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Background: Ascending and abdominal aortic aneurysms (AAs) are asymptomatic, permanent dilations of the aorta with surgical intervention as the currently available therapy. Hippo-Yap signaling cascade plays a critical role in stem cell self-renewal, tissue regeneration and organ size control. By using XMU-MP-1, a pharmacological inhibitor of the key component of Hippo-Yap signaling, MST1/2, we examined the functional contribution of Hippo-Yap in the development of AAs in Angiotensin II (AngII)-infused hypercholesterolemic mice. Methods and Results: MST, p-MST, p-YAP, p-MOB and TAZ proteins in AngII-infused ascending and abdominal aortas were assessed by immunohistochemical and western blot analyses. To examine the effect of MST1/2 inhibition on AAs, western diet-fed low density lipoprotein (LDL) receptor −/− mice infused with AngII were administered with either vehicle or XMU-MP-1 for 5 weeks. Hippo-YAP signaling proteins were significantly elevated in AngII infused ascending and abdominal aortas. XMU-MP-1 administration resulted in the attenuation of AngII-induced ascending AAs without influencing abdominal AAs and aortic atherosclerosis. Inhibition of Hippo-YAP signaling also resulted in the suppression of AngII-induced matrix metalloproteinase 2 (MMP2) activity, macrophage accumulation, aortic medial hypertrophy and elastin breaks in the ascending aorta. Conclusions: The present study demonstrates a pivotal role for the Hippo-YAP signaling pathway in AngII-induced ascending AA development.

miR-146a, an anti-inflammatory microRNA, is shown to be a negative regulator of adipocyte inflammation. However, the functional contribution of miR-146a in the development of obesity is not defined. In order to determine whether miR-146a influences diet-induced obesity, mice that were either wild type (WT) or miR-146a deficient (KO) were fed with high (60% kcal) fat diet (HFD) for 16 weeks. Deficiency of miR-146a did not influence obesity measured as HFD-induced body weight and fat mass gain, or metabolism of glucose and insulin tolerance. In addition, adipocyte apoptosis, adipose tissue collagen and macrophage accumulation as detected by TUNEL, Picro Sirius and F4/80 immunostaining, respectively, were comparable between the two groups of mice. Although, miR-146a deficiency had no influence on HFD-induced hepatic lipid accumulation, interestingly, it significantly increased obesity-induced inflammatory responses in liver tissue. The present study demonstrates that miR-146a deficiency had no influence on the development of HFD-induced obesity and adipose tissue remodeling, whereas it significantly increased hepatic inflammation in obese mice. This result suggests that miR-146a regulates hepatic inflammation during development of obesity.

Aim Since 1998, the leading cause of chronic hemodialysis in Japan has been diabetic nephropathy. Diabetes mellitus is known to be a risk factor for frailty, but it still remains unknown whether diabetic nephropathy is associated with frailty in chronic dialysis patients. The authors carried out the present study to reveal the association between frailty and diabetic nephropathy in chronic hemodialysis patients. Methods A total of 355 patients who were on hemodialysis were recruited. Participants were divided into two groups of either patients who suffered diabetic nephropathy with end-stage renal disease (DN group, n = 150) or not (Non-DN group, n = 205). The authors investigated the difference of the prevalence of frailty between the two groups. Furthermore, the authors examined the risk factors for frailty. Results The prevalence of frailty in the DN group was significantly higher than that in the Non-DN group (28.0% vs 16.5%, P = 0.0161). To evaluate the association between frailty and its risk factors, we compared frail patients (n = 71) and non-frail patients (n = 262). After adjusting their interrelationships by using multivariate logistic regression analysis, diabetic nephropathy was determined as a significant risk factor for frailty. Conclusions The authors found the close association between frailty and diabetic nephropathy in chronic hemodialysis patients. Geriatr Gerontol Int 2018; 18: 1597-1602.

