Urinary angiotensinogen excretion is associated with blood pressure in obese young adults.

Intrarenal RAS has been suggested to be involved in the pathogenesis of hypertension. It was recently reported that urinary angiotensinogen excretion levels are associated with intrarenal RAS. However, few markers predicting intrarenal RAS have been investigated in obese young subjects. The present study evaluated the association between blood pressure and intrarenal RAS activity, inflammation and oxidative stress in obese young adults. Urinary angiotensinogen excretion and urinary monocyte chemotactic protein (MCP)-1, and urinary thiobarbituric acid reaction substance (TBARS) as markers of intrarenal RAS activity, inflammation, and oxidative stress, respectively, were determined from morning urine of 111 young male adults. Participants were divided into two groups based on the body mass index (BMI). Natural log-transformed urinary angiotensinogen excretion level was significantly associated with blood pressure, MCP-1 excretion, and TBARS excretion elevation in the obese group (BMI ≥25 kg/m(2)). Multivariable analyses showed that every 1 standard deviation increase in natural-log transformed urinary angiotensinogen and MCP-1 excretion, but not TBARS excretion level was associated with elevated blood pressure in the obese group. These results indicate that urinary angiotensinogen and MCP-1 excretion were associated with blood pressure elevation in this population of obese young adults. It suggested that inappropriate RAS activity and inflammation precedes hypertension in obese young subjects and urinary angiotensinogen could be a screening maker for hypertension in young obese subjects.

Clinical characteristics of young-onset and medical treatment-requiring hypertension identified by targeted screening in university health check-up.

Based on targeted screening for hypertension at a university health check-up, we previously reported a high incidence of white-coat hypertension and estimated prevalence of hypertension requiring medical treatments (HT) as around 0.1% in young population aged less than 30. In spite of such low prevalence, continuous screening for seven consecutive years (2003-2009) increased the number of HT students to 20 (19 males and 1 female). We presently assessed the clinical characteristics of these HTs. Renovascular hypertension was found in the only female HT and aortic valve regurgitation in two HTs. Resting 17 HTs were diagnosed as having essential hypertension (EH). A father and/or a mother had EH in 16 out of 17 EHs, and blood pressure (BP) at home was slightly elevated (135-145 mm Hg in systolic) except three obese EHs (body mass index more than 30) who demonstrated more than 160 mm Hg in systolic. Plasma aldosterone-renin ratio (ARR) of EHs did not differ from that of normal controls, and Pearson correlation coefficient (R) between ARR and systolic BP (SBP) was -0.2. Its partial correlation coefficient, however, was statistically significant (R = -0.55, P = .026) after correcting for body mass index, which was significantly correlated with both SBP (P = .006, after correcting for ARR) and ARR (P = .004, after correcting for SBP). In conclusion, most of young-onset HTs are male EHs, and aortic valve regurgitation should be carefully checked. Excess plasma renin activity would be one of additional characteristics of young-onset EH to male gender, genetic background, and increased body mass.

[Chronic obstructive pulmonary disease (COPD)].

Insomnia is common in many patients with chronic obstructive pulmonary disease (COPD). The causes of insomnia are sleep induced pathophysiological effect of COPD itself, COPD comorbidities and the presence of coexisted obstructive sleep apnea. Sleep has profound adverse effects on respiration and gas exchange in patients with COPD. There are several mechanisms underlying oxygen desaturation during sleep. They include decreased functional residual capacity, decreased ventilatory responses to hypoxia and hypercapnia, impaired respiratory mechanical effectiveness, respiratory muscle fatigue, decreased respiratory drive, and increased upper airway resistance. COPD comorbidities include DM, cardiovascular diseases, osteoporosis, depression, and GERD. The coexistence of COPD and sleep apnea-hypopnea syndrome has been denominated "overlap syndrome".

Characteristics of young-onset white coat hypertension identified by targeted screening for hypertension at a university health check-up.

