Cardiac Channelopathies syndrome

1. CHANNELOPATHIES
January 3, 2018
Ashok Adhikari, MD
Adult cardiology fellow, Perpetual Succour
Hospital, Cebu City

2. ChannelopathiesTypes
■ Brugada Syndrome
■ LQTS
■ SQTS
■ CPVT

3. Channelopathies

4. Ion Channel Mutations
 Loss of Function
 SCN5A  Brugada
 IKs  LQT1
 IKr  LQT2
 Gain of Function
 SCN5A  LQT3
 IKs  Fam. A. Fib., Short QT
 IKr Short QT
4
0
1 2
3
Na
Ca > Na
IKr & IKs

5. Brugada Syndrome
■ Inheritable form of idiopathic ventricular arrhythmia
■ Loss Of Functional Mutations in the SCN5A gene [encodes for the α-subunit of the sodium channel]
■ Autosomal Dominant, predominantly in males; presentation at 40yrs
■ Prevalence- 1–5 per 10,000 worldwide [highest in Southeast Asia]
■ Family history of unexplained sudden death
■ ECG:ST-segment elevation in right precordial leads with right bundle branch block-like morphology
■ Increased risk for potentially lethal polymorphic VT or VF
[particularly during sleep in the absence of structural heart disease]

6. Gene Mutations in BrS

7. ECG Abnormalities

8. Pathophysiology
■ Loss of INa
■ Increased Ito current [Ito
Epi>>Endo]
■ Reduced in conditions
increasing ICaL currents
(catecholamines),
increasing AP duration

9. Pathophysiology
■ RV epicardium Ito conc maximum, hence there
is brugada pattern Action potential notch in
Right sided leads.
■ Prolongation of repolarization in the right
ventricular epicardial (Epi), but not endocardial
(Endo), cells results in T-wave inversion in the
surface electrocardiogram leadV1.
■ Since there is an increased contribution of the
transient outward current (Ito) in this area, this
discriminating electrophysiological mechanism
has been thought to be associated with ST-
segment elevation (Jwave) and T wave
inversion in BrS.

10. Pathophysiology
■ In a human study using the activation recovery interval (ARI) method, demonstrated that an
invertedT wave associated with a type 1 ECG pattern is due to preferential epicardialARI
prolongation secondary to accentuation of the AP notch in the RVOT
■ Fever increases Na channel inactivation

11. Pathophysiology
Cardiovascular Research 67 (2005) 367 – 378

12. Pathophysiology
Depolarization Disorder Hypothesis- conduction delay in RVOT

13. Diagnosis
■ Type 1  pronounced elevation of the J point and coved – type ST-
segment elevation >2 mm changes in > 1 right precordial lead (V1 toV3),
in the presence or absence of a Na channel blocker [Ajmaline, Flecainide,
and Procainamide] and one of the following
1. DocumentedVF
2. Self terminating polymorphicVT
3. Family history of SCD (<45 years)
4. Coved type ECGs in family members
5. Electrophysiological inducibility
6. Syncope
7. Nocturnal agonal respiration.

14. Diagnosis
■ Type 2  ECG pattern consists of
saddleback-type ST- segment
elevation of >2 mm (0.2mV)
followed by either a positive or
biphasicT wave.
■ Type3Type 3 shows either
saddleback- or coved-type ST-
segment elevation <1mm

15. Avoid
■ A febrile state
■ Electrolyte disturbances (hyperkalemia and hypercalcemia)
■ class ia/ic antiarrhythmic drugs
■ Vagotonic agents
■ Beta- adrenergic antagonists
■ Tricyclic antidepressants,
■ Antihistamines
■ Cocaine
all can induce ECG aggravation andVF

