EKG and Cardiac Electrical Properties Lecture Slides PDF

Cardiac Electrical Activity and the ECG Key abbreviations: OVP: Optional Video-podcast available on Canvas FYI: For your information. Discussed topics are relevant for your understanding but you will not be tested on this material at the exam....

Cardiac Electrical Activity and the ECG Key abbreviations: OVP: Optional Video-podcast available on Canvas FYI: For your information. Discussed topics are relevant for your understanding but you will not be tested on this material at the exam. Marcello Rota, PhD BSB #617 [email protected] Berne & Levy: Chapter 16 Guyton: Chapters 9-13 All materials found in this document may be subject to copyright Costanzo: Chapter 4 protection, and are restricted from further dissemination, retention or copying. 1  Learning Objectives At the conclusion of this lectures, participants will be able to: 1. describe ionic currents underlying the five phases of the cardiac action potential; 2. discuss the diversity of the action potential in the heart; 3. define the effective and relative refractory periods and their implications; 4. explain mechanisms underlying the spontaneous rhythmicity of the heart (automaticity or pacemaker activity); 5. report the pathway of conduction of the electrical excitation in the heart during a normal heartbeat; 6. discuss information provided by the electrocardiogram; 7. show the relationship of cardiac action potentials to the electrocardiogram; 8. describe some clinical examples of electrophysiological abnormalities 2 Function of the heart: to pump blood in the body Boron and Boulpaep Textbook of Medical Physiology 3  Function of the heart: to pump blood in the body Rota et al, unpublished (BIDMC Center for Basic MR Research) Aorta LA LV RA RV Boron and Boulpaep Textbook of Medical Physiology Cardiac Cycle: Diastole: the phase of the heartbeat when the heart muscle relaxes and allows the chambers to fill with blood. Cardiac cycle in a mouse using Magnetic Resonance Imaging (MRI). Systole: the phase of the heartbeat when the heart muscle contracts and pumps blood from the chambers into the arteries. 4 1-OVP Excitation-contraction coupling Myocyte excitation involves a change in transmembrane potential (action potential, AP) CARDIOMYOCYTE Cardiomyocyte During the AP Ca2+ enters the cell and triggers translocation of Ca2+ into the cytoplasm Rota, unpublished Mouse ventricular myocyte loaded with a Ca2+ indicator and electrically stimulated every second (1 Hz). Brightness of the fluorescent signal is proportional to Ca2+ level in the cytoplasm. The increase in Ca2+ is coupled with contraction of the cell. Ca2+ binds myofilaments eliciting cell contraction Excitation-contraction coupling involves excitation of myocytes, changes in intracellular Ca2+, and binding of Ca2+ to myofilaments promoting contraction. 5 1-OVP Properties of Cardiac Cells - Excitability - Automaticity - Conductivity - Ability to contract Sinoatrial (SA) node LA RA LV RV Conduction System Guyton et al. Textbook of Medical Physiology 6 1-OVP Excitability Electrical excitability: property of cells in which depolarization of the membrane above a certain threshold triggers an action potential. Action potential (AP): a rapid, all-or-none change in the membrane potential followed by a return to the resting membrane potential. 7 1-OVP Membrane potential (or transmembrane potential, Vm) is the difference in electric potential between the interior and the exterior of a cell. Cardiomyocyte kept in a physiological (extracellular) solution Rota and Vassalle, unpublished Vin - - - - - - - - - + + + + + + + + + Vout Extracellular solution Transmembrane potential Vm=Vin–Vout 8 1-OVP Measurement of transmembrane potential (Vm) in a cardiomyocyte Intracellular Cardiomyocyte kept in electrode a physiological (extracellular) solution Rota and Vassalle, unpublished - - - - - - - - - + + + + + + + + + Extracellular Extracellular solution electrode Transmembrane potential Vm=Vin–Vout At rest: transmembrane resting potential = ~ -88 mV 9 1-OVP Measurement of transmembrane potential (Vm) in a cardiomyocyte Intracellular electrode Rota and Vassalle, unpublished Extracellular Extracellular solution electrode 10 Signore et al. Circulation 2013 1-OVP Excitability Electrical excitability: property of cells in which depolarization of the membrane above a certain threshold triggers an action potential. Action potential (AP): a rapid, all-or-none change in the membrane potential followed by a return to the resting membrane potential. 11 Signore et al. Circulation 2013 1-OVP Cardiac (Ventricular) Action Potential (AP): 5 Phases Partial (early) repolarization Plateau Repolarization Rapid Resting (diastolic) depolarization potential (upstroke) Berne & Levy, 2001 ~300 ms 12 1-OVP Recording of transmembrane potential in a cardiomyocyte using patch-clamp technique 13  1-OVP Transmembrane potential (blue trace) collected in a ventricular myocyte electrically stimulated at 0.5 Hz (1 stimulus every 2 sec) to elicit action potentials. Partial (early) repolarization Plateau Repolarization Rota et al., unpublished Resting (diastolic) potential Rapid depolarization (upstroke) Berne & Levy, ~300 ms 2001 14 1-OVP Cardiac Action Potential: the change in membrane potential is mediated by the flux of charges (Na+, Ca2+, and K+ ions) across the membrane Vm= +20 mV + + + + + + + + + - - - - - - - - - Positive (+) charges leave the cell (repolarization) Vm= -88 mV Positive (+) Vm= -88 mV charges enter the cell (depolarization) - - - - - - - - - - - - - - - - - - + + + + + + + + + + + + + + + + + + Berne & Levy, 2001 Vm=Vin-Vout ~300 ms 15 1-OVP FYI Transmembrane IONIC fluxes are involved in the generation of the action potential. Transmembrane IONIC fluxes depends on: - Opening of voltage-gated ion channels - Existence of a driving force for ion movement across the membrane 16 1-OVP FYI Transmembrane IONIC fluxes are involved in the generation of the action potential. Transmembrane IONIC fluxes depends on: - Opening of voltage-gated ion channels - Existence of a driving force for ion movement across the membrane Vm=-88 mV Vm=-60 mV + + + + + + + + + - + - + + + + + + Representation of a myocyte - - - - - - - - - + - + - - - - - - - - - - - - - - + + + + + + + + Na+ channel Na+ channel Behavior of ion channels (biophysical properties): - Voltage-gated: opening of channels depends on membrane potential; - Time-dependent: opening and closing of channels is time-dependent (with some exceptions); - Selective: channels are permeable to specific species of ions. Opening/closing of channels determines their conductance (reciprocal of resistance, R) to a specific ion. 17 1-OVP FYI Transmembrane IONIC fluxes are involved in the generation of the action potential. Transmembrane IONIC fluxes depends on: - Opening of voltage-gated ion channels - Existence of a driving force for ion movement across the membrane - Electrical gradient (negative charges inside of the cell attract positive ions) - Chemical gradient (ions will diffuse from high to low concentration areas) Vm=-88 mV Vm=-60 mV + + + + + + + + + - + - + + + + + + - - - - - - - - - + - + - - - - - - - - - - [Na+]i 10 mM - - - - [Na+]i 10 mM + + + + [Na+]o 145 mM + + + + [Na+]o 145 mM Na+ 18 1-OVP FYI Transmembrane IONIC fluxes are involved in the generation of the action potential. Transmembrane IONIC fluxes depends on: - Opening of voltage-gated ion channels (R, resistance) - Existence of a driving force for ion movement across the membrane - Electrical gradient (Vm, membrane potential) This can be - Chemical gradient (Ex, equilibrium potential) quantified by the Ohm’s law Vm=-88 mV Vm=-60 mV + + + + + + + + + - + - + + + + + + - - - - - - - - - + - + - - - - - - - - - - [Na+]i 10 mM - - - - [Na+]i 10 mM + + + + [Na+]o 145 mM + + + + [Na+]o 145 mM Na+ ∆V Vm − ENa Ohm’s law INa = = I = current (flux of ions) R R ΔV = driving force (factors promoting ion flux) R = resistance (opening of channel) Vm = transmembrane membrane potential ENa = equilibrium potential for Na+ ions (Nernst equation) 19 1-OVP FYI Transmembrane IONIC fluxes are involved in the generation of the action potential. Transmembrane IONIC fluxes depends on: - Opening of voltage-gated ion channels (R, resistance) - Existence of a driving force for ion movement across the membrane - Electrical gradient (Vm, membrane potential) This can be - Chemical gradient (Ex, equilibrium potential) quantified by the Ohm’s law Vm=-88 mV Vm=-60 mV + + + + + + + + + - + - + + + + + + - - - - - - - - - + - + - - - - - - - - - - [Na+]i 10 mM - - - - [Na+]i 10 mM + + + + [Na+]o 145 mM + + + + [Na+]o 145 mM Na+ ∆V Vm − ENa Ohm’s law INa = = I = current (flux of ions) R R ΔV = driving force (factors promoting ion flux) 𝑵𝒆𝒓𝒏𝒔𝒕 𝑬𝒒𝒖𝒂𝒕𝒊𝒐𝒏 R = resistance (opening of channel) 61.5 𝑋𝑖 Vm = transmembrane membrane potential 𝐸𝑋 = − 𝑙𝑜𝑔10 ENa = equilibrium potential for Na+ ions (Nernst equation) 20 𝑧𝑋 𝑋𝑜 1-OVP FYI Transmembrane IONIC fluxes are involved in the generation of the action potential. Transmembrane IONIC fluxes depends on: - Opening of voltage-gated ion channels (R, resistance) - Existence of a driving force for ion movement across the membrane - Electrical gradient (Vm, membrane potential) - Chemical gradient (Ex, equilibrium potential) Ion [X]in (mM) [X]out (mM) EX (mV) Na+ 10 145 +72 Vm=-60 mV - + - + + + + + + + - + - - - - - - - - - - [Na+]i 10 mM + + + + [Na+]o 145 mM Na+ !! "#"# "%& "()*+) "-.+ Electrophysiological convention: INa = = = NEGATIVE current value: flow of positive ions inside of the cell $ $ $ POSITIVE current value: flow of positive ions outside of the cell 21 1-OVP The action potential of ventricular cardiomyocytes and ionic currents There are 3 types of voltage-gated ion channels that contribute to the generation of the ventricular action potential: - Na+ channels (1 type only) - Ca2+ channels (1 type only) - K+ channels (3 subtypes of channels) When open, these channels allow for the passage, respectively, of Na+, Ca2+, and K+ ions across the membrane of myocytes. 22 1-OVP The action potential of ventricular cardiomyocytes and ionic currents There are 3 types of voltage-gated ion channels that contribute to the generation of the ventricular action potential: - Na+ channels (1 type only) - Ca2+ channels (1 type only) - K+ channels (3 subtypes of channels) When open, these channels allow for the passage, respectively, of Na+, Ca2+, and K+ ions across the membrane of myocytes. The direction of the flux of a particular ion X depends on the driving force for ion X across the membrane (Vm - EX). Driving force is part of the Ohm’s law: Vm − E X IX = ionic current for a particular ion X IX = Vm = membrane potential R Ex = equilibrium potential for a particular ion X R = Membrane resistance resistance At any given moment, the driving force for ion X depend on Vm and the equilibrium potential EX. 23 1-OVP The action potential of ventricular cardiomyocytes and ionic currents