Search

Abstract Background Muscle thickness (MT) and echo intensity (EI) measurements are ultrasound alternatives to magnetic resonance imaging (MRI) for evaluating muscle quantity and quality. The vastus medialis (VM) is a clinically important muscle, and assessment methods that most accurately reflect its quantity and quality are required. This study aimed to examine the correlation between MT and EI measured in the supine and sitting postures with corresponding MRI-measured muscle quantity and quality indices. Methods In total, 134 adults (91 older and 43 young) participated in this study. Ultrasound images of the VM were acquired in the supine and sitting postures, and MT and EI were measured. The cross-sectional area (CSA), muscle volume (MV), and intramuscular adipose tissue (intraMAT) of the VM were evaluated from MRI images using T1-weighted and Dixon methods. Pearson’s coefficients were used to quantify the correlation strength amongst pairs of dependent variables. Meng’s test was used to test for correlation coefficient differences between the two measurement postures (supine and sitting). Results The correlation coefficients amongst MT, CSA, and MV were significantly higher in the sitting posture than in the supine posture. EI measured in the supine and sitting postures correlated significantly with intraMAT, and in young individuals, these correlation coefficients were significantly higher in the sitting posture than in the supine posture. Conclusions These findings suggest that assessment of VM muscle quantity in the sitting posture is superior for young and older individuals, and assessment of VM muscle quality in the sitting posture is most effective in younger individuals.

Abstract Background The characteristics of muscle degeneration in individual quadriceps in early knee osteoarthritis (OA) and the association of muscle quantity and quality on knee dysfunction remain unclear. This study aimed to clarify the characteristics of muscle degeneration in individual quadriceps muscles in early knee OA and elucidate the association of muscle volume and intramuscular adipose tissue (intraMAT) with knee dysfunction, including functional disabilities, symptoms, and joint morphology. Methods Fifty participants were categorized into early knee OA and healthy control groups. 3.0 T magnetic resonance imaging (MRI) using T1-weighted and Dixon methods and 3D SPACE in the thigh muscle and knee joint regions was performed. Quadriceps muscle volume, intraMAT, and whole-organ MRI score (WORMS) were assessed. The Knee Society Score (KSS) was used to evaluate functional disabilities and knee symptoms. Univariate analysis of variance was conducted with covariates to clarify the differences in muscle volume and intraMAT between the two groups. Multiple linear regression analyses were performed using the KSS function and symptom subcategories and WORMS as dependent variables and muscle volume, intraMAT, and the presence of early knee OA as independent variables, such as potential confounders. Results The quadriceps intraMAT, especially in the vastus medialis (VM), was significantly higher in patients with early knee OA than in healthy controls. The VM intraMAT, not muscle volume, was significantly associated with KSS function [B = − 3.47; 95% confidence interval [CI], − 5.24 to − 1.71; p

Muscle echo intensity, as measured by ultrasonography, could be used as a new marker of functional performance in older populations. This scoping review aimed to present evidence on the utility of muscle echo intensity as determined by ultrasonography for assessing functional performance in older adults. The eligibility criterion included observational studies that investigated the associations between muscle echo intensity and functional performance in older adults. Terms, such as “echo intensity” and “older adults”, were searched for in databases, such as PubMed, Web of Science, the Cochrane database of systematic reviews, and the Cumulative Index of Nursing and Allied Health Literature, in April 2021. Two independent reviewers screened and extracted the data; 46 papers, of which almost one-third were Japanese, were subsequently identified for inclusion. The representative functional performances included in this review were muscle strength, gait speed, sit-to-stand test results, and timed up-and-go test results. Poor to moderate associations were found between muscle echo intensity and functional performance; however, heterogeneities were observed in the characteristics of study participants. Moreover, the accurate effect size and causal inferences between muscle echo intensity and functional performance remained unclear. Further longitudinal studies are needed to determine these causal inferences.

Right ventricular (RV) failure is clinically crucial, but there is no specific therapy. Here, the authors show that the complement alternative pathway is activated in RV failure and that blockade of the pathway ameliorates RV failure in mice.

Thrombolytic therapy using heparin, urokinase, and tissue plasminogen activator (tPA) has been the standard treatment for hyperacute ischemic stroke (HIS) with worsening carotid artery stenosis. In recent years, endovascular treatments (thrombectomy and carotid artery stenting) have attracted attention, and neurosurgeons are increasingly participating in these treatments. A 70-year-old Japanese male presented to our hospital with aphasia and right hemiparesis. Emergency computed tomography ([CT] CT angiography and perfusion CT) revealed a small infarct core and a large hemiparesis due to occlusion near the left common carotid artery orifice. Because of hemorrhagic sequelae, tPA was not administered, and emergency endovascular treatment failed. Therefore, a bilateral common carotid artery bypass surgery was performed. Revascularization was performed within 51 min of the start of the surgery, and the time from onset to revascularization was 5 h. Aphasia and right hemiparesis resolved immediately after surgery. The only sequela observed was mild dyskinesia. Our report is the first to show that bilateral common carotid artery bypass is a novel and effective treatment for HIS.

Pulmonary hypertension (PH) is recognized as a pathophysiological disorder encompassing a wide spectrum of clinical conditions related to various cardiovascular and respiratory diseases [...]

Abstract Background Both multiple fall experiences and fear of falling (FoF) would make people susceptible to another fall; however, the associations are unknown. This study investigates the association of FoF with fall occurrence among older adults according to their fall history. Methods In this study, we adopted a longitudinal observational design. We visited 20 community centers to recruit 1,025 older adults (aged 65 years or older). At baseline, FoF was assessed using a single-item questionnaire. The number of falls in the past year was obtained via a self-questionnaire and participants were classified into three fall history groups (0: non-faller, 1: single faller, 2 or more: multiple faller). After a year of following-up, the number of falls during the year was considered as the main outcome. Poisson regression models clarified the influence of FoF on fall occurrence during the one-year follow-up, according to the participants’ fall history. Results The final sample comprised 530 individuals (follow-up rate: 530/801, 66.4%). Fall history, FoF, and interaction between multiple fallers and FoF were significant in the adjusted statistical model (rate ratio [95% confidence interval]: single faller = 2.81 [1.06, 6.30], multiple faller = 13.60 [8.00, 23.04], FoF = 3.70 [2.48, 5.67], multiple faller*FoF = 0.37 [0.20, 0.68]). Conclusions We found that FoF was associated with the occurrence of falls in community-dwelling older adults. However, its association was lower in multiple fallers.

