Acute myocardial infarction (AMI) remains a leading cause of global cardiovascular mortality and morbidity, posing a major public health challenge (1). Significant advances in reperfusion therapies, such as percutaneous coronary intervention and thrombolysis, alongside improved pharmacological management, have markedly reduced acute-phase mortality in recent years (2). However, the risk of subsequent major adverse cardiovascular events (MACE), including post-infarction heart failure, remains unacceptably high (3). Although dual antiplatelet therapy (DAPT) with varying treatment durations is currently widely recommended in clinical practice due to its lower risk of adverse events, this regimen still carries the drawback of increasing bleeding risks, which can severely impact patients' long-term prognosis and quality of life (4). Consequently, elucidating the underlying mechanisms of AMI onset and progression, and identifying novel targets for effective risk prediction and intervention, continue to be central focuses in cardiovascular research.

Inflammation contributes significantly to coronary artery disease (CAD) (5). In recent years, growing interest has been directed toward understanding the critical role of inflammation in the development and progression of cardiovascular diseases (CVDs), including atherosclerosis, myocardial infarction, heart failure, and pericarditis (6). Multiple studies have found that reducing inflammation levels may have beneficial effects in patients at high risk of CVDs by using anti-inflammatory drugs, supporting intervention through inflammatory pathways as an effective strategy for secondary prevention of CVDs (7). Excessive or dysregulated inflammation can exacerbate myocardial injury and promote maladaptive ventricular remodeling, thereby driving disease progression (8). Against this backdrop, biomarkers capable of precisely quantifying the systemic inflammatory status, such as the Systemic Inflammation Response Index (SIRI), have attracted growing interest. As a novel composite inflammatory index, SIRI integrates neutrophil, monocyte, and lymphocyte counts, offering a more comprehensive reflection of the body's inflammatory-immune balance (9). Recent studies (10, 11) have revealed significant associations between SIRI and both the severity of coronary artery disease and the risk of major adverse cardiovascular events following myocardial infarction, highlighting its promising potential as a risk prediction tool.

However, the prognostic value of SIRI in specific myocardial infarction populations, as well as its advantages over traditional inflammatory markers, require further clarification through additional evidence. Therefore, this study aims to thoroughly investigate the association between SIRI and long-term clinical outcomes in patients with myocardial infarction. We anticipate that this work will contribute a novel and effective biomarker for risk stratification and prognosis assessment in myocardial infarction, while also providing a theoretical foundation for future precision treatment strategies targeting inflammatory pathways.

Cardiovascular diseases (CVDs) continue to be among the leading causes of mortality globally and are associated with substantial health burden and increased healthcare costs (26). Patients with established atherosclerotic cardiovascular disease (ASCVD) face a heightened risk of recurrent cardiovascular events, including myocardial infarction, stroke, and cardiovascular death. Over the past several decades, inflammation has emerged as a key contributor to this residual risk (27–29).

This meta-analysis indicates that an elevated Systemic Inflammation Response Index (SIRI) is moderately associated with an increased risk of major adverse cardiovascular events (MACE) (OR = 1.42), all-cause mortality (OR = 1.28), stroke (OR = 1.11), subsequent acute myocardial infarction (OR = 1.21), and higher coronary severity as measured by the Gensini score (OR = 6.89) in patients with myocardial infarction. Despite significant heterogeneity in some analyses, the findings were robust in sensitivity analyses. These results underscore the strong prognostic value of SIRI, a readily available biomarker derived from routine blood counts, for risk stratification in MI patients. The findings suggest that SIRI can help identify high-risk individuals who may benefit from more intensive monitoring and tailored management strategies, potentially including anti-inflammatory therapies, to improve long-term cardiovascular outcomes.

Based on the subgroup analysis data, the sources of heterogeneity in the association between SIRI and MACE can be partially elucidated. Significant heterogeneity was observed across studies, particularly when stratified by sample size and SIRI cut-off values. Studies with smaller sample sizes (<960) showed a higher pooled OR (1.86) and greater heterogeneity (I² = 95%), compared to larger studies (≥960) with a lower OR (1.25) and moderate heterogeneity (I² = 57%). Similarly, a higher SIRI cut-off (>2) was associated with a stronger effect estimate (OR = 1.85) and high heterogeneity (I² = 94%), whereas a lower cut-off (≤2) yielded a more moderate OR (1.40) with lower heterogeneity (I² = 75%). These variations suggest that differences in study size and SIRI threshold definitions are key contributors to heterogeneity, possibly due to differing patient characteristics, study designs, or outcome ascertainment methods across smaller or higher-threshold studies. In contrast, age-based subgroups showed consistent associations and similar heterogeneity levels, indicating that age may not be a major source of heterogeneity.

