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Cardiac Physiology QUB CardioSoc T eaching Series James Cartlidge wcartlidge02@qub.ac.ukOverview • Cardiac Electrophysiology • Cardiac Cycle • Cardiac Output • Control of Arterial / Blood Pressure • Control of Regional Blood Flow • Capillary Function • Venous Return Electrophysiology – Cardiac Pacemaker Cells • Specialised pacemaker cells generate electrical impulses • Systole – coordinated contraction • Potential difference generates AP – intra- vs. extra • Occurs in SAN & AVN • SAN (upper wall of right atrium) • Natural automaticity – generates own APs • AVN & Purkinje Fibres • PM activity capable First Aid – USMLE – Step 1 • Normally overridden by SAN – due to slower natural rate • Fastest pacing dictates rate – SAN controls Electrophysiology – Cardiac Pacemaker Cells • Phase 4 • Slow spontaneous diastolic depolarization • ‘Funny current’ – ‘If’ channels • Activated by hyperpolarization • HCN activation • Slow mixed Na+ inward / K+ outward current • Automaticity of SAN & AVN • Phase 0 (upstroke) • Opening of voltage-gated Ca2+ channels • Fast voltage-gated Na+ channels inactivated • HCN inactivation • Phase 3 - Repolarization • Inactivation of Ca2+ channels • ↑ activation of K+ channels → ↑ K+ efflux • Autonomic NS Control First Aid – USMLE – Step 1 • HR affected by PNS & SNS – innervate SAN & AVN • PNS → ACh → M2 muscarinic receptors (SAN) → ↓HR • SNS → NA → β1 adrenoceptors → ↑ HRQ1 • Which of these locations is normally the natural pacemaker site of cardiac muscle? A. Sinoatrial node (SAN) B. Atrioventricular node (AVN) C. Coronary Sinus D. Ventricular myocytes E. Purkinje FibresQ1 • Which of these locations is normally the natural pacemaker of cardiac muscle? A. Sinoatrial node (SAN) B. Atrioventricular node (AVN) C. Coronary Sinus D. Ventricular myocytes E. Purkinje FibresQ2 • When the parasympathetic nervous system releases acetylcholine to act to decrease heart rate, what receptor does it act on? A. Beta 1 adrenoceptor B. Mu opioid receptor C. Alpha 1 adrenoceptor D. Muscarinic 2 receptorQ2 • When the parasympathetic nervous system releases acetylcholine to act to decrease heart rate, what receptor does it act on? A. Beta 1 adrenoceptor B. Mu opioid receptor C. Alpha 1 adrenoceptor D. Muscarinic 2 receptor Electrophysiology – Ventricular Action Potentials • Ventricular myocyte APs trigger Ca2+ entry → contraction • Gap Junctions • Regulated pores connecting adjacent cardiomyocytes • Connexins → Connexons (at intercalated discs) • Electrical coupling → synchronous contraction • instant APion down electrochemical gradient → • Unidirectional AP spread TeachMe Physiology https://teachmephysiology.com • 5 Phases (0-4) • Main channels – Na+, K+, Ca2+ • Driven by opening/closing of specific ion channels Electrophysiology – Ventricular Action Potentials • Phase 4 – Baseline • K+ channels open • K+ currents main determinant of RMP– Ek = ~ - 70mV • 3Na+/2K+ pump restores RMP – uses ATP • Phase 0 - Fast Depolarization • Depolarization spread through GJs • Voltage-gated Na+ channels open → Na+ influx → +ve feedback loop → steep depolarization • Na+ channels inactivated immediately after opening – refractory period • Some L-type Ca2+ channels open • Phase 1 – Notch • Transient K+ channel opening – K+ efflux First Aid – USMLE – Step 1 Electrophysiology – Ventricular Action Potentials • Phase 2 – Plateau • K+ channels remain open – K+ efflux • Ca2+ channels open – Ca2+ influx • Ca2+-induced Ca2+-release • Essential for excitation-contraction coupling • Phase 3 – Repolarization • Ca2+ channels close, K+ channels open • ↑ K+ channel permeability • MP toward Ek - rapid K+ efflux • Na+ channels recover, cycle restarts First Aid – USMLE – Step 1Q3 • What ion in phase 2 of the ventricular action potential maintains the plateau phase, preventing rapid repolarization? A. Na+ B. K+ C. Ca2+ D. Cl- E. Mg2+Q3 • What ion in phase 2 of the ventricular action