InternalMed_Harrison

InternalMed_Harrison. Bacterial Infections Most bacterial infections can involve the heart occasionally through direct invasion and abscess formation, but do so rarely. More commonly, systemic inflammatory responses depress contractility in severe infection and sepsis. Diphtheria specifically affects the heart in almost one-half of cases, and cardiac involvement is the most common cause of death in patients with this infection. The prevalence of vaccines has shifted the incidence of diphtheria from children worldwide to countries without routine immunization and to older populations who have lost their immunity. The bacillus releases a toxin that impairs protein synthesis and may particularly affect the conduction system. The specific antitoxin should be administered as soon as possible, with higher priority than antibiotic therapy. Other systemic bacterial infections that can involve the heart include brucellosis, chlamydophila, legionella, meningococcus, mycoplasma, psittacosis, and salmonellosis, for


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InternalMed_Harrison. than antibiotic therapy. Other systemic bacterial infections that can involve the heart include brucellosis, chlamydophila, legionella, meningococcus, mycoplasma, psittacosis, and salmonellosis, for which specific treatment is directed at the systemic infection.


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InternalMed_Harrison. Clostridial infections cause myocardial damage from the released toxin. Gas bubbles can be detected in the myocardium, and occasionally abscesses can form in the myocardium and pericardium. Streptococcal infection with β-hemolytic streptococci is most commonly associated with acute rheumatic fever and is characterized by inflammation and fibrosis of cardiac valves and systemic connective tissue, but it can also lead to a myocarditis with focal or diffuse infiltrates of mononuclear cells. Tuberculosis can involve the myocardium directly as well as through tuberculous pericarditis, but rarely does so when the disease is treated with antibiotics. Whipple’s disease is caused by Tropheryma whipplei. The usual manifestations are in the gastrointestinal tract, but pericarditis, coronary arteritis, valvular lesions, and occasionally clinical heart failure may also occur. Multidrug antituberculous regimens are effective, but the disease tends to relapse even with appropriate treatment.


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InternalMed_Harrison. Other Infections Spirochetal myocarditis has been diagnosed from myocardial biopsies containing Borrelia burgdorferi that causes Lyme disease. Lyme carditis most often presents with arthritis and conduction system disease that resolves within 1–2 weeks of antibiotic treatment, only rarely implicated in chronic heart failure. Fungal myocarditis can occur due to hematogenous or direct spread of infection from other sites, as has been described for aspergillosis, actinomycosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, and mucormycosis. However, cardiac involvement is rarely the dominant clinical feature of these infections. The rickettsial infections, Q fever, Rocky Mountain spotted fever, 1561 and scrub typhus are frequently accompanied by ECG changes, but most clinical manifestations relate to systemic vascular involvement.


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InternalMed_Harrison. Myocardial inflammation can occur without apparent preceding infection. The paradigm of noninfective inflammatory myocarditis is cardiac transplant rejection, from which we have learned that myocardial depression can develop and reverse quickly, that noncellular mediators such as antibodies and cytokines play a major role in addition to lymphocytes, and that myocardial antigens are exposed by prior physical injury and viral infection.


InternalMed_Harrison

InternalMed_Harrison. The most commonly diagnosed noninfective inflammation is granulomatous myocarditis, including both sarcoidosis and giant cell myocarditis. Sarcoidosis, as discussed in Chap. 390, is a multisystem disease most commonly affecting the lungs. Although classically presenting with higher prevalence in young African-American men, the epidemiology appears to be changing, with increasing recogni tion of sarcoidosis in Caucasian patients in nonurban areas. Patients with pulmonary sarcoid are at high risk for cardiac involvement, but cardiac sarcoidosis also occurs without clinical lung disease. Regional clustering of the disease supports the suspicion that the granulomatous reaction is triggered by an infectious or environmental allergen not yet identified.


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InternalMed_Harrison. The sites and density of cardiac granulomata, the time course, and the degree of extracardiac involvement are remarkably variable. Patients may present with rapid-onset heart failure and ventricular tachyarrhythmias, conduction block, chest pain syndromes, or minor cardiac findings in the setting of ocular involvement, an infiltrative skin rash, or a nonspecific febrile illness. They may also present less acutely after months to years of fluctuating cardiac symptoms. When ventricular tachycardia or conduction block dominates the initial presentation of heart failure without coronary artery disease, suspicion should be high for these granulomatous myocarditides.


InternalMed_Harrison

InternalMed_Harrison. Depending on the time course, the ventricles may appear restrictive or dilated. There is often right ventricular predominance of both dilation and ventricular arrhythmias, sometimes initially attributed to arrhythmogenic right ventricular dysplasia. Small ventricular aneurysms are common. Computed tomography of the chest often reveals pulmonary lymphadenopathy even in the absence of clinical lung disease. Metabolic imaging (positron emission tomography (PET]) of the whole chest can highlight active sarcoid lesions that are avid for glucose. Magnetic resonance imaging (MRI) of the heart can identify areas likely to be inflammatory. To rule out chronic infections, such as tuberculosis or histoplasmosis as the cause of adenopathy, the diagnosis usually requires pathologic confirmation. Biopsy of enlarged mediastinal nodes may provide the highest yield. The scattered granulomata of sarcoidosis can easily be missed on cardiac biopsy (Fig. 287-8).


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InternalMed_Harrison. Immunosuppressive treatment for sarcoidosis is initiated with high-dose glucocorticoids, which are often more effective for arrhythmias than for the heart failure. Patients with sarcoid lesions that persist or recur during tapering of corticosteroids are considered candidates for other immunosuppressive therapies, frequently with agents also used for cardiac transplantation. Pacemakers and implantable defibrillators are generally indicated to prevent life-threatening heart block or ventricular tachycardia, respectively. Because the inflammation often resolves into extensive fibrosis that impairs cardiac function and provides pathways for reentrant arrhythmias, the prognosis for improvement is best when the granulomata are not extensive and the ejection fraction is not severely reduced.


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InternalMed_Harrison. Giant cell myocarditis is less common than sarcoidosis, but accounts for 10–20% of biopsy-positive cases of myocarditis. Giant cell myocarditis typically presents with rapidly progressive heart failure and tachyarrhythmias. Diffuse granulomatous lesions are surrounded by extensive inflammatory infiltrate unlikely to be missed on endomyocardial biopsy, often with extensive eosinophilic infiltration. Associated conditions are thymomas, thyroiditis, pernicious anemia, other autoimmune diseases, and occasionally recent infections. Glucocorticoid therapy is less effective than for sarcoidosis and is


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InternalMed_Harrison. FIGURE 287-8 Sarcoidosis. Microscopic image of an endomyocardial biopsy showing a noncaseating granuloma and associated interstitial fibrosis typical of sarcoidosis. No microorganisms were present on special stains, and no foreign material was identified. Hematoxylin and eosin–stained section, 200× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) sometimes combined with other immunosuppressive agents. The course is generally of rapid deterioration requiring urgent transplantation. Although the severity of presentation and myocardial histology are more fulminant than with sarcoidosis, the occasional finding of giant cell myocarditis after sarcoidosis suggests that they may in some cases represent different stages of the same disease spectrum.


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InternalMed_Harrison. Eosinophilic myocarditis can be an important manifestation of the hypereosinophilic syndrome, which in Western countries is often idiopathic, although in Mediterranean and African countries, it is likely a consequence of antecedent infection. It may also be seen with systemic eosinophilic syndromes such as Churg-Strauss syndrome or malignancies. Hypersensitivity myocarditis is often an unexpected diagnosis, made when the biopsy reveals infiltration with lymphocytes and mononuclear cells with a high proportion of eosinophils. Most commonly, the reaction is attributed to antibiotics, particularly those taken chronically, but thiazides, anticonvulsants, indomethacin, and methyldopa have also been implicated. Occasional associations with the smallpox vaccine have been reported. Although the circulating eosinophil count may be slightly elevated in hypersensitivity myocarditis, it does not reach the high levels of the hypereosinophilic syndrome. High-dose glucocorticoids and discontinuation


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InternalMed_Harrison. eosinophil count may be slightly elevated in hypersensitivity myocarditis, it does not reach the high levels of the hypereosinophilic syndrome. High-dose glucocorticoids and discontinuation of the trigger agent can be curative for hypersensitivity myocarditis.


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InternalMed_Harrison. Myocarditis is often associated with systemic inflammatory diseases, such as polymyositis and dermatomyositis, which affect skeletal and cardiac muscle. Although noninfective inflammatory myocarditis is sometimes included in the differential diagnosis of cardiac findings in patients with connective tissue disease such as systemic lupus erythematosus, pericarditis, vasculitis, pulmonary hypertension, and accelerated coronary artery disease are more common cardiac manifestations of connective tissue disease.


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InternalMed_Harrison. Peripartum cardiomyopathy (PPCM) develops during the last trimester or within the first 6 months after pregnancy, with a frequency between 1:2000 and 1:15,000 deliveries. Risk factors are increased maternal age, increased parity, twin pregnancy, malnutrition, use of tocolytic therapy for premature labor, and preeclampsia or toxemia of pregnancy. Heart failure early after delivery was previously common in Nigeria, when the custom for new mothers included salt ingestion while reclining on a warm bed, which likely impaired mobilization of the excess circulating volume after delivery. In the Western world, lymphocytic myocarditis has sometimes been found on myocardial biopsy. This inflammation has been hypothesized to reflect increased susceptibility to viral myocarditis or an autoimmune myocarditis due to cross-reactivity of anti-uterine antibodies against cardiac muscle. Another proposed mechanism invokes an abnormal prolactin cleavage fragment, which is induced by oxidative stress and


InternalMed_Harrison

InternalMed_Harrison. due to cross-reactivity of anti-uterine antibodies against cardiac muscle. Another proposed mechanism invokes an abnormal prolactin cleavage fragment, which is induced by oxidative stress and may trigger myocardial apoptosis; this observation has led to preliminary investigation of bromocriptine as possible therapy.


InternalMed_Harrison

InternalMed_Harrison. Very recently, PPCM has been found to be associated with increased antiangiogenic signaling, a process that is exacerbated by preeclampsia. In animal models of this disease, proangiogenic therapies have proven curative. As the increased circulatory demand of pregnancy can aggravate other cardiac disease that was clinically unrecognized, it is crucial to the diagnosis of PPCM that there be no evidence for a preexisting cardiac disorder. By contrast, heart failure presenting earlier in pregnancy has been termed pregnancy-associated cardiomyopathy (PACM). Both PPCM and PACM have been found in some families with other presentations of dilated cardiomyopathy, in some cases with known sarcomeric protein mutations. Pregnancy may, thus, represent an environmental trigger for accelerated phenotypic expression of genetic cardiomyopathy.


