Robbins: The Heart

Turner Syndrome

Monosomy X

Down Syndrome

Trisomy 21. most common cause of congenital heart disease. AV septa most commonly affected.

D. Rheumatic Fever and Rheumatic Heart Disease only cause of MS. Type II molecular mimicry with anti strep M protein antibodies binding myocardial cell self-antigens. Activates complement, as well as Fc receptor binding cells (PMNs and Macrophages) Combo: antibody and T cell mediated. Aschoff bodies: T cells, plasma cells, plump activated macrophages(called Aitschkow cells) PATHOGNOMOIC FOR RF. These macrophages have abundant cytoplasm and central round-to-ovoid nuclei (occasionally binucleate) in which the chromatin condenses into a central, slender, wavy ribbon (hence the designation "caterpillar cells"). Aschoff bodies found in any layer of the heart: so can lead to pericarditis, endocarditis, myocarditis. Fibrinoid necrosis is typically present, in cusps or tendinous cords. VERRUCAE: small vegetations overlying necrotic foci. Subendocardial lesions perhaps exacerbated by regurgitant jets can induce irregular thickenings called MacCallum plaques, usualy in Let Atrium DIFFERNENT KINDS OF VEGETATIONS: RH: small warty in a single line along edge of valves. IE: large, irregular, often invade chordae tendinae. Non bacterial thrombotic endocarditis: small, bland, larger than RHD at line along edge of valves. SLE/Libman Sacks: small/medium on EITHER OR BOTH SIDES of valve leaflets. In chronic RHD: leaflet thickening, commisural fusion, shortening, thickening, fusion of chordae tendinae. !!!!!!!!!!!!!! MITRAL STENOSIS DUE TO RF: LV largely unaffected. RVH can result if pulmonary hypetension proceeds backwards from LA pressure overload. LA will be enlarged due to pressure overload. If pulmonary hypertension is presnet, will see signs on cxr (kerley b lines, vascular redistribution, edema). ASCHOFF BODIES USUALLY NOT PRESENT, ONLY THERE DURING INITIAL RF, and this often occurs years before CRHD manifests itself. In RF acute: JONES criteria. migratory polyarthritis pancarditis subcutaneous nodules erytema marginatum of skin Sydenham Chorea- involuntary rapid, purposeles movements. RF occurs 10 days -6 weeks after strep infection.GROUP A strep. STrep cultures usually negative when RF actally presents itself. ASO however, is usually present. Carditis and arthritis (more common in adults) 1% die of fulminant RF involvement of the heart. AFTER initial attack, there is increased vulnerability to reactivation of disease with subsequent pharyngeal infections... with the same symptoms, Damage to the valves is cumulative. turbulance by valvular deformities leds to additional fibrosis. Years or decades later after INITIAL RF, can see various murmurs, hypertrophy, ilation, heart failure, arrhythmias, thrombus, infective endocarditis. VARIABLE progosis. Surgical or replacement are good treatments.

acute, immunologically mediated, multisystem inflammatory disease classically occurring a few weeks after an episode of group A streptococcal pharyngitis -Can follow impetigo too. -Acute rheumatic carditis is a manifestation of active RF. May progress over time to Chronic RHD, manifesting as valvular abnormalities. deforming fibrotic valvular disease, particularly involving the mitral valve; indeed, RHD is virtually the only cause of mitral stenosis. Mostly a problem of undeveloped countries. Type II molecular mimicry with anti strep M protein antibodies binding myocardial cell self-antigens. Activates complement, as well as Fc receptor binding cells (PMNs and Macrophages) Combo: antibody and T cell mediated. Aschoff bodies: T cells, plasma cells, plump activated macrophages(called Aitschkow cells) PATHOGNOMOIC FOR RF. These macrophages have abundant cytoplasm and central round-to-ovoid nuclei (occasionally binucleate) in which the chromatin condenses into a central, slender, wavy ribbon (hence the designation "caterpillar cells"). During acute RF, diffuse inflammation and Aschoff bodies may be found in any of the three layers of the heart, resulting in pericarditis, myocarditis, or endocarditis ( pancarditis ). Inflammation of the endocardium and the left-sided valves typically results in fibrinoid necrosis within the cusps or tendinous cords. Overlying these necrotic foci and along the lines of closure are small (1 to 2 mm) vegetations, called verrucae . Thus, RHD is one of the forms of vegetative valve disease, each of which exhibit their own characteristic morphologic features ( Fig. 12-24 ). Subendocardial lesions, perhaps exacerbated by regurgitant jets, can induce irregular thickenings called MacCallum plaques , usually in the left atrium. The cardinal anatomic changes of the mitral valve in chronic RHD are leaflet thickening, commissural fusion and shortening, and thickening and fusion of the tendinous cords ( Fig. 12-23 D ). In chronic disease the mitral valve is virtually always involved. The mitral valve is affected in isolation in roughly two thirds of RHD, and along with the aortic valve in another 25% of cases. Tricuspid valve involvement is infrequent, and the pulmonary valve is only rarely affected. Because of the increase in calcific aortic stenosis (see earlier) and the reduced frequency of RHD, rheumatic aortic stenosis now accounts for a small fraction of cases of acquired aortic stenosis. In rheumatic mitral stenosis, calcification and fibrous bridging across the valvular commissures create "fish mouth" or "buttonhole" stenoses. With tight mitral stenosis, the left atrium progressively dilates and may harbor mural thrombi that can embolize. Long-standing congestive changes in the lungs may induce pulmonary vascular and parenchymal changes; over time, these can lead to right ventricular hypertrophy. The left ventricle is largely unaffected by isolated pure mitral stenosis. Microscopically, valves show organization of the acute inflammation, with post-inflammatory neovascularization and transmural fibrosis that obliterate the leaflet architecture. Aschoff bodies are rarely seen in surgical specimens or autopsy tissue from patients with chronic RHD, as a result of the long intervals between the initial insult and the development of the chronic deformity. Clinical Features. RF is characterized by a constellation of findings: (1) migratory polyarthritis of the large joints, (2) pancarditis, (3) subcutaneous nodules, (4) erythema marginatum of the skin, and (5) Sydenham chorea, a neurologic disorder with involuntary rapid, purposeless movements. The diagnosis is established by the so-called Jones criteria: evidence of a preceding group A streptococcal infection, with the presence of two of the major manifestations listed earlier or one major and two minor manifestations (nonspecific signs and symptoms that include fever, arthralgia, or elevated blood levels of acute-phase reactants). Acute RF typically appears 10 days to 6 weeks after a group A streptococcal infection in about 3% of patients. It occurs most often in children between ages 5 and 15, but first attacks can occur in middle to later life. Although pharyngeal cultures for streptococci are negative by the time the illness begins, antibodies to one or more streptococcal enzymes, such as streptolysin O and DNase B, can be detected in the sera of most patients with RF. The predominant clinical manifestations are carditis and arthritis, the latter more common in adults than in children. Arthritis typically begins with migratory polyarthritis (accompanied by fever) in which one large joint after another becomes painful and swollen for a period of days and then subsides spontaneously, leaving no residual disability. Clinical features related to acute carditis include pericardial friction rubs, tachycardia, and arrhythmias. Myocarditis can cause cardiac dilation that may culminate in functional mitral valve insufficiency or even heart failure. Approximately 1% of affected individuals die of fulminant RF involvement of the heart. After an initial attack there is increased vulnerability to reactivation of the disease with subsequent pharyngeal infections, and the same manifestations are likely to appear with each recurrent attack. Damage to the valves is cumulative. Turbulence induced by ongoing valvular deformities leads to additional fibrosis. Clinical manifestations appear years or even decades after the initial episode of RF and depend on which cardiac valves are involved. In addition to various cardiac murmurs, cardiac hypertrophy and dilation, and heart failure, individuals with chronic RHD may suffer from arrhythmias (particularly atrial fibrillation in the setting of mitral stenosis), thromboembolic complications, and infective endocarditis (see later). The long-term prognosis is highly variable. Surgical repair or prosthetic replacement of diseased valves has greatly improved the outlook for persons with RHD.

CPVT

childhood with life-threatening arrhythmias due to adrenergic stimulation (stress-related). No characteristic ECG changes.

Stable Angina

deep poorly localized pressure with exertion. Relieved by rest (decreased demand), responds to nitroglycerin(increasing perfusion) and calcium channel blockers (increase perfusion)

Unstable/crescendo angina

increasingly frequent, prolonged or severe angina. -Frank pain, precipitated by progressively lower levels of physical activity or even at rest. caused by the disruption of an atherosclerotic plaque with superimposed partial thrombosis and possibly embolization or vasospasm (or both). Approximately one-half of patients with unstable angina have evidence of myocardial necrosis; for others, acute MI may be imminent.

A. Left to Right Shunts(Cyanotic at first) -laughable lala

initially no cyanosis. elevate volume and pressure in low pressure low resistance pulmonary circulation. To maintain normal distal pulmonary capillary and venous pressures, muscular arteries undergo medial hypertrophy and vasoconstriction. Eisenmener syndrome reverses the shunt direction causing cyanosis etc.

left ventricle

largely derives from cells originating in the first heart field

Long QT Syndrome

prolonged repolarization stress-induced syncope or sudden cardiac death (SCD), and some forms are associated with swimming.

outflow tract,right ventricle, and most of the atria

second heart field

X. Cardiomyopathies failure of myocardial performance often genetic. SEE CHART, know what risk factors lead to what kind of cardiomyopathy

"[C]ardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic. Cardiomyopathies either are confined to the heart or are part of generalized systemic disorders, often leading to cardiovascular death or progressive heart failure-related disability."

1. Tetralogy of Fallot

(1) VSD, (2) obstruction of the right ventricular outflow tract (subpulmonary stenosis), (3) an aorta that overrides the VSD, and (4) right ventricular hypertrophy All occur from anterosuperior displacement of the infundibular bseptum. BOOT SHAPED heart. due to RVH VSD large with aortic valve at superior border, overriding the defect and both ventricular chambers. -If the subpulmonary stenosis is mild, the abnormality resembles an isolated VSD, and the shunt may be left-to-right, without cyanosis (so-called "pink tetralogy"). With more severe right ventricular outflow obstruction, right-sided pressures approach or exceed left-sided pressures, and right-to-left shunting develops, producing cyanosis (classic TOF) . Most infants with TOF are cyanotic from birth or soon thereafter.

Brugada Syndrome

(ST segment elevations and right bundle branch block) in the absence of structural heart disease; patients classically present with syncope or SCD during rest or sleep, or after large meals.

2. VSD

-90% in membranous VS. remainder occur below pulmonary valve. -Most occur as part of TofF in children. In adults, they are more likely isolated. -approximately 50% of small muscular VSDs close spontaneously. Large defects are usually membranous or infundibular, and they generally cause significant left-to-right shunting, leading to early right ventricular hypertrophy and pulmonary hypertension. Over time, large unclosed VSDs almost universally lead to irreversible pulmonary vascular disease, ultimately resulting in shunt reversal, cyanosis, and death. Surgical or catheter-based closure of asymptomatic VSD is generally delayed beyond infancy, in hope of spontaneous closure. Early correction, however, must be performed for large defects to prevent the development of irreversible obstructive pulmonary vascular disease.

D. Blood Supply

-Almost exclusively oxidative phosphorylation, high mitochondrial density, myocardial energy generation also requires constant supply of oxygenated blood, so myocardium is very vulnerable to ischemia. -Coronary arteries take off distal to aortic valve, fill during diastole. Initially course along epicardium, penetrate myocardium (intramural), branch into arterioles, and arborize so that each myocyte roughy contacts 3 capillaries. -corona at base of the heart: LAD (divides to form diagonal branches) and LCX (divides to form marginal branches) arteries arise from L main coronary artery. and RCA. -During diastole, myocardium is not contracted, perfusion occurs here. Shortened when HR rises, hindering coronary perfusion.

B. Valves

-Atrioventricular valves: Mitral(L) and Tricuspid(R) -Semilunar valves: Aortic and Pulmonic -Maintain unidirectional flow. -Mobility, pliability, structural integrity of the leaflets of the AV valves, cusps of semilunar valves. -3 Layers: dense collagenous core (fibrosa) at outflow surface connected to valvular supporting structures, central core of loose connective tissues (spongiosa), rich elastin layer (ventricularis or atrialis) on the inflow surface) -Collagen: mechanical integrity -Elastin in atrialis/ventricularis: rapid recoil for prompt closure. -Proteoglycan rich spongiosum facilitates interactions of collagenous and elastic layers through cardiac cycle. -VALVULAR INTERSTITIAL CELLS are prevalent and homogeneously spread throughout the valve area, synthesize ECM, express MMPs and inhibitors that remodel collagen and other matrix components. Can alter phenotypes in response to changing stresses. -Semilunar valves: cuspal attachments must be integrals and coordinated. -Atrioventricular valves: chordae tendinae and papillary muscles of ventricular wall must be in correct orientation and function (no dilatation, ruptured cords, papillary muscle dysfunction) -Scant blood vessels, only proximal portions are perfused. -Pathological processes of valves: damage to collagen that weakens the leaflets as in mitral valve prolapse. nodular calcification beginning in interstitial cells, as in calcific aortic stenosis. fibrotic thickening, as in rheumatic heart disease.

A. Myocardium

-LV myocytes arranged in spiral form to help generate coordinated wave of contraction from apex to base. RV and atria are more haphazard organization. -Contractile apparatus: series of sarcomeres, made of thick filaments: myosin(middle) and thin filaments: actin (attached to ends). Troponin and tropomyosin are regulatory proteins. -Contraction results in ratcheting adjacent actin filaments toward the center, shortening the sarcomere. Force of contraction determined by extent of sarcomere shortening. -So moderate dilation (preload) before contraction increases stretch, allows more distance to cover, increases force of contraction until the dilation is too strong and overlap is insufficient to eject enough blood. -Atria generate weaker force because of haphazard arrangement of myocytes. ANP is stored in electron dense storage granules. -ANP facilitates diuresis and vasodilation-helpful in hypertension and congestive heart failure. -Coordinating beating of myocytes relies on intercalated discs, specialized gap junctions that facilitate synchronized waves of depolarization between adjoining cells.

III. Overview of Cardiac Pathophysiology

-Pump failure: weak contractions during systole, inadequate CO. or inadequate relaxation during diastole, inadequate ventricular filling. -Flow obstruction: atherosclerotic plaque prevents flow through a vessel or present valve opening. May cause increased chamber pressure (aortic stenosis, systemic HTN, aortic coarctation) Increased pressure overloads chamber the pumps against the obstruction. -Regurgitatnt Flow: portion of output from each contraction flows backward through incompetent valve-adds volume overload to affected atria or ventricles (LV in aortic regurgitation, LA and LV in mitral regurgitation) -Shunted flow: blood diverted from one part of heart to another (ie. from L V to R V). Shunted flow can also occur between blood vessels -Disorders of cardiac conduction -Rupture of heart or major vessel: gunshot to LV aortic dissection and rupture. Exsanguination internal or external.

3. PDA Machine like murmur

-intrauterine life, it permits blood flow from the pulmonary artery to the aorta, thereby bypassing the unoxygenated lungs. Shortly after birth in healthy term infants, the ductus constricts and is functionally closed after 1 to 2 days; this occurs in response to increased arterial oxygenation, decreased pulmonary vascular resistance, and declining local levels of prostaglandin E 2 . Complete structural obliteration occurs within the first few months of extrauterine life to form the ligamentum arteriosum. Ductal closure is often delayed (or even absent) in infants with hypoxia (due to respiratory distress or heart disease), or when PDA occurs in association with other congenital defects, particularly VSDs that increase pulmonary vascular pressures. PDAs account for about 7% of cases of congenital heart disease ( Table 12-2 and Fig. 12-4 C ), and 90% of these are isolated defects. PDA produces a characteristic continuous harsh "machinery-like" murmur. The clinical impact of a PDA depends on its diameter and the cardiovascular status of the individual. PDA is usually asymptomatic at birth, and a narrow PDA may have no effect on the child's growth and development. Because the shunt is initially left-to-right, there is no cyanosis. However, with large shunts, the additional volume and pressure overloads eventually produce obstructive changes in small pulmonary arteries, leading to reversal of flow and its associated consequences. In general, isolated PDA should be closed as early in life as is feasible. Conversely, preservation of ductal patency (by administering prostaglandin E) may be life saving for infants with various congenital malformations that obstruct the pulmonary or systemic outflow tracts. In aortic valve atresia, for example, a PDA may provide the entire systemic blood flow.

2. Calcific Stenosis of Congenitally Bicuspid Aortic Valve 18q, 5q, 13q inheritance. NOTCH1 on 9q specifically involved in some families. Larger cusp has a raphe: which is frequent site of deposits. Inherited, or Rheumatic valve disease can cause fused commissure. aortic dilation, cusp prolapse, infective endocarditis. structural abnormalities of aortic wall also commonly accompany BAV.

18q, 5q, 13q inheritance. NOTCH1 on 9q specifically involved in some families. Larger cusp has a raphe: which is frequent site of deposits. Valves that become bicuspid because of an acquired deformity (e.g., rheumatic valve disease) have a fused commissure that produces a conjoined cusp that is generally twice the size of the nonconjoined cusp. BAVs may also become incompetent as a result of aortic dilation, cusp prolapse, or infective endocarditis. The mitral valve is generally normal in patients with a congenitally bicuspid aortic valve. Although BAV is usually asymptomatic early in life, late complications include aortic stenosis or regurgitation, infective endocarditis, and aortic dilation and/or dissection. Structural abnormalities of the aortic wall also commonly accompany BAV, even when the valve is hemodynamically normal, and this may potentiate aortic dilation or aortic dissection (see later).

in 50% of those with DiGeorge syndrome:

22q11.2 deletion. 3 and 4 pharyngeal pouches (thymus, parathyroids, heart) develop abnormally. (catch 22: cardiac abnormality, abnormal facies, thyme aplasia, cleft palate, hypocalcemia, all on chromosome 22)

C. Right Sided Heart Failure

Aka cor pulmonale -Pure right heart failure most often caused by left heart failure-eventually back flow pressure through lungs causes R H Failure. Second most frequent cause is pulmonary disease. -Isolated RHF: pulmonary congestion is minimal while engorgement of the systemic and portal venous systems is pronounced. -RA and RV hypertrophied often in isolated RHF due to primary lung disease raising pressures. -Liver: congestion of hepatic and portal vessels produces pathologic changes in liver, spleen, GI. Liver increases in size and weight due to prominent passive congestion, greatest around central veins. Congested red brown pericentral zones, nutmeg liver. Cirrhosis with fibrosis if it is chronic. Portal venous hypertension also causes enlargement of the spleen with platelet sequestration (congestive splenomegaly) , and can also contribute to chronic congestion and edema of the bowel wall. The latter may be sufficiently severe as to interfere with nutrient (and/or drug) absorption. -Centrolobular necrosi occurs when LEFT SIDED HF results in low liver perfusion. -Pleural, pericardial, peritoneal effusion due to systemic edema. -Subcutaneous Tissues: peripheral and dependent portions of the body especially ankle and pretrial edema. -Renal congestion is MORE MARKED WITH RHF than LHF. GREATER FLUID RETENTION AND PERIPHERAL EDEMA, more pronounced azotemia. -Venous congestion and hypoxia of central nervous system can produce deficits of mental function akin to LHF hypo perfusion. -Drugs that relieve fluid overload (e.g., diuretics), that block the renin-angiotensin-aldosterone axis (e.g., angiotensin converting enzyme inhibitors), and that lower adrenergic tone (e.g., beta-1 adrenergic blockers) are all particularly beneficial. The efficacy of the latter two classes of drugs supports the concept that neurohumoral changes in CHF (e.g., renin and norepinephrine elevations) are maladaptive contributions to heart failure.

A. Angina PEctoris

Angina pectoris is characterized by paroxysmal and usually recurrent attacks of substernal or precordial chest discomfort caused by transient (15 seconds to 15 minutes) myocardial ischemia that is insufficient to induce myocyte necrosis. The pain itself is likely a consequence of the ischemia-induced release of adenosine, bradykinin, and other molecules that stimulate sympathetic and vagal afferent nerves. • Stable (typical) angina is the most common form of angina; it is caused by an imbalance in coronary perfusion (due to chronic stenosing coronary atherosclerosis) relative to myocardial demand , such as that produced by physical activity, emotional excitement or psychological stress. Typical angina pectoris is variously described as a deep, poorly localized pressure, squeezing, or burning sensation (like indigestion), but unusually as pain, and is usually relieved by rest (decreasing demand) or administering vasodilators, such as nitroglycerin and calcium channel blockers (increasing perfusion). • Prinzmetal variant angina is an uncommon form of episodic myocardial ischemia; it is caused by coronary artery SPASM. Although individuals with Prinzmetal variant angina may well have significant coronary atherosclerosis, the anginal attacks are unrelated to physical activity, heart rate, or blood pressure. Prinzmetal angina generally responds promptly to vasodilators. • Unstable or crescendo angina refers to a pattern of increasingly frequent, prolonged (>20 min), or severe angina or chest discomfort that is described as frank pain, precipitated by progressively lower levels of physical activity or even occurring at rest. In most patients, unstable angina is caused by the DISRUPTION of an atherosclerotic plaque with superimposed partial thrombosis and possibly embolization or vasospasm (or both). Approximately one-half of patients with unstable angina have evidence of myocardial necrosis; for others, acute MI may be imminent.

