Development of Human-Like Advanced Coronary Plaques in Low-Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques.

BACKGROUND: Although clinical trials have proved that statin can be used prophylactically against cardiovascular events, the direct effects of statin on plaque development are not well understood. We generated low-density lipoprotein receptor knockout (LDLR(-/-)) pigs to study the effects of early statin administration on development of atherosclerotic plaques, especially advanced plaques. METHODS AND RESULTS: LDLR(-/-) pigs were generated by targeted deletion of exon 4 of the LDLR gene. Given a standard chow diet, LDLR(-/-) pigs showed atherosclerotic lesions starting at 6 months of age. When 3-month-old LDLR(-/-) pigs were fed a high-cholesterol, high-fat (HCHF) diet for 4 months (HCHF group), human-like advanced coronary plaques developed. We also fed 3-month-old LDLR(-/-) pigs an HCHF diet with pitavastatin for 4 months (Statin Prophylaxis Group). Although serum cholesterol concentrations did not differ significantly between the 2 groups, intravascular ultrasound revealed 52% reduced plaque volume in statin-treated pigs. Pathological examination revealed most lesions (87%) in the statin prophylaxis group were early-stage lesions, versus 45% in the HCHF diet group (P<0.01). Thin-cap fibroatheroma characterized 40% of the plaques in the HCHF diet group versus 8% in the statin prophylaxis group (P<0.01), intraplaque hemorrhage characterized 11% versus 1% (P<0.01), and calcification characterized 22% versus 1% (P<0.01). CONCLUSIONS: Results of our large animal experiment support statin prophylaxis before the occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and ensure lesion stability. In addition, the LDLR(-/-) pigs we developed represent a large animal model of human-like advanced coronary plaque suitable for translational research.

A Cross-sectional Study of the Relationship Between Habitual Tea Consumption and Arterial Stiffness.

BACKGROUND AND AIMS: To explore the relationship between habitual tea consumption and arterial stiffness. METHODS: This is a cross-sectional, epidemiological survey of 6589 male and female residents aged 40-75 in Wuyishan, Fujian Province, China. Tea consumption and other lifestyle characteristics were obtained by structured questionnaires. Pulse wave velocity (PWV) and ankle-brachial pressure index (ABI) were measured using an automated analyzer. RESULTS: Among the 5006 analyzed subjects, 1564 adults (31.2%) consumed tea once or more per week for at least one year. The levels of brachial-ankle pulse wave velocity (ba-PWV) were lowest among subjects who consumed tea habitually for more than 10 years compared with the other 3 subgroups (nonhabitual, 1 to 5 years, and 6 to 10 years habitual tea drinkers), and the levels of ba-PWV were lower with subjects who consumed 10-20 and >20 g/d tea habitually compared to nonhabitual tea drinkers. As the duration and the daily amount of habitual tea consumption increased the average ba-PWV decreased. Multiple logistic regression models revealed that habitual tea consumption was a positive predictor for ba-PWV (odds ratio [OR] = 0.63, 95% confidence interval [CI], 0.57-0.70). CONCLUSIONS: Habitual tea consumption may have a protective effect against arterial stiffness, especially for subjects who have habitually consumed tea for more than 6 years and >10 g daily.

Atherosclerotic plaque identification by virtual histology intravascular ultrasound in a rabbit abdominal aorta model of vulnerable plaque.

This study aimed to evaluate the utility of virtual histology intravascular ultrasound (VH-IVUS) for recognizing vulnerable plaque compared to histological pathological analysis. Four-month-old New Zealand rabbits (n = 16) were randomly divided into two groups: one fed a high-fat diet and subjected to balloon injury (experimental, n = 10) and one fed a high-fat diet alone (control, n = 6). Blood lipid profiles of overnight-fasted rabbits were measured at week 2 (beginning of study) and week 12 (end of study). At week 12, experimental group rabbits underwent IVUS under anaesthesia. Rabbits were sacrificed and a 5-cm segment of the abdominal aorta was removed. Arterial sections were subjected to pathological and immunohistochemical analyses. Serum lipid levels increased in all rabbits fed with high-fat diet, with low-density lipid cholesterol (LDL-C) levels increasing the most. Levels of six biomarkers (high sensitivity C-reactive protein, matrix metalloproteinase-3, interleukin [IL]-1, IL-10, tumour necrosis factor-α, and oxidized [ox]-LDL) showed no differences between the two groups at week 2, but were higher in the experimental group at week 12. A total of 276 atherosclerotic plaques in the experimental group were analysed. VH-IVUS had sensitivities of 87% and 92% for detection of noncalcified and calcified thin-cap fibroatheromas, respectively. VH-IVUS correctly identified 85% and 89% of noncalcified and calcified fibroatheromas, respectively. For detection of pathological intimal thickening, VH-IVUS showed a sensitivity of 79% and positive predictive value of 78%. Linear regression analysis showed a strong correlation between histology and VH-IVUS for the percent area of fibrous fibro-fatty tissue, necrotic calcified tissue, and confluent necrotic core. The intra-observer and inter-observer variability of the intimal and medial-adventitial boundaries was low. Endothelial injury followed by a high-fat diet in rabbits is a viable method for inducing atheroma, and VH-IVUS is a feasible, reproducible, and valuable means of vulnerable plaque identification in vivo.