Previously we estimated the prevalence of essential hypertension (EH) as around 0.1% and suggested that male gender, obesity, and strong genetic background (hypertension in parents) were risk factors for EH in a young population aged less than 30 based on targeted screening for hypertension at a university health check-up. This study also revealed a high incidence of white coat hypertension (WCH) in university students, and thus, we continued this screening for four consecutive years, and examined the prognosis and clinical characteristics of young-onset WCH. Three occasions of casual blood pressure (BP) measurement and additional home BP measurement revealed 72 WCH and 15 EH students (all males) during the 4-year study period. None of the WCH students had elevated home BP to the level of hypertension during their stay at university, and 26 out of 38 WCH students participating screening in the following years showed normal casual BP. Although WCH students showed a significantly higher pulse rate than controls, WCH could not be fully differentiated from EH either by pulse rate or by correlation between casual BP value and pulse rate. These findings indicate the requirement of longer follow-up after graduation to determine the prognosis of young-onset WCH, though EH and WCH in the young population share the same risk factors and, possibly, autonomic nervous system dysfunction. Since diagnosis of WCH has limited importance for university students, screening of EH following a general health check-up would elevate the clinical validity of casual BP measurement at the university.

Urinary Angiotensinogen Excretion Level Is Associated With Elevated Blood Pressure in the Normotensive General Population.

BACKGROUND: Inflammation, intrarenal renin-angiotensin system (RAS) activation, oxidative stress, and carbonyl stress have been postulated to play a fundamental role in controlling blood pressure. However, little is known about the association among renal RAS activation, carbonyl stress, and blood pressure elevation. METHODS: We evaluated the relationship between blood pressure elevation and either renal RAS activity or carbonyl stress in the general population (N = 355) in Japan. To minimize the effect of antihypertensive drug therapy, we divided participants into 3 groups (normotensive, hypertensive-with-non-medication, and hypertensive-with-medication). Intrarenal RAS activity and carbonyl stress were indicated by the urinary angiotensinogen (AGT) and carbonyl compound excretion levels, respectively. RESULTS: The urinary AGT and carbonyl compound excretion levels were significantly associated with blood pressure. Using a stepwise multiple regression analysis, we found that the urinary AGT excretion levels were strongly associated with blood pressure elevation, compared with inflammation, oxidative stress, and carbonyl stress markers, in all groups. Urinary carbonyl compound excretion was significantly associated with blood pressure in only the hypertensive-without-medication group. Furthermore, blood pressure was significantly increased in these participants, and both the urinary AGT and carbonyl compound levels were high. The urinary AGT excretion levels were strongly associated with elevated blood pressure in normotensive people, and inappropriate renal RAS activity and carbonyl stress independently contributed to the development of hypertension. CONCLUSIONS: These findings suggest that RAS activation, particularly renal RAS activation exert a fundamental role in the pathogenesis of hypertension in the general population.

Augmented chemosensitivity in black-eyed white Mitfmi-bw mice, lacking melanocytes.

Microphthalmia-associated transcription factor (Mitf) is responsible for differentiation of melanocytes, and a recessive Mitf mutant, black-eyed white (bw) mouse, is characterized by the lack of melanocytes in the skin and inner ear. To search for the hitherto unknown roles of melanocytes, we analysed the ventilatory responses of unanaesthetized bw mice by whole body plethysmography. During air breathing, bw mice showed lower breathing frequency and larger tidal volume, compared with age-matched wild-type mice, although there was no difference in the minute ventilation. Importantly, bw mice present normal haematocrit values and red blood cell counts. We next measured the immediate ventilatory responses to acute hypoxia (10% O2) and to hyperoxic hypercapnia (10% CO2). Hypoxic and hypercapnic ventilatory responses represent the functions of the chemoreceptors in the carotid body and the brainstem, respectively. The bw mice retain the peripheral hypoxic and central hypercapnic sensing functions, but exhibited augmented ventilatory responses to both hypoxia and hypercapnia. Unexpectedly, RT-PCR analysis has shown the expression of melanocyte-specific Mitf mRNA in the brain of bw mice, suggesting the presence of leptomeningeal melanocytes. These findings suggest a functional link between skin melanocytes and the central respiratory controller that generates respiratory rhythm and pattern.

