Transthyretin Amyloid Cardiomyopathy: Current Diagnostic Approach and Risk Stratification with Multimodality Imaging

Abstract

Amyloidosis is an infiltrative disease that may cause cardiomyopathy if the precursor protein that misfolds and forms the amyloid is transthyretic or plasma abnormal light chains. Transthyretin amyloid cardiomyopathy has to be diagnosed timely and accurately since there are specific treatment options to support the patients. Multimodality imaging including electrocardiography, echocardiography with strain imaging and cardiac magnetic resonance applying late gadolinium enhancement imaging, native T1 mapping and extracellular volume, raise a high suspicion of the disease and bone scintigraphy set the diagnosis even without the need of biopsy. However, the morbidity and mortality remain high and the need for risk stratification and assessment of the response to treatment are of paramount importance. Cardiac imaging biomarkers offer a thoughtful insight into the prognosis of these patients at diagnosis and after treatment. The current narrative review aims to enlighten the use of multimodality cardiac imaging in transthyretic amyloid cardiomyopathy throughout the disease pathogenesis and evolution from diagnosis to prognosis and response to treatment in a personalized manner.

Keywords: ATTR; DPD scintigraphy; cardiac amyloidosis; cardiac magnetic resonance; cardiomyopathy; diagnosis; echocardiography; imaging; transthyretin.

Figure 1

Summary of the role of multimodality imaging in ATTR-CM patients. ATTR-CM: Transthyretin amyloid cardiomyopathy, CMR: Cardiac magnetic resonance, ECHO: Echocardiography.

Figure 2

Diagnostic algorithm for cardiac amyloidosis as proposed in the position statement of the European Society of Cardiology Working group on Myocardial and Pericardial diseases for the diagnosis and treatment of cardiac amyloidosis [2]. AL: light-chain amyloidosis, ATTR: transthyretin amyloidosis, CA: cardiac amyloidosis, CMR: cardiac magnetic resonance, ECHO: echocardiography, SPECT: single-photon emission computed tomography, TTR: transthyretin, 99mTc-DPD: 99m technetium 3,3-diphosphono-1,2-propanodicarboxylic acid, 99mTc-HMDP: 99m technetium hydroxymethylene diphosphonate, and 99mTc-PYP: 99m technetium pyrophosphate.

Figure 3

Electrocardiogram of a ATTR-CM patient showing a pseudo-infarction pattern in anterior and inferior leads, low-voltage QRS complexes and atrial fibrillation with slow ventricular response. ATTR-CM: transthyretin amyloid cardiomyopathy.

Figure 4

Conventional echocardiographic red flags in ATTR-CM. (A,B) Concentric hypertrophy of the left ventricle demonstrated at parasternal long axis view (A) and short axis view (B). (C) Thickened mitral valve leaflets (arrow). (D–F) Grade III diastolic dysfunction demonstrated by (D) Transmitral flow (E) tissue doppler of the lateral wall and (F) tissue doppler of the intraventricular septum. (G) Four chamber view demonstrating biatrial enlargement, interatrial septum thickening, right ventricular free wall hypertrophy and pericardial effusion. (H) Color doppler imaging demonstrating the significant tricuspid regurgitation. (I) Subcostal view demonstrating hypertrophy of the right ventricle and the thickened interatrial and interventricular septum, visible pacemaker lead in the right ventricle (arrow). ATTR-CM: transthyretin amyloid cardiomyopathy, IVSd: interventricular septum diameter, LVPWd: left ventricular posterior wall diameter, MV: mitral valve, MV DecT: mitral valve deceleration time, and RVFWd: right ventricular free wall diameter.

Figure 5

Advanced echocardiographic red flags in ATTR-CM (A.i.,A.ii.) versus hypertrophic cardiomyopathy (HCM) patients (B.i.,B.ii.). (A.i.) Bull’s eye plots of left ventricular global longitudinal strain (GLS) and myocardial work index (MWI) in an ATTR-CM individual demonstrating an apical sparing pattern versus (B.i.) the respective Bull’s eye plots of a HCM individual demonstrating reduced left ventricular GLS and MWI of the hypertrophic interventricular septum. (A.i.) and (B.i.) LVEF/GLS ratio is higher in CA compared to HCM (cut-off value LVEF/GLS ratio > 4.1 to diagnose CA with 89% sensitivity and 91% specificity) [55]. (A.ii.) Left atrial strain (LAS) analysis of the ATTR-CM patient versus (B.ii.) the respective LAS analysis of the HCM patient, indicating the lower peak values of left atrial reservoir (LASr) and contractile strain characterizing ATTR-CM. ATTR-CM: transthyretin amyloid cardiomyopathy, CA: cardiac amyloidosis, GLS: global longitudinal strain, HCM: hypertrophic cardiomyopathy, LAS: left atrial strain, LASr: left atrial reservoir strain, LVEF: left ventricular ejection fraction, and MWI: myocardial work index.

Figure 6

CMR in a patient with CA. (A) End-diastolic frame from horizontal long axis cine demonstrating left ventricular hypertrophy (LVH) and pericardial and pleural effusions (black asterisks *). (B,C) Late gadolinium images in the horizontal long axis (B) and mid short axis (C) showing the characteristic diffuse subendocardial/transmural myocardial enhancement (white arrows) and dark blood pool. Infiltration of the right ventricle, atrial walls and papillary muscles is also seen. (D) Modified Look Locker Inversion Recovery Native T1 Mapping showing markedly elevated T1 times in all myocardial segments. Extracellular volume (ECV) was also significantly elevated (ECV of 52%, normal values 22–27%). CA: cardiac amyloidosis, ECV: extracellular volume, and LVH: left ventricular hypertrophy.

Figure 7

Perugini Score assessment: Grades—(A) Grade 0, no cardiac uptake; (B) Grade 1, cardiac uptake less than the bone uptake; (C) Grade 2, mild cardiac uptake equal to bone uptake; (D) Grade 3, intense cardiac uptake with faint/absent bone visualization. Type of imaging obtained 2 h post injection of 20 mCi 99mTc-DPD—(i) Whole-body images; (ii) SPECT images; (iii) SPECT/CT images. 99mTc-DPD: 99m technetium 3,3-diphosphono-1,2-propanodicarboxylic acid, and SPECT/CT: single-photon emission tomography with computed tomography.