Membrane action potentials & Channelopathies

Dr Nithin P G

Membrane Action Potential

Introduction

• Ions

• Channels/Pores/Carriers & Pumps

– Channels- Aqueous channel/ Conformational change/ Action usually regulated/ Open to both environment/ Large number of molecules diffuse across

– Pores- Continuously open to both environment/ No conformational changes/ Always open.

– Carriers & Pumps- Not open simultaneously to both environments/ Binding sites/ Limited number of molecules diffuse across

Carriers & Pumps maintain the concentration gradients

Concepts of Bioelectricity

I= V/R

Concepts of Bioelectricity

+

+-

-

Concepts of Bioelectricity

Concepts of Bioelectricity

What makes ions to move across?

Steady state is reached when the magnitude of the chemical and electric gradients are equal

What makes ions to move across?

• Nernst equationEK =RT/ZF ln [K]2 / [K]1

Where, • T is temperature [370 C]• R is the gas constant • F is the Faraday constant• Z is the valence of ion [1]

• [K]2 and [K]1 are the final concentrations of potassium in compartments 2 and 1, respectively. [150mmol, 5 mmol]

• EK is the equilibrium potential for potassium [-90mV]

– At equilibrium potential net diffusion is 0– All ions try to reach equilibrium i.e., tries to drive the membrane

potential towards its equilibrium potential

What makes ions to move across?

• Goldman–Hodgkin–Katz (GHK) equation

Vm = RT/F ln { PK [K]o+ PNa [Na]o+ PCl [Cl]i / PK [K]i+ PNa [Na]i+ PCl [Cl]o }

Where, PNa, PK, PCl l are the permeabilities of the membrane to sodium, potassium, and

chloride

– At RMP, membrane is permeable mostly to potassium , hence RMP is close to the EK

Simplified circuit of an excitable membrane

Ix = (Vm −Ex )Gx

Some Terms

• Inward current

• Outward current

• Rectifying– Rectifier or diodes allow current only in one direction

• Delayed (s) vs fast/ rapid (r)

• Gating & Inactivation

Gating & Inactivation

• Closing and opening of channels• Voltage, Metabolic, Stretch

Gating & Inactivation

The N-terminal or “ball and chain” mechanism of K channel inactivation

m gate (3)

h gate

Membrane Action Potential

• 2 factors – Electromechanical gradient– Open Channels

• MAP – Sum of AP generated by

different channels [amplitude & direction]

– Number of open channels

Some terms

• Threshold potential- potential at which net inward membrane current becomes large enough to initiate autoregenerative depolarization

• Refractory Period- The interval of time during which the cell cannot be re-excited [Absolute RP]

– Relative RP

– Supranormal Excitability

• Automaticity - spontaneous impulse initiation [results from progressive depolarization of diastolic MP (diastolic depolarization)

Foot Potential

Phase 0• INa [ICaL, Ito, ICaT]

• INa = dV/dtmax [ICaLin SAN,AVN]

• ARP [INa unavailable] RRP [Balance b/w inward & outward current, partial availability of INa, AP with slow upstroke and

conductance] SN [max INa, lower threshold required]

• Post repolarization refractoriness in cases of elevated diastolic potentials [since rate of IO depends

on voltage]

• Na-K ATPase- maintain gradients

• TTX, STX, Class I antiarrhythmics [acts during depolarized states, less atrial action since shorter AP]

Phase1

• Transient outward current

• Beginning of repolarization

• Increased HR & Premature repolarization – only partial availability

• Subepicardium & subendocardium

Ito

Max. Ito availability

Phase 2

• Inward- Ca [ ICaL, INCX] some Na

• Outward- K currents [IKr, IKs, IKur (atrial)] delayed rectifiers

• IKs accumulates during successive cycles at fast ratesincreased IKshorter AP duration [IKs increased by hypercalcemia,

digitalis & catecholamines]

• Na K pump- activates during plateau

• K or Ca- fluctuation in membrane potentials [EAD- persistance of membrane potentials in the ‘window’ of ICaL]

Na & Ca

IK

IKr IKs IKur

Phase 3

• IKs activation

• ICaL full inactivation

• IK1 starts to conduct

• EAD [phase 2 & 3]

IKs

Phase 4IK1 Current- Membrane stabilizing current [inward rectification]

•Others-TWIK-1/2 (KCNK1/6), TASK-1 (KCNK3), and TRAAK (KCNK4)

