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Primary Arrhythmogenic Cardiomyopathies. Channelopathies  

CPVT is an 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), the absence of structural heart disease and the appearance of bidirectional TV, syncope and SCD triggered by adrenergic stimulation, especially physical exertion or emotional stress.

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 seven and twelve years (Leenhardt et al 1995, Priori et al 2002; Postma et al 2005), although onset as late as the fourth decade of life has been reported. Family history of sudden death in relatives younger than age 40 years is present in approximately 30% of probands with CPVT (Priori et al 2002; Watanabe et al 2013). Patients with CPVT often present history of palpitations, dizziness and syncope in response to exercise or emotions, but sometimes the first presentation can be a SCD, and a family history of syncope or SCD is present in 30% of patients (Napolitano et al., 2007). It 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 in untreated subjects (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). Younger age at CPVT diagnosis is a predictor of future cardiac events (Hayashi et al., 2009). In fact, 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).

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1. Diagnosis

The clinical manifestations of CPVT usually occur in the first decade of life and are prompted by physical activity or emotional stress (Priori et al., 2002). The diagnosis is mostly based on family history, symptoms and the detection of arrhythmias during exercise stress test or i.v. administration of catecholamines. Under these conditions, 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.

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.

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2. Role of ryanodine and calsequestrin

CPVT is the result of an abnormality in the regulation of intracellular Ca2+ involving two proteins located on the sarcoplasmic reticulum: the ryanodine channel (RyR2) and calsequestrin. The cardiac ryanodine receptor (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 Ca2+ ions bind to and activates RyRs at high-affinity cytosolic Ca2+ activation sites. When RyR channels open, a much larger amount of Ca2+ is released to the cytoplasm, leading to 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 SERCA2a, 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. Each monomer has 6 transmembrane segments forming the pore region of the channel and has a long cytoplasmatic N- terminal which extends intracytoplasmatic in the space between the SR and the T tubule membranes. This cytoplasmic domain 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 at the junctional face membrane in the SR, which also regulates the [Ca2+]i during the cardiac cycle, reducing cytoplasmic Ca2+ overload. CASQ2 normally limits RyR2 open probability and contributes to RyR deactivationafter each Ca2+ release.

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3. Genetic basis

A majority of CPVT cases (up to 70%) are associated with dominant mutations in the RyR2 gene with variable penetrance (mean 80%) (Laitinen et al., 2001; Piori et al., 2001; Tiso et al., 2001; Ackerman et al., 2011). Mutations are located in certain regions of “hot zones” nown as N-terminal (residues 77-466), central (2113-2534) and C-terminal domain (3778-4959) (Ackerman et al., 2011; Leenhardt et al., 2012). A minority of cases (2%) 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). Mutations in other genes (KCNJ2, TRDN, CALM, and ANK2) 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).

The arrhythmogenic mechanisms in CPVT involve the catecholamine-induced activation of cyclic AMP–dependent protein kinase A, which phosphorylates several key Ca2+-handling proteins, including RYR2. This 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 attendant increased release of Ca2+ (Wilde et al., 2008).

The mechanisms for enhanced Ca2+ release during SR overload in mutated RyR2 channels remains uncertain. However, the arrhythmogenic potential of some mutations is attributable to a marked increase in the Ca2+ sensitivity of RyR2 channel, which resulted in the increased frequency of Ca2+ sparks and Ca2+ waves, which was further amplified by either isoproterenol or high pacing rates and lowers the threshold for triggered activity (Fernández-Valasco et al., 2009). Further studies confirmed mutation-linked dysfunction of RyR2, namely spontaneous Ca2+ release events and DAD (Kannankeril et al., 2006). Occasionally, the mutation sensitizes the channel to agonists [eg, cAMP-induced aberrant Ca2+ release events (Ca2+ sparks/waves) occurred at much lower sarcoplasmic reticulum Ca2+ content ] and reduces the threshold of luminal [Ca2+] for activation, primarily mediated by defective interdomain interaction within the RyR2 (Uchinoumi et al., 2010).

CASQ2 mutations increase the diastolic SR Ca2+ leak and cause premature spontaneous SR Ca2+ release and triggered beats resulting in arrhythmias (Liu et al., 2009). 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).

Mutations in the ANK-2 gene encoding ankyrin-2 (Mohler et al., 2004) and in the KCNJ2 gene 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.

Genome-wide linkage analysis has implicated calmodulin 1 (CALM1) in CPVT4 (Nyegaard et al., 2013). Calmodulin  participated in the Ca2+-dependent ICa inactivation and it also stabilizes the RyR2 channel and variants in CALM1 may easily cause Ca2+ overload. Candidate gene screening has identified mutations in triadin (TRDN) as a cause of CPVT5 (Roux-Biuisson et al., 2012). Triadin is a protein that connects CASQ to RyR2, and stabilizes the RyR2 channel. The mutation may lead to diastolic leak of Ca2+ and Ca2+ overload in the myocytes.

