HBF-ii_2024-L9_notes-chung.pdf

Human Body Foundations II: Cardiac Electrophysiology and Cardiac Function (Physiology) 2024 Faculty Charles S Chung PhD Associate Professor of Physiology [email protected] Note: In most cases, if a statement text is in a gray color, it is either an exercise or additional information. Throughout...

Human Body Foundations II: Cardiac Electrophysiology and Cardiac Function (Physiology) 2024 Faculty Charles S Chung PhD Associate Professor of Physiology [email protected] Note: In most cases, if a statement text is in a gray color, it is either an exercise or additional information. Throughout the notes, essential concepts are underlined, but studying all components is important to prepare for additional topics. Lecture 9-Cardiac Function Learning Objectives Define Laplace’s Law Recreate the Wiggers’ Diagram and define its phases by ventricular valve opening and closure Describe the major heart sounds and their genesis Recreate the relationship between the Wiggers’ Diagram and a Pressure-Volume Loop Understand how changing afterload normally alters the Pressure-Volume loop and its relationship to contractility Describe the Frank-Starling relationship, how the relationship requires a change in preload, and its link to length-dependent activation Determine cardiac output 1 Role of the Heart: Cardiac Output A heart must move blood through the body Blood is a fluid We’ve learned about the cell physiology How does this translate to the whole heart and relate to cardiac output? What other indexes might we observe? Suggested Review Concepts Cardiac Anatomy Ventricular chambers Atrial Chambers Major Veins and Arteries All 4 Valves Krebs Cycle The purpose of the heart is to generate cardiac output, i.e. drive blood into the rest of the body. This section is mean to integrate all of the prior content to understand how the heart achieves this goal. Remember that the heart has 4 chambers and 4 valves. However, much of the discussion of this lecture will focus on the Left Ventricle (LV) because it has the largest muscle mass and is the part of the heart that is responsible for pumping blood through the body. Remember also Bernoulli’s principle, i.e. that fluid moves with a pressure gradient from higher pressure to lower pressure. We’re working with contraction that can generate this pressure. Valves prevent flow going in the “wrong” direction as they only open with a pressure gradient. LaPlace’s Law LaPlace’s Law relates the pressure within a shape (sphere) to the wall stress (i.e. tension or force) of the surrounding wall. The equation reads: 2 𝜎𝜎 𝑢𝑢 𝑃𝑃 = 𝑟𝑟 Where: Wall stress (force, tension, σ) in the wall Radius (r) of the sphere Thickness (u) of the wall Note: If it hasn’t already, Laplace’s law will come up again in physiology Cylinders won’t have the “2” Often won’t see thickness (u), for example: alveoli The equation above is for a sphere, which the heart is not, but its close enough. Essentially, this relationship says that if you add wall tension (i.e. squeeze the sphere), the pressure goes up. The easy analogy is a balloon. If you add pressure to inflate the balloon, the wall stress goes up as the rubber is stretched. You can obtain the size parameters from cardiac ultrasound (Echocardiography) 2  Short axis B-Mode PLAX B-Mode M-Mode (Mid Myocardial,PLAX) r u u 2r https://www.asecho.org/guidelines-search/ FIGURE: Example echocardiography images with the wall thickness and radius shown. Wiggers’ Diagram The Wiggers’ Diagram is used to show the sequence of events in the cardiac cycle. The sequence links pressure and volume (or flow, the change in volume). An easy way to start drawing the Diagram is to start with the fact that action potentials cause contraction (Excitation-Contraction Coupling) and that contraction increases tension, which (by LaPlace) will increase pressure in the heart. Guyton 9-8 FIGURE: Wiggers’ diagram 3 The phases of the cardiac cycle are broken down into: Systole Mitral (atrio-ventricular) valve closure to aortic valve closure Contraction and ejection Diastole Aortic valve closure to mitral (atrio-ventricular) valve closure Relaxation and Filling Following the ECG, we can follow what is happening to the ventricle: P-wave is atrial depolarization and contraction So this is a phase of atrial contraction and filling of the ventricle Note, there will be a slight delay from the excitation contraction coupling, so don’t measure from the p-wave, measure from changes in flow QRS complex is ventricular depolarization and contraction Ventricular pressure goes up, closing the mitral valve All valves are closed, so phase is isovolumic (same-volume) i.e. Isovolumic Contraction Note, there will be a slight delay from the excitation contraction coupling, so don’t measure from the QRS complex, measure from mitral valve closure When the LV pressure exceeds the pressure in the aorta (dashed line), the aortic valve opens Blood exits from the heart, reducing its volume i.e. Ejection As the heart’s contraction fades and the heart begins to relax, the aortic valve closes The heart relaxes and pressure falls (wall tension drops) despite