Effect of omega-3 fatty acids on cardiovascular events in high-risk patients with hypertriglyceridemia in Japan: a 3-year post-marketing surveillance study (OCEAN3 survey).

BACKGROUND: Studies on the efficacy of prescription omega-3 polyunsaturated fatty acids to reduce cardiovascular events have produced conflicting results. RESEARCH DESIGN AND METHODS: This 3-year prospective post-marketing surveillance study evaluated the effect of omega-3-acid ethyl esters (O3AEE; usual dosage 2 g/day) on cardiovascular events in high-risk statin-treated Japanese patients with hypertriglyceridemia. Statin-treated patients not receiving O3AEE were included as a reference cohort. The composite primary endpoint was cardiovascular death, myocardial infarction, stroke, angina requiring coronary revascularization, or peripheral arterial disease requiring surgery or peripheral arterial intervention. RESULTS: At 3 years, Kaplan-Meier estimated cumulative incidence of the primary endpoint was 2.5% (95% confidence interval, 2.1%-2.9%) in O3AEE-treated patients (N = 6,580) and 2.7% (2.4%-3.1%) in non-O3AEE-treated patients (N = 7,784; hazard ratio, 0.99; 95% confidence interval, 0.79-1.23). Incidence of heart failure requiring hospitalization was 0.4% with O3AEE versus 0.8% in non-O3AEE-treated patients (hazard ratio, 0.47; 95% confidence interval, 0.28-0.78; P < 0.05). CONCLUSIONS: Among patients receiving statins, cardiovascular event incidence did not differ significantly between O3AEE-treated patients and non-O3AEE-treated patients. Further studies are required before definitive conclusions can be drawn on the effect of O3AEE on cardiovascular event incidence in high-risk patients with hypertriglyceridemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02285166.

Prediction of aortic stenosis-related events in patients with systolic ejection murmur using pocket-sized echocardiography.

BACKGROUND: We have previously reported the usefulness of our newly developed visual aortic stenosis (AS) score in screening for AS using pocket-sized echocardiography. The objective of this study was to investigate whether the visual AS score and/or conventional aortic valve calcification score derived from pocket-sized echocardiography can be used to predict AS-related events. METHODS: One hundred and nine patients with systolic ejection murmur (SEM) or known AS (64 males, age 75±9 years) were enrolled and a visual AS score and an aortic valve calcification score were assessed using pocket-sized echocardiography. The primary endpoint was defined as AS-related events, including cardiac death and aortic valve replacement, during the follow-up period. RESULTS: In a multivariate Cox proportional hazards analysis, AS-related events were independently predicted by an aortic valve calcification score ≥3 (HR, 3.5; 95% CI, 1.1-11; p=0.033) and a visual AS score ≥3 (HR, 15; 95% CI, 1.8-125; p=0.013). During 18±9 months of follow-up, the event-free survival rate was 98% in patients with both a visual AS score <3 and an aortic valve calcification score <3, 90% in patients with either a visual AS score ≥3 or an aortic valve calcification score ≥3 (p<0.0001), and 62% in patients with both a visual AS score ≥3 and an aortic valve calcification score ≥3 (p<0.0001). CONCLUSIONS: The combination of visual AS score and aortic valve calcification score derived from pocket-sized echocardiography is useful for predicting AS-related events in patients with SEM.

Pre-Load-Induced Changes in Forward LV Stroke and Functional Mitral Regurgitation: Echocardiographic Detection of the Descending Limb of Starling's Curve.

