Cardiac Electrophysiology 2023 Students.pptx

Electric al activity of the heart Marina Ioudina MD, PhD, MS Readings • Levy and Pappano. Cardiovascular physiology. 10th Ed. The Mosby Physiology Monograph series: Chapter 2 (entire chapter) (Touro Library Catalog: https://www.clinicalkey.com/#!/content/book/3-s2.0B9780323594844000023) • Recommen...

Electric al activity of the heart Marina Ioudina MD, PhD, MS Readings • Levy and Pappano. Cardiovascular physiology. 10th Ed. The Mosby Physiology Monograph series: Chapter 2 (entire chapter) (Touro Library Catalog: https://www.clinicalkey.com/#!/content/book/3-s2.0B9780323594844000023) • Recommended for Electrical activity of the heart: • Boron & Boulpaep: Ch. 21 • Guyton & Hall. Chs. 10 &11 • http://cvphysiology.com/index.html Medical physiology objectives: electrophysiology • Sketch the action potential and the refractory period in a cardiac muscle, and the temporal relationship between an action potential and the resulting contraction (twitch) of that cell. On the basis of that graph, explain why cardiac muscle cannot remain in a state of sustained (tetanic) contraction. (https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780323594844000023) • Sketch a typical action potential in a ventricular muscle and a pacemaker cell, labeling both the voltage and time axes accurately. Describe how ionic currents contribute to the four phases of the cardiac action potential. Use this information to explain differences in shapes of the action potentials of different cardiac cells. • Describe the ion channels that contribute to each phase of the cardiac action potential. How do differences in channel population influence the shape of the action potential in the nodal, atrial muscle, ventricular muscle, and Purkinje fiber cardiac cells. Objectives (cont) • Explain what accounts for the long duration of the cardiac action potential and the resultant long refractory period. What is the advantage of the long plateau of the cardiac action potential and the long refractory period? • Beginning in the SA node, diagram the normal sequence of cardiac activation (depolarization) and the role played by specialized cells. • Explain why the AV node is the only normal electrical pathway between the atria and the ventricles, and explain the functional significance of the slow conduction through the AV node. • Explain the ionic mechanism of pacemaker automaticity and rhythmicity, and identify cardiac cells that have pacemaker potential and their spontaneous rate. • Contrast the sympathetic and parasympathetic nervous system influence on heart rate and cardiac excitation in general. Discuss ionic mechanisms of these effects on both working myocardium and pacemaker cells. • Explain the effects of voltage-gated sodium channels blockers, calcium channels blockers, potassium channel blockers, and changes in serum potassium levels on cardiac electrical activity Cardiac cycle events: Electrical impulses in the heart initiate contractions Lecture outline • Conduction system of the heart. Automaticity and conduction • Action potential in contracting and conducting myocytes • Action potential in pacemaker cells • Autonomic regulation of the pacemaker activity • Changes in cardiac electrical activity in response to changes in serum potassium levels Conduction system of the heart • Cardiac myocytes • Sinoatrial node (SA node in RA) • Atrioventricular node (AV node in RA) • AV bundle (!connects RA and RV) • R & L bundle branches (of His) • Purkinje fibers Cardiac pacemaker cells Automaticity • Spontaneous generation of action potentials (automaticity) • SA node cells – specialized for automaticity, primary “pacemaker cells”, have the highest intrinsic rate • AV node cells – secondary pacemaker cells, become the pacemaker if SA node cells are damaged, • Purkinje cells - tertiary pacemaker cells Conducting cardiac myocytes Conduction • All cardiac myocytes conduct electrical impulses, but the following are particular specialized for this function • Internodal pathways (in RA) • AV node cells - slow conduction (for functional delay btwn atrial and ventricular excitation!) • Purkinje cells: AV bundle, bundle of His, and Purkinje fibers – rapid conduction Cells Conduction (m/sec) Pacemaker activity (b/min) SA node 0.02 – 0.1 60-100 Atria 0.3 -1.0 AV node 0.02 -0.1 Bundle of His 1.0 Purkinje fiber 1.0 - 4.0 Ventricle 0.3 - 1.0 40-60 25-40 Sequence of electrical excitation of the heart • The electrical events in the heart initiate cardiac contraction • Rhythmical electrical activity coordinates mechanical activity generating rhythmical contraction of the heart (see “Cardiac Cycle diagram”) Two types of AP in the heart • Cardiac myocyte AP (fast response – conducting/contracting myocytes)) • The resting membrane potential is about (-90 mV) – ( 80 mV) • Fast conduction velocity • Pacemaker AP (slow response): • pace-maker