16. 1. Drug Challange
■ Pharmacological provocation should only be performed when the baseline ECG
is not diagnostic of BS.
■ Intravenous administration of Na+ channel blocking drugs like ajmaline,
flecainide, pilscanide and, procainamide, are useful in bringing out Type 1
Brugada pattern on the ECG when ECG changes are not diagnostic.
■ There is no advantage of inducing VT/VF, in performing it in the presence of
Type 1 BS pattern in the baseline ECG.
■ Drug administration should be stopped if:
■ Type 1 pattern becomes apparent on the ECG
■ Patient develops ventricular arrhythmias
■ QRS widens to 130% of the baseline
■ A total of 150mg flecainide is administered

17. Drug Challange
■ The patient needs to be monitored until the ECG is normalized.
■ Plasma half-life of flecainide is 20 hours.
■ Isoprenaline infusion may be employed to counteract if serious ventricular
arrhythmias develop.
■ Provocative drug challenge is helpful in asymptomatic family members of BS
and where the baseline ECG showsType 2 or 3 changes.
■ It is also performed as a part of investigations in survivors of cardiac arrest
without any apparent cause.
■ PR prolongation in the baseline ECG is a contraindication because of the risk of
inducing AV block.

18. 2. Positive EP study in BS
■ The protocol used for electrophysiological study used by Brugada et al
included:
 Measurement of conduction intervals and programmed electrical
stimulation from the RV apex with a minimum of 3 ventricular extra
stimuli at 3 different pacing rates.
 The shortest coupling interval was limited to 200 ms
 The test was considered positive if sustained arrhythmia lasting >30 s
or requiring intervention was induced.

19. 3. Risk stratification
■ Risk of life threatening arrhythmias in asymptomatic patients who only have
spontaneousType 1 ECG changes is moderate, between 0.24 and 1.7
■ Type 1 ST changes appear only after pharmacological provocation, the patients
are at minimal risk for arrhythmic events.
■ BS patients who have atrial fibrillation and fragmentation of QRS complexes in
their ECG are reported to be at a higher risk of spontaneousVF.
■ Patients presenting with aborted sudden death are at the highest risk.

20. 4. Asymptomatic individuals
■ The consensus report recommends:
1) EPS in asymptomatic patients with spontaneousType 1 ECG and
2) ICD implantation be recommended if the EPS is positive (Class 2A)
3) Close follow up, if the EP is negative
■ If the patient is asymptomatic and BS ECG changes are brought out only after a
drug challenge, it recommends EPS and ICD implantation if EPS is positive,
(Class 2B indication).
■ Several authorities have, however, questioned these recommendations and the
role of EPS in risk stratification.
■ ICD implantation in BS has been reported to have a high complication rate and
most authorities do not recommend it for asymptomatic patients.
■ A family history of sudden death does not translate into increased risk in
relatives.

21. Asymptomatic individuals
■ Febrile state causes loss of function of Ina channel, therefore
aggressive treatment of all febrile episodes is recommended
with antipyretics like aspirin and paracetamol and cold sponges.
■ Hypokalemia, large carbohydrate meals and alcohol and very
hot baths have also been incriminated and should be avoided.

22. 5. Indication for ICD in BS
■ A spontaneous type 1 ECG and the presence of at least two
multiparametric risk factors,
– syncope
– a family history
– a positive electrophysiological (EP) study
are the only criteria used to correctly identify patients requiring
ICD placement.
Source: Indication of ICD in Brugada syndrome - Journal of Arrhythmia

23. Management

24. Prognosis

25. LONG QT SYNDROME

26. Long QT Syndrome
■ Genetic disorder (1:5,000-10,000)
■ ECG evidence: QTc interval prolonged
■ >440 ms in males
■ >450 ms in females
■ Hallmark arrhythmia: Torsade de pointesVT
■ Persistently inward INa in LQT3 and reduced Ikr in LQT2 and Iks in
LQT1
■ Primary presenting symptom: Syncope
■ SCD in children or young adults

