BMS 200 Cardiac Cell Physiology PDF

BMS 200 – Cellular Physiology of the Heart Learning Outcomes Contrast the roles of atrial cardiomyocytes, ventricular cardiomyocytes, Purkinje fibres, and automatic cells in the cardiac cycle Describe how sodium voltage-gated channels, “funny current” channels, calcium channels, and pot...

BMS 200 – Cellular Physiology of the Heart Learning Outcomes Contrast the roles of atrial cardiomyocytes, ventricular cardiomyocytes, Purkinje fibres, and automatic cells in the cardiac cycle Describe how sodium voltage-gated channels, “funny current” channels, calcium channels, and potassium channels contribute to the electrophysiologic and contractile activity of automatic and contractile cardiac cells Describe the electrophysiologic basis for automaticity in the heart and the importance of the cardiac syncytium and conduction system in coordinating cardiac chambers Compare the histologic features, process of excitation- contraction coupling, calcium physiology, and electrophysiological characteristics of cardiac myocytes, Purkinje fibres, automatic cells, and skeletal muscle fibres Relate contractility to calcium handling in the cardiac myocyte Learning Outcomes Describe the general energy metabolism of the cardiac myocyte Describe the anatomy and function of the following elements of the conduction system: Sinoatrial node and atrioventricular node and bundle Left and right bundle branches, anterior and posterior fascicles of the left bundle branches Relate the electrical events of the conduction system and cardiac myocytes to the following electrocardiographic waveforms: P-wave, P-R interval, QRS waveform, QRS interval, QT interval Question: A new compound is developed that decreases the activity of the SERCA in a cardiac myocyte. What do you think the impact will be on overall cardiac function? SERCA The SERCA (Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase) pump plays a crucial role in cardiac muscle function by -3 regulating calcium reuptake into the sarcoplasmic reticulum (SR) after a contraction.  Answer Decreased SERCA activity in cardiac myocytes would impair calcium reuptake, leading to prolonged - muscle - relaxation (diastolic dysfunction) reduced calcium release for contraction, causing weaker heartbeats (negative inotropy). - Over time, this could lead to heart failure due to decreased cardiac output and hypertrophy, as well as an increased risk of arrhythmias due - to calcium imbalance. - Review – skeletal myocyte excitation-contraction coupling 1. Ach released near motor endplate ! opening of nicotinic receptor ! initial depolarization - 2. Na+ VGC open ! depolarization of sarcolemma (AP) ! opening of Ca+2 VGC 3. **L-type Ca+2 VGC allows a little calcium into the cell, but MAIN action is opening of the ryanodine receptor in the SR ▪ T-tubules convey the AP deeper into the myocyte, and most calcium that enters the cytoplasm comes from the SR Review – skeletal myocyte excitation-contraction coupling 4. Increased cytosolic Ca+2 binds to troponin ! “opening” of myosin binding sites on actin 4. Tropomyosin is “moved out of the way” when troponin binds to calcium 5. Cross-bridge cycle and force generation 6. Calcium levels decrease when the action potential(s) stop 1. Due to pumping calcium into the ECF or into the SR 7. As calcium levels decease, tropomyosin again “covers” the myosin binding sites ! relaxation of the sarcomere -  Cross-Bridge Cycle Events 1. At rest, adenosine diphosphate (ADP) and inorganic phosphate are bound to the myosin head, which is in position to interact with actin. The interaction, however, is blocked allosterically by tropomyosin 2. Inhibition of actin–myosin interaction is removed by binding of calcium to troponin-C; the myosin head binds to actin. The release of ADP and phosphate 3. changes the conformation of the myosin head from 90° to 45°, A, actin; M, myosin; Pi, stretching the myosin S2 region inorganic phosphate ion; −, chemical bond. 4. Recoil of the S2 region creates the power stroke -D  Cross-Bridge Cycle Events 5. The still-attached cross-bridge is now in the rigor state. 