Association of Circulating Follistatin-Like 1 Levels with Inflammatory and Oxidative Stress Markers in Healthy Men.

OBJECTIVES: Follistatin-like 1 (Fstl1) is a circulating glycoprotein that plays a crucial role in cardiovascular diseases and inflammation-related disorders. We have shown that Fstl1 acts as an anti-inflammatory factor that protects against ischemic heart disease and chronic kidney disease. Here we examined whether plasma level of Fstl1 associates with markers of inflammation and oxidative stress in apparently healthy Japanese men. METHODS AND RESULTS: Plasma Fstl1 levels were measured by enzyme-linked immunosorbent assay. Circulating Fstl1 concentrations positively correlated with levels of fasting immune-reactive insulin (FIRI), high-sensitive CRP (hsCRP) and derivatives of reactive oxidative metabolites (dROMs), an indicator of oxidative stress. The levels of hsCRP positively associated with Fstl1, body mass index (BMI), triglyceride, FIRI and dROMs levels. dROMs levels positively associated with Fstl1, Hemoglobin A1c and hsCRP levels. Multiple regression analysis with confounding factors revealed that Fstl1 levels, together with BMI and FIRI, correlated with hsCRP and that Fstl1 levels correlated with dROMs. CONCLUSION: Our observations indicate that measurement of plasma Fstl1 levels can be valuable for assessment of pro-inflammatory and oxidative stress conditions.

Association of circulating C1q/TNF-related protein 1 levels with coronary artery disease in men.

OBJECTIVE: Obesity is a major risk factor for cardiovascular disease. Recent evidence demonstrates that dysregulation of fat-derived hormones, also known as adipokines, is linked with the pathogenesis of obesity-related disorders including coronary artery disease (CAD). Here, we investigated whether circulating level of an adipokine C1q/TNF-related protein (CTRP) 1 is associated with the prevalence of CAD. METHODS AND RESULTS: Consecutive 76 male CAD patients were enrolled from inpatients that underwent coronary angiography. Sixty four healthy male subjects served as controls. Plasma CTRP1 concentration was determined by enzyme-linked immunosorbent assay. CTRP1 levels were correlated positively with systolic blood pressure (BP) and triglyceride levels, and negatively with HDL cholesterol levels in all subjects. Plasma levels of CTRP1 were significantly higher in CAD patients than in control subjects (CAD: 443.3±18.6 ng/ml, control: 307.8±21.5 ng/ml, p<0.001). Multiple logistic regression analysis with body mass index, systolic BP, glucose, total cholesterol, HDL cholesterol, triglyceride, adiponectin and CTRP1 revealed that CTRP1 levels, together with systolic BP and HDL cholesterol, correlated with CAD. CONCLUSIONS: Our data indicate the close association of high CTRP1 levels with CAD prevalence, suggesting that CTRP1 represents a novel biomarker for CAD.

Circulating cathepsin K as a potential novel biomarker of coronary artery disease.

BACKGROUND: Cathepsin K (CatK) is one of the most potent mammalian collagenases involved in atherosclerosis-based vascular disease. We investigated whether circulating CatK is associated with the prevalence of coronary artery disease (CAD). METHODS: Two-hundred fifty-two consecutive subjects were enrolled from among patients who underwent coronary angiography and intravascular ultrasound analyses. One-hundred thirty-two age-matched subjects served as controls. Plasma CatK, intact procollagen type I N-terminal propeptide (I-PINP), and linked carboxy-terminal telopeptide of collagen type I (ICTP) were measured. RESULTS: Patients with CAD had higher CatK levels (44.0 ± 31.2 versus 15.5 ± 8.3 ng/mL, P < 0.001) and ICTP/I-PINP ratios (0.2 ± 0.1 versus 0.04 ± 0.03, P < 0.001) than the controls. Patients with acute coronary syndrome had higher CatK levels than those with stable angina pectoris. Overall, linear regression analysis showed that the CatK levels correlated positively with ICTP/I-PINP ratios (r = 0.41, P < 0.001). Multiple logistic regression analysis showed that CatK levels were independent predictors of CAD (odds ratio, 1.15; 95% CI, 1.07 to 1.23; P < 0.01). Furthermore, CatK levels were also correlated positively with percent plaque volumes and inversely with percent fibrous volumes by intravascular ultrasound. CONCLUSIONS: These data indicated that high levels of CatK are closely linked with the presence of CAD and that CatK serves as a novel biomarker for CAD.

