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Objective In an extremely aging society, it is beneficial to reconsider the value of medical treatment for extremely elderly patients. We therefore focused on the efficacy of statin therapy in extremely elderly patients. This study investigated the efficacy of statins for secondary prevention in patients over 75 years old. Methods This prospective multicenter registry included 1,676 consecutive extremely elderly patients with coronary artery disease who underwent successful percutaneous coronary intervention (PCI). The patients were followed up clinically for up to three years or until the occurrence of major adverse cardiac events (MACEs), defined as a composite of all-cause death and non-fatal myocardial infarction. Using propensity score methodology to eliminate selection bias, in a 1:1 matching ratio, we selected 466 pairs of patients for the analysis. Results During the median follow-up period of 25 months, MACEs occurred in 176 patients. The Kaplan-Meier analysis showed that statin treatment correlated with a lower probability of initial MACE occurrences within 30 days compared with no statin treatment (log-rank test, p0.001). According to a landmark analysis at day 30, statin treatment still showed consistent effectiveness for reducing MACE occurrence during the follow up period (p=0.04). A multivariable Cox hazard analysis showed that statin therapy significantly reduced MACE occurrence (hazard ratio 0.55 [0.40-0.75], p0.001). In the stratification analysis, statin therapy was especially beneficial in patients without symptomatic heart failure. Conclusion Statins were effective in preventing MACEs in extremely elderly patients after PCI.

Aims It was suggested that group V secretory phospholipase A2 (sPLA2-V) existed in the nucleus. This study examined whether nuclear sPLA2-V plays a role in endocytosis of acetylated low-density lipoprotein (AcLDL) in monocyte/macrophage-like cell line RAW264.7 cells. Methods RAW264.7 cells were transfected with shRNA vector targeting sPLA2-V (sPLA2-V-knockdown [KD] cells) or empty vector (sPLA2-V-wild-type [WT] cells). AcLDL endocytosis was assessed by incubation with 125I-AcLDL or AcLDL conjugated with pHrodo. Actin polymerization was assessed by flow cytometry using Alexa Fluor 546-phalloidin. Results In immunofluorescence microscopic studies, sPLA2-V was detected in the nucleus. ChIP-Seq and ChIP-qPCR analyses showed binding of sPLA2-V to the promoter region of the phosphoglycerate kinase 1 (Pgk1) gene. In the promoter assay, sPLA2-V-KD cells had lower promoter activity of the Pgk1 gene than sPLA2-V-WT cells, and this decrease could be reversed by transfection with a vector encoding sPLA2-V-H48Q that lacks enzymatic activity. Compared with sPLA2-V-WT cells, sPLA2-V-KD cells had decreased PGK1 protein expression, beclin 1 (Beclin1) phosphorylation at S30, and class III PI3-kinase activity that could also be restored by transfection with sPLA2-V-H48Q. sPLA2-V-KD cells had impaired actin polymerization and endocytosis, which was reversed by introduction of sPLA2-V-H48Q or PGK1 overexpression. In sPLA2-V-WT cells, siRNA-mediated depletion of PGK1 suppressed Beclin1 phosphorylation and impaired actin polymerization and intracellular trafficking of pHrodo-conjugated AcLDL. Conclusions Nuclear sPLA2-V binds to the Pgk1 gene promoter region and increases its transcriptional activity. sPLA2-V regulates AcLDL endocytosis through PGK1-Beclin1 in a manner that is independent of its enzymatic activity in RAW264.7 cells.

Aim To examine whether improvement in flow-mediated endothelium-dependent dilatation (FMD) of the brachial artery and brachial-ankle pulse wave velocity (baPWV) has an additive effect on achieving optimal goals of traditional risk factors to reduce cardiovascular risk in patients with coronary artery disease (CAD). Methods We assessed 323 patients with CAD and impaired vascular function, defined as an impaired FMD of the brachial artery (＜5.5%) and increased baPWV (＞1,440 cm/sec). After FMD and baPWV measurements at 24 weeks of optimal medical treatment (OMT), the study patients were followed up for ＜60 months or until a composite of cardiac death, nonfatal myocardial infarction (MI), unstable angina, or ischemic stroke occurs. Results During the median follow-up period of 35 months, cardiovascular events occurred in 72 patients. Multivariate Cox hazards analysis showed that patients with an improvement in FMD and baPWV had the lowest probability of future cardiovascular events. In addition, the improvement in FMD and baPWV had a significant incremental effect on the predictive value of the achievement of optimal goals for blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and hemoglobin A1c (HbA1c) using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Conclusions The improvement in FMD and baPWV had additive effects on risk reduction of the achievement of the optimal goals of traditional risk factors in patients with CAD. Thus, serial measurements of FMD and baPWV may be useful for identifying CAD patients at residual risk for adverse cardiovascular events following OMT.

Ultrasound assessment of the carotid artery provides prognostic information on coronary events. This study examined whether ultrasound assessments of plaque echolucency of the carotid artery are useful for identifying patients with coronary artery disease (CAD) who are at high risk but could benefit from lipid-lowering therapy for secondary prevention.Ultrasound assessment of carotid plaque echolucency with integrated backscatter (IBS) analysis was performed in 393 chronic CAD patients with low-density lipoprotein cholesterol (LDL-C) levels100 mg/dL on statin therapy. All patients were prospectively followed up for a maximum of 96 months or until the occurrence of one of the following coronary events: cardiac death, nonfatal myocardial infarction, or unstable angina pectoris requiring unplanned revascularization.During the follow-up period, 45 coronary events occurred. Patients were stratified by IBS (≤-16.3 or-16.3 dB, median value) and LDL-C level (70 or 70-99 mg/dL). Multivariate Cox proportional hazards analysis showed that patients with lower IBS and LDL-C 70-99 mg/dL had significantly higher probabilities of coronary events compared with those with higher IBS and LDL-C70 mg/dL, after adjustment for a baseline model of risk factors (hazard ratio 5.15; 95% confidence interval 1.21-22.0, p = 0.03). In contrast, patients with lower IBS and LDL-C70 mg/dL had an improved prognosis comparable with those with higher IBS. Addition of LDL-C levels to the baseline model of risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) in patients with lower IBS (NRI, 0.44, p = 0.04; and IDI, 0.035, p 0.01), but not in those with higher IBS.Evaluation of echolucency of the carotid artery was useful for selecting CAD patients at high risk of secondary coronary events but who could benefit from lipid-lowering therapy.

The relationship between low body mass index (BMI) and prognostic factors for patients with coronary artery disease, commonly observed in elderly individuals in Japan, is important. Few studies have evaluated the prognosis for patients with low BMI after percutaneous coronary intervention (PCI). Using a multivariable-adjusted model and data from a prospective cohort registry, we analyzed the risk associated with low BMI for patients after PCI.This prospective, multicenter registry included 5965 consecutive patients with coronary artery disease who underwent successful PCI. The patients were followed-up clinically for up to 3 years or until the occurrence of major adverse cardiac events. The primary endpoint was all-cause death and nonfatal myocardial infarction composite.Primary events occurred in 639 (10.7%) patients during the follow-up period. A risk analysis of the primary endpoint adjusted for the multivariable model showed a significant increase in risk for elderly individuals, underweight individuals [HR 1.43 (95% confidence interval (CI), 1.10-1.85), P＜0.001], those with diabetes mellitus (DM), peripheral artery disease, low left ventricular ejection fraction or acute coronary syndrome (ACS), and smokers. A stratified adjusted risk analysis based on BMI levels showed that the risk associated with underweight status was significantly pronounced for male patients, those aged 60-74 years, and those with DM or ACS.Underweight patients with several risk factors significantly increased risk after PCI. Furthermore, the risk associated with low BMI was significantly more pronounced for men, individuals aged 60-74 years, and patients with DM or ACS.

