Cardiac channelopathies

1. Cardiac Channelopathies
ATUL SHARMA

2. INTRODUCTION
• Group of inherited arrhythmogenic diseases (IADs)
caused by mutation on genes encoding for ion channel
proteins and proteins that regulate ion channels.
• Potentially lethal and inheritable arrhythmia syndromes
with the propensity to produce fatal arrhythmias in the
setting of a structurally normal heart can occur.

3. • There is 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 fact, it is now recognized that almost one third of autopsy-
negative sudden unexplained death (SUD) in young persons
and approximately 10% of sudden infant death syndrome
(SIDS) stem from these genetically inherited cardiac
channelopathies.

4. • Comprehensive management include diagnosing and
treating the proband and identifying and protecting
affected family members.
• Accurate diagnosis is of critical importance based on
history and ECG findings.
• Molecular advances in the field of cardiovascular
genetics have uncovered the underlying genetic basis
responsible for many inherited cardiac arrhythmia
syndromes.
• Theoretically, genetic testing is the “gold standard” to
determine the preventive and follow-up plan, therapeutic
strategy and prognostic estimation for these patients.

5. Channelopathies of Clinical Significance
Brugada syndrome
Long QT synrome
Short QT syndrome
Catecholaminergic polymorphic VT
Other channelopathies including Early
repolarisation syndromes ,Idiopathic
ventricular fibrillation , Sick Sinus Syndrome,
Pogressive CCD, Familial Atrial Fibrillation.

7. Ion Channel Mutations
 Loss of Function
 SCN5A Brugada
 IKs LQT1
 IKr LQT2
 Gain of Function
 SCN5A LQT3
 IKs  ShortQT
 IKr ShortQT
4
0
1 2
3
Na
Ca > Na
IKr & IKs
(Ito)
IK1
4

8. Brugada syndrome (BrS)
• Brugada syndrome (BrS) is an heritable arrhythmia syndrome
characterized by an ECG pattern consisting of coved-type ST-
segment elevation (≥2 mm) followed by a negative T wave in
the right precordial leads V1 through V3 (often referred to as
type 1 Brugada ECG pattern) .
• There is increased risk for SCD resulting from episodes of
polymorphic ventricular tachyarrhythmias.
• The penetrance and expressivity of the disorder are highly
variable, ranging from lifelong asymptomatic individuals to
SCD during the first year of life.

9. • BrS is generally considered a disorder involving young
male adults, greatest among Southeast Asian men.
• The arrhythmogenic manifestation first occurring at an
average age of 40 years.
• However, BrS has been demonstrated in children and
infants.
• Prevalence- 1–5 per 10,000 worldwide [highest
in Southeast Asia]
• SCD typically occurs during sleep.

10. ECG
Abnormalities

12. Genetic Basis
• BrS is inherited as an autosomal dominant trait, although
more than half of BrS cases may be sporadic.
• Approximately 20% to 30% of BrS cases result from loss-of-
function mutations in the SCN5A-encoded cardiac sodium
channel and are classified as Brugada syndrome type 1
(BrS1).
• To date, 18 genes have been implicated in BrS pathogenicity,
but only SCN5A shows a significant contribution to the
disease.

13. Gene Mutations in BrS

14. Pathophysiology
•Decreases in the inward
sodium(INa)
•And increases in
the outward (Ito)potassium
current produce the BrS
phenotype.

15. Pathophysiology
■ RV epicardium Ito conc. is
maximum, hence there is brugada
pattern Action potential notch in
Right sided leads.
■ 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.
■ Prolongation of repolarization in
the right ventricular epicardial
(Epi), but not endocardial (Endo),
cells results in T-wave inversion in
the surface electrocardiogram .

16. Mechanism of arrhythmia in Brugada Syndrome
• Phase 2 reentry has been
implicated in the genesis of
VT-VF associated with
Brugada syndrome.
• Heterogeneous loss of the
action potential dome during
the plateau phase (phase 2) in
the right ventricular
epicardium, leads to a
marked dispersion of
repolarization and
refractoriness and the
potential for phase 2 reentry.

17. Reentry
• Electrical activity during each normal cardiac cycle begins in
the sinoatrial node and continues until the entire heart has
been activated.
• Each cell becomes activated in turn, and the cardiac
impulse dies out when all fibers have been discharged and
are completely refractory.
• During this absolute refractory period, the cardiac impulse
has “no place to go.”
• It must be extinguished and restarted by the next sinus
impulse.
• If, however, a group of fibers not activated during the initial
wave of depolarization recovers excitability in time to be
reactivated before the impulse dies out, the fibers may
serve as a link to reexcite areas that were just discharged
and have now recovered from the initial depolarization.

