Cardiovascular System and Lymphatic Vessels
Structure
Development of the Heart and Great Vessels
The heart is a conical, muscular organ that in mammals has evolved into a four-chambered pump with four valves. During early fetal development, it is converted from an elongated muscular tube into a C-shaped structure by a process termed looping (Fig. 10-1). Subsequently, septation occurs to produce the right and left atrial and ventricular chambers and separation of the common truncus arteriosus into the aorta and pulmonary artery, respectively. The heart is interposed as a pump into the vascular system, with the right side supplying the pulmonary circulation and the left side the systemic circulation (Web Fig. 10-1; also see Chapter 2). The vascular system is subdivided into arterial, capillary, venous, and lymphatic segments. The arteries are classified into three types: elastic arteries, muscular arteries, and arterioles. The venous vessels are termed venules and veins. The lymphatic vasculature includes lymphatic capillaries and lymphatic vessels. Interposed between the arterial and venous segments are the capillary beds. A vascular segment termed the microcirculation (systemic capillary beds) includes arterioles, capillaries, and venules and is the major area of exchange between the circulating blood and the peripheral tissue (see Web Fig. 10-1; also see Chapter 2).
Fig. 10-1 Heart development, emphasizing the three sources of cells.A, Day 15. First heart field (FHF) cells (shown in red) form a crescent shape in the anterior embryo with second heart field (SHF) cells (shown in yellow) near the FHF. B, Day 21. SHF cells lie dorsal to the straight heart tube and begin to migrate (arrows) into the anterior and posterior ends of the tube to form the right ventricle (RV), conotruncus (CT), and part of the atria (A). C, Day 28. Following rightward looping of the heart tube, cardiac neural crest cells (shown in blue) also migrate (arrow) into the outflow tract from the neural folds to septate the outflow tract and pattern the bilaterally symmetric aortic arch arteries (III, IV, and VI). D, Day 50. Septation of the ventricles, atria, and atrioventricular valves (AVV) results in the appropriately configured four-chambered heart. Ao, Aorta; AS, aortic sac; DA, ductus arteriosus; LA, left atrium; LCA, left carotid artery; LSCA, left subclavian artery; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RCA, right carotid artery; RSCA, right subclavian artery; V, ventricle. (Modified from Srivastava D: Making or breaking the heart: from lineage determination to morphogenesis, Cell 126:1037, 2006. In Kumar V, Abbas A, Fausto N et al: Robbins & Cotran pathologic basis of disease, ed. 8, Philadelphia, 2009, Saunders.)
Web Fig. 10-1 Schematic diagram showing serially connected pulmonary and systemic circulatory systems and how to trace the flow of blood.A, Right heart chambers propel unoxygenated blood through the pulmonary circulation, and the left heart propels oxygenated blood through the systemic circulation. B, The direction of blood flow begins at the left ventricle of the heart, flows to the arteries, arterioles, capillaries of each body organ, venules, veins, right atrium, right ventricle, pulmonary artery, lung capillaries, pulmonary veins, left atrium, and then goes back to the left ventricle. RA, Right atrium; RV, right ventricle; LA, left atrium, LV, left ventricle. (From McCance, K: Pathophysiology: The biologic basis for disease in adults and children, ed 6, St Louis, 2009, Mosby.)
Macroscopic Structure
The heart lies within a fibroelastic sac called the pericardium, and the wall of the heart is composed of three layers: the epicardium, the myocardium, and the endocardium (Fig. 10-2). Structurally, the heart contains in order of blood flow four major blood vessels (vena cava, pulmonary artery, pulmonary vein, and aorta), four chambers (right atrium/auricle, right ventricle, left atrium/auricle, and left ventricle), and four valves (tricuspid, pulmonic semilunar, mitral, and aortic semilunar) (Fig. 10-3).
Fig. 10-2 Wall of the heart.This section of the heart wall shows the fibrous pericardium, the parietal and visceral layers of the serous pericardium (with the pericardial space between them), the myocardium, and the endocardium. Note the fatty connective tissue between the visceral layer of the serous pericardium (epicardium) and the myocardium. Note also that the endocardium covers beamlike projections of myocardial muscle tissue called trabeculae. (From Huether SE, McCance KL: Understanding pathophysiology, ed 4, St Louis, 2007, Mosby.)
Fig. 10-3 Normal heart, pig.A, Aorta; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle. (Courtesy School of Veterinary Medicine, Purdue University.)
Pericardium and Epicardium
The pericardium, which normally contains a small amount of clear, serous fluid (see Fig. 10-2), is composed of an outer fibrous component and an inner serous layer, which form the sac surrounding the heart. The outer component is continuous with the mediastinal pleura. The base of the fibrous pericardium surrounds and blends with the adventitia of the greater arteries and veins exiting and entering the heart. The serous pericardium forms a closed sac surrounding the heart.
