“A classification serves to bridge the gap between ignorance and knowledge.” J. F. Goodwin
INTRODUCTION
Historically, restrictive cardiomyopathies were among the three primary forms of idiopathic heart muscle disease characterized by the World Health Organization as “restrictive filling and reduced diastolic volume of either or both ventricles with normal or near-normal systolic function.” This early grouping of cardiomyopathies highlighted the readily evident morphological and functional features of these disorders, which were largely of unknown cause. With advances in diagnostic testing (biochemistry, genetics, immunology, and pathology) and cardiac imaging techniques (echocardiography, computed tomography [CT], magnetic resonance imaging [MRI]), the etiology of many cardiomyopathies can now be identified. The most recent classification proposal of the American Heart Association (AHA) defines primary (involving predominantly the heart) and secondary (related to systemic disorders) cardiomyopathies. Using this new classification, except for primary restrictive cardiomyopathy, the entity of “restrictive cardiomyopathy” no longer exists, and most infiltrative and storage disorders are considered specific secondary cardiomyopathies (i.e., amyloid cardiomyopathy).
From the point of view of the clinician, however they are compiled, these are disorders in which diastolic dysfunction is at least initially the predominant pathophysiological derangement. They are rare diseases, generally with a poor prognosis and often presenting with advanced right- or left-sided heart failure. Much of the data regarding these diseases are based on observational retrospective studies from tertiary centers with little prospective and randomized information. Although a cardiologist will often initiate testing, a multidisciplinary team of geneticists, pathologists, radiologists, hematologists, and oncologists is often required to refine the diagnosis and determine management strategies. Since infiltrative and storage cardiomyopathies occur as part of a multisystem disorder, treatments with chemotherapeutic agents, stem cells, and enzyme replacement are increasingly becoming options.
This chapter will review primary restrictive cardiomyopathy and the most prevalent forms of infiltrative and storage disorders encountered among patients surviving into adulthood. A practical approach to diagnosis, differentiation, and exclusion of other, more common disorders with similar pathophysiology and structural appearance will be presented along with current treatment options.
PATHOPHYSIOLOGY
Most primary restrictive cardiomyopathies are characterized by at most mild degrees of increased wall thickness on gross inspection. Cardiac biopsy will distinguish whether at the cellular level there is myocyte hypertrophy (increased myocte diameter and nuclear area), endocardial and interstitial fibrosis (increased collagen to muscle ratio), or both ( Fig. 21-1 ). Exclusion of fiber disarray, inflammation, eosinophilia, lymphocytes, amyloid or iron deposits, and pericardial disease via light and electron microscopy is required to distinguish primary restrictive diseases. Absence of an endocardial fibrotic shell with extension into the myocardium excludes endomyocardial disease.
Structural characteristics of primary restrictive cardiomyopathies include (a) biatrial enlargement, (b) nondilated or reduced left ventricular (LV) cavity size, and (c) normal or mild wall thickness. The pathogenesis of diastolic impairment may be secondary to myocyte abnormalities, including abnormal calcium handling, accumulation of desmin (a cytoskeletal component), myocyte hypertrophy, and extracellular matrix interstitial fibrosis with proliferation of collagen fibers and elastic elements. A marked increase in stiffness of the myocardium or endocardium causes the ventricular pressure to rise dramatically with only small changes in volume, causing an upward shift of the LV pressure-volume relationship and a “dip and plateau” or “square root” hemodynamic pattern. Both ventricles are affected by the process, but usually the pressures are higher on the left than the right, which may reflect the relatively decreased compliance of the left ventricle compared with the right ventricle.
Secondary infiltrative and storage cardiomyopathies result from the presence of myocardial cellular or extracellular substances that impair diastolic function. In infiltrative diseases, there is localization to the interstitium (between myocardial cells), as with cardiac amyloidosis; whereas in storage disorders, the deposits are within cells, as with hemochromatosis and Fabry’s disease. The infiltrative and storage cardiomyopathies may have heterogeneous morphological and hemodynamic findings, depending on the specific underlying process and the stage of disease, which often involves LV dysfunction, increased wall thickness, and nonrestrictive diastolic filling patterns.
