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

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.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(© 2024 Ascione, Bruno, Johnson, Sammut, Bond, Lopez-Baz, Deutsch, Bailey, Chiribiri, Patel, Baker and Modarai.)