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Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis

Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis
Author:
Marianna Fontana, MD
Section Editor:
Donna Mancini, MD
Deputy Editor:
Todd F Dardas, MD, MS
Literature review current through: Aug 2023.
This topic last updated: Aug 16, 2022.

INTRODUCTION — Cardiac amyloidosis is a disorder caused by amyloid fibril deposition in the extracellular space of the heart. It can present with cardiac signs or symptoms or may be diagnosed as the result of screening in patients who manifest extracardiac signs of amyloidosis. The approach to diagnosis depends upon the clinical presentation and the results of initial testing.

This topic will review the epidemiology, clinical manifestations, and diagnosis of cardiac amyloidosis. The treatment of cardiac amyloidosis and an overview of amyloidosis are discussed separately. (See "Cardiac amyloidosis: Treatment and prognosis" and "Overview of amyloidosis".)

TYPES OF AMYLOIDOSIS — The clinical syndrome associated with cardiac amyloid infiltration in the heart is referred to as "cardiac amyloidosis" [1]. Two of the most common types of cardiac amyloidosis are transthyretin amyloidosis (ATTR amyloidosis) and light chain amyloidosis (AL amyloidosis), which are named after the precursor protein of the amyloid deposit:

Transthyretin amyloidosis (ATTR amyloidosis) – Transthyretin amyloidosis results from the misfolding and deposition of transthyretin (TTR, formerly known as prealbumin), a tetrameric protein synthesized by the liver that normally functions to transport thyroid hormone and retinol (vitamin A). ATTR amyloidosis can be further divided into two subtypes:

Wild-type amyloidosis (wtATTR amyloidosis) – Wild-type transthyretin amyloidosis (previously known as senile systemic amyloidosis) is caused by the deposition of misfolded wild-type (normal) transthyretin. The mechanism by which normal transthyretin causes pathogenic deposits is unclear.

Hereditary amyloidosis (hATTR amyloidosis) – Hereditary transthyretin amyloidosis is caused by gene mutations in the transthyretin gene (TTR) that predispose the tetrameric structure of transthyretin to instability, misfolding, and deposition. The typical transmission of hATTR is autosomal dominant inheritance with variable penetrance, and there are more than 120 known mutations of TTR associated with hATTR amyloidosis [2]. (See 'Epidemiology' below.)

Light chain amyloidosis (AL amyloidosis) – Light chain amyloidosis (AL amyloidosis; also known as primary systemic amyloidosis) results from deposition of misfolded immunoglobulin light chains from a plasma cell dyscrasia. (See "Overview of amyloidosis", section on 'AL amyloidosis'.)

Other types of amyloid – Rare causes of cardiac amyloidosis include serum amyloid A amyloidosis (AA), hereditary apolipoprotein A-1 (AApoA-1), and apolipoprotein A-4 (AApoA-4) amyloidosis (table 1). (See "Overview of amyloidosis", section on 'AA amyloidosis'.)

EPIDEMIOLOGY — Cardiac amyloidosis is a rare form of cardiomyopathy. Approximately 95 percent of cases of cardiac amyloidosis are caused by the deposition of transthyretin (TTR) or immunoglobulin light chains [3-5]. The epidemiology of common causes of cardiac amyloidosis is described below:

Wild-type transthyretin amyloidosis – The overall prevalence of cardiac ATTR amyloidosis is unknown. However, studies in which patients were systematically screened for cardiac wild-type transthyretin amyloidosis (wtATTR amyloidosis) suggest that it is relatively common in populations of older adult patients with heart failure with preserved ejection fraction (HFpEF) and severe aortic stenosis. As examples:

In a study of patients >60 years of age with HFpEF who underwent screening for cardiac ATTR amyloidosis, the prevalence of cardiac ATTR amyloidosis was relatively high (6 percent) and higher than in patients who did not undergo dedicated amyloid screening (1 percent) [6]. This study suggests that cardiac ATTR amyloidosis may be underdiagnosed in patients with HFpEF.

In another study of 120 patients with HFpEF (age >60 years old) who were admitted to a hospital with HF and screened for amyloidosis with bone scintigraphy, genetic testing, and cardiac biopsy, the prevalence of cardiac wtATTR amyloidosis was 13 percent [7]. No cases of cardiac hATTR amyloidosis were detected.

In a cohort of 151 patients with aortic stenosis who underwent transcatheter aortic valve implantation, screening with bone scintigraphy identified cardiac wtATTR amyloidosis in 16 percent [8].

