Insulin Resistance, Body Mass Index and Coronary Atherosclerotic Stenosis in Obese Adults

Background: Obesity is associated with an increased risk of all-cause mortality. Mortality related to excess body weight occurs mostly due to coronary artery disease(CAD). This study is to observe the prevalence of coronary atherosclerotic stenosis in obese young-middle adults and outcomes of coronary stenosis in patients with obesity after metabolic surgery. Methods: Patients with obesity undergoing metabolic surgery were included from December 2015 to June 2017.Coronary computed tomography angiography(CTA) was examined preoperatively. Patients were divided into the stenosis group and the non-stenosis group and differences in clinical indicators and Homeostasis model assessment insulin resistance(HOMA-IR)were compared between the two groups. After metabolic surgery, the clinical indicators and severity of coronary stenosis were compared with those before metabolic surgery. Results: Among 217 consecutive obese patients with a mean body mass index(BMI) of 37.92±6.14kg/m 2 , 58(26.72%) patients were diagnosed with coronary atherosclerotic stenosis. Compared with the non-stenosis group, patients in the stenosis group had a more elder age, higher rates of male, smoking, hypertension and type 2 diabetes mellitus(T2DM), and higher levels of glycated haemoglobin(HbA1C),fasting blood glucose(FBG),fasting C-peptide and HOMA-IR(P<0.05). While there was no signicant difference in BMI, waist circumstance(WC), serum lipid levels (P (cid:0) 0.05). The multivariate binomial logistic regression analysis showed that the age(β=0.070, OR=1.073, 95% CI 1.028-1.120, P<0.001),smoking(β=1.371, OR=3.941, 95% CI 1.257-12.357, P=0.019), and HOMA-IR(β=0.040, OR=1.041, 95% CI 1.000-1.083, P=0.047) were independent risk factors of coronary stenosis. After metabolic surgery, coronary stenosis relieved in 11/19 cases (57.89%), in which 9 cases got complete remission; coronary stenosis was aggravated in one case and remained the same in another one case. Conclusions: HOMA-IR, as well as age and smoking, is an independent risk factor for CAD in obese patients. Metabolic surgery is possibly helpful to reverse mild to moderate coronary atherosclerotic stenosis in patients with obesity.

Conclusions: HOMA-IR, as well as age and smoking, is an independent risk factor for CAD in obese patients. Metabolic surgery is possibly helpful to reverse mild to moderate coronary atherosclerotic stenosis in patients with obesity.

Background
Obesity is an important cause of metabolic syndrome (including dyslipidemia, hypertension and hyperglycemia), together with smoking, insulin resistance, in ammatory changes and vascular endothelial damage, which constitute risk factors for coronary artery disease(CAD).For overweight/obese patients, 9.60%-13.97% of male patients and 11.13%-19.22% of female patients had CAD [1]. According to a study of nearly 70 million people published by the global burden of disease study, obesity accounted for 7.1% of all deaths in 2015, with cardiovascular disease accounting for 41.4%;cardiovascular disease(CVD) is also the leading cause of death among overweight people, at 23.9% [2]. With the increase of obese patients, the prevalence will be higher.
Obesity, especially central obesity is linked to insulin resistance [3]. Some studies suggest that insulin resistance is associated with CAD in type 1 diabetes mellitus(T1DM) [4], type 2 diabetes mellitus(T2DM) [5] and non-diabetic subjects [6][7][8]. However, there was less studies about the association of insulin resistance and CAD in obese population.
Interesting, there is a hot debate on the controversial points on the obesity paradox in patients with CAD [9][10][11].It appears to be an obesity paradox that patients with body weight index(BMI) in the range of 30 to 34 kg/m2 have a protective effect against cardiovascular diseases.While a recent meta-analysis found that compared with metabolically healthy normal-weight individuals are at increased risk for adverse long-term CVD events even in the absence of the metabolic abnormalities, suggesting there is no healthy pattern of increased weight [12]. Besides, a recent report indicated that weight loss is associated with signi cantly higher incidence of adverse cardiovascular outcomes in patients with coronary heart disease [13]. Thus, in the present study we sought to investigate the interplay of insulin resistance, BMI and CAD in obese young-middle aged adults and outcomes of metabolic surgery on coronary stenosis in patients with obesity.

