Amyloid-Journal of Protein Folding Disorders最新文献

Background: Previously, T2-relaxation time (T2_app) and proton spin density (ρ) detected nerve injury in a small group of ATTRv amyloidosis. Here, we aim to quantify peripheral nerve impairment in a large cohort of symptomatic and asymptomatic ATTRv amyloidosis and correlate T2-relaxometry markers with clinical parameters and nerve conduction studies (NCS).

Methods: Eighty participants with pathologic variants of the transthyretin gene (TTRv) and 40 controls prospectively underwent magnetic resonance neurography. T2-relaxometry was performed, allowing to calculate tibial ρ, T2_app and cross-sectional-area (CSA). Detailed clinical examinations and NCS of tibial and peroneal nerves were performed.

Results: Forty participants were classified as asymptomatic TTRv-carriers, 40 as symptomatic patients with polyneuropathy. ρ, T2_app and CSA were significantly higher in symptomatic ATTRv amyloidosis (484.2 ± 14.8 a.u.; 70.6 ± 1.8 ms; 25.7 ± 0.9 mm²) versus TTRv-carriers (413.1 ± 9.4 a.u., p < 0.0001; 62.3 ± 1.3 ms, p = 0.0002; 19.0 ± 0.8 mm², p < 0.0001) and versus controls (362.6 ± 7.5 a.u., p < 0.0001; 59.5 ± 1.0 ms, p < 0.0001; 15.4 ± 0.5 mm², p < 0.0001). Only ρ and CSA differentiated TTRv-carriers from controls. ρ and CSA correlated with NCS in TTRv-carriers, while T2_app correlated with NCS in symptomatic ATTRv amyloidosis. Both ρ and T2_app correlated with clinical score.

Conclusion: ρ and CSA can detect early nerve injury and correlate with electrophysiology in asymptomatic TTRv-carriers. T2_app increases only in symptomatic ATTRv amyloidosis in whom it correlates with clinical scores and electrophysiology. Our results suggest that T2-relaxometry can provide biomarkers for disease- and therapy-monitoring in the future.

Background: This study aimed to assess the prognostic value of cardiac magnetic resonance (CMR) variables and compare them with biological and echocardiographic markers in patients with AL cardiac amyloidosis (CA).

Methods: We conducted a prospective study across three tertiary centres, where patients underwent clinical examination, blood tests, echocardiography, and CMR. The primary endpoint was all-cause mortality.

Results: A total of 176 patients with AL CA were included, with a median age of 68 years (IQR 58-75). According to the 2004 Mayo Clinic staging, 121 patients (69%) were in stage 3. During a median follow-up of 22 months (IQR 8-48), 45 patients died, and 55 were hospitalized for heart failure. Patients who died had higher NT-proBNP and troponin levels, and lower LVEF, cardiac output, and longitudinal strain. Among CMR variables, extracellular volume (ECV) was most strongly associated with all-cause mortality. In multivariate Cox models, including Mayo Clinic staging, ECV ≥ 0.45 was independently associated with mortality (HR 2.36, CI 95% 1.47-5.60) and also with heart failure hospitalizations (HR 4.10, 95%CI 2.15-8.8).

Conclusion: ECV is a powerful predictor of outcomes in AL CA, providing additional prognostic value on top of Mayo Clinic staging.

Background: Diarrhoea is one of the most serious complications in hereditary ATTR (ATTRv) amyloidosis. However, its precise pathomechanism remains unknown. The present study investigated the involvement of bile acid in diarrhoea along with the therapeutic effect of colestimide, a bile acid sequestrant, in ATTRv amyloidosis.

Methods: We prospectively enrolled 19 ATTRv amyloidosis patients (9 with refractory diarrhoea and 10 without diarrhoea) and 20 healthy individuals for measurements of serum 7a-hydroxy-4-cholesten-3-one (C4) levels. The patients with diarrhoea were then treated with oral colestimide (1.5 g twice daily) for 28 days. The frequency of diarrhoea and C4 level were evaluated before and after colestimide treatment.

Results: Mean serum C4 level was significantly higher in ATTRv patients with diarrhoea (62.3 ng/mL) than in ATTRv patients without diarrhoea (24.0 ng/mL, p = 0.03). Colestimide treatment significantly decreased mean diarrhoea frequency (pre-treatment period: 9.1 times/week, colestimide treatment period, 6.6 times/week, p = 0.04) and increased mean C4 level (before treatment: 66.2 ng/mL, after treatment: 187.1 ng/mL, p = 0.02).

Conclusions: Bile acid status was significantly associated with diarrhoea in ATTRv amyloidosis. Colestimide and other bile acid sequestrants may reduce diarrhoea frequency in afflicted patients.

Background: The NEURO-TTRansform trial showed that after 66 weeks of treatment, eplontersen significantly reduced neuropathic impairment and improved quality of life (QoL) in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). In this secondary analysis from NEURO-TTRansform, autonomic impairment, and the impact of eplontersen on autonomic impairment progression was evaluated through 85 weeks in patients randomised to eplontersen (n = 144) versus external placebo (n = 60; through Week 66 from the NEURO-TTR trial).

Methods: Change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score, and the Neuropathy Symptoms and Change (NSC) total score was evaluated. Exploratory assessments were change in autonomic components of these instruments, Composite Autonomic Symptom Score-31 (COMPASS-31) total score, and nutritional status (modified body mass index [mBMI]).

Results: Patients reported profound autonomic dysfunction at baseline. Improvements with eplontersen versus placebo were observed up to Week 66 in autonomic components of mNIS+7, Norfolk QoL-DN, NSC, and mBMI; eplontersen results were sustained up to Week 85, including improvements in COMPASS-31 (Week 81).

Conclusions: Eplontersen demonstrated benefit across multiple measures of autonomic impairment known to progress rapidly and negatively impact QoL without treatment, without deterioration in nutritional status.

Background: A high incidence of valvular involvement of amyloid in the setting of aortic stenosis (AS) has been reported. Amyloid derived from ApoAI (AApoAI) can form local amyloid deposits in the aortic valve. Although a high prevalence of concomitant severe AS and cardiac transthyretin-type amyloidosis (ATTR) has been reported, the prevalence of valvular involvement by ATTR and AApoAI is unclear.

Methods: Using immunostaining and mass spectrometry, we analysed amyloid proteins in 97 aortic valves removed for valve replacement due to AS at Kyoto Prefectural University of Medicine between 2014 and 2021. Clinical information was also reviewed.

Results: Amyloid deposits were found in 44 cases (45%), of which 30 cases (68%) involved ATTR and 33 cases (75%) AApoAI. Statistical analysis showed significantly lower age and E/e' among amyloid-positive cases compared with amyloid-negative cases and significantly lower brain natriuretic peptide, higher fractional shortening, and higher left ventricular ejection fraction among ATTR-positive cases compared with ATTR-negative cases. Seven recent patients underwent bone scintigraphy and ATTR cardiomyopathy was observed in only one case.

Conclusions: AS symptoms can manifest earlier in patients with amyloid or ATTR deposition in the aortic valve than in patients without such deposition, even though left ventricular function is preserved.