Lecture 12 Introduction to the Cardiovascular System_2023.pdf

Introduction to the Cardiovascular System and Cardiac Electrophysiology MABS Physiology Lecture 13 Reference: Chapter 4 (pp. 117 – 119; 127-144) – Physiology 5th ed. Costanzo Jim Mahaney, PhD With Robert Augustyniak, PhD and Chevon Thorpe, PhD Learning Objectives 1. Recall the major components of...

Introduction to the Cardiovascular System and Cardiac Electrophysiology MABS Physiology Lecture 13 Reference: Chapter 4 (pp. 117 – 119; 127-144) – Physiology 5th ed. Costanzo Jim Mahaney, PhD With Robert Augustyniak, PhD and Chevon Thorpe, PhD Learning Objectives 1. Recall the major components of the circulatory system. 2. Recall the major cell groups of the heart as contractile cells and conducting cells, and relate the purpose of having separate atrial and ventricle syncytia. 3. Beginning in the SA node, relate the normal sequence of cardiac activation (depolarization) and the role played by specialized cells, and relate these to the events of a normal ECG tracing. 4. Relate why the AV node is the only normal electrical pathway between the atria and the ventricles and relate the functional significance of the slow conduction through the AV node in the context of AV block. 5. Recall the ionic channels/currents that contribute to cardiac action potentials in contracting cells vs conducting cells. 6. Compare and contrast an action potential in contracting cells vs conducting cells. 7. Recall the refractory period of an action potential, and relate the role of the L-type Ca2+ in creating a plateau phase to lengthen the absolute refractory period in contractile cell action potentials. 8. Contrast sympathetic and parasympathetic nervous system influence on heart rate (chronotropic effects). Make note of the related terms dromotropic and inotropic (later lectures). 9. Electrocardiogram (ECG) information will be limited to the introductory level presented at the depth of the slides. Recall the major features of the ECG (P wave, QRS wave, S-T segment and T wave) and relate what electrical signals in the heart correspond with these features. 10.Relate the method of determining heart rate from an ECG recording, and recall the terms normal sinus rhythm, sinus tachycardia and sinus bradycardia. 2 Overview: The Circulatory System Objective 1 Primary Function of the Cardiovascular System Deliver blood to all tissues providing essential nutrients to the cells and removing waste products from the cells Components: Heart: Serves as a pump upon contracting generates the pressure to drive blood through a series of vessels Arteries: carry oxygenated blood away from the heart to tissues (high pressure) Veins: carry oxygen-poor blood from tissues back to the heart (low pressure) Capillaries: thin-walled vessels interposed between the arteries and veins. Exchange of nutrients and waste and fluid occurs across the capillary walls Slide: Dr. Chevon Thorpe 3 Overview: The Circulatory System Objective 1 arteriole venule capillary artery vein Slide: Dr. Chevon Thorpe 4 Overview: The Circulatory System Objective 1 • The heart consists of two pumps in a series – Right ventricle to propel blood through the lungs for exchange of O2 and CO2 (pulmonary circulation) – Left ventricle to propel blood to all other tissues of the body (systemic circulation) • The total flow of blood out of the left ventricle is known as cardiac output (CO) • Rhythmic contraction of the heart is an intrinsic property where the sino-atrial node pacemaker generates action potentials spontaneously • Action potentials are propagated in an orderly manner to trigger contraction and pump blood throughout the system. Slide: Dr. Chevon Thorpe 5 Objective 2 Cells of the Heart • Main focus is usually the myocardium, containing the contractile cells, which is between the inner endocardium and the outer epicardium. – Primarily Type I fibers: oxidative metabolism, moderate contraction velocity, low fatiguability. – Main ATP production pathways = aerobic – Can use glycolysis (anaerobic ATP generation) Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. • Cardiomyocytes resemble bricks in a wall, where the mortar is the extracellular matrix, produced by fibroblasts. • Special conducting cells carry electrical signals rapidly (cardiac conduction system). • Blood vessels bring nutrients and oxygen into muscle cells and carry waste products away from the cells. 