An overview of the application and potential mechanism on the triglyceride glucose index with multi-vessel coronary disease

Abstract

Multi-vessel coronary disease (MVCD) is a severe form of coronary artery disease (CAD) that significantly increases the risk of acute coronary syndrome (ACS) and heart attacks. The triglyceride glucose (TyG) index is a reliable and convenient marker for insulin resistance (IR). Recent studies have demonstrated its predictive value for CAD in patients with MVCD. This review aims to explore the application of the TyG index in managing MVCD and its underlying pathogenesis to enhance risk stratification and improve therapeutic decision-making.

Multi-vessel coronary disease and triglyceride glucose index

The high mortality rate associated with coronary artery disease (CAD) continues to be a significant public health burden globally [1]. Despite advances in prevention and treatment, challenges remain in the early diagnosis of high-risk groups and the prognosis assessment of this disease. Additionally, the mortality rate escalates for individuals experiencing acute coronary syndrome (ACS), a spectrum of serious clinical syndromes that includes ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP). Multi-vessel coronary disease (MVCD), characterized by stenosis of more than 50% in at least two coronary arteries, is quite a serious type among CAD. Patients with MVCD are more likely to experience severe ACS and exhibit higher mortality. Also, among these groups, the incidence of major adverse cardiovascular events (MACE) has increased a lot [2]. The growing prevalence of MVCD, fueled by a rise in ACS cases and unhealthy lifestyles, highlights the need for early identification of high-risk patients to develop more effective clinical strategies.

Extensive research has shown that metabolic disorders, particularly insulin resistance (IR), are strongly linked to the development and progression of CAD [3]. Researchers have identified IR as a factor in the pathophysiology of ACS and as a predictor of its occurrence. Therefore, detecting IR in the population is essential. Current research supports the TyG index, an indicator of measuring glucose and lipid metabolism comprehensively, to represent a convenient and reliable surrogate for IR. It can be easily obtained by the formula ln [fasting triglycerides (mg/dL) × fasting blood glucose (mg/dL) / 2] [4]. There is growing interest in the issue that the TyG index probably provide certain prognostic value for patients with MVCD. However, no existing literature has yet to synthesize findings, and the deeper mechanisms at play remain largely unexplored. This review will discuss them. It aims to summarize recent findings on the applications and mechanisms of the relationship between the TyG index and MVCD, to enhance risk stratification and improve prognostic accuracy.

Application of the TyG index in MVCD

Previous studies have delved into the TyG index across various manifestations of CAD, including coronary artery calcification, atherosclerosis, heart failure, and atrial fibrillation [5,6,7,8]. Studies consistently show that the predictive value may exist between the TyG index and CAD including both ACS and chronic coronary syndrome (CCS). A recent study involving 935 Chinese patients with ACS and diabetes demonstrated that high TyG index is accompanied with elevated incidence of MACE, advocating for its use in enhancing risk stratification [8]. Building on this, a prospective study involving 2531 ACS patients revealed a positive correlation that the TyG index is positively related to the risk of MACE among the UAP group, although this association was not significant in the NSTEMI and STEMI groups [9]. Another study involving 823 patients revealed the notable correlation of the TyG index with various echocardiographic parameters that indicate cardiac remodeling. Notably, the TyG index was proven to be positively related to left atrial diameter and negatively to left ventricular ejection fraction (LVEF) and ankle-brachial index (ABI), though no correlation was found with brachial-ankle pulse wave velocity (baPWV) [10]. These analyses indicate the TyG index as a useful predictor of cardiac remodeling and dysfunction. Additionally, a cohort study into the long-term effects of the TyG index on CAD with 44,064 individuals showed that prolonged high exposure of the TyG index is correlated to elevated incidence of cardiovascular disease, likely due to persistent inflammation and endothelial dysfunction caused by sustained high levels of the TyG index [11].

