Intro to CVS Physiology Lecture 1 PDF

Introduction to CV Physiology Electrical Activity Mechanical Activity (Heart as a Pump) The Vascular System Cardio-vascular Regulation February 19, 2024 Cardiac Action Potentials ECG Cardiac Cycle Cardiac Performance Arteries, Veins Coupling with Cardiac Function Microcirculation and Lymphatics Regu...

Introduction to CV Physiology Electrical Activity Mechanical Activity (Heart as a Pump) The Vascular System Cardio-vascular Regulation February 19, 2024 Cardiac Action Potentials ECG Cardiac Cycle Cardiac Performance Arteries, Veins Coupling with Cardiac Function Microcirculation and Lymphatics Regulation of Arterial BP Local Control of Blood Flow Changes in Health & Disease Dr. J. Mohan 1 Electrical Activity of Cardiac Cells 19 February, 2024 J. Mohan, PhD. Lecturer, Physiology Unit, Faculty of Medical Sciences, U.W.I., St Augustine. Room 104, Physiology Unit. [email protected] References:  Hall, J.E. (2021). Guyton and Hall Textbook of Medical Physiology. 14th Edition, Elsevier, Saunders.  Costanzo L.S. (2014). Physiology. 5th Edition, Elsevier, Saunders.  Costanzo L.S. (2019). BRS Physiology (Board Review Series). 7th Edition, LWW.  Koeppen B.E. & Stanton B.A. (2010). Berne & Levy Physiology. 6th Edition. Mosby, Elsevier.  Marieb, E. & Hoehn, K. (2010). Human Anatomy & Physiology. 8th Edition, Pearson, Benjamin Cummings.  Le T, Hwang W, Muralidhar V, White J. (2017). First Aid for the Basic Sciences: Organ Systems, 3rd Edition (First Aid Series) 3rd Edition, McGraw-Hill.  Klabunde, Richard E. Cardiovascular Physiology Concepts. (3rd Edition). Wolters Kluwer, 2022. Objectives 1.1. Describe Describe the physical properties of sound waves. in the the generation of action potentials normal heart and the ionic basis for automaticity. 2. Explain transduction and processing of sound. 2. Sketch the action potentials of pacemaker cells, anduse contractile cardiacincells, describing the 3. Purkinje Describe the of Fourier analysis the processing of sound. phases and the ionic bases for these. 4. Describe Brainstem Auditory Evoked Potentials (BAEPs) and their 5. Explain the principles underlying audiometric tests. 3. Discuss the sequence and time course of conduction clinical applications. of the cardiac action potential through the normal heart. 4. Compare the effects of sympathetic and parasympathetic stimulation (including their target receptors) on the SA and AV nodes. February 19, 2024 Dr. J. Mohan 4 The Heart Beat https://www.istockphoto.com/video/human-circulatory-system-heart-beat-anatomy-gm1184438235-333418275 February 19, 2024 Dr. J. Mohan 5 Cardiac Action Potentials Origin and Spread of Excitation within the Heart Types of cells in the heart Contractile Conducting – Specialised cells – Spread AP’s rapidly – Generate AP’s spontaneously Figure 10-1; Guyton& Hall, 2021 February 19, 2024 Dr. J. Mohan 6 Cardiac Action Potentials Origin and Spread of Excitation within the Heart t Figure 4-11; Costanzo, 2014 Begins in the sinoatrial (S-A) node Internodal pathway to atrioventricular (A-V) node Impulse delayed in A-V node and bundle (allows time for ventricles to fill before contracting) February 19, 2024 Dr. J. Mohan 7 Cardiac Action Potentials Origin and Spread of Excitation within the Heart t Figure 4-11; Costanzo, 2014 A-V bundle takes impulse into ventricles Left and right bundle branches and then Purkinje fibers take impulses to all parts of ventricles February 19, 2024 Dr. J. Mohan 8 Cardiac Action Potentials Ionic basis of the Ventricular Action Potential Phases of the ap Phase 0 – Upstroke Rapid depolarisation caused by : Na+ conductance (gNa)  inward Na+ current (Na+ influx into the cell) = I Na This drives the membrane potential towards the Na+ equilibrium potential (~ +65mV) At peak of the upstroke, the membrane potential is depolarized to ~ +20mV) Figure 4-13; Costanzo, 2014 February 19, 2024 Dr. J. Mohan 9 Cardiac Action Potentials Ionic basis of the Ventricular Action Potential Phases of the ap Phase 1- initial repolarisation caused by a NET outward current:  Closure of inactivation gates on the Na+ channels in response to depolarisation (causes  Na+ conductance (gNa)and ceases the inward Na+ current (I Na).  