potential maintains the plateau phase? A. Na+ B. K+ C. Ca2+ D. Cl- E. Mg2+Electrophysiology – Ventricular Action Potentials TeachMe Physiology https://teachmephysiology.com Key Questions in Cardiac Surgery Cardiac Conduction System • Conduction System • Collection of nodes & specialized conduction cells • Initiate & coordinate contraction • Sequence of Conduction • SAN → spread across atria (atrial systole) → AVN (delay ~120 ms) → bundle of His (membranous interventricular septum) → L&R bundle branches → Purkinje fibres (subendocardial plexus) → ventricular systole First Aid – USMLE – Step 1Q4 • At what cardiac structure is the electrical action potential delayed by ~120ms? A. Sinoatrial node B. Atrioventricular node C. Purkinje Fibres D. Bundle of His E. Membranous interventricular septumQ4 • At what cardiac structure is the electrical action potential delayed by ~120ms? A. Sinoatrial node B. Atrioventricular node C. Purkinje Fibres D. Bundle of His E. Membranous interventricular septum Electrocardiogram • Trace • P wave • Atrial depolarization • Q wave • Initial ventricular depolarization • R wave • Bulk of ventricular depolarization • S wave • Depolarization from ventricular apex to base • T wave • Ventricular repolarization • ECG Cardiac Territories • Inferior – II, III, aVF – RCA, LCx • Lateral – I, aVL, aVR, V5, V6 – LCx (branch of LAD) • Anterior – V3, V4 – LAD First Aid – USMLE – Step 1 • Septal – V1, V2 – LAD Contraction of Cardiac Muscle • Cardiomyocytes contract according to sliding filament theory • Ca2+ Induced Ca2+ Release • Via IP3 • Gq protein coupling – Ca2+ release from SR • Gq activates PLC → breakdown of PIP2 → IP3 + DAG → Ca2+ channels on SR open → Ca2+ efflux • Via Ryanodine Receptors • Depolarization opens voltage-operated Ca2+ channels in T tubules → Ca2+ release • Ca2+ binds to RyR on SR → RyR activation → Ca2+ release from SR stores → Ca2+ spike • Activates cross-bridge cycling mechanism → contraction • Ca2+ Removal • Enters SR via SERCA or via Na+/Ca2+ exchanger TeachMe Physiology https://teachmephysiology.com Contraction of Cardiac Muscle • Sliding Filament Theory • Ca2+ bound to troponin-C • Conformational change of tropomyosin • Myosin head binds to actin • ADP & iPO4 released from myosin head • Permits power stroke • Myosin head pivots & bends • Pulls on actin moving it • Muscle contraction • New ATP binds to myosin head • Myosin detaches from actin • ATP hydrolyzed into ADP & iPO4 • Cycle repeats, further contraction TeachMe Physiology https://teachmephysiology.com Cardiac Cycle 4 Stages • Filling / Inflow Phase • systole (contraction)g diastole (passive flow) & atrial • AV valves open, SL valves closed • Isovolumetric Contraction • Ventricles contract • S1/SL valves closed – ventricular pressure build-up – • Outflow Phase • At/PAicular systole – ventricular pressure exceeds • Valves open → blood ejected into great vessels • Isovolumetric Relaxation • cycle repeatslax, At/PA pressure exceeds ventricles • AV/SL closed (S2) → AV valves open First Aid – USMLE – Step 1Q5 • At what phase of the cardiac cycle may S1 be heard? A. Inflow phase B. Isovolumetric contraction C. Outflow phase D. Isovolumetric relaxationQ5 • At what phase of the cardiac cycle may S1 be heard? A. Inflow phase B. Isovolumetric contraction C. Outflow phase D. Isovolumetric relaxation Cardiac Cycle Auscultation • S1 (‘lub’) • AV valves shut – start of isovolumetric contraction • S2 (‘dub’) • Outflow (semilunar) valves shut – start of isovolumetric relaxation • S3 • Early diastole (after S2) • Older patients – CHFetes • Decleration of blood from LA to LV • S4 • Late diastole, before S1 • Reduced ventricular compliance or LVH First Aid – USMLE – Step 1Cardiac Cycle First Aid – USMLE – Step 1 Cardiac Cycle Central (Jugular) Venous Pressure Waveform • ‘a’ wave • Atrial contraction • ‘c’ wave • closed tricuspidntraction of RV, bulging • ‘x’ descent • phase, downwards displacement ofction closed