BMS Test 2 (Week 5 Notes) - Cardiac Physiology - PDF

[BMS Test 2 ] **[WEEK 5]** **Sept 30 -- Physiology of the Cardiac Cycle** Which ventricle pumps more blood / minute? The right or the left ventricle? Factors to consider: - The pressures that both ventricles develop - The thickness of the walls - Their vascular connections **Force of c...

[BMS Test 2 ] **[WEEK 5]** **Sept 30 -- Physiology of the Cardiac Cycle** Which ventricle pumps more blood / minute? The right or the left ventricle? Factors to consider: - The pressures that both ventricles develop - The thickness of the walls - Their vascular connections **Force of contraction** - Force that a cardiomyocyte generates with each systole depends on 2 things: 1\) Amount of calcium available to bind to troponin -- this is known as **[inotropy]** \- Factors that increase inotropy: \- increased sympathetic nervous system stimulation \- increased heart rate ("loads" more calcium in the SR during relaxation) \- things that increase SNS effectiveness -- thyroid hormone, cortisol, etc. \- optimal overall b/t actin + myosin during diastole \- this is mostly determined by the state of ventricular filling -- also known as **[preload]** **Factors that affect strength of contraction in skeletal muscle** - **Positive inotropic agents**, like certain hormones (e.g., epinephrine) and drugs (e.g., digitalis), can increase the force of contraction, leading to increased sarcomere shortening. - **Negative inotropic agents**, on the other hand, reduce the force of contraction, which can be associated with reduced sarcomere shortening. The effects of changes in inotropic state on the isometric length--tension relationship in cardiac muscle and its effect on isotonic contractions in the heart. Isometric length--tension relationship also represents the limit of how far muscle can shorten during an isotonic contraction against an afterload. Therefore, at any given combination of preload and afterload, a positive inotropic stimulus allows cardiac muscle to shorten farther, whereas a negative inotropic influence will reduce the extent of shortening. - Better overlap of actin and myosin increased force development A diagram of a graph Description automatically generated - In the top diagram, the bottom black line represents the preload (prior to contraction) - the red line directly above it represents the force that is generated during systole at that preload Effect of filament overlap on force generation. 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. **Review: ECG -- timing** How do the ECG waves and intervals correspond to the conduction pathway? A graph with lines and symbols Description automatically generated **The Wiggers Diagram** - Commonly includes: - Pressures in the left ventricle, aorta, and left atrium - ECG - Left ventricular volume - Phonocardiogram   - Examine the atrial pressure tracing (bottom dashed line) - What causes the following phenomena in the left atrium? - a, c, v waves - x and y descent **Atrial Pressure Tracing** A diagram of heart and ventricular sinuses Description automatically generated **Ventricular pressure and volume curves:** Important terms - isovolumetric = change in pressure but no change in volume - are valves open or closed? - systole = when the chamber applies pressure work - diastole = when the chamber no longer applies pressure work to blood through contraction - the Wiggers diagram is a good way to illustrate that the ventricle CANNOT: - eject blood into the great artery until its pressure is \> than that in the artery - accept blood from the atria unless its pressure is \< than that in the atria - valves ensure that blood only flows one direction despite the large changes in ventricular pressure - note the rapid & slower phases of ventricular filling, & the final "bump" in volume as the atria contract - rapid ventricular filling is due to the rapid expansion of the ventricle + the drop in volume that ensues - AKA passive filling, and it is responsible for 80% of ventricular filling at rest - Passive filling takes time decreased with increased heart rates **Aortic pressure curve** - Aortic pressure oscillates b/t systolic + diastolic pressure - After the aortic valve closes, a secondary wave can be seen - The division b/t these 2 waves = the dicrotic notch - The dicrotic notch = likely the most accurate marker of aortic valve closure - The secondary wave is thought to be formed by the elastic recoil of the aorta against a closed aortic valve - Likely also partially impacted by complex vibrations due to the "weird" shape of the aorta **Phonocardiogram** - S3 often found in healthy young adults and children - New emergence is usually pathological in adults (often indicator of myocardial ischemia) - Blood enters a non-compliant or "not-fully-relaxed" ventricle during rapid filling - "Kentucky" (ee is S3) - S4 usually pathologic - Ventricle "straining" as the atria contract and "force" blood into a non-compliant ventricle - "Tennessee" (Tenn is S4) **How about events in the right side of the heart?** - Almost identical Wiggers diagrams - Note the lower pressures that develop in the R ventricle and pulmonary arteries - Pulmonary artery pressure is \~25/7 mmHg - Slightly lower atrial pressures in the right vs. left A diagram of heart and heart valves Description automatically generated with medium confidence **Summary of normal pressures within the cardiac chambers and great vessels** - Higher of the two pressure values in the right ventricle (*RV*) and left ventricle (*LV*) represent the normal peak pressures during ejection - Lower pressure values in ventricles represent normal end-diastolic pressures - Pressures in the right atrium (*RA*) and left atrium (*LA*) represent values at the end of ventricular filling - Just as atrial contraction is ending - Arterial pressures are systolic on diastolic  **Cardiac calculations and parameters** - **End diastolic volume** (EDV) -- the volume in the ventricle at the end of diastole - **End systolic volume** (ESV) -- the volume in the ventricle at the end of systole - Look at the Wiggers diagram -- what is the approximate volume of each? - **Stroke volume** -- the volume ejected with each heartbeat - SV = EDV -- ESV - **Cardiac output** is the volume ejected by each systole X heart rate - CO = SV X HR - **Ejection fraction** is the proportion of EDV that is ejected each beat - EF = SV/EDV = (EDV -- ESV)/EDV - EDV corresponds to preload - Optimal preload greater force of contraction due to optimal overlap of actin and myosin in sarcomeres - Stroke volume is impacted by **[three major parameters]**: - **[Preload]** - **[Contractility]** (same as inotropy) -- dependent on calcium handling within the cardiomyocyte -- *intrinsic* ability - **[Afterload]** - The pressure that the heart must overcome to eject blood into the great arteries. - Factors that increase afterload -- aortic stenosis, elevated blood pressure - Cardiac output is one of the major factors that determines delivery of oxygen and nutrients to tissues - Other major factor vascular tone in the tissue receiving blood - Ejection fraction is often measured as an "estimate" of heart function in heart failure - More in heart failure lecture **The Pressure-Volume loop of the ventricle** Diagram of a pressure curve Description automatically generated with medium confidence How do you read this thing? 