6. Detachment is possible when a new adenosine triphosphate (ATP) molecule binds to the myosin head and is subsequently hydrolyzed. Energy from ATP hydrolysis resets the myosin head from a 45° conformation back to its original 90° conformation 7. thereby returning the myosin and actin positions to their original resting state. These cyclic reactions supply remains and activation via * can continue as long as the ATP A, actin; M, myosin; Pi, Ca2+ maintained. inorganic phosphate ion; −, chemical bond. Review – the sarcomere Note the thick and thin filament zones and the necessity of overlap ▪ Organized structure is responsible for the striated appearance of skeletal and cardiac muscle  Review – the sarcomere Key Points: Thick and Thin Filaments: min overlap between thick (myosin) and thin (actin) filaments for proper muscle contraction. This overlap enables the formation of cross-bridges between myosin and actin, which is crucial for generating muscle tension during contraction. Striated Appearance: The organized structure of overlapping filaments is responsible for the striated appearance of skeletal and cardiac muscle. This it means that under a microscope, you can see alternating light and dark bands. Sarcomere Anatomy: E 3 sarcomere structure between two Z-lines. Key regions include: A band: Contains the full length of thick (myosin) filaments, including areas where thin (actin) filaments overlap with thick filaments. I band: Contains only thin filaments (actin) and appears lighter under a microscope. H zone: Contains only thick filaments and is visible when the muscle is relaxed. M line: The center of the sarcomere, where thick filaments are anchored. Z line: The boundaries of each sarcomere where thin filaments are anchored.  Review – the sarcomere Key Points:. Diagram B: Thick and Thin Filament Overlap: This shows a cross-section of the sarcomere at different regions (I band, overlap, H zone). The thick and thin filaments are represented by the dots (green = thick actin filaments; red = thin myosin filaments). Diagram C: Sarcomere Shortening: This section illustrates how increased overlap of actin and myosin filaments leads to sarcomere shortening, which is the basis of muscle contraction. As the overlap increases, the muscle shortens and generates force. Review – factors that affect strength of contraction in skeletal muscle The first two contractions are examples of individual muscle twitches in response to 2 single action potentials; the second action potential occurs after complete muscle relaxation from the first action potential When the interval between successive activations shortens such that individual twitches do not relax completely between successive action potentials; peak muscle - tension increases but oscillates. - This is called partial tetanus. As the interval between successive stimuli decreases more, twitches fuse on top of one another resulting in a sustained generation of force many times greater 2 - - than a single twitch. This condition is called tetanus. Review – factors that affect strength of contraction in skeletal muscle Higher levels of cytosolic calcium increase engagement of myosin with actin ! increased force development ▪ Seen here as muscle twitches accumulate ! tetany ▪ APs are too frequent to allow clearance of calcium from the cytosol Better overlap of actin and myosin ! increased force development Review – factors that affect strength of contraction in skeletal muscle The force a muscle can produce depends on the amount of overlap between the thick and thin filaments because this determines how - - many cross-bridges can - interact effectively. Better overlap of actin and myosin ! increased force development Skeletal vs Cardiac Myocytes Similarities: So o Striated, involve actin: myosin overlap Parabolic isometric length: tension relationship Peak isometric forces matches optimum passive resting length T-tubules exist in both Ca2+ ATPase pumps to remove Ca2+ into SR Differences: No tetanic contraction in cardiac myocytes due to long electrical refractory period Syncytium: cardiac myocytes are interconnected via branches and intercalated disks (gap junctions and desmosomes) T tubules play a less important to the excitation- contraction coupling of cardiac cells; they are larger but fewer Cardiac cells have 1 single nucleus and LOTS of mitochondria A bit more detail Striated, Ac0n-Myosin Overlap Both skeletal and cardiac muscles are striated due to the arrangement of acQn and myosin filaments in sarcomeres. The interacQon between these filaments generates the force required for contracQon in both muscle types. In both, the overlap of acQn (thin filaments) and myosin (thick filaments) leads to cross-bridge cycling during contracQon. Parabolic Isometric Length-Tension Rela0onship Both cardiac and skeletal muscles exhibit a parabolic length-tension relaQonship, meaning the force generated by the muscle depends on its length. There is an opQmal muscle length (sarcomere length) where the overlap between acQn and myosin filaments is ideal, generaQng