patients varies from only vasovagal syncope or long QT syndrome (LQTs) with normal QT interval (QTc) to severe arrhythmia and seizure[5],[6]. Atypical cases have also been reported that some patients suffer from malignant hyperthermia, paroxysmal atrial fibrillation (AF), or sudden cardiac death during sleep[5],[6],[7].

  Diagnosis of catecholaminergic polymorphic ventricular tachycardia Top

It has been reported that CPVT can be diagnosed with various methods such as 12-lead EKG, exercise stress test, Holter monitoring, echocardiogram (for excluding structural defect), medical genetics consultation, and catecholamine or isoproterenol infusion[3],[8]. The EKG features captured on 12-lead EKG during exercise or emotional test include mono- or polymorphic couplets, nonsustained ventricular tachycardia (VT), premature ventricular contractions, polymorphic VT, polymorphic or bidirectional VT, and monomorphic ventricular extrasystoles with episodes of bigeminus[3],[9],[10]. Although the sensitivity of Holter monitor is lower than EKG, it is suitable for patients who are unable to endure adequate exercise stress[10]. The exercise stress test is the most recommended diagnostic method for CPVT[4]. It has been indicated that when heartbeat reaches around 100–120 beats/min in CPVT patients during programmed ventricular stimulation, VT, polymorphic ventricular arrhythmia, and multifocal premature ventricular contractions will be induced, polymorphic VT is less common to be induced[9]. The majority of children with CPVT have bradycardia (≤60 bpm) compared with the healthy children (around 80–100 bpm)[11]. However, if the patients or their family member experienced unexplainable adrenergic triggering syncope events, implantable loop recorders and exercise stress test on a full dose of beta-blockers should be recommended[12],[13]. The genetic test is recommended for the patient and the patient's family members who have been diagnosed with LQTs or suspected of having CPVT due to numerous reports associated with misdiagnosis of CPVT as LQTs. Letsas et al. have reported that both a 16-year-old female and her mother were previously diagnosed with LQTs and treated with implantable cardioverter-defibrillator. After the genetic test, the results showed that both of them were misdiagnosed[14]. Similar to LQTs, there are many diseases including Andersen-Tawil syndrome and arrhythmogenic right ventricular cardiomyopathy, present with similar feature of CPVT. Similar to LQTs, many diseases, including Andersen-Tawil syndrome and arrhythmogenic right ventricular cardiomyopathy, present similar feature of CPVT. Using mutational analysis, it is impossible to distinguish these three diseases, mainly because they have overlapping gene mutations. Thus, it is important to differentially diagnose them from CPVT when receiving young episodic syncope or arrhythmia patients[3],[15],[16].

  Intracellular calcium handling dysfunction and catecholaminergic polymorphic ventricular tachycardia Top

In cardiomyocytes, calcium ions (Ca2+) are mainly involved in the formation of excitation–contraction coupling (E-C coupling), which is initiated by a mechanism known as Ca2+-induced Ca2+ release. During membrane depolarizing, the action potential (AP) activates the voltage-dependent L-type Ca2+ channel (CaV1.2) in the transverse tubular (T-tubules) membrane, leading to a small Ca2+ influx[17], which in turn activates ryanodine receptor 2 (RyR2) on the sarcoplasmic reticulum (SR) membrane, thereby causing Ca2+ to be released into the cytosol. The released Ca2+ binds to troponin C, subsequently causing a cascade of conformational changes in the myofilaments, and ultimately induces muscle contraction[17]. During the relaxation phase, the released Ca2+ is pumped back to the SR by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) or extruded to the extracellular space by the Na+/Ca2+ exchanger (NCX). This event effectively lowers the cytosolic Ca2+ concentration and allows Ca2+ dislocated from the myofilaments. The mishandling of Ca2+ during E-C coupling can cause Ca2+ store overload. The overload of the SR may cause spontaneous Ca2+ release after repolarization, which is termed store overload-induced Ca2+ release. The released Ca2+ exits the cell through the 3Na+/Ca2+-exchanger, subsequently leading to delayed after depolarizations (DADs)[17],[18],[19]. There are numerous proteins related to Ca2+ handlings, such as RyR2, phospholamban (PLB or PLN), SERCA, calsequestrin 2 (CSQ2), L-type Ca2+ channels, NCX, calmodulin (CaM), Ca2+/CaM-dependent protein kinase II (CaMKII), protein kinase A (PKA), triadin, junctin, ankyrin-B, and TECRL[17],[20],[21]. It is believed that mutation or malfunction in these proteins can cause Ca2+ release from the SR prematurely or spontaneously, hence inducing both atrial arrhythmia and VA[22],[23]. The malfunction of these proteins is mostly related to the genetic mutation. These genes include RYR2 for RYR2, CASQ2 for CSQ2, CALM1, CALM2, and CALM3 for CaM, JCN for junctin, ANK2 for ankyrin B, TECRL for trans-2,3-enoyl-CoA reductase-like, and TRDN for triadin[21]. RyR2 and CASQ2 mutations account for the majority of CPVT patients which can be categorized in CPVT type 1 and CPVT type 2. RyR2 mutation alone accounts for 60% of cases[24],[25]. It has been reported that a small number of patients carrying RYR2 gene mutations displayed a LQTs phenotype or an overlapping phenotype of LQTs and CPVT[26],[27]. Further, mutation of TECRL can cause CPVT type 3, which presents a mixed phenotype of CPVT and LQTs[27]. CPVT types 4 and 5 are considered as minority and account for <1% of CPVT cases[3]. CPVT type 4, the result of ANK2 and CALM gene mutations, starts around the age of 4 and has about 18% of sudden cardiac death. Mutation in the ANK2 gene causes the ankyrin-B syndrome, which presents with long QT interval and impaired conduction of electrical impulses between chambers or even heart block. CPVT type 5, the result of TRDN gene mutation, starts around the age of 2–3 and has 25% of sudden cardiac death[3].

