Day-to-Day Blood Pressure Variability and Risk of Dementia in a General Japanese Elderly Population: The Hisayama Study.

BACKGROUND: Several observational studies have reported that higher visit-to-visit blood pressure variability is a risk factor for cognitive impairment and dementia. However, no studies have investigated the association of day-to-day blood pressure variability assessed by home blood pressure measurement with the development of dementia. METHODS: A total of 1674 community-dwelling Japanese elderly without dementia, ≥60 years of age, were followed up for 5 years (2007-2012). Home blood pressure was measured 3 times every morning for a median of 28 days. Day-to-day systolic (SBP) and diastolic blood pressure variabilities, calculated as coefficients of variation (CoV) of home SBP and diastolic blood pressure, were categorized into quartiles. The hazard ratios and their 95% confidence intervals of the CoV levels of home blood pressure on the development of all-cause dementia, vascular dementia (VaD), and Alzheimer disease (AD) were computed with a Cox proportional hazards model. RESULTS: During the follow-up, 194 subjects developed all-cause dementia; of these, 47 had VaD and 134 had AD. The age- and sex-adjusted incidences of all-cause dementia, VaD, and AD increased significantly with increasing CoV levels of home SBP (all P for trend <0.05). These associations remained unchanged after adjustment for potential confounding factors, including home SBP. Compared with subjects in the first quartile of CoV levels of home SBP, the risks of the development of all-cause dementia, VaD, and AD were significantly higher in those in the fourth quartile (hazard ratio=2.27, 95% confidence interval=1.45-3.55, P<0.001 for all-cause dementia; hazard ratio=2.79, 95% confidence interval=1.04-7.51, P=0.03 for VaD; hazard ratio=2.22, 95% confidence interval=1.31-3.75, P<0.001 for AD). Similar associations were observed for CoV levels of home diastolic blood pressure. Meanwhile, home SBP levels were significantly associated with the risk of VaD but not with the risks of all-cause dementia and AD. There was no interaction between home SBP levels and CoV levels of home SBP on the risk of each subtype of dementia. CONCLUSIONS: Our findings suggest that increased day-to-day blood pressure variability is, independently of average home blood pressure, a significant risk factor for the development of all-cause dementia, VaD, and AD in the general elderly Japanese population.

Metyrapone-responsive ectopic ACTH-secreting pheochromocytoma with a vicious cycle via a glucocorticoid-driven positive-feedback mechanism.

In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hypercatecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid-driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year-old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor. 18F-FDG positron emission tomography showed uptake in the area of the adrenal tumor, while 123I-metaiodobenzylguanidine scintigraphy showed no accumulation. His plasma ACTH level paradoxically became elevated after a dexamethasone suppression test. After metyrapone administration, not only serum cortisol but also plasma ACTH levels were exponentially decreased almost in parallel, suggesting a glucocorticoid-driven positive-feedback regulation in this rapidly exacerbated ectopic ACTH-producing pheochromocytoma. Interestingly enough, plasma catecholamine levels were also decreased by metyrapone, although they remained extremely high. He became severely dehydrated due to hypoadrenalism requiring hydrocortisone supplementation. His clinical signs and symptoms were improved, and right adrenalectomy was performed uneventfully, resulting in complete remission of pheochromocytoma and Cushing's syndrome. A glucocorticoid-driven positive-feedback regulation in this ectopic ACTH-secreting pheochromocytoma created a vicious cycle with rapid exacerbation of both hypercortisolemia and hypercatecholaminemia with extremely elevated plasma ACTH level. Metyrapone was clinically effective to stop this vicious cycle; nonetheless, great care must be taken to avoid hypoadrenalism especially when hypercatecholaminemia remained.

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.

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.

Endothelium-Dependent Hyperpolarization (EDH) in Hypertension: The Role of Endothelial Ion Channels.

