Central and brachial pulse pressure predicts cardiovascular and renal events in treated hypertensive patients.

PURPOSES: Central blood pressure is a stronger predictor of cardiovascular prognosis rather than brachial blood pressure. The reflection wave reaches the abdominal aorta sooner than ascending aorta. Thus, the contribution of central pulse pressure (cPP) to renal events may differ from that of cardiovascular events. METHODS: The subanalysis of the ABC-J II study was performed. Subjects were 3434 treated hypertensive patients with a mean follow-up of 4.7 years. Left ventricular hypertrophy, an index of cardiovascular risk, correlated with cPP better than central systolic blood pressure in this cohort. The contribution of brachial pulse pressure (bPP) and cPP to cardiovascular and renal events was analysed. RESULTS: Cox proportional-hazard analysis revealed that sex (p < 0.001), height (p < 0.05), history of cardiovascular diseases (p < 0.001), number of antihypertensive drugs (p < 0.05), and cPP (p < 0.05) contributed to cardiovascular events. However, Cox proportional-hazard analysis disclosed that baseline serum creatinine (p < 0.001) and bPP (p < 0.05) predicted renal events. After adjusting for the history of cardiovascular diseases, Cox regression demonstrated only sex as a significant predictor of cardiovascular events. After adjusting for baseline serum creatinine, no parameters were shown to predict renal events. CONCLUSIONS: The present findings support our previous data that the absence of cardiovascular or renal diseases is an important determinant for event-free survival, and suggest that cPP and bPP contribute to cardiovascular and renal events in treated hypertensive patients.

Influence of AHRR Pro189Ala polymorphism on kidney functions.

The function of aryl hydrocarbon receptor repressor (AHRR) in the kidney is unclear. The present study investigated associations between AHRR Pro189Ala polymorphism and estimated glomerular filtration rates (eGFR), serum creatinine, and hemoglobin levels in 2775 Japanese adults without diabetes. In addition, we examined whether AHRR expression levels in the kidney of control and chronic kidney disease (CKD) rats were changed. Multiple linear regression analyses showed that carriers of the Ala allele had increased eGFR and lower concentrations of serum creatinine and hemoglobin (p < 0.05). Immunohistochemical analysis showed that the expression of AHRR was upregulated in the kidneys of rats with CKD. These findings suggest that AHRR plays distinct roles in kidney functions and hemoglobin values. The effects of the AHRR polymorphism might be intensified in the kidneys of patients with CKD.

Identification of deleterious rare variants in MTTP, PNPLA3, and TM6SF2 in Japanese males and association studies with NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive fat deposits in hepatocytes without excessive alcohol intake. NAFLD is influenced by genetic factors, and the heritability has been estimated at 0.35 to 0.6 by twin studies. We explored rare variants in known NAFLD-associated genes to investigate whether these rare variants are involved in the susceptibility to NAFLD. METHODS: The target genes for re-sequencing were PNPLA3, TM6SF2, and MTTP. All exons of these three genes were amplified from a discovery panel of 950 Japanese males, and the identified rare variants were further tested for genetic association in 3014 individuals from the Japanese general population and for in vitro functional evaluation. RESULTS: Target re-sequencing analysis using next-generation sequencing identified 29 rare variants in 65 Japanese males (6.84%), 12 of which were newly identified base substitutions. A splicing mutation in TM6SF2 that resulted in deletion of 31 amino acids was identified in an NAFLD case. Among eight genotyped rare single-nucleotide polymorphisms (SNPs; minor allele frequency < 0.02), rs143392071 (Tyr220Cys, PNPLA3) significantly increased (odds ratio = 3.52, P = 0.008) and rs756998920 (Val42Ile, MTTP) significantly decreased (odds ratio = 0.03, P = 0.019) the NAFLD risk. Functional assays showed that these two SNPs disrupted protein functions and supported the genetic association. CONCLUSION: Collectively, 1.79% of individuals in our studied population were estimated carriers of rare variants that are potentially associated with NAFLD.

