Impact of extracellular matrix on engraftment and maturation of pluripotent stem cell-derived cardiomyocytes in a rat myocardial infarct model

Pluripotent stem cell-derived cardiomyocytes show great promise in regenerating the heart after myocardial infarction; however, several uncertainties exist that must be addressed before clinical trials. One practical issue is graft survival following transplantation. Although a pro-survival cocktail with Matrigel has been shown to enhance graft survival, the use of Matrigel may not be clinically feasible. The purpose of this study was to test whether a hyaluronan-based hydrogel, HyStem, could be a substitute for Matrigel. Human induced pluripotent stem cell-derived cardiomyocytes diluted with HyStem alone, HyStem plus pro-survival factors, or a pro-survival cocktail with Matrigel (PSC/MG), were transplanted into a rat model of acute myocardial infarction. Histological analysis at 4 weeks post transplantation revealed that, among the three groups, recipients of PSC/MG showed the largest graft size. Additionally, the grafted cardiomyocytes in the recipients of PSC/MG had a more matured phenotype compared to those in the other two groups. These findings suggest that further studies will be required to enhance not only graft size, but also the maturation of grafted cardiomyocytes.ArticleScientific reports 7(1) : 8630-(2017)journal articl

Increased predominance of the matured ventricular subtype in embryonic stem cell-derived cardiomyocytes in vivo

Accumulating evidence suggests that human pluripotent stem cell-derived cardiomyocytes can affect “heart regeneration”, replacing injured cardiac scar tissue with concomitant electrical integration. However, electrically coupled graft cardiomyocytes were found to innately induce transient post-transplant ventricular tachycardia in recent large animal model transplantation studies. We hypothesised that these phenomena were derived from alterations in the grafted cardiomyocyte characteristics. In vitro experiments showed that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) contain nodal-like cardiomyocytes that spontaneously contract faster than working-type cardiomyocytes. When transplanted into athymic rat hearts, proliferative capacity was lower for nodal-like than working-type cardiomyocytes with grafted cardiomyocytes eventually comprising only relatively matured ventricular cardiomyocytes. RNA-sequencing of engrafted hESC-CMs confirmed the increased expression of matured ventricular cardiomyocyte-related genes, and simultaneous decreased expression of nodal cardiomyocyte-related genes. Temporal engraftment of electrical excitable nodal-like cardiomyocytes may thus explain the transient incidence of post-transplant ventricular tachycardia, although further large animal model studies will be required to control post-transplant arrhythmia

Effects of psychotherapy for middle-aged individuals with anxiety disorders in a general medicine practice

Background: Anxiety disorders are mental disorders that cause somatic symptoms for which patients may seek care from generalmedicine departments. We focused on anxiety disorders in middle-aged patients and examined the effect of a psychotherapeuticintervention.Materials and Methods: The participants were 14 middle-aged patients diagnosed with an anxiety disorder. Patients receivedpretreatment assessments and were randomly assigned to a pharmacotherapy group (n = 8) or a pharmacotherapy and psychotherapygroup (n = 6). The duration of the study was three months. Pre-and post-treatment, the Medical Outcomes Study 36-ItemShort-Form Health Survey (SF-36), State-Trait Anxiety Inventory (STAI), and a visual analog scale (VAS) were administered. Inthe pharmacotherapy and psychotherapy group, salivary cortisol was collected pre- and post-psychotherapy at the first and finalpsychotherapy sessions.Result: Four patients in the pharmacotherapy group withdrew from the study. There were no significant differences in the totalscores of the SF-36 or STAI between groups. Improvement was seen in the pharmacotherapy and psychotherapy group pre- andpost- treatment. SF-36 subscales of bodily pain (p = 0.02) and mental health (p = 0.04) were significantly higher than posttreatment.The state anxiety score on the STAI improved post-treatment (p = 0.03). On the VAS, the pharmacotherapy and psychotherapygroup’s symptoms were significantly improved (p = 0.02).Conclusion: This suggests that psychotherapy for middle-aged individuals contributes to the improvement of anxiety states andHRQoL in general medicine departments. It promotes the recognition of curative effects and prevents doctor shopping

Association of serum gamma-glutamyltransferase (GGT) and diabetes with triglycerides-to-HDL cholesterol ratio in Japanese subjects: The Nagasaki Study

Background: Although we reported in a previous study that diabetes with a high serum triglycerides to high-density lipoproteincholesterol (TG-HDL) ratio constitutes a risk for atherosclerosis, associations in terms of TG-HDL ratio between diabetes and gamma-glutamyltransferase (GGT), which is also known as an independent risk factor for atherosclerosis, have not yet been clarified. The purpose of this study was to test the hypothesis that a positive association between GGT and diabetes may be confined to high TG-HDL. Methods: This was a cross-sectional study of 2,302 Japanese subjects who were undergoing a general health check in 2014. All subjects were divided into TG-HDL level tertiles and serum GGT and diabetes status were investigated. Results: Of 207 diabetes patients identified in this study, 94 had high TG-HDL, 63 intermediate TG-HDL, and 50 low TG-HDL. Independent of classical cardiovascular risk factors, serum GGT showed a positive association with diabetes in patients with high TG-HDL, but not in patients with intermediate and low TG-HDL diabetes. The multivariable adjusted odds ratios (OR) and 95% coincidence intervals (95%CI) of diabetes for 1 standard deviation (SD) increment of GGT were 1.64 (95%CI: 1.16-2.31) for high TG-HDL, 1.46 (95%CI: 0.95-2.26) for intermediate TG-HDL, and 1.04 (95%CI: 0.60-1.79) for low TG-HDL diabetes. Conclusion: Serum GGT is positively associated with diabetes in patients with high TG-HDL but not with intermediate or low TG-HDL diabetes. This finding may prove to be an efficient tool for estimating atherosclerotic risk in diabetes patients

