Mechanisms of Arrythmogenesis

1. Myocardial Action Potential
and
Mechanisms of Arrythmogenesis
Basic Concepts & Clinical Implications
Dr. S.Deep Chandh Raja

2. SYNOPSIS
• Anatomy of the Conduction System
• Ion channels and Clinical Implications
• Myocardial Action Potential
• Basis of Arrythmogenesis
• ECG examples of Arrythmias
• Concept of Entrainment

3. Anatomy of the Conduction System
SA Node

5. SA NODE
• Spindle shaped, 10-20 mm, jxn. Of SVC and
Right Atrium in the sulcus terminalis
• 60% RCA,
• Spindle and spider cells possess pacemaker
characteristics
• Β1, B2, M2 receptors
• Neurotransmitters- Neuropeptide Y, VIP
• Postvagal Tachycardia

6. Internodal Tracts
• Theory questioned
• Transitional tissue of Atrium muscle

7. AV NODE
• Inferior nodal extension,
Compact Portion,
Penetrating bundle
• Koch’s triangle
• AV nodal artery from
crux of RCA (90%)
• Slow propagation
velocity

8. Bundle of HIS
• Continuation of the penetrating bundle of AV
node
• Located in the upper portion of IVS
• Dual blood supply
• Resistant to ishemia
CONDUCTION AV NODE HIS BUNDLE
ATROPINE IMPROVES WORSENS

9. Bundle branches
• Right BB continuation of HIS bundle
• LBB has 2-3 fascicles which are not exactly
bundles, variable anatomy
• LP fascicle resistant to ischemia, dual blood
supply

10. Purkinje Fibres
• Interweaving networks of fibres on the
endocardial surface penetrating 1/3 rd of
endocardium
• Concentrated more at apex and less at base
and papillary muscle tips
• Large surface area and resistant to ischemia

11. What are false tendons?

12. Heart Rhythm, Volume 11, Issue 2, Pages 321–
324, February 2014
“ Successful ablation of a narrow complex
tachycardia arising from a left ventricular false
tendon: Mapping and optimizing energy
delivery”

13. Tissues susceptible to ischemia
• SA node
• AV node
• Bundle branches
• HIS bundle, Purkinje fibres resistant to
ischemia

14. Electrophysiological Properties

15. Few important concepts on
Nervous distribution
• Sidedness- Right stellate ganglion and vagal nerves
affect the SA node more,
• The left sympathetic and vagal nerves affect the
AV node more
• Tonic vagal stimulation causes greater absolute
reduction in SA rate in presence of tonic
background sympathetic stimulation—
ACCENTUATED ANTAGONISM
• Differential distribution of Sympathetic and
parasympathetic nerves- sympathetic more at
base, PS more in the inferior myocardium
(responsible for vagomimetic effects of Inferior MI)

16. SYNOPSIS
• Anatomy of the Conduction System
• Ion channels and Clinical Implications
• Myocardial Action Potential
• Basis of Arrythmogenesis
• ECG examples of Arrythmias
• Concept of Entrainment

17. Ion channels

18. Ion Channels
• Named after the Ion like Na,
K, Ca or the NT affecting the
channel like Ik.ach, Ik.atp
• Gating of channels
• Voltage dependence (RMP
of the membrane its
situated on)
• Time dependence

19. Salient features and clinical correlation

20. Na+ Channel
• Nav 1.5 is an alpha subunit coded by SCN5A
gene
• LQT3 –disrupted inactivationprolonged APD
• SIDS-diminished inactivation
• Brugada syndrome- reduced activity

21. Ca2+ channels
• L Ca2+
• T Ca2+
channel

22. K+ channel
MUTATIONS IN:
LQT1 KCNQ1 unit of K channel
LQT2 KCNH2
LQT5 KCNE1

23. Inward Rectifying K+ channels
• I k.ATP ischemic preconditioning, nicorandil
and diazoxide open these channels,
glibenclamide inhibit
• I k.ACH  decreases spontaneous
depolarisation in SA node and slows AV
conduction, ADENOSINE increases activity

24. CARDIAC PACEMAKER CHANNEL
• Pacemaker current Funny current “If”
• Encoded by HCN4 gene
• Mutation familial sinus bradycardia

