Relationship between time-varying status of reflux esophagitis and Helicobacter pylori and progression to long-segment Barrett's esophagus: time-dependent Cox proportional-hazards analysis.

BACKGROUND: Reflux esophagitis (RE) and absence of Helicobacter pylori (non-H. pylori) are considered to be associated with the progression to long-segment Barrett's esophagus (LSBE). However, it is difficult to assess this association because RE and H. pylori status can change during follow-up. Additionally, the association between H. pylori eradication and LSBE remains unclear. METHODS: A total of 11,493 asymptomatic Japanese subjects who underwent medical check-ups and were endoscopically diagnosed with short-segment Barrett's esophagus (SSBE) between May 2006 and December 2015 were enrolled. The hazards of progression to LSBE were compared between time-varying RE and H. pylori infection/eradication by time-dependent multivariable Cox proportional hazards models. RESULTS: A total of 7637 subjects who underwent additional medical check-ups after being diagnosed with endoscopic SSBE were analyzed. Subjects with RE and without current/past H. pylori infection were strongly associated with a higher rate of progression to LSBE (adjusted hazard ratio [HR]: 7.17, 95% confidence interval [CI]: 2.48-20.73, p < 0.001 for RE and non-H. pylori vs. non-RE and H. pylori groups). Subjects with H. pylori had a lower rate of progression to LSBE (adjusted HR: 0.48, 95% CI: 0.22-1.07, p = 0.07 for H. pylori vs. non-H. pylori). Hazards of progression to LSBE were still lower in the H. pylori eradication group than that of the non-H. pylori group (adjusted HR: 0.51, 95% CI: 0.18-1.46, p = 0.21). CONCLUSIONS: RE and non-H. pylori were associated with the progression to LSBE, considering the changes in exposures. H. pylori infection was associated with the prevention of the development of LSBE irrespective of RE. The environment preventive of the development of LSBE persists for at least a few years after H. pylori eradication.

Association Between Helicobacter pylori Infection and Short-segment/Long-segment Barrett's Esophagus in a Japanese Population: A Large Cross-Sectional Study.

GOAL: The goal of this study was to investigate the relationship between Helicobacter pylori (H. pylori) infection and short-segment and long-segment Barrett's esophagus (SSBE and LSBE). BACKGROUND: H. pylori infection is reported to be inversely associated with Barrett's esophagus (BE) in western countries. However, the impact of BE segment length on the association between BE and H. pylori infection has scarcely been investigated. MATERIALS AND METHODS: The study subjects were 41,065 asymptomatic Japanese individuals who took medical surveys between October 2010 and September 2017. Using this large database of healthy Japanese subjects, we investigated the association between H. pylori infection and SSBE/LSBE. We used multivariable logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among the study subjects, 36,615 were eligible for the analysis. H. pylori seropositivity was significantly associated with a lower rate of LSBE (OR: 0.42; 95% CI: 0.16-0.91) and a higher rate of SSBE (OR: 1.66; 95% CI: 1.56-1.78) after multivariate adjustment. In the subgroup analysis, H. pylori seropositivity was significantly associated with a high rate of SSBE in subjects without reflux esophagitis (RE) (OR: 1.73; 95% CI: 1.61-1.85). However, H. pylori seropositivity was not associated with SSBE in subjects with RE (OR: 1.07; 95% CI: 0.84-1.37). CONCLUSION: In a Japanese population, H. pylori infection was inversely associated with LSBE but significantly associated with SSBE only in subjects without RE. H. pylori may be a risk factor for SSBE, especially in individuals without RE.

Association between visceral abdominal obesity and long-segment Barrett's esophagus in a Japanese population.

