pitavastatin and Heart-Failure

The effects of lipophilic statins in heart failure (HF) were controversial. The goal of the present study was to systematically review all randomised controlled trials evaluating the effects of lipophilic statins in patients with HF.. We performed a comprehensive literature search to identify eligible trials that prospectively randomised patients with HF to lipophilic statins or control. Primary end points were all-cause mortality, cardiovascular mortality, hospitalisation for worsening HF, left ventricular ejection fraction (LVEF), and low-density lipoprotein cholesterol. Risk ratios (RRs) and Weighted mean differences (WMDs) were calculated using fixed-effects models or random-effects models.. A total of 13 randomised trials with 1,532 subjects were included in this analysis. Ten trials randomised patients to atorvastatin, two to simvastatin, and one to pitavastatin. Overall, lipophilic statins significantly decreased all-cause mortality (RR 0.53, P<0.001), cardiovascular mortality (RR 0.66, P=0.04), and hospitalisation for worsening HF (RR 0.60, P<0.001). Subgroup analyses showed that the effects of lipophilic statins in HF were not modified by age, baseline LVEF, and cause of HF. In addition, patients randomised to lipophilic statins had a significant increase in LVEF (WMD 3.91%, P<0.001) and decrease in low-density lipoprotein cholesterol (WMD 0.90 mmol/L, P<0.001).. It appears that further studies are needed to determine if lipophilic statins are beneficial for HF patients.

Topics: Atorvastatin; Cholesterol, LDL; Disease Progression; Heart Failure; Heptanoic Acids; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyrroles; Quinolines; Randomized Controlled Trials as Topic; Simvastatin; Stroke Volume; Ventricular Dysfunction, Left

This study was designed to evaluate the dose-effect relationship of statins in patients with ischemic congestive heart failure (CHF), since the role of statins in CHF remains unclear.. The South koreAn Pitavastatin Heart FaIluRE (SAPHIRE) study was designed to randomize patients with ischemic CHF into daily treatments of 10 mg pravastatin or 4 mg pitavastatin.. The low density lipoprotein cholesterol level decreased by 30% in the pitavastatin group compared with 12% in the pravastatin (p < 0.05) group. Left ventricular systolic dimensions decreased significantly by 9% in the pitavastatin group and by 5% in the pravastatin group. Left ventricular ejection fraction (EF) improved significantly from 37% to 42% in the pitavastatin group and from 35% to 39% in the pravastatin group. Although the extent of the EF change was greater in the pitavastatin group (16% vs. 11%) than that in the pravastatin group, no significant difference was observed between the groups (p = 0.386). Exercise capacity, evaluated by the 6-min walking test, improved significantly in the pravastatin group (p < 0.001), but no change was observed in the pitavastatin group (p = 0.371).. Very low dose/low potency pravastatin and high dose/high potency pitavastatin had a beneficial effect on cardiac reverse remodeling and improved systolic function in patients with ischemic CHF. However, only pravastatin significantly improved exercise capacity. These findings suggest that lowering cholesterol too much may not be beneficial for patients with CHF.

Topics: Aged; Biomarkers; Cholesterol, LDL; Down-Regulation; Dyslipidemias; Exercise Tolerance; Female; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Myocardial Ischemia; Pravastatin; Prospective Studies; Quinolines; Recovery of Function; Republic of Korea; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

Recent clinical trials using rosuvastatin, a hydrophilic statin, did not show beneficial effects on cardiovascular events in patients with heart failure. We examined the cardioprotective effects of pitavastatin, a lipophilic statin, on Japanese patients with chronic heart failure (CHF).. A total of 574 Japanese patients with CHF were randomly assigned to the pitavastatin group (n=288) or the control group (n=286). There was no significant difference between the 2 groups for the primary outcome, which was a composite of cardiac death and hospitalization for worsening HF (adjusted hazard ratio (aHR): 0.922, 95% confidence interval (CI): 0.632-1.345, P=0.672). A strongly significant statistical interaction between the effect of pitavastatin and left ventricular ejection fraction (LVEF) was found (P=0.004). In patients with LVEF ≥30%, a significant reduction in the primary outcome (aHR: 0.525, 95% CI: 0.308-0.896, P=0.018) was observed in the pitavastatin group. Pitavastatin did not show any effects on the primary outcome (aHR: 1.582, 95% CI: 0.890-2.813, P=0.118) in the subgroup of patients with LVEF <30%.. Pitavastatin did not reduce cardiac death or hospitalization for worsening HF in Japanese patients with CHF. (UMIN-ID: UMINC000000428).