25. CONNEXINS
• Proteins forming the gap junctions which are
responsible for anisotropy in heart
• Connexin 43 abundant in human cardiac
myocardium
MUTATIONS IN:
Carvajal syndrome Desmoplakin
Naxos Disease Plakoglobin
ARVD Plakophilin2

26. Clinical implications of
knowing about Ion channels

28. Summary of Ion Channels

29. SYNOPSIS
• Anatomy of the Conduction System
• Ion channels and Clinical Implications
• Myocardial Action Potential
• Basis of Arrythmogenesis
• ECG examples of Arrythmias
• Concept of Entrainment

30. SA NODE AUTOMATICITY
• CALCIUM CLOCKMEMBRANE CLOCK

31. Heart Rhythm
Volume 11, Issue 7, Pages 1210–19, July 2014
“Synchronization of sinoatrial node pacemaker
cell clocks and its autonomic modulation impart
complexity to heart beating intervals”

32. RESTING MEMBRANE POTENTIAL
• The RMP of a cell is the same as the Nernst
potential of the predominant active ion
channels in the cell
• For Cardiac cells, that which determines the
RMP are the POTASSIUM CHANNELS
• Hence the RMP of a resting cell approximates
– 90 mv (The Nernst potential of K+ channel)

33. Action Potential
• Deviation from RMP as a result of influx and
efflux of ions, leading to increase in positive
charges (Depolarisation) and decrease in
positive charges (Repolarisation)

34. Action potential of the cardiac muscles
• The cardiac action potential is made
of 3 phases:
1. Depolarization:
2. Plateau:
3. Replarization:

35. MAP OF NODE VS MYOCARDIUM
• SA NODE
• AV NODE
• DISEASE MYOCARDIUM
• ATRIAL MUSCLE
• VENTRICULAR MUSCLE
• PURKINJE FIBRE

36. Electrophysiological Properties

37. MAP OF MYOCARDIUM
• PHASE 4- THE RMP
• PHASE 0- RAPID UPSTROKE
• PHASE 1- INITIAL DOWNSTROKE
• PHASE 2- PLATEAU
• PHASE 3- FINAL DOWNSTROKE

39. PHASE 4
• 3 MAIN CHANNELS
o Inward rectifying potassium channels-
Potassium efflux helps maintain negativity
o Na-Ca exchanger
o Na-K ATPase

40. PHASE 0
• 2 inward currents
• SUDDEN INCREASE IN MEMBRANE INFLUX OF
Na+
• Stimulus should be enough to take the MP
past the threshold, beyond which “the size of
AP is independent of the strength of the
stimulus- ALL OR NONE RESPONSE”
• Later part of upstroke is contributed by Slow
Inward Ca channel opening

41. • Initial curve- FAST RESPONSE Na channels
Time dependent inactivation, usually close at
around + 60 mv
• Later curve- SLOW RESPONSE L-Ca channels
Activated at around -30 mv, continue into the
plateau phase
Class 1A inhibit
Class IV inhibit

42. Phase 1-Early rapid repolarisation
• Inactivation of inward Na current
• Activation of 3 main outward currents leading
to efflux of positive charges
o K+
o Cl-
o Na/Ca exchanger
• Typical notch

43. Phase 1 notch

44. Phase 2-Plateau phase
• Competition between the outward and inward
currents lead to Plateau phase
• Steady state phase

45. Phase 3-Final rapid repolarisation
• Time dependent inactivation of Inward L-Ca
current
• Activation of a number of K+ channels-Ikr, Iks,
Ik.ach, Ik.ca-leading to outward K+ current and
loss of positivity return to a more negative
steady state (the RMP)

47. K+ channels-Ikr, Iks, Ik.ach, Ik.ca
Prolongation of plateau phase
Prolongation of action potential
LONG QT
HERG
mutation
Erythromycin
Ketoconazole

48. MAP OF SA & AV NODE
• PHASE 4- SLOW DIASTOLIC DEPOLARISATION
“PACEMAKER POTENTIAL”
• PHASE 0- SLOW UPSTROKE
• PHASE 3- DOWNSTROKE

50. PHASE 4 “PACEMAKER POTENTIAL”
• SLOW DIASTOLIC DEPOLARISATION- “no REST
for SA node, AV node”
• Maintained by Funny currents “If”
• Hyperpolarisation current activated by Na and
K+, Transient Ca2+ channels
• Influenced by adrenergic and cholinergic
neurotransmitters

