Arterial Stiffness Is Associated With Small Vessel Disease Irrespective of Blood Pressure in Stroke-Free Individuals.

BACKGROUND: Arterial stiffness and hypertension are important risk factors for cerebral small vessel disease (CSVD). Clinically, there are hypertensive patients with low pulse wave velocity (PWV) and nonhypertensive individuals with high PWV. We aimed to determine the effects of arterial stiffness on CSVD in normotensive individuals. METHODS: An observational cross-sectional study was conducted in 1894 stroke-free participants who underwent brain magnetic resonance imaging and brachial-ankle pulse wave velocity (baPWV) measurements at a health checkup between 2013 and 2020. CSVD was defined as any of following: white matter hyperintensities, cerebral microbleeds, silent lacunar infarcts, and enlarged perivascular spaces. baPWV was measured using an automatic oscillometric device. Participants were divided into 4 groups according to the following cutoff points: low blood pressure (BP, <120/80 mm Hg) with low baPWV (<14.63 m/s, a cutoff value that predicted CSVD); high BP (≥120/80 mm Hg) with low baPWV; low BP with high baPWV (≥14.63 m/s); and high BP with high baPWV. RESULTS: The mean age of the participants was 57±13 years (41% women). The prevalence of CSVD was 718 (38%), which was higher in the low BP with high baPWV (56%) and high BP with high baPWV (55%) groups than in the high BP with low baPWV (24%) and low BP with low baPWV (22%) groups. Compared with the low BP with low baPWV group, the low BP with high baPWV group (odds ratio, 1.63 [95% CI, 1.09-2.43]) and the high BP with high baPWV group (odds ratio, 1.86 [95% CI, 1.39-2.49]) had a significantly higher multivariable-adjusted risk for CSVD. CONCLUSIONS: Individuals with a high baPWV had a higher prevalence of CSVD, independent of BP status. Higher arterial stiffness is likely to be a more important risk factor for CSVD than BP status in stroke-free individuals.

C-reactive Protein Levels and Cardiovascular Outcomes After Febuxostat Treatment in Patients with Asymptomatic Hyperuricemia: Post-hoc Analysis of a Randomized Controlled Study.

PURPOSE: Inflammation plays an important role in the initiation and progression of atherosclerosis, leading to poor clinical outcomes. Hyperuricemia is associated with the activation of the Nod-like receptor protein 3 inflammasome. Here, we investigated whether inhibition of inflammation using febuxostat lowered the risk of cardiovascular events. METHODS: This is a post-hoc analysis of the randomized trial, Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED). In total, 1067 patients (736 men and 331 women) were included in the analysis. We compared the serial changes in high-sensitivity C-reactive protein (hs-CRP) levels between febuxostat and non-febuxostat groups and assessed the correlation between the changes in uric acid (UA) and hs-CRP levels after febuxostat treatment. We also determined whether febuxostat could reduce a hard endpoint, defined as a composite of cardiovascular events and all-cause mortality. RESULTS: Serum UA levels in the febuxostat group were significantly lower than those in the non-febuxostat group after randomization (p < 0.05). However, hs-CRP levels were comparable between the two groups during the study. No significant correlation was observed between the changes in UA and hs-CRP levels after febuxostat treatment. The hard endpoints did not differ significantly between the two groups. In patients with baseline hs-CRP levels > 0.2 mg/dL or those administered 40 mg of febuxostat, the drug did not reduce hs-CRP levels or decrease the hard endpoint. CONCLUSION: Febuxostat reduced the UA levels but did not affect the CRP levels, and therefore may fail to improve cardiovascular outcomes after treatment. TRIAL REGISTRATION: ClinicalTrial.gov (NCT01984749). https://clinicaltrials.gov/ct2/show/NCT01984749.

Optimal uric acid levels by febuxostat treatment and cerebral, cardiorenovascular risks: post hoc analysis of a randomized controlled trial.