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InternalMed_Harrison. Cardiotoxicity has been reported with multiple environmental and pharmacologic agents. Often these associations are seen only with very high levels of exposure or acute overdoses, in which acute electrocardiographic and hemodynamic abnormalities may reflect both direct drug effect and systemic toxicity.


InternalMed_Harrison

InternalMed_Harrison. Alcohol is the most common toxin implicated in chronic dilated cardiomyopathy. Excess consumption may contribute to more than 10% of cases of heart failure, including exacerbation of cases with other primary etiologies such as valvular disease or previous infarction. Toxicity is attributed both to alcohol and to its primary metabolite, acetaldehyde. Polymorphisms of the genes encoding alcohol dehydrogenase and the angiotensin-converting enzyme increase the likelihood of alcoholic cardiomyopathy in an individual with excess consumption. Superimposed vitamin deficiencies and toxic alcohol additives are rarely implicated. The alcohol consumption necessary to produce cardiomyopathy in an otherwise normal heart has been estimated to be five to six drinks (about 4 ounces of pure ethanol) daily for 5–10 years, but frequent binge drinking may also be sufficient. Many patients with alcoholic cardiomyopathy are fully functional in their daily lives without apparent stigmata of alcoholism. The


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InternalMed_Harrison. for 5–10 years, but frequent binge drinking may also be sufficient. Many patients with alcoholic cardiomyopathy are fully functional in their daily lives without apparent stigmata of alcoholism. The cardiac impairment in severe alcoholic cardiomyopathy is the sum of both permanent damage and a substantial component that is reversible after cessation of alcohol consumption. Atrial fibrillation occurs commonly both early in the disease (“holiday heart”) and in advanced stages. Medical therapy includes neurohormonal antagonists and diuretics as needed for fluid management. Withdrawal should be supervised to avoid exacerbations of heart failure or arrhythmias, and ongoing support arranged. Even with severe disease, marked improvement can occur within 3–6 months of abstinence. Implantable defibrillators are generally deferred until an adequate period of abstinence, after which they may not be necessary if the ejection fraction has improved. With continued consumption, the prognosis is


InternalMed_Harrison

InternalMed_Harrison. defibrillators are generally deferred until an adequate period of abstinence, after which they may not be necessary if the ejection fraction has improved. With continued consumption, the prognosis is grim.


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InternalMed_Harrison. Cocaine, amphetamines, and related catecholaminergic stimulants can produce chronic cardiomyopathy as well as acute ischemia and tachyarrhythmias. Pathology reveals microinfarcts consistent with small vessel ischemia, similar to those seen with pheochromocytoma. Chemotherapy agents are the most common drugs implicated in toxic cardiomyopathy. Judicious use of these drugs requires balancing the risks of the malignancy and the risks of cardiotoxicity, as many cancers have a chronic course with better prognosis than heart failure.


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InternalMed_Harrison. Anthracyclines cause characteristic histologic changes of vacuolar degeneration and myofibrillar loss. Generation of reactive oxygen species involving heme compounds is currently the favored explanation for myocyte injury and fibrosis. Disruption of the large titin protein may contribute to loss of sarcomere organization. Risk for cardiotoxicity increases with higher doses, preexisting cardiac disease, and concomitant chest irradiation. There are three different presentations of anthracycline-induced cardiomyopathy. (1) Heart failure can develop acutely during administration of a single dose, but may clinically resolve in a few weeks. (2) Early-onset doxorubicin cardiotoxicity develops in about 3% of patients during or shortly after a chronic course, relating closely to total dose. It may be rapidly progressive, but may also resolve to good, but not normal, ventricular function. (3) The chronic presentation differs according to whether therapy was given before or after puberty.


InternalMed_Harrison

InternalMed_Harrison. It may be rapidly progressive, but may also resolve to good, but not normal, ventricular function. (3) The chronic presentation differs according to whether therapy was given before or after puberty. Patients who received doxorubicin while still growing may have impaired development of the heart, which leads to clinical heart failure by the time the patient reaches the early twenties. Late after adult exposure, patients may develop the gradual onset of symptoms or an acute onset precipitated by a reversible second insult, such as influenza or atrial fibrillation. Doxorubicin cardiotoxicity leads to a relatively nondilated ventricle, perhaps due to the accompanying fibrosis. Thus, the stroke volume may be severely reduced with an ejection fraction of 30–40%, which would be well tolerated in a patient with a larger ventricle typical of other cardiomyopathies with systolic dysfunction. Therapy includes angiotensin-converting enzyme inhibitors and β-adrenergic blocking agents used for


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InternalMed_Harrison. in a patient with a larger ventricle typical of other cardiomyopathies with systolic dysfunction. Therapy includes angiotensin-converting enzyme inhibitors and β-adrenergic blocking agents used for other causes of heart failure, with careful suppression of “inappropriate” sinus tachycardia, and attention to postural hypotension that can occur in these patients. Once thought to have an inexorable downward course, some patients with doxorubicin cardiotoxicity improve under careful management to near-normal clinical function for many years.


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InternalMed_Harrison. Trastuzumab (Herceptin) is a monoclonal antibody that interferes with cell surface receptors crucial for some tumor growth and for cardiac adaptation. The incidence of cardiotoxicity is lower than for anthracyclines but enhanced by coadministration with them. Although considered to be more often reversible, trastuzumab cardiotoxicity does not always resolve, and some patients progress to clinical heart failure and death. As with anthracycline cardiotoxicity, therapy is as usual for heart failure, but it is not clear whether the spontaneous rate of improvement is enhanced by neurohormonal antagonists.


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InternalMed_Harrison. Cardiotoxicity with cyclophosphamide and ifosfamide generally occurs acutely and with very high doses. 5-Fluorouracil, cisplatin, and some other alkylating agents can cause recurrent coronary spasm that occasionally leads to depressed contractility. Acute administration of interferon-α can cause hypotension and arrhythmias. Clinical heart failure occurring during repeated chronic administration usually resolves after discontinuation.


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InternalMed_Harrison. Many small-molecule tyrosine kinase inhibitors are under development for different malignancies. Although these agents are “targeted” at specific tumor receptors or pathways, the biologic conservation of signaling pathways can cause these inhibitors to have “off-target” effects that include the heart and vasculature. Recognition of cardiotoxicity during therapy with these agents is complicated because they occasionally cause peripheral fluid accumulation (ankle edema, periorbital swelling, pleural effusions) due to local factors rather than elevated central venous pressures. Therapeutic approaches include withdrawal of the tyrosine kinase inhibitor (when possible) and substitution with a congener (when available), as well as conventional treatment for heart failure. Prophylactic treatment with beta blockers and angiotensin-converting enzyme inhibitors prior to and during chemotherapy is a topic of ongoing investigation.


InternalMed_Harrison

InternalMed_Harrison. Other therapeutic drugs that can cause cardiotoxicity during chronic use include hydroxychloroquine, chloroquine, emetine, and antiretroviral therapies. Toxic exposures can cause arrhythmias or respiratory injury acutely during accidents. Chronic exposures implicated in cardiotoxicity include hydrocarbons, fluorocarbons, arsenicals, lead, and mercury.


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InternalMed_Harrison. Endocrine disorders affect multiple organ systems, including the heart. Hyperthyroidism and hypothyroidism do not often cause clinical heart failure in an otherwise normal heart, but commonly exacerbate heart failure. Clinical signs of thyroid disease may be masked, so tests of thyroid function are part of the routine evaluation of cardiomyopathy. Hyperthyroidism should always be considered with new-onset atrial fibrillation or ventricular tachycardia or atrial fibrillation in which the rapid ventricular response is difficult to control. The most common current reason for thyroid abnormalities in the cardiac population is the treatment of tachyarrhythmias with amiodarone, 1563 a drug with substantial iodine content. Hypothyroidism should be treated with very slow escalation of thyroid supplements to avoid exacerbating tachyarrhythmias and heart failure. Hyperthyroidism and heart failure are a dangerous combination that merits very close supervision, often hospitalization, during


InternalMed_Harrison

InternalMed_Harrison. supplements to avoid exacerbating tachyarrhythmias and heart failure. Hyperthyroidism and heart failure are a dangerous combination that merits very close supervision, often hospitalization, during titration of antithyroid medications, during which decompensation of heart failure may occur precipitously and fatally.


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InternalMed_Harrison. Pheochromocytoma is rare, but should be considered when a patient has heart failure and very labile blood pressure and heart rate, sometimes with episodic palpitations (Chap. 407). Patients with pheochromocytoma often have postural hypotension. In addition to α-adrenergic receptor antagonists, definitive therapy requires surgical extirpation. Very high renin states, such as those caused by renal artery stenosis, can lead to modest depression in ejection fraction with little or no ventricular dilation and markedly labile symptoms with flash pulmonary edema, related to sudden shifts in vascular tone and intravascular volume.


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InternalMed_Harrison. Controversies remain regarding whether diabetes and obesity are sufficient to cause cardiomyopathy. Most heart failure in diabetes results from epicardial coronary disease, with further increase in coronary artery risk due to accompanying hypertension and renal dysfunction. Cardiomyopathy may result in part from insulin resistance and increased advanced-glycosylation end products, which impair both systolic and diastolic function. However, much of the dysfunction can be attributed to scattered focal ischemia resulting from distal coronary artery tapering and limited microvascular perfusion even without proximal focal stenoses. Diabetes is a typical factor in heart failure with “preserved” ejection fraction, along with hypertension, advanced age, and female gender.


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InternalMed_Harrison. The existence of a cardiomyopathy due to obesity is generally accepted. In addition to cardiac involvement from associated diabetes, hypertension, and vascular inflammation of the metabolic syndrome, obesity alone is associated with impaired excretion of excess volume load, which, over time, can lead to increased wall stress and secondary adaptive neurohumoral responses. Fluid retention may be aggravated by large fluid intake and the rapid clearance of natriuretic peptides by adipose tissue. In the absence of another obvious cause of cardiomyopathy in an obese patient with systolic dysfunction without marked ventricular dilation, effective weight reduction is often associated with major improvement in ejection fraction and clinical function. Improvement in cardiac function has been described after successful bariatric surgery, although all major surgical therapy poses increased risk for patients with heart failure. Postoperative malabsorption and nutritional deficiencies, such as


InternalMed_Harrison

InternalMed_Harrison. after successful bariatric surgery, although all major surgical therapy poses increased risk for patients with heart failure. Postoperative malabsorption and nutritional deficiencies, such as calcium and phosphate deficiencies, may be particularly deleterious for patients with cardiomyopathy.


