32 - 270 Amyloidosis and Other Restrictive Cardiomyopathies

270 Amyloidosis and Other Restrictive Cardiomyopathies

■ ■FURTHER READING Arany Z: Peripartum cardiomyopathy. N Engl J Med 390:154, 2024. Cardinale D et al: Early detection of anthracycline cardiotoxicity and

improvement with heart failure therapy. Circulation 131:1981, 2015. Davis MB et al: Peripartum cardiomyopathy. J Am Coll Cardiol 75: 207, 2020. Lyon AR et al: 2022 ESC Guidelines on cardio-oncology developed in PART 6 Disorders of the Cardiovascular System collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS): Developed by the task force on cardio-oncology of the European Society of Car­ diology (ESC). Eur Heart J 43:4229, 2022. Packer M: Cobalt cardiomyopathy: A critical reappraisal in light of a recent resurgence. Circ Heart Fail 9:e003604. 2016. Rasoul D et al: Alcohol and heart failure. Eur Cardiol 18:e65, 2023. Quiroz-Aldave JE et al: Thyrotoxic cardiomyopathy: State of the art. touchREV Endocrinol 19:78, 2023. Singh T et al: Manganese-enhanced magnetic resonance imaging in takotsubo syndrome. Circulation 146:1823, 2022. Wood JC: Guidelines for quantifying iron overload. Hematology Am Soc Hematol Educ Program 1:210, 2014.

Amyloidosis and

Other Restrictive Cardiomyopathies Rodney H. Falk, Neal K. Lakdawala,

Lynne Warner Stevenson, Joseph Loscalzo RESTRICTIVE CARDIOMYOPATHY Restrictive cardiomyopathy (RCM) is dominated by abnormal diastolic function within a noncompliant ventricle, often with mildly decreased contractility and ejection fraction (usually 30–50%). Both atria are enlarged, sometimes massively. Mild left ventricular dilation can be present. End-diastolic pressures are usually elevated in both ventricles, with preservation of resting 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 heart sound in sinus rhythm, but atrial fibrillation is com­ mon. Jugular venous pressures often show rapid Y descents and may increase during inspiration (positive Kussmaul sign). Most causes of RCM are “infiltrative,” due to infiltration of abnor­ mal substances between myocytes, with the amyloidoses being the most common causes of RCM. RCM can also result from storage of abnormal metabolic products within myocytes. RCM due to acquired fibrotic injury is most commonly caused by radiation or connective tissue disease and less commonly by hypereosinophilic injury (see Chap. 268 and Table 270-1). RCM can also be secondary to genetic causes of primary cardiomy­ opathy, including variants in DES or as a forme fruste of hypertrophic cardiomyopathy caused by sarcomere variants. The most common differential diagnosis is between RCM and constrictive pericardial disease, as both often present with dominant right-sided heart failure. In the absence of specific therapy for the etiology of RCM, such as is now available for some patients with amyloidosis, general strategies are

TABLE 270-1  Causes of Restrictive Cardiomyopathies (RCM) Infiltrative (Between Myocytes) Amyloidosis   Light chain (AL) amyloid   Familial (variant transthyretin)a   Wild-type (normal) transthyretin Inherited metabolic defectsa Storage (Within Myocytes) Hemochromatosis (iron),a also with dilated cardiomyopathy phenotype when advanced Inherited metabolic defectsa   Fabry’s disease   Glycogen storage disease (II, III) Fibrotic Radiation Scleroderma Endomyocardial Possibly related fibrotic diseases   Tropical endomyocardial fibrosis   Hypereosinophilic syndrome (Löffler’s endocarditis) Carcinoid syndrome Radiation Drugs: e.g., serotonin, ergotamine Genetic Variants Affecting Cardiomyocyte Function Occasional RCM due to genetic variants more commonly associated with dilated or hypertrophic cardiomyopathy RCM and skeletal muscle involvement with desminopathy due to pathogenic DES variants aContribution of genetic background. focused on maintenance of optimal volume status, which is generally a compromise between adequate ventricular filling and systemic decon­ gestion. As ventricular filling and stroke volume are often restricted, therapy with beta blockers can reduce heart rate, contractility, cardiac output, and functional reserve. Vasodilation may not be well tolerated. Other than diuretics, therapies proven effective for dilated cardiomy­ opathy and other heart failure with reduced ejection fraction are not recommended for routine use in RCM. AMYLOIDOSIS Amyloidosis is a systemic disease characterized by the deposition of fibrillar proteinaceous material primarily in the extracellular space of one or more organs. Although there are many precursor proteins that have been shown to cause amyloidosis (see Chap. 117), the unifying feature of all types of amyloid is its staining characteristics. Amyloid is a noncellular material deposited in the extracellular space that stains with Congo red and exhibits “apple-green birefringence” when viewed under polarized light microscopy. When viewed with electron microscopy, amyloid deposits are seen to consist of nonbranching fibrils ~10 nm in diameter and a few micrometers in length. From a cardiac standpoint, there are two main precursor proteins that cause most cases of amyloid cardiomyopathy: transthyretin (TTR), produced in the liver, and light chains produced by abnormal plasma cells. TTR amyloidosis may be caused by a genetic variant of TTR (ATTRv) or by wild-type TTR (ATTRwt), and variant TTR is generally considered to be less stable than wild-type TTR. Once a diagnosis of amyloidosis has been made, it is critically important to determine the precise precursor protein because treatment is specific to the type of amyloid and incor­ rect typing will lead to inappropriate therapy. ■ ■PATHOLOGIC MECHANISMS OF HEART FAILURE IN CARDIAC AMYLOIDOSIS All forms of cardiac amyloidosis have a similar appearance on gross and microscopic examination (Figs. 270-1 and 270-2).

