Oleic acid to stearic acid ratio might be a potential marker for insulin resistance in non-obese Japanese.

Results from a recent study indicate that a higher level of oleic acid/stearic acid ratio was associated with metabolically unhealthy obesity. This was further validated in cross-sectional and interventional studies; however, this was not extensively studied in a non-obese population. We recruited 260 Japanese subjects with serum free fatty acid profiles undergoing anti-aging health examinations. The determinants for oleic acid/stearic acid ratio were investigated using multiple regression analyses. To compare different markers, the subjects were classified based on oleic acid/stearic acid ratio and the combination of oleic acid/stearic acid ratio and triglyceride levels. The oleic acid/stearic acid ratio exhibited a positive correlation with the logmatic transformed triglyceride/high-density lipoprotein cholesterol ratio and the fasting triglycerides-glucose index, both of which were used as markers for insulin resistance. Multiple regression analyses revealed that the triglyceride/high-density lipoprotein cholesterol ratio and fasting triglyceride-glucose index were positively associated with the oleic acid/stearic acid ratio. Most markers were the worst in the highest triglyceride group in both oleic acid/stearic acid groups. In addition, most markers were worse in high oleic acid/stearic acid ratio group than low group. In conclusion, oleic acid/stearic acid ratio might be a useful marker for insulin resistance in non-obese Japanese subjects.

A Dipeptidyl Peptidase-4 Inhibitor, Teneligliptin, Decreases Plasma Triglyceride-Rich Lipoprotein Remnants in Diabetic Patients with Chronic Kidney Disease Undergoing Hemodialysis.

OBJECTIVE: A high plasma level of remnant-like particle cholesterol (RLP-C), which is equivalent to triglyceride-rich lipoprotein remnant, is an important coronary risk marker. RLP-C level is high, independent of other plasma lipids, in patients with chronic kidney disease (CKD) undergoing hemodialysis. The effect of teneligliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, on plasma levels of RLP-C in patients with diabetes mellitus and CKD under hemodialysis was studied. METHODS: Teneligliptin 20 mg/day was administered to 15 patients with diabetes and CKD undergoing hemodialysis for 12 weeks. Ten patients with diabetes and CKD undergoing hemodialysis were allocated to the control group. Blood was sampled following a 12-h fast. Fasting plasma glucose (FPG), C-peptide, triglyceride, low-density lipoprotein (LDL)-cholesterol (C), high-density lipoprotein (HDL)-C, RLP-C, apolipoprotein (apo) B, oxidized LDL, lipoprotein lipase, and glycated hemoglobin (HbA1c) were measured. RESULTS: HbA1c decreased in the teneligliptin group but significantly increased in the control group. FPG and RLP-C significantly decreased in the teneligliptin group. Plasma lipoprotein-related parameters except RLP-C were not affected by teneligliptin treatment. CONCLUSION: Teneligliptin treatment significantly reduced plasma levels of RLP-C, FPG, and HbA1c in patients with diabetes with CKD who are undergoing hemodialysis.

A Comparison of the Abdominal Fat Distribution and Coronary Risk Markers in Body Mass Index-matched Subjects with and without Fatty Liver.

Objective The close relationship between fatty liver and metabolic syndrome suggests that individuals with fatty liver may have multiple coronary risk factors. In the present study, we investigated the relationships among fatty liver, abdominal fat distribution, and coronary risk markers. Methods and Results Eighty-seven pairs of men and 42 pairs of women who were matched for age and body mass index were enrolled in the present study. The obesity-related markers, abdominal fat distribution (examined by CT), and coronary risk markers were compared in subjects with and without fatty liver. The visceral fat area was significantly larger in the men with fatty liver than in the men without fatty liver. The plasma levels of triglyceride and low-density lipoprotein cholesterol (LDL-C), as well as the homeostasis model assessment-insulin resistance level, were higher in both males and females with fatty liver than in those without fatty liver, while the plasma levels of high-density lipoprotein cholesterol (HDL-C) and adiponectin were lower in the males and females with fatty liver. The plasma levels of apolipoprotein B, remnant-like particle cholesterol (RLP-C), and oxidized LDL were higher in men with fatty liver, but not in women with fatty liver. Conclusion Both males and females with fatty liver had lower insulin sensitivity, lower plasma levels of HDL-C and adiponectin, and higher triglyceride and LDL-C levels. However, the plasma levels of apolipoprotein B, RLP-C, and oxidized LDL were only higher and closely associated with fatty liver in men. Men with fatty liver had a higher risk of coronary disease than women with fatty liver.

