Noritoshi Fukushima

Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice

Cardiac progenitor cells are a potential source of cell therapy for heart failure. Although recent studies have shown that transplantation of cardiac stem/progenitor cells improves function of infarcted hearts, the precise mechanisms of the improvement in function remain poorly understood. The present study demonstrates that transplantation of sheets of clonally expanded stem cell antigen 1-positive (Sca-1-positive) cells (CPCs) ameliorates cardiac dysfunction after myocardial infarction in mice. CPC efficiently differentiated into cardiomyocytes and secreted various cytokines, including soluble VCAM-1 (sVCAM-1). Secreted sVCAM-1 induced migration of endothelial cells and CPCs and prevented cardiomyocyte death from oxidative stress through activation of Akt, ERK, and p38 MAPK. Treatment with antibodies specific for very late antigen-4 (VLA-4), a receptor of sVCAM-1, abolished the effects of CPC-derived conditioned medium on cardiomyocytes and CPCs in vitro and inhibited angiogenesis, CPC migration, and survival in vivo, which led to attenuation of improved cardiac function following transplantation of CPC sheets. These results suggest that CPC transplantation improves cardiac function after myocardial infarction through cardiomyocyte differentiation and paracrine mechanisms mediated via the sVCAM-1/VLA-4 signaling pathway.

Telmisartan induces proliferation of human endothelial progenitor cells via PPARγ-dependent PI3K/Akt pathway

OBJECTIVE Although recent clinical trials have suggested that angiotensin II type 1 receptor blockers (ARBs) reduced cardiovascular events, the precise mechanisms involved are still unknown. Telmisartan, an ARB, has recently been identified as a ligand of peroxisome proliferator-activated receptor-gamma (PPARgamma). On the other hand, since endothelial progenitor cells (EPCs) are thought to play a critical role in ischemic diseases, we investigated effects of telmisartan on proliferation of EPCs. METHODS AND RESULTS Human peripheral blood mononuclear cells were isolated from healthy volunteers, and cultured on fibronectin-coated dishes in the presence or absence of telmisartan. Four days after starting culture, adherent cells were collected, and equal numbers of cells were reseeded into methylcellulose medium with or without telmisartan. In the presence of telmisartan, numbers of colonies increased in a dose-dependent manner. DiI-AcLDL uptake and lectin and CD31, CD34 staining revealed that these colonies were EPCs. Increase in colony number by treatment with telmisartan was absolutely inhibited when cultured with a specific inhibitor of PPARgamma. In addition, we observed that specific inhibitors of phosphoinositide-3 kinase (PI3K) abolished telmisartan-stimulated increase of monocytic EPC-like cells and telmisartan induced phosphorylation of Akt. Furthermore, mRNA expression of p21 was downregulated in a dose dependent manner, suggesting that growth inductive effects of telmisartan might be regulated by the PI3K/Akt and p21 signaling pathway. CONCLUSIONS These findings suggest that telmisartan might contribute to endothelial integrity and vasculogenesis in ischemic regions by increasing numbers of EPCs.

Correlation between left atrial appendage morphology and flow velocity in patients with paroxysmal atrial fibrillation

AIMS Reduction of left atrial appendage (LAA) flow velocity (FV) is a risk factor for thrombus formation and increases the risk of stroke in patients with atrial fibrillation (AF). Furthermore, LAA morphology is correlated with stroke in patients with AF. The aim of this study was to correlate LAAFV with LAA morphology in patients with AF. METHODS AND RESULTS We studied 96 patients (age 59.0 ± 10.2 years, 75% male) referred for radiofrequency catheter ablation for paroxysmal AF. All patients underwent computed tomography (CT) and transthoracic and transoesophageal echocardiography during sinus rhythm. LAA morphology was classified as one of the four types (chicken wing, windsock, cactus, and cauliflower) on CT images. There were significant differences in LAAFV among LAA morphologies (chicken wing 73.7 ± 21.9 cm/s, windsock 61.9 ± 19.6 cm/s, cactus 55.3 ± 14.1 cm/s, cauliflower 52.7 ± 18.1 cm/s, P = 0.008). Post hoc multiple comparisons showed that LAAFV was higher in patients with chicken wing than in those with cactus (P = 0.006, vs. chicken wing) and cauliflower (P = 0.006, vs. chicken wing), but not with windsock (P = 0.102). After adjustment for clinical and LAA anatomical covariates (orifice area, volume, and trabeculation), multiple linear regression analyses revealed that LAA morphology was an independent determinant of LAAFV [chickens wing: standardized partial regression coefficients (β) = 0.317, P = 0.0014; windsock: β = 0.303, P = 0.038]. CONCLUSION LAA morphology is a significant determinant of LAAFV, suggesting an underlying mechanism for the association between LAA morphology and embolic events.

