Impact of obstructive sleep apnea on blood pressure and cardiovascular risk factors in Japanese men: A cross-sectional study in work-site group.

It has been shown that obstructive sleep apnea (OSA) is related to hypertension and cardiovascular disease; however, the prevalence of OSA in general population and the impact of it on blood pressure especially in Japan has not been well determined. We have conducted a screening test for OSA from 2003 to 2011. In addition, a cross-sectional analysis was performed in 2012 to determine the association of OSA and cardiovascular risk factors in Japanese men (18-69 years of age; mean age, 44.4 ± 0.2). The study group consisted of 2208 male employees, and OSA was evaluated by using the 4% oxygen desaturation index and apnea-hypopnea index (AHI). The prevalence of mild-to-moderate (5≤AHI<30) and severe (AHI≥30) OSA in the studied subjects were 7.1%, and 6.1%, respectively. Among the 135 severe OSA subjects, 105 (77.8%) had been treated with continuous positive airway pressure. Both systolic and diastolic blood pressures (DBP) were significantly increased in the subjects with severe OSA compared with those without OSA. These associations in DBP remained observed after adjustment for age, body mass index (BMI), estimated glomerular filtration rate, HbA1c, current alcohol intake, current smoking habits, and OSA treatment. DBP in severe OSA subjects were significantly increased in 1807 subjects who were not treated for hypertension or OSA. However, the levels of blood pressures were not decreased by OSA treatment. These results suggest that the prevalence of OSA is relatively high in middle-aged Japanese men and that blood pressures were elevated in the subjects with severe OSA.

Role of renin-angiotensin aldosterone system on short-term blood pressure variability in hypertensive patients.

The relationship between the renin-angiotensin aldosterone system and short-term blood pressure variability has not been well elucidated. Here, we investigated whether blood pressure variability determined by ambulatory blood pressure monitoring differed among patients with primary aldosteronism (PA), renovascular hypertension (RVHT), and essential hypertension (EHT). We examined 25 patients with PA, 28 patients with RVHT, and 18 patients with EHT. Ambulatory blood pressure monitoring was conducted in all patients. Short-term blood pressure variability was evaluated by calculating the standard deviation (SD), coefficient of variation (CV), and average real variability (ARV) of 24-h, daytime, and nighttime blood pressure values. Day-night differences in blood pressure were also determined. The mean 24-h systolic blood pressure (SBP) and the mean diastolic blood pressure (DBP) in the PA and RVHT groups were found to be comparable to those in the EHT group. The SD, the CV, nor the ARV of the 24-h, daytime, and nighttime blood pressures showed any significant differences among the three groups. The day-night differences in blood pressure were comparable among the three groups. The short-term blood pressure variabilities evaluated by ambulatory blood pressure monitoring were comparable among the patients with EHT, RVHT, and PA. The results suggest that the renin-angiotensin aldosterone system may contribute little to short-term blood pressure variability in individuals with hypertension.

Disruption of xanthine oxidoreductase gene attenuates renal ischemia reperfusion injury in mice.

AIMS: We examined the roles of xanthine oxidoreductase (XOR) in renal ischemia reperfusion (IR) injury. MAIN METHODS: XOR+/+ and XOR+/- mice were subjected to 24-h reperfusion after a 45-min bilateral renal artery occlusion or sham operation. We evaluated the renal damage based on the concentrations of blood urea nitrogen (BUN) and serum creatinine (Cr), and histological changes were detected by PAS staining. Xanthine dehydrogenase, oxidase (XO) and XOR activities, amounts of blood and urine 8-OHdG, and expressions of TNF-α and MCP-1 mRNA were examined. F4/80 and nitrotyrosine-positive cells were assessed by immunohistochemical staining. KEY FINDINGS: The BUN and Cr concentrations in the XOR+/+IR mice were increased significantly compared to those in XOR+/-IR and allopurinol-treated XOR+/+IR mice. XO and XOR activity, which were increased in IR mice, were reduced in the allopurinol-treated XOR+/+IR and XOR+/-IR mice compared to the XOR+/+IR mice. The concentrations of blood and urine 8-OHdG, and the expressions of MCP-1 and TNF-α mRNA were increased significantly in the XOR+/+IR mice compared to those in the XOR+/-IR mice. The histological analysis revealed that the XOR+/-IR and allopurinol-treated XOR+/+IR mice showed less tubular injury than the XOR+/+IR mice in the cortex regions, with the reduction of inflammation and oxidative stress assessed by the immunohistological staining for F4/80 and nitrotyrosine. SIGNIFICANCE: Both the disruption of XOR gene in XOR+/- mice and the reduction of XOR activity in allopurinol-treated XOR+/+IR mice attenuated renal tissue injury in this IR model. Reduced XOR activity during renal IR could be a beneficial treatment target.