Hemoglobin as a response marker of endothelial cell damage in elderly nonoverweight non-anemic subjects.

　An independent positive correlation between hemoglobin level and risk of hypertension has been reported for non-anemicnon-overweight men and women. Additionally, serum hepatocyte growth factor (HGF) concentration in hypertensive subjects was reported to be significantly higher than in normotensive subjects. However no studies have reported on the correlation betweenhemoglobin and HGF. A cross-sectional study of 695 elderly non-overweight non-anemic Japanese subjects (231 men and 464 women; range 60-92 years old; Body mass index (BMI)<25kg/m2; Hemoglobin (Hb)?13g/dL for men and Hb?12g/dL for women) who were undergoing general health checkups in 2014 was conducted. Multiple linear regression analysis adjustment for classical cardiovascular risk factors showed a significant positive correlation between hemoglobin and serum HGF concentration(parameter estimate (β) =31.8, P<0.001) for men and (β=21.7, P<0.001) for women. An independent positive correlation between hemoglobin and HGF was observed in elderly non-anemic non-overweight Japanese subjects. Since HGF level may become elevated in response to endothelial cell damage (vascular remodeling), these findings suggest that measuring hemoglobin level is clinically relevant for estimating the response to endothelial cell damage

Association between Alkaline Phosphatase and Anemia in Rural Japanese Men: The Nagasaki Islands study

Although bone metabolism is reportedly associated with production and maturation of blood corpuscles, and serum alkaline phosphatase (ALP) levels have been associated with bone metabolism, no published study has investigated the association between ALP and anemia. Furthermore, although ALP is known as an enzyme affected by alcohol consumption, there are no reports in the literature on associations between ALP and the risk of anemia in relation to drinking status. We conducted a cross-sectional study of 907 men aged 30-89 years undergoing a general health check-up to investigate the associations between ALP and anemia in relation to drinking status. Of the 907 participants, 120 men were diagnosed with anemia. The association between ALP and anemia was J-shaped. With the second quartile of ALP (194-228 IU/L) (Q2) as the reference group, the multivariable adjusted OR and 95%CI for anemia were 1.91 (95%CI: 0.96-3.82) for 277 IU/L (Q4). When the analysis was limited to non-drinkers, the associations became stronger with corresponding values of 3.34 (95%CI: 1.28-8.74), 3.18 (95%CI: 1.28-7.88) and 3.22 (95%CI:1.37-7.59). Not only lower but also higher levels of serum ALP are associated with anemia for men, especially non-drinkers. For analyses of associations between ALP and anemia, alcohol consumption should thus be considered a potential confounder

Association between white blood cell count and diabetes in relation to triglycerides-to-HDL cholesterol ratio in a Japanese population: The Nagasaki Islands study

Although our previous study found that diabetes combined with a high serum triglycerides to high-density lipoprotein cholesterol (TG-HDL) ratio constitutes a risk for atherosclerosis and chronic kidney disease (CKD), the association, in terms of TG-HDL ratio, between diabetes and white blood cell (WBC) count, which is an independent risk factor for atherosclerosis, has not been clarified. To investigate this association, we conducted a cross-sectional study of 3,998 Japanese subjects aged 30-89 years undergoing a general health check. We investigated the associations between WBC count and diabetes for all subjects, who were divided into tertiles according to TG-HDL level. Independent of classical cardiovascular risk factors, WBC count of both men and women was positively associated with diabetes combined with high but not with low TG-HDL. The multivariable odds ratios (ORs) and 95% confidence intervals (95%CIs) of 1SD (standard deviation) increment in WBC count (1,538/μL for men, 1,382/μL for women) for high TG-HDL diabetes and low TG-HDL diabetes were 1.39 (95%CI: 1.04-1.85) and 0.88 (95%CI: 0.66-1.19) for men, and 1.83 (95%CI: 1.45-2.33) and 0.91 (95%CI: 0.64-1.29) for women, respectively. In conclusion, for both men and women, WBC count is associated with high TG-HDL diabetes but not with low TG-HDL diabetes. These findings suggest that measuring WBC count is clinically relevant for estimating the risk of atherosclerosis and CKD in patients with diabetes categorized according to TG-HDL ratio

Body mass index and triglyceride-to-HDL-cholesterol ratio in relation to risk of diabetes: The Nagasaki Islands study