BACKGROUND: Visceral abdominal obesity is associated with Barrett's esophagus (BE), especially long-segment BE (≥ 3 cm) (LSBE), in white individuals. However, the association between central obesity and LSBE has not been well investigated in Asia. The aim of this study was to investigate the association between central obesity and LSBE in the Japanese population. METHODS: A total of 38,298 healthy subjects who took medical surveys between April 2006 and November 2018 were enrolled. We investigated the association between LSBE and central obesity indices [visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and the VAT to SAT ratio (VAT/SAT)] using a multivariable logistic regression model. RESULTS: A total of 37,686 subjects were eligible for the analysis. LSBE rates in the middle and high VAT/SAT groups were higher than those in the low VAT/SAT group [odds ratio (OR) 1.70, 95% confidence interval (CI) 1.07-2.69 for middle vs low; OR 2.02, 95% CI 1.17-3.49 for high vs low). These associational trends between VAT/SAT and LSBE remained in subgroups with and without reflux esophagitis. From subgroup analyses by SAT, we found that the OR between VAT and LSBE is higher in the low SAT subgroup (OR 2.43, 95% CI 1.34-4.40 for middle vs low; OR 2.55, 95% CI 1.01-6.40 for high vs low); but not large or imprecise due to limited event numbers in the middle and high SAT subgroups. CONCLUSIONS: VAT was associated with LSBE, especially among subjects with low SAT accumulation, who are seemingly not obese. VAT/SAT was associated with LSBE regardless of the presence of reflux esophagitis in a Japanese population.

Relationship between Alcohol Intake and Risk Factors for Metabolic Syndrome in Men.

OBJECTIVE: The precise relationship between alcohol intake and metabolic syndrome (MetS) is still unclear, and the results from previous studies have been inconclusive. Thus, we examined the effect of alcohol intake on the risk of MetS in men in order to gain more information on a potential relationship. METHODS: This study included 22,349 men who were divided into four groups according to their average alcohol intake [non-, light (less than 20 g ethanol/day), heavy (equal or more than 20 g and less than 60 g ethanol/day) and very heavy (equal and greater than 60 g ethanol/day) drinkers]. We measured each subject's body mass index (BMI), waist circumference and blood pressure (BP) and conducted a blood test to obtain a complete blood count and biochemical panel. These results were used to obtain the MetS prevalence. Additionally, fatty liver was diagnosed using abdominal ultrasonography. RESULTS: Light drinkers had smaller waist circumferences. Heavy and very heavy drinkers had larger waist circumferences, a higher BMI, a higher BP, higher fasting plasma glucose levels, higher triglycerides (TG) levels and higher high-density lipoprotein (HDL) cholesterol levels while they had lower low-density lipoprotein cholesterol levels than nondrinkers. The prevalence of high BP, hyperglycemia and high TG was significantly higher in heavy and very heavy drinkers than in nondrinkers. The prevalence of low HDL cholesterol levels decreased with an increase in alcohol consumption. The prevalence of MetS was significantly lower in light drinkers and higher in very heavy drinkers compared with nondrinkers. CONCLUSION: Alcohol intake significantly influences the risk of MetS in men. A significant association was seen between an alcohol intake of 60 g/day or higher and the prevalence of MetS.

Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker, valsartan, on atherosclerosis.

We investigated the effects of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) on the inhibitory effects of an angiotensin II type-1 receptor (AT1) blocker on atherosclerosis and explored cellular mechanisms. We gave apolipoprotein E null mice a high-cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition. Neither 1 mg/kg per day of valsartan nor 3 mg/kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration; however, both drugs decreased plaque area and lipid deposition after 10 weeks. We then reduced the doses of both drugs to 0.1 mg/kg per day and 1 mg/kg per day, respectively. At these doses, neither drug had an effect on atherosclerotic lesions. When both drugs were combined at these doses, a significant reduction in atherosclerotic lesions was observed. Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase subunits p22phox and p47phox, production of superoxide anion, the expression of monocyte chemoattractant protein-1, and intercellular adhesion molecule-1 expression were observed. These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade, particularly when given concomitantly, blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects.

Calcium channel blocker azelnidipine enhances vascular protective effects of AT1 receptor blocker olmesartan.

