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Exclusive preview pocket companions to robbins & cotran pathlogic basis of disease 8e by mitchell

Exclusive preview pocket companions to robbins & cotran pathlogic basis of disease 8e by mitchell



Pocket Companions To Robbins & Cotran Pathlogic Basis of Disease 8e by Mitchell. To order call us at +91 8527622422

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    Exclusive preview pocket companions to robbins & cotran pathlogic basis of disease 8e by mitchell Exclusive preview pocket companions to robbins & cotran pathlogic basis of disease 8e by mitchell Document Transcript

    • 12The HeartEffects of Aging on the Heart (p. 531)• Reduced ventricular cavity size (base-to-apex) leading to bulging of the basal ventricular septum and partial functional outflow obstruction (sigmoid septum)• Valve sclerosis and calcification leading to stenosis (aortic valve)• Valve degenerative changes leading to insufficiency (mitral valve)• Reduced myocyte number and increased interstitial fibrosis causing reduced contractility and complianceHeart Disease: Overviewof Pathophysiology (p. 532)Heart disease is the leading cause of morbidity and death world-wide; it accounts for 40% of deaths in the United States. Cardiacdisease occurs as a consequence of one (or more) of the followinggeneral mechanisms:• Failure of the pump, due to either poor contractile function or inability to relax to allow filling• Blood flow obstruction (e.g., due to atherosclerosis, thrombosis, hypertension, or valvular stenosis)• Regurgitant flow (e.g., due to valvular insufficiency); output from each contraction is directed backward, causing volume overload and diminished forward flow• Shunts that allow abnormal blood flow either right-to-left (bypassing the lungs) or left-to-right (causing volume overload)• Abnormal cardiac conduction leading to uncoordinated myocardial contractions• Rupture of the heart or major vesselsHeart Failure (p. 533)Congestive heart failure (CHF) is the common end point of manyforms of heart disease and affects 2% of the United States popula-tion; it is the cause of death in roughly 300,000 patients annually.CHF occurs when impaired function renders the heart unable tomaintain output sufficient for the metabolic requirements of thebody or when it can only do so at elevated filling pressures. CHFis characterized by diminished cardiac output (forward failure),accumulation of blood in the venous system (backward failure),or both. When cardiac function is impaired or the workload increases,compensatory mechanisms attempt to maintain arterial pressureand organ perfusion:282
    • The Heart 283• Frank-Starling mechanism: Increased filling pressures dilate the heart, thereby increasing functional cross-bridge formation within sarcomeres and enhancing contractility• Myocardial hypertrophy with increased expression of contractile apparatus proteins• Activation of neurohumoral systems Autonomic nervous system adrenergic stimulation, which increases heart rate, contractility, and vascular reistance Modulating blood volume and pressures by activation of renin- angiotensin-aldosterone system and release of atrial natri- uretic peptide While initially adaptive, these compensatory changes impose fur-ther demands on cardiac function. Moreover, when superimposedon further pathologic insults (e.g., myocyte apoptosis, cytoskeletalchanges, and increased extracellular matrix), CHF may supervene.• Most frequently heart failure occurs due to progressive deterio- ration of myocardial contractile function (systolic dysfunction); causes include ischemia, pressure or volume overload due to val- vular disease, or primary myocardial failure.• Occasionally, CHF results from the inability of the heart cham- ber to relax and fill during diastole (diastolic dysfunction); causes include hypertrophy (most common), fibrosis, amyloid deposition, or constrictive pericarditis. Diastolic failure occurs predominantly in patients over the age of 65, and more often in women than men.• With the exception of frank myocyte death, the mechanisms of myocardial decompensation in CHF are not well understood.Cardiac Hypertrophy: Pathophysiology andProgression to Failure (p. 533)• Because adult myocytes cannot classically proliferate, the heart responds to pressure or volume overload by increasing myocyte size (myocyte hypertrophy); similar hypertrophy is stimulated by chronic trophic signals (i.e., driven by b-adrenergic receptor acti- vation). The result is an enlarged heart. Notably, similar compen- satory changes can occur in residual viable myocardium after myocardial infarction irreversibly damages part of the heart.• Although the mechanism(s) that translate exogenous stressors into cellular changes is uncertain, individual myocytes exhibit increased DNA ploidy, increased numbers of mitochondria, and increased numbers of sarcomeres. The genetic expression pattern also shifts to a more embryonic phenotype, including fetal isoforms of b-myosin heavy chain, natriuretic peptides, and collagen.• While hypertrophy is initially adaptive, it can make myocytes vulnerable to injury. The capillary density does not increase in proportion to the cell size increase or metabolic demands. Hypertrophy is also accompanied by interstitial matrix deposi- tion that can diminish cardiac compliance.• Heart failure may eventually result from a combination of aber- rant myocyte metabolism, alterations in intracellular calcium flux, apoptosis, and genetic reprogramming. Increased heart mass is also an independent risk factor for sudden (presumably arrhythmic) cardiac death.• Physiologic hypertrophy (with aerobic exercise) is a volume-load hypertrophy that tends also to induce beneficial effects including increased capillary density, decreased resting heart rate, and decreased blood pressure.