Morphologic analyses of mandible and upper airway soft tissue by MRI of patients with obstructive sleep apnea hypopnea syndrome.

STUDY OBJECTIVES: To evaluate the morphological features of the mandible and the volume of the upper airway soft tissues in determining the anatomical risk factors for the upper airway in Japanese male patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: Five morphological parameters of the mandible at the mandibular base plane and three volumetric parameters of the upper airway soft tissue were analyzed using three-dimensional (3D) magnetic resonance imaging software in 31 OSAHS and 20 controls. RESULTS: There were no significant differences between the two groups in mandibular internal width (the distance between the internal right and left gonia [IRG and ILG]) and mandibular bony thickness. However, the patients with OSAHS had a significantly wider mandibular divergence (the angle between the spina mentalis (SM)- IRG line and SM- ILG line), a smaller mandibular internal length (the perpendicular distance from SM to the RG- LG line), and a smaller area than the normal subjects at the mandibular base plane. There were no significant differences in these morphological parameters for the mandible between obese and nonobese OSAHS patients. The volumes of the tongue, soft palate, and lateral pharyngeal walls were not significantly different between the OSAHS and the control groups. CONCLUSIONS: Japanese male OSAHS patients had specific anatomical features in the bottom part of the mandible; however, obesity seemed to be a less significant risk factor. Investigators and clinicians must realize that ethnicity may modify the effects of obesity and abnormal craniofacial anatomy as risk factors for the pathogenesis of OSAHS.

Characteristics of young-onset hypertension identified by targeted screening performed at a university health check-up.

Since the prevalence and clinical characteristics of young-onset hypertension are still to be elucidated, we performed targeted-screening at an annual university health check-up for two consecutive years. Out of 16,464 subjects in 2003 and 17,032 in 2004 that were aged less than 30 years, 22 and 26 students (all males) exhibited high blood pressure (BP), respectively, on three occasions during casual BP measurements at the Tohoku University Health Center (systolic and diastolic BP of 140 and/or 90 mmHg or greater, respectively). These students were asked to measure their BP at home, and 9 subjects in total were diagnosed as having essential hypertension (EH). The remaining students were diagnosed as having white coat hypertension (WCH). In 8 out of 9 EH students, their father and/or mother had also been treated with antihypertensive medication. Adjustment by attendance ratio for each BP measurement suggested that the incidence of EH was around 0.1% and that of hypertension (EH and WCH) was around 0.5% in university students aged less than 25 years, since most of the subjects and hypertensive students were between 18 and 24 years old. Body mass index of the EH, which was more than 25 kg/m2 (overweight), was significantly higher than that with WCH. In conclusion, the combination of repeated casual BP measurements and home BP effectively identified young-onset EH. The clinical parameters indicated that male gender, genetic background, and excessive weight were risk factors for young-onset hypertension.

[Predicted vales of respiratory function tests in young Japanese aged from 10 to 20 years].

To find predicted values of respiratory function tests in young persons in Japan, we measured slow vital capacity and forced vital capacity in 1,141 subjects aged from 10 to 20 years. The values obtained from 636 persons (363 males and 273 females) who were not smokers or had no suspected rhinitis or asthma were analyzed. Although FEV1% by the Gaensler and Tiffeneau methods were almost constant regardless of age, all other values of respiratory function tests increased with age and then reached a plateau level in late teens. Excluding the Gaensler and Tiffeneau FEV1%, in a single regression analysis using gender, age, and height, both the contribution ratio and regression coefficient were the highest using height, followed by age. In addition, the result was similar with multiple regression analysis. Therefore, for a young person aged from 10 to 20 years, body height is the most important predictor variable of respiratory function tests, compared to gender and age. For each respiratory function test, we showed the prediction relation according to gender obtained from multiple linear regression analysis using 2 variables of height and age.

Effects of lung volume reduction surgery for emphysema on oxygen cost of breathing.