Hereditary transthyretin amyloidosis – The prevalence of hereditary transthyretin amyloidosis (hATTR amyloidosis) is unknown. There are over 120 pathogenic gene variants known to be associated with cardiac hATTR amyloidosis. Some of these variants are more prevalent in specific geographic regions or ethnic groups, while others are more widely distributed [9-18]. Across populations, some of the most common variants are Val122Ile, Val30Met, Thr60Ala, Glu89Gln, Leu111Met, Ile68Leu, and Ser77Tyr [19,20].

Light chain amyloidosis – Cardiac light chain amyloidosis (AL amyloidosis) is a rare condition associated with plasma cell dyscrasias that has an annual incidence of approximately 1 per 100,000 people in the United States [9].

CLINICAL MANIFESTATIONS — The clinical manifestations of amyloidosis are diverse, depending on the pattern of organ involvement. The variable clinical phenotype and generally nonspecific clinical features makes diagnosis difficult and contributes to diagnostic delays.

Age of onset and disease distribution — The usual age of onset of symptoms and disease distribution varies among the various types of amyloidosis [9].

Patients with light chain cardiac amyloidosis (AL amyloidosis) typically present at age ≥40 years. Systemic AL amyloidosis is a multisystem disorder which commonly affects the liver, kidneys, spleen, the autonomic and peripheral nervous systems, lungs, and heart. Cardiac amyloid infiltration is present in most patients with AL amyloidosis (50 to 70 percent) and it is the main determinant of prognosis [21,22]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Clinical presentation'.)

Patients with transthyretin cardiac amyloidosis (ATTR amyloidosis) typically present at age ≥60 years, and most commonly >70 years. Various transthyretin mutations are associated with differing ages of onset (ranging from 30 to 70 years) and differing risks of cardiomyopathy. Cardiac amyloidosis is the dominant feature of wild-type ATTR amyloidosis (ATTRwt amyloidosis) and for some ATTR variants (eg, Val122Ile, Thr60Ala, Ile58Leu, and Leu111Met) [9,16-18].

Cardiac involvement — Cardiac amyloidosis typically presents with symptoms and signs such as dyspnea, lower extremity edema, elevated jugular venous pressure, hepatic congestion, and ascites, which are caused by restrictive cardiomyopathy with predominantly right ventricular failure; symptoms and signs of low cardiac output (eg, diminished pulse pressure and diminished capillary refill) are features of advanced disease. Angina is uncommon, although microvascular dysfunction is a frequent finding. Amyloidogenic light chains may be toxic to myocardial cells as suggested by in vitro studies [23,24] as well as clinical observation of worse symptoms in patients with AL amyloidosis compared with patients with ATTR amyloidosis with similar degrees of cardiac involvement.

Patients with cardiac amyloidosis also frequently present with syncope or presyncope [25]. Syncope is frequently caused by bradyarrhythmias or advanced atrioventricular block and is infrequently caused by ventricular arrhythmia. Patients with ATTR amyloidosis (wild-type or hereditary) often develop progressive conduction system disease and pacemaker implantation is often required. In contrast, patients with AL amyloidosis infrequently develop high-degree atrioventricular block or symptomatic sinus node dysfunction [26]. Other conditions may contribute to the risk of syncope in patients with amyloid cardiomyopathy including postural or exertional hypotension caused by excessive diuresis or autonomic neuropathy.

Patients with amyloid cardiomyopathy, particularly those with AL amyloidosis or atrial fibrillation, are at risk for cardiac thromboembolism. Amyloid deposits in atrial as well as ventricular walls and thus causes atrial dysfunction including atrial electromechanical dissociation during sinus rhythm with associated risk of atrial thrombus formation [27-29].

Patients who develop wtATTR amyloidosis and aortic stenosis have similar demographic features, and some patients have both cardiac wtATTR amyloidosis and aortic stenosis [8,23-25]. Cardiac ATTR amyloidosis has been identified in a substantial minority of patients with severe aortic stenosis undergoing surgical valve replacement (6 to 12 percent [30,31]) or transcatheter aortic valve implantation (TAVI; 16 percent [32]). It has been postulated that ATTR amyloidosis with associated restrictive cardiomyopathy may be a contributing cause of low-flow, low-gradient aortic stenosis [8]. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis".)

Extracardiac involvement — Extracardiac involvement varies among the types of amyloidosis.

Al amyloidosis — The clinical manifestations of AL amyloidosis include nonspecific symptoms (fatigue, poor appetite, early satiety, and weight loss) as well as more specific symptoms and signs of the following disorders: kidney disease (including asymptomatic proteinuria and nephrotic syndrome), peripheral neuropathy, carpal tunnel syndrome, gastrointestinal involvement (including hepatomegaly and gastrointestinal bleeding), macroglossia (which is nearly pathognomonic), purpura (including periorbital purpura, which is nearly pathognomonic), and bleeding diathesis. These clinical manifestations are discussed in detail separately. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Clinical presentation'.)

