Background

Coronary computed tomography angiography (CTA) has achieved significant clinical validation for accurate detection and evaluation of coronary artery disease (CAD)1. Computed tomography–derived fractional flow reserve (CT-FFR) has recently been recommended as a class 2a for evaluating lesion-specific ischemia in patients with intermediate stenosis and it is expected to simplify the clinical care pathway2. In addition, the updated 2022 Coronary Artery Disease Reporting and Data System (CAD-RADS) 2.0 has added CT-FFR as a new modifier for lesion-specific ischemia assessment, as an increasing number of studies have demonstrated excellent consistency between CT-FFR and invasive FFR had better clinical management guidance than coronary CTA alone1.

Most studies have focused on the assessment and management of patients with obstructive CAD (i.e., stenosis > 70% or lumen stenosis > 50%)3. However, previous studies have shown that a significant portion (up to 70%) of patients receiving coronary CTA belongs to non-obstructive CAD4. Compared with patients with no CAD, the presence of non-obstructive CAD detected by coronary CTA was associated with more severe cardiovascular events5,6.

The triglyceride glucose (TyG) index was originally proposed as a reliable substitute to indicate insulin resistance and metabolic syndrome which composed of fasting blood glucose (FBG) and triglycerides7. Researches have indicated a strong relationship between the TyG index and cardiovascular disease (CVD) events8,9. Insulin resistance has been shown to promote atherosclerosis and plaque progression via several mechanisms, including the down-regulation of the insulin and signaling endothelial cell damage pathway10. Clinical studies have confirmed that insulin resistance is associated with CAD and the progression of coronary atherosclerosis. Thus, we speculated that the TyG index was related to CAD and the degree of CAD severity. A higher TyG index has been demonstrated to be associated with a higher incidence of CVD. Moreover, a recent study including 1841 hypertensive patients revealed that the TyG index was positively associated with the incidence of obstructive CAD (odds ratios [ORs] from 2.01 to 2.63 as a categorical variable and OR = 1.49 as a continuous variable)11. However, research focusing on the association between the TyG index and the incidence of myocardial ischemia in patients with minimal to moderate CAD, is still lacking. We therefore aimed to investigate the association between the TyG index and the incidence of myocardial ischemia in patients with minimal to moderate CAD.

Methods

Study population

This was an observational cross-sectional study. The study included patients who underwent coronary CTA examinations at our hospital from November 2018 to December 2020. The inclusion criteria were adults over 18 years old of age who underwent CCTA examination via a 64- or above detector row scanner and well-documented electronic records. We excluded patients who (1) previously underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) surgery; (2) were missing basic clinical data or coronary CTA images; (3) had poor CTA image quality; (4) had missing information on FBG or triglycerides; (5) were lost to follow-up; or (6) had a CAD-RADS score of 0, 4 A, 4B or 5, as defined by coronary CTA. Finally, 1,697 patients with CAD-RADS 1–3 were included in the present study. The flowchart of the study design and patients recruitment was showed in Fig. 1. The study protocol was approved by the Ethics Review Committee of The Central Hospital of Wuhan (WHZXKYKL2022-140) and the written informed consent was waived by the institutional ethics committee of The Central Hospital of Wuhan because of the retrospective observational nature of the study. We confirm that all methods were performed in accordance with the relevant guidelines and regulations.

Fig. 1
figure 1

Flowchart of the study design. CTA, computed tomography angiography; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; TyG, triglyceride glucose; CAD-RADS, Coronary Artery Disease Reporting and Data System.

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Data collection and definitions

All the basic parameters (age, sex, smoking status and drink status), clinical history (hypertension and diabetes), and laboratory test information were collected from electronic medical records. The laboratory tests included triglyceride, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), serum creatinine (SCR) and FBG. The TyG index was calculated according to the following formula: Ln [(triglyceride, mg/dl) × (FBG, mg/dl)/2].

