Reduced neutrophil oxidative burst capacity in patients with cardiovascular diseases is associated with major adverse cardiac events and infection

Background: Neutrophils are key in acute and chronic cardiovascular diseases (CVD) by mediating inflammation contributing to myocardial infarction, stroke and heart failure. Reactive oxygen species (ROS) generated by neutrophil NADPH oxidase 2 (NOX2), have been linked to CVD pathology by inducing tissue injury via oxidative stress. However, there is only limited data investigating the impact of neutrophil-derived ROS on clinical outcome in patients with CVD. This study measured neutrophil oxidative burst capacity (NOBC) in patients with CVD and its association with major adverse cardiac events (MACE).

Methods: In a population of 201 (median age 69 years (interquartile range (IQR): 61-80 years); 33.4% female) out of 2,845 patients from the prospective all-comer Essen registry of coronary artery disease II (ECAD II registry). NOBC was measured using a Seahorse XF analyzer with phorbol-12-myristat-13-acetat (PMA) stimulation. Based on NOBC measurement the study collective was divided by median split. The primary endpoint was MACE, comprising of myocardial infarction, stroke or hospitalization for heart failure with a median follow-up time of 287 days (IQR: 225-349 days). As secondary endpoint occurrence of infection was assessed with a median follow-up time of 273 days (IQR: 214-332 days). 

Results: Patients with low NOBC showed a mean reduction of 22% in total burst capacity (100.4 ± 9.6 nmol (high NOBC) vs. 78.0 ± 8.5 nmol (low NOBC); p < 0,001). In this group we observed a significantly higher portion of females (26.7% (high NOBC) vs. 41.0% (low NOBC); p = 0.03). Occurrence of MACE was significantly increased in patients with low NOBC (hazard ratio (HR): 2.78; 95% confidence interval (CI) 1.17-6.63; p = 0.02). Low NOBC also associated with infection (HR: 3.67; CI: 1.16-11.62; p = 0.03). The association of low NOBC and incidence of MACE remained significant after adjusting for further relevant confounders, while the association with infection lost its significance.

Conclusion: Low NOBC, indicating less neutrophil-derived ROS production potential, is associated with increased MACE and infection. These partly surprising findings challenge the current understanding of neutrophil function in CVD, indicating a potential cardioprotective role of neutrophil-derived ROS in our study collective. Therefore, future studies are needed for further validation of these observations.