Cardiac Electrophysiology Qiang XIA (夏强), PhD Department of Physiology Room C518, Block C, Research Building, School of Medicine Tel:

The major types of cardiac muscle: –Atrial muscle –Ventricular muscle –Specialized excitatory and conductive muscle Contractile cells （收缩细胞） Autorhythmic cells （自律细胞）

Conducting system of the heart

Cardiac muscle

The sinoatrial node is the heart’s pacemaker because it initiates each wave of excitation with atrial contraction. The Bundle of His and other parts of the conducting system deliver the excitation to the apex of the heart so that ventricular contraction occurs in an upward sweep. Sequence of cardiac excitation

General process of excitation and contraction of cardiac muscle Initiation of action potentials in sinoatrial node Conduction of action potentials along specialized conductive system Excitation-contraction coupling Muscle contraction

Transmembrane potentials recorded in different heart regions

Transmembrane potentials in epicardium and endocardium

Transmembrane potential of ventricular cells and its ionic mechanisms Resting Potential: -90 mV Action Potential Phase 0: Depolarization Phase 1: Early phase of rapid repolarization Phase 2: Plateau （平台期） Phase 3: Late phase of rapid repolarization Phase 4: Resting phase

Resting potential –K + equilibrium potential –Na + -inward background current –Electrogenic Na + -K + pump Ionic mechanisms

Phase 0  Threshold potential (-70mV)  Opening of fast Na + channel  Regenerative cycle （再生性循环） The action potential of a myocardial pumping cell.

Phase 1  Transient outward current, Ito K+ current  activated at –20 mV  opening for 5~10 ms

Phase 2 Inward currentOutward current (Ca 2+ & Na + ) (K + current)

Types of Ca 2+ channels in cardiac cells: (1) L-type (long-lasting) (Nowycky, 1985) (2) T-type (transient) (Nowycky, 1985)

Ca 2+ channels Duration of currentlong-lastingtransient Activation kineticsslowerfaster Inactivation kineticsslowerfaster Thresholdhigh (-35mV)Low (-60mV) cAMP/cGMP-regulatedYesNo Phosphorylation-regulatedYesNo OpenersBay-K BlockersvarapamilTetramethrin nifedipine, diltiazemNi 2+ Inactivation by [Ca 2+ ] i Yesslight Patch-clamp recordingrun-downrelatively stable L-type T-type

Outward current (K + current): (1) inward rectifier K + current (I K1 ) (2) delayed rectifier K + current (I K )

Phase 3 Inactivation of Ca 2+ channel Outward K + current dominates I K : Progressively increased I K1 : Regenerative K+ Outward Current

Phase 4 Na + -Ca 2+ exchange Sarcolemmal Ca 2+ pump SR Ca 2+ pump Na + -K + pump

a, The key ion channels (and an electrogenic transporter) in cardiac cells. K+ channels (green) mediate K+ efflux from the cell; Na+ channels (purple) and Ca2+ channels (yellow) mediate Na+ and Ca2+ influx, respectively. The Na+/Ca2+ exchanger (red) is electrogenic, as it transports three Na+ ions for each Ca2+ ion across the surface membrane. b, Ionic currents and genes underlying the cardiac action potential. Top, depolarizing currents as functions of time, and their corresponding genes; centre, a ventricular action potential; bottom, repolarizing currents and their corresponding genes. From the following article: Cardiac channelopathies Eduardo Marbán Nature 415, (10 January 2002) doi: /415213a

Transmembrane potentials recorded in different heart regions

Transmembrane potential of autorhythmic cells and its ionic mechanisms

Purkinje cells: Fast response autorhythmic cells 4

Contractile cellsAutorhythmic cells Phase 4 stable potentialPhase 4 spontaneous depolarization （ 4 期自动去极化） Resting potentialMaximal repolarization potential （最大复极电位）

Ionic mechanism Phase 0~3 ： similar to ventricular cells Phase 4 ： –(1) I f – Funny current, Pacemaker current （起搏电流） –(2) I k Decay （钾电流衰减）

Characteristics of I f channel Na +, K + Voltage- & time-dependent Activation── Repolarized to -60mV Full activation── Hyperpolarized to -100mV Inactivation── Depolarized to -50mV Blocked by Cs, not by TTX

Sinoatrial cells

Maximal repolarization potential -70mV Threshold potential -40mV Phase 0, 3, 4 Sinoatrial cells: Slow response autorhythmic cells 4 03

Ionic mechanism  Phase 0: I Ca (I Ca,L ) 4 03

 Phase 3:  Inactivation of L-type Ca 2+ channel  Outward K + current (I k ) 4 03

Phase 4 ：  I k decay Inactivated when repolarized to -60mV  I Ca,T Activated when depolarized to -50mV  I f

The action potential of an autorhythmic cardiac cell.

