Jyun-ei Obata

Persistent Impairment of Endothelial Vasomotor Function Has a Negative Impact on Outcome in Patients With Coronary Artery Disease

OBJECTIVES We assessed the hypothesis that changes in endothelial vasomotor function in response to optimized therapy for atherosclerotic coronary artery disease predict future cardiovascular events. BACKGROUND Although endothelial vasomotor dysfunction is a predictor of cardiovascular events, it remains unclear whether reversibility of endothelial dysfunction in response to risk factor reduction provides prognostic information. METHODS This study included 251 patients with newly diagnosed coronary artery disease and an impaired flow-mediated dilation (FMD) of the brachial artery (FMD <5.5%). Measurement of FMD was repeated after 6 months for individualized and optimized therapy to reduce risk factors according to American College of Cardiology/American Heart Association guidelines. Patients were followed up for 36 months or until 1 of the following events occurred: cardiac death, nonfatal myocardial infarction, recurrent and refractory angina pectoris requiring coronary revascularization, or ischemic stroke. RESULTS FMD was persistently impaired (<5.5%) in 104 (41%) patients after 6 months of optimized therapy, whereas it improved (FMD > or =5.5%) in the remaining 147 (59%) patients. During 36 months of follow-up, events occurred in 27 (26%) patients with persistently impaired FMD and in 15 (10%) patients with improved FMD (p < 0.01 by chi-square test). Multivariate Cox hazards analysis showed that persistent impairment of FMD was an independent predictor of events (hazard ratio: 2.9, 95% confidence interval: 1.5 to 6.2, p < 0.01). Baseline FMD before the optimized therapy to reduce risk factor had no significant prognostic information. CONCLUSIONS Persistent impairment of endothelial vasomotor function despite optimized therapy to reduce risk factors has an adverse impact on outcome in coronary artery disease patients.

Reduction in Myocardial Ischemia/Reperfusion Injury in Group X Secretory Phospholipase A2-Deficient Mice

Background— Group X secretory phospholipase A2 (sPLA2-X) has the most potent hydrolyzing activity toward phosphatidylcholine and elicits a marked release of arachidonic acid among several types of sPLA2. sPLA2-X is expressed in neutrophils, but its pathogenic role remains unclear. Methods and Results— We generated mice that lack sPLA2-X and studied their response to myocardial ischemia/reperfusion. The sPLA2-X−/− mice had a significant reduction in myocardial infarct size and a decrease in myocardial myeloperoxidase activity compared with sPLA2-X+/+ mice. Myocardial infarct size was also significantly reduced in lethally irradiated sPLA2-X+/+ mice reconstituted with sPLA2-X−/− bone marrow compared with sPLA2-X+/+ bone marrow. The extent of myocardial ischemia/reperfusion injury was comparable between sPLA2-X−/− and sPLA2-X+/+ mice in Langendorff experiments using isolated hearts and blood-free perfusion buffer, supporting a potential role of sPLA2-X in blood in myocardial ischemia/reperfusion injury. In the infarcted myocardium of sPLA2-X+/+ mice, sPLA2-X was released from neutrophils but not myocardial tissues and platelets and was undetectable in the peripheral serum. The sPLA2-X−/− mice had lower accumulation of neutrophils in ischemic myocardium, and the isolated sPLA2-X−/− neutrophils had lower release of arachidonic acid and attenuated cytotoxic activities including respiratory burst compared with sPLA2-X+/+ neutrophils. The attenuated functions of sPLA2-X−/− neutrophils were reversible by the exogenous addition of sPLA2-X protein. Furthermore, administration of a sPLA2 inhibitor reduced myocardial infarct size and suppressed the cytotoxic activity of sPLA2-X+/+ neutrophils. Conclusions— Myocardial ischemia/reperfusion injury was attenuated in sPLA2-X−/− mice partly through the suppression of neutrophil cytotoxic activities.

Adiponectin is released from the heart in patients with heart failure

BACKGROUND Plasma levels of adiponectin are decreased in patients with ischemic heart disease, but increased in patients with heart failure (HF). The source of increased adiponectin levels in patients with HF remains unknown. This study examined whether adiponectin, an adipocyte-derived protein with cardioprotective actions, is released from the heart in patients with HF. METHODS Plasma adiponectin levels sampled from the aorta, coronary sinus (CS), and peripheral vein (PV) were measure by ELISA in 138 consecutive patients with left ventricular ejection fraction (LVEF) <40% and in 40 normal controls. RESULTS PV adiponectin levels were significantly higher in patients with either non-ischemic HF (n=81) or ischemic HF (n=57) than controls; levels were similar between patients with non-ischemic HF and those with ischemic HF. There was a significant step-up in adiponectin levels from the aorta to the CS in patients with either non-ischemic HF or ischemic HF but not in controls. The CS-aorta difference in adiponectin levels, which reflect cardiac release of adiponectin, positively correlated with PV levels in patients with either non-ischemic HF or ischemic HF. The CS-aorta difference in adiponectin levels positively correlated with PV levels of brain natriuretic peptide and inversely with LVEF in patients with either non-ischemic HF or ischemic HF. CONCLUSIONS Adiponectin is released from the heart into the peripheral circulation in proportion to the extent of LV dysfunction in patients with HF irrespective of etiologies of HF.

