Design and Protocol for Beijing Hospital Takayasu Arteritis (BeTA) Biobank.

BACKGROUND: Although hundreds of studies have been conducted, our understanding of the pathogenesis, indications for surgical intervention, and disease markers of Takayasu arteritis (TAK) are still limited. Collection of biological specimens, clinical data and imaging data will facilitate translational research and clinical studies. In this study, we aim to introduce the design and protocol for the Beijing Hospital Takayasu Arteritis (BeTA) Biobank. METHODS: Based in the Department of Vascular Surgery of Beijing Hospital and Beijing Hospital Clinical Biological Sample Management Center, the BeTA Biobank is composed of clinical data and sample data from patients with TAK requiring surgical treatment. All clinical data of participants are collected, including demographic characteristics, laboratory tests, imaging results, operation information, perioperative complications, follow-up data, etc. Both blood samples including plasma, serum and cells, and vascular tissues or perivascular adipose tissue are collected and stored. These samples will promote the establishment of a multiomic database for TAK and help to identify disease markers and to explore potential targets for specific future drugs for TAK.

Perioperative urinary thromboxane metabolites and outcome of coronary artery bypass grafting: a nested case-control study.

OBJECTIVE: As a marker of in vivo thromboxane generation, high-level urinary thromboxane metabolites (TXA-M) increase the occurrence of cardiovascular events in high-risk patients. To investigate whether perioperative urinary TXA-M level is associated with major adverse cardiac and cerebrovascular events (MACCE) after coronary artery bypass graft (CABG) surgery, we designed a nested case-control study. DESIGN: Observational, nested case-control study. SETTING: Single-centre outcomes research in Fuwai Hospital, Beijing, China. PARTICIPANTS: One thousand six hundred and seventy Chinese patients undergoing CABG surgery from September 2011 to October 2013. METHODS: We obtained urinary samples from 1670 Chinese patients undergoing CABG 1 hour before surgery (pre-CABG), and 6 hours (post-CABG 6 hours) and 24 hours after surgery (post-CABG 24 hours). Patients were followed up for 1 year, and we observed 56 patients had MACCE. For each patient with MACCE, we matched three control subjects. Perioperative urinary TXA-M of the three time spots was detected in these 224 patients. RESULTS: Post-CABG 24 hours TXA-M is significantly higher than that of patients without MACCE (11 101vs8849 pg/mg creatine, P=0.007). In addition, patients in the intermediate tertile and upper tertile of post-CABG 24 hours urinary TXA-M have a 2.2 times higher (HR 2.22, 95% CI 1.04 to 4.71, P=0.038) and a 2.8 times higher (HR 2.81, 95% CI 1.35 to 5.85, P=0.006) risk of 1 year MACCE than those in the lower tertile, respectively. CONCLUSIONS: In conclusion, post-CABG 24 hours urinary TXA-M elevation is associated with an increase of 1 year adverse events after CABG, indicating that the induction of cyclo-oxygenase-2 by surgery-related inflammatory stimuli or platelet turnover may be responsible for the high levels of post-CABG urinary TXA-M. TRIAL REGISTRATION NUMBER: NCT01573143.

Association between a Genetic Risk Score Based on Single Nucleotide Polymorphisms of Coronary Artery Disease-Related Genes and Left Main Coronary Artery Disease.

Coronary artery disease (CAD) is the leading cause of mortality and morbidity worldwide. Left main coronary artery disease (LMCAD) is a severe phenotype of CAD and has a genetic component. Previous studies identified 3 inflammation-related single nucleotide polymorphisms (SNPs) contributing to the development of LMCAD. We integrated these SNPs into a genetic risk score for the prediction of LMCAD. We enrolled 1544 patients with CAD between 2007 and 2011. The individual associations of the 3 SNPs with LMCAD were assessed. We then calculated the genetic risk score for each patient and stratified patients into low-risk, intermediate-risk, and high-risk categories of genetic risk. In univariable logistic regression analysis, the odds of LMCAD for the high-risk group were 2.81 (95% confidence interval [CI]: 1.72-4.60; P = 0.02) times those of the low-risk group. After adjustment for CAD-related clinical variables, the high-risk group (adjusted OR: 2.78; 95% CI: 1.69-4.58; P = 0.02) had increased odds of LMCAD when compared with the low-risk group. Comparison of model c-statistics showed greater predictive value with regard to LMCAD for the genetic risk score model than the models including single SNPs.

A Variant in COX-2 Gene Is Associated with Left Main Coronary Artery Disease and Clinical Outcomes of Coronary Artery Bypass Grafting.