Comparison of the effects of low-dose rosuvastatin on plasma levels of cholesterol and oxidized low-density lipoprotein in 3 ultracentrifugally separated low-density lipoprotein subfractions.

BACKGROUND: Plasma-oxidized (ox) low-density lipoprotein (LDL) is an atherogenic lipoprotein. The distribution of ox-LDL in plasma LDL subfractions and the effect of statins on this distribution have not been investigated in detail. OBJECTIVE: We examined the distribution of cholesterol and ox-LDL in 3 ultracentrifugally separated plasma LDL subfractions and investigated the effects of a statin, rosuvastatin, on the levels of these lipoproteins. MATERIALS AND METHODS: Thirty-one polygenic hypercholesterolemic subjects were included in this study. Levels of cholesterol and ox-LDL in 3 plasma LDL subfractions and plasma levels of remnant-like particle cholesterol, ox-LDL, and adiponectin were measured after 0, 3, 6, and 12 months of treatment with rosuvastatin. Sequential ultracentrifugation was performed to subfractionate plasma lipoproteins. RESULTS: The mean daily dose of rosuvastatin over the 12 months of treatment was 2.9 ± 1.0 mg (mean ± standard deviation). The cholesterol subfraction distribution was 43 ± 10% as low-density LDL, 46 ± 8% as medium-density LDL, and 13 ± 5% as high-density LDL. Similarly, the distribution of ox-LDL was 31 ± 10% as low-density LDL, 48 ± 7% as medium-density LDL, and 22 ± 8% as high-density LDL. After 12 months of treatment with rosuvastatin, the level of cholesterol was significantly reduced in all 3 subfractions (P < .0001), as was the level of ox-LDL (P < .0001). Furthermore, the plasma cholesterol level in high-density lipoprotein2 increased significantly. CONCLUSIONS: The distribution of ox-LDL in plasma LDL subfractions was more skewed toward the denser subfractions, compared with cholesterol. Rosuvastatin treatment significantly reduced plasma levels of cholesterol and ox-LDL in all LDL subfractions.

Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia after treatment with atorvastatin.

BACKGROUND: Plasma levels of low-density lipoproteins (LDLs) are decreased through stimulation of their hepatic uptake by statins via an LDL receptor. However, it is unclear whether statins equally stimulate the hepatic uptake of all LDL subfractions. OBJECTIVE: We compared the effects of atorvastatin on 3 LDL subfractions, and their associations with LDL-receptor activities, in Japanese patients with polygenic hypercholesterolemia (PHC), familial combined hyperlipoproteinemia (FCHL), and familial hypercholesterolemia (FH). MATERIALS AND METHODS: Atorvastatin was administered to patients with PHC (n = 11), FCHL (n = 16), and FH (n = 13). We measured plasma levels of lipids, remnant-like particle cholesterol, apoproteins, and cholesterol in lipoprotein fractions. Sequential ultracentrifugation was performed to subfractionate the plasma lipoproteins, and lymphocyte LDL-receptor activities were estimated using flow cytometry. RESULTS: The average daily dosage of atorvastatin was 10, 27, and 40 mg in patients with PHC, FCHL, and FH, respectively; after 12 months of atorvastatin treatment, LDL cholesterol (LDL-C) plasma levels decreased by 44%, 50%, and 53%, respectively (all, P < .0001). Atorvastatin reduced low-density LDL-C plasma levels in patients with PHC (48% reduction), FCHL (53%), and FH (46%) (all, P < .0001). Plasma levels of medium-density and high-density LDL-C were also significantly reduced in the 3 patient groups (all, P ≤ .0147). LDL-receptor activity was negatively correlated with baseline levels of medium-density LDL-C and with the decreases in plasma md-LDL-C levels. CONCLUSION: Atorvastatin decreased the levels of the 3 LDL fractions. The md-LDL decrease appeared to be mainly because of stimulation of LDL-receptor activity.

