The 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides defined anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) as necrotising vasculitis with few or no immune deposits, as well as small-vessel vasculitis affecting mainly capillaries, venules, arterioles, and occasionally small arteries [1
]. In principle, AAV is composed of three subtypes, microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic GPA (EGPA), according to the histopathological features including the presence of granulomas and the types of infiltrated immune cells [1
]. Additionally, clinical features such as allergic components, surrogate markers suggesting GPA, ANCA positivity and type, and renal vasculitis contribute to AAV diagnosis [4
Cardiovascular involvement of AAV includes loss of pulses, valvular heart disease, pericarditis, ischaemic cardiac pain, cardiomyopathy, and congestive cardiac failure [5
]. Its frequency is relatively low compared to those of other organ involvements: up to 15%, 20%, and 50% in MPA, GPA, and EGPA, respectively [6
]. Our recent study found that the overall frequency of cardiovascular manifestations at AAV diagnosis was 21.6%, whereas those of renal and pulmonary manifestations were 68.8% and 64.8%, respectively. Furthermore, 6.8% of patients experienced acute coronary syndrome (ACS) during follow-up [7
]. Other recent data indicate that cardiovascular disease was the sixth leading cause of mortality due to vasculitis in the United States [8
]. As such, since the mortality due to acute coronary syndrome can be one of the leading aetiologies of all-cause mortality in AAV patients, its serious clinical implication cannot be ignored. Therefore, if a novel index to predict the occurrence of ACS during follow-up is developed at the time of AAV diagnosis, it will help physicians to make decisions and enable more aggressive treatment of AAV.
The triglyceride-glucose (TyG) index, which is derived from fasting triglyceride (TG) and fasting blood glucose levels, has been proposed as a reliable surrogate marker of insulin resistance (IR). Several studies have shown that the TyG index is closely associated with traditional cardiovascular risk factors, including hyperglycaemia, hypertension, and metabolic syndrome (MetS) in a general population [9
]. Recently, the TyG index was demonstrated to be useful in assessing the risk of cardiovascular disease (CVD), particularly ACS [12
]. Therefore, it could be reasonably speculated that the TyG index could be a novel index to predict the occurrence of ACS in AAV patients; however, to date, there has been no study on the clinical implication of the TyG index in AAV patients. Hence, in this study, we investigated whether the TyG index at AAV diagnosis could predict the occurrence of ACS during follow-up in AAV patients.
In this study, we investigated whether the TyG index at AAV diagnosis could predict the occurrence of ACS during follow-up in AAV patients and obtained several interesting findings. First, AAV patients with the highest tertile of the TyG index at AAV diagnosis exhibited a significantly lower cumulative ACS-free survival rate than the others. However, the highest tertile of the TyG index could not predict ACS independently, and its statistical significance did not exceed that of the male sex in the Cox analysis. Second, the TyG index independently estimated concurrent MetS in AAV patients. Third, AAV patients with BVAS ≥ 11.5 showed a significantly higher RR for ACS compared to patients in the lower BVAS group. Lastly, AAV patients with concurrent MetS and BVAS ≥ 11.5 exhibited significantly lower cumulative ACS-free survival rates than those without. Therefore, we conclude that various factors such as IR and MetS reflected by the TyG index, BVAS, and other conventional risks are involved in the occurrence of ACS.
In this study, we demonstrated that the TyG index could be used to estimate concurrent MetS at AAV diagnosis. This has two meanings. First, we verified that our study population showed clinical characteristics similar to the population to which the TyG index had been applied in previous studies, and that the clinical implication of TyG in AAV patients may be similar to that in the general population [21
]. The other is that the TyG index may ultimately estimate an increase in the risk of coronary artery disease in AAV patients through MetS as one of the mechanistic hypotheses that can lead to ACS [22
]. To prove this assumption, we investigated the relationship between the TyG index and the presence of MetS frequency at AAV diagnosis. We applied a TyG index ≥ 9.011, which was a significant cut-off for the occurrence of ACS during follow-up. AAV patients with a TyG index ≥ 9.011 had MetS more frequently and exhibited a significantly lower cumulative ACS-free survival rate than those with a TyG index < 9.011. Therefore, although the exact mechanism remains uncertain, we conclude that the TyG index at diagnosis can predict the occurrence of ACS during follow-up in AAV patients by easily assessing concomitant metabolic abnormalities that may contribute to the occurrence of coronary arterial disease in general.
