(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Heart-Failure

Previous studies regarding rhythm control in patients with atrial fibrillation (AF) could not sufficiently demonstrate the efficacy of available anti-arrhythmic drugs. 'Upstream therapy' has emerged as a potential strategy for the prevention and treatment of AF. The use of angiotensin II receptor blockers and statins has been suggested to decrease new-onset AF, but which remains inadequately explored. This study was designed to examine whether valsartan or fluvastatin can reduce the risk of non-permanent AF in patients with hypertension.. The VF-HT-AF study is a multicenter, randomized, open-label, four-arm parallel group study with comparative evaluation of valsartan and fluvastatin as upstream therapies for the treatment of non-permanent AF complicated by hypertension. The primary outcome measure is change in the development of paroxysmal AF into persistent or permanent AF, the development of persistent AF to permanent AF, and change in incidence of overall and persistent AF recurrence, as evaluated by 7-days ambulatory electrocardiograph monitoring (Holter) and patients' diaries during 2 years' follow-up. Secondary outcome measures of this study include the occurrence of: (1) fatal and nonfatal myocardial infarction; (2) heart failure (New York Heart Association stage III or IV); (3) cardiogenic shock; (4) serious bleeding necessitating hospitalization; (5) malignant ventricular arrhythmia; (6) revascularization therapy; (7) radiofrequency catheter ablation of AF; (8) changes of left atrial dimension, as measured by ultrasound echocardiography; (9) stroke; (10) cardiovascular mortality; and (11) all-cause mortality. A total of 1879 patients will be investigated from 15 medical centers throughout China to obtain the relevant information.. This is the first study in hypertensive patients complicated non-permanent AF in the Chinese population. Results of this study will inform the use of upstream therapies of AF.. chictr.org, ChiCTR-TRC-12002642.

Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atrial Fibrillation; Blood Pressure; China; Clinical Protocols; Electrocardiography, Ambulatory; Fatty Acids, Monounsaturated; Fluvastatin; Heart Failure; Heart Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Indoles; Myocardial Infarction; Prospective Studies; Recurrence; Research Design; Risk Assessment; Risk Factors; Shock, Cardiogenic; Time Factors; Treatment Outcome; Valsartan

Experimental data demonstrated that inflammatory mediators, such as pro-inflammatory and anti-inflammatory cytokines and their receptors might have important role in the development and the progression of heart failure (HF). Statins were shown to downregulate inflammatory cytokines in HF. Interleukin (IL)-10 is one of the most important anti-inflammatory cytokines. The effect of statin therapy on plasma IL-10 levels is not known in patients with HF. We conducted this study to investigate the effects of fluvastatin therapy on plasma IL-10 cytokine concentration in patients with HF.. A total of 29 patients with ischemic HF were included in this prospective uncontrolled study. Patients were assigned to fluvastatin (80 mg/day) after baseline examinations. Determination of biochemical parameters including lipids, IL-10, and tumor necrosis factor-alpha were performed at baseline and 12 weeks after the initiation of fluvastatin therapy. All participants also underwent symptom-limited exercise tolerance test at baseline and 12 weeks, and heart rate recovery (HRR) was calculated.. A significant elevation in the plasma levels of IL-10 after 12 weeks of fluvastatin treatment (4.8+ or -1.0 vs. 6.5+ or -1.3 pg/ml, P=0.002) was observed. Plasma tumor necrosis factor-alpha levels were significantly decreased after fluvastatin therapy (6.3+ or -2.3 vs. 4.8+ or -1.4 pg/ml, P=0.003). Fluvastatin therapy significantly improved HRR at 1 min after 12 weeks compared with baseline (19+ or -7 vs. 24+ or -9 bpm, P<0.001). A positive correlation between the change in the levels of IL-10 and the change in HRR at 1 min (r=0.57, P<0.001) was observed.. Fluvastatin therapy might lead to an increase in plasma IL-10 levels and an associated improvement in vagal tonus as assessed by HRR at 1 min in patients with HF. These findings might partly explain the possible benefit observed in statin trials.

Topics: Aged; Chronic Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Heart Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Interleukin-10; Male; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Up-Regulation

