Chapter 12 The Heart PDF

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R The Heart Richard N. Mitchell Andrew J. Connolly...

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R The Heart Richard N. Mitchell Andrew J. Connolly 12 CHAPTER CONTENTS Cardiac Structure and Pulmonary Stenosis and Atresia 541 Endocarditis of Systemic Lupus Erythematosus Specializations 528 Aortic Stenosis and Atresia 541 (Libman-Sacks Disease) 565 Myocardium 528 Ischemic Heart Disease 542 Carcinoid Heart Disease 565 Valves 528 Angina Pectoris 543 Complications of Prosthetic Valves 565 Conduction System 528 Myocardial Infarction 543 Cardiomyopathies 567 Blood Supply 528 Chronic Ischemic Heart Disease 553 Dilated Cardiomyopathy (DCM) 568 Cardiac Regeneration 529 Arrhythmias 554 Arrhythmogenic Cardiomyopathy 572 Effects of Aging on the Heart 529 Sudden Cardiac Death 555 Hypertrophic Cardiomyopathy 572 Overview of Cardiac Hypertensive Heart Disease 555 Restrictive Cardiomyopathy 574 Pathophysiology 529 Systemic (Left-Sided) Hypertensive Heart Amyloidosis 574 Heart Failure 530 Disease 555 Myocarditis 575 Cardiac Hypertrophy: Pathophysiology Pulmonary (Right-Sided) Hypertensive Other Causes of Myocardial Disease 577 and Progression to Heart Failure 530 Heart Disease (Cor Pulmonale) 556 Cardiotoxic Drugs 577 Left-Sided Heart Failure 532 Valvular Heart Disease 557 Radiation 577 Right-Sided Heart Failure 533 Calcific Valvular Degeneration 557 Pericardial Disease 577 Cardiac Development 534 Calcific Aortic Stenosis 557 Pericardial Effusion and Congenital Heart Disease 534 Calcific Stenosis of Congenitally Bicuspid Aortic Hemopericardium 577 Left-to-Right Shunts 536 Valve 559 Pericarditis 577 Atrial Septal Defect 536 Mitral Annular Calcification 559 Acute Pericarditis 577 Patent Foramen Ovale 537 Mitral Valve Prolapse (Myxomatous Chronic or Healed Pericarditis 578 Ventricular Septal Defect 537 Degeneration of the Mitral Valve) 559 Tumors of the Heart 579 Patent Ductus Arteriosus 538 Rheumatic Fever and Rheumatic Heart Primary Cardiac Tumors 579 Right-to-Left Shunts 538 Disease 560 Metastatic Neoplasms 580 Tetralogy of Fallot 538 Infective Endocarditis (IE) 563 Cardiac Transplantation 580 Transposition of the Great Arteries 539 Noninfected Vegetations 564 Cardiac Devices 580 Tricuspid Atresia 540 Nonbacterial Thrombotic Endocarditis Ventricular Assist Devices 581 Obstructive Lesions 540 (NBTE) 564 Coarctation of the Aorta 540 The human heart is a remarkably efficient, durable, and than the number of deaths caused by all forms of cancer reliable pump, propelling more than 7500 L of blood through combined. the body each day, and beating more than 40 million times This chapter begins with a brief review of the normal a year—the wellspring for tissue oxygenation, nutrition, heart because most cardiac diseases manifest as struc- and waste removal. In utero, the heart and vasculature tural and/or functional changes in one or more cardiac are the first fully functional organ system (at roughly components. General principles underlying cardiac 8 weeks of gestation). Without a vascular supply and a hypertrophy and failure—common end points of several beating heart, further development cannot occur and fetal of the different forms of heart disease—are also discussed, demise is inevitable. When the heart fails postnatally, the before exploring the major categories of cardiac disease: results are equally catastrophic. Cardiovascular disease congenital heart abnormalities, ischemic heart disease (including coronary artery disease [CAD], stroke, and (IHD), hypertensive heart disease, diseases of the cardiac peripheral vascular disease) is the number-one cause of valves, and primary myocardial disorders. The chapter worldwide mortality. In the United States alone, cardio- concludes with a few comments about pericardial diseases vascular disease accounts for roughly 1 in 4 of all deaths, and cardiac neoplasms, as well as cardiac transplantation totaling about 610,000 individuals each year—greater and devices. 527 528 C H A P T E R 12 The Heart Because they are thin enough to be nourished by diffusion CARDIAC STRUCTURE AND from the blood, normal leaflets and cusps have only scant SPECIALIZATIONS blood vessels limited to the proximal portion of the valve. Valve endothelium also does not express ABO or histocom- Heart weight varies with body habitus, averaging approxi- patibility antigens, so cryopreserved valvular tissues can mately 0.4% to 0.5% of body weight (250 to 320 g in the be transplanted with relative impunity. average adult female and 300 to 360 g in the average adult male). Increased heart weight or ventricular thickness Conduction System indicates hypertrophy, and an enlarged chamber size implies dilation; both reflect compensatory changes in response to Coordinated contraction of the cardiac muscle depends on volume and/or pressure overloads (see later). Increased the initiation and rapid propagation of electrical impulses— cardiac weight or size (or both)—resulting from hypertrophy accomplished through specialized myocytes in the conduction and/or dilation—is called cardiomegaly. system. The frequency of electrical impulses is sensitive to neural inputs (e.g., vagal stimulation), extrinsic adrenergic Myocardium agents (e.g., circulating adrenaline), hypoxia, and potassium concentration (i.e., hyperkalemia can block signal transmis- The pumping function of the heart occurs through coordinated sion altogether). contraction (during systole) and relaxation (during diastole) The components of the conduction system include the of cardiac myocytes (the myocardium). Left ventricular following: myocytes are arranged in a spiral circumferential orientation Sinoatrial (SA) node pacemaker, at the junction of the right to generate vigorous coordinated waves of contraction atrial appendage and superior vena cava spreading from the cardiac apex to the base of the heart. In Atrioventricular (AV) node, located in the right atrium contrast, right ventricular myocytes have a less structured along the interatrial septum organization, generating overall less robust contractile forces. Bundle of His (AV bundle), connecting the right atrium to Contraction is achieved by shortening of serial contractile the ventricular septum elements (sarcomeres) within parallel myofibrils. Although Right and left bundle branch divisions that stimulate their the heart is primarily a pump, it is worth remembering that respective ventricles via further arborization into the it also has other functions (e.g., endocrine). For example, Purkinje network atrial cardiomyocytes have cytoplasmic storage granules that contain atrial natriuretic peptide, and ventricular myocytes The cells of the cardiac conduction system depolarize contain B-type natriuretic peptide. Both of these are protein spontaneously, potentially enabling all of them to function hormones that are released in response to increased stretch; as cardiac pacemakers. Because the normal rate of spontane- they both promote arterial vasodilation and stimulate renal ous depolarization in the SA node (60 to 100 beats/min) is salt and water elimination (natriuresis and diuresis). faster than the other components, it normally sets the pace. However, if nodal tissues become dysfunctional, other cells Valves in the conduction system can take over, generating, for example, a junctional escape rhythm (usually at a much The four cardiac valves—tricuspid, pulmonary, mitral, and slower rhythm). The AV node has a gatekeeper function; aortic—maintain unidirectional blood flow. Valve function by delaying the transmission of signals from the atria to depends on the mobility, pliability, and structural integrity the ventricles, it ensures that atrial contraction precedes of the leaflets of the atrioventricular valves (tricuspid ventricular systole. and mitral) or cusps of the semilunar valves (aortic and pulmonary). Blood Supply The function of the semilunar valves depends on the integrity and coordinated movements of the cuspal attach- Cardiac myocytes rely almost exclusively on oxidative ments. Thus, dilation of