Genetics and Mechanisms of Catecholaminergic Polymorphic Ventricular Tachycardia

Hiroshi Watanabe* and Tohru Minamino

Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Japan

*Corresponding author: Hiroshi Watanabe, Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, 1-754 Asahimachidori, Niigata, Japan

Received: January 27, 2014; Accepted: February 20, 2014; Published: February 24, 2014

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by ventricular tachyarrhythmia induced by adrenergic stress in the absence of structural heart disease and high incidence of sudden cardiac death. Five causative genes of CPVT have been identified. There is a common mechanism by which mutations in these genes cause CPVT: Ca²⁺ leakage through the destabilized ryanodine channel complex in sarcoplasmic reticulum. Spontaneous Ca²⁺ release through ryanodine channel leads to delayed after depolarization, triggered activity, and bidirectional⁄polymorphic VT. Implantable cardioverter defibrillators (ICDs) are used for prevention of sudden death in patients with CPVT. However, because painful shocks can trigger further adrenergic stress and tachyarrhythmias, ICD socks delivered to initiating triggered arrhythmias have nearly always failed and deaths have occurred despite appropriate ICD shocks. Treatment with β–adrenergic blockers reduces arrhythmia burden and mortality, but is not completely effective. The beneficial effects of Ca²⁺ channel blocker verapamil in combination with β–blocker have been reported, but the role of verapamil has not been well assessed. Flecainide directly inhibits ryanodine channels and prevent CPVT. Left cardiac sympathetic denervation may be an effective alternative treatment in combination with ICD, especially for patients whose arrhythmias are not controlled by drug therapies. Catheter ablation for premature ventricular beats triggering CPVT has recently been effective.

Keywords: Arrhythmias; Genetics; Mechanism; Ryanodine channel; Therapy

Introduction

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by ventricular tachyarrhythmia induced by adrenergic stress in the absence of structural heart disease and high incidence of sudden cardiac death [1–4]. The age of CPVT onset is usually before 10 years, although the much later onset has been reported [4]. The diagnosis is made based on reproducible ventricular tachyarrhythmias including bidirectional VT, which is characterized by a beat–to–beat 180° rotation of the QRS axis and polymorphic VT during exercise testings and⁄or epinephrine administration. Five causative genes of CPVT have been identified (Table 1). There is a common mechanisms by which mutations in these genes cause CPVT: Ca²⁺ leakage through the destabilized ryanodine channel complex in sarcoplasmic reticulum (Figure 1) [5]. Spontaneous Ca²⁺ release through ryanodine channel leads to delayed after depolarization, triggered activity, and bidirectional⁄polymorphic VT. Therefore, ryanodine channel block can be therapeutic for CPVT, and it has recently discovered that flecainide directly inhibits ryanodine channels and prevent CPVT [6–8].

Table 1: Causative genes of CPVT.



  
    Gene 
    Protein 
    Transmission mode 
    Frequency 
  
  
    RYR2
    Ryanodine    receptor
    Autosomal    dominant
    60%
  
  
    CASQ2
    Calsequestrin
    Autosomal    recessive
    1-2%
  
  
    TRDN
    Triadin
    Autosomal    recessive
    Rare
  
  
    KCNJ2
    Inward    rectifier K+ channel, Kir 2.1
    Autosomal    dominant
    Rare
  
  
    CALM1
    Calmodulin
    Autosomal    dominant
    Unknown



Table 1:  Causative genes of CPVT.

RYR2, cardiac ryanodine receptor Ca²⁺ release channel

RYR2 is the first gene associated with the autosomal dominant form of CPVT [9]. Ryanodine channels open in response to Ca²⁺ entry from the outside of cardiomyocytes through L–type Ca²⁺ channel and release Ca²⁺ from the sarcoplasmic reticulum into the cytosol (Figure) [10]. Mutations in RYR2 are identified in ˜60% of patients with CPVT, and the vast majority of the genotype–positive CPVT patients have RYR2 mutations [4]. RyR2 channels open in response to Ca²⁺ entry from the outside of cardiomyocytes through L–type Ca²⁺ channel and release Ca²⁺ from the sarcoplasmic reticulum into thecytosol (Figure 1) [10]. There have been three proposed mechanisms underlying leaky RyR2 channels that cause spontaneous Ca²⁺ release leading to CPVT as a result of RYR2 mutations: 1) enhanced basalactivity of RyR2 channels [11–13]. , 2) disruption of ryanodine channel–stabilizing protein FKBP12.6 (or calstabin2) binding, [14]and 3) defective inter–domain folding to ryanodine receptor [15,16].

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Citation: Watanabe H, Minamino T. Genetics and Mechanisms of Catecholaminergic Polymorphic Ventricular Tachycardia. Austin J Clin Cardiolog. 2014;1(2): 1011. ISSN 2381-9111

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