Diagnosis
Role of ryanodine and calsequestrin
Genetic basis
Treatment
References

CPVT is a malignant inherited channelopathy caused an abnormal Ca²⁺ handling with onset during the pediatric age (Leenhardt et al., 1995). It is characterized by a normal ECG pattern at rest (although some patients present sinus bradycardia and a limit QT interval) and the appearance of bidirectional TV, syncope and SCD triggered by adrenergic stimulation, especially physical exercise or emotional stress in young patients with structurally normal hearts.

Exact prevalence of CPVT is unknown, with estimates of approximately 1:7.000-10.000. The mean age of onset of CPVT symptoms (usually a syncopal episode) is between age 7 and 12 years, and exercise-induced syncopal episodes tend to be worse in males (Leenhardt et al 1995, Priori et al 2002; Postma et al 2005), although onset as late as the 3rd or 4th decade of life has been reported. CPVT is a highly lethal disease associated with a 30% risk of SCD below the age of 30 and reaching 50% by the age of 40 without -blocker therapy (Napolitano et al., 2007; Ferrero-Miliani et al., 2010). It is identified as the underlying cause of sudden death in 13% of patients without heart disease (Modi et al., 2011). SCD episodes appear between 2 and 9 years of age for carriers of RyR2 mutations and between 7 and 11 years in carriers of CASQ2 mutations (Cerrone et al., 2009).

Patients with CPVT often present history of palpitations, dizziness and syncope in response to exercise or emotions, but in approximately one-third of cases a cardiac arrest is the first symptom of the disease, and a family history of syncope or SCD is present in 30% of patients (Priori et al 2002; Napolitano et al., 2007; Watanabe et al 2013). Younger age at CPVT diagnosis is a predictor of future cardiac events (Hayashi et al., 2009). Supraventricular dysrhythmias such as AF and sick sinus syndrome are present in 16–26% of the patients. These supraventricular arrhythmias are hypothesized to arise from dysfunctional Ca²⁺ handling in atrial cardiomyocytes (∼ to the ventricular phenotype).

Diagnosis

The diagnosis is mostly based on family history, symptoms and the detection of arrhythmias during exercise stress test or i.v. administration of catecholamines. During exercise or the i.v. administration of catecholamines (in patients who cannot perform an exercise test) CPVT patients develop ventricular extrasístoles at frequencies above 100-120 bpm, followed by an increase in the complexity ventricular extrasystoles and short runs of non-sustained VT. With continued exercise the duration of VT increases and a bidirectional VT (characterized by beat-to-beat 180º rotation of the QRS complex) appears that confirms the diagnosis (Napolitano et al., 2007). Some patients, however, can develop a polymorphic VT during the exercise test (Cerrone et al., 2009). Finally, FV, syncope and SCD appear. Once the exercise or stress test ends, the ECG changes reversed in the same way that occurred. Some CPVT patients also present supraventricular arrhythmias, mainly bursts of supraventricular tachycardia or atrial fibrillation that overlap with ventricular extrasystoles and VT. In asymptomatic relatives of CPVT patients the exercise test has a specificity of 97% and a sensitivity of 50% for predicting the presence of the familial CPVT-associated mutation.

The differential diagnosis should be made with the hidden LQT1, because these patients may also present syncope or SCD during exercise (Tester et al., 2005). The stress test or the administration adrenaline aid the diagnosis, as patients with CPVT show bidirectional VT in response to adrenergic stimulation, while patients with occult LQT1 show a lengthening of the QTc interval (Ackerman et al., 2002). Patients with the Andersen-Tawil syndrome can also present bidirectional TV. However, the abnormalities associated with Andersen–Tawil syndrome (affecting the head, face, and limbs) and the QT prolongation help to the diagnosis.

Because of the strong family history, all first-degree relatives should be studied (ECG, Holter monitoring and exercise stress). An echocardiography might be useful to demonstrate the presence of structural heart diseases (coronary disease, ventricular arrhythmogenic dysplasia or hypertrophic cardiomyopathy) ruling out that a primary arrhythmogenic syndrome.

The risk of arrhythmic events is considered to be higher in patients with aborted cardiac arrest, and in patients carrying recessively inherited CASQ2 mutations. However, mutation-carrying CPVT patients with no ventricular arrhythmias during exercise testing (so-called silent mutation carriers) are at risk of arrhythmic events as well.