Randomized control trials of statins have not demonstrated significant benefits in outcomes of heart failure (HF). However, randomized control trials may not always be generalizable. The aim was to determine whether statin and statin type-lipophilic or -hydrophilic improve long-term outcomes in Africans with HF.. This was a retrospective longitudinal study of HF patients aged ≥18 years hospitalized at a tertiary healthcare center between January 1, 2009 and December 31, 2013 in Ghana. Patients were eligible if they were discharged from first admission for HF (index admission) and followed up to time of all-cause, cardiovascular, and HF mortality or end of study. Multivariable time-dependent Cox model and inverse-probability-of-treatment weighting of marginal structural model were used to estimate associations between statin treatment and outcomes. Adjusted hazard ratios were also estimated for lipophilic and hydrophilic statin compared with no statin use. The study included 1488 patients (mean age 60.3±14.2 years) with 9306 person-years of observation. Using the time-dependent Cox model, the 5-year adjusted hazard ratios with 95% CI for statin treatment on all-cause, cardiovascular, and HF mortality were 0.68 (0.55-0.83), 0.67 (0.54-0.82), and 0.63 (0.51-0.79), respectively. Use of inverse-probability-of-treatment weighting resulted in estimates of 0.79 (0.65-0.96), 0.77 (0.63-0.96), and 0.77 (0.61-0.95) for statin treatment on all-cause, cardiovascular, and HF mortality, respectively, compared with no statin use.. Among Africans with HF, statin treatment was associated with significant reduction in mortality.

Topics: Aged; Atorvastatin; Atrial Fibrillation; Black People; Cardiomyopathy, Dilated; Cardiovascular Diseases; Cause of Death; Comorbidity; Coronary Artery Disease; Diabetes Mellitus; Fatty Acids, Monounsaturated; Fluvastatin; Ghana; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Indoles; Kaplan-Meier Estimate; Longitudinal Studies; Middle Aged; Mortality; Multivariate Analysis; Probability; Proportional Hazards Models; Renal Insufficiency, Chronic; Retrospective Studies; Rosuvastatin Calcium; Simvastatin; Treatment Outcome

Statins have been reported to prevent adverse cardiovascular events in patients with myocardial infarction (MI). However, the association of statin use and the risk of pneumonia requiring hospitalization in MI patients remains unclear.. A nested case-control study was conducted by using data from the National Health Insurance Research Database of Taiwan. Among 24,975 patients with MI, 2686 case patients with pneumonia requiring hospitalization were age- and sex-matched with 10,726 control patients using the incidence density sampling approach. Duration and dosage of statin use were obtained from pharmaceutical claims. Conditional logistic regression analyses were used to estimate the risk of hospitalization for pneumonia associated with statin use adjusted for patient's demographics, medical conditions and prescribed medications.. Statin use was associated with a 15% reduced risk of pneumonia requiring hospitalization among MI patients (adjusted odds ratio [aOR] = 0.85, 95% confidence interval [CI] = 0.77-0.95, P = 0.004). The association was more significant for MI patients unexposed to statin pretreatment (aOR = 0.76, 95% CI = 0.64-0.90, P = 0.001). Statins also exhibited favorable benefits in a time- and dose-dependent manner. The results were consistent in various subgroup analysis of the patients who were female, age ≥ 65 years, a low CHADS2 (i.e. congestive heart failure, hypertension, diabetes mellitus, previous stroke and age > 75 years old) score, and fewer comorbidities. Atorvastatin, fluvastatin and simvastatin were the most common prescribed statins and had similar effects.. Statins might be considered as an adjunctive therapy to reduce the risk of hospitalization for pneumonia for MI patients under thorough evaluation of individual comorbidities, previous statin use and optimal dosage.

Topics: Aged; Atorvastatin; Case-Control Studies; Comorbidity; Diabetes Mellitus; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Incidence; Indoles; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Pneumonia; Protective Factors; Retrospective Studies; Risk Factors; Simvastatin; Stroke; Taiwan

Chronic heart failure (CHF) is characterized by left ventricular (LV) dysfunction along with impaired autonomic control functions. Herbal drugs are increasingly being used in the treatment of cardiovascular disorders. The present study was designed to examine the protective effect of Terminalia arjuna (T arjuna) bark extract on LV and baroreflex function in CHF and to elucidate the possible mechanistic clues in its cardioprotective action. The baroreflex was evaluated by measuring the changes in heart rate (HR) with changes in arterial blood pressure induced by bolus injections of phenylephrine (vasoconstrictor) and sodium nitroprusside (vasodilator). T arjuna bark extract and fluvastatin were tested/administered therapeutically and prophylactically in isoproterenol-induced rat model of CHF. Fifteen days after isoproterenol administration, rats exhibited cardiac dysfunction, hypertrophy, and LV remodeling along with reduced baroreflex sensitivity. Prophylactic and therapeutic treatment with T arjuna improved cardiac functions and baroreflex sensitivity. It also attenuated hypertrophy and fibrosis of the LV. Fluvastatin treatment exerted a similar protective effect against myocardial remodeling and heart failure. Further, T arjuna and fluvastatin significantly reduced oxidative stress and inflammatory cytokine level in CHF rats. In conclusion, T arjuna exerts beneficial effect on LV functions, myocardial remodeling, and autonomic control in CHF possibly through maintaining endogenous antioxidant enzyme activities, inhibiting lipid peroxidation and cytokine levels.

