Amyloid-Journal of Protein Folding Disorders最新文献

Background: Cardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction because these remain unknown. Our prior work focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations.

Objectives: To evaluate mechanisms of tissue dysfunction in cardiac AL and ATTR using a full biopsy tissue proteomics approach.

Methods: We performed proteomics analysis on 76 ATTR and 27 AL diagnostic endomyocardial biopsies.

Results: Stage-3 AL patients exhibited increased coagulation, extracellular matrix remodelling (ECM), epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia, and clathrin-mediated endocytosis pathways vs. stages-1/2, with decreased healthy cardiac metabolism. In stages-2 and 3 ATTR, immunoglobulin proteins, complement, and keratinisation pathways were increased compared to stage-1. Unsupervised analyses identified an ATTR group with worse survival characterised by upregulated complement and downregulated metabolic pathways. Compared to ATTR, AL had higher clathrin-mediated endocytosis, mRNA splicing, and ribosomal proteins, while ATTR had higher complement levels.

Conclusions: This study identifies known processes dysregulated in heart failure with preserved ejection fraction as well as novel pathways responsible for tissue damage. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis, especially among patients with worse outcomes.

Background: Wild-type transthyretin cardiac amyloidosis (ATTRwt) is an infiltrative disease leading to restrictive cardiomyopathy. We aimed to characterise exercise capacity in ATTRwt and to identify predictors of cardiopulmonary fitness, focusing on echocardiographic and clinical parameters.

Methods: We studied 110 ATTRwt patients from a prospective single-centre registry (2020-2024) by cardiopulmonary exercise testing (CPET). Besides CPET, all patients underwent comprehensive clinical assessment including follow-up for mortality. In 32 patients follow-up CPET after 1 year was available.

Results: In ATTRwt, reduced aerobic capacity (pVO2 16 [13-18] ml/kg/min), and ventilatory inefficiency (VE/VCO2 slope 35 [30-43]) were common. In the multivariable regression analysis, we identified TAPSE/sPAP ratio as predictive for pVO2 (p = 0.019) and ventilatory efficiency (p = 0.004), while left ventricular ejection fraction or measures of left ventricular hypertrophy were not predictive. Concordantly, TAPSE/sPAP ratio assessed at baseline predicted pVO2 at 1-year follow-up (p = 0.009). Furthermore, patients with a TAPSE/sPAP ratio below the median of 0.38 mm/mmHg presented a higher risk of all-cause death (p = 0.009).

Conclusion: In ATTRwt the TAPSE/sPAP ratio, a marker of right ventricular coupling, was an independent predictor of aerobic capacity assessed by CPET, at baseline and after 1 year, highlighting the importance of right ventricular assessment for risk stratification.

Background: Proteomics is routinely used to type clinical amyloid deposits, and offers additional benefit of identifying genetic variants, which can be diagnostically useful. Reviewing the proteomics data for ATTR patients attending our Centre revealed an unusually large number of samples containing a rare pathogenic H90D TTR variant alongside the more common H90N variant.

Methods: These findings raised questions to their source. Proteomics was used to monitor the generation of H90D/H90N variants in fresh, frozen, stored samples during extraction and digestion, and also following Cu²⁺-mediated oxidation.

Results: There was no evidence that the variants were present in the circulation, except in one patient with genetically confirmed H90D TTR, in fresh fat aspirates or tissues from an ATTR amyloid mouse model. The variant could be generated in vitro from both wild-type TTR and ex vivo ATTR fibrils by non-enzymic oxidation of histidine at position 90. These data suggest that the H90D variant can be generated artefactually from wild-type 90H TTR through a radical-mediated oxidation of histidine, followed by its conversion to asparagine and aspartic acid. This probably occurs during storage.

Conclusions: In the absence of genetic data, the identification of H90D TTR in stored tissue by proteomics should be treated with caution.

Background: Each monoclonal antibody light chain associated with AL amyloidosis has a unique sequence. Defining how these sequences drive amyloid deposition could facilitate faster diagnosis and lead to new treatments.

Methods: Light chain sequences are collected in the AL-Base repository. Monoclonal sequences from AL amyloidosis, multiple myeloma and the healthy polyclonal immune repertoire were compared to identify differences in precursor gene use, mutation frequency and physicochemical properties.

