ELECTRICAL PROPERTIES OF THE HEART Sandor Gyorke, Ph.D. Office: DHLRI 507 Telephone: 292-3969 Email: sandor.gyorke@osumc.edu ELECTRICAL PROPERTIES OF THE HEART

At the end of this module, you will learn to Learning Objectives Differentiate pacemaker cells from myocardial cells by action potential characteristics and ion transport during depolarization and repolarization and response to sympathetic and parasympathetic stimulation. Describe the sequence of activation of the heart and relate to the components of the electrocardiogram. Identify the components of the conduction system of the heart.

Learning Resources Pathophysiology of Heart Disease. Fifth Edition, Ed. L.S. Lilly, Lippincott Williams & Wilkins, Baltimore, MD, 2011 (pp. 12-23; 75-112) D.E. Mohrman & L.J. Heller. Cardiovascular Physiology, 8th edition, McGraw-Hill, New York 2014.

Topics Membrane excitability Cardiac resting potential Cardiac action potentials Heart rhythm The sequence of electrical activation of the heart Cardiac electrocardiogram (ECG)

Introduction The heart is composed of cardiac muscle cells, cardiomyocytes. Cardiac myocytes are electrically excitable cells capable of generating and conducting action potentials Electrical excitation Contraction There are two types of cardiac cells: “working” cardiomyocytes with fast action potential (in ventricles and atria) and cardiac pacemaker cells with slow action potential. All electrical phenomena in the heart rely on movement of ions across membranes Disturbances in normal periodic electrical activity result in cardiac arrhythmia.

Transport and Distribution of Ions in Cardiac Myocytes Na+ Ca2+ Channels sarcolemma K+ Na+ Ca2+ Ca2+ Pumps Na+ K+ Internal External [Na+] 15 mM 150 mM [K+] 150 mM 5 mM [Cl-] 5 mM 120 mM [Ca2+] 10-7 M 2 mM Sarcolemma: Phospholipid bilayer Pumps/transporters Ion channels

Major Cardiac Voltage-gated Membrane Currents Current Abbreviation Role Gene Fast Depolarizing (INa) Initial depolarization SCN5A Na+ current of cardiac action potentials Slow Ca2+ current (ICa) Important for plateau phase α 1C of action potential Delayed repolarizing (IK) Helps to terminate action HERG K+ current potential plateau Background (IKr) Responsible for generation Kir2.1 K+ current of the resting potential Diastolic pacemaker (If) Responsible for spontaneous HCN2 current depolarization in pacemaker cells

Na - K ATPase (The Sodium- Potassium ATPase pump) ADP outside 3 Na+ inside P P 2 K+ in/out: 15/150 mM Na+ 3Na+/2K+ 150 cycles/sec Maintenance of Na+ and K+ gradients requires ~20% of total ATP produced by the cell Na+ 3 Na+ ATPase K+ 2 K+ K+ in/out: 150/5 mM

The Resting Membrane Potential Polarized state that makes possible generation of electrical signals 1 2 [K+]i (150 mM) VM = -90 mV [K+]o (5 mM) V IKr K+ K+ 1) The Na/K-ATPase generates a K+ gradient by utilizing energy stored in ATP; 2) K+ flows out of the cell through K+ channels leaving behind anions; 3) K+ moves back attracted by the negative charge at the inner membrane face; + - Na+ + - 3 + -

The Cardiac Action Potential Basis for signal-carrying ability of cardiac myocytes Allows large areas of the heart to contract almost simultaneously Drives cardiac rhythm Two main types: fast (non-pacemaker) and slow (pacemaker)

The Fast Action Potential Nerve and skeletal muscle +50 Can be recorded throughout most of the heart except the pacemaker and conduction regions The cardiac AP is much longer than the nerve and skeletal AP and is composed of a fast upstroke and a slow plateau Membrane potential (mV) -100 Cardiac myocyte +50 -100 Upstroke Plateau

Phases of the Fast Action Potential +50 1 (Initial Repolarization) Membrane potential (mV) 2 (Plateau) (Depolarization) 3 (Repolarization) 4 4 (Resting Potential) -100 gNa INa ICa ION CONDUCTANCES gCa gK IKr IK IKr

