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An abstract of the article "Intra- and interobserver variability of left ventricular diastolic inflow parameters measured by three chamber view 2D cine threedirectionally encoded (3Ch. 2D-cine-3 dir.) Phase contrast MR velocity vector map," by Munemura Suzuki and colleagues is presented.

Background Anemia is common in older adults and, together with heart failure and chronic kidney disease, forms a vicious cycle, whereas diseases such as chronic inflammation and cancer are associated with the anemia of chronic disease (ACD). Researchers have linked growth differentiation factor-15 (GDF-15) to a variety of conditions such as cardiovascular disease, inflammation, cancer, and kidney disease, and have reported hepcidin as a biomarker for iron regulation in ACD. Therefore, anemia, GDF-15, and hepcidin have significance in aging physiology. Hypothesis GDF-15 and hepcidin play important physiological roles in community-dwelling older adults. This study sought to explore the relationship between these biomarkers and anemia, inflammation, or other health outcomes. Methods This was a prospective study of 73 community-dwelling older adults (six men and 67 women, mean age of 76.3 years). Their serum iron level, percentage transferrin saturation (TSAT), high-sensitivity C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) were measured. Enzyme-linked immunosorbent assays were used to assess their serum GDF-15, ferritin, and hepcidin levels. The participants' grip strength and walking speed were measured. The skeletal muscle mass index (SMI) of each participant was determined by bioelectrical impedance analysis. Results The GDF-15 level was significantly inversely correlated with serum iron, ferritin, and hepcidin levels; percentage TSAT; the eGFR; and gait speed. Serum hepcidin was positively correlated with levels of ferritin, albumin, and hemoglobin. Handgrip strength, SMI, and hs-CRP were not correlated with either GDF-15 or hepcidin levels. After adjusting for age, sex, and body mass index (BMI), multivariate analysis identified the log GDF-15 and serum iron level (log GDF-15: β=-0.248, iron: β=0.296) as significant factors determining hemoglobin levels, whose findings have significance due to novel results. Multivariate analysis identified eGFR and levels of hemoglobin and hepcidin as significant factors associated with log GDF-15 (eGFR: β=-0.406, hemoglobin: β=-0.269, hepcidin: β=-0.235). Similarly, ferritin and albumin levels were identified as significant factors associated with hepcidin levels (ferritin: β=0.590, Alb: β=0.277). Conclusions Anemia in community-dwelling older adults was determined not only by increasing serum iron levels but also by decreasing GDF-15 levels. Also, the increasing GDF-15 level was determined by a decreasing hepcidin level as well as the presence of anemia and renal dysfunction, and the decreasing hepcidin level was determined by decreasing stored iron and decreasing albumin levels. Serum GDF-15 and hepcidin could potentially inform diagnostic or treatment strategies for anemia or age-related health conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Fukuda et al.)

Objective: Making the diagnosis of sarcopenia is not always easy and this is especially true for those with cardiovascular disease. The purpose of this study is to investigate whether it is possible to diagnose sarcopenia by using ultrasound-guided measurements of anterior femoral muscle thickness., Methods: We investigated the utility of ultrasound-guided measurements of anterior femoral muscle thickness in 1075 hospitalized patients with cardiovascular disease (675 men). As a comparison, sarcopenia was assessed by skeletal muscle mass index using bioelectrical impedance analysis and the Asia Working Group for Sarcopenia criteria., Results: When the receiver operating characteristic curve using muscle thickness was examined, we found this could be used to make the diagnosis of sarcopenia (men: cutoff value 2.425 cm, area under the curve 0.796; women: cutoff value 1.995 cm, area under the curve 0.746). The prevalence of sarcopenia according to the criteria with skeletal muscle mass index was 34.2% in men and 51.8% in women, while its prevalence according to the cutoff value of muscle thickness was 29.2% in men and 36.7% in women., Conclusion: Ultrasound-guided measurement of the anterior femoral muscle thickness is a simple and useful method to help make the diagnosis of sarcopenia in patients with cardiovascular disease., Competing Interests: The authors have no conflict of interest to declare., (© Published by Medical Journals Sweden, on behalf of the Foundation for Rehabilitation Information.)