51. How does the SA node fasten its rate?

52. PHASE 0
• SLOW UPSTROKE
• Due to Slow channel
• Upstroke contributed mainly by the inward
slow L-Ca current rather than the fast Na
current

53. PHASE 3
• K+ channel opening-outward movement of
positive charges

54. • Other phases are the same

55. SUMMARY OF AP

56. POST REPOLARISATION REFRACTORINESS
• Even after the restoration
of RMP in a cell, it
continues to remain in a
state of refractoriness to
stimuli and hence non
excitable
• This period is called
POST REPOLARISATION
REFRACTORINESS, which is
a time dependent
phenomenon

57. Classification of Antiarrhythmic Drugs
based on Drug Action
CLASS ACTION DRUGS
I. Sodium Channel Blockers
1A. Moderate phase 0 depression and
slowed conduction (2+); prolong
repolarization
Quinidine,
Procainamide,
Disopyramide
1B. Minimal phase 0 depression and slow
conduction (0-1+); shorten
repolarization
Lidocaine
1C. Marked phase 0 depression and slow
conduction (4+); little effect on
repolarization
Flecainide
II. Beta-Adrenergic Blockers Propranolol, esmolol
III. K+ Channel Blockers
(prolong repolarization)
Amiodarone, Sotalol,
Ibutilide
IV. Calcium Channel Blockade Verapamil, Diltiazem

58. Classification of Anti-Arrhythmic Drugs

59. Heart Rhythm
Volume 11, Issue 3, Page e1, March 2014
“Propranolol, a β-adrenoreceptor blocker, prevents
arrhythmias also by its sodium channel blocking effect”

60. SYNOPSIS
• Anatomy of the Conduction System
• Ion channels and Clinical Implications
• Myocardial Action Potential
• Basis of Arrythmogenesis
• ECG examples of Arrythmias
• Concept of Entrainment

61. MECHANISM OF ARRYTHMOGENESIS
-Genetic basis
-Role of ANS
-Proposed mechanisms

62. Key elements contributing to the development of acquired arrhythmias

63. Genetic basis of Arrythmias

65. ROLE OF ANS
• Alterations in vagal and sympathetic
innervation and sensitivites to the same,
can lead to heterogeneity within the
myocardium and hence serve a substrate to
various arrthymias
• AUTONOMIC REMODELLING

66. ROLE OF ANS
• Alterations in vagal and sympathetic
innervation and sensitivites to the same,
can lead to heterogeneity within the
myocardium and hence serve a substrate to
various arrthymias
• AUTONOMIC REMODELLING

67. Neural remodelling

68. BIOLOGICAL CLOCK
• EARLY MORNING NADIR
(12.00 AM TO 06.00 AM)
• MORNING PEAK
(06.00 AM TO 12.00 PM)
• MONDAY PEAK

71. DISORDERS OF IMPULSE FORMATION
• AUTOMATICITY
• TRIGGERED ACTIVITY

72. AUTOMATICITY
• Property of a fibre to initiate an impulse
spontaneously, without need for an initial
stimulation

73. Normal Automaticity
• Normal pacemaker mechanism behaving
inappropriately
Eg:
1.Persistent sinus tachycardia at rest
2.Sinus Bradycardia during exercise

74. Abnormal Automaticity
• Escape of a latent pacemaker
• Due to abnormal ionic mechanisms, other
pacemaker sites gain predominance over SA
node
• Secondary to spontaneous submembrane Ca
elevations, abnormal electric and ionic mileu
leading to spontaneous depolarisation
(Eg-Myocardial infarction)

75. Egs of abnormal automaticity
• Slow atrial rhythms
• Ventricular escape rhythms
• Digitalis assoc. Atrial tachycardias
• Accelerated Junctional tachycardia
• Idioventricular rhythms
• Parasystole

77. PARASYSTOLE
• Fixed rate asynchronously discharging
pacemaker
• Not altered by the dominant rhythm (Entrance
Block)
• Inter discharge interval is multiple of a basic
interval
• May be Phasic or Modulated

78. Parasystole

79. DISORDERS OF IMPULSE FORMATION
• AUTOMATICITY
• TRIGGERED ACTIVITY

80. TRIGGERED ACTIVITY
• Initiated by AFTER DEPOLARISATIONS
o EARLY AFTER DEPOLARISATION
o DELAYED AFTER DEPOLARISATION
Not all after depolarisations reach the threshold
potential (all or none response), but if they do,
they would self perpetuate

