DOI: 10.1161/circ.148.suppl_1.15064 ISSN: 0009-7322

Abstract 15064: Programmed Death-Ligand 1 Attenuates Myocardial Injury Following Myocardial Infarction

Yuanjia Zhu, Sabrina K Walsh, Akshay Venkatesh, Seung Hyun Lee, Danielle Mullis, Charles J Stark, Nicholas Tran, Sidarth Ethiraj, Luca E Lin, Catherine A Wu, Amanda S Padilla Lopez, Basil M Baccouche, Umayr Syed, Long T Doan, Shin Yajima, Stefan Elde, Hanjay Wang, Matthew H Park, Christopher Jackson, Michael Lim, Y Joe Woo
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Introduction: Myocardial infarction (MI) represents a major global cause of morbidity and mortality. Immune therapy to mitigate the secondary injury to myocardial tissues following MI is lacking. Programmed death-1 (PD-1) is an inhibitory protein expressed by immune cells during activation. Programmed death-ligand 1 (PDL1) binds to PD-1 and limits collateral damage in diseases with chronic inflammatory response. The objective of this study was to evaluate the impact of PDL1 on myocardial injury following MI.

Methods: 56 C57BL/6 male and female mice underwent left anterior descending artery (LAD) ligation. Mice were randomized to receive 50 μg of PDL1 (14 intramyocardial, 14 intraperitoneal) or PBS (12 intramyocardial, 16 intraperitoneal) immediately after LAD ligation. Echocardiography was obtained at baseline and 2 weeks after MI. Mice hearts were then explanted and sectioned for Masson’s trichrome staining. An additional 25 mice after MI without treatment were terminated on postoperative day 1, 3, 5, 7, and 14. Peripheral blood and myocardium were stained for CD45, CD11b, Ly6c, and PD-1 for flow cytometry.

Results: Myocardial infarct size reduction was observed after PDL1 treatment ( Fig. A-C ). Compared with controls, PDL1 delivered intramyocardially significantly improved ejection fraction from 29.8 ± 12.4 % to 41.4 ± 14.0 % (p = 0.04), and when delivered intraperitoneally, from 32.5 ± 9.4 % to 47.7 ± 8.0 % (p < 0.0001, Fig. D ). In the myocardium, the percentage of monocytes that were PD-1+ surged from 0.2 ± 0.2 % on day 1 to 83.8 ± 17.7 % on day 3 and remained elevated 14 days after MI at 31.5 ± 23.6 % ( Fig. E ).

Conclusions: PDL1 can attenuate myocardial injury and partially preserve cardiac function following MI in a rodent model. PD-1+ monocytes may be one of the key mediators of secondary myocardial injury after MI. Future studies will determine the mechanism of how PDL1 salvage myocardial damage to help develop a potential novel therapy.

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