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Rupture of an atherosclerotic plaque is a key event in the development of cardiovascular disorders, in which matrix metalloproteinase-1 (MMP-1) plays a crucial role by degradation of extracellular matrix resulting in plaque instability. Cardiotrophin-1 (CT-1), a member of interleukin-6-type proinflammatory cytokines, has potent cardiovascular actions and is highly expressed in vascular endothelium, however its role in atherosclerosis has not been fully elucidated to date. The present study was designed to investigate whether CT-1 induces MMP-1 in human aortic endothelial cells (HAECs). Ribonuclease protection assay demonstrated that MMP-1 gene level in HAECs was enhanced by the treatment of CT-1 in a dose- and time-dependent manner. Immunocytochemical staining, Western immunoblot analysis and enzyme-linked immunosorbent assay revealed that CT-1 augmented MMP-1 protein synthesis and secretion. MMP-1 activity assay revealed that MMP-1 present in the supernatant of HAECs was exclusively precursor form. Casein zymography disclosed proteolytic activity in the supernatant of HAECs, which was enhanced by CT-1 treatment. Furthermore, pharmacological inhibitor study indicated the important roles of extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in mediating CT-1-induced MMP-1 gene and protein expression. These data reveal for the first time that CT-1 induces the proteolytic potential in HAECs by upregulating MMP-1 expression through ERK1/2, p38 MAP kinase, JNK and JAK/STAT pathways, and suggest that CT-1 may play an important role in the pathophysiology of atherosclerosis and plaque instability.

The prevalence, intensity, safety, and efficacy of oral anticoagulation (OAC) in addition to dual antiplatelet therapy (DAPT) in “real-world” patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) have not yet been fully evaluated. In the Coronary REvascularization Demonstrating Outcome Study in Kyoto registry cohort-2, a total of 1,057 patients with AF (8.3%) were identified among 12,716 patients undergoing first PCI. Cumulative 5-year incidence of stroke was higher in patients with AF than in no-AF patients (12.8% vs 5.8%, p <0.0001). Although most patients with AF had CHADS2 score ≥2 (75.2%), only 506 patients (47.9%) received OAC with warfarin at hospital discharge. Cumulative 5-year incidence of stroke in the OAC group was not different from that in the no-OAC group (13.8% vs 11.8%, p = 0.49). Time in therapeutic range (TTR) was only 52.6% with an international normalized ratio of 1.6 to 2.6, and only 154 of 409 patients (37.7%) with international normalized ratio data had TTR ≥65%. Cumulative 5-year incidence of stroke in patients with TTR ≥65% was markedly lower than that in patients with TTR <65% (6.9% vs 15.1%, p = 0.01). In a 4-month landmark analysis in the OAC group, there was a trend for higher cumulative incidences of stroke and major bleeding in the on-DAPT (n = 286) than in the off-DAPT (n = 173) groups (15.1% vs 6.7%, p = 0.052 and 14.7% vs 8.7%, p = 0.10, respectively). In conclusion, OAC was underused and its intensity was mostly suboptimal in real-world patients with AF undergoing PCI, which lead to inadequate stroke prevention. Long-term DAPT in patients receiving OAC did not reduce stroke incidence.

ObjectivesElevated serum urate (SU) levels are associated with arterial atherosclerosis and subsequent cardiovascular events. However, an optimal therapeutic target SU level for delaying atherosclerotic progression in patients with hyperuricaemia remains uncertain. The aim of this analysis was to assess an association between changes in SU level and carotid intima–media thickness (IMT) to examine whether an optimal SU concentration exists to delay atherosclerotic progression.MethodsThis was a post hoc analysis of the PRIZE (programme of vascular evaluation under uric acid control by xanthine oxidase inhibitor, febuxostat: multicentre, randomised controlled) study of Japanese adults with asymptomatic hyperuricaemia. The primary endpoint of this analysis was an association between changes in SU levels and mean common carotid artery IMT (CCA-IMT) after 24 months of febuxostat treatment.ResultsAmong subjects treated with febuxostat (n=239), a total of 204 who had both data on SU and mean CCA-IMT at baseline and 24 months were included in this analysis. The mean baseline SU level was 7.7±1.0 mg/dL, and febuxostat treatment significantly reduced SU concentrations at 24 months (estimated mean change ‒3.051 mg/dL, 95% CI ‒3.221 to ‒2.882). A multivariable linear regression analysis revealed that a reduction in SU level was associated with changes in mean CCA-IMT values at 24 months (p=0.025). In contrast, the achieved SU concentrations were not associated with changes in mean CCA-IMT at 24 months.ConclusionA greater reduction in SU, but not its achieved concentrations, may be associated with delayed progression of carotid IMT in patients with asymptomatic hyperuricaemia treated with febuxostat.Trial registration numberUMIN000012911

