Summary
Despite extensive research there is still no consensus on an optimal biomarker of long-term left ventricular function in patients after myocardial infarction. Neutrophil-to-lymphocyte ratio, a marker of immunological imbalance, emerges as a promising biomarker of poorer outcome in patients after myocardial infarction. In the present analysis a higher ratio was associated with greater all-cause mortality and inferior left ventricle function in a long-term observation. The ease of implementation and low cost of this measurement make it attractive for everyday clinical practice and risk stratification of patients after myocardial infarction.
Introduction
Myocardial infarction (MI) is a complex cardiovascular condition with significant implications for both short-term prognosis and long-term clinical outcomes [1–5]. Its pathophysiology involves a complex interplay of atherosclerosis, thrombosis, and myocardial ischemia, often leading to adverse cardiac remodeling, heart failure, and increased early mortality risk. All these factors, along with the presence of comorbidities, particularly in aging populations, contribute to the poor and often uncertain prognosis of MI survivors over time. Nevertheless, advances in early revascularization strategies, intensive cardiac care, and tailored pharmacotherapy have reduced early complications and mortality rates in these patients. However, despite significant progress in the treatment of ischemic heart disease, there remains a substantial need for improved MI management, particularly regarding long-term outcomes.
Inflammation is a key factor involved in the progression and outcomes of cardiovascular diseases [6]. It contributes to the development of atherosclerosis by promoting endothelial dysfunction, plaque formation, and destabilization, leading to acute coronary syndrome (ACS). In this setting, cardiac necrosis and subsequent degradation of cardiac extracellular matrix leads to an inflammatory response and sudden disruption of immune system homeostasis.
Among leukocytes, neutrophils are first-line responders of the immune system, and their rapid migration to the ischemic region triggers further inflammatory pathways that play key roles in ischemia, reperfusion injury, and post-MI heart failure [6–8]. In this context, both the neutrophil count alone and the ratio of neutrophils to total leukocytes, most importantly to lymphocytes, have been found to be independent predictors of cardiovascular outcomes in ACS patients. These measures correlate well with the severity and complexity of coronary artery disease (CAD), infarct size, decline in left ventricular ejection fraction (LVEF), recurrent ischemic events, and ultimately mortality rates [9–12].
To date, despite extensive research, only a few biomarkers are used in clinical practice as possible predictors of mortality, myocardial remodeling, and re-infarction, namely natriuretic peptides and enzymes of myocardial cell necrosis [13–16]. There is still no consensus on optimal biomarkers for risk stratification of MI patients in terms of short- and long-term prognosis. Gaining further insights into mechanisms linking inflammation to underlying cardiovascular pathophysiological processes remains essential for developing targeted therapeutic strategies to reduce the disease burden and improve patient outcomes.
Aim
The aim of the study was to assess neutrophil-to-lymphocyte ratio (NLR) as an easily accessible inflammation biomarker in patients hospitalized with acute MI and evaluate its predictive value for clinical and echocardiographic outcomes.
Material and methods
Study design
This analysis was based on a retrospective registry of patients hospitalized due to MI, treated in a single center between 2016 and 2019. It was an all-comers registry with the sole inclusion criterion being acute MI, including both ST-elevation and non-ST-elevation MI presentations. There were no exclusion criteria. Patients’ demographics, clinical characteristics, blood biochemistry and hematology parameters, angiographic and echocardiographic details, as well as clinical follow-up, were analyzed. Follow-up information was collected from available data from clinical and echocardiographic observations, routinely performed in patients after MI. Clinical follow-up included data about mortality and re-infarction. Reinfarction was defined as repeated hospital admission with diagnosis of MI, with an exclusion of peri-procedural MI. In follow-up echocardiographic examination, we set an outcome of long-term reduced LVEF, defined as a value < 40%. The primary clinical outcome was all-cause mortality. The study was approved by the institutional ethics committee, approval number: 1072.6120.130.2017.