Relationships between the visceral fat area on CT and coronary risk factor markers.

OBJECTIVE: The visceral fat area (VFA) was measured, and the relationships between the VFA and the body mass index (BMI), waist circumference, blood pressure, and indices of lipid and sugar metabolism were evaluated. METHODS: The subjects included 607 consecutive patients who underwent VFA examinations using computed tomography (CT) scans. In addition to the routine examination parameters, the levels of adiponectin and homeostasis model assessment as an index of insulin resistance (HOMA-IR) were measured in all subjects, and the levels of malondialdehyde-modified low-density lipoprotein (MDA-LDL), remnant-like particles (RLP), lipoprotein (a) (Lp(a)), apolipoprotein (Apo) AI, ApoB and ApoE were measured in 270 subjects. RESULTS: In both men and women, the VFA showed significant positive correlations with the age, BMI, waist circumference, subcutaneous fat area, visceral fat area/subcutaneous fat area (v/s) ratio, systolic blood pressure, diastolic blood pressure, the fasting blood sugar (FBS), the hemoglobin A1c (HbA1c), high-density lipoprotein cholesterol (HDLC), triglyceride (TG), uric acid, HOMA-IR and ApoB and the ApoB/LDLC ratio and significant negative correlations with the levels of HDLC and adiponectin. The levels of the total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), non-HDLC, MDA-LDL and Lp(a) and the ApoB/ApoAI ratio were not correlated with the VFA in either men or women. The RLP exhibited a significant positive correlation with the VFA in women. CONCLUSION: The VFA exhibited high positive correlations with the waist circumference, blood pressure and TG level and a negative correlation with the HDLC level, regardless of gender, supporting the validity of the present diagnostic method for evaluating metabolic syndrome (MS). Although the LDLC level is not included in the diagnostic criteria for MS, the positive correlations between the VFA and the ApoB level and ApoB/LDLC ratio observed in both men and women indicate qualitative abnormalities of lipoproteins, such as an increase in the amount of small dense LDL. Measuring the levels of apolipoproteins in addition to lipoproteins during health screening is therefore useful for evaluating of atherogenicity.

Skew of plasma low- and high-density lipoprotein distributions to less dense subfractions in normotriglyceridemic chronic kidney disease patients on maintenance hemodialysis treatment.

BACKGROUND: Plasma levels of small, dense low-density lipoprotein (LDL) were reported to increase in chronic kidney disease (CKD) patients on hemodialysis (HD), but most of these patients were hypertriglyceridemic. Plasma levels of small, dense LDL are known to increase in hypertriglyceridemic subjects. Therefore, to investigate the direct effect of CKD on the distribution of LDL subfractions, we investigated the distribution of LDL subfractions in normotriglyceridemic CKD patients on HD. METHODS: The levels of plasma lipoprotein subfractions and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), which markedly influence the distributions of plasma LDL and high-density lipoprotein (HDL) subfractions, were compared between 40 HD patients and 40 normolipidemic controls. Plasma lipoproteins were subfractionated into seven subfractions by ultracentrifugation. RESULTS: Plasma levels of cholesterol (C) in remnant-like particle, which is equivalent to the triglyceride (TG)-rich lipoprotein remnant, were twice as high in HD patients as those in controls with matched TG levels. Plasma levels of C and TG in VLDL and IDL (intermediate density lipoprotein) were slightly higher in HD patients than in controls. The C/TG ratio of VLDL was significantly higher in HD patients than in controls. In comparison with the corresponding values in controls, the C and TG levels in low-density LDL and HDL2 in HD patients were high, whereas those in medium-density LDL, high-density LDL, and HDL3 were low. Plasma LCAT activity and CETP mass were lower in HD patients than in controls. CONCLUSION: Distribution of LDL and HDL skewed toward less dense fractions in normotriglyceridemic CKD patients on HD. A decrease in reverse C transport likely played an important role in these changes in the patients.