18. Diagnosis
Type 1 pattern pronounced elevation of
the J point
coved – type ST- segment elevation >2 mm
changes in > 1 right precordial lead (V1 to
V3),
placed in the second, third, or fourth
intercostal space,
occurring spontaneously is diagnostic.

19. Diagnosis
 Only type 1 is diagnostic of BrS.
•Type 2 and Type 3 a type 2 or 3 pattern
is only diagnostic when it converts to a type
1 pattern with class I drug provocation
with one additional clinical feature:
• documented VF or VT,
•syncope of probable arrhythmic cause,
•family history of SCD before age 45,
•family history of Brugada type 1
pattern, or
•nocturnal agonal respirations.

20. Drug Challange
■ Pharmacological provocation should only be performed
when the baseline ECG is not diagnostic of BS (in the
absence of a diagnostic type 1 ECG pattern ).
■ Intravenous administration of Na+ channel blocking drugs
like ajmaline, flecainide 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 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

22. Role of EP study in BS
• EPS to risk-stratify patients remain controversial.
• EPS may be considered in asymptomatic patients with type 1
Brugada pattern.
• An ICD should be considered if such a patient has inducible
VT/VF with two or less extrastimuli.
Genetic Testing
• Mutations in SCN5A account for 18% to 28% of BrS cases,
voltage-gated calcium channel accounting for about another
13%.
• A variety of mutations in other genes have been rarely
reported.
• Genetic testing may not be helpful in risk stratification,
• although it can be helpful in family screening if there is an
identifiable causative mutation.

23. Risk stratification
HIGH RISK GROUP
•A spontaneous ECG pattern of BrS (type 1),
•a history of syncope,
•Patients presenting with aborted sudden death
•Atrial fibrillation and QRS fragmentation

24. Prognosis

25. Management
Avoid
■ A febrile state
■ hyperkalemia
■ class ia antiarrhythmic drugs
■ Vagotonic agents
■ Beta- adrenergic antagonists
■ Tricyclic antidepressants
■ Antihistamines
■ Cocaine
all can induce ECG aggravation andVT/VF

26. Management
ICD implantation is warranted in patients with BrS with
• Aborted SCD or spontaneous VT/VF (class I indication) or
• with a history of syncope (class IIa).
• ICD implantation may be considered in patients with a type 1
ECG pattern and inducible VT/VF with two or less extrastimuli
on EPS.

27. • Ablation in the epicardium of the anterior RV outflow tract
can normalize the ECG and suppress VT, eliminating the Ito-
rich area.
• Ablation may be considered in patients with frequent ICD
shocks (class IIb).
• Quinidine can normalize the ECG and suppress the VT,
presumably by blocking the transient outward potassium
current (Ito), or perhaps a late sodium current.
• Quinidine has been effective in patients with frequent or
storms of VT/VF on ICD (Class IIb). and
• in patients who qualify for an ICD but either refuse or are
otherwise contraindicated (class IIa).

28. • In patients with VT storm secondary to Brugada
syndrome, low-dose isoproterenol can also be
effective in suppressing the arrhythmia.

29. LONGQT
SYNDROME

30. • Congenital long-QT syndrome (LQTS) comprises a distinct
group of cardiac channelopathies characterized by delayed
repolarization of the myocardium, QT prolongation (QTc
>480 msec as the 50th percentile among individuals with
genetically confirmed LQTS).
• There is increased risk for syncope, seizures, and sudden
cardiac death (SCD) in the setting of a structurally normal
heart and otherwise healthy individual.
• The incidence of LQTS may exceed 1 in 2500 persons.

31. • Individuals with LQTS may or may not manifest QT
prolongation on a resting 12-lead surface electrocardiogram
(ECG).
• Most common presenting symptom: unexplained syncope
• Hallmark arrhythmia: Torsade de pointesVT
• LQTS may explain approximately 20% of autopsy-negative SUD
in young persons and 10% of SIDS cases.

32. Genetic Basis
• LQTS is a genetically heterogeneous disorder largely inherited in an
autosomal dominant pattern, previously known as “Romano-Ward
syndrome.”
• To date, hundreds of mutations have now been identified in 14
LQTS susceptibility genes.
• Approximately 75% of patients with a clinically robust diagnosis of
LQTS host either loss-of-function or gain-of-function mutations in
one of three major LQTS genes
• KCNQ1-encoded Iks potassium channel (LQT1, approximately 35%;
loss of function)
• KCNH2-encoded IKr potassium channel (LQT2, 30%; loss of
function), and
• SCN5A-encoded sodium channel (LQT3, 10%; gain of function).
• Approximately 5% to 10% of patients have multiple mutations in
these genes, and patients with multimutation LQTS present at a
younger age and with greater expressivity.

