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Kozo Okada,
Noriaki Iwahashi,
Tsutomu Endo,
Hideo Himeno,
Kazuki Fukui,
Shunichi Kobayashi,
Makoto Shimizu,
Yuji Iwasawa,
Yukiko Morita, Atsushi Wada,
Tomohiko Shigemasa,
Yasuyuki Mochida,
Tomoaki Shimizu,
Reimin Sawada,
Kazuaki Uchino,
Satoshi Umemura,
Kazuo Kimura
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ABSTRACT: To assess the mechanism of long-term LDL-C-lowering effect of ezetimibe-plus-statin.
Coronary artery disease patients whose LDL-C ≥70 mg/dL after treatment with atorvastatin 10 mg/day or rosuvastatin 2.5 mg/day were randomly assigned to receive ezetimibe 10 mg/day + statin (n = 78) or double-dose statin (n = 72) for 52 weeks.
Greater LDL-C reduction was observed and maintained until 52 weeks in ezetimibe-plus-statin, while LDL-C levels re-increased after 12 weeks in double-dose statin. Although lathosterol/TC increased, campesterol/TC decreased more in ezetimibe-plus-statin. In contrast, lathosterol/TC unchanged and campesterol/TC increased, increasing campesterol/lathosterol ratio for 52 weeks in double-dose statin. Plasma PCSK9 levels were higher in double-dose statin than in ezetimibe-plus-statin at 12 weeks, but similar at 52 weeks.
Although the difference in PCSK9 between 2 groups was transient, that in both campesterol and lathosterol persisted until 52 weeks. These results demonstrated simultaneous inhibition of cholesterol absorption and synthesis provides stable and greater decrease in LDL-C levels.
Atherosclerosis 08/2012; 224(2):454-6. · 3.79 Impact Factor
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Kozo Okada,
Kazuo Kimura,
Noriaki Iwahashi,
Tsutomu Endo,
Hideo Himeno,
Kazuki Fukui,
Shunichi Kobayashi,
Makoto Shimizu,
Yuji Iwasawa,
Yukiko Morita, Atsushi Wada,
Tomohiko Shigemasa,
Yasuyuki Mochida,
Tomoaki Shimizu,
Reimin Sawada,
Kazuaki Uchino,
Satoshi Umemura
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ABSTRACT: Ezetimibe-plus-statin therapy has been reported to provide greater reduction in low-density lipoprotein cholesterol (LDL-C) level than statin monotherapy. The aim of the present study was to evaluate the relationship between LDL-C lowering effect and baseline cholesterol absorption and synthesis markers in patients with coronary artery disease (CAD).
A total of 171 patients with CAD whose LDL-C level was ≥ 100 mg/dl after treatment with atorvastatin (10mg/day) or rosuvastatin (2.5 mg/day) for 4 weeks were assigned to additionally receive ezetimibe (10mg/day) plus a statin or a double dose of statin for 12 weeks. The decreases in LDL-C (-30.0 ± 15.6 mg/dl vs. -19.2 ± 14.2 mg/dl) and the ratio of campesterol, an absorption marker, to total cholesterol levels (-1.35 ± 0.90 µg/mg vs. 0.33 ± 0.74 µg/mg) were greater in the ezetimibe-plus-statin group (P<0.05, respectively). The decrease in LDL-C level in the ezetimibe-plus-statin group was greatest in patients with baseline levels of higher absorption and lower synthesis markers and smallest in patients with baseline levels of lower absorption and higher synthesis markers (-34.3 ± 15.6 mg/dl vs. -21.5 ± 16.7 mg/dl, P<0.05). The decrease in LDL-C did not differ, irrespective of baseline levels of cholesterol absorption and synthesis markers, in the double-dose statin group, and was similar to that in patients with lower absorption and higher synthesis markers in the ezetimibe-plus-statin group.
Ezetimibe-plus-statin therapy may be useful for lowering LDL-C level, irrespective of baseline levels of cholesterol absorption and synthesis markers.
Circulation Journal 08/2011; 75(10):2496-504. · 3.77 Impact Factor
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Naoki Nakayama,
Kazuo Kimura,
Tsutomu Endo,
Kazuki Fukui,
Hideo Himeno,
Yuji Iwasawa,
Yasuyuki Mochida,
Yukiko Morita,
Makoto Shimizu,
Tomoaki Shimizu,
Takahiro Takei,
Keiko Yoshida, Atsushi Wada,
Satoshi Umemura
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ABSTRACT: The door-to-balloon time (DTB) is an important predictor of the outcome for patients with ST-elevation myocardial infarction (STEMI). In Japan, percutaneous coronary intervention (PCI) can be performed at many hospitals, and the predominant strategy for reperfusion therapy is primary PCI. However, it remains unclear how rapidly reperfusion is achieved at these hospitals.
