Abstract P3078: Stress-induced Early Recruitment Of Neutrophils To The Infarcted Hearts Influence Cardiac Outcomes.

Myocardial infarction (MI)-induced heart failure is one of the leading causes of death in the modern world. This is in part due to abnormal cardiac remodeling, instigated by a large influx of neutrophils immediately following MI. These activated neutrophils in the heart release a plethora of proteolytic enzymes and exacerbate tissue injury leading to cardiac failure and death. The role of neutrophils during MI is complex with the intensity and duration of their residency dictating the ensuing remodeling process. We have previously shown that the recruitment of neutrophils to heart post-MI is mirrored by an increased proliferation of progenitors (granulopoiesis) in the bone marrow (BM). However, the increase in the number of neutrophils at the infarct begins much earlier (< 6 hours post MI) than the peak granulopoiesis (24 hours post-MI) in the BM. These finding suggest that sources other than granulopoiesis may contribute heavily to the initial neutrophil burden of the heart. One such source is the marginated pool. In the circulation, the marginated pool of neutrophils represents the same size as that of the circulating pool. We hypothesize that “ demargination of neutrophils from the vascular wall contribute to the neutrophil burden of the heart particularly during the early hours after MI ”. To test this hypothesis, we created a mouse model of MI by permanent ligation of the left anterior descending coronary artery and studied the impact of early recruitment of neutrophil to ischemic heart. We found that the initial wave of neutrophils recruited to the ischemic heart were exclusively sourced from the vasculature and not granulopoiesis in the BM/ Spleen. The neutrophils that were recruited to the heart exhibit distinct hallmarks of demargination including decreased F-actin, CD62L and increased Adam17 expression. This early recruitment of neutrophils was orchestrated by catecholamine stress as strategies aimed at inhibition of catecholamine biosynthesis or blockade of β adrenergic receptors (β-AR) significantly reduced neutrophil burden and improved cardiac function. Interestingly, this protective effect was lost when neutrophil recruitment was suppressed over a longer period. In conclusion we show that while short-term blockade of β-AR signaling suppresses the early neutrophil swarming, suppression beyond the reparative phase (> 3 days post-MI) adversely impact the cardiac function. Together these data suggest that catecholamine stress induced-demargination constitute the major source of neutrophils during the early hours of MI. Understanding the precise signaling mechanisms that drive demargination and optimizing the right dose/duration of a specific β-AR blocker may help suppress the initial onslaught of neutrophils without compromising their overall beneficial function during the reparative phase of inflammation.