Abstract Background This study aimed to determine in how many individuals the iliocapsularis muscle (IC) could be identified on magnetic resonance imaging (MRI) and whether age and sex are associated with the cross-sectional area (CSA) of the IC. Methods Thirty-seven healthy younger adults and 40 healthy older adults were assigned to four groups: 1) 20 younger men; 2) 17 younger women; 3) 20 older men; and 4) 20 older women. The CSAs of the IC, IP, the rectus femoris (RF) and the quadriceps (QUAD) were quantified on an axial MRI. Results The number of individuals with the identified IC was n = 17 (85.0%) of 20 younger men, n = 15 (88.2%) of 17 younger women, n = 18 (90.0%) of 20 older men, and 19 (95.0%) of 20 older women. Our results showed the main effect of sex, but not age, in the CSA of the IC. The men-groups had larger CSA of the IC than the women-groups; however, no difference in CSA of the IC was found between the younger and older groups. Meanwhile, the main effects of age and sex were found for the IP, RF, and QUAD; thus, younger or men groups have larger CSAs of the three muscles than the older or women groups. The IC muscle can be discriminated in 85% – 95% of healthy individuals. Conclusion Although sex and age are associated with the CSA of lower-limb muscles other than the IC, only sex is associated with the CSA of the IC.

BackgroundDespite the advances in the treatment of cardiovascular diseases, effective treatment remains to be established to improve the quality of life and prognosis of patients with chronic coronary syndromes. This study was aimed to evaluate the effectiveness and safety of the low-intensity pulsed ultrasound (LIPUS) therapy, which we have developed as a novel non-invasive angiogenic therapy through upregulation of endothelial nitric oxide synthase (eNOS).Methods and findingsWe conducted a randomized, double-blind, placebo-controlled (RCT) pilot trial of the LIPUS therapy for patients with refractory angina pectoris. The patients who received optimal medical therapy without indication of PCI or CABG due to the lack of graftability or complexity of coronary lesions were enrolled. They were randomly divided into the LIPUS treatment group (N = 31) and the placebo group (N = 25) in a 1:1 fashion. The LIPUS therapy was performed in a transthoracic manner for 20 min for 3 sections each (mitral, papillary muscle, and apex levels) under the conditions that we identified; frequency 1.875 MHz, intensity 0.25 MPa, and 32 cycles. The primary endpoint was weekly use of nitroglycerin. Secondary endpoints included stress myocardial perfusion imaging and others. The average weekly nitroglycerin use (times/week) was decreased from 5.50 to 2.44 in the LIPUS group and from 5.94 to 2.83 in the placebo group. The changes in the average weekly nitroglycerin use were comparable; -3.06 (95% CI: -4.481 to -1.648) in the LIPUS group (PConclusionsIn the present study, the LIPUS therapy did not further ameliorate chest pain as compared with optimal medications alone in patients with refractory angina pectoris. The present findings need to be confirmed in another trial with a large number of patients. (Registration ID: UMIN000012369).

Myocardial infarction (MI) can result in fatal myocardial rupture or heart failure due to adverse remodeling and dysfunction of the left ventricle. Although recent studies have shown that exogenous interleukin (IL)-22 shows cardioprotective effect after MI, the pathophysiological significance of endogenous IL-22 is unknown. In this study, we investigated the role of endogenous IL-22 in a mouse model of MI. We produced MI model by permanent ligation of the left coronary artery in wild-type (WT) and IL-22 knock-out (KO) mice. The post-MI survival rate was significantly worse in IL-22KO mice than in WT mice due to a higher rate of cardiac rupture. Although IL-22KO mice exhibited a significantly greater infarct size than WT mice, there was no significant difference in left ventricular geometry or function between WT and IL-22KO mice. IL-22KO mice showed increase in infiltrating macrophages and myofibroblasts, and altered expression pattern of inflammation- and extracellular matrix (ECM)-related genes after MI. While IL-22KO mice showed no obvious changes in cardiac morphology or function before MI, expressions of matrix metalloproteinase (MMP)-2 and MMP-9 were increased, whereas that of tissue inhibitor of MMPs (TIMP)-3 was decreased in cardiac tissue. Protein expression of IL-22 receptor complex, IL-22 receptor alpha 1 (IL-22R1) and IL-10 receptor beta (IL-10RB), were increased in cardiac tissue 3 days after MI, regardless of the genotype. We propose that endogenous IL-22 plays an important role in preventing cardiac rupture after MI, possibly by regulating inflammation and ECM metabolism.

Abstract Elevated serum uric acid is a cardiovascular risk factor in patients with hypertension, even when blood pressure (BP) is well controlled. Xanthine oxidoreductase inhibitors (XORi) reduce serum uric acid levels and have several other potential effects. This multicenter, randomized, open‐label study compared the effects of two XORi, topiroxostat and febuxostat, on arterial stiffness, uric acid levels, and BP in hypertensive patients with hyperuricemia. Patients received topiroxostat 40–160 mg/day or febuxostat 10–60 mg/day, titrated to maintain serum uric acid

Abstract Background There is little data on the association between the lower nutrition represented by serum albumin levels and related factors in a general population. The present study aimed to determine whether the albumin level positioned as some kind of biomarker with frailty measures, trace elements, and an inflammation marker. Methods In 2018, we performed an epidemiological survey in 1368 subjects who resided in Tanushimaru, Japan, in which we examined the blood chemistry including albumin, trace elements, hormone levels, and carotid ultrasonography. Albumin levels were categorized into 4 groups (G1 [3.2–3.9 mg/dL], G2 [4.0–4.3 mg/dL], G3 [4.4–4.6 mg/dL], and G4 [4.7–5.3 mg/dL]). The participants underwent measurements of handgrip strength and were tested by asking to walk 5 m. Their cognitive functions were evaluated by the mini-mental state examination (MMSE). Results Multiple stepwise regression analysis demonstrated that albumin levels were significantly and independently associated with age (inversely), systolic blood pressures, estimated glomerular filtration rate (eGFR), MMSE score, frailty measures (handgrip strength), an inflammation marker (high-sensitivity C-reactive protein), hormones (growth hormone (inversely) and insulin-like growth factor-1), and trace elements (calcium, magnesium, iron, and zinc), with a linear trend. Conclusions Lower albumin levels, even in the normal range, were found to be related factors of frailty measures, trace elements, and an inflammation marker in a general population.