There is an outward K+ current (Ito) This is caused by the large outward driving force on K+. At the peak of the upstroke, the inside of the cell is +ve ; also [K+] inside the cell > [K+] outside the cell; therefore K+ flow out of the cell down the steep electrochemical gradient February 19, 2024 Dr. J. Mohan Figure 4-13; Costanzo, 2014 10 Cardiac Action Potentials Ionic basis of the Ventricular Action Potential Phase 1- gate activity Figure 3-3 Open and closed states of fast sodium channels in cardiac myocytes. In the resting (closed) state, the m-gates (activation gates) are closed, although the h-gates (inactivation gates) are open. Rapid depolarization to threshold opens the m-gates (voltage activated), thereby opening the channel and enabling sodium to enter the cell. Shortly thereafter, as the cell begins to repolarize, the h-gates close and the channel becomes inactivated. Toward the end of repolarization, the m-gates again close and the hgates open. This brings the channel back to its resting state. Figure 3-3; Klabunde, 2022 February 19, 2024 Dr. J. Mohan 11 t Cardiac Action Potentials Ionic basis of the Ventricular Action Potential Phases of the ap Phase 2- Plateau A period of 150-200 msec of relatively stable depolarised membrane potential A balance of inward and outward currents  Ca2+ conductance (gCa)  inward Ca 2+ current = I Ca ; L-type Ca2+ channels To balance the inward Ca2+ current there is an outward K+ current (I Ks, I Kr ) – voltage –gated delayed rectifier potassium channels Stable depolarised Vm February 19, 2024 Dr. J. Mohan Figure 4-13; Costanzo, 2014 12 t Cardiac Action Potentials Ionic basis of the Ventricular Action Potential Phases of the ap Phase 3 – repolarisation Movement of the membrane potential towards the resting membrane potential Results from a combination of a decrease in gCa  the inward Ca2+ current (Ica) and an increase in gK  outward K+ current (I Ks, I Kr ) Figure 4-13; Costanzo, 2014 February 19, 2024 Dr. J. Mohan 13 t Cardiac Action Potentials Ionic basis of the Ventricular Action Potential Phases of the ap Phase 4- resting membrane potential Vm is stable again, and inward (Na+ & Ca2+) and outward K+ current (IK1), currents (inward rectifier channel) are equal The resting membrane potential approaches the K+ equilibrium potential, reflecting the high resting conductance to K+ Figure 4-13; Costanzo, 2014 K+ channels and current different from those Dr. J. Mohan responsible for repolarisation in Phase 3 February 19, 2024 14 t Cardiac Action Potentials Ionic basis of the Ventricular Action Potential Types of K+ channels and K+ currents IK1- Maintains resting potential; current of the inward rectifying potassium channel I to -Transient outward potassium current; responsible for phase 1 of action potential I Ks, I Kr - Delayed rectifier potassium currents of slow (I Ks) and rapid (I Kr) types; repolarising currents that are active during phases 2 and 3 of action potential February 19, 2024 Dr. J. Mohan Figure 4-13; Costanzo, 2014 15 t Cardiac Action Potentials Ionic basis of the Ventricular Action Potential Refractory periods ARP (absolute refractory period) - cell is unexcitable to stimulation ERP (effective refractory period) includes a brief time beyond the ARP during which stimulation produces a localized depolarisation that does not propagate RRP (relative refractory period) stimulation produces a weak action potential that propagates, but more slowly than usual SNP (supranormal period) - a weakerthan-normal stimulus can trigger an action potential Figure 4-15; Costanzo, 2014 February 19, 2024 Dr. J. Mohan 16 Cardiac Action Potentials Ventricular, Atrial, and Purkinje (1) Long duration of AP (& long refractory periods) vs nerve, skeletal muscle (2) Stable resting Vm (3) Plateau Figure 4-12; Costanzo, 2014 February 19, 2024 Dr. J. Mohan 17 Cardiac Action Potentials SA Node : differences from