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J Thorac Cardiovasc Surg 2007;133:1685-1686
© 2007 The American Association for Thoracic Surgery

Letter to the Editor

High-dose atorvastatin is associated with impaired myocardial angiogenesis in response to vascular endothelial growth factor in hypercholesterolemic swine: Relevance to the human situation?

Department of Cardiology, University of Maastricht, Maastricht, The Netherlands

To the Editor:

We read with great interest the article by Boodhwani and colleagues¹ regarding the impact of high-dose statin therapy on vascular endothelial growth factor-A (VEGF-A)–induced myocardial angiogenesis in a hypercholesterolemic pig model of chronic ischemia. This article demonstrated that collateral-dependent myocardial perfusion remained impaired in hypercholesterolemic and atorvastatin-treated pigs in response to additional treatment with VEGF-A relative to a normocholesterolemic control group. It concluded that a high-dose statin therapy was not associated with improved myocardial neovascularization. In that study, however, the hypercholesterolemic pigs were treated with an atorvastatin dosage of 3 mg/(kg · d), which exceeds the maximal possible dosage in patients (80 mg/d) by a factor of about 3.

To achieve at least moderate cholesterol lowering, pigs need to be treated with high-dose statins because of lesser lipid-lowering potency and efficacy in pigs relative to human beings.² One must remain aware, however, of the increased risk of adverse events with extremely high statin dosages. In their article, Boodhwani and colleagues¹ described a clearly decreased capillary endothelial cell density in the ischemic territory in the hypercholesterolemic and atorvastatin-treated pigs relative to the normocholesterolemic pigs and even the untreated hypercholesterolemic animals. To exclude the possibility that the hypercholesterolemic and atorvastatin-treated pigs suffered potential toxic (cellular) side effects of atorvastatin that might explain the neovascularization impairment, the investigators should have incorporated a control group of normocholesterolemic pigs treated with the same atorvastatin dosage. Moreover, treatment of the hypercholesterolemic pigs with lower atorvastatin dosages, more relevant to the human situation, might demonstrate whether there are potential dose-dependent toxic cellular side effects. Indeed, a recently published article by Chade and associates³ indicates that statins used in an intermediate (human) dosage in pigs do lead to a stimulation of arteriogenesis. Furthermore, a retrospective clinical study supports the view that intensified statin treatment is associated with an improved arteriogenic response in human beings.⁴

Another piece of evidence for statin overdose in the hypercholesterolemic pigs of Boodhwani and colleagues¹ might be the observation of prolonged Akt activation in the atorvastatin-treated pigs. Therefore, the Akt downstream signal transduction pathways in endothelial cells might not any longer be able to respond adequately to other pathophysiologic stimuli. Indeed, it has been demonstrated that a prolonged Akt activation is associated with detrimental cardiac effects in an ischemic mouse model,⁵ as was even cited by Boodhwani and colleagues¹ in their article.

Taken together, we believe that it is not appropriate to compare directly the arteriogenic effects of high-dose statin treatment in pigs and human beings in light of the approximately 3-fold higher statin dosage used in pigs.

References

1. Boodhwani M, Mieno S, Voisine P, Feng J, Sodha N, Li J, et al. High-dose atorvastatin is associated with impaired myocardial angiogenesis in response to vascular endothelial growth factor in hypercholesterolemic swine. J Thorac Cardiovasc Surg 2006;132:1299-1306.[Abstract/Free Full Text]
   
2. Hasler-Rapacz J, Kempen HJ, Princen HM, Kudchodkar BJ, Lacko A, Rapacz J. Effects of simvastatin on plasma lipids and apolipoproteins in familial hypercholesterolemic swine. Arterioscler Thromb Vasc Biol 1996;16:137-143.[Abstract/Free Full Text]
   
3. Chade AR, Zhu X, Mushin OP, Napoli C, Lerman A, Lerman LO. Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia. FASEB J 2006;20:1706-1708.[Abstract/Free Full Text]
   
4. Dincer I, Ongun A, Turhan S, Ozdol C, Ertas F, Erol C. Effect of statin treatment on coronary collateral development in patients with diabetes mellitus. Am J Cardiol 2006;97:772-774.[Medline]
   
5. Nagoshi T, Matsui T, Aoyama T, Leri A, Anversa P, Li L, et al. PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury. J Clin Invest 2005;115:2128-2138.[Medline]
   

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Czepluch, F. S. Articles by Waltenberger, J. Search for Related Content PubMed PubMed Citation Articles by Czepluch, F. S. Articles by Waltenberger, J. Related Collections Cardiac - physiology Related Article