The major findings of this study are as follows: TyG index was significantly lower in patients with good CCC than those with poor one. TyG index was associated with various traditional cardiovascular risk factors, a strongest correlation was found between TyG index and components of MetS. Multiple logistic regression analysis and subgroup analysis showed that TyG index remains to be strongest risk indicator of coronary collateralization after adjustment for various confounding factors. Its risk assessment value was better than traditional lipid or glucose related parameters, like TG, FPG and HbA1c. Adding TyG index to the baseline model shows the most significant incremental effect on the risk discrimination for assessing the development of coronary collateral growth. To the best of our knowledge, this is the first study focusing on the correlation of TyG index and coronary collateralization.
Impact Of Ir On Impaired Coronary Collateralization
Coronary collateralization is a network of anastomose connecting epicardial coronary branches from different regions within heart, which conduct little blood flow to produce cardioprotection because of its small caliber and high resistance in physiological conditions. However, when epicardial arteries were severely obstructed, especially in those with chronic total occlusion, those anastomoses can turn into functional branch collaterals to compensate for the blood supply to the myocardial regions dominated by the stenotic arteries. In ideal circumstances, a well-developed coronary collaterals can perform myocardial salvaging effect to limit the ischemic area caused by CAD and preserve normal cardiac function[5]. previous study found that the coronary collateral could expand four times bigger from a caliber of 10–200 µm to 100–800 µm in the presence of CAD[25]. Mechanism underlying the formation of functional collateral network in adult animals mainly involves the abluminal expansion and wall thickening of preexisting one called coronary collateral growth (CCG), also termed as arteriogenesis.[26] Although the mechanism of arteriogenesis remained to be incompletely understood, clinical evidence has shown that CCG is impaired in patients with MetS[10, 27]. The current study revealed that TyG index, as a simple surrogate index of IR, is independently associated with less developed CCC, indicating that IR may play a pivotal role in the development of collateral circulation. IR, as a key parameter of MetS, affected factors that impaired the development of CCG, such as decreased expression of proangiogenic growth factors, increased production of reactive oxidative species (ROS) and continued endothelial dysfunction. The complete obstruction of coronary artery leads to the elevated pressure gradient of arterioles and therefore increasing tangential fluid shear stress (FSS) to activate monocytes to release some angiogenic growth factors, like MCP-1, TGF-β[28]. Recent study has shown that monocyte-derived dendritic cells (Mo-DCs) tend to be functionally defective in the context of IR and thus increasing vascular inflammation, which would deteriorate the development of collateral growth[29]. Overproduction of ROS is another reason for less developed CCC. IR-induced hyperglycemia leads to the increase of polyol (sorbitol) pathway influx, advanced glycation end-product (AGE) production, hexosamine pathway influx and the activation of protein kinase C (PKC) and thus causing the hyperglycemia-induced overproduction of ROS by the activating those pathways and the mitochondrial electron-transport chain[30]. People with IR are characterized by the impairment of endothelial function and IR was inversed associated with median colony forming unit endothelial cells (CFU-ECs), causing the decreased density of collaterals in response of cardiac ischemia[10]. Recent study has revealed that IR could decrease the expression of MicroRNA-21 (MiR-21), an important mediator to regulate the secretion of NO and ET-1, via the inhibition of PTEN/AKT/eNOS pathway and activation of MAPK/ET-1 pathway and thereby causing endothelial dysfunction[31]. While present study provided clinical evidence for evaluating the impact of IR on collateral growth, more clinical and basic researches are still needed to clarify the underlying mechanisms of IR-induced poor collateralization.
Relationship Between Tyg Index And Coronary Collateral Circulation
To the best of our knowledge, this is the first study to show that the TyG index is strongly associated with the development of CCC even after adjusting for various confounding factors. Several recent cohort studies about TyG index in predicting long-term cardiovascular outcomes in patients with ACS have been published in succession. Mao et. al[17] for the first time proved that TyG index is independently related to coronary artery disease severity and could act as a strong predictor of MACEs in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) after a 12-month follow-up. However, the conclusion of this study was easily influenced by relatively small sample sizes and short follow-up period. Besides, this study also failed to take acute myocardial infarction (AMI) patients into consideration. A cohort study conducted by Zhang et. al[19] tried to substantiate this conclusion in AMI patients with T2DM and found TyG index is positively associated with cardiovascular death, non-fatal MI, cardiac rehospitalization, revascularization and composite MACEs with the optimal cut-off value of 9.30, which suggested its potential role in risk stratification and prediction of prognosis in patients with AMI and T2DM. Besides, its predictive value was also applicable for those ACS patients undergoing PCI. A study of 776 ACS patients accepting PCI showed that TyG index could be a valuable predictor of cardiovascular outcomes after PCI in ACS patients with T2DM[32]. Another cohort study consisting of 2531 ACS patients undergoing non-invasive or invasive therapy with a 3-year follow-up also showed that the incidence of MACE, defined as all-cause death, non-fatal myocardial infarction and non-fatal stroke increased with the increasing TyG index tertiles with an optimal cut-off value of 9.323 and TyG index had an incremental value on the prognostic model for predicting MACE, but subgroup analysis failed to show that TyG index was an independent predictor for MACE in NSTEMI and STEMI subgroups[16]. In addition, the prognostic value of TyG index in nondiabetic ACS patients was also assessed. Zhang et. al found in ACS patients with LDL-C below 1.8 mmol/L,high TyG index was associated with increasing incidence of AMI, larger infarct size and increasing revascularization rates[18]. Although the mechanism underlying the association of TyG index with adverse cardiovascular outcomes has not been fully elucidated, considering the beneficial role of CCC in preventing cardiac ischemia and further myocardial infarction, the present study indicates that CAD patients with prominent coronary stenosis whose TyG index ≥ 9.11 tend to form less developed CCC and at least provides a new clinical insight into understanding the role of TyG index in predicting the long-term prognosis of CAD patients.
