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The Impella 5.0 is a catheter-mounted left ventricular assist device that is inserted through the patient's subclavian artery. This device allows patient mobilization. Early mobility improves outcomes, including physical function and exercise tolerance, in critically ill patients and those with heart failure (HF). However, there have been no studies regarding the safety of early mobilization during the period of Impella 5.0 insertion based on hemodynamic assessment.A 39-year-old man with idiopathic dilated cardiomyopathy and cardiogenic shock was transferred to our hospital for Impella 5.0 insertion. We started neuromuscular electrical stimulation (NMES) and mobilization eight days after Impella 5.0 insertion. The safety of NMES and mobilization was assessed based on mean blood pressure, heart rate (HR), and mean pulmonary artery pressure measurements as hemodynamic indicators. Muscle strength was also assessed using the Medical Research Council (MRC) scale. Throughout the interventions, only the HR increased slightly during mobilization, and there were no hemodynamic abnormalities. Also, the MRC scale score improved as mobilization progressed. The results presented here suggest that NMES and mobilization are safe and feasible in patients with Impella 5.0 insertion, and therefore should be widely adopted.

The simplified frailty scale is a simple frailty assessment tool modified from Fried's phenotypic frailty criteria, which is easy to administer in hospitalized patients. The applicability of the simplified frailty scale to indicate prognosis in elderly hospitalized patients with cardiovascular disease (CVD) was examined.This cohort study was performed in 895 admitted patients ≥ 65 years (interquartile range, 71.0-81.0, 541 men) with CVD. Patients were classified as robust, prefrail, or frail based on the five components of the simplified frailty scale: weakness, slowness, exhaustion, low activity, and weight loss. The primary endpoint was the composite outcome of all-cause mortality and unplanned readmission for CVD.Patients positive for greater numbers of frailty components showed higher risk of all-cause mortality or unplanned CVD-related readmission (P for trend < 0.001). Classification as both frail (adjusted HR: 3.27, 95% confidence interval [CI]: 1.49-7.21, P = 0.003) and prefrail (adjusted HR: 2.19, 95% CI: 1.00-4.79, P = 0.049) independently predicted the composite endpoint compared with robust after adjusting for potential confounding factors. The inclusion of prefrail, frail, and number of components of frailty increased both continuous net reclassification improvement (0.113, P = 0.049; 0.426, P < 0.001; and 0.321, P < 0.001) and integrated discrimination improvement (0.007, P = 0.037; 0.009, P = 0.038; and 0.018, P = 0.002) for the composite endpoint.Higher scores on the simplified frailty scale were associated with increased risk of mortality or readmission in elderly patients hospitalized for CVD.

The aim of this single-arm pilot study was to determine the effects of whole-body vibration training (WBVT) on endothelial function in elderly patients with cardiovascular diseases, as well as its safety. A total of 20 elderly patients with stable cardiovascular diseases underwent WBVT, which consisted of five static resistance training exercises (squats, wide stance squats, toe-stands, squats + band, and front lunges). The parameters of WBVT included vertical vibrations, 30 Hz frequency, and a 3-mm peak-to-peak amplitude. Each vibration session lasted 30 seconds, with 120 seconds of rest between sessions. Before and after WBVT, the reactive hyperemia peripheral arterial tonometry index (RH-PAT index) and transcutaneous oxygen pressure (tcPO 2 ) were recorded as a measure of endothelial function and peripheral blood circulation. Systolic blood pressure, diastolic blood pressure, heart rate, and arterial oxygen saturation of pulse oximetry (SpO 2 ) were measured at each rest interval as well as before and after WBVT. All patients completed our WBVT protocol without adverse events. The RH-PAT index significantly increased following WBVT (1.42 to 2.06, P < 0.001). There were no significant changes in heart rate (P = 0.777), systolic blood pressure (P = 0.183), diastolic blood pressure (P = 0.925), or SpO 2 (P = 0.248) during WBVT. In conclusion, we demonstrated the acute effects of WBVT on endothelial function, with no reports of adverse events. These findings support the need for further randomized controlled studies to investigate the long-term effects of WBVT.