6 Cardiomyocyte Characteristics Objective 2 2 Types of Cardiac Muscle Cells Contractile Cells Conducting Cells (specialized) Where?- Majority of atrial and ventricular tissue Where? – Sinoatrial node (SA node), atrial internodal tracts, Atrioventricular node (AV node), the bundle of His and the Purkinje system Function: Working cells of the heart • Action potentials lead to muscle contraction, which generates of force for pumping blood. Function: Rapidly spread action potentials • Do not contribute to generation of force ** Capacity to generate action potentials spontaneously (normally suppressed except for SA node) 7 Cardiomyocyte Characteristics Objective 2 (SA node = “sinoatrial” node) Figure 14-17 from Silverthorn’s Human Physiology 5th ed 8 Cardiomyocyte Characteristics Objective 2 Intercalated Disks Link Adjacent Cardiac Myocytes Mechanically and Electrically Gap Junction Latticework of cells = syncytium* Cells are “synced” into one operating unit Heart is composed of two syncytiums: Atrial syncytium Ventricular syncytium As such, the atria work as a coordinated unit and the ventricles work as a coordinated unit Gap junctions link adjacent myocytes electro-chemically Allows sequential action of atria first followed by ventricles second, producing coordinated, unidirectional movement of blood. *pronounced “sihn-si-shee-uhm” 9 Origin and Spread of Excitation in the Heart Bachmann's Bundle Objective 3 Sequence of cardiac action potential 1. SA (sinoatrial) Node – initiation of action potential, pacemaker 2. Atrial internodal tracts and atria – tracts carry action potential to right and left atria 3. AV (atrioventricular) node – action potential from right and left atria simultaneously conduct to AV node. **Slow conduction velocity 4. Bundle of His, Purkinje fibers, and ventricles – from the AV node, the action potential enters the His-purkinje system of the ventricles **Fast conduction velocity Fibrous tissue between the atria and ventricles are characterized by high electrical resistance such that myocardial action potential propagated from the atrial syncytium to the ventricular syncytium has to go through the specialized conduction system called the AV node (atrioventricular (AV) bundle). 10 Conduction Velocity Conduction velocity is the speed at which action potentials propagate within the tissue measured in meters per second (m/sec) • Slowest in AV node (0.01 to 0.05 m/sec) • Fastest in the Purkinje fibers (2 to 4 m/sec) • Conduction through AV node (AV delay) requires almost ½ of total conduction time (100msec) Objective 4 Timing of activation of the myocardium Why is conduction velocity important? … implications for physiologic functions Slow conduction velocity of AV node ensures ventricles do not activate too early (i.e. before they have time to fill with blood from atria) Rapid conduction velocity of Purkinje fibers ensures ventricles are activated quickly in a smooth sequence for the efficient ejection of blood. The numbers superimposed on the myocardium indicate the cumulative time, in m/sec, from the initiation of the action potential in the SA node (time 0). 