there being no open valves i.e. isovolumic relaxation The heart’s relaxation makes the LV pressure drop below the atrial pressure so the mitral valve opens This begins filling of the heart This filling is typically rapid i.e. Early Rapid Filling E-wave (flow) on transmitral Doppler echocardiography If the heart rate is slow enough, there is a separation of the early rapid filling and the next p- wave There is little flow during this period, it is a “rest” phase i.e. Diastasis A new P-wave occurs, causing more atrial filling. This phase is considered “late” because it comes after the prior filling i.e. Late Atrial Filling or Atrial Systole o Note: The P-wave indicates the depolarization of atrial tissue, i.e. atrial contraction and ejection (sometimes called ‘atrial systole’). However, this contraction fills the ventricle with blood. Since Wiggers’ Diagram describes the cardiac cycle from the ventricular perspective, it is still diastolic. A-wave (flow) on transmitral Doppler echocardiography CAUTION: The ECG drawn on these Wiggers’ Diagrams are schematic. The R-wave does not always align with mitral valve closure. Remember that the QRS indicates the depolarization of ventricular tissue, but in order for the mitral valve to close, the depolarization needs to cause calcium release, thin filament activation, and myosin binding, i.e. there is a latent period. 4 Notes about right ventricle (RV) versus left ventricle (LV) RV wall is thinner (smaller u from Laplace’s equation) RV does not generate as much pressure o peak RV pressure ~25 mmHg o Peak LV pressure ~120 mmHg RV and LV contract at slightly different times, but usually overlap Pathophysiologic when they are dyssynchronous Echocardiography can be used to identify the phases because it can be used to determine when the valves open and close. M-Mode (Mitral valve, PLAX) E A https://www.asecho.org/guidelines-search/ FIGURE: Example M-Mode echocardiography with the mitral valve (MV) and early rapid filling (E) and late atrial filling (A) marked. At right is an anatomical schematic. Echocardiography can also be used to look at the blood flow (derivative of volume; rate of change of volume) in the heart. Doppler echocardiography is used. Pulsed Wave Doppler (transmitral flow, Apical 4-ch) E A Derivative of Volume =Flow E-wave A-wave Diastasis IVRT Guyton 9-8 Ao Ejection https://www.asecho.org/guidelines-search/ FIGURE: Left: Wiggers’ Diagram with flow shown schematically below the volume. Right: Transmitral Pulsed Wave Doppler Echocardiography. The features of the diastolic period are shown/labeled. E- and A-waves don’t change much with heart rate. Diastasis is shortened (lost) Chung Karamanoglu Kovacs Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H2003-8. FIGURE: During lecture, I discussed the major changes in phases when heart rate increases is the loss of diastasis. Exercise: Why might the E-wave or ejection duration change if a P-wave fires earlier? What is constant? 5 Heart Sounds Auscultation is the practice of listening to sounds of the body. Common sounds to listen for are Common: heart, lung, pulse pressure (Korotkoff sound). Auscultation of the heart listens to sounds of the heart and provides information about how blood is flowing through the heart. There are two sources of heart sounds: Valves: Most associated with 1st and 2nd heart sounds When valves shut, they vibrate Deceleration of Blood Associated with the 3rd and 4th heart sounds Slowing of blood or loss of blood velocity can cause a sound wave Most common in pathologic hearts (or young hearts) Associated with stiff hearts, such as hearts that are dialated. There are four heart sounds 1st occurs as the mitral valve closes/aortic valve opens. “Lub” 2nd occurs as the aortic valve closes/mitral valve opens. “Dub” 3rd occurs as blood decelerates during early rapid filling 4th occurs as blood decelerates during late atrial filling A sound may split. Normally, sounds from the left and right ventricles will overlap because they are synchronized. However, if the RV does not close the pulmonary valve at the same time the LV closes the aortic valve, it may “Split”. S2 becomes A2, P2, for an aortic and pulmonary sound. 4th Lub Dub Lub Dub Guyton 9-8 FIGURE: Wiggers’ diagram with heart sounds shown. 6 Pressure Volume Relationships The Pressure-Volume loop traces the cardiac cycle in a counter-clockwise direction. The “corners” are defined by valve closures. 120 Ejection 100 AoVC AoVO Pressure 80 60 IVR IVC 40 20 MVO A E MVC 0 30 90 130 Volume Diastasis FIGURE: Left: Pressure-volume relationship with phases of the cardiac cycle labeled. Right: Wiggers’ Diagram for reference. Several important measurements can be made and indexes calculated from the pressure- volume relationship: End diastolic volume (EDV) volume of the blood when the mitral valve closes End systolic volume (ESV) volume of blood in the heart when the aortic valve closes Stroke volume (SV) difference between EDV and ESV Ejection fraction (EF) percent of blood ejected 100*SV/EDV 100*(EDV-ESV)/EDV Normal is >50% 7 Contractility/Inotropy by changing Afterload: Changing afterload, i.e. changing the systemic/aortic blood pressure, changes when the aortic valve opens. It does not change mitral valve closure- i.e. it does not change preload. Aortic valve closure/end systolic volume also changes, but this allows us to calculate an index of contractility or inotropy (interchangeable). Connecting the points at end systole (pressure at aortic valve closure for the y-values, end systolic volume for the x-values) with different afterloads creates a line whose slope is an index of contractility. 