The present studies were undertaken to investigate the potential effect of a calcium channel blocker (CCB) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular injury and the cellular mechanism of the effect of CCB on vascular remodeling. In polyethylene cuff-induced vascular injury of the mouse femoral artery, proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation associated with activation of extracellular signal-regulated kinase (ERK), and tyrosine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3, inflammatory response assessed by monocyte chemoattractant protein-1 and tumor necrosis factor-alpha expression, as well as oxidative stress such as expression of NADH/NADPH oxidase p22(phox) subunit and superoxide production, were less in AT1a receptor null mice. Administration of nonhypotensive doses of a CCB, azelnidipine (0.5 or 1 mg/kg per day) attenuated these parameters in wild-type and AT1a receptor null mice. Coadministration of lower doses of an ARB, olmesartan (0.5 mg/kg per day), and azelnidipine (0.1 mg/kg per day), which did not affect vascular remodeling, significantly inhibited these parameters in wild-type mice. Moreover, the effective dose of azelnidipine (1 mg/kg per day) exaggerated the inhibitory action of olmesartan at effective doses of 1 or 3 mg/kg per day on VSMC proliferation in the injured arteries. These results suggest that azelnidipine could inhibit vascular injury at least partly independent of the inhibition of AT1 receptor activation and that azelnidipine could exaggerate the vascular protective effects of olmesartan, suggesting clinical possibility that the combination of CCB and ARB could be more effective in the treatment of vascular diseases.

Nicotine enhances angiotensin II-induced mitogenic response in vascular smooth muscle cells and fibroblasts.

OBJECTIVE: The pathogenetic mechanism of tobacco-related cardiovascular diseases is still not well defined. We examined the potential possibility of an interaction between nicotine, a major component of cigarette smoke, and angiotensin II (Ang II), which plays an important role in the pathogenesis of cardiovascular diseases characterized by Ang II type 1 (AT1) receptor-mediated abnormal growth of vascular smooth muscle cells (VSMC) and fibroblasts. METHODS AND RESULTS: Nicotine or Ang II-stimulated [3H]thymidine incorporation and c-fos expression in adult rat aortic VSMC and adventitial fibroblast. The nicotine-induced DNA synthesis was not affected by valsartan, an AT1 receptor-specific blocker, or PD123319, an Ang II type 2 (AT2) receptor-specific antagonist. Nicotine or Ang II stimulation rapidly increased extracellular signal-regulated kinase (ERK) activation, tyrosine- and serine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3, and p38 mitogen-activated protein kinase (p38 MAPK), in both cell types. Interestingly, co-administration of nicotine and Ang II at lower doses, which did not affect cell growth, induced DNA synthesis and c-fos expression accompanied by enhancement of ERK, STAT, and p38MAPK activity. PD98059, a mitogen-activated protein kinase/ERK kinase inhibitor, or SB23058, a p38MAPK inhibitor, significantly attenuated the vasotrophic effect of nicotine and Ang II. CONCLUSIONS: These results suggest that nicotine exerts a growth-promoting effect on vascular cells and enhances the Ang II-induced vasotrophic effect, which is at least partly mediated by the activation of ERK, STAT, and p38MAPK.

Regulation of collagen synthesis in mouse skin fibroblasts by distinct angiotensin II receptor subtypes.