A novel missense mutation in SCN5A (I141V) in a highly conserved region of the SCN5A gene has been implicated in exercise-induced polymorphic ventricular arrhythmias. The mutation shifted the activation curve toward more negative potentials and increased the window current (Swan et al., 2014). Genome-wide scanning has revealed another locus at chromosome 7p22–p14 (homozygous) in a family with CPVT and an autosomal recessive pattern of inheritance (Bhuiyan et al., 2007).

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Table. Genetic loci and genes associated with CPVT

Syndrome

Locus

Gene

Protein

Current

F unction

CPVT1 (60%, AD)

1q42-43

RYR2

RyR2 Spontaneous Ca2+ leak from the SR during the diastole (+)
CPVT2 (AR) 1p13.3-p11 CASQ2 Calsequestrin Spontaneous Ca2+ leak from the SR during the diastole (-)

CPVT?

4q25

ANK2

Ankyrin-N Spontaneous Ca2+ leak from the SR during the diastole (+)

CPVT3

17q23

KCNJ2

α subunit Kir2.1 IK1 (+)

CPVT4 (AD)

 

CALM1

Calmodulin   (-)

CPVT4 (AR)

 

TRDN

RyR2 Triadin (-)

AD: autosomal dominant. AR: autosomal recessive.

4. Treatment

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). Additionally, the mortality is very high as 30-58% of patients died before 40 years of age without b-blocker therapy (Napolitano et al., 2007). Thus, exercise restriction and high doses of b-blockers without intrinsic sympathomimetic activity are the first-line therapy for all patients diagnosed with CPVT and history of ventricular tachyarrhythmias (van der Werf et al., 2012); even asymptomatic patients should be treated as well. Nadolol is generally preferred for its long half-life. The benefit of b-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. It has been suggested that verapamil may be useful when administered in combination with b-blockers (Rosso et al.; 2007 Swan et al., 2005), although this has not been demonstrated in a long-term study.
It has been shown that flecainide decreases channel opening probability of RyR2 channels, inhibits early afterdepolarizations genesis and the onset of TV (Watanabe et al., 2009). This suggests that flecainide can be coadministered with b-blockers in patients refractory to these agents (Van der Werf et al., 2012; Watanabe et al., 2009). A combination of flecainide and nadolol allowed complete suppression of AF along with ventricular arrhythmias in a child with CPVT (Di Pino et al., 2014). The mechanism of flecainide involves suppression of spontaneous Ca2+ release from the sarcoplasmic reticulum by direct RyR2 inhibition and suppression of triggered beats by sodium channel block (Watanabe et al., 2009, 2011).
The ICD implantation associated with b-blockers is preferred in patients who survived cardiac arrest and in selected high risk patients with a strong family history of SCD (Zipes et al., 2006), but we must remember that the complications of this treatment (reinterventions, revision/extraction/ replacement) are higher in children than in adults. Patients with CPVT who experience syncope or sustained VT whilst receiving b-blockers are considered to have a class IIa indication for an ICD implantation. However, it should be taken into consideration that children have a higher risk of ICD complications than adults. ICD treatment without concomitant use of b-blockers is dangerous because of the risk of electrical storm induced by the adrenergic surge related to a shock (Mohamed et al., 2006).
Selective left cardiac sympathetic denervation can be a therapeutic alternative in patients in whom b-blockers are contraindicated or not adhered to, 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).
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) Lifestyle changes in all patients with a diagnosis of CPVT: avoidance of competitive sports, strenuous exercise and stressful environments (Level of evidence: I, C).
2) Beta-blockers are recommended in all patients with a clinical diagnosis of CPVT, based on the presence of documented spontaneous or stress-induced ventricular arrhythmias  (Level of evidence: I, C).
3) ICD implantation in addition to beta-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 (Level of evidence: I, C).
4) Therapy with beta-blockers should be considered for genetically positive family members, even after a negative exercise test  (Level of evidence: IIa, C).
5) Flecainide should be considered in addition to beta-blockers in patients with a diagnosis of CPVT who experience recurrent syncope or polymorphic/bidirectional VT while on beta-blockers, when there are risks/contraindications for an ICD or an ICD is not available or rejected by the patient (Level of evidence: IIa).
6) Flecainide should be considered in addition to beta-blockers in patients with a diagnosis of CPVT and carriers of an ICD to reduce appropriate ICD shocks (Level of evidence: IIC).
7) Left cardiac sympathetic denervation may be considered in patients with a diagnosis of CPVT who experience recurrent syncope or polymorphic/bidirectional VT/several appropriate ICD shocks while on beta-blockers or beta-blockers plus flecainide and in patients who are intolerant or have contraindication to beta-blockers (Level of evidence: IIb, C).

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5. References

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