Additionally, more researchers are focusing on investigating the link of the TyG index with MVCD. A retrospective cohort study revealed that the TyG index has a positive association with MVCD. The study identified the TyG index is a risk factor which likes several other traditional factors for MVCD. It is capable of predicting CAD severity. With the increase of the TyG index, the incidence of MVCD rises. The incidence of MVCD in the highest TyG index group (≥ 7.38 ) was 1.496-fold higher than that in the lowest group (< 6.87 ). Moreover, this relationship was found to be related to glucose metabolic states and was particularly pronounced in patients with pre-diabetes mellitus (DM) [12]. However, another multi-center retrospective study noted that this association was more pronounced in patients with DM [13]. Therefore, the correlation of the TyG index with MVCD across different glucose metabolic states warrants further investigation.

Beyond the TyG index, a multitude of other predictive factors are being explored in CAD. For instance, the coronary artery calcium score (CACS) is a non-invasive method. It uses computed tomography to quantify coronary artery calcification (CAC). CACS serves as an indicator of coronary artery stenosis severity [14] and been shown to predict adverse cardiovascular outcomes in hypertensive patients [15]. Despite its utility, CACS still has limitations. For example, the use of high doses of contrast agents can potentially harm the kidney or cause allergic reaction. Wang’s study suggested that the TyG index could be identified to be a credible and practical alternative predictor for CACS, with an independently predictive value of MVCD in ACS patients. This study demonstrated that the incidence of MVCD risen by 1.213 times for each unit rise in the TyG index. This indicates a considerable relationship of the TyG index with the severity of CAD, showing that higher level of the TyG index is associated with more severe CAD. The results suggest that the TyG index has comparable prognostic strength and diagnostic capability for CAD to those of CACS. However, the study did not find a significant benefit in combining the two methods for CAD prediction. Other emerging indicators being explored include cardiac Troponin I (cTnI), neutrophil-to-lymphocyte ratio (NLR), and Lipoprotein(a) (Lp(a)), although no studies have yet compared these factors with the TyG index [16, 17].

Underlying mechanisms between the TyG index and MVCD

Lipid metabolism

The pathogenesis underlying the TyG index with MVCD is still incompletely understood. However, based on the components used to calculate the TyG index, it is logical to deduce that both lipid and glucose metabolisms play crucial roles.

In the pathogenesis of CAD, imbalanced lipid metabolism is a key factor. It is generally considered that low-density lipoprotein cholesterol (LDL-C) is a primary contributor to atherosclerosis. Conversely, high-density lipoprotein cholesterol (HDL-C) enhances cholesterol efflux from foam cells, facilitating reverse cholesterol transport and potentially delaying atherosclerosis [18]. Disorders in lipid metabolism like elevated LDL-C or reduced HDL-C cause LDL accumulation in the subendothelial spaces, initiating foam cell formation and atherosclerosis. Moreover, oxidized LDL (ox-LDL) can damage endothelial cells, and elevated LDL levels are often associated with more severe forms of CAD, such as MVCD [19]. Cholesterol also promotes mitochondrial fission and further generates the reactive oxygen species (ROS) in macrophages [20]. Elevated Lp(a) levels contribute to the formation of atherosclerotic plaques [17]. Hypertriglyceridemia is linked to subclinical atherosclerosis. Triglycerides (TG) can be hydrolyzed by lipoprotein lipase, releasing pro-inflammatory mediators that harm endothelial cells. Additionally, hypertriglyceridemia facilitates the formation of lipoprotein remnants, which are rapidly taken up by macrophages to form foam cells [21]. Importantly, disruptions in lipid metabolism often accompaniment with insulin resistance, which is identified by elevated free fatty acid (FFA) levels, further exacerbating insulin resistance [22]. This complex interplay between lipid imbalances and glucose metabolism highlights that the TyG index has the potential to reflect the incidence of MVCD.

