In this study, SHR was significantly associated with the incidence of IHCA in ACS patients treated with PCI. SHR showed a dose-response relationship with the incidence of IHCA. The AUC of SHR for predicting the incidence of IHCA in ACS patients treated with PCI was 0.64, which is considered to have some predictive power.
SIH in ACS patients may result from pancreatic β-cell dysfunction and insulin resistance[19, 20]. Reportedly, pancreatic β-cell dysfunction affects insulin release[21, 22], thereby increasing glucagon and glucose levels in patients with ACS[23, 24]. In addition, dysregulation of the sympathetic nervous system and the renin-angiotensin-aldosterone system in the context of ACS leads to increased stimulation of adrenergic and angiotensin II receptors and the occurrence of insulin resistance[25]. ABG refers to the random blood glucose measured within the first 24 hours after a patient's admission to the hospital[2, 26]. Prior research has characterized SIH using ABG[2, 27–32], wherein SIH is described as a transient elevation of blood glucose linked to the stress experienced during the disease and identified as an independent factor associated with unfavorable short- and long-term clinical outcomes in patients diagnosed with ACS[1–3]. Hyperglycemia exerts direct deleterious effects on the ischemic myocardium through various mechanisms, including oxidative stress, inflammation, apoptosis, endothelial dysfunction, hypercoagulability, platelet aggregation, and impairment of ischemic preadaptation[33–36]. However, it remains controversial whether elevated ABG (SIH) is merely a manifestation of severe disease or is associated with serious consequences such as complications or death[37–39]. High values of ABG do not necessarily indicate elevated blood glucose levels after an acute MI (AMI), especially in patients with DM accompanied by chronic elevated blood glucose[4]. Therefore, Robert et al. [4]proposed the SHR. The formula [28.7 x HbA1c (%) -46.7] can determine chronic blood glucose levels to gain new insights into the relationship between blood glucose and poor prognosis by correcting blood glucose levels for HbA1c[16, 40]. Several studies have examined the predictive value of SHR for short-term adverse prognosis in patients with ACS[9, 11–13]. Xu et al. [11] enrolled 7,476 patients with STEMI with the primary endpoints of adverse cardiovascular events (MACE) and all-cause mortality with a follow-up period of 30 days and showed that SHR was independently associated with the risk of developing MACE and mortality. Chen et al. [12] consecutively enrolled patients aged 75 years or older with a confirmed diagnosis of AMI in 341 patients with the study endpoints of in-hospital all-cause mortality and in-hospital major adverse cardiovascular and cerebrovascular events (MACCE), suggesting that SHR may serve as a simple and independent indicator of adverse outcomes during hospitalization in non-DM patients. Marenzi et al. [13]recruited 474 patients with DM combined with AMI, with the primary endpoint of acute kidney injury, and found that SHR was a better predictor of the occurrence of acute kidney injury than ABG. Marenzi et al. [9]recruited 1,553 patients with AMI, with the primary endpoints of in-hospital mortality, acute pulmonary edema, and cardiogenic shock. SHR was a better predictor of morbidity and mortality during hospitalization than ABG. Other studies have examined the predictive value of SHR for long-term adverse prognosis in patients with ACS[5–8].Yang et al. [5] recruited 5,562 consecutive patients with ACS treated with PCI, with the primary endpoint being MACC and a 2-year follow-up. During a median follow-up period of 28.3 months, they found that SHR correlated in a U-shape with 2-year MACCE and MACE rates and a J-shape with in-hospital cardiac mortality and MI in a J-shaped correlation. Cui et al. [6] demonstrated a significant positive correlation between SHR and long-term mortality in patients with AMI with and without DM by conducting a prospective, multicenter study of 6,892 patients with AMI with the primary endpoint of 2-year all-cause mortality. Sia et al. [7]recruited 5,841 patients with STEMI and 4,105 patients with NSTEMI. The study endpoint was all-cause mortality with a follow-up period of 1 year, revealing that SHR was the most consistent independent predictor of 1-year all-cause mortality in both DM and non-DM STEMI patients, whereas glucose was the best predictor in NSTEMI patients. Yang et al. [8]enrolled 4,362 coronary artery disease patients with the study endpoint of MACCE and a median follow-up period of 2.5 years and showed that SHR is a useful predictor of MACCE after PCI, especially in non-DM patients with STEMI. To the best of our knowledge, the current study may be the first to show a dose-response relationship between SHR and IHCA in ACS patients treated with PCI. In our study, we included 1,939 ACS patients treated with PCI. The results showed that SHR was significantly associated with the incidence of IHCA in ACS patients (OR = 6.46; 95% CI = 1.20–34.73, P = 0.03), and the OR of IHCA was significantly increased when SHR > 0.97, even after adjusting for other confounders. Further RCS analysis showed that this correlation was a dose-response relationship, and the sensitivity analysis results illustrated the results' robustness. In addition, baseline data showed that DM incidence and insulin or glucose-lowering medication use were higher in the T3 group than in the T1 group. We hypothesized that patients in the T3 group might experience more hyperglycemic episodes due to inappropriate use of insulin or glucose-lowering medication, which has been shown to increase the risk of cardiovascular events[41, 42]. P values for all interactions were > 0.05 in the subgroup analyses, and the different results in the subgroup analyses may be due to insufficient sample size. However, the underlying mechanisms by which SHR shows a dose-response relationship with IHCA in patients with ACS remain uncertain and may include the following mechanisms. The duration of hyperglycemia appears to be critical in determining whether hyperglycemia is protective or harmful, i.e., long-term hyperglycemia is harmful, whereas short-term hyperglycemia is beneficial[43, 44]. Hyperglycemia in the context of acute disease is an evolutionarily conserved adaptive response that increases the host's chances of survival[45]. Hyperglycemia can trigger compensatory mechanisms that offer protection against ischemia and potentially guard against post-ischemic cell death by promoting anti-apoptotic and cell survival pathways and angiogenesis[46, 47]. Therefore, in this study, mild to moderate SHR values < 0.97 might have conferred some protective effect against IHCA events. Conversely, true SIH may have been more prevalent at SHR values > 0.97. When SHR < 0.97, it indicates chronic hyperglycemia (high HbA1c), with either good current glycemic control or overcontrol (low ABG). Hence, the curve's steepness will be higher for outcomes closely linked to acute responses, while the curve will be relatively flat for outcomes more connected to chronic hyperglycemia. In the future, larger prospective cohort studies should be conducted to determine the threshold of SHR for the diagnosis of SIH and to explore its predictive value for cardiovascular outcomes in patients with ACS. In conclusion, although there was no interaction of SHR on IHCA between the DM and non-DM subgroup (P = 0.979), the dose-response relationship between SHR and IHCA may be partly due to DM status.
Strength and limitations
This is the first time a dose-response relationship between SHR and IHCA in ACS patients has been proposed using RCS analysis, and the linear correlation between SHR and ICHA events was analyzed and evaluated. However, this study has some shortcomings. First, it was a single-center study that included only Asian patients, and these results should be interpreted with caution. Second, the current study is limited by its retrospective design, and causality cannot be inferred in this study; further prospective multicenter studies are needed to validate these results. In addition, we cannot completely exclude the possibility of unmeasured or unknown confounding factors that may explain the associations observed in this study.