81. EARLY AFTER DEPOLARISATION
• TYPE 1 -occurs during PHASE 2 of MAP
• TYPE 2 –occurs during PHASE 3 of MAP
• Substrate-
- prolonged plateau phase (action potential duration)
- leads to excess intracellular calcium,
-invokes a series of pumps (the Na+ pump), causing
depolarisation

83. Egs of EAD
• LONG QT SYNDROME AND ASSOCIATED
VENTRICULAR TACHYCARDIAS (inc. TdP)
- GENETIC CAUSES
- ACQUIRED CAUSES (class Ia and III
antiarrythmics, Macrolide antibiotics)
• Magnesium and Potassium channel openers
like Nicorandil suppress these EADs

84. LONG QT

85. TORSADES DE POINTES
Molecular mechanism of TdP in inherited LQTS
Shah M et al. Circulation 2005;112:2517-2529

86. TdP

87. DELAYED AFTER DEPOLARISATION
• Occur after completion of Phase 4 of MAP
• Activation of calcium sensitive inward current
Eg:
• Mutations in RYR2 gene encoding
Calsequestrinincreased sensitivity of RyR2
channel to catecholaminesDADCPVT
ABNORMAL CALCIUM HANDLING

89. Proposed scheme of events leading to
delayed after depolarizations and triggered tachyarrhythmia

90. CPVT
DAD-mediated CPVT. Mutations in the ryanodine receptor (RyR) result in leakage of Ca2+
from sarcoplasmic reticulum (SR) into cytoplasm.

91. Summary of “triggerred activity”

92. DISORDERS OF IMPULSE CONDUCTION
• Blocks
- tissue blocks, rate dependent blocks
- responsible for some of the bradyarrythmias
• Reentry
- heterogeneity in tissues
- responsible for most of the tachyarrythmias

93. Blocks
• Tissue becomes “inexcitable” and when there
is no escape to the propagating impulse, it
manifests as bradyarrythmias
• Can occur at any level of the conduction
system
• Anatomic reasons (fibrosis-degenerative or as
a consequence to the pathological process)
• Functional reasons (Rate dependent blocks)

95. Rate dependent blocks
• Deceleration dependent blocks
-Reduced ‘spontaneous diastolic depolarisation’ at
slow rates is the cause
-? Role of digitalis
• Tachycardia dependent blocks
-post repolarisation refractoriness (incomplete recovery of
excitabilty when the next impulse arrives) of 1 or the other
bundle branches, is the cause

96. BRADYCARDIA DEPENDENT BLOCK

97. Exercise induced LBBB

98. DISORDERS OF IMPULSE CONDUCTION
• Blocks
- tissue blocks, rate dependent blocks
- responsible for some of the bradyarrythmias
• Reentry
- heterogeneity in tissues
- responsible for most of the tachyarrythmias

99. REENTRY
• Heterogeneity in spread of depolaristion
within a tissue is the cause
• Slow and Fast pathways
• Repeated Impulse reentry into the conduction
system through an excitable pathway leads to
sustaining of the tachycardia
reentrant tachycardia/ reciprocating
tachy/circus movement/ echo beat

100. REENTRY

101. Types of Reentry
• Anatomical reentry
- 2 distinct heterogeneous pathways of
conduction, each with differrent
electrophysiological properties, creating a slow
and a fast pathway
- can occur at level of SA node, Atrium, AV node,
Ventricle, Accessory pathways (WPW pattern)
• Functional reentry
-dispersion of excitability, refractoriness or both
within a tissue
-Egs: Post Infarction, failing heart

102. Demonstration of Drug induced Reentry

103. TACHYCARDIAS CAUSED BY REENTRY

104. SINUS REENTRY
-SVT
-Usually less symptomatic
-in cases of refractory tachycardia, ABLATION may be required

105. Atrial Flutter
-TYPICAL FLUTTER,
counterclockwise moving
from caudocranial
direction in the interatrial
septum
-recurrence can occur in
cases of other pathways of
reeentry, specially seen in
cases like ASD with
AFlutter

106. Atrial Flutter
-Slowing of
conduction occurs in
the posteromedial
area of the right
atrium
-this location is used
to ablate