ObjectivesThe clinical condition of frailty is a common problem in the elderly population. However, the relationship between peripheral artery disease and frailty in hemodialysis patients remains unknown. The aim of this study was to identify the relationships between peripheral artery disease and frailty in Japanese chronic hemodialysis patients.MethodsA total of 362 chronic hemodialysis patients who regularly visited six institutions were enrolled. To evaluate frailty, the modified Fried’s frailty phenotype adjusted for Japanese were used. Peripheral artery disease was defined as ankle-brachial index ResultsOf 362 patients, 62 patients (17.1%) were categorized as peripheral artery disease group and 300 patients (82.9%) as Non-peripheral artery disease group. The prevalence of frailty in the peripheral artery disease group was significantly higher than in the Non-peripheral artery disease group (34% vs. 18%, P = 0.0103). Non-shunt side grip strength was significantly stronger in the Non-peripheral artery disease group (23.6 kg vs. 17.0 kg, P ConclusionsIt is concluded that peripheral artery disease is closely associated with frailty in hemodialysis patients.

Introduction: Autologous snuff-box arteriovenous fistula (sAVF) is the first choice procedure as the primary AVF for chronic hemodialysis at this institution. The patency of the autologous AVF in the forearm was reported to be 43% to 85% at 1 year and 40 % to 69 % at 2 years. However, little is known about the patency of sAVF alone to date. In addition, there is a paucity of evidence for risk factors of its failure. Objectives: The purpose of this study was to describe the patency of sAVF and to verify the risk factors for its failure. Methods: Clinical records were retrospectively reviewed in 185 patients (114 male and 71 female patients) who underwent sAVF creation at our institution between March 2011 and December 2016. The average age was 64 ± 14 years (range, 23 to 90 years). The sAVF was created in the left and right arms in 155 patients and 30 patients, respectively. Nine patients had collagen vascular disease (CVD). Results: The primary patency rates were 93.0%, 66.9%, and 59.0% at 1 month, 1 year, and 2 years after surgery, respectively. The secondary patency rates were 98.9%, 89.3%, and 85.4% at 1 month, 1 year, and at 2 years after surgery, respectively. On multivariate analysis, female gender ( P = 0.002), sAVF creation in the right arm ( P = 0.013), and steroid use ( P = 0.019) were the significant risk factors for the decreased primary patency rate. CVD ( P = 0.001) and steroid use ( P = 0.005) were the significant risk factors for the decreased secondary patency rate. Conclusions: The patency rate of sAVF in our institution was comparable to previously reported patency rates for the forearm AVF. A careful observation for sAVF is needed in patients with female gender, history of smoking, sAVF creation in the right arm, CVD, and steroid use.

Objective: Chronic angiotensin II (AngII) infusion promotes both ascending (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Previously, we demonstrated that exogenous vasohibin-2 (VASH-2) exacerbated AngII-induced TAAs in normolipidemic mice. The purpose of this study was to examine whether exogenous VASH-2 influenced AngII-induced AAAs in mice. Methods and Results: In the initial study, male C57BL/6J mice (10 weeks old) were injected with VASH2 or LacZ expressing adenovirus (Ad; 7.5 x 109 vp/100 μ L) via tail vein at 2 week intervals. One week after the first injection, subcutaneous infusion of AngII (1,000 ng/kg/min) by mini osmotic pumps was initiated for 3 weeks. Consequently, mice were divided into 2 groups: AngII + Ad VASH2 in C57BL/6J mice (n=22) and AngII + Ad LacZ in C57BL/6J mice (n=21). VASH-2 overexpression had no effect on systolic blood pressure, heart rate, body weight, or serum total cholesterol concentrations. Exogenous VASH-2 did not affect ex vivo measurements of maximal diameters of abdominal aortas (AngII + Ad VASH2; 1.36 ± 0.39 mm, AngII + LacZ 1.34 ± 0.24 mm, n.s.) in AngII-infused mice. In a subsequent study, male apolipoprotein E-deficient (apoE-/-) mice (9 to 13 weeks old) were injected with VASH2 or LacZ as described for C57BL/6J mice. Consequently, mice were divided into 2 groups: AngII + Ad VASH2 in apoE-/- mice (n=14) and AngII + Ad LacZ in apoE-/- mice (n=14). Similarly, overexpression of VASH-2 had no effect on systolic blood pressure, heart rate, body weight, or serum total cholesterol concentrations in apoE-/- mice. Furthermore, exogenous VASH-2 did not affect ex vivo measurement of maximal diameter of abdominal aorta (AngII + Ad VASH2; 1.70 ± 0.61 mm, AngII + Ad LacZ; 1.61 ± 0.43 mm, n.s.) in AngII-infused apoE-/- mice. Conclusion: Despite our previous demonstration of the effects on TAA, exogenous VASH-2 did not influence AngII-induced AAA formation in either normolipidemic or apoE-/- mice.