Summary: Aortic dissection (AD) is the acute destruction of aortic wall and is reportedly induced by inflammatory response. Here we investigated the role of smooth muscle Socs3 (a negative regulator of Janus kinases/signal transducer and activator of transcription signaling) in AD pathogenesis using a mouse model generated via β-aminopropionitrile and angiotensin II infusion. Socs3 deletion specifically in smooth muscle cells yielded a chronic inflammatory response of the aortic wall, which was associated with increased fibroblasts, reinforced aortic tensile strength, and less-severe tissue destruction. Although an acute inflammatory response is detrimental in AD, smooth muscle-regulated inflammatory response seemed protective against AD. Key Words: aortic dissection, inflammation, Jak/Stat, smooth muscle cells

Major cardiology societies' guidelines support integrating palliative care into heart failure (HF) care. This study aimed to identify the effectiveness of the HEart failure Palliative care Training program for comprehensive care providers (HEPT), a physician education program on primary palliative care in HF. We performed a pre- and post-test survey to evaluate HEPT outcomes. Physician-reported practices, difficulties and knowledge were evaluated using the Palliative Care Self-Reported Practices Scale in HF (PCPS-HF), Palliative Care Difficulties Scale in HF (PCDS-HF), and Palliative care knowledge Test in HF (PT-HF), respectively. Structural equation models (SEM) were used to estimate path coefficients for PCPS-HF, PCDS-HF, and PT-HF. A total of 207 physicians participated in the HEPT between February 2018 and July 2019, and 148 questionnaires were ultimately analyzed. The total PCPS-HF, PCDS-HF, and PT-HF scores were significantly improved 6 months after HEPT completion (61.1 vs 67.7, p

PurposePreventing falls in patients is one of the most important concerns in acute hospitals. Balance disorder and hypnotic drugs lead to falls. The Standing Test for Imbalance and Disequilibrium (SIDE) is developed for the evaluation of static standing balance ability. There have been no reports of a comprehensive assessment of falls risk including hypnotic drugs and SIDE. The purpose of this study was to investigate the fall rate of each patient who took the hypnotic drug and the factor associated with falls.MethodsFall rates for each hypnotic drug were calculated as follows (number of patients who fell/number of patients prescribed hypnotic drug x 100). We investigated the hypnotic drugs as follows; benzodiazepine drugs, Z-drugs, melatonin receptor agonists, and orexin receptor antagonists. Hypnotic drug fall rate was analyzed using Pearson's chi-square test. Decision tree analysis is the method we used to discover the most influential factors associated with falls.ResultsThis study included 2840 patients taking hypnotic drugs. Accidents involving falls were reported for 211 of inpatients taking hypnotic drugs. Z-drug recipients had the lowest fall rate among the hypnotic drugs. We analyzed to identify independent factors for falls, a decision tree algorithm was created using two divergence variables. The SIDE levels indicating balance disorder were the initial divergence variable. The rate of falls in patients at SIDE level ≦ 2a was 14.7%. On the other hand, the rate of falls in patients at SIDE level ≧ 2b was 2.9%. Gender was the variable for the second classification. In this analysis, drugs weren't identified as divergence variables for falls.ConclusionThe SIDE balance assessment was the initial divergence variable by decision tree analysis. In order to prevent falls, it seems important not only to select appropriate hypnotic drugs but also to assess patients for balance and implement preventive measures.

Acute aortic dissection occurs due to a primary tear in the aortic intima, with blood from the aortic lumen entering the adjacent diseased media. In the clinical setting, practitioners often hesitate before the use of anti-thrombotic drugs in the acute phase of aortic dissection. Therefore, we examined the clinical course in patients who had already received antithrombotic therapies at the onset of acute aortic dissection, and who were given anti-thrombotic drugs in the acute phase during hospitalization. We retrospectively enrolled 685 consecutive patients with acute aortic dissection (type A/B: 454/231), who were transferred to Kurume University Hospital from 2004 to 2020. In types A and B, there were no significant differences between in-hospital mortality with or without antithrombotic therapies at the onset (14.3% vs. 16.4%, p = 0.66 in type A, 2.6% vs. 7.3%, p = 0.29 in type B). Patients in type A who survived more than a day and were treated with anti-thrombotic drugs during hospitalization had significantly lower in-hospital mortality compared with those who received no anti-thrombotic drugs in the acute phase (2.2% vs. 16.1%, p < 0.001), while there was no significant difference between in-hospital mortality in the two type-B groups (2.4% vs. 4.9%, p = 0.48). Although there were variations in response among patients with acute aortic dissection, anti-thrombotic drugs did not worsen in-hospital mortality for patients with acute aortic dissection, indicating that medical staff should not hesitate to administer anti-thrombotic drugs if indicated.

Ischemic preconditioning (IPC) is the most powerful endogenous cardioprotective form of cellular adaptation. However, the inhibitory or augmenting mechanism underlying cardioprotection via IPC remains largely unknown. Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible potent negative feedback regulator of the signal transducer and activator of transcription-3 (STAT3) signaling pathway. Here, we aimed to determine whether cardiac SOCS3 deficiency and IPC would synergistically reduce infarct size after myocardial ischemia reperfusion injury. We evaluated STAT3 activation and SOCS3 induction after ischemic conditioning (IC) using western blot analysis and real-time PCR, and found that myocardial IC alone transiently activated myocardial STAT3 and correspondingly induced SOCS3 expression in wild-type mice. Compared with wild-type mice, cardiac-specific SOCS3 knockout (SOCS3-CKO) mice showed significantly greater and more sustained IC-induced STAT3 activation. Following ischemia reperfusion, IPC substantially reduced myocardial infarct size and significantly enhanced STAT3 phosphorylation in SOCS3-CKO mice compared to in wild-type mice. Real-time PCR array analysis revealed that SOCS3-CKO mice after IC exhibited significantly increased expressions of several anti-apoptotic genes and SAFE pathway-related genes. Moreover, real-time PCR analysis revealed that myocardial IC alone rapidly induced expression of the STAT3-activating cytokine erythropoietin in the kidney at 1 h post-IC. We also found that the circulating erythropoietin level was promptly increased at 1 h after myocardial IC. Myocardial SOCS3 deficiency and IPC exert synergistic effects in the prevention of myocardial injury after ischemia reperfusion. Our present results suggest that myocardial SOCS3 is a potent inhibitor of IPC-induced cardioprotection, and that myocardial SOCS3 inhibition augment IPC-mediated cardioprotection during ischemia reperfusion injury.