Topics: Animals; Antioxidants; Baroreflex; Chronic Disease; Cytokines; Disease Models, Animal; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoproterenol; Male; Nitroprusside; Oxidative Stress; Phenylephrine; Plant Bark; Plant Extracts; Rats; Rats, Wistar; Terminalia; Ventricular Dysfunction, Left

The present study demonstrated prophylactic and therapeutic potential of Terminalia arjuna bark extract in isoproterenol (ISO)-induced chronic heart failure (CHF). Fifteen days after injection of ISO (85 mg/kg twice at an interval of 24 h, s.c), rats showed decline in maximal rate of rise and fall of left ventricular pressure (LV (dP/dt)(max) and LV (dP/dt)(min)), cardiac contractility index (LV (dP/dt)(max)/LVP), cardiac output and rise in LV end-diastolic pressure. CHF rats showed a significant increase in serum creatine kinase isoenzyme-MB (CK-MB) and malondialdehyde levels, as well as fall in the activities of superoxide dismutase, reduced glutathione. Altered lipid profile and increased level of cytokine tumour necrosis factor-α (TNF-α) along with histological changes in heart were also observed in CHF rats. T. arjuna bark extract (500 mg/kg, p.o) treatment prior and 15 days after ISO injection significantly attenuated cardiac dysfunction and myocardial injury in CHF rats. Cardioprotective action of T. arjuna was comparable to fluvastatin, a synthetic drug. The results suggest that T. arjuna bark extract has a significant prophylactic and therapeutic beneficial effect on protection of heart against ISO-induced CHF possibly through maintaining endogenous antioxidant enzyme activities, inhibiting lipid peroxidation and cytokine levels.

Topics: Animals; Cardiac Output; Cardiotonic Agents; Chronic Disease; Creatine Kinase, MB Form; Disease Models, Animal; Fatty Acids, Monounsaturated; Fluvastatin; Glutathione; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoproterenol; Lipids; Malondialdehyde; Myocardial Contraction; Myocardium; Plant Bark; Plant Extracts; Rats; Rats, Wistar; Superoxide Dismutase; Terminalia; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Function, Left; Ventricular Pressure

Topics: Animals; Anticholesteremic Agents; Evidence-Based Medicine; Fatty Acids, Monounsaturated; Fluvastatin; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Prospective Studies; Treatment Outcome

Statins may provide additional benefits in patients with cardiac failure due to their pleiotropic effects besides their cholesterol-lowering actions. In this study, we aimed to evaluate the impact of 12-week fluvastatin therapy on the inflammatory cytokines and the ventricular performance markers in patients with heart failure.. Fourty chronic heart failure patients, twenty with idiopathic dilated cardiomyopathy (DCM group) and 20 with ischemic cardiomyopathy (ICM group), for whom statin treatment was indicated according to Adult Treatment Panel III were included to this open label and prospective study. After a 12-week treatment with fluvastatin 80 mg/day; clinical functional capacity, echocardiographic indices of cardiac performance and inflammatory markers were evaluated. After the treatment, functional capacity (in DCM group: 2.05+/-0.4 versus 1.65+/-0.6, p=0.005; in ICM group: 2.25+/-0.5 versus 1.8+/-0.6, p=0.003), left ventricular ejection fraction, LVEF (from 30+/-5% to 33+/-5%, p=0.001 in DCM and 29+/-4% to 31+/-5%, p=0.001 in ICM group) and tissue Doppler mitral annular systolic velocity, Sm (5.8+/-1 cm/s to 7+/-1 cm/s, p=0.001 in DCM and 5.4+/-0.8 cm/s to 7+/-1 cm/s, p=0.001 in ICM group) improved. Tumor necrosis factor-alpha and interleukin-6 levels decreased, but no significant changes in high sensitive C-reactive protein and brain natriuretic peptide levels were detected with the fluvastatin treatment in both groups.. Fluvastatin improved cardiac functions and the clinical symptoms in HF patients with either idiopathic dilated or ischemic etiology. This positive effect of fluvastatin which might be secondary to inflammatory modulation was more marked in patients with ischemic etiology. Statins in HF deserves special attention by means of further large-scale trials.