WITHDRAWN: Pulp management for caries in adults: maintaining pulp vitality.

BACKGROUND: There is a range of treatment options for the management of the pulp in extensively decayed teeth. These include direct and indirect pulp capping, pulpotomy or pulpectomy. If the tooth is symptomatic or if there are periapical bone changes, then endodontic treatment is required. However, if the tooth is asymptomatic but the caries is extensive, there is no consensus as to the best method of management. In addition, there has been a recent move towards using alternative materials and methods such as the direct or indirect placement of bonding agents and mineral trioxide aggregate.Most studies have investigated the management of asymptomatic carious teeth with or without an exposed dental pulp using various capping materials (e.g. calcium hydroxide, Ledermix, Triodent, Biorex, etc.). However, there is no long term data regarding the outcome of management of asymptomatic, carious teeth according to different regimens. OBJECTIVES: This study aims to assess the effectiveness of techniques used to treat asymptomatic carious teeth and maintain pulp vitality. SEARCH METHODS: Electronic searches of the following databases were undertaken: The Cochrane Oral Health Group's Trials Register (March 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 1), MEDLINE (1966 to week 4, February 2006), EMBASE (1974 to 13 March 2006), National Research Register (March 2006), Science Citation Index - SCISEARCH (1981 to March 2006). Detailed search strategies were developed for each database. Handsearching and screening of reference lists were undertaken. There was no restriction with regard to language of publication. SELECTION CRITERIA: Studies included were randomised controlled trials (RCTs). Asymptomatic vital permanent teeth with extensive caries were included. Studies were those which compared techniques to maintain pulp vitality. Outcome measures included clinical success and adverse events. DATA COLLECTION AND ANALYSIS: Data were independently extracted by three review authors. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The Cochrane Collaboration's statistical guidelines were followed. MAIN RESULTS: Only four RCTs were identified. Interventions examined included: Ledermix, glycerrhetinic acid/antibiotic mix, zinc oxide eugenol, calcium hydroxide, Cavitec, Life, Dycal, potassium nitrate, dimethyl isosorbide, and polycarboxylate cement. Only one study showed a statistically significant finding; potassium nitrate/dimethyl isosorbide/polycarboxylate cement resulted in fewer clinical symptoms than potassium nitrate/polycarboxylate cement or polycarboxylate cement alone when used as a capping material for carious pulps. AUTHORS' CONCLUSIONS: It was disappointing that there were so few studies which could be considered as being suitable for inclusion in this review. The findings from this review do not suggest that there should be any significant change from accepted conventional practice procedures when the pulp of the carious tooth is considered. Further well designed RCTs are needed to investigate the potential of contemporary materials which may be suitable when used in the management of carious teeth. It is recognised that it is difficult to establish the 'ideal' clinical study when ethical approval for new materials must be sought and strict attention to case selection, study protocol and interpretation of data is considered. It is also not easy to recruit sufficient numbers of patients meeting the necessary criteria.

Replication analysis of genetic association of the NCAN-CILP2 region with plasma lipid levels and non-alcoholic fatty liver disease in Asian and Pacific ethnic groups.