Upon stimulation with agonists and shear stress, the vascular endothelium of different vessels selectively releases several vasodilator factors such as nitric oxide and prostacyclin. In addition, vascular endothelial cells of many vessels regulate the contractility of the vascular smooth muscle cells through the generation of endothelium-dependent hyperpolarization (EDH). There is a general consensus that the opening of small- and intermediate-conductance Ca2+-activated K⁺ channels (SKCa and IKCa) is the initial mechanistic step for the generation of EDH. In animal models and humans, EDH and EDH-mediated relaxations are impaired during hypertension, and anti-hypertensive treatments restore such impairments. However, the underlying mechanisms of reduced EDH and its improvement by lowering blood pressure are poorly understood. Emerging evidence suggests that alterations of endothelial ion channels such as SKCa channels, inward rectifier K⁺ channels, Ca2+-activated Cl- channels, and transient receptor potential vanilloid type 4 channels contribute to the impaired EDH during hypertension. In this review, we attempt to summarize the accumulating evidence regarding the pathophysiological role of endothelial ion channels, focusing on their relationship with EDH during hypertension.

Morning and Evening Blood Pressures Are Associated With Intima-Media Thickness in a General Population　- The Hisayama Study.

BACKGROUND: The association of morning and evening home blood pressures (HBPs) with carotid atherosclerosis has been uncertain in general populations, so we aimed to investigate it in a general Japanese population.Methods and Results:We performed a cross-sectional survey of 2,856 community-dwelling individuals aged ≥40 years to examine the association of morning and evening HBPs with carotid mean intima-media thickness (IMT). The age- and sex-adjusted geometric averages of carotid mean IMT increased significantly with increasing morning HBP (optimal: 0.67 mm; normal: 0.69 mm; high normal: 0.72 mm; grade 1 hypertension: 0.74 mm; and grade 2+3 hypertension: 0.76 mm) and with increasing evening HBP (0.68 mm, 0.71 mm, 0.73 mm, 0.76 mm, and 0.78 mm, respectively) (both P for trend <0.001). These associations remained significant even after adjusting for potential confounding factors. Likewise, both isolated morning hypertension (morning HBP ≥135/85 mmHg and evening HBP <135/85 mmHg) and isolated evening hypertension (evening HBP ≥135/85 mmHg and morning HBP <135/85 mmHg) as well as sustained hypertension (both morning and evening HBP ≥135/85 mmHg) were significantly associated with thicker mean IMT. CONCLUSIONS: Our findings suggested that both morning and evening HBPs were significantly associated with carotid atherosclerosis in this general Japanese population.

Salt Intake, Home Blood Pressure, and Perinatal Outcome in Pregnant Women.

BACKGROUND: The relationship between salt (sodium chloride) intake and pregnancy-induced hypertension (PIH) remains unclear. The aim of this study was therefore to investigate the current status of salt intake during pregnancy and identify effective predictors for PIH. METHODS AND RESULTS: Participants were 184 pregnant women who collected 24-h home urine as well as early morning urine samples. We investigated urinary salt excretion, home blood pressure (HBP) measurements for 7 consecutive days before the 20th and after the 30th gestational week, and the development of PIH. Urinary salt excretion according to early morning urine before the 20th gestational week was 8.6±1.7 g/day, and was significantly correlated with that measured from 24-h collected urine. Early morning urine estimated urinary salt excretion was slightly but significantly increased during pregnancy. HBP was 102±10/63±8 mmHg before the 20th gestational week and 104±12/64±10 mmHg after the 30th gestational week. On multiple regression analysis, serum uric acid and body mass index, but not urinary salt excretion, contributed to HBP both before the 20th and after the 30th gestational week. Fourteen participants (7.6%) developed PIH. On multivariate analysis, higher HBP and older age, but not urinary salt excretion, were significantly associated with PIH. CONCLUSIONS: Higher HBP and older age, but not urinary salt excretion, are predictors of PIH. (Circ J 2016; 80: 2165-2172).

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.

Effect of losartan on serum uric acid in hypertension treated with a diuretic: the COMFORT study.

It has been shown that losartan, an angiotensin II receptor blocker (ARB), reduces serum uric acid levels. However, the effects of losartan on serum uric acid levels in the patients treated with a thiazide diuretic have not been fully elucidated. We have investigated the effects of losartan compared with other ARBs on blood variables and blood pressure control in hypertensive patients treated with a thiazide diuretic using data from the COMFORT study. The present analysis included a total of 118 hypertensive subjects on combination treatment with ARBs except for losartan and a diuretic who were randomly assigned to a daily regimen of a combination pill (losartan 50 mg/hydrochlorothiazide 12.5 mg) or to continuation of two pills, an ARB except for losartan and a diuretic. Blood pressures were evaluated at 1, 3, and 6 months after randomization and changes in blood variables including serum uric acid were evaluated during 6 months treatment period. Mean follow-up blood pressure levels were not different between the combination pill (losartan treatment) group and the control (ARBs except for losartan) group. On the other hand, serum uric acid significantly decreased in the combination pill group compared with the control group (-0.44 versus + 0.10 mg/dl; p = 0.01), although hematocrit, serum creatinine, sodium and potassium were not different between the groups. These results suggest that the treatment regimen switched from a combination therapy of ARBs except for losartan and a diuretic to a combination pill (losartan/ hydrochlorothiazide) decreases serum uric acid without affecting blood pressure control.