ECa ≈ +123 mV There are 3 types of voltage-gated ion channels that contribute to the generation of the ventricular action ENa ≈ +72 mV potential: - Na+ channels (1 type only) - Ca2+ channels (1 type only) - K+ channels (3 subtypes of channels) When open, these channels allow for the passage, respectively, of Na+, Ca2+, and K+ ions across the membrane of myocytes. The direction of the flux of a particular ion X depends on the driving force for ion X across the membrane (Vm - EX). Driving force is part of the Ohm’s law: Vm − E X IX = ionic current for a particular ion X IX = Vm = membrane potential R EK ≈ -88 mV Ex = equilibrium potential for a particular ion X R = Membrane resistance resistance Ion [X]in (mM) [X]out (mM) EX (mV) At any given moment, the driving force for ion X depend on Vm and the equilibrium potential EX. Na+ 10 145 +72 The equilibrium potentials for Na+, Ca2+, and K+ are stable in Ca2+ 0.0001 1 +123 normal conditions. Pathological conditions may alter ionic balance K+ 120 4.5 -88 and equilibrium potentials. 24 1-OVP The action potential of ventricular cardiomyocytes and ionic currents ECa ≈ +123 mV For a particular ion X, the current flowing through channels tends to move Vm closer to EX, the equilibrium potential for ion X. ENa ≈ +72 mV - Na+ current: inward current (Na+ enters to the cell) Fast Na+ current (INa) Positive Na+ ion entering the cells tends to move Vm closer to ENa DEPOLARIZING CURRENT - Ca2+ current: inward current (Ca2+ enters the cell) L-type Ca2+ current (ICa) Positive Ca2+ ion entering the cells tends to move Vm closer to ECa DEPOLARIZING CURRENT - K+ current: outward current (K+ moves out of the cell) Transient outward K+ current (Ito) EK ≈ -88 mV Delayed rectifier K+ current (IK) Inward rectifier K+ current (IK1) Positive K+ ion leaving the cells tends to move Vm closer to EK REPOLARIZING CURRENT Vm − E X IX = IX = ionic current for a particular ion X R Vm = membrane potential Ex = equilibrium potential for a particular ion X R = Membrane resistance resistance 25  Ionic currents underlying the ventricular AP Berne and Levy, Physiology 7th edition Vm − EX IX = R IX = ionic current for a particular ion X Vm = membrane potential Ex = equilibrium for a particular ion X R = Membrane resistance resistance Phase 0: Phase 1: Phase 2: Phase 3: Phase 4: Rapid depolarization Partial repolarization Plateau Repolarization Resting potential (upstroke) (early repolarization) The AP is the end result of the interplay of ionic currents generated by the opening (and closing) of ion channels. The interplay of ionic currents determines the shape of the AP. 26  Ionic currents underlying the ventricular AP Phase 0: Vm − EX Rapid depolarization IX = (upstroke) R Th Ion [X]in (mM) [X]out (mM) EX (mV) Na+ 10 145 +72 K+ 120 4.5 -88 Ca2+ 0.0001 1 +123 Fast Na+ current (INa) Berne and Levy, Physiology 7th edition 27  Ionic currents underlying the ventricular AP Phase 1: Vm − EX Partial repolarization IX = (early repolarization) R Ion [X]in (mM) [X]out (mM) EX (mV) Na+ 10 145 +72 K+ 120 4.5 -88 Ca2+ 0.0001 1 +123 Transient outward K+ current (Ito) Berne and Levy, Physiology 7th edition 28  Ionic currents underlying the ventricular AP Phase 2: Vm − EX Plateau IX = R Ion [X]in (mM) [X]out (mM) EX (mV) Na+ 10 145 +72 K+ 120 4.5 -88 Ca2+ 0.0001 1 +123 - L-type Ca2+ current (ICaL) - Delayed rectifier K+ current (IK) Berne and Levy, Physiology 7th edition Nearly equal Ca2+ influx and K+ efflux 29  Ionic currents underlying the ventricular AP Phase 3: Berne and Levy, Physiology 7th edition Vm − EX Repolarization IX = R Ion [X]in (mM) [X]out (mM) EX (mV) Na+ 10 145 +72 - Delayed rectifier K+ current (IK) - Inward rectifier K+ current (IK1) K+ 120 4.5 -88 30 Ca2+ 0.0001 1 +123  Ionic currents underlying the ventricular AP Berne and Levy, Physiology 7th edition Phase 4: Vm − EX Resting potential IX = R Ion [X]in (mM) [X]out (mM) EX (mV) Inward rectifier K+ current (IK1) + Na 10 145 +72 K+ 120 4.5 -88 Because of the conductance of inward rectifier K+ channels, resting membrane potential is close to the equilibrium potential of K+ ions (EK) 31 Ca2+ 0.0001 1 +123  Ionic currents underlying the ventricular AP Berne and Levy, Physiology 7th edition Vm − EX IX = R INa Ito IK, IK1 ICaL, IK Na+, K+ ATPase (3 Na+ vs 2 K+) Contribute to maintain ionic concentration Na/Ca exchange (NCX, or antiporter) gradients across the membrane (3 Na+ vs 1 Ca2+) 32  Key Points The cardiac action potential results from ionic currents related to voltage- and time-dependent ion channels. The upstroke of the action potential is the result of the fast inward Na+ current. The ventricular action potential exhibits a plateau phase, which is the result of nearly equal Ca2+ influx and K+ efflux. The resting membrane potential of ventricular myocytes is dictated by membrane permeability to K+ ions due to inward rectifier channels. 