Week 2 PSL PDF

CARDIOVASCULAR SYSTEM (PSL301H) 2022 - 8 lectures Lecture Title 1 The Heart: Cardiac Muscle and Action Potential 2 Cardiac Excitability: Heart Rate and ECG 3 The Heart as a Pump: Cardiac Cycle 4 Regulation of Cardiac Output, Blood vessel Introduction 5 Blood flow: Pressure gradients and resistance 6...

CARDIOVASCULAR SYSTEM (PSL301H) 2022 - 8 lectures Lecture Title 1 The Heart: Cardiac Muscle and Action Potential 2 Cardiac Excitability: Heart Rate and ECG 3 The Heart as a Pump: Cardiac Cycle 4 Regulation of Cardiac Output, Blood vessel Introduction 5 Blood flow: Pressure gradients and resistance 6 Blood Pressure Control 7 Microvasculature, Lymph and Venous Return 8 Cardiovascular Health and Disease Silverthorn Textbook Chapter 14: Cardiovascular Physiology Chapter 15: Blood flow and control of blood pressure Professor Scott Heximer Physiology, 661 University Avenue, Rm 1414 E-mail: [email protected] About these lectures Goals: To understand: (1) the basic science of the heart and blood vessels (2) how dysfunction leads to disease To achieve this: Learn the anatomy and physiology of the cardiovascular system Understand: muscle biochemistry Consider: Heart as a pump in closed system Understand: pressure/ volume/ flow/ resistance PSL301H – Lecture 1: The heart: cardiac muscle and cardiac action potential What are the main functions of the CIRCULATORY SYSTEM? ‘What’ is being transported and ‘where’? Describe the structures of the heart and cardiac muscle How does an electrical signaling lead to contraction? **Please review my action potential review video Silverthorn 7th ed: 443-452, 435-439, 8th ed: 440-449, 432-436 What are the main functions of the “CIRCULATORY SYSTEM”? 1. Transport and distribute essential substances to the tissues. 2. Remove metabolic byproducts. 3. Adjustment of oxygen and nutrient supply in different physiologic states. 4. Regulation of body temperature. 5. ‘Humoral’ communication. Cardiovascular system anatomy The cardiovascular system is a closed loop with two pumps working in series. The heart contains two pumps working simultaneously to circulate blood through the system. Arteries take blood away from the heart, and veins carry blood back to the heart. Pulmonary Circuit: Right ventricle ! pulmonary trunk ! pulmonary arteries (branches) ! lungs pulmonary veins return O2-rich blood to the left atrium. Systemic Circuit: Left ventricle !Aorta carrying O2rich blood from the left ventricle! branches with an artery to each organ. Arteries divide into arterioles and capillaries which then lead to venules. Structure of the Heart The heart is composed mostly of myocardium (muscle) 2 pumps – need muscle to squeeze STRUCTURE OF THE HEART Aorta Pulmonary artery Superior vena cava Pericardium Right atrium Auricle of left atrium Coronary artery and vein BASE Right ventricle Diaphragm (e) The heart is encased within a membranous fluid-filled sac, the pericardium. Left ventricle APEX (f) The ventricles occupy the bulk of the heart. The arteries and veins all attach to the base of the heart. The Cardiovascular System The Heart has 4 Valves to direct one-way blood flow Bicuspid (mitral) valve. Tricuspid valve. Pulmonary valve. Aortic valve. " Semilunar valves " cup-like leaflets, found at ventricular exit points " Pulmonary valve – between RV and pulmonary trunk " Aortic valve – between LV and aorta " Atrioventricular valves " found between the atria and ventricles " tricuspid valve on the right AV junction " bicuspid (mitral) valve on the left AV junction " valves are re-enforced by chordae tendinae attached to muscular projections within the ventricles. Copyright © 2009 Pearson Education, Inc. Anatomy of the Heart: Major vessels, input and output Aorta Right pulmonary arteries Superior vena cava Right atrium Pulmonary semilunar valve Left pulmonary arteries Left pulmonary veins Left atrium Cusp of the AV (bicuspid) valve Cusp of a right AV (tricuspid) valve Chordae tendineae Papillary muscles Left ventricle Right ventricle