Catecholaminergic polymorphic ventricular tachycardia

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

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. Since it is caused by mutations in genes encoding for channel-proteins that regulate cardiac electrical activity, CPVT is referred to as a channelopathy. There are no associated structural abnormalities of the heart in catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) was first described by Reid et al in 1975. It 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 (RyR2) mutations were first implicated in the pathogenesis of catecholaminergic polymorphic ventricular tachycardia (CPVT). Subsequent experimental studies demonstrated that the abnormal calcium release from the sarcoplasmic reticulum caused arrhythmias mediated by delayed afterdepolarizations and triggered activity.

Catecholaminergic polymorphic ventricular tachycardia can be classified based upon the underlying pathogenic mutation.

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.

Catecholaminergic polymorphic ventricular tachycardia is a genetic disorder. It is caused by mutations in the genes such as RYR2, CASQ2, CALM1 and TRDN.

Catecholaminergic polymorphic ventricular tachycardia must be differentiated from Arrhythmogenic right ventricular dysplasia, Short-coupled ventricular tachycardia (SC-torsade de pointes [TdP]), Long QT syndrome and Andersen-Tawil syndrome.

Catecholaminergic polymorphic ventricular tachycardia is a rare disorder with the prevalence estimated to be 1 per 10,000 individuals. CPVT is more common among young individuals.

Possible risk factors in the development of catecholaminergic polymorphic ventricular tachycardia (CPVT) include young age, exercise, stress, family history of syncope or sudden death, and family history of CPVT.

There is insufficient evidence to recommend routine screening for Catecholaminergic polymorphic ventricular tachycardia. But screening among relatives is indicated when a likely pathogenetic mutation is identified in clinically affected index cases. Screening methods for CPVT are exercise stress testing and genetic testing.

If left untreated, approximately 30% of patients experience at least one cardiac arrest and up to 80% one or more syncopal spells. Common complications of catecholaminergic polymorphic ventricular tachycardia include ventricular fibrillation, sudden cardiac arrest, and sudden cardiac death. Prognosis is generally poor, and the 10-year mortality of patients with catecholaminergic polymorphic ventricular tachycardia is approximately 40%.

Syncope triggered by exercise or emotion is the initial manifestation in the majority of the cases of catecholaminergic polymorphic ventricular tachycardia. Sudden cardiac death during exercise or emotion may also be the initial manifestation in a relevant proportion of cases. Most of the patients have a positive family history of CPVT or sudden cardiac death.

Patients with catecholaminergic polymorphic ventricular tachycardia usually appear normal. Physical examination should include thorough cardiovascular examination, lung examination, and close monitoring of vital signs.

There are no diagnostic laboratory findings associated with catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia patients usually have a normal resting ECG. However, in a subset of patients, sinus bradycardia, prominent U-waves, and supraventricular arrhythmias are seen.

Exercise Stress Testing is the primary diagnostic test and the most helpful clinical tool in diagnosing CPVT as it can reproducibly evoke the typical ventricular tachycardia during acute adrenergic activation (exercise). During exercise stress testing, sinus rhythm accelerates and beyond a heart rate of 120-130 beats per minute, isolated and often monomorphic ventricular premature beats (VPBs) typically occur first and then increase with heart rate to bigeminy. Subsequently, the VPBs become polymorphic or bidircetional, and as the exercise increase, they form bursts of non-sustained polymorphic ventricular tachycardia or bidirectional ventricular tachycardia (VT). With continuous activity, the arrhythmia persists and becomes more rapid, eventually assuming the appearance of polymorphic ventricular tachycardia (VT), which is very fast, fibrillation-like and leads to syncope. The arrhythmias disappear on stopping the exercise. Bidirectional ventricular tachycardia (VT) is the hallmark finding of catecholaminergic polymorphic ventricular tachycardia.

Genetic testing helps in the confirmation of the diagnosis of catecholaminergic polymorphic ventricular tachycardia. It allows the identification of mutations in up to 65% of patients with a clinical diagnosis of CPVT. There are HRS/EHRA Expert Consensus Recommendations for Genetic testing in Catecholaminergic polymorphic ventricular tachycardia.