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InternalMed_Harrison. Nutritional deficiencies can occasionally cause dilated cardiomyopathy but are not commonly implicated in developed Western countries. Beri-beri heart disease due to thiamine deficiency can result from poor nutrition in undernourished populations and in patients deriving most of their calories from alcohol, and has been reported in teenagers subsisting only on highly processed foods. This disease is initially a vasodilated state with very high output heart failure that can later progress to a low output state; thiamine repletion can lead to prompt recovery of cardiovascular function. Abnormalities in carnitine metabolism can cause dilated or restrictive cardiomyopathies, usually in children. Deficiency of trace elements such as selenium can cause cardiomyopathy (Keshan’s disease).


InternalMed_Harrison

InternalMed_Harrison. Calcium is essential for excitation-contraction coupling. Chronic deficiencies of calcium, such as can occur with hypoparathyroidism (particularly postsurgical) or intestinal dysfunction (from diarrheal syndromes and following extensive resection), can cause severe chronic heart failure that responds over days or weeks to vigorous calcium repletion. Phosphate is a component of high-energy compounds needed for efficient energy transfer and multiple signaling pathways. Hypophosphatemia can develop during starvation and early refeeding following a prolonged fast, and occasionally during hyperalimentation. Magnesium is a cofactor for thiamine-dependent reactions and for the sodium-potassium adenosine triphosphatase (ATPase), but 1564 The most recognizable familial cardiomyopathy syndromes with extra-cardiac manifestations are the muscular dystrophies. Both Duchenne’s and the milder Becker’s dystrophy result from abnormalities in the X-linked dystrophin gene of the sarcolemmal membrane.


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InternalMed_Harrison. extra-cardiac manifestations are the muscular dystrophies. Both Duchenne’s and the milder Becker’s dystrophy result from abnormalities in the X-linked dystrophin gene of the sarcolemmal membrane. Skeletal myopathy is present in multiple other genetic cardiomyopathies (Table 287-3), some of which are associated with creatine kinase elevations. Families with a history of atrial arrhythmias, conduction system disease, and cardiomyopathy may have abnormalities of the nuclear membrane lamin proteins. While all dilated cardiomyopathies carry a risk of sudden death, a family history of cardiomyopathy with sudden death raises suspicion for a particularly arrhythmogenic mutation; affected family members may be considered for implantable defibrillators even before meeting the reduced ejection fraction threshold for primary prevention of sudden death. A prominent family history of sudden death or ventricular tachycardia before clinical cardiomyopathy suggests genetic defects in the desmosomal


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InternalMed_Harrison. threshold for primary prevention of sudden death. A prominent family history of sudden death or ventricular tachycardia before clinical cardiomyopathy suggests genetic defects in the desmosomal proteins (Fig. 287-10). Originally described as affecting the right ventricle (arrhythmogenic right ventricular dysplasia [ARVD]), this disorder (arrhythmogenic ventricular dysplasia) can affect either or both ventricles. Patients often present first with ventricular tachycardia. Genetic defects in proteins of the desmosomal complex disrupt myocyte junctions and adhesions, leading to replacement of myocardium by deposits of fat. Thin ventricular walls may be recognized on echocardiography but are better visualized on MRI. Because desmosomes are also important for elasticity hypomagnesemia rarely becomes sufficiently profound to cause clini-of hair and skin, some of the defective desmosomal proteins are cal cardiomyopathy. associated with striking “woolly hair” and thickened skin on the


InternalMed_Harrison

InternalMed_Harrison. becomes sufficiently profound to cause clini-of hair and skin, some of the defective desmosomal proteins are cal cardiomyopathy. associated with striking “woolly hair” and thickened skin on the Hemochromatosis is variably classified as a metabolic or storage palms and soles. Implantable defibrillators are usually indicated to disease (Chap. 428). It is included among the causes of restrictive prevent sudden death. There is variable progression to right, left, or cardiomyopathy, but the clinical presentation is often that of a dilated biventricular failure. cardiomyopathy. The autosomal recessive form is related to the HFE Left ventricular noncompaction is a condition of unknown prevagene. With up to 10% of the population heterozygous for one muta-lence that is increasingly revealed with the refinement of imaging tion, the clinical prevalence might be as high as 1 in 500. The lower techniques. The diagnostic criteria include the presence of multiple observed rates highlight the limited


InternalMed_Harrison

InternalMed_Harrison. refinement of imaging tion, the clinical prevalence might be as high as 1 in 500. The lower techniques. The diagnostic criteria include the presence of multiple observed rates highlight the limited penetrance of the disease, suggest-trabeculations in the left ventricle distal to the papillary muscles, creing the role of additional genetic and environmental factors for clinical ating a “spongy” appearance of the apex. Noncompaction has been expression. Hemochromatosis can also be acquired from iron overload associated with multiple genetic variants in the sarcomeric and other due to hemolytic anemia and transfusions. Excess iron is deposited genes, such as TAZ (encoding tafazzin). The diagnosis may be made in the perinuclear compartment of cardiomyocytes, with resulting incidentally or in patients previously diagnosed with cardiomyopathy, disruption of intracellular architecture and mitochondrial function. in whom the criteria for noncompaction may appear and resolve with Diagnosis is


InternalMed_Harrison

InternalMed_Harrison. patients previously diagnosed with cardiomyopathy, disruption of intracellular architecture and mitochondrial function. in whom the criteria for noncompaction may appear and resolve with Diagnosis is easily made from measurement of serum iron and trans-changing left ventricular size and function. The three cardinal clinical ferrin saturation, with a threshold of >60% for men and >45–50% for features are ventricular arrhythmias, embolic events, and heart failure. women. MRI can help to quantitate iron stores in the liver and heart, Treatment generally includes anticoagulation and early consideration and endomyocardial biopsy tissue can be stained for iron (Fig. 287-9), for an implantable defibrillator, in addition to neurohormonal antagowhich is particularly important if the patient has another cause for nists as indicated by stage of disease. cardiomyopathy. If diagnosed early, hemochromatosis can often be Some families inherit a susceptibility to viral-induced myocarditis. managed by


InternalMed_Harrison

InternalMed_Harrison. cause for nists as indicated by stage of disease. cardiomyopathy. If diagnosed early, hemochromatosis can often be Some families inherit a susceptibility to viral-induced myocarditis. managed by repeated phlebotomy to remove iron. For more severe This propensity may relate to abnormalities in cell surface receptors, iron overload, iron chelation therapy with desferrioxamine (deferox-such as the coxsackie-adenovirus receptor, that bind viral proteins. amine) or deferasirox can help to improve cardiac function if myocyte loss and replacement fibrosis are not too severe. Inborn disorders of metabolism occasionally present with dilated cardiomyopathy, although they are most often associated with restrictive cardiomyopathy (Table 287-4).


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InternalMed_Harrison. The genetic basis for cardiomyopathy is discussed in the section, “Genetic Etiologies of Cardiomyopathy.” The recognized frequency of familial involvement in dilated cardiomyopathy has increased to over 30%. Mutations in TTN, encoding the giant sarcomeric protein titin, are the most common cause of dilated cardiomyopa-AB thy, accounting for up to 25% of familial disease. FIGURE 287-10 Arrhythmogenic right ventricular dysplasia. A. Cross-sectional slice of On average, men with TTN mutations develop a pathology specimen removed at transplantation, showing severe dysplasia of the right cardiomyopathy a decade before women, without ventricle (RV) with extensive fatty replacement of right ventricular myocardium. B. The distinctive clinical features. Mutations in thick and remarkably thin right ventricular free wall is revealed by transillumination. LV, left ventricle. thin filament genes account for ~8% of dilated car-(Images courtesy of Gayle Winters, MD, and Richard Mitchell, MD, PhD,


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InternalMed_Harrison. ventricular free wall is revealed by transillumination. LV, left ventricle. thin filament genes account for ~8% of dilated car-(Images courtesy of Gayle Winters, MD, and Richard Mitchell, MD, PhD, Division of Pathology, diomyopathy and may manifest in early childhood. Brigham and Women’s Hospital, Boston.)


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InternalMed_Harrison. FIGURE 287-9 Hemochromatosis. Microscopic image of an endo-myocardial biopsy showing extensive iron deposition within the cardiac myocytes with the Prussian blue stain (400× original mag-nification). (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) Some may have partial homology with viral proteins such that an autoimmune response is triggered against the myocardium.


InternalMed_Harrison

InternalMed_Harrison. Some may have partial homology with viral proteins such that an autoimmune response is triggered against the myocardium. Prognosis and therapy of familial dilated cardiomyopathy are dictated primarily by the stage of clinical disease and the risk for sudden death. In some cases, the familial etiology facilitates prognostic decisions, particularly regarding the likelihood of recovery after a new diagnosis, which is unlikely for familial disease. The rate of progression of disease, once manifest, is, to some extent, heritable, although marked variation can be seen. However, there have been cases of remarkable clinical remission after acute presentation, likely after a reversible additional insult, such as prolonged tachycardia or infective myocarditis.


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InternalMed_Harrison. The apical ballooning syndrome, or stress-induced cardiomyopathy, occurs typically in older women after sudden intense emotional or physical stress. The ventricle shows global ventricular dilation with basal contraction, forming the shape of the narrow-necked jar (takotsubo) used in Japan to trap octopi. Originally described in Japan, it is increasingly recognized elsewhere during emergency cardiac catheterization and intensive care unit admissions for noncardiac conditions. Presentations include pulmonary edema, hypotension, and chest pain with ECG changes mimicking an acute infarction. The left ventricular dysfunction extends beyond a specific coronary artery distribution and generally resolves within days to weeks. Animal models and ventricular biopsies suggest that this acute cardiomyopathy may result from intense sympathetic activation with heterogeneity of myocardial autonomic innervation, diffuse microvascular spasm, and/or direct catecholamine toxicity. Coronary angiography


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InternalMed_Harrison. may result from intense sympathetic activation with heterogeneity of myocardial autonomic innervation, diffuse microvascular spasm, and/or direct catecholamine toxicity. Coronary angiography may be required to rule out acute coronary occlusion. No therapies have been proven beneficial, but reasonable strategies include nitrates for pulmonary edema, intraaortic balloon pump if needed for low output, combined alpha and beta blockers rather than selective beta blockade if hemodynamically stable, and magnesium for arrhythmias related to QT prolongation. Anticoagulation is generally withheld due to the occasional occurrence of ventricular rupture. While the prognosis is generally good, recurrences have been described in up to 10% of patients.


