SECTION A: BLOOD

1. BLOOD CELLS
   1. Blood is composed of cells (erythrocytes, leukocytes, and platelets) and plasma, the liquid in which the cells are suspended.
   2. Plasma contains proteins (albumins, globulins, and fibrinogen), nutrients, metabolic end products, hormones, and inorganic electrolytes.
   3. Erythrocytes, which make up more than 99 percent of blood cells, contain hemoglobin, an oxygen-binding protein. Oxygen binds to the iron in hemoglobin.
      1. Erythrocytes are produced in the bone marrow and destroyed in the spleen and liver.
      2. Iron, folic acid, and vitamin B are essential for erythrocyte formation.
      3. The hormone erythropoietin, which is produced by the kidneys in response to low oxygen supply, stimulates erythrocyte differentiation and production by the bone marrow.

   4. The leukocytes include three types of polymorphonuclear granulocytes (neutrophils, eosinophils, and basophils), monocytes, and lymphocytes.
   5. Platelets are cell fragments essential for blood clotting.
   6. Blood cells are descended from stem cells in the bone marrow. Their production is controlled by hematopoietic growth factors.

SECTION B: OVERALL DESIGN OF THE CARDIOVASCULAR SYSTEM

1. PRESSURE, FLOW, AND RESISTANCE
   1. The cardiovascular system consists of two circuits: the pulmonary circulation, from the right ventricle to the lungs and then to the left atrium; and the systemic circulation, from the left ventricle to all peripheral organs and tissues and then to the right atrium
   2. Arteries carry blood away from the heart, and veins carry blood toward the heart
      1. In the systemic circuit, the large artery leaving the left heart is the aorta, and the large veins emptying into the right heart are the superior vena cava and inferior vena cava. The analogous vessels in the pulmonary circulation are the pulmonary trunk and the four pulmonary veins.
      2. The microcirculation consists of the vessels between arteries and veins: the arterioles, capillaries, and venules.

   3. Flow between two points in the cardiovascular system is directly proportional to the pressure difference between the points and inversely proportional to the resistance: F = P/R
   4. Resistance is directly proportional to the viscosity of a fluid and to the length of the tube. It is inversely proportional to the fourth power of the tube's radius, which is the major variable controlling changes in resistance.

SECTION C: THE HEART

1. ANATOMY
   1. The atrioventricular (AV) valves prevent flow from the ventricles back into the atria.
   2. The pulmonary and aortic valves prevent back flow from the pulmonary trunk into the right ventricle and from the aorta into the left ventricle.
   3. Cardiac muscle cells are joined by gap junctions that permit action potentials to be conducted from cell to cell.
   4. The myocardium also contains specialized muscle cells that constitute the conducting system of the heart, initiating the cardiac action potentials and speeding their spread through the heart.

2. HEARTBEAT COORDINATION
   1. Cardiac muscle cells must undergo action potentials for contraction to occur.
      1. The rapid depolarization of the action potential in atrial and ventricular cells (other than those in the conducting system) is due mainly to a positive feedback increase in sodium permeability.
      2. Following the initial rapid depolarization, the membrane remains depolarized (the plateau phase) almost the entire duration of the contraction because of prolonged entry of calcium into the cell through slow plasma-membrane channels.

   2. The SA node generates the current that leads to depolarization of all other cardiac muscle cells.
      1. The SA node manifests a pacemaker potential, which brings its membrane potential to threshold and initiates an action potential.
      2. The impulse spreads from the SA node throughout both atria and to the AV node, where a small delay occurs. The impulse then passes in turn into the bundle of His, right and left bundle branches, Purkinje fibers, and nonconducting-system ventricular fibers.

   3. Calcium, mainly released from the sarcoplasmic reticulum (SR), functions as the excitation- contraction coupler in cardiac muscle, as in skeletal muscle, by combining with troponin.
      1. The major signal for calcium release from the SR is calcium entering through voltage-gated calcium channels in the plasma membrane during the action potential.
      2. The amount of calcium released does not usually saturate all troponin binding sites, and so the number of active cross bridges can be increased if cytosolic calcium is increased still further.

