Triglyceride-glucose index and triglyceride to high-density lipoprotein cholesterol ratio predict the prognosis in patients with type B aortic dissection receiving thoracic endovascular aortic repair

Introduction

Type B aortic dissection (TBAD) is one of the most fatal cardiovascular diseases (CVDs); it is classified as the entry tear distal to the left subclavian artery with sparing of the ascending aorta (1). The incidence of aortic dissection (AD) is the highest in age group of 65 to 75 years, with 35 cases per 100,000 people per year in this population (2). Hypertension, dyslipidemia and genetic disorders are considered as other contributing factors (3). Patients with TBAD are typically treated with medication and thoracic endovascular aortic repair (TEVAR) (4), which has been found to lower the incidence of aortic-related adverse events (ARAEs) and mortality and led to favorable aortic remodeling in TBAD patients (5,6). However, ARAEs such as retrograde type A dissection (RTAD), aortic rupture, aortic dilatation, etc., after TEVAR may undermine its advantage (7). Therefore, it is crucial to have better risk stratification of patients, which is also a challenge for the facilitation of the management of patients with TBAD.

A number of factors including D-dimer, platelets, neutrophil-to-lymphocyte ratio (NLR), etc. have been proposed to be possibly related with the outcomes of TBAD patients who undergo TEVAR (8-10). Our previous study found that peripheral eosinophil count was associated with 1-year all-cause mortality in TBAD patients (11). Additional indicators mediated by novel mechanisms may improve the effectiveness of the current prognostic model for TBAD patients undergoing TEVAR.

Insulin resistance (IR) refers to diminished or impaired reactivity to endogenous and exogenous insulin in the tissues and organs that are dependent on insulin (12). IR has been proven to be a significant risk factor for the development of CVD and type 2 diabetes mellitus (T2DM) (13). Triglyceride-glucose (TyG) index and triglyceride to high-density lipoprotein cholesterol (TG/HDL-c) ratio were also suggested as straightforward and reliable surrogate indicators of IR as a result of strongly correlating with the euglycemic hyperinsulinemia clamp and are appropriate for clinical use and large epidemiological studies (14,15). TyG index has been found to be positively correlated with coronary heart disease risk and reflect coronary atherosclerosis severity (16). An analysis of UK Biobank data also revealed that TyG index and TG/HDL-c ratio were potential CVD risk factors (17).

However, very few studies focused on the influence of the TG/HDL-c ratio and TyG index on the prognosis of TBAD patients who undergo TEVAR. Consequently, our study aims to explore the effect of the baseline TG/HDL-c ratio and TyG index on 30-day and 1-year outcomes in TBAD patients. We present this article in accordance with the TRIPOD reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1411/rc).

Methods

Study cohort and design

This is a retrospective cohort study. From January 2005 to June 2021, a total of 1,425 consecutive TBAD patients underwent TEVAR at The First Affiliated Hospital of the Navy Medical University, Shanghai, China. The exclusion criteria included: (I) traumatic AD; (II) Marfan syndrome, Turner’s syndrome, bicuspid aortic valve, Bechet’s disease, Ehlers-Danlos syndrome, giant cell arteritis, ankylosing spondylitis, or Takayasu arteritis; (III) previous aortic surgery; (IV) suspected familial hypertriglyceridemia (plasma TGs ≥500 mg/dL); (V) a history of malignancy; (VI) and missing admission glucose or TG measurement (Figure 1). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The research protocol was approved by The First Affiliated Hospital of the Navy Medical University central ethics committee (CHEC-Y2021, March 1, 2021). Informed consent was waived due to the retrospective nature of the study.

Figure 1 Flowchart of the patient selection process. MACCEs, major adverse cardiovascular and cerebrovascular events; TG/HDL-c, triglyceride to high-density lipoprotein cholesterol.

Data collection and definitions

The electronic medical records were used to gather information on sociodemographic characteristics, medical history, smoking status, comorbidities, laboratory testing, and intra-operative details. The imaging department provided the image information. TBAD was classified as an AD with an entry tear in zone 3 or 4 (18). AD was categorized as acute (1–14 days), subacute (15–90 days), and chronic (>90 days) according to Society for Vascular Surgery (SVS)/Society of Thoracic Surgeons (STS) recommendations (18). ARAEs included aortic rupture, malperfusion, RTAD, aortic dilation, and type I/III endoleak (7). The blood samples of patients who received surgery that are not performed in urgent/emergency setting were collected at 6 a.m. on the day of surgery. If it was an emergency surgery, the blood samples were obtained in the emergency room or during surgery. Standard biochemical methods were used at the Clinical Laboratory of The First Affiliated Hospital of the Navy Medical University to assess laboratory parameters such as D-dimer, creatinine, glucose, TG, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and uric acid. The following equation was used to construct the TyG index: ln [TG (mg/dL) × glucose (mg/dL)/2] (19). The TG/HDL-c ratio was computed by dividing the TG (mg/dL) by the HDL-C (mg/dL) levels (17). Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m².