the aortic root can result in valvular phosphorylation for their energy needs. Besides a high regurgitation. In contrast, the competence of the atrioven- density of mitochondria (20% to 30% of myocyte volume), tricular valves depends on the proper function not only of myocardial energy generation also requires a constant supply the leaflets but also the tendinous cords and the attached of oxygenated blood—rendering myocardium extremely papillary muscles of the ventricular wall. Left ventricular vulnerable to ischemia. Nutrients and oxygen are delivered dilation, a ruptured cord, or papillary muscle dysfunction via the coronary arteries, with ostia immediately distal to can all interfere with mitral valve closure, causing valvular the aortic valve. These initially course along the external insufficiency. surface of the heart (epicardial coronary arteries) and then Cardiac valves are lined by endothelium and share a penetrate the myocardium (intramural arteries), subsequently similar, trilayered architecture: branching into arterioles, and forming a rich arborizing Fibrosa layer. A dense collagenous layer at the outflow vascular network so that each myocyte contacts roughly surface, connected to the valvular supporting structures three capillaries. and providing mechanical integrity The right and left coronary arteries function as end Spongiosa layer. A central core of loose connective tissue arteries, although anatomically most hearts have numerous Ventricularis or atrialis layer (depending on which chamber intercoronary anastomoses (connections called collateral it faces). A layer rich in elastin on the inflow surface, circulation). Blood flow to the myocardium occurs during providing leaflet recoil ventricular diastole, after closure of the aortic valve, and  Overview of cardiac pathophysiology 529 when the microcirculation is not compressed by cardiac Table 12.1 Changes in the Aging Heart contraction. At rest, diastole comprises approximately two- Chambers thirds of the cardiac cycle; with tachycardia (increased heart Increased left atrial cavity size rate), the relative duration of diastole also shortens, thus Decreased left ventricular cavity size potentially compromising cardiac perfusion. Sigmoid-shaped ventricular septum Valves Cardiac Regeneration Aortic valve calcific deposits Mitral valve annular calcific deposits There is considerable interest in exploring the possibility Fibrous thickening of leaflets of replacing damaged myocardium by inducing cardiac Buckling of mitral leaflets toward the left atrium regeneration in vivo or implanting stem cell–derived cardiac Lambl excrescences cells. Although cardiac regeneration in metazoans such as Epicardial Coronary Arteries newts and zebrafish is well described, the myocardium of Tortuosity mammals has a very low replicative potential after fetal Diminished compliance and neonatal life, averaging less than 1% cardiomyocyte Calcific deposits turnover per year in adult humans. Increasing evidence, Atherosclerotic plaque however, indicates that cardiomyocyte proliferation can be Myocardium augmented in mice. The potential for stimulating cardiac Decreased mass regeneration in vivo in humans is tantalizing because it Increased subepicardial fat could facilitate recovery of myocardial function after a host Brown atrophy of injurious stimuli. Another area of vigorous investigation Lipofuscin deposition is ex vivo expansion and subsequent administration of stem Basophilic degeneration cell–derived myocardial cells into areas of myocardial Amyloid deposits injury. Unfortunately, results thus far have been less than Aorta exciting. Implanted cells may show some cardiomyocyte Dilated ascending aorta with rightward shift differentiation, but the durability of this benefit has been Elongated (tortuous) thoracic aorta limited, and they do not contribute significantly to the Sinotubular junction calcific deposits restoration of contractile force; moreover, failure to suc- Elastic fragmentation and collagen accumulation cessfully integrate these cells into the conduction pathways Atherosclerotic plaque of the host heart carries the very real risk of autonomous arrhythmic foci. Effects of Aging on the Heart Failure of the pump. In the most common situation, the cardiac muscle contracts weakly and the chambers cannot Most forms of heart disease become more prevalent with empty properly—so-called systolic dysfunction. In some each advancing decade. Consequently, as the average cases, the myocardium cannot relax sufficiently to permit populations in high income countries get progressively older, ventricular filling, resulting in diastolic dysfunction. aging-associated changes in the cardiovascular system Obstruction to flow. Lesions that prevent valve opening become ever more significant (Table 12.1). (e.g., calcific aortic valve stenosis) or cause increased The size of the left ventricular cavity, particularly in the ventricular chamber pressures (e.g., systemic hypertension base-to-apex dimension, is reduced in later life; this volume or aortic coarctation) can overwork the myocardium, change is exacerbated by systemic hypertension as the which has to pump against the obstruction. basal ventricular septum protrudes into the left ventricu- Regurgitant flow. Valve pathology that allows backward lar outflow tract (so-called sigmoid septum). Compared flow of blood results in increased volume workload and with younger myocardium, the “elderly” heart typically may overwhelm the pumping capacity of the affected has fewer myocytes (due to degenerative attrition) and chambers. increased connective tissue; octogenarians (and older) Shunted flow. Defects (congenital or acquired) that divert also frequently have deposition of extracellular amyloid blood inappropriately from one chamber to another, or (most often poorly catabolized transthyretin; Chapter 6) from one vessel to another, lead to pressure and volume that stiffens the heart and reduces diastolic filling. Valvular overloads. aging changes are major contributors to significant valvular Disorders of cardiac conduction. Uncoordinated cardiac disease (see later), and progressive atherosclerosis, with a impulses or blocked conduction pathways can cause strong aging component (Chapter 11), is the major cause arrhythmias that slow contractions or prevent effective of IHD. pumping altogether. Rupture of the heart or major vessel. Loss of circulatory continuity (e.g., a gunshot wound through the thoracic OVERVIEW OF CARDIAC aorta) may lead to massive blood loss, hypotensive shock, PATHOPHYSIOLOGY and death. Although a host of diseases can affect the cardiovascular Most cardiovascular disease results from a complex system, the pathophysiologic pathways that result in a interplay of genetics and environmental factors; these can “broken” heart distill down to six principal mechanisms: disrupt signaling pathways that control morphogenesis, 530 C H A P T E R 12 The Heart affect myocyte survival after injury, or affect contractility remodeling is the general term applied to the collective or electrical conduction in the face of biomechanical stressors. molecular, cellular, and structural changes that occur in Indeed, the pathogenesis of many congenital heart defects response to injury or altered ventricular loading. involves an underlying genetic abnormality whose expression is modified by environmental factors (see later). Moreover, Although such adaptive mechanisms can potentially genes that control the development of the heart may also maintain adequate cardiac output in the face of acute regulate the response to various forms of injury including perturbations, their capacity to do so may ultimately be aging. Subtle polymorphisms can significantly affect the overwhelmed. Heart failure can result from progressive risk of many forms of heart disease, and, as discussed later, deterioration of myocardial contractile function (systolic a number of adult-onset heart disorders have a fundamentally dysfunction)—reflected as a decrease in ejection fraction genetic basis. Thus, cardiovascular genetics provides an (EF, the