BACKGROUND: Patients with severe pulmonary emphysema have a greatly increased oxygen cost of breathing (O(2) cost), and this is the cause of serious malnutrition, or respiratory cachexia, in such patients. STUDY OBJECTIVES: To clarify the effect of lung volume reduction surgery (LVRS) on respiratory function and the nutritional state of these patients through a reduction in the O(2) cost of the respiratory muscles. DESIGN: Prospective cohort study. Setting, patients, and interventions: Twenty-three patients who underwent LVRS in Tohoku University Hospital. MEASUREMENTS: Pulmonary function and O(2) cost were measured perioperatively by utilizing a method of continuous dead space. In addition, we calculated the proportion of oxygen consumption (O(2)) of respiratory muscles to total O(2) (%O(2)resp) from the measured energy expenditure and the predicted values. RESULTS: FEV(1) and arterial oxygen pressure increased after surgery while lung volume and dyspnea decreased (p < 0.01), and O(2) cost was also reduced from 0.044 to 0.026 log(mL/min)/(L/min) [p < 0.001]. Moreover, the change in O(2) cost had a strong negative correlation with that of FEV(1) (r = - 0.70, p < 0.001), and a moderate positive correlation with that of the ratio of residual volume to total lung capacity (r = 0.54, p < 0.01). %O(2)resp was 23.1% at rest and 55.5% at maximal ventilation. LVRS reduced %O(2)resp at maximal ventilation to 49.0% (p < 0.05), but %O(2)resp at rest did not decrease after surgery. CONCLUSIONS: LVRS reduces energy expenditure of respiratory muscles especially during exercise by decreasing small airway obstruction and hyperinflated lung volume. This may reverse the malnourished state in end-stage emphysema.

Application of impulse oscillometry for within-breath analysis in patients with chronic obstructive pulmonary disease: pilot study.

BACKGROUND: The impulse oscillometry is increasingly used for assessing the oscillatory mechanics of the respiratory system. The within-breath behaviour of the oscillatory mechanics in chronic obstructive pulmonary disease (COPD) is a well-known physiological feature. The purpose of this study was to develop a new approach for assessing this feature using impulse oscillometry. METHODS: The oscillatory mechanics were assessed by a commercially available impulse oscillometry device. The respiratory system resistance (Rrs) and reactance (Xrs) were measured during tidal breathing in patients with COPD (n=39) and healthy subjects (n=5). Selected data, the Rrs at 5 Hz (R5), Rrs at 20 Hz (R20), Xrs at 5 Hz (X5), and resonant frequency of Xrs (Fres) every 0.2 s, were extracted from the device. These data were divided into eight time fractions during the respiratory cycle to form averaged respiratory phases. RESULTS: The time courses of the R5 and X5 were notably dependent on the respiratory cycles in patients with COPD, while there was little such dependency in healthy subjects. Irrespective of respiratory phase, R5 and Fres increased, and X5 fell to a more negative level in patients with COPD in a severity-dependent fashion. The increase in the R5 and negative level in the X5 were more prominent in the middle of the expiratory phase. The severity dependence in the R20 was relatively small compared with that in the R5. CONCLUSIONS: The results of this study suggest that impulse oscillometry can assess the within-breath behaviour of the oscillatory mechanics with high temporal resolution, which may be helpful for evaluating the severity of COPD. Further studies are needed to reveal which biomarkers obtained with this approach would be suitable for evaluating the airway obstruction.

Investigation of major genetic polymorphisms in the Renin-Angiotensin-aldosterone system in subjects with young-onset hypertension selected by a targeted-screening system at university.

Although polymorphisms in renin-angiotensin-aldosterone (RAA) system genes for angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE I/D), angiotensin II type 1 receptor (AT1 A/C1166), and aldosterone synthase (CYP11B2-344T/C) have been major targets for genetic investigation in association with essential hypertension (EH), the influence of these genetic factors is still to be determined. Because patients with young-onset EH are thought to possess a stronger genetic background than EH patients who show elevated BP relatively late in life, the targeted screening of hypertensive students in Tohoku University was completed for the selection of subjects for genetic investigation. Out of 16,434 students (12,794 males and 3,670 females) younger than 30, 22 students showed a high blood pressure (BP) (systolic and diastolic BP of 140 and/or 90 mmHg or greater, respectively, on two occasions and more than 135 and/or 85 mmHg, respectively, at a third measurement during casual BP measurements at the Tohoku University Health Center. These 22 students were asked to measure their BP at home (HBP). Six of the students had a systolic HBP of more than 135 mmHg and/or a diastolic HBP of more than 85 mmHg, and these students subsequently received medical examinations at Tohoku University Hospital and were diagnosed with EH. Genotyping for the four major genetic polymorphisms mentioned above was performed on the six students with EH and on 12 of the remaining 16 students whose HBP was within the normal range (white coat hypertension: WCH). Neither the EH nor the WCH students showed a different distribution of genotypes and allelic frequencies, compared to those found in the general Japanese population. Hence, the present study suggests that none of the major genetic polymorphisms in the RAA system strongly influence the onset of EH.