33  There are two main types of APs in the heart Fast response APs Slow response APs (with fast upstroke) (with slow upstroke) Sinoatrial (SA) node LA Atrio-ventricular (AV) node RA LV RV Guyton et al. Textbook of Medical Boron and Boulpaep Textbook of Medical Physiology Physiology 34  Slow- vs. fast-response action potentials Slow AP Fast AP Berne & Levy (2001) Properties SA node cells Mechanism Ventricular myocytes Mechanism 35  Slow- vs. fast-response action potentials Slow AP Fast AP Berne & Levy (2001) Properties SA node cells Mechanism Ventricular myocytes Mechanism Maximum ~-65 mV ~-90 mV diastolic potential 36  Slow- vs. fast-response action potentials Slow AP Fast AP Berne & Levy (2001) Properties SA node cells Mechanism Ventricular myocytes Mechanism Maximum ~-65 mV Lack of IK1 ~-90 mV IK1 (inward diastolic rectifier K+ potential current) 37  Slow- vs. fast-response action potentials Slow AP Fast AP Berne & Levy (2001) Properties SA node cells Mechanism Ventricular myocytes Mechanism Maximum ~-65 mV Lack of IK1 ~-90 mV IK1 (inward diastolic rectifier K+ potential current) Diastolic Diastolic Due to Resting diastolic No “pacemaker” potential depolarization “pacemaker” potential currents currents 38  Slow- vs. fast-response action potentials Slow AP Fast AP Berne & Levy (2001) Properties SA node cells Mechanism Ventricular myocytes Mechanism Maximum ~-65 mV Lack of IK1 ~-90 mV IK1 (inward diastolic rectifier K+ potential current) Diastolic Diastolic Due to Resting diastolic No pacemaker potential depolarization pacemaker potential currents currents Phase 0 Low amplitude and Due to ICa Large amplitude and Due to INa slow depolarization Lack of INa fast depolarization (dV/dt) (dV/dt) 39  Experimentally, fast APs in Purkinje fibers can be converted to slow APs if INa is blocked TTX: 0 0.3 nM 30 nM 3 µm 3 µm Berne and Levy, Physiology 7th edition Slower upstroke with smaller Tetrodotoxin (TTX): blocker of INa amplitude INa is a critical component of the fast action potential. 40  Key Points There are two main types of cardiac action potentials (APs): fast and slow responses. Lack of inward rectifier channels (mediating IK1) in sinoatrial and atrioventricular cells makes maximum diastolic potential of slow responses less negative with respect to fast responses AP. Lack of the fast Na+ channels (mediating INa) in sinoatrial and atrioventricular cells makes the upstroke slow and small in amplitude. 41  Refractory Period Refractory period: interval during the AP in which a second or multiple APs cannot be induced. After the onset of the AP, the depolarized cells in not able initiate another AP until it has partly repolarized. Berne and Levy, Physiology 7th edition 42  Refractory Period Refractory period: interval during the AP in which a second or multiple APs cannot be induced. After the onset of the AP, the depolarized cells in not able initiate another AP until it has partly repolarized. Sodium channels open upon depolarization O Inacti va tio n Activation I va rom n cti ry f tio Ina ove C c Re Berne and Levy, Physiology 7th edition During the first AP, Na+ channels open and then close with time by inactivation. Repolarization is needed to make these channels closed but available to open. 43  Refractory Period Refractory period: interval during the AP in which a second or multiple APs cannot be induced. After the onset of the AP, the depolarized cells in not able initiate another AP until it has partly repolarized. Slow action potentials have refractory periods that persist beyond the duration of the action potential. Berne and Levy, Physiology 7th edition 44  Effective and Relative Refractory Period Berne & Levy (2001) Effective (Absolute) Refractory Period (ERP): Phase in which a new AP cannot be induced. Relative Refractory Period (RRP): Phase in which a new AP can be generated with a larger-than-normal stimulus. 45  Functional implication of the refractory period Berne & Levy (2001) The long refractory period of the cardiac AP prevents summation or tetanization of contractions, a condition not compatible with the rhythmic beating of the heart. The long refractory period in the atrio-ventricular node cells allows them to serve as a “frequency filter” during atrial fibrillation, atrial flutter, or atrial tachycardia. 46  Key Points The refractory period is the interval during the AP in which a second or multiple APs cannot be induced. The long refractory periods of cardiac AP prevent premature re-excitation of cardiac cells and prevent tetanization of cardiac muscle. 47  Properties of Cardiac Cells - Excitability - Automaticity - Conductivity Atrioventricul - Ability to contract ar (AV) node (70-90 bpm) Sinoatrial (SA) node (100-120 bpm) Automaticity (pacemaker activity): ability to undergo a LA spontaneous time-dependent depolarization of cell membrane that leads to an AP. Ability of self-excitation. RA Rhythmicity: regularity of pacemaker activity. LV Purkinje Dominant and subsidiary pacemakers: anatomical structures RV fibers that present hierarchical pacemaker activity. (30-40 bpm) Purkinje Guyton et al. Textbook of Medical fibers Physiology 48 Cells of the SA node have diastolic depolarization of the membrane that can reach the threshold potential for the upstroke of the AP resulting spontaneous firing. Threshold Berne & Levy (2001) Phase 4 Phase 4 = diastolic depolarization = pacemaker potential 49 Pacemaker potential in nodal cells: the “classical” model involving If, ICa, and IK Berne & Levy (2001) 50  Pacemaker potential in nodal cells: the “classical” model involving If, ICa, and IK Berne & Levy (2001) Phase 4 If: “funny” current. If has unusual behavior (funny) because channels (HCN) activates upon hyperpolarization of Vm, rather than on depolarization. If is carried mostly by Na+ ions, although HCN channels conduct to both Na+ and K+. If contributes (together with other currents) to the diastolic depolarization (phase 4). HCN: hyperpolarization activated cyclic nucleotide gated channel 51 Pacemaker potential in nodal cells: the “classical” model involving If, ICa, and IK Phase Berne & Levy (2001) 0 Phase 4 Cells of the SA node have no INa (the fast sodium current), which is present in cells with fast response AP. ICa becomes important in the late phase 4 and upstroke (phase 0) of the AP 52  Pacemaker potential in nodal cells: the “classical” model involving If, ICa, and IK Phase Berne & Levy (2001) 3 Phase 4 IK: the delayed rectifier K+ current is responsible for phase 3 repolarization. Also, as IK turns off, it contributes to the depolarization of phase 4. 