Long-term prognostic value of coronary atherosclerosis progression in patients with and without diabetes mellitus

Introduction

Diabetes mellitus (DM), which is a major public health challenge worldwide, exerts a significant socioeconomic burden on the society (1,2). It is a well-known independent risk factor for coronary artery disease (CAD) and cardiovascular events (3-6), and CAD is the main cause of death in DM (7).

Coronary computed tomography angiography (CCTA) is a noninvasive imaging technique for CAD detection. In symptomatic cases wherein CAD cannot be ruled out via clinical evaluation alone, CCTA is recommended as an initial test based on guidelines (8). CCTA can provide information about atherosclerotic burden. Using baseline CCTA, previous studies have demonstrated that patients with DM have higher atherosclerotic burden and experience a greater number of major adverse cardiovascular events (MACE) than those without DM (9,10); moreover, they exhibit greater atherosclerosis progression based on serial CCTA (11,12). Several studies have revealed that atherosclerosis progression is associated with an increased risk of MACE (13,14); however, none of the studies have focused on patients with DM. It remains unclear whether coronary atherosclerosis progression has the same prognostic value for MACE in patients with and without DM. Yang et al. (15) evaluated the relationship between atherosclerotic progression and MACE in patients with asymptomatic DM and a median follow-up of 41.8 months. The long-term prognostic value beyond 5 years of atherosclerosis progression in DM and non-DM groups has not been adequately explored.

Therefore, this study aimed to explore the long-term prognostic value of coronary atherosclerosis progression through serial CCTA in the DM and non-DM groups. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2961/rc).

Methods

Study population

This retrospective, single-center, observational study was performed at our institution. Patients with suspected or known CAD who had baseline CCTA between January 2010 and December 2013 and serial CCTA before September 2020 were included in the study. The inclusion criteria were as follows: (I) interscan interval for serial CCTA scans >12 months and (II) no MACE occurred between the serial CCTA scans. The exclusion criteria were as follows: (I) unavailable baseline clinical data; (II) poor CCTA image quality at baseline or follow-up CCTA scans; and (III) lost to follow up. The demographics and clinical characteristics of the patients were obtained from the medical records or gathered via phone call. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Fuwai Hospital (No. 2022-1870) and individual consent for this retrospective analysis was waived.

CCTA scanning protocol

All scans were performed on the dual-source computed tomography (CT) scanner (SOMATOM Definition or SOMATOM Definition Flash, Siemens Healthcare, Forchheim, Germany). Non-contrast enhanced coronary artery calcium score (CACS) scan was performed using standardized scan parameters (120 kV, 3 mm slice thickness). Slice collimation was performed at 2 mm × 32 mm × 0.6 mm/2 mm × 64 mm × 0.6 mm using a z-flying focal spot, with a gantry rotation time of 330/280 ms, tube voltage of 100–120 kV, tube current with automatic exposure modulation, section thickness of 0.75 mm, reconstruction increment of 0.5 mm, and field of view of 20–25 cm. The contrast medium (iopromide, 370 mgI/mL; Bayer Healthcare, Berlin, Germany) was injected into the antecubital vein at a flow rate of 4–5 mL/s. The protocol was composed of three phases: 50–60 mL of undiluted contrast medium, 30 mL of a 30%:70% mixture of contrast medium and saline, and 30 mL of saline.

