Serum levels of NT-proBNP as surrogate for cardiac amyloid burden: new evidence from gadolinium-enhanced cardiac magnetic resonance imaging in patients with amyloidosisLehrke, Stephanie; Steen, Henning; Kristen, Arnt V.; Merten, Constanze; Lossnitzer, Dirk; Dengler, Thomas J.; Katus, Hugo A.; Giannitsis, Evangelos
doi: 10.3109/13506120903421538pmid: 19922329
Background. The prognostic value of NT-proBNP has been recognized in patients with amyloidosis complicated by cardiac involvement. We aimed to use contrast enhanced cardiac magnetic resonance imaging (CMR) to identify functional and structural alterations related to levels of NT-proBNP better to understand the mechanisms of its release in cardiac amyloidosis.Methods and Results. CMR was performed on a 1.5-T scanner in 34 patients with biopsy proven amyloid light chain (AL; n = 27) or hereditary transthyretin related (TTR; n = 7) amyloidosis. NT-proBNP was higher in patients with (n = 25) compared to patients without cardiac involvement (n = 9) (2931 (IQR: 972–8629; min-max: 25–27,277) pg/ml vs. 177 (IQR: 71–1431; min-max: 22–7935) pg/ml, p = 0.008). ROC analysis identified a NT-proBNP of <2426.5 pg/ml as optimal discriminator for event free survival (682 ± 65 days). NT-proBNP did not correlate with LV- ejection fraction, end-diastolic and end-systolic volumes or stroke volume. There was a moderate correlation between NT-proBNP and LV-mass (R = 0.52, p = 0.003) and extent of late gadolinium enhancement (LGE; R = 0.41, p = 0.04).Conclusions. This study confirms the prognostic value of NT-proBNP in patients with AL and TTR amyloidosis and provides the novel finding that NT-proBNP correlates with surrogates of myocardial amyloid burden such as LV-mass and LGE, supporting the concept of NT-proBNP as a biomarker reflecting the severity of cardiac amyloid infiltration.
Differential affinity of serum amyloid A1 isotypes for high-density lipoproteinYamada, Toshiyuki; Sato, Junji; Okuda, Yasuaki
doi: 10.3109/13506120903421546pmid: 19922330
Serum amyloid A (SAA), a precursor of reactive amyloid deposits, is a multigene product. SAA1, predominant both as an amyloid precursor and in plasma, consists of three allelic variants (SAA1.1, SAA1.3, and SAA1.5). Several investigations have shown that the SAA1.3 allele is associated with susceptibility to AA-amyloidosis in Japanese, and the SAA1.5 allele is related with higher serum concentrations of SAA. However, these results have not been interpreted functionally. This study assessed the affinity of SAA isotypes for high-density lipoprotein (HDL), to which SAA binds in plasma. Using a surface plasmon resonance-based apparatus (BIAcore), the affinity between immobilized recombinant human SAAs and HDL was determined. The SAA concentration was measured in fractions after ultracentrifugation (d = 1.23) of sera from patients with rheumatoid arthritis, whose SAA1 genotypes were determined. In the BIAcore analysis, as the dissociation reaction under the conditions used was too rapid to fit the typical kinetic model, the steady-state affinity model was used. The affinity (kd) of SAA1.1, SAA1.3, and SAA1.5 for HDL was 1.4 × 10−5, 1.8 × 10−5, and 3.7 × 10−6, respectively. rSAA1.5 showed significantly (p < 0.05) stronger affinity than the other two. The fraction of lipid-free SAA in serum was significantly (p < 0.001) lower in the patients with larger numbers of the 1.5 allele at the SAA1 locus. These results suggest that the relatively high affinity of SAA1.5 may cause the high serum concentration and may be related to the low susceptibility to amyloidosis.
Isolation and characterization of monoclonal antibodies against bovine serum amyloid A1 proteinTaira, Yuto; Inoshima, Yasuo; Ishiguro, Naotaka; Murakami, Tomoaki; Matsui, Takane
doi: 10.3109/13506120903421595pmid: 19922333
Bovine AA amyloidosis is the most frequently encountered amyloid type in cattle, and it is characterized by an extracellular deposition of pathological amyloid A (AA) protein. Because of the lack of a specific monoclonal antibody (mAbs) against bovine amyloid A (bAA) protein and its precursor, bovine serum amyloid A1 (bSAA1), at present anti-bAA rabbit antiserum and anti-human AA or SAA mAbs are widely used for diagnosis and analysis of bovine AA amyloidosis. In this study, three specific mAbs against bSAA1 were isolated by immunization using synthetic peptides of bSAA1, and these mAbs showed higher detection ability and specificity to bAA and bSAA1 than rabbit antiserum and anti-human AA or SAA mAbs in Western blot analysis and immunohistochemistry. These novel mAbs will be valuable in the development of a more precise immunochemical diagnostic tool for bovine AA amyloidosis, as well as for studying the pathophysiological mechanisms involved in this disease.
Usefulness of labial salivary gland biopsy in familial amyloid polyneuropathy Portuguese typeDo Amaral, Barbas; Coelho, T.; Sousa, A.; Guimarães, A.
doi: 10.3109/13506120903421850pmid: 19922336
Background. The diagnosis of amyloidosis of all types is definitively made by demonstration of Congo red binding material in the affected tissues. Nerve biopsy was classically used to diagnose amyloid polyneuropathy but less invasive alternative types of biopsies have been proposed including labial salivary gland (LSG) biopsy, a minimally invasive procedure.Method. LSG biopsies were done in 87 subjects with molecular diagnosis of TTRVal30Met mutation. The group includes 76 patients in different stages of familial amyloid polyneuropathy and 11 asymptomatic carriers. They were all submitted to a stomatological and a neurological observation to evaluate oral health problems and to determine the neurological stage of the disease. No major oral health problems were found. Mean age of onset of the symptomatic disease was 32.8 years (±9.69 SD).Conclusions. No significant side effects occurred after the surgical procedure, and adequate material for pathological analysis was always obtained. Amyloid deposition was found in 91% of the patients. Patients with negative biopsies (N = 7) were all in the earlier stage of the disease. Two asymptomatic carriers had biopsies with amyloid deposition. We conclude that LSG biopsy is a useful, sensitive and minimal invasive method to detect amyloid deposition.
Primary systemic amyloidosis and persistent pleural effusionsSchwarz, Dan; Jue, Christopher; Sikov, William
doi: 10.3109/13506120903421900pmid: 19922337
Persistent pleural effusions are not common in patients with primary systemic amyloidosis (AL). A recent review of this complication of the disease hypothesized that the pathophysiology of these effusions is pleural amyloid deposition, disrupting lymphatic drainage. We report the case of a 73-year-old woman with primary systemic AL and persistent bilateral pleural effusions, refractory to diuresis and repeated thoracenteses. The patient's cardiac and renal dysfunction was not severe enough to explain these persistent effusions. Thus, despite a lack of biopsy-proven amyloid deposition, we suggest that these effusions may be secondary to pleural amyloid deposition.