Small low-density lipoprotein cholesterol concentration is a determinant of endothelial dysfunction by peripheral artery tonometry in men.

AIM: Endothelial dysfunction is an initial step in the progression of atherosclerosis. Precise measurements of lipoprotein subclass distribution by high-performance liquid chromatography (HPLC) have been established. Here, we investigated the potential associations between lipoprotein subclass cholesterol concentrations and endothelial dysfunction evaluated by digital reactive hyperemia peripheral arterial tonometry (PAT). METHODS: We recruited 120 apparently healthy Japanese men. Endothelial function was assessed by digital reactive hyperemia PAT, expressed as the logarithmic-scaled reactive hyperemia index (RHI). Plasma cholesterol concentrations in lipoproteins and their subclasses were determined by HPLC with gel permeation columns. RESULTS: RHI was inversely correlated with age (r=-0.258, p=0.004), followed by LDL cholesterol (r=-0.236, p=0.010) and small LDL cholesterol (r=-0.223, p=0.014). In addition, RHI was significantly inversely associated with heart rate, hemoglobin A1c, total cholesterol, medium LDL cholesterol, apolipoprotein B100, and non-HDL cholesterol. In stepwise multiple regression analysis, age (ß=-0.266, p=0.024), small LDL cholesterol (ß=-0.213, p=0.015), and heart rate (ß=-0.183, p=0.036) were found to be independent determinants of RHI (adjusted R(2) =0.132, p<0.001). CONCLUSIONS: Small LDL cholesterol concentration was an important, independent determinant of endothelial dysfunction in men.

Omentin as a novel biomarker of metabolic risk factors.

BACKGROUND: Omentin is an adipocytokine that is abundantly expressed in visceral fat tissue. We investigated the association of omentin with the number of metabolic risk factors. FINDING: The study population comprised 201 Japanese men who underwent annual health checkups. Plasma omentin levels were determined by enzyme-linked immunosorbent assay. We divided the subjects into 4 groups according to omentin levels. A reduction of plasma omentin levels significantly correlated with an increase in the mean number of metabolic risk factors such as increased waist circumference, dyslipidemia, high blood pressure and glucose intolerance. CONCLUSIONS: Circulating omentin levels negatively correlated with the multiplicity of metabolic risk factors, suggesting that omentin acts as a biomarker of metabolic disorders.

Cholesterol and triglyceride concentrations in lipoproteins as related to carotid intima-media thickness.

Since distinct cholesterol and triglyceride concentrations in major lipoproteins and their subclasses may be related to atherosclerosis, we investigated the relationship of cholesterol and triglyceride concentrations in lipoprotein subclasses and the severity of carotid intima-media thickness (IMT), a surrogate marker of subclinical atherosclerosis. We studied 116 apparently healthy Japanese men (53 ± 9 years) without a history of cardiovascular diseases who were not taking any medication. Carotid IMT was measured by means of high-resolution vascular ultrasound. Plasma cholesterol and triglyceride concentrations in major lipoproteins and their subclasses were determined by HPLC with gel permeation columns. By univariate analyses, carotid IMT was the most closely related to age (r = 0.528, P < 0.001), followed by smoking habit expressed as pack-year cigarette consumption (r = 0.409, P < 0.001). In addition to total cholesterol and LDL cholesterol, carotid IMT was significantly associated with cholesterol and triglyceride concentrations in several LDL and VLDL subclasses. Stepwise multiple linear regression analysis revealed that age (ß = 0.436, P < 0.001), smoking (pack-years) (ß = 0.225, P = 0.007), and large LDL cholesterol (ß = 0.175, P = 0.023) were independent predictors of determining carotid IMT (adjusted R(2) = 0.347, P < 0.001). These results indicate that large LDL cholesterol is an important, independent determinant of carotid IMT in healthy men.

Comparison between valsartan and amlodipine regarding cardiovascular morbidity and mortality in hypertensive patients with glucose intolerance: NAGOYA HEART Study.