percentage of blood volume ejected from the ventricle important window on the pathogenesis of heart disease, during systole; normal is approximately 45% to 65%). and molecular diagnoses are increasingly a critical part of Reduction in EF can occur with ischemic injury, inadequate its classification. adaptation to pressure or volume overload due to hyperten- sion or valvular disease, or ventricular dilation. Increasingly, heart failure is recognized as resulting from an inability of HEART FAILURE the heart chamber to expand and fill sufficiently during diastole (diastolic dysfunction), for example, due to left Heart failure, often called congestive heart failure (CHF), ventricular hypertrophy, myocardial fibrosis, constrictive is a common, usually progressive condition with a poor pericarditis, or amyloid deposition. prognosis. Each year in the United States, CHF affects more than 5 million individuals (approximately 2% of the popula- Cardiac Hypertrophy: Pathophysiology and tion), necessitating more than 1 million hospitalizations, Progression to Heart Failure and contributing to the death of nearly 300,000 people. Roughly one-half of patients die within 5 years of receiving Sustained increase in mechanical work of either ventricle a diagnosis of CHF, and 1 in 9 deaths in the United States due to pressure overload, volume overload, or trophic include heart failure as a contributory cause. signals (e.g., those mediated through the activation of Heart failure is defined as the condition in which a heart β-adrenergic receptors) causes myocytes to increase in size cannot pump blood to adequately meet the metabolic (cellular hypertrophy); cumulatively, this increases the size demands of peripheral tissues, or can do so only at elevated and weight of the heart (Fig. 12.1). Hypertrophy requires filling pressures. It is the common end stage of many forms increased protein synthesis to form additional sarcomeres, of chronic heart disease, often emerging insidiously from as well as increasing the numbers of mitochondria. Hyper- the cumulative effects of chronic work overload (e.g., in trophic myocytes also have multiple or enlarged nuclei, valve disease or hypertension) or IHD (e.g., after myocardial attributable to increased DNA ploidy resulting from DNA infarction [MI] with heart damage). However, acute hemo- replication in the absence of cell division. dynamic stresses, such as fluid overload, abrupt valvular The pattern of hypertrophy reflects the nature of the dysfunction, or myocardial infarction, can all precipitate stimulus. sudden CHF. In pressure-overload hypertrophy (e.g., due to hypertension When cardiac workload increases or cardiac function is or aortic stenosis), new sarcomeres are predominantly compromised, several physiologic mechanisms swing into assembled in parallel to the long axes of cells, expanding action, and can at least initially maintain arterial pressure the cross-sectional area of myocytes in ventricles and and organ perfusion: causing a concentric increase in wall thickness. Frank-Starling mechanism: Increased filling volumes dilate In contrast, volume-overload hypertrophy (e.g., due to the heart, thereby increasing actin-myosin cross-bridge valvular regurgitation) is characterized by new sarcomeres formation, and enhancing contractility and stroke volume. being assembled in series within existing sarcomeres, Activation of neurohumoral systems: These augment heart leading primarily to ventricular dilation. As a result, in function and/or regulate filling volumes and pressures dilation due to volume overload, or dilation that accom- (and many of the therapies for CHF affect these systems panies failure of a previously pressure overloaded heart, when they become maladaptive). the wall thickness may be increased, normal, or less than Release of norepinephrine by adrenergic nerves of the normal. Consequently, heart weight, rather than wall autonomic nervous system, elevating heart rate, thickness, is the best measure of hypertrophy in dilated augmenting myocardial contractility and increasing hearts. vascular resistance Activation of the renin-angiotensin-aldosterone system, Heart disease can lead to dramatic levels of cardiac promoting water and salt retention (augmenting hypertrophy. Patients with systemic hypertension, IHD, circulatory volume) and increasing vascular tone aortic stenosis, mitral regurgitation, or dilated cardiomy- Release of atrial natriuretic peptide, counterbalancing the opathy frequently have heart weights double or triple the renin-angiotensin-aldosterone system through diuresis average, and aortic regurgitation or hypertrophic cardio- and vascular smooth muscle relaxation myopathy can produce heart weights threefold to fourfold Myocardial adaptations: In many pathologic states, heart greater than normal. failure is preceded by cardiac hypertrophy, a compensa- Important changes at the tissue and cell level occur with tory response to increased mechanical work. Ventricular cardiac hypertrophy. Significantly, myocyte hypertrophy  Heart failure 531 A B C D Figure 12.1 Left ventricular hypertrophy. (A) Pressure hypertrophy due to left ventricular outflow obstruction. The left ventricle is on the lower right in this apical four-chamber view of the heart. (B) Left ventricular hypertrophy with and without dilation, viewed in transverse heart sections. Compared with a normal heart (center), the pressure-hypertrophied hearts (left and in A) have increased mass and a thick left ventricular wall, and the hypertrophied, dilated heart (right) has increased mass and an apparently normal wall thickness. (C) Normal myocardium. (D) Hypertrophied myocardium (C and D are photomicrographs at the same magnification). Note the increases in both cell size and nuclear size in the hypertrophied myocytes, and the interstitial cells remain small. (A and B, Reproduced with permission from Edwards WD: Cardiac anatomy and examination of cardiac specimens. In Emmanouilides GC, et al., editors: Moss and Adams Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adults, ed 5, Philadelphia, 1995, Williams & Wilkins, p 86.) is not accompanied by a proportional increase in capillary hemodynamic overload, myocytes can even express genes numbers. As a result, the supply of oxygen and nutrients usually only seen during fetal cardiac development (including to the hypertrophied heart, particularly one undergoing fetal forms of myosin, natriuretic peptides, and collagen). pressure-overload hypertrophy, is more tenuous than in The proposed sequence of initially adaptive—and later the normal heart. At the same time, cardiac hypertrophy is harmful—events in response to increased cardiac work is associated with heightened metabolic demands due to summarized in Fig. 12.2. As illustrated, heart failure eventu- increases in mass, heart rate, and contractility (inotropic ally supervenes. The degree of anatomic abnormality does state, or force of contraction), all of which increase cardiac not always reflect the severity of dysfunction; indeed, the oxygen consumption. As a result of these changes, the gross appearance of the “failing heart” does not adequately hypertrophied heart is vulnerable to ischemia-related convey the underlying structural, biochemical, and molecular decompensation, which can evolve to cardiac failure. Adding basis for myocardial contractile failure. The hearts of patients insult to injury, hypertrophy is also typically accompanied with CHF are generally heavy and dilated, but can be rela- by deposition of fibrous tissue (interstitial fibrosis), causing tively thin-walled, and histologically they exhibit variable increased resistance to diastolic filling. degrees of myocyte hypertrophy. Loss of myocardial mass Molecular changes in hypertrophied cardiomyocytes in the setting of infarction leads to work-related hypertrophy include the expression of immediate-early genes (e.g., FOS, of the surrounding viable myocardium. In valvular heart JUN, MYC, and EGR1) (Chapter 2) putatively driving cellular disease, the increased pressure or volume overloads the growth and altered protein