1. 심장생리
1. Cardiac muscle의 특성; EC coupling의 특성;
활동전압의 기능; 활동전압의 component; 활동전압의 전도
2,3. Ionic mechanism of action potentials; Cardiac Ion Channels;
4. Mechanism of EKG
5. Mechanical properties; Cardiac cycle
6. Autonomic control of cardiac function and the mechanism
7. Pathophysiology: Arrhythmias; Ischemic heart disease;
heart failure

2. Heart as a pump 250 - 300 g 70 - 75 beat/min, 5 l/min automaticity
Regulated by: autonomic nervous system metabolic demand
(right) atrium: volume receptor endocrine organ (ANP)

3. Contractility

4. Microscopic structure of a cardiac myocyte
Myofibrils: cell volume의 1/2 차지; thick filament와 thin filament의 규칙적 배열로 sarcomere 형성; I-band/A-band/Z-line
Mitochondria: cell volume의 1/3 차지; aerobic metabolism using fatty acid and lactate
Tubular System
- T-tubule: extension of the surface membrane into cell interior; located at Z-line
- Sarcoplasmic Reticulum: surrounding myofilament; Ca 저장고.

5. 심장근의 구조적 특징 - Multicellular tissue, but functional syncytium
- Mechanical & electrical coupling via characteristic cell junction
- gap junction in intercalated disc electrical synapse 형성

7. Spontaneous Rhythm generation
Cardiac Function
Spontaneous Rhythm generation
Conduction
Contraction
Initiated and Regulated by Action Potentials

8. 심장근 활동전압의 특징
Long Duration Long Refractory Period

9. Long Refractory Period No Tetanus

10. Cardiac Cycle 수축 (Systole) : 세포내 Ca2+ 농도의 증가
이완 (Diastole) : 세포내 Ca2+ 농도의 감소

11. 심장근 흥분-수축 연결(E-C coupling)의 특징
1. 활동전압과 수축과의 시간적 관계
2. 세포밖 Ca2+에 의존적

12. 활동전압과 수축과의 관계 특징
골격근
심장근

13. Ca2+ source for contraction
1. Ca2+ entry
: Ca2+ channel during action potential
2. Ca2+-induced Ca2+ release (CICR)
:from sarcoplasmic reticulum

14. Ca2+ removal during diastole
1. Reuptake to Sarcoplasmic Reticulum
: Ca2+-ATPase (Ca2+ Pump)
2. Extrusion to extracellular space
: Na/Ca Exchange

16. 심장근과 골격근의 비교

17. Spontaneous Rhythm generation
Cardiac Function
Spontaneous Rhythm generation
Conduction
Contraction
Initiated and Regulated by Action Potentials

18. Atrio-Ventricular Node
Pacemaker and Specialized conduction system
Sino-Atrial Node
Atrial Track AM
Atrio-Ventricular Node
His Bundle
Purkinje fibre VM

19. Specialized conduction system
Leading pacemaker site in SA node

20. Isolated cardiac myocytes
Ventricular myocyte
Atrial myocyte
15 m
Sinoatrial node cell

21. Regional difference in cardiac action potentials

22. Phase of cardiac action potential
Repolarization
Upstroke
(Phase 0)
Resting or diastolic Potential
(Phase 4)

23. Three phases of repolarization

24. Phase 4 1 2 3

25. Important Factors of Action Potential
1. Resting Membrane Potential
or Spontaneous Depolarization
2. Upstroke velocity (dV/dt)
3. Duration of AP (APD)

26. Phase 4
Resting Membrane Potential : VM, AM
Spontaneous Depolarization : SA, AV, PF
Dominent pacemaker/Latent pacemaker

27. Fast Action Potential : VM, AM, PF Slow Action Potential : SA, AV
Phase 0:
- Upstroke velocity is determined by the negativity of RMP
- Upstroke velocity determines the conduction velocity
Fast Action Potential : VM, AM, PF
Slow Action Potential : SA, AV

28. Action Potential Duration
APD
Related with 1. Refractory period
2. Contractile force

29. Early After Depolarization (EAD)

30. Ventricular AP Sinoatrial AP MDP -65 mV RMP -90 mV Repolarization
Upstroke
MDP
-65 mV
RMP
-90 mV

31. Ionic Basis of Action Potentials:
How to understand
the generation of electrical signal (V)
from the characteristics of ion channels and currents (I)
I vs V

32. Recording of action potentials and ionic currents
using patch clamp technique

33. Ventricular myocyte 80 mV -80 mV -120 mV mV pA Action potential (mV)
-50 50
100
150
200
250
300
350
-80
-60
-40
-20 20 40 60 80
Action potential (mV) ms
-150
-100
-50 50
100
-5000
-4000
-3000
-2000
-1000
1000
2000
3000 pA mV

34. Ionic Currents in Cardiac Myocytes
Inward Current:
Cause depolarization
I(Ca)
I(Na/Ca)
I(back)
I(Na)
I(K)
I(to)
I(pump)
Outward Current ;
Cause repolarization
or hyperpolarization

35. Ventricular Action Potential
Depolarization
Inward>Outward
Outward>Inward
Depolarizing current conducted
from neighbouring cells
Repolarization
Resting

36. Oscillation of the Balance between Inward and Outward Currents
Depolarization
Inward>Outward
Outward>Inward
Repoarization

37. Oscillation of the Balance between Inward and Outward Currents in Sinoatrial Node

39. Na current Ca current pA mV 40 mV -35 mV -50 mV -80 mV -80mV -50mV
-100
-80
-60
-40
-20 20 40 60
-5000
-4000
-3000
-2000
-1000
1000 pA mV pA
-60
-40
-20 20 40 mV
-500
-1000
-1500
-2000
-2500

