Diagnosis and Management of the Cardiac Amyloidoses

HomeCirculationVol. 112, No. 13Diagnosis and Management of the Cardiac Amyloidoses Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBDiagnosis and Management of the Cardiac Amyloidoses Rodney H. Falk, MD Rodney H. FalkRodney H. Falk From the Department of Cardiology, Harvard Vanguard Medical Associates, and Cardiovascular Genetics Center, Brigham and Women’s Hospital, Boston, Mass. Search for more papers by this author Originally published27 Sep 2005https://doi.org/10.1161/CIRCULATIONAHA.104.489187Circulation. 2005;112:2047–2060Cardiac amyloidosis is a manifestation of one of several systemic diseases known as the amyloidoses.1,2 This uncommon disease is probably underdiagnosed, and even when a diagnosis of amyloidosis of the heart is made, the fact that there are several types of amyloid, each with its unique features and treatment, is often unrecognized. This can lead to errors in management and in the information conveyed to the patient. The purpose of this review is to familiarize the reader with the clinical features of amyloidosis and to address the approach to the patient with this disease, focusing on the various types of amyloidosis, their prognosis and treatment.The common feature of this group of diseases is the extracellular deposition of a proteinaceous material that, when stained with Congo red, demonstrates apple-green birefringence under polarized light and that has a distinct color when stained with sulfated Alcian blue (Figure 1). Viewed with electron microscopy, the amyloid deposits are seen to be composed of a β-sheet fibrillar material (Figure 2). These nonbranching fibrils have a diameter3 of 7.5 to 10 nm and are the result of protein misfolding.4,5 Cardiac involvement in amyloidosis may be the predominant feature or may be found on investigation of a patient presenting with another major organ involvement. The presence of cardiac amyloidosis and its relative predominance varies with the type of amyloidosis. Thus, senile systemic amyloidosis and some forms of transthyretin amyloidosis invariably affect the heart, whereas cardiac involvement ranges from absent to severe in amyloidosis derived from a light-chain precursor (AL amyloidosis). Secondary amyloidosis almost never affects the heart in any clinically significant manner.6 The specific composition of the fibrils differs in the different types of amyloid7 and are outlined in the Table. Both on the basis of common usage and for the sake of simplicity, “cardiac amyloidosis” is used here to describe involvement of the heart by amyloid deposition, whether as part of systemic amyloidosis (as is most commonly the case) or as a localized phenomenon. Download figureDownload PowerPointFigure 1. A, Endomyocardial biopsy specimen, stained with hematoxylin and eosin, from a patient with cardiac amyloidosis. The amyloid stains light pinkish red and is seen as an amorphous material that separates the darker staining myocytes. B, Staining of the tissue from the same patient using sulfated Alcian blue. The amyloid stains turquoise green and the myocytes stain yellow, characteristic of amyloid. Courtesy of Dr Gayle Winters, Brigham and Women’s Hospital. Boston, Mass.Download figureDownload PowerPointFigure 2. Myocardial biopsy in cardiac amyloidosis viewed under electron microscopy. At the lower portion of the figure is the edge of a myocyte; above it is a mass of amyloid fibrils. Original magnification ×15 000.Summary of the Main Forms of Amyloidosis That Affect the HeartNomenclaturePrecursor of Amyloid FibrilOrgan InvolvementTreatmentCommentALImmunoglobulin light chainHeartChemotherapyPlasma cell dyscrasia related to (but usually not associated with) multiple myelomaKidneyLiverPeripheral/autonomic nervesHeart disease occurs in 1/3 to 1/2 of AL patients; heart failure tends to progress rapidly and has a very poor prognosisSoft tissueGastrointestinal systemATTR (familial)Mutant transthyretinPeripheral/autonomic nerveLiver transplantation? New pharmacological strategies to stabilize the TTRAutosomal dominant; amyloid derived from a mixture of mutant and wild-type TTR; if present before, cardiac amyloid may progress despite liver transplantationHeartAApoA1Mutant apolipoproteinKidney? Liver transplantationKidney disease is the commonest presentation; heart involvement rareHeartSenile systemic amyloidWild-type transthyretinHeartSupportive? New pharmacological strategies to stabilize the TTR.Almost exclusively found in elderly men; slowly progressive symptomsAASerum amyloid AKidneyTreat underlying inflammatory processHeart disease rare and, if present, rarely clinically significantHeart (rarely)AANPAtrial natriuretic peptideLocalized to the atriumNone requiredVery common; may increase risk of atrial fibrillation and/or be deposited in greater amounts in the fibrillating atriumRegardless of the underlying pathogenesis of amyloid production, cardiac amyloidosis is a myocardial