Background Although animal studies showed that Follistatin-like 1 (FSTL1) exerts cardioprotective effects against ischemic injury, little is known in humans. We examined whether FSTL1 is secreted in an infarcted myocardium and whether its production is associated with left ventricular (LV) remodeling in survivors of acute myocardial infarction. Methods and Results FSTL1 levels were measured by enzyme-linked immunosorbent assay in plasma collected from the aortic root and the anterior interventricular vein in 93 patients with anterior acute myocardial infarction. Measurement of FSTL1 levels and left ventriculography were repeated during the early phase (2 weeks) and the chronic phase (6 months) after MI. A persistent increment in FSTL1 levels from the aortic root to the anterior interventricular vein, reflecting FSTL1 production in the infarcted myocardium at both the early and chronic phases, was seen in 22 patients (24%). A linear regression analysis revealed that a persistent transmyocardial increment in FSTL1 levels was significantly associated with percent changes in LV end-diastolic volume index, LV end-systolic volume index, and LV ejection fraction from the early to the chronic phase (r = 0.44, 0.51, and −0.43, respectively, all P Conclusions The persistent production of FSTL1 in the infarcted myocardium was associated with adverse LV remodeling in survivors of acute myocardial infarction.

It is still unclear whether optimal medical therapy (OMT) after percutaneous coronary intervention (PCI) has beneficial effects on long-term clinical outcomes in patients aged ≥80 years with coronary artery disease (CAD).This study analyzed the time to the first major adverse clinical event including death or nonfatal myocardial infarction (MI), for up to 3 years after PCI using multicenter registry data. Data for 1056 patients aged80 years successfully treated with PCI were included in the analysis. OMT was defined as a combination of antiplatelet drug, statin, beta-blocker, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker.In total, 204 (19%) patients in this study received OMT and 852 (81%) received sub-OMT. During a median follow-up of 725 days, adverse clinical events occurred in 183 patients (death, n=177; nonfatal MI, n=6). Kaplan-Meier analysis showed that patients who received OMT had a lower probability of adverse clinical events than those who received sub-OMT (p0.01, log-rank test). Propensity score matching yielded 202 patient-pairs treated with OMT or sub-OMT, in whom 64 adverse clinical events (death, n=56, nonfatal MI, n=4) occurred during follow-up. OMT remained significant in the reduction of the risk of adverse clinical events in a multivariate Cox proportional hazards model (hazard ratio 0.44; 95% confidence interval 0.26-0.75; p=0.003).OMT after PCI was associated with significantly fewer adverse clinical events, including all-cause death and nonfatal MI, in patients aged ≥ 80 years with CAD. OMT might be safe and effective for these very elderly patients.

Reactive oxygen species that increase during cardiovascular disease (CVD) react with protein cysteine residues to form a glutathione adduct by S-glutathionylation, which is selectively removed by glutaredoxin-1 (Glrx). We previously showed that S-glutathionylation and Glrx play important roles in mouse models of CVD, such as heart failure and peripheral artery disease models. However, there are few clinical studies on Glrx in CVD. Although Glrx is a cytosolic protein expressed in various organs, it is detectable in human plasma. Studies have reported that Glrx in plasma is a potential disease maker, such as CVD and chronic kidney disease and diabetes, however, it remains unclear whether Glrx is related to the prognosis of patients with CVD. The purpose of this study was to elucidate whether Glrx levels in plasma are associated with future events in patients with CVD. Plasma levels of Glrx were measured in 555 patients with CVD who underwent cardiac catheterization using enzyme-linked immunosorbent assay. All patients were followed prospectively for ≤36 months or until occurrence of adverse events, including all-cause death, non-fatal myocardial infarction, and worsening heart failure. During a mean follow-up period of 33 months, 54 adverse events occurred. Kaplan-Meier analysis showed that higher levels of Glrx (0.622 ng/mL, determined by receiver-operating characteristic curve) resulted in a higher probability for adverse events compared with lower levels of Glrx (≤0.622 ng/mL) (P 0.01, log-rank test). Multivariate Cox proportional hazards analysis showed that Glrx was a significant predictor of adverse events after adjustment for known risk factors. In conclusion, levels of plasma Glrx0.662 ng/mL can predict future events in patients with CVD.

Background: Although the complex roles of macrophages in myocardial injury are widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. Methods: To examine the regulation and function of neutrophils in pressure overload–induced cardiac hypertrophy, mice underwent treatment with Ly6G antibody to deplete neutrophils and then were subjected to transverse aortic constriction. Results: Neutrophil depletion diminished transverse aortic constriction–induced hypertrophy and inflammation and preserved cardiac function. Myeloid deficiency of Wnt5a, a noncanonical Wnt, suppressed neutrophil infiltration to the hearts of transverse aortic constriction–treated mice and produced a phenotype that was similar to the neutropenic conditions. Conversely, mice overexpressing Wnt5a in myeloid cells displayed greater hypertrophic growth, inflammation, and cardiac dysfunction. Neutrophil depletion reversed the Wnt5a overexpression–induced cardiac pathology and eliminated differences in cardiac parameters between wild-type and myeloid-specific Wnt5a transgenic mice. Conclusions: These findings reveal that Wnt5a-regulated neutrophil infiltration has a critical role in pressure overload–induced heart failure.

BACKGROUND This study examined the predictive value of remnant lipoprotein levels for cardiovascular events (CVEs) in patients with stable coronary artery disease (CAD) and low-density lipoprotein cholesterol (LDL-C) levels

Stromal cell-derived factor-1α (SDF-1α) is an inflammatory chemokine that plays a critical role in cardiovascular disease. Although persistent inflammation causes renal dysfunction, it remains unclear whether SDF-1α is related to progression of chronic kidney disease. This study examined whether high levels of SDF-1α are associated with future declines in renal function in patients with coronary artery disease (CAD). Plasma levels of SDF-1α in the peripheral blood were measured by enzyme-linked immunosorbent assay in 344 patients with CAD. All patients were followed for 24 months or until the occurrence of renal dysfunction, defined as ≥ 25% decrease in estimated glomerular filtration rate (eGFR) from baseline. During the follow-up period, 36 patients developed renal dysfunction. Multivariate logistic regression analysis showed that high plasma levels of SDF-1α were significantly associated with progression of renal dysfunction (odds ratio 1.65; 95% confidence intervals 1.07–2.35, p = 0.03). In addition, high plasma levels of SDF-1α had a significant incremental effect on the predictive value of known risk factors for renal dysfunction in analyses using net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.58 [0.07–1.02], p