Myocardium
The myocardium is the muscular layer of the heart. It consists of cardiac muscle cells (cardiac myocytes [also known as cardiac rhabdomyocytes]) arranged in overlapping spiral patterns. These sheets of cells are anchored to the fibrous skeleton of the heart, which surrounds the atrioventricular valves and the origins of the aorta and pulmonary artery. The myocardial thickness is related to the pressure present in each chamber; thus the atria are thin walled and the ventricles are thicker. In adult animals, the thickness of the left ventricular free wall is approximately threefold that of the right ventricle, measured in a transverse section across the middle of the ventricles, because the pressure is greater in the systemic circulation than in the pulmonary circuit.
The arterial supply to the heart is the left and right coronary arteries, which arise from the aorta at the sinus of Valsalva behind the left and right cusps of the aortic valves. The arteries course over the heart in the subepicardium and give off perforating intramyocardial arteries that supply a rich capillary bed throughout the myocardium. Extensive anastomoses occur between the capillaries that tend to run parallel to the elongated cardiac muscle cells. The ratio of the area of capillaries to that of muscle cells is approximately 1 : 1, a fact evident when the myocardium is viewed histologically in cross-section.
Cardiac Conduction System
The heart is a muscular four chamber pump that simultaneously supplies blood to the pulmonary and systemic circulatory beds (see Web Fig. 10-1 and Fig. 2-1). Mechanical pumping is composed of sequential contraction (systole) and relaxation (diastole) that must be preceded by an electrophysiologic process that triggers a coordinated chronologic sequence of electrical events that result in muscle contractions. This electrophysiologic process is made possible by a network of special conducting fibers that are collectively referred to as the cardiac conduction system.
The major pacemaker of the cardiac conduction system is the SAN. This disk-shaped structure lies between the wall of the cranial vena cava and the external wall of the right auricular appendage. Four internodal pathways connect the SAN with the AVN. The AVN is present in the wall of the right atrium dorsal to the septal cusp of the tricuspid valve. For the atria to be electrically insulated from the ventricles, so that an unwarranted ectopic conduction wave will not activate the ventricles (or vice versa) and disrupt the synchronous events of the cardiac cycle, a fibrous cardiac skeleton composed of a layer of dense collagen (central fibrous body [CFB]), as well as occasional plates of chondroid and osseous metaplasia, separates the atrial from the ventricular myocardium. This skeleton forms two fibrous rings around the AV orifices and the aortic and pulmonic orifices. Conduction fibers arising from the AVN, known as the bundle of His or AV bundle, pierce through the CFB into the ventricles and continue along the subendocardium of the interventricular septum. The AV bundle then splits into the right and left bundle branches that further split and ramify into many other smaller branches that blend into the ventricular myocardium. Purkinje fibers constitute the AV bundle and downstream conduction pathways.
Endocardium and Heart Valves
The endocardium is the innermost layer of the heart and lines the chambers and extends over projecting structures such as the valves, chordae tendineae, and papillary muscles. The endocardium of the atria is thicker than that of the ventricles and thus normally appears white to gray on gross examination. The surface of the endocardium is endothelium that lies on a thin layer of vascularized connective tissue; the subendocardial layer contains blood vessels, nerves, and connective tissue. Purkinje fibers are distributed in the subendocardium throughout both ventricles. The heart valves (tricuspid valve [right AV valve], mitral valve [left AV valve], aortic valve, and pulmonary valve) are attached to fibrous rings and have thin avascular cusps. The valves open and close to regulate blood flow through the heart. During embryogenesis, endocardial cushions (mesenchymal tissue covered by endothelium) are precursors of the valve cusps. By remodeling, growth, and elongation, the cushions become thin mature cusps composed of connective tissue with an endothelial covering.
Blood and Lymphatic Vascular Systems
Blood Vessels: The aorta originates from the left ventricle and provides oxygenated blood to the entire body via arteries. In a treelike manner, arteries branch and become smaller arterioles as they approach capillary beds (see Web Fig. 10-1; also see Chapter 2). These beds and postcapillary venules provide the site for exchange of oxygen, carbon dioxide, nutrients, and waste. Small venules return the exchanged fluid and blood to larger veins and eventually the postcava and precava drain into the right atrium. The poorly oxygenated blood enters the pulmonary artery from the right ventricle. Oxygen exchange occurs in the capillaries of the lung, and oxygenated blood is returned to the heart via the pulmonary veins into the left atrium.
Lymphatic Vessels: Lymphatic vessels are thin walled, endothelial-lined channels that originate near the capillary beds and serve as a drainage system for returning interstitial tissue fluid and inflammatory cells to the blood. Afferent lymphatic vessels drain lymph into regional lymph nodes, which then filter and provide immunologic surveillance of the lymph, its cells, and the foreign matter it contains. The filtered lymph continues into larger efferent lymphatic vessels, which eventually drain into the caval blood via the thoracic duct. Both lymphatic vessels and veins have valves to prevent backflow of fluid. A more complete description can be found in Chapter 2.
