Intravenous Interferon-β1a for the Treatment of Ischemia-Reperfusion Injury in Acute Myocardial Infarct in Pigs

Authors

  • Siiri Deomic Niittynen, MD Doctoral Programme in Clinical Research, University of Turku, Turku, Finland
  • Laura Liikamaa, MD Doctoral Programme in Clinical Research, University of Turku, Turku, Finland
  • Juho Jalkanen, MD, PhD Faron Pharmaceuticals, Turku, Finland
  • Sirpa Jalkanen, MD, PhD Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland
  • Timo Savunen, MD, PhD Heart Center, Turku University Hospital and University of Turku, Turku, Finland
  • Jarmo Gunn, MD, PhD Heart Center, Turku University Hospital and University of Turku, Turku, Finland
  • Vesa Anttila, MD, PhD Heart Center, Turku University Hospital and University of Turku, Turku, Finland
  • Laura Virtanen, MSc Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, Turku, Finland
  • Pekka Taimen, MD, PhD Department of Pathology, Turku University Hospital, Turku, Finland
  • Maija Hollmén, PhD Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland
  • Emily Pan, MD, PhD Heart Center, Turku University Hospital and University of Turku, Turku, Finland
  • Emmi Saura, MD Päijät-Häme Central Hospital, Lahti, Finland
  • Markus Malmberg, MD, PhD Heart Center, Turku University Hospital and University of Turku, Turku, Finland

DOI:

https://doi.org/10.1532/hsf.3639

Keywords:

interferon ß 1a, ischemia-reperfusion injury, myocardial reperfusion injury, acute myocardial infarct, cardioprotection

Abstract

Background: To investigate the potential of intravenously administered porcine recombinant interferon-β1a (IFN-β1a) for myocardial protection during acute ischemia-reperfusion (IR) injury in an experimental
animal model.

Methods: Twenty-two piglets (mean ± standard deviation, 26.7 ± 1.65 kg) were assigned to either the IFN group (n = 12) or the control group (n = 10). IR injury was induced by occluding the distal left descending coronary artery for 30 minutes, with a reperfusion period of 6 h. In the IFN group, the animals received 12.5 µg IFN-β1a intravenously repeatedly; the control group received saline solution. The levels of interleukin-6 (IL-6) and cardiac troponin I (TnI) were measured, and the amount of myocardial damage was quantified by analyzing myocardial apoptosis and the mean fluorescence intensity (MFI) of methylene blue–stained cardiac tissue.

Results: In the IFN group, significantly more premature deaths occurred compared with the control group (25% versus 17%, P = .013). Between the groups, the mean heart rate was higher in the IFN group (102 ± 22 versus 80 ± 20 beats per minute, P = .02). IL-6 and TnI levels were comparable between the groups, with no significant difference, and there was no difference between the study groups in myocardial apoptosis in the infarcted myocardium. The percentage of MFI differed significantly between the IFN and control groups (90.75% ± 4.90% versus 96.02% ± 2.73%, P = .01).

Conclusion: In this acute IR injury animal model, IFN-β1a did not protect the myocardium from IR injury, but rather increased some of the unfavorable
outcomes studied.

References

Barrabes JA, Botker HE, Hausenloy DJ, et al. Ischaemic conditioning and targeting reperfusion injury: A 30 year voyage of discovery. Basic Res Cardiol 2016;111:70-74.

Bellingan G, Howell DC, Maksimow M, et al. The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: An open-label study. Lancet Respir Med 2014;2:98-107.

Bellingan G, Brealey D, Mancebo J, et al. Comparison of the efficacy and safety of FP-1201-lyo (intravenously administered recombinant human interferon beta-1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: Study protocol for a randomized controlled trial. Trials 2017;18:536.

Bolli R, Canty JM, Lindsey ML, et al. Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 2018;314:H812-H838.

Charles E, Mehaffey J, Money D, et al. Adenosine 2A receptor activation attenuates ischemia reperfusion injury during extracorporeal cardiopulmonary resuscitation. Ann Surg 2019;269:1176-1183.

Chen H, Wu Q, Yao L, et al. Hydrogen-rich saline alleviates inflammation and apoptosis in myocardial I/R injury via PINK-mediated autophagy. Int J Mol Med 2019;44:1048-1062.

Crawford TC, Grimm JC, Magruder T, et al. Complications after cardiac operations: All are not created equal. Ann Thorac Surg 2017;103:32-40.

Eltzschig HK, Ibla JC, Thompson LF, et al. Crucial role for ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia. J Exp Med 2004;200:1395.

Eltzschig HK, Robson SC, Sitkovsky MV. Purinergic signaling during inflammation. N Engl J Med 2013;367:2322-2333.

Foo RS, Movassagh M. Simplified apoptotic cascades. Heart Fail Rev 2008;13:111-119.

Gao XM, Kiriazis H, Wu QZ, Kiriazis H, et al. Microvascular leakage in acute myocardial infarction: Characterization by histology, biochemistry, and magnetic resonance imaging. Am J Physiol Heart Circ Physiol 2017;312:H1068-H1075.

Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: A neglected therapeutic target. J Clin Investigation 2013;123:92-100.

Heusch G. Molecular Basis of cardioprotection signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 2015;116:674-699.

Kasper LH, Reder AT. Immunomodylatory activity of interferon-beta. Ann Clin Transl Neurol 2014;1:622-631.

Kiss J, Koskinen K, Yegutkin GG, et al. IFN-β protects from vascular leakage via up-regulation of CD73. Eur J Immunol 2007;37:3334-3338.

Kuo PC, Scofield BA, Yu IC, et al. Interferon-β modulates inflammatory response in cerebral ischemia. J Am Heart Assoc 2016;8;5:e002610.

Lee HT, Rabadi MM. Adenosine receptors and renal ischemia reperfusion injury. Acta Physiol (Oxf) 2015;213:222-231.

Malmberg M, Parkka J, Vähäsilta T, et al. Cardiomyocyte apoptosis after cardioplegic ischemia: Comparison to unprotected regional ischemia-reperfusion. Eur Surg Res 2011;46:19-25.

National Institutes of Health. Guide for the Care and Use of Laboratory Animals. Institute for Laboratory Animal Research, National Research Council (US). National Academies Press; 1996.

PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998;20;352:1498-1504.

Published

2021-04-27

How to Cite

Deomic Niittynen, S., Liikamaa, L., Jalkanen, J., Jalkanen, S., Savunen, T., Gunn, J., Anttila, V., Virtanen, L., Taimen, P., Hollmén, M., Pan, E., Saura, E., & Malmberg, M. (2021). Intravenous Interferon-β1a for the Treatment of Ischemia-Reperfusion Injury in Acute Myocardial Infarct in Pigs. The Heart Surgery Forum, 24(2), E409-E413. https://doi.org/10.1532/hsf.3639

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