Renal dysfunction, defined as a lower estimated glomerular filtration rate (eGFR), has been shown to be related to cardiovascular events in patients with myocardial infarction (MI). However, the contribution of renal tubulointerstitial damage to the predictive value for cardiovascular events has not been established. The aim of this study was to elucidate whether renal tubulointerstitial damage is associated with the occurrence of cardiac death and recurrence of MI in patients who have had MI.Urinary β2-microglobulin (β2MG) was measured in 681 consecutive patients with MI in our hospital. All patients were followed up for12 years or until the occurrence of cardiac death and MI. During a median follow-up period of 6 years, the cumulative cardiac death rate was 5.4%, and the MI rate was 3.1%. When outcomes were divided into two groups according to the β2MG levels, cardiac death and MI rates were lower in patients with lower levels of β2MG (0.319 mg/gCre: determined by receiver operating characteristic analyses) than in those with β2MG ≥0.319 mg/gCre (5.9% versus 17.1%, p0.01). When outcomes were stratified according to the β2MG levels in combination with eGFR levels, Kaplan-Meier analyses showed that cardiac death and MI rates increased depending on an increase in the β2MG levels (p0.05). Moreover, multivariate Cox analyses revealed that high levels of β2MG were a significant independent predictor of adverse events (hazard ratio: 1.956; 95% confidence interval: 1.014-3.774; p = 0.045). The addition of high levels of β2MG to conventional risk factors, including eGFR and urinary albumin, improved the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.5447, p = 0.0002; IDI 0.0126, p = 0.0454).Renal tubulointerstitial damage, as assessed by urinary β2MG, is associated with the occurrence of cardiac death and recurrence of MI independent of renal glomerular function in patients with MI.

Although coronary endothelial vasomotor dysfunction predicts future coronary events, few human studies have shown the relationship between persistent endothelial vasomotor dysfunction and major adverse cardiovascular events (MACE) using serial assessments in the same coronary artery. This study examined whether persistent endothelial vasomotor dysfunction is related to MACE occurrence in the infarct-related coronary artery (IRA) of ST-segment elevation myocardial infarction (STEMI) survivors using serial assessments of the coronary vasomotor response to acetylcholine (ACh). This study included 169 consecutive patients with a first acute STEMI due to left anterior descending coronary artery (LAD) occlusion and successful reperfusion therapy with percutaneous coronary intervention. Vasomotor response to ACh in the LAD was measured within 2 weeks of acute myocardial infarction (AMI) (first test) and repeated 6 months (second test) after AMI under optimal anti-atherosclerotic therapy. MACE was defined as the composite of all-cause death, non-fatal MI, angina recurrence requiring percutaneous intervention or surgical bypass, and hospitalization for heart failure. We followed up 126 patients for a period of ≤ 60 months until MACE occurrence after second test. Nineteen MACEs occurred during the follow-up. The log-rank test, Kaplan–Meier curves and univariate Cox proportional hazards regression analysis showed that MACE occurrence was significantly associated with the persistent impairment of epicardial coronary artery dilation and coronary blood flow increases in response to ACh (log-rank test, p

Background Patients having type 2 diabetes mellitus (DM) and chronic kidney disease (CKD) are at high risk of cardiovascular events. Triglyceride-rich lipoprotein levels are synergistically increased in patients with DM and CKD. This study examined the predictive value of remnant lipoprotein levels for cardiovascular events in patients with DM and CKD. Methods Three hundred and sixty-five patients with type 2 DM and CKD were enrolled. Serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method. All patients were followed prospectively for a period of 45 ± 23 months or until occurrence of one of the following events: cardiac death, non-fatal myocardial infarction, unstable angina requiring unplanned coronary revascularization, or ischemic stroke. Results During the follow-up period, 59 patients had cardiovascular events. Multivariate Cox analysis revealed that high levels of RLP-C (≥4.3 mg/dL; median value) were a significant risk factor for cardiovascular events, independent of traditional risk factors (HR: 1.30; 95% CI: 1.04–1.63; p = 0.02). The addition of high levels of RLP-C to traditional risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.36, p = 0.01; and IDI 0.03, p = 0.02). Conclusions RLP-C is useful for risk assessment of future cardiovascular events in patients having type 2 DM and CKD.

Aim Although coronary endothelial vasomotor dysfunction predicts future coronary events, there are few human studies showing the relationship between endothelial vasomotor dysfunction and atheroma plaque progression in the same coronary artery. This study examined whether endothelial vasomotor dysfunction is related to atheroma plaque progression in the infarct-related coronary artery of ST-segment elevation myocardial infarction (STEMI) survivors using serial assessment of coronary plaque size with intravascular ultrasound (IVUS) and coronary vasomotor responses to acetylcholine (ACh). Methods This study included 50 patients with a first acute STEMI due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy with percutaneous coronary intervention (PCI). IVUS and vasomotor response to ACh in the LAD were measured within two weeks of acute myocardial infarction (AMI) (1st test) and repeated six months (2nd test) after AMI under optimal anti-atherosclerotic therapies. Results Percent atheroma volume (PAV) and total atheroma volume (TAV) in the LAD progressed over six months of follow-up in 18 and 14 patients, respectively. PAV and TAV progression was significantly associated with persistent impairment of epicardial coronary artery dilation and coronary blood flow increase in response to ACh at both the 1st and 2nd tests. PAV and TAV progression had no significant association with traditional risk factors, PCI-related variables, medications, and the coronary vasomotor responses to sodium nitroprusside, an endothelium-independent vasodilator. Conclusions Persistent impairment of endothelial vasomotor function in the conduit arterial segment and the resistance arteriole was related to atheromatous plaque progression in the infarct-related coronary arteries of STEMI survivors.

Remnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment.A total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD;5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6-9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD.Treatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = -0.18, p = 0.03), RLP-C (r = -0.39, p 0.001), RLP-C/TG (r = -0.34, p 0.001), and CRP (r = -0.27, p 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels.Improvement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.

The precise mechanisms underlying the high prevalence of pulmonary hypertension (PH) with increased pulmonary vascular resistance (PVR) in heart failure with preserved ejection fraction (HFpEF) remain largely unknown. Measurements of brachial-ankle pulse wave velocity (baPWV) have been shown to be useful for risk assessment in HF patients. Thus, this study sought to define the association of PVR with baPWV and clinical outcomes in HFpEF.Patients with HFpEF (n = 198) had measurements of baPWV and PVR by right heart catheterization, and were prospectively followed-up for96 months or until the occurrence of a composite of all-cause death, hospitalization with worsening HF, and nonfatal acute coronary syndrome.Multivariate logistic analysis showed that baPWV was independently associated with PH with increased PVR (P.001). During the follow-up period, 46 clinical events occurred. Multivariate Cox proportional hazards analysis showed that PH with increased PVR was a significant predictor of adverse outcomes after adjustment for conventional risk factors (HR 1.96, 95% CI 1.03-3.76, P = .04).PH with increased PVR was associated with increased baPWV and adverse clinical outcomes in HFpEF. Thus, increased arterial stiffness may contribute to increased risk predictability of PVR for patients with HFpEF.

Aims Phospholipase A2 receptor 1 (PLA2R) has multiple biological functions other than functioning as a receptor for secretory PLA2s. Two nonsynonymous polymorphisms in the C-type lectin-like domains (CTLD) 1 of PLA2R gene have been associated with idiopathic membranous nephropathy. This study examined whether the same PLA2R polymorphisms may alter functions of PLA2R in cells expressing the variant PLA2R. In addition, the clinical relevance of the experiment was examined. Methods Two nonsynonymous polymorphisms (T/C at rs3749117 and G/C at rs35771982) in CTLD1 of PLA2R gene were completely linked. HEK293 cells expressing human wild-type PLA2R (T at rs3749117 and G at rs35771982) or human mutant PLA2R that had double mutations (C at rs3749117 and C at rs35771982) were constructed. Results HEK293 cells expressing mutant PLA2R had lower migratory and proliferative responses to collagen I compared with cells expressing wild-type PLA2R. In 580 male patients, PLA2R gene polymorphisms were associated with an increase in maximum intima-media thickness (maxIMT) of the carotid artery. The multivariate regression model showed that PLA2R gene polymorphisms were a risk factor of an increased maxIMT that was independent of conventional risk factors (OR=1.93, 95% CI: 1.17-3.19, p＜0.01). Conclusions The nonsynonymous common variants of PLA2R gene altered biological functions in cells expressing variant PLA2R. PLA2R gene polymorphisms present a genetic risk of an increased IMT of the carotid artery in male. The functional changes in the variant PLA2R may potentially be responsible for its association with an increased IMT of the carotid artery.