InternalMed_Harrison

InternalMed_Harrison. Idiopathic dilated cardiomyopathy is a diagnosis of exclusion, when all other known factors have been excluded. Approximately two-thirds of dilated cardiomyopathies are still labeled as idiopathic; however, a substantial proportion of these may reflect unrecognized genetic disease. Continued reconsideration of etiology during chronic heart failure management often reveals specific causes later in a patient’s course.


InternalMed_Harrison

InternalMed_Harrison. The limitations of our phenotypic classification are revealed through the multiple overlaps between the etiologies and presentations of the three types. Cardiomyopathy with reduced systolic function but without severe dilation can represent early dilated cardiomyopathy, “minimally dilated cardiomyopathy,” or restrictive diseases without marked increases in ventricular wall thickness. For example, sarcoidosis and hemochromatosis can present as dilated or restrictive disease. Early stages of amyloidosis are often mistaken for hypertrophic cardiomyopathy. Progression of hypertrophic cardiomyopathy into a “burned-out” phase occurs occasionally, with decreased contractility and modest ventricular dilation. Overlaps are particularly common with the inherited metabolic disorders, which can present as any of the three major phenotypes (Fig. 287-4).


InternalMed_Harrison

InternalMed_Harrison. Multiple genetic disorders of metabolic pathways can cause myocardial disease, due to infiltration of abnormal products or cells containing them between the myocytes, and storage disease, due to their accumulation within cells (see HPIM 18e, Table 238-4, and 287-5). The restrictive phenotype is most common, but mildly dilated cardiomyopathy may occur. Hypertrophic cardiomyopathy may be mimicked by the myocardium thickened with these abnormal products causing “pseudohypertrophy.” Most of these diseases are diagnosed during childhood. Inherited metabolic defectsa Fabry’s disease Glycogen storage disease (II, III) Drugs: e.g., serotonin, ergotamine Overlap with Other Cardiomyopathies aCan be familial.


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InternalMed_Harrison. Fabry’s disease results from a deficiency of the lysosomal enzyme alpha-galactosidase A caused by one of more than 160 mutations. This disorder of glycosphingolipid metabolism is an X-linked recessive disorder that may also cause clinical disease in female carriers. Glycolipid accumulation may be limited to the cardiac tissues or may also involve the skin and kidney. Electron microscopy of endomyocardial biopsy tissue shows diagnostic vesicles containing concentric lamellar figures (Fig. 287-11). Diagnosis is crucial because enzyme replacement can reduce abnormal deposits and improve cardiac and clinical function. The magnitude of clinical impact has not been well-established for this therapy, which requires frequent infusions of the enzyme at a cost of over $100,000 a year. Enzyme replacement can also improve the course of Gaucher’s disease, in which cerebroside-rich cells accumulate in multiple organs due to a deficiency of beta-glucosidase. Cerebrosiderich cells infiltrate the


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InternalMed_Harrison. can also improve the course of Gaucher’s disease, in which cerebroside-rich cells accumulate in multiple organs due to a deficiency of beta-glucosidase. Cerebrosiderich cells infiltrate the heart, which can also lead to a hemorrhagic pericardial effusion and valvular disease.


InternalMed_Harrison

InternalMed_Harrison. Glycogen storage diseases lead to accumulation of lysosomal storage products and intracellular glycogen accumulation, particularly with glycogen storage disease type III, due to a defective debranching enzyme. There are more than 10 types of mucopolysaccharidoses, in which autosomal dominant or X-linked deficiencies of lysosomal enzymes lead to the accumulation of glycosaminoglycans in the skeleton, nervous system, and occasionally the heart. With characteristic facies, short stature, and frequent cognitive impairment, most individuals are diagnosed early in childhood and die before adulthood.


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InternalMed_Harrison. Carnitine is an essential cofactor in long-chain fatty acid metabolism. Multiple defects have been described that lead to carnitine deficiency, causing intracellular lipid inclusions and restrictive or dilated cardiomyopathy, often presenting in children. Fatty acid oxidation requires many metabolic steps with specific enzymes that can be deficient, with complex interactions with carnitine. Depending on the defect, cardiac and skeletal myopathy can be ameliorated with replacement of fatty acid intermediates and carnitine. FIGURE 287-11 Fabry’s disease. Transmission electron micrograph of a right ventricular endomyocardial biopsy specimen at high magnification showing the characteristic concentric lamellar inclusions of glycosphingolipids accumulating as a result of deficiency of the lysosomal enzyme alpha-galactosidase A. Image taken at 15,000× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)


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InternalMed_Harrison. Two monogenic metabolic cardiomyopathies have recently been described as causes of increased ventricular wall thickness without an increase of muscle subunits or an increase in contractility. Mutations in the gamma-2 regulatory subunit of the adenosine monophosphate (AMP)-activated protein kinase important for glucose metabolism (PRKAG2) have been associated with a high prevalence of conduction abnormalities, such as AV block and ventricular preexcitation (WolffParkinson-White syndrome). Several defects have been reported in an X-linked lysosome-associated membrane protein (LAMP2). This defect can be maternally transmitted or sporadic and has occasionally been isolated to the heart, although it often leads to a syndrome of skeletal myopathy, mental retardation, and hepatic dysfunction referred to as Danon’s disease. Extreme left ventricular hypertrophy appears early, often in childhood, and can progress rapidly to end-stage heart failure with low ejection fraction. Electron microscopy


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InternalMed_Harrison. to as Danon’s disease. Extreme left ventricular hypertrophy appears early, often in childhood, and can progress rapidly to end-stage heart failure with low ejection fraction. Electron microscopy of these metabolic disorders shows that the myocytes are enlarged by multiple intracellular vacuoles of metabolic by-products.


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InternalMed_Harrison. The least common of the physiologic triad of cardiomyopathies is restrictive cardiomyopathy, which is dominated by abnormal diastolic function, often with mildly decreased contractility and ejection fraction (usually >30–50%). Both atria are enlarged, sometimes massively. Modest left ventricular dilation can be present, usually with an end-diastolic dimension <6 cm. End-diastolic pressures are elevated in both ventricles, with preservation of cardiac output until late in the disease. Subtle exercise intolerance is usually the first symptom but is often not recognized until after clinical presentation with congestive symptoms. The restrictive diseases often present with relatively more right-sided symptoms, such as edema, abdominal discomfort, and ascites, although filling pressures are elevated in both ventricles. The cardiac impulse is less displaced than in dilated cardiomyopathy and less dynamic than in hypertrophic cardiomyopathy. A fourth heart sound is more common than a third


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InternalMed_Harrison. in both ventricles. The cardiac impulse is less displaced than in dilated cardiomyopathy and less dynamic than in hypertrophic cardiomyopathy. A fourth heart sound is more common than a third heart sound in sinus rhythm, but atrial fibrillation is common. Jugular venous pressures often show rapid Y descents and may increase during inspiration (positive Kussmaul’s sign). Most restrictive cardiomyopathies are due to infiltration of abnormal substances between myocytes, storage of abnormal metabolic products within myocytes, or fibrotic injury (Table 287-5). The differential diagnosis should include constrictive pericardial disease, which may also be dominated by right-sided heart failure.


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InternalMed_Harrison. Amyloidosis is the major cause of restrictive cardiomyopathy (Figs. 287-12, 287-13, and 287-14). Several proteins can self-assemble to form the beta-sheets of amyloid proteins, which deposit with different consequences depending on the type of protein. The systemic amyloidoses are discussed in Chap. 137. In addition to cardiac infiltration, neurologic involvement occurs commonly with primary amyloidosis (immunoglobulin light chains) and with familial amyloidosis (genetic abnormalities of transthyretin). There are over 100 identified mutations in transthyretin on chromosome 13, among which the V122I transthyretin mutation has been identified in about 4% of African Americans and in 10% of African Americans with heart failure and may contribute importantly to heart failure in general in the elderly African-American population. Organ dysfunction was previously attributed solely to physical disruption from the infiltrating amyloid fibrils, but newer information suggests additional direct


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InternalMed_Harrison. elderly African-American population. Organ dysfunction was previously attributed solely to physical disruption from the infiltrating amyloid fibrils, but newer information suggests additional direct toxicity from the immunoglobulin light chain and abnormal transthyretin protein aggregates themselves. In senile amyloidosis, there is abnormal accumulation of normal transthyretin or natriuretic peptide folding, detected in 10% of people over 80 years and half of those over 90 years but often without apparent clinical disease. Men show a greater burden of amyloid deposition and 20-fold greater likelihood of clinical disease with senile amyloidosis. The aging of the population will soon render senile amyloidosis the most common of the amyloidoses.


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InternalMed_Harrison. Cardiac amyloid is classically suspected from thickened ventricular walls with an ECG that shows low voltage. However, low voltage is not always present and is less common in familial or senile amyloidosis than in primary AL amyloidosis. A characteristic refractile brightness in the septum on echocardiography is suggestive of the diagnosis, but neither sensitive nor specific. Both atria are dilated, often dramatically, and diastolic dysfunction may be more obvious than in left ventricular hypertrophy from other causes. Amyloid infiltration can also be detected with gadolinium enhancement in MRI.


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InternalMed_Harrison. FIGURE 287-12 Restrictive cardiomyopathy—amyloidosis. Gross specimen of a heart with amyloidosis. The heart is firm and rubbery with a waxy cut surface. The atria are markedly dilated, and the left atrial endocardium, normally smooth, has yellow-brown amyloid deposits that give texture to the surface. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) LV LA Septum RA RV Pacing lead in RV Lateral wall of LV Pericardial effusion FIGURE 287-13 Restrictive cardiomyopathy—amyloidosis.


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InternalMed_Harrison. FIGURE 287-13 Restrictive cardiomyopathy—amyloidosis. Echocardiogram showing thickened walls of both ventricles without major chamber dilation. The atria are markedly dilated, consistent with chronically elevated ventricular filling pressures. In this example, there is a characteristic hyperrefractile “glittering” of the myocardium typical of amyloid infiltration, which is often absent (especially with more recent echocardiographic systems of better resolution). The mitral and tricuspid valves are thickened. A pacing lead is visible in the right ventricle (RV), and a pericardial effusion is evident. Note that the echocardiographic and pathologic images are vertically opposite, such that the left ventricle (LV) is by convention on the top right in the echocardiographic image and bottom right in the pathologic images. LA, left atrium; RA, right atrium. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.)


