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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.

Background: Chronic angiotensin II (AngII) infusion promotes ascending aortic dilation in C57BL/6J mice. Meanwhile, vasohibin-2 (VASH2) is an angiogenesis promoter in neovascularization under various pathologic conditions. The aim of this study was to investigate whether exogenous VASH2 influences chronic AngII-induced ascending aortic dilation. Methods and Results: Eight–ten-week-old male C57BL/6J mice were injected with adenovirus (Ad) expressing either VASH2 or LacZ. One week after the injection, mice were infused with either AngII or saline s.c. for 3 weeks. Mice were divided into 4 groups: AngII+VASH2, AngII+LacZ, saline+VASH2, and saline+LacZ. Overexpression of VASH2 significantly increased AngII-induced intimal areas as well as the external diameter of the ascending aorta. In addition, VASH2 overexpression promoted ascending aortic medial elastin fragmentation in AngII-infused mice, which was associated with increased matrix metalloproteinase activity and medial smooth muscle cell (SMC) apoptosis. On western blot analysis, accumulation of apoptotic signaling proteins, p21 and p53 was increased in the AngII+VASH2 group. Furthermore, transfection of human aortic SMC with Ad VASH2 increased p21 and p53 protein abundance upon AngII stimulation. Positive TUNEL staining was also detected in the same group of the human aortic SMC. Conclusions: Exogenous VASH2 exacerbates AngII-induced ascending aortic dilation in vivo, which is associated with increased medial apoptosis and elastin fragmentation.

Objective: Cytoskeletal structural proteins maintain cell structural integrity by bridging extracellular matrix with contractile filaments. During abdominal aortic aneurysm (AAA) development, (1) aortic medial degeneration is associated with loss of smooth muscle cell integrity and (2) fibrogenic mesenchymal cells mediate extracellular matrix remodeling. Calpains cleave cytoskeletal proteins that maintain cell structural integrity. Pharmacological inhibition of calpains exert beneficial effects on Ang II (angiotensin II)–induced AAAs in LDLR −/− (low-density receptor deficient) mice. Here, we evaluated the functional contribution of fibrogenic mesenchymal cells-derived calpain-2 on (1) cytoskeletal structural protein and extracellular matrix alterations and (2) AAA progression. Approach and Results: Calpain-2 protein and cytoskeletal protein (filamin and talin) fragmentation are significantly elevated in human and Ang II–induced AAAs in mice. To examine the relative contribution of calpain-2 in AAA development, calpain-2 floxed mice in an LDLR −/− background were bred to mice with a tamoxifen-inducible form of Cre under control of either the ubiquitous promoter, chicken β-actin, or fibrogenic mesenchymal cell-specific promoter, Col1α2 (collagen type 1 alpha 2). Ubiquitous or fibrogenic mesenchymal cell-specific depletion of calpain-2 in mice suppressed Ang II–induced AAAs, filamin/talin fragmentation, while promoting extracellular matrix protein, collagen in the aortas. Calpain-2 silencing in aortic smooth muscle cells or fibroblasts reduced Ang II–induced filamin fragmentation. In addition, silencing of filamin in aortic SMCs significantly reduced collagen protein. Furthermore, calpain-2 deficiency suppressed rupture of established Ang II–induced AAAs in mice. Conclusions: Our studies implicate that calpain-2 deficiency prevents (1) Ang II–induced cytoskeletal structural protein fragmentation and AAA development and (2) stabilize and suppress rupture of established AAAs in mice.

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.

In studying a dynamical process of the chemical reaction, it is decisive to get appropriate information from an electronic current density. To this end, we divide one-body electronic density into a couple of densities, that is, an electronic sharing density and an electronic contraction density. Since the one-body electronic current density defi ned directly through the microscopic electronic wave function gives null value under the Born-Oppenheimer molecular dynamics, we propose to employ the Maxwell's displacement current density de fined by means of the one-body electronic density obtained under the same approximation. Applying the electronic sharing and the electronic contraction current densities to a hydrogen molecule, we show these densities give important physical quantities for analyzing a dynamical process of the covalent bond.

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.