Laboratory analysis and imaging assessment
The analysis was performed on available laboratory results and imaging data from echocardiographic studies. No specific time-points of these analyses were formally scheduled. However, blood morphology data with cardiac enzymes were typically collected during admission with repeated measurement of cardiac enzymes during the following days of hospitalization according to the local protocol. NLR was calculated as the ratio of neutrophil to lymphcoyte concentration in µl of peripheral blood. In cases where multiple measurements of blood morphology were taken, the one closest to hospital admission and onset of MI was used in the analysis. Transthoracic echocardiography was usually performed on the day of admission or during the first 3 days of hospital stay. The assessment included standard scans of long and short axis parasternal views with left ventricle internal diameter measurement and apical 2-, 3-, and 4-chamber views of the left ventricle with regional wall motion assessment and LVEF calculation by the Simpson bi-plane method.
Statistical analysis
Quantitative variables were summarized using mean with standard deviation for normally distributed data and median with first (Q1) and third (Q3) quartiles for non-normally distributed data. Categorical variables were presented as counts and representative percentages. The Shapiro-Wilk test was used to determine data normality. ROC analysis with area under the curve (AUC) calculation was used to assess the predictive value of NLR for all-cause mortality. An optimal cut-off value for this parameter was determined by analyzing the Youden index. A comparison of the study population in relation to NLR was performed. Student’s t-test was used to compare variables with normal distribution. The Mann-Whitney U test was applied for comparison of non-normally distributed data. Comparison of baseline and follow-up LVEF was performed using the Wilcoxon test. Statistical analysis of data expressed on a binary scale was performed using the χ2 test. The correlation between NLR and baseline LVEF was assessed using Spearman analysis. Survival in relation to NLR was assessed using the Kaplan-Meier method. Logistic regression analyses were used to identify the predictive value of NLR for mortality and reduced LVEF during long-term follow-up. Variables including demography, clinical characteristics, angiographic parameters and biomarker levels were considered by calculating simple models. Multiple models were constructed using stepwise technique. The statistical significance threshold was set at an α value of < 0.05. All statistical analyses were performed using IBM SPSS Statistics software, version 29.0 (IBM Corporation, Armonk, NY, USA).
Results
This registry included 412 patients hospitalized due to MI. Characteristics of the analyzed population are described in Table I. Most patients were male (65%), with typical cardiovascular risk factors including arterial hypertension (78%), diabetes mellitus (33%), smoking (43%), and previous MI (23%). The most frequent presentation was non-ST-elevation MI (63%). The majority of patients were treated with primary percutaneous coronary intervention (PCI, 85%). A small proportion of patients underwent coronary artery bypass grafting (2%). The remaining patients either did not have significant coronary obstruction in angiography or were treated conservatively. Results of peripheral blood morphology with smear for NLR calculation were available in 93 patients (23%). The median NLR was 4.3 (Q1: 2.6; Q3: 7.8). Table I also presents a comparison of patients’ characteristics in relation to higher (> 8.7) and lower NLR (≤ 8.7). Patients with higher NRL had significantly lower baseline LVEF, worse kidney function, and higher mortality during follow-up.
Table I
Characteristics of study population
[i] ACEI – angiotensin-converting enzyme inhibitor, ARB – angiotensin receptor blocker, CABG – coronary artery bypass grafting, GFR – glomerular filtration rate, LAD – left anterior descenging artery, LVEF – left ventricle ejection fraction, MI – myocardial infarction, NLR – neutrophil-to-lymphocyte ratio, PCI – percutaneous coronary intervention.
