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

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

The Association of Smoking and Hyperuricemia with Renal Arteriolosclerosis in IgA Nephropathy.

The combination effects of smoking (SMK) and hyperuricemia (HU) on renal arteriolosclerosis in patients with IgA nephropathy remain unknown. We examined the cross-sectional association between smoking (current or former) and renal arteriolar hyalinosis and wall thickening with or without HU [uric acid (UA) level ≥ 7 and ≥5 mg/dL in men and women] in 87 patients with IgA nephropathy who underwent renal biopsy. Arteriolar hyalinosis and wall thickening were assessed by the semiquantitative grading of arterioles. The SMK/HU subgroup showed the highest indices for hyalinosis and wall thickening, followed by the non-SMK/HU, SMK/non-HU, and non-SMK/non-HU subgroups. Multiple logistic analysis showed that SMK/HU, but not SMK/non-HU, was significantly associated with an increased risk of higher-grade renal arteriolar wall thickening. However, this did not occur with hyalinosis compared to non-SMK/non-HU. The adjusted odds ratio (95% confidence interval, p value) for SMK/HU was 12.8 (1.36-119, p < 0.05) for wall thickening. An association between SMK and renal arteriolar wall thickening might be prevalent only among patients with HU and in patients with IgA nephropathy. Further prospective studies are needed to determine whether patients with HU and SMK history exhibit rapid eGFR deterioration.

Achievement rate of target blood pressure in patients with hypertension treated by hypertension specialists and non-specialists in a real-world setting.

Hypertension remains a major global healthcare issue. Considering that most Japanese patients with hypertension are managed by general practitioners, hypertension specialists should be involved in actual clinical practice. We investigated the blood pressure (BP), guidelines recommended for achievement rate of the target BP, and clinical variables of patients with hypertension treated by hypertension specialists and those treated by non-specialists in a real-world setting. Factors associated with the target BP achievement in this population were also investigated. Outpatients with hypertension from 12 medical facilities in Okinawa Prefecture were enrolled (n = 1469 [specialist group, 794; non-specialist group, 675]; mean age, 64.2 years; females, 45.8%). For all patients, BP and rate of the target BP achievement were 129.0 ± 15.5/74.6 ± 10.6 mmHg, and 51.8%, respectively. BP and the rate of target of BP achievement were 128.0 ± 15.1/73.4 ± 10.4 mmHg and 56.7% in the specialist group, and they were 130.1 ± 15.9/76.0 ± 10.8 mmHg and 46.1% in the non-specialist group. The urinary salt excretion and obesity rates were comparable between the specialist and non-specialist groups. Multivariable logistic analyses indicated that hypertension specialists and good medication adherence were positive factors, whereas obesity, chronic kidney disease, diabetes mellitus, and urinary salt excretion were inverse factors associated with target BP achievement in this population. Initiatives for salt reduction, medication adherence, and proper obesity management are crucial to improving BP management in patients with hypertension. Hypertension specialists are expected to play an essential role in them. For all patients, the target blood pressure (BP) achievement rate were 51.8%. Hypertension specialists and good medication adherence were positive factors in achieving target BP; conversely, obesity, diabetes mellitus, chronic kidney disease, and high urinary salt excretion were inverse factors in achieving target BP among patients with hypertension.

Urate-lowering drugs for chronic kidney disease with asymptomatic hyperuricemia and hypertension: a randomized trial.

