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.

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.

A case of aortic valve laceration after balloon aortic valvuloplasty with morphological features.

A 71-year-old man suffered from congestive heart failure due to severe aortic stenosis. We performed balloon aortic valvuloplasty (BAV) as a bridge to transcatheter aortic valve replacement using transesophageal echocardiogram (TEE) by the retrograde approach. Balloon dilatation was carefully performed using an 18 mm balloon. After balloon dilation, TEE showed right coronary cusp (RCC) laceration and severe aortic regurgitation. We discontinued the procedure despite the incomplete result. Aortic valve laceration is a rare complication considered to be mainly caused by the use of large balloon or by balloon slipping. In the present case, TEE showed that the commissure of RCC fused strongly with both the other cusps by thick calcification, and the center of RCC had a spotty low echoic area with soft tissue. The force of the balloon dilatation concentrated to soft tissue area and lacerated the center of RCC. We verified the finding in the operative specimen. When performing BAV, we should pay attention to the morphology of the aortic valve using TEE to avoid aortic valve laceration as a fatal complication. .

Effective treatment of congestive heart failure using adaptive servo-ventilation in an end-stage renal disease patient on hemodialysis.

A 61-year-old man who was being treated with hemodialysis (HD) for end-stage renal disease presented with symptoms of severe congestive heart failure (CHF). Removing excess intravascular fluid during HD was difficult due to the patient's chronic hypotension induced by severe left ventricular (LV) dysfunction. The application of adaptive servo-ventilation (ASV) increased the patient's cardiac output and blood pressure during HD, thus resulting in the effective removal of excess intravascular fluid. Therefore, ASV may be effective for treating CHF in HD patients with LV dysfunction and chronic hypotension.

Superoxide dismutase mimetic, tempol, aggravates renal injury in advanced-stage stroke-prone spontaneously hypertensive rats.

OBJECTIVE: The aim of this study was to determine whether antioxidant therapy could relieve hypertension and retard the progression of renal damage in advanced-stage hypertensive rats. METHODS: Twenty-four-week-old spontaneously hypertensive stroke-prone rats were treated for 8 weeks with the superoxide dismutase mimetic tempol, low-dose or high-dose candesartan (an angiotensin receptor blocker), or hydralazine, and blood pressure and renal damage were compared. RESULTS: Elevated blood pressure and renal damage with heterogeneity were present after 8 weeks, with greater glomerulosclerosis in the juxtamedullary glomeruli than in the superficial glomeruli. Although both tempol and candesartan effectively reduced reactive oxygen species production in the kidney, tempol did not decrease blood pressure and exacerbated urine protein and histological damage, such as glomerulosclerosis and interstitial fibrosis, particularly in juxtamedullary nephrons (tempol vs. untreated: glomerulosclerosis index, 2.0 vs. 1.5, P<0.01; fibrosis, 15 vs. 10%, P<0.001). In contrast, high-dose candesartan and hydralazine prevented these forms of renal damage with lowering blood pressure. Low-dose candesartan also prevented this renal damage without lowering blood pressure. Moreover, there were increased numbers of larger and smaller glomeruli in the juxtamedullary cortex of tempol-treated rats, suggesting that changes in glomerular hemodynamics may be responsible for the exacerbation of glomerulosclerosis. Both candesartan- and hydralazine-treated rats had glomeruli that were slightly decreased in size. CONCLUSION: These results suggest that single-antioxidant therapy starting at an advanced-stage may be ineffective for hypertension and rather exacerbate renal damage in nonsalt loaded SHRSP. Furthermore, lowering blood pressure and inhibiting the renin-angiotensin system could be critical for slowing the progression of hypertensive renal damage at an advanced stage.

Pioglitazone, a thiazolidinedione derivative, attenuates left ventricular hypertrophy and fibrosis in salt-sensitive hypertension.