B. Arrhythmogenic RV Cardiomyopathy causing right ventricular failure and rhythm disturbances (particularly ventricular tachycardia or fibrillation) with sudden death. RV wall significantly thinned, accompanied by extensive fatty infiltration and fibrosis. Infalmmation may be present, but not primarily an inflammatory process. AUTOSOMAL DOMINANT inheritance with variable penetrance

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease of myocardium causing right ventricular failure and rhythm disturbances (particularly ventricular tachycardia or fibrillation) with sudden death. Left-sided involvement with left-sided heart failure may also occur. Morphologically, the right ventricular wall is severely thinned due to loss of myocytes, accompanied by extensive fatty infiltration and fibrosis ( Fig. 12-33 ). Although myocardial inflammation may be present, ARVC is not considered an inflammatory cardiomyopathy. Classical ARVC has autosomal dominant inheritance with a variable penetrance. The disease has been attributed to defective cell adhesion proteins in the desmosomes that link adjacent cardiac myocytes. Naxos syndrome is a disorder characterized by arrhythmogenic right ventricular cardiomyopathy and hyperkeratosis of plantar palmar skin surfaces specifically associated with mutations in the gene encoding the desmosome-associated protein plakoglobin. showing dilation of the right ventricle and near-transmural replacement of the right ventricular free-wall by fat and fibrosis. The left ventricle has a virtually normal configuration in this case, but can also be involved by the disease process. B, Histologic section of the right ventricular free wall, demonstrating replacement of myocardium (red) by fibrosis (blue, arrow ) and fat (Masson trichrome stain).

A. Dilated Cardiomyopathy characterized morphologically and functionally by progressive cardiac dilation and contractile (SYSTOLIC) dysfunction, usually with concomitant hypertrophy. 30-50% Genetic causes: More than 20 genes involved. Cystokeleton, sarcolemma, nuclear envelope (Laminin A/C). TTN (titin) gene accounts for 20% of all DCM. Largest protein expressed by humans. Limits passive range of motion when sarcomere is stretched, functions like a molecular spring AD inheritance usually, can also be Xlinked, AR, mitochonrial. ox phos b ox of fatty acids dystorphin(with or without other symptoms of duchenne or becker muscular dystrophies) conduction abnormalities progression from myocarditis to DCM. VIRAL Myocarditis may be caussal here. ALCOHOL metabolites directly toxic to heart. Also thiamine deficiency can lead to Beriberi (indistinguishable from DCM) childbirth iron overload supraphysiologic stress: persistent tachycardia, hyperthyroidism, or even during development, as in the fetuses of insulin-dependent diabetic mothers Excess catecholamines , in particular, may result in multifocal myocardial contraction band necrosis from a pheocrhromocytoma cocaine, vasopressor agents like dopamine TAKOTSUBO: LV contractile dysfunction, extreme psych duress stunned or necrosis of multifocal contraction band. LV apex most often affected. fishing pot for traping octopus. apical ballooning. catecholamines might cause stress induced DCM becaue of direct myoctye toxicity due to CALCIUM OVERLOAD, or to focal vasoconstricction of coronary arterial circulation, in the face of an increasing heart rate.... similar changes might result from recoverd hypotensive episodes, ischemia reperfusion cycles, subsequent inflmmation. Reduced EF at end stage. Slow progression to CHF signs: dyspnea, easy fatigability, poor exertional capacity. Secondary Mitral Regurgitation often occurs, abnormal rhuthms Emboli from within the huge ventricle. Progressive cardiac failure or arrhythmia, can be sudden death. SOME respond to pharm. Cardiac transplant is helpful, long term mechanicla cardiac support or short term. CHAMBERS ENLARGED, heavy, flabby. Thrombi common, NO VALVULAR ALTERATIONS, only get mitral regurgitation if FUNCITONAL, a result of dilation. Variable myocyte hypertrophy, interstitial fibrosis with colllagen. Usually do not point to a specific etiology.

By the time of diagnosis, DCM has typically progressed to end-stage disease; the heart is dilated and poorly contractile. Unfortunately, at that point, even an exhaustive evaluation frequently fails to suggest a specific etiology. Increasingly, familial (genetic) forms of DCM are recognized, but the final pathology can also result from various acquired myocardial insults; as this implies, several different pathways can lead to DCM ( Fig. 12-31 ). • Genetic Influences. DCM is familial in at least 30% to 50% of cases, in which it is caused by mutations in a diverse group of more than 20 genes encoding proteins involved in the cytoskeleton, sarcolemma, and nuclear envelope (laminin A/C). In particular, mutations in TTN , a gene that encodes titin (so-called because it is the largest protein expressed in humans), may account for approximately 20% of all cases of DCM ( Fig. 12-30 ). In the genetic forms of DCM, autosomal dominant inheritance is the predominant pattern; X-linked, autosomal recessive, and mitochondrial inheritance are less common. In some families there are deletions in mitochondrial genes that result in defects in oxidative phosphorylation; in others there are mutations in genes encoding enzymes involved in β-oxidation of fatty acids. Mitochondrial defects typically manifest in the pediatric population, while X-linked DCM typically presents after puberty and into early adulthood. X-linked cardiomyopathy can also be associated with mutations affecting the membrane-associated dystrophin protein that couples cytoskeleton to the extracellular matrix; recall that dystrophin is mutated in the most common skeletal myopathies (i.e., Duchenne and Becker muscular dystrophies; Chapter 27 ). Some patients and families with dystrophin gene mutations have DCM as the primary clinical feature. Interestingly, and probably resulting from the common developmental origin of contractile myocytes and conduction elements, congenital abnormalities of conduction may also be associated with DCM. • Myocarditis . Sequential endomyocardial biopsies have documented progression from myocarditis to DCM. In other studies, the detection of the genetic fingerprints of coxsackie B and other viruses within myocardium of patients with DCM suggests that viral myocarditis can be causal (see later discussion). • Alcohol and other toxins . Alcohol abuse is strongly associated with the development of DCM, raising the possibility that ethanol toxicity ( Chapter 9 ) or a secondary nutritional disturbance can underlie myocardial injury. Alcohol or its metabolites (especially acetaldehyde) have a direct toxic effect on the myocardium. Moreover, chronic alcoholism may be associated with thiamine deficiency, which can lead to beriberi heart disease (also indistinguishable from DCM). Nevertheless, no morphologic features serve to distinguish alcoholic cardiomyopathy from DCM of other causes. In other cases, some other toxic insult can progress to eventual myocardial failure. Particularly important is myocardial injury caused by certain chemotherapeutic agents, including doxorubicin (Adriamycin), and even targeted cancer therapeutics (e.g., tyrosine kinase inhibitors). Cobalt is an example of a heavy metal with cardiotoxicity and has caused DCM in the setting of inadvertent tainting (e.g., in beer production). • Childbirth. A special form of DCM, termed peripartum cardiomyopathy , can occur late in pregnancy or up to months postpartum. The mechanism underlying this entity is poorly understood but is probably multifactorial. Pregnancy-associated hypertension, volume overload, nutritional deficiency, other metabolic derangements, or an as yet poorly characterized immunological reaction have been proposed as causes. Recent work suggests that the primary defect is a microvascular angiogenic imbalance within the myocardium leading to functional ischemic injury. Thus, peripartum cardiomyopathy can be elicited in mouse models by increased levels of circulating antiangiogenic mediators including vascular endothelial growth factor inhibitors (e.g., sFLT1, as occurs with preeclampsia) or antiangiogenic cleavage products of the hormone prolactin (which rises late in pregnancy). Proangiogenic approaches, including the blockade of prolactin secretion by bromocriptine, represent new therapeutic strategies for treating this disease. • Iron overload in the heart can result from either hereditary hemochromatosis ( Chapter 18 ) or from multiple transfusions. DCM is the most common manifestation of such iron excess, and may be caused by interference with metal-dependent enzyme systems or to injury from iron-mediated production of reactive oxygen species. • Supraphysiologic stress can also result in DCM. This can happen with persistent tachycardia, hyperthyroidism, or even during development, as in the fetuses of insulin-dependent diabetic mothers. Excess catecholamines , in particular, may result in multifocal myocardial contraction band necrosis that can eventually progress to DCM. This can happen in individuals with pheochromocytomas , tumors that elaborate epinephrine ( Chapter 24 ); use of cocaine or vasopressor agents such as dopamine can have similar consequences. Such "catecholamine effect" also occurs in the setting of intense autonomic stimulation, for example, secondary to intracranial lesions or emotional duress. Thus, takotsubo cardiomyopathy is an entity characterized by left ventricular contractile dysfunction following extreme psychological stress; affected myocardium may be stunned or show multifocal contraction band necrosis. For unclear reasons, the left ventricular apex is most often affected leading to "apical ballooning" that resembles a "takotsubo," Japanese for "fishing pot for trapping octopus" (hence, the name). The mechanism of catecholamine cardiotoxicity is uncertain, but likely relates either to direct myocyte toxicity due to calcium overload or to focal vasoconstriction in the coronary arterial macro- or microcirculation in the face of an increased heart rate. Similar changes may be encountered in individuals who have recovered from hypotensive episodes or have been resuscitated from a cardiac arrest; in such cases, the damage is a result of ischemia-reperfusion (see earlier) with subsequent inflammation. DCM can occur at any age, including in childhood, but it most commonly affects individuals between the ages of 20 and 50. It presents with slowly progressive signs and symptoms of CHF including dyspnea, easy fatigability, and poor exertional capacity. At the end stage, ejection fractions are typically less than 25% (normal = 50% to 65%). Secondary mitral regurgitation and abnormal cardiac rhythms are common, and embolism from intracardiac thrombi can occur. Death usually results from progressive cardiac failure or arrhythmia, and can occur suddenly. Although the annual mortality is high (10% to 50%), some severely affected patients respond well to pharmacologic therapy. Cardiac transplantation is also increasingly performed, and long-term ventricular assist can be beneficial. Interestingly, in some patients, relatively short-term mechanical cardiac support can induce durable improvement of cardiac function. heart is usually enlarged, heavy (often weighing two to three times normal), and flabby, due to dilation of all chambers ( Fig. 12-32 ). Mural thrombi are common and may be a source of thromboemboli. There are no primary valvular alterations; if mitral (or tricuspid) regurgitation is present, it results from left (or right) ventricular chamber dilation ( functional regurgitation ). Either the coronary arteries are free of significant narrowing or the obstructions present are insufficient to explain the degree of cardiac dysfunction. Four-chamber dilatation and hypertrophy are evident. There is a mural thrombus ( arrow ) at the apex of the left ventricle (on the right in this apical four-chamber view). The coronary arteries were patent. B , Histologic section demonstrating variable myocyte hypertrophy and interstitial fibrosis (collagen is highlighted as blue in this Masson trichrome stain).

I. Cardiac Structure and Specializations

Cardiomegaly Hypertrophy: increased ventricular wall thickness or weight. Dilation: enlarged chamber size.

F. Other Causes of Myocardial Disease . The anthracyclines doxorubicin and daunorubicin are the chemotherapeutic agents most often associated with toxic myocardial injury; they cause dilated cardiomyopathy with heart failure attributed primarily to peroxidation of lipids in myocyte membranes. lithium, phenothiazines, and chloroquine can idiosyncratically induce myocardial injury and sometimes sudden death. myofiber swelling, cytoplasmic vacuolization, and fatty change. AMYLOIDOSIS: extracellular accumulation of protein fibrils that are prone to forming insoluble β-pleated sheets CAN BE: systemic amyloidosis (e.g., due to myeloma or inflammation-associated amyloid) or can be restricted to the heart, particularly in the aged ( senile cardiac amyloidosis - better prognosis ). SENILE: transthyretin , a normal serum protein synthesized in the liver that trans ports thy roxine and retin ol-binding protein. Mutant forms of transthyretin can accelerate the cardiac (and associated systemic) amyloid deposition Isolated atrial amyloidosis can also occur secondary to deposition of atrial natriuretic peptide, but its clinical significance is uncertain. The chambers are usually of normal size, but can be dilated and have thickened walls. Heart becomes firm and rubbery . semitranslucent nodules resembling drips of wax may be seen on the atrial endocardial surface, particularly on the left. hyaline eosinophilic deposits of amyloid may be found in the interstitium, conduction tissue, valves, endocardium, pericardium, and small intramural coronary arteries Congo red, which produces classic apple-green birefringence when viewed under polarized light

Cardiotoxic Drugs. Cardiac complications of cancer therapy are an important clinical problem; cardiotoxicity has been associated with conventional chemotherapeutic agents, tyrosine kinase inhibitors, and certain forms of immunotherapy. The anthracyclines doxorubicin and daunorubicin are the chemotherapeutic agents most often associated with toxic myocardial injury; they cause dilated cardiomyopathy with heart failure attributed primarily to peroxidation of lipids in myocyte membranes. Anthra cycline toxicity is dose-dependent, with the cardiotoxicity risk increasing when cumulative life-time doses exceed 500 mg/m 2 . Many other therapeutic agents, including lithium, phenothiazines, and chloroquine can idiosyncratically induce myocardial injury and sometimes sudden death. Common findings in affected myocardium include myofiber swelling, cytoplasmic vacuolization, and fatty change. Discontinuing the offending agent often leads to prompt resolution, without apparent sequelae. Occasionally, however, more extensive damage produces myocyte necrosis that can evolve to a dilated cardiomyopathy. Amyloidosis. Amyloidosis results from the extracellular accumulation of protein fibrils that are prone to forming insoluble β-pleated sheets ( Chapter 6 ). Cardiac amyloidosis can appear as a consequence of systemic amyloidosis (e.g., due to myeloma or inflammation-associated amyloid) or can be restricted to the heart, particularly in the aged ( senile cardiac amyloidosis ). Senile cardiac amyloidosis characteristically occurs in individuals 70 years and older, and has a far better prognosis than systemic amyloidosis. Senile cardiac amyloid deposits are largely composed of transthyretin , a normal serum protein synthesized in the liver that trans ports thy roxine and retin ol-binding protein. Mutant forms of transthyretin can accelerate the cardiac (and associated systemic) amyloid deposition; 4% of African-Americans have a transthyretin mutation substituting isoleucine for valine at position 122 that produces a particularly amyloidogenic protein, responsible for autosomal dominant familial transthyretin amyloidosis. Isolated atrial amyloidosis can also occur secondary to deposition of atrial natriuretic peptide, but its clinical significance is uncertain. Cardiac amyloidosis most frequently produces a restrictive cardiomyopathy, but it can also be asymptomatic, manifest as dilation or arrhythmias, or mimic ischemic or valvular disease. The varied presentations depend on the predominant location of the deposits, for example, interstitium, conduction system, vasculature, or valves. Morphology In cardiac amyloidosis the heart varies in consistency from normal to firm and rubbery. The chambers are usually of normal size, but can be dilated and have thickened walls. Small, semitranslucent nodules resembling drips of wax may be seen on the atrial endocardial surface, particularly on the left. Histologically, hyaline eosinophilic deposits of amyloid may be found in the interstitium, conduction tissue, valves, endocardium, pericardium, and small intramural coronary arteries ( Fig. 12-36 ); they can be distinguished from other deposits by special stains such as Congo red, which produces classic apple-green birefringence when viewed under polarized light ( Fig. 12-36 B ). Intramural arteries and arterioles may have sufficient amyloid in their walls to compress and occlude their lumens, inducing myocardial ischemia ("small-vessel disease").

B. Left Sided Heart Failure

Causes: HTN, Ischemic heart disease, aortic and mitral valve disease, primary myocardial disease. -The clinical and morphologic effects of left-sided CHF are a consequence of passive congestion (blood backing up in the pulmonary circulation), stasis of blood in the left-sided chambers, and inadequate perfusion of downstream tissues leading to organ dysfunction. -LV is usually hypertrophied. sometimes dilated. Fibrosis and hypertrophy are present. Usually LA is dilated, with risk of atrial fibrillation, thrombus within LAA. -Pulmonary congestion and edema produce heavy, wet lungs. Can be edema perivascular and interstitial in septa (Kerley B and C lines). Progressive widening of septa, accumulation of fluid in alveolar spaces. RBCs end up in lungs in fluid, make hemosiderin laden macrophages (HEART FAILURE CELLS), indicate previous pulmonary edema. Pleural effusions can result from elevated pleural capillary pressures, resultant transudation of fluid into pleural cavities -1st pulmonary congestion-cough, dyspnea. -Paroxysmal nocturnal dyspnea- at night induces feeling of suffocation. -orthopnea-dyspnea while supine. -Reduced EF leads to diminished renal perfusion. This causes a perceived hypotension and activation of RAAS, expansion of fluid volumes. Exacerbates ongoing pulmonary edema. Can lead to kidney pre renal azotemia because of low perfusion. Hypoxic encephalopathy cerebral hypo perfusion. -Systolic cause: EF low due to loss of contraction function. -Diastolic cause;

II. Effects of Aging on the Heart

Chambers Increased left atrial cavity size Decreased left ventricular cavity size (with HTN causes bulging and sigmoid shape) Sigmoid-shaped ventricular septum (bulging basal ventricular septum into LV outflow tract) Valves Aortic valve calcific deposits Mitral valve annular calcific deposits Fibrous thickening of leaflets Buckling of mitral leaflets toward the left atrium Lambl excrescences ( small filiform processes on closure lines of aortic and mitral valves-small thrombi organized) Epicardial Coronary Arteries Tortuosity Diminished compliance Calcific deposits Atherosclerotic plaque Myocardium Decreased mass Increased subepicardial fat Brown atrophy Lipofuscin deposition (oxidant stress, catabolism) Basophilic degeneration(gray blue product of glycogen metabolism) Amyloid deposits (ANP in atria only, or transthyretin) Aorta Dilated ascending aorta with rightward shift Elongated (tortuous) thoracic aorta Sinotubular junction calcific deposits Elastic fragmentation and collagen accumulation Atherosclerotic plaque

Mostly Autosomal Dominant Inheritance

Channelopathies that lead to arrhythmias

E. Cardiac Stem Cells

Classically: no replicative potential. Perhaps some bone marrow based cells within myocardium capable of repopulating mammalian heart, generating new lineages (5-10 % of heart). -Cardiac stem cells great in neonates, decreases with age. By 50, 45% of myocytes have been renewed. -Following irreversible myocardial damage, cells do not recover significantt function in necrotic zone.

VII. Arrhythmias

Disorder Gene Function Long QT syndrome † KCNQ1 K + channel (LOF) KCNH2 K + channel (LOF) SCN5A Na + channel (GOF) CAV3 Caveolin, Na + current (GOF) Short QT syndrome † KCNQ1 K + channel (GOF) KCNH2 K + channel (GOF) Brugada syndrome † SCN5A Na + channel (LOF) CACNB2b Ca ++ channel (LOF) SCN1b Na + channel (LOF) * CPVT syndrome † RYR2 Diastolic Ca ++ release (GOF) CASQ2 Diastolic Ca ++ release (LOF) † Long QT syndrome manifests as arrhythmias associated with excessive prolongation of the cardiac repolarization; patients often present with stress-induced syncope or sudden cardiac death (SCD), and some forms are associated with swimming. Short QT syndrome patients have arrhythmias associated with abbreviated repolarization intervals; they can present with palpitations, syncope, and SCD. Brugada syndrome manifests as ECG abnormalities (ST segment elevations and right bundle branch block) in the absence of structural heart disease; patients classically present with syncope or SCD during rest or sleep, or after large meals. CPVT does not have characteristic ECG changes; patients often present in childhood with life-threatening arrhythmias due to adrenergic stimulation (stress-related).

Nonsyndromic ASD or conduction defects NKX2.5 Transcription factor ASD or VSD GATA4 Transcription factor Tetralogy of Fallot ZFPM2 or NKX2.5 Transcription factors Syndromic † Alagille syndrome—pulmonary artery stenosis or tetralogy of Fallot JAG1 or NOTCH2 Signaling proteins or receptors Char syndrome—PDA TFAP2B Transcription factor CHARGE syndrome—ASD, VSD, PDA, or hypoplastic right side of the heart CHD7 Helicase-binding protein DiGeorge syndrome—ASD, VSD, or outflow tract obstruction TBX1 Transcription factor Holt-Oram syndrome—ASD, VSD, or conduction defect TBX5 Transcription factor Noonan syndrome—pulmonary valve stenosis, VSD, or hypertrophic cardiomyopathy PTPN11, KRAS, SOS1 Signaling proteins

GATA4, TBX3 and NKX2-5 all bind together to regulate expression of target genes required for normal cardiac development. GATA4 and TBX20 are also mutated in rare forms of ADULT onset cardiomyopathy Mutations in the Notch pathway are also associated with bicuspid aortic valves and TofF. Fibrilllin mutations are associated with Marfan Syndrome Hyperactive TGF beta pathway contributes to Marfan and Loeys-Dietz.

C. Hypertrophic Cardiomyopathy Common, heterogenous, poorly compliant LV myocardium, abnormal diastolic filling and outflow obstruction in some cases. LV thick, , HYPERCONTRACTILE, as opposed to hypocontraction in DCM. DIASTOLIC DYSFUNCTION Easily confused with HTN (with age related sub aortic septal hypertrophy) and deposition disease (amyloidosis and Fabry disease). Occasionally aortic stenosis can mimiic HCM. Autosomal dominant with variable penetrance. Muts in sarcomeric protiens. over 400 . most common mutation is β-myosin heavy chain (β-MHC), then nT, α-tropomyosin, and myosin-binding protein C (MYBP-C) MASSIVE LV hypertropy, usually without dilatation . Especially the free wall, not the septum. Usually concentric and symmetrical hypertrophy. Banana curved septum. LV outflow tract near aortic valve is often thickened and plaqued. Histologic appearance demonstrating myocyte disarray, extreme hypertrophy, and exaggerated myocyte branching, as well as the characteristic interstitial fibrosis (1) massive myocyte hypertrophy, with transverse myocyte diameters frequently greater than 40 µm (normal, approximately 15 µm); (2) haphazard disarray of bundles of myocytes, individual myocytes, and contractile elements in sarcomeres within cells (termed myofiber disarray ); and (3) interstitial and replacement fibrosis The central abnormality in HCM is reduced stroke volume due to impaired diastolic filling. -banana septum with LVOT obstruction -USE BETA BLOCKERS -Reduced stroke volume due to reduced preload, as well as pulmonary backup. Common focal necrosis due to increased myocardial oxygen demand. trial fibrillation, mural thrombus formation leading to embolization and possible stroke, intractable cardiac failure, ventricular arrhythmias, and, not infrequently, sudden death, reduce septum girth: controlled septal infarction through a catheter-based infusion of alcohol.

