The clots removed from ischaemic stroke patients by mechanical thrombectomy are amyloid in nature DOI Creative Commons
Justine M. Grixti, Arun Chandran,

Johann Pretorius

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

Abstract Ischemic stroke due to large vessel occlusion results from the blockage of a major cerebral artery by clot; however, origins and molecular composition these clots remain poorly understood. Mechanical thrombectomy has become standard treatment remove obstructive clots, providing unique opportunity analyze their properties. We previously demonstrated that blood can clot into an amyloid-like form, generating fibrinaloid microclots (2–200 μm) are highly resistant fibrinolysis. In this study, archived eight ischemic patients with were examined, using samples stored in Walton Centre Clot Bank Liverpool, UK. All exhibited strong, heterogeneous amyloid staining, revealing pervasive component. These findings represent unreported characteristic highlighting potential for amyloid-targeted therapies overcome fibrinolytic resistance foundational new insight ischaemic pathophysiology treatment.

Language: Английский

Cellular and molecular cross‐talk in atrial fibrillation: The role of non‐cardiomyocytes in creating an arrhythmogenic substrate DOI Creative Commons
Zhenyu Dong, Ruben Coronel, Joris R. de Groot

et al.

The Journal of Physiology, Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Atrial fibrillation (AF) is a complex arrhythmia. Various modulating factors influence its triggers and substrate. Fibroblasts, adipocytes, inflammatory cells the coagulation system can disrupt cardiomyocyte function. Cardiomyocytes fibroblasts release cytokines that promote local systemic inflammation, enhancing fibroblast activation extracellular matrix deposition, leading to myocardial fibrosis. Fibrosis essential for induction of reentrant arrhythmias, including AF. Adipocytes contribute arrhythmogenesis by secreting pro-inflammatory pro-fibrotic factors, exacerbating inflammation metabolic dysregulation. Inflammatory mediators activate system, which augments this vicious cycle producing promoting fibrosis arrhythmias at same time as increasing risk thrombosis. Understanding these interconnected roles in development progress atrial arrhythmogenic substrate may point potential novel therapeutic targets stabilise or antagonise eventually prevent This review examines role interplay between cardiomyocytes, fibroblasts, contributing AF initiation perpetuation.

Language: Английский

Citations

0
Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots DOI
Douglas B. Kell, Etheresia Pretorius

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 17, 2024

Abstract In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils fibrils exhibiting a cross-β motif parallel or antiparallel β-sheets oriented perpendicular to fibre direction. These can intertwine mature fibres. Similar phenomena occur in blood from individuals circulating inflammatory molecules (also those originating viruses bacteria). presence inflammagens, pathological clotting occur, that results an anomalous termed fibrinaloid microclots. Previous proteomic analyses these microclots have shown non-fibrin(ogen) proteins, suggesting more complex mechanism than simple entrapment. We provide evidence against entrapment model, noting clot pores are too large centrifugation would removed weakly bound proteins. Instead, we explore whether co-aggregation into may involve axial (multiple proteins within same fibril), lateral (single-protein contributing fibre), both types integration. Our analysis data different diseases shows no significant overlap normal plasma proteome correlation between abundance Notably, abundant like α-2-macroglobulin, fibronectin, transthyretin absent microclots, while less such as adiponectin, periostin, von Willebrand Factor well represented. Using bioinformatic tools including AmyloGram AnuPP, found entrapped exhibit high amyloidogenic tendencies, their integration elements structures. This likely contributes microclots’ resistance proteolysis. findings underscore role cross-seeding microclot formation highlight need for further investigation structural properties implications thrombotic diseases. insights foundation developing novel diagnostic therapeutic strategies targeting disorders.

Language: Английский

Citations

2
Spectrum of Non-Obstructive Coronary Artery Disease and Its Relationship with Atrial Fibrillation DOI Open Access
Alexandru Florinel Oancea, Paula Cristina Morariu,

Ana Maria Buburuz

et al.

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(16), P. 4921 - 4921

Published: Aug. 21, 2024

This article aims to analyze the relationship between non-obstructive coronary artery disease (NOCAD) and atrial fibrillation (AF), exploring underlying pathophysiological mechanisms implications for clinical management. NOCAD AF are prevalent cardiovascular conditions that often coexist, yet their interrelation is not well understood. can lead ischemic necrosis of cardiomyocytes replacement with fibrous tissue, sustaining focal ectopic activity in myocardium. Atrial fibrillation, on other hand, most common sustained cardiac arrhythmia, able accelerate atherosclerosis increase oxygen consumption myocardium, creating a mismatch supply demand, thus promoting development or worsening ischemia. Therefore, seem be complex interplay one begets another.

Language: Английский

Citations

1
Proteomic Evidence for Amyloidogenic Cross-Seeding in Fibrinaloid Microclots DOI Open Access
Douglas B. Kell, Etheresia Pretorius

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10809 - 10809

Published: Oct. 8, 2024

In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils fibrils exhibiting a cross-β motif parallel or antiparallel β-sheets oriented perpendicular to fibre direction. These can intertwine mature fibres. Similar phenomena occur in blood from individuals circulating inflammatory molecules (and also some originating viruses bacteria). Such pathological clotting result an anomalous termed fibrinaloid microclots. Previous proteomic analyses these microclots have shown presence non-fibrin(ogen) proteins, suggesting more complex mechanism than simple entrapment. We thus provide evidence against such entrapment model, noting that clot pores are too large centrifugation would removed weakly bound proteins. Instead, we explore whether co-aggregation into may involve axial (multiple proteins within same fibril), lateral (single-protein contributing fibre), both types integration. Our analysis data different diseases shows no significant quantitative overlap normal plasma proteome correlation between abundance their Notably, abundant like α-2-macroglobulin, fibronectin, transthyretin absent microclots, while less as adiponectin, periostin, von Willebrand factor well represented. Using bioinformatic tools, including AmyloGram AnuPP, found entrapped exhibit high amyloidogenic tendencies, integration elements structures. This likely contributes microclots’ resistance proteolysis. findings underscore role cross-seeding microclot formation highlight need for further investigation structural properties implications thrombotic diseases. insights foundation developing novel diagnostic therapeutic strategies targeting disorders.

Language: Английский

Citations

1
The clots removed from ischaemic stroke patients by mechanical thrombectomy are amyloid in nature DOI Creative Commons
Justine M. Grixti, Arun Chandran,

Johann Pretorius

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

Abstract Ischemic stroke due to large vessel occlusion results from the blockage of a major cerebral artery by clot; however, origins and molecular composition these clots remain poorly understood. Mechanical thrombectomy has become standard treatment remove obstructive clots, providing unique opportunity analyze their properties. We previously demonstrated that blood can clot into an amyloid-like form, generating fibrinaloid microclots (2–200 μm) are highly resistant fibrinolysis. In this study, archived eight ischemic patients with were examined, using samples stored in Walton Centre Clot Bank Liverpool, UK. All exhibited strong, heterogeneous amyloid staining, revealing pervasive component. These findings represent unreported characteristic highlighting potential for amyloid-targeted therapies overcome fibrinolytic resistance foundational new insight ischaemic pathophysiology treatment.

Language: Английский

Citations

1