The association between endothelial function, evaluated using flow-mediated dilatation (FMD), and the severity of coronary artery disease remains to be elucidated.A total of 245 consecutive patients with stable angina were prospectively enrolled. FMD was evaluated in the brachial artery before percutaneous coronary intervention. Patients were divided into 2 groups according to the FMD value (lower FMD group [FMD < 2.0], n = 82; higher FMD group [FMD ≥ 2.0], n = 163). The severity of coronary artery disease was evaluated using findings of angiography and optical coherence tomography, and compared between the 2 groups.The prevalence of left main (LM) disease was significantly higher in the lower FMD group than in the higher FMD group (8.5% versus 2.5%, P = 0.046), although the prevalence of multivessel disease was comparable between the groups. Lower FMD was independently associated with a higher prevalence of LM disease (odds ratio, 3.89; 95% confidence interval, 1.12-15.5; P = 0.033). A general linear model with multiple variables revealed that the minimal lumen area (MLA) in the culprit lesion was significantly smaller in patients with lower FMD than in those with higher FMD (regression coefficient b, -0.249 mm 2 ; 95% confidence interval, -0.479--0.018 mm 2 ; P = 0.035). The prevalence ofvulnerable plaque characteristics was comparable between the 2 groups.Patients with lower FMD had a higher incidence of LM disease and a smaller MLA in the culprit lesion. FMD may be a useful, noninvasive indicator for identifying patients with severe coronary artery disease.

Cognitive impairment is frequently represented in elderly patients with cardiovascular disease (CVD); yet, the mechanism is uncertain. Recent studies have suggested the association between the vascular endothelial dysfunction and cognitive impairment. The aim of this study was to clarify the association between endothelial dysfunction and cognitive impairment in elderly patients with CVD.A total of 80 elderly patients (> 70 years old) with CVD were included. Patients who had already pharmacologically intervened for cognitive impairment were excluded. The endothelial dysfunction was assessed by the reactive hyperemia-peripheral arterial tonometry (RH-PAT). Cognitive impairment was diagnosed by the Mini-mental state examination.The RH-PAT index was significantly lower in cognitive impairment (median 1.60 [interquartile range (IQR) 1.34 to 1.89], n = 51) as compared with non-cognitive impairment (median 1.75 [IQR 1.55 to 2.30], n = 29, P = 0.005). By a multivariate analysis, the RH-PAT index was independently associated with cognitive impairment (odds ratio: 0.89; 95% confidence interval: 0.81 to 0.97; per 0.1, P = 0.044). In the receiver-operating characteristic analysis, the best cut-off of the RH-PAT index to identify cognitive impairment was 1.65 (area under the curve 0.67; P = 0.011) with limited the sensitivity (63%) and specificity (66%).A lower RH-PAT index was significantly associated with the presence of cognitive impairment in elderly CVD patients. Further studies are required to clarify the mechanism and the causal relationship between the endothelial dysfunction and cognitive impairment in patients with CVD.

This study aimed to investigate whether a single session of neuromuscular electrical stimulation (NMES) can enhance vascular endothelial function and peripheral blood circulation in patients with acute myocardial infarction (AMI). Thirty-four male patients with AMI were alternately assigned to 2 groups, and received NMES with muscle contraction (NMES group, n = 17) or without muscle contraction (control group, n = 17) after admission. NMES was performed for quadriceps and gastrocnemius muscles of both legs for 30 minutes. We measured systolic blood pressure as a parameter of cardiovascular responses and the low-frequency component of blood pressure variability as an index of sympathetic activity. Reactive hyperemia peripheral arterial tonometry (RH-PAT) index and transcutaneous oxygen pressure in foot (Foot-tcPO 2 ) were also measured as parameters of vascular endothelial function and peripheral blood circulation, respectively. All patients completed the study without severe adverse events. Systolic blood pressure and the low-frequency component increased significantly during the NMES session in both groups (P < 0.01 and P < 0.05, respectively). However, elevation from systolic blood pressure at rest was < 10 mmHg in both groups. In the NMES group, the RH-PAT index and Foot-tcPO 2 increased significantly after NMES (P < 0.05 and P < 0.001, respectively). No significant changes were observed in these parameters throughout the session in the control group. In conclusion, a single session of NMES with muscle contraction enhanced vascular endothelial function, leading to improvement in peripheral blood circulation without inducing excessive cardiovascular and autonomic responses in patients with AMI (UMIN000014196).