Particular human leukocyte antigen alleles are associated with biochemical traits in the Japanese population.

We analyzed genetic associations among 7 biochemical traits (fasting plasma glucose, HbA1c, total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein cholesterol, triglyceride, and uric acid) and 6 HLA loci using 1,616 individuals who visited the Health Evaluation and Promotion Center at Tokai University Hospital. Significant differences between the individuals carrying particular HLA alleles and those not carrying the alleles in certain biochemical traits were observed by Mann-Whitney U test. In female subjects, DPB1*03:01 was significantly associated with HbA1c (p = 0.0000665), and DRB1*14:03 was associated with total cholesterol concentration (p = 0.0015). In male subjects, C*14:02 demonstrated significant associations with fasting plasma glucose with p values of 0.0041. By contrast, Fisher's exact test indicated that female DRB1*14:03 was associated with a high concentration of total cholesterol (p = 000323, odds ratio [OR] = 4.32, 95% confidence interval [95% CI] = 1.83-10.36), whereas female DPB1*02:01 had a protective effect against a high concentration of LDL cholesterol (p =0.0043, OR = 0.41, 95% CI = 0.19-0.79). These associations have a statistical power of more than 0.8 and still retain significance after Bonferroni correction.

Decrease in glomerular filtration rate by plasma low-density lipoprotein cholesterol in subjects with normal kidney function assessed by urinalysis and plasma creatinine.

OBJECTIVE: It has not been well defined whether plasma low-density lipoprotein cholesterol (LDL-C) progresses arteriolosclerosis (arteriosclerosis of small arteries) or not. Estimated glomerular filtration rate (e-GFR) is an indicator of the function of renal arterioles and capillaries of glomeruli. The relationship between e-GFR and plasma LDL-C was studied to estimate the effect of plasma LDL-C on the function of renal arterioles and capillaries of glomeruli to speculate the effect of plasma LDL-C on arteriolosclerosis. METHODS AND RESULTS: Major coronary risk factors; blood pressure, plasma lipids, and fasting plasma glucose were compared among 4 groups of examinees of a health evaluation and promotion center separated by e-GFR, namely, Control group, Group 1, 2, 3 from highest e-GFR to lowest e-GFR. Numbers of total male and female subjects were 4602 and 2920, respectively. Plasma LDL-C levels were significantly high in Group 2 and 3 in all male subjects and high in Group 1, 2, and 3 in male subjects with age of fifties, compared with Control group. Plasma LDL-C levels were significantly high in Group 1, 2, and 3 in all female subjects and high in Group 2 and 3 in female subjects with age of fifties, compared with Control group. Plasma levels of LDL-C were not significantly different at each years of age in subjects with age of fifties in both sex. BMI and waist circumference were higher in male subjects with low e-GFR but not in female subjects. Blood pressure and fasting plasma glucose were not high in subjects in Group 1, 2, and 3, compared with Control group in all subjects and subjects with age of fifties in both sex. CONCLUSIONS: We concluded that the high plasma level of LDL-C was the major risk factor among coronary risk factors to reduce GFR probably due to impairing the function of renal arterioles and capillaries of glomeruli in subjects with normal kidney function assessed by urinalysis and plasma creatinine.

Clinical profile and prognosis of hospitalized patients with congestive heart failure in Isehara, Japan.

