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Molecular Basis of Statin-associated Actions
S142 Journal of Cardiac Failure Vol. 15 No. 7S September 2009
Symposium 4 S4-1 Molecular Basis of Statin-associated Actions KEIJIRO SAKU Department of cardiology, Fukuoka University, Fukuoka, Japan Statins effectively reduced low-density lipoprotein cholesterol, an important risk factor for coronary artery disease, and also reduced related heart events. First of this symposium, molecular basis of statin-associated actions are introduced: how statin can interfere with protein modification at multiple steps of dysprenylation, inhibition of glycosylation, mitochondrial dysfunction, etc., which may help to understand to affect the disease of heart failure.
S4-2
S4-4 The Effects of Statin and Lipoprotein Metabolism in Heart Failure SHIN-ICHIRO MIURA, NATSUMI MORITO, YOSHINARI UEHARA, KEIJIRO SAKU Department of Cardiology, Fukuoka University, Fukuoka, Japan Statin therapy may have beneficial effects on clinical outcomes in patients with heart failure (HF). HF is associated with lipoprotein components in statin-treated patients with coronary heart disease. Recent study suggested that lower high-density lipoprotein (HDL) was the strongest predictor of worsening HF. In addition, serum total cholesterol represents a novel prognostic factor for patients with HF. Although the levels of HDL, apolipoprotein A-I, triglyceride and low-density lipoprotein are associated with the occurrence of onset HF and/or an adverse prognosis in patients with HF, it is not clearly defined which lipoprotein is the important one in this context. Among these lipoproteins, HDL protects against cardiac events by mediating the enhancement of reverse cholesterol transport. Moreover, since HDL has pleiotropic effects, such as anti-oxidant, anti-inflammatory and anti-thrombotic properties, and since cytokines and endotoxins stimulate cholesterol synthesis, the increase in HDL may therefore be a therapeutic target in HF. Therefore, we discuss about the molecular mechanisms and metabolism of HDL for preventing HF.
The Role of Statins in the Treatment of Heart Failure MASAHIKO KURABAYASHI Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Japan The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors, or statins, have been shown to reduce cardiovascular morbidity and mortality among a wide spectrum of patients with established atherosclerotic vascular disease. However, their role in the treatment of heart failure, including heart failure due to coronary artery disease, has been controversial since beneficial as well as possible harmful effects may occur. Beneficial effects include attenuation of cardiac hypertrophy, improvement in endothelial function, anti-inflammatory effects, reduction in the activity of matrix metalloproteinases, reduction in apoptosis, interference with neurohormones, and improved homeostasis. Two large-scale randomized studies designed to confirm the beneficial effects on the clinical outcome of chronic heart failure patients have been recently reported. Contrary to the expectation, data from Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico-Heart Failure and Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) suggest that statins did not have any effect on outcome despite significant reduction in low-density lipoprotein and high sensitivity C-reactive protein. Thus, there is no evidence to support initiating statin therapy in patients with symptomatic New York Heart Association IIIV heart failure, regardless of the cause.
S4-3
S4-5 Protective Effects of Statins Against Myocardial Remodeling HIROYUKI TSUTSUI Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, can lower plasma cholesterol and have been associated with reduced morbidity and mortality in patients with coronary artery disease. It is presumed that statins may cause regression or stabilization of atherosclerotic plaques by lowering serum cholesterol levels and thus exert vascular protective action. Moreover, previous experimental studies demonstrated that statins could exert direct protective effects against myocardial hypertrophy and failure. These effects of statins are attributable to their various cellular and subcellular actions independent of cholesterol lowering, including the inhibition of neurohumoral activation, the upregulation of NO, the anti-inflammatory as well as antioxidant effects, and the inhibition of matrix metalloproteinase (MMPs). We have reported that the administration of fluvastatin can improve the survival and inhibit the development of myocardial remodeling, cardiac myocyte hypertrophy and interstitial fibrosis of the noninfarcted area, after myocardial infarction in mice. These effects were associated with the attenuation of an increase of myocardial MMPs. Even though recent large-scale clinical trials such as CORONA and GISSI-HF could not demonstrate the survival benefit in heart failure patients, the potential cardioprotective effects of statins remain a subject of intensive experimental investigation.