FIGURE 270-1  Gross pathology of the heart in amyloid cardiomyopathy. The left ventricle (LV) is severely thick due to amyloid infiltration. The LV cavity is small with markedly thick walls due to amyloid infiltration. The right ventricle is mildly thickened, and the left atrium (partly excised) is dilated. (Courtesy of Dr. Richard Mitchell, Brigham and Women’s Hospital Department of Pathology.) The extracellular deposits of amyloid result in an increase in the mass of the heart, due to expansion of the extracellular space. Both left and right ventricular walls demonstrate increased thickness, and decreased compliance and the left ventricular cavity may be relatively small, leading to a restrictive pathophysiology. The right ventricular cavity is often normal in size but may dilate in advanced disease. The atria are usually dilated due to the chronic elevation of biventricular diastolic filling pressure and may dilate further with the onset of atrial arrhythmias. Histologically, amyloid deposits are widespread through­ out the heart so that endomyocardial biopsy is almost always diagnos­ tic in cases of cardiac amyloidosis. FIGURE 270-2  Histology of amyloid cardiomyopathy. Left panel: Hematoxylin and eosin stain showing extensive extracellular cardiac amyloid deposition resulting in separation and distortion of cardiomyocytes. The amyloid stains light pink and the myocytes are nucleated and stain a deeper pink. Right panel: Specimen from same patient stained with sulfated Alcian blue. The amyloid stains “sea green,” and the myocytes are pale yellow-gray. Magnification ×60. (Courtesy of Dr. Richard Mitchell, Brigham and Women’s Hospital Department of Pathology.)

■ ■CLINICAL FEATURES OF CARDIAC AMYLOIDOSIS There are some clinical features of light chain (AL) amyloidosis and TTR amyloidosis that suggest one or the other diagnosis, but the cardiac features are similar enough that the final diagnosis of amy­ loid type often relies upon precise typing of a cardiac or extracardiac tissue biopsy. The most common clinical presentation is congestive heart failure. Although both ventricles are usually heavily infiltrated by the time congestive heart failure occurs, patients tend to present with symptoms of predominant right heart failure, namely peripheral edema and, not infrequently, ascites. Despite the clinical predominance of right ventricular failure, cardiac catheterization will reveal consider­ able elevation of both left and right ventricular filling pressure. Atrial arrhythmia, particularly atrial fibrillation, is a common presenting feature, particularly in TTR amyloidosis, and may occur at a time when the left ventricle is only mildly thick, precipitating heart failure in a previously asymptomatic patient. The onset of atrial fibrillation may be associated with symptoms of dyspnea, often more severe than is seen in nonamyloid patients with this arrhythmia. Refractory atrial arrhyth­ mia, whether to antiarrhythmic drugs or characterized by failure to maintain sinus rhythm after repeated ablation procedures, should raise the possibility of TTR cardiac amyloidosis, particularly if occurring in a patient in the mid-60s or older without other apparent reason for the atrial fibrillation.

