Neutrophil counts in patients with ventricular arrhythmia associated to myocardial infarction

Lukas Barth (Berlin)1, N. Berndt (Nuthetal)2, J. Grune (Berlin)1, W. Kübler (Berlin)3, N. Kränkel (Berlin)4, N. Hegemann (Berlin)5, P. Attanasio (Berlin)4, D. Meteva (Berlin)1

1Deutsches Herzzentrum der Charite (DHZC) Berlin, Deutschland; 2German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) Department of Molecular Toxicology Nuthetal, Deutschland; 3Deutsches Herzzentrum der Charite (DHZC) Institut für Physiologie Berlin, Deutschland; 4Charité - Universitätsmedizin Berlin CC 11: Med. Klinik für Kardiologie Berlin, Deutschland; 5Charité - Universitätsmedizin Berlin CC2: Institut für Physiologie, CCO Berlin, Deutschland


Ventricular arrhythmias (VA), especially ventricular tachycardia and fibrillation, occur regularly in the setting of myocardial infarction (MI). Cumulative evidence demonstrates expansion of circulatory neutrophilic granulocytes (hereinafter referred to as neutrophils) after acute MI. Our preclinical data indicates that neutrophils are causally involved into VA burden after MI, but if neutrophil expansion in the context of MI has predictive value for arrhythmia risk stratification of MI patients remains unknown. Here, we present preliminary data on neutrophil biology in healthy volunteers, preparing for a prospective clinical trial phenotyping MI patients with long-term ECG recordings to assess arrhythmia burden and in-depth flow cytometry to define neutrophil dynamics after MI with the ultimate goal to explore neutrophils role in MI-associated arrhythmia risk.
Preliminary data of two separate patient cohorts were analyzed in a retrospective manner as a base for this study. 1. From the Oxford University Hospital Registry, we analyzed ST-elevation myocardial infarction (STEMI) patients (n=217) who underwent primary percutaneous coronary intervention and subsequent continuous ECG monitoring for up to 48 hours. 2. From the Mass. General Brigham’s, we sampled follow-up data from acute MI patients (n=795), STEMI and non-ST-elevation myocardial (NSTEMI) and tested if neutrophil expansion is associated with outcome and survival 30-days after MI. Preliminary data showed that a higher neutrophil count was linked to VA severity in the first 48 hours post-MI in the Oxford cohort, and this association remained significant even after adjusting for confounding factors such as infarct size, ischemic time, and beta-blocker use. In the Mass. General Brigham’s cohort, higher neutrophil counts were linked to a 4-fold increased risk of cardiac arrest or death at 30 days post-MI, even after controlling for age, sex, peak troponin level, monocyte count, and creatinine.
To explore neutrophil’s predictive value regarding arrhythmia risk in MI patients, we designed a prospective clinical trial (OPTICO-ACS II), sampling central and peripheral blood from STEMI and NSTEMI patients at hospitalization before intervention and follow-ups at the following time points: 1 and 2 days, dehospitalization, 30, 90 and 180 days, 1, 2 and 5 years.
Blood samples are currently getting analyzed with multicolor flow cytometry, proteomics and migration assays to screen neutrophil abundance, subsets and expression patterns. VA occurrence will be monitored via long-term ECG monitoring during hospitalization, short-term ECG monitoring during each follow-up and Biomonitor III implantation in a subset of patients. The data collected will be used for correlation analyses on arrhythmia occurrence and the presence of total neutrophils and their subsets. Special attention is given to neutrophil’s secretome to identify potential pro-arrhythmic neutrophilc proteins. We found Lipopolysaccharides (LPS) (1,25ng/ml), Pam3CSK4 (Pam3) (50ng/ml) and hypoxia exposure suitable to trigger secretion of neutrophilic proteins in isolated neutrophils, which is currently getting analyzed with proteomics.
Neutrophil expansion associates with VA in MI patients, emphasizing the potential value of neutrophils as biomarkers in predicting arrhythmia risk in this patient cohort. Through the ongoing prospective study, we aim to gain a deeper mechanistic understanding of neutrophil’s role in MI-associated arrhythmia.
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