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Patients with known or suspected amyloidosis
KEY POINTS
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Cardiac amyloidosis is often underdiagnosed, misdiagnosed, or diagnosed late in the natural course of the disease.
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Accurate diagnosis and typing of cardiac amyloidosis are both critical for initiation of appropriate therapy.
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Novel therapies appear to be more effective in early-stage ATTR cardiac amyloidosis and so early detection is important.
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Global longitudinal strain on echocardiography and expanded ECV on CMR are early markers of cardiac amyloid infiltration. Nevertheless, although characteristic features may accurately distinguish amyloid from nonamyloid heart disease, they are not adequate to distinguish AL from ATTR cardiac amyloidosis.
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Endomyocardial biopsy proof of amyloidosis and extracardiac biopsy proof with typical imaging features or with abnormal cardiac biomarkers (AL) can diagnose cardiac amyloidosis.
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A nonbiopsy diagnosis of cardiac ATTR amyloidosis is now possible and requires three components: (1) HF, (2) an echocardiogram or CMR with typical imaging features, and (3) the exclusion of AL amyloidosis by serum free light chain assay and serum and urine immunofixation electrophoresis studies.
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A nonbiopsy diagnosis makes possible screening for cardiac amyloidosis. Screening patients with clinical or imaging red flags for amyloidosis may help identify early disease.
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A diagnosis of ATTR cardiac amyloidosis based on 99m Tc-bone scintigraphy requires SPECT imaging to visualize myocardial tracer uptake grade 2 or 3 and to exclude blood pool activity. Imaging 2 to 3 hours after injection of the radiotracer minimizes interference from blood pool activity.
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Serum cardiac biomarkers, the eGFR, serum free light chain levels, and structural features on echocardiography, as well as increased semiquantitative myocardial uptake of 99m Tc-bone–avid SPECT tracers, are high-risk features.
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18 F-labeled amyloid tracer PET scans are positive in both AL and ATTR cardiac amyloidosis and offer the potential for quantitation of amyloid burden.
Introduction
The name amyloid is derived from the Latin word amylum (starch). Amyloidosis is a protein folding disorder that is characterized by extracellular deposition of a fibrillar protein in soft tissues, visceral organs, and the peripheral nervous system. Amyloid deposits progressively interfere with the structure and function of affected organs throughout the body. Amyloidosis is a life-threatening, progressive, infiltrative multisystem disease that is often underdiagnosed or misdiagnosed. There are two dozen proteins that are known to form amyloid fibrils in vivo. There are two predominant types that involve the heart: amyloid light chain (AL) amyloidosis, which is typically associated with plasma cell dyscrasia, and amyloid transthyretin (ATTR) amyloidosis. ATTR amyloidosis is further subdivided into variant (ATTRv) and wild-type (ATTRwt) forms.
AL amyloidosis is caused by abnormal immunoglobin light chains, which change into amyloid fibrils and undergo extracellular systemic deposition. Among the three types (AL, ATTRv, and ATTRwt), patients with cardiac AL amyloidosis have the worst prognosis. The median survival of untreated AL patients with heart failure (HF) is 6 months. ATTRv amyloidosis is caused by variants of the transthyretin (TTR) gene, which show an autosomal dominant inheritance pattern. The prognosis of cardiac ATTRv amyloidosis is better than that of AL amyloidosis. ATTRwt amyloidosis is caused by the accumulation of wild-type TTR. The median survival of ATTRwt is better than that of ATTRv patients. Effective disease-modifying therapies are now available to treat ATTRv and ATTRwt. Therefore, early detection is important to improve outcomes.
Epidemiology
AL amyloidosis is a rare disease. There are around 2500 new cases diagnosed each year. Of those with systemic AL amyloidosis, around 50% have cardiac involvement. ATTRv is not quite as rare. In fact, V122I is the most common TTR gene mutation in the United States. It is inherited as an autosomal dominant pattern and is predominantly present in African Americans. Approximately 3% to 4% of African Americans are carriers of this mutation, but penetrance is age dependent. There are approximately 25,000 to 120,000 cases in the United States. , ATTRwt is not rare. It is the most common of the three types and is classically described in older white males. ATTRwt is demonstrated in the hearts of approximately 25% of patients older than 80 years. Around 10% to 15% of elderly HF preserved ejection fraction (HFpEF) patients have ATTRwt, and it is estimated that there may be around 1 million patients with ATTRwt. Although there has been an increase in the detection of cardiac amyloidosis in the United States since 2001, data derived from death certificates and from Medicare fee-for-service data indicate substantial regional differences with underdiagnosis in the southern states.