Background: Ultrasound assessment of either intima-media thickness (IMT) or plaque echolucency of the carotid artery provides prognostic information on coronary events. This study examined the hypothesis that IMT and plaque echolucency of the carotid artery may remain useful for prediction of coronary events in patients with coronary artery disease (CAD) after achievement of LDL-C goals on statin therapy. Methods and Results: Ultrasound assessment of carotid maximum IMT (maxIMT) and plaque echolucency with integrated backscatter (IBS) analysis was performed in 357 chronic CAD patients with LDL-C

Background Rapid plaque progression and positive remodeling are recognized as vulnerable coronary plaque characteristics. This study examined whether serial carotid ultrasonography might be of value for assessment of coronary plaque progression and positive remodeling, measured by serial intravascular ultrasound (IVUS), in survivors of acute myocardial infarction (AMI). Methods Thirty-nine patients with AMI had repeated examinations by IVUS of culprit coronary arteries and echolucency of the coronary artery on admission (1st test) and 6 months later (2nd test). Plaque volume and external elastic membrane area of the native segment (15 ± 9 mm in length) beginning 5 mm proximal to the stent edge in the culprit coronary artery were measured using volumetric IVUS. Echolucency of the carotid artery was assessed by integrated backscatter (IBS) analysis. Lower IBS reflects an echolucent and lipid-rich plaque. Results Increase in coronary plaque volume and positive remodeling over 6 months occurred in 17 and 12 patients, respectively. The % change in carotid IBS value over 6 months was correlated with the % change in the coronary plaque volume (r = −0.69, p

Aims Chronic depletion of myocardial glutathione (GSH) may play a role in cardiac remodelling and dysfunction. This study examined the relationship between chronic GSH depletion and cardiac failure induced by pressure overload in mice lacking the modifier subunit (GCLM) of glutamate–cysteine ligase, the rate-limiting enzyme for GSH synthesis. In addition, we examined the association between idiopathic dilated cardiomyopathy (DCM) in humans and –588C/T polymorphism of the GCLM gene, which reduces plasma levels of GSH. Methods and results Pressure overload in mice was created by transverse aortic constriction (TAC). Myocardial GSH levels after TAC in GCLM−/− mice were 31% of those in GCLM+/+ mice. TAC resulted in greater heart and lung-weight-to-body-weight ratios, greater dilation and dysfunction of left ventricle, more extensive myocardial fibrosis, and worse survival in GCLM−/− than GCLM+/+ mice. Supplementation of GSH diethyl ester reversed the left-ventricular dilation and contractile dysfunction and the increased myocardial fibrosis after TAC in GCLM−/− mice. The prevalence of –588T polymorphism of the GCLM gene was significantly higher in DCM patients ( n = 205) than in age- and sex-matched control subjects ( n = 253) (36 vs. 19%, respectively, P < 0.001). The –588T polymorphism increased the risk of DCM that was independent of age, diabetes, and systolic blood pressure (OR 3.13, 95% CI: 2.28–4.44; P < 0.0001). Conclusion Chronic depletion of GSH exacerbates remodelling and dysfunction in the pressure-overloaded heart. The clinical relevance of this mouse model is supported by a significant association between –588T polymorphism of the GCLM gene and patients with DCM.

It remains undefined whether reversibility of endothelial dysfunction after optimized therapies for heart failure (HF) provides prognostic information in patients with HF. This study examined whether changes in endothelial vasomotor function after therapies for HF may predict future outcomes in patients with stable HF.This study included 245 patients with stable chronic ischemic HF and an impaired flow-mediated dilation (FMD) of the brachial artery (FMD5.5%). Measurement of FMD was repeated after 6 months for individualized and optimized therapy for HF and atherosclerotic risk factors. Patients were followed for 36 months or until the occurrence of cardiac death or hospitalization with decompensated HF.FMD was persistently impaired (5.5%) in 130 (53%) patients after 6 months of the optimized therapy, whereas it improved (FMD ≥5.5%) in the remaining 115 (47%) patients. During follow-up, an event occurred in 26 (20%) patients with persistently impaired FMD and in 7 (6%) patients with improved FMD (p0.01). Multivariate Cox hazards analysis showed that persistent impairment of FMD was an independent predictor of cardiac events (hazard ratio 3.0, 95% CI 1.3-6.9, p=0.013). Persistently impaired FMD had a significantly incremental effect on the predictability of brain natriuretic peptide levels for cardiac events. Baseline FMD before the therapy for HF and atherosclerotic risk factors had no significant prognostic information.Persistent endothelial vasomotor dysfunction despite therapies for HF and atherosclerotic risk factors was a predictor of cardiac events in patients with chronic ischemic HF.

Group IVA cytosolic phospholipase A2(cPLA2α), which preferentially cleaves arachidonic acid from phospholipids, plays a role in apoptosis and tissue injury. Downstream signals in response to tumor necrosis factor (TNF)-α, a mediator of myocardial ischemia-reperfusion (I/R) injury, involve cPLA2α activation. This study examined the potential role of cPLA2α and its mechanistic link with TNF-α in myocardial I/R injury using cPLA2α knockout (cPLA2α−/−) mice. Myocardial I/R was created with 10-wk-old male mice by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. As a result, compared with wild-type (cPLA2α+/+) mice, cPLA2α−/−mice had a 47% decrease in myocardial infarct size, preservation of echocardiographic left ventricle (LV) function (%fractional shortening: 14 vs. 21%, respectively), and lower content of leukotriene B4and thromboxane B2(62 and 50% lower, respectively) in the ischemic myocardium after I/R. Treatment with the TNF-α inhibitor (soluble TNF receptor II/IgG1 Fc fusion protein, sTNFR:Fc) decreased myocardial I/R injury and LV dysfunction in cPLA2α+/+mice but not cPLA2α−/−mice. sTNFR:Fc also suppressed cPLA2α phosphorylation in the ischemic myocardium after I/R of cPLA2α+/+mice. Similarly, sTNFR:Fc exerted protective effects against hypoxia-reoxygenation (H/R)-induced injury in the cultured cardiomyocytes from cPLA2α+/+mice but not cPLA2α−/−cardiomyocytes. H/R and TNF-α induced cPLA2α phosphorylation in cPLA2α+/+cardiomyocytes, which was reversible by sTNFR:Fc. In cPLA2α−/−cardiomyocytes, TNF-α induced apoptosis and release of arachidonic acid to a lesser extent than in cPLA2α+/+cardiomyocytes. In conclusion, disruption of cPLA2α attenuates myocardial I/R injury partly through inhibition of TNF-α-mediated pathways.