Follow-up and endpoints

Research was conducted with qualified researchers by phone survey or by reviewing the medical records of all patients. Furthermore, adverse events were assessed in the comprehensive clinical files of patients requiring re-admission or reviewed in clinic. Study endpoints included the following 30-day outcomes: 30-day all-cause death; 30-day stroke and 1-year outcomes: 1-year all-cause death and 1-year major adverse cardiovascular and cerebrovascular events (MACCEs). ARAEs, which were traditionally believed to be only associated with technical failure, were also depicted in this study. Two clinicians experienced in the diagnosis and treatment of TBAD blindly evaluated the adverse events and patients’ outcome.

Statistical analysis

The participants were classified into five groups [Quintile 1 (Q1) (n=186, TG/HDL-c ratio <1.44), Quintile 2 (Q2) (n=187, 1.44≤ TG/HDL-c ratio <2.09), Quintile 3 (Q3) (n=188, 2.09≤ TG/HDL-c ratio <2.97), Quintile 4 (Q4) (n=186, 2.97≤ TG/HDL-c ratio <4.11), and Quintile 5 (Q5) (n=188, TG/HDL-c ratio ≥4.11)], by the quintiles of TG/HDL-c ratio, and the Q4 group was used as the reference group, and the characteristics were depicted. Variables with continuous distributions were compared using a student t-test or Mann-Whitney test based on the means, standard deviations or medians (quintiles 1 through 5). Categorical variables were reported as percentages and tested with Chi-squared or Fisher’s exact tests. TG/HDL-c ratio was originally input as a continuous variable and then modeled as a categorical variable. We calculated cumulative survival curves using Kaplan-Meier (KM) methods and used log-rank tests to differentiate between groups.

Univariable and multivariable Cox regression models for 1-year all-cause mortality, as well as Cox regression models for 1-year ARAEs, were applied to investigate the relationship between the preoperative TG/HDL-c ratio and 1-year outcomes. Variables with a P value of 0.1 in the univariable analysis were introduced into the multivariable models using a stepwise forward approach. Moreover, we employed general additive models (GAMs) with restricted cubic splines (RCS) (giving 4 degrees of freedom) for visual analysis to evaluate the nonlinear correlations between continuous variables and outcomes. The statistical analyses were performed using R version 3.6.3 and EmpowerStats software (www.empowerstats.com). A P value of 0.05 was chosen as the statistical significance level.

Results

Clinical characteristics

Table 1 demonstrates the participant characteristics both overall and stratified by the quintiles of the TG/HDL-c ratio. The mean age of the included 935 patients was 59.8±13.3 years, with 759 (81.2%) men (P=0.001). Q1 group was significantly older in the all groups (P<0.001). Smoking history and sex were statistically different among the groups (P=0.001). The body mass index (BMI) of the five quintiles were 23.5±3.7, 24.0±3.9, 24.4±3.3, 24.9±3.1, and 25.4±3.7 kg/m², respectively, which was significantly different (P<0.001). Systolic blood pressure (SBP), and diastolic blood pressure (DBP) did not differ significantly among the groups (all P>0.05). There was no significant difference in comorbidities among groups (all P>0.05). In terms of laboratory tests, the difference in platelet (P=0.002), creatinine (P=0.012), total cholesterol (P<0.001) and LDL-C (P=0.028) was statistically significant among groups. The uric acid was remarkably higher in Q5 group (231.9±2,323.6 mg/dL, P<0.001) compared with the other groups. The difference in other laboratory tests [white blood cell (WBC), hemoglobin, D-dimer and glucose] was not significant (all P>0.05). Branch, adjunct, and hybrid technique utilization and the timing of TEVAR among groups were not statistically different (all P>0.05). Besides, the anatomical characteristics of the five groups were comparable (all P>0.05) except for the extent of proximal thrombosis of the false lumen (P<0.001).