27. LQTS: Identification of Risk
■ Most common presenting symptom: unexplained syncope.
■ Syncope on exertion in pediatric patients should be
considered malignant until proven otherwise.
■ History & ECG:
– Onset and offset of syncopal episode
– Siblings, or family members with unexplained syncope or
sudden death
– Family history of “seizures” or congenital deafness
– Prolonged QTc on ECG

28. Syncope
SlowOnset Abrupt Onset AbruptOnset
SlowOffset Abrupt Offset SlowOffset
Seizure disorderHyperventilation
Hypoglycemia
Obstructive Arrhythmic Vascular
Aortic Stenosis,
HCM, Myxoma
Brady
Tachy
Vasovagal,
Orthostatic
Hypotension

29. LQTS: Clinical Features
Symptoms
■Syncope
■Seizures
■Sudden death
■Palpitations or
“chest pain”
ECG Signs
■Prolonged QTc
■Torsade de pointes

30. LQTS ECG Patterns

31. LQTS- channels
LQT11 7q21-q22 AKAP9 Yotiao Potassium (Iks)
LQT12 20q11.2 SNTA1 Syntrophin-a1 Sodium (INa)

32. Pathophysiology
■ EAD (R onT VT)
■ DAD
■ Reentry- TdP
– [HypoK, HypoMg, K blocking
drugs (I, III), bradycardia]

33. Early After Depolarization(EAD)
■ EAD occurs when large inward current during platue phase occurs
resulting in prolongation of plateau.This provides time for
reactivation of Ical. It is this second phase of reactivation of
inward Ical that produces EAD by depolarizing cell membrane.
■ A delicate balance between depolarizing and repolarizing currents
controls the plateaue phase of the AP.An increase in inward
current and or decrease in outward current may induce EADs.
■ Example include persistently inward INa in LQT3 and reduced Ikr in
LQT2 and Iks in LQT1
■ Ical is the primary depolarizing factor responsible for EAD

34. Delayed after Depolarizations
■ Delayed after depolarizations (DADs) begin during
phase 4, after repolarization is completed but
before another action potential would normally
occur via the normal conduction systems of the
heart.
■ They are due to elevated
cytosolic calcium concentrations, classically seen
with digoxin toxicity.
■ The overload of the sarcoplasmic reticulum may
cause spontaneous Ca2+ release after
repolarization, causing the released Ca2+ to exit
the cell through the 3Na+/Ca2+-exchanger. This
results in a net depolarizing current.

35. Pathophysiology

36. Pathophysiology

37. Pathophysiology

38. Pathophysiology

39. Triggering Events for Syncope or SCD
■ 3 main factors contributing to syncope or SCD
– Exercise (LQT1), especially swimming
– Emotions or emotional stress (LQT2)
– Events occurring during sleep or at rest,
with or without arousal (LQT3)

40. Triggers

41. 62
26
3
13
43
29
13
19
39
0
10
20
30
40
50
60
70
LQT1 LQT2 LQT3
Exercise
Emotional Stress
Rest
Percent
Occurrence of Gene-SpecificTriggers

42. Probability of a Cardiac Event

43. Hereditary varients
■ Jervell and Lange-Nielsen syndrome:
-longQT syndrome, associated with severe, bilateral sensorineural hearing loss
-mutation on KCNQ1 or KCNE1 genes (LQT1- Iks)
-most severe variant of LQTS (autosomal recessive)
- 90% have cardiac event by age 3
-ICD should be seriously considered
■ Romano-ward syndrome :
-LongQT syndrome, not associated with hearing loss
-Mutations in the ANK2, KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes can cause
Romano–Ward syndrom
-most common form of LQTS (autosomal dominanat)

44. Hereditary varients
■ Andersen tawil syndrome: LQT7
periodic paralysis, dysmorphic feature, ventricular arrhythmia
mean age 5 years
prolonged terminalT wave, wideTU junction, biphasic and enlarge U wave
■ Timothy syndrome: LQT8
highly lethal arrhythmia disorder, fetal bradycardia, extreme prolongation of QT,
microscopicT wave alterans, 2:1 AV block at birth, syndactyly, dysmorphic feature.
■ Ankyrin B Syndrome: LQT4