tricuspid • ‘v’ wave • Venous return against closed tricuspid • ‘y’ descent • Open tricuspid, emptying in RA Key Questions in Cardiac SurgeryQ6 • Concerning the jugular venous pressure, which cardiac valve is most important in explaining its waveform? A. Aortic valve B. Pulmonary valve C. Tricuspid valve D. Mitral valveQ6 • Concerning the jugular venous pressure, which cardiac valve is most important in explaining its waveform? A. Aortic valve B. Pulmonary valve C. Tricuspid valve D. Mitral valve Cardiac Output • Cardiac Output = Stroke Volume x Heart Rate • Stroke Volume • SV = EDV– ESV, amount of blood expelled each cardiac cycle • Preload • Central venous pressure • ↑ CVP = ↑ SV (up to certain point) • ↑ CVP → ↑preload → ↑ diastolic filling pressure / stretching cardiomyocytes • (Starling’s Law)ntricular contraction → ↓ ESV • Afterload • Total peripheral resistance • arteries – dictates ease for expelling bloodgh First Aid – USMLE – Step 1 Cardiac Output • Starling’s Law • More heart chamber fills, stronger ventricular contraction (↑ SV) • ↑ CVP = ↑ SV • Heart chamber stretches/fills • More regions of overlap for actin-myosin cross-bridges • Greater force of contraction • Optimal muscle fibre length for most forceful contraction • Above this, fibres can’t overlap more, may become overstretched • Preload too high, optimal fibre length surpassed → ↓contractility ↓ SV First Aid – USMLE – Step 1 Cardiac Output • ANS Regulation of Stroke Volume • SNS & PNS act to ↑/↓ HR & contractility (inotropy) • SNS → β1 adrenoceptors → ↑ contractility (+ve inotropic effect) • PNS → M2 receptors → ↓ contractility (-ve inotropic effect) • ANS control regulated by medulla oblongata in brainstem • Sensory input from peripheral/central baro- & chemo- receptors • Carotid sinus, arch of aorta, carotid body First Aid – USMLE – Step 1 Cardiac Output • Heart Rate (CO = HRxSV) • HR established by SAN - ~60-100bpm • Nerve impulses & hormones influence rate of SAN • ANS Control • PNS – input via vagus nerve • Vagus synapses in SAN & AVN • ↓HR (-ve chronotropic effect)PM potential slope→ • SNS – input via superficial & deep cardiac plexuses • Innervates SAN & AVN • NA acts on β1 adrenceptors→ ↑ PM potential slope → ↑HR (+ve chronotropic/inotropic effect) • At rest, PNS input to SAN dominates First Aid – USMLE – Step 1 Cardiac Output • Baroreceptor Reflex • Mechanoreceptors • Carotid sinus & aortic arch • Sensitive to changes in stretch & tension • Communicates changes to medulla oblongata (brainstem) • Via CNIX & CNX • Medullary centres responsible for ANS output • ↑ arterial pressure • PNS activated → activates cardiac decelerator centre • Cardioinhibitory centres impulses via CNX ↓HR • ↓ arterial pressure • SNS activation, no PNS • Cardiac accelerator centre activated ↑ HR & contractility • Hormonal • Adrenaline from adrenal medulla → ↑ HR First Aid – USMLE – Step 1Q7 • What structure in the brainstem regulates autonomic nervous system control, which in turn controls influence on cardiac output? A. Midbrain B. Pons C. Medulla oblongataQ7 • What structure in the brainstem regulates autonomic nervous system control, which in turn controls influence on cardiac output? A. Midbrain B. Pons C. Medulla oblongataControl of Blood Pressure • Stable BP maintained through homeostasis • mmHg • Systolic pressure – pressure during contraction • Diastolic pressure – pressure at relaxation • Mean arterial BP = cardiac output x total peripheral resistance • Factors affecting BP • CO - ↑ CO, ↑ blood volume in vessels, ↑ vessels pressure • TPR - ↓ vessel diameter, ↑ resistance, ↑ BP • Blood viscosity • Vessel length Control of Blood Pressure • Short Term Regulation of BP • Controlled by ANS • BP changes – baroreceptors – aortic arch, carotid sinus • ↑ arterial pressure → PNS (vagus) → ↓BP • ↓ arterial pressure → SNS → ↑HR / contractility → ↑BP • Long-Term Regulation of BP • Renin-Angiotensin- Aldosterone System • Anti-Diuretic Hormone • Atrial