Aortic dissection (AD) results from the interplay between structural abnormalities of the aortic media and hemodynamic disturbances. When the aortic intima is disrupted, hemodynamic forces drive blood into the medial layer, separating the intima and media. The Stanford classification system categorizes these events based on anatomical involvement: Type A aortic dissections (TAAD) affect the ascending aorta, while Type B aortic dissections (TABD) involve the descending thoracic aorta and distal segments, sparing the ascending aorta (1). Epidemiological data indicate an incidence of 2.8–6.0 cases per 100,000 population per year (2). TAAD represents the most common and life-threatening variant of AD. Its mortality exceeds 50% within 24 h of onset and increases by 1%–2% each subsequent hour. Despite surgical intervention, postoperative mortality remains 10%–30% (3, 4). Therefore, prompt and accurate diagnosis and appropriate treatment are crucial.

Inflammatory responses significantly contribute to AD pathogenesis (5). Histopathological studies show macrophage infiltration and increased matrix metalloproteinase (MMP) activity in the aortic wall of AD patients, with MMP-12 identified as a marker of aortic wall disease irrespective of genetic predisposition (6). The neutrophil-to-lymphocyte ratio (NLR) is an accessible marker of systemic inflammation and may predict disease severity and outcomes in cardiovascular conditions (7). Ustaalioglu et al. reported a strong association between elevated NLR and mortality in AD (8), whereas Donmez et al. found higher NLR in both deceased and surviving patients without statistical significance (9). Hung et al.'s 2021 meta-analysis of four TAAD studies identified preoperative NLR as a predictor of in-hospital mortality after surgury (10).

Based on these findings, a meta-analysis evaluating the prognostic significance of NLR in AD patients was conducted. This study aims to synthesize recent evidence to assess NLR's prognostic value, improve risk stratification, and inform individualized intervention strategies, and to propose perspectives on translating inflammatory mechanisms into clinical application for AD patients.

Substantial evidence indicates that AD is closely related to inflammation (24). Although AD is regarded as a multifactorial disease, inflammatory mechanisms is associated with aortic medial degeneration (25). Histopathological examination has revealed marked macrophage and T lymphocyte infiltration and increased expression of apoptosis-related protein. Cifani et al. further elucidated that macrophage recruitment and activation in the aortic wall are early events in Stanford-A AAD; macrophages release proinflammatory cytokines and MMPs that promote matrix degradation and neoangiogenesis (6). Serum inflammatory markers levels may reflect disease severity. Beyond tissue-level inflammation, elevated circulating inflammatory markers are independent predictors of various cardiovascular conditions (26).

The prognostic utility of NLR extends beyond aortic dissection to other acute and chronic vascular conditions. Taurino et al. demonstrated that a preoperative NLR >5 was a strong independent predictor of 30-day amputation (OR: 9.65) and mortality (OR: 9.88) in patients with acute limb ischemia (27). Similarly, Sirignano et al. recently reported that an elevated NLR (>5) was associated with worse long-term limb salvage rates following popliteal artery aneurysm repair, with multivariable analysis identifying NLR as an independent predictor of freedom from major amputation (28). These consistent findings across vascular pathologies reinforce NLR's role as a marker of systemic inflammatory burden in vascular diseases.

Our investigation, by synthesizing available evidence, suggests that elevated NLRs may be associated with heightened mortality risk following surgical intervention in AD patients. Sensitivity analysis confirmed the result's stability, indicating it was not dependent on any single study. However, the observed publication bias may undermine the reliability of our findings. This bias might stem from various factors including geographic region, sample size, and demographic characteristics, necessitating additional investigation for confirmation. A meta-analysis by Chung et al. (10), encompassing four studies and 502 TAAD patients, found that NLR was substantially increased both in those with TAAD and especially in patients who succumbed after surgery. Their findings supported the use of NLR as a practical prognostic tool for in-hospital mortality following TAAD surgery. Recent literature further supports the prognostic capacity of NLR for mortality risk across both TAAD and TBAD (8, 11), which is similar to our results. Therefore, NLR should be monitored for clinical risk stratification and early identification of high-risk patients to permit timely intervention.

Publication bias was evident in our analysis. To address this limitation, subgroup analyses were performed to examine the association between elevated NLR and mortality in AD. The subgroup results showed a significant association in cohort studies (P = 0.0005), whereas no significant relationship was found in case-control studies (P = 0.28). Cohort studies generally provide higher-quality evidence than case-control studies because exposures are measured before outcomes, establishing temporality and facilitating control of confounding; incidence and other measures can also be directly estimated. In contrast, case-control studies are retrospective and are more susceptible to recall and selection biases and cannot directly calculate incidence. When results conflict, evidence from cohort studies should therefore be prioritized. Analyses of large samples were non-significant results while smaller studies showed significant association, suggesting possible small-study effects. Only three included studies had sample sizes ≥ 200, which may have produced weight imbalance and increased heterogeneity. Therefore, future research incorporating larger cohorts will be essential to confirm NLR's predictive utility.

