approach to inherited arrhythmogenic diseases

1. Approach to
Channelopathies
DR. NEERAJ VARYANI
ASSISTANT PROFESSOR
CARDIOLOGY DEPARTMENT
SUPER SPECIALITY PAEDIATRIC
HOSPITAL & POST GRADUATE
TEACHING INSTITUTE, NOIDA

2. Definition: Group of inherited arrhythmogenic diseases
(IADs) caused by mutation on genes encoding for ion
channel proteins and proteins that regulate ion
channels.
Incomplete penetrance and variable expressivity -
distinctive ECG patterns may be concealed.
Although rare they are potentially fatal but
preventable causes of sudden cardiac death (SCD) in
children.

4. Comprehensive management of IADs include
diagnosing and treating the proband and
identifying and protecting affected family
members.
The concept of cardiogenetics and molecular
autopsy.
Case based rather than a disease based strategy
is the key to success.

5. Classification of
Channelopathies
Channelopathies Associated With Prolonged
Repolarization- Long QT syndrome (LQTS)
Channelopathies Associated With Abbreviated
Repolarization and Conduction Defects- Brigade
Syndrome (BrS), Short QT syndrome (SQTS), early
repolarization syndrome, Sinus node dysfunction, and
progressive conduction defects and overlap syndromes.
Channelopathies Associated With Abnormal
Calcium Handling- CPVT

7. LQTS
Definitions and epidemiology: either QTc>=480ms in repeated
12-lead ECGs or LQTS risk score ( Schwartz score) >3 or
presence of confirmed pathogenic mutation irrespective of the QT
duration in the absence of secondary causes for QT prolongation(
COR: I LOE: C).
Presence of QTc>=460ms in repeated 12-lead ECGs in patients
with an unexplained syncopal episode in absence of secondary
causes for QT prolongation.
QT interval measurement- traces with constant RR interval for at
least 10 to 20 beats and excluding traces with HR >100 bpm and
< 50 bpm.

10. Mean age- 12-14 years. Manifest with syncope and cardiac
arrest.
Annual rate of SCD in untreated patients is 0.33 - 0.9% and
syncope is around 5%.
10 to 35% of genetically affected patients show normal QTc.
QTc is most important indicator of risk.
Mutation in 13-19 genes have been associated with LQTS.
Genetic screening identifies a disease causing mutation in 75% of
cases and 3 main genes (KCNQ1,KCNH2 and SCN5A) account
for 90% of positively genotyped cases.

13. Subtypes of LQTS may be grouped into 3 categories:
Autosomal dominant LQTS (Romano-Ward syndrome; prevalence 1 in 2500.
Autosomal dominant LQTS with extra cardiac manifestation,
- LQT7 (Anderson Tawil syndrome) has mild QT prolongation with
prominent U wave, polymorphic or bidirectional VT, facial dysmorphisms and
hyper-/hypokalemic periodic paralysis and LQT8 ( Timothy syndrome)
characterized by marked QT prolongation, syndactyly, paroxysmal
hypoglycemia, atrioventricular block, congenital heart defects, autism and
immunodeficiency.
Autosomal Recessive LQTS ( Jervell and Lange-Nielsen syndrome),
prolonged QT with sensineural deafness.

14. Risk stratification and management in LQTS
Clinical, electrocardiographic and genetic parameters are
considered for risk stratification.
Survivors of cardiac arrest have a high risk of recurrence
even on beta-blockers(14% within 5 years on therapy): this
evidence supports use of ICD in this group. ( COR I LOE B)
Syncope and/or VT on beta-blockers: ICD (COR IIa LOE B)
Asymptomatic carriers of KCNH2 or SCN5A when
QTc>500ms: ICD ( COR IIb LOE C)

16. Silent carriers of pathogenic mutations : risk of cardiac
events around 10% between birth and age 40 years; beta-
blockers should be considered.(COR IIa LOE B)
Women with LQTS have an increased risk during the 9
month post-partum period(especially women with LQT2
Genotype) prophylactic ICD may be considered.
Patients with QTc > 500ms and signs of electrical instability
and patients with high risk genetic features (Jervell and
Lange-Nielsen syndrome or Timothy syndrome)-
prophylactic ICD may be.

17. Lifestyle changes: avoidance of QT prolonging
drugs(http://www.crediblemeds.org);correct
dyselectrolytemia;avoidance of genotype specific triggers.(COR I LOE
B)
Beta-blockers recommended with diagnosis of LQTS.(COR I LOE B)
Left cardiac sympathetic denervation (LCSD) in symptomatic LQTS
- beta-blockers not effective, not tolerated or contraindicated;ICD
therapy contraindicated or refused; patients on beta-blockers with an
ICD experience multiple shocks.(COR IIa LOE C)
Sodium channel blockers (mexiletine,flecainide or ranolazine) may
be considered as add on therapy for LQTS3 with QTc>500ms.(COR
IIb LOE C)

18. Brugada syndrome
“Right bundle branch block, persistent ST segment elevation, and
sudden death syndrome”/“ sudden unexplained nocturnal death
syndrome”;bangungut in Philippines,pokkuri in Japan or lai tai in
thailand.
Definitions and epidemiology: ST-segment elevation with type 1
(coved) morphology>= 2mm in one or more leads among the right
precordial leads V1 and/or V2 positioned in the second, third or fourth
intercostal space, occurring either spontaneously or after provocative
drug test with intravenous sodium channel blockers ( ajmaline,
flecainide,procainamide or pilsicainide) ( COR I LOE C)
South east Asia > western countries; prevalence 1 in 1000 to 1 in
10000.