INTRODUCTION: Xanthine oxidase (XO) inhibitors may slow down chronic kidney disease (CKD) progression. The comparative effectiveness of the different urate-lowering drugs is unknown. The aim of this study was to determine whether urate-lowering therapy with an XO inhibitor (febuxostat) and that with a uricosuric drug (benzbromarone) are comparable in slowing renal function decline in patients with CKD complicated with hypertension and hyperuricemia. METHODS: This study was an open-label randomized parallel-group clinical trial of 95 patients with stage G3 CKD in Japan. The patients had hypertension and hyperuricemia without a history of gout. They were randomized to receive febuxostat ( n  = 47; febuxostat group) or benzbromarone ( n  = 48; benzbromarone group) and titrated to reduce their serum urate level to <6.0 mg/dl. The primary end-point was change in estimated glomerular filtration rate (eGFR) from baseline to 52 weeks. The secondary end-points included changes in uric acid level, blood pressure, urinary albumin-to-creatinine ratio, and XO activity. RESULTS: Of the 95 patients, 88 (92.6%) completed the trial. There were no significant differences in change in eGFR (in ml/min/1.73 m 2 ) between the febuxostat [-0.23, 95% confidence interval (CI), -2.00 to 1.55] and benzbromarone (-2.18, 95% CI, -3.84 to -0.52) groups (difference, 1.95; 95% CI, -0.48 to 4.38; P  = 0.115) nor in the secondary end-points, except for XO activity. Febuxostat significantly reduced XO activity ( P  = 0.010). There were no significant differences in primary and secondary outcomes between the groups. A decrease in eGFR was significantly less in the febuxostat group than that of the benzbromarone group in the CKDG3a, but not in CKDG3b, in the subgroup analysis. There were no adverse effects specific to either drug. CONCLUSIONS: No significant differences were found in the effects of febuxostat and benzbromarone in renal function decline in stage G3 CKD complicated with hyperuricemia and hypertension.

Association between visceral fat mass and arterial stiffness among community-based screening participants.

Obesity and arterial stiffness are important risk factors for disease development. However, the relationship between obesity and arterial stiffness remains unclear. We examined the relationship of visceral fat area (VFA) and anthropometric obesity indices with arterial stiffness. This cross-sectional study was conducted among 2 789 participants (50% women) who underwent both VFA and brachial-ankle pulse wave velocity (baPWV) measurements during health checkups. Body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), a body shape index (ABSI), and body roundness index (BRI) were assessed. Visceral fat area was quantified using abdominal computed tomography. In women, VFA and all anthropometric indices positively correlated with age. In men, VFA, WHtR, ABSI, and BRI positively correlated with age; BMI inversely correlated with age; and WC did not correlate with age. Visceral fat area significantly correlated with anthropometric indices, but its correlation with ABSI was modest. In women, baPWV showed modest correlations with VFA and anthropometric indices and little correlations with BMI. In men, baPWV modestly correlated with VFA, WHtR, ABSI, and BRI, but inversely correlated with BMI and did not significantly correlate with WC. The multivariable-adjusted model showed that VFA and anthropometric indices, except ABSI, were inversely associated with baPWV; however, they were positively associated with metabolic syndrome components, including hypertension, dyslipidemia, and hyperglycemia. A body-shaped index weakly associated positively with baPWV, but misclassified individuals at risk for metabolic syndrome components. Visceral fat area and most anthropometric obesity indices were positively associated with hypertension, dyslipidemia, and hyperglycemia, but inversely associated with baPWV. Visceral fat area and anthropometric indices, except a body-shaped index, were inversely associated with brachial-ankle pulse wave velocity but positively associated with metabolic syndrome components, including hypertension, dyslipidemia, and hyperglycemia.

Acquired factor V inhibitor with erythema and eosinophilia in a patient with end-stage renal disease.

Autoimmune factor V deficiency (AiFVD) is a rare bleeding disorder caused by factor V inhibitors. In this report, we present the case of an 89-year-old man who developed bleeding tendency during surgery to create arteriovenous fistula for hemodialysis. The bleeding tendency developed with prolongation of activated partial thromboplastin and prothrombin time, following drug-induced eruption and eosinophilia. Significant reduction in coagulation factor activity and inhibitory pattern in cross-mixing tests suggested the presence of inhibitors to coagulation factors. Subsequently, we detected a factor V inhibitor and anti-factor V autoantibodies was confirmed using enzyme-linked immunosorbent assay with purified human plasma factor V. Thus, the patient was 'definitely diagnosed' with AiFVD in accordance with the diagnostic criteria enacted by the Japanese Ministry of Health, Labor, and Welfare. The bleeding tendency improved after initiating oral prednisolone 50 mg (1 mg/kg) followed by normalization of activated partial thromboplastin time and prothrombin time at the 34th day. After improving the coagulation system prolongation, the inhibitor and autoantibodies has been eradicated. Since it is suggested that drug-induced immune response can cause AiFVD, AiFVD should be considered in patients who undergo hemodialysis and develop failure of hemostasis and drug-induced eruption.

Comparative evaluation of standard maintenance-dose clopidogrel versus low-dose prasugrel in patients with stable coronary artery disease after percutaneous coronary intervention.