ATTR amyloidosis — Patients with ATTR amyloidosis (wild-type or hereditary) can develop autonomic or peripheral nerve disease. Wild-type TTR amyloid deposits are found in about one-third of older adults undergoing carpal tunnel decompression [26]. Spinal stenosis and biceps tendon rupture are also relatively common in patients with wtATTR amyloidosis.

Initial tests

Initial laboratory tests — Laboratory test abnormalities in patients with cardiac amyloidosis include proteinuria which may or may not be accompanied by elevations of serum BUN and creatinine in patients with kidney disease and liver biochemical abnormalities (eg, elevation in serum bilirubin) in patients with congestive hepatopathy. (See "Renal amyloidosis" and "Congestive hepatopathy", section on 'Laboratory testing'.)

Natriuretic peptides and troponin T and I levels are commonly elevated in patients with cardiac amyloidosis [27,28]. (See "Cardiac amyloidosis: Treatment and prognosis".)

Electrocardiogram — A hallmark of cardiac amyloidosis is discordance between increased left ventricular (LV) wall thickness (identified by cardiac imaging such as echocardiography) and QRS voltage, which is often reduced. However, this feature of cardiac amyloidosis has low sensitivity and the prevalence of low voltage varies markedly with etiology, with higher frequency in patients with AL amyloidosis (60 percent) than in patients with ATTR amyloidosis (20 percent) [29,33]. Thus, the absence of low QRS voltage does not exclude cardiac amyloidosis, particularly in patients with wtATTR amyloidosis.

Among patients with wtATTR amyloidosis, 30 percent have voltage criteria for LV hypertrophy (LVH) or left bundle branch block, and 70 percent have pseudo-infarction patterns; conduction abnormalities affecting the sinus node and His-Purkinje systems are also common [34]. Thus, the presence of atrioventricular (AV) block in an older patient with LVH should prompt consideration of cardiac amyloidosis. (See 'Cardiac involvement' above.)

Atrial fibrillation is common in patients with cardiac amyloidosis (15 percent in one series), with highest prevalence in patients with wtATTR amyloidosis (40 percent) and lower prevalence with hATTR amyloidosis (11 percent) and AL amyloidosis (9 percent) [30].

DIAGNOSIS

When to suspect cardiac amyloidosis — The following are clinical settings in which cardiac amyloidosis should be suspected:

Patients with unexplained LV hypertrophy (LVH; with or without HF).

Patients with HF and unexplained LVH – Echocardiography is the first-line cardiac imaging test for patients presenting with HF and may identify LVH (as well as other abnormalities), which should raise suspicion of cardiac amyloidosis. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Echocardiography' and "Determining the etiology and severity of heart failure or cardiomyopathy", section on 'Echocardiography'.)

Patients with presyncope, syncope, angina, or no cardiac symptoms with unexplained LVH – Echocardiography is commonly performed in patients with presyncope and syncope, as well as for other indications such as suspected valve disease, and may identify LVH.

Patients with aortic stenosis with features associated with cardiac amyloidosis, such as presence of low-flow, low-gradient aortic stenosis and/or echocardiographic detection of impaired longitudinal strain (eg, mitral annular S' ≤6 cm/s) [8,31]. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis", section on 'Additional evaluation based upon type of low gradient AS'.)

Patients with HF and symptoms or signs commonly seen in AL and/or ATTR amyloidosis. For example, a history of bilateral carpel tunnel syndrome prior to development of unexplained symptoms of HF in an older adult should prompt evaluation for possible cardiac ATTR amyloidosis.

Patients with a condition highly associated with cardiac amyloidosis (eg, systemic AL amyloidosis, ATTR-related peripheral neuropathy or ATTR mutation carrier state).

How to diagnose cardiac amyloidosis — We recommend the following approach to diagnosis of cardiac amyloidosis.

The initial diagnostic evaluation of the patient with suspected cardiac amyloidosis includes a clinical examination to identify and assess cardiac and extracardiac symptoms and signs, laboratory tests, and an electrocardiogram, as described above. (See 'Clinical manifestations' above.)

An echocardiogram is the initial cardiac imaging test for patients with suspected cardiac amyloidosis. While nearly all echocardiographic findings are non-specific, some findings are highly suggestive of cardiac amyloidosis in the appropriate clinical setting (particularly the finding of relative apical sparing of longitudinal strain) [23]. (See 'Echocardiography' below.)

