cerivastatin and Heart-Failure

HMG CoA reductase inhibitors (statins) may exert a wide array of cholesterol independent effects including antihypertrophic effects on the heart. Their role in the treatment of heart failure has not been studied.. 15 patients with heart failure NYHA II-III based on non-ischemic dilated cardiomyopathy were randomized in a double-blind study to 0.4 mg cerivastatin or placebo for an average treatment period of 20 weeks. Quality of life and exercise capacity increased significantly in the statin treatment but not in the placebo group (Minnesota Living with Heart Failure Questionnaire, 6 min walking test). Concomitantly, there was a trend towards increased left ventricular ejection fraction (radionuclear ventriculography) and improved endothelial function (forearm blood flow). Statins decreased plasma concentrations of troponine T, high sensitive C-reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1) and tumor necrosis factor alpha (TNFalpha).. Statins induce beneficial effects in patients with non-ischemic cardiomyopathy leading to improvement of quality of life and exercise capacity disclosing a promising novel treatment strategy for patients with heart failure.

Topics: Anticholesteremic Agents; Cardiomyopathy, Dilated; Double-Blind Method; Exercise Test; Female; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation Mediators; Male; Middle Aged; Prospective Studies; Pyridines; Quality of Life; Stroke Volume; Treatment Outcome

The effects of statin treatment in the setting of heart failure have already been shown. Nevertheless, there is little knowledge about its influence on adrenergic pathways in cardiomyocytes. Therefore, this study investigated the impact of cerivastatin on adrenoceptor-mediated signalling pathways in isolated adult ventricular cardiomyocytes. It focused on two endpoints: hypertrophic growth and TGFbeta expression. Cultured cardiomyocytes were used to study rac activation (analysed by its translocation into the membrane fraction), ROS formation (H(2)DCF fluorescence) and hypertrophic growth ((14)C-phenylalanine incorporation). Alpha- and beta-adrenoceptor stimulation showed significant differences regarding rac activation, ROS formation, and p38 MAP kinase activation. Both alpha- and beta-adrenoceptor stimulation induced TGFbeta expression. Upon activation of alpha-adrenergic signalling - although ROS formation was not influenced by cerivastatin - TGFbeta expression decreased. Following beta stimulation, TGFbeta expression as well as rac and p38 MAP kinase activation were reduced after pre-treatment with cerivastatin. Statin treatment did not show any influence on hypertrophic growth. In summary, this study clearly demonstrates the ability of adrenoceptor stimulation to increase TGFbeta expression. One component of the beneficial effects of statin therapy on heart failure might therefore be due to a dominant reduction and inhibition of TGFbeta, which is involved in many pathophysiological processes in cardiomyocytes.

Topics: Animals; Cells, Cultured; Enzyme Activation; Gene Expression Regulation; Heart Failure; Heart Ventricles; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; MAP Kinase Signaling System; Myocytes, Cardiac; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Pyridines; Rats; Rats, Wistar; Reactive Oxygen Species; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Transforming Growth Factor beta

The aim of the present study was to determine whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have preventive effects on the development of cardiac hypertrophy and heart failure.. Statins have been reported to have various pleiotropic effects, such as inhibition of inflammation and cell proliferation.. Dahl rats were divided into three groups: LS, the rats fed the low-salt diet (0.3% NaCl); HS, the rats fed the high-salt diet (8% NaCl) from the age of 6 weeks; and CERI, the rats fed the high-salt diet with cerivastatin 1 mg/kg/d by gavage from the age of 6 weeks.. In HS rats, cardiac function was markedly impaired and all rats showed the signs of heart failure within 17 weeks of age. In CERI rats, cardiac function was better than that of HS and no rats were dead up to 17 weeks of age. The development of cardiac hypertrophy and fibrosis was attenuated, and the number of apoptotic cells and expression of proinflammatory cytokine interleukin (IL)-1beta gene were less as compared with HS rats. Pretreatment of cerivastatin suppressed the adriamycin-induced apoptosis of cultured cardiomyocytes of neonatal rats.. These results suggest that statins have a protective effect on cardiac myocytes and may be useful to prevent the development of hypertensive heart failure.

Topics: Animals; Apoptosis; Cardiomegaly; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-1; Male; Pyridines; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Time Factors

