小林 欣夫

Purpose: We evaluated the consistency of different-assessors in estimating three-dimensional (3D) global-longitudinal-strain (GLS) of left (LV) and right ventricle (RV) using transthoracic-echocardiography (TTE) for LV and RV systolic-function. We compared results from two-independent-specialists using this-approach for 3D LV and RV parameters in a population with 74% hypertrophic-cardiomyopathy (HCM) patients. Methods: 58 patients (43 HCM(32 male; 62 +/- 15 years) and 15 controls (5 male; 53 +/- 22 years)) underwent TTE (Vivid-E9) to measure 2D and 3D GLS of the LV and RV by two-independent-specialists. Results: Consistencies of estimates of 3D LV end-diastolic volume (EDV), end-systolic volume (ESV), and ejection-fraction (EF) between the two-assessors were 0.872 (3D LVEDV, P < 0.001), 0.797 (3D LVESV, P < 0.001), and 0.215 (3D LVEF, P = 0.105). Consistencies of 2D and 3D LV GLS between two-assessors were 0.900 (2D LVGLS, P < 0.001) and 0.874 (3D LVGLS, P < 0.001). Consistencies of estimates of 3D RVEDV, RVESV, and RVEF between two assessors were 0.781 (3D RVEDV, P < 0.001), 0.755 (3D RVESV, P < 0.001), and 0.26 (3D RVEF, P = 0.049). Consistencies of 2D and 3D GLS of whole RV and those of RV free wall only between two-assessors were 0.886 (2D GLS of whole RV, P < 0.001), 0.687 (3D GLS of whole RV, P < 0.001), 0.707 (2D GLS of RV free wall, P < 0.001), and 0.630 (3D GLS of RV free wall, P < 0.001). Conclusions: Consistencies of independent-estimates of 3D GLS of the LV and RV using TTE between two-assessors were worse than for 2D GLS of the LV and RV, but better than for 3D LVEF and RVEF in a population with 74% HCM patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Background: The pharmacodynamic effects of changing from standard-dose clopidogrel to low-dose (3.75 mg) prasugrel in Japanese patients are largely unknown. Methods and Results: A total of 53 consecutive Japanese patients with stable coronary artery disease (CAD) who received aspirin and clopidogrel were enrolled. Clopidogrel was switched to 3.75 mg prasugrel. At day 14, prasugrel was switched to 75 mg clopidogrel. Platelet reactivity was measured using the Verify Now assay at baseline, day 14, and day 28. VerifyNow P2Y12 reaction units (PRU) >208 was defined as high on-treatment platelet reactivity (HPR). The prevalence of HPR (18.9% vs. 41.5% vs. 44.2%, P<0.001) and the PRU level (154.3 +/- 54.2 vs. 196.2 +/- 55.5 vs. 194.6 +/- 55.8, P<0.001) were significantly lower on prasugrel maintenance therapy compared with the clopidogrel therapy before and after switching. The CYP2C19 genotypes that account for the 3 phenotypes (ie, extensive metabolizer, intermediate metabolizer, and poor metabolizer) had a significant impact on platelet reactivity with clopidogrel (174.9 +/- 54.0 vs. 193.1 +/- 56.5 vs. 240.6 +/- 25.4 PRU, P<0.001) but not prasugrel (147.0 +/- 51.9 vs. 147.5 +/- 58.3 vs. 184.4 +/- 38.3 PRU, P=0.15). Conclusions: Low-dose prasugrel achieves stronger platelet inhibition than clopidogrel in Japanese patients with stable CAD.

