An abdominal aortic aneurysm (AAA) is characterized by an irreversible and progressive dilation of the abdominal aorta and often presents an 80% mortality rate after rupturing occurs [1, 2, 3]. Currently, the main surgical methods for treating an AAA are open surgical repair (OSR) and endovascular aortic repair (EVAR) [4]. Strong evidence from large randomized controlled trials has confirmed that EVAR is associated with reduced short-term mortality rates similar to mid- and long-term survival rates, although with higher reintervention rates during follow-up [5, 6, 7, 8]. Choosing a suitable surgical strategy is important to evaluate carefully the additional risk factors influencing prognosis, the patient’s anatomical characteristics, and preferences regarding follow-up [9, 10]. In this context, it is necessary to discover new, easily accessible, and generally applicable indicators for risk stratification in long-term survival conditions, thus, guiding treatment decisions [11].

Systemic chronic inflammation status is evaluated using novel systemic inflammatory markers (SIMs) derived from the whole blood cell count ratio. These markers include the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), hemoglobin-to-red cell distribution width ratio (HRR), systemic immune-inflammatory index (SIII), and systemic inflammatory response index (SIRI) [12, 13, 14]. These markers can more accurately indicate systemic inflammation for prognostic assessment [13]. Multiple studies have demonstrated a correlation between the novel SIMs and cardiovascular disease [15, 16], cancer prognosis [14, 17, 18, 19], and all-cause mortality [20]. The formation and development of the abdominal aorta are also closely related to the systemic inflammatory response [21, 22], and a cohort study has demonstrated a strong correlation between higher neutrophil count and abdominal aortic dissection [23]. Therefore, novel SIMs, which can serve as potential prognostic markers that are easy to obtain and widely used, are expected to be useful tools for identifying patients with poor survival outcomes after EVAR.

NLR has been proven to be associated with the perioperative morbidity of ruptured AAA and mortality after selective EVAR [24, 25]. However, the correlation between novel SIMs and the long-term survival rates after EVAR remains uncertain. Therefore, this study aimed to ascertain the accuracy of novel SIMs as prognostic indicators for predicting all-cause mortality in patients following EVAR.

We presented a detailed analysis of clinical factors and hematologic markers that have predictive significance for death in AAA patients undergoing EVAR, particularly the relationship between SIMs and long-term death. The results suggested that an increased preoperative NLR and a decreased HRR were associated with increased death after EVAR. AAA patients with an NLR $\ge$2.77 or HRR 10.64 may have a higher risk of death during the follow-up after EVAR. In addition, multivariate Cox regression analysis suggested that HRR is an independent risk factor for death after EVAR, with a prediction accuracy of 0.78.

Recently, SIMs have received considerable attention as independent prognostic indicators for mortality and morbidity in several diseases, such as cancers, cardiovascular and cerebrovascular diseases, and inflammatory conditions [28, 29, 30, 31]. Thus, using SIMs as inexpensive and easily accessible prognostic indicators for follow-up is steadily increasing in clinical and academic settings. The application of NLR in the prognosis of mortality and morbidity in coronary artery disease [32], atherosclerosis [15], and peripheral artery disease [33] has been widely studied. In terms of coronary artery disease, higher NLR values can predict not only the progression of coronary atherosclerosis [34] but also the risk of death after CABG and PCI [35, 36]. In addition, in five randomized trials involving 600,875 participants, NLR has been a proven predictor of incident major adverse cardiovascular events (MACEs) and all-cause mortality [15]. However, SII and SIRI use three blood cell subtypes and might provide a more accurate representation of the balance between inflammatory and immunological responses. Several studies have shown that elevated SII is associated with an increased incidence and severity of coronary heart disease [37, 38] and with a higher risk of MACEs (HR: 1.65) and total major events (HR: 1.53) in coronary artery disease (CAD) patients [39]. Similarly, SIRI was an independent predictor of MACEs in acute coronary syndrome (ACS) patients undergoing PCI [40]. However, there are relatively limited studies on HRR. In a retrospective study of 6046 hospitalized coronary atherosclerotic heart disease patients undergoing PCI, decreased levels of HRR (HRR 10.25) were associated with a 1.470-fold and 1.479-fold higher risk of long-term all-cause and cardiac mortality, respectively [41]. SIMs provide significant potential for application in cardiovascular disease prognosis research.