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InternalMed_Harrison. The diagnosis of primary or familial amyloidosis can sometimes be made from biopsies of an abdominal fat pad or the rectum, but cardiac amyloidosis is most reliably identified from a biopsy of the heart, in which amyloid fibrils infiltrate the myocardium diffusely, particularly around the conduction system and coronary vessels (Fig. 287-14). Diagnosis of the type of amyloid protein requires immunohistochemistry of biopsied tissue rather than serum or urine electrophoresis, which can lead to incorrect classification.


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InternalMed_Harrison. Therapy for all types of amyloid is predominantly for symptoms 1567 of fluid retention, which often requires high doses of loop diuretics. Digoxin bound to the amyloid fibrils can reach toxic levels, and should therefore be used only in very low doses, if at all. There is no evidence regarding use of neurohormonal antagonists in amyloid heart disease, where the possible theoretical benefit has to be balanced against the possibility of aggravating postural hypotension and diminishing the crucial heart rate reserve. The risk of intracardiac thrombi may warrant chronic anticoagulation.


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InternalMed_Harrison. The prognosis is worst for primary amyloid, with a median sur vival of 6–12 months after symptoms of heart failure. If present, multiple myeloma is treated with chemotherapy, the extent of which is often limited by the potential of worsening cardiac dysfunction. Immunoglobulin-associated amyloid has occasionally been treated with sequential heart transplantation and delayed bone marrow transplant, with frequent recurrence of amyloid in the transplanted heart. Abnormal transthyretin-associated cardiac amyloid has a somewhat better prognosis and can be treated in selected patients with heart and liver transplantation. Senile cardiac amyloid has the slowest progres sion and best overall prognosis.


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InternalMed_Harrison. Progressive fibrosis can cause restrictive myocardial disease without ventricular dilation. Thoracic radiation, common for breast and lung cancer or mediastinal lymphoma, can produce early or late restrictive cardiomyopathy. Patients with radiation cardiomyopathy may present with a possible diagnosis of constrictive pericarditis, as the two conditions often coexist. Careful hemodynamic evaluation and, often, endomyocardial biopsy should be performed if considering pericardial stripping surgery, which is unlikely to be successful in the presence of underlying restrictive cardiomyopathy.


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InternalMed_Harrison. Scleroderma causes small vessel spasm and ischemia that can lead to a small, stiff heart with reduced ejection fraction without dilation. The pulmonary hypertension associated with scleroderma may lead to more clinical right heart failure because of concomitant fibrotic disease of the right ventricle. Doxorubicin causes direct myocyte injury usually leading to dilated cardiomyopathy, but the limited degree of dilation may result from increased fibrosis, which restricts remodeling.


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InternalMed_Harrison. The physiologic picture of elevated filling pressures with atrial enlargement and preserved ventricular contractility with normal or reduced ventricular volumes can result from extensive fibrosis of the endocardium, without transmural myocardial disease. For patients who have not lived in the equatorial regions, this picture is rare, and when seen is often associated with a history of chronic hypereosinophilic syndrome (Löffler’s endocarditis), which is more common in men than women. In this disease, persistent hypereosinophilia of >1500 eos/mm3 for at least 6 months can cause an acute phase of eosinophilic injury in the endocardium (see earlier discussion of eosinophilic myocarditis), with systemic illness and injury to other organs. There is usually no obvious cause, but the hypereosinophilia can occasionally be explained by allergic, parasitic, or malignant disease. It is postulated to be followed by a period in which cardiac inflammation is replaced by evidence of fibrosis with


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InternalMed_Harrison. can occasionally be explained by allergic, parasitic, or malignant disease. It is postulated to be followed by a period in which cardiac inflammation is replaced by evidence of fibrosis with superimposed thrombosis. In severe disease, the dense fibrotic layer can obliterate the ventricular apices and extend to thicken and tether the AV


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InternalMed_Harrison. FIGURE 287-14 Amyloidosis—microscopic images of amyloid involving the myocar-valve leaflets. The clinical disease may present with dium. The left panel (hematoxylin and eosin stain) shows glassy, grey-pink amorphous heart failure, embolic events, and atrial arrhythmaterial infiltrating between cardiomyocytes, which stain a darker pink. The right panel mias. While plausible, the sequence of transition shows a sulfated blue stain that highlights the amyloid green and stains the cardiac from eosinophilic myocarditis or Löffler’s endocarmyocytes yellow. (The Congo red stain can also be used to highlight amyloid; under ditis to endomyocardial fibrosis has not been clearly polarized light, amyloid will have an apple-green birefringence when stained with Congo demonstrated. red.) Images at 100× original magnification. (Image courtesy of Robert Padera, MD, PhD, In tropical countries, up to one-quarter of heart Department of Pathology, Brigham and Women’s Hospital, Boston.) failure may be due


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InternalMed_Harrison. original magnification. (Image courtesy of Robert Padera, MD, PhD, In tropical countries, up to one-quarter of heart Department of Pathology, Brigham and Women’s Hospital, Boston.) failure may be due to endomyocardial fibrosis, 1568 affecting either or both ventricles. This condition shares with the previous condition the partial obliteration of the ventricular apex with fibrosis extending into the valvular inflow tract and leaflets; however, it is not clear that the etiologies are the same for all cases. Pericardial effusions frequently accompany endomyocardial fibrosis but are not common in Löffler’s endocarditis. For endomyocardial fibrosis, there is no gender difference, but a higher prevalence in African-American populations. While tropical endomyocardial fibrosis could represent the end-stage of previous hypereosinophilic disease triggered by endemic parasites, neither prior parasitic infection nor hypereosinophilia is usually documented. Geographic nutritional deficiencies have


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InternalMed_Harrison. end-stage of previous hypereosinophilic disease triggered by endemic parasites, neither prior parasitic infection nor hypereosinophilia is usually documented. Geographic nutritional deficiencies have also been proposed as an etiology. Medical treatment focuses on glucocorticoids and chemotherapy to suppress hypereosinophilia when present. Fluid retention may become increasingly resistant to diuretic therapy. Anticoagulation is recommended. Atrial fibrillation is associated with worse symptoms and prognosis, but may be difficult to suppress. Surgical resection of the apices and replacement of the fibrotic valves can improve symptoms, but surgical morbidity and mortality and later recurrence rates are high. The serotonin secreted by carcinoid tumors can produce fibrous plaques in the endocardium and right-sided cardiac valves, occasionally affecting left-sided valves, as well. Valvular lesions may be stenotic or regurgitant. Systemic symptoms include flushing and diarrhea. Liver disease


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InternalMed_Harrison. and right-sided cardiac valves, occasionally affecting left-sided valves, as well. Valvular lesions may be stenotic or regurgitant. Systemic symptoms include flushing and diarrhea. Liver disease from hepatic metastases may play a role by limiting hepatic function and thereby allowing more serotonin to reach the venous circulation.


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InternalMed_Harrison. Hypertrophic cardiomyopathy is defined as left ventricular hypertrophy that develops in the absence of causative hemodynamic factors, such as hypertension, aortic valve disease, or systemic infiltrative or storage diseases (Figs. 287-15 and 287-16). It has previously been termed hypertrophic obstructive cardiomyopathy (HOCM), asymmetric septal hypertrophy (ASH), and idiopathic hypertrophic subaortic stenosis (IHSS). However, the accepted terminology is now hypertrophic


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InternalMed_Harrison. FIGURE 287-15 Hypertrophic cardiomyopathy. Gross specimen of a heart with hypertrophic cardiomyopathy removed at the time of transplantation, showing asymmetric septal hypertrophy (septum much thicker than left ventricular free wall) with the septum bulging into the left ventricular outflow tract causing obstruction. The forceps are retracting the anterior leaflet of the mitral valve, demonstrating the characteristic plaque of systolic anterior motion, manifest as endocardial fibrosis on the interventricular septum in a mirror-image pattern to the valve leaflet. There is patchy replacement fibrosis, and small thick-walled arterioles can be appreciated grossly, especially in the interventricular septum. IVS, interventricular septum; LV, left ventricle; RV, right ventricle. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)


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InternalMed_Harrison. FIGURE 287-16 Hypertrophic cardiomyopathy. This echocardiogram of hypertrophic cardiomyopathy shows asymmetric hypertrophy of the septum compared to the lateral wall of the left ventricle (LV). The mitral valve (MV) is moving anteriorly toward the hypertrophied septum in systole. The left atrium (LA) is enlarged. Note that the echocardiographic and pathologic images are vertically opposite, such that the LV is by convention on the top right in the echocardiographic image and bottom right in the pathologic images. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.) cardiomyopathy with or without obstruction. Prevalence in North America, Japan, and China is about 1:500. It is the leading cause of sudden death in the young and is an important cause of heart failure. Although pediatric presentation is associated with increased early morbidity and mortality, the prognosis for patients diagnosed as adults is generally favorable.


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InternalMed_Harrison. The clustering of hypertrophic cardiomyopathy within families has been appreciated since recognition of the disease approximately 55 years ago. Echocardiographic screening of families revealed an autosomal dominant pattern of inheritance. Initial genetic studies using linkage analysis in large families identified disease-causing mutations in sarcomeric genes. A sarcomere mutation is present in ~60% of patients with hypertrophic cardiomyopathy and is more common in those with familial disease and characteristic asymmetric septal hypertrophy. More than nine different sarcomere genes with over 1400 mutations have been implicated, although ~80% of patients have a mutation in either MYH7 or MYBPC3 (Table 287-3), most of which are unique to individual families (“private” mutations).


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InternalMed_Harrison. Hypertrophic cardiomyopathy is characterized by age-dependent and incomplete penetrance. The defining phenotype of left ventricular hypertrophy is rarely present at birth and usually develops later in life. Accordingly, screening of family members should begin in adolescence and extend through adulthood. In MYBPC3 mutation carriers, the average age of disease development is 40 years, while 30% remain free from hypertrophy after 70 years. Related individuals who carry the same mutation may have a different extent and pattern of hypertrophy (e.g., asymmetric versus concentric), occurrence of outflow tract obstruction, and associated clinical outcomes (e.g., sudden death, atrial fibrillation).


