Yoshifumi Fukushima

Relationship between Advanced Glycation End Products and Plaque Progression in Patients with Acute Coronary Syndrome: The JAPAN-ACS Sub-study

BackgroundThe Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS) trial demonstrated that early aggressive statin therapy in patients with ACS significantly reduces plaque volume (PV). Advanced glycation end products (AGEs) and the receptors of AGEs (RAGE) may lead to angiopathy in diabetes mellitus (DM) and may affect on the development of coronary PV. The present sub-study of JAPAN-ACS investigates the association between AGEs and RAGE, and PV.MethodsIntravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) was undertaken, followed by the initiation of statin treatment (either 4 mg/day of pitavastatin or 20 mg/day of atorvastatin), in patients with ACS. In the 208 JAPAN-ACS subjects, PV using IVUS in non-culprit segment > 5 mm proximal or distal to the culprit lesion and, serum levels of AGEs and soluble RAGE (sRAGE) were measured at baseline and 8–12 months after PCI.ResultsAt baseline, no differences in the levels of either AGEs or sRAGE were found between patients with DM and those without DM. The levels of AGEs decreased significantly with statin therapy from 8.6 ± 2.2 to 8.0 ± 2.1 U/ml (p < 0.001), whereas the levels of sRAGE did not change. There were no significant correlations between changes in PV and the changes in levels of AGEs as well as sRAGE. However, high baseline AGEs levels were significantly associated with plaque progression (odds ratio, 1.21; 95% confidence interval, 1.01 - 1.48; p = 0.044) even after adjusting for DM in multivariate logistic regression models.ConclusionsHigh baseline AGEs levels were associated with plaque progression in the JAPAN-ACS trial. This relationship was independent of DM. These findings suggest AGEs may be related to long-term glucose control and other oxidative stresses in ACS.Trial registrationNCT00242944

Single Administration of α-Glucosidase Inhibitors on Endothelial Function and Incretin Secretion in Diabetic Patients With Coronary Artery Disease - Juntendo University Trial: Effects of Miglitol on Endothelial Vascular Reactivity in Type 2 Diabetic Patients With Coronary Heart Disease (J-MACH) -

Background: Post-prandial hyperglycemia, hyperlipidemia, and endothelial dysfunction play an important role in the pathogenesis of atherosclerosis. Improvement in post-prandial hyperglycemia on α-glucosidase inhibitors (α-GIs) is associated with a risk reduction of cardiovascular diseases, but the post-prandial effects of α-GIs on endothelial function and incretin secretion in type 2 diabetic patients with coronary artery disease (CAD) remain unclear. Methods and Results: The post-prandial effects of a single administration of miglitol and voglibose on endothelial function and changing levels of glucose, insulin, lipids, glucagon-like peptide (GLP)-1, and gastric inhibitory polypeptide (GIP) were compared after a standard meal loading in 11 diabetic patients with CAD, using a placebo-controlled cross-over design. The changing levels of glucose, insulin and triglycerides at 60 min were significantly lower in the miglitol group than in the voglibose and placebo groups (all P<0.01). GLP-1 levels were significantly higher at 120 min (P<0.05) and GIP levels were significantly lower at 30 min and 60 min (P<0.05) in the miglitol group compared to other treatments. The reactive hyperemia duration at 120 min was significantly maintained in the miglitol group compared to the other groups. Conclusions: A single administration of miglitol significantly improved post-prandial glucose/lipid metabolism, incretin secretion, and endothelial dysfunction in diabetic patients with CAD, suggesting that miglitol may be a useful anti-atherogenic agent (UMIN000002264).  (Circ J 2010; 74: 1471 - 1478)

Small dense LDL cholesterol is a robust therapeutic marker of statin treatment in patients with acute coronary syndrome and metabolic syndrome