the greatest force. If the muscle is too stretched or too compressed, the force producQon decreases. -  A bit more detail Peak Isometric Forces at Op0mum Passive Res0ng Length In both muscle types, the peak isometric force occurs when the muscle is at its opQmum passive resQng length, meaning the sarcomeres are at an opQmal length for generaQng - maximum force during contracQon. This is the point where acQn-myosin overlap is ideal. T-tubules in Both Both cardiac and skeletal muscles have T-tubules (transverse tubules), which are invaginaQons of the sarcolemma (muscle cell membrane). They help propagate acQon potenQals deep into the muscle fibers, ensuring that the excitaQon reaches the myofilaments in the interior of the muscle cell for synchronized contracQon. Ca²⁺ ATPase Pumps in SR Both cardiac and skeletal muscle fibers have Ca²⁺ ATPase pumps (SERCA) in their sarcoplasmic reQculum (SR). These pumps acQvely transport calcium back into the SR aZer a contracQon, reducing - intracellular calcium levels and allowing muscle relaxaQon. -- Proper regulaQon of calcium is criQcal for the contracQon-relaxaQon cycle.  Differences: A bit more detail No Tetanic Contraction in Cardiac Myocytes Cardiac muscle cells cannot undergo tetanic contraction (sustained contraction) because they have a long electrical refractory period. This long refractory period prevents another action potential from being initiated immediately after the first, ensuring that cardiac muscle relaxes fully between beats and avoids dangerous sustained contraction, which is crucial for proper heart function. Syncytium in Cardiac Myocytes C Cardiac muscle cells function as a syncytium, meaning the cells are interconnected through branches and intercalated disks. The intercalated disks contain gap junctions (allowing ions to flow directly between cells) and - desmosomes (providing structural support), which enable coordinated contraction across the - entire heart, making it function as a unified organ. This is unlike skeletal muscle, where each fiber contracts independently.  Differences: A bit more detail T-Tubules Play a Less Central Role in Cardiac Muscle While T-tubules exist in both cardiac and skeletal muscle, they play a less critical role in cardiac muscle’s excitation-contraction coupling. In cardiac myocytes, the T-tubules are larger but fewer in number. Cardiac cells rely more on extracellular calcium influx (through L-type calcium channels) than skeletal muscle, where the T-tubule system is more integral for calcium release from the SR. Cardiac Cells Have One Nucleus and Many Mitochondria Cardiac myocytes typically contain a single nucleus, whereas skeletal muscle fibers are multinucleated. Additionally, cardiac cells have a much higher density of mitochondria to meet the energy demands of continuous, rhythmic contraction. This is essential for sustaining the heart's workload, as it requires a constant and high supply of ATP for its ongoing activity, especially in comparison to skeletal muscle. Cardiomyocyte histology - review One nucleus/fibre, every contractile cell full of mitochondria Branched structure with adjacent cardiomyocytes connected to each other via gap junctions ▪ Gap junctions cross the intercalated disks ▪ Syncytium = all cells are ultimately electrically connected Triad has a somewhat different structure than in skeletal myocytes ▪ Instead of SR cisterns extending “circumferentially” (skeletal myocyte) around the cell they extend radially from the T-tubule The cardiomyocyte – electrical events Four major types of APs in the heart Myocyte APs: ▪ Atrial ▪ Ventricular Purkinje cell APs ▪ Almost the same as ventricular, but “unstable” phase 4 kind of like an automatic cell Automatic cell APs Four major types of APs in the heart Take a minute and note the differences in all four phases between cell types ▪ Phase 4 – resting membrane potential (RMP) ▪ Phase 0 – the rapid depolarization phase (upstroke) ▪ Phase 1 & 2 – prolonged depolarization/plateau phase ▪ Phase 3 - repolarization Four major types of APs in the heart Summary of Key Differences: Atrial and Ventricular APs: Both have distinct phases of depolarization, plateau, and repolarization, but atrial APs are shorter, allowing for faster contraction cycles. Purkinje Cell APs: Similar to ventricular APs but with a slightly unstable phase 4, giving them the ability to spontaneously generate action potentials in abnormal conditions. Automatic Cell APs: Pacemaker cells (SA and AV nodes) have unstable phase 4 and depolarize spontaneously due to the funny current (If), setting the