120 120 100 AoVO 100 Pressure 80 AoVO Pressure 80 60 60 AoVO 40 40 20 20 MVC 0 0 30 90 130 30 90 130 Volume Volume FIGURE: Left: Three pressure-volume loops at varying afterloads. The slope of the golden line provides an index of inotropy. Right: multiple loops were removed for simplicity, but the straight green line (in comparison to the golden line) shows reduced inotropy. As discussed in Lecture 7, contractility can be reduced by reducing the calcium release from the sarcoplasmic reticulum, reducing thin filament activation, or slowing/inhibiting the myosin ATPase. 8 Frank Starling Relationship (Preload/Length Dependent Activation) When preload is changed, the stroke volume should also change. Like when calcium was discussed for length dependent activation, one might think that the stroke volume should increase proportionally to the end diastolic volume increase- i.e. that the ejection fraction should stay the same. However, it is generally not the case. 120 100 Pressure 80 AoVO 60 40 20 MVC MVC MVC 0 30 90 130 Volume FIGURE: When changing preload, the volume of mitral valve closure changes (the aortic valve opening does not change because we didn’t change afterload). However, in most hearts, the stroke volume increases, relatively maintaining the prior end systolic volume. The Frank-Starling Law states that at longer length/higher volume, myocytes/heart contract more vigorously. This relates back to Length Dependent Activation. But Length Dependent Activation and Frank Starling can both be broken. In Lecture 7, a normal heart showed the property of Length Dependent Activation. However, a sick heart can loose that property. 9  Heart Failure/ CVD Low Calcium High Calcium Low Calcium High Calcium Heart Failure/ CVD Low Calcium High Calcium Low Calcium High Calcium Sequeira et al Circulation Research. 2013;112:1491–1505 FIGURE: Length Dependent Activation. In the donor heart, the force generated by the muscle at longer length but a moderate calcium is higher than expected. In Heart Failure (right), the force generated by the muscle at longer length is proportional to that of the muscle at shorter lengths. The pressure-volume loops can reflect the changes that occur in with length dependent activation Normal Heart: Myocardium generates more tension than expected at longer length Contributes to greater stroke volume Dysfunctional Heart: Myocardium generates same force at all lengths Inhibits ability to contract Reduces EF 120 120 100 100 80 80 Pressure Pressure 60 60 40 40 20 20 0 0 30 90 130 30 90 130 Normal Volume Dysfunction Volume FIGURE: Pressure volume loops that correspond to the ventricular function of the muscles shown in the prior figure. In the heart failure heart, increasing preload (end diastolic volume) does not maintain the end systolic volume. The slope of the contractility curve (ESPVR) is also reduced. 10 A summary of the Frank-Starling Law In summary, a larger preload would generate a larger stroke volume. The ejection fraction would not be maintained, but at a larger preload, the ejection fraction would increase. This is equivalent to generating more tension than anticipated by scaling the length-tension relationship. Increasing inotropy, will enhance this property. Increased inotropy Stroke Volume Preload FIGURE: graphical relationship between stroke volume and preload. If there was no length dependent activation (no Frank-starling), it would be a more linear, not curvilinear shape. Note: the preload axis is can be multiple units, end diastolic volume, end diastolic pressure, and right atrial pressure. The end diastolic volume and end diastolic pressures are linked (by the end diastolic pressure volume relationship), so it makes sense that those can be replaced. The use of right atrial pressure can relate to total peripheral resistance (cardiovascular function). A note about the contractility and passive stiffness curves. As described above, the inotropy is determined by the relationship of the end systolic (aortic valve closure) points after changing afterload. The passive properties (preload) of the heart are found by connecting the pressure volume points during mitral valve closure when changing preload. These curves, the End Systolic Pressure Volume Relationship (ESPVR) and the End Diastolic Pressure Volume Relationship (EDPVR) are directly related to the cellular contractility and passive stiffness. (Mostly because of LaPlace’s Law!) Tension (% of maximal) End Systolic Pressure- 120 Total Force Volume Relationship (Inotropy, Contractility) 100 100 Calcium Release Excitation- Thin Filament Activation 80 Contraction 80 Myosin ATPase Coupling Pressure 60 60 Actual tension End Diastolic Pressure- 40 Volume Relationship 40 (Passive Stiffness) Titin 20 Titin Collagen Extracellular matrix 20 Tension Expected 0 from LDA 30 90 130 0 Volume % Length 80 100 120 1.6 2.0 2.4 Approx cardiac Sarcomere Length [um] FIGURE: The pressure-volume relationship of the heart corresponds to the contractility and passive stiffness of the muscle (right, Lecture 7). 