30-day outcomes

The average length of stay in the hospital following TEVAR was 11.8±6.6 days in the Q1 group, 12.4±7.4 days in the Q2 group, 11.4±6.2 days in the Q3 group, 11.2±5.7 days in the Q4 group, and 12.8±9.5 days in the Q5 group (P=0.129). In hospitalization or 30 days after TEVAR, there were no significant differences in mortality among the five groups (3.2% vs. 1.1% vs. 1.6% vs. 1.1% vs. 2.7%, P=0.441). There was also no statistical difference in the 30-day stroke after TEVAR (1.1% vs. 0.5% vs. 0.0% vs. 0.5% vs. 1.6%, P=0.444). The 30-day outcomes are detailed in Table 2.

1-year outcomes

The cumulative incidence rates for 1-year all-cause mortality and MACCEs are reported in Table 2. A total of 20 MACCEs and 46 fatalities were found during the 1-year follow-up. There was no significant difference in the cumulative incidence of 1-year all cause death (8.54% vs. 4.01% vs. 4.87% vs. 2.71% vs. 9.16%, P=0.052) and 1-year MACCEs (1.89% vs. 4.82% vs. 1.53% vs. 1.51% vs. 3.62%, P=0.264) among the five groups (Table 2). However, there were significant difference in the 1-year all-cause mortality between Q4 and Q1 (P=0.02), as well as Q4 and Q5 (P=0.02) (Figure 2).

Figure 2 Kaplan-Meier survival analysis of 1-year outcomes for TBAD patients undergoing TEVAR. (A) The 1-year overall survival probability. (B) The 1-year freedom from MACCEs. Quintile 1: TG/HDL-c ratio <1.44. Quintile 2: 1.44≤ TG/HDL-c ratio <2.09. Quintile 3: 2.09≤ TG/HDL-c ratio <2.97. Quintile 4: 2.97≤ TG/HDL-c ratio <4.11. Quintile 5: TG/HDL-c ratio ≥4.11. MACCEs, major adverse cardiovascular and cerebrovascular events; TBAD, type B aortic dissection; TEVAR, thoracic endovascular aortic repair; TG/HDL-c, triglyceride to high-density lipoprotein cholesterol.

Table 3 reveals the findings of the Cox proportional hazard modeling evaluation. Multivariable Cox regression analysis indicated that TG/HDL-c ratio (modeled as a continuous variable) was strongly linked with 1-year all cause death [hazard ratio (HR) =1.07; 95% confidence interval (CI): 1.00–1.15; P=0.041] (Table 3, Table S1). Other independent predictors for 1-year all-cause mortality included stroke (HR =2.64; 95% CI: 1.09–6.41; P=0.031), CKD (HR =2.71; 95% CI: 1.08–6.82; P=0.034), and pericardial effusion (HR =0.69; 95% CI: 1.55–8.80; P=0.003) (Table S1). As a categorical variable, patients with TG/HDL-c ratio <1.44 (HR =4.67; 95% CI: 1.46–14.94; P=0.001) and TG/HDL-c ratio ≥4.11 (HR =4.84; 95% CI: 1.55–15.13; P=0.007) had higher risk of 1-year all-cause mortality (Table 3, Table S2). However, continuous TyG index was not found to be related to 1-year all-cause death and 1-year MACCEs (all P>0.05) (Table S3).

Additionally, we performed subgroup analyses to investigate the impacts of various potential confounding factors, including smoking history, gender, age, SBP, DBP, high blood pressure (HBP), coronary artery disease (CAD), diabetes mellitus, stroke, chronic obstructive pulmonary disease (COPD), CKD and timing of operation (Figure 3). There was no interaction in the all subgroups (all P for interaction >0.05). Moreover, neither TG/HDL-c nor TyG index were found to be related to 1-year MACCEs in the univariate Cox proportional hazard modeling (Table 3); the details are presented in Table S4.

Figure 3 Subgroup analysis for association between TG/HDL-c and 1-year outcomes. HR, hazard ratio; CI, confidence interval; TG/HDL-c, triglyceride to high-density lipoprotein cholesterol; SBP, systolic blood pressure; DBP, diastolic blood pressure; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease.

The RCS identified non-linear relationships between TG/HDL-c, TyG index and 1-year outcomes (Figure 4). Unexpectedly, there seemed to be a U-shaped correlation between TG/HDL-c and 1-year all-cause outcomes. The log relative risk (RR) for 1-year all-cause mortality was higher when the TG/HDL-c ratio was below 2.72 and when it was above 2.72. There were no obvious associations between TyG and 1-year MACCEs, nor between TG/HDL-c and 1-year MACCEs.