Left Atrial Appendage Flow Velocity and Time from P-Wave Onset to Tissue Doppler–Derived A' Predict Atrial Fibrillation Recurrence after Radiofrequency Catheter Ablation

Atrial fibrillation (AF) is associated with atrial remodeling. We investigate the abilities of preprocedural echocardiographic parameters reflecting atrial remodeling to predict AF recurrence after radiofrequency catheter ablation (RFCA) for paroxysmal AF (PAF).

A crucial role of activin A-mediated growth hormone suppression in mouse and human heart failure.

Infusion of bone marrow-derived mononuclear cells (BMMNC) has been reported to ameliorate cardiac dysfunction after acute myocardial infarction. In this study, we investigated whether infusion of BMMNC is also effective for non-ischemic heart failure model mice and the underlying mechanisms. Intravenous infusion of BMMNC showed transient cardioprotective effects on animal models with dilated cardiomyopathy (DCM) without their engraftment in heart, suggesting that BMMNC infusion improves cardiac function via humoral factors rather than their differentiation into cardiomyocytes. Using conditioned media from sorted BMMNC, we found that the cardioprotective effects were mediated by growth hormone (GH) secreted from myeloid (Gr-1(+)) cells and the effects was partially mediated by signal transducer and activator of transcription 3 in cardiomyocytes. On the other hand, the GH expression in Gr-1(+) cells was significantly downregulated in DCM mice compared with that in healthy control, suggesting that the environmental cue in heart failure might suppress the Gr-1(+) cells function. Activin A was upregulated in the serum of DCM models and induced downregulation of GH levels in Gr-1(+) cells and serum. Furthermore, humoral factors upregulated in heart failure including angiotensin II upregulated activin A in peripheral blood mononuclear cells (PBMNC) via activation of NFκB. Similarly, serum activin A levels were also significantly higher in DCM patients with heart failure than in healthy subjects and the GH levels in conditioned medium from PBMNC of DCM patients were lower than that in healthy subjects. Inhibition of activin A increased serum GH levels and improved cardiac function of DCM model mice. These results suggest that activin A causes heart failure by suppressing GH activity and that inhibition of activin A might become a novel strategy for the treatment of heart failure.

Comparability of activity monitors used in Asian and Western-country studies for assessing free-living sedentary behaviour

This study aims to compare the outputs of the waist-worn Active style Pro HJA-350IT (ASP; used in studies with Asian populations), the waist-worn ActiGragh™GT3X+ using the normal filter (GT3X+) and the thigh-worn activPAL3 (AP) in assessing adults’ sedentary behaviour (total sedentary time, number of breaks) under free-living conditions. Fifty healthy workers wore the three monitors simultaneously during their waking hours on two days, including a work day and a non-work day. Valid data were at least 10 hours of wearing time, and the differences between monitors on the sedentary outputs using the AP as criterion measurement were analyzed by ANOVA. The number of participants who had complete valid data for work day and non-work day was 47 and 44, respectively. Total sedentary time and breaks estimated by the AP were respectively 466.5 ± 146.8 min and 64.3 ± 24.9 times on the work day and 497.7 ± 138.3 min and 44.6 ± 15.4 times on the non-work day. In total sedentary time, the ASP estimated 29.7 min (95%CI = 7.9 to 51.5) significantly shorter than the AP on the work day but showed no significant difference against the AP on the non-work day. The GT3X+ estimated 80.1 min (54.6 to 105.6) and 52.3 (26.4 to 78.2) significantly longer than the AP on the work day and the non-work day, respectively. For the number of breaks from sedentary time, on both days, the ASP and the GT3X+ estimated significantly more than the AP: 14.1 to 15.8 times (6.3 to 22.5) for the ASP and 27.7 to 28.8 times (21.8 to 34.8) for the GT3X+. Compared to the AP as the criterion, the ASP can underestimate total sedentary time and the GT3X+ can overestimate it, and more so at the lower levels of sedentary time. For breaks from sedentary time, compared to the AP, both the GT3X+ the ASP can overestimate.