It has not been fully examined whether angiotensin II receptor blocker is superior to calcium channel blocker to reduce cardiovascular events in hypertensive patients with glucose intolerance. A prospective, open-labeled, randomized, controlled trial was conducted for Japanese hypertensive patients with type 2 diabetes mellitus or impaired glucose tolerance. A total of 1150 patients (women: 34%; mean age: 63 years; diabetes mellitus: 82%) were randomly assigned to receive either valsartan- or amlodipine-based antihypertensive treatment. Primary outcome was a composite of acute myocardial infarction, stroke, coronary revascularization, admission attributed to heart failure, or sudden cardiac death. Blood pressure was 145/82 and 144/81 mm Hg, and glycosylated hemoglobin was 7.0% and 6.9% at baseline in the valsartan group and the amlodipine group, respectively. Both of them were equally controlled between the 2 groups during the study. The median follow-up period was 3.2 years, and primary outcome had occurred in 54 patients in the valsartan group and 56 in the amlodipine group (hazard ratio: 0.97 [95% CI: 0.66-1.40]; P=0.85). Patients in the valsartan group had a significantly lower incidence of heart failure than in the amlodipine group (hazard ratio: 0.20 [95% CI: 0.06-0.69]; P=0.01). Other components and all-cause mortality were not significantly different between the 2 groups. Composite cardiovascular outcomes were comparable between the valsartan- and amlodipine-based treatments in Japanese hypertensive patients with glucose intolerance. Admission because of heart failure was significantly less in the valsartan group.

Relation of plasma catecholamine levels with pulse wave velocity in hypertensive patients compared with normotensive subjects.

Although the circadian variation of catecholamine has been reported, that of the pulse wave velocity (PWV) has not. Brachial ankle (ba) PWV is associated with well-established indices of central stiffness. It is not known whether arterial stiffness is associated with catecholamine. The aim of the present study was to evaluate the changes in baPWV and those on the plasma epinephrine and norepinephrine levels in the morning and evening in hypertensive patients (HPs) and normotensive subjects (NSs). The baPWV and blood pressure (BP) were measured in 14 NSs (14 males, 39 ± 5 years) and 10 HPs (9 males and 1 female, 55 ± 13 years) at 06:00 h, noon, 18:00 h, and midnight, respectively. The plasma epinephrine and norepinephrine levels were measured in 14 NSs and 5 HPs at 06:00 h and 18:00 h, respectively. There was no significant difference in BPs at 06:00 h, noon, 18:00 h, and midnight in either NSs or HPs. The baPWV at 06:00 h was significantly lower than that at noon, 18:00 h, and midnight in NSs (P = 0.01, 0.04, and 0.0008, respectively). The plasma epinephrine and norepinephrine levels at 06:00 h were markedly lower than those at 18:00 h in NSs (P = 0.002 and 0.003, respectively). There were no significant changes in the baPWV of HPs at 06:00 h, noon, 18:00 h, or midnight. The plasma epinephrine and norepinephrine levels at 06:00 h were notably lower than those at 18:00 h in HPs (P = 0.004 and 0.01, respectively). Only NSs showed a significant reduction in the baPWV with a decrease in the plasma catecholamine levels in the morning, suggesting that the baPWV of NSs may be correlated with the variation of the plasma catecholamine levels.

Comparison of wavefront-guided aspheric laser in situ keratomileusis for myopia: coaxially sighted corneal-light-reflex versus line-of-sight centration.

PURPOSE: To compare refractive outcomes, higher-order aberrations (HOAs), and contrast sensitivity of myopic wavefront-guided aspheric laser in situ keratomileusis centered on the coaxially sighted corneal light reflex or on the line of sight. SETTING: Okamoto Eye Clinic, Ehime, Japan. DESIGN: Comparative case series. METHODS: Data at 3 months were compared based on the distance between the coaxially sighted corneal light reflex and the line of sight (P-distance) as follows: distance greater than 0.25 mm (high-distance group), distance greater than 0.15 mm and less than 0.25 mm (intermediate-distance group), and distance less than 0.15 mm (low distance group). RESULTS: The chart review included 317 eyes in the corneal-light-reflex group and 269 eyes in the line-of-sight group. The mean postoperative manifest refraction spherical equivalent was +0.123 diopter (D) ± 0.378 (SD) and +0.187 ± 0.480 D, respectively (P = .07). The safety and efficacy indices were significantly higher in the corneal-light-reflex group, including the high-distance subgroup and eyes with a P-distance less than 0.25 mm (P<.05, all cases). The HOAs (P<.001) and coma (P = .001) were significantly higher in the line-of-sight group (P<.001 and P = .001, respectively). The line-of-sight group had a significantly greater change in contrast sensitivity (P = .026). CONCLUSIONS: Centration on the coaxially sighted corneal light reflex resulted in better safety, effectiveness, and contrast sensitivity than line-of-sight centration. Centration on the coaxially sighted corneal light reflex was safer for myopic eyes with P-distances greater than 0.25 mm. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. Additional disclosures are found in the footnotes.

