Comparison of the Japan Society of Clinical Chemistry reference method and CDC method for HDL and LDL cholesterol measurements using fresh sera.

OBJECTIVES: In 2009, the Japan Society of Clinical Chemistry (JSCC) recommended a reference method for the measurement of serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels. This automated method uses cholesterol esterase-cholesterol dehydrogenase to measure cholesterol levels in fractions obtained after ultracentrifugation and dextran sulfate/magnesium chloride precipitation. In the present study, using fresh samples, we compared the LDL-C and HDL-C levels measured using this method with those measured using the traditional Centers for Disease Control and Prevention (CDC)-beta-quantification (BQ) method. DESIGN: and methods: Using both the JSCC and CDC-BQ methods, LDL-C/HDL-C levels were measured in 47 non-diseased and 126 diseased subjects, whose triglyceride levels were lower than 11.29 â€‹mmol/L (1000 â€‹mg/dL). RESULTS: For LDL-C, the equation of the line representing the correlation between the two methods was y â€‹= â€‹0.991x + 0.009 â€‹mmol/L; r â€‹= â€‹0.999; and Sy/x â€‹= â€‹0.025 â€‹mmol/L, where x is the mean LDL-C level measured using the CDC-BQ method. Similarly, for HDL-C, the equation of the line representing the correlation between the two methods was y â€‹= â€‹0.988x + 0.041 â€‹mmol/L, r â€‹= â€‹0.999, and Sy/x â€‹= â€‹0.019 â€‹mmol/L, where x is the mean HDL-C level measured using the CDC-BQ method. CONCLUSIONS: The JSCC method agreed with the CDC-BQ method in cases of both non-diseased and diseased subjects, including those with dyslipidemia.

Impact of sitagliptin combination therapy and hypoglycemia in Japanese patients with type 2 diabetes: a multi-center retrospective observational cohort study.

BACKGROUND: Patients with diabetes are at higher risk of developing polypharmacy because of the high frequency of comorbidities. There have been several reports on the hypoglycemic risk of the combination of hypoglycemic agents and other medications. This study aimed to investigate the hypoglycemic risk of drug-drug interaction between sitagliptin and other oral hypoglycemic agents or antihypertensive agents in Japanese patients with type 2 diabetes. METHODS: From January 2010 to March 2012, a total of 3247 patients were recruited and evaluated at outpatient clinics at Juntendo University Hospital, other satellite hospitals, and private clinics. This study was a sub-analysis of the Sitagliptin Registration Type 2 Diabetes-Juntendo Collaborating Project. Participants were limited to those treated with oral hypoglycemic agents, excluding insulin users, to investigate the association of the first hypoglycemic events with oral hypoglycemic agents or other medications within 6 months after starting sitagliptin. The factors related to the first hypoglycemic event were analyzed using Cox regression analysis. RESULTS: In total, 2956 patients with a mean age of 65.1 ± 11.3 years were included. A total of 46 hypoglycemic events (1.6%) were observed. One patient had severe hypoglycemia followed by emergency transport to the hospital. Sitagliptin was not associated with hypoglycemia, but its combination with sulfonylurea (hazard ratio: 4.42, 95% confidential interval: 1.36-14.42) or ß-blocker (hazard ratio, 3.50, 95% confidential interval: 1.54-7.96) was significantly associated with hypoglycemia. CONCLUSIONS: The drug-drug interactions between sitagliptin and sulfonylurea or ß-blocker likely increases the hypoglycemic risk in Japanese patients with type 2 diabetes. Pharmacists should consider potential adverse events from drug-drug interaction in type 2 diabetes with polypharmacy, particularly those who are managed by several doctors or clinics.

The Goal of Achieving Atherosclerotic Plaque Regression with Lipid-Lowering Therapy: Insights from IVUS Trials.

