Cardiac Physiology II 2024-25 MBChB Slides for KLE PDF

Cardiac physiology II: Electrical activity of the heart Dr Margaux Horn Senior Lecturer in Physiology [email protected] c.uk December 202...

Cardiac physiology II: Electrical activity of the heart Dr Margaux Horn Senior Lecturer in Physiology [email protected] c.uk December 2024 MBChB – Unit 4 “Emergencies” Please note – these are animated slides and may consist of multiple (layered) elements. If you wish to print the slides to make notes, static images may not appear exactly as intended.  Intended learning outcomes (ILOs): Describe the phases of the ventricular and sinoatrial nodal action potentials Explain how the ventricular action potential triggers contraction of the cardiac myocyte Explain how the heart can generate its own action potential Explain propagation of the cardiac action potential and how this is controlled through the cardiac conduction system  What did we cover in the last lecture? Rapid Diastasi filling s Isovolumetric Atrial relaxation contractio n Ejection Isovolumetric contraction How is the heart able to contract and relax in a rhythmic,  Basic concepts of cell excitability (a reminder...) Polarisation = a difference in charge on either side of the membrane -80 mV Polarised  intracellular is more negative (i.e. the cell at rest) Depolarised  intracellular becomes less negative (more positive) Repolarised  becoming more negative following depolarisation + + + + + + + + + + + + + + + + + + + + - - - - - - - - - - - - - - - - - - - - Voltage = the difference in positive charge from one side of the membrane to the other -80 mV means there are fewer positive charges inside than outside Current (I) = the flow of charged particles Influx  flow of ions into the cell Efflux  flow of ions out of the cell  Important ion channels and transporters in the Na+ Na+ heart K+ Na+ VG = voltage-gated Na+ Na+ Na+ Na+ VI = voltage- Na+ Ca2 Na+ Na+ + Na+ Na+ independent K Na+ Ca2 + Na+ Na + Ca2 Na+ Ca2 + + Na+ Na+ K+ + Na+ Ca2 Na+ Na+ Na+ Na+ Na+ Na+ Na + + Na + K + Na+ Na+ Ca 2 + Na+ Ca2 Na+ Na+ K+ Na+ Ca2 K+ + Na+ Na+ + Na+ Na+ Na+ VI K+ VG K+ VG Na+ L-type Ca2+ Ca2 3Na channel channel channel channel + + Extracellular Na+-Ca2+ Na+-K+ exchanger ATPase Sarcolemma (NCX) Intracellular (sarcoplasm) K+ K+ 3Na 2K+ K+ K K+ K+ K+ + K+ + K+ K+ K+ K+ K + K+ K+ K+ Na+ Na + K+ K Ca2 K+ + Na+ K+ K + K + K + K+ K+ + K+ K+ K+ Na+ K+ K+ K+ K+ K+ K+ K+ K + K+ K+ K+ K+ K+ K+ K+ K+ K+ K + K+ Na+-K+-ATPase and Na+-Ca2+ exchanger restore ionic gradients  The big picture… Myocyte Action potential of the SA node Cardiac conduction system Ventricular action potential Ca2+-induced Ca2+ release Myocyte contraction  The cardiac (ventricular) action potential 40 1 Membrane Potential (mV) 2 0 “Spike and plateau” Neuronal Phase 0 = 0 action 3 -40 potential Depolarisation Phase 1 = Initial 4 4 -80 ~1-3ms repolarisation Phase 2 = Plateau 0 100 200 300 Time (ms) Phase 3 = Repolarisation Phase 4 = Resting Which ions are responsible for the cardiac action potential  Phase 4 – “Resting membrane potential” 40 Membrane potential (mV) 0 1. Voltage-independent (VI) K+ channels open -40 2. K+ tends to diffuse out (leaving 4 negatively 3. Resting charged potential = ~ proteins -80 mV behind) -80 0 100 200 300 Time (ms) -80 mV VI K+ VG K+ VG Na+ L-type Ca2+ channel channel channel channel Only K+ shown (for now...) K+ K+ K+ K+ K+ K+ K + K+ K+ K+ K+ K + K + K+ K+ K+ K+ K + K+ K + K+ K+ K+ K+ K+  Phase 0 – “Rapid depolarisation” 40 Membrane potential (mV) 1. Upon