myocardial action potential and basis of arrythmogenesis
TRANSCRIPT
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Myocardial Action Potentialand
Mechanisms of ArrythmogenesisBasic Concepts & Clinical Implications
Dr. S.Deep Chandh Raja
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SYNOPSIS
• Anatomy of the Conduction System
• Ion channels and Clinical Implications
• Myocardial Action Potential
• Basis of Arrythmogenesis
• ECG examples of Arrythmias
• Concept of Entrainment
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Anatomy of the Conduction System
SA Node
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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
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Internodal Tracts• Theory questioned
• Transitional tissue of Atrium muscle
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AV NODE
• Inferior nodal extension, Compact Portion, Penetrating bundle
• Koch’s triangle
• AV nodal artery from crux of RCA (90%)
• Slow propagation velocity
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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
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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
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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
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What are false tendons?
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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”
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Tissues susceptible to ischemia
• SA node
• AV node
• Bundle branches
• HIS bundle, Purkinje fibres resistant to ischemia
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Electrophysiological Properties
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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)
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SYNOPSIS
• Anatomy of the Conduction System
• Ion channels and Clinical Implications
• Myocardial Action Potential
• Basis of Arrythmogenesis
• ECG examples of Arrythmias
• Concept of Entrainment
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Ion channels
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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
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Salient features and clinical correlation
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Na+ Channel• Nav 1.5 is an alpha subunit coded by SCN5A
gene
• LQT3 –disrupted inactivationprolonged APD
• SIDS-diminished inactivation
• Brugada syndrome- reduced activity
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Ca2+ channels
• L Ca2+
• T Ca2+ channel
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K+ channelMUTATIONS IN:
LQT1 KCNQ1 unit of K channel
LQT2 KCNH2
LQT5 KCNE1
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Inward Rectifying K+ channels
• I k.ATP ischemic preconditioning, nicorandiland diazoxide open these channels, glibenclamide inhibit
• I k.ACH decreases spontaneous depolarisation in SA node and slows AV conduction, ADENOSINE increases activity
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CARDIAC PACEMAKER CHANNEL
• Pacemaker current Funny current “If”
• Encoded by HCN4 gene
• Mutation familial sinus bradycardia
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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
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Clinical implications of knowing about Ion channels
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Summary of Ion Channels
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SYNOPSIS
• Anatomy of the Conduction System
• Ion channels and Clinical Implications
• Myocardial Action Potential
• Basis of Arrythmogenesis
• ECG examples of Arrythmias
• Concept of Entrainment
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SA NODE AUTOMATICITY
• CALCIUM CLOCKMEMBRANE CLOCK
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Heart RhythmVolume 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”
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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)
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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)
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Action potential of the cardiac muscles
• The cardiac action potential is made
of 3 phases:
1. Depolarization:
2. Plateau:
3. Replarization:
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MAP OF NODE VS MYOCARDIUM
• SA NODE
• AV NODE
• DISEASE MYOCARDIUM
• ATRIAL MUSCLE
• VENTRICULAR MUSCLE
• PURKINJE FIBRE
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Electrophysiological Properties
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MAP OF MYOCARDIUM
• PHASE 4- THE RMP
• PHASE 0- RAPID UPSTROKE
• PHASE 1- INITIAL DOWNSTROKE
• PHASE 2- PLATEAU
• PHASE 3- FINAL DOWNSTROKE
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PHASE 4
• 3 MAIN CHANNELS
o Inward rectifying potassium channels-
Potassium efflux helps maintain negativity
o Na-Ca exchanger
o Na-K ATPase
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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
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• 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
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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
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Phase 1 notch
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Phase 2-Plateau phase
• Competition between the outward and inward currents lead to Plateau phase
• Steady state phase
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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)
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K+ channels-Ikr, Iks, Ik.ach, Ik.ca
Prolongation of plateau phase
Prolongation of action potential
LONG QT
HERG mutation
ErythromycinKetoconazole
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MAP OF SA & AV NODE
• PHASE 4- SLOW DIASTOLIC DEPOLARISATION
“PACEMAKER POTENTIAL”
• PHASE 0- SLOW UPSTROKE
• PHASE 3- DOWNSTROKE
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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
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How does the SA node fasten its rate?
