The field of regenerative cardiology has long pursued an effective strategy for remuscularization after myocardial infarction. After two decades of intensive research and unsuccessful attempts, recent research by Jebran et al., published in Nature (1), represents a significant advance in this domain, demonstrating the feasibility, safety, and efficacy of engineered heart muscle (EHM) allografts in non-human primates and, crucially, in a first-in-human clinical trial. The findings of the study provide substantial evidence that supports the clinical translation of tissue-engineered heart repair for patients suffering from advanced heart failure.

Overcoming Barriers in Cardiac Regeneration

Despite extensive efforts in cell-based therapies, challenges such as cell retention, vascularization, and arrhythmogenicity have impeded their clinical implementation to date. Prior studies on cardiomyocyte transplantation, particularly those employing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), faced significant hurdles related to immune rejection, poor engraftment, and the risk of engraftment-induced arrhythmias (2-4). Jebran et al. tackle these challenges through the use of innovative patches of EHM allografts composed of iPSC-CMs and stromal cells, which they characterized in detail by single-nucleus RNA sequencing. The EHMs were implanted as epicardial grafts onto the infarct rather and evidence for structured tissue integration and minimized proarrhythmic risks was demonstrated.

From Preclinical Models to First-in-Human Trial

Utilising rhesus macaques as a homologous large-animal model, the study demonstrated long-term (up to six months) EHM graft retention with functional integration and no adverse arrhythmias or tumorigenic risks. The EHM patches enhanced myocardial wall thickness and contractility in both healthy and chronic heart failure models (ischemia/reperfusion injury), supporting their therapeutic potential. Epicardial engraftment of the EHMs stipulated their mechanically triggered contractile entrainment over time as basis for the EHM-dependent delivery of myocardial performance (5, 6). Importantly, a critical finding of this study was the successful vascularization of the EHM grafts, as confirmed by gadolinium-enhanced perfusion MRI and histopathological analyses. Unsurprisingly, successful engraftment was only possible under strong immunosuppression. A particularly salient finding is that these compelling preclinical results facilitated the approval of the BioVAT-HF-DZHK20 Phase I/II clinical trial (NCT04396899), which assesses EHM allografts in human patients with advanced heart failure. The fortunate circumstance that one enrolled patient received a heart transplant allowed the histomorphological investigation of the explanted heart three months after EHM patch implantation. The study confirmed successful remuscularisation, thereby demonstrating the viability and translatability of EHM-based therapy to the clinic.

Implications for Clinical Practice and Future Directions

This study delivers on a new paradigm for myocardial regenerative therapy, transitioning from cell injection methodologies to structured tissue grafting. The absence of arrhythmogenic complications, concomitant with sustained functional enhancement, positions EHM allografts as a promising candidate for cardiac regeneration, or at the very least, as a viable bridge-to-transplant treatment in cases of advanced heart failure.