Elevated serum uric acid (SUA) level is known to be a prognostic factor in patients with acute coronary syndrome (ACS). However, the pathogenesis of the relation between SUA level and coronary plaque characteristics has not been fully evaluated. The aim of this study was to investigate the relation between SUA level and plaque composition of nonculprit lesions in patients with ACS. A total of 81 patients with ACS who underwent intravascular ultrasound (IVUS)-guided percutaneous coronary intervention were included. They were classified into 3 groups according to tertiles of SUA level. Using integrated backscatter (IB) -IVUS system, tissue components were classified into 4 categories: calcium deposits, dense fibrosis, fibrosis, and lipid. Tertiles of SUA level were as follows: low tertile <5.0 mg/dl; intermediate tertile 5.0 to 6.4 mg/dl; and high tertile >6.4 mg/dl. There was a trend toward greater vessel volume in the high tertile group than in the low and intermediate tertile groups (19.4 +/- 3.7 vs 17.4 +/- 4.4 vs 16.7 +/- 4.1 mm(3)/mm, p = 0.05). There was no significant difference in lumen volume between the 3 groups. Plaque volume was significantly greater in the high than in the low tertile group (8.6 +/- 2.4 vs 6.7 +/- 2.2 mm(3)/mm, p = 0.01). IB-IVUS analysis demonstrated greater lipid (59.1 +/- 9.1% vs 49.7 +/- 10.9% vs 51.1 +/- 9.3%, p = 0.001) and less fibrous components (36.8 +/- 7.8% vs 44.3 +/- 7.8% vs 43.2 +/- 6.7%, p < 0.001) in the high than in the low and intermediate tertile groups. Multivariate analysis showed high SUA as an independent predictor of increasing lipid volume. In conclusion, elevated SUA level is associated with greater lipid content of coronary plaque in patients with ACS than in patients with normal levels. (C) 2015 Elsevier Inc. All rights reserved.

Background: Adipose tissue is one of the sources of mesenchymal stem cells, which have the potential to differentiate into various types of cells, including myocytes. Whether brown adipose tissue (BAT)-derived cells might differentiate into the cardiac pacemaking-conducting cells, and have the potential to regenerate the cardiac conduction system (CCS), is investigated in this study. Methods and Results: BAT was isolated from the interscapular area of mice and enzymatically digested before culture. Round or fusiform cells showed spontaneous beating at 4-7 days after culturing of BAT-derived cells. Reverse transcriptase-polymerase chain reaction analysis and immunocytochemical analysis revealed that BAT-derived cells expressed several cardiomyocytes, the CCS and pacemaker (PM) cell marker genes and proteins. Patch-clamp techniques revealed that spontaneous electrical activity and the shape of the action potential showed properties of cardiac PM cells. Next, a complete atrioventricular (AV) block was created in mice and green fluorescent protein-positive (GFP (+)) BAT-derived cells were injected intramyocardially around the AV node. At 1 week after transplantation, 50% of BAT-derived cells injected mice showed a sinus rhythm or a 2:1 AV block. Immunohistochemical analysis revealed that injected GFP (+) cells were engrafted and some GFP (+) cells co-expressed several cardiac PM cell marker proteins. Conclusions: BAT-derived cells differentiate into the CCS and PM-like cells in vitro and in vivo, and may become a useful cell source for arrhythmia therapy.

Rationale: In right ventricular hypertrophy associatedwith severe pulmonary hypertension (PH), a shift of energy metabolism toward glycolysis occurs. There are few investigations regarding fatty acid metabolism in patients with PH and right ventricular hypertrophy. Objectives: To assess whether there is fatty acid accumulation in the hypertrophied right ventricle in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to determine whether this accumulation is related to hemodynamic variables obtained by right heart catheterization. Methods: To assess fatty acid accumulation in the right ventricle, 123I-β-methyl iodophenyl pentadecanoic acid (BMIPP) analog imaging was performed in control subjects (n = 16) and patients with CTEPH (n = 13) before (n = 13) and after (n = 8) pulmonary thromboendarterectomy. Measurements and Main Results: There was increased 123IBMIPP uptake in the right ventricle of subjects with CTEPH before pulmonary endarterectomy. Right ventricular 123I-BMIPP uptake decreased significantly after thromboendarterectomy (P = 0.003) in parallel with the change of hemodynamic variables. The right ventricular BMIPP uptake was significantly correlated with the mean pulmonary artery pressure (r = 0.51, P = 0.0228) but not with pulmonary vascular resistance (r = 0.39, P = 0.0932). Conclusions: This is the first study that uses 123I-BMIPP uptake imaging to show that fatty acid accumulates in the right ventricle of patients with CTEPH and that the increased accumulation is reversible after pulmonary thromboendarterectomy. This study suggests that this imaging modality may be useful for monitoring right ventricle metabolic functions in severe PH.

