title: Complement system modulation as a target for treatment of arrhythmogenic cardiomyopathy.
abstract: Inflammation may contribute to disease progression in arrhythmogenic cardiomyopathy (ACM). However, its role in this process is unresolved. Our goal was to delineate the pathogenic role of the complement system in a new animal model of ACM and in human disease. Using cardiac histology, echocardiography, and electrocardiography, we have demonstrated that the desmin-null mouse (Des-/-) recapitulates most of the pathognomonic features of human ACM. Massive complement activation was observed in the Des-/- myocardium in areas of necrotic cells debris and inflammatory infiltrate. Analysis of C5aR-/-Des-/- double-null animals and a pharmaceutical approach using a C5a inhibitor were used to delineate the pathogenic role of the complement system in the disease progression. Our findings indicate that inhibiting C5aR (CD88) signaling improves cardiac function, histopathology, arrhythmias, and survival after endurance. Containment of the inflammatory reaction at the initiation of cardiac tissue injury (2-3 weeks of age), with consequently reduced myocardial remodeling and the absence of a direct long-lasting detrimental effect of C5a-C5aR signaling on cardiomyocytes, could explain the beneficial action of C5aR ablation in Des-/- cardiomyopathy. We extend the relevance of these findings to human pathophysiology by showing for the first time significant complement activation in the cardiac tissues of patients with ACM, thus suggesting that complement modulation could be a new therapeutic target for ACM.
authors: Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece, emavroeid@bioacademy.gr.
authors: Manolis
authors: M
authors: Mavroidis
authors: Constantinos H
authors: CH
authors: Davos
authors: Stelios
authors: S
authors: Psarras
authors: Aimilia
authors: A
authors: Varela
authors: Nikolaos
authors: N
authors: C Athanasiadis
authors: Michalis
authors: M
authors: Katsimpoulas
authors: Ioanna
authors: I
authors: Kostavasili
authors: Christian
authors: C
authors: Maasch
authors: Axel
authors: A
authors: Vater
authors: J Peter
authors: JP
authors: van Tintelen
authors: Yassemi
authors: Y
authors: Capetanaki
mesh_terms: D000328:Adult; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000276:immunology / Q000473:pathology; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000276:immunology* / Q000473:pathology; D015936:Complement C5a / Q000276:immunology*; D003893:Desmin / Q000172:deficiency; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D011951:Receptors, Complement / Q000276:immunology*
chemical_list: D003893:Desmin; D011951:Receptors, Complement; D015936:Complement C5a