Glucose metabolism

Compared to lipid metabolism, the impact of hyperglycemia on the cardiovascular system is less well-defined. However, numerous studies have established that hyperglycemia is an independent factor to predict the cardiovascular adverse events. Hyperglycemia induces a hypercoagulable and inflammatory state, endothelial dysfunction, and obstruction of coronary microcirculation. Diffuse changes in the coronary artery caused by hyperglycemia make the development of MVCD more likely [23]. A large-scale, multi-center retrospective study has underscored a noticeable relevance of the TyG index with MVCD, particularly in diabetic groups, as opposed to other glucose metabolic states [13]. The underlying mechanisms may include the formation of advanced glycation end products (AGEs) and oxygen free radicals during hyperglycemia, which promotes atherosclerosis [24]. Increased levels of AGEs, such as glycated LDL, accelerate foam cell formation, while oxygen free radicals diminish the levels of nitric oxide (NO), a protective vascular factor produced by endothelial cells [25]. Moreover, research has revealed that elevated glycolysis is positively associated with heightened plaque vulnerability and inflammation [26]. Accelerated glycolysis can lead to mitochondrial dysfunction, accumulation of ROS, and oxidation of LDL [27]. Additionally, higher glucose concentrations are associated with increased levels of coagulation factors such as factor VIII, XI and fibrinogen, which accelerates the process of venous thrombosis (VT) [28]. And these coagulation factors have been recognized as important predictors for CAD in recent years. Factor XI is positively associated with arterial thromboembolic events including myocardial infarction, stroke, and CV mortality [29]. Factor VIII has a positive correlation with the incidence of CAD events and all-cause mortality among African Americans. The study also demonstrated a relation between factor VIII and incident heart failure regardless of other risk factors like B-type natriuretic peptide [30].The increase of fibrinogen accelerates blood coagulation and increases the risk of CAD, and this association eliminates the effect of several risk factors like C-reactive protein (CRP) [31].

Moreover, the occurrence and development of CAD is closely related to IR. As the TyG index is widely regarded as a credible alternative of IR, the correlation of the TyG index with MVCD may partly attribute to IR. IR may impair the PI-3-kinase pathway in endothelial cells, which affects the activation of NO synthase and reduces NO levels. This decrease in NO contributes to endothelial dysfunction and atherosclerosis [32]. Furthermore, IR participates in pro-inflammatory processes and lipid dysregulation, further accelerating plaque progression.

Hypertension

Hypertension, playing a significant role in the pathogenesis of MVCD, is considered to be a principal contributor of CAD. Firstly, recent studies have identified associations between CAD and multiple gene polymorphisms in hypertensive patients [33,34,35], such as those related to the endothelin-1 gene and the renin-angiotensin-aldosterone system (RAAS). Secondly, the activation of the RAAS and increased angiotensin secretion contribute to vasoconstriction and myocardial hypertrophy in these individuals. The release of humoral factors such as endothelin and transforming growth factor-β (TGF-β) also involves in atherosclerosis. Thirdly, chronic hypertension exerts long-term mechanical stress, activating angiotensin II, which applies pressure to the vascular wall and reduces its elasticity, resulting in arterial stiffness [36].

Recent research has also examined that how hypertension influences the relationship between TyG index and CAD. A recent prospective cohort study investigated the correlation of the incidence of hypertension and the TyG index. As the TyG index increased, so did the cumulative incidence of hypertension [37]. Additionally, another cohort study involving 320 patients with hypertension and CAD revealed a positive correlation of the TyG index with the degree of coronary stenosis and the incidence of MVCD [38].

Inflammation

Recently, inflammation has garnered increasing public concern on the development of atherosclerosis. Chronic inflammation of the arterial walls is now recognized as a central mechanism in the development of CAD [39]. Inflammation is intricately involved in the processes of plaque formation, erosion, and rupture. The initiation of an inflammatory response can increase plaque instability. The detachment of such unstable plaques may result in myocardial injury or infarction. Inflammatory cells such as macrophages are activated followed by the production of cytokines and adhesion factors. Certain cytokines, like IL-1 and TNF-α, can increase the generation of metalloproteinases, which destroy interstitial collagen and reduce the stability of the plaque [40].

