Regenerative therapies for improving myocardial perfusion in patients with cardiovascular disease: failure to meet expectations but optimism for the future.

Cardiovascular disease continues to be a major cause of death in the Western world and has been extending into areas previously seemingly immune to its effects. Catheter-based interventions and coronary artery bypass surgery have markedly improved cardiovascular health, but a number of patients with coronary artery disease cannot undergo repeated interventions or they receive an incomplete revascularization with standard revascularization methods, which has been associated with a poor clinical outcome. Despite early demonstration of improvement in myocardial perfusion and function with growth factor, gene therapy or cellular therapies, clinical studies have found little if any real benefit. The discordance between positive pre-clinical studies and essentially negative clinical trials may in part be explained by a number of factors including abnormal vascular signaling, oxidative stress, a hostile local myocardial environment and technical issues related to the administration of these therapies. Patients with end-stage coronary disease are vastly different from the young, healthy animals that are generally used for pre-clinical testing. The presence of diabetes, hypercholesterolemia, and other conditions associated with endothelial dysfunction and coronary disease and altered vascular signaling can significantly limit the effectiveness of growth factors on the development of collateral vessels. This paper summarizes the results of regenerative therapies for the treatment of coronary disease and discusses the reasons why growth factor protein, gene therapies and cellular therapies have not been overall successful to date.