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Impact of diabetes mellitus on long-term clinical and graft outcomes after off-pump coronary artery bypass grafting with pure bilateral skeletonized internal thoracic artery grafts

Background The effect of diabetes mellitus (DM) on the long-term outcomes of coronary artery bypass graft (CABG) remained debatable and various strategies exist for CABG; hence, clarifying the effects of DM on CABG outcomes is difficult. The current study aimed to evaluate the effect of DM on clinical and graft-related outcomes after CABG with bilateral internal thoracic artery (BITA) grafts. Methods From January 2001 to December 2017, 3395 patients who underwent off-pump CABG (OPCAB) with BITA grafts were enrolled. The study population was stratified according to preoperative DM. The primary endpoint was cardiac death and the secondary endpoints were myocardial infarction (MI), revascularization, graft failure, stroke, postoperative wound infection, and a composite endpoint of cardiac death, MI, and revascularization. Multiple sensitivity analyses, including Cox proportional hazard regression and propensity-score matching analyses, were performed to adjust baseline differences. Results After CABG, the DM group showed similar rates of cardiac death, MI, or revascularization and lower rates of graft failure at 10 years (DM vs. non-DM, 19.0% vs. 24.3%, hazard ratio [HR] 0.711, 95% confidence interval [CI] 0.549–0.925; P = 0.009) compared to the non-DM group. These findings were consistent after multiple sensitivity analyses. In the subgroup analysis, the well-controlled DM group, which is defined as preoperative hemoglobin A1c (HbA1c) of < 7%, showed lower postoperative wound infection rates (well-controlled DM vs. poorly controlled DM, 3.7% vs. 7.3%, HR 0.411, 95% CI 0.225–0.751; P = 0.004) compared to the poorly controlled DM group, which was consistent after propensity-score matched analysis. Conclusions OPCAB with BITA grafts showed excellent and comparable long-term clinical outcomes in patients with and without DM. DM might have a protective effect on competition and graft failure of ITA. Strict preoperative hyperglycemia control with target HbA1c of < 7% might reduce postoperative wound infection and facilitate the use of BITA in CABG. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-022-01687-2.

Background Coronary artery bypass graft (CABG) is the recommended treatment for revascularization in patients with diabetes mellitus (DM) and coronary artery disease (CAD), especially in three-vessel diseases [1]. However, DM could worsen the prognosis after CABG because it frequently involves diffuse CAD that involves the left main, multi-vessel, or smaller vessels [2] and has higher chances of recurrent myocardial infarction (MI) and other comorbidities postoperatively [3,4]. Additionally, the effect of DM on the long-term outcomes of CABG remained debatable based on published studies so far [5][6][7][8][9].
Importantly, various strategies exist for CABG, and when these are mixed in the same study, clarifying the effects of DM on CABG outcomes becomes difficult [5][6][7]9]. Particularly, regarding graft selection, a wide variety of graft selection strategies exist in previous studies although internal thoracic artery (ITA) is proven patent in the long-term and is the graft choice for left anterior descending artery anastomosis [5][6][7][8][9]. Additionally, offpump CABG (OPCAB) might remove the detrimental effects of cardiopulmonary bypass; however, a great deal of variability related to use of cardiopulmonary bypass exists for each center [5,7]. Therefore, this study aimed to determine the effects of DM on patients who underwent OPCAB using bilateral ITA (BITA) grafts only.
Postoperative sternal wound infection is one of the most worrisome complications after CABG using BITA. Preoperative hemoglobin A1c (HbA1c) has been studied as a prognostic factor for postoperative wound infection in patients with DM who underwent cardiac surgery [10,11]. The effect of HbA1c on postoperative morbidities, including mediastinal wound infection, was tried to define in this homogenous cohort.

