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1.
Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease.
Nakamura, T, Uematsu, M, Yoshizaki, T, Kobayashi, T, Watanabe, Y, Kugiyama, K
Journal of cardiology. 2020;(3):270-274
Abstract
BACKGROUND Remnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment. METHODS A total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD; <5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6-9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD. RESULTS Treatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = -0.18, p = 0.03), RLP-C (r = -0.39, p < 0.001), RLP-C/TG (r = -0.34, p < 0.001), and CRP (r = -0.27, p < 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels. CONCLUSION Improvement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.
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2.
High remnant lipoprotein predicts recurrent cardiovascular events on statin treatment after acute coronary syndrome.
Nguyen, SV, Nakamura, T, Kugiyama, K
Circulation journal : official journal of the Japanese Circulation Society. 2014;(10):2492-500
Abstract
BACKGROUND After acute coronary syndrome (ACS), there is a high risk of recurrent cardiovascular events. Triglyceride-rich lipoproteins influence residual cardiovascular risk in patients taking statin. This study examined the predictive value of remnant lipoprotein level for secondary cardiovascular events in patients treated with statins after ACS. METHODS AND RESULTS A total of 190 patients treated with statins after ACS were enrolled in the study. The serum level of remnant lipoproteins (remnant-like lipoprotein particle cholesterol; RLP-C) was measured using an immunoseparation method. All the patients were followed prospectively for a maximum period of 70 months or until the occurrence of one of the following events: cardiac death, non-fatal myocardial infarction, unstable angina requiring unplanned coronary revascularization, or ischemic stroke. During the follow-up period, 42 patients had a secondary event. Multivariate Cox analysis showed that a high level of RLP-C (≥5.4 mg/dl; determined on receiver operating characteristic curve analysis) was a significant risk factor for secondary events, independent of conventional risk factors (hazard ratio, 2.94; 95% confidence interval: 1.40-6.18; P<0.01). The addition of high RLP-C to traditional risk factors enhanced net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI, 0.66, P=0.0003; and IDI, 0.08, P=0.0002). CONCLUSIONS RLP-C is useful for risk assessment of secondary cardiovascular events in patients treated with statins after ACS.
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3.
Echolucency of carotid plaque is useful for assessment of residual cardiovascular risk in patients with chronic coronary artery disease who achieve LDL-C goals on statin therapy.
Uematsu, M, Nakamura, T, Sugamata, W, Kitta, Y, Fujioka, D, Saito, Y, Kawabata, K, Obata, JE, Watanabe, Y, Watanabe, K, et al
Circulation journal : official journal of the Japanese Circulation Society. 2014;(1):151-8
Abstract
BACKGROUND Ultrasound assessment of either intima-media thickness (IMT) or plaque echolucency of the carotid artery provides prognostic information on coronary events. This study examined the hypothesis that IMT and plaque echolucency of the carotid artery may remain useful for prediction of coronary events in patients with coronary artery disease (CAD) after achievement of LDL-C goals on statin therapy. METHODS AND RESULTS Ultrasound assessment of carotid maximum IMT (maxIMT) and plaque echolucency with integrated backscatter (IBS) analysis was performed in 357 chronic CAD patients with LDL-C <100mg/dl on statin therapy. All patients were prospectively followed up until the occurrence of one of the following coronary events: cardiac death, non-fatal myocardial infarction, or unstable angina pectoris requiring unplanned revascularization. During a mean follow-up of 32±18 months, 33 coronary events occurred. On multivariate Cox proportional hazards analysis, plaque echolucency (lower IBS value) was a significant predictor of coronary events (HR, 0.44; 95% CI: 0.29-0.73; P=0.009), whereas maxIMT was not. The addition of plaque echolucency to traditional risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI; NRI, 0.59; P=0.0013; and IDI, 0.075; P=0.0009). CONCLUSIONS Measurement of echolucency of the carotid artery was useful for assessment of residual coronary risk in CAD patients after LDL-C goal attainment on statin treatment.
