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Membrane action potentials & Channelopathies

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

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Membrane action potentials & Channelopathies

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  1. Membrane action potentials & Channelopathies Dr Nithin P G

  2. Membrane Action Potential

  3. 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

  4. Concepts of Bioelectricity I= V/R

  5. Concepts of Bioelectricity - + - +

  6. Concepts of Bioelectricity

  7. Concepts of Bioelectricity

  8. What makes ions to move across? Steady state is reached when the magnitude of the chemical and electric gradients are equal

  9. What makes ions to move across? • Nernst equation EK =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

  10. 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, PCll 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

  11. Simplified circuit of an excitable membrane Ix = (Vm −Ex )Gx

  12. Some Terms • Inward current • Outward current • Rectifying • Rectifier or diodes allow current only in one direction • Delayed (s) vs fast/ rapid (r) • Gating & Inactivation

  13. Gating & Inactivation • Closing and opening of channels • Voltage, Metabolic, Stretch

  14. Gating & Inactivation m gate (3) h gate The N-terminal or “ball and chain” mechanism of K channel inactivation

  15. Membrane Action Potential • 2 factors • Electromechanical gradient • Open Channels • MAP • Sum of AP generated by different channels [amplitude & direction] • Number of open channels

  16. 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

  17. 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 IO depends on voltage] • Na-K ATPase- maintain gradients • TTX, STX, Class I antiarrhythmics[acts during depolarized states, less atrial action since shorter AP]

  18. Phase1 Ito • Transient outward current • Beginning of repolarization • Increased HR & Premature repolarization – only partial availability • Subepicardium & subendocardium Max. Ito availability

  19. Phase 2 • Inward- Ca [ ICaL, INCX] some Na • Outward- K currents [IKr, IKs, IKur(atrial)] delayed rectifiers • IKs accumulates during successive cycles at fast ratesincreasedIKshorter 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 IKsIKur

  20. Phase 3 • IKs activation • ICaL full inactivation • IK1 starts to conduct • EAD [phase 2 & 3] IKs

  21. Phase 4 IK1 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

  22. Phase 0 Phase 2&3 Phase 2&3 Phase 1 Phase 2&3 Phase 2&3 Phase 2&3 Phase 4

  23. Atrial & Ventricular MAP • Phase 2- increased Calcium current • Phase 3- increased Kr & Ks activity • Phase 4- increased IK1

  24. 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

  25. 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]

  26. 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

  27. Channelopathies

  28. Types • Brugada Syndrome • LQTS • SQTS • CPVT

  29. Channelopathies

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

  31. ECG Abnormalities Circulation 2002, 106:2514-2519

  32. Pathophysiology • Loss of INa • Unabated Ito current [ItoEpi>>Endo] • Reduced in conditions increasing ICaL currents (catecholamines), increasing AP duration, block of Ito (quinidine)

  33. Dispersion of repolarization

  34. Pathophysiology Yan and Antzelevitch- Faulty repolarization Cardiovascular Research 67 (2005) 367 – 378

  35. Pathophysiology Depolarization Disorder Hypothesis- conduction delay in RVOT Cardiovascular Research 67 (2005) 367 – 378

  36. Differential Diagnosis

  37. 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 • Documented VF • Self terminating polymorphic VT • Family history of SCD (<45 years) • Coved type ECGs in family members • Electrophysiological inducibility • Syncope • 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

  38. Prognosis

  39. Management • 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 J Am CollCardiol 2003;41:1665–71

  40. 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.

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

  42. Pathophysiology • EAD- R on T  VT • DAD • Reentry- vortex like (spiral waves)  TdP • [HypoK, HypoMg, K blocking drugs (I, III), bradycardia]

  43. Pathophysiology

  44. Pathophysiology

  45. Diagnosis & Prognosis

  46. 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]

  47. 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.

  48. Pathophysiology 5 genes Gain of function mutations in K channel- KCNH2 [IKr] (SQT1), KCNQ1 [IKs] (SQT2), and KCNJ2 [IK1] (SQT3) Loss of function mutationsin 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

  49. 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

  50. 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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