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Vol. 56. Issue 6.
Pages 631 (June 2003)
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Vol. 56. Issue 6.
Pages 631 (June 2003)
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Angiogenesis and Statins, the Highest the Dose the Best?
Angiogénesis y estatinas, ¿a mayor dosis, mayor beneficio?
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José Luis Ibáñeza, Francisco Marína, Vanessa Roldánb
a Servicio de Cardiología. Hospital General Universitario de Alicante. España.
b Unidad de Hematología. Hospital de San Vicente. Alicante. España.
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To the Editor,

We read with great interest the excellent review article by Llevadot and Asahara on the effect of statins in angiogenesis.1 Although it was suggested that angiongenesis might be involved in the progression of coronary lesions,2 as its name indicates, this is a complex process that leads to the formation of new vessels from preexisting ones.3 Thus, induction of angiogenesis by this group of drugs may be just another of their various nonlipidic properties,4 such as improved endothelial function, reduced inflammatory response and attenuated plaque thrombogenicity. These effects may be involved in the clinically observed benefits in both primary and secondary prevention in clinical trials that have tested statins.

In recent years proof of the benefits of greater reductions in lipid levels as a result of increased doses of statins5 has raised the following questions: do the be-nefits increase with decreasing lipid levels? Do they increase with higher doses of statins?

Hypercholesterolemia has been seen to lead to worsening angiogenesis.6 In their review, Llevadot and Asahara1 show how statins reverse this condition. How-ever, the considerable antiinflammatory effect of statins7 may have important consequences, which are not always favorable. When attacked, the endothelium undergoes functional and structural changes. In principle the inflammatory response is beneficial in protecting the individual against noxious agents. Ischemia and inflammation are among the main angiogenesis-stimulating agents.8 Thus, in patients with coronary arteriosclerosis, suppressing the «adaptive» inflammatory mechanism might delay the development of collateral circulation in response to episodes of ischemia. Expe-rimental studies recently showed that statins can have a biphasic effect on angiogenesis.9,10 At low doses they increased angiogensis, whereas this effect was significantly reduced at higher doses. These findings confirm the need for further studies to analyze the effect of high doses of statins in humans, and to evaluate their long-term clinical benefits.

Bibliography
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Llevadot J, Asahara T..
Efecto de las estatinas en la inducción de angiogénesis y vasculogénesis..
Rev Esp Cardiol, 55 (2002), pp. 838-44
[2]
Inoue M, Itoh H, Ueda M, Nakuro T, Kojima A, Komatsu R, et al..
Vascular Endothelial Growth Factor (VEGF) expression in human coronary atherosclerotic lessions. Possible pathophysiological significance of VEGF in progression of atherosclerosis..
Circulation, 98 (1998), pp. 2108-16
[3]
Risau W..
Mechanism of angiogenesis..
Nature, 386 (1997), pp. 671-4
[4]
Rosenson RS, Tangney CC..
Antiatherothrombotic properties of statins: implications for cardiovascular event reduction..
JAMA, 279 (1998), pp. 1643-50
[5]
Heart Protection Study Collaborative Group..
MRC/BHF «Heart Protection Study». Study of cholesterol lowering with simvastatin in 20.536 high-risk individuals: a randomised placebo-controled trial»..
[6]
Van Belle E, Rivard A, Chen D, Silver M, Bunting S, Ferrara N, et al..
Hypercholesterolemia attenuates angiogenesis but does not preclude augmentation by angiogenic cytokines..
Circulation, 96 (1997), pp. 2667-74
[7]
Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S..
Effect of hydroymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels..
Circulation, 103 (2001), pp. 1933-5
[8]
Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, et al..
Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization..
Nat Med, 5 (1999), pp. 434-8
[9]
Weis M, Heeschen C, Glassford AJ, Cooke JP..
Statins have biphasic effects on angiogenesis..
Circulation, 105 (2002), pp. 739-45
[10]
Urbich C, Dernbach E, Zeiher AM, Dimmeler S..
Double-edged role of statins in angiogenesis signaling..
Cir Res, 90 (2002), pp. 737-44
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Revista Española de Cardiología (English Edition)

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