•Na/K Pump- 3/2 outward; At fast HR RMP more negative

•Low [K]o leads to less IK1 activity, more excitability

•Digoxin inhibits Na/K pump

Phase 0

Phase 1

Phase 2&3

Phase 4

Phase 2&3

Phase 2&3

Phase 2&3

Phase 2&3

Atrial & Ventricular MAP

• Phase 2- increased Calcium current

• Phase 3- increased Kr & Ks activity

• Phase 4- increased IK1

Rate dependency of MAP

• At fast rates, AP duration shortens preservation of diastolic interval– Fast component- incomplete deactivation of delayed rectifiers,

incomplete recovery from inactivation of ICaL, Ito

– Slow component- Na K Pump

• Rate of adaption increased by adrenergic influences

Normal Automaticity•SA node- [-50to-65 mV, diff b/w Emax to Eth is only 30 mV, no INa, depol by ICaL, lower permeability to K [ reduced IK1]

•ICaL [slow responses, recovery from inactivation is slow, RP longer

than AP]

•If- inward Na current, turned on

by hyperpolarization [Autonomic agonists & adenosine]

•ICaT; IKAch&IKAdo[instant

outward shortens AP, Hyperpolarizes E max, reduces diastolic depolarization, reduce HR]

Automaticity-Purkinje Fibers

• Higher IK1 activity [more

complete depol.]

• AP upstroke by INa

• Overdrive suppression [increased rate of Na influx faster Na K pump hyperpolarized Emax further suppression of pacemaker current]

Abnormal automaticity– Directly block K current– Membrane potential to ~ -50

mV IK1 action negligible

Channelopathies

Types

• Brugada Syndrome

• LQTS

• SQTS

• CPVT

Channelopathies

Brugada Syndrome

• Inheritable form of idiopathic ventricular arrhythmia

• LOF Mutations in the SCN5A gene [encodes for the α-subunit of the sodium channel]

• Autosomal Dominant [incomplete or low penetrance]; predominantly in males [presentation at 40yrs]

• Prevalence- 1–5 per 10,000 worldwide [highest in Southeast Asia SUNDS]

• Family history of unexplained sudden death

• Associated ECG abnormalities [transient ST changes Rt precordial leads]

• Increased risk for potentially lethal polymorphic VT or VF [particularly during sleep in the absence of structural heart disease]

ECG Abnormalities

Circulation 2002, 106:2514-2519

Pathophysiology

• Loss of INa

• Unabated Ito current [Ito Epi>>Endo]

• Reduced in conditions increasing ICaL currents (catecholamines), increasing AP duration, block of Ito (quinidine)

Dispersion of repolarization

Pathophysiology

Cardiovascular Research 67 (2005) 367 – 378

Yan and Antzelevitch- Faulty repolarization

Pathophysiology

Cardiovascular Research 67 (2005) 367 – 378

Depolarization Disorder Hypothesis- conduction delay in RVOT

Differential Diagnosis

Diagnosis• Type 1 changes in > 1 right precordial lead (V1 to V3), in the

presence or absence of a Na channel blocker [Ajmaline (1 mg/kg body weight; 10 mg/min), Flecainide (2 mg/kg, max. 150 mg; in 10 minutes), and Procainamide (10 mg/kg; 100 mg/min)] and one of the following

1. Documented VF

2. Self terminating polymorphic VT

3. Family history of SCD (<45 years)

4. Coved type ECGs in family members

5. Electrophysiological inducibility

6. Syncope

7. Nocturnal agonal respiration.

[No other factor to account for the ECG abnormality, only ECG idiopathic Brugada ECG pattern]

• Type 2 Type 1 after drug challenge, drug-induced ST-segment elevation to a value 2 mm

• Type3 Type 1 after drug challenge Circulation 2002, 106:2514-2519

Prognosis

Management

J Am Coll Cardiol 2003;41:1665–71

•Cardiac arrest Survivor (I)•Syncope or Documented VT not resulting in cardiac arrest (IIa) [Annual event rate (2.6% @ 3 yr f/up); device-related complic. (8.9%/year). Inapprop. shocks 2.5 times more frequent]

IIa - electrical storms

IIb - electrical storms

LQTS

• Delayed repolarization of the myocardium, QT prolongation (QTc > 480 msec as the 50th percentile among LQTS cohorts)

• Increased risk for syncope, seizures, and SCD in the setting of a structurally normal heart

• 1/2500 persons.[20% of autopsy-negative sudden unexplained deaths in the young and 10% of SIDS cases]

• Usually asymptomatic, certain triggers leads to potentially life-threatening TdP

• 50% of SCD usually has prior warning/ family history, 5% SCD- sentinel event.