CHAPTER 270 Amyloidosis and Other Restrictive Cardiomyopathies Cardiovascular physical examination in the symptomatic patient with cardiac amyloidosis reveals a normal or low pulse pressure. The apex beat may be difficult to palpate but, if felt, is usually only mildly displaced. The jugular venous pressure is almost always elevated and frequently demonstrates a paradoxical rise on inspiration (Kussmaul sign). The first and second heart sounds tend to be normal. Despite congestive heart failure, a third heart sound is very rarely heard, due to the restrictive pathophysiology and its associated impairment of ven­ tricular relaxation. Similarly, a fourth heart sound is also unusual as the infiltrated atrium is rarely able to generate much contractile pressure. Pleural effusions, primarily caused by heart failure (but occasionally aggravated by associated hypoalbuminemia from nephrotic syndrome or by the presence of pleural amyloidosis) are quite common. Cardiac murmurs due to amyloid-associated valve disease are relatively uncom­ mon, although a tricuspid regurgitation murmur may occasionally be present. There is an association between aortic valve stenosis and TTR amyloidosis, and a murmur of aortic stenosis may be present. Whether amyloid causes aortic stenosis or simply aggravates or precipitates heart failure in a patient with unrelated aortic valve disease is unclear. In addition to the cardiovascular examination, a careful systemic physical examination is mandatory. In advanced heart failure, hepatomegaly due to congestive heart failure is common, but an unusually hard liver may represent amyloid infiltration of the liver—something that occurs in AL amyloidosis but not TTR. The blood pressure should be checked in the supine, seated, and standing positions, seeking an abnormal pos­ tural drop. If present, this likely represents associated autonomic neu­ ropathy, which is a feature of AL amyloidosis and some forms of variant TTR amyloidosis but not wild-type TTR amyloidosis. Macroglossia or periorbital bruising, if present, strongly suggest AL amyloidosis, whereas a history of bilateral carpal tunnel syndrome or the finding of a ruptured biceps tendon points toward TTR amyloidosis. ■ ■DIFFERENTIAL DIAGNOSIS The differential diagnosis of a patient with biventricular failure mani­ festing predominantly as edema, in association with a thick left ventri­ cle but without a history of severe hypertension, is small. Hypertensive heart disease is usually associated with left ventricular hypertrophy on the electrocardiogram (ECG), whereas this ECG finding is uncommon in amyloidosis, and it requires several years of severe uncontrolled hypertension to produce the degree of wall thickening equal to that seen in amyloidosis. While amyloidosis, particularly ATTR, can have asymmetric left ventricular thickening, the clinical distinction between hypertrophic cardiomyopathy and amyloidosis is usually fairly clear, since the former rarely presents with peripheral edema and usually has left ventricular hypertrophy (LVH) on the ECG. Other infiltra­ tive cardiomyopathies such as Fabry disease may have typical skin

manifestations and usually LVH on the ECG. The rare mitochondrial cardiomyopathies may have an echocardiographic appearance similar to amyloidosis but have different noncardiac clinical features, such as maternally inherited diabetes, deafness, and recurrent strokes. Patients with advanced diabetes may have heavy proteinuria and heart failure, but their history of diabetes is obvious, and the echocardiogram does not show features suggestive of amyloid heart disease. In the era before echocardiography, constrictive pericarditis, often presenting with edema, ascites, and elevated jugular venous pressure with a Kussmaul sign, was the major differential of amyloid heart disease. Constrictive pericarditis is less common nowadays, and echocardiography can eas­ ily distinguish between the two entities.

PART 6 Disorders of the Cardiovascular System ■ ■AL AMYLOIDOSIS OF THE HEART AL amyloidosis is a plasma cell disorder closely related to multiple myeloma. It is described in detail in Chap. 117. An excessive produc­ tion of abnormal lambda, or (less commonly) kappa, free light chains produced by abnormal clonal bone marrow plasma cells results in amyloid deposits in multiple organs, with heart and kidney being the most common organs involved. AL amyloidosis is closely related to multiple myeloma, with which it may occasionally overlap. It is an aggressive disease, and cardiac involvement, either alone or in combi­ nation with other major organ involvement, carries the worst survival, with a median survival from onset of heart failure to death in untreated patients of ~6 months. This short survival underscores the urgency of pursuing a diagnosis of AL amyloidosis once suspected, as therapy can markedly improve duration and quality of life and must be instituted as soon as the diagnosis is made. In addition to the general features of heart failure noted above, there are several clinical noncardiac clues to AL amyloidosis as the etiology of congestive heart failure. These indicate the presence of a multisystem disease and include significant proteinuria, neuropathy, periorbital purpura (virtually pathognomonic of AL amyloidosis and occurring in 20–30% of cases), and macroglos­ sia (~10% of cases). ■ ■TTR AMYLOIDOSIS OF THE HEART Patients with wild-type TTR amyloidosis cardiomyopathy and those with amyloid cardiomyopathy caused by variant TTR may have subtle differences in presentation. The less common variant TTR cardiomy­ opathy may be associated with amyloid neuropathy, which can vary between mild sensory neuropathy and a rapidly progressive severe sensorimotor neuropathy with or without autonomic nervous system involvement. Myocardial infiltration may be extensive in patients with severe variant transthyretin neuropathy, but cardiac symptoms can be relatively mild in these patients, either because the limitation of physical activity due to the neuropathy masks exercise intolerance or because autonomic neuropathy acts to reduce peripheral resistance, decreasing the work of the heart. If autonomic neuropathy is present, postural hypotension can be highly symptomatic and postural mea­ surements of blood pressure are mandatory. A family history of neu­ ropathy or cardiomyopathy may be elicited in these patients and, when neuropathy is present, may have been misdiagnosed as other neuro­ logic conditions. In the United States, the most common TTR variant causing TTR amyloid cardiomyopathy is the substitution of valine for isoleucine at position 122, Val122Ile. This variant is present in ~3.5% of the U.S. population of African descent and presents as a late-onset restrictive cardiomyopathy usually in the seventh decade onward. The penetrance of clinical disease is incomplete, and the family history is often lacking or unknown. Neuropathy in this mutation is very mild or absent, although carpal tunnel syndrome, often preceding the onset of heart failure by several years, is commonly present. The clinical fea­ tures of other forms of variant TTR amyloidosis can vary considerably, somewhat dependent on the transthyretin mutation, but in the case of the Val122Ile variant, it tends to be a relatively rapid progressive infil­ trative cardiomyopathy with a median survival of 2–3 years following the onset of heart failure in untreated patients. Once considered a rare form of cardiac amyloidosis, TTR deposition derived from native (wild-type) transthyretin is now considered the

