Amyloid-Journal of Protein Folding Disorders最新文献

Background: Patients with AL amyloidosis present sustained paradoxical vasodilation in response to sympathetic stimulation by cold pressor test (CPT). The clinical relevance is unknown.

Methods: Peripheral and central systolic (SBP) and diastolic blood pressure (DBP) were measured at 3 min (end of CPT) and at 6 min, before and 12 months after treatment initiation in 113 treatment-naïve AL amyloidosis patients. Ten healthy volunteers were assessed at baseline. All-cause and cardiovascular mortality were recorded.

Results: Percentage reductions in central SBP and peripheral DBP at 6 min [AL vs controls: %CSBP6min (mean, SD) 0.7 ± 8.44 vs 7.57 ± 5.59; %DBP6min (mean, SD) 0.64 ± 8.91 vs 14 ± 9.11; p < 0.01 for both] were associated with all-cause and cardiovascular death (%CSBP6min HR = 0.945 and HR = 0.946 respectively; %DBP6min HR = 0.949 and HR = 0.916 respectively; p < 0.05 for all) after adjustment for disease-related risk factors. %CSBP6min provided incremental value over Mayo stage and was associated with neurological and cardiac dysfunction and myocardial infiltration. At 12 months, %CSBP6min further decreased in patients with earlier poor hematologic treatment response.

Conclusions: %CSBP6min, a noninvasive, readily available marker, was associated with cardiac dysfunction, poor survival, and its further post-treatment reduction was associated with hematologic response.

Background: Cross-seeding and co-assembly of multiple amyloid species are increasingly recognised in various organs and amyloidoses. Medin and wild-type transthyretin (TTR) both form age-related amyloid deposits and have been identified within the aortic wall. Given the emerging role of amyloid in aortic disease, this study investigates the potential colocalisation of TTR and medin in the aorta.

Methods: Medin and TTR levels were measured in thoracic aortic wall samples from 30 patients undergoing surgical replacement for aortic aneurysm. Immunohistochemistry was performed on five aortic wall samples and two excised aortic valves to assess colocalisation patterns. In vitro assays, including Thioflavin T fluorescence and immunogold labelling electron microscopy, evaluated protein co-aggregation and fibril formation. Cellular toxicity assays examined the impact of TTR on medin aggregates.

Results: A positive correlation was observed between medin and TTR levels in the aortic wall. In vitro assays revealed enhanced fibril formation and co-aggregation, with TTR reducing the cellular toxicity of medin aggregates, suggesting altered fibril properties. Immunohistochemistry confirmed colocalisation of medin and TTR in both aortic wall and valve samples.

Conclusions: This study identifies a novel association between medin and TTR, highlighting a potential role for co-aggregation in vascular amyloid deposition.

The peripheral nervous system (PNS) is commonly affected in immunoglobulin light chain amyloid protein (AL) amyloidosis. PNS involvement and particularly small fiber neuropathy (SFN) is often clinically underestimated, requiring a standardized approach for comprehensive assessment. We prospectively evaluated the prevalence and clinical significance of SFN in 81 patients with newly diagnosed AL amyloidosis using clinical examination, nerve conduction studies (NCSs), quantitative sensory testing (QST) examination and distal-leg skin biopsy. Neuropathy was detected in 89% of patients and SFN in 65%. Combined small and large fiber neuropathy was seen in 48.1%, pure large fiber neuropathy in 20% and pure SNF in 10%. Older age was a significant risk factor for SFN (OR 1.06, 95% CI 1.01-1.12, p = .014); patients with SFN were also more likely to have soft tissue involvement (OR 7.1, 95% CI 1.5-33.4, p = .013). After a median follow-up of 37.5 months, SFN was associated with poorer overall survival (OS) and it emerged as an independent prognostic factor for early mortality (<12 months) in multivariate analysis (HR 4.3 95% CI 1.23-15.04, p = .023). Our study demonstrates the high prevalence and clinical significance of SFN as an adverse factor for survival and indicates the need for multiparametric neurological evaluation in patients with AL amyloidosis at diagnosis.

Background: We explored sex differences in wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) and determined survival and prognostic factors.

Methods: In a retrospective cohort study at a reference centre in France from 1 January 2008 to 31 December 2022, multiple regression analyses, supervised clustering, Cox models, and a Kaplan-Meier analysis were used to compare women and men in each age quartile (Q1: ≤77 years; Q2: 78-82; Q3: 83-86; Q4 > 86).

Results: We included 1062 patients with ATTRwt-CM (180 women, 16%). The women had a higher median [IQR] left ventricular ejection fraction (LVEF; 52% [45-60] vs. 50 [43-58] in men) and a thinner interventricular septum. 12% of women and 4.1% of men had a septum thickness <12 mm (p = 0.004). The women in Q1 had lower LVEF and global longitudinal strain values and a higher prevalence of a septum <12 mm (15.8%, vs 2.0% in men) than men and older women (Q2-Q3-Q4). Women had a greater risk of sudden death than men (13.8% vs. 4.6%, respectively; odds ratio [95% confidence interval]: 3.24 [1.56-6.64]; p = 0.001).

Conclusions: In women, the ATTRwt-CM phenotype and prognosis are related to age at diagnosis. Decreasing the septum thickness cut-off would increase the frequency of ATTR-CM diagnosis in women.