There are no x-ray findings associated with catecholaminergic polymorphic ventricular tachycardia.

There are no echocardiography/ultrasound findings associated with catecholaminergic polymorphic ventricular tachycardia.

There are no CT scan findings associated with catecholaminergic polymorphic ventricular tachycardia.

There are no MRI findings associated with catecholaminergic polymorphic ventricular tachycardia.

There are no other imaging findings associated with Catecholaminergic polymorphic ventricular tachycardia.

Other diagnostic studies for catecholaminergic polymorphic ventricular tachycardia include epinephrine infusion and holter monitoring. In patients who cannot perform an exercise stress test, epinephrine infusion and Holter monitoring help to establish the diagnosis of CPVT.

Pharmacologic medical therapies for CPVT include beta blockers, flecainide and verapamil. Beta blockers remain the first-line therapeutic option for all the patients with catecholaminergic polymorphic ventricular tachycardia.

Implantable cardioverter defibrillator should be used with pharmacologic therapy. It is recommended in patients who are at high risk of cardiac arrest, patients who have survived a sudden cardiac arrest and patients who have experienced syncope or sustained VT despite optimal medical therapy.

Surgery is not the first-line treatment option for patients with catecholaminergic polymorphic ventricular tachycardia. Sympathectomy or left cardiac sympathetic denervation is usually reserved for patients who experience recurrent symptoms and/or implantable cardioverter-defibrillator (ICD) shocks despite optimal medical therapy or in those who are intolerant or have contraindications to beta blockers

There are no established measures for the primary prevention of catecholaminergic polymorphic ventricular tachycardia. However, episodes of syncope and sudden cardiac arrest can be prevented with lifestyle modifications, holter monitoring and compliance with medical therapy.

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

Catecholaminergic polymorphic ventricular tachycardia (CPVT) was first described by Reid et al in 1975. It 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 (RyR2) mutations were first implicated in the pathogenesis of catecholaminergic polymorphic ventricular tachycardia (CPVT). Subsequent experimental studies demonstrated that the abnormal calcium release from the sarcoplasmic reticulum caused arrhythmias mediated by delayed afterdepolarizations and triggered activity.

• Catecholaminergic polymorphic ventricular tachycardia (CPVT) was first described by Reid et al in 1975, followed by Coumel et al in 1978.^[1]
• 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 (RyR2) mutations were first implicated in the pathogenesis of catecholaminergic polymorphic ventricular tachycardia (CPVT).^[2]
• 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.^[3][4]
• 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.^[5]
• In 2006, subsequent experimental studies demonstrated that the abnormal calcium release caused arrhythmias mediated by delayed afterdepolarizations and triggered activity.^[6]

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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]

Catecholaminergic polymorphic ventricular tachycardia can be classified based upon the underlying pathogenic mutation.

CPVT may be classified based upon the underlying pathogenic mutation into the following subtypes:^[1]

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

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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]

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

Catecholaminergic polymorphic ventricular tachycardia is a genetic disorder. It is caused by mutations in the genes such as RYR2, CASQ2, CALM1 and TRDN.

• Catecholaminergic polymorphic ventricular tachycardia is caused by mutation in the following genes:^[1][2]
  • RYR2 encoding Ryanodine receptor 2
  • CASQ2 encoding Calsequestrin 2
  • CALM1 encoding Calmodulin 1
  • TRDN encoding Triadin

To review risk factors for the development of CPVT, click here

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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]

Catecholaminergic polymorphic ventricular tachycardia must be differentiated from Arrhythmogenic right ventricular dysplasia, Short-coupled ventricular tachycardia (SC-torsade de pointes [TdP]), Long QT syndrome and Andersen-Tawil syndrome.