Background Aortic stenosis (AS) is highly prevalent in patients with atherosclerotic cardiovascular disease. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play a pivotal role for vascular calcification in atherosclerosis. We hypothesize that the AGEs–RAGE axis could also be involved in the pathophysiological mechanism of calcified AS. Methods and Results A total of 54 patients with calcified AS who underwent aortic valve replacement were prospectively enrolled from 2014 to 2016 (mean age 75.3±7.7 years). Aortic valve specimens were obtained from 47 patients and 16 deceased control subjects without aortic valve disease (mean age 63.2±14.5 years). The valvular expression of RAGE was evaluated by immunohistochemistry. Serum levels of AGEs and soluble RAGE were measured in 50 patients with calcified AS and 70 age‐matched and sex‐matched control subjects without heart disease. The valvular RAGE expression in patients with calcified AS was higher than controls (P=0.004) and was significantly associated with a decreased ankle‐brachial pressure index (P=0.007) and an increased intima‐media thickness (P=0.026). RAGE and α–smooth muscle actin were coexpressed and were partially costained with osteocalcin and alkaline phosphatase. The serum levels of AGEs and soluble RAGE were significantly higher in the patients with calcified AS than in the controls (P=0.013 and P

BACKGROUND Interleukin (IL)‐22, a member of the IL‐10 cytokine family, is the only known cytokine that is secreted by immune cells but does not target immune cells; it mainly targets epithelial cells. In this study, we aimed to determine whether IL‐22 administration could activate the myocardial STAT3 (signal transducer and activator of transcription‐3) signaling pathway, and thus prevent myocardial injury, in a mouse model of ischemia reperfusion injury. METHODS AND RESULTS We evaluated the STAT3 activation after IL‐22 injection by Western blot analysis and immunostaining for phosphorylated STAT3 in the heart and found that STAT3 activation in heart tissue rapidly peaked after IL‐22 injection. Coimmunostaining of phosphorylated STAT3 and α‐actinin revealed that STAT3 activation occurred in cardiomyocytes after IL‐22 administration. In heart tissue from intact mice, real‐time PCR demonstrated significant expression of IL‐22 receptor subunit 1, and coimmunostaining of IL‐22 receptor subunit 1 and α‐actinin showed IL‐22 receptor subunit 1 expression in cardiomyocytes. In cultured cardiomyocytes, IL‐22 activated STAT3, and we detected IL‐22 receptor subunit 1 expression. Overall, these results indicated that IL‐22 directly activated the myocardial IL‐22‐receptor subunit 1–STAT3 signaling pathway. Following ischemia reperfusion, compared with PBS‐treated mice, IL‐22‐treated mice exhibited a significantly reduced infarct size, significantly reduced myocardial apoptosis, and significantly enhanced phosphorylated STAT3 expression. Moreover, heart tissue from IL‐22‐treated mice exhibited a significantly reduced expression ratio of phosphorylated p53 to p53. CONCLUSIONS Our present findings suggest that IL‐22 directly activated the myocardial STAT3 signaling pathway and acted as a cardioprotective cytokine to ameliorate acute myocardial infarction after ischemia reperfusion.

Critical limb ischemia (CLI) is a potentially life-threatening condition that involves severely reduced blood flow to the peripheral arteries due to arteriosclerosis obliterans (ASO) of the limbs or a similar condition. CLI patients must undergo revascularization to avoid amputation of the lower limbs and improve their survival prognosis. However, the outcomes of conventional surgical revascularization or endovascular therapy are inadequate; therefore, establishing further effective treatment methods is an urgent task. We perform therapeutic angiogenesis using autologous bone marrow-derived mononuclear cells in clinical practice and demonstrated its safety and efficacy for CLI patients for whom conventional treatments failed or are not indicated. Exercise therapies must be devised for CLI patients who have undergone therapeutic angiogenesis to save their limbs and improve survival. Because evidence regarding the efficacy and safety of exercise therapy for CLI patients is lacking, we plan to perform a prospective trial of the efficacy and safety of optimal exercise therapy following therapeutic angiogenesis for CLI patients.The trial will enroll 30 patients between 20 and 79 years with Rutherford category 4 or 5 CLI caused by ASO who will undergo therapeutic angiogenesis. Participants will be randomly allocated to receive either optimal exercise therapy or fixed exercise therapy. Those receiving optimal exercise therapy will undergo tissue muscle oxygen saturation monitoring using near-infrared spectroscopy while performing exercises and will be prescribed optimal exercise therapy. The optimal amount of exercise will be determined on day 8, 31, 61, 91 and 181 after therapeutic angiogenesis. Ethics and dissemination: This protocol was approved by the Institutional Review Boards of Kyoto Prefectural University of Medicine. In accordance with the Helsinki Declaration, written informed consent has been obtained from all participants prior to enrollment. The results of this trial will be disseminated by publication in a peer-reviewed journal. Trial registration: This trial is registered at http://www.umin.ac.jp/ctr/index.htm (identifier: UMIN000035288). Keywords: Critical limb ischemia, Arteriosclerosis obliterans, Therapeutic angiogenesis, Optimal exercise therapy, Tissue muscle oxygen saturation, Near-infrared spectroscopy

Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and pro-apoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.

