| Background and ObjectiveEpicardial adipose tissue (EAT) is directly deposited around coronary arteries and pericardium, and it’s closely correlated with heart and coronary arteries. Studies have shown that increased EAT volume is significantly associated with the formation and composition of coronary atherosclerotic plaque, the degree of coronary lumen stenosis and the calcification progression. But, whether increased EAT volume can exacerbate the incidence of in-stent restenosis (ISR) and the progression of high-risk coronary plaque composition, still less been studied. Moreover, there is little research aiming EAT as therapeutic target. This study use CCTA as an nonivasving imaging method, to explore whether increased EAT volume is associated with ISR and high-risk coronary atherosclerotic plaque components progression; In addition, use olmesartan medoxomil as therapeutic drug, to further explore whether it can reduce EAT volume, regulate the active cytokine secretion of EAT, and ultimately improve coronary atherosclerosis.MethodsFirst part From October 2011 to December 2014, a total of 364 patients with suspected CHD that underwent CCTA examination, and then underwent PCI in our hospital for the first time within one month and at 1 year accepted the coronary angiography follow-up were enrolled. According to the results of coronary angiography, patients were divided into ISR group (46 cases) and NISR group (318 cases). ISR related variables were analyzed by univariate and multivariate regression analysis.Second part From May 2013 to April 2015, a total of 284 patients with CHD that underwent CCTA examination at baseline, and then accepted CCTA follow-up for coronary atheclerosis progression at 1 year were enrolled. According to characteristics progression of the high-risk plaques, patients were divided into plaque progression group (52 cases) and non-plaque progression group (232 cases). Variables related to plaque progression were analyzed by univariate and multivariate regression analysis.Third part 30 rabbits were randomly divided into high-fat group (n=10), low-dose olmesartan medoxomil group (n=10) and high-dose olmesartan medoxomil group (n=10),3 groups were given high-fat diet for 12 weeks to establish atherosclerosis model. After atherosclerosis model successfully established, low-dose group was fed with high-fat diet plus 5mg/Kg/d olmesartan medoxomil, and high-dose group was fed with high-fat diet plus 15mg/Kg/d olmesartan medoxomil, all rabbits were fed for 16 weeks and then blood and pathological specimens were collected. Weighing the rabbits and measuring the lipid changes. EAT, coronary arteries and aorta specimens were stained with HE staining in each group to detect the morphological changes; western blot was used to detect the TNF-a and adiponectin protein expression levels of EAT; RT-PCR was used to detect the TNF-a, IL-6, adiponectin and ACE2 mRNA expression levels of EAT.ResultsFirst part EAT volume in ISR group was significantly higher than that of NISR group (154.5 ± 74.6 ml vs.131.0 ± 52.2 ml, P<0.001). The diagnostic threshold of ROC curves to detect ISR was EAT volume≥126.42 ml (sensitivity and specificity were 63.0% and 45.0%, the area under the AUC curve was 0.591,95%CI:0.593-0.680, P=0.046). Multivariate analysis further adjusted for traditional risk factors, and found that EAT volume≥126.42 ml was still risk predictor for ISR [OR (95%CI): 2.497(1.163-5.360), P=0.019]. Goup use ROC curve recommended diagnostic threshold showed that ARBs application rate in EAT volume≥126.42 ml group was significantly lower than that of EAT volume<126.42 ml group, and the ISR rate was significantly increased.Second part EAT volume in plaque progression group was significantly higher than that of non-progression group (172.24 ± 56.24 ml vs.129.50 ± 47.78 ml, P< 0.001). The diagnostic threshold of ROC curves to detect plaque progression was EAT volume≥121.38 ml (sensitivity and specificity were 86.5% and 47.8%, the area under the AUC curve was 0.722,95%CI:0.644-0.800, P<0.001). Multivariate regression analysis further adjusted for traditional risk factors such as age, BMI, hypertension, diabetes, smoking and total cholesterol, and found that EAT volume≥121.38 ml was still independent predictors for plaque progression[OR (95%CI):5.178 (2.083-12.871), P<0.001].Third part 16 weeks end, I/M area of aortic and coronary arteries in low-dose and high-dose olmesartan medoxomil group were significantly smaller than that of high-fat group (P<0.001), with high-dose group reduced the most. EAT cell average area of low-dose and high-dose olmesartan medoxomil group were significantly smaller than that of high-fat group (P<0.001), with high-dose group reduced the most. Adiponectin protein expression levels in EAT of low-dose and high-dose olmesartan medoxomil group were significantly higher than that of high-fat group (P<0.05), with high-dose group reduced the most; TNF-α protein expression level in EAT of low-dose showed a down trend comparied with that of high-fat group, although with no significant difference, TNF-α protein expression level in EAT of high-dose olmesartan medoxomil group were significantly lower than that of high-fat group (P<0.05). RT-PCR assay showed that TNF-α and IL-6 mRNA expression levels in EAT of low-dose and high-dose group were lower than that of high-fat group; and adiponectin and ACE2 mRNA were significantly increased in low-dose and high-dose group compared to high-fat group, with high-dose group changed the most.ConclusionsFirst part Use CCTA as a noninvasving method for imaging coronary atherosclerosis and EAT volume, found that EAT volume≥126.42 ml is the risk predictor of ISR at 1 year follow-up. Increased EAT deposition maybe an early warning of ISR, we should pay more attention to EAT volume in patients with drug-eluting stents implantation.Second part Use CCTA as a noninvasving method for imaging coronary atherosclerosis and EAT volume, found that EAT volume was significantly associated with high risk plaques progression. EAT volume≥121.38 ml is an independent predictor of high-risk plaques progression. EAT may be used as targets for drug therapy, and reduce EAT volume may inhibite the progression of high-risk plaque.Third part Olmesartan medoxomil can reduce coronary atherosclerosis, it’s related with EAT volume reduction. Olmesartan may down regulate the TNF-α and IL-6 expression levels of EAT, while up regulate the adiponectin and ACE2 expression level of EAT, and ultimately achieve the anti-atherosclerosis role. |
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