Introduction on Cardiac Amyloid – An Update
Amyloidosis is a condition characterised by accumulation of pathologic fibrillar proteins in organs causing dysfunction.1 Several protein precursors have been shown to cause amyloidosis.2 Cardiac amyloidosis, when waxy, starch-like deposits infiltrate the heart, is most commonly secondary to the accumulation of amyloid fibrils derived from immunoglobulin light chains (AL) or transthyretin (ATTR). Most of the early literature regarding cardiac amyloidosis investigated the AL type, which is often associated with extra-cardiac manifestations with multi-organ involvement. The Mayo staging criteria, as reported by Dispenzeiri et al., are used to grade systemic AL amyloidosis associated with plasma cell dyscrasias. Prognosis in AL amyloidosis correlates with cardiac biomarkers troponin and brain natriuretic peptide (BNP), regardless of confirmed cardiac involvement by routine assessment.3 Cardiac AL amyloidosis has poor prognosis, with most studies reporting median survival of 6–12 months from the date of diagnosis.4,5
More recently, the ATTR subtype has been identified as an important cause of cardiac amyloidosis.6 ATTR amyloidosis is further subdivided into senile cardiac amyloidosis, due to amyloid fibrils composed of wild-type non-mutant transthyretin (ATTRwt), and hereditary forms caused by gene mutations in the transthyretin gene on chromosome 18 (ATTRm). Overall prognosis for cardiac ATTR amyloidosis is better than for the AL type, with median survival typically 2–6 years.7–9
Amyloidosis remains a histological diagnosis, with confirmation requiring microscopic examination of amorphous material in affected tissue in which Congo red displays apple-green birefringence when viewed under high-intensity cross-polarised light.10 Immunohistochemical staining of the amyloid deposits is performed using the peroxidise anti-peroxidase method to confirm the amyloid fibril type, using purified immunoglobulin G (IgG) fractions of monospecific antibodies reactive with serum amyloid A protein (SAA), transthyretin (TTR) and with kappa and lambda immunoglobulin light chains.11 Laser microdissection and proteomic analysis using mass spectrometry is now considered the gold standard test to identify the amyloid type but is not widely available.12 A summary of useful investigations in patients with presumed cardiac amyloidosis can be found in Table 1 with further explanation throughout the text.