Gensini Score as a Predictor for in-Stent Restenosis in Patients with Coronary Artery Disease (CAD)

Background: Despite Drug-eluting stent (DES) have considerably reduced the rates of in-stent restenosis (ISR). ISR is still the most common limitation of percutaneous coronary intervention (cid:0) PCI). The aim of this study was to investigate potential predictors on ISR in patients with DES implantation for Coronary heart disease (CAD). Methods: A retrospective case-control study was conducted. A total of 916 patients who underwented DESs implantations and angiography follow-up within one year at the First Aliated hospital of Xinjiang medical University, between September, 2013, and September, 2016, were included. The subjects were divided into 2 groups, ISR (n=315) and non-ISR (n=601), ISR was dened as a diameter stenosis of ≥ 50% located within a coronary stent or up to 5 mm beyond the stent edges. Clinical data and angiographic characteristics were collected. CAD severity was evaluated by calculating the Gensini score. The logistic regression and ROC analysis were pereformed to screen out ecient predictors. Results: Comparation between the ISR group and the non-ISR group, Gensini Score, diastolic pressure, waist, blood glucose, left ventricular end diastolic diameter (LVED), left ventricular end systolic diameter (LVES) levels were higher in ISR group, and ApoA1, ejection fraction (EF%), and accidence of myocardial infarction (MI) were lower in the ISR group. Comparation of angiographic characteristics between the groups, the results showed the occurrence of stenosis in vessels of left main coronary artery (LM), left anterior descending artery(LAD), or right coronary artery (RCA) have more vulnerability to ISR. Patients in the ISR group have been implanted more stents. In univariate regression analysis, diastolic pressure, waist, history of MI, ApoA1, number of implanted stents, and Gensini Score were associated with ISR. After multiple logistic regression analysis, Gensini score was screen out to be an independent risk factor of ISR. Receiver operating characteristic curve analysis identied that the Gensini score was a reliable predictor for ISR, area under curve (AUC): 0.80 (0.78-0.83), Sensitivity and specicity were 73.33% and 72.33%, respectively. Conclusions: Gensini score was independently associated with ISR, and was a good predictor for ISR in patients with DES implantaion.


Introduction
For patients with coronary heart disease (CAD), percutaneous coronary intervention(PCI)was the most effective method to therapy and prevent acute mycardial infartion (AMI), which could improve survival rate and prognosis. Drug-eluting stent (DES) reduced the probability of repeat revascularization, compared with bare-metal stent (BMS) [1], However, despite the use of DES and other novel medication at large, In-stent restenosis (ISR) remains the most common complication after PCI, approximately 10% occurred in stents implanted patients [2,3]. Several studies showed that laboratory serological parameters or microRNAs which detected before the coronary stenting procedure could predict ISR [4][5][6][7].
However, there is not yet an e cient predicter which based on CAD severity survey.
The pathophysiological process of ISR has distinguishing mechanisms from that of natural coronary atherosclerosis, and its main mechanisms including vascular in ammation, vascular remodeling, and excessive proliferation and migration of vascular smooth muscle cells [8]. and dysfunction of these processes may lead to adverse arterial remodeling, neointimal hyperplasia, and restenosis [9].
Gensini score is one of the most widely used angiographic scoring system for quantifying the severity of CAD [10] and it is more likely to describe the complexity of CAD, since it involved mutiple in uence factors, as severity of lesion, cumulative effects of multiple obstructions, importance of their location, and importance of collateral changes affecting the size and mass of the distal vessels, as well as functional status of the myocardium [11]. There were studies shown that higher Gensini scores are associated with higher cardiac mortality in patients with heart failure after PCI, which suggesting that residual coronary atherosclerotic burden may contribute to a higher risk of cardiac events, such as blockages of coronary artery [12,13]. While, as an important indicator of stenosis degree and predictor of cardiovascular disease (CVD), the values of Gensini score on ISR are still less evaluated.
Investigation of risk factors and predictors for ISR may contribute to make strategies of CAD therapy and risk striti cation for patients with CAD with stents implantaion. This study was set out to explore an effecient predicter for ISR in CAD implanted with DES.

Ethnic approval
The Ethics Committee of the First A liated Hospital of Xinjiang Medical University has approved this study. All procedures were executed in accord with the standards of the Declaration of Helsinki.