CLINICAL RELEVANCE
Primary Restrictive Cardiomyopathies
Case 1
A 23-year-old woman presents to her family physician complaining of fatigue, exercise intolerance, muscle aches, and dyspnea with exertion. No other past medical history (PMH) is present. Family history is significant for an aunt with hypertrophic cardiomyopathy (HCM). On examination, she is found to be tachycardic. The cardiac exam is notable for an elevated jugular venous pressure of 10 cm H 2 O, an S 3 gallop, and 1+ lower extremity pitting edema. An electrocardiogram (ECG) shows first-degree atrioventricular (AV) block with a P-R interval of 240 msec. A chest x-ray (CXR) shows mild pulmonary congestion. Brain natriuretic peptide (BNP) level is 750 pg/ml, and the creatine phosphokinase (CPK) level is 280 units/L. An echocardiogram shows normal LV and RV size and function, with moderately dilated atria, stage 3 diastolic dysfunction (restrictive filling pattern), E/E′ of 15, and a delayed color M-mode slope of 35 cm/sec. Cardiac MRI shows normal pericardial thickness and reduced tissue signal intensity. Subsequent cardiac catheterization is notable for pressures (mmHg) as follows: right atrial, 15; right ventricular end diastolic, 17; left ventricular end diastolic, 24; pulmonary artery systolic pressure, 55; pulmonary capillary wedge pressure, 25; and cardiac index, 2.3 L/min/m 2 . Cardiac biopsy confirms idiopathic restrictive cardiomyopathy and excludes specific infiltrative and storage diseases.
Diagnosis
Primary (or idiopathic) restrictive cardiomyopathy is a rare disorder of advanced diastolic impairment, often leading to biventricular diastolic heart failure and sudden cardiac death. It was first described by Benotti et al. in nine patients with heart failure, elevated RV and LV filling pressures, normal systolic function, and dip-and-plateau hemodynamic tracing. In children, the disease is more common in females, and the prognosis is worse compared with adults. Familial autosomal dominant transmission and the association with skeletal myopathies (predominantly distal) and heart block have been reported in several generations of families. Other associations include family members with HCM and Noonan’s syndrome. Genetic linkage analysis studies have shown mutations in cardiac troponin-I (TNNI3) and defects in genes coding for myocyte desmin accumulation in patients with restrictive cardiomyopathy.
The clinical signs and symptoms of primary restrictive cardiac disease relate closely to the degree of left atrial (LA) hypertension required to compensate for reduced ventricular filling. Initially, there is exercise intolerance and fatigue, progressing to dyspnea with minimal effort. Exertional chest pain is usually absent. Atrial fibrillation is common due to the atrial enlargement. Ventricular arrhythmias or heart block are commonly present in advanced cases and are often the causes of death. Symptoms of proximal or distal myopathy may be present. Cardiac examination may reveal pulmonary congestion, jugular venous distention with a prominent X and Y descent, an S 3 depending on the filling characteristics, hepatomegaly, ascites, peripheral edema, and anasarca in advanced cases. Kussmaul’s sign can be detected, while apical retraction (as in constrictive pericarditis) is not seen.
Laboratory testing may provide supportive information. BNP levels are elevated proportional to the level of filling pressures and stage of diastolic dysfunction. Elevated BNP levels also may aid in excluding constrictive physiology. CPK levels may be elevated with concomitant myopathy. No data are available on troponin levels in patients with idiopathic restrictive cardiomyopathy.