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4.
A comparison of the efficacy of combined ezetimibe and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy.
Nakamura, T, Hirano, M, Kitta, Y, Fujioka, D, Saito, Y, Kawabata, K, Obata, JE, Watanabe, Y, Watanabe, K, Kugiyama, K
Journal of cardiology. 2012;(1):12-7
Abstract
BACKGROUND AND PURPOSE It remains undetermined whether the addition of ezetimibe to ongoing statin therapy is more effective than increasing the dose of statin for reducing remnant lipoprotein levels in patients with remnant lipoproteinemia on previous statin treatment. This study examined whether combined ezetimibe and statin therapy resulted in a greater improvement in remnant lipoprotein levels and endothelial function than with the dose of statin in patients with remnant lipoproteinemia on previous statin treatment. METHODS AND RESULTS A total of 63 patients with stable coronary artery disease and high levels of remnant-like lipoprotein particle cholesterol (RLP-C) (≥5.0 mg/dL) on statin treatment were assigned randomly to two groups and treated with either addition of ezetimibe (10mg/day, n=32) or doubling of statin dose (n=31). The lipid profiles and flow-mediated dilation (FMD) of the brachial artery were measured at enrollment and after 6 months of treatment. Statin and ezetimibe combined therapy reduced RLP-C and improved FMD to a greater extent than doubling the statin dose (% reduction in RLP-C, 48 ± 18% vs. 33 ± 24%, respectively, p=0.01; % improvement in FMD, 47 ± 48% vs. 24 ± 23%, respectively, p=0.02). CONCLUSIONS The addition of ezetimibe to ongoing statin treatment reduced RLP-C levels and improved endothelial dysfunction to a greater extent than doubling the statin dose in patients with high RLP-C levels on previous statin treatment. The present results are preliminary and should be confirmed by further studies on a larger number of study patients.
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5.
Potential benefit of statin therapy for dyslipidemia with chronic kidney disease: Fluvastatin Renal Evaluation Trial (FRET).
Inoue, T, Ikeda, H, Nakamura, T, Abe, S, Taguchi, I, Kikuchi, M, Toyoda, S, Miyazono, M, Kishi, T, Sanai, T, et al
Internal medicine (Tokyo, Japan). 2011;(12):1273-8
Abstract
BACKGROUND Dyslipidemia is a common complication of chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality of CKD patients. AIM: The aim of the present study was to determine whether fluvastatin, which is mostly characterized by its pleiotropic anti-oxidant effects, has renoprotective effects in dyslipidemic patients with CKD. METHODS In 43 dyslipidemic patients with CKD taking fluvastatin 10 mg/day, 20 mg/day or 30 mg/day, renal functions as well as lipid profiles were assessed. RESULTS After 3 months of treatment with fluvastatin, LDL-cholesterol level significantly decreased. Serum creatinine level, estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), urinary liver-type fatty acid binding protein (L-FABP) level and urinary 8-hydroxydeoxyguanosine (8-OHdG) level did not change in overall patients. However, in patients with microalbuminuria (baseline UAE ≥ 30 mg/g·creatinine; n = 23), the UAE significantly decreased [2.43 ± 0.67 to 1.98 ± 0.80 log(mg/g·creatinine), p = 0.01]. In patients with high L-FABP group (baseline L-FABP ≥ 11 µg/g·creatinine; n = 18), the urinary L-FABP level was significantly decreased (1.52 ± 0.45 to 1.26 ± 0.43 µg/g·creatinine, p < 0.01). In the limited 23 patients with microalbuminuria, the L-FABP level was significantly decreased [1.20 ± 0.62 to 1.03 ± 0.49 log(µg/g·creatinine), p = 0.042], although the LDL-cholesterol level (139 ± 28 to 129 ± 23 mg/dL, p = 0.08) only showed a tendency to decrease. The 8-OHdG level also was significantly decreased (13.6 ± 9.6 to 9.8 ± 3.8 ng/g·creatinine, p = 0.043). In the overall patients, changes in the values for UAE and urinary L-FABP were not correlated with the changes in LDL-levels. CONCLUSION Fluvastatin reduces both UAE and the urinary L-FABP level, and thus, has renoprotective effects, independent of its lipid lowering effects in dyslipidemic patients with CKD.
