This Review is part of a thematic series on Cardiovascular Gene Therapy, which includes the following articles: Gene Therapy in Heart Failure Human Studies of Angiogenic Gene Therapy Gene Therapy for Cardioprotection Gene Therapy for Arrhythmias New Vecto

Abstract—With increasing knowledge of basic molecular mechanisms governing the development of heart failure (HF), the possibility of specifically targeting key pathological players is evolving. Technology allowing for efficient in vivo transduction of myocardial tissue with long-term expression of a transgene enables translation of basic mechanistic knowledge into potential gene therapy approaches. Gene therapy in HF is in its infancy clinically with the predominant amount of experience being from animal models. Nevertheless, this challenging and promising field is gaining momentum as recent preclinical studies in larger animals have been carried out and, importantly, there are 2 newly initiated phase I clinical trials for HF gene therapy. To put it simply, 2 parameters are needed for achieving success with HF gene therapy: (1) clearly identified detrimental/beneficial molecular targets; and (2) the means to manipulate these targets at a molecular level in a sufficient number of cardiac cells. However, several obstacles do exist on our way to efficient and safe gene transfer to human myocardium. Some of these obstacles are discussed in this review; however, it primarily focuses on the molecular target systems that have been subjected to intense investigation over the last decade in an attempt to make gene therapy for human HF a reality. (Circ Res. 2008;102:1458-1470.) Key Words: gene therapy heart failure cardiomyocyte myocardial contractility Heart failure (HF) (a cardiac condition that impairs theability of the ventricle to fill with or eject blood) is the ultimate consequence of a vast number of cardiovascula