Background: Myostatin is a negative regulator of skeletal muscle mass. On the other hand, growth differentiation factor (GDF)-15 is associated with lower muscle strength and muscle mass. We investigated the relationship between serum GDF-15, myostatin, and sarcopenia in patients receiving cardiovascular surgery through a ROC curve and a multivariate regression analysis., Methods: Skeletal muscle mass index (SMI) by bioelectrical impedance analysis, hand-grip strength, knee extension strength, and walking speed were measured. Preoperative serum GDF-15 and myostatin levels were determined by ELISA. The sarcopenia index could be expressed as: -0.0042 × [myostatin] + 0.0007 × [GDF-15] + 0.0890 × age + 1.4030 × sex - 0.2679 × body mass index (BMI) - 2.1186. A ROC curve was plotted to identify the optimal cutoff level of the sarcopenia index to detect sarcopenia., Results: 120 patients receiving cardiovascular surgery were included in the study. SMI, hand-grip strength, knee extension strength, and walking speed inversely correlated with GDF-15, but positively correlated with myostatin. In the multivariate stepwise regression analysis, SMI was a determinant of myostatin, and both GDF-15 and myostatin were determinants of SMI and muscle thickness, even after adjustment for age, sex, and BMI. A ROC curve showed that the sarcopenia index was a determinant of sarcopenia (cutoff value -1.0634, area under the curve 0.901, sensitivity 96.9%, specificity 70.9%)., Conclusion: GDF-15 and myostatin are associated with skeletal muscle volume in patients receiving cardiovascular surgery, but these associations are different. The sarcopenia index calculated from GDF-15 and myostatin levels may be a biomarker of sarcopenia., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Purpose: Sarcopenia is closely associated with postoperative prognosis in patients undergoing cardiovascular surgery. Growth differentiation factor (GDF)-15 is involved in the pathogenesis of cardiovascular disease. We examined the relationship between the serum GDF-15 concentration and muscle function in patients receiving aortic valve replacement and healthy elderly subjects., Methods: Forty-three female patients undergoing aortic valve surgery (79.9 ± 6.4 years; transcatheter aortic valve replacement [TAVR] n = 19, conventional surgical aortic valve replacement [SAVR] n = 24) and 64 healthy elderly female subjects (75.9 ± 6.1 years) were included. Walking speed, grip strength, and skeletal muscle mass index (SMI) by a multifrequency bioelectrical impedance analyzer were measured to determine the presence of sarcopenia. Preoperative serum GDF-15 concentration was measured by enzyme-linked immunosorbent assay., Results: The GDF-15 level was higher in patients receiving aortic valve replacement than in healthy elderly subjects (aortic valve replacement: 1624 ± 1186 pg/mL vs. healthy: 955 ± 368 pg/mL, p < 0.001). Multivariate linear regression analysis showed that the serum GDF-15 level determined grip strength independently of the high-sensitivity C-reactive protein level and eGFR, even after adjusting for age (β = -0.318, p = 0.025). Sarcopenia was found in 12.5% of healthy elderly subjects, 83.3% of patients with TAVR, and 64.3% of patients with SAVR. The GDF-15 concentration that defined sarcopenia was 1109 pg/mL in subjects including patients receiving aortic valve replacement., Conclusions: The preoperative serum GDF-15 concentration, which was higher in female patients receiving aortic valve replacement than in healthy elderly subjects, may be a serum marker of sarcopenia., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Objective The aim of this study was to clarify the circadian and seasonal variations in addition to identify sex-based differences in Japanese patients with Takotsubo syndrome (TTS). Methods The authors conducted a retrospective observational study to analyse the differences between the groups based on sex. Patients The patients were registered out of each institute registry of the acute coronary syndrome (ACS) which contains a total of 10,622 cases in eight academic hospitals in east Japan. Results Data for 344 consecutive TTS (73 male and 271 female) were extracted from each hospital registry. In-hospital mortality was higher in the male group than in the female group (18% vs. 7%; p=0.005). With regard to the circadian variations in all study patients, TTS events occurred most often in the afternoon and least often during the night. Moreover, the patterns of circadian variations in the female and male groups were the same as that of all study patients. TTS events occurred most frequently in the autumn and least often in the spring in the whole study cohort. Moreover, the seasonal variation in the female group showed the same pattern as that of the whole cohort. However, there were no significant seasonal differences in the incidence of TTS in the male group. Conclusion In a multicenter study in Japan, seasonal variation was observed in the female group but not in the male group. Circadian variation was observed in both groups. These results suggested that the pathogenesis and clinical features of TTS might therefore differ according to sex.

Purpose: Anemia and sarcopenia associated with renal dysfunction caused by cytokine imbalance can contribute to decreased quality of life for older individuals. Growth differentiation factor-15 (GDF-15) is associated with renal dysfunction, although whether it is related to anemia or sarcopenia is unclear. In this study we examined the association of GDF-15 with renal function, hemoglobin and sarcopenia in healthy community-dwelling older females in Japan., Methods: A total of 66 healthy older community-dwelling females (age: 75.8 ± 6.2 years) were enrolled for this study. Skeletal muscle mass index was determined by bioelectrical impedance analysis. Hand-grip strength and walking speed were also assessed. Serum GDF-15 concentration was determined by enzyme-linked immunosorbent assay and both hemoglobin (Hb) level and estimated glomerular filtration rate (eGFR) were measured., Results: Serum GDF-15 levels positively correlated with age but negatively correlated with eGFR and walking speed. In multiple regression analysis, eGFR and hemoglobin (Hb) were independent variables to predict serum GDF-15 levels, even after adjusting for age and body mass index (eGFR: β = -0.423, p < 0.001; Hb: β = -0.363, p = 0.004). Serum GDF-15 level was an independent variable to predict eGFR and Hb., Conclusions: Both Hb and eGFR are predictors for serum GDF-15 concentration in healthy older females. In these community-dwelling older females, renal dysfunction via GDF-15 may be accompanied by anemia, but not sarcopenia., Competing Interests: The authors report no relationships that could be construed as a conflict of interest., (© 2020 The Author(s).)