Echocardiography is often the first-line test and may be virtually diagnostic. Atrial enlargement with nondilated ventricles with near normal systolic function is uniformly present on echocardiography. Mild LV dysfunction may develop among patients with advanced disease requiring transplantation. Generally, if hypertrophy is present, it is mild. The pathophysiological findings of advanced diastolic dysfunction are evident with a comprehensive echocardiographic Doppler study (elevated filling pressures ± restrictive physiology). Restrictive physiology may not be present, depending on the stage of disease and loading conditions, but abnormal diastolic function should be evident by evaluation of mitral and tricuspid inflow patterns, pulmonary and hepatic venous flows, and isovolumic relaxation time (IVRT). Tissue Doppler echocardiography (TDE) E and A annular velocities are low, with mitral E/E annular ratios elevated consistent with high filling pressures. Concomitantly, the color M-mode propagation slope is slow. TDE and color M-mode, along with pulsed Doppler flow patterns with a respirometer, can help distinguish restrictive from constrictive physiology.
MRI and CT may be useful to exclude increased pericardial thickness, septal bounce, or conical compression. Cine MRI may show abnormal filling patterns in early and advanced stages of restrictive cardiomyopathy similar to echocardiography. MRI is capable of distinguishing tissue characteristics and shows a diffuse reduction in signal intensity due to fibrosis in idiopathic restrictive cardiomyopathy, with more specific patterns in other infiltrative processes like amyloidosis or hemochromatosis.
Cardiac catheterization is often used as a confirmatory test. Using strict criteria, either right- or left-sided filling pressures are elevated, with a typical dip-and-plateau RV and LV filling pattern and an “M”- or “W”-shaped venous filling pattern with prominent X and Y descents. LV diastolic pressures are greater than 5 mmHg more than RV filling pressures. Cardiac index is reduced, and pulmonary artery pressure is greater than 50 mmHg in most patients with a ratio of RV systolic to diastolic pressure greater than 1/3. Often RV endomyocardial biopsy is done at the same time as hemodynamic assessment and importantly excludes other specific etiologies.
Management
The prognosis of idiopathic restrictive cardiomyopathy depends most on the age of the patient and presenting hemodynamic factors. Although variable, the course is usually progressive and generally poor among the pediatric population, with survival rates of less than 50% over 2 years. A serial study of 18 children (9 male; mean age, 4.3 years) evaluated over a course of 31 years at Texas Children’s Hospital found that predictors of sudden death included female sex, chest pain, syncope, and ischemia on Holter monitor. The annual mortality rate was 7%, with sudden death occurring in 28% of patients. Predictors of poor outcome in the pediatric population include age, female sex, ischemic manifestations, decreased cardiac index, pulmonary venous congestion, and elevated pulmonary vascular resistance.
Beta blockers are the primary therapy to reduce the risk of sudden death. Additional medical therapy includes diuretics for symptomatic relief and consideration of antiplatelet agents or anticoagulation, due to the high risk of atrial fibrillation and embolism reported in some series. Vasodilators should be used cautiously unless LV dysfunction is present, since they may cause hypotension. Pacemakers are often required for heart block. Implantable cardioverter-defrillators are recommended for any patients with ischemic manifestations, along with listing for transplantation. Transplantation can substantially improve survival and is usually required within 4 years of diagnosis, optimally before pulmonary vascular resistance is irreversibly high. Heart-lung transplantation is an option for some children. When concomitant skeletal myopathy is present, the benefits of transplantation may be partial.
Idiopathic restrictive cardiomyopathy may also be diagnosed in adults after exclusion of secondary causes of restrictive physiology ( Fig. 21-2 ). A large series of 94 patients (mean age, 64 years) was identified from 1979 to 1996 at the Mayo Clinic, with typical structural and hemodynamic features of restrictive cardiomyopathy. At follow-up of 68 months, 50% of patients had died, primarily from cardiac causes, and 4 required heart transplantation. Using multivariate analysis, predictors of death included male sex, LA dimension greater than 60 mm, age older than 70 years, and advanced New York Heart Association class ( Fig. 21-3 ).
Infiltrative Cardiomyopathies
Using the most recent AHA classification, cardiac amyloidosis is the most important infiltrative cardiomyopathy in adults. Sarcoidosis has been recategorized as a secondary inflammatory disorder. The exceedingly rare infiltrative disorders—Gaucher’s, Hurler’s, and Hunter’s diseases—are familial defects in metabolism that involve multiple systems, including the heart, and will not be discussed in this chapter.
