Catecholaminergic polymorphic ventricular tachycardia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mounika Reddy Vadiyala, M.B.B.S.[2]

Synonyms and keywords: CPVT, bidirectional tachycardia induced by catecholamines, catecholamine-induced polymorphic ventricular tachycardia, familial polymorphic ventricular tachycardia, FPVT

Overview

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare inherited arrhythmogenic disorder characterized by syncopal attacks, ventricular arrhythmias, and even sudden cardiac death, mostly in young patients. It is caused by mutations in calcium handling proteins such as RyR2 and CASQ2 within the sarcoplasmic reticulum, which results in ventricular arrhythmias in the setting of a high adrenergic tone such as during physical exercise or strong emotions. There are no associated structural abnormalities of the heart.

Historical Perspective

• Catecholaminergic polymorphic ventricular tachycardia (CPVT) was first described by Reid et al in 1975 and by Coumel et al in 1978.
• CPVT was described as a familial cardiac arrhythmia that occurs in patients with structurally normal heart and causes exercise or emotion triggered syncope and sudden death with a distinguishing pattern of ventricular and supraventricular arrhythmias.
• In 2001, Cardiac Ryanodine Receptor Gene (hRyR2) mutations were first identified in the pathogenesis of Catecholaminergic polymorphic ventricular tachycardia.
• In 1995 and 2002, the clinical studies by Leenhardt et al and Priori et al, respectively, have contributed to the understanding of the natural history of CPVT.
• In 2004, studies showed that RyR2 mutations reduced the threshold for Store-Overload-Induced Ca2+ Release (SOICR) and increased the tendency for triggered arrhythmia. Thus it appeared evident that catecholaminergic polymorphic ventricular tachycardia was caused by uncontrolled Ca2+ release from the sarcoplasmic reticulum.
• In 2006, subsequent experimental studies demonstrated that the abnormal calcium release caused arrhythmias mediated by delayed afterdepolarizations and triggered activity.

Classification

Type	OMIM	Gene	Protein	Mode of inheritance	Locus
CPVT1	604772	RyR2	Ryanodine receptor 2	Autosomal dominant	1q42.1-q43
CPVT2	611938	CASQ2	Calsequestrin 2	Autosomal recessive	1p13.3-p11
CPVT3	614021	Unknown	-	Autosomal recessive	7p14–p22
CPVT4	614916	CALM1	Calmodulin 1	Autosomal dominant	14q32.11
CPVT5	615441	TRDN	Triadin	Autosomal recessive	6q22.31

Pathophysiology

The voltage-gated ion channel mutation associated with CPVT intermittently causes the heart to develop polymorphic ventricular tachycardia in response to the natural release of catecholamines. 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%).
  • Genetic linkage studies revealed the disease-causing locus with an autosomal dominant inheritance pattern on chromosome 1q42–q43.
  • 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.

• CASQ2:
  • Mutations in cardiac calsequestrin gene CASQ2 accounts for CPVT 2, for approximately 2–5% of the CPVT cases.
  • 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.

The genes encoding cardiac ryanodine-calcium release channel RyR2 or, infrequently, cardiac calsequestrin CASQ2 are thus involved in the release of calcium from the sarcoplasmic reticulum and mutations therein result in inappropriate calcium leak from the sarcoplasmic reticulum. 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.

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.
  • 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.
  • 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.

• TRDN:
  • Mutations in Triadin gene TRDN accounts for CPVT 5, for approximately 1-2% of the CPVT cases.
  • 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.
  • 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, or by a reduction of CASQ2 protein levels., 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):

• KCNJ2- encoding for Inward-rectifier potassium ion channel - autosomal dominant - 17q24.3
• ANKB- encoding for ankyrin B, a cytoskeletal protein - autosomal dominant - 4q25

Differentiating Catecholaminergic polymorphic ventricular tachycardia from other Diseases

Catecholaminergic polymorphic ventricular tachycardia must be differentiated from other diseases that cause syncope, ventricular tachycardia, and sudden cardiac death, such as:

• Arrhythmogenic right ventricular dysplasia
• Short-coupled ventricular tachycardia (SC-torsade de pointes [TdP])
• Long QT syndrome
• Andersen-Tawil syndrome

Epidemiology and Demographics

The incidence of CPVT is 10/100,000 people. CPVT is estimated to cause 15% of all unexplained sudden cardiac deaths in young people.

Natural History, Complications, Prognosis

The majority of events occur during childhood and more than 60% of affected individuals will have the first episode of syncope or cardiac arrest by age 20. The polymorphic ventricular tachycardia may self-terminate or it may degenerate into ventricular fibrillation, causing sudden cardiac death.

Diagnosis

Symptoms

The most common symptom is syncope, as a result of exercise-induced ventricular arrhythmias which occur during physical activity or acute emotion. The symptoms usually appear during the first or second decade of life.

Electrocardiogram

The resting electrocardiogram is usually unremarkable but can show sinus bradycardia and a prominent U wave.

Exercise Stress Testing

CPVT is a diagnosis based on reproducing ventricular arrhythmias during exercise stress testing, syncope occurring during physical activity and acute emotion, and a history of exercise or emotion-related palpitations and dizziness with an absence of structural cardiac abnormalities.

Genetic Testing

Genetic testing is available in some locations and may be useful in diagnosing the presence of the genetic disorder among related individuals before the onset of aborted sudden death or sudden cardiac death.

Treatment

CPVT is treated with beta blockers, verapamil or an ICD (implantable cardiac defibrillator).

Pharmacotherapy

Medications to treat CPVT include beta blockers and verapamil.

According to recent research published in Nature Medicine, flecainide inhibits the release of the cardiac ryanodine receptor–mediated Ca²⁺, and is therefore believed to medicate the underlying molecular cause of CPVT in both mice and humans.

Implantable cardioverter-defibrillator

Implantable cardioverter-defibrillators are used to prevent sudden death.

Sympathectomy

In recent reports, left cardiac sympathetic denervation and bilateral thoracoscopic sympathectomy have shown promising results in individuals whose symptoms cannot be controlled by beta blockers.

ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death (DO NOT EDIT)

Class I

"1. Beta blockers are indicated for patients who are clinically diagnosed with CPVT on the basis of the presence of spontaneous or documented stress-induced ventricular arrhythmias. (Level of Evidence: C)"

"2. Implantation of an ICD with use of beta blockers is indicated for patients with CPVT who are survivors of cardiac arrest and who have reasonable expectation of survival with a good functional status for more than 1 y. (Level of Evidence: C)"

Class IIa

"1. Beta blockers can be effective in patients without clinical manifestations when the diagnosis of CPVT is established during childhood based on genetic analysis. (Level of Evidence: C)"

"2. Implantation of an ICD with the use of beta blockers can be effective for affected patients with CPVT with syncope and/or documented sustained VT while receiving beta blockers and who have reasonable expectation of survival with a good functional status for more than 1 y. (Level of Evidence: C)"

Class IIb

"1. Beta blockers may be considered for patients with CPVT who were genetically diagnosed in adulthood and never manifested clinical symptoms of tachyarrhythmias. (Level of Evidence: C)"

References

Electrocardiography