Statistics recently published by the American Heart Association clearly outline the magnitude of the medical and economic problems associated with heart failure.1 It is estimated that 6 million people in the United States are affected by this disease, with a yearly incidence of new episodes (per 1000 people) of 15.2 between 65 and 74 years of age, a figure that is two times higher between 75 and 84 years of age. Still in the United States, the number of hospitalizations for heart failure has thus increased from 877,000 to 1,106,000 in a 10-year time frame (1996–2006), but the problem is now worldwide. The mortality remains high as 80% of men and 70% of women under the age of 65 years in whom heart failure has been diagnosed are expected to die within the next 8 years with a risk of sudden death which is six to nine times that of the general population. As expected, these figures translate into a heavy economic burden with costs estimated to 37 billion dollars in 2008.
Although heart transplantation remains the only radical treatment for end-stage heart failure, its use is limited by organ shortage and the complications associated with major immunosuppression. Surgical remodeling procedures require well-defined anatomical indications, and the failure of the STITCH2 trial may lead to revisit them. Mechanical assist devices are still primarily used as bridges to transplant (or recovery) and, despite its ability to provide symptomatic relief, biventricular stimulation fails in 20 to 30% of patients.3 Finally, none of the large trials implemented over the last decade to investigate new drugs has yielded a positive outcome allowing to improve the survival of heart failure patients. Put together, these observations have provided a rationale for exploring new therapeutic options, among which “regeneration” of the chronically failing heart by stem cells has raised a tremendous interest. From the onset, however, it is fair to state that regeneration bona fide, ie, generation of a new myocardial tissue with the same properties as the native one, is a concept, a target, and a hope, but not yet a reality. This chapter first summarizes the current status of stem cell trials, then describes the strategies that can be considered for effecting a true myocardial regeneration, and finally emphasizes the importance of addressing the low cell engraftment issue to make these strategies successful.
So far, two types of stem cells, both of adult origin, have been tested clinically: skeletal myoblasts and bone marrow–derived cells.
In June, 2000, we performed the first human transplantation of autologous myoblasts in a patient with severe ischemic heart failure4 who underwent a concomitant coronary artery bypass grafting (CABG). This case initiated a 10-patient pilot trial that was soon followed by three other adjunct-to-CABG myoblast transplantation studies,5–7 which only differed from ours in that they systematically entailed a concomitant revascularization of the myoblast-injected areas.