Laboratory Studies
Laboratory tests include measurements of the following:
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Troponin: Elevated levels of troponin T have been seen in patients with familial amyloid polyneuropathy (FAP), systolic dysfunction, and left ventricular (LV) hypertrophy (LVH). [39]
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B-type natriuretic peptide (BNP): High plasma BNP levels may be useful as prognostic markers of cardiac function in patients with senile systemic amyloidosis (but not FAP). [21]
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N-terminal pro-brain natriuretic peptide (NT-proBNP): Elevated NT-pro-BNP levels, whether or not accompanied by findings of increased LV filling pressures, have been noted in patients with FAP, systolic dysfunction, and/or LVH. [39] NT-proBNP has high sensitivity for cardiac involvement in patients with systemic light chain amyloidosis; the combination of NT-proBNP with echocardiography appears to make the diagnosis of cardiac amyloidosis without the need for endomyocardial biopsy. [40] A negative NT-proBNP appears to exclude clinically meaningful cardiac involvement and may remove the need for routine use of TTE in patients at low clinical suspicion for cardiac amyloidosis. [40]
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Urine for proteinuria
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Serum and urine protein electrophoresis
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Serum and urine immunofixation (more sensitive than electrophoresis)
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Genetic studies: Identification of the specific type of amyloidosis is important. [30]
Echocardiography
Two-dimensional transthoracic echocardiography (2D-TTE) [41, 42, 43] is most commonly used in the initial assessment [44] and may reveal the following abnormalities:
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Left ventricular (LV) thickening (most common) in the absence of hypertension is highly suggestive of an infiltrative heart disease (not specific for amyloidosis and also seen in other conditions, such as sarcoidosis, hemochromatosis, and glycogen storage diseases). Lack of LV hypertrophy (LVH) on electrocardiography (ECG) and septal thickness greater than 1.98 cm had a sensitivity of 72% and specificity of 91% to detect amyloidosis. [45]
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LV myocardium has granular or sparkling appearance (poor sensitivity: seen only in 26% cases; see the images below).
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Long axis parasternal view: Left ventricular hypertrophy (LVH) with sparkling appearance, pericardial effusion.
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Short axis view: Left ventricular hypertrophy (LVH), pericardial effusion, normal RV size.
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Normal or small LV cavity dimensions is seen.
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Preserved LV ejection fraction (LVEF) is common, and reduced LV systolic function is seen late in the course of the disease.
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Impairment of long axis contraction is seen early. This can be shown on abnormalities of strain rate imaging. [46]
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Diastolic dysfunction is the hallmark of the disease and progresses over time, resulting in restrictive mitral in-flow filling pattern on Doppler evaluation. [47, 48] Tissue Doppler imaging of the mitral annulus shows reduced diastolic velocities with cardiac amyloidosis and is useful to differentiate it from constrictive physiology, in which early diastolic mitral annular velocity (E') is above 8 cm/s. [49] Longitudinal strain of the LV basal segments and E/e' ratio (the ratio between early mitral inflow velocity and mitral annular early diastolic velocity) can help to differentiate primary cardiac amyloidosis from hypertensive LVH. [50] Investigators found that cardiac amyloidosis was predicted by basal longitudinal strain of -11.3% or below (63.3% sensitivity, 100% specificity) and an E/e' of 12.3 or greater (69.7% sensitivity, 83.3% specificity). [50] Longitudinal strain can also be used as a measure of pretreatment cardiac functional impairment in light chain cardiac amyloidosis; in addition, it can predict survival and early cardiac functional improvement following chemotherapy. [51]
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Right ventricular (RV) hypertrophy (RVH)
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RV dilatation (a marker of poor prognosis): RV dysfunction is common in cardiac amyloidosis, and a tricuspid annular plane systolic excursion (TAPSE) below 14 mm is an independent predictor of adverse cardiac events. [52] Independent determinants of TAPSE below 14 mm are LVEF, E/E', N-terminal pro b-type natriuretic peptide (NT-proBNP) levels, and pulmonary artery pressure, but not RV late gadolinium-enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). [52]
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Thickened interatrial septum
