A genome-wide association study identifies novel genetic loci that modify pharmacokinetic-pharmacodynamic responses to clopidogrel

OBJECTIVE Genetic variants in the pharmacokinetic(PK)mechanism are the main underlying factors that modify the antiplatelet efficacy of clopidogrel.Hence,joint analysis of genetic variants that modify pharmacodynamic(PD)and PK responses to clopidogrel should be effective for identifying the genetic variants affecting the antiplatelet response to the drug.METHODS A genome-wide association study was conducted to identify new genetic loci that modify PD responses to clopidogrel and its active metabolite H4 in 115 Chinese patients with coronary heart disease(CHD).RESULTS We identified novel variants in two transporter genes(rs12456693 in SLC14A2 and rs2487032 in ABCA1)and in N6AMT1(rs2254638)associated with clopidogrel-treated P2Y12reaction unit(PRU)and plasma H4 concentration.The associations between these single nucleotide polymorphisms(SNPs)and PK parameters of clopidogrel and H4 were observed in 31 additional CHD patients(P<0.05).The new variants,together with CYP2C19*2 and clinical factors,dramatically improved the predictability of PRU variability to 37.7%compared with the published value of approximately 20%.The function of these SNPs on the activation of clopidogrel was validated in 32 liver S9 fractions,and the N6AMT1 rs2254638 T variant was found to be associated with decreased formation of H4(P=0.0386).Meanwhile,N6AMT1 rs2254638 was further identified to exert a marginal risk effect for MACE in an independent CHD patient cohort(OR:1.428,95%CI:0.978-2.086,P=0.0653,FDR=0.4726).In conclusion,we systematically identified new genetic variants as risk factors for the reduced efficacy of clopidogrel.CONCLUSION Our study findings enhanced the understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.

心肌灌注分型对冠状动脉慢性完全闭塞病变介入治疗的疗效评估

【目的】探讨心肌声学造影(MCE)在优选冠状动脉慢性闭塞病变患者的临床应用价值。【方法】连续性地选取从2019年2月至2020年3月共50例冠状动脉慢性闭塞病变患者为研究对象,于介入治疗前及术后12月完善MCE及二维斑点追踪技术(2D-STI)。术后通过电话及门诊进行随访,主要终点事件为主要不良心血管事件(MACE)。根据术前心肌声学造影的心肌灌注水平对患者进行分组,通过二维超声心动图及左室整体纵向应变(GLS)对左心功能改善情况进行评估。【结果】相较于灌注异常组,灌注正常组GLS改善幅度更大(P=0.028);PCI术前灌注异常组室壁运动评分(WMSI)相较于灌注正常组更高(P=0.002)。在成功PCI术后一年灌注异常组WMSI相比于灌注正常组术后更高(P<0.001)。灌注正常组术后的GLS(P=0.008)、WMSI(P=0.016)及左室舒张末(LVEDV)容积(P=0.032)较术前改善;灌注异常组患者术后的灌注评分有明显改善(P=0.032)。【结论】MCE优选CTO-PCI患者具有临床应用价值。不同心肌灌注分型的CTO患者在PCI术后获益不同。

Guidezilla^(TM)延长导管在冠状动脉慢性完全闭塞病变反向控制性前向与逆向内膜下寻径技术中的应用

目的探讨Guidezilla^(TM)延长导管在冠状动脉慢性完全闭塞病变(chronic total occlusion,CTO)行逆向经皮冠状动脉介入治疗时协助导丝通过闭塞病变与导丝体外化的可行性以及安全性。方法回顾性分析广东省人民医院119例CTO患者。其中,2015年1月至2015年10月入选80例未使用Guidezilla^(TM)延长导管的反向控制性前向与逆向内膜下寻径(controlled anterograde and retrograde sub-intimal tracking,CART)技术的患者(Non-Guidezilla组),2015年10月至2016年11月入选39例使用Guidezilla^(TM)延长导管的反向CART技术的患者(Guidezilla组)。结果本研究中反向CART技术总体成功率为84.0%(100/119)。Guidezilla组成功率(100%比76.2%,P<0.05)高于Non-Guidezilla组,差异有统计学意义;两组患者平均J-CTO评分为2.67,Guidezilla组手术困难(35.9%比15.0%,P<0.001)和非常困难(61.5%比32.5%,P<0.001)的患者比例均高于Non-Guidezilla组,差异均有统计学意义;Guidezilla组二次手术率(25.6%比63.8%,P<0.001)及开口/分叉病变比例(30.8%比62.5%,P=0.002)均低于Non-Guidezilla组,差异均有统计学意义;Guidezilla组闭塞近段刀割状(53.8%比32.5%,P=0.030)、闭塞段长度>20 mm(89.7%比72.5%,P=0.035)及闭塞段弯曲>45°(84.6%比63.8%,P=0.020)的比例均高于Non-Guidezilla组,差异均有统计学意义。结论对于长迂曲的复杂CTO患者,逆向导丝与微导管难以通过病变并进入正向指引时,Guidezilla^(TM)延长导管能提供安全有效的解决方案。

