Manabu Uematsu

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.

The combined assessment of flow-mediated dilation of the brachial artery and brachial-ankle pulse wave velocity improves the prediction of future coronary events in patients with chronic coronary artery disease

BACKGROUND AND PURPOSE Measurement of either flow-mediated endothelium-dependent dilatation (FMD) of the brachial artery, brachial-ankle pulse wave velocity (baPWV), or intima-media thickness (IMT) of the carotid artery is useful for risk assessment of future cardiovascular events. This study examined whether combination of these vascular parameters may have an additive effect on the ability of traditional risk factors to predict coronary events in patients with chronic coronary artery disease (CAD). METHODS Patients (n=923) with stable CAD had measurements of FMD, baPWV, and maximum IMT (maxIMT), and were prospectively followed up for <8.5 years or until a coronary event - cardiac death, non-fatal myocardial infarction (MI) or unstable angina pectoris (uAP) requiring unplanned coronary revascularization. RESULTS During the follow-up period, 116 events occurred (29 cardiac deaths, 46 non-fatal MIs and 41 cases of uAP). A multivariate Cox proportional hazards analysis showed that FMD (HR 0.50, 95% CI 0.38-0.66) and baPWV (HR 1.52, 95% CI 1.27-1.82) but not maxIMT were significant predictors of coronary events. Based on the concordance statistics, the predictive value of traditional risk factors [area under the receiver operating characteristic curve (AUC), 0.67] was increased more by the addition of FMD and baPWV combined (AUC, 0.75) compared with the addition of either maxIMT, FMD, or baPWV alone, or the combination of maxIMT and FMD or maxIMT and baPWV (AUC, 0.67, 0.71, 0.71, 0.71 and 0.71, respectively). CONCLUSIONS The combined addition of FMD and baPWV to the risk assessment algorithms may be useful for risk stratification of chronic CAD patients.

Insulin resistance negatively affects long-term outcome in non-diabetic patients with coronary artery disease after therapies to reduce atherosclerotic risk factors

BACKGROUND Insulin resistance (IR) is a predictor of cardiovascular (CV) events even before the onset of diabetes. However, it is unclear whether changes in IR after a reduction of atherosclerotic burden may affect long-term outcome in patients with coronary artery disease (CAD). This study examined whether changes in IR after therapy to reduce atherosclerotic risk factors provides prognostic information on future CV events in non-diabetic patients with CAD. METHODS AND RESULTS This study enrolled 175 non-diabetic patients with newly diagnosed CAD and IR. IR was defined as the homeostasis model assessment of IR (HOMA-IR)>/=2.5. Evaluation of HOMA-IR was repeated at entry (1st test) and 6 months after individualized, optimized therapy including medications and lifestyle changes (2nd test). After the 2nd test, all patients were prospectively followed-up for 3 years or until the occurrence of one of the following events: CV death, nonfatal myocardial infarction, unstable angina requiring coronary revascularization, or ischemic stroke. IR was improved (HOMA-IR<2.5) after 6 months in 71 (41%) patients, whereas IR persisted in 104 (59%) patients. During the follow-up period, events occurred in 21 (20%) of the 104 patients with persistent IR and 3 (4%) of the 71 patients with improved IR (p<0.01). In multivariate stepwise Cox proportional hazards analysis, persistent IR was an independent predictor of future CV events (HR 4.8, 95% CI 1.4-11.2, p<0.01). CONCLUSIONS The presence of IR despite optimized therapies to reduce atherosclerotic risk factors represents an adverse outcome predictor in non-diabetic patients with CAD.

Myocardial Production of Plasminogen Activator Inhibitor-1 is Associated with Coronary Endothelial and Ventricular Dysfunction after Acute Myocardial Infarction.

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.

Sustained myocardial production of stromal cell-derived factor-1α was associated with left ventricular adverse remodeling in patients with myocardial infarction.