Since the clinical profile and prognosis of heart failure depending on time of the study performed, regional characteristics of background population and different race, we attempted to evaluate the prognosis of symptoms and life expectancy of Japanese patients with heart failure. We evaluated the clinical profiles and prognoses of 1,015 consecutive patients with congestive heart failure (CHF) for whom hospitalization was required. A total of 1,015 consecutive CHF patients (584 males and 431 females) were enrolled in this study, however the total number of events investigated was 1,409. Of these patients, survival was confirmed in 413 patients, death was confirmed in 299 patients, and the prognoses of 303 patients remained unknown due to transfer to other hospitals or for some other reasons. The mean age on admission was 68.4 +/- 14.9 years. In both males and females, the peak age at the onset of CHF was in the seventies, and for patients in their eighties, the number of female patients with CHF was larger than that of male patients. Major underlying heart diseases consisted of ischemic heart disease (34%), valvular heart disease (22%), dilated cardiomyopathy (11%), and hypertension (10%). Most CHF patients who had dilated cardiomyopathy as an underlying disease were hospitalized several times, and 45% of them were hospitalized 3 times or more. The life expectancy of patients with CHF caused by ischemic heart disease was the poorest, and their 5-year and 10-year survival rates were 55% and 38%, respectively. Similarly, 5-year and 10-year survival rates of patients with CHF caused by valvular heart disease, hypertension, and dilated cardiomyopathy were 62% and 44%, 58% and 53%, and 70% and 65%, respectively. In 299 deceased patients, the mean age at death was 72.2 +/- 13.9 years. In all these deceased patients, direct causes of death were sudden death (16.1%), CHF (42.2%), others (31.4%), and unknown (10.4%). The frequency of sudden death was highest (25%) in patients with CHF caused by dilated cardiomyopathy, followed by those with CHF caused by valvular heart disease (18%) and those with CHF caused by ischemic heart disease (17.5%). In addition, the frequency of death from CHF was highest (60%) in those with CHF caused by dilated cardiomyopathy, followed by those with CHF caused by ischemic heart disease (49.2%).

A case of familial hypercholesterolemia; secession from LDL-apheresis by the drug treatment with potent statin and resin.

Low density lipoprotein (LDL)-apheresis is a useful tool for the treatment of familial hypercholesterolemia (FH) with coronary artery disease (CAD). However, it gives economic, physical and mental burdens for the patients. We reports a case of FH in whom LDL-apheresis treatment was seceded with drug treatment with a potent statin and bile acid-sequestering resin. A 54-year-old woman was admitted for evaluation of atherosclerotic lesion after 4 years of LDL-apheresis and 1 year of drug medication with a potent statin, atorvastatin and resin, cholestimide with coronary angiography. She had been diagnosed as heterozygous FH when she was 46 years old. Oral medication was initiated at the outpatient clinic. LDL-cholesterol (C) level was not successfully controlled despite the administration of a statin, pravastatin, a fibrate, clinofibrate and probucol at maximum doses Concomitantly. Therefore, as combination therapy, LDL-apheresis was introduced in May 1997. However, the patient strongly complained of the economic, physical, and mental burdens of LDL-apheresis and requested discontinuation of apheresis. Therefore, LDL-apheresis was discontinued in July 2000, and oral medication was subsequently changed to a combination of atorvastatin and cholestimide, resulting in successful control of serum LDL-C level by oral medication alone. We compared coronary arteriographic findings between 1997 and 2001. No advancement of lesions was observed. We think that strong drug treatment can secede from the LDL-apheresis for treatment of patients with FH.

[Efficacy of Nifekalant hydrochloride for life-threatening ventricular tachyarrhythmias in patients with resistance to lidocaine: a study of patients with out-of-hospital cardiac arrest].

