2026-08-11 | Vitronectin-driven amyloid deposition disrupts mitochondrial homeostasis via integrin-mediated pathway in a humanized mouse model of transthyretin cardiac amyloidosis.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive cause of heart failure, especially in the ageing society, but cellular biological mechanism studies are limited by the lack of robust animal models. Vitronectin (VTN), an extracellular matrix (ECM) glycoprotein enriched in amyloid deposits, may contribute to amyloidogenesis, yet its pathogenic role in ATTR-CM remains undefined. Humanized knock-in mice expressing either wild-type (hTTRWT) or V142I mutant transthyretin (hTTRV142I) were generated. Amyloid burden, cardiac structure, and function were assessed by Congo red staining, electron microscopy, echocardiography, and cardiac magnetic resonance. The functional role of VTN and integrin signalling was studied using genetic silencing and pharmacological intervention with low-dose cilengitide. Both hTTRWT and hTTRV142I mice developed age-dependent cardiac amyloidosis with diastolic dysfunction and reduced survival, especially in the hTTRV142I strain. VTN co-localized with TTR fibrils, promoted fibril aggregation, reduced amyloid burden upon its knockdown, and preserved cardiac function. Mechanistically, TTR amyloid suppressed integrin αvβ3/FAK/Akt signalling, leading to marked mitochondrial dysregulation characterized by excessive fission, enhanced mitophagy, and impaired oxidative phosphorylation. Restoration of αvβ3 signalling with cilengitide normalized mitochondrial dynamics, improved bioenergetics, and ameliorated diastolic dysfunction despite persistent amyloid stress. Two reproducible ATTR-CM models that recapitulate the steadily progressive course of human disease were established. Furthermore, VTN actively drives cardiac amyloid deposition, and disruption of integrin αvβ3/FAK/Akt signalling links amyloid-ECM interactions to mitochondrial dysfunction. Therefore, modulation of integrin signalling represents a potential complementary therapeutic strategy in ATTR-CM beyond TTR suppression.

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2026-06-17 | Differential Transthyretin Stabilization in Patients With Wild Type and Variant Transthyretin Amyloidosis.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease caused by transthyretin (TTR) tetramer destabilization, leading to amyloid deposition from either age-related wild type TTR or pathogenic TTR variants. TTR variants are less stable than wild type TTR, leading to lower serum TTR (sTTR) and worse clinical outcomes. TTR stabilizers, tafamidis and acoramidis, are approved for treatment of patients with ATTR-CM. The aim of this study was to evaluate the differences in stabilizing effect and magnitude of sTTR increases for acoramidis and tafamidis using data from the ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy) trial. Stabilizing potency was analyzed using sTTR as an in vivo readout and by applying 2 orthogonal pharmacodynamic assays: Western blot and fluorescent probe exclusion. In vitro analyses used blood samples from patients with variant ATTR-CM at clinically relevant concentrations of acoramidis (10 μM) and tafamidis (16-26 μM). In ATTRibute-CM, treatment with acoramidis (n = 234) resulted in a greater rise in sTTR from baseline to month 30 vs placebo plus tafamidis (n = 34). Acoramidis achieved greater TTR stabilization than placebo plus tafamidis at month 30 by Western blot (90.2% [n = 83] vs 60.6% [n = 6]) and fluorescent probe exclusion (99.7% [n = 71] vs 68.0% [n = 4]), although this was limited by a small sample size. Subsequent in vitro analysis corroborated acoramidis was a more effective TTR stabilizer than tafamidis across all 51 individual participant samples tested, representing 17 unique variants. Acoramidis is a near-complete stabilizer of wild type and variant TTR. Although in vitro comparisons between acoramidis and tafamidis suggest greater stabilization by acoramidis, randomized prospective trial data comparing these TTR stabilizers are lacking, and further investigation is warranted. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).

