LAUSR

It has been estimated that nearly 1 billion cardiomyocytes (CM) die in a typical acute myocardial infarction (MI). There is an ongoing search for safe, reliable, sufficient replacement strategy for the lost CM to restore functional mass. All organs possess some regenerative capacity but in a spectrum of ability. In some organs, this is an integral part of their continuous physiological self-renewal (e.g., blood, skin, gut). In other organs, a mixture of cell-cycle re-entry, hyperplasia, differentiation, and hypertrophy compensate for lost cell mass (e.g., liver, skeletal muscle). In the adult heart, regeneration is currently inconsequential after injury. In the absence of CM renewal, remodeling is the default (eventually leading to decompensatory heart failure). The intense proliferation of fibroblasts and scarring secure the cardiac structure but at the risk of diastolic dysfunction, dilatation, or arrhythmia on top of systolic impairment from lost contractile tissue. Fibrotic remodelling also occurs in the peri-infarct and, to a lesser degree, in remote regions of the heart. Further, the residual CM undergo concentric hypertrophy as they adapt to the increased workload leftover by lost CM, a process necessary to restore cardiac output towards normal levels. The “holy-grail” of therapy would be to survive this redistribution of hemodynamic load after injury and outrace scar formation with functional contractile capacity. A race regrettably lost far too often in the clinic. The unrelenting hemodynamic and metabolic demands upon an adult mammalian heart don’t allow for safe cellcycle re-entry in any functionally meaningful way—at least naturally. And so, facilitating any and all potential avenues to expand and bring new hope to restore lost heart muscle has been pursued earnestly [1]. There was at first burgeoning hope for undifferentiated medullary stem or progenitor cells to commit to CM. Unfortunately, this produced false flags and alas only the modification of the sterile inflammation and the paracrine milieu for neovascularization and survival of at-risk nascent CM can be certain [2, 3]. A hopeful glimmer remains for a resident progenitor cell pool in the myocardium or epicardium [4, 5]. So far, it is lacking capacity for en masse expansion, the ability to survive reintegration, or the engineered maturity to form with the endogenous cardiac syncytium. As the search for an autologous hero abated, new insights into induced pluripotent and transdifferentiated cells of CM lineages appeared [6, 7]. This unlimited expansion capacity from iPSC-CM or the ability for cellular conversion of non-CM into CM by transcription factor, miRNA, or epigenetic manipulation opened new opportunities. Integration challenges remain. This invariably led the field back to fundamental science for a more complete understanding and appreciation of the components— interand intra-cellular—necessary for heart formation. A realization took form. Better understanding of the natural course balancing hemodynamic load with metabolic demand that nature designed and refined to grow a heart to maturity could reveal the “holy-grail” approach to MI therapy. Interestingly, in some species (amphibians and fishes) [8] safe cell-cycle re-entry occurs naturally in a functionally meaningful way to elicit cardiac regeneration—so why don’t adult mammals do this? Hauck et al. [9] sought to investigate whether CM proliferation can be regulated in a mouse model of MI through Pkm2, an important metabolic and signaling regulator in the developing heart and re-expressed after injury. This was examined by cardiac-specific Pkm2 gene knockout. Heart weight ratios and cardiomyocyte area post-MI were less than controls. Yet, there was no left ventricle dilatation nor evidence of significant fetal gene reactivation and less residual infarct scarring with an overall greater survival rate. This suggested a lack of hypertrophy induction and fibrotic remodeling with loss of CM-Pkm2, while * Keith R. Brunt [email protected]