Stress, Hyperglycemia, and Insulin Resistance Correlate With Neutrophil Activity and Impact Acute Myocardial Infarction Outcomes

Abstract

Introduction Acute insulin resistance (IR) and hyperglycemia are frequently observed during acute myocardial infarction (AMI), significantly influencing both immediate and long-term patient outcomes, irrespective of diabetic status. Neutrophilia and increased neutrophil activity, which are common in these scenarios, have been associated with poorer prognoses, as demonstrated in our recent findings. While it is well established that neutrophils and stress-induced hyperglycemia exacerbate inflammation and hinder recovery, the complex interplay between these factors and their combined impact on AMI prognosis remains inadequately understood. This study aims to investigate the effects of stress hyperglycemia and IR on AMI patients at the onset of the event and to elucidate the relationship between these metabolic disturbances and inflammatory markers, particularly neutrophils. Methods We conducted a longitudinal prospective study on 219 AMI patients at Elias Emergency Hospital in Bucharest, Romania, from April 2021 to September 2022. Patients were included within 24 hours of AMI with ST-segment elevation and excluded if they had acute infections or chronic inflammatory diseases. Blood samples were collected to study inflammatory biomarkers, including neutrophil extracellular traps (NETs), S100A8/A9, interleukin (IL)-1β, IL-18, and IL-6. Diabetic and pre-diabetic statuses were defined using glycated hemoglobin (HbA1c) and medical history (ADA 2019 criteria). To assess glycemic parameters, we employed the glycemia ratio (GR) and the homeostatic model assessment of insulin resistance (HOMA-IR) index, enabling a precise evaluation of stress hyperglycemia, acute IR, and their prognostic implications. Patients were stratified into groups based on GR calculations, categorized as under-average glycemia, normal glycemia, and stress hyperglycemia. Results The majority of patients in the stress hyperglycemia group exhibited an unfavorable prognosis. This group also demonstrated significantly elevated neutrophil counts and neutrophil-to-lymphocyte ratios (NLR). The GR was significantly and positively correlated with inflammation markers, including neutrophil count (Pearson's R = 0.181, P = 0.008) and NLR (Pearson's R = 0.318, P < 0.001), but showed no significant correlation with other evaluated inflammatory markers. Conclusions Our findings suggest that poor outcomes in AMI patients may be associated with stress hyperglycemia, as indicated by GR. AcuteIR, quantified by GR and HOMA-IR, exhibits a strong correlation with neutrophil count and NLR within the first 24 hours of AMI onset. However, no significant correlation was observed with other inflammatory markers, such as IL-1β, IL-18, and IL-6, underscoring the specific interplay between IR and neutrophil activity in this setting.

Keywords: acute insulin resistance; acute myocardial infarction; inflammatory markers; neutrophil-to-lymphocyte ratio; stress hyperglicemia.

Figure 1. Prognosis depending on acute glycemia group: under average, normal, and hyperglycemia

Figure 2. Comparison between HOMA-IR values and insulinemia values in acute glycemia groups

(A) HOMA-IR values between acute glycemia groups; (B) insulinemia values between acute glycemia groups. The statistical significance shown on the graph refers to the outcomes of Tukey's test for multiple comparisons. (n.s., not significant; *p < 0.05; **p < 0.01) HOMA-IR: homeostatic model assessment of insulin resistance index

Figure 3. Parameters values between acute glycemia groups

(A) neutrophil-to-lymphocyte ratio (NLR); (B) white blood cells (WBC); (C) lymphocytes; (D) neutrophils; (E) neutrophil extracellular traps (NETs); (F) S100A8/A9. The statistical significance shown on the graph refers to the outcomes of Tukey's test for multiple comparisons (n.s.: not significant, *p < 0.05, **p < 0.01).

Figure 4. A scatterplot showing the correlation between glycemia ratio and the following inflammatory markers: (A) neutrophils, (B) neutrophil-to-lymphocyte ratio (NLR), (C) lymphocytes, (D) interleukin (IL)-18, (E) IL-6, and (F) IL-1 beta.

N: non-diabetic; PD: pre-diabetic; D: diabetic; prog: prognosis; fav: favorable; unfav: unfavorable

Figure 5. Correlation matrix for inflammatory and glycemic markers

Cell colors indicate the direction and strength of correlations: blue (for positive correlations), red (for negative correlations), and orange (for significant correlations). The values indicated in the cells represent the p-value of the correlation. The parameters are grouped according to their similarity of association with the other parameters by the unweighted pair group method with an arithmetic mean. LVEF: left ventricular ejection fraction; HOMA-IR: homeostatic model assessment of insulin resistance; IL: interleukin; NETs: neutrophil extracellular traps; NLR: neutrophil-to-lymphocyte ratio; WBC: white blood cell; HbA1C: glycated hemoglobin; ESR: erythrocyte sedimentation rate