CCTA analysis

For CCTA analysis, all raw data were transferred to a post-processing workstation (Syngo.via; Siemens Healthcare). Two experienced radiologists, who were blinded to the patient clinical characteristics and follow-up data, analyzed the images. Any discrepancies in the interpretations of the two observers were resolved via consensus. CACS was quantified according to the protocol proposed by Agatston et al. (16). The coronary tree was divided into 16 segments according to the modified American Heart Association classification (17), and segments with a diameter of >1.5 mm were included in the analysis. Coronary plaques were defined as any lesion with an area of >1 mm² within or adjacent to the artery lumen, which was differentiated from the vessel lumen and surrounding pericardial tissue (18). High-risk plaque was defined as having at least two high-risk features [spotty calcification (calcification size <3 mm), positive remodeling (remodeling index >1.1), low attenuation plaque (CT attenuation <30 Hounsfield units) and napkin-ring sign (a peripheral rim of high CT attenuation with central area of low CT attenuation)] in a plaque (19-21). The extent of stenosis in each segment was assessed based on the Coronary Artery Disease-Reporting and Data System (CAD-RADS): 0, 0%; 1, 1–24%; 2, 25–49%; 3, 50–69%; 4, 70–99%; and 5, 100% (22). Per-patient basis stenosis was the highest grade of stenosis at all segments. Obstructive CAD was defined as CAD-RADS 3–5 in any segment and was categorized into one-, two-, and three-vessel CAD. The segment involvement score (SIS) was calculated as the total number of involved coronary segments with atherosclerotic plaque, ranging from 0 to 16. The segment stenosis score (SSS) was calculated as the total number of involved segments multiplied by the grading of segment stenosis (0%, 0; 1–49%, 1; 50–69%, 2; and 70–100%, 3), ranging from 0 to 48 (18). Considering interscan variability in CACS, the square root transformed difference (ΔCACS=CACSfollow-up−CACSbaseline) was used to analyze changes in CACS (23). Changes in SIS (ΔSIS) and SSS (ΔSSS) were defined as the SSS and SIS at follow-up CCTA minus those at baseline CCTA. As the interval between follow-up and baseline CCTA varied between patients, differences in atherosclerosis over time [change in atherosclerosis/interscan time (year)] were calculated.

Definitions of atherosclerosis progression

Patients were considered to have undergone coronary atherosclerosis progression if they met any of the following criteria (23,24):

• $\Delta \sqrt{\text{CACS}}$ value of >2.5.
• ΔSIS value of >0.
• ΔSSS value of >0.

Follow-up

Follow-up information was obtained via telephone interviews and medical records by trained study personnel who were blinded to demographics, clinical characteristics, and CCTA results. A standard questionnaire was used during telephone interviews. In this study, the outcome was MACE following the follow-up CCTA, which included a composite of all-cause mortality, myocardial infarction (MI), and coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting). To adjudicate whether a patient had MACE during the follow-up period, all patient data and medical records were reviewed by an experienced radiologist who was blinded to CCTA results. If patients could not be contacted or could not provide accurate information, they were considered lost to follow up.

Statistical analysis

The Shapiro-Wilk test was used to determine the normality of continuous variables. Body mass index (BMI) was expressed as mean ± standard deviation (normally distributed data) and compared between DM and non-DM groups using unpaired Student’s t-test. Other continuous variables such as age, CACS, SIS, SSS, ΔCACS/year, ΔSIS/year, and ΔSSS/year were expressed as median (25^th–75^th quartiles) (non-normally distributed data) and compared using the Mann-Whitney U test. Categorical variables were represented as frequencies and percentages and compared using the χ² test or Fisher’s exact test. The Wilcoxon signed-rank test was used to compare CACS, SIS, and SSS between baseline and follow-up CCTA. Cumulative event-free survival rates based on the presence or absence of DM and atherosclerosis progression were calculated using Kaplan-Meier survival estimates, and the log-rank test was used to compare them. The relationships among demographics, clinical characteristics, CCTA results, and MACE were evaluated using univariable Cox proportional hazards models. Variables with P values of <0.1 in univariable analysis were used in multivariable Cox proportional hazard analysis with forward stepwise. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. All statistical analyses were performed using SPSS 26.0 (SPSS Inc., Chicago, IL, USA) and MedCalc 19.7.2 (MedCalc Software Ltd., Ostend, Belgium). A two-tailed P value of <0.05 was considered to indicate statistical significance.