Further evaluation with imaging is based upon the patient's clinical presentation (reason for suspecting cardiac amyloidosis) (figure 1):

For patients with unexplained LVH, aortic stenosis with features associated with cardiac amyloidosis, or HF with symptoms or signs typical of amyloidosis (consistent with AL amyloidosis or with both ATTR and AL amyloidosis), we recommend cardiovascular magnetic resonance (CMR) imaging. (See 'Cardiovascular magnetic resonance' below.)

If CMR findings are consistent with cardiac amyloidosis, all three tests for evidence of monoclonal protein are performed (serum kappa/lambda free light chain ratio analysis, serum protein immunofixation, and urine protein immunofixation) (see "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Evidence of monoclonal plasma cells' and "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Diagnosis'):

-If monoclonal protein is identified by one or more of these tests, referral to a hematologist is recommended for evaluation and further assessment. Bone marrow biopsy is generally performed. Additional tissue biopsy may be required such as fat pad aspirate or biopsy of other tissues. Noncardiac biopsy with amyloid of AL type and a CMR consistent with cardiac amyloidosis is sufficient in the majority of cases for the diagnosis of cardiac AL amyloidosis. Tissue specimens are examined to determine the type of amyloid. While the presence of monoclonal protein is suggestive of AL amyloidosis, other causes include ATTR with a monoclonal gammopathy of undetermined significance (MGUS), or other type of amyloidosis (eg, AApoA-1 or AA) with MGUS [24,25]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Tissue biopsy' and "Diagnosis of monoclonal gammopathy of undetermined significance".)

-If monoclonal protein is not identified by any of these three tests, management is based upon the results of bone tracer cardiac scintigraphy performed with 99mtechnetium pyrophosphate (99mTc-pyrophosphate [PYP]), 99mTc 3,3-diphosphono-1,2-propanodicarboxylic acid [DPD], or 99mTc-hydroxymethylene diphosphonate [HMDP] to identify the presence and extent of cardiac uptake:

Grade 0 scintigraphy in this setting suggests the CMR images should be reviewed. If the CMR images are highly suggestive of cardiac amyloidosis or if the clinical suspicion remains high, an endomyocardial biopsy may be helpful to exclude cardiac AL amyloidosis, cardiac ATTR amyloidosis caused by rare TTR gene variants, and rare forms of cardiac amyloidosis such as AApoA-1, AApoA-4 amyloidosis, and AA amyloidosis. Other nonamyloid diagnoses should also be considered. (See 'Differential diagnosis' below.)

Grade 1 scintigraphy is seen with various types of cardiac amyloidosis. Further evaluation includes peripheral or endomyocardial biopsy for confirmation and typing. Possible diagnoses include early ATTR cardiac amyloidosis (hereditary or wild-type) or AL cardiac amyloidosis, or less commonly, other types of amyloidosis (eg, AApoA-1 and AApoA-4).

Grade 2 or 3 scintigraphy, coupled with lack of evidence of a plasma cell dyscrasia, is highly specific for ATTR cardiac disease, so tissue biopsy is not required [32]. In patients diagnosed with cardiac ATTR amyloidosis, genetic testing is performed to distinguish hATTR from wtATTR amyloidosis.

If CMR findings are not consistent with cardiac amyloidosis, cardiac amyloidosis is unlikely and other causes of LVH should be considered. (See 'Differential diagnosis' below.)

For patients with systemic AL amyloidosis or HF with symptoms or signs typical for AL (but not ATTR) amyloidosis, we recommend CMR. (See 'Cardiovascular magnetic resonance' below.)

If CMR findings suggest cardiac amyloidosis and confirmed systemic AL amyloidosis is present, the diagnosis of cardiac amyloidosis is confirmed, as studies have shown high specificity and sensitivity in this clinical setting [35-39]. Bone scintigraphy is not very useful in patients with systemic AL amyloidosis as it is negative in approximately 60 percent of patients with cardiac AL amyloidosis, with the remainder showing only grade 1 uptake (grade 2 and 3 cardiac uptake is a rare occurrence) [34].

If CMR findings suggest cardiac amyloidosis and AL amyloidosis is suspected, evaluation includes testing for monoclonal protein (by performing serum protein immunofixation, urine protein immunofixation, and serum free light chain ratio analysis); if one or more of these tests is positive, tissue biopsy (including bone marrow) is indicated. While the presence of monoclonal protein is suggestive of AL amyloidosis, tissue biopsy is important because other possible causes include ATTR with a monoclonal gammopathy of undetermined significance (MGUS), or other type of amyloidosis (eg, AApoA-1, AApoA-4, or AA) with MGUS. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

If CMR findings are not consistent with cardiac amyloidosis, the diagnosis is unlikely. If LVH or HF is present, other causes should be considered. (See 'Differential diagnosis' below.)