Objective: Chronic angiotensin II (AngII) infusion promotes both thoracic (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Vasohibin-2 (VASH2) is known to cause angiogenesis at the sprouting front of neovascularization. The purpose of this study was to examine whether VASH2 influenced AngII-induced TAAs. Methods: Male C57BL/6J mice (10-week-old) were injected with VASH2 or LacZ expressing adenovirus (Ad; 7.5 x 10 9 vp/100 μL) via tail vein at 2 week intervals. One week after the first injection, subcutaneous infusion of either AngII (1,000 ng/kg/min) or saline by mini osmotic pumps was started for 3 weeks. Consequently, mice were divided into 4 groups: AngII + Ad VASH2 (n=22), AngII + Ad LacZ (n=21), saline + Ad VASH2 (n=10), saline + Ad LacZ (n=8). Next, in order to examine whether VASH2 affected TAAs via VEGF regulation, bevacizumab was intraperitoneally administrated into mice; AngII + Ad VASH2 + saline (n=15), AngII + Ad VASH2 + bevacizumab (n=15). TAAs were evaluated in all mice by en face method. Third, human aortic smooth muscle cells (hSMCs) were infected with Ad VASH2 or Ad LacZ, stimulated with or without AngII to evaluate further mechanism. Result: Intima area of aortic arch was significantly larger in AngII + Ad VASH2 group than in AngII + Ad LacZ group (19.78 ± 0.40 mm 3 vs 17.74 ± 0.44 mm 3 , P < 0.001). Gelatin zymography demonstrated that AngII upregulated latent MMP-2 expression, and activated MMP-2 most prominently in AngII + VASH2 group. Protein expression of p21 and p53 in thoracic aortas was enhanced in AngII + VASH2 group. Positive TUNEL staining was observed in thoracic aortic wall of AngII + VASH2 group. No significant difference in intima area of aortic arch between AngII + Ad VASH2 + saline group and AngII + Ad VASH2 + bevacizumab group. In vitro, the same results were observed regarding protein expression of p21 and p53, and TUNEL staining. In addition, Annexin-V staining was detected only in AngII + VASH2 group. Conclusion: Overexpression of VASH2 accelerated development of AngII-induced TAAs in vivo. VASH2-induced cell apoptosis may influence AngII-induced TAA formation independent of VEGF.

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.

We study the dynamical electron mechanism of “double proton transfer” in formic acid dimer, which is a prototype of many double proton transfers in chemical and biological systems. Since the presen...

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.

Backgrounds: Systemic right ventricular circulation after Fontan procedures is known to have late hemodynamic complications. Although a number of studies have investigated the factors that may impact on survival, postoperative outcomes after palliations remain to be elucidated. Objective: The purpose of this study is to investigate the prognostic value of myocardial fibrosis identified by cardiac magnetic resonance imaging (cMRI) in patients with single ventricular physiology. Methods: Consecutive 23 patients undergoing Fontan procedures were prospectively scheduled to have cMRI study with late gadolinium enhancement (LGE) imaging and ventricle circumferential strain measurement before and 4 months after Fontan operation. Results: Of 23 patients (mean age 3.3±0.9 years), 7 were positive for LGE (LGE+) and median percent LGE was 3.0% (interquartile range 3.0% to 7.5%). Pre-Fontan examinations revealed that patients with LGE+ showed an increase in end-diastolic volume index (139.7±26.8 ml/BSA vs. 113.3±20.9 ml/BSA; P=0.02) and end-systolic volume index (ESVI: 99.9±32.2 ml/BSA vs. 70.8±20.0 ml/BSA; P=0.01) compared with those without LGE (LGE-). In contrast to LGE- group, LGE+ patients showed lower global circumferential strain (4.1±2.3% vs. 7.9±2.7%, P=0.006), decreased ejection fraction (EF: 29±9.1% vs. 38±8.7%; P=0.04), and reduced end-systolic elastance (1.1±0.3 mm Hg/ml/m2 vs. 1.7±0.5 mm Hg/ml/m2). In addition, LGE+ group had higher levels of BNP (91.0±72.4 pg/ml vs. 30.9±44.0 pg/ml, P=0.02) and New York University Pediatric Heart Failure Index (10.9±3.3 vs. 7.8±1.1, P=0.02) than LGE- group. This was validated by positive correlations between the area of LGE versus ESVI (r=0.85, P=0.01) and BNP levels (r=0.82, P=0.02), respectively. At 4 months after Fontan procedure, LGE- group showed higher EF (37.5±8.6% vs. 24.0±8.9%, P=0.02) compared with those in LGE+ patients, and increased global circumferential strain (6.5±2.0% to 7.4±2.7%, P=0.04). Conclusion: LGE identified by cMRI before operation may be associated with lower ventricular elastance that resulted in poorer functional recovery after staged palliation. This novel strategy may provide a prognostic value of latent myocardial dysfunction after Fontan procedure.