Study design and populations
This retrospective and the observational study included 6691 consecutive patients who underwent CABG using BITA in a single large tertiary center from January 2001 to December 2017. Patients younger than 18 years (n = 14), with missing angiographical data (n = 40), who underwent CABG other than BITA grafts (n = 1916), on-pump CABG (n = 781), concomitant heart surgery (n = 456), and had previous CABG history (n = 89) were excluded (Fig. 1). Patients were divided into two groups, the non-DM and DM groups. Patients in the DM group were divided into two subgroups, namely, the well-controlled (preoperative HbA1c of < 7%) and poorly controlled DM groups (HbA1c of ≥ 7%) [12].
The Institutional Review Board of Samsung Medical Center approved this study (SMC 2021-11-157, date of approval: December 1, 2021), which waived informed Keywords: Diabetes mellitus, Coronary artery bypass graft, Internal thoracic artery, Graft failure, Wound infection Fig. 1 Study flow diagram. A total of 3395 patients who underwent OPCAB with a bilateral internal thoracic artery in a single tertiary center were enrolled. Patients were divided into non-DM and DM groups. Patients in the DM group were divided into well-controlled (HbA1c < 7%) and poorly controlled DM groups (HbA1c ≥ 7%). OPCAB indicates off-pump coronary artery bypass graft; DM: diabetes mellitus; HbA1c: hemoglobin A1c Park et al. Cardiovascular Diabetology (2022) 21:243 consent from individual patients because this retrospective study poses minimal risk for patients.

Data collection and clinical follow-up
The baseline demographic, echocardiographic, laboratory, and follow-up clinical outcomes were retrospectively collected through medical record review. Extracted data were revalidated by our research coordinators and physicians for clarity. The primary endpoint was cardiac death at 10 years postoperative and the secondary endpoints included MI, revascularization, graft failure, stroke, postoperative wound infection, and major adverse cardiovascular events (MACE; a composite endpoint of cardiac death, MI, and revascularization). The mean clinical outcome follow-up duration was 4.01 years. The mortality data for patients who were lost to follow-up were confirmed using the National Death Records. MI was defined as elevated cardiac troponin or myocardial band fraction of creatine kinase that is greater than the upper reference limit with concomitant ischemic symptoms or electrocardiography findings indicative of ischemia. Left ventricular dysfunction was classified as follow: normal (left ventricular ejection fraction more than 50%); mild dysfunction (left ventricular ejection fraction 40% to 49%); ≥ moderate dysfunction (left ventricular ejection fraction less than 40%). Graft patency was assessed using coronary computed tomography angiography or invasive coronary angiography, according to operator discretion (Additional file 1: Table S1). Grafts were evaluated following the FitzGibbon A, B, and O classification and interpreted by an independent cardiology expert who was blinded to treatment strategy. Postoperative early clinical outcomes included clinical outcomes within 30 days of the surgery. Outcome variables were defined according to the definition of the Society of Thoracic Surgeons Adult Cardiac Surgery Database version 4.20 [13].

Surgical procedure and perioperative management
The surgical technique for OPCAB was performed following relevant standard guidelines [1,14]. and described in our earlier report in detail [15]. BITA was prepared using the skeletonization technique. After opening the pericardium, the right ITA was anastomosed to the left side of the left ITA as a Y-composite graft. Achieving complete revascularization of all vessels with a 1-mm or larger diameter and 50% or more angiographic diameter stenosis was intended in all patients. The left ITA was first anastomosed to the left anterior descending artery and its branches, and the right ITA was sequentially anastomosed to branches of the circumflex artery. The right coronary territory was revascularized last. The quality of the anastomosis was assessed by transit-time flow measurement with a Transsonic Flowmeter (Transonic Systems, Ithaca, NY).
Strict glycemic control before, during, and after the surgery has been implemented under standard institutional protocols. Target blood glucose control in patients with DM was set to < 180 mg/dL [12,16] by intermittent regular insulin injection (Humulin; Eli Lilly and Company, Indianapolis, Ind) intraoperatively and continuous regular insulin infusion postoperatively in the intensive care unit (ICU). Blood glucose level was measured every 1 h in the operative room and every 4 h in the ICU. If the ideal glycemic control was not made, glucose concentration was checked at an interval of 2 h until the target level was achieved in the ICU.
Guideline-directed medical therapy including a combination of antiplatelet agents, beta-blockers, statins, and angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) was applied to all patients undergoing CABG, unless contraindicated [1,17].

