Comprehensive Notes on Blood, Heart, and Circulation

Functions of the Circulatory System

  • Transportation
    • Respiratory gases
    • Nutrients
    • Wastes
  • Regulation
    • Hormonal
    • Temperature
  • Protection
    • Clotting
    • Immunity

Major Components of the Circulatory System

  • Cardiovascular system
    • Heart: four-chambered pump
    • Blood vessels: arteries, arterioles, capillaries, venules, and veins
  • Lymphatic system
    • Lymphatic vessels
    • Lymphoid tissues
    • Lymphatic organs (spleen, thymus, tonsils, lymph nodes)

Composition of the Blood

  • Average adult volume is about 5 liters.
  • Arterial blood
    • Leaving the heart
    • Bright red, oxygenated (except for blood going to the lungs)
  • Venous blood
    • Entering the heart
    • Dark red, deoxygenated (except for blood coming from the lungs)
  • Made of approximately 45% formed elements and approximately 55% plasma (by volume)

Constituents of blood

  • Plasma

    • Fluid part of blood
    • Water
    • Dissolved solutes
    • Plasma proteins
      • Make up 7-8% of the plasma
      • Albumin: creates osmotic pressure to help draw water from tissues into capillaries to maintain blood volume and pressure
      • Globulins
        • Alpha and beta globulins – transport lipids and fat-soluble vitamins
        • Gamma globulins – antibodies that function in immunity
      • Fibrinogen: helps in clotting after becoming fibrin
        • Serum – blood without fibrinogen
    • Plasma volume
      • Regulatory mechanisms maintain plasma volume to maintain blood pressure
      • Osmoreceptors in the hypothalamus cause the release of ADH from the posterior pituitary gland if fluid is lost

  • Formed elements of the blood

    • Erythrocytes (red blood cells – RBCs)
      • Flattened, biconcave discs
      • Transport oxygen
      • Lack nuclei and mitochondria
      • Count – approximately 5 million/mm^3 blood
      • Have a 120-day life span
      • Each contain about 280 million hemoglobin molecules
      • Iron heme is recycled from the liver and spleen; carried by transferrin (globulin) in the blood to the red bone marrow
    • Leukocytes (white blood cells – WBCs)
      • Have nuclei and mitochondria
      • Move in amoeboid fashion
      • Exhibit Chemotaxis – movement directed by attraction to stimulus (chemicals)
      • Diapedesis/Extravasation – movement through the capillary wall into connective tissue to site of infection/injury
      • Count – approximately 5000-9000/mm^3 blood
      • Types of leukocytes:
        • Granular leukocytes: neutrophils, eosinophils, and basophils
        • Agranular leukocytes: monocytes and lymphocytes
    • Platelets (thrombocytes)
      • Smallest formed element, fragments of large cells called megakaryocytic
      • Lack nuclei
      • Very short-lived (5−9 days)
      • Clot blood with several other chemicals and fibrinogen
      • Release serotonin that stimulates vasoconstriction
      • Count – 130,000 – 400,000/mm^3 blood

Hemopoiesis (Hematopoiesis)

  • Process of blood cell formation
  • Hematopoietic stem cells – embryonic cells that give rise to all blood cells
  • Process occurs in myeloid tissue (red bone marrow) and lymphoid tissue (lymph nodes, spleen, tonsils, thymus)
  • As cells differentiate, they develop membrane receptors for chemical signals

Erythropoiesis

  • Formation of red blood cells
  • Red bone marrow produces about 2.5 million RBCs/sec
  • Regulation of erythropoiesis:
    • Process stimulated by erythropoietin (EPO) from the kidneys that respond to low blood O_2 levels
    • Process takes about 3-4 days
    • Most iron is recycled from old RBCs, the rest comes from the diet
    • Intestinal iron secreted into blood through ferroportin channels
    • All iron travels in blood bound to transferrin
    • Major regulator of iron homeostasis is the hormone hepcidin which removes ferroportin channels to promote cellular storage of iron and lowers plasma iron levels

Leukopoiesis (WBCs)

