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Different Effects of a High-Cholesterol Diet on Ischemic Cardiac Dysfunction and Remodeling Induced by Coronary Stenosis and Coronary Occlusion

First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan

Manuscript received June 3, 2004; revised manuscript received February 28, 2005, accepted March 10, 2005.

^_* Reprint requests and correspondence: Dr. Yukio Maruyama, Professor and Chairman, First Department of Internal Medicine, Fukushima Medical University, Hikarigaoka 1, Fukushima 960-1295, Japan (Email: maruyama{at}fmc.ac.jp).

OBJECTIVES: The aim of the study was to assess whether and how the high-cholesterol diet (HCD)-related worsening of heart failure differs between coronary stenosis (CS)-induced myocardial ischemia and coronary occlusion-induced myocardial infarction (MI).

BACKGROUND: An HCD, a risk factor for coronary artery disease, also worsens ischemic heart failure. Although accelerated coronary plaque formation may be a cause of this, other mechanism(s), such as its effects through the coronary microcirculation, remain to be clarified.

METHODS: In rats fed a normal chow diet or HCD, CS or MI was created surgically, and we assessed left ventricular (LV) function by echocardiography and myocardial inflammation by histopathology. In the CS groups, CS severity by histopathology, myocardial perfusion by microspheres, myocardial protein kinase C (PKC) translocation by Western blotting, and myocardial endothelial nitric oxide (NO) function were also investigated by the in vitro myocardial oxygen consumption method.

RESULTS: Coronary stenosis impaired myocardial endothelial NO function and reduced coronary flow reserve, evoking myocardial ischemia, as shown by PKC- activation, myocardial inflammation, fibrosis, cardiac dysfunction, and remodeling. By itself, HCD greatly augmented such CS-induced myocardial abnormalities without modulating the CS severity. Such detrimental effects of HCD were ameliorated by supplying a cofactor of endothelial NO synthase—tetrahydrobiopterin. In contrast, MI-induced heart failure was not aggravated by HCD.

CONCLUSIONS: The CS-induced ischemic myocardium seems to be more susceptible to the pro-inflammatory effect of HCD than infarcted myocardium, leading to aggravation of LV dysfunction and remodeling via modification of the coronary circulation downstream of the epicardial CS site, partly through impairment of endothelial NO.

Abbreviations and Acronyms   CS = coronary stenosis   eNOS = endothelial nitric oxide synthase   HCD = high-cholesterol diet   IPC = ischemic preconditioning   L-NAME = N--nitro-L-arginine methyl ester   LV = left ventricular   MCP-1 = monocyte chemoattractant protein-1   MI = myocardial infarction   MVO2 = myocardial oxygen consumption   NCD = normal chow diet   NO = nitric oxide   PKC = protein kinase C

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