Patient selection
Obese patients who underwent coronary computed tomography angiography (CTA) on a dual-source CT scanner before metabolic surgery from December 2015 to June 2017 were respectively included. The inclusion criteria was a, patients aged 18-59 years old; b, patients with BMI ≥ 28Kg/m2; c, patients with detailed medical record and distinct CTA images; d, patients without malignant tumors and other diseases which affect the body weight. This study was approved by the Research Ethics Committee of Beijing Friendship Hospital, and written informed consent was obtained from all patients.
Coronary atherosclerotic stenosis was de ned as the presence of any atherosclerotic lesion (> 1% stenosis) in one or more coronary artery segments. According to coronary stenosis or not, the patients were divided into two groups, the stenosis group and the non-stenosis group.

Surgical therapy and follow-up
The patients who met the surgical indications in surgical treatment guidelines for obesity and T2DM in China (2014) [14], were preformed metabolic surgery(sleeve gastrectomy and Roux-en-Y gastric bypass).CTA was rechecked 1 year after surgery, and OGTT and other clinical indicators were tested again.

Statistical analysis
All statistical calculations were performed using SPSS25.0. Continuous variables are displayed as means ± standard deviations(SDs) or medians (interquartile ranges) and categorical variables as numbers (percentages). Differences between the stenosis group and the non-stenosis group were determined by independent-samples T Test or nonparametric tests according to the Normality.
Differences between pre and post-metabolic surgery were analyzed by Paired-samples T Test. A multivariable binomial logistic regression analysis was performed to detect associations of age, sex, smoking, hypertension, T2DM, BMI, HbA1C and HOMA-IR with the odds of having coronary stenosis. Statistical signi cance was set at p < 0.05.

Baseline characteristics
A total of 217 consecutive obese patients(male:23.5%) had a mean age of 33.62 ± 8.91 years(range 18-59 years) and a mean BMI of 37.92 ± 6.14 kg/m 2 (range 28.0-60.5 kg/m 2 ). They were divided into two groups, 58 cases(26.72%) in the stenosis group and 159 cases(73.28%) in the non-stenosis group.

Association of clinical indicators with coronary stenosis
Baseline clinical characteristics in the non-stenosis group and the stenosis group were showed in Table1.Compared with the non-stenosis group, patients in the stenosis group had a more elder age(P < 0.001), higher rates of men(P = 0.040), smoking(P < 0.001),hypertension(P < 0.010) and T2DM(P = 0.002), elevated levels of glycated haemoglobin(HbA1C)(P = 0.006),fasting blood glucose(FBG, P < 0.001) and fasting C-peptide(P = 0.012) and Homeostasis model assessment insulin resistance(HOMA-IR, P = 0.038) ( Table 1).  To detect the relationship of HOMA-IR and BMI, further association was analyzed. The Pearson association analysis showed there was no linear association of HOMA-IR and BMI(P=0.231, Fig.1).

Metabolic and coronary outcomes after metabolic surgery
Table3 showed that1-year post metabolic surgery, BMI, blood pressure, and levels of ALT, lipids and uric acid, HbA1C and HOMA-IR were signi cantly improved (P 0.05). Besides, the ratios of diabetes and hypertension were totally relieved(100%).  Fig. 2); coronary stenosis was aggravated in 1 case (5.26%, ), who had 80% of stenosis in the left anterior descending branch; coronary stenosis remained the same in 1 case (5.26%). 6 cases (31.58%) without coronary stenosis pre-surgery had no progression.