Circulating omentin is associated with coronary artery disease in men.

OBJECTIVE: Obesity is closely associated with an increased risk for cardiovascular morbidity and mortality. Omentin is a fat-derived secreted factor that is downregulated in obesity. We investigated whether circulating omentin associates with the prevalence of coronary artery disease (CAD). METHODS: The consecutive 78 male subjects were enrolled from patients who underwent coronary angiography. Sixty one age-matched male subjects served as controls. Plasma omentin concentration was measured by enzyme-linked immunosorbent assay. RESULTS: Plasma levels of omentin correlated negatively with body mass index (BMI), systolic blood pressure, hemoglobin A1c and total cholesterol levels, and positively with HDL cholesterol and adiponectin levels. Circulating omentin was independently associated with hemoglobin A1c and HDL cholesterol in a multiple regression analysis. Plasma levels of omentin were markedly lower in CAD patients than in control subjects (CAD: 102.8 ± 69.0 ng/ml, control: 454.7 ± 128.6 ng/ml, P < 0.001). Multiple logistic regression analysis with BMI, systolic blood pressure, glucose, hemoglobin A1c, HDL cholesterol, adiponectin and omentin revealed that plasma omentin levels were independently correlated with CAD. CONCLUSION: These data indicate that low levels of omentin are closely linked with the presence of CAD and that omentin serves as a novel biomarker for CAD.

Association of a fat-derived plasma protein omentin with carotid artery intima-media thickness in apparently healthy men.

Obesity is causally linked with the development of atherosclerosis. Omentin is an adipocytokine whose concentrations are reduced in obese individuals. Here we examined the relationship between plasma omentin levels and carotid intima-media thickness (IMT), a marker of early atherosclerosis, in apparently healthy Japanese men. Participants were 100 Japanese men who underwent a medical checkup. Maximal IMT (max-IMT) and mean-IMT in common carotid artery were measured by high-resolution carotid ultrasound system. Plasma omentin concentrations were determined by enzyme-linked immunosorbent assay. Circulating omentin levels correlated negatively with body mass index, waist circumference, fasting glucose, creatinine, max-IMT and mean-IMT, and positively with estimated glomerular filtration rates (eGFR). Single regression analysis demonstrated that max-IMT associated with age, eGFR and omentin levels, and that mean-IMT associated with age, fasting glucose, eGFR and omentin levels. Multiple regression analysis revealed that omentin levels, together with age, correlated with max-IMT and mean-IMT. Our data document that circulating omentin levels independently and negatively associate with carotid IMT in this population, suggesting that measurement of omentin may be useful for assessment of carotid IMT.

Estimation of focal and extra-focal radiation profiles based on Gaussian modeling in medical linear accelerators.

The X-ray source or focal radiation is one of the factors that can degrade the conformal field edge in stereotactic body radiotherapy. For that reason, it is very important to estimate the total focal radiation profiles of linear accelerators, which consists of X-ray focal-spot radiation and extra-focal radiation profiles. Our purpose in this study was to propose an experimental method for estimating the focal-spot and extra-focal radiation profiles of linear accelerators based on triple Gaussian functions. We measured the total X-ray focal radiation profiles of the accelerators by moving a slit in conjunction with a photon field p-type silicon diode. The slit width was changed so that the extra-focal radiation could be optimally included in the total focal radiation. The total focal radiation profiles of an accelerator at 4-MV and 10-MV energies were approximated with a combination of triple Gaussian functions, which correspond to the focal-spot radiation, extra-focal radiation, and radiation transmitted through the slit assembly. As a result, the ratios of the Gaussian peak value of the extra-focal radiation to that of the focal spot for 4 and 10 MV were 0.077 and 0.159, respectively. The peak widths of the focal-spot and extra-focal radiation profiles were 0.57 and 25.0 mm for 4 MV, respectively, and 0.60 and 22.0 mm for 10 MV, respectively. We concluded that the proposed focal radiation profile model based on the triple Gaussian functions may be feasible for estimating the X-ray focal-spot and extra-focal radiation profiles.