Medical treatment for asymptomatic carotid artery stenosis (ACAS) has advanced recently. The outcomes of medical treatment and surgical treatment were evaluated to clarify the optimal treatment for ACAS.Patients with ACAS of ≥ 50% luminal narrowing underwent serial follow-up carotid artery ultrasonography for one year or more at the Center for Cardiovascular Disease Prevention between November 2006 and October 2013. The incidence of cardiovascular events (stroke, myocardial infarction, cardiovascular death) was examined in 64 patients (medical treatment group), and in 47 patients (surgical group) who underwent surgical treatment (carotid endarterectomy or carotid artery stenting) during this same period at the Department of Neurosurgery.Annual cardiovascular event rate was 0.91% (2/219 person-year) in the group of guideline-oriented medical treatment with an annual check-up for disease management and 5.6% (6/107 person-year) in the surgical group (log-rank P = 0.027; HR in the medical treatment group, 0.19 [medical treatment/surgical]; 95% confidence interval [CI], 0.028 to 0.87). Annual stroke event rate was 0.46% (1/219 person-year) in the medical treatment group and 4.7% (5/107 personyear) in the surgical group (log-rank P = 0.016; HR in the medical treatment group, 0.11 [medical treatment/surgical]; 95% CI, 0.0057 to 0.70). Multivariate logistic analysis showed that the surgical group was an independent variable associated with cardiovascular events (P = 0.049).Annual cardiovascular and stroke event rates were low in patients receiving medical treatment for ACAS and better than surgical treatment. The present study shows that medical treatment is an important option for ACAS.

Cell migration, proliferation, and differentiation of cardiac fibroblasts (CFs) play a central role in cardiac fibrosis. Factor Xa (FXa)-dependent protease-activated receptor (PAR)-1 and PAR-2 have been reported as important targets in proinflammatory and fibroproliferative diseases. From this viewpoint, we aimed to investigate whether treatment of rivaroxaban, an approved oral direct FXa inhibitor, attenuates functional changes in angiotensin (Ang) II-induced mouse CFs.Confluent cultured mouse CFs were pretreated with or without rivaroxaban. Ang II-induced cell migration was decreased by 73% in rivaroxaban induced cells. Rivaroxaban inhibited Ang II-induced cell proliferation by 27% at 0.01 μg/ mL, 69% at 0.1 μg/mL, 71% at 1 μg/mL, and 69% at 5 μg/mL. In mouse cytokine array measuring 40 cytokines, the productions of interleukin-16, TIMP-1, and tumor necrosis factor-α (TNF-α) were significantly reduced with 0.1 μg/mL of rivaroxaban pretreatment (all P < 0.05). TIMP-1 levels in the culture supernatant measured by ELISA were also decreased by rivaroxaban pretreatment in Ang II-induced CFs (35% decrease at 0.01 μg/mL, 47% at 0.1 μg/mL, 47% at 1 μg/mL, and 57% at 5 μg/mL). In the dual reporter assay analysis, rivaroxaban inhibited various inflammatory signal pathways, including the nuclear factor-kappa B (NF-κB), active protein-1 (AP-1), and mitogen-activated protein kinase (MAPK) pathways (decreases of 82%, 78%, and 75%, respectively).These data suggest that rivaroxaban inhibits Ang II-induced functional activation in cultured mouse CFs via inhibiting NF-κB and MAPK/AP-1 signaling pathways, which may be a possible target of heart failure, through the antifibrotic and anti-inflammatory efficacy of rivaroxaban in Ang II-stimulated cardiac fibroblasts.

The purpose of this study was to clarify the effect of standing balance training on walking speed (short-term outcome) and cardiac events (long-term outcome) in elderly ischemic heart disease (IHD) patients. This was a retrospective cohort study. Ninety-two elderly (≥ 65 years) IHD patients who underwent an inpatient cardiac rehabilitation program were assigned to two groups: a balance group that received standing balance training in addition to conventional (aerobic and resistance) training and a conventional group. Standing balance was assessed by one-leg standing time and a postural stability index reflecting dynamic balance, and normal walking speed was measured at baseline and hospital discharge. Patients were followed for up to 3 years or until a cardiac event occurred. There were no significant differences in clinical characteristics between the groups. Both groups showed a significant change in normal walking speed from baseline to hospital discharge (P < 0.001, respectively), and normal walking speed was significantly higher in the balance group compared to the conventional group (P = 0.001). The postural stability index improved significantly only in the balance group (P = 0.005). Multivariable analyses using Cox proportional hazards model confirmed that standing balance training (hazard ratio [HR]: 0.408; 95% confidence interval [CI]: 0.162-1.029; P = 0.058) and fast walking speed (HR: 0.362; 95% CI: 0.137-0.957; P = 0.041) were associated with cardiac events. These findings show that standing balance training improves walking speed and reduces cardiac events, and suggests that such training can be an effective intervention for elderly IHD patients.