PURPOSE: Exercise capacity of fewer than 5 metabolic equivalents (METs) has been associated with high risk of death and poor physical functioning in male patients with heart failure (HF). Therefore, we aimed to determine upper and lower extremity muscle strength levels required to attain an exercise capacity of 5 or more METs in male outpatients with HF. METHODS: We enrolled 148 male HF patients (age 60.1 +/- 1.0 years). Peak oxygen uptake (peak o2) was assessed by cardiopulmonary exercise testing (CPX). After CPX, we further divided the patients into groups according to exercise capacity: 5 or more METs (group A, n = 85) and fewer than 5 METs (group B, n = 63). Handgrip strength and knee extensor and flexor muscle strengths were assessed as indices of upper and lower extremity muscle strength, respectively. Receiver operating characteristic curves were used to select cutoff values for upper and lower extremity muscle strength resulting in an exercise capacity of 5 or more METs in these patients. RESULTS: Exercise capacity of 5 or more METs in male HF patients was equivalent to approximately 35.2 kgf of handgrip strength and 1.70 Nm/kg of knee extensor and 0.90 Nm/kg of knee flexor muscle strengths. CONCLUSIONS: These upper and lower extremity muscle strength values may be useful target goals for improvement of exercise capacity, risk management, and activities of daily living in male HF patients.

Background: The resolution of hyperglycemia is associated with suppression of in-hospital cardiac complications in patients with acute coronary syndromes (ACS). This study evaluated carotid artery plaque echolucency using ultrasound in patients with ACS and type 2 diabetes mellitus (DM) to determine whether acarbose, an α-glucosidase inhibitor, may rapidly stabilize unstable atherosclerotic plaques. Methods and Results: ACS patients with type 2 DM and carotid plaques (n=44) were randomly assigned to treatment with acarbose (150 or 300 mg/day, n=22) or a control group (no acarbose, n=22). Acarbose treatment was initiated within 5 days after the onset of ACS. Unstable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) before, and at 2 weeks, 1 and 6 months after the initiation of treatment. An increase in the IBS value reflected an increase in carotid plaque echogenicity. As results, the IBS value of echolucent carotid plaques showed a significant increase at 1 month and a further increase at 6 months after treatment in the acarbose group, but there was minimal change in the control group. The increase in IBS values was significantly correlated with a decrease in C-reactive protein levels. Conclusions: Acarbose rapidly improved carotid plaque echolucency within 1 month of therapy in patients with ACS and type 2 DM.

Mechanisms for the lack of efficacy of anti-angiogenic strategies for cancer have not been elucidated. We previously demonstrated that up-regulated glutaredoxin-1 (Glrx) inhibited endothelial cell (EC) angiogenic properties. Glrx is a small cytosolic enzyme which reverses glutathione adducts on protein thiols. Global Glrx transgenic mice had impaired ischemic limb vascularization, while Glrx knockout mice showed enhanced ischemic revascularization in association with HIF-1a activation. Here we generated EC-specific Glrx transgenic mice (EC-Glrx TG) by crossing VE-cadherin tTA mice and tet-operated Glrx mice. Similar to global Glrx TG mice, EC-Glrx TG mice showed impaired blood flow recovery after femoral artery ligation. Subcutaneous Matrigel implants contained significantly lower hemoglobin content compared to control mice, indicating less EC migration in EC-Glrx TG mice. Potential suppression of tumor angiogenesis was tested in EC-Glrx TG mice. When B16F0 mouse melanoma cells were subcutaneously implanted for 2 weeks, isolectin B4 staining in tumors indicated fewer EC markers in EC-Glrx TG tumors. Unexpectedly, B16F0 tumor weight was not inhibited, but rather dramatically promoted in EC-Glrx TG mice (667 ± 160 vs. 1229 ± 202 mg, n=12, 8, respectively, P

Triglycerides-rich lipoproteins are related to residual cardiovascular risk in patients on lipid-lowering treatment who achieve low-density lipoprotein cholesterol (LDL-C) goals. This study examined the predictive value of remnant lipoprotein levels for cardiovascular events in patients with coronary artery disease (CAD) with LDL-C levels100mg/dL on lipid-lowering therapy.Serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 560 patients with CAD who had LDL-C levels100mg/dL on lipid-lowering therapy, including statin (58%), fibrate (13%) or diet only (29%). All the patients were followed prospectively for a period of ≤ 36 months or until occurrence of one of the following events: cardiac death, non fatal myocardial infarction, unstable angina requiring coronary revascularization, or ischemic stroke.During a mean follow-up period of 33 months, 40 events occurred. Stepwise multivariate Cox proportional hazard analysis showed that RLP-C was a significant predictor of cardiovascular events after adjustment for known risk factors and lipid variables including triglycerides, non-high-density lipoprotein (HDL)-C, and total apolipoprotein B (HR 1.53, 95% CI 1.35-1.97, p0.01). The c-statistics showed that addition of RLP-C had a greater incremental effect on the predictive value of conventional risk factors than addition of non-HDL-C or total apolipoprotein B.RLP-C was superior to non-HDL-C for predicting cardiovascular events in CAD patients with LDL-C levels100mg/dL on lipid-lowering treatment. Remnant lipoprotein may therefore be an important target for residual risk reduction after LDL-C goals on lipid lowering therapy.

This study examined whether endothelial vasomotor dysfunction in the brachial artery predicted early renal dysfunction in patients with coronary artery disease (CAD). Endothelial function in the renal vasculature plays an important role in the regulation of renal hemodynamics. As endothelial dysfunction is a systemic disorder, there may be a relationship between endothelial function in the brachial artery and renal vasculature.Flow-mediated endothelium-dependent dilation (FMD) in brachial artery and renal functional parameters were measured in 757 patients with CAD without macroalbuminuria.In a cross-sectional data, an impaired FMD was associated with higher serum creatinine levels and urinary albumin excretion (UAE), lower creatinine clearance rate and estimated glomerular filtration rate (eGFR) at baseline in multiple linear regression analysis. In a follow-up study including a subgroup of 448 patients with normal renal function (serum creatinine level1.0mg/dL, UAE25mg/day and eGFR ≥ 60 mL/min/1.73 m(2) at baseline), 96 patients had an endpoint of early stage renal dysfunction (serum creatinine levels ≥ 1.2mg/dL, UAE ≥ 30 mg/day and/or eGFR60 mL/min/1.73 m(2)) during 12 month follow-up. Multivariate logistic regression analysis showed that impaired FMD was significantly associated with progression to the early stage renal dysfunction after adjustment with age, diabetes mellitus, hypertension and C-reactive protein levels.Endothelial vasomotor dysfunction in the brachial artery is independently associated with progression from normal renal function to early stage renal dysfunction in patients with CAD. Measurement of FMD may therefore be useful for assessing risk of future renal dysfunction.

Objectives MIF is proatherogenic and is highly expressed in unstable atherosclerotic plaques. Circulating levels of MIF are increased in patients with impaired glucose tolerance or type 2 diabetes mellitus (IGT/T2DM). We examined whether high circulating levels of macrophage migration inhibitory factor (MIF) are related to increased risk of future coronary events in patients with coronary artery disease (CAD) and IGT/T2DM. Methods Plasma MIF levels after overnight fast were measured by ELISA in 617 patients with stable CAD including 79 patients with IGT and 215 patients with T2DM. All patients were prospectively followed for 60 months or until occurrence of one of the coronary events: cardiac death, nonfatal myocardial infarction, unstable angina pectoris requiring coronary revascularization. Results During the follow-up period, an event occurred in 77 (26%) patients with IGT/T2DM and 50 (15%) patients without IGT/T2DM. In patients with IGT/T2DM, higher MIF levels were a significant predictor of coronary events in a multivariate Cox proportional hazards analysis that included the known risk factors, C-reactive protein levels and medication as covariates (HR 3.3, 95% CI 1.6–8.3, p =0.006). The c -statistic showed that the predictive value of MIF levels was incremental over that of the conventional predictors for coronary events (area under ROC curve; 0.70 and 0.61, respectively, p =0.001). In contrast, MIF levels were not significantly related to future coronary events in patients without IGT/T2DM. Conclusions High MIF levels are an independent risk factor for future coronary events in CAD patients with IGT/T2DM.