High serum concentrations of pentosidine, an advanced glycation end product, are associated with low normal value of ankle-brachial index in apparently healthy men.

The ankle-brachial index (ABI) is widely used for peripheral arterial disease screening and is associated with future cardiovascular events. Pentosidine, an advanced glycation end product, accumulates with age and in diabetes and end-stage renal disease; but the significance of elevated serum pentosidine is not well known. We investigated the relationship of the ABI to circulating pentosidine concentrations as well as other atherogenic factors in apparently healthy men. The study group consisted of a total of 170 apparently healthy men (age, 55 ± 9 years). Serum pentosidine concentrations were measured by enzyme-linked immunosorbent assay. The mean ABI and pentosidine concentrations of the whole study group were 1.16 ± 0.07 (range, 0.98-1.35) and 36.1 ± 10.6 ng/mL (range, 11.2-81.0), respectively. Univariate analysis showed that the ABI was inversely correlated with pentosidine (P = .0004), small low-density lipoprotein (LDL) cholesterol (P = .017), LDL cholesterol (P = .019), apolipoprotein B (P = .024), fasting insulin (P = .028), very small LDL cholesterol (P = .036), difference in ABIs between legs (P = .037), malondialdehyde-modified LDL (P = .044), and homeostasis model assessment of insulin resistance (P = .047). Stepwise multiple linear regression analysis revealed that increased pentosidine, fasting insulin, small LDL cholesterol, difference in ABIs between legs, difference in systolic blood pressure between arms, and reduced body mass index were independent determinants of reduced ABI (adjusted R(2) = 0.237, P < .0001). Serum pentosidine was an important, independent determinant of ABI in healthy men. Subjects with an ABI less than 1.10 showed higher pentosidine concentrations.

Very small low-density lipoprotein cholesterol level is a determinant of arterial stiffness in men with impaired glucose metabolism.

AIM: Pulse wave velocity (PWV), an estimate of arterial stiffness, is an important predictor of cardiovascular risk. The aim of this study was to investigate the relationship between lipoprotein subclasses and brachial-ankle PWV (baPWV). METHODS: A total of 131 apparently healthy Japanese men without a history of cardiovascular disease were divided into two groups: normal glucose metabolism (n =87) and impaired glucose metabolism (n =44). Cholesterol concentrations of major lipoproteins and their subclasses were determined by HPLC with gel permeation columns. RESULTS: In the normal glucose metabolism group, age, systolic blood pressure, and diastolic pressure were associated with increased baPWV, and a stepwise multiple linear regression analysis revealed that age (p =0.022) and systolic blood pressure (p < 0.001) were significantly independent determinants of baPWV. In the impaired glucose metabolism group, age (p =0.002), very small LDL cholesterol (p =0.012), systolic blood pressure (p =0.021), and the fasting plasma glucose concentration (p =0.038) were identified as independent determinants of baPWV, although a univariate analysis revealed significant relationships of several plasma lipid compositions or species to baPWV. CONCLUSIONS: In addition to aging, hypertension and glucose levels, very small LDL cholesterol levels appear to play an important role in the development of arterial stiffness in men with impaired glucose metabolism.

Comparison of myopic LASIK centered on the coaxially sighted corneal light reflex or line of sight.

