Mechanism of Arrhythmias and mechanism of drugs for respective arrhythmia

Cardiology

1. Mechanism of Cardiac TachyArrhythmias Under guidance of Dr S S Kothari Sir Dr Shomu Bohora Sir Dr Raghav Bansal Sir Dr Sameer Rane Sir Dr Priyanka mam Dr Shubham Sir Dr Vicky sir

2. Outline of the seminar: Basics of Cardiac Action Potential Basic Mechanism of Arrhythmogenesis : Impulse generation :1) Abnormal Automaticity 2) Triggered Activity Impulse conduction : 3) Re entry Newer classification of Antiarrhythmic Drugs and clinical correlation Effects of Autonomic Nervous System and Arrhythmogenesis Electrophysiology and Arrhythmogenesis of Various Arrhythmias

3. Phase 0 :Rapid Depolarisation Phase 1: Early Rapid Repolarization Phase 2: Plateau Phase 3: Final Rapid Repolarization Phase 4: Diastolic Depolarisation

4. Resting membrane potential: Intracellular potential: -50 to -95 mV. Na - K ATPase pump G protein coupled K channel Digitalis inhibits Na K ATPase Adenosine and ACh activate G- protein coupled K channel: major hyperpolarizing effect in SA and AV nodes : slows automaticity and conduction.

5. Phase 0: Upstroke ( Rapid Depolarization) Mainly by I Na channels and some contribution by L type Ca channel Conduction velocity and AP duration depends upon dV/dt Rate of depolarisation during phase 0 : rate of Na entry into cell Hyperkalemia : reduction in transmembrane K gradient:slow depolarisation : slows Na entry and increases APD and decrease conduction velocity. SCN5 loss of function mutation in Brugada slowing slope of phase 0.( Depolarisation theory)

6. Phase 1: (Early Rapid Repolarization) Inactivation of Na I Na channels I to channel : outward K current Rapidly activates ( producing a notch) rapidly inactivates LV and RV transmural gradients depends upon inactivation and density of these channels Epicardium to endocardium density decreases and inactivation slows ( Brugada syndrome Repolarization theory) I cl channel: Ca dependent Cl channel

7. Phase 2: plateau I Ca,L ,I k1 and NCX Ca influx through L type Ca channel : further release of Ca from Sarcoplasmic Reticulum, leading to cardiac excitation contraction coupling. I ks and I kr channels: mutation of I ks in long QT syndrome LQTS type 1 leading to prolonged Repolarization… At Rapid Heart Rates slowly operating channels accumulate and AP abbreviate leading to Arrhythmias

8. Phase 3 : Final Rapid Repolarization I ks and I kr I k1 in terminal part Ca activate I k Ca I kr mutation : loss of HERG gene mutation in LQTS type 2 Other drugs erythromycin ketoconazole inhibit I kr.

9. Phase 4 : Diastolic Depolarisation Atrial and ventricular potential remain stable SA & AV nodal cells and his purkinje cells : gradually depolarize When certain voltage reaches phase 0 starts: Na channels in His purkinje Ca channels in SA and AV nodes. Intric spontaneous cycle Length SA maintain dominance

10. Normal Automaticity membrane clock model HCN channels I f ( funny current) : time dependent: during diastolic interval ions involving Na ( mainly) but K also. Calcium clock model: periodic increase in Ca works as internal generator rapid upstroke increase in calcium> Ca release from SR> NCX channels> membrane type Ca channel > generation of action potential.

11. Normal Conduction system : SA node AV node Bundle of His Right and left bundle branches Purkinje fibres. Gap junction and Anisotropy If there is in conduction delay due to slowly conducting tissue among Normal tissue will lead to Arrhythmogenesis.

