This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Osipov, R. M. Articles by Sellke, F. W. PubMed Articles by Osipov, R. M. Articles by Sellke, F. W. Related Collections Contractile function Animal models of human disease Apoptosis Risk Factors Ischemic biology - basic studies Acute myocardial infarction Oxidant stress

(Circulation. 2009;120:S22-S30.)
© 2009 American Heart Association, Inc.

Myocardial Protection, Perioperative Management, and Vascular Biology

Effect of Hypercholesterolemia on Myocardial Necrosis and Apoptosis in the Setting of Ischemia-Reperfusion

Robert M. Osipov, MD; Cesario Bianchi, MD, PhD; Jun Feng, MD, PhD; Richard T. Clements, PhD; Yuhong Liu, MD; Michael P. Robich, MD; Hilary P. Glazer; Neel R. Sodha, MD; Frank W. Sellke, MD, FAHA, FACS

From the Division of Cardiothoracic Surgery (R.M.O., C.B., J.F., R.T.C., Y.L., M.P.R., H.P.G., F.W.S.) and the Department of Surgery (N.R.S.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; and the Alpert Medical School of Brown University (F.W.S.), Providence, RI.

Correspondence to Frank W. Sellke, MD, Division of Cardiothoracic Surgery, Alpert School of Medicine at Brown University, Rhode Island Hospital, 2 Dudley St, Providence, RI 02905. E-mail Frank_Sellke{at}brown.edu

Background— Hypercholesterolemia is prevalent in patients who experience myocardial ischemia-reperfusion injury (IR). We investigate the impact of dietary-induced hypercholesterolemia on the myocardium in the setting of acute IR.

Methods and Results— In normocholesterolemic (NC, n=7) and hypercholesterolemic (HC, n=7) Yucatan male pigs, the left anterior descending coronary artery was occluded for 60 minutes, followed by reperfusion for 120 minutes. Hemodynamic values were recorded, and TTC staining was used to assess necrosis. Oxidative stress was measured. Specific cell death and survival signaling pathways were assessed by Western blot and TUNEL staining. Infarct size was 45% greater in HC versus NC (42% versus 61%, P<0.05), whereas the area at risk (AAR) was similar in both groups (P=0.61). Whereas global LV function (+dP/dt, P<0.05) was higher during entire period of IR in HC versus NC, regional function deteriorated more following reperfusion in HC (P<0.05). Ischemia increased indices of myocardial oxidative stress such as protein oxidation (P<0.05), lipid peroxidation (P<0.05), and nitrotyrosylation in HC versus NC, as well as the expression of phospho-eNOS (P<0.05). The expression of myeloperoxidase, p38 MAPK, and phospho-p38 MAPK was higher in HC versus NC (all P<05). Ischemia caused higher expression of the proapoptotic protein PARP (P<0.05), and lower expression of the prosurvival proteins Bcl2 (P<0.05), phospho-Akt, (P<0.05), and phospho-PKC (P<0.05) in the HC versus NC. TUNEL-positive cell count was 3.8-fold (P<0.05) higher in the AAR of HC versus NC.

Conclusions— This study demonstrates that experimental hypercholesterolemia is associated with increased myocardial oxidative stress and inflammation, attenuation of cell survival pathways, and induction of apoptosis in the ischemic territory, which together may account for the expansion of myocardial necrosis in the setting of acute IR.

Key Words: apoptosis • hypercholesterolemia • ischemia • myocardial infarction • risk factors