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Published on: September 30, 2021
Severe deficiency of coagulation Factor VII results in spontaneous cardiac fibrosis in mice
H Xu1, F Noria, M J Sandoval-Cooper
1W. M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Abstract:
Mice genetically modified to produce low levels (approximately 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 TGFbeta, TNFalpha 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.
Insights
Severe Factor VII (FVII) deficiency in mice led to cardiac fibrosis and restrictive cardiomyopathy. Bleeding and inflammation caused heart abnormalities, including reduced ventricular function and collagen deposition.
Area of Science:
- Cardiovascular Biology
- Hematology
- Pathology
Background:
- Coagulation Factor VII (FVII) is crucial for hemostasis.
- FVII deficiency is rare but can cause bleeding disorders.
- The impact of severe FVII deficiency on cardiac tissue is not well understood.
Purpose of the Study:
- To investigate the cardiac consequences of severe FVII deficiency.
- To elucidate the mechanisms underlying FVII deficiency-induced cardiac pathology.
- To characterize the resulting cardiac abnormalities and their functional impact.
Main Methods:
- Echocardiography was used to assess cardiac structure and function in low-FVII mice.
- Histopathological analysis examined heart tissue for fibrosis, inflammation, and haemosiderin deposition.
- Gene expression analysis (mRNA) identified key mediators of cardiac remodeling.
- Time-course studies traced the origin of cardiac fibrosis.
Main Results:
- Low-FVII mice exhibited echocardiographic signs of restrictive cardiomyopathy, with reduced ventricular size and impaired systolic/diastolic function.
- Histology revealed severe patchy fibrosis, haemosiderin deposition, increased inflammatory cells, and collagen deposition in low-FVII hearts.
- Elevated mRNA levels of TGF-beta, TNF-alpha, and matrix metalloproteinases indicated active cardiac remodeling.
- Fibrosis was linked to bleeding events, leukocyte recruitment, inflammation, and subsequent cardiomyocyte necrosis.
Conclusions:
- Severe FVII deficiency induces cardiac fibrosis and restrictive cardiomyopathy in mice.
- Hemorrhagic and inflammatory responses are key drivers of FVII deficiency-associated cardiac pathology.
- This study highlights a novel link between coagulation factor deficiency and cardiovascular disease development.