We examined the possibility of whether angiotensin (Ang) II type 1 (AT1) and type 2 (AT2) receptor stimulation differentially regulates collagen production in mouse skin fibroblasts. Both AT1 and AT2 receptors were expressed in neonatal skin fibroblasts prepared from wild-type mice to a similar degree, and the AT1a receptor was exclusively expressed as opposed to the AT1b receptor. In wild-type fibroblasts, Ang II increased collagen synthesis accompanied by an increase in expression of tissue inhibitor of metalloproteinase (TIMP)-1, and these increases were inhibited by valsartan, an AT1 receptor blocker, but augmented by PD123319, an AT2 receptor antagonist. Ang II decreased basal and IGF-I-induced collagen production and inhibited TIMP-1 expression in neonatal skin fibroblasts prepared from AT1a knockout (KO) mice. These Ang II-mediated inhibitory effects on collagen production and TIMP-1 expression observed in AT1a KO fibroblasts were attenuated by the addition of PD123319 or a tyrosine phosphatase inhibitor, sodium orthovanadate, but not affected by a serine/threonine phosphatase inhibitor, okadaic acid. Moreover, we demonstrated that transfection of a catalytically inactive, dominant negative SHP-1 (Src homology 2-containing protein-tyrosine phosphatase-1) mutant inhibited the Ang II-mediated inhibitory effect on both collagen synthesis and TIMP-1 expression in AT1a KO fibroblasts. These results suggest that AT1a receptor stimulation increases collagen production in skin fibroblasts at least in part due to the inhibition of collagen degradation via the increase in TIMP-1 expression, whereas AT2 receptor stimulation exerts inhibitory effects on TIMP-1 expression, which is mediated at least partially by the activation of SHP-1, thereby possibly inhibiting collagen production.

Role of AT2 receptor in the brain in regulation of blood pressure and water intake.

The effects of intracerebroventricular (ICV) injection of angiotensin II (ANG II) on blood pressure and water intake were examined with the use of ANG II receptor-deficient mice. ICV injection of ANG II increased systolic blood pressure in a dose-dependent manner in wild-type (WT) mice and ANG type 2 AT(2) receptor null (knockout) (AT(2)KO) mice; however, this increase was significantly greater in AT(2)KO mice than in WT mice. The pressor response to a central injection of ANG II in WT mice was inhibited by ICV preinjection of the selective AT(1) receptor blocker valsartan but exaggerated by the AT(2) receptor blocker PD-123319. ICV injection of ANG II also increased water intake. It was partly but significantly suppressed both in AT(2)KO and AT(1)aKO mice. Water intake in AT(2)/AT(1)aKO mice did not respond to ICV injection of ANG II. Both valsartan and PD-123319 partly inhibited water intake in WT mice. These results indicate an antagonistic action between central AT(1)a and AT(2) receptors in the regulation of blood pressure, but they act synergistically in the regulation of water intake induced by ANG II.

Low-dose doxazosin improved aortic stiffness and endothelial dysfunction as measured by noninvasive evaluation.

Evaluation of atherosclerosis is important in the treatment of hypertension. To evaluate the preventive effects of a small amount of alpha-blockade, arterial and endothelial dysfunction were measured by noninvasive tests, i.e., pulse wave velocity, acceleration plethysmography and strain-gauge plethysmography, in patients with essential hypertension. Fifteen patients (65+/-3 years old) with essential hypertension (WHO stage I or II) were analyzed in this study. We performed noninvasive evaluations to measure aortic stiffness and endothelial dysfunction, in addition to measuring blood pressure, cholesterol profile, and levels of cells adhesion molecules and nitric oxide before and 6 and 12 months after the start of doxazosin treatment (1.0 mg/day). Blood pressure and heart rate did not significantly change during treatment. The pulse wave velocity index was significantly reduced both at 6 (7.72+/-0.23 m/s; p<0.05) and 12 (7.34+/-0.26 m/s; p<0.05) months after the start of treatment compared to the pretreatment level that at baseline. There was also a significant improvement in b/a after 12 months (-0.46+/-0.04; p<0.05) and in d/a after 6 months (-0.38+/-0.03; p<0.05) and 12 months (-0.39+/-0.03; p=0.05) compared to the pretreatment values. Moreover, reactive hyperemia evaluated by strain-gauge plethysmography after 6 months (1.34+/-0.11; p<0.05) and 12 months (1.49+/-0.16; p<0.05) was significantly improved compared to that before treatment, and NOx was significantly increased after 12 months (89.7+/-15.7 micromol/l; p<0.005). These data suggest that a low dose of doxazosin may play an important role in improving arterial stiffness and endothelial dysfunction without changing cardiac hemodynamics.