Different effects of a high-cholesterol diet on ischemic cardiac dysfunction and remodeling induced by coronary stenosis and coronary occlusion.

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.

Different therapeutic responses to treadmill exercise of heart failure due to ischemia and infarction in rats.

OBJECTIVE: The effects of exercise, a therapeutic tool in ischemic heart disease (IHD), may differ in ischemic and infarcted hearts. METHODS AND RESULTS: To assess this, we created coronary stenosis (CS), which reduced coronary flow reserve (CFR), or coronary occlusion to induce myocardial infarction (MI) in rats, and subjected them to treadmill exercise for either 5 (5-min Ex) or 15 min/day (15-min Ex) for 12 weeks. Left ventricular (LV) diameters were increased and ejection fractions decreased by echocardiography, and myocardial nitric oxide (NO) activity, measured by the in vitro MVO2 method, was reduced in both CS and MI rats compared with the sham. In CS rats, myocardial wall thickening fractions were not affected at 5 min of exercise, whereas they were reduced at 15 min of exercise, suggesting exercise-induced ischemia. Despite no changes in CS severity, the 5-min Ex increased CFR, ameliorated myocardial NO activity, attenuated left ventricular (LV) dysfunction and remodeling, reduced serum brain natriuretic peptide (BNP) levels, and improved survival, whereas the 15-min Ex aggravated LV dysfunction and remodeling. In contrast, neither of the exercise protocols improved these parameters in MI rats. CONCLUSIONS: Therapeutic responses to exercise differed in ischemic and infarcted hearts, partly via circulatory modulation downstream of the epicardial CS in relation to exercise-induced ischemia. When employing exercise for IHD, the causes of IHD, as well as the exercise protocols, need to be considered to achieve optimal effects.