reaching threshold, VG Na+ 0 2. channels Na+ influxopen along electrochemical gradient -40 0 3. Intracellular gains positive charge  -80 DEPOLARISATION 0 100 200 300 Time (ms) -80 mV +20 mV Na+ Na+ Na+ Na+ Na+ Na+ Na + Na+ Na+ Na+ Na+ Na+ Na+ VI K + VG K + VG Na + L-type Ca 2+ channel channel channel channel K+ K+ K+ K+ K+ K+ K+ K+ K+ K+ K + K + K+ K+ K+ K + Na+ K+ K + K+ K+ K+ K+ K+  Phase 1 – “Initial repolarisation” 40 Membrane potential (mV) 1 1. VG Na+ channels quickly inactivate 0 2. Fast VG K+ channels open -40 3. K+ efflux  intracellular loses positive charge  SHORT REPOLARISATION -80 4. Fast VG K+ channels quickly inactivate 0 100 200 300 +20 mV ~0 mV Time (ms) VI K+ VG K+ VG Na+ L-type Ca2+ channel channel channel channel K+ K+ Na+ K+ K+ Na + K+ K+ K+ K+ K+ K+ Na+ K + Na K + + Na+ K+ Na K + K K+ Na+ Na+ K+ Na+ K+ K+ + + K + Na + K+ K+ K+  Phase 2 – “Plateau” 40 Membrane potential (mV) 2 1. VG L-type Ca2+ channels open 0 2. Ca2+ influx (slow)  PLATEAU -40 3. Initiating step leading to myocyte contraction (see later) -80 4. L-type Ca2+ inactivate slowly 0 100 200 300 Time (ms) ~ 0 mV Ca2 Ca2 Ca2 + Ca2 Ca2 + + + Ca2 + Ca2 + Ca 2 Ca2 VI K + + VG K+ VG Na + L-type Ca 2+ + + channel channel channel channel K+ K+ K+ K+ K+ K+ K+ K+ K + K + Ca2 K+ K+ K+ K+ + K + K+ K+ K+  Phase 3 – “Repolarisation” 40 Membrane potential (mV) 1. Slow VG K+ channels open 0 2. K+ efflux  intracellular loses positive -40 3 charge  REPOLARISATION Refractory 3. VI K+ channels contribute -80 4. Absolute refractory period 0 100 200 300 throughout (until ~ -50 mV) Time (ms) -80 ~ 0 mV VI K+ VG K+ VG Na+ L-type Ca2+ channel channel channel channel Returns to resting potential… K+ K+ K+ K+ K+ K+ K+ K+ K + K + K+ K+ K + K+ K+ K+ K+ K+  Summary so far: K+ efflux 40 (fast) Ca2+ 1 influx Membrane Potential (mV) 2 0 K+ efflux Na+ (slow) influx 0 3 -40 Resting Potential 4 4 -80 0 100 200 300 Time (ms) Different ion channels contribute to the cardiac action potential which further complicates the picture…  Ultrastructure of cardiac muscle Myocyte B A M y o cy t e Intercalated disc (ID) Two types of junction: B Sarcolemma Gap junction 1. Desmosome – mechanical Desmosome coupling A 2. Gap junction – electrical coupling 50 μm How does the action potential spread between Kanzaki et al (2010). Circulation myocytes?  Cardiac muscle forms a “functional syncytium” Na+ Na Na+ Na + + Na+ Na + Na+ Na + Na+ Na+ Direction of Na+ Na+ propagation Local current Gap junction +-+ -+ - -+ - ++ - - -+ + -+ +- +- ++ -+ - --+ -+ +-+ -+-+-+ - -+ +- -+ +- +-+ -+ -+ -+ - A + + + + - B Depolarised Refractory Resting Depolarised Resting Potential difference Mexican Wave 1. Na+ influx depolarises the 2. Local depolarisation brings membrane adjacent membrane closer to 3. threshold Potential difference across intercalated disc drives current 4. Triggers through depolarisation gap junction of adjacent myocyte  The big picture so far… Action potential of the SA Myocyte node Cardiac conduction system Ventricular action ✓ potential Ca2+-induced Ca2+ release Myocyte contraction What happens when the action potential reaches the sarcolemma? The cardiac AP triggers Ca2+-induced Ca2+- release Ca2 + Ca2 Ca2 Ca2 + + + Na+-K+ NCX PMCA ATPase + + + + Ca2 Ca2 + Ca2 + + + Ca2 Ca2 + Ca2 Ca 2 + + SERCA + + Ca2 Ca2 + + Ca2 L-type Ca2+ RyR Ca2 channels Ca + + 2 + + + Sarcoplasmi + + c reticulum + + + T-tubule Mitochondria + + ++ ++ Myofilament s Ca2+ release from the sarcoplasmic reticulum leads to myocyte Binding of Ca2+ to myofilaments causes contraction Striated