heart rate through automatic, rhythmic action potentials. Important Notes The action potential events seen here are electrical events of the 2. sarcolemma (cell membrane) ▪ Flow of ions across the cell membrane through channels down their electrochemical gradient ▪ Gradients mostly established by pumps Although they bring about contraction and force development indirectly, they are not measures of contraction *D ▪ Electrical events, not force generation Action Potential Arrives at Cardiac Myocyte What happens when an action potential arrives next to the cardiac myocyte? Phase 4: resting membrane potential (leaky K+ channels are open) Phase 0: rapid depolarization achieved by the opening of voltage-gated sodium channels (VGC Na+); Na+ influx Phase 1: initial rapid repolarization due to the closure of Na+ VGC as well as opening of fast K+ VGC allowing K+ efflux Phase 2: plateau due to the opening of L-type Ca2+ channels that allow Ca2+ to influx for quite some time No summation is possible due to the prolonged depolarization of the myocyte, no further action potential can be delivered to the cardiac myocyte Phase 3: slow repolarization due to the closure of Ca2+ channels and opening of slow K+ VGCs Myocyte Action Potentials - Overview Phase 4 – RMP ▪ Potassium leak channels are open (iK1) ▪ no other channels ▪ Potassium flow is at equilibrium, as per its Phase 4 Nernst potential (-84 mV) Phase 0 – rapid depolarization Phase 0 ▪ Cell quickly reaches threshold and all sodium VGC open  N close /fast open + L-type CattVGC Myocyte Action - Slow KI outward Potentials - Overview CLOSE Ope Phase 1 – transient repolarization Sallc in ▪ After sodium VGC close, a ↳o s set of potassium channels open briefly (fast transient Phase 1 outward potassium current) ▪ Brings the membrane potential closer to zero Phase 2 Phase 2 – plateau phase ▪ Two major voltage-gated currents: L-type calcium VGC A group of “slow” outward K+ currents Myocyte Action Potentials - Overview Why does the membrane potential “plateau” at Phase 2? ▪ There is a significant inward current generated by the movement of calcium into the cell Phase 1 (through the L-type Ca+2 VGC) ▪ There is a significant Phase 2 outward current generated by the movement of K+ out of the cell (a bunch of channels, all voltage-or time-gated) O ▪ They “balance each other out” Myocyte Action Potentials - Overview Phase 3 – repolarization ▪ By the time the L-type Ca+2 channel closes, significant calcium has accumulated in the cell ▪ Since there is no more calcium entering the cell Phase 3 but the potassium channels remain open until the cell is repolarized, the cell approaches resting membrane potential ▪ Increased intracellular calcium increases the opening probability of some K+ channels Myocyte Action Potentials - Overview Back to phase 4 ▪ With time and repolarization, the slow VG K+ channels close Phase 4 and the potassium leak channel is the only one that remains open Text flow chart of the events associated with the ventricular action potential Formal name for the K+ leak 33 channel is the K+ inward rectifying channel The names of other channels are found in the notes under the previous slides  What’s the point of this complicated myocyte action potential? We depend on extracellular calcium to trigger intracellular calcium release in the myocyte ▪ Every single “twitch” in the cardiac muscle cell has to be long enough to get enough calcium into the cell to trigger a useful (force-wise) contraction ▪ Long-lasting calcium increases mandate longer calcium influx and longer action potentials in the heart We can’t have tetany in the cardiac myocyte ▪ Would be very difficult to “guarantee” that the myocytes relax (and then there’s no filling) ▪ The long action potential gives the cell time to start clearing calcium out of the cytosol prior to the next action potential Excitation-Contraction Coupling & Calcium Handling in the Myocyte Examine the diagram on the next slide ▪ What are the mechanisms that increase cytosolic calcium? ▪ What are the mechanisms that decrease cytosolic calcium? ▪ What is the impact of sympathetic nervous system stimulation? Excitation- Contraction Coupling & Calcium Handling in the Myocyte  Excitation-Contraction Coupling & Calcium Handling in the Myocyte When a single calcium VGC opens, it elicits a small amount of calcium release from the neighbouring ryanodine receptor on the SR ▪ Known as a calcium - spark ▪ The increase in cytosolic calcium in a myocyte is mostly due to the summation of all of the sparks, with some contribution from ECF calcium entry  