most common form of amyloidosis. It affects mainly men in the latter half of their seventh decade and eighth decades but may occasionally present at a younger age and often presents in the ninth decade onward. Men are almost 20 times more likely than women to be diagnosed with wild-type TTR amyloidosis, and when it does occur in women, it tends to present at a later age and to have a more indolent course. On average, the untreated median survival from the onset of heart failure to death is around 4–5 years, with death being due primarily to pro­ gressive congestive heart failure rather than to sudden death. Current therapies have slowed the disease progression and improved survival. Both wild-type and mutant TTR cardiomyopathy have a subclinical phase, probably of several years, during which there is a progressive infiltration of the heart with amyloid, and by the time heart failure occurs, 30–50% of the involved heart weight is due to amyloid. Atrial arrhythmias, most commonly atrial fibrillation or atrial flutter, may be the presenting feature of the disease, and when they occur, they often precipitate or worsen heart failure. In contrast to AL amyloidosis, the heart in ATTRwt is the sole major organ to be clinically involved, although histologic examination of the lungs and gut often shows fairly extensive amyloid deposits. TTR also had a predilection for ligaments and tendons, and a history of carpal tunnel syndrome, spinal stenosis, or ruptured bicep tendon, often occurring 5–8 years before heart fail­ ure, can be elicited in about half the patients with this disorder. ■ ■DIAGNOSIS The diagnosis of cardiac amyloidosis rests upon a clinical suspicion combined with imaging findings and, in many cases, a confirmatory biopsy. ECG voltage may be abnormally low, particularly in AL amyloi­ dosis, but this is not always the case. Echocardiography is an extremely useful imaging modality. The echocardiogram in all forms of cardiac amyloidosis with heart failure shows increased left ventricular wall thickness without ventricular dilation and, frequently, biatrial enlarge­ ment (Fig. 270-3). The right ventricle may also show increased thickness of the free wall. Diastolic function is abnormal, and a restrictive pattern, con­ sistent with elevated left ventricular diastolic pressures, is often seen. Although the left ventricular ejection fraction may be normal or near-normal, left ventricular longitudinal strain imaging, a tool for measuring the contraction of the left ventricle in the longitudinal plane, often shows a pattern in which strain is relatively preserved at the left ventricular apex and severely impaired at the base of the heart. Color-coding of this pattern results in a “bull’s-eye” appearance, which is highly suggestive of cardiac amyloidosis (Fig. 270-4). Atrial function is often impaired, particularly in AL amyloidosis, and this is characterized by a very small transmitral A wave in patients FIGURE 270-3  Echocardiogram (apical four-chamber view) showing typical appearance of amyloidosis. The left ventricular cavity is normal in size with thick walls, and there is biatrial enlargement. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

FIGURE 270-4  Left ventricular strain in amyloidosis. Left panels show outline of left ventricle divided into seven segments with numbers in bottom panel representing the percentage longitudinal systolic shortening of each segment. Right top panel shows corresponding curves for each segment, and bottom right panel shows color coding in which the apex codes bright red and base pink due to near-normal apical contraction, resulting in typical “bull’s-eye” pattern of amyloidosis. in sinus rhythm. This appearance may be associated with an increased risk of thromboembolism. Echocardiography with the typical appearance may be enough to proceed to further laboratory evaluation for amyloidosis, but cardiac magnetic resonance is increasingly used in the diagnosis of suspected cardiomyopathy. The ventricle is seen to be abnormally thick, measure­ ment of extracellular volume demonstrates marked expansion of the extracellular space due to amyloid deposition, and there is often exten­ sive delayed gadolinium enhancement of the myocardium, associated with abnormal nulling of the images (Figs. 270-5 and 270-6). Taken together, these features are virtually pathognomonic of amy­ loid cardiomyopathy. Once amyloid cardiomyopathy is suspected, it is critical to determine the specific type of amyloid deposition. Tracers developed for bone imaging (technetium pyrophosphate or technetium 3,3-diphosphono-1,2-propanodicarboxylic acid [DPD]) are not usually taken up by the normal heart or in other forms of cardiac pathology, but there may be avid tracer uptake in patients with transthyretin amy­ loid cardiomyopathy (Fig. 270-7). Because patients with AL amyloid cardiomyopathy may occasion­ ally have myocardial uptake of these tracers, it is critically important to measure serum free light chains, serum and urine protein electropho­ resis, and serum and urine immunofixation to rule out a plasma cell dyscrasia. If these lab tests are all negative and the nuclear scan is posi­ tive, a diagnosis of transthyretin amyloidosis can be confidently made, provided that echocardiography or cardiac magnetic resonance is consistent with this diagnosis. Monoclonal gammopathy of unknown significance not uncommonly coexists with transthyretin amyloidosis and will be associated with abnormalities in testing for plasma cell dys­ crasia. Thus, if light chain amyloidosis remains a possibility, despite the presence of a strongly positive pyrophosphate scan, consultation with

