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Light chain (AL) amyloidosis, caused by deposition of amyloidogenic immunoglobulin light chains (LCs), is the most common systemic form in industrialized countries. Still open questions, and premises for developing targeted therapies, concern the mechanisms of amyloid formation in vivo and the bases of organ targeting and dysfunction. Investigating amyloid material in its natural environment is crucial to obtain new insights on the molecular features of fibrillar deposits at individual level. To this aim, we used Fourier transform infrared (FTIR) microspectroscopy for studying in situ unfixed tissues (heart and subcutaneous abdominal fat) from patients affected by AL amyloidosis. We compared the infrared response of affected tissues with that of ex vivo and in vitro fibrils obtained from the pathogenic LC derived from one patient, as well as with that of non amyloid-affected tissues. We demonstrated that the IR marker band of intermolecular β-sheets, typical of protein aggregates, can be detected in situ in LC amyloid-affected tissues, and that FTIR microspectroscopy allows exploring the inter- and intra-sample heterogeneity. We extended the infrared analysis to the characterization of other biomolecules embedded within the amyloid deposits, finding an IR pattern that discloses a possible role of lipids, collagen and glycosaminoglycans in amyloid deposition in vivo. more...

The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients' age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients. more...

In cardiac (light chain) AL amyloidosis, a decrease in circulating free light chains (FLCs) higher than 50% is associated with reduced N-terminal natriuretic peptide type B (NT-proBNP) serum concentration, improvement of heart failure symptoms, and prolonged survival. To assess the functional correlates of these changes, echocardiographic indices of systolic and diastolic regional function were compared at diagnosis and after response achievement in 32 patients. FLCs and NT-proBNP were concomitantly measured. No significant change in left ventricular wall thicknesses, chamber dimensions, indices of diastolic dysfunction or ejection fraction was observed after chemotherapy. In contrast, systolic longitudinal excursion of both the interventricular septum and the lateral wall was increased (from 5.2 +1.4 to 6.8 +1.5 and from 6.2 +1.3 to 7.7 +1.4 mm, respectively; p50.05 for both). These changes were significantly correlated with the extent of FLCs (p=0.05) and NT-proBNP (p=0.05) reduction. In cardiac AL amyloidosis, hematological response to chemotherapy and reduction of cardiac biomarkers are associated with improved indices of regional systolic functioavailable more...