  Catecholaminergic polymorphic ventricular tachycardia-associated ryanodine receptor mutations Top

Ryanodine receptors, which are Ca2+-release channels located on the ER and SR membranes, contain three isoforms: RyR1, RyR2, and RyR3. RyR2 is the most important Ca2+ channel on the cardiac SR and plays a critical role in E-C coupling[28],[29]. The activation of RyR2 depends on the phosphorylation of serine-2808 by CaMKII and serine-2030 by PKA[30]. It has also been suggested that serine-2811 might be the potential spot for CaMKII phosphorylation[31]. It has been reported that phosphorylation of RyR2 by both PKA and CaMKII increases the open probability and further releases Ca2+ from the SR[32],[33],[34]. Using the cardiomyocytes derived from CPVT patient-specifically induced pluripotent stem cells (iPSCs), Pölönen et al. discovered that patients carrying exon 3 deletions (E3D) and RYR2-p.L4115F increase the amount of DADs and early after depolarizations (EADs) after adrenaline exposure. E3D-CPVT hiPSC-CMs have the shortest AP duration, lowest AP amplitude, upstroke velocity, and more depolarized diastolic potential than control. Further, E3D-CPVT hiPSC-CMs have an increased amount of DADs, EADs, and tachyarrhythmia[35]. Using cardiac tissue isolated from RyR2 P2328S homozygous mice, Salvage et al. discovered that this type of mutation increases the sensitivity to Ca2+ and reduces both the activation and inactivation threshold. Their discovery suggests that RyR2 P2328S homozygous mutation increases the total release of Ca2+ from the SR, causing AF and VA[36]. Using the RyR2 R4496C mouse model of CPVT crossing with the C×40EGFP/+ transgenic mouse, Herron et al. discovered that variation of RyR2 R4496C effects on Ca2+ homeostasis not only in ventricular myocytes but also in cardiac Purkinje cells[37]. Gallegos-Cortez et al. reported that a 12-year-old girl suffering from multiple falls while cycling was finally diagnosed with CPVT. She did not have any family history of syncope or sudden cardiac death. The genetic test showed that she carries a missense RYR2 mutation (p.Gly3946Ser) in a heterozygous state[9]. This kind of mutation has been predicted as pathogenic in the ClinVar database and reported in other patients[9],[38]. Tung et al. analyzed a 108-member proband and reported three of the member's variation in the RYR2 gene (c. 527G>T, p.R176L). The RyR2 R176L increases DADs causing CPVT-associated sudden cardiac arrest[39].