Types of social participation and psychological distress in Japanese older adults: A five-year cohort study

Introduction The most effective type of social participation against psychological distress in older adults is not well documented. The aim of this study was to examine whether different types of social participation are associated with changes in psychological distress level in older men and women in Japan. Methods Two thousand seven hundred community-dwelling older adults (aged 65–74 years, 50% women) were randomly selected from the resident registry of three cities. Of these, participants who reported social participation and psychological distress level in the baseline survey in 2010 were followed up. Psychological distress was evaluated based on K6 scales at baseline and follow-up (in 2015). Social participation level was examined using question items from the National Health and Nutrition Survey in Japan. Exploratory factor analysis was used to derive the underlying factor structure. Multiple linear regression analysis was used to examine the association between social participation and changes in psychological distress level after adjusting for covariates stratified by both gender and age group or living arrangement. Results Data from 825 community-dwelling older adults (45.3% women) were analyzed. Social participation was categorized into two types using factor analysis: community involvement (volunteer activities, community events, clubs for the elderly) and individual relationship (friendship, communication with family and friends, hobbies). During the 5-year follow-up, 29.5% of participants reported a deterioration in psychological distress. Higher community involvement was independently associated with lower risk of psychological distress for older women (β = 0.099, p = 0.047), whereas there were no associations with individual relationship for either gender. Furthermore, in older women living with others, higher community involvement was also associated with lower risk of psychological distress (β = 0.110, p = 0.048). Conclusion Community involvement provides older women with mental health benefits regardless of individual relationship level. Promoting community involvement may be an effective strategy for healthy mental aging.

Social participation among older adults not engaged in full- or part-time work is associated with more physical activity and less sedentary time

Social participation provides health benefits for older adults. However, there is the need to identify whether higher social participation is associated with older adults being more physically active and less sedentary (sitting time). We examined the associations of social participation with physical activity, and sedentary time, in a population‐based sample of older Japanese adults.

Comparison of accelerometer-measured sedentary behavior, and light- and moderate-to-vigorous-intensity physical activity in white- and blue-collar workers in a Japanese manufacturing plant

The times spent in sedentary behavior (SB) and moderate‐to‐vigorous physical activity (MVPA) are independently associated with health outcomes; however, objective data on physical activity levels including SB among different occupations is limited. We compared accelerometer‐measured times spent in SB, light‐intensity physical activity (LPA), and MVPA, and the patterns associated with prolonged bouts of SB between white‐ and blue‐collar workers.

Drivers are more physically active than non-drivers in older adults

Car use has been identified as sedentary behavior, although it may enhance mobility, particularly in the older population. This cross-sectional study aimed to compare the time spent in objectively determined sedentary behavior (SB) and physical activity (PA) between older drivers and non-drivers. Four hundred and fifty Japanese older adults (74.3 ± 2.9 years) who had valid accelerometer data were included. They were asked to respond to a questionnaire and wear an accelerometer (HJA-350IT, Omron Healthcare) on their waist for 7 consecutive days in 2015. To compare activity time between drivers and non-drivers, we calculated estimated means using analysis of covariance, adjusting for sociodemographic, physical, and psychological factors and accelerometer wear time. Compared to non-drivers, drivers engaged in more light-intensity PA (LPA) (drivers: 325.0 vs. non-drivers: 289.0 min/day) and moderate-to-vigorous PA (drivers: 37.5 vs. non-drivers: 30.0 min/day) and less SB (drivers: 493.4 vs. non-drivers: 535.9 min/day) (all p < 0.05). After stratification by age, sex, and residential area, larger effect of driving on PA time was found in older-older adults, in men, and in rural residents. Older drivers were found to be more physically active than non-drivers, suggesting more access to outdoor activities or expanding social network.