Thiazolidinediones, which stimulate peroxisome proliferator-activated receptor gamma, have been shown to prevent cardiovascular injury. However, little is known about their effects on salt-sensitive hypertension. We thus investigated whether or not pioglitazone affects left ventricular (LV) hypertrophy in Dahl salt-sensitive rats, then compared its effects to those of an angiotensin II receptor blocker, candesartan. Rats were used at 16 weeks of age after they had been fed either a low-salt (0.3%; DSL) or high-salt (8%; DSH) diet for 10 weeks; some of the DSH rats were treated with pioglitazone (10 mg/kg/day) or candesartan (4 mg/kg/day). Both drugs decreased the elevated blood pressure in DSH rats, although it was still higher than in DSL rats. Both drugs decreased plasma insulin levels, but neither affected plasma glucose levels. The thiobarbituric acid reactive substance level in the LV was decreased by both drugs. LV hypertrophy evaluated by echocardiography in DSH rats was nearly normalized by both drugs, whereas only candesartan decreased LV diameter. In histological analysis, both drugs ameliorated LV fibrosis and myocardial cell hypertrophy. Both drugs decreased elevated gene expression levels of transforming growth factor-beta1 and collagen type I, although the pioglitazone action was slightly modest. The metalloproteinase activity was increased in DSH rats, but both drugs decreased this level. Taken together, these findings indicate that pioglitazone reduced LV hypertrophy and fibrosis in salt-sensitive hypertension. Improvement in blood pressure, insulin level, and oxidative stress may be associated with this beneficial action of pioglitazone.

Beneficial effects of pioglitazone on left ventricular hypertrophy in genetically hypertensive rats.

Beneficial effects of thiazolidinediones, peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, on cardiovascular injuries have been reported. However, the effects of these agonists on left ventricular (LV) hypertrophy have not been clarified. To investigate whether pioglitazone improves LV hypertrophy, we used 32-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) that had been treated or not treated with pioglitazone (10 mg/kg/day) for 8 weeks, and Wistar Kyoto rats (WKY). We evaluated LV geometry by echocardiography; myocyte hypertrophy, tissue fibrosis, and appearance of myofibroblasts by histological examination; mRNA expression by real-time polymerase chain reaction (PCR); protein expression by Western blot; activities of matrix metalloproteinase (MMP) by zymography; and production of reactive oxygen species (ROS) by electron spin resonance spectroscopy or thiobarbituric acid reactive substances (TBARS). SHR-SP showed concentric hypertrophy of the LV, but WKY did not. The myocyte diameter, fraction of tissue fibrosis, and number of myofibroblasts were greater in SHR-SP. mRNA expressions of collagen type I and type III, tissue growth factor (TGF)-beta1, and brain natriuretic peptide (BNP); protein expression of connective tissue growth factor (CTGF); activities of MMP2 and MMP9; and ROS were increased in SHR-SP. Pioglitazone did not decrease blood pressure, but partially normalized LV geometry in addition to decreasing myocyte diameter, interstitial fibrosis and number of myofibroblasts; mRNA levels of collagen type I and BNP; MMP2 activity; and protein level of CTGF. However, the mRNA level of collagen type III and TGF-beta1, MMP9 activity, and ROS production were not improved. In conclusion, pioglitazone reversed the concentric LV remodeling independently from blood pressure or oxidative stress in chronic hypertension.

Spsgt1, a new essential gene of Schizosaccharomyces pombe, is involved in carbohydrate metabolism.