11 Energy and Work The heart utilizes a lot of energy. Energy in the body is created using oxygen (mitochondrial respiration). We discussed two ATPases that modify contractility: SERCA and the myosin ATPase. These, especially the latter, require incredible amounts of energy with the heart utilizing more than twice the amount of oxygen that of the brain (per unit mass) at rest, and ~20 times as much when at peak exercise. As the myosin ATPase is the primary user of ATP in the heart, when there is a reduction in the ATP, there must be a change in energy utilization from fatty acids to glucose. However, there’s another problem if ATP availability has gone down. Recall that ATP is required to take the ATPase from the rigor state to the detached state. Without ATP, the heart will not relax properly! MVO2 Cardiac State (ml O2/min per 100g) Arrested heart 2 Resting heart rate 8 Heavy exercise 70 O2 Consumption Organ (ml O2/min per 100g) Brain 3 Kidney 5 Skin 0.2 Resting muscle 1 Contracting muscle 50 FIGURE: Energy utilization in the heart External Work Because the heart is delivery blood to the body, it must do work to push blood out of the ventricle and into the arterial system. ATP is converted to Work (effort) used to move blood out of the left ventricle. Work=area of PV loop For the course, one can assume that it’s a rectangle The top is the mean arterial pressure (MAP) The bottom is diastolic pressure Work=stroke volume x (MAP-diastolic pressure). 12  120 120 100 100 Pressure Pressure 80 80 60 60 40 40 20 20 0 0 30 90 130 30 90 130 Volume Volume FIGURE: Left: a pressure volume loop. From thermodynamics, we know that the area in the loop is the work done. Right: when calculating this (at least for the purposes of this course), one may estimate this as a rectangle. The end diastolic and end systolic volumes are the sides and the mean arterial pressure and diastolic pressure are the top and bottom. Cardiac Output The rate of oxygen utilization in the body can be quantified. The gold standard method to quantify this is Fick’s Method: CO = O2 uptake (ml O2/min.) / A-V O2 diff. (ml O2/L blood) = rate of O2 consumption / (arterial O2 content - venous O2 content) Units of L/min Measure O2/CO2 Measure arterial and venousoxygen content Fick’s method relates the oxygen use to the cardiac output, i.e. how much blood is pumped through the body. The cardiac output is an important index of health of a person and reflects the rate of blood delivered to the body. Since the amount of blood ejected for each beat (stroke volume) over a minute (heart rate), gives the total amount of blood delivered, the cardiac output can also be calculated as: CO = SV x HR’ 13 Clinically relevant considerations/ integrations/self-exercises. Based on your knowledge of the content of the cardiac electrophysiology and cardiac function lectures, you might consider how the concepts apply in clinic. Cardioplegia solution is typically a high potassium concentration solution used for stopping cardiac contraction Why is cardioplegia important during transplant? Hint: Given the energy requirements for the myosin ATPase, SERCA, why is it good to not depolarize the heart? How can you adjust CO? Lung parameters? Heart parameters? If a person bleeds out, what will happen to preload? Afterload? Diastolic Function Most of the content in this lecture focused on delivering blood to the body (i.e. contractility/inotropy). But diastolic function is becoming increasing important to cardiologists The two components that are of current interest are Cardiac Relaxation (associated with isovolumic relaxation) and Stiffness (related to filling and EDPVR). A final note on integration The lectures were designed to give you a sense of why things happen. If you only remember the how (the basics of each learning objective), you will possibly do fine. However, knowing the how and all of the connections will (hopefully) help you understand the pharmacology and pathophysiology better when you treat your patients. This is the sequence connecting these lectures: 1. Myocyte action potential and excitation driven by sodium (myocytes), potassium,… 2. Myocyte excitation moves from cell to cell via gap junctions 3. The electrocardiogram can track the path of depolarization 4. Calcium-induced calcium release by RyR causes increases in cytosolic calcium 5. Increased cytosolic calcium allows troponin/tropomyosin to move and allow myosin binding 6. Myosin ATPase generates force 7. Cardiac structure transmits force (tension/stress) into pressure 8. Cardiac output generated, impacted by all of the above If you understand how each step can be modified and its subsequent impact on the next steps, you’ll be able to understand most issues in cardiac function. 14