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: Copyright © American Heart Association

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

QT Prolonging Drugs Albuterol epinephrineroxithromycin Alfuzosin erythromycinsalmeterol Amiodarone famotidinesertraline Amphetamine flecainidesotalol Azithromycin gatifloxacintamoxifen Ciprofoxacin imipramineterbutaline Clarythhromycin ketoconazoleSXT Diphenhydramin levofloxacinvardenafil Dobutamine moxifloxacin Dopamine ofloxacin

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)

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

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: 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:

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