An Update on Engineered Heart Muscle Tissue Applied as Patches to an Injured Heart
The heart is one of the least regenerative organs in the mammalian body, and the scarring that follows injuries such as that sustained during a heart attack impairs function. Transplantation of cardiomyocyte cells to produce regeneration of scarred heart tissue has been a work in progress for going on twenty years now. It is possible to produce patient-matched cardiomyocytes from induced pluripotent stem cells, but such cells exhibit minimal survival and perform poorly when transplanted. The development of artificial tissues using nanoscale scaffolds, enabling the production of thin patches of heart muscle made up of cardiomyocytes, has improved matters. More cells survive following transplantation, and functional improvements are observed in animal models of heart injury. The latest concerns have revolved around whether heart electrical function remains disrupted by the introduction of new cells, causing arrhythmia or worse, but as noted here even that problem seems to be yielding to the latest state of the art.
Cardiomyocytes can be implanted to remuscularize the failing heart. Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques.
After confirmation of in vitro and in vivo (nude rat model) equivalence of the newly developed rhesus macaque EHM model with a previously established Good Manufacturing Practice-compatible human EHM formulation, long-term retention (up to 6 months) and dose-dependent enhancement of the target heart wall by EHM grafts constructed from 40 to 200 million cardiomyocytes/stromal cells were demonstrated in macaques with and without myocardial infarction-induced heart failure. In the heart failure model, evidence for EHM allograft-enhanced target heart wall contractility and ejection fraction, which are measures for local and global heart support, was obtained. Histopathological and gadolinium-based perfusion magnetic resonance imaging analyses confirmed cell retention and functional vascularization. Arrhythmia and tumour growth were not observed.
The obtained feasibility, safety and efficacy data provided the pivotal underpinnings for the approval of a first-in-human clinical trial on tissue-engineered heart repair. Our clinical data confirmed remuscularization by EHM implantation in a patient with advanced heart failure.