The predictive significance of SIMs in aortic-related surgery has also received increasing attention. Several studies have proposed the predictive value of SIMs for long-term survival after EVAR. King et al. [24] found that preoperative NLR (NLR $>$4) was a strong independent predictor of mid-term mortality after EVAR. Kordzadeh et al. [42] showed that a preoperative NLR $>$5, irrespective of age, gender, AAA size, blood loss, length of stay, and comorbidities is an independent marker of 30-day death in patients with a ruptured AAA. The study by Lecumberri et al. [25] revealed that NLR, PLR, and SII exhibited independent associations with survival outcomes in a 5-year follow-up of AAA patients who underwent EVAR. However, only NLR demonstrated a moderate enhancement in predicting a survival score. Hence, an NLR $\ge$3 can be used to identify patients with poor outcomes and help in decision-making [25]. In addition, Zhao et al. [12] conducted a survival study and found that patients in the higher-SIRI group (SIRI $>$4) had a 4.3 times higher risk of experiencing adverse outcomes after EVAR compared to patients with a lower-SIRI. However, it is important to note that the optimal thresholds selected by different research teams for various characteristics in the prognosis of SIMs in AAA exhibit significant heterogeneity. Currently, there is no widely agreed upon threshold of SIMs to predict perioperative complications, mid- and long-term survival, and length of hospital stay of AAA patients following EVAR. Therefore, further supplementation and improvement of relevant studies are required. We comprehensively investigated the prognostic value of SIMs, while to the best of our knowledge, this is the first study that assessed the relationship between HRR and long-term survival after EVAR.

NLR represents a chronic, mild systemic inflammatory response, often accompanied by elevated levels of proinflammatory cytokines. This reaction enables the body to respond to inflammatory stimuli, activating inflammatory cells within the plaque and leading to a catastrophic cascade. Conversely, chronic inflammation appears to be significantly involved in the development of AAA [43]. Inflammatory cells, such as neutrophils, can generate oxygen-derived free radicals that can trigger apoptosis and induce phenotypic alterations in vascular smooth muscle cells. This process eventually results in a partial decline in the production and repair capability of the vascular matrix [44]. In addition, proteases secreted by inflammatory cells such as neutrophils might result in the fragmentation of microfibrils inside the matrix, ultimately causing a reduction in the elasticity of the cell wall [45]. When the extracellular matrix (ECM) structure is destroyed and the media loses its elasticity, soluble blood components, including various inflammatory cells, can move and build up in the media through the highly vascularized adventitia. This, combined with platelet aggregation and coagulation system activation, encourages the development of luminal thrombosis. As a result, the aorta dilates and becomes more susceptible to rupturing in cases of AAA [46]. On the other hand, the development of atherothrombosis relies on the systemic chronic inflammatory response. The high neutrophil count is positively associated with the risk of plaque rupturing [47, 48] and increases the risk of microcirculation thrombosis [49]. Monocytes also play a role in initiating and promoting atherosclerosis, and their counts have been described as predictors of cardiovascular diseases (CVD) mortality, independent of other classical risk factors [50, 51]. Lymphopenia is an immunosuppressive and adverse physiologically stressful state that is associated with poor outcomes [52, 53]. Therefore, a rise in NLR may be linked to a high incidence of cardiovascular and cerebrovascular events, as supported by our subgroup analysis findings, which indicate that patients with a high NLR value had more cardiovascular and cerebrovascular deaths. Moreover, while NLR does not independently predict the postoperative prognosis of AAA, its predictive performance is relatively better than that of novel SIMs, such as PLR, SII, and SIRI. This may be attributed to the stability of NLR levels over time, as reported by Wang et al. [54]. In five contemporary randomized trials, Adamstein et al. [15] found that NLR levels remained stable over time among patients assigned to the placebo, and this consistency over time provides a clinical rationale for their use as a simple and reliable measure for follow-up. The study has also shown that medication interventions such as aspirin and statins may regulate NLR by reducing the inflammatory response through pleiotropic effects [15]. Patients with high preoperative NLR should be closely monitored for the development of cardiovascular and cerebrovascular events during the perioperative period and in the long term. Additionally, assessing the need for prolonged administration of lipid-lowering and antiplatelet medications for preventive purposes is important.