BACKGROUND: The Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups. Recent genome-wide resequence studies identified a missense single-nucleotide polymorphism (SNP) (rs58542926) of the transmembrane 6 superfamily member 2 (TM6SF2) gene in the NCAN-CILP2 region related to hepatic triglyceride content. This study aims to analyze the influences of SNPs in this region on NAFLD and plasma lipid levels in the Asian and Pacific ethnic groups and to reveal the reasons behind positive and negative genetic associations dependent on ethnicity. METHODS: Samples and characteristic data were collected from 3,013 Japanese, 119 Palauan, 947 Mongolian, 212 Thai and 401 Chinese people. Hepatic sonography data was obtained from the Japanese individuals. Genotyping data of five SNPs, rs58542926, rs735273, rs1009136, rs1858999, and rs16996148, were used to verify the effect on serum lipid levels by multiple linear regression, and the association with NAFLD in the Japanese population was examined by logistic regression analysis. RESULTS: rs58542926 showed significant association with the plasma triglyceride (TG) level in Japanese (P = 0.0009, effect size = 9.5 (± 3.25) mg/dl/allele) and Thai (P = 0.0008, effect size = 31.6 (± 11.7) mg/dl/allele) study subjects. In Mongolian individuals, there was a significant association of rs58542926 with total cholesterol level (P = 0.0003, 11.7 (± 3.2) mg/dl/allele) but not with TG level. In multiple comparisons in Chinese individuals, rs58542926 was weakly (P = 0.022) associated with TG levels, although the threshold for statistical significance was not reached. In Palauan individuals, there was no significant association with the studied SNPs. rs58542926 also showed significant association with Japanese NAFLD. The minor allele (t) increased NAFLD risk (OR 1.682, 95 % CI 1.289-2.196, p value 0.00013). CONCLUSION: This study confirmed the genetic association of missense SNP of TM6SF2, rs58542926, with plasma lipid levels in multiple East Asian ethnic groups and with NAFLD in Japanese individuals.

Common variants of GIP are associated with visceral fat accumulation in Japanese adults.

Animal studies have demonstrated that glucose-dependent insulinotropic polypeptide (GIP) and GIP receptor (GIPR) contribute to the etiology of obesity. In humans, genomewide association studies have identified single nucleotide polymorphisms (SNPs) in the GIPR gene that are strongly associated with body mass index (BMI); however, it is not clear whether genetic variations in the GIP gene are involved in the development of obesity. In the current study, we assessed the impact of GIP SNPs on obesity-related traits in Japanese adults. Six tag SNPs were tested for associations with obesity-related traits in 3,013 individuals. Multiple linear regression analyses showed that rs9904288, located at the 3'-end of GIP, was significantly associated with visceral fat area (VFA). Moreover, rs1390154 and rs4794008 showed significant associations with plasma triglyceride levels and hemoglobin A1c levels, respectively. Among the significant SNPs, rs9904288 and rs1390154 were independently linked with SNPs in active enhancers of the duodenum mucosa, the main GIP-secreting tissue. The haplotypes of these two SNPs exhibited stronger associations with VFA. Numbers of VFA-increasing alleles of rs9904288 and BMI-increasing alleles of previously identified GIPR SNPs showed a strong additive effect on VFA, waist circumference, and BMI in the subject population. These novel results support the notion that the GIP-GIPR axis plays a role in the etiology of central obesity in humans, which is characterized by the accumulation of visceral fat.

Positive natural selection of TRIB2, a novel gene that influences visceral fat accumulation, in East Asia.

Accumulation of visceral fat increases cardiovascular mortality in industrialized societies. However, during the evolution of the modern human, visceral fat may have acted as energy storage facility to survive in times of famine. Therefore, past natural selection might contribute to shaping the variation of visceral fat accumulation in present populations. Here, we report that the gene encoding tribbles homolog 2 (TRIB2) influenced visceral fat accumulation and was operated by recent positive natural selection in East Asians. Our candidate gene association analysis on 11 metabolic traits of 5,810 East Asians revealed that rs1057001, a T/A transversion polymorphism in 3'untranslated region (UTR) of TRIB2, was strongly associated with visceral fat area (VFA) and waist circumference adjusted for body mass index (P = 2.7 × 10(-6) and P = 9.0 × 10(-6), respectively). rs1057001 was in absolute linkage disequilibrium with a conserved insertion-deletion polymorphism in the 3'UTR and was associated with allelic imbalance of TRIB2 transcript levels in adipose tissues. rs1057001 showed high degree of interpopulation variation of the allele frequency; the low-VFA-associated A allele was found with high frequencies in East Asians. Haplotypes containing the rs1057001 A allele exhibited a signature of a selective sweep, which may have occurred 16,546-27,827 years ago in East Asians. Given the predominance of the thrifty gene hypothesis, it is surprising that the apparently non-thrifty allele was selectively favored in the evolution of modern humans. Environmental/physiological factors other than famine would be needed to explain the non-neutral evolution of TRIB2 in East Asians.

