Light-chain cardiac amyloidosis: strategies to promote early diagnosis and cardiac response

Abstract

Amyloid light chain (AL) amyloidosis is a systemic disease characterised by the aggregation of misfolded immunoglobulin light chain (LC), predominantly in the heart and kidneys, causing organ failure. If untreated, the median survival of patients with cardiac AL amyloidosis is 6 months from the onset of heart failure. Protracted time to establish a diagnosis, often lasting >1 year, is a frequent factor in poor treatment outcomes. Cardiologists, to whom patients are often referred, frequently miss the opportunity to diagnose cardiac AL amyloidosis. Nearly all typical cardiac support measures, with the exception of diuretics, are ineffective and may even worsen clinical symptoms, emphasising the need for accurate diagnosis. Patients with severe cardiac involvement face poor outcomes; heart transplantation is rarely an option because of multiorgan involvement, rapid clinical decline and challenges in predicting which patients will respond to treatment of the underlying plasma cell disorder. Early diagnosis and prompt treatment with ââ'¬Ëœsource therapiesââ'¬â"¢ that limit the production of amyloidogenic LC are associated with better survival and improvement in organ function after a median of 2.4 months following haematological complete response. However, organ recovery is often incomplete because these source therapies do not directly target deposited amyloid. Emerging amyloid-directed therapies may attenuate, and potentially reverse, organ dysfunction by clearing existing amyloid and inhibiting fibril formation of circulating aggregates. Improved recognition of AL amyloidosis by cardiologists allows for earlier treatment and improved outcomes.

Keywords: Cardiac imaging and diagnostics; Infiltrative cardiomyopathies.

Figure 1

Pathophysiology of amyloid light chain (AL) amyloidosis illustrating three key mechanisms: (1) amyloid fibril infiltration, depicted as green, results in wall thickening and diastolic dysfunction. (2) Local effects of fibril infiltration contribute to myocyte dysfunction and apoptosis. (3) Circulating free light chains contribute to myocardial dysfunction. Reproduced with permission from the Mayo Clinic.

Figure 2

Diagnostic algorithm for cardiac amyloidosis. In patients with diagnosed amyloid light chain (AL) amyloidosis, NT-proBNP and troponin measures carry prognostic significance. *Clinical presentation does not distinguish AL from ATTR amyloidosis. ^†Serum protein electrophoresis without immunofixation is not sufficient. ^‡Heart or other affected organ, proceeding with organ biopsy along either arm of the algorithm, combined with mass spectrometry when positive, allows for the identification of rare types of cardiac amyloid. ^§Depending on local expertise, CMR can be considered as an initial imaging test. ^¶Although mass spectrometry is available at only a few centres, specimens can be sent for review; immunohistochemical techniques may lead to inaccurate typing. +, positive test result; –, negative test result; AL, amyloid light chain amyloidosis; ATTRm, hereditary transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CMR, cardiac MR; DPD, ^99m3,3diphosphono-1, 2-propanodicarboxylic acid; ECHO, echocardiography; NT-proBNP, N-terminal fragment of pro-brain natriuretic peptide; PYP, ^99mTc-pyrophosphate. Modified with permission from Gertz M et al, Nat Rev Cardiol 2015;12:91–102.

Figure 3

Examples of patient assessments showing cardiac involvement. (A) ECG of a 62-year-old patient with amyloid light chain (AL) amyloidosis initially diagnosed with hypertrophic cardiomyopathy. (B) Although the limb lead voltage is slightly above the threshold for low voltage, the voltage is discordant with the degree of left ventricular wall thickening (interventricular septum and posterior wall both measure 18 mm). ECG demonstrated an anteroseptal infarct pattern, but no regional wall motion abnormalities were observed and the patient had no history of myocardial infarction. (C) The typical echocardiographic pattern of abnormal global longitudinal strain in cardiac amyloid is demonstrated with markedly abnormal basal function and preserved apical function leading to a bull's eye pattern. This pattern may be a clue to cardiac amyloid when other echocardiographic findings are subtle or absent. (D) Cardiac MRI in amyloidosis demonstrating difficulty ‘nulling’ the myocardium (myocardium appears similar to blood pool) and diffuse abnormalities of delayed gadolinium enhancement. CMR, cardiovascular MR; ECHO, echocardiography.

Figure 4

Suggested plasma cell-directed treatment for patients with newly diagnosed disease based on their Mayo stage, as described in the mSMART guidelines. ASCT, autologous stem cell transplantation; BMPC, bone marrow plasma cell; CRAB criteria for myeloma (C = calcium (elevated), R = renal failure, A = anaemia, B = bone lesions); CyBorD, cyclophosphamide, bortezomib, dexamethasone; dFLC, difference in serum free light chain; Mel-Dex, melphalan–dexamethasone; PR, partial haematological response (dFLC decrease ≥50%; assessable in patients with baseline dFLC ≥50 mg/L); VGPR, very good partial haematological response (defined as dFLC <40 mg/L).