Mice with blunted hypoxic ventilatory response are susceptible to respiratory disturbance during hypoxia.

Hypoxia causes a life-threatening situation, and the ventilatory response to hypoxia plays an important role in preventing death. We have hypothesized that persons with a blunted hypoxic ventilatory response may have a weak defense response to hypoxic episodes and be susceptible to fatal respiratory disturbances. However, precise correlations between the hypoxic ventilatory response and respiratory disturbances are not well understood. In the present study we examined the hypoxic and hypercapnic ventilatory responses in nine inbred mouse strains (A/J, AKR/N, BALB/c, C3H/He, C57BL/6, DBA/2, NZW, SWR/J, and 129Sv). Breathing frequency, tidal volume and minute ventilation of unanesthetized and unrestrained mice were assessed by whole body plethysmography. Age-matched mice were exposed for 3 min to 10% O(2) in N(2) gas or 10% CO(2) in hyperoxic gas to determine the acute ventilatory response to chemical stimuli. Basal respiratory variables and hypoxic ventilatory responses differed among the strains, but the hypercapnic ventilatory response did not differ. The hypoxic ventilatory response was the highest in AKR/N mice and the lowest in SWR/J mice. These findings suggest that genetic factors may have influenced the hypoxic ventilatory response but not the hypercapnic ventilatory response. To examine the effects of severe hypoxic stress on the respiratory cycle, we exposed the strain with the highest or lowest hypoxic ventilatory response to 6% O(2) in N(2) until the onset of apnea. The "appearance time of apnea", which is defined as the time from the hypoxic loading to the onset of apnea, was shorter in the SWR/J strain than in the AKR/N strain. We suggest that a lower hypoxic ventilatory response may be a risk factor for apnea under hypoxia.

Clinical characteristics of obesity-hypoventilation syndrome in Japan: a multi-center study.

OBJECTIVE: To clarify the prevalence and clinical characteristics of obesity-hypoventilation syndrome (OHS) in a large number of patients with moderate to severe obstructive sleep apnea syndrome (OSAS). METHODS: Subjects comprised 611 patients with OSAS registered from 7 sleep centers and clinics and analyzed according to the definitions of the Respiratory Failure Research Group of the Japanese Ministry of Health and Welfare. Baseline characteristics, polysomnographic data during sleep, laboratory blood examinations, excessive daytime sleepiness, pulmonary functions, and arterial blood gases were compared between OHS and non-OHS patients. Determinants of daytime hypercapnia were also examined in OHS patients. RESULTS: OHS was identified in 55 of the 611 patients with OSAS (9%). OHS patients were younger, heavier, and more somnolent than non-OHS patients and displayed more severe OSAS, liver dysfunctions, higher total cholesterol, and impaired pulmonary function. However, these differences were resolved except for pulmonary function after correction for obesity. Daytime hypercapnia was associated with impaired pulmonary function. Percent vital capacity (%VC) was most closely correlated with PaCO2 in OHS. CONCLUSION: OHS patients display numerous abnormalities due to obesity compared with non-OHS patients. Impaired pulmonary function, particularly %VC, may play an important role in the development of daytime hypercapnia independent of obesity in OHS patients.

Prevalence of chronic obstructive pulmonary disease in Japanese people on medical check-up.