    • 284 Systemic PathologyLeft-Sided Heart Failure (p. 535)Major causes include ischemic heart disease, hypertension, aorticand mitral valve disease, and intrinsic myocardial disease. Left-sided failure is manifested by:• Pulmonary congestion and edema due to regurgitant flow or impaired pulmonary outflow• Left atrial dilation with atrial fibrillation• Reduced renal perfusion: Salt and water retention Ischemic acute tubular necrosis (ATN) Impaired waste excretion, causing prerenal azotemia• Hypoxic encephalopathy due to reduced central nervous system perfusionRight-Sided Heart Failure (p. 536)Right-sided heart failure is most commonly caused by left-sided fail-ure; thus, in most cases, patients present with biventricular CHF.Isolated right-sided heart failure is caused by tricuspid or pulmonicvalvular disease or by intrinsic pulmonary or pulmonary vasculardisease causing functional right ventricular outflow obstruction(e.g., cor pulmonale). Right-sided failure is manifested by:• Right atrial and ventricular dilation and hypertrophy• Edema, typically in dependent peripheral locations (e.g., feet, ankles, sacrum) with serous effusions in pericardial, pleural, or peritoneal spaces• Hepatomegaly with centrilobular congestion and atrophy, pro- ducing a nutmeg appearance (chronic passive congestion). With severe hypoxia, there is centrilobular necrosis, and elevated right-sided pressures cause central hemorrhage. Subsequent cen- tral fibrosis creates “cardiac cirrhosis.”• Congestive splenomegaly with sinusoidal dilation, focal hemor- rhages, hemosiderin deposits, and fibrosis• Renal congestion, hypoxic injury, and ATN (more marked in right- versus left-sided CHF)Congenital Heart Disease (p. 537)Congenital heart disease (CHD) refers to cardiac or great vesselabnormalities present at birth; most are attributable to faultyembryogenesis during weeks 3 to 8 of gestation, when major car-diovascular structures develop. Severe anomalies are incompatiblewith intrauterine survival; thus, defects that permit developmentto birth generally involve only specific chambers or regions, withthe remainder of the heart being normal. Congenital disorders con-stitute the most common cardiac disease among children, with anincidence of 1% of live births; the incidence is higher in prematureinfants and stillborns. The most frequent disorders (constituting85% of cases) are listed in Table 12-1.Pathogenesis (p. 538)• The main known causes of CHD are sporadic genetic abnor- malities, either single-gene mutations or chromosomal deletions or additions. Single-gene mutations typically involve signaling pathways or transcription factors that regulate cardiac development; some of the transcription factors (e.g., GATA-4) are mutated in rare forms of adult-onset cardiomyopathy, suggesting an additional role in maintaining normal post-natal cardiac function.
    • The Heart 285 TABLE 12-1 Frequencies of Congenital Cardiac Malformations* Incidence per Million Malformation Live Births % Ventricular septal defect 4482 42 Atrial septal defect 1043 10 Pulmonary stenosis 836 8 Patent ductus arteriosus 781 7 Tetralogy of Fallot 577 5 Coarctation of aorta 492 5 Atrioventricular septal defect 396 4 Aortic stenosis 388 4 Transposition of great arteries 388 4 Truncus arteriosus 136 1 Total anomalous pulmonary 120 1 venous connection Tricuspid atresia 118 1 Total 9757*Presented as upper quartile of 44 published studies. Percentages do not add to 100%owing to rounding.From Hoffman JIE, Kaplan S: The incidence of congenital heart disease, J Am Coll Cardiol39:1890, 2002. Deletion of chromosome 22q11.2 in DiGeorge syndrome affects the development of the third and fourth pharyngeal pouches with thymic, parathyroid, and cardiac defects. The most common genetic cause of CHD is trisomy 21 (i.e., Down syn- drome); 40% of patients have one or more cardiac defects.• Beyond known associations, genetics likely also contribute to many lesions; first-degree relatives of affected patients are at increased risk of CHD relative to the general population.• Environmental (e.g., congenital rubella infection or teratogens) and maternal factors (e.g., gestational diabetes) also contribute to the incidence of CHD.Clinical Features (p. 539)Children with CHD have direct hemodynamic sequelae, as well asretarded development and failure to thrive. They are at increasedrisk for chronic illness and infective endocarditis due to abnormalvalves or endocardial injury from jet lesions.• CHD are either obstructions or shunts. Obstructions include abnormal narrowing of chambers, valves, or vessels; a complete obstruction is called an atresia. Shunts denote abnormal communications between heart chambers, between vessels, or between chambers and vessels. Depending on pressure relationships, blood is shunted from right to left, or from left to right (more common). • Right-to-left shunts bypass the lungs, leading to hypoxia and tissue cyanosis. Right-to-left shunts also allow venous emboli to enter the systemic circulation (paradoxical emboli). Secondary findings in long-standing cyanotic heart disease include finger and toe clubbing (also called hypertrophic osteoarthropathy) as well as polycythemia.
    • 286 Systemic Pathology • Left-to-right shunts cause pulmonary volume overload. If the shunt is prolonged, the vasculature responds with medial hypertrophy and increased vascular resistance to maintain nor- mal pulmonary capillary and venous pressures. As pulmonary resistance approaches systemic levels, a right-to-left shunt occurs (Eisenmenger syndrome). Once there is significant pul- monary hypertension, the underlying structural defects are no longer candidates for surgical correction. Altered hemodynamics usually cause chamber dilation and/or hypertrophy; however, defects occasionally lead to diminished chamber volume and muscle mass. This is called hypoplasia if it occurs during development or atrophy if it occurs postnatally.Left-to-Right Shunts (p. 540)The major congenital left-to-right shunts are (Fig. 12-1):• Atrial septal defect (ASD)• Ventricular septal defect (VSD)• Patent ductus arteriosus (PDA) Ao Ao PT PT LA LA RA RA LV LV RV RV A ASD B VSD Ao Ao PT PT LA LA RA RA LV RV RV LV C PDA D Large VSD with Irreversible Pulmonary HypertensionFIGURE 12-1 Schematic of the most important congenital left-to-right shunts.Arrows indicate the direction of blood flow. A, Atrial septal defect (ASD).B, Ventricular septal defect (VSD). In VSD, the shunt is left to right withequilibration of pressures in both ventricles. Pressure hypertrophy of the rightventricle, and volume hypertrophy of the left ventricle are usually present.C, Patent ductus arteriosus (PDA). D, Large VSD with irreversible pulmonaryhypertension. Long-standing pressure overload in the pulmonary circulation hasled to increased resistance, and eventually sufficient right ventricularhypertrophy to generate pressures in excess of the left ventricle; at this point,flow reversal occurs with a right-to-left shunt. Ao, Aorta; LA, left atrium; LV, leftventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle.
