Cardiac Electrophysiology 2024 PDF

MOHD1 CARDIAC ELECTROPHYSIOLOGY 2024 Christopher J. Benson, M.D. Dept. of Internal Medicine, Division of Cardiovascular Medicine and Dept. Pharmacology 3184 ML, UIHC; 335-8412; [email protected] Suggested Read...

MOHD1 CARDIAC ELECTROPHYSIOLOGY 2024 Christopher J. Benson, M.D. Dept. of Internal Medicine, Division of Cardiovascular Medicine and Dept. Pharmacology 3184 ML, UIHC; 335-8412; [email protected] Suggested Reading Assignment: Boron and Boulpaep, Medical Physiology, 2017, Chapters 6,7, and 21. Learning Objectives: 1. The role of the Na+/K+ pump and ion channels in setting the resting membrane potential in cardiac muscle. 2. The ionic basis of “fast” and “slow” action potentials, including the mechanism of automaticity 3. Autonomic nervous system regulation of heart rate 4. The structural and functional basis of cardiac tissue that determines action potential propagation (conduction) 5. Ionic basis and functional significance of relative and effective refractory periods Key Terms: Sino-atrial node (SA node) Atrio-ventricular node (AV node) Bundle of His Bundle branches (left and right) Purkinje fibers Resting membrane potential Equilibrium (Nernst or reversal) potential IKir – leak current Na+-K+ pump Phases of the action potential INa ICa IK Ion channel inactivation Ion channel recovery from inactivation Pacemaker activity Automaticity Diastolic depolarization Conduction velocity Ohm’s law Gap junction Effective refractory period Relative refractory period 1-adrenergic receptors (1ARs) Muscarinic (M2) receptors Parasympathetic and sympathetic nervous systems MOHD1 Cardiac Electrophysiology page 1 Christopher J. Benson, M.D.  I. INTRODUCTION – heart cells are “electrically excitable” A. The heart is just a pump that uses electricity to solve the following problems: 1. The generation of spontaneous excitation (action potentials) 2. Conduction of action potentials intra- and inter-cellularly 3. Production of rhythmic, synchronous contractions 4. Coordination of contraction between the four chambers B. Review of gross structure of the heart 1. working myocardium – packed with contractile elements 2. specialized conduction system (Fig. 1) – a series of specialized myocytes that form pathways that are particularly adept at conducting electrical signals through the heart Figure 1 C. Propogation of the cardiac impulse (Fig. 1; the numbers represent the time (sec) after the SA node fires an action potential) 1. Sino-atrial (SA) or Sinus node – a group of cells of which any one can assume the role of the normal cardiac “pacemaker”. The mechanism of how these cells fire spontaneously will be explained later. 2. Atrial conduction – internodal pathways – atrial muscle tissue oriented to promote preferential conduction from the SA to the AV node. 3. Atrio-ventricular (AV) node – normally the only electrical conduction pathway between the atria and the ventricles due to dense fibrous rings that prevent conduction around the AV valves. 4. Ventricular conduction MOHD1 Cardiac Electrophysiology page 2 Christopher J. Benson, M.D.  a) Bundle of His – sits just below the AV node. b) Purkinje fibers – fastest conduction velocity (4 meters/sec) due to large diameter of cells (70-80 m) and large number of Na+ channels and gap junctions. Together the bundle of His and the Purkinje fibers form the His-Purkinje system. c) ventricular myocardium – (10-15 m myocyte diameter; 1 meter/sec conduction velocity). Conduction spreads from endocardium out to epicardium. II. ELECTROPHYSIOLOGY OF CARDIAC CELLS A. Ionic basis of resting membrane potential: 1. sodium-potassium pump (Fig. 2) – “pumps” 3 Na+ ions out of cell in exchange for 2 K+ ions into the cell to generate ionic gradients a) uses energy (ATP) b) electrogenic – causes slightly negative resting membrane potential (Vm) to about –30 mV c) inhibited by digitalis (digoxin) d) responsible for the relatively high intracellular concentration of K+, and high extracellular concentration of Na+ (Table 1) Figure 2 Figure 3 2. Final resting membrane potential (Vm) is dependent on flux (movement) of ions through ion channels according to the following equation: Vm = GK EK + GNa ENa + GCa ECa + GCl ECl … Gm Gm Gm Gm a) EX = equilibrium potential for a given ion; GX = conductance of a given ion; Gm = total membrane conductance; such that Vm is the sum of equilibrium potentials (EX)(see Table 1), each weighted by the ion’s fractional conductance (GX/Gm). Conductance is the ease at which ions can move across the cell membrane – primarily due to the number of ion channel in the open state at any given time. b) The equilibrium potential (EX) (also call the Nernst potential or reversal potential) of a given ion x determines