Catecholaminergic polymorphic ventricular tachycardia must be differentiated from other diseases that cause syncope, ventricular tachycardia, and sudden cardiac death, such as:Closing </ref> missing for <ref> tag

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

On the basis syncope, sudden cardiac death, and ventricular tachycardia, Catecholaminergic polymorphic ventricular tachycardia must be differentiated from Arrhythmogenic right ventricular dysplasia, Short-coupled ventricular tachycardia (SC-torsade de pointes TdP), Long QT syndrome, Andersen-Tawil syndrome and Brugada syndrome.

Diseases	Cause	Clinical manifestations	ECG		Structural abnormalities
			ECG during rest	ECG during exercise or stress
Catecholaminergic polymorphic ventricular tachycardia	Mutations in RYR2 and CASQ2 genes	Symptoms are exercise or emotion related Syncope Sudden cardiac death Ventricular tachycardia	Sinus bradycardia, Prominent U-waves, and Supraventricular arrhythmias	Monomorphic PVCs Polymorphic or bidirectional PVCs with bigeminy Polymorphic VT Bidirectional VT	–
Arrhythmogenic right ventricular dysplasia	Usually caused by mutations in genes encoding for desmosomal proteins.	Symptoms are usually exercise-related Syncope Ventricular tachycardia symptoms such as palpitations, dizziness Sudden cardiac death Symptoms and signs related to right ventricular failure may also be seen.	T-wave inversion in the right precordial leads. Epsilon waves. Right bundle branch block.	Left bundle branch block pattern during tachycardia	It primarily affects the right ventricle (RV). Changes seen are: Fatty infiltration of the RV free wall Thinning of the RV myocardium RV Dilation and Regional Wall Motion Abnormalities
Short QT syndrome	Mutations in KCNH 2 gene for SQTS 1, KCNQ 1 for SQT 2, KCNJ 2 gene for SQTS 3, CACNA1C for SQTS 4, and CACNB2b for SQTS 5 Hypercalcemia Digoxin	Symptoms are not exercise-related or triggered Sudden death Syncope Atrial fibrillation and Palpitations. Physical examination is normal.	Short QTc interval (<320 ms) Lack of variability in the QTc with heart rate, Either a tall peaked T wave or Brugada pattern in V1 and V2, Early repolarization and paroxysmal atrial fibrillation as a rhythm.	–	–
Long QT syndrome	Mutations in genes encoding for sodium and potassium ion channels in the heart.	Symptoms are triggered by exercise, stress, certain drugs, etc Syncope Palpitations Sudden cardiac death	Prolongation of the QTc interval (>460 ms) Abnormal T-wave morphology	Prolongation of the QTc interval (>460 ms) Abnormal T-wave morphology	–
Andersen-Tawil syndrome	Mutation in KCNJ2 gene.	Symptoms are not related to adrenergic activation Syncope, Periodic paralysis, Ventricular arrhythmias, Muscular weakness, seizures, Sudden cardiac death (low risk) Other significant findings include: hypoplastic mandible, Micrognathia, Broad nose, Low set ears and Clinodactyly.	A long QTc (LQT) interval Characteristic T-U patterns Prominent U-wave A wide T-U junction Prolonged terminal T-wave Premature ventricular contractions(PVC) especially at “rest” Polymorphic ventricular tachycardia (PMVT) which is called bidirectional ventricular tachycardia (BiVT) VF on further deterioration which can lead to sudden death	–	–
Brugada syndrome	Mutation in SCN5A gene.	Symptoms occur predominantly during sleep or at rest Syncope Seizures Difficulty breathing Sudden death Other findings: Ventricular tachycardia	ST elevation in the right precordial leads Right Bundle Branch Block pattern Polymorphic ventricular tachycardia	–	–
Short-coupled ventricular tachycardia (SC-torsade de pointes TdP)	Unknown	Symptoms are not related to adrenergic stimuli, Syncope Sudden cardiac death Ventricular tachycardia	Polymorphic ventricular tachycardia Typical TdP with a remarkably short coupling interval (always less then 300 ms) of the first TdP beat Multiple ventricular premature beats with short coupling interval	–	–

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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]

Catecholaminergic polymorphic ventricular tachycardia is a rare disorder with the prevalence estimated to be 1 per 10,000 individuals. CPVT is more common among young individuals.