Figure 4 The association between TG/HDL-c and 1-year outcomes and the association between TyG index and 1-year outcomes. (A) The relationship between TG/HDL-c and log RR for 1-year mortality. (B) The relationship between TG/HDL-c and log RR for 1-year MACCEs. (C) The relationship between TyG index and log RR for 1-year mortality. (D) The relationship between TyG index and log RR for 1-year MACCEs. TG/HDL-c, triglyceride to high-density lipoprotein cholesterol; MACCEs, major adverse cardiovascular and cerebrovascular events; TyG, triglyceride-glucose; RR, relative risk.

A discriminant analysis (Wilks’ Lambda) was also performed to investigate the potential influences of 1-year ARAEs (Tables S5,S6).

Discussion

IR is a systemic condition that affects insulin-regulated pathways and multiple organs and is characterized by diminished tissue sensitivity or reaction to circulating insulin, which may be related to obesity, genetic abnormalities, or anti-insulin receptor (20,21). Euglycemic clamp is the gold standard for measuring IR; however, due to the sophisticated procedures, it is not ideal to utilize it as a routine screening item for admission and inappropriate for large-scale investigations (22). Previous studies have shown that TyG index and TG/HDL-c ratio are simple and reliable surrogate markers for IR, that are applicable to both clinical practice and large epidemiological studies (23,24). It has been shown that TG/HDL-c ratio and TyG index were associated with adverse cardiovascular events such as acute coronary syndrome, chronic coronary syndrome, myocardial infarction, ischemic stroke, and cardiac death (17,25). The study has been designed specifically to analyse a potential relationship between TG/HDL-c ratio and the 1-year prognosis of TBAD patients undergoing TEVAR, which may have a role to play in the management of the residual disease. We found a strong association between the TG/HDL-c ratio and 1-year all-cause mortality. The independent association remained statistically significant after adjustment for the well-established AD risk factors and potential confounding risk factors.

The impact of the TG/HDL-c ratio on the outcomes of TBAD patients may be mediated by inflammation. AD is recognized as an inflammatory-related vascular disease (26,27). Local neutrophils recruitment and activation has been observed to trigger aortic rupture while disruption of IL-6 significantly decreases dilatation of the dissected aorta (28). Inflammatory factors may influence the progression and outcome of AD patients. A previous study found that perioperative NLR and systemic inflammatory response index were associated with re-intervention and 1-year outcomes of TBAD patients (29,30). IR is a prominent comorbidity of obesity, arising from a combination of fat excess-triggered abnormalities, including lipotoxicity and meta-inflammation (31). Perry et al. revealed a critical role for inflammation as a divulged etiology for IR (32). Patients with IR may have higher levels of inflammatory cytokine release, leading to adverse events of TBAD patients. Besides, a study found that mitophagy-mediated adipose inflammation leads to type 2 diabetes with hepatic IR (33). Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury (34). Adachi et al. showed that the beiging (brown adipose tissue-like phenotype change) of PVAT fine-tunes inflammatory response and thus regulates the vascular remodeling (35). PVAT density, which measures vessel inflammation, has been found to be independently associated with the progression of coronary atherosclerosis (36). TG/HDL-c ratio has been used to predict outcomes of numerous cardiovascular inflammatory disorders (37,38).

In addition, IR may have a profound effect on aortic structural cells. The progression of thoracic AD is directly correlated with the breakdown of extracellular matrix and the switch from contractile to synthetic vascular smooth muscle cells (VSMCs) (39). Zheng et al. found that IR promotes the formation of AD by inducing the phenotypic switch of VSMCs (40). Except for VSMCs in the media, endothelial cells are a key component of the intima of the aorta. It has been recently shown that the disruption of endothelial tight junctions’ function is an early event prior to TAAD formation (41). Insulin stimulates the phosphatidylinositol 3-kinase pathway, resulting in endothelial nitric oxide generation and vasodilation, while IR compromises this pathway and leads to vascular dysfunction (42). According to the available research, IR is a secondary cause of progressive endothelial dysfunction, disorders of glucolipid metabolism, vascular damage brought on by lipid deposition and oxidative stress in the vascular wall, an inflammatory response, and the release of chemoattractants and cytokines, which worsen IR and endothelial dysfunction (43).

