Angiotensin II type 1 receptor blocker losartan attenuates bioprosthetic valve leaflet calcification in a rabbit intravascular implant modelAngiotensin II receptor blocker인 losartan

Abstract

There are some evidences that angiotensin II type I receptor blocker (ARB) could reduce the structural valve deterioration. However, the anticalcification effect on the bioprosthetic heart valve is not yet investigated. Thus, we investigated the effects of the ARB on calcification of implanted bovine pericardial tissue in a rabbit intravascular implant model. A total of 16 male New Zealand White rabbits (20 weeks old, body weight: 2.98~3.34 kg) were used in this study. Commercially available bioprosthetic heart valve leaflet of bovine pericardium was trimmed to a 3-mm triangle shape and implanted to both external jugular veins of the rabbit. The ARB group (n=8) was given 25 mg/kg of powdered losartan daily until 6 weeks after surgery by directly administration in buccal pouch of the animals. The control group (n=8) was given 5 ml of normal saline with the same method. After 6 weeks, quantitative calcium determination, histological evaluation, and western blot analysis about interleukin-6, osteopontin, and BMP-2 were performed to identify the anti-calcification effect and its mechanisms of losartan. No deaths or complications such as infection or hematoma were recorded during the experiment. All animals were euthanized on the planned date. Calcium measurements level in the ARB group (2.28 ± 0.65 mg/g) was significantly lower than that in the control group (3.68 ± 1.00 mg/g) (p = 0.0281). Immunohistochemistry analyses revealed that bone morphogenetic protein 2 (BMP-2)-positive reactions were significantly attenuated in the ARB group. Western blot analysis showed that losartan suppressed the expression of interleukin-6, osteopontin, and BMP-2. Our results indicate that losartan significantly attenuates post-implant degenerative calcification of bovine pericardial bioprosthesis in a rabbit intravascular implant model. Further studies are required to assess the effects of ARBs on bioprosthetic heart valve tissue in orthotopic implantations using a large animal model.