Cardiac Amyloidosis
Case 2
A 44-year-old man presents to a cardiologist for a second opinion regarding amyloid cardiomyopathy. He complains of dyspnea with exertion, orthopnea, orthostasis, abdominal distention, and lower extremity swelling and numbness. No other PMH is present. The man is African American. Family history is significant for his father and brother, who died in their forties with cardiomyopathy. On examination, he appears cachectic and has a supine blood pressure of 96/64 and upright 80/68 mmHg. The cardiac exam is notable for jugular venous distention to the jaw. There is S 3 gallop, reduced intensity heart sounds and a moderate apical regurgitant murmur. There is ascites and 3+ lower extremity pitting edema. An ECG shows low voltage in the limb leads and an intraventricular conduction delay. CXR shows a globular heart silhouette and mild pulmonary congestion. BNP level is 4000 pg/ml. An echocardiogram shows severe biventricular increased wall thickness with moderately impaired systolic function. The atria are dilated and the pulmonary artery pressure is 60 mmHg. There is moderate mitral regurgitation. There is stage 2 diastolic dysfunction (pseudonormal filling pattern), E/E′ of 18, with a delayed color M-mode slope of 40 cm/sec. There is a moderate-sized pericardial effusion. Serum and urine electro-phoresis with immunofixation and bone marrow biopsy shows no evidence of abnormal immunoglobulin. A laboratory analysis shows a mutation in transthyretin (TTR) protein, confirming the diagnosis of familial TTR amyloidosis.
Etiology and Classification
Cardiac amyloidosis is the prototype of infiltrative cardiomyopathies and the most frequently encountered in clinical practice. There are several types of cardiac amyloidoses, each with its own clinical presentations, treatment strategies, and prognosis ( Table 21-1 ). Amyloidosis is a multisystem disease in which linear, nonbranching, aggregated protein fibrils with a cross-β pleated configuration are deposited in various organs of the body, including the heart. Within the heart, the amyloid particles can infiltrate the myocardium (atria and ventricles), valves, pericardium, conduction system, and coronary arteries. The fibrils deposit between cells (interstitial), with a replacement of the normal tissue structures. When stained with Congo red, this material shows apple-green birefringence under a polarizing microscope. Alcian blue can also be used to diagnose amyloid.
| TYPE | PROTEIN | CARDIAC INVOLVEMENT | OTHER ORGAN INVOLVEMENT | ASSOCIATED DISORDERS | TREATMENT |
|---|---|---|---|---|---|
| AL (primary) | Immunoglobulin light chain (λ, κ) | Common | Liver, kidney, nervous system, gastrointestinal tract, skin | Plasma cell dyscrasias (e.g., multiple myelomas) | Chemotherapy; cardiac transplant if isolated cardiac |
| AA (secondary) | Nonimmunoglobulin, serum protein A | Rare | Kidney | Inflammatory diseases (e.g., rheumatoid arthritis, familial Mediterranean fever, tuberculosis) | Underlying disease |
| ATTR (familial) | Nonimmunoglobulin, transthyretin | Common | Nervous system | None | Liver transplant if no cardiac involvement |
| SSA (senile) | Nonimmunoglobulin, transthyretin | Common | None | Congestive heart failure | Supportive treatment for congestive heart failure |
| AANP (atrial) | Nonimmunoglobulin, atrial natriuretic peptide | Common | None | Atrial fibrillation | Supportive treatment for atrial fibrillation |
Amyloidosis can be classified by the type of protein deposited. The primary type is the most common form, occurring in 85% of patients with fibrils composed of kappa or lambda immunoglobulin light chains (AL type for amyloid light chain), often associated with a plasma cell dyscrasia such as multiple myeloma. There may be extracellular deposition of amyloid protein in the kidney, heart, liver, nerves, skin, and tongue, resulting in tissue damage and organ malfunction. The most common manifestations include nephrotic syndrome or renal failure, congestive heart failure, sensorimotor peripheral neuropathy, and orthostatic hypotension. Nearly half of patients have cardiac involvement, including congestive heart failure; however, the heart is involved in most all patients by pathological examination. Death from cardiac involvement secondary to congestive heart failure or arrhythmia occurs in greater than 50% of patients with systemic amyloidosis.