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6.
Co-administration of ezetimibe enhances proteinuria-lowering effects of pitavastatin in chronic kidney disease patients partly via a cholesterol-independent manner.
Nakamura, T, Sato, E, Fujiwara, N, Kawagoe, Y, Ueda, Y, Suzuki, T, Ueda, S, Fukami, K, Okuda, S, Yamagishi, S
Pharmacological research. 2010;(1):58-61
Abstract
Since co-administration of ezetimibe, a specific inhibitor of cholesterol absorption into the intestine, has been shown to augment lipid-lowering effects of statins, ezetimibe plus statins is a novel therapeutic strategy for the treatment of dyslipidemia in high-risk patients. Statins have been shown to ameliorate renal function and reduce proteinuria in patients with chronic kidney disease (CKD). However, effects of co-administration of ezetimibe with statins on renal damage and dysfunction in CKD patients remain unknown. In this study, we examined whether co-administration of ezetimibe with pitavastatin could augment renoprotective properties of pitavastatin in non-diabetic CKD patients with dyslipidemia. Total cholesterol, LDL-cholesterol and triglycerides levels were reduced more by co-administration of ezetimibe (10mg/day) with pitavastatin (2mg/day) (n=10) than by pitavastatin alone (n=10). In addition, ezetimibe plus pitavastatin treatment produced significant incremental reduction in proteinuria related to pitavastatin therapy alone. In univariate analyses, proteinuria was correlated with plasma levels of total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol (inversely), asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, and urinary excretion levels of L-fatty acid binding protein (L-FABP), a marker of tubular injury and 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker. Multiple stepwise regression analysis revealed that LDL-cholesterol (p<0.001) and urinary excretion levels of L-FABP (p=0.001) and 8-OHdG (p<0.001) were independently related to proteinuria (R(2)=0.969). Our present study demonstrated for the first time that co-administration of ezetimibe enhanced proteinuria-lowering effects of pitavastatin in non-diabetic CKD patients partly via a cholesterol-independent manner. Ezetimibe may have pleiotropic actions that could contribute to renoprotective properties of this lipid-lowering agent.
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7.
Rapid stabilization of vulnerable carotid plaque within 1 month of pitavastatin treatment in patients with acute coronary syndrome.
Nakamura, T, Obata, JE, Kitta, Y, Takano, H, Kobayashi, T, Fujioka, D, Saito, Y, Kodama, Y, Kawabata, K, Mende, A, et al
Journal of cardiovascular pharmacology. 2008;(4):365-71
Abstract
We determined time course of stabilization of echolucent carotid plaques by statin therapy in patients with acute coronary syndrome (ACS). Treatment with 4 mg/d pitavastatin (n = 33) or placebo (n = 32) was initiated within 3 days after onset of ACS in 65 patients with echolucent carotid plaque. Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) analysis before and 1 month after treatment in all patients. The calibrated IBS value (intima-media IBS value minus adventia IBS) of vulnerable carotid plaques favorably changed at 1 month after treatment in both groups, but the echolucency at 1 month improved more in the pitavastatin than in the placebo group (pitavastatin group: -18.7 +/- 3.3 dB at pretreatment versus -12.7 +/- 2.3 dB at 1 month *P < 0.001; placebo: -19.0 +/- 3.5 dB versus -16.9 +/- 3.2 dB, P < 0.05, *P < 0.01 versus the value at 1 month in placebo group). Levels of CRP, VEGF, and TNFalpha at 1 month were significantly lower in pitavastatin than placebo group. In conclusion, pitavastatin improved carotid plaque echolucency within 1 month of therapy in patients with ACS, in association with decrease in the inflammatory biomarkers related to vulnerable plaques.
