Ann Thorac Surg 2006;81:2225-2226
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Invited commentary
Jun Feng, MD, PhD,
Frank W. Sellke, MD
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, DA 880, Boston, MA 02215
(Email: jfeng{at}caregroup.harvard.edu; fsellke{at}caregroup.harvard.edu).
Li and colleagues [1] in the present study provide provocative in vivo experimental data to support the notion that pravastatin (5 or 50 mg/kg/d) improves remodeling and cardiac function after acute myocardial infarction through anti-inflammatory mechanisms, rather than pro-angiogenic pathways. Furthermore, combination of pravastatin (50 mg/kg/d) with bone marrow mononuclear cells (BM-MNCs) implantation failed to induce synergistic effects of angiogenesis. These interesting and provocative findings heated current controversies on the issues of potential statins-related myocardial and angiogenic effects.
"From bench to bedside," statins have been found to reduce the risk of coronary event by cholesterol-lowering dependent and independent mechanisms [2, 3]. From bench-scientists' reports, however, the effects of statins on angiogenesis are controversial. Collectively, the effects of statins on angiogenesis appear to be biphasic and dose-dependent. Low-dose statins promote angiogenesis, whereas, higher-dose statins appear to be anti-angiogenic. Indeed, it has recently been found that high-dose atorvastatin (3 mg/kg/d) improved endothelial function without improving collateral-dependent myocardial perfusion in hypercholesterolemic pigs [4]. Furthermore, atorvastatin also impaired the myocardial angiogenesis response to chronic ischemia in normocholesterolemic pigs [5]. The mechanism underlying statins-induced impairment of the angiogenetic response at high doses is still the subject of debate, but is likely multifactorial and involves a reduction in the release of vascular endothelial growth factor (VEGF). Li and colleagues in this study [1] support these findings, indicating that high-dose statins may reduce the secretion of VEGF, but that low-dose statins did not inhibit VEGF from cultured blood peripheral mononuclear cells.
Like all good experimental studies, some limitations still exist in the present investigation. First, the authors only used morphologic marker (microvascular density) to examine the development of angiogenesis. Combinations with other methods, such as myocardial perfusion with microspheres, and collateral imaging with angiograph, single photon emission computed tomography and positron emission tomography may be very helpful to identify the development of angiogenesis. However, these techniques are well proved in large animal model, but not in the rat model. Second, the majority of previous studies have shown that low-dose statins promote the mobilization of endothelial progenitor cells (EPCs), but pravastatin (5 mg/kg/d) in this study failed to affect circulation EPCs. Third, the authors did not examine the same protocols in normal rats without hypercholesterolemia since the angiogenic and other myocardial beneficial effects of statins have been found to be cholesterol-lowering independent (pleiotropic), and even beyond anti-inflammatory. Fourth, the present data cannot explain why there was no additive protection when combining pravastatin with BM-MNCs transplantation. In other words, they have provided no mechanistic information other than the findings of no synergistic effects. Finally, the clinical relevance of current findings on the effects of pravastatin is still questionable since the concentrations (5-50 mg/kg/d) used in this study are about 10-100 fold higher than those (20-40 mg/d) achieved in patients. Thus, a word of caution should be permitted with regard to the interpretation of results. Further studies will be necessary to understand the full implications of their findings in patients and other clinically mimicked experimental models, such as large animal models with chronic ischemia.
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- Li T-S, Takahashi M, Suzuki R, et al. Pravastatin improves remodeling and cardiac function after myocardial infarction by an antiflammatory mechanism rather than by the induction of angiogenesis Ann Thorac Surg 2006;81:2217-2226.[Abstract/Free Full Text]
- Werba JP, Tremoli E, Massironi P, et al. Statins in coronary bypass surgeryrationale and clinical use. Ann Thorac Surg 2003;76:2132-2140.[Abstract/Free Full Text]
- Pascual DA, Arribas JM, Tornel PL. Preoperative statin therapy and troponin T predict early complications of coronary artery surgery Ann Thorac Surg 2006;81:78-83.[Abstract/Free Full Text]
- Boodhwani M, Nakai Y, Voisine P, Sellke FW. High dose atorvastatin improves hypercholesterolemic endothelial dysfunction without improving collateral-dependent myocardial perfusionrole of endostatin and vascular endothelial growth factor. Circulation 2005;112(Suppl II):II-376.
- Boodhwani M, Voisine P, Feng J, et al. Atorvastatin impairs myocardial angiogenic response to chronic ischemia in normocholesteromic swine Circulation 2005;112(Suppl II):II270.
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