Objective To delineate the metabolomic differences in plasma samples between patients with coronary artery disease (CAD) and those with concomitant CAD and type 2 diabetes mellitus (T2DM), and to pinpoint distinctive metabolites indicative of T2DM risk. Method Plasma samples from CAD and CAD-T2DM patients across three centers underwent comprehensive metabolomic and lipidomic analyses. Multivariate logistic regression was employed to discern the relationship between the identified metabolites and T2DM risk. Characteristic metabolites' metabolic impacts were further probed through hepatocyte cellular experiments. Subsequent transcriptomic analyses elucidated the potential target sites explaining the metabolic actions of these metabolites. Results Metabolomic analysis revealed 192 and 95 significantly altered profiles in the discovery (FDR < 0.05) and validation (P < 0.05) cohorts, respectively, that were associated with T2DM risk in univariate logistic regression. Further multivariate regression analyses identified 22 characteristic metabolites consistently associated with T2DM risk in both cohorts. Notably, pipecolinic acid and L-pipecolic acid, lysine derivatives, exhibited negative association with CAD-T2DM and influenced cellular glucose metabolism in hepatocytes. Transcriptomic insights shed light on potential metabolic action sites of these metabolites. Conclusions This research underscores the metabolic disparities between CAD and CAD-T2DM patients, spotlighting the protective attributes of pipecolinic acid and L-pipecolic acid. The comprehensive metabolomic and transcriptomic findings provide novel insights into the mechanism research, prophylaxis and treatment of comorbidity of CAD and T2DM.

BackgroundThe relationship between the combined hematological parameters and echocardiography and long‐term prognosis in patients with coronary artery disease (CAD) remains unclear.MethodsWe examined the ability of hematological parameters to predict all‐cause death and major adverse cardiovascular events (MACE) based on Lasso Cox regression analysis. The significant predictors of hematological parameters from the Lasso Cox model were analyzed via multivariate Cox regression analysis and by adjusting for echocardiographic data. We calculated the continuous net reclassification improvement (cNRI) and integrated discrimination improvement (IDI) of the hematological parameters to assess the improvement in prediction.ResultsA low hemoglobin and lymphocyte ratio and high hematocrit, red blood cell distribution width‐coefficient of variation, and monocyte ratio significantly increased the risk of MACE and death in CAD patients. Neutrophil‐to‐lymphocyte ratio was associated with MACE but not death in CAD patients. After adjustment for echocardiographic parameters, hemoglobin, hematocrit, and lymphocyte ratio remained independently related to death and MACE. The addition of hematological and echocardiographic parameters to the Framingham risk score model significantly improved the area under the curve of mortality (0.794 vs. 0.713, p = 0.0007) and reclassification with cNRI of 30.6% (p = 0.002) and IDI of 0.055 (p < 0.001). Mendelian randomization analyses identified that fibrinogen and neutrophil‐to‐lymphocyte ratio were associated with increased brain natriuretic peptide and decreased left ventricular ejection fraction.ConclusionsThese findings suggest that the blood immune inflammatory indicators fibrinogen and neutrophil‐to‐lymphocyte ratio were causally associated with the risk of heart failure after CAD. The combination of hematological biomarkers and echocardiography parameters as predictor variables is a useful predictive tool for all‐cause mortality in patients with CAD.

目的 研究基因变异对服用瑞舒伐他汀的造影患者发生造影剂相关的急性肾损伤事件的影响.方法 考察贵州省人民医院和广东省人民医院服用瑞舒伐他汀患者造影前后48 h的肾功能和造影剂相关的急性肾损伤事件,采用Sequenom Mass Array system对瑞舒伐他汀的药动学和药效学相关基因进行分型.结果 共635人纳入了研究,其中30名患者发生造影剂相关的急性肾损伤.ABCG2 rs2231142(421C>A)突变组的造影剂相关急性肾损伤风险显著高于未突变组(OR:2.049;95％CI:1.185～3.542,P=0.010).经基线校正后,差异仍具有显著意义(OR:2.283;95％CI:1.247～4.182,Padj=0.008).结论 ABCG2421C>A是服用瑞舒伐他汀患者发生造影剂相关的急性肾损伤事件独立的危险因素,服用瑞舒伐他汀且携带ABCG2 rs2231142 A等位基因的患者行造影时需警惕造影剂相关的急性肾损伤的发生.

