Heart disease is a leading cause of mortality. The underlying pathology is typically loss of heart muscle cells that leads to heart failure. Because heart muscle has little or no regenerative capacity after birth, current therapeutic approaches are limited for the over 5 million Americans who suffer from heart failure. Our recent findings regarding direct reprogramming of a type of structural cell of the heart, called fibroblasts, into cardiac muscle-like cells using just three genes offers a novel approach to achieving cardiac regeneration. We simulated a heart attack in mice by blocking the coronary artery, and have regenerated damaged hearts by converting existing mouse cardiac fibroblasts into new muscle by delivering the three genes into the heart. We have found that a combination of the three genes used in mice plus two additional factors were sufficient to identified to reprogram human and pig cardiac fibroblasts and are optimizing a gene therapy approach to introduce cardiac reprogramming genes into the heart of pigs. In a pig model of cardiac injury, we identified the optimal combination of factors that was able to convert non-muscle cells into new muscle in the area of injury. We have completed a pilot study of these five factors for functional improvement using MRI to measure cardiac output 3 days after injury and 2 months after treatment with the reprogramming factors. We also found a viral vector that can preferentially infect the fibroblasts compare to the muscle cells and have confirmed this activity. We are now testing for functional improvement in pigs using various viral vectors.