Several types of secretory phospholipase A2 (sPLA2) are expressed in lung tissue, yielding various eicosanoids that might cause pulmonary edema. This study examined whether inhibition of sPLA2 activity attenuates acute cardiogenic pulmonary edema in mice. Acute cardiogenic pulmonary edema was induced in C57BL/6J male mice by an increase in heart rate with continuous intravenous infusion of isoproterenol (ISP) (10 mg/kg/h) at 2 weeks after the creation of myocardial infarction by left coronary artery ligation. Just before ISP infusion, a single intraperitoneal injection of 100 mg/kg LY374388, a prodrug of LY329722 that inhibits sPLA2 activity, or vehicle was administered. The ISP infusion after myocardial infarction induced interstitial and alveolar edema on lung histology. Furthermore, it increased the lung-to-body weight ratio, pulmonary vascular permeability evaluated by the Evans blue extravasation method, lung activity of sPLA2, and lung content of thromboxane A2 and leukotriene B4. These changes were significantly attenuated by LY374388 treatment. In Kaplan-Meier analysis, the survival rate during the ISP infusion after myocardial infarction was significantly higher in LY374388- than in vehicle-treated mice. Similar results were obtained with another inhibitor of sPLA2 activity, para-bromophenacyl bromide. In conclusion, inhibition of sPLA2 activity suppressed acute cardiogenic pulmonary edema.

Background— Sirolimus-eluting stent (SES) implantation aggravated endothelial vasomotor dysfunction in infarct-related coronary arteries. Methods and Results— This study examined the effect of SES implantation on the duration of reperfusion-induced endothelial vasomotor dysfunction in infarct-related coronary arteries and on postinfarct left ventricular dysfunction in acute myocardial infarction (AMI). Patients with a first AMI due to occlusion of the left anterior descending coronary artery and successful reperfusion using SES (n=15) or bare metal stents (BMS; n=18) were examined. The vasomotor response of the left anterior descending coronary artery to acetylcholine and left ventriculography were examined 2 weeks and 6 months after AMI. At 6 months after AMI, the impairment of epicardial coronary artery dilation and coronary blood flow increase in response to acetylcholine was recovered from 2 weeks after AMI in BMS-treated patients, whereas the responses of SES-treated patients improved but remained impaired compared with BMS-treated patients (% increase in blood flow, 77�12% in SES versus 116�15% in BMS at 10 μg/min of acetylcholine, P P Conclusions— SES implantation may delay recovery of reperfusion-induced endothelial vasomotor dysfunction in infarct-related coronary arteries and left ventricular regional dysfunction for at least 6 months after AMI.

Amino acid (AA) administration can stimulate heat accumulation in the body, as especially found under anesthetic conditions. To test our hypothesis that marked rise in plasma insulin concentrations following AA administration plays an important role in the heat storage, we intravenously administered either a balanced AA mixture or saline over 3 h, both with and without a primed-constant infusion of somatostatin in propofol-anesthetized rats. Rats on AA but lacking marked rise in plasma insulin by somatostatin treatment failed to show: attenuation of fall in core body temperature; partial increases in oxygen consumption; and stimulated muscle protein synthesis. Furthermore, the AA’s stimulatory effects on phosphorylation of mTOR, 4E-BP1, and S6K1 were partially blocked by somatostatin. Our findings strongly suggest that the marked rise in insulin following AA administration promote translation initiation activities and stimulate muscle protein synthesis, which facilitates heat accumulation in the body.

Aim Although plasminogen activator inhibitor-1 (PAI-1) is abundantly expressed in infarcted myocardium, the pathogenic role of myocardial PAI-1 remains unknown. This study examined whether PAI-1 in the infarcted lesion contributes to coronary endothelial dysfunction and left ventricular (LV) dysfunction in patients with acute myocardial infarction (AMI). Methods Plasma levels of PAI-1 activity and tissue-plasminogen activator (tPA) antigen were measured 2 weeks and 6 months after MI by ELISA in plasma obtained from the aortic root (AO) and anterior interventricular vein (AIV) in 28 patients with a first AMI due to occlusion of the left anterior descending coronary artery (LAD). Coronary blood flow responses in LAD to intracoronary infusion of acetylcholine (ACh) and left ventriculography were measured at the same time points: 2 weeks and 6 months after MI. Results The trans-myocardial gradient of PAI-1 from AO to AIV, reflecting production/release of PAI-1 in the infarcted lesion, was inversely correlated with the coronary blood flow response to ACh 6 months after MI (r=-0.43, p=0.02) and with the percentage change in LV regional motion in the LAD territory from 2 weeks to 6 months after MI (r=-0.38, p=0.04). The trans-myocardial gradient of tPA level showed no significant correlations. Conclusions PAI-1 produced in the infarcted myocardium and released into the coronary circulation is associated with endothelial dysfunction in resistance vessels of the infarct-related coronary arteries and with progressive dysfunction of the infarcted region of the left ventricle in AMI survivors.

Aim Functional and structural abnormalities of the peripheral arteries are associated with renal dysfunction, independent of the presence of renal artery stenosis. This study investigated whether echolucent carotid plaque is associated with a future decline in the renal function in patients with coronary artery disease (CAD). Methods Ultrasound assessments of carotid plaque echolucency with integrated backscatter (IBS) analyses were performed in 327 patients with stable CAD and carotid plaque who exhibited a normal renal function (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m(2)) at baseline. A lower IBS value reflects the presence of echolucent and lipid-rich unstable plaque. All patients were followed up for 36 months or until the occurrence of renal dysfunction, defined as an eGFR of ＜45 mL/min/1.73 m(2). Results During the follow-up period, 39 patients developed renal dysfunction. A multivariate logistic regression analysis showed that the presence of carotid plaque with a low IBS value was significantly associated with progression to renal dysfunction (odds ratios 0.48; 95% CI 0.30-0.78, p= 0.003). In addition, carotid plaque with a low IBS value had a significant incremental effect on the predictive value of known risk factors for renal dysfunction in analyses using c-statistics (AUC of the baseline risk model with and without IBS: 0.83 vs. 0.79, respectively, p=0.04), net reclassification improvement (index=0.549, p=0.001) and integrated discrimination improvement (index=0.068, p=0.002). Conclusions Echolucency of the carotid arteries is associated with future renal dysfunction in patients with stable CAD, indicating that the mechanisms related to plaque instability may be involved in the onset of renal dysfunction.