Coronary CTA examination and features

All coronary CTA examinations were performed with prospectively or retrospectively with an ECG- triggered on a dual-source CT scanner (Somatom Definition Flash, Siemens Medical Solutions, Forchheim, Germany). The coronary CTA images were subsequently analyzed automatically via an AI platform (Computer Aided Diagnosis of Coronary Artery, Version 6.0, Shukun technology, Beijing, China). Interpretation of the AI-based structured reporting for coronary CTA includes the severity, extent, ___location of coronary stenosis, component of coronary plaque, and CT-FFR values. Details of this AI-based coronary CTA platform were presented in previous work12,13 and the National Medical Products Administration has approved this platform (No.20203210844 and No.20233210146). The standardized anatomical CAD-RADS classification using coronary CTA images was defined with the highest degree of coronary artery stenosis: CAD-RADS 0 (0%), CAD-RADS 1 (1–24%), CAD-RADS 2 (25–49%), CAD-RADS 3 (50–69%), CAD-RADS 4 A (70–99% in 1 or 2 vessels), CAD-RADS 4B (left main > 50% or 70–99% in 3-vessels) and CAD-RADS 5 (100%). Minimal to moderate CAD classification was defined as CAD-RADS 1 to 3 (stenosis 1–69%). Computed tomography-adapted Leaman score (CT_LeSc) is a comprehensive coronary CTA score that uses 3 categories of weighting factors, incorporating ___location, severity and plaque component. In the present study, CT_LeSc was evaluated in two categories: CT_LeSc (≤ 5) and CT_LeSc (> 5). Myocardial ischemia was defined as a CT-FFR value ≤ 0.80.

Statistical analysis

Non-normally and normally distributed continuous variables were presented as medians (interquartile ranges, IQRs) and means (standard deviations, SDs), respectively. Categorical variables were showed as absolute values (percentages). One-way analysis of variance or the Kruskal-Wallis test was performed to compare the differences between continuous variables. Categorical variables were compared via Chi-square tests or Fisher’s exact tests. To evaluate the association between the TyG index and myocardial ischemia, univariable and multivariable logistic regression analyses with ORs and 95% confidence intervals (CIs) were conducted. Three models of multivariable logistic regression with backward stepwise selection were performed. Model 1 was adjusted for age, gender, smoke, hypertension, and diabetes. Model 2 was adjusted for age, gender, smoke, hypertension, diabetes, and SCR. Model 3 was adjusted for age, gender, smoke, hypertension, diabetes, SCR, CT_LeSc, and coronary stenosis. In addition, the results of logistic regression were showed based on TyG tertiles (categorical variables) with the T1 group (lowest tertile) used as the reference and by the increase per SD in the TyG index (continuous variable) in the interpretation of the results. The Restricted cubic spline regression was performed to evaluate the non-linear connection between the TyG index and myocardial ischemia. Finally, analyses stratified by sex, hypertension, CT_LeSc and stenosis were performed with an adjusted model. P < 0.05 was considered to indicate statistical significance. All the statistical analyses were carried out via the R statistical package (version 4.3.3, R foundation for Statistical Computing, Vienna, Austria) and SPSS (version 18, SPSS, Inc., Chicago, IL, USA).

Results

Basic characteristics of the study patient

A total of 1,697 patients with non-obstructive CAD were finally analyzed in the current study. The average age of the 1,697 patients was 62.7 ± 9.9 years, and 50.7% were male. The median TyG index was 8.82 (IQR, 8.54–9.09). Compared with patients in the T1 group, patients in the T3 group were more likely to be younger, smokers, drinkers, had a history of hypertension and diabetes. In addition, the prevalence of CT_LeSc > 5 and myocardial ischemia (CT-FFR ≤ 0.8) was increased in the T3 group than in the T1 group (Table 1).

Table 1 Basic characteristics of the study patients.
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Associations between the TyG index and myocardial ischemia

To analysze the non-linear association between the TyG index and myocardial ischemia, restricted cubic splines were performed for flexible modeling. The restricted cubic splines curve appeared to be J-shaped (Fig. 2). The OR (per SD) for the occurrence of myocardial ischemia was significantly increased to 1.38 (1.12–1.69, p = 0.002), with a TyG index ≥ 8.82. However, for the TyG index < 8.82, the OR per SD was 1.03 (95% CI, 0.69–1.53; p = 0.888), which was not significantly associated with the occurrence of myocardial ischemia.

Fig. 2
figure 2

The restricted cubic spline of TyG index and the incidence of myocardial ischemia. The purple columns present the distribution density of the TyG index. The black dashed line represents the OR = 1. The pink line shows the OR value. The pink shaded area represents the 95% CI. TyG, triglyceride glucose; OR, odds ratio; CI, confidence interval; SD, standard deviation; *, statistically significant (P < 0.05).

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In univariable analysis, the T3 group was associated with a significantly higher risk of myocardial ischemia than the T1 group (OR, 1.41; 95% CI, 1.01–1.91; p = 0.027). When TyG was regarded as a continuous variable, TyG per SD showed a similar trend (OR, 1.24; 95% CI, 1.09–1.40; p = 0.001) (Table 2). After adjusting for other variables, the T3 group remained associated with a higher risk of myocardial ischemia when the T1 group was regarded as the reference in Model 1, Model 2 and Model 3 (OR, 1.45, 95% CI, 1.04–2.01, p = 0.029; OR, 1.45, 95% CI, 1.01–2.02, p = 0.028; OR, 1.43, 95% CI, 1.01–2.04, p = 0.047) (Table 3; Fig. 3A). Moreover, a 1-SD increase in the TyG index was correlated with a 19–24% elevated risk of myocardial ischemia in the three models (all p < 0.05) (Table 3; Fig. 3B).