Enormous effort has been put into the prevention of atherosclerosis through risk modification, especially with lipid-lowering therapies. Regression, that is, the reversal of the atherosclerosis process, has long been a goal of atherosclerosis research among basic and clinical investigators. Intravascular ultrasound (IVUS) was developed in the 1990s as an intracoronary imaging technique to observe the details of the vessel walls and to measure the vessel lumen and plaque area with high reproducibility. Compared with the coronary angiogram, IVUS provides far more detailed information on the vessel wall. In this article, we review lipid-lowering trials that have used IVUS and discuss the current understanding of the effectiveness of aggressive lipid-lowering therapy, which inhibits atherosclerotic progression and induces regression and plaque stabilization.

Real-World Data on the Incidence of Macrovascular Complications in Japanese Patients with Type 2 Diabetes: The Sitagliptin Registration Type 2 Diabetes-Juntendo Collaborating Project.

INTRODUCTION: Type 2 diabetes is associated with vascular complications that deteriorate the quality of life and decrease the life expectancy of individuals. We previously reported the efficacy of sitagliptin for glucose control in patients with type 2 diabetes in the Sitagliptin Registration Type 2 Diabetes-Juntendo Collaborating Project (SPIRITS-J). Through the results of the SPIRITS-J study, we expected that optimal comprehensive management of type 2 diabetes according to current clinical practice guidelines in addition to achieving individualized glycemic goals would reduce macrovascular complications and all-cause mortality in Japan. The aim of this study was to evaluate this hypothesis. METHODS: We investigated the clinical outcomes prospectively in the extended SPIRITS-J study and compared these to previous Japanese cohort studies in the era before widespread use of guidelines. The primary clinical outcome was a composite of myocardial infarction (MI), stroke, and all-cause mortality. RESULTS: Mean duration of follow-up was 3.5 ± 1.3 years. The crude incidence of the primary outcome per 1000 person-years was 13.9 (non-fatal MI 1.44, non-fatal stroke 4.22, all-cause mortality 8.79 per 1000 person-years, respectively). It is noteworthy that the incidence of MI in the SPIRITS-J study was very much lower than that in a previous Japanese cohort study. In multivariate analysis, both the history of coronary artery disease and low-density lipoprotein cholesterol (LDL-C) were independently associated with incidence of primary clinical outcome. CONCLUSION: The extended SPIRITS-J study demonstrated that optimal comprehensive management in patients with type 2 diabetes according to the recent practice guidelines has succeeded in preventing macrovascular complications in Japan. This study suggests that more intensive LDL-C-lowering therapy is important for further prevention of macrovascular complications even in Japanese patients with type 2 diabetes (UMIN 000004121).

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.

Estrogen variation during the menstrual cycle does not influence left ventricular diastolic function and untwisting rate in premenopausal women.

BACKGROUND: Although a cardioprotective effect of estrogen has been suggested by experimental studies, clinical data on the influence of estrogen on left ventricular (LV) diastolic function are sparse. The LV untwisting rate obtained by 2D speckle tracking echocardiography (2D-STE) is correlated with the time constant of LV pressure decay (tau), and this correlation is independent of left atrial pressure. Therefore, we used conventional Doppler echocardiography and 2D-STE to investigate changes in LV diastolic function during a single menstrual cycle in premenopausal women. METHODS: Twenty healthy premenopausal woman (mean age, 28.1±2.7 years) were enrolled. Clinical and echocardiographic data were obtained during the follicular phase (F-phase) and luteal phase (L-phase) of a single menstrual cycle. We compared the clinical and echocardiographic data, and estrogen levels between the two phases. RESULTS: There were no significant differences in LV diastolic parameters derived from Doppler echocardiography (E/A, p=0.295; E/e', p=0.449, DcT, p=0.178) or 2D-STE (peak untwisting rate, p=0.892; time-to-peak untwisting, p=0.951) between the two phases of the menstrual cycle. However, there was a significant decrease in estrogen levels between the F- and L-phases (177±119pg/ml vs. 35±12pg/ml, p<0.0001). CONCLUSIONS: LV diastolic function in healthy premenopausal women did not significantly change during the menstrual cycle. Estrogen does not appear to have a significant acute effect on LV diastolic function in premenopausal woman.