Hypertrophic cardiomyopathy (HCM) is a common (incidence, 1 in 500), clinically heterogeneous, genetic disorder characterized by myocardial hypertrophy, poorly compliant left ventricular myocardium leading to abnormal diastolic filling, and (in about one third of cases) intermittent ventricular outflow obstruction. It is the leading cause of left ventricular hypertrophy unexplained by other clinical or pathologic causes. The heart is thick-walled, heavy, and hyper contracting, in striking contrast to the flabby, hypo contracting heart of DCM. HCM causes primarily diastolic dysfunction; systolic function is usually preserved. The two most common diseases that must be distinguished clinically from HCM are deposition diseases (e.g., amyloidosis, Fabry disease) and hypertensive heart disease coupled with age-related subaortic septal hypertrophy (see earlier discussion under Hypertensive Heart Disease). Occasionally, valvular or congenital subvalvular aortic stenosis can also mimic HCM. Pathogenesis. In most cases, the pattern of transmission is autosomal dominant with variable penetrance. HCM is caused by mutations in any one of several genes that encode sarcomeric proteins; there are more than 400 different known mutations in nine different genes, most being missense mutations. Mutations causing HCM are found most commonly in the gene encoding β-myosin heavy chain (β-MHC), followed by the genes coding for cardiac TnT, α-tropomyosin, and myosin-binding protein C (MYBP-C); overall, these account for 70% to 80% of all cases. Different affected families may have distinct mutations involving the same protein. For example, approximately 50 different mutations of β-MHC are known to cause HCM. The prognosis of HCM varies widely and correlates strongly with specific mutations. Although it is clear that these genetic defects are critical to the etiology of HCM, the sequence of events leading from mutations to disease is still poorly understood. As discussed above, HCM is a disease caused by mutations in proteins of the sarcomere. Although such sarcomeric alterations have been thought to be pathologic on the basis of abnormal cardiac contraction causing a secondary compensatory hypertrophy, newer evidence suggests that HCM may instead arise from defective energy transfer from its source of generation (mitochondria) to its site of use (sarcomeres). In addition, the interstitial fibrosis in HCM probably occurs secondary to exaggerated responses of the myocardial fibroblasts to the primary myocardial dysfunction. In contrast, DCM is mostly associated with abnormalities of cytoskeletal proteins ( Fig. 12-30 ), and can be conceptualized as a disease of abnormal force generation, force transmission, or myocyte signaling. To complicate matters, mutations in certain genes, depicted in Figure 12-30 , can give rise to either HCM or DCM, depending on the site and nature of the mutation. The essential feature of HCM is massive myocardial hypertrophy, usually without ventricular dilation ( Fig. 12-34 ). The classic pattern involves disproportionate thickening of the ventricular septum relative to the left ventricle free wall (with a ratio of septum to free wall greater than 3 : 1), termed asymmetric septal hypertrophy . In about 10% of cases, the hypertrophy is concentric and symmetrical. On longitudinal sectioning, the normally round-to-ovoid left ventricular cavity may be compressed into a "banana-like" configuration by bulging of the ventricular septum into the lumen ( Fig. 12-34 A ). Although marked hypertrophy can involve the entire septum, it is usually most prominent in the subaortic region. The left ventricular outflow tract often exhibits a fibrous endocardial plaque associated with thickening of the anterior mitral leaflet. Both findings result from contact of the anterior mitral leaflet with the septum during ventricular systole; they correlate with the echocardiographic "systolic anterior motion" of the anterior leaflet, with functional left ventricular outflow tract obstruction during mid-systole. Hypertrophic cardiomyopathy with asymmetric septal hypertrophy. A, The septal muscle bulges into the left ventricular outflow tract, and the left atrium is enlarged. The anterior mitral leaflet has been reflected away from the septum to reveal a fibrous endocardial plaque (arrow) (see text). B, Histologic appearance demonstrating myocyte disarray, extreme hypertrophy, and exaggerated myocyte branching, as well as the characteristic interstitial fibrosis (collagen is blue in this Masson trichrome stain). The most important histologic features of HCM myocardium are (1) massive myocyte hypertrophy, with transverse myocyte diameters frequently greater than 40 µm (normal, approximately 15 µm); (2) haphazard disarray of bundles of myocytes, individual myocytes, and contractile elements in sarcomeres within cells (termed myofiber disarray ); and (3) interstitial and replacement fibrosis ( Fig. 12-34 B ). Clinical Features. The central abnormality in HCM is reduced stroke volume due to impaired diastolic filling. This is a consequence of a reduced chamber size, as well as the reduced compliance of the massively hypertrophied left ventricle. In addition, approximately 25% of patients with HCM have dynamic obstruction to the left ventricular outflow. The compromised cardiac output in conjunction with a secondary increase in pulmonary venous pressure explains the exertional dyspnea seen in these patients. Auscultation discloses a harsh systolic ejection murmur, caused by the ventricular outflow obstruction as the anterior mitral leaflet moves toward the ventricular septum during systole. Because of the massive hypertrophy, high left ventricular chamber pressure, and frequently thick-walled intramural arteries, focal myocardial ischemia commonly results, even in the absence of concomitant coronary artery disease. Major clinical problems in HCM are atrial fibrillation, mural thrombus formation leading to embolization and possible stroke, intractable cardiac failure, ventricular arrhythmias, and, not infrequently, sudden death, especially with certain specific mutations. Indeed, HCM is one of the most common causes of sudden, otherwise unexplained death in young athletes. The natural history of HCM is highly variable. Most patients can be helped by pharmacologic intervention (e.g., β-adrenergic blockade) to decrease heart rate and contractility. Some benefit can also be gained by reducing the septal myocardial mass, thus relieving the outflow tract obstruction. This can be achieved either by surgical excision of muscle or by carefully controlled septal infarction through a catheter-based infusion of alcohol.

A. Cardiac Hypertrophy: Pathophysiology and Progression to Heart Failure

Hypertrophy requires addition of new protein synthesis, additional sarcomeres. Also have enlarged nuclei, increased DNA policy due to DNA replication in absence of cell division. Pressure overload: new sarcomeres in parallel0 concentric hypertrophy Volume overload: new sarcomeres in series, ventricular dilation, eccentric hypertrophy -Heaviest hearts: aortic regurgitation or hypertrophic cardiomyopathy. -Heavy hearts: systemic hypertension, ischemic heart disease, aortic stenosis, mitral regurgitation, or dilated cardiomyopathy. -HYPERTROPHY DOES OT COME WITH INCREASE IN CAPILLARY NUMBERS, so risk of ischemia is higher. And oxygen use is higher. -Often accompanied by fibrous tissue deposition. Molecular changes include the expression of immediate-early genes (e.g., FOS, JUN, MYC, and EGR1 ), With prolonged hemodynamic overload, there may be a shift to a gene expression pattern resembling that seen during fetal cardiac development (including selective expression of embryonic/fetal forms of β-myosin heavy chain, natriuretic peptides, and collagen). -Good short term increase in CO, long term risk of ischemia due to bigger heart. -Long term aerobic exercise may cause dilated hypertrophy with increase in capillaries. Weight lifting leads to pressure overload. -Whatever its basis, CHF is characterized by variable degrees of decreased cardiac output and tissue perfusion (sometimes called forward failure), as well as pooling of blood in the venous capacitance system (backward failure); the latter may cause pulmonary edema, peripheral edema, or both.

VI. Ischemic Heart Disease

MI risk is correlated with genetic variants that modify leukotriene B4 metabolism. not correlated with coronary atherosclerosis. -75% obstruction, angina with exercise, compensatory reserve vasodilation no longer enough to meet increases in demand. -90% obstruction: inadequate coronary blood flow even at rest. -Clinically significant plaques can be located anywhere along the course of the vessels, particularly the RCA, although they tend to predominate within the first several centimeters of the LAD and LCX. - atherosclerosis of the intramural (penetrating) branches is rare -inflammation usually causes rupture and leads to symptoms. • Stable angina results from increases in myocardial oxygen demand that outstrip the ability of stenosed coronary arteries to increase oxygen delivery; it is usually not associated with plaque disruption. • Unstable angina is caused by plaque DISRUPTION that results in THROMBOSIS and vasoconstriction, and leads to severe but transient reductions in coronary blood flow. In some cases, microinfarcts can occur distal to disrupted plaques due to thromboemboli. • Myocardial infarction (MI) is often the result of acute plaque change that induces an abrupt thrombotic occlusion, resulting in myocardial necrosis. • Sudden cardiac death may be caused by regional myocardial ischemia that induces a fatal ventricular arrhythmia.

2. Endocarditis of Systemic Lupus Erythematous (Libman-Sacks Disease) BOTH SIDES OF VALVE. small, sterile, mitral and tricuspid. multiple or sterile. PINK VERUCOUS warty. finely granular, fibrinous eosinophilic material containing cellular debris including nuclear remnants. can occur on chordae too intense vlavulitis: fibrinoid necrosis caused by Fc receptor binding cells recruitment. antiphospholipid syndrome, which can also induce a hypercoagulable state ( Chapter 4 ). The mitral valve is more frequently involved than the aortic valve, and regurgitation is the usual functional abnormality.

Mitral and tricuspid valvulitis with small, sterile vegetations, called Libman-Sacks endocarditis , is occasionally encountered in systemic lupus erythematosus. Due to the use of steriods, the incidence of this complication has been greatly reduced. The lesions are small (1 to 4 mm in diameter), single or multiple, sterile, pink vegetations with a warty (verrucous) appearance. They may be located on the undersurfaces of the atrioventricular valves, on the valvular endocardium, on the chords, or on the mural endocardium of atria or ventricles. Histologically the vegetations consist of a finely granular, fibrinous eosinophilic material containing cellular debris including nuclear remnants. Vegetations are often associated with an intense valvulitis, characterized by fibrinoid necrosis of the valve substance and reflecting the activation of complement and recruitment of Fc-receptor-bearing cells. Thrombotic heart valve lesions with sterile vegetations or rarely fibrous thickening can occur in the setting of the antiphospholipid syndrome, which can also induce a hypercoagulable state ( Chapter 4 ). The mitral valve is more frequently involved than the aortic valve, and regurgitation is the usual functional abnormality.

