The main findings of this study are as follow: 1) The value of CTI was significantly higher in participants suffered from MACCEs than those free of MACCEs. 2) The CTI was associated with the incidence of MACCEs within one year in heart failure patients undergoing PCI treatment and this association remained significant after adjusting for various confounding factors. Further, this study also found that compared with those with low CTI, high CTI indicated a higher risk of MACCEs within a certain range (CTI ≥ 9.47), and enhanced the cardiovascular outcome risk by 67% over the one-year follow-up in that population. 3) the predictive value of CTI for risks of MACCEs within one year is better than single component of CTI (inflammatory biomarker: CRP, IR biomarker: TyG index). Adding the CTI into the baseline model shows the most significant incremental effect on risk discrimination for predicting the risk of MACCEs within one year. To the best of our knowledge, this is the first study focusing on the evaluating the prognostic value of CTI for the risk of major adverse cardiovascular outcomes in patients with cardiovascular diseases. The predictive ability of CTI provides an effective and convenient tool used for assessing prognosis and also indicates a detrimental role of inflammation and IR in the progression of cardiovascular diseases.
CTI is mainly determined by two critical components, the one is inflammation represented by the CRP, the other one is IR represented by the TyG index. Inflammation and IR are both important components of residual cardiovascular risk factors and confer an enhanced risk of AMI and heart failure[24–27]. The prevalence of diabetes has increased by more than tenfold since the 1980s in China owing to the ageing populations and improving socioeconomic status[2]. Diabetic patients have twofold to eightfold higher cardiovascular event rates as compared with age-matched nondiabetic individuals and 75% of death in diabetic patients can be attributed to various cardiovascular diseases. Although hyperglycemia correlates with macro- and microvascular diseases, IR itself promotes atherosclerosis even before the onset of clinical diabetes, and available data corroborate the role of IR as independent risk factor for atherothrombosis[28]. This finding has promoted attention for increased surveillance for the status of IR in the management of cardiovascular disease patients. However, the homeostasis model assessment- IR is not very applicable for clinical practice because the serum insulin level is not a common laboratory measurement for cardiovascular disease patients, especially for those nondiabetic patients. The TyG index as a surrogate marker for IR accompanied by hypertriglyceridemia and hyperglycemia has been proven to be strongly associated with the gold standard for evaluating IR[29]. Recent studies concentrating on evaluating the effect of the TyG index on the cardiovascular events have substantiated the prognostic value of TyG index for predicting heart failure, AMI and cardiovascular death in cardiovascular patients[11–13, 28]. While conflicting result that the TyG index is not an effective predictor for cardiovascular events in nondiabetic patients undergoing PCI treatment has also been reported[30], which is in accordance with the conclusion in current study. One plausible explanation could be that the prognostic role of IR for major adverse cardiovascular outcomes could be partially mediated by the inflammatory status. Recent study conducted by Li et al. demonstrated that a significant partial mediating effect of systemic inflammation on the association of IR with adverse cardiovascular events in chronic coronary syndrome diabetic patients, implying the mediated effect of inflammation on IR-related cardiovascular outcomes[16]. The underlying mechanism could be that IR could activate different inflammatory signaling cascades in cardiomyocytes which contribute to cell hypertrophy, apoptosis and dysfunction[31]. In addition, exposure of endothelial cell to IR exerts a detrimental effect on endothelial function linked to ROS formation and upregulation of inflammatory cytokine expression via activating IκB kinase, NF-κB and nucleotide-binding domain, leucine-risk-containing family, pyrin domain 3 (NLRP3) inflammasome signaling pathway[4]. The current study demonstrate that the CTI is associated with the incidence of major adverse cardiovascular outcomes in heart failure undergoing PCI treatment, implying the potential use of CTI in evaluating IR-related cardiovascular prognosis in that population. Besides, this study also provides clinical evidence for the role of inflammation and IR in the progression of cardiovascular diseases.
The conclusion of this study that the comprehensive indicator of inflammation and IR determines the prognosis also provide clinical proof for selected anti-inflammatory therapies in heart failure patients undergoing PCI treatment. Recently, burgeoning evidence from large clinical trials of therapies targeting inflammation in atherosclerotic cardiovascular disease individuals is now emerging. It was not until 2017 with the publication of the CANTOS trial that proof of inflammation targets in atherosclerosis was provided. In the CANTOS trial, Canakinumab lowered cardiovascular event rates by 15–17% compared with placebo without affecting LDL-C and apolipoprotein B levels, demonstrating that inhibition of the NLRP3 to interleukin-1 to interleukin-6 pathway was a crucial treatment target for atherosclerosis[7]. In contrast, the Cardiovascular Inflammation Reduction Trial (CIRT) of 4786 stable atherosclerosis patients with diabetes or metabolic syndrome reported that low-dose methotrexate did not reduce major adverse cardiovascular events[32]. In addition, low-dose methotrexate also failed to reduce interleukin-1β and interleukin-6 level. The conflicting results of CIRT and CANTOS trial support the concept that adequate inhibition of the NLRP3 to interleukin-6 pathway of innate immunity is necessary to secure long-term cardiovascular benefits. Increased NLRP3 inflammasome expression can be observed under the condition of IR, which lead to chronic low-grade inflammation[33]. Hence, therapeutic interventions targeting at IR could be a promising strategy for patients with IR and high inflammatory burden to further reduce the incidence of cardiovascular events. Multiple randomized trials now demonstrate cardiovascular risk reduction among those with diabetes or not using novel glucose-lowering agents, in particular for glucagon-like peptide-1 receptor agonist (GLP-1RA) and for sodium-glucose cotransporter 2 (SGLT2) inhibitors, which both reduce cardiovascular events, improve IR status and alleviate inflammatory burden[8–10, 34, 35]. The potential anti-inflammatory effect of GLP-1RA could be that it could effectively lower the level of CD163, a biomarker for macrophage activation, and reversal changes in leukocyte recruitment, rolling, and adhesion/extravasation related to the inflammatory response were also observed in animal models after GLP-1RA treatment[36]. The current study demonstrated that CTI could be a favorable inflammatory and IR indicator for predicting cardiovascular prognosis, which can be viewed as a promising therapeutic target to for intervening cardiovascular disease patients with IR and high inflammatory burden and initiating novel glucose-lowering therapy in that population.
Subgroup analysis indicated that there existed an interaction between the presence of hypertension and CTI-related cardiovascular outcomes and suggested a possible role of IR for mediation through hypertension. Recent study has demonstrated a mediating role of controlled hypertension on the effect of IR on cardiovascular outcomes in patients with CAD and hypertension[13]. These might indicate an intimate association of both IR and hypertension with adverse prognosis of cardiovascular disease patients. Previous study has discussed the deteriorative role of IR in hypertension via upregulating inflammatory cytokine expression and diminished NO production, leading to endothelial dysfunction[4]. While the exact underlying mechanism remain elusive, further investigations are needed to clarify the association.
To the best of our knowledge, this is the first study to evaluate the potential use of CTI in heart failure patients undergoing PCI treatment. However, several limitations should be acknowledged. First, this was a single-center observational retrospective cohort study, so potential selection bias invariably existed. Second, the enrolled population in this study underwent only one-year of follow-up with a relatively low MACCE rate, which may limit the statistical analysis and make it difficult to find a connection between the CTI value with a single component of MACCEs. Third, the current study lacks serial measurements of CTI, so the effect of dynamic change of CTI after discharge on cardiovascular outcomes need to be further studied. Lastly, this study only selects TyG index and CRP as a simple surrogate marker for IR and inflammation, while the predictive value of many other IR and inflammatory indicators for MACCEs remained elusive.