Inferior vena cava Descending aorta The heart valves ensure one-way flow Passage of Blood Through the Heart Blood follows this sequence through the heart: → superior and inferior vena cava → right atrium → tricuspid (AV) valve → right ventricle → pulmonary (semilunar) valve → pulmonary trunk and arteries to the lungs → pulmonary veins leaving the lungs → left atrium → bicuspid (AV/mitral) valve → left ventricle → aortic (semilunar) valve → aorta → to the body. Path of blood through the heart and body Review question: A red blood cell is just leaving the foot. Arrange the following structures in the order that the red blood cell will encounter them on its path if it travels once around the body back to the foot. 1) Inferior vena cava 2) Mitral valve 3) Pulmonary artery 4) Aorta 5) Pulmonary semilunar valve Coronary artery circulation Cardiac Muscle: Central piece in CV physiology Myocardial muscle cells are branched, have a single nucleus, and are attached to each other by specialized junctions known as intercalated disks. Intercalated disks Myocardial muscle cell Intercalated disk (sectioned) Nucleus Intercalated disk Mitochondria Cardiac muscle cell Contractile fibers Unique properties of cardiac muscle Cardiac Muscle Properties Syncytial network – branched myocyte connections (1 cell may be connected to several –think about waves of dominoes) Connected by intercalated disks containing desmosomes (VelcroTM) to allow force transfer, and gap junctions for electrical connectivity Mitochondria occupy one-third of cell volume A schematic diagram of a cardiac muscle shows T-tubules, sarcoplasmic reticulum and myofilaments in skeletal muscle D. M. Bers, Excitation-Contraction Coupling and Cardiac Contractile Force, 2nd ed. (2002) Cardiac Muscle: Excitation-contraction coupling 10 Ca2+ 1 ECF 3 2 K+ ATP ICF Na+ 9 Ca2+ 1 Action potential enters from adjacent cell. NCX 3 Na+ RyR 2 Ca2+ 2+ 2+ 3 Ca induces Ca release through ryanodine receptor-channels (RyR). 2 3 SR L-type Ca2+ channel Ca2+ 4 2+ Ca sparks Sarcoplasmic reticulum (SR) 2+ Ca stores release causes 4 Local 2+ Ca spark. ATP T-tubule Voltage-gated Ca2+ channels open. Ca2+ enters cell. 2+ 5 Summed Ca sparks create a Ca2+ signal. 8 2+ 6 Ca ions bind to troponin to initiate contraction. 5 Ca2+ signal 6 Contraction Ca2+ 7 Relaxation occurs when Ca2+ unbinds from troponin. Ca2+ 7 7 Relaxation Actin Myosin 2+ 8 Ca is pumped back into the sarcoplasmic reticulum for storage. 2+ 9 Ca is exchanged with Na+ by the NCX antiporter. 10 Na+ gradient is maintained by the Na+-K+-ATPase. Side view of Ca2+-dependent regulation of acto-myosin interaction in cardiac muscle Copyright © 2009 Pearson Education, Inc. Action Potentials transmit electrical signals in the heart Copyright © 2009 Pearson Education, Inc. ke upstro (mV) resting potential -90 1 ms Number of open channels Downstroke phase: Na+ permeability decreases as Na+ channels inactivate. K permeability increases as K+ channels open. Membrane potential approaches EK 0 ENa oke n s tr Upstroke phase: Na+ permeability increases as Na+ channels open. Membrane potential approaches ENa +61 dow Ion channels alter membrane permeability EK Membrane hyperpolarized Na+ channels K+ channels Action Potentials propagate through the heart tissue Propagation: Rest Stimulated (local depolarization) Propagation (current spread) Na+ channel open generates local depolarization Local depolarization activates adjacent Na+ channels… and so on… Copyright © 2009 Pearson Education, Inc. Cardiac action potentials are unique Cardiac muscle action potentials differ considerably from action potentials found in neural and skeletal muscle cells. Main difference Main difference is duration: Nerves, about 1 ms. Skeletal muscle cells, 2-5 ms. Cardiac action potentials range from 200 to 400 ms. Membrane potential (mV) Myocardial Contractile Cell Action Potential 1 +20 PX = Permeability to ion X PNa 2 PK and PCa 0 –20 3 –40 0 –60 PNa –80 4 PK and PCa 4 –100 0 Phase 100 200 Time (msec) 300 