Background. We investigated whether or not the addition of myocardial mass at risk (MMAR) to quantitative coronary angiography was useful for diagnosing functionally significant coronary stenosis in the daily practice. Methods. We retrospectively enrolled 111 consecutive patients with 149 lesions who underwent clinically indicated coronary computed tomography angiography and subsequent elective coronary angiography with fractional flow reserve (FFR) measurement. MMAR was calculated using a workstation-based software program with ordinary thin slice images acquired for the computed tomography, and the minimal lumen diameter (MLD) and the diameter stenosis were measured with quantitative coronary angiography. Results. The MLD and MMAR were significantly correlated with the FFR, and the MMAR-to-MLD ratio (MMAR/MLD) showed a good correlation. The area under the receiver operating characteristic curve (AUC) of MMAR/MLD for FFR ≤ 0.8 was 0.746, and the sensitivity, specificity, positive predictive value, and negative predictive value were 60%, 83%, 68%, and 77%, respectively, at a cut-off value of 29.5 ml/mm. The addition of MMAR/MLD to diameter stenosis thus made it possible to further discriminate lesions with FFR ≤ 0.8 (AUC = 0.750). For the proximal left coronary artery lesions, in particular, MMAR/MLD showed a better correlation with the FFR, and the AUC of MMAR/MLD for FFR ≤ 0.8 was 0.919 at a cut-off value of 31.7 ml/mm. Conclusions. The index of MMAR/MLD correlated well with the physiological severity of coronary stenosis and showed good accuracy for detecting functional significance. The MMAR/MLD might be a useful parameter to consider when deciding the indication for revascularization.

Background. Transcatheter closure of patent ductus arteriosus (TC-PDA), conventionally guided by aortography, has become the standard treatment of this disease. The purposes of this study were to evaluate whether intracardiac echocardiography (ICE) may be used for measuring PDA size and be used as a guide for TC-PDA. Methods. This study had 2 phases. In phase 1, we compared the measurements of PDA size: pulmonary artery side diameter (PA-D), length, and aortic side diameter (Ao-D) of PDA, as measured by ICE with those measured by aortography or cardiac computed tomography (AoG/CCT) in 23 patients who underwent TC-PDA. In phase 2, we compared the demographics, fluoroscopic time, contrast volume, and complications of the TC-PDAs between 10 adult patients with ICE guidance and 16 without it. Results. In phase 1, we found great correlation and agreement between ICE and AoG/CCT in PA-D (r = 0.985, bias −0.077 to 0.224), but moderate to poor correlation and agreement in length (r = 0.653, bias −0.491 to 3.065) and Ao-D (r = 0.704, bias 0.738 to 4.732), respectively. Nevertheless, all patients underwent successful TC-PDA with ICE guidance that allowed us to continuously monitor the whole process. In phase 2, TC-PDA required a significantly lower contrast volume with ICE guidance than without it, and there was no significant difference in the remaining variables between the 2 groups. Conclusion. ICE is comparable to AoG/CCT in providing accurate PA-D of the PDA and may be a safe alternative to guide TC-PDA as compared to conventional aortography.

Background Beta-blockers are often not the preferred treatment for patients with vasospastic angina. However, nebivolol, beta-blocker with nitric oxide-releasing effect, could theoretically improve coronary vasospasm. We compared nebivolol versus diltiazem in improving coronary vasospasm and quality of life in patients with hypertensive vasospastic angina during a 12-week follow-up. Methods Fifty-one hypertensive patients with documented coronary vasospasm were randomly allocated into 3 treatment groups: (1) Nebivolol Group (5mg for 2 weeks/10mg for 10 weeks); (2) Diltiazem Group (90mg for 2 weeks/180mg for 10 weeks); (3) Low-dose Combination Group (2.5mg + 45mg for 2 weeks/5mg + 90mg for 10 weeks). The primary endpoint was to compare the percent changes in coronary vasospasm at 12 weeks from baseline among the 3 groups. The secondary endpoints included changes in quality of life based on the Seattle Angina Questionnaire and changes in blood pressure at 12 weeks from baseline. Results Significant improvements in coronary vasospasm were found in all groups; however, the improvement in percent changes in coronary artery spasm was greatest in the Diltiazem Group (50.4±8.8% vs. 67.8±12.8% vs. 46.8±12.3%, Nebivolol Group vs. Diltiazem Group p = 0.008; Nebivolol Group vs. Low-dose Combination Group p = 0.999; Diltiazem Group vs. Low-dose Combination Group p = 0.017). The overall Seattle Angina Questionnaire scores were significantly elevated at 12 weeks compared to the baseline in entire study population. There were no significant differences between the three groups in the overall Seattle Angina Questionnaire score changes and blood pressure changes. Conclusions Both nebivolol and diltiazem showed significant coronary vasospasm reduction effect, but the effect was greater for diltiazem.

Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the prevalence of morning hypertension increases with age, treatment of morning hypertension has not been established, particularly in Very-Elderly patients. We compared the safety and efficacy of a losartan/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension between Very-Elderly (≥75 years) and Young/Elderly patients (

Unhealthy food intake and insufficient physical activities are related with obesity or life-style diseases, which can cause cardiovascular diseases, finally leading to death [...]

The association between body mass index (BMI) and frailty in elderly patients with disabilities is unclear. We aimed to investigate the association between BMI and frailty in the elderly with disabilities according to sex. This cross-sectional study included 280 elderly patients with disabilities from an elderly daycare center. BMI classification for the Asian population was used to categorize the patients into four groups: underweight, normal, overweight, and obese. Frailty score was based on the phenotypic definition of frailty and consisted of five criteria derived from the revised Japanese version of the Cardiovascular Health Study. Those who had three or more criteria were considered frail. Logistic regression models were constructed to investigate the associations between frailty and BMI in each group (males and females). In females, being underweight was significantly associated with frailty after adjusting for confounders (age and Mini-Mental State Examination score); after adding medical history as a confounder, the aforementioned association was not significant. In males, BMI was not significantly associated with frailty. The association between BMI and frailty differed according to sex among the elderly with disabilities. This finding provides important information regarding frailty risk to workers in daycare facilities.

