Cardiac Electrophysiology Lecture 01 PDF

Cardiac Electrophysiology Lecture 01 Richard Klabunde, PhD Professor of Physiology MU-WCOM 1 Learning objectives 1. Explain how changes in ion concentrations, ion channel function, and electrogenic ion pump activity af...

Cardiac Electrophysiology Lecture 01 Richard Klabunde, PhD Professor of Physiology MU-WCOM 1 Learning objectives 1. Explain how changes in ion concentrations, ion channel function, and electrogenic ion pump activity affect resting membrane potential 2. Describe the electrophysiological basis for cardiac pacemaker and non- pacemaker action potentials 3. Identify the normal pathways for electrical conduction within the heart and describe the cellular basis for conduction 4. Describe the mechanisms by which autonomic nerves alter pacemaker activity and electrical conduction 2 Learning resources Klabunde, mini-lecture video on cardiac membrane potentials: cvphysiology.com Klabunde, Cardiovascular Physiology Concepts, Wolters Kluwer: 3e, Ch 3: 28-56 (Available at MU library) Links found on slides Klabunde RE. Cardiac electrophysiology: normal and ischemic ionic currents and the ECG. Adv Physiol Educ 41:29-37, 2017. (Posted on Canvas) cvphysiology.com (see Guided Learning for cardiac electrophysiology and electrocardiogram) 3 CARDIAC ACTION POTENTIALS 4 Cardiac action potentials How they differ from nerve and muscle action potentials Cardiac action potential duration is >10-times longer than in skeletal muscle and nerve Cardiac APs not initiated by nerves and neurotransmitters Some cardiac cells have spontaneous pacemaker activity in the heart 5 Non-pacemaker vs. pacemaker action potentials Non-pacemaker cells (fast-response) ○ Atrial and ventricular contracting myocytes; Purkinje fibers ○ True resting potential ○ Rapid depolarization with a prolonged plateau phase followed by repolarization Pacemaker cells (slow-response) ○ Sinoatrial and atrioventricular nodes ○ No "resting" potential ○ Spontaneous depolarization and repolarization 6 How are membrane potentials generated in the heart? Ion movement across membrane – ion currents 1. Ion concentration gradients a. Primary ions: Na+, Ca++ and K+ b. Maintained by ion transport pumps 2. Ion conductances (Goldman-Hodgkin- Electrogenic Katz equation) Ion transport 3. Electrogenic ion transport (Na/K-ATPase, Na/Ca exchanger, Ca-ATPase) Time-dependent changes in ion conductances through gated ion channels result in depolarization and repolarization * REQUIRED Mini-lecture at: https://cvphysiology.com/Arrhythmias/A007 7 Cardiac ion channels SODIUM Fast Na+ Phase 0 depolarization of non-pacemaker cardiac action potentials Slow Na+ "Funny" pacemaker current (If) in cardiac nodal tissue POTASSIUM Inward rectifier (Iir or IK1) Contributes to late phase 3 repolarization; maintains phase 4 negative potential Transient outward (Ito) Contributes to phase 1 of non-pacemaker cardiac action potentials Delayed rectifiers (IKr and IKs) Phase 3 repolarization of cardiac action potentials ATP-sensitive (IK, ATP) KATP channels; inhibited by ATP; therefore, open when ATP decreases during hypoxia Acetylcholine-activated (IK, ACh) Activated by acetylcholine; Gi-protein coupled Calcium-activated (IK, Ca or BKCa) Open in response to increased intracellular Ca++ CALCIUM L-type (ICa-L) Slow inward, long-lasting current; phase 2 non-pacemaker cardiac action potentials and late phase 4 and phase 0 of SA and AV nodal cells T-type (ICa-T) Transient current that contributes to early phase 4 pacemaker currents in SA and AV nodal cells 8 PACEMAKER ACTION POTENTIALS (Slow-response APs) 9 Pacemaker action potentials (“slow-response” action potentials found in SAN and AVN) Phase 4 - Pacemaker potential ERP ○ Pacemaker (“funny”) current (If; primarily slow inward Na+) responsible for initiating spontaneous depolarization ○ Ca++ (↑gCa) and K+ (↓gK) currents also contribute ○ Threshold potential Phase 0 - Depolarization ○ Primarily Ca++ dependent (↑gCa) Phase 3 - Repolarization ○ Primarily K+ dependent (↑gK) ○ ↓gCa contributes Note: Em ≅ g'K (-96 mV) + g'Ca (+134 mV) + g’Na(+52 mV) ERP spans phases 0 → 3 10 Location of pacemaker cells Sinoatrial (SA) node (slow-response) Atrioventricular (AV) node (slow-response) Purkinje fibers (fast-response) 11 SA nodal firing rate is primarily controlled by sympathetic and parasympathetic nerves Parasympathetic (vagal) activation decreases rate (negative