Daisuke Fujioka

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.

Rapid Stabilization of Vulnerable Carotid Plaque Within 1 Month of Pitavastatin Treatment in Patients With Acute Coronary Syndrome

We determined time course of stabilization of echolucent carotid plaques by statin therapy in patients with acute coronary syndrome (ACS). Treatment with 4 mg/d pitavastatin (n = 33) or placebo (n = 32) was initiated within 3 days after onset of ACS in 65 patients with echolucent carotid plaque. Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) analysis before and 1 month after treatment in all patients. The calibrated IBS value (intima-media IBS value minus adventia IBS) of vulnerable carotid plaques favorably changed at 1 month after treatment in both groups, but the echolucency at 1 month improved more in the pitavastatin than in the placebo group (pitavastatin group: -18.7 ± 3.3 dB at pretreatment versus -12.7 ± 2.3 dB at 1 month *P < 0.001; placebo: -19.0 ± 3.5 dB versus -16.9 ± 3.2 dB, P < 0.05, *P < 0.01 versus the value at 1 month in placebo group). Levels of CRP, VEGF, and TNFα at 1 month were significantly lower in pitavastatin than placebo group. In conclusion, pitavastatin improved carotid plaque echolucency within 1 month of therapy in patients with ACS, in association with decrease in the inflammatory biomarkers related to vulnerable plaques.

Polymorphism in Glutamate-Cysteine Ligase Modifier Subunit Gene Is Associated With Impairment of Nitric Oxide–Mediated Coronary Vasomotor Function

Background—The minor −588T allele of polymorphism −588C/T of a modifier subunit gene in glutamate-cysteine ligase (GCLM), a rate-limiting enzyme for glutathione (GSH) synthesis, was associated with lower plasma GSH levels and was a risk factor for myocardial infarction. Methods and Results—We examined effects of the −588C/T polymorphism on coronary arterial diameter and blood flow responses to intracoronary infusion of acetylcholine in 157 consecutive subjects who had normal coronary angiograms. In multivariate linear regression analysis with covariates including traditional risk factors, the minor −588T allele had an independent association with impaired dilation or enhanced constriction of epicardial coronary arteries in response to acetylcholine, and it was independently associated with blunted increase in coronary flow response to acetylcholine. In a subgroup of 59 consecutive subjects, constrictor responses of epicardial coronary diameter to intracoronary infusion of NG-monomethyl-l-arginine, reflecting the presence of coronary nitric oxide (NO) bioactivity, had an inverse and independent association with the −588T allele in multivariate analysis. Conclusions—The −588T polymorphism of the GCLM gene causes a decrease in endothelial NO bioactivity, leading to impairment of endothelium-dependent vasomotor function in large and resistance coronary arteries. The GCL–GSH–NO axis may play a role in the defense system against coronary artery disease.

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.

High plasma levels of macrophage migration inhibitory factor are associated with adverse long-term outcome in patients with stable coronary artery disease and impaired glucose tolerance or type 2 diabetes mellitus

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.

Assessment of carotid plaque echolucency in addition to plaque size increases the predictive value of carotid ultrasound for coronary events in patients with coronary artery disease and mild carotid atherosclerosis

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.

Predictive value of remnant lipoprotein for cardiovascular events in patients with coronary artery disease after achievement of LDL-cholesterol goals

OBJECTIVES 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 levels <100mg/dL on lipid-lowering therapy. METHODS 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 levels <100mg/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. RESULTS 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, p<0.01). 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. CONCLUSIONS RLP-C was superior to non-HDL-C for predicting cardiovascular events in CAD patients with LDL-C levels <100mg/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.

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.

Group V secretory phospholipase A2 plays a pathogenic role in myocardial ischaemia–reperfusion injury

AIMS 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. METHODS AND RESULTS 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. CONCLUSION sPLA(2)-V plays an important role in the pathogenesis of myocardial I/R injury partly in concert with the activation of cPLA(2).