During which phase of the ventricular action potential is the membrane potential closest to the K+ equilibrium potential? (A) Phase 0 (B) Phase 1 (C) Phase 2 (D) Phase 3 (E) Phase 4

During which phase of the ventricular action potential is the conductance to Ca2+ highest? (A) Phase 0 (B) Phase 1 (C) Phase 2 (D) Phase 3 (E) Phase 4

Which phase of the ventricular action potential coincides with diastole? (A) Phase 0 (B) Phase 1 (C) Phase 2 (D) Phase 3 (E) Phase 4

The low-resistance pathways between myocardial cells that allow for the spread of action potentials are the (A) gap junctions (B) T tubules (C) sarcoplasmic reticulum (SR) (D) intercalated disks (E) mitochondria

Electrocardiogram (ECG) （心电图） The electrocardiogram (ECG) measures changes in skin electrical voltage/potential caused by electrical currents generated by the heart

The relationship between the electrocardiogram (ECG), recorded as the difference between currents at the left and right wrists, and an action potential typical of ventricular myocardial cells. Electrocardiogram (ECG)

The standard 12 lead ECG Einthoven’s Triangle Limb leads (Bipolar) (I, II, III) Augmented limb leads (Unipolar) (aVR, aVL, aVF) Chest leads (Unipolar) (V1, V2, V3, V4, V5, V6) I II III aVRaVL aVF V1 V2 V3 V4 V5 V6 Willem Einthoven: Dutch physiologist. He won a 1924 Nobel Prize for his contributions to electrocardiography.

Placement of electrodes in electrocardiography

Normal ECG 0.04 sec ECG interpretation Measurements Rhythm analysis Conduction analysis Waveform description Comparison with previous ECG (if any)

Animation of a normal ECG wave

P wave: the sequential depolarization of the right and left atria QRS complex: right and left ventricular depolarization ST-T wave: ventricular repolarization U wave: origin for this wave is not clear - but probably represents "afterdepolarizations" in the ventricles

PR interval: time interval from onset of atrial depolarization (P wave) to onset of ventricular depolarization (QRS complex) QT interval: duration of ventricular depolarization and repolarization ST segment: the time period between the end of the QRS complex and the beginning of the T wave, during which each myocyte is in the plateau phase (phase 2) of the action potential

Normal Partial block Complete block

Excitability Autorhythmicity Conductivity Contractility Electrophysiological properties （电生理特性） Mechanical property （机械特性） Physiological properties of cardiac cells

 Factors affecting excitability –Resting potential –Threshold potential –Status of Na + or Ca 2+ channels  Excitability （兴奋性）

Hyperkalemia （高钾血症） The QRS complexes may widen so that they merge with the T waves, resulting in a “sine wave” appearance. The ST segments disappear when the serum potassium level reaches 6 mEq/L and the T waves typically become tall and peaked at this same range. The P waves begin to flatten out and widen when a patient‘s serum potassium level reaches about 6.5 mEq/L; this effect tends to disappear when levels reach 7-9 mEq/L. Sinus arrest may occur when the serum potassium level reaches about 7.5 mEq/L, and cardiac standstill or ventricular fibrillation may occur when serum levels reach 10 to 12 mEq/L.

 Periodic changes in excitability

Postrepolarization refractoriness of slow response cells

Valuable protective mechanism The long refractory period means that cardiac muscle cannot be restimulated until contraction is almost over & this makes summation & tetanus of cardiac muscle impossible

Premature systole & compensatory pause (extrasystole)

A 39-year-old lady presenting with frequent palpitations lasting a few months A 39-year-old lady presents to you with frequent palpitations lasting a few months, which are not associated with dizziness, syncope or angina. She has enjoyed good health and is not on any medication or herbal medicine. She is a non-smoker and has no known diabetes, hypertension or hypercholesterolaemia. Her menses is regular and physical examination is unremarkable other than a few premature beats. This is her ECG. Answers: Ventricular premature beats are noted.

