Mice severely deficient in coagulation Factor (F)VII that survive to adulthood have been developed, thus allowing the study of spontaneous bleeding and inflammatory phenotypes under conditions of a deficiency of extrinsic coagulation, especially in organs e.g., the heart, that continually undergo normal mechanical challenge. Mice genetically modified to produce very low levels (∼1% of wild-type) of coagulation FVII (FVIItTA/tTA) spontaneously developed heart abnormalities that were revealed by echocardiography. There were no significant differences between groups at baseline for the hemodynamic and respiratory parameters: temperature and heart rate (HR). The end-systolic functions of FVIItTA/tTA mice heart were comparable to wild-type (WT) controls. However, there were significant changes in the end-diastolic parameters of FVIItTA/tTA hearts. The diameter at end-diastole in FVIItTA/tTA mice was smaller compared to WT mice, which was due to the stiffness of the interventricular wall. When viewed from the parasternal short-axis, these mice had evidence of hypokinesis, indicating alteration of the elastic properties of the left ventricular (LV) wall. Correspondingly, the stroke volume, ejection fraction, fractional shortening, and cardiac output were lower in FVIItTA/tTA mice, compared to WT mice. Mitral valve inflow was compromised in FVIItTA/tTA mice, as demonstrated by the reduced early/late (E/A) filling ratio. We found that the spontaneous impaired cardiac function in FVIItTA/tTA mice was associated with an increased ratio of heart weight to body weight. Decreases in ventricular size, accompanied by reductions in systolic and diastolic functions, suggest a restrictive cardiomyopathy, consistent with an infiltrative myopathic process. Microscopic analysis of mouse hearts showed severe patchy fibrosis in FVIItTA/tTA mice. Hemosiderin deposition in hearts of these mice, along with large increases in inflammatory cells, ultimately resulting in widespread collagen deposition, were found. Significant increases in mRNA levels of TGF-beta, TNF-alpha, and a variety of matrix metalloproteinases, beginning at early ages in FVIItTA/tTA mice, supported the fibrotic pathology. The results of this study demonstrated that hemorrhagic and inflammatory responses to a severe FVII deficiency resulted in the development of cardiac fibrosis, manifest echocardiographically as a restrictive cardiomyopathy, with significantly compromised ventricular diastolic and systolic functions. These data also suggest that a FVII deficiency differentially regulates the expression level of inflammation and extracellular matrix proteins, which result in compromised cardiac function.

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