Downregulation of Endothelial Transient Receptor Potential Vanilloid Type 4 Channel and Small-Conductance of Ca2+-Activated K+ Channels Underpins Impaired Endothelium-Dependent Hyperpolarization in Hypertension.

Endothelium-dependent hyperpolarization (EDH)-mediated responses are impaired in hypertension, but the underlying mechanisms have not yet been determined. The activation of small- and intermediate-conductance of Ca2+-activated K+ channels (SKCa and IKCa) underpins EDH-mediated responses. It was recently reported that Ca2+ influx through endothelial transient receptor potential vanilloid type 4 channel (TRPV4) is a prerequisite for the activation of SKCa/IKCa in endothelial cells in specific beds. Here, we attempted to determine whether the impairment of EDH in hypertension is attributable to the dysfunction of TRPV4 and S/IKCa, using isolated superior mesenteric arteries of 20-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto (WKY) rats. In the WKY arteries, EDH-mediated responses were reduced by a combination of SKCa/IKCa blockers (apamin plus TRAM-34; 1-[(2-chlorophenyl)diphenylmethl]-1H-pyrazole) and by the blockade of TRPV4 with the selective antagonist RN-1734 or HC-067047. In the SHRSP arteries, EDH-mediated hyperpolarization and relaxation were significantly impaired when compared with WKY. GSK1016790A, a selective TRPV4 activator, evoked robust hyperpolarization and relaxation in WKY arteries. In contrast, in SHRSP arteries, the GSK1016790A-evoked hyperpolarization was small and relaxation was absent. Hyperpolarization and relaxation to cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine, a selective SKCa activator, were marginally decreased in SHRSP arteries compared with WKY arteries. The expression of endothelial TRPV4 and SKCa protein was significantly decreased in the SHRSP mesenteric arteries compared with those of WKY, whereas function and expression of IKCa were preserved in SHRSP arteries. These findings suggest that EDH-mediated responses are impaired in superior mesenteric arteries of SHRSP because of a reduction in both TRPV4 and SKCa input to EDH.

Trends in blood pressure control and medication use during 20 years in a hypertension clinic in Japan.

Guidelines for the management of hypertension have recommended strict control of blood pressure to help prevent cardiovascular disease. The aim of the present study was to evaluate the current status of blood pressure control and trends over the past two decades. Four hundred patients treated for hypertension at Kyushu University Hospital were included in the present study. Blood pressure levels and prescribed antihypertensive drugs were examined in 2011. The average blood pressure was 129/74 mmHg, and the number of prescribed antihypertensive drugs was 2.2. Angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, alpha-blockers, and beta-blockers were prescribed in 66%, 5%, 78%, 21%, 12%, and 27% of the cases, respectively. Systolic blood pressure was significantly higher, and diastolic blood pressure was significantly lower in patients aged 80 years or older compared with the younger patients (<80 and ≥80 years, 128/75 mmHg and 133/68 mmHg, respectively). The number of prescribed antihypertensive drugs was similar between the two groups. Sixty-five patients were continuously treated for 20 years. The average blood pressure of these patients significantly decreased from 142/87 mmHg in 1991 to 128/71 mmHg in 2011, accompanied with an increase in the number of antihypertensive drugs from 1.6 in 1991 to 2.7 in 2011. These findings suggest that the revised guidelines for the management of hypertension may have contributed to increased awareness and better management of blood pressure levels.

Mice heterozygous for the xanthine oxidoreductase gene facilitate lipid accumulation in adipocytes.