Clinical characteristics of resistant hypertension evaluated by ambulatory blood pressure monitoring.

Strict control of blood pressure is important to prevent cardiovascular disease, although it is sometimes difficult to decrease blood pressure to target levels. The aim of this study was to investigate the clinical characteristics of resistant hypertension evaluated by ambulatory blood pressure monitoring. One hundred in-hospital patients, whose 24-hour average blood pressure was higher than 130/80 mmHg even after treatment with more than three antihypertensive drugs, were included in the present analysis. Circadian variation of blood pressure was evaluated by nocturnal fall in systolic blood pressure. Average blood pressures of all patients were high in both daytime and nighttime, 150.0/82.9 and 143.8/78.2 mmHg, respectively. Twenty patients had been treated with hemodialysis or peritoneal dialysis. In 63 patients out of the other 80 patients (79%), estimated glomerular filtration rate (eGFR) was also decreased (<60 mL/min/1.73 m²). The patients classified into dipper, non-dipper, riser and extreme-dipper were 20%, 43%, 34% and 3%, respectively. In addition, in 17 patients whose eGFR was preserved, 12 patients showed a non-dipper or riser pattern, suggesting that it was difficult to account for this altered circadian blood pressure variation only by renal dysfunction. These results show that a large number of the patients with resistant hypertension suffered from renal dysfunction, although it was difficult to explain altered circadian blood pressure variation based on renal dysfunction alone.

[Rare case of systemic lupus erythematosus with encapsulating peritoneal sclerosis during hemodialysis].

A 57-year old male patient was admitted to our hospital because of severe vomiting and abdominal pain with massive ascites. He had been diagnosed as mixed connective tissue disease in 1997 and lupus nephritis ISN III (A/C) + V in 2003. Treatment was started with intravenous steroid pulse therapy combined with an immunosuppressant resulting in improvement of his proteinuria and serological activity. In 2008, the disease activity flared and he was admitted to our hospital with nephrotic syndrome. Hemodialysis was unavoidable, despite treatment with intravenous steroid pulse therapy and plasma exchange. We continued to treat him with oral prednisolone and tacrolimus. However, for personal reasons, he terminated tacrolimus treatment and massive ascites remained because of insufficient hemodialysis. Since the end of 2011, he suffered repeated abdominal pain with ileus and encapsulating peritoneal sclerosis (EPS) was detected. In February 2013, he underwent synechotomy for EPS. Here, we present a rare case of EPS in a hemodialysis patient.

Effects of the superoxide dismutase mimetic tempol on impaired endothelium-dependent and endothelium-independent relaxations in type II diabetic rats.

Endothelium-derived hyperpolarizing factor (EDHF)-mediated hyperpolarization and relaxation, and endothelium-independent relaxations to the nitric oxide donor sodium nitroprusside and the adenosine 5'-triphosphate (ATP)-sensitive K(+)-channel opener levcromakalim were both impaired in mesenteric arteries of type II diabetic Goto-Kakizaki rats. The treatment with the superoxide dismutase mimetic tempol or its combination with the angiotensin II type 1 receptor blocker candesartan failed to improve EDHF-mediated responses, although both treatments partially improved endothelium-independent relaxations. These findings suggest that increased oxidative stress may in part account for the impaired endothelium-independent relaxations in diabetes, while it does not play a major role in the impaired EDHF-mediated responses.

Xanthine oxidoreductase is a regulator of adipogenesis and PPARgamma activity.