OBJECTIVES: The purpose of this study was to clarify the prognostic significance of diagnosing whether the failing heart is functioning on the descending limb of the Starling curve by using echocardiography with passive leg lifting (PLL). BACKGROUND: Patients with advanced heart failure can shift to the descending limb of the Starling curve, in which pre-load does not lead to an expected increase in forward left ventricular stroke volume (LVSV). METHODS: Thirty-five consecutive patients with left ventricular (LV) ejection fraction of <40% underwent echocardiography at rest during baseline and during PLL to increase pre-load. RESULTS: Despite PLL, a paradoxical decrease in forward LVSV was observed in 15 (43%) patients. Changes in forward LVSV inversely correlated with those in functional mitral regurgitation (r = -0.56). The primary endpoint of cardiac death or hospitalization due to worsening heart failure occurred in 15 (43%) patients during follow-up (2.8 ± 2.2 years). There were a number of significant predictors of the primary endpoint in the univariate Cox analysis: baseline E/A ratio (p = 0.0002), paradoxical decrease in LVSV despite PLL (hazard ratio: 4.44; 95% confidence interval: 1.41 to 14.0; p = 0.011), baseline LV end-systolic volume (p = 0.023), and baseline LV ejection fraction (p = 0.034). In the bivariate Cox analysis, an addition of the paradoxical decrease in LVSV significantly enhanced the predictive power of all other univariate predictors. CONCLUSIONS: Heart failure patients with LV systolic dysfunction on the descending limb of the Starling curve can be recognized by the paradoxical decrease in LVSV despite PLL, and the prognostic predicting power is additive to the other traditional echocardiographic predictors. Also, our results suggest that functional mitral regurgitation is an important reason for the descending limb of the Starling curve, which is clinically recognized as the pre-load-induced decrease in forward LVSV.

Gender-specific correlation between plasma myeloperoxidase levels and serum high-density lipoprotein-associated paraoxonase-1 levels in patients with stable and unstable coronary artery disease.

OBJECTIVE: Low high-density lipoprotein (HDL) cholesterol is well-established as a negative risk factor for coronary artery disease (CAD) and its anti-oxidant property has been attributed mainly to the HDL-bound enzyme paraoxonase-1 (PON-1). Recently, myeloperoxidase (MPO), a pro-oxidant enzyme released from activated neutrophils, has been shown to alter the atheroprotective function of HDL to a dysfunctional form. This study investigated the relationship between plasma MPO and serum PON-1 levels in patients with stable (SAP) and unstable angina pectoris (UAP). METHODS: Plasma MPO levels and serum PON-1 concentration/activity were measured in patients with SAP (n = 226), UAP (n = 151) and in control subjects (n = 99). RESULTS: Plasma MPO levels in UAP patients were significantly higher than those in SAP patients or in control subjects (UAP, 21.6[16.7-44.6]; SAP, 19.3[15.7-29.1]; control, 15.9[14.7-18.7] ng/mL; P < 0.0001). Serum PON-1 concentrations in UAP and SAP patients were significantly lower than those in control subjects (UAP, 55.6[45.9-69.7]; SAP, 55.0[46.9-64.9]; control, 62.5[51.1-78.8] µg/mL; P = 0.0002). Plasma MPO levels showed a weak inverse correlation with serum PON-1 concentrations in all subjects (R = -0.163, P < 0.0005). Moreover, in women, plasma MPO levels showed a significant inverse correlation with serum PON-1 concentrations and PON-arylesterase activity in SAP (concentration: R = -0.537, P < 0.0001; arylesterase-activity: R = -0.469, P < 0.001) and UAP (concentration: R = -0.340, P < 0.05; arylesterase-activity: R = -0.350, P < 0.05) patients, but not in men. CONCLUSION: This study demonstrates that plasma MPO levels have a significant inverse correlation with PON-1 levels, especially in women, in SAP and UAP patients, and suggests that an imbalance between pro-oxidants and anti-oxidants may contribute to the progression of coronary plaque instability.

Association between hemoglobin scavenger receptor and heme oxygenase-1-related anti-inflammatory mediators in human coronary stable and unstable plaques.