Near-infrared light-inducible Z-scheme overall water-splitting photocatalyst without an electron mediator.

We facilely prepared a solid-state heterojunction photocatalyst in which silver vanadium oxide (Ag2V4O11) and zinc rhodium oxide (ZnRh2O4) as oxygen and hydrogen evolution photocatalysts, respectively, were directly connected to generate Ag2V4O11/ZnRh2O4. Ag2V4O11/ZnRh2O4 photocatalyzed overall pure-water splitting without any electron mediator under irradiation with near-infrared light at wavelengths of up to 910 nm. The key points are that the conduction bottom potential of Ag2V4O11 is almost the same as the valence band top potential of ZnRh2O4, and that the bandgaps of Ag2V4O11 and ZnRh2O4 are 1.4 and 1.2 eV, respectively.

Sex-specific Association of Primary Aldosteronism With Visceral Adiposity.

Context: The association between primary aldosteronism and obesity, especially its sex difference, remains unknown. Objective: To assess the association for each subtype of primary aldosteronism with obesity parameters including visceral adipose tissue and differences between sexes. Methods: In this case-control study, 4 normotensive controls were selected for each case with primary aldosteronism. Multivariable conditional logistic regression models were used to estimate the association between each type of primary aldosteronism and obesity indicators. We used a random forest to identify which visceral or subcutaneous tissue areas had a closer association with disease status. Results: The study subjects included 42 aldosterone-producing adenoma cases (22 women) and 68 idiopathic hyperaldosteronism cases (42 women). In multivariable conditional logistic regressions, aldosterone-producing adenoma was significantly associated with body mass index only in men (odds ratio [OR] [95% CI)], 4.62 [1.98-10.80] per 2.89 kg/m2) but not in women (OR [95% CI], 1.09 [0.69-1.72] per 3.93 kg/m2) compared with the matched controls, whereas idiopathic hyperaldosteronism was associated with body mass index in both men (OR [95% CI], 3.96 [2.03-7.73] per 3.75 kg/m2) and women (OR [95% CI], 2.65 [1.77-3.96] per 3.85 kg/m2) compared with the matched controls. In random forests, visceral adipose tissue areas were the better predictor of both aldosterone-producing adenoma and idiopathic hyperaldosteronism than subcutaneous adipose tissue. Conclusions: Aldosterone-producing adenoma cases were obese among men, but not among women. Idiopathic hyperaldosteronism cases were obese among both men and women. Visceral adipose tissue may contribute to the pathophysiology of primary aldosteronism.

Genome-Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate Locus.

Nonalcoholic fatty liver disease (NAFLD) is supposed to manifest its metabolic phenotype in the liver, but it is common to have lean individuals diagnosed with NAFLD, known as lean NAFLD. We conducted a two-stage analysis to identify NAFLD-associated loci in Japanese patients. In stage I, 275 metabolically healthy normal-weight patients with NAFLD were compared with 1,411 non-NAFLD controls adjusted for age, sex, and alcohol consumption by a genome-wide association study (GWAS). In stage II, human leukocyte antigen (HLA) in chromosome 6 (chr6) (P = 6.73E-08), microRNA (MIR) MIR548F3 in chr7 (P = 4.25E-07), myosin light chain 2 (MYL2) in chr12 (P = 4.39E-07), and glycoprotein precursor (GPC)6 in chr13 (P = 5.43E-07), as suggested by the GWAS, were assessed by single nucleotide polymorphism (SNP) association analysis of whole NAFLD against non-NAFLD in 9,726 members of the general population. A minor allele of the secondary lead SNP in chr6, rs2076529, was significantly associated (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.11-1.28; P = 2.10E-06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04-1.27; P = 6.19E-03) with increased NAFLD risk. Imputation-based typing of HLA showed a significant difference in the distribution of HLA-B, HLA-DR-beta chain 1 (DRB1), and HLA-DQ-beta chain 1 (DQB1) alleles in lean NAFLD GWAS. Next-generation sequence-based typing of HLA in 5,649 members of the general population replicated the significant difference of HLA-B allele distribution and the significant increase of the HLA-B*54:01 allele in whole NAFLD. Fecal metagenomic analysis of 3,420 members of the general population showed significant dissimilarity in beta-diversity analysis of rs2076529 and HLA-B*54:01 allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and HLA-B*54:01 allele carriers as in NAFLD. Conclusion: HLA was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota.

