CHAPTER 11 Blood Components, Immunity, and Hemostasis 197 portion is catabolized by proteases into constituent amino on their appearance after staining with polychromatic acids that are used in protein synthesis. Heme is broken dyes, such as Wright’s stain. While monocytes and lym- 3 down into free iron (Fe ) and biliverdin, a green substance phocytes may also possess cytoplasmic granules, they are that is further reduced to bilirubin (see Chapter 27). not clearly visualized with commonly used stains. There- fore, monocytes and lymphocytes are often referred to as Iron Recycling. Most of the iron needed for new hemo- agranular leukocytes. globin synthesis is obtained from the heme of senescent red The nuclei of most mature granulocytes are divided into cells. Iron released by macrophages is transported in the fer- two to five oval lobes connected by thin strands of chro- ric state in plasma bound to the iron transporting protein, matin. This nuclear separation imparts a multinuclear ap- transferrin. Cells that need iron (e.g., for heme synthesis) pearance to granulocytes, which are, therefore, also known possess membrane receptors to which transferrin binds. The as polymorphonuclear leukocytes. Three distinct types of receptor-bound transferrin is then internalized. The iron is granulocytes have been identified based on staining reac- released, reduced intracellularly to the ferrous state, and ei- tions of their cytoplasm with polychromatic dyes: neu- ther incorporated into heme or stored as ferritin, a complex trophils, eosinophils, and basophils. of protein and ferrous hydroxide. Iron is also stored as fer- ritin by macrophages in the liver. A portion of the ferritin is Neutrophils. Neutrophils are usually the most prevalent catabolized to hemosiderin, an insoluble compound con- leukocyte in peripheral blood. These dynamic cells re- sisting of crystalline aggregates of ferritin. The accumula- spond instantly to microbial invasion by detecting foreign tion of large amounts of hemosiderin formed during periods proteins or changes in host defense network proteins. Neu- of massive hemolysis can result in damage to vital organs, in- trophils provide an efficient defense against pathogens that cluding the heart, pancreas, and liver. have gotten past physical barriers such as the skin. Defects The recycling of iron is quite efficient, but small in neutrophil function quickly lead to massive infection— amounts are continuously lost. Iron loss increases sub- and, quite often, death. stantially in women during menstruation. Iron stores Neutrophils are amoeba-like phagocytic cells. Invading must be replenished by dietary uptake. The majority of bacteria induce neutrophil chemotaxis—migration to the iron in the diet is derived from heme in meat (“organic site of infection. Chemotaxis is initiated by the release of iron”), but iron can also be provided by the absorption of chemotactic factors from the bacteria or by chemotactic inorganic iron by intestinal epithelial cells. In these cells, factor generation in the blood plasma or tissues. Chemo- iron attached to heme is released and reduced to the fer- tactic factors are generated when bacteria or their products rous form (Fe 2 ) by intracellular flavoprotein. The re- bind to circulating antibodies, by tissue cells when infected duced iron (both released from heme and absorbed as the with bacteria, and by lymphocytes and platelets after inter- inorganic ion) is transported through the cytoplasm action with bacteria. bound to a transferrin-like protein. When it is released to After neutrophils migrate to the site of infection, they the plasma, it is oxidized to the ferric state and bound to engulf the invading pathogen by the process of phagocy- transferrin for use in heme synthesis. tosis. Phagocytosis is facilitated when the bacteria are coated with the host defense proteins known as opsonins. A burst of metabolic events occurs in the neutrophil af- Platelets Participate in Clotting ter phagocytosis (Fig. 11.6). In the phagocytic vacuole or phagosome, the bacterium is exposed to enzymes that Platelets are irregularly shaped, disk-like fragments of the were originally positioned on the cell surface. Thus, membrane of their precursor cell, the megakaryocyte. phagocytosis involves invagination and then vacuolization Megakaryocytes shed platelets in the bone marrow sinu- of the segment of membrane to which a pathogen is soids. From there the platelets are released to the blood, bound. Membrane-bound enzymes, activated when the where they function in hemostasis. Several factors stimu- phagocytic vacuole closes, work in conjunction with en- late megakaryocytes to release platelets, including the hor- zymes secreted from intracellular granules into the phago- mone thrombopoietin, which is generated and released cytic vacuole to destroy the invading pathogen efficiently. into the bloodstream when the number of circulating One important membrane-bound enzyme, nicotinamide platelets drops. Platelets have no defined nucleus. They are adenine dinucleotide phosphate (NADPH) oxidase, pro- one fourth to one third the size of erythrocytes. Platelets duces superoxide anion (O 2 ). Superoxide is an unstable possess physiologically important proteins, stored in intra- free radical that kills bacteria directly. Superoxide also cellular granules, which are secreted when the platelets are participates in secondary free radical reactions to generate activated during coagulation. The role of platelets in blood clotting is discussed below. other potent antimicrobial agents, such as hydrogen per- oxide. Superoxide generation in the phagocytic vacuole proceeds at the expense of reducing agents oxidized in the cytoplasm. The reducing agent, NADPH, is generated Leukocytes Participate in Host Defense from glucose by the activity of the hexose monophos- Each of the three general types of leukocytes—myeloid, phate shunt. Aerobic cells generate reduced nicotinamide lymphoid, and monocytic—follows a separate line of de- adenine dinucleotide (NADH) and ATP when glucose is velopment from primitive cells (see Fig. 11.2). Mature oxidized to carbon dioxide. The hexose monophosphate cells of the myeloid series are termed granulocytes, based shunt operates in neutrophils and other cells when large
198 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY 1. Recognition 2. Invagination chemiluminescence) when they oxidize components in the bacterial cell wall. Other bactericidal agents and processes operate in neu- trophils to ensure efficient bacterial killing. Phagocytized bacteria encounter intracellular defensins, cationic proteins that bind to and inhibit the replication of bacteria. De- fensins and other antibacterial agents pour into the phago- cytic vacuole after phagocytosis. Agents stored in neu- trophil granules include lysozyme, a bacteriolytic enzyme, Cell-surface receptors Cell membrane sense invading pathogens surrounds microbes and myeloperoxidase, which reacts with hydrogen perox- ide to generate potent, bacteria-killing oxidants. One of the oxidants generated by the myeloperoxidase reaction is hypochlorous acid (HOCl), the killing agent found in 4. Killing of pathogen 3. Phagosome formation household bleach. Granules also contain collagenase and other proteases. Eosinophils. Eosinophils are rare in the circulation but are easily identified on stained blood films. As the name im- plies, the eosinophil takes on a deep eosin color during polychromatic staining; the large, refractile cytoplasmic granules of these cells stain orange-red to bright yellow. Cellular granules release contents into vacuole; membrane Like neutrophils, eosinophils migrate to sites where they NADPH oxidase is activated are needed and exhibit a metabolic burst when activated. Eosinophils participate in defense against certain parasites, Steps in phagocytosis and intracellular FIGURE 11.6 and they are involved in allergic reactions. The exposure of killing by neutrophils. 1, Cell-surface recep- allergic individuals to an allergen often results in a transient tors, including those for exposed opsonins, sense invading increase in eosinophil count known as eosinophilia. Infec- pathogens. 2, The neutrophil plasma membrane invaginates to tion with parasites often results in a sustained overproduc- surround the organisms. 3, A membrane-bounded vesicle formed from the invagination of the cell membrane, called a phagosome, tion of eosinophils. traps the bacteria inside the neutrophil. 4, Potent metabolic processes are activated to kill the ingested microbes, including ac- Basophils. Basophils are polymorphonuclear leukocytes tivation of the respiratory burst, resulting in the generation of po- with multiple pleomorphic, coarse, deep-staining tent oxidants within the phagosome, and the secretion of bacte- metachromatic granules throughout their cytoplasm. ria-killing enzymes into the phagosome from neutrophil granules. These granules contain heparin and histamine, which have anticoagulant and vasodilating properties, respectively. The release of these and other mediators by basophils in- creases regional blood flow, facilitating the transport of other leukocytes to areas of infection and allergic reactivity amounts of NADPH are needed to maintain intracellular or other forms of hypersensitivity. reducing activity. Oxygen reduction by the NADPH oxidase that gener- Monocytes and Lymphocytes. In contrast to granulo- ates superoxide in neutrophils is driven by an increased cytes, monocytes and lymphocytes are mononuclear cells. availability of NADPH after phagocytosis: Monocytes are phagocytic cells but lymphocytes are not; NADPH 2O 2 → 2O 2 NADP H (4) both participate in multiple aspects of immunity. Mono- cytes were originally differentiated from lymphocytes NADPH oxidase based on morphological characteristics. The cytoplasm of A complex set of biochemical events unfolds after monocytes appears pale blue or blue-gray with Wright’s phagocytosis to activate the neutrophil NADPH oxidase, stain. The cytoplasm contains multiple fine reddish-blue which is dormant in resting cells. The oxidase is activated granules. The monocyte nucleus may be shaped like a kid- by its interaction with an activated G protein and cy- ney bean, indented, or shaped like a horseshoe. Frequently, tosolic molecules that are generated during phagocyto- however, it is rounded or ovoid. Upon activation, mono- sis. The NADPH oxidase is activated in a manner that al- cytes transform into macrophages—large, active mononu- lows the enzyme to secrete the toxic free radical, clear phagocytes. superoxide, into the phagocytic vacuole while oxidizing Morphologically, circulating lymphocytes have been NADPH in the cell’s cytoplasm. This explosion of meta- assigned to two broad categories: large and small lym- bolic activity, collectively termed the respiratory burst, phocytes. In blood, small lymphocytes are more numer- leads to the generation of potent, reactive agents not oth- ous than larger ones; the latter closely resemble mono- erwise generated in biological systems. These agents are cytes. Small lymphocytes possess a deeply stained, coarse so reactive that they actually generate light (biological nucleus that is large in relation to the remainder of the
CHAPTER 11 Blood Components, Immunity, and Hemostasis 199 cell, so that often only a small rim of cytoplasm appears door to the development of a variety of new pharmacolog- around parts of the nucleus. In contrast, a broad band of ical agents that have proved useful in the treatment of can- cytoplasm surrounds the nucleus of large lymphocytes; cer, immune disorders, and other diseases. the nucleus of these cells is similar in size and appearance to that of small lymphocytes. The morphological homogeneity of lymphocytes ob- Blood Cells Are Born in the Bone Marrow scures their functional heterogeneity. As is discussed be- Mature cells are transient residents of blood. Erythrocytes low, lymphocytes participate in multiple aspects of the im- survive in the circulation for about 120 days, after which mune response. Lymphocyte subtypes in blood (see Fig. they are broken down and their components recycled, as 11.2) are often identified based on their reaction with fluo- discussed above. Platelets have an average lifespan of 15 to rescent monoclonal antibodies. The majority of circulating 45 days in the circulation; many, if not most, of these cells lymphocytes are T cells or T lymphocytes (for “thymus- are consumed as they continuously participate in day-to- dependent lymphocytes”). These cells participate in certain day hemostasis. The rate of platelet consumption acceler- types of immune responses that do not depend on anti- ates rapidly during the repair of bleeding caused by trauma. body. T cells comprise 40 to 60% of the total circulating Leukocytes have a variable lifespan. Some lymphocytes cir- pool of lymphocytes. culate for 1 year or longer after production. Neutrophils, Subtypes of T cells have been identified using fluores- constantly guarding body fluids and tissues against infec- cent monoclonal antibodies to specific cell-surface anti- tion, have a circulating half-life of only a few hours. Neu- gens, known as CD antigens. All T cells possess the com- trophils and other blood cells must, therefore, be continu- mon CD3 antigen. So-called helper T cells possess the ously replenished. CD4 antigen cluster, while suppressor T cells lack CD4 As mentioned earlier, the process of blood cell genera- but possess CD8. Patients with AIDS show decreased cir- tion, hematopoiesis, occurs in healthy adults only in the culating levels of CD4-positive cells. Natural killer (NK) bone marrow. Extramedullary hematopoiesis (e.g., the cells are T lymphocytes that possess the ability to kill tu- generation of blood cells in the spleen) is observed only in mor cells without prior exposure or priming. some disease states, such as leukemia. Hematopoietic cells Some 20 to 30% of circulating lymphocytes are B cells, are found in high levels in the liver, spleen, and blood of the which have immunoglobulin or antibody on their surface. developing fetus. Shortly before birth, blood cell produc- B cells are bone marrow-derived lymphocytes; when im- tion gradually begins to shift to the marrow. In newborns, munologically activated, they transform into plasma cells the hematopoietic cell content of the circulating blood is that secrete immunoglobulin. Lymphocytes not character- relatively high; hematopoietic cells are also found in the istic of either T cells or B cells are called null cells. The en- blood of adults, but in extremely low numbers. Large num- tire scope of the function of null cells, which comprise only bers of hematopoietic cells can be recovered from aspirates 1 to 5% of circulating lymphocytes, is unknown, but it has of the iliac crest, sternum, pelvic bones, long bones, and been established that null cells are capable of destroying tu- ribs of adults. Within the bones, hematopoietic cells ger- mor cells and virus-infected cells. minate in extravascular sinuses, called marrow stroma. Cir- While B cells mediate immune responses by releasing culating factors and factors released from capillary en- antibody, T cells often exert their effects by synthesizing dothelial cells, stromal fibroblasts, and mature blood cells and releasing cytokines, hormone-like proteins that act by regulate the generation of immature blood cells from binding specific receptors on their target cells. Recent re- hematopoietic cells and the subsequent differentiation of search has led to the discovery of many cytokines, with ac- newly formed immature cells. tivities ranging from tumor destruction, a function of tumor Blood cell production begins with the proliferation of necrosis factor, to the promotion of blood cell production. pluripotent (uncommitted) stem cells. Depending on the Cytokines that limit viral replication in cells, known as in- stimulating factors, the progeny of pluripotent stem cells terferons, suppress or potentiate the function of T cells, may be other uncommitted stem cells or stem cells commit- stimulate macrophages, and activate neutrophils. ted to development along a certain lineage. The committed In some cases, cytokines, like other hormones, can exert stem cells include myeloblasts, which form cells of the potent effects when supplied exogenously. For example, myeloid series (neutrophils, basophils, and eosinophils); ery- colony-stimulating factors injected into cancer patients can throblasts; lymphoblasts; and monoblasts (Fig. 11.7; see prevent decreases in the production of leukocytes that re- also Fig. 11.2). Promoted by hematopoietins and other cy- sult from the administration of chemotherapeutic drugs or tokines, each of these blast cells differentiates further, a radiation therapy. The technology of molecular biology is process that ultimately results in the formation of mature used to produce cytokines for therapy. In this process, sec- blood cells. This is a dynamic process; the hematopoietic tions of lymphocyte DNA containing the gene that codes cells of the bone marrow are among the most actively repro- for the specified cytokine are isolated and then transfected ducing cells of the body. Interruption of hematopoiesis (e.g., into a bacterial cell, fungus, or rapidly growing mammalian by cancer treatment) results in the eventual disappearance of cell. These cells then produce the cytokine and release it granulocytes from the blood, a condition known as granulo- into their culture supernatant, from which it can be puri- cytopenia, or, when specific to neutrophils, neutropenia, in fied, concentrated, and sterilized for injection. The biolog- a matter of hours. Platelets disappear next—thrombocy- ical diversity and potency of the cytokines has opened the topenia—followed by erythrocytes, a sequence that reflects
200 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY Pluripotent (uncommitted) stem cell CFU-GEMM CFU-GM (phagocytic stem cell) Lymphoid stem cell BFU-E CFU-MEG CFU-M CFU-G CFU-Eo CFU-Bas Pro-B cell Pre-T cell (Erythroid (Platelet (Monocyte (Granulocyte (Eosinophil (Basophil stem cell) stem cell) stem cell) stem cell) stem cell) stem cell) Erythrocyte Megakaryoblast Monoblast Myeloblast Eosinophil Basophil Pre-B cell Subcortical differentiation Myeloblast Myeloblast thymocyte Megakaryocyte Promonocyte Myelocyte Eosinophil Basophil Early B cell Medullary thymocyte Myelocyte Myelocyte Monocyte Mature B cell Blood/lymph node thymocyte Erythrocyte Platelets Macrophage Neutrophil Eosinophil Basophil Plasma Memory Suppressor Helper Cytotoxic cell cell T cell T cell T cell Hematopoiesis. All circulating blood cells are megakaryocyte colony-forming unit; CFU-GM, granulocyte- FIGURE 11.7 believed to be derived from a common, uncom- macrophage colony-forming unit; BFU-E, erythroid burst forming mitted bone marrow progenitor, the pluripotent stem cell. This unit; CFU-MEG, megakaryocyte colony-forming unit; CFU-M, cell differentiates along different lineages, depending on the con- macrophage colony-forming unit; CFU-G, granulocyte colony- ditions it encounters and the levels of individual hematopoietins forming unit; CFU-Eo, eosinophil colony-forming unit; CFU-Bas, available. CFU-GEMM, granulocyte-erythrocyte-macrophage- basophil colony-forming unit. the circulating lifespan of each cell. Often, hematopoiesis ing together, elements of the innate and adaptive immune can be restored after its interruption by an infusion of viable systems provide a considerable obstacle to the establish- hematopoietic cells, e.g., a bone marrow transplant (see ment and long-term survival of infectious agents. Clinical Focus Box 11.1). Administration of committed stem cells shows promise in treating specific blood cell defects (see Clinical Focus Box 11.2). The Innate Immune System Consists of Nonspecific Defenses Infectious agents cannot easily penetrate intact skin, the THE IMMUNE SYSTEM first line of defense against infection. Infection is a major Immunity or resistance to infection derives from the activ- complication when the intact skin barrier is compromised, ity and intact functioning of two tightly interrelated sys- such as by burns or trauma. Even a small needle prick can tems, the innate immune system and the adaptive immune result in a fatal infection. system. Elements of the innate or natural immune system Natural openings to body cavities and glands are an ef- include exterior defenses, such as skin and mucous mem- fective entry point of infectious agents. Usually, however, branes; phagocytic leukocytes; and serum proteins, which these openings are protected from invasion by pathogens act nonspecifically and quickly against microbial invaders. in at least two ways. First, they are coated with mucus and Microbes that escape the onslaught of cells and molecules other secretions that contain secretory immunoglobulins as of the innate immune system face destruction by T cells and well as antibacterial enzymes, such as lysozyme. Second, B cells of the adaptive immune system. Activation of the organisms that invade these openings cannot easily reach adaptive immune system results in the generation of anti- the blood but, instead, lodge in an organ that communi- bodies and cells that specifically target the inducing organ- cates with both the exterior and the interior of the body, ism or foreign molecule. Unlike the innate system, adaptive such as a lung or the stomach. Many pathogens cannot sur- or acquired immune responses develop gradually but ex- vive the low pH of stomach acid. In the lungs, organisms hibit memory. Therefore, repeat exposure to the same in- face the efficient phagocytic activity of alveolar fectious agent results in improved resistance mediated by macrophages. These cells, derived from blood monocytes, the specific aspects of the adaptive immune system. Work- are mobile but confined to the pulmonary capillary net-
CHAPTER 11 Blood Components, Immunity, and Hemostasis 201 CLINICAL FOCUS BOX 11.1 Bone Marrow Transplantation tation of bone marrow obtained from unrelated donors. When a patient has a terminal bone marrow disease, such Unrelated transplants were never possible before these as leukemia or aplastic anemia, often the only possibility advances because GVHD would almost certainly develop, for a cure is a bone marrow transplant. In this proce- even when the antigenic type of the donor’s leukocytes dure, healthy bone marrow cells are used to replace the closely matched that of the recipient’s. Thus, many pa- patient’s diseased hematopoietic system. These cells are tients died for lack of a related donor. Today, transplants of obtained from a donor who is usually a close relative of the unrelated marrow are common. patient. To identify a suitable donor, relatives’ blood leuko- Many problems remain, however. One of the most seri- cytes are screened to determine whether their antigenic ous, and the most common, is donor identification. An un- pattern matches that of the patient. The antigenic compo- related transplant is successful only if the donor’s leukocyte sition of leukocytes in bone marrow and peripheral blood antigens closely match those of the recipient. Since there are identical, so analysis of blood leukocytes usually pro- are several antigenic determinants and each can be occu- vides enough information to determine whether the trans- pied by any one of several genes, there are thousands of planted cells will engraft successfully. If significantly dif- possible combinations of leukocyte antigens. The chance ferent from the recipient’s tissue type, transplanted that any individual’s cells will randomly match those of an- leukocytes may be recognized as foreign by the patient’s other is less than one in a million. Therefore, the identifica- immune system and, therefore, rejected. tion of a suitable donor is a little more complicated than More commonly, sufficient differences between the en- finding a needle in a haystack. On the other hand, these grafted cells and the host’s own tissue lead to debilitating odds virtually guarantee that suitable donors are not only consequences as a result of graft-versus-host disease available but, in all probability, plentiful in the general pop- (GVHD). In GVHD, functional T cells in the proliferating ulation. Finding them is a formidable problem that often graft recognize host tissue as foreign and mount an im- generates intense frustration when donors for terminally ill mune response. The disease often begins with a skin rash, transplant candidates are not quickly identified. as transplanted lymphocytes invade the dermis, and ends To address this problem, bone marrow transplant reg- in death as lymphocytes destroy every organ system in the istries have been established. In these registries, the re- marrow recipient. sults of extensive leukocyte antigen typing are stored in a Recent discoveries have led to useful ways to limit or computer. Typing is performed on leukocytes isolated prevent GVHD. These advances have decreased the mor- from a small sample of blood, so the procedure does not bidity of marrow transplants and have substantially in- significantly inconvenience prospective donors. For some creased the potential pool of bone marrow donors for a registries, potential donors of a specific ethnic background given patient. Immunosuppressive agents, including are targeted; in others, blood samples are obtained from steroids, cyclosporin, and anti-T cell antiserum, effectively as many healthy individuals as possible, regardless of their decrease the immune function of the transplanted lym- heritage. The database is searched when an individual in phocytes. Another useful approach involves “purging”— need of a transplant cannot identify a suitable relative. In the physical removal of T cells from bone marrow prior to conjunction with continued development of methods to re- transplantation. T cell-depleted bone marrow is much less duce or eliminate GVHD, the expanding bone marrow capable of causing acute GVHD than untreated marrow. transplant registries may someday allow identification of a These techniques have enabled the successful transplan- donor for anyone who needs a bone marrow transplant. work. As efficient phagocytic cells, they continuously pa- redness, heat, and swelling (edema) of the affected tissue. trol the pulmonary vasculature to remove inhaled microbes. Blood cells participating in the inflammatory response re- Microbes that successfully break through these physical lease a variety of inflammatory mediators that perpetuate barriers face destruction by the fixed macrophages of the the response. If the pathogens persist, the inflammatory re- monocyte-macrophage system. These cells line the sinu- sponse may become chronic and may itself cause substan- soids and vasculature of many organs, including the liver, tial tissue damage. Not only microbes, but also proteins, spleen, and bone marrow. The nonmobile, fixed phago- chemicals, and toxins the body recognized as foreign, can cytic macrophages efficiently remove foreign particles, in- induce an inflammatory response. cluding bacteria, from the circulation. Certain inflammatory mediators increase blood flow to the inflamed area. Other mediators increase capillary per- meability, allowing diffusion of large molecules across the Inflammation Is a Multifaceted Process endothelium and into the infected site. These molecules Microbial invaders that lodge in body tissues and begin to may be plasma proteins, or they may be generated by proliferate trigger an inflammatory response (Fig. 11.8). In- plasma proteins or substances released by blood leuko- flammation provides a multifaceted defense against tissue cytes. They often play important roles in eliminating the invasion by pathogens. The inflammatory response is initi- pathogenic agent or enhancing the inflammatory response. ated by circulating proteins and blood cells when they con- Finally, chemotactic factors produced by cells that arrived tact invaders in a tissue. The response results in increased early in the inflammatory cascade cause polymorphonu- blood flow to the affected tissues, which accelerates the de- clear leukocytes to migrate from the blood to the affected livery of immune system elements to the site. The result is area. Neutrophils are an important participant in the in-
202 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY CLINICAL FOCUS BOX 11.2 Hematotherapy and Stem Cell Research: neutrophil progenitors may be useful for cancer patients Clinical Tools of the Future during aggressive therapy. Red cell progenitors may be Many diseases result from a specific defect in the immune successfully cultivated and infused for those with certain or hematopoietic system. These diseases may be effec- anemias. Platelet progenitors may be used in patients with tively treated by infusion of specific precursors of the de- one of the many forms of inborn or acquired thrombocy- fective cells, a process termed hematotherapy. In a typi- topenia. In addition, this emerging therapeutic approach cal bone marrow transplant, the entire hematopoietic may soon be enhanced by genetic engineering. In this system (and, consequently, the immune system) of the re- process, new or modified genes are inserted into the grow- cipient is ablated and restored with cells from the donor. In ing stem cells to replace defective or missing ones. For ex- this situation, the most primitive stem cells of the immune ample, a patient may be unable to mount an appropriate or hematopoietic system are eliminated and replaced. In immune response because of the lack of a specific enzyme situations such as AIDS, thrombocytopenia, certain ane- secreted by healthy leukocytes. Stem cells of these pa- mias, and genetic immunodeficiency, however, only spe- tients may be modified in culture to eliminate this defect cific committed progenitor cells of the hematopoietic or and infused back into the patient. If the infused cells take immune system are affected. We may soon be able to re- hold and generate sufficient progeny, the patient’s im- place these and keep the healthy portion of the patient’s mune defect may be reversed, resulting in a cure of a once hematopoietic system intact. fatal disease. In recent years, much interest has focused on the isola- By far, the major clinical use of stem cells to date has tion, identification, and propagation of the stem cells of been to restore the hematopoietic system of patients various tissues. Hematopoietic stem cells have recently treated with radiation or chemotherapy for cancer. Less been grown in culture and may soon be used for thera- frequently, hematopoietic stem cells have been used to peutic purposes. Hematopoietic stem cells are either com- augment the defective immune system of patients born mitted or pluripotent. As such, they either are destined to with genetic defects. New uses of stem cells appear to be generate a specific lineage of cells or are capable of gener- on the horizon. In recent years, several groups have an- ating further developed stem cells that can commit to de- nounced the successful isolation and culture of primitive, velopment along any one of several lineages. Pluripotent nonhematopoietic stem cells from human embryos and stem cells are needed to reconstitute hematopoiesis after fetal tissue. In addition, current reports indicate that the complete disruption that occurs during whole-body ir- these primitive stem cells, cells that can be induced to radiation or after the infusion of chemotherapeutic agents differentiate into any type of cell in the body, can be suc- to treat leukemia and solid tumors. cessfully isolated from adult tissues, including tissues Committed stem cells may be used for specific defects. that would otherwise be discarded, such as fat obtained For example, in AIDS, virus-laden T cells are rapidly elimi- during liposuction. Stem cells could be potentially used nated, resulting in low circulating levels. Although phar- for the regeneration and reconstruction of all types of maceutical progress has resulted in extended survival for damaged tissues. these patients, they are at high risk for life-threatening in- fection resulting from low T cell levels. It may be possible References to support patients by periodic infusions of T cell precur- Aldhous P. Stem cells. Panacea, or Pandora’s box? Nature sors, generated in efficient bioreactors from the patient’s 2000;408:897–898. own primitive stem cells. These bioreactors would be fu- Anonymous. Stem cells. Medicine’s new frontier. Mayo eled by specific cytokines that direct the stem cells to Clin Health Lett 2000;18:1–3. specifically generate committed T cell progenitors. Stem Asahara T, Kalka C, Isner JM. Stem cell therapy and gene cells used to initiate the culture would be obtained from transfer for regeneration. Gene Ther 2000;7:451–457. the patient’s marrow and grown under virus-free condi- Helmuth L. Neuroscience. Stem cells hear call of injured tions. After sufficient T cell progenitors were generated, tissue. Science 2000;290:1479–1481. the cultures would be processed to isolate and concentrate Noble M. Can neural stem cells be used to track down and the cells. Patients would receive an infusion whenever destroy migratory brain tumor cells while also providing a their T cell counts plummeted, protecting them against in- means of repairing tumor-associated damage? Proc Natl fection and allowing sustained survival. Acad Sci U S A 2000;97:12393–12395. In addition to AIDS, hematotherapy holds promise for Spangrude GJ, Cooper DD. Paradigm shifts in stem-cell bi- several other diseases and conditions as well. Infusions of ology. Semin Hemat 2000;37(1 Suppl 2):3–10. flammatory response. They can exert potent antimicrobial matory response without compromising its antimicrobial effects, as well as release a variety of agents that can further efficiency. They do this by neutralizing inflammatory me- amplify and perpetuate the response. diators or by preventing inflammatory cells from releasing The remarkable ability of the inflammatory response to or responding to inflammatory mediators. sustain itself while it generates potent cytolytic agents can result in many undesirable effects, including extensive tis- Defensive Mechanisms Are Integrated Systems sue damage and pain. A variety of antiinflammatory agents control some of these undesirable effects. These agents are As discussed above, the innate and adaptive immune sys- designed to block some of the consequences of the inflam- tems work together in ways that obscure their differences.