For patients with ATTR-associated polyneuropathy, ATTR mutation carrier state, or HF with symptoms and signs typical for ATTR (but not AL) amyloidosis, we suggest either bone scintigraphy or CMR as the next step to evaluate for cardiac infiltration with evaluation similar to that described above for unexplained LVH. Further is needed as there are limited data to guide the choice of tests in this setting.

Diagnostic tests

Echocardiography — Echocardiography is the initial imaging test of choice for diagnosis of cardiac amyloidosis.

Relative apical sparing of longitudinal strain is a key feature — Reduction in global longitudinal strain (a measure of systolic function) is one of the earliest markers of cardiac amyloidosis and presents with a characteristic pattern of relative apical sparing of longitudinal strain (ie, the ratio of apical longitudinal strain/average of mid and basal longitudinal strain >1.0) [40]. This pattern of longitudinal strain alteration has high sensitivity (93 percent) and specificity (82 percent) for cardiac amyloidosis with proven utility in differentiating cardiac amyloidosis from other hypertrophic phenocopies [40,41].

General features — Infiltration of the ventricular walls produces an appearance of hypertrophy (commonly biventricular) with nondilated or small ventricles; a dilated phenotype is rare. Common findings include thickening of the valves and the interatrial septum. The atria are almost invariably dilated. There are some structural and functional differences between AL and ATTR amyloidosis (including greater increase in LV and right ventricular [RV] mass and more systolic dysfunction with ATTR than AL amyloidosis) but there is significant overlap between these types [40]. LVH is typically symmetric in AL amyloidosis but asymmetric with predominantly septal hypertrophy in ATTR amyloidosis; in ATTR amyloidosis, asymmetric septal hypertrophy is associated with a sigmoid septum (in 70 percent of cases) or reverse septal curvature (in 30 percent) [41]. LV outflow obstruction is rare [23].

While echocardiographic findings of unexplained LVH raise suspicion of cardiac amyloidosis, identification of LVH is not required to proceed with CMR in patients with AL amyloidosis, ATTR-related peripheral neuropathy, or ATTR mutation carrier state. In patients with cardiac amyloidosis, CMR abnormalities may be identified prior to the development of LVH [41].

Cardiac amyloidosis is one of the conditions in the differential diagnosis for HF with preserved systolic function. This terminology does not fully characterize the functional phenotype for cardiac amyloidosis, which typically involves diastolic as well as systolic impairment although the LV ejection fraction (LVEF) is typically normal until end-stage, in which it is typically is only mildly reduced [42]. Stroke volume index (stroke volume divided by body surface area) is a better marker of systolic function in this clinical setting, and is invariably reduced, even at very early stages of infiltration [42]. Reduction in peak systolic wall motion velocities, disproportionally affecting the longitudinal rather than the radial axes, are also an early disease marker.

Diastolic dysfunction is almost invariably affected with early impaired relaxation, which then invariably progresses to typical restrictive physiology [42]. Similar changes are present in the structure and systolic and diastolic function of the RV. (See "Tests to evaluate left ventricular systolic function" and "Echocardiographic evaluation of left ventricular diastolic function in adults" and "Echocardiographic assessment of the right heart".)

The pulmonary artery systolic pressure, as estimated from the peak velocity of the tricuspid valve regurgitant jet, may indicate moderate pulmonary hypertension (estimated pulmonary artery pressure of 40 to 50 mmHg). This is almost invariably secondary to the markedly elevated LV diastolic pressure and does not indicate primary pulmonary hypertension or cor pulmonale.

Pericardial and pleural effusions are common findings, especially in AL amyloidosis.

Cardiovascular magnetic resonance — CMR is a key test in the diagnosis of cardiac amyloidosis and is generally performed with contrast [43]. CMR provides a detailed assessment of cardiac structure (including identification and quantification of LVH) and function as well as unique information on the characteristics of the myocardial tissue. CMR can detect early cardiac amyloidosis before the development of LVH. However, CMR cannot distinguish cardiac AL from ATTR amyloidosis [44,45].

