Keita Sano

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.

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.

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.

High serum levels of remnant lipoproteins predict ischemic stroke in patients with metabolic syndrome and mild carotid atherosclerosis

BACKGROUND AND OBJECTIVE Metabolic syndrome is prevalently associated with stroke. Triglyceride-rich lipoproteins contribute to atherothrombotic complications in metabolic syndrome. This study examined whether high levels of remnant lipoprotein, atherogenic triglyceride-rich lipoprotein, may be associated with future ischemic stroke in metabolic syndrome. METHODS AND RESULTS We followed up 292 consecutive patients with metabolic syndrome meeting ATP III criteria and mild carotid plaques for a period of </=24 months until occurrence of an ischemic stroke. Remnant lipoprotein (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method. Twenty-two ischemic stroke events occurred during follow-up. A multivariate Cox proportional hazards models showed that high RLP-C levels were a significant and independent predictor of ischemic stroke events (p<0.01). Echolucent carotid plaques were also a significant predictor of ischemic stroke that was independent of other carotid ultrasound parameters in Cox proportional hazards models (p<0.01). High RLP-C levels were intimately and independently associated with carotid plaque echolucency (p<0.01). CONCLUSIONS High RLP-C levels are an independent risk factor for future ischemic strokes in metabolic syndrome. High RLP-C levels may be related to echolucent carotid plaque, partly accounting for high risk for ischemic stroke in metabolic syndrome.

Ultrasound assessment of brachial endothelial vasomotor function in addition to carotid plaque echolucency for predicting cardiovascular events in patients with coronary artery disease

BACKGROUND Single assessment of either flow-mediated vasodilatation of the brachial artery (FMD) or carotid plaque echolucency provides prognostic information for both cerebrovascular and coronary events. OBJECTIVES This study tested the hypothesis that combined assessment using carotid plaque echolucency and FMD may have an additive effect when predicting cardiovascular events in patients with coronary artery disease (CAD). METHODS Ultrasound assessment of carotid plaque echolucency with integrated backscatter (IBS) analysis (calibrated IBS=intima-media IBS value-adventitia IBS) and FMD was performed in 547 consecutive patients with CAD. All the study patients were followed up prospectively for a period of ≤ 60 months until the occurrence of one of the following cardiovascular events: cardiac death, non-fatal myocardial infarction, unstable angina requiring coronary revascularization, or ischemic stroke. RESULTS During a mean follow-up period of 52 ± 10 months, 69 cardiovascular events occurred. A multivariate Cox proportional hazard model after 1000 bootstrapped resampling demonstrated that calibrated IBS and FMD were significant, independent predictors of future cardiovascular events after adjustment for known risk factors (calibrated IBS, HR 0.88, 95% CI 0.83-0.93; FMD, HR 0.76, 95% CI 0.68-0.85). The c-statistics, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses showed that the combination of calibrated IBS and FMD values had a greater incremental effect on the predictive value of known risk factors for cardiovascular events. CONCLUSIONS Combined assessment of brachial endothelial function and carotid plaque echolucency is an independent predictor of cardiovascular events and improves risk prediction when added to known risks.

Rapid improvement of carotid plaque echogenicity within 1 month of pioglitazone treatment in patients with acute coronary syndrome

OBJECTIVE This study examined whether pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, may stabilize vulnerable plaque with use of ultrasound evaluation of carotid artery plaque echolucency in patients with acute coronary syndrome (ACS) and type 2 diabetes mellitus (DM). METHODS AND RESULTS Treatment with pioglitazone (15 or 30mg/day, n=31) or placebo (n=30) was randomly assigned and initiated within 5 days after the onset of ACS in 61 patients with type 2 DM and echolucent carotid plaques. Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) before, at 2 weeks, and 1 month and 6 months after initiation of treatment. An increase in IBS value reflects an increase in carotid plaque echogenicity. Calibrated IBS value (intima-media IBS value minus adventitia IBS value) of echolucent carotid plaques did not change at 2 weeks but was significantly increased at 1 month after treatment in the pioglitazone group but not in the placebo group. The increase in calibrated IBS value was not significantly correlated with the effect of pioglitazone on glycemia. CONCLUSIONS Pioglitazone rapidly improved carotid plaque echolucency within 1 month of therapy initiation in patients with ACS and type 2 DM.

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.

Endothelial vasomotor dysfunction in the brachial artery predicts the short-term development of early stage renal dysfunction in patients with coronary artery disease.

BACKGROUND 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. METHODS Flow-mediated endothelium-dependent dilation (FMD) in brachial artery and renal functional parameters were measured in 757 patients with CAD without macroalbuminuria. RESULTS 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 level <1.0mg/dL, UAE <25mg/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 eGFR <60 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. CONCLUSIONS 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.