冠状动脉慢性完全闭塞病变行逆向经皮冠状动脉介入治疗中微导管通过闭塞段新技术:控制性正向导引技术

目的引入控制性正向导引(CAN)技术并评估其对于冠状动脉慢性完全闭塞(CTO)病变行逆向经皮冠状动脉介入治疗(PCI)中微导管通过闭塞病变的有效性及安全性。方法入选2018年1月1日至2019年1月31日行PCI的368例CTO病变患者中使用CAN技术的患者10例。CAN关键步骤为逆向导丝进入正向微导管后,尽量推送逆向微导管前进至最远距离,然后送入正向球囊锚定逆向导丝,接着向外牵拉正向指引导管,导引逆向微导管前进至正向指引内,最后将正向指引导管重新送入冠状动脉开口,进一步通过标准逆向技术实现导丝体外化,并完成PCI。收集CAN技术手术成功率及其并发症资料。结果本研究对10例患者采用CAN技术。所有患者均取得了手术成功(10/10),且未观察到手术相关并发症发生。结论CAN新技术是安全有效可行的。

完全经桡动脉与经股动脉入路在冠状动脉慢性完全闭塞病变逆向经皮冠状动脉介入治疗中的比较

目的探讨完全经桡动脉途径(fully transradial approach,fTRA)在冠状动脉慢性完全闭塞性病变(chronic total occlusion,CTO)逆向经皮冠状动脉介入(percutaneous coronary intervention,PCI)治疗的可行性。方法本研究连续入选2015年1月至2019年6月于东莞康华医院及广东省人民医院南海分院住院行冠状动脉造影明确为CTO并行逆向PCI治疗的患者。收集两组患者临床、血管及介入治疗的资料,同时对比fTRA及经股动脉途径(transfemoral approach,TFA)在J-CTO评分及逆向CTO评分下介入治疗成功率、效率及安全性。结果本研究共纳入682例行逆向PCI治疗的CTO患者,其中fTRA组173例,TFA组509例。fTRA和TFA组不同J-CTO评分患者的手术成功率比较,差异无统计学意义(P>0.05)。fTRA和TFA组逆向CTO评分0分患者手术成功率比较,差异亦无统计学意义(99%vs.99%,P=0.998)。而fTRA和TFA组逆向CTO评分1分(87%vs.92%,P=0.022)及2~3分(63%vs.72%,P<0.001)患者中,TFA组手术成功率较高,差异具有统计学意义。结论逆向CTO评分能协助逆向CTO介入治疗入路的选择:对于低分组,fTRA安全有效;而对于复杂逆向CTO介入治疗,应酌情考虑TFA。