Excitation-Contraction Coupling & Calcium Handling in the Myocyte Calcium is sequestered by: SERCA – smooth endoplasmic reticulum calcium ATP-ase ▪ Pumps calcium into the SR, regulated by a mediator known as phospholamban ▪ Phosphorylation of phospholamban ! ↑ increased SERCA activity  Excitation-Contraction Coupling & Calcium Handling in the Myocyte Calcium is sequestered by: Sarcolemmal calcium ATP- ase Sodium-calcium exchanger ▪ Brings in 3 sodium and extrudes one calcium ▪ Impact on membrane potential? ↳ depolarization  Excitation-Contraction Coupling & Calcium Handling in the Myocyte Activation of the sympathetic nervous system (beta-1 receptors) ! increased cAMP: Phosphorylation of phospholamban Phosphorylation of troponin ▪ Decreased calcium affinity - Phosphorylation of the L-type calcium VGC ▪ Increased entry of calcium ▪ “fills” the SR more and increases the amount of calcium released with each spark  A Summary Calcium Influx: Action potentials trigger the opening of L-type 1,4 dihydropyridine (DHP) Ca²⁺ channels, allowing Ca²⁺ to enter the cell from the extracellular space. Calcium-Induced Calcium Release (CICR): The influx of calcium through these channels stimulates calcium release from the sarcoplasmic reticulum (SR) through calcium release channels, causing a "calcium spark." This amplification of calcium levels initiates muscle contraction. -- Modulation of Contractility: Calcium influx through DHP channels is modulated by G protein-coupled receptor mechanisms (via stimulatory G proteins, Gs, and inhibitory G proteins, Gi). These pathways allow for control over the inotropic state (force of contraction) of the cardiac cell.  A Summary cAMP and β-adrenergic Receptors: The β-adrenergic pathway, via cyclic AMP (cAMP), enhances contractility and also speeds relaxation of the cell by promoting faster calcium reuptake into the SR. Calcium Removal: After contraction, calcium is returned to low levels between action potentials by: Calcium pumps (ATPases) in the SR (SERCA pump) and plasma membrane (PMCA). Secondary active transport mechanisms, such as the sodium-calcium exchanger (NCX) in the plasma membrane. This system ensures proper calcium cycling, allowing cardiac muscle cells to contract and relax efficiently in response to electrical signals. Impact of SNS activation on the myocyte Increased cytosolic calcium release with each action potential ▪ Engages more myosin heads ! greater force of contraction Increased rate of relaxation after the action potential has ended ▪ Reduced troponin affinity ! “faster” release of calcium when calcium starts to drop ! faster relaxation ▪ Increased activity of the SERCA ! increased clearance of calcium into the SR Net result – more forceful, “quick” contractions and a quicker transition to relaxation ▪ What happens in the heart during the phase of myocyte relaxation? Diastole - filling up with blood Force of contraction The force that a cardiomyocyte generates with each systole depends on two things: ▪ Amount of calcium available to bind to troponin – this is known as inotropy Factors that increase inotropy: - 3 ▪ Increased sympathetic nervous system 3 stimulation · ▪ Increased heart rate (“loads” more calcium in the SR during relaxation) ▪ Things that increase SNS effectiveness – thyroid hormone, cortisol, etc. ▪ Optimal overlap between actin and myosin during diastole (see next slide) This is mostly determined by the state of ventricular filling – also known as preload Preload and force of contraction What is the optimal myocyte length? What happens when the ventricle is: ▪ Not full enough? ▪ Just right? ▪ Too full?  Preload and force of contraction Curves on the Graph: Resting Force (Diastolic): The lower black curve shows the resting force (diastolic tension) generated when the heart muscle is stretched before contraction (passive tension). As the muscle length increases, the resting force also increases but remains relatively low at shorter muscle lengths. This is due to the passive resistance of the muscle to stretch before any active contraction occurs. Active Force (Systolic): The red curve represents the active force (systolic tension), which is the force generated during muscle contraction. This force increases with muscle length, reaching an optimum length (the peak of the curve). Beyond this length, active force starts to decline, as sarcomeres are overstretched, reducing the overlap between actin and myosin filaments, which is necessary for cross-bridge formation during contraction. Total Force: The upper black curve represents the total force, which is the sum of both active (systolic) and passive (diastolic) forces. At longer muscle lengths, the total force continues to rise due to the increasing passive resistance, even as active force declines. This reflects the combination of the resting tension from the passive stretch and the active contraction force.  