Prognostic impact of systemic inflammatory response index in patients with myocardial infarction with non-obstructive coronary arteries

To the Editor: Ischemic heart disease (IHD) remains a major contributor to global mortality, with acute myocardial infarction (AMI) posing a significant public health issue. Although the majority of AMI cases involve obstructive coronary artery disease (MI-CAD), approximately 5–10% of patients present with myocardial infarction with non-obstructive coronary arteries (MINOCA).[1] While percutaneous coronary intervention is effective for MI-CAD, patients with MINOCA, despite the lack of significant stenosis in major coronary vessels, often experience outcomes as poor as, or worse than, those of MI-CAD patients due to inadequate treatment approaches. MINOCA tends to occur more frequently in younger female patients with fewer conventional risk factors, suggesting distinct pathophysiological mechanisms compared to MI-CAD.[1] The primary causes of MINOCA include plaque disruption, coronary artery spasm (CAS), and coronary microvascular dysfunction (CMVD), with inflammation playing a key role.[2] Recent studies have identified a connection between inflammation markers, such as C-reactive protein and the neutrophil-to-lymphocyte ratio (NLR), and worse outcomes in MINOCA patients.[3,4] The systemic inflammatory response index (SIRI) is an emerging, readily available biomarker that integrates neutrophils, lymphocytes, and monocytes. SIRI has shown significant associations with cardiovascular events, occasionally outperforming the NLR.[5] However, its prognostic relevance in MINOCA patients remains unclear. Identifying biomarkers with prognostic value is essential for improving understanding of disease mechanisms and facilitating early risk assessment, which could improve patient management and outcomes. Therefore, we conducted a prospective observational study to assess the correlation between admission SIRI levels and long-term adverse outcomes in MINOCA patients. The study was approved by the Ethics Committee of Fuwai Hospital, Chinese Academy of Medical Sciences (Approval No.: 2024-2293), and written informed consent was obtained from all participants. A total of 23,460 patients hospitalized for AMI between January 2015 and December 2019 were included in the study, encompassing both ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction cases. MINOCA was defined in accordance with the 4th universal definition of myocardial infarction (MI), excluding patients with significant epicardial coronary artery stenosis (>50%).[2] Exclusion criteria comprised MI-CAD (n = 21,696), prior revascularization (n = 312), thrombolytic therapy for STEMI (n = 126), and conditions such as myocarditis, heart failure (HF), takotsubo syndrome, pulmonary embolism, or sepsis (n = 46). Additionally, patients with incomplete baseline data (n = 33) or those lost to follow-up (n = 68) were excluded, leaving 1179 MINOCA patients for analysis [Supplementary Figure 1, https://links.lww.com/CM9/C362]. All patients received optimal medical treatment during hospitalization, including dual antiplatelet therapy, statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and β-blockers. Data on demographics, medical history, laboratory results, echocardiography, and medications were gathered through consultations and medical records. SIRI was calculated using the formula: SIRI = neutrophil count × monocyte count/lymphocyte count. Body mass index (BMI) was calculated as weight (kg) divided by height (m2). Hemoglobin A1c (HbA1c), fasting blood glucose (FBG), lipids, creatinine, and high-sensitive C-reactive protein (hsCRP) were measured using automated analyzers, based on samples collected after 12 h of fasting within 48 h of admission. N-terminal pro-B-type natriuretic peptide (NT-proBNP) and peak cardiac troponin I (cTnI) levels were recorded. Left ventricular ejection fraction (LVEF) was measured via echocardiography using the biplane Simpson method. Diabetes mellitus (DM) was defined as a known history or newly diagnosed DM with HbA1c ≥6.5%, FBG ≥7.0 mmol/L, or 2-h plasma glucose ≥11.1 mmol/L.[6] Hypertension was identified by repeated blood pressure measurements of ≥140/90 mmHg or the use of antihypertensive medications. Dyslipidemia was defined as a known history, low-density lipoprotein cholesterol ≥3.4 mmol/L, high-density lipoprotein cholesterol <1.0 mmol/L, or triglycerides ≥1.7 mmol/L.[7] The primary outcome measure was major adverse cardiovascular events (MACE), which included death, non-fatal MI, stroke, revascularization, and hospitalization due to unstable angina (UA) or HF. Secondary outcomes consisted of the individual components of MACE and a composite hard endpoint of death, MI, stroke, and revascularization. Re-infarction was defined according to the 4th universal definition of MI, while stroke was described as neurological impairment due to cerebral ischemia or hemorrhage. Revascularization procedures were conducted at the operator’s discretion. UA was identified by ischemic chest pain at rest or recent worsening without significant changes in cTnI levels. HF was diagnosed based on symptoms such as dyspnea or edema, elevated NT-proBNP, and impaired cardiac function. Patients were followed up every six months through direct clinic interviews or telephone consultations by a team of independent, well-trained researchers who were unaware of the study’s objectives and were not involved in the patients’ care. All endpoints were verified and confirmed by at least two professional cardiologists who were also blinded to the study data. Continuous variables were assessed for normality and presented as mean ± standard deviation or median with interquartile range. Group comparisons were performed using either analysis of variance (ANOVA) or Kruskal–Wallis H tests, while categorical variables were compared using Pearson’s χ2 or Fisher’s exact tests. Event rates were analyzed using Kaplan–Meier curves and log-rank tests. Cox proportional hazards models were employed to examine the relationship between SIRI and outcomes, while restricted cubic splines were used to assess potential non-linear associations between SIRI and MACE. The predictive