In an effort to identify novel candidate regulators of adipogenesis, gene profiling of differentiating 3T3-L1 preadipocytes was analyzed using a novel algorithm. We report here the characterization of xanthine oxidoreductase (XOR) as a novel regulator of adipogenesis. XOR lies downstream of C/EBPbeta and upstream of PPARgamma, in the cascade of factors that control adipogenesis, and it regulates PPARgamma activity. In vitro, knockdown of XOR inhibits adipogenesis and PPARgamma activity while constitutive overexpression increases activity of the PPARgamma receptor in both adipocytes and preadipocytes. In vivo, XOR -/- mice demonstrate 50% reduction in adipose mass versus wild-type littermates while obese ob/ob mice exhibit increased concentrations of XOR mRNA and urate in the adipose tissue. We propose that XOR is a novel regulator of adipogenesis and of PPARgamma activity and essential for the regulation of fat accretion. Our results identify XOR as a potential therapeutic target for metabolic abnormalities beyond hyperuricemia.

Does a combination pill of antihypertensive drugs improve medication adherence in Japanese? A randomized controlled trial.

BACKGROUND: In order to achieve target blood pressure levels to prevent cardiovascular disease, combination therapy of antihypertensive drugs is often required, although it is thought that requiring a patient to take many different pills would reduce adherence to the medication regimen. Whether antihypertensive treatment with a single pill combining antihypertensive drugs would improve medication adherence and blood pressure control was investigated. METHODS AND RESULTS: A total of 207 hypertensive subjects were randomly assigned to a combination pill group (losartan 50mg/hydrochlorothiazide 12.5mg; n=103) or a control group (an angiotensin receptor blocker and a thiazide diuretic; n=104). Medication adherence was evaluated by pill counts at 1, 3, and 6 months after randomization. The mean adherence rates over 6 months were not different between the 2 groups: 98% in the combination pill group and 98% in the control group. Moreover, the 2 groups included similar numbers of subjects with relatively poor adherence rates (<90%) in each treatment period. The mean blood pressures over the 6-month treatment period were not different between the groups: 131/75 mmHg in the combination pill group and 130/75 mmHg in the control group (P=0.84/0.96). CONCLUSIONS: There were no appreciable effects of the combination pill of antihypertensive drugs on medication adherence or blood pressure control in Japanese patients over a 6-month period.

Association of body mass index with glomerular filtration rate in Japanese: a cross-sectional study in work-site population.

It has been shown that aging and hypertension are important risk factors to promote renal damage. However, little data are available on the effect of obesity on the progression of renal damage, especially in young and middle-aged individuals. The aim of this study was to determine the association between body mass index (BMI) and renal function evaluated by estimated glomerular filtration rate (eGFR) in Japanese men. We studied the cross-sectional association of BMI with eGFR in 3872 Japanese men in a work-site population (18-64 y; mean age 42.1 ± 0.2 y). Estimated glomerular filtration rate was calculated by a novel equation for Japanese men. Estimated glomerular filtration rate was negatively correlated with age, systolic blood pressure (SBP), hemoglobin A1c (HbA1c), and BMI. We performed multiple regression analysis, controlling for factors, such as SBP, low-density lipoprotein-cholesterol, gamma-glutamyl transpeptidase, age, HbA1c, and uric acid. The association between age and eGFR was highly statistically significant. In addition, BMI was still significantly associated with eGFR independently of SBP. Moreover, mean eGFR, which was adjusted for age, SBP, HbA1c, serum uric acid, and gamma-glutamyl transpeptidase, decreased from 88.9 mL/min/1.73 m(2) in the first quartile of BMI to 87.5 mL/min/1.73 m(2) in the second, 86.9 mL/min/1.73 m(2) in the third, and 85.9 mL/min/1.73 m(2) in the fourth quartile (test for trend, P < .0001). These results show that a close relationship is present between obesity and decreased eGFR in Japanese men. Keeping appropriate body weight, in addition to appropriate blood pressure, in young and middle age may be important to prevent renal damage in older age.

Association of serum uric acid with blood pressure in Japanese men. Cross-sectional study in work-site group.