评价血管内冲击波碎石术在小型猪冠状动脉中应用的安全性

目的评价血管内冲击波碎石术对比雅培非顺应性球囊在正常小型实验猪冠状动脉中应用的安全性。方法将12头正常巴马小型猪的36支冠状动脉随机平均分为两组,放弃直径小于2.5 mm的血管,最后入选实验组和对照组的冠状动脉分别为15支和11支。实验组使用冲击波冠状动脉球囊进行扩张,对照组使用雅培非顺应性球囊进行扩张。使用血管内超声(IVUS)评估扩张前后冠状动脉管腔内面积变化以及扩张后血管损伤情况。实验动物按1∶1∶1分为三组,分别于术后0 d、7 d和28 d复查冠状动脉造影并处死,处死后取球囊作用部位血管进行病理形态学检查和扫描电子显微镜检查。结果两组靶血管术中冠状动脉造影及IVUS检查均未见冠状动脉夹层、穿孔、血肿及血栓形成。球囊扩张前后,IVUS在两组靶血管分别测得内弹力膜面积、外弹力膜面积、内弹力膜面积/外弹力膜面积,差异均无统计学意义(均P<0.05)。病理学结果示:术后7 d,实验组内膜面积较对照组大[(0.07±0.06)mm~2比(0.05±0.02)mm~2,P=0.019];而术后28 d,实验组管腔面积较对照组小[(0.28±0.15)mm~2比(0.31±0.04)mm~2,P=0.032];两组病理学结果可见内膜脱落、内弹力膜和部分中膜肌纤维断裂、黏液聚集和胶原纤维增生;但未见炎症细胞浸润、血栓形成、壁间血肿和外弹力膜断裂。此外,实验组标本内膜增生、黏液聚集和胶原纤维增生较对照组明显。结论血管内冲击波碎石术在正常小型实验猪冠状动脉中应用具有良好的安全性。

The effect and safety of chronic total occlusion etrograded recanalization by epicardial collateral channel

Background Data on retrograde recanalization of epicardial collateral channels in patients with chronic total occlusion(CTO) undergoing percutaneous coronary intervention(PCI) are limited. Fearing about the complications of perforation, few CTO patients have chosen retrograde recanalization of epicardial collateral channels. Methods A retrospective analysis was conducted in this study. We followed up eligible patients who underwent continuous CTO via epicardial CCS from August 2011 to October 2018 in our center, and analyzed the detailed clinical baseline and angiographic data, surgical success rate and hospital complications to determine the efficacy and safety. The Cox model was used to compare major adverse cardiac events(MACE) and related co-variables between CTO patients with epicardial CCS perforation and non-perforated PCI patients. Results The study enrolled 191 patients with epicardial CCs PCI of CTO and the long term follow-up time was 24.03±19.18 months.Successful CCs PCI of CTO was achieved in 161(84.8 %) patients. Procedural collateral perforation occurred in23(12.0%) patients. MACEs occurred in 18 patients(9.4%) at 1-year follow-up. Kaplan-Meier curves showed no significant difference in MACEs between perforating recanalization of CCs PCI of CTO and non-perforating PCI of CTO.( adjusted hazard ratios(HR): 0.467; 95% confidence intervals(CI): 0.13 to 1.69, P=0.245). The multivariate Cox regression analysis identified the Werner score=0/1(HR: 5.80; 95% CI: 1.89 to 17.8; P=0.002) as significant independent predictors of perforation of CCs PCI of CTO. Conclusions The major complication of the procedure is collateral perforation. Recanalization of CTOs through epicardial collateral channel is safe and effective. It may be a available choice for recanalization of complex CTO.[S Chin J Cardiol 2019;20(1):37-43]

N-terminal pro-B-type natriuretic peptide levels after hospital discharge in patients with acute myocardial infarction for predicting long term outcome

Background N-terminal-pro-brain natriuretic peptide(NT-pro-BNP)is associated with worse outcome in patients with acute myocardial infarction(AMI). However,the role of short-term follow-up of NT-pro-BNP level remains unclear. Methods Three hundred and sixty-two patients diagnosed with AMI were retrospectively enrolled in this study from March 2014 to March 2017 in our center. Blood samples were obtained at initial admission and again within 1 month after hospital discharge. The univariate and multivariate cox regression analyses including significant covariables were performed on NT-pro-BNP level at admission,discharge,or change from admission to discharge to predict adverse cardiovascular events(MACE)as study endpoints. Results There were 211 cases in NT-pro-BNP decrease group,while 151 cases in NT-pro-BNP increase group. The median follow-up was 365 days(interquartile range[IQR],322-861 days). After adjusting the covariables in the multiple logistic regression analysis,follow-up NT-pro-BNP level was still a significant independent predictor for MACE(OR,1.395;95% CI,1.102-1.869,P=0.005). However,the initial NT-pro-BNP level or change of NT-pro-BNP level had no significant predictive value for MACE. Conclusions A short-term follow-up NT-pro-BNP level after hospital discharge is a powerful prognostic biomarker for MACE in patients with AMI.