OBJECTIVES: Hyperuricaemia is recognized as an independent risk marker for cardiovascular and renal diseases. However, uric acid is a powerful free-radical scavenger, and the optimal level of serum uric acid (SUA) determining outcomes is unknown. This study explored whether interventional treatments for excessive SUA reduction were harmful and what constituted the optimal lowering of SUA levels for the prevention of events in patients with asymptomatic hyperuricaemia. METHODS: This was a post hoc analysis of a randomized trial (Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy [FREED]) in which 1070 older patients with asymptomatic hyperuricaemia were enrolled and allocated to febuxostat (n = 537) or non-febuxostat treatment group (n = 533). We assessed the relationship between the endpoint (withdrawal or study completion) SUA levels and clinical outcomes. Primary endpoint was defined as a composite of all-cause mortality, cerebral and cardiorenovascular events. RESULTS: In the febuxostat group, patients achieving SUA levels ≤4 mg/dl (hazard ratio: 2.01 [95% CI: 1.05, 3.87]), >4 to ≤5 mg/dl (2.12 [1.07, 4.20], >6 to ≤7 mg/dl (2.42 [1.05, 5.60]), and >7 mg/dl (4.73 [2.13, 10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels >5 to ≤6 mg/dl (P = 0.003 [log-rank test]). This J-shaped relationship applied to patients with renal impairment (P = 0.007 [Gray's test]) and was not significant in the non-febuxostat treatment group (P = 0.212 [log-rank test]). CONCLUSION: Optimal SUA level by febuxostat treatment is 5-6 mg/dl for reducing all-cause mortality, cerebral, cardiovascular and renal events. Excessive SUA reduction may be harmful in older hyperuricaemic populations. TRIAL REGISTRATION: ClinicalTrial.gov, https://clinicaltrials.gov, NCT01984749.

Power spectral analysis of heart rate variability is useful as a screening tool for detecting sympathetic and parasympathetic nervous dysfunctions in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder that causes motor symptoms and autonomic dysfunction. However, autonomic function tests commonly performed in PD can only evaluate either the sympathetic or parasympathetic nervous system. Therefore, the purpose of this pilot study is to investigate whether power spectral analysis of heart rate variability could detect both sympathetic and parasympathetic nervous dysfunctions in patients with PD. METHODS: Seventeen patients with PD and 11 healthy control subjects underwent electrocardiogram recording for the spectral analysis of heart rate variability to obtain values of low-frequency (LF) (0.04-0.15 Hz) and high-frequency (HF) (0.15-0.4 Hz) powers. Moreover, we examined the coefficient of variation of R-R intervals (CVRR) as a parameter of parasympathetic function in all participants and performed 123I-metaiodobenzylguanidine scintigraphy to measure the heart-to-mediastinum ratio as a parameter of cardiac sympathetic innervation in patients with PD. RESULTS: The median age of control subjects and PD patients was 63 and 66 years old, respectively. The median Hoehn and Yahr scale of PD patients was stage 2. The values of resting LF and HF powers widely varied. The median values of resting LF powers of control subjects and PD patients and those of HF powers were 169 and 70 ms2, 279 and 65 ms2, respectively, the difference was statistically insignificant. Approximately 41% of patients with PD had values below the first quartile of resting LF powers (< 58 ms2) or HF powers (< 50 ms2); however, no control subject had such low values. Positive correlations were found between resting LF powers and heart-to-mediastinum ratios of 123I-metaiodobenzylguanidine uptake (r = 0.6) and between resting HF powers and CVRRs (r = 0.7). The resting LF power was also associated with CVRRs and constipation. Furthermore, a positive correlation was observed between resting LF powers and resting HF powers in patients with PD (r = 0.8). CONCLUSIONS: The power spectral analysis of heart rate variability may be useful as a screening tool for detecting autonomic dysfunctions by detecting low resting LF and HF powers in patients with PD. Sympathetic and parasympathetic nerves may be concurrently damaged in patients with PD.

Effect of Novel Stratified Lipid Risk by "LDL-Window" and Flow-Mediated Dilation on the Prognosis of Coronary Artery Disease Using the FMD-J Study A Data.

BACKGROUND: Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index.Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG ≥150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C ≥170 mg/dL; and high-risk group (n=19) with TG ≥150 mg/dL and non-HDL-C ≥170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index ≥7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE. CONCLUSIONS: Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.

Triglyceride/low-density-lipoprotein cholesterol ratio is the most valuable predictor for increased small, dense LDL in type 2 diabetes patients.