Microscopic Structure
The pericardial sac is composed of parietal and visceral pericardium, both of which are covered by mesothelium. Beneath the visceral mesothelium is a thin layer of fibrous connective tissue, adipocytes, and vascular structures. This organization forms the subepicardium and interdigitates with the myocardium. The parietal pericardium is composed of an inner layer of mesothelium that interdigitates with the dense connective tissue forming the outer pericardial sac.
Myocardium
The myocardium consists of cardiac muscle cells surrounded by interstitial components that include blood and lymphatic vessels, nerves, and connective tissue cells, such as fibroblasts, histiocytes, mast cells, pericytes, primitive mesenchymal stem cells, and extracellular matrix elements of connective tissue, including collagen fibrils, elastic fibers, and acid mucopolysaccharides. Cardiac muscle cells can be divided into two populations: the contracting myocytes and the specialized fibers of the conduction system. The contracting myocyte is a cross-striated branching fiber of an irregular cylindric shape that measures 60 to 100 µm in length and 10 to 20 µm in diameter, with centrally located, elongated nuclei. Myocytes in young animals are smaller and have small amounts of sarcoplasm. Atrial myocytes are smaller than ventricular myocytes. Adjacent myocytes are joined end-to-end by specialized junctions known as intercalated disks and less frequently by side-to-side connections termed lateral junctions. Multinucleated fibers with nuclei arranged in central rows are frequently seen in hearts of growing pigs (Fig. 10-4). The myocytes of old animals commonly have large polyploid nuclei. The cytoplasm (sarcoplasm) of myocytes is largely occupied by the contractile proteins that are highly organized into sarcomeres, the repeating contractile units of the myofibril (see Figs. 15-3 and 15-8). Myofibrils are formed by end-to-end attachment of many sarcomeres. The cross-striated or banded appearance of myocytes is the result of sarcomere organization into A bands composed of myosin in the form of “thick” filaments (12 to 16 nm in diameter), I bands composed of actin in the form of “thin” filaments (5 to 8 nm in diameter), and dense Z bands at the end of each sarcomere. Thick and thin filaments interdigitate and provide the basis for the sliding mechanism of muscle contraction. Myocytes are enclosed by the sarcolemma, which consists of the plasma membrane and the covering basal lamina (external lamina). Other important components of cardiac muscle cells are generally only apparent in electron micrographs and include abundant mitochondria, a highly organized network of intracellular tubules termed the sarcoplasmic reticulum, cylindric invaginations of the plasma membrane called T tubules, ribosomes, cytoskeletal filaments, glycogen particles, lipid droplets, Golgi complexes, atrial granules (contain atrial natriuretic factor), lysosomes, and residual bodies (Web Fig. 10-2).
Fig. 10-4 Normal cardiac muscle.Left ventricular myocardium, longitudinal section, normal young pig. The multiple nuclei in a myocyte are readily seen and evaluated in a longitudinal section. H&E stain. (Courtesy School of Veterinary Medicine, Purdue University.)
Web Fig. 10-2 Normal cardiac muscle.Heart, left ventricular myocytes, longitudinal section, normal rat. Numerous dense mitochondria (arrows) lie between myofibrils, which have prominent bands. N, Nucleus. TEM. Uranyl acetate and lead citrate stain. (Courtesy School of Veterinary Medicine, Purdue University.)
Cardiac Conduction System
The morphologic features of the cardiac muscle cells that form specialized conduction tissues, including the SAN, AVN, AV bundle (bundle of His), and bundle branches, vary greatly at different sites and among animal species but generally are thin, branching nodal muscle cells with scarce myofibrils separated by highly vascularized connective tissue (Fig. 10-5; Web Fig. 10-3). Autonomic nerve fibers are contained within the SAN. The Purkinje fibers (cardiac conduction fibers) are distinguished by their large diameters (in horse, ox) and abundant pale eosinophilic sarcoplasm rich in glycogen and poor in myofibrils.
Fig. 10-5 Cardiac conduction system.A, Sinoatrial (SA) node, foal. The center of the SA node (1) contains a nodal artery (2). H&E stain. A1, Higher magnification. Haphazardly oriented myofibers are embedded within abundant loose collagenous and elastic connective tissue. H&E stain. A2, Higher magnification. Nodal myofibers have discrete cell borders, a moderate amount of wavy sarcoplasm and an elongated nucleus. H&E stain. B, Atrioventricular (AV) node, goat. The AV node (1) is composed of interconnecting nodal myofibers that are supported by loose collagenous and elastic fibrous stroma. The node is embedded in adipose tissue (2). Note that in this illustration the AV node (1) is a poorly demarcated region (see B1 for greater detail) that is elongated (flattened) from top to bottom and that it and its surrounding adipose tissue are positioned adjacent to the cardiac fibrous skeleton (arrows) that has undergone focal chondroid metaplasia (3). The position and overall shape of the AV node in a histologic section is dependent upon the plane of section. Endocardium (arrowhead). H&E stain. B1, AV node, goat. In this higher magnification of B, AV nodal myofibers have a characteristic pale eosinophilic and thin sarcoplasm, with abundance of distinct striations and a short oval to elongated nucleus with dispersed chromatin. An autonomic myelinated nerve is present in the AV node (arrow). H&E stain. C, AV bundle, goat. The AV bundle (1) travels diagonally through the center of the figure from the lower left to the upper right margins. It is formed by an interweaving pseudosyncytium of cardiac myofibers supported by a loose to dense intervening collagenous stroma (see C1 for greater detail) and may be surrounded by adipose tissue (2). Cardiac cartilaginous skeleton (3). H&E stain. C1, Higher magnification. The AV bundle myofibers of the pseudosyncytium have moderate to large, pale eosinophilic sarcoplasm with prominent striations and large nuclei with fine stippled chromatin. H&E stain. (Courtesy Drs. A. Gal and J.F. Zachary, College of Veterinary Medicine, University of Illinois.)