Expression of circulating smooth muscle actin(ACTG2) in the patients with unstable angina

Background Acute coronary syndrome(ACS) is a leading cause of mortality and morbidity worldwide,which comprises unstable angina(UA) and acute myocardial infarction(AMI), and the investigation of biological markers to assess those most at risk of recurrent cardiovascular events is necessary. Methods Sixty-six healthy control people and 67 cases of UA patients were enrolled in Guangdong general hospital. Enzyme linked immunosorbent assay(ELISA) was used to detect the level of plasma ACTG2. The receiver operating characteristic curve(ROC) was used to analyze the prediction value of ACTG2 for UA. According to the average level of plasma ACTG2 in UA patients, UA patients were divided into the low ACTG2 group( < average level) and the high ACTG2 group(≥ average level), and the differences in clinical characteristics between the two groups were investigated. Results The ELISA result showed that the level of plasma ACTG2 was67.823 ± 58.479 pg / m L in healthy people, while the plasma ACTG2 was 94.514 ± 65.453 pg / m L in UA patients, with a significant difference(P < 0.05). ROC analysis result showed that the Area under curve(AUC)for the prediction of UA was 0.653(95% CI 0.559-0.747), with a high statistical significance, indicating that circulating ACTG2 may possess high prediction value for UA. In addition, among the 67 UA patients, 39 were allocated to the low ACTG2 group and 28 to the high ACTG2 group. Comparison of the baseline characteristics between the two groups showed that patients in the high ACTG2 group were older than those in the low ACTG2 group. In addition, levels of Lipoprotein(a)(Lpa), Total bilirubin(TBIL) and Pro-Brain Natriuretic Peptide(Pro BNP) in the high ACTG2 group were also higher than those in the low ACTG2 group.Conclusions Circulating ACTG2 could significantly increase in UA patients, which may be used as a biomarker for the prediction of UA.

Impact of deferred stent implantation on clinical outcome in ST-segment elevation myocardial infarction patients with high thrombus burden

Background It was controversial that deferred stenting strategy could reduce no-reflow phenomena or major adverse cardiovascular events(MACEs)in primary percutaneous coronary intervention(PCI)for patients with STsegment elevation myocardial infarction(STEMI).Methods A total of 513 STEMI patients with high thrombus burden were retrospectively enrolled from January 2015 to January 2020.These patients were divided into two groups:experimental(with deferred stent implantation strategy,n=118)and control group(with immediate stenting strategy,n=395).The primary endpoint of this study was the incidence of no-reflow events.The secondly endpoints the in-hospital MACEs and one-year follow-up.Results The baseline characteristics were compared between the two groups.The occurrence of no-reflow phenomenon was significantly lower in the experiment group than the control group(16.9%vs.23.8%,P=0.035),which was mainly driven by the slow-flow(13.5%in experiment group vs.17.2%in control group,P=0.041).No significant difference was found between two groups in terms of in-hospital adverse events.The experiment group was associated with lower MACE rate than the control group(8.5%vs.15.7%,P=0.013)at one-year follow-up.Conclusions Deferred stenting had potential effect to reduce the risk no-reflow phenomenon in STEMI patients with high thrombus burden.This method was relatively safe and was associated with better clinical outcome.

Septal collateral distal tip injection during retrograde percutaneous coronary intervention for chronic total occlusion

Background The use of collateral channels(CCs)in crossing the occlusion plays a pivotal role in the retrograde PCI approach,but the impact of septal collateral distal tip injection(DTI)on contemporary septal collateral channels(CCs)crossing is still unknown.Methods 264 chronic total occlusion(CTO)cases in which the retrograde approach via septal collateral channels were enrolled after reviewing the coronary angiograms of 1300 patients from Jan 2014 to Dec 2019.This study collected the clinical and angiography data of those patents for analyzing the usefulness of this technology.In addition,a forward multivariable logistic-regression model was applied to identify the independent predictors of CC crossing failure.Results A total of 264 retrograde cases were divided into successful CCs crossing group(n=233,88.3%)and failure group(n=31,11.7%).Univariate statistics showed successful cases had low proportion of collateral channel tortuosity(42.1%vs.67.7%,P=0.011)and JCTO≥3 lesions(68.7%vs.90.3%,P=0.002)while had higher proportion of Werner CC2 collateral(52.8%vs.16.1%,P<0.001).Multivariate statistics found that the use of DTI was not significantly associated with increasing CCs crossing success rate.Twenty cases in success group performed DTI after CCs crossing failure.Conclusions Successful CTO PCI via septal CCs was not enhanced by the use of DTI before CCs attempt.