BACKGROUND Small dense low-density lipoprotein (sd-LDL) is an atherogenic LDL subfraction and often increased in metabolic syndrome (MetS). This study aimed to determine whether sd-LDL cholesterol (sd-LDL-C) is a therapeutic marker of statin treatment in patients with acute coronary syndrome (ACS) and MetS. METHODS We examined 71 patients with ACS and 50 non-ACS subjects with normal coronary arteries (controls). The patients with ACS were treated with life-style modifications (n=36) or those plus 20mg atorvastatin daily (n=35) for 6 months. We measured sd-LDL-C by a novel detergent-based homogenous assay and calculated buoyant LDL-C (b-LDL-C). RESULTS The patients with ACS had higher sd-LDL-C than did the controls (30±14 vs. 22±8 mg/dl, p<0.001). Furthermore, sd-LDL-C was higher in the patients with ACS and MetS (n=31) than in those without MetS (n=40) (35±17 vs. 27±11 mg/dl, p<0.05). Atorvastatin reduced LDL-C and sd-LDL-C by 31% (102±23 to 70±28 mg/dl, p<0.0001) and 24% (29±15 to 22±13 mg/dl, p<0.01). The reduction in sd-LDL-C by atorvastatin was 5.5-fold greater in the patients with ACS and MetS than in those without MetS (p<0.001). Contrary, that in b-LDL-C was similar between the groups. CONCLUSIONS sd-LDL-C is a superior therapeutic marker of statin treatment in patients with ACS and MetS.

Albumin concentration determined by the modified bromocresol purple method is superior to that by the bromocresol green method for assessing nutritional status in malnourished patients with inflammation

Background The controlling nutritional status (CONUT) score (CS), a simple score for assessing nutritional status, is calculated using laboratory data, including serum albumin concentration. Although dye-binding assays such as the bromocresol green (BCG) and modified bromocresol purple (mBCP) methods are widely used for albumin measurement, acute-phase proteins interfere with the BCG method. Objective We aimed to determine whether the choice of albumin assay affects assessment of nutritional status using CONUT scores (CSs). Design We measured serum albumin concentrations by the BCG (ALBBCG) and mBCP (ALBmBCP) methods in 44 malnourished inpatients, 27 of whom underwent nutritional intervention, and compared them to 30 age-matched healthy volunteers. In treated patients, CSs were calculated by ALBBCG (CS-BCG) and ALBmBCP (CS-mBCP). Results C-reactive protein (CRP) concentrations were positively correlated with the difference between ALBBCG and ALBmBCP in malnourished inpatients (r = 0.59, p < 0.001). CS-BCG was always lower than CS-mBCP (lower CS indicates superior nutritional status) in treated patients with persistently high CRP levels. However, in patients whose CRP decreased gradually, this difference diminished over the clinical course. CS-BCG and CS-mBCP were similar throughout their courses in patients with normal CRP concentrations. Adding haptoglobin to the human albumin solutions increased ALBBCG in a dose-dependent manner. Conclusions The choice of albumin assay affected the assessment of nutritional status using CSs in patients with inflammation. We recommend that the modified BCP assay be used to assess nutritional status, particularly in patients with inflammation.

Circadian change of serum concentration of small dense LDL-cholesterol in type 2 diabetic patients

BACKGROUND Type 2 diabetic patients have a higher risk of atherosclerosis than non-diabetic subjects. This difference may be attributable to increased levels of small dense low-density lipoprotein-cholesterol (sLDL-C) in diabetic patients. As the sLDL-C concentration is elevated in hypertriglyceridemia, which is exaggerated postprandially, we examined whether the sLDL-C level increases postprandially in type 2 diabetes. METHODS We obtained 7 blood samples (30min before and 2h after each meal, and at midnight) from 15 patients with diabetes and ten normal controls. Following the precipitation of very low-density lipoprotein and large buoyant LDL (bLDL) with heparin-Mg(2+), the sLDL-C concentration was determined as the cholesterol concentration by a homogeneous assay. RESULTS The fasting sLDL-C concentration was 60.3% higher in the diabetic patients than in the controls (1.01+/-0.21 vs. 0.63+/-0.21mmol/l, p<0.001). The sLDL-C concentrations in both groups were highest in the fasting state, decreased after breakfast, and remained low until midnight. The maximal reduction in the absolute sLDL-C concentration was 56.5% greater in the diabetic patients than in the controls (0.36+/-0.13 vs. 0.23+/-0.16mmol/l, p<0.05). Thus, the sLDL-C/bLDL-cholesterol (bLDL-C) ratio was reduced with increases in bLDL-C. CONCLUSIONS The sLDL-C concentration decreases postprandially in diabetes. This absolute reduction in sLDL-C may contribute to an acceleration of atherosclerosis in diabetic patients.