CHAPTER 270 Amyloidosis and Other Restrictive Cardiomyopathies a hematologist is important to help clarify the diagnosis. If uncertainty remains, an endomyocardial biopsy (or biopsy from other tissue) with definitive tissue typing (ideally by mass spectrometry) is required. Almost all patients with light chain amyloidosis will have evidence of a plasma cell dyscrasia, and almost all of them will have elevation of either serum free lambda light chains or (less commonly) serum free kappa light chains. If light chain amyloidosis is clinically suspected and serum free light chains are elevated, it is mandatory to obtain a tissue biopsy to confirm the presence of amyloid deposits. Most patients with light chain amyloidosis have widespread systemic involvement, and a subcutaneous fat pad aspirate or deep skin biopsy will show amyloid deposits in the majority of cases, thus avoiding the necessity for a car­ diac biopsy. If skin/fat biopsy is negative, it is reasonable to proceed to an endomyocardial biopsy. If amyloid heart disease is present, this will be positive in well over 90% of cases. In all cases, appropriate typing of the amyloid should be done to confirm the appropriate therapy. An algorithm with a suggested workup of suspected amyloidosis is shown in Fig. 270-8. ■ ■DIAGNOSIS AND TYPING OF CARDIAC AMYLOIDOSIS Laboratory evaluation in patients with cardiac amyloidosis is generally nonspecific but may give some support to a suspected diagnosis. Elec­ trolytes and complete blood count are usually normal or near normal. N-terminal prohormone of brain natriuretic peptide (NTproBNP) may be higher than anticipated for the degree of congestive heart failure, often in the range of 1000 to 2000 pg/mL even in the presence of relatively mild congestive heart failure. High-sensitivity troponin is frequently mildly elevated and may lead to a misdiagnosis of isch­ emic heart disease. In AL amyloidosis with renal involvement, heavy

PART 6 Disorders of the Cardiovascular System LV RV PE A FIGURE 270-5  Typical cardiac magnetic resonance imaging (MRI) in amyloidosis. A. A typical cardiac MRI appearance in amyloid cardiomyopathy. The left ventricular (LV) cavity is small with a mildly dilated right ventricular (RV) cavity and thick LV walls. B. The appearance of late gadolinium enhancement after injection of gadolinium in the same patient. Two typical appearances are seen: the distinction between myocardium (straight line) and LV cavity is poor, due to delayed nulling of the myocardium, a near pathognomonic feature of cardiac amyloidosis. There is also extensive, transmural delayed gadolinium myocardial uptake due to severe amyloid infiltration. Another aspect of cardiac amyloidosis quantifiable by MRI (not shown) is measurement of extracellular volume, which is markedly increased in cardiac amyloidosis and helps to differentiate amyloid infiltration from true LV hypertrophy. PE, pericardial effusion. (Image courtesy of Dr. Sarah A. M. Cuddy, Brigham and Women’s Hospital, Section of Cardiology.) proteinuria is often found, and this may cause hypoalbuminemia. Renal involvement is not a feature of transthyretin amyloidosis. Rarely, in AL amyloidosis with hepatic involvement, the alkaline phospha­ tase is significantly elevated. Although AL amyloidosis is a plasma cell disorder closely related to multiple myeloma, the sedimentation rate is usually normal or only minimally elevated, unlike the marked elevation that may be seen in myeloma. Hypogammaglobulinemia may be present in AL amyloidosis, but serum and urine protein elec­ trophoresis often do not reveal a monoclonal gammopathy, as the paraprotein level is low. Thus, in suspected AL amyloidosis, serum and urine immunofixation should be performed as these are more sensitive (although nonquantitative) than serum or urine protein electrophoresis. In almost all patients with AL amyloidosis, the level of circulating serum free light chains, either lambda or, less commonly, FIGURE 270-6  Technetium pyrophosphate (PYP) scan in a patient with wild-type transthyretin amyloidosis. The top three images are obtained in three separate views with single-photon emission computed tomography (CT) imaging alone, and the bottom three views with added cardiac CT imaging. Both modalities show marked myocardial uptake (orange) with absence of blood pool uptake (central clearing) and normal bone uptake. The lower images more precisely localize the uptake to the fused CT images of the heart, which in more equivocal cases helps to localize uptake to the myocardium and prevents misinterpretation as a positive scan due to blood pool uptake without myocardial uptake. PYP uptake is highly sensitive and specific for transthyretin amyloidosis but can occasional be present in AL amyloidosis; thus, exclusion of a plasma cell dyscrasia is mandatory when interpreting this imaging. In the normal heart and almost all other pathologies, there is no myocardial uptake of bone tracers such as PYP.