V. Congenital Heart Disease

Most congenital heart disease arises from faulty embryogenesis during gestational weeks 3 through 8, when major cardiovascular structures form and begin to function. -Defects that affect individual chambers or discrete regions of the heart are often compatible with embryologic maturation and eventual live birth. In this category are septation defects, unilateral obstructions, and outflow tract anomalies. -Septal defects, or "holes in the heart", include atrial septal defects (ASDs) or ventricular septal defects (VSDs). -Stenotic lesion can be at the level of the cardiac valve or entire cardiac chamber, as in hypoplastic left heart syndrome. -Outflow tract anomalies include inappropriate routing of the great vessels from the ventricular mass. These forms of congenital heart disease usually produce clinically important manifestations only after birth—unveiled by the transition from fetal to perinatal circulation. -VSD>ASD>Pulm Sten>PDA>ToF>Coarctationof aorta<AVSD>Aortic S>TGA>truncus arteriosus>total anomalous pulmonary venous connection>tricuspid atresia. Heart Development: Save Email Print Top of Book Chapter Cardiac Development. Go to:Outline Cover of Robbins and Cotran Pathologic Basis of Disease Robbins and Cotran Pathologic Basis of Disease Ninth Edition Copyright © 2015, 2010, 2004, 1999, 1994, 1989, 1984, 1979, 1974 by Saunders, an imprint of Elsevier Inc. Get rights and content BOOK CHAPTER The Heart PDF not available through ClinicalKey Frederick J. Schoen and Richard N. Mitchell Robbins and Cotran Pathologic Basis of Disease, Chapter 12, 523-578 Chapter Contents Cardiac Structure and Specializations 523 Myocardium 524 Valves 524 Conduction System 524 Blood Supply 525 Cardiac Stem Cells 525 Effects of Aging on the Heart 525 Overview of Cardiac Pathophysiology 526 Heart Failure 526 Cardiac Hypertrophy: Pathophysiology and Progression to Heart Failure 527 Left-Sided Heart Failure 529 Right-Sided Heart Failure 530 Congenital Heart Disease 531 Left-to-Right Shunts 533 Atrial Septal Defect 534 Ventricular Septal Defect 535 Patent Ductus Arteriosus 535 Right-to-Left Shunts 535 Tetralogy of Fallot 535 Transposition of the Great Arteries 536 Tricuspid Atresia 537 Obstructive Lesions 537 Coarctation of the Aorta 537 Pulmonary Stenosis and Atresia 537 Aortic Stenosis and Atresia 537 Ischemic Heart Disease 538 Angina Pectoris 539 Myocardial Infarction 540 Chronic Ischemic Heart Disease 550 Arrhythmias 550 Sudden Cardiac Death (SCD) 551 Hypertensive Heart Disease 552 Systemic (Left-Sided) Hypertensive Heart Disease 552 Pulmonary (Right-Sided) Hypertensive Heart Disease (Cor Pulmonale) 553 Valvular Heart Disease 554 Calcific Valvular Degeneration 554 Calcific Aortic Stenosis 554 Calcific Stenosis of Congenitally Bicuspid Aortic Valve 555 Mitral Annular Calcification 556 Mitral Valve Prolapse (Myxomatous Degeneration of the Mitral Valve) 556 Rheumatic Fever and Rheumatic Heart Disease 557 Infective Endocarditis 559 Noninfected Vegetations 561 Nonbacterial Thrombotic Endocarditis 561 Endocarditis of Systemic Lupus Erythematosus (Libman-Sacks Disease) 562 Carcinoid Heart Disease 562 Complications of Prosthetic Valves 563 Cardiomyopathies 564 Dilated Cardiomyopathy 565 Arrhythmogenic Right Ventricular Cardiomyopathy 568 Hypertrophic Cardiomyopathy 568 Restrictive Cardiomyopathy 570 Myocarditis 570 Other Causes of Myocardial Disease 571 Pericardial Disease 573 Pericardial Effusion and Hemopericardium 573 Pericarditis 573 Acute Pericarditis 573 Heart Disease Associated with Rheumatologic Disorders 575 Tumors of the Heart 575 Primary Cardiac Tumors 575 Cardiac Effects of Noncardiac Neoplasms 576 Cardiac Transplantation 577 The human heart is a remarkably efficient, durable, and reliable pump, distributing more than 6000 liters of blood through the body each day, and beating 30 to 40 million times a year—providing tissues with vital nutrients and facilitating waste excretion. Consequently, cardiac dysfunction can have devastating physiologic consequences. Cardiovascular disease (including coronary artery disease, stroke, and peripheral vascular disease) is the number one cause of worldwide mortality, with about 80% of the burden occurring in developing countries. In the United States alone, cardiovascular disease accounts for roughly a third of all deaths, totaling about 800,000 individuals—or nearly 1.5 times the number of deaths caused by all forms of cancer combined. Disruption of any element of the heart—myocardium, valves, conduction system, and coronary vasculature—can adversely affect pumping efficiency, thus leading to morbidity and mortality. The major categories of cardiac disease described in this chapter include congenital heart abnormalities, ischemic heart disease, hypertensive heart disease, diseases of the cardiac valves, and primary myocardial disorders. A few comments about pericardial diseases and cardiac neoplasms, as well as cardiac transplantation, are also presented. This chapter begins with a brief review of the normal heart since most cardiac diseases manifest as structural and/or functional changes in one or more cardiac components. General principles underlying cardiac hypertrophy and failure—common end points of several of the different forms of heart disease—are also discussed. Cardiac Structure and Specializations Heart weight varies with body habitus, averaging approximately 0.4% to 0.5% of body weight (250 to 320 gm in females and 300 to 360 gm in males); the right ventricle wall thickness is usually 0.3 to 0.5 cm, while the left ventricle wall is 1.3 to 1.5 cm thick. Increases in heart weight or ventricular thickness above these normal limits indicates hypertrophy , and an enlarged chamber size implies dilation ; both can represent compensatory changes in response to heart disease and to volume and/or pressure overloads (see later). Increased cardiac weight or size (or both)—resulting from hypertrophy and/or dilation—is called cardiomegaly. Myocardium The pumping function of the heart is accomplished via the coordinated contraction (during systole ) and relaxation (during diastole ) of the cardiac myocytes that comprise the myocardium . Left ventricular myocytes are arranged circumferentially in a spiral orientation that helps to generate a coordinated wave of contraction that spreads from the apex to the base of the heart. In contrast, right ventricular myocytes have a somewhat less structured organization. The contractile apparatus within myocytes is organized into a series of subunits called sarcomeres , composed of highly ordered networks of thick filaments (primarily myosin in the center of the sarcomere) interlaced with thin filaments (largely actin, attached to the end of the sarcomere) and regulatory proteins such as troponin and tropomyosin. The actin and myosin filaments partially overlap with each other, giving rise to the striated appearance of cardiac myocytes (overlapping areas of actin and myosin are dark while the intervening areas are light). Contraction results as myosin filaments ratchet adjacent actin filaments toward the center—shortening individual sarcomeres, and collectively leading to myocyte shortening. The amount of force generated is determined by the distance each sarcomere contracts. Thus, moderate ventricular dilation during diastole creates a greater distance over which the sarcomere can subsequently shorten and augment the force of systolic contraction. This compensatory mechanism serves to accommodate differing volume and pressure demands. Unfortunately, there is an upper limit to the benefit of increased stretching during diastole. With excessive dilation, the overlap of the actin and myosin filaments is reduced and the force of contraction decreases sharply, leading to heart failure. Atrial myocytes are relatively haphazardly arranged, and thus generate weaker contractile forces than the ventricles. Some atrial cells have distinctive cytoplasmic electron-dense storage granules that contain atrial natriuretic peptide ; this is a peptide hormone that promotes arterial vasodilation and stimulates renal salt and water elimination ( natriuresis and diuresis ), actions that are beneficial in the setting of hypertension and congestive heart failure. The coordinated beating of cardiac myocytes depends on intercalated discs —specialized intercellular junctions that facilitate cell-to-cell mechanical and electrical (ionic) coupling. Within the intercalated discs (and at the lateral borders of adjacent myocytes), gap junctions facilitate synchronized waves of myocyte contraction by permitting rapid movement of ions (e.g., sodium, potassium, calcium) between adjoining cells. Abnormalities in the spatial distribution of gap junctions in a variety of heart diseases can cause electromechanical dysfunction ( arrhythmia ) and/or heart failure. Valves The four cardiac valves—tricuspid, pulmonary, mitral, and aortic—maintain unidirectional blood flow. Valve function depends on the mobility, pliability, and structural integrity of the leaflets of the atrioventricular valves (tricuspid and mitral) or cusps of the semilunar valves (aortic and pulmonary). Cardiac valves are lined by endothelium and share a similar, tri-layered architecture: • A dense collagenous core ( fibrosa ) at the outflow surface and connected to the valvular supporting structures • A central core of loose connective tissue ( spongiosa ) • A layer rich in elastin ( ventricularis or atrialis depending on which chamber it faces) on the inflow surface The collagen of the ventricularis is largely responsible for the mechanical integrity of a valve, while the elastic tissue of the atrialis/ventricularis imparts a rapid recoil to achieve prompt valve closure. The proteoglycan-rich spongiosa facilitates the interactions of the collagenous (relatively stiff) and elastic layers during the cardiac cycle. Crucial to function are the valvular interstitial cells, the most abundant cell type in the heart valves, and distributed throughout all of its layers. Valvular interstitial cells synthesize extracellular matrix (ECM) and express matrix degrading enzymes (including matrix metalloproteinases [MMPs], along with inhibitors that remodel collagen and other matrix components. Valvular interstitial cells comprise a diverse and dynamic population of resident cells that can alter their phenotypes and functions in response to changing hemodynamic stresses. The function of the semilunar valves depends on the integrity and coordinated movements of the cuspal attachments. Thus, dilation of the aortic root can hinder coaptation of the aortic valve cusps during closure and result in valvular regurgitation. In contrast, the competence of the atrioventricular valves depends on the proper function not only the leaflets but also the tendinous cords and the attached papillary muscles of the ventricular wall. Left ventricular dilation, a ruptured tendinous cord, or papillary muscle dysfunction can all interfere with valve closure, causing valvular insufficiency. Because they are thin enough to be nourished by diffusion from the blood, normal leaflets and cusps have only scant blood vessels limited to the proximal portion. Pathologic changes of valves are largely of three types: damage to collagen that weakens the leaflets, exemplified by mitral valve prolapse; nodular calcification beginning in interstitial cells, as in calcific aortic stenosis; and fibrotic thickening, the key feature in rheumatic heart disease (see later). Conduction System Coordinated contraction of the cardiac muscle depends on propagation of electrical impulses—accomplished through specialized excitatory and conducting myocytes within the cardiac conduction system that regulate heart rate and rhythm. The frequency of electrical impulses that course through the conduction system is sensitive to neural inputs (e.g., vagal stimulation), extrinsic adrenergic agents (e.g., adrenaline), hypoxia, and potassium concentration (i.e., hyperkalemia can block signal transmission altogether). Inputs from the autonomic nervous system can increase the heart rate to twice normal within seconds, and are important for physiologic responses to exercise or other states associated with increased oxygen demand. The components of the conduction system include: • Sinoatrial (SA) node pacemaker (at the junction of the right atrial appendage and superior vena cava) • Atrioventricular ( AV) node (located in the right atrium along the atrial septum) • Bundle of His , connecting the right atrium to the ventricular septum • Subsequent divisions into the right and left bundle branches that stimulate their respective ventricles via further arborization into the Purkinje network The cells of the cardiac conduction system depolarize spontaneously, enabling them to function as cardiac pacemakers. Because the normal rate of spontaneous depolarization in the SA node (60 to 100 beats/minute) is faster than the other components, it normally sets the pace. The AV node has a gatekeeper function; by delaying the transmission of signals from the atria to the ventricles, it ensures that atrial contraction precedes ventricular systole. Blood Supply Cardiac myocytes rely almost exclusively on oxidative phosphorylation for their energy needs. Besides a high density of mitochondria (20% to 30% of myocyte volume), myocardial energy generation also requires a constant supply of oxygenated blood—rendering myocardium extremely vulnerable to ischemia. Nutrients and oxygen are delivered via the coronary arteries , with takeoffs immediately distal to the aortic valve. These initially course along the external surface of the heart (epicardial coronary arteries) and then penetrate the myocardium (intramural arteries), subsequently branching into arterioles, and eventually forming a rich arborizing vascular network so that each myocyte contacts roughly three capillaries. There are three major epicardial coronary arteries (so-called because they form a crown or corona at the base of the heart): • Left anterior descending (LAD) and left circumflex (LCX) arteries arise from the left (main) coronary artery • Right coronary artery The divisions of the LAD are called diagonal branches, and those of the LCX are marginal branches. The right and left coronary arteries function as end arteries, although anatomically most hearts have numerous intercoronary anastomoses (connections called collateral circulation). Blood flow to the myocardium occurs during ventricular diastole, following closure of the aortic valve, and when the microcirculation is not compressed by cardiac contraction. At rest, diastole comprises approximately two thirds of the cardiac cycle; with tachycardia (increased heart rate), the relative duration of diastole also shortens, thus potentially compromising cardiac perfusion. Cardiac Stem Cells Although cardiac regeneration in metazoans (e.g., newts and zebrafish) is well described, the myocardium of higher order animals is classically depicted as a permanent cell population without replicative potential. However, increasing evidence points to the presence of bone marrow-derived precursors—as well as a small population of stem cells within the myocardium—that are capable of repopulating the mammalian heart. Besides self-renewal, these cardiac stem cells generate all cell lineages seen within the myocardium. They constitute up to 5% to 10% of normal atrial cellularity, but represent only roughly 1 in 100,000 cells in a normal ventricle. Cardiac stem cells have a very slow rate of proliferation, which is greatest in neonates, and decreases with age. The human adult heart replaces roughly 1% of its total population each year, so that by the age of 50 years, almost 45% of the total cardiomyocytes have been renewed. While stem cell numbers and progeny increase after myocardial injury or hypertrophy, albeit to a limited extent, hearts that suffer myocardial cell loss (e.g., due to infarction) do not recover any significant function in the necrotic zone (one of several features that distinguish humans from fish and newts). Nevertheless, the potential for stimulating proliferation and differentiation of these cells in vivo is tantalizing since it could facilitate recovery of myocardial function following irreversible myocardial damage. Similarly, ex vivo expansion and subsequent administration of stem cells is another strategy being explored in the unfulfilled quest to heal a broken heart. Until then a trip to the local jewelry store will have to suffice! Effects of Aging on the Heart The prevalence of most forms of heart disease increases with each advancing decade. Consequently, as the average population in developed countries ages, changes in the cardiovascular system that accrue with aging become increasingly significant ( Table 12-1 ). Table 12-1 Changes in the Aging Heart Chambers Increased left atrial cavity size Decreased left ventricular cavity size Sigmoid-shaped ventricular septum Valves Aortic valve calcific deposits Mitral valve annular calcific deposits Fibrous thickening of leaflets Buckling of mitral leaflets toward the left atrium Lambl excrescences Epicardial Coronary Arteries Tortuosity Diminished compliance Calcific deposits Atherosclerotic plaque Myocardium Decreased mass Increased subepicardial fat Brown atrophy Lipofuscin deposition Basophilic degeneration Amyloid deposits Aorta Dilated ascending aorta with rightward shift Elongated (tortuous) thoracic aorta Sinotubular junction calcific deposits Elastic fragmentation and collagen accumulation Atherosclerotic plaque Epicardial fat increases, while the detritus of years of intracellular catabolism and oxidant stress accumulate in the form of intracellular lipofuscin. Basophilic degeneration , a gray-blue byproduct of glycogen metabolism within cardiac myocytes, is also increased. The size of the left ventricular cavity, particularly in the base-to-apex dimension, is reduced; this volume change is exacerbated by systemic hypertension and bulging of the basal ventricular septum into the left ventricular outflow tract (termed sigmoid septum ). Valvular aging changes include calcification of the mitral annulus and aortic valve, the latter frequently leading to aortic stenosis. In addition, the valves can develop fibrous thickening, and the mitral leaflets tend to buckle back toward the left atrium during ventricular systole, simulating a prolapsing (myxomatous) mitral valve. As this happens, increasing volume and pressure overloads lead to left atrial dilation, and with it, an increased incidence of atrial arrhythmias (e.g., fibrillation). With time, small filiform processes (Lambl excrescences) form on the closure lines of aortic and mitral valves, probably resulting from the organization of small thrombi. The aorta becomes progressively stiffer, owing to the fragmentation and loss of elastic tissue and increased collagen deposition, along with the accumulation of atherosclerotic plaque. The result is less elasticity, and increased pressure spikes with each cardiac contraction that are transmitted to distal organs. Compared with younger myocardium, "elderly" myocardium has fewer myocytes, increased collagenized connective tissue and, often the deposition of extracellular amyloid (most commonly due to poorly catabolized transthyretin; see Chapter 6 ). Most importantly, the progressive atherosclerosis ( Chapter 11 )—over a period of 50 to 60 years—finally ends up causing significant stenosis, or weakens the wall sufficiently to give rise to catastrophic dissection of the aortic wall (see later). Overview of Cardiac Pathophysiology Cardiovascular dysfunction can be attributed to one (or more) of six principal mechanisms: • Pump f ailure. In some conditions, the myocardium contracts weakly during systole and there is inadequate cardiac output. Conversely, myocardium may relax insufficiently during diastole to permit adequate ventricular filling. • Flow obstruction. Lesions can obstruct blood flow through a vessel (e.g., atherosclerotic plaque) or prevent valve opening or otherwise cause increased ventricular chamber pressure (e.g., aortic valvular stenosis, systemic hypertension, or aortic coarctation). In the case of a valvular blockage, the increased pressure overloads the chamber that pumps against the obstruction. • Regurgitant flow. A portion of the output from each contraction flows backward through an incompetent valve, adding a volume overload to the affected atria or ventricles (e.g., left ventricle in aortic regurgitation; left atrium and left ventricle in mitral regurgitation). • Shunted flow. Blood can be diverted from one part of the heart to another (e.g., from the left ventricle to the right ventricle), through defects that can be congenital or acquired (e.g., following myocardial infarction). Shunted flow can also occur between blood vessels, as in patent ductus arteriosus (PDA). • Disorders of cardiac conduction. Conduction defects or arrhythmias due to uncoordinated generation or transmission of impulses (e.g., atrial or ventricular fibrillation) lead to nonuniform and inefficient myocardial contractions, and may in fact be lethal. • Rupture of the heart or a major vessel . In such circumstances (e.g., gunshot to the left ventricle, or aortic dissection and rupture), there is cataclysmic exsanguination, either into body cavities or externally. Most cardiovascular disease results from a complex interplay of genetics and environmental factors; these may disrupt signaling pathways that control morphogenesis, impact myocyte survival after injury, or affect contractility or electrical conduction in the face of biomechanical stressors. Indeed, the pathogenesis of many congenital heart defects involves an underlying genetic abnormality whose expression is modified by environmental or maternal factors (see later). Moreover, genes that control the development of the heart may also regulate the response to various forms of injury including aging. Subtle polymorphisms can significantly impact the risk of many forms of heart disease, and, as discussed later, a number of adult-onset heart disorders have a fundamentally genetic basis. Thus, cardiovascular genetics provides an important window on the pathogenesis of heart disease and increasingly molecular diagnoses are becoming a critical part of its classification. Heart Failure Heart failure, often called congestive heart failure (CHF) , is a common, usually progressive condition with a poor prognosis. Each year in the United States, CHF affects more than 5 million individuals (approximately 2% of the population), necessitating more than a million hospitalizations, and contributing to the death of nearly 300,000 people. CHF occurs when the heart is unable to pump blood at a rate sufficient to meet the metabolic demands of the tissues or can do so only at an elevated filling pressure. It is the common end stage of many forms of chronic heart disease, often developing insidiously from the cumulative effects of chronic work overload (e.g., in valve disease or hypertension) or ischemic heart disease (e.g., following myocardial infarction with heart damage). However, acute hemodynamic stresses, such as fluid overload, abrupt valvular dysfunction, or myocardial infarction, can all precipitate sudden CHF. When cardiac workload increases or cardiac function is compromised, several physiologic mechanisms maintain arterial pressure and organ perfusion: • Frank-Starling mechanism , in which increased filling volumes dilate the heart and thereby increase subsequent actin-myosin cross-bridge formation, enhancing contractility and stroke volume • Myocardial adaptations, including hypertrophy with or without cardiac chamber dilation. In many pathologic states, heart failure is preceded by cardiac hypertrophy, the compensatory response of the myocardium to increased mechanical work. The collective molecular, cellular, and structural changes that occur as a response to injury or changes in loading conditions are called ventricular remodeling. • Activation of neurohumoral systems to augment heart function and/or regulate filling volumes and pressures • Release of norepinephrine by adrenergic cardiac nerves of the autonomic nervous system (which increases heart rate and augments myocardial contractility and vascular resistance) • Activation of the renin-angiotensin-aldosterone system • Release of atrial natriuretic peptide. The latter two factors act to adjust filling volumes and pressures. These adaptive mechanisms may be adequate to maintain normal cardiac output in the face of acute perturbations, but their capacity to do so may ultimately be overwhelmed. Moreover, superimposed pathologic changes, such as myocyte apoptosis, intracellular cytoskeletal alterations, and extracellular matrix deposition, may cause further structural and functional disturbances. Heart failure can result from progressive deterioration of myocardial contractile function (systolic dysfunction) —reflected as a decrease in ejection fraction (EF, the percentage of blood volume ejected from the ventricle during systole; normal is approximately 45% to 65%). Reduction in EF can occur with ischemic injury, inadequate adaptation to pressure or volume overload due to hypertension or valvular disease, or ventricular dilation. Increasingly, heart failure is recognized as resulting from an inability of the heart chamber to expand and fill sufficiently during diastole (diastolic dysfunction) , for example, due to left ventricular hypertrophy, myocardial fibrosis, constrictive pericarditis, or amyloid deposition. Cardiac Hypertrophy: Pathophysiology and Progression to Heart Failure Sustained increase in mechanical work due to pressure or volume overload (e.g., systemic hypertension or aortic stenosis) or trophic signals (e.g., those mediated through the activation of β-adrenergic receptors) cause myocytes to increase in size (hypertrophy) ; cumulatively, this increases the size and weight of the heart ( Fig. 12-1 ). Hypertrophy requires increased protein synthesis, thus enabling the assembly of additional sarcomeres, as well as increasing the numbers of mitochondria. Hypertrophic myocytes also have enlarged nuclei, attributable to increased DNA ploidy resulting from DNA replication in the absence of cell division. The pattern of hypertrophy reflects the nature of the stimulus. In pressure-overload hypertrophy (e.g., due to hypertension or aortic stenosis), new sarcomeres are predominantly assembled in parallel to the long axes of cells, expanding the cross-sectional area of myocytes in ventricles and causing a concentric increase in wall thickness. In contrast, volume-overload hypertrophy is characterized by new sarcomeres being assembled in series within existing sarcomeres, leading primarily to ventricular dilation. As a result, in dilation due to volume overload, or dilation that accompanies failure of a previously pressure overloaded heart, the wall thickness may be increased, normal, or less than normal. Consequently, heart weight, rather than wall thickness, is the best measure of hypertrophy in dilated hearts. Open full size image 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, while the hypertrophied, dilated heart (right) has increased mass and a normal wall thickness. C, Normal myocardium. D, Hypertrophied myocardium (panels C and D are photomicrographs at the same magnification). Note the increases in both cell size and nuclear size in the hypertrophied myocytes. ( A,B, Reproduced with permission from Edwards WD: Cardiac anatomy and examination of cardiac specimens. In Emmanouilides GC, et al [eds]: Moss and Adams Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adults, 5th ed. Philadelphia, Williams & Wilkins, 1995, p 86.) Cardiac hypertrophy can be substantial in clinical heart disease. Heart weights of two to three times normal are common in patients with systemic hypertension, ischemic heart disease, aortic stenosis, mitral regurgitation, or dilated cardiomyopathy, and heart weights can be three- to four-fold greater than normal in those with aortic regurgitation or hypertrophic cardiomyopathy. Important changes at the tissue and cell level occur with cardiac hypertrophy. Importantly, myocyte hypertrophy is not accompanied by a proportional increase in capillary numbers. As a result, the supply of oxygen and nutrients to the hypertrophied heart, particularly one undergoing pressure overload hypertrophy, is more tenuous than in the normal heart. At the same time, oxygen consumption by the hypertrophied heart is elevated due to the increased workload that drives the process. Hypertrophy is also often accompanied by deposition of fibrous tissue (interstitial fibrosis). Molecular changes include the expression of immediate-early genes (e.g., FOS, JUN, MYC, and EGR1 ) ( Chapter 2 ). With prolonged hemodynamic overload, there may be a shift to a gene expression pattern resembling that seen during fetal cardiac development (including selective expression of embryonic/fetal forms of β-myosin heavy chain, natriuretic peptides, and collagen). At a functional level, cardiac hypertrophy is associated with heightened metabolic demands due to increases in mass, heart rate, and contractility (inotropic state, or force of contraction), all of which increase cardiac oxygen consumption. As a result of these changes, the hypertrophied heart is vulnerable to ischemia-related decompensation, which can evolve to cardiac failure and eventually lead to death. The proposed sequence of initially beneficial—and later harmful—events in response to increased cardiac work is summarized in Figure 12-2 . The molecular and cellular changes in hypertrophied hearts that initially mediate enhanced function may themselves contribute to the development of heart failure. This can occur through: • Abnormal myocardial metabolism • Alterations of intracellular handling of calcium ions • Myocyte apoptosis • Reprogramming of gene expression, which may occur in part through changes in expression of miRNAs, small noncoding RNAs that inhibit gene expression ( Chapter 1 ). Open full size image Figure 12-2 Schematic representation of the causes and consequences of cardiac hypertrophy. The degree of structural abnormality of the heart in CHF does not always reflect the severity of dysfunction, and the structural, biochemical, and molecular basis for myocardial contractile failure can be obscure. At autopsy, the hearts of patients with CHF are generally heavy and dilated, and may be relatively thin-walled; they exhibit microscopic evidence of hypertrophy, but the extent of these changes is extremely variable. In hearts that have suffered myocardial infarction, loss of pumping capacity due to myocyte death leads to work-related hypertrophy of the surrounding viable myocardium. In valvular heart disease, the increased pressure or volume overloads the myocardium globally. Increased heart mass owing to disease is correlated with excess cardiac mortality and morbidity; indeed, cardiomegaly is an independent risk factor for sudden death. In contrast to pathologic hypertrophy (which is often associated with contractile impairment), hypertrophy induced by regular strenuous exercise has varied effects on the heart depending on the type of exercise. Aerobic exercise (e.g., long distance running) tends to be associated with volume-load hypertrophy that may be accompanied by increases in capillary density (unlike other forms of hypertrophy) and decreases in resting heart rate and blood pressure—effects that are all beneficial. These changes are sometimes referred to as physiologic hypertrophy . Static exercise (e.g., weight lifting) is associated with pressure hypertrophy and appears more likely to be associated with deleterious changes. Whatever its basis, CHF is characterized by variable degrees of decreased cardiac output and tissue perfusion (sometimes called forward failure), as well as pooling of blood in the venous capacitance system (backward failure); the latter may cause pulmonary edema, peripheral edema, or both. As a result, many of the significant clinical features and morphologic changes noted in CHF are actually secondary to injuries induced by hypoxia and congestion in tissues away from the heart. The cardiovascular system is a closed circuit. Thus, although left-sided and right-sided failure can occur independently, failure of one side (particularly the left) often produces excessive strain on the other, terminating in global heart failure. Despite this interdependence, it is easiest to understand the pathology of heart failure by considering right- and left-sided heart failure separately. Left-Sided Heart Failure Left-sided heart failure is most often caused by: • Ischemic heart disease • Hypertension • Aortic and mitral valvular diseases • Primary myocardial diseases The clinical and morphologic effects of left-sided CHF are a consequence of passive congestion (blood backing up in the pulmonary circulation), stasis of blood in the left-sided chambers, and inadequate perfusion of downstream tissues leading to organ dysfunction. MORPHOLOGY Heart. The heart findings depend on the disease process, ranging from 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), the left ventricle is usually hypertrophied and often dilated, sometimes massively. The microscopic changes are nonspecific: primarily myocyte hypertrophy and variable degrees of interstitial fibrosis. Impaired left ventricular function usually causes secondary dilation of the left atrium, which increases the risk of atrial fibrillation. This in turn results in stasis of blood, particularly in the atrial appendage, which is a common site of thrombus formation. 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 and interstitial edema, particularly in the interlobular septa, responsible for the characteristic Kerley B and C lines noted on chest X-ray study in CHF, (2) progressive edematous widening of alveolar septa, and (3) accumulation of edema fluid in the alveolar spaces. Some red cells and plasma proteins extravasate into the edema fluid within the alveolar spaces, where they are phagocytosed and digested by macrophages, which store the iron recovered from hemoglobin in the form of hemosiderin. These hemosiderin-laden macrophages (also known as heart failure cells ) are telltale signs of previous episodes of pulmonary edema. Pleural effusions arise from elevated pleural capillary pressure and the resultant transudation of fluid into the pleural cavities. Early left-sided heart failure symptoms are related to pulmonary congestion and edema and may be subtle. Initially, cough and dyspnea (breathlessness) may occur only with exertion. As CHF progresses, worsening pulmonary edema may cause orthopnea (dyspnea when supine, relieved by sitting or standing) or paroxysmal nocturnal dyspnea (dyspnea usually occurring at night that is so severe that it induces a feeling of suffocation). Dyspnea at rest may follow. Atrial fibrillation , an uncoordinated, chaotic contraction of the atrium, exacerbates CHF owing to the loss of the atrial "kick" and its 10% to 15% contribution to ventricular filling. A reduced ejection fraction leads to diminished renal perfusion, causing activation of the renin-angiotensin-aldosterone system as a compensatory mechanism to correct the "perceived" hypotension. This leads to salt and water retention, with expansion of the interstitial and intravascular fluid volumes ( Chapters 4 and 11 ) that then exacerbate the ongoing pulmonary edema. If the hypoperfusion of the kidney becomes sufficiently severe, impaired excretion of nitrogenous products may cause azotemia (called prerenal azotemia because of its vascular origin; Chapter 20 ). In far-advanced CHF, cerebral hypoperfusion can give rise to hypoxic encephalopathy ( Chapter 28 ), with irritability, loss of attention span, and restlessness that can progress to stupor and coma with ischemic cerebral injury. Left-sided heart failure can be divided into systolic and diastolic failure: • Systolic failure is defined by insufficient ejection fraction (pump failure), and can be caused by any of the many disorders that damage or derange the contractile function of the left ventricle. • In diastolic failure , the left ventricle is abnormally stiff and cannot relax during diastole. Thus, although cardiac function is relatively preserved at rest, the heart is unable to increase its output in response to increases in the metabolic demands of peripheral tissues (e.g., during exercise). Moreover, because the left ventricle cannot expand normally, any increase in filling pressure is immediately transferred back into the pulmonary circulation, producing rapid onset pulmonary edema ( flash pulmonary edema ). Diastolic failure predominantly occurs in patients older than age 65 years and for unclear reasons is more common in women. Hypertension is the most common underlying etiology; diabetes mellitus, obesity, and bilateral renal artery stenosis may also contribute to risk. Reduced left ventricular relaxation may stem from myocardial fibrosis (e.g., in cardiomyopathies and ischemic heart disease), and infiltrative disorders associated with restrictive cardiomyopathies (e.g., cardiac amyloidosis). Diastolic failure may appear in older patients without any known predisposing factors, possibly as an exaggeration of the normal stiffening of the heart with age. Constrictive pericarditis (discussed later) can also limit myocardial relaxation and therefore mimics primary diastolic dysfunction. Right-Sided Heart Failure 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 burdens the right side of the heart. Consequently, the causes of right-sided heart failure include all of those that induce left-sided heart failure. Isolated right-sided heart failure is infrequent and typically occurs in patients with one of a variety of disorders affecting the lungs; hence it is often referred to as cor pulmonale . Besides parenchymal lung diseases, cor pulmonale can also arise secondary to disorders that affect the pulmonary vasculature, for example, primary pulmonary hypertension ( Chapter 15 ), recurrent pulmonary thromboembolism ( Chapter 4 ), or conditions that cause pulmonary vasoconstriction (obstructive sleep apnea, altitude sickness). The common feature of these disorders is pulmonary hypertension (discussed later), which results in hypertrophy and dilation of the right side of the heart. In extreme cases, leftward bulging of the interventricular septum can even cause left ventricular dysfunction. The major morphologic and clinical effects of primary right-sided heart failure differ from those of left-sided heart failure in that pulmonary congestion is minimal while engorgement of the systemic and portal venous systems is pronounced. MORPHOLOGY Heart. As in left-heart failure, the cardiac morphology varies with cause. Rarely, structural defects such as tricuspid or pulmonary valvular abnormalities or endocardial fibrosis (as in carcinoid heart disease) may be present. However, since isolated right heart failure is most often caused by lung disease, most cases exhibit only hypertrophy and dilation of the right atrium and ventricle. Liver and Portal System. Congestion of the hepatic and portal vessels may produce pathologic changes in the liver, the spleen, and the GI tract. The liver is usually increased in size and weight (congestive hepatomegaly) due to prominent passive congestion , greatest around the central veins ( Chapter 4 ). Grossly, this is reflected as congested red-brown pericentral zones, with relatively normal-colored tan periportal regions, producing the characteristic "nutmeg liver" appearance ( Chapter 4 ). In some instances, especially when left-sided heart failure with hypoperfusion is also present, severe centrilobular hypoxia produces centrilobular necrosis . With longstanding severe right-sided heart failure, the central areas can become fibrotic, eventually culminating in cardiac cirrhosis ( Chapter 18 ). Portal venous hypertension also causes enlargement of the spleen with platelet sequestration (congestive splenomegaly) , and can also contribute to chronic congestion and edema of the bowel wall. The latter may be sufficiently severe as to interfere with nutrient (and/or drug) absorption. Pleural, Pericardial, and Peritoneal Spaces. Systemic venous congestion can lead to fluid accumulation in the pleural, pericardial, or peritoneal spaces ( effusions ; peritoneal effusions are also called ascites ). Large pleural effusions can impact lung inflation, causing atelectasis, and substantial ascites can also limit diaphragmatic excursion, causing dyspnea on a purely mechanical basis. Subcutaneous Tissues. Edema of the peripheral and dependent portions of the body, especially ankle (pedal) and pretibial edema, is a hallmark of right-sided heart failure. In chronically bedridden patients presacral edema may predominate. Generalized massive edema ( anasarca ) may also occur. The kidney and the brain are also prominently affected in right-sided heart failure. Renal congestion is more marked with right-sided than left-sided heart failure, leading to greater fluid retention and peripheral edema, and more pronounced azotemia. Venous congestion and hypoxia of the central nervous system can also produce deficits of mental function akin to those seen in left-sided heart failure with poor systemic perfusion. Although we have discussed right and left heart failure separately, it is again worth emphasizing that in many cases of chronic cardiac decompensation, patients present in biventricular CHF with symptoms reflecting both right-sided and left-sided heart failure. Standard therapy for CHF is mainly pharmacologic. Drugs that relieve fluid overload (e.g., diuretics), that block the renin-angiotensin-aldosterone axis (e.g., angiotensin converting enzyme inhibitors), and that lower adrenergic tone (e.g., beta-1 adrenergic blockers) are all particularly beneficial. The efficacy of the latter two classes of drugs supports the concept that neurohumoral changes in CHF (e.g., renin and norepinephrine elevations) are maladaptive contributions to heart failure. Newer approaches to improving cardiac function include mechanical assist devices, and resynchronization of electrical impulses to maximize cardiac efficiency. Interestingly, some patients treated by mechanical assist can recover sufficient function to be weaned from the device. There is also considerable enthusiasm for novel therapies, including cell-based approaches, although several hurdles remain in their implementation. KEY CONCEPTS Heart Failure ▪ CHF occurs when the heart is unable to provide adequate perfusion to meet the metabolic requirements of peripheral tissues; inadequate cardiac output is usually accompanied by increased congestion of the venous circulation. ▪ Left-sided heart failure is most commonly due to ischemic heart disease, systemic hypertension, mitral or aortic valve disease, and primary diseases of the myocardium; symptoms are mainly a consequence of pulmonary congestion and edema, although systemic hypoperfusion can cause secondary renal and cerebral dysfunction. ▪ Right heart failure is most often due to left heart failure, and less commonly to primary pulmonary disorders; symptoms are chiefly related to peripheral edema and visceral congestion. Congenital Heart Disease Congenital heart disease (CHD) is a general term designating abnormalities of the heart or great vessels that are present at birth. Most congenital heart disease arises from faulty embryogenesis during gestational weeks 3 through 8, when major cardiovascular structures form and begin to function. The most severe anomalies are incompatible with intrauterine survival and significant heart malformations are common among premature infant and stillborns. On the other hand, defects that affect individual chambers or discrete regions of the heart are often compatible with embryologic maturation and eventual live birth. In this category are septation defects, unilateral obstructions, and outflow tract anomalies. Septal defects, or "holes in the heart", include atrial septal defects (ASDs) or ventricular septal defects (VSDs). Stenotic lesion can be at the level of the cardiac valve or entire cardiac chamber, as in hypoplastic left heart syndrome. Outflow tract anomalies include inappropriate routing of the great vessels from the ventricular mass. These forms of congenital heart disease usually produce clinically important manifestations only after birth—unveiled by the transition from fetal to perinatal circulation. Incidence. With an incidence of up to 5%, congenital cardiovascular malformations are among the most prevalent birth defects and are the most common type of pediatric heart disease. Approximately 1% of individuals have significant forms of congenital heart disease that are diagnosed in the first year of life. However, milder forms of congenital heart disease such as bicuspid semilunar valves, with an incidence itself of 1-2%, may not become evident until adulthood. Twelve disorders account for about 85% of cases; their frequencies are listed in Table 12-2 . Table 12-2 Frequencies of Congenital Cardiac Malformations * Malformation Incidence per Million 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 the aorta 492 5 Atrioventricular septal defect 396 4 Aortic stenosis 388 4 Transposition of the great arteries 388 4 Truncus arteriosus 136 1 Total anomalous pulmonary venous connection 120 1 Tricuspid atresia 118 1 Total 9757 Source: Hoffman JIE, Kaplan S: The incidence of congenital heart disease. J Am Coll Cardiol 39:1890, 2002. * Presented as upper quartile of 44 published studies. Percentages do not add up to 100% because of rounding. The number of individuals who survive into adulthood with congenital heart disease is increasing rapidly and is estimated at nearly 1 million individuals in the United States. Many have benefited from advances in early postnatal (and even intrauterine) surgical repair of their structural defects. In some cases, however, surgical repairs fail to restore complete normalcy; patients may have already sustained pulmonary or myocardial changes that are no longer reversible, or may suffer from arrhythmias due to surgical scarring. Other factors that impact the long-term outcome include risks associated with the use of prosthetic materials and devices (e.g., substitute valves or myocardial patches), and the cardiovascular stressors associated with childbearing that may tip a repaired heart into failure. Cardiac Development. -The earliest cardiac precursors originate in lateral mesoderm and move to the midline in two migratory waves to create a crescent of cells consisting of the first and second heart fields by about day 15 of development. Both fields contain multipotent progenitor cells that can produce all of the major cell types of the heart: endocardium, myocardium, and smooth muscle cells. -the first heart field expresses the transcription factor Hand1, whereas the second heart field expresses the transcription factor Hand2 and the secreted protein fibroblast growth factor-10. -Day 21. Initial cell crescent is a beating tube, ,which loops around to the RIGHT becomes basic heart chambers. SHF cells lie dorsal to the straight heart tube and begin to migrate (arrows) into the anterior and posterior ends of the tube to form the right ventricle, conotruncus (CT), and part of the atria (A). At same time: (1) neural crest-derived cells migrate into the outflow tract, where they participate in the septation of the outflow tract and the formation of the aortic arches, and (2) interstitial connective tissue that will become the future atrioventricular canal and outflow tract enlarges to produce swellings known as endocardial cushions. -Day 50. Septation of the ventricles, atria, and atrioventricular valves (AVV) results in the appropriately configured four-chambered heart. -Wnt, hedgehog, vascular endothelial growth factor (VEGF), bone morphogenetic factor, TGFβ, fibroblast growth factor, and Notch pathways.micro-RNAs -Many of the inherited defects that affect heart development involve genes that encode transcription factors; these typically cause partial loss of function and are autosomal dominant (discussed later).

