Mst1/2 Kinases Inhibitor, XMU-MP-1, Attenuates Angiotensin II-Induced Ascending Aortic Expansion in Hypercholesterolemic Mice.

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.

Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice.

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Vasohibin-2 Aggravates Development of Ascending Aortic Aneurysms but not Abdominal Aortic Aneurysms nor Atherosclerosis in ApoE-Deficient Mice.

BACKGROUND: Vasohibin-2 (VASH2) has been isolated as a homologue of vasohibin-1 (VASH1) that promotes angiogenesis counteracting with VASH1. Chronic angiotensin II (AngII) infusion promotes both ascending and abdominal aortic aneurysms (AAs) in mice. The present study aimed to investigate whether exogenous VASH2 influenced AngII-induced vascular pathology in apolipoprotein E-deficient (ApoE-/-) mice. METHODS: Male, ApoE-/- mice (9-14 weeks old) were injected with Ad LacZ or Ad VASH2. After a week, saline or AngII (1,000 ng/kg/minute) was infused into the mice subcutaneously via mini-osmotic pumps for 3 weeks. Consequently, all these mice were divided into 4 groups: saline + LacZ (n = 5), saline + VASH2 (n = 5), AngII + LacZ (n = 18), and AngII + VASH2 (n = 17). RESULTS: Exogenous VASH2 had no significant effect on ex vivo maximal diameters of abdominal aortas (AngII + LacZ: 1.67 ± 0.17 mm, AngII + VASH2: 1.52 ± 0.16 mm, n.s.) or elastin fragmentation and accumulation of inflammatory cells. Conversely, exogenous VASH2 significantly increased intima areas of aortic arches (AngII + LacZ: 16.6 ± 0.27 mm2, AngII + VASH2: 18.6 ± 0.64 mm2, P = 0.006). VASH2 effect of AngII-induced ascending AAs was associated with increased cleaved caspase-3 abundance. AngII-induced atherosclerosis was not altered by VASH2. CONCLUSIONS: The present study demonstrated that augmented VASH2 expression had no effect of AngII-induced abdominal AAs or atherosclerosis, while increasing dilation in the ascending aorta.

miR-146a Deficiency Accelerates Hepatic Inflammation Without Influencing Diet-induced Obesity in Mice.

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.

Exogenous Vasohibin-2 Exacerbates Angiotensin II-Induced Ascending Aortic Dilation in Mice.

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.

Diabetic nephropathy is associated with frailty in patients with chronic hemodialysis.

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.

The Prevalence of Frailty and its Associated Factors in Japanese Hemodialysis 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.

Peripheral artery disease is associated with frailty in chronic hemodialysis patients.

Objectives The 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. Methods A 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 <0.9. Results Of 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 < 0.0001). Thigh circumferences were also significantly larger in the Non-peripheral artery disease group (41.7 cm vs. 39.7 cm, P = 0.0054). A multivariate logistic regression analysis demonstrated that the factors independently associated with peripheral artery disease were as follows: frailty (odds ratio = 2.06, 95% confidence interval 1.09-3.89) and myocardial infarction (odds ratio = 3.74, 95% confidence interval 2.05-6.83). Conclusions It is concluded that peripheral artery disease is closely associated with frailty in hemodialysis patients.

Chronic Kidney Disease Is Positively and Diabetes Mellitus Is Negatively Associated with Abdominal Aortic Aneurysm.

BACKGROUND AND AIMS: Chronic 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). METHODS: 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, in order to investigate the prevalence of AAA in each group, we enrolled 1126 patients with CKD and 400 patients with DM. RESULTS: 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 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%. CONCLUSION: CKD is a positively associated with the presence of AAA. In contrast, DM is a negatively associated with the presence of AAA in Japanese population.

Novel Model of Pulmonary Artery Banding Leading to Right Heart Failure in Rats.

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.

Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome: the TICAP prospective phase 1 controlled trial.

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.

[Endovascular repair for ruptured thoracic aortic aneurysm and traumatic aortic injury].

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.