• The prevalence of catecholaminergic polymorphic ventricular tachycardia is estimated to be 1 per 10,000 individuals. Although the true prevalence is unknown.^[1]

• Catecholaminergic polymorphic ventricular tachycardia onset is more commonly observed during childhood and adolescence with the mean age of onset of symptoms between age 7 and 12 years.^[2][3][4]
• CPVT has also been reported in adults with onset as late as the fourth decade.^[5]

• CPVT affects males and females equally;^[6] although males are more likely to present at an earlier age (in childhood or adolescence), while females are more likely to present at an older age (20 years, mean).^[2]

• There is no racial predilection for CPVT.

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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]

Possible risk factors in the development of catecholaminergic polymorphic ventricular tachycardia (CPVT) include young age, exercise, stress, family history of syncope, or sudden death, and family history of CPVT.

The possible risk factors in the development of catecholaminergic polymorphic ventricular tachycardia (CPVT) include:^[1][2]

• Physical activity such as exercise,
• Stress,
• Young age,
• Family history of syncope or sudden death, and
• Family history of CPVT.

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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]

There is insufficient evidence to recommend routine screening for Catecholaminergic polymorphic ventricular tachycardia. But screening among relatives is indicated when a likely pathogenetic mutation is identified in clinically affected index cases. Screening methods for CPVT are exercise stress testing and genetic testing.

• Screening of all the first-degree relatives is indicated when a likely pathogenetic mutation is identified in clinically affected index cases.
• Clinical and genetic evaluation, including exercise stress testing is recommended for both first- and second-degree relatives.
• Exercise stress testing has a specificity of 97% and a sensitivity of 50% for predicting the presence of the familial CPVT-associated mutation in asymptomatic relatives of CPVT patients.^[1][2][3]
• Genetic testing for RyR2 and CASQ2 mutations should also be considered in first-degree relatives, even with a negative clinical phenotype.
• Screening by repeat exercise testing is also recommended in first-degree relatives of mutation-negative patients with CPVT, depending on the age of the relative.^[4]

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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]

If left untreated, approximately 30% of patients experience at least one cardiac arrest and up to 80% one or more syncopal spells. Common complications of catecholaminergic polymorphic ventricular tachycardia include ventricular fibrillation, sudden cardiac arrest, and sudden cardiac death. Prognosis is generally poor, and the 10-year mortality of patients with catecholaminergic polymorphic ventricular tachycardia is approximately 40%.

• The symptoms of CPVT usually develop during childhood and adolescence, in the first and second decades of life, and start with symptoms such as episodes of syncope.
• More than 30% of affected individuals will experience symptoms before the age of 10 years and the majority (60% to 80%) of the patients will have one or more symptomatic arrhythmia episodes before age 40.^{[1] [2] [3] [4]}
• However, molecular analysis showed that there is a small group of patients who remain asymptomatic, even after exercise tests suggesting them to be having normal phenotype CPVT (mutation carriers). Some of these phenotypically normal patients with CVPT do experience syncope and sudden death.^[5]
• If left untreated, CPVT is highly lethal, as approximately 30% of patients experience at least one cardiac arrest and up to 80% one or more syncopal spells.^[1][2]
• The polymorphic ventricular tachycardia may self-terminate or it may degenerate into ventricular fibrillation, causing sudden cardiac death.

• Common complications of catecholaminergic polymorphic ventricular tachycardia include:
  • Ventricular fibrillation
  • Sudden cardiac arrest
  • Sudden cardiac death

• Prognosis is generally poor, and the 10-year mortality of patients with CPVT is approximately 40%.^[3]
• Studies show that there is a correlation between the age of the first syncope and the severity of the disease, with a worse prognosis in the case of early occurrence.^[1]
• If left untreated, patients with CPVT have a mortality rate of 30% before age 40.^[2][5]

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