Role of ryanodine and calsequestrin

CPVT is the result of an abnormality in the regulation of intracellular Ca²⁺ involving two main proteins located on the sarcoplasmic reticulum (SR): the ryanodine channel (RyR2) and calsequestrin. The cardiac RyR2 controls intracellular Ca²⁺ release and plays an important role in the excitation-contraction coupling. This process is initiated by the influx of extracellular Ca²⁺ following the activation of L-type Ca²⁺ channels during the lateau phase of the AP. This small entry of Ca²⁺ is insuffient to directly trigger a contractile response, but it can activate the RyR2 and facilitates the release of Ca²⁺ stored in the SR to the cytoplasm, leading to the activation of contractile proteins. This mechanism is known as Ca²⁺-induced Ca²⁺ release). During diastole, the [Ca²⁺]_i decreases as a consequence of the activation of the Ca²⁺-ATPase pump (SERCA) that increases the uptake of Ca²⁺ into the SR, the Na⁺/Ca²⁺ exchanger located in the cell membrane (1 Ca²⁺:3 Na⁺) and the Ca²⁺-ATPase (PMCA) located in the cell membrane. RyR2 is a homotetramer composed of four subunits of 4959 amino acids with a long cytoplasmatic N-terminal which extends intracytoplasmatic in the space between the SR and the T tubule membranes. Each monomer has 6 transmembrane segments forming the pore region of the channel. This N-terminal acts as a scaffold for regulatory subunits, enzymes, modulators (Ca²⁺, ATP, calmodulin) and drugs (caffeine and ryanodine) that regulate channel activity. Calsequestrin is the major Ca²⁺ fixing protein of 399 amino acids located in the SR and the release of calsequestrin-bound Ca²⁺ (through RyR2 channels) triggers muscle contraction. It also regulates the [Ca²⁺]_i during the cardiac cycle, reducing cytoplasmic Ca²⁺ overload. Calsequestrin is the most abundant Ca²⁺ binding protein in the cardiac SR. CASQ2 normally limits RyR2 open probability and contributes to RyR deactivation after each Ca²⁺ release, so that it procides a large pool of Ca²⁺ releasable from the SR and at the same time limits RyR2 open probability and contributes to RyR deactivation after each Ca²⁺ release, so that it maintains the concentrations of free cytosolic Ca²⁺ at sufficiently low levels during the diastole.

The arrhythmogenic mechanisms in CPVT involve the activation of cardiac α-adrenergic receptors by catechoalmines which activated the adenylyl cyclase-cyclic AMP–dependent protein kinase A pathway. Protein kinase A phosphorylates several key Ca²⁺-handling proteins, including RyR2 channels and increases the release of Ca²⁺ from the SR. Mutations on RyR2 and CASQ2 genes increase the spontaneous release of Ca²⁺ (leak) from the SR during the diastole. The increase in cytoplasmic Ca²⁺ may lead to the activation of the Na⁺/Ca²⁺ exchanger causes transient inward depolarization current (ITI), which causes a delayed after-depolarizations, triggered activity and ventricular arrhythmias (Watanabe et al., 2011). If the amplitude of the delayed after-depolarizations is sufficiently high to reach the threshold potential a triggered arrhythmia can occur. The association of sinus bradycardia with mutations in SR Ca²⁺ channel proteins lends further support or the Ca²⁺ block hypothesis in SA pacemaking. Therefore, the two most critical steps in the arrhythmogenesis of CPVT are the increase in the catecholamine level and the increased release of Ca²⁺ to the cytosol during the diastolic interval (Wilde et al., 2008).

The mechanisms for enhanced Ca²⁺ release during SR overload in mutated RyR2 channels remains uncertain, but it can be related to: a) an increase in the open probability of RyR2 channels that increases the spontaneous release of Ca²⁺ from the SR during the diastole which in turn induces spontaneous Ca²⁺ sparks and delayed aftrdepolarizations, leading to CPVT (Liu et al., 2009; Kannankeril et al., 2006); b) a marked increase in Ca²⁺ sensitivity of RyR2 channels, so that cAMP-induced aberrant Ca²⁺ release events (Ca²⁺ sparks/waves) occurred at much lower SR Ca²⁺ content and this effect is amplified by catechoamines or high pacing rates (Fernández-Valasco et al., 2009); c) a decrease in the threshold of luminal [Ca²⁺] for activation, primarily mediated by defective interdomain interaction within the RyR2 (Uchinoumi et al., 2010); d) sensitizes the RyR2 channel to activation by luminal [Ca²⁺] for activation, primarily mediated by defective interdomain interaction within the RyR2; e) a decrease in the ability of the SR to store Ca²⁺; and f) a remodeling of the SR ultrastructure.

