Catecholaminergic polymorphic ventricular tachycardia pathophysiology

Catecholaminergic polymorphic ventricular tachycardia is caused by mutations in genes encoding channel proteins that regulate the cardiac electrical function, resulting in inappropriate calcium leak from the sarcoplasmic reticulum during electrical diastole and thus leading to triggered arrhythmias, in the absence of structural cardiac abnormalities. CPVT is thus an inherited disorder and may have both autosomal dominant and autosomal recessive pattern of inheritance. Genes associated with CPVT include RYR2, CASQ2, CALM1 and TRDN.

• CPVT is primarily due to the mutations in voltage-gated ion channel that regulate cardiac electrical function; which intermittently causes the heart to develop polymorphic ventricular tachycardia in response to the natural release of catecholamines.
• The genes encoding cardiac ryanodine-calcium release channel RyR2 or, infrequently, cardiac calsequestrin CASQ2 are involved in the release of calcium from the sarcoplasmic reticulum.
• Mutations in the genes encoding cardiac ryanodine-calcium release channel RyR2 or cardiac calsequestrin CASQ2 or other related genes, therein result in inappropriate calcium leak from the sarcoplasmic reticulum during electrical diastole, with a subsequent increase in the cytosolic calcium concentration.^[1][2][3]
• The cytosolic calcium overload activates the sodium-calcium exchanger, leading to a transient inward current, and delayed after-depolarizations that in turn can lead to triggered arrhythmias, particularly under conditions of high β-adrenergic tone.^[4][5]
• Thus, in the absence of structural abnormalities in the heart, the equilibrium of ionic currents that generate the cardiac action potential and control the excitation-contraction coupling in the cardiomyocytes is altered in CPVT, resulting in the onset of life-threatening arrhythmias.

• Catecholaminergic polymorphic VT may have both autosomal dominant and autosomal recessive pattern of inheritance. The following genes are associated with CPVT:
  • RYR2:
    • Mutations in cardiac ryanodine receptor gene RyR2 accounts for CPVT 1, and majority of the cases (approximately 50-65%).^[6][7]
    • Genetic linkage studies revealed the disease-causing locus with an autosomal dominant inheritance pattern on chromosome 1q42–q43.^[8]
    • RyR2 is involved in intracellular calcium homeostasis and in the excitation-contraction coupling of the heart.
    • Mutations in RYR2 cause uncontrolled calcium leakage from the sarcoplasmic reticulum during electrical diastole, with a subsequent increase in the cytosolic calcium concentration.^[1][6]
  • CASQ2:
    • Mutations in cardiac calsequestrin gene CASQ2 accounts for CPVT 2, for approximately 2–5% of the CPVT cases.^[9]
    • The chromosome involved is located on 1p13.3-p11 with an autosomal recessive pattern of inheritance.
    • CASQ2 is a Ca2+ buffering protein within the sarcoplasmic reticulum that plays a role in the control of calcium release from the sarcoplasmic reticulum to the cytosol.

• Other genes that have been associated with CPVT are:
  • Unknown:
    • CPVT 3 has been linked to chromosome 7p14–p22 with an autosomal recessive pattern of inheritance.^[10]
    • This novel phenotype is highly malignant form of CPVT, characterized by exercise-induced ventricular arrhythmia and a minor exercise-induced QT-prolongation.
  • CALM1
    • Mutations in Calmodulin 1 gene CALM1 accounts for CPVT 4, for approximately <1% of the CPVT cases.
    • Mutation in the CALM1 gene was first identified in a Swedish family with a history of exercise-induced ventricular arrhythmias, syncope, and sudden death.^[11]
    • The chromosome involved is located on 14q32 with an autosomal dominant pattern of inheritance.
    • Calmodulin is a calcium-binding protein that stabilizes RYR2 and controls its opening during diastole.^[11]
  • TRDN:
    • Mutations in Triadin gene TRDN accounts for CPVT 5, for approximately 1-2% of the CPVT cases.^[12]
    • Mutations in the gene encoding Triadin (TRDN) were identified in the probands of 2 families in whom mutations for RYR2 and CASQ2 were not identified.^[12]
    • The chromosome involved is located on 6q22 with an autosomal recessive pattern of inheritance.
    • Triadin is a protein within the sarcoplasmic reticulum, physically and functionally related to the ryanodine receptor that plays a role in the control of calcium release from the sarcoplasmic reticulum to the cytosol.
    • TRDN mutations impair FKBP12.6–RYR2 interaction, thus destabilizing the RyR2 channel opening,^[13] or by a reduction of CASQ2 protein levels.^[12], thus affecting calcium release and resulting in a calcium leak during diastole similar to that observed for RyR2 mutants.

• More recently, two other genes have been reported to cause CPVT-like phenotype (phenocopy):^[14][15]
  • KCNJ2– encoding for Inward-rectifier potassium ion channel – autosomal dominant – 17q24.3
  • ANKB– encoding for ankyrin B, a cytoskeletal protein – autosomal dominant – 4q25

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