    • The Heart 287Atrial Septal Defect (p. 541) (see Fig. 12-1, A)Atrial spetal defects are the most common congenital cardiacanomalies seen in adults. Even large ASDs are usually asymptomaticuntil adulthood, when either right-sided heart failure can occur orright-sided hypertrophy and pulmonary hypertension can induceright-to-left shunting with cyanosis.• Primum type: 5% of ASD; these occur adjacent to mitral and tri- cuspid valves.• Secundum type: 90% of ASD; results from deficient or fenes- trated fossa ovalis in the central atrial septum, and is usually not associated with other anomalies.• Sinus venosus type: 5% of ASD; occurs near the superior vena cava entrance and can be associated with anomalous right pul- monary vein drainage.Patent Foramen Ovale (p. 541)Patent foramen ovale is a small hole resulting from defective post-natal closure of the fossa ovalis flap; these occur in 20% ofindividuals and can be a conduit for paradoxical emboli in thesetting of elevated right-sided pressures.Ventricular Septal Defect (p. 541) (Fig. 12-1, B)Ventricular septal defects are the most common congenital cardiacanomaly overall. Depending on VSD size, the clinical outcome rangesfrom fulminant CHF to late cyanosis to spontaneous closure (50% ofthose that are less than 0.5 cm diameter). Surgical correction is desir-able before right-sided overload and pulmonary hypertension develop.• VSD are frequently associated with other anomalies, particularly tetralogy of Fallot (TOF), but 20% to 30% are isolated.• 90% involve the membranous septum (membranous VSD) near the aortic valve, while the remainder are muscular.Patent Ductus Arteriosus (p. 541) (Fig. 12-1, C)The ductus arteriosus (just distal to the left subclavian artery)allows blood flow between the aorta and pulmonary artery duringfetal development, thus bypassing the lungs. The ductus normallycloses within 1 to 2 days of life; depending on its caliber, persistentpatency can cause left-to-right shunting that eventually inducesEisenmenger physiology.• 90% of PDAs are isolated defects; the remainder are associated with VSD, aortic coarctation, or valvular stenosis.• Most are initially asymptomatic but produce a harsh continuous machinery-like heart murmur. Large PDAs cause right-sided volume and pressure overload.• Early closure—surgically or with prostaglandin synthesis inhibitors—is advocated, unless other concurrent CHD (e.g., aortic valve atresia) is present; in the later case, the PDA may be the only means to provide systemic perfusion.Right-to-Left Shunts (p. 542) (Fig. 12-2)The major congenital right-to-left shunts (Fig. 12-2) are:• Tetralogy of Fallot• Transposition of the great arteries (TGA)Tetralogy of Fallot (p. 542) (Fig. 12-2, A)The cardinal findings are:• VSD• Pulmonary stenosis with right ventricle outflow obstruction
    • 288 Systemic Pathology Ao PT LA RA RV LV A Classic Tetralogy of Fallot Ao Ao PT PT LA LA RA RA LV LV RV RV With VSD Without VSD B Complete TranspositionFIGURE 12-2 Schematic of the most important congenital right-to-left (cyanotic)shunts. A, Tetralogy of Fallot (TOF). The degree of shunting across the VSDdepends on the degree of subpulmonic stenosis; if the pulmonary stenosis issevere, a right-to-left shunt occurs (arrow). B, Transposition of the great arterieswith and without VSD. Ao, Aorta; LA, left atrium; LV, left ventricle; PT,pulmonary trunk; RA, right atrium; RV, right ventricle.• Overriding aorta• Right ventricular hypertrophy Symptom severity is directly related to the extent of right ventri-cle outflow obstruction. With a large VSD and mild pulmonarystenosis, there is minimal left-to-right shunt and no cyanosis.More severe pulmonary stenosis produces a cyanotic right-to-leftshunt. With complete pulmonary obstruction, survival can occur onlyby flow through a PDA or dilated bronchial arteries. Surgical cor-rection can be delayed provided that the child can tolerate the levelof oxygenation. Pulmonary outflow stenosis protects the lung fromvolume and pressure overload, and right ventricular failure is rare.Transposition of the GreatArteries (p. 543) (Fig. 12-2, B)Systemic and pulmonary venous return—to the right and left atria,respectively—are normal; however, the aorta arises from the rightventricle and the pulmonary artery from the left, so that the pul-monary and systemic circulations are functionally separated.• Normal fetal development occurs because venous and systemic blood mixes through the ductus arteriosus and a patent foramen ovale.• Postnatal life critically depends on ongoing blood mixing (e.g., a PDA, VSD, ASD, or patent foramen ovale).
    • The Heart 289• Prognosis depends on the severity of tissue hypoxia and the abil- ity of the right ventricle to maintain systemic aortic pressures. Untreated, most infants die within months.Obstructive Congenital Anomalies (p. 544)Although these will cause ventricular hypertrophy, none cause cya-nosis unless there is an additional shunt present.Coarctation of the Aorta (p. 544)Coarctation of the aorta is a constriction of the aorta; 50% occuras isolated defects; the remainder occur with other anomalies, mostcommonly a bicuspid aortic valve. Males are affected twice as oftenas females, although coarctations are common in Turner syndrome.Besides left ventricular hypertrophy, additional clinical manifesta-tions depend on the location and severity of the constriction andon ductus arteriosus patency.• Preductal coarctation manifests early in life (“infantile form”) and can be rapidly fatal. Survival depends on the ability of a PDA to provide adequate systemic blood flow.• Postductal coarctation (“adult form”) can be asymptomatic unless severe; effects are also dependent on ductus arteriosus patency: An associated PDA leads to right-to-left shunting with lower body cyanosis; survival requires surgical intervention. A closed ductus may be aymptomatic but can lead to upper extremity hypertension and lower extremity hypotension with arterial insufficiency (claudication, cold sensitivity). Flow around the coarctation generally develops via internal mam- mary and axillary artery collaterals; such vascular dilation causes intercostal rib notching notable on x-ray films. Surgical resection and end-to-end anastomoses or conduit inser- tion yields an excellent outcome.Pulmonary Stenosis and Atresia (p. 544)Pulmonary stenosis and atresia can be isolated or occur with otheranomalies (e.g., transposition or TOF).• Valvar stenoses are associated with right ventricular hypertrophy and post-stenotic pulmonary artery dilation.• In subvalvar stenoses, the right ventricular pressures are not transmitted to the pulmonary circulation; the pulmonary trunk is not dilated, and it may be hypoplastic.• In complete pulmonary atresia, blood flow to the lungs occurs via an ASD and PDA, and the right ventricle is hypoplastic.Aortic Stenosis and Atresia (p. 544)• Valvar aortic stenosis can be caused by a small hypoplastic valve, thickened dysplastic cusps, or abnormal numbers of cusps (i.e., bicuspid or unicuspid)• Infants with severe aortic stenosis or atresia can only survive via PDA flow to the aorta and coronaries; there is left ventricular under-development (i.e., hypoplastic left heart syndrome).• Subaortic stenosis due to a discrete ring or diffuse collar of endo- cardial fibrosis is associated with infective endocarditis, left ventricle hypertrophy, post-stenotic aortic dilation, and sudden death.• Supravalvar stenosis is a heritable form of aortic dysplasia with a thickened wall; it may be due to elastin gene mutations, or it may be part of a multi-organ developmental disorder due to partial chromosome 7 deletion (Williams-Beuren syndrome).