In the arterial wall, macrophages phagocytized ox-LDL and form foam cells. Ox-LDL can induce the formation of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome within macrophages and lead to macrophage pyroptosis [41]. And macrophage pyroptosis further aggravates plaque vulnerability and local inflammatory response [42]. In addition to LDL, some studies have shown that TG can also cause inflammation and promote atherosclerosis. A recent study investigated the correlation between CRP and the TyG index, suggesting a potential relation between TG and inflammation in CAD [43]. Studies have shown that TG induce inflammatory cytokines like TNF-α, IL-6 and several signaling pathways, which further contributes to oxidation stress and endothelial cell dysfunction [44]. Besides, one study showed that fibrinogen increase in chronic inflammatory conditions, which can lead to hypercoagulability and increase the incidence of cardiovascular events [31]. Apart from local chronic inflammation at the vascular wall, systemic inflammatory response can also lead to the occurrence of ACS [45].

Coronary artery calcification

CAC is a common pathological lesion in the pathophysiology of ACS and can be used to detect subclinical patients and identify advanced atherosclerosis in those with CAD. Based on the mineral deposition site, it is categorized into intimal calcification and medial calcification. Current studies have linked CAC closely with vascular inflammation [46, 47]. The primary mechanism of intimal calcification involves chronic inflammation and macrophage infiltration, where inflammatory cytokines and adhesion factors play a key role in promoting CAC development [48]. During inflammatory states, the death of inflammatory cells such as macrophages is accompanied by the release of vesicles. Hydroxyapatite crystals are deposited on these vesicles, inducing microcalcification. With persistent chronic inflammation and the involvement of monocytes and macrophages, these microcalcifications develop further and exacerbate CAC [49].

Medial calcification often involves vascular smooth muscle cells (VSMCs), which conduct an important process, the osteogenic switch. Pathological factors like hyperglycemia and modified LDL can induce osteogenic differentiation of VSMCs and endothelial cells by activating specific signaling pathways, such as Wnt/beta-catenin and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) [50, 51]. With the upregulation of osteogenic genes like runt-related transcription factor 2 (Runx2), the development of CAC further promotes. Bone morphogenetic proteins (BMPs) and endothelial-mesenchymal transition contribute to cardiac fibrosis and vascular calcification [52]. Moreover, in the context of inflammation, hyperlipidemia may synergistically affect the development of coronary calcification [53]. A study by Annemarie Witz showed that enzymatically modified LDL (eLDL) is involved in CAC development by activating the p38 MAPK pathway and upregulating cytokines such as IL-6 and IL-33 [54]. Besides, Lp(a) is a strong predictor of calcium deposition in coronary arteries and aortic valves. The elevation of Lp(a) is correlated to valve calcification. As Lp(a) rises, the degree of multiple valves calcification in the coronary increases [55].

As the degree of CAC increases and affects a broader range of coronary vessels, the incidence of MVCD escalates. Recent studies indicate that the coronary calcification score is positively correlated with the severity and prognosis of CAD [8, 56]. Generally, simple CAC does not induce acute coronary events through lumen stenosis. However, when combined with risk factors such as hyperglycemia and inflammation, it significantly accelerates the progression of coronary atherosclerosis, potentially leading to MVCD and MACE.

The enlightenment of the TyG index for MVCD therapy

Given the high occurrence of STEMI, the elevated risk of MACE, and the poor prognosis in patients with MVCD, identifying optimal revascularization strategies for these patients is crucial. Recent clinical trials have concluded that coronary artery bypass grafting (CABG) has priority over percutaneous coronary intervention (PCI) regarding the treatment of MVCD, particularly those with diabetes [57]. However, in practice, patients often prefer PCI because it involves less surgical trauma and allows for quicker postoperative recovery. A study by Robich M. indicated that patients undergoing CABG experienced a decreased risk of repeat revascularization and higher 10-year survival outcomes [58]. Yet, another analysis revealed that compared to PCI, CABG carries a higher risk of stroke within five years for individuals with MVCD [59]. Despite these risks, long-term mortality rates after CABG or PCI appear similar [57]. Therefore, it is essential to explore new indicators that can better guide the revascularization strategy for patients with MVCD.