Meanwhile, the nature of cardiac amyloidosis is changing. In the late 1990s to early 2000s, AL was the most common form, but now ATTR-cardiomyopathy (CM) is the most common. ATTRwt is the most prevalent form of ATTR-CM.
Clinical presentation
Clinical features
Cardiac amyloidosis commonly occurs in systemic amyloidosis patients. Patients have heterogeneous symptoms because of multiple-system involvement. The diagnosis may be expedited by recognizing clinical features such as:
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HFpEF without hypertension, particularly in men;
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evidence of right-sided HF,
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intolerance of angiotensin-converting enzyme (ACE) inhibitors or beta blockers,
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periorbital purpura or nephrotic range protein (both signs of AL),
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conduction disease in patients older than 50 years;
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atrial fibrillation/flutter,
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autonomic or sensory polyneuropathy,
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atypical multiple myeloma,
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bilateral carpal tunnel syndrome (in ATTR),
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lumbar spinal stenosis and biceps tendon rupture.
Biochemical features
No plasma or urine biomarker is available for the diagnosis of ATTR. Nevertheless, very high levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) that are disproportionate compared with the degree of HF and elevated troponin levels in a patient with a hypertrophic phenotype on echocardiography are suggestive of TTR-CM. NT-proBNP is elevated early in ATTRv CM before cardiac symptoms appear, especially among asymptomatic carriers of ATTR gene mutations or patients with neurologic symptoms.
Electrocardiographic and imaging features
Electrocardiographic features
Electrocardiographic (ECG) features include an infarct pattern in the absence of coronary artery disease (CAD), low voltage, conduction disease, and atrial fibrillation.
Echocardiographic features
Echocardiographic features may include increased biventricular wall thickness, a thickened interatrial septum, valvular thickening, biatrial enlargement, diastolic dysfunction, restrictive phenotype, pericardial effusion, preserved ejection fraction (early), or systolic dysfunction (late). There may be apical sparing on the strain imaging (in the form of a bull’s eye or cherry on top) and a low myocardial contraction fraction. There is also a low voltage-to-mass ratio.
Magnetic resonance imaging features
In addition to the cardiac structural changes noted on echocardiography, magnetic resonance imaging (MRI) can provide specific clues to myocardial tissue characterization in amyloidosis. It may show diffuse late gadolinium enhancement (LGE), increased extracellular volume (ECV) and T1, and an inability to suppress the myocardial signal. LGE is seen in almost all patients with cardiac amyloidosis. The pattern of LGE can be transmural or subendocardial. , Atrial LGE and right ventricular (RV) LGE have also been described. Suboptimal myocardial nulling and altered gadolinium kinetics with myocardial nulling before blood pool nulling are characteristic features of amyloidosis. Increased ECV is also common in LGE and is an early marker of myocardial infiltration, which can be noted in myocardial segments without LGE. Native T1 times, a measure of myocardial tissue characteristics without the need for gadolinium, are increased in patients with cardiac amyloidosis AL and ATTR .
Radionuclide imaging features
Radionuclide imaging features will be in discussed in detail in the following sections.
Radionuclide imaging
The list of single photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers for cardiac amyloidosis imaging is shown in Table 24.1 .
TABLE 24.1
Radiotracers to Image Cardiac Amyloidosis
| Tracer Type | Tracer Name | SPECT or PET |
|---|---|---|
| Bone-seeking tracers | ||
| 99m Tc-pyrophosphate (PYP) | SPECT | |
| 99m Tc-hydroxymethylene diphosphonate (HMDP) | SPECT | |
| 99m Tc-3.3-diphosphono-1,2-propanodicarboxylic acid (DPD) | SPECT | |
| 18 F-sodium fluoride | PET | |
| Sympathetic innervation tracers | ||
| 123 I-metaiodobenzyl guanidine (mIBG) | SPECT | |
| Amyloid PET tracers | ||
| 11 C-Pittsburgh B compound | PET | |
| 18 F-florbetapir | PET | |
| 18 F-florbetapir | PET | |
| 18 F-florbetaben | PET |
PET , Positron emission tomography; SPECT , single photon emission computed tomography; Tc , technetium.
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