Coronary artery disease (CAD), a multifactorial fatal disease, has a high global prevalence. According to the latest heart disease statistics published in 2021 (1), an estimated 20.1 million Americans ≥ 20 years old had CAD. Although superior evidence-based strategies such as optimizing drug treatment and revascularization have been widely developed and applied in recent years, CAD patients, especially those who have suffered from acute coronary syndromes (ACS), continue to be at high risk for adverse cardiovascular deaths. The gold standard for ACS diagnosis is invasive coronary angiography. When coronary angiography shows that the stenosis has reached 75% or more of the diameter of the coronary lumen, patients will be advised to undergo myocardial revascularization (MRT) (2). A risk-factor assessment is critical for ACS patients, and insulin resistance (IR) has been considered to be a prognostic predictor of CAD.

Insulin resistance occurs when tissues are not sufficiently sensitive to the effects of insulin despite normal or, more often, elevated levels. Hyperinsulinaemic-euglycaemic clamp is the gold standard technique for IR. However, it has limitations in clinical application due to the complexity of detecting technology. The requirement to measure fasting insulin level also limits the homeostasis model assessment of IR (HOMA-IR) as a common clinical testing method. The triglyceride-glucose index (TyG index) is a new IR indicator, and it is calculated from fasting triglyceride (TG) and fasting plasma glucose (FPG). The TyG index is significantly associated with IR measured by the hyperinsulinaemic-euglycaemic clamp, and it outperforms HOMA-IR in non-diabetic and diabetic patients (3, 4). Previous studies have linked the TyG index to atherosclerotic cardiovascular diseases such as carotid atherosclerosis (5), arterial stiffness (6), adverse cardiovascular events in diabetes (7), and poor prognosis in patients undergoing percutaneous coronary intervention (PCI) (8).

Serum uric acid (SUA), an ultimate product of purine metabolism, has been associated with the pathogenesis of many cardiovascular diseases. For example, Niu et al. (9) discovered a relationship between SUA and hypertension in Chinese population, while Chen et al. (10) found that high levels of SUA are significantly related to the prevalence of atrial fibrillation. Furthermore, SUA has been associated with chronic kidney diseases, heart failure, and cardiovascular death (11). However, to our knowledge, there is no study on the interaction between TyG index with various levels of SUA in MRT for new-onset ACS. Therefore, this study aimed to explore the relationship between the TyG index/SUA panel and MRT in new-onset ACS, as well as whether TyG index predicts the risk of MRT in new-onset ACS patients.

In 13,271 patients with new-onset ACS of this retrospective study, an elevated TyG index was found to be associated with an increased risk of MRT. To our knowledge, this is the first study to investigate the relationship between the TyG index and MRT at different SUA levels in new-onset ACS patients. However, SUA levels were inversely associated with MRT among new-onset ACS patients. Furthermore, the interaction between TyG index and SUA profile showed that patients in higher quartiles of TyG index grouped by SUA component still had a higher chance of receiving MRT. Similar results were obtained after excluding patients with T2DM.

Previous studies have reported correlation between IR and cardiovascular diseases. Silva et al. (12) found that the TyG index was positively correlated with a higher prevalence of symptomatic CAD. After a 3-year follow-up, Wang et al. (7) reveal that the TyG index is an independent predictor of adverse cardiovascular events. According to Zhao et al. (13) an elevated TyG index is significantly associated with a higher risk of arterial stiffness and nephric microvascular damage in elderly patients. The incidence of coronary artery calcification (CAC) progression in 12,326 asymptomatic Korean adults was 30.6% after a mean 3.3 years. The incidence of CAC progression was markedly elevated with higher TyG index, especially in patients without heavy baseline CAC (14). Furthermore, Luo et al. (8) showed that a higher TyG index was correlated with an increased risk of future cardiovascular diseases in STEMI patients undergoing PCI. In a large prospective cohort study from northern China, Tian et al. (15) observed that the TyG index is associated with MI risk, even in people with normal FPG and TG levels. After a median follow-up of 11.03 years, participants in the fourth quantile of the baseline and updated average TyG index, as well as those with threefold higher TyG index, were at a higher risk of MI than other groups. These studies suggest that TyG index is closely related to CAD.

In general, FPG values mainly reflect IR from the liver, whereas fasting TG levels primarily reflect IR from fat cells. Therefore, the TyG index can reflect IR from two aspects. Moreover, the TyG index has been associated with hypertension, dyslipidemia, hyperglycemia, and metabolic syndrome, all of which are risk factors for CAD (16–19). What’s more, it can be explained from the IR represented by the TyG index itself. IR is known to be the major pathophysiologic factors driving T2DM. As a heterogeneous syndrome, T2DM is an independent risk factor for CAD and affects the prognosis. In recent years, prediabetes has been proposed as a separate concept (20), it is defined by FPG is higher than normal level but lower than the thresholds for T2DM. Results indicated that prediabetes was associated with an increased risk of CAD, heart failure and all-cause death in the general population (21, 22). As an early indicator to identify risk factors for CAD, the TyG index can reflect IR in the general population during prediabetes. This is beneficial in providing preventive measures in the event of elevated FPG but below the diagnosis of T2DM.