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InternalMed_Harrison. FIGURE 287-17 Hypertrophic cardiomyopathy. Microscopic image of hypertrophic cardiomyopathy showing the characteristic disordered myocyte architecture with swirling and branching rather than the usual parallel arrangement of myocyte fibers. Myocyte nuclei vary markedly in size and interstitial fibrosis is present. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)


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InternalMed_Harrison. At the level of the sarcomere, hypertrophic cardiomyopathy mutations lead to enhanced calcium sensitivity, maximal force generation, and ATPase activity. Calcium handling is affected through modification of regulatory proteins. Sarcomere mutations lead to abnormal energetics and impaired relaxation, both directly and as a result of hypertrophy. Hypertrophic cardiomyopathy is characterized by misalignment and disarray of the enlarged myofibrils and myocytes (Fig. 287-17), which can also occur to a lesser extent in other cardiac diseases. Although hypertrophy is the defining feature of hypertrophic cardiomyopathy, fibrosis and microvascular disease are also present. Interstitial fibrosis is detectable before overt hypertrophy develops and likely results from early activation of profibrotic pathways. In the majority of patients with overt cardiomyopathy, focal areas of replacement fibrosis can be readily detected with MRI. These areas of “scar” may represent substrate for the development


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InternalMed_Harrison. In the majority of patients with overt cardiomyopathy, focal areas of replacement fibrosis can be readily detected with MRI. These areas of “scar” may represent substrate for the development of ventricular arrhythmias. Increased thickness and decreased luminal area of the intramural vessels in hypertrophied myocardium contribute to microvascular ischemia and angina. Microinfarction of hypertrophied myocardium is a hypothesized mechanism for replacement scar formation.


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InternalMed_Harrison. Macroscopically, hypertrophy is typically manifest as nonuniform ventricular thickening (Fig. 287-15). The interventricular septum is the typical location of maximal hypertrophy, although other patterns of hypertrophic remodeling include concentric and midventricular. Hypertrophy confined to the ventricular apex (apical hypertrophic cardiomyopathy) is less often familial and has a different genetic substrate, with sarcomere mutations present in only ~15%. Left ventricular outflow tract obstruction represents the most common focus of diagnosis and intervention, although diastolic dysfunction, myocardial fibrosis, and microvascular ischemia also contribute to contractile dysfunction and elevated intracardiac pressures. Obstruction is present in ~30% of patients at rest and can be provoked by exercise in another ~30%. Systolic obstruction is initiated by drag forces, which push an anteriorly displaced and enlarged anterior mitral leaflet into contact with the hypertrophied ventricular


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InternalMed_Harrison. by exercise in another ~30%. Systolic obstruction is initiated by drag forces, which push an anteriorly displaced and enlarged anterior mitral leaflet into contact with the hypertrophied ventricular septum. Mitral leaflet coaptation may ensue, leading to posteriorly directed mitral regurgitation. In order to maintain stroke volume across outflow tract obstruction, the ventricle generates higher pressures, leading to higher wall stress and myocardial oxygen demand. Smaller chamber size and increased contractility exacerbate the severity of obstruction. Conditions of low preload, such as dehydration, and low afterload, such as arterial vasodilation, may lead to transient hypotension and near-syncope. The systolic ejection murmur of left ventricular outflow tract obstruction is harsh and late peaking and can be enhanced by bedside maneuvers that diminish ventricular volume and transiently worsen obstruction, such as stand-1569 ing from a squatting position or the Valsalva maneuver.


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InternalMed_Harrison. The substantial variability of hypertrophic cardiomyopathy pathology is reflected in the diversity of clinical presentations. Patients may be diagnosed after undergoing evaluations triggered by the abnormal physical findings (murmur) or symptoms of exertional dyspnea, angina, or syncope. Alternatively, diagnosis may follow evaluations prompted by the detection of disease in family members. Cardiac imaging (Fig. 287-16) is central to diagnosis due to the insensitivity of examination and ECG and the need to exclude other causes for hypertrophy. The identification of a disease-causing mutation in a proband can focus family evaluations on mutation carriers, but this strategy requires a high degree of certainty that the mutation is truly pathogenic and not a benign DNA variant. Biopsy is not needed to diagnose hypertrophic cardiomyopathy but can be used to exclude infiltrative and metabolic diseases. Rigorous athletic training (athlete’s heart) may cause intermediate degrees of physiologic


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InternalMed_Harrison. to diagnose hypertrophic cardiomyopathy but can be used to exclude infiltrative and metabolic diseases. Rigorous athletic training (athlete’s heart) may cause intermediate degrees of physiologic hypertrophy difficult to differentiate from mild hypertrophic cardiomyopathy. Unlike hyper-trophic cardiomyopathy, hypertrophy in the athlete’s heart regresses with cessation of training, and is accompanied by supernormal exercise capacity (VO2max >50 mL/kg/min), mild ventricular dilation, and normal diastolic function.


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InternalMed_Harrison. Management focuses on treatment of symptoms and prevention of sudden death and stroke (Fig. 287-18). Left ventricular outflow tract obstruction can be controlled medically in the majority of patients. β-Adrenergic blocking agents and L-type calcium channel blockers (e.g., verapamil) are first-line agents that reduce the severity of obstruction by slowing heart rate, enhancing diastolic filling, and decreasing contractility. Persistent symptoms of exertional dyspnea or chest pain can sometimes be controlled with the addition of disopyramide, an antiarrhythmic agent with potent negative inotropic properties. Patients with or without obstruction may develop heart failure symptoms due to fluid retention and require diuretic therapies for venous congestion. Severe medically refractory symptoms develop in ~5% of patients, for whom surgical myectomy or alcohol septal ablation may be effective. Developed over 50 years ago, surgical myectomy effectively relieves outflow tract obstruction by


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InternalMed_Harrison. develop in ~5% of patients, for whom surgical myectomy or alcohol septal ablation may be effective. Developed over 50 years ago, surgical myectomy effectively relieves outflow tract obstruction by excising part of the septal myocardium involved in the dynamic obstruction. In selected patients, perioperative mortality is extremely low with excellent long-term survival free from recurrent obstruction and symptoms. Mitral valve repair or replacement is usually unnecessary as associated eccentric mitral regurgitation resolves with myectomy alone. Alcohol septal ablation in patients with suitable coronary anatomy can relieve outflow tract obstruction via a controlled infarction of the proximal septum, which produces similar periprocedural outcomes and gradient reduction as surgical myomectomy. Until long-term outcomes are demonstrated for this procedure, it is relegated primarily to patients who wish to avoid surgery or who have limiting comorbidities. Neither procedure has been shown to


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InternalMed_Harrison. Until long-term outcomes are demonstrated for this procedure, it is relegated primarily to patients who wish to avoid surgery or who have limiting comorbidities. Neither procedure has been shown to improve outcomes other than symptoms. With both procedures, the most common complication is the development of complete heart block necessitating permanent pacing. However, ventricular pacing as a primary therapy for outflow tract obstruction is ineffective and not generally advised.


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InternalMed_Harrison. Patients with hypertrophic cardiomyopathy have an increased risk of sudden cardiac death from ventricular tachyarrhythmias. Vigorous physical activity and competitive sport are prohibited. Factors that increase the risk of sudden death from a baseline of 0.5% per year are presented in Table 287-6. As sudden death has not been reduced by medical or procedural interventions, an implantable cardioverter-defibrillator is advised for patients with two or more risk factors and is advised on a selected basis for patient with one risk factor. Nevertheless, the positive predictive value of most risk factors is low, and many patients receiving a defibrillator


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InternalMed_Harrison. Use diuretics with caution to avoid hypovolemia, particularly in presence of outflow gradient Evidence of fluid retention? In all pts, evaluate risk for sudden death Symptomatic? If low follow with serial evaluation Try disopyramide or amiodarone Evidence of severe progressive LV dysfunction? Titrate beta blocker or calcium channel blockerIf high, consider ICD No Yes Yes No Yes Persistent symptoms Outflow gradient? Rarely, consider cardiac transplantation Refractory severe symptoms FIGURE 287-18 Treatment algorithm for hypertrophic cardiomyopathy depending on the presence and severity of symptoms and the presence of an intraventricular gradient with obstruction to outflow. Note that all patients with hypertrophic cardiomyopathy should be evaluated for atrial fibrillation and risk of sudden death, whether or not they require treatment for symptoms. ICD, implantable cardioverter-defibrillator; LV, left ventricular.


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InternalMed_Harrison. LV, left ventricular. never receive an appropriate therapy. Long-term use of a defibrillator may be associated with serious device-related complications, particularly in young active patients. Refinement of sudden death risk through the application of contemporary technologies such as cardiac MRI is ongoing. History of cardiac arrest or spontaneous sustained ventricular tachycardiaa Family history of sudden cardiac death Abnormal blood pressure response to exerciseb Nonvagal, often with or after exertion Present in <10% of patients Systolic blood pressure fall or failure to increase at peak exercise History


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InternalMed_Harrison. Present in <10% of patients Systolic blood pressure fall or failure to increase at peak exercise History Atrial fibrillation is common in patients with hypertrophic cardiomyopathy and may lead to hemodynamic deterioration and embolic stroke. Rapid ventricular response is poorly tolerated and may worsen outflow tract obstruction. β-Adrenergic blocking agents and L-type calcium channel blockers slow AV nodal conduction and improve symptoms; cardiac glycosides should be avoided, as they may increase contractility and worsen obstruction. Symptoms exacerbated by atrial fibrillation may persist despite adequate rate control due to loss of AV synchrony and may require restoration of sinus rhythm. Disopyramide and amiodarone are the preferred antiarrhythmic agents, with radiofrequency ablation considered for medically refractory cases. Anticoagulation to prevent embolic stroke in atrial fibrillation is recommended.


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InternalMed_Harrison. PROGNOSIS The general prognosis for hypertrophic cardiomyopathy is good, better than in early studies of referral populations. For patients diagnosed as adults, survival is comparable to an age-matched population without cardiomyopathy. The sudden death risk is less than 1% per year; however, up to 1 in 20 patients will progress to overt systolic dysfunction with a reduced ejection fraction with or without dilated remodeling (“burned out” or end-stage hypertrophic cardiomyopathy). These patients suffer from low cardiac output and have a high risk of death from progressive heart failure and sudden death unless they undergo cardiac transplantation. aImplantable cardioverter-defibrillator advised for patients with prior arrest or sustained ventricular tachycardia regardless of other risk factors. b Prognostic value most applicable to patients less than 40 years old. Abbreviation: LV, left ventricle.