Backgrounds: The impact of myocardial fibrosis on cardiac performance and clinical outcomes in patients with a functional single ventricle before stage-3 operation is unknown. Objective: The purpose of this study is to investigate the prognostic value of myocardial fibrosis identified by cardiac magnetic resonance imaging (cMRI) in patients with univentricular heart diseases. Methods: Consecutive 23 patients undergoing staged-3 surgical palliation with single ventricle physiology were prospectively scheduled to have cMRI study with late gadolinium enhancement (LGE) imaging and ventricle circumferential strain were examined. Results: Of 23 patients (mean age 3.3±0.9 years), 6 (26%) had positive late gadolinium enhancement (LGE+) in the ventricular myocardium, median percent LGE was 3.0% (interquartile range 3.0% to 14.0%). Pre-Fontan examinations revealed that patients with LGE+ had increased end-diastolic volume index (142.8 ml/BSA vs. 113.8 ml/BSA; P=0.02), increased end-systolic volume index (101.0 ml/BSA vs. 72.2 ml/BSA); P=0.01) compared with those without LGE (LGE-). Patients with LGE have shown to have lower ventricular circumferential strain compared with the area without LGE (basal: −1.9±1.9% vs. −4.0±3.0%, P=0.046; mid: −3.9±2.1% vs −8.0±3.9%, P=0.007; apical: −3.9±2.4% vs. −8.2±2.8%, P=0.004). In contrast to LGE- group, patients in LGE+ group had decreased right ventricular ejection fraction (27.7±8.8% vs. 38.2±8.4%; P=0.02) as well as higher levels of BNP (99.2±75.7 pg/ml vs. 32.6±44.3 pg/ml, P=0.02). In addition, patients with LGE+ had higher score of Ross classification (2.5±0.55 vs. 2.0±0, P=0.02) and New York University Pediatric Heart Failure Index (11.0±3.5 vs. 7.8±1.1, P=0.01) than in LGE- group. Age at stage-2 palliation was significantly older in patients with LGE+ group than LGE- subjects (16.8±16 months vs. 8.8±3.4 months, P=0.03). Conclusion: In this pre-stage-3 cMRI study, the age to stage-2 palliation may attribute to substantial myocardial fibrosis. The area of LGE was associated with impaired regional circumferential strain as well as disturbed ventricular performance. This novel strategy may provide a possible prognostic value of latent myocardial dysfunction after staged palliation.

Backgrounds: Hypoplastic left heart syndrome (HLHS) is a severe congenital heart malformation. Objective: The aim of this study is to determine whether intracoronary delivery of autologous cardiosphere-derived cells (CDCs) was feasible and safe to treat the children with HLHS. Methods: Four-teen patients with HLHS undergoing staged palliations were prospectively enrolled in this trial between January, 2011, and January, 2012. Seven patients constitutively assigned to receive intracoronary CDCs injection followed by 7 patients allocated to a control group with standard care alone. The primary endpoint was to assess the safety and the secondary endpoint was the preliminary efficacy by assessing the improvements of the right ventricular function during the follow-up. Results: No major complications were reported within 24 months of CDC infusion. Echocardiography showed that improvement of right ventricular ejection fraction (RVEF) was greater in the CDC-treated group (+5.3±3.2%) than in controls (+0.1±3.4%, P=0.01) at 3-month follow up. This cardiac function enhancement was manifested even in long-term observation (+7.8±4.9% vs. +2.2±3.1% at 1 year, P=0.03; +8.8±3.7% vs. +3.4±6.4% at 2 years, P=0.04). The absolute improvements in RVEF between 2 groups was confirmed by using right ventriculogram (RVG: +8.9±7.6% vs. +2.0±2.8% at 1 year, P=0.02; +8.1±6.0% vs. +2.9±3.9% at 2 years, P=0.04). In addition, RVEF on cMRI was also markedly improved in CDC-treated patients from 36.1±7.5% at baseline to 42.7±8.7% at 1 year (P=0.04) and to 42.4±7.6% at 2 years (P=0.047). Heart failure status was reduced in CDC-treated group as shown by significant decrease in Ross Heart Failure Class (2.6±0.8 at baseline vs. 1.4±0.5 at 2 years, P=0.01). Moreover, Z scores for weight-for-age was significantly increased from −4.0±2.7 at baseline to −2.2±1.4 at 2 year (P=0.02), whereas all of these parameters did not change in control subjects. Conclusion: These results of 2-year follow-up of TICAP trial suggest that intracoronary infusion of autologous CDCs is feasible and safe to treat the children with HLHS. This novel therapeutic strategy may impact on cardiac function as well as clinical symptom of heart failure status and somatic growth in long-term outcome.