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2026-06-01 | Spectrum of cardiac amyloidosis in clinical practice: insights from a single centre

Abstract Background Cardiac amyloidosis (CA) is a frequently underdiagnosed cause of heart failure. Early identification of affected patients and close interdisciplinary collaboration are essential for accurate diagnosis, appropriate subtyping, and timely initiation of disease-specific therapy. Methods From January 2023 to December 2025, 78 consecutive patients with suspected cardiac amyloidosis were referred to a specialized outpatient clinic. Referrals originated predominantly from cardiology (53.8%) and neurology departments (29.4%), followed by internal medicine (3.8%), hematology (5.1%), and radiology (1.3%). All patients underwent a comprehensive diagnostic evaluation including echocardiography, cardiac magnetic resonance imaging, bone scintigraphy, laboratory assessment, genetic testing, and endomyocardial biopsy when clinically indicated. Results Cardiac amyloidosis was confirmed in 44 of 78 patients (56.4%). Wild-type transthyretin amyloidosis (ATTRwt) was the most prevalent subtype (n=26), followed by light-chain amyloidosis (AL, n=12) and hereditary transthyretin amyloidosis (ATTRh, n=6). The median age was 73 years (IQR 66,2–80,5), and 70% of patients were male. All ATTRh patients presented with concomitant polyneuropathy. Compared with ATTRwt, AL patients were younger (median 67.5 vs. 77 years; p=0.007) and more frequently exhibited renal impairment (60% vs. 71%; p=0.01). Biomarker analysis revealed significantly higher NT-proBNP and troponin T levels in AL amyloidosis (p=0.05 and p=0.02, respectively). Echocardiography demonstrated preserved left ventricular ejection fraction across subtypes (median EF: AL 50%, ATTRwt 55%, ATTRh 60%) and increased interventricular septal thickness (median IVSd: 18 mm in AL and ATTRwt, 16 mm in ATTRh). Cardiac magnetic resonance imaging was most frequently utilized in AL patients (80%), whereas bone scintigraphy confirmed the diagnosis in all ATTRwt and ATTRh cases. Endomyocardial biopsy established the diagnosis in 8 patients (5 AL, 3 ATTRwt). Standard heart failure therapy included diuretics (84%), mineralocorticoid receptor antagonists (up to 70%), and SGLT2 inhibitors, particularly in ATTRwt patients (62%). Disease-specific treatment comprised tafamidis in 88% of ATTRwt patients and patisiran in 33% of ATTRh patients. Overall mortality during the study period was 10%. Conclusion This single-centre experience demonstrates the growing recognition of cardiac amyloidosis and emphasizes the necessity of a multidisciplinary diagnostic strategy. ATTRwt amyloidosis was the predominant subtype, characterized by distinct clinical, echocardiographic, and therapeutic features. Accurate and timely subtyping is crucial for guiding tailored therapy and improving patient outcomes.

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2026-06-01 | TSAT as a sole marker influence of iron deficiency during treatment with TTR stabilizers in patients with wild type ATTR amyloidosis without anaemia