Topics: Aged; Asian People; Cardiotonic Agents; Chronic Disease; Female; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Japan; Male; Middle Aged; Prospective Studies; Quinolines; Stroke Volume

HMG-CoA reductase inhibitors (statins) are known to have pleiotropic effects in addition to their lipid-lowering effect. Many studies have suggested cardioprotective effects of statins, however, recent large-scale clinical trials using rosuvastatin, a hydrophilic statin, have failed to show beneficial effects on cardiovascular events in patients with severe heart failure. We have designed the study to evaluate the effects of pitavastatin, a lipophilic statin, on Japanese patients with mild to moderate heart failure.. Five hundred seventy-seven patients with chronic heart failure were enrolled. We used a prospective, randomized, open-label, and blinded-endpoint evaluation (PROBE) design. Patients aged 20-79 years old with symptomatic (NYHA functional class II or III) heart failure and a left ventricular ejection fraction of ≤ 45% were randomly allocated to either receive pitavastatin (2mg/day) or not in addition to conventional therapy for heart failure by using the minimization method. Follow-up will be continued until March 2011. The primary endpoint is a composite of cardiac death and hospitalization for worsening heart failure.. The PEARL study will provide important data on the role of pitavastatin in the treatment of Japanese patients with mildly symptomatic heart failure (UMIN-ID: UMINC000000428).

Topics: Aged; Asian People; Chronic Disease; Death; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Prospective Studies; Quinolines; Treatment Outcome

Topics: Animals; Disease Models, Animal; Drug Delivery Systems; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Injections, Intravenous; Macrophages; Male; Mice; Mice, Inbred C57BL; Monocytes; Myocardial Infarction; Nanoparticles; Quinolines; Ventricular Remodeling

Topics: Cardiotonic Agents; Female; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Quinolines

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are widely used to lower plasma cholesterol levels, have been reported to have various pleiotropic effects such as protective effect of endothelial cells, angiogenic effect, antioxidant effect and anti-inflammatory effect. It is unclear, however, whether statins have any effects on the progression from left ventricular (LV) hypertrophy to heart failure in the established hypertrophied heart.. C57BL/6 mice were treated with pitavastatin (pitava) or vehicle (control) from 2 weeks (established hypertrophy stage) after transverse aortic constriction (TAC) and the treatment was continued for 4 weeks. Pitavastatin significantly inhibited the progression from LV hypertrophy to heart failure as assessed on echocardiography. The cardiomyocyte cross-sectional area was significantly increased in the control group compared to the sham-operated mice (sham group), but it was not significantly different between the control group and the pitava group at 6 weeks after TAC. Moreover, pitavastatin induced myocardial angiogenesis (ratio of number of endothelial cells to cardiomyocytes) and decreased the myocardial fibrosis and oxidative stress. The expression of angiopoietin-1 in the heart was significantly increased by pitavastatin at 6 weeks after TAC.. Pitavastatin has preventive effects on the progression of heart failure even in the hypertrophied heart.

Topics: Angiopoietin-1; Animals; Blood Pressure; Fibrosis; Gene Expression Regulation; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Mice; Myocardium; Neovascularization, Pathologic; Oxidative Stress; Quinolines; Time Factors

Activation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling by statins increases the activity of endothelial nitric oxide synthase (eNOS). We investigate whether statins (pitavastatin) improve cardiac function and remodeling via eNOS production associated with the PI3K-Akt signaling pathway, Rho-kinase (ROCK) pathway, and the development of oxidative stress in Dahl salt-sensitive (DS) hypertensive rats with heart failure (DSHF).. Pitavastatin (3 mg/kg per day), or pitavastatin plus specific PI3K inhibitor, wortmannin (1 mg/kg per day), or wortmannin alone were administered from the age of 11-18 weeks. Age-matched male Dahl salt-resistant (DR) rats served as a control group.. Decreased end-systolic elastance (Ees) and percent fractional shortening (%FS) in failing rats was significantly ameliorated by pitavastatin, but not pitavastatin plus wortmannin or wortmannin alone. Upregulation of eNOS and Akt phosphorylation by pitavastatin was suppressed by pitavastatin plus wortmannin or wortmannin alone. Pitavastatin effectively inhibited the vascular lesion formation such as medial thickness and perivascular fibrosis, but not pitavastatin plus wortmannin or wortmannin alone. Activated RhoA and myosin light chain phosphorylation and RhoA, ROCK expression was inhibited by pitavastatin or a specific ROCK inhibitor, Y-27632, and downregulated eNOS expression and Akt phosphorylation was ameliorated by Y-27632. Increased expression of NAD(P)H oxidase subunits and activated p65 nuclear factor (NF)-kappaB, p44/p42 extracellular signal-regulated kinases and its downstream effector p90 ribosomal S6 kinase phosphorylation in failing rat hearts was inhibited by pitavastatin.. These findings suggest that pitavastatin may improve cardiac function and remodeling via eNOS production associated with the PI3K-Akt signaling pathway, the ROCK pathway and oxidative stress.

