World Heart Federation Consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)

Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability of new disease-modifying therapies has made successful treatment a reality. Transthyretin amyloid cardiomyopathy can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms). It is a systemic disease, and while the genetic forms may exhibit a variety of symptoms, a predominant cardiac phenotype is often present. This document aims to provide an overview of ATTR-CM amyloidosis focusing on cardiac involvement, which is the most critical factor for prognosis. It will discuss the available tools for early diagnosis and patient management, given that specific treatments are more effective in the early stages of the disease, and will highlight the importance of a multidisciplinary approach and of specialized amyloidosis centres. To accomplish these goals, the World Heart Federation assembled a panel of 18 expert clinicians specialized in TTR amyloidosis from 13 countries, along with a representative from the Amyloidosis Alliance, a patient advocacy group. This document is based on a review of published literature, expert opinions, registries data, patients' perspectives, treatment options, and ongoing developments, as well as the progress made possible via the existence of centres of excellence. From the patients' perspective, increasing disease awareness is crucial to achieving an early and accurate diagnosis. Patients also seek to receive care at specialized amyloidosis centres and be fully informed about their treatment and prognosis.

Keywords: Amyloidosis; Heart Failure; Transthyretin amyloid cardiomyopathy (ATTR-CM); diagnosis; patients’ perspective; treatment.

Figure 1

The most frequent amyloidosis subtypes that affect the heart.

Figure 2

Representative two-dimensional echocardiographic findings of cardiac amyloidosis in a patient with ATTR-CM. (A) Parasternal longitudinal view (B) Short axis view (C) Apical 4-chamber view (D) Subcostal view Concentric left ventricular and right ventricle free wall hypertrophy, thickened interatrial septum, and atrioventricular valves. (Images courtesy of Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal).

Figure 3

Two-dimensional speckle-tracking strain imaging echocardiography of a patient with ATTRwt-CM (the same patient as in Figure 2). Reduced left ventricular longitudinal strain in the middle and basal segments with relatively preserved strain in the apex (i.e., apical sparing) is observed. A bull’s eye is shown in the lower right panel (Images courtesy of Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal).

Video 1

37-second recording in real-time showing typical echocardiographic features of a patient with ATTR-CM (the same patient as in Figures 2 and 3): concentric left ventricular hypertrophy, interatrial septum thickening, biatrial enlargement, and decreased global longitudinal strain with relative apical sparing. There is mild mitral and aortic regurgitation. The ejection fraction of both the left (LV) and right ventricle (RV) is preserved (4D analysis, LV in red, RV in blue). The patient gave informed consent for imaging and video use. https://dulcebritocardiologista.com/wp-content/uploads/2023/01/Amyloidosis-Final.edited.video_.mp4

Figure 4

Cardiac magnetic resonance imaging. (A) Myocardial native T1 mapping (short axis) (B) Native T1 global polar map with abnormally increased T1 relaxation time (myocardial T1 values: 1,512±72 ms) (C) Post-contrast T1 (D) Global extracellular volume map, calculated from both native and post-contrast T1 myocardial values: in this case high above normal: 44±9%. (Images courtesy of Lusíadas Hospital, Lisboa, Portugal).

Figure 5

Cardiac magnetic resonance imaging findings with representative examples. (A) Cine: four-chamber view – SSFP (steady-state free precession) acquisition, depicting asymmetric left ventricular (LV) hypertrophy, inter-atrial septum thickening, and mild pericardial effusion (B) Short axis view – SSFP, asymmetric LV hypertrophy (C) Late gadolinium enhancement (LGE) at the 4-chamber view with subendocardial LGE at the left ventricle, atrial Wall, and inter-atrial septum (D) Short axis view, showing subendocardial and subepicardial LGE at the left ventricle and also at the right ventricle. (Images courtesy of Lusíadas Hospital, Lisboa, Portugal).

