Introduction
Ischemic stroke (IS) occupied approximately 70% of stroke cases, and was the leading cause of disability and death disease globally [
1]. Although endovascular therapy and intravenous t-PA have been used, the risk of adverse clinical outcomes in patients with IS still remains high, especially in critically ill patients [
2,
3]. Several researchers have suggested that the incidence of IS is closely related to pathological and behavioral conditions, including diet, metabolic disorders, and smoking [
4]. Various studies have also provided similar elucidations for associations between IS and metabolic disorders, such as hyperlipidemia and hyperglycemia [
5,
6]. Published studies have demonstrated that triglyceride (TG) and diabetes are the main risk factors of cardiovascular disease (CAD) and cerebrovascular disease (CVD) [
7,
8]. The triglyceride-glucose (TyG) index, consisting of fasting blood glucose (FBG) and TG, has become a convincing surrogate marker of insulin resistance (IR) [
9,
10]. Furthermore, an increasing number of studies have reported that the TyG index is closely associated with increased poor cardiovascular events in the general population [
11,
12], and in many other high-risk patient cohorts, such as stroke [
13], diabetes [
14] and hypertension [
15].
TyG index provided an available approach to analyze the both of lipid metabolism and glucose status [
16,
17]. Previous studies mostly concentrate on the level of TyG index in the general population to predict the adverse outcomes of CAD and CVD [
11,
12]. Many scholars demonstrated that increased TyG index was strongly related to higher incidence of coronary atherosclerosis progression and death, which was verified by various coronary heart disease studies [
18,
19]. In addition, several studies have also indicated the predictive power of the TyG index for the risk of stroke recurrence, morbidity, and even death in IS patients [
20,
21]. Growing evidence have found that an elevated TyG index was significantly associated with higher risk of all-cause mortality [
22,
23]. However, whether this association still existed in critically ill patients with IS, who usually had worse pathophysiological condition, remained unknown. Therefore, to assess whether the TyG index is a potential predicting tool for critically ill patients with IS may contribute to determining individuals at high risk of all-cause mortality for healthcare management or possible timely treatment.
Based on the current research status, the aim of this study was to assess the role of the TyG index in predicting all-cause mortality in critically ill patients with IS by analysing the Medical Information Mart for Intensive Care III (MIMIC-IV).
Discussion
In the present study, we assessed the association between the TyG index and clinical outcomes in critically ill population with IS from a United States (US) cohort. The results of this study indicated that a higher TyG index had associations with all-cause ICU and hospital mortality in critically ill patients with IS. Even after adjustment for the confounding risk factors, the TyG index was still strongly associated with all-cause ICU and hospital mortality. Thus, the TyG index might be a promising decision-making tool for clinicians and may be an independent risk factor in critically ill patients with IS.
The TyG index, consisting of TG and FBG, has been suggested as a potential indicator of metabolic disorders, atherosclerotic disease, and cardiovascular disease [
22,
29,
30]. Several clinical studies have investigated the relationship between the TyG index and cardiovascular disease morbidity and mortality in the general population or other patient populations. Yang et al. reported that increased TyG index was associated with a higher risk of neurologic worsening and mortality [
31]. Lee et al. found that the TyG index may contribute to predicting the short-term functional outcome in patients with acute IS who received reperfusion therapy [
32]. Liu et al. revealed the predictive effect of TyG index on clinical outcomes in acute IS patients with diabetes mellitus [
30]. And for patients with coronary artery disease, the TyG index may be a promising predictor for future cardiovascular events in patients with coronary artery disease [
33]. Another study that involving 5695 participants has suggested that monitoring the changes in the TyG index may play a role in predicting adverse cardiovascular events [
34]. These studies indicated TyG held promise to predict clinical outcomes of cerebrovascular and cardiovascular related diseases.
However, several researchers have questioned the clinical efficacy of the TyG index for prognosis in IS patients [
35,
36]. Firstly, the TyG index may be influenced by hyperglycemia and hyperlipidemia. Thus, the TyG index might not be applied in cerebrovascular disease patients if patients have extremely high TG and glucose levels [
37]. In addition, compared to the TyG index, TG and FBG were more intuitive. And the TyG index may not reveal the longitudinal link between itself and cerebrovascular risk [
35]. Thirdly, most of studies about the TyG index focused on elderly patients, and the predictive value of the TyG index is uncertainty in young individuals [
38]. Some studies have offered the convincing answer to the above concerns. Insulin resistance (IR) is proven to be associated with several symptoms of metabolic syndrome including hyperlipidemia, obesity and hypertension. The HOMA-IR index, which has been widely employed to detect the function of β-cell and insulin resistance, is also limited in patients who have received insulin therapy or without functioning β-cells [
39]. To demonstrate its clinical efficacy, the TyG index has been applied to evaluate IR in high-risk patients in large clinical trials. Guerroro et al. found that the TyG index can be an optimal method to assess the insulin resistance (IR) and had a high predictive power in young and middle-aged patients [
9]. David et al. suggested that the TyG index seemed to be a better indicator than FBG and TG of the diagnosis of type II diabetes [
40]. In other words, in certain situations, the TyG index is superior to single glucose or triglyceride and better reflects the development of the disease. Another study by Laura et al. revealed that the TyG index was closely associated with adverse cardiovascular events including cerebrovascular disease, peripheral arterial disease, and coronary heart failure, even independent of confounding risk factors [
11]. Therefore, the TyG has been proven to be a strong hallmark of various cardiovascular, cerebrovascular diseases, and other metabolic-related diseases.