The role of stromal cell-derived factor-1α (SDF-1α) expressed in infarcted myocardium is unknown in humans. We examined whether SDF-1α produced in an infarcted myocardial lesion may play a role in left ventricle (LV) remodeling and dysfunction in patients with acute myocardial infarction (AMI). We measured SDF-1α levels in plasma obtained from aortic root (AO) and anterior interventricular vein (AIV) in the early phase (2 wk after MI) and the chronic phase (6 mo after MI) in 80 patients with anterior MI. An increment in SDF-1α level from AO to AIV, reflecting SDF-1α release from infarcted myocardium, was more frequent in patients with MI in the early phase of MI [n = 52 (65%), P = 0.03] but not in the chronic phase of MI [n = 46 (58%), P = 0.11] compared with that in control patients [n = 6/17 (35%)]. On linear regression analysis, the transmyocardial gradient in SDF-1α level in the chronic phase of MI was correlated with percentage changes in LV end-diastolic volume index (r = 0.39, P < 0.001), LV end-systolic volume index (r = 0.38, P < 0.001), and LV ejection fraction (r = -0.26, P = 0.01) 6 mo after AMI. By contrast, the transmyocardial gradient of SDF-1α in the early phase of MI had no significant correlations. In conclusion, the production of SDF-1α in infarcted myocardium in the chronic phase of MI was associated with LV adverse remodeling and progressive dysfunction in AMI survivors.

Remnant lipoproteinemia predicts cardiovascular events in patients with type 2 diabetes and chronic kidney disease

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 (≥4.3mg/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.

High levels of stromal cell-derived factor-1α predict secondary cardiac events in stable patients with a history of myocardial infarction

BACKGROUND We recently showed that stromal cell-derived factor (SDF)-1α, a pro-inflammatory mediator, is produced in infarcted myocardium and is associated with left ventricular (LV) adverse remodeling and progressive dysfunction following acute myocardial infarction (AMI). The current study examined whether SDF-1α levels in the peripheral vein can provide prognostic information of outcomes in stable patients with a history of MI. METHODS Plasma levels of SDF-1α in the peripheral vein were measured by enzyme-linked immunosorbent assay in 192 stable patients with a history of MI. All patients were followed prospectively for a period of 90 months or until occurrence of one of the following cardiac events: cardiac death, non-fatal myocardial infarction, unstable angina requiring unplanned coronary revascularization, or worsening heart failure requiring hospital admission. RESULTS During the follow-up period (77±26 months), 30 patients had cardiac events. Multivariate Cox analysis revealed that high levels of SDF-1α (≥2162pg/mL; a cut-off value determined by receiver-operating characteristic analysis) were a significant predictor of cardiac events, independent of traditional risk factors (HR: 1.98; 95% CI: 1.38-2.85; p<0.001). The addition of high levels of SDF-1α to conventional risk factors including brain natriuretic peptide improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.90, p<0.0001; and IDI 0.05, p=0.002). CONCLUSIONS High levels of SDF-1α predicted secondary cardiac events in stable patients with a history of MI. SDF-1α levels may be a useful risk assessment tool in patients with a history of MI.

Phospholipase A2 Receptor Gene Polymorphisms Alter its Functions and Present a Genetic Risk of an Increased Intima-Media Thickness of the Carotid Artery

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.

Angiotensin II receptor blockers suppress the release of stromal cell-derived factor-1α from infarcted myocardium in patients with acute myocardial infarction

BACKGROUND Although angiotensin II receptor blockers (ARBs) have been shown to have anti-inflammatory effects on infarcted myocardium in experimental models, little is known in humans. Stromal cell-derived factor-1α (SDF-1α), a pro-inflammatory chemokine, is released from infarcted tissue in patients with acute myocardial infarction (AMI). This study examined whether ARBs suppress SDF-1α production in the infarcted lesion in patients with AMI. METHODS SDF-1α levels were measured by enzyme-linked immunosorbent assays in plasma obtained from the aortic root (AO) and the anterior interventricular vein (AIV) in 50 patients with an anterior AMI. Measurement of SDF-1α levels and left ventriculography were repeated at discharge and 6 months after AMI. Patients were divided into 2 groups according to treatment with ARBs, which were administered at the discretion of the attending physician after admission. RESULTS The AIV-AO gradient of SDF-1α, reflecting SDF-1α release from the infarcted myocardial region, decreased between the time of discharge and 6 months after AMI in patients taking an ARB. In contrast, the SDF-1α transcardiac gradient did not change in patients not taking an ARB. Among the clinical parameters tested, only the use of ARBs was significantly associated with percent changes in the SDF-1α transcardiac gradient from the time of discharge to 6 months after AMI in a linear regression analysis (r=-0.31, p=0.03). The SDF-1α transcardiac gradient 6 months after AMI was inversely correlated with the percent change in left ventricular (LV) ejection fraction (r=-0.52, p<0.01) and positively correlated with the percent change in LV end-diastolic volume index (r=0.57, p<0.01) and LV end-systolic volume index (r=0.54, p<0.01) during 6 months after AMI. CONCLUSIONS ARB treatment suppressed SDF-1α release from the infarcted myocardial region, which was associated with improvement in LV dysfunction and adverse remodeling in AMI survivors.