Hemoglobin A1c is associated with severity of coronary artery stenosis but not with long term clinical outcomes in diabetic and nondiabetic patients with acute myocardial infarction undergoing primary angioplasty

Background Acute myocardial infarction (AMI) patients with type 2 diabetes mellitus are known to present with multiple vessel lesions during coronary angiography. The underlying mechanism remains elusive and there is a shortage of serum prediction markers. In this study, we investigate the relationship between admission HbA1c and severity of coronary artery stenosis and subsequent prognosis in AMI patients with or without diabetes. Research design and methods We measured admission HbA1c, and vessel scores based on the number of diseased coronary vessels with significant stenosis in 628 patients diagnosed with AMI. Simple and multi-regression analysis were performed to investigate the correlation between HbA1c and the severity of coronary artery stenosis. Major adverse cardiovascular events (MACE), including new-onset myocardial infarction, acute heart failure and cardiac death, were documented during the follow-up. 272 non-DM participants and 137 DM participants were separated into two groups based on HbA1c levels for survival analysis during a 2-year follow up. Results 448 non-DM patients and 180 DM patients were included in the initial observational analysis. 272 non-DM patients and 137 DM patients were included in the follow-up survival analysis. The admission HbA1c level was found to be significantly positively correlated to the number of affected vessels suffering from significant coronary artery stenosis both in DM (R square = 0.012; 95% CI 0.002 to 0.623, P = 0.049) and non DM patients (R square = 0.025; 95% CI 0.009 to 0.289, P = 0.037). Kaplan–Meier survival analysis revealed no significant difference with regard to different HbA1c levels either in DM or non-DM patients at the end of follow-up. Conclusions In patients with AMI, admission HbA1c is an important predictor for the severity of coronary artery stenosis in non-DM and DM patients. Further studies are needed to determine whether longer term follow-up could further identify the prognosis effect of HbA1c on MACE.


Introduction
Acute myocardial infarction (AMI) is one of the leading health threatening diseases in the world [1, 2] and it remains the most common cause for morbidity and mortality in patients with type 2 diabetes disease (T2DM) [3]. On the one hand, although AMI patients with T2DM are known to present with multiple vessel lesion during coronary angiography, the underlying mechanism remains elusive and there is a shortage of serum prediction markers [4,5]. On the other hand, glucometabolic disturbance is common in AMI and is found to be associated with significantly increased rate of all-cause mortality, congestive heart failure and shock [6]. However, due to stress hyperglycemia, which commonly occurs secondary to increased catecholamine levels in AMI, plasma glucose level at the onset of AMI is considered not a good morbidity and mortality predictor [7,8].
Glycated hemoglobin A 1c (HbA 1c ), measured primarily to identify 3-month average plasma glucose concentration, is accepted as a marker for long term glucose control in diabetes management [9]. Recent studies have revealed an association between chronic glucose dysregulation, assessed by HbA 1c levels, and prognosis of AMI [10]. However, although lowering HbA 1c levels is proven to have beneficial effects on microvascular complications [11,12], the effects on macrovascular complications including AMI remain under explored.
It is reported that admission HbA 1c level is a prognostic factor associated with mortality after acute myocardial infarction [13]. Moreover, quantitative relationship between HbA 1c and atherosclerosis plaque textures is reported among diabetes mellitus (DM) patients with cardiovascular disease [14]. It is noteworthy that patients suffering from diabetes exhibit higher incidence of multi-vessel lesions during coronary artery angiography. However, it still remains unclear whether HbA 1c level correlates to the severity of coronary artery stenosis. Besides, although some studies identify HbA 1c as an effective marker in predicting major adverse cardiac events (MACE) in AMI patients with or without DM [15], others show no prognostic value or different results between diabetic and nondiabetic patients [16].
In this prospective cohort study, we investigate the relationship between admission HbA 1c and the severity of coronary artery stenosis in AMI patients with or without diabetes. We subsequently carry survival analysis to investigate the effects of admission HbA 1c levels on long term mortality and morbidity in AMI patients.