  Catecholaminergic polymorphic ventricular tachycardia-associated calsequestrin (CASq) mutations Top

CASQ, a 399 amino acid protein, binds 40–50 Ca2+ and serves as a high capacity but low affinity Ca2+ buffering protein[40],[41]. CASQ has two isoforms: CASQ1 and CASQ2, encoded by two different genes, CASQ1 and CASQ2. CASQ2 can be found in both cardiac and slow-twitch skeletal muscle[41]. CASQ2 localizes to the junctional SR of the muscle and forms multimers, which are anchored to RyR2 by triadin and junctin on the luminal SR membrane[42]. Using the cardiac SR vesicles isolated from sheep hearts, Wei et al. discovered that CASQ2 increases the open probability of both RyR1 and RyR2 channels[42]. The interaction between CASQ2 and RyR2 may contribute to the refractory period of Ca2+ release[43]. The mutation of CASQ2 might affect the Ca2+-binding ability, causing intra-SR Ca2+ concentration to rise much faster than normal. Thus, this loss of Ca2+ buffering may easily trigger RyR2 to open and cause CPVT. Ng et al. discovered numerous CASQ2 mutations, such as CASQ2 R251H, CASQ2 K180R, CASQ2 W361R, CASQ2 R33*Q, CASQ2 E39*, CASQ2 D340*, CASQ2 S173I, and CASQ2 D325E. Using turbidity assays, they discovered that CASQ2 D325E and CASQ2 K180R have filament defects with half capability of Ca2+ binding. CASQ2 R33Q and CASQ2 Y55C completely lose their ability to bind with Ca2+. CASQ2 P308L and CASQ2 S173I have a similar situation to CASQ2 Y55C, but they restore around 25% of its capability 20 min after Ca2+ addition. CASQ2 R251H seems to have no effect on Ca2+ binding in normal pH, while losing about 25% of capability in pH 5.6, which is closer to physiological condition near the SR luminal membrane[44]. Postma et al. reported that three mutations in CASQ2 in three CPVT families, a nonsense R33X, a splicing 532 + 1 G > A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons. Three mutations share similar phenotypic variations. In total 16 heterozygous carriers of these mutations, only two of them have VAs on EKG during exercise tests and the rest of them are devoid of clinical symptoms or EKG anomalies[45].

  Catecholaminergic polymorphic ventricular tachycardia-associated calmodulin mutation Top

CaM, an essential Ca2+ sensing, is a signal-transducing protein commonly conserved in eukaryotes and consists of four classical Ca2+-binding EF-hands (EF1–4) located in two globular N-terminal (N-lobe) and C-terminal (C-lobe) domains connected by a short flexible linker region. These separated EF-hands can bind to Ca2+ with very high cooperativity that induces a structural modification, forming a Ca2+/CaM complex and severing its universal function: amplification of the Ca2+ signal[22],[46]. In the heart, CaM can modulate the gating of RyR2, L-type Ca2+, Na+, and K+ channels and trigger CaMKII[20],[23],[47]. It has been known that CaM plays a critical role in E-C coupling, and mutation in this protein is highly associated with CPVT and LQTs. CaM is encoded by three different genes, CALM1, CALM2, and CALM3. Mutation in these genes is called calmodulinopathies, and most of them are associated with life-threatening cardiac disorders, such as LQTs and CPVT[46]. There are many variations in CaM that have been associated with CPVT or CPVT/LQTs mix phenotypes, including CaM N53I, CaM N97I, CaM N98S, CaM F89L, CaM D95V, CaM D130G, CaM D132E, CaM E141G, and CaM Q136P[48],[49],[50],[51]. Holt et al. found that structures of the arrhythmogenic CaM N53I variants are highly similar to wild-type the CaM, and variation in N53I alone can alter the intramolecular dynamics of CaM N-domain. Thus, it changes the interaction between the CaM N-domain and RyR2, thereby causing arrhythmia and CPVT[48]. Analyzing the crystal structure of various genetic modified CaM associated with LQTs, CPVT, or LQTs/CPVT mix from purified IQ domain of human CaV1.2 and full length human CaM, Wang et al. discussed the interaction changes between CaM and CaV1.2 IQ domain. CaM D130G completely separates EF-hands within the C-lobe and loses Ca2+ binding in EF-hand 4[46]. CaM Q136P severely reduces the affinity for the IQ domain. CaM N98S creates different conformations with either one or two Ca2+ bound to the C-lobe that possibly disrupts the cooperativity[46],[49]. CaM N54I is lobe variant which has no major changes in complexity with the IQ domain but causes severe stress-induced arrhythmia[46],[49]. Using heterozygous CaM N98S transgenic mice generated by using CRISPR/Cas9 technology, Tsai et al. reported that this variation exhibits sinus bradycardia, QTc interval prolongation, and catecholaminergic bidirectional VT. Furthermore, CaM N98S significantly increases the peak density and induces slow inactivation and left shift of the activation curve of ICa.L during β-adrenergic stimulation. They proposed that tachycardia-induced DAD and pause-dependent EAD originated in the His–Purkinje network and ventricular myocytes via reentry or focal mechanisms constitute potential sources of arrhythmia in CaM N98S heart[52].