Lower hemoglobin is a crucial marker of potential inflammatory states and is associated with poor prognosis in several diseases [55]. In studies of AAAs, lower hemoglobin concentration is independently associated with higher probabilities of 30-day death, more in-hospital adverse outcomes, and reduced long-term survival after EVAR [56, 57]. Meanwhile, red cell distribution width (RDW) can reflect the underlying inflammatory state and is associated with adverse cardiovascular disease outcomes [58, 59]. Förhécz et al. [60] conducted a retrospective cohort study involving 195 patients diagnosed with chronic heart failure. The findings revealed a significant correlation between RDW and inflammatory markers, including C-reactive protein and other soluble cytokines [60]. A higher preoperative RDW level is linearly and high-risk associated with 5-year survival after EVAR [23]. The reason may be that inflammatory factors promote the formation of lysophosphatidylcholine in systemic inflammation, and increased phosphatidylserine exposure leads to lipid remodeling of the erythrocyte membrane, thereby impacting the function and longevity of erythrocytes. Inflammation accelerates the clearance of red blood cells (RBCs) by activating macrophages, reducing the life span of RBCs, and decreasing hemoglobin levels. An increase in RDW may reflect an elevation in the number of nonfunctional RBCs or the destruction of healthy cells [61, 62, 63]. The decrease in hemoglobin (Hb) represents the impaired oxygen-carrying function, while the rise in RDW reflects the negative effect of inflammation and other causes on the erythroid function of the bone marrow [41]. The HRR, calculated by Hb/RDW, reflects the superposition of these phenomena and has a broader range of applications. A meta-analysis reported the advantage of combining RDW with Hb for cardiovascular disease prognostic ratios, indicating that HRR is a highly effective strategy for predicting cardiovascular disease outcomes [64]. In addition, Qu et al. [65] analyzed 233 elderly patients with coronary heart disease (CHD) and found that HRR was a stronger predictor of frailty compared to hemoglobin or RDW; moreover, frailty was identified as a significant indication of prognostic factors for AAA. However, this measure has only been studied in a particular fraction of cancer and cardiovascular disease instances [66, 67, 68]. There is a lack of data on HRR in patients undergoing endovascular repair of AAAs. This is the first study to include HRR in the prognosis analysis of AAA, and it shows that decreased HRR indicates increased death after AAA surgery and can be used as an independent risk factor for long-term death. Subgroup analysis showed that cardiovascular and cerebrovascular mortality was more obviously increased in the lower-HRR group. Thus, the Hb/RDW ratio is a simple and practical prediction tool that can help clinicians estimate the risk stratification of EVAR patients.

Caution should still be exercised when considering using novel SIMs as a surgical consideration for AAA, as our studies have several limitations. First, as a single-center retrospective observational study, this study is limited by its relatively small sample size, leaving certain confounding factors unmeasured. Secondly, only preoperative whole blood cell counts were collected and used to calculate the SIMs, and there were no relevant data regarding the follow-up. Therefore, it is hard to study the impact of the variation in these SIMs, while their stability may also be uncertain. In previous studies, the cut-off values of inflammatory indicators in each system exhibited significant variation. There is a lack of consensus on the best threshold and the degree of association with various outcomes. Thirdly, the relevant pathophysiological mechanisms remain uncertain. Lastly, it should be emphasized that these SIMs have been reported to be associated with other types of cardiovascular diseases. Moreover, the use of SIMs as predictive markers for AAA patients has potential overlap and can make it be complicated by the fact that they can also be present in other types of aortic disease, such as thoracic aortic aneurysm, aortic dissection-renal aneurysm, and splenic aneurysm. These issues may hinder the clinical application of SIMs. Therefore, SIMs require additional comprehensive and carefully designed multicenter investigations with large sample sizes to validate these findings since they have the potential to serve as a valuable clinical tool for categorizing the risk of EVAR patients.

High preoperative NLR and low preoperative HRR indicate a decreased long-term survival rate of patients with an AAA after elective EVAR. HRR was identified as an independent risk factor for postoperative prognosis following elective EVAR via multivariate Cox regression. Patients whose HRR is below 10.64 should have perioperative and long-term cardiovascular and cerebrovascular events closely monitored, and the extension of anti-lipid and anti-platelet drug therapies should be considered necessary. However, further comprehensive and meticulously planned multicenter investigations are required to confirm these findings due to the existing limitations.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

YL, YJL designed the research study and provided help and advice all the time. WXZ, NZ collected the data. ZYW, YPD analyzed the data. WXZ, ZYW wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was approved by the Ethics Committee of Beijing Hospital. The ethical approval opinion number was 2023BJYEC-128-01. The clinical trial poses little risk to the subjects and has been reviewed and approved by the ethics committee after being exempt from informed consent of the subjects.

We would like to thank the Department of Vascular Surgery, Beijing Hospital, National Center for Geriatrics for the great support of successful collection of relevant materials. We would like to express our sincere appreciation to all the doctors and nurses in the vascular surgery department of Beijing Hospital for their efforts in the treatment process.

This research was funded by the National High Level Hospital Clinical Research Funding (No. BJ-2021-205); the National Key Research and Development Project of China (No. 2020YFC2008003); the Beijing Hospital Clinical Research 121 Project (No. BJ-2018-089); CAMS Innovation Fund for Medical Sciences (CIFMS. 2021-I2M-1-050); PUMC Discipline Construction Project (No. 201920102101).

The authors declare no conflict of interest.