Results: AL-Base now contains 2,200 monoclonal light chain sequences from AL amyloidosis and other plasma cell dyscrasias. Sixteen germline precursor genes were enriched in AL amyloidosis, relative to multiple myeloma and the polyclonal repertoire. Two genes, IGKV1-16 and IGLV1-36, were infrequently observed but highly enriched in AL amyloidosis. The number of mutations varied widely between light chains. AL-associated κ light chains harboured significantly more mutations compared to multiple myeloma and polyclonal sequences, whereas AL-associated λ light chains had fewer mutations. Machine learning tools designed to predict amyloid propensity were less accurate for new sequences than their original training data.

Conclusions: Rarely-observed light chain variable genes may carry a high risk of AL amyloidosis. New approaches are needed to define sequence-associated risk factors for AL amyloidosis. AL-Base is a foundational resource for such studies.

The clinical efficacy of transthyretin (TTR) tetramer stabilisers and TTR gene silencers in addition to liver transplantation has been established for hereditary ATTR (ATTRv) amyloidosis. Accordingly, non-central nervous system (CNS) systemic amyloidosis manifestations, such as peripheral neuropathy and cardiomyopathy, are now being overcome. However, emerging disease-modifying therapeutics have limited effects on CNS amyloidosis since they target the blood-circulating TTR produced in the liver, and not the cerebral spinal fluid (CSF) TTR synthesised in the choroid plexus. CNS involvement is therefore becoming the most common and severe complication in patients with ATTRv amyloidosis, including transient focal neurologic episodes, haemorrhagic and ischaemic stroke, cognitive decline, and cranial nerve dysfunction. Pathologically, extensive amyloid depositions are observable in the leptomeninges and leptomeningeal vessels, which are in direct contact with the CSF. Amyloid positron emission tomography is a useful biomarker for the early detection and treatment evaluation of early-onset ATTRv amyloidosis with the V30M (p.V50M) variant. Treatment-wise, blood-brain barrier-permeable stabilisers, intrathecal injection of silencers, and monoclonal antibodies against misfolded TTR and/or ATTR amyloid may potentially ameliorate CNS ATTR amyloidosis. The development of novel imaging/CSF biomarkers and disease-modifying therapies are the greatest unmet medical need in ATTRv amyloidosis and require further clinical trials.

Background: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive fatal disorder caused by deposition of mutant transthyretin (TTR) amyloids mainly in the nerves and heart. Autonomic dysfunction is a major disabling manifestation, affecting 90% of patients with late-onset ATTRv-PN. The current study aimed to investigate brain functional alterations associated with dysautonomia due to peripheral autonomic nerve degeneration in ATTRv-PN.

Methods: Resting-state functional MRI data were acquired from 43 ATTRv-PN patients predominantly of A97S (p.A117S) genotype, and the functional connectivity of central autonomic regions was assessed.

Results: Compared with age-matched healthy controls, the ATTRv-PN patients exhibited (1) reduced functional connectivity of the central autonomic regions such as hypothalamus, amygdala, anterior insula, and middle cingulate cortex with brain areas of the limbic, frontal, and somatosensory systems, and (2) correlations of reduced functional autonomic connectivity with the severity of autonomic dysfunction especially orthostatic intolerance, decreased heart rate variability, and greater clinical disability.

Conclusions: Our findings provide evidence linking peripheral autonomic dysfunction with altered connectivity in the central autonomic network in ATTRv-PN.

Introduction: Although sudden death (SD) is a recognized complication of cardiac amyloidosis, there is scarce data about its incidence, mechanisms, and predictors. The aim of this study was to describe incidence of SD and to analyze possible risk factors.

Methods: Consecutive patients with ATTR or AL cardiac amyloidosis evaluated at two European centers were identified. SD was defined as unexpected death in clinically stable patients. Cox proportional hazard regression was performed to assess risk factors in univariate analysis. Those statistically significant were then assessed through age-adjusted multivariate analysis.

Results: Analysis included 784 patients, 569 with ATTR amyloidosis (mean age 74.1 ± 12.1 years) and 215 with AL amyloidosis (mean age 64.5 ± 10.8 years). After a median follow-up of 1.9 years, SD rate at 2 years was 1.8% in ATTR. Previous pacemaker implantation (PPM) was associated with increased risk after age-adjusted analysis (HR 4.97; 95%CI: 1.39-17.7; p = 0.01). SD rate in AL amyloidosis patients at 2 years was 8.0% after a median follow-up of 1.2 years. Betablockers and NYHA III-IV were independently associated with an increased risk after age-adjusted multivariate analysis (HR 7.06 95%CI (2.31-21.5) p = 0.001) and (HR 4.56 95%CI (1.51-13.8) p = 0.007) respectively.

Conclusions: SD is more frequent in AL than in ATTR cardiac amyloidosis. SD is associated with different risk factors in both entities.