Study population
This was a retrospective, single-center study. We enrolled 916 patients who were successfully treated with DES implantation for symptomatic CAD in the First A liated hospital of Xinjiang medical University from September 2013 to September 2016, and who had an angiographic follow-up more than 1 year. Patients who had infectious diseases, coronary artery bypass surgery, acute or chronic heart failure, coronary artery dissection, severe liver or kidney disease, and malignant tumors were rule out.

Data collection
Baseline parameters were collected, including gender, age, medical history as hypertension, diabetes, and, life style likesmoking status, alcohol intake, medical examine contains echocardiographic data and angiography results, laboratory detectedresults, On the basis of angiography, the degree and severity of CAD were expressed as Gensini score.
Angiographic data, such as target vessel, stent length, number of implanted stents were also recorded by experienced interventional cardiologists at baseline and follow-up for coronary angiography analysis. ISR is de ned as 50% luminal diameter narrowing of the stented or peri-stent segment (de ned as a length of 5 mm proximal and distal to the stent edge) at follow-up angiography analysis, whereas non-ISR was de ned as stenosis degree < 50% or no stenosis [14].
We evaluated the degree of coronary atherosclerosis according to the Gensini score.The Gensini score is calculated by scoring the severity of each coronary artery stenosis according to the degree of stenosis and the importance of the stenosis location. A reduction in the lumen diameter, and the angiographic appearance of concentric lesions and eccentric plaques were quantitatively evaluated. More speci cally, reductions of 25%, 50%, 75%, 90%, 99% and complete occlusion were given Gensini score of 1, 2, 4, 8, 16 and 32, respectively [15].
Hypertension was de ned as a systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg, or currently taking antihypertensive medications [16]. Diabetes mellitus (DM) was de ned as fasting blood glucose (FBG) ≥ 7.0 mmol/L and/or random glucose level ≥ 11.1 mmol/L or previously diagnosed DM treated with medicine [17].

Statistical analyses
Statistical tests were performed using SPSS for Windows, Version 23.0 statistical package (SPSS Inc., Chicago, IL, USA). Distributions were analysed via the Kolmogorov-Smirnov test to determine if the distribution of continuous variables was normal or not. Data are presented as numbers and frequencies for categorical variables and as means ± SD for continuous variables. To compare groups, the χ 2 test (or Fisher's exact test, when any expected cell count was < 5 for a 2 × 2 table) was used for categorical variables, and an unpaired Student's t-test or one-way analysis of variance was applied for continuous variables. Univariate and multivariate logistic regression analyses were used to evaluate associations between the baseline clinical characteristics and risk of ISR. Based on receiver operating characteristic (ROC) curves, the optimal cut-off values for the Gensini score that could predict ISR risk were determined.
The statistical tests were two sided and a P-value < 0.05 was considered statistically signi cant.

Baseline character of ISR and Non-ISR group
A total of 916 patients were enrolled in this study, Of these 916 patients, 727 (79%) were male. The mean age of the study population was 58.40 ± 12.52 years. The baseline characteristic, clinical data of the participants are presented in Table 1. The status of diastolic pressure, waist, blood glucose, ApoA1, diastolic pressure, waist, LVED, LVES level were signi cantly different between the 2 groups. The mean Gensini score was signi cantly higher in patients with ISR than it was in those with no restenosis (50.68 ± 38.4 vs. 18.27 ± 24.41; p < 0.001). Comparation between the angiographic characteristics Comparation between the angiographic characteristics, the incidence of stenosis in the LM, LAD or RCA have a more chance of ISR. Patients in the ISR group had implanted more stents. (Table 2)

Univariate logistic regression analysis and multiple logistic regression analysis results
In the univariate logistic regression analysis, diastolic pressure, waist, history of MI, ApoA1, number of implanted stents and the Gensini Score were associated with ISR. According to multiple logistic regression analysis, we adjusted diastolic pressure, waist, blood glucose, ApoA1, waist, LVED, LVES, EF, WBC, LY, NE, number of implanted stents, MI, Gensini score were still independently associated with ISR (OR 1.029; 95% CI 1.013-1.046) ( Table 3).

