Transthyretin cardiac amyloidosis

Abstract

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) and mortality worldwide. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have shifted ATTR-CA from a rare and untreatable disease to a relatively prevalent condition that clinicians should consider on a daily basis. Amyloid fibril formation results from age-related failure of homoeostatic mechanisms in wild-type ATTR (ATTRwt) amyloidosis (non-hereditary form) or destabilizing mutations in variant ATTR (ATTRv) amyloidosis (hereditary form). Longitudinal large-scale studies in the United States suggest an incidence of cardiac amyloidosis in the contemporary era of 17 per 100 000, which has increased from a previous estimate of 0.5 per 100 000, which was almost certainly due to misdiagnosis and underestimated. The presence and degree of cardiac involvement is the leading cause of mortality both in ATTRwt and ATTRv amyloidosis, and can be identified in up to 15% of patients hospitalized for HF with preserved ejection fraction. Associated features, such as carpal tunnel syndrome, can preceed by several years the development of symptomatic HF and may serve as early disease markers. Echocardiography and cardiac magnetic resonance raise suspicion of disease and might offer markers of treatment response at a myocardial level, such as extracellular volume quantification. Radionuclide scintigraphy with 'bone' tracers coupled with biochemical tests may differentiate ATTR from light chain amyloidosis. Therapies able to slow or halt ATTR-CA progression and increase survival are now available. In this evolving scenario, early disease recognition is paramount to derive the greatest benefit from treatment.

Keywords: Cardiac magnetic resonance; Cardiac scintigraphy with bone tracers; Prognostic stratification; TTR; Therapy; Transthyretin cardiac amyloidosis.

Graphical Abstract

Grey zones and future directions in transthyretin cardiac amyloidosis. AC-TIVE, interpretation of echocardiographic findings according to the AC-TIVE study; ATTR, transthyretin amyloidosis; CMR; cardiac magnetic resonance; ECG, electrocardiography; ECV, extracellular volume; HCM, hypertrophic cardiomyopathy; HFpEF, heart failure with preserved ejection fraction; LGE, late gadolinium enhancement; PET, positron emission tomography; SPECT; single-photon emission computed tomography; TTR, transthyretin.

Figure 1

Pathophysiology of transthyretin synthesis with main pathways of the amyloidogenic cascade and consequences of organ involvement. BNP, brain natriuretic peptide; HF, heart failure; NT-proBNP, N terminal brain natriuretic peptide; TTR, transthyretin.

Figure 2

Diagnostic algorithm for patients with suspected cardiac amyloidosis. 99mTc-DPD, 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid; 99mTc- HMDP, 99mTc-hydroxymethylene diphosphonate; 99mTc-PYP, 99mTc-pyrophosphate; AApoA1, apolipoprotein A-I; AL, light chain; CMR, cardiac magnetic resonance; SPECT, single-photon emission tomography imaging; TTR, transthyretin. Readapted with permission from Gillmore et al.

Figure 3

Echocardiographic findings in a patient with advanced transthyretin cardiomyopathy. Parasternal long axis and four-chamber view demonstrating increased biventricular thickening with a ‘speckled’ myocardium (top left panels) with 2D-strain using speckle tracking echocardiography in the same patient (top right panel). Peak systolic strain for individual myocardial segments in the four-chamber view panel and the strain curve samples in each of the corresponding coloured myocardial segments panel can then generate a longitudinal strain map (bottom). The characteristic basal to apical gradient of impaired longitudinal function is observed here.

Figure 4

A 63-year-old gentleman with lumbar canal stenosis and a 3-month history of exertional breathlessness diagnosed with transthyretin cardiac amyloidosis associated Ser97Tyr variant. Legend: Panel A. Top raw: increased wall thickness on steady-state free precession cine imaging. Middle raw: transmural late gadolinium enhancement with marked involvement of the right ventricle. Bottom raw: High native T1 value and extracellular volume fraction. Panel B: Perugini grade 1 abnormal cardiac uptake of bone tracer on planar (top) and single-photon emission tomography (bottom) imaging.

Figure 5

Spectrum of cardiac uptake of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) on planar scintigraphy. Legend: Grade 0: no cardiac uptake; Grade 1: mild cardiac uptake, less than bone uptake; Grade 2: moderate cardiac uptake accompanied by attenuated bone uptake; Grade 3, strong cardiac uptake with mild/absent bone uptake. Legend: AApoAI, ApoAI amyloidosis; AL, light chain; ATTR, transthyretin amyloidosis; CMR; cardiac magnetic resonance; ECG, electrocardiography; SPECT; single-photon emission computed tomography; TTR, transthyretin.

Figure 6

Diagnostic algorithm for patients with suspected cardiac amyloidosis. 99mTc-DPD, 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid; 99mTc- HMDP, 99mTc-hydroxymethylene diphosphonate; 99mTc-PYP, 99mTc-pyrophosphate; AApoA1, apolipoprotein A-I; AL, light chain; CMR, cardiac magnetic resonance; SPECT, single-photon emission tomography imaging; TTR, transthyretin. Readapted with permission from Gillmore et al..