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that is induced by intraplaque hemorrhage and degrades free heme and releases ferrous iron, which is rapidly sequestered by ferritin. In vitro studies have shown that binding of hemoglobin to hemoglobin scavenger receptor (CD163) induces HO-1 and the anti-inflammatory mediator interleukin (IL)-10. We immunohistochemically examined the relationship between CD163 expression in macrophages and intraplaque hemorrhage, HO-1, IL-10, and ferritin using coronary atherectomy specimens from patients with stable (SAP) or unstable angina pectoris (UAP). A total of 67 patients underwent atherectomy for SAP (n = 33) or UAP (n = 34). Samples were stained with antibodies against smooth muscle cells, macrophages, glycophorin-A (a protein specific to erythrocyte membranes), CD163, HO-1, IL-10, and ferritin. To identify cell types of HO-1-positive cells, double immunostaining was also performed. Double immunostaining for HO-1 and macrophages revealed that the vast majority of HO-1-positive cells were macrophages. Morphometric analysis demonstrated that CD163-positive macrophage score and the percentage of glycophorin-A-, HO-1-, IL-10-, and ferritin-positive areas were significantly higher in UAP than in SAP patients (CD163, P < .005; glycophorin-A, P < .0001; HO-1, P < .0001; IL-10, P < .005; ferritin, P = .0001). Moreover, CD163-positive macrophage score was positively associated with the percentage of glycophorin-A-, HO-1-, IL-10-, and ferritin-positive areas (glycophorin-A, r = 0.60, P < .0001; HO-1, r = 0.67, P < .0001; IL-10, r = 0.45, P < .0005; ferritin, r = 0.61, P < .0001). These findings suggest that enhanced expression of HO-1 and HO-1-related atheroprotective molecules plays an important role in exerting anti-inflammatory, antioxidant, and scavenging functions, which could contribute to plaque stabilization.

Thrombus aspiration therapy and coronary thrombus components in patients with acute ST-elevation myocardial infarction.

Inflammation and oxidative stress play key roles in atherosclerotic plaque instability, and plaque rupture/erosion and subsequent thrombus formation constitute the principal mechanisms of total vessel occlusion and acute ST-elevation myocardial infarction (STEMI). Plaque disruption triggers the formation of initial platelet aggregates that grow in association with an increase in fibrin formation, leading to persistent coronary flow obstruction and blood coagulation. The fibrin network may trap large numbers of erythrocytes and inflammatory cells to form an erythrocyte-rich thrombus. In fact, previous clinical studies have shown that not only platelet-rich white thrombi, but also erythrocyte-rich red thrombi can be visualized using angioscopy in patients with acute coronary syndrome. Recently, the development of thrombus aspiration and distal protection devices has significantly improved the clinical outcomes of percutaneous intervention in STEMI patients and has enabled the evaluation of antemortem coronary artery thrombi. This is important because previous autopsy studies were unable to differentiate coronary thrombi responsible for myocardial ischemia from postmortem clots. Using frozen samples of aspirated thrombi and specific monoclonal antibodies, we investigated the cellular components of thrombi (platelets, erythrocytes, fibrin and inflammatory cells, such as myeloperoxidase-positive cells) and pathologically evaluated the relationships between erythrocyte-rich thrombi and inflammation, oxidative stress and clinical outcomes in STEMI patients. Therefore, this review article focuses on the efficacy of thrombus aspiration therapy and the components of aspirated intracoronary thrombi in STEMI patients and presents the results of recent studies regarding the relationship between the composition of aspirated intracoronary thrombi and clinical outcomes.

Positive association between plasma levels of oxidized low-density lipoprotein and myeloperoxidase after hemodialysis in patients with diabetic end-stage renal disease.

End-stage renal disease (ESRD) patients undergoing hemodialysis (HD) have a high prevalence of cardiovascular events. Low-density lipoprotein (LDL) in dialysis patients has been shown to be susceptible to in vitro peroxidation; therefore, oxidized-LDL (ox-LDL) could be generated in these patients. Moreover, myeloperoxidase (MPO) released from activated neutrophils may play a role in the induction of LDL oxidation. The purpose of this study was to investigate the relationship between plasma ox-LDL levels, plasma MPO levels, and serum high-sensitivity C-reactive protein (hs-CRP) levels during initial HD in patients with diabetic ESRD. Patients (n=28) had serial venous blood samples drawn before and after HD at the initial, second, and third sessions. Plasma ox-LDL levels were measured using a specific monoclonal antibody (DLH3), and plasma MPO levels were measured using an enzyme-linked immunosorbent assay kit. Plasma ox-LDL levels and MPO levels after a single HD session increased significantly (ox-LDL, P<0.005; MPO, P<0.0001) compared with levels before that HD session. However, the increase was transient since the levels returned to pre-HD session levels. Additionally, plasma MPO levels showed a positive correlation with plasma ox-LDL levels during HD (R=0.62, P=0.0029). No significant change was observed in serum hs-CRP levels before and after each HD session. This study demonstrates that plasma MPO levels are directly associated with plasma ox-LDL levels in diabetic ESRD patients during initial HD. These findings suggest a pivotal role for MPO and ox-LDL in the progression and acceleration of atherosclerosis in patients undergoing HD.