Table 2 Univariable logistic regression analysis for myocardial ischemia.
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Table 3 Association between TyG index and myocardial ischemia.
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Fig. 3
figure 3

Risk of myocardial ischemia based on model 3. TyG index was regarded as categorical variable (A) and continuous variable (B). Model 3 was adjusted by adjust by age, gender, smoke, hypertension, diabetes, SCR, CT_LeSc, coronary stenosis. TyG, triglyceride glucose; SCR, serum creatinine; CT_LeSc, computed tomography-adapted Leaman score; *, statistically significant (P < 0.05).

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Subgroup analysis

The associations between the TyG index and myocardial ischemia were further evaluated according to several subgroups by adjusting for confounding factors. The subgroup analysis revealed that female sex, no hypertension, and CT_LeSc > 5 were positively correlated with myocardial ischemia and the TyG index. In addition, 50-69% stenosis showed borderline significance between myocardial ischemia and the TyG index (Fig. 4).

Fig. 4
figure 4

Stratified analyses for the association of TyG with myocardial ischemia based on model 3. Model 3 was adjusted by adjust by age, gender, smoke, hypertension, diabetes, SCR, CT_LeSc, coronary stenosis. TyG, triglyceride glucose; SCR, serum creatinine; CT_LeSc, computed tomography-adapted Leaman score; *, statistically significant (P < 0.05).

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Discussion

In our cross-sectional study, we found a significant positive correlation between the TyG index and the incidence of myocardial ischemia in patients with minimal to moderate CAD. Consequently, this study revealed that a higher TyG index was correlated with a 19–24% elevated risk of myocardial ischemia detected by CT-FFR in patients with minimal to moderate CAD. These findings suggest that the TyG index may help identify patients at high risk of myocardial ischemia and guide further examinations and treatments in patients with minimal to moderate CAD.

Historically, coronary CTA has been widely used to diagnose CAD in patients with low to moderate cardiovascular risk and the vast majority of myocardial infarction (MI) cases are caused by non-obstructive plaques14. Furthermore, accumulated evidence from recent coronary CTA trials has confirmed that the MI observed in the follow-up of patients with non-obstructive CAD is as common as that in patients with obstructive CAD15,16. Moreover, recent studies have shown that approximately 50% to two-thirds of patients who undergo coronary CTA have non-obstructive CAD17,18. In addition, researches assessing the presence and degree of stenosis, as well as the plaque ___location and plaque burden of coronary atherosclerosis in patients with non-obstructive CAD, have indicated of strong associations with the prediction of future cardiovascular events4,19,20,21. Other studies further increased the discrepancy of the results. Hadamitzky et al. reported an observational single-center study involving 1,584 suspected CAD patients who underwent coronary CTA during 5.6 years of follow-up and revealed that the non-obstructive CAD for predicting composite endpoint (all-cause death and non-fatal MI) was significant compared with no CAD (HR, 2.46; 95% CI: 1.02–5.90), whereas cardiac events (cardiac death and MI) were not (HR, 6.16; 95% CI: 0.80–47.3)21. Maddox et al. further investigated a large cohort of 37, 674 patients with a 1-year follow-up and reported that 1-vessel or 2-vessel of non-obstructive CAD was not associated with mortality, whereas 3-vessel of non-obstructive CAD was significantly associated with mortality (HR, 1.6; 95% CI: 1.1–2.5)20. Together, these findings indicate the clinical importance of non-obstructive CAD, and most importantly, further risk stratification is needed. CT-FFR has gained a reliable role in assessing lesion-specific ischemia beyond stenosis on coronary CTA for predicting clinical outcomes22. Currently, a CT-FFR ≤ 0.80 is regarded as a positive result of myocardial ischemia and has been proven valuable for guiding treatment and assessing prognosis. However, few studies have focused on myocardial ischemia in patients with non-obstructive CAD. A recent study reported that the current clinical management would have missed nearly 20% of non-obstructive CAD patients with myocardial ischemia23. The current study revealed that 16.9% (286/1697) of non-obstructive patients had myocardial ischemia according to the CT-FFR values, which was similar to the findings of a previous study.