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InternalMed_Harrison. Pericardial Disease Eugene Braunwald NORMAL FUNCTIONS OF THE PERICARDIUM The normal pericardium is a double-layered sac; the visceral peri-cardium is a serous membrane that is separated by a small quantity (15–50 mL) of fluid, an ultrafiltrate of plasma, from the fibrous parietal 288 pericardium. The normal pericardium, by exerting a restraining force, prevents sudden dilation of the cardiac chambers, especially the right atrium and ventricle, during exercise and with hypervolemia. It also restricts the anatomic position of the heart, and probably retards the spread of infections from the lungs and pleural cavities to the heart. Nevertheless, total absence of the pericardium, either congenital or after surgery, does not produce obvious clinical disease. In partial left pericardial defects, the main pulmonary artery and left atrium may bulge through the defect; very rarely, herniation and subsequent strangulation of the left atrium may cause sudden death.


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InternalMed_Harrison. Acute pericarditis, by far the most common pathologic process involving the pericardium (Table 288-1), has four principal diagnostic features: 1.


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InternalMed_Harrison. Chest pain is usually present in acute infectious pericarditis and in many of the forms presumed to be related to hypersensitivity or autoimmunity. The pain of acute pericarditis is often severe, retrosternal, and left precordial, and referred to the neck, arms, or left shoulder. Frequently the pain is pleuritic, consequent to accompanying pleural inflammation (i.e., sharp and aggravated by inspiration and coughing), but sometimes it is steady, constricting, radiates into either arm or both arms, and resembles that of myocardial ischemia; therefore, confusion with acute myocardial infarction (AMI) is common. Characteristically, however, pericardial pain may be relieved by sitting up and leaning forward and is intensified by lying supine (Chap. 19). Pain is often absent in slowly developing tuberculous, postirradiation, and neoplastic, uremic, and constrictive pericarditis.


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InternalMed_Harrison. The differentiation of AMI from acute pericarditis may become perplexing when, with acute pericarditis, serum biomarkers of myocardial damage such as troponin and creatine kinase-MB rise, presumably because of concomitant involvement of the epicardium in the inflammatory process (an epi-myocarditis) with resulting myocyte necrosis. However, these elevations, if they occur, are quite modest given the extensive electrocardiographic ST-segment elevation in pericarditis. This dissociation is useful in differentiating between these conditions. 2. A pericardial friction rub is audible at some point in about 85% of patients with acute pericarditis, may have up to three components per cardiac cycle, is high-pitched, and is described as rasping, scratching, or grating (Chap. 267). It is heard most frequently at end expiration with the patient upright and leaning forward. 3.


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InternalMed_Harrison. 3. The electrocardiogram (ECG) in acute pericarditis without massive effusion usually displays changes secondary to acute subepicardial inflammation (Fig. 288-1). It typically evolves through four stages. In stage 1, there is widespread elevation of the ST segments, often with upward concavity, involving two or three standard limb leads and V2 to V6, with reciprocal depressions only in aVR and sometimes V1. Also, there is depression of the PR segment below the TP segment, reflecting atrial involvement. Usually there are no significant changes in QRS complexes. After several days, the ST segments return to normal (stage 2), and only then, or even later, do the T waves become inverted (stage 3). Weeks or months after the onset of acute pericarditis, the ECG returns to normal (stage 4). In contrast, in AMI, ST elevations are convex, and reciprocal depression is usually more prominent; these changes may return to normal within a I. Acute pericarditis (<6 weeks) A. Fibrinous


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InternalMed_Harrison. I. Acute pericarditis (<6 weeks) A. Fibrinous B. Effusive (serous or sanguineous) II. Subacute pericarditis (6 weeks to 6 months) A. B. III. A. B. C. I. Infectious pericarditis A. Viral (coxsackievirus A and B, echovirus, mumps, adenovirus, hepatitis, HIV) B. Pyogenic (pneumococcus, Streptococcus, Staphylococcus, Neisseria, Legionella) C. Tuberculous D. Fungal (histoplasmosis, coccidioidomycosis, Candida, blastomycosis) E. Other infections (syphilitic, protozoal, parasitic) II. A. B. C. 1. Primary tumors (benign or malignant, mesothelioma) 2. Tumors metastatic to pericardium (lung and breast cancer, lymphoma, leukemia) D. Myxedema E. Cholesterol F. Chylopericardium G. Trauma 1. 2. H. Aortic dissection (with leakage into pericardial sac) I. Postirradiation J. Familial Mediterranean fever K. Familial pericarditis 1. Mulibrey nanisma L. Acute idiopathic M. Whipple’s disease N. Sarcoidosis III.


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InternalMed_Harrison. I. Postirradiation J. Familial Mediterranean fever K. Familial pericarditis 1. Mulibrey nanisma L. Acute idiopathic M. Whipple’s disease N. Sarcoidosis III. Pericarditis presumably related to hypersensitivity or autoimmunity A. B. Collagen vascular disease (systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, scleroderma, acute rheumatic fever, granulomatosis with polyangiitis [Wegener’s]) C. Drug-induced (e.g., procainamide, hydralazine, phenytoin, isoniazid, minoxidil, anticoagulants, methysergide) D. 1. 2. 3. aAn autosomal recessive syndrome characterized by growth failure, muscle hypotonia, hepatomegaly, ocular changes, enlarged cerebral ventricles, mental retardation, ventricular hypertrophy, and chronic constrictive pericarditis day or two. Q waves may develop, with loss of R-wave amplitude, and T-wave inversions are usually seen within hours before the ST segments have become isoelectric (Chaps. 294 and 295).


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InternalMed_Harrison. 4. Pericardial effusion is usually associated with pain and/or the ECG changes mentioned above, as well as electrical alternans. FIGURE 288-1 Acute pericarditis. There are diffuse ST-segment elevations (in this case in leads I, II, aVF, and V2 to V6) due to a ventricular current of injury. There is PR-segment deviation (opposite in polarity to the ST segment) due to a concomitant atrial injury current.


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InternalMed_Harrison. Pericardial effusion is especially important clinically when it develops within a relatively short time because it may lead to cardiac tamponade (see below). Differentiation from cardiac enlargement may be difficult on physical examination, but heart sounds may be fainter with pericardial effusion. The friction rub and the apex impulse may disappear. The base of the left lung may be compressed by pericardial fluid, producing Ewart’s sign, a patch of dullness and increased fremitus (and egophony) beneath the angle of the left scapula. The chest roentgenogram may show enlargement of the cardiac silhouette, with a “water bottle” configuration, but may be normal.


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InternalMed_Harrison. Diagnosis Echocardiography (Chap. 270e) is the most widely used imaging technique. It is sensitive, specific, simple, noninvasive, may be performed at the bedside, and can identify accompanying cardiac tamponade (see below) (Fig. 288-2). The presence of pericardial fluid is recorded by two-dimensional transthoracic echocardiography as a relatively echo-free space between the posterior pericardium and left ventricular epicardium in patients with small effusions and as a space between the anterior right ventricle and the parietal pericardium just beneath the anterior chest wall. In patients with large effusions, the a patient with a large pericardial effusion. Ao, aorta; LV, left ventricle; heart may swing freely within the pericardial sac. When severe, the pe, pericardial effusion; RV, right ventricle. (From M Imazio: Curr Opin extent of this motion alternates and may be associated with electrical


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InternalMed_Harrison. Cardiol 27:308, 2012.) alternans (Fig. 288-3). Echocardiography allows localization and identification of the quantity of pericardial fluid. FIGURE 288-3 Electrical alternans. This tracing was obtained from a patient with a large pericardial effusion with tamponade. (Reproduced from DM Mirvis, AL Goldberger: Electrocardiography, in RO Bonowet al [eds]: Braunwald’s Heart Disease, 9th ed. Philadelphia: Elsevier, 2012.) The diagnosis of pericardial fluid or thickening may be confirmed by computed tomography (CT) or magnetic resonance imaging (MRI). These techniques may be superior to echocardiography in detecting loculated pericardial effusions, pericardial thickening, and the identification of pericardial masses.


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InternalMed_Harrison. There is no specific therapy for acute idiopathic pericarditis, but bed rest and anti-inflammatory treatment with aspirin (2–4 g/d), with gastric protection (e.g., omeprazole 20 mg/d), may be given. If this is ineffective, one of the nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (400–600 mg tid) or indomethacin (25–50 mg tid), should be tried. In responsive patients, these doses should be continued for 1–2 weeks and then tapered over several weeks. In patients who are unresponsive, colchicine (0.5 mg bid, given for 4–8 weeks) has been found to be effective, not only in acute pericarditis, but also in reducing the risk of recurrent pericarditis. Colchicine is concentrated in and interferes with the migration of neutrophils, is contraindicated in patients with hepatic or renal dysfunction, and may cause diarrhea and other gastrointestinal side effects. Glucocorticoids (e.g., prednisone 1 mg/kg per day) usually suppress the clinical manifestations of acute pericarditis


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InternalMed_Harrison. dysfunction, and may cause diarrhea and other gastrointestinal side effects. Glucocorticoids (e.g., prednisone 1 mg/kg per day) usually suppress the clinical manifestations of acute pericarditis in patients who have failed therapy with the anti-inflammatory therapies described above, but appear to increase the risk of subsequent recurrence. Therefore, full-dose corticosteroids should be given for only 2–4 days and then tapered. Anticoagulants should be avoided because their use could cause bleeding into the pericardial cavity and tamponade.


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InternalMed_Harrison. In patients with recurrences that are multiple, frequent, disabling, continue for more than 2 years, and are not prevented by colchicine and other NSAIDs and are not controlled by glucocorticoids, pericardial stripping may be necessary to terminate the illness, and 1573 usually does so. The accumulation of fluid in the pericardial space in a quantity sufficient to cause serious obstruction of the inflow of blood into the ventricles results in cardiac tamponade. This complication may be fatal if it is not recognized and treated promptly. The most common causes of tamponade are idiopathic pericarditis and pericarditis secondary to neoplastic disease. Tamponade may also result from bleeding into the pericardial space after leakage from an aortic dissection, cardiac operations, trauma, and treatment of patients with acute pericarditis with anticoagulants.


InternalMed_Harrison

InternalMed_Harrison. The three principal features of tamponade (Beck’s triad) are hypo-tension, soft or absent heart sounds, and jugular venous distention with a prominent x descent but an absent y descent. The limitations of ventricular filling are responsible for a reduction of cardiac output. The quantity of fluid necessary to produce cardiac tamponade may be as small as 200 mL when the fluid develops rapidly to as much as >2000 mL in slowly developing effusions when the pericardium has had the opportunity to stretch and adapt to an increasing volume. Tamponade may also develop more slowly, and in these circumstances, the clinical manifestations can resemble those of heart failure, including dyspnea, orthopnea, and hepatic engorgement.