Background: Late and very late stent thrombosis after drug-eluting stent implantation is a major concern. The present study evaluated difference in the effects of sirolimus, paclitaxel and zotarolimus on endothelial cells. Methods: Mouse endothelial cells were seeded in a 6-well plate. Cells were cultured with an antiproliferative drug at the expected concentrations for each well for 24 hours before making 3 scratch lines with a pipette tip. After a 4.5 hour incubation period, 3 reference scratch lines, vertically across the original scratch lines, were made in the same way. The experiment was repeated at least 6 times (6 plates). Measurements were performed at 9 crossings of each well. Wound healing ratio was calculated as 1 - (distance of the first scratch/distance of the second scratch). % cell migration was calculated as (wound healing ratio at an expected drug concentration/wound healing ratio with no drug). × 100 Average % cell migration at 54 crossings of 6 plates was calculated. Results: Paclitaxel inhibited cell migration in a concentration-dependent manner. On the other hand, concentration-dependent inhibition was not observed for sirolimus or zotarolimus. Sirolimus showed a stronger inhibitory effect on migration of endothelial cells compared to zotarolimus. Conclusions: The difference in the effect of antiproliferative drugs of drug-eluting stents on endothelial cells may be associated with relatively faster re-endothelialization of zotarolimus-eluting stent compared to the 1st generation DES.

We report a case of right ventricular (RV) diastolic dysfunction due to a large hematoma posterior to the left ventricle (LV) after cardiac surgery. An 80-year-old woman underwent cardiac surgery. After surgery, her physical findings revealed right heart failure. Localized hematoma posterior to the pericardial space and the RV compression to the sternum were shown by computed tomography. Transthoracic Doppler echocardiography demonstrated restrictive physiology of the RV although there was no evidence of constrictive pericarditis. These findings suggest that RV diastolic dysfunction could have occurred due to the hematoma posterior to the LV. Since pleural effusion had persisted despite medical therapy, the hematoma was removed surgically. Soon after surgery, dyspnea and pretibial edema were diminished bilateral pleural effusion dramatically disappeared. RV diastolic dysfunction estimated by echocardiography was improved and RV compression disappeared.We speculate that there are two physiological mechanisms for the RV compression: (1) the localized hematoma elevated the intrapericardial pressure and (2) the hematoma shifted the entire heart to the sternum. In conclusion, this is the first case report of RV diastolic dysfunction due to large hematoma posterior to the LV.&lt . Learning objective: Localized hematoma posterior to the left ventricle can be a cause of right ventricular compression that leads to onset of severe right ventricular diastolic dysfunction.&gt .