chronotropy) ○ Muscarinic (M2) receptors Sympathetic activation increases rate (positive chronotropy) ○ β1-adrenoceptors (1° receptor) To increase heart rate from rest to maximal rate during exercise, sympathetic nerve activity increases and vagal activity https://www.cvphysiology.com/Arrhythmias/A005 decreases 12 Autonomic regulation of nodal action potentials Sympathetic activation Decreases time to reach threshold ○ Increases If and opens Ca++ channels earlier ○ Increases slope of phase 4 ○ Decreases AP duration Vagal activation Increases time to reach threshold ○ Decreases If and opens Ca++ channels later ➝ ↓ phase 4 slope ○ Increases AP duration Opens K+ channels ➝↑ hyperpolarization 13 Pacemaker activity is also influenced by: Hormones ○ Thyroxine ○ Catecholamines Potassium ions SAN ischemia/hypoxia → ↓HR Drugs 14 NON-PACEMAKER ACTION POTENTIALS (fast-response APs) 15  Non-pacemaker action potentials (“Fast-response” action potentials) Atrial and ventricular myocytes; Purkinje fibers Responsible for triggering contraction Phase 4: Resting potential ○ ↑gK (↓gNa, ↓gCa) Phase 0: Rapid depolarization (threshold = ~ -70 mV) ○ ↑gNa, ↑gCa (↓gK) Phases 1-3: Repolarization ○ Phase 1: ↑gK & ↓gNa ○ Phase 2 ("plateau phase“): ↑gCa Note: Em ≅ g'K (-96 mV) + g'Na (fast) (+52 mV) + g'Ca (+134 mV) ○ Phase 3: ↑gK ERP spans phases 0, 1, 2 and 3 16 Sodium channels – timing of activation and inactivation Activation occurs during phase 0 ○ Triggered by rapid depolarization to threshold ○ Short duration Inactivation occurs during phases 2 & 3 ○ Cell is not excitable Resting state occurs during phase 4 ○ Cell becomes excitable 17 Fast response action potentials with normally suppressed pacemaker activity Specialized cells within the His-Purkinje system exhibit typical fast responses; however, they can also undergo slow spontaneous depolarization during phase 4 Removal of overdrive suppression (e.g., during 3° AV block) can permit these cells to display slow (30 – 40 depolarizations/min), spontaneous action potentials that can drive ventricular rate 18 CONDUCTION OF ACTION POTENTIALS WITHIN THE HEART 19 Cardiac action potentials are conducted from cell-to- cell, and along specialized conduction pathways Cell-to-cell propagation occurs within nodal and non-nodal tissues of the heart Depolarization of cell A during its action potential results in current leakage to cell B B through low resistance gap junctions A Current leak from cell A depolarizes cell B, which triggers an action potential in cell B This sequence is repeated among all excitable, adjacent cells, thereby conducting Klabunde, Cardiovascular Physiology Concepts, 3e the electrical impulse "Functional syncytium" 20 Cardiac conduction system – activation sequence 1. Sinoatrial node (SAN, 1° pacemaker) 2. Cell-to-cell and specialized atrial fibers (internodal tracts) 3. Atrioventricular node (AVN) ○ Slowest conduction ○ Delays conduction into ventricles 4. Bundle of His ○ Rapid conduction 5. Left & right bundle branches ○ Rapid conduction 6. Purkinje fibers ○ Fastest conduction 7. Cell-to-cell ○ Slow conduction 21 What normally alters conduction within the heart? Autonomic nerve activity Sympathetic activation (via β1 receptors) increases conduction velocity (positive dromotropy) (e.g., during exercise) Parasympathetic (vagal) activation (via M2 receptors) decreases conduction velocity (negative dromotropy) primarily at the AV node Circulating catecholamines (via β1 receptors) Increases conduction velocity (positive dromotropy) 22 Ion mechanisms responsible for changes in phase 0 slope and alter conduction velocity Decreased phase 0 slope in AVN cells decreases conduction velocity by: Ca++ channel inactivation or blockade ○ Increased vagal tone relative to sympathetic tone ○ L-type Ca++ channel blockers Decreased phase 0 slope in non-nodal cells decreases conduction velocity by: ○ Na+ channel inactivation or blockade ○ Decreased sympathetic tone 23 Abnormal Conduction: conduction blocks & ectopic foci 24 What can cause abnormal conduction? Functional abnormalities ○ Ischemic injury related to coronary artery disease Depolarizes cells and inactivates fast Na+ channels (non-nodal tissue), which decreases the slope of phase 0 and decreases conduction velocity ○ Severe hyperkalemia (depolarizes cells) ○ Abnormal pacemaker sites (e.g., ectopic foci) ○ Excessive vagal activation of AV node Anatomic abnormalities ○ Congenital