cardiac muscle: Troponin- Actin Myosin Tropomyosin Ca2 Ca2 complexCa2 Ca2 + + + + Ca2 Ca2 Ca2 Ca2 + + + + Ca2 Ca2 Ca2 Ca2 + + + + Ca2 Ca2 Ca2 Ca2 + + + + Ca2 Ca2 Ca2 Ca2 + + + + Sarcomere shortening = Sarcomere CONTRACTION Ca2+ binding to myofilaments causes sarcomere see recommended reading list for shortening more detailed “Crossbridge Cycling” mechanism (which you need to Ca2+ must go back into the SR for myocyte relaxation Na Na Na + + + Ca2 Ca2 + + Na+-K+ NCX ATPase PMCA Ca2 + SERCA Ca2 + L-type Ca2+ RyR Ca2 channels Ca2 + + Sarcoplasmi c reticulum Ca2 Ca2 Ca2 + Ca 2 + Ca2 + Ca+2 + + Mitochondria Ca2 T-tubule + Ca2 Ca2 + + Myofilament s Ca2+ reuptake occurs predominantly by SERCA  The big picture so far… Action potential of the SA Myocyte node Cardiac conduction system Ventricular action ✓ potential Ca2+-induced Ca2+ release ✓ Myocyte contraction ✓ Sino-atrial (SA) node Where does the wave of excitation  Where does the wave of excitation begin? The cardiac conduction system delivers electrical excitation throughout the heart in a coordinated manner NOT SA node NERVES! LA RA 5 mm Torrente et al (2015). PNAS. 112:9769-9774 Cardiac muscle exhibits “automaticity” SA nodal myocyte (pacemaker) action potentials are self-generated Autonomic nervous system regulates the intrinsic rate set by the pacemaker (60- 100More bpm)on this in the lecture on “Neural control of the The pacemaker (SA nodal) action potential Ventricular action +20 potential SA nodal action potential 0 Key phases of the SA Membrane potential 0 0 nodal action potential 3 3 -40 4 4 Phase 4 – Pacemaker potential Phase 0 – Depolarisation (mV) -80 Phase 3 - Repolarisation 0 1 2 Time (s) How has the SA nodal action potential adapted to  Phase 4 – Pacemaker potential 1. Following repolarisation (~ - +20 Membrane potential (mV) 0 60mV) HCN channels open – 1. “leaky” 2. No fast Slow Na+ofchannels influx Na+ (funny current) -40 4  SPONTANEOUS 2. No VI K+ channels 3. depolarisation VG noT-type Ca2+ open true resting membrane -80  Influx of Ca2+ - contributes to potential 0 1 2 decay of pacemaker potential Time (s) Na+ Ca2 Ca2 Na+ Na+ K + Ca2 Na+ + Na+ + Na+ Na+ Na + Na + Na+ Na+ + Na+ Na+ Na+ Na+ Ca2 Ca2 K+ + + Na+ K + HCN T-type Ca2+ L-type Ca2+ VG K+ channel channel channel channel closing…. K+ K+ K+ K+ K+ K+ K + K+ K+ K+ K+ K + K + K+ K+ Na+ K+ K+ K + Na+ K+ K + K+ K+ K+ K+ K+  Phase 0 – Depolarisation +20 Membrane potential (mV) 0 1. Decay of pacemaker potential reaches 0 threshold (~ -40 mV), L-type Ca2+ -40 channels open 2. Further influx of Ca2+ along -80 electrochemical gradient  0 1 2 DEPOLARISATION Time (s) Na+ Ca2 Ca2 Na+ K + Na+ + Na+ + Na+ Na+ Na + Na+ Na + Na+ Na+ Na+ Ca2 Ca2 K+ + + Na+ K + HCN T-type Ca2+ L-type Ca2+ VG K+ channel channel channel channel Na+ K+ K+ K+ K+ K+ K+ K + K+ K+ K+ K+ Na + K + K + K+ K+ Na+ K+ Na K + + K + Na+ K+ K + Ca 2 K+ K+ K+ K+ K+  Phase 3 – Repolarisation 1. L-type Ca2+ channels inactivate and VG +20 Membrane potential (mV) K+ channels open 0 2. K+ efflux along electrochemical 3 -40 gradient  REPOLARISATION 3. VG K+ channels remain open  -80 Hyperpolarisation HYPERPOLARISATION 4. Which activates HCN channel… 0 1 2 Time (s) Na+ Na+ K + Na+ Na+ Na+ Na+ Na + Na+ Na + Na+ Na+ Na+ K+ Na+ K + HCN T-type Ca2+ L-type Ca2+ VG K+ channel channel channel channel Na+ closing…. K+ Ca2 Ca2 K+ K + K + K+ + K+ K + K+ + K+ K+ K+ K+ K+ K+ K+ Ca2 Na+ K+ K Na+ K+ K+ K+ K+ + K + Ca 2 Ca 2 + K+ K+ K+  Action potential propagation and conduction velocity ∆ Voltage Myocytes have: Current= Resistance 