expression; with prolonged myocardium globally. Increased heart mass owing to disease 532 C H A P T E R 12 The Heart HYPERTENSION VALVULAR DISEASE MYOCARDIAL INFARCTION Left-Sided Heart Failure Pressure Pressure and/or Regional dysfunction Left-sided heart failure is most often caused by the overload volume overload with volume overload following: IHD Cardiac work Hypertension Aortic and mitral valvular diseases Wall stress Primary myocardial diseases Cell stretch The clinical and morphologic effects of left-sided CHF are a consequence of passive congestion (blood backing Hypertrophy and/or dilation up in the pulmonary circulation), stasis of blood in the Characterized by left-sided chambers, and inadequate perfusion of down- heart size and mass stream tissues leading to organ dysfunction. protein synthesis induction of immediate-early genes induction of fetal gene program MORPHOLOGY abnormal proteins fibrosis Heart. The findings depend on the disease process, ranging from inadequate vasculature myocardial infarcts, to stenotic or regurgitant valves, to intrinsic myocardial pathology. Except for failure caused by mitral valve stenosis or unusual restrictive cardiomyopathies (described later), Cardiac dysfunction the left ventricle is usually hypertrophied and often dilated, Characterized by sometimes massively. Left ventricular diastolic dysfunction or heart failure (systolic/diastolic) dilation with mitral valve incompetence causes secondary dilation arrhythmias of the left atrium, increasing the risk of atrial fibrillation. This in neurohumoral stimulation turn results in stasis of blood, particularly in the atrial appendage, which is a common site of thrombus formation. The microscopic Figure 12.2 Schematic representation of the causes and consequences of changes in the failing heart are nonspecific: variable degrees of cardiac hypertrophy. myocyte hypertrophy and interstitial fibrosis. Lungs. Pulmonary congestion and edema produce heavy, wet lungs, as described elsewhere (Chapters 4 and 15). Pulmonary changes—from mildest to most severe—include (1) perivascular is correlated with excess cardiac mortality and morbidity; and interstitial edema, particularly in the interlobular septa, (2) indeed, cardiomegaly is an independent risk factor for progressive edematous widening of alveolar septa, and (3) accumula- sudden death. tion of edema fluid in the alveolar spaces. Extravasated red cells In contrast to the pathologic hypertrophy associated with and plasma proteins in the alveoli are phagocytosed and digested persistent mechanical stressors, regular exercise can promote by macrophages; the accumulated iron is stored as hemosiderin. potentially beneficial physiologic hypertrophy. Aerobic These hemosiderin-laden macrophages (also known as heart exercise (e.g., long-distance running) tends to be associated failure cells) are telltale signs of previous episodes of pulmonary with volume-load hypertrophy accompanied by increases edema. Pleural effusions (typically serous) arise from elevated in capillary density (unlike other forms of hypertrophy); pleural capillary and lymphatic pressure and the resultant transuda- regular aerobic activity also decreases the resting heart rate tion of fluid into the pleural cavities. and blood pressure—effects that are all beneficial. In com- parison, purely static exercise (e.g., weight lifting) induces mild pressure hypertrophy (e.g., secondary to recurring Early left-sided heart failure symptoms are related to Valsalva maneuvers) and less beneficial remodeling. pulmonary congestion and edema. Initially, cough and Whatever its basis, CHF is characterized by variable dyspnea (breathlessness) may occur only with exertion. As degrees of decreased cardiac output and tissue perfusion CHF progresses, worsening pulmonary edema may cause (forward failure), as well as pooling of blood in the venous orthopnea (dyspnea when supine, relieved by sitting or capacitance system (backward failure); the latter may cause standing) or paroxysmal nocturnal dyspnea (dyspnea usually pulmonary edema, peripheral edema, or both. As a result, occurring at night that is so severe that it induces a feeling many of the significant clinical features and morphologic of suffocation). Dyspnea at rest may follow. The respiratory changes noted in CHF are actually secondary to disorders symptoms are characteristically associated with fine rales induced by hypoxia and congestion in noncardiac peripheral at the lung bases, caused when edematous pulmonary alveoli tissues. snap open during inspiration. Other manifestations of left The cardiovascular system is a closed circuit. Thus, ventricular failure include an enlarged heart (cardiomegaly, although left-sided and right-sided failure can occur inde- apparent on imaging), tachycardia, a third heart sound due pendently, failure of one side (particularly the left) often to volume overload (S3), or a fourth heart sound (S4) due produces excessive strain on the other, terminating in global to increased myocardial stiffness. If heart failure is associated heart failure. Despite this interdependence, it is easiest to with progressive ventricular dilation, the papillary muscles understand the pathology of heart failure by considering are displaced outward, causing mitral regurgitation. Sub- right- and left-sided heart failure separately. sequent chronic dilation of the left atrium can cause atrial  Heart failure 533 fibrillation, and such uncoordinated, chaotic atrial contrac- hypertension (discussed later), which results in hypertrophy tions reduce the atrial contribution to ventricular filling, and dilation of the right side of the heart. In extreme cases, thus reducing the ventricular stroke volume. leftward bulging of the interventricular septum can even In moderate CHF, a reduced ejection fraction leads to cause left ventricular dysfunction. The major morphologic diminished renal perfusion, causing activation of the renin- and clinical effects of primary right-sided heart failure differ angiotensin-aldosterone system as a compensatory mecha- from those of left-sided heart failure in that pulmonary nism to correct the “perceived” hypotension. This leads to congestion is minimal while engorgement of the systemic salt and water retention, with expansion of the interstitial and portal venous systems is pronounced. and intravascular fluid volumes (Chapters 4 and 11) exac- erbating the ongoing pulmonary edema. If the hypoperfusion of the kidney becomes sufficiently severe, impaired excretion MORPHOLOGY of nitrogenous products may cause azotemia (called prerenal Heart. As in left-heart failure, the cardiac morphology varies azotemia; Chapter 20). In far-advanced CHF, cerebral with cause. Rarely, structural defects such as tricuspid or pulmonary hypoperfusion can give rise to hypoxic encephalopathy valvular abnormalities or endocardial fibrosis (as in carcinoid (Chapter 28), with irritability, loss of attention span, and heart disease) may be present. However, because isolated right restlessness that can progress to stupor and coma with heart failure is most often caused by lung disease, most cases ischemic cerebral injury. exhibit only hypertrophy and dilation of the right atrium and Left-sided heart failure can be divided into systolic and ventricle. diastolic failure: Liver and Portal System. Congestion of the hepatic and Systolic failure is defined by insufficient ejection fraction portal vessels may produce pathologic changes in the liver, the (pump failure) and can be caused by any of the many spleen, and the gastrointestinal tract. The liver is usually increased disorders that damage or derange the contractile function in size and weight (congestive hepatomegaly) caused by of the left ventricle. passive congestion, greatest around the central veins (Chapter In diastolic failure, the left ventricle is abnormally stiff 4). Grossly, this is reflected as congested red-brown pericentral and cannot relax during diastole. Thus, although cardiac zones, with relatively normal-colored tan periportal regions, function is relatively preserved at rest, the