OBJECTIVE: Xanthine oxidoreductase (XOR) catalyzes the production of uric acid with concomitant generation of reactive oxygen species. XOR has been shown to regulate adipogenesis through the control of peroxisome proliferator-activated receptor γ, but its role in adipose tissue remains unclear. The aim of this study was to examine the role of XOR in adipose tissue using XOR genetically modified mice. APPROACH AND RESULTS: Experiments were performed using 2-, 4-, and 18-month-old XOR heterozygous mice (XOR(+/-)) and their wild-type littermates to evaluate the physiological role of XOR as the mice aged. Stromal vascular fraction cells were prepared from epididymal white adipose tissue in 2-month-old XOR mice to assess adipogenesis. At 18 months, XOR(+/)- mice had significantly higher body weight, higher systolic blood pressure, and higher incidence of insulin resistance compared with wild-type mice. At 4 months, blood glucose and the expressions of CCAAT enhancer-binding protein ß, peroxisome proliferator-activated receptor γ, monocyte chemoattractant protein-1, and tumor necrosis factor α mRNA in epididymal white adipose tissue were significantly higher in XOR(+/-) than in wild-type mice. Furthermore, histological analysis of epididymal white adipose tissue in XOR(+/-) mice revealed that adipocyte size and the F4/80-positive macrophage count were increased. Experiments with a high-fat diet exhibited that body weight gain was also significantly higher in XOR(+/-) than in wild-type mice. In stromal vascular fraction cells derived from XOR(+/-) mice, the levels of peroxisome proliferator-activated receptor γ, fatty acid-binding protein 4, and CCAAT enhancer-binding protein α mRNA were upregulated, and oxidative stress levels were elevated during differentiation into adipocytes. CONCLUSIONS: These results suggest that the reduction in XOR gene expression in mice augments lipid accumulation in adipocytes, accompanied by an increase in oxidative stress, and induces obesity with insulin resistance in older age.

Low diastolic blood pressure was one of the independent predictors of ischemia-like findings of electrocardiogram in patients who underwent coronary angiography.

BACKGROUND: The underlying cause of a high cardiovascular event rate in the population with low diastolic blood pressure (DBP) has not been fully elucidated. METHODS AND RESULTS: The relationship between DBP and ischemia-like findings on electrocardiography (ECG) was investigated in 187 patients who underwent coronary angiography. Patients with conditions affecting ECG (e.g. patients taking digitalis or those with old myocardial infarction, complete right bundle branch block, or hypokalemia) were excluded from the analyses. Ischemia-like ECG was defined as having one or more of the following: borderline Q wave [Minnesota code (MC) I 3], ST depression (MC IV 1-3), negative T wave (MC V 1-3), and complete left bundle branch block (MC VII 1). Based on this definition, 70 of 187 patients (37%) had ischemia-like ECG. Compared with the group without it, the group with ischemia-like ECG included more females (p<0.01), and had lower values of body mass index (p = 0.01), DBP (p<0.01), estimated glomerular filtration rate (p<0.01), left ventricular ejection fraction (LVEF; p<0.01), and higher values of age (p<0.01) and left ventricular mass index (LVMI; p<0.01). The severity of coronary artery disease did not differ between the groups. Receiver operating characteristics curve analysis revealed that 74.5 mmHg was the optimal cut-off point of DBP to predict ischemia-like ECG (area under curve, 0.63; 95% confidence interval, 0.55-0.71, p = 0.003). There were no significant relationships between systolic blood pressure and ischemia-like ECG. A multivariate analysis showed that female sex, low DBP (≤ 74.5 mmHg), LVMI, and LVEF were the significant factors for the ischemia-like ECG. The odds ratio of low DBP was 2.53 (95% confidence interval, 1.19-5.40; p = 0.02). CONCLUSIONS: Low DBP was one of the significant predictors of the ischemia-like ECG in the present study. Myocardial ischemia may be a part of the cause of high cardiovascular morbidity in the population with low DBP.

Effects of intravenous nicorandil on the mid-term prognosis of patients with acute heart failure syndrome.

BACKGROUND: Acute heart failure syndrome (AHFS) remains a major clinical challenge because of its poor prognosis. Nicorandil, a hybrid compound of a potassium-channel opener and nitric oxide donor, has been reported to improve the prognosis of ischemic heart disease. We sought to evaluate the effect of intravenous nicorandil on the mid-term prognosis of AHFS. METHODS AND RESULTS: A total of 402 consecutive patients who were hospitalized for AHFS were divided into 2 groups according to the use of intravenous nicorandil: 78 patients in the Nicorandil group and 324 patients in the Control group. During the 180-day follow-up, death or rehospitalization for heart failure occurred in 7 patients in the Nicorandil group (9.0%) and in 75 patients (23.2%) in the Control group. Event-free survival rates were significantly higher in the Nicorandil group than in the Control group (P=0.006). Multivariate Cox hazard analysis revealed that age (hazard ratio (HR)=1.066, P<0.0001), systolic blood pressure (HR=0.983, P=0.0023), New York Heart Association class III/IV (HR=6.550, P<0.0001), log creatinine (HR=3.866, P=0.0106), and use of intravenous nicorandil (HR=0.179, P<0.0001) were significant predictive factors for the occurrence of death or rehospitalization for heart failure. CONCLUSIONS: Intravenous nicorandil treatment from the urgent phase of AHFS may improve the prognosis.