Coronary artery disease is the most frequent cardiovascular disorder in Western societies, and typically leads to acute myocardial infarction and ultimately heart failure. Heart failure is one of the major causes of morbidity and mortality. The human heart contains approximately 5 billion cardiomyocytes. An estimated 1 billion cardiomyocytes die after myocardial infarction. Despite the development of new pharmacological and device-based therapies, no approaches currently exist to compensate for the irreversible depletion of cardiomyocytes in the damaged heart, which adapts to stress via cardiomyocyte hypertrophy and cardiac fibroblast proliferation. This results in accelerated myocyte death and deleterious development of fibrosis, a situation associated with very unfavorable prognosis. The only option for end-stage heart failure remains therefore heart transplantation, which is limited due to the increased demand and scarcity of donor hearts. Heart failure is therefore evolving into a global epidemic, for which medicine has no viable option and is in need of rapid innovation.
One area that has engendered considerable interest over the last decade is the premise of promoting cardiac regeneration. Evidence that the heart holds regenerative capacity comes from observations in adult zebrafish and newts, and in neonatal mice. In these instances, new cardiomyocytes arise from pre-existing cardiomyocytes that undergo a process involving dedifferentiation, proliferation and redifferentiation into mature cardiomyocytes. The regenerative capacity of the mammalian heart is however lost early after birth, at a time when cardiomyocytes exit from the cell cycle. Using various approaches, cardiomyocytes in the adult human heart were found to be generated at a rate of approximately 1% a year, a renewal capacity that is unable to generate enough cardiomyocytes to replenish the heart following infarction. In this context, the main avenues to cardiac regeneration include transfer of cardiomyocyte precursors into the injured heart or activation of endogenous dormant regenerative mechanisms. Therapeutic intervention should target the most important populations in the heart, namely cardiomyocytes and cardiac fibroblasts. This could be achieved via reprogramming the transcriptome and the epigenome in these two cardiac subsets to readjust cell identity and favor regeneration.