Xuebo Liu

Inhibitory effect of atorvastatin on AGE-induced HCAEC apoptosis by upregulating HSF-1 protein.

This study evaluates effect and mechanism of atorvastatin on human coronary artery endothelial cells (HCAEC) apoptosis. Results have shown that HCAEC apoptosis had increased with increasing concentration of AGEs. Atorvastatin may decrease HCAEC apoptosis, but the effect can be attenuated by PI3K inhibitor. Secretion of PI3K and P-Akt in HCAEC increased with increasing concentration of AGEs. Secretion of PI3K in HCAEC may be decreased by atorvastatin. The effect may be attenuated by PI3K inhibitor. HSF-1, HSP-70 mRNA expression level decreased with increasing concentration of AGEs. Atorvastatin may attenuate AGEs-induced HSF-1, HSP-70 mRNA expression in HCAEC, but the effect can be attenuated by PI3K inhibitor. It can be concluded that AGE can dose-dependently promote HCAEC apoptosis by the PI3K/AKT pathway. Atorvastatin may attenuate the effect possibly by upregulating HSF-1.

Modified clopidogrel loading dose according to platelet reactivity monitoring in patients carrying ABCB1 variant alleles in patients with clopidogrel resistance.

OBJECTIVESnThe aim of the present study was to investigate the impact of a adjusted clopidogrel loading dose (LD) according to platelet reactivity index in carriers of ABCB1 mutant allele undergoing percutaneous coronary intervention (PCI).nnnMETHODSnAll patients met the inclusion criteria were recruited in the present study. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index. High treatment platelet reactivity (HTPR) was determined by a cut-off value of >50%. The genetic polymorphism of ABCB1 was determined by allele-specific polymerase chain reaction (PCR). In patients carrying ABCB1 and HTPR after a first 300-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 300-mg LDs to obtain a VASP index<50%. The rate of major adverse cardiovascular events (MACE) and major or minor bleeding in one month were recorded.nnnRESULTSn536 patients were included in the present study. One hundred seventy-two patients (32%) carried ABCB1 mutant allele (11 homozygotes [2%] and 161 heterozygotes [30%]). The VASP index in these patients was significantly higher than in homozygotic patients for the wild allele (65.5±13.8% vs. 47.6±21.8%; p<0.001). Of the 172 ABCB1 mutant allele carriers, 130 were considered to have HTPR. After a second clopidogrel LD, the VASP index was significantly decreased in these patients (66.9±12.8% vs.50.2±18.3%; <0.001). Finally, dose adjustment according to platelet reactivity monitoring enabled 88% of ABCB1 mutant allele carriers and 91% of wild allele carriers exhibiting HTPR to reach a VASP index<50%. The rate of MACE and major or minor bleeding in one-month follow-up between the wild allele carriers and the mutant allele carriers didnt differentiate significantly.nnnCONCLUSIONSnIncreased and adjusted clopidogrel loading dose according to platelet reactivity monitoring attenuated clopidogrel resistance in carriers of ABCB1 mutant allele.

Fibroblast growth factor receptor 4 polymorphisms and susceptibility to coronary artery disease.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play crucial roles in vascular smooth muscle cell proliferation and atherosclerosis and, therefore, may potentially affect the development of coronary artery disease (CAD). FGFR4 rs351855 (Gly388Arg) polymorphism has shown to be a risk factor for many diseases. The aim of this study was to investigate the association between FGFR4 polymorphisms and the susceptibility to CAD in the Chinese population. Two polymorphisms, rs351855 (Gly388Arg) and rs641101, were detected by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing in 687 CAD cases and 732 age-matched controls. Data were analyzed using the chi-square test. Results showed that frequencies of GA genotype, AA genotype, and A allele in rs351855 (Gly388Arg) polymorphism were significantly lower in CAD patients than in controls (odds ratio (OR)=0.78, 95% confidence intervals (CIs): 0.62-0.98, p=0.034; OR=0.58, 95% CI: 0.42-0.80, p=0.001; and OR=0.77, 95% CI: 0.66-0.90, p=0.001, respectively). The rs641101 polymorphism did not show any correlation with CAD. Haplotype analysis revealed that rs351855 and rs641101 AG haplotype also had lower frequency in CAD patients (OR=0.79, 95% CI: 0.67-0.92, p=0.002). Our data suggested that the FGFR4 rs351855 (Gly388Arg) polymorphism and AG haplotype (rs351855 and rs641101) could act as protective factors against CAD in the Chinese population and indicated that a single gene polymorphism could have diverse functions in different diseases.

