Myocardial action potential and Basis of Arrythmogenesis

Myocardial Action Potentialand

Mechanisms of ArrythmogenesisBasic Concepts & Clinical Implications

Dr. S.Deep Chandh Raja

SYNOPSIS

• Anatomy of the Conduction System

• Ion channels and Clinical Implications

• Myocardial Action Potential

• Basis of Arrythmogenesis

• ECG examples of Arrythmias

• Concept of Entrainment

Anatomy of the Conduction System

SA Node

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

Internodal Tracts• Theory questioned

• Transitional tissue of Atrium muscle

AV NODE

• Inferior nodal extension, Compact Portion, Penetrating bundle

• Koch’s triangle

• AV nodal artery from crux of RCA (90%)

• Slow propagation velocity

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

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

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

What are false tendons?

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”

http://www.heartrhythmjournal.com/issue/S1547-5271(13)X0014-1

Tissues susceptible to ischemia

• SA node

• AV node

• Bundle branches

• HIS bundle, Purkinje fibres resistant to ischemia

Electrophysiological Properties

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)

SYNOPSIS







Ion channels

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

Salient features and clinical correlation

Na+ Channel• Nav 1.5 is an alpha subunit coded by SCN5A

gene

• LQT3 –disrupted inactivationprolonged APD

• SIDS-diminished inactivation

• Brugada syndrome- reduced activity

Ca2+ channels

• L Ca2+

• T Ca2+ channel

K+ channelMUTATIONS IN:

LQT1 KCNQ1 unit of K channel

LQT2 KCNH2

LQT5 KCNE1

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

CARDIAC PACEMAKER CHANNEL

• Pacemaker current Funny current “If”

• Encoded by HCN4 gene

• Mutation familial sinus bradycardia

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

Clinical implications of knowing about Ion channels

Summary of Ion Channels

SYNOPSIS







SA NODE AUTOMATICITY

• CALCIUM CLOCKMEMBRANE CLOCK

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”


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)

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)

Action potential of the cardiac muscles

• The cardiac action potential is made

of 3 phases:

1. Depolarization:

2. Plateau:

3. Replarization:

MAP OF NODE VS MYOCARDIUM

• SA NODE

• AV NODE

• DISEASE MYOCARDIUM

• ATRIAL MUSCLE

• VENTRICULAR MUSCLE

• PURKINJE FIBRE

Electrophysiological Properties

MAP OF MYOCARDIUM

• PHASE 4- THE RMP

• PHASE 0- RAPID UPSTROKE

• PHASE 1- INITIAL DOWNSTROKE

• PHASE 2- PLATEAU

• PHASE 3- FINAL DOWNSTROKE

PHASE 4

• 3 MAIN CHANNELS

o Inward rectifying potassium channels-

Potassium efflux helps maintain negativity

o Na-Ca exchanger

o Na-K ATPase

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

• 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

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

Phase 1 notch

Phase 2-Plateau phase

• Competition between the outward and inward currents lead to Plateau phase

• Steady state phase

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)

K+ channels-Ikr, Iks, Ik.ach, Ik.ca

Prolongation of plateau phase

Prolongation of action potential

LONG QT

HERG mutation

ErythromycinKetoconazole

MAP OF SA & AV NODE

• PHASE 4- SLOW DIASTOLIC DEPOLARISATION

“PACEMAKER POTENTIAL”

• PHASE 0- SLOW UPSTROKE

• PHASE 3- DOWNSTROKE

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

How does the SA node fasten its rate?

PHASE 0

• SLOW UPSTROKE

• Due to Slow channel

• Upstroke contributed mainly by the inward slow L-Ca current rather than the fast Na current

PHASE 3

• K+ channel opening-outward movement of positive charges

• Other phases are the same

SUMMARY OF AP

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

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

Classification of Anti-Arrhythmic Drugs

Heart RhythmVolume 11, Issue 3, Page e1, March 2014

“Propranolol, a β-adrenoreceptor blocker, prevents arrhythmias also by its sodium channel blocking effect”


SYNOPSIS







MECHANISM OF ARRYTHMOGENESIS-Genetic basis

-Role of ANS-Proposed mechanisms

Key elements contributing to the development of acquired arrhythmias

Genetic basis of Arrythmias

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

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

Neural remodelling

BIOLOGICAL CLOCK

• EARLY MORNING NADIR

(12.00 AM TO 06.00 AM)

• MORNING PEAK

(06.00 AM TO 12.00 PM)

• MONDAY PEAK

DISORDERS OF IMPULSE FORMATION

• AUTOMATICITY

• TRIGGERED ACTIVITY

AUTOMATICITY

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

Normal Automaticity

• Normal pacemaker mechanism behaving inappropriately

Eg:

1.Persistent sinus tachycardia at rest

2.Sinus Bradycardia during exercise

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)

Egs of abnormal automaticity

• Slow atrial rhythms

• Ventricular escape rhythms

• Digitalis assoc. Atrial tachycardias

• Accelerated Junctional tachycardia

• Idioventricular rhythms

• Parasystole

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

Parasystole

DISORDERS OF IMPULSE FORMATION

• AUTOMATICITY


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

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

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

LONG QT

TORSADES DE POINTESMolecular mechanism of TdP in inherited LQTS

Shah M et al. Circulation 2005;112:2517-2529

TdP

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

Proposed scheme of events leading todelayed after depolarizations and triggered tachyarrhythmia

CPVTDAD-mediated CPVT. Mutations in the ryanodine receptor (RyR) result in leakage of Ca2+

from sarcoplasmic reticulum (SR) into cytoplasm.

Summary of “triggerred activity”

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

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)

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

BRADYCARDIA DEPENDENT BLOCK

Exercise induced LBBB

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

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

REENTRY

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

Demonstration of Drug induced Reentry

TACHYCARDIAS CAUSED BY REENTRY

SINUS REENTRY

-SVT

-Usually less symptomatic

-in cases of refractory tachycardia, ABLATION may be required

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

Atrial Flutter

-Slowing of conduction occurs in the posteromedialarea of the right atrium

-this location is used to ablate

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)

Heart Rhythm Volume 11, Issue 7, Pages 1229–1232, July 2014

Marshall bundle reentry: A novel type of macroreentrant atrial tachycardia


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

AV REENTRYLocation of accessory pathways

-Accessory bundles of conducting tissue

“Preexcitation”impulses conducted to ventricles thru’ these pathways earlier than the usual oneWPW PATTERN

WPW PATTERN AND SYNDROME

VENTRICULAR TACHYCARDIAS MECHANISMS

• AUTOMACITY (rare)


- EAD TdP, Left Ventricular Fascicular Tachycardias

- DAD RVOT Tachycardias

• REENTRY

-Post MI, Heart failureFunctional reentry

-Brugada Syndrome

-ARVD

Fascicular VT

RVOT TACHYCARDIA

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.

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

DRUG INDUCED BRUGADA

VENTRICULAR FIBRILLATION

• Maintained solely by reentry

• Numerous hypothesis

-The Mother-Rotor hypothesis

-Wandering wavelet hypothesis

• Calcium alternansAPDalternansT wave alternans

• Spatio-Temporal disorganisation

“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

SYNOPSIS







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

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

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

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”

REFERENCES

• BRAUNWALD TEXTBOOK

• HURST TEXTBOOK

• ZIPES’ ELECTROPHYSIOLOGY

• LITERATURE SEARCH OF 2013-2014 ISSUES

“HEART RHYTHM”, “JACC”

THANK YOU

Health & Medicine

Myocardial action potential and Basis of Arrythmogenesis