Aim: To investigate the influence of DNA methylation on ticagrelor major metabolite M8 elimination and platelet function recovery after ticagrelor discontinuation. Materials & methods: Among healthy Chinese subjects, a causal inference test was conducted to identify CpG sites located on absorption, distribution, metabolism and excretion genes that mediate genetic variants on M8 elimination. Colocalization analysis was used to identify the CpG sites that shared causal variants with platelet function recovery. Results: cg05300248 (CHST9), cg05640674 (SLC22A5) and cg00846580 (DHRS7) mediated genetic variants on the M8 elimination. cg06338150 (NOTCH1) and cg17456097 (RPS6KA1) were demonstrated to have strong evidence of colocalization with platelet function recovery. Conclusion: The results provide new biological insights into the impact of DNA methylation on M8 elimination and platelet function recovery after ticagrelor discontinuation. Clinical trial registration: clinicaltrials.gov, identifier: NCT03092076.

目的 探究贝利尤单抗对自身免疫模型大鼠甲状腺激素水平的影响.方法 给予左甲状腺素钠模拟体内高甲状腺激素水平,建立甲状腺功能亢进模型.按照体重将SD雌性大鼠随机分为3组:正常组、模型组和实验组,每组10只.正常组灌胃给予生理盐水,模型组灌胃给予左甲状腺素钠0.75μg·g-1,均持续29 d;实验组在造模期间的第15,29天皮下注射贝利尤单抗10μg·g-1.第30天,检测外周血白细胞(WBC)、中性粒细胞的绝对值(NEU)和淋巴细胞的绝对值(LYM),并检测甲状腺功能三项,包括游离甲状腺素3(FT3)、游离甲状腺素4(FT4)和促甲状腺激素(TSH)的水平.结果 正常组、模型组和实验组的FT3分别为(4.71±0.36),(10.22±0.52)和(16.53±0.58)pmol·L-1;FT4分别为(21.75±2.05),(44.95±3.19)和(62.11±4.54)pmol·L-1;TSH分别为(5.80±0.60),(11.30±0.60)和(7.60±0.08)mu·mL-1;WBC分别为(4.53±0.17),(4.60±0.56)和(1.72±0.37)×109/L;NEU分别为(0.32±0.04),(0.37±0.06)和(1.11±0.23)×109/L;LYM分别为(3.64±0.15),(3.96±0.51)和(0.43±0.10)×109/L.上述指标:模型组与正常组相比,或实验组与模型相比,差异均有统计学意义(均P<0.05).结论 贝利尤单抗可使血液中甲状腺激素水平显著升高,这或可用于治疗桥本氏甲状腺炎所致的甲状腺功能低下.

This study aims to evaluate the association between free triiodothyronine (FT3) and outcomes of coronary artery disease (CAD) patients, as well as to assess the predictive power of FT3 and related functional markers from the perspective of potential mechanism. A total of 5104 CAD patients with an average follow-up of three years were enrolled into our study. Multivariate Cox regression was used to evaluate the associations between FT3, FT4 (free thyroxin), FT3/FT4 and death, MACE. We developed and validated an age, biomarker, and clinical history (ABC) model based on FT3 indicators to predict the prognosis of patients with CAD. In the multivariable Cox proportional hazards model, FT3 and FT3/FT4 were independent predictors of mortality (Adjusted HR = 0.624, 95% CI = 0.486–0.801; adjusted HR = 0.011, 95% CI = 0.002–0.07, respectively). Meanwhile, emerging markers pre-brain natriuretic peptide, fibrinogen, and albumin levels are significantly associated with low FT3 ( p < 0.001). The new risk death score based on biomarkers can be used to well predict the outcomes of CAD patients (C index of 0.764, 95% CI = 0.731–0.797). Overall, our findings suggest that low levels of FT3 and FT3/FT4 are independent predictors of death and MACE risk in CAD patients. Besides, the prognostic model based on FT3 provides a useful tool for the death risk stratification of CAD patients.