Traditionally, patients with end-stage heart failure (HF) have rarely been involved in end-of-life care (EOLC) discussions in Japan. The purpose of this study was to examine the impact of HF-specific palliative care team (HF-PCT) activities on EOLC discussions with patients, HF therapy and care, and food intake at the end of life. We retrospectively analyzed 52 consecutive patients with HF (mean age, 70 ± 15 years; 42% female) who died at our hospital between May 2013 and July 2020 and divided them into two groups: before (Era 1, n = 19) and after (Era 2, n = 33) the initiation of HF-PCT activities in June 2015. Compared to Era 1, Era 2 showed a decrease in invasive procedures, an increase in opioid and non-intubating sedative use for symptom relief, improved quality of meals at the end of life, and an increase in participation in EOLC discussions. The administration of artificial nutrition in the final three days was associated with non-ischemic cardiomyopathy etiology, the number of previous hospitalizations for HF, and multidisciplinary EOLC discussion support. HF-PCT activities may provide an opportunity to discuss EOLC with patients, reduce the burden of physical and psychological symptoms, and shift the goals of end-of-life nutritional intake to ensure comfort and quality of life.

Background: Clinical characteristics of nutrition status in acute myocardial infarction (AMI) patients with cancer remains unknown. Therefore, this study aimed to clarify the differences of clinical parameters, including nutrition status, between AMI patients with and without history of cancer. Methods and Results: This retrospective cohort study, using the database of AMI between 2014 and 2019 in Kurume University Hospital, enrolled 411 patients; AMI patients without cancer (n = 358, 87.1%) and with cancer (n = 53, 12.9%). AMI patients with cancer were significantly older with lower body weight, worse renal function, and worse nutrition status. Next, we divided the patients into 4 groups by cancer, age, and plaque area, detected by coronary image devices. The prediction model indicated that nutrition, lipid, and renal functions were significant predictors of AMI with cancer. The ordinal logistic regression model revealed that worse nutrition status, renal dysfunction, lower uric acid, and elevated blood pressure were significant predictors. Finally, we were able to calculate the probability of the presence of cancer, by combining each factor and scoring. Conclusions: Worse nutrition status and renal dysfunction were associated with AMI with cancer, in which nutrition status was a major different characteristic from those without cancer.

Background: Unresolved thromboemboli in the pulmonary arteries (PA) is known to cause chronic thromboembolic pulmonary hypertension (CTEPH). However, it remains unknown if vascular dysfunction in pulmonary arteries exists in patients with CTEPH. Methods and results: We enrolled 7 female patients with CTEPH in this study, who have stable pulmonary hemodynamics after balloon pulmonary angioplasty (age; 73.6 ± 3.0 years old, mean right atrial pressure; 4.1 ± 0.4 mm Hg, mean pulmonary arterial pressure; 29.4 ± 2.7, mean pulmonary artery wedge pressure; 8.1 ± 1.2, pulmonary vascular resistance; 397.3 ± 51.7 dynes, cardiac index; 3.1 ± 0.2 L/min/m2). Pulmonary artery vascular function was evaluated by measuring pulmonary artery vasomotion in response to acetylcholine (Ach) at 10-month follow-up after balloon pulmonary angioplasty. All pulmonary vasoactive drugs were discontinued on the day of the procedures. The endothelium-dependent vasomotor response was evaluated by intra-pulmonary artery infusion of Ach at the dose of 10−8 mol/l, and the vaso-spastic response was at 10−6 mol/l. We evaluated vasomotor responses at the same segment in each patient, by measuring % changes of luminal area detected by quantitative pulmonary arterial optical frequency-domain imaging (OFDI), where OFDI catheter was fixed during the procedure. Endothelial dysfunction was observed at the dose of Ach at 10−8 mol/l and vasoconstriction was also confirmed at the dose of Ach at 10−6 mol/l in the diseased pulmonary arteries in CTEPH. Conclusions: These results indicated that the pulmonary artery dysfunction exists in patients with CTEPH, which may be involved in the pathogenesis and progression of CTEPH.

A 28-year-old male was referred to our hospital with dyspnea. He was diagnosed as having chronic thromboembolic pulmonary hypertension, and a pulmonary endarterectomy (PEA) was performed. However, exertional dyspnea remained because of residual pulmonary hypertension; therefore, the patient was re-admitted to our hospital 1 year after PEA. We performed computed tomography and pulmonary angiography and found web and band lesions in the distal pulmonary artery with a high pulmonary artery pressure. Although further management was complicated because the patient had an anaphylactic shock to iodine-based contrast media, we eventually completed five sessions of balloon pulmonary angioplasty (BPA) using gadolinium contrast medium. His symptoms and hemodynamics dramatically improved after a series of BPA. After 15 months, mean pulmonary arterial pressure reduced from 67 mmHg to 20 mmHg, and subjective symptoms improved from stage Ⅳ to I as per the WHO classification system. BPA is a potential procedure for residual pulmonary hypertension after PEA and could be safely performed using gadolinium contrast medium for patients with iodine allergy.

Aortic dissection (AD) is a serious clinical condition that is unpredictable and frequently results in fatal outcome. Although rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has been reported to be effective in preventing aortopathies in mouse models, its mode of action has yet to be clarified. A mouse AD model that was created by the simultaneous administration of β-aminopropionitrile (BAPN) and angiotensin II (AngII) for 14 days. Rapamycin treatment was started either at day 1 or at day 7 of BAPN+AngII challenge, and continued throughout the observational period. Rapamycin was effective both in preventing AD development and in suppressing AD progression. On the other hand, gefitinib, an inhibitor of growth factor signaling, did not show such a beneficial effect, even though both rapamycin and gefitinib suppressed cell cycle activation in AD. Rapamycin suppressed cell cycle-related genes and induced muscle development-related genes in an AD-related gene expression network without a major impact on inflammation-related genes. Rapamycin augmented the activation of Akt1, Akt2, and Stat3, and maintained the contractile phenotype of aortic smooth muscle cells. These findings indicate that rapamycin was effective both in preventing the development and in suppressing the progression of AD, indicating the importance of the mTOR pathway in AD pathogenesis.