Familial amyloidosis results from the production of a mutant pre-albumin protein (i.e., TTR), and there are different types, which present with cardiomyopathy, neuropathy, or nephropathy. TTR is made up of 125 pairs of amino acids, and more than 100 mutations have been recognized. This type of amyloidosis is important to recognize because liver transplantation may be lifesaving, though optimally it should be performed before cardiac involvement has occurred. Laboratory testing should be performed to test for TTR if a family history is present or there is no evidence of AL type amyloid on biopsy. In familial amyloidosis, cardiac involvement occurs in 28% of patients at the time of diagnosis; however, it usually presents later in the course of the disease and is less ominous prognostically compared with AL (primary) amyloidosis. Peripheral neuropathy may be the presenting feature, but cardiac manifestations may subsequently predominate. The disease was reported over 30 years ago in a Danish family but has also been described in several other families of different ethnic origin and has an autosomal dominant expression. Cardiac failure or cardiac arrhythmia is responsible for the deaths in over 50% of patients. Familial amyloidosis has been reported in African Americans as a cause of heart failure secondary to a mutation in TTR isoleucine-122 (substitution for valine). This mutation has been found in nearly 4% of African Americans in the United States and in approximately one-quarter of elderly patients with cardiac amyloidosis.
Senile systemic amyloidosis (SSA) occurs in elderly men from the production of a wild-type TTR and has been associated with congestive heart failure without significant noncardiac involvement. Survival is reasonably good relative to AL amyloid or other etiologies of congestive heart failure. There may be extensive deposits in the heart producing congestive heart failure, or there may be minor deposits in the atria with no symptoms. The prevalence of senile amyloid at autopsy appears to be highest in African Americans. It is important to differentiate senile cardiac amyloidosis from immunoglobulin-derived amyloidosis (AL type) and familial amyloidosis because the treatment regimens differ. The favorable prognosis of SSA relative to AL is concordant with the accumulating evidence that light chains are responsible for toxicity and poor outcome in AL amyloidosis.
Secondary amyloidosis (AA type) is rare, with the fibrils consisting of protein A, a nonimmunoglobulin acute phase reactant resulting from a multitude of chronic inflammatory conditions (e.g., tuberculosis, familial Mediterranean fever, rheumatoid arthritis, inflammatory bowel disease). Cardiac involvement is unusual in secondary amyloidosis, with renal manifestations being predominant. Isolated atrial amyloidosis is often found limited to the atria at autopsy in the elderly and derives from atrial natriuretic peptide. It is more common in females and seems to be associated with the presence of atrial fibrillation.
Clinical Presentation
Cardiac amyloidosis may present with a spectrum of disease severity. In the nonfamilial forms, it generally affects males over age 30. In early cardiac amyloidosis, patients may be asymptomatic, while those with advanced disease will have the typical evidence of restrictive cardiomyopathy with severe right-heart failure, ascites, and peripheral edema. Left-heart failure is a less common manifestation. Additional symptoms include chest pain, presyncope/syncope, and sudden cardiac death. Chest pain resembling angina pectoris may be present despite normal epicardial coronary arteries due to partial obliteration of the distal coronary arteries by amyloid infiltration or intramyocardial vessels. Orthostatic hypotension occurs in 10%–15% of patients secondary to amyloid infiltration of the autonomic nervous system, with symptoms of syncope, diarrhea, lack of sweating, and impotence. Renal involvement with nephrotic syndrome and adrenal disease may aggravate postural hypotension. Syncope may be due to postural hypotension or supraventricular or ventricular arrhythmias. Other symptoms may be attributable to peripheral neuropathy, macroglossia, or carpal tunnel syndrome.