disease characterized by extracellular amyloid infiltration throughout the heart.8 Amyloid deposits occur in the ventricles and atria, as well as perivascularly (particularly in the small vessels) and in the valves. The conduction system may also be involved. The infiltrative process results in biventricular wall thickening with nondilated ventricles. The ensuing elevation of pressure in the thin-walled atria is associated with atrial dilation, despite thickening of the atrial walls by amyloid deposition.Because cardiac involvement very frequently coexists with significant dysfunction of other major organs, the initial suspicion of cardiac amyloidosis is often triggered by the recognition that the heart disease is part of a multiorgan disorder. Conversely, if other organ dysfunction such as nephrotic syndrome predominates, recognition of a cardiac problem may be delayed because of the focus on these organ systems. Because the clinical manifestations and progression of the disease may vary considerably on the basis of the amyloid fibril precursor, the various types of amyloid heart disease are dealt with individually in this review.AL AmyloidosisThe commonest form of amyloidosis is that associated with a plasma cell dyscrasia. Amyloid is produced from clonal light chains, so the disease is referred to as AL amyloidosis. The commonest plasma cell dyscrasia is multiple myeloma, and AL amyloidosis overlaps with it. However, only a minority of myeloma patients develop amyloidosis, and most patients with AL amyloidosis do not have multiple myeloma. Although AL amyloidosis is considered an uncommon disease, it has an incidence similar to better-known diseases such as Hodgkin disease or chronic myelocytic leukemia,9 with an estimated 2000 to 2500 new cases annually in the United States. The heart in AL amyloidosis is affected in close to 50% of cases (Figure 3), and congestive heart failure is the presenting clinical manifestation in about half of these patients.10 Even among patients in whom another organ system dysfunction predominates, the presence of cardiac amyloidosis is frequently the worst prognostic factor.11 Once congestive heart failure occurs, the median survival is <6 months in untreated patients10,11; therefore, early recognition of the disease and prompt initiation of therapy is critical. Download figureDownload PowerPointFigure 3. Autopsy specimen of a heart with extensive amyloid infiltration. Note the nondilated ventricles with biventricular thickening and the biatrial enlargement with thickening of the atrial septum. Atrial infiltration leads to atrial failure and can be associated with atrial thrombi.Clinical FeaturesThe typical patient with heart failure resulting from AL amyloidosis frequently presents with rapidly progressive signs and symptoms. Progressive dyspnea is common, almost always associated with evidence of elevated right-sided filling pressure. Peripheral edema may be profound, and in late-stage disease, ascites is not uncommon. Weight loss, which is common, may represent the effects of the systemic disease or may be a manifestation of cardiac cachexia. Patients with cardiac amyloidosis may present with chest discomfort. Most commonly, this is not typical of angina and is associated with congestive heart failure, but typical angina can occur because of involvement of the small vessels of the heart.12 Imaging studies may be positive, leading to cardiac catheterization with apparently normal epicardial coronary arteries on coronary angiography. Myocardial flow reserve in such patients is impaired13 because of the small vessel involvement, and a small but persistent elevation in serum troponin may be present, leading to a misdiagnosis of non–Q-wave infarction.14–18 Presumably, the troponin elevation represents ongoing myocyte necrosis, and it has been shown be a negative prognostic factor.15–17 Small vessel cardiac amyloid may occur in the absence of wall thickening on the echocardiogram, although there is often a mild elevation of left ventricular filling pressure, suggesting diastolic abnormalities of the ventricle. This presentation of amyloidosis is rare; it is seen in only 1% to 2% of patients with cardiac involvement.Although sudden death is common in AL amyloidosis, ventricular arrhythmias are an uncommon presenting feature.19 Monitored sudden death in severe cardiac amyloid is often found to have been due to electromechanical dissociation rather than ventricular arrhythmia; in this, amyloidosis is similar to other forms of very severe heart disease.20 The management of syncope is discussed below, but a careful history may help distinguish arrhythmia-induced syncope from other sources such as autonomic neuropathy. Sustained ventricular tachycardia or resuscitation from ventricular fibrillation is a rare presenting manifestation that occurs in patients with less severe heart failure, presumably because patients with more advanced disease do not survive an