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Thickened atrioventricular valves
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Small pericardial effusion
Three-dimensional speckle tracking TTE (3D-TTE) may allow earlier detection of LV systolic dysfunction in patients with systemic light-chain amyloidosis than 2D-TTE. [44] In a study of 58 patients with confirmed light chain amyloidosis and 21 healthy control subjects, investigators noted 3D-TTE demonstrated significantly worse LV systolic function in Mayo Clinic (MC) stage II and III patients compared to control subjects, and that MC III patients had significantly worse global circumferential strain and area tracking. In addition, although 2D-TTE revealed apparently preserved LVEF in patients with light chain amyloidosis in MC stage II and III, 3D-TTE showed evidence of LV systolic dysfunction using LVEF and strain analysis. Worse LV involvement by light chain amyloidosis was associated with more impaired 3D-TTE LV systolic parameters. [44]
Cardiovascular Magnetic Resonance Imaging
Late gadolinium-enhanced (LGE) cardiovascular magnetic resonance imaging (CMRI) is of a great diagnostic value in the evaluation of cardiac amyloidosis. Amyloid infiltration leads to the expansion of extracellular space that retains gadolinium, resulting in signal enhancement in comparison with normal myocardium, which can be detected in the late washout phase during delayed enhanced imaging. Global subendocardial enhancement is the most common pattern. [28, 55, 56, 57, 58]
The gadolinium wash-out time is increased, and the myocardium appears bright in contrast to normal myocardium that appears black. CMRI is the most accurate predictor of biopsy positive cardiac amyloidosis, with a sensitivity and specificity of 88% and 95%, respectively. T1 kinetics (intramyocardial T1 gradient) to denote lower epicardial gadolinium uptake is a marker of better survival in patients with amyloidosis.
A study by Barison et al indicated that the measurement of myocardial extracellular volume with CMRI with or without gadolinium enhancement can be used in the diagnosis and monitoring of cardiac amyloidosis. [59] Using a novel T1-mapping technique, the investigators found that the cardiac extracellular volume was significantly greater in patients with amyloidosis than in control individuals, with the volume difference being apparent whether or not LGE was used. They also found that a correlation existed between extracellular volume and a patient’s LVEF and LV diastolic function and with the mean wall thickness of the left ventricle, as well as with the RVEF, cardiac troponin level, and N-terminal fragments of proBNPs. In addition, using an extracellular volume cutoff value of over 0.316, Barison et al found that extracellular volume could be used to distinguish between patients with amyloidosis and control individuals with a 79% sensitivity and 97% specificity. [59]
Using CMRI and echocardiographic evaluation to study 22 patients with biopsy-proven cardiac amyloidosis, 37 with systemic hypertension, and 22 with nonischemic dilated cardiomyopathy, Kwong et al found that patients with cardiac amyloidosis may have extensive LGE of the left atrial myocardium, associated with markedly reduced left atrial emptying function. [54] The extent of the left atrial LGE was highly predictive for cardiac amyloidosis. [54]
In patients with LGE-negative systemic amyloidosis on CMRI, CMR strain analysis appears to have the ability to detect early systolic and diastolic strain impairment. [60] In a study that evaluated 34 patients (17 each) with LGE-positive or LGE-negative light-chain amyloidosis and 17 healthy controls, Kuetting et al found that regardless of whether patients had LGE or not, their early diastolic strain rate (EDSR) and peak systolic longitudinal strain (PSLS) values were significantly lower than that of their healthy cohorts. Quantitative LGE-enhancement analysis showed increased enhancement in qualitative LGE-negative patients relative to the healthy control group. [60]
Other Imaging Studies
Nuclear imaging
Nuclear imaging was not typically used for the diagnosis of amyloidosis. Increased uptake of radio-labeled technetium has been reported in patients with cardiac amyloidosis and correlates well with cardiac involvement. [61, 62] Technetium-99m pyrophosphate scintigraphy (99mTc-PYP) is used to differentiate ATTR from AL with a sensitivity of 97% and specificity of 100%. [63]
Radiolabeled serum amyloid P (SAP) component scintigraphy
SAP component plasma glycoprotein is seen in all types of amyloid deposits. After intravenous injection of radiolabeled SAP, scanning is done to assess its distribution and extent of organ involvement. This method cannot be used for evaluation of cardiac amyloidosis because of the heart's movement, but it is of value in assessment of systemic amyloidosis. [64]
Electrocardiography and Holter Monitoring
Electrocardiography (ECG)
The following ECG abnormalities have been reported: [17, 45, 65]
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Low voltage complexes (QRS amplitude ≤ 0.5 mV in limb leads or ≤ 1.0 mV in all precordial leads) are seen in 46% of cases (see image below).