Web Fig. 10-3 Heart, fibrous stroma of the cardiac conduction system, goat.A, Atrioventricular (AV) node. The AV node (1) is composed of interconnecting nodal myofibers that are supported by loose collagenous and elastic fibrous stroma. The node is embedded in adipose tissue (2) that is adjacent to the cardiac fibrous skeleton (arrows) that has undergone focal chondroid metaplasia (3). Endocardium (arrowhead). H&E stain. A1, AV node, goat. Serial section of A. Note the overall deposition of collagen fibers (blue) in the structures labeled 1 and 3 in Web Fig. 10-3, A. Masson’s trichrome stain. B, AV bundle. In this illustration, the AV bundle (1) travels diagonally through the center of the image from the lower left to the upper right margins. It is supported by a loose to dense intervening interstitial collagenous stroma and is surrounded by adipose tissue (2). Cardiac cartilaginous skeleton (3). H&E stain. B1, AV bundle, goat. Serial section of B. Note the overall deposition of collagen fibers (blue) in the structures labeled in Web Fig. 3, B. Masson’s trichrome stain. (Courtesy Drs. A. Gal and J.F. Zachary, College of Veterinary Medicine, University of Illinois.)
Sinoatrial Node: The SAN is positioned adjacent to the epicardial adipose tissue and is often centered around a branch of the right coronary artery (Fig. 10-5, A). Several large autonomic nervous system ganglions can occasionally be seen clustering in the epicardium adjacent to the node. The SAN lacks discrete structure, and its ill-defined borders merge with the adjacent atrial wall. It structurally consists of a collection of haphazardly oriented myofibers that appear as a pseudosyncytium and are embedded within abundant loose collagenous and elastic connective tissue, with rare cores of epicardially oriented dense collagen fibers (Fig. 10-5, A1). The nodal myofibers have discrete cell borders, a moderate amount of wavy sarcoplasm with sparse myofibrils, and an elongated nucleus that contains clumps of coarse chromatin (Fig. 10-5, A2).
Atrioventricular Node, Atrioventricular Bundle, and Bundle Branches: The AVN lies within the right atrial subendocardium and consists of a discrete, compact to loose mass of interconnecting myofibers that are often embedded within adipose tissue. A small nodal artery, parasympathetic ganglia, and large myelinated autonomic nerves are often present adjacent to the AVN. The nodal myofibers that have characteristic pale eosinophilic and thin sarcoplasm generally run parallel to each other but occasionally have an interweaving pattern with intervening loose collagen fibers. These myofibers contain a moderate amount of sarcoplasm with abundance of distinct striations and a short oval to elongated nucleus with dispersed chromatin.
The AV bundle (Fig. 10-5, B) emerges from the cranial pole of the AVN (Fig. 10-5, B1) and pierces through the CFB, approximately at the level of the annuli of the aortic and mitral valves (Fig. 10-5, B2), to become the left and right bundle branches. The size of an AV bundle myofiber progressively enlarges and its cytomorphology transitions from a pale eosinophilic, small and thin (AVN-like morphology) myofiber to a pale eosinophilic, foamy to waxy, large, and somewhat rectangular myofiber that lacks cross striations (a Purkinje-like cellular morphology) (Fig. 10-5, C).
Autonomic Nervous System: The nerve supply to the heart is autonomic and includes sympathetic, parasympathetic, and nonadrenergic noncholinergic innervation. Histologically, large nerves can be seen in the epicardium and adjacent to the coronary blood vessels, whereas special staining techniques are required for demonstration of neural tissue elsewhere. Electron microscopy and immunohistochemistry allow differentiation between sympathetic and parasympathetic nerves that are otherwise indistinguishable with H&E stain. Preganglionic parasympathetic fibers pass to the heart through the cardiac branch of the vagal nerve and synapse with parasympathetic ganglionic neurons. Postganglionic neurons are distributed to the SAN and AVN, as well as to atrial and, to a much lesser extent, ventricular myocardium (however, the ventricular conduction system is well supplied by cholinergic innervation). Postganglionic sympathetic fibers arising from the cervicothoracic and middle cervical ganglia intensely innervate the SAN and AVN and to lesser extent the AV bundle. The atrial endocardium, myocardium, and epicardium are evenly innervated, whereas the ventricles are considerably less innervated with epicardium more densely populated by neural tissue than the endocardium.