Background: Although a number of studies have uncovered heterozygous mutations in cardiac regulatory genes caused hypoplastic left heart syndrome (HLHS), the identified genetic variants may not be directly correlated with the disease development. The aim of this study is to determine the epigenetic and transcriptional network responsible for myocardial patterning and morphogenesis during cardiac development in HLHS by using patient-derived induced pluripotent stem (iPS) cells. Methods: Five-independent iPS cell lines were generated from HLHS and biventricle (BV) heart-derived cardiac progenitor cells (CPCs). Global gene expression analysis, real-time RT-PCR, mutation analysis, ChIP assay, and cardiac-specific gene promoter activities were examined during differentiation. Results: We found one synonymous single nucleotide polymorphism in NKX2-5 and five in NOTCH1, respectively. Cardiac transcriptional factors such as NKX2-5, HAND1, and NOTCH/HEY, those are known to drive primary heart field and outflow tract development, were significantly reduced in HLHS-derived iPS cells after differentiation compared with BV- and control 201B7 iPS-derived cardiomyocytes. ChIP assay showed that a marked decrease in dimethylated histone H3-lysine 4 and acetylated histone H3 was found within the NKX2-5 promoter regions, whereas a significantly increased trimethylated H3-lysine 27 was identified in differentiated HLHS-derived iPS cells. To specify the target transcripts responsible for cardiac development of HLHS, cardiac troponin-T and natriuretic peptide A promoter analyses were performed. We found that both promoter activities were significantly suppressed in HLHS-derived CPCs and iPS cells compared with those from BV hearts. These repressed promoter activities could be fully restored by transient transfection of NKX2-5, HAND1, and NOTCH1 genes into these stem/progenitor cells by synergistic manner. Conclusions: These findings suggest that patient-specific iPS cells provide a potential to dissecting the complex cardiac malformations in human. The epigenetic and transcriptional regulation of NKX2-5, HAND1, and NOTCH1 may mutually participate in the development of myocardial growth, patterning, and morphogenesis in HLHS.

The borylated products (III) and (V) can be readily converted to the corresponding boronic acids under acidic conditions.

In contrast to high mortality of open surgery for thoracic aortic catastrophes including ruptured thoracic aortic aneurysm (RTAA) and traumatic aortic injury (TAI), excellent short-term outcomes of thoracic endovascular aortic repair (TEVAR) have recently been reported. We report our single-center experiences with TEVAR for aortic catastrophes. Thirteen patients with thoracic aortic catastrophes (RTAA in 7 patients, TAI in 6 patients) have received TEVAR from February 2004 to June 2010. In cases of RTAA, 5 descending aortic aneurysm ruptures and 2 aortic arch aneurysm ruptures were included. In patients with arch aneurysm ruptures, fenestrated stent grafting (SG) and SG combined with arch debranching were performed. In all cases of TAI, aortic injuries occurred near the isthmus and 5 patients received fenestrated SG. The initial success rate was 100% and there was no perioperative death. Mean duration of observation was 24 months, which revealed 4 late deaths. The causes of late death were liver failure, cerebral contusion, senility and unknown. A patient with RTAA experienced a type III endoleak as an aorta-related event 24 months after operation. There was no enlargement of aneurysm in any patient. TEVAR for aortic catastrophes seems to be performed safely with acceptable outcomes. Although morphological incompatibility, unstable preoperative haemodynamics and longer time for preparation may become impediments to perform TEVAR, we believe that TEVAR should be the 1st choice for life-threatening aortic catastrophes. However, a careful follow-up is necessary because TEVAR has several unique late complications.

The borylated products (III) and (V) can be readily converted to the corresponding boronic acids under acidic conditions.