Cardiac amyloidosis has a highly characteristic appearance on CMR imaging performed with late gadolinium enhancement (LGE): Initially, there may be diffuse subendocardial LGE, while later in the course of disease, there is a transmural myocardial LGE pattern [35]. The three progressive LGE patterns identified in cardiac amyloidosis (none, subendocardial, and transmural) correlate with the degree of myocardial infiltration [46]. In a systematic review of studies comparing LGE with endomyocardial biopsy and/or echocardiography and other clinical features, the pooled sensitivity of LGE for cardiac amyloidosis was 85 percent (95% CI 77-91 percent) and the pooled specificity was 92 percent (95% CI 83-97 percent) [47]. Limitations of LGE include lack of quantitative results (which limits the ability to track changes over time) and limited applicability since gadolinium-based contrast agents are relatively contraindicated in patients with a severe reduction in renal function (which is relatively common in patients with AL amyloidosis). (See "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging" and "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

T1 mapping can overcome some of the limitations of LGE but center-specific reference ranges are required for early disease detection [48]. T1 mapping provides quantitative measures of myocardial T1 relaxation time (precontrast [native] or postcontrast). Native myocardial T1 increases with cardiac amyloid infiltration and correlated with markers of systolic and diastolic dysfunction [49]. Native myocardial T1 elevation is an early disease marker with high diagnostic accuracy for cardiac amyloidosis when the pretest probability is high [50]. In a study of 868 patients with suspected cardiac amyloidosis (222 with cardiac AL amyloidosis, 214 patients with cardiac ATTR amyloidosis, and 427 with no cardiac involvement), T1 mapping diagnosed cardiac amyloidosis with a sensitivity of 85 percent and specificity of 87 percent [51]. T1 mapping may be particularly helpful in patients with severely impaired kidney function, in whom gadolinium contrast is contraindicated (see "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging", section on 'Approach to preventing nephrogenic systemic fibrosis'). However, native T1 is a composite myocardial signal from both interstitium and myocytes that does not distinguish among the underlying processes (fibrosis, edema, amyloid, myocyte volume) and while the T1 elevation is marked with advanced disease, the lower elevations in early disease can be accurately identified only by referencing the center-specific normal range.

Extracellular volume (ECV) fraction measurement using intravenous gadolinium-based contrast agent is an ancillary method for identification and assessment of cardiac amyloidosis that helps to quantify the amount of cardiac amyloid. ECV elevation may be detected early before the development of LV hypertrophy, LGE or elevation in serum biomarkers [52]. ECV elevation correlates with markers of disease activity, including cardiac function, serum biomarkers, patient functional performance [53], and prognosis [41,54]. Native T2 mapping is another technique that may be helpful; T2 elevations demonstrate that edema is part of cardiac amyloidosis (particularly AL) and is linked to prognosis [55].

Bone tracer cardiac scintigraphy — Bone tracer cardiac scintigraphy (using 99m technetium [Tc]-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid [DPD], 99mTc-labeled pyrophosphate [PYP], or 99mTc-labeled hydroxymethylene diphosphonate [HMDP]) is a pivotal test for identifying ATTR amyloidosis (figure 2). The diagnostic utility of 99mTc-PYP imaging for ATTR cardiac amyloidosis was demonstrated using the Perugini staging system based on simple visual scoring of the three-hour planar image: grade 0 being negative (no cardiac uptake) and grades 1 to 3 defined as detection of progressively greater cardiac uptake and decrease in the bone uptake [56]. A subsequent multicenter study showed that ATTR cardiac amyloidosis is particularly avid for bone tracers (the mechanism is not understood); in contrast, in cardiac AL amyloidosis, there is either absent or only grade 1 uptake (grade 1 being present in approximately 40 percent of patients) [32]. As illustrated by a systematic review, the presence of grade 1, 2, or 3 scintigraphy had high sensitivity (pooled value of 82 percent) and specificity (98.8 percent) for cardiac amyloidosis as compared with tissue biopsy in studies evaluating the diagnostic performance of scintigraphy for cardiac amyloidosis [44]. Presence of grade 2 or 3 positive bone tracer cardiac scintigraphy in a patient without monoclonal protein (ie, free light chain ratio is normal and serum and urine immunofixation results are both normal) is highly specific for ATTR cardiac amyloid and thus sufficient for diagnosis of this condition without tissue biopsy [32].

The main limitation of bone tracer scintigraphy is lack of quantification of amyloid burden, a parameter that might prove useful for assessing response to therapy in the era of disease modifying agents. Novel quantitative positron emission tomography (PET) imaging using bone or amyloid binding tracers might prove useful in this context [57].