Atrial vs. ventricular myocyte action potentials The atria do not need to generate as much force as the ventricles ▪ Systole and [3 the action potential overall are shorter ▪ Local differences in ion channel expression Atrial vs Ventricular Myocyte Action Potential There are some difference in the ion channels of the atria and ventricles that result in changes in action potential: Resting membrane potential (phase 4) of atria is slightly more depolarized than of ventricles due to reduce - potassium - Lower plateau (phase 2) of atrial action potential due to - lack of Ca2+ channels -  Automatic Cell Action Potentials - Overview Automated cell action potentials refer to the electrical activity in specialized heart cells, such as those in the sinoatrial (SA) node, atrioventricular (AV) node, and Purkinje fibers, which generate action potentials spontaneously. These cells have the ability to depolarize automatically without external stimuli, allowing them to act as the heart's natural pacemakers, maintaining a rhythmic heartbeat.  Automatic Cell Action Potentials - Overview As the name suggests, automatic cells are… automatic ▪ They depolarize spontaneously ▪ The heart does not depend on the nervous system to initiate contraction Many populations of cells have the ability to act as pacemakers in health Almost every cell can act as a pacemaker during severe cardiac disease (not a good idea) The heart rate is governed by whatever automatic cells depolarize most frequently ▪ The action potentials then travel through the syncytium to all cardiomyocytes  Automatic Cell Action Potentials Phase 4 – the “resting” membrane potential ▪ Phase 4 is not stable, like it is in cardiomyocytes ▪ There is a weird channel that conducts sodium and a bit of potassium, and it is 203 open during hyperpolarization and closes during depolarization ▪ Known as the funny current (mostly accounted for by gNa+i and a bit of the gK+ ▪ Potassium conductance also decreases near the end of phase 4 The net result is that in between action potentials, automatic cells spontaneously depolarize because they “leak” positive charge into the cell  Automatic Cell Action Potentials Phase 0 – depolarization ▪ Note how positive the RMP is – at this potential sodium VGC would be closed and “locked” ▪ The depolarization phase is due to reaching the threshold for L-type calcium channels (around -45 mV) and calcium influx ▪ These channels close eventually after enough time has passed  Automatic Cell Action Potentials Phase 3 – repolarization ▪ As the calcium VGC close, potassium channels open ! potassium effux ! more negative membrane potential  Automatic Cell Action Potentials What are those dashed lines for? ▪ Red dashed line – sympathetic nervous system stimulation ▪ Blue dashed line – parasympathetic nervous system stimulation How does activation of the parasympathetic NS change the characteristics of the automatic action potential? ▪ 3 major ways  Automatic Cell Action Potentials Parasympathetic control effects: Increased K⁺ Conductance leads to hyperpolarization and a slower rate of depolarization. Decreased Ca²⁺ Influx slows down depolarization during phase 0. Increased Atrial Refractory Period extends the time between action potentials, further decreasing heart rate. These combined effects lead to * 3 a slower heart rate reduced cardiac output during parasympathetic activation  Automatic Cell Action Potentials The rate of depolarization of automatic cells is known as chronotropy ▪ Positive inotropy – SNS increases the rate of depolarization and renders the RMP somewhat more positive ▪ Negative inotropy – PNS decreases rate of spontaneous depolarization, increases the threshold for calcium VGC, and makes the RMP somewhat more negative  Key Features of Automatic Cells: Unstable resting membrane potential: Unlike non-pacemaker cells, pacemaker cells do not have a stable resting membrane potential. Instead, their membrane potential gradually depolarizes during phase 4, leading to spontaneous action potentials. No plateau phase: The typical plateau (phase 2), seen in atrial and ventricular myocytes due to Ca²⁺ and K⁺ balance, is absent in automatic cells. Calcium-based depolarization: Phase 0 is dominated by Ca²⁺ influx, as opposed to the Na⁺ influx seen in atrial and ventricular myocytes, making the depolarization slower.  