  • Formation of white blood cells
  • Several types of Cytokines (signaling molecules used for intercellular communication) stimulate the production of the different WBC subtypes. Cytokines include:
    • Multipotent growth factor-1
    • Interleukin-1
    • Interleukin-3
    • Granuloctye colony stimulating factor
    • Granulocyte-monocyte colony-stimulating factor

Thrombopoiesis:

  • Thrombopoietin (cytokine from liver and kidneys) stimulates growth of megakaryocytes
  • Megakaryocytes are large, multinucleated cells that secrete (“bud off”) cell fragments = platelets

Blood Clotting

  • Hemostasis: cessation of bleeding when a blood vessel is damaged
  • Damage exposes collagen fibers to blood, producing:
    • Vasoconstriction
    • Formation of platelet plug
    • Formation of fibrin protein web
  • Platelets and blood vessel walls
    • Intact endothelium secretes prostacyclin (PG_{12} a prostaglandin) and nitric oxide (NO), which:
      • Vasodilate
      • Inhibit platelet aggregation
    • and CD39 (enzyme), which:
      • Breaks down ADP into AMP and Pi to inhibit platelet aggregation further
    • Damaged endothelium exposes collagen
      • Platelets bind to collagen.
      • Von Willebrand factor (protein produced by endothelial cells) holds them there.
      • Platelets recruit more platelets and form a platelet plug by secreting: (Platelet release reaction)
        • ADP (sticky platelets)
        • Serotonin (vasoconstriction)
        • Thromboxane A (TXA_2 a prostaglandin - sticky platelets and vasoconstriction)
      • Activated platelets also activate plasma clotting factors (12 in total)
    • Clotting factors:
      • Formation of Fibrin:
        • Fibrinogen is converted to fibrin via one of two pathways:
          • Intrinsic: Activated by exposure to collagen. Factor XII activates a cascade of other blood factors.
          • Extrinsic: Initiated by tissue thromboplastin (factor III). This is a more direct pathway.
      • Next, calcium and phospholipids (from the platelets) convert prothrombin to the active enzyme thrombin, which converts fibrinogen to fibrin.
      • Vitamin K is needed by the liver to make several of the required clotting factors
    • Dissolution of clots
      • Factor XII activates Kallikrein > plasminogen > plasmin digests fibrin
    • Clotting can be prevented with certain drugs:
      • Calcium chelators (sodium citrate or EDTA)
      • Heparin: blocks thrombin
      • Coumadin: inhibits vitamin K
      • Aspirin: inhibits COX Enzyme, inhibits prostaglandin production (TXA_2)

Structure of the Heart

  • Four chambers; two upper (atria), two lower (ventricles)
  • Right atrium: receives deoxygenated blood from the body
  • Left atrium: receives oxygenated blood from the lungs
  • Right ventricle: pumps deoxygenated blood to the lungs
  • Left ventricle: pumps oxygenated blood to the body
  • Fibrous skeleton
    • Separates atria from ventricles. The atria therefore work as one unit, while the ventricles work as a separate unit.

Pulmonary and Systemic Circulations

  • Pulmonary: between heart and lungs
    • Blood pumps to lungs via pulmonary arteries.
    • Blood returns to heart via pulmonary veins.
  • Systemic: between heart and body tissues
    • Blood pumps to body tissues via aorta.
    • Blood returns to heart via superior and inferior venae cavae.

Atrioventricular & Semilunar Valves

  • Atrioventricular (AV) valves: located between the atria and the ventricles
    • Tricuspid: between right atrium and ventricle
    • Bicuspid or mitral: between left atrium and ventricle
    • Papillary muscles and chordae tendineae prevent the valves from prolapsing
  • Semilunar valves: located between the ventricles and arteries leaving the heart
    • Pulmonary: between right ventricle and pulmonary trunk
    • Aortic: between left ventricle and aorta
  • Heart Sounds
    • Produced by closing valves
      • “Lub” = closing of AV valves; occurs at ventricular systole
      • “Dub” = closing of semilunar valves; occurs at ventricular diastole
    • Heart Murmur
      • Abnormal heart sounds produced by abnormal blood flow through heart.
      • Many caused by defective heart valves.
      • Mitral stenosis: Mitral valve calcifies and impairs flow between left atrium and ventricle.
        • May result in pulmonary hypertension.
      • Incompetent valves: do not close properly
        • May be due to damaged papillary muscles
        • Mitral valve prolapse – most common cause of chronic mitral regurgitation
      • Septal defects: holes in interventricular or interatrial septa which allows blood to cross sides.