Metabolic syndrome is associated with the incidence of CVD. A previous Canadian cohort study revealed that 51% of the CAD population had metabolic syndrome24. In addition, metabolic syndrome severity has been reported to be closely correlated with the angiographic severity of CAD25. Recent researches have indicated that the blood flow function of the coronary artery (e.g., CT-FFR) outweights the effect of the anatomy of the coronary artery on clinical outcomes26. Although the precise mechanism underlying the relationship between metabolic syndrome and the CT-FFR value is unclear, insulin resistance and metabolic syndrome can impair vasodilation of the coronary arteries and cause inflammation, thus damaging hemodynamic function and reducing the blood flow of the coronary artery27,28.

Accumulated studies have indicated that the TyG index palys a positive role in identifying those at a high risk for developing atherosclerosis in asymptomatic patients. A retrospective registered study recruited 888 asymptomatic type 2 diabetics without CAD history and revealed that the highest tertile of the TyG index was significantly correlated with a high risk of coronary artery stenosis detected by coronary CTA after adjustment for clinical confounders (OR: 3.19; 95% CI, 1.371–7.424)29. Moreover, consistent clinical studies have revealed that an elevated TyG index is associated with an increased incidence of obstructive CAD in patients with type 2 diabetes, non-alcoholic fatty liver disease, established CAD and hypertension29,30,31,32. Nevertheless, compared with previous results, the current study focused on the functional significant stenosis of minimal to moderate CAD subjects detected by coronary CTA and CT-FFR and revealed that the highest tertile of the TyG index was positively associated with an increased incidence of myocardial ischemia in patients with minimal to moderate CAD, which fills some gaps in the research field of the associations between the TyG index and CAD. In addition, subgroup analysis was further conducted to verify the universality of the conclusions and the results suggested that a higher TyG index can predict the occurrence of myocardial ischemia on the basis of CT-FFR in patients with minimal to moderate CAD, irrespective of sex, hypertension, CT_LeSc and coronary stenosis. Thus, the conclusions of the present study have broad practicality in patients with minimal to moderate CAD.

In addition to being associated with an increased incidence of CAD, the TyG index has recently been reported as a useful marker for predicting the prognosis and risk stratification of patients with acute coronary syndrome (ACS), ST-segment elevation myocardial infarction (STEMI) with and without type 2 diabetes, prefrail hypertension, and PCI in STEMI. Wang et al. recruited 101,113 ACS patients and reported that a higher TyG index was associated with an increased risk of in-hospital major adverse cardiovascular events (MACEs)33. Similarly, Rokicka et al. reported that the TyG index was an independent risk factor for in-hospital mortality in patients with STEMI or NoN-ST-segment elevation myocardial infarction (NSTEMI)34. Moreover, a recent retrospective study recruited 404 patients with new-onset STEMI and reported that the prediction nomogram based on the TyG index had greater predictive value for the long-term prognosis of new onset STEMI after PCI35. Furthermore, the TyG index combined with plaque characteristics presented strong diagnostic value for predicting MACEs after PCI in STEMI patients36. In addition, Santulli et al. reported that insulin resistance, defined by the TyG index was significantly associated with physical impairment in older adults with prefrail hypertension37. These studies support the view that the TyG index is an independent marker that might be used to predict poor prognosis both in CAD patients and in individuals after revascularization. Because the TyG index is easier to obtain and less expensive than coronary CTA is, it can be used to screen high-risk patients for further follow-up examinations and more effective clinical strategies.

This study has several strengths. We included relatively large samples. Additionally, we used different models and two perspectives (the TyG index as categorical and continuous variables) to increase the credibility of the results. The current study also has several limitations. First, because the present study relied on observational data, rather than on the results of a cohort or a randomized trial, the potential for patient selection bias remains, and a causal relationship between the TyG index and myocardial ischemia risk could not be determined. Thus, further prospective and multi-center studies are needed to confirm these findings. Second, although the study adjusted for potential clinical risk factors of myocardial ischemia and CAD, some unmeasured or residual confounding factors still exist in the present study, such as other parameters of metabolic syndrome and as some treatments, such as antiplatelets, statins and anti-diabetic drugs which may cause confounding bias in the statistical results. Third, invasive FFR is still the gold standard for determining specific myocardial ischemia rather than CT-FFR, although the perfect consistency between these two examinations has been proven. Finally, the generalizability of our findings is limited by the single-center enrollment.

Conclusions

In conclusion, the present study revealed that a higher TyG index was associated with a higher risk of myocardial ischemia detected by CT-FFR in patients with minimal to moderate CAD. This may provide useful information in risk stratification for myocardial ischemia, directing further detections and guiding more aggressive treatments in patients with minimal to moderate CAD.