33. LQTS- channels

34. • Patient with the acquired of long QT interval
developing from various drugs may also have an
underlying genetic predisposition .

35. Pathophysiology
■ EAD (R onT VT)
has been implicated
in the genesis of VT-
VF associated with
LQTS.

36. 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 theAP.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
■ EADs can trigger a propagated response and
thus elicit an extra beat ,which can initiate a
tachycardia.

37. Pathophysiology

38. Long QT progressing to torsade
de pointe

39. LQTS: Presentation
■ 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
– ProlongedQTc on ECG

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

41. Triggers

42. • Among the 221 symptomatic LQT1 patients, their first
cardiac event was most often associated with exercise
(62%), followed by emotions (26%), sleep (3%), and
nonspecific (10%) triggers.
• Whereas the 204 symptomatic LQT2 patients most often
had their first event associated with emotions (43%) or
sleep(29%), and only 13% of the symptomatic LQT2
patients had an exercise-induced first event.
• In addition, LQT1 male patients younger than 13 years had
an almost threefold increase in risk for exercise triggered
events, whereas LQT1 females age 13 and older had a 3.5-
fold increase in risk for sleep/rest nonarousal events.

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

45. Diagnosis

46. Management
• For LQTS patients who don’t have syncope, complex
ventricular arrhythmias, a family history of SCD, or a QTc
interval of 500 milliseconds or more, no therapy or
treatment with a beta blocker is generally recommended.
• In asymptomatic patients but with h/o complex
ventricular arrhythmias, a family history of early SCD, or
a QTc interval of 500 milliseconds or more, beta
adrenoceptor blockers such as nadolol at maximally
tolerated doses are recommended.

47. • For both LQT1 and LQT2 patients, beta blockade was
associated with a pronounced 71% (LQT2 patients) to
78% (LQT1 patients) reduction in the risk for exercise-
triggered cardiac events,
• but had no statistically significant effect on the apparent
risk for arousal- or sleep/rest-triggered events.
• For LQT3 targeting the pathologic late sodium current
with agents such as mexiletine, flecainide, and ranolazine
may represent a gene-specific therapeutic option.

48. • ICD is indicated In patients with syncope or aborted
sudden death.
• These patients should also be treated with concomitant beta
blockers.
• Use of an ICD in patients without syncope but with a long QT
interval and a strong family history of SCD is still controversial.
• Implantation of a permanent pacemaker to prevent the
bradycardia or pauses that may predispose to the
development of TdP may be indicated.

49. • Left-sided cervicothoracic sympathetic
ganglionectomy that interrupts the stellate ganglion and
the first three or four thoracic ganglia may be helpful and can
be done thorascopically.
• For patients with the acquired form and TdP, IV magnesium
and atrial or ventricular pacing are initial choices.
• Avoidance of precipitating drugs is mandatory.

50. Hereditary varients
■ Jervell and Lange-Nielsen syndrome(LQT10):
-most severe variant of LQTS (autosomal
recessive)
-longQT syndrome, associated with severe,
bilateral sensorineural hearing loss
-mutation on KCNQ1 or KCNE1 genes (LQT1- Iks)
- 90% have cardiac event by age 3
-ICD should be seriously considered

51. Andersen tawil syndrome: LQT7
• A rare, multisystem disorder.
• Characteristic triad : periodic paralysis, dysmorphic features,
and ventricular arrhythmias.
• Autosomal dominant , incomplete penetrance.
• The mean age of onset for periodic paralysis- 5 years and 13
years for cardiac symptoms.
• Mutations in KCNJ2 (loss of function of IK1 )
• ECG abnormalities include pronounced QTU prolongation,
prominent U waves, and ventricular ectopy, including
polymorphic ventricular tachycardia (VT), bigeminy, and
bidirectional VT.

52. Timothy syndrome: LQT8
• Timothy syndrome is an extremely rare (<30 patients described
worldwide), multisystem, highly lethal arrhythmia disorder.
• Is associated with both cardiac and extracardiac abnormalities.
• The typical cardiac manifestations of TS include fetal
bradycardia, extreme prolongation of the QT interval (QTc >500
msec) often with macroscopic T wave alternans and 2 : 1 AV
block at birth.
• Extracardiac abnormalities often consist of simple syndactyly
(webbing of toes and fingers), dysmorphic facial features,
abnormal dentition, immune deficiency, severe hypoglycemia,
and developmental delay (including autism).
• Currently, the majority of TS patients die before reaching
puberty.
• Mutations in CACNA1C (gain of function).

