This single-center, observational, retrospective study was conducted in Xiangtan Central Hospital, which included patients who underwent PCI for CTO between January 1, 2016, and July 31, 2021. The inclusion criteria of the study were that the patient had to have at least one CTO in a main coronary artery, stable vital signs, a LVEF of 40% or less, and a successful revascularization via PCI. All patients who received the treatment for CTO revascularization had symptoms suggestive of stable angina and/or noninvasive imaging for functional ischemia preference. The criteria for exclusion included (1) severe coagulation abnormalities, malignant tumors, unstable hemodynamics, cardiogenic shock with a projected life span of less than one year, or other terminal conditions; (2) acute myocardial infarctions included ST-segment elevation myocardial infarction (STEMI) and non-STEMI; (3) a previous history of coronary artery bypass grafting (CABG); (4) unsuccessful CTO-PCI; (5) an LVEF $>$40%; (6) CTO was located in a small vessel (reference vessel diameter $\le$2.5 mm) and its side branch vessels; (7) lack of medical records or additional details; (8) revascularized by CABG; (9) refused CABG and PCI and chose conservative therapy (Fig. 1). The Ethics Committee of Xiangtan Central Hospital approved the research, which followed the principles outlined in the updated 2013 Declaration of Helsinki. Each participant provided informed consent before their participation (X201781019-1).

Fig. 1.

Study flowchart. CABG, coronary artery bypass grafting; CTO, chronic total occlusion; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; LVEF, left ventricular ejection fraction.

A diagnosis of CTO was made when angiographic evidence revealed a thrombolysis in myocardial infarction (TIMI) flow grade of 0 in an occluded artery segment that was present for more than three months [16]. We classified non-CTO lesions as having a stenosis diameter of 50% for the left main (LM) artery and 70% for non-LM CAD within vessels with a diameter of at least 2.5 mm [17]. DM was identified by the administration of oral hypoglycemic agents or insulin, a fasting plasma glucose level of $\ge$7.0 mmol/L (126 mg/dL), or a 2-hour plasma glucose level of $\ge$11.1 mmol/L (200 mg/dL) after a standard 75-gram oral glucose tolerance test [18]. Multicenter chronic total occlusion registry in Japan (J-CTO) is a multicenter registry in Japan [19] that focuses on CTO cases. We recommended revascularization in cases where angiography revealed a severe narrowing of the vessels with a decrease in diameter of at least 70% and where a fractional flow reserve of less than 0.80 indicated a significant loss in blood flow. We defined complete revascularization as the process of treating all major stenoses in the coronary epicardial vessels within the same hospital stay [20]. The definition of technical success for CTO-PCI involved achieving blood flow through the blocked artery with a TIMI flow grade of 3 and a residual narrowing of less than 30% [16]. In patients with chronic kidney disease (CKD), their estimated glomerular filtration rate (eGFR) had to be less than 60 mL/min/1.73 m² for a minimum of three months, or they required chronic dialysis [21]. Two-dimensional transthoracic echocardiography was used to measure the LVEF using the biplane Simpson’s method [22]. A cutoff value of 40% for LVEF was used to identify individuals with LV systolic dysfunction, consistent with previous clinical trials [23]. Patients were diagnosed with systolic LV failure when echocardiographic data revealed an ejection fraction (EF) of 40% or less and were receiving optimal medical therapy, as recommended by the guidelines [24].

We selectively performed PCI on symptomatic patients suffering from non-CTO lesions. For the CTO-PCI procedure, standard methods and guidelines were used, including bilateral injections, the hybrid algorithm, tapered-tip guidewires, stiff wires, parallel wires, microcatheters, and the retrograde method upon availability [25]. After a previous balloon angioplasty procedure, drug-eluting stents were inserted, and anticoagulant medication was administered during the PCI. Dual antiplatelet therapy for a minimum of one year and cardiovascular drugs, such as beta-blockers, calcium channel blockers, inhibitors of the renin–angiotensin–aldosterone inhibitors system, and statins, was also administered during the follow-up period.

MACEs were defined as cardiac death, myocardial infarction, target vessel revascularization, and all-cause mortality [26]. Meanwhile, in-hospital MACEs, including the above clinical adverse events, were assessed before hospital discharge. The primary endpoint was a MACE, with cardiac mortality as the secondary endpoint. Patients were evaluated at one-, six-, and twelve months post-PCI and annually after that for a maximum of 24 months through hospital record reviews, telephone interviews, and outpatient visits conducted by research coordinators.

The categorical variables were analyzed using either the Chi-square or Fisher’s exact tests, with results presented as frequencies and percentages. Continuous variables were expressed as the mean $\pm$ standard deviation. They were compared between cohorts employing Student’s t-test. We calculated the cumulative survival incidence without adverse events using Kaplan–Meier analysis and evaluated it using log-rank testing. Stepwise variable selection was employed to create multi-variable Cox proportional hazard models, with the entrance and exit criteria set at a significance level of p $\le$ 0.1. We calculated the hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs). A statistically significant result was defined as a two-sided p-value of below 0.05. SPSS 26.0 tool (IBM Corp., Armonk, NY, USA) was used for the analyses.