CHAPTER 11 Blood Components, Immunity, and Hemostasis 203 Tissue injury While characteristics of the innate and adaptive im- mune system differ, each system depends on elements of the other for optimal functioning. The initiation of re- Microbial invasion sponses by the innate system, as well as efficient phago- cytosis by neutrophils in the tissues, often depends on the presence of a small amount of specific antibody in Antibody binds to blood plasma. Antibody is generated by cells of the adap- microorganisms tive immune system in response to specific foreign mole- cules called antigens. In turn, the effective functioning of antibodies and other mediators of the adaptive immune Generation of bioactive peptides system depends on neutrophils and other effector agents usually associated with the innate immune system. Thus, the innate and the adaptive systems depend on highly Neutrophil adherence, evolved, interactive, defensive mechanisms to kill and re- and chemotaxis to move microbial intruders. infected area Adaptive Immunity Is Specific and Acquired Phagocytosis of microbes, neutrophil activation The adaptive immune system can be considered at three levels: • The afferent arm, which gives the system its remarkable Extracellular release of ability to recognize specific antigenic determinants of a inflammatory mediators wide range of infectious agents (free radicals, granule enzymes) • The efferent arm, which supplies a cellular and molecu- Steps in the inflammatory response. Inflam- lar assault on the invading pathogens FIGURE 11.8 mation can proceed along several divergent • Immunological memory, which specifically accelerates pathways, each involving inflammatory cells (e.g., neutrophils) and potentiates subsequent responses to the same acti- and mediators. This shows a possible route of inflammation initi- vating agent or antigen ated by tissue injury. The specificity of the recognition, effector, and mem- ory aspects of the adaptive immune system derives from the specificity of antibody molecules as well as that of Indeed, consideration of these two systems as distinct, in- receptors on T cells and B cells. The lymphocytes of the dividual entities is neither justified nor correct, owing to immune system are capable of recognizing and specifi- their extensive interdependence. They are described indi- cally responding to hundreds of thousands of potential vidually only as an aid to their presentation. In this respect, antigens, which may be presented, for example, as gly- it is important to define the characteristics that differenti- coproteins on the surface of bacteria, the coat protein of ate each system (Table 11.3). In general, responses of the viruses, microbial toxins, or membranes of infected cells. innate immune system are neither specific nor inducible; Only a few circulating lymphocytes need to recognize that is, the response is not programmed by or directed an individual antigen initially. This initial recognition against a specific pathogen and is not amplified as a result induces proliferation of the responsive cell, a process of previous encounters with the pathogen. The adaptive re- known as clonal selection (Fig. 11.9). Clonal selection sponse, in contrast, is both specific and inducible; the re- amplifies the number of specific T cells or B cells (i.e., T sponse is set in motion by a particular pathogen and devel- or B lymphocytes programmed to respond to the incit- ops against that specific pathogen. ing stimulus). While all of the cells generated after a single clone has expanded are specific for the inducing antigen, they may not all possess the same functional characteristics. Some of Characteristics of the Innate and Adap- TABLE 11.3 the daughter lymphocytes may be effector cells. For exam- tive Immune Systems ple, when B cells are activated, their progeny plasma cells Innate Adaptive are capable of generating antibodies. Other progeny in the expanded clone may play an afferent recognition role and, Resistance Not improved by Improved by previous repeat infection infection thereby, function as memory cells. The increased number Specificity Not directed toward Targeted response of these cells, which mimic the reactive specificity of the specific pathogen directed by specific original lymphocytes that responded to the antigen, accel- elements of immune erate responsiveness when the antigen is encountered system again. Memory cells thus account for one of the primary Soluble factors Lysozyme, complement, Antibodies tenets of immunity: Resistance is increased after initial ex- acute phase proteins, posure to the infectious agent. Long-term immunity to interferon, cytokines many viruses—such as influenza, measles, smallpox, and Cells Phagocytic leukocytes, T cells, B cells polio—can be induced by vaccination with a killed or mu- NK Cells tant form of the pathogen.
204 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY cells or helper T cells, respectively; and the secretion of cy- totoxic or immunomodulating cytokines, such as tumor necrosis factor and interleukin-2. T cells and their products may act directly or exert their effects in concert with other effector cells, such as neutrophils and macrophages. The immune responses mediated by antibodies and T lymphocytes differ in several important respects. In general, antibodies are known to induce immediate responses to antigens and, thereby, provoke immediate hypersensitivity reactions. For example, allergy or anaphylactic hypersensi- tivity results when a certain type of antibody on the surface of fixed mast cells binds to its specific antigen. Antibody binding leads to the release of histamine and other media- tors of the allergic response from intracellular granules. Immediate hypersensitivity reactions also occur when circulating antibodies bind antigen in the tissues, thereby forming immune complexes that activate the complement system, a group of at least nine distinct proteins that circu- late in plasma. A cascade of events occurs when the first protein recognizes preformed immune complexes, a large cross-linked mesh of antigen molecules bound to antibod- ies. In addition, complement can be activated when one of the proteins is exposed to the cell wall of certain bacteria. Initiation of this system results in edema, an influx of acti- vated phagocytic cells (chemotaxis), and local inflamma- tory changes. In contrast to the rapid onset of biological responses when antigen binds antibody, the consequences of T cell activation are not noticeable until 24 to 48 hours after antigen challenge. During this time, the T cells that initially recognize the anti- gen secrete factors that recruit and activate other cells (e.g., Clonal selection of committed lympho- FIGURE 11.9 macrophages) and release factors that damage the antigen, cytes. In this model, only the clone of lympho- cells possessing the antigen, or the surrounding tissue. A com- cytes that has the unique ability to recognize the antigen of inter- mon example is the delayed-type hypersensitivity reaction est proliferates, generating memory cells as well as effector cells specific to the inducing stimulus. This proliferation is initiated by to purified protein derivative (PPD), a response used to assess the interaction of a specific recognition lymphocyte (afferent prior exposure to the bacteria that cause tuberculosis. Injected cell) with the antigen. Cells then proliferate and differentiate into under the skin of sensitive individuals, PPD elicits the famil- either memory cells, which potentiate subsequent responses to iar inflammatory reaction characterized by local erythema the inciting antigen, or plasma cells, which secrete antibody. and edema 1 to 2 days later. Cell-mediated immune responses, while slow to de- velop, are potent and versatile. These delayed responses provide for defense against many pathogens, including The Adaptive Immune Response Involves viruses, fungi, and bacteria. T cells are responsible for the Cellular and Humoral Components rejection of transplanted tissue grafts and containment of Depending on the nature of the stimulus, its mode of pres- the growth of neoplastic cells. A deficiency in T cell im- entation, and prior challenges to the immune system, an munity, such as that associated with AIDS, predisposes the antigen may elicit either a cellular or humoral immune re- affected patient to a wide array of serious, life-threatening sponse. Both are ultimately mediated by lymphocytes, the infections. cellular response by T cells and humoral response by B cells. As discussed above, stimulated B cells differentiate Humoral Immunity. Humoral immunity consists of de- into plasma cells, which secrete antibody specific for the fense mechanisms carried out by soluble mediators in the inciting stimulus. The antibody can be found in a variety of blood plasma. Antibodies (also called immunoglobulins) body fluids, including saliva, other secretions, and plasma. are glycoproteins secreted by plasma cells. Antibodies are found in high levels in plasma and other body fluids. They Cell-Mediated Immunity. Cell-mediated immunity (or have the ability to bind specifically to the antigenic deter- cellular immunity) is accomplished by activated T cells. minant that induced their secretion. The effector cells of this response do not secrete antibody but exert their influence by a variety of cellular mecha- Antibodies Bind Antigens nisms. These effector processes include direct cytotoxicity mediated by cytotoxic T cells; the suppression or activa- The primary structure of an antibody is illustrated in Figure tion of immune mechanisms in other cells—suppressor T 11.10. Each antibody molecule consists of four polypeptide
CHAPTER 11 Blood Components, Immunity, and Hemostasis 205 be generated by protease digestion and separated by chro- matography. Fc fragments can bind to cells such as neu- trophils, monocytes, and mast cells through their Fc recep- tors. Fc receptor binding amplifies the biological activity of antigen-bound antibody. In addition to the ability to bind antigen, the antibody molecule may have a variety of other important biological functions, depending on its class. Table 11.4 summarizes some characteristics and func- tions of the five major classes of antibodies; these classes are grouped based on differences in the amino acid compo- sition of the constant region of the heavy chains. IgG is the S-S bonds most prevalent antibody in serum and is responsible for adaptive immunity to bacteria and other microorganisms. Carbohydrate Bound to antigen, IgG can activate serum complement, which releases several inflammatory and bactericidal medi- ators. At the surface of bacteria, exposed Fc portions of IgG Heavy chain molecules facilitate the phagocytosis of bacteria by blood 450 amino acids phagocytes, a process called opsonization. IgG exists in serum as a monomer. It can cross the placenta and is se- The structure of a typical antibody or im- creted into colostrum, protecting the fetus as well as the FIGURE 11.10 munoglobulin. Each molecule consists of two newborn from infection. heavy chains and two light chains held together in a Y configura- Unlike IgG, both IgM and IgA usually exist as polymers tion by disulfide bonds. Each heavy chain and light chain pos- of the fundamental Y-shaped antibody unit. In most IgA sesses a constant region (where the amino acid sequence of indi- molecules, two antibody units are held together by a secre- vidual molecules is similar) and a variable region, where tory piece (J chain), a protein synthesized by epithelial alterations in the amino acid sequence convey to the antibody its individual antigen specificity. cells. In this conformation, IgA is actively secreted into saliva, tears, colostrum, and mucus. IgA is thus known as se- cretory immunoglobulin. IgM is the first antibody secreted chains (two heavy chains and two light chains) held together after an initial immune challenge and provides resistance as a Y-shaped molecule by one or more disulfide bridges. early in the course of infection. IgM consists of five Y units. Each polypeptide chain possesses both a conserved constant Its size and large number of antigen-binding sites provide region and a variable region, where considerable amino acid the molecule with an excellent capacity for agglutination, sequence heterogeneity is found even within a single anti- the ability to clump particulate antigens, such as bacteria body class. This amino acid variability accounts for the and blood cells. Clumped antigens are efficiently and widely diverse antigen-binding ability of antibody molecules, quickly removed by fixed phagocytic cells of the mono- for it is the variable region that actually combines with the cyte-macrophage system. antigen, and there are millions of different antigens, ranging IgE, a monomeric antibody slightly larger than IgG, from viruses and proteins on bacterial cell walls to insect avidly binds cells that store and release mediators of allergy venom, pollen, and fluids secreted by plants. and anaphylaxis, including mast cells and basophils. These The amino terminal portions of the variable regions, the cells are heavily granulated. The granules contain histamine, antigen-binding sites, are known as the Fab regions. Each leukotrienes, and other biologically active agents that in- antibody unit possesses two identical antigen-binding sites, crease vascular permeability, dilate blood vessels (and, one at each end of the “Y.” The carboxy terminal end of the thereby, reduce blood pressure), and contract smooth mus- heavy chain is termed the Fc region. Polypeptide fragments cle cells in lung airways. The granules are released when IgE, consisting of Fc and Fab regions of antibody molecules can bound to mast cells at the Fc region, binds its specific anti- TABLE 11.4 Characteristics of Different Antibody Classes IgG IgA IgM IgD IgE 3 Molecular weight ( 10 ) 150 150, 400 900 180 190 Y units/molecule 1 1–2 5 1 1 Serum concentration (mg/dL) 600–1500 85–300 50–400 15 0.01–0.03 Crosses placenta Enters secretions Agglutinates particles Allergic reactions Complement fixation Fc receptor binding to monocytes and neutrophils
206 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY body. The ensuing allergic responses range from hay fever, openings in blood vessels. The aggregates form a physical hives, and bronchial asthma (induced by local or inhaled al- barrier that begins to limit blood loss soon after the open- lergens) to systemic anaphylaxis, a potentially fatal response ing occurs. Second, phospholipids on the platelet plasma triggered when antigen is given systemically. membrane activate the enzyme thrombin, which initiates a IgD, found in plasma and on the surface of some imma- cascade of events ending in clot formation. Finally, ture B cells, has no known function. platelets possess multiple storage granules, which they dis- charge (secrete) to enhance coagulation. Platelet activation results in the sequential responses of ad- HEMOSTASIS herence, aggregation, and secretion. Adherence is initiated when one or more substances, released from cells or activated Circulating in a high-pressure, closed system that communi- in plasma at the site of a hemorrhage, bind to receptors in the cates with all tissues and cells in the body, blood exchanges platelet plasma membrane. Receptor binding results, via sec- oxygen, nutrients, and wastes and provides necessary compo- ond messengers, in adherence (to other platelets and the in- nents for host defense. This communication takes place largely ner, endothelial surface of blood vessels) and secretion. in the complex and dynamic networks of capillary beds that Disruption of the endothelium at sites of tissue injury ex- provide oxygen to almost every cell in the body (only the poses a variety of proteins in the subendothelial matrix, cornea and intervertebral disks are avascular; these tissues re- such as collagen and laminin, which either induce or sup- ceive oxygen by diffusion). Disruption of the integrity of the port platelet adherence. Endothelial cells also rapidly de- fragile capillaries may result from minor tissue injury associ- ploy cellular adherence antigens known as integrins on the ated with normal physical activity or from massive tissue outer surface of their plasma membranes during wound trauma as a result of serious injury or infection, and may healing. These adherence antigens are deployed to the cell quickly lead to death. Any opening in the vascular network membrane by cellular processes set in motion by factors may lead to massive bruising or blood loss if left unrepaired. generated during coagulation or by factors released from To minimize bleeding and prevent blood loss after tissue platelets during clotting. In turn, activated endothelial cells injury, components of the hemostatic system are activated. release substances that participate in hemostasis. von The components of this dynamic, integrated system in- Willebrand factor, a protein synthesized by endothelial clude blood platelets, endothelial cells, and plasma coagu- cells and megakaryocytes, enhances platelet adherence by lation factors. They may be activated on exposure to for- forming a bridge between cell surface receptors and colla- eign surfaces during bleeding, or by torn tissue at the site of gen in the subendothelial matrix. The protein thrombin, injury, or by products released from the interior of dam- which is generated by the plasma coagulation cascade, is a aged cells. Hemostasis can be viewed as four separate but potent activator of platelet adherence and secretion. Rup- interrelated events: tured cells at the site of tissue injury release adenosine • Compression and vasoconstriction, which act immedi- diphosphate (ADP), which causes platelets to aggregate at ately to stop the flow of blood the damaged site. These aggregates effectively stop the • Formation of a platelet plug flow of blood from the ruptured vessels. • Blood coagulation • Clot retraction Blood Coagulation Results in the Production of Fibrin Physical Factors Immediately Act to Constrain Bleeding Platelet aggregates are trapped in a highly organized, firm, and degradable network of fibrin, an insoluble pro- Immediately after tissue injury, blood flow through the dis- tein generated in plasma as a consequence of activation rupted vessel is slowed by the interplay of several important of either the intrinsic or extrinsic clotting cascades, dis- physical factors, including compression or back-pressure cussed below. The fibrin network traps red cells, leuko- exerted by the tissue around the injured area, and vasocon- cytes, platelets, and serum at sites of vascular damage, striction. The degree of compression varies in different tis- thereby forming a blood clot. The stable, fibrin-based sues; for example, bleeding below the eye is not readily de- blood clot eventually replaces the unstable platelet ag- terred because the skin in this area is easily distensible. gregate formed immediately after tissue injury. Fibrin is Back-pressure increases as blood which leaks out of the dis- an insoluble polymer of proteolytic products of the rupted capillaries accumulates. In some tissues, notably the plasma protein fibrinogen. Fibrin molecules are cleaved uterus after childbirth, contraction of underlying muscles from fibrinogen by thrombin, which is generated in compresses blood vessels supplying the tissue and mini- plasma during clotting. In the initial step of fibrin for- mizes blood loss. Damaged cells at the site of tissue injury mation, thrombin cleaves four small peptides (fib- release potent substances that directly cause blood vessels rinopeptides) from each molecule of fibrinogen. The fib- to constrict, including serotonin, thromboxane A 2 , epi- rinogen molecule devoid of these fibrinopeptides is nephrine, and fibrinopeptide B. called fibrin monomer. The fibrin monomers sponta- neously assemble into ordered fibrous arrays of fibrin, resulting in an insoluble matrix of fibrous strands. At this Platelets Form a Hemostatic Plug stage, the clot is held together by noncovalent forces. A Platelets regulate bleeding in three stages. First, they form plasma enzyme, fibrin stabilizing factor (Factor XIII), multicellular aggregates linked by protein strands at sites of catalyzes the formation of covalent bonds between
CHAPTER 11 Blood Components, Immunity, and Hemostasis 207 strands of polymerized fibrin, stabilizing and tightening the blood clot. The Coagulation Cascade. Blood clotting is mediated by the sequential activation of a series of coagulation factors, proteins synthesized in the liver that circulate in the plasma in an inactive state. They are referred to by number (designated by a Roman numeral) in a sequence based on the order of the discovery of each factor. The plasma coagulation factors and their common names are listed in Table 11.5. The sequential activation of a series of inactive mole- cules resulting in a biological response is called a metabolic cascade. The sequential activation of coagulation factors resulting in the conversion of fibrinogen to fibrin (and, hence, clotting) is called the coagulation cascade. The de- ficiency or deletion of any one factor of the cascade has se- vere consequences. Individuals deficient in factor VIII (an- tihemophilic factor), for example, display prolonged bleeding time on tissue injury, as a result of delayed clot- ting. Those who lack factor VIII have hemophilia, a condi- tion resulting in severe coagulation defects. Two separate coagulation cascades result in blood clotting in different circumstances. The two systems are the intrinsic coagulation pathway and the extrinsic co- agulation pathway (Fig. 11.11). The final steps in fibrin formation are common to both pathways. In the intrinsic FIGURE 11.11 Steps in the coagulation cascade. The ex- pathway, all the factors required for coagulation are pres- trinsic pathway is initiated by tissue factor (fac- 2 ent in the circulation. For initiation of the extrinsic path- tor III) released from damaged cells. In the presence of Ca , fac- tor III converts factor VII to factor VIIa, which then forms a way, a factor extrinsic to blood but released from injured complex with factor III and Ca . This complex converts factor X 2 tissue, called tissue thromboplastin or tissue factor (fac- to factor Xa. In the intrinsic system, factor XII is first converted to tor III), is required. Phospholipids are required for activa- factor XIIa following its exposure to foreign surfaces, such as tion of both coagulation pathways. Phospholipids pro- subendothelial matrix. Factor XIIa initiates a cascade of events, in- vide a surface for the efficient interaction of several cluding activation of factor X, subsequent conversion of pro- factors. A component of tissue factor provides the neces- thrombin to thrombin, and, finally, fibrin formation. sary phospholipid for the extrinsic pathway. Phospho- lipids required for the activation of the intrinsic pathway are found on platelet membranes. The final events leading to fibrin formation by both pathways result from the activation of the common path- way. The common pathway is initiated by the conversion of inactive clotting factor X to its active form, factor Xa (see Fig. 11.11) and results in the conversion of prothrombin to TABLE 11.5 Factors of the Coagulation Cascade thrombin, thereby catalyzing the generation of fibrin. Thrombin also enhances the activity of clotting factors V Scientific and VIII, accelerating “upstream” events in the coagulation Name Common Name Other Names pathway. Finally, thrombin is a potent platelet and en- Factor I Fibrinogen dothelial cell stimulus and enhances the participation of Factor II Prothrombin these cells in coagulation. Factor III Tissue thromboplastin Tissue factor Factor X is activated during both the extrinsic and the Factor IV Calcium intrinsic pathways. In the extrinsic pathway, factor X is ac- Factor V Proaccelerin Labile factor tivated by a complex consisting of activated factor VII, Factor VII Proconvertin Serum prothrombin 2 conversion accelerator Ca , and factor III (tissue factor). Activation of this com- (SPCA) plex by tissue factor bypasses the requirement for coagula- Factor VIII Antihemophilic factor Platelet cofactor 1 tion factors VIII, IX, XI, and XII used in the intrinsic path- Factor IX Christmas factor Platelet thromboplastin way. In the intrinsic pathway, clotting is initiated by the component activation of factor XII by contact to exposed surfaces, such Factor X Stuart factor as collagen in the subendothelial matrix. The activation of Factor XI Plasma thromboplastin factor XII requires several cofactors, including kallikrein antecedent and high-molecular-weight kininogen. In this pathway, Factor XII Hageman factor Contact factor factor X is activated by a complex consisting of factor VIII, Factor XIII Fibrin stabilizing factor 2 factor IXa, platelet factor 3, and Ca .