    • 290 Systemic PathologyIschemic Heart Disease (p. 545)Ischemic heart disease (IHD) comprises multiple pathophysiologicallyrelated syndromes related to myocardial ischemia, that is, mismatchbetween cardiac demand and vascular supply of oxygenated blood.The consequences are oxygen insufficiency (hypoxia, anoxia), inade-quate nutrient supply, and diminished metabolite removal. In theUnited States, IHD is annually responsible for 500,000 deaths. Ischemia results from three possible causes:• Reduced coronary blood flow is commonly due to coronary athero- sclerosis (more than 90% of cases), vasospasm, and/or thrombo- sis. Atherosclerosis causes chronic progressive narrowing of the coronary lumens, a process that can be punctuated by acute plaque disruption and thrombosis (Chapter 11). Uncommon causes of compromised flow include arteritis, emboli, and hypo- tension (e.g., shock).• Increased myocardial demand (e.g., tachycardia, hypertrophy).• Hypoxia due to diminished oxygen transport (nutrient supply and metabolite removal are not affected); causes include anemia, lung disease, cyanotic CHD, carbon monoxide (CO) poisoning, or cigarette smoking. There are four overlapping ischemic syndromes, differing inseverity and tempo:• Angina pectoris• Myocardial infarction• Chronic IHD• Sudden cardiac deathAngina Pectoris (p. 546)This is paroxysmal substernal pain; ischemia duration and severityare not sufficient to cause infarction. Three patterns are recognizedbased on etiology:• Stable angina reliably occurs with the same level of exertion and diminishes with rest; this is typically associated with 70% or greater chronic stable stenosis (i.e., a fixed supply that becomes limiting with increased demand).• Prinzmetal angina is due to vasospasm; symptoms are unrelated to exertion and respond promptly to vasodilators.• Unstable (crescendo) angina is a pattern of pain occurring with successively lesser amounts of exertion or even at rest; it occurs when atherosclerotic plaque is disrupted—often with associated thrombosis or vasospasm. Myocardial death does not occur, because thrombi either fragment spontaneously or undergo fibrinolysis; alternatively, vasospasm can subside. Although the duration and extent of luminal obstruction in unstable angina is insufficient to cause cell death, it is a harbin- ger of myocardial infarction.Myocardial Infarction (p. 547)Myocardial infarction (MI) is myocyte cell death caused by vascu-lar occlusion. In the United States, 1.5 million MIs occur annuallywith risk increasing progressively with age; 10% occur inindividuals who are 40 years old or younger; 45% occur in peoplewho are 65 years of age or younger.Pathogenesis (p. 547)MIs are most commonly due to intraplaque hemorrhage, plaqueerosion, or plaque rupture with superimposed thrombosis. In 10%of cases, vascular occlusion is a consequence of vasospasm or
    • The Heart 291embolization in the coronary circulation or due to smaller vesselobstruction (e.g., vasculitis, amyloidosis, sickle cell disease, etc.).• Coronary occlusion causes myocardial ischemia, dysfunction, and, potentially, myocyte death; the outcome depends on the severity and duration of flow deprivation (Fig. 12-3). Reversible phase: Glycogen depletion; mito- Electron chondrial swelling, relaxation of myofibrils microscopy Irreversible phase: Sarcolemmal disruption; mitochondrial amorphous densities Histo- TTC staining defect chemistry 100 Onset of Ischemic myocardium irreversibleFraction of at-risk myocardium potentially salvageable injury ATP and Lactate 80 (arbitrary units) by timely intervention Reversible phase 60 te cta Irreversible La phase 40 ATP 20 0 5 10 15 20 3040 50 Cumulative Minutes dead myocardium 0 1 2 3 4 5 6 12 18 24 3 4 5 6 7 8 910 6 Time Hours Days Weeks with strong neutrophil Coagulation necrosis macrophage infiltrate Myocyte breakdown; Granulation tissue Early coagulation Light microscopy Wavy fibers necrosis infiltrate Scar edge; depressed center Soft with vascularized Hyperemic border; central softening Gross changes Scar PallorFIGURE 12-3 Temporal sequence of biochemical, ultrastructural, histochemical,and histologic findings after onset of severe myocardial ischemia. Forapproximately half an hour after onset of ischemia, myocardial injury is potentiallyreversible. Thereafter, progressive loss of viability occurs and is complete by 6 to12 hours. The benefits of reperfusion are greatest when it is achieved early withprogressively smaller benefit occurring as reperfusion is delayed. ATP, Adenosinetriphosphate; TTC, triphenyl tetrazolium chloride. (Data from Schoen FJ: Pathologicconsiderations of the surgery of adult heart disease. In Edmunds LH (ed): Cardiacsurgery in the adult, New York, 1997, McGraw-Hill, p. 85.)