ROC
Receiver operating characteristic curve analysis was used to explore the relationship between Gensini score and ISR. The area under curve (AUC) of Gensini score was 0.804 (95% CI 0.78-0.83), for diagnosis of ISR, and its optimal cut off value of Gensini score in the prediction ISR is 21.50 with sensitivity of 73.33% and speci city of 72.33%. It is related to the degree of coronary stenosis and effective in diagnosing ISR (Fig. 1).

Discussion
In our study, the main nding is that the Gensini score is positively associated with an increased risk of ISR in CAD patients who underwent DES implantation. The optimal cut off value of Gensini score in the prediction ISR is 21.50, with a good sensitivity and speci city. Compared to other factors that predict ISR, the Gensini score is a reliable and easily calculated scoring tool and may be applied in practice to predict ISR.
At present, CAD is one of the leading causes of morbidity and mortality in the world [18,19]. PCI is currently the most effective treatment for coronary artery stenosis. Drug-eluting stents (DES) have a higher e cacy and safety pro le than bare metal stents (BMS), and international guidelines recommend their use as rst-line treatment [20]. Although stent technology has made great progress in recent years, the incidence of ISR has not improved signi cantly and has become one of the major clinical challenges in the treatment of CAD [21]. Chronic in ammation and/or endothelial dysfunction may induce late de novo neoatherosclerosis inside. So, neoatherosclerosis has become the prime suspect in the pathogenesis of late stent failure [22]. However, there was no reliable tools to evaluate the neoatherosclerosis progress and predict stent failure. Some clinical symptom-based scoring systems such as CHA2DS2-VASc Score have been used to predict ISR [23]. At the same time, some coronary angiographic variables, such as minimum lumen diameter and stent dilation rate, have been shown to be associated with stent restenosis after PCI [24]. However, a scoring system based on angiography itself has not been established to identify patients at high risk for ISR.
The SYNTAX score is also used to evaluate coronary angiography, but it is mainly used for the left main coronary artery disease and/or three-vessel coronary artery disease. It is used to quantitatively evaluate the complexity of coronary artery disease according to the anatomical characteristics such as bifurcation calci cation and the severity of the lesion location rather than the degree of CAD [25]. So we're stick with Gensini score.
In contrast to other available ISR risk strati cation tools, the Gensini score is a reliable and easily calculated scoring tool and therefore may be applied in daily practice to predict ISR with DES. The Gensini score was originally intended to quantify the severity of CAD, Razi et al. [26] found a signi cant positive correlation between Gensini score and the duration of diabetes. However, subsequent studies have shown that it is able to identify patients at high risk of adverse events treated with PCI [27,28]. The Gensini score has also been reported to predict short-term major adverse cardiovascular events following PCI in patients with acute myocardial infarction [29].
The current study shows that patients with higher Gensini scores have an increased risk of developing ISR, independent of other clinical variables. This is the rst report on the relationship between Gensini score and ISR in patients with DES implantation.

Study limitations
Our study has some inherit limitations. First and foremost, it has a retrospective and single-center design.
Patients with a history of CABG, previous PCI, or STEMI and reperfusion with thrombolytic drug administration were excluded. Thus, the results of this study may not be extrapolated to all patients. Additionally, the study did not use intravascular ultrasound or optical computed tomography to assess the degree of in-stent re-narrowing. Despite these limitations, we believe that our results indicate a valuable predictor for ISR.

Conclusion
By screening 916 patients with coronary angiography, we found that Gensini score was independently associated with ISR in patients with DES implantation, and was a good predictor for ISR in patients with CAD and DES, which could provide an important tools for ISR prevention and risk strati cation.

Contribution of the Authors
The experiments were designed and conceived by SY who also wrote the draft of the experiment's manuscript; data collections as well as analyses inclined to the statistics were done by MG; the laboratory experiments were conducted by MMW while the critical comments that were pertained to the draft were given by YM who also took part in the writing of the manuscript. This study was under supervision and had its clinical assessments review done by MG, SY as well as BC. The nal approval of the whole study was given by all the authors who had gone through whole of the study. Our gratitude and thanks goes to all the patients who accepted and took part in this study.

Con ict of Interests
A declaration was made by the authors that this study has no competing interests.

Materials and data Availability
There will be no sharing of the obtained data since it will be required in another study.

Consent for publication
Not applicable.

Approval of Ethics and the participation consent
The hospital of Xinjiang medical University had their board (Ethical Review board of the institution rst a liate university) approve this study that also had the patients enroll the written informed consent.