The Potential Treatment Strategy Using Statin for Patients With Heart Failure and Normal Left Ventricular Ejection Fraction KATSUYA ONISHI Department of Cardiology, Mie University Graduate School of Medicine No therapy has been shown to improve survival in heart failure (HF) with normal ejection fraction (HFnEF). Recent data suggested that treatment with a statin was associated with a substantial improvement in survival after adjustment for differences in baseline clinical variables (hypertension, diabetes, coronary artery disease, and serum creatinine). In fact, statins have several properties that are not shared by current medical therapies for HF, suggesting that this class of drugs might result in added benefit for HFnEF patients receiving current HF therapies. Using a quantitative analysis of stress myocardial perfusion MRI, the myocardial blood flow (MBF) in subendocardial myocardium was significantly impaired during vasodilator stress in HFnEF patients, suggesting that subendocardial ischemia may be involved in the pathophysiology of HFnEF. From the point of view, statins might improve MBF in subendocardial myocardium through their beneficial effects on systemic inflammation, oxidative stress, endothelial function, and angiogenesis. The potential treatment strategy using statins for patients with HFnEF will be discussed with our preliminary perfusion MRI study. Gadolinium enhanced myocardial perfusion MR images were acquired during ATP stress and at rest using a saturation recovery balanced TFE MR sequence. Absolute MBF and myocardial perfusion reserve in subepicardial and subendocardial sides of LV wall were determined by Patlak plots.
S4-6 Effects of Statin on Heart Failure and Atrial Fibrillation ISSEI KOMURO Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan Although it has been suggested that statin has beneficial effects on heart failure and atrial fibrillation, their molecular mechanisms remain elusive. We have recently reported that pressure overload induces the transition from cardiac hypertrophy to heart failure by upregulating p53. Adriamycin induced an increase of p53 in the murine heart and cardiac dysfunctin, which were inhibited by statin. Statin also inhibited the transition from cardiac hypertrophy to heart failure of pressure-overload mice model. We are now conducting the clinical trial to elucidate the effects of statin on heart failure of Japanese. I will talk about the molecular mechanisms of atrial fibrillation, which we have recently discovered.
Symposium 4 S4-1 Molecular Basis of Statin-associated Actions KEIJIRO SAKU Department of cardiology, Fukuoka University, Fukuoka, Japan Statins effectively reduced low-density lipoprotein cholesterol, an important risk factor for coronary artery disease, and also reduced related heart events. First of this symposium, molecular basis of statin-associated actions are introduced: how statin can interfere with protein modification at multiple steps of dysprenylation, inhibition of glycosylation, mitochondrial dysfunction, etc., which may help to understand to affect the disease of heart failure.
S4-2
S4-4 The Effects of Statin and Lipoprotein Metabolism in Heart Failure SHIN-ICHIRO MIURA, NATSUMI MORITO, YOSHINARI UEHARA, KEIJIRO SAKU Department of Cardiology, Fukuoka University, Fukuoka, Japan Statin therapy may have beneficial effects on clinical outcomes in patients with heart failure (HF). HF is associated with lipoprotein components in statin-treated patients with coronary heart disease. Recent study suggested that lower high-density lipoprotein (HDL) was the strongest predictor of worsening HF. In addition, serum total cholesterol represents a novel prognostic factor for patients with HF. Although the levels of HDL, apolipoprotein A-I, triglyceride and low-density lipoprotein are associated with the occurrence of onset HF and/or an adverse prognosis in patients with HF, it is not clearly defined which lipoprotein is the important one in this context. Among these lipoproteins, HDL protects against cardiac events by mediating the enhancement of reverse cholesterol transport. Moreover, since HDL has pleiotropic effects, such as anti-oxidant, anti-inflammatory and anti-thrombotic properties, and since cytokines and endotoxins stimulate cholesterol synthesis, the increase in HDL may therefore be a therapeutic target in HF. Therefore, we discuss about the molecular mechanisms and metabolism of HDL for preventing HF.
