Goran Marinković1, Helena Grauen Larsen2, Troels Yndigegn2, Istvan Adorjan Szabo3, Razvan Gheorghita Mares3, Lisa de Camp4, Matthew Weiland4, Lukas Tomas1, Isabel Goncalves1,2, Jan Nilsson1, Stefan Jovinge4,5,6, Alexandru Schiopu1,2,3. 1. Department of Clinical Sciences Malmö, Lund University, CRC 91:12, Jan Waldenströms gata 35, SE-214 28, Malmö, Sweden. 2. Department of Cardiology, Skane University Hospital Malmö, Carl-Bertil Laurells gata 9, SE-214 28 Malmö, Sweden. 3. Department of Pathophysiology, University of Medicine, Pharmacy, Sciences and Technology of Targu-Mures, Gheorghe Marinescu str. 38, 540139 Targu-Mures, Romania. 4. DeVos Cardiovascular Research Program, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA. 5. DeVos Cardiovascular Research Program, Fredrik Meijer Heart & Vascular Institute, Spectrum Health, 100 Michigan Street NE, Grand Rapids, MI 49503, USA. 6. Cardiovascular Institute, Stanford Medical School, 265 Campus Drive, Stanford, CA 94305, USA.
Abstract
AIMS: Neutrophils have both detrimental and beneficial effects in myocardial infarction (MI), but little is known about the underlying pathways. S100A8/A9 is a pro-inflammatory alarmin abundantly expressed in neutrophils that is rapidly released in the myocardium and circulation after myocardial ischaemia. We investigated the role of S100A8/A9 in the innate immune response to MI. METHODS AND RESULTS: In 524 patients with acute coronary syndrome (ACS), we found that high plasma S100A8/A9 at the time of the acute event was associated with lower left ventricular ejection fraction (EF) at 1-year and increased hospitalization for heart failure (HF) during follow-up. In wild-type C57BL/6 mice with MI induced by permanent coronary artery ligation, treatment with the S100A9 blocker ABR-238901 during the inflammatory phase of the immune response inhibited haematopoietic stem cell proliferation and myeloid cell egression from the bone marrow. The treatment reduced the numbers of neutrophils and monocytes/macrophages in the myocardium, promoted an anti-inflammatory environment, and significantly improved cardiac function compared with MI controls. To mimic the clinical scenario, we further confirmed the effects of the treatment in a mouse model of ischaemia/reperfusion. Compared with untreated mice, 3-day ABR-238901 treatment significantly improved left ventricular EF (48% vs. 35%, P = 0.002) and cardiac output (15.7 vs. 11.1 mL/min, P = 0.002) by Day 21 post-MI. CONCLUSION: Short-term S100A9 blockade inhibits inflammation and improves cardiac function in murine models of MI. As an excessive S100A8/A9 release is linked to incident HF, S100A9 blockade might represent a feasible strategy to improve prognosis in ACS patients. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Neutrophils have both detrimental and beneficial effects in myocardial infarction (MI), but little is known about the underlying pathways. S100A8/A9 is a pro-inflammatory alarmin abundantly expressed in neutrophils that is rapidly released in the myocardium and circulation after myocardial ischaemia. We investigated the role of S100A8/A9 in the innate immune response to MI. METHODS AND RESULTS: In 524 patients with acute coronary syndrome (ACS), we found that high plasma S100A8/A9 at the time of the acute event was associated with lower left ventricular ejection fraction (EF) at 1-year and increased hospitalization for heart failure (HF) during follow-up. In wild-type C57BL/6 mice with MI induced by permanent coronary artery ligation, treatment with the S100A9 blocker ABR-238901 during the inflammatory phase of the immune response inhibited haematopoietic stem cell proliferation and myeloid cell egression from the bone marrow. The treatment reduced the numbers of neutrophils and monocytes/macrophages in the myocardium, promoted an anti-inflammatory environment, and significantly improved cardiac function compared with MI controls. To mimic the clinical scenario, we further confirmed the effects of the treatment in a mouse model of ischaemia/reperfusion. Compared with untreated mice, 3-day ABR-238901 treatment significantly improved left ventricular EF (48% vs. 35%, P = 0.002) and cardiac output (15.7 vs. 11.1 mL/min, P = 0.002) by Day 21 post-MI. CONCLUSION: Short-term S100A9 blockade inhibits inflammation and improves cardiac function in murine models of MI. As an excessive S100A8/A9 release is linked to incident HF, S100A9 blockade might represent a feasible strategy to improve prognosis in ACS patients. Published on behalf of the European Society of Cardiology. All rights reserved.
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