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  • Review Article
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Therapeutic angiogenesis for critical limb ischaemia

Nature Reviews Cardiology volume 10, pages 387–396 (2013)Cite this article

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Abstract

Peripheral arterial disease (PAD) is caused by occlusive atherosclerosis in a vascular bed other than the heart. The lower extremity is the most-common location for PAD. Critical limb ischaemia (CLI) is the most-severe clinical manifestation of PAD. Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death. The primary goal of therapy in CLI is to achieve blood flow to the distal limb vessels with angioplasty or bypass surgery. However, many patients with CLI are unsuitable for revascularization, or the procedure is unsuccessful. Angiogenesis is the growth and proliferation of blood vessels from an existing vascular structure. In therapeutic angiogenesis, attempts are made to utilize blood vessel growth to augment perfusion. In this Review, data from phase II and III clinical trials of therapeutic angiogenesis in patients with PAD will be presented and discussed. Potential explanations for the limited success of therapeutic angiogenesis in humans will be viewed in the context of advances in our understanding of the complex mechanisms underlying angiogenesis and vascular remodelling. This Review will also cover how advances in systems biology, genetics, and gene therapy might still allow the development of new approaches to therapeutic angiogenesis and achieve the goal of restoring perfusion.

Key Points

  • Peripheral arterial disease is a manifestation of systematic atherosclerosis that causes impaired blood flow to the leg; critical limb ischaemia is the most-severe form of peripheral arterial disease

  • Angiogenesis is the growth of blood vessels from existing vascular structures, whereas 'therapeutic angiogenesis' is a strategy that seeks to promote blood vessel growth to improve tissue perfusion

  • Vascular remodelling that is sufficient to augment tissue perfusion is likely to involve a combination of the processes of angiogenesis, arteriogenesis, and vasculogenesis

  • Although a series of randomized, double-blind, placebo-controlled trials in therapeutic angiogenesis have been completed, the degree of success in these studies has been limited

  • Future research directions in therapeutic angiogenesis and gene therapy include the identification of new vectors to improve gene transfer, as well as new genes designed to improve tissue perfusion

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Figure 1: Symptomatic peripheral arterial disease resulting from atherosclerotic occlusion in the arteries of the lower extremities.
Figure 2: Delivery of blood to the distal muscle bed through inflow arteries and feeder vessels, in healthy individuals and in the setting of peripheral arterial disease.

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Acknowledgements

The author's work is supported by grant 1R01HL101200 from the National Heart Lung and Blood Institute.

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  1. Division of Cardiovascular Medicine, Department of Medicine, Robert M.Berne Cardiovascular Research Center, University of Virginia, 1215 Lee Street, PO Box 800158, Charlottesville, 22908, VA, USA

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Annex, B. Therapeutic angiogenesis for critical limb ischaemia. Nat Rev Cardiol 10, 387–396 (2013). https://doi.org/10.1038/nrcardio.2013.70

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