    • 292 Systemic Pathology Severe ischemia leads to ATP depletion and loss of contractile function (but not cell death) within 60 seconds; this may pre- cipitate myocardial failure long before there is cell death. Complete deprivation of blood flow for 20 to 30 minutes leads to irreversible myocardial injury. Severe compromise of flow for prolonged periods (i.e., 2 to 4 hours) can also cause irreversible injury; this delay before cell death provides impetus for “late” therapeutic interventions to salvage myocardium during an MI. Necrosis is usually complete within 6 hours of severe ischemia; however, with extensive coronary collateral circulation, necro- sis can follow a more protracted course (i.e., more than 12 hours).• The distribution of myocardial necrosis depends on the vessel involved (e.g., left anterior descending versus right coronary artery) and collateral perfusion, as well as the location of the occlusion within the vessel and the cause of diminished perfusion. Most MIs occur within the distribution of a single coronary artery and are transmural (the full thickness of the ventricular wall); these are due to atherosclerosis and acute plaque change with thrombosis. These characteristically show electrocar- diographic ST elevations (“ST elevation MI”) Subendocardial MIs are limited to the inner 30% to 50% of the ventricle and may involve more territory than is perfused by a single coronary. These result in non-ST elevation MI. Causes include: • Lysis of a thrombotic occlusion before full-thickness infarction • Chronic atherosclerotic disease in the setting of increased myocardial demand (e.g., tachycardia) or systemically dimin- ished supply (e.g., hypotension, anemia, lung disease)• Reflow to (i.e., reperfusion of) precariously injured cells (e.g., by intervention with thrombolytics) may restore viability but leave the cells poorly contractile (stunned) for 1 to 2 days (p. 553). Reperfused myocardium is usually somewhat hemorrhagic due to ischemic vascular injury; irreversibly injured myocytes that are reperfused also show contraction band necrosis due to calcium overload and hyper-tetanic contraction. Finally, reperfusion can potentially cause additional injury by heightened recruitment of inflammatory cells and perfusion-induced microvascular injury with capillary occlusion.Morphology (p. 550)After infarction, myocardium undergoes characteristic gross andmicroscopic changes (see Fig. 12-3): Gross changes:• 6 to 12 hours: MIs are usually grossly inapparent but can be highlighted by histochemical stains; triphenyltetrazolium chlo- ride is a lactate dehydrogenase substrate; viable myocardium turns the substrate red-brown, while nonviable areas are pale.• 18 to 24 hours: Infarcted tissue becomes apparent as pale to cya- notic areas.• 1 week: Lesions become progressively more defined, yellow, and softened.• 7 to 10 days: Hyperemic granulation tissue appears at the infarct edges; with time, granulation tissue progressively fills in the infarct.• 1 to 2 months: White fibrous scar is usually well established.
    • The Heart 293 Microscopic changes:• Less than 1 hour: Intercellular edema, and wavy myocytes at the infarct margin; coagulative necrosis is not yet evident.• 12 to 72 hours: Dead myocytes become hypereosinophilic with loss of nuclei (coagulative necrosis); neutrophils also progres- sively infiltrate necrotic tissue.• 3 to 7 days: Dead myocytes are digested by invading macrophages.• 7 to 10 days: Granulation tissue progressively replaces necrotic tissue.• More than 2 weeks: Granulation tissue is progressively replaced by fibrous scar.Clinical Features (p. 553)MI diagnosis is based on symptoms (e.g., chest pain, nausea, dia-phoresis, dyspnea), electrocardiographic changes, and serum eleva-tion of cardiomyocyte-specific proteins released from dead cells(e.g., creatine kinase MB [CK-MB] isoform or various troponins).In 10% to 15% of patients (especially diabetic or geriatric),symptoms are absent (silent MI).• Nearly all transmural MIs affect the left ventricle; 15% also involve the right ventricle, particularly in posterior-inferior left ventricle infarcts. Isolated right ventricle infarction occurs in 1% to 3% of cases.• Half of MI-associated deaths occur within the first hour; most patients die before reaching a hospital. Overall, mortality is 30% in the first year after an MI, with 3% to 4% mortality per annum thereafter.• Therapies in the acute setting include anticoagulation, oxygen, nitrates, b-adrenergic blockade, angiotensin-converting enzyme inhibitors, and fibrinolytics; coronary angioplasty, stenting, or surgical bypass can also be performed. Complications of an MI depend on the size and location of injury, aswell as functional myocardial reserves:• Contractile dysfunction occurs roughly in proportion to the extent of infarction; effects include systemic hypotension and pulmonary edema (e.g., CHF). Severe pump failure (cardiogenic shock) occurs in 10% to 15% of patients, typically with loss of 40% or more left ventricular mass. Cardiogenic shock has a 70% mortality rate.• Arrhythmias.• Ventricular rupture (1% to 2% of transmural MIs) can occur typically within the first 10 days (median, 4 to 5 days). Rupture of the free wall causes pericardial tamponade; septal rupture causes a left-to-right shunt with right-sided volume overload; papillary muscle infarction (with or without ventricular rupture) causes mitral regurgitation.• Fibrinous pericarditis (Dressler syndrome) is common 2 to 3 days after MI.• Mural thrombosis adjacent to a noncontractile area can be a source of peripheral embolization.• Stretching of a large area of transmural infarction (expansion) may heal into a ventricular aneurysm; both are prone to mural thrombosis.• Infarction adjacent to existing MI (extension) can occur. After MI, non-infarcted myocardium undergoes hypertrophyand dilation (ventricular remodeling). While initially hemodynami-cally beneficial, such changes can become substrate for aneurysmsor for areas of secondary ischemia and arrhythmia.