Study design and participants
This was a single-center, prospective cohort study. Consecutive patients admitted to the cardiology department of the First Affiliated Hospital of Xi'an Jiaotong University for AMI between January 2013 and December 2016 were selected. The inclusion criteria were: (1) confirmed admission diagnosis of AMI, (2) successful treatment by angioplasty, (3) without diabetic ketosis or nonketotic hyperosmolar coma. The exclusion criteria were: (1) severe noncardiac disease with expected survival of less than 1 year and unwillingness to participation, (2) patients refusing angioplasty, (3) patients over the age of 80 years or living far away from the hospital's catchment area. A patient could only be included once. Information about patients' present medication, vascular risk factors and detailed medical history were obtained via questionnaires. Follow-up information was obtained via telephone questionnaires by the general practitioner (GP). AMI and DM were defined based on the universal definition criteria by the American Cardiology College and the American Diabetes Association criteria, respectively [17,18]. Patients' MACE, including new-onset myocardial infarction, acute heart failure and cardiac death, were documented during follow-up. Written informed consent was obtained from all study participants, with ethnic committee approval at the First Affiliated Hospital of Xi'an Jiaotong University.

Assessment of HbA 1c and coronary artery stenosis
Blood HbA 1c levels of all patients were measured within 3 h of admission, regardless of whether they had been fasting, using Siemens DCA analyzer for quantitative assay of HbA 1c in blood. Both the concentrations of specific HbA 1c and the concentration of total hemoglobin were measured. The ratio was reported as percent HbA 1c . The HbA 1c was studied as a continuous variable.
Selective coronary angiography was performed in multiple views. Coronary angiograms were analyzed by two experienced observers who were blinded to the identities and clinical information of the patients. Vessel scores were assessed based on the number of diseased coronary vessels with significant stenosis (greater than 50% stenosis of the lumen diameter). Next, the relationships between admission HbA 1c and the results of coronary angiography were statistically evaluated.

Statistical analysis
All statistical analyses were performed by using SPSS for Windows 17.0 (SPSS Inc, Chicago, IL). Data were presented as frequencies and percentages for categorical variables and mean ± SD for continuous variables, unless otherwise indicated. One-way ANOVA was used to compare continuous variables. Simple linear analysis was used for calculating correlation between HbA 1c and the severity of coronary artery stenosis. To ascertain the independent contribution to coronary artery stenosis, multivariate regression analysis was conducted. Kaplan-Meier survival curve analysis was used to represent the proportional risk of all-cause mortality and MACE for the admission HbA 1c values in patients with or without DM. Patients were divided into two groups based on medians of HbA 1c levels in DM and non-DM groups separately. A value of P < 0.05 was considered statistically significant.

Study population
From January 2013 till December 2016, a total of 2054 patients were enrolled in the study; 448 non-DM patients and 180 DM patients were included in the initial observational analysis, while 272 non-DM patients and 137 DM patients were included in the follow-up survival analysis (Fig. 1). The main reason for exclusion were that patients refused consent for full screen (53.2%), that they were over the age of 80 (16.5%), and that they refused angioplasty (5.9%). Baseline patients' characteristics are shown in Table 1a for patients without DM and in Table 1b for patients with DM in whole and divided based on medians of HbA 1c . The mean age was 59.84 ± 10.71 years in non-DM and 61.00 ± 10.41 years in DM patients. The mean HbA 1c was 5.73 ± 0.76% in non-DM and 7.86 ± 1.56% in DM patients. The median points of HbA 1c were 5.7% in non-DM and 7.1% in DM patients. No significant difference in risk factors at baseline were seen in different HbA 1c groups in either non-DM or DM patients.

Association between HbA 1c and severity of coronary artery stenosis
To investigate the relationship between HbA 1c and the severity of coronary artery stenosis, we utilized simple linear regression analysis. The admission HbA 1c levels were found to be significantly positively correlated with the numbers of affected vessels suffering from significant coronary artery stenosis both in DM (R square = 0.012; 95% CI 0.002 to 0.623, P = 0.049) and non-DM patients (R square = 0.025; 95% CI 0.009 to 0.289, P = 0.037) ( Fig. 2; Table 2).
Multi-regression analysis was then utilized to further determine the association of severity of coronary artery lesions and baseline characteristics including admission HbA 1c . Interestingly, although HbA 1c level was found to be significantly positively correlated to the severity of coronary artery stenosis in DM patients (95% CI 0.040 to 0.312, P = 0.011), the P value was yet close to significance in non-DM patients (95% CI −0.648 to 0.032, P = 0.076) (Table 3a, b).