208 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY Any attempt to describe a distinct division of coagula- been associated with abnormalities in protein C, protein S, tion into two separate pathways is an oversimplification, antithrombin III, and plasminogen. and the cascade theory has been extensively modified. While the blood clot resolves, multiple factors partici- There are many points of interaction between the two pate in wound healing. Optimal wound healing requires the pathways, and no one pathway will account for hemosta- recruitment or generation of new tissue cells as well as new sis. For example, thrombin generated during activation of blood vessels to nourish the repairing tissue. Thus, secreted the extrinsic pathway is an essential cofactor for factor VIII proteins and lipids that attract cells (chemoattractants), in- of the intrinsic pathway. Factor VIIa of the extrinsic path- duce cells to proliferate (mitogens), and induce primitive way directly activates factor IX of the intrinsic system. Fac- cells to differentiate (growth factors) are called into play. tor VII can be activated by factors IXa, Xa, and XIIa and These agents act in concert to induce the formation of new thrombin. The many additional points of interaction are tissue and repair the injured area. The healing area is vas- beyond the scope of this discussion, but the concept of in- cularized by a process known as angiogenesis, the forma- dependently acting intrinsic versus extrinsic coagulation tion of new blood vessels from preexisting ones. Platelets, pathways has been abandoned. However, the activity of activated during clotting, play an important role in the an- the intrinsic system and the extrinsic system are monitored giogenic response because they secrete factors that induce individually in clinical coagulation tests for diagnostic pur- proliferation, migration, and differentiation of two of the poses. The test used to monitor activity of the intrinsic sys- major components of blood vessels, endothelial cells, and tem is the partial thromboplastin time (PTT). The extrin- smooth muscle cells. sic system is evaluated by determination of the Of the factors released from platelets involved in the an- prothrombin time (PT). giogenic response, a novel lipid—sphingosine 1-phos- To a large extent, the interaction of coagulation fac- phate—plays an important role in wound healing and an- tors occurs on the surfaces of platelets and endothelial giogenesis. Released during clotting and acting in cells. While plasma can eventually clot in the absence of conjunction with protein growth factors, this lipid induces surface contact, localization and assembly of coagulation the proliferation of new tissue cells to replace damaged factors on cell surfaces amplifies reaction rates by several ones and drives the formation of new blood vessels until the orders of magnitude. healing process is complete. It does so by inducing the mi- Clot retraction is a phenomenon that usually occurs gration, proliferation, and differentiation of fibroblasts, within minutes or hours after clot formation. The clot draws smooth muscle cells, and endothelial cells at the site of tis- together, extruding a very large fraction of the serum. The sue repair. Sphingosine 1-phosphate exerts its effects opti- retraction requires platelets. Clot retraction decreases the mally when acting in conjunction with protein growth fac- breakdown of the clot and enhances wound healing. tors that possess angiogenic capabilities, including vascular endothelial growth factor (VEGF) and fibroblast growth Fibrinolysis and Wound Healing. Several important factor (FGF). Recent research has been undertaken to de- mechanisms exist to regulate and eventually reverse the fi- fine, in detail, the biochemical events that drive the angio- nal consequence of coagulation in order to allow healing to genic response because directed regulation of angiogenesis proceed. Platelet function is strongly inhibited, for exam- has profound clinical implications. For example, exoge- ple, by the endothelial cell metabolite prostacyclin (PGI 2 ), nously applied angiogenic factors may prove useful in ac- which is generated from arachidonic acid during cellular celerating repair of tissue damaged by thrombi in the pul- activation. Activated endothelial cells also release tissue monary, cerebral, or cardiac circulation. In addition, plasminogen activator (TPA), which converts plasmino- angiogenic factors may assist in the repair of lesions that gen to plasmin, a protein that hydrolyzes fibrin, resulting normally repair slowly—or not at all—such as skin ulcers in in dissolution of the fibrin clot in a process called fibrinol- patients who are bedridden or diabetic. ysis. Thrombin bound to thrombomodulin on the surface Inhibition of angiogenesis may have profound clinical of endothelial cells converts protein C to an active pro- implications also, since unwanted tissues, such as growing tease. Activated protein C and its cofactor, protein S, re- tumors, require the development of blood vessels to sur- strain further coagulation by proteolysis of factors Va and vive. Therefore, agents which interfere with the angiogenic VIIIa. Furthermore, activated protein C augments fibrinol- response, either by acting on the factors involved or the ysis by blocking an inhibitor of TPA. Finally, antithrombin cells that respond to them, may prove particularly useful in III is a potent inhibitor of proteases involved in the coagu- the treatment of patients with cancer. Several novel phar- lation cascade, such as thrombin. The activity of an- maceuticals are currently being evaluated for their use as tithrombin III is accelerated by small amounts of heparin, a regulators of angiogenesis, including thrombospondin, an- mucopolysaccharide present in the cells of many tissues. giostatin, and endostatin, which block neovascularization Deficiencies or abnormalities in proteins that regulate or in tumors and have shown great promise in laboratory test- constrain coagulation may result in thrombotic disorders, ing. Further research will determine if these agents are ef- in which intravascular clot formation leads to severe prob- fective in patients and will identify new, specific regulators lems, including embolism and stroke. Such disorders have of this fundamental process.
CHAPTER 11 Blood Components, Immunity, and Hemostasis 209 REVIEW QUESTIONS DIRECTIONS: Each of the numbered (E) Adult thymus (D) Release of tissue thromboplastin items or incomplete statements in this 5. What is the process that amplifies the (E) Conversion of fibrinogen to section is followed by answers or by number of T cells or B cells fibrin completion of the statement. Select the programmed to respond to a specific ONE lettered answer or completion that is infectious stimulus? SUGGESTED READING BEST in each case. (A) Hematopoiesis Browder T, Folkman J, Pirie-Shepherd S. (B) Hematotherapy The hemostatic system as a regulator 1. Which type of hemoglobin is not (C) Inflammation of angiogenesis. J Biol Chem normally found within human (D) Innate immunity 2000;275:1521–1524. erythrocytes? (E) Clonal selection Busslinger M, Nutt SL, Rolink AG. Lin- (A) HbA 6. The response to the antigen used in eage commitment in lymphopoiesis. the tuberculosis skin test, PPD, is not Curr Opin Immunol (B) HbA 2 (C) HbCO noticeable until 24 to 48 hours after 2000;12:151–158. injection because Claman HN. The biology of the immune (D) HbO 2 (E) Reduced hemoglobin (Hb) (A) It takes that long for B cells to response. JAMA 1992;268:2790–2796. 2. A reactant generated by neutrophils respond English D, Garcia JGN, Brindley DN. that plays an important role in (B) It takes that long for T cells to Platelet-released phospholipids link he- bacterial killing is respond mostasis and angiogenesis. Cardiovasc (A) NADPH oxidase (C) It takes that long for neutrophils to Res 2001;49:588–599. (B) Hexose monophosphate shunt arrive at the site Fischer A. Severe combined immunodefi- (C) G proteins (D) It takes that long for eosinophils to ciencies (SCID). Clin Exp Immunol (D) Superoxide anion respond 2000;122:143–149. (E) Myeloperoxidase (E) The skin test antigen is slowly Fleisher TA, Bleesing JJ. Immune function. 3. Which cell type is defective in patients converted to a more reactive antigen Pediatr Clin North Am with AIDS? that quickly initiates the skin response 2000;4:1197–1209. (A) T cells 7. Antibody specificity is determined by Grignani G, Maiolo A. Cytokines and he- (B) B cells the amino acid sequence within the mostasis. Haematologica (C) Neutrophils (A) Fc region 2000;85:967–972. (D) Monocytes (B) Constant region Hoffman R, Benz EJ, Shattil SJ, et al. (E) Basophils (C) Variable region Hematology: Basic Principles and Prac- 4. Which of the following would be (D) Fc receptors tice. New York: Churchill Livingstone, expected to contain relatively high (E) J chain 1991. numbers of functional hematopoietic 8. The first step in the extrinsic Lanier LL. The origin and functions of nat- cells? coagulation pathway is ural killer cells. Clin Immunol (A) Adult liver (A) Activation of factor X 2000;95:S14–S18. (B) Umbilical cord blood (B) Activation of factor XII Seaman WE. Natural killer cells and natu- (C) Adult circulating blood (C) Conversion of prothrombin to ral killer T cells. Arthritis Rheum (D) Adult spleen thrombin 2000;43:1204–1217.
An Overview of the CHAPTER 12 12 Circulation and Hemodynamics Thom W. Rooke, M.D. Harvey V. Sparks, Jr., M.D. CHAPTER OUTLINE ■ ONCE AROUND THE CIRCULATION ■ SYSTOLIC AND DIASTOLIC PRESSURES ■ HEMODYNAMIC PRINCIPLES OF THE ■ TRANSPORT IN THE CARDIOVASCULAR SYSTEM CARDIOVASCULAR SYSTEM ■ THE LYMPHATIC CIRCULATION ■ PRESSURES IN THE CARDIOVASCULAR SYSTEM ■ CONTROL OF THE CIRCULATION KEY CONCEPTS 1. The circulatory system contributes to the maintenance of (along the length of the blood vessels) occurs by bulk flow the internal environment by transporting nutrients to and whereas transport over short distances (across the capil- waste products away from individual cells of the body. It lary walls) occurs via diffusion. also participates in the maintenance of the electrolyte and 4. Pressure, flow, and resistance are related by Ohm’s law. thermal environment of cells. 5. Poiseuille’s law shows how the radius and length of a ves- 2. The circulatory system consists of two pumps in series. sel and blood viscosity contribute to vascular resistance. The right heart pumps blood into the lungs. The left heart 6. The contractions of the heart generate the pressure that pumps blood through the rest of the body. drives blood through the pulmonary and systemic circula- 3. The transport of nutrients and wastes over long distances tions. he physiological and medical importance of the car- the leading causes of death and morbidity include myocar- Tdiovascular system has been apparent since William dial infarction, stroke, hypertension, congestive heart fail- Harvey first described the circulation of blood in 1628. A ure, and an assortment of other cardiovascular problems. properly functioning, well-regulated cardiovascular system Knowledge of the structure and function of the cardiovas- is essential to the maintenance of the internal environment cular system is, therefore, crucial for understanding many of the body. Each cell must receive oxygen from the lungs aspects of health and disease. and a variety of nutrients from the gastrointestinal tract. Each cell produces waste products that must be removed from its environment and taken to the lungs, kidneys, or ONCE AROUND THE CIRCULATION other organs for metabolism and/or excretion. Cells in en- docrine glands communicate with cells in other tissues by An understanding of the circulation depends on knowl- releasing hormones that are carried throughout the body edge of the physical principles governing blood flow. But by the circulation. Heat produced by the work of the body first, we will briefly describe the cardiovascular system is brought to the surface of the body where it can be lost to (Fig. 12.1). Contractions of the left ventricle propel blood the external environment by way of the circulation. into the aorta, the large arteries, and the vasculature be- The circulatory system must perform all of these func- yond. Because of their elasticity, the aorta and large arter- tions in the face of a variety of challenges, such as exercise, ies are distended by each injection of blood from the heart. hot and cold environments, changes in posture, pregnancy The aorta and large arteries recoil between ventricular con- and childbirth, and the hypoxia caused by high altitudes. tractions, continuing the flow of blood to the periphery. Unfortunately, failure of the cardiovascular system to per- Several regulatory mechanisms normally keep aortic form normally occurs all too often. In developed countries, pressure within a narrow range, providing a pulsatile but 210
CHAPTER 12 An Overview of the Circulation and Hemodynamics 211 Blood flows from capillaries into venules and small veins. These vessels have larger diameters and thinner walls than the companion arterioles and small arteries. Because of their larger caliber they hold a larger volume of blood. When the smooth muscle in their walls contracts, the vol- ume of blood they contain is reduced. These vessels, along with larger veins, are referred to as capacitance vessels. The pressure generated by the contractions of the left ven- tricle is largely dissipated by this point; blood flows through the veins to the right atrium at much lower pres- sures than are found on the arterial side of the circulation. The right atrium receives blood from the largest veins, the superior and inferior vena cavae, which drain the entire body except the heart and lungs. The thin wall of the right SVC atrium allows it to stretch easily to store the steady flow of Aorta blood from the periphery. Because the right ventricle can receive blood only when it is relaxing, this storage function of the right atrium is critical. The muscle in the wall of the right atrium contracts at just the right time to help fill the IVC right ventricle. Contractions of the right ventricle propel blood through the lungs where oxygen and carbon dioxide are exchanged in the pulmonary capillaries. Pressures are much lower in the pulmonary circulation than in the sys- temic circulation. Blood then flows via the pulmonary vein to the left atrium, which functions much like the right atrium. The thick muscular wall of the left ventricle devel- ops the high pressure necessary to drive blood around the systemic circulation. The mechanisms that regulate all of the above anatomic elements of the circulation are the subject of the next few chapters. In this chapter, we consider the physical princi- ples on which the study of the circulation is based. A model of the cardiovascular system. The HEMODYNAMIC PRINCIPLES OF THE FIGURE 12.1 right and left hearts are aligned in series, as are CARDIOVASCULAR SYSTEM the systemic circulation and the pulmonary circulation. In con- trast, the circulations of the organs other than the lungs are in Hemodynamics is the branch of physiology concerned parallel; that is, each organ receives blood from the aorta and re- with the physical principles governing pressure, flow, re- turns it to the vena cava. Exceptions are the various “portal” circu- sistance, volume, and compliance as they relate to the car- lations, which include the liver, kidney tubules, and hypothala- diovascular system. These principles are used in the next mus. SVC, superior vena cava; IVC, inferior vena cava; RA, right few chapters to explain the performance of each part of the atrium; RV, right ventricle; LA, left atrium; LV, left ventricle. cardiovascular system. consistent pressure and driving blood to the small arteries Poiseuille’s Law Describes the Relationship and arterioles. Smooth muscle in the relatively thick walls of small arteries and arterioles can contract or relax, causing Between Pressure and Flow large changes in flow to a particular organ or tissue. Because Fluid flows when a pressure gradient exists. Pressure is of their ability to adjust their caliber, small arteries and ar- force applied over a surface, such as the force applied to terioles are called resistance vessels. The prominent pres- the cross-sectional surface of a fluid at each end of a rigid sure pulsations in the aorta and large arteries are damped by tube. The height of a column of fluid is often used as a the small arteries and arterioles. Pressure and flow are measure of pressure. For example, the pressure at the bot- steady in the smallest arterioles. tom of a container containing a column of water 100 cm Blood flows from arterioles into the capillaries. Capillar- high is 100 cm of H 2 O. The height of a column of mer- ies are small enough that red blood cells flow through them cury (Fig. 12.2) is frequently used for this purpose because in single file. They are numerous enough so that every cell it is dense (approximately 13 times more dense than wa- in the body is close enough to a capillary to receive the nu- ter), and a relatively small column height can be used to trients it needs. The thin capillary walls allow rapid ex- measure physiological pressures. For example, mean arte- changes of oxygen, carbon dioxide, substrates, hormones, rial pressure is equal to the pressure at the bottom of a col- and other molecules and, for this reason, are called ex- umn of mercury approximately 93 mm high (abbreviated change vessels. 93 mm Hg). If the same arterial pressure were measured
212 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY Pressure Height of mercury column Pressure expressed as the height of a col- FIGURE 12.2 umn of fluid. For the measurement of arterial pressures it is convenient to use mercury instead of water be- cause its density allows the use of a relatively short column. A variety of electronic and mechanical transducers are used to measure blood pressure, but the convention of expressing pres- sure in mm Hg persists. using a column of water, the column would be approxi- mately 4 ft (or 1.3 m) high. The flow of fluid through rigid tubes is governed by the pressure gradient and resistance to flow. Resistance depends on the radius and length of the tube as well as the viscosity of the fluid. All of this is summarized by Poiseuille’s law. While not exactly descriptive of blood flow through elastic, tapering blood vessels, Poiseuille’s law is useful in under- standing blood flow. The volume of fluid flowing through a rigid tube per unit time (Q) is proportional to the pressure difference (P) between the ends of the tube and inversely proportional to the resistance to flow (R): The influence of tube length and radius on Q P/R (1) FIGURE 12.3 flow. Because flow is determined by the fourth When fluid flows through a tube, the resistance to flow power of the radius, small changes in radius have a much greater (R) is determined by the properties of both the fluid and the effect than small changes in length. Furthermore, changes in tube. Poiseuille found that the following factors determine blood vessel length do not occur over short periods of time and are not involved in the physiological control of blood flow. The resistance to steady, streamlined flow of fluid through a pressure difference (P) driving flow is the result of the height of rigid, cylindrical tube: the column of fluid above the openings of tubes A and B. R 8L/r 4 (2) where r is the radius of the tube, L is its length, and is the though blood viscosity increases with hematocrit and with viscosity of the fluid; 8 and are geometrical constants. plasma protein concentration, blood viscosity only rarely Equation 2 shows that the resistance to blood flow in- changes enough to have a significant effect on resistance. creases proportionately with increases in fluid viscosity or Numerous control systems exist for the sole purpose of tube length. In contrast, radius changes have a much maintaining the arterial pressure relatively constant so greater influence because resistance is inversely propor- there is a steady force to drive blood through the cardio- tional to the fourth power of the radius (Fig. 12.3). Equa- vascular system. Small changes in arteriolar radius can tion 1 shows that if pressure and flow are expressed in units cause large changes in flow to a tissue or organ because flow of mm Hg and mL/min, respectively, R is in mm Hg is related to the fourth power of the radius. /(mL/min). The term peripheral resistance unit (PRU) is often used instead. Poiseuille’s law incorporates all of the factors influencing Conditions in the Cardiovascular System Deviate flow, so that From the Assumptions of Poiseuille’s Law 4 Q Pr /8L(3) Despite the usefulness of Poiseuille’s law, it is worthwhile to In the body, changes in radius are usually responsible for examine the ways the cardiovascular system does not variations in blood flow. Length does not change. Al- strictly meet the criteria necessary to apply the law. First,
CHAPTER 12 An Overview of the Circulation and Hemodynamics 213 the cardiovascular system is composed of tapering, branch- ing, elastic tubes, rather than rigid tubes of constant diam- eter. These conditions, however, cause only small devia- tions from Poiseuille’s law. Application of Poiseuille’s law requires that flow be steady rather than pulsatile, yet the contractions of the heart cause cyclical alterations in both pressure and flow. Despite this, Poiseuille’s law gives a good estimate of the re- lationship between pressure and flow averaged over time. Another criterion for applying Poiseuille’s law is that flow be streamlined. Streamline (laminar) flow describes the movement of fluid through a tube in concentric layers that slip past each other. The layers at the center have the fastest velocity and those at the edge of the tube have the slowest. This is the most efficient pattern of flow velocities, in that the fluid exerts the least resistance to flow in this configuration. Turbulent flow has crosscurrents and ed- dies, and the fastest velocities are not necessarily in the middle of the stream. Several factors contribute to the ten- dency for turbulence: high flow velocity, large tube diame- ter, high fluid density, and low viscosity. All of these fac- tors can be combined to calculate Reynolds number (N R ), FIGURE 12.5 Axial streaming and flow velocity. The dis- which quantifies the tendency for turbulence: tribution of red blood cells in a blood vessel de- pends on flow velocity. As flow velocity increases, red blood cells N R vd/ (4) move toward the center of the blood vessel (axial streaming), where v is the mean velocity, d is the tube diameter, is the where velocity is highest. Axial streaming of red blood cells low- fluid density, and is the fluid viscosity. Turbulent flow oc- ers the apparent viscosity of blood. curs when N R exceeds a critical value. This value is hardly ever exceeded in a normal cardiovascular system, but high flow velocity is the most common cause of turbulence in pathological states. that streamline flow breaks into eddies and crosscurrents Figure 12.4 shows that the relationship between pres- (i.e., turbulent flow). Once turbulence occurs, a given in- sure gradient along a tube and flow changes at the point crease in pressure gradient causes less increase in flow be- cause the turbulence dissipates energy that would other- wise drive flow. Under normal circumstances, turbulent flow is found only in the aorta (just beyond the aortic valve) and in certain localized areas of the peripheral sys- tem, such as the carotid sinus. Pathological changes in the cardiac valves or a narrowing of arteries that raise flow velocity often induce turbulent flow. Turbulent flow generates vibrations that are transmitted to the surface of Streamline flow Turbulent flow the body; these vibrations, known as murmurs and bruits, can be heard with a stethoscope. Finally, blood is not a strict newtonian fluid, a fluid that exhibits a constant viscosity regardless of flow velocity. When measured in vitro, the viscosity of blood decreases as the flow rate increases. This is because red cells tend to Flow Critical velocity collect in the center of the lumen of a vessel as flow veloc- ity increases, an arrangement known as axial streaming (Fig. 12.5). Axial streaming reduces the viscosity and, therefore, resistance to flow. Because this is a minor effect in the range of flow velocities in most blood vessels, we usually assume that the viscosity of blood (which is 3 to 4 Pressure gradient times that of water) is independent of velocity. Streamline and turbulent blood flow. Blood FIGURE 12.4 flow is streamlined until a critical flow velocity is reached. When flow is streamlined, concentric layers of fluid PRESSURES IN THE CARDIOVASCULAR SYSTEM slip past each other with the slowest layers at the interface be- Pressures in several regions of the cardiovascular system are tween blood and vessel wall. The fastest layers are in the center of the blood vessel. When the critical velocity is reached, turbulent readily measured and provide useful information. If arterial flow results. In the presence of turbulent flow, flow does not in- pressure is too high, it is a risk factor for cardiovascular dis- crease as much for a given rise in pressure because energy is lost eases, including stroke and heart failure. When arterial in the turbulence. The Reynolds number defines critical velocity. pressure is too low, blood flow to vital organs is impaired.