BACKGROUND: Treatment with low-dose prasugrel might be more beneficial even in chronic stable coronary artery disease (CAD) patients treated with clopidogrel. We compared platelet reactivity between standard maintenance-dose and low-dose prasugrel in stable CAD patients. METHODS: This multicenter study enrolled 164 stable CAD patients receiving dual antiplatelet therapy with aspirin and clopidogrel. Patients were randomly assigned to continue treatment with 75-mg clopidogrel daily (n = 80) or switch to 3.75-mg prasugrel daily (n = 84). Platelet reactivity was evaluated by measuring P2Y12 reaction unit (PRU) before randomization and at 5 and 30 days thereafter using the VerifyNow® assay. Patients were classified into three groups according to CYP2C19-clopidogrel metabolic phenotype: extensive (without a *2 or *3 allele), intermediate (one *2 or *3 alleles), or poor (two *2 or *3 alleles) metabolizers. RESULTS: The PRU level was comparable between the two groups at baseline but was significantly lower in the prasugrel group than in the clopidogrel group on days 5 (133.0 vs. 156.8 PRU, P = 0.005) and 30 (124.3 vs. 158.0 PRU, P < 0.001). On day 30, the PRU level was lower in the prasugrel group among patients categorized as poor and intermediate metabolizers but not among extensive metabolizers. CONCLUSIONS: Low-dose prasugrel achieves more consistent antiplatelet effects than clopidogrel irrespective of the metabolic phenotype in Japanese patients with stable CAD. Low-dose prasugrel might be also beneficial in the chronic phase without increasing the bleeding risk among stable CAD patients in other countries.

Effects of a Low-Salt and High-Potassium Diet on Arterial Stiffness and Left Ventricular Function in Indigenous Papuans.

Background A sodium-restricted diet represents a potential non-pharmacological strategy for improving blood pressure, arterial stiffness, and left ventricular (LV) diastolic function. We investigated age-related differences in LV structure and function and the relationship between LV function and central hemodynamics in an indigenous Papuan population, who maintain a traditional lifestyle, including a low-salt and high-potassium diet. Methods and Results We measured LV dimensions, transmitral blood flow, and mitral annular tissue velocities through echocardiography and Doppler imaging. Blood pressure and brachial-ankle pulse wave velocity were measured using an automatic device (Omron). Central blood pressure and wave reflection parameters were estimated via oscillometry (Mobil-O-Graph, using European calibrations). A total of 82 native Papuans (median age, 42 years; 38 women; no blood pressure treatment) were enrolled. Age-related difference in brachial systolic pressure was modest but significant, and brachial-ankle pulse wave velocity significantly increased with age; however, LV mass index remained unchanged. LV ejection fraction and global longitudinal strain were preserved; mitral A-wave velocity and average E/e´ increased; and e´ and E/A decreased with age. Brachial-ankle pulse wave velocity and spot urine Na/K were positively and independently correlated with E/e´. Age and heart rate were inversely associated with E/A. In conclusion, LV systolic function was preserved; however, LV diastolic function decreased with age in Papuans. Moreover, age-related arterial stiffening, but not wave reflections, was inversely related to LV diastolic function. Conclusions Our results suggest that arterial and LV stiffness may not be altered by sodium restriction. Longitudinal studies are warranted to elucidate the effects of diet on arterial and LV function.

Salt and potassium intake evaluated with spot urine and brief questionnaires in combination with blood pressure control status in hypertensive outpatients in a real-world setting.

Reducing salt and increasing potassium intake are recommended lifestyle modifications for patients with hypertension. The estimated 24-h urinary salt excretion value from spot urine using Tanaka's formula and the salt check-sheet scores, questionnaire-based scores of salt intake, are practical indices of daily salt intake. However, few studies have evaluated salt intake with these methods in hypertensive outpatients. We examined salt and potassium intake with the spot urine method and the salt check-sheet scores of hypertensive outpatients in a multi-facility, real-world setting and examined whether the salt or potassium intake evaluated with these methods related to inadequate blood pressure control. Hypertensive outpatients from 12 medical facilities in the Okinawa prefecture were enrolled from November 2011 to April 2014 (n = 1559, mean age 63.9 years, 46% women). The mean blood pressure, urinary salt excretion value, urinary potassium excretion value, and total score on the salt check-sheet were 129/75 mmHg, 8.7 g/day, 1.6 g/day, and 10.4 points, respectively. The urinary salt excretion value and total score on the salt check-sheet but not urinary potassium excretion value were associated with inadequate blood pressure control (≥140/90 mmHg). Higher body mass index, estimated glomerular filtration rate, urinary potassium excretion value, total score on the salt check-sheet, and presence of inadequate blood pressure control were associated with high urinary salt excretion (≥10.2 g/day). In conclusion, hypertensive outpatients with high urinary salt excretion values estimated using Tanaka's formula or with high scores on the salt check sheet may be candidates for more intensive salt reduction guidance.