   4. Cardiac muscle cannot undergo summation of contractions because it has a very long refractory period.

3. MECHANICAL EVENTS OF THE CARDIAC CYCLE
   1. The cardiac cycle is divided into systole (ventricular contraction) and diastole (ventricular relaxation).
      1. At the onset of systole, ventricular pressure rapidly exceeds atrial pressure, and the AV valves close. The aortic and pulmonary valves are not yet open, however, and so no ejection occurs during this isovolumetric ventricular contraction.
      2. When ventricular pressures exceed aortic and pulmonary trunk pressures, the aortic and pulmonary valves open, and ventricular ejection of blood occurs.
      3. When the ventricles relax at the beginning of diastole, the ventricular pressures fall significantly below those in the aorta and pulmonary trunk, and the aortic and pulmonary valves close. Because AV valves are also still closed, no change in ventricular volume occurs during this isovolumetric ventricular relaxation.
      4. When ventricular pressures fall below the pressures in the right and the left atria, the AV valves open, and the ventricular filling phase of diastole begins.
      5. Filling occurs very rapidly at first so that atrial contraction, which occurs at the very end of diastole, usually adds only a small amount of additional blood to the ventricles.

   2. The amount of blood in the ventricles just before systole is the end diastolic volume. The volume remaining after ejection is the end-systolic volume, and the volume ejected is the stroke volume.
   3. Pressure changes in the systemic and pulmonary circulations have similar patterns but the pulmonary pressures are much lower.
   4. The first heart sound is due to the closing of the AV valves, and the second to the closing of the aortic and pulmonary valves.

4. THE CARDIAC OUTPUT
   1. The cardiac output is the volume of blood pumped by each ventricle and equals the product of heart rate and stroke volume.
      1. Heart rate is increased by stimulation of the sympathetic nerves to the heart and by epinephrine; it is decreased by stimulation of the parasympathetic nerves to the heart.
      2. Stroke volume is increased by an increase in end-diastolic volume (the Frank-Starling mechanism) and by an increase in contractility due to sympathetic-nerve stimulation or to epinephrine.

1. ARTERIES
   1. The arteries function as low-resistance conduits and as pressure reservoirs for maintaining blood flow to the tissues during ventricular relaxation.
   2. The difference between maximal arterial pressure (systolic pressure) and minimal arterial pressure (diastolic pressure) during a cardiac cycle is the pulse pressure.
   3. Mean arterial pressure can be estimated as diastolic pressure plus one-third pulse pressure.

2. ARTERIOLES
   1. Arterioles, the dominant site of resistance to flow in the vascular system, play major roles in determining mean arterial pressure and in distributing flows to the various organs and tissues.
   2. Arteriolar resistance is determined by local factors and by reflex neural and hormonal input.
      1. Local factors that change with the degree of metabolic activity cause the arteriolar vasodilation and increased flow of active hyperemia.
      2. Flow autoregulation, a change in resistance that maintains flow constant in the face of a change in arterial blood pressure, is due to local metabolic factors and to arteriolar myogenic responses to stretch.
      3. The sympathetic nerves are the only innervation of most arterioles and cause vasoconstriction via alpha-adrenergic receptors. In certain cases noncholinergic, non-adrenergic neurons that release nitric oxide or other noncholinergic vasodilators also innervate blood vessels.
      4. Epinephrine causes vasoconstriction or vasodilation, depending on the proportion of alpha- and beta-adrenergic receptors in the organ.
      5. Angiotensin II and vasopressin cause vasoconstriction.
      6. Some chemical inputs act by stimulating endothelial cells to release vasodilator or vasoconstrictor paracrine agents, which then act on adjacent smooth muscle. These paracrine agents include the vasodilators nitric oxide (endothelium-derived relaxing factor) and prostacyclin, and the vasoconstrictor endothelin-1.

   3. Arteriolar control in specific organs varies considerably, including influences from metabolic factors, physical forces, autoregulation, and sympathetic nerves.