Key Features of Automatic Cells: Examples of Automatic Cells: Sinoatrial (SA) Node: The primary pacemaker of the heart. The SA node sets the rhythm by spontaneously generating action potentials, which spread through the atria, causing them to contract. Atrioventricular (AV) Node: Located between the atria and ventricles, the AV node can also generate action potentials * but at a slower rate. It serves as a backup pacemaker and helps coordinate the contraction between the atria and ventricles. Purkinje Fibers: While Purkinje fibers are mainly responsible for rapid conduction of action potentials through the ventricles, they can also act as pacemaker cells under certain conditions if the SA and AV nodes fail.  Key Features of Automatic Cells: Summary of Phases: Phase 4: Gradual depolarization due to funny Na⁺ current (I_f) and T-type Ca²⁺ influx. Phase 0: Rapid depolarization caused by L-type Ca²⁺ influx. Phase 3: Repolarization due to K⁺ efflux. Phase 1 and 2 are absent. Pacemakers and Automaticity 3 Pacemaker – highly specialized cell with an intrinsic ability to depolarize rhythmically and initiate an action potential Generate the rhythm for the entire heart SA node: 60-100 bpm – the fastest pacemakers take the lead! AV node: 40-60 bpm Purkinje fibers: 20-40 bpm If SA node fails (AP is not conducted to the AV node), the AV node can generate its own rhythm and so on For example, in complete heart block – the impulses can’t be conducted from atria to the ventricle and the Purkinje fibers provide the action potential necessary to generate muscle contraction  Locations of Automatic Cells Sinoatrial node and atrioventricular node cells have classic automatic action potentials ▪ The sinoatrial node has the quickest rate of depolarization – therefore it is the usual pacemaker Purkinje fibres have a very slowly “automatically depolarizing” phase 4 ▪ They only act as pacemakers in pathologic states ▪ Otherwise, Purkinje fibres have identical action potentials to myocytes  The Conduction System Network of automatic cells and bundles of Purkinje fibres that carry APs to the ventricular and atrial myocytes SA node – usual pacemaker ▪ When it depolarizes, AP spreads to AV node and across both atria AV node – a set of automatic cells that allow the AP to enter the AV bundle, but delay conduction ▪ Automatic and Purkinje fibres here have fewer gap junctions ! higher resistance  The Conduction System Importance of the “delay” at the AV node ▪ Gives the atria time to eject blood into the ventricle prior to ventricular contraction ▪ As heart rate increases, the conduction through the AV node slows a little more (better filling) The Bundles of His (AV bundles) carry the AP along the septum (first part of the ventricle to depolarize) Purkinje fibres then carry the AP to the apex and then towards the base of the heart  The Conduction Pathway Summary 1. Impulse Generation: The SA node generates an action potential. 2. Atrial Contraction: The impulse spreads through the atrial muscle, causing atrial contraction. 3. AV Node Delay: The impulse reaches the AV node, where it is delayed, allowing the ventricles to fill. 4. Bundle of His: The impulse travels down the Bundle of His into the right and left bundle branches. 5. Purkinje Fibers: Finally, the impulse spreads through the Purkinje fibers, causing simultaneous contraction of the ventricles.  Conduction System of the Heart – No Muscle The fibrous skeleton prevents direct conduction from atria to ventricles, isolating them and ensuring that the only electrical communication occurs through the AV node. The AV node and Bundle of His serve as critical junctions for electrical signals 93 Left bundle branch further divided into anterior and posterior fascicles Right bundle branch has a single fascicle. Bachmann's Bundle allows for rapid conduction from the right atrium to the left atrium, facilitating simultaneous atrial contraction. https://en.wikipedia.org/wiki/Bachmann%27s_bundle#/media/File:ConductionsystemoftheheartwithouttheHeart-en.svg ECGs – an Introduction ECGs are essential for initial evaluation of the heart 93 ▪ Arrhythmias ▪ Estimation of abnormal cardiac size ▪ Electrolyte abnormalities ▪ Cardiac ischemia ▪ Sometimes useful findings in: Pericarditis Pulmonary emboli ECGs only evaluate electrical events in large numbers of cells – they can only “see” electrical events in myocytes ▪ They also record the changes in extracellular potential (not intracellular), so the waveforms are actually the inverse of what is happening in the myocyte