accessory pathways ○ Degenerative disease Chemical ○ β-adrenoceptor agonists or antagonists; muscarinic (M 2) agonists/antagonists ○ Antiarrhythmic drugs (e.g., sodium channel blockers; calcium channel blockers) 25 Possible sites of conduction blocks AV blocks ○ AV node ○ bundle of His ○ left & right bundle branches Bundle branch blocks ○ left bundle branch ○ right bundle branch 26 AV block 1° AV block ○ Delayed conduction through AV node ○ Still has sinus rhythm 2° AV block ○ Some atrial action potentials fail to be conducted into ventricles ○ There may be 2 or 3 atrial depolarizations/ventricular depolarization ○ Ventricular bradycardia 3° AV block ○ Complete dissociation between atrial and ventricular depolarizations and contractions ○ Ventricular bradycardia 27 AV block causes ventricular bradycardia AV block results in distal pacemaker sites generating the ventricular rhythm ○ Junctional (e.g., Bundle of His) 40-60 bpm ○ Ventricular 30-40 bpm These secondary pacemaker sites have a lower intrinsic rate than the SA node 28 Abnormal conduction caused by ectopic foci Ectopic foci generate action potentials that do not follow normal conduction pathways – therefore, the ventricles take longer to depolarize Ventricular ectopic foci cause a wide QRS complex because normal (fast) conduction pathways are not followed − e.g., PVC, ventricular tachyarrhythmia 29 Abnormal conduction caused by reentry Global reentry ○ Between atria and ventricles ○ Causes supraventricular tachycardia (SVT) ○ e.g., Wolff-Parkinson-White syndrome (WPW) Local reentry ○ Within atria or ventricles causes atrial or ventricular tachycardia ○ Within AV node (not illustrated) causes SVT impulses spread into atria and Klabunde, Cardiovascular Physiology Concepts, 3e ventricles 30 Requirements for reentry Partial depolarization of a conduction pathway Unidirectional block Critical timing – reentry must occur beyond the ERP Klabunde, Cardiovascular Physiology Concepts, 3e 31 Changes in autonomic function can initiate or stop reentry Sympathetic activation (of AV node and ventricular conduction pathways) ○  conduction velocity ○  ERP Vagal activation (of AV node) ○  conduction velocity ○  ERP 32 Summary of major concepts Cardiac cell membrane potentials are determined primarily by Na +, K+ and Ca++ relative conductances SAN pacemaker activity and conduction velocity are regulated by autonomic nerves, hormones, and electrolytes Afterdepolarizations and ischemic injury can trigger tachycardia or other abnormal rhythms, such as ectopic beats Specialized conduction pathways between AVN and ventricular muscle ensure rapid activation of ventricles AVN conduction blocks can desynchronize atrial and ventricular contractions, and lead to ventricular bradycardia Reentry circuits can cause local or global tachyarrhythmias 33 END 34 QUESTIONS 35 Q1: Which of the following drug mechanisms of action would decrease sinus firing rate? A. β-adrenoceptor agonist B. Fast Na+ channel blocker C. Ca++ channel blocker D. Muscarinic receptor antagonist 36 Q2: An increase in the extracellular concentration of K+ surrounding ventricular myocytes would most likely A. Increase SA nodal firing rate B. Increase outward K+ currents C. Depolarize the resting membrane potential D. Increase the conduction velocity of Purkinje fibers 37 Q3: If a patient has a complete AV block, the most likely consequence will be which of the following? A. Atrial rate will be higher than ventricular rate B. Both the atria and ventricles will cease to contract C. Only the ventricles will cease to contract 38 39 Answers to questions Q1: C ○ CCBs block L-type Ca++ channels, which reduces the phase 4 slope thereby decreasing firing rate of SAN pacemakers. Note that “funny” currents, and inward Ca ++ currents through T and L-type Ca++ channels, largely determine the slope of phase 4. Q2: C ○ Based on the Nernst and GHK equations, an increase in external K + concentration decreases the K+ chemical gradient and outward (hyperpolarizing) K + currents, which leads to depolarization. Q2: A ○ With a complete AV block (3° block), atrial action potentials are not conducted to the ventricles. The SAN continues to fire normally, and the ventricles in the absence of overdrive suppression will exhibit intrinsic pacemaker activity, but at a lower rate than the SAN. Therefore, ventricular rate will be lower than atrial rate and the two rhythms will be asynchronous. 40