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
Channels- contain an aqueous channel. Hydrophilic molecules of the right size and shape can diffuse through this channel. In many cases, whether a channel is open or closed can be regulated; they can be turned on and off. Channel is opened with a conformational switch, it is open to both environment simultaneously (extracellular and intracellular); channels are either in open state or closed state.
Pores-Pores are continuously open to these both environment, because they do not undergo conformational changes. They are always open.
Carriers & Pumps-Pathway in a carrier protein is not open smiltaneously to the both environment. Either its inner gate is open, or outer gate is open, or both gates are closed. Carrier has binding sites, but porins and channel proteins have not. When a channel is opened, thousands to millions of ions can pass through the membrane in one time, but only one or a small amount of molecules can pass through a carrier molecule. A carrier molecule can be a pump (active transport); cotransporter or antiporter
Biological membranes leak {since semipermeable}– without the constant addition of energy, the energy stored in concentration gradients across a membrane would dissipate over time, 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, 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

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. The N-terminal or “ball and chain” mechanism of K channel inactivation
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 Transient outward current Beginning of repolarization
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increased IK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 IKs IKur

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

21. IK1 Current- Membrane stabilizing current [inward rectification]
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 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 INa Unabated Ito current [Ito Epi>>Endo]
Reduced in conditions increasing ICaL currents (catecholamines), increasing AP duration, block of Ito (quinidine)
Fever increases Na channel inactivation
RV epicardium Ito conc maximum, hence brugada pattern in Right sided leads
Ach reduces ICaL, increases IK; B blockers increases Ical
Ito blocker- 4AP; INa blocker alone- flecainide, ajmaline, Procainamide; Both Ito & INa blocker- Quinidine & Disopyramide

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:

38. Prognosis

39. Management 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
J Am Coll Cardiol 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)
LQT q SNTA 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 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

49. SQTS Surface ECG Quinidine normalizes APD ICD may also be indicated
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
Ca2+ release through defective SR release (Ryanodine receptor or RyR2)
DAD

52. 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

53. Thank You

54. MCQ’s 1. False regarding Channels No conformational change occurs
Open to both sides
Action usually regulated
Large number of molecules diffuse through

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

56. MCQ’s 3. Correct match Phase I- Ina Phase II- ICaL Phase III- If
Phase IV- IKur

57. MCQ’s
4. Membrane stabilizing current
IK1
INa
IKs
Ito

58. MCQ’s 5. False regarding If Inward Ca current
Turned on by hyper polarization
Increased by adrenergic stimulation
Cause for diastolic depolarization

59. MCQ’s 6. False regarding Brugada Syndrome
Inheritable form of idiopathic ventricular arrhythmias
LOF mutation in SCN5A
Autosomal Recessive
Structurally normal heart

60. MCQ’s
7. Least chance for VT during exercise
LQT1
LQT2
LQT3
CPVT

61. MCQ’s 8. False regarding LQTS QTc > 480msec
Structurally Normal Heart
Patients with LQTS usually symptomatic throughout their childhood
50% of SCD usually had prior warning

62. MCQ’s 9. False regarding SQTS Quinidine normalizes APD
ICD may be tried
Transmural dispersion of repolarization
Defective K channels & Na channels

63. MCQ’s 10. False regarding CPVT Manifest in childhood & early adulthood
Structurally normal heart
Bidirectional VT or PMVT
Ppted usually during deep sleep