Results

Patient characteristics

This study initially enrolled 577 patients, and 525 (91.0%) patients could be successfully followed up (Figure 1). The demographics and clinical characteristics of these patients are shown in Table 1, stratified by the presence of DM. The median patient age was 56 (49–63) years, and 355 (67.6%) of them were men. There were 115 patients in the DM group and 410 patients in the non-DM group. The median age of the DM group was 56 (50–65) years, and 71 (61.7%) patients in this group were men. The median age of the non-DM group was 56 (49–63) years, and 284 (69.3%) patients in this group were men. The DM group was comparable to the non-DM group in terms of male sex, age, BMI, hypertension, hyperlipidemia, family history of CAD, and history of smoking (P>0.05 for all). The interscan period between baseline and follow-up CCTA was not different between DM and non-DM groups (38 vs. 45 months, P=0.058). The follow-up period was 69 (43–95) months after follow-up CCTA and 121 (106–134) months after baseline CCTA.

Figure 1 Flowchart of the study. CAD, coronary artery disease; CCTA, coronary computed tomography angiography.

CCTA findings and CACS

CCTA findings and CACS in DM and non-DM groups are summarized in Tables 2,3, as well as Figure 2. At baseline CCTA, the DM group had higher SIS [3 (2–5) vs. 2 (1–3), P<0.001], SSS [4 (2–6) vs. 2 (1–4), P<0.001], and CACS [58 (10–160) vs. 16 (0–108) Agatston units (AU), P<0.001] than the non-DM group. The frequency of CAD-RADS 4–5 and three-vessel obstructive CAD was higher in the DM group (20.9% vs. 11.2%, P=0.007; 8.7% vs. 2.0%, P=0.002), whereas the frequency of CAD-RADS 0, 1–2, 3 and one- and two-vessel obstructive CAD was comparable between the two groups (P>0.05). The DM group had more patients with high-risk plaque (16.5% vs. 8.3%, P=0.010).

Figure 2 Coronary atherosclerotic burden at baseline and at follow-up and change in coronary atherosclerotic burden/year in DM and non-DM groups. (A) Baseline and follow-up CACS. (B) Baseline and follow-up SIS and SSS; white plot, median; black box, 25th–75th quartiles. (C) ΔCACS/year, ∆SIS/year and ∆SSS/year; white plot, median; black box, 25th–75th quartiles. AU, Agatston units; BL, baseline; CACS, coronary artery calcium score; DM, diabetes mellitus; FU, follow-up; SIS, segment involvement score; SSS, segment stenosis score.

At follow-up CCTA, SIS, SSS, and CACS were significantly different between the DM and non-DM groups [SIS: 4 (3–7) vs. 3 (1–5), P<0.001; SSS: 6 (3–9) vs. 3 (2–6), P<0.001; CACS: 113 (21–371) vs. 53 (5–213) AU, P=0.001]. The DM group had more patients with CAD-RADS 4–5 (31.3% vs. 19.0%, P=0.005), two-vessel involvement (19.1% vs. 11.0%, P=0.021) and high-risk plaque (23.5% vs. 8.3%, P<0.001). The difference in ∆SIS/year [0.23 (0.00–0.55) vs. 0.15 (0.00–0.42)] in the DM and non-DM groups as well as ∆SSS/year [0.32 (0.00–0.77) vs. 0.22 (0.00–0.62)] in both groups did not reach statistical significance (P>0.05), whereas the ΔCACS/year was higher in the DM group than in the non-DM group [0.85 (0.20–1.79) vs. 0.64 (0.00–1.25), P=0.023].