Membrane channels 0 Na+ channels open 1 Na+ channels close 2 Ca2+ channels open; fast K+ channels close 3 Ca2+ channels close; slow K+ channels open 4 Resting potential Myocardial Contractile Cells: Refractory period Refractory period in cardiac muscle Skeletal Contractile Cells: Refractory period Refractory period in skeletal muscle Figure 14-14 - Overview Cardiac Na+ channels : inactivation and resetting upon repolarization n io de po la ri za t t za ri la po re io n Closed/Primed by repolarized state Inactivation open Copyright © 2009 Pearson Education, Inc. Inactivated by depolarized state Shown are the action potential (red) and muscle contraction profiles (blue) for skeletal and cardiac muscle in response to an electrical stimulus at time 0 ms (black arrowhead). If you give a second stimulus 50 ms after the first (red arrowhead), when would you expect the next action potential to begin for the two different muscle cells. Skeletal A. Skeletal, 50 ms; Cardiac, 50 ms. C. Skeletal, Never; Cardiac, 50 ms E. Skeletal, 50 ms; Cardiac, 300 ms Cardiac B. Skeletal, 100 ms; Cardiac, 300 ms D. Skeletal, 50 ms; Cardiac, Never Action Potentials in Skeletal muscle vs Myocardium One down – seven to go # PSL301H Lecture 5: Hemostasis Learning objectives Describe the three phases of hemostasis Learn about the coagulation cascade Describe the newer cell-based model of blood coagulation Explain how anticoagulants act Predict the effect of an excess or inadequate levels of clotting factors on the coagulation pathways Understand some of the clinical relevance of coagulation Textbook reading: 8th ed. 522-528 (7th ed. 523-530; 6th ed. 557-564; 5th ed. 558-565) and https://cmijournal.files.wordpress.com/2016/04/53-58cell-based-model.pdf Case studies 1) Dave is a 55-year-old man who recently had a mild heart attack. His physician has prescribed one baby aspirin per day. 2) Kristy is 18 and a competitive figure skater. She has von Willebrand disease. She constantly worries about internal bleeding injuries. For more see: http://www.hemophilia.ca/en/our-stories/ Case studies cont’d 3) Dilan has hemophilia A. His parents infuse him each week with factor VIII. 4) Jason is a 50-year-old man who was taken to the hospital because he was having vision problems, weakness in one arm and a severe headache. His doctor confirms that he has just had a stroke caused by a blood clot and quickly administers tissue plasminogen activator (tPA). For more see: http://www.hemophilia.ca/en/our-stories/ Recall: Hematopoiesis Figure 16.2 Platelets are needed for blood clotting Half-life of platelets = 10 days Thrombopoietin increases platelet numbers Figure 16.7 Three phases of hemostasis 3. Coagulation phase 1. Vascular phase 2. Platelet phase Figure 16.8 1) Vascular phase Neurogenic and myogenic control Vasoconstriction prolonged by: Serotonin Endothelin-1 Thromoboxane A2 2. Platelet phase Exposed collagen - Binds & activates platelets Factors released from platelet Factors attract more platelets Platelets aggregate; form plug Figure 16.9 Platelet phase details Exposed collagen - Binds & activates platelets Factors released from platelet Factors attract more platelets via vonWillebrand factor e.g. ADP, platelet activating factor (PAF), serotonin, thromboxane A2 Platelets aggregate; form plug von Willebrand factor made by endothelial cells and platelets. Binds to both collagen and platelets. ADP PAF Serotonin Thromboxane A2 Platelet aggregation Vasoconstriction Figure 16.9 Platelet activation Figure 16.7 Note: Without injury platelets are NOT activated Prostacyclin (prostaglandin I2, PGI2) and nitric oxide (NO) - prevent platelet adhesion and are vasodilators Figure from Silverthorn 5th ed Dave: Mild heart attack; one baby aspirin/day Arachidonic acid Cyclooxygenase PGH2 Prostaglandins Thromboxane A2 _ Aspirin Prostacyclin Given the pathways, how does aspirin reduce the risk of a subsequent heart attack? a) Reduces platelet aggregation by inhibiting thromboxane A2 synthesis b) Reduces