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

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

Effect of Mineralocorticoid Receptor Blockade on Arterial Stiffness and Endothelial Function: A Meta-Analysis of Randomized Trials.

Although numerous studies have confirmed the beneficial effects of pharmacological therapy for arterial stiffness and endothelial dysfunction, which are predictors/therapeutic targets for cardiovascular diseases, only a few overall quantitative evaluations of MRAs (mineralocorticoid receptor antagonists) exist. We searched PubMed and Cochrane CENTRAL (Cochrane Central Register of Controlled Trials) for randomized trials evaluating MRA effects on arterial stiffness measured by pulse wave velocity (PWV) or augmentation index and endothelial function measured by flow-mediated dilation. Data from the included trials were pooled by using random-effects meta-analysis of the weighted mean difference (MD) between the comparator groups. The primary outcome was the MD of PWV. In 11 trials including 515 patients, the MRA treatment reduced the PWV when compared with control (MD, -0.75 m/s [95% CI, -1.12 to -0.39], P<0.00001), without heterogeneity. There were comparable effects of MRA on carotid-femoral PWV and those on other forms of PWV (P=0.705 for heterogeneity). The effects of MRA on PWV were independent of blood pressure reduction related to the treatment according to meta-regression analysis. The MRA treatment reduced the augmentation index compared with control in 5 trials including 283 patients (MD, -6.74% [95% CI, -10.26 to -3.21], P=0.0002) and increased the flow-mediated dilation in 11 trials including 570 patients (MD, 1.18% [95% CI, 0.14 to 2.23], P=0.03). In conclusion, the current meta-analysis demonstrates the beneficial effects of MRA on PWV, augmentation index, and flow-mediated dilation.

A high normal ankle--brachial index is associated with electrocardiography-determined left ventricular hypertrophy: the Okinawa Peripheral Arterial Disease Study (OPADS).

OBJECTIVES: We aimed to determine if the ankle--brachial index (ABI) increased with age as a result of increased arterial stiffness and wave reflection, and whether this was associated with left ventricular hypertrophy (LVH). METHODS: An observational cross-sectional study was conducted in 13 396 participants aged 19-89 years who attended a health check-up. Brachial and ankle blood pressures were measured by an automatic oscillometric method. Electrocardiography-determined LVH (ECG-LVH) was defined by computer-interpreted Minnesota codes using resting 12-leads ECG. RESULTS: The mean age of the participants was 53 years (54% women). The prevalence of ECG-LVH was 13%; this was the lowest in participants with normal blood pressure and increased with an increase in the hypertension grade. The ABI was higher in participants with ECG-LVH than in those without (1.13±â€Š0.07 vs. 1.15 ±â€Š0.07, P < 0.001). The prevalence of ECG-LVH was the highest in participants with the highest quartile of ABI (16%), followed by those with the third quartile (14%), second quartile (12%), and the lowest quartile of ABI (9%). The odds ratio for ECG-LVH was significantly higher for participants with a higher quartile of ABI than those with the lowest, before and after adjustment for several covariates. Similar results were observed in sensitivity analysis of individuals with normal kidney function, younger than 65 years, and without diabetes mellitus, performed in order to reduce the influence of a medial arterial calcification-mediated increase in ABI. CONCLUSION: High ABI is a possible marker of arterial stiffness and/or wave reflection that, even in the normal range, is associated with ECG-LVH.

A high normal ankle-brachial index is associated with biopsy-proven severe renal small artery intimal thickening and impaired renal function in chronic kidney disease.