Monoclonal protein — Identification of monoclonal protein (by serum protein immunofixation, urine protein immunofixation, or serum free light chain ratio analysis) along with echocardiographic or CMR findings consistent with cardiac amyloidosis is suggestive of AL amyloidosis but may also be caused by ATTR (or a rarer cause of cardiac amyloidosis) with an unrelated monoclonal gammopathy of undetermined significance (MGUS) [58]. Thus it is important to identify the specific cause of cardiac amyloidosis even when monoclonal protein has been identified, particularly in patients with features that are atypical for AL amyloidosis. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis" and "Laboratory methods for analyzing monoclonal proteins" and "Diagnosis of monoclonal gammopathy of undetermined significance".)

Tissue biopsy — Tissue biopsy is required for some, but not all, patients undergoing diagnostic evaluation of cardiac amyloidosis, as described above. (See 'How to diagnose cardiac amyloidosis' above.)

Tissue biopsy is not required when other findings are diagnostic for the presence and type of cardiac amyloidosis. As described above, the presence of grade 2 or 3 positive bone tracer cardiac scintigraphy in the absence of monoclonal protein is diagnostic for cardiac ATTR amyloidosis, and thus no tissue biopsy is required. The presence of CMR findings consistent with cardiac amyloidosis in a patient with previously confirmed systemic AL amyloidosis is diagnostic for cardiac AL amyloidosis, so endomyocardial biopsy is not indicated.

In patients with suspected AL amyloidosis, evaluation typically includes bone marrow biopsy and other tissue biopsy (eg, fat pad aspirate, endomyocardial) as discussed separately. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

Low power microscopic examination of tissue with amyloid infiltration shows amorphous hyaline deposits seen predominantly in the extracellular space. Diagnostic characteristics of extracellular amyloid deposits include typical apple-green birefringence with Congo red dye under polarized light microscopy and unique cross–β-pleated sheets under electron microscopy. The fibrils also bind thioflavine T (producing an intense yellow-green fluorescence), and sulfated Alcian blue (producing a green color) (picture 1A-B). The type of amyloid fibril may be identified using immunohistochemistry, immunofluorescence or immunoelectron microscopy but laser microdissection with mass spectrometry is considered the gold standard for identifying the precursor protein and amyloidosis type [59]. (See 'Types of amyloidosis' above and "Overview of amyloidosis", section on 'Pathology' and "Overview of amyloidosis", section on 'Types of amyloidosis'.)

DIFFERENTIAL DIAGNOSIS — In patients with LV hypertrophy (LVH), the differential diagnosis includes hypertrophic cardiomyopathy, LVH associated with hypertension, HF with preserved ejection fraction (HFpEF; which overlaps with hypertensive LVH) and Anderson Fabry disease.

Echocardiography is helpful since the finding of relative apical sparing of longitudinal strain is suggestive of cardiac amyloidosis. Additional imaging with CMR is helpful as CMR has high sensitivity for both AL and ATTR types of cardiac amyloidosis and typical LGE findings are specific for cardiac amyloidosis. Although late gadolinium enhancement (LGE) is frequently seen in patients with hypertrophic cardiomyopathy or Fabry disease, the pattern of LGE in those conditions differs from that seen with cardiac amyloidosis. (See 'Cardiovascular magnetic resonance' above and "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Cardiovascular magnetic resonance' and "Fabry disease: Cardiovascular disease", section on 'Cardiovascular magnetic resonance'.)

Patients with cardiac amyloidosis with HF typically have preserved LVEF until advanced stages, and other causes of this presentation should be excluded (table 2). Many of the alterative causes of HF with a normal ejection fraction can be identified by echocardiography, including valvular heart disease, right HF, and pericardial disease. The differential diagnosis of HFpEF, including non-HF and HF conditions, is discussed separately (see "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis", section on 'Differential diagnosis'). Evaluation of the cause of HF (with reduced or preserved ejection fraction) is discussed separately. (See "Determining the etiology and severity of heart failure or cardiomyopathy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac amyloidosis" and "Society guideline links: Cardiomyopathy" and "Society guideline links: Heart failure in adults" and "Society guideline links: Immunoglobulin light chain (AL) amyloidosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: AL amyloidosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Types of amyloidosis – Classification of amyloidosis is based upon the type of precursor protein (table 1). The common types of cardiac amyloidosis are transthyretin amyloidosis (ATTR amyloidosis), which includes the wild-type (wtATTR amyloidosis) and hereditary (hATTR amyloidosis) subtypes, and light chain amyloidosis (AL amyloidosis). (See 'Types of amyloidosis' above.)

