심장생리

1. Cardiac muscle 의 특성 ; EC coupling 의 특성 ;활동전압의 기능 ; 활동전압의 component; 활동전압의 전도2,3. Ionic mechanism of action potentials; Cardiac Ion Channels;4. Mechanism of EKG 5. Mechanical properties; Cardiac cycle6. Autonomic control of cardiac function and the mechanism7. Pathophysiology: Arrhythmias; Ischemic heart disease;heart failure

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)

Contractility

Microscopic structure of a cardiac myocyte

• Myofibrils: cell volume 의 1/2 차지 ; thick filament 와 thin filament 의 규칙적 배열로 sarcomere 형성 ; I-band/A-band/Z-line

• Mitochondria: cell volume 의 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 .

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

Spontaneous Rhythm generationConductionContraction

Cardiac Function

Initiated and Regulated by Action Potentials

Long Duration Long Refractory Period

심장근 활동전압의 특징

Long Refractory Period No Tetanus

수축 (Systole) : 세포내 Ca2+ 농도의 증가

이완 (Diastole) : 세포내 Ca2+ 농도의 감소

Cardiac Cycle

심장근 흥분 - 수축 연결 (E-C coupling) 의 특징

1. 활동전압과 수축과의 시간적 관계2. 세포밖 Ca2+ 에 의존적

활동전압과 수축과의 관계 특징

골격근

심장근

Ca2+ source for contraction

1. Ca2+ entry : Ca2+ channel during action potential

2. Ca2+-induced Ca2+ release (CICR) :from sarcoplasmic reticulum

Ca2+ removal during diastole

1. Reuptake to Sarcoplasmic Reticulum : Ca2+-ATPase (Ca2+ Pump)

2. Extrusion to extracellular space : Na/Ca Exchange

C ell M em brane S arcoplasm ic R eticu lum

C a channel

N a/C a Exchange

C a R elease

C a R euptake

R E G U LATIO N O F IN TR A C E LLU LA R C A LC IU M

S R

[C a ]2 +

심장근과 골격근의 비교

Spontaneous Rhythm generationConductionContraction

Cardiac Function

Initiated and Regulated by Action Potentials

Sino-Atrial Node

Atrial Track AM

Atrio-Ventricular Node

His Bundle

Purkinje fibre VM

Pacemaker and Specialized conduction system

Specialized conduction system

Leading pacemaker site in SA node

Atrial myocyteVentricular myocyte

15 m

Isolated cardiac myocytes

Sinoatrial node cell

Regional difference in cardiac action potentials

Resting or diastolic Potential (Phase 4)

Upstroke(Phase 0)

Phase of cardiac action potential

Repolarization

Phase 4

Phase 0

Phase 1

Phase 2

Phase 3

Three phases of repolarization

Phase 4 0

3

12

Important Factors of Action Potential

1. Resting Membrane Potential or Spontaneous Depolarization

2. Upstroke velocity (dV/dt)

3. Duration of AP (APD)

Resting Membrane Potential : VM, AM

Spontaneous Depolarization : SA, AV, PF

Dominent pacemaker/Latent pacemaker

Phase 4

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

Action Potential Duration

APD

Related with 1. Refractory period 2. Contractile force

Early After Depolarization (EAD)

R epo larizationU pstroke

Pacem aker Depolarization ? ? ?

RMP-90 mV

MDP-65 mV

UpstrokeRepolarization

Ventricular AP Sinoatrial AP

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

5 0 0 m s

0

- 2 0

0

- 0 .2

2 0 0 m s

m V

n A0

- 1

2 0 0 m s

n A

- 4 0

- 4 0

- 3 0

+ 5 0- 5 0

- 9 0

Recording of action potentials and ionic currents using patch clamp technique

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Ventricular myocyte -80 mV

80 mV

-120 mV

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Outward Current ;

Cause repolarization

or hyperpolarization

Cause depolarization

Inward Current:

I(Ca) I(Na/Ca)I(back)

I(Na)

I(K)I(to)I(pump)

Ionic Currents in Cardiac Myocytes

Inward>Outward Outward>Inward

Depolarization

Repolarization

Ventricular Action Potential

Resting

Depolarizing current conducted from neighbouring cells

Oscillation of the Balance between Inward and Outward Currents

Inward>Outward Outward>Inward

Depolarization

Repoarization

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

D epolarization R epolarization

Inw ard>O utw ard O utw ard> Inw ard

Ion Channels

Na channels

Ca channels:L-type

T-type

K channels: Inward rectifier

Delayed rectifier (rapid/slow)

Transient outward

ACh-activated

ATP-sensitive

Hyperpolarization-activated inward current

Cl channels

Electrogenic transporters Na-K pump

Na/Ca exchanger

5 nA

10 ms

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60mV

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-80 mV-50 mV

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Na current Ca current

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 ms 내에 곧 비활성화 (inactivation) 되므로 지속적으로 내향전류를 발생하지는 않음 .