PURPOSE: To compare refractive outcomes of myopic LASIK with centration on the coaxially sighted corneal light reflex (CSCLR) to centration on the center of the pupil (line of sight [LOS]). METHODS: The NIDEK CXIII excimer laser was used to treat 268 eyes with centration on the CSCLR (CSCLR group) and 288 eyes with centration on the LOS (LOS group). For the CSCLR group, the laser ablation was delivered 80% closer to the visual axis. One-month postoperative outcomes were compared. RESULTS: Preoperative manifest refraction spherical equivalent (MRSE) was -4.88+/-1.55 diopters (D) (range: -8.50 to -1.25 D) in the CSCLR group and -5.05+/-1.63 D (range: -9.75 to -1.50 D) in the LOS group. The postoperative MRSE was 0.17+/-0.39 D (range: -1.38 to -1.25 D) in the CSCLR group and 0.19+/-0.48 D (range: -1.63 to +1.88 D) in the LOS group. Safety (1.18) and efficacy (1.047) indices were statistically significantly higher in the CSCLR group compared to the LOS group (1.138 and 0.997, respectively) (P<.05). This trend was accentuated in a subgroup analysis of patients with >0.25-mm difference between the CSCLR and LOS, favoring the CSCLR group. A statistically significantly greater induction of higher order aberrations (P=.04) and coma (P<.01) was noted in the LOS group postoperatively. CONCLUSIONS: Myopic LASIK centered on the CSCLR was significantly safer and more effective than LASIK centered on the pupil (LOS), with significantly lower induction of coma and total higher order aberrations.

Circulating malondialdehyde-modified low-density lipoprotein is strongly associated with very small low-density lipoprotein cholesterol concentrations in healthy men.

BACKGROUND: Despite the importance of oxidized LDL and small LDL particles as atherogenic lipoproteins, the relationship between oxidized LDL and the distributions of size subclasses of lipoproteins is not fully proved. We investigated the relationship of circulating malondialdehyde-modified (MDA)-LDL, an oxidized form of LDL, and lipoprotein subclasses in healthy men. METHODS: The study group consisted of a total of 170 healthy Japanese men (55+/-9 y). Plasma cholesterol concentrations in major lipoproteins and their subclasses were determined by HPLC with gel permeation columns. RESULTS: In univariate analysis, body mass index, waist circumference, blood pressure, white blood cell count, C-reactive protein, uric acid, fasting insulin, HOMA-IR, total cholesterol, triglycerides, each VLDL subclass cholesterol, each LDL subclass cholesterol, small HDL cholesterol, and very small HDL cholesterol were positively correlated with MDA-LDL, whereas adiponectin and large HDL cholesterol were inversely correlated with MDA-LDL. In stepwise multiple regression analysis, very small LDL cholesterol, medium VLDL cholesterol, very small HDL cholesterol, small HDL cholesterol, and systolic blood pressure were identified as independent determinants of MDA-LDL (R(2)=0.718, p<0.0001). CONCLUSIONS: Circulating MDA-LDL concentrations are strongly associated with very small LDL cholesterol concentrations in healthy men. HDL size heterogeneity has a biphasic effect on MDA-LDL.

Inverse relationship between obesity and serum prostate-specific antigen level in healthy Japanese men: a hospital-based cross-sectional survey, 2004-2006.

OBJECTIVES: To confirm an inverse relationship between obesity and serum prostate-specific antigen (PSA) levels in Japanese men with a smaller body mass index (BMI) than white and African-American men. METHODS: We analyzed 5246 apparently healthy Japanese men aged >20 years who visited our medical center for a health checkup from January 2004 to December 2006. The men were divided into 6 groups by age decade, and the BMI was categorized into 5 groups. The body fat percentage (BFP) was also used and was grouped into quartiles. The Mantel-Haenszel chi(2) test was used to check for trends in proportions of subjects with abnormal PSA values for each cutoff point (2.5 and 4.0 ng/mL) in these groups. The relationships between the PSA levels and BMI or BFP were examined using multivariate analysis. RESULTS: The median age, BMI, BFP, and PSA level was 46 years, 23.2 kg/m(2), 21.5%, and 0.78 ng/mL, respectively. The proportion of subjects with an abnormal PSA value increased significantly with age (P for trend < .0001); however, no trends were found across the BMI or BFP categories. The geometric mean PSA level increased significantly with age (P for linear trend < .0001) and decreased with BMI and BFP categories (P for linear trend = .001 and P for linear trend = .002, respectively). CONCLUSIONS: Our findings have demonstrated an inverse relationship between obesity and PSA levels even in Japanese men with a low prevalence of obesity, such as was previously reported for American men. Therefore, in prostate cancer screening, obesity, which can affect the accuracy of PSA testing, independent of race and ethnicity, should be taken into account.