12. Mechanism of Arrhythmogenesis Impulse formation: Automaticity and triggered activity Impulse conduction : Re entry Can be started by one and perpetuated by another mechanism That is More common in re enterant arrhythmias. Entrainment and ablation of slow pathways are the basic of re entrant arrhythmias

13. Abnormal Automaticity: Phase 4 Depolarisation Reduced maximal diastolic potential Positive to -50mV : activation range of I k or I Ca. Or by activation of I f channels Electronic effects of surrounding normally polarised or more depolarized cells leads to abnormal automaticity.

14. Warm up and cool down phenomenon : very important in identifying mechanism of arrhythmias. Examples: Slow atrial ventricular or junctional escape rhythms. Certain atrial tachycardias Idioventricular rhythms

15. Triggered Activity Initiated by after depolarisation. It is a misnomer: not self generated Related to consequence of previous impulses. There are certain triggers eg : exercise, sympathetic stimulation, parasympathetic stimulation, electrolyte imbalance leading to triggered activity.

16. Delayed Afterdepolarization: Delayed afterDepolarization (DAD): Mutation in RYR2 gene and CASQ2 gene : diastolic leakage of calcium. Trigerring escape rhythms and perpetuate arrhythmias Eg: CPVT, Atrial ectopics, RVOT vpcs,digitalis induced arrhythmias Not easily suppressed; overdrive pacing does not help. Triggered activity caused by DAD is more easily induced by rapid pacing than single premature stimulus whereas as reentry is more easily inducible by premature stimulation. During initiation of DAD - dependent triggered rhythms, as pacing cycle length decrease, coupling interval from last stimulated impulse to first tachycardia impulse shortens Opposite in reentry.

17. Early Afterdepolarisation: Acquired and congenital forms of LQTS Delaying Repolarization Prolonged Action potential Duration and QT interval When the AP is excessively prolonged, the membrane potential remains at levels that allow recovery of enough steady-state Ca (particularly during phase 2) or Na (during phase 3) current to depolarize the cell, producing an EAD. It appears that Purkinje cells are particularly sensitive to EAD-inducing interventions. Purkinje cell EADs raise to threshold adjacent ventricular muscle cells that have already repolarized, producing an unstimulated extrasystole.

18. Sympathetic stimulation increases inward Calcium channels and outward potassium channels and increase EAD amplitude and produce ventricular arrhythmias . Acquired QT prolongation: drugs like quinidine erythromycin: I kr HERG subunit block Prolong APD and provoke EAD .

19. Re entry : Concept : SA node -> AV node -> His purkinje system Cardiac impulse stop propagating when all fibres have discharged During this RP cardiac impulse has no place to go If there is an extra group of fibres not depolarized initially hence not refractory and can cause reentrant tachycardia.

20. Anatomical re entry Here,anatomical barrier separating alternate conduction pathways. The lengthy of the pathway is fixed and determined by anatomy Examples of Anatomical re entry are preexcitation , AVNRT, some Atrial flutters and some VTs.

21. Concept : spiral wave rotor The pattern of propagation : a circle or ellipse, shape depending on tissue property , anisotropic and heterogeneity Eg VTs, atrial and ventricular fibrillations Detector rotors in tissues can be facilitated by use of “ phase mapping”. Activation of each point in space relative to the phase in an activation cycle in which it occurs.

22. Functional re- entry: Lacks confining anatomical boundaries. Functional heterogeneities in electrophysiologic properties of myocardium: generation and maintenance of tachycardia Fixed: spatial redistribution of gap junction in failing heart or scarred tissue Dynamic: acute ischemia and vagal AF

23. Entrainment It is a pacing manoeuver that has been applied during microreentrant tachycardia to determine whether pacing site is a part of circuit. basic principles of Entrainment: Entrainment is the continual resetting of a reentrant tachycardia by each of a series of consecutive beats of a pacing train.