cells of the SA and AV nodes • Auto-rhythmic • The resting membrane potential is -60 mV • Slow conduction velocity Lecture outline • Conduction system of the heart. Automaticity and conduction • Action potential in contracting and conducting myocytes • Action potential in pacemaker cells • Autonomic regulation of the pacemaker activity • Changes in cardiac electrical activity in response to changes in serum potassium levels Action potential recorded from the ventricular cardiac myocyte • • • • • Phase Phase Phase Phase Phase 0: 1: 2: 3: 4: Rapid depolarization Early partial repolarization Plateau phase Final repolarization Resting potential Klabunde. Cardiovascular physiology concepts Cardiac myocyte AP: Ionic currents Berne & Levy Action potential recorded from the ventricular cardiac myocyte • Phase 0: Rapid depolarization • rapid Na+ influx through the voltage-gated Na + channels (fast Na+ channels) • Phase 1: Early partial repolarization • the efflux of K+, the transient outward K+ current (I to) • Phase 2: Plateau phase • is due to increased Ca++ conductance • Phase 3: Final repolarization • the efflux of K+ exceeds the influx of Ca++ • Phase 4: Resting potential • is determined mainly by the K+ conductance Refractory period in the ventricular myocytes • It is long • It is protective • Blocks premature activations of the atria that are conducted through the AV junction • Depends on heart rate • The effective RP is prolonged at slower heart rates Refractory period in cardiac myocyte • Effective refractory period (ERP, absolute) • During phase 0, 1, and first-half of phase 3 (Vm > +30mV) • Voltage-gated Na+ channels are inactivated (h gate is closed) • Relative refractory period (RRP) (+30mV > Vm ≥ -90 mV) • During the second-half of phase 3 (before phase 4) • Not all Na+ channels are completely reactivated • Suprathreshold stimuli are required to elicit and AP Berne & Levy Refractory period in cardiac myocyte • The length of the refractory period limits the frequency of action potentials and therefore contractions. • The refractory period ends at the end of phase 3 • During the ERP, stimulation of the cell does not produce new, propagated AP • The ERP acts as a protective mechanism in the heart by preventing multiple APs • Preventing tetany Guyton & Hall Ion channels involved in Purkinje and ventricular myocyte membrane potential ↓- inward current ↑- outward current NCX- 3Na-1Ca exchanger NCX- 3Na-1Ca exchanger Cardiac potassium channels Pharmacologic al agents affecting human K+ channels Ion channels involved in cardiac myocytes membrane CHANNEL CHARACTERISTICS Sodium Channels Fast Na+ Slow Na (If) + Voltage-gated channels, phase 0 depolarization of non-pacemaker cardiac action potentials "Funny" pacemaker current (If) in cardiac nodal tissue. Channels have mixed Na (inward) and K (outward) permeability. Hyperpolarization induces inward Na current. Potassium Channels Inward rectifier (IK1) Maintains resting membrane potential (phase 4), permits K outflow at highly negative potential in cardiac cells Transient outward (Ito) Contributes to phase 1 by transiently permitting K outflow at positive membrane potential Delayed rectifier (IKs, IKr) Phase 3 repolarization of cardiac action potentials, permits K outflow ATP-sensitive (IK, ATP) KATP channels; inhibited by ATP; therefore, open when ATP decreases during hypoxia Acetylcholine-activated (IK, ) and adenosine-activated ACh Activated by Ach and adenosine; G-protein coupled, hyperpolarizes membrane during phase 4 and shortens phase 3 Calcium Channels L-type (ICa-L) T-type (ICa-T) Voltage-gated channels, slow inward, long-lasting current; phase 2 nonpacemaker cardiac action potentials Transient current that contributes to phase 4 pacemaker currents in SA and AV nodal cells. ICa-T is insignificant in normal conducting/contracting myocytes Lecture outline • • • • • Conduction system of the heart. Automaticity and conduction Action potential in contracting and conducting myocytes Action potential in pacemaker cells Autonomic regulation of the pacemaker activity Changes in cardiac electrical activity in response to changes in serum potassium levels Pacemaker cells: Autorhythmic cells • Initiate action potentials • Have unstable resting membrane (phase 4) potential: prepotential , or slow depolarization • Ionic basis for automaticity in the AV node is identical to that in the SA node • Use Ca++ influx for rising (upstroke) phase (phase 0) of the action potential Berne & Levy Pacemaker action potential: Ionic currents • Phase 0: Upstroke (depolarization) • Phase 3: Repolarization • Phase 4: Slow depolarization Klabunde. Cardiovascular physiology concepts Pacemaker AP: phase 4 1. Na+ inward current (funny current, If) through Na+ channels • opens when the cell hyperpolarizes (- 60 mV) and closes when the membrane depolarizes (-20 mV). 