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.

No abstract

No abstract

No abstract

Dilated cardiomyopathy (DCM) is a myocardial disease of dogs and humans characterized by progressive ventricular dilation and depressed contractility and it is a frequent cause of heart failure. Conventional pharmacological therapy cannot reverse the progression of the disease and, in humans, cardiac transplantation remains the only option during the final stages of heart failure. Cytoprotective gene therapy with vascular endothelial growth factor-B167 (VEGF-B167) has proved an effective alternative therapy, halting the progression of the disease in experimental studies on dogs. The aim of this work was to test the tolerability and feasibility of intracoronary administration, under fluoroscopic guidance, of VEGF-B167 carried by adeno-associated viral vectors in canine DCM patients. Ten patients underwent the gene delivery procedure. The intraoperative phase was well tolerated by all dogs. Clinical and echocardiographic assessments at 7- and 30-days post-procedure showed stable conditions compared to the pre-procedure phase. The results of this work indicate that intracoronary VEGF-B167 gene delivery is feasible and tolerated in dogs with DCM. Further monitoring/investigations are ongoing to evaluate the effects of this therapy on disease progression.