vasoconstriction by inhibiting thromboxane A2 synthesis c) Reduces platelet aggregation by inhibiting prostacyclin synthesis d) Reduces vasoconstriction by inhibiting prostacyclin synthesis 3. Coagulation cascade Figure 16.11 Common pathway details Inactive plasma clotting factors (white boxes) converted to active enzymes. Figure 16.10 Extrinsic pathway Figure 16.10 von Willebrand factor regulates levels of VIII Vitamin K needed for the synthesis of thrombin, VII, IX and X Anticoagulant called Coumadin (Warfarin) – blocks the action of Vitamin K Instrinsic pathway Figure 16.10 von Willebrand factor regulates levels of VIII Vitamin K needed for the synthesis of thrombin, VII, IX and X Anticoagulant called Coumadin (Warfarin) – blocks the action of Vitamin K Summary Figure 16.10 But problems with this model e.g. Individuals with factor IX or factor VIII deficiency have severe bleeding even though their extrinsic and common pathways are normal and should be sufficient to promote clotting Newer model: Cell-based theory of coagulation Tissue factor (factor III) Watch video at: https://www.youtube.com/watch?v=T4MG7bzQ2NI Cell-based: Initiation phase Cell membrane of smooth muscle cells or fibroblasts in sub-endothelial layer Exposure of tissue factor (TF) starts this phase produces small amount of thrombin https://cmijournal.files.wordpress.com/2016/04/53-58-cell-based-model.pdf Amplification phase Thrombin activates factors V, XI, and VIII on surface of platelets https://cmijournal.files.wordpress.com/2016/04/53-58-cell-based-model.pdf Propagation phase Active factors on the surface of platelets form tenase and then prothrombinase results in LARGE amounts of thrombin = thrombin burst Thrombin cleaves fibrinogen and factor XIII to result in fibrin formation and crosslinking https://cmijournal.files.wordpress.com/2016/04/53-58-cell-based-model.pdf Summary Figure 16.10 Case study #2 Kristy competitive figure skater with has von Willebrand disease Most common coagulation disorder (1:100) Problems in quality or quantity of von Willebrand factor (vWf) Areas with high number of small capillaries (skin, gi tract, uterus) most susceptible Question: What are the step(s) in hemostasis that are impaired in Kristy? a) Platelet aggregation at wound site b) Ability to bind factor VIII on the surface of platelets c) Ability to fully activate factor X d) All of the above Case study #3 Dilan has hemophilia A; regularly infused with factor VIII X-linked recessive trait; deficiency in factor VIII Factor VIII forms a complex with factor IX to activate factor X Suffer internal and external bleeds Question: What are the step in hemostasis that are impaired in Dilan? a) Platelet aggregation at wound site b) Ability to form the tenase complex c) Ability to fully activate factor X d) b and c Figure 16.10 (Note: Hemophilia B due to deficiency in factor IX) How is the clot removed after healing has taken place? tPA released slowly by damaged endothelium Figure 16.11 Case study #4 Jason just had a stroke caused by a blood clot. Thrombus – Blood clot attached to vessel wall Embolus – Floating blood clot Case study #4 cont’d Doctor quickly administers tissue plasminogen activator (tPA) tPA must be administered within 3-4 hours following a stroke Helps to breakup clot and reduces tissue damage Must ensure stroke not caused by hemorrhage How does tPA act as an anticoagulant? a) Inhibits the action of thrombin b) Blocks the action of Vitamin K c) Stimulates the conversion of plasminogen to plasmin d) Enzymatically breaks down fibrin Physiological anticoagulants Name Released from Activated by Liver tPA and thrombin Many tissues Normally present Plasminogen/ plasmin Tissue plasminogen activator (tPA) Antithrombin III Liver Heparin Prostacyclin N/A See Table 16.5 Endothelial cells Function Breaks down fibrin Activates plasminogen Blocks IX, X, XI, XII, thrombin Inhibits platelet aggregation Next class Cardiovascular system with Professor Scott Heximer Dr. Heximer would like to watch this video