BACKGROUND: Small, dense low-density lipoprotein (sd-LDL) increases in type 2 diabetes patients and causes arteriosclerosis. Non-high-density-lipoprotein cholesterol (non-HDL-C) is thought to be useful for predicting arteriosclerosis and sd-LDL elevation; however, there are no data about whether the triglyceride /low-density-lipoprotein cholesterol (TG/LDL-C) ratio is a valuable predictor for sd-LDL. METHODS: A total of 110 type 2 diabetes patients with hypertriglyceridemia were analyzed. No patients were treated with fibrates, but 47 patients were treated with statins. LDL-C was measured by the direct method. LDL-migration index (LDL-MI) using electrophoresis (polyacrylamide gel, PAG) was calculated, and a value ≥0.400 was determined to indicate an increase in sd-LDL. Simple regression analyses were carried out between LDL-MI and lipid markers. Receiver operating characteristic curves of lipid markers for predicting high LDL-MI were applied to determine the area under the curve (AUC), sensitivity, specificity, and cut-off point. RESULTS: LDL-MI correlated negatively with LDL-C (P = 0.0027) and PAG LDL fraction (P < 0.0001) and correlated positively with TGs, non-HDL-C, TG/LDL-C ratio, TG/HDL-C ratio, and non-HDL-C/HDL-C ratio among all study patients. Similar results were obtained for patients analyzed according to statin treatment. The AUCs (95% confidence interval) were 0.945 (0.884-1.000) for TG/LDL-C ratio and 0.614 (0.463-0.765) for non-HDL-C in patients without statins (P = 0.0002). The AUCs were 0.697 (0.507-0.887) for TG/LDL-C and 0.682 (0.500-0.863) for non-HDL-C in patients treated with statins. The optimal cut-off point for TG/LDL-C ratio for increased LDL-MI was 1.1 (molar ratio) regardless of statin treatment. The sensitivity and specificity of the TG/LDL-C ratio (90.0 and 93.9%, respectively) were higher than those of non-HDL-C (56.7 and 78.8%, respectively) in patients without statins. CONCLUSIONS: The TG/LDL-C ratio is a reliable surrogate lipid marker of sd-LDL and superior to non-HDL-C in type 2 diabetes patients not treated with statins.

The Association between Glomerular Diameter and Secondary Focal Segmental Glomerulosclerosis in Chronic Kidney Disease.

INTRODUCTION: When nephron loss occurs, the glomerular filtration rate (GFR) is suggested to be maintained by glomerular hypertrophy, but excessive hypertrophy can rather lead to the formation of focal segmental glomerulosclerosis (FSGS), thereby causing progressive kidney damage. However, it is not clear how much glomerular hypertrophy leads to the formation of FSGS. We examined the association between glomerular diameter and FSGS lesions in chronic kidney disease (CKD) patients. METHODS: We recruited 77 patients who underwent renal biopsy during 2016-2017; however, those identified with primary FSGS and glomerulonephritis with active glomerular lesion were excluded. We evaluated the maximal glomerular diameter (Max GD), an indicator of glomerular size, in each renal biopsy specimen and examined its association with FSGS lesion. RESULTS: The median age, blood pressure, and estimated GFR of the patients were 53 years, 122/70 mm Hg, and 65 mL/min/1.73 m2, respectively. The optimal cutoff threshold of Max GD for predicting the presence of FSGS lesions, assessed by receiver operating characteristic curve analysis, was determined to be at 224 µm (area under the curve, 0.81; sensitivity, 81%; specificity, 72%). Multivariate logistic regression analyses demonstrated that Max GD ≥224 µm was significantly associated with the presence of FSGS lesions, independent of other confounding factors (odds ratio, 11.70; 95% confidence interval, 1.93-70.84). DISCUSSION/CONCLUSION: Glomerular hypertrophy (Max GD ≥224 µm) has been associated with FSGS lesions in CKD patients and may reflect the limits of the compensatory process.

Clinical features of inherited neuropathy with BSCL2 mutations in Japan.

Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene have been reported with different clinical phenotypes including Silver syndrome (SS)/spastic paraplegia 17 (SPG17), distal hereditary motor neuropathy type V (dHMN-V), and Charcot-Marie-Tooth (CMT) disease type 2. We screened 407 Japanese patients who were clinically suspected of having CMT by exome sequencing and searched mutations in BSCL2. As a result, we identified five patients with heterozygous mutations in BSCL2. We confirmed three cases of known mutations (p.N88S and p.S90L) and two cases of novel mutations (p.N88T and p.S141A). The clinical features of the cases with known mutations in Japan were similar to those previously reported in other countries. In particular, there were many cases with sensory disturbance. The case with p.N88T mutation showed severe phenotype such as early onset age and prominent vocal cord paresis. The case with p.S141A mutation showed characteristics of demyelinating neuropathy such as CMT disease type 1 by electrophysiological examination. In this article, we report the clinical features and spread of cases with BSCL2 mutation in a Japanese cohort.

Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy.

AIMS: To compare the occurrence of cerebral, cardiovascular, and renal events in patients with hyperuricaemia treated with febuxostat and those treated with conventional therapy with lifestyle modification. METHODS AND RESULTS: This multicentre, prospective, randomized open-label, blinded endpoint study was done in 141 hospitals in Japan. A total of 1070 patients were included in the intention-to-treat population. Elderly patients with hyperuricaemia (serum uric acid >7.0 to ≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease, defined by the presence of hypertension, Type 2 diabetes, renal disease, or history of cerebral or cardiovascular disease, were randomized to febuxostat and non-febuxostat groups and were observed for 36 months. Cerebral, cardiovascular, and renal events and all deaths were defined as the primary composite event. The serum uric acid level at endpoint (withdrawal or completion of the study) in the febuxostat (n = 537) and non-febuxostat groups (n = 533) was 4.50 ± 1.52 and 6.76 ± 1.45 mg/dL, respectively (P < 0.001). The primary composite event rate was significantly lower in the febuxostat group than in non-febuxostat treatment [hazard ratio (HR) 0.750, 95% confidence interval (CI) 0.592-0.950; P = 0.017] and the most frequent event was renal impairment (febuxostat group: 16.2%, non-febuxostat group: 20.5%; HR 0.745, 95% CI 0.562-0.987; P = 0.041). CONCLUSION: Febuxostat lowers uric acid and delays the progression of renal dysfunction. REGISTRATION: ClinicalTrials.gov (NCT01984749).

Target of Triglycerides as Residual Risk for Cardiovascular Events in Patients With Coronary Artery Disease　- Post Hoc Analysis of the FMD-J Study A.

BACKGROUND: Circulating triglyceride (TG) levels are a current focus as a residual risk for cardiovascular (CV) events. We evaluated the relationship between circulating TG levels and future CV events in patients with coronary artery disease (CAD) who were treated with conventional therapy. Methods and Results: We analyzed data for 652 patients who were enrolled in the FMD-J Study A. We investigated the associations between serum TG levels and first major CV events (death from CV cause, nonfatal acute coronary syndrome (ACS), nonfatal stroke, and CAD) for a 3-year follow-up period. Patients were divided into 4 groups based on serum TG level: low-normal (<100 mg/dL), high-normal (100-149 mg/dL), borderline hypertriglyceridemia (150-199 mg/dL), and moderate hypertriglyceridemia (≥200 mg/dL). During a median follow-up period of 46.6 months, 14 patients died (9 from CV causes), 16 had nonfatal ACS, 6 had nonfatal stroke, and 54 had CAD. The Kaplan-Meier curves for first major CV event among the 4 groups were significantly different (P=0.04). After adjustment for various confounders, serum TG level ≥100 mg/dL were significantly associated with an increased risk of first major CV events compared with serum TG level <100 mg/dL. CONCLUSIONS: Serum TG level may be a surrogate marker for predicting CV events in patients with CAD.

Responsiveness of α2-adrenoceptor/I1-imidazoline receptor in the rostral ventrolateral medulla to cardiovascular regulation is enhanced in conscious spontaneously hypertensive rat.

Stimulation of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla decreases the blood pressure via sympathoinhibition. However, alteration of receptor responses in genetically hypertensive rats remains unclear. We examined cardiovascular responses of α2-adrenoceptor/I1-imidazoline receptor agonist and antagonists microinjected into the rostral ventrolateral medulla of conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Injection of 2-nmol clonidine-an α2-adrenoceptor/I1-imidazoline receptor agonist-unilaterally into the rostral ventrolateral medulla decreased the blood pressure, heart rate, and renal sympathetic nerve activity; the responses were significantly enhanced in spontaneously hypertensive rats than in Wistar Kyoto rats. Co-injection of 2-nmol 2-methoxyidazoxan (a selective α2-adrenoceptor antagonist) or 2-nmol efaroxan (an I1-receptor antagonist) with 2 nmol of clonidine attenuated the hypotensive and bradycardic effects of clonidine-only injection. Injection of 2-methoxyidazoxan alone increased the blood pressure and heart rate in spontaneously hypertensive rats, but not in Wistar Kyoto rats. These results suggest enhanced responsiveness of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats.

Add-On Effect of Angiotensin Receptor Blockade (Candesartan) on Clinical Remission in Active IgA Nephropathy Patients Treated with Steroid Pulse Therapy and Tonsillectomy: a Randomized, Parallel-Group Comparison Trial.