A novel and simple method using pocket-sized echocardiography to screen for aortic stenosis.

BACKGROUND: Pocket-sized echocardiography may serve as an initial tool to screen for aortic stenosis (AS). The purpose of this study was to evaluate the usefulness of a novel and simple method using pocket-sized echocardiography to screen for AS. METHODS: Subjects (n= 130) with systolic ejection murmur or known AS were studied. After physical examination, each aortic cusp's opening was visually scored using pocket-sized echocardiography as follows: 0= not restricted, 1= restricted, or 2= severely restricted. The sum of the scores was defined as the visual AS score. On the basis of high-end echocardiography, an aortic valve area index <0.60 cm(2)/m(2) and an aortic valve area index of 0.60 to 0.85 cm(2)/m(2) were considered to indicate severe and moderate AS, respectively. RESULTS: For diagnosing severe AS (n= 27), a visual AS score ≥ 4 had sensitivity of 85% and specificity of 89%. For diagnosing moderate to severe AS (n= 57), a visual AS score ≥ 3 had sensitivity of 84% and specificity of 90%. The areas under the receiver operating characteristic curves for diagnosing severe and moderate to severe AS with a visual AS score (0.946 and 0.936, respectively) were slightly larger than those for a skilled physical examination (0.917 and 0.898, respectively) (P= NS for both) but were significantly larger than for an aortic valve calcification score also obtained using pocket-sized echocardiography (areas under the curve, 0.816 [P= .0015] and 0.827 [P= .0001], respectively). CONCLUSIONS: A novel and simple method using pocket-sized echocardiography is useful for rapid grading of AS in subjects with systolic ejection murmur.

Relationship of thrombus characteristics to the incidence of angiographically visible distal embolization in patients with ST-segment elevation myocardial infarction treated with thrombus aspiration.

OBJECTIVES: This study sought to investigate the association between pathological characteristics of aspirated intracoronary thrombi and the incidence of angiographically visible distal embolization (AVDE) during primary percutaneous coronary intervention (p-PCI) in patients with ST-segment elevation myocardial infarction (STEMI) treated with thrombus aspiration. BACKGROUND: AVDE of atherosclerotic and thrombotic material has been shown to impair myocardial perfusion and contribute to poor clinical outcome in patients with STEMI. Recent studies have shown that thrombus composition and size are associated with the incidence of AVDE. METHODS: Aspirated thrombi from 164 STEMI patients within 12 h of symptom onset were investigated immunohistochemically using antibodies against platelets, erythrocytes, and inflammatory cells. RESULTS: The angiographic results showed that AVDE during p-PCI occurred in 22 (13.4%) patients. Pathological analysis revealed that thrombi from patients with AVDE had a greater erythrocyte-positive area (60 ± 15% vs. 43 ± 21%, p < 0.0005) and more myeloperoxidase-positive cells (943 ± 324 cells/mm(2) vs. 592 ± 419 cells/mm(2), p < 0.0005) than those from patients without AVDE. Thrombus size, quantified as the thrombus surface area, was positively correlated with the erythrocyte component (r = 0.362, p < 0.0001). Moreover, multivariate logistic analysis demonstrated that erythrocyte-positive area in the thrombi, glucose levels on admission, larger vessel diameter (≥ 3.5 mm), and pre-balloon dilation were independent predictors of the incidence of AVDE. CONCLUSIONS: This study demonstrated that the erythrocyte-rich component of aspirated thrombi may be associated with the incidence of AVDE during p-PCI in patients with STEMI.

