Catecholaminergic Polymorphic VT
- 1. CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA Dr Abhishek Rathore Sri Jayadeva Institute of Cardiovascular Science and research, Bangalore
- 2. Characterized by adrenergically mediated polymorphic ventricular arrythmias without structural heart disease. Prevalence 1 in 10,000 Mortality in severly affected, untreated patients is upto 50% before 20 yrs of age. A significant cause of SIDS Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
- 3. DEFINITION (ESC 2015) A definitive diagnosis of CPVT requires the presence of a structurally normal heart, normal ECG and exercise- or emotion- induced bidirectional or polymorphic VT. CPVT is diagnosed in patients who are carriers of a pathogenic mutation(s) in the genes RyR2 or CASQ2.
- 4. The hallmark of CPVT is bidirectional VT, characterized by beat-to-beat 180-degree alternating QRS axis (observed in minority of patients).
- 5. CLINICAL PRESENTATION Syncope. Aborted cardiac arrest. Sudden cardiac death. Some misdiagnosed as epilepsy (because CPVT-related syncope may include convulsive movements and urinary or fecal incontinence). Symptom onset in childhood ( between 7 to 9 yrs) Classical family history under similar conditions, but not always.
- 6. CARDIOLOGIC EXAMINATION Most patients have an unremarkable 12-lead resting ECG including a normal QTc interval. However, sinus bradycardia and prominent U waves on resting ECG can present.
- 7. The gold standard for diagnosis is provocative testing. Preferably through exercise. Typically, a gradual increase in ventricular arrhythmia burden and complexity is observed, starting with isolated VPBs at HR of 110 to 130 per minute. VPBs are late-coupled with a coupling interval of approximately 400 milliseconds. LBBB inferior axis and RBBB superior axis morphologies have consistently been shown in CPVT & VPB morphologies are reproducible in an individual patient.
- 9. Further exercise increases the number of isolated VPBs & eventually, polymorphic couplets or NSVT including bidirectional VT may be induced. In rare cases, this may further escalate to polymorphic sustained VT or VF. Ventricular arrhythmias rapidly recedes after exercise is terminated.
- 10. Holter monitoring, during which a patient should be encouraged to perform exercise, although its sensitivity is low. For example, it may be useful in young children or in other patients who are unable to perform an adequate exercise test.
- 11. Adrenaline infusion (initiated at a dose of 0.05 µg/kg/min and then titrated at 5-minute intervals to a maximum dose of 0.2 µg/kg/min) in CPVT has been advocated. But NOT RECOMMENDED Adrenaline infusion–provoked VAs consistent with CPVT when exercise testing or Holter monitoring is inconclusive. Sensitivity (28%) is less bec Max HR achieved was markedly lower than during exercise testing but specificity (98%) is more.
- 12. ROLE OF EP STUDY ?? No role in CPVT diagnosis. Because ventricular arrhythmias cannot be triggered other than by adrenergic stimulation.
- 13. ROLE OF CARDIAC IMAGING ?? In an index patient cardiac imaging is mandatory to exclude other causes of exercise-induced polymorphic tachyarrhythmias. Cardiac imaging by definition, unremarkable in CPVT. However some exceptions; Mutations in RYR2 in patients with fibrofatty myocardial replacement in the right ventricle, mimicking ARVD.
- 14. SUPRAVENTRICULAR DISEASE MANIFESTATIONS The most common supraventricular manifestation of CPVT is sinus bradycardia and/or sinus node dysfunction. RYR2 mutation carriers had a lower average resting heart rate. Heart rates tended to be lowest in males and in RYR2 mutation carriers. Other supraventricular dysrhythmias (16%): Intermittent ectopic atrial rhythm.
- 15. GENETIC BASIS
- 16. CARDIAC RYANODINE RECEPTOR GENE (CPVT 1) Disease locus: Ch 1q42-q43. AD RYR2 governs the release of calcium from SR, which initiates cardiac muscle contraction. More than 130 missense mutations in RYR2 are identified. Mutations in RYR2 are identified in approximately 60% of patients with a strong CPVT phenotype
- 17. CARDIAC CALSEQUESTRIN GENE (CPVT 2) AR CASQ2 - pivotal role in calcium homeostasis. Less than 5% of CPVT index cases.