53  Pacemaker potential in nodal cells: the “classical” model involving If, ICa, and IK Berne & Levy (2001) The internal rhythmicity of the SA nodal cells resides in the interaction among the voltage-gated and time-dependent currents If, ICa, and IK. 54  Firing rate is modulated by the duration of diastolic depolarization (1) In B, DD slope is attenuated leading to a prolongation of diastolic Diastolic A B depolarization and slower firing rate, with respect to A. depolarization (DD) e s lop slope D D (2) In B, MDP is more negative and it takes longer for the membrane Maximum diastolic to reach the threshold for the upstroke, with respect to A, resulting potential (MDP) in slower firing rate. A Maximum Diastolic Potential (MDP) B (3) Threshold for the upstroke B A Threshold In B, threshold for the upstroke is less negative and it takes longer for the membrane to reach the threshold potential and to fire an action potential, with respect to A, resulting slower firing rate. Boron and Boulpaep Textbook of Medical Physiology 55  Divisions of the autonomic nervous system Parasympathetic nerves Guyton et al. Textbook of Medical Physiology Parasympathetic vagus nerve releases acetylcholine (ACh). Sympathetic nerves release norepinephrine. 56  Acetylcholine Reduces Heart Rate Acetylcholine (parasympathetic nerve activity): Reduces If: - reduces slope of DD (1); (1) Diastolic Reduces ICa: - reduces slope of DD (1); depolarization (DD) - shifts the threshold of ICa activation and the slope upstroke to less negative potentials (3); Activates ligand-gated KACh channels (inward rectifier) IKACh: - promotes repolarization; - MDP becomes more negative (2). (2) Maximum diastolic potential (MDP) (3) Threshold for the upstroke Berne & Levi (2001) Boron and Boulpaep Textbook of Medical Physiology 57  Catecholamines Increase Heart Rate Norepinephrine (sympathetic nerve activity) and epinephrine (circulating): (1) Diastolic Increase If: - increases the slope of DD (1); depolarization (DD) slope Increase ICa: - increases the slope of DD (1); - shifts of the threshold for the upstroke to more negative potentials (3). (3) Threshold for the upstroke Berne & Levi (2001) Boron and Boulpaep Textbook of Medical Physiology 58  Divisions of the autonomic Complete autonomic blockade nervous system reveals intrinsic heart rate Parasympathetic nerves Bene and Levy, Redrawn from Katona PG, et al. J Appl Physiol. 1982;52:1652. Atropine: a muscarinic receptor antagonist (blocks parasympathetic effects). Guyton et al. Textbook of Medical Physiology Propranolol: a β-adrenergic receptor antagonist (blocks sympathetic effects). Intrinsic heart rate: the rate at which the heart beats when all cardiac neural and hormonal inputs are removed. 59  Intrinsic Pacemaker Rate Atrioventricular Dominant (AV) node pacemaker (70-90 bpm) Sinoatrial (SA) node (100-120 LA Subsidiary bpm) pacemakers RA LV Purkinje RV fibers (30-40 bpm) Guyton et al. Textbook of Medical Physiology Intrinsic pacemaker rate of the SA node is faster than other latent pacemaker sites in the heart. Because of the faster rate, the SA node is the dominant pacemaker of the heart. FYI: Fast firing of the SA node suppresses automaticity of other pacemakers via overdrive suppression, a mechanism involving cytoplasmic Na+ accumulation and Na+ extrusion via the Na+,K+-ATPase (3 Na+ ions extruded vs. 2 K+ ions entering the cell: net outward current. The net outward current tends to hyperpolarize the cell making it quiescent). 60  Key Points Automaticity is the ability of dominant and subsidiary pacemakers to undergo a spontaneous time-dependent depolarization of cell membrane that leads to an AP. Ability of self-excitation. The internal rhythmicity of the SA nodal cells resides in the interaction among the voltage-gated and time- dependent currents If, ICa, and IK. Sympathetic nerves can increase, and parasympathetic nerves can decrease the SA node pacemaker rate. The SA node is the normal (dominant) cardiac pacemaker, but cells in the AV node and Purkinje fibers can operate as subsidiary pacemakers. 61 2-OVP Properties of Cardiac Cells - Excitability - Automaticity - Conductivity Atrioventricular - Ability to contract (AV) node Sinoatrial Bundle (SA) node of His Left and Conductivity: ability to propagate electrical impulse LA right bundle from one cell to another. branches RA Specialized cardiac cells form the conduction LV Purkinje system. RV fibers Purkinje Guyton et al. Textbook of Medical fibers mV Physiology Time 62 2-OVP Conductivity Mitral valve Properties of the heart: - Cells electrically coupled (functional syncytium) - Plane of valves electrically inert except for AV node - “normal” conduction path is the same for each beat - conduction velocity varies significantly along route Berne and Levy, Physiology 7th edition Tricuspid valve 63 2-OVP Heterogeneous conduction velocity in the heart Properties SA and Purkinje Atrial and AV node fibers ventricular myocytes Conduction 0.05 4 1 velocity (m/s) Rapid in atria Remarkably slow in 0.16 The conduction of excitation throughout the the AV node ventricles occurs in ~60 ms. Strikingly rapid in Purkinje fibers Rapid in the ventricular Guyton et al. Textbook of Medical Physiology myocardium 64 2-OVP Functional Syncytium Intercalated disk Gap Junctions Guyton et al. Textbook of Medical Physiology Intercalated disks: transverse bands that separate adjacent myocytes. Gap junctions: intercellular communication between neighboring cells. Gap junctions are made of proteins called connexins. 