Low-dose dobutamine induces left ventricular mechanical dyssynchrony in patients with dilated cardiomyopathy and a narrow QRS: a study using real-time three-dimensional echocardiography.

AIMS: The effects of inotropic agents on left ventricular (LV) synchrony in heart failure patients are still unknown. The purpose of this study was to investigate the effects of dobutamine on LV mechanical dyssynchrony and LV systolic performance in patients with dilated cardiomyopathy (DCM) and a narrow QRS using real-time three-dimensional echocardiography (RT3DE). METHODS AND RESULTS: Thirty-three patients with idiopathic DCM and a narrow QRS underwent low-dose dobutamine stress echocardiography (LDSE) with RT3DE. A time-global LV volume curve and time-regional LV volume curves were derived from RT3DE. Regional LV stroke volumes were summed in each stage, and the dobutamine-induced increase in the sum of regional LV stroke volumes was considered as the sum of regional contractile reserve. Systolic dyssynchrony index (SDI) was calculated as follows: (standard deviation of time to minimal volume for regional LV segments)×100/RR duration. Among the 33 patients, low-dose dobutamine increased global LV stroke volume (SV) in 28 (85%), but decreased global LVSV in the remainder (15%). The sum of regional contractile reserve was modestly correlated with the dobutamine-induced increase in global LVSV (R=0.57, p<0.001). In contrast, low-dose dobutamine increased SDI in 14 (42%) patients without a significant change in QRS duration, and there was an inverse correlation between the increase in SDI and the increase in global LVSV induced by dobutamine (R=-0.67, p<0.001). CONCLUSIONS: Dobutamine may induce LV mechanical dyssynchrony in a substantial proportion of patients with DCM and a narrow QRS. In such cases, regional LV contractile reserve does not fully contribute to an increase in global LVSV.

Association between abnormal myocardial fatty acid metabolism and cardiac-derived death among patients undergoing hemodialysis: results from a cohort study in Japan.

BACKGROUND: Detecting myocardial ischemia in hemodialysis patients is crucial given the high incidence of silent ischemia and the high cardiovascular mortality rates. Abnormal myocardial fatty acid metabolism as determined by imaging with (123)I-labeled BMIPP (ß-methyl iodophenyl-pentadecanoic acid) might be associated with cardiac-derived death in hemodialysis patients. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: Asymptomatic hemodialysis patients with one or more cardiovascular risk factors, but without known coronary artery disease, were followed up for 3 years at 48 Japanese hospitals (406 men, 271 women; mean age, 64 years). PREDICTOR: Baseline BMIPP summed scores semiquantified using a 17-segment 5-point system (normal, 0; absent, 4). OUTCOMES: Cardiac-derived death, including cardiac and sudden death. MEASUREMENTS: HRs were estimated using a Cox model for associations between BMIPP summed scores and cardiac-derived death, adjusting for potential confounders of age, sex, body mass index, dialysis duration, and cardiovascular risk factors. RESULTS: Rates of all-cause mortality and cardiac-derived death were 18.5% and 6.8%, respectively. Cardiac-derived death (acute myocardial infarction [n = 10], congestive heart failure [n = 13], arrhythmia [n = 2], valvular heart disease [n = 1], and sudden death [n = 20]) accounted for 36.8% of all-cause deaths. Cardiac-derived death (n = 46) was associated with age, history of heart failure, and BMIPP summed scores of 4 or higher (HR, 2.9; P < 0.001). Three-year cardiac-derived death-free survival rates were 95.7%, 90.6%, and 78.8% when BMIPP summed scores were 3 or lower, 4-8, and 9 or higher, respectively. BMIPP summed score also was a predictor of all-cause death (HR, 1.6; P = 0.009). LIMITATIONS: Sudden death of unknown cause was considered to have been cardiac derived, although a coronary origin was not confirmed. CONCLUSIONS: Abnormal myocardial fatty acid metabolism is associated with cardiac-derived death in hemodialysis patients. BMIPP single-proton emission computed tomography appears clinically useful for predicting cardiac-derived death in this population.