initial episode.Fewer than 5% of patients with AL amyloidosis involving the heart have clinically isolated cardiac disease.10 Complaints of noncardiac symptoms should be sought because their presence is a clue to the systemic nature of the disease. The patient should be carefully questioned about dizziness and syncope with emphasis on the positional nature of any such symptoms because there are several potential mechanisms of syncope in amyloidosis.20 Dermatological manifestations such as easy bruising and periorbital purpura may occur21,22; the latter is virtually pathognomonic of the disease. Macroglossia, characterized by a stiffening and enlargement of the tongue, often with tooth indentation, is seen in 10% to 20% of patients and sometimes produces dysphonia or dysgeusia. It may occasionally be profound enough to interfere with eating, swallowing, or breathing. A subtle change in the voice (particularly hoarseness toward the end of the day), a quite common complaint, probably represents vocal cord involvement.23 Neurological symptoms include carpal tunnel syndrome and peripheral and autonomic neuropathy. Right upper quadrant discomfort may be due to hepatic congestion or with amyloid hepatic infiltration.24 Carpal tunnel syndrome often precedes other organ involvement by a few years, and a history of surgical carpal tunnel release is not uncommon. Although widespread lymphadenopathy is present in only a small minority of patients, submandibular swelling caused by lymph node and salivary gland infiltration is not uncommon and often is accompanied by macroglossia. Nail dystrophy (brittle and slow-growing nails) is sometimes seen, particular in the hands, and when present is a clue to the systemic nature of the cardiac disease.25The cardiovascular physical examination in a patient with heart failure resulting from amyloidosis usually reveals sinus rhythm with a normal to low radial pulse volume, although atrial arrhythmias (most commonly atrial fibrillation) occur in 10% to 15% of patients. When present, atrial fibrillation is associated with a very high incidence of thromboembolism. The jugular venous pressure is often markedly elevated, and the waveform is generally unrevealing, but occasionally, a prominent X and Y descent is noted.26,27 In contrast to constrictive pericarditis, with which it may be confused, Kussmaul’s sign is very rarely present. The apex beat is frequently impalpable and, when it can be felt, is generally not displaced. The first and second heart sounds are usually normal in character. A left ventricular third heart sound is rarely heard, but in advanced cases, a right ventricular S3, which often is associated with right ventricular dilation and dysfunction on the echocardiogram, may be heard best at the left parasternal edge. Despite the increased stiffness of the left ventricle, a fourth heart sound is almost never present, possibly because of atrial dysfunction resulting from amyloid infiltration.28,29 Blood pressure is often low, even in the absence of postural hypotension; this may represent decreased cardiac output in conjunction with early autonomic dysfunction. Blood pressure may fall further on standing, particularly if autonomic neuropathy is present,30 and should be measured in the supine, seated, and standing positions both immediately after standing and after at least 2 minutes because the systolic pressure may continue to drift down in the presence of autonomic dysfunction. Hypertension is unusual, and in patients with a history of hypertension, “spontaneous” resolution of hypertension over the preceding few months is common. Examination of the chest may reveal bilateral pleural effusions, but rales are rarely present, even in association with advanced heart failure. The pleural effusions in a patient with AL amyloidosis may simply represent heart failure, but patients with cardiac amyloid may also have pleural infiltration with amyloid, resulting in disproportionately large effusions that are diuretic resistant and rapidly recur after a pleural tap.31Splenomegaly is rare, whereas hepatomegaly is common and is due either to congestion from right heart failure or to amyloid infiltration.32,33 When extensive amyloid infiltration of the liver is present, the organ is rock-hard and not tender, often extending several centimeters below the costal margin and crossing the midline. This contrasts with the firm, sometimes tender, liver of heart failure. Peripheral edema may be profound, and if it appears disproportionate to the degree of heart failure, the possibility of associated nephrotic syndrome should be considered. In addition to autonomic dysfunction, amyloidosis may cause a sensory neuropathy, and the patient may complain of numbness or painful extremities.11 A history of weight loss is common, and proteinuria, frequently reaching nephrotic range (≥3 g/24 h), coexists with cardiac disease in 30% to 50% of cases.Low voltage on the ECG (defined as all