E. Myocarditis Infective or inflamamtory coxsackievirus, ECHO, influenza, HIV, cytomegalovirus) Chlamydiae Rickettsiae Bacteria: corynebacterium diptheriae, neiseeria meningococcus, Borrelia (lyme) Infective or inflammatory. U.S.: viruses, particuarly Coxsackie viruses A and B, other enteroviruses. HIV, influenza. Chagas (S America protozoan Trypanosoma cruzi), Trichinosis (trichinela spiralis) helmolinth. Borrelia burdorferi in 5% of Lyme Disease patientss: may require temp pacemaker. Noninfectious: giant cell myocarditis, hypersensitivity myocarditis. Heart dilates, hypertophy perhaps if long enough. Flabby an mottled, pale foci or hemorrhagic lesions. Mural thrombi. A diffuse, mononuclear, predominantly lymphocytic infiltrate is most common -viral Hypersensitivity myocarditis: characterized by interstitial inflammatory infiltrate composed largely of EOSINOPHILS and mononuclear inflammatory cells, predominantly localized to perivascular and expanded interstitial spaces. Giant Cell myocarditis: mononuclear inflammatory infiltrate containing lymphocytes and macrophages, extensive loss of muscle, and multinucleated giant cells (fused macrophages). Chagas: Chagas disease is distinctive by virtue of the parasitization of scattered myofibers by trypanosomes accompanied by a mixed inflammatory infiltrate of neutrophils, lymphocytes, macrophages, and occasional eosinophils VARIABLE COURSE

Myocarditis is a diverse group of pathologic entities in which infectious microorganisms and/or a primary inflammatory process cause myocardial injury. Myocarditis should be distinguished from conditions such as ischemic heart disease, where myocardial inflammation is secondary to other causes. Pathogenesis. In the United States, viral infections are the most common cause of myocarditis. Coxsackie viruses A and B and other enteroviruses probably account for most of the cases. Other less common etiologic agents include cytomegalovirus, HIV, and influenza ( Table 12-13 ). In some (but not all) cases, the responsible virus can be ascertained by serologic studies or by identifying viral nucleic acid sequences in myocardial biopsies. Depending on the pathogen and the host, viruses can potentially cause myocardial injury either as a direct cytopathic effect, or by eliciting a destructive immune response. Inflammatory cytokines produced in response to myocardial injury can also cause myocardial dysfunction that is out of proportion to the degree of actual myocyte damage. Nonviral agents are also important causes of infectious myocarditis, particularly the protozoan Trypanosoma cruzi , the agent of Chagas disease. Chagas disease is endemic in some regions of South America, with myocardial involvement in most infected individuals. About 10% of patients die during an acute attack; others develop a chronic immune-mediated myocarditis that may progress to cardiac insufficiency in 10 to 20 years. Trichinosis ( Trichinella spiralis ) is the most common helminthic disease associated with myocarditis. Parasitic diseases, including toxoplasmosis, and bacterial infections such as Lyme disease and diphtheria, can also cause myocarditis. In the case of diphtheritic myocarditis, the myocardial injury is a consequence of diphtheria toxin release by the causal organism, Corynebacterium diphtheriae ( Chapter 8 ). Myocarditis occurs in approximately 5% of patients with Lyme disease, a systemic illness caused by the bacterial spirochete Borrelia burgdorferi ( Chapter 8 ); it manifests primarily as a self-limited conduction system disorder that may require a temporary pacemaker. AIDS-associated myocarditis may reflect inflammation and myocyte damage without a clear etiologic agent, or a myocarditis attributable directly to HIV or to an opportunistic pathogen. There are also noninfectious causes of myocarditis . Broadly speaking they are either immunologically mediated ( hypersensitivity myocarditis ) or idiopathic conditions with distinctive morphology ( giant cell myocarditis ) suspected to be of immunologic origin ( Table 12-13 ). Grossly, the heart in myocarditis may appear normal or dilated; some hypertrophy may be present depending on disease duration. In advanced stages the ventricular myocardium is flabby and often mottled by either pale foci or minute hemorrhagic lesions. Mural thrombi may be present. Active myocarditis is characterized by an interstitial inflammatory infiltrate associated with focal myocyte necrosis ( Fig. 12-35 ). A diffuse, mononuclear, predominantly lymphocytic infiltrate is most common ( Fig. 12-35 A ). Although endomyocardial biopsies are diagnostic in some cases, they can be spuriously negative because inflammatory involvement of the myocardium may be focal or patchy. If the patient survives the acute phase of myocarditis, the inflammatory lesions either resolve, leaving no residual changes, or heal by progressive fibrosis. . A, Lymphocytic myocarditis, associated with myocyte injury. B, Hypersensitivity myocarditis, characterized by interstitial inflammatory infiltrate composed largely of eosinophils and mononuclear inflammatory cells, predominantly localized to perivascular and expanded interstitial spaces. C, Giant-cell myocarditis, with mononuclear inflammatory infiltrate containing lymphocytes and macrophages, extensive loss of muscle, and multinucleated giant cells (fused macrophages). D, The myocarditis of Chagas disease. A myofiber distended with trypanosomes (arrow) is present along with individual myofiber necrosis, and modest amounts of inflammation. Hypersensitivity myocarditis has interstitial infiltrates, principally perivascular, composed of lymphocytes, macrophages, and a high proportion of eosinophils ( Fig. 12-35 B ). A morphologically distinctive form of myocarditis, called giant-cell myocarditis , is characterized by a widespread inflammatory cellular infiltrate containing multinucleate giant cells (fused macrophages) interspersed with lymphocytes, eosinophils, plasma cells, and macrophages. Focal to frequently extensive necrosis is present ( Fig. 12-35 C ). This variant likely represents the fulminant end of the myocarditis spectrum and carries a poor prognosis. The myocarditis of Chagas disease is distinctive by virtue of the parasitization of scattered myofibers by trypanosomes accompanied by a mixed inflammatory infiltrate of neutrophils, lymphocytes, macrophages, and occasional eosinophils ( Fig. 12-35 D ). The clinical spectrum of myocarditis is broad. At one end, the disease is entirely asymptomatic, and patients can expect a complete recovery without sequelae; at the other extreme is the precipitous onset of heart failure or arrhythmias, occasionally with sudden death. Between these extremes are the many levels of involvement associated with symptoms such as fatigue, dyspnea, palpitations, precordial discomfort, and fever. The clinical features of myocarditis can mimic those of acute MI. As noted previously, patients can develop dilated cardiomyopathy as a late complication of myocarditis.

1. Nonbacterial Thrombotic Endocarditis SMall, sterile thrombi along the line of the leaflets or cusps. BLAND, loosely attached. NOT INVASIVE, no INFLAMMATORY REACTION. Usually inconsequential, but can embolize. BLAND. thrombi. cancer or septic malnutrition. DVT, PE often co occur due to a common hypercoagulable states. Mucinous adenocarcinomas especially are often relatd!!!!!!!!!!due to tumor derived mucin or tissue factor that are pro coagulant. migratory thrombophlebitis too. Indwelling catheter endocardial trauma also predisposing condition. or pulmonary artery catheters.

Nonbacterial thrombotic endocarditis (NBTE) is characterized by the deposition of small sterile thrombi on the leaflets of the cardiac valves ( Figs. 12-24 and 12-26 ). The lesions are 1 to 5 mm in size, and occur as single or multiple vegetations along the line of closure of the leaflets or cusps. Histologically, they comprise bland thrombi that are loosely attached to the underlying valve; the vegetations are not invasive and do not elicit any inflammatory reaction. Thus, although the local effect of the vegetations is usually trivial, they can be the source of systemic emboli that produce significant infarcts in the brain, heart, or elsewhere. complete row of thrombotic vegetations along the line of closure of the mitral valve leaflets. bland thrombus, with virtually no inflammation in the valve cusp (c) or the thrombotic deposit (t). The thrombus is only loosely attached to the cusp (arrow). NBTE is often encountered in debilitated patients, such as those with cancer or sepsis—hence the previous term marantic endocarditis (root word marasmus , relating to malnutrition) . It frequently occurs concomitantly with deep venous thromboses, pulmonary emboli, or other findings suggesting an underlying systemic hypercoagulable state ( Chapter 4 ). Indeed, there is a striking association with mucinous adenocarcinomas, potentially relating to the procoagulant effects of tumor-derived mucin or tissue factor that can also cause migratory thrombophlebitis (Trousseau syndrome, Chapter 4 ). Endocardial trauma, as from an indwelling catheter, is another well-recognized predisposing condition, and right-sided valvular and endocardial thrombotic lesions frequently track along the course of pulmonary artery catheters.

A. Pericardial Effusion and Hemopericardium 50mL of straw colored clear fluid in healthy can be expaned with a pericardial effusion, blood, or pus. Long standing, chronic, there is time to accommodate, can hold 500mL with no symptoms other than CXR shadow. Rapidly develpig effusions- at 200 mL, produce devastating compression of thin walled atria and vena cava, or ventricles themselves, even. Restricted ventricular filling causes CARDIAC TAMPONADE

Normally, the pericardial sac contains less than 50 mL of thin, clear, straw-colored fluid. Under various circumstances the parietal pericardium may be distended by serous fluid (pericardial effusion) , blood ( hemopericardium ), or pus ( purulent pericarditis ). With long-standing cardiac enlargement or with slowly accumulating fluid, the pericardium has time to dilate. This permits a slowly accumulating pericardial effusion to become quite large without interfering with cardiac function. Thus, with chronic effusions of less than 500 mL in volume, the only clinical significance is a characteristic globular enlargement of the heart shadow on chest radiographs. In contrast, rapidly developing fluid collections of as little as 200 to 300 mL—e.g., due to hemopericardium caused by a ruptured MI or aortic dissection—can produce clinically devastating compression of the thin-walled atria and venae cavae, or the ventricles themselves; cardiac filling is thereby restricted, producing potentially fatal cardiac tamponade

B. Pericarditis

Pericardial inflammation can occur secondary to a variety of cardiac, thoracic, or systemic disorders, metastases from remote neoplasms, or cardiac surgical procedures. Primary pericarditis is unusual and almost always of viral origin. The major causes of pericarditis are listed in Table 12-14 . Most evoke an acute pericarditis, but a few, such as tuberculosis and fungi, produce chronic reactions.

XIII. Tumors of the Heart The most common primary cardiac tumors, in descending order of frequency (overall, including adults and children) are myxomas, fibromas, lipomas, papillary fibroelastomas, rhabdomyomas, and angiosarcomas. THESE ARE ALL BENIGN(80-90%) except for ANGIOSARCOMAS (10-20%)

Primary tumors of the heart are rare; in contrast, metastatic tumors to the heart occur in about 5% of persons dying of cancer. The most common primary cardiac tumors, in descending order of frequency (overall, including adults and children) are myxomas, fibromas, lipomas, papillary fibroelastomas, rhabdomyomas, and angiosarcomas. The five most common tumors are all benign and collectively account for 80% to 90% of primary tumors of the heart.

B. Pulmonary (Right Sided) Hypertensive Heart Disease aka Cor Pulmonale= right heart failure due to pulmonary hypertension RV is DILATED and with a THICKENED FREE WALL and HYPERTROPHIED TRABECULAE RVH, dilation, failure. chronic: emphysema, primary pulmonary HTN acute: PE. BUT MOST FREQUENT CAUSE IS LEFT HEART FAILURE

Pulmonary hypertensive heart disease (for pulmonale): RV dilation and hypertrophy of trabecular Normally, because the pulmonary vasculature is the low pressure side of the circulation, the right ventricle has a thinner and more compliant wall than the left ventricle. Isolated pulmonary HHD, or cor pulmonale , stems from right ventricular pressure overload. Chronic cor pulmonale is characterized by right ventricular hypertrophy, dilation, and potentially right-sided failure. Typical causes of chronic cor pulmonale are disorders of the lungs, especially chronic parenchymal diseases such as emphysema, and primary pulmonary hypertension ( Table 12-7 ; see also Chapter 15 ). Acute cor pulmonale can follow massive pulmonary embolism. Nevertheless, it should also be remembered that pulmonary hypertension most commonly occurs as a complication of left-sided heart disease . More subtle right ventricular hypertrophy may take the form of thickening of the muscle bundles in the outflow tract, immediately below the pulmonary valve, or thickening of the moderator band, the muscle bundle that connects the ventricular septum to the anterior right ventricular papillary muscle. Sometimes, the hypertrophied right ventricle compresses the left ventricular chamber, or leads to regurgitation and fibrous thickening of the tricuspid valve.

H. Complications of Prosthetic Valves Thromboembolism= thrombotic occlusion of the prosthesis or emboli released from thrombi formed on the valve. Blood flow in all mechanical devices is nonlaminar. foci of stasis and turbulence. Also hemorrhage: can be due to anticoagulants Structural deteriorateion Infective Endocarditis S. epidermidis, aureus, strep, fungi. can cause RING ABSCESS PERIVALVULAR LEAK. inadequate healing, fibrous tissue, valve orifice disproportion, IV hemolysis from shear forces. excessive noise owing to moving contacts.

Replacement of damaged cardiac valves with prostheses is a common and often lifesaving mode of therapy. There are two types of valvular prostheses: Mechanical valves . These consist of different configurations of rigid nonphysiologic material, such as caged balls, tilting disks, or hinged semicircular flaps (bi-leaflet tilting disk valves). Tissue valves ( bioprostheses ). Porcine aortic valves or bovine pericardium are preserved in a dilute glutaraldehyde solution and then mounted on a prosthetic frame. Alternatively, frozen human valves from deceased donors (called cryopreserved "homografts") can also be used. Tissue valves are flexible and function similarly to natural semilunar valves. However, the chemical treatment of the animal valves cross-links the valvular proteins, especially collagen, and renders the tissue nonviable. Similarly, the freezing and thawing of human homografts may also render them largely nonviable. Approximately 60% of substitute valve recipients develop a serious prosthesis-related problem within 10 years after the surgery. The complications that occur depend on which type of valve has been implanted ( Table 12-10 and Fig. 12-28 ). • Thromboembolism is the major consideration with mechanical valves ( Fig. 12-28 A ); this may take the form of either thrombotic occlusion of the prosthesis or emboli released from thrombi formed on the valve. Because blood flow in all mechanical devices is nonlaminar, foci of turbulence and stasis are produced by prostheses that predispose to thrombus formation. The risk of such complications necessitates long-term anticoagulation in all individuals with mechanical valves, with the attendant risk of hemorrhagic stroke or other forms of serious bleeding. • Structural deterioration rarely causes failure of mechanical valves in current use. However, virtually all bioprostheses eventually become incompetent due to calcification and/or tearing ( Fig. 12-28 B ). • Infective endocarditis is a potentially serious complication of any valve replacement. The vegetations of prosthetic valve endocarditis are usually located at the prosthesis-tissue interface, and often cause the formation of a ring abscess, which can eventually lead to a paravalvular regurgitant blood leak. In addition, vegetations may directly involve the tissue of bioprosthetic valvular cusps. The major organisms causing such infections are staphylococcal skin contaminants (e.g., S. epidermidis ) , S. aureus, streptococci, and fungi. • Other complications include paravalvular leak due to inadequate healing, obstruction due to overgrowth of fibrous tissue during healing, valve-orifice disproportion (where the effective valve area is too small for the needs of the patient, leading to a relative stenosis), intravascular hemolysis due to high shear forces, or excessive noise owing to hard contacts of moving rigid parts.

