Cardiac Electrophysiology Notes

NOTES NOTES CARDIAC ELECTROPHYSIOLOGY ACTION POTENTIALS IN PACEMAKER CELLS osms.it/pacemaker-cell-action-potentials Pacemaker cells ▪ Groups of cardiac muscle cells with ability to spontaneously create action potential (automaticity) and comprise intrinsic conduction system ▪ Directly influenced by sympathetic and parasympathetic nervous systems ▪ Comprise about 1% of heart cells ▪ Differ in speed of spontaneous depolarization ▪ Cells with fastest rate of depolarization at any given time determine heart rhythm ▫ Remaining/slower cells called latent pacemakers Figure 17.1 Locations of pacemaker cells within the heart. SA node ▪ Primary pacemaker cells located in wall of right atrium ▪ Rate: 60–100bpm ▫ Usually determines normal heart rhythm Action potentials in pacemaker cells ▪ Rapid electrical changes across membrane of pacemaker cells ▪ Conducted to rest of heart Latent pacemaker cells ▪ AV node ▫ Located at base of right atrium, near septum ▫ Rate: 40–60bpm ▪ Bundle of His ▫ Divides into right and left bundle branches, travels through septum between ventricles ▫ Rate: 20–40bpm ▪ Purkinje fibers ▫ Spread throughout ventricles ▫ Rate: 20–40bpm Action potential phases ▪ Phase 4: sodium moves into cell through funny channels (open in response to hyperpolarization); slowly depolarizes cell until threshold potential met ▫ Responsible for instability of resting membrane potential ▪ Phase 0: strong inward calcium current; responsible for rapid depolarization ▪ Phase 3: strong potassium current moves out of cell; responsible for repolarization ▫ Phases 1, 2 absent in pacemaker cells → no plateau OSMOSIS.ORG 121

Figure 17.2 Graph depicting the action potential of a pacemaker cell. ACTION POTENTIALS IN MYOCYTES osms.it/myocyte-action-potentials Myocytes ▪ Receive signal from from pacemaker cells causing them to contract ▪ Able to depolarize, spread action potentials ▪ Action potential phases: ▫ Phase 0 (depolarization phase): rapid influx of sodium into cell (inward current); responsible for rapid depolarization ▫ Phase 1: sodium current stops, potassium slowly flows out of cell; depolarization stops, re-polarization starts ▫ Phase 2: calcium current moves into cell, balances potassium current moving out of cell; charge balance between inside, outside of cell creates plateau 122 OSMOSIS.ORG ▫ Phase 3: calcium current moving into cell stops; potassium current moving out of cell continues; repolarization continues ▫ Phase 4: potassium current moving out of cell approaches equilibrium between inside, outside of cell; sodium, calcium current moving into cell balance outward potassium current; resting membrane potential achieved

Chapter 17 Cardiovascular Physiology: Cardiac Electrophysiology ELECTRICAL CONDUCTION IN THE HEART osms.it/heart-electrical-conduction ▪ Transmission of electrical signals across heart cells leads to rhythmic myocardial contraction ▪ Intercalated discs connect cells and allow myocardium to act as syncytium ▫ Contain desmosomes (holds cells together) and gap junctions (areas of low resistance to electrical flow) ▪ Cardiac action potential: sequential flow of electrons across ion channels in cardiac cell membranes, resulting in electrical activation of myocardial cells ▫ Depolarization: cation movement into cell, producing positive cell charge relative to outside ▫ Polarization: anion movement into cell, producing negative cell charge relative to outside ▪ Pathway of electrical conduction ▫ Sinoatrial node (SA node) → atrial internodal fibers → atrioventricular node (AV node) → bundle of His → Purkinje fibers → ventricular myocytes ▫ These structures responsible for electrical conduction, spontaneous depolarization; do not generate contractile force Figure 17.3 Desmosomes and gap junctions present at intercalated discs allow the myocardium to act as a syncytium. CARDIAC CONDUCTION VELOCITY osms.it/cardiac-conduction-velocity ▪ Speed at which depolarization wave spreads among myocardial cells ▫ Measured in meters per second (m/s) ▪ Each myocardial structure has a different conduction speed related to its purpose ▫ Slowest: AV node ▫ Fastest: Purkinje fibers ▪ AV delay: slow conduction through AV node ensures adequate ventricular filling ▫ Speed: 0.01–0.05m/s ▫ Blood flows from atria to ventricles ▪ Rapid conduction through Purkinje fibers ensures adequate blood ejection ▫ Speed: 2–4m/s Velocity depends on two factors ▪ Amount of ions going into cell during action potential ▫ More ions → faster depolarization → faster spread ▫ Fewer ions → slower depolarization → slower spread OSMOSIS.ORG 123

▪ Interconnectedness of myocardial conduction cells ▫ More gap junctions → more interconnected cells → less resistance to ion flow between cells ▫ Fewer gap junctions → fewer interconnected cells → increased resistance to ion flow between cells Figure 17.4 Conduction speeds of different myocardial structures. EXCITABILITY & REFRACTORY PERIODS osms.it/excitability-refractory-periods Refractory period ▪ Time in which myocardial cell cannot be depolarized ▪ Absolute refractory period: no stimulus, no matter its size, can depolarize cell ▫ Phases 0, 1; part of phase 2 ▪ Effective refractory period: large stimulus can generate action potential ▫ However, too weak to be conducted ▪ Relative refractory period: large stimulus can generate action potential ▫ Big enough to be conducted 124 OSMOSIS.ORG Excitability ▪ Ability of myocardial cells to depolarize in response to incoming depolarizing current ▪ Supranormal period: < normal stimulus may produce action potential large enough to be conducted ▫ Resting membrane potential has not yet been achieved ▫ Membrane potential closer to threshold than normal, refractory periods over