Epidemiology – Cardiac amyloidosis is a rare form of cardiomyopathy whose overall frequency in the population is not well described, though more is known about the epidemiology of specific types of cardiac amyloidosis. Among patients who have cardiac amyloidosis, approximately 95 percent of cases are caused by the deposition of transthyretin (ATTR amyloidosis) or immunoglobulin light chains (AL amyloidosis). (See 'Epidemiology' above.)

Clinical manifestations – Clinical manifestations in patients with cardiac amyloidosis are diverse, depending on the pattern of organ involvement. The variable clinical phenotype and generally nonspecific clinical features makes diagnosis difficult and contributes to diagnostic delays. (See 'Clinical manifestations' above.)

Patients with AL cardiac amyloidosis typically present at age ≥40 years. Systemic AL amyloidosis is a multisystem disorder which commonly affects the liver, kidneys, the autonomic and peripheral nervous systems, lung as well as heart. Cardiac amyloid infiltration is present in most patients (50 to 70 percent) and is the main determinant of prognosis.

Patients with ATTR cardiac amyloidosis typically present at age ≥60 years, and most commonly >70 years. Various transthyretin mutations are associated with differing ages of onset (ranging from 30 to 70 years) and differing risks of cardiomyopathy. Cardiac amyloidosis is the dominant feature of wtATTR amyloidosis and for some ATTR variants.

Electrocardiogram – A hallmark of cardiac amyloidosis is discordance between increased left ventricular (LV) wall thickness (identified by cardiac imaging such as echocardiography) and QRS voltage, which is often reduced. However, this is feature of cardiac amyloidosis has low sensitivity and the prevalence of low voltage varies markedly with etiology, with higher frequency in patients with AL amyloidosis (60 percent) than in patents with ATTR amyloidosis (20 percent). (See 'Electrocardiogram' above.)

When to suspect cardiac amyloidosis – Cardiac amyloidosis should be suspected in patients with unexplained LV hypertrophy (LVH; with or without heart failure [HF]), patients with aortic stenosis with features associated with cardiac amyloidosis (such as presence of low-flow, low-gradient aortic stenosis and/or echocardiographic detection of impaired longitudinal strain [eg, mitral annular S' ≤6 m/sec]), patients with symptoms or signs typical of AL or ATTR amyloidosis and HF, and patients with a condition highly associated with cardiac amyloidosis (eg, systemic AL amyloidosis, ATTR-related peripheral neuropathy, or ATTR mutation carrier state). (See 'When to suspect cardiac amyloidosis' above.)

How to diagnose cardiac amyloidosis – The diagnostic evaluation for cardiac amyloidosis starts with an initial clinical examination to assess cardiac and extracardiac symptoms and signs, initial laboratory tests, an electrocardiogram, and an echocardiogram. Further evaluation is based upon the patient’s clinical presentation. (See 'How to diagnose cardiac amyloidosis' above.)

Suspected cardiac amyloidosis without known systemic amyloidosis – For patients with unexplained LVH, aortic stenosis with features associated with cardiac amyloidosis, or HF with symptoms or signs typical of amyloidosis (consistent with AL and ATTR amyloidosis), we recommend cardiovascular magnetic resonance (CMR) imaging. (See 'Cardiovascular magnetic resonance' above.)

-If CMR findings suggest cardiac amyloidosis, we recommend testing for evidence of monoclonal protein (by serum protein immunofixation, urine protein immunofixation, and serum free light chain ratio analysis). If monoclonal protein is identified, hematology referral and tissue biopsy (including bone marrow biopsy) are indicated. If monoclonal protein is not identified, further evaluation is based upon the results of bone tracer cardiac scintigraphy . (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Evidence of monoclonal plasma cells' and "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Diagnosis'.)

-If CMR is not suggestive of cardiac amyloidosis, cardiac amyloidosis is unlikely and other causes of LVH and/or HF should be considered. (See 'Differential diagnosis' above.)

Known systemic amyloidosis – For patients with systemic AL amyloidosis, we recommend CMR. (See 'Cardiovascular magnetic resonance' above.)

-If CMR findings suggest cardiac amyloidosis, the diagnosis of cardiac amyloidosis is confirmed.

-If CMR findings do not suggest cardiac amyloidosis, the diagnosis is unlikely. Other causes of LVH and/or HF should be considered. (See 'Differential diagnosis' above.)

Patients at high-risk for cardiac ATTR – For patients with ATTR-associated polyneuropathy or ATTR mutation carrier state, we suggest either bone scintigraphy or CMR as the next step to evaluate for cardiac infiltration. Further studies are needed to determine the optimum diagnostic approach in this setting. (See 'How to diagnose cardiac amyloidosis' above.)

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Topic 122846 Version 8.0

References

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