Cardiac amyloidosis: the need for early diagnosis

Abstract

Amyloidosis is a collection of systemic diseases characterised by misfolding of previously soluble precursor proteins that become infiltrative depositions, thereby disrupting normal organ structure and function. In the heart, accumulating amyloid fibrils lead to progressive ventricular wall thickening and stiffness, resulting in diastolic dysfunction gradually progressing to a restrictive cardiomyopathy. The main types of cardiac amyloidosis are amyloid light chain (AL) amyloidosis caused by an underlying plasma cell dyscrasia, amyloid transthyretin (TTR) amyloidosis of wild-type (normal) TTR at older age (ATTRwt) and hereditary or mutant amyloid TTR (ATTRm) in which a genetic mutation leads to an unstable TTR protein. Overall survival is poor once heart failure develops, underlining the need for early referral and diagnosis. Treatment for AL amyloidosis has improved markedly over the last decades, and TTR amyloidosis gene silencers and orally available transthyretin stabilisers are ready to enter the clinical arena after recent positive outcome trials. Novel therapies aiming at fibril degradation with monoclonal antibodies are under investigation. In this review, we focus on 'red flag' signs and symptoms, diagnosis and management of cardiac amyloidosis which differs considerably from the general management of heart failure. Only by increasing awareness, prognosis for patients with this devastating disease can be improved.

Keywords: Amyloidosis; Awareness; Diagnosis; HFpEF; Heart; Left ventricular hypertrophy; Treatment.

Fig. 1

Overview of amyloidogenesis, clues for early diagnosis and treatment of TTR and light chain cardiac amyloidosis. ^asiRNA (patisiran), antisense oligonucleotide (inotersen). ^btafamidis (selective stabiliser); diflunisal (non-selective stabiliser). ^cantibody-mediated phagocytosis, doxycycline. ATTR amyloid transthyretin, AL amyloid light chain, TTR transthyretin, FLC free light chains, HFpEF heart failure with preserved ejection fraction, AF atrial fibrillation, LVH left ventricular hypertrophy, GLS global longitudinal strain, GI gastro-intestinal, ANS autonomous nervous system, PNS peripheral nervous system, CTS carpal tunnel syndrome, SCT stem cell transplantation

Fig. 2

Echocardiography in cardiac amyloidosis. a–b Granular echogenic appearance of the left ventricular wall with clear hypertrophy and some pericardial effusion. Left ventricular ejection fraction is preserved (c), septal tissue Doppler longitudinal movement is reduced (d). Longitudinal strain analysis from the 3 apical views showing characteristic apical sparing (bull’s eye) with reduced strain at the mid and basal level (e)

Fig. 3

Cardiac magnetic resonance imaging in cardiac amyloidosis. a–b Cardiac magnetic resonance imaging showing a 4‐chamber and short axis view with left ventricular hypertrophy mainly in the septal region. Corresponding short axis view showing generalised subendocardial late gadolinium enhancement not fitting a coronary territory. Note the reduced signal of the blood pool (dark blood), which is specific for cardiac amyloidosis (c). Native T1 mapping analysis showing an increased T1 value of 1214 ± 31 ms (d) and subsequent ECV map which is increased giving a value of 51 ± 2.8% (e), both acquired with a field strength of 1.5 T

Fig. 4

Flow chart for the diagnosis of cardiac amyloidosis. ^aserum-free light chain assay, serum/urine immunofixation. ^bPerugini grade 1 or 2 with or w/o positive AL amyloidosis screening, grade 3 with positive AL amyloidosis screening. HFpEF heart failure with preserved ejection fraction, AF atrial fibrillation, SVT supraventricular tachycardia, LVH left ventricular hypertrophy, HCM hypertrophic cardiomyopathy, AS aortic stenosis, ECG electrocardiogram, CMR cardiac magnetic resonance, AL amyloid light chain, ATTR amyloid transthyretin, EMB endomyocardial biopsy, IHC immunohistochemistry, MS mass spectrometry, AA amyloid serum A protein, AApoA1 amyloid apolipoprotein A1, MGUS monoclonal gammopathy of unknown significance, TTR transthyretin