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Membrane action potentials & Channelopathies Dr Nithin P G.

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Presentation on theme: "Membrane action potentials & Channelopathies Dr Nithin P G."— Presentation transcript:

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



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 E K =RT/ZF ln [K] 2 / [K] 1 Where, T is temperature [37 0 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] E K 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 V m = RT/F ln { P K [K] o + P Na [Na] o + P Cl [Cl] i / P K [K] i + P Na [Na] i + P Cl [Cl] o } Where, P Na, P K, P Cl 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 E K

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 Closing and opening of channels Voltage, Metabolic, Stretch

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

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 I Na [I CaL, I to, I CaT ] I Na = dV/dtmax [I CaL in SAN,AVN] ARP [ I Na unavailable ] RRP [ Balance b/w inward & outward current, partial availability of I Na, AP with slow upstroke and conductance ] SN [ max I Na, 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 Transient outward current Beginning of repolarization Increased HR & Premature repolarization – only partial availability Subepicardium & subendocardium I to Max. I to availability

19 Phase 2 Inward- Ca [ I CaL, I NCX ] some Na Outward- K currents [I Kr, I Ks, I Kur (atrial)] delayed rectifiers I Ks accumulates during successive cycles at fast rates  increased I K  shorter AP duration [ I Ks 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 IKIK I Kr I Ks I Kur

20 Phase 3 I Ks activation I CaL full inactivation I K1 starts to conduct EAD [phase 2 & 3] I Ks

21 Phase 4 I K1 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 I K1 activity, more excitability Digoxin inhibits Na/K pump

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

23 Atrial & Ventricular MAP Phase 2- increased Calcium current Phase 3- increased K r & K s activity Phase 4- increased I K1

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 I CaL, I to – Slow component- Na K Pump Rate of adaption increased by adrenergic influences

25 Normal Automaticity SA node- [ -50to-65 mV, diff b/w E max to E th is only 30 mV, no I Na, depol by I CaL, lower permeability to K [ reduced I K1 ] ICaL [slow responses, recovery from inactivation is slow, RP longer than AP ] I f - inward Na current, turned on by hyperpolarization [Autonomic agonists & adenosine] I CaT ; I KAch &I KAdo [instant outward shortens AP, Hyperpolarizes E max, reduces diastolic depolarization, reduce HR]

26 Automaticity-Purkinje Fibers Higher I K1 activity [more complete depol.] AP upstroke by I Na 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 Rt precordial 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:

32 Pathophysiology Loss of I Na Unabated I to current [I to Epi>>Endo] Reduced in conditions increasing I CaL currents (catecholamines), increasing AP duration, block of I to (quinidine)

33 Dispersion of repolarization

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

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

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 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:

38 Prognosis

39 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 3 yr f/up); device-related complic. (8.9%/year). Inapprop. shocks 2.5 times more frequent] Cardiac arrest Survivor (I) Syncope or Documented VT not resulting in cardiac arrest (IIa ) [ Annual event rate 3 yr f/up); device-related complic. (8.9%/year). Inapprop. shocks 2.5 times more frequent] IIa - electrical storms IIb - electrical storms

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 (I ks ) LQT12 20q11.2 SNTA1 Syntrophin-  1 Sodium (I Na ) LQT11 7q21-q22 AKAP9 Yotiao Potassium (I ks ) LQT12 20q11.2 SNTA1 Syntrophin-  1 Sodium (I Na )

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

43 Pathophysiology


45 Diagnosis & Prognosis

46 Management Life style modification  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  blocker resistant, considered in high risk groups [LQT2, LQT3, QT>500ms] [Left cardiac sympathetic denervation considered for symptomatic  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 1/3 rd. Syncope or cardiac arrest most often during Rest or Sleep.

48 Pathophysiology 5 genes Gain of function mutations in K channel- KCNH2 [I Kr ] (SQT1), KCNQ1 [I Ks ] (SQT2), and KCNJ2 [I K1 ] (SQT3) Loss of function mutations in I CaL - 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 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

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

52 Management Risk stratification is based entirely on clinical considerations. Regular follow-up visits, TMT constitute an effective approach for  blocker dose titration and arrhythmia monitoring Holter monitoring [sometimes acute emotions ppt] Mainstay of Management  Blockers [long term follow up 40% have symptom recurrence] ICD in  blocker ineffective cases or survivor of Cardiac arrest

53 Thank You

54 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

55 MCQ’s 2. At equilibrium potentials, net diffusion is a)Ln [K2/K1] b)Maximum c)Zero d)10 times more than average

56 MCQ’s 3. Correct match a)Phase I- Ina b)Phase II- ICaL c)Phase III- If d)Phase IV- IKur

57 MCQ’s 4. Membrane stabilizing current a)IK1 b)INa c)IKs d)Ito

58 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

59 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

60 MCQ’s 7. Least chance for VT during exercise a)LQT1 b)LQT2 c)LQT3 d)CPVT

61 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

62 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

63 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

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