Intramyocardial immunomodulation with human CD16+ monocytes to treat myocardial infarction in pig: a blind randomized preclinical trial

Raimondo Ascione; Vito D Bruno; Tom Johnson; Eva Sammut; Andrew Bond; Daniel Lopez-Baz; Julia Deutsch; Mick Bailey; Amedeo Chiribiri; Ashish Patel; Andrew Baker; Bijan Modarai

doi:10.3389/fcvm.2024.1427023

Intramyocardial immunomodulation with human CD16⁺ monocytes to treat myocardial infarction in pig: a blind randomized preclinical trial

Front Cardiovasc Med. 2024 Aug 7:11:1427023. doi: 10.3389/fcvm.2024.1427023. eCollection 2024.

Authors

Affiliations

¹ Faculty of Health Science, Bristol Heart Institute and Translational Biomedical Research Centre, University of Bristol, Bristol, United Kingdom.
² Faculty of Health Science, Langford Vets and Translational Biomedical Research Centre, University of Bristol, Bristol, United Kingdom.
³ School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom.
⁴ Vascular Surgery, King's College London, London, United Kingdom.
⁵ Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Abstract

Background: Human CD16⁺ monocytes (hCD16⁺ Ms) have proangiogenic properties. We assessed the feasibility, safety and efficacy of hCD16⁺ Ms in a porcine model of myocardial infarction (MI).

Methods and results: A total of 27 female Large White pigs underwent MI with reperfusion and cardiac magnetic resonance (CMR). Five days later, animals received intramyocardial injections of hCD16⁺ Ms in saline (n = 13) or saline only (n = 14). hCD16⁺ Ms were selected from leucocyte cones. Feasibility/safety endpoints included injury at injected sites, malignant arrhythmias, cancer, haematoma, left ventricular (LV) dilatation, troponin release and downstream organ injury. Co-primary efficacy outcome included LV scar and ejection fraction (LVEF) at 30-day post-injections by CMR. Immunohistochemistry included neo-angiogenesis, fibrosis, markers of myofibroblast and inflammation. Four animals were excluded before injections due to untreatable malignant arrhythmias or lung injury. Median cell number and viability were 48.75 million and 87%, respectively. No feasibility/safety concerns were associated with the use of hCD16⁺ Ms. The LV scar dropped by 14.5gr (from 25.45 ± 8.24 to 10.8 ± 3.4 gr; -55%) and 6.4gr (from 18.83 ± 5.06 to 12.4 ± 3.9gr; -30%) in the hCD16⁺ Ms and control groups, respectively (p = 0.015). The 30-day LVEF did not differ between groups, but a prespecified sub-analysis within the hCD16⁺ Ms group showed that LVEF was 2.8% higher and LV scar 1.9gr lower in the subgroup receiving a higher cell dose. Higher tissue levels of neo-angiogenesis, myofibroblast and IL-6 and lower levels of TGF-β were observed in the hCD16⁺ Ms group.

Conclusions: The use of hCD16⁺ Ms in acute MI is feasible, safe and associated with reduced LV scar size, increased tissue levels of neo-angiogenesis, myofibroblasts and IL-6 and reduced pro-fibrotic TGF-β at 30-day post-injections. A higher cell dose might increase the LVEF effect while reducing scar size, but this warrants validation in future studies.

Keywords: immunomodulation; intramyocardial delivery; ischemic heart failure; monocytes; myocardial infarction; treatment.

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article.