214 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY Pressures in the various chambers of the heart are useful in where V is the change in volume and P TM is the change evaluating cardiac function. in transmural pressure. A more compliant structure exhibits a greater change in volume for a given transmural pressure change. The lower The Contractions of the Heart Produce the compliance of a vessel, the greater the pressure that will Hemodynamic Pressure in the Aorta result when a given volume is introduced. For example, The left ventricle imparts energy to the blood it ejects into each time the left ventricle contracts and ejects blood into the aorta, and this energy is responsible for the blood’s cir- the aorta, the aorta expands; in doing so, it exerts an elastic cuit from the aorta back to the right side of the heart. Most force on the increased volume of blood it contains. This of this energy is in the form of potential energy, which is force is measured as the pressure in the aorta. With aging, the pressure referred to in Poiseuille’s law. This is hemody- the aorta becomes less compliant, and aortic pressure rises namic pressure, produced by contractions of the heart and more for a given increase in aortic volume. Veins, which stored in the elastic walls of the blood vessels. A much have thinner walls, are much more compliant than arteries. smaller component of the energy imparted by cardiac con- This means that, when we stand up and increased hydro- tractions is kinetic energy, which is the inertial energy as- static pressure is exerted on both the veins and the arteries sociated with the movement of blood. The next section de- of the legs, the volume of the veins expands much more scribes a third form of energy, hydrostatic pressure, derived than that of the arteries. from the force of gravity on blood. Mean Arterial Pressure Depends on Cardiac A Column of Fluid Exerts Hydrostatic Pressure Output and Systemic Vascular Resistance Fluid standing in a container exerts pressure proportional A simple model is useful in seeing how the pressures, flows to the height of the fluid above it. The pressure at a given and volumes are established in the cardiovascular system. depth depends only on the height of the fluid and its den- Imagine a circuit such as is shown in Figure 12.6. A pump sity and not on the shape of the container. This hydro- propels fluid into stiff tubing that is of a large enough di- static pressure is caused by the force of gravity acting on ameter to offer little resistance to flow. Midway around the the fluid. When a person stands, blood pressure is greater circuit is a narrowing or stenosis of the tubing where almost in the vessels of the legs than in analogous vessels in the all of the resistance to blood flow is located. The tubing arms because hydrostatic pressure is added to hemody- downstream from the stenosis is 20 times more compliant namic pressure. The hydrostatic pressure difference is than the tubing upstream from the stenosis. It has the same proportional to the height of the column of blood be- diameter as the upstream tubing and also offers almost no tween the arms and legs. resistance to flow. Two conventions are observed when measuring blood First imagine that the pump is turned off and the tub- pressure. First, ambient atmospheric pressure is used as a zero ing is completely collapsed. At this point, enough fluid reference, so the mean arterial pressure is actually about 93 is infused into the circuit to fill all of the tubing and just mm Hg above atmospheric pressure. Second, all cardiovascu- begin to stretch the walls of the upstream and down- lar pressures are referred to the level of the heart. This takes stream tubing. Once the infused fluid comes to rest in- into account the fact that pressures vary depending on posi- side the tubing, the pressure inside the tubing is the tion because of the addition of hydrostatic to hemodynamic same throughout because the pump is not adding energy pressure. (As we will see in Chapter 16, when capillary pres- to the circuit and there is no flow. The pressure inside sure is discussed, the term hydrostatic pressure is used to mean the tubing is the pressure needed to “inflate” or fill the hemodynamic plus hydrostatic pressure. Although this is not tubing in the resting state. The pressure outside the tub- strictly correct, it is the conventional usage.) ing is assumed to be atmospheric, and so the inside pres- sure equals the transmural pressure. Because the trans- mural pressure is the same throughout, and the left side of the circuit is made up of more compliant tubing, its Transmural Pressure Stretches Blood Vessels volume is larger than the volume of the right side (see in Proportion to Their Compliance equation 6). Thus far, we have discussed pressure and flow in the car- Imagine that the pump turns one cycle and shifts a small diovascular system as if blood vessels were rigid tubes. But volume of fluid from the high-compliance tubing to the blood vessels are elastic, and they expand when the blood low-compliance tubing. The drop in volume on the left side in them is under pressure. The degree to which a distensi- has little effect on pressure because of its high compliance. ble vessel or container expands when it is filled with fluid is However, an equivalent increase in volume on the low- determined by the transmural pressure and its compliance. compliance right side causes a 20-fold larger change in Transmural pressure (P TM ) is the difference between the pressure. The pressure difference between the right and left pressure inside and outside a blood vessel: side initiates flow from right to left. With only one stroke of the pump, the pressures on the two sides of the stenosis (5) P TM P inside P outside soon equalize as the volumes return to their resting values. At this point, flow ceases. Compliance (C) is defined by the equation: If the pump is turned on and left on, net volume is (6) transferred from left to right until the pump has created C V/P TM
CHAPTER 12 An Overview of the Circulation and Hemodynamics 215 Flow difference between point A (P A ) and point D (P D ) divided High-compliance, Low-compliance, low-resistance low-resistance by the resistance (R) to flow (see equation 1): tubing D A tubing Rate of pump transfer of volume from D to A Q (P A – P D )/R (7) We can think about the coupling of the output of the left heart to the flow through the systemic circulation in an anal- C B ogous fashion. The systemic circulation is filled by a volume of blood that inflates the blood vessels. The pressure re- quired to fill the blood vessels is the mean circulatory filling High-resistance stenosis pressure. This pressure can be observed experimentally by 100 temporarily stopping the heart long enough to let blood flow out of the arteries into the veins, until pressure is the same everywhere in the systemic circulation and flow Pressure (mm Hg) 50 Filling pressure with ceases. When this is done, the pressure measured through- out the systemic circulation is approximately 7 mm Hg. Just as in the model, when the heart restarts after tem- porarily stopping, a net volume of blood is transferred to pump stopped the arterial side from the venous side of the systemic cir- culation. Net transfer continues until the pressure differ- 0 ence builds up in the aorta and decreases in the right A B C D atrium enough to create a pressure difference to drive the blood to the venous side of the circulation at a flow rate A model of the systemic circulation. When FIGURE 12.6 equal to the output from the left ventricle. Because the ve- the pump is turned off, there is no flow and the nous side of the systemic circulation is approximately 20 pressures are the same everywhere in the circulation. This pres- times more compliant than the arterial side, the increase sure is called the filling pressure, shown as a dotted line. When in pressure on the arterial side is 20 times the drop in pres- the pump is turned on, a small volume of fluid is transferred from the high compliance left-hand side (D) to the low compliance “ar- sure on the venous side. terial” side (A). This causes a small decrease in pressure in the left- The pumping action of the heart in combination with hand tubing and a large increase in pressure in the right-hand tub- the elasticity of the aorta and large arteries make the aor- ing. The difference in the changes in pressures is because of the tic and arterial pressures pulsatile. In this discussion, we differences in compliance. Flow around the circulation occurs be- will concern ourselves with the mean arterial pressure cause of pressure difference established by transfer of fluid from (P a ), the pulsatile pressure averaged over the cardiac cy- the left- to the right-hand side of the model. Almost all of the re- cle. Pressure in the aorta and large arteries is almost the sistance to flow is located at the high resistance stenosis between same: there is only a 1 or 2 mm Hg pressure drop from the B and C. Because of this, almost all of the pressure drop occurs aorta to the large arteries. With vascular disease, the pres- across the stenosis between B and C. This is shown by the pres- sures (solid line) observed when the pump is operating and the sure drop in the large arteries can be much greater (see circulation is in a steady state. Clinical Focus Box 12.1). For most purposes, mean arterial pressure refers to the pressure measured in the aorta or any of the large arteries. Flow through the aorta and large arteries (Q art ), and on to the rest of the systemic circulation, is equal to the car- a pressure difference sufficient to drive flow around the diac output in the steady state. It is proportional to the dif- circuit equal to the output of the pump. In this new ference between mean arterial pressure and pressure in the steady state, the pressure on the left side is slightly be- right atrium (right atrial pressure, P ra ). It is inversely pro- low the filling pressure and the pressure on the right side portional to the resistance to flow offered by the systemic is much higher than the filling pressure. Although the circulation, the systemic vascular resistance (SVR). As volume removed from the right side exactly equals the stated earlier, most of this resistance to flow is located in volume added to the right side, the difference in the the small arteries, arterioles, and capillaries. Physiological changes in pressures reflects the different compliances changes in SVR are primarily caused by changes in radius on the two sides of the pump. of small arteries and arterioles, the resistance vessels of the The graph in Figure 12.6 shows that there is a small pres- systemic circulation. This is discussed in more detail in sure drop from the outlet of the pump (A) to just before the Chapter 15. The relationship between cardiac output, flow stenosis (B), a large pressure drop occurs across the steno- through the aorta and large arteries, mean arterial pressure, sis, and a very small pressure drop exists from just after the and systemic vascular resistance is analogous to the model stenosis (C) to the inlet to the pump (D). This is because al- (equation 7): most all of the resistance to flow is located at the stenosis between B and C. Cardiac output Q art (P a P ra )/SVR (8) In the steady state, flow (Q) through the circuit equals Systemic vascular resistance is calculated from cardiac the rate at which volume is transferred from D to A by the output, mean arterial pressure, and right atrial pressure. Be- pump. In the steady state, Q is also equal to the pressure cause right atrial pressure is normally close to zero and
216 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY CLINICAL FOCUS BOX 12.1 Effect of Vascular Disease on Arterial Resistance The pressure gradient along large and medium-sized ar- teries, such as the aorta and renal arteries, is usually very small, due to the minimal resistance typically provided by these vessels. However, several disease processes can produce arterial narrowing and, thus, increase vascular re- sistance. Arterial narrowing exerts a profound effect on ar- terial blood flow because resistance varies inversely with the fourth power of the luminal radius. The most common such disease is atherosclerosis, in which plaques composed of fatty substances (including cholesterol), fibrous tissue, and calcium form in the intimal layer of the artery. Atherosclerosis is the largest cause of morbidity and mortality in the United States: Myocardial infarction secondary to coronary atherosclerosis occurs more than 1 million times annually and accounts for over 700,000 deaths. Cerebrovascular infarction caused by carotid atherosclerosis is also a major cause of morbidity A and mortality. Figure 12.A is an arteriogram from a pa- tient with severe aortoiliac disease. The irregular luminal contour and focal narrowings of the iliac arteries (large ar- An arteriogram of the abdominal aorta FIGURE 12.A rowheads) and narrowing of the superior mesenteric ar- and iliac arteries, demonstrating athero- sclerotic changes. tery (small arrowheads) are all caused by ather- osclerosis. Other disease processes, such as inflamma- tion, blunt trauma, and clotting abnormalities can also lead to significant arterial narrowing or occlusion. One such entity, fibromuscular dys- plasia, is a condition in which the blood vessel wall develops structural irregularities. Fibromus- cular dysplasia can affect people of any age or gender, but most commonly involves young women. The arteriogram in Figure 12.B shows a series of narrowings in the renal artery caused by this dysplastic disease. B FIGURE 12.B An arteriogram of the left renal artery, demonstrating changes of fibromuscular dysplasia. mean arterial pressure is much higher (e.g., 90 mm Hg), culation can be analyzed in the same terms as our discus- right atrial pressure is often ignored: sion of the systemic circulation (the pulmonary circulation is discussed in Chapter 20). Our assumption that in the Cardiac output Q art P a /SVR (9) steady state, the outputs of the right and left hearts are ex- Cardiac output and systemic vascular resistance are actly equal is true. However, transient differences between regulated physiologically. Their regulation allows control the outputs of the left and right heart occur and are physi- of mean arterial pressure. Regulation of cardiac output and ologically important (see Chapter 14). systemic vascular resistance is discussed in subsequent chapters. An assumption in the above discussion is that the right SYSTOLIC AND DIASTOLIC PRESSURES heart and pulmonary circulation faithfully transfer blood flow from the systemic veins to the left heart. In fact, cou- Thus far, we have discussed only mean arterial pressure, pling of the output of the right heart and the pulmonary cir- despite the fact that the pumping of blood by the heart
CHAPTER 12 An Overview of the Circulation and Hemodynamics 217 is a cyclic event. In a resting individual, the heart ejects Bulk Flow and Diffusion Are Influenced by blood into the aorta about once every second (i.e., the Blood Vessel Size and Number heart rate is about 60 beats/min). The phase during which cardiac muscle contracts is called systole, from The aorta has the largest diameter of any artery, and the the Greek for “a drawing together.” During atrial systole, subsequent branches become progressively smaller the pressures in the atria increase and push blood into down to the capillaries. Although the capillaries are the the ventricles. During ventricular systole, pressures in smallest blood vessels, there are several billion of them. the ventricles rise and the blood is pushed into the pul- For this reason, the total cross-sectional area of the lu- monary artery or aorta. During diastole (“a drawing mens of all systemic capillaries (approximately 2,000 2 apart”), the cardiac muscle relaxes and the chambers fill cm ) greatly exceeds that of the lumen of the aorta (7 2 from the venous side. Because of the pulsatile nature of cm ). In a steady state, the blood flow is equal at any two the cardiac pump, pressure in the arterial system rises cross sections in series along the circulation. For exam- and falls with each heartbeat. The large arteries are dis- ple, the flow through the aorta is the same as the total tended when the pressure within them is increased (dur- flow through all of the systemic capillaries. Because the ing systole), and they recoil when the ejection of blood combined cross-sectional area of the capillaries is much falls during the latter phase of systole and ceases entirely greater and the total flow is the same, the velocity of during diastole. This recoil of the arteries sustains the flow in the capillaries is much lower. The slower move- flow of blood into the distal vasculature when there is no ment of blood through the capillaries provides maximum ventricular input of blood into the arterial system. The opportunity for diffusional exchanges of substances be- peak in systemic arterial pressure occurs during ventric- tween the blood and the tissue cells. In contrast, blood ular systole and is called systolic pressure. The nadir of moves quickly in the aorta, where bulk flow, not diffu- systemic arterial pressure is called diastolic pressure. sion, is important. The difference between systolic pressure and diastolic pressure is the pulse pressure. We will discuss these THE LYMPHATIC CIRCULATION three pressure types thoroughly in Chapter 15. In vessels that are thin-walled and relatively permeable (e.g., capillaries and small venules), there is a net transfer of fluid out of the vessels and into the interstitial space. This fluid eventually returns from the interstitial space to the TRANSPORT IN THE CARDIOVASCULAR SYSTEM systemic circulation via another set of vessels, the lym- phatic vessels. This movement of fluid from the systemic The cardiovascular system depends on the energy provided and pulmonary circulation into the interstitial space and by hemodynamic pressure gradients to move materials over then back to the systemic circulation via the lymphatic ves- long distances (bulk flow) and the energy provided by con- sels is referred to as the lymphatic circulation (see Chapter centration gradients to move material over short distances 16). If the lymphatic circulation is interrupted, fluid accu- (diffusion). Both types of movement are the result of differ- mulates in the interstitial space. ences in potential energy. As we have seen, bulk flow oc- curs because of differences in pressure. Diffusion occurs be- CONTROL OF THE CIRCULATION cause of differences in chemical concentration. The healthy cardiovascular system is capable of providing appropriate blood flow to each of the organs and tissues of the body under a wide range of conditions. This is done by Hemodynamic Pressure Gradients Drive Bulk Flow; Concentration Gradients Drive Diffusion • Maintaining arterial blood pressure within normal limits • Adjusting the output of the heart to the appropriate level Blood circulation is an example of transport by bulk flow. • Adjusting the resistance to blood flow in specific organs This is an efficient means of transport over long distances, and tissues to meet special functional needs such as those between the legs and the lungs. Diffusion is The regulation of arterial pressure, cardiac output, and accomplished by the random movement of individual mol- regional blood flow and capillary exchange is achieved by ecules and is an effective transport mechanism over short using a variety of neural, hormonal, and local mecha- distances. Diffusion occurs at the level of the capillaries, nisms. In complex situations (e.g., standing or exercise), where the distances between blood and the surrounding tis- multiple mechanisms interact to regulate the cardiovascu- sue are short. The net transport of molecules by diffusion lar response. In abnormal situations (e.g., heart failure), can occur within hundredths of a second or less when the regulatory mechanisms that have evolved to handle nor- distances involved are no more than a few microns. In con- mal events may be inadequate to restore proper function. trast, minutes or hours would be needed for diffusion to oc- The next few chapters describe these regulatory mecha- cur over millimeters or centimeters. nisms in detail.
218 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY REVIEW QUESTIONS DIRECTIONS: Each of the numbered (B) Mean arterial pressure SUGGESTED READING items or incomplete statements in this (C) Transmural pressure Fung, YC. Biomechanics: Circulation. 2nd section is followed by answers or by (D) Mean circulatory filling pressure Ed. New York: Springer, 1997.Janicki completions of the statement. Select the (E) Hydrostatic pressure JS, Sheriff DD, Robotham JL, Wise, ONE lettered answer or completion that is 4. Blood flow becomes turbulent when RA. Cardiac output during exercise: BEST in each case. (A) Flow velocity Contributions of the cardiac, circula- exceeds a certain value tory and respiratory systems. In: Rowell (B) Blood viscosity exceeds a certain 1. Flow through a tube is proportional to value LB, Shepherd, JT, eds. Handbook of the (C) Blood vessel diameter exceeds a Physiology. Exercise: Regulation and (A) Square of the radius certain value Integration of Multiple Systems. New (B) Square root of the length (D) Reynolds number exceeds a certain York: Oxford University Press, (C) Fourth power of the radius value 1996;649–704. (D) Square of the length 5. The volume of an aorta is increased by Li JK-J. The Arterial Circulation. Totowa, (E) Square root of the radius 30 mL with an associated pressure NJ: Humana Press, 2000. 2. Changes in transmural pressure increase from 80 to 120 mm Hg. The Rowell LB. Human Cardiovascular Con- (A) Can only be caused by changes in compliance of the aorta is trol. New York: Oxford University Press, 1993. pressure inside a blood vessel (A) 1.33 mm Hg/mL (B) Cause changes in blood vessel (B) 4.0 mm Hg/mL volume, depending on the viscosity of (C) 0.75 mm Hg/mL A the blood (D) 1.33 mL/mm Hg (C) Cause changes in blood vessel (E) 0.75 mL/mm Hg 95 mL/min volume, depending on the compliance 6. In the tube in the of the blood vessel diagram to the right, the (D) Cause proportional changes in inlet pressure is 75 mm Hg and the outlet blood flow pressure at A and B is 25 (E) Are proportional to the length of a mm Hg. The resistance blood vessel to flow is 3. The pressure measured in either the (A) 2 PRU 5 mL/min arterial or the venous circulation when (B) 0.5 PRU B the heart has stopped long enough to (C) 2 (mL/min)/mm Hg allow the pressures to equalize is called (D) 0.75 mm the Hg/(mL/min) (A) Hemodynamic pressure (E) 0.5 (mL/min)/mm Hg
The Electrical Activity CHAPTER 13 13 of the Heart Thom W. Rooke, M.D. Harvey V. Sparks, Jr., M.D. CHAPTER OUTLINE ■ THE IONIC BASIS OF CARDIAC ELECTRICAL ■ THE INITIATION AND PROPAGATION OF CARDIAC ACTIVITY: THE CARDIAC MEMBRANE POTENTIAL ELECTRICAL ACTIVITY ■ THE ELECTROCARDIOGRAM KEY CONCEPTS 1. The electrical activity of cardiac cells is caused by the se- 6. Electrical activity spreads across the atria, through the atri- lective opening and closing of plasma membrane channels oventricular (AV) node, through the Purkinje system, and for sodium, potassium, and calcium ions. to ventricular muscle. 2. Depolarization is achieved by the opening of sodium and 7. Norepinephrine increases pacemaker activity and the calcium channels and the closing of potassium channels. speed of action potential conduction. 3. Repolarization is achieved by the opening of potassium 8. Acetylcholine decreases pacemaker activity and the speed channels and the closing of sodium and calcium of action potential conduction. channels. 9. Voltage differences between repolarized and depolarized 4. Pacemaker potentials are achieved by the opening of chan- regions of the heart are recorded by an electrocardiogram nels for sodium and calcium ions and the closing of chan- (ECG). nels for potassium ions. 10. The ECG provides clinically useful information about rate, 5. Electrical activity is normally initiated in the sinoatrial (SA) rhythm, pattern of depolarization, and mass of electrically node where pacemaker cells reach threshold first. active cardiac muscle. he heart beats in the absence of any nervous connections action potential; phase 1 is the small repolarization just af- Tbecause the electrical (pacemaker) activity that generates ter rapid depolarization; phase 2 is the plateau of the action the heartbeat resides within the cardiac muscle. After initia- potential; phase 3 is the repolarization to the resting mem- tion, the electrical activity spreads throughout the heart, brane potential; and phase 4 is the resting membrane po- reaching every cardiac cell rapidly with the correct timing. tential in atrial, ventricular, and Purkinje cells and the pace- This enables coordinated contraction of individual cells. maker potential in nodal cells. In resting ventricular muscle The electrical activity of cardiac cells depends on the ionic cells, the potential inside the membrane is stable at approx- gradients across their plasma membranes and changes in per- imately 90 mV relative to the outside of the cell (see meability to selected ions brought about by the opening and phase 4, Fig. 13.1A). When the cell is brought to threshold, closing of cation channels. This chapter describes how these an action potential occurs (see Chapter 3). First, there is a ionic gradients and changes in membrane permeability result rapid depolarization from 90 mV to 20 mV (phase 0). in the electrical activity of individual cells and how this elec- This is followed by a slight decline in membrane potential trical activity is propagated throughout the heart. (phase 1) to a plateau (phase 2), at which time the mem- brane potential is close to 0 mV. Next, rapid repolarization (phase 3) returns the membrane potential to its resting THE IONIC BASIS OF CARDIAC ELECTRICAL value (phase 4). ACTIVITY: THE CARDIAC MEMBRANE POTENTIAL In contrast to ventricular cells, cells of the sinoatrial (SA) node and atrioventricular (AV) node exhibit a pro- The cardiac membrane potential is divided into 5 phases, gressive depolarization during phase 4 called the pace- phases 0 to 4 (Fig. 13.1). Phase 0 is the rapid upswing of the maker potential (see Fig. 13.1B). When the membrane po- 219
220 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY A Major Channels Involved in Purkinje and +20 1 2 TABLE 13.1 Ventricular Myocyte Membrane Poten- 0 tials -20 mV -40 0 3 Voltage (V)- SA -60 or Ligand(L)- -80 4 Name Gated Functional Role -100 200 msec Voltage-gated V Phase 0 of action potential Na channel (permits influx of Na ) B (fast, I Na ) +20 0 Voltage-gated V Contributes to phase 2 of 0 Ca 2 channel action potential (permits -20 4 3 (long-lasting, influx of Ca ) when 2 mV -40 I CaL ) membrane is -60 depolarized). -80 -adrenergic agents -100 increase the probability 400 msec of channel opening and C raise Ca 2 influx. ACh +20 1 lowers the probability 0 of channel opening. 2 -20 Inward rectifying V Maintains resting mV -40 3 K channel membrane potential -60 0 (i K1 ) (phase 4) by permitting -80 4 outflux of K at highly negative membrane -100 200 msec potentials. Outward (transient) V Contributes briefly to Cardiac action potentials (mV) recorded rectifying K phase 1 by transiently FIGURE 13.1 from A, ventricular, B, sinoatrial, and C, atrial channel (i to1 ) permitting outflux of cells. Note the difference in the time scale of the sinoatrial cell. K at positive Numbers 0 to 4 refer to the phases of the action potential (see text). membrane potentials. Outward (delayed) V Cause phase 3 of action rectifying K potential by permitting tential reaches threshold potential, there is a rapid depolar- channels outflux of K after a ization (phase 0) to approximately 20 mV. The mem- (i Kr , i Ks ) delay when membrane brane subsequently repolarizes (phase 3) without going depolarizes. I Kr channel through a plateau phase, and the pacemaker potential re- is also called HERG sumes. Other myocardial cells combine various character- channel. istics of the electrical activity of these two cell types. Atrial G protein-activated L G protein operated channel, opened by K channel cells, for example (see Fig. 13.1C), have a steady diastolic (i K.G , i K.ACh , ACh and adenosine. resting membrane potential (phase 4) but lack a definite i K.ado ) This channel plateau (phase 2). hyperpolarizes membrane during phase 4 and shortens phase 2. The Cardiac Membrane Potential Depends on Transmembrane Movements of Sodium, Potassium, and Calcium 2 The membrane potential of a cardiac cell depends on con- Ca -ATPase and partially by an antiporter that uses en- centration differences in Na , K , and Ca 2 across the cell ergy derived from the Na electrochemical gradient to re- membrane and the opening and closing of channels that move Ca 2 from the cell. If the energy supply of myocar- transport these cations. Some Na , K , and Ca 2 channels dial cells is restricted by inadequate coronary blood flow, (voltage-gated channels) are opened and closed by changes ATP synthesis (and, in turn, active transport) may be im- in membrane voltage, and others (ligand-gated channels) paired. This situation leads to a reduction in ionic concen- are opened by a neurotransmitter, hormone, metabolite, tration gradients that eventually disrupts the electrical ac- and/or drug. Tables 13.1 and 13.2 list the major membrane tivity of the heart. channels responsible for conducting the ionic currents in The magnitude of the intracellular potential depends on 2 cardiac cells. the relative permeability of the membrane to Na , Ca , The ion concentration gradients that determine trans- and K . The relative permeability to these cations at a par- membrane potentials are created and maintained by active ticular time depends on which of the various cation chan- transport. The transport of Na and K is accomplished by nels listed in Table 13.1 are open. For example, during rest, the plasma membrane Na /K -ATPase (see Chapter 2). mostly K channels are open and the measured potential is Calcium is partially transported by means of a close to that which would exist if the membrane were per-
