Genetic Testing in Patients with Arrhythmia and Risk for Sudden Cardiac Death : Indications and Implications for Practice

Mary Gertrude Ong-Cordovez, M.D.

Cebu City

Inherited Cardiac Arrhythmias

• Channelopathy (ion channel disease)• LQTS• CPVT• Brugada Syndrome

• Primary Structural Heart Disease (cardiomyopathies)• ARVC/D• HOCM• Familial DCM

Epidemiology

• 1:500 (HOCM)• 1:1000 (ARVD)• 1:2000 (LQTS, CPVT, Brugada syndrome)• 1:2500 (DCM)

Ion Channel Diseases

LQTS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 (65%)

Brugada syndrome: SCN5A (25% to 30%)

CPVT: RYR2 (60%), possibly CASQ2

Cardiomyopathies

ARVD: PKP2, DSP, DSG2 (60%)

HOCM: MYH7, MYBPC3, TNNT2 (60%)

DCM: LMNA, MYH7, TNNT2, SCN5A (20% to 30%)

LQTS

Genotype-phenotype correlations in long-QT syndrome.

Tester D J , Ackerman M J Circulation 2011;123:1021-1037

Copyright © American Heart Association

LQTS

• Management• Beta Blockers• Mexilitene, flecainide, propanolol• Treat hypokalemia and hypomagnesemia• ICD• Avoid QT prolonging drugs

QT Prolonging Drugs

• Albuterol epinephrine roxithromycin• Alfuzosin erythromycin salmeterol• Amiodarone famotidine sertraline• Amphetamine flecainide sotalol• Azithromycin gatifloxacin tamoxifen• Ciprofoxacin imipramine terbutaline• Clarythhromycin ketoconazole SXT• Diphenhydramin levofloxacin vardenafil• Dobutamine moxifloxacin• Dopamine ofloxacin

www.qtdrugs.org

Ion Channel Diseases

LQTS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 (65%)

Brugada syndrome: SCN5A (25% to 30%)

CPVT: RYR2 (60%), possibly CASQ2

ARVD: PKP2, DSP, DSG2 (60%)

Recommendations for Genetic Testing

• Cardiac arrest survivor ++• Syncope

• QTc abnormal ++• QTc borderline +/-• QTc normal _

• Asymptomatic • QTc abnormal ++• QTc borderline _

• First degree relative• Proband genotype + ++• Proband genotype _ _

Canadian J of Cardiology 27(2011) 232-248

Brugada Syndrome

Brugada Syndrome

• Management• Beta blocker and amiodarone• Quinidine• Aggressive fever control• Avoid strenuous physical activity• ICD• Avoid sodium channel blocker

Na Channel Blockers

• Anti-arrhythmic drugs• Flecainide, propafenone, ajmalin, procainamide

• Psychotropic Drugs• Amitriptyline, lithium, nortriptyline, trifluoperazine

• Anesthetics/Analgesics• Bupivacaine, procaine, profolol

• Others• Acetylcholine, alcohol, cocaine, ergonovine

Ion Channel Diseases

LQTS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 (65%)

Brugada syndrome: SCN5A (25% to 30%)

CPVT: RYR2 (60%), possibly CASQ2

Recommendations for Genetic Testing (Brugada Syndrome)

• Cardiac arrest survivor• Type I Brugada ECG pattern ++• Type 2 or 3 ECG pattern __

• Syncope• Type I Brugada ECG pattern ++• Type 2 or 3 ECG pattern __

• Asymptomatic• Type I Brugada ECG pattern ++• Type 2 or 3 ECG pattern __

• First Degree Relative• Proband genotype positive ++

• Proband genotype negative ___

CPVT

CPVT

• Management• Beta blockers• Flecainide/cardiac sympathectomy• ICD• Avoid intense physical exercise

Ion Channel Diseases

LQTS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 (65%)

Brugada syndrome: SCN5A (25% to 30%)

CPVT: RYR2 (60%), possibly CASQ2

Recommendations for Genetic Testing (CPVT)

• Clinically suspected CPVT ++

• First degree relative• Proband genotype + ++

ARVD/C

• Task Force Criteria • RV function• Tissue characteristic of the myocardium• ECG repolarization abnormalities• Arrhythmias• Family history• Genetic testing

ARVD

• Management• Avoid competitive sports• ICD

• Documented ventricular arrhythmias

Cardiomyopathies

ARVD: PKP2, DSP, DSG2 (60%-70%)

HOCM: MYH7, MYBPC3, TNNT2 (60%)

DCM: LMNA, MYH7, TNNT2, SCN5A (20% to 30%)

Recommendations for Genetic Testing (ARVD)

• Clinical ARVD ++• Clincal ARVD no ID at risk family members __• Clinically suspected ARVD ++• First degree relative

• Genotype positive ++• Genotype negative __

HOCM

• Echocardiography• MRI

Management

• Asymptomatic• Treat risk factors- HPN, DM, dyslipidemia, obesity

• Beta-blockers• Angina and dyspnea

• verapamil• Septal reduction Rx

• surgical septal myectomy/ alcohol septal ablation• Drug refractory and LVOT obstruction

• ICD

Indications for ICDs in HCM. *SCD risk modifiers include established risk factors and emerging risk modifiers (Section 9.4.2).

et al. Circulation 2011;124:2761-2796

Copyright © American Heart Association

Management

• Asymptomatic• Treat risk factors- HPN, DM, dyslipidemia, obesity

• Beta-blockers• Angina and dyspnea

• verapamil• Septal reduction Rx

• surgical septal myectomy/ alcohol septal ablation• Drug refractory and LVOT obstruction

• ICD• Exercise restriction

HOCM

• Exercise• Permitted

• Bowling, brisk walking, golf, skating, snorkeling, treadmill, biking

• Strongly discouraged• Basketball, body building, rock climbing , sprinting,

soccer, tennis , wind surfing, scuba diving

Circulation 2011;124:2761-2796

Cardiomyopathies

ARVD: PKP2, DSP, DSG2 (60%-70%)

HOCM: MYH7, MYBPC3, TNNT2 (60%)

DCM: LMNA, MYH7, TNNT2, SCN5A (20% to 30%)

Recommendationf for Genetic Testing (HOCM)

• Clinically diagnose HOCM• Family screening ++• Diagnosis __• Risk stratification/Rx decisions __

DCM

• Cardiac imaging studies• Cardiac biopsy- diagnostic tool

• Management• ACEI, B blockers, spironolactone• ICD - EF <35%• Biventricular pacing

Cardiomyopathies

ARVD: PKP2, DSP, DSG2 (60%-70%)

HOCM: MYH7, MYBPC3, TNNT2 (60%)

DCM: LMNA, MYH7, TNNT2, SCN5A (20% to 30%)

Recommendation for Genetic Testing (DCM)

• Clinically Dx DCM __

• Clinically Dx DCM w/ atrial arrhythmias/high grade conduction disease ++

(LMNA, SCNA5)

Future Perspective

• Gene sequencing will be faster and available more cheaply

• Multidisciplinary approach• Gray areas • Gene therapy