In-stent Restenosis: Circulating MicroRNAs As Biomarkers And Trimetazidine For Prevention

Background and Objective: There are still some patients will develop in-stent restenosis(ISR) after the first DES implantation procedure at follow-up. It is important to identifypatients at high risk of ISR. Furthermore, until now, we lack of effective method to reduceISR. In general, this study aim to find some tools to predict, identify patients at high risk ofISR and also to investigate whether trimetazidine (TMZ) could reduce ISR or not.Methods:⑴Pre-DES implantation plasma levels of microRNAs predict ISR:MicroRNA array was used to detect the difference of microRNAs expression using bloodsample extracted before PCI between30ISR patients and30non-ISR (NISR) patients andthe results were validated by quantitative RT-PCR (qRT-PCR). Selected microRNAs weredetected by qRT-PCR in the remaning178ISR patients and178NISR patients. Logisticregression analysis was used to identify factors associated with ISR. The final targetmicroRNAs were used to establish microRNA score and its predictive value for ISR wereanalyzed by ROC curve.⑵Plasma levels of microRNAs identify patients with ISR:MicroRNA array was used to detect the difference of microRNAs expression using bloodsample extracted at follow-up before coronary angiography (CAG) between30ISRpatients and30non-ISR (NISR) patients and the results were validated by quantitativeRT-PCR (qRT-PCR). Target microRNAs were detected by qRT-PCR in the remaning179ISR patients and179NISR patients. A microRNA score was established using modifiedcycle threshold (Ct) of target microRNAs and its diagnostic value for ISR was analysed byROC curve.⑶Effect of TMZ on ISR: A total of768patients were enrolled and randomlyassigned to TMZ treatment group (TG) and control group (CG). Patients in TG wereadministrated with TMZ20mg tid. Major adverse cardiovascular events (MACEs) atfollow-up were recorded and echocardiography was conducted at30day follow-up whileCAG was conducted at9-13months follow-up. Results:⑴Pre-DES implantation plasma levels of microRNAs predict ISR:MicroRNA array and qRT-PCR revealed that pre-PCI plasma levels of microRNA-143,145,208,425and let-7g were significantly differ between ISR patients and NISR patients.Logistic regression analysis demonstrated that down-regulation of microRNA-143(OR=2.36,95%CI:1.43-3.67) and microRNA-145(OR=2.12,95%CI:1.56-3.48), DM(OR=1.32,95%CI:1.09-1.97), LDL-C≥2.6mmol/L (OR=1.24,95%CI:1.09-2.01) andcurrent smoking (OR=1.21,95%CI:1.03-1.78) were indepent risk factors for ISR.MicroRNA score derived from microRNA-143,145also differ significantly between ISRpatients and NISR patients and its predictive value assessed by ROC curve had a AUC of0.821(95%CI:0.716-0.926, P＜0.01).⑵Plasma levels of microRNAs identify patientswith ISR: MicroRNA array and qRT-PCR revealed that at follow-up pre-CAG plasmalevels of microRNA-143,145,21and100were significantly differ between ISR patientsand NISR patients. MicroRNA score derived from these four microRNAs also differsignificantly between ISR patients and NISR patients and its diagnostic value assessed byROC curve had a AUC of0.903(95%CI:0.825-0.981, P＜0.01) and had a strongrelationship with the severity of restenosis (r2=0.6365，P＜0.001).⑶Effect of TMZ onISR: In final analysis,312patients were included into TG and323patients were includedinto CG respectively. At1year follow-up, there were13patients (4.2%) in TG and36patients (11.1%) in CG developed angiographic ISR (P=0.001). TG also had a lowerincidence of MACEs compared with CG (19cases,6.1%vs.35cases,10.8%). Logisticanalysis demonstrated that TMZ treatment could effectively reduce ISR after DESimplantation (OR=0.376，95%CI：0.196－0.721，P=0.003).Conclusions:⑴Lower plasma levels of microRNA-143, microRNA-145before DESimplantation predict high risk of ISR.⑵At follow-up, combination plasma levels ofmicroRNA-21,100,143and145could identify patients with ISR.⑶TMZ treatment couldeffectively reduce ISR and MACEs at follow-up after DES implantation.