Acute myocardial infarction (MI) triggers a rapid immune response, with neutrophilic granulocytes (hereafter referred to as neutrophils) being the first responders getting recruited to the site of injury. Excessive and chronic neutrophil activation is associated with adverse cardiac remodeling and worsen outcomes in patients with MI. Aging is the major non-modifiable risk factor for cardiovascular disease and linked to distinct immune responses.
Here, we present data from the prospective clinical trial OPTICO-ACS II investigating neutrophil biology in MI patients, following the hypothesis that older MI patients have unique neutrophil signatures which contribute to arrhythmia risk and MI outcome.
In OPTICO-ACS II, we recruited patients (36-85 yrs, median age: 65) with a diagnosis of ST-elevation MI (STEMI, n=22) or non-ST-elevation MI (NSTEMI, n=12) who provided informed consent. Lesional and peripheral blood samples were taken during percutaneous coronary intervention at hospitalization. Healthy donors (HDs) of comparable age, BMI and sex served as controls. All blood samples were processed for multicolor flow cytometry to assess neutrophil counts, phenotypes, expression patterns and oxidative stress production. Patients were stratified by biological age using 65 yrs as cutoff to decipher age-associated neutrophil dynamics.
Neutrophil counts were elevated in peripheral samples in STEMI patients immediately post-MI compared to NSTEMIs and HDs. Neutrophil surface marker analysis revealed a downregulation of CD282 (Toll-like receptor 2), CD354 (Triggering Receptor Expressed on Myeloid cells 1), and CXCR4 (C-X-C chemokine receptor type 4) - all of which markers for neutrophil activation and migration - in patients with NSTEMI and STEMI compared to HDs.
Age-stratified analyses revealed reduced expression of activation markers such as CD10, CD11b, CD282 and CXCR4 in both, STEMI and NSTEMI patients over 65 compared to younger patients, respectively. Lesional blood from patients over 65 yrs showed reduced expression levels of CD10+, CD11b+, and CXCR4+ on neutrophils compared to younger patients.
When analyzed by MI subtype, both STEMI and NSTEMI patients showed lower CD11b+ expression levels with age, while reductions in CXCR4+, CD354+, and CD282+ were mainly seen in older STEMI patients. Additionally, there was a trend towards increased oxidative stress production in neutrophils from older patients in peripheral blood samples.
We found, reduced neutrophil activation/migration marker expression in MI patients over 65, with similar trends in both STEMI and NSTEMI when compared to HDs, suggesting that biological age impacts post-MI neutrophil function. How age-associated neutrophil biology contributes to patient outcome, including arrhythmias, is part of ongoing analyses. Ongoing patient recruitment, proteomic profiling, and systematic arrhythmia assessment will help to explore neutrophil-related mechanisms relevant for clinical outcome.