As a particular severe phenotype of coronary artery disease (CAD), left main coronary artery disease (LMCAD) is heritable. Genetic variants related to prostaglandin metabolism are associated with LMCAD. Cyclooxygenase-2 (COX-2), a key synthase in prostaglandin pathways, displays high density in atherosclerotic lesions and promotes early atherosclerosis in CAD progression. We hypothesized that genetic variants in COX-2 gene contribute to LMCAD phenotype susceptibility compared to more peripheral coronary artery disease (MPCAD). In this study, we genotyped COX-2 rs5275, rs5277, and rs689466 of 1544 CAD patients undergoing coronary artery bypass grafting (CABG) and found that rs5277 C allele carriage was associated with LMCAD (adjusted OR: 1.590; 95% CI: 1.103~2.291; p = 0.013). Furtherly, long-term follow-up data suggested that rs5277 C allele carriage increased risk of major adverse cardiac and cerebrovascular events (MACCE) in the whole cohort (adjusted HR: 1.561; 95% CI: 1.025~2.377; p = 0.038) and LMCAD subgroup (adjusted HR: 2.014; 95% CI: 1.036~3.913; p = 0.039) but not in MPCAD subgroup (adjusted HR: 1.375; 95% CI: 0.791~2.392; p = 0.259). In conclusion, we demonstrate that COX-2 rs5277 C allele increases the risk of left main coronary artery lesion and is also correlated with poor prognosis of LMCAD patients with CABG therapy.

Common Variant in Glycoprotein Ia Increases Long-Term Adverse Events Risk After Coronary Artery Bypass Graft Surgery.

BACKGROUND: This study was aimed to investigate the clinical relevance between glycoprotein Ia (GPIA) rs1126643C/T polymorphism and the outcome of coronary artery disease after coronary artery bypass graft (CABG) surgery and explore the involved potential mechanisms. METHODS AND RESULTS: We genotyped GPIA rs1126643 polymorphism of 1592 patients who underwent CABG and followed up for a median period of 72.8 months. Patients who are GPIA rs1126643 T-allele carriers have a higher major adverse cardiac or cerebrovascular events risk post-CABG than those who are CC homozygotes (hazard ratio [HR]=1.29; P=0.022). The clinical association between the risk allele (T) carriage and major adverse cardiac or cerebrovascular events was confirmed in another cohort study, which included 646 CABG patients from various health centers across China. Meanwhile, rs1126643 T allele was also linked with increased risk of major adverse cardiac or cerebrovascular events (HR=1.73; P=0.019). To explore the underlying mechanisms, we prospectively recruited 131 coronary artery disease patients, assessed their platelet aggregation function, and focused on detecting their GPIA mRNA level and protein expression. Results showed that patients with rs1126643 T allele have elevated platelet aggregation activity (P=0.029) when protein expression is increased (P<0.001) and not affected by glycoprotein Ia mRNA level. CONCLUSIONS: The synonymous common variant, GPIA rs1126643, increases the long-term adverse events risk of CABG by augmenting GPIa protein expression and enhancing platelet aggregation function. This finding can serve as the implication of improving secondary prevention of CABG patients.

C-C Motif Chemokine Receptor 9 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction.

BACKGROUND: Maladaptive cardiac hypertrophy is a major risk factor for heart failure, which is the leading cause of death worldwide. C-C motif chemokine receptor 9 (CCR9), a subfamily of the G protein-coupled receptor supergene family, has been highlighted as an immunologic regulator in the development and homing of immune cells and in immune-related diseases. Recently, CCR9 was found to be involved in the pathogenesis of other diseases such as cardiovascular diseases; however, the effects that CCR9 exerts in cardiac hypertrophy remain elusive. METHODS AND RESULTS: We observed significantly increased CCR9 protein levels in failing human hearts and in a mouse or cardiomyocyte hypertrophy model. In loss- and gain-of-function experiments, we found that pressure overload-induced hypertrophy was greatly attenuated by CCR9 deficiency in cardiac-specific CCR9 knockout mice, whereas CCR9 overexpression in cardiac-specific transgenic mice strikingly enhanced cardiac hypertrophy. The prohypertrophic effects of CCR9 were also tested in vitro, and a similar phenomenon was observed. Consequently, we identified a causal role for CCR9 in pathological cardiac hypertrophy. Mechanistically, we revealed a lack of difference in the expression levels of mitogen-activated protein kinases between groups, whereas the phosphorylation of AKT/protein kinase B and downstream effectors significantly decreased in CCR9 knockout mice and increased in CCR9 transgenic mice after aortic binding surgery. CONCLUSIONS: The prohypertrophic effects of CCR9 were not attributable to the mitogen-activated protein kinase signaling pathway but rather to the AKT-mammalian target of rapamycin-glycogen synthase kinase 3ß signaling cascade.