LV CAVITY LV WALL B kappa free light chains, is elevated. It is important to recognize that findings suggestive of a plasma cell dyscrasia in a patient with a cardio­ myopathy needs to be interpreted in the context of the clinical picture, as monoclonal gammopathy of unknown significance is common in the older population and may be unrelated to the cardiomyopathy. Unlike TTR cardiomyopathy, there is no definitive noninvasive test to diagnose AL amyloid cardiomyopathy, and thus a tissue biopsy is always needed. A subcutaneous fat pad aspirate or deep-skin needle aspiration biopsy has a high yield of positivity, but needs to be evalu­ ated by a skilled pathologist. A biopsy positive for AL amyloid from a noncardiac site in the presence of imaging consistent with amyloid cardiomyopathy is adequate to conclude that cardiac involvement is present. Immunohistochemistry, performed by many pathology labs, is fraught with diagnostic uncertainty and should be used with great

A B FIGURE 270-7  Technetium pyrophosphate (PYP) scan. A. A normal (negative) PYP scan. The planar images (top) show rib and sternal isotope uptake, but there is no uptake in the heart. Bottom panel shows single-photon emission computed tomography–computed tomography (SPECT-CT) fusion showing normal appearance of nonamyloid heart after PYP imaging (no isotope uptake). B. Positive PYP scan in a patient with cardiac transthyretin amyloidosis. There is intense cardiac uptake on the planar imaging (top) which is confirmed to be in the wall of the heart on feud SPECT-CT images (lower panel). (Courtesy of Dr. Sharmila Dorbala, Brigham and Women’s Hospital.) caution and always interpreted in the setting of the clinical picture. It is thus strongly recommended that typing of the amyloid ideally be done by mass spectrometry (available as a “send-out test” in the United States). Unless a diagnosis of AL amyloidosis is clear, sequencing of the TTR gene should be done to rule out familial transthyretin amyloidosis as this has obvious ramifications for the family.

CHAPTER 270 Amyloidosis and Other Restrictive Cardiomyopathies TREATMENT Cardiac Amyloidosis The treatment of systemic amyloidosis is addressed in detail in Chap. 117. Here, we will concentrate on specific issues related to

Suspicion for CA based on echocardiogram, CMR, or strongly suggestive clinical scenario PART 6 Disorders of the Cardiovascular System Assess for plasma cell dyscrasia by serum and urine PEP and IFE, and serum free light chains ABNORMAL* Assessment of other possible organ involvement (renal, hepatic, neurologic) Referral to hematology for full evaluation including bone marrow biopsy Fat pad or deep skin biopsy with staining for amyloid POSITIVE with positive typing for light chain amyloid*** NEGATIVE Proceed to cardiac or other affected organ biopsy AL (LIGHT CHAIN) AMYLOIDOSIS Genetic testing positive for variant TTR gene NEGATIVE FOR AMYLOID DEPOSITS AMYLOIDOSIS EXCLUDED FAMILIAL TTR AMYLOIDOSIS WILD-TYPE TTR AMYLOIDOSIS FIGURE 270-8  Diagnostic algorithm. Algorithm for the workup of suspected cardiac amyloidosis (CA). This is a suggested algorithm but, depending on initial degree of suspicion for amyloidosis type, may vary slightly in order. Asterisk footnotes are as follows: *Normal values in workup for a plasma cell dyscrasia are negative serum and urine protein electrophoresis and immunofixation, with normal values for free serum kappa and lambda light chains adjusted for renal function. Abnormalities may not always reflect light chain amyloidosis, as monoclonal gammopathy of unknown significance not uncommonly coexists with TTR amyloidosis and thus expert evaluation of all abnormalities is mandatory. **Patients with bone-imaging uptake present but less than rib uptake should be carefully evaluated to ensure that this is not just blood pool isotope uptake and, if not, should be considered as possible amyloidosis with further evaluation based on expert evaluation of likely cardiac amyloid. ***Typing for amyloidosis should ideally be performed by mass spectrometry, generally only available in specialized centers. Immunohistochemistry, while often used, may be misleading and should be interpreted cautiously within the context of the clinical features of the disease. CMR, cardiac magnetic resonance; CT computed tomography; DPD, technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid; HMDP, technetium-99m–hydroxymethylene diphosphonate; IFE, immunofixation electrophoresis; PYP, technetium-99m–pyrophosphate; PEP, protein electrophoresis; SPECT, single-photon emission computed tomography. the cardiac disease. It is important, when considering treatment of cardiac amyloidosis, not simply to focus on therapies aimed at slowing or stopping the production of the precursor protein but also to address the manifestations of the disease. Sodium restric­ tion is an integral part of management of heart failure in all forms of cardiac amyloidosis with congestive heart failure. The restrictive pathophysiology renders the patient particularly vulnerable to small changes in blood volume, and sodium restriction can significantly improve the response to diuretics. There are no specific clinical trials that evaluate the best way to treat congestive heart failure in cardiac amyloidosis, but it is generally recognized that diuretics are the mainstay of therapy. The combination of a loop diuretics such as furosemide or (preferably) torsemide with spironolactone or eplere­ none is usually well tolerated. Renal function should be monitored while adjusting diuretic dose, particularly in patients with ATTRw amyloidosis who tend to be older and to have more baseline renal impairment. The use of other drugs commonly used in congestive