the direction of ion flow through an open ion channel. It is the membrane potential (voltage) where the two driving forces for ion flow, the 1) chemical (diffusional), and the 2) electrostatic force, sum to equal zero (Fig. 4). The chemical force is determined by the concentration gradient of the MOHD1 Cardiac Electrophysiology page 3 Christopher J. Benson, M.D.  ion across the membrane. When the channel opens, Na+ diffuses into the cell down it’s concentration gradient (chemical force), and as a positively charged ion (cation), Na+ also flows into the cell because it is attracted to the negative charge within the cell (electrostatic force). Na+ will flow into the cell until the voltage reaches the equalibrium potential of Na+ (+72 mV), at which flow will cease. At Vm greater than +72 mV, Na+ flow will reverse and be outward. c) In cardiac myocytes at rest, K+ channels are 100 times more conductive (more likely to be open) than other ion channels. Thus, the resting membrane potential is very close to EK, the equilibrium potential for K+. The outwardly directed flow of K+ is termed potassium “leak” current (Fig. 3). Since EK is dependent upon the K+ gradient across the cell, and the resting membrane potential parallels EK, one can understand why small changes in extracellular K+ concentration can have profound and dangerous effects upon the cardiac electrical conduction system. d) Relatively few K+ ions need to “leak” out of the cell to make the resting membrane potential more negative. At intracellular [K+] = 120 mM, leakage of 0.004% of the intracellular K+ ions will cause Vm = -70 mV, and so has very little effect on K+ concentrations. Table 1. Ionic concentrations and equilibrium potentials B. Electrical excitation of a myocyte (action potential) – review of voltage-gated ion channel function: 1. Ion channels function to alter relative conductances of ions across membrane; 2. Voltage-gated ion channels display voltage- and time-dependence for opening and closure; 3. Hodgkin-Huxley model of fast Na+ voltage-gated channels (Fig. 5): MOHD1 Cardiac Electrophysiology page 4 Christopher J. Benson, M.D.  Resting Activated Inactivated Recovery Figure 5 a) “m” (activation) gate on extracellular side of the membrane and “h” (inactivation) gate on intracellular side b) exists in any of 3 states: 1) resting or closed (m closed, h open); 2) open or activated (m & h both open); and 3) inactivated (m gate open & h gate closed); Na+ can pass through pore only when in the open state c) m gate opening is voltage-dependent and very fast (0.1- 0.2 msec); h gate is voltage- and time-dependent and closes more slowly (1-2 msec). d) from the inactive state (h gate closed), the myocyte must repolarize to a more negative potential to open the h gate (i.e. recover from inactivation), which allows the Na+ channels to be reactivated again. e) remember that flow of Na+ is driven by the ‘electro-chemical’ gradient into the cell. If Vm were to become more positive than the equilibrium potential for Na+ (ENa), Na+ will flow out of the cell. f) INa is conducted by a “family” of voltage-gated Na+ channels, each with similar, but slightly different properties. All of the ionic current types described below represent a sum of currents by one or more related channels. The molecular identity of some of these proteins (subunits) that form the channels have been elucidated, others are being actively pursued. MOHD1 Cardiac Electrophysiology page 5 Christopher J. Benson, M.D.  C. Action potential characteristics (Fig. 6) – Note that the initial upslope, shape, and duration of the action potential, as well as the properties SA NODE during the resting phase, are distinctive for ATRIUM different parts of the heart – reflecting their AV NODE different functions. These distinctions occur because the cells express different sets of ion channels and have different anatomy. We will HIS BUNDLE compare myocytes that fire “fast” vs. “slow” type action potentials. PURKINJE FIBER VENTRICLE 0 200 400 600 TIME (msec) Figure 6 D. Ionic basis of “fast” action potentials (Fig. 7, left panel) – note that a given action potential can display up to 5 different phases Fast-type action potential slow-type action potential Figure 7 1. phase 0 – upstroke -- voltage-gated, fast Na+ and Ca2+ channels open simultaneously allowing for rapid influx of Na+ and Ca2+ into the cell; creates action potential with a steep slope and large amplitude. 2. phase 1 – partial, rapid repolarization a) fast Na+ channels close b) Ito (“transient outward” K+ current) open 3. phase 2 – plateau a) continued ICa (Ca2+ current) MOHD1 Cardiac Electrophysiology page 6 Christopher J. Benson, M.D.  (1) T-type (transient) Ca2+ channels – inactivate rapidly (2) L-type (long-lasting) Ca2+ channels – inactivate slowly (maintains plateau); responsible for the broad action potential in cardiac myocytes compared to nerve cells; cause increase in intracellular [Ca2+], which is essential for excitation-contraction (EC) coupling (covered in subsequent lecture) 4. phase 3 – final repolarization a) increase in IK potassium current (increased outward current) – e.g. delayed rectifier K+ channels b) closure of ICa channels 5. phase 4 – resting membrane potential a) the potassium leak current b) no channels change their conductance - thus, membrane potential stays at resting level until another action potential comes along. E. Ionic basis of “slow” action potentials (Fig. 7, right panel) 1. upstroke (phase 0) – due to ICa only; these cells do not have fast Na+ channels 2. lack phases 1 and 2 3. phase 3 – repolarization mechanisms are similar to that of fast-type action potentials. 4. the other major difference occurs during phase 4 – consistent slow depolarization until action potential threshold is reached; thus diastolic depolarization can be described by a cell’s maximum diastolic potential and the slope of depolarization during phase 4 (see Fig. 8); this pacemaker activity, or automaticity causes these cells to spontaneously fire action potentials at a regular rate. The following currents contribute to diastolic depolarization (remember that inward cation currents cause depolarization – less negative Vm; outward currents cause hyperpolarization – more negative Vm. Things can get really complicated if you think about the flow of anions, like Cl-. Luckily, Cl- conductance doesn’t factor into action potential generation too much). a) If (“funny”) – a slow inward cation current – due to the hyperpolarization- activated, cyclic nucleotide-gated (HCN) channel b) ICa – calcium current c) IK – outward potassium current – slowly decreases its conductance, thus causing a depolarization MOHD1 Cardiac Electrophysiology page 7 Christopher J. Benson, M.D.  F. Summary of characteristics of fast response vs. slow response action potentials (Fig. 8) slow-type action potential Fast-type action potential SLOW ACTION FAST ACTION POTENTIALS POTENTIALS Phases 0, 3, 4 0,1,2,3,4 Fast Na+ channels No Yes Calcium current Yes (mainly phase 0) Yes (mainly phase 2) Resting or maximal Maximal diastolic potential Resting Vm (-80 to -90 mV) diastolic potential (-45 to -60 mV) Threshold potential -35 to -40 mV -65 mV Upstroke (phase 0) Slow (5 to 10 V/sec) Fast (200 to 800 V/sec) velocity Conduction velocity Slow (0.05 to 0.1 m/sec) Fast (purkinje 1 to 3 m/sec) (working myocytes 0.3 to 1 m/sec) Atrial and ventricular myocytes Cell Types SA and AV nodal His-purkinje cells Figure 8 MOHD1 Cardiac Electrophysiology page 8 Christopher J. Benson, M.D.  G. Regulation of diastolic depolarization in sinus nodal cells determines heart rate 1. mechanisms for changes in heart rate (automaticity)(Fig. 9) a) slope of diastolic depolarization (going from action potential (AP) 1 to AP 2 will lengthen the time between AP’s and decrease heart rate) b) level of threshold potential (AP 3 vs AP 4) c) level of maximal diastolic potential (AP 4 vs AP 5) 2. Heart rate is principally regulated by the autonomic nervous system (Fig. 10) a) Parasympathetic input to slow heart rate predominates at rest. It functions to: 1) potentiate K+ “leak” channels resulting in a more negative maximal diastolic potential; 2) inhibit If to reduce the steepness of diastolic depolarization (AP 1 to 2); and 3) inhibit ICa to reduce the steepness (AP 1 to 2) and increase the threshold (AP 3 to 4). b) Sympathetic input takes over during exercise or stress to speed up heart rate. It functions to potentiate If and ICa, which will combine to increase the steepness of diastolic depolarization and lower the threshold for action potential generation. + 20 0 mV 2 Slope of - 20 1 depolarization TP Threshold - 40 Potential - 60 - 80 100 ms 0 mV 3 5 - 20 4 TP - 1 - 40 TP - 2 Maximal - 60 diastolic potential - 80 Figure 9 MOHD1 Cardiac Electrophysiology page 9 Christopher J. Benson, M.D.  MEDULLA dorsal motor nucleus of vagus vagus nerve (parasympathetic nucleus preganglionic) ambiguus paramedian reticular Ach nucleus bulbospinal tract Ach (sympathetic preganglionic) NE Ach NE intermediolateral Ach cell column SYMPATHETIC GANGLION (parasympathetic HEART postganglionic) THORACO-LUMBAR (sympathetic SPINAL CORD postganglionic) Figure 10. The autonomic nervous system – the major regulator of the heart c) Sympathetic nerves – the postganglionic fibers innervate the SA node, atria, the AV node and ventricles. They release norepinephrine, which acts on 1- adrenergic receptors (1ARs)(Fig. 11). d) Parasympathetic nerves – the postganglionic fibers innervate the SA node, atria, AV node, and to a lesser extent, the ventricles. They release acetylcholine, which activates muscarinic (M2) receptors. e) Both 1ARs and M2 receptors are G protein-coupled receptors. 