Surgical methods for cardiac gene transfer.

Abstract

Over the last few decades, progress in the molecular biology of cardiomyocytes and the decoding of their genome through DNA sequencing has improved our insight into the pathophysiological mechanisms underlying the development of many heart diseases. The further evolution of genetic methods to investigate signal transduction, microarray analysis, and the development of transgenic animal models of various diseases including myocardial hypertrophy and others has contributed to the emergence of cardiovascular gene therapy as an important new paradigm in clinical and experimental research. These factors have resulted in the translation of cardiovascular therapy from animal studies to clinical applications more rapidly than expected. Successful plasmid DNA transfection after direct injection into beating rat hearts was demonstrated by expression of a recombinant β-galactosidase gene after 3–4 weeks. These “The further evolution of genetic methods ... has contributed to the emergence of cardiovascular gene therapy as an important new paradigm in clinical and experimental research.” results showed for the first time that cardiac muscle has a unique ability to take up and express injected recombinant DNA without recipient cell division [2]. The next historical step was the proof that viral-mediated gene transfer after intramyocardial injection is thousands of times more efficient than plasmid DNA; however, the percentage of cardiomyocytes expressing marker genes was largely limited to regions adjacent to the injection site [3,4]. Subsequent development involved intracoronary infusion of adenovirus. Viral DNA was detected in the rabbit myocardium for 2 weeks after delivery, although significant gene expression in other main organs was also recorded [5]. These and other data obtained two decades ago showed that: the route of gene delivery is no less important than the choice of vector system; and the basic methods of cardiac gene transfer were primarily intramyocardial injection and intracoronary infusion. Over time, although, it became clear that both of these methods had severe limitations and did not adequately reflect all the potentially more novel technologies of gene delivery. A classification of existing cardiac gene delivery techniques