11 Review: Electrochemical Potential Terms Terms to Know The concepts applied to cardiac action potentials are the same concepts that are applied to action potentials in nerve, skeletal, and smooth muscle Membrane Potential – determined by the relative conductance's or permeabilities to ions and the concentration gradients for the permeant ion. [expressed in millivolts – mV] Membrane Conductance – the number of channels that are open in a membrane. If conductance is increasing, channels are opening. Equilibrium potential – If cell membrane has a high permeability to an ion , that ion will flow down its electrochemical gradient and attempt to drive the membrane potential towards equilibrium. [Nernst equation] Resting membrane potential – the voltage difference across the cell membrane at rest. Depolarization – membrane potential has become less negative. Net movement of positive charge into the cell, which is called inward current Hyperpolarization – membrane potential has become more negative. Net movement of positive charge out of the cell, which is called outward current. Threshold potential – potential difference at which there is a net inward current. Depolarization becomes self-sustained and gives rise to the upstroke. 12 Objective 5 Ions and Ion Channels Involved in Cardiac Action Potentials Resting Ventricular Myocyte K+ (150 mM) -90 mV Na+ (20 mM) Ca2+ (0.0001 mM) • • • K+ (4 mM) Na+ Equilibrim Potential -94 mV +70 mV (145 mM) Ca2+ (2.5 mM) +132 mV Resting membrane is determined primarily by K+ Na+-K+ ATPase maintains gradients across the cell Changes in membrane potential are caused by the flow of ions into or out of the cell which results from: • Changes in the electrochemical gradient for a permeant ion • Changes in conductance of an ion HCN channel- hyperpolarization-activated cyclic nucleotide-gated channel Figure 17-5 from Preston and Wilson’s Physiology 13 Objective 6 Sinoatrial (SA) and Atrioventricular (AV) nodes SLOW +20 0 -20 0 -40 -60 3 4 -80 -100 100 msec • • • • Exhibit automaticity More positive resting membrane potential Unstable resting membrane potential No sustained plateau Membrane Potential (mV) Membrane Potential (mV) Cardiac Action Potentials Atrial, ventricular and Purkinje fibers FAST +20 1 2 0 -20 -40 0 3 -60 -80 4 -100 100 msec • • • Long duration (150-250 msec) Stable resting membrane potential (~-85mV) Plateau 14 Action Potentials in the SA and AV node SA Node = natural pacemaker of the heart Features of SA Node Action Potentials • Automaticity: generate action potentials spontaneously without neural input - caused by pacemaker potential • Unstable resting membrane potential “pacemaker potential” - Notice region 4 not flat • No sustained plateau - No discernable phase 2 Objective 6 +20 0 -20 -40 Threshold -60 -80 -100 Pacemaker potential Action potential Time (msec) 15 Action Potentials in the SA and AV Node Phase 0 – Upstroke • ↑Ca2+ entry into SA cells … inward Ca2+ current (primarily “Transient” (or T-type) Ca2+ channels Phase 3 – Repolarization • ↑ K+ exits cells … outward K+ current Phase 4 – Spontaneous depolarization or “pacemaker potential” • HCN Channels – hyperpolarization-activated cyclic nucleotide gated channels. OPEN as Vm approaches -65 mV. • Maximum diastolic potential = ~ -65 mV • Opening of Na+ channels and inward Na+ current called If (‘f’ stands for funny) creates slow depolarization • If is turned on by repolarization from the preceding action potential (ensures each AP in the SA node will be followed by another AP) • Once If brings the potential to the threshold, T-type Ca2+ channels open for the upstroke NOTE: Rate of phase 4 depolarization sets the heart rate: modified by agents that affect heart rate. Objective 5, 6 +20 0 ICa 0 -20 -40 IK 3 “funny current” -60 -80 If 4 Threshold Pacemaker potential Action potential Time (msec) -100 K+ outside inside Na+ (HCN channel) Ca2+ (L) 16 Latent Pacemakers Objective 4 • Pacemaker cells with the fastest rate of phase 4 depolarization controls heart rate • Cells of AV node, bundle of His and Purkinje fibers are referred to as latent pacemakers • Overdrive suppression is the mechanism that suppresses latent pacemakers from driving the heart rate • When a latent pacemaker takes over and becomes the pacemaker of the heart, it is called an ectopic focus 17 Objective 5, 6 Action Potential in the Atria, Ventricles, and Purkinje Fibers Phase 0 - upstroke • Rapid depolarization caused by ↑in Na+ conductance (gNa) produced by depolarization-induced opening of activation gates on Na+ channels • ↑ gNa causes inward Na+ current INa • Drives membrane potential towards Na+ equilibrium of ~+65 mV ICa INa • At peak of upstroke, membrane potential is depolarized to ~ +20mV Phase 1 – initial repolarization • Brief period of repolarization following upstroke • Inactivation gates to Na+ channels close… ↓gNa…inward INa ceases • Net outward current of K+ down electrochemical gradient IK IK 1 Phase 2 - plateau • Stable depolarized membrane potential (shorter in atrial fibers) caused by no net current flow across the membrane • ↑ gCa.. Inward ICa (slow- L-type) • Outward IK driven by electrochemical gradient 18 Objective 5, 6 Action Potential in the Atria, Ventricles, and Purkinje Fibers Phase 3 - repolarization • Outward currents are greater than inward currents • ↓ gCa …↓ inward Ca2+ current (ICa) • ↑gK … ↑ outward K+ current (IK) down steep electrochemical gradient • At the end of phase 3, outward IK is reduced because repolarization brings membrane potential closer to EK (↓driving force) ICa INa IK IK 1 Phase 4 – resting membrane potential • Return resting level of ~ -90 mV • Inward and outward currents are equal • K+ channels and current responsible for phase 4 are different from those responsible for repolarization (phase 3) , therefore conductance is gK1 and current is IK1 • High gK1 … outward IK1 • Outward current is balanced by inward current of Na+ and Ca2+ maintained by Na+-K+ ATPase and Na+-Ca2+ exchanger 19 Review: Regulation of Voltage Gated Na+ outside inside Na+ Channels Na+ m h Resting (closed) Activated (open) Depolarization Cardiac action potential phase: Na+ + Na Phase 4 m gate closed Phase 0 At a membrane potential of -55 mV, voltage-gated Na+ channels (m gate) open and Na+ flows in Inactivated (closed) Resting (closed) Repolarization Phases 1, 2, 3 At peak of phase 0, 99% of Na+ channels are closed (h gate) because rapid depolarization inactivates them 1 Phase 4 Channels reset when membrane potential becomes repolarized below -50 mV 2 3 0 4 4 Figure 2-4 from Klabunde’s Cardiovascular Physiology Concepts 2nd ed 20 Review: Refractory Period Excitability – the amount of inward current required to bring a myocardial cell to the threshold potential. The excitability of a myocardial cell varies over the course of the AP, and these changes are reflected in refractory periods. Objective 7 Absolute refractory period (ARP) • Incl. upstroke, plateau, and some repolarization • Most Na+ channels are closed • Complete refractory – cell is incapable of generating action potential Effective refractory period (ERP) • Slightly longer than ARP, Na+ channels start to recover • “Effective” means a conducted AP cannot be generated Relative refractory period (RFP) • Begins @ end of ARP and continues until cell is repolarized (more Na+ channels recovered) • Possibility to generate 2nd AP BUT greater-than normal stimulus is required • AP generated during this period will have abnormal configuration and shortened plateau Supranormal refractory period (SNP) • Cells more excitable than normal (-70 mV to -85 mV) 21 Autonomic Effects on Heart Rate Sympathetic • cardiac sympathetic nerves release norepinephrine which ­ heart rate Right Parasympathetic nerves (vagi) • The right cardiac nerve dominates the SA node and impacts heart rate (chronotropicity) • The left cardiac nerve dominates innervation of the left ventricle, and effects contractility (inotropicity) Cardiac sympathetic nerves Objective 8 Parasympathetic Left • Vagus nerves release acetylcholine which ¯ heart rate • The right vagus dominates the SA node and impacts HR (chronotropicity) • The left vagus dominates the AV node and impacts conduction velocity (dromotropicity) Figure 9-12 from Guyton and Hall’s Textbook of Medical Physiology 12th ed 22 Introduction: Autonomic Effects of Heart and Blood Vessels 23 Sympathetic Nerves Increase Heart Rate Objective 8 Increased rate of depolarization • Norepinephrine (NE) acts at β1-adrenergic receptors on SA Nodal cells. – – • • • • Receptor à G-protein à adenyate cyclase à increased cAMP cAMP binding to HCN