BACKGROUND: It has been reported that elevated levels of serum uric acid are related to hypertension and cardiovascular disease. Recent studies, however, have found little association between hyperuricemia and hypertension. METHODS AND RESULTS: The association of serum uric acid with blood pressure was examined in 3,960 Japanese male workers (18-64 years of age; mean age, 42.3±0.2 years). Systolic blood pressure was significantly correlated with serum uric acid. Multiple regression analysis also showed that both systolic and diastolic blood pressures were independently associated with serum uric acid. When subjects were divided into 6 groups according to blood pressure on the basis of the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009), serum uric acid was elevated in a linear fashion as blood pressure increased. A similar relationship was found even in 3,608 subjects who were not taking anti-hypertensive or uric acid-lowering agents. In contrast, no relation was found between serum uric acid and blood pressure in 352 subjects taking anti-hypertensive medicine. CONCLUSIONS: Blood pressure is closely associated with serum uric acid. Serum uric acid might be associated with the increase in blood pressure, because there is no relation between serum uric acid and blood pressure in the subjects treated with anti-hypertensive medications.

Relationship between casual serum triglyceride levels and the development of hypertension in Japanese.

OBJECTIVE: The purpose of the present study was to investigate the effects of serum triglyceride levels on the risk of new-onset hypertension in Japanese. METHODS: Five thousand nine hundred and thirty-three Japanese workers without hypertension at baseline, who participated in medical check-ups from 2006 to 2018, were followed retrospectively. The participants were divided into quartiles of casual serum triglyceride levels and were followed from the first to last visit of the study period. The outcome was development of hypertension. Risk estimates were computed using Cox's proportional hazards model. RESULTS: During the follow-up period (average: 6.7 years), 946 individuals developed hypertension. The crude incidence rates of hypertension (per 1000 person-years) increased with rising serum triglyceride levels: 10.1 for quartile 1 (<0.76 mmol/l), 19.6 for quartile 2 (0.76-1.17 mmol/l), 26.0 for quartile 3 (1.18-1.84 mmol/l), and 36.5 for quartile 4 (>1.84 mmol/l) (P < 0.0001 for trend). These associations remained significant even after adjustment for other risk factors: the multivariable-adjusted hazard ratio was 1.29 (1.01-1.66) for the second quartile, 1.27 (0.99-1.63) for the third quartile, and 1.39 (1.09-1.77) for the highest quartile compared with the lowest. There were comparable effects of serum triglyceride levels for incidence of hypertension between subgroups defined by sex, obesity, and diabetes (all P > 0.1 for interaction), whereas stronger associations were observed for participants under 40 years of age than for those aged 40 or above (P = 0.002 for interaction). CONCLUSION: Serum triglyceride levels were significantly associated with development of hypertension in a Japanese worksite population.

Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension.

Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage-driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia-induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA-induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L-norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR-knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia-exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

Xanthine oxidoreductase knockout mice with high HPRT activity were not rescued by NAD+ replenishment.

Although xanthinuria is nonfatal in human, xanthine oxidoreductase knockout (Xor-KO) mice have only a short lifespan. Hypoxanthine phosphoribosyltransferase activity (HPRT) in human and wild mice is higher than in laboratory mice. The aim of this study was to investigate the underlying mechanisms that give rise to the longer lifespan of high-HPRT/Xor-KO mice. Before Xor-KO mice die, urinary excretion of hypoxanthine increased with a corresponding decrease in excretion of xanthine. The switch of excretion from xanthine to hypoxanthine might be a cause of death for Xor-KO mice, suggesting inhibition of NAD+-dependent IMP dehydrogenase. Because hypoxanthine inhibits the synthesis of nicotinamide mononucleotide (NMN), a precursor of NAD+, the accumulation of hypoxanthine in Xor-KO mice may cause a depletion in the levels of NAD+. Moreover, urinary excretion of urate in high-HPRT/Uox-KO/Xor-KO mice means urate derived from gut microbiota is absorbed by the intestine. Likewise, over excretion of oxypurine in mice may be caused by intestinal absorption of oxypurine. For NAD+ replenishment, oral supplementation with 1% L-tryptophan, an alternative precursor of NAD+, resulted in a recovery of body weight gain in high-HPRT/Uox-KO/Xor-KO mice. In conclusion, the death of Xor-KO mice by renal failure seems to be caused by a depletion in NAD+ levels due to the intracellular accumulation of hypoxanthine. NAD+ replenishment by oral supplementation of NMN or tryptophan was complicated by the effect of gut microbiota and failed to rescue high-HPRT/Xor-KO mice. The attenuation of intestinal absorption of oxypurines seems to be necessary to avoid hypoxanthine accumulation and over excretion of oxypurine.