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
1:1000
1:2000
1:2500
(HOCM)
(ARVD)
(LQTS, CPVT, Brugada syndrome)
(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
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•
•
•
•
•
•
•
•
•
Albuterol
Alfuzosin
Amiodarone
Amphetamine
Azithromycin
Ciprofoxacin
Clarythhromycin
Diphenhydramin
Dobutamine
Dopamine
epinephrine
erythromycin
famotidine
flecainide
gatifloxacin
imipramine
ketoconazole
levofloxacin
moxifloxacin
ofloxacin
roxithromycin
salmeterol
sertraline
sotalol
tamoxifen
terbutaline
SXT
vardenafil
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