OBJECTIVES: Class I antiarrhythmic agents are not always effective in the treatment of life-threatening ventricular tachycardia/ventricular fibrillation (VT/VF) especially in patients with cardiopulmonary arrest. Nifekalant hydrochloride(NIF) is a novel class III antiarrhythmic agent for malignant VT/VF. This study prospectively evaluated NIF efficacy for life-threatening VT/VF observed after cardiopulmonary arrest. METHODS: Thirty-two of 145 patients who were transferred to the emergency room in Tokai University Hospital showed VT/VF after resuscitation from cardiopulmonary arrest from June 2000 to March 2001. These 32 patients were treated with 12 mg (mean) epinephrine and 1.0-2.0 mg/kg lidocaine following direct current application(200 to 360J), and then classified into two groups. Eleven patients received intravenous 0.15 to 0.3 mg/kg NIF followed by intravenous infusion of 0.3 to 0.4 mg/kg/hr NIF(NIF group). The other 21 patients received 1.0 to 2.0 mg/kg of lidocaine(non-NIF group). RESULTS: Sinus rhythm was restored in the nine patients(82%) in the NIF group but only four patients (19%) in the non-NIF group. QTc was not prolonged(0.45 +/- 0.04 sec, n = 9) and no torsades de pointes was observed in the NIF group. Two patients survived but the remaining nine patients died in the NIF group. Five patients died of cardiac standstill following sinus bradycardia and repeated sinus arrest within 2 to 27 hr after admission, two patients died of sudden cardiac arrest from sinus rhythm, and two patients died of persistent VT/VF. In contrast, all 21 patients in the non-NIF group died. Seventeen patients died of persistent VT/VF before hospitalization, one patient died of recurrent VT/VF, and three patients died of cardiac standstill following sinus bradycardia. CONCLUSIONS: NIF effectively suppresses VT/VF which is refractory to direct current shock in patients with cardiopulmonary arrest. However, NIF may rather worsen electrophysiological function in the sinus node after administration of high doses of epinephrine, and may induce sinus bradycardia and/or sinus arrest. Careful observation, such as monitoring of electrocardiography and blood pressure and temporary cardiac pacemaker use, is needed to prevent death in patients surviving after cardiopulmonary arrest if NIF is administered following high dose epinephrine infusion.

[Significance of electrocardiographic QRS width in patients with congestive heart failure: a marker for biventricular pacing].

OBJECTIVES: Biventricular pacing may be valuable for the treatment of patients with intractable heart failure, but how many patients in Japan would benefit from this type of therapy remains uncertain. This study investigated the incidence of intraventricular conduction delay in the electrocardiogram(ECG) as a marker of the need for biventricular pacing, as well as the underlying etiology of heart failure in patients admitted with congestive heart failure. METHODS: Patients with heart failure admitted to the Tokai University Hospital from January 1990 to September 2000 were studied retrospectively. The distribution of age, sex and underlying diseases, and that of the rhythm and the QRS width in ECG recordings were analyzed. Patients with a QRS width of over 121 msec in the ECG were classified as the 'wide QRS' group. RESULTS: Of a series of 1,200 consecutive patients with heart failure, 872 patients, 499 males and 373 females (mean age 67.9 +/- 13.9 years) were admitted to the hospital and 71 had 'wide QRS' by ECG. Among those in the 'wide QRS' group, 37% had ischemic heart disease and 14% had dilated cardiomyopathy. The widest QRS complexes were encountered in patients with dilated cardiomyopathy and the largest number of wide QRS complexes was encountered in patients with ischemic heart disease. CONCLUSIONS: The most frequent causes of heart failure among patients considered suitable for biventricular pacing were ischemic heart disease and dilated cardiomyopathy, which is consistent with previous reports. Compared with the statistics reported from western countries, the incidence of ischemic heart disease and the incidence of intraventricular conduction delay were lower in Japanese patients with heart failure. The incidence of intraventricular conduction delay among patients with heart failure was 8.6%. Therefore, fewer patients need biventricular pacing in Japan than in western countries. Nevertheless, patients with heart failure resistant to other therapies might still benefit from this type of therapy.