Coronary Artery Aneurysm Differs From Coronary Artery Ectasia Angiographic Characteristics and Cardiovascular Risk Factor Analysis in Patients Referred for Coronary Angiography

The differences in angiographic characteristics and cardiovascular (CV) risk factors between coronary artery aneurysm (CAA) and coronary artery ectasia (CAE) have not been compared systematically. Of 10 876 patients undergoing coronary angiography, patients with CAA (n = 85) and CAE (n = 51) were screened. The prevalence of CAA was greater than that of CAE (P < .05). The right coronary artery was the most involved (70.6%) in CAE compared with left circumflex (52.9%) and left anterior descending (41.2%). Coronary artery aneurysm coexisted with coronary artery disease (CAD) more frequently than CAE (P = .002), and the modified Gensini score of CAA was also higher than that of CAE (P < .001). The average maximum diameter was smaller, and corrected Thrombolysis in Myocardial Infarction (TIMI) frame count was lower in CAA than CAE in all 3 coronary arteries (P < .001). Multivariate analysis showed that hyperlipidemia (P = .02), smoking (P = .04), and family history of CAD (P = .02) were the independent variables most strongly associated with CAA, but not CAE. This study suggests that there are significant differences in coronary angiographic characteristics and CV risk factors between CAA and CAE.

Effect of genetic and coexisting polymorphisms on platelet response to clopidogrel in Chinese Han patients with acute coronary syndrome

Polymorphisms of CYP2C19 are associated with platelet response to clopidogrel. This study was conducted to evaluate the contribution of the previously identified polymorphisms to the response of clopidogrel in a cohort of Chinese Han patients. A total of 222 acute coronary syndrome patients undergoing percutaneous coronary intervention treated with clopidogrel were enrolled from September 2012 to June 2013. Residual platelet aggregations for all patients were measured by the VerifyNow P2Y12 system. Sixteen single-nucleotide polymorphisms among nine genes were genotyped including CYP2C19, ABCB1 and PON1. In this study, CYP2C19*2 and CYP2C19*17 were strongly associated with higher platelet aggregation and lower platelet aggregation to clopidogrel treatment, respectively (P<0.001). Patients with CYP2C19*2 allele had a higher risk of high on-treatment platelet reactivity than non carriers (adjusted OR, 5.434; 95% CI, 1.918–15.399, P=0.01). The coexistence of CYP2B6*9 (rs8192719) and P2Y12 (rs2046934) and the coexistence of CYP2B6*1B (rs7254579) and P2Y12 (rs2046934) were also associated with poor response to clopidogrel. No significant relation of CYP2C19*3 and other polymorphisms to the platelet aggregation was found. In conclusion, CYP2C19*2, CYP2C19*17 coexistence of CYP2B6*9 (rs8192719) and P2Y12 (rs2046934) and coexistence of CYP2B6*1B (rs7254579) and P2Y12 (rs2046934) were identified to be associated with response to clopidogrel treatment in Chinese Han patients.

Combination of P2Y12 reaction unit and percentage of platelet inhibition assessed by VerifyNow P2Y12 assay is a useful predictor of long-term clinical outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention

INTRODUCTIONnHigh on-treatment platelet reactivity is a well-known risk factor for adverse events in patients undergoing percutaneous coronary intervention (PCI). This study was to investigate the value of a novel platelet reactivity-based system, named the COP-INH (COmbination of P2Y12 reaction unit [PRU] and percentage of platelet inhibition [%INH]), assessed by VerifyNow P2Y12 assay, for predicting the long-term ischaemic events in patients with acute coronary syndrome (ACS) undergoing PCI.nnnMATERIALS AND METHODSnThe COP-INH was calculated on the basis of data obtained at 30days after PCI: patients with both an elevated PRU (≥230) and decreased %INH (<40%) were allocated a score of 2, and patients showing one or neither were allocated a score of 1 or 0, respectively. The primary endpoint was the composite of cardiovascular death, nonfatal myocardial infarction, and target vessel revascularization at 1year follow-up. The relationship between the COP-INH score and primary endpoint was analyzed.nnnRESULTSn207 patients were enrolled. Baseline characteristics were similar between patients with COP-INH=2 and patients with COP-INH=1 or 0, except for diabetes mellitus (43.8% vs. 21.7%, p=0.015) and previous coronary artery bypass grafting (CABG) (21.9% vs. 6.86%, p=0.007). During the observation period, the incidence of major adverse cardiovascular events (MACE) in patients with COP-INH=2 was significantly higher than patients with COP-INH=1 or 0 (18.8% vs. 4.6%, p=0.007). Multivariate analysis of clinical characteristics and platelet reactivity selected by univariate analysis showed that the COP-INH=2 was an independent predictor of MACE in patients with ACS undergoing PCI (OR 2.745; 95% CI 1.369-9.851; p=0.024), whereas neither PRU≥230 nor %INH<40% was.nnnCONCLUSIONnThe COP-INH is considered to be a useful predictor of long-term ischaemic events of patients with ACS undergoing PCI.