1\. Start from point A -- this is where the ventricle is at its lowest volume and is just starting to be filled 2\. As it fills (in a relaxed state) the pressure increases somewhat towards point B - Even though it is not contracting, the hydrostatic pressure of the blood within it exerts force against the wall 3\. From B C, the ventricle contracts, but no change in volume - What do we call that? 4\. From C D, the ventricle ejects blood...and its volume falls 5\. From D A, the ventricle relaxes, but does not yet fill - What do we call that? - ***Make sure you read it counterclockwise*** - If you go the other direction, you will get confused - Stroke volume is the distance between line AD and CB - Preload is point B (also known as EDV) - The inotropy (contractility) is represented by the tangent line at close to point D - This is known as the ESPVR -- the end-systolic pressure-volume relationship - The more vertical it is, the higher the inotropic state - Afterload is represented by the purple line - The more vertical it is, the higher the afterload - The total area within the curve is the cardiac workload A word about workload: - Hearts that "work too hard for too long" endure histologic & molecular changes that will be discussed in our heart failure lecture - Changes save energy, but often compromise force of contraction - The majority of work done by the ventricle is pressure-volume work - Indicated by the area within the P-V loop - The minority of cardiac work is due to actually ejecting blood from the ventricle into the artery (kinetic energy) **The Pressure-Volume Loop** A diagram of a pressure curve Description automatically generated **Pressure-Volume loop -- increased afterload** - Note the higher pressures that accompany increases in afterload - Increasing afterload **[decreases]** stroke volume and ejection fraction - Increasing the afterload in the heart tends to increase the myocardial oxygen demand more than increasing inotropy or overall force of contraction... - Hypertension is energetically expensive  A word about afterload... - Afterload is technically determined NOT by the systolic blood pressure, but by the **[tension]** that the ventricle needs to develop to open the aortic valve - Remember Laplace's law? - Wall stress = σ - P = pressure - r = radius - h = wall thickness \ [\$\$\\mathbf{\\sigma}\\mathbf{= \\ }\\frac{\\mathbf{P\\ \\bullet r}}{\\mathbf{h}}\$\$]{.math.display}\ What happens to wall tension as the ventricle enlarges in radius? In thickness? **Pressure-Volume loop -- Increased Contractility** - Note the higher end diastolic volume and resulting greater stroke volume - The heart is an elegant machine with elegant fail-safes - If the heart's strength of contraction decreases, there's "more left" at the end of diastole... - This leads to increased preload - Increased stroke volume Diagram of a normal volume graph Description automatically generated with medium confidence **Pressure-Volume loop -- Increased Preload** - Note the lower stroke volume as inotropy decreases - As it decreases, then the amount left at the end of systole also decreases... - Representing a decrease in ejection fraction - A normal ejection fraction is \> 50% - What is the ejection fraction for each one of these curves?  **Pressure Volume Loops** - The previous changes in the P-V loops that accompanied changes in preload, afterload, and contractility were done in "non-physiologic" situations - Isolated heart preparations, outside of the organism - The P-V loops below are examples found in intact hearts, showing the interdependence of the factors that impact stroke volume A diagram of a normal pressure Description automatically generated with medium confidence - Curve A -- increased venous return increased preload increased stroke volume... but also a slight increase in afterload as the wall tension increases (increase in pressure) - Curve B -- afterload increases decreased stroke volume increased preload a new "steady state" with slightly elevated preload but a greater increase in afterload - Curve C -- inotropy increases increased stroke volume decreased volume left after systole a slightly lower preload **Modifiers of cardiac output** - How do the following affect cardiac output? - Catecholamines? - Parasympathetic stimulation? - Stretching of the ventricles? - Isolated increases in heart rate (chronotropic and inotropic)? - Increases or decreases in central blood volume? - Increases or decreases in systolic blood pressure? - Recall the equation for cardiac output as you work on this - Additional FYI points: - Fever increases cardiac output -- for every degree, heart rate increases approximately 10 beats/min - As you stretch the right atrium, a reflex is initiated (Bainbridge reflex) that activates the cardiac sympathetic nervous system **Sympathetic Nervous System -- impact on cardiac output**  **Modifiers of cardiac output**... and back to preload - Preload and venous return to the heart (closely related) may be the most determinant of cardiac output - As the heart delivers more blood to peripheral tissues, then venous return increases - Force of contraction will also increase as preload increases - This will eventually be limited by the increase in afterload that occurs as blood pressure rises Use the concept of interdependence of preload and venous return to explain why the cardiac output of the right and left ventricle must be equal **Question** - Which ventricle pumps more blood per minute? - Right or left? - Think about: the pressure that both ventricles develop, the thickness of the walls, vascular contractions - Cardiac output must be equal between the left and right ventricles for multiple reasons: - Proper tissue perfusion & oxygen delivery - Preventing pulmonary congestion and systemic hypoperfusion - **PRELOAD OF ONE VENTRICLE DEPENDS ON THE CARDIAC OUTPUT OF THE OTHER.** The top panel shows the human heart with the arteries and veins labeled. The bottom panel shows the human circulatory system. **Oct 1 -- Cellular Physiology of the Heart** **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 - 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**  Picture 3 Fig 10.8 Anat and Phys RYR is subject to regulation by cytoplasmic \[Ca2\], \[Mg2+\], calmodulin, protein kinase A (PKA) and Ca-calmodulin dependant kinases. In the fight-or-flight response, the sympathetic autonomic nervous system activates β-adrenergic receptors, causing PKA-mediated phosphorylation of RYR1 and other muscle proteins; this results in faster and larger increases in cytoplasmic Ca2+, and thus stronger skeletal muscle contraction 4. Increased cytosolic Ca^+2^ binds to troponin "opening" of myosin binding sites on actin - 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 - 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  Picture 8 Events in the cross-bridge cycle of skeletal muscle.