1. Greater potential difference 2. Increased density of gap junctions  Diameter =  Resistance 3. Increased length Length 4. Increased diameter Ventricular + + + Diamete r + + + + - + + + A B Depolarised = + 20 Resting = -80 mV ∆Voltage = 100 mV mV + - Nodal + + + + A + + + B High resistance Depolarised = 0 High “Resting” = -60 mV resistance High ∆Voltage resistance = 60 mV mV Action potentials propagate faster through myocytes  The big picture so far… Myocyte Action potential of the SA node ✓ Cardiac conduction system Ventricular action ✓ potential Ca2+-induced Ca2+ release ✓ Myocyte contraction ✓ How does excitation spread from SA node to the  Electrical events in the cardiac cycle: Atrial depolarisation: 1. Action potential generated by the SA node 2. Wave of excitation spreads across both atria  atrial depolarisation  contraction SA node 3. Wave of excitation travels slowly through the AV node AV node Myocyte conduction velocity = ~ 1 Annulus m/s fibrosus AV nodal conduction velocity = ~ 0.05 m/s AV node delay – allows ventricular filling to complete Internodal Overall mean direction of pathways Anterior depolarisation of the atria is interatrial downwards and left* (Bachmann’s) *keep this in mind for the “ECG”  Electrical events in the cardiac cycle: Ventricular 4. Action potential travels to depolarisation: the Atrioventricular bundle 5. Action potential propagates along both the left and right bundle branches 6. Excites Purkinje fibre network  apex to base 7. Ventricular depolarisation initiates ventricular contraction during systole Purkinje fibre conduction velocity = ~ 3-5 m/s As wave of excitation spreads, endocardial myocytes are Atrioventricular depolarised before epicardial bundle (Bundle of myocytes His) Right bundle Overall mean direction of branchLeft bundle Purkinje depolarisation is downwards and branch fibres  Electrical events in the cardiac cycle: Ventricular repolarisation: 8. Following depolarisation, the ventricles will repolarise slowly, in the opposite direction to depolarisation 9. Repolarisation initiates ventricular relaxation Endocardial (inner myocyte) Epicardial (outer myocyte) Bundle of His Time Right bundle Overall mean direction of branch Left bundle Purkinje repolarisation is upwards and branch fibres  www.activephysiology. com -w o r k for Pre ct i c al r a ECG p eek! w next https://activephysiology.com/topics/cardiovascular-videos/introduction -to-ecg/  Resources: Quiz- egr ated! int Videos covering the core concepts discussed in this lecture: “The cardiac action potential” – https://activephysiology.com/topics/cardiovascular-videos/the-cardiac-action-potential/ “Excitation-contraction coupling in the heart” – https://activephysiology.com/topics/cardiovascular-videos/excitation-contraction-coupling/ “The cardiac conduction system” - https://activephysiology.com/topics/cardiovascular-videos/the-cardiac-conduction-system/ www.activephysiology.com Further Office hour Herring & Paterson reading: - ”Levick’s Introduction to Cardiovascular Physiology”, 6th Edition: Non-compulsory Q&A – Mon https://www.vlebooks.com/Vleweb/Product/Index/2024669?page=0 16th Dec: Guyton & Hall – “Textbook of Medical Physiology”, 13th Edition: 9.00-10.00 – Room DJW 0.116 https://www.vlebooks.com/Vleweb/Product/Index/748473?page=0 11.00-12.00 – Room DJW 1.74 Boron & Boulpaep – “Medical Physiology”, 3rd Edition: https://www.vlebooks.com/Vleweb/Product/Index/808100?page=0 Please bring your questions to http://www.cvphysiology.com/ a useful (and reliable!) website this session!