Myocardial action potential and Basis of Arrythmogenesis

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 C onduction System SA Node

4. 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 Β 1, B2, M2 receptors Neurotransmitters- Neuropeptide Y, VIP Postvagal Tachycardia

5. Internodal Tracts Theory questioned Transitional tissue of Atrium muscle

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

7. 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

8. 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

9. 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

10. What are false tendons?

11. 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”

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

13. Electrophysiological Properties

14. 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)

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

16. Ion channels

17. 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

18. Salient features and clinical correlation

19. 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

20. Ca2+ channels L Ca2+ T Ca2+ channel

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

22. 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

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

24. 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

25. Clinical implications of knowing about Ion channels

26. Summary of Ion Channels

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

28. SA NODE AUTOMATICITY CALCIUM CLOCK MEMBRANE CLOCK

29. 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”

30. 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)

31. 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 )

32. Action potential of the cardiac muscles The cardiac action potential is made of 3 phases: Depolarization : Plateau: Replarization :

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

34. Electrophysiological Properties

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

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

37. 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

38. 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

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

40. Phase 1 notch

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

42. 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)

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

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

45. 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

46. How does the SA node fasten its rate?

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

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

49. Other phases are the same

50. SUMMARY OF AP

51. 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

52. 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

53. Classification of Anti-Arrhythmic Drugs

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

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

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

57. Key elements contributing to the development of acquired arrhythmias

58. Genetic basis of Arrythmias

59. 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

60. 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

61. Neural remodelling

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

63. DISORDERS OF IMPULSE FORMATION AUTOMATICITY TRIGGERED ACTIVITY

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

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

66. 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)

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

68. 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

69. Parasystole

70. DISORDERS OF IMPULSE FORMATION AUTOMATICITY TRIGGERED ACTIVITY

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

72. 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

73. 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

74. LONG QT

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

76. TdP

77. 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

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

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

80. Summary of “ triggerred activity”

81. 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

82. 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)

83. 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

84. BRADYCARDIA DEPENDENT BLOCK

85. Exercise induced LBBB

86. 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

87. 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

88. REENTRY

89. 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

90. Demonstration of Drug induced Reentry

91. TACHYCARDIAS CAUSED BY REENTRY

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

93. 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

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

95. 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)

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

97. 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

98. 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

99. WPW PATTERN AND SYNDROME

100. 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

101. Fascicular VT

102. RVOT TACHYCARDIA

103. 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.

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

105. DRUG INDUCED BRUGADA

106. 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

107. “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

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

109. 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

110. 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

111. 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

112. 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”

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

114. THANK YOU