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Catecholaminergic polymorphic ventricular tachycardia (CPVT)

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CPVT is an uncommon condition associated with developing complex, polymorphic, or bidirectional ventricular tachycardia in response to exercise or emotional stress in a structurally normal heart.[1][2][3]

Lately, significant cardiac events caused by CPVT have been described in the literature also occurring during rest or regular activities of daily life, challenging previous understanding of the condition.[4] The ECG of a person who has CPVT shows no resting abnormalities.[5] In a small number of cases, the disease can be acquired during the lifetime, but in most cases, it is hereditary.[6] The condition's other names are familial polymorphic ventricular tachycardia, catecholamine-induced polymorphic ventricular tachycardia, and bidirectional tachycardia induced by catecholamines.

Epidemiology

The rare disease is estimated to be present in one out of 10,000 people. [1][2][7] However, based on recent information, CPVT is suggested to cause 12% of sudden death in a normal heart.[8] The disease has a bimodal distribution. Most cases are identified before age 20, frequently within the first 10 years of life,[1] although some cases are diagnosed later, 32 to 48.[8] Females that have no identifiable genetic mutation are more frequently diagnosed at a later age.

Genetics

The disease has been associated with mutations affecting calcium homeostasis in cardiac myocytes.[5] More than 160 mutations are known to cause CPVT.[5] A mutation affecting the cardiac ryanodine receptor (RYR2) is the CPVT's predominant cause (60-70%).[2][3][4][5][6][9] Most cases with a change in the RYR2 gene inherit the disease in an autosomal dominant pattern.[4][5] In a small number of cases, RYR gene region duplication causing CPVT was inherited in an autosomal recessive pattern.[5][10]

The other well-known mutation causing CPVT affects gene coding for the calsequestrin 2 protein of cardiac muscle cells (CASQ2). It is considered the cause of CPVT in only 2 – 5% of the cases.[3] CALM1 or CALM3, TRDN, TECRL, KCNJ2, NKYRN-B, and PKP2 are less prevalent gene mutations associated with the development of CPVT.[5] Some other genes will likely be found in the future as no mutations were identified in more than 20% of the patients with PCVT. The disease has variable expressivity.[5]

Clinical presentation, diagnosis

Cardiac symptoms are present at the time of diagnosis in more than ¾ of the patients. Syncope is the most common presenting abnormality.[4] Palpitations, vertigo, and dizzy spells are some of the other symptoms. Cardiac arrest and sudden death can also be the first presentations. Normal resting ECG may cause the diagnosis to be missed early in the course of the disease. In some cases, the arrhythmia is brief and terminates on its own. A person may be asymptomatic, or symptoms resolve with the termination of the arrhythmia.[1][2][5] However, bidirectional or polymorphic ventricular tachycardia both have a high risk of transforming into ventricular fibrillation and once it happens, immediate resuscitation is necessary to avoid sudden death.

The exercise stress test (EST) is used for diagnosis and can be substituted with epinephrine infusion in patients who cannot exercise.[6] Holter or loop monitor tests may also be helpful in individuals who experience symptoms predominantly with emotional stress. Rhythm analysis with stress will show premature ventricular contractions that increase in frequency and complexity with activity and may transform into non-sustained or sustained ventricular tachycardia (VT). Both bidirectional and polymorphic VT are characteristic of the condition.[2][5][6][11] Bidirectional VT is characterised by a beat-to-beat shifting of the QRS complex frontal axis from right to left. Polymorphic VT shows QRS complexes of multiple morphologies that continuously change.[6]

Diagnostic criteria based on the Expert Consensus Statement endorsed in 2013 are presented below.[1]

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Diagnostic criteria

  1. CPVT is diagnosed in the presence of a structurally normal heart, normal ECG, and unexplained exercise or catecholamine-induced bidirectional VT or polymorphic ventricular premature beats or VT in an individual <40 years of age.
  2. CPVT is diagnosed in patients (index case or family member) with a pathogenic mutation.
  3. CPVT is diagnosed in family members of a CPVT index case with a normal heart who manifest exercise-induced premature ventricular contractions (PVCs) or bidirectional/polymorphic VT.
  4. CPVT can be diagnosed in the presence of a structurally normal heart and coronary arteries, normal ECG, and unexplained exercise or catecholamine-induced bidirectional VT or polymorphic ventricular premature beats or VT in an individual > 40 years of age.

Genetic testing

Genetic testing is not required for diagnosis when symptoms and/or evidence of catecholamine-induced arrhythmia meet the diagnostic criteria. However, a genetic test is necessary to diagnose asymptomatic individuals who have family members with the condition. Negative EST does not exclude the disease in such cases.[5] RYR2 and CASQ2 are recommended for all patients, and RYR2 is expected to be the most frequent causative mutation. If a proband's mutation is unknown, in addition to RYR2 and CASQ2, the following genes are frequently added as a second line: KCNJ2, TRDN, CALM 1, CALM3, TECRL. [12][13]

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Treatment

Exercise restriction and avoidance of stressful situations are essential in patients with CPVT. Medication such as beta-blockers is a first-line treatment for the condition.[1][2][5] Beta-blockers are recommended both for symptomatic and asymptomatic patients.[2][14] Flecainide reduces the risk of ventricular arrhythmias with exercise and is frequently included in the treatment.[5]

Implantable cardiac defibrillators (ICDs), which are frequently the treatment of choice in some other channelopathies, must be used more carefully in PCVT patients. ICDs have an additional risk for PCVT patients, as the electric shock may trigger an electrical storm due to adrenergic stimulation.[14][15] Due to such risk, ICD may be ineffective and usually is considered in combination with antiarrhythmic medication if pharmacologic treatment is insufficient.