2. Ca2+ inward current through T-type Ca2+ channels • open only briefly at ~ -50mV. 3. As potential becomes more positive L-type Ca2+ channels begin to open until threshold is reached Pacemaker AP: phase 0 (upstroke) • Mediated by inward Ca2+ current through the voltage gated L- type Ca2+ channels (open at Vm -40 mV) • depolarizes membrane towards EeqCa2+ (+123 mV) • L- type Ca2+ channels are slower than the Na+ channel in non-pacemaker cells • Accompanied (opposed) by an outward K+ current • NO fast Na+ channels in SA and AV nodes Pacemaker AP: phase 3 (repolarization) • Voltage gated Ca2+ channels (L-type) become inactivated • Voltage gated delayed rectifier K+ channels open • K+ outflow dominates, membrane potential moves toward – 88 mV (K+ equilibrium potential) • Membrane potential reaches -60mV Refractory period in pacemaker cells • Relative refractory period (RRP) extends beyond phase 3 • Post-repolarization refractoriness • The recovery of full excitability is much slower than in fast-response AP • The RRP ends early during phase 4 • Impulses that arrive early in the RRP are conducted slower than those that arrive late in the RRP Ion channels involved in pacemaker potential CHANNEL Sodium Channels Slow Na+ (If) Potassium Channels Delayed rectifier (IKr) ATP-sensitive (IK, ATP) G-protein coupled receptors: Ach-activated (IK, ) and adenosine-activated ACh CHARACTERISTICS Modified from: Klabunde. Cardiovascular physiology concepts "Funny" pacemaker current (If) in cardiac nodal tissue, it is hyperpolarization–induced inward current Phase 3 repolarization of cardiac action potentials KATP channels; inhibited by ATP; therefore, open when ATP decreases during hypoxia Activated by Ach and adenosine; G-protein coupled, hyperpolarizes membrane during phase 4 slowing pacemaker potential Calcium Channels L-type (ICa-L) T-type (ICa-T) Slow inward, long-lasting current; phase 2 non-pacemaker cardiac action potentials and phases 4 and 0 of SA and AV nodal cells; important in vascular smooth muscle contraction Transient current that contributes to phase 4 pacemaker currents in SA and AV nodal cells Summary: Compare fast- and slow-response action potentials in the heart Lecture outline • • • • • Conduction system of the heart. Automaticity and conduction Action potential in contracting and conducting myocytes Action potential in pacemaker cells Autonomic regulation of the pacemaker activity Changes in cardiac electrical activity in response to changes in serum potassium levels Normal heart rate • Normal heart rhythm is called normal sinus rhythm • conduction of electrical impulses is normal: SA → AV → ventricles • Normal heart rate (HR) varies: 60 bpm < HR < 100 bpm (at rest) • Tachycardia: HR > 100 bmp • <100 bpm can be normal during exercise • Bradycardia: HR < 60 bpm • Can be normal especially in endurance athletes Autonomic nervous system controls the heart and vasculature • The vagus nerve controls predominantly the heart • The sympathetic nerve fibers innervate both the heart and vessels http://www.cvpharmacology.com/autonomic_ganglia Autonomic innervation of the heart • The vagus nerve has projections on the SA and AV node (predominantly) • The sympathetic nerve fibers innervate both cardiac muscle (predominantly) and to some (very little) extent pacemaker cells Right vagus n. Left vagus n. Guyton & Hall Autonomic regulation of the heart • Heart electrical activity is controlled by autonomic nervous system • Sympathetic (NE) neurons stimulate the heart via  1-AR: • Causing positive chronotropic (↑HR), dromotropic (↑conduction velocity of electrical impulses) and inotropic (↑contractile forces) effects • Parasympathetic (Ach) neurons inhibit the heart via M2 muscarinic receptor: • Causing negative chronotropic, dromotropic, and inotropic • Cardiac myocytes have adrenergic and cholinergic receptors  1 +cAMP - dromotropy Adrenergic and cholinergic signal transduction in the heart CVphysiology Parasympathetic control of nodal excitability • Ach is released from post-ganglionic fiber • Decreases HR (SA node), conduction velocity (AV node) through the AV node • Acts on M2 receptors (Gi coupled receptors), decreases cAMP level, opens K+ channels, reduces Ca++ current • Hyperpolarizes, reduces slope of pacemaker potential Effect of vagal stimulation on SA pace maker cells. Fig. 3- The effect of parasympathetic stimulation on pacemaker firing: If • Ach decreases If current in reduccing steepness of phase 4 Boron & Boulpaep The effect of parasympathetic stimulation on pacemaker firing: ICa • Reduces Ca++ current (ICa) channels • reducing steepness of phase 4, and • moving threshold more positive Boron & Boulpaep The effect of parasympathetic stimulation on pacemaker firing: IK, Ach • Ach opens G-protein coupled K+ channels • increasing K+ conductance and maxing diastolic potential more negative (hyperpolarizing membrane) Boron & Boulpaep Sympathetic stimulation