  Catecholaminergic polymorphic ventricular tachycardia-associated calcium/calmodulin-dependent protein kinase ii mutation Top

CaMKII, a multifunctional serine/threonine kinase, mediates multiple physiological responses[53]. There are four different isoforms of CaMKII (α, β, γ, and δ) with different Ca2+/CaM binding affinity (γ > β > δ > α). CaMKIIδ and CaMKIIγ are predominantly expressed in the heart[54]. It can not only regulate numerous ion channels directly but also phosphorylate PLB and activate SERCA[55],[56]. Endogenous CaMKII can phosphorylate RyR2, hence increasing its sensitivity to Ca2+-dependent activation and the frequency of Ca2+ sparks[34],[56]. This action leads to RyR2-mediated SR Ca2+ leak, subsequently causing DAD, and thereby triggers severe cardiac arrhythmias and CPVT[57]. The activation of CaMKII is strictly regulated by two sets of highly conserved phosphorylation sites in the regulatory segment (Thr 286 and Thr 305/Thr 306) that are blocked by the regulatory segment and released once Ca2+/CaM attaches to CaMKII. CaMKII mutation in its own structure rarely occurs in CPVT or other inherited arrhythmias. Several studies suggested that using viral vector to deliver gene fragments, which encode CaMKII inhibitor peptides, can be a potential therapeutic strategy for inherited arrhythmias. Bezzerides et al. used an adeno-associated viral vector fused with CaMKII inhibitory peptide (autocamptide-2 related inhibitor peptide [AIP]) and systemically delivered to heterozygous RyR2 R176Q mice. The CaMKII inhibitory peptide is designed to selectively inhibit cardiac CaMKII due to the modified gene, which can only be expressed from a cardiomyocyte selective promoter. They reported that the inhibition of CaMKII successfully suppressed VA induced by either β-adrenergic stimulation or programmed ventricular pacing, without significantly proarrhythmic effect. They also reported that CaMKII inhibition reverses the arrhythmia phenotype in human CPVT iPSC-CM models with different pathogenic mutations[58]. These findings suggested that upon various genetic mutations in CPVT, administration of CaMKII inhibitor peptide (AIP) delivered by viral vector might be an effective therapeutic approach.

  Catecholaminergic polymorphic ventricular tachycardia-associated triadin mutations Top

Triadin, which is expressed in the striated muscle, has at least three isoforms (Trisk 95, Trisk 51, and Trisk 32) due to the alternative splicing of the TRDN gene[59]. Trisk 32 is majorly expressed in cardiac muscle. CASQ2 is anchored to RyR2 by triadin and junction, forming a quaternary complex within SR[41],[43],[60]. It has been shown that CPVT patients with TRDN mutations all experienced cardiac arrest at a very young age (<6 years), suggesting a severe CPVT phenotype due to triadin mutations[59],[61],[62],[63]. This mutation identified in CPVT patients is homozygous or compound heterozygous[59],[61],[62],[64]. Using COS-7 cells and cardiomyocytes of triadin-knockout mouse, Roux-Buisson et al. reported that the mutation of Trisk 32 produces the mutant protein Trisk 32 T59R. They reported that Trisk 32 T59R is very unstable and tends to be degraded, suggesting that mutation of Trisk 32 T59R results in the absence of triadin and the cause of CPVT. They also discovered two other variations of the triadin in two CPVT families: p.D18Afs*13 and p.Q205*. These mutations also lead to the absence of triadin[61]. However, using triadin knockout mice and adeno-associated virus, Cacheux et al. demonstrated that Trisk 32 T59R does not abolish the ability of triadin to interact with CSQ2 as a chaperone. They also reported that loss of triadin is associated with an 80% reduction of CSQ2, a 30% reduction in RyR2, and a reduction in the SR Ca2+ load[63]. Using genome sequencing and a TRDN gene-specific trio analysis on RNA and protein isolated from patient-specific human iPSC-CMs, Clemens et al. discovered that alternative splicing on exon 6a-containing TRDN transcript in the normal heart leads to the absence of triadin, thereby causing triadin-knockout syndrome[65].