CHAPTER 13 The Electrical Activity of the Heart 221 Major Channels Involved in Nodal Mem- Sodium equilibrium potential TABLE 13.2 +60 brane Potentials +40 Voltage (V)- or Ligand(L)- +20 Name Gated Functional Role 0 Voltage-gated Ca 2 V Phase 0 of action potential mV channel of SA and AV nodal -20 (long-lasting, i CaL ) cells (carries influx of Ca 2 when membrane -40 is depolarized); contributes to early -60 pacemaker potential of -80 nodal cells. -adrenergic agents -100 increase the probability Potassium equilibrium potential of channel opening and raise Ca 2 influx. ACh FIGURE 13.2 Effect of ionic permeability on membrane lowers the probability potential, primarily determined by the rela- 2 of channel opening. tive permeability of the membrane to Na , K , and Ca . Voltage-gated Ca 2 V Contributes to the Relatively high permeability to K places the membrane poten- channel pacemaker potential. tial close to the K equilibrium potential, and relatively high per- (transient, i CaT ) meability to Na places it close to the Na equilibrium potential. 2 Mixed cation channel V Carries Na (mostly) and The same is true for Ca . An equilibrium potential is not shown 2 (funny, I f )Kinward when for Ca because, unlike Na and K , it changes during the ac- 2 activated by tion potential. This is because cytosolic Ca concentration hyperpolarization. changes approximately 5-fold during excitation. During the 2 Contributes to plateau of the action potential, the equilibrium potential for Ca pacemaker potential. is approximately 90 mV. Membrane permeability to Na , K , K channel (delayed V Contributes to phase 3 of and Ca 2 depends on ion channel proteins (see Table 13.1). outward rectifier, i K ) action potential. Closing early in phase 4 contributes to pacemaker potential. channels and the resulting changes in membrane perme- G protein-activated K L G protein operated ability determine the membrane potential. Figures 13.3 and channel (i K.G , channel, opened by ACh 13.4 depict the membrane changes that occur during an ac- i K.ACh , i K.ado ) and adenosine. This channel hyperpolarizes tion potential in ventricular cells. membrane during phase 4, slowing pacemaker Depolarization Early in the Action Potential: Selective potential. Opening of Sodium Channels. Depolarization occurs when the membrane potential moves away from the K equilibrium potential and toward the Na equilibrium po- tential. In ventricular cell membranes, this occurs passively at first, in response to the depolarization of adjacent mem- meable only to K (potassium equilibrium potential). In branes (discussed later). Once the ventricular cell mem- contrast, when open Na channels predominate (as occurs brane is brought to threshold, voltage-gated Na channels at the peak of phase 0 of the action potential), the measured open, causing the initial rapid upswing of the action poten- potential is closer to the potential that would exist if the tial (phase 0). The opening of Na channels causes Na membrane were permeable only to Na (sodium equilib- permeability to increase. As permeability to Na exceeds rium potential) (see Fig. 13.2). The opening of Ca 2 chan- permeability to K , the membrane potential approaches nels causes the membrane potential to be closer to the cal- the Na equilibrium potential, and the inside of the cell be- cium equilibrium potential, which is also positive; this comes positively charged relative to the outside. occurs in phase 2. Specific changes in the number of open Phase 1 of the ventricular action potential is caused by a channels for these three cations are responsible for changes decrease in the number of open Na channels and the in membrane permeability and the different phases of the opening of a particular type of K channel (see Fig. 13.3 action potential. and Table 13.1). These changes tend to repolarize the membrane slightly. The Opening and Closing of Cation Channels Late Depolarization (Plateau): Selective Opening of Cal- Causes the Ventricular Action Potential cium Channels and Closing of Potassium Channels. In the normal heart, the sodium-potassium pump and cal- The plateau of phase 2 results from a combination of the cium ion pump keep the ionic gradients constant. With closing of K channels (see Fig. 13.3 and Table 13.1) and constant ion gradients, the opening and closing of cation the opening of voltage-gated Ca 2 channels. These chan-
222 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY Area of depolarization resulting in their absence, serious disorders of cardiac electrical ac- from artificial stimulus or pacemaker tivity can develop. i Kr and i Ks channels close 2 and i K1 channels open The Opening of Na and Ca and the Closing Phase of K Channels Causes the Pacemaker Potential + 4 Na channels activate of the SA and AV Nodes Positive charges Resting membrane potential When the electrical activity of a cell from the SA or AV displaced into node is compared with that of a ventricular muscle cell, adjacent areas three important differences are observed (see Fig. 13.1, Fig. 13.5): (1) the presence of a pacemaker potential, (2) the slow rise of the action potential, and (3) the lack of a i Kr and i Ks channels open Depolarization well-defined plateau. The pacemaker potential results from Phase changes in the permeability of the nodal cell membrane to 3 Membrane potential all three of the major cations (see Table 13.2). First, K approaches K + equilibrium potential channels, primarily responsible for repolarization, begin to close. Second, there is a steady increase in the membrane Threshold is reached + Na channels open Phase Membrane potential 0 2 + approaches Na + Ca channels open +20 1 equilibrium potential and i to1 channels close 2 then: 0 Ca 2 + channels close -20 Phase Membrane potential 2 and i K1 channels close mV -40 0 3 (mV) -60 Membrane potential -80 4 stays near zero -100 i to High + Na channels inactivated + i K permeability i K1 * K1 and i channels open Phase to1 i 1 Low Ks Membrane potential nears zero i Kr High Events associated with the ventricular ac- FIGURE 13.3 tion potential. (See Table 13.1 for channel + Na permeability details.) (fast channel) Low nels open more slowly than voltage-gated Na channels and do not contribute to the rapid upswing of the ventric- ular action potential. High Ca 2 + permeability Repolarization: Selective Opening of Potassium Channels. (slow channel) The return of the membrane potential (phase 3, or repolar- Low ization) to the resting state is caused by the closing of Ca 2 channels and the opening of particular classes of K chan- 0 100 200 300 400 Time (msec) nels (see Fig. 13.3 and Table 13.1). This relative increase in permeability to K drives the membrane potential toward FIGURE 13.4 Changes in cation permeabilities during a the K equilibrium potential. Purkinje fiber action potential (compare with Fig. 13.3). The rise in action potential (phase 0) is caused Resting Membrane Potential: Open Potassium Channels. by rapidly increasing Na current carried by voltage-gated Na The resting (diastolic) membrane potential (phase 4) of channels. Na current falls rapidly because voltage-gated Na ventricular cells is maintained primarily by K channels channels are inactivated. K current rises briefly because of open- ing of i to1 channels and then falls precipitously because i K1 chan- that are open at highly negative membrane potentials. nels are closed by depolarization (*closing of i K1 channels). Ca 2 They are called inward rectifying K channels because, channels are opened by depolarization and are responsible, along when the membrane is depolarized (e.g., by the opening of with closed i K1 channels, for phase 2. K current begins to in- voltage-gated Na channels), they do not permit outward crease because i Kr and i Ks channels are opened by depolarization, movement of K . Other specialized K channels help sta- after a delay. Once repolarization occurs, Na channels are acti- bilize the resting membrane potential (see Table 13.1) and, vated. Reopened i K1 channels maintain phase 4.
CHAPTER 13 The Electrical Activity of the Heart 223 40 Neurotransmitters and Other Ligands Can Influence Membrane Ion Conductance a b c 20 The normal pacemaker cells are under the influence of Membrane potential (mV) 20 (ACh) and the cardioaccelerator nerves release norepi- parasympathetic nerves (vagus) and sympathetic nerves (cardioaccelerator). The vagus nerves release acetylcholine 0 nephrine at their terminals in the heart. ACh slows the heart rate by reducing the rate of spontaneous depolariza- tion of pacemaker cells (see Fig. 13.5), increasing the time 40 bradycardia, or when the heart rate is below 60 beats/min. ACh exerts this effect by increasing the number of open K 60 required to reach threshold. Slowed heart rate is called channels and decreasing the number of open channels car- 2 rying Na and Ca ; both actions hold the pacemaker po- 80 Time (msec) tential closer to the K equilibrium potential. In contrast, norepinephrine causes an increase in the Sinoatrial plasma membrane potential as a FIGURE 13.5 slope of the pacemaker potential so that the threshold is function of time. Normal pacemaker potential reached more rapidly and the heart rate increases. In- (b) is affected by norepinephrine (a) and acetylcholine (c). The creased heart rate is called tachycardia, or when the heart dashed line indicates threshold potential. The more rapidly rising rate is above 100 beats/min. Norepinephrine increases the pacemaker potential in the presence of norepinephrine (a) results from increased Na permeability. The hyperpolarization and slope of the pacemaker potential by opening channels car- 2 slower rising pacemaker potential in the presence of ACh results rying Na and Ca and closing K channels. Both effects from decreased Na permeability and increased K permeability, result in faster movement of the pacemaker potential to- 2 due to the opening of ACh-activated K channels. ward the Na and Ca equilibrium potentials. Norepi- nephrine and ACh exert these effects via G s and G i protein- mediated events. Many other ligands, including metabolites (e.g., adeno- permeability to Na caused by the opening of a cation sine) and drugs (e.g., those which act on the autonomic channel. Third, calcium moves in through the voltage- nervous system), alter the heart rate by mechanisms similar gated Ca 2 channel early in diastole. All three of these to the ones outlined above. changes move the membrane potential in a positive direc- tion toward the Na and Ca 2 equilibrium potentials. An action potential is triggered when threshold is reached. THE INITIATION AND PROPAGATION This action potential rises more slowly than the ventricular OF CARDIAC ELECTRICAL ACTIVITY action potential because the fast voltage-gated Na chan- nels play an insignificant role. Instead, the opening of slow Cardiac electrical activity is normally initiated and spread voltage-gated Ca 2 channels is primarily responsible for in an orderly fashion. The heart is said to be a functional the upstroke of the action potential in nodal cells. The ab- syncytium because the excitation of one cardiac cell even- sence of a well-defined plateau occurs because K channels tually leads to the excitation of all cells. The cellular basis open and pull the membrane potential toward the K equi- for the functional syncytium is low-resistance areas of the librium potential. intercalated disks (the end-to-end junctions of myocardial Purkinje fibers are also capable of pacemaker activity, cells) called gap junctions (see Chapter 10). Gap junctions but the rate of depolarization during phase 4 is much slower between adjacent cells allow small ions to move freely from than that of the nodal cells. In the normal heart, phase 4 of one cell to the next, meaning that action potentials can be Purkinje fibers is usually thought to be a stable resting propagated from cell to cell, similar to the way an action membrane potential. potential is propagated along an axon (see Chapter 3). The Refractory Period Is Caused by a Delay Excitation Starts in the SA Node Because in the Reactivation of Na Channels SA Cells Reach Threshold First As discussed in Chapter 10, cardiac muscle cells display Excitation of the heart normally begins in the SA node be- long refractory periods and, as a result, cannot be cause the pacemaker potential of this tissue (see Fig. 13.1) tetanized by fast, repeated stimulation. A prolonged re- reaches threshold before the pacemaker potential of the AV fractory period eliminates the possibility that a sustained node. The pacemaker rate of the SA node is normally 60 to contraction might occur and prevent the cyclic contrac- 100 beats/min versus 40 to 55 beats/min for the AV node. tions required to pump blood. The refractory period be- Pacemaker activity in the bundle of His and the Purkinje gins with depolarization and continues until nearly the system is even slower, at 25 to 40 beats/min. Normal atrial end of phase 3 (see Fig. 10.2). This occurs because the and ventricular cells do not exhibit pacemaker activity. Na channels that open to cause phase 0 close and are in- Many cells of the SA node reach threshold and depolar- active until the membrane repolarizes. ize almost simultaneously, creating a migration of ions be-
224 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY tween these depolarized SA nodal cells and nearby resting cell (compared with a large atrial or ventricular cell), and atrial cells. This leads to depolarization of the neighboring the relatively smaller current brings neighboring cells to right atrial cells and a wave of depolarization begins to threshold more slowly, decreasing the rate at which elec- spread over the right and left atria. trical activation spreads. Other significant factors are the slow upstroke of the action potential because it depends on slow voltage-gated Ca 2 channels and, possibly, weak elec- The Action Potential Is Propagated by Local trical coupling as a result of relatively few gap junctions. Currents Created During Depolarization Propagation of the action potential through the AV node As Na ions enter a cell during phase 0, their positive takes approximately 120 msec. Excitation then proceeds charge repels intracellular K ions into nearby areas where through the AV bundle (bundle of His), the left and right depolarization has not yet occurred. Potassium is even bundle branches, and the Purkinje system. driven into adjacent resting cells through gap junctions. The AV node is the weak link in the excitation of the The local buildup of K depolarizes adjacent areas until heart. Inflammation, hypoxia, vagus nerve activity, and cer- threshold is reached. The cycle of depolarization to tain drugs (e.g., digitalis, beta blockers, and calcium entry threshold, Na entry, and subsequent displacement of pos- blockers) can cause failure of the AV node to conduct some itive charges into nearby areas explains the spread of elec- or all atrial depolarizations to the ventricles. On the other trical activity. Excitation proceeds as succeeding cycles of hand, its tendency to conduct slowly is sometimes of ben- local ion current and action potential move out of the SA efit in pathological situations in which atrial depolariza- node and across the atria. This process is called the propa- tions are too frequent and/or uncoordinated, as in atrial gation of the action potential. flutter or fibrillation. In these conditions, not all of the elec- trical impulses that reach the AV node are conducted to the ventricles, and the ventricular rate tends to stay below the Excitation Usually Spreads From the SA Node level at which diastolic filling is impaired (see Chapter 14). to Atrial Muscle to the AV Node to the Purkinje The benefit of slow AV nodal conduction in a normal heart System to Ventricular Muscle is that it allows the ventricular filling associated with atrial systole to occur before the ventricles are excited. A fibrous, nonconducting connective tissue ring separates the atria from the ventricles everywhere except at the AV Rapid Conduction Through the Ventricles. The Purkinje node. For this reason, the transmission of electrical activity system is composed of specialized cardiac muscle cells with from the atria to the ventricles occurs only through the AV large diameters. These cells rapidly conduct (conduction ve- node. Action potentials in atrial muscle adjacent to the AV locity up to 2 m/sec) action potentials throughout the suben- node produce local ion currents that invade the node and docardium of both ventricles. Depolarization then proceeds trigger intranodal action potentials. from endocardium to epicardium (see Fig. 13.6). The con- duction velocity through ventricular muscle is 0.3 m/sec; Slow Conduction Through the AV Node. Excitation pro- complete excitation of both ventricles takes approximately ceeds throughout the atria at a speed of approximately 1 75 msec. The rapid completion of excitation of the ventricles m/sec. It requires 60 to 90 msec to excite all regions of the assures synchronized contraction of all ventricular muscle atria (Fig. 13.6). Propagation of the action potential con- cells and maximal effectiveness in ejecting blood. tinues within the AV node, but at a much slower velocity (0.05 to 0.1 m/sec). The slower conduction velocity is par- tially explained by the small size of the nodal cells. Less THE ELECTROCARDIOGRAM current is produced by the depolarization of a small nodal The electrocardiogram (ECG) is a continuous record of cardiac electrical activity obtained by placing sensing elec- trodes on the surface of the body and recording the voltage A B differences generated by the heart. The equipment ampli- fies these voltages and causes a pen to deflect proportion- AV bundle SVC ally on a paper moving under it. This gives a plot of voltage as a function of time. SA node Left bundle .07 branch .01 .09 .03 .22 The ECG Records the Dipoles Produced .05 .02 .03 by the Electrical Activity of the Heart .19 .07 .16 .16 .21 AV To understand the ECG, it is necessary to understand the node .19 .18 behavior of electrical potentials in a three-dimensional .17 .17 IVC .18 conductor of electricity. Consider what happens when .21 wires are run from the positive and negative terminals of a Right bundle Ventricular .20 battery into a dish containing salt solution. Positively branch septum charged ions flow toward the negative wire (negative pole) The timing of excitation of various areas of and negatively charged ions simultaneously flow in the op- FIGURE 13.6 the heart (in fractions of a second). posite direction toward the positive wire (positive pole).
CHAPTER 13 The Electrical Activity of the Heart 225 The combination of two poles that are equal in magnitude and opposite in charge and located close to one another, is called a dipole. The flow of ions (current) is greatest in the region between the two poles, but some current flows at every point surrounding the dipole, reflecting the fact that voltage differences exist everywhere in the solution. Measurement of the Voltage Associated With a Dipole. What points encircling the dipole in Figure 13.7 have the greatest voltage difference between them? Points A and B do because A is closest to the positive pole and B is closest to the negative pole. Positive charges are drawn from the area around point B by the negative end of the dipole, which is relatively near. The positive end of the dipole is relatively distant and, therefore, has little ability to attract negative charges from point B (although it can draw nega- tive charges from point A). As positive charges are drawn away, point B is left with a negative charge (or negative voltage). The opposite happens between the positive end of the dipole and point A, leaving A with a net positive FIGURE 13.8 Effect of dipole position and magnitude on charge (or voltage). Points C and D have no voltage differ- recorded voltage. In a salt solution, the dipole ence between them because they are equally distant from can be represented as a vector having a length and direction de- both poles and are, therefore, equally influenced by posi- termined by the dipole magnitude and position, respectively. In tive and negative charges. Any other two points on the cir- this example, electrodes for the voltmeter are at points C and D. When a vector is directed parallel to a line between C and D, the cle, E and F, for example, have a voltage difference between voltage is maximum. If the magnitude of the vector is decreased, them that is less than that between A and B and greater than the voltage decreases. that between C and D. This is also true of other combina- tions of points, such as A and C, B and D, and D and F. Voltage differences exist in all cases and are determined by the relative influences of the positive and negative ends of edges of a dish of salt solution in which the dipole can be the dipole. rotated. This solution is analogous to that depicted in Fig- ure 13.7, except the dipole position is changed relative to Changes in Dipole Magnitude and Direction. What the electrodes instead of the electrode being changed rela- would happen if the dipole were to change its orientation tive to the dipole. Figure 13.8 shows the changes in meas- relative to points C and D? Figure 13.8 diagrams an appa- ured voltage that occur if the dipole is rotated 90 degrees. ratus in which electrodes from a voltmeter are placed at the The measured voltage increases slowly as the dipole is turned and is maximal when the positive end of the dipole points to C and the negative end points to D. In each posi- tion, the dipole sets up current fields similar to those shown in Figure 13.7. The voltage measured depends on how the electrodes are positioned relative to those currents. Figure 13.8 also shows that the voltage between C and D will de- crease to a new steady-state level as the voltage applied to the wires by the battery is decreased. These imaginary ex- periments illustrate two characteristics of a dipole that de- termine the voltage measured at distant points in a volume conductor: direction of the dipole relative to the measuring points and magnitude (voltage) of the dipole; this is an- other way of saying that a dipole is a vector. Portions of the ECG Are Associated With Electrical Activity in Specific Cardiac Regions We can use this analysis of a dipole in a volume conductor to rationalize the waveforms of the ECG. Of course, the ac- tual case of the heart located in the chest is not as simple as the dipole in the tub of salt solution for two main reasons. Creating a dipole in a tub of salt solution. First, excitation of the heart does not create one dipole; in- FIGURE 13.7 The dashed lines indicate current flow; the stead, there are many simultaneous dipoles. We will focus current flows from the positive to the negative poles (See text with the net dipole emerging as an average of all the indi- for details.). vidual dipoles. Second, the body is not a homogeneous vol-
226 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY ume conductor. The most significant problem is that the Consider the voltage changes produced by a two-di- lungs are full of air, not salt solution. Despite these prob- mensional model in which the body serves as a volume con- lems, the model is useful in an initial understanding of the ductor and the heart generates a collection of changing generation of the ECG. dipoles (Fig. 13.10). An electrocardiographic recorder (a At rest, myocardial cells have a negative charge inside voltmeter) is connected between points A and B (lead I, see and a positive charge outside the cell membrane. As cells below). By convention, when point A is positive relative to depolarize, the depolarized cells become negative on the point B, the ECG is deflected upward, and when B is posi- outside, whereas the cells in the region ahead of the de- tive relative to A, downward deflection results. The black polarized cells remain positive on the outside (Fig. 13.9). arrows show (in two dimensions) the direction of the net When the entire myocardium is depolarized, no voltage dipole resulting from the many individual dipoles present at differences exist between any regions of myocardium be- any one time. The lengths of the arrows are proportional to cause all cells are negative on the outside. When the cells the magnitude (voltage) of the net dipole, which is related in a given region depolarize during normal excitation, to the mass of myocardium generating the net dipole. The that portion of the heart generates a dipole. The depolar- colored arrows show the magnitude of the dipole compo- ized portion constitutes the negative side, and the yet-to- nent that is parallel to the line between points A and B (the be-depolarized portion constitutes the positive side of the recorder electrodes); this component determines the volt- dipole. The tub of salt solution is analogous to the rest of age that will be recorded. the body in that the heart is a dipole in a volume conduc- tor. With electrodes located at various points around the The P Wave and Atrial Depolarization. Atrial excitation volume conductor (i.e., the body), the voltage resulting results from a wave of depolarization that originates in the from the dipole generated by the electrical activity of the SA node and spreads over the atria, as indicated in panel 1 heart can be measured. of Figure 13.10. The net dipole generated by this excitation has a magnitude proportional to the mass of the atrial mus- cle involved and a direction indicated by the solid arrow. The head of the arrow points toward the positive end of the dipole, where the atrial muscle is not yet depolarized. The negative end of the dipole is located at the tail of the arrow, where depolarization has already occurred. Point A is, therefore, positive relative to point B, and there will be an upward deflection of the ECG as determined by the mag- nitude and direction of the dipole. Once the atria are com- pletely depolarized, no voltage difference exists between A and B, and the voltage recording returns to 0. The voltage change associated with atrial excitation appears on the ECG as the P wave. The PR Segment and Atrioventricular Conduction. Af- ter the P wave, the ECG returns to the baseline present be- k fore the P wave. The ECG is said to be isoelectric when there is no deflection from the baseline established before the P wave. During this time, the wave of depolarization moves slowly through the AV node, the AV bundle, the bundle branches, and the Purkinje system. The dipoles cre- ated by depolarization of these structures are too small to produce a deflection on the ECG. The isoelectric period between the end of the P wave and the beginning of the QRS complex, which signals ventricular depolarization is called the PR segment. The P wave plus the PR segment is the PR interval. The duration of the PR interval is usually taken as an index of AV conduction time. The QRS Complex and Ventricular Depolarization. The depolarization wave emerges from the AV node and travels along the AV bundle (bundle of His), bundle branches, and Purkinje system; these tracts extend down the interventricu- lar septum. The net dipole that results from the initial depo- larization of the septum is shown in panel 2 of Figure 13.10. Cardiac dipoles. Partially depolarized or re- FIGURE 13.9 polarized myocardium creates a dipole. Arrows Point B is positive relative to point A because the left side of show the direction of depolarization (or repolarization). Dipoles the septum depolarizes before the right side. The small are present only when myocardium is undergoing depolarization downward deflection produced on the ECG is the Q wave. or repolarization. The normal Q wave is often so small that it is not apparent.