BACKGROUND/AIMS: Angiotensin receptor blockers (ARBs) may be beneficial for clinical remission during conventional therapy with tonsillectomy and steroid pulse (TSP) for active IgA nephropathy. METHODS: Seventy-seven patients with active IgA nephropathy were randomly assigned to the control arm with conventional regimen (TSP followed by oral prednisolone) (n = 37) or the ARB arm with conventional regimen plus ARB candesartan for the first 6 months (n = 40). Patients not achieving proteinuria remission at 12 months in either arm were administered candesartan, which was titrated until the 24-month follow-up. The primary endpoints were remission of proteinuria (< 0.3 g/gCr) and hematuria at 12 months. RESULTS: Baseline proteinuria (g/g Cr) were comparable between the control and ARB arm (1.02 vs. 0.97, P = 0.97). Similarly, cumulative remission rates at 6, 12, and 24 months were comparable between the control and ARB arms (37.8% vs. 35% [P = 0.80], 48.7% vs. 38.5% [P = 0.37], 71.4% vs. 51.3% [P = 0.08]). Proteinuria, which was slightly worse in the control arm than in the ARB arm at 6 months, was comparable afterwards (0.20 vs. 0.23 g/g Cr at 12 months; 0.12 vs. 0.13 g/g Cr at 24 months). Significant reductions observed in urinary angiotensinogen were almost comparable between the two treatment arms at both 6 and 12 months. CONCLUSION: Early candesartan treatment combined with TSP may not benefit clinical remission regardless of the blood pressure. ARB titration later during the treatment might provide benefit for patients with active IgA nephropathy.

Hyponatremia and mortality among very elderly residents in a geriatric health service facility.

INTRODUCTION: Hyponatremia is common among elderly patients. This study aimed to examine the prognostic value of hyponatremia among elderly residents in a geriatric facility. METHODS: We retrospectively examined the association between serum sodium levels and mortality among 118 residents (82% female, mean age 85.5 years) in a single geriatric health service facility. We defined hyponatremia as Na < 135 mEq/L. On the basis of single measurements of serum sodium at periodic examinations, the patients were divided into hyponatremia and non-hyponatremia groups. Multivariable Cox proportional hazards models were used to evaluate the effect of hyponatremia on mortality from May 2005 to April 2007. RESULTS: Thirty-three patients (28%) had hyponatremia. Over a 1-year follow-up period, the cumulative survival rate was significantly lower in patients with hyponatremia than in those without hyponatremia. In a multivariate analysis, including traditional risk factors for death, hyponatremia was associated with an increased mortality risk (adjusted hazard ratio 2.73; 95% confidence interval 1.01-5.16; p = 0.047). CONCLUSIONS: Hyponatremia is common and is a predictor of mortality in the near future among very elderly residents of a geriatric facility.

Intratracheal Administration of Autologous Bone Marrow-Derived Cells Ameliorates Monocrotaline-Induced Pulmonary Vessel Remodeling and Lung Inflammation in Rats.

PURPOSE: Inflammation is a feature of lung injury and plays a critical role in pulmonary vascular remodeling. Bone marrow-derived cells (BMCs) have anti-inflammatory properties and favor macrophage differentiation into an alternatively activated regulatory M2 profile. We investigated the effect of autologous BMCs on monocrotaline-induced pulmonary vessel remodeling and lung inflammation in rats, by direct administration into lungs via the airway. METHODS: BMCs were isolated and plastic-adherent cells were cultured for 3 weeks. 1 week following monocrotaline (60 mg/kg) treatment, fluorescently labeled autologous BMCs (1 × 106 cells) or vehicle were administered intratracheally to male Sprague-Dawley rats. 4 weeks following monocrotaline treatment, lung pathology was evaluated. RESULTS: Monocrotaline increased pulmonary vessel wall thickness, perivascular infiltration, alveolar septal thickening, and inflammatory cell infiltration including T lymphocytes and monocytes/macrophages in alveolar areas, and also increased mRNA expression of inflammatory-related cytokines including IL-10 in the lung. Intratracheal administration of autologous BMCs prevented pulmonary vessel wall thickening and perivascular infiltration, and increased CD163-positive M2-like macrophages in perivascular areas. BMC administration inhibited the thickening of alveolar septa and reduced monocrotaline-induced inflammatory cell infiltration in lung parenchyma compared with monocrotaline-vehicle-treated-rats. Furthermore, BMCs administration increased expression of CD163-positive cells in perivascular areas and maintained the increased mRNA expression of IL-10. CONCLUSIONS: Intratracheal administration of autologous BMCs prevented monocrotaline-induced pulmonary vessel remodeling and lung inflammation, at least in part, through induction of alternatively activated macrophages and regulation of the local lung environment toward resolving inflammation.

Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice.

AIMS/HYPOTHESIS: Nitric oxide (NO) is synthesised not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice. METHODS: To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low-nitrite/nitrate chow, in which the contents of L-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. RESULTS: Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota. CONCLUSIONS/INTERPRETATION: These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.

Association Between Waist-to-Height Ratio and Endothelial Dysfunction in Patients With Morbidity　- A Report From the FMD-J Study.

BACKGROUND: Waist circumference (WC), waist-to-height ratio (WHtR) and body mass index (BMI) are known as easy anthropometric markers of abnormal obesity and screening tools for predicting cardiovascular outcomes, but which indices are best is unclear. We therefore investigated the superiority and association between each index and low flow-mediated dilatation (FMD) as a surrogate marker for cardiovascular outcomes in patients with morbidity in a large Japanese prospective cohort.Methods and Results:A total of 1,645 Japanese patients who had coronary artery disease and hypertension or diabetes mellitus were enrolled, and 1,087 of them were analyzed. The high-WHtR group (≥0.5) showed greater morbidity and increased inflammation in association with atherosclerosis compared with the low-WHtR group. High WHtR and advanced age were identified as predictors of low FMD (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.02-1.88, P=0.037 and OR 1.55, 95% CI 1.19-2.01, P=0.001, respectively). However, WC was not associated with that risk in either sex (male: OR 1.37, 95% CI 0.97-1.93, P=0.076; female: OR 1.08, 95% CI 0.68-1.73, P=0.74), and no association was evident between high BMI and low FMD (OR 0.92, 95% CI 0.71-1.19, P=0.54). CONCLUSIONS: WHtR offers a superior predictor of decreased FMD than other anthropometric indices, and progression of arteriosclerosis might be detected more sensitively. Further study is needed to investigate the relationship between cardiovascular mortality and WHtR.

A questionnaire survey to assess lower urinary tract symptoms in patients with chronic stroke.

OBJECTIVES: In this study, we evaluated the prevalence of lower urinary tract symptoms and the associated clinical features in patients with chronic stroke. METHODS: Patients with stroke who had been regularly followed up at general medical hospitals in Okinawa, Japan were enrolled in the study. The patients were asked to complete a self-reported questionnaire regarding their physical activity, medical history, and the core lower urinary tract symptom score (CLSS) questionnaire, with anonymity. The association between each urinary disturbance category and the clinical characteristics of the patients such as age, gender, physical activity, and underlying disease was evaluated. RESULTS: In total, 51 patients (33 men and 18 women; mean age, 71.7 years) were eligible for analysis. The average time after the first stroke onset was 8.5 years. Nocturia and urgency incontinence had the greatest impact on the quality of life. Overactive bladder symptoms such as nocturia, urgency, urgency incontinence, and stress urinary incontinence were associated with age, female sex, and having a co-existing medical condition (such as ischemic heart disease, hypertension, and depression). Voiding symptoms such as slow stream and straining were associated with age and physical activity after stroke. CONCLUSIONS: Storage symptom is associated with not only neurological deficits but also sex and the presence of general diseases, whereas voiding symptom is influenced by physical activity in patients with chronic stroke. Therefore, lower urinary tract symptoms should be carefully monitored and physical rehabilitation should also be considered in patients with stroke.

Change in Ankle-Brachial Index Over Time in a Screened Japanese Cohort　- The Okinawa Peripheral Arterial Disease Study.

BACKGROUND: The temporal change in ankle-brachial index (ABI) in the general population, especially in those aged <40 years, remains unclear. METHODS AND RESULTS: ABIs of 23,673 individuals were measured in 1-day health checkups between 2003 and 2010. Among them, 1,117 participants aged 28-76 years (mean 53±9 years) whose ABI was measured at least twice within an interval of ≥4 years (mean: 4.9 years) were selected for this study. Baseline ABI was the lowest at age <40 years and increased with age. ABI significantly increased in participants aged <40 and 40-49 years, but not in participants aged 50-59 and ≥60 years. ABI increased in participants with borderline-low baseline ABI (0.9