LAUSR

The scientific history of systemic amyloidosis is replete with reports of incremental advancements reflecting developments in diagnostic tools and therapies, punctuated by frequent paradigm shifts that challenge the conventional wisdom of the day. First identified as a carbohydrate in the 19th century by Virchow, amyloid was subsequently reclassified as a protein, and then later as a category of proteins. Clinically too, the field of amyloidosis has evolved to represent a growing spectrum of disease manifestations. While the principal proteins that cause systemic amyloidosis were initially thought to be derived from immunoglobulin light chain fragments (AL amyloidosis) or from acute phase reactants (AA amyloidosis), it was soon discovered that pre-albumin (now known as transthyretin amyloid or ATTR) was the culprit in familial amyloidotic polyneuropathy and cardiomyopathy. We now know that ATTR amyloidosis can result from genetically abnormal TTR protein (ATTRm) and, at present, >100 TTR mutations have been identified. ATTR amyloidosis can also result from genetically normal or wild-type TTR, resulting in ATTRwt (formerly known as senile cardiac) amyloidosis. Cardiac amyloidosis is an infiltrative cardiomyopathy characterized by increased biventricular wall thickness, restrictive left ventricular (LV) filling, and, often, a non-dilated LV cavity with preserved or mildly depressed LV systolic function. AL amyloidosis typically affects multiple organ systems including renal and gastrointestinal systems, with cardiac involvement seen as a common manifestation in up to 70% of cases. In contrast, cardiac involvement in ATTRm amyloidosis is variable and depends on the specific mutation. While AL cardiac amyloidosis is rightly considered a rare disease (estimated incidence 1:100 000), recent evidence suggests that ATTRwt amyloidosis is probably much more common than is widely appreciated in elderly patients with heart failure with preserved ejection fraction (HFpEF). The diagnosis and appropriate typing of cardiac amyloidosis is critical for the clinical management of these patients so that life-extending chemotherapy can be administered in AL amyloidosis, and the TTR-stabilizing agent tafamidis (Vyndaqel, Pfizer Inc., available in Europe but not the USA) in ATTR amyloidosis. With the development of promising new therapies for systemic amyloidosis, early and accurate diagnosis of the precursor protein has tremendous potential to prolong survival and improve outcomes. Diagnosis is challenging, however, because features of cardiac amyloidosis must be disentangled from other more common ‘hypertrophic’ processes including hypertensive remodelling, hypertrophy in response to aortic stenosis, or hypertrophic cardiomyopathy (HCM). The diagnostic algorithm requires different clinical inputs including history, physical findings, and imaging, including echocardiography, cardiac magnetic resonance imaging (CMR), and, most recently, the highly ATTR-specific bone avid nuclear tracers Tc-PYP (pyrophosphate) and Tc-DPD (3,3-diphosphono-1,2-propanodicarboxylic acid). This issue of the journal features two distinct but complementary studies that separately refine the methodology employed for diagnosis of cardiac amyloidosis and identify heretofore less appreciated clinical features of the most common form of the disease (ATTRwt amyloidosis). In the first study, Quarta et al. assessed the diagnostic performance of an abdominal fat aspirate, perhaps the most easily accessible tissue biopsy, for the identification of cardiac amyloidosis. While advances in imaging have made it possible to definitively diagnose ATTR cardiac amyloidosis non-invasively, a tissue diagnosis remains important, particularly in AL disease, to confirm the type of the protein involved. In the early 1980s, Libbey and colleagues at Boston University first reported that Congo Red staining of abdominal fat obtained by fine needle aspiration diagnosed amyloidosis in 95% of patients with AL amyloidosis and 86% of patients with ATTRm amyloidosis. Unlike cardiac or gastrointestinal biopsy, the procedure is easily performed in the clinical exam room, with local anaesthesia, and minimal complication. Six hundred patients (an exceptionally large cohort) with an established diagnosis of cardiac amyloidosis referred to the National Amyloidosis Centre in London,