Statistical analysis
Descriptive statistics for categorical variables were reported as frequency and percentage, whereas continuous variables were reported as mean ± standard deviation or median (range). Categorical variables were compared between the groups using the χ 2 test or Fisher's exact test, whereas continuous variables were compared using the two-sample t-tests or the Wilcoxon rank-sum test. Continuous data were checked for distribution normality using the Shapiro-Wilk test and graphical methods. The cumulative incidence of clinical events is estimated using a Fine-Gray model to account for the competing risk of death from non-cardiovascular causes.
Multiple sensitivity analyses, including multivariable Cox proportional hazard regression and propensity-score matched analyses, were performed to reduce biased effects. The Cox proportional hazard regression model considered variables that were significant in the univariable analysis or clinically relevant in the multivariable analysis. Variables included age, sex, body mass index, DM, HbA1c, an initial diagnosis of ischemic heart disease, hypertension, dyslipidemia, smoking history, end-stage renal disease requiring dialysis, previous cerebrovascular accident, abdominal aortic aneurysm, peripheral arterial disease, chronic obstructive pulmonary disease, peak troponin I, peak creatine kinase-MB, glomerular filtration rate, ejection fraction, left ventricular dysfunction, 3 vessel disease, left main involvement, and urgent surgery. The backward elimination method was used for model selection in the multivariable analysis. The results were reported as hazard ratio (HR) and 95% confidence interval (CI).
Propensity-score analyses were used to adjust covariate differences between the two groups. The variables included in the propensity-score model were as follows: age, sex, body mass index, angina, hypertension, dyslipidemia, previous stroke history, chronic kidney disease, chronic obstructive pulmonary disease, smoking history, left ventricular dysfunction, preoperative significant mitral valve regurgitation, urgent surgery, the number of anastomoses, and the number of diseased coronary arteries. A total of 1393 patients in the non-DM group and 1393 patients in the DM group were matched in a 1:1 manner using nearest-neighbor matching. Additionally, for subgroup analysis, a total of 452 patients in the wellcontrolled DM group and 452 patients in the poorly controlled DM group were matched in a 1:1 manner using nearest-neighbor matching. The balance between the two groups after propensity-score matching was assessed by calculating the standardized mean difference (SMD) between selected variables, with an SMD of < 0.20 suggesting an appropriate balance (Additional file 2: Fig. S1, Additional file 1: Tables S2 and S3).
All statistical tests were two-sided, with an alpha level of 0.05. Statistical analysis was performed using Statistical Package for the Social Sciences software (version 25.0, SPSS, Chicago, IL, USA) and R statistical software (version 4.0.2; R Foundation of Statistical Computing, Vienna, Austria).
Patients with DM were older (64.16 years vs. 62.62 years, P < 0.001) and more likely to have hypertension, smoking history, an end-stage renal disease requiring dialysis, previous cerebrovascular accident, abdominal aortic aneurysm, and peripheral arterial disease compared to patients without DM (Table 1). Additionally, patients with DM had a higher proportion of left ventricular dysfunction (25% vs. 16%, P < 0.001) and three-vessel diseases (75.6% vs. 64.8%, P < 0.001) and a bigger number of anastomosis (4.10 vs. 3.87, P < 0.001) during CABG than those without DM.
In the long-term, no differences were found in the rates of cardiac death, MI, repeat revascularization, stroke, and MACE between the DM and non-DM groups ( Table 2).
Multivariable Cox proportional hazard models and propensity-score matched analyses consistently showed similar results for patients in both groups (

Subgroup analysis
Compared with patients with poorly controlled DM, patients with well-controlled DM were older and more likely to have hypertension, end-stage renal disease that requires dialysis, and previous cerebrovascular accidents (Table 3). However, no statistical differences were seen between the two groups regarding preoperative echocardiography, coronary angiography, and operative characteristics. In the long-term, there were no differences found in the rates of cardiac death, MI, repeat revascularization, stroke, and MACE between the well-controlled DM and poorly controlled DM groups (Additional file 2: Figs. S2 and S3). However, patients with well-controlled DM had a lower proportion of postoperative wound infection (3.7% vs. 7.3%, HR = 2.064, 95% CI 1.210-2.521, P = 0.0007; Table 4). Multivariable Cox proportional hazard models and propensity-score matched analyses consistently showed similar results for patients in the well-controlled and poorly controlled DM groups.