When and how aortic stenosis is first diagnosed: A single-center observational study.

BACKGROUND: The development of clinical symptoms is associated with cardiovascular events in patients with aortic stenosis (AS). Thus, early diagnosis of AS is clinically important. However, there are few data on symptom status or the severity of AS when patients are first diagnosed, or on how AS is detected in routine practice. We aimed to investigate when and how AS patients are first diagnosed in our hospital. METHODS: We retrospectively enrolled 198 AS patients diagnosed from 1989 to 2009, and identified their symptoms and AS severity at the time of the first diagnosis. We also assessed the reasons why they came to the hospital based on their medical records. RESULTS: Of the 198 patients, 82 (41.6%) had voluntarily visited or been referred to our hospital after developing clinical symptoms (Symptomatic group). The remaining 116 patients (58.4%) had been asymptomatic, and cardiovascular disease was suspected during an annual or occasional health checkup (Asymptomatic group). The initial findings in the Asymptomatic group that led to the diagnosis of AS were: a systolic murmur on auscultation (62%), abnormal electrocardiography (27%), or abnormal echocardiography (11%). The Symptomatic group had significantly greater AS severity and an increased left ventricular mass index, and experienced more cardiac events (valve replacement or cardiac death) during the follow-up period. CONCLUSIONS: About 40% of the AS patients in this study were not diagnosed until they developed clinical symptoms, suggesting that many other patients in the community might have a latent risk of cardiovascular events. Auscultation plays an important role in the early diagnosis of AS.

Efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes.

BACKGROUND: The aim of this study was to investigate the clinical efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes. METHODS: A total of 3,247 subjects treated with sitagliptin were retrospectively recruited. Glucose parameters were collected at baseline, and 1, 3 and 6 months after initiation of sitagliptin. In addition, we explored factors that can be used to predict sitagliptin-induced reduction in HbA1c using linear mixed effect model. Factors associated with hypoglycemic events were examined by logistic analyses. RESULTS: We analyzed the available data of 3,201 subjects (1,287 females). Treatment of sitagliptin significantly reduced HbA1c level from 7.44±1.20% at baseline to 6.73±0.99% at 6 months (P < 0.0001). Linear mixed effect model analyses demonstrated that reduction of HbA1c was associated with higher baseline HbA1c level, younger age, lower BMI and sitagliptin monotherapy. During this study, 82 cases of hypoglycemia were recorded. Logistic analyses indicated that hypoglycemic events were more frequent in female patients, and patients with low BMI, long history of type 2 diabetes, high HbA1c and on combination therapy experienced. Other adverse events were rare and mild. CONCLUSIONS: Sitagliptin is effective for diabetic management and generally well tolerated in Japanese patients with type 2 diabetes. This trial was registered with UMIN (no. 000004121).

Early hemodynamic performance of the trifecta bioprosthetic valve in patients with aortic valve disease.

BACKGROUND: The Trifecta valve (St Jude Medical) is a novel supra-annular aortic bioprosthesis designed to improve hemodynamic performance. We hypothesized that the Trifecta may offer better hemodynamic performance in Japanese patients, in whom the annulus is smaller, compared with Western populations. We compared the early results of hemodynamic performance between the Trifecta and the Magna (Edwards Lifescience) valves at our institution. METHODS AND RESULTS: The Trifecta was implanted in 33 patients and the Magna was implanted in 41 patients who had aortic valve disease. Postoperative echocardiography was performed just before discharge, and the mean pressure gradient (MPG), effective orifice area (EOA) index and energy loss coefficient (ELCo) index were compared between the 2 groups. The average prosthesis size was similar between the 2 groups (21.1 vs. 21.3mm). The Trifecta group had a significantly lower MPG (P=0.001) and larger EOA index and ELCo index than the Magna group (P<0.001 for both). On multivariate linear regression analysis, use of the Trifecta was the strongest independent determinant of postoperative MPG, EOA and ELCo index. CONCLUSIONS: The Trifecta valve provides excellent early postoperative hemodynamic performance in Japanese patients. Patients with a small annulus size relative to body size may benefit more from the Trifecta in terms of postoperative hemodynamic performance.