Impact of Lipoprotein(a) as Residual Risk on Long-Term Outcomes in Patients After Percutaneous Coronary Intervention

Cardiovascular risk remains uncertain in patients with cardiovascular disease despite achieving target lipid levels. Serum levels of lipoprotein(a) [Lp(a)] can be risk factors for adverse events. The aim of this study was to determine the role of Lp(a) as a residual risk factor in patients who achieve target lipid levels by the time of treatment by percutaneous coronary intervention (PCI). A total of 3,508 patients were treated by PCI from 1997 to 2011 at our institution. Among them, we analyzed consecutive 569 patients who achieved target lipid levels of low-density lipoprotein cholesterol <100 mg/dl, high-density lipoprotein cholesterol ≥40 mg/dl, and triglycerides <150 mg/dl at PCI. A total of 411 eligible patients were assigned to groups according to Lp(a) levels of ≥30 mg/dl (high Lp(a); n = 119) or <30 mg/dl (low Lp(a); n = 292). The primary outcome was a composite of all-cause death and acute coronary syndrome. The median follow-up period was 4.7 years. Cumulative event-free survival was significantly worse for the group with high Lp(a) than with low Lp(a) group (p = 0.04). Multivariate analysis selected a high Lp(a) level as an independent predictor of primary outcomes (hazard ratio 1.68, 95% confidence interval 1.03 to 2.70, p = 0.04). In conclusion, a high Lp(a) value (≥30 mg/dl) could be associated with a poor prognosis after PCI even for patients who achieved target lipid levels.

Non-high-density lipoprotein cholesterol is a practical predictor of long-term cardiac death after coronary artery bypass grafting

BACKGROUND Recent studies have demonstrated that non-high-density lipoprotein cholesterol (non-HDL-C) can predict the risk of cardiovascular events among general population without coronary heart disease (CHD). However, few studies have investigated the predictive value of non-HDL-C for long-term prognosis in patients with CHD. The purpose of this study was to investigate whether non-HDL-C can predict long-term cardiovascular events in patients with CHD who underwent coronary artery bypass grafting (CABG). METHODS We enrolled 1074 consecutive patients who underwent CABG at Juntendo University Hospital between 1984 and 1994, and obtained mortality data through 2000. We divided the patients into 2 groups by the median non-HDL-C level at baseline (180 mg/dL) and used Kaplan-Meier method with log-rank test for survival analyses. Cox proportional-hazard regression model was used to calculate the relative risk (RR) of cardiac death. RESULTS The mean follow-up period was 10.6±3.5 years. The survival rate of cardiac death was significantly lower in the high non-HDL-C group than that in the low non-HDL-C group (log-rank test; p=0.006). Furthermore, in proportional regression analysis adjusted for conventional coronary risk factors, metabolic syndrome, statin treatment, and use of artery bypass graft, the increased levels of non-HDL-C were significant and independent predictor of cardiac death beyond other lipid parameters (RR1.22; by 10 mg/dL non-HDL-C increasing, 95% confidence interval 1.03-1.44; p<0.05). CONCLUSIONS The increased levels of non-HDL-C were significantly associated with an increased risk of cardiac death. Baseline non-HDL-C levels may be a practical predictor of long-term cardiac death in patients with CHD after CABG.