value of SIRI was evaluated through receiver operator characteristic curve (ROC) analysis, with the area under the curve (AUC) values categorized as small (0.56–0.63), moderate (0.64–0.70), or strong (≥0.71). Comparisons between AUC values were made using DeLong’s test. Statistical significance was defined as P <0.05. Data analysis was conducted using SPSS Statistics (version 22.0; IBM Corp., Chicago, IL, USA), with plots generated via R version 4.4.1 (R Foundation, Vienna, Austria). Patients were divided into two groups based on a median SIRI value of 1.05, with one group having higher SIRI levels and the other lower. As shown in Supplementary Table 1, https://links.lww.com/CM9/C362, patients in the higher SIRI group tended to be older, predominantly male, and exhibited lower LVEF, higher heart rates, and more advanced Killip classes. Their blood tests revealed elevated neutrophil and monocyte counts, reduced lymphocyte counts, and increased levels of hsCRP, creatinine, FBG, peak cTnI, and NT-proBNP. However, there were no significant differences between the two groups in terms of BMI, blood pressure, lipid levels, or histories of hypertension, DM, or dyslipidemia, as well as no differences in in-hospital medications. Despite having similar traditional risk factors, the higher SIRI group displayed a more severe clinical condition. During a median follow-up of 41.7 months, 168 patients experienced MACE. The incidence of MACE was significantly higher in the elevated SIRI group (18.4% vs. 10.0%, P <0.001), as was the composite hard endpoint (11.8% vs. 5.4%, P <0.001). Additionally, the higher SIRI group had increased risks of death, MI, revascularization, and hospitalization for HF [Supplementary Table 2, https://links.lww.com/CM9/C362]. Kaplan–Meier curves illustrated a higher cumulative incidence of both MACE and the composite hard endpoint in the higher SIRI group [Figure 1].Figure 1: Incidence of the composite event among MINOCA patients with lower or higher SIRI. Kaplan–Meier curves showing the cumulative incidence of MACE (A) and the composite hard endpoint of death, non-fatal MI, stroke, or revascularization (B). CI: Confidence interval; HR: Hazard ratio; MACE: Major adverse cardiovascular events; MI: Myocardial infarction; MINOCA: Myocardial infarction with non-obstructive coronary arteries; SIRI: Systemic inflammatory response index.Multivariate Cox regression analysis identified SIRI as a significant predictor of MACE, both as a continuous variable (hazard ratio [HR]: 1.17, 95% confidence interval [CI]: 1.04–1.31, P = 0.007) and as a categorical variable (HR: 1.84, 95% CI: 1.34–2.54, P <0.001) [Supplementary Table 3, https://links.lww.com/CM9/C362]. Elevated SIRI consistently emerged as a strong predictor of MACE across the entire cohort (unadjusted HR: 1.92, 95% CI: 1.40–2.64, P <0.001) and across various subgroups defined by gender, age, BMI, MI type, hypertension, diabetes, dyslipidemia, and cTnI levels (all P <0.05) [Supplementary Figure 2, https://links.lww.com/CM9/C362]. Restricted cubic splines were employed to further investigate the relationship between SIRI and MACE [Supplementary Figure 3, https://links.lww.com/CM9/C362], revealing a non-linear association (P for non-linear = 0.027). SIRI showed a positive correlation with MACE when it was ≤2.6 (HR: 1.56, 95% CI: 1.18–2.05, P = 0.002). However, when SIRI exceeded 2.6, no significant association was observed between SIRI and MACE. Importantly, only 8.1% of MINOCA patients in the cohort had SIRI values greater than 2.6, suggesting that the positive relationship between SIRI and MACE holds across the majority of the patient population. The ROC curve analysis demonstrated that SIRI had a moderate predictive value for MACE, with an AUC of 0.64 (95% CI: 0.62–0.67, P <0.001). In comparison, the AUCs for hsCRP and NLR in predicting MACE were 0.56 (95% CI: 0.53–0.59, P = 0.019) and 0.60 (95% CI: 0.57–0.63, P <0.001), respectively. The DeLong test confirmed that SIRI significantly outperformed both hsCRP (ΔAUC = 0.09, P = 0.002) and NLR (ΔAUC = 0.04, P = 0.003) in predicting MACE [Supplementary Figure 4, https://links.lww.com/CM9/C362]. Inflammation plays a key role in both atherosclerosis and microvascular dysfunction, which are essential factors in MINOCA. Advanced imaging methods, such as optical coherence tomography (OCT) and cardiac magnetic resonance (CMR), are providing insights into the pathogenesis of MINOCA, showing that over half of the cases may involve atherosclerosis, with plaque erosion being a frequent cause.[8] CAS also plays a crucial role. Inflammation, oxidative stress, and smooth muscle contraction contribute to CAS,[9] while CMVD is linked to oxidative stress and inflammatory processes.[10] These mechanisms often overlap, with inflammation potentially worsening both plaque disruption and microvascular dysfunction, leading to poor outcomes in MINOCA patients. Anti-inflammatory therapy has demonstrated the potential in reducing cardiovascular events in recent AMI cases, as shown in the CANTOS and COLCOT trials. However, its effectiveness in MINOCA remains unexplored, despite inflammation likely being a central factor in this condition. Given the connection between elevated SIRI and worse outcomes in MINOCA patients, further research is needed to determine whether anti-inflammatory treatments could improve prognosis in this group of patients with increased systemic inflammation. This study has several limitations. First, as an observational study, it faces challenges in fully addressing potential confounding factors, despite adjustments being made for many variables. Second, the single-center design may introduce selection bias, which could limit the generalizability of our findings. Third, only a small proportion of patients had their underlying mechanisms investigated using OCT and CMR. Lastly, we only assessed baseline SIRI levels at admission without considering changes in inflammatory activity over time. In conclusion, elevated SIRI is strongly linked to poor prognosis in MINOCA patients. As an inflammation marker, SIRI holds promise for identifying high-risk individuals early and could potentially guide anti-inflammatory therapy for these patients.