Rationale: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. Objective: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. Methods and Results: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P =0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P =0.049), improved somatic growth ( P =0.0005), reduced heart failure status ( P =0.003), and lower incidence of coil occlusion for collaterals ( P =0.007). Conclusions: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01273857.

Objective: The clinical condition of frailty is a common problem in the elderly population. Chronic hemodialysis (HD) patients often have peripheral artery disease (PAD) as a vascular complication. However, the relationship between PAD and frailty in Japanese HD patients remains unknown. The aim of this study was to identify the relationships among PAD and risk factors in Japanese chronic HD patients. Method: This study was a multi-center, cross-sectional and observational investigation which was conducted at 6 institutions, including 5 general hospitals and 1 private clinic. Subjects were all chronic HD patients who regularly visited the institutions. To evaluate frailty, we used the modified Fried’s frailty phenotype adjusted for Japanese as the self-reported questionnaire, and measured each physical domain. Furthermore, we calculated ankle-brachial index (ABI) to define PAD. PAD was defined as ABI < 0.9 in our study. Result: Of the 542 patients in all institutions, 362 were enrolled in this study. Sixty-two patients (17.1%) were categorized as PAD group and 300 patients (82.9%) as non-PAD group. In the PAD group, the prevalence of frailty was significantly higher than in the non-PAD group (34% vs 18%). Non-shunt side grip strength was significantly stronger in the non-PAD group (23.6 kg vs 17.0 kg, P P =0.0054). Univariate regression analyses showed that frailty, age, number of oral medicine, and history of myocardial infarction (MI) had significant correlations with PAD. Multivariate logistic regression analysis demonstrated that the factors independently associated with PAD were as follows: frailty (OR = 2.061, 95% C.I. 1.091-3.894) and MI (OR = 3.742, 95% C.I. 2.051-6.831). Conclusion: PAD is associated with frailty in HD patients.

The population undergoing dialysis is aging worldwide, particularly in Japan. The clinical condition of frailty is the most problematic expression in the elderly population. Potential pathophysiological factors of frailty present in patients with CKD and are accentuated in patients with ESRD. The aim of this study was to identify the prevalence and predictors of frailty in Japanese HD patients. This study was a multicenter, cross-sectional and observational investigation conducted at 6 institutions. To evaluate frailty, the modified Fried's frailty phenotype adjusted for Japanese as the self-reported questionnaire was used. Of the 542 patients visiting each institution, 388 were enrolled in this study. In total, 26.0% of participants were categorized as not-frailty, 52.6% as pre-frailty and 21.4% as frailty. The prevalence of frailty increased steadily with age and was more prevalent in females than in males and the subjects with frailty received polypharmacy. A multivariate logistic regression analysis revealed that the factors independently associated with frailty were the following: female gender (odds ratio [OR] = 3.661, 95% confidence interval [CI] 1.398-9.588), age (OR = 1.065, 95% CI 1.014-1.119), age ≥ 75 years old (OR = 4.892, 95% CI 1.715-13.955), body mass index (BMI) < 18.5 (OR = 0.110, 95% CI 0.0293-0.416), number of medications being taken (OR = 1.351, 95% CI 1.163-1.570), diabetes mellitus (DM) (OR = 2.765, 95% CI 1.081-7.071) and MNA-SF ≤ 11 (OR = 7.405, 95% CI 2.732-20.072). Frailty was associated with the accumulation of risk factors. The prevalence of frailty in Japanese patients with HD was relatively lower than that previously reported in Western developed countries; however, it was extremely high compared to the general population regardless of age. Our findings suggest that frailty might be associated with an increase in the prevalence of adverse health outcomes in patients with HD.