It is widely accepted that genetic polymorphisms impact atorvastatin (ATV) metabolism, clinical efficacy, and adverse events. The objectives of this study were to identify novel genetic variants influencing ATV metabolism and outcomes in Chinese patients with coronary artery disease (CAD). A total of 1079 CAD patients were enrolled and followed for 5 years. DNA from the blood and human liver tissue samples were genotyped using either Global Screening Array-24 v1.0 BeadChip or HumanOmniZhongHua-8 BeadChip. Concentrations of ATV and its metabolites in plasma and liver samples were determined using a verified ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) method. The patients carrying A allele for the rs4148323 polymorphism ( UGT1A1 ) showed an increase in 2-hydroxy ATV/ATV ratio ( p = 1.69E−07, false discovery rate [FDR] = 8.66E−03) relative to the value in individuals without the variant allele. The result was further validated by an independent cohort comprising an additional 222 CAD patients ( p = 1.08E−07). Moreover, the rs4148323 A allele was associated with an increased risk of death (hazard ratio [HR] 1.774; 95% confidence interval [CI], 1.031–3.052; p = 0.0198). In conclusion, our results suggested that the UGT1A1 rs4148323 A allele was associated with increased 2-hydroxy ATV formation and was a significant death risk factor in Chinese patients with CAD.

目的 研究他克莫司对心脏移植患者术后早期血肌酐水平的影响.方法 收集2016年11月～2020年12月于我院行心脏移植手术并使用他克莫司的患者病历资料进行回顾性分析.根据血肌酐较术前升高倍数分为升高＜1.5倍、1.5～2.0倍、2.0～3.0倍和≥3.0倍或启动透析,根据他克莫司血药谷浓度分为≤15 ng·mL-1和＞15 ng·mL-1两组.收集术前和术后1周、1月和3月的血肌酐及他克莫司血药谷浓度值,分析血肌酐变化情况与他克莫司血药浓度的关系.结果 纳入分析患者共117例.对比他克莫司血药浓度≤15 ng·mL-1和＞15 ng·mL-1两组患者的血肌酐上升(超过基线1.5倍)的发生率,术后1周分别为38例(36.2％)和10例(83.3％),发生率差异有统计学意义(P＜0.01),术后1月分别为38例(34.5％)和6例(85.7％),发生率差异有统计学意义(P＜0.01),术后3月发生率差异无统计学意义(P＞0.05).术后1周(P＜0.01)和术后1月(P＜0.01)他克莫司血药浓度＞15 ng·mL-1的患者,血肌酐升高的倍数更高,差异具有统计学意义.结论 术后1周和术后1月他克莫司血药浓度超出治疗窗的患者血肌酐升高的发生率和升高倍数更高.心脏移植患者术后早期使用他克莫司应定期进行血药浓度监测并根据检测结果及时调整药物剂量,严格控制血药浓度不超过15 ng·mL-1.

目的 通过对真菌性心内膜炎患者的临床特征、治疗方案等分析,为其早期诊断与治疗提供参考.方法 对广东省人民医院2012年4月至2017年4月收治的14例真菌性心内膜炎患者的临床资料进行回顾性分析.结果 14例真菌性心内膜炎患者中,5例(35.7％)有风湿性心脏病,6例(42.9％)曾行瓣膜置换术,50％出现栓塞并发症,病原菌均为念珠菌属,主要为近平滑念珠菌(42.9％).出院1个月病死率为38.5％,一年内病死率为53.8％.治疗方式上,50％接受了外科手术治疗,50％单纯药物治疗,两组患者病死率比较,差异无统计学意义(28.6％vs.83.3％,P=0.103).结论 真菌性心内膜炎在风湿性心脏病和瓣膜置换术病史患者中多见,病死率高,需根据患者具体情况权衡利弊,选择最佳治疗方式.

目的 通过动作分析原理对智能药柜进行精细化管理,从而减轻药师工作强度,提高工作效率,为智能化药房新型工作模式发展提供参考.方法 调取某院门诊药房2016年6～12月的处方信息,结合药品的发药频次,运用工业工程学的动作分析原理优化智能药柜药品储位.通过对比优化前后智能药柜发药率和实时窗口患者候药时间,评价该方法应用效果.结果 智能药柜的平均发药率由优化前5.70％上升到优化后7.80％;患者的平均候药时间由优化前3.08 min缩短至优化后2.35 min.各指标优化前后比较,差异有统计学意义(P＜0.000 1).结论 动作分析原理应用于智能药柜精细管理,持续优化智能药柜药品储位,可减少药师不必要的工作,从而提高药师工作效率,缩短患者候药时间.

This nested case–control study aimed to evaluate the association of candidate genetic variants with statin-induced myotoxicity in Chinese patients with coronary artery disease (CAD).

