MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs

Prompt coronary catheterization and revascularization have dramatically improved the outcome of myocardial infarction, but also have resulted in a growing number of survived patients with permanent structural damage of the heart, which frequently leads to heart failure. Finding new treatments for this condition is a largely unmet clinical need 1, especially because of the incapacity of cardiomyocytes to replicate after birth and thus achieve regeneration of the lost contractile tissue 2. Here we show that expression of human microRNA-199a in infarcted pig hearts is capable of stimulating cardiac repair. One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, the treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size. These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation. At longer follow-up, however, persistent and uncontrolled expression of the microRNA resulted in sudden arrhythmic death of most of the treated pigs. Such events were concurrent with myocardial infiltration of proliferating cells displaying a poorly differentiated myoblastic phenotype. These results show that achieving cardiac repair through the stimulation of endogenous cardiomyocyte proliferation is attainable in large mammals, however this therapy needs to be tightly dosed.