A methodological distinction was revealed by our subgroup analysis: the association between elevated NLR and mortality was significant in cohort studies (P = 0.0005) but not in case-control studies (P = 0.28). This discrepancy is plausible and reflects the higher evidentiary strength of cohort designs in prognostic research. Cohort studies, through prospective or longitudinal follow-up, establish temporal sequence—exposure (high NLR) precedes outcome (mortality)—which is fundamental for causal inference and are less susceptible to selection and recall biases than retrospective case-control designs. In case-control studies, in which patients are selected by outcome and prior NLR is assessed, NLR measurement may be affected by post-outcome conditions or biased control selection. Therefore, cohort evidence should be weighted more heavily. Our conclusion that NLR predicts mortality in AD is supported by the more methodologically rigorous cohort studies included in this meta-analysis.

Inflammation processes are central to the development and progression of acute cardiovascular events. Neutrophils, in particular, function as primary mediators in vascular injury and subsequent inflammatory cascades. They rapidly migrate to sites of tissue damage, establishing the initial defensive barrier in inflammatory responses (29). They remove pathogens and cellular debris via phagocytosis and by releasing proteolytic enzymes and reactive oxygen species. When excessive, these mediators cause collateral tissue injury, worsening disease severity and contributing to AD complications (30). This is consistent with findings that neutrophil-derived MMP-9 can trigger acute aortic dissection (6). This functional duality of neutrophils holds considerable significance in understanding AD pathophysiology. Elevated neutrophil counts in AD patients suggest active inflammatory involvement and may correlate with disease severity. Consequently, the NLR emerges as an effective parameter reflecting inflammatory burden.

Lymphocytes are essential components of adaptive immunity, providing protection against viral and bacterial pathogens (31). During severe vascular events such as AD, lymphocytes contribute to immune regulation and tissue repair. Lymphocytes undergo antigen-specific proliferation, generating specialized immune responses that modulate inflammation. T lymphocytes exert anti-inflammatory and tissue-protective effects, while B lymphocytes produce antibodies that neutralize pathogens (32). Lymphocyte functionality significantly influences AD progression and outcomes. Lymphopenia typically indicates immunosuppression in severe infection or systemic inflammation. Thus, elevated NLR, reflecting neutrophilia and lymphopenia, provides an objective measure of inflammatory severity and tissue stress. Increased NLR in AD patients indicates this immunological imbalance and is associated with higher mortality, supporting NLR's potential utility in clinical risk stratification, which warrants future investigation.

Significant publication bias was identified, particularly among smaller studies, which also showed larger effect estimates. This pattern suggests that the pooled effect might be inflated due to preferential publication of positive findings from underpowered studies. However, several factors support the robustness of our primary conclusion. First, the leave-one-out sensitivity analysis confirmed that no single study disproportionately influenced the pooled estimate. Second, the significant association persisted in subgroup analyses of cohort studies—a design generally less susceptible to recall and selection biases. Third, the biological plausibility of NLR as a marker of systemic inflammation is well-established in cardiovascular pathophysiology. Nevertheless, the influence of small-study effects cannot be fully excluded, and the observed OR should be interpreted as potentially representing the upper bound of the true effect size. Future well-powered prospective studies are needed to provide a more precise estimate.

Several limitations of this meta-analysis should be noted. First, all included investigations were conducted in Asia, predominantly Turkey and China, limiting generalizability to other regions. Second, most studies had small sample sizes, with limited large-scale experimental data. Third, substantial heterogeneity in NLR cut-off values (ranging from 4.1 to 20.22) was observed, which hinders direct clinical application of a specific NLR value. An exploratory subgroup analysis by cut-off value could not be meaningfully performed because only 4 out of 12 comparative groups reported specific thresholds. Without individual patient data, harmonization of NLR values or derivation of a unified cut-off was not feasible. Additionally, publication bias was evident and may have favored studies with significant findings or those aligning with prevailing hypotheses, thus failing to comprehensively represent the research landscape. Future investigations require expanded datasets to enhance robustness and address heterogeneity in these findings.

Furthermore, it is crucial to recognize the potential impact of regional variations in clinical practice patterns on AD management. Our analysis included studies conducted only in Turkey and China, and differences in healthcare systems, surgical expertise, timing of intervention, postoperative care protocols, and availability of advanced therapies between these and other regions may influence patient outcomes independently of the NLR. While NLR, as a measure of systemic inflammation, is likely to retain its fundamental prognostic value across settings, the specific risk thresholds and the magnitude of its effect could be modulated by these external factors. For instance, a healthcare setting with rapid access to specialized care might mitigate the risk associated with a high NLR, thereby altering its predictive performance. Therefore, the generalizability of our findings to populations in Europe, North America, or other regions should be approached with caution. Future research should not only validate NLR's utility in multi-ethnic cohorts but also seek to understand how it integrates into specific clinical pathways and healthcare contexts to ensure its effective implementation.

Our results suggest an association between higher NLR and elevated mortality risk in individuals with aortic dissection, with both subgroup and sensitivity analyses supporting the robustness of this relationship. Despite the observed publication bias and potential overestimation in smaller studies, the consistency of NLR's prognostic value across multiple study designs and its biological plausibility strengthen its candidacy as a useful clinical biomarker. The consistency of NLR's prognostic value across aortic dissection, acute limb ischemia, and popliteal artery aneurysm repair underscores its utility as a general inflammatory biomarker in vascular diseases. However, considering this study's limitations—including restricted sample sizes and predominant focus on Asian populations—additional international, multicenter prospective clinical trials are warranted to further validate the relationship between NLR and AD mortality, to determine optimal patient populations, and to establish precise parameters for clinical implementation.