Impact of Hyperinsulinemia on Long-Term Clinical Outcomes of Percutaneous Coronary Intervention in Non-Diabetes Patients With Acute Myocardial Syndrome.

Background and Objectives: Hyperinsulinemia plays a key role in development of cardiovascular impairment in patients with Metabolic syndrome. The aim of this study was to evaluate the inuence of hyperinsulinemia on long-term Clinical outcomes of percutaneous coronary intervention (PCI) in patients with acute myocardial syndrome. Methods: Between March 2016 and January 2019, patients of ACS without diabetes mellitus and received primary PCI were enrolled. 368 patients were divided into low insulin group (n=157), medium insulin group (n=154) and high insulin group (n=157) according to tertiles of fasting insulin (FINS) level. The primary endpoint was major adverse cardiac events (MACE; all-cause death, non-fatal myocardial infarction, target vessel revascularization (TVR)) at 24 months. Second endpoint was angina-hospitalization. Results: High insulin group had an unfavorable prognosis, with higher rate of MACE (34.39%) compared with low insulin group (22.29%) and medium insulin group (23.37%) at 24 months (P<0.05). This difference was mainly driven by the increase of TVR. High insulin group also had higher rate of angina-hospitalization than low insulin group. Multivariate logistic regression showed that high insulin level (OR2.636, 95%CI 1.378-5.023), small vessel lesion (OR2.636, 95%CI 1.378-5.023), bifurcation lesion (OR3.506, 95%CI 1.048-11.922) and Syntax score(OR1.116, 95%CI 1.054-1.182) were independent predictors of MACE in ACS patients after PCI Conclusion: Hyperinsulinemia might valid ACS ST-segment lipoprotein-cholesterol; HDL-C,


Introduction
Metabolic syndrome (MetS) has a high prevalence around the world [1]. MetS is associated with the development of coronary atherosclerosis, plaque instability, and cardiovascular events in patients with or without type 2 diabetes [2][3]. The cores of metabolic syndrome are insulin resistance (IR) and hyperinsulinemia [4]. A new concept of selective insulin resistance indicates that tissues become resistant to insulin's effect on glucose transport but remain sensitive to its lipogenic effect [5]. IR may be compensatory in the body's response to prevent the metabolic syndrome. Hyperinsulinemia is more common than IR and may play a primary role in development of cardiovascular impairment in patients with MetS [6].
Our previous study demonstrated that hyperinsulinemia impaired functions of endothelial progenitor cells, which play a key role in maintaining endothelial function and vascular repairmen [7]. Other studies also indicated that hyperinsulinemia interfered with arteriolar vasodilation and NO bioavailability in obese, insulin resistant and healthy subjects [4,8].
However, the impact of hyperinsulinemia on major clinical outcomes following percutaneous coronary intervention (PCI) is largely unknown. The aim of this study is to evaluate the impact of hyperinsulinemia on major clinical outcomes in patients with acute myocardial syndrome (ACS) undergoing PCI.

Study population
Between March 2016 and January 2019, patients with acute myocardial syndrome and received PCI were retrospectively enrolled. The including criteria is as following: 1. Patients of at least 18 years of age, who had ACS. ACS was de ned as ST segment elevated myocardial infarction (STMEI), non-ST segment elevated myocardial infarction and unstable angina (UA) [9]. 2. Patients received primary PCI with drugeluting stent (DES). The following conditions were excluded from the study: 1. Patients who were diagnosed with diabetes. Diabetes mellitus was de ned according to the American Diabetes Association criteria [10]; 2. Patients without previously known diabetes but with glycated hemoglobin A1c( HbA1c) >6.5% on admission; 3. Angiography showed in-stent restenosis; 4.insulin or insulin sensitizer users. This study was approved by the ethics committee of Qinhuangdao First Hospital and all patients provided written informed consent.

Interventional procedure
Patients were administered 300 mg of aspirin and a loading dose of 300 mg Clopidogrel or 180mg Ticagrelor. Coronary angiograpy and percutaneous coronary intervention were performed in all patients by transradial or transfemoral approach. The angiographic ndings were analysized by quantitative coronary angiography (QCA) system (GE QCA, Centricity AI 1000 -GE Mnet Version 4.1.15.07). With the outer diameter of the contrast-lled catheter as the calibration standard, the minimal lumen diameter (MLD), lesion length were measured in diastolic frames.The Syntax score of each patient was calculated according to the results of coronary angiography.

Follow-up and study endpoints
All patients received aspirin (100 mg QD) and Clopidogrel (75 mg QD) or Ticagrelor (90mg BID). Patients underwent clinical observation for at least 36 months. Clinical follow up was performed at one month, six months, 12 months, 24 months.
The primary endpoint was major adverse cardiac events (MACE), including overall death, non-fatal myocardial infarction MI , target vessel revascularization (TVR) . MI was diagnosed by an elevation of serum creatine kinase or troponin three times the upper limit of normal, together with chest pain lasting more than 30 minutes [11]. TVR was de ned as any repeat revascularisation of the stent treated vessel [11].
The second endpoint was angina pectoris requiring hospitalization.