(*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°, stretching the myosin S2 region (*4*). Recoil of the S2 region creates the power stroke (*5*). The still-attached cross-bridge is now in the rigor state. Detachment (*6*) 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 can continue as long as the ATP supply remains and activation via Ca^2+^ maintained. (See text for further details.) A, actin; M, myosin; P~i~, inorganic phosphate ion; −, chemical bond. **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°, stretching the myosin S2 region 4. Recoil of the S2 region creates the power stroke **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  Picture 4 **Key Points:** - **Thick and Thin Filaments:** - 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 means that under a microscope, you can see alternating light and dark bands. - **Sarcomere Anatomy:** - 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. **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 than a single twitch. - This condition is called tetanus.  Twitch contraction, temporal summation, and fused tetanus. 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 than a single twitch. This condition is called *tetanus.* Effect of filament overlap on force generation. 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. - 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 - 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: ] - Striated, involve actin: myosin overlap - Parabolic isometric length: tension relationship - Peak isometric forces match optimum passive resting length - T-tubules exist in both - Ca^2+^ 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, Actin-Myosin Overlap** - Both skeletal and cardiac muscles are striated due to the arrangement of actin and myosin filaments in sarcomeres. - The interaction between these filaments generates the force required for contraction in both muscle types. - In both, the overlap of actin (thin filaments) and myosin (thick filaments) leads to cross-bridge cycling during contraction. **Parabolic Isometric Length-Tension Relationship** - Both cardiac and skeletal muscles exhibit a parabolic length-tension relationship, meaning the force generated by the muscle depends on its length. - There is an optimal muscle length (sarcomere length) where the overlap between actin and myosin filaments is ideal, generating the greatest force. - If the muscle is too stretched or too compressed, the force production decreases. **Peak Isometric Forces at Optimum Passive Resting Length** - In both muscle types, the peak isometric force occurs when the muscle is at its optimum passive resting length, meaning the sarcomeres are at an optimal length for generating maximum force during contraction. - This is the point where actin-myosin overlap is ideal. **T-tubules in Both** - Both cardiac and skeletal muscles have T-tubules (transverse tubules), which are invaginations of the sarcolemma (muscle cell membrane). - They help propagate action potentials deep into the muscle fibers, ensuring that the excitation reaches the myofilaments in the interior of the muscle cell for synchronized contraction. **Ca²⁺ ATPase Pumps in SR** - Both cardiac and skeletal muscle fibers have Ca²⁺ ATPase pumps (SERCA) in their sarcoplasmic reticulum (SR). - These pumps actively transport calcium back into the SR after a contraction, reducing intracellular calcium levels and allowing muscle relaxation. - Proper regulation of calcium is critical for the contraction-relaxation 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** - 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. **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. Picture 1 **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**  A diagram of different types of heart Description automatically generated - 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  **Important Notes** - The action potential events seen here are electrical events of the 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 - 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 Ca^2+^ channels that allow Ca^2+^ 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 Ca^2+^ channels and opening of slow K^+^ VGCs Discussion of the cardiac myocyte action potential, focusing on: - The general shape of the action potential - The main ion channels and ion conductances that are responsible for the shape of the action potential - Na+ VGC, L-type Ca+2 channels, fast and slow K+ VGC, K+ leak channels **Myocyte Action Potentials -- Overview** - Phase 4 -- RMP - Potassium leak channels are open (i~K1~) - no other channels - Potassium flow is at equilibrium, as per its Nernst potential (-84 mV) - Phase 0 -- rapid depolarization - Cell quickly reaches threshold and all sodium VGC open Picture 3 Changes in ionic currents responsible for the formation of the fast response action potential in ventricular muscle cells.I, current flow; downward deflections indicate current flow into the cell, whereas upward deflections indicate current flow out of the cell. The rise in action potential (phase 0) is caused by rapidly increasing Na^+^ current carried by voltage-gated Na^+^ channels. Na^+^ current falls rapidly because voltage-gated Na^+^ channels are self-inactivating by depolarization. K^+^ current rises briefly, causing phase 1 (i~to,f~ and i~to,s~) and then falls precipitously as transient outward currents cease and I~K1~ channels close. Ca^2+^ channels are opened by depolarization and are responsible, along with closed I~K1~ channels, for phase 2. K^+^ current begins to increase because of the delayed opening of I~Kr~ and I~Ks~ channels by depolarization and an increase in intracellular calcium concentration. These currents are responsible for rapid repolarization in phase 3. Once repolarization occurs, Na^+^ and Ca^2+^ channels are returned to their resting state. Repolarization reopens I~K1~ channels and reestablishes phase 4. i~Na~, inward sodium current; i~CaL~, inward calcium current; i~to,f~, transient outward fast potassium current; i~to,s~, transient outward slow potassium current; i~Ks~, delayed slow outward potassium current; i~Kr~, delayed rapid outward potassium current; i~K1~, resting outward potassium current. - Phase 1 -- transient repolarization - After sodium VGC close, a set of potassium channels open briefly (fast transient outward potassium current) - Brings the membrane potential closer to zero - Phase 2 -- plateau phase - Two major voltage-gated currents: - L-type calcium VGC - A group of "slow" outward K+ currents - Why does the membrane potential "plateau" at Phase 2? - There is a significant inward current generated by the movement of calcium into the cell (through the L-type Ca^+2^ VGC) - There is a significant outward current generated by the movement of K^+^ out of the cell (a bunch of channels, all voltage-or time-gated) - They "balance each other out" - 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 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  - Back to phase 4 - With time and repolarization, the slow VG K+ channels close 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 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 Picture 3 A representation of a cardiac muscle action potential and is associated isometric twitch contraction. The duration of the mechanical twitch in the muscle is completed before the muscle refractory period is completely over. Therefore, twitch contractions cannot be summed on one another and the muscle cannot be tetanized. ARP, absolute refractory period; RRP, relative refractory period; SNP, period of supranormal excitability. **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?  - 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 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 - Sarcolemma calcium ATP-ase - Sodium-calcium exchanger - Brings in 3 sodium and extrudes one calcium - Impact on membrane potential? 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. **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? **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: - Increased sympathetic nervous system 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? Picture 4  **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 the action potential overall are shorter - Local differences in ion channel expression **Atrial vs Ventricular Myocyte Action Potential** - There are some differences 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 Ca^2+^ 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. - 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 - 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 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 Picture 3 - 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 - Phase 3 -- repolarization - As the calcium VGC close, potassium channels open potassium effux more negative membrane potential - 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 - 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 - a slower heart rate - reduced cardiac output during parasympathetic activation - 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. **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. **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 - 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 - 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. Picture 3 **ECGs -- an Introduction** - ECGs are essential for initial evaluation of the heart - 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" Picture 3  **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) Picture 3  **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 Picture 3 **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. - **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) **Oct 4 -- Cardiovascular Embryology** **Clinical Case** - A mother presents to your clinic with her new son -- he is 4 months of age. She is curious about feeding options and whether supplements impact a child's health early in development. The baby seems quite well and is developing appropriately for his age. As you listen to his heart you hear a clear systolic murmur over the precordium. **Pre-Assessment** If you place a stethoscope at the 2nd right intercostal space at the sternal border, what cardiac structure are you likely listening to? A. The aortic valve B. The pulmonic valve C. The tricuspid valve D. The mitral valve What structure brings oxygenated blood to the embryonic heart? A. The cardinal vein B. The umbilical artery C. The dorsal aorta D. The umbilical vein What is the papillary muscle attached to? A. The chordae tendinae of a semilunar valve B. The chordae tendinae of an atrioventricular valve C. Both the left and right aspects of the interventricular septum D. Both the left and right aspects of the interatrial septum **Mediastinum** - It is the middle of the thorax: - Between the mediastinal pleura - Posterior to the sternum - Anterior to the vertebrae - Superior to the diaphragm - Separates the two lateral pleural cavities - Subdivisions: - Superior - Inferior - Anterior - Middle - Posterior  The **superior mediastinum **extends from the superior thoracic aperture to the horizontal plane that includes the sternal angle anteriorly and passes approximately through the junction (IV disc) of T4 and T5 vertebrae posteriorly, often referred to as the transverse thoracic plane. The **inferior mediastinum**---between the transverse thoracic plane and the diaphragm---is further subdivided by the pericardium into anterior, middle, and posterior parts. The pericardium and its contents (heart and roots of its great vessels) constitute the **middle mediastinum**. Some structures, such as the esophagus, pass vertically through the mediastinum and therefore lie in more than one mediastinal compartment.  The heart and roots of the great vessels within the pericardial sac are posterior to the sternum, costal cartilages, and anterior ends of the 3rd--5th ribs on the left side. **Heart** - The heart and pericardial sac are approximately 2/3^rd^ to the left and 1/3^rd^ to the right of the median plane (middle mediastinum). A person\'s chest with a diagram on it Description automatically generated  Anterior view A diagram of a human heart Description automatically generated Posterior view  **Heart -- Open** - Anterior view or posterior? A diagram of the human heart Description automatically generated **Auscultatory Locations -- Heart**  **Pericardium** - Fibrous membrane that encloses the heart and the roots of the great vessels. - Anchors and protects the heart - Prevents overfilling - Allows it to work in a friction-free environment - Two layers: - Outer **fibrous pericardium** (tough, inelastic CT) - Inner **serous pericardium**. - **Parietal layer** (inner surface of the pericardium) - **Visceral layer** (lines outer surface of the heart = epicardium) - The fibrous pericardium is continuous with the central tendon of the diaphragm (**pericardiophrenic ligament**). A diagram of the anatomy of the human body Description automatically generated **Chamber Walls** - The wall of each heart chamber consists of three layers, from superficial to deep:  1.  **Endocardium:** a thin internal layer (endothelium and subendothelial connective tissue) or lining membrane of the heart that also covers its valves 2.  **Myocardium:** a thick, helical middle layer composed of cardiac muscle 3.  **Epicardium:** a thin external layer (mesothelium) formed by the visceral layer of serous pericardium **Pericardium & Epicardium** - Epicardium is the outermost layer of the heart wall, also called the visceral layer of the serous pericardium - The **serous pericardium **is composed mainly of **mesothelium**.  - Subepicardial layer of loose CT contains the coronary vessels, nerves and ganglia, also an area of fat storage of the heart.  **Myocardium Components** **Contains contractile cells and impulse generating/ conducting cells:** - **Cardiomyocytes** are the individual muscle cells that make up the myocardium. - Striated, uninuclear, often with one or two branches - Full of myofibrils and mitochondria - **Purkinje fibers** are specialized cardiac muscle fibers that play a crucial role in the conduction of electrical signals within the heart. - Glycogen-filled, large diameter fibres, gap junctions, few myofibrils or mitochondria - Pale-staining Most of the heart wall is composed of the **myocardium**, consisting of bundles of cardiac muscle that are attached to the thick collagenous CT skeleton of the heart. - **Papillary muscles:** located in the ventricles of the heart. - Connected to the AV valves by **chordae tendineae**. - **Pectinate muscles:** muscular structures found in the walls of the atria, particularly in the right atrium. - Contribute to the contraction of the atria. - **Trabeculae carneae:** irregular, mesh-like ridges or muscular columns found on the inner walls of the ventricles. - Structural support for ventricles & maintain integrity of myocardium. **Histology -- Myocardium** - Intercalated discs (arrows) have **desmosomes** and **gap junctions**.  This high-magnification photomicrograph of a longitudinal section of the myocardium displays the centrally placed **nucleus** (N) of cardiac muscle cells as well as the intercalated disks (*arrows*) that connect individual muscle fibers to each other. Note the presence of a rich **vascular supply** (BV).×540. **[Intercalated discs: have desmosomes & gap junctions]** **Histological Features** - Intercalated discs: - **Desmosomes:** hold cells together; prevent cells from separating during contraction - **Gap junctions**: directly connect the cytoplasm of 2 cells -- allow ions to pass from cell to cell; electrically couple adjacent cells - Allows heart to be a functional syncytium, a single coordinated unit - **Fascia adherens**: anchors actin filaments, helps to transmit contractile forces **Endocardium** - The **endocardium** forms the lining of the atria and ventricles and is composed of: - Simple squamous epithelium (**endothelium)** - Underlying layer of fibroelastic connective tissue with scattered fibroblasts - Deeper layer of subendothelial fibroelastic CT. - Contains: small blood vessels & nerves, Purkinje fibers - **Endocardial cells** are specialized cells that make up the endocardium. - Form the **inner lining of the AV and semilunar valves**, ensuring they open and close efficiently during the cardiac cycle. A close-up of a microscope Description automatically generated Purkinje fibers are larger and stain paler than typical cardiomyocytes because of abundant glycogen stored in the sarcoplasm; however, as they travel further down, they eventually merge with and become indistinguishable from other cardiac muscle cells.  This low-magnification photomicrograph of the heart displays the simple squamous **endothelial lining** (En) of the ventricle, the subendothelial **connective tissue** (CT), and the well-defined **Purkinje fibers** (PF), branches of the conducting system of the heart. Observe the thick **myocardium** (My). ×135.  This figure displays a **valve leaflet** (Le) as well as the **endocardium** (EC) of the heart. The leaflet is in the **lumen** (L) of the ventricle, as evidenced by the numerous trapped **red blood cells** (RBC). The **endothelial** (En) lining of the endocardium is continuous with the endothelial lining of the leaflet. The three layers of the endocardium are clearly evident, as are the occasional **smooth muscle cells** (SM) and **blood vessels** (BV). The core of the leaflet is composed of dense collagenous and elastic **connective tissue** (CT), housing numerous cells whose nuclei are readily observed. Because the core of these leaflets is devoid of blood vessels, the connective tissue cells receive their nutrients directly from the blood in the lumen of the heart via simple diffusion. The connective tissue core of the leaflet is continuous with the skeleton of the heart, which forms a fibrous ring around the opening of the valves. **Cardiac Muscle Fibers** - Cardiac muscle cells: striated, short, branched, fat, interconnected - Uninuclear cells - Nucleus is situated at the center of the cell body - Cells connected at intercalated discs - Many gap junctions populate the intercalated discs - Contain numerous large mitochondria (25--35% of cell volume) that afford resistance to fatigue - Rest of volume composed of sarcomeres - Z discs, A bands, and I bands all present - T tubules and cisternae present - Sarcoplasmic Reticulum is simpler than in skeletal muscle - T-tubules are larger A diagram of a structure of a human body Description automatically generated **Fibrous Skeleton** - The cardiac muscle fibers are anchored to the fibrous skeleton of the heart. - This is a complex framework of dense collagen/**fibroblastic tissue** forming **four fibrous rings** that surround the orifices of the valves, a **right and left fibrous trigone **(formed by connections between rings), and the **membranous parts of the interatrial and interventricular septa.**  **Left vs. Right Sides** **Features** **Right Side** **Left Side** ----------------------- -------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------- **Myocardial Walls** **More trabeculated, less muscle mass, thinner** **Less trabeculated, more muscle mass, thicker** **AV Valves** **Tricuspid (3 leaflets, 3 sets of papillary muscles: anterior, posterior, septal)** **Mitral/ Bicuspid (2 leaflets, 2 sets of papillary muscles: anterior and posterior)** **Conduction System** **SA node and AV nodes are in the right atrium** **-** **Features of the Heart** - Interatrial Septum: Separates the right and left atria - Note: **Fossa Ovalis** - Interventricular Septum: Separates the right and left ventricles - Inferior: Large, muscular - Superior: Small, membranous - Corresponds to the anterior and posterior IV sulcus. A diagram of a human heart Description automatically generated - Auricles: - Increase the capacity of the atrium and the volume of blood can be contained.  **Conduction System -- SA Node** - **Pacemaker of the heart**. - Located near the opening of the SVC in the RA. Sends \~70 impulses/ min.  - The contraction signal spreads myogenically in **both atria**. - Innervated by the **sympathetic division** of the autonomic nervous system and is inhibited by the **parasympathetic division**. A diagram of the heart Description automatically generated  - At the IVS, the AV bundle divides into right and left bundles and form subendocardial branches (**Purkinje fibres**), which extend into the walls of the respective ventricles. - The **subendocardial branches of the right bundle **stimulate the muscle of the IVS, the anterior papillary muscle through the septomarginal trabecula (moderator band), and the wall of the right ventricle. - The** left bundle **divides near its origin into approximately six smaller tracts, which give rise to subendocardial branches that stimulate the IVS, the anterior and posterior papillary muscles, and the wall of the left ventricle.  - The AV node is supplied by the **AV nodal artery**, the largest and usually the first IV septal branch of the posterior IV artery. **Innervation of the Heart** - The heart is supplied by autonomic nerve fibres from the **cardiac plexus**, which is divided into superficial and deep portions. - Located on the anterior surface of the bifurcation of the trachea and at the posterior aspect of the aorta and pulmonary trunk. - The cardiac plexus is formed of both **sympathetic and parasympathetic** as well as **visceral afferent fibres** conveying reflexive and nociceptive fibres from the heart. Additional note: General visceral afferent fibers convey visceral information such as distention of organs and chemical conditions from the blood vessels, heart, lungs, digestive system, and other organ systems and glands into the central nervous system via both spinal and cranial (glossopharyngeal and vagus) nerves. - The **parasympathetic supply **is from the presynaptic fibres of the **vagus nerves**. Postsynaptic parasympathetic cell bodies (intrinsic ganglia) are near the SA and AV nodes and along the coronary arteries.  - Visceral afferent components of the cardiac plexus travel with the sympathetic (pain sensation) and parasympathetic (baroreceptors and chemoreceptors). A diagram of the human body Description automatically generated **Vasculature of the Heart** - Coronary arteries/ cardiac veins supply and drain the myocardium. - **End circulation**: only source of blood supply - Note: The endocardium and some of the subendocardial tissue receive oxygen and nutrients through diffusion or **microvasculature**. - Vessels are typically embedded in fat and run beneath the epicardium. - Parts of these blood vessels are embedded within the myocardium to ensure the myocardium receives oxygen and nutrients. - The blood vessels of the heart are autonomic control. **Coronary Arteries** - Right and left: first branches of the aorta, supply the **myocardium and epicardium**. - Arise from **aortic sinuses,** superior to the aortic valve, and pass around opposite sides of the pulmonary trunk. - The coronary arteries supply both the atria and the ventricles.  **Right Coronary Artery** - The right coronary artery (RCA) runs in the coronary/ **atrioventricular sulcus**. - Gives an ascending **SA nodal brand** at its origin. - Continues in the sulcus and gives the **right marginal branch** which supplies the right border. - Turns left, gives posterior interventricular branch, also called the **right posterior descending** (RPD). - At the posterior junction of the interatrial and interventricular septum, gives rise to the **AV nodal branch.** A diagram of a human heart Description automatically generated  **Left Coronary Artery** - The **left coronary artery** (LCA) arises from the left aortic sinus of the ascending aorta, passes between the left auricle and the left side of the pulmonary trunk, and runs in the AV sulcus. - Splits into 2 branches: - **Anterior IV branch** (supplies walls of the ventricles) - Provides a **diagonal branch** - **Circumflex branch** (supplies walls of LV & LA) - Provides a **marginal branch** A diagram of the heart Description automatically generated In approximately 40% of people, the SA nodal branch arises from the circumflex branch of the LCA and ascends on the posterior surface of the left atrium to the SA node.  **Dominance** - The dominance of the coronary arterial system is defined by which artery gives rise to the **posterior interventricular (IV) branch**.  **A.** In the most common pattern (67%), the RCA is dominant, giving rise to the posterior interventricular branch. **B and C.** The LCA gives rise to the posterior interventricular branch in approximately 15% of individuals, including LCA dominant (**B**), and agenesis (absence) of RCA (**C**). **D.** Many other variations occur, such as RCA replacing left recurrent branch. **Cardiac Veins** - Cardiac veins empty into the **coronary sinus** or into the right atrium. - The **coronary sinus**, the main vein of the heart, runs from left to right in the posterior part of the coronary sulcus. - The coronary sinus receives the **great cardiac vein** (of anterior IV sulcus)**, middle cardiac vein** (of posterior IV sulcus), and **small cardiac veins** (from the inferior margin). - The **left posterior ventricular vein** and **left marginal vein** also open into the coronary sinus.  A diagram of the heart and the veins Description automatically generated - The first part of the great cardiac vein, the **anterior interventricular vein**, begins near the apex and runs with the anterior IV artery. - At the coronary sulcus, it turns left, and its second part runs with the circumflex branch of the LCA to reach the coronary sinus. - *Note: Blood is flowing in the same direction within a paired artery and vein!* - The great cardiac vein drains the areas of the heart supplied by the LCA.  - Small and middle cardiac veins drain the right side of the heart. - The **middle cardiac vein** (posterior IV vein) accompanies the posterior interventricular arterial branch.  **BMS 150 Review** - Vasculogenesis development of brand-new blood vessels from mesodermal cells (angioblasts) - Angiogenesis "sprouting" of existing blood vessels formed by vasculogenesis - Connects blood vessels to each other A diagram of the human body Description automatically generated **Vasculogenesis and Angiogenesis** - Primitive circulation develops by week 3 - Mesenchymal cells **angioblasts** **blood islands** - begins in extraembryonic mesoderm before intraembryonic mesoderm (umbilical vesicle and allantois) - Small cavities appear within the blood islands - Angioblasts flatten to form endothelial cells that "coat" the inside of the cavities in the blood island -- early endothelium  - The endothelium-lined cavities fuse to form networks of channels = vasculogenesis - Vessels "sprout" into adjacent areas by endothelial budding and fuse with other vessels = angiogenesis - Mesenchyme surrounding the channels develops into the muscular and connective tissue of a blood vessel **Development of the Embryonic Vessels\ (BMS 150-Review)** - Three paired veins drain into the tubular heart of a 4-week embryo - ***Vitelline vein*** return poorly oxygenated blood from the umbilical vesicle. - Follow the omphaloenteric duct (former yolk stalk) into the embryo - They then enter the sinus venosus (venous end of the embryonic heart) - ***Umbilical vein*** carry well-oxygenated blood from the chorion to the fetus - ***Common cardinal veins*** return poorly oxygenated blood from the body of the embryo - ***Dorsal aorta --*** blood to the embryo - ***Umbilical artery** --* Returns blood to the placenta A diagram of a human body Description