45. Diagnosis

46. Risk Stratification

47. Management
■ Life style modification
■ b blockers in LQTS clinical diagnosis (ecg) [ may be given in patient
with molecular diagnosis alone]
■ PPI in cases with sustained pause dependentVT +/- QT prolongation
■ ICD in survivors of cardiac arrest, may be given in b blocker resistant,
considered in high risk groups [LQT2, LQT3, QT>500ms]
[Left cardiac sympathetic denervation considered for symptomatic b
blocker resistant]

48. Management by Genotype
■ LQT1 and LQT2 benefit the most from ß-blocker therapy
■ The benefit of ß-blocker therapy is less clear in LQT3.
■ ICDs indicated:
– if the patient presents as SCD survivor or aborted cardiac arrest
– if ß-blockers are not effective in preventing cardiac events

49. Drugs associated with prolong QT

50. SUMMARY

51. Long QT progressing to torsade de pointe

52. Short QT Syndrome

53. ■ Short QT syndrome (SQTS) is a rare, inheritable channelopathy
characterised by abnormally short QT intervals on the
electrocardiogram (ECG) and an increased propensity to develop atrial
and ventricular tachyarrhythmias in the absence of structural heart
disease.
■ SQTS was first described as a new clinical entity by Gussak et al. in
2000.
■ Before 2000, shortening of the QT interval had only been reported in
the context of electrolyte imbalances (hyperkalaemia,
hypercalcaemia), hyperthermia, acidosis and endocrine disorders.
■ Gaita et al.described six patients with SQTS in two unrelated European
families with a family history of sudden death in association with short
QT intervals on the ECG.
Short QT Syndrome

54. ■ Since its recognition in 2000, significant
progress has been made in defining the
clinical, molecular and genetic basis of
SQTS as well as the therapy options.
■ Today, SQTS is usually defined as QTc ≤330
ms and one or more of the following:
– History of cardiac arrest or syncope,
– Family history of sudden cardiac death
(SCD) at age 40 or younger
– Family history of SQTS.
Short QT Syndrome

55. ■ Population-based and genetic studies show that QTc interval <330 ms is extremely
rare.
■ Data from over 10,000 adults suggest that, in the healthy population, the
prevalence of QTc <340 ms is approximately 0.5 %
■ Males with QTc ≤330 ms and females with QTc ≤340 ms have abnormally short QT
and should be considered to have SQTS, even if they are asymptomatic.
■ It should be emphasised that the prognosis of patients with asymptomatic SQTS
still remains undefined.
■ Individuals with QTc <320 ms who reached adulthood without developing life-
threatening arrhythmias have been reported
Short QT Syndrome

56. Other ECG Findings
■ The QRS complex is directly followed by a
T wave; ST segment is usually absent.
■ T waves are tall, peaked, symmetrical and
narrow-based
■ Often a prominent U wave can be
observed, separated by an isoelectric T–U
segment.
■ Longer Tpeak – Tend interval may be
observed, suggestive of augmented
transmural dispersion of refractoriness.
■ Depression of the PQ segment, due to a
heterogeneous abbreviation of atrial
repolarisation, most prominently in
inferior and anterior leads.