Coagulation factors are known to play a role in wound healing by stimulating fibroblasts and might be associated with tissue fibrosis, however, only limited data exist. Protease-activated receptor 1 (PAR1), activated by thrombin or factor (F) Xa, and PAR2, activated by FXa, have recently been reported to play roles not only in the coagulation system, but also in cardiac fibrosis. Furthermore, a previous report found that FX deficiency in mice led to the development of cardiac fibrosis. Therefore, in the present study, we evaluated cellular biological function under conditions of overexpressed thrombin and FXa in fibroblasts.Cell migration and proliferation with FXa (1U/mL) and thrombin (1U/mL) stimulation were evaluated. Cells incubated without FXa or thrombin were used as control. H2O2 and TGF-β1 production were measured using ELISA. Signal pathways were evaluated using a signal pathway reporter assay.Cell migration and proliferation were increased in FXa-stimulated cells (4.1-fold increase for migration, 1.3-fold for proliferation compared with control, respectively) and thrombin (4.1-fold increase for migration, 1.3-fold for proliferation as compared to control, respectively). H2O2 production was higher in FXa-stimulated cells compared to thrombin (1.3-fold increase) and control cells (1.4-fold increased). TGF-β1 production was up-regulated after FXa addition (12.6-fold increase compared with thrombin, 1.8-fold increase compared with control, respectively). In FXa-stimulated cells, AP-1 and NF-kB were increased compared to control (P < 0.05).These data suggest that FXa and thrombin play important roles in the fibrotic process that could also lead to cardiac fibrosis, and that at least some of these signalings are more accelerated with FXa compared to thrombin.

Soluble fms-like tyrosine kinase 1 (sFlt-1) is an endogenous inhibitor of vascular endothelial growth factor, which is involved in cardiovascular remodeling and atherosclerosis development. To examine the predictive role of sFlt-1 levels in patients with asymptomatic heart failure, we measured circulating sFlt-1 in patients with or without coronary artery disease (CAD). We analyzed 88 Japanese patients with CAD or patients at high risk for atherosclerosis and who were undergoing total risk management for cardiovascular disease prevention. Circulating sFlt-1 levels correlated with the increase in plasma brain natriuretic peptide levels (ΔBNP) from baseline to the observed levels 5 years later in CAD patients, patients with previous myocardial infarction, and men. ΔBNP levels correlated with sFlt-1 levels in the high-sFlt-1 patients with CAD (r = 0.511, P < 0.01). In all patients, end-systolic volume index (ΔESVI) increased in correlation with a decrease in left ventricular ejection fraction (ΔEF) in the long-term observation, independent of their history of myocardial infarction (ΔESVI = 2.5 mL/m(2) increase/year). Baseline level of sFlt-1 was independent of ΔESVI or ΔEF. The present 5-year observational study demonstrated that high sFlt-1 levels predicted moderate increases in BNP levels in CAD patients. Moreover, ΔBNP was correlated with ΔESVI/year in CAD patients with high-sFlt-1 levels. These data suggest that high sFlt-1 levels may be an effective biomarker to predict the progression of heart failure in patients with CAD.

This study aimed to evaluate the degree of reduction in walking speed in patients with acute myocardial infarction (AMI) compared to age-matched community-dwelling people and identify factors associated with walking speed. The subjects were 210 middle-aged and 188 elderly patients with a first AMI (AMI group) and 198 age-matched community-dwelling people with no medical events (non-AMI group). We measured maximum walking speed in all subjects and collected clinical data, including that related to motor function, at the end of a supervised cardiac rehabilitation program in the AMI group. Data were analyzed based on age and sex. Walking speed in men and women in the middle-aged AMI subgroup decreased to 77.9% and 75.7% relative to that of the non-AMI subgroup matched by sex, respectively; walking speed in men and women in the elderly AMI subgroup decreased to 78.7% and 74.2% relative to that of the non-AMI subgroup matched by sex, respectively. Moreover, 6.4% of men and 23.8% of women in the middle-aged AMI subgroup, and 28.8% of men and 43.5% of women in the elderly AMI subgroup, had a slower walking speed compared to their respective non-AMI groups, which may contribute to an increased risk for cardiovascular mortality. Stepwise multiple regression analysis for motor function revealed that only leg strength in the middle-aged AMI subgroup, and both leg strength and standing balance in the elderly AMI subgroup, were associated with walking speed, regardless of sex after adjusting for clinical characteristics. These results suggest that evaluation and management of walking speed are necessary in implementing effective disease management for patients with first AMI.