Purpose: In order to evaluate compensatory mechanisms in hypertrophic-cardiomyopathy (HCM) subjects with preserved left-ventricular (LV) ejection-fraction (EF), we measured myocardial percentage endocardial strain dependency, as represented by 2D LV global longitudinal (GLS) and circumferential-strain (GCS), using a novel, multi-layer, speckle-tracking transthoracic-echocardiography (TTE) technique. Methods: A total of 60 subjects (40 HCM with preserved LV EF (30 male; 62 +/- 15 years, all LV EF > 50%)) and 20 controls (10 male; 59 +/- 10 years) underwent TTE (Vivid-E9). Quantitative strain-measurements of: endocardial, all and epicardial layers were performed at each-site. We defined percentage endocardial strain dependency as the ratio of endocardial strain to epicardial strain. Results: Absolute GLS values at all views in all, endocardial and epicardial myocardial layers were significantly smaller in HCM subjects than in controls (all P < 0.001). There were no significant differences between both groups in absolute GCS values in the endocardial layers, at the mitral valve and papillary muscle levels. Percentage endocardial GCS dependency at all levels were greater in HCM subjects than in controls (all P < 0.01). In HCM subjects, percentage endocardial GCS dependency at the mitral valve and papillary muscle levels revealed significant, moderate, negative correlations with LV end-diastolic and systolic dimensions (correlation coefficients -0.505, -0.451 (mitral valve level) and -0.533, -0.591 (papillary muscle level), respectively). Conclusions: In HCM subjects with preserved LV EF, 2D LV GLS was lower than in controls, but endocardial GCS was maintained in compensation for reduction in endocardial GLS; thus percentage endocardial GCS dependency may increase, and the larger the LV size, the smaller this compensatory effect. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Purpose: In evaluating coronary arteries by 64-256 slice CT, atrial fibrillation (AF) is usually an exclusion criterion. We used CHADS2 score to predict coronary arteriosclerosis estimated by 320-slice CT and prognosis in AF subjects. Methods: A total of 183 consecutive subjects (148 male; 64.1 +/- 11.1 years, 97 hypertension, 60 hyperlipidemia, 21 diabetes mellitus, 76 smoking habits, body mass index 23.4 +/- 3.5) who were diagnosed previously as chronic (N=104) or paroxysmal AF (N=79), andwho underwent electrocardiogram-gated 320-slice CT were enrolled. The composite end point of cardiac death or sudden death was assessed. Results: A total of 183 AF subjects were divided into 3 groups: CHADS2 scores of 0 (N=53), 1 (N=57) and = 2 (N=73). Frequency of the presence of calcified plaque, non-calcified plaque, mixed plaque, any plaque, and N50% stenosis and Agatston calcium score was significantly lower in CHADS2 score 0 group compared with score 1 or score >= 2 groups. In logistic-regression models for prediction of calcified plaque, or any plaque on CT, the odds ratios of CHADS2 score >= 2 group to CHADS2 score 0 or 1 group were 2.03 and 2.12, respectively (both P < 0.05). During a median of 19.2 months, the composite-event-rate was significantly higher in subjects with CHADS2 score >= 2 than those with CHADS2 score 0 (P= 0.049) in Kaplan-Meier survival analysis. Conclusions: The CHADS2 score is a useful predictor of coronary arteriosclerosis on CT and may correlate with prognosis in AF subjects. Subjects with high CHADS2 score should be examined for coronary arteriosclerosis in addition to cerebral infarction. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Background: The aimof this study is to predict the risk of coronary-arteriosclerosis and prognosis in subjects with chronic-atrial-fibrillation (CAF) using the CHADS2 and CHA2DS2-VASc scores by 320-slice-CT and invasive-coronary-angiography (ICA) in a two-center-study. Methods: 53 CAF subjects who underwent 320-slice-CT and ICA within 6-months (43 male; 69 +/- 9 years; CHADS2 score 2.2 +/- 1.3; CHA2DS2-VASc score 3.5 +/- 1.6) in the two-institutes were analyzed. CT and ICA data were transferred to the analysis-center and were analyzed by cardiologists. Results: Agatston-calcium-score and frequencies of the presence of various-kinds of plaques and >50% and >75% coronary artery stenosis were significantly higher in the subjects with CHA2DS2-VASc score >= 3 compared with thosewith score <3. However there were no-significant differences in the Agatston-calcium-score and frequencies of the presence of various-kinds of plaques and >50% and >75% coronary artery stenosis evaluated by 320-slice CT between the subjects with CHADS2 score >= 2 and <2. Frequency of N50% coronary artery stenosis by ICA was significantly higher in the subjects with CHA2DS2-VASc score >= 3 compared with those with score <3. However, there were no-significant differences in the frequencies of N50% and >75% coronary artery stenosis by ICA between the subjects with CHADS2 score >= 2 and <2. During a mean of 15.9 months, composite rate of cardiac death and heart failure did not differ between subjects with CHADS2 score >= 2 and score <2 and between subjects with CHA2DS2-VASc score >= 3 and score <3. Conclusions: The CHA2DS2-VASc score is a useful predictor of not prognosis but coronary-arteriosclerosis in subjects with CAF compared with CHADS2 score in this two-center-study. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Purpose: To compare diagnostic-accuracy of prospective and retrospective-ECG-gated acquisition in 320-slice-CT for detecting coronary-artery stenosis in subjects with chronic-atrial-fibrillation (CAF) in a two-center study. Materials and methods: 53 CAF subjects who underwent 320-slice-CT, and invasive-coronary-angiogram (ICA) within 6-months (43 male; 69 +/- 9 years; CHADS2 score 2.2 +/- 1.3; CHA2DS2-VASc score 3.5 +/- 1.6) in the two institutes were analyzed. In Institute-1, prospective-ECG-gated acquisition was routinely performed (N = 33). In Institute-2, retrospective-ECG-gated acquisition was routinely performed (N = 20). CT and ICA data were transferred to the analysis center and were analyzed by cardiologists blinded to the clinical-data. Results: Prevalence of >50 and >75% on ICA was 79 and 61% in Institute-1, and 30 and 15% in Institute-2, respectively. In a patient-by-patient analysis, Institute-2 had higher negative-predictive-value (NPV) and accuracy of >75% stenosis on CT in predicting >75% stenosis on ICA. In a vessel-by-vessel analysis, there were no significant-differences of sensitivity, specificity, positive-predictive-value (PPV) and NPV of >50% stenosis on CT in predicting >50% stenosis on ICA between both institutes. But sensitivity, specificity, and NPV of >75% stenosis on CT in predicting >75% stenosis on ICA were significantly higher in Institute-2 than in Institute-1. This is mainly because of more severe coronary-artery disease including calcification in Institute-1; there might also have been an influence of differences in scanning and reconstruction methods. Conclusions: 320-slice-CT shows relatively high diagnostic-accuracy for the detection of significant coronaryartery stenosis compared with ICA even in CAF subjects, in a two-center analysis. Retrospective-ECG-gated acquisition in 320-slice-CT shows significantly higher diagnostic-accuracy than prospective-ECG-gated acquisition for detection of >75% coronary-artery stenosis. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Purpose: We used bolus-tracking CT-images, which are usually used only to detect contrast-material in target organs for optimal-starting of acquisition, as virtual first pass myocardial perfusion images. Methods: Retrospective-analysis of 14 patients (10 male, 63 +/- 10 years) diagnosed with >= 75% stenosis confined to left-anterior-descending-artery (LAD) (7 patients, Group-1) or insignificant stenosis of any coronary artery (7 patients Group-2) diagnosed using invasive-coronary-angiograms (ICA) and enhanced 320-slice-CT within 3-months and without incident between examinations. Bolus-tracking CT-images were acquired at mid-level left-ventricle (LV) until CT-attenuation of descending-aorta increased to 200HU. We measured CT-attenuation (HU) in the LV anterior-wall (AW), the basal inter-ventricular-septum (BIVS), and LV basal lateral-wall (BLW) in end-systole using both bolus-tracking images and routine, enhanced, early-phase CT-images. Results: In the bolus-tracking images, the Group-1 LV AW, BIVS, BLW CT-attenuation and ratio of LV AW CT attenuation to the average of BIVS and BLW were 36 +/- 7HU, 62 +/- 11HU, 58 +/- 25HU, and 0.6 +/- 0.1 respectively. In Group-2, they were 53 +/- 14HU, 56 +/- 9HU, 54 +/- 15HU, and 1.0 +/- 0.3 respectively. LV AW CT-attenuation and the ratio of LV AW CT values to the average of BIVS and BLW, were significantly lower in Group-1 (both P < 0.05). These values were not significant using routine, enhanced, early-phase CT-images. Conclusions: Bolus-tracking CT-imagesmay be useful to detect the LAD-confined stenosis that cannot be detected using routine, enhanced, early-phase CT-images. This can be achieved by measuring the local-reduction in CT-attenuation of the LV AW compared with the average of those of the BIVS and BLW and without the need for drugs, exercise or additional radiation-exposure. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Background-Cardiac cell therapy has been proposed as one of the new strategies against myocardial infarction. Although several reports showed improvement of the function of ischemic heart, the effects of cell therapy vary among the studies and the mechanisms of the beneficial effects are still unknown. Previously, we reported that clonal stem cell antigen-1-positive cardiac progenitor cells exerted a therapeutic effect when transplanted into the ischemic heart. Our aims were to identify the cardiac progenitor-specific paracrine factor and to elucidate the mechanism of its beneficial effect. Methods and Results-By using an antibody array, we found that soluble junctional adhesion molecule-A (JAM-A) was abundantly secreted from cardiac progenitor cells. Pretreatment of neutrophils with conditioned medium from cultured cardiac progenitor cells or soluble JAM-A inhibited transendothelial migration and reduced motility of neutrophils. These inhibitory effects were attenuated by anti-JAM-A neutralizing antibody. Injection of cardiac progenitor cells into infarct heart attenuated neutrophil infiltration and expression of inflammatory cytokines. Injection of soluble JAM-A-expressing, but not of JAM-A siRNA-expressing, cardiac progenitor cells into the infarct heart prevented cardiac remodeling and reduced fibrosis area. Conclusions-Soluble JAM-A secreted from cardiac progenitor cells reduces infiltration of neutrophils after myocardial infarction and ameliorates tissue damage through prevention of excess inflammation. Our finding may lead to a new therapy for cardiovascular disease by using the anti-inflammatory effect of JAM-A.