57. Pathophysiology
5 genes
Gain of function mutations in K channel-
KCNH2 [IKr] (SQT1),
KCNQ1 [IKs] (SQT2),
KCNJ2 [IK1] (SQT3)
Loss of function mutations in ICaL –
CACNA1C (SQT4)
CACNB2b (SQT5)
•Atrial & Ventricular-very short
APD & RP vulnerable to reentry
& easily inducible.
•Relatively prolonged T peak-T end
interval suggesting augmented
transmural dispersion of
repolarization

58. Pathophysiology
The ion channelopathies that cause SQTS not only abbreviate repolarization
but they significantly increase DISPERSION OF REPOLARIZATION, thus
creating the cellular basis for both the substrate and trigger necessary for
the initiation of reentry

59. Pathophysiology

60. Pathophysiology

61. Clinical Presentation
■ Approximately 62% of the patients are symptomatic.
■ Cardiac arrest is the most frequently (34%) reported symptom, and in 28% of patients it was the
first clinical presentation.
■ Palpitations is the second most frequently reported symptom (31%), followed by syncope (24%).
■ AF is the first presenting symptom in 17% of patients.
■ Strong family history of arrhythmic symptoms including SCD is a common finding
■ Many patients had frequent ventricular extrasystoles.
■ Approximately 38% patients were asymptomatic and were diagnosed due to strong family history.

62. Self-terminating episode of polymorphic
VT in a patient with SQTS

63. ICD
■ First line therapy: SQTS patients are at a high risk of SCD because of malignant ventricular
arrhythmia. ICD implantation is strongly recommended for secondary prevention of SCD
■ Risk of inappropriate shock delivery- oversensing

64. Quinidine
■ Class: Ia (sodium channel blocker)
■ Blocks: INa, IKr, IKs, Ito, L-type Ca2+, IK1(in.rect.), & IKATP  QT
increase.
■ Adverse effects: diarrhea, SLE, thrombocytopenia, hepatitis,
(tinnitus,TdP, many drug interactions by blocking of CYP2D6.

67. Cholinergic PolymorphicVentricularTachycardia
(PSVT)

68. Cholinergic PolymorphicVentricularTachycardia
■ Lethal familial disease that usually manifests in childhood and adolescence
■ Mortality among untreated patients is up to 30% by the age of 40yrs, SCD may be first
presentation
■ Stress or exercise-induced bidirectional ventricular tachycardia (biVT) or PMVT leading to
syncope and/or SCD
■ Structurally intact heart and no ECG changes at rest.
■ Induced by exercise especially swimming

69. Pathophysiology
Ca2+ release through defective SR
release (Ryanodine receptor or
RyR2)
DAD

70. Delayed after Depolarizations
■ Delayed after depolarizations (DADs) begin during
phase 4, after repolarization is completed but
before another action potential would normally
occur via the normal conduction systems of the
heart.
■ They are due to elevated
cytosolic calcium concentrations.
■ The overload of the sarcoplasmic reticulum may
cause spontaneous Ca2+ release after
repolarization, causing the released Ca2+ to exit
the cell through the 3Na+/Ca2+-exchanger. This
results in a net depolarizing current.

71. Sign and Symptoms
■ The most common symptom is dizziness or syncope which often occurs during
exercise or as a response to emotional stress
■ Symptoms are typically precipitated ("triggered") by exercise-induced
ventricular arrhythmias during periods of physical activity or acute emotional
stress
■ CPVT typically start manifesting during the first or second decade of life.
■ The majority of events occur during childhood with more than 60% of affected
individuals having their first episode of syncope or cardiac arrest by age 12-20

72. Diagnosis
■ Affected patients demonstrate no structural problems of the heart upon
echocardiographic, CT or MRI imaging.
■ CPVT diagnosis is based on reproducing irregularly shaped ventricular
arrhythmias during ECG exercise stress testing, syncope occurring during physical
activity and acute emotion, and a history of exercise or emotion-related palpitations
and dizziness
withan absence of structural cardiac abnormalities

73. Management
■ Risk stratification is based entirely on
clinical considerations.
■ Regular follow-up visits, TMT constitute
an effective approach for B-blocker dose
titration and arrhythmia monitoring
■ Holter monitoring [sometimes acute
emotions ppt]
■ Mainstay of Management B-Blockers
[long term follow up 40% have
symptom recurrence]
■ ICD in B-blocker ineffective cases or
survivor of Cardiac arrest

74. THANK YOU