CHAPTER 13 The Electrical Activity of the Heart 227 1 P B A SA - R + B AV A T P Q S 2 B A Q - + R R 3 4 5 T B A B A B A Q - + S - S - + + The sequence of major dipoles giving rise the yet-to-be-repolarized region of the myocardium (negative) FIGURE 13.10 to ECG waveforms. The black arrows are and the head points to the repolarized region (positive). The last vectors that represent the magnitude and direction of a major di- areas of the ventricles to depolarize are the first to repolarize, i.e., pole. The magnitude is proportional to the mass of myocardium repolarization appears to proceed in a direction opposite to that of involved. The direction is determined by the orientation of depo- depolarization. The projection of the vector (colored arrow) for larized and polarized regions of the myocardium. The vertical repolarization points to the more positive electrode (A) as op- dashed lines project the vector onto the A-B coordinate (lead I); it posed to the less positive electrode (B), and so an upward deflec- is this component of the vector that is sensed and recorded (col- tion is recorded on this lead. ored arrow). In panel 5, the tail of the vector (black arrow) shows The wave of depolarization spreads via the Purkinje sys- duration of the QRS complex is roughly equivalent to the tem across the inside surface of the free walls of the ventri- duration of the P wave, despite the much greater mass of cles. Depolarization of free wall ventricular muscle pro- muscle of the ventricles. The relatively brief duration of the ceeds from the innermost layers of muscle QRS complex is the result of the rapid, synchronous exci- (subendocardium) to the outermost layers (subepicardium). tation of the ventricles. Because the muscle mass of the left ventricle is much greater than that of the right ventricle, the net dipole dur- The ST Segment and Phase 2 of the Ventricular Action Po- ing this phase has the direction indicated in panel 3. The tential. The ST segment is the period between the end of deflection of the ECG is upward because point A is positive the S wave and the beginning of the T wave. The ST seg- relative to point B, and it is large because of the great mass ment is normally isoelectric, or nearly so. This indicates that of tissue involved. This upward deflection is the R wave. no dipoles large enough to influence the ECG exist because The last portions of the ventricle to depolarize generate all ventricular muscle is depolarized; that is, the action po- a net dipole with the direction shown in panel 4. Point B is tentials of all ventricular cells are in phase 2 (Fig. 13.11). positive compared with point A, and the deflection on the ECG is downward. This final deflection is the S wave. The The T Wave and Ventricular Repolarization. Repolariza- ECG tracing returns to baseline as all of the ventricular tion, like depolarization, generates a dipole because the muscle becomes depolarized and all dipoles associated with voltage of the depolarized area is different from that of the ventricular depolarization disappear. The Q, R, and S repolarized areas. The dipole associated with atrial repolar- waves together are known as the QRS complex and show ization does not appear as a separate deflection on the ECG the progression of ventricular muscle depolarization. The because it generates a very low voltage and because it is
228 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY PR interval QRS ST segment subepicardial myocardium. The longer duration of suben- docardial action potentials means that even though suben- R docardial cells were the first to depolarize, they are the last +1.0 to repolarize. Because subepicardial cells repolarize first, ECG the subepicardium is positive relative to the subendo- cardium (see Fig. 13.9). That is, the polarity of the net di- +0.5 pole of repolarization is the same as the polarity of the di- mV P T pole of depolarization. This results in an upward deflection because, as in depolarization, point A is positive with re- spect to point B. This deflection is the T wave (see panel 5, 0 Fig. 13.10). The T wave has a longer duration than the QRS Q complex because repolarization does not proceed as a syn- chronized, propagated wave. Instead, the timing of repo- S -0.5 larization is a function of properties of individual cells, such as numbers of particular K channels. +20 The QT Interval. The QT interval is the time from the be- 0 ginning of the QRS complex to the end of the T wave. If ven- tricular action potential and QT interval are compared, the -20 Membrane QRS complex corresponds to depolarization, the ST segment potential to the plateau, and the T wave to repolarization (see Fig. mV -40 13.11). The relationship between a single ventricular action -60 potential and the events of the QT interval are approximate because the events of the QT interval represent the combined -80 influence of all of the ventricular action potentials. The QT interval measures the total duration of ventric- -100 ular activation. If ventricular repolarization is delayed, the QT interval is prolonged. Because delayed repolarization is 0 0.2 0.4 0.6 associated with genesis of ventricular arrhythmias, this is Sec clinically significant (see Clinical Focus Box 13.1). The timing of the ventricular membrane po- FIGURE 13.11 tential and the ECG. Note that the ST seg- ment occurs during the plateau of the action potential. ECG Leads Give the Voltages Measured Between Different Sites on the Body masked by the much larger QRS complex that is present at An electrocardiographic lead is the pair of electrical conductors the same time. used to detect cardiac potential differences. An ECG lead is Ventricular repolarization is not as orderly as ventricular also used to refer to the record of potential differences made depolarization. The duration of ventricular action poten- by the ECG machine. Bipolar leads give the potential differ- tials is longer in subendocardial myocardium than in ence between two electrodes placed at different sites. Elec- CLINICAL FOCUS BOX 13.1 Long QT Syndrome called ventricular fibrillation. With ventricular fibrilla- Some families have a rare inherited abnormality called tion, there is no synchronized contraction of ventricular congenital long QT syndrome (LQTS). Individuals with muscle and the heart cannot pump the blood. Arterial pres- LQTS are often discovered because the individual or a fam- sure drops, blood flow to the brain and other parts of the ily member presents to a physician with episodes of syn- body ceases, and sudden death occurs. cope (fainting) or because an otherwise healthy person A single mutation of one of at least four genes, each of dies suddenly and an alert physician suggests that their which codes for a particular cardiac muscle ion channel, close relatives get an ECG. The ECG of affected individuals causes LQTS. Mutations of three potassium channels have reveals either a long, irregular T wave, a prolonged ST been discovered. The mutations decrease their function, segment, or both. Their hearts have delayed repolariza- decreasing potassium current and, thereby, increasing the tion, which prolongs the ventricular action potential. In ad- tendency of the membrane to depolarize. A mutation of the dition, when repolarization does occur, the freshly repolar- sodium channel has also been found in some patients with ized myocardium is subject to sudden, early LQTS. This mutation increases the sodium channel func- depolarizations, called afterdepolarizations. These oc- tion, increasing sodium current and the tendency of the cur because the membrane potential in a small region of membrane to depolarize. myocardium begins to depolarize before it has stabilized at Individuals with congenital LQTS may be children or the resting value. Afterdepolarizations may disrupt the adults when the abnormality is identified. It is now appar- normal, synchronized pattern of depolarization, and the ent that at least one cause of sudden infant death syn- ventricles may begin to depolarize in a chaotic pattern drome (SIDS) involves a form of LQTS.
CHAPTER 13 The Electrical Activity of the Heart 229 trodes of the traditional bipolar limb leads are placed on the _ left arm, right arm, and left leg (Fig. 13.12). The potential + differences between each combination of two of these elec- trodes give leads I, II, and III. By convention, the left arm in lead I is the positive pole, and the left leg is the positive pole in leads II and III. A unipolar lead is the pair of electrical con- ductors giving the potential difference between an exploring electrode and a reference input, sometimes called the indif- ferent electrode. The reference input comes from a combi- nation of electrodes at different sites, which is supposed to give roughly zero potential throughout excitation of the heart. Assuming this to be the case, the recorded electrical V 1 V 2 activity is the result of the influence of cardiac electrical ac- V 3 V 4 V 5 V 6 tivity on the exploring electrode. By convention, when the exploring electrode is positive relative to the reference input, an upward deflection is recorded. The exploring electrode for the precordial or chest leads is the single electrode placed on the anterior and left lateral chest wall. For the chest leads, the reference input is obtained by connecting the three limb electrodes (Fig. 13.13). The observed ECGs recorded from the chest leads are each the result of voltage changes at a specified point on the surface of the chest. Unipolar chest leads are desig- nated V 1 to V 6 and are placed over the areas of the chest _ + FIGURE 13.13 Unipolar chest leads. V 1 is just to the right of the sternum in the fourth intercostal space. V 2 is just to the left of the sternum in the fourth interspace. V 4 is in the fifth interspace in the midclavicular line. V 3 is midway be- tween V 2 and V 4. V 5 is in the fifth interspace in the anterior axil- lary line. V 6 is in the fifth interspace in the midaxillary line. The three limb leads are combined to give the reference voltage (zero) for the unipolar chest lead (V). _ + _ I _ shown in Figure 13.13. The generation of the QRS com- plex in the chest leads can be explained in a way similar to that for lead I. The exploratory electrode for an augmented limb lead is an electrode on a single limb. The reference input is the two other limb electrodes connected together. Lead aVR gives the potential difference between the right arm (ex- II III ploring electrode) and the combination of the left arm and the left leg (reference). Lead aVL gives the potential differ- _ _ ence between the left arm and the combination of the right + + arm and left leg. Lead aVF gives the potential difference be- tween the left leg and the combination of the left arm and right arm. A standard 12-lead ECG, including six limb leads and six + chest leads, is shown in Figure 13.14. The ECG is calibrated so that two dark horizontal lines (1 cm) represent 1 mV, + and five dark vertical lines represent 1 second. This means that one light vertical line represents 0.04 sec. Einthoven triangle. Einthoven codified the FIGURE 13.12 analysis of electrical activity of the heart by The ECG Provides Information About Cardiac proposing that certain conventions be followed. The heart is con- Dipoles as Vectors sidered to be at the center of a triangle, each corner of which serves as the location for an electrode for two leads to the ECG Cardiac dipoles are vectors with both magnitude and di- recorder. The three resulting leads are I, II, and III. By conven- rection. The net vector produced by all cardiac dipoles at a tion, one electrode causes an upward deflection on the recorder given time can be determined from the ECG. The direction when it is under the influence of a positive dipole relative to the of the vectors can be determined in the frontal and hori- other electrode. zontal planes of the body.
230 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY I I V1V1 V4 V4 aVRaVR V5 IIII aVLaVL V2V2 V5 V6 aVFaVF V3V3 V6 IIIIII Standard 12-lead ECG. Six limb leads and six chest leads are shown. Two dark horizon- FIGURE 13.14 tal lines (10 mm) are calibrated to be 1 mV. Dark vertical lines represent 0.2 sec. The bipolar limb leads (leads I, II, and III) and the aug- ward the positive end of the axis of a lead results in the mented limb leads (aVR, aVL, and aVF) provide informa- recording of an upward deflection. A net cardiac dipole with tion about the electrical activity of the heart as observed in its positive charge directed toward the negative end of the the frontal plane. As we have seen, lead I is the record of axis of a lead results in a downward deflection. A net cardiac potential differences between the left and right arms. It dipole with its positive charge directed at a right angle to the records only the component of the electrical vector that is axis of a lead results in no deflection. The hexaxial reference parallel to its axis. Lead I can be symbolized by a horizon- system can be used to predict the influence of a cardiac di- tal line (axis) going through the center of the chest (Fig. pole on any of the six leads in the frontal plane. As we will 13.15A) in the direction of right arm to left arm. Likewise, see, this system is useful in understanding changes in the lead II can be symbolized by a 60 line drawn through the leads of the ECG associated with different diseases. middle of the chest in the direction of right arm to left leg. The unipolar chest leads provide information about car- The same type of representation can be done for lead III diac dipoles generated in the horizontal plane (Figure and for the augmented limb leads. The positive ends of the 13.15B). Each chest lead can be represented as having an leads are shown by the arrowheads (see Fig. 13.15A). The axis coming from the center of the chest to the site of the diagram that results (see Fig. 13.15A) is called the hexaxial exploring electrode in the horizontal plane. The deflec- reference system. tions recorded in each chest lead can be understood in A net cardiac dipole with its positive charge directed to- terms of this axial system. Superior -90 Posterior -120 -60 -150 -30 aVL aVR I +180180 0 _ + _ Right Left Right Left V 6 0 +30 +150 +30 +150 III aVF II V 5 30 +120 +60 +90 V 4 V 1 V 2 V 3 60 75 A Inferior Anterior B Hexaxial reference system. A, The limb leads the frontal plane. B, Chest leads are influenced by dipole vectors FIGURE 13.15 give information on cardiac dipole vectors in in the horizontal plane.
CHAPTER 13 The Electrical Activity of the Heart 231 The Mean QRS Electrical Axis Is Determined Lead I _ From the Limb Leads RA _ 0 +5 +10 + _ LA As explained above, changes in the magnitude and direction of the cardiac dipole will cause changes in a given ECG lead, as predicted by the axial reference system. By examining the -10 limb leads, the observer can determine the mean electrical -5 axis during ventricular depolarization. One approach in- 0 0 0 0 volves the use of Einthoven’s triangle. Einthoven’s triangle is Lead II +5 Lead III an equilateral triangle with each side representing the axis of +10 one of the bipolar limb leads (Fig. 13.16). The net magnitude of the QRS complex of any two of the three leads is meas- ured and plotted on the appropriate axis. A perpendicular is + LL + dropped from each of the plotted points. A vector drawn be- tween the center of the triangle and the intersection of the +9 mm +5 mm two perpendiculars gives the mean electrical axis. In this ex- ample, the data taken from the ECG in Figure 13.14 give a mean electrical axis of 3 degrees. A second approach employs the hexaxial reference sys- tem (see Fig. 13.15A). First, the six limb leads are inspected to find the one in which the net QRS complex deflection is closest to zero. As discussed earlier, when the cardiac di- pole is perpendicular to a particular lead, the net deflection I II is zero. Once the net QRS deflection closest to zero is iden- -4 mm tified, it follows that the mean electrical axis is perpendicu- lar to that lead. The hexaxial reference system can be con- sulted to determine the angle of that axis. In Figure 13.14, the lead in which the net QRS deflection is closest to zero is lead aVF (the bipolar limb leads and lead aVF are en- larged in Figure 13.16). Lead I is perpendicular to the axis of lead aVF (see Fig. 13.15A). Because the QRS complex is III aVF upward in lead I, the mean electrical axis points to the left arm and is estimated to be about 0 degrees. Mean QRS electrical axis. This axis can be The mean QRS electrical axis is influenced by (a) the FIGURE 13.16 estimated by using Einthoven’s triangle and the position of the heart in the chest, (b) the properties of the net voltage of the QRS complex in any two of the bipolar limb cardiac conduction system, and (c) the excitation and re- leads. It can also be estimated by inspection of the six limb leads polarization properties of the ventricular myocardium. Be- (see text for details). ECG tracings are from Figure 13.14. cause the last two of these influences are most significant, the mean QRS electrical axis can provide valuable informa- tion about a variety of cardiac diseases. Figure 13.17A shows respiratory sinus arrhythmia, an increase in the heart rate with inspiration and a decrease with expiration. The presence of a P wave before each QRS The ECG Permits the Detection and Diagnosis of complex indicates that these beats originate in the SA Irregularities in Heart Rate and Rhythm node. Intervals between successive R waves of 1.08, 0.88, The ECG provides information about the rate and rhythm 0.88, 0.80, 0.66, and 0.66 seconds correspond to heart rates of excitation, as well as the pattern of conduction of excita- of 56, 68, 68, 75, 91, and 91 beats/min. The interval be- tion throughout the heart. The following illustrations of tween the beginning of the P wave and the end of the T cardiac rate and rhythm irregularities are not comprehen- wave is uniform, and the change in the interval between sive; they were chosen to describe basic physiological prin- beats is primarily accounted for by the variation in time be- ciples. Disorders of cardiac rate and rhythm are referred to tween the end of the T wave and the beginning of the P as arrhythmias. wave. Although the heart rate changes, the interval during Figure 13.14 shows the standard 12-lead ECG from an which electrical activation of the atria and ventricles occurs individual with normal sinus rhythm. We see that the P does not change nearly as much as the interval between wave is always followed by a QRS complex of uniform beats. Respiratory sinus arrhythmia is caused by cyclic shape and size. The PR interval (beginning of the P wave to changes in sympathetic and parasympathetic neural activ- the beginning of the QRS complex) is 0.16 sec (normal, ity to the SA node that accompany respiration. It is ob- 0.10 to 0.20 sec). This measurement indicates that the con- served in individuals with healthy hearts. duction velocity of the action potential from the SA node Figure 13.17B shows an ECG during excessive stimula- to the ventricular muscle is normal. The average time be- tion of the parasympathetic nerves. The stimulation re- tween R waves (successive heart beats) is about 0.84 sec, leases ACh from nerve endings in the SA and AV nodes; making the heart rate approximately 71 beats/min. ACh suppresses the pacemaker activity, slows the heart
232 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY A B C D E ECGs (lead II) showing abnormal rhythms. with vagal escape. C, Atrial fibrillation. D, Premature ventricular FIGURE 13.17 A, Respiratory sinus arrhythmia. B, Sinus arrest complex. E, Complete atrioventricular block. rate, and increases the distance between P waves. The merous disease states, such as cardiomyopathy, pericarditis, fourth and fifth QRS complexes are not preceded by P hypertension, and hyperthyroidism, but it sometimes oc- waves. When a QRS complex is recorded without a pre- curs in otherwise normal individuals. ceding P wave, it reflects the fact that ventricular excitation The ECG in Figure 13.17D shows a premature ventric- has occurred without a preceding atrial contraction, which ular complex (PVC). The first three QRS complexes are means that the ventricles were excited by an impulse that preceded by P waves; then after the T wave of the third originated below the atria. The normal configuration of the QRS complex, a QRS complex of increased voltage and QRS complex suggests that the new pacemaker was in the longer duration occurs. This premature complex is not pre- AV node or bundle of His and that ventricular excitation ceded by a P wave and is followed by a pause before the proceeded normally from that point. This is called junc- next normal P wave and QRS complex. The premature ven- tional escape. tricular excitation is initiated by an ectopic focus, an area The ECG in Figure 13.17C is from a patient with atrial of pacemaker activity in other than the SA node. In panel fibrillation. In this condition, atrial systole does not occur D, the focus is probably in the Purkinje system or ventricu- because the atria are excited by many chaotic waves of de- lar muscle, where an aberrant pacemaker reaches threshold polarization. The AV node conducts excitation whenever it before being depolarized by the normal wave of excitation. is not refractory and a wave of atrial excitation reaches it. Once the ectopic focus triggers an action potential, the ex- Unless there are other abnormalities, conduction through citation is propagated over the ventricles. The abnormal the AV node and ventricles is normal and the resulting QRS pattern of excitation accounts for the greater voltage, complex is normal. The ECG shows QRS complexes that change of mean electrical axis, and longer duration (ineffi- are not preceded by P waves. The ventricular rate is usually cient conduction) of the QRS complex. Although the ab- rapid and irregular. Atrial fibrillation is associated with nu- normal wave of excitation reached the AV node, retrograde
CHAPTER 13 The Electrical Activity of the Heart 233 conduction usually dies out in the AV node. The next nor- tions are conducted by the AV node, it is second-degree mal atrial excitation (P wave) occurs but is hidden by the atrioventricular block. If atrial excitation never reaches the inverted T wave associated with the abnormal QRS com- ventricles, as in the example in Figure 13.17E, it is third-de- plex. This normal wave of atrial excitation does not result gree (complete) atrioventricular block. in ventricular excitation. Ventricular excitation does not occur because, when the impulse arrives, a portion of the The ECG Provides Three Types of Information AV node is still refractory following excitation by the pre- About the Ventricular Myocardium mature complex. As a consequence, the next “scheduled” ventricular beat is missed. A prolonged interval following a The ECG provides information about the pattern of excita- premature ventricular beat is the compensatory pause. tion of the ventricles, changes in the mass of electrically ac- Premature beats can also arise in the atria. In this case, tive ventricular myocardium, and abnormal dipoles result- the P wave is abnormal but the QRS complex is normal. ing from injury to the ventricular myocardium. It provides Premature beats are often called extrasystoles, frequently a no direct information about the mechanical effectiveness of misnomer because there is no “extra” beat. However, in the heart; other tests are used to study the efficiency of the some cases, the premature beat is interpolated between two heart as a pump (see Chapter 14). normal beats, and the premature beat is indeed “extra.” In Figure 13.17E, both P waves and QRS complexes are The Pattern of Ventricular Excitation. Disease or injury present, but their timing is independent of each other. This can affect the pattern of ventricular depolarization and pro- is complete atrioventricular block in which the AV node duce an abnormality in the QRS complex. Figure 13.18 fails to conduct impulses from the atria to the ventricles. shows a normal QRS complex (Fig. 13.18A) and two exam- Because the AV node is the only electrical connection be- ples of complexes that have been altered by impaired con- tween these areas, the pacemaker activities of the two be- duction. In Figure 13.18B, the AV bundle branch to the come entirely independent. In this example, the distance right side of the heart is not conducting (i.e., there is right between P waves is about 0.8 sec, giving an atrial rate of 75 bundle-branch block), and depolarization of right-sided beats/min. The distance between R waves averages 1.2 sec, myocardium, therefore, depends on delayed electrical ac- giving a ventricular rate of 50 beats/min. The atrial pace- tivity coming from the normally depolarized left side of the maker is probably in the SA node, and the ventricular pace- heart. The resulting QRS complex has an abnormal shape maker is probably in a lower portion of the AV node or because of aberrant electrical conduction and is prolonged bundle of His. because of the increased time necessary to fully depolarize AV block is not always complete. Sometimes the PR in- the heart. In Figure 13.18C, the AV bundle branch to the terval is lengthened, but all atrial excitations are eventually left side of the heart is not conducting (i.e., there is left conducted to the ventricles. This is first-degree atrioven- bundle-branch block), also resulting in a wide, deformed tricular block. When some, but not all, of the atrial excita- QRS complex. ECGs (leads V 2 and V 6 ) of patients with QRS complex. B, patient with right bundle-branch block. C, pa- FIGURE 13.18 various conditions. A, patient with normal tient with left bundle-branch block.