NEGATIVE Technetium imaging PYP, DPD or HMDF with SPECT imaging and, ideally, cardiac CT Cardiac uptake equal or greater than ribs No cardiac uptake** AMYLOIDOSIS UNLIKELY AND WORKUP CAN STOP BUT if suspicion still high, proceed to cardiac biopsy to exclude rare forms of amyloidosis including rare variant TTR forms that have negative TTR imaging TTR AMYLOIDOSIS Genetic testing negative for variant TTR gene Biopsy positive Biopsy negative AMYLOIDOSIS EXCLUDED MASS SPECTROMETRY TO DETERMINE PRECISE AMYLOID PROTEIN heart failure is more controversial. In light chain amyloidosis, auto­ nomic function is often impaired even in the absence of postural hypotension, and the use of angiotensin-converting enzyme inhibi­ tors or angiotensin receptor blockers may be associated with pro­ found hypotension. Thus, they are generally avoided. Beta-blockade is also often problematic and associated with decreased exercise tolerance. If a patient is receiving beta blockers when initially seen, we routinely taper and stop their use and reassess the patient’s sense of well-being, which, not infrequently, improves. For patients with atrial fibrillation and a rapid ventricular response, beta-blockade may be needed but digoxin can also be used. However, restoration of sinus rhythm is preferable. The use of sodium-glucose cotrans­ porter 2 (SGLT2) inhibitors appears to be clinically well-tolerated. This class of drug has efficacy across the spectrum of patients with heart failure and preserved ejection fraction and those with heart failure and reduced ejection fraction and may be of value in cardiac amyloidosis.

Cardiac arrhythmias in both AL and TTR amyloidosis are com­ mon. Most frequently seen is atrial fibrillation or flutter, the onset of which is often associated with clinical deterioration. There is a high risk of thromboembolism in patients with cardiac amyloido­ sis, and anticoagulation in patients with atrial fibrillation or flutter is mandatory. There does not appear to be increased risk of major bleeding among patients taking anticoagulants in either light chain or transthyretin amyloidosis. Restoration of sinus rhythm should be considered in all patients, particularly since rate-controlling agents are poorly tolerated. Amiodarone appears to be the most effective antiarrhythmic drug for atrial arrhythmias and should ideally be given, starting with a loading dose, prior to elective elec­ trical cardioversion. If a patient is adequately anticoagulated before and during electrical cardioversion, there is no reason to perform transesophageal echocardiography prior to the procedure. If atrial arrhythmias are associated with clinical deterioration and sinus rhythm cannot be maintained despite antiarrhythmic therapy, con­ sideration should be given to an invasive electrophysiologic proce­ dure. Pulmonary venous isolation/atrial fibrillation ablation is often more complex than in nonamyloid patients, with a higher recur­ rence rate, and we therefore tend to limit ablation procedures to patients with atrial flutter and no evidence of atrial fibrillation. For those with symptomatic atrial fibrillation, atrioventricular nodal ablation with the implantation of a biventricular pacemaker is an effective way of both controlling and regularizing the ventricular rate. Sudden cardiac death may occur in cardiac amyloidosis, being more common in advanced AL amyloidosis, but a prophylactic implantable defibrillator is generally ineffective in preventing this. Thus, consideration of an implantable defibrillator should be highly selective and probably limited to patients with a prior resuscitated cardiac arrest or a history of sustained ventricular tachycardia. Patients with TTR amyloidosis are at a high risk for the develop­ ment of high-degree atrioventricular block. This is usually preceded on ECG by bifascicular block or left bundle branch block. Patients should be questioned about unexplained, nonpostural dizzy spells or syncope, and if these occur in the setting of one of these ECG abnormalities, strong consideration should be given to cardiac pac­ ing. If a pacemaker is to be placed, we would generally recommend biventricular pacing, as right ventricular pacing produces abnor­ malities of septal contraction that, in the presence of a small cavity ventricle, may decrease cardiac output. SPECIFIC THERAPY OF CARDIAC AMYLOIDOSIS:

AL AMYLOIDOSIS The most common regimen for treating patients with light chain amyloidosis includes daratumumab, bortezomib, cyclophospha­ mide, and dexamethasone. Dexamethasone may aggravate sodium retention, and it is critical that the cardiologist experienced in TABLE 270-2  Rare Forms of Amyloidosis FREQUENCY OF CARDIAC DISEASE AMYLOID TYPE PRECURSOR PROTEIN AA Serum amyloid A (an inflammatory protein) <5% Kidney, liver Usually associated with longstanding chronic inflammation. Uncommon in developed countries, and cardiac involvement rarely the predominant factor. AApoA1 Apolipoprotein 1 25–30% Kidney, liver, spleen, nervous system, larynx AapoA4 Apolipoprotein 4 65–70% Kidney Family history often not present. Renal involvement without proteinuria is common, and cardiac involvement is usually present but often relatively mild. Afib Fibrinogen A-alpha (gene mutation) Not described Kidney, spleen Rare. Proteinuria that progresses to renal failure. Typical renal biopsy with glomerular obliteration by amyloid. Typical amyloid cardiomyopathy absent. ALECT2 Leukocyte cell-derived chemotaxin 2 Not described Kidney Liver involvement common. ALECT2 predominantly found in Hispanics. Gelsolin Gelsolin Unknown prevalence. Usually mild, and manifesting as conduction disease

amyloidosis co-manages AL amyloidosis patients with cardiac involvement along with the treating hematologist. During therapy, an increased diuretic dose may be needed and/or a reduction in the dexamethasone dose. The other medications are generally well tolerated, but rarely, bortezomib may cause acute, reversible cardiac toxicity. Bortezomib may also cause a neuropathy and aggravate autonomic neuropathy of AL amyloidosis. High-dose melphalan chemotherapy with autologous stem cell transplantation is used in some patients with light chain amyloidosis and may be associated with considerable fluid retention or atrial arrhythmias in patients with cardiac involvement. For patients with AL cardiac amyloidosis, it is mandatory that the patient being considered for this therapy have a pretherapy cardiac evaluation to assess the risk-benefit ratio, along with regular posttransplant follow-up in the acute stage. Fol­ lowing successful chemotherapy (defined as a hematologic remis­ sion, with normalization of the serum free light chains), congestive heart failure often improves and is associated with an improvement in left ventricular longitudinal strain. However, some patients remain with very poor cardiac function. Such patients may benefit from cardiac transplantation, but this requires a very careful evalu­ ation at an expert center to determine the extent of extracardiac amyloidosis and its likely effect on posttransplant prognosis.

CHAPTER 270 Amyloidosis and Other Restrictive Cardiomyopathies SPECIFIC THERAPY OF CARDIAC AMYLOIDOSIS: TTR AMYLOIDOSIS Currently, the aim of treatment of TTR cardiac amyloidosis is focused on reducing or stopping any further amyloid deposition. Tafamidis, a small molecule that stabilizes the tetrameric structure of transthyretin, is effective at slowing disease progression and may halt progression among patients treated early in the clinical presentation of the disease. It is extremely well tolerated. A similar drug, acoramidis, has shown similar efficacy in a pivotal clinical trial. An alternative class of drugs, the TTR silencers, significantly reduce the production of transthyretin by the liver and are approved in the United States for the treatment of familial amyloid polyneu­ ropathy. At the time of writing, two drugs (both of which are only approved for amyloid neuropathy), eplontersen and vutrisiran, both administered subcutaneously, are completing clinical trials for the treatment of transthyretin amyloid cardiomyopathy. Rarer forms of cardiac amyloidosis are listed in Table 270-2. Their rarity relates to the very uncommon nature of the type of amyloid with which they are associated or, as in the example of AA amyloido­ sis, the uncommon nature of cardiac involvement despite extensive other involvement. The diagnosis of most of these forms of cardiac amyloidosis will be made on mass spectrometry of a tissue biopsy after cardiac amyloidosis is suspected but when there is no evidence of a plasma cell dyscrasia or abnormality on technetium imaging. OTHER ORGAN INVOLVEMENT COMMENT Rare condition, with family history in many cases. Cardiac disease, when present, may be predominantly right-sided with tricuspid valve involvement. Corneal lattice dystrophy Skin and neurologic features Predominantly found in Finnish patients.