Background: Cilostazol, a phosphodiesterase-3 inhibitor, plays vasoprotective roles such as an improvement of endothelial function, a vasodilatation and a suppression of proliferation of vascular smooth muscle cells. The aim of study was to investigate a cardioprotective effect of cilostazol. Method: Male apolipoprotein E deficient mice (8-12 weeks old) were fed with either normal chow diet or cilostazol-containing (0.1% wt/v) diet. After 1 week of cilostazol administration, mice were infused subcutaneously with either angiotensin II (AngII, 1,000 ng/kg/min, n = 16 - 19) or saline (n = 5 - 6) by osmotic minipumps for 4 weeks. Results: AngII equivalently increased systolic blood pressure, irrespective of cilostazol administration. Cilostazol had no effect on serum cholesterol concentrations, triglycerides, high-density lipoprotein-cholesterol, body weights, heart rates, and systolic blood pressures. AngII increased heart weight but was attenuated by cilostazol administration (6.7±0.8 to 6.0±0.7 mg/gBW, p < 0.05). Cilostazol prevented both perivascular and interstitial cardiac fibrosis induced by AngII (p < 0.05, each). Quantitative real-time PCR revealed that mRNA expressions of Ctgf , Collagen I , Collagen III , Tgf- , Hgf and Spp-1 increased by AngII infusion but were attenuated by cilostazol administration (p < 0.05). Immunohistochemical analysis demonstrated that AngII administration enhanced OPN expression in heart but was suppressed by cilostazol administration. Further, to investigate the mechanism, human cardiac myocytes were cultured and stimulated with AngII (1x10 -7 M). Co-treatment of Cilostazol (1x10 -7 to 1x10 -5 M) attenuated AngII-induced increase of Spp-1 gene expression in dose-dependent manner. This effect was mimic by a treatment with forskolin, which was diminished by co-treatment with H-89. Conclusion: Cilostazol attenuated AngII-induced cardiac fibrosis in vivo. Cilostazol attenuated AngII-induced increment of Spp-1 gene expression through cAMP-PKA dependent pathway.

Objective: Abdominal aortic aneurysm (AAA) is the most common aortic aneurysm. Chronic kidney disease (CKD) and diabetes mellitus (DM) are considered as risk factors for cardiovascular diseases. However, the association between CKD and AAA remains unknown. Although DM has been reported to exert protective effect on the incidence and development of AAA in western population, such protective role of DM was not explored in the Asian population. The purpose of this study was to determine the relationship of CKD and DM and the presence of AAA. We performed a cross-sectional retrospective case-control study in Asian population. Methods and Results: We enrolled 261 patients with AAA (AAA+) and age-and-sex matched 261 patients without AAA (AAA-) at two hospitals between 2008 and 2014, and examined the association between the risk factors and the presence of AAA. Furthermore, to investigate AAA prevalencein each group, we enrolled 1126 patients with CKD and 400 patients with DM. The presence of CKD in patients with AAA+ was significantly higher than that in patients with AAA- (AAA+; 65 %, AAA-; 52 %, P = 0.004). The presence of DM in patients with AAA+ was significantly lower than that in patients with AAA- (AAA+; 17 %, AAA-; 35 %, P < 0.001). A multivariate logistic regression analysis demonstrated that hypertension, ischemic heart disease and CKD were independent determinants, whereas, DM was the only independent protective factor, for the presence of AAA. The prevalence of AAA in patients with CKD 65 years old and above was 5.1 %, whereas, that in patients with DM 65 years old and above was only 0.6 %. Conclusion: CKD is a positively associated with the presence of AAA. In contrast, DM is a negatively associated with the presence of AAA.