MACE predictors

During the follow-up, 114 MACE occurred. In the DM group, 3 (2.6%) patients had all-cause mortality, 1 (0.9%) suffered from MI, and 36 (31.3%) required coronary revascularization. In the non-DM group, 8 (2.0%) patients had all-cause mortality, 4 (1.0%) suffered from MI, and 62 (15.1%) required coronary revascularization. The multivariable Cox regression analysis (Table 4) showed that CAD-RADS 4–5 (HR =2.32; 95% CI: 1.21–4.47; P=0.012), high-risk plaque (HR =2.85; 95% CI: 1.41–5.76; P=0.004) and atherosclerosis progression (HR =3.15; 95% CI: 1.21–8.19; P=0.019) were significant predictors of MACE in the DM group. In the non-DM group, hyperlipidemia (HR =2.25; 95% CI: 1.27–4.00; P=0.006), CAD-RADS 4–5 (HR =2.03; 95% CI: 1.17–3.55; P=0.012), high-risk plaque (HR =1.99; 95% CI: 1.09–3.65; P=0.026) and atherosclerosis progression (HR =2.40; 95% CI: 1.28–4.50; P=0.006) were independent predictors of MACE. Atherosclerosis progression was associated with the highest risk of MACE in both DM and non-DM groups.

Kaplan-Meier curves

The Kaplan-Meier curves showed that the cumulative event-free survival rates of the DM and non-DM groups were 60.4% and 78.1%, respectively (log-rank test, P<0.001) (Figure 3A). The cumulative event-free survival rates based on the presence or absence of DM and atherosclerosis progression were also calculated using Kaplan-Meier survival estimates (Figure 3B). The DM group with atherosclerosis progression had the lowest event-free survival rate (49.1%) among the four groups (log-rank test, P≤0.006), followed by the non-DM group with atherosclerosis progression (73.6%). The cumulative event-free survival rate was lower in the non-DM group with atherosclerosis progression than in the non-DM group without atherosclerosis progression (73.6% vs. 87.9%; log-rank test, P=0.001). The event-free survival rate of the DM group without atherosclerosis progression was similar to that of the non-DM group without atherosclerosis progression (82.7% vs. 87.9%; log-rank test, P=0.345). However, no differences were observed between the DM group without atherosclerosis progression and non-DM group with atherosclerosis progression (82.7% vs. 73.6%; log-rank test, P=0.328). A representative case of DM with atherosclerosis progression is presented in Figure 4.

Figure 3 Kaplan-Meier analyses of MACE-free survival rates. The event-free survival rate was significantly lower in the DM group than in the non-DM group (A). The DM group with atherosclerosis progression had the lowest event-free survival (B). AP, atherosclerosis progression; DM, diabetes mellitus; MACE, major adverse cardiovascular events.

Figure 4 Representative case of a patient with diabetes mellitus and atherosclerosis progression. A woman aged 57 years. Baseline CCTA findings (top row of images): CACS =54 AU, SIS =3, and SSS =4. Follow-up CCTA findings (bottom row of images) for worsening chest pain after 4 years and 9 months: CACS =120 AU, SIS =5, and SSS =9. Seven months after follow-up CCTA, the patient underwent percutaneous coronary intervention. AU, Agatston units; CACS, coronary artery calcium score; CCTA, coronary computed tomography angiography; SIS, segment involvement score; SSS, segment stenosis score.

Discussion

This study showed that the DM group had a higher atherosclerotic burden and was associated with a greater increase in CACS than the non-DM group. Notably, atherosclerosis progression was the strongest predictor of MACE in both DM or non-DM groups, and the DM group with atherosclerosis progression had the lowest cumulative event-free survival rate. To the best of our knowledge, this is the first study to demonstrate the long-term prognostic value of coronary atherosclerosis progression in patients with and without DM using serial CCTA.

The DM group had higher atherosclerotic burden measured by the SIS, SSS, and CACS, which were used as parameters to evaluate the atherosclerotic burden in many previous studies. Our result was in concordance with prior results (9,25).

A previous study from the Multi-Ethnic Study of Atherosclerosis demonstrated that DM had the greatest effect on coronary artery calcium (CAC) progression (26). We also found that CACS progressed rapidly in the DM group compared with the non-DM group. The detailed mechanisms underlying the faster progression of calcification with DM are unclear and may include the following mechanisms. One possible reason is the high glucose (27,28). Won et al. (29) examined the relationship between glycemic status and CAC progression and showed that DM was an independent risk factor for CAC progression but prediabetic status was not. Glycemic status also was strongly associated with coronary functional progression (30). Another possible reason is insulin resistance (31). The triglyceride glucose index is a surrogate marker of insulin resistance. Park et al. (32) showed that the triglyceride glucose index was an independent predictor of CAC progression.