Topics: Aged; Biomarkers; Chronic Disease; Cytokines; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Prospective Studies; Time Factors; Ventricular Function, Left

Innate immune activation mediated by myocardial Toll-like receptors (TLRs) is involved in cardiovascular disease. The function and role of TLRs on peripheral leukocytes in human chronic heart failure (CHF) are not known.. We measured whole blood TLR4 and TLR2 expressions in 28 patients with CHF (64+/-2 years, New York Heart Association [NYHA] functional class 2.2+/-0.1, left ventricular (LV) ejection fraction 32+/-2%) and 13 healthy subjects of similar age and gender.. As assessed by flow cytometry, TLR4 and TLR2 were detected on CD14+ monocytes. Unstimulated monocyte TLR4 expression was significantly higher in CHF patients compared to controls (mean fluorescence intensity, 3.57+/-0.57 vs. 1.72+/-0.32, p<0.05). TLR2 expressions were similar in CHF patients and control subjects (p=0.5). TLR4 levels correlated with the severity of CHF (NYHA class I/II: 2.66+/-0.40, and NYHA class III/IV: 5.08+/-1.24, p<0.01) and with serum lipid levels (total cholesterol, r=-0.44, p<0.01 and high-density lipoprotein, r=-0.68, p<0.001). After stimulation of monocytes by lipopolysaccharide (LPS, 10 ng/ml, 3 h), activated TLR4 was higher in CHF patients (p<0.05). Pre-incubation with fluvastatin for 24 h inhibited dose-dependently ex vivo monocyte TLR4 and TLR2 expressions (p<0.001).. This study suggests that upregulation of monocyte TLR4 may contribute to the pathophysiology of chronic heart failure. Fluvastatin may prevent excessive innate immune response in vitro in chronic heart failure by inhibition of monocyte Toll-like receptor signaling.

Topics: Aged; Analysis of Variance; Case-Control Studies; Chronic Disease; Fatty Acids, Monounsaturated; Female; Flow Cytometry; Fluvastatin; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Monocytes; Statistics, Nonparametric; Toll-Like Receptor 4

Heart rate recovery is the difference in heart rate at peak exercise and at a specific time interval following the onset of recovery. Attenuated heart rate recovery is an independent predictor of mortality in patients with a history of coronary artery disease. The aim of the present study was to evaluate the effect of a statin on heart rate recovery, particularly in patients with ischemic heart failure and hyperlipidemia. Twenty-nine consecutive hyperlipidemic, stable coronary artery disease patients with heart failure and 19 healthy subjects were enrolled. Heart rate recovery values at the 1st and 3rd minutes and lipid profiles of the patients were evaluated at baseline and following 3 months of treatment with fluvastatin. Compared with healthy subjects, the heart rate recovery values were significantly lower in the heart failure patients in both the 1st and 3rd minutes, respectively (31 +/- 6 versus 19 +/- 7, P < 0.0001; 66 +/- 7 versus 47 +/- 8, P < 0.0001). Heart rate recovery in the 1st and 3rd minutes increased from 19 +/- 7 to 24 +/- 9 and 47 +/- 8 to 57 +/- 11, respectively, following treatment (P < 0.001, P < 0.001). There were no significant correlations among the changes in lipid parameters or HRR in the first and third minutes in the recovery period. The results revealed an improvement in heart rate recovery in heart failure patients by fluvastatin treatment. If this association can be confirmed by other studies, it would be interesting to perform further studies into the mechanism underlying this finding.

Topics: Aged; Anticholesteremic Agents; Coronary Artery Disease; Exercise; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Heart Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Lipids; Male; Middle Aged; Parasympathetic Nervous System; Recovery of Function

Short-term administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to attenuate ischemia-reperfusion injury. However, the effects of long-term administration of statins on left ventricular (LV) remodeling and failure after myocardial infarction remain unknown.. Mice were subjected to coronary artery ligation and were treated for 4 weeks with vehicle or fluvastatin (10 mg/kg per day PO). Fluvastatin increased survival (61% versus 86%; P<0.05) without affecting the infarct size (52+/-2% versus 49+/-3%; P=NS). Fluvastatin not only attenuated LV dilatation but also decreased LV end-diastolic pressure and lung weight. Furthermore, it reduced cardiac myocyte hypertrophy and interstitial fibrosis of the noninfarcted LV and also improved LV ejection performance. LV matrix metalloproteinase (MMP)-2 and MMP-13 were increased in myocardial infarction, which was attenuated in fluvastatin-treated mice.. Fluvastatin increased survival in a murine model of postinfarct heart failure, which was associated with the amelioration of LV structural remodeling and contractile failure. Moreover, these effects were associated with the attenuation of increased MMP activity. Thus, long-term treatment with fluvastatin might be beneficial also in patients with heart failure and might improve their long-term survival.

Topics: Administration, Oral; Animals; Blotting, Western; Body Weight; Dilatation, Pathologic; Disease Models, Animal; Echocardiography; Fatty Acids, Monounsaturated; Fluvastatin; Heart Failure; Hemodynamics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lung; Male; Matrix Metalloproteinases; Mice; Myocardial Infarction; Myocardium; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Organ Size; Peptidyl-Dipeptidase A; Survival Rate; Ventricular Function, Left; Ventricular Remodeling