automatically generated - **Lateral folding** brings the heart tube into the anterior part of the embryo, positioning it within the chest cavity. - **Cranial folding** brings the heart tube **ventrally and caudally** - The **intra-embryonic coelom** near the heart tube develops into the pericardial cavity, pleural cavity, and peritoneal cavity - The paired heart tubes are connected with the extra-embryonic vessels once the heart starts to beat on day 21 - The red blood cells develop first in the extra-embryonic vessels - Allantois, umbilical vesicle vessels - By the 5^th^ week RBCs arise from the dorsal aorta **Development of the Heart** - At around 18-19 days of gestation, the heart and great vessels begins to form in a special region of the embryo called the **cardiogenic area**. - Paired, longitudinal endothelial-lined channels---the **endocardial heart tubes**---develop during the 3rd week and fuse to form a primordial heart tube  **Establishment of the Heart** - Primary Heart Field: - Earliest region involved in heart development, located in the anterior lateral plate mesoderm. - Gives rise to the initial heart tube, which forms during the third week of development. This tube eventually differentiates into a portion of the atria and the left ventricle. - Secondary Heart Field: - Located adjacent to the PHF; visceral mesoderm ventral to the pharynx. - Contributes to the elongation of the heart tube. It forms the right ventricle, the outflow tract of both ventricles (conus cordis and truncus arteriosus), and parts of the atria. - Neural Crest Cells: - Originate from the neural tube. - Contributes to the cardiac outflow tract and the aorticopulmonary septum. A diagram of a human body Description automatically generated The aorticopulmonary septum becomes the IV septum **Laterality** - Both the PHF and the SHF exhibit left--right patterning.  - SHF: Cells on the right side contribute to the left of the outflow tract region and those on the left contribute to the right; it explains the spiralling nature of the pulmonary artery and aorta.  **Cardiac Loop** - As the outflow tract lengthens, the cardiac tube begins to bend on **day 23.** - The cephalic portion of the tube bends ventrally, caudally, and to the right; and the atrial (caudal) portion shifts dorsocranially and to the left. - This bending creates the cardiac loop by day 28. Formation of the cardiac loop. - The **atrial portion** forms a common atrium and is incorporated into the pericardial cavity. - The **bulbus cordis **forms the trabeculated part of the right ventricle. The midportion, the **conus cordis**, will form the outflow tracts of both ventricles. The distal part of the bulbus, the **truncus arteriosus**, will form the roots and proximal portion of the aorta and pulmonary artery. - **[Bulboventricular loop]** - When looping is completed, the smooth-walled heart tube begins to form primitive trabeculae in two sharply defined areas. The **primitive ventricle**, which is now trabeculated, is called the **primitive left ventricle**. - Likewise, the trabeculated proximal third of the bulbus cordis is called the **primitive right ventricle**.   **Summary** **Embryonic Structure** **Adult Structure** ------------------------- ------------------------------------------------------------------------------------------- Sinus Venosus Smooth part of atria, coronary sinus, nodal tissue Atrium Rough part of the atrium Ventricle Left ventricle Bulbus Cordis Trabeculated part of the right ventricle, outflow tracts of the ventricles (conus cordis) Truncus Arteriosus Outflow Tract (Pulmonary Trunk & Aorta) **Early Development of the Heart** - Blood flows from the sinus venosus into the primordial atrium, from there to primordial ventricle - Ventricle contracts, pushing blood into the bulbus cordis and truncus arteriosus - Passes cranially to the pharyngeal arches arteries - Passes caudally to the dorsal aorta - Distributed to the placenta, umbilical vesicle, and the rest of the embryo  **Endocardial Cushions** - Towards the end of the 4th week**, endocardial cushions** form on the dorsal and ventral walls of the atrioventricular (AV) canal - As these masses of tissue are invaded by mesenchymal cells during the 5th week, **the AV endocardial cushions** approach each other and fuse, dividing the AV canal into right and left AV canals - These canals partially separate the primordial atrium from the primordial ventricle, and the endocardial cushions function as AV valves. - **The endocardial cushions are involved in the development of the atrial and ventricular septa, as well as the atrioventricular valves** **Development of partitioning between the left and right sides -- atria** - During embryonic life, the blood from all chambers mixes, such that the heart acts like just one massive chamber - However, the basic structure for separate right- and left-sided circulations must be developed and ready to operate once the child is born A diagram of a human body Description automatically generated **Key events:** - **Septum primum** grows from the roof of the atria towards the endocardial cushions - The space underneath is called the **foramen primum** - It meets the endocardial cushions (primordial septum) and abruptly becomes holey and forms another foramen (**foramen secundum**) -- this will remain until birth  The **septum secundum** now starts to develop, on the right side of the septum primum - between the two flaps remains the **foramen secundum** Note how the development of the septum primum, the septum secundum, and the foramen secundum allow one-way shunting of blood from right to left - If pressure in the left atrium increases, the valve (formed by what?) will close Diagram of a diagram of the ovary Description automatically generated with medium confidence **Atrial Septum** - Remnant of septum primum is now called the "valve of the oval foramen" - Blood flows from the right atrium to the left atrium through the foramen ovale by pushing through the septum primum.  **Ventricular partitioning** The ridge of the interventricular septum grows towards the endocardial cushions Until the seventh week, there is a crescent-shaped **Interventricular (IV) foramen** between the free edge of the IV septum and the fused endocardial cushions - usually closes by the end of the 7^th^ week The superior part is called the **membranous IV septum** A diagram of the heart Description automatically generated  **Ventricular outflow** - At 6 weeks, the **aorticopulmonary septum**, formed partially by **neural crest cells,** descends into the developing heart from the **endocardial cushions**. This septum separates the outflow tracts into the aorta (left outflow tract) and the pulmonary artery (right outflow tract). - The spiralization of the aorticopulmonary septum helps align the aorta and pulmonary artery with their respective ventricles, allowing for proper oxygenated and deoxygenated blood flow after birth. A diagram of the heart Description automatically generated **The venous system -- from week 6 to post-partum** **Vitelline veins:** - Enter the sinus venosus, and eventually the **right vitelline** vein forms most of the hepatic portal system and IVC, while the **left disappears**  A diagram of veins and arteries Description automatically generated Figure 13-4 Illustrations of the primordial veins of the trunk in the human embryo (ventral views). Initially, three systems of veins are present: the umbilical veins from the chorion, the vitelline veins from the umbilical vesicle (yolk sac), and the cardinal veins from the body of the embryo. Next the subcardinal veins appear, and finally the supracardinal veins develop. **A,** At 6 weeks. **B,** At 7 weeks. **C,** At 8 weeks. **D,** Adult. This drawing illustrates the transformations that produce the adult venous pattern. - The **anterior cardinal veins** (mostly right) develop into the SVC - The posterior mostly form visceral veins and part of the IVC **The venous system -- umbilical vein** - The right umbilical vein and the cranial part of the left umbilical vein between the liver and the sinus venosus degenerate - Now a single **umbilical vein** - carries all the blood from the placenta to the embryo - A large venous shunt-the **ductus venosus (DV)**-develops within the liver - connects the umbilical vein with the inferior vena cava (IVC) - DV bypasses the liver so most of the blood goes straight to the heart   Figure 13-5 Dorsal views of the developing heart. **A,** During the fourth week (approximately 24 days), showing the primordial atrium and sinus venosus and veins draining into them. **B,** At 7 weeks, showing the enlarged right sinus horn and venous circulation through the liver. The organs are not drawn to scale. **C,** At 8 weeks, indicating the adult derivatives of the cardinal veins. **Fetal Circulation** - Shunts: - **The ductus arteriosus** - From pulmonary trunk to aorta - The **foramen ovale** - from right atrium to left atrium - The **ductus venosus** - Bypasses liver, fetal blood flows right into the inferior vena cava Diagram of a human body with labeled organs Description automatically generated **Circulation After Birth** - **Closure of the umbilical arteries**: used to carry deoxygenated blood from embryo to placenta - Remnant: Medial Umbilical Ligament - **Closure of umbilical veins:** used to carry oxygenated blood from placenta to embryo - Remnant: Ligamentum Teres - **Closure of ductus venosus:** shunt that allows oxygenated blood in the umbilical vein to bypass the liver - Remnant: Ligamentum Venosum - **Closure of foramen ovale:** increased pressure in the left atrium, combined with a decrease in pressure on the right side - Remnant: Fossa Ovalis - **Ductus arteriosus**: used to connect the fetal pulmonary artery to the aorta - Remnant: Ligamentum Arteriosum  **Congenital heart disease -- a quick overview** A screenshot of a table Description automatically generated - over 1 million people in North America are living with congenital heart diseases - comprises about 1% of live births - can be serious illnesses that necessitate early surgical correction, or can resolve on their own over time **Atrial septal defect (ASD)** - Most are **septum secundum** ASDs (90%) -- the rest are septum primum ASDs or sinus venosus defects - Usually shunts blood from the left atrium to the right atrium - can increase pulmonary blood flow by 2-4X if severe - Patent foramen ovale -- the septum primum does not "seal over" and the flap can open - usually only with increases in intrathoracic pressures - Small ASDs may remain asymptomatic. Larger defects can lead to symptoms such as fatigue, exertional dyspnea, palpitations, and recurrent respiratory infections. Over time, they can cause right-sided heart enlargement and pulmonary hypertension.  **Ventricular septal defect (VSD)** - most are holes in the membranous septum, many are about the size of the aortic orifice - some of them look like a collection of small holes -- "swiss cheese" look A cross section of a heart Description automatically generated - Incomplete closure of the ventricular septum will cause **left-to-right shunting** and is the most common anomaly at birth - **Clinical features** - Larger VSDs can lead to symptoms such as rapid breathing, poor feeding, failure to thrive, and recurrent respiratory infections. Over time, they can lead to pulmonary hypertension and right-sided heart enlargement. - Minor defects will have limited clinical significance  **Patent Ductus Arteriosus (PDA)** - The ductus arteriosus remains patent (open) - A defect that causes large pressure differences between the aorta and pulmonary trunk can increase blood flow through the ductus arteriosus, preventing its closure. - A large shunt may divert blood from the aorta to the pulmonary artery. Left ventricular hypertrophy and heart failure ensue owing to increased demand for cardiac output. - In patients with large PDAs, the increased volume and pressure of blood in the pulmonary circulation eventually lead to pulmonary hypertension and cardiac complications. A diagram of a heart Description automatically generated **Coarctation of Aorta** - The aortic lumen below the origin of the left subclavian artery is significantly narrowed. Constriction may be above or below the entrance of the ductus arteriosus. - In the **preductal type**, the ductus arteriosus persists, whereas in the **postductal type**, which is more common, this channel is usually obliterated. - Classic clinical signs associated with this condition include hypertension in the right arm concomitant with lowered blood pressure in the legs.  The prognosis is good with early diagnosis and intervention. Treatment often involves surgery to repair the coarctation and restore normal blood flow. Long-term prognosis is generally excellent, but ongoing monitoring may be necessary. **Factors Leading to Embryological Defects** 1. Interference with the left-right determination of the body axis - Example: **dextrocardia** (heart located on the right side) or **situs inversus** (complete reversal of left and right organ positions). 2. Improper migration of precursor cells to their target area in the embryo - For instance, improper neural crest cell migration can affect the formation of structures like the aorticopulmonary septum. 3. Improper regression of embryological structures - Example: Patent Ductus Arteriosus. **Class Discussion** - A mother presents to your clinic with her new son -- he is 4 months of age. She is curious about feeding options and whether supplements impact a child's health early in development. The baby seems quite well and is developing appropriately for his age. As you listen to his heart you hear a clear systolic murmur over the precordium. - Embryological Disorder? Further Investigations? One possibility is a Ventricular Septal Defect (VSD). VSD is a common congenital heart defect where there is an abnormal opening between the two ventricles, allowing blood to flow from the left ventricle to the right ventricle.