CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Frank D. Kolodgie, PhD,
Jagat Narula, MD, PhD, FACC,
Chun Yuan, PhD,
Aloke V. Finn, MD,
Herman K. Gold, MD, FACC and
Renu Virmani, MD, FACC*
* CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, Maryland 20878 (Email: rvirmani{at}cvpath.org).
Koutouzis et al. (1) propose the paradigm of statins eliminating plaque angiogenesis and, thus, lesion instability. These authors recently showed pathologic data of reduced microvascular density in carotid plaques from patients receiving statins at least 3 months. However, direct evidence of decreased intraplaque angiogenesis attributed to statins and clinical improvement is lacking. Moreover, magnetic resonance imaging shows statins to be more effective in debulking nonhemorrhagic plaques as necrotic core volume in lesions with intraplaque hemorrhage increases, despite statin use (2). Large-scale clinical trials in parallel angiogenic disorders such as age-related macular degeneration (3) or tumor growth (4) have failed to show a consistent association between statins and disease regression. These results are in opposition to the potent antiangiogenic effects of statins in angiogenic assays (5) or animal models (6).
Although statins down-regulate various gene products that mediate cell proliferation, including vascular endothelial growth factor (7), there is an increasing redundancy of angiogenic factors creating the potential to circumvent drugs targeting specific pathways (8). Further, the expression of pro- and antiangiogenic mediators is likely dependent on lesion stage, possibly compromising the efficacy of a single drug. The identification of reliable biomarkers or imaging methods to gauge the effectiveness of antiangiogenic therapy also remains an obstacle because the current end point is limited to evaluation of surgical tissue.
Finally, it is not clear whether decreased neovascularlization or "normalization" of existing vessels is the more favorable approach because the pathology is not dictated by the mere presence of vessels, but by the fact that these structures are dysfunctional as they are fragile and leaky. A normalized, less leaky vasculature, characterized by a more restrictive basement membrane surrounded by pericytes (9), may support a more favorable microenvironment promoting plaque stabilization.
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References
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- Koutouzis M, Nomikos A, Nikolidakis S, et al. Statin treated patients have reduced intraplaque angiogenesis in carotid endarterectomy specimens Atherosclerosis 2007;192:457-463.[CrossRef][ISI][Medline]
- Takaya N, Yuan C, Chu B, et al. Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study Circulation 2005;111:2768-2775.[Abstract/Free Full Text]
- Klein R, Knudtson, MD, Klein BE. Statin use and the five-year incidence and progression of age-related macular degeneration Am J Ophthalmol 2007;144:1-6.[CrossRef][ISI][Medline]
- Dulak J, Jozkowicz A. Anti-angiogenic and anti-inflammatory effects of statins: relevance to anti-cancer therapy Curr Cancer Drug Targets 2005;5:579-594.[CrossRef][ISI][Medline]
- Park HJ, Zhang Y, Georgescu SP, Johnson KL, Kong D, Galper JB. Human umbilical vein endothelial cells and human dermal microvascular endothelial cells offer new insights into the relationship between lipid metabolism and angiogenesis Stem Cell Rev 2006;2:93-102.[Medline]
- Vincent L, Soria C, Mirshahi F, et al. Cerivastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, inhibits endothelial cell proliferation induced by angiogenic factors in vitro and angiogenesis in in vivo models Arterioscler Thromb Vasc Biol 2002;22:623-629.[Abstract/Free Full Text]
- Ahn KS, Sethi G, Aggarwal BB. Simvastatin potentiates TNF-alpha-induced apoptosis through the down-regulation of NF-kappaB-dependent antiapoptotic gene products: role of IkappaBalpha kinase and TGF-beta-activated kinase-1 J Immunol 2007;178:2507-2516.[Abstract/Free Full Text]
- Jubb AM, Oates AJ, Holden S, Koeppen H. Predicting benefit from anti-angiogenic agents in malignancy Nat Rev Cancer 2006;6:626-635.[CrossRef][ISI][Medline]
- Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy Science 2005;307:58-62.[Abstract/Free Full Text]
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