Cardiac Cycle

  • Repeating pattern of contraction and relaxation of the heart.
    • Systole: contraction of heart muscles
    • Diastole: relaxation of heart muscles
    • End-diastolic volume (EDV) – total volume of blood in the ventricles at the end of diastole
    • End-systolic volume (ESV) – the amount of blood left in the left ventricle after systole (1/3 of the end-diastolic volume)
  • Pressure Changes During the Cardiac Cycle
    • Ventricles begin contraction, pressure rises, and AV valves close (lub); isovolumetric contraction
    • Pressure builds, semilunar valves open, and blood is ejected into arteries.
    • Pressure in ventricles falls; semilunar valves close (dub); isovolumetric relaxation
    • Pressure in ventricles falls below that of atria, and AV valve opens. Ventricles fill.
    • Atria contract, sending last of blood to ventricles

Electrical Activity of the Heart and the Electrocardiogram

  • Cardiac muscle cells are interconnected by gap junctions called intercalated discs.
  • Once stimulation is applied, the impulse flows from cell to cell.
  • The area of the heart that contracts from one stimulation event is called a myocardium or functional syncytium.
  • The atria and ventricles are separated electrically by the fibrous skeleton.
  • Electrical Activity of the Heart:
    • Automaticity – automatic nature of the heartbeat
    • Sinoatrial node (SA node) - “pacemaker”; located in right atrium
    • AV node and Purkinje fibers are secondary pacemakers of ectopic pacemakers; slower rate than the “sinus rhythm”

Pacemaker potential

  • A slow, spontaneous depolarization; also called diastolic depolarization – between heartbeats, triggered by hyperpolarization
  • At −40mV, voltage-gated Ca^{2+} channels open, triggering action potential and contraction.
  • Repolarization occurs with the opening of voltage-gated K^+ channels.
  • Pacemaker cells in the SA node depolarize spontaneously, but the rate at which they do so can be modulated:
    • Epinephrine and norepinephrine (sympathetic NS) increase the production of cAMP, which keeps cardiac pacemaker channels open.
      • Called HCN channels – hyperpolarization-activated cyclic nucleotide-gated channels
      • Speeds heart rate due to Na^+ inflow
    • Parasympathetic neurons secrete acetylcholine,
      • Opens K^+ channels to
      • Slows the heart rate

Myocardial action potentials

  • Cardiac muscle cells have a RMP of −85mV.
  • They are depolarized to threshold by action potentials from the SA node.
  • Voltage-gated Na^+ channels (fast Na^+) open, and membrane potential plateaus at -15mV for 200−300 msec.
  • Due to balance between slow influx of Ca^{2+} and efflux of K^+
  • More K^+ are opened, and repolarization occurs.
  • Long plateau prevents summation and tetanus

Conducting tissues of the heart

  • Action potentials spread via intercalated discs (gap junctions).
  • SA node to AV node to stimulate atrial contraction
  • AV node at base of right atrium and AV bundle (bundle of His) conduct stimulation to ventricles.
  • In the interventricular septum, the bundle of His divides into right and left bundle branches.
  • Branch bundles become Purkinje fibers, which stimulate ventricular contraction.

Conduction of Impulses

  • Action potentials from the SA node spread rapidly
    • 0.8–1.0 meters/second
  • At the AV node, things slow down (= AV nodal delay).
    • 0.03−0.05 m/sec
    • This accounts for half of the time delay between atrial and ventricular contraction.
  • The speed picks up in the bundle of His, reaching 5 m/sec in the Purkinje fibers.
    • Ventricles contract 0.1–0.2 seconds after atria.