Genetic basis

CPVT is associated with mutations in RyR2, CASQ2, KCNJ2, TRDN, CALM1, and ANK2 genes which are implicated in cardiac intracellular calcium hemostasis. Mutations in RyR2 gene encoding the cardiac ryanodine receptor/Ca²⁺ release channel are found in approximately 65% of individuals and are inherited as an autosomal dominant disorder, with 80% penetrance (Laitinen et al., 2001; Piori et al., 2001; Tiso et al., 2001; Ackerman et al., 2011m, Rodriguez-Calvo et al., 2008; Modi et al., 2011). Mutations are located in certain regions of “hotspot areas” known as N-terminal (residues 77-466), central (2113-2534) and C-terminal domain (3778-4959) (Ackerman et al., 2011; Leenhardt et al., 2012). A deletion of exon 3 of RYR2 has been shown to cause a distinct subtype of CPVT characterized by sinoatrial node and atrioventricular node dysfunction, supraventricular arrhythmias, and dilated cardiomyopathy. A minority of cases (2-5%) result from recessive mutations in the cardiac calsequestrin isoform 2 (CASQ2) gene (Lahat et al., 2001; Di Barletta et al., 2006; Knollmann et al., 2006). Bilayer experiments demonstrated that removal of CASQ2 increases RyR2 open probability at fixed intraluminal Ca²⁺ suggesting that CASQ2 influences the open probability of RyR2 (Gyorke et al., 2004). CPVT2 is considered a more severe phenotype.

Mutations in other genes (Table 2) involved in cardiac intracellular Ca²⁺ hemostasis have been identified in patients with clinical features similar to CPVT, but it is unclear whether they are phenocopies of CPVT (Roux-Buisson et al., 2012; Priori et al., 2013). Autosomal recessive forms of the disorder are associated with mutations in either: a) CASQ2, encoding the SR Ca²⁺-binding protein calsequestrin. b) TRDN, encoding triadin, which links RYR2 with calsequestrin and stabilizes the RyR2 channel (Bhuiyan et al., 2007; Roux-Buisson et al., 2012). Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were identified in a cohort of 97 CPVT patients leading to diastolic leak of Ca²⁺ and Ca²⁺ overload in the cardiomyocytes (Roux-Buisson et al., 2012). Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the p.T59R missense mutation when expressed in COS-7 cells resulted in intracellular retention and degradation of the mutant protein (Roux et al). Loss of triadin may also predispose to unregulated SR Ca²⁺ release. In Trdn knockout mice, attenuated Ca²⁺-dependent inactivation of L-type Ca²⁺ channels appears to promote SR Ca²⁺ overload and the predisposition to aberrant SR Ca²⁺ release. c) Genome-wide linkage analysis have implicated CALM1 gene encoding calmodulin 1 (CALM1) in CPVT4 (Nyegaard et al., 2013). Calmodulin participates in the Ca²⁺-dependent ICa inactivation process, stabilizes the RyR2 channel and reduces the probability of its opening during diastole and variants in CALM1 may easily cause Ca²⁺ overload. Mutations in CALM1 have also been associated with the LQTS and idiopathic VF. Mutations in the CALM2 gene have been associated with overlapping features of the congenital LQTS and CPVT. d) TECRL gene which encodes the trans-2,3-enoyl-CoA reductase-like protei (Devalla et al., 2016). Neverthelesss, approximately one-third of CPVT cases remain gene-elusive to date.