Interleukin-10 expression mediated by an adeno-associated virus vector prevents monocrotaline-induced pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH) is a fatal disease associated with inflammation and pathological remodeling of the pulmonary artery (PA). Interleukin (IL)-10 is a pleiotropic antiinflammatory cytokine with vasculoprotective properties. Here, we report the preventive effects of IL-10 on monocrotaline-induced PAH. Three-week-old Wistar rats were intramuscularly injected with an adeno-associated virus serotype 1 vector expressing IL-10, followed by monocrotaline injection at 7 weeks old. IL-10 transduction significantly improved survival rates of the PAH rats 8 weeks after monocrotaline administration compared with control gene transduction (75% versus 0%, P<0.01). IL-10 also significantly reduced mean PA pressure (22.8+/-1.5 versus 29.7+/-2.8 mm Hg, P<0.05), a weight ratio of right ventricle to left ventricle plus septum (0.35+/-0.04 versus 0.42+/-0.05, P<0.05), and percent medial thickness of the PA (12.9+/-0.3% versus 21.4+/-0.4%, P<0.01) compared with controls. IL-10 significantly reduced macrophage infiltration and vascular cell proliferation in the remodeled PA in vivo. It also significantly decreased the lung levels of transforming growth factor-beta1 and IL-6, which are indicative of PA remodeling. In addition, IL-10 increased the lung level of heme oxygenase-1, which strongly prevents PA remodeling. In vitro analysis revealed that IL-10 significantly inhibited excessive proliferation of cultured human PA smooth muscle cells treated with transforming growth factor-beta1 or the heme oxygenase inhibitor tin protoporphyrin IX. Thus, IL-10 prevented the development of monocrotaline-induced PAH, and these results provide new insights into the molecular mechanisms of human PAH.

The influence of wave reflection on left ventricular hypertrophy in hypertensive patients is modified by age and gender.

It has been established that a positive association exists between the augmentation index (AIx) and left ventricular mass (LVM) in hypertensives, but it remains unclear whether this association is affected by age or gender. The aim of the study was to assess the effect of age and gender on the association between carotid AIx and LVM in hypertensive patients. We performed arterial tonometry and echocardiography in 512 treated hypertensive patients who were divided into 4 groups by gender and age (older or younger than 65 years). Correlations between carotid AIx and echocardiographic indices were evaluated by univariable and multivariable models. In females, carotid AIx increased with age up to 60 years, but decreased thereafter. In univariable analyses, carotid AIx was positively correlated with the LVM index in younger females (r=0.25, p=0.04) and males (r=0.48, p<0.001), but not in the older age groups. Multivariable analyses showed that this positive correlation in younger males remained significant (beta=0.39, p<0.001) after adjusting for age, body mass index, and mean arterial pressure. In contrast, in the older subjects, carotid AIx was negatively correlated with relative wall thickness in females (beta= -0.14, p=0.034) and males (beta= -0.17, p=0.037) independent of age and mean arterial pressure. A significant association between carotid AIx and LVM index was seen only in younger males. The lack of any such association in older hypertensives can be explained by both the plateau in the values of carotid AIx, and the fact that LVM increased with age.

Elevated pulse amplification in hypertensive patients with advanced kidney disease.