heart is unable producing the characteristic “nutmeg liver” appearance (Chapter to increase its output in response to increases in the 4). In some instances, especially when left-sided heart failure with metabolic demands of peripheral tissues (e.g., during hypoperfusion is also present, severe centrilobular hypoxia produces exercise). Moreover, because the left ventricle cannot centrilobular necrosis. With longstanding severe right-sided expand normally, any increase in filling pressure is heart failure, the central areas can become fibrotic, eventually immediately transferred back into the pulmonary circula- culminating in cardiac cirrhosis (Chapter 18). Portal venous tion, producing pulmonary edema. Hypertension is the hypertension also causes enlargement of the spleen with platelet most common underlying etiology; diabetes mellitus, sequestration (congestive splenomegaly) and can also con- obesity, and bilateral renal artery stenosis can also be tribute to chronic congestion and edema of the bowel wall. The causal. Reduced left ventricular relaxation may stem from latter may be sufficiently severe as to interfere with nutrient myocardial fibrosis (e.g., in cardiomyopathies and IHD) (and/or drug) absorption. or infiltrative disorders associated with restrictive car- Pleural, Pericardial, and Peritoneal Spaces. Systemic venous diomyopathies (e.g., cardiac amyloidosis). Diastolic failure congestion can lead to fluid accumulation (effusions) in the may appear in older patients without any known pre- pleural, pericardial, or peritoneal spaces (a peritoneal effusion is disposing factors, possibly as an exaggeration of the also called ascites). Large pleural effusions can impact lung inflation, normal stiffening of the heart with age. Constrictive causing atelectasis, and substantial ascites can also limit diaphrag- pericarditis (discussed later) can also limit myocardial matic excursion, causing dyspnea on a purely mechanical basis. relaxation and therefore mimics primary diastolic Subcutaneous Tissues. Edema of the peripheral and dependent dysfunction. portions of the body, especially foot/ankle (pedal) and pretibial edema, is a hallmark of right-sided heart failure. In chronically Right-Sided Heart Failure bedridden patients, presacral edema may predominate. Generalized massive edema (anasarca) can also occur. Right-sided heart failure is most commonly caused by left-sided heart failure, as any increase in pressure in the pulmonary circulation from left-sided failure inevitably The kidney and the brain are also prominently affected burdens the right side of the heart. Consequently, the causes in right-sided heart failure. Renal congestion is more marked of right-sided heart failure include all the etiologies for left- with right-sided than with left-sided heart failure, leading sided heart failure. Isolated right-sided heart failure is to greater fluid retention and peripheral edema, and more infrequent and typically occurs in patients with one of a pronounced azotemia. Venous congestion and hypoxia of variety of disorders affecting the lungs; hence it is often the central nervous system can also produce deficits of mental referred to as cor pulmonale. Besides parenchymal lung function akin to those seen in left-sided heart failure with diseases, cor pulmonale can also arise secondary to disorders poor systemic perfusion. that affect the pulmonary vasculature, for example, primary Although we have discussed right and left heart failure pulmonary hypertension (Chapter 15), recurrent pulmonary separately, it is again worth emphasizing that in many cases thromboembolism (Chapter 4), or conditions that cause of chronic cardiac decompensation, patients with biven- pulmonary vasoconstriction (obstructive sleep apnea, altitude tricular CHF have symptoms reflecting both right-sided and sickness). The common feature of these disorders is pulmonary left-sided heart failure. Besides a careful history and physical 534 C H A P T E R 12 The Heart examination, serum levels of B-type (or brain) natriuretic ventricle, whereas those in the second wave become the factor (BNP) have become a popular tool to quantitatively outflow tract, right ventricle, and most of the atria. Thus, assess the extent of CHF. Recall that BNP is released by defects in one or the other anlage can explain some of the ventricular cardiomyocytes during increased wall stress; a CHDs involving discrete structures. By day 20 of develop- low value has a high negative predictive value for CHF. ment, the nascent heart has become a beating tube, which Echocardiography is also an extremely valuable tool in begins to form the basic heart chambers roughly 8 days following patients with CHF, providing a measure of ejection later. At about the same time, (1) neural crest–derived cells fraction, wall motion, valvular function, and possible mural migrate into the outflow tract, where they participate in the thrombosis. septation of the aortic and pulmonic outflow tracts and the Treatment for CHF is initially focused on correcting any formation of the aortic arch; and (2) interstitial connective underlying cause, for example, a valvular defect or inad- tissue expands to become definitive endocardial cushions equate cardiac perfusion. Beyond that, the clinical approach that will become the future atrioventricular canals and includes salt restriction or pharmacologic agents that vari- outflow tracts. By day 50, further septation of the ventricles, ously reduce volume overload (e.g., diuretics), increase atria, and atrioventricular valves produces a four-chambered myocardial contractility (so-called positive inotropes), or heart. reduce afterload (via adrenergic blockade or inhibitors of Proper orchestration of these remarkable transformations angiotensin-converting enzymes [ACE]). Although many depends on a network of transcription factors that are of these medications provide benefit through effects on regulated by a number of signaling pathways, particularly neurohumoral pathways, ACE inhibitors also limit myocyte the Wnt, hedgehog, vascular endothelial growth factor hypertrophy and cardiac remodeling. Although cardiac (VEGF), bone morphogenetic protein, transforming growth resynchronization therapy (exogenous pacing of both the factor-β (TGF-β), fibroblast growth factor, and Notch right and left ventricles) and mechanical ventricular assist pathways (Chapter 1). It is not too surprising then that devices (VADs, discussed later) have also been added to many of the inherited defects that affect heart development the cardiologist’s armamentarium, CHF remains a serious involve genes that encode transcription factors; these typically cause of human morbidity and mortality. cause partial loss of function and are autosomal dominant (discussed later). In addition, specific micro-RNAs play critical roles in cardiac development by coordinating patterns KEY CONCEP TS and levels of transcription factor expression. HEART FAILURE Heart failure occurs when the heart is unable to provide adequate perfusion to meet the metabolic requirements of CONGENITAL HEART DISEASE peripheral tissues; inadequate cardiac output is usually accom- CHD refers to abnormalities of the heart or great vessels panied by increased congestion of the venous circulation. that are present at birth. Most CHD arises from faulty Left-sided heart failure is most commonly due to IHD, systemic embryogenesis during gestational weeks 3 to 8, when major hypertension, mitral or aortic valve disease, and primary diseases cardiovascular structures form and begin to function. The of the myocardium; symptoms are mainly a consequence of pul- most severe anomalies preclude intrauterine survival, and monary congestion and edema, although systemic hypoperfusion significant heart malformations are common among stillborn can cause secondary renal and cerebral dysfunction. infants. On the other hand, circumscribed defects affecting Right-sided heart failure is most often due to left heart failure, discrete regions of the heart or individual chambers can be and less commonly to primary pulmonary disorders; symptoms