Severe deficiency of coagulation Factor VII results in spontaneous cardiac fibrosis in mice

• Published in: The Journal of pathology Vol. 217; no. 3; pp. 362 - 371
• Main Authors: Xu, H, Noria, F, Sandoval-Cooper, MJ, Menchen, H, Donahue, DL, Ploplis, VA, Castellino, FJ
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-02-2009; Wiley
• Subjects: animal models of human disease; Animals; Biological and medical sciences; cardiac failure; cardiomyopathy; coagulation; Collagen - analysis; cytokines; Echocardiography, Doppler; endothelium; factor VII; Factor VII Deficiency - pathology; Fibrosis; fibrosis, cardiac failure; gene-altered mice; Heart Diseases - pathology; Hematologic and hematopoietic diseases; Hemorrhage - pathology; Immunohistochemistry; Inflammation; Investigative techniques, diagnostic techniques (general aspects); left ventricle; Male; Medical sciences; metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron, Transmission; Myocardium - chemistry; Myocardium - pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Platelet diseases and coagulopathies; Reverse Transcriptase Polymerase Chain Reaction; systolic dysfunction; vascular leakage; Heart; Blood coagulation; Animal model; cardiac failure; vascular leakage; factor VII; Cardiomyopathy; Spontaneous; Cardiovascular disease; Metalloendopeptidases; Hemopathy; Myocardial disease; Gene; Heart disease; Blood vessel; Genetics; Metalloproteinase; Coagulation factor deficiency; Human; Heart failure; Enzyme; Rodentia; Cytokine; Leak; Left ventricle; Endothelium; Peptidases; Vertebrata; animal models of human disease; gene-altered mice; coagulation; endothelium; cytokines; metalloproteinases; cardiomyopathy; systolic dysfunction; left ventricle; fibrosis; Mammalia; Mouse; Dysfunction; Animal; Fibrosis; Hydrolases; Circulatory system; Severe; Coagulopathy
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2454

Mice genetically modified to produce low levels (~1% of wild-type) of coagulation FVII presented with echocardiographic evidence of heart abnormalities. Decreases in ventricular size and reductions in systolic and diastolic functions were found, suggestive of a restrictive cardiomyopathy and consistent with an infiltrative myopathic process. Microscopic analysis of mouse hearts showed severe patchy fibrosis in the low-FVII mice. Haemosiderin deposition was discovered in hearts of these mice, along with increases in inflammatory cell number, ultimately resulting in widespread collagen deposition. Significant increases in mRNA levels of TGFβ, TNFα and several matrix metalloproteinases in low-FVII mice, beginning at early ages, supported a state of cardiac remodelling associated with the fibrotic pathology. Mechanistic time-course studies suggested that cardiac fibrosis in low-FVII mice originated from bleeding in heart tissue, resulting in the recruitment of leukocytes, which released inflammatory mediators and induced collagen synthesis and secretion. These events led to necrosis of cardiomyocytes and collagen deposition, characteristics of cardiac fibrosis. The results of this study demonstrated that haemorrhagic and inflammatory responses to a severe FVII deficiency resulted in the development of cardiac fibrosis, observed echocardiographically as a restrictive cardiomyopathy, with compromised ventricular diastolic and systolic functions. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.