Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis

Abstract

Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping.

Keywords: amyloid; cardiomyopathies; diagnosis; heart failure; rare diseases.

Figures

Figure 1.

Genotype–phenotype correlations in ATTRm amyloidosis. ATTR, transthyretin amyloidosis.

Figure 2.

Proposed timeline of appropriate diagnostic tests based on typical disease process. 11C-PIB, Pittsburgh compound B; 99mTc-DPD, 99mtechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid; 99mTc-HMDP, hydroxymethylene diphosphonate; 99mTc-PYP, technetium pyrophosphate; ATTR-CM, transthyretin amyloidosis with predominant cardiomyopathy (either wild-type or hereditary); CA, cardiac amyloidosis; ECG, electrocardiography; LVST, left ventricular septal thickness.

Figure 3.

Typical ECHO and CMR findings in a patient with cardiac amyloidosis. Parasternal longitudinal axis (A) and apical 4-chamber (B) ECHO views show considerably increased LVWT in the absence of ventricular dilation; the myocardial walls appear hyperechogenic. Other characteristic findings include biatrial enlargement and thickening of valve leaflets (A, B) of the interatrial septum (B) and RV free wall (C). A generalized small pericardial effusion is also noticeable (A-C). The profile of LV filling (D) is restrictive, with markedly elevated E wave, reduced A wave, and decreased deceleration time. A decreased E’ wave measurement can be observed on lateral wall tissue Doppler imaging (E). The longitudinal systolic function is impaired with decreased S’ measurement on lateral wall tissue Doppler imaging (E) and markedly reduced longitudinal strain evident on the apical 4-chamber view (F). LV longitudinal strain (F) is preserved at the LV apex but is significantly impaired at the midbasal segments. Each colored curve shows longitudinal strain at 1 of the 6 LV measured segments. Dotted line is the mean. Color map represents the 6 LV segments, with time corresponding to the x-axis. The “bulls-eye” appearance (with apex at the center of the color-coding map) is typical of cardiac amyloidosis. Cardiac magnetic resonance images (G) include 4-chamber cine, corresponding native T1 maps, LGE image with phase-sensitive reconstruction and ECV maps in a patient with no cardiac amyloidosis (upper row) and 2 patients with cardiac amyloidosis (middle row and bottom row). In the upper row, the patient with no cardiac amyloidosis has no LGE and normal native T1 and ECV maps; in the middle row, the patient with cardiac amyloidosis has subendocardial LGE, elevated T1 values and elevated ECV values; in the bottom row, the patient with cardiac amyloidosis has a very high cardiac amyloid load, with transmural LGE, very high native T1 values, and very high ECV values. CMR, cardiac magnetic resonance; ECHO, echocardiography; ECV, extracellular volume; LGE, late gadolinium enhancement; LV, left ventricle; LVWT, left ventricular wall thickness; RV, right ventricle.

Figure 4.

99mTechnetium imaging procedures for cardiac amyloidosis. Adapted with permission from Dorbala S et al. ASNC Practice Points. SPECT imaging to identify myocardial retention of technetium-based isotopes is particularly useful in discriminating blood pool on planar scans that result in in a false-positive test from myocardial uptake of the isotope indicative of ATTR-CM. 99mTechnetium-pyrophosphate imaging for transthyretin cardiac amyloidosis. ASNC, American Society of Nuclear Cardiology. https://www.asnc.org/files/Practice%20Resources/Practice%20Points/ASNC%20Practice%20Point-99mTechnetiumPyrophosphateImaging2016.pdf. Accessed March 6, 2019.

Figure 5.

Semiquantitative approach to 99mTc-PYP/DPD/HMDP imaging in cardiac amyloidosis. Semiquantitative methods to generate HCL ratios with a target ROI over the heart (A, B, red arrows) mirrored over the contralateral chest for a background ROI (A, B, green arrows). An HCL ratio of >1.5 on 1-hour imaging is diagnostic of ATTR-CM. Comparatively, 99mTc DPD includes a whole-body scan, 25–30 mCi of radiotracer, 200 minutes of study time, with heart-to-whole-body ratios generated by a target ROI over the heart (C, D, red arrows) as well as background ROIs over the kidneys and bladder (C, D, green arrows). 99mTc HMDP was validated for diagnosing ATTR CA, and representative scans show diffuse myocardial uptake in a patient with cardiac transthyretin amyloidosis at baseline. 99mTc-DPD, 99mtechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid; 99mTc-HMDP, hydroxymethylene diphosphonate; 99mTc-PYP, technetium pyrophosphate; ATTR-CM, transthyretin amyloidosis with predominant cardiomyopathy (either WT or hereditary); HCL, heart-to-contralateral; ROI, region of interest. Panels C and D are modified with permission from Perugini E et al. J Am Coll Cardiol. 2005;6:1076–1084.

Figure 6.. Diagnostic algorithm for patients with suspected cardiac amyloidosis.

Note that urine protein electrophoresis with immunofixation can be performed on spot or 24-hour urine collection. AL, light chain amyloidosis; ATTR, transthyretin amyloidosis; ATTRm, mutant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; ECG, electrocardiography; Echo, echocardiogram; MGUS, monoclonal gammopathy of undetermined significance; MRI, magnetic resonance imaging. Figure modified with permission from Nativi-Nicolau and Maurer. Curr Opin Cardiol. 2018;33:571–579.