Profiles of inflammatory markers and lipoprotein subclasses in patients undergoing continuous ambulatory peritoneal dialysis

BACKGROUND Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) often have inflammation and dyslipidemia that accelerate to atherosclerosis. This study aimed to evaluate chronic inflammation and dyslipidemia in CAPD patients. METHODS We measured inflammatory markers and lipoprotein subclasses in 20 CAPD patients (12 men and 8 women, aged 59.5 ± 9.9 y) and 20 gender-matched controls. Lipoproteins were separated by high-performance liquid chromatography (HPLC) using an anion-exchange column. RESULTS High-sensitivity C-reactive protein and serum amyloid A protein (SAA) were higher among CAPD patients vs. controls (1.6 ± 2.2 vs. 0.8 ± 1.2 mg/l, p<0.05; 11.9 ± 12.8 vs. 4.5 ± 2.4 mg/l). HPLC analysis revealed that chylomicron, VLDL, and IDL cholesterol levels were higher among CAPD vs. controls. In contrast, HDL cholesterol was lower among CAPD patients vs. controls. In the subgroup analysis, SAA levels were significantly lower among patients receiving CAPD for >3 y than among controls. However, IDL cholesterol was consistently higher among CAPD patients vs. controls. CONCLUSIONS CAPD patients have chronic inflammation and dyslipidemia. IDL cholesterol is the only lipoprotein subclass that is consistently elevated regardless of CAPD duration. More attention should be paid to dyslipidemia in the management of the CAPD patients.

Ezetimibe decreases serum oxidized cholesterol without impairing bile acid synthesis in Japanese hypercholesterolemic patients

OBJECTIVE Cholesterol and diet-derived oxidized cholesterol are absorbed in the small intestine and eliminated by bile acids. We determined whether ezetimibe, a selective cholesterol absorption inhibitor, changes serum oxidized cholesterol levels. METHODS We measured levels of plant sterols, cholesterol precursors, and oxysterols by gas chromatography-mass spectrometry in 47 hypercholesterolemics and 32 controls. Twenty-four hypercholesterolemics received 10 mg ezetimibe/day for 4 weeks. RESULTS Plant sterols were 30-42% higher in hypercholesterolemics than in controls and positively correlated with low-density lipoprotein-cholesterol (LDL-C). Ezetimibe decreased plant sterols by 21-53%, but did not change bile acid synthesis markers. 7β-hydroxycholesterol, a marker for non-enzymatic oxidation of cholesterol, was 66% higher in hypercholesterolemics than controls. Ezetimibe decreased 7β-hydroxycholesterol levels by 15% regardless of LDL-C reduction. CONCLUSIONS Ezetimibe decreases serum oxidized cholesterol generated by non-enzymatic reactions without impairing bile acid synthesis. Ezetimibe may maintain cholesterol excretion into bile and alleviate the diet-derived oxidative burden.

Estimated Prevalence of Heterozygous Familial Hypercholesterolemia in Patients With Acute Coronary Syndrome

Heterozygous familial hypercholesterolemia (FH) represents a strong risk for development of premature coronary artery disease (CAD). However, the majority of patients with FH are undiagnosed and the prevalence likely represents an underestimate in most countries. In Japan, the possible contribution of FH to the development of CAD may be higher because of the low incidence of CAD among the general population. We estimated the prevalence of heterozygous FH by measuring Achilles tendon thickness (ATT) in patients with acute coronary syndrome (ACS).A total of 359 patients suffering from ACS were enrolled in this multicenter registration study. Heterozygous FH was defined according to the diagnostic criteria proposed by the Japan Atherosclerosis Society. After excluding 63 patients because of missing ATT data or plasma triglyceride levels that were 4.5 mmol/L or more, 296 patients were eligible for inclusion in the study. The number of patients with ATT of 9 mm or more was 53 (17.9%). They were significantly younger and had significantly higher LDL cholesterol levels than patients with an ATT less than 9 mm. The prevalence of heterozygous FH was 5.7% (1/17.5) and more prominent in younger patients who were less than 60 years old (7.8%). In patients with ATT of 9 mm or more, approximately 1 in 3.5 fulfilled the criteria for heterozygous FH.We demonstrated the usefulness of measuring ATT by radiography and the high prevalence of heterozygous FH in patients with ACS in Japan, especially in younger patients who were less than 60 years old.