Atrial, Ventricular and Purkinje fibers SA node : (1) exhibits automaticity; that is, it can spontaneously generate action potentials without neural input (2) has an unstable resting membrane potential (3) has no sustained plateau Figure 4-12; Costanzo, 2014 February 19, 2024 Dr. J. Mohan 18 t Action Potentials in the SA Node Phase 0 increase in gCa and an inward Ca2+ current (mainly -L-type Ca2+ channels (slow) + partially - T-type Ca 2+) Phases 1 and 2 absent Phase 3 - repolarisation an increase in gK and outward K+ current (I Ks, I Kr ) Figure 4-13 modified; Costanzo, 2014 February 19, 2024 Dr. J. Mohan 19 t Action Potentials in the SA Node Phase 4 spontaneous depolarisation or pacemaker potential longest portion of the SA node AP accounts for the automaticity of SA node cells the most negative value of the Vm is ~ −65 mV, but slow depolarisation causes the Vm to gradually rise towards threshold potential Figure 4-13 modified; Costanzo, 2014 February 19, 2024 Dr. J. Mohan 20 t Action Potentials in the SA Node Phase 4 slow depolarisation – opening of Na+ channels and an inward Na+ current called If If is turned on by repolarisation from the preceding action potential Once If and slow depolarisation bring the membrane potential to threshold, the Ca2+ channels are opened for the upstroke The rate of phase 4 depolarisation sets the heart rate. Figure 4-13 modified; Costanzo, 2014 February 19, 2024 Dr. J. Mohan 21 Rhythmical Discharge of Sinus Nodal Fiber Figure 10-2; Guyton & Hall, 2021 February 19, 2024 Dr. J. Mohan 22 SA Node Is Cardiac Pacemaker Normal rate of discharge in sinus node is 70–80 impulses /min – other cells have the capacity for spontaneous phase 4 depolarisation, but slower rate A-V node—40-60 impulses /min Bundle of His- 40 impulses /min Purkinje fibers—15-20 impulses /min SA node is the pacemaker of the heart (i.e. sets the HR) because of it has the fastest rate of phase 4 depolarisation Also, the shortest action potential (~150 msec) of all myocardial cells  shortest refractory periods February 19, 2024 Dr. J. Mohan 23 Latent Pacemaker A-V node —40-60 impulses /min Bundle of His - 40 impulses /min Purkinje fibers —15-20 impulses /min Overdrive Suppression- suppressed by the faster firing rate of the SA node (latent) Ectopic pacemaker/ectopic focus. - a latent pacemaker takes over and becomes the pacemaker of the heart if : SA node firing rate decreases (e.g., due to vagal stimulation) or stops completely (e.g., because the SA node is destroyed, removed, or suppressed by drugs)  the intrinsic rate of firing of one of the latent pacemakers becomes faster than that of the SA node  the conduction of action potentials from the SA node to the rest of the heart is blocked because of disease in the conducting pathways February 19, 2024 Dr. J. Mohan 24 Conduction of the Action Potential through the Myocardium Conduction velocity (meters/sec) determines how long it takes the action potential to spread to various locations in the myocardium February 19, 2024 Dr. J. Mohan Time = 0 msec – SA Node Time = 220 msec - Atria, AV node, and His-Purkinje system to farthest points in ventricles 25 Conduction of the Action Potential through the Myocardium AV node (called AV delay) ~ 100 msec - conduction velocity in the AV node is slowest (0.01 to 0.05 m/sec) His- Purkinje – conduction velocity is fastest (2-4 m/s) February 19, 2024 Dr. J. Mohan ensures that the ventricles have time to fill with blood from the atria & low CV limits frequency of impulses travelling through AV Node & activating the ventricle (imp. in high atrial rates) ensures that the ventricles can be activated quickly and in a smooth sequence for efficient ejection of blood 26 Conduction of the Action Potential through the Myocardium Importance of normal functioning conduction system within the heart – it permits rapid, organized, near-synchronous depolarization and coordinated contraction of ventricular myocytes - essential to generate pressure efficiently during ventricular contraction – damage or dysfunction to conduction system (ischemic