Objective: Chronic angiotensin II (AngII) infusion promotes both ascending (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Previous studies demonstrated that vascular endothelial growth factor (VEGF) enhanced AngII-induced AAA formation, and VEGF significantly increased AngII-induced AAA diameter in hypercholesterolemic mice. Vasohibin-1 (VASH-1) is induced by VEGF and inhibits angiogenesis at the termination zone under various pathologic conditions such as those of tumors, arterial intimal thickening and retinal neovasucularization. In contrast, a VASH-1 homolog, Vasohibin-2 (VASH-2), promotes angiogenesis at the sprouting front. Therefore, we hypothesized that exogenous VASH-2 influences AngII-induced TAAs in normocholesterolemic mice. The purpose of this study was to examine whether VASH-2 influenced AngII-induced TAAs. Methods and Results: Male C57BL/6J mice (10 weeks old) were fed a normal laboratory diet. Mice were injected 10^9 plaque-forming unit VASH-2 or Lac Z expressing adenovirus (Ad) via tail vein every other week. They were also infused subcutaneously with either AngII (1,000 ng/kg/min) or saline by osmotic mini-pumps for 3 weeks. The study mice had 4 groups: AngII + Ad VASH-2 (n=23), AngII + Ad Lac Z (n=23), Saline + Ad VASH-2 (n=13), Saline + Ad Lac Z (n=9). There were no significant differences between 4 groups in body weight. Plasma total cholesterol and VEGF concentrations were significantly increased in AngII infused groups (P < 0.05). Mortality ratio was 8.7% in AngII + Ad VASH-2 group and 4.3% in AngII + Ad Lac Z group. Intima area of aortic arch was significantly larger in AngII + Ad VASH-2 group than in AngII + Ad Lac Z group (19.78 ± 0.40 mm^3 vs 17.70 ± 0.41 mm^3, P < 0.01). AngII infusion significantly increased ex vivo maximal diameters of abdominal aorta, but there was no significant difference between VASH-2- and Lac Z-injected mice. Conclusion: Exogenous VASH-2 exacerbated AngII-induced ascending aortic aneurysms in male C57BL/6 mice.

Background. Congenital heart diseases often involve chronic pressure overload of the right ventricle (RV) which is a major cause of RV dysfunction. Pulmonary artery (PA) banding has been used to produce animal models of RV dysfunction. We have devised a new and easier method of constricting the PA and compared it directly with the partial ligation method.Methods. Eight-week-old male Sprague-Dawley rats (240–260 g) were divided into three groups: sham operation, partial pulmonary artery ligation (PAL) procedure, and pulmonary artery half-closed clip (PAC) procedure. RV function and remodeling were determined by echocardiography and histomorphometry.Results. Surgical mortality was significantly lower in the PAC group while echocardiography revealed significantly more signs of RV dysfunction. At the 8th week after surgery RV fibrosis rate was significantly higher in the PAC group.Conclusions. This procedure of pulmonary artery banding in rats is easier and more efficient than partial ligation.

Author(s): Takeuchi, Hidemi; Okuyama, Michihiro; Uchida, Haruhito A; Kakio, Yuki; Umebayashi, Ryoko; Okuyama, Yuka; Fujii, Yasuhiro; Ozawa, Susumu; Yoshida, Masashi; Oshima, Yu; Sano, Shunji; Wada, Jun | Abstract: Background and aimsChronic kidney disease (CKD) and diabetes mellitus (DM) are considered as risk factors for cardiovascular diseases. The purpose of this study was to clarify the relationship of CKD and DM with the presence of abdominal aortic aneurysm (AAA).MethodsWe enrolled 261 patients with AAA (AAA+) and age-and-sex matched 261 patients without AAA (AAA-) at two hospitals between 2008 and 2014, and examined the association between the risk factors and the presence of AAA. Furthermore, in order to investigate the prevalence of AAA in each group, we enrolled 1126 patients with CKD and 400 patients with DM.ResultsThe presence of CKD in patients with AAA+ was significantly higher than that in patients with AAA- (AAA+; 65%, AAA-; 52%, P = 0.004). The presence of DM in patients with AAA+ was significantly lower than that in patients with AAA- (AAA+; 17%, AAA-; 35%, P l 0.001). A multivariate logistic regression analysis demonstrated that hypertension, ischemic heart disease and CKD were independent determinants, whereas, DM was a negatively independent determinant, for the presence of AAA. The prevalence of AAA in patients with CKD 65 years old and above was 5.1%, whereas, that in patients with DM 65 years old and above was only 0.6%.ConclusionCKD is a positively associated with the presence of AAA. In contrast, DM is a negatively associated with the presence of AAA in Japanese population.