ACS, which occurs in the general population with IR represented by elevated levels of fasting plasma glucose and TG, is mainly characterised by chronic atherosclerotic lesions [13
]. Therefore, more aggressive correction and closer follow-up of IR in the general population have a benefit of lowering ACS frequency. Conversely, ACS in AAV patients is more frequently associated with acute thrombotic events due to vasculitis itself and increased vasculitis activity in addition to chronic atherosclerosis lesions compared to the general population. Therefore, with improvement of IR, control of AAV activity is needed to prevent the occurrence of ACS during the follow-up. A previous article reported an interesting case of acute MI without evidence of typical advanced atherosclerotic lesions, including necrotic core, in a patient with MPO-ANCA-associated vasculitis [25
]. This case may support our assumption of the association of ACS with not only IR and MetS but also inflammation related to vasculitis itself. To prove this assumption, we investigated the effect of BVAS on the occurrence of ACS. When the multivariable Cox analysis included BVAS as a continuous variable, BVAS could not predict ACS significantly (Table 2
). Also, when BVAS ≥ 11.5 was included in the multivariable Cox analysis instead of BVAS, BVAS ≥ 11.5 could not predict ACS independently in the multivariable Cox analysis (Supplementary Table S3
). Nevertheless, we found that the occurrence of ACS was more frequent in AAV patients with BVAS ≥ 11.5 than those with BVAS < 11.5. Furthermore, AAV patients with BVAS ≥ 11.5 exhibited a significantly lower cumulative ACS-free survival rate than those with BVAS < 11.5. Therefore, we conclude that AAV activity, in addition to IR and MetS, may contribute to the occurrence of ACS during follow-up in AAV patients.
MetS has been considered as an important risk factor for cardiovascular disease even in patients with ANCA-associated vasculitis. Our research group had also demonstrated that MetS was associated with poor health outcomes including ACS in patients with MPO-ANCA-associated vasculitis [26
]. However, measuring waist circumference is an operator-dependent examination. Thus, an easier and more precise tool such as TyG index in addition to MetS is desired in actual clinical settings. Furthermore, due to the dichotomous nature of MetS, it cannot be quantified and is hard to track over time to assess the changes in insulin resistance status and overall metabolic risk. Moreover, insulin resistance is a main pathogenic factor for MetS and cardiovascular disease [27
]. As insulin resistance usually occurs prior to MetS, the assessment of insulin resistance status in individuals may be more important in clinical practice. However, assessing conventional insulin resistance requires a special laboratory which is not available in most clinical settings. The TyG index has been suggested as a reliable surrogate marker of insulin resistance, and gives us insight on prediction of cardiovascular disease in the general population [12
]. In the present study, we demonstrated the predictive ability of TyG for MetS and the close association between TyG, MetS and cardiovascular disease in patients with AAV. Therefore, considering the fact that serum glucose and TG level is easy to obtain and the calculation of TyG index is simple in clinic, it is an applicable index for most physicians as opposed to MetS.
The overall hypotheses are summarised in Figure 4
. From other previous studies, IR and MetS are already known as a risk factor for ACS occurrence [10
]. Also, TyG index and MetS is known as a surrogate marker for IR and reflects the severity of metabolic abnormalities in individuals [12
]. Next, IR and MetS subsequently provoke chronic atherosclerotic lesions in the coronary arteries and ultimately contribute to the occurrence of ACS. Therefore, the TyG index may predict the occurrence of ACS in AAV patients. Second, in terms of the occurrence of ACS demonstrated by AAV activity based on BVAS, high BVAS induces not only chronic atherosclerotic lesions but also acute thrombotic lesions in coronary arteries, in proportion to the inflammatory burden. There was no direct correlation between the TyG index and BVAS at diagnosis, whereas the TyG index tended to correlate with ESR. Therefore, we assumed that the TyG index may predict the occurrence of ACS during follow-up by reflecting the extent of inflammation in AAV patients. Third, chronic inflammation can increase the severity of IR, which may accelerate and aggravate the progression to ACS in AAV patients [29
This is the first study to elucidate the clinical implications of the TyG index in estimating concurrent MetS and its anticipation of the occurrence of ACS in AAV patients. Furthermore, we hypothesised that the TyG index could predict future ACS in AAV patients.
The small number of AAV patients did not allow for subgroup analyses according to AAV subtypes. In particular, it was impossible to determine the association between the TyG index and the patterns of coronary arterial lesions in 12 AAV patients with ACS. The retrospective study design did not permit direct measurement of IR, and furthermore, it resulted in the omission of patients whose medical records were not sufficient to know whether metabolic syndrome could be classified; hence, we could not reveal the effect of IR on ACS in AAV patients. Another limitation is that there were no data regarding specific treatments that may directly influence overall cholesterol levels and cardiovascular disease risks such as anti-dyslipidemia agents or anti-platelet agents. Moreover, we also could not collect data on smoking history among study participants. A prospective future study with a larger number of AAV patients will compensate for these limitations and provide more reliable information on the application to AAV patients in real clinical settings.