Comparison of two-dimensional and real-time three-dimensional transesophageal echocardiography in the assessment of aortic valve area.

BACKGROUND: The accuracy of two-dimensional transesophageal echocardiography (2D-TEE) for the measurement of aortic valve area (AVA) in patients with aortic stenosis (AS) depends upon the cross-section selected for imaging. Real-time three-dimensional transesophageal echocardiography (3D-TEE) may overcome this limitation of 2D-TEE. The goal of this study was to compare 3D-TEE with 2D-TEE for the measurement of AVA. METHODS AND RESULTS: Twenty-five patients with AS underwent TEE. In 2D-TEE, the aortic valve image was obtained at the orifice level in the short-axis view, and AVA was measured by planimetry of the acquired images (2D-AVA). In 3D-TEE, 3D data containing the entire aortic valve were obtained. Then, a short-axis cross-section containing the smallest orifice in mid-systole was cut from the 3D data during image postprocessing, and the AVA was measured by planimetry (3D-AVA). The 3D-AVA was significantly smaller than the 2D-AVA (0.79±0.35cm(2) vs. 0.93±0.40cm(2), p<0.0001), but there was a strong correlation between 3D-AVA and 2D-AVA (R=0.94). Although the frame rate was lower in 3D-TEE than in 2D-TEE (17±6Hz vs. 58±16Hz), the 3D-AVA determined at each frame during systole showed that the difference between 3D-AVA and 2D-AVA was not explained by the lower frame rate. The time required for image acquisition of the aortic valve was shorter with 3D-TEE than with 2D-TEE (p=0.0005). CONCLUSIONS: The geometric AVA is smaller with 3D-TEE than with 2D-TEE, and the difference is not due to the lower frame rate of 3D-TEE. The improved accuracy of 3D-TEE along with reduced image acquisition time indicates that 3D-TEE is superior to 2D-TEE for the assessment of AVA.

Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion.

AIMS: Recent studies have demonstrated that erythrocytes are a potential component in atheromatous lesions and thrombus formation in patients with ST-elevation myocardial infarction (STEMI). The purpose of this study was to determine the associations of red blood cell (RBC) component of coronary thrombi with oxidative stress and myocardial reperfusion. METHODS AND RESULTS: Aspirated thrombi from 178 STEMI patients within 12 h of symptom onset were investigated immunohistochemically using antibodies against platelets, RBCs, fibrin, macrophages, and neutrophils [myeloperoxidase (MPO)]. The thrombi were divided into tertiles according to the percentage of glycophorin-A-positive area: low (glycophorin-A-positive area <33%; n = 60), intermediate (<54 to 33%; n = 59), and high group (≥54%; n = 59). We also measured plasma MPO levels on admission. In the thrombi, the number of MPO-positive cells in the high-RBC group was significantly greater than that in the low-RBC group (high, 927 ± 385; intermediate, 765 ± 406; low, 279 ± 220 cells/mm(2); P< 0.0001). Plasma MPO levels were significantly higher in the high-RBC group than that in the low-RBC group [low 43.1 (25.0-71.6); intermediate 71.0 (32.9-111.2); high 74.3 (31.1-126.4)ng/mL; P< 0.005]. Distal embolization occurred more frequently in the high-RBC group (P= 0.0009). Moreover, the signs of impaired myocardial reperfusion, as indicated by incomplete ST-segment resolution (STR) and lower myocardial blush grades (MBG), and progression of left ventricular remodelling at 6 months were frequently observed in the high-RBC group (high vs. low: STR, P= 0.056; MBG, P< 0.01; remodelling, P< 0.01). CONCLUSION: The present study demonstrated that erythrocyte-rich thrombi contain more inflammatory cells and reflect high thrombus burden, leading to impaired myocardial reperfusion in STEMI patients.

Angiotensin receptor blocker-based therapy and cardiovascular events in hypertensive patients with coronary artery disease and impaired renal function.