The study group comprised 369 patients with STEMI who presented within 12 h of symptom onset to a tertiary emergency center (TEC) or at 11 community hospitals (CHs) in 2006 and underwent emergency coronary angiography. Median DTB was shorter in the TEC (63 vs 104 min, P<0.001), and the rate of DTB within 90 min was higher in the TEC (96% vs 39%, P<0.001). Lateral myocardial infarction, presentation during off-hours, and non-cardiologist as the first-contact physician were significantly associated with a prolonged DTB in CHs. There was a trend toward lower 30-day mortality from all causes in the TEC (2.0% vs 4.8%, P=0.08). Multiple logistic regression analysis demonstrated that prolonged DTB (>90 min) was an independent predictor of 30-day mortality (odds ratio 12.6; 95% confidence interval 1.85-86.2, P=0.01).
Establishment of emergency cardiac care systems with the goal of DTB within 90 min is required in PCI-capable hospitals to improve clinical outcomes.
Circulation Journal 01/2009; 73(3):484-9. · 3.77 Impact Factor
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ABSTRACT: N(G)-methyl-L-arginine (L-NMMA) has been widely used for nitric oxide (NO) research, particularly for the assessment of NO-dependent vasodilatation evoked by agonists. However, such experiments may not be straightforward because L-NMMA causes vasoconstriction, which itself must non-specifically affect responses to any vasoactive agents. Therefore, in order to more accurately estimate the roles of NO in human vessels in vivo, we developed an NO clamp technique that uses co-infusion of an NO donor with L-NMMA. To assess the validity and feasibility of this technique, we compared the effects of intra-arterial infusion of L-NMMA on the forearm blood flow responses to vasodilators with and without the NO clamp technique in healthy males. All drugs were intra-arterially infused and changes in forearm blood flow (FBF) were measured by strain-gauge plethysmography. Vasodilatation evoked by atrial natriuretic peptide was significantly attenuated by L-NMMA alone (p = 0.001) but not by the NO clamp technique. L-NMMA significantly attenuated the responses to acetylcholine either with or without the NO clamp technique. However, the ratio of the area under the curve (AUC) of acetylcholine with L-NMMA to that without L-NMMA was significantly higher when the NO clamp technique was not used (AUC ratio: 0.62 +/- 0.13 vs. 0.48 +/- 0.14, respectively; p = 0.031). The contribution of NO to the FBF responses to vasodilators may be more properly assessed by the co-infusion of L-NMMA with the NO clamp technique than by L-NMMA alone. Our NO clamp technique thus appears to be valid and feasible for human NO research.
Hypertension Research 06/2004; 27(5):351-7. · 2.58 Impact Factor
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ABSTRACT: The development of tolerance to organic nitrates limits their usefulness in the treatment of heart disease. Activation of the renin-angiotensin system by heart failure itself and by nitrate therapy may be one possible mechanism underlying nitrate tolerance. We investigated the effect of subpressor doses of angiotensin II on the vasodilating effect of glyceryl trinitrate in human forearm resistance vessels of healthy male subjects by using venous occlusion strain-gauge plethysmography.
Glyceryl trinitrate was infused intra-arterially with angiotensin II or vehicle. The effect of blockade of angiotensin II type 1 receptors by candesartan or an antioxidant, vitamin C, on the interaction between angiotensin II and glyceryl trinitrate was also investigated.
Angiotensin II infused at 5 pmol/min significantly attenuated the vasodilating effect of glyceryl trinitrate (mean +/- standard deviation [SD] of percentage change in forearm blood flow [FBF]: 28% +/- 20%, 79% +/- 59%, and 208% +/- 72% at 100, 250, and 1000 ng/min of glyceryl trinitrate with placebo; 8% +/- 18%, 47% +/- 41%, and 173% +/- 98% with angiotensin II at 1 pmol/min; and 2% +/- 27%, 39% +/- 40%, and 132% +/- 74% with angiotension II at 5 pmo;/min; P =.0259). Either a single dose of candesartan or coinfusion with vitamin C abolished the angiotensin II-induced attenuation of vasodilation of glyceryl trinitrate.
Our results suggest that angiotensin II may attenuate the arterial vasodilating effect of glyceryl trinitrate through angiotensin type 1 receptors and presumably through receptor-mediated superoxide production, which may be relevant to the development of nitrate tolerance.
Clinical Pharmacology & Therapeutics 07/2002; 71(6):440-7. · 6.04 Impact Factor