BackgroundAbdominal aortic aneurysm (AAA) is a potentially life‐threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial. Methods and ResultsWe investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application of CaCl2, and in human AAA. Both human and mouse AAA tissue showed B‐cell infiltration. Mouse AAA tissue showed deposition of IgG and activation of Syk, a key molecule in B‐cell activation and immunoglobulin function, which were localized to infiltrating cells including B cells and macrophages. B‐cell–deficient muMT mice showed suppression of AAA development that was associated with reduced activation of Syk and less expression of matrix metalloproteinase‐9. Administration of exogenous immunoglobulins restored the blunted Syk activation and AAA development in muMT mice. Additionally, exogenous immunoglobulins induced interleukin‐6 and metalloproteinase‐9 secretions in human AAA tissue cultures. Furthermore, administration of R788, a specific Syk inhibitor, suppressed AAA expansion, reduced inflammatory response, and reduced immunoglobulin deposition in AAA tissue. ConclusionsFrom these results, we concluded that B cells and immunoglobulins participated in AAA pathogenesis by promoting inflammatory and tissue‐destructive activities. Finally, we identified Syk as a potential therapeutic target.

Electrocardiogram (ECG) has been widely used for assessment of right ventricular (RV) hypertrophy (RVH) in patients with pulmonary hypertension (PH). However, it still remains unclear which ECG criteria of RVH are useful to predict for the severity of PH. The aim of our study was to examine the utility of ECG findings of RVH in assessment of PH. A total of 53 patients (42 women, mean age; 57.6 ± 16.4 years) with pre-capillary PH, who were diagnosed by right heart catheterization, underwent blood sampling, ECG, and cardiac magnetic resonance within a week before the right heart catheterization. We assessed the traditional ECG criteria of RVH in PH patients, and compared to age- and gender-matched control subjects without PH confirmed by 2-dimensional echocardiography (n = 42, mean age 55.3 ± 15.9 years). We also analyzed the clinical variables associated with ECG findings in patients with PH. Mean pulmonary arterial pressure (mPAP), cardiac index, and pulmonary vascular resistance (PVR) in PH patients were 35.3 ± 11.9 mmHg, 2.82 (2.09-3.45) L/min/m2, and 576 ± 376 dyne·sec·cm-5, respectively. The prevalence of right axis deviation (43.4%), R:S ratio V1 > 1 (32.1%), and RV1+SV5/6 > 10.5 mm (69.8%) in PH patients was greater than those in control subjects (p < 0.001). In univariate analysis, mPAP, PVR, RV wall thickness, RV mass index, RV volume, and RV ejection fraction (EF) (inversely) were significantly correlated with the amplitude of RV1+SV5/6. Multiple regression analysis revealed that mPAP and RVEF (inversely) were independently associated with the amplitude of RV1+SV5/6 (R2 = 0.282). Also, we performed the survival analysis among pre-capillary PH patients. During a mean follow-up of 3.7 years, patients with ≥ 16.4 mm of RV1+SV5/6 had worse prognosis than those with < 16.4 mm (Log rank p = 0.015). In conclusion, the amplitude of SV1+RV5/6 could be the most useful factor reflected for RV remodeling, hemodynamics and survival in patients with pre-capillary PH.

BackgroundFew studies have examined the relationship between accurate monitoring of sodium or potassium consumption and mortality. We aimed to investigate the association between 24‐hour urinary sodium or potassium excretion and ≈30‐year mortality in a Japanese population using 24‐hour urine collection. Methods and ResultsWe enrolled a total of 1291 participants, aged 21 to 85 years, who underwent health checkups, including a blood test and 24‐hour urine collection. They were followed up for 27.5±9.9 years by December 31, 2015, and the final follow‐up rate was 95.8%. Cox proportional hazards regression analysis was used to assess the association between 24‐hour urinary sodium or potassium excretion and all‐cause mortality. At baseline, the mean 24‐hour urinary sodium and potassium excretions were 5.80±2.28 g/d and 1.85±0.82 g/d, respectively. There were 631 deaths during the follow‐up. The cumulative survival rate was significantly decreased in the lowest quartile compared with the other higher groups. In the Cox proportional hazard model after adjustment for age and sex, 24‐hour urinary potassium excretion, but not sodium excretion, was inversely associated with all‐cause mortality. We divided the 24‐hour urinary potassium excretion levels into quartiles. After adjustment for confounding factors, the hazard ratio of all‐cause mortality in the highest quartile of 24‐hour urinary potassium excretion versus the lowest was 0.62 (95% confidence interval, 0.48–0.79; P

BackgroundAortic dissection (AD) is a life‐threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin‐6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin‐6 in macrophages in pathogenesis of AD. Methods and ResultsWe characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild‐type (WT) mice, but progressed to AD in mice with macrophage‐specific deletion of Socs3 gene (mSocs3‐KO). mSocs3‐KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue‐destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction. ConclusionsThese findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.

The lower limb muscle may play an important role in decreasing the heart's pumping workload. Aging and inactivity cause atrophy and weakness of the muscle, leading to a loss of the heart-assisting role. An electrical lower limb muscle stimulator can prevent atrophy and weakness more effectively than conventional resistance training; however, it has been reported to increase the heart's pumping workload in some situations. Therefore, more effective tools should be developed.We newly developed a cardiac cycle-synchronized electrical lower limb muscle stimulator by combining a commercially available electrocardiogram monitor and belt electrode skeletal muscle electrical stimulator, making it possible to achieve strong and wide but not painful muscle contractions. Then, we tested the stimulator in 11 healthy volunteers to determine whether the special equipment enabled lower limb muscle training without harming the hemodynamics using plethysmography and a percutaneous cardiac output analyzer.In 9 of 11 subjects, the stimulator generated diastolic augmentation waves on the dicrotic notches and end-diastolic pressure reduction waves on the plethysmogram waveforms of the brachial artery, showing analogous waveforms in the intra-aortic balloon pumping heart-assisting therapy. The heart rate, stroke volume, and cardiac output significantly increased during the stimulation. There was no change in the systolic or diastolic blood pressure during the stimulation.Cardiac cycle-synchronized electrical muscle stimulation for the lower limbs may enable muscle training without harmfully influencing the hemodynamics and with a potential to reduce the heart's pumping workload, suggesting a promising tool for effectively treating both locomotor and cardiovascular disorders.