hSGT1 (human suppressor of Gcr two) was isolated as a suppressor gene of the gcr2 mutation. Since Gcr2p is a key regulatory factor of glycolytic gene expression in Saccharomyces cerevisiae, hSGT1 is a candidate for a novel human transcription factor involved in carbohydrate metabolism. SGT1 appears to be conserved from Schizosaccharomyces pombe to human but not present in S. cerevisiae. To further study its function, we cloned the hSgt1p orthologue of Sz. pombe (Spsgt1) from Sz. pombe genomic DNA. Overall identity and similarity between SpSgt1p and hSgt1p are 24% and 37%, respectively. Disruption of Spsgt1 showed that Spsgt1 is essential for growth and, using a construct which conditionally expresses sgt1, which with low level expression growth was severely affected on glucose but normal on non-fermentable carbon sources. DNA microarray analyses showed that the transcription of many genes involved in carbohydrate metabolism and amino acid metabolism were upregulated in the mutant, suggesting that SpSgt1p may be involved in the regulation of carbohydrate metabolism. Furthermore, a GFP fusion of SpSgt1p was localized to the nucleus, fitting with the possibility of SpSgt1p as a transcription factor.

Expression of GCR1, the transcriptional activator of glycolytic enzyme genes in the yeast Saccharomyces cerevisiae, is positively autoregulated by Gcr1p.

When regulation of GCR1 expression was analysed using a GCR1-lacZ fusion, lacZ expression levels were decreased in the Deltagcr1 or Deltagcr2 mutant. RT-PCR analysis of genomic GCR1 transcript confirmed the dependency of GCR1 expression on the Gcr1p-Gcr2p complex. Examination of the 5' non-coding region of GCR1 identified three putative Gcr1p binding sites (CT-boxes) in the -100 to -200 region of GCR1, and the putative binding sites for Rap1p (RPG-box) and Abf1p were also identified nearby. The region containing putative cis-elements was analysed by cloning it upstream of the CYC1TATA-lacZ fusion. The GCR1(UAS)-CYC1TATA-lacZ fusion showed a moderate activity and, as expected, the activity was drastically reduced in the Deltagcr1 or Deltagcr2 mutant. Systematic deletion and mutation analyses of cis-elements in this region demonstrated that the putative binding sites for Rap1p and Abf1p were not involved in the promoter activity of GCR1(UAS) and only one of the three CT-boxes showed GCR1- and GCR2-dependent promoter activity. In contrast to the expression of glycolytic genes, where a RPG-box adjacent to the CT-box is required for strong promoter activities, CT-box-dependent expression of GCR1 did not require the RPG-box. Also, a contribution of Sgc1p, an E-box binding transcription factor, to the expression of GCR1 was suggested, based on its disruption analysis.

Role of the N-terminal region of Rap1p in the transcriptional activation of glycolytic genes in Saccharomyces cerevisiae.

In the yeast two-hybrid system, the N-terminal region of Rap1p was shown to interact with Gcr1p and Gcr2p. Disruption of gcr1 and/or gcr2 in the two-hybrid reporter strain demonstrated that the interaction with Gcr1p does not require Gcr2p, whereas the interaction with Gcr2p is mediated through Gcr1p. Deletion of the N-terminal region of Rap1p alone did not show a growth phenotype, but a growth defect was observed when this mutation was combined with a gcr2 deletion. The poor growth of the gcr1 null mutant was not affected further by the N-terminal deletion of Rap1p, but the growth of gcr1 strains with mutations in the DNA binding region of Gcr1p was affected by the removal of the N-terminal region of Rap1p. These results suggest that one function of the N-terminal region of Rap1p, presumably the BRCT domain, is to facilitate the binding of Gcr1p to the promoter by a protein-protein interaction.

Isolation and characterization of Candida albicans homologue of RAP1, a repressor and activator protein gene in Saccharomyces cerevisiae.

To study the function of RAP1, a Candida albicans gene (CaRAP1) that shows sequence similarity to RAP1 of Saccharomyces cerevisiae was isolated by colony hybridization. DNA sequencing predicted an open reading frame of 429 amino acids with an overall identity of 24% to the ScRap1p. The DNA binding domain (DBD) was highly conserved, and EMSA using a GST-CaRap1p fusion protein confirmed its binding ability to the RPG-box of S. cerevisiae ENO1. In contrast, the N-terminus was less conserved and a moderate homology was observed in the BRCT domain. Interestingly, CaRap1p did not contain the C-terminal activation/repression region of ScRap1p.