limb leads <5 mm in height) is found in a high proportion of patients and is often associated with extreme left- or right-axis deviation (Figure 4). Although voltage criteria for left ventricular hypertrophy have been described in the precordial leads of some patients with AL amyloidosis, increased limb lead voltage is extremely uncommon.34 When increased limb or precordial lead voltage is present, it is frequently a result of an unrelated coexistent condition such as hypertension. Interestingly, right bundle-branch block is uncommon, and left bundle-branch block is very unusual unless it is a preexisting condition.10 The reason for the virtual absence of left bundle-branch block in patients with AL amyloidosis is unclear. However, because amyloid deposition affects the heart uniformly, the more vulnerable right bundle is anticipated to be involved before the left bundle, so sparing of the right bundle with complete left bundle-branch block would be very unlikely. Download figureDownload PowerPointFigure 4. Typical appearance of the ECG in AL amyloidosis of the heart. There is low voltage with an abnormal axis and poor R-wave progression in the precordial leads. The association of low voltage of this degree with thickening of the left ventricle on echocardiogram is highly suggestive of an infiltrative cardiomyopathy.The echocardiographic features of advanced cardiac AL amyloidosis are distinctive. The initial descriptions concentrated on patients with severe cardiac disease and depicted nondilated ventricles with concentric left ventricular thickening, right ventricular thickening, prominent valves, and infiltration of the atrial septum. The myocardial texture was abnormal and described as “granular sparkling.”26,35–37 Subsequent changes in image processing produced a myocardial appearance that is less “granular” in appearance, but advanced amyloid heart disease still demonstrates an increased echogenicity of the myocardium and often of the valves (Figure 5). The classic appearance of a restrictive pattern by Doppler echocardiography and associated increased echogenicity, biventricular thickening, and valvular infiltration is limited to patients in the end stage of the disease. More commonly, the ventricle appears thickened to a degree that is disproportionate to the degree of current or prior hypertension, and the Doppler features depend on the stage of the disease, with serial studies demonstrating a progression of diastolic dysfunction as myocardial infiltration progresses.36 The left ventricular ejection fraction is normal or nearly normal until late in the disease, and because the left ventricle does not dilate, a reduced ejection fraction is associated with a substantially reduced stroke volume. Because the thickening of the ventricle in amyloidosis is due to myocardial infiltration rather than hypertrophy, the ECG limb lead voltage tends to decrease as the ventricle thickens. This results in a decreased ratio of voltage to left ventricular mass, a finding that strongly suggests an infiltrative cardiomyopathy, of which amyloidosis is the commonest cause.38 In ≈5% of patients with cardiac amyloidosis, left ventricular infiltration may mimic hypertrophic cardiomyopathy on the echocardiogram.10,39,40 These patients often have normal or even mildly hyperdynamic left ventricular function with normal voltage on the ECG. Associated postural hypotension is common in these patients, and low afterload may in part account for the normal to increased ejection fraction. Unlike true hypertrophic cardiomyopathy, ventricular hypertrophy on the ECG limb leads is almost never seen and systolic anterior motion of the mitral valve is uncommon, although chordal anterior motion may be present with an associated outflow tract murmur. Download figureDownload PowerPointFigure 5. Selection of echocardiographic images from a patient with severe AL cardiac amyloidosis. Top left, Parasternal long-axis view showing concentric left ventricular thickening with a pericardial effusion. The echogenicity of the myocardium is increased, and the valves are seen unusually clearly suggestive of infiltration. Top right, Apical 4-chamber view showing normal biventricular dimensions and biatrial enlargement. The atrial septum is thickened, and a pacemaker/ICD lead is seen in the right ventricle. Bottom left, Transmitral Doppler flow showing a restrictive pattern with a short deceleration time and reduced A-wave velocity. Bottom right, Tissue Doppler recorded from the lateral mitral annulus. There is reduced myocardial velocity throughout systole and both phases of diastole, compatible with a restrictive pathophysiology.Doppler echocardiography is also useful in cardiac amyloidosis. In advanced disease, there is a restrictive transmitral flow pattern characterized by a short deceleration time of the E wave and a low-velocity A wave, with associated abnormalities in pulmonary venous flow.26,41,42 The decreased transmitral