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PHASE 0
• SLOW UPSTROKE
• Due to Slow channel
• Upstroke contributed mainly by the inward slow L-Ca current rather than the fast Na current
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PHASE 3
• K+ channel opening-outward movement of positive charges
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• Other phases are the same
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SUMMARY OF AP
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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
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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
repolarizationLidocaine
1C. Marked phase 0 depression and slow
conduction (4+); little effect on
repolarizationFlecainide
II. Beta-Adrenergic Blockers Propranolol, esmolol
III. K+ Channel Blockers
(prolong repolarization)
Amiodarone, Sotalol,
Ibutilide
IV. Calcium Channel Blockade Verapamil, Diltiazem
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Classification of Anti-Arrhythmic Drugs
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Heart RhythmVolume 11, Issue 3, Page e1, March 2014
“Propranolol, a β-adrenoreceptor blocker, prevents arrhythmias also by its sodium channel blocking effect”
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SYNOPSIS
• Anatomy of the Conduction System
• Ion channels and Clinical Implications
• Myocardial Action Potential
• Basis of Arrythmogenesis
• ECG examples of Arrythmias
• Concept of Entrainment
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MECHANISM OF ARRYTHMOGENESIS-Genetic basis
-Role of ANS-Proposed mechanisms
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Key elements contributing to the development of acquired arrhythmias
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Genetic basis of Arrythmias
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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
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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
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Neural remodelling
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BIOLOGICAL CLOCK
• EARLY MORNING NADIR
(12.00 AM TO 06.00 AM)
• MORNING PEAK
(06.00 AM TO 12.00 PM)
• MONDAY PEAK
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DISORDERS OF IMPULSE FORMATION
• AUTOMATICITY
• TRIGGERED ACTIVITY
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AUTOMATICITY
• Property of a fibre to initiate an impulse spontaneously, without need for an initial stimulation
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Normal Automaticity
• Normal pacemaker mechanism behaving inappropriately
Eg:
1.Persistent sinus tachycardia at rest
2.Sinus Bradycardia during exercise
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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 mileuleading to spontaneous depolarisation(Eg-Myocardial infarction)
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Egs of abnormal automaticity
• Slow atrial rhythms
• Ventricular escape rhythms
• Digitalis assoc. Atrial tachycardias
• Accelerated Junctional tachycardia
• Idioventricular rhythms
• Parasystole
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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
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Parasystole
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DISORDERS OF IMPULSE FORMATION
• AUTOMATICITY
• TRIGGERED ACTIVITY
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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
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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
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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
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LONG QT
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TORSADES DE POINTESMolecular mechanism of TdP in inherited LQTS
Shah M et al. Circulation 2005;112:2517-2529
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TdP
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DELAYED AFTER DEPOLARISATION
• Occur after completion of Phase 4 of MAP
• Activation of calcium sensitive inward current
Eg:
• Mutations in RYR2 gene encoding Calsequestrinincreased sensitivity of RyR2 channel to catecholaminesDADCPVT
ABNORMAL CALCIUM HANDLING
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Proposed scheme of events leading todelayed after depolarizations and triggered tachyarrhythmia
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CPVTDAD-mediated CPVT. Mutations in the ryanodine receptor (RyR) result in leakage of Ca2+
from sarcoplasmic reticulum (SR) into cytoplasm.
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Summary of “triggerred activity”
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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
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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)
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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
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BRADYCARDIA DEPENDENT BLOCK
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Exercise induced LBBB
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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
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REENTRY
• Heterogeneity in spread of depolaristionwithin 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
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REENTRY
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Types of Reentry
• Anatomical reentry- 2 distinct heterogeneous pathways of conduction, each with differrentelectrophysiological 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
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Demonstration of Drug induced Reentry
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TACHYCARDIAS CAUSED BY REENTRY
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SINUS REENTRY
-SVT
-Usually less symptomatic
-in cases of refractory tachycardia, ABLATION may be required
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Atrial Flutter-TYPICAL FLUTTER, counterclockwise moving from caudocranialdirection in the interatrialseptum
-recurrence can occur in cases of other pathways of reeentry, specially seen in cases like ASD with AFlutter
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Atrial Flutter
-Slowing of conduction occurs in the posteromedialarea of the right atrium
-this location is used to ablate
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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)
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Heart Rhythm Volume 11, Issue 7, Pages 1229–1232, July 2014
Marshall bundle reentry: A novel type of macroreentrant atrial tachycardia
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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
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AV REENTRYLocation of accessory pathways
-Accessory bundles of conducting tissue
“Preexcitation”impulses conducted to ventricles thru’ these pathways earlier than the usual oneWPW PATTERN
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WPW PATTERN AND SYNDROME
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VENTRICULAR TACHYCARDIAS MECHANISMS
• AUTOMACITY (rare)
• TRIGGERED ACTIVITY
- EAD TdP, Left Ventricular Fascicular Tachycardias
- DAD RVOT Tachycardias
• REENTRY
-Post MI, Heart failureFunctional reentry
-Brugada Syndrome
-ARVD
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Fascicular VT
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RVOT TACHYCARDIA
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BRUGADA SYNDROME
BRUGADA PATTERN
-Phase 2 reentry
-Mutations in genes encoding Na+ channels (SCN5A gene)->alterations in Na channel currentheterogeneity in AP in RV epicardium
-ICDs are the only proven therapies to avert SCD in such pts.
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• Importance of using PROPER ECG ELECTRODE POSITIONS and HIGH PASS FILTERS (0.05-0.35 HZ) during a recording of ECG
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DRUG INDUCED BRUGADA
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VENTRICULAR FIBRILLATION
• Maintained solely by reentry
• Numerous hypothesis
-The Mother-Rotor hypothesis
-Wandering wavelet hypothesis
• Calcium alternansAPDalternansT wave alternans
• Spatio-Temporal disorganisation
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“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
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SYNOPSIS
• Anatomy of the Conduction System
• Ion channels and Clinical Implications
• Myocardial Action Potential
• Basis of Arrythmogenesis
• ECG examples of Arrythmias
• Concept of Entrainment
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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 tachycardiasuggest the underlying mechanism of arrythmia is REENTRY
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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
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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
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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”
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REFERENCES
• BRAUNWALD TEXTBOOK
• HURST TEXTBOOK
• ZIPES’ ELECTROPHYSIOLOGY
• LITERATURE SEARCH OF 2013-2014 ISSUES
“HEART RHYTHM”, “JACC”
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THANK YOU