Several studies have assessed the prognostic value of high-risk plaque, CACS and SIS in the DM and non-DM groups. A previous study (33) found that high-risk plaque was associated with MACE in DM group, which is consistent with our finding. The difference is that we found high-risk plaque was also a predictor of MACE in non-DM group. Tesche et al. (33,34) found that CACS was a predictor of MACE in the non-DM group. van den Hoogen et al. (9) revealed that SIS was independently associated with MACE in both the DM and non-DM groups. While the above studies only considered the baseline CCTA information, the present study showed that the baseline CCTA atherosclerotic burden can no longer predict MACE when atherosclerosis progression was considered. Baseline CCTA information reflects the static information of the patient at the time of examination, failing to represent the changes after the baseline examination. Our study included atherosclerosis progression obtained by serial CCTA, which captures longitudinal atherosclerosis dynamics. Atherosclerosis progression is a comprehensive manifestation of drug therapy, risk factor control, and lifestyles. This may also explain why most baseline traditional risk factors showed no associated with MACE when atherosclerotic progression was considered. In this study, the DM and non-DM groups showed no significant difference in ∆SSS/year and ∆SIS/year, likely because these characteristics prioritize segment involvement or stenosis severity over plaque volume. For instance, a lesion may grow in volume without expanding to new segments or increasing stenosis, rendering ΔSSS/ΔSIS insensitive to true progression. Therefore, a full quantitative analysis of plaque burden is needed in subsequent studies.

Atherosclerosis progression was an independent risk factor for MACE. Our study showed that the MACE-free survival rate was significantly lower in both DM and non-DM groups with atherosclerosis progression. In contrast, the DM group without atherosclerosis progression had similar event-free survival rates as the non-DM group without atherosclerosis progression. The absence of atherosclerosis progression indicated that the patient’s diseases such as DM were well controlled, thereby offsetting the negative effects of DM. The difference between event-free survival rates of the DM group without atherosclerosis progression and non-DM group with atherosclerosis progression did not reach statistical significance. This may be due to the large difference in sample sizes between the two groups. Considering this situation, this result should be interpreted with caution, and further research with a larger sample size is warranted.

This study has several limitations. First, this is a single-center, retrospective observational study, in which selection bias was inevitable. Second, this study did not divide DM into type 1 and 2 DM. It remained unclear whether the progression of coronary atherosclerosis had the same effect on the occurrence of events in type 1 and 2 DM, thus requiring further investigation. Third, SIS and SSS are not sensitive indicators of progression, and a full quantitative analysis of atherosclerotic burden is warranted. Fourth, information on medical treatment of all patients was not obtained, which may have affected the results. Therefore, a future prospective large cohort study is warranted. Finally, the sample size was limited, and patients were unevenly distributed between the two groups. This may have affected the statistical results; however, this distribution was in line with real-world data. Larger cohort or case-control studies are warranted in the future to validate our findings.

Conclusions

The DM group had a higher atherosclerotic burden and was associated with a greater increase in CACS, whereas no significant association was found for the increases in SIS or SSS when compared to the non-DM group. Atherosclerosis progression, rather than baseline atherosclerotic burden, was the strongest predictor of MACE in both DM and non-DM groups, and the DM group with atherosclerosis progression had the lowest cumulative event-free survival rate.

Acknowledgments

The abstract of this paper was accepted as an oral presentation for the 16^th Congress of Asian Society of Cardiovascular Imaging (ASCI 2023).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2961/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2961/dss

Funding: This work was supported by the CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1–008).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2961/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Fuwai Hospital (No. 2022-1870) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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