Relationship between clopidogrel-related polymorphisms and variable platelet reactivity at 1 year: A cohort study from Han Chinese

Background: This study was designed to investigate the effect of clopidogrel-related gene polymorphisms on platelet reactivity and clinical outcome in Chinese Han patients. Materials and Methods: Three hundred and thirty-six percutaneous coronary intervention - treated patients were recruited and followed for 1 year. Blood samples were collected from all patients for DNA genotyping. The platelet reactivity unit was measured by the VerifyNow technique. The CYP2C19*2, CYP2C19*3, CYP2C19*17, ATP-binding cassette subfamily B member 1, ITGB3, CYP2C9*3, CYP2B6*9, and P2Y12 alleles were assessed. Results: The clinical endpoints were related to previous heart disease history (11.90% vs. 28.57%, P = 0.017), stroke (12.24% vs. 16.67%, P = 0.039), and diabetes (27.55% vs. 52.38%, P = 0.047). High on-treatment platelet reactivity (HTPR) was frequent in advanced age (P = 0.019), male gender (P = 0.016), hypertension (P = 0.033), and chronic renal failure (P = 0.040). There were more endpoints in the CYP2C19*2 and P2Y12 mutant carriers (76.19% vs. 43.20%, P < 0.001; 50.00% vs. 35.71%, P = 0.001, respectively), whereas fewer in the CYP2C19*17 mutant carriers (11.90% vs. 56.46%, P = 0.001). CYP2C19*2 and P2Y12 polymorphism manifested HTPR (194.25 ± 45.91 vs. 151.38 ± 58.14, P < 0.001; 180.33 ± 67.25 vs. 161.89 ± 56.49, P = 0.008, respectively), whereas CYP2C19*17 mutant improved platelet reactivity (97.17 ± 45.38 vs. 169.08 ± 57.15, P = 0.003). However, there were no further cardiovascular deaths in endpoint patients. Conclusion: In Han Chinese people of mainland China, clopidogrel-related gene polymorphisms are related to variable platelet reactivity after clopidogrel maintenance dosing, which influences major adverse cardiovascular events, without an effect on cardiac death.

Mechanical stretch changes coronary artery fibroblasts function by upregulating HSF1 protein expression.

The study is designed to investigate effect of mechanical stretch on the function of fibroblast cells. Human coronary artery fibroblasts were cultured. They were divided into two groups: stretch group (stretch for 24h) and no-stretch group (did not stretch). ELISA analysis was used for detection of collagen secretion. CCK-8 method was used for detection of cells proliferation. RT-PCR method was used for detection of MMP, TIMP, IL-6, alpha-SMA, HSF1 and HSP70 mRNA expression. Western-blotting method was used for detection of HSF1 protein expression. Results showed that cells proliferation in stretch group was stronger than that in no-stretch group. Hydroxyproline secretion in stretch group was more than that in no-stretch group. MMP-9/TIMP, alpha-SMA, IL-6, HSF1 and HSP70 in stretch group was higher than those in no-stretch group. Western-blotting analysis showed that HSF1 protein expression was upregulated in stretch group. It can be concluded that mechanical stretch changed human coronary artery fibroblasts cells proliferation, collagen formation, the secretion of inflammatory factor possibly by upregulating HSF1 protein expression.

Phenotypic transformation of smooth muscle cells from porcine coronary arteries is associated with connexin 43

The current study aimed to investigate the relevance of the gap junction protein connexin Cx43 in coronary artery smooth muscle cell (SMC) heterogeneity and coronary artery restenosis. SMCs were isolated from the coronary artery of 3-month-old pigs using enzymatic digestion. Two distinct SMC populations were isolated: Rhomboid (R) and spindle-shaped (S) cells. S-SMCs exhibited relatively lower rates of proliferation, exhibiting a classic hills-and valleys growth pattern; R-SMCs displayed increased proliferation rates, growing as mono- or multi-layers. Immunofluorescent staining, polymerase chain reaction and western blotting were used to assess the expression of Cx40 and Cx43 in SMCs. For further evaluation, cultured SMCs were treated with 10 ng/ml platelet-derived growth factor (PDGF)-BB with or without the gap junction blocker 18α-glycyrrhetinic acid. Stent-induced restenosis was assessed in vivo. Different expression patterns were observed for Cx40 and Cx43 in R- and S-SMCs. Cx40 was the most abundant Cx in S-SMCs, whereas CX43 was identified at relatively higher levels than Cx40 in R-SMCs. Notably, PDGF-BB converted S-SMCs to R-SMCs, with increased Cx43 expression, while 18α-glycyrrhetinic acid inhibited the PDGF-BB-induced phenotypic alterations in S-SMCs. Additionally, restenosis was confirmed in pigs 1-month subsequent to stent placement. R-SMCs were the major cell population isolated from stent-induced restenosis artery tissues, and exhibited markedly increased Cx43 expression, in accordance with the in vitro data described above. In conclusion, the phenotypic transformation of coronary artery SMCs is closely associated with Cx43, which is involved in restenosis. These observations provide a basis for the use of Cx43 as a novel target in restenosis prevention.