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$$$mm^3$$ 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$$$mm^3$$ 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$$$mm^3$$ 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$$$O_2$$ 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}$$$PG_{12}$$ 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$$$TXA_2$$ 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$$$TXA_2$$)

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+}$$$Ca^{2+}$$ channels open, triggering action potential and contraction.

• Repolarization occurs with the opening of voltage-gated $K^+$$$K^+$$ 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^+$$$Na^+$$ inflow

  • Parasympathetic neurons secrete acetylcholine,

    • Opens $K^+$$$K^+$$ 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^+$$$Na^+$$ channels (fast $Na^+$$$Na^+$$) open, and membrane potential plateaus at -15mV for 200−300 msec.

• Due to balance between slow influx of $Ca^{2+}$$$Ca^{2+}$$ and efflux of $K^+$$$K^+$$

• More $K^+$$$K^+$$ 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+}$$$Ca^{2+}$$-stimulated $Ca^{2+}$$$Ca^{2+}$$ release

  • Action potentials conducted along the sarcolemma and T tubules, open voltage-gated $Ca^{2+}$$$Ca^{2+}$$ channels

  • $Ca^{2+}$$$Ca^{2+}$$ diffuses into cells and stimulates the opening of calcium release channels of the SR

  • $Ca^{2+}$$$Ca^{2+}$$ (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+}$$$Ca^{2+}$$ concentration in cytoplasm reduced by active transport back into the SR and extrusion of $Ca^{2+}$$$Ca^{2+}$$ through the plasma membrane by the $Na^+ - Ca^{2+}$$$Na^+ - Ca^{2+}$$ 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