Introduction: Antiplatelet effects of clopidogrel appear to be affected by various factors including genetic polymorphism. So far, there has been little information about the response of clopidogrel in Asians, whose prevalence of a CYP2C19 loss-of-function (LOF) allele is high. Methods and Results: We investigated background and clinical factors affecting on-clopidogrel platelet reactivity in Japanese patients undergoing coronary stent implantation (n = 114). In univariate analysis, antiplatelet effects of clopidogrel in a steady state were associated with not only CYP2C19 genotypes but also several factors including dyslipidemia. In addition, we developed an algorithm that can estimate P2Y12 Reaction Units (PRU) in a steady state by multiple regression analysis and evaluated the adequacy of the algorithm by the Akaike Information Criterion. Conclusions: We revealed several factors influencing on-clopidogrel platelet reactivity in Japanese patients. We also succeeded in developing an algorithm that estimates PRU in a steady state, although it is uncertain whether the algorithm can be applied to other populations. (C) 2014 Elsevier Ltd. All rights reserved.

Aims For successful ablation of ventricular outflow tract arrhythmia, estimation of its origin prior to the procedure can be useful. Morphology and lead placement in the right thoracic area may be useful for this purpose. Electrocardiography using synthesized right-sided chest leads (Syn-V3R, Syn-V4R, and Syn-V5R) is performed using standard leads without any additional leads. This study evaluated the usefulness of synthesized right-sided chest leads in estimating the origin of ventricular outflow tract arrhythmia. Methods and results This retrospective study included 63 patients in whom successful ablation of ventricular outflow tract arrhythmia was performed. Numbers of arrhythmias originating from the left ventricle, the septum of the right ventricle, and the free wall of the right ventricle were 11, 40, and 13, respectively. In one patient, two different left ventricular outflow tract origins were found. Electrocardiographic recordings from right-sided chest leads were divided into three types as follows: those in which an R > S concordance, a transitional zone, or an R < S concordance were detected. In all left arrhythmia cases, R > S concordance was observed. A transitional zone was evident in 34 of 40 cases of right ventricular outflow tract arrhythmia originating in the ventricular septum, and an R < S concordance was observed in 6 of the 40 cases. However, an R < S concordance was found in all cases of right ventricular outflow tract arrhythmia originating in the free wall. Conclusion Synthesized right-sided chest lead electrocardiography may be useful for estimating the origin of ventricular outflow tract arrhythmia.

Risk factors for atherosclerosis accelerate the senescence of vascular endothelial cells and promote atherogenesis by inducing vascular inflammation. A hallmark of endothelial senescence is the persistent up-regulation of pro-inflammatory genes. We identified CDC42 signaling as a mediator of chronic inflammation associated with endothelial senescence. Inhibition of CDC42 or NF-kappa B signaling attenuated the sustained up-regulation of pro-inflammatory genes in senescent human endothelial cells. Endothelium-specific activation of the p53/p21 pathway, a key mediator of senescence, also resulted in up-regulation of pro-inflammatory molecules in mice, which was reversed by Cdc42 deletion in endothelial cells. Likewise, endothelial-specific deletion of Cdc42 significantly attenuated chronic inflammation and plaque formation in atherosclerotic mice. While inhibition of NF-kappa B suppressed the pro-inflammatory responses in acute inflammation, the influence of Cdc42 deletion was less marked. Knockdown of cdc-42 significantly down-regulated pro-inflammatory gene expression and restored the shortened lifespan to normal in mutant worms with enhanced inflammation. These findings indicate that the CDC42 pathway is critically involved in senescence-associated inflammation and could be a therapeutic target for chronic inflammation in patients with age-related diseases without compromising host defenses.

Evolutionarily conserved Notch signaling controls cell fate determination and differentiation during development, and is also essential for neovascularization in adults. Although recent studies suggest that the Notch pathway is associated with age-related conditions, it remains unclear whether Notch signaling is involved in vascular aging. Here we show that Notch signaling has a crucial role in endothelial cell senescence. Inhibition of Notch signaling in human endothelial cells induced premature senescence via a p16-dependent pathway. Conversely, over-expression of Notch1 or Jagged1 prolonged the replicative lifespan of endothelial cells. Notch1 positively regulated the expression of inhibitor of DNA binding 1 (Id1) and MAP kinase phosphatase 1 (MKP1), while MKP1 further up-regulated Id1 expression by inhibiting p38MAPK-induced protein degradation. Over-expression of Id1 down-regulated p16 expression, thereby inhibiting premature senescence of Notch1-deleted endothelial cells. These findings indicate that Notch1 signaling has a role in the regulation of endothelial cell senescence via a p16-dependent pathway and suggest that activation of Notch1 could be a new therapeutic target for treating age-associated vascular diseases.