to help you understand action potentials in the heart This will help you with cardio lectures 1 and 2 (best to watch before these lectures) https://play.library.utoronto.ca/NFo421uzmKj2 PSL301H—Blood and Immune System Lecture 4: Acquired Immunity cont’d Learning outcomes Describe T cell activation Give examples of when our immune system helps us and when it does not Explain why knowing your blood type important Explain the connection between Rh factor and pregnancy Provide the immunological basis of how doctors prevent hemolytic disease of the newborn Textbook reading: 8th ed. 772-775, 777-778 (7th ed. 770-773, 777-778; 6th ed. 818-824; 5th ed. 798-804) Defence against pathogens Innate Immunity rapid, non-specific To be continued Acquired Immunity slower, specific Figure from Interactive Physiology Recall: T cell receptors bind to antigens that are bound to MHC T cell receptor Viral antigen Major histocompatability complex (MHC) Figure from Interactive Physiology T cells activation MHC-antigen complex 1 Cell binds to T lymphocyte. 2 Signal transduction activates T lymphocyte. T-cell receptor MHC receptor T lymphocyte Figure 24.15 Copyright © 2010 Pearson Education, Inc. Key types of T cells Helper T cells (CD4) Bind MHC class II & antigen Release cytokines Activate T and B cells Cytotoxic T cells (CD8) Bind MHC class I & antigen Kill infected/cancerous cells Figure from Interactive Physiology Details: functions of activated T cells Figure 24.15 MHC class II Located on dendritic cells, macrophages and B cells Present exogenous antigen Activate helper T cells Dendritic cell Figure from Martini (2006) Fundamentals of Anatomy and Physiology Activation of helper T cells Co-stimulation Cytokines will stimulate – helper T cells, cytotoxic T cells and B cells Figure from Martini (2006) Fundamentals of Anatomy and Physiology Recall activation of B cells MHC class II T cell receptor B cell receptor B cell Antigen Helper T cell + cytokines Review question Which of these lymphocytes will bind to an antigen originating from a bacterium that was digested by a macrophage? A) B) C) D) Helper T cell Cytotoxic B Cell Cytotoxic T cell NK Cell MHC class I Located on all nucleated cells Present endogenous antigen Activate cytotoxic T cells Figure from Martini (2006) Fundamentals of Anatomy and Physiology Infected/cancerous cell or dendritic cell Activation of cytotoxic T cells Dendritic cell + IL-2, interferon g Infected cell Figure from Martini (2006) Fundamentals of Anatomy and Physiology Putting it all together: Immune response to a virus 1 1 Virus invades host Macrophage ingests virus MHC-II 2 2 MHC-I Viral antigen Uninfected host cell Interferon- Viral antigen 3 3 Activates helper T cell Cytokines Infected host cell Inflammatory response Helper T cell activates 4 55 Virus Attacked by cytotoxic T cells Perforins, granzymes T-cell receptor Cytotoxic T cell B lymphocytes Plasma cells Infected cell undergoes apoptosis and dies. Antibodies Figure 24.17 Review question Which of the following is needed to mount an immune response to intracellular pathogens but is not used to rid the body of extracellular pathogens? A) Helper T cells B) Cytotoxic T cells C) B cells D) Complement Lalit has a condition in which his body cells under express MHC class I, which of the following is correct? A. His helper T cells cannot bind antigen B. His B cells cannot be activated C. His cytotoxic T cells will attack his own body cells D. He may not be able to mount an adequate acquired immune response Immune system: Friend or foe? Immune response 1. 2. Grafted organ Unmatched blood 3. 4. Case study: Beatrice is a 26-year-old pregnant woman with blood type A-. Her partner is type O+. Questions: 1) Why is this cause for concern? 