INTRODUCTION In recent years, there have been spectacular advances in our knowledge of myocardial angiogenesis, both in the physiology and in the molecular mechanisms of this complex biological process. Since myocardial ischemia continues to be the leading cause of morbidity and mortality in our society, it is of little surprise that attempts are being made to rapidly apply this knowledge clinically to benefit the vast number of patients who are candidates for this therapy. Unfortunately, in spite of the optimistic earlier findings of many pioneering clinical trials, more recent larger and better designed clinical trials have come up with disappointing results. In this review, we will attempt to critically reappraise the strategies used in these trials, and to suggest alternative approaches for future studies. BRIEF REVIEW OF RECENT CLINICAL TRIAL RESULTS There are many different growth factors implicated in the process of angiogenesis (Figure 1). These factors, both the growth factor protein molecules and the genes encoding them, have been studied individually, in combination, or in sequence, using various animal models in vitro and in vivo. However, in human clinical trials, the studies have virtually all focused on a single growth factor for therapy, most commonly vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF). VASCULAR ENDOTHELIAL GROWTH FACTOR Many phase I clinical trials involved the administration of VEGF to a small number of patients suffering from ischemic heart disease (Table 1). Rosengart and colleagues 1 used an E1 – E3 – adenovirus gene-transfer vector expressing human VEGF 121 . Patients received either VEGF 121 alone or with concomitant coronary artery bypass grafting (CABG). The results showed a trend towards improvement as measured by coronary angiography and stress sestamibi assessment of wall motion 30 days after therapy. Patients also reported improvement of anginal class. Only the group with VEGF 121 showed increased treadmill exercise times. The improvement in anginal class and exercise times persisted for the group with VEGF 121 without CABG at the 6-month follow-up. 1 Rosengart and colleagues 1 point out that it is difficult to interpret data from the group that received both VEGF 121 and CABG. To what extent the observed improvement can be attributed to the administration of VEGF 121 rather than CABG-related watershed perfusion cannot be easily ascertained. Furthermore, this study lacked a control group so the possibility of a placebo effect exists. Indeed, in a phase I trial in which assessment of safety is the primary focus, the ethical considerations of performing a minithoracotomy with no administration of the therapeutic agent make it difficult to include a control placebo group. Therefore, control groups were absent REVIEW PAPER Reappraisal of Recent Clinical Trials of Angiogenic Therapy in Myocardial Ischemia Carolyn J Ten g, MD, Kevin Lacha pelle , FRCSC, Ray CJ Chiu , FRCSC McGill University Health Centre Royal Victoria Hospital Montreal, Canada For reprint information contact: Kevin Lacha pelle , FRCSC Tel: 1 514 843 1519 Fax: 1 514 843 1603 Email: kevin.lachapelle@mcgill.ca Royal Victoria Hospital, 687 Pine Ave West, Suite S8.30, Montreal H3A 1A1, Canada. ASIAN CARDIOVASCULAR & THORACIC ANNALS 90 2005, VOL. 13, NO. 1 ABSTRACT We review the clinical trials of angiogenic therapy for myocardial ischemia, focusing on why the results are unsatisfactory in more recent larger and better designed trials. Critical reappraisal of such trials, in view of the pathophysiologic complexity of the angiogenic process at a molecular level, suggests that the strategy of therapies based on a single growth factor protein or gene may not be adequate for optimal therapeutic response. (Asian Cardiovasc Thorac Ann 2005;13:90–7)