The high molecular weight adiponectin level is associated with the atherogenic lipoprotein profiles in healthy Japanese males.

AIM: Circulating adiponectin comprises high, medium and low molecular weight (HMW, MMW, and LMW) forms. Decreased adiponectin levels have been demonstrated to correlate with the atherogenic lipoprotein profile in patients with metabolic syndrome(MS). However, the associations of these isoforms with the atherogenic lipoprotein profiles in the healthy population remain unclear. METHODS: Apparently healthy male subjects were divided into non-MS(n=132) and MS(n=63) groups. We measured the total, HMW, MMW and LMW adiponectin levels by ELISA, and determined the detailed lipoprotein profiles by high-performance liquid chromatography. RESULTS: The total and HMW adiponectin levels in the MS group were significantly lower than those in the non-MS group(3.8±1.9 vs. 4.9±2.4µg/mL, p＜0.001 and 1.6±1.2 vs. 2.5±1.9µg/mL, p＜0.001, respectively), whereas the MMW and LMW levels did not differ significantly between the groups. The total and HMW adiponectin levels correlated with the atherogenic lipoprotein profiles, including the following: 1) increased cholesterol levels in the small LDL subclasses; 2) decreased cholesterol levels in the larger HDL subclasses; 3) increased triglycerides(TGs) in almost all VLDL and LDL subclasses and 4) decreased TGs in the large HDL and increased TGs in the small HDL subclasses. In addition, a multivariate analysis demonstrated that the HMW adiponectin level was an independent predictor of the small LDL and HDL levels(p=0.02 for both). CONCLUSIONS: The HMW, but not MMW or LMW, adiponectin levels are associated with the typical atherogenic lipoprotein profiles, independent of MS components. Measurement of the HMW adiponectin levels could be useful for identifying the atherogenicity in apparently healthy males.

Validation of homogeneous assays for HDL-cholesterol using fresh samples from healthy and diseased subjects.

BACKGROUND: High-density lipoprotein-cholesterol (HDL-C) is a negative risk factor for cardiovascular events. Although several homogeneous HDL-C assays are available, their accuracy has not been validated, particularly in subjects with disease. We aimed to clarify whether HDL-C concentrations measured by homogeneous assays [HDL-C (H)] agree with those determined by the reference measurement procedures [HDL-C (RMP)] using ultracentrifugation and precipitation with heparin-manganese reagent in fresh clinical samples. METHODS: HDL-C concentrations in samples from 48 healthy subjects and 119 subjects with disease were determined using 12 homogeneous assays and RMPs. RESULTS: All reagents showed excellent intra- and inter-assay CVs (<2.23%) for two pooled sera. Furthermore, the mean bias was within ± 1.0% in nine reagents using samples from healthy subjects and in eight reagents using samples from subjects with disease. In a single HDL-C (H) determination, the total error requirement of the National Cholesterol Education Program (95% of results < 13%) was fulfilled in nine reagents using samples from healthy subjects and six reagents in those from subjects with disease. Error component analysis revealed that only one reagent exceeded ± 10% total error in samples from healthy subjects, whereas four reagents exceeded this error in samples from subjects with disease. Correlations between HDL-C (H) and HDL-C (RMP) revealed that the slopes were within 1.00 ± 0.06 in six reagents in healthy subjects, and eight reagents in subjects with disease. CONCLUSIONS: Except for three reagents, HDL-C (H) agrees well with HDL-C (RMP) in subjects with common disease, but not in those with extremely low HDL-C or abnormal HDL composition.

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. 7ß-hydroxycholesterol, a marker for non-enzymatic oxidation of cholesterol, was 66% higher in hypercholesterolemics than controls. Ezetimibe decreased 7ß-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.

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.