Body mass index (BMI) is well known as an independent risk factor for insulin resistance. In addition, lower BMI and lower insulin levels are recognized as specific characteristics of Asian diabetes patients. Since the triglyceride-to-HDL-cholesterol ratio (TG-HDL) is positively associated with insulin level, but inversely associated with insulin sensitivity, we supposed that diabetes combined with high but not with low TG-HDL might be positively associated with BMI. We therefore conducted a cross-sectional study of 2,431 Japanese subjects (905 men and 1,526 women) aged 30-79 years, who underwent a general health check, to investigate associations between BMI, diabetes and its subtypes that we defined on the basis of TG-HDL levels, which in turn were categorized according to sex-specific tertiles. Among the 172 diabetic patients identified in the study group, 45 showed low TG-HDL and 82 high TG-HDL. We found a significant inverse association between low-TG-HDL diabetes and BMI, and a significant positive association between high-TG-HDL diabetes and BMI. The multivariable-adjusted odds ratio and 95%CI for a 1SD increment in BMI (3.03 kg/m2 for men and 3.44 kg/m2 for women) for low-TG-HDL diabetes was 0.53 (95%CI: 0.36-0.77) and 1.57 (95%CI: 1.24-2.01) for high-TG-HDL diabetes. These findings demonstrated that for Japanese subjects associations between diabetes and BMI are strongly influenced by the TG-HDL status. Since a previous study of ours found that diabetes combined with high TG-HDL ratios constitutes a risk for atherosclerosis, these findings may serve as an effective tool for estimating risk of atherosclerosis for diabetes patients

Effects of smoking cessation on gastric emptying in smokers.

BACKGROUND: Smoking cessation can lead to changes in appetite and weight gain in some patients; thus, smoking cessation may alter gastrointestinal motility. Effects of smoking cessation on gastric emptying in smokers have not been established. AIM: This study sought to determine how smoking cessation affects gastric emptying in smokers. METHODS: Participant group comprised 53 habitual smokers and 12 healthy nonsmokers. Habitual smokers were treated for 2 months with transdermal nicotine patches. Gastric emptying was studied using C acetate breath tests at the beginning of the study, and at 1 week and 9 weeks after cessation of patch use. Maximal CO2 excretion time (Tmax), CO2 excretion half-life (T1/2), and parameters beta and kappa, representing initial and subsequent gastric-emptying phases, respectively, were determined using conventional formulae. RESULTS: Before smoking cessation, Tmax was reached significantly later in smokers (0.94+/-0.3 h, P=0.014) than in controls (0.89+/-0.1 h). At 1 week after the end of treatment, Tmax was significantly decreased (from 1.05+/-0.32 h to 0.72+/-0.64 h, P=0.003). T1/2 also tended to decrease, but not significantly. Although beta was decreased significantly (from 2.46+/-0.40 to 2.17+/-0.58, P=0.022), kappa was unchanged. However, by 9 weeks after the end of treatment, Tmax (1.28+/-0.69 h) had increased to levels seen before treatment. CONCLUSIONS: Smoking cessation temporarily accelerates gastric emptying, and decreases in beta suggest that initial-phase gastric emptying accelerates after smoking cessation. The temporary acceleration of gastric emptying after smoking cessation may be involved in the temporary increase in appetite and weight gain seen after smoking cessation

Admission systolic blood pressure as a prognostic predictor of acute decompensated heart failure: A report from the KCHF registry

[Background] Admission systolic blood pressure has emerged as a predictor of postdischarge outcomes of patients with acute decompensated heart failure; however, its validity in varied clinical conditions of this patient subset is unclear. The aim of this study was to further explore the prognostic value of admission systolic blood pressure in patients with acute decompensated heart failure. [Methods] The Kyoto Congestive Heart Failure (KCHF) registry is a prospective, observational, multicenter cohort study enrolling consecutive patients with acute decompensated heart failure from 19 participating hospitals in Japan. Clinical characteristics at baseline and prognosis were examined by the following value range of admission systolic blood pressure: <100, 100–139, and ≥140 mmHg. The primary outcome measure was defined as all-cause death after discharge. Subgroup analyses were done for prior hospitalization for heart failure, hypertension, left ventricular ejection fraction, and medications at discharge. We excluded patients with acute coronary syndrome or insufficient data. [Results] We analyzed 3564 patients discharged alive out of 3804 patients hospitalized for acute decompensated heart failure. In the entire cohort, lower admission systolic blood pressure was associated with poor outcomes (1-year cumulative incidence of all-cause death: <100 mmHg, 26.8%; 100–139 mmHg, 20.2%; and ≥140 mmHg, 15.1%, p<0.001). The magnitude of the effect of lower admission systolic blood pressure for postdischarge all-cause death was greater in patients with prior hospitalization for heart failure, heart failure with reduced left ventricular ejection fraction, and β-blocker use at discharge than in those without. [Conclusions] Admission systolic blood pressure is useful for postdischarge risk stratification in patients with acute decompensated heart failure. Its magnitude of the effect as a prognostic predictor may differ across clinical conditions of patients