234 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY Effects of A, Large P waves (lead III) caused FIGURE 13.20 by atrial hypertrophy. B, Altered QRS complex (leads V 1 and V 5) produced by left ventricular hypertrophy. tricular hypertrophy (see Fig. 13.20B). Left ventricular hy- Right ventricular hypertrophy. Leads I, aVF, FIGURE 13.19 pertrophy rotates the direction of the major dipole associ- and V 1 of a patient are shown. ated with ventricular depolarization to the left, causing large S waves in V 1 and large R waves in V 5. Abnormal Dipoles Resulting From Ventricular Myocar- Changes in the Mass of Electrically Active Ventricular My- dial Injury. Myocardial ischemia is present when a por- ocardium. The recording in Figure 13.19 shows the ef- tion of the ventricular myocardium fails to receive sufficient fect of right ventricular enlargement on the ECG. The in- blood flow to meet its metabolic needs. In this case, the creased mass of right ventricular muscle changes the supply of ATP may decrease below the level required to direction of the major dipole during ventricular depolariza- maintain the active transport of ions across the cell mem- tion, resulting in large R waves in lead V 1 . The large S brane. The resulting alterations in the membrane potential waves in lead I and the large R waves in lead aVF are also in the ischemic region can affect the ECG. Normally, the characteristic of a shift in the dipole of ventricular depolar- ECG is at baseline (zero voltage) during ization to the right. This illustrates how a change in the • The interval between the completion of the T wave and mass of excited tissue can affect the amplitude and direc- the onset of the P wave (the TP interval), during which tion of the QRS complex. all cardiac cells are at their resting membrane potential Figure 13.20 shows the effects of atrial hypertrophy on • The ST segment, during which depolarization is com- the P waves of lead III (see Fig. 13.20A) and the altered plete and all ventricular cells are at the plateau (phase 2) QRS complexes in leads V 1 and V 5 associated with left ven- of the action potential Electrocardiogram changes in myocardial tential plateau), all areas are depolarized and true zero is recorded. FIGURE 13.21 injury. A, Dark shading depicts depolarized Because zero baseline is set arbitrarily (on the ECG recorder), a ventricular tissue. ST segment elevation can occur with myocar- depressed diastolic baseline (TP segment) and an elevated ST seg- dial injury. The apparent zero baseline of the ECG before depo- ment cannot be distinguished. Regardless of the mechanism, this larization is below zero because of partial depolarization of the is referred to as an elevated ST segment. B, The ECG (lead V 1) of injured area (shading). After depolarization (during the action po- a patient with acute myocardial infarction.
CHAPTER 13 The Electrical Activity of the Heart 235 With myocardial ischemia, the cells in the ischemic re- ST interval because depolarization is uniform and complete gion partially depolarize to a lower resting membrane po- in both injured and normal tissue (this is the plateau period tential because of a lowering of the potassium ion concen- of ventricular action potentials). Because the ECG is de- tration gradient, although they are still capable of action signed so that the TP interval is recorded as zero voltage, potentials. As a consequence, a dipole is present during the the true zero during the ST interval is recorded as a positive TP interval in injured hearts because of the voltage differ- or negative deflection (Fig. 13.21). These deflections dur- ence between normal (polarized) and abnormal (partially ing the ST interval are of major clinical utility in the diag- polarized) tissue. However, no dipole is present during the nosis of cardiac injury. REVIEW QUESTIONS DIRECTIONS: Each of the numbered (E) Pacemaker channels (C) Proceeds from the subendocardium items or incomplete statements in this 5. Atrial repolarization normally occurs to subepicardium section is followed by answers or by during the (D) Is initiated during the plateau completions of the statement. Select the (A) P wave (phase 2) of the ventricular action ONE lettered answer or completion that is (B) QRS complex potential BEST in each case. (C) ST segment (E) Results from pacemaker potentials (D) T wave of ventricular cells 1. Rapid depolarization (phase 0) of the (E) Isoelectric period 10.AV nodal cells action potential of ventricular muscle 6. The P wave is normally positive in lead (A) Exhibit action potentials results from opening of I of the ECG because characterized by rapid depolarization (A) Voltage-gated Ca 2 channels (A) Depolarization of the ventricles (phase 0) (B) Voltage-gated Na channels proceeds from subendocardium to (B) Exhibit increased conduction (C) Acetylcholine-activated K subepicardium velocity when exposed to channels (B) When the ECG electrode attached acetylcholine (D) Inward rectifying K channels to the right arm is positive relative to (C) Conduct impulses more slowly (E) ATP-sensitive K channels the electrode attached to the left arm, than either atrial or ventricular cells 2. A 72-year-old man with an atrial rate an upward deflection is recorded (D) Are capable of pacemaker activity of 80 beats/min develops third-degree (C) AV nodal conduction is slower at an intrinsic rate of 100 beats/min (complete) AV block. A pacemaker site than atrial conduction (E) Exhibit slowed conduction velocity located in the AV node below the (D) Depolarization of the atria when exposed to norepinephrine region of the block triggers ventricular proceeds from right to left 11.Stimulation of the parasympathetic activity, but at a rate of only 40 (E) When cardiac cells are depolarized, nerves to the normal heart can lead beats/min. What would be observed? the inside of the cells is negative to complete inhibition of the SA (A) One P wave for each QRS relative to the outside of the cells node for several seconds. During that complex 7. Stimulation of the sympathetic nerves period (B) An inverted T wave to the normal heart (A) P waves would become larger (C) A shortened PR interval (A) Increases duration of the TP (B) There would be fewer T waves (D) A normal QRS complex interval than QRS complexes 3. To ensure an adequate heart rate, a (B) Increases the duration of the PR (C) There would be fewer P waves temporary electronic pacemaker lead is interval than T waves attached to the apex of the right (C) Decreases the duration of the QT (D) There would be fewer QRS ventricle, and the heart is paced by interval complexes than P waves electrically stimulating this site at a (D) Leads to fewer P waves than QRS (E) The shape of QRS complexes rate of 70 beats/min. When the ECG complexes would change during pacing is compared with the (E) Decreases the frequency of QRS 12.The R wave in lead I of the ECG ECG before pacing, there would be a complexes (A) Is larger than normal with right (A) Shortened PR interval 8. A drug that raises the heart rate from ventricular hypertrophy (B) QRS complex similar to that seen 70 to 100 beats per minute could (B) Reflects a net dipole associated with left bundle-branch block (A) Be an adrenergic receptor with ventricular depolarization (C) QRS complex of shortened antagonist (C) Reflects a net dipole associated duration (B) Cause the opening of with ventricular repolarization (D) P wave following each QRS acetylcholine-activated K channels (D) Is largest when the mean electrical complex (C) Be a cholinergic receptor agonist axis is directed perpendicular to a line (E) QRS complex similar to that seen (D) Be an adrenergic receptor agonist drawn between the two shoulders with right bundle-branch block (E) Cause the closing of voltage-gated (E) Is associated with atrial 4. What is most responsible for phase 0 Ca 2 channels depolarization of a cardiac nodal cell? 9. Excitation of the ventricles 13.The ST segment of the normal ECG (A) Voltage-gated Na channels (A) Always leads to excitation of the (A) Occurs during a period when both (B) Acetylcholine-activated K atria ventricles are completely repolarized channels (B) Results from the action of (B) Occurs when the major dipole is (C) Inward rectifying K channels norepinephrine on ventricular directed from subendocardium to (D) Voltage-gated Ca 2 channels myocytes subepicardium (continued)
236 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY (C) Occurs during a period when both ment. Baltimore: Williams & Wilkins, ease. 2nd Ed. Baltimore: Williams & ventricles are completely depolarized 1995. Wilkins, 1998. (D) Is absent in lead I of the ECG Katz AM. Physiology of the Heart. 3rd Mirvis DM, Goldberger AL. Electrocardio- (E) Occurs during depolarization of Ed. Philadelphia: Lippincott Williams & graphy. In: Braunwald E, Zipes DP, the Purkinje system Wilkins, 2001. Libby P, eds. Heart Disease. 6th Ed. Lauer MR, Sung RJ. Physiology of the Philadelphia: WB Saunders, 2001. SUGGESTED READING conduction system. In: Podrid PJ, Kow- Rubart M, Zipes DP. Genesis of cardiac ar- Fisch C. Electrocardiogram and mecha- ley PR, eds. Cardiac Arrhythmia Mech- rhythmias: Electrophysiological consid- nisms of arrhythmias. In: Podrid PJ, anisms, Diagnosis and Management. erations. In: Braunwald E, Zipes DP, Kowley PR, eds. Cardiac Arrhythmia: Baltimore: Williams & Wilkins, 1995. Libby P, eds. Heart Disease. 6th Ed. Mechanisms, Diagnosis and Manage- Lilly LS. Pathophysiology of Heart Dis- Philadelphia: WB Saunders, 2001.
The Cardiac Pump CHAPTER 14 14 Thom W. Rooke, M.D. Harvey V. Sparks, Jr., M.D. CHAPTER OUTLINE ■ THE CARDIAC CYCLE ■ THE MEASUREMENT OF CARDIAC OUTPUT ■ CARDIAC OUTPUT ■ THE ENERGETICS OF CARDIAC FUNCTION KEY CONCEPTS 1. Learning to correlate the ECG, pressures, volumes, flows, 6. Cardiac output can be measured by methods that rely on and heart sounds in time is fundamental to a working mass balance or cardiac imaging. knowledge of the heart. 7. Cardiac energy production depends primarily on the sup- 2. Cardiac output is the product of stroke volume times heart ply of oxygen to the heart. rate. 8. Cardiac energy consumption depends on the work of the 3. Stroke volume is determined by end-diastolic fiber length, heart. contractility, afterload, and hypertrophy. 9. The external work of the heart depends on the volume of 4. Heart rate influences ventricular filling time and stroke blood pumped and the pressure against which it is volume. pumped. 5. The influence of heart rate on cardiac output depends on simultaneous effects on ventricular contractility. he heart consists of a series of four separate chambers that the pressures are higher on the left side. The focus is T(two atria and two ventricles) that use one-way valves on the left side of the heart, beginning with electrical acti- to direct blood flow. Its ability to pump blood depends on vation of the atria. the integrity of the valves and the proper cyclic contraction and relaxation of the muscular walls of the four chambers. Atrial Systole and Diastole. The P wave of the electrocar- An understanding of the cardiac cycle is a prerequisite for diogram (ECG) reflects atrial depolarization, which initiates understanding the performance of the heart as a pump. atrial systole. Contraction of the atria “tops off” ventricular filling with a final, small volume of blood from the atria, pro- ducing the a wave. Under resting conditions, atrial systole is THE CARDIAC CYCLE not essential for ventricular filling and, in its absence, ven- tricular filling is only slightly reduced. However, when in- The cardiac cycle refers to the sequence of electrical and creased cardiac output is required, as during exercise, the ab- mechanical events occurring in the heart during a single sence of atrial systole can limit ventricular filling and stroke beat and the resulting changes in pressure, flow, and vol- volume. This happens in patients with atrial fibrillation, ume in the various cardiac chambers. The functional inter- whose atria do not contract synchronously. relationships of the cardiac cycle described below are rep- The P wave is followed by an electrically quiet period, dur- resented in Figure 14.1. ing which atrioventricular (AV) node transmission occurs (the PR segment). During this electrical pause, the mechani- cal events of atrial systole and ventricular filling are concluded Sequential Contractions of the Atria and Ventricles Pump Blood Through the Heart before excitation and contraction of the ventricles begin. Atrial diastole follows atrial systole and occurs during The cycle of events described here occurs almost simulta- ventricular systole. As the left atrium relaxes, blood en- neously in the right and left heart; the main difference is ters the atrium from the pulmonary veins. Simultane- 237
238 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY Ventricular Ventricular Ventricular Systole. The QRS complex reflects excita- systole diastole tion of ventricular muscle and the beginning of ventricular systole (see Fig. 14.1). As ventricular pressure rises above atrial pressure, the left atrioventricular (mitral) valve closes. Contraction of the papillary muscles prevents the the valve to prevent the regurgitation of blood into the Atrial systole Isovolumetric contraction Rapid ejection Reduced ejection Isovolumetric relaxation Rapid ventricular filling Reduced ventricular filling Atrial systole mitral valve from everting into the left atrium and enables atrium as ventricular pressure rises. The aortic valve does not open until left ventricular pressure exceeds aortic pres- sure. During the interval when both mitral and aortic valves 120 are closed, the ventricle contracts isovolumetrically (i.e., the ventricular volume does not change). The contraction Aortic 100 valve causes ventricular pressure to rise, and when ventricular opens pressure exceeds aortic pressure (at approximately 80 mm 80 * * Aortic Hg), the aortic valve opens and allows blood to flow from mm Hg 60 closes Aortic the ventricle into the aorta. At this point, ventricular mus- valve cle begins to shorten, reducing the volume of the ventricle. pressure When the rate of ejection begins to fall (see the aortic Mitral blood flow record in Fig. 14.1), the aortic and ventricular 40 valve Mitral pressures decline. Ventricular pressure actually decreases closes Left atrial 20 pressure v valve slightly below aortic pressure prior to closure of the aortic a c c * opens valve, but flow continues through the aortic valve because * 0 of the inertia imparted to the blood by ventricular contrac- tion. (Think of a rubber ball connected to a paddle by a 45 Left ventricular pressure rubber band. The ball continues to travel away from the paddle after you pull back because the inertial force on the L/min 30 ball exceeds the force generated by the rubber band.) 15 Aortic blood flow Ventricular Diastole. Ventricular repolarization (produc- (ventricular outflow) ing the T wave) initiates ventricular relaxation or ventricu- lar diastole. When the ventricular pressure drops below the 0 atrial pressure, the mitral valve opens, allowing the blood 120 accumulated in the atrium during systole to flow rapidly into the ventricle; this is the rapid phase of ventricular fill- ing. Both pressures continue to decrease—the atrial pres- Ventricular volume sure because of emptying into the ventricle and the ven- mL 85 tricular pressure because of continued ventricular relaxation (which, in turn, draws more blood from the atrium). About midway through ventricular diastole, filling slows as ven- tricular and atrial pressures converge. Finally, atrial systole Heart 50 sound tops off ventricular volume. S 4 S 1 S 2 S 3 S 4 Pressures, Flows, and Volumes in the Cardiac R P T Electrocardiogram Chambers, Aorta, and Great Veins Can Be Matched With the ECG and Heart Sounds Q S The pressures, flows, and volumes in the cardiac chambers, 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 aorta, and great veins can be studied in conjunction with Time (sec) the ECG and heart sounds to yield an understanding of the The timing of various events in the cardiac coordinated activity of the heart. Ventricular diastole and FIGURE 14.1 cycle. systole can be defined in terms of both electrical and me- chanical events. In electrical terms, ventricular systole is de- fined as the period between the QRS complex and the end of the T wave. In mechanical terms, it is the period between ously, blood enters the right atrium from the superior and the closure of the mitral valve and the subsequent closure of inferior vena cavae. The gradual rise in left atrial pressure the aortic valve. In either case, ventricular diastole com- during atrial diastole produces the v wave and reflects its prises the remainder of the cycle. filling. The small pressure oscillation early in atrial dias- The first (S 1 ) and second (S 2 ) heart sounds signal the be- tole, called the c wave, is caused by bulging of the mitral ginning and end of mechanical systole. The first heart sound valve and movements of the heart associated with ven- (usually described as a “lub”) occurs as the ventricle contracts tricular contraction. and ventricular pressure rises above atrial pressure, causing
CHAPTER 14 The Cardiac Pump 239 the atrioventricular valves to close. The relatively low- pitched sound associated with their closure is caused by vi- TABLE 14.1 Factors Influencing Cardiac Output brations of the valves and walls of the heart that occur as a re- sult of their elastic properties when the flow of blood I. Stroke volume through the valves is suddenly stopped. In contrast, the aor- A. Force of contraction tic and pulmonic valves close at the end of ventricular sys- 1. End-diastolic fiber length (Starling’s law, preload) tole, when the ventricles relax and pressures in the ventricles a. End-diastolic pressure fall below those in the arteries. The elastic properties of the b. Ventricular diastolic compliance aortic and pulmonic valves produce the second heart sound, 2. Contractility which is relatively high-pitched (typically described as a a. Sympathetic stimulation via norepinephrine acting on 1 receptors “dup”). Mechanical events other than vibrations of the valves b. Circulating epinephrine acting on 1 receptors (minor) and nearby structures contribute to these two sounds, espe- c. Intrinsic changes in contractility in response to changes cially S 1 ; these factors include movement of the great vessels in heart rate and afterload and turbulence of the rapidly moving blood. The second d. Drugs (positive inotropic drugs, e.g., digitalis; negative heart sound often has two components—the first corre- inotropic drugs, e.g., general anesthetics; toxins) sponds to aortic valve closure and the second to pulmonic e. Disease (coronary artery disease, myocarditis, cardiomy- valve closure. In normal individuals, splitting widens with in- opathy, etc.) spiration and narrows or disappears with expiration. 3. Hypertrophy A third heart sound (S 3 ) results from vibrations during B. Afterload 1. Ventricular radius the rapid phase of ventricular filling and is associated with 2. Ventricular systolic pressure ventricular filling that is too rapid. Although it may be II. Heart rate (and pattern of electrical excitation) heard in normal children and adolescents, its appearance in a patient older than age 35 usually signals the presence of a cardiac abnormality. A fourth heart sound (S 4 ) may be heard during atrial systole. It is caused by blood movement resulting from atrial contraction and, like S 3 , is more com- Stroke Volume Is a Determinant mon in patients with abnormal hearts. of Cardiac Output Stroke volume increases with increases in the force of con- traction of ventricular muscle and decreases with increases CARDIAC OUTPUT in the afterload. The force of contraction is affected by Cardiac output (CO) is defined as the volume of blood end-diastolic fiber length, contractility, and hypertrophy. ejected from the heart per unit time. The usual resting val- Afterload, the force against which the ventricle must con- ues for adults are 5 to 6 L/min, or approximately 8% of tract to eject blood, is affected by the ventricular radius and body weight per minute. Cardiac output divided by body ventricular systolic pressure. Because the pressure drop surface area is called the cardiac index. When it is neces- across the aortic valve is normally small, aortic pressure is sary to normalize the value to compare the cardiac output often used as a substitute for ventricular pressure in such among individuals of different sizes, either cardiac index or considerations. cardiac output divided by body weight can be used. Car- diac output is the product of heart rate (HR) and stroke Effect of End-Diastolic Fiber Length. The relationship volume (SV), the volume of blood ejected with each beat: between ventricular end-diastolic fiber length and stroke volume is known as Starling’s law of the heart. Within lim- CO SV HR (1) its, increases in the left ventricular end-diastolic fiber Stroke volume is the difference in the volume of blood in length augment the ventricular force of contraction, which the ventricle at the end of diastole—end-diastolic volume— increases the stroke volume. This reflects the relationship and the volume of blood in the ventricle at the end of sys- between the length of a muscle and the force of contraction tole—end-systolic volume. This is shown in Figure 14.1. (see Chapter 10). After reaching an optimal diastolic fiber If heart rate remains constant, cardiac output increases in length, stroke volume no longer increases with further proportion to stroke volume, and stroke volume increases stretching of the ventricle. in proportion to cardiac output. Table 14.1 outlines the fac- End-diastolic fiber length is determined by end-diastolic tors that influence cardiac output. volume, which is dependent on end-diastolic pressure. Ejection fraction (EF) is a commonly used measure of End-diastolic pressure is the force that expands the ventri- cardiac performance. It is the ratio of stroke volume to end- cle to a particular volume. In Chapter 10, preload was de- diastolic volume (EDV), expressed as a percentage: fined as the passive force that establishes the muscle fiber length before contraction. For the intact heart, preload can EF (SV/EDV) 100 (2) be defined as end-diastolic pressure. For a given ventricular Ejection fraction is normally more than 55%. It is de- compliance (change in volume caused by a given change in pendent on heart rate, preload, afterload, and contractility pressure), a higher end-diastolic pressure (preload) in- (all to be discussed below) and provides a nonspecific index creases both diastolic volume and fiber length. The end-di- of ventricular function. Still, it has proved to be valuable in astolic pressure depends on the degree of ventricular filling predicting the severity of heart disease in individual pa- during ventricular diastole, which is influenced largely by tients. atrial pressure.
240 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY In heart disease, ventricular compliance can decrease be- left ventricular pressure and left ventricular end-diastolic cause of impaired ventricular muscle relaxation or a build fiber length increase both the force of contraction and the up of connective tissue within the walls of the heart. In ei- stroke volume of the left ventricle. If the stroke volume rises ther case, the relationship between ventricular filling, end- too much, the left heart begins to pump more blood than diastolic pressure, and end-diastolic volume is altered. The the right heart and left atrial pressure drops; this decreases effect is a decrease in end-diastolic fiber length and a re- left ventricular filling and reduces stroke volume. The sulting decrease in stroke volume. process continues until left heart output is exactly equal to The curve expressing the relationship between ventricu- right heart output. lar filling and ventricular contractile performance is called The descending limb of the ventricular function curve, a Starling curve or a ventricular function curve (Fig. 14.2). analogous to the descending limb of the length-tension This curve can be plotted with end-diastolic volume, end- curve (see Chapter 10), is probably never reached in a liv- diastolic pressure, or atrial pressure as the abscissa, as prox- ing heart because the resistance to stretch increases as the ies for end-diastolic fiber length. end-diastolic volume reaches the limit for optimum stroke The ordinate on the plot of Starling’s law (Fig. 14.2) can volume. Further enlargement of the ventricle would require also be a variable other than stroke volume. For example, if end-diastolic pressures that do not occur. As a result of in- heart rate remains constant, cardiac output can be substituted creased resistance to stretch or decreased compliance, the for stroke volume. The effect of arterial pressure on stroke atrial pressures necessary to produce further filling of the volume can also be taken into account by plotting stroke ventricles are probably never reached. The limited compli- work on the ordinate. Stroke work is stroke volume times ance, therefore, prevents optimal sarcomere length from mean arterial pressure. An increase in arterial pressure (after- being exceeded. In heart failure, the ventricles can dilate load) decreases stroke volume by increasing the force that beyond the normal limit because they exhibit increased opposes the ejection of blood during systole. If stroke work compliance. Even under these conditions, optimal sarcom- is on the ordinate, any increase in the force of contraction ere length is not exceeded. Instead, the sarcomeres appear that results in either increased arterial pressure or stroke vol- to realign so that there are more of them in series, allowing ume shifts the stroke work curve upward and to the left. If the ventricle to dilate without stretching sarcomeres be- stroke volume alone were the dependent variable, a change yond their optimal length. in the performance of the heart causing increased pressure would not be expressed by a change in the curve. Effect of Changes in Contractility. Factors other than end- Starling’s law explains the remarkable balancing of the diastolic fiber length can influence the force of ventricular output between the two ventricles. If the right heart were contraction. Different conditions produce different relation- to pump 1% more blood than the left heart each minute ships between stroke volume (or work) to end-diastolic fiber without a compensatory mechanism, the entire blood vol- length. For example, increased sympathetic nerve activity ume of the body would be displaced into the pulmonary causes release of norepinephrine (see Chapter 3). Norepi- circulation in less than 2 hours. A similar error in the oppo- nephrine increases the force of contraction for a given end- site direction would likewise displace all the blood volume diastolic fiber length (Fig. 14.3). The increase in force of into the systemic circuit. Fortunately, Starling’s law pre- contraction causes more blood to be ejected against a given vents such an occurrence. If the right ventricle pumps aortic pressure and, thus, raises stroke volume. A change in slightly more blood than the left ventricle, left atrial filling (and pressure) will increase. As left atrial pressure increases, Norepinephrine Normal Digitalis Cardiac output Stroke volume Stroke work Stroke work Stroke volume Failure End-diastolic fiber length End-diastolic volume End-diastolic pressure Atrial pressure End-diastolic fiber length End-diastolic ventricular pressure A Starling (ventricular function) curve. Stroke FIGURE 14.2 work increases with increased end-diastolic fiber Effect of norepinephrine and heart failure FIGURE 14.3 length. Several other combinations of variables can be used to plot a on the ventricular function curve. Norepi- Starling curve, depending on the assumptions made. For example, nephrine raises ventricular contractility (i.e., stroke volume and/or cardiac output can be substituted for stroke volume if heart rate is stroke work are elevated at a given end-diastolic fiber length). In constant, and stroke volume can be substituted for stroke work if ar- heart failure, contractility is decreased, so that stroke volume terial pressure is constant. End-diastolic fiber length and volume are and/or stroke work are decreased at a given end-diastolic fiber related by laws of geometry, and end-diastolic volume is related to length. Digitalis raises the intracellular calcium ion concentration end-diastolic pressure by ventricular compliance. and restores the contractility of the failing ventricle.