An 11-year-old boy developed occlusion of the left internal carotid artery (ICA) following surgical correction of atypical coarctation of the aorta. The patient was admitted to our hospital after presenting with severe hypertension secondary to abdominal aortic hypoplasia and renal artery stenosis. Reconstruction of the abdominal aorta with bypass grafting was performed without complication. However, in the postoperative period, the patient experienced recurrent transient ischemic attacks manifesting as paresthesia of the right upper limbs, dysarthria, and right-sided weakness. Cerebral angiography revealed occlusion of the C2 portion of the left ICA and decreased resting cerebral blood flow in the left hemisphere. Extracranial-intracranial arterial bypass was performed, and the patient suffered no further adverse neurological events. Coarctation of the aorta is an uncommon congenital condition that may result in cerebral ischemic disease. The cerebrovascular circulation should be evaluated, even in patients without a pre-existing history of cerebral ischemic symptoms.

Contrast-enhanced ultrasound (CEUS) of the carotid artery is a potential technique for imaging plaque neovascularization, a feature of unstable atherosclerotic plaques. This study examined whether assessment of intra-plaque neovascularization of the carotid artery using CEUS provides prognostic information in patients with coronary artery disease (CAD).A total of 206 patients with stable CAD underwent a CEUS examination of the carotid artery and were followed up prospectively for38 months or until a cardiac event (cardiac death, non-fatal myocardial infarction (MI), unstable angina pectoris (uAP) requiring unplanned coronary revascularization, or heart failure requiring hospitalization). The degree of contrast signals measured within the carotid plaque was quantified by calculating the mean gray scale level within the region of interest of the carotid plaque, expressed as plaque enhanced intensity.During the follow-up period, 31 events occurred (2 cardiac deaths, 7 non-fatal MIs, 16 uAP, and 6 heart failure). Multivariate Cox proportional hazard analysis showed that plaque enhanced intensity was a significant predictor of cardiac events independent of traditional risk factors (HR, 1.13; 95% CI, 1.05-1.21; p0.001). The addition of the plaque enhanced intensity to traditional risk factors resulted in net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.62, p=0.001; and IDI 0.106, p=0.002).The assessment of carotid plaque neovascularization using quantitative analysis of CEUS may be useful for risk stratification in patients with CAD.

Glutaredoxin-1 (Glrx) is a cytosolic enzyme that regulates diverse cellular function by removal of GSH adducts from S-glutathionylated proteins including signaling molecules and transcription factors. Glrx is up-regulated during inflammation and diabetes. Glrx overexpression inhibits VEGF-induced endothelial cell (EC) migration. The aim was to investigate the role of up-regulated Glrx in EC angiogenic capacities and in vivo revascularization in the setting of hind limb ischemia. Glrx overexpressing EC from Glrx transgenic mice (TG) showed impaired migration and network formation and secreted higher level of soluble VEGF receptor 1 (sFlt), an antagonizing factor to VEGF. After hind limb ischemia surgery Glrx TG mice demonstrated impaired blood flow recovery, associated with lower capillary density and poorer limb motor function compared to wild type littermates. There were also higher levels of anti-angiogenic sFlt expression in the muscle and plasma of Glrx TG mice after surgery. Non-canonical Wnt5a is known to induce sFlt. Wnt5a was highly expressed in ischemic muscles and EC from Glrx TG mice, and exogenous Wnt5a induced sFlt expression and inhibited network formation in human microvascular EC. Adenoviral Glrx-induced sFlt in EC was inhibited by a competitive Wnt5a inhibitor. Furthermore, Glrx overexpression removed GSH adducts on p65 in ischemic muscle and EC, and enhanced nuclear factor kappa B (NF-kB) activity which was responsible for Wnt5a-sFlt induction. Taken together, up-regulated Glrx induces sFlt in EC via NF-kB -dependent Wnt5a, resulting in attenuated revascularization in hind limb ischemia. The Glrx-induced sFlt may be a part of mechanism of redox regulated VEGF signaling.

Rationale: Recent evidence indicates that the biological effects of secretory phospholipase A 2 (sPLA 2 ) cannot be fully explained by its catalytic activity. A cell surface receptor for sPLA 2 (PLA 2 receptor 1 [PLA 2 R]) and its high-affinity ligands (including sPLA 2 -IB, sPLA 2 -IIE, and sPLA 2 -X) are expressed in the infarcted myocardium. Objective: This study asked whether PLA 2 R might play a pathogenic role in myocardial infarction (MI) using mice lacking PLA 2 R (PLA 2 R –/– ). Methods and Results: MI was induced by permanent ligation of the left coronary artery. PLA 2 R –/– mice exhibited higher rates of cardiac rupture after MI compared with PLA 2 R wild-type (PLA 2 R +/+ ) mice (46% versus 21%, respectively; P =0.015). PLA 2 R –/– mice had a 31% decrease in collagen content and a 45% decrease in the number of α-smooth muscle actin–positive fibroblasts in the infarcted region compared with PLA 2 R +/+ mice. PLA 2 R was primarily found in myofibroblasts in the infarcted region. PLA 2 R –/– myofibroblasts were impaired in collagen-dependent migration, proliferation, and activation of focal adhesion kinase in response to sPLA 2 -IB. Binding of sPLA 2 -IB to PLA 2 R promoted migration and proliferation of myofibroblasts through functional interaction with integrin β1, independent of the catalytic activity of sPLA 2 -IB. In rescue experiments, the injection of PLA 2 R +/+ myofibroblasts into the infarcted myocardium prevented post-MI cardiac rupture and reversed the decrease in collagen content in the infarcted region in PLA 2 R –/– mice. Conclusions: PLA 2 R deficiency increased the susceptibility to post-MI cardiac rupture through impaired healing of the infarcted region. This might be partly explained by a reduction in integrin β1–mediated migratory and proliferative responses of PLA 2 R –/– myofibroblasts.

Background: Contrast-enhanced ultrasound (CEUS) in the carotid artery has potential as a technique for imaging plaque neovascularization. This study examined whether CEUS could provide information on the severity and instability of coronary artery disease (CAD). Methods and Results: A total of 304 patients with CAD and carotid plaque underwent CEUS examination of the carotid artery. Intraplaque neovascularization was identified on the basis of microbubbles within the plaque and graded as: G0, not visible; G1, moderate; or G2, extensive microbubbles. The complexity and extent of the coronary lesions were assessed angiographically. A higher grade of CEUS-assessed plaque neovascularization of the carotid artery was associated significantly with greater complexity (ρ=0.48 by Spearman’s rank correlation test) and extent (ρ=0.51) of coronary lesions. G2 plaque neovascularization was a risk for acute coronary syndrome, independent of traditional risk factors (odds ratio 1.91, 95% confidence interval 1.04–3.53, P

Intracoronary thrombus is a source of active lipid mediators including eicosanoids that play a critical role in the pathogenesis of acute myocardial infarction (AMI). Eicosanoids are derived from arachidonic acid generated by phospholipase A(2) (PLA(2)). This study examined whether PLA(2) is expressed in the aspirated coronary thrombus and whether PLA(2) expression in the thrombus may be related to recurrence of cardiac events and development of atherosclerosis in the culprit coronary artery after AMI.Intracoronary thrombus was obtained using an aspiration catheter from 48 patients with AMI, who had successful emergent treatment with percutaneous coronary intervention (PCI). Repeated intravascular ultrasound in the culprit coronary artery was performed at emergent PCI and 6 months later in a subgroup of 20 patients.There was a higher prevalence of cells in the thrombus that were immunopositive to group IIA, IVA, V and X PLA2s in patients with (n = 11) than without (n = 37) cardiac events during 6 months of follow-up (P0.05 for all). The prevalence of the cells that were immunopositive to group IIA, IVA and V PLA2s in the thrombus was significantly associated with the percent increase in atheroma volume (r = 0.60, 0.55 and 0.45, respectively, P0.05 for all) after 6 months in the native coronary segment distal to the culprit coronary lesion.PLA(2) expression in coronary thrombus is associated with recurrence of cardiac events and development of atherosclerosis in the culprit coronary artery in AMI survivors.