  Catecholaminergic polymorphic ventricular tachycardia-associated HRC mutations Top

Similar to CASQ2, histidine-rich Ca2+ binding protein (HRC) also has low affinity and high capacity of Ca2+ binding and is expressed predominantly in the cardiac SR lumen of the striated muscle[66]. The interaction between HRC and triadin is Ca2+ sensitive[66],[67]. Using cardiac homogenates from wild-type mice and postmortem human specimens, Arvanitis et al. discovered that the binding affinity of HRC to SERCA and triadin is very distinct. A recent study reported that the affinity of HRC for triadin increases as Ca2+ concentration rises from 10− 8 to 10− 3 M. The peak affinity between HRC and SERCA appears at pKa 7, whereas between HRC and triadin appears at pKa 4. They also reported that an increase of Ca2+ concentration in SR reduces the interaction between HRC and SERCA, whereas the interaction between HRC and triadin is increased[66]. These findings suggested that HRC may sense and regulate Ca2+ uptake and release, hence constantly changing the binding partners in SR during E-C coupling[66],[68]. Using HRC and CASQ2 double-knockout mice, Liu et al. reported that the absence of HRC and CASQ2 can ameliorate the predisposition to VA and arrhythmogenic Ca2+ waves. They proposed that HRC enhances the RyR2 activity through facilitating RyR2 recovery from refractoriness and CASQ2 stabilizes RyR2 rendering it refractory in the diastolic phase. Thus, the losses of Ca2+ buffering of CASQ2 combined with normal HRC can lead to RyR2 frequently open and cause CPVT. Surprisingly, with HRC also absent in this scenario, it ablates CPVT[60]. Their discovery suggested a new thinking pathway for CPVT patients with CASQ2 mutation. Using HEK-293 cells, Zhang et al. demonstrated that HRC S96A leads to an increase in spontaneous Ca2+ release and ultimately cause arrhythmias by disrupting the regulation of intra-store free Ca2+. They proposed that this phenomenon is primarily due to an impaired ability to act as an effective bulk and local micro-domain store Ca2+ buffer[69].

  Catecholaminergic polymorphic ventricular tachycardia-associated TECRL mutations Top

TECRL is a 12 exon gene located on chromosomal segment 4q13. The protein encoded by this gene is called trans-2,3-enoyl-CoA reductase-like, which belongs to the steroid 5-alpha reductase and is predominantly expressed in the ER of cardiomyocytes[27].

The trans-2,3-enoyl-CoA reductase-like plays a crucial role in intracellular Ca2+ regulation. TECRL mutation presents a mixed phenotype of CPVT and LQTs termed CPVT 3, and variants in TECRL may cause up to 5% of all CPVT cases[3],[27]. Using DNA samples from CPVT patients, Moscu-Gregor et al. discovered that a point mutation in Gln139* results in a premature stop codon and loss of the trans-2,3-enoyl-CoA reductase-like function. Homozygous variants NM_001010874.4:c. 869C>A, p.Pro290His from CPVT patients are probably leading to an altered folding of the 3-oxo-5-alpha steroid 4-dehydrogenase domain of the trans-2,3-enoyl-CoA reductase-like. However, the large population cohort study of this variation has not been done yet. It only has been predicted by silico-prediction as pathogenic[27]. NM_001010874.4:c. 893T>C, p.(Val298Ala), and c. 926C>A, p.(Ser309*) are suggested to affect the transmembrane complex and parts of the 3-oxo-5-alpha steroid 4-dehydrogenase domain and have a high possibility of a loss of function[27]. Devalla et al. reported that two French–Canadian probands carried identical homozygous variants (p.Arg196Gln), which were diagnosed with CPVT. They compared the difference between homozygous variation and healthy persons and reported that the intracellular Ca2+ transient is slower than normal in the rising and decay phase. Moreover, the SR Ca2+ storage is lower than normal. The homozygous variation presents with longer AP and significantly increases the propensity for triggered activity by noradrenaline[70].

  Management of catecholaminergic polymorphic ventricular tachycardia Top

Current therapeutic management for patients with CPVT includes beta-blockers, flecainide, verapamil, ivabradine, left cardiac sympathetic denervation (LCSD), bilateral thoracoscopic sympathectomy via a minimally invasive video-assisted thoracoscopic surgery (VATS-LCSD), implantable cardiac defibrillators, and catheter ablation[3],[71]. Above all, limiting physical exercise, reducing or preventing stress, or emotion-induced matters should be the top priority[72].