CHAPTER 14 The Cardiac Pump 241 the force of contraction at a constant end-diastolic fiber length reflects a change in the contractility of the heart. B (The cellular mechanisms governing contractility are dis- cussed in Chapter 10.) A shift in the ventricular function A curve to the left indicates increased contractility (i.e., more force and/or shortening occurring at the same initial fiber length), and shifts to the right indicate decreased contractil- ity. When an increase in contractility is accompanied by an Ventricular pressure increase in arterial pressure, the stroke volume may remain constant, and the increased contractility will not be evident by plotting the stroke volume against the end-diastolic fiber length. However, if stroke work is plotted, a leftward shift of the ventricular function curve is observed (see Fig. 14.3). A ventricular function curve with stroke volume on the ordi- nate can be used to indicate changes in contractility only Time when arterial pressure does not change. During heart failure, the ventricular function curve is shifted to the right, causing a particular end-diastolic fiber length to be associated with less force of contraction and/or shortening and a smaller stroke volume. As described in Ventricular volume Chapter 10, cardiac glycosides, such as digitalis, tend to B normalize contractility; that is, they shift the ventricular curve of the failing heart back to the left (see Fig. 14.3). A The collection of ventricular function curves reflecting Time changes in contractility in a particular heart is known as a family of ventricular function curves. Effect of Hypertrophy. In the normal heart, the force of contraction is also increased by myocardial hypertrophy. Velocity of shortening Regular, intense exercise results in increased synthesis of A contractile proteins and enlargement of cardiac myocytes. B The latter is the result of increased numbers of parallel my- ofilaments, increasing the number of actomyosin cross- bridges that can be formed. As each cell enlarges, the ven- tricular wall thickens and is capable of greater force Force (load) development. The ventricular lumen may also increase in size, and this is accompanied by an increase in stroke vol- FIGURE 14.4 Effect of aortic pressure on ventricular ume. The hearts of appropriately trained athletes are capa- function. Ventricular pressure, ventricular ble of producing much greater stroke volumes and cardiac volume, and the force-velocity relationship are shown for (A) normal and (B) elevated aortic pressure. Increased afterload outputs than those of sedentary individuals. These changes slows the velocity of shortening, decreasing ventricular empty- are reversed if the athlete stops training. Myocardial hy- ing, and stroke volume. pertrophy also occurs in heart disease. In heart disease, al- though myocardial hypertrophy initially has positive ef- fects, it ultimately has negative effects on myocardial force development. A thorough discussion of pathological hy- Fortunately, the heart can compensate for the de- pertrophy is beyond the scope of this book. crease in left ventricular stroke volume produced by in- creased afterload. Although a sudden rise in systemic ar- Effect of Afterload. The second determinant of stroke terial pressure causes the left ventricle to eject less blood volume is afterload (see Table 14.1), the force against per beat, the output from the right heart remains con- which the ventricular muscle fibers must shorten. In normal stant. Left ventricular filling subsequently exceeds its circumstances, afterload can be equated to the aortic pres- output. As the end-diastolic volume and fiber length of sure during systole. If arterial pressure is suddenly in- the left ventricle increase, the ventricular force of con- creased, a ventricular contraction (at a given level of con- traction is enhanced. A new steady state is quickly tractility and end-diastolic fiber length) produces a lower reached in which the end-diastolic fiber length is in- stroke volume. This decrease can be predicted from the creased and the previous stroke volume is maintained. force-velocity relationship of cardiac muscle (see Chapter Within limits, an additional compensation also occurs. 10). The shortening velocity of ventricular muscle de- During the next 30 seconds, the end-diastolic fiber creases with increasing load, which means that for a given length returns toward the control level, and the stroke duration of contraction (reflecting the duration of the ac- volume is maintained despite the increase in aortic pres- tion potential), the lower velocity results in less shortening sure. If arterial pressure times stroke volume (stroke and a decrease in stroke volume (Fig. 14.4). work) is plotted against end-diastolic fiber length, it is
242 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY apparent that stroke work has increased for a given end- diastolic fiber length. This leftward shift of the ventricu- lar function curve indicates an increase in contractility. Effect of the Ventricular Radius. The ventricular radius influences stroke volume because of the relationship be- tween ventricular pressures (P v ) and ventricular wall ten- sion (T). For a hollow structure, such as a ventricle, Laplace’s law states that P v T (1/r 1 1/r 2 )(3) where r 1 and r 2 are the radii of curvature for the ventricular Effect of the radius of a cylinder on ten- wall. Figure 14.5 shows this relationship for a simpler struc- FIGURE 14.6 sion. The pressure inside an inflated balloon is ture, in which curvature occurs in only one dimension (i.e., the same everywhere. With the same inside pressure, the tension a cylinder). In this case, r 2 approaches infinity. Therefore: in the wall is proportional to the radius. The tension is lower in the portion of the balloon with the smaller radius. (4) P v T (1/r 1 ) or T P v r 1 The internal pressure expands the cylinder until it is ex- actly balanced by the wall tension. The larger the radius, ume. In this situation, compensatory events increase central the larger the tension needed to balance a particular pres- blood volume and end-diastolic pressure (see Chapter 18). A sure. For example, in a long balloon that has an inflated part higher end-diastolic pressure stretches the stiffer ventricle with a large radius and an uninflated parted with a much and helps restore the stroke volume to normal. The physio- smaller radius, the pressure inside the balloon is the same logical price for this compensation is higher left atrial and everywhere, yet the tension in the wall is much higher in pulmonary pressures. Several pathological consequences, in- the inflated part because the radius is much greater cluding pulmonary congestion and edema, can result. (Fig. 14.6). This general principle also applies to noncylin- drical objects, such as the heart and tapering blood vessels. When the ventricular chamber enlarges, the wall tension Pressure-Volume Loops Provide Information required to balance a given intraventricular pressure in- Regarding Ventricular Performance creases. As a result, the force resisting ventricular wall Figure 14.7A shows a plot of left ventricular pressure as a shortening (afterload) likewise increases with ventricular function of left ventricular volume. One cardiac cycle is size. Despite the effect of increased radius on afterload, an represented by one counterclockwise circuit of the loop. At increase in ventricular size (within physiological limits) point 1, the mitral valve opens and the volume of the ven- raises both wall tension and stroke volume. This occurs be- tricle begins to increase. As it does, diastolic ventricular cause the positive effects of adjustment in sarcomere length pressure rises a little, depending on given ventricular dias- overcompensate for the negative effects of increasing ven- tolic compliance. (Remember that compliance is V/P.) tricular radius. However, if a ventricle becomes pathologi- The less the pressure rises with the filling of the ventricle, cally dilated, the myocardial fibers may be unable to gen- the greater the compliance. The volume increase between erate enough tension to raise pressure to the normal point 1 and point 2 occurs during rapid and reduced ven- systolic level, and the stroke volume may fall. tricular filling and atrial systole (see Fig. 14.1). At point 2, the ventricle begins to contract and pressure rises rapidly. Effect of Diastolic Compliance. Several diseases—includ- Because the mitral valve closes at this point and the aortic ing hypertension, myocardial ischemia, and cardiomyopa- valve has not yet opened, the volume of the ventricle can- thy—cause the left ventricle to be less compliant during di- not change (isovolumetric contraction). At point 3, the aor- astole. In the presence of decreased diastolic compliance, a tic valve opens. As blood is ejected from the ventricle, ven- normal end-diastolic pressure stretches the ventricle less. Re- tricular volume falls. At first, ventricular pressure continues duced stretch of the ventricle results in lowered stroke vol- to rise because the ventricle continues to contract and build up pressure—this is the period of rapid ejection in Figure 14.1. Later, pressure begins to fall—this is the period of re- duced ejection in Figure 14.1. The reduction in ventricular volume between points 3 and 4 is the difference between end-diastolic volume (3) and end-systolic volume (4) and equals stroke volume. At point 4, ventricular pressure drops enough below aor- tic pressure to cause the aortic valve to close. The ventricle continues to relax after closure of the aortic valve, and this is reflected by the drop in ventricular pressure. Because the Pressure and tension in a cylindrical blood mitral valve has not yet opened, ventricular volume cannot FIGURE 14.5 vessel. The tension tends to open an imaginary change (isovolumetric relaxation). The loop returns to slit along the length of the blood vessel. The Laplace law relates point 1 when the mitral valve opens and, once more, the pressure (P), radius, and tension (T), as described in the text. ventricle begins to fill.
CHAPTER 14 The Cardiac Pump 243 A B 150 150 Pressure (mm Hg) 100 4 3 Pressure (mm Hg) 100 4 3 50 50 2 2 1 1 50 100 150 50 100 150 Volume (mL) Volume (mL) C 150 D 150 4 3 4 Pressure (mm Hg) 100 Pressure (mm Hg) 100 3 50 50 1 2 2 1 50 100 150 50 100 150 Volume (mL) Volume (mL) Pressure-volume loops for the left ventri- addition of a loop with increased preload. C, The addition of a FIGURE 14.7 cle. 1: Mitral valve opens. 2. Mitral valve loop with increased afterload. D, The addition of a loop with in- closes. 3. Aortic valve opens. 4: Aortic valve closes. A, The loop creased contractility. with normal values for ventricular volumes and pressures. B, The Increased Preload. Figure 14.7B shows a pressure-volume Because the ventricle did not empty as much during systole loop from the same heart in the presence of increased pre- and the atrium delivers as much blood during diastole, end- load. After opening of the mitral valve at point 1 in Figure diastolic volume and pressure (preload) are increased. 14.7B, diastolic pressure and volume increase to a higher value than in Figure14.7A. When isovolumetric contraction Increased Contractility. Figure 14.7D shows the effect of begins at point 2, end-diastolic volume is higher. Because af- increased contractility on the pressure-volume loop. In this terload is unchanged, the aortic valve opens at the same pres- idealized situation, there is no change in end-diastolic vol- sure (point 3). In the idealized graph in Figure 14.7B, the ume, and mitral valve closure occurs at the same pressure and greater force of contraction associated with higher preload volume (point 2). Afterload is also the same; therefore, the causes the ventricle to eject all of the extra volume that en- aortic valve opens at the same arterial pressure (point 3). The tered during diastole. This means that, when the aortic valve increased force of contraction causes the ventricle to eject closes at point 4, the volume and pressure of the ventricle are more blood and the aortic valve closes at a lower end-systolic identical to the values in Figure 14.7A. The difference in vol- volume (point 4). This means that the mitral valve opens at a ume between points 3 and 4 is larger, representing the larger lower end-diastolic volume (point 1). Because diastolic com- stroke volume associated with increased preload. pliance is unchanged, filling proceeds along the same pres- sure-volume curve from point 1 to point 2. Increased Afterload. Figure 14.7C shows the effect of in- When there are changes in diastolic compliance, the creased afterload on the pressure-volume loop. In this situ- pressure-volume curve between (1) and (2) is changed. This ation, the aortic valve opens (point 3) at a higher pressure and other changes, such as heart failure, are beyond the because aortic pressure is increased, as compared with Fig- scope of this text. ure 14.7A. The higher aortic pressure decreases stroke vol- ume, and the aortic valve closes (point 4) at a higher pres- Heart Rate Interacts With Stroke Volume sure and volume. Mitral valve opening and ventricular filling (point 1) begin at a higher pressure and volume be- to Influence Cardiac Output cause more blood is left in the ventricle at the end of sys- Heart rate can vary from less than 50 beats/min in a resting, tole. Filling of the ventricle proceeds along the same dias- physically fit individual to greater than 200 beats/min dur- tolic pressure-volume curve from point 1 to point 2. ing maximal exercise. If stroke volume is held constant, in-
244 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY creases in heart rate cause proportional increases in cardiac inephrine by sympathetic nerves not only increases the output. However, heart rate affects stroke volume; changes heart rate (see Chapter 13) but also dramatically increases in heart rate do not necessarily cause proportional changes the force of contraction (see Fig. 14.3). Furthermore, nor- in cardiac output. In considering the influence of heart rate epinephrine increases conduction velocity in the heart, re- on cardiac output, it is important to recognize that as the sulting in a more efficient and rapid ejection of blood from heart rate increases and the duration of the cardiac cycle the ventricles. These effects, summarized in Figure 14.8, decreases, the duration of diastole decreases. As the dura- maintain the stroke volume as the heart rate increases. tion of diastole decreases, the time for filling of the ventri- When the heart rate increases physiologically as a result of cles is diminished. Less filling of the ventricles leads to a re- an increase in sympathetic nervous system activity (as dur- duced end-diastolic volume and decreased stroke volume. ing exercise), cardiac output increases proportionately over a broad range. Effect of Decreased Heart Rate on Cardiac Output. A consequence of the reciprocal relationship between heart Influences on Stroke Volume and rate and the duration of diastole is that, within limits, de- Heart Rate Regulate Cardiac Output creasing the rate of a normal resting heart does not decrease cardiac output. The lack of a decrease in cardiac output is In summary, cardiac output is regulated by changing because stroke volume increases as heart rate decreases. stroke volume and heart rate. Stroke volume is influenced Stroke volume increases because as the heart rate falls, the by the contractile force of the ventricular myocardium duration of ventricular diastole increases, and the longer and by the force opposing ejection (the aortic pressure or duration of diastole results in greater ventricular filling. The afterload). Myocardial contractile force depends on ven- resulting elevated end-diastolic fiber length increases tricular end-diastolic fiber length (Starling’s law) and my- stroke volume, which compensates for the decreased heart ocardial contractility. Contractility is influenced by four rate. This balance works until the heart rate is below 20 major factors: beats/min. At this point, additional increases in end-dias- 1) Norepinephrine released from cardiac sympa- tolic fiber length cannot augment stroke volume further be- thetic nerves and, to a much lesser extent, circulating cause the maximum of the ventricular function curve has norepinephrine and epinephrine released from the adre- been reached. At heart rates below 20 beats/min, cardiac nal medulla output falls in proportion to decreases in heart rate. 2) Certain hormones and drugs, including glucagon, isoproterenol, and digitalis (which increase contractility) Effect of Increased Heart Rate as a Result of Electronic and anesthetics (which decrease contractility) Pacing. If an electronic pacemaker is attached to the right atrium and the heart rate is increased by electrical stimula- tion, surprisingly little increase in cardiac output results. Sympathetic neural activity This is because as the heart rate increases, the interval be- tween beats shortens and the duration of diastole decreases. The decrease in diastole leaves less time for ventricular fill- β 1 β 1 β 1 β 1 ing, producing a shortened end-diastolic fiber length, which Speed of Rate of rise subsequently reduces both the force of contraction and the Force of Conduction contraction and of pacemaker stroke volume. The increased heart rate is, therefore, offset contraction velocity relaxation potential by the decrease in stroke volume. When the rate increases above 180 beats/min secondary to an abnormal pacemaker, stroke volume begins to fall as a result of poor diastolic fill- Duration of systole Heart ing. A person with abnormal tachycardia (e.g., caused by an (small effect) rate ectopic ventricular pacemaker) may have a reduction in car- diac output despite an increased heart rate. Duration of diastole Increase Events in the myocardium compensate to some degree Decrease for the decreased time available for filling. First, increases in Stroke volume heart rate reduce the duration of the action potential and, Decrease Treppe thus, the duration of systole, so the time available for dias- Increase (small effect) tolic filling decreases less than it would otherwise. Second, faster heart rates are accompanied by an increase in the Cardiac force of contraction, which tends to maintain stroke vol- output ume. The increased contractility is sometimes called treppe or the staircase phenomenon. These internal adjustments are not very effective and, by themselves, would be insuffi- FIGURE 14.8 Effects of increased sympathetic neural ac- cient to permit increases in heart rate to raise cardiac output. tivity on heart rate, stroke volume, and car- diac output. Various effects of norepinephrine on the heart com- pensate for the decreased duration of diastole and hold stroke Effects of Increased Heart Rate as a Result of Changes in volume relatively constant, so that cardiac output increases with Autonomic Nerve Activity. Increased heart rate usually increasing heart rate. The words “Increase” and “Decrease” in occurs because of decreased parasympathetic and in- small type denote quantitatively less important effects than the creased sympathetic neural activity. The release of norep- same words in large type.
CHAPTER 14 The Cardiac Pump 245 3) Disease states, such as coronary artery disease, my- ocarditis (see Chapter 10), bacterial toxemia, and alter- ations in plasma electrolytes and acid-base balance 4) Intrinsic changes in contractility with changes in heart rate and/or afterload Heart rate is influenced primarily by sympathetic and parasympathetic nerves to the heart and, by a lesser extent, by circulating norepinephrine and epinephrine. The effect of heart rate on cardiac output depends on the extent of A concomitant changes ventricular filling and contractility. Heart failure is a major problem in clinical medicine (see C Clinical Focus Box 14.1). A V = C THE MEASUREMENT OF CARDIAC OUTPUT mg The ability to measure output accurately is essential for per- mL = mg/mL forming physiological studies involving the heart and man- aging clinical problems in patients with heart disease or FIGURE 14.9 The measurement of volume using the indi- cator dilution method. The indicator is a dye. heart failure. Cardiac output is measured either by one of The volume (V) of liquid in the beaker equals the amount (A) of several applications of the Fick principle or by observing dye divided by the concentration (C) of the dye after it has dis- changes in the volume of the heart during the cardiac cycle. persed uniformly in the liquid. Cardiac Output Can Be Measured Using Variations of the Principle of Mass Balance A C V(5) The use of mass balance to measure cardiac output is best Because A is known and C can be measured, V can be understood by considering the measurement of an un- calculated: known volume of liquid in a beaker (Fig. 14.9). The vol- ume can be determined by dispersing a known quantity of V A/C (6) dye throughout the liquid and then measuring the con- When the principle of mass balance is applied to cardiac centration of dye in a sample of liquid. Because mass is output, the goal is to measure the volume of blood flowing conserved, the quantity of dye (A) in the liquid is equal to through the heart per unit of time. A known amount of dye the concentration of dye in the liquid (C) times the vol- or other indicator is injected and concentration of the dye ume of liquid (V): or indicator is measured over time. CLINICAL FOCUS BOX 14.1 Congestive Heart Failure loid or hemochromatosis), inflammatory conditions (e.g., Heart failure occurs when the heart is unable to pump myocarditis), and various types of cardiomyopathies (a di- blood at a rate sufficient to meet the body’s metabolic verse assortment of conditions in which the heart becomes needs. One possible consequence of heart failure is that pathologically dilated, hypertrophied, or stiff). blood may “back up” on the atrial/venous side of the fail- The treatment of heart failure hinges on treating the un- ing ventricle, leading to the engorgement and distention of derlying problem, when possible, and the judicious use of veins (and the organs they drain) as the venous pressure medical therapy. Medical treatment may include diuretics rises. The signs and symptoms typically associated with to reduce the venous fluid overload, cardiac glycosides this occurrence constitute congestive heart failure (e.g., digitalis) to improve myocardial contractility, and af- (CHF). This syndrome can be limited to the left ventricle terload reducing agents (e.g., arterial vasodilators) to (producing pulmonary venous distention, pulmonary reduce the load against which the ventricle must contract. edema, and symptoms such as dyspnea or cough) or the Angiotensin converting enzyme inhibitors, aldos- right ventricle (producing symptoms such as pedal edema, terone antagonists, and beta blockers have all been abdominal edema or ascites, and hepatic venous conges- shown to be effective in the treatment of CHF. tion), or it may affect both ventricles. Left heart failure Heart transplantation is becoming an increasingly vi- (which increases pulmonary venous pressure) can eventu- able option for severe, intractable, unresponsive CHF. Al- ally cause pulmonary artery pressure to rise and right though tens of thousands of patients worldwide have re- heart failure to occur. Indeed, left heart failure is the most ceived new hearts for end-stage heart failure, the supply of common reason for right heart failure. donor hearts falls far below demand. For this reason, car- The causes of CHF are numerous and include acquired diac-assist devices, artificial hearts, and genetically modi- and congenital conditions, such as valvular disease, my- fied animal hearts are undergoing intensive development ocardial infarction, assorted infiltrative processes (e.g., amy- and evaluation.
246 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY The Indicator Dilution Method. In the indicator dilution minute (rather than volume, as in equation 6). In the nu- method, a known amount of indicator (A) is injected into the merator on the right is amount of indicator and in the de- circulation, and the blood downstream is serially sampled af- nominator is the mean concentration over time (rather than ter the indicator has had a chance to mix (Fig. 14.10). The concentration, as in equation 6). Concentration, volume, indicator is usually injected on the venous side of the circu- and amount appear in both equations 6 and 7, but time is lation (often into the right ventricle or pulmonary artery but, present in the denominator on both sides in equation 7. occasionally, directly into the left ventricle), and sampling is performed from a distal artery. The resulting concentration The Thermodilution Method. In most clinical situations, of indicator in the distal arterial blood (C) changes with time. cardiac output is measured using a variation of the indica- First, the concentration rises as the portion of the indicator tor dilution method called thermodilution. A Swan-Ganz carried by the fastest-moving blood reaches the arterial sam- catheter (a soft, flow-directed catheter with a balloon at the pling point. Concentration rises to a peak as the majority of tip) is placed into a large vein and threaded through the indicator arrives and falls off as the indicator carried by the right atrium and ventricle so that its tip lies in the pul- slower moving blood arrives. Before the last of the indicator monary artery. The catheter is designed to allow a known arrives, the indicator carried by the blood flowing through amount of ice-cold saline solution to be injected into the the shortest pathways comes around again (recirculation). right side of the heart via a side port in the catheter. This To correct for this recirculation, the downslope of the curve solution decreases the temperature of the surrounding is assumed to be semilogarithmic and the arterial value is ex- blood. The magnitude of the decrease in temperature de- trapolated to zero indicator concentration. The average con- pends on the volume of blood that mixes with the solution, centration of indicator can be determined by measuring the which depends on cardiac output. A thermistor on the indicator concentration continuously from its first appear- catheter tip (located downstream in the pulmonary artery) ance (t 1 ) until its disappearance (t 2 ). The average concentra- measures the fall in blood temperature. The cardiac output – tion during that period (C) is determined and cardiac output can be determined using calculations similar to those de- is calculated as: scribed for the indicator dilution method. A CO – (t 2 – t 1 )(7) C The Fick Procedure. Another way the principle of mass Note the similarity between this equation and the one balance is used to calculate cardiac output takes advantage for calculating volume in a beaker. On the left is volume per of the continuous entry of oxygen into the blood via the Dye (A), mg Mixer Flow mL/min Withdrawal syringe Sample site Lamp A A Flow = = C (t -t ) t 2 2 1 Cdt Photocell t 1 Densitometer Dye concentration concentration Beginning of recirculation Average dye Extrapolation t 1 t 2 0 Time The indicator dilution method for deter- Note the analogy between this time-dependent measurement FIGURE 14.10 mining flow through a tube. The volume (volume/time) and the simple volume measurement in Figure per minute flowing in the tube equals the quantity of indicator 14.9. The downslope of the dye concentration curve shows the (in this example, a dye) injected divided by the average dye effects of recirculation of the dye (solid line) and the semiloga- – concentration (C) at the sample site, multiplied by the time be- rithmic extrapolation of the downslope (dashed line) used to tween the appearance (t 1 ) and disappearance (t 2 ) of the dye. correct for recirculation.
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