Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive expansion of myocardial leukocyte populations, including polymorphonuclear neutrophils. Here, we aim to study the role of neutrophils in the pathogenesis of ventricular tachycardia (VT) associated with myocardial infarction in humans and mice.

To investigate the role of neutrophils in MI-associated VTs, we developed a new mouse model for ventricular arrhythmias, based on hypokalemia and permanent ligation of the left coronary artery (MI). ECGs were recorded in freely moving, ambulatory mice for 24-hours post-MI. Only occasional ventricular extrasystoles were detected in hypokalemic mice without and normokalemic mice with MI, but Spontaneous Tachycardia OccuRred frequently in hypokalemic mice with Myocardial infarction (in the following referred to as STORM model). VT was particularly common during the first day after MI, and most episodes occurred during the first eight hours, a timeline that mirrors the clinical situation. In STORM mice, VT and ventricular fibrillation (Vfib) reached an incidence of 90% and 31%, respectively. The average VT burden of STORM mice was greater than 10,000 cardiac cycles, which translates to over 12 min of ventricular arrhythmia within 24 h post-MI.

Neutrophils accumulate in the infarct within minutes of ischemia onset and reach their peak abundance after 24 h, but it remains unclear whether they contribute to ventricular arrhythmias. Hence, we depleted circulating neutrophils with antibody injections against neutrophil surface markers in our STORM model. Flow cytometry confirmed neutrophil depletion in STORM mice. Importantly, neutrophil depletion lowered the ECG-monitored VT burden when compared to STORM mice with regular neutrophil counts, indicating that neutrophils promote ventricular arrhythmias. Neutrophils are well-known to induce oxidative stress via increased formation of reactive oxygen species. Five hours after coronary ligation, a fluorescent ROS imaging sensor was enriched in the infarct, yet to a lesser degree so if neutrophils were depleted, indicating that neutrophils contribute to oxidative stress in the early infarct.

To assess the relevance of neutrophils in the clinical setting, we retrospectively studied patients with ST-elevation MI (STEMI, n=217) who underwent primary percutaneous coronary intervention and subsequent continuous ECG monitoring for up to 48 hours. A higher circulating neutrophil count was associated with an increased risk of early VT. In a separate retrospective analysis, we studied the link between circulating neutrophils and clinical outcomes in a patient cohort with acute MI (both STEMI and NSTEMI, n=795). A high neutrophil count, dichotomized at the median of 6.6x10⁹/L for this cohort, was associated with a 4-fold elevated risk of cardiac arrest or death at 30 days as compared to neutrophil counts <6.6x10⁹/L.

These data demonstrate that neutrophil expansion is associated with the occurrence of ventricular arrhythmias and adverse prognosis in MI patients. Viewed together with mechanistic data from STORM mice in which neutrophil depletion reduced the VT burden, these data provide proof-of-concept for neutrophils promoting ventricular arrhythmia.