Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics

Key Points Endogenous regeneration seen in animal models provides a template for optimal repair of the human heart following myocardial infarction. In the regenerating heart, new cardiomyocytes are produced by proliferation of the existing cardiomyocyte pool. Understanding and targeting the intrinsic mechanisms that regulate cardiomyocyte cell cycle re-entry could enable therapeutic regeneration in the human heart. Repair is modulated by epicardial activation, neoangiogenesis, the immune response and the extracellular matrix. Biological insights from regenerative models, combined with use of high-throughput phenotypic screens and in vivo discovery approaches, are uncovering novel therapeutic targets and compounds to improve repair. Regenerative strategies that emerge from increased understanding of cardiomyocyte lineage specification include transplantation of in vitro -produced cardiomyocytes and in vivo reprogramming of fibroblasts. Current efforts to improve engraftment, maturation and targeting will enable a next generation of clinical trials. Distinct approaches are required for patients in the immediate post-myocardial infarction period and for those with chronic heart failure, and high-risk strategies should initially be targeted at patients with end-stage heart failure. Clinical trial design should be tailored to incorporate informed biological end points alongside functional end points. Regeneration of the heart by cardiomyocyte reconstitution represents an attractive approach to treat heart failure. Here, Riley and colleagues discuss recent insights into the biology of heart regeneration and highlight emerging therapeutic regenerative strategies for heart failure. Challenges and considerations in the translation of regenerative therapies into the clinic are discussed. Current therapies for heart failure after myocardial infarction are limited and non-curative. Although regenerative approaches are receiving significant attention, clinical efforts that involve transplantation of presumed stem and progenitor cells have largely failed to deliver. Recent studies of endogenous heart regeneration in model organisms, such as zebrafish and neonatal mice, are yielding mechanistic insights into the roles of cardiomyocyte proliferation, resident stem cell niches, neovascularization, the immune system and the extracellular matrix. These findings have revealed novel pathways that could be therapeutically targeted to stimulate repair following myocardial infarc