D. Restrictive Cardiomyopathy Primary disease is loss of ventricular compliance ventricles are of approximately normal size or slightly enlarged, the cavities are not dilated, and the myocardium is firm and noncompliant. BOTH ATRIA OFTEN SHOW dilation is commonly observed. patchy or diffuse interstitial fibrosis, which can vary from minimal to extensive. Hemachromatosis-from Lilly radiation fibrosis, amyloidosis, sarcoidosis, metastatic tumors, or the deposition of metabolites that accumulate due to inborn errors of metabolism. other causes: endomyocardial fibrosis Loeffler endomyocaridtis (large mural thrombi eosinophilia, myeloproliferation, PDGFR TK constitutive activity), endocardial fibroelastosis (before year 2)

Restrictive Cardiomyopathy Restrictive cardiomyopathy is characterized by a primary decrease in ventricular compliance, resulting in impaired ventricular filling during diastole. Because the contractile (systolic) function of the left ventricle is usually unaffected, the functional abnormality can be confused with that of constrictive pericarditis or HCM. Restrictive cardiomyopathy can be idiopathic or associated with distinct diseases or processes that affect the myocardium, principally radiation fibrosis, amyloidosis, sarcoidosis, metastatic tumors, or the deposition of metabolites that accumulate due to inborn errors of metabolism. The morphologic features are not distinctive. The ventricles are of approximately normal size or slightly enlarged, the cavities are not dilated, and the myocardium is firm and noncompliant. Biatrial dilation is commonly observed. Microscopically, there may be only patchy or diffuse interstitial fibrosis, which can vary from minimal to extensive. Endomyocardial biopsy can often reveal a specific etiology. An important specific subgroup is amyloidosis (described later). Several other restrictive conditions merit brief mention. • Endomyocardial fibrosis is principally a disease of children and young adults in Africa and other tropical areas, characterized by fibrosis of the ventricular endocardium and subendocardium that extends from the apex upward, often involving the tricuspid and mitral valves. The fibrous tissue markedly diminishes the volume and compliance of affected chambers and so causes a restrictive functional defect. Ventricular mural thrombi sometimes develop, and indeed the endocardial fibrosis may result from thrombus organization. The etiology is unknown. • Loeffler endomyocarditis also results in endomyocardial fibrosis, typically with large mural thrombi, with an overall morphology similar to the tropical disease. However, in addition to the cardiac changes, there is often a peripheral eosinophilia and eosinophilic infiltrates in multiple organs, including the heart. The release of toxic products of eosinophils, especially major basic protein, is postulated to initiate endomyocardial necrosis, followed by scarring of the necrotic area, layering of the endocardium by thrombus, and finally organization of the thrombus. Many patients with Loeffler endomyocarditis have a myeloproliferative disorder associated with chromosomal rearrangements involving either the platelet-derived growth factor receptor (PDGFR)-α or -β genes ( Chapter 13 ). These rearrangements produce fusion genes that encode constitutively active PDGFR tyrosine kinases. Treatment of such patients with the tyrosine kinase inhibitor imatinib has resulted in hematologic remissions associated with reversal of the endomyocarditis, which is otherwise often rapidly fatal. • Endocardial fibroelastosis is an uncommon heart disease characterized by fibroelastic thickening that typically involves the left ventricular endocardium. It is most common in the first 2 years of life; in a third of cases, it is accompanied by aortic valve obstruction or other congenital cardiac anomalies. Endocardial fibroelastosis may actually represent a common morphologic end-point of several different insults including viral infections (e.g., intrauterine exposure to mumps) or mutations in the gene for tafazzin, which affects mitochondrial inner membrane integrity. Diffuse involvement may be responsible for rapid and progressive cardiac decompensation and death.

Pathology time course

Reversible Injury 0- hr None None Relaxation of myofibrils; glycogen loss; mitochondrial swelling Irreversible Injury -4 hr None Usually none; variable WAVINESS of fibers (tug of heart on non contractile dead fibers) at border Sarcolemmal disruption; mitochondrial amorphous densities 4-12 hr Dark mottling (occasional) Early coagulation necrosis; edema; hemorrhage 12-24 hr Dark mottling Ongoing coagulation necrosis; pyknosis of nuclei; myocyte hypereosinophilia; marginal contraction band necrosis; early neutrophilic infiltrate 1-3 days Mottling with yellow-tan infarct center Coagulation necrosis, with loss of nuclei and striations; brisk interstitial infiltrate of neutrophils 3-7 days Hyperemic border; central yellow-tan softening Beginning disintegration of dead myofibers, with dying neutrophils; early phagocytosis of dead cells by macrophages at infarct border 7-10 days Maximally yellow-tan and soft, with depressed red-tan margins Well-developed phagocytosis of dead cells; granulation tissue at margins 10-14 days Red-gray depressed infarct borders Well-established granulation tissue with new blood vessels and collagen deposition 2-8 wk Gray-white scar, progressive from border toward core of infarct Increased collagen deposition, with decreased cellularity >2 mo Scarring complete Dense collagenous scar

C. Conduction System

Sensitive to neural inputs (vagal stimulation, extrinsic adrenergic agents, hypoxia, potassium concentration (hypokalemia can block signal altogether)) -Autonomic control can double the heart rate in seconds. -SA node pacemaker at RAA and SVC -AV node at RA long atrial septum -Bundle of His- connecting RA to Ventricular Septum -Subsequent divisions into R and L Bundle Branches stimulate their ventricles via further arborization into purkinje network. -intrinsic automaticity. SA node 60-100BPM intrinsic rate. AV node has gatekeeper function, delays signals from atria ensures atrial contraction precedes ventricular.

Short QT Syndrome

Shortened repolarization. palpitations, syncope, and SCD

A. Systemic (Left Sided )Hypertensive Heart Disease Most common in the Left Heart due to systemic hypertension. LVH due to pressure overload and hypertensive end organ damage

Systemic hypertensive heart disease: LVH. 1) left ventricular hypertrophy (usually concentric) in the absence of other cardiovascular pathology and (2) a clinical history or pathologic evidence of hypertension in other organs (e.g., kidney). Compensated systemic HHD may be asymptomatic, producing only electrocardiographic or echocardiographic evidence of left ventricular enlargement. In many patients, systemic HHD comes to attention due to new atrial fibrillation induced by left atrial enlargement, or by progressive CHF. Depending on the severity, duration, and underlying basis of the hypertension, and on the adequacy of therapeutic control, the patient may (1) enjoy normal longevity and die of unrelated causes, (2) develop IHD due to both the potentiating effects of hypertension on coronary atherosclerosis and the ischemia induced by increased oxygen demand from the hypertrophic muscle, (3) suffer renal damage or cerebrovascular stroke as direct effects of hypertension, or (4) experience progressive heart failure or SCD. Lower BP, most problems go away.

2. Transposition of the Great Arteries

TGA produces ventriculoarterial discordance. Thus, the aorta lies anterior and arises from the right ventricle, while the pulmonary artery is relatively posterior and emanates from the left ventricle . The atrium-to-ventricle connections are normal (concordant), with the right atrium joining the right ventricle and the left atrium emptying into the left ventricle. The embryologic defect in complete TGA stems from abnormal formation of the truncal and aortopulmonary septa. The result is separation of the systemic and pulmonary circulations, a condition incompatible with postnatal life unless a shunt exists for adequate mixing of blood. -The outlook for infants with TGA depends on the degree of blood "mixing," the magnitude of tissue hypoxia, and the ability of the right ventricle to maintain the systemic circulation. Patients with TGA and a VSD (approximately 35%) often have a stable shunt. However, dependence on a patent foramen ovale or ductus arteriosus for blood mixing (approximately 65%) is problematic. These systemic-to-pulmonary connections to close early and thus require intervention to create a new shunt within the first few days of life (e.g., balloon atrial septostomy). With time, right ventricular hypertrophy becomes prominent, because this chamber functions as the systemic ventricle. Concurrently, the left ventricle becomes thin-walled (atrophic) as it supports the low-resistance pulmonary circulation. Without surgery, most patients die within months. However, improving surgical interventions allow many patients with TGA to survive into adulthood. Abnormal narrowing of chambers, valves, or blood vessels; these include coarctation of the aorta, aortic valvular stenosis, and pulmonary valvular stenosis . A complete obstruction is called an atresia. In some disorders (e.g., Tetralogy of Fallot [TOF]), an obstruction (pulmonary stenosis) and a shunt (right-to-left through a VSD) are both present. -The more severe the subpulmonic stenosis, the more hypoplastic are the pulmonary arteries (i.e., smaller and thinner-walled), and the larger is the overriding aorta. -As the child grows and the heart increases in size, the pulmonic orifice does not expand proportionally, making the obstruction progressively worse. The subpulmonary stenosis, however, protects the pulmonary vasculature from pressure overload, and right ventricular failure is rare because the right ventricle is decompressed by the shunting of blood into the left ventricle and aorta. Complete surgical repair is possible but becomes complicated for individuals with pulmonary atresia and dilated bronchial arteries.

C. Chronic Ischemic Heart Disease CONSEQUENCE OF PROGRESSIVE ACCUMULATED MYOCARDIAL ISCHEMIA. Mostly leads to Congestive Heart Failure cardiomegaly, thrombi, fibrous thickening, scars, fibrosis.

The designation chronic IHD (often called ischemic cardiomyopathy by clinicians) is used here to describe progressive congestive heart failure as a consequence of accumulated ischemic myocardial damage and/or inadequate compensatory responses. In most instances there has been prior MI and sometimes previous coronary arterial interventions and/or bypass surgery. Chronic IHD usually appears postinfarction due to the functional decompensation of hypertrophied noninfarcted myocardium (see earlier discussion of cardiac hypertrophy). However, in other cases severe obstructive coronary artery disease may present as chronic congestive heart failure in the absence of prior infarction. Patients with chronic IHD account for almost 50% of cardiac transplant recipients.

XII. Heart Disease Associated Rheumatologic Disorders rheumatoid arthritis, SLE, systemic sclerosis, ankylosing spondylitis, and psoriatic arthritis RA: fibrinous pericarditis that may progress to fibrous thickening of the visceral and parietal pericardium and dense adhesions. Granulomatous rheumatoid nodules resembling the subcutaneous nodules may also occur in the myocardium, endocardium, valves, and aortic root. Rheumatoid valvulitis can lead to marked fibrous thickening and secondary calcification of the aortic valve cusps, producing changes resembling those of chronic rheumatic valvular disease.

The heart (vessels, myocardium, valves, or pericardium) can be significantly impacted by chronic rheumatologic diseases (e.g., rheumatoid arthritis, SLE, systemic sclerosis, ankylosing spondylitis, and psoriatic arthritis). Indeed, as improved therapies lead to longer life expectancies, the cardiovascular manifestations of such systemic inflammation are increasingly recognized. In addition, ischemic heart disease can be accelerated in the setting of systemic inflammation. Although rheumatoid arthritis is primarily a joint disorder, it also has several extra-articular manifestations, including subcutaneous rheumatoid nodules, vasculitis, and neutropenia ( Chapter 26 ). The heart is also involved in 20-40% of severe cases. The most common finding is a fibrinous pericarditis that may progress to fibrous thickening of the visceral and parietal pericardium and dense adhesions. Granulomatous rheumatoid nodules resembling the subcutaneous nodules may also occur in the myocardium, endocardium, valves, and aortic root. Rheumatoid valvulitis can lead to marked fibrous thickening and secondary calcification of the aortic valve cusps, producing changes resembling those of chronic rheumatic valvular disease. The Libman-Sacks valvular lesions associated with SLE were discussed previously.

XI. Pericardial Disease Usuallly a consequence of systemic disease or cardiac pathology

The most important pericardial disorders cause fluid accumulation, inflammation, fibrous constriction, or some combination of these processes, usually in association with other cardiac pathology or a systemic disease; isolated pericardial disease is unusual.

XIV. Cardiac Transplantation Transplantation of cardiac allografts: common for intractable heart failure of diverse cause (DCM and IHD usually) improvements made in trransplants: better immuosuppressants, early diagosis of rejection, careful matching llograft arteriopathy is the single most important long-term limitation for cardiac transplantation. It is a late, progressive, diffusely stenosing intimal proliferation in the coronary arteries ( Fig. 12-39 B ), leading to ischemic injury. Within 5 years of transplantation, 50% of patients develop significant allograft arteriopathy, and virtually all patients have lesions within 10 years. The pathogenesis of allograft arteriopathy involves immunologic responses that induce local production of growth factors that promote intimal smooth muscle cell recruitment and proliferation with ECM synthesis. Allograft arteriopathy is a particularly vexing problem because it can lead to silent MI (transplant patients have denervated hearts and do not experience angina), progressive CHF, or sudden cardiac death. EBV B cell lymphomas that arise in chronic T cell immunosuppresion. good survival though. 5 year survival is 60%/

Transplantation of cardiac allografts is now frequently performed (approximately 3000 per year worldwide) for severe, intractable heart failure of diverse causes—most commonly DCM and IHD. Three major factors have contributed to the improved outcome of cardiac transplantation since the first human to human transplant in 1967: (1) more effective immunosuppressive therapy (including the use of cyclosporin A, glucocorticoids, and other agents), (2) careful selection of candidates, and (3) early histopathologic diagnosis of acute allograft rejection by endomyocardial biopsy. Of the major complications, allograft rejection is the primary problem requiring surveillance; routine endomyocardial biopsy is the only reliable means of diagnosing acute cardiac rejection before substantial myocardial damage has occurred and at a stage that is reversible in the majority of instances. Classic cellular rejection is characterized by interstitial lymphocytic inflammation with associated myocyte damage; the histology resembles myocarditis ( Fig. 12-39 A ). There may also be interstitial edema due to vascular injury, and local cytokine elaboration can impact myocardial contractility without necessarily eliciting myocyte damage. Increasingly, antibody-mediated rejection is also recognized as a pathologic mechanism of injury; donor-specific antibodies directed against major histocompatibility complex proteins lead to complement activation and the recruitment of Fc-receptor-bearing cells. Mild rejection may resolve spontaneously, while prompt recognition of more severe episodes allows successful treatment by augmenting baseline levels of immunosuppression; occasionally aggressive anti-T cell or anti-B cell immunotherapy, with or without plasmapheresis may be necessary. Allograft arteriopathy is the single most important long-term limitation for cardiac transplantation. It is a late, progressive, diffusely stenosing intimal proliferation in the coronary arteries ( Fig. 12-39 B ), leading to ischemic injury. Within 5 years of transplantation, 50% of patients develop significant allograft arteriopathy, and virtually all patients have lesions within 10 years. The pathogenesis of allograft arteriopathy involves immunologic responses that induce local production of growth factors that promote intimal smooth muscle cell recruitment and proliferation with ECM synthesis. Allograft arteriopathy is a particularly vexing problem because it can lead to silent MI (transplant patients have denervated hearts and do not experience angina), progressive CHF, or sudden cardiac death. Other postoperative problems include infection and malignancies, particularly Epstein-Barr virus-associated B-cell lymphomas that arise in the setting of chronic T-cell immunosuppression. Despite these problems, the overall outlook is good; the 1-year survival is 90% and 5-year survival is greater than 60%.

3. Tricuspid Atresia

Tricuspid atresia represents complete occlusion of the tricuspid valve orifice . It results embryologically from unequal division of the AV canal; thus, the mitral valve is larger than normal, and there is right ventricular underdevelopment (hypoplasia). The circulation can be maintained by right-to-left shunting through an interatrial communication (ASD or patent foramen ovale), in addition to a VSD that affords communication between the left ventricle and the pulmonary artery arising from the hypoplastic right ventricle. Cyanosis is present virtually from birth, and there is a high early mortality.

1. Calcific Aortic Stenosis CUSPS!~! not annulus (asin mitral) BICUSPIDS CALCIFY EARLIER Usually results from hyperlipidemia, HTN, inflammation, etc. BUT: Hydroxyappetite (same calcium found in bone), from actual OSTEOBLASTS on the abnormal valves. reducing atherosclerotic risk does not change as. In congenital and rheumatic AS: commissural fusion. In senile/bicuspid AS: NO commmisural fusion. RHD: affects mitral first, so all with AS also have MS. Pressure overloaded LV. LV pressure must be hiked up above aorta. VH causes ischemia and angina, decompensation, congestive heart failure, systolic and diastolic function. Onset of angina, syncope, CHF IS BAD NEWS. poor prognosis TX: valve replacement. meds are ineffective

Usually the result of age-related wear and tear. Bicuspid aortic valves just calcify earlier (50-70) than normal senile aortic stenosis (70-90). Usually results from hyperlipidemia, HTN, inflammation, etc. Leads to Hydroxyappetite (same calcium found in bone), from actual OSTEOBLASTS on the abnormal valves. mounded calcified masses within the aortic cusps that ultimately protrude through the outflow surfaces into the sinuses of Valsalva, and prevent cuspal opening. The free edges of the cusps are usually not involved Bicuspid valves under more mechanical stress, so calcify faster. Tx: interventions that improve atherosclerotic risk do NOTHING FOR AS. IF RHEUMATIC IN ORIGIN, people usually have THE SAME ABNORMALITIES ON MITRAL VALVE!!!!! Results: -Pressure overloaded LV. INCREASED PRESSURE GRADIENT ACROSS Aortic Valve. Normally aorta and LV have equals pressures during systole, but here, LV must be hiked up. Serious consequences, LVH causes ischemia and angina, decompensation, congestive heart failure, systolic and diastolic function. ONSET OF ANGINA, CHF, SYNCOPE heralds CARDIAC DECOMPENSATION and POOR PROGNOSIS (within 5 years of developing angina, 3 years of syncope, 2 years of CHF) TX: valve replacement. meds are ineffective

IX. Valvular Heart Disease Functional regurgitation/insufficiency: normal valve regurgitates because of other abnormalities: esp. ischemia or dilated cardiomyopathy. (mitral regurgitation is especially important) Timing: acute: infective endocarditis of aortic valve: acute, massive, fatal regurgitation. chronic: mitral valve stenosis due to rheumatic heart disease, many years. Pregnancy: increased output demands, exacerbates valve disease. GENERALLY, REGURGITATION LEADS TO VOLUME OVERLOAD STENOSIS LEADS TO PRESSURE OVERLOAD, ALSO JETS THAT DAMAGE ENDOCARDIUM OR BLOOD VESSELS. COMMONEST CAUSES: AORTIC STENOSIS: CALCIFICTION/SCLEROSIS, ESP CONGENITALLY BICUSPID VALVES. AORTIC REGURGITATION: DILATION OF ASCENDING AORTA SECONDARY TO HTN OR AGING MS: RHD MITRAL REGURGITATION: MYXOMATOUS DEGENERATION (MVP)

Valvular disease can come to clinical attention due to stenosis, insufficiency (synonyms: regurgitation or incompetence), or both. Stenosis is the failure of a valve to open completely, which impedes forward flow. Insufficiency results from failure of a valve to close completely, thereby allowing reversed flow. These abnormalities can be present alone or coexist, and may involve only a single valve, or more than one valve. Functional regurgitation is used to describe the incompetence of a valve stemming from an abnormality in one of its support structures, as opposed to a primary valve defect. For example, dilation of the right or left ventricle can pull the ventricular papillary muscles down and outward, thereby preventing proper closure of otherwise normal mitral or tricuspid leaflets. Functional mitral valve regurgitation is particularly common and clinically important in IHD, as well as in dilated cardiomyopathy. The clinical consequences of valve dysfunction vary depending on the valve involved, the degree of impairment, the tempo of disease onset, and the rate and quality of compensatory mechanisms. For example, sudden destruction of an aortic valve cusp by infection (infective endocarditis; see later) can cause acute, massive, and rapidly fatal regurgitation. In contrast, rheumatic mitral stenosis typically develops indolently over years, and its clinical effects can be well tolerated for extended periods. Certain conditions can complicate valvular heart disease by increasing the demands on the heart; for example, the increased output demands of pregnancy can exacerbate valve disease and lead to unfavorable maternal or fetal outcomes. Valvular stenosis or insufficiency often produces secondary changes, both proximal and distal to the affected valve, particularly in the myocardium. Generally, valvular stenosis leads to pressure overload cardiac hypertrophy, whereas mitral or aortic valvular insufficiency leads to volume overload; both situations can culminate in heart failure. In addition, the ejection of blood through narrowed stenotic valves can produce high speed "jets" of blood that injure the endocardium where they impact. Valvular abnormalities can be congenital (discussed earlier) or acquired. Acquired valvular stenosis has relatively few causes; it is almost always a consequence of a remote or chronic injury of the valve cusps that declares itself clinically only after many years. In contrast, acquired valvular insufficiency can result from intrinsic disease of the valve cusps or damage to or distortion of the supporting structures (e.g., the aorta, mitral annulus, tendinous cords, papillary muscles, ventricular free wall). Thus, valvular insufficiency has many causes and may appear acutely, as with rupture of the cords, or chronically in disorders associated with leaflet scarring and retraction. The causes of acquired heart valve diseases are summarized in Table 12-8 . The most frequent causes of the major functional valvular lesions are: • Aortic stenosis: calcification and sclerosis of anatomically normal or congenitally bicuspid aortic valves • Aortic insufficiency: dilation of the ascending aorta, often secondary to hypertension and/or aging • Mitral stenosis: rheumatic heart disease • Mitral insufficiency: myxomatous degeneration ( mitral valve prolapse )

B. Cardiac Effects of Noncardiac Neoplasms mets to heart: lung and breast, melanomas, leukemias, and lymphomas Renal tumors can go up renal vein to IVC cause IVC syndrome. Bronchogenic carcinoma or malignant lymphoma can go through SVC to cause SVC syndrome. Tumor products in ciruculation are of note: nonbacterial thrombotic endocrditis, carcioid heart disease, pheocrhromocytoma associated myocardial damage, myeloma associated AL type amyloidosis.