Endocardium and Heart Valves
The endocardium, lining the atrium and ventricles, consists of a continuous endothelium, subendothelium, and subendocardium. The subendothelial layer contains dense irregular fibroblasts intermixed with collagen and elastic fibers and occasional smooth muscle cells. Elastic fibers are abundant within the subendocardium of the atria. The subendocardial layer contains vascular structures, elastic and collagen bands, and fibroblasts and is continuous with the myocardium. Purkinje fibers are located in the subendocardium. The heart valves are poorly vascularized, endocardial folds covered by endothelium. The subendothelial layer is composed of fibroblasts with abundant elastic and collagen fibers. The AV valves (AVVs) consist of a layer of stratum spongiosum and stratum fibrosum. The stratum spongiosum consists of loosely arranged fibroblasts with moderate amounts of collagen and elastin fibers and vascular structures. The stratum fibrosis contains fibroblasts and collagen, which are continuous with the annulus fibrosis and chordae tendineae.
Blood and Lymphatic Vascular Systems
The overall design of the blood and lymphatic vessels is similar, except that luminal diameter, wall thickness, and the presence of other anatomic features, such as valves, vary between the different segments. The luminal surface of all vessels is lined by longitudinally aligned endothelial cells covering a basal lamina. Vessel walls are divided into three layers or tunics: intima, media, and adventitia. However, some of the layers can be absent or all of the layers can be thinned in some segments of the vascular system, depending on the intravascular pressures. The large elastic arteries, such as the aorta, have (1) an intima composed of endothelium and subendothelial connective tissue, (2) a very thick tunica media composed of fenestrated elastic laminae with interposed smooth muscle cells and ground substance and bordered internally by the internal elastic lamina and externally by the external elastic lamina, and (3) an outer tunica adventitia layer composed of collagen and elastic fibers and connective tissue cells with penetrating blood vessels, termed the vasa vasorum, supplying nutrients to the adventitia and the outer half of the media. In muscular arteries and arterioles, the tunica media is composed largely of smooth muscle cells arranged in a circumferential pattern. Arterioles are the smallest arterial channels and are generally less than 100 µm in diameter and with one to three layers of smooth muscle cells in the tunica media.
Capillaries are 5 to 10 µm in diameter, and their endothelium is one of three types: (1) continuous, (2) fenestrated (as in the endocrine glands), or (3) porous (as in renal glomeruli). The endothelium rests on an external lamina surrounded by pericytes. Pericytes are located abluminally to capillaries and postcapillary venules and because of their location, contractility, and cytoskeletal proteins may play a role in regulating capillary and venular blood flow. Lesions of the endothelium might not be evident by light microscopy, and electron microscopy is required for characterization.
Veins have thin walls in relation to their luminal size when compared with those of arteries, in which blood pressure is greater. The adventitia is the thickest layer. Valves are present to prevent retrograde blood flow (i.e., away from the heart).
Lymphatic capillaries lack a basal lamina. Large lymphatic vessels are similar in structure to veins and generally have large lumina, thin walls, and intimal valves but contain lymph.
The morphology of large arteries, veins, microvasculature, and lymphatic vessels is described in Chapter 2 and is not discussed further in this chapter.
Necropsy Assessment of Heart and Vascular Structures
Information on this topic including Web Appendix 10-1 and Web Figs. 10-4 and 10-5 is available at evolve.elsevier.com/Zachary/McGavin/.
Web Fig. 10-4 Postmortem “chicken fat” arterial cast, dog.Note how the clot conforms to the shape of the lumens of the vessels from which it was removed. Chicken fat clots consist primarily of clotted plasma and fibrin and other proteins of the coagulation cascade. They are often indicative of anemia; however, in all animals their formation by the separation of the red blood cells from the rest of the components of blood depends on the erythrocyte sedimentation rate (ESR). Separation can occur in all animals in response to systemic inflammation, which increases the ESR, but the horse normally has a high ESR because equine erythrocytes clump together in rouleau formation, which increases the ESR. Thus depending on the ESR, postmortem clots may be pale white to yellow (“chicken fat” clot) or shiny red (“currant jelly” clot) or sometimes a mixture. (Courtesy Dr. R.K. Myers, College of Veterinary Medicine, Iowa State University.)
Web Fig. 10-5 Focal hemorrhage and discoloration, intracardiac injection, euthanasia solution, left ventricle, dog.Euthanasia solution is often injected into the left ventricle. In this case, solution was injected into the myocardium and caused a localized area of hemorrhage and discoloration. A mixture of euthanasia solution and blood often form a brownish sludge in the ventricle. (Courtesy College of Veterinary Medicine, University of Illinois.)
Examination of the Cardiovascular System and Lymphatic Vessels at Necropsy and Tissue Sampling for Histopathologic Evaluation
Information on this topic including Web Appendix 10-2 and Web Fig. 10-6 is available at evolve.elsevier.com/Zachary/McGavin/.