Natriuretic Peptide • Prostaglandins TeachMe Physiology https://teachmephysiology.com Circulation – Blood Flow in Vessels • Flow • Volume of fluid passing given point per unit time • Flow = pressure / resistance • Velocity greatest in centre of vessel • Decreases closer to vessel wall (↑ resistance) • Pressure • Liquid flows down gradient – high (arterial) → low (venous) • Resistance • Force opposing blood flow • Poiseuille’s Law – resistance = (8 x viscosity x length) / (3.14 x TeachMe Physiology https://teachmephysiology.com radius ) • Radius - ↓ radius ↑ resistance • Flow = CSA x velocity, as vessel CSA ↓ avg velocity ↑ - capillary beds, collective large CSA, slow flow • Viscosity • Relatively consistent • Vessel Length • Length directly proportional to resistance - ↑ length ↑ resistance • Virchow’s Triad – stasis, hypercoagulability, vessel injury Circulation – Peripheral Circulation Flow • Circulation • arterioles → metarterioles → capillaries → tissueeries → • Total peripheral resistance • Arterioles – resistance vessels • Diameter <0.1mm, muscular layer, single layer of smooth muscle cells • CO = HR x SV = ~5L/min • Regulating arteriolar tone • Vasomotor tone of arterioles controls blood flow to capillary beds TeachMe Physiology https://teachmephysiology.com • At rest, high vasomotor tone • SNS → NA → ɑ1 GPCRs → vasoconstriction • Vasodilator metabolites • MCO2, K+, adenosine, lactate)release vasodilator metabolites (H+, • Reduce vasomotor tone → vasodilation → ↓ resistance → ↑ blood flow • Transports metabolites away limiting potential toxic effects First Aid – USMLE – Step 1Q8 • What variable in Poiseuille’s Law has the greatest impact on the resistance of a blood vessel? A. Radius B. Viscosity C. LengthQ8 • What variable in Poiseuille’s Law has the greatest impact on the resistance of a blood vessel? A. Radius B. Viscosity C. Length Circulation – Capillary Exchange • Capillary exchange between blood & tissue • Delivers nutrients, removes waste products • Fick’s Law • Rate of diffusion proportional to concentration difference & area available for diffusion • Rate of diffusion inversely proportional to diffusion distance • Many capillaries supply same tissue → ↑ diffusion area • Constant blood flow, maintains large concentration gradient • Capillaries in parallel ↓ resistance • Thin endothelium, small diameter → ↓ diffusion distance • Small lipid soluble molecules (O2/CO2) – freely diffuse • Molecule exchange via specialized channels/pores Circulation – Capillary Exchange • Starling Forces • Blood hydrostatic pressure • wallsure exerted by blood against capillary • Forces fluid out of capillary • Blood colloid osmotic (oncotic) pressure • Pressure exerted by proteins in blood (mostly albumin) • Attempts to pull fluid into blood • Proteins too large to diffuse into interstitium • Interstitial hydrostatic pressure • Pressure of fluid in interstitium • Forces fluid back into capillary First Aid – USMLE – Step 1 • Interstitial colloid osmotic (oncotic) pressure) • Pressure of proteins in interstitium • Pulls fluid out of capillaryCirculation – Venous Return • Blood flow back to heart – via veins • Low pressure, low resistance vessels • Venous pressure driving force for filling heart • Venous pressure affected by • Rate blood entering veins • Linked to peripheral resistance • ↑ resistance, ↓ rate blood entering veins, ↓ venous pressure • ↓ resistance, ↑ rate blood entering veins, ↑ venous pressure • Cardiac output • ↓ CO, blood backs up, ↑ venous blood volume, ↑ venous pressure • CVP is BP in vena cava near RA – normal ~2-6mmHg • High capacitance vessels, valve for unidirectional flow • Factors affecting venous return • Skeletal muscle pump, respiration, venous compliance, gravity, blood volume, COReferences / Resources • TeachMe Physiology https://teachmephysiology.com • Quesmed https://quesmed.com/ • Key Questions in Cardiac Surgery • First Aid – USMLE – Step 1Feedback Any Questions?