NT-proBNP appeared to be the most sensitive index of myocardial dysfunction and the most powerful prognostic determinant in AL amyloidosis. It adds prognostic information for newly diagnosed patients and can be useful in designing therapeutic strategies and monitoring response. NT-proBNP is a sensitive marker of heart toxicity caused by amyloidogenic light chains.

All types of amyloidosis are structurally characterized by the cross beta-pleated sheet conformation of the fibrils, irrespective of their biochemical composition. The clinical observation that the anthracycline 4'-iodo-4'-deoxy-doxorubicin (IDOX) can induce amyloid resorption in patients with immunoglobulin light chain amyloidosis was the starting point for this investigation of its possible mechanism of action. IDOX binds strongly to all five types of natural amyloid fibrils tested: immunoglobulin light chains, amyloid A, transthyretin (methionine-30 variant), beta-protein (Alzheimer), and beta 2-microglobulin. Quantitative binding studies showed that IDOX, but not doxorubicin, binds strongly to amyloid fibrils. This binding is saturable and involves two apparently distinct binding sites with Kd values of 5.9 x 10(-11) M and 3.4 x 10(-9) M. IDOX inhibited in vitro insulin amyloid fibrillogenesis. In vivo studies using the experimental amyloid murine model confirmed the specific targeting of IDOX to amyloid deposits. Preincubation of amyloid enhancing factor with IDOX significantly reduced the formation of amyloid deposits. It is hypothesized that IDOX exerts its beneficial effects through the inhibition of fibril growth, thus increasing the solubility of existing amyloid deposits and facilitating their clearance. IDOX may represent the progenitor of a class of amyloid-binding agents that could have both diagnostic and therapeutic potential in all types of amyloidoses.

Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by extracellular deposition of monoclonal light-chain variable region (V) fragments in the form of amyloid fibrils. Light-chain amyloid is rare, and it is not fully understood why it occurs in only a fraction of patients with a circulating monoclonal component and why it typically associates with isotype and VI family light-chain proteins. To provide insights into these issues, we obtained complete nucleotide sequences of monoclonal V regions from 55 consecutive unselected cases of primary amyloidosis and the results were compared with the light-chain expression profile of polyclonal marrow plasma cells from 3 healthy donors (a total of 264 sequences). We demonstrated that: (1) the III family is the most frequently used both in amyloidosis (47%) and in polyclonality (43%); (2) both conditions are characterized by gene restriction; (3) a very skewed repertoire is a feature of amyloidosis, because just 2 germline genes belonging to the III and VI families, namely 3r (22% of cases, III) and 6a (20%, VI), contributed equally to encode 42% of amyloid V regions; (4) these same 2 gene segments have a strong association with amyloidosis if their prevalences are compared with those in polyclonal conditions (3r, 8.3%, P ‫؍‬ .024; 6a, 2.3%, P ‫؍‬ .0008, 2 test); (5) the J 2/3 segment, encoding the fourth framework region, appears to be slightly overrepresented in AL (83% versus 67%, P ‫؍‬ .03), and this might be related to preferential J 2/3 rearrangement in amyloid (11 of 12 cases) versus polyclonal 3r light chains (13 of 22 cases). These findings demonstrate that V -J expression is more restricted in plasma cells from amyloidosis than from polyclonal bone marrow and identify 3r as a new disease-associated gene segment. Overusage of just 2 gene segments, 3r and 6a, can thus account for the light-chain overrepresentation typical of this disorder. (Blood. 2002;100: 948-953)