hyperpolarization activated cyclic nucleotide gated) channel increases channel opening = faster depolarization. ­ the If thereby increasing the rate of spontaneous depolarization. ↑ Ica … more functional L-type Ca2+ channels… less depolarization to reach threshold In sum, NE ­gNa+, ­gCa2+, ­ gK+ Heart rate increases SA Nodal Action Potential 0 * mV -40 -60 Time *Positive chronotropic effects of sympathetic nerve activation 24 Objective 8 Parasympathetic Nerves Decrease Heart Rate – cAMP levels drop, HCN channel opens less • ↓If • ¯ If decreases the rate of spontaneous depolarization to threshold. • Delays opening of L-type calcium channels • Heart rate decreases SA Nodal Action Potential Membrane potential (mV) Decreased rate of depolarization • Acetylcholine acts at Muscarinic M2 receptors on SA Nodal cells. (2 effects) • M2 receptors are coupled to GK that inhibits adenylyl cyclase… 20 0 * * -20 -40 -60 -80 Time *Negative chronotropic effects of parasympathetic nerve activation 25 Objective 8 Parasympathetic Nerves Decrease Heart Rate SA Nodal Action Potential Membrane potential (mV) Negative shift in the maximum diastolic potential • Gk directly increases the conductance of K+ channel called K+-ACh and increases outward K+ current (IK-ACh) • K+ exits nodal cells causing them to hyperpolarize the maximum diastolic potential • Threshold potential increases b/c ↓ ICa • Heart rate decreases 20 0 * * -20 -40 -60 -80 Time * Negative shift in maximum diastolic potential with activation of the parasympathetic nerve activation 26 Autonomic Effects on Conduction Velocity in the AV Node Sympathetic Nervous System Parasympathetic Nervous System • Increase in conduction velocity through AV node (positive dromotropic effect) • ↑ ICa …↑inward current \↑conduction velocity (Recall: Ca2+ is • Decrease in conduction velocity through AV node (negative dromotropic effect) • ↓ICa … ↓ inward current • ↑IK-Ach… ↑outward K+ current • ERP of AV nodal cells is prolonged • If conduction velocity though AV node is slowed sufficiently, some action potentials may not be conducted at all from atria to ventricles = heart block responsible for the upstroke in AV node) • ↑ ICa …shortens ERP so AV node recover earlier and have increased firing rate 27 Electrocardiogram (ECG or EKG) • • • Objective 9 Various waves represent depolarization or repolarization of different portions of the myocardium and are given lettered names. Intervals and segments between the waves are also named. Intervals include waves, segments do not include waves Recall: The entire myocardium is not depolarized at once. The result of the sequence and timing of depolarization and repolarization establishes potential differences between different parts of the heart that can be detected by electrodes. 28 Electrocardiogram (ECG) Objective 9 • P wave – Depolarization of the atria – Duration correlates with conduction time through atria – Does not include atrial repolarization, which is “buried” in the QRS complex • PR interval (P wave + PR segment) – Time from initial depolarization of the atria to initial depolarization of the ventricles – PR segment – an isoelectric flat portion of ECG that corresponds to AV node conduction – PR interval is normally 160 milliseconds • ↑ conduction velocity through AV node ↓ PR interval • ↓ conduction velocity through AV node ↑ PR interval 29 Electrocardiogram (ECG) Objective 9 • QRS Complex (3 waves- Q,R,& S) – Collectively represent depolarization of the ventricles (normally < 120msec) • T wave – Repolarization of the ventricles • QT interval (QRS complex + ST segment + T wave) – Represents the first ventricular depolarization to last ventricular repolarization – ST segment is an isoelectric portion of the QT interval that correlates with the plateau of the ventricular action potential 30 Altered Sinoatrial Rhythms Objective 10 Normal Sinus Rhythm 60-100 beats/min Sinus Tachycardia >100 beats/min Cause: exercise, hypovolemia, fever Sinus Bradycardia <60 beats/min Cause: exercise training, hypothermia, medication 31