The Role of Statins in the Treatment of Heart Failure MASAHIKO KURABAYASHI Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Japan The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors, or statins, have been shown to reduce cardiovascular morbidity and mortality among a wide spectrum of patients with established atherosclerotic vascular disease. However, their role in the treatment of heart failure, including heart failure due to coronary artery disease, has been controversial since beneficial as well as possible harmful effects may occur. Beneficial effects include attenuation of cardiac hypertrophy, improvement in endothelial function, anti-inflammatory effects, reduction in the activity of matrix metalloproteinases, reduction in apoptosis, interference with neurohormones, and improved homeostasis. Two large-scale randomized studies designed to confirm the beneficial effects on the clinical outcome of chronic heart failure patients have been recently reported. Contrary to the expectation, data from Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico-Heart Failure and Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) suggest that statins did not have any effect on outcome despite significant reduction in low-density lipoprotein and high sensitivity C-reactive protein. Thus, there is no evidence to support initiating statin therapy in patients with symptomatic New York Heart Association IIIV heart failure, regardless of the cause.
S4-3
S4-5 Protective Effects of Statins Against Myocardial Remodeling HIROYUKI TSUTSUI Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, can lower plasma cholesterol and have been associated with reduced morbidity and mortality in patients with coronary artery disease. It is presumed that statins may cause regression or stabilization of atherosclerotic plaques by lowering serum cholesterol levels and thus exert vascular protective action. Moreover, previous experimental studies demonstrated that statins could exert direct protective effects against myocardial hypertrophy and failure. These effects of statins are attributable to their various cellular and subcellular actions independent of cholesterol lowering, including the inhibition of neurohumoral activation, the upregulation of NO, the anti-inflammatory as well as antioxidant effects, and the inhibition of matrix metalloproteinase (MMPs). We have reported that the administration of fluvastatin can improve the survival and inhibit the development of myocardial remodeling, cardiac myocyte hypertrophy and interstitial fibrosis of the noninfarcted area, after myocardial infarction in mice. These effects were associated with the attenuation of an increase of myocardial MMPs. Even though recent large-scale clinical trials such as CORONA and GISSI-HF could not demonstrate the survival benefit in heart failure patients, the potential cardioprotective effects of statins remain a subject of intensive experimental investigation.
The Potential Treatment Strategy Using Statin for Patients With Heart Failure and Normal Left Ventricular Ejection Fraction KATSUYA ONISHI Department of Cardiology, Mie University Graduate School of Medicine No therapy has been shown to improve survival in heart failure (HF) with normal ejection fraction (HFnEF). Recent data suggested that treatment with a statin was associated with a substantial improvement in survival after adjustment for differences in baseline clinical variables (hypertension, diabetes, coronary artery disease, and serum creatinine). In fact, statins have several properties that are not shared by current medical therapies for HF, suggesting that this class of drugs might result in added benefit for HFnEF patients receiving current HF therapies. Using a quantitative analysis of stress myocardial perfusion MRI, the myocardial blood flow (MBF) in subendocardial myocardium was significantly impaired during vasodilator stress in HFnEF patients, suggesting that subendocardial ischemia may be involved in the pathophysiology of HFnEF. From the point of view, statins might improve MBF in subendocardial myocardium through their beneficial effects on systemic inflammation, oxidative stress, endothelial function, and angiogenesis. The potential treatment strategy using statins for patients with HFnEF will be discussed with our preliminary perfusion MRI study. Gadolinium enhanced myocardial perfusion MR images were acquired during ATP stress and at rest using a saturation recovery balanced TFE MR sequence. Absolute MBF and myocardial perfusion reserve in subepicardial and subendocardial sides of LV wall were determined by Patlak plots.
S4-6 Effects of Statin on Heart Failure and Atrial Fibrillation ISSEI KOMURO Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan Although it has been suggested that statin has beneficial effects on heart failure and atrial fibrillation, their molecular mechanisms remain elusive. We have recently reported that pressure overload induces the transition from cardiac hypertrophy to heart failure by upregulating p53. Adriamycin induced an increase of p53 in the murine heart and cardiac dysfunctin, which were inhibited by statin. Statin also inhibited the transition from cardiac hypertrophy to heart failure of pressure-overload mice model. We are now conducting the clinical trial to elucidate the effects of statin on heart failure of Japanese. I will talk about the molecular mechanisms of atrial fibrillation, which we have recently discovered.