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Cardiovascular Research Advance Access published online on January 4, 2008
Cardiovascular Research, doi:10.1093/cvr/cvm116
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

CARDIOVASCULAR RISK FACTORS IMPAIR NATIVE COLLATERAL DEVELOPMENT AND MAY IMPAIR EFFICACY OF THERAPEUTIC INTERVENTIONS

Tim Kinnaird, MD, MRCP1,*, Eugenio Stabile, MD, PhD2, Stephan Zbinden, MD3, Mary-Susan Burnett, PhD3 and Stephen E. Epstein, MD3

1 University Hospital of Wales, Cardiff, UK
2 University of Chieti, Chieti, Italy
3 Cardiovascular Research Institute, Washington Hospital Center, Washington, DC

* Corresponding author: Tim Kinnaird, University Hospital Wales, Heath Park, Cardiff, CF14 0SA, Tel: 01144-29-20744988, Fax: 01144-29-20745432, Email: tim.kinnaird{at}cardiffandvale.wales.nhs.uk

Animal and early clinical studies of gene therapy for tissue ischemia suggested that this approach might provide benefit to patients with coronary artery disease not amenable to traditional revascularization. This enthusiasm was then tempered by the subsequent disappointing results of randomized clinical trials and led researchers to develop strategies using progenitor cells as an alternative to improve collateral function. However, the recent publication of several randomized clinical trials reporting either negative or weakly positive results using this approach have led to questions regarding its effectiveness. There are several factors that need to be considered in explaining the discordance between the positive studies of such treatments in animals and the disappointing results seen in randomized patient trials. Aside from the practical issues of arteriogenic therapies, such as effective delivery, vascular remodelling is an extraordinarily complex process, and the administration of a single agent or cell in the hope that it would lead to lasting physiological effects may be far too simplistic an approach. In addition, however, evidence now suggests that many of the traditional cardiovascular risk factors - such as age and hypercholesterolemia - may impair the host response not only to ischemia but, critically, to treatment as well. This review discusses the evidence and mechanisms for these observations and highlights future directions that might be taken in an effort to provide more effective therapies.


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