    • 294 Systemic PathologyChronic Ischemic Heart Disease (p. 558)The term designates progressive heart failure due to ischemicmyocardial damage; it may result from postinfarction cardiacdecompensation or slow ischemic myocyte degeneration.• Invariably, there is some degree of obstructive coronary athero- sclerosis, often with evidence of prior healed infarcts. Microscop- ically, there is myocyte hypertrophy, diffuse subendocardial myocyte vacuolization, and interstitial and replacement fibrosis.• Patients need not have a prior diagnosed MI; diagnosis depends on excluding other causes of CHF.Sudden Cardiac Death (p. 558)Sudden cardiac death (SCD) is defined as unexpected cardiac deathwithin 1 hour of symptom onset. More than 300,000 cases occurannually in the United States, and the vast majority of cases aredue to lethal arrhythmia. IHD is the dominant cause, with 80%to 90% of victims having significant atherosclerotic stenoses, oftenwith acute plaque disruption. In patients who survive SCD (by car-diac resuscitation), only 25% actually develop an MI, indicatingthat a fatal arrhythmia (e.g., asystole or ventricular fibrillation) isthe most common cause of death. Arrhythmias are presumably trig-gered by conduction system scarring, acute ischemic injury, or electri-cal instability resulting from an ischemic focus. SCD is infrequently aconsequence of myocardial hypertrophy (e.g., due to aortic valvularstenosis or hypertrophic cardiomyopathy), hereditary or acquiredconduction system abnormalities, electrolyte derangements, mitralvalve prolapse, myocardial depositions, or myocarditis. Some SCD is attributable to hereditable conditions with recog-nizable structural abnormalities (e.g., mitral valve prolapse orhypertrophic cardiomyopathy). Others are primarily electricaldisorders related to defects either in conduction pathways (e.g.,Wolff-Parkinson-White syndrome) or mutations in ion channels.The latter, called channelopathies, are typically autosomal domi-nant disorders involving ion channel proteins (for Naþ, Kþ, orCa2þ transport) or accessory molecules that conduct the electricalcurrents that control myocardial contraction. Long QT syndrome isprototypical; mutations in one of at least seven different genesresult in diminished Kþ currents that, in turn, prolong the QTrepolarization interval and increase the susceptibility to malignantarrhythmias.Hypertensive Heart Disease (p. 559)Systemic (Left-Sided) Hypertensive HeartDisease (p. 559)Hypertrophy of the heart is an adaptive response to chronically ele-vated pressures; with continued overload, the result can be dys-function, dilation, CHF, or SCD. The minimal criteria fordiagnosing systemic hypertensive heart disease is a history or path-ologic evidence of hypertension plus left ventricular hypertrophy(typically concentric) in the absence of other lesions that inducecardiac hypertrophy (e.g., aortic valve stenosis, aortic coarctation).• Myocyte hypertrophy increases the content of contractile proteins. However, thickened myocardium reduces left ventricle compliance, impairing diastolic filling while increasing oxygen demand. Hypertrophy is also usually accompanied by interstitial fibrosis that also reduces compliance.• Depending on the severity and duration of underlying hyperten- sion (and adequacy of therapy) patients can have normal
    • The Heart 295 longevity, develop IHD as a consequence of the potentiating effects of hypertension and atherosclerosis, suffer the renal or cerebrovascular complications of hypertension, or experience progressive CHF or even SCD.Pulmonary (Right-Sided) Heart Disease(Cor Pulmonale) (p. 559)Cor pulmonale is the right-sided counterpart to systemic hyperten-sive heart disease; disorders that affect lung structure or function(e.g., emphysema or primary pulmonary hypertension) can causepulmonary vascular hypertension, resulting in right ventricularhypertrophy, dilation, and/or failure. Recall that the most commoncause of pulmonary venous hypertension is left-sided heart disease.• Acute cor pulmonale with right ventricular dilation occurs after massive pulmonary embolization• Chronic cor pulmonale results from chronic right ventricular pressure overload (e.g., CHD or primary lung disease)Valvular Heart Disease (p. 560)Causes of acquired valvular heart disease (CHD constitutes a thirdof total valvular disease):• Degeneration (e.g., calcific aortic stenosis, mitral annular calcifi- cation, mitral valve prolapse)• Inflammatory processes (e.g., rheumatic heart disease)• Infection (e.g., infective endocarditis)• Changes secondary to myocardial disease (e.g., IHD causing ischemic mitral regurgitation) The clinical consequences depend on the valve involved, thedegree of impairment, whether the lesion is stenotic (pressureoverload) or regurgitant (volume overload), the tempo of onset,compensatory changes, and any co-morbid disease.Calcific Aortic Stenosis (p. 561)Calcific aortic stenosis is a common (i.e., occurs in 2% of the pop-ulation) degenerative age-related lesion that typically becomes clin-ically significant in individuals older than 70 years. Earlier onset(i.e., patients between the ages of 50 and 60 years) occurs mostcommonly in congenitally bicuspid valves (about 1% of the popu-lation); bicuspid valves are responsible for roughly half of adultaortic stenosis. Although “wear and tear” has been cited as an eti-ology for calcific aortic stenosis, newer data implicate chronicinjury due to hypertension, hyperlipidemia, and inflammation.Morphology (p. 562)• Sclerosis (valve fibrosis) is an early, hemodynamically inconse- quential stage.• Nodular, rigid calcific subendothelial masses on the valve out- flow surface impede mobility and aortic outflow.• There is no commissural fusion, and the thickening spares the cuspal free edges.• Concentric left ventricular hypertrophy is common due to chronic pressure overload.Clinical Features (p. 562)The failure of compensatory hypertrophy mechanisms is heralded byangina (reduced perfusion in hypertrophied myocardium), syncope(with increased risk of SCD), or CHF; if untreated, there is a 50% mor-tality within 2 to 5 years. Surgical valve replacement improves survival.