Chapter 17 Cardiovascular Physiology: Cardiac Electrophysiology CARDIAC EXCITATIONCONTRACTION COUPLING osms.it/cardiac_excitation-contraction_coupling ▪ Plateau in action potential of myocyte membrane allows influx of calcium, stimulating muscle contraction ▫ Calcium enters cell via L-type voltage gated channels ▫ Higher intracellular Ca2+ triggers release of more Ca2+ from sarcoplasmic reticulum through ryanodine receptors (AKA calcium-induced release) ▫ Released Ca2+ attaches to troponin C → tropomyosin moves → actin-myosin cross bridges → contraction ▪ Cross bridges last as long as Ca2+ occupies troponin ▫ Tension is proportional to intracellular Ca2+ concentration ▪ Intracellular Ca2+ removed by two mechanisms that induce relaxation, keep Ca2+ from damaging cell contents ▫ Ca2+ ATPase uses ATP energy, Na+/ Ca2+ ATP exchanger uses Na+ inward current to remove Ca2+ from cell through sarcolemmal membrane, remove Na+ through Na+/K+ ATPase ▫ Ca2+ ATPase removes Ca2+ into sarcoplasmic reticulum; calsequestrin 2 inside sarcoplasmic reticulum binds Ca2+, keeping it inside Figure 17.5 Depolarization of a cardiomyocyte by calcium-induced calcium release. OSMOSIS.ORG 125

CARDIAC LENGTH TENSION osms.it/cardiac-length-tension ▪ Degree filament overlap correlates to tension ▫ Lmax = 2.2 µm is maximal tension ▫ In shorter/longer cells, tension will be decreased ▪ ↑ L → ↑ Ca2+ sensitivity of troponin C → ↑ Ca2+ release from sarcoplasmic reticulum ▪ Can extend to ventricle length/tension relationship curve ▫ Cardiac muscle < elastic than skeletal; only ascending curve demonstrates its contraction ▪ ↑ resting tension: small changes produce ↑ tension ▪ Frank–Starling basis; ↑ fiber length → stronger contraction ▫ Preload = LV end-diastolic volume (L), if ↑ means ventricular fiber length ↑ ▫ Afterload = aortic pressure; if preload ↑ → afterload tension and pressure ↑ CARDIAC CONTRACTILITY osms.it/cardiac-contractility ▪ Positive inotropes: ↑ force of myocardial contraction ▪ Negative inotropes: ↓ force of myocardial contraction ▪ Proportional to Ca2+ concentration ▫ Proportional to Ca2+ released ▫ Depends on storage, current size WHAT AFFECTS INOTROPISM? AUTONOMIC NERVOUS SYSTEM Sympathetic ▪ Positive inotropic effects: ↑ contractility ▪ Causes faster relaxation, faster refill, increased heart rate (HR) ▪ Increased tension development rate ▫ ϐ1 receptor is Gs coupled, activates adenylyl cyclase → cAMP produced ▫ pKA activated → phosphorylation → ↑ sarcolemmal Ca2+ channel activity → ↑ contraction ▫ Phospholamban phosphorylation; stops sarcoplasmic Ca2+ ATPase inhibition, decreasing time of IC Ca2+, making HR 126 OSMOSIS.ORG faster, systole shorter; Frank–Starling effective ▫ Na+/K+ ATPase phosphorylation; increases relaxation due to secondary channel activations ▫ Troponin I phosphorylation; Ca2+ binds less troponin C → effect on excitation contraction coupling, prolongs filling, higher ejection fraction Parasympathetic ▪ Negative inotropic effects: ↓ contractility on atria via muscarinic receptors ▪ Acidosis also has negative inotropic effect → ↓ contractility ▪ Gk (type of Gi), adenylyl cyclase couple, resulting in ▫ Decreased Ca2+ plateau current ▫ ACh increases IkACh ▫ → ↓ action potential duration → ↓ Ca2+ current → ↓ AP width ▪ Phosphodiesterase metabolises cAMP, inhibit phosphodiesterase, increase contractility IP3 stimulates Ca release in SR, increases force of contraction

Chapter 17 Cardiovascular Physiology: Cardiac Electrophysiology Heart rate (HR) ▪ HR increases contractility ▪ Diastole affected more than systole ▪ Ca can’t be removed as quickly as it accumulates → new equilibrium ▫ ↑ action potentials/time: increased total trigger Ca2+, increased inward current ▫ ↑ Ca2+ influx → ↑ stores; phospholamban phosphorylated, thus inhibited ▪ Positive staircase effect/Bowditch staircase/Treppe phenomenon ▫ On first, beat still no extra Ca2+ ▫ Afterward, Ca2+ accumulates until max Ca2+ storage achieved ▪ Postextrasystolic potentiation ▫ Same effect as positive staircase ▫ Extrasystole < powerful, but creates one more chance for calcium entry ▫ Because the voltage channels are open more, postextrasystolic beat has higher tension than extrasystolic WHAT AFFECTS INOTROPISM? DRUGS Cardiac glycosides ▪ Digoxin, digitoxin, ouabain; congestive heart failure treatment ▫ Inhibit Na+/K+ ATPase; + inotropic, ↑ intracellular Na+ changes Na/Ca → decreases exchange → intracellular calcium increases → increases tension ▫ Nifedipine also acts on Ca2+ by blocking ryanodine receptors Beta adrenergics ▪ Isoproterenol, norepinephrine, epinephrine, dopamine, dobutamine ▫ ↑ cAMP → ↑ contractility OSMOSIS.ORG 127