LQTS- channels

LQT11 7q21-q22 AKAP9 Yotiao Potassium (Iks) LQT12 20q11.2 SNTA1 Syntrophin-a1 Sodium (INa)

Pathophysiology

• EAD- R on T VT

• DAD

• Reentry- vortex like (spiral waves) TdP– [HypoK, HypoMg, K blocking

drugs (I, III), bradycardia]

Pathophysiology

Pathophysiology

Diagnosis & Prognosis

Management

• Life style modification

• b blockers in LQTS clinical diagnosis (ecg) [ may be given in pts with molecular diagnosis alone]

• PPI in cases with sustained pause dependent VT +/- QT prolongation

• ICD in survivors of cardiac arrest, may be given in b blocker resistant, considered in high risk groups [LQT2, LQT3, QT>500ms] [Left cardiac sympathetic denervation considered for symptomatic b blocker

resistant]

SQTS

• Structurally intact heart and an increased susceptibility to arrhythmias and sudden death [paroxysmal atrial fibrillation, syncope, and an increased risk for SCD]

• Remarkably accelerated repolarization that is reflected in a shorter-than-normal QTc [<320 msec]

• Syncope 25% pts, Family history of SCD 30% pts, AF in 1/3rd.

• Syncope or cardiac arrest most often during Rest or Sleep.

Pathophysiology

5 genes

Gain of function mutations in K channel-

KCNH2 [IKr] (SQT1), KCNQ1 [IKs] (SQT2), and KCNJ2 [IK1] (SQT3)

Loss of function mutations in ICaL -

CACNA1C (SQT4) and CACNB2b (SQT5)•Atrial & Ventricular-very short APD & RP vulnerable to reentry & easily inducible.•Relatively prolonged T peak-T end interval suggesting augmented transmural dispersion of repolarization

SQTS

• Surface ECG– T symmetric in SQT1 but

asymmetric in SQT [2 to 4]. – SQT2- inverted T waves can

be observed. – SQT5- BrS–like ST elevation

in the right precordial lead

• Quinidine normalizes APD

• ICD may also be indicated

CPVT

• Lethal familial disease that usually manifests in childhood and adolescence [mortality among untreated patients is up to 30% by the age of 40yrs, SCD may be first presentation]

• Stress or exercise-induced bidirectional ventricular tachycardia (biVT) or PMVT leading to syncope and/or SCD [SVT also may be seen]

• Structurally intact heart and no ECG changes at rest.

• Ppted by exercise especially swimming

Pathophysiology

DAD

Ca2+ release through defective SR release (Ryanodine receptor or RyR2)

Management

• Risk stratification is based entirely on clinical considerations.

• Regular follow-up visits, TMT constitute an effective approach for b blocker dose titration and arrhythmia monitoring

• Holter monitoring [sometimes acute emotions ppt]

• Mainstay of Management b Blockers [long term follow up 40% have symptom recurrence]

• ICD in b blocker ineffective cases or survivor of Cardiac arrest

Thank You

MCQ’s

1. False regarding Channels

a) No conformational change occurs

b) Open to both sides

c) Action usually regulated

d) Large number of molecules diffuse through

MCQ’s

2. At equilibrium potentials, net diffusion is

a) Ln [K2/K1]

b) Maximum

c) Zero

d) 10 times more than average

MCQ’s

3. Correct match

a) Phase I- Ina

b) Phase II- ICaL

c) Phase III- If

d) Phase IV- IKur

MCQ’s

4. Membrane stabilizing current

a) IK1

b) INa

c) IKs

d) Ito

MCQ’s

5. False regarding If

a) Inward Ca current

b) Turned on by hyper polarization

c) Increased by adrenergic stimulation

d) Cause for diastolic depolarization

MCQ’s

6. False regarding Brugada Syndrome

a) Inheritable form of idiopathic ventricular arrhythmias

b) LOF mutation in SCN5A

c) Autosomal Recessive

d) Structurally normal heart

MCQ’s

7. Least chance for VT during exercise

a) LQT1

b) LQT2

c) LQT3

d) CPVT

MCQ’s

8. False regarding LQTS

a) QTc > 480msec

b) Structurally Normal Heart

c) Patients with LQTS usually symptomatic throughout their childhood

d) 50% of SCD usually had prior warning

MCQ’s

9. False regarding SQTS

a) Quinidine normalizes APD

b) ICD may be tried

c) Transmural dispersion of repolarization

d) Defective K channels & Na channels

MCQ’s

10. False regarding CPVT

a) Manifest in childhood & early adulthood

b) Structurally normal heart

c) Bidirectional VT or PMVT

d) Ppted usually during deep sleep