For patients who still have arrhythmia despite pharmacologic treatment or a combination of ICD and medical therapy, left ventricle sympathetic denervation (LVSD) is an alternative treatment. However, the procedure is not widely available.[2][5][15]

In an isolated case, cardiac transplantation was done for a patient with CPVT with refractory arrhythmia, resulting in a cure for the condition.[1][14]

Mortality risk

Based on 2003 data, mortality was 40% within 10 years after diagnosis.[7] With time, survival has shown improvement. Based on the literature review, it is clear that a number of challenges associated with the condition predispose to an unfavourable outcome: Diagnosis is challenging at an early stage, and 9 years may pass between the first presentation and diagnosis.[8] Also, not adhering to recommended protocols appears to be an issue in the number of studies in treated patients. Young age at the time of diagnosis has been identified as an independent predictor of higher mortality. Recent studies have noted that breakthrough arrhythmia with beta-blockers ranges from 3% to 11% annually.[16] Beta-blockers are not effective as a single medication in the long run. When added to beta-blockers, flecainide has reduced exertional arrhythmia in 85% of the cases, but based on a microscopic study with only 14 patients.[7][16] It demonstrated 74% efficacy in genotype-positive and 92% efficacy in negative-genotype individuals.[17]

An international study, published in 2015, evaluated left ventricular sympathetic denervation (LVSD) in 63 participants with CPVT, most of whom had RYR2 mutation.

The median follow-up of the study post-treatment was 37 months. There was a demonstrated reduction of arrhythmic events, and in some cases, previously symptomatic patients had no arrhythmia during follow-up. However, 24% of previously symptomatic individuals had arrhythmia recurrence.[18][19] Patients on ICD demonstrated arrhythmia followed by appropriate shocks less frequently, from 3.6 events per person per year to 0.6, which was favourable. Also, previously asymptomatic patients did not develop symptoms or significant arrhythmia within the time of observation. The treatment has rare risks (Horner's syndrome and pneumothorax). Based on the study, the treatment has benefits. However, the arrhythmia recurrence rate is still high in previously symptomatic individuals. The treatment is not yet widely available. In the case of previously asymptomatic individuals, a more extended observation period is desirable.

In a study published in 2019, ICD efficacy and side effects were assessed in patients with newly diagnosed CPVT and a history of sudden cardiac arrest.

The study included 136 participants from the International CPVT Registry. ICDs were implanted in 58% of the patients, while others only had treatment with beta-blockers, flecainide, and/or LVSD and were considered adequately protected with such measures. ICD was used primarily in older patients (median age 16 years). The median age of patients without ICD was 11 years. During the follow-up of 4.8 years, sudden cardiac death (SCD) was registered in 3.8% of the patients treated with ICD and in no patients without ICD. Also, SCD, appropriate shock, and SCA were more frequent in patients with ICD (46.8% vs. 15.8%) or 9.7 events per 100 person-years compared to 2.3 events in 100 person-years. Inappropriate shocks and device-related complications were also high, 24.7% and 28.9%, respectively. Thus, ICD was not found to be providing improved survival for these patients.[17] Analysis of the study noted that in the group that did not receive ICD, the frequency of occurrence of the composite outcome of SCA and syncope was still high to consider underwriting. Non-adherence to medication mentioned in the literature before the study and in the study confirms the same in the younger than 14 with or without ICD.[17]

A study, published in 2012, included 116 asymptomatic relatives of probands identified through genetic screening (RYR2 mutations).

Of the 116 asymptomatic individuals, 88 did not demonstrate VT during the initial investigation and testing. Some of them were lost to follow-up, and 65 were re-evaluated. Out of these 65 individuals, 6 (9.2%) developed non-sustained ventricular tachycardia despite treatment in a median follow-up of only 2.4 years.[20] According to the study's results, the risk of developing significant arrhythmia in asymptomatic patients is still high.

Conclusions

Successful therapy of PCVT patients remains challenging. Pharmacologic therapy alone is not always sufficient. Some other treatment choices exist, such as cardiac sympathetic denervation, but longer observation time is necessary to assess successful treatment in both previously symptomatic and asymptomatic patients. ICD therapy does not provide sufficient benefit in many cases of CPVT.

It does not seem feasible to make offers to individuals diagnosed with PCVT and who had symptoms or cardiac events before diagnosis. There is no sufficient evidence of acceptable risk to consider offers to individuals diagnosed with CPVT that are asymptomatic at the time of application even if on treatment. Once the diagnosis is made, the mortality risk is still too high to offer.