Although ezetimibe has potential value as an add-on therapy to statins, it is not established whether the addition of ezetimibe to statin therapy is more effective than double-dose statin monotherapy. We conducted a crossover design study. Twenty-one coronary artery disease (CAD) patients whose lipid profiles had not achieved Japanese guideline recommendations (JAS 2017), despite receiving low-dose statin therapy, were divided into two groups. Group A received ezetimibe 10 mg in addition to the baseline dose of statin for the first 3 months and was then switched to monotherapy with a double dose of statin for the next 3 months. Group B first received a double dose of statin for 3 months and was then switched to ezetimibe 10 mg in addition to a baseline dose of statin for the next 3 months. Compared with the baseline, double-dose statin therapy reduced low-density lipoprotein (LDL)-cholesterol (from 118 ± 22 to 104 ± 15 mg/dL, P < 0.05) and malondialdehyde-modified LDL (MDA-LDL) (from 142 ± 35 to 126 ± 24 U/L, P < 0.05) but did not lower high-sensitivity C-reactive protein (hsCRP) (3.02 ± 0.47 and 2.98 ± 0.41 log [ng/ml]). The addition of ezetimibe to a baseline dose of statin further reduced LDL-cholesterol (to 89 ± 15, P < 0.0001) and MDA-LDL (to 114 ± 22 U/L, P < 0.001) and reduced hsCRP (to 2.78 ± 0.38 log (ng/ml), P < 0.05). The changes in the levels of MDA-LDL (R = 0.548, P = 0.010) and hsCRP (R = 0.473, P < 0.05) were significantly correlated with the change in the LDL-cholesterol level after the addition of ezetimibe. Add-on ezetimibe treatment appears superior to double-dose statin therapy in CAD patients with poorly controlled dyslipidemia in terms of reductions in LDL-cholesterol level, lipid peroxidation, and inflammation.

Normalized optical density (NOD) measured by optical coherence tomography represents neointimal maturity after coronary stent implantation and is correlated with morphologic information provided by both light and electron microscopy. We aimed to test the hypothesis that even second generation drug-eluting stents (DESs) are problematic in terms of neointimal maturity. We implanted bare-metal stents (BMS: n = 14), everolimus-eluting stents (EESs: n = 15) or zotarolimus-eluting stents (ZESs: n = 12) at 41 sites in 32 patients with stable coronary artery disease. OCT was performed at up to 12 months of follow-up, and the average optical density of neointima covering struts was evaluated. NOD was calculated as the optical density of stent-strut covering tissue divided by the optical density of the struts. We also measured circulating CD34+ /CD133+ /CD45low cells, and serum levels of stromal cell-derived factor (SDF)-1, interleukin (IL)-8 and matrix metalloproteinase (MMP)-9 at baseline and follow-up. NOD was lower in the EES (0.70 ± 0.06) group than in the BMS (0.76 ± 0.07, P < 0.05) and ZES (0.76 ± 0.06, P < 0.05) groups. The mean neointimal area (R = 0.33, P < 0.05) and mean neointimal thickness (R = 0.37, P < 0.05) were correlated with NOD. Although NOD was not correlated with percent changes in circulating endothelial progenitor cells, and the levels of SDF-1 and IL-8, it was negatively correlated with the change in MMP-9 level (R = - 0.51, P < 0.01). Neointimal maturity might be lower at EES sites than BMS or ZES sites. This might lead to impaired neointimal tissue growth and matrix degradation. These results suggest a specific pathophysiology after DES implantation.

A long-acting loop diuretic, azosemide, has been shown to improve long-term prognosis in patients with heart failure compared with a short-acting loop diuretic, furosemide. However, the therapeutic advantages of azosemide over furosemide have not been clearly established. In this study, we retrospectively analyzed clinical outcomes and laboratory data in patients with congestive heart failure treated with furosemide or azosemide, and the efficacy of these agents was compared. First, we screened 1900 patients and selected 124 (furosemide group: n = 40; azosemide group: n = 84) as the total study population. From these patients, we next selected 72 patients for the propensity score-matched analysis (furosemide group: n = 36; azosemide group: n = 36). The incidence of all-cause death and rehospitalization due to worsening heart failure during 24 months of follow-up was similar between the furosemide and azosemide groups in both the total study population and the propensity score-matched population. However, in the propensity score-matched analysis, the estimated glomerular filtration rate time-dependently decreased during 36 months of follow-up in the furosemide group (56.5 ± 19.5-43.2 ± 16.3 mL/min/1.73 m), whereas it did not change in the azosemide group (58.6 ± 22.0-50.3 ± 17.8 mL/min/1.73 m) (P = 0.032). Azosemide might have some potential advantage for renal protection over furosemide in patients with congestive heart failure.