With enhanced patient survival due to diagnostic and therapeutic advances, significant cardiovascular effects of noncardiac neoplasms and their therapy are increasingly encountered ( Table 12-15 ). The pathologic consequences include direct tumor infiltration, effects of circulating mediators, and therapeutic complications. \ The most frequent metastatic tumors involving the heart are carcinomas of the lung and breast, melanomas, leukemias, and lymphomas. Metastases can reach the heart and pericardium by retrograde lymphatic extension (most carcinomas), by hematogenous seeding (many tumors), by direct contiguous extension (primary carcinoma of the lung, breast, or esophagus), or by venous extension (tumors of the kidney or liver). Clinical symptoms are most often associated with pericardial spread, which can cause symptomatic pericardial effusions or a mass-effect that is sufficient to restrict cardiac filling. Myocardial metastases are usually clinically silent or have nonspecific features, such as a generalized defect in ventricular contractility or compliance. Bronchogenic carcinoma or malignant lymphoma may infiltrate the mediastinum extensively, causing encasement, compression, or invasion of the superior vena cava with resultant obstruction to blood coming from the head and upper extremities (superior vena cava syndrome) . Renal cell carcinoma often invades the renal vein, and may grow as a continuous column of tumor up the inferior vena cava and into the right atrium, blocking venous return to the heart. Noncardiac tumors may also affect cardiac function indirectly, sometimes via circulating tumor-derived substances. The consequences include nonbacterial thrombotic endocarditis, carcinoid heart disease, pheochromocytoma-associated myocardial damage and myeloma-associated AL-type amyloidosis. Complications of chemotherapy were discussed earlier in this chapter. Radiation used to treat breast, lung, or mediastinal neoplasms can cause pericarditis, pericardial effusion, myocardial fibrosis, and chronic pericardial disorders. Other cardiac effects of radiation therapy include accelerated coronary artery disease and mural and valvular endocardial fibrosis.

IV. Heart Failure

aka CHF. -unable to pump blood at a rate sufficient to meet metabolic demands of tissues, or can do so only at elevated filling pressure. -End stage of many diseases, often developing insidiously from cumulative effects of chronic work overload (valve disease/HTN) or ischemic heart disease (following MI with heart damage). -Acute hemodynamic stresses: fluid overload, abrupt valvular dysfunction, MI can all precipitate CHF suddenly. Compensation mechanisms 1. Frank-starling mechanism: increased filling volumes dilate heart, increase subsequent actin-myosin crossbred formation, enhancing contractility and stroke volume. 2. Myocardial adaptations including hypertrophy with or without cardiac chamber dilation. Ventricular remodeling. 3. Activation of neurohumoral systems to augment heart function, regulate filling volumes and pressures: NE from SNS increases HR, augments contractility, vasoCONSTRICTION. RAAS. ANP .

C. Obstructive Lesions

aortic or pulmonary valve stenosis or atresia, and coarctation of the aorta. Or like in TofF a sub pulmonary stenosis.

Pizmental variant angina is uncommon episodic myocardial ischemia

caused by coronary artery spasm, not related to HR, physical activity, blood pressure. Responds promptly to vasodilators.

B. Right to Left Shunts (Cyanotic) ruh-roh

cyanosis clubbing paradoxical emboli polycythemia

Carcinoid heart disease

endocardial fibrosis

3. Mitral Annular Calcification fibrous annulus, not cusps (as in aortic stenosis) Usually no effect. Can be a problem when: -regurgitation by interference with physiological contraction of valve ring. -Stenosis by impairing opening of mitral leaflets -Arrhythmias and sudden death if deep enough to impinge AV conduction system. -A site for thrombus formation -A site for infective endocarditis.

fibrous annulus, not cusps (as in aortic stenosis) irregular, stony hard, occasionally ulcerated nodules AT THE BASE OF THE LEAFLETS. USUALLY has NO EFFECT ON VALVULAR FUNCTION, in exceptional cases, can lead to -regurgitation by interfering with physiological contraction of the valve ring. -Stenosis by impairing opening of mitral leaflets -Arrhythmias and sudden death due to impingement on AV conduction system (must be to a sufficient depth) calcific nodules may also provide a site for thrombus formation, patients with mitral annular calcification have an increased risk of embolic stroke, and the calcific nodules can become a nidus for infective endocarditis. CXR: sometimes see ringlike opacities. Echo: visualized. IN women over 60, those with MVP.

G. Carcinoid Heart Disease The carcinoid syndrome refers to a systemic disorder marked by flushing, diarrhea, dermatitis, and bronchoconstriction that is caused by bioactive compounds such as serotonin released by carcinoid tumors Cardiac lesions do not typically occur until there is a massive hepatic metastatic burden, since the liver normally catabolizes circulating mediators before they can affect the heart. endocardium and valves of the RIGHT heart are primarily affected since they are the first cardiac tissues bathed by the mediators released by GASTROINTESTINAL carcinoid tumors. Pulmonary vasculature degrades mediators, so LEFT HEARD IS RELATIVELY PROTECTED, unless a right to left shunt exists (ASD or septal defects, or primary pulmonary carcinoid tumors) Usually SEROTONIN, histamine, kalikrein, bradykinin, histamine, PGEs, tachykinins. serotonin and 4HO Indoleacetic acid most important. VALVULAR PLAQUES resemble fenfluramine or ergot alkaloids valvular plaques, who effect systemic serotonin metabolism. glistening white intimal plaquelike thickenings of the endocardial surfaces of the cardiac chambers and valve leaflets composed of smooth muscle cells and sparse collagen fibers embedded in an acid mucopolysaccharide-rich matrix material. Underlying structures are intact. myocardial elastic tissue (black) underlying the acid mucopolysaccharide-rich lesion

he carcinoid syndrome refers to a systemic disorder marked by flushing, diarrhea, dermatitis, and bronchoconstriction that is caused by bioactive compounds such as serotonin released by carcinoid tumors ( Chapter 17 ). Carcinoid heart disease refers to the cardiac manifestations caused by the bioactive compounds and occurs in roughly half of the patients in whom the systemic syndrome develops. Cardiac lesions do not typically occur until there is a massive hepatic metastatic burden, since the liver normally catabolizes circulating mediators before they can affect the heart. Classically, endocardium and valves of the right heart are primarily affected since they are the first cardiac tissues bathed by the mediators released by gastrointestinal carcinoid tumors. The left side of the heart is afforded some measure of protection because the pulmonary vascular bed degrades the mediators. However, left heart carcinoid lesions can occur in the setting of atrial or septal defects and right-to-left flow, or can be elicited by primary pulmonary carcinoid tumors. Pathogenesis. The mediators elaborated by carcinoid tumors include serotonin (5-hydroxytryptamine), kallikrein, bradykinin, histamine, prostaglandins, and tachykinins. Although it is not clear which of these is causal, plasma levels of serotonin and urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid correlate with the severity of the cardiac lesions. The valvular plaques in carcinoid syndrome are also similar to lesions that occur in patients taking fenfluramine (an appetite suppressant) or ergot alkaloids (for migraine headaches); interestingly, these agents affect systemic serotonin metabolism. Similarly, left-sided plaques have been reported following methysergide or ergotamine therapy for migraines; notably, these drugs are metabolized to serotonin as they pass through the pulmonary vasculature. Despite this tantalizing evidence, however, it is not known how serotonin might induce the observed cardiac changes, nor has it been proven that treatment with serotonin inhibitors has any effect on the development or progression of heart lesions.

B. Myocardial Infarction CORONARY THROMBOSIS cTNT, cTNI are most sensitive and specific, rise 3-12 hours, peak 12-48 hours

men>women before menopause. After menopause, women are more likely to have CAD. Not understood. -Pathogenesis: • A coronary artery atheromatous plaque undergoes an acute change consisting of intraplaque hemorrhage, erosion or ulceration, or rupture or fissuring. • When exposed to subendothelial collagen and necrotic plaque contents, platelets adhere, become activated, release their granule contents, and aggregate to form microthrombi. • Vasospasm is stimulated by mediators released from platelets. • Tissue factor activates the coagulation pathway, adding to the bulk of the thrombus. • Within minutes, the thrombus can expand to completely occlude the vessel lumen. Onset of ATP depletion Seconds Loss of contractility <2 min ATP reduced to 50% of normal 10 min to 10% of normal 40 min Irreversible cell injury 20-40 min Microvascular injury >1 hr -Ischemia most pronounced in endocardium because of perfusion pattern from epic to end, and because of pressure inside the ventricles is high. -NECROSIS: involves 1/2 the thickness of myocardium after 2-3 hours of ischemia. After 6 it is transmural. If in a well perfused area, might be slower. -LAD branch of the left coronary artery supplies most of the apex of the heart, the anterior wall of the left ventricle, and the anterior two thirds of the ventricular septum. -Right dominant circulation (present in approximately 80% of individuals), the RCA supplies the entire right ventricular free wall, the posterobasal wall of the left ventricle, and the posterior third of the ventricular septum, while the LCX generally perfuses only the lateral wall of the left ventricle.Thus, RCA occlusions can potentially lead to left ventricular damage. -TRANSMURAL infarcts result from epicardial vessel. Full thickness of ventricular wall is necrotic. Chronic coronary atherosclerosis and acute plaque change, superimposed thrombosis -Subendocardial infarction at subendocardial zone is normally least perfused, most vulnerable. prolonged hypotension, shock • Left anterior descending coronary artery (40% to 50%): infarcts involving the anterior wall of left ventricle near the apex; the anterior portion of ventricular septum; and the apex circumferentially • Right coronary artery (30% to 40%): infarcts involving the inferior/posterior wall of left ventricle; posterior portion of ventricular septum; and the inferior/posterior right ventricular free wall in some cases • Left circumflex coronary artery (15% to 20%): infarcts involving the lateral wall of left ventricle except at the apex -Triphenyltetrazolium chloride stains LDH active cardio tissue bright red. Yellow means cell death. scarring is white. -myocyte vacuolization or myocytolysis , which reflects intracellular accumulations of salt and water within the sarcoplasmic reticulum. -necrotic muscle elicits acute inflammation (most prominent between 1 and 3 days). Thereafter, macrophages remove the necrotic myocytes (most noticeable by 3 to 7 days), and the damaged zone is progressively replaced by the ingrowth of highly vascularized granulation tissue (most prominent at 1 to 2 weeks); as healing progresses, this is replaced by fibrous tissue. In most instances, scarring is well advanced by the end of the sixth week, but the efficiency of repair depends on the size of the original lesion, as well as the relative metabolic and inflammatory state of the host. -A, One-day-old infarct showing coagulative necrosis and wavy fibers (elongated and narrow, as compared with adjacent normal fibers at right ). Widened spaces between the dead fibers contain edema fluid and scattered neutrophils. B, Dense polymorphonuclear leukocytic infiltrate in an acute myocardial infarction that is 3 to 4 days old. C, Removal of necrotic myocytes by phagocytosis (approximately 7 to 10 days). D, Granulation tissue characterized by loose collagen and abundant capillaries. E, Healed myocardial infarct, in which the necrotic tissue has been replaced by a dense collagenous scar. The residual cardiac muscle cells show evidence of compensatory hypertrophy. -he laboratory evaluation of MI is based on measuring the blood levels of proteins that leak out of irreversibly damaged myocytes; the most useful of these molecules are cardiac-specific troponins T and I (cTnT and cTnI), and the MB fraction of creatine kinase (CK-MB) The most sensitive and specific biomarkers of myocardial damage are cardiac-specific proteins, particularly cTnT and cTnI. Following an MI, levels of both begin to rise at 3-12 hours; cTnT levels peak somewhere between 12-48 hours while cTnI levels are maximal at 24 hours. -Creatine kinase is an enzyme expressed in brain, myocardium, and skeletal muscle; it is a dimer composed of two isoforms designated "M" and "B." While MM homodimers are found predominantly in cardiac and skeletal muscle, and BB homodimers in brain, lung, and many other tissues, MB heterodimers are principally localized to cardiac muscle (with considerably lesser amounts found in skeletal muscle). Thus, the MB form of creatine kinase (CK-MB) is sensitive but not specific, since it can also be elevated after skeletal muscle injury. CK-MB begins to rise within 3 to 12 hours of the onset of MI, peaks at about 24 hours, and returns to normal within approximately 48 to 72 hours. • Time to elevation of CKMB, cTnT and cTnI is 3 to 12 hrs • CK-MB and cTnI peak at 24 hours • CK-MB returns to normal in 48-72 hrs, cTnI in 5-10 days, and cTnT in 5 to 14 days

C. Mitral Valve Prolapse (Myxomatous Degeneration of the Mitral Valve) MVP Usually due to weakened structures. OFTEN MARFAN: Fibrillin1 mutation on chromosome 15, TGF beta aberrant signaling. AUTOSOMAL DOMINANT -marked thickening of the spongiosa layer with deposition of mucoid (myxomatous) material, called myxomatous degeneration ; there is also attenuation of the collagenous fibrosa layer of the valve, on which the structural integrity of the leaflet depends - auscultation of mid-systolic clicks, sometimes followed by a mid to late systolic murmur.

mitral valve leaflets are "floppy" and prolapse , or balloon back, into the left atrium during systole. 7x more likely in women. incidental in most, can complicate in others. Usually due to weakened structures. OFTEN MARFAN: Fibrillin1 mutation on chromosome 15, TGF beta aberrant signaling. AUTOSOMAL DOMINANT -affected leaflets are often enlarged, redundant, thick, and rubbery. The associated tendinous cords may be elongated, thinned, or even ruptured, and the annulus may be dilated. -marked thickening of the spongiosa layer with deposition of mucoid (myxomatous) material, called myxomatous degeneration ; there is also attenuation of the collagenous fibrosa layer of the valve, on which the structural integrity of the leaflet depends Secondary changes reflect the stresses and tissue injury incident to the billowing leaflets: (1) fibrous thickening of the valve leaflets, particularly where they rub against each other; (2) linear fibrous thickening of the left ventricular endocardial surface where the abnormally long cords snap or rub against it; (3) thickening of the mural endocardium of the left ventricle or atrium as a consequence of friction-induced injury induced by the prolapsing, hypermobile leaflets; (4) thrombi on the atrial surfaces of the leaflets or the atrial walls; and (5) focal calcifications at the base of the posterior mitral leaflet. Notably, mitral valve myxomatous degeneration can also occur as a secondary consequence of regurgitation of other etiologies (e.g., ischemic dysfunction). -collagen in the fibrosa is loose and disorganized, proteoglycan deposition (asterisk) in the spongiosa is markedly expanded, and elastin in the atrialis is disorganized. - auscultation of mid-systolic clicks, sometimes followed by a mid to late systolic murmur. -DX Echo confirmation. -Many have chest pain mimicking angina without exertion. Some have dyspnea-related to mitral regurgitation. approximately 3% develop one of four serious complications: (1) infective endocarditis; (2) mitral insufficiency, sometimes with chordal rupture; (3) stroke or other systemic infarct, resulting from embolism of leaflet thrombi; or (4) arrhythmias, both ventricular and atrial. Rarely, MVP is the only finding in sudden cardiac death. LOW RISK unless mitral regurgitation, man, arrhythmias. -Valve surgery can be done for symptomatic with risk for complications.

1. Coarctation of the Aorta

narrowing/constriction. Turner Syndrome associated 1 infantile form -symptomatic in early childhood., with tubular hypoplasia of the aortic arch proximal to a PDA 2. adult form with a discrete ridge like infolding of the aorta just opposite the closed ductus arterioles distal to the arch vessels. -50% of cases it is accompanied by a bicuspid aortic valve and may also be associated with congenital aortic stenosis, ASD, VSD, mitral regurgitation, or berry aneurysms of the circle of Willis. -Coarctation of the aorta with a PDA usually manifests early in life; indeed, it may cause signs and symptoms immediately after birth. In such cases, the delivery of unsaturated blood through the PDA produces cyanosis localized to the lower half of the body. Hard to survive without intervention. -WITHOUT PDA: asymptomatic, and the disease may go unrecognized until well into adult life. hypertension in the upper extremities with weak pulses and hypotension in the lower extremities, associated with manifestations of arterial insufficiency (i.e., claudication and coldness). Particularly characteristic is the development of collateral circulation between the pre-coarctation and post-coarctation arteries through enlarged intercostal and internal mammary arteries, often producing radiographically visible erosions ("notching") of the undersurfaces of the ribs. -murmurs are present throughout systole; sometimes a vibratory "thrill" is also present. -long-standing pressure overload leads to concentric left ventricular hypertrophy.

2. Pulmonary Stenosis and Atresia

obstruction at the level of the pulmonary valve. -isolated or part of a more complex anomaly—either TOF or TGA -Right ventricular hypertrophy typically develops, and there is sometimes poststenotic dilation of the pulmonary ARTERY due to injury of the wall by "jetting" blood. - When the valve is entirely atretic, there is no communication between the right ventricle and lungs. In such cases the anomaly is associated with a hypoplastic right ventricle and an ASD; blood reaches the lungs through a PDA. -Mild stenosis may be asymptomatic and compatible with long life

1. ASD

persistent opening between atria. septum primum-crescent shaped membranous ingrowth. osmium premium is open. Closes, and ostium secundum holes form in septum primum. septum secundum-membranous second portion ingrowth to RIGHT and FORWARD of septum primum. Leaves septum secundum/fORAMEN OVALE open. At brith,pressures drop in R side, Flap forces back on itself.from L to R, seals. ASDs usually are secundum ASDs, less commonly premium anomalies or sinus venous defects-located near entrance of SVC- anomalous pulmonary venous return to R atrium. -Asymptomatic before age 30, irreversible pulmonary hypertension is unusual. ASD closure reverses abnormalities. PFO: unsealed flap can open if right-sided pressures become elevated. Thus, sustained pulmonary hypertension or even transient increases in right-sided pressures, for example, during a bowel movement, coughing, or sneezing, can produce brief periods of right-to-left shunting, with the possibility of paradoxical embolism.

3. Aortic Stenosis and Atresia WILLIAMsCHR 7 ELASTIN supra ventricular aortic stenosis.

three locations: valvular, subvalvular, and supravalvular. isolated lesion in 80% of cases. -valvular aortic stenosis: the cusps may be hypoplastic (small), dysplastic (thickened, nodular), or abnormal in number (usually acommissural or unicommissural). -Hypoplastic left heart syndrome: In severe congenital aortic stenosis or atresia, obstruction of the left ventricular outflow tract leads to hypoplasia of the left ventricle and ascending aorta, sometimes accompanied by dense, porcelain-like left ventricular endocardial fibroelastosis. The ductus must be open to allow blood flow to the aorta and coronary arteries. Unless a palliative procedure is done to preserve PDA patency, duct closure in the first week of life is generally lethal. But less severe aortic stenosis is survivable, with long life. -Subaortic stenosis is caused by a thickened ring or collar of dense endocardial fibrous tissue below the level of the cusps. -Supravalvular aortic stenosis is a congenital aortic dysplasia with thickening of ascending aortic wall and consequent luminal constriction. In some cases it is a component of a multiorgan developmental disorder resulting from deletions on CHROMOSOME 7 that include the gene for ELASTIN. Other features of the syndrome include hypercalcemia, cognitive abnormalities, and characteristic facial anomalies ( Williams-Beuren syndrome ). !!!!!!!!Elastin gene mutations may cause supravalvular stenosis by disrupting elastin-smooth muscle cell interactions during aortic morphogenesis.

A. Sudden Cardiac Death most of these deaths are thought to result from myocardial ischemia-induced irritability that initiates malignant ventricular arrhythmias. Coronary artery disease is the leading cause of SCD, responsible for 80% to 90% of cases; unfortunately, SCD is often the first manifestation of IHD. The mechanism of SCD is most often a lethal arrhythmia (e.g., asystole or ventricular fibrillation) . Notably, infarction need not occur; 80% to 90% of patients who suffer SCD but are successfully resuscitated do not show any enzymatic or ECG evidence of myocardial necrosis—even when the original cause was ischemic heart disease. When a lethal arrhythmia is to blame, there is rarely any myocardial necrosis. Marked coronary atherosclerosis with a critical (>75% cross-sectional area) stenosis involving one or more of the three major vessels High grade stenoses in most. Ruptured plaque in half. In 25%, MI that moves too quickly.

SCD is most commonly defined as unexpected death from cardiac causes either without symptoms, or within 1 to 24 hours of symptom onset (different authors use different criteria); this happens in some 300,000 to 400,000 individuals each year in the United States alone. Coronary artery disease is the leading cause of SCD, responsible for 80% to 90% of cases; unfortunately, SCD is often the first manifestation of IHD. Interestingly, there is typically only chronic severe atherosclerotic disease; acute plaque disruption is found in only 10% to 20% of cases. Healed remote MIs are present in about 40%. With younger victims, other nonatherosclerotic causes are more common etiologies for SCD: • Hereditary or acquired abnormalities of the cardiac conduction system • Congenital coronary arterial abnormalities • Mitral valve prolapse • Myocarditis or sarcoidosis • Dilated or hypertrophic cardiomyopathy • Pulmonary hypertension • Myocardial hypertrophy. Increased cardiac mass is an independent risk factor for SCD; thus, some young individuals who die suddenly—including athletes—have hypertensive hypertrophy or unexplained increased cardiac mass as the only finding. • Other miscellaneous causes, such as pericardial tamponade, pulmonary embolism, systemic metabolic and hemodynamic alterations, catecholamines, and drugs of abuse, particularly cocaine and methamphetamine. The mechanism of SCD is most often a lethal arrhythmia (e.g., asystole or ventricular fibrillation) . Notably, infarction need not occur; 80% to 90% of patients who suffer SCD but are successfully resuscitated do not show any enzymatic or ECG evidence of myocardial necrosis—even when the original cause was ischemic heart disease. Although ischemic injury (and other pathologies) can directly affect the major components of the conduction system, most cases of fatal arrhythmia are triggered by electrical irritability of myocardium distant from the major elements of the conduction system. The prognosis of patients vulnerable to SCD is markedly improved by pharmaceutical intervention, and particularly by implantation of automatic cardioverter defibrillators that can sense and electrically counteract episodes of ventricular fibrillation.