The purpose of this study was to evaluate the validity of brachial–ankle pulse wave velocity (baPWV) and the cardio–ankle vascular index (CAVI) as measures of arterial stiffness in hemodialysis (HD) patients. We studied 160 consecutively enrolled HD patients (mean age: 59±13 years; 91 male patients). We measured baPWV and CAVI using a VaSera VS-1000, maximum intima-media thickness (max IMT) of the carotid artery by ultrasonography and blood renal and lipid parameters. As a control, baPWV and CAVI were also measured in age- and gender-matched healthy volunteers. Both baPWV and CAVI were significantly higher in HD patients than in controls (baPWV: 1698±355 vs. 1454±263 cm s −1 , P < 0.0001; CAVI: 9.3±1.4 vs. 8.9±1.2, P < 0.01). BaPWV correlated positively with age ( r =0.549, P < 0.0001), systolic blood pressure (SBP) ( r =0.510, P < 0.0001), diastolic blood pressure ( r =0.203, P < 0.0001), pulse pressure (PP) ( r =0.499, P < 0.0001), Kt V −1 ( r =0.221, P < 0.01), Brinkman index ( r =0.186, P < 0.05) and max IMT ( r =0.285, P < 0.001). CAVI also correlated positively with age ( r =0.562, P < 0.0001), SBP ( r =0.395, P < 0.0001), PP ( r =0.490, P < 0.0001), Kt V −1 ( r =0.216, P < 0.01), Brinkman index ( r =0.238, P < 0.01) and max IMT ( r =0.280, P < 0.001). Multiple regression analysis demonstrated baPWV and CAVI correlated independently with age and SBP. Receiver operating characteristics (ROC) curve analysis demonstrated that baPWV and CAVI had similar power to predict increases in max IMT. We also measured baPWV and CAVI immediately before and after HD, and showed CAVI was influenced by changes in water volume. Both baPWV and CAVI are therefore useful indices of arterial stiffness in HD patients.

Relation of antiplatelet therapy (APT) discontinuation with the risk of serious cardiovascular events has not been fully addressed yet. This study is aimed to evaluate the risk of ischemic event after APT discontinuation based on long-term APT status of large cohort. In the CREDO-Kyoto Registry Cohort-2 enrolling 15939 consecutive patients undergoing first coronary revascularization, 10470 patients underwent percutaneous coronary intervention either with bare-metal stents (BMS) only (N=5392) or sirolimus-eluting stents (SES) only (N=5078). Proportions of patients taking dual-APT were 67.3% versus 33.4% at 1-year, and 48.7% versus 24.3% at 5-year in the SES and BMS strata, respectively. We evaluated daily APT status (dual-, single- and no-APT) and linked the adverse events to the APT status just 1-day before the events. No-APT as compared with dual- or single-APT was associated with significantly higher risk for stent thrombosis (ST) beyond 1-month after SES implantation (cumulative incidence rates beyond 1-month: 1.23 versus 0.15/0.29, P<0.001/P<0.001), while higher risk of no-APT for ST was evident only until 6-month after BMS implantation (incidence rates between 1- and 6-month: 8.43 versus 0.71/1.20, P<0.001/P<0.001, and cumulative incidence rates beyond 6-month: 0.31 versus 0.11/0.08, P=0.16/P=0.08). No-APT as compared with dual- or single-APT was also associated with significantly higher risk for spontaneous myocardial infarction (MI) and stroke regardless of the types of stents implanted. Single-APT as compared with dual-APT was not associated with higher risk for serious adverse events, except for the marginally higher risk for ST in the SES stratum. In conclusion, discontinuation of both aspirin and thienopyridines was associated with increased risk for serious cardiovascular events including ST, spontaneous MI and stroke beyond 1-month after coronary stenting.

Bilirubin can prevent oxidation of low-density lipoprotein (LDL) and may protect against atherosclerosis and coronary heart disease (CHD). The goal of this study was to characterize the relationship between bilirubin and CHD through measurements of bilirubin concentration, coronary endothelial function, and markers of oxidative stress, inflammation, and lipid/glucose metabolism. The study population consisted of 141 patients without CHD who underwent Doppler flow study. Vascular reactivity was examined by intracoronary administration of papaverine, acetylcholine (ACh) and nitroglycerin using a Doppler guide wire. Serum bilirubin, high-sensitivity C-reactive protein (hsCRP), malondialdehyde-modified LDL, LDL cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG), and immunoreactive insulin were also measured. Homeostasis model assessment insulin resistance index and estimated glomerular filtration rate (eGFR) were calculated. Univariate analysis revealed that both percent change in coronary blood flow (CBF) and coronary artery diameter induced by ACh correlated positively with log-transformed bilirubin ( r = 0.22, P < 0.05; r = 0.20, P < 0.05, respectively). Percent change in CBF in response to ACh correlated positively with eGFR ( r = 0.24, P < 0.05) and correlated inversely with age, LDL-C, and log-transformed FPG ( r = −0.24, P < 0.05; r = −0.17, P < 0.05, r = −0.22, P < 0.05, respectively). Multivariate analysis revealed that log-transformed bilirubin was the only independent predictor of percent change in CBF in response to ACh. Multivariate analysis revealed that log-transformed hsCRP and HDL-C were independent predictors of log-transformed bilirubin. These results suggest that a high level of bilirubin is associated with favorable coronary endothelial function, which may be mediated via the effect of bilirubin on inflammation and HDL-C.