The aim of this study was to test the feasibility of cine magnetic resonance imaging (MRI) for assessment of the infarcted rat and mouse heart and to compare the results with established methods. These models have been proven to predict genesis and prevention of heart failure in patients. The value of cine MRI was tested in studies investigating interventions to change the course of the remodeling process. MRI was performed for determination of left ventricular (LV) volumes and mass, myocardial infarct (MI) size and cardiac output. LV wet weight was determined after MRI. Rats underwent conventional hemodynamic measurements for determination of cardiac output and LV volumes by electromagnetic flowmeter and pressure-volume curves. Infarct size was determined by histology. MRI-acquired MI-size (18.5+/-2%) was smaller than that found by histology (22.8+/-2.5%, p<0.05) with close correlation (r=0.97). There was agreement in LV mass between MRI and wet weight (r=0.97, p<0.05) and in the MRI- and flowmeter measurements of cardiac output (r=0.80, p<0.05). Volume by MRI differed from pressure-volume curves with good correlation (r=0.96, p<0.05). In a serial study of mice after coronary ligation, LV hypertrophy at 8 weeks was detected (Sham 105.1+/-7.9 mg, MI 144.4+/-11.7 mg, p<0.05). Left ventricles were enlarged in infarcted mice (end-diastolic volume, week 8: Sham 63.5+/-4 microl, MI 94.2 microl, p<0.05). In conclusion, cine MRI is a valuable diagnostic tool applicable to the rat and mouse model of MI. Being non-invasive and exact it offers new insights into the remodeling process after MI because serial measurements are possible. The technique was applied to study several interventions and proved its usefulness.

Topics: Animals; Cardiac Output; Disease Models, Animal; Heart Failure; Heart Ventricles; Humans; Ischemia; Magnetic Resonance Imaging, Cine; Mice; Myocardial Infarction; Myocardial Ischemia; Pyridines; Rats; Reproducibility of Results; Sensitivity and Specificity; Species Specificity; Statistics as Topic; Stroke Volume; Testosterone; Ventricular Dysfunction, Left; Ventricular Remodeling

Blood levels of cytokines are commonly elevated in severe congestive heart failure (CHF) and in coronary artery disease (CAD). While the adverse effects of cytokines on contractile function and myocardial cell integrity are well studied, little is known on whether cardiac cells are only targets or active players in these inflammatory reactions.. We tested if human coronary artery endothelial cells (HCAEC) may become a source of cytokine and adhesion molecule expression when stimulated with bacterial lipopolysaccharide (LPS). Analysis of HCAEC supernatants by ELISA identified enhanced secretion of IL-6, IL-8, and MCP-1 while endothelin-1 was not increased. IL-1beta, IL-10, or TNF-alpha were not detectable by ELISA while RT-PCR revealed enhanced mRNA expression of IL-1beta and TNF-alpha but not IL-10. FACS analysis showed an LPS-induced upregulation of ICAM-1, VCAM, and ELAM-1. LFA-1 could not be detected. We further characterized receptors involved in LPS-induced signaling. Our results indicate that activation of HCAEC by LPS requires Toll-like receptor (TLR) 4. Pretreating the cells with the 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase inhibitor Cerivastatin reduced IL-6 release.. Taken together, our results indicate that activated HCAEC may act as inflammatory cells and thus directly contribute to the progression of CHF and CAD.

Topics: Cell Adhesion Molecules; Cells, Cultured; Chemokine CCL2; Coronary Vessels; Cytokines; Drosophila Proteins; E-Selectin; Endothelium, Vascular; Glycolipids; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-6; Interleukin-8; Lipid A; Lipopolysaccharides; Membrane Glycoproteins; Pyridines; Receptors, Cell Surface; RNA, Messenger; Stimulation, Chemical; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) attenuate angiotensin II-induced cellular signaling. Because angiotensin II is involved in left ventricular (LV) remodeling after myocardial infarction (MI), we examined the effects of statin treatment in an experimental model of chronic heart failure after MI.. Rats with extensive MI were treated with placebo or cerivastatin (0.3 mg/kg per day) as a dietary supplement or via gavage for 11 weeks starting on the 7th postoperative day. Infarct size and cholesterol levels were similar among all groups. LV cavity area, an index of LV dilatation, was reduced in MI rats on cerivastatin compared with placebo. LV end-diastolic pressure was increased in MI rats on placebo (24.1+/-4.1 mm Hg versus sham: 5.1+/-0.3 mm Hg; P<0.01), and it was significantly reduced by cerivastatin treatment (13.7+/-2.7 mm Hg; P<0.05 versus placebo). Cerivastatin partially normalized LV dP/dt(max) and dP/dt(min), indices of LV systolic and diastolic function, which were significantly reduced in MI rats on placebo. Improvement of LV function by cerivastatin was accompanied by a reduced expression of collagen type I and beta-myosin heavy chain. LV endothelial nitric oxide synthase was increased, whereas the nitrotyrosine protein level was decreased in MI rats by cerivastatin treatment.. Cerivastatin improved LV remodeling and function in rats with heart failure. This effect was associated with an attenuated LV expression of fetal myosin heavy chain isoenzymes and collagen I. Statin treatment may retard the progression of chronic heart failure.

Topics: Animals; Blotting, Northern; Blotting, Western; Collagen; Gene Expression Regulation; Heart Failure; Heart Ventricles; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Myocardial Contraction; Myocardial Infarction; Myosin Heavy Chains; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pyridines; Rats; Rats, Wistar; RNA, Messenger; Tyrosine