The progression of chronic kidney disease (CKD) inverts the arterial stiffness gradient. However, central hemodynamic pressure profiles in CKD have not been fully examined. A cross-sectional study was performed to assess the relationship between the CKD stage and central hemodynamic processes. The study enrolled 2020 hypertensive patients who had undergone echocardiography and measurement of their serum creatinine levels. Radial tonometry was applied to all patients to measure central blood pressure. Patients were classified according to six CKD stages based on their estimated glomerular filtration rate. Central (PP2) and brachial pulse pressure (PP) were elevated at stages 3a and 3b, respectively. Diastolic blood pressure (DBP) was higher at stage 1 compared to the other stages. The left ventricular mass index was greater at CKD stages 3b-5 than that at stage 1. Either PP or PP2 was sensitive for detecting the presence of left ventricular hypertrophy (LVH). Age, weight, pulse rate, brachial blood pressure, and antihypertensive medication differed among the six stages. Pulse amplification (PA) adjusted for these confounders was the lowest in CKD stages 3a and 3b. The present observations support that cardiovascular risk is higher in CKD stages 3b and later. Our findings indicate that PA is inverted in CKD stages 4 and 5. The present results suggest that aortic stiffening and the subsequent elevation in PA during CKD progression relate to a reduction in the ability of PP2 to predict LVH.

Risk factors for nasal bleeding in patients undergoing transnasal gastrointestinal endoscopy.

Transnasal endoscopy is widely used in screening for upper gastrointestinal lesions because of less associated pain. Nasal bleeding is the most severe adverse effect, but specific risk factors have not been identified. The aim of this study is to identify risk factors for nasal bleeding during transnasal endoscopy. Nasal bleeding occurred in 160/3035 (5.3%) of patients undergoing transnasal endoscopy as part of health checkups. Patient data were retrospectively evaluated including anthropometric, medical, and life-style parameters with multiple logistic regression analysis. Multiple logistic regression revealed that nasal bleeding was significantly associated with age in decades [odds ratio/10 years 0.78, 95% confidence interval (CI) 0.63-0.97, p = 0.027], female gender (2.15, 95% CI 1.48-3.12, p < 0.001), a history of previous upper gastrointestinal endoscopy (0.55, 95% CI 0.36-0.82, p = 0.004), and chronic/allergic rhinitis (0.60, 95% CI 0.36-0.98, p = 0.043). Other factors including the use of antiplatelet and/or anticoagulant drugs were not significantly associated with nasal bleeding. Female and young patients are significantly associated with an increased risk of bleeding from transnasal endoscopy, but antiplatelet and/or anticoagulant medications and a history of chronic/allergic rhinitis may not be associated.

High central blood pressure is associated with incident cardiovascular events in treated hypertensives: the ABC-J II Study.

It is not established whether central blood pressure (BP) evaluated by a radial pulse wave analysis is useful to predict cardiovascular prognoses. We tested the hypothesis that central BP predicts future cardiovascular events in treated hypertensive subjects. We conducted a multicenter, observational cohort study of 3566 hypertensives being treated with antihypertensive medications at 27 institutions in Japan. We performed the radial pulse wave analyses using applanation tonometry in all subjects. The primary outcome was the incidence of any of the following: stroke, myocardial infarction (MI), sudden cardiac death, and acute aortic dissection. The mean age of the subjects was 66.0 ± 10.9 years, and 50.6% were male. The mean brachial SBP and central SBP were 138 ± 18 mm Hg and 128 ± 19 mm Hg, respectively. When the central SBP was divided into quintiles, the number of events was least in the 2nd quintile, and we set it as the reference. In the Cox regression analysis adjusting for age, sex, body mass index, creatinine, diabetes, use of ß-blocker, and history of MI/stroke, the patients in the 3rd (hazard ratio (HR) 3.55, 95% confidence interval 1.29-9.78, p = 0.014), 4th (HR 4.12, 95% CI 1.53-11.10, p = 0.005), and 5th quintiles (HR 2.87, 95% CI 1.01-8.18, p = 0.048) had a significantly higher incidence of cardiovascular events compared to the 2nd quintile. The results were essentially unchanged when brachial DBP was additionally adjusted. In conclusion, in treated hypertensives, high central SBP was associated with worse cardiovascular outcomes.

Mild hypertension in young Kurosawa and Kusanagi-hypercholesterolaemic (KHC) rabbits.