Clinical observation lasted a median of 32 months (Q1: 9; Q3: 66). Echocardiographic assessment was performed after a median of 24 months from baseline admission (Q1: 9, Q3: 55). During follow-up, we observed a significant improvement in LVEF from 40% at baseline (Q1: 25; Q3: 50) to 52% in the long-term observation (Q1: 40; Q3: 60; p < 0.001). Higher NLR was associated with poorer initial left ventricular function and correlated negatively with both baseline and follow-up LVEF (r = –0.214; p = 0.043 and r = –0.3; p < 0.001, respectively). In regression analysis, NLR was a significant predictor of long-term reduced EF (OR = 4.01; p < 0.001). Other significant covariates included patient age, baseline LVEF, and renal function (Table II).
Table II
Regression analysis of predictors of reduced ejection fraction during long-term observation
All-cause mortality was 14% during long-term follow-up observation. In regression analysis, NLR was a significant predictor of mortality (OR = 1.16; p = 0.008). Other significant predictive factors included patient’s age, presence of diabetes mellitus, baseline LVEF, and renal function. However, in a multiple model only NLR remained a significant predictor (Table III). In ROC analysis NLR demonstrated significant predictive value for all-cause long-term mortality (AUC = 0.65, p = 0.04) (Figure 1). After analyzing the Youden index, we established an optimal cut-off value of 8.7 for NLR for predicting mortality in ROC analysis (Youden index = 0.4, sensitivity = 0.5 and specificity = 0.88). In Kaplan-Meier survival analysis, patients with NLR > 8.7 had significantly poorer survival compared to those with lower ratios (Figure 2).
Figure 1
ROC analysis of neutrophil-to-lymphocyte ratio as a predictor of long-term all-cause mortality
ROC – receiver operating characteristic, AUC – area under the curve.
Figure 2
Kaplan-Meier survival analysis stratified by neutrophil-to-lymphocyte ratio
NLR – neutrophil-to-lymphycyte ratio.
Table III
Regression analysis of predictors of all-cause mortality
Discussion
The results from the present study support current evidence that NLR is associated with poorer left ventricular function and higher mortality in patients after MI in long-term observation. Furthermore, NLR was found to be an independent predictor of worse left ventricular function both at baseline and during long-term follow-up, highlighting its possible role as a biomarker for the risk stratification of MI.
The population in our study was similar to those reported in previous publications in terms of clinical and demographic characteristics of MI patients [9–12]. NLR as a parameter was introduced over 20 years ago and was found to have significant predictive value for cardiovascular risk [17]. Our analysis demonstrated that higher NLR was associated with poorer left ventricular function both during the acute phase of MI and in long-term follow-up, as well as worse baseline renal function and increased long-term mortality. These findings align with previous studies, which have shown that elevated NLR in MI patients is linked to a higher risk of cardiovascular and all-cause mortality, as well as heart failure, and correlates negatively with LVEF [18–20]. However, in our study, NLR was not associated with an increased incidence of recurrent MI, a result consistent with the prior meta-analysis [21].
The relationship between elevated inflammatory markers and cardiovascular diseases has been extensively researched since the 1970s [22], and several studies have assessed the prognostic value of both white blood cell count and its subpopulations, including the evaluation of NLR. As the most numerous types of leukocytes, neutrophils are key components of immune reactions during infections and tissue injury, and neutrophil count is used as a routine inflammation biomarker along with C-reactive protein and interleukin-6. Beyond their role in immune defense, neutrophils have been studied for their contribution to atherosclerosis development and calcific atherosclerotic plaque location in both clinical and preclinical models [23–25]. Briefly, their proatherogenic activity is based on disrupting the endothelium through degranulation of reactive oxygen species and myeloperoxidase, which facilitate low-density lipoprotein extravasation and promote foam cell formation [26]. Further plague progression involves neutrophil extracellular traps that amplify inflammation and, in advanced atherosclerosis, contribute to plaque destabilization, increasing the risk of rupture and thrombotic events [26]. Additionaly, serum oxidative stress factors predict myocardial ischemia reperfusion injury after percutaneous coronary intervention in patients with acute myocardial infarction [27]. Thus, the associations between higher neutrophil count and ischemic heart disease of atherosclerotic etiology identified in numerous studies are not surprising [28–30]. The PARIS study demonstrated that the acute presentation of coronary artery disease did not alter the association between elevated white blood cell counts and adverse cardiovascular outcomes after PCI, highlighting the significance of inflammatory markers in risk stratification [31]. Similarly, among patients undergoing PCI, elevated NLR was strongly associated with an increased risk of major adverse cardiovascular events and all-cause mortality in ACS patients but not in those with chronic conditions [11]. Higher NLR was also linked to an increased risk of bleeding in both acute and chronic settings [11].