Catecholamines: β1-AR mediated effect The effect of sympathetic stimulation on pacemaker firing: • Catecholamines act through β1 adrenergic receptors to increase heart rate (chronotropy) by: • increasing If in SA → • increasing steepness of phase 4 • increasing Ca2+ current in all myocardial cells → • moving threshold level to more negative Lecture outline • Conduction system of the heart. Automaticity and conduction • Action potential in contracting and conducting myocytes • Action potential in pacemaker cells • Autonomic regulation of the pacemaker activity • Changes in cardiac electrical activity in response to changes in serum potassium levels Effect of hypokalemia on cardiac electrical activity • Resting membrane potential of non-pacemakers depend on the gradient between extracellular K (low) and intracellular K (high) • HypoK causes • Shortening phase 3 (phase 3 slope is decreased) due to effect on IKr • plateau phase is shortened (imbalance between Ca++ influx and K+ efflux; • shortening of ERP • Hyperpolarization and more negative resting membrane potential • prolonging the RRP (due to hyperpolarization) • A longer RRP increases time of ventricular repolarization Effect of hyperkalemia on cardiac electrical activity • HyperK decreases electrochemical gradient for diffusion of K+, increases intracellular K+ and increases the resting membrane potential (RMP) • If the RMP is about -70 mV , the threshold potential is decreased, and cardiac excitability is increased • Severe hyperK may increase the RMP up to -60 mV (the same as a pacemaker potential) and cause transformation of a non-pacemaker action potential into pacemaker action potential. • Mechanism: At the -60 mV the inactivation gate of the voltage-gated Na+ channels is closed; and the fast channels are inactivated. The phase 0 would be due to the influx of Ca++ thought the L-type Ca channels. Effect of hyperK and hypoK on cardiac electrical activity Review slides Voltage-gated Na+ channel Practice questions is your STUDY GUIDE • Answers to practice questions will NOT be posted (be confident!) Using the diagram below indicate when the KACh channels are open https://www.itaca.edu.es/cardiac-action-potential.htm What is the effect of parasympathetic stimulation on the ventricular cardiomyocyte? 1. 2. 3. 4. Increases the duration of phase 3 Hyperpolarization Increases the duration of phase 2 Blocks the phase 0 What is a possible effect of a voltage-gated Na+ channel blocker? A. B. C. D. E. Increases the duration of phase 3 Hyperpolarization Increases the duration of phase 2 Blocks the phase 0 in sinoatrial node cells Causes transformation of fast-response potentials into slowresponse potentials What is the effect of treatment arrhythmia with a voltage-gated Na+ channel blocker? A. Prevents the generation of action potentials in ventricular myocytes B. Hyperpolarization C. Positive chronotropic effect D. Stimulates the generation of pacemaker potentials in the Pukrinje fibers E. Negative dromotropic effect When does final repolarization begin? A. With opening of the K B. C. D. E. Ach channels Alter the peak of action potential With closing of the L-type Ca channels With closing of the voltage-gated Na channels With closing the h-gate of the voltage gated Na+ channels Blocking sympathetic input to the heart: A. Increases heart rate B. Decreases heart rate C. Has no effect on heart rate D. Increases myocardial contractility Blocking the cardiac funny current (If): A. Increases heart rate B. Decreases heart rate C. Has no effect on heart rate Does Ach decrease heart rate? A. Yes B. No Does Ach have an effect on both pacemaker cells and non-pacemaker cells? A. Yes B. No Ach decreases heart rate primarily acting on: A. Pacemaker cells B. Contracting myocytes C. Conducting myocytes Does Ach increase IK in both pacemaker cells and non-pacemaker cells? + A. Yes B. No K+ channel blockers (blocking IKr): A. B. C. D. ↓ ↓ ↑ ↑ HR HR HR HR by by by by increasing the duration of the refractory period decreasing the duration of the refractory period increasing the duration of the refractory period decreasing the duration of the refractory period What is the effect of severe hyperkalemia? A. B. C. D. Hyperpolarization Inactivation of the voltage-gated Na+ channels Inactivation of the L-type calcium channels Increased K+ efflux Opening the Ach-activated K+ channels in pacemaker cells _____. A. B. C. D. E. F. Increases duration of phase 3 Decreases duration of phase 3 Decreases duration of phase 4 Increases duration of phase 4 Increases duration of phase 3 and phase 4 Decreases duration of phase 3 and increases duration phase 4 What is the primary ionic mechanism of phase 0 in cardiac pacemaker cells? A. B. C. D. Na+ inward current, I f K+ outward current, IK Ca++ inward current, ICaL Na+ inward current through fast Na channels E. K+ inward current, IK F. Ca+ + inward current, ICaT