    • 296 Systemic PathologyMitral Annular Calcification (p. 563)Mitral annular calcificiation is due to degenerative, non-inflammatorycalcific deposits, most commonly in women older than 60 years or inindividuals with mitral valve prolapse (see later discussion). Whileusually inconsequential, annular calcification can cause:• Regurgitation due to poor systolic contraction of the mitral valve ring• Stenosis due to poor leaflet excursion over bulky deposits• Impingement on conduction pathways, causing arrhythmias• Rarely, a focus for infective endocarditis.Mitral Valve Prolapse (p. 563)One or both mitral valve leaflets are enlarged, redundant, myxo-matous, and floppy; they balloon back (prolapse) into the leftatrium during systole. Mitral valve prolapse affects 3% of theUnited States population, most commonly young women. The eti-ology is uncertain; a high frequency in Marfan syndrome suggestsabnormal extracellular matrix synthesis potentially related todysregulated TGF-b signaling.Morphology (p. 563)• Grossly: Redundancy and ballooning is seen with elongated, attenuated, or occasionally ruptured chordae tendineae.• Microscopically: The fibrosa layer (on which the strength of the leaflet depends) shows thinning and degeneration with myxoma- tous expansion of the spongiosa.• Secondary changes include: fibrous thickening of valve leaflets at points of contact; thickened ventricular endocardium at sites of contact with prolapsing leaflets; atrial thrombosis behind the ballooning cusps.Clinical Features (p. 563)Some patients also have aortic, tricuspid, or pulmonary valve myx-omatous degeneration. Mitral valve prolapse is generally asymptom-atic and discovered only as a mid-systolic click on auscultation;more severe cases may also have mitral regurgitation. Importantly,3% of patients develop complications secondary to:• Infective endocarditis• Mitral insufficiency resulting in CHF• Arrhythmias and/or SCD• Embolization of atrial or leaflet thrombiRheumatic Fever and Rheumatic HeartDisease (p. 565)Rheumatic fever (RF) is an acute inflammatory disease classicallyoccurring in children after group A streptococcal infection (usuallypharyngitis). It is attributed to host anti-streptococcal antibodiesand/or T cells that cross-react with cardiac antigens. The cell andantibody responses in turn cause progressive valve damage withfibrosis (rheumatic heart disease [RHD]). Solitary mitral involve-ment occurs in 65% to 70% of cases with combined aortic andmitral involvement in 20% to 25%; tricuspid and pulmonaryvalves are less frequently affected. RHD is virtually the only causeof acquired mitral valve stenosis.Morphology (p. 565)Acute phase:• Aschoff bodies are pathognomonic for RF; these are myocardial, pericardial, or endocardial foci of fibrinoid necrosis surrounded
    • The Heart 297 by mononuclear inflammatory cells. Activated macrophages in these lesions, called Anitschkow cells, have characteristic wavy chro- matin aggegation, giving rise to the designation caterpillar cells.• Inflammatory valvulitis is characterized by beady fibrinous vegetations (verrucae) along the lines of valve closure.• With time, these inflammatory foci are replaced by scar. Chronic (or healed) phase:• Diffuse fibrous thickening of valve leaflets, with fibrous commis- sural fusion generating “fishmouth” or “buttonhole” stenoses• Thickened, fused, and shortened chordae• Subendocardial collections of Aschoff nodules, usually in the left atrium, forming thickened MacCallum plaquesClinical Features (p. 566)Diagnosis of RF is based on clinical history and a constellation offindings, called Jones criteria, that include: erythema marginatum(a skin rash), Sydenham chorea (a neurologic disorder with rapid,involuntary, purposeless movements), carditis (involving myocar-dium, endocardium, or pericardium), subcutaneous nodules, and/or migratory large joint polyarthritis. Death (most frequently sec-ondary to myocarditis) occurs rarely in acute rheumatic fever. Typ-ically, myocarditis and arthritis are transient and resolve withoutcomplications; however, valvular involvement can deform and scarthe valve, causing permanent dysfunction (RHD) and subsequentCHF. RHD is most likely when the first attack is in early child-hood, when it is particularly severe, or if there are recurrentattacks. Changes secondary to mitral stenosis include:• Left atrial hypertrophy and enlargement, occasionally with mural thrombi• Atrial fibrillation secondary to atrial dilation• CHF with chronic pulmonary congestive changes• Increased risk of infective endocarditisInfective Endocarditis (p. 566)Infective endocarditis (IE) reflects microbial colonization or invasionof valves, leading to friable, infected vegetations, often with valvedamage. Traditionally, these are classified as acute or subacute forms:• Acute IE is caused by highly virulent organisms (e.g., Staphylo- coccus aureus), typically seeding a previously normal valve to produce necrotizing, ulcerative, and invasive infections. Clini- cally, there is rapid onset of fever with rigors, malaise, and weak- ness. Larger vegetations can cause embolic complications; splenomegaly is common.• Subacute IE is typically caused by moderate to low-virulence organisms (e.g., Streptococcus viridans) seeding an abnormal or previously injured valve; there is less valvular destruction than in acute infective endocarditis. This pattern occurs insidiously with nonspecific malaise, low-grade fever, weight loss, and a flulike syndrome. Vegetations tend to be small so that embolic complications occur less frequently. The disease tends to have a protracted course even without treatment and has a lower mor- tality rate than acute IE.Pathogenesis (p. 567)IE is caused by blood-borne organisms, usually bacteria that derivefrom infections elsewhere in the body, intravenous (IV) drugabuse, dental or surgical procedures, or otherwise trivial injury togut, urinary tract, oropharynx, or skin. Contributory conditionsinclude neutropenia and immunosuppression.