The coexistence of hypertension and hypercholesterolaemia from youth may increase the prevalence of and mortality from cardiovascular disease and stroke. We thus investigated haemodynamics of mild hypertension in young Kurosawa and Kusanagi-hypercholesterolaemic (KHC) rabbits aged 10-12 months old, as models of heritable hypercholesterolaemia. Pressure and flow waves were simultaneously recorded at the ascending aorta with a catheter-tip micromanometer and ultrasonic flow meter under pentobarbital anaesthesia, respectively. Systolic (119.3 +/- 6.5 and 138.4 +/- 7.4 mmHg (mean +/- SD) for control and KHC rabbit groups; p < 0.001), diastolic (95.7 +/- 6.1 and 109.8 +/- 5.2; p < 0.001), mean (105.8 +/- 6.5 and 122.5 +/- 4.9; p < 0.001) and pulse (23.7 +/- 2.5 and 28.6 +/- 4.0; p < 0.001) pressures as well as total peripheral vascular resistance (0.32 +/- 0.02 and 0.37 +/- 0.03 mmHg/ml/min; p < 0.001) were significantly greater in the KHC rabbit group than those in the age-matched control rabbit group, respectively, while there were no significant differences in the mean aortic flow, heart rate or stroke volume between the two rabbit groups. Aortic input impedance (p < 0.05) and reflection coefficient (p < 0.05) were significantly greater at lower frequency in the KHC rabbit group than in the control rabbit group, whereas there was no significant difference in the characteristic impedance between the two rabbit groups. Plasma angiotensin I (p < 0.01) and II (p < 0.01) levels and serum angiotensin converting enzyme activity (p < 0.05) were significantly greater in the KHC rabbit group than in the age-matched control rabbit group. Atheromatous plaque was in the early stage and composed mainly of abundant foam cells. Neither sclerotic lesions nor stenosis were observed in main peripheral arteries. The mild hypertension in young KHC rabbits was due partly to the increased activity of the renin-angiotensin system. These findings may be thought provoking in elucidating the mechanism and developing preventive and therapeutic strategies in young patients with coexistent hypertension and hypercholesterolaemia.

Changes in Central Hemodynamics in Women With Hypertensive Pregnancy Between Before and After Delivery.

The authors tested the hypothesis that central hemodynamic parameters in women with hypertensive disorders of pregnancy (HDP) change between before and after delivery. A total of 137 pregnant women were studied: 72 with HDP, 42 with chronic hypertension (CH), and 23 with white-coat hypertension (WCH; control group). Aortic augmentation index adjusted by heart rate 75 beats per minute (AIx@75), central pulse pressure (PP), total peripheral resistance (TPR), and cardiac output (CO) before and after delivery were recorded. AIx@75 and central PP were higher in the HDP group than in the control group, but both parameters declined after delivery until they were similar to the controls. AIx@75 and central PP, but not TPR or CO, were significantly decreased after delivery in the HDP group, but no such effects were seen in the other groups. These findings suggest that increased wave reflection caused by the stiffened aorta could be a key factor in the pathophysiology of HDP.

Why the radial augmentation index is low in patients with diabetes: The J-HOP study.