Excitation-contraction Coupling

  • Ca^{2+}-stimulated Ca^{2+} release
    • Action potentials conducted along the sarcolemma and T tubules, open voltage-gated Ca^{2+} channels
    • Ca^{2+} diffuses into cells and stimulates the opening of calcium release channels of the SR
    • Ca^{2+} (mostly from SR) binds to troponin to stimulate contraction
    • These events occur at signaling complexes on the sarcolemma where it is close to the SR
  • Repolarization
    • Ca^{2+} concentration in cytoplasm reduced by active transport back into the SR and extrusion of Ca^{2+} through the plasma membrane by the Na^+ - Ca^{2+} exchanger
    • Myocardium relaxes

Refractory Periods

  • Because the atria and ventricles contract as single units, they cannot sustain a contraction.
  • Because the action potential of cardiac cells is long, they also have long refractory periods before they can contract again.

Atherosclerosis and Cardiac Arrhythmias

  • Atherosclerosis
    • Most common form of arteriosclerosis (hardening of the arteries)
    • Contributes to 50% of the deaths due to heart attack and stroke
    • Plaques protrude into the lumen and reduce blood flow.
    • Serve as sites for thrombus formation
    • Plaques form in response to damage done to the endothelium of a blood vessel.
    • Caused by smoking, high blood pressure, diabetes, high cholesterol
  • Developing Atherosclerosis
    • Lipid-filled macrophages and lymphocytes assemble at the site of damage within the tunica interna (fatty streaks).
    • Next, layers of smooth muscle are added.
    • Finally, a cap of connective tissue covers the layers of smooth muscle, lipids, and cellular debris.
    • Progress promoted by inflammation stimulated by cytokines and other paracrine regulators.
  • Cholesterol and Lipoproteins
    • Low-density lipoproteins (LDLs) carry cholesterol to arteries.
    • People who consume or produce a lot of cholesterol have more LDLs.
    • This high LDL level is associated with increased development of atherosclerosis
    • High-density lipoproteins (HDLs) carry cholesterol away from the arteries to the liver for metabolism.
    • This takes cholesterol away from the macrophages in developing plaques (foam cells).
    • Statin drugs (e.g., Lipitor), fibrates, and niacin increase HDL levels.
  • Inflammation in Atherosclerosis
    • Atherosclerosis is now believed to be an inflammatory disease.
    • C-reactive protein (a measure of inflammation) is a better predictor for atherosclerosis than LDL levels.
    • When endothelial cells engulf LDLs, they become oxidized LDLs that damage the endothelium
    • Antioxidants may be future treatments for this condition.
  • Ischemic Heart Disease
    • Ischemia is a condition characterized by inadequate oxygen due to reduced blood flow.
    • Atherosclerosis is the most common cause.
    • Associated with increased production of lactic acid and resulting pain, called angina pectoris (referred pain).
    • Eventually, necrosis of some areas of the heart occurs, leading to a myocardial infarction (heart attack or MI).
    • Nitroglycerin produces vasodilation:
      • Improves blood flow
    • Dead myocardial cells cannot be replaced by mitosis of neighboring cells
    • Reperfusion injury may cause death of neighboring cells to enlarge the infarct

Detecting Ischemia

  • Depression of the S-T segment of an electrocardiogram
  • Plasma concentration of blood enzymes:
    • Creatine phosphokinase (CPK) – 3-6 hours, return to normal in 3 days
    • Lactate dehydrogenase (LDH) – 48-72 hours, elevated about 11 days
    • Troponin I – today’s most sensitive test
    • Troponin T

Lymphatic System

  • Functions of the Lymphatic System
    • Transports excess interstitial fluid (lymph) from tissues to the veins
    • Produces and houses lymphocytes for the immune response
    • Transports absorbed fats from intestines to blood
  • Vessels of the Lymphatic System
    • Lymphatic capillaries: smallest; found within most organs
      • Interstitial fluids, proteins, microorganisms, and fats can enter.
    • Lymph ducts: formed from merging capillaries
      • Similar in structure to veins
    • Lymph is filtered through lymph nodes
    • Thoracic trunk and right lymphatic trunk
      • From merging lymphatic ducts
      • Deliver lymph into right and left subclavian veins
  • Organs of the Lymphatic System
    • Tonsils, thymus, spleen
    • Sites for lymphocyte production – lymphoid tissue