Low adiponectin levels predict late in-stent restenosis after bare metal stenting in native coronary arteries ☆

BACKGROUND Adiponectin, the most abundant protein secreted from adipose tissue, possesses anti-atherogenic properties. This study tested whether adiponectin plasma levels predict in-stent restenosis (ISR) after successful percutaneous coronary intervention (PCI) with bare-metal stents. METHODS The study included 148 consecutive patients who had elective PCI with bare-metal stents in de novo lesions of native coronary arteries for symptomatic coronary artery disease. Adiponectin levels were measured by ELISA 3 days or less before PCI. RESULTS Angiographic ISR (defined as >50% diameter stenosis) was found in 49 (33%) patients during 6 months of the follow-up. Adiponectin levels were lower in patients with ISR than those without ISR (3.5+/-0.3 vs. 6.9+/-0.4 microg/ml, respectively, p<0.01). Adiponectin levels were inversely correlated with late luminal loss of the stented lesions (r=-0.40, p<0.01). Using multivariate logistic regression analysis, low adiponectin levels (<4.5 microg/ml, arbitrarily determined from a receiver operating characteristic curve) served as a predictor of ISR that was independent of angiographic and procedural variables, and clinical factors known to be associated with ISR (odds ratio, 7.9; 95% CI, 3.0-21; p<0.01). Furthermore, low adiponectin levels also independently predicted target lesion revascularization (n=35) during follow-up (odds ratio, 3.7; 95% CI, 1.4-9.7; p<0.01). CONCLUSIONS Low adiponectin levels have a predictive value for late ISR after PCI with bare-metal stents in native coronary arteries.

Predictive value of serial assessment of endothelial function in chronic heart failure

BACKGROUND 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. METHODS This study included 245 patients with stable chronic ischemic HF and an impaired flow-mediated dilation (FMD) of the brachial artery (FMD <5.5%). 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. RESULTS 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 (p<0.01). 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. CONCLUSIONS Persistent endothelial vasomotor dysfunction despite therapies for HF and atherosclerotic risk factors was a predictor of cardiac events in patients with chronic ischemic HF.

Short-term progression of maximum intima-media thickness of carotid plaque is associated with future coronary events in patients with coronary artery disease.

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 0.97 mm (mean, -0.006 ± 0.319 mm). 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.

Treatment of Acute Myocardial Infarction With Sirolimus-Eluting Stents Results in Chronic Endothelial Dysfunction in the Infarct-Related Coronary Artery

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 &mgr;g/min of acetylcholine, P<0.01). Left ventricular regional wall dysfunction in the left anterior descending coronary artery territory improved from 2 weeks to 6 months after AMI in BMS-treated patients but not in SES-treated patients (% improvement of average SD/chord, 6% in SES versus 19% in BMS, P<0.05), although left ventricular global ejection fraction was similar between the groups at any time points. 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.

In‐stent restenosis is inhibited in a bare metal stent implanted distal to a sirolimus‐eluting stent to treat a long de novo coronary lesion with small distal vessel diameter

This study examined whether sirolimus‐eluting stent (SES) implantation exerts an antiproliferative action on a bare metal stent (BMS) placed distally in the same coronary artery.

Usefulness of a collateral channel dilator for antegrade treatment of chronic total occlusion of a coronary artery.

OBJECTIVES  The aim of this study was to clarify the effectiveness of a collateral channel dilator microcatheter in antegrade percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) of a coronary artery. BACKGROUND  The Corsair microcatheter, which was originally developed as a collateral channel dilator, has been reported to be useful for retrograde CTO-PCI. METHODS  We compared the success rate of the Corsair microcatheter collateral channel dilator for antegrade CTO-PCI with a previously available microcatheter. We analyzed the data from 27 patients (32 CTOs) using the FinecrossMG (Finecross group) and the data from 31 patients (34 CTOs) using the Corsair (Corsair group). RESULTS  There were no significant differences in the clinical or lesion characteristics between the 2 groups. The success rate for crossing the CTO by the microcatheter was 62.5% in the Finecross group and 85.3% in the Corsair group (P < 0.05). After the Corsair crossed the CTO, a 2-mm diameter balloon catheter crossed the lesion in all the cases, but it crossed the lesion in only 17 of 20 cases in the Finecross group (85.0%, P < 0.05). The number of balloon catheters used for predilation was significantly less in the Corsair group compared with the Finecross group (P < 0.05). CONCLUSIONS  The success rate for crossing of the microcatheters and the balloon catheters through the occlusion in antegrade CTO-PCI was better with the Corsair than with the FinecrossMG. In addition, the use of the Corsair reduced the number of balloon catheters used for predilation in antegrade CTO-PCI.

Measurement of the platelet retention rate in a column of collagen-coated beads is useful for the assessment of efficacy of antiplatelet therapy.

INTRODUCTION A simple, validated method to measure platelet function is unavailable for bedside use. Measurement of platelet retention rate using a column of collagen-coated beads and whole blood is a new, simple assay that reflects platelet aggregation. This study was aimed to examine the utility of this assay to assess efficacy of antiplatelet drug therapy. METHODS Citrated whole blood (1.5 ml) in a syringe was passed through a polyvinyl tube packed with collagen-coated beads for 40 seconds using a syringe pump. Platelet retention rate in the column was calculated from platelet counts in blood before and after passage. An increase in the retention rate reflects an increase in platelet activity. This new platelet retention assay and the traditional optical aggregometry assay were performed in 331 patients with stable coronary artery disease (CAD). RESULTS The retention rate was significantly reduced in patients taking dual antiplatelet therapy (aspirin plus clopidogrel or ticlopidine) compared with aspirin alone. There was a significant linear correlation between the platelet retention rate and platelet aggregability measured by the traditional method (r=0.44, p<0.001). In multivariate Cox proportional hazards analysis, higher platelet retention rate was an independent predictor of future cardiovascular events in patients on dual antiplatelet therapy (hazard ratio 3.9, 95% CI 1.6 to 9.5, p=0.003). CONCLUSIONS Measurement of the platelet retention rate in a column of collagen-coated beads may be useful for monitoring the efficacy of antiplatelet drug therapy in patients with CAD.