compatible with live birth. In this latter category are the are chiefly related to peripheral edema and visceral congestion. following: Septal defects, or “holes in the heart,” including atrial septal defects (ASDs) or ventricular septal defects (VSDs) CARDIAC DEVELOPMENT Stenotic lesions, either at the level of valves, or the entire cardiac chamber as in hypoplastic left heart syndrome The heart is a mechanical organ that generates pulsatile Outflow tract anomalies including inappropriate routing blood within just 3 weeks after fertilization. It is therefore of the great vessels from the ventricles, or anomalous likely that hemodynamic forces play an important role in coronary arteries cardiac development, just as they influence adaptations in the adult heart such as hypertrophy and dilation. Such “tolerated” forms of CHD usually produce clinically The diverse malformations seen in congenital heart disease important manifestations only after birth—uncovered by (CHD) are caused by errors that occur during the complex the transition from fetal to perinatal circulation; roughly migration and folding that constitutes cardiac morphogenesis. one-half will be diagnosed in the first year of life, although Derived from cells in the lateral mesoderm, the earliest some milder forms may not be discovered until adulthood cardiac precursors move to the midline in two migratory (e.g., ASD). waves (called the first and second heart fields) within the first 15 days of fetal development. Although these are Incidence multipotent progenitor cells that can produce all of the major The incidence of CHD depends on what is counted as a cell types of the heart (endocardium, myocardium, and defect. Thus, if echocardiography is performed routinely smooth muscle cells), they rapidly assume distinct fates; on neonates, small muscular VSDs or ASDs are detected in cells in the first wave largely populate the developing left over 5% of live births. However, these typically close  Congenital heart disease 535 Table 12.2 Frequencies of Congenital Cardiac syndrome). Indeed, the most common known genetic cause Malformationsa of CHD is trisomy 21 (Down syndrome); roughly 40% of Incidence per patients with Down syndrome have one or more heart Malformation Million Live Births % defects, most often affecting structures derived from the Ventricular septal defect 4482 42 second migratory wave of cells (e.g., the atrioventricular Atrial septal defect 1043 10 septae). The mechanisms by which aneuploidy causes CHD likely involve the dysregulated expression of multiple genes. Pulmonary stenosis 836 8 A notable example of a small chromosomal lesion causing Patent ductus arteriosus 781 7 CHD is deletion of chromosome 22q11.2, occurring in patients Tetralogy of Fallot 577 5 with DiGeorge syndrome. In this syndrome, the fourth Coarctation of the aorta 492 5 branchial arch and the derivatives of the third and fourth pharyngeal pouches (which contribute to the formation of Atrioventricular septal defect 396 4 the thymus, parathyroid glands, and heart) develop abnor- Aortic stenosis 388 4 mally. Of the 30 or so genes present on this chromosome Transposition of the great arteries 388 4 segment, deletion of the TBX1 transcription factor gene is Truncus arteriosus 136 1 probably the culprit lesion. TBX1 regulates neural crest Total anomalous pulmonary 120 1 migration, as well as the expansion of cardiac progenitors venous connection in the second migratory wave. Interestingly, deletions in Tricuspid atresia 118 1 this region are also associated with mental illness, including schizophrenia. Total 9757 In the case of single-gene mutations, the affected genes a Presented as upper quartile of 44 published studies. Percentages do not add up encode proteins belonging to several different functional to 100% because of rounding. Does not include bicuspid aortic valves. classes (Table 12.3); as mentioned earlier, many of these Data from: Hoffman JI, Kaplan S: The incidence of congenital heart disease, J Am Coll Cardiol 39(12):1890–1900, 2002. involve transcription factors. Because affected patients are heterozygous for such mutations, it follows that a 50% reduction in the activity of these factors (or even less) may spontaneously in the first year of life, and they probably should not be tallied with the burden of CHD. Similarly, Table 12.3 Selected Examples of Gene Defects Associated bicuspid aortic valve—with an incidence of 1% to 2%—clearly With Congenital Heart Diseasea persists beyond infancy, but often has modest manifestations Gene Product and may not become evident until late adulthood. If the Disorder Gene(s) Function accounting is restricted to more serious defects, the world- Nonsyndromic wide incidence of congenital cardiovascular malformations ASD or conduction defects NKX2.5 Transcription factor is slightly less than 1%—still ranking CHD among the most ASD or VSD GATA4 Transcription factor prevalent birth defects. Twelve disorders account for about 85% of cases; their frequencies are listed in Table 12.2. Tetralogy of Fallot ZFPM2 or Transcription factors The number of individuals who survive into adulthood NKX2.5 with CHD is increasing rapidly and is estimated at nearly Syndromicb 1.5 million people in the United States alone. Many have Alagille syndrome— JAG1 or Signaling proteins or benefited from surgical advances that increasingly permit pulmonary artery stenosis NOTCH2 receptors early postnatal repair of structural defects. In some cases, or tetralogy of Fallot however, surgical intervention fails to restore complete Char syndrome—PDA TFAP2B Transcription factor normalcy; patients may have already sustained pulmonary CHARGE syndrome—ASD, CHD7 Helicase-binding or myocardial changes that are no longer reversible, or VSD, PDA, or hypoplastic protein conversely, may suffer from arrhythmias due to surgical right side of the heart scarring. Other factors that impact the long-term outcome DiGeorge syndrome—ASD, TBX1 Transcription factor include complications associated with the use of prosthetic VSD, or outflow tract materials and devices (e.g., substitute valves or myocardial obstruction patches), and the cardiovascular stressors associated with Holt-Oram syndrome—ASD, TBX5 Transcription factor childbearing that may tip a repaired heart into failure. VSD, or conduction defect Noonan syndrome— PTPN11, Signaling proteins Etiology and Pathogenesis pulmonary valve stenosis, KRAS, Environmental exposures (e.g., congenital rubella infection, VSD, or hypertrophic SOS1 teratogens—including some therapeutic drugs, and gesta- cardiomyopathy tional diabetes) and genetic factors are the best characterized ASD, Atrial septal defect; CHARGE, posterior coloboma, heart defect, choanal causes but still account for a minority of CHD cases. Nutri- atresia, retardation, genital and ear anomalies; PDA, patent ductus arteriosus; VSD, ventricular septal defect. tional factors can also influence risk; folate supplementation a Different mutations can cause the same phenotype, and mutations in some during early pregnancy reduces CHD incidence. genes can cause multiple phenotypes (e.g., NKX2.5). Many of these congenital Genetic factors include specific loci implicated in familial lesions also can occur sporadically, without specific genetic mutation. forms of CHD and certain chromosomal abnormalities (e.g., b Only the cardiac manifestations of the syndrome are listed; the other skeletal, facial, neurologic, and visceral changes are not. trisomies 13, 15, 18, and 21, and monosomy X/Turner 536 C H A P T E R 12 The Heart be sufficient to derange cardiac development. Even relatively of the tips of the fingers and toes that can include bony minor decrements in activity of particular genes can result changes (called hypertrophic osteoarthropathy). The most in significant defects. Thus, transient environmental stresses important causes of right-to-left shunts are tetralogy of Fallot during the first trimester of pregnancy that alter the synthesis (TOF), transposition of the great arteries (TGA), persistent or activity of these same genes can conceivably lead