Web Fig. 10-6 Schematic diagram of the gross and microscopic examination of the heart.Diagrams A to D illustrate the heart opened. The numbers indicate the area and the shape of the blocks of tissue removed for histopathology. A, Right ventricle and right atrium. B, Right ventricular cavity and pulmonary outflow tract. C, Left ventricle and left atrium. D, Left ventricle and aortic outflow tract. 1, Right ventricular free wall, atrioventricular valve, and atrium. 2, Pulmonic valve, right ventricular outflow tract, and pulmonary artery. 3, Right auricular appendage. 4, Sinoatrial node. 5, Left auricular appendage. 6, Left atrioventricular valve, ventricle, and atrium. 7 and 8, Left ventricular free wall and papillary muscles. 9, Atrioventricular node, right atrioventricular valve, and atrium. 10, Interventricular septum. 11, Aortic valve, left aortic outflow tract, and aorta. (From Bishop SP: Necropsy techniques for the heart and great vessels. In Fox P, Sisson D, Moise N, eds: Textbook of canine and feline cardiology, ed 2, Philadelphia, 1999, Saunders.)
Function
The primary function of the cardiovascular and lymphatic systems is to maintain an adequate and steady supply of nutrients to and facilitate the removal of waste products from all organs and tissues of the body. Cardiac myocytes provide the force of contraction; the conduction system and the nervous system control the flow and volume.
Pericardium and Epicardium
The pericardium contains a small amount of serous fluid, which allows frictionless cardiac movement of the mesothelial surfaces of the pericardium and epicardium on each other. The pericardial sac can adapt to changes in the heart size provided adequate time. The pericardium functions to provide a protective environment for cardiac function. Rapid, abnormal filling with blood (hemopericardium), fluid (hydropericardium), or exudate (pyopericardium) can result in compression of the heart (cardiac tamponade), particularly the large veins, right atrium, and right ventricle. Animals can survive without a pericardial sac.
Myocardium
The results of normal cardiac function include the maintenance of adequate blood flow, called cardiac output, to peripheral tissues that provide delivery of oxygen and nutrients, the removal of carbon dioxide and other metabolic waste products, the distribution of hormones and other cellular regulators, and the maintenance of adequate thermoregulation and glomerular filtration pressure (urine output). The normal heart has a threefold to fivefold functional reserve capacity, but this capacity can eventually be lost in cardiac disease and the result is impaired function.
Cardiac Pathophysiology: Myocardial Dysfunction
Cardiovascular dysfunction is the result of one or more of six basic pathophysiologic mechanisms (Box 10-1). Compensatory mechanisms operate in both normal and diseased hearts in an attempt to meet both the short- and long-term demands for adequate cardiac output. These mechanisms include cardiac dilation, myocardial hypertrophy, increase in heart rate, increase in peripheral resistance, increase in blood volume, and redistribution of blood flow. These compensatory mechanisms can maintain cardiac output that is adequate for some time, even in animals with severe cardiac disease sufficient to compromise cardiac function from loss of myocardial contractility, sustained pressure overload, or sustained volume overload. Cardiac dilation can occur as a terminal lesion in many cardiac diseases (Fig. 10-6, A). As a compensatory response to achieve increased cardiac output, dilation allows stretching of cardiac muscle cells to increase contractile force according to the Frank-Starling phenomenon and increased stroke volume is the result. However, stretching beyond certain limits decreases contractile strength. Myocardial hypertrophy is an important long-term compensatory response of the heart to maintain adequate cardiac output in the face of increased pressure or volume overload (see the discussion on the myocardium in the section on Responses to Injury) (Fig. 10-6, B).
Fig. 10-6 Cardiac dilation and hypertrophy, heart, transected ventricles, dog.A, Cardiac dilation. Note the thin walls of both dilated ventricles. LV, Left ventricle. B, Cardiac hypertrophy (fixed tissue). Note that the right ventricular and left ventricular (LV) walls are approximately the same thickness, indicating that there is right ventricular hypertrophy. (A courtesy Dr. Y. Niyo, College of Veterinary Medicine, Iowa State University; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia. B courtesy College of Veterinary Medicine, University of Florida; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia.)
Syndromes of Cardiac Failure or Decompensation
WEB TABLE 10-1
Experimental Models of Heart Failure
Modified from Smith HJ, Nuttall A: Cardiovasc Res 19:181-186, 1985.
Cardiac Syncope
Cardiac syncope, an acute expression of cardiac disease, is characterized clinically by collapse, loss of consciousness, and extreme changes in heart rate and blood pressure, and with or without demonstrable lesions. Syncope can be caused by massive myocardial necrosis, ventricular fibrillation, heart block, arrhythmias, and reflex cardiac inhibition (e.g., that associated with high intestinal blockage).
Types of Heart Failure
A wide variety of experimental animal models of heart failure exist (see Web Table 10-1). The models have been used to develop an understanding of human cardiac diseases.