65 2-OVP Propagation of Excitation in the Myocardium FYI A B CELL A Boron and Boulpaep Textbook of Medical Physiology CELL B Depolarization of CELL A originates flow of positive charges from CELL A to CELL B via gap-junctions (intracellular current). Positive charges depolarize CELL B and release extracellular positive charges (associated with the membrane, which acts as a capacitor). Release of extracellular positive charges originates an extracellular current from CELL B to CELL A. Intracellular and extracellular currents are equal and opposite. Capacitor: a device used to store an electric charge, consisting of one or more pairs of conductors separated by an insulator. The capacitor accumulates charge proportional to the voltage across it. The membrane of the cell acts as a capacitor. 66 2-OVP FYI Cell Morphology Mouse Rabbit SAN SAN SAN SAN SAN Atria SAN Atria Mangoni, and Nargeot Physiol Rev 2008;88:919-982 Properties SA and AV node Purkinje fibers Atrial and ventricular myocytes Cell diameter Small Largest Large ∆VAB IAB = Conductivity of the cytosol of a cell depends RAB on its cross-sectional area Boron and Boulpaep Textbook of Medical Physiology 67 2-OVP FYI AP properties ∆VAB IAB = RAB Boron and Boulpaep Textbook of Medical Physiology Properties SA and AV node Purkinje fibers Atrial and ventricular myocytes Amplitude and slope of phase 0 (ΔVAB) 68 2-OVP FYI AP properties in different regions of the heart ∆VAB IAB = RAB Boron and Boulpaep Textbook of Gernot Schram et al. Circ Res. 2002;90:939-950 Medical Physiology Properties SA and AV node Purkinje fibers Atrial and ventricular myocytes Amplitude and Low amplitude and Largest amplitude and Large amplitude and fast slope of phase 0 slow depolarization fastest depolarization depolarization (ΔVAB) 69 2-OVP FYI Cell-to-cell coupling: gap-junctions Guyton et al. Textbook of Medical Physiology ∆VAB IAB = Boron and Boulpaep Textbook of Medical Physiology RAB Properties SA and AV node Purkinje fibers Atrial and ventricular myocytes Gap-junction Small and sparse Highest permeability of gap- Mainly Cx43 and Cx40 density (mainly Cx45) junction (mainly Cx40) (RAB) 70 2-OVP FYI Factors responsible for the heterogenous conduction velocity Boron and Boulpaep Textbook of Medical Physiology Properties SA and AV node Purkinje fibers Atrial and ventricular myocytes Conduction 0.05 4 1 velocity (m/s) Cell diameter Small Largest Large Gap-junction Small and sparse Highest permeability of gap- Mainly Cx43 and Cx40 density (mainly Cx45) junction (mainly Cx40) Amplitude and Low amplitude and Largest amplitude and Large amplitude and fast slope of phase 0 slow depolarization fastest depolarization depolarization 71 2-OVP Key Points Impulses are conducted through the heart along a relatively invariant pathway, with slow conduction through the AV node and very rapid conduction though the Purkinje fibers and ventricular myocardium. Thus, conduction velocity in the heart is heterogeneous. Propagation of excitation in the myocardium involves passage of intracellular currents via gap-junction allowing the activation of neighboring tissue. Conduction velocity is influenced by cell dimension, density and properties of gap-junctions, and amplitude and slope of the upstroke (phase 0) of the AP. 72  The Electrocardiogram (ECG or EKG) The electrocardiogram is the recording of the changes of potential at the skin surface resulting from the depolarization and repolarization of heart muscle. An ECG lead is formed by two electrodes placed on the patient skin and connected to a device that measures the difference of potential between the two sites where electrodes are placed. An ECG lead measures properties of the cardiac dipole over time originating an ECG tracing. Arms and legs act as electrical extension of electrodes. Boron and Boulpaep Textbook of Medical Physiology 73  Electric Dipole Propagation of the depolarization of cardiac tissue creates, at any given moment, an electric dipole (charge separation) between resting and active areas of the myocardium. The dipole is a vector and has a magnitude and a direction. Example of propagation of a wave of excitation in a cardiac fiber. The electric dipole can be assessed with electrodes connected to a measuring device. Berne and Levy, Physiology 7th edition 74  Lead Measurement A lead is formed by two electrodes connected to a device that measures the difference of potential between the two sites where electrodes are placed. At this moment → potential (mV) Difference of Ve = Voltage measured in a lead → Time (ms) Vdip = Voltage of the dipole q = angle between dipole and lead d = distance of lead to dipole Electric dipole and lead are parallel cos 0º = 1 Berne and Levy, Physiology 7th edition Boron and Boulpaep Textbook of Medical Physiology 75  Position of the lead with respect to the wave of depolarization (dipole) Ve = Voltage measured in a lead Vdip = Voltage of the dipole q = angle between dipole and lead d = distance of lead to