Review Article

Animal Models of Calcific Aortic Valve Disease

Table 2

Characteristics of rabbit and swine Models of CAVD.

ModelInsult*, duration, (treatment)Total cholResults, (treatment)Study

Rabbit

NZWR2% chol., 10% soybean, 2 & 3 wk↑L associated with Col and PG fibresNievelstein-Post et al. 1994 [76]
NZWR2% chol., 10% soybean, 2 wk↑L associated with Col, FcHaberland et al. 2001 [77]
NZWR2% chol., 10% soybean, 4 wk↑L associated with Col in clusters, fusingZeng et al. 2007 [81]
Chinchilla0.5% or 2% chol., 5% butter, 2–10 wk↑L, ECM fragment, followed by ↑M and Fc, to ↑Col and CFilip et al. 1987 [75]
NZWR1% chol., 12 wk2235 ± 162↑HDL, TG, Fc, apoptosis of M and FbRajamannan et al. 2001 [79]
NZWR1% chol., 8 wk, (atorvastatin)3235 ± 328↑ALP, Runx2, OPN, M, PCNA, hsCRP, T, (all but hsCRP; TC)Rajamannan et al. 2002 [78]
JWR1% chol., 8 wk, (ARB)1510 ± 265VEC integrity, eNOS; ↑L, M, OPN, My, Runx2, ACE, (all trends reversed)Arishiro et al. 2007 [95]
NZWR1% chol., 8 wk, (eplerenone)1206 ± 160↑C, L, Fc, M, ACE, (all; ↑aldosterone levels)Gkizas et al. 2010 [96]
NZWR0.5% chol., 3 mo, (atorvastatin)1725 ± 637↑hsCRP, T, C; nitrate, (hsCRP, T, C, TC; ↑eNOS, nitrate)Rajamannan et al. 2005 [85]
NZWR1% chol., VitD2 50,000 IU [daily], 12 wk1670 ± 150↑T, D, Col, L, C, Cl, M, My, TF, TVG; ADVMarechaux et al. 2009 [97]
NZWR0.5% chol., VitD2 50,000 IU [daily], 12 wk~1737↑TVG, serum calcium, C; AVADrolet et al. 2003 [80]
NZWR0.5% chol., VitD2 50,000 IU [3 times/wk], 10 wk↑TVG, E, C, Tc, M, My, serum calcium & phosphate; AVADrolet et al. 2008 [82]
NZWR0.5% chol., VitD2 100,000 IU [daily], 12 wk, (tempol) (Lipoic acid)1363 ± 90↑M, T, Cl, Col, C, E, OPN, Runx2, OC, SO, HP, N/OS, OS, SCP, SC; AVA, (↑C, OC, HP, OS; SO, Cl, N/OS) (C, E, SO, HP, N/OS)Liberman et al. 2008 [19]
NZWR0.25% chol., 20 & 40 wk822 ± 61↑T, L, Col, reorganization of Col & elastin, M, OPNCimini et al. 2005 [74]
NZWR0.12–0.25% chol., 15 & 30 mo, (atorvastatin)500 titrated↑L, M, Tc, T, Col, C, OPN, R, (L, M, Tc, T, OPN)Hamilton et al. 2011 [83]
NZWRVitD2 25,000  IU[4 times/wk], 8 wk↑TV, TVG, E, L, C, M, Lc, TXNIP, SCP, TC, SC, LVH; AVA, VEC fnNgo et al. 2008 [98]
NZWRVitD2 25,000  IU[4 times/wk], 8 wk, (ramipril)Same as above, (TV, E, LVH, TXNIP, SCP; ↑VEC fn)Ngo et al. 2011 [99]
WHHL0.25% chol., 6 mo, (atorvastatin)1329 ± 141↑T, Lpr5, PCNA, OPN, p42/44, C, My, (all & TC)Rajamannan et al. 2005 [84]

Swine

Yorkshirenormal (N) or chol, fat, diabetes(HCD), 6 moHCD has L and C; N Aortic VEC are antioxidative, non-I, and permissive to CSimmons et al. 2005 [100]
Yorkshire1.5% chol., 15% lard, 2 wk & 6 mo549 ± 114↑L, C; Aortic VEC are anti-I, and anticalcificGuerraty et al. 2010 [101]

*Rabbit and porcine diets are expressed as % weight added over base diet.
mg/dL. Normal total cholesterol ranges: human: 197 ± 23 mg/dL [61], mouse: 90–110 mg/dL, rabbit: 30–60 mg/dL, WHHL: 284 ± 29 mg/dL, swine: 60–75 mg/dL.
↑: increased compared to control, : decreased compared to control, ACE: angiotensin-converting enzyme, ADV: aortic Doppler velocity, ALP: alkaline phosphatase activity, ARB: angiotensin receptor blocker, AVA: aortic valve area, C: calcification, Cl: cellularity, Col: collagen, D: ECM disorganization, E: echogenicity, ECM: extracellular matrix, Fb: fibroblasts, Fc: foam cells, fn: function, HDL: high density lipoproteins, HP: hydrogen peroxide, hsCRP: highly sensitive C-reactive protein, I: inflammatory, JWR: Japanese white rabbit, L: lipid deposition, Lc: leukocyte (CD45), LVH: left ventricle hypertrophy, M: macrophage, My: myofibroblast, n/a: not applicable, N/OS: nitro/oxidative stress, NZWR: New Zealand white rabbit, OC: osteoclasts, OPN: osteopontin, OS: NAD(P)H oxidase subunits, PCNA: proliferating cell nuclear antigen, PG: proteoglycans, R: regurgitant flow, SC: serum creatinine, SCP: serum calcium-phosphate, SO: superoxide, T: thickness, Tc: T-cell, TC: total cholesterol, TF: tissue factor, TG: triglycerides, TVG: transvalvular pressure gradient, TV: transvalvular velocity, and VEC: valve endothelial cells.