A standard 12-lead ECG As with all complicated things, it’s always best to have an approach  ECG generalities ECGs measure electrical differences across the heart ▪ If the whole heart is depolarized, the ECG tracing is at baseline ▪ If the whole heart is repolarized, the ECG tracing is at baseline When there is a difference in electrical state in 2 separate areas of the heart, there is a “wave” *  ECG generalities The “height” of a wave corresponds to how large the electrical potential difference is across two separate parts of the heart “Size of difference” corresponds to the length of the vector in this picture Placement of ECG leads - overview ECG leads are placed to give a “3-D” view of the electrical activity of the heart Coronal view (left and right arms, left leg) Cross-sectional view (precordial leads)  What does the ECG measure? Electrical potential changes across the heart over time Time – x-axis, in seconds Electrical potential changes – voltage in mV, y-axis “little box” – 0.1 mV high, and 0.04 seconds wide Each “big box” is 0.5 mV by 0.2 seconds What is a wave vs. an interval? A “wave” is a deflection from baseline in across the heart voltage ▪ Examples of waves: P waves QRS waves T waves An “interval” is a “space” between and often including waves ▪ Examples of intervals: P-R interval QRS interval QT interval ECG - timing How do the ECG waves and intervals correspond to the excitation along the conduction pathway?  P-QRS-T 1 horizontal mm = 40ms 1 vertical mm = 0.1mV P wave – atrial depolarization Timing: This occurs during the first part of the cardiac cycle, and the P wave typically lasts about 0.08 to 0.12 seconds. PR Interval: - The time taken for the impulse to travel from the SA node through the atria and AV node to the ventricles. The AV node provides a crucial delay to ensure the ventricles fill completely before they contract. Timing: Normal duration is 0.12 to 0.20 seconds. QRS complex – ventricular depolarization Timing: The QRS complex lasts about 0.06 to 0.10 seconds.  P-QRS-T ST Segment - The period when the ventricles are fully depolarized and before they repolarize. T wave – ventricular repolarization Timing: The T wave typically lasts about 0.10 to 0.25 seconds. PR interval – time it takes for action potential to travel from SA node to the AV node Normally 0.12-0.20 seconds QRS interval – time it takes for action potential to travel from the end of the AV node and throughout the ventricles QT interval – includes combined ventricle depolarization and repolarization  Summary of Correspondence: P Wave: Atrial depolarization initiated by the SA node. PR Interval: Delay at the AV node allowing for ventricular filling. QRS Complex: Rapid depolarization of the ventricles via the conduction pathway (Bundle of His and Purkinje fibers). ST Segment: Ventricles in a depolarized state before repolarization. T Wave: Ventricular repolarization returning the heart to its resting state. QT Interval: Total time for ventricular depolarization and repolarization.  How does an ECG tracing correspond to: ▪ The atrial action potential ▪ The ventricular action potential? Atrial Action Potential: P Wave: Corresponds to the rapid depolarization (Phase 0) of the atria. PR Interval: Reflects the duration of atrial depolarization and conduction through the AV node. Ventricular Action Potential: QRS Complex: Corresponds to the rapid depolarization (Phase 0) of the ventricles. T Wave: Corresponds to the repolarization (Phase 3) of the ventricles. QT Interval: Represents the total time for ventricular depolarization and repolarization. Cardiac Metabolism – In Brief Cardiac myocytes have a lot of mitochondria ▪ Depend on oxidative metabolism – preferential use of fats ▪ Very little glycogen storage – use of circulating FFAs ▪ Energy efficient, high-energy ATP source ▪ Anaerobic metabolism provides very little ATP – therefore myocytes require constant blood flow (“stunning” and death within minutes) The Purkinje fibres and automatic cells have a lower oxygen requirement (no sarcomeres) Introduction to Pathological Terms Heart failure Contractility is significantly impaired resulting in reduced ejection fraction (how much is pumped out versus how much remains in the ventricle) Cardiac arrest Heart suddenly and unexpectedly stops pumping, often caused by ventricular arrhythmia’s, such as ventricular fibrillation or ventricular tachycardia Angina Pain brought on by ischemia, that doesn’t result in permanent heart damage Tachyarrhythmia Abnormal heart rhythm (arrhythmia) with a heartbeat of >100 beats per minute (tachycardia)