The exact biological mechanism underlying the relationship of the TyG index with the development and progression of cerebrovascular disease and mortality remains uncertain. The possible pathway may be related to insulin resistance. A previous study revealed that glucose may reflect IR from the liver, whereas TG reflects IR from adipose tissue. Thus, the TyG index may be strongly associated with IR from two aspects [
41]. The TyG index is a biomarker of IR, which caused endothelium impairment, and inflammatory responses, accelerated the formation of foam cells, and promoted smooth muscle cell proliferation in the initiation of atherosclerosis [
42‐
44]. Miao et al. reported that the TyG index was related to the degree of carotid atherosclerosis in patients with IR, and held promise to be atherosclerotic marker [
45]. Ahn et al. suggested that the TyG index, calculated by lipid-related and glucose-related predictors, may become a creditable marker of IR [
46]. Che et al. also indicated that a higher TyG index was associated with an elevated risk of cardiovascular disease after adjustment for the established confounding factors [
47]. Several studies explained that IR is not only in the development of atherogenesis but also in advanced plaque progression through triggering apoptosis of vascular smooth muscle cells. Firstly, the TyG index could represent the situation of glucose metabolism, inflammatory responses, and oxidative stress. Secondly, the TyG index may reflect the metabolism of glycosylation products, and platelet reactivity, which can result in endothelial cell-dependent vasodilation [
48]. Finally, an increased TyG index may elevate the level of free fatty acids, which may accompany IR. Lowering the TyG index seems to be an additional goal in patients at high risk of cerebrovascular disease [
49‐
51]. All these physiological changes can contribute to the initiation and development of cerebrovascular diseases, and leading to poor clinical outcomes.
Current literature on the relationship between the TyG index and critically ill patients is few. Zhai et al. and Zhang et al. indicated that TyG index was strongly associated with in-hospital mortality in critically ill patients with heart disease [
22,
52]. Zhang et al. found that the TyG index was associated with mortality in critically ill patients with stroke (including hemorrhage stroke and IS) [
53]. However, in our specific cohort of ICU patients with IS, results showed the TyG index was a significant independent risk factor of greater mortality in critically ill patients. Additionally, for IS, a prevalent disease with high morbidity and mortality, we found that the TyG index could identify patients with high risk, which plays a role in clinical healthcare to reduce future major adverse outcomes.
In addition, this study further analyzed the risk stratification of various subgroups. Our subgroup analysis suggested that the value of the TyG index in predicting ICU mortality was consistent in male and female patients. However, we did not find any link between the TyG index and in-hospital all-cause mortality in included patients with diabetes, sepsis, atrial fibrillation, or heart failure at baseline. The reasons accounted for this phenomenon might be reverse causality: patients who have been diagnosed with these comorbidities were more likely to have accepted appropriate treatment or adopted healthy lifestyle habits. Therefore, their prognosis might be improved despite their high risk of all-cause mortality [
11]. Moreover, the current study revealed that the predictive value of IR, evaluated by the TyG index seemed to be more prominent in patients without atrial fibrillation [HR (95% CI) without atrial fibrillation 1.602 (1.250–2.053) vs. with atrial fibrillation 1.043 (0.798–1.363), P for interaction = 0.022], indicating that atrial fibrillation treatment may have an important effect on the predictive performance of TyG index for all-cause mortality. The reason for this inconsistency might be atrial fibrillation patients are more likely to have accepted anticoagulant therapy before stroke. Previous studies have revealed that atrial fibrillation with earlier appropriate anticoagulation may decrease stroke mortality [
54,
55]. Another interesting finding of the present study was that patients with higher TyG index were younger, and the association between TyG index and all-cause mortality seemed to be more significant in younger patients, which was also mentioned by the previous study [
22]. Contrary to popular wisdom, clinicians may pay more attention to older patients because they may have more comorbidities, whereas our study calls for the same attention to be given to younger patients because they may have a higher mortality rate. In the present study, we also found a significant linear relationship between the TyG index and in-hospital mortality, indicating that the TyG index may be an accessible tool for detecting a high risk of mortality in critically ill patients with IS. Thus, maintaining optimal TG and glucose levels and taking better management of the TyG index play a role in reducing future major adverse clinical outcomes. In summary, the results of our analysis showed that the TyG index should not be regarded as a sole diagnostic tool, but should be used as a substitute along with other clinical and laboratory parameters to provide a more comprehensive assessment of an individual’s metabolic health and risk stratification of developing clinical outcomes such as post-stroke mortality during the clinical practice.
The major strength of this study was that we verified that elevated TyG index was an important independent risk factor of higher mortality in critically ill patients with IS in a US cohort. However, our study also had several limitations. First of all, due to its nature of retrospective design, this study could not definitively establish causality. Although multivariate adjustment and subgroup analyses were used, residual confounding factors could still have influenced the clinical outcomes. The potential confounders, such as IS subtypes, National Institutes of Health Stroke Scale elimination, time of stroke, and cause of death was unobtainable in this database. Secondly, only the baseline TyG index was analyzed in this study. Dynamic changes of the TyG index were unavailable during the hospital and ICU stay. Therefore, the predictive power of the TyG index change is also needed to be evaluated in future research. Thirdly, our study did not perform the hyperinsulinemic-euglycemic clamp test, so we cannot evaluate the association between the TyG index and the gold standard of insulin resistance.
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