Ameliorative effect of astaxanthin on endothelial dysfunction in streptozotocin-induced diabetes in male rats.

The present study was designed to examine whether astaxanthin (ASX, 3,3-dihydroxybeta, beta-carotene-4,4-dione, CAS 472-61-7), a dietary antioxidant carotenoid that is naturally present in algae, crustaceans, and fish, has a protective effect on endothelial dysfunction of aortas in diabetic rats and the possible molecular mechanism involved. Male Wistar rats were randomly divided into four groups: control rats, diabetic rats, diabetic rats treated with ASX (10 mg/kg/d), and control rats treated with ASX. Type 1 diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/ kg). STZ-induced diabetes in rats was complicated with excessive oxidative stress and endothelial dysfunction, increased serum oxidized low-density lipoprotein (ox-LDL) and aortic malondialdehyde (MDA) levels, inhibited endothelium-dependent vasorelaxation to acetylcholine (ACh) and unaffected endothelium-dependent vasorelaxation to sodium nitroprusside (SNP). Simultaneously, lectin-like oxLDL receptor-i (LOX-1) expression was enhanced and endothelial nitric oxide (NO) synthase (eNOS) expression was reduced in the aortas of diabetic rats. ASX treatment could significantly decrease serum oxLDL and aortic MDA levels, attenuate blunted endothelium-dependent vasodilator responses to ACh, upregulate eNOS expression, and decrease LOX-1 expression. These results indicated that ASX could ameliorate diabetic endothelial dysfunction by inhibiting the ox-LDLLOX-1-eNOS pathway. Treatment with ASX might be clinically useful for diabetic complications associated with endothelial dysfunction.

Choice of stenting strategy in true coronary artery bifurcation lesions.

BACKGROUND: The optimal stenting strategy in true coronary artery bifurcation lesions has not been determined. In this study, a strategy of always stenting both the main vessel and the side branch (MV plus SB) was compared with a strategy of stenting the MV only with optional stenting of the SB. Stents used were sirolimus-eluting stents and paclitaxel-eluting stents. METHODS: A total of 108 patients with true coronary bifurcation lesions were randomly assigned to either routine stenting with drug-eluting stents (DES) in both the branches (group MV plus SB) or provisional stenting with DES placement in the main branch and DES placement in the SB only if MV stenting alone provided inadequate results (group MV). The primary end points were major adverse cardiac events (MACE) at 8 months, including myocardial infarction, cardiac death, and stent thrombosis or target vessel revascularization by either percutaneous coronary intervention or coronary artery bypass grafting. RESULTS: Angiographic follow-up revealed 28.91+/-20.43% stenosis of the SB after provisional stenting and 18.93+/-15.34% (P<0.01) after routine stenting. The corresponding binary restenosis rates were 35.2 and 14.8% (P=0.015). SB stents were implanted in 16.7% of patients in the provisional stenting group and 94.4% of patients in the routine stenting group. In the main branch, binary restenosis rates prebifurcation were 11.1% after provisional and 7.4% after routine stenting (P=0.51), whereas binary restenosis rates postbifurcation were 14.8 and 9.3% (P=0.38), respectively. The overall 8-month incidence of target lesion reintervention was 31.5% after provisional and 7.4% after routine stenting (P<0.01), and cumulative MACE were 38.9 and 11.1% (P<0.01), respectively. CONCLUSION: Routine stenting significantly improved the MACE outcome of percutaneous coronary intervention in true coronary bifurcation and bifurcation angle of 60 or less lesions as compared with provisional stenting.