Phases of the Fast Action Potential +50 1 (Initial Repolarization) Membrane potential (mV) Phase 4 2 (Plateau) (Resting Potential ) (Depolarization) 3 (Repolarization) 4 4 (Resting Potential) -100 gNa Outside INa Inside Outside ICa ION CONDUCTANCES gCa Inside IKr K+ IK gK Outside Inside IKr IK IKr K+

Phases of the Fast Action Potential +50 1 (Initial Repolarization) Membrane potential (mV) Phase 0 2 (Plateau) (Depolarization ) (Depolarization) 3 (Repolarization) 4 4 (Resting Potential) -100 Na+ gNa Outside INa Inside Outside ICa ION CONDUCTANCES gCa Inside IKr IK gK Outside Inside IKr IK IKr

Phases of the Fast Action Potential +50 1 (Initial Repolarization) Membrane potential (mV) Phase 0 2 (Plateau) (Depolarization ) (Depolarization) 3 (Repolarization) 4 4 (Resting Potential) -100 Na+ gNa Outside INa Inside Na+ Outside ICa ION CONDUCTANCES gCa Inside IKr IK gK Outside Inside IKr IK IKr

Phases of the Fast Action Potential +50 1 (Initial Repolarization) Membrane potential (mV) Phase 1 2 (Plateau) (Initial Repolarization ) (Depolarization) 3 (Repolarization) 4 4 (Resting Potential) -100 gNa Outside INa Inside Outside ICa ION CONDUCTANCES gCa Inside IKr IK gK Outside Inside IKr IK IKr

Phases of the Fast Action Potential +50 1 (Initial Repolarization) Membrane potential (mV) Phase 2 2 (Plateau) (Plateau) (Depolarization) 3 (Repolarization) 4 4 (Resting Potential) -100 gNa Outside INa Inside Ca2+ Outside ICa ION CONDUCTANCES gCa Inside IKr IK gK Outside Inside IKr IK IKr K+

Phases of the Fast Action Potential +50 1 (Initial Repolarization) Membrane potential (mV) Phase 3 2 (Plateau) (Repolarization) (Depolarization) 3 (Repolarization) 4 4 (Resting Potential) -100 gNa Outside INa Inside Outside ICa ION CONDUCTANCES gCa Inside IKr IK gK Outside Inside IK IKr IKr K+ K+

Refractory Periods Skeletal muscle fiber Cardiac myocyte Contraction Action Potential Relative refractory period refractory period Absolute refractory period Inability to respond to further stimulation Allows the ventricles sufficient time to empty their content and refill before the next cardiac contraction

The Pacemaker Action Potential Repolarization SA Node Depolarization Membrane potential (mV) AV Node 3 Threshold 4 4 -70 Pacemaker potential If gNa ICa gCa ION CONDUCTANCES gK IK

Properties of If Conducts both K+ and Na+ Opens (inward current) at hyperpolarized potentials cAMP accelerates activation kinetics Responsible for initial phase of spontaneous depolarization in the nodal tissue

Modulation of Pacemaker Activity Vagal Symp Vagal Symp ACH Intrinsic Rate (60-100 bpm) 50 200 bpm ACH NE SA Node + Norepinephrine + Acetylcholine Threshold Positive chronotropic effect Negative chronotropic effect

Molecular Mechanisms of Positive Chronotropic Effects of β-AGONISTS Ca2+ Channel Na+/K+ Channel b -Agonist AC b -R Gs P P ATP cAMP C ADP R C ATP PKA

Molecular Mechanisms of Negative Chronotropic Effects of Acetylcholine Ca2+ Channel Na+/K+ Channel Ach AC AchR Gi ATP cAMP P P

Conduction of Action Potentials Through the Heart Electrical coupling of myocytes via gap junctions Cardiac conduction system

Propagation of the Action Potential Along Cardiac Cells - - - - - - + + + + + + + + + + + + + - - - - - - Connexons Large-conductance pores permeable for ions and small molecules Consist of two sets of six subunits (connexons) Responsible for electrical coupling of myocytes Gap junctions

Propagation of the Action Potential Along Cardiac Cells - - - - - - - - - - - - - - - + + + + + + + + + + + + + + + + + + + + + - - - - - - Connexons Large-conductance pores permeable for ions and small molecules Consist of two sets of six subunits (connexons) Responsible for electrical coupling of myocytes Gap junctions

The Cardiac Conduction System AV Node Bundle of His SA Node LA RA Left Bundle Branch Right Bundle Branch LV RV Purkinje fibers