107. Atrial Fibrillation
-micro entry circuits due
to spatio-temporal
disorganisation within
the atrium
-MULTIPLE WAVELET
HYPOTHESIS
-anatomic remodelling
-electric remodelling of
the atrium
-Role of Micro RNAs
-Ion channel
abnormalities
-Familial AF (KCNQ1)

109. Heart Rhythm Volume 11, Issue 7,
Pages 1229–1232, July 2014
Marshall bundle reentry: A novel type of
macroreentrant atrial tachycardia

110. AV NODAL REENTRY
-Sudden onset and
termination
-Variation in cycle length
“exposes” the AV nodal
heterogeneity and stats
the reentry
•SLOW-FAST pathway
(Typical)
•FAST-SLOW pathway
•SLOW-SLOW pathway

111. AV REENTRY
Location of accessory pathways
-Accessory bundles of
conducting tissue
“Preexcitation”impulses
conducted to ventricles
thru’ these pathways
earlier than the usual
oneWPW PATTERN

112. WPW PATTERN AND SYNDROME

114. VENTRICULAR TACHYCARDIAS
MECHANISMS
• AUTOMACITY (rare)
• TRIGGERED ACTIVITY
- EAD  TdP, Left Ventricular Fascicular
Tachycardias
- DAD  RVOT Tachycardias
• REENTRY
-Post MI, Heart failureFunctional reentry
-Brugada Syndrome
-ARVD

115. Fascicular VT

116. RVOT TACHYCARDIA

117. BRUGADA
SYNDROME
BRUGADA PATTERN
-Phase 2 reentry
-Mutations in genes
encoding Na
+ channels (SCN5A gene)-
>alterations in Na channel
currentheterogeneity in
AP in RV epicardium
-ICDs are the only proven
therapies to avert SCD in
such pts.

118. • Importance of using PROPER ECG ELECTRODE
POSITIONS and HIGH PASS FILTERS (0.05-0.35 HZ)
during a recording of ECG

119. DRUG INDUCED BRUGADA

121. VENTRICULAR FIBRILLATION
• Maintained solely by
reentry
• Numerous hypothesis
-The Mother-Rotor hypothesis
-Wandering wavelet
hypothesis
• Calcium alternansAPD
alternansT wave
alternans
• Spatio-Temporal
disorganisation

122. “Rotor Stability Separates Sustained
Ventricular Fibrillation From Self-Terminating
Episodes in Humans”
J Am Coll Cardiol. 2014;63(24):2712-
2721. doi:10.1016/j.jacc.2014.03.037

123. SYNOPSIS
• Anatomy of the Conduction System
• Ion channels and Clinical Implications
• Myocardial Action Potential
• Basis of Arrythmogenesis
• ECG examples of Arrythmias
• Concept of Entrainment

124. OVERDRIVE PACING
• After cessation of pacing,
- It can increase the amplitude and shorten the
cycle length of the complexes (overdrive
acceleration) suggest the mechanism of
arrythmia is DELAYED AFTER DEPOLARISATION
- It can terminate the underlying
tachycardiasuggest the underlying
mechanism of arrythmia is REENTRY

126. ENTRAINMENT
• “En-training” the tachycardia simply means
increasing the rate of tachycardia by pacing
• Resetting of the reentrant circuit with the pacing
induced activation
• Resumption of the intrinsic rate of the
tachycardia when the pacing is stopped
• Implications:
-used to prove the reentrant mechanism of the
tachycardia,
-used to locate the reentrant pathway

128. SUMMARY
• ANATOMY OF CONDUCTION SYSTEM
• IMPORTANT ION CHANNELS AND THEIR
CLINICAL IMPORTANCE
• MYOCARDIAL ACTION POTENTIAL
• MECHANISMS OF ARRYTHMOGENESIS
• FEW CONCEPTS-
Overdrive Pacing, Entrainment,
Drugs Causing And Treating Arrythmias

129. CONCLUSION
“An attempt should be made to study the
basis of each arryhthmia we come across, in
order to terminate it with appropriate
pharmacological/ intervention and also
prevent its recurrence”

130. REFERENCES
• BRAUNWALD TEXTBOOK
• HURST TEXTBOOK
• ZIPES’ ELECTROPHYSIOLOGY
• LITERATURE SEARCH OF 2013-2014 ISSUES
“HEART RHYTHM”, “JACC”

131. THANK YOU