Premature ventricular beats unmask the P waves

Hemodynamic tracings to demonstrate the increased variability of systolic BP (SBP), diastolic BP (DBP), and heart period (HP) in MI rat with frequent VPB

 Autorhythmicity （自律性）

 Autorhythmicity SA node100 times/min AV node 50 times/min Bundle of His 40 times/min Purkinje fibers 25 times/min

Normal pacemaker （正常起搏点）  SA node Latent pacemaker （潜在起搏点） (Ectopic pacemaker [ 异位起搏点 ] under pathophysiological conditions)  AV node  Bundle of His  Purkinje fibers

The mechanisms of SA node to control latent pacemakers –Capture （夺获） –Overdrive suppression （超速抑制）

Factors Affecting Autorhythmicity  Maximal repolarization potential  Threshold potential  The rate of phase 4 spontaneous depolarization

Sinus Bradycardia （窦性心动过缓）

Pacemaker

 Conductivity （传导性）

Gap junction

SA nodeAtriaA-V node 0.05 m/s0.4 m/s0.02~0.05 m/s His bundlePurkinje fiber Ventricle 1.2~2.0 m/s2.0~4.0 m/s1.0 m/s Conducting velocity Atrioventricular delay （房室延搁） : Asynchronization of atrial and ventricular depolarization to provide adequate cardiac output

Factors Affecting Conductivity  Structural factors Diameter of cardiac cells Gap junctions at Intercalated disk  Physiological factors The velocity and amplitude of phase 0 depolarization Excitability of adjacent region

First Degree AV Block Definition: 1AVB is a rhythm in which the electrical impulse which leaves the SA node and travels through the atria, AV node, Bundle of His to purkininjie fibers is slowed down and takes longer than normal to arrive at its destination. The normal PR interval is seconds. A 1AVBT is greater than 0.20 seconds. The cause ranges from coronary heart disease, inferior wall MI's, hyperkalemia, congenital abnormalities, and medications such as quinidine, digitalis, beta blockers, and calcium channel blockers.

Second degree AV Block type 1 (Mobitz) Definition: Second degree AV block is also known as Second Degree Type I, Mobitz I, or Wenckelbach. This arrhythmia is characterized by a progressive delay of the conduction at the AV node, until the conduction is completely blocked. This occurs because the impulse arrives during the absolute refractory period, resulting in an absence of conduction, and no QRS. The next P wave occurs and the cycle begins again. Possible causes are acute inferior wall myocardial infraction, digitalis, beta blockers, calcium channel blockers, rheumatic fever, myocarditis, or excessive vagal tone.

Mobitz II is characterized by 2-4 P waves before each QRS. The PR of the conducted P wave will be constant for each QRS. It is usually associated with acute anterior or anteroseptal myocardial infarction. Other causes are cardiomyopathy, rheumatic heart disease, coronary artery disease, digitalis, beta blockers, and calcium channel blockers. Mobitz II has the potential of progressing into a third degree heart block or ventricular standstill. Second degree AV Block Type II

A third degree atrial ventricular block is also know as a complete heart block artrioventricular block of 3degree AV block. It is a problem with electrical conduction. All electrical conduction from the atria are blocked at the AV junction, therefore, the atria and the ventricles beat independently from each other. This arrhythmia is dangerous because it significantly decreases cardiac output, and could lead to asystole. Possible causes: acute inferior and anterior myocardic infraction, coronary heart disease, excessive vagal tone, myocarditis, endocarditis, age, edema from heart surgery, and meditation toxicity from digitalis, beta blockers, calcium channel blockers. Third Degree -- Complete Block

Reentry （折返） Model Reentry can take place within a small local region within the heart or it can occur, for example, between the atria and ventricles (global reentry). For reentry to occur, certain conditions must be met that are related to the following: 1.the presence of a unidirectional block within a conducting pathway; 2.critical timing; 3.the length of the effective refractory period of the normal tissue.

Q-T interval recorded on an ECG primarily corresponds to: A Ventricular repolarization B Ventricular depolarization plus ventricular repolarization C Ventricular depolarization and atrial repolarization D Atrial depolarization and conduction through AV node E Purkinje fibers repolarization

The resting membrane potential of a sinus nodal fiber is A -124 mV B -91 mV C -85 mV D -55 mV E -25 mV

You see a 55-year-old, white female for a routine check-up. On the ECG you see a prolonged PQ interval suggesting a first-degree atrioventricular block. What is the primary pacemaker of the heart? A Sinoatrial node B Atrioventricular node C Atrioventricular bundle D Right and left bundle branches E Purkinje fibers

The End.