dipole Boron and Boulpaep Textbook of Medical Physiology Berne and Levy, Physiology 7th edition Electric dipole and lead are parallel Electric dipole and lead are perpendicular cos 0º = 1 cos 90º = 0 76  Lead Measurement A lead is formed by two electrodes connected to a device that measures the difference of potential between the two sites where electrodes are placed. At this moment → potential (mV) Difference of Ve = Voltage measured in a lead → Time (ms) Vdip = Voltage of the dipole q = angle between dipole and lead d = distance of lead to dipole Electric dipole and lead are parallel cos 0º = 1 Berne and Levy, Physiology 7th edition Boron and Boulpaep Textbook of Medical Physiology 77  Lead Measurement Magnitude of the dipole changes with the propagation of the depolarization, originating a waveform on the tracing of the lead. Boron and Boulpaep Textbook of Medical Physiology B Berne and Levy, Physiology 7th edition C A Resting state (no propagation) Resting state A B C 78  Position of the lead with respect to the wave of depolarization (dipole) Ve = Voltage measured in a lead Vdip = Voltage of the dipole q = angle between dipole and lead d = distance of lead to dipole Boron and Boulpaep Textbook of Medical Physiology Berne and Levy, Physiology 7th edition Electric dipole and lead are parallel Electric dipole and lead are perpendicular cos 0º = 1 cos 90º = 0 79  Position of the lead with respect to the wave of depolarization (dipole) Ve = Voltage measured in a lead Vdip = Voltage of the dipole q = angle between dipole and lead d = distance of lead to dipole Boron and Boulpaep Textbook of Medical Physiology Berne and Levy, Physiology 7th edition A single oscillation Electric dipole and lead are parallel Electric dipole and lead are perpendicular cos 0º = 1 cos 90º = 0 80  Cardiac Dipole The cardiac dipole at any moment reflects the geometric average potential difference (charge separation) between resting and active areas of the heart. Amplitude and direction of the cardiac dipole change throughout the cardiac cycle, originating various waveforms of the ECG. Berne and Levy, Physiology 7th edition 0.16 Boron and Boulpaep Textbook of Medical Physiology 81  Waveforms of the Electrocardiogram Shape and timing parameters of deflections of the ECG provide information on the Boron and Boulpaep Textbook of electrical activation of the heart. Medical Physiology 0.2 sec 0.16 Guyton et al. Textbook of Medical Physiology There are three main deflections per cardiac cycle: P wave: corresponds to atrial depolarization; QRS complex: corresponds to ventricular depolarization; T wave: corresponding to ventricular repolarization. Atrial repolarization is small in amplitude and is masked by the QRS complex 82  Waveforms of the Electrocardiogram 0.2 sec Guyton et al. Textbook of Medical Physiology There are three main deflections per cardiac cycle: P wave: corresponds to atrial depolarization; QRS complex: corresponds to ventricular depolarization; T wave: corresponding to ventricular repolarization. 83 http://163.178.103.176/Fisiologia/cardiovascular/pracb_1/cardio_pracb_1_14_8.html  Relationship between APs and the Electrocardiogram QRS interval and T wave Clancy and Kass, Physiol Rev 2005;85:33-47 P wave: it starts in correspondence of the first atrial AP. P wave ends in correspondence of the depolarization phase of the last atrial AP. QRS interval: reflects the conduction of excitation through the ventricles. QRS begins in correspondence of depolarization phase of the first ventricular AP (bundle of His) and ends in correspondence of the depolarization phase of the last ventricular AP. QT interval: interval from the beginning (depolarization) of the first ventricular AP to the end (repolarization) of the last AP. Repolarization of the ventricles occurs in the opposite direction of ventricular depolarization because cells that are depolarized initially have longer AP duration. Thus, QRS complex and T wave have similar polarity. 84  Determinants of the Waveforms of the ECG 1. MASS of tissue that depolarizes or repolarizes Bigger mass produces bigger dipole (Vdip) 2. CONDUCTION VELOCITY Determines (in part) timing of occurrence and duration of waveforms 3. VECTORIAL ORIENTATION Orientation of the cardiac dipole respect to the recording lead (angle q) 4. DISTANCE between electrodes and dipole (distance d) Ve = Voltage measured in a lead Vdip = Voltage of the dipole q = angle between dipole and lead d = distance of lead to dipole 85  Determinants of the Waveforms of the ECG 1. MASS of tissue that depolarizes or repolarizes QRS complex is bigger Bigger mass produces bigger dipole (Vdip) than the P wave because the ventricles are bigger than the atria. 