Statistics analysis
All statistics analyses were performed by SPSS 17 (SPSS, Chicago, Illinois, USA). Continuous variables were expressed as mean ± standard deviation of the mean, and were compared by use of the one-way Anova test; The data of non normal distribution are transformed by logarithm. Categorical variables were compared with the χ 2 statistics or Fisher exact test. Multivariate logistic regression was used to estimate the predictors of MACE.MACE incidence rates of two year adverse cardiac events were estimated by the Kaplan-Meier method. A probability value < 0.05 was considered statistically signi cant. A probability value <0.05 was considered statistically signi cant.

Results
The enrolled patients were divided into three groups according to tertile of fasting insulin (FINS) level (low insulin group, FINS < 7.89µIU/mL; medium insulin group, 7.89µIU/mL ≤ FINS < 14.33µIU/mL; high insulin group, FINS ≥ 14.33µIU/mL). Baseline clinical characteristics were shown in Table 1. The three groups were balanced in age, gender, family history, hypertension, smoking, prior myocardial infarction and clinical presentation. There were no signi cant differences in laboratory characteristics such as left ventricular ejection fraction (LVEF), cholesterol, triglyceride, low density lipoprotein-cholesterol .Low insulin group had higher high density lipoprotein than high insulin group (P < 0.05). BMI, waistline, HOMA-IR and serum Urine in high insulin group were higher than that in low insulin group and medium insulin group. The angiographic and procedural characteristics were shown in Table 2. The target vessel had no signi cant difference among the three groups. QCA analysis revealed that high insulin group had longer lesion length and longer stents than low insulin group. Syntax scores were higher in high insulin group than that in low insulin group. High insulin group also had more target vessel stenosis and bifurcation lesions than low insulin group.    The baseline clinical characteristics of the patients strati ed by the primary endpoint are summarized in Table 3. Compared with event-free group, patients with MACE had higher levels of FINS. Patients with MACE also showed higher rates of prior myocardial infartction, higher level of HOMA-IR, BMI, creatinine and waistline. As shown in Table 4, patients with MACE had smaller vessel diameter. At the mean while, patients with MACE showed higher Syntax scores and longer lesion length.    Clinical follow-up was completed in all survival patients. Kaplan-meier survival analyses showed that the high insulin group had an unfavorable prognosis, with higher rates of MACE and angina hospitalization compared with the other two groups at 24 months ( Fig. 1 and Fig. 2). As shown in Table 5, the incidence of the primary endpoint in high insulin group was signi cantly higher than that in low insulin group (P < 0.05). This difference was mainly driven by the increase in target vessel revascularization. However, the incidence of overall death, non-fatal MI during follow-up were similar among the FINS tertiles.

Discussion
The main nding of this study is that high insulin level is associated with increased risk of MACE in ACS patients without diabetes mellitus. Hyperinsulinemia might be a valid predictor of clinical outcomes in ACS patients undergoing PCI.
Weakened insulin signalling or insulin resistance, together with the associated diminution in glucose transport, promotes compensatory increase of insulin that results in hyperinsulinemia [12]. As we know, insulin has double-phase effect on atherogenesis. Under physiological conditions, insulin stimulates the uptake of glucose and maintains glucose homeostasis [13]. But at hyper-physiological concentration, insulin stimulates proliferation of vascular smooth muscle cells and triggers in ammation [14]. Clinical and experimental evidence suggests that hyperinsulinemia can promote obesity and endothelial dysfunction [15][16].
Some previous studies explored the impact of insulin resistance on clinical outcomes of PCI, but the results were controversial. Yun et al analyzed 98 consecutive non-diabetic patients who underwent elective coronary angioplasty, and revealed that IR (HOMA index ≥2.6) was an independent predictor of in-hospital and 30 day MACE rates [17]. Hwang et al evaluated one year outcomes of 229 consecutive non-diabetic CAD patients treated with DES. The results found that despite worse trend in angiographic outcomes in the IR group (HOMA index ≥2.5), it was not translated into worse 1-year major clinical outcomes following PCI with DES as compared to the non-IR group [18].
The current study found that non-diabetic patients with hyperinsulinemia had increased MACE rate after undergoing PCI. As far as we know, this is the rst study to discuss the direct impact of hyperinsulinemia on clinical outcomes of PCI. Actually, the incidence of MACE was mainly driven by the increase of target vessel revascularization.
In this study, we also found that patients with hyperinsulinemia had more angina-hospitalization than patients with low and middle insulin level. The mechanism of angina may be impaired microcirculation. Impaired coronary microcirculation is frequently observed in patients with insulin resistance and T2DM.
This impairment is driven by reduced levels of bioavailable nitric oxide. Our previous study demonstrated that hyperinsulinemia impaired endothelial progenitor cell's function by down regulation of PI-3K/Akt/eNOS pathway [7]. NO is a key regulator in modulating endothelial function. Impaired NO reproduction may explain the results of the current study.

Limitations
This study has several limitations. First, it was a single center study, the sample size was relative small. Second, it is a retrospective but not a randomized controlled study, it may have selection bias. The third limitation was the relative short duration of 24 months of follow-up. It may be a limiting factor to evaluate important clinical effects of hyperinsulinemia. We still need more investigation and more time to testify the impact of insulin in patients undergoing PCI.