The association between an elevated SIRI and poor prognosis in myocardial infarction is underpinned by a complex inflammatory immunopathological process. A high SIRI, indicative of elevated neutrophil and monocyte counts, directly contributes to atherosclerotic plaque instability. Plaque rupture is facilitated through several key mechanisms: the release of neutrophil extracellular traps (NETs) (30, 31), the degradation of the fibrous cap by matrix metalloproteinases (MMPs, such as MMP-9), and the generation of reactive oxygen species (ROS) (32–34). Simultaneously, monocytes infiltrate the vascular wall, differentiate into macrophages, and phagocytose lipids to form foam cells, exacerbating local inflammation through the secretion of pro-inflammatory factors like TNF-α and IL-1β (35). Furthermore, revascularization (e.g., PCI) following MI induces reperfusion injury, and a high SIRI signifies a heightened inflammatory response that may aggravate this damage. These inflammatory cells also interact to promote a pro-thrombotic state, thereby increasing the risk of stent thrombosis and recurrent MI.

In summary, a high SIRI reflects a systemic inflammatory state dominated by neutrophil and monocyte activation, coupled with impaired lymphocyte-mediated immunoregulation. This state contributes to the poor prognosis of myocardial infarction through multiple parallel pathways, including the destruction of plaque stability, aggravation of reperfusion injury, interference with cardiac reparative remodeling, and the promotion of thrombosis. Although SIRI is not traditionally recognized as a diagnostic criterion for AMI, its strong association with the condition enables it to complement established risk stratification tools such as the Killip classification and the GRACE score. By integrating SIRI into clinical assessment, a more comprehensive evaluation of patient risk can be achieved, thereby moderately enhancing the predictive accuracy for mortality and major adverse cardiovascular events. Moreover, for patients with less obvious symptoms in clinical practice (such as Killip class I or intermediate-risk in GRACE score), SIRI demonstrates added value in identifying individuals at higher risk, facilitating earlier and more intensive therapeutic interventions.

While this meta-analysis provides comprehensive evidence supporting the prognostic value of SIRI in patients with myocardial infarction, several important limitations should be acknowledged and considered when interpreting the results.

First, the geographic and ethnic representation of the included studies is narrow. The vast majority were conducted in Chinese populations, with only three comparative groups from other regions (the USA and Italy). This predominance limits the generalizability of our findings to other ethnicities and healthcare settings, where genetic backgrounds, inflammatory profiles, and clinical management may differ substantially. Second, we observed substantial statistical heterogeneity in several meta-analyses, particularly for MACE (I² = 90%) and the Gensini score (I² = 97%). Although subgroup analyses were performed—suggesting that sample size and SIRI cut-off values may partly explain the variability—significant residual heterogeneity persists. Therefore, future studies based on more consistent SIRI thresholds and prospective designs would help reduce such heterogeneity, thereby providing more precise and generalizable evidence for risk assessment. Third, the definitions of the primary outcome, MACE, varied meaningfully across studies in terms of included components (e.g., whether heart failure, revascularization, or arrhythmias were consistently incorporated). This variability introduces potential outcome misclassification and heterogeneity, which could not be fully explored through subgroup analysis due to insufficient reporting in the original articles. We have therefore emphasized this as an important source of clinical and methodological heterogeneity. Fourth, the SIRI cut-off values used to define “high” vs. “low” SIRI groups differed widely across studies (ranging from 0.13 to 7.8), and no standardized or consensus-based threshold currently exists. Although we respected each study's original cut-off in our analysis, this variability complicates clinical interpretation and translation, representing a major barrier to the implementation of SIRI in routine practice. Fifth, all included studies were observational in design. While they consistently report an association between elevated SIRI and worse outcomes, residual confounding cannot be excluded, and causality cannot be inferred. Furthermore, for the MACE outcome, Egger's test indicated potential publication bias (p = 0.0001), suggesting that smaller studies with null results might be underrepresented. Although sensitivity analyses supported the robustness of the findings, the possibility of bias warrants a more cautious interpretation of the strength of association.

Finally, while SIRI emerges as a promising prognostic marker, current evidence does not yet support its use as a validated tool for guiding clinical decisions. Future studies—especially prospective, multi-ethnic cohorts with standardized SIRI thresholds and outcome definitions—are needed to confirm these findings and assess the clinical utility of SIRI in risk stratification and tailoring of management.

In conclusion, this systematic review and meta-analysis demonstrates that an elevated Systemic Inflammation Response Index (SIRI) is moderately and consistently associated with an increased risk of adverse clinical outcomes in patients with myocardial infarction, including major adverse cardiovascular events, all-cause mortality, stroke, subsequent AMI, and greater coronary artery disease severity. These findings underscore the robust prognostic value of SIRI, a readily accessible and cost-effective inflammatory biomarker derived from routine blood counts. The findings indicate that SIRI may be a useful tool for risk stratification, helping to identify MI patients at higher risk who could benefit from closer monitoring and individualized management strategies. Future studies should explore establishing standardized SIRI cut-off values and investigating whether SIRI can guide targeted anti-inflammatory therapies to ultimately improve long-term cardiovascular prognosis.