membrane action potentials & channelopathies dr nithin p g
TRANSCRIPT
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Membrane action potentials & Channelopathies
Dr Nithin P G
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Membrane Action Potential
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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
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Concepts of Bioelectricity
I= V/R
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Concepts of Bioelectricity
+
+-
-
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Concepts of Bioelectricity
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Concepts of Bioelectricity
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What makes ions to move across?
Steady state is reached when the magnitude of the chemical and electric gradients are equal
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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
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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
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Simplified circuit of an excitable membrane
Ix = (Vm −Ex )Gx
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Some Terms
• Inward current
• Outward current
• Rectifying– Rectifier or diodes allow current only in one direction
• Delayed (s) vs fast/ rapid (r)
• Gating & Inactivation
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Gating & Inactivation
• Closing and opening of channels• Voltage, Metabolic, Stretch
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Gating & Inactivation
The N-terminal or “ball and chain” mechanism of K channel inactivation
m gate (3)
h gate
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Membrane Action Potential
• 2 factors – Electromechanical gradient– Open Channels
• MAP – Sum of AP generated by
different channels [amplitude & direction]
– Number of open channels
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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
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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]
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Phase1
• Transient outward current
• Beginning of repolarization
• Increased HR & Premature repolarization – only partial availability
• Subepicardium & subendocardium
Ito
Max. Ito availability
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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
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Phase 3
• IKs activation
• ICaL full inactivation
• IK1 starts to conduct
• EAD [phase 2 & 3]
IKs
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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
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Phase 0
Phase 1
Phase 2&3
Phase 4
Phase 2&3
Phase 2&3
Phase 2&3
Phase 2&3
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Atrial & Ventricular MAP
• Phase 2- increased Calcium current
• Phase 3- increased Kr & Ks activity
• Phase 4- increased IK1
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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
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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]
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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
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Channelopathies
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Types
• Brugada Syndrome
• LQTS
• SQTS
• CPVT
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Channelopathies
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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]
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ECG Abnormalities
Circulation 2002, 106:2514-2519
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Pathophysiology
• Loss of INa
• Unabated Ito current [Ito Epi>>Endo]
• Reduced in conditions increasing ICaL currents (catecholamines), increasing AP duration, block of Ito (quinidine)
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Dispersion of repolarization
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Pathophysiology
Cardiovascular Research 67 (2005) 367 – 378
Yan and Antzelevitch- Faulty repolarization
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Pathophysiology
Cardiovascular Research 67 (2005) 367 – 378
Depolarization Disorder Hypothesis- conduction delay in RVOT
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Differential Diagnosis
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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
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Prognosis
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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
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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.
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LQTS- channels
LQT11 7q21-q22 AKAP9 Yotiao Potassium (Iks) LQT12 20q11.2 SNTA1 Syntrophin-a1 Sodium (INa)
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Pathophysiology
• EAD- R on T VT
• DAD
• Reentry- vortex like (spiral waves) TdP– [HypoK, HypoMg, K blocking
drugs (I, III), bradycardia]
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Pathophysiology
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Pathophysiology
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Diagnosis & Prognosis
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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]
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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.
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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
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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
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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
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Pathophysiology
DAD
Ca2+ release through defective SR release (Ryanodine receptor or RyR2)
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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
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Thank You
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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
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MCQ’s
2. At equilibrium potentials, net diffusion is
a) Ln [K2/K1]
b) Maximum
c) Zero
d) 10 times more than average
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MCQ’s
3. Correct match
a) Phase I- Ina
b) Phase II- ICaL
c) Phase III- If
d) Phase IV- IKur
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MCQ’s
4. Membrane stabilizing current
a) IK1
b) INa
c) IKs
d) Ito
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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
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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
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MCQ’s
7. Least chance for VT during exercise
a) LQT1
b) LQT2
c) LQT3
d) CPVT
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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
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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
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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