Abstract Introduction Iron deficiency (ID) is common in patients with heart failure and there are established treatment effects of correcting ID in patients with HFrEF and HFpEF. However, data for patients with ATTR amyloidosis is rare as patients are mostly excluded from large randomized trials. This study investigates the prevalence of ID in treatment naïve patients and the influence of treatment with TTR stabilizers. Methods We retrospectively analysed a cohort of consecutive patients presented at our institution from 2021 to 2025 with confirmed cardiac wtATTR-cardiomyopathy (wtATTR-CM). Markers of iron deficiency (Hb, TSAT, Ferritin) and baseline characteristics were recorded and patients with ID without anemia according to ESC recommendations (Ferritin<100µg/l, or Ferritin 100-300µg/l and TSAT< 20%, Hb>7.4 mmol/l in females and >8.1 mmol/l in males) were included. After initial evaluation all patients received guideline directed disease modifying therapy with TTR stabilizers and were re-evaluated after 12 months of therapy. Patients with events (either 3 months before or during treatment) that suggests significant changes in iron status (e.g. major surgery, severe infection, iron supplementation, blood loss or bone marrow supressing therapy) were excluded. Between group differences were calculated using Mann-Whitney-U test or Wilcoxon signed rank test if applicable. Descriptive risks for ID are expressed using odds-ratios. Results We identified 51 patients (19,6% female, mean age 78,1 ± 6,8 years) who fulfilled the inclusion and exclusion criteria. The second investigation was performed after a median of 370 days of TTR-stabilizer therapy. 54,9% of patients had atrial fibrillation and concomitant oral anticoagulation. Ventricular function was decreased and NT-pro-BNP markedly elevated (3193 ± 4423 pg/ml). 33 (64,7%) of patients were NAC stage 1 according to the latest 4 strata staging recommendation. ID was prevalent in 17,6% of patients. After 12 months of treatment the prevalence was 23,5% .Over all timepoints ID was associated with elevated NAC stage (stage 1 vs. stage 2-4: OR of having ID 8.13; 95 % CI: 2.21 to 29.90, z statistic: 3.151;P = 0.0016) based on TSAT alone. Addiing Ferritin levels did not increase ID diagnosis. Conclusion ID without anaemia is common in patients with wtATTR-CM and associated with advanced disease stage and might reflect disease progression. Treatment with TTR stabilizers alone did not improve ID in this cohort so intravenous ID correction might be considered to improve symptoms in these patients. The addition of Ferritin levels in this cohort had no influence on stratifying the cohort so an analysis of TSAT alone seems feasible as recently suggested for general heart failure.For image description, please refer to the figure legend and surrounding text.

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2026-05-22 | Clinical And Genetic Profile Of Hereditary Transthyretin (ATTRv) Amyloidosis In The Middle East: A Single-Center Report

Background and Purpose: Transthyretin (ATTR) amyloidosis, including wild-type (ATTRwt) and hereditary (ATTRv) forms, is a rare but increasingly recognized disease. This first report from the Middle East presents our experience diagnosing ATTRv amyloidosis at the Abdali National Amyloidosis Center Methods: All referred patients underwent comprehensive evaluation. ATTR amyloidosis was established by a Perugini grade 2 or 3 positive pyrophosphate (PYP) scan, with exclusion of light chain monoclonality by serum and urine immunofixation and free light chain assay. Confirmed cases subsequently underwent genetic testing for TTR mutations Results: Between July 2021 and October 2025, 21 patients with ATTRv amyloidosis were identified (19 men, 2 women), mean age 59 years (range 40-75). Fifteen were from Iraq, two from Libya, two from Jordan, and one each from Sudan and Syria. Twenty patients had a Perugini grade 3 positive PYP scan and in one patient with the Thr60Ala mutation, the grade was 0. Mutations included Thr60Ala (n=16, Northern Iraq, Jordan, Syria), Lys55Asn (n=2, Libya), Val142Ile (n=1, Sudan), Ser43Asn (n=1, Iraq), and Val50Met (n=1, Jordan). Clinical features were heart failure in 16, neuropathy (peripheral/autonomic) in 14, diarrhea in 9, and weight loss (6-35 kg) in 14. Symptom duration ranged from 4 months to 6 years. Electrocardiographic findings included low voltage (n=7), atrial fibrillation (n=3), QRS prolongation (n=10), and permanent pacemaker implantation (n=4). All had elevated BNP/NT-proBNP and hs-troponin. Echocardiography showed left ventricular hypertrophy in 20 and pericardial effusion in 14; left ventricular ejection fraction ranged from 28-69%. Genetic screening of 16 relatives (7 men, 9 women) identified 12 carriers, with further workup confirming ATTRv in one Conclusions: This first report from the Middle East highlights the clinical profile and genetics of ATTRv amyloidosis in the region, underscoring the need for greater awareness and continued research.

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