Abstract Pulmonary vein isolation (PVI) was the main strategy for catheter ablation of atrial fibrillation (AF) until a remarkable report was published by Nademanee et al. in 2004. The ablation targeting complex fractionated atrial electrograms (CFAE) achieved not only a high rate of AF termination but also excellent outcomes in both paroxysmal and persistent AF without isolating pulmonary veins. AF is thought to be caused by random or spiral reentry, as the fixed circuit to maintain AF may not exist, although the CFAE-guided ablation strategy is based on the theory that AF is not entirely random. CFAEs play an important role in identifying AF substrates, and have temporal and spatial stability, thus representing desirable targets for AF ablation; however, CFAE-guided ablation has not been fully replicated by others. In reports showing that CFAE ablation did not yield a good outcome either alone or combined with PVI, the AF termination rates were extremely low. Although AF termination is not mandatory in CFAE-ablation, terminating AF in the majority of patients appears to be necessary to yield good outcomes; therefore, this review will discuss AF ablation guided by CFAE with or without PVI, with particular emphasis given to practical aspects of achieving AF termination.

A 26-year-old woman with intermittent fever was admitted to our hospital, and gradually developed facial edema. Examinations including computed tomography, transesophageal echocardiography, digital subtraction angiography, and pulmonary perfusion scintigraphy revealed intracardiac thrombus, superior vena cava syndrome, and pulmonary embolism. Clinical findings and laboratory data led us to make a diagnosis of Behçet's disease. Combination of intracardiac thrombus, superior vena cava syndrome, and pulmonary embolism are rare complications in Behçet's disease. Behçet's disease should be considered in the differential diagnosis of intracardiac mass of the right heart, and early diagnosis and treatment are essential for the management of Behçet's disease especially with large-vessel manifestations. In addition to a case report, we review the literature and report the characteristics of intracardiac thrombus in Behçet's disease.

An unhealthy lifestyle can increase the risk of cardiovascular disease. However, the mechanism by which lifestyle influences the development of cardiovascular disease remains unclear. Since coronary endothelial function is a predictor of cardiovascular prognosis, the goal of this study was to characterize the effect of enjoying hobbies on coronary endothelial function and cardiovascular outcomes. A total of 121 consecutive patients (76 men, 45 women) with almost normal coronary arteries underwent Doppler flow study of the left anterior descending coronary artery following sequential administration of papaverine, acetylcholine, and nitroglycerin. On the basis of responses to questionnaires, patients were divided into two groups; the Hobby group ( n = 71) who enjoyed hobbies, and the Non-hobby group ( n = 50) who had no hobbies. Cardiovascular outcomes were assessed at long-term follow-up using medical records or questionnaire surveys for major adverse cardiovascular events (MACE).The average follow-up period was 916 ± 515 days. There were no significant differences in demographics when comparing the two groups. The percent change in coronary blood flow and coronary artery diameter induced by acetylcholine was significantly greater in the Hobby group than in the Non-hobby group (49% ± 77% vs 25% ± 37%, P < 0.05, 4% ± 13% vs −3% ± 20%, P < 0.05, respectively). The MACE rate was significantly lower in the Hobby group than in the Non-hobby group ( P < 0.01). Enjoyment of hobbies was the only independent predictor of MACE (odds ratio 8.1 [95% confidence interval 1.60, 41.90], P = 0.01) among the variables tested. In the early stages of arteriosclerosis, enjoying hobbies may improve cardiovascular outcomes via its favorable effects on coronary endothelial function.

The comparative long-term antianginal efficacy of long-acting nitrates versus calcium channel antagonists remains unclear. The goal of the present study was to compare the coronary endothelial cell function and coronary artery vasoconstriction between patients with normal or mildly diseased coronary arteries treated with long-acting nitrates or calcium channel antagonists. Forty-two patients suspected to have angina pectoris and with normal or mildly diseased coronary arteries underwent Doppler flow study of the left anterior descending coronary artery. All patients were suspected to have angina pectoris and were receiving either long-acting nitrates ( n = 18; Nitrates group) or calcium channel antagonists ( n = 24; Ca-antagonists group) for at least 1 year. Vascular reactivity was assessed by intracoronary administration of papaverine, acetylcholine (Ach), and nitroglycerin using a Doppler guidewire. Segments that showed the greatest constrictive response to Ach were used for assessment of vasoconstriction. The percent increase in coronary blood flow (CBF) and coronary artery diameter (CAD) induced by Ach was significantly smaller in the Nitrates group than in the Ca-antagonists group (33% ± 74% vs 83% ± 77%, P < 0.05; −3% ± 16% vs 11% ± 12%, P < 0.01, respectively). The percent diameter reduction in the region of greatest constrictive response to Ach was significantly greater in the Nitrates group than in the Caantagonists group (44% ± 39% vs 15% ± 32%, P < 0.02). Long-term treatment with long-acting nitrates may produce less favorable effects on coronary endothelial function and the constrictive response to Ach when compared with long-acting calcium channel antagonists in patients with normal or mildly diseased coronary arteries.