A total of 185 patients underwent successful PCI for CTO, of which 99 (53.5%) had DM. The clinical features of patients are listed in Table 1. Chronic kidney disease was significantly increased in patients with DM compared to those without DM (29.3 vs. 18.6%, p 0.001). DM patients also had higher serum creatinine (147.2 $\pm$ 28.0 vs. 93.8 $\pm$ 18.6 µmol/L, p 0.001) and hemoglobin A1c (7.9 $\pm$ 1.8 vs. 5.8 $\pm$ 0.4, p 0.001) and lower eGFR (66.9 $\pm$ 21.0 vs. 83.2 $\pm$ 25.0 mL/min/1.73 m², p 0.001) than patients without DM. In addition, DM individuals had a lower incidence of angiotensin-converting enzyme inhibitors (24.2 vs. 54.7%, p 0.001) and angiotensin receptor blockers (18.2 vs. 29.1%, p = 0.010) compared to those without DM.

Table 2 displays the angiographic details and procedure features. Patients with DM exhibited a significantly higher prevalence of multi-vessel disease compared to those with no DM (85.9% vs. 73.3%, p = 0.017). Patients with DM exhibited a greater number of lesions per patient (2.61 $\pm$ 0.93 vs. 2.20 $\pm$ 0.98, p = 0.001) and higher J-CTO scores (2.48 $\pm$ 1.13 vs. 2.01 $\pm$ 1.15, p = 0.015) and Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) scores (23.64 $\pm$ 8.71 vs. 21.17 $\pm$ 8.33, p = 0.041). The rates of complete revascularization were comparable between patients with DM (82.8%) and those without DM (86.0%).

Table 3 shows the clinical outcomes between patients with and without DM in-hospital and two years. No significant differences in in-hospital MACEs were detected between the DM and non-DM groups. During the two-year follow-up, 35 (18.9%) patients experienced MACEs, and death occurred in 12 patients (6.5%). The DM group had higher incidences of MACEs (24.2 vs. 12.8%, p 0.001), all-cause mortality (9.1 vs. 3.5%, p = 0.002), cardiac death (8.1 vs. 1.2%, p 0.001), and target vessel revascularization (TVR) (18.2 vs. 7.1%, p 0.001). Kaplan–Meier curve analysis corroborated these findings (Fig. 2).

Fig. 2.

Kaplan–Meier survival curves for 2 years. (A) MACEs. (B) All-cause death. (C) Cardiac death. (D) MI. (E) TVR. MACEs, major adverse cardiac events; MI, myocardial infarction; TVR, target vessel revascularization.

The univariate and multivariate regression analyses in Table 4 indicated that the presence of DM is not an independent predictor of MACEs (HR: 0.58; 95% CI: 0.32 to 1.03; p = 0.260); meanwhile, multi-vessel disease (HR: 1.69; 95% CI: 1.21 to 2.36; p = 0.002) and CKD (HR: 1.38; 95% CI: 1.08 to 1.78; p = 0.011) were independent predictors of MACEs and complete revascularization was associated with a reduced incidence of MACEs (HR: 0.36; 95% CI: 0.14 to 0.88; p = 0.026).

In this study, 53.5% (99 out of 185) of patients with LV systolic dysfunction undergoing CTO-PCI were diagnosed with DM. This finding aligns with previous studies reporting a 27–45% DM prevalence among CTO patients [5, 7, 8]. It has been consistently observed that patients with DM exhibit a more accelerated progression of atherosclerotic burden and more widespread coronary atherosclerosis compared to non-DM individuals [4, 27]. In addition, previous research has shown that DM patients are more likely to experience hypertension, previous PCIs, and strokes [10]. Our findings further indicate that DM patients have higher rates of chronic kidney disease, elevated serum creatinine and hemoglobin A1c levels, and reduced eGFR. Patients with DM are more prone to have complex and severe CAD. This condition frequently involves the presence of multi-vessel disease, diffuse narrowing, and calcifications in the coronary arteries [28]. This study also revealed that diabetic patients more often present with multi-vessel disease, higher J-CTO scores, and SYNTAX scores compared to non-diabetic patients, as reported in earlier studies [5, 8, 10]. In patients suffering from complex or multi-vessel CAD who have PCI, the occurrence of CTO was demonstrated to have a negative impact on the extent of revascularization and long-term clinical outcomes, including death, repeat revascularization, and stent thrombosis [29]. This impact is notably more pronounced in DM patients, who exhibit a two-fold higher prevalence of CTOs than non-diabetic individuals [30]. Furthermore, while DM significantly worsens the prognosis in CAD patients undergoing coronary revascularization, other cardiovascular risk factors, and comorbidities that adversely affect outcomes are also more prevalent in this group [31]. As a result, diabetic patients who have CTO-PCI have a greater cardiovascular risk profile compared to those without diabetes [6].