    • 298 Systemic Pathology• Although endocarditis can occur on normal valves, infection is more likely to occur in the setting of previous valve pathology (e.g., CHD [particularly tight shunts or stenoses with jet streams], RHD, MVP, degenerative calcific stenoses, bicuspid aortic valves, or prosthetic valves).• IE in IV drug abusers is most commonly caused by S. aureus infecting a normal valve; right-sided valves are involved more commonly than left.• Besides S. viridans (50% to 60% of cases), low virulence organisms include enterococci and the so-called HACEK group of oral commensals (i.e., Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella).• IE on prosthetic valves is caused most commonly by S. epidermidis; sewing ring abscesses are a common feature.• In 10% to 15% of IE, no organisms are identified (culture- negative).Morphology (p. 567)• Acute IE is typically associated with bulky (i.e., 1 to 2 cm) vegetations causing valve destruction; invasion into adjacent myocardium or aorta can cause abscesses. Distal embolization with septic infarcts or mycotic aneurysms can occur.• Subacute IE has smaller vegetations that rarely penetrate the leaflets.Clinical Features (p. 568)• Valvular and myocardial damage as described earlier• Embolic complications as described earlier• Renal injury, including embolic infarction or infection and antigen- antibody complex–mediated glomerulonephritis (with nephrotic syndrome, renal failure, or both).• Diagnosis is confirmed by the Duke criteria; blood cultures are critically important for directing therapy.Nonbacterial Thrombotic Endocarditis (p. 568)Nonbacterial thrombotic endocarditis (NBTE), also called maranticendocarditis, characteristically occurs in settings of cancer (particu-larly adenocarcinomas) or prolonged debilitating illness (e.g., renalfailure, chronic sepsis) with disseminated intravascular coagulationor other hypercoagulable states.• Small (i.e., 1 to 5 mm) sterile, bland fibrin and platelet thrombi are loosely adherent to valve leaflets along closure lines, without significant inflammation or valve damage.• Vegetations can embolize systemically.Endocarditis of Systemic Lupus Erythematosus(Libman-Sacks Disease) (p. 569)Endocarditis of systemic lupus erythematosus (Libman-Sacksdisease) occurs in systemic lupus erythematosus and in anti-phospholipid syndrome, presumably due to immune complexdeposition. Findings include small fibrinous, sterile vegetationson either side of valve leaflets, with associated fibrinoid necrosisand inflammation. Valve scarring and deformation can result; theseresembles RHD and may require surgery.Carcinoid Heart Disease (p. 569)Carcinoid tumors (Chapter 17) elaborate bioactive products (e.g.,serotonin, kallikrein, bradykinins, histamine, prostaglandins,and tachykinins P and K) that can cause cardiac lesions. The pre-cise agent responsible is uncertain, although it is presumably
    • The Heart 299rapidly metabolized in lung and liver, because cardiac lesionsdo not occur unless there is extensive hepatic metastaticspread. Right-sided heart lesions (valvular and endocardial)predominate.Morphology (p. 569)• Lesions are characterized by plaque-like intimal thickening (composed of smooth muscle cells and associated ECM) of the tricuspid and pulmonary valves and right ventricular outflow tract; left-sided lesions are uncommon except in primary pulmo- nary carcinoids.• Tricuspid insufficiency and pulmonic stenosis are the typical valvular consequences.• Similar lesions occur in the setting of drugs that have sero- toninergic effects (e.g., methylsergide, ergotamine, some anti- parkinsonian medications, and fenfluramine [part of the fen-phen appetite suppressant combination with phentermine]).Complications of Artificial Valves (p. 570)Prosthetic valves are of two basic types: mechanical (rigid, synthetic)and bioprosthetic (chemically fixed animal tissues). Roughly 60% ofvalve recipients develop a significant valve-related complicationwithin 10 years of surgical implantation:• Thromboembolic complications, either local obstruction by thrombus or distal embolization, are the major complications of mechanical valves; this complication necessitates long-term anticoagulation in such valve recipients, with the attendant risks of hemorrhagic stroke or other bleeding complication.• Infective endocarditis, infection at the valve sewing ring, often leads to ring abscesses and paravalvular regurgitation.• Structural deterioration is uncommon with mechanical valves, but valvular calcification or degenerative tears often cause bioprosthetic valve failure.• Occlusion occurs due to tissue overgrowth.• Intravascular hemolysis occurs due to high shear forces or paravalvular leak due to poor healing.Cardiomyopathies (p. 571)Although myocardial dysfunction can occur secondary to ischemic,valvular, hypertensive, or other heart diseases, the term cardiomy-opathy implies a principal cardiac dysfunction. Causes of suchmyocardial disease can be primary (i.e., predominantly affectingheart) or secondary (i.e., part of a larger systemic disorder):• Infections (e.g., viral, bacterial, fungal, protozoal)• Toxic exposures (e.g., alcohol, cobalt, chemotherapeutic agents)• Metabolic disorders (e.g., hyperthyroidism, nutritional deficiency)• Genetic abnormalities in cardiomyocytes (e.g., storage disorders, muscular dystrophies)• Infiltrative lesions (e.g., sarcoid, carcinoma, radiation-induced fibrosis)• Immunologic disorders (e.g., autoimmune myocarditis, rejection) Cardiomyopathy is divided into three main functional and path-ologic patterns: dilated, hypertrophic, and restrictive (Fig. 12-4 andTable 12-2).Dilated Cardiomyopathy (p. 572)Dilated cardiomyopathy (DCM) is characterized by gradual four-chamber hypertrophy and dilation; there is systolic dysfunction
    • 300 Systemic Pathology LA LA Ao Ao LV LV Dilated Normal cardiomyopathy LA LA Ao Ao LV LV Hypertrophic Restrictive cardiomyopathy cardiomyopathyFIGURE 12-4 Schematics of the three distinctive forms of cardiomyopathy; eachform can have a variety of causes. Ao, Aorta; LA, left atrium; LV, left ventricle.with hypocontraction. It typically presents as indolent, progressiveCHF. Only 25% of patients survive more than 5 years after symptomonset. Although the cause is frequently unknown (idiopathic DCM),certain pathologic mechanisms can contribute (Fig. 12-5):• Genetic influences: 20% to 50% of DCM is familial; autosomal dominant inheritance is most common. Known genetic abnormalities commonly involve cytoskeletal proteins (e.g., dys- trophin in X-linked cardiomyopathy [Duchenne and Becker muscular dystrophies]). Others involve mutations of enzymes involved in fatty acid b-oxidation or mitochondrial gene deletions causing abnormal oxidative phosphorylation.• Alcohol toxicity: DCM is attributed to direct toxicity of alcohol or a metabolite (especially acetaldehyde) on the myocardium. No morphologic features distinguish alcohol-induced cardiac dam- age from other forms of idiopathic DCM or chronic thiamine deficiency.• Peripartum cardiomyopathy: DCM is discovered within several months before or after delivery. Although the mechanism is uncertain, the association with pregnancy suggests possible etiologies of chronic hypertension, volume overload, nutritional deficiency, metabolic derangement, or immunologic response.• Myocarditis (see later discussion): even after resolution of the infection, injury related to myocarditis can progress to DCM.