1ARs are coupled to Gs, which activates adenylyl cyclase to increase intracellular levels of cyclic AMP. cAMP activates protein kinase A (PKA), which phosphorylates specific proteins. M2 receptors are coupled to Gi, which inhibits the cAMP-PKA pathway. The para- and sympathetic systems often, but not always, work in opposition to each other. Figure 11 MOHD1 Cardiac Electrophysiology page 10 Christopher J. Benson, M.D.  f) At rest the parasympathetic system has a greater influence on HR – Figure 12 demonstrates the effect of sequential dosing of either atropine (a muscarinic receptor antagonist) or propranolol (a  -adrenergic receptor antagonist). When both divisions of the autonomic nervous system are blocked, the average resting HR increases from ~ 70 beats/min. to ~ 100 beats/min. During exercise or stress, sympathetic activation takes over and can profoundly increase heart rate. g) Parasympathetic activation produces very fast effects on HR (Fig. 13) – this allows the parasympathetics to regulate HR on a beat-to-beat basis. Whereas the effects of the sympathetics on HR are slower. Figure 12 Figure 13 MOHD1 Cardiac Electrophysiology page 11 Christopher J. Benson, M.D.  III. CONDUCTION IN CARDIAC FIBERS A. Cell to cell conduction (Fig. 14): principles are the same as AP propagation in neurons Figure 14 1. Note the intracellular current propagating to the right is matched by an equal extracellular current in the opposite direction. This extracellular current is what is recorded with an electrocardiogram (ECG), as we will learn in the next lecture. 2. Conduction velocity: Ohm’s law tells us that current flowing from cell A to adjacent cell B (IAB) is proportional to the voltage difference VA – VB, or VAB, and inversely proportional to the resistance between them (RAB): IAB = VAB RAB 3. Factors that effect the voltage difference VAB include: a) The amplitude (total voltage change from resting potential to maximum action potential height) and rate of rise (the slope or dV/dt of phase 0) of the action potential – these properties are dependent upon the number and type of ion channels that underlie the action potential (recall difference in phase 0 properties between fast and slow action potentials). Increasing either of these properties will depolarize the adjacent membrane faster, and speed the conduction velocity. b) The resting membrane potential (Vm) – the more negative VB is, the greater VAB will be. 4. Factors that effect the resistance (RAB) include: a) Gap junctions (Fig. 15) – located in longitudinal region of intercalated disk. They project between cells creating pores or intercellular channels that allow rapid conduction of electrical impulses; allows heart to behave as a “functional syncytium” – essentially a single electrical unit. MOHD1 Cardiac Electrophysiology page 12 Christopher J. Benson, M.D.  Figure 15 b) Cell size – large cell diameter reduces resistance leading to increased conduction velocity B. refractory periods (Fig. 16) – cardiac myocytes need to fire repeatedly, but there are limits to how quickly they can fire another action potential. Also, explains why action potentials can’t propagate backwards (ion channels/cells/tissue are refractory) 1. effective (absolute) refractory period (ERP) – time from beginning of an action potential until cell is able to conduct another action potential; 2. relative refractory period (RRP) – time from end of effective refractory period until cell regains normal excitability; stimulation of an action potential during this period results in an action potential with a slower phase 0 upstroke and lower amplitude because some, but not all, of the Na+ channels (and/or Ca2+ channels) are still in an inactivated state. MOHD1 Cardiac Electrophysiology page 13 Christopher J. Benson, M.D.  ERP RRP Resting Open RRP Inactivated recovery Figure 16 MOHD1 Cardiac Electrophysiology page 14 Christopher J. Benson, M.D.  C. Summary of structure-function relationships of different cardiac tissues (Fig. 17) STRUCTURE FUNCTION RELATIONSHIP SMALL MEDIUM LARGE DIAMETER 5-10 um 10-15 um 50 um SHAPE round,ovoid cylindrical cylindrical INTERCELLULAR GAP JUNCTIONS few abundant very abundant CONNECTIONS CONDUCTION slow rapid very rapid VELOCITY MYOFIBRILS few abundant few CONTRACTILE weak strong weak ACTIVITY FUNCTION pacemaker working very rapid conduction EXAMPLES SA node, atrial and His bundle, AV node ventricular bundle branch, muscle Purkinje cells Figure 17 MOHD1 Cardiac Electrophysiology page 15 Christopher J. Benson, M.D.