Tetsuya Hara1, Norie Tsukada2, Mitsumasa Okano3, Tatsuro Ishida3, Ken-Ichi Hirata3, Masashi Shiomi4. 1. Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan. Electronic address: thara@med.kobe-u.ac.jp. 2. Institute for Experimental Animals and Division of Comparative Pathophysiology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Japan. 3. Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan. 4. Institute for Experimental Animals and Division of Comparative Pathophysiology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Japan. Electronic address: ieakusm@med.kobe-u.ac.jp.
Abstract
BACKGROUND AND AIMS: Aortic valve stenosis (AS) is the most common valvular heart disease and can be life-threatening. The pathogenesis of aortic valve calcification remains largely unknown, primarily due to the lack of an adequate animal model. The high-cholesterol diet-induced AS model in rabbits is one of the established models, but it has the significant limitation of liver dysfunction leading to low survival rates. We hypothesized that a myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbit, an animal model of familial hypercholesterolemia and atherosclerosis, is a useful animal model of AS. METHODS: WHHLMI rabbits, aged 20 months and 30 months (n = 19), and control Japanese White rabbits (n = 4), aged 30 months, were used and evaluated by echocardiography under anesthesia. Pathological evaluation and quantitative analyses by polymerase chain reaction (PCR) were also performed. RESULTS: The lipid profile was similar between 20 months and 30 months. Two rabbits died due to spontaneous myocardial infarction during the study. Thirty-month-old WHHLMI rabbits exhibited significantly smaller aortic valve area (0.22 ± 0.006 cm2vs. 0.12 ± 0.01 cm2, p < 0.05) and higher maximal transvalvular pressure gradient (7.0 ± 0.32 vs. 9.9 ± 0.95 mmHg, p < 0.05) than 20 month-old rabbits. Macroscopic examination of excised aortic valves demonstrated thickened and degenerated valve leaflets at 30 months. Histological evaluation confirmed thickened leaflets with calcified nodules at 30 months. Real-time PCR of resected aortic valve also showed increased expression level of calcification-related molecules including osteopontin, Sox9, Bmp2, RANKL, osteoprotegerin, and Runx2 (p < 0.05 each) in 30-month-old rabbits. CONCLUSIONS: WHHLMI rabbits may be useful models of early-stage AS in vivo.
BACKGROUND AND AIMS: Aortic valve stenosis (AS) is the most common valvular heart disease and can be life-threatening. The pathogenesis of aortic valve calcification remains largely unknown, primarily due to the lack of an adequate animal model. The high-cholesterol diet-induced AS model in rabbits is one of the established models, but it has the significant limitation of liver dysfunction leading to low survival rates. We hypothesized that a myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbit, an animal model of familial hypercholesterolemia and atherosclerosis, is a useful animal model of AS. METHODS: WHHLMI rabbits, aged 20 months and 30 months (n = 19), and control Japanese White rabbits (n = 4), aged 30 months, were used and evaluated by echocardiography under anesthesia. Pathological evaluation and quantitative analyses by polymerase chain reaction (PCR) were also performed. RESULTS: The lipid profile was similar between 20 months and 30 months. Two rabbits died due to spontaneous myocardial infarction during the study. Thirty-month-old WHHLMI rabbits exhibited significantly smaller aortic valve area (0.22 ± 0.006 cm2vs. 0.12 ± 0.01 cm2, p < 0.05) and higher maximal transvalvular pressure gradient (7.0 ± 0.32 vs. 9.9 ± 0.95 mmHg, p < 0.05) than 20 month-old rabbits. Macroscopic examination of excised aortic valves demonstrated thickened and degenerated valve leaflets at 30 months. Histological evaluation confirmed thickened leaflets with calcified nodules at 30 months. Real-time PCR of resected aortic valve also showed increased expression level of calcification-related molecules including osteopontin, Sox9, Bmp2, RANKL, osteoprotegerin, and Runx2 (p < 0.05 each) in 30-month-old rabbits. CONCLUSIONS: WHHLMI rabbits may be useful models of early-stage AS in vivo.
Authors: Christine Quast; Frank Kober; Katrin Becker; Elric Zweck; Jasmina Hoffe; Christoph Jacoby; Vera Flocke; Isabella Gyamfi-Poku; Fabian Keyser; Kerstin Piayda; Ralf Erkens; Sven Niepmann; Matti Adam; Stephan Baldus; Sebastian Zimmer; Georg Nickenig; Maria Grandoch; Florian Bönner; Malte Kelm; Ulrich Flögel Journal: Basic Res Cardiol Date: 2022-05-29 Impact factor: 12.416