conditions or myocardial infarction), can lead to altered pathways of conduction and decreased conduction velocity within the heart – functional consequence - diminished the ability of the ventricles to generate pressure – damage to the conducting system can precipitate arrhythmias February 19, 2024 Dr. J. Mohan 27 Effects of the ANS on HR Sympathetic NS Positive chronotropic (HR) Activation of β1 receptors in the SA node produces – an increase in If, which increases the rate of phase 4 depolarisation – an increase in ICa, which means there are more functional Ca2+ channels and thus less depolarisation is required to reach threshold (i.e., threshold potential decreases)  the SA node is depolarised to threshold potential more frequently & fires more action potentials per unit time (i.e., increased heart rate) February 19, 2024 Dr. J. Mohan Figure 4.16 Costanzo 2014 28 Effects of the ANS on HR Sympathetic NS Positive chronotropic ( cAMP If   rate of phase 4 depolarisation  HR) Figure 2-7 Costanzo 2014 February 19, 2024 Dr. J. Mohan 29 Effects of the ANS on HR Parasympathetic NS Negative chronotropic (HR) Acetylcholine (ACh) activates M2 receptors in the SA node (1) slowing the rate of phase 4 depolarisation (2) increase in I K-Ach  hyperpolarising the Vm so that more inward current is required to reach threshold potential, and (3) decrease in I Ca2+  more depolarisation required to reach threshold potential the SA node is depolarised to threshold less frequently and fires fewer action potentials per unit time (i.e., decreased heart rate) Figure 4.16 Costanzo 2014 February 19, 2024 Dr. J. Mohan 30 Effects of the ANS on HR Parasympathetic NS Negative chronotropic 1. Parasympathetic nerve fibers  ACh)  activates M2 in the SA node M2 receptors are coupled to a type of Gi protein called GK   adenylyl cyclase   cAMP   If   the rate of phase 4 depolarisation 2. Gk directly increases the conductance of a K+ channel called K+ACh and increases an outward K+ current (similar to IK1) called IK-ACh.  hyperpolarises the Vm so that the SA nodal cells are further from threshold 3. a decrease in ICa, which means there are fewer functional Ca2+ channels and thus more depolarisation is required to reach threshold (i.e., threshold potential increases). February 19, 2024 Dr. J. Mohan 31 Effect of ANS on Conduction Velocity Most important physiologic effects of ANS on conduction velocity are those on the AV Node which alter the rate at which action potentials are conducted from the atria to the ventricles Sympathetic NS Positive dromotropic ( CV through the AV Node)  rate at which action potentials are conducted from the atria to the ventricles.  Ica   inward current   CV  Ica  shortens ERP  shorter recovery from inactivation   CV February 19, 2024 Dr. J. Mohan 32 Effect of ANS on Conduction Velocity Parasympathetic NS Negative dromotropic ( CV through the AV Node)  rate at which action potentials are conducted from the atria to the ventricles.  Ica   inward current   CV  IK-ACh  outward K+ current  CV  Ica  lengthens ERP  longer recovery from inactivation   CV Physiological importance: If CV through the AV node is slowed sufficiently (e.g., by  parasympathetic activity or by damage to the AV node), some action potentials may not be conducted at all from the atria to the ventricles, producing heart block. The degree of heart block may vary: in milder forms, conduction of action potentials from atria to ventricles is simply slowed; in severe cases, action potentials may not be conducted to the ventricles at all. February 19, 2024 Dr. J. Mohan 33 Summary of effects of the ANS on HR and CV Table 3.1 BRS Physiology, Costanzo 2019 February 19, 2024 Dr. J. Mohan 34 Summary of effects of the ANS and Drugs on Pacemaker Action Potentials Stimulation Effect on Effect HR on CV Effect on Slope of Phase 4 depolariation  ACh (parasympathetic ANS)  Adenosine   blockers  More negative  (due to If)  Catecholamines (sympathetic ANS, caffeine, cocaine)  More positive  (due to If) Adapted Table 1-6 Le T et al, 2017 February 19, 2024 Dr. J. Mohan 35