Other factors may underpin the potential association between the TG/HDL-c ratio and prognosis of TBAD patients. The indicator is not closely related to various comorbidities, including hypertension, diabetes mellitus, stroke, etc. It has been reported that dyslipidemia, diabetes mellitus, and hypertension explained 45.8%, 27.0%, and 15.0% of TyG index’s association with CVD in mediation analyses, respectively (17). However, after adjustment of the confounding factors in the multivariate Cox analyses, TG/HDL-c ratio is still independent risk factor for 1-year outcomes (Table 3). In stratified analysis (Figure 3), we discovered that the covariates did not substantially modify the correlation of TG/HDL-c ratio with the prognosis of TBAD patients treated with TEVAR, suggesting that the results of this study are relevant to most of the general population. Furthermore, Tripolino et al. revealed that a high TyG index is associated with increased wall shear stress in the common carotid artery, which may explain the higher risk of 1-year aortic dilation after TEVAR (44).

Moreover, we discovered a fascinating phenomenon in our study: the relationship between TG/HDL-c ratio and 1-year prognosis showed a slight U-shaped relationship. A lower TG/HDL-c ratio also led to an increased risk of adverse events and mortality. According to a cohort study, people with CAD have a paradoxically increased mortality risk when their HDL-C levels are quite high (45). It has also been indicated that men and women in the general population with extremely high HDL-C paradoxically have high all-cause mortality (46). This may be an important reason for the association between low TG/HDL-c ratio and poor prognosis.

Overall, our findings reinforce the predictive value of TG/HDL-c ratio, which may represent new mechanisms affecting the prognosis of patients with TBAD. Compared with other detection methods, TG/HDL-c ratio detection is simple, rapid and reproducible, and they are an ideal clinical monitoring index that has high clinical relevance for preoperative evaluation, postoperative monitoring and prevention of complications. Implementing the TG/HDL-c ratio into routine clinical assessments requires more standardized protocols for measuring fasting triglyceride and glucose levels. Establishing threshold values indicating increased risk and developing guidelines for clinical decision-making based on these values would be essential. Large-scale prospective studies are needed to confirm its reliability and reproducibility across diverse patient populations. Patients with a higher TG/HDL-c ratio than the threshold might be considered for more intensive monitoring post-TEVAR or could receive more aggressive management of cardiovascular risk factors, such as stricter blood pressure control and the utilization of antihypertensive drugs. Follow-up criteria for TBAD patients who have undergone TEVAR includes regular imaging studies, which are essential to evaluate the aortic repair site; regular clinical examinations to assess symptoms, including chest or back pain, signs of organ malperfusion; strict blood pressure control that is vital in preventing aortic expansion and reducing the risk of further dissection or rupture; periodic blood tests which can help assess renal function, monitor for end-organ damage, and evaluate metabolic parameters; medication adherence that ensure patients are compliant with prescribed medications, including antihypertensives, antiplatelet agents, or anticoagulants, if indicated.

Finally, TyG index and the TG/HDL-c ratio, representing the IR mechanism which is often neglected in the treatment of TBAD patients, may be used to improve the precision of traditional predication models. Combination indexes, such as TyG-platelets index, may also be made by integrating the TyG index and other traditional risk factors such as NLR, platelets, and D-dimer etc.

Limitations

This study has several limitations. (I) This study was a retrospective study. Data records for certain patients may be inaccurate, resulting in increased margins of error. (II) The role of TG/HDL-c ratio and TyG index in the diagnosis of TBAD needs further study, including in combination with other biomarkers. (III) The study was not originally planned for the TG/HDL-c ratio and TyG index, but is a retrospective assessment of computer-collected data, including the TyG index.

Conclusions

The findings of this study indicated that continuous TG/HDL-c ratio, TG/HDL-c ratio <1.44, and TG/HDL-c ratio ≥4.11 were independent risk factors related to increased risks of 1-year all-cause death for TBAD patients receiving TEVAR. Special attention should be paid to TBAD patients with continuous TG/HDL-c and too low or too high TG/HDL-c ratio.

Acknowledgments

The authors thank all members of the Department of Vascular Surgery at The First Affiliated Hospital of the Navy Medical University, Shanghai, China, for their assistance in the data investigation.

Funding: The study, and collection, analysis, interpretation of data, and preparation of the manuscript were supported by the source of funding as follows: the National Natural Science Foundation of China (Nos. 82270513, 82170500, and 82000464) and National Innovation Talent Promotion Plan (No. 2019RA2132).

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1411/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1411/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1411/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1411/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The research protocol was approved by The First Affiliated Hospital of the Navy Medical University central ethics committee (CHEC-Y2021, March 1, 2021). Informed consent was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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