3. CAPILLARIES
   1. Capillaries are the site of exchange of nutrients and waste products between blood and tissues.
   2. Blood flows through the capillaries more slowly than in any other part of the vascular system because of the huge cross-sectional area of the capillaries.
   3. Capillary blood flow is determined by the resistance of the arterioles supplying the capillaries and by the number of open precapillary sphincters.
   4. Diffusion is the mechanism by which nutrients and metabolic end-products exchange between capillary plasma and interstitial fluid.
      1. Lipid-soluble substances move across the entire endothelial wall, whereas ions and polar molecules move through water-filled intercellular clefts or fused-vesicle channels.
      2. Plasma proteins move across most capillaries only very slowly, either by diffusion through water-filled channels or by vesicle transport.
      3. The diffusion gradient for a substance across capillaries arises as a result of cell utilization production of the substance. Increased metabolism increases the diffusion gradient and increases the rate of diffusion.

   5. Bulk flow of protein-free plasma or interstitial fluid across capillaries determines the distribution of extracellular fluid between these two fluid compartments.
      1. Filtration from plasma to interstitial fluid is favored by the hydrostatic pressure difference between the capillary and the interstitial fluid. Absorption from interstitial fluid to plasma is favored by the plasma protein concentration difference between the plasma and the interstitial fluid.
      2. Filtration and absorption do not change the concentrations of crystalloids in the plasma and interstitial fluid because these substances move together with water.
      3. There is normally a small excess of filtration over absorption.

4. VEINS
   1. Veins serve as low-resistance conduits for venous return.
   2. Veins are very compliant and contain most of the blood in the vascular system.
      1. Their diameters are reflexively altered by sympathetically-mediated vasoconstriction so as to maintain venous pressure and venous return.
      2. The skeletal-muscle pump and respiratory pump increase venous pressure locally and enhance venous return. Venous valves permit the pressure to produce only flow toward the heart.

5. THE LYMPHATIC SYSTEM
   1. The lymphatic system provides a one-way route for movement of interstitial fluid to the cardiovascular system.
   2. Lymph returns the excess fluid filtered from the blood vessel capillaries, as well as the protein that leaks out of the blood vessel capillaries.
   3. Lymph flow is driven mainly by contraction of smooth muscle in the lymphatic vessels but also by the skeletal-muscle pump and the respiratory pump.

SECTION E: INTEGRATION OF CARDOVASCULAR FUNCTION

1. REGULATION OF SYSTEMIC ARTERIAL PRESSURE
   1. Mean arterial pressure, the primary regulated variable in the cardiovascular system, equals the product of cardiac output and total peripheral resistance.
   2. The factors that determine cardiac output and total peripheral resistance are complex and include venous pressure, inspiration, stroke volume, and nervous activity.

2. BARORECEPTOR REFLEXES
   1. The primary baroreceptors are the arterial baroreceptors--the two carotid sinuses and the aortic arch. Nonarterial baroreceptors are located in the systemic veins, pulmonary vessels, and walls of the heart.
   2. The firing rates of the arterial baroreceptors are proportional to mean arterial pressure and to pulse pressure.
   3. An increase in firing of the arterial baroreceptors due to an increase in pressure causes, by way of the medullary cardiovascular center, an increase in parasympathetic outflow to the heart and a decrease in sympathetic outflow to the heart, arterioles, and veins. The result is a decrease in cardiac output and total peripheral resistance and, hence, a decrease in mean arterial pressure. The opposite occurs when the initial change is a decrease in arterial pressure.

3. BLOOD VOLUME AND LONG-TERM REGULATION OF ARTERIAL PRESSURE
   1. The baroreceptor reflexes are short-term regulators of arterial pressure but adapt to a maintained change in pressure.
   2. The most important long-term regulator of arterial pressure is the blood volume.

SECTION F: CARDIOVASCULAR PATTERNS IN HEALTH AND DISEASE

1. HEMORRHAGE AND OTHER CAUSES OF HYPOTENSION
   1. The physiological responses to hemorrhage are summarized in Figures 14-60, 14-62, and 14-63.
   2. Hypotension can be caused by loss of body fluids, by strong emotion, and by liberation of vasodilator chemicals.
   3. Shock is any situation in which blood flow to the tissues is low enough to cause damage to them.

2. THE UPRIGHT POSTURE
   1. In the upright posture, gravity acting upon unbroken columns of blood reduces venous return by increasing vascular pressures in the veins and capillaries in the limbs.
      1. The increased venous pressure distends the veins, causing venous pooling, and the increased capillary pressure causes increased filtration out of the capillaries.
      2. These effects are minimized by contraction of the skeletal muscles in the legs.