- 18. OTHER CPVT TYPES Another autosomal recessive form, caused by mutations in triadin (TRDN). Triadin is a transmembrane SR protein and a component of calcium homeostasis. Skeletal muscle weakness is an associated feature of this CPVT form. Mutations in the gene encoding the potassium inwardly rectifying channel Kir2.1 (KCNJ2), which generally are associated with Andersen-Tawil syndrome, may cause a CPVT phenocopy, including the typical bidirectional ventricular tachycardia . Others- Ank 2, CALM1 gene mutation However, at the present time it is not clear whether they are phenocopies of CPVT
- 19. GENETIC TESTING IN CPVT Genetic testing has diagnostic but no therapeutic or prognostic value. According to HRS/EHRA, comprehensive CPVT genetic testing is indicated in probands in whom “a cardiologist has established a clinical index of suspicion for CPVT based on patient’s clinical history, FH & expressed ECG phenotype during provocative stress testing with cycle, treadmill or catecholamine infusion.” Genetic testing should be performed in young children, possibly even at birth because of young age of manifestation and its association with SIDS.
- 20. CASQ2 and TRDN screening is performed in consanguineous families. In mutation-negative cases with a strong CPVT phenotype from nonconsanguineous families, the remaining exons of RYR2 and CASQ2 are screened. KCNJ2 genetic testing is considered when an abundance of supraventricular or ventricular ectopy is present on Holter monitoring and/or a resting ECG correspond to Andersen-Tawil syndrome.
- 21. In relatives, genetic testing is critically important for identifying asymptomatic mutation-carrying relatives. Relatives who are noncarriers of the familial CPVT-causing mutation can be reassured and dismissed from further cardiologic evaluation.
- 22. DIFFERENTIAL DIAGNOSIS Long QT syndrome. Andersen-Tawil syndrome. Concealed structural heart disease (arrhythmogenic or hypertrophic cardiomyopathy , MVP & myocardial ischemia may be alternate diagnoses).
- 24. CPVT THERAPEUTIC INTERVENTIONS: RECOMMENDATIONS (ESC 2015) Class I 1. lifestyle changes: Avoid competitive sports/ strenuous exercise/ stressful environments. 2. Beta-blockers (either spontaneous or stress induced VAs). 3. ICD in addition to BB with or without flecainide in those who experience cardiac arrest, recurrent syncope or polymorphic/bidirectional VT despite OMT.
- 25. CPVT THERAPEUTIC INTERVENTIONS: RECOMMENDATIONS CONT... (ESC 2015) Class IIa Flecainide in addition to BB who experience recurrent syncope or polymorphic/bidirectional VT while on BB. Flecainide in addition to BB in patients with a diagnosis of CPVT and carriers of an ICD to reduce appropriate ICD shocks. BB in carriers of a pathogenic CPVT mutation even after negative exercise stress test. Class IIb LCSD in patients who experience recurrent syncope or polymorphic/bidirectional VT/several appropriate ICD shocks while on BB or BB plus Flecainide and in patients who are intolerant or with contraindication to BB. Class III Invasive EPS with PVS is not recommended for stratification of SCD risk.
- 26. RISK STRATIFICATION At present, very little is known about risk stratification. In general, CASQ2 mutation–related CPVT display a more severe phenotype as compared with RYR2mutation carriers. Young age at diagnosis & history of aborted cardiac arrest were associated with future cardiac events.
- 27. Two studies have reported promising results with verapamil in CPVT patients, but its long-term efficacy has been disappointing. When ventricular arrhythmias cannot be controlled by drug therapy, left cardiac sympathetic denervation (LCSD), is indicated. The lower half of the left stellate ganglion and thoracic ganglia T2 to T4 are removed.
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