A significant relationship has been established between central hemodynamics and renal microvascular damage. We hypothesized that the increase in the ankle-brachial index (ABI) with age is due to increased arterial stiffness and wave reflection and is thus associated with the pathogenesis of the renal small artery in patients with chronic kidney disease (CKD). We recruited 122 patients with CKD (stages 1-5) who underwent renal biopsy and ABI measurements between 2010 and 2013. Renal small artery intimal thickening (SA-IT) severity was assessed by semiquantitative grading. The median age was 47 years, with a range of 15-86 years (47% women). The median estimated glomerular filtration rate (eGFR) was 62 mL/min/1.73 m2. Compared with patients with the lowest 1-3 SA-IT index quartile, those with the highest quartile of the SA-IT index were older in age had higher mean arterial pressure, ABI, brachial-ankle pulse wave velocity, and lower eGFR. ABI was positively associated with SA-IT severity and inversely associated with eGFR. Multivariate logistic regression analyses showed that ABI was significantly associated with the highest quartile of the SA-IT index (odds ratio per SD increase in ABI, 1.83; 95% confidence interval, 1.08-3.26) and low eGFR (<60 mL/min/1.73 m2) (odds ratio per SD increase in ABI, 1.74; 95% confidence interval, 1.03-3.03). In conclusion, a high normal ABI was associated with severe renal small artery intimal thickening and low eGFR in patients with CKD.

Incidental detection of Corynebacterium jeikeium endocarditis via regular blood examination in an afebrile hemodialysis patient.

Herein, we describe a rare case of Corynebacterium jeikeium endocarditis that silently progressed in a 65-year-old man undergoing hemodialysis. Because routine monthly blood examination revealed high C-reactive protein levels, blood cultures were collected, although he had no symptom and was afebrile. After 2 days, a Gram-positive rod was detected in one set of the blood culture. Furthermore, transthoracic echocardiography revealed new aortic regurgitation (AR) and vegetations, and, therefore, infective endocarditis was suspected. Transesophageal echocardiography showed vegetations with a maximum diameter of 8 mm on his aortic valve, with some valve destruction. C. jeikeium was identified in three sets of blood cultures. Administration of daptomycin was started because he had vancomycin allergy. Judging from the high risk of embolization due to vegetations, emergency aortic valve replacement was performed on the second day. C. jeikeium was detected in a resected cardiac valve specimen and blood. This case emphasizes that physicians should always consider the possibility of infective endocarditis even in hemodialysis patients without any symptoms.

Association between high-normal ankle-brachial index and hypertension incidence: the Okinawa Peripheral Arterial Disease Study.

OBJECTIVES: Arterial stiffness is associated with longitudinal increases in blood pressure and hypertension development. A screened cohort was used to test whether increases in the ankle-brachial index (ABI) with age occur as a result of increasing arterial stiffness and wave reflection and is associated with hypertension incidence. METHODS: We analysed the data of 1344 participants without hypertension at baseline who underwent ABI measurements at least twice with an interval of at least 36 months. Participants with abnormal ABI values were excluded. RESULTS: The median age of participants was 51 years (55% women). The ABI was lowest for participants younger than 40 years and increased with age. At the time of the follow-up visit (median follow-up period, 47 months), 224 (17%) participants had developed hypertension. Multiple linear regression analysis revealed that baseline ABI was positively and independently associated with the yearly change in brachial SBP and hypertension incidence. Compared with participants with a normal ABI (1.00-1.19), the adjusted odds ratio for hypertension incidence was significantly higher for participants with a high-normal ABI (1.20-1.39) before and after multivariate adjustment for conventional risk factors (odds ratio, 2.17, 95% confidence interval 1.20-3.95). Addition of ABI to a model containing conventional risk factors did not improve the c-statistics but the net reclassification index of ABI was 0.17 (95% confidence index 0.01-0.37) for hypertension incidence. CONCLUSION: Baseline ABI was positively and independently associated with the yearly change in SBP and hypertension incidence.

Intracerebroventricular administration of bone marrow-derived cells attenuates angiotensin II-initiated neurogenic hypertension in rats.