3. EXERCISE
   1. The cardiovascular changes that occur in endurance-type exercise are illustrated in Figures 14-65 and 14-66.
   2. The changes are due to active hyperemia in the exercising skeletal muscles and heart, to increased sympathetic outflow to the heart, arterioles, and veins, and to decreased parasympathetic outflow to the heart.
   3. The increase in cardiac output depends not only on the autonomic influences on the heart but on factors that help increase venous return.
   4. Training can increase a person's maximal oxygen consumption by increasing maximal stroke volume and hence cardiac output.

4. HYPERTENSION
   1. Hypertension is usually due to increased total peripheral resistance resulting from increased arteriolar vasoconstriction.
   2. More than 95 percent of hypertension is termed primary in that the cause of the increased arteriolar vasoconstriction is unknown.

5. HEART FAILURE
   1. Heart failure can occur as a result of diastolic dysfunction or systolic dysfunction; in both cases cardiac output becomes inadequate.
   2. This leads to fluid retention by the kidneys and formation of edema because of increased capillary pressure.
   3. Pulmonary edema can occur when the left ventricle fails.

6. CORONARY ARTERY DISEASE
   1. Insufficient coronary blood flow can cause damage to the heart.
   2. Acute death from a heart attack is usually due to ventricular fibrillation.
   3. The major cause of reduced coronary blood flow is atherosclerosis, an occlusive disease of arteries.
   4. Persons may suffer intermittent attacks of angina pectoris without actually suffering a heart attack at the time of the pain.
   5. Atherosclerosis can also cause strokes and symptoms of inadequate blood flow in other areas.

SECTION G: HOMEOSTASIS:

1. THE PREVENTION OF BLOOD LOSS
   1. The initial response to blood-vessel damage is vasoconstriction and the sticking together of the opposed endothelial surfaces.
   2. The next events are formation of a platelet plug followed by blood coagulation (clotting).

2. FORMATION OF A PLATELET PLUG
   1. Platelets adhere to exposed collagen in a damaged vessel and release the contents of their secretory vesicles.
      1. These substances help cause platelet activation and aggregation.
      2. This process is also enhanced by vonWillebrand factor, secreted by the endothelial cells, and by thromboxane A2 produced by the platelets.
      3. Fibrinogen forms the bridges between aggregating platelets.
      4. Contractile elements in the platelets compress and strengthen the plug.

   2. The platelet plug does not spread along normal endothelium because the latter secretes prostacyclin and nitric oxide, both of which inhibit platelet aggregation.

3. BLOOD COAGULATION: CLOT FORMATION
   1. Blood is transformed into a solid gel when, at the site of vessel damage, plasma fibrinogen is converted into fibrin molecules, which bind to each other to form a mesh
   2. This reaction is catalyzed by the enzyme thrombin, which also activates factor XIII, a plasma protein that stabilizes the fibrin meshwork.
   3. The formation of thrombin from the plasma protein prothrombin is the end result of a cascade of reactions in which an inactive plasma protein is activated and then enzymatically activates the next protein in the series.
      1. Thrombin exerts a positive feedback stimulation of the cascade by activating platelets and several clotting factors.
      2. Activated platelets, which display platelet factor and binding sites for several activated plasma factors, are essential for the cascade.

   4. In the body, the cascade usually begins via the extrinsic clotting pathway when tissue factor forms a complex with factor VIIa. This complex activates factor X, which then catalyzes the conversion of small amounts of prothrombin to thrombin. This thrombin then recruits the intrinsic pathway by activating factor XI and factor VIII, as well as platelets, and this pathway generates large amounts of thrombin.
   5. Vitamin K is required by the liver for normal production of prothrombin and other clotting factors.

4. ANTICLOTTNG SYSTEMS
   1. Clotting is limited by three events: (1) Tissue factor pathway inhibitor inhibits the tissue factor-factor VIIa complex; (2) protein C, activated by thrombin, inactivates factors VIII and V;and (3) antithrombin III inactivates thrombin and several other clotting factors.
   2. Clots are dissolved by the fibrinolytic system.
      1. A plasma proenzyme, plasminogen, is activated by plasminogen activators to plasmin, which digests fibrin.
      2. Tissue plasminogen activator is secreted by endothelial cells and is activated by fibrin in a clot.