In Japan, spirometry has not been included as an item in medical check-ups for all persons. The purpose of this study was to show evidence to recommend spirometry routinely on medical check-up for the early detection of chronic obstructive pulmonary disease (COPD). There were 12,760 enrolled persons who underwent medical check-up. COPD was defined as a ratio of forced expiratory volume in one second to slow vital capacity of 70% or less. We investigated the prevalence and its characteristics of COPD in people on medical check-up. The prevalence of COPD was 3.6% in all subjects, 4.5% in males, and 1.8% in females. In the comparison between males and females, the prevalence of COPD in males of most age groups was higher than that of females, and this difference was greater with aging. Males in their 50s and over 60 years old and females over 60 years old showed remarkably high prevalences. Occupations associated with a high smoking rate such as transportation-related occupations showed a higher prevalence of COPD. These results suggest that spirometry for all persons in medical check-ups can identify many COPD patients not aware of this disease. Spirometry should be carried out routinely on medical check-up.

Digital recording and analysis of esophageal pressure for patients with obstructive sleep apnea-hypopnea syndrome.

To evaluate sleep-related obstructive breathing events in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), we developed a technique for digital recording and analysis of esophageal pressure (Pes) and elucidated the Pes parameters. Pes was recorded overnight with a microtip-type pressure transducer in 74 patients with OSAHS. Simultaneously, in all patients digital polysomnography was recorded. The mean nadir end-apneic Pes swing (Pes Nadir) ranged from -20.2 to -147.4 cmH(2)O, with a mean of -53.6+/-2.9 cmH(2)O. Correlation of the mean Pes Nadir indicated a linear relationship with the mean ratio of maximal Pes swing to apnea duration (r(2)=0.70) and the mean area of the Pes (Pes Area) (r(2)=0.82). Significant correlations were noted between the mean Pes Nadir and apnea-hypopnea index (AHI, ranging from 7.9 to 109.5 per hour; r(2)=0.66), minimum SpO(2) (r(2)=0.60), oxygen desaturation index (ODI) of more than 3 (r(2)=0.65), arousal index (r(2)=0.54), and between the mean Pes Area and AHI (r(2)=0.63), minimum percutaneous arterial oxygen saturation (SpO(2); r(2)=0.57), ODI (r(2)=0.69), and arousal index (r(2)=0.41). Pes parameters were found to be significant in the evaluation of the severity of the respiratory effort during the sleep-related obstructive breathing events for patients with OSAHS.

Quality of life in obesity hypoventilation syndrome.

The first paper of this issue of Sleep and Breathing reports that the quality of life (QOL) assessed by the SF-36 and the Epworth Sleepiness Scale (ESS) in obesity hypoventilation syndrome (OHS) was compared with age- and body mass index-matched patients without hypoventilation (obese OSA), nonobese OSA patients, and healthy subjects. The QOL in OHS was worst among these four groups. After 3 to 6 months of nasal continuous positive airway pressure (CPAP) treatment, the QOL in OHS improved to the normal level similar to the two other OSA groups. We have observed severe nonobese OSA patients with hypoventilation. One of the risk factors, which related to a severe general condition, seems to be a small craniomandibular structure, which could induce an increase in upper airway resistance during sleep. Characteristics of Japanese OSA patients may be different from those in other countries. Although belatedly, the clinical study and management of sleep disordered breathing have just begun.

Pulmonary hypertension in patients with chronic obstructive pulmonary disease: recent advances in pathophysiology and management.

In patients with chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH) is associated with a worse prognosis. Recently, information has been increasing concerning the cellular and molecular aspects of the pathophysiology of PH in COPD. The most striking finding is the role of vascular endothelial cells and endogenous mediators released by these cells. Endothelial cell-dependent relaxation is impaired in COPD patients with PH. Moreover, vascular remodelling in these patients is mainly responsible for irreversible PH in advanced COPD. Smoking cessation will slow down the progression of the disease process and may prevent the development of PH in COPD. The timing of initiation of long-term oxygen therapy is important for the effective management of PH in COPD. Research on therapeutic agents for the effective treatment of PH is still needed in the management aspect of patients with COPD. This review focuses on the recent advances in our understanding of the pathophysiology and treatment of PH in COPD.