With a positive family history, in the areas where genetic testing results can be taken into consideration, the CPVT-causing mutation of the family member is known, and the applicant's genetic test is negative, the offer can be made without loading. Otherwise, with a positive family history, the risk is too high to consider an offer.

Author

Dr Tea Mamaladze

Medical Consultant

Life & Health - Risk Assessment

February 2025

References

  1. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):1932-1963. doi:10.1016/j.hrthm.2013.05.014.
  2. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the Europea. European Heart Journal. 2015;36(41):2793-2867l. doi:10.1093/eurheartj/ehv316.
  3. Ng K, Titus EW, Lieve K v., et al. An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2 -Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation. Published online 2020:932-947. doi:10.1161/CIRCULATIONAHA.120.045723.
  4. Roston TM, Yuchi Z, Kannankeril PJ, et al. The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: Findings from an international multicentre registry. Europace. 2018;20(3):541-547. doi:10.1093/europace/euw389.
  5. Baltogiannis GG, Lysitsas DN, di Giovanni G, et al. CPVT: Arrhythmogenesis, Therapeutic Management, and Future Perspectives. A Brief Review of the Literature. Frontiers in Cardiovascular Medicine. 2019;6. doi:10.3389/fcvm.2019.00092.
  6. Catecholaminergic polymorphic ventricular tachycardia - UpToDate. Accessed March 22, 2021. https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia?source=autocomplete&index=0~1&search=CPV#H2803097562.
  7. Sumitomo N. Current topics in catecholaminergic polymorphic ventricular tachycardia. Journal of Arrhythmia. 2016;32(5):344-351. doi:10.1016/j.joa.2015.09.008.
  8. The Athlete With Catecholaminergic Polymorphic Ventricular Tachycardia - American College of Cardiology. Accessed March 18, 2021. https://www.acc.org/latest-in-cardiology/articles/2017/07/27/07/49/the-athlete-with-catecholaminergic-polymorphic-ventricular-tachycardia.
  9. Tester DJ, Ackerman JP, Giudicessi JR, et al. Plakophilin-2 Truncation Variants in Patients Clinically Diagnosed With Catecholaminergic Polymorphic Ventricular Tachycardia and Decedents With Exercise-Associated Autopsy Negative Sudden Unexplained Death in the Young. JACC: Clinical Electrophysiology. 2019;5(1):120-127. doi:10.1016/j.jacep.2018.09.010.
  10. Tester DJ, Bombei HM, Fitzgerald KK, et al. Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 among Children with Exertion-Related Unexplained Sudden Deaths in the Amish Community. JAMA Cardiology. 2020;5(3):340-345. doi:10.1001/jamacardio.2019.5400.
  11. Schwartz PJ, Ackerman MJ, George AL, Wilde AAM. Impact of genetics on the clinical management of channelopathies. Journal of the American College of Cardiology. 2013;62(3):169-180. doi:10.1016/j.jacc.2013.04.044.
  12. Orphanet: Catecholaminergic polymorphic ventricular tachycardia. Accessed March 30, 2021. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3286.
  13. Genetic testing for Cardiac arrest, Catecholaminergic polymorphic ventricular tachycardia (CPVT), Syncope and collapse, Abnormal ECG | Blueprint Genetics. Accessed March 30, 2021. https://blueprintgenetics.com/tests/panels/cardiology/catecholaminergic-polymorphic-ventricular-tachycardia-cpvt-panel/.
  14. Roy S, Hong W, Wasilewski M, Ellenbogen KA. Cardiac Transplantation for Refractory Catecholaminergic Polymorphic Ventricular Tachycardia. JACC: Case Reports. 2020;2(11):1757-1761. doi:10.1016/j.jaccas.2020.07.017
  15. Lüscher TF. Ischaemic and genetic causes of fatal arrhythmias and sudden death. European Heart Journal. 2019;40(35):2927-2930. doi:10.1093/eurheartj/ehz635.
  16. Kannankeril PJ, Moore JP, Cerrone M, et al. Efficacy of flecainide in the treatment of catecholaminergic polymorphic ventricular tachycardia a randomized clinical trial. JAMA Cardiology. 2017;2(7):759-766. doi:10.1001/jamacardio.2017.1320.
  17. van der Werf C, Lieve K v., Bos JM, et al. Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest. European Heart Journal. 2019;40(35):2953-2961. doi:10.1093/eurheartj/ehz309.
  18. de Ferrari GM, Dusi V, Spazzolini C, et al. Clinical management of catecholaminergic polymorphic ventricular tachycardia the role of left cardiac sympathetic denervation. Circulation. 2015;131(25):2185-2193. doi:10.1161/CIRCULATIONAHA.115.015731.
  19. Dusi V, de Ferrari GM, Pugliese L, Schwartz PJ. Cardiac Sympathetic Denervation in Channelopathies. Frontiers in Cardiovascular Medicine. 2019;6:27. doi:10.3389/fcvm.2019.00027.
  20. van der Werf C, Nederend I, Hofman N, et al. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. Circulation: Arrhythmia and Electrophysiology. 2012;5(4):748-756. doi:10.1161/CIRCEP.112.970517.

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