Figure 6

Whole body anterior planar views performed 3 hours post-injection of Tc99 m-DPD. Four different patients with different Perugini visual scores. (Images courtesy of Lisbon Medical School, Faculdade de Medicina da Universidade de Lisboa, Portugal).

Figure 7

Clues (‘red flags’) to the presence of cardiac ATTR, Transthyretin amyloidosis; BNP or NT-proBNP, brain natriuretic peptides; CMR, cardiac magnetic resonance; ECG, electrocardiogram; ECV, extracellular volume; HF, heart failure; ICD, implanted cardioverter defibrillator; LGE, late gadolinium enhancement; LS, longitudinal strain; LV, left ventricle; PM, pacemaker.

Figure 8

Whole body anterior and posterior planar views (shown at two intensities) performed 3 hours post-injection of Tc99 m HDP, investigating an 85-year-old man with back pain. He had no history of Heart Failure. (Images courtesy of Cabrini Health, Victoria, Australia).

Figure 9

After viewing the planar study, a SPECT-CT was performed. This representative slice in axial, sagittal, and coronal plains (top row = SPECT, middle row = CT, bottom row = merged) confirms the uptake as cardiac and not blood pool. Echocardiogram at the time was normal. The patient developed echo and clinical features of cardiac ATTR amyloid approximately two years later. (Images courtesy of Cabrini Health, Victoria, Australia).

Figure 10

(A) ECG of a 48-year-old female (African ancestry), showing complete atrial-ventricular block on hospital admission after a syncope. She had mild hypertension, a history of paroxysmal atrial fibrillation, and right carpal tunnel syndrome. No known family history of amyloidosis. (B) ECG after pacemaker implantation. Echocardiographic images: (C) Parasternal longitudinal long-axis (D) Apical 3-chamber views, showing only mild and localized (basal septum) LVH (12 mm). Cardiac magnetic resonance (E-H) was also normal: no cardiac hypertrophy, and (F, H) no late gadolinium enhancement; (I) ^{99 m}Tc-3,3-diphosphono-1,2 propanodicarboxylic acid (DPD) scintigraphy (chest images) showed no cardiac uptake three hours after radiotracer administration. Genetic testing identified the pathogenic mutation p.Val142Ile in the TTR gene (no other mutations in a large panel of genes studied by next-generation sequencing). Of her three children (adolescents), two have the mutation (no phenotype). (Images courtesy of Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal).

Figure 11

Diagnosis criteria of cardiac amyloidosis. (A) Criteria for diagnosis of cardiac amyloidosis. (B) Echocardiographic and cardiac magnetic resonance criteria for diagnosis of cardiac amyloidosis. Modified from [22104]. *Classification of the amyloid fibril protein must follow (mass spectrometry or immunohistochemistry). ATTR, Transthyretin Amyloidosis; CMR, Cardiac magnetic resonance; Echo, echocardiogram; ECV, extracellular volume; LS, longitudinal strain; LGE, late gadolinium enhancement; LV, left ventricle; SSFP, steady-state free precession; ULN, upper limit of normal.

Figure 12

Algorithm for the diagnosis of Cardiac Amyloidosis. *Reference intervals for free light chain ratio according to renal function must be considered; AL-CM, Light chain cardiac amyloidosis; ATTR-CM, Transthyretin cardiac amyloidosis; ATTRv, genetic (hereditary) ATTR-CM; ATTRwt, wild type ATTR-CM; CMR, cardiac magnetic resonance; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; Echo, echocardiography; EMB, endomyocardial biopsy; HMDP, hydroxymethylene-diphosphonate; K/L, kappa/lambda; PYP, pyrophosphate; ^{99 m}Tc, technetium-99 m.

Video 2

Testimonials of patients with amyloidosis. https://dulcebritocardiologista.com/wp-content/uploads/2023/01/Amyloidosis-The-Voice-of-the-Patient.mp4

Figure 13

Transthyretin Amyloidosis: a multidisciplinary approach.