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8.
Effect of cerivastatin on proteinuria and urinary podocytes in patients with chronic glomerulonephritis.
Nakamura, T, Ushiyama, C, Hirokawa, K, Osada, S, Inoue, T, Shimada, N, Koide, H
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2002;(5):798-802
Abstract
BACKGROUND We previously reported urinary podocytes to be a marker of glomerular injury. The aim of the present study was to determine whether cerivastatin, a newly developed, potent synthetic statin, affects proteinuria and urinary podocyte excretion in patients with chronic glomerulonephritis (CGN). METHODS We randomly assigned 40 normotensive hypercholesterolemic patients with CGN to receive either cerivastatin 0.15 mg/day (n=20) or placebo (n=20). Subjects comprised 24 men and 16 women, with a mean age of 40.8+/-14.4 years; 27 had IgA nephropathy and 13 had non-IgA proliferative glomerulonephritis. Treatment was continued for 6 months. Plasma total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides, urinary protein excretion and the number of podocytes were measured before treatment and at 3 and 6 months after treatment. RESULTS After 6 months, a significant reduction in total cholesterol (P<0.001), LDL-cholesterol (P<0.001) and triglycerides (P<0.05), and a significant increase in HDL-cholesterol (P<0.001) were observed in the group treated with cerivastatin. Urinary protein excretion decreased from 1.8+/-0.6 to 0.8+/-0.4 g/day, (P<0.01) in this group, and urinary podocyte excretion decreased from 1.6+/-0.6 to 0.9+/-0.4 cells/ml (P<0.01). However, placebo showed little effect on these lipid levels, urinary protein excretion and urinary podocyte excretion. The differences between the cerivastatin group and the placebo group were significant (cholesterol, P<0.001; LDL-cholesterol, P<0.001; triglycerides, P<0.05; HDL-cholesterol, P<0.001; urinary protein, P<0.01; and urinary podocytes, P<0.01). CONCLUSION Statins such as cerivastatin may be beneficial for restoration of injured podocytes in patients with CGN and hypercholesterolaemia.
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9.
Effect of cerivastatin on urinary albumin excretion and plasma endothelin-1 concentrations in type 2 diabetes patients with microalbuminuria and dyslipidemia.
Nakamura, T, Ushiyama, C, Hirokawa, K, Osada, S, Shimada, N, Koide, H
American journal of nephrology. 2001;(6):449-54
Abstract
BACKGROUND/AIMS: To determine whether cerivastatin, a newly developed novel synthetic potent statin, exerts a renoprotective effect, we assessed urinary albumin excretion (UAE) and plasma and urinary endothelin (ET)-1 concentrations in normotensive microalbuminuric type 2 diabetes patients with dyslipidemia. METHODS Sixty normotensive type 2 diabetic patients (38 men and 22 women; mean age 56.5 years) with microalbuminuria (20-200 microg/min) and dyslipidemia (total cholesterol >200 mg/dl, LDL cholesterol >160 mg/dl, HDL cholesterol <35 mg/dl, and triglyceride >150 mg/dl) were enrolled in a double-blind study for 6 months, receiving either cerivastatin (0.15 mg/day) or placebo. Plasma and urinary ET-1 concentrations were measured by radioimmunoassay. RESULTS Cerivastatin did not affect serum creatinine and HbA(1c) levels, and reduced systolic blood pressure slightly, but not significantly. Plasma levels of total cholesterol and LDL cholesterol were significantly reduced (p < 0.01), and plasma triglyceride levels were also reduced significantly (p < 0.05) after 6 months of cerivastatin treatment. A concomitant significant decrease in UAE (p < 0.01), and urinary and plasma ET-1 concentrations (p < 0.01) were found during this period. CONCLUSION The use of cerivastatin is associated with decreased microalbuminuria and plasma and urinary ET-1 levels in microalbuminuric patients with type 2 diabetic mellitus and speculate that this may represent an amelioration of renal injury.