A wave in AL amyloidosis is related not only to late-stage restrictive pathophysiology but also to atrial amyloid infiltration, which results in intrinsic atrial dysfunction28,29,43–46; thus, a normal deceleration time can be seen in association with a diminutive A wave. Further insights into cardiac function in AL amyloidosis can be gained by pulsed tissue Doppler imaging, which can demonstrate the presence of diastolic dysfunction more accurately than transmitral and pulmonary flow and can provide evidence of longitudinal systolic impairment before the ejection fraction becomes abnormal.47,48 Strain and strain rate imaging are even more sensitive than tissue Doppler, demonstrating long-axis dysfunction in early cardiac amyloidosis and often showing disproportionate impairment of longitudinal contraction despite apparently preserved fractional shortening (Figure 6). In addition to giving sensitive information about myocardial function, tissue Doppler and strain and strain rate imaging may have potential for evaluating the prognosis in AL amyloidosis.47–49Download figureDownload PowerPointFigure 6. Color-coded map of myocardial long-axis strain (percentage change in length) recorded from the ventricular septum. Note the top left image recorded in the apical 4-chamber view, with a bar representing a key to the color coding. The numbers on the ventricular septum correspond to the numbers on the map; the apical septal strain is represented on the top part of the map, and the base is represented at the bottom. A, Recording from a normal subject. Immediately after the onset of systole (arrow indicates R wave), there is a brief light blue vertical line, representing isovolumic systole, followed by a broad, uniform orange/red-coded band representing ventricular contraction. This is followed by early relaxation in blue, diastasis in green, and a late diastolic relaxation represented in a second brief blue area. B, Strain map from a patient with cardiac amyloid, heart failure, and a mildly reduced ejection fraction. The arrow again represents the onset of the QRS complex. There is almost no longitudinal motion in any portion of the septum, with the large area of green representing absent motion and the brief patches of color representing slight elongation in late diastole (light blue). Systolic strain is almost absent except for some severely reduced longitudinal motion at the base and a brief, reduced contraction in midsystole near the apical septum (yellowish orange.)Other imaging modalities such as cardiac magnetic resonance show promise for diagnosing cardiac amyloidosis if echocardiographic features are suspicious.50 Recent descriptions of cardiac MRI in advanced cardiac amyloidosis show an unusual pattern characterized by global subendocardial late gadolinium enhancement and associated abnormal myocardial and blood-pool gadolinium kinetics.50 However the sensitivity of this technique for detecting early disease is not known, and the specificity of the described abnormalities is likely to be low in an unselected population of patients.51Cardiac CatheterizationThe noninvasive imaging features of amyloidosis described above are usually sufficient to strongly suspect the correct diagnosis. Thus, cardiac catheterization, other than to obtain an endomyocardial biopsy, to better assess hemodynamics, or to evaluate coronary anatomy, currently is of limited value in the routine evaluation of a patient with suspected amyloidosis. Nevertheless, many patients with an eventual diagnosis of cardiac amyloidosis undergo cardiac catheterization during the workup, and if a full hemodynamic study is done, careful examination of the pressure tracing may provide clues to the diagnosis. Impaired ventricular filling in advanced cardiac amyloidosis is associated with an elevated left ventricular end-diastolic pressure, and the pressure tracings may reveal a dip-and-plateau waveform52 (Figure 7). It has been suggested that, unlike constrictive pericarditis, amyloidosis is associated with a left ventricular end-diastolic pressure that exceeds right ventricular end-diastolic pressure by at least 7 mm Hg.52 However, this is not always the case, and both disorders may manifest a dip-and-plateau diastolic pressure tracing with pressure equalization.53,54 A pulmonary artery systolic pressure >50 mm Hg is rarely seen in “uncomplicated” constrictive pericarditis but may occur in cardiac amyloidosis,55 and the finding of an inspiratory rise in right ventricular pressure with an associated fall in left ventricular pressure, representing ventricular interdependence, has been proposed as a specific sign of constrictive pericarditis that distinguishes it from restrictive cardiomyopathy.56 However, although certain hemodynamic clues suggest one diagnosis or the other, overlap remains, and the diagnosis should not be made on hemodynamic data alone. In suspected cases of amyloidosis, clinical examination and review of the