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

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 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.

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

심장근 활동전압의 특징 Long Duration Long Refractory Period

Long Refractory Period No Tetanus

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

심장근 흥분-수축 연결(E-C coupling)의 특징 1. 활동전압과 수축과의 시간적 관계 2. 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

심장근과 골격근의 비교

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

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

Specialized conduction system Leading pacemaker site in SA node

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

Regional difference in cardiac action potentials

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

Three phases of repolarization

Phase 4 1 2 3

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

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

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

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

Early After Depolarization (EAD)

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

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

Recording of action potentials and ionic currents using patch clamp technique

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

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

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

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

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

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

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)

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.

Contribution of INa : Simulation study Ventricle SA node

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

Effect of Ca channel blocker

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)

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

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.

Epicardial cell M cell Endocardial cell

Ventricle Contribution of Ito : Simulation study Phase 1 repolarization에 중요

Contribution of IK : Simulation study Ventricle

Contribution of IK : Simulation study SA node

Inward rectifier K+ channel Step pulse IV - Curve Current

-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

Contribution of IK1 : Simulation study Ventricle SA node

Effect of external K concentration

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

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

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

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

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

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 opener들이 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