2. CONDUCTION VELOCITY Determines (in part) timing of occurrence and duration of waveforms 3. VECTORIAL ORIENTATION Orientation of the cardiac dipole respect to the recording lead (angle q) 4. DISTANCE between electrodes and dipole (distance d) Berne and Levy, Physiology 7th edition Ve = Voltage measured in a lead Vdip = Voltage of the dipole q = angle between dipole and lead d = distance of lead to dipole 86  Determinants of the Waveforms of the ECG 1. MASS of tissue that depolarizes or repolarizes The short duration of the Bigger mass produces bigger dipole (Vdip) QRS complex reflects the fast conduction of the 2. CONDUCTION VELOCITY His/Purkinje system Determines (in part) timing of occurrence and duration of waveforms 3. VECTORIAL ORIENTATION Orientation of the cardiac dipole respect to the recording lead (angle q) 4. DISTANCE between electrodes and dipole (distance d) Berne and Levy, Physiology 7th edition Ve = Voltage measured in a lead Vdip = Voltage of the dipole q = angle between dipole and lead d = distance of lead to dipole 87  Determinants of the Waveforms of the ECG 1. MASS of tissue that depolarizes or repolarizes Bigger mass produces bigger dipole (Vdip) 2. CONDUCTION VELOCITY ECG tracings are Determines (in part) timing of occurrence and duration of waveforms different for various recording leads 3. VECTORIAL ORIENTATION Orientation of the cardiac dipole respect to the recording lead (angle q) 4. DISTANCE between electrodes and dipole (distance d) Ve = Voltage measured in a lead Vdip = Voltage of the dipole q = angle between dipole and lead d = distance of lead to dipole 88  Determinants of the Waveforms of the ECG 1. MASS of tissue that depolarizes or repolarizes Bigger mass produces bigger dipole (Vdip) 2. CONDUCTION VELOCITY Determines (in part) timing of occurrence and duration of waveforms 3. VECTORIAL ORIENTATION Orientation of the cardiac dipole respect to the recording lead (angle q) Standard leads 4. DISTANCE between electrodes and dipole (distance d) eliminates this with equilateral triangle Ve = Voltage measured in a lead Vdip = Voltage of the dipole q = angle between dipole and lead d = distance of lead to dipole 89  Key Points The ECG reflects the conduction of electrical depolarization/repolarization through the heart. ECG intervals reflect conduction times and action potential durations. ECG waveforms are determined by the mass of tissue producing the electrical signal, the conduction velocity, the orientation of the lead relative to the electrical activity in the heart, and the distance of the lead from the heart. 90  The ECG allows to determine: - Heart rate (HR) - Conduction in the heart - Direction of cardiac depolarization/repolarization (electrical axis) - Damage to the heart - Arrhythmias - DOES NOT provide direct information about pumping or mechanical events in the heart. 91 The ECG is a standard clinical tool and provides the following information: - Heart rate - Conduction pattern in the heart - Direction of the cardiac vector (mean electrical axis) - Damage to the heart muscle - Arrhythmia The ECG paper On the horizontal axis (time): Each 1 mm division (small box) = 40 ms; Each 5 mm division (large box) = 200 ms On the vertical axis (difference of potential): Each 1 mm division (small box) = 0.1 mV; Each 5 mm division (large box) = 0.5 mV www.en.my-ekg.com 92 The ECG is a standard clinical tool and provides the following information: - Heart rate ✓ - Conduction pattern in the heart - Direction of the cardiac vector (mean electrical axis) - Damage to the heart muscle - Arrhythmia RR interval: 4.5 boxes = 4.5 boxes x 0.2 sec/box = 0.9 sec 0.2 sec RR interval Heart rate (number of large (beats/min) 4.5 boxes boxes of 0.2 sec) 1 300 2 150 3 100 4 75 5 60 Guyton et al. Textbook of Medical Physiology 6 50 𝟔𝟎 𝒔𝒆𝒄/𝒎𝒊𝒏 60 𝑠𝑒𝑐/𝑚𝑖𝑛 𝑯𝑹 = = = 67 𝑏𝑒𝑎𝑡𝑠/𝑚𝑖𝑛 7 43 𝒙 𝒔𝒆𝒄/𝒃𝒆𝒂𝒕 0.9 𝑠𝑒𝑐/𝑏𝑒𝑎𝑡 93 The ECG is a standard clinical tool and provides the following information: - Heart rate ✓ - Conduction pattern in the heart ✓ - Direction of the cardiac vector (mean electrical axis) - Damage to the heart muscle - Arrhythmia Normal Ranges: PR Interval: 0.12 – 0.2 sec QRS Complex: 0.06 – 0.1 sec 0.2 sec QT Interval: 0.4 sec Guyton et al. Textbook of Medical Physiology 94 The ECG is a standard clinical tool and provides the following information: - Heart rate ✓ - Conduction pattern in the heart ✓ - Direction of the cardiac vector (mean electrical axis) - Damage to the heart muscle Waves of depolarization moving in - Arrhythmia different directions in the cardiac tissue at a given moment. https://cvphysiology.com/arrhythmias/a016 The wave of depolarization that spreads across the muscle moves in many directions simultaneously. Thus, at any given moment the spread of excitation is composed of many electrical vectors (black arrows). This mean electrical vector (red arrow) represents the sum of all of the individual vectors at a given instant in time. 95  Mean Electrical Axis (MEA) of the QRS Complex https://cvphysiology.com/arrhythmias/a016 At any given moment, the red arrow represents the mean electrical vector. 96  Mean Electrical Axis (MEA) of the QRS Complex https://cvphysiology.com/arrhythmias/a016 At any given moment, the red arrow The mean electrical axis is the average of all the represents the mean electrical vector. instantaneous mean electrical vectors occurring sequentially during depolarization of the ventricles. The mean electrical axis (MEA) of the QRS complex is the average direction of ventricular depolarization. 97  Mean Electrical Axis (MEA) of the QRS Complex https://cvphysiology.com/arrhythmias/a016 The mean electrical axis of the QRS The mean electrical axis is the average of all the complex can be evaluated using instantaneous mean electrical vectors occurring information from various leads of the sequentially during depolarization of the ventricles. ECG. The mean electrical axis (MEA) of the QRS complex is the average direction of ventricular depolarization. 98  The ECG is a standard clinical tool and provides the following information: - Heart rate ✓ - Conduction pattern in the heart ✓ - Direction of the cardiac vector (mean electrical axis) ✓ - Damage to the heart muscle ✓ - Arrhythmia The mean electrical axis (MEA) of the QRS complex is the av