The aim of this study was to assess the effects of angiotensin receptor blocker (ARB)-based therapy on cardiovascular events in high-risk hypertensive patients with coronary artery disease (CAD) and impaired renal function in post hoc analysis of HIJ-CREATE (Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease). Patients (n=2049) were randomly assigned to candesartan-based or non-ARB treatment arms; 1022 patients (age 70 ± 6 years, 28% female) with impaired renal function, defined as creatinine clearance <60 ml/min at baseline. There was no difference in major adverse cardiac event (MACE), a composite of cardiovascular death, non-fatal myocardial infarction, unstable angina, heart failure, stroke and other cardiovascular events requiring hospitalization between the two arms in patients without impaired renal function. However, there was a lower incidence of MACE in the candesartan-based treatment arm than in the non-ARB treatment arm (HR=0.79, 95% CI 0.63-0.99, p=0.039) in patients with impaired renal function. Among the MACE, candesartan-based treatment reduced hospitalization for unstable angina (HR=0.71, 95% CI 0.52-0.96, p=0.028). Although candesartan-based treatment was not superior to non-ARB treatment in prevention of cardiac mortality, ARB-based therapy may be beneficial in reducing risk of coronary events in hypertensive patients with CAD and impaired renal function.

A novel echocardiographic index of inefficient left ventricular contraction resulting from mechanical dyssynchrony.

OBJECTIVES: The purpose of this study was to explore the possibility of using our novel echocardiographic index of inefficient left ventricular (LV) contraction in patient selection for cardiac resynchronization therapy (CRT). METHODS: Forty consecutive patients with LV ejection fraction < or = 35% were divided into 2 groups, 9 CRT candidates and 31 non-CRT candidates based on conventional criteria. A global LV time-area curve and regional LV time-area curves in 6 radial sectors were obtained using two-dimensional echocardiography in the short-axis view with speckle tracking. Fractional inefficient contraction (FIC, %) was calculated as follows: (1-global LV area change/sum of regional LV area changes) x 100. LV dyssynergy and dyssynchrony were quantified as the standard deviations of minimal values of circumferential speckle-tracking strain and their timings in the 6 sectors, respectively. RESULTS: There was no significant difference in LV dyssynchrony between CRT candidates and non-CRT candidates (79 + or - 61 ms vs. 58 + or - 26 ms, respectively). In contrast, FIC was significantly larger in CRT candidates than in non-CRT candidates (15.7 + or - 11.0% vs. 5.4 + or - 3.5%, respectively, p=0.0018), with less overlap between groups. FIC showed a positive correlation with dyssynchrony (r=0.64) and a negative correlation with dyssynergy (r=-0.42). CONCLUSIONS: Our novel echocardiographic index of inefficient LV contraction, which increases with more dyssynchrony or less dyssynergy, may prove more useful in patient selection for CRT than other indices that focus on LV temporal dyssynchrony alone.

Relation of elevated levels of plasma myeloperoxidase to impaired myocardial microcirculation after reperfusion in patients with acute myocardial infarction.

Previous studies have shown that oxidative stress and endothelial dysfunction are related to impaired myocardial microcirculation after reperfusion. Moreover, elevated myeloperoxidase (MPO) levels are associated with endothelial dysfunction. Plasma MPO levels were measured in patients with ST-segment elevation acute myocardial infarction (n = 160) who had undergone percutaneous coronary stenting within 12 hours of symptom onset. We investigated whether the plasma MPO level at admission was associated with impaired myocardial microcirculation, as indicated by ST-segment resolution and myocardial blush grade after reperfusion, and left ventricular ejection fraction and remodeling at 6 months. The patients were divided into 2 groups according to the median MPO value for the entire cohort (low-MPO group < or =50 ng/ml, n = 80; high-MPO group >50 ng/ml, n = 80). ST-segment resolution and the myocardial blush grade were significantly lower in the high-MPO than in the low-MPO group (48 +/- 27% vs 61 +/- 24%, p <0.005; and 2.1 +/- 0.8 vs 2.4 +/- 0.7, p <0.01; respectively). Moreover, the percentage of increase in the left ventricular end-diastolic volume index was significantly greater and the left ventricular ejection fraction at 6 months was significantly lower in the high-MPO group than in the low-MPO group (8.2 +/- 24.7% vs -1.9 +/- 23.5%, p <0.05; and 46 +/- 9% vs 54 +/- 9%, p <0.0001, respectively). Multiple regression analysis showed that the plasma MPO level was an independent predictor of incomplete ST-segment resolution (odds ratio 6.94, 95% confidence interval 2.10 to 22.9, p = 0.0015). In conclusion, elevated plasma MPO levels at admission were associated with impaired myocardial microcirculation after reperfusion in patients with acute myocardial infarction.