1. Acute Pericarditis Serous: noninfectious inflammation: SLE, RF, scleroderma, tumor, uremia. sometimes it is a sequelae of a real infection-pleuritis or URI, etc. Could also be viral myocarditis that spreads. Tumors can invade lymphatics. Mild inflammation in epicardial fat, with lymphocytes. Fibrous adhesion may occur. Fibrinous and serofibrinous- MOST FREQUENT type. Acute MI (Dressler syndrome= autoimmune response appearing days to weeks after an MI), uremia, chest radiation RF, SLE, trauma. Following Cardiac surgery. Serous fluid admixed with some fibrous exudate. Fibrinous :Dry, fine granular roughening. serofibrinous-More intense inflammatory process induces accumulation of yellow to brown turbid fluid, with leukocytes, erythrocytes, fibrin. Pericardial friction rub, pleuritic pain, congestive failure, fever. Purulent or suppurtive pericarditis: active infection by microbial invasion. Thin cloudy fluid and pus, serosal surfaces are red, granular, coated with exudate. Organization by scarring is most common outcome. CAn prouce CONSTRICTIVE PERICARDITIS- a serious problem. spiking fevers and rigors Hemorrhagic pericarditis: blood, fibrous suppurtive effusion, mostly caused by spread of malignant neoplasm to pericardial space, shown with neoplastic cells i space. underlying bleeding diathesis, TB, Following cardiac surgery or tamponade, requiring re-operatio. Caseous pericarditis, TUBERCULOSIS until proven otherwise. Fungal infections can provoke similar. Antecedent of disabling, fibrocalcific, chronic constictive pericarditis. Organization: plaque like fibrous thickenings or thin delicate adhesions. In other oases, fibrosis in the form of mesh like stringy adhesions completely obliterates pericardial sac-but this has no effect on cardiac function. Adhesive MEDIASTINOpericarditis obliterates pericardial sac, adhering external perietal layer to surrounding structures.... STRAINING CARDIAC FUNCTION. Heart puls against rib catge and diphragm. PULSUS PARADOXUS, SYSTOLIC RETRACTION OF RIB CAGE AND DIAPHRAGM may be seen. Increased work load causes severe cardiac hypertophy and dilation. CONSTRICTIVE PERICARDITIS: dense fibrous fibrocalcific scar, limits diastolic expansion and cardiac output. up to 1cm thick, sometimes calcifying, can resembe a plaster mold. Dense scar, hypertophy and dilation cannot occur. Output reduced at rest, cannot respond at all to increased systemic demand. Distand, muffled heart sounds, elevateed JVP, peripheral edema. REMOVE PERICARDIAL SAC

Serous pericarditis is characteristically produced by noninfectious inflammatory diseases, including rheumatic fever, SLE, and scleroderma, as well as tumors and uremia. An infection in the tissues contiguous to the pericardium—for example, a bacterial pleuritis—may incite sufficient irritation of the parietal pericardial serosa to cause a sterile serous effusion that can progress to serofibrinous pericarditis and ultimately to a frank suppurative reaction. In some instances a well-defined viral infection elsewhere—upper respiratory tract infection, pneumonia, parotitis—antedates the pericarditis and serves as the primary focus of infection. Infrequently, usually in young adults, a viral pericarditis occurs as an apparent primary infection that may be accompanied by myocarditis (myopericarditis) . Tumors can cause a serous pericarditis by lymphatic invasion or direct contiguous extension into the pericardium. Histologically, serous pericarditis elicits a mild inflammatory infiltrate in the epipericardial fat consisting predominantly of lymphocytes; tumor-associated pericarditis may also exhibit neoplastic cells. Organization into fibrous adhesions rarely occurs. Fibrinous and serofibrinous pericarditis are the most frequent types of pericarditis ; these are composed of serous fluid variably admixed with a fibrinous exudate. Common causes include acute MI ( Fig. 12-18 D ), postinfarction (Dressler) syndrome (an autoimmune response appearing days-weeks after an MI), uremia, chest radiation, rheumatic fever, SLE, and trauma. A fibrinous reaction also follows routine cardiac surgery. In fibrinous pericarditis the surface is dry, with a fine granular roughening. In serofibrinous pericarditis a more intense inflammatory process induces the accumulation of larger amounts of yellow to brown turbid fluid, containing leukocytes, erythrocytes, and fibrin. As with all inflammatory exudates, fibrin may be lysed with resolution of the exudate, or can become organized ( Chapter 3 ) Symptoms of fibrinous pericarditis characteristically include pain (sharp, pleuritic, and position dependent) and fever; congestive failure may also be present. A loud pericardial friction rub is the most striking clinical finding. However, the collection of serous fluid can actually prevent rubbing by separating the two layers of the pericardium. Purulent or suppurative pericarditis reflects an active infection caused by microbial invasion of the pericardial space; this can occur through: • Direct extension from neighboring infections, such as an empyema of the pleural cavity, lobar pneumonia, mediastinal infections, or extension of a ring abscess through the myocardium or aortic root • Seeding from the blood • Lymphatic extension • Direct introduction during cardiotomy The exudate ranges from a thin cloudy fluid to frank pus up to 400 to 500 mL in volume. The serosal surfaces are reddened, granular, and coated with the exudate ( Fig. 12-37 ). Microscopically there is an acute inflammatory reaction, which sometimes extends into surrounding structures to induce mediastinopericarditis . Complete resolution is infrequent, and organization by scarring is the usual outcome. The intense inflammatory response and the subsequent scarring frequently produce constrictive pericarditis , a serious consequence (see later). Clinical findings in the active phase resemble those seen in fibrinous pericarditis, although the frank infection leads to more marked systemic symptoms including spiking fevers and rigors. Hemorrhagic pericarditis has an exudate composed of blood mixed with a fibrinous or suppurative effusion; it is most commonly caused by the spread of a malignant neoplasm to the pericardial space. In such cases, cytologic examination of fluid removed through a pericardial tap often reveals neoplastic cells. Hemorrhagic pericarditis can also be found in bacterial infections, in persons with an underlying bleeding diathesis, and in tuberculosis. Hemorrhagic pericarditis often follows cardiac surgery and is occasionally responsible for significant blood loss or even tamponade, requiring re-operation. The clinical significance is similar to that of fibrinous or suppurative pericarditis. Caseous pericarditis is, until proved otherwise, tuberculous in origin; infrequently, fungal infections evoke a similar reaction. Pericardial involvement occurs by direct spread from tuberculous foci within the tracheobronchial nodes. Caseous pericarditis is a common antecedent of disabling, fibrocalcific, chronic constrictive pericarditis. Chronic or Healed Pericarditis. In some cases organization merely produces plaque-like fibrous thickenings of the serosal membranes ("soldier's plaque") or thin, delicate adhesions that rarely cause impairment of cardiac function. In other cases, fibrosis in the form of mesh-like stringy adhesions completely obliterates the pericardial sac. In most instances, this adhesive pericarditis has no effect on cardiac function. Adhesive mediastinopericarditis may follow infectious pericarditis, previous cardiac surgery, or mediastinal irradiation. The pericardial sac is obliterated, and adherence of the external aspect of the parietal layer to surrounding structures strains cardiac function. With each systolic contraction, the heart pulls not only against the parietal pericardium but also against the attached surrounding structures. Systolic retraction of the rib cage and diaphragm, pulsus paradoxus, and a variety of other characteristic clinical findings may be observed. The increased workload causes occasionally severe cardiac hypertrophy and dilation. In constrictive pericarditis the heart is encased in a dense, fibrous or fibrocalcific scar that limits diastolic expansion and cardiac output, features that mimic a restrictive cardiomyopathy. A prior history of pericarditis may or may not be present. The fibrous scar can be up to a centimeter in thickness, obliterating the pericardial space and sometimes calcifying; in extreme cases it can resemble a plaster mold (concretio cordis) . Because of the dense enclosing scar, cardiac hypertrophy and dilation cannot occur. Cardiac output may be reduced at rest, but more importantly the heart has little if any capacity to increase its output in response to increased systemic demands. Signs of constrictive pericarditis include distant or muffled heart sounds, elevated jugular venous pressure, and peripheral edema. Treatment consists of surgical resection of the shell of constricting fibrous tissue (pericardiectomy).

E. Infective Endocarditis Acute infective endocarditis is typically caused by infection of a previously normal heart valve by a highly virulent organism (e.g., Staphylococcus aureus ) rapidly produces necrotizing and destructive lesions. These infections may be difficult to cure with antibiotics alone, and usually require surgery. Despite appropriate treatment, death can ensue within days to weeks. subacute IE is characterized by organisms with lower virulence (e.g., viridans streptococci) that cause insidious infections of deformed valves with overall less destruction. In such cases the disease may pursue a protracted course of weeks to months, and cures can be achieved with antibiotics. RHD INCREASES THE RISK with valvular scarring. or MVP, degenerative calcific valvular stenosis, bicuspid aortic valve, artifical valve, congenital defects either repaired or unrepaired. HIGH RISK GROUPS: Strep viridans from oral cavity: previously damaged or abnormal valve, most common causative organism. Staph aureus: IV Drug users (TC VAlve mostly), infects healthy or derformed valves. Second most common. HACEK enterococci also common, also commensals in oral cavity. Staph epidermidis: Most common for prosthetic valves. Rare gram negative and fungi. Usually there is no blood culture. CULTURE NEGATIVE. because deeply embedded, previous antibiotics, or difficulty isolating it. usually seeding, dental procedure, contaminated sharps, trivial breaks in gut, oral cvity, skin. Oral prophylaxis can lower risk with known valve abnormaliteies. FRIABLE, BULKY vegetations on heart valves with fibrin, inflammatory cells, and bacteria Aortic and mitral are most common. single or multiple. can prouce abscesses. VERY PRONE TO EMBOLIS. OFTEN SEPTIC EMBOLI subacute: subacute IE typically exhibit granulation tissue at their bases indicative of healing. With time, fibrosis, calcification, and a chronic inflammatory infiltrate can develop. ACUTE ENDOCARDITIS: stormy onset, fever, chills,weakness, lassitude murmurs if it is mitral or aortic valve. may be from preexisting condition. DUKE CRITERIA major: new valv regurgitation, echo valve related abscess or mass or septation of artificial valve. blood cultures.

Infective endocarditis (IE) is a microbial infection of the heart valves or the mural endocardium that leads to the formation of vegetations composed of thrombotic debris and organisms, often associated with destruction of the underlying cardiac tissues. The aorta, aneurysms, other blood vessels, and prosthetic devices can also become infected. Although fungi and other classes of microorganisms can be responsible, most infections are bacterial (bacterial endocarditis). Prompt diagnosis, identification of the offending agent, and effective treatment of IE is important in limiting morbidity and mortality. Traditionally, IE has been classified on clinical grounds into acute and subacute forms. This subdivision reflects the range of the disease severity and tempo, which are determined in large part by the virulence of the infecting microorganism and whether underlying cardiac disease is present. Acute infective endocarditis is typically caused by infection of a previously normal heart valve by a highly virulent organism (e.g., Staphylococcus aureus ) that rapidly produces necrotizing and destructive lesions. These infections may be difficult to cure with antibiotics alone, and usually require surgery. Despite appropriate treatment, death can ensue within days to weeks. In contrast, subacute IE is characterized by organisms with lower virulence (e.g., viridans streptococci) that cause insidious infections of deformed valves with overall less destruction. In such cases the disease may pursue a protracted course of weeks to months, and cures can be achieved with antibiotics. Pathogenesis. Although highly virulent organisms can infect previously normal valves, a variety of cardiac and vascular abnormalities increase the risk of developing IE. Rheumatic heart disease with valvular scarring has historically been the major antecedent disorder; as RHD becomes less common, it has been supplanted by mitral valve prolapse, degenerative calcific valvular stenosis, bicuspid aortic valve (whether calcified or not), artificial (prosthetic) valves, and unrepaired and repaired congenital defects. The causal organisms differ among the major high-risk groups. Endocarditis of native but previously damaged or otherwise abnormal valves is caused most commonly (50% to 60% of cases) by Streptococcus viridans , a normal component of the oral cavity flora. In contrast, more virulent S. aureus organisms commonly found on the skin can infect either healthy or deformed valves and are responsible for 20% to 30% of cases overall; notably, S. aureus is the major offender in IE among intravenous drug abusers. Other bacterial causes include enterococci and the so-called HACEK group ( Haemophilus, Actinobacillus, Cardiobacterium, Eikenella , and Kingella ), all commensals in the oral cavity. Prosthetic valve endocarditis is caused most commonly by coagulase-negative staphylococci (e.g., S. epidermidis ). Other agents causing endocarditis include gram-negative bacilli and fungi. In about 10% of all cases of endocarditis, no organism can be isolated from the blood ("culture-negative" endocarditis); reasons include prior antibiotic therapy, difficulties in isolating the offending agent, or because deeply embedded organisms within the enlarging vegetation are not released into the blood. Foremost among the factors predisposing to endocarditis are those that cause microorganism seeding into the blood stream (bacteremia or fungemia). The source may be an obvious infection elsewhere, a dental or surgical procedure, a contaminated needle shared by intravenous drug users, or seemingly trivial breaks in the epithelial barriers of the gut, oral cavity, or skin. In patients with valve abnormalities, or with known bacteremia, IE risk can be lowered by antibiotic prophylaxis. Vegetations on heart valves are the classic hallmark of IE; these are friable, bulky, potentially destructive lesions containing fibrin, inflammatory cells, and bacteria or other organisms ( Figs. 12-24 and 12-25 ). The aortic and mitral valves are the most common sites of infection, although the valves of the right heart may also be involved, particularly in intravenous drug abusers. Vegetations can be single or multiple and may involve more than one valve; they can occasionally erode into the underlying myocardium and produce an abscess (ring abscess; Fig. 12-25 B ). Vegetations are prone to embolization; because the embolic fragments often contain virulent organisms, abscesses frequently develop where they lodge, leading to sequelae such as septic infarcts or mycotic aneurysms. The vegetations of subacute endocarditis are associated with less valvular destruction than those of acute endocarditis, although the distinction can be subtle. Microscopically, the vegetations of subacute IE typically exhibit granulation tissue at their bases indicative of healing. With time, fibrosis, calcification, and a chronic inflammatory infiltrate can develop. Acute endocarditis has a stormy onset with rapidly developing fever, chills, weakness, and lassitude. Although fever is the most consistent sign of IE, it can be slight or absent, particularly in older adults, and the only manifestations may be nonspecific fatigue, loss of weight, and a flulike syndrome. Murmurs are present in 90% of patients with left-sided IE, either from a new valvular defect or from a preexisting abnormality. The so-called modified Duke criteria ( Table 12-9 ) facilitate evaluation of individuals with suspected IE that takes into account predisposing factors, physical findings, blood culture results, echocardiographic findings, and laboratory information. Diagnosis by these guidelines, often called the Duke Criteria, requires either pathologic or clinical criteria; if clinical criteria are used, 2 major, 1 major + 3 minor, or 5 minor criteria are required for diagnosis. VASCULAR LESIONS: † Janeway lesions are small erythematous or hemorrhagic, macular, nontender lesions on the palms and soles and are the consequence of septic embolic events. IMMUNOLOGICAL LESION ‡ Osler nodes are small, tender subcutaneous nodules that develop in the pulp of the digits or occasionally more proximally in the fingers and persist for hours to several days. § Roth spots are oval retinal hemorrhages with pale centers. Complications of IE generally begin within the first few weeks of onset, and can include glomerular antigen-antibody complex deposition causing glomerulonephritis ( Chapter 20 ). Earlier diagnosis and effective treatment has nearly eliminated some previously common clinical manifestations of long-standing IE—for example, microthromboemboli (manifest as splinter or subungual hemorrhages), erythematous or hemorrhagic nontender lesions on the palms or soles (Janeway lesions), subcutaneous nodules in the pulp of the digits (Osler nodes), and retinal hemorrhages in the eyes (Roth spots).

A. Primary Cardiac Tumors primitive multipotent mesenchymal cells. activating mutations in the GNAS1 gene, encoding a subunit of G protein (Gsα) (in association with McCune-Albright syndrome) or null mutations in PRKAR1A , encoding a regulatory subunit of a cyclic-AMP-dependent protein kinase ( Carney complex ). ATRIA LEFT SIDE 4:1 sessile or pedunculated globular hard masses mottled with hemorrhage or to soft, translucent, papillary, or villous lesions having a gelatinous appearance. The pedunculated form is often sufficiently mobile to move during systole into the atrioventricular valve opening, causing intermittent obstruction that may be position-dependent. Sometimes mobile tumors exert a "wrecking-ball" effect, causing damage to the valve leaflets. stellate or globular myxoma cells embedded within an abundant acid mucopolysaccharide ground substance Peculiar vessel-like or gland-like structures are characteristic. Hemorrhage and mononuclear inflammation are usually present. IL-6 produced by some myxomas, which causes inflammation. Echo Surgery, but can recur later LIPOMAS: Mature fat cells LV, RA, or atrial septum. white and brown asdipose tissue with myocardium interspersed. Papillary fibroelastomas: curious, usually incidental, sea-anemone-like lesions, most often identified at autopsy. Can embolize. Unusual benign- wtih cytogenetic abnoramlaiteis. Resemble Lambl excrescences that are organzed thrombi on aortic valves in elderly Papillary fibroelastomas are usually (>80%) located on valves, particularly the ventricular surfaces of semilunar valves and the atrial surfaces of atrioventricular valves. distinctive cluster of hairlike projections up to 1 cm in length. Histologically, the projections are covered by a surface endothelium surrounding a core of myxoid connective tissue with abundant mucopolysaccharide matrix and elastic fibers. PEDIATRICS obstructing valvular orifices or cardiac chambers. TUBEROUS SCLEROSIS (TSC1 or 2 tumor suppresors hamartin and tuberin) normally inhibit mTOR, target of rapamycin, and stimulating growth or regulation of size. Causes myocyte overgrowth. Gray white masses: PREFER VENTRICLES and protrude into the LUMEN. BIZARRE ENLARGED MYOCYTES, ABUndant cytoplasm with thin strands that stretch to membrane from nucleus (SPIDER CELLS)

Myxomas are the most common primary tumor of the adult heart ( Fig. 12-38 ). These are benign neoplasms thought to arise from primitive multipotent mesenchymal cells. Although sporadic myxomas do not show consistent genetic alterations, familial syndromes associated with myxomas have activating mutations in the GNAS1 gene, encoding a subunit of G protein (Gsα) (in association with McCune-Albright syndrome) or null mutations in PRKAR1A , encoding a regulatory subunit of a cyclic-AMP-dependent protein kinase ( Carney complex ). About 90% of myxomas arise in the atria, with a left-to-right ratio of approximately 4 : 1. The tumors are usually single, but can rarely be multiple. The region of the fossa ovalis in the atrial septum is the favored site of origin. Myxomas range from small (<1 cm) to large (≥10 cm), and can be sessile or pedunculated lesions ( Fig. 12-38 A ). They vary from globular hard masses mottled with hemorrhage to soft, translucent, papillary, or villous lesions having a gelatinous appearance. The pedunculated form is often sufficiently mobile to move during systole into the atrioventricular valve opening, causing intermittent obstruction that may be position-dependent. Sometimes mobile tumors exert a "wrecking-ball" effect, causing damage to the valve leaflets. Histologically, myxomas are composed of stellate or globular myxoma cells embedded within an abundant acid mucopolysaccharide ground substance ( Fig. 12-38 B ). Peculiar vessel-like or gland-like structures are characteristic. Hemorrhage and mononuclear inflammation are usually present. The major clinical manifestations are due to valvular "ball-valve" obstruction, embolization, or a syndrome of constitutional symptoms, such as fever and malaise. Sometimes fragmentation and systemic embolization calls attention to these lesions. Constitutional symptoms are probably due to the elaboration by some myxomas of the cytokine interleukin-6, a major mediator of the acute-phase response. Echocardiography provides the opportunity to identify these masses noninvasively. Surgical removal is usually curative; rarely, presumably with incomplete excision, the neoplasm can recurs months to years later. Lipoma. Lipomas are localized, well-circumscribed, benign tumors composed of mature fat cells that can occur in the subendocardium, subepicardium, or myocardium. They may be asymptomatic, or produce ball-valve obstructions or arrhythmias. Lipomas are most often located in the left ventricle, right atrium, or atrial septum. In the atrial septum, nonneoplastic depositions of fat sometimes occur that are called "lipomatous hypertrophy." These lesions include white and brown adipose tissue, as well as small interspersed areas of myocardium. Papillary Fibroelastoma. Papillary fibroelastomas are curious, usually incidental, sea-anemone-like lesions, most often identified at autopsy. They may embolize and thereby become clinically important. Clonal cytogenetic abnormalities have been reported, suggesting that fibroelastomas are unusual benign neoplasms. They resemble the much smaller, usually trivial, Lambl excrescences that may represent remotely organized thrombus on the aortic valves of older individuals. Papillary fibroelastomas are usually (>80%) located on valves, particularly the ventricular surfaces of semilunar valves and the atrial surfaces of atrioventricular valves. Each lesion, typically 1 to 2 cm in diameter, consists of a distinctive cluster of hairlike projections up to 1 cm in length. Histologically, the projections are covered by a surface endothelium surrounding a core of myxoid connective tissue with abundant mucopolysaccharide matrix and elastic fibers. Rhabdomyoma. Rhabdomyomas are the most frequent primary tumor of the pediatric heart, and are commonly discovered in the first years of life because of obstruction of a valvular orifice or cardiac chamber. Approximately half of cardiac rhabdomyomas are due to sporadic mutations; the other 50% of cases are associated with tuberous sclerosis ( Chapter 28 ), with mutations in the TSC1 or TSC2 tumor suppressor gene. The TSC1 and TSC2 proteins (hamartin and tuberin, respectively) function in a complex that inhibits the activity of the mammalian target of rapamycin (mTOR), a kinase that stimulates cell growth and regulates cell size. TSC1 or TSC2 expression is often absent in tuberous sclerosis-associated rhabdomyomas, providing a mechanism for myocyte overgrowth. Because rhabdomyomas often regress spontaneously, they may be considered as hamartomas rather than true neoplasms. Rhabdomyomas are gray-white myocardial masses that can be small or up to several centimeters in diameter. They are usually multiple and involve the ventricles preferentially, protruding into the lumen. Microscopically, they are composed of bizarre, markedly enlarged myocytes. Routine histologic processing often artifactually reduces the abundant cytoplasm to thin strands that stretch from the nucleus to the surface membrane, an appearance referred to as "spider" cells. Sarcoma. Cardiac angiosarcomas and other sarcomas are not clinically or morphologically distinctive from their counterparts in other locations, and so require no further comment here.