The angiotensin II type 1 receptor blocker losartan attenuates bioprosthetic valve leaflet calcification in a rabbit intravascular implant model.
OBJECTIVE
There is evidence that angiotensin II type I receptor blocker (ARB) could reduce structural valve deterioration. However, the anticalcification effect on the bioprosthetic heart valve (BHV) has not been investigated. Thus, we investigated the effects of losartan (an ARB) on calcification of implanted bovine pericardial tissue in a rabbit intravascular implant model.


METHODS
A total of 16 male New Zealand White rabbits (20 weeks old, 2.98-3.34 kg) were used in this study. Commercially available BHV leaflet of bovine pericardium was trimmed to the shape of a 3-mm triangle 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 direct administration in the buccal pouch of the animals. The control group (n = 8) was given 5 ml of normal saline by the same method. After 6 weeks, quantitative calcium determination, histological evaluation and western blot analysis of interleukin-6 (IL-6), osteopontin and bone morphogenetic protein 2 (BMP-2) were performed to investigate the mechanisms of the anticalcification effect of losartan.


RESULTS
No deaths or complications such as infection or haematoma were recorded during the experiment. All animals were euthanized on the planned date. The calcium measurement 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 = 0.0092). Immunohistochemistry analyses revealed that BMP-2-positive reactions were significantly attenuated in the ARB group. Western blot analysis showed that losartan suppressed the expression of IL-6, osteopontin and BMP-2.


CONCLUSIONS
Our results indicate that losartan significantly attenuates postimplant degenerative calcification of a bovine pericardial bioprosthesis in a rabbit intravascular implant model. Further studies are required to assess the effects of ARBs on BHV tissue in orthotopic implantations using a large animal model.
Division of Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea.|Department of Thoracic and Cardiovascular Surgery, Chungbuk National University Hospital, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.
Hong Ju
HJ
Shin
Division of Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea.
Dae-Hyun
DH
Kim
Division of Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea.
Han Ki
HK
Park
Division of Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea yhpark@yuhs.ac.
Young Hwan
YH
Park
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001705:Bioprosthesis; D015153:Blotting, Western; D002114:Calcinosis / Q000517:prevention & control*; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation / Q000379:methods; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D011817:Rabbits; D014654:Vascular Patency
D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan
Animal model; Bioprosthetic heart valve; Degenerative calcification; Intravenous implantation; Rabbit