Recent researches have explored the selective prognostic value of the TyG index for various revascularization strategies. A retrospective study found a positive link of the TyG index with the incidence of in-stent restenosis (ISR) following drug-eluting stent (DES) implantation [60]. Zhang Y’s study revealed that elevated TyG index accompanies with a high rate of major adverse cardiovascular and cerebrovascular events (MACCEs) in patients who underwent PCI with DES [61]. Additionally, a multicenter retrospective cohort study demonstrated a positive relation of the TyG index with the incidence of MACE in patients after CABG [62]. Another similar study showed that the hazard ratio of MACE increased by 1.38 with every one standard deviation increase in the TyG index [63]. A 7.5-year cohort of 8,862 patients with three-vessel disease who received CABG, PCI, and medical therapy (MT) was investigated to assess the predictive value of the TyG index and its influence on therapeutic decisions. Among groups with a normal TyG index, those who received CABG and PCI had a significant survival benefit, with CABG showing a lower risk of MACE. However, in the group with an increased TyG index, the incidence of MACE under different revascularization strategies depended on the diabetes status. In groups with elevated TyG index, the incidence of MACE was equivalent between the two revascularization strategies unless the patients were diabetic. Additionally, among patients with stable angina pectoris (SAP) and an increased TyG index, CABG, PCI, and MT were associated with a similar incidence of MACE, eliminating the effect of diabetes [64]. The TyG index potentially benefits the optimization of treatment strategies in patients with MVCD. However, this relationship requires further verification through more clinical research.

Perspective of the TyG index and MVCD

This review has several advantages. First, it integrates the research findings of the TyG index with CAD in recent years, laying the foundation for the follow-up study of the application of the TyG index with CAD. Second, it contributes to the early identification and treatment of patients with MVCD by analyzing up-to-date clinical studies on the TyG index and MVCD. Thirdly, this review explores several possible mechanisms between the TyG index and MVCD, which will help to provide direction for the health management of related high-risk patients.

Up to now, although numerous researches have investigated the correlation of the TyG index with MVCD, several limitations still exist. Firstly, since most studies are single-center, there is a need to conduct more large-scale and multi-center studies to confirm these findings across different populations. Secondly, the mechanisms linking the TyG index and MVCD remain unclear and require further exploration, which will be crucial for drug development and refining clinical strategies.

In contemporary clinical practice, for patients at elevated risk of MVCD, the utilization of hypoglycemic and lipid-lowering therapies remains essential. The potential benefits of anti-inflammatory treatment are still under investigation. Despite the emphasis on pharmacotherapy, surgery remains the more recommended treatment for most patients with MVCD. However, choosing between PCI and CABG still requires clinicians to consider the overall condition of the patient. It is anticipated that a better understanding of the correlation of the TyG index with MVCD will lead to more informed decision-making.

Increasing studies have highlighted the predictive value of the TyG index in focusing on MVCD, which undoubtedly further aids in risk stratification and the clinical management of patients. Patients with higher TyG index should have a low-salt and low-fat diabetic diet and strengthen physical exercise to avoid MVCD. To further decrease the incidence of CAD as well as improving outcomes, it is vital to enhance control of blood glucose, lipids, and blood pressure, and to promote healthy lifestyles among those at high risk or already affected by cardiovascular diseases.

Conclusion

In conclusion, this review demonstrates that the TyG index is positively correlated with MVCD and the potential mechanisms may include the disorder of glucose metabolism and lipid metabolism, hypertension and inflammation. Given that the TyG index is convenient and easy to obtain, it is of great significance for the identification and management of patients with MVCD in clinical practice. Therefore, more studies are needed to further exploring the relationship between the TyG index and MVCD and underlying mechanisms in the future.