to truncus arteriosus, tricuspid atresia, and total anomalous acquired defects that mimic those produced by heritable pulmonary venous connection. mutations. In addition, many of the transcription factors In contrast, left-to-right shunts (e.g., ASD, VSD, and patent interact in large protein complexes, providing a rationale ductus arteriosus [PDA]) increase pulmonary blood flow for why mutations in any one of several genes can produce but are not initially associated with cyanosis. However, similar defects. Thus, GATA4, TBX5, and NKX2-5, three left-to-right shunts chronically elevate both volume and transcription factors that are mutated in some patients with pressure in the normally low-pressure, low-resistance atrial and ventricular septal defects, all bind to one another pulmonary circulation. To maintain relatively normal distal and co-regulate the expression of target genes required for pulmonary capillary and venous pressures, the muscular proper cardiac development. pulmonary arteries (20 min), or severe angina, thrombus that partially or completely occludes the artery. precipitated by progressively lower levels of physical It remains to be seen whether aggressive anti-inflammatory activity or even occurring at rest. Unstable angina is regimens are a means to reduce such acute coronary events. associated with plaque disruption and superimposed thrombosis, distal embolization of the thrombus, and/ Consequences of Myocardial Ischemia or vasospasm; it is an important harbinger of MI, poten- Stable angina results from increases in myocardial oxygen tially portending complete vascular occlusion. demand that outstrip the ability of coronary arteries with fixed stenoses to increase oxygen delivery; it is usually Myocardial Infarction not associated with plaque disruption. Unstable angina is caused by acute plaque change that MI, also commonly referred to as “heart attack,” is the death results in thrombosis and/or vasoconstriction, and leads of cardiac muscle due to prolonged ischemia. Roughly 1.5 to incomplete or transient reductions in coronary blood million individuals in the United States suffer an MI each flow. In some cases, microinfarcts can occur distal to year, causing approximately 610,000 deaths annually. The disrupted plaques due to thromboemboli. major underlying cause of IHD is atherosclerosis; although MI is often the result of acute plaque change that induces MIs can occur at virtually any age, 10% of MIs occur in an abrupt thrombotic occlusion, resulting in myocardial people younger than 40 years of age, and 45% occur in people necrosis. younger than 65 years of age. Nevertheless, the frequency Sudden cardiac death may be caused by regional myocardial rises progressively with increasing age and with increasing ischemia that induces a fatal ventricular arrhythmia. This atherosclerotic risk factors (Chapter 11). Through middle can result from a fixed stenosis or acute plaque change. age, male gender increases the relative risk of MI; indeed, women are generally protected against MI during their Each of these important syndromes is discussed in detail reproductive years. However, postmenopausal decline in next, followed by an examination of the important myocardial estrogen production is usually associated with accelerated consequences. CAD, and IHD is the most common cause of death in older 544 C H A P T E R 12 The Heart women. Unfortunately, postmenopausal hormonal replace- other mechanisms may be responsible for the reduced ment therapy has not been shown to be protective, and in coronary blood flow: fact, in some cases, may be detrimental. Vasospasm with or without coronary atherosclerosis, perhaps in association with platelet aggregation or due Pathogenesis to drug ingestion (e.g., cocaine or ephedrine). Coronary Arterial Occlusion. The following sequence of Emboli from the left atrium in association with atrial events likely underlies most MIs (see Chapter 11 for addi- fibrillation, a left-sided mural thrombus, vegetations of tional details): infective endocarditis (IE), intracardiac prosthetic material, An atheromatous plaque is eroded or suddenly disrupted or paradoxical emboli from the right side of the heart or by endothelial injury, intraplaque hemorrhage, or the peripheral veins traversing a patent foramen ovale mechanical forces, exposing subendothelial collagen and and into the coronary arteries necrotic plaque contents to the blood. Uncommon causes of MI without atherothrombosis include Platelets adhere, aggregate, and are activated, releasing disorders of small intramural coronary vessels (e.g., thromboxane A2, adenosine diphosphate (ADP), and vasculitis), hematologic abnormalities (e.g., sickle cell serotonin—causing further platelet aggregation and disease), amyloid deposition in vascular walls, vascular vasospasm (Chapter 4). dissection, marked hypertrophy (e.g., due to aortic stenosis), Activation of coagulation by tissue factor and other lowered systemic blood pressure (e.g., shock), or inadequate mechanisms adds to the growing thrombus. myocardial “protection” during cardiac surgery. Within minutes, the thrombus can evolve to completely occlude the coronary artery lumen. Myocardial Response. Coronary arterial obstruction diminishes blood flow to a region of myocardium, causing The evidence for this scenario derives from autopsy studies ischemia, rapid myocardial dysfunction, and eventually— of patients dying of acute MI, as well as imaging studies with prolonged vascular compromise—myocyte death. The demonstrating a high frequency of thrombotic occlusion anatomic region supplied by that artery is referred to as early after MI; interestingly, comparison to prior angiograms the area at risk. The outcome depends predominantly on shows that these thrombi are usually at a site that did not the severity and duration of flow deprivation (Fig. 12.9). previously have a critical (>70%) fixed stenosis. Typically, The early biochemical consequence of myocardial ischemia when angiography is performed within 4 hours of the onset is the cessation of aerobic metabolism within seconds, leading of MI, it demonstrates coronary thrombosis in almost 90% to inadequate production of high-energy phosphates (e.g., of cases. However, when angiography is performed 12 to creatine phosphate and adenosine triphosphate) and accu- 24 hours after onset of symptoms, evidence of thrombosis mulation of potentially noxious metabolites (e.g., lactic acid) is seen in only 60% of patients, even without intervention. (see Fig. 12.9A). Because of the exquisite dependence of Thus, at least some occlusions clear spontaneously through myocardial function on oxygen and nutrients, myocardial lysis of the thrombus or relaxation of spasm. This sequence of contractility ceases within a minute or so of the onset of events in a typical MI also has therapeutic implications: early severe ischemia. Such loss of function contributes to thrombolysis and/or angioplasty can be highly successful decreased systolic function long before myocyte death occurs. in limiting the extent of myocardial necrosis. As detailed in Chapter 2, ultrastructural changes (includ- In approximately 10% of cases, MI occurs in the absence ing myofibrillar relaxation, glycogen depletion, cell and of the typical coronary atherothrombosis. In such situations, mitochondrial swelling) also develop within a few minutes 100 6 Onset of irreversible injury ATP and Lactate (arbitrary units) Ischemic myocardium Fraction of at-risk myocardium 80 potentially salvageable 5 by timely intervention te Irreversible phase Reversible phase cta 4 La 60 3 40 2 20 1 ATP Cumulative dead myocardium 0 0 5 10 15 20 30 40 50 0 1 2 3 4 5 6 12 18 A Minutes B Time Hours Figure 12.9 Temporal sequence of early biochemical findings and progression of cardiomyocyte necrosis after onset of severe myocardial ischemia. (A) Early changes include loss of adenosine triphosphate (ATP) and accumulation of lactate. (B) For approximately 30 minutes after the onset of even the most severe ischemia, myocardial injury is potentially reversible. Thereafter, progressive loss of viability occurs that becomes complete by 6 to 12 hours. The benefits of reperfusion are greatest when it is achieved early and are progressively lost when reperfusion is delayed. (Originally modified with permission from Antman E: Acute myocardial infarction. In Braunwald E, et al., editors: Heart Disease: a Textbook of Cardiovascular Medicine, ed 6, Philadelphia, 2001, WB Saunders, pp 1114–1231.)  