Discussion
Obesity is associated with an increased risk of all-cause mortality. Mortality related to excess body weight occurred mostly due to coronary artery disease. Compared to subjects with normal weight or overweight, obesity is an independent risk factor for CAD. In this study, it was HOMA-IR not BMI that was associated with presence of CAD, independent of the presence of DM and hypertension, age, sex, smoking, BMI and HbA1C. The prevalence of CAD in was 26.72% among the studied young-middle obese adults.Data from other studies ranged from 4.5-52% [15][16][17], owing to differences of race, age, sex ratio, radiology examination methods (CTA or angiography) or de nitions of CAD.
However, the relationship between BMI, other cardiovascular risk factors, and the risk of CAD are complex.
There is an ongoing debate in light of this con icting result. In subgroup analysis by region or ethnicity, signi cant differences in all of the ethnic groups and regions was not observed [16]. In this study, it was HOMA-IR not BMI that associated with CAD in obese adults with a BMI of 28 to 60 Kg/m 2 . Obesity and/or an increased BMI are independently associated with greater risk of insulin resistance, metabolic syndrome, diabetes, hypertension, and dyslipidemia, and these complications may be more important markers of CAD risk than obesity/BMI alone. Another possible reason may be attributed to the inherent limitations of BMI as a marker of obesity or severe obesity, without exactly re ecting body fatness and lean body mass. For example, a person with increased muscle mass would have the same BMI as a person with increased fat percentage. Thirdly, we suppose that once a person's BMI 28 (Chinese guideline) or 30 Kg/m 2 , his/her risk for CAD may be higher, irrespective of the different degrees of obesity, and the risks should be determined by HOMA-IR and other insulin resistance factors. Finally, the sample of this study was a limitation, which weak the strength of the association. And associations of BMI with extent of coronary stenosis hadn't been studied.
Insulin resistance is a major component of obesity, metabolic syndrome, T2DM and CAD. HOMA-IR is a commonly used marker of insulin resistance which incorporates both glucose and insulin concentrations. An meta-analysis of 65 studies published in 2012, which included 516,325 participants, also revealed that insulin resistance, evaluated by HOMA-IR, was a good predictor for cardiovascular disease [8].In this study, HOMA-IR was independently associated with having coronary stenosis in obese patients. While the Pearson analysis showed no association between HOMA-IR and BMI. It illustrates why the two factors did not relate to the risks of CAD simultaneously. This indicates that maybe we should pay more attention to insulin resistance than BMI alone to evaluate the CAD risks in obese patients.
Currently, statins are generally considered as important drugs that can improve the condition of coronary plaque. According to a study published by JACC in 2018 involving more than 3,500 patients who used coronary CTA to evaluate coronary artery plaques, statins can delay the progression of coronary artery plaques and facilitate the transformation of plaques to stable plaques but cannot reverse the degree of coronary artery stenosis [18]. As shown in Table 3, metabolic surgery has signi cant remission effect on various risk factors of CAD. This could be the cause of remission in coronary stenosis. As is proved by other studies [19], the mechanism might be: a) By limiting food intake (all types of metabolic surgery) and nutrient intake (gastric bypass surgery), thereby promoting the remission of metabolic syndrome and improving cardiovascular conditions, b) Studies have shown that metabolic surgery simultaneously improves gastrointestinal hormones, intestinal ora, central nervous system and other systemic factors, thus improving metabolic syndrome. Metabolic surgery is likely to be a promising therapeutic approach for obese patients with CAD except weight loss. However, the number of follow-up cases was too few, which needs multi-centered large sample studies to yield stronger ndings.
Limitation of our study: a) There was a bias in sex ratio(male,32.76%vs 19.50% respectively),owing to the women had more willing to visit Bariatric Clinics. While men were more susceptible to CAD. As we know, men usually have higher BMI and weight, so the strength of the association might be weakened; b) Another shortage was the small sample size, especially in the postoperative cases, and the limited sample size of our study did not allow for subgroup analysis  Coronary arterial stenosis was relieved in a 25 year-old male patient 1 year after metabolic surgery(the upper gure showed 65% stenosis in the left circum ex artery before surgery; the lower one showed no stenosis in the same position after metabolic surgery)