Group V secretory phospholipase A(2) (sPLA(2)-V) is highly expressed in the heart. This study examined (i) the role of sPLA(2)-V in myocardial ischaemia-reperfusion (I/R) injury and (ii) the cooperative action of sPLA(2)-V and cytosolic PLA(2) (cPLA(2)) in myocardial I/R injury, using sPLA(2)-V knockout (sPLA(2)V(-/-)) mice.Myocardial I/R injury was created by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. The sPLA(2)V(-/-) mice had a 44% decrease in myocardial infarct size, a preservation of echocardiographic LV function (%fractional shortening: 40 ± 3.5 vs. 21 ± 4.6, respectively), and lower content of leucotriene B(4) (LTB(4)) and thromboxane B(2) (TXB(2)) (40 and 37% lower, respectively) in the ischaemic myocardium after I/R compared with wild-type (WT) mice. Intraperitoneal administration of AACOCF3 or MAFP, inhibitors of cPLA(2) activity, decreased myocardial infarct size and myocardial content of LTB(4) and TXB(2) in both genotyped mice. The decrease in myocardial infarct size and content of LTB(4) and TXB(2) after cPLA(2) inhibitor administration was greater in WT mice than in sPLA(2)V(-/-) mice. I/R increased phosphorylation of extracellular signal-related kinase 1/2, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases in the ischaemic myocardium in association with cPLA(2) phosphorylation. The I/R-induced increase in the phosphorylation of p38 and cPLA(2) was less in sPLA(2)-V(-/-) mice than in WT mice. Pretreatment with the p38 inhibitor SB202190 suppressed an increase in cPLA(2) phosphorylation after I/R in WT mice.sPLA(2)-V plays an important role in the pathogenesis of myocardial I/R injury partly in concert with the activation of cPLA(2).

Objective This study examined whether changes in maximum intima-media thickness of carotid plaque (plaque-IMTmax) over 6 months predict future coronary events in patients with carotid plaque and coronary artery disease (CAD). Methods This study included 240 patients with CAD who had a carotid plaque (IMT≥1.1mm) at entry. A carotid ultrasound examination was performed at entry (1st test) and after 6 months (2nd test). The carotid plaque with the greatest axial thickness at the 1st test was selected as the target plaque for monitoring the change in plaque-IMTmax. After the 2nd test, patients were prospectively followed-up for 3 years or until the occurrence of one of the following coronary events: cardiac death, non-fatal myocardial infarction, or unstable angina pectoris requiring coronary revascularization. Results The change in plaque-IMTmax over 6 months ranged from −0.85 to 0.97mm (mean, −0.006±0.319mm). There were 41 events during follow-up. In a stepwise multivariate Cox proportional hazards model, the change in plaque-IMTmax was a significant predictor of coronary events after adjustment for known risk factors (HR per 0.1mm increase over 6 months, 1.21; 95%CI, 1.10–1.33, p =0.0001). Analysis of receiver operating characteristic (ROC) curves showed that the addition of the change in plaque-IMTmax to conventional risk factors resulted in a greater area under the ROC curve compared with conventional risk factors alone (0.81 and 0.70, respectively, p =0.02). Conclusion Short-term progression of carotid plaque-IMTmax was associated with future coronary events in patients with CAD.

Background: Remnant lipoproteinemia is a strong risk factor for cardiovascular (CV) diseases. This study examined which of 2 common lipid-lowering drugs (fibrates and statins) is more effective in patients with remnant lipoproteinemia and if lowering remnant lipoprotein levels can reduce CV risk. Methods and Results: Remnant lipoprotein levels were measured by an immunoseparation method (remnant-like lipoprotein particles cholesterol: RLP-C) in 274 patients with coronary artery disease and high RLP-C levels (≥5.0 mg/dl). They were randomly assigned to receive bezafibrate (200-400 mg/day) or pravastatin (10-20 mg/day), and were prospectively followed-up for 1 year or until the occurrence of CV events. Complete follow-up data were obtained in 180 patients. RLP-C levels at 1 year of treatment were reduced more by bezafibrate than pravastatin (37% and 25% from baseline, respectively). During follow-up, bezafibrate-treated patients had 3 CV events, compared with 12 events in pravastatin-treated patients (P

Objectives This study examined whether combined ultrasound assessment of plaque size and echolucency in the carotid artery had an additive effect for predicting coronary events in patients with coronary artery disease (CAD). Ultrasound assessment of either plaque size or echolucency of carotid artery provides prognostic information on coronary events. Combined assessment of plaque size and echolucency of carotid artery has the advantage of obtaining both structural and compositional information in the same artery in a single session. Methods and results Ultrasound assessment of carotid plaque maximum intima-media thickness (plaque-IMTmax) and echolucency with integrated backscatter analysis was performed in 413 patients with CAD and carotid plaque. All study patients were followed up prospectively for 54 months or until the occurrence of a coronary event. During the follow-up period, 49 coronary events occurred including 2 cardiac deaths, 10 non-fatal acute myocardial infarctions and 37 recurrent and refractory unstable angina. Multivariate Cox hazards analysis showed plaque-IMTmax alone (HR 2.01, 95%CI 1.30–3.10), plaque echogenicity alone (HR 0.86, 95%CI 0.80–0.91) and combination of high plaque-IMTmax and low echogenicity on categorical data (HR 2.56, 95%CI 1.39–4.74) were independent predictors of coronary events. Analysis using c -statistics showed that plaque-IMTmax and plaque echolucency in combination had a significant incremental effect on the predictive value of the conventional risk factors for coronary events. Conclusions Combined ultrasound assessment of carotid plaque size and echolucency has an additive value for prediction of coronary events. Further studies need to evaluate the clinical utility of both ultrasound measurements for risk stratification in CAD.

Summary Background and purpose It remains undetermined whether the addition of ezetimibe to ongoing statin therapy is more effective than increasing the dose of statin for reducing remnant lipoprotein levels in patients with remnant lipoproteinemia on previous statin treatment. This study examined whether combined ezetimibe and statin therapy resulted in a greater improvement in remnant lipoprotein levels and endothelial function than with the dose of statin in patients with remnant lipoproteinemia on previous statin treatment. Methods and results A total of 63 patients with stable coronary artery disease and high levels of remnant-like lipoprotein particle cholesterol (RLP-C) (≥5.0 mg/dL) on statin treatment were assigned randomly to two groups and treated with either addition of ezetimibe (10 mg/day, n = 32) or doubling of statin dose ( n = 31). The lipid profiles and flow-mediated dilation (FMD) of the brachial artery were measured at enrollment and after 6 months of treatment. Statin and ezetimibe combined therapy reduced RLP-C and improved FMD to a greater extent than doubling the statin dose (% reduction in RLP-C, 48 ± 18% vs. 33 ± 24%, respectively, p = 0.01; % improvement in FMD, 47 ± 48% vs. 24 ± 23%, respectively, p = 0.02). Conclusions The addition of ezetimibe to ongoing statin treatment reduced RLP-C levels and improved endothelial dysfunction to a greater extent than doubling the statin dose in patients with high RLP-C levels on previous statin treatment. The present results are preliminary and should be confirmed by further studies on a larger number of study patients.