Reverse remodeling and improved function by antihypertensive treatment in hypertensive patients with coronary artery disease.

BACKGROUND: Although antihypertensive therapy reduces cardiovascular events, it is unclear whether there are differences in cardiac remodeling and function between treatments with nifedipine retard and angiotensin-converting enzyme inhibitors (ACE-Is). It is also not clear how antihypertensive therapy influences cardiac remodeling and function. METHODS: Hypertensive patients with coronary artery disease were randomly assigned to the nifedipine retard (n = 108) or ACE inhibitors groups (n = 102) and treated for 3 years. The primary endpoints were changes in end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) as indices of cardiac remodeling, whereas the secondary endpoints were changes in ejection fraction (EF), stroke volume index (SVI), cardiac index (CI) and regional wall motion as indices of cardiac function. Left ventriculography was performed at baseline and after 3 years of treatment. Fifty-eight and 61 patients, respectively, were subjected to the final analysis. RESULTS: Comparable changes in remodeling and function were obtained in the nifedipine retard group and the ACE-Is group. Both groups showed a significant reduction of EDVI and ESVI, and a significant increase in EF, SVI, and CI, whereas the decreased regional wall motion significantly improved. In both groups, weak but significant correlations were noted between treatment-induced changes of systolic blood pressure and those of primary and secondary endpoints. CONCLUSION: The above findings show that treatments with nifedipine retard or ACE-Is cause a comparable change in remodeling and cardiac function. Lowering of the blood pressure by either drug leads to reverse remodeling or improvement of cardiac function. In addition to alleviation of coronary artery damage by reducing blood pressure, there is a favorable effect on the left ventricular structure and function. Reducing the blood pressure is critically important for hypertensive patients with coronary artery disease.

Elevated levels of neopterin are associated with carotid plaques with complex morphology in patients with stable angina pectoris.

OBJECTIVE: Neopterin is an activation marker for monocytes/macrophages, and circulating levels of neopterin are elevated in patients with coronary complex lesions in unstable angina pectoris. We investigated the possible association between neopterin and complex carotid plaques which may be associated with the risk of ischemic stroke in patients with stable angina pectoris (SAP). METHODS: We measured plasma levels of neopterin in 102 patients with SAP and carotid ultrasound was performed for evaluation of the presence of carotid plaques and plaque surface characteristics categorized as complex or noncomplex. In addition, endarterectomy specimens of extracranial high-grade carotid stenosis with complex plaques from five patients with SAP were immunohistochemically examined with antibodies to smooth muscle cells, endothelial cells, platelets, macrophages, and T cells. RESULTS: Plasma neopterin levels were significantly higher in patients with complex carotid plaques than in those with noncomplex plaques (median [interquartile range]: 24.2 [19.2-39.3]nmol/L vs. 19.4 [11.9-25.1]nmol/L; P=0.01) or without any plaques (18.8 [14.9-23.6]nmol/L; P=0.001). On multivariate logistic analyses after adjustment for traditional atherosclerotic risk factors, multi-vessel coronary disease and high sensitivity C-reactive protein, neopterin levels were independently associated with the presence of complex carotid plaques (adjusted OR 2.21 per SD increase, 95%CI 1.13-4.33, P=0.02). Immunohistochemical staining revealed abundant neopterin-positive macrophages in carotid complex lesions. CONCLUSION: These findings demonstrate that carotid plaques with complex morphology have increased circulating neopterin levels and immunohistochemical localization of neopterin in patients with SAP. Neopterin can be considered an important biomarker of plaque destabilization in carotid artery atherosclerotic lesions in this population.