53. Ankyrin B Syndrome: LQT4
• Inherited cardiac arrhythmia, with an increased risk for SCD
associated with a prolonged QT interval and severe sinus
bradycardia.
• Loss-of-function mutations of ANK2.
• The ANK2 gene encodes ankyrin B protein, involved in
anchoring the Na+,K+-ATPase, Na+/Ca+ exchanger to
specialized microdomains in the cardiomyocyte transverse
tubules.

54. •Short-QT syndrome (SQTS), is a rare, inheritable
channelopathy characterised by abnormally short
QT interval (usually ≤320 msec), paroxysmal atrial
fibrillation, syncope, and an increased risk for SCD.
•Symptoms, including syncope and cardiac arrest, most
often occurred during periods of rest or sleep.
The typical ECG pattern consists of a QT interval of 320
milliseconds or less (QTc ≤340 msec) and tall, peaked T
waves in the precordial leads with either no or a short ST
segment present.
Short QT Syndrome

56. Genetic Basis
• SQTS is most often inherited in an autosomal dominant
manner.
• 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)

58. Pathophysiology

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

60. 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 includingSCD is a common
finding
■ Many patients had frequent ventricular extrasystoles.
■ Approximately 38% patients were asymptomatic and were diagnosed due to
strong family history.

61. Diagnostic criteria includes
• QTc of 330 milliseconds or less or
• QTc of 360 milliseconds or less and at least one clinical
criterion: pathogenic mutation, family history of SQTS or SCD
before or at age 40, or survival of VT/VF arrest without heart
disease.
• In many patients with SQTS, the QT does not change with the
heart rate, and thus the conventional formulas for QT
correction may not apply to these patients.
• Other causes of SQTS, such as hyperkalemia, hypercalcemia,
hyperthermia, acidosis, and digitalis, should be excluded

62. Management
• ICDs are considered the treatment of choice in symptomatic
patients with SQTS to prevent SCD.
• AADs that prolong refractoriness have reportedly been
effective in some patients.
• In particular, quinidine was effective in patients with a gain-of-
function mutation in the HERG (KCNH2) gene.

63. Cholinergic Polymorphic Ventricular
Tachycardia(CPVT)
■ 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 induced or adrenergically-mediated bidirectional ventricular
tachycardia (biVT) or PMVT leading to syncope and/orSCD
■ Structurally intact heart and no ECG changes at rest.
■ Induced by exercise especially swimming

64. • Age of first presentation can range from infancy to 40
years.
• CPVT is potential lethality.
• There is presence of a positive family history of young
(<40 years) SCD for more than one third of CPVT
individuals and in as many as 60% of families hosting the
pathologic mutations.
• Moreover, approximately 15% of autopsy-negative SUD
in young persons and some cases of SIDS have been
attributed to CPVT.

65. Genetic Basis
• Inherited in an autosomal dominant
manner.
• Mutations in the RYR2-encoded
cardiac ryanodine receptor/calcium
release channel represent the most
common genetic subtype of CPVT
(CPVT1), accounting for 60% of
cases.
• Gain-of-function mutations in
RYR2 lead to leaky calcium release
channels and excessive calcium
release, particularly during
sympathetic stimulation that can
precipitate calcium overload,
delayed depolarizations, and
ventricular arrhythmias.

66. Pathophysiology
DAD

67. 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 due to
increased leakage from SR.
This leads to intracellular Ca2+waves
and triggered activity (DADs).

68. Sign and Symptoms
• A presentation of exercise or stress induced syncope and a QTc
less than 460 milliseconds should always prompt first
consideration to rule out CPVT.
• As with LQT1, swimming is a potentially lethal arrhythmia-
precipitating trigger in CPVT.
• In fact, both LQT1 and CPVT have been shown to underlie
several cases of unexplained drowning or near-drowning in
young, healthy swimmers.
• During exercise, typical responses include initial sinus
tachycardia and ventricular extrasystoles, followed by salvoes of
monomorphic or bidirectional VT, which eventually lead to
polymorphic VT as exercise continues.

69. FIGURE. ECG obtained during an exercise treadmill test in a patient with
catecholaminergic polymorphic VT. A, During the early phase of exercise, short runs of
polymorphic VT and PVCs occur. B, With further exercise, bidirectional VT ensues.

70. Management
• The treatment of choice is beta blockers and an ICD.
• Left-sided or bilateral sympathectomy has been
reported to be effective in a few cases.
• Flecainide inhibits ryanodine receptor–mediated
calcium release and has had some clinical success.
• Patients with CPVT should be instructed to avoid
vigorous exercise.

71. Thanks