目的 研究中国人群CYP2D6基因多态性对阿托伐他汀(A)在体外人肝微粒体代谢的影响,探讨CYP2D6基因在阿托伐他汀代谢过程的作用.方法 收集肝胆手术患者手术旁正常肝组织样本,并提取人肝微粒体(HLM)及肝组织DNA.使用Taqman基因分型技术测定CYP2D6*3、*4、*5、*6、*9、*10和*41这7个位点多态性.采用HLM孵育A使其代谢,并用LC-MS/MS方法测定A及其代谢产物2-羟基阿托伐他汀(2A)和4-羟基阿托伐他汀(4A)的浓度,分析CYP2D6基因多态性对A体外代谢的影响.按照相关文献及分型结果将样本的CYP2D6代谢表型分为强代谢型(EMs)和中等代谢型(IMs)表现型.结果 A在人肝微粒体中生成2A和4A的酶反应速率常数分别为53.7及48.5 μmol/L;最大反应速率分别为140.2及181.7 pmol/(mg· min).A在55例人肝微粒体中的代谢呈现多态性,最小和最大速率分别为109.9和9.3 pmol/(mg· min).本研究中CYP2D6*3、*4、*5、*6、*9、*10、* 41等位基因突变频率分别为0％、1.82％、2.73％、0％、0％、69.09％、2.73％.CYP2D6*4、*5、*10、*41等位基因突变对阿托伐他汀在人肝微粒体反应体系中的代谢无明显影响.A的减少速率在EMs组比在IMs组高,但差异无统计学意义(P＞0.05).2A的生成速率在EMs和IMs组分别为(14.68±7.62) vs.(8.70±3.50) pmol/(mg·min),P=0.06.4A的生成速率在EMs和IMs组分别为(20.32±13.10) vs.(11.04±4.88)pmol/(mg· min),P=0.07.结论 CYP2D6*4、*5、* 10、*41等位基因突变对阿托伐他汀代谢影响较小,而CYP2D6*4、*5、*10、* 41多等位基因突变引起的代谢表型的差异对阿托伐他汀体外代谢生成2-羟基阿托伐他汀、4-羟基阿托伐他汀有一定的影响.

AIM:To investigate whether plasma miRNAs targeting CYP3A4/5 have an impact on the variance of pharmacokinetics of clopidogrel.MATERIALS & METHODS:The contribution of 13 miRNAs to the CYP3A4/5 gene expression and activity was investigated in 55 liver tissues. The association between plasma miRNAs targeting CYP3A4/5 mRNA and clopidogrel pharmacokinetics was analyzed in 31 patients with coronary heart disease who received 300 mg loading dose of clopidogrel.RESULTS:Among 13 miRNAs, miR-142 was accounting for 12.2% (p = 0.002) CYP3A4 mRNA variance and 9.4% (p = 0.005) CYP3A5 mRNA variance, respectively. Plasma miR-142 was negatively associated with H4 Cmax (r = -0.5269; p = 0.0040) and associated with H4 AUC0-4h (r = -0.4986; p = 0.0069) after 300 mg loading dose of clopidogrel in coronary heart disease patients.CONCLUSION:miR-142 could account for a part of missing heritability of CYP3A4/5 functionality related to clopidogrel activation.

To evaluate the independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and atorvastatin metabolism, the relationships among three levels of factors, namely (1) clinical characteristics, CYP3A4/5 genotypes and miRNAs, (2) CYP3A4 and CYP3A5 mRNAs and (3) CYP3A activity, as well as their individual impacts on atorvastatin metabolism, were assessed in 55 human liver tissues. MiR-27b, miR-206 and CYP3A4 mRNA respectively accounted for 20.0%, 5.8% and 9.5% of the interindividual variations in CYP3A activity. MiR-142 was an independent contributor to the expressions of CYP3A4 mRNA (partial R 2 = 0.12, P = 0.002) and CYP3A5 mRNA (partial R 2 = 0.09, P = 0.005) but not CYP3A activity or atorvastatin metabolism. CYP3A activity was a unique independent predictor of variability of atorvastatin metabolism, explaining the majority of the variance in reduction of atorvastatin (60.0%) and formation of ortho-hydroxy atorvastatin (78.8%) and para-hydroxy atorvastatin (83.9%). MiR-27b and miR-206 were found to repress CYP3A4 gene expression and CYP3A activity by directly binding to CYP3A4 3′-UTR, while miR-142 was found to indirectly repress CYP3A activity. Our study indicates that miRNAs play significant roles in bridging the gap between epigenetic effects and missing heritability in CYP3A functionality.