According to Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society (HRS/EHRA/APHRS) recommendation, beta-blockers without intrinsic sympathomimetic activity, such as nadolol, propranolol, and carvedilol, are the first-line therapeutic options for CPVT patients[3],[71]. For prophylactic management, nadolol is more preferable than other beta-blockers due to its long-acting characteristic[3],[71]. For countries that nadolol is not available, a nonselective beta-blocker, such as propranolol, is equally effective as nadolol[71]. Flecainide is capable of reducing the frequency of spontaneous Ca2+ waves and RyR2-mediated Ca2+ waves in vitro. Moreover, flecainide can inhibit INa and dramatically reduce the number of ectopic beats during isoproterenol-induced CPVT[73]. Flecainide has been reported to successfully reduce exercise-induced VAs in a 33-CPVT patient trial, and HRS/EHRA/APHRS has recommended it as the first addition to beta-blockers when control of arrhythmias is incomplete[3],[74].

Ivabradine, a funny channel pacemaker current inhibitor target specifically on the pacemaker activity of the sinoatrial node, has been recommended for heart failure treatment. In 2020, Kohli et al. reported that an 18-year-old male with a large in-frame RYR2 E3D, malignant syncope, and CPVT was given nadolol and flecainide and underwent sympathectomy. However, these managements remain ineffective. His VA was successfully suppressed after the initiation of ivabradine treatment. Kohli et al. suggested that ivabradine could be an important add-on therapy for CPVT patients, who are drug-refractory or unable to continue conventional therapies[75]. Using CASQ2 D307H/D307H mice and iPSC-CM, Bueno-Levy et al. discovered TRAM-34, a Ca2+-activated potassium channel selective blocker, can manage the depolarization of maximal diastolic potential, reduce the heart rate, and attenuate VAs in CPVT patients[76]. All three drugs still need further investigation and human trials to understand the exact mechanism, potential side effects, and adaptability on CPVT patients. Verapamil is also a beta-blocking agent that has been recommended for women during pregnancy and postpartum with LQTs or CPVT[74]. Verapamil has been shown to be beneficial for some CPVT patients in short-term follow-up, whereas its long-term effect remains controversial[71],[77]. Cather ablation is commonly used in various VAs[77]. It triggers VF in patients with refractory CPVT and could be used as adjunctive therapy for bidirectional ventricular premature beats[71]. However, it is not recommended for standard CPVT treatment due to the vast experimental trials still not available[71]. LCSD is another surgical management for CPVT and has been shown to be beneficial in short-term arrhythmic events recovery[71]. VAT-LCSD, an improved version of LCSD, can operate via minimal invasion, resulting in significantly less morbidity and a shorted hospital stay. It is suitable for patients in recurrent VTs with congenital LQTs and CPVT[3]. Furthermore, it has been shown to have an anti-arrhythmic and anti-fibrillatory effect and thereby provides a critical adjunct to existing medical therapies and should be considered for all patients with life-threatening refractory arrhythmias, especially those patients on maximal medical therapy[3]. However, both LCSD and VAT-LCSD are lacking massive clinical trials and long-term follow-up results to support its capability of improving quality of life, effectiveness, and safety in CPVT patients[3],[71].


  Conclusion Top

In this review, we provide a brief introduction of the molecular mechanism associated with CPVT as presented in [Figure 1]. We also provide a summary of those CPVT-related protein mutations and their influence in CPVT as shown in [Table 1]. In conclusion, CPVT is an early onset disease that usually presents with episodic syncope, arrhythmia, or even sudden cardiac death. Early diagnosis with exercise stress tests and genetic tests are beneficial for patients and their families. Various Ca2+ handling protein mutations cause severe Ca2+ imbalance within cardiomyocytes. The exact mechanism underlying mutation protein-induced disturbances of Ca2+ handling is still not fully understood. The current treatments of CPVT have been focused on symptom treatments. As the knowledge of CPVT has grown massively, the experimental gene therapy may provide us a new therapeutic strategy.
Figure 1: The molecular mechanism of Ca2+ handling related to catecholaminergic polymorphic ventricular tachycardia

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Table 1: Summary of catecholaminergic polymorphic ventricular tachycardia-related protein's mutation and their biophysical effects in catecholaminergic polymorphic ventricular tachycardia

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Financial support and sponsorship

This study was supported by the grant of Buddhist Tzu Chi Medical Foundation (TCMMP109-01-02).

Conflicts of interest

There are no conflicts of interest.

  References Top

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