BACKGROUND: Radial augmentation index (rAI), a marker of aortic wave reflection, is usually lower in patients with diabetes (DM) than in non-DM subjects, even though atherosclerotic change is advanced in DM. OBJECTIVE: We sought to explore why rAI in DM is lower than in non-DM. METHODS: We performed radial applanation tonometry in 1787 subjects who had at least one cardiovascular risk factor. The rAI was defined as [late systolic shoulder pressure amplitude (PP2)]/[radial pulse pressure (rPP)]. The late systolic shoulder blood pressure (SBP2) and PP2 of a radial pressure wave were used as estimates of the central SBP and PP (cPP), respectively. RESULTS: The age (65.8 ± 9.8 vs. 65.8 ± 12.1 yrs) and mean brachial SBP (141 ± 16 vs. 141 ± 17 mmHg) were similar between the DM and non-DM groups. The rAI was significantly lower in the DM group (83.3 ± 14.1 vs. 87.3 ± 15.7%, p < 0.001), but clinic PP (62 ± 14 vs. 59 ± 14 mmHg, p < 0.001) and cPP (51 ± 15 vs. 49 ± 15 mmHg, p = 0.019) were significantly greater in the DM group than in the non-DM group. In multivariable analyses adjusting for covariates, the significant determinants of rAI were the estimated glomerular filtration rate (eGFR) (ß = 0.17, p < 0.001) in the DM group, and the log-transformed homeostatic model assessment of insulin resistance (HOMA-IR) (ß = -0.15, p < 0.001) in the non-DM group. The same trends were also seen for central SBP and cPP. CONCLUSIONS: The lower rAI in DM associated with higher cPP compared to non-DM suggests proximal conduit-predominant arterial stiffening causing reduced reflection coefficients at systemic reflection sites. As renal function decreases, a cPP increase may overcome the increase of augmentation pressure in the DM group.

[Reduced arterial compliance with advancing age].

The term "compliance" is generally used as softness of the arterial wall. Fundamentally, compliance characterizes property of a chamber, being defined as deltaV/deltaP. It implies that how easily volume (V) of the chamber changes in response to unit pressure (P) change. However, in reality, the arterial system is not such a simple chamber but a complicated branched tubing system, in which compliance components are distributed along the tubing. It can be simplified as a single tube model, in which we can regard compliance as the sum of proximal portion as a determinant of characteristic impedance of the aorta and distal portion consisting of terminal impedance of the peripheral arterial bed. Such distributed model enables us to simulate pulse wave propagation and reflection, actually occurred in real arteries. This paper deals with parameters relating to arterial compliance corresponding to such distributed model. Arterial compliance is reduced with advancing age. This phenomenon has been widely recognized by epidemiological studies on blood pressure, in which systolic and pulse pressures are increased with aortic reflection without significant change in diastolic pressure. Also, many investigators reported age-dependent compliance declines by assessing compliance-relating parameters including cross-sectional compliance, pulse wave velocity and augmentation index. This reduced compliance may affect the heart as a pulsatile afterload and adversely alter myocardial energy balance.

AAV-mediated VEGF gene transfer into skeletal muscle stimulates angiogenesis and improves blood flow in a rat hindlimb ischemia model.

OBJECTIVES: Clinical trials on therapeutic angiogenesis using vascular endothelial growth factor (VEGF) are ongoing, however the benefits of these therapies are still controversial. To establish a more efficient gene transfer method for ischemic diseases, we investigated the therapeutic potential of adeno-associated virus (AAV)-mediated VEGF gene transfer. METHODS: We produced VEGF(165)-expressing AAV vectors (AAV-VEGF). HEK-293 cells were transduced with AAV-VEGF in vitro and VEGF expression and secretion were examined. We used a rat ischemic hindlimb model and AAV-VEGF was administered intramuscularly into the ischemic limb. Gene expression was evaluated by RT-PCR and ELISA. Six weeks after gene transfer, we measured the blood flow of limb vessels and the skin temperature of limbs. Histochemical examination was performed to illustrate capillary growth. RESULTS: Western blotting and ELISA revealed VEGF protein expression and secretion from AAV-VEGF-transduced HEK-293 cells. VEGF mRNA and protein expression was consistently observed in the injected muscle at least 10 weeks after the injection, while no VEGF mRNA could be detected at remote organs. The mean blood flow in AAV-VEGF-transduced ischemic limbs was significantly higher than in AAV-LacZ-transduced limbs. Capillary density was significantly higher in AAV-VEGF-injected tissues than in AAV-LacZ-injected tissues. CONCLUSIONS: This study demonstrates that (1) AAV-mediated VEGF gene transfer into rat skeletal muscles is efficient and stable without ectopic expression, and (2) AAV-mediated VEGF gene transfer stimulates angiogenesis and thereby improves blood flow in a rat hindlimb ischemia model. These findings suggest that AAV-mediated VEGF gene transfer may be useful for treatment of ischemic diseases.