Molecular Therapeutic Approaches for Myocardial Protection

Alok S. Pachori, PhD, Luis G. Melo, PhD, and Victor J. Dzau, md



Stategies and Tools for Genetic Manipulation of the Myocardium Gene Therapy for Myocardial Protection Perspectives and Future Directions References


Heart failure associated with coronary artery disease is a major cause of morbidity and mortality. Recent developments in the understanding of the molecular mechanisms of heart failure have led to the identification of novel therapeutic targets which, combined with the availability of efficient gene delivery vectors, offer the opportunity for the design of gene therapies for protection of the myocardium. Viral and cell-based therapies have been developed to treat polygenic and complex diseases such as myocardial ischemia, hypertension, atherosclerosis, and restenosis. In addition, cell-based therapies may have potential application in neovascularization and regeneration of ischemic and infarcted myocardium. The recent isolation of regeneration-competent endothelial precursor cells from adult bone marrow provides a novel opportunity for repair of the failing heart using autologous cell transplantation. In this chapter we will focus on the latest advances in the field of gene- and cell-based therapies for treatment of heart failure, and their clinical applications.

Key Words: Gene therapy; cell-based therapy; myocardial protection.


Despite significant advances in the clinical management of cardiovascular disease, acute myocardial infarction (MI), and heart failure (HF) resulting from coronary artery disease (CAD), cardiomyopathy and systemic vascular disease remain the prevalent

From: Contemporary Cardiology: Cardiovascular Genomics Edited by: M. K. Raizada, et al. © Humana Press Inc., Totowa, NJ

causes of premature death across all age and racial groups (1). The epidemiological impact of heart disease imposes a severe physical and financial strain on health delivery systems. The complexity of the pathological processes leading to heart disease and the lack of specific predictive markers has been a major impediment to the development of effective preventive therapies, despite the identification of various risk factors and sensitive risk assessment technologies (2-4). Consequently, the focus has been on the design of "rescue" treatments for overt symptoms of the disease, such as hyperlipidemia, myocardial ischemia, left-ventricular pump failure, and hemodynamic overload (5). Although these therapies have improved the clinical outlook for patients afflicted by MI and HF, morbidity and mortality associated with these diseases remain high, indicating the need for more effective treatments.

The current availability of efficient vector systems, such as adeno-associated virus (AAV) (6,7) and the recent identification of several gene targets associated with heart disease (8,9) offer opportunities for the design of gene therapies for myocardial protection and rescue. The ability of AAV to confer long-term and stable protein expression with a single administration of the therapeutic gene (10-12) renders them ideally suited for delivery of therapeutic genes. In addition, the repair and vascularization of injured myocardium using autologous cell transplantation may be possible with the recent identification and isolation of cardiomyocyte and endothelial progenitor cells from adult bone marrow and peripheral blood (13-16).

In this chapter we review the major advances in gene- and cell-based therapies for heart disease, with emphasis on strategies for protection and rescue of the heart from failure, their clinical feasibility, and a perspective on future developments in the field. We will highlight the breakthroughs, the challenges in making the transition from preclinical studies to clinical application, and the opportunities ahead in this exciting and growing field.


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