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InternalMed_Harrison. A high index of suspicion for cardiac tamponade is required because in many instances no obvious cause for pericardial disease is apparent, and this diagnosis should be considered in any patient with otherwise unexplained enlargement of the cardiac silhouette, hypotension, and elevation of jugular venous pressure. There may be reduction in amplitude of the QRS complexes, and electrical alternans of the P, QRS, or T waves should raise the suspicion of cardiac tamponade (Fig. 288-3). Table 288-2 lists the features that distinguish acute cardiac tamponade from constrictive pericarditis. Thickened pericardium – +++ – ++ Cardiac catheterization Equalization of diastolic +++ +++ – ++ pressures Abbreviations: +++, always present; ++, usually present; +, rare;–, absent; DC, diastolic collapse; ECG, electrocardiograph; RA, right atrium; RV, right ventricle; RVMI, right ventricular myocardial infarction. Source: Adapted from GM Brockington et al: Cardiol Clin 8:645, 1990, with permission.


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InternalMed_Harrison. Source: Adapted from GM Brockington et al: Cardiol Clin 8:645, 1990, with permission. 1574 Paradoxical Pulse This important clue to the presence of cardiac tamponade consists of a greater than normal (10 mmHg) inspiratory decline in systolic arterial pressure. When severe, it may be detected by palpating weakness or disappearance of the arterial pulse during inspiration, but usually sphygmomanometric measurement of systolic pressure during slow respiration is required.


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InternalMed_Harrison. Because both ventricles share a tight incompressible covering, i.e., the pericardial sac, the inspiratory enlargement of the right ventricle in cardiac tamponade compresses and reduces left ventricular volume; leftward bulging of the interventricular septum reduces further the left ventricular cavity as the right ventricle enlarges during inspiration. Thus, in cardiac tamponade, the normal inspiratory augmentation of right ventricular volume causes an exaggerated reduction of left ventricular volume, stroke volume, and systolic pressure. Paradoxical pulse also occurs in approximately one-third of patients with constrictive pericarditis (see below), and in some cases of hypovolemic shock, acute and chronic obstructive airway disease, and pulmonary embolus. Right ventricular infarction (Chap. 295) may resemble cardiac tamponade with hypotension, elevated jugular venous pressure, an absent y descent in the jugular venous pulse, and, occasionally, a paradoxical pulse (Table 288-2).


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InternalMed_Harrison. Low-pressure tamponade refers to mild tamponade in which the intrapericardial pressure is increased from its slightly subatmospheric levels to +5 to +10 mmHg; in some instances, hypovolemia coexists. As a consequence, the central venous pressure is normal or only slightly elevated, whereas arterial pressure is unaffected and there is no paradoxical pulse. These patients are asymptomatic or complain of mild weakness and dyspnea. The diagnosis is aided by echocardiography, and both hemodynamic and clinical manifestations improve after pericardiocentesis.


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InternalMed_Harrison. Diagnosis Because immediate treatment of cardiac tamponade may be lifesaving, prompt measures to establish the diagnosis by echocardiography should be undertaken. When pericardial effusion causes tamponade, Doppler ultrasound shows that tricuspid and pulmonic valve flow velocities increase markedly during inspiration, whereas pulmonic vein, mitral, and aortic flow velocities diminish (as in constrictive pericarditis, see below) (Fig. 288-4). In tamponade, there is late diastolic inward motion (collapse) of the right ventricular free wall and the right atrium. Transesophageal echocardiography, CT, or cardiac MRI may be necessary to diagnose a loculated effusion responsible for cardiac tamponade.


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InternalMed_Harrison. FIGURE 288-4 Constrictive pericarditis. Doppler schema of respirophasic changes in mitral and tricuspid inflow. Reciprocal patterns of ventricular filling are assessed on pulsed Doppler examination of mitral valve (MV) and tricuspid valve (TV) inflow. IVC, inferior vena cava; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. (Courtesy of Bernard E. Bulwer, MD; with permission.) Patients with acute pericarditis should be observed frequently for the development of an effusion; if a large effusion is present, pericardiocentesis should be carried out or the patient watched closely for signs of tamponade. Arterial and venous pressures should be monitored and serial echocardiograms obtained.


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InternalMed_Harrison. If manifestations of tamponade appear, echocardiographically guided pericardiocentesis using an apical, parasternal, or, most commonly, subxiphoid approach must be carried out at once because reduction of the elevated intrapericardial pressure may be lifesaving. Intravenous saline may be administered as the patient is being readied for the procedure, but the pericardiocentesis must not be delayed. If possible, intrapericardial pressure should be measured before fluid is withdrawn, and the pericardial cavity should be drained as completely as possible. A small, multiholed catheter advanced over the needle inserted into the pericardial cavity may be left in place to allow draining of the pericardial space if fluid reaccumulates. Surgical drainage through a limited (subxiphoid) thoracotomy may be required in recurrent tamponade, when it is necessary to remove loculated effusions, and/or when it is necessary to obtain tissue for diagnosis.


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InternalMed_Harrison. Pericardial fluid obtained from an effusion often has the physical characteristics of an exudate. Bloody fluid is most commonly due to neoplasm, renal failure, or dialysis in the United States and tuberculosis in developing nations but may also be found in the effusion of acute rheumatic fever, after cardiac injury, and after myocardial infarction. Transudative pericardial effusions may occur in heart failure. The pericardial fluid should be analyzed for red and white blood cells and cytologic studies, and cultures should be obtained. The presence of DNA of Mycobacterium tuberculosis determined by the polymerase chain reaction strongly supports the diagnosis of tuberculous pericarditis (Chap. 202).


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InternalMed_Harrison. In many instances, acute pericarditis occurs in association with illnesses of known or presumed viral origin and probably is caused by the same agent. Commonly, there is an antecedent infection of the respiratory tract, and viral isolation and serologic studies are negative. In some cases, coxsackievirus A or B or the virus of influenza, echovirus, mumps, herpes simplex, chickenpox, adenovirus, or cytomegalovirus has been isolated from pericardial fluid and/or appropriate elevations in viral antibody titers have been noted. Pericardial effusion is a common cardiac manifestation of HIV; it is usually secondary to infection (often mycobacterial) or neoplasm, most often lymphoma. Frequently, a viral cause cannot be established, and the term idiopathic acute pericarditis is then appropriate.


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InternalMed_Harrison. Viral or idiopathic acute pericarditis occurs at all ages but is more common in young adults and is often associated with pleural effusions and pneumonitis. The almost simultaneous development of fever and precordial pain, often 10–12 days after a presumed viral illness, constitutes an important feature in the differentiation of acute pericarditis from AMI, in which chest pain precedes fever. The constitutional symptoms are usually mild to moderate, and a pericardial friction rub is often audible. The disease ordinarily runs its course in a few days to 4 weeks. The ST-segment alterations in the ECG usually disappear after 1 or more weeks, but the abnormal T waves may persist for several years and be a source of confusion in persons without a clear history of pericarditis. Pleuritis and pneumonitis frequently accompany viral or idiopathic acute pericarditis. Accumulation of some pericardial fluid is common, and both tamponade and constrictive pericarditis are possible, but infrequent,


InternalMed_Harrison

InternalMed_Harrison. frequently accompany viral or idiopathic acute pericarditis. Accumulation of some pericardial fluid is common, and both tamponade and constrictive pericarditis are possible, but infrequent, complications.


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InternalMed_Harrison. The most frequent complication is recurrent (relapsing) pericarditis, which occurs in about one-fourth of patients with acute idiopathic pericarditis. In a smaller number, there are multiple recurrences. For treatment, see earlier section on treatment of acute pericarditis. Postcardiac Injury Syndrome Acute pericarditis may appear in a variety of circumstances that have one common feature—previous injury to the myocardium with blood in the pericardial cavity. The syndrome may develop after a cardiac operation (postpericardiotomy syndrome), after blunt or penetrating cardiac trauma (Chap. 289e), or after perforation of the heart with a catheter. Rarely, it follows AMI.


InternalMed_Harrison

InternalMed_Harrison. The clinical picture mimics acute viral or idiopathic pericarditis. The principal symptom is the pain of acute pericarditis, which usually develops 1–4 weeks after the cardiac injury but earlier (1–3 days) after AMI. Recurrences are common and may occur up to 2 years or more following the injury. Fever, pleuritis, and pneumonitis are the outstanding features, and the bout of illness usually subsides in 1 or 2 weeks. The pericarditis may be of the fibrinous variety, or it may be a pericardial effusion, which is often serosanguineous but rarely causes tamponade. ECG changes typical of acute pericarditis may also occur. This syndrome is probably the result of a hypersensitivity reaction to antigen(s) that originate from injured myocardial tissue and/or pericardium.


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InternalMed_Harrison. Often no treatment is necessary aside from aspirin and analgesics. When the illness is severe or followed by a series of disabling recurrences, therapy with an NSAID, colchicine, or a glucocorticoid, such as described for treatment of acute pericarditis, is usually effective.


InternalMed_Harrison

InternalMed_Harrison. Because there is no specific test for acute idiopathic pericarditis, the diagnosis is one of exclusion. Consequently, all other disorders that may be associated with acute fibrinous pericarditis must be considered. A common diagnostic error is mistaking acute viral or idiopathic pericarditis for AMI and vice versa. When acute fibrinous pericarditis is associated with AMI (Chap. 295), it is characterized by fever, pain, and a friction rub in the first 4 days after the development of the infarct. ECG abnormalities (such as the appearance of Q waves, brief ST-segment elevations with reciprocal changes, and earlier T-wave changes in AMI) and the extent of the elevations of markers of myocardial necrosis (higher in AMI) are helpful in differentiating pericarditis from AMI.


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InternalMed_Harrison. Pericarditis secondary to postcardiac injury is differentiated from acute idiopathic pericarditis chiefly by timing. If it occurs within a few days or weeks of an AMI, a chest blow, a cardiac perforation, or a cardiac operation, it may be justified to conclude that the two are probably related. It is important to distinguish pericarditis due to collagen vascular disease from acute idiopathic pericarditis. Most important in the differential diagnosis is the pericarditis due to systemic lupus erythematosus (SLE; Chap. 378) or drug-induced (procainamide or hydralazine) lupus. When pericarditis occurs in the absence of any obvious underlying disorder, the diagnosis of SLE may be suggested by a rise in the titer of antinuclear antibodies. Acute pericarditis is an occasional complication of rheumatoid arthritis, scleroderma, and polyarteritis nodosa, and other evidence of these diseases is usually obvious.