Acute myocardial ischemia triggers a reaction of the immune system and inflammatory responses, and, in that setting, NLR acts as an indicator of immune system homeostasis [21]. Elevated neutrophil counts and consequently increased NLR are observed in various conditions, including infections, ACS, stroke, major trauma, and cancer [32]. A lower NLR is generally associated with a more favorable prognosis, reflecting a well-preserved immune balance. While there is no universally established cut-off distinguishing normal from pathological NLR values, studies suggest that in a healthy population, it typically ranges between 0.8 and 3.5 [32]. Notably, elevated NLR has been linked to increased mortality in sepsis, cancer, and even in the general population [33, 34].
Atherosclerotic cardiovascular disease, the underlying cause of MI, remains a leading and growing contributor to death and disability worldwide [6]. Owing to advances in early revascularization, personalized antiplatelet and antithrombotic therapy, and intensive cardiac care, the focus of MI management has shifted from acute complications to the long-term challenge of chronic heart failure. This condition primarily results from myocardial remodeling, an adverse process triggered by ischemia and sustained by an imbalance in tissue degradation, mediated by proteolytic enzymes and their inhibitors. Activation of fibroblasts, reparative mechanisms leading to scar formation, and hemodynamic stress further contribute to alterations in left ventricular size, geometry, and function. In clinical practice, post-MI remodeling is typically defined by imaging findings, such as increased ventricular volume and/or reduced LVEF, not by biochemical parameters. Our analysis revealed that higher NLR was associated with poorer left ventricular function both during the acute phase of MI and in long-term follow-up. Similar associations were seen for worse baseline renal function and increased long-term mortality.
Neutrophils play a dual role in MI and ischemia-reperfusion injury, not only driving inflammation but also contributing to healing and remodeling processes [6, 8]. During cardiovascular inflammation-related complications, such as neointima formation, they support tissue repair by promoting endothelial regrowth and angiogenesis [6]. Screening neutrophils in the post-MI setting for potential mediators of reparative processes may help identify novel therapeutic targets. As a result, modulating neutrophil-driven inflammation presents a promising strategy for preventing myocardial injury and improving outcomes.
In everyday clinical practice, higher NLR may serves as an indicator for more careful follow-up of patients after MI, including more frequent echocardiographic assessment.
The present study has several limitations. First, it is a retrospective registry with no specific protocol or time points for blood sampling and biochemical and hematological analyses. Second, morphology with peripheral smear was available in only a small proportion (23%) of screened MI patients. This might introduce bias and possible population selection, since full blood morphology with neutrophil and lymphocyte assessment has been tested more frequently in patients with initially higher risk of infection and worse clinical outcomes. Third, data about co-existing oncological or hemtaological disorders, which could impact the NLR, as well as results of other inflamamtary paramters including C-reactive protein, are missing. Finally, there was no specific schedule for clinical or echocardiographic follow-up. The results were based only on available data in medical records. Thus, the follow-up time point was not the same in all patients, and some follow-up data may potentially be missing. On the other hand, this study included a relatively large patient cohort gathered from a real-world MI registry with extended follow-up duration and had the advantage of comprehensive echocardiographic data availability.
Conclusions
Our findings indicate that a higher NLR is independently predictive of poorer left ventricular function and increased long-term mortality in patients following MI. Given its ready availability from routine blood counts, NLR emerges as a simple, cost-effective biomarker to refine long-term risk stratification in this population.