Patients suffering from DM had a higher incidence of CTOs [30]. However, diabetic patients undergo PCI for CTO less often compared to non-diabetic patients [7, 32]. This phenomenon, known as the treatment-risk paradox, reflects the less frequent intervention in high-risk compared to lower-risk patients within the PCI population [4]. Patients with diabetes continue to have an increased risk of long-term MACEs following PCI, even with the use of newer-generation drug-eluting stents. This is mainly because they are more likely to require repeat procedures to reopen the blocked blood vessels, regardless of the severity of their underlying CAD [33]. Guo et al. [8] revealed a significant increase in MACEs among diabetes patients after a successful PCI for CTO. Similarly, Sanguineti F et al. [9] reported elevated MACE rates in diabetic CTO patients during a 4.2-year follow-up period. Systematic reviews have consistently indicated that diabetic patients undergoing successful CTO-PCI have an increased risk of adverse clinical outcomes compared to non-diabetic patients [34, 35]. Zhu et al. [36] found that diabetic patients experienced higher rates of MACEs following successful CTO-PCI, particularly within follow-up periods shorter than three years. Wang et al. [37], analyzing 5-year outcomes in 719 patients post-successful CTO-PCI (316 diabetic and 403 non-diabetic), noted that non-diabetic patients showed superior long-term survival benefits in terms of MACEs contrasted with diabetic patients. However, in several studies, there were no statistically significant variations in MACE rates involving diabetic and non-diabetic patients over follow-up periods ranging from 1.7 to 5 years [11, 12, 13]. In these present studies, MACEs were consistently increased in diabetic patients compared to non-diabetic patients following successful CTO-PCI.

Patients with DM are more prone to developing cardiomyopathy associated with LV systolic dysfunction, potentially leading to significant decreases in the viability of myocardium downstream from a CTO [9, 38]. Furthermore, the presence of a CTO in a myocardial infarction-affected artery often results in a significant scar and, notably, a larger area surrounding the scar [39]. This larger border zone is associated with an increased incidence of arrhythmias and sudden cardiac death [39]. Revascularizing the viable or ischemic myocardium in the CTO region can improve survival by reducing scar tissue formation after a heart attack [39]. Our research sample found no significant disparities in the rates of complete revascularization between the diabetic and non-diabetic cohorts. A Study has shown that performing complete myocardial revascularization is associated with lower mortality rates, a reduced incidence of MI, and a decreased need for repeat revascularization [40]. DM patients who undergo incomplete revascularization are at a higher risk of long-term MACEs, including death, MI, stroke, or the need for repeat revascularization [41]. Our study indicates that LV systolic dysfunction patients with DM may experience more unfavorable long-term clinical outcomes following successful CTO PCI because of multiple contributing factors. DM, which is a well-known risk factor for CAD, is associated with more negative angiographic and clinical features [6, 31]. Moreover, patients with DM typically present with an increased number of lesions per patient, potentially increasing the risk of adverse outcomes [42]. Secondly, DM may exacerbate the risk of adverse outcomes by negatively affecting post-procedure blood glucose levels, lipid metabolism, insulin resistance, susceptibility to coronary plaque formation, and vascular endothelial function [43, 44]. The increased amount of platelet aggregation among DM patients and hypo-responsiveness to anti-platelet drugs such as aspirin and clopidogrel result in increased adverse outcomes. The impaired coronary collateralization seen in DM patients might also play a role in their unfavorable prognosis [45].

Consistent with previous studies, our findings corroborate that multi-vessel disease is linked to increased risks of MACEs [35]. Although the prevalence of CTOs was comparable across coronary territories between the two groups, in our CTO cohort, diabetic patients exhibited a higher rate of multi-vessel disease, which could predispose them to elevated long-term mortality and MACEs. Previous studies also found a strong link between CKD and a higher frequency of MACEs. Previous studies have identified renal insufficiency as a strong independent predictor of poor clinical outcomes post-PCI for CTO [11, 13]. The influence of CKD on patients with CTO requires further investigation to determine whether the observed adverse outcomes are attributable solely to the additional risk posed by CKD in conjunction with DM or if CKD alone constitutes an independent risk variable that contributes to negative cardiovascular findings within patients suffering from CTO lesions. In our research, complete revascularization was independently associated with a decreased risk of MACEs. Our results suggest that complete revascularization might mitigate future coronary events by alleviating the burden on non-CTO arteries in patients with DM. This is because the myocardial territory supplied by a CTO artery receives collateral blood flow from other coronary arteries [46]. Our results indicate that all patients exhibited multi-vessel disease, involving at least half of the coronary system. Therefore, complete revascularization could alleviate the functional burden on non-CTO arteries. Moreover, in the event of subsequent coronary incidents, the revascularized CTO artery could potentially support the affected artery [47, 48]. Similar to the results of previous studies [11, 13], our research has shown that DM was not an independent predictor for MACEs. This result may be due to the evolution of equipment, new application techniques, and the accumulation of recent CTO-PCI experience.