Proteins targeting ischaemic-reperfusion injury and repair after myocardial infarction: a systematic literature review.

Clinical Snapshot

Key Findings

• P Value: Not reported at review level

• Effect Size: No pooled effect size reported; qualitative synthesis indicates that recombinant or modified proteins administered transiently after acute MI have potential to promote lasting improvements in heart function via pleiotropic mechanisms

• Primary Outcome: Cardioprotective effects of protein-based therapies post-MI, including limitation of MIRI and promotion of cardiac repair and ventricular remodelling

• Nnt Or Sensitivity: Not calculable from this systematic review; a few proteins demonstrated consistent and robust effects across multiple outcomes and both small and large animal models in reperfused and non-reperfused settings

• Confidence Interval: Not reported (no meta-analysis performed)

Clinical Application

Protein-based therapies face significant translational barriers including pharmacokinetic challenges (short half-life, immunogenicity, delivery route), cost of manufacture, and the need for administration in the acute peri-infarct window. No protein therapy for MIRI is currently approved for clinical use. The review identifies 46 candidate proteins but does not provide a clinical development roadmap. No protein-based therapy targeting MIRI is currently listed on the Australian Pharmaceutical Benefits Scheme (PBS) or approved by the Therapeutic Goods Administration (TGA) for this indication. Current Australian management of STEMI follows NHFA/CSANZ guidelines emphasising timely reperfusion (primary PCI). RACGP and cardiology society guidelines do not currently recommend any adjunctive protein therapy for MIRI. This review does not change Australian clinical practice but may inform future TGA regulatory submissions and NHMRC-funded translational research priorities. The findings are relevant to Australian cardiovascular researchers and industry partners engaged in post-MI cardioprotection drug development. Patients presenting with acute myocardial infarction undergoing reperfusion therapy (primary PCI or thrombolysis); the evidence base is predominantly preclinical and not yet directly applicable to clinical patient populations

Abstract

Following myocardial infarction (MI), reperfusion strategies ensure that blood flow is promptly restored to salvage the ischaemic myocardium. However, the sudden restoration of blood flow can inflict further damage to the ischaemic tissue, known as myocardial ischaemia/reperfusion injury (MIRI). Therapeutic strategies aimed at reducing MIRI and promoting cardiac repair remain an important clinical need. Protein-based therapies might exert benefits that limit damage and promote cardiac repair post-MI. To explore this further, we performed a systematic review of data from preclinical studies and clinical trial registries evaluating the cardioprotective effects of proteins post-MI. Medline and EMBASE were searched for preclinical studies that examined the potential cardioprotective effects of protein-based therapies to limit damage and/or mediate cardiac repair when administered after MI and/or reperfusion. Studies registered with ClinicalTrials.gov and EudraCT were also reviewed. In total, 84 studies were included in the final analysis, which included 46 different proteins. Overall, our findings support the concept that transiently applying recombinant or modified proteins after acute MI has the potential to promote lasting improvements in heart function via multiple pleiotropic mechanisms. Many of these proteins converge on a limited set of well-established signalling pathways involved in cardiac repair and remodelling after MI, with a few proteins demonstrating consistent and robust effects across multiple outcomes and models (small and large animals; reperfused and non-reperfused models). Despite this, the high potential cardioprotective benefit reported in preclinical studies has not translated into approved therapies for use in patients. Although the previous failure of protein therapies in clinical development does not invalidate the potential relevance of their downstream pathways, our research underlines the challenges in translating preclinical findings of protein-based therapies into the clinical setting. Future preclinical and clinical research should examine the optimal treatment effect and fully characterize the therapeutic potential of proteins involved in post-MI remodelling.

References

1. 1.Gardev, A., Hausenloy, D. J., & Pekcec, A. (2026). Proteins targeting ischaemic-reperfusion injury and repair after myocardial infarction: a systematic literature review. Cardiovascular Research. https://doi.org/10.3791/1438