The Cardiac Conduction System AV Node SA Node

The Cardiac Conduction System AV Node Conduction velocity ~0.5-1 m/sec Atrium activation occurs within ~100 ms nearly synchronously SA Node

The Cardiac Conduction System AV Node Conduction velocity slows to ~0.2 m/sec This permits atrial relaxation occur before ventricular Contraction begins

The Cardiac Conduction System Bundle of His Left Bundle Branch Right Bundle Branch Conduction velocity is fast ~4 m/sec so the entire ventricle is activated simultaneously

The Cardiac Conduction System Conduction velocity is fast ~4 m/sec so the entire ventricle is activated nearly simultaneously Purkinje fibers

The Electrocardiogram ECG is a noninvasive recording of electrical activity of the working heart A most commonly used diagnostic tool that provides information on: Anatomical orientation of the heart Relative sizes of chambers Disturbances of rhythm and conduction Extent, location of ischemic damage Represents the sum of action potentials occurring simultaneously in many individual cells

Extracellular Recording of Depolarization and Repolarization in a Strip of Cardiac Muscle - - - - - - - - + + + + + + + + + + + + + + + + + + - - - - - - - - (+) (-) - - - - - - - - + + + + + + + + + - - - - - - - - + + + + + + + + + + + + + + + + + + - - - - - - - - - - - - - - - - + + + + + + + + + + + + + + + + + + - - - - - - - - + + + + + + + + + - - - - - - - -

ECG Recording as a Wave of Depolarization Along the Longitudinal Axis of Heart - - - + RA (-) - - + + LL (+) + + Polarity: When LL becomes positive with respect to RA an upward deflection is recorded

Components of a Typical ECG Recording QRS complex PR segment ST segment P wave – atrial depolarization QRS complex – ventricular depolarization T wave – ventricular repolarization PR interval – passage through the AV conduction system QT interval – period of electrical systole P wave T wave RA (-) R LL (+) T P Polarity: When LL becomes positive with respect to RA an upward deflection is recorded Q S PR interval <0.2 s QT interval ~0.4 s

Components of a Typical ECG Recording QRS complex PR segment ST segment P wave – atrial depolarization QRS complex – ventricular depolarization T wave – ventricular repolarization PR interval – passage through the AV conduction system QT interval – period of electrical systole P wave T wave RA (-) R LL (+) T P Polarity: When LL becomes positive with respect to RA an upward deflection is recorded Q S PR interval <0.2 s QT interval ~0.4 s

The Sequence of Activation of Heart in Relation to ECG _ AV Node SA Node P QRS T +

The Sequence of Activation of Heart in Relation to ECG _ AV Node SA Node P QRS T Atrial depolarization +

The Sequence of Activation of Heart in Relation to ECG _ AV Node SA Node P QRS T Depolarization of the intraventricular septum +

The Sequence of Activation of Heart in Relation to ECG _ AV Node SA Node P QRS T Depolarization of large part of ventricular myocardium +

The Sequence of Activation of Heart in Relation to ECG _ AV Node SA Node P QRS T Depolarization of a small portion of ventricular myocardium near the base +

The Sequence of Activation of Heart in Relation to ECG _ AV Node SA Node P QRS T Depolarization of whole ventricular myocardium +

The Sequence of Activation of Heart in Relation to ECG _ AV Node SA Node P QRS T Ventricular repolarization (progresses from the apex to the base) +

Summary For contraction to occur cardiac cells rely on action potentials (APs). The rapid upstroke of APs of atrial and ventricular cells is due to a Na+ current (INa). The prolonged plateau phase of these APs is due to a Ca2+ current (ICa), repolarization to potassium currents (IK), and the resting potential is due to another potassium current called IK1. APs in pacemaker cells rely on ICa for their upstroke, IK to repolarize, and on a funny current (If) to provide the diastolic pacemaker potential which slowly depolarizes the membrane between APs. Normally APs are generated in the SA node. The impulse propagates from the SA node to both atria and to the AV node, where a delay occurs. The impulse then passes into the bundles of His, right and left bundle branches, Purkinje fibers, and working ventricular myocytes. The electrocardiogram (ECG) is recorded from the surface of the body and traces the conduction of the cardiac impulse through the heart.

Electrical Properties of the Heart Quiz

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