Physical examination may reveal signs of cardiac cachexia in advanced disease. Low cardiac output may cause decreased blood pressure, and orthostatic hypotension may still occur. Macroglossia, periorbital edema, petechia, and bruising may be evident on general examination. The cardiac exam may reveal an S 4 (very early disease) or S 3 (advanced disease) on auscultation from either the right or the left heart. Mitral and tricuspid valvular regurgitation may also be present, though usually not severe. There is often evidence of biventricular heart failure with predominant right-heart failure. The jugular venous pulse will be elevated with a prominent X and Y descent, and hepatomegaly, ascites, and peripheral edema will be present, especially in the advanced disease. Neurological examination may reveal findings consistent with peripheral neuropathy.
The cardiac silhouette on CXR is usually enlarged in patients with advanced disease with evidence of pulmonary congestion or pericardial effusion. The electrocardiogram typically has low voltage in the limb leads and shows a pseudoinfarction pattern with Q waves simulating a myocardial infarction in the precordial leads (∼50% of patients). More specifically, patients with cardiac amyloidosis have a low ratio of electrocardiographic voltage to LV wall thickness. However, the usefulness of this ratio is limited by the presence of coexisting diseases that may result in reduced voltage. Arrhythmias, especially atrial fibrillation, are common, and sick-sinus syndrome may be present. AV conduction defects may be present, especially in familial amyloidosis associated with myopathy, though right and left bundle branch block is uncommon. Ventricular arrhythmias are not as common as expected and are not often the cause of sudden cardiac death in nonfamilial forms.
Echocardiography
Two-dimensional and Doppler echocardiography are the procedures of choice for diagnosis, serial follow-up, and prognostic determination of patients with cardiac amyloidosis, which gives a distinctive appearance on two-dimensional echocardiography and is associated with abnormal LV and RV diastolic function. The findings of a normal or small LV cavity size with markedly thickened myocardium associated with a highly abnormal texture often described as “granular sparkling” in appearance is the classical presentation ( Fig. 21-4 ). Other disorders that cause increased LV wall thickness must be considered ( Fig. 21-5 ). The sparkling appearance is thought to be due to the acoustic mismatch between the highly reflective amyloid deposits in the endocardium, myocardium, and pericardium and the normal tissue. Moreover, autopsy and clinical biopsy series have demonstrated the presence of amyloid fibrils in the myocardium at the site of the sparkling echoes. However, the specificity of this finding is reduced with improved echocardiographic imaging techniques, including harmonic imaging. Global LV systolic function is usually preserved in early disease, whereas systolic function is usually impaired in advanced disease. The interatrial septum and valve leaflets are thickened. Both atria are enlarged, and small to moderate pericardial effusions are usually present.
Cardiac amyloidosis has traditionally been considered to require a restrictive pattern of ventricular filling. However, a spectrum of LV filling abnormalities using pulsed-wave Doppler echocardiography is detected in patients with cardiac amyloidosis. In a study of 53 patients with the classic echocardiographic features of cardiac amyloidosis, those with advanced disease demonstrated a mean LV wall thickness greater than 15 mm and a “restrictive” physiology pattern of LV filling. Furthermore, in serial studies of individual patients, the “impaired relaxation” pattern gradually evolved into a “restrictive” pattern through a “pseudonormal,” or intermediate, phase in the progression of the disease. The mechanism for this serial change in LV filling pattern is thought to be the gradual decrease in the compliance of the left ventricle with progressive deposition of amyloid fibrils in the myocardium, leading to loss of myocardial cells from pressure necrosis. When the duration of the pulmonary venous atrial reversal wave is longer than the mitral A-wave duration, filling pressures are elevated and the disease is advanced with restrictive physiology. Eventually the pulmonary atrial reversal wave may be lost due to atrial involvement of amyloid infiltration.
RV diastolic impairment also may occur in patients with cardiac amyloidosis. The RV filling pattern is often similar to that of the left ventricle or may be less advanced. In early cases, there is an RV free wall thickness of less than 7 mm and abnormal relaxation. In advanced cases, the RV wall is greater than 7 mm in thickness, with restrictive physiology present. The systolic forward flows by Doppler echocardiography in the superior vena cava and hepatic vein are also decreased with advanced disease, and the diastolic flow is increased compatible with restrictive physiology.