The mechanism underlying the correlation between TyG index and CAD remains unknown. According to Valeska et al. (23), IR mainly promotes the development of CVD via atherosclerotic plaque formation, ventricular hypertrophy, and diastolic abnormalities. Furthermore, IR is significantly correlated with endothelial dysfunction, oxidative stress, cardiovascular remodeling, coagulation imbalance, and inflammation (23, 24). Glycolysis accounts for less than 10% of total ATP synthesis in a healthy heart for cardiomyocytes. Insulin stimulates glucose uptake by inducing the translocation of glucose transporters type 4 (GLUT4) from intracellular storage sites to the plasma membrane, where the transporter facilitates glucose diffusion into cell (25). When IR occurs, the transformation ability of myocardial cells is impaired, and fatty acids become the only source of energy. Lipotoxicity occurs when fatty acids increase excessively in cardiomyocytes (26). Lipid buildup can potentially cause apoptosis by impairing mitochondrial function, cardiac hypertrophy, and contractile dysfunction (27, 28). These may serve as potential mechanisms to explain the relationship between TyG index and CAD, and undoubtedly this requires more studies.

Serum uric acid, a byproduct of purine metabolism, is a natural antioxidant. The relationship between SUA and CADs has been hotly debated, Zand et al. (29) thought SUA is not an independent risk factor for CAD. However, the study had only 473 patients and was mostly middle-aged (age < 45 years for male and <55 years for female). In large cohort study with decades of follow-up, SUA has been shown to be an independent risk factor for HTN (30), atrial fibrillation (31), and CAD (32, 33). What’s more, Çanga et al. (34) found SUA levels were correlated with long-term major adverse cardiovascular events (MACEs) during long-term follow-up in NSTEMI, which suggested that SUA is a risk factor for CAD. In this study we found that ACS patients with higher SUA had a lower risk of MRT. As a classic antioxidant, this phenomenon may be associated with the status of acute stress. It was reported that SUA has a protective effect on prognosis in acute ischemic events (35, 36). Acute oxidative stress changes when an acute ischemic event occurs. In this case, the subsequent SUA concentration is elevated due to ischemic tissue metabolism of adenosine (37, 38), nitric oxide-induced loss of xanthine oxidase inhibition (39), and impaired oxidative metabolism (40) are similar findings. Therefore, an increase in SUA could be a protective measure against the adverse effects of free radical activity and oxidative stress. Acute increase in SUA may provide short-term protection to ACS patients.

As for the mechanism between SUA and IR, SUA induces IR by inhibiting insulin signaling by reducing the phosphorylated Akt levels in adipose tissue and skeletal muscle, while promoting fat accumulation and glucose production in liver cells (41). Accordingly, SUA enhances lipogenesis by activating ATP-citrate lyase and inhibiting both mitochondrial aconitase activity and AMP-activated kinase (AMPK) phosphorylation, thus predisposing to hepatic steatosis. Furthermore, SUA activates hepatic gluconeogenesis, increases glucose production and aggravates hyperglycemia by reducing AMPK activation (42). SUA is a potent antioxidant that can neutralize superoxide and hydroxyl free radicals in the plasma. However, it can also act as a powerful pro-oxidant by increasing the production of reactive oxygen species (ROS), thereby promoting lipid and glucose metabolism disorders (43). Furthermore, SUA-induced oxidative stress has been reported to induce adipose tissue dysfunction in adipocytes, which subsequently leads to pro-inflammatory endocrine imbalances, resulting in low-grade inflammation and IR (44, 45).

More importantly, more evidence has emerged in recent decades showing that SUA levels have increased during the prediabetes period, indicating that SUA plays a role in the pathogenesis of T2DM (46). Binh et al. (47) discovered significant correlation between hyperuricemia and isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), combined IFG-IGT, and T2DM independent of the confounding factors in a Vietnamese population. After a 7.5-year follow-up period, a Rotterdam prospective cohort study (10) found that SUA is a risk factor for prediabetes and T2DM, and that SUA is more closely associated with early-phase mechanisms in the development of T2DM than late-phase mechanisms. Overall, hyperuricemia is associated with prediabetes and contributes to the development of diabetes. One of the characteristics of diabetes and prediabetes is IR. As a new indicator of IR, the TyG index effectively reflects the IR during prediabetes. And the prediabetes is considered a risk factors for CAD (21, 22). In our study, we found the rate of MRT increased with increasing the TyG index. Due to the severe IR in diabetes, we excluded the diabetes in the sensitivity analysis. Similar results were found in the non-diabetic population.

One of the strengths of this study was the large number of new-onset ACS patients who were adjusted to minimize residual confounding factors. The detection of SUA and TyG index would be useful for further risk stratification in prediabetes. The increase of the TyG index is beneficial to provide early preventive measures for prediabetes, before the elevated FPG reaches the threshold of T2DM. However, this research has certain limitations. First, this was a single-center study. Furthermore, the exclusion criteria were narrow, which reduced the generalizability of the study. Thirdly, historical TyG index data of the patients was missing, resulting in an inability to dynamically respond to IR. Finally, our study lacked direct test for IR, due to the high cost and complex detection methods, insulin levels are rarely detected. Therefore, further research is needed to confirm whether the discovered relationship exists among other ethnic groups.

Patients with a higher TyG index have a higher proportion of myocardial revascularization in new-onset ACS. This result also applies to patients with different levels of SUA during new-onset ACS.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by The First Hospital of Dalian Medical University Institutional Review Board approved this study. The patients/participants provided their written informed consent to participate in this study.

JL and YL contributed to the data collection and analysis and wrote the manuscript. HL, RF, LL, and XW were responsible for the collection of patient information. Y-LX contributed to provide the funding. BZ and XY were responsible for all the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.