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Pseudo-infarct pattern is seen in 46% of cases (most common anteriorly).
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Both low voltage complexes and pseudo-infarct pattern are seen in 25% of cases.
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Left ventricular (LV) hypertrophy is unusual.
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Atrial fibrillation and flutter are most common arrhythmias (20%).
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Intraventricular conduction delay is seen.
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High-degree atrioventricular (AV) block is unusual (3%).
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Low-voltage complexes on ECG and increased mass on echocardiography are the best predictors of infiltrative cardiomyopathy.
Signal-averaged ECG
Late ECG potentials are seen in 31% patients with echocardiographic evidence of cardiac amyloidosis and are predictive of sudden cardiac death. [66]
Holter monitoring
Cardiac Holter monitoring may show lack of heart rate variability due to autonomic dysfunction. It is an important predictor of 1-year mortality. [67] Detecting ventricular arrhythmias and conduction abnormalities is also helpful.
Electrophysiologic Abnormalities
Electrophysiologic studies reveal the following feature:
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Sinus and atrioventricular node functions are preserved in most patients.
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Infra-His conduction interval is usually prolonged (> –55 ms).
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In one study in which 23 patients who died during follow-up, infra-His prolongation was the sole independent predictor of sudden death by multivariate analysis (P = 0.05). [68]
Histologic Findings
Endomyocardial biopsy
Electromyocardia biopsy (EMB) is considered the criterion standard for diagnosis. Amyloid tissue, when stained with Congo red, appears as an amorphous pink deposit under light microscopy and has a green-apple birefringence under polarized microscopy. Sulfated Alcian blue can be used as an alternative stain with a high specificity for the diagnosis of amyloidosis. EMB has a great sensitivity (almost 100%) due to the diffuse cardiac involvement and is a safe procedure in experienced hands. EMB is also of a great value in differentiating cardiac amyloidosis from other infiltrative myocardial conditions. [69, 70, 71]
Rectal submucosal biopsy
Rectal submucosal biopsy has been a traditional site in the past. It has a sensitivity of greater than 75% for detecting amyloidosis but carries a risk of bleeding and rectal perforation. [72]
Abdominal fat biopsy
Needle aspiration biopsy of the abdominal fat is a simple and commonly performed procedure in the patient suspected of having amyloidosis with a sensitivity of approximately 75%. If positive, it obviates the need for a cardiac biopsy in the right clinical setting. [73]
Bone marrow biopsy
Bone marrow biopsy is useful to assess plasma cell burden and to exclude myeloma and other disorders like Waldenstrom macroglobulinemia.
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Low voltage complexes, atrial fibrillation.
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Long axis parasternal view: Left ventricular hypertrophy (LVH) with sparkling appearance, pericardial effusion.
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Short axis view: Left ventricular hypertrophy (LVH), pericardial effusion, normal RV size.
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Short axis left ventricle: Global subendocardial gadolinium enhancement.