Discussion
This study revealed the following key findings: (1) DM had no significant impact on long-term clinical outcomes, including cardiac death and MACE after OPCAB with BITA, (2) patients with DM had lower rates of postoperative graft failure compared to those without DM, and (3) patients with well-controlled DM, which is defined as preoperative HbA1c of < 7%, had a lower proportion of postoperative wound infection compared to those with poorly controlled DM. Patients with DM who undergo intervention for CAD might have a poorer prognosis than those without DM, although the impact of DM on long-term mortality remained controversial [5,6,8,18]. Patients with DM have more left main or multi-vessel CAD with a diffuse disease that involves smaller vessels [2], and they have a greater atherosclerotic burden and increased number of lipid-rich plaques, which are prone to rupture [19][20][21].
However, long-term survival and MACE between the DM group and non-DM groups in this study were not statistically different due to several reasons. First, CABG might have a protective effect against recurrent MI in patients with DM [22]. In complex CAD, the most common cause of mortality might be MI-related death [23], which tends to cluster within the proximal third of major coronary vessels [24]. CABG might provide the coverage of anatomic zones at risk for MI [25] and have the effect of preventing recurrent MI in patients with DM because graft insertion sites seem to be consistently located distal to acute thrombosis sites in patients with CABG. Another important question is the influence of DM on the long-term patency of ITA grafts. Raza et al. [26] investigated postoperative angiograms quantifying stenosis in ITA grafts in patients who underwent primary isolated CABG and found that DM did not influence the long-term patency of bypass grafts. Early ITA graft patency was even better in patients with DM than in those without DM in the same study [26]. Additionally, Ralf et al. found that not having DM was a predictor    of ITA graft failure and which might have been caused by competitive flow in their well-designed study with completed angiographic follow-up [27]. ITA grafts can autoregulate depending on flow requirements; thus, they may close due to competitive blood flow in the native vessel, especially in patients without DM [28][29][30]. In the current study, the non-DM group had higher rates of graft failure than the DM group and most of the cases were within the early phase, which is consistent with previously described studies. We might infer that most graft failures might have been caused by competition, not by surgical occlusion or atherosclerosis from the observation that most graft failures occurred in the early phase, not in the immediate postoperative or late phase. Additionally, most graft failures occurred in the form of occlusion rather than stenosis, and in RITA rather than in LITA, which might have a lower chance of competition due to the low number of anastomosis per graft [27] compared to RITA. Severe stenotic coronary disease in DM might have a protective effect on graft patency, which might need further investigation. Fractional flow reserve-guided CABG, which is now in practice at our center, might avoid graft failure caused by competition and enhance long-term outcomes, especially in patients without DM [31,32].
HbA1c, which reflects the mean glycemia over the previous 8-12 weeks [33,34], has been investigated as a parameter exerting an adverse influence on outcomes in patients with DM who underwent cardiac surgery [10,11]. In this study, postoperative wound infection, which is the major drawback of using bilateral ITA grafts for CABG in patients with DM, was significantly lower in the well-controlled DM group, although without differences regarding cardiac mortality and MACE between the wellcontrolled and poorly controlled DM groups. The preoperative strict control of hyperglycemia might lower the incidence of postoperative wound infection and facilitate the use of BITA when performing CABG.
The present study has the following limitations. First, this is a retrospective study in a single tertiary center and might have selection bias. Second, we did not routinely perform invasive coronary angiography or coronary computed tomography angiography after CABG and the graft-related outcomes might be overestimated. Last, the adherence of medical treatment was lower than expected and not considered in the present analysis. However, important strengths of our study include its large sample size, homogeneous group using identical strategy in performing CABG, and strict adjustment for confounding factors using multiple sensitivity analysis.
In conclusion, OPCAB with BITA grafts showed excellent and comparable long-term clinical outcomes in patients with and without DM. DM might have a protective effect on competition and graft failure of