Bone marrow-derived cells exert anti-inflammatory actions and can migrate into the brain. However, their role in the development of neurogenic hypertension remains unclear. A hyperactive renin-angiotensin system and inflammation in the brain are mechanisms that contribute to angiotensin II-initiated neurogenic hypertension. We hypothesized that bone marrow-derived cells in the brain attenuate the overactive brain renin-angiotensin system and inflammation, thereby reducing neurogenic hypertension. We cultured plastic-adherent bone marrow-derived cells for 3 weeks. Seven days after initiation of vehicle or angiotensin II infusions, the rats underwent intracerebroventricular administration of either serum-free medium or autologous bone marrow-derived cells (106 cells). After 23 days of infusion, the mean arterial pressure was recorded, and the sympathetic tone was evaluated. Rats infused with angiotensin II demonstrated significant increases in the resting mean arterial pressure and the peak depressor response to ganglionic blockade (vehicle vs. angiotensin II infusion, 119 ± 4 vs. 178 ± 6 mmHg and -34 ± 6 vs. -74 ± 5 mmHg, respectively). Intracerebroventricularly administered bone marrow-derived cells attenuated the angiotensin II-mediated increases in the resting mean arterial pressure and peak depressor response (142 ± 11 and -52 ± 4 mmHg, respectively). The cells also reduced the angiotensin II-induced increases in angiotensin II type 1 receptor and transforming growth factor-ß expression in the brain. In conclusion, bone marrow-derived cells in the brain may have a protective role against the development of angiotensin II-induced neurogenic hypertension by modulating angiotensin II type 1 receptor expression and inflammatory processes.

Arterial stiffness, not systolic blood pressure, increases with age in native Papuan populations.

Systolic blood pressure (SBP) and arterial stiffness are closely related and may behave reciprocally as cause or effect, interacting in a vicious cycle. Both SBP and arterial stiffness increase with age in populations in most developed countries. However, the age-related increase in SBP appears to be absent in indigenous populations, partially because of their lifelong low-sodium and high-potassium diets, whereas age-related arterial stiffening in these populations remains to be determined. We performed a field survey of the indigenous population of Soroba, a small village located in the central highlands of Papua, Indonesia. Blood pressure levels and brachial-ankle pulse wave velocity (baPWV) were measured using an automatic device. A total of 125 native Papuans 16-75 years of age (59% women) were included in this study. SBP and pulse pressure were not correlated with age. However, diastolic and mean arterial pressure levels increased with age. The prevalence of hypertension was 5% (n = 6; all women), and baPWV significantly increased with age. Compared with participants 45 years of age and older, those younger than 45 years had a higher body mass index (BMI) and spot urine sodium-to-potassium ratio but lower baPWV; however, SBP was not different between these age groups. Multivariate linear regression analysis revealed that SBP was independently associated with baPWV, sex and BMI but not with age; baPWV was independently associated with SBP, age, BMI, sex and heart rate. SBP and baPWV were closely related, but the age-related changes in these measurements differed in this highland Papuan population.

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

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

Excess of Aminopeptidase A in the Brain Elevates Blood Pressure via the Angiotensin II Type 1 and Bradykinin B2 Receptors without Dipsogenic Effect.

Aminopeptidase A (APA) cleaves angiotensin (Ang) II, kallidin, and other related peptides. In the brain, it activates the renin angiotensin system and causes hypertension. Limited data are available on the dipsogenic effect of APA and pressor effect of degraded peptides of APA such as bradykinin. Wistar-Kyoto rats received intracerebroventricular (icv) APA in a conscious, unrestrained state after pretreatment with (i) vehicle, (ii) 80 µg of telmisartan, an Ang II type-1 (AT1) receptor blocker, (iii) 800 nmol of amastatin, an aminopeptidase inhibitor, and (iv) 1 nmol of HOE-140, a bradykinin B2 receptor blocker. Icv administration of 400 and 800 ng of APA increased blood pressure by 12.6 ± 3.0 and 19.0 ± 3.1 mmHg, respectively. APA did not evoke drinking behavior. Pressor response to APA was attenuated on pretreatment with telmisartan (vehicle: 22.1 ± 2.2 mmHg versus telmisartan: 10.4 ± 3.2 mmHg). Pressor response to APA was also attenuated with amastatin and HOE-140 (vehicle: 26.5 ± 1.1 mmHg, amastatin: 14.4 ± 4.2 mmHg, HOE-140: 16.4 ± 2.2 mmHg). In conclusion, APA increase in the brain evokes a pressor response via enzymatic activity without dipsogenic effect. AT1 receptors and B2 receptors in the brain may contribute to the APA-induced pressor response.