20. Autosomal dominant with age and sex related penetrance.
Mean age 3rd to 4th decade; M:F= 8:1(hormones); during
sleep or rest.
Incidence of arrhythmic events( VT/VF, appropriate ICD
therapy or sudden death): 13.5%/yr ( h/o cardiac arrest),
3.2%/yr ( h/o syncope) and 1%/yr (asymptomatic).
12 to 24 genes have been associated with BrS.
Results of genetic screening do not influence prognosis or
treatment.

23. Risk stratification and management in BrS
Survivors of aborted cardiac arrest and/or documented
sustained VT : ICD recommended (COR I LOE C)
Spontaneous type 1 ECG pattern and h/o syncope : ICD
should be considered (COR IIa LOE C)
ICD may be considered for VF during PVS with two or three
extra stimuli at two sites. (COR IIb LOE C)
Catheter ablation may be considered with h/o electrical storms
or repeated appropriate ICD shocks. (COR IIb LOE C)

24. Quinidine and isoproterenol should be considered in patients
with BrS with electrical storms.(COR IIa LOE C)
Quinidine should be considered in patients who qualify for
ICD but present a contraindication or refuse it and to treat
Supraventricular arrhythmias.(COR IIa LOE C)
Life style changes: Avoid drugs that may induce ST-segment
elevation in right precordial
leads(http://www.brugadadrugs.org);avoid excessive alcohol
intake and large meals; prompt treatment of fever with
antipyretics. (COR I LOE C)

25. Short QT syndrome
(SQTS)
Definitions and epidemiology:
Diagnosis: QTc<=340ms(COR I LOE C).
SQTS should be considered with QTc<= 360ms and one or more of the following:
confirmed pathogenic mutation; family h/o SQTS; family h/o sudden death at < 40
years; survival from a VT/VF episode in absence of heart disease
5-6 genes have been linked , but yield of genetic screening remains low ( around
20%). Autosomal dominant with high penetrance.
Peak of incidence during first year of life followed by a quiescent phase
encompassing adolescence and another peak at old age.
Cardiac arrest probability by age of 40 years is 40%.
Symptoms: cardiac arrest(40%), syncope(25%), AF (20%)

26. Additional ECG findings that facilitate diagnosis: tall, peaked, symmetrical, and
narrow based T waves, prominent U waves, depression of PQ segment, or a QRS
complex directly followed by a T wave. QTc should be measured at different values
of HR and mostly around 60 bpm.

27. Risk stratification and management in SQTS
Survivors of aborted cardiac arrest, and/or documented
spontaneous sustained VT: ICD recommended (COR I LOE C)
Quinidine or sotalol may be considered in patients who qualify for
ICD but present a contraindication or refuse it (COR IIb LOE C)
Quinidine or sotalol may be considered in asymptomatic SQTS
patients with family h/o SCD (COR IIB LOE C)
Invasive EPS with PVS is not recommended for SCD risk
stratification (COR III LOE C)

28. Catecholaminergic Polymorphic
Ventricular Tachycardia (CPVT)
Definitions and epidemiology
CPVT is diagnosed in presence of structurally normal heart, normal ECG and
exercise or emotion- induced bidirectional or polymorphic VT.(COR I LOE C)
CPVT is diagnosed in patients who are carriers of pathogenic mutation(s) in
genes RyR2 (autosomal dominant) or CASQ2 (autosomal recessive) (COR I LOE
C)
Prevalence 1 in 10000. Presents during first decade.Physical activity or
emotional stress induced syncope and cardiac arrest leading to SCD.
Differences from LQTS are more severe clinical manifestation, reduced
response to beta-blockers, higher penetrance, short runs of AF and supra
ventricular arrhythmias during exercise, typical pattern of reproducible
arrhythmias and their prompt decrease on interruption of exercise.

30. Risk stratification and management in CPVT
Diagnosis in childhood, lack of beta-blocker therapy and persistence of
complex arrhythmias during exercise stress test on a full dose of beta-
blockers are predictors for arrhythmia events.
CPVT patients who experience cardiac arrest, recurrent syncope, or
polymorphic/bidirectional VT despite optimal therapy: ICD in addition to
beta-blockers with or without flecainide is recommended(COR I LOE C)
ICD should be programmed with long delays before shock delivery to
avoid malignant cycle of ICD shocks and death.
PVS has no diagnostic or prognostic value.

31. Beta-blockers are recommended in all patients (COR I
LOE C)
Therapy with beta-blockers for genetically positive family
members even after negative stress test(COR IIa LOE C)
Flecainide should be considered in addition to beta-
blockers in patients with recurrent syncope or
polymorphic/bidirectional VT while on beta-blockers when
there are risk/contraindications for ICD or ICD not
available or rejected by the patient (COR IIa LOE C)
31

33. Flecainide should be considered in addition to beta-blockers
in carriers of ICD to reduce appropriate ICD shocks(COR IIA
LOE C)
LCSD may be considered-recurrent syncope or
polymorphic/bidirectional VT/several appropriate ICD shocks
while on beta-blockers and beta-blockers plus flecainide and
patients who are intolerant/contraindication to beta-blockers.
(COR IIb LOE C)
Life-style changes are recommended like avoidance of
triggers (COR I LOE C)

34. Concluding remarks
SCD major cause of death mainly in young
populations.
Comprehensive genotype-phenotype studies in large
cohort of families are needed for IADs.
Cardiogenetic Team approach including cardiologist,
geneticists, genetic counselors, and even
psychologists.
Judicious use of genetic testing in patients with definite
phenotype.

35. THANK YOU