Mutations in the ANK-2 gene encoding ankyrin-2 and in the KCNJ2 gene encoding the potassium inwardly rectifying channel Kir2.1 have been reported in patients with exercise induced bi-directional VT (Mohler et al., 2004). Ankyrin-B mutations resulted in a loss of expression and abnormal coordination of NCX, Na+/K+-ATPase and the insositol-3-phosphate (InsP3) receptor. It has been also described an overlapping between TVPC and SQTL7, but its gravity is unknown. A novel missense mutation(I141V) in a highly conserved region of the SCN5A gene has been implicated in exercise-induced polymorphic ventricular tachyarrhythmias. The mutation shifted the activation curve toward more negative potentials and increased the window current (Swan et al., 2014). A yet-to-be-identified gene on chromosome 7p14–p22 (homozygous) has been linked to a highly malignant autosomal recessive form of CPVT (Bhuiyan et al., 2007). This phenotype is characterised by exercise-induced ventricular arrhythmia, and patients have a minor QT prolongation.

Interestingly, approximately 40 % of the CPVT cases remain mutation negative. However, in mutation-carrying CPVT patients with no ventricular arrhythmias during exercise testing (so-called silent mutation carriers) are at risk of arrhythmic events as well.

Genetic basis

The 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death (Priori et al., 2013) recommend:

1. Changes in lifestyle. Because either physical or emotional exertion can trigger ventricular tachycardia patients should be cautioned against virtually all forms of vigorous physical activity (Maron et al., 2004).
2. β-blocker therapy. The cornerstone of management of CPVT is exercise restriction and β-blockers without intrinsic sympathomimetic activity at the highest tolerable dose (van der Werf et al., 2012). Current guidelines recommend β-blockers in all patients with a clinical diagnosis of CPVT (Class I, C) and for genetically positive family members, even after a negative exercise test (Class IIa, C). All phenotypically and/or genotypically diagnosed CPVT patients should receive appropriate therapy, although in clinical practice exceptions are made in asymptomatic patients over 60 years of age who are newly diagnosed by cascade screening. However, the risk of arrhythmic events (defined as aborted cardiac arrest, appropriate ICD shocks, and sudden cardiac death), despite β-blocker therapy during a mean follow-up period of 8 years (Napolitano and Priori, 2007).

A robust comparison between different types of βBs has not been performed, but there is evidence that nadolol, a long-acting non-selective drug with a half-life of 12-24 hours, is the most effective βB in terms of ventricular arrhythmia suppression and cardiac event rates during exercise testing. Hayashi et al observed lower cardiac event rates in patients treated with nadolol compared with other β-blockers. However, this study did not indicate which type and dose of β-blocker the patients who were not on nadolol were receiving. Nadolol has a more pronounced chronotropic effect than other β-blockers and because of its long half-life (14-24 hours) offers the most stable, lasting degree of β-blockade and can be administered once daily (>1.5 mg/kg/day), which may result in improved adherence. Peopranolol, another nonselective β-blocker might be an alternative where nadolol is not available. The benefit of β-blockers has been attributed to their ability to block the adrenergic tone, but they can also modulate rate-dependent Ca²⁺ overload and reduce L-type Ca²⁺ channel current uring adrenergic stimulation. However, up to 30% of patients develop an arrhythmic event while on therapy (Napolitano and Priori, 2007). Patients who do not respond to treatment should be considered at very high risk.

Current expert consensus guidelines have given a class IIa recommendation for the use of flecainide. The proposed underlying mechanism is: a) a direct blocking effect on voltage-gated sodium channels that raises the threshold for delayed afterdepolarization-induced triggered activity (Bannister ML et al. 2015; Liu N et al., Circ Res 2011; Sikkel MB et al., 2013), and b) the blockade of the open state of RyR2 channels (or an indirect effect on RyR2 through binding to calmodulin or other modulators of RyR2) that decreases the open probability of the channels, prevents RyR2-mediated premature Ca²⁺ release, inhibits early afterdepolarizations genesis and the onset of TV (Watanabe et al., 2009). RyR2-mediated sarcoplasmic reticulum Ca²⁺ regulates the beating rate of sinoatrial nodal cells in response to catecholamines. Flecainide reduces the rate of spontaneous SR Ca²⁺ release which may explain why maximum hearts rates are significantly lower in flecainide-treated patients even though workloads were higher compared with baseline exercise testing.

In isolated cardiomyocytes flecainide reduces the duration of RyR2 channel opening and the spontaneous calcium spark frequency and in a CPVT CASQ2 knockout mouse model, flecainide reduces ventricular arrhythmia burden.

