Atorvastatin impairs the myocardial angiogenic response to chronic ischemia in normocholesterolemic swine

• Published in: The Journal of thoracic and cardiovascular surgery Vol. 135; no. 1; pp. 117 - 122
• Main Authors: Boodhwani, Munir, MD, MMSc, Mieno, Shigetoshi, MD, Feng, Jun, MD, PhD, Sodha, Neel R., MD, Clements, Richard T., PhD, Xu, Shu-Hua, PhD, Sellke, Frank W., MD
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Mosby, Inc 2008; AATS/WTSA; Elsevier
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Atorvastatin Calcium; Biological and medical sciences; Cardiology. Vascular system; Cardiothoracic Surgery; Cholesterol - blood; Collateral Circulation - drug effects; Coronary Circulation - drug effects; Coronary heart disease; Female; Heart; Heptanoic Acids - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; In Vitro Techniques; Male; Medical sciences; Microcirculation - drug effects; Myocardial Ischemia - physiopathology; Myocarditis. Cardiomyopathies; Neovascularization, Physiologic - drug effects; Pneumology; Pyrroles - pharmacology; Swine; 23; isotope-labeled microsphere; eNOS; fibroblast growth factor; FGF; 16; 17; VEGF; vascular endothelial growth factor; 29; endothelial nitric oxide synthase; ILM; Enzyme; Enzyme inhibitor; Cardiovascular disease; Myocardial ischemia; Statin derivative; Hypocholesterolemic agent; Coronary heart disease; Myocardial disease; Vascular disease; Response; Vertebrata; Chronic; Mammalia; Swine; HMG-CoA reductase inhibitor; Atorvastatin; Hydroxymethylglutaryl-CoA reductase; Anesthesia; Artiodactyla; Oxidoreductases; Circulatory system; Cardiology; Ungulata; Antilipemic agent
• ISSN: 0022-5223; 1097-685X
• DOI: 10.1016/j.jtcvs.2007.04.021

Objective Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, used routinely in patients with coronary disease, can improve endothelial function but can have biphasic and dose-dependent effects on angiogenesis. In vitro evidence suggests that the proangiogenic effects of statins are linked to activation of Akt, a mediator of endothelial cell survival and an activator of endothelial nitric oxide synthase. We investigated the functional and molecular effects of atorvastatin supplementation on microvascular function and the endogenous angiogenic response to chronic myocardial ischemia in normocholesterolemic swine. Methods Yucatan miniswine were fed a normal diet with (ATOR, n = 7) or without (control, n = 8) atorvastatin (1.5 mg/kg/d) for 20 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Myocardial perfusion was assessed at 3 and 7 weeks using isotope-labeled microspheres. In vitro microvessel relaxation responses and myocardial protein expression were evaluated. Results Endothelium-dependent relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside were intact in both groups. The ATOR group demonstrated impaired microvessel relaxation to vascular endothelial growth factor (53% ± 3% vs 70% ± 7%, ATOR vs NORM at 10−10 mol/L, P = .05) and fibroblast growth factor-2 (35% ± 3% vs 57% ± 5%, ATOR vs NORM at 10−10 mol/L, P = .04). Baseline-adjusted myocardial perfusion in the ischemic circumflex territory was significantly reduced in the ATOR group (−0.29 ± 0.10 mL/min/g vs NORM, P = .009). Phosphorylation of Akt was significantly increased in the ATOR group (+235% ± 72%, P = .009 vs NORM), as was the myocardial expression of endostatin, an antiangiogenic protein (+51% ± 9%, P < .001 vs NORM). Expression of vascular endothelial growth factor, Tie-2, fibroblast growth factor receptor-1, and endothelial nitric oxide synthase was similar in both groups. Conclusions Atorvastatin supplementation is associated with impaired growth factor–mediated microvessel relaxation and a significant reduction in collateral-dependent perfusion. Chronic Akt activation, increased myocardial expression of endostatin, and impaired growth factor signaling may account for the diminished endogenous angiogenic response observed with atorvastatin treatment.