비활성화 (inactivation) 의 장애 -- 재분극 지연 -- APD 증가로 인한 long QT syndrome 의 원인 .

Na channel blocker: - TTX - 복어독 - local anesthetics (lidocain, quinidine 등 ) 은 Na 통로의 비활성화를 negative 로 shift -- 부정맥 치료에도 사용 (anti-arrhythmic drug)

Ca Channel 활성화되었을 때 Ca 이온이 세포내로 유입되며 내향전류가 발생한다 .

Na 통로에 비해 activation, inactivation 이 느림

심실근 , 심방근에서의 Ca 전류는 활동전압의 plateau 유지에 기여

동방결절이나 방실결절 같이 안정막전압이 낮아서 Na channel 은 비활성인 세포에서는 활동전압의 upstroke 에 기여 : upstroke dV/dt 느림 --- slow AP --- slow conduction

유입된 Ca 은 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 .

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C D

Ventricle SA node

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Density : 1

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Contribution of INa : Simulation study

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nA

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V)

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L-Ca density 0

L-Ca density 0.8

L-Ca density 1

A. SA-Node

B. Ventricle

-1.2

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Actio

n P

oten

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V)

Time(ms)

L-Ca density 0

L-Ca density 0.5

L-Ca density 1

Contribution of ICa : Simulation study

Effect of Ca channel blocker

K Channel

활성화되면 K 이온이 전기화학적 경사에 의해 세포외로 유출되어 외향전류가 발생되므로 , 활동전압을 재분극 시키는 역할 .

내향전류와의 balance 에 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)

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nA

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ICa

IKr

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Ito

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nA

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0.0

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mV

IV-curve

Transient outward K current in ventricle

-Phase 1 repolarization 에 주로 기여 .-Myocardium region 에 따라 density 가 다름 : Purkinje fiber, epicardial, midmyocardial region 에 phase 1 notch 가 prominent, endocardial region 은 less prominent.

Epicardial cell

M cell

Endocardial cell

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-0.20.00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.03.23.43.6

Density 0.1

Density 1

Density 5

mV

ms

Ventricle

Phase 1 repolarization 에 중요

Contribution of Ito : Simulation study

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Density : 10Density : 1Density : 0 B

C D

Ventricle

Contribution of IK : Simulation study

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Density : 1 B C D

SA node

Contribution of IK : Simulation study

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Step pulse

Current IV - Curve

Inward rectifier K+ channel

I-V relationship of inward rectifier K current, IK1

-Large conductance at RMP-Allow little outward current at plateau

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C DVentricle

SA node

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C D

Contribution of IK1 : Simulation study

Effect of external K concentration

Acetylcholine-activated K current

IN Gi/o

OUTACh

m2

KACh channel

2 min

500 pA

ACh ACh

a b c d

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0

1000

I (pA)

cb

a, d

mV

R epo larizationU pstroke

Pacem aker Depolarization ? ? ?

RMP-90 mV

MDP-65 mV

UpstrokeRepolarization

Ventricular AP Sinoatrial AP

RMPIK1

UpstrokeINa

Ventricular AP

ICa

IK

ICa

Ito

IK and IK1

Balance betweenIK and ICa INa/Ca

IK

5 0 0 m s

0

- 2 0

0

- 0 .2

2 0 0 m s

m V

n A0

- 1

2 0 0 m s

n A

- 4 0

- 4 0

- 3 0

+ 5 0- 5 0

- 9 0

SA node cell

Pacemaker current (If, Ih) : hyperpolarization-activated inward currents

ICa

IK

R epo larizationU pstroke

Pacem aker Depolarization ? ? ?

MDP

Sinoatrial Node

ICaIK

IK decay, If , ICa, Ib

Ib, IK,Absence of IK1

Ionic Currents contributing to AP

Simulation study: contribution of each current

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 opener 들이 부정맥 , 고혈압의 치료제로 쓰임 .

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