echocardiogram are generally extremely valuable in favoring a diagnosis of cardiac amyloidosis if present and should never be omitted. Download figureDownload PowerPointFigure 7. Simultaneous right and left ventricular pressure tracings in a patient with AL amyloidosis and atrial fibrillation. After a longer R-R interval, several beats show a dip and plateau morphology of the diastolic wave form with equalization of right and left ventricular pressures, mimicking constrictive pericarditis.Tissue DiagnosisThe diagnosis of amyloidosis requires a tissue biopsy that demonstrates apple-green birefringence when stained with Congo red and viewed under a polarizing microscope. Sulfated Alcian blue is an alternative stain with a high specificity for amyloid57 (Figure 1). It is not necessary to biopsy the heart if the echocardiographic appearances are typical for cardiac amyloidosis, providing that a histological diagnosis has been made from another tissue. Fine-needle aspiration of the abdominal fat is a simple procedure that is positive for amyloid deposits in >70% of patients with AL amyloidosis.58,59 If the diagnosis is not confirmed by biopsy of another tissue, endomyocardial biopsy is a safe and relatively simple procedure in skilled hands; it is virtually 100% sensitive because the amyloid is widely deposited throughout the heart.60,61 In patients with known amyloid deposits in other organs and a history of poorly controlled hypertension, there may be uncertainty as to whether ventricular thickening represents amyloid infiltration or hypertensive heart disease. In such cases, endomyocardial biopsy may be helpful to determine whether the heart is infiltrated with amyloid.Once a tissue diagnosis of amyloid has been established, the confirmation that this is AL amyloid requires a search for the presence of a plasma cell dyscrasia. Serum and urine immunofixation should be performed rather than serum and urine electrophoresis because the amount of serum or urine paraprotein may be small and immunofixation is a much more sensitive test. Even more sensitive is the recently introduced serum free-light-chain assay, which can detect circulating free light chains with >10-fold sensitivity than immunofixation62,63 This is a quantitative test. In AL amyloidosis, free lambda or (less commonly) free kappa levels are elevated. The normal serum range of kappa free light chains is 3.3 to 19.4 mg/dL; for lambda, 5.7 to 26.3 mg/dL with a kappa-to-lambda ratio of 0.26 to 1.65.62,63 It is important to assess the ratio of kappa to lambda free light chains because they are renally excreted and renal impairment elevates kappa and lambda levels without changing the ratio. In AL amyloidosis with renal impairment, elevated levels of both free lambda and free kappa will be seen because renal impairment reduces light-chain excretion. However, the kappa-to-lambda ratio remains abnormal and should always be calculated in addition to the absolute values. A kappa-to-lambda ratio <0.26 strongly suggests the presence of a population of plasma cells producing clonal lambda free light chains, whereas a ratio >1.65 suggests production of clonal kappa free light chains. In 110 patients with AL amyloidosis, serum immunofixation was positive in 69%, urine immunofixation was positive in 83%, and the kappa-to-lambda ratio was abnormal in 91%. The combination of an abnormal kappa lambda ratio and a positive serum immunofixation identified 99% of patients with AL amyloidosis.64 A bone marrow biopsy is mandatory to assess the percentage of plasma cells, and immunoperoxidase staining will determine whether the abnormal plasma cells are producing kappa or lambda light chains.65 Bone marrow biopsy is also required to exclude myeloma and other less common disorders that can be associated with AL amyloidosis such as Waldenstrom’s macroglobulinemia. It is important to recognize that a monoclonal band present on serum immunofixation may be seen as an apparently incidental finding in 5% to 10% of patients >70 years of age (“monoclonal gammopathy of uncertain significance”).66 The serum free-light-chain assay is often normal in such cases,67 but if any doubt exists about the clinical picture, further testing must be done to exclude familial or senile forms of amyloid. Such testing includes either special staining techniques of the amyloid such as immunogold electron microscopy68–70 or genetic testing to rule out familial forms of amyloid.71ManagementManagement of cardiac amyloidosis requires a 2-fold approach: management of the cardiac-related symptoms and treatment of the underlying disease. The mainstay of the treatment of heart failure in AL amyloidosis is the use of diuretics; higher doses than anticipated may be required if the albumin level is low as a result of concomitant nephrotic syndrome. In a patient with anasarca, intravenous diuresis is often needed because absorption of diuretics may be impaired. Resistant, large, pleural effusions may