Subgroup analysis of this study showed that the association between TyG index and coronary collateralization remained significant across all subgroups, but we failed to substantiate significant interaction between TyG index and HTN and inflammatory status for evaluating the formation of CCC, considering hypertension and inflammation having impact on the coronary collateralization in precious studies, more researches are needed to understand the mechanism underlying the development of coronary collateralization.
Apart from showing the independent relationship between the TyG index and poor collateralization, the current study also found that adding TyG index to the baseline risk models had a significantly higher incremental effect on the risk assessment value for the formation of CCC than FPG, TG and another IR surrogate marker TG/HDL-C, indicating that TyG index would be more valuable in evaluating the incidence of poor CCC beyond TG, FPG and TG/HDL-C. In addition, Fig. 5 showed the AUC of baseline model, baseline model + TG/HDL-C, baseline model + HbA1c and baseline model + TyG index for assessing the incidence of poor CCC, a significant improvement on risk discriminative efficacy was found when adding TyG index into the baseline model when compared with TG/HDL-C and HbA1c. Several recent studies have compared the predictive value of TyG index, FPG and HbA1c for cardiovascular events in ACS patients and attained positive results for TyG index[33–35]. Discordance analysis conducted by Hu et. al[34] indicated that high TyG index was always associated with relatively high risk of cardiovascular events in ACS patients accepting PCI when dividing those patients into different groups based on low/high FPG or HbA1c categories, highlighting its role of better predicting cardiovascular risks than FPG or HbA1c. Better predictive value for MACCE were also substantiated when adding TyG index into baseline risk model than FPG or HbA1c in AMI patients with diabetes (AUC 0.685 for baseline model + TyG index vs. 0.661 for baseline model + HbA1c vs. 0.664 for baseline model + FPG, P < 0.001; NRI 0.190, P < 0.001; IDI 0.027, P < 0.001) and NSTE-ACS patients with non-diabetes (AUC 0.853 for baseline model + TyG index vs. 0.835 for baseline model + HbA1c vs. 0.837 for baseline model + FPG, P < 0.001; NRI 0.194, P < 0.001; IDI 0.023, P < 0.001)[35]. Considering the relatively easier access to acquire and more accurately predictive value for cardiovascular events than traditional diabetic status marker, such as TG/HDL-C or HbA1c, our study would provide more evidence for putting TyG index into clinical practice to identify patients with high cardiovascular risks, especially for those without diabetes.
Correlation Between Tyg Index And Mets
Given the high prevalence of MetS in CAD patients, there’s a need to develop convenient and low-cost screening tools to predict MetS and evaluate long-term cardiovascular risks in those MetS-related CAD patients. Our current study found the strongest link between MetS and TyG index (r = 0.624, P < 0.001) by using Spearman’s correlation analysis and the value of TyG index increases with the number of components of MetS. This is the first study to evaluate the association between TyG index and the components of MetS in ACS patients, especially in those with complicated coronary lesions. Recent studies have shown the efficacy of using TyG index to identify MetS. A population-based study containing 5000 participants found TyG index exhibited the best performance value in identifying MetS among obesity-related indices[36]. A large cross-sectional study from Korea also found the best cut-off value of TyG index for predicting MetS in middle-aged and older populations was 8.81 and they also showed the value of TyG index increased stepwise with the increasing components of MetS[37], which is in accordance with our current findings. In addition, TyG index could also predict the potential of developing MetS in healthy populations. A cohort study conducted by Lin et. al[12] showed that subjects with higher TyG index are more likely to develop MetS in healthy populations over 5-year follow-up and its predictive value was better than that of blood leukocyte indices, with an optimal cut-off value of 8.52. The current study would provide clinical evidence for using TyG index as an efficient tool to evaluate MetS in ACS patients, suggesting a therapeutic potential of TyG index in treating cardiometabolic diseases. However, given current studies mainly focused on evaluating TyG index and MetS in general population, more researches are needed to assess TyG index and MetS in patients with CAD.