Topics: Amides; Androstadienes; Animals; Cardiotonic Agents; Heart; Heart Failure; Male; NADPH Oxidases; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyridines; Quinolines; Rats; Rats, Inbred Dahl; rhoA GTP-Binding Protein; Ventricular Remodeling; Wortmannin

HMG-CoA reductase inhibitors (statins) have recently been reported to improve cardiac function, and decrease the incidence of heart failure (HF) in hyperlipidemic patients. However, evidence for statin treatment in patients with HF remains a subject of debate. Thus, a study was initiated to examine the effects of pitavastatin on cardiac function evaluated by echocardiographic findings and plasma brain natriuretic peptide (BNP) levels in patients with HF. Twenty-three patients with HF were treated with pitavastatin 1-2 mg/day in addition to standard therapy for 7.5 +/- 3.8 months. Left ventricular end-diastolic dimension (LVDd) and left ventricular end-systolic dimension (LVDs) were determined by echocardiography. Left ventricular ejection fraction (LVEF) was calculated using Teichholz's formula. Serum lipid and plasma BNP levels were also measured. During the follow-up period, LVEF was increased from 42 +/- 11 to 48 +/- 13% (P = 0.002). LVDs was reduced from 43 +/- 10 to 40 +/- 10 mm (P < 0.001), while there was no change in LVDd. E/A (n = 10) and deceleration time (n = 7), obtained in some patients, did not change significantly (0.89 +/- 0.33 to 0.77 +/- 0.17%, and 215 +/- 46 to 227 +/- 72 msec, respectively). In addition, the plasma BNP level was moderately, but significantly decreased from 94 +/- 78 to 70 +/- 56 pg/mL (P = 0.005). In subgroup analysis, LVEF was improved in both patients with ischemic and nonischemic HF. There was no significant correlation between the percent change in serum total cholesterol and the percent change in LVEF by pitavastatin treatment. Serum total cholesterol, LDL-cholesterol, and triglycerides decreased by 21%, 30%, and 15%, respectively, and HDL-cholesterol increased by 12%. Pitavastatin improved cardiac function in patients with HF, which generally worsens with time. The results suggest that pitavastatin may be beneficial for treatment of HF.

Topics: Aged; Aged, 80 and over; Echocardiography; Enzyme Inhibitors; Female; Heart Failure; Hemodynamics; Humans; Lipids; Male; Middle Aged; Natriuretic Peptide, Brain; Quinolines; Stroke Volume; Ventricular Function, Left

The vascular NAD(P)H oxidase-derived superoxide anion (O(2)-) plays a crucial role in the pathological progression of hypertension and atherosclerosis, and HMG-CoA reductase inhibitors (statins) have vascular antioxidant effects. However, it is unclear whether the vascular NAD(P)H oxidase is involved in the endothelial dysfunction of congestive heart failure (CHF) and whether HMG-CoA reductase inhibitors (statins) exert their vasoprotective effects in CHF. The present study examined both the involvement of vascular NAD(P)H oxidase in endothelial dysfunction in dogs with tachycardia-induced CHF and the therapeutic effect of a statin (pitavastatin).. Femoral blood flow (FBF) responses to acetylcholine was significantly impaired in the CHF group, but were improved by pitavastatin. Vascular O(2)- production, NAD(P)H oxidase activity and Nox4 and p47phox expression were significantly elevated in CHF compared with the normal group. The elevated O(2)-production in the CHF group was suppressed by the NAD(P)H oxidase inhibitor, apocynin, to the normal level. In contrast, neither the gene expression nor the activity of endothelial nitric oxide synthase (eNOS) differed significantly between the normal and CHF groups. However, pitavastatin significantly suppressed O(2)- production, NAD(P)H oxidase activity and Nox4 and p47phox expression and increased eNOS expression and activity compared with the CHF group.. The activated vascular NAD(P)H oxidase contributes to endothelial dysfunction in CHF, which was partly improved by pitavastatin via its inhibition of NAD(P)H oxidase.

Topics: Acetylcholine; Animals; Aorta; Blood Vessels; Calcium; Dogs; Endothelium, Vascular; Enzyme Inhibitors; Femoral Artery; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; NADPH Oxidases; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroglycerin; Quinolines; Regional Blood Flow; Superoxides; Vasodilator Agents