Flecainide suppress ventricular arrhythmias in patients without a proven pathogenic mutation in the RYR2, CASQ2 or KCNJ2 genes (Watanabe H et al. Heart Rhythm 2013). In 33 genotype-positive patients who were either symptomatic or had persistent severe ventricular arrhythmias despite maximally tolerated standard therapy partial or complete suppression of the ventricular arrhythmias was achieved in 76% of patients and no patient experienced worsening of exercise-induced ventricular arrhythmias (Van der Werf et al., 2011). During a mean follow-up of 20 months, 1 patient suffered from an episode of several appropriate ICD shocks related to confirmed non-compliance. Similar findings were subsequently observed in patients with CASQ2 mutations and genotype-negative CPVT patients. Thus, flecainide could be added to β-blocker therapy when symptoms or either spontaneous or exercise-induced ventricular arrhythmias persist. Therefore, flecainide can be coadministered with β-blockers in patients refractory to these agents (Van der Werf et al., 2012; Watanabe et al., 2009). This combination is particularly effective in patients who received drug therapy that could be considered suboptimal (i.e., an unusual β-blockers like bisoprolol, carvedilol, or sotalol) because nadolol is not available in their country or a low β-blocker dose (atenolol, metoprolol, or nadolol <1 mg/kg body weight daily) was administered. Optimal dosing of flecinide is 150–300 mg/day; doses below 100 mg/day have been associated with a lack of therapeutic response. At these doses the adverse effects of flecainide are mild and rarely lead to discontinuation of therapy. Nevertheless, it is recommended that heart rate-related QRS prolongation is closely monitored on the exercise test; if the QRS interval is prolonged by >25 %, flecainide dosing should be decreased or discontinued.

One small study evaluated the efficacy of flecainide as a monotherapy in 9 patients carrying RYR2 mutations either intolerant to or had experienced severe side effects of β-blockers (Padfield GJ et al., 2016). None of these patients suffered from treatment failure during a median follow-up of 37 months. However, even when flecainide monotherapy may potentially be considered an option for patients that are intolerant to β-blockers the routine use of flecainide monotherapy is not recommended because the evidence is scarce.

Propafenone was also tested in a 22-year-old patient with CPVT carrying the p.L4105F RYR2 mutation who suffered from frequent appropriate ICD discharges and who was refractory to conventional therapy (excluding flecainide). Propafenone (900 mg/day) led to a significant decrease in the frequency of ICD discharges and complete ventricular arrhythmia suppression on exercise testing at 12 months of follow-up (Hwang HS 2011).

Because Ca²⁺ influx through the L-type calcium channels increases Ca²⁺-induced Ca²⁺ release through the defective or inappropriately regulated RYR2 channels it was proposed that verapamil may be useful when administered in combination with β-blockers (Rosso et al.; 2007 Swan et al., 2005). However, the initial benefit wasnot confirmed in a long-term study. Other pharmacological agents, including Na+-channel blockers, amiodarone, and magnesium, lack of efficacy in CPVT patients (Leenhardt A et al. Circulation 1995; Sumitomo et al. Heart 2003).

An implantable cardioverter-defibrillator (ICD) in addition to β-blockers with or without flecainide is recommended in patients with a diagnosis of CPVT who experience cardiac arrest, recurrent syncope or polymorphic/bidirectional VT despite optimal therapy (Class I, C). However, ICDs are not fully protective and there is a significant risk of arrhythmic death, and ICD treatment without concomitant use of β-blockers is dangerous because both appropriate and inappropriate ICD shocks can trigger catecholamine release, subsequently resulting in multiple shocks (arrhythmic storm), and death (Mohamed et al., 2006). Therefore, the ICD should be implanted in addition to β-blockers, particularly in patients who survived cardiac arrest and in selected high risk patients with a strong family history of SCD (Zipes et al., 2006). ICDs should be programmed to shock after a long delay, to cardiovert VF rather than worsen the VT. Moreover, because many CPVT patients are children, we must remember that the complications of ICD implantation (reinterventions, revision/extraction/ replacement) are higher in children than in adults.

Selective left cardiac sympathetic denervation may provide excellent long-term rhythm control and can be a therapeutic alternative in patients in whom β-blockers are contraindicated or in cases of noncompliance, which are not uncommon in the chronic administration of β-blockers in younger individuals, when an ICD cannot be placed or is not wanted and in patients with recurrent VT despite an ICD and maximal medical treatment (Wilde et al., 2008; Olde Nordkamp et al., 2014; Hofferberth et al., 2014).

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