Congestive Heart Failure: Congestive heart failure usually develops slowly from gradual loss of cardiac pumping efficiency coupled with either pressure or volume overload or myocardial damage (Figs. 10-7 and 10-8; also see Figs. 8-29, 8-30, and 9-39). Pathophysiologically, congestive heart failure is initiated by development of cardiac disease (e.g., myocardial, valvular, congenital) or increased workload associated with pulmonary, renal, or vascular disease leading to loss of cardiac reserve and development of decreased blood flow to peripheral tissue (forward failure) and accumulation of blood behind the failing chamber (backward failure). Reduced renal blood flow creates hypoxia in the kidneys and increases renin release from the juxtaglomerular apparatus, resulting in stimulation of aldosterone release from the zona glomerulosa of the adrenal cortex. Sodium and water retention are the results of the action of aldosterone on the renal tubules; increased plasma volume follows, as does accumulation of edema fluid (mainly in body cavities). Hypoxia also stimulates increased erythropoiesis in bone marrow and extramedullary organs, such as the spleen, causing polycythemia and thus increased viscosity of the blood. The hypervolemia from aldosterone-induced water retention increases the workload on the already failing heart. Thus a vicious cycle of cardiac decompensation is initiated that eventually leads to death from cardiac failure unless therapeutic intervention occurs. Cardiac dilation, hypertrophy, and increased heart rate can provide some compensation for the increased workload.
Fig. 10-7 Ascites, congestive heart failure, furazolidone cardiotoxicity, heart and liver, duckling.Note prominent accumulations of serous fluid in the abdomen and fibrin deposits over the surface of the liver. The heart (H) is dilated. (Courtesy School of Veterinary Medicine, Purdue University.)
Fig. 10-8 Subcutaneous edema, high altitude disease with congestive heart failure (“brisket disease”), presternal, sternal, and caudal sternocephalic regions (brisket), cow.The extensive subcutaneous edema is the result of chronic congestive heart failure. (Courtesy School of Veterinary Medicine, Purdue University.)
Acute and Chronic Left-Sided Heart Failure: Acute left-sided heart failure is manifested by pulmonary congestion and edema, whereas chronic left-sided heart failure is manifested by chronic passive pulmonary congestion, chronic pulmonary edema, hemosiderosis (“heart failure cells”; see Fig. 9-39), and fibrosis. The most common causes are (1) myocardial contractility loss associated with myocarditis, myocardial necrosis, or cardiomyopathy; (2) dysfunction of the mitral or aortic valves; and (3) several congenital heart diseases.
Acute and Chronic Right-Sided Heart Failure: Acute right-sided heart failure results in acute passive congestion (see Fig. 2-35) leading to hepatomegaly and splenomegaly (see Figs. 2-35 and 13-50, A), whereas chronic right-sided heart failure (see Fig. 2-36) results in hepatic congestion (nutmeg liver) (see Fig. 8-30) and more severe sodium and water retention than in left-sided heart failure. Edema is evident predominantly as ventral subcutaneous edema in horses and ruminants (see Fig. 10-8), ascites in dogs, and hydrothorax in cats. Causes of right-sided failure include (1) pulmonary hypertension, (2) cardiomyopathy, and (3) disease of the tricuspid and pulmonary valves. (See Chapters 8 and 9 for further details on hepatic and pulmonary lesions, respectively, associated with congestive heart failure.)
Cardiac Conduction System
Cells of the cardiac conduction system are modified cardiac myofibers that are able to spontaneously depolarize, which is also called autoexcitation, and function to (1) coordinate the sequence of events required for efficient ventricular filling during diastole and ejection during systole and (2) maintain the pressure in the pulmonary and systemic circuits (see Web Fig. 10-1).
Depolarization of the membrane of these pacemaker cells is due to a transiently increased rapid permeability to sodium ions and a slightly longer lasting increase in permeability to calcium ions that results in their influx into the myofiber sarcoplasm, thus changing the membrane potential (see Chapter 14). As this transient permeability is lost, membranal potassium channels open, and rapid outward potassium flux results in myofiber membranal hyperpolarization (along with sodium and calcium efflux), ultimately bringing the membrane potential back to a “normal” steady state (resting potential). During this period of time (refractory period), the myocyte cannot depolarize again because of a special conformation of membrane sodium channels that is transiently lost with depolarization and regained only with hyperpolarization. Intrinsically, the resting membrane potential of pacemaker cells is more positive than that of contracting cardiomyocytes and slightly more negative than the membrane threshold potential. This difference is due to leakiness of the pacemaker cell membrane to sodium and calcium ions and a steady low-grade influx of these ions.
When an electric signal (a propagating depolarization front) is generated in the SAN and spreads throughout the atria from cell to cell and eventually reaches the AVN, it is also conveyed through the specialized internodal conducting fibers. The conduction in these fibers is approximately three times faster than that of the atrial myofibers. By conveying the signal through these fibers, both atria can contract simultaneously and in a coordinated manner that allows the process of pushing of blood into the ventricles. Correlating with their special fast conducting function, these cells have a Purkinje-like morphology. The conduction velocity is then slowed down when propagating through the AVN. The time it takes to conduct the signal through the AVN and penetrating AV bundles is approximately four times longer than the time it takes for it to be conducted from the SAN to the AVN. This delay in conduction serves to empty the atria from blood before the ventricles start to contract. It also contributes to the unidirectional blood flow between the atria and the ventricles, above and beyond the similar role played by the AVVs.