24. 1) constant fusion :Entrainment with fusion manifest entrainment

25. 2) Progressive fusion:Degree of fusion is dependent on the pacing cycle length

26. 3) Localized conduction block to a site for 1 paced beat is associated with interruption of tachycardia, followed by activation of that site by next paced beat from a different direction and shorter conduction time. Entrainment was demonstrated to occur up to the pacing rate at which the paced impulses resulted in bidirectional block and tachycardia terminates.

27. Quinidine : Blocks I to channels Reverse use dependence Suppress perkinje fibres Automaticity Role in Brugada Syndrome and Idiopathic VF. Lidocaine : Decrease Vmax Acidosis, hyperkalemia as in acute ischemia block I Na channels. Decreases cardiac sympathetic activity. Mexiletine: Decrease Vmax Suppress perkinje fibre automaticity by Na channel blockage.

28. Flecainide : Use dependence Slowest binding and slowest dissociation Prolonged Repolarization Increase refractories in Accessory pathways Used in AF, Flutter and AT. Inhibits RYR2 ( use in refractory CPVT). Amiodarone : Blocks all 3 channels in such a way that increase refractoriness of all cardiac fibres but no effects on resting membrane potential. But various side effects.

29. Autonomic Nervous system and arrhythmias Sidedness: right sided sympathetic and parasympathetic plexus SA node whereas left sided plexus AV node with some degree of overlap. Cardioneuropathy : damage to cardiac nerves and Stellate ganglion via viral infection can cause sympathetic hyperinnervation that cause arrhythmias Hyperinnervation and denervation supersensitivity

30. CPVT & LQTS type 1 & 2 MI hyper sympathetic stimulation Left Cardiac sympathetic denervation has a role in refractory CPVT. AF : sympathetic and parasympathetic both involved . The junctions between PVs and the left atrium are highly innervated sympathetic and parasympathetic nerves are localised and concen-trated in "ganglionated plexuses" around the PVs. It’s selective ablation & regional ablation targeting anatomic areas containing ganglionated plexuses, has been shown to prevent paroxysmal AF in some but not all clinical and experimental studies

31. Atrial Flutter: Re entry in typical flutter CTI ( cavotricuspid isthmus dependent flutter) Counterclockwise direction: caudocranial direction in IAS and craniocaudal direction in RA free wall. CTI : area of slow conduction amenable to ablation. Different re entry circuits in other atypical forms eg. post surgery , post ablation, ASD ptaients etc making ablation more challenging.

32. Atrial Fibrillation: All three mechanisms Pulmonary veins are prone host both focal and rotor ( re enterant) sources. Pulmonary vein ablation. Familial AF and lone AF genetic association Tissue fibrosis allowing re entry. Connexin expression and function.

33. AVRT Anatomic reentry Beta blockers and calcium channel blockers Ablation of Acessory pathway main stay of therapy AVNRT Anatomic reentry Beta blockers and calcium channel blockers Slow pathway modification via ablation.

34. Brugada Syndrome: Depolarisation and Repolarization abnormalities Loss of Na and Calcium current with functionally abnormal voltage gated Na channels. ablation of epicardial triggeres. Ablation having mixed results. Na channel inhibitors class 1 A CPVT: DAD RYR2 mutation and increased sensitivity to adrenergic tone Diastolic Calcium leak from SR Triggered activity Beta blockers mainstay of management.

35. OT VT: Triggered activity due to DAD VPCs with a short coupling interval If refractory on antiarrhythmics Then Ablation of triggered substrates in RVOT should be done. ARVC Progressive fibrofatty replacements and inflammatory infiltration Re enterant VT Medical management & ICD mainstay of therapy. Ablation of epicardial substrates( case reports) Higher rates of complication.

36. LQTS Triggered activity : EAD Medical management with drugs. EPicardial RVOT substrate modification by RFCA ( case reports). Bundle branch and fascicular V T Re entry as main mechanism Very good candidate for ablation. Scar VT: Functional Re entry due to scar. If Symptomatic on antiarrhythmics or recurrent ICD shocks Should undergo Ablation therapy.

37. Thank you