Although the pathogenesis of abdominal aortic aneurysm (AAA) remains unclear, evidence is accumulating to support a central role for inflammation. Inflammatory responses are coordinated by various soluble cytokines of which IL-6 is one of the major proinflammatory cytokines. In this study we examined the role of IL-6 in the pathogenesis of experimental AAA induced by a periaortic exposure to CaCl2 in mice. We now report that the administration of MR16-1, a neutralizing monoclonal antibody specific for the mouse IL-6 receptor, mildly suppressed the development of AAA. The inhibition of IL-6 signaling provoked by MR16-1 also resulted in a suppression of Stat3 activity. Conversely, no significant changes in either NFκB activity, Jnk activity or the expression of matrix metalloproteinases (Mmp) -2 and -9 were identified. Transcriptome analyses revealed that MR16-1-sensitive genes encode chemokines and their receptors, as well as factors that regulate vascular permeability and cell migration. Imaging cytometric analyses then consistently demonstrated reduced cellular infiltration for MR16-1-treated AAA. These results suggest that IL-6 plays an important but limited role in AAA pathogenesis, and primarily regulates cell migration and infiltration. These data would also suggest that IL-6 activity may play an important role in scenarios of continuous cellular infiltration, possibly including human AAA.

Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.

Background In patients with cardiovascular diseases, inflammatory and hemostatic biomarkers are significant indicators of prognosis. We investigated whether circulating inflammatory and hemostatic biomarkers were predictive markers for all-cause death and cancer death in a population of community-dwelling Japanese. Methods We studied 1,920 healthy Japanese adults who underwent health examinations in 1999. Those who reported a history of inflammatory diseases and malignancy on a baseline questionnaire were excluded. Inflammatory and hemostatic biomarkers were measured in the remaining 1,862 participants, who were followed up periodically for 10 years. Multivariate proportional hazards regression analysis was used to estimate all-cause and cancer mortality. Results A total of 258 participants died during follow-up: 87 from cancer, 38 from cerebro-cardiovascular diseases, and 133 from other diseases. Mean C-reactive protein (CRP) levels at baseline were significantly higher in decedents than in survivors. Mean von Willebrand factor (vWF) levels at baseline were significantly higher in decedents than in survivors. The Cox proportional hazards model after adjustments for age and sex showed that CRP (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.06-1.51) and vWF (HR, 1.01; 95% CI, 1.00-1.01) were independent predictors of all-cause death. CRP (HR, 1.40; 95% CI, 1.06-1.86) and vWF (HR, 1.01; 95% CI, 1.00-1.02) were also independent predictive markers for cancer death. Conclusions Serum CRP and vWF were predictors of all-cause death and cancer death in the population of community dwelling Japanese.

BACKGROUND: Metabolic disorders, caused by excessive calorie intake and low physical activity, are important cardiovascular risk factors. Rho-kinase, an effector protein of the small GTP-binding protein RhoA, is an important cardiovascular therapeutic target and its activity is increased in patients with metabolic syndrome. We aimed to examine whether Rho-kinase inhibition improves high-fat diet (HFD)-induced metabolic disorders, and if so, to elucidate the involvement of AMP-activated kinase (AMPK), a key molecule of metabolic conditions. METHODS AND RESULTS: Mice were fed a high-fat diet, which induced metabolic phenotypes, such as obesity, hypercholesterolemia and glucose intolerance. These phenotypes are suppressed by treatment with selective Rho-kinase inhibitor, associated with increased whole body O2 consumption and AMPK activation in the skeletal muscle and liver. Moreover, Rho-kinase inhibition increased mRNA expression of the molecules linked to fatty acid oxidation, mitochondrial energy production and glucose metabolism, all of which are known as targets of AMPK in those tissues. In systemic overexpression of dominant-negative Rho-kinase mice, body weight, serum lipid levels and glucose metabolism were improved compared with littermate control mice. Furthermore, in AMPKα2-deficient mice, the beneficial effects of fasudil, a Rho-kinase inhibitor, on body weight, hypercholesterolemia, mRNA expression of the AMPK targets and increase of whole body O2 consumption were absent, whereas glucose metabolism was restored by fasudil to the level in wild-type mice. In cultured mouse myocytes, pharmacological and genetic inhibition of Rho-kinase increased AMPK activity through liver kinase b1 (LKB1), with up-regulation of its targets, which effects were abolished by an AMPK inhibitor, compound C. CONCLUSIONS: These results indicate that Rho-kinase inhibition ameliorates metabolic disorders through activation of the LKB1/AMPK pathway, suggesting that Rho-kinase is also a novel therapeutic target of metabolic disorders.

The effects of therapeutic angiogenesis by intramuscular injection of early pro-angiogenic cells (EPCs) to ischemic limbs are unsatisfactory. Oxidative stress in the ischemic limbs may accelerate apoptosis of injected EPCs, leading to less neovascularization. Forkhead transcription factor 4 (FOXO4) was reported to play a pivotal role in apoptosis signaling of EPCs in response to oxidative stress. Accordingly, we assessed whether FOXO4-knockdown EPCs (FOXO4KD-EPCs) could suppress the oxidative stress-induced apoptosis and augment the neovascularization capacity in ischemic limbs. We transfected small interfering RNA targeted against FOXO4 of human EPCs to generate FOXO4KD-EPCs and confirmed a successful knockdown. FOXO4KD-EPCs gained resistance to apoptosis in response to hydrogen peroxide in vitro. Oxidative stress stained by dihydroethidium was stronger for the immunodeficient rat ischemic limb tissue than for the rat non-ischemic one. Although the number of apoptotic EPCs injected into the rat ischemic limb was greater than that of apoptotic EPCs injected into the rat non-ischemic limb, FOXO4KD-EPCs injected into the rat ischemic limb brought less apoptosis and more neovascularization than EPCs. Taken together, the use of FOXO4KD-EPCs with resistance to oxidative stress-induced apoptosis may be a new strategy to augment the effects of therapeutic angiogenesis by intramuscular injection of EPCs.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs. METHODS AND RESULTS: Experimental AAA was induced in Apolipoprotein E-deficient (ApoE(-/-)) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects. CONCLUSIONS: Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.