Ischemic heart disease 545 of the onset of ischemia. Nevertheless, these early manifesta- Table 12.4 Approximate Time of Onset of Key Events in tions of ischemic injury are potentially reversible. Indeed, Ischemic Cardiac Myocytes experimental and clinical evidence shows that only severe Feature Time ischemia (blood flow 10% or less of normal) lasting 20 to Onset of ATP depletion Seconds 30 minutes or longer leads to irreversible damage (necrosis) Loss of contractility 1 hour disruption of the integrity of the sarcolemmal membrane, ATP, Adenosine triphosphate. allowing intracellular macromolecules to leak out of necrotic cells into the cardiac interstitium and ultimately into the microvasculature and lymphatics. This escape of intracellular myocardial proteins into the circulation forms the basis for The progression of ischemic necrosis in the myocardium blood tests that can sensitively detect irreversible myocyte is summarized in Fig. 12.10. Irreversible injury of ischemic damage, and are important for managing MI (see later). myocytes first occurs in the subendocardial zone. This region With prolonged severe ischemia, injury to the microvascu- is especially susceptible to ischemia because it is the last lature follows injury to the cardiac myocytes. The temporal area to receive blood delivered by the epicardial vessels, progression of these events is summarized in Table 12.4. and also because it is exposed to relatively high intramural Aorta Pulmonary artery Left circumflex coronary artery Right coronary Left anterior descending artery coronary artery Acute coronary arterial occlusion Zone of perfusion (area at risk) Completed infarct Cross-section involving nearly the of myocardium entire area at risk Obstructed coronary artery Endocardium Zone of Zone of Zone of perfusion necrosis necrosis (area at risk) 0 hr 2 hr 24 hr Figure 12.10 Progression of myocardial necrosis after coronary artery occlusion. Necrosis begins in a small zone of the myocardium beneath the endocardial surface in the center of the ischemic zone. The area that depends on the occluded vessel for perfusion is the “at risk” myocardium (shaded). Note that a very narrow zone of myocardium immediately beneath the endocardium is spared from necrosis because oxygen and nutrition can be provided by diffusion from the ventricle. 546 C H A P T E R 12 The Heart pressures, which act to impede the inflow of blood. With supplies most of the apex of the heart, the anterior wall of more prolonged ischemia, a wavefront of cell death moves the left ventricle, and the anterior two-thirds of the ven- through other regions of the myocardium, driven by progres- tricular septum. By convention, the coronary artery—either sive tissue edema and myocardial-derived reactive oxygen RCA or LCX—that perfuses the posterior third of the septum species and inflammatory mediators. is called “dominant” (even though the LAD and LCX col- The location, size, and specific morphologic features of lectively perfuse the majority of the left ventricular myo- an acute MI depend on the following: cardium). In a right dominant circulation (present in The location, severity, and rate of development of coronary approximately 80% of individuals), the RCA supplies the obstructions due to atherosclerosis and thromboses entire right ventricular free wall, the posterobasal wall of The size of the vascular bed perfused by the obstructed the left ventricle, and the posterior third of the ventricular vessels septum, and the LCX generally perfuses only the lateral The duration of the occlusion wall of the left ventricle. Thus, RCA occlusions can potentially The metabolic and oxygen needs of the myocardium at risk lead to left ventricular damage. The extent of vascular collateralization Although most hearts have numerous intercoronary The presence, site, and severity of coronary arterial spasm anastomoses (collateral circulation), relatively little blood Other factors, such as heart rate, cardiac rhythm, and blood normally courses through these. However, when a coronary oxygenation artery is progressively narrowed over time, blood flows via the collaterals from the high- to the low-pressure circulation An infarct usually achieves its full extent within 3 to 6 causing the channels to enlarge. Through such progressive hours; in the absence of intervention, an infarct caused by dilation and growth of collaterals, stimulated by ischemia, occlusion of an epicardial vessel can involve the entire wall blood flow is provided to areas of myocardium that would thickness (transmural infarct). Clinical intervention within otherwise be deprived of adequate perfusion. Indeed, this critical window of time can lessen the size of the infarct in the setting of extensive collateralization, the normal within the territory at risk. epicardial perfusion territories may be so expanded that subsequent occlusion leads to infarction in paradoxical Patterns of Infarction. The distribution of myocardial distributions. necrosis correlates with the location and cause of the Transmural infarctions occur when there is occlusion decreased perfusion (Fig. 12.11). of an epicardial vessel (in the absence of any therapeutic Knowledge of the areas of myocardium perfused by intervention)—the necrosis involves virtually the full thick- the major coronary arteries allows correlation of specific ness of the ventricular wall in the distribution of the affected vascular obstructions with their corresponding areas of coronary. This pattern of infarction is usually associated MI. Typically, the LAD branch of the left coronary artery with a combination of chronic coronary atherosclerosis, acute TRANSMURAL INFARCTS NON-TRANSMURAL INFARCTS Restoration of flow (reperfusion) Permanent Transient/partial occlusion of left anterior obstruction descending regional branch subendocardial infarct Posterior Permanent Global occlusion of hypotension left circumflex RV LV circumferential branch subendocardial infarct Anterior Permanent occlusion of Small right coronary intramural artery (or its vessel posterior occlusions descending microinfarcts branch) Figure 12.11 Distribution of myocardial ischemic necrosis correlates with the location and nature of decreased perfusion. Left, the positions of transmural acute infarcts resulting from occlusions of the major coronary arteries; top to bottom, left anterior descending, left circumflex, and right coronary arteries. Right, the types of infarcts that result from a partial or transient occlusion, global hypotension, or intramural small vessel occlusions.  Ischemic heart disease 547 plaque change, and superimposed thrombosis (discussed coronary artery save for a narrow rim (approximately 0.1 mm) earlier). of viable subendocardial myocardium that is preserved by diffusion Subendocardial (nontransmural) infarctions can occur of oxygen and nutrients from the ventricular lumen. as a result of a plaque disruption followed by a coronary The frequencies of involvement of each of the three main thrombus that becomes lysed (therapeutically or spontane- arterial trunks and the corresponding sites of myocardial lesions ously) before myocardial necrosis extends across the full resulting in infarction (in the typical right dominant heart) are as thickness of the wall. Subendocardial infarcts can also result follows (left side of Fig. 12.11): from prolonged, severe reduction in systemic blood pressure, Left anterior descending coronary artery (40% to 50%): as in shock superimposed on chronic, otherwise noncritical, infarcts involving the anterior wall of left ventricle near the coronary stenoses. In the subendocardial infarcts that occur apex; the anterior portion of ventricular septum; and the apex as a r