Finally, the signal is delivered through the AV bundle, bundle branches, and Purkinje fibers in a velocity approximately 150 times faster than that of the AVN. The bundle branches run along the subendocardium of the interventricular septum and free ventricular walls and give rise to Purkinje fibers that supply the myocardium in a subendocardial-to-epicardial direction. This organization allows for a rapid and synchronous contraction of both ventricles at an order that ultimately enables blood to be “squeezed” from apex-to-base, toward both outflow tracts.
Cardiac myofibers have a unique property of intrinsic coupling of the electrical stimulation with mechanical contraction, which is fundamental for cardiac function. Diastole starts immediately at the end of ventricular contraction, as the cardiac muscle (myocardium) starts to relax. For a brief moment, relaxation leads to a rapid fall in ventricular pressure, without change in ventricular volume as the AVVs are still sealed off (isovolumetric relaxation). Because of the fall in ventricular pressure, the blood that has pooled in the atria during systole, along with incoming blood that constantly flows from systemic and pulmonary veins through the atria, pushes the AVV open and rapidly and passively fills the ventricles (rapid-filling phase). Next, because of the resultant pressure rise in the ventricles, the flow of blood that continues to enter the ventricles through the atria abruptly ends (diastasis phase). The last phase of diastole is active contraction of the atria, which pushes blood into the (now somewhat less compliant) ventricles and further raises their pressure (“atrial kick”).
In systole, the myocardium contracts, leading to a rapid increase in intraventricular pressure. Since the aortic and pulmonary valves are shut during diastole, the sudden rise in pressure leads to closure of the AVVs. In this brief period, which is termed isovolumetric contraction, the change in ventricular pressure has not led to a change in ventricular volume, since the blood had not yet been ejected into the aorta and pulmonary arteries. When the pressure in the ventricles exceeds the pressure in the great arteries, the aortic and pulmonary valves (semilunar valves) open and the ejection of the blood through the right and left side outflow tracts ensues (ejection phase). Simultaneously with the ejection phase, the atria relax, atrial pressure falls, and blood enters the atria and pools within it passively.
An additional level of complexity is brought about by the innervation of the autonomous nervous system (ANS). In general, the ANS influences heart rate (chronotropy), alters the rate of conduction (dromotropy), and controls myocardial contractility (inotropy) and the rate of mechanical relaxation (lusitropy). Parasympathetic postganglionic nerve terminals secrete acetylcholine that affects muscarinic (M2) receptors, whereas sympathetic postganglionic nerve terminals secrete norepinephrine that predominantly acts on the β1-adrenergic receptors. The latter, when stimulated by catecholamines, lead to a chain of intracellular events that increases calcium influx, increases the magnitude of potassium and chloride repolarization, and shortens the refractory period. Therefore adrenergic agonists are said to be positive chronotropes, inotropes, dromotropes, and lusitropes, whereas parasympathetic agonists have the opposite effects. Heart rate is primarily regulated by opposing effects of adrenergic and cholinergic nerve terminals on the SAN and at the same time by modulation of conduction velocity of the AVN and AV bundle. Physiologically, the force of contraction represents the sum of interactions between myocardial contractility, which is positively modulated by adrenergic nerve terminals that act on β1 receptors on ventricular myocardial myofibers (positive inotropic effect), and by the volume of blood that is present in the ventricles just before contraction (preload), as well as by the resistance in front of which contraction actually takes place (afterload).
Endocardium and Heart Valves
The endocardium lines the myocardium and contains Purkinje nerve fibers, which transmit a rhythmic action potential throughout the myocardium leading to contraction. The endocardium is lined by endothelial cells, which modulate many aspects of normal hemostasis. In normal states, the endothelial cells are antithrombotic preventing circulating cells from attaching and thus allowing normal flow of blood through the heart and blood vessels. The endocardium is continuous with the endothelium of blood and lymphatic vessels. Normal flow of blood through the heart depends on functional valves (see Chapter 2). Properly functioning valves serve as one-way valves, allowing blood to flow either from one chamber to another (AVVs) or exiting from the heart to either the pulmonary circulation (pulmonic valve) or the systemic circulation (aortic valve).
Blood and Lymphatic Vascular Systems
Blood and lymphatic vessels have several important functions. Blood vessels regulate the differential distribution of blood flow to tissues. Blood vessels actively synthesize and secrete vasoactive substances that regulate vascular tone and antithrombotic substances, which maintain the fluidity of the blood. Blood and lymphatic vessels play an important role in transporting and controlling inflammation and thrombosis. Blood and lymphatic vessels also constitute an important pathway for disease dissemination through transport of bacteria and tumor cells to distant sites.

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