40. Na Channel  활성화(activation)되면 전기화학적 경사에 의해 Na 이온이 세포내로 유입되어 내향전류가 발생.
 심실근 활동전압의 빠른 upstroke (수십 V/s)는 Na 통로의 활성화에 기인:
fast action potential fast conduction velocity
 Na 통로는 수 ms내에 곧 비활성화(inactivation)되므로 지속적으로 내향전류를 발생하지는 않음.
 비활성화(inactivation)의 장애 --재분극 지연 -- APD 증가로 인한 long QT
syndrome의 원인.
 Na channel blocker: - TTX - 복어독
- local anesthetics (lidocain, quinidine등)은 Na 통로의
비활성화를 negative로 shift -- 부정맥 치료에도 사용
(anti-arrhythmic drug)

41. Ca Channel  활성화되었을 때 Ca 이온이 세포내로 유입되며 내향전류가 발생한다.
 Na 통로에 비해 activation, inactivation이 느림
 심실근, 심방근에서의 Ca 전류는 활동전압의 plateau유지에 기여
 동방결절이나 방실결절 같이 안정막전압이 낮아서 Na channel은 비활성인
세포에서는 활동전압의 upstroke에 기여: upstroke dV/dt 느림 --- slow AP
--- slow conduction
 유입된 Ca은 흥분-수축 연결에서 작용 : 수축의 유발, 수축 크기 결정에 기여.
 Ca channel blocker-- inorganic blocker: Mn, Co, Ni
-- organic blocker: verapamil, D-600, diltiazem, nifedipine 등.
부정맥, 고혈압 치료에 쓰임.

42. Contribution of INa : Simulation study
Ventricle
SA node

43. Contribution of ICa : Simulation study
-0.6
-0.4
-0.2
0.0
0.2 nA
A. SA-Node
L-Ca density 0
L-Ca density 0.8
L-Ca density 1
B. Ventricle
L-Ca density 0
L-Ca density 0.5
L-Ca density 1

44. Effect of Ca channel blocker

46. K Channel
 활성화되면 K 이온이 전기화학적 경사에 의해 세포외로 유출되어 외향전류가 발생되므로, 활동전압을 재분극 시키는 역할.
 내향전류와의 balance에 의해 action potential duration(APD)가 결정됨.
 다양성이 특징이라 할 수 있을 정도로 종류가 많음.
- Inward rectifier (IRK, IK1) : resting membrane potential
- Transient outward (Ito): phase 1 repolarization
- Delayed rectifier : rapidly activating -- IKr
slowly activating --- IKs
- ATP-dependent K channel (KATP)
- Acetylcholine-activated K channel (KACh)

47. Ito IKr ICa +50 +50 -80 -40 -70 -30 nA -0.2 200 ms ms pA 6000 5000
4000
-0.2
200 ms nA
3000
2000
1000
200
400
600
800
1000
1200
1400
-1000 ms
-2000
-3000
-4000 pA
-5000
-6000
ICa

48. Transient outward K current in ventricle
IV-curve
Phase 1 repolarization에 주로 기여.
Myocardium region에 따라 density가 다름
: Purkinje fiber, epicardial, midmyocardial region에 phase 1 notch 가 prominent, endocardial region 은 less prominent.

49. Epicardial
cell
M cell
Endocardial
cell

50. Ventricle Contribution of Ito : Simulation study
Phase 1 repolarization에 중요

51. Contribution of IK : Simulation study
Ventricle

52. Contribution of IK : Simulation study
SA node

53. Inward rectifier K+ channel
Step pulse
IV - Curve
Current

54. -Large conductance at RMP -Allow little outward current at plateau
I-V relationship of inward rectifier K current, IK1
-Large conductance at RMP
-Allow little outward current at plateau

55. Contribution of IK1 : Simulation study
Ventricle
SA node

56. Effect of external K concentration

57. Acetylcholine-activated K current
Gi/o
OUT
ACh m2
KACh channel
-120
-80
-40 40
-2000
-1000
1000
I (pA) c b
a, d mV
ACh
a b c d
500 pA
2 min

58. Ventricular AP Sinoatrial AP MDP -65 mV RMP -90 mV Repolarization
Upstroke
MDP
-65 mV
RMP
-90 mV

59. Ventricular AP RMP Ito Balance between IK and ICa INa/Ca Upstroke INa
IK and IK1 IK IK
RMP
IK1

60. SA node cell Pacemaker current (If, Ih) :IK
ICa
Pacemaker current (If, Ih) :
hyperpolarization-activated inward currents

61. Sinoatrial Node MDP IK ICa Ib, IK,Absence of IK1
IK decay, If , ICa, Ib

63. Ionic Currents contributing to AP

64. Simulation study: contribution of each current

65. Cardiac Ion Channels
 Electrical properties (Resting Membrane Potential, Action Potential)를 결정지을 뿐 아니라, 수축의 발생 및 조절과도 밀접한 관계.
 Pathophysiology of Diseases, 또는 side effect of drug 와 관련됨.
 Target of therapeutics: Ion channel blocker, Ion channel opener들이 부정맥, 고혈압의 치료제로 쓰임.

66. Target of therapeutics:
Antiarrhythmic drug: Class I : Na channel blocker
Class II: sympathetic blocker
Class III: K channel blocker
Class IV: Ca channel blocker
Antihypertensive drug: Ca channel blocker
KATP channel opener