2) What have Beatrice’s doctors done to alleviate this concern? Blood types and blood donation ABO blood groups 42% 9% 3% 46% Rh blood group Europeans: Rh positive = 85%; Rh negative =15% Asians, Africans, Native Americans: Rh pos= 99%; Rh neg = 1% ~Figure 24.19 Why is knowing your blood type important? Cross-reactions occur during blood transfusions if antigens on donor RBC meet antibodies in recipients plasma Figure from Martini (2006) Fundamentals of Anatomy and Physiology ~Figure 24.19 19 For example: Type B blood donor to Type A recipient type B antigens on donor’s red blood cells anti-B antibodies in recipient 20 Predict what would happen with the following combinations of donors and recipients Donor O Recipient A B O (anti-A, anti-B) A (anti-B) B (anti-A) AB + = agglutination - = no agglutination AB What is the connection between Rh factor (D antigen) and pregnancy? Unlike the ABO blood group, Rh- individuals do not normally have anti-D antibodies, but these can develop by: transfusion of Rh- individual with Rh+ (D antigen) blood pregnancy Rh- mother and Rh+ baby 22 Rh antigen and pregnancy Hemolytic disease of the newborn: Anemia, jaundice, enlarged liver and spleen, and severe edema. Figure from Martini (2006) Fundamentals of Anatomy and Physiology Rh+ means that the red blood cells have the D antigen 23 How do doctors prevent hemolytic disease of the newborn? Inject anti-D antigen antibodies into Rh- mother during and following her pregnancy The antibodies bind to and remove fetal red blood cells in mother’s bloodstream before they can trigger an immune response in the mother Thus, B cells are not activated in the mother and no immunological memory of the D antigen is acquired Therefore in a subsequent pregnancy with an Rh+ fetus, the mother does not produce anti-D antigen antibodies upon exposure to fetal red blood cells with D antigen Review question Lalit has suffered a wound on the job at the construction company he works at and requires a blood transfusion. His blood type is B-. Which blood type could you transfuse him with and why? A. O+ This type lacks anti-A and anti-B antibodies. B. B- or O- These types lack A antigens and would not react with the anti-A antibodies in his blood. C. B- This is the only blood type that you can transfuse because he has Rh negative blood. D. A- This type lacks B antigens and has anti-B antibodies Summary: Cells of the immune system Types of Cells Monocytes Basophils Neutrophils Lymphocytes Eosinophils Dendritic Cells Mast Cells Macrophages Classifications Plasma Cells Phagocytes Granulocytes Cytotoxic cells (some types) Cytotoxic cells Antigen-presenting cells % of WBCs in blood Rare Subtypes and nicknames Primary function(s) 50–70% 1–3% Called “polys” or “segs.” Immature forms called “bands” or “stabs.” Release chemicals that mediate inflammation and allergic responses Ingest and destroy invaders Destroy invaders, particularly antibodycoated parasites 1–6% 20–35% NA Called the mononuclear phagocyte system B lymphocytes Plasma cells Memory cells T lymphocytes Cytotoxic T cells Helper T cells Natural killer cells Also called Langerhans cells, veiled cells Ingest and destroy invaders. Antigen presentation Specific responses to invaders, including antibody production Recognize pathogens and activate other immune cells by antigen presentation Summary Figure from Martini (2006) Fundamentals of Anatomy and Physiology Next class Textbook reading: 8th ed. 522-528 (7th ed. 523-530; 6th ed. 557-564; 5th ed. 558-565) and https://cmijournal.files.wordpress.com/2016/04/53-58-cell-based-model.pdf 1) Dave is a 55-year-old man who recently had a mild heart attack. His physician has prescribed one baby aspirin per day. 2) Kristy is 18 and a competitive figure skater. She has von Willebrand disease. She constantly worries about internal bleeding injuries. Case studies cont’d 3) Dilan has hemophilia A. His parents infuse him each week with factor VIII. 4) Jason is a 50-year-old man who was taken to the hospital because he was having vision problems, weakness in one arm and a severe headache. His doctor confirms that he has just had a stroke caused by a blood clot and quickly administers tissue plasminogen activator (tPA). For more see: http://www.hemophilia.ca/en/our-stories/