Newer diagnostic techniques, including TDE, strain and strain rate, and two-dimensional strain imaging, have been utilized to characterize early systolic dysfunction in patients with cardiac amyloidosis before the onset of congestive symptoms or reduced LV ejection fraction. Using these methods, it has been shown that there are differences between the longitudinal basal peak systolic strain rate and strain among amyloid patients with no cardiac involvement, cardiac involvement and no symptoms, and cardiac involvement with symptoms ( Figs. 21-6 and 21-7 ). This finding allows for detection of patients with early amyloid heart disease to be targeted for therapy.
Other Diagnostic Tools
Cardiac amyloidosis can be diagnosed noninvasively antemortem in most cases from the typical features obtained from the history, examination, ECG, and echocardiogram. However, confirmatory testing is needed before treatment is initiated, and further classification of the subtype of amyloid is necessary. Serum and urine protein immunofixation and electrophoresis are recommended to assess for the secretion of a monoclonal protein associated with a plasma cell dyscrasia. Although some patients with AL amyloid will have multiple myeloma, a greater proportion may have unassociated monoclonal gammopathies of uncertain significance. In 10% of cases, there is no monoclonal protein secreted (nonsecretory primary amyloidosis). Laboratory testing of antisera against TTR, the kappa and lambda light chains, and protein A in biopsy or blood samples can be performed. A serum free–light chain assay is available to assess the ratio of kappa-to-lambda free light chains and may be more sensitive than immunofixation. A positive serum immunofixation plus an abnormal kappa/lambda ratio are highly sensitive to diagnose AL amyloidosis.
Noncardiac sites of biopsy can include the bone marrow, fat pad, rectum, gingiva, kidney, and liver, though fat aspirate may detect amyloidosis in most patients (>70%). If the echocardiogram is not diagnostic or the fat pad aspirate is negative and cardiac amyloidosis is still suspected, an endomyocardial biopsy can be performed to make the diagnosis. A confirmatory cardiac biopsy may be particularly important if there are other confounding causes of increased LV mass, such as LV hypertrophy (LVH) or HCM. The presence of low electrocardiographic voltage favors a diagnosis of amyloidosis rather than hypertensive or hypertrophic cardiomyopathy; however, endomyocardial biopsy may be necessary in some cases to give a definitive diagnosis because of the grim prognostic implications of a diagnosis of cardiac amyloidosis. Although systolic anterior motion (SAM) of the mitral valve on echocardiogram is thought to be pathopneumonic of hypertrophic cardiomyopathy, it has also been recognized in a series of patients with cardiac amyloidosis.
MRI can be used to identify the increased myocardial thickness and small LV cavity in cardiac amyloidosis. It can be used to demonstrate the lack of increased pericardial thickening with the ancillary findings of biatrial enlargement and inferior vena cava dilatation, similar to echocardiography. Myocardial wall thickening due to hypertrophy or amyloid infiltration may be distinguishable. A pattern of global and subendocardial late gadolinium enhancement and specific features of T-1 blood pool kinetics are seen in patients with suspected amyloidosis. Subendocardial late enhancement involves the right and left ventricles, including the septum, causing the so-called zebra appearance of the septum ( Fig. 21-8 ). This subendocardial late enhancement matches the deposition of amyloid seen histologically. The sensitivity of this finding in a series of 30 patients with echocardiographic features of amyloid was 69%.
Nuclear medicine techniques have been used to diagnose cardiac amyloidosis, including technetium-99m pyrophosphate scintigraphy and imaging of indium-labeled antimyosin anti-bodies, though the reported sensitivities of these techniques are low. However, a recent small study with technetium-99m dicarboxypropane diphosphonate (DPD) was 100% specific for differentiating TTR amyloid from AL type. Figure 21-9 shows the diagnostic evaluation of suspected amyloidosis.
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