All cause mortality and MACE
At the end of the follow-up, within non-DM patients 14 (5.1%) patients died for all cause, 11 (4.0%) for cardiac cause, 30 (11.0%) for acute heart failure, and 12 (4.4%) had new-onset myocardial infarction. Within DM patients, 5 (3.6%) died for all cause, 2 (1.5%) for cardiac cause, 13 (9.5%) for acute heart failure, and 9 (6.5%) had new-onset myocardial infarction.   Kaplan-Meier survival analysis was utilized to evaluate the survival curve in different HbA 1c groups in non-DM and DM patients. The analysis revealed no significant difference with regard to different HbA 1c levels both in DM and non-DM patients, shown in Fig. 3.

Discussion
In this study, serum HbA 1c is found to be associated with the severity of coronary artery stenosis in diabetic and nondiabetic patients with acute myocardial infarction undergoing primary angioplasty. Moreover, admission serum HbA 1c level exhibits no effect on all cause mortality rate and MACE rate either in non-DM or DM patients in 2-year follow-up.
The important implication of the present study is that HbA 1c is identified as a serum predictor for severity of cardiovascular lesions in non-DM and DM patients. Previous study indicates a non-linear relationship between HbA 1c and major vascular outcomes and mortality [16]. It is also known that poor glycemic control is associated with multiple vessel lesions in coronary artery disease [19,20]. However, few studies have addressed the question whether HbA 1c is related to the severity of coronary artery stenosis under non-DM and DM background. The major outcome of this study shows a positive correlation between admission HbA 1c concentrations and the number of stenosis coronary arteries in patients with acute myocardial infarction, indicating that HbA 1c level is a potential indicator for multiple coronary vessel lesions. Moreover, the significant correlation between HbA 1c and coronary artery stenosis is identified both in non-DM and DM population, implying that HbA 1c level monitoring might be beneficial even for patients without diabetes.
Data are mean ± SD and number (%) DM diabetes mellitus, HbA 1c , hemoglobin A 1c , BMI body mass index, BP blood pressure, FBG fasting blood glucose, CHF chronic heart failure, PCI percutaneous coronary intervention, CABG coronary artery bypass graft, LDL-C low density lipoprotein-cholesterol, CCB calcium channel blocker   Acute hyperglycemia has been reported to be associated with acute adrenergic signal of stress [16,21] and endothelial cell dysfunction in acute myocardial infarction, which is partially attributed to endothelial cell apoptosis [22,23], reactive oxygen species (ROS) over production [24], and inflammation [25]. However, the effect of chronic hyperglycemia on vascular function and coronary artery complications has been less reported. It is shown before that long-term glucose dysregulation is associated with increased cell death signaling [26], inflammatory changes and fibrosis [27], and subsequent cardiomyopathy [28]. In this study, long term uncontrolled glucose level, indicated by HbA 1c is shown to be correlated with the severity of coronary artery complications. Besides, this correlation could be further identified in patients without diabetes but with relatively higher level of HbA 1c .
There is conflicting evidence regarding HbA 1c level and major cardiovascular outcomes [13,16,29,30]. In this study, HbA 1c is not associated with all cause mortality and MACE in both non-DM and DM group over a 2-year follow up. The less clear association between HbA 1c and cardiovascular outcomes could be due to a limited number of patients with a relatively short follow-up in the present study [16]. It is speculated that HbA 1c may have limited predictive power for short-term prognosis in patients with AMI, but its association with long-term prognosis may be stronger [31]. As a result, more welldesigned and long-term studies as well as systemic analysis are needed to investigate whether HbA 1c will play an important role in the prognosis of AMI.

Study limitations
This is a single centre based observational cohort study. The sample size in this study is relatively small, especially in patients with T2DM, therefore, comparisons of some subgroups may lack power to detect significant differences for selected variables. Although HbA 1c level is associated with the number of the stenosis coronary arteries, a complex and systemic score, i.e. SYNTAX score, could be further recorded to predict the severity of coronary artery stenosis more accurately.

Conclusions
In patients with AMI, admission HbA 1c may be an important predictor for severity of coronary artery stenosis in non-DM and DM patients. The results of this study