Right atrial pressure (RAP), a representative parameter of right heart failure, is very important for prognostic evaluation and risk assessment in pulmonary hypertension. However, its measurement requires invasive cardiac catheterization. In this study, we determined the most accurate echocardiographic surrogate of catheterization-based RAP. In 23 patients with pulmonary hypertension, a total of 66 cardiac catheterization procedures were performed along with 2-dimensional echocardiography. We evaluated tricuspid E/A, E', A' and E/E', and estimated RAP by the respirophasic variation of the inferior vena cava diameter (eRAP-IVCd) as possible surrogates of catheterization-based RAP. In simple linear regression analysis, E/A (R = 0.452, P = 0.0001) and eRAP-IVCd (R = 0.505, P < 0.0001) were positively correlated with catheterization-based RAP, whereas A' (R = - 0.512, P < 0.0001) was negatively correlated with RAP. In multiple regression analysis, A' was the most significant independent predictor of catheterization-based RAP (R = - 0.375, P = 0.0007). In 16 patients who had multiple measurements, there were a total of 43 measurements before and after medication changes. The absolute change in catheterization-based RAP was negatively correlated with the percent change in A'. Receiver operating characteristic curve analysis indicated that the optimal cut-off value of A' to predict a catheterization-based RAP > 10 mmHg was 11.3 cm/s (area under the curve = 0.782, sensitivity = 0.70, specificity = 0.78). In 20 measurements of 20 patients with left heart failure, catheterization-based RAP was not correlated with any of 5 echocardiographic parameters. However, it was closely correlated with catheterization-based pulmonary capillary wedge pressure. The echocardiographic parameter, A', was the best surrogate of catheterization-based RAP in patients with pulmonary hypertension.

Background: Hyperuricemia has a close relationship with cardiovascular diseases including heart failure. However, it is controversial whether xanthine oxidase inhibition has benefits for patients with chronic heart failure. We designed the Effect of Xanthine Oxidase Inhibitor in Chronic Heart Failure Patients Complicated with Hyperuricemia study (Excited-UA study) to compare the beneficial effects between a novel xanthine oxidoreductase inhibitor, topiroxostat, and a conventional agent, allopurinol, in patients with chronic heart failure and hyperuricemia. We focus on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level, echocardiography-based cardiac function, vascular endothelial function, renal function, inflammation, and oxidative stress., Methods: The excited-UA is a prospective, randomized, open-label, blinded-endpoint clinical trial designed to prove our hypothesis that topiroxostat is more effective than allopurinol in patients with chronic heart failure and hyperuricemia. A total of 140 patients with chronic heart failure and hyperuricemia (plasma brain natriuretic peptide level ≥ 40 pg/mL and serum uric acid level ≥ 7.0 mg/dL) are randomly assigned (ratio 1:1) into either the topiroxostat group (40-160 mg/day) or allopurinol group (100-300 mg/day), to achieve the target uric acid level of 6.0 mg/dL. According to the protocol, all patients are followed up annually for 24 weeks. The primary endpoint is percent change in serum NT-proBNP level at 24 weeks from baseline., Conclusions: The Excited-UA study would provide novel evidence for the clinical relevancy of xanthine oxidoreductase inhibitor treatment in patients with chronic heart failure and hyperuricemia.

This study was designed to investigate the effects of uric acid on vascular endothelial function in measurements carried out either at the bedside or the laboratory bench. First, we performed reactive hyperemia peripheral arterial tonometry using an EndoPAT 2000 device and measured serum uric acid levels in 92 outpatients with hypertension. The reactive hyperemia index (RHI) showed no correlation with serum uric acid level (R = -0.125, P = 0.235) in either overall patients or in a high-risk group of 51 patients with complications such as cardiovascular and cerebrovascular diseases, chronic kidney disease, and/or diabetes (R = -0.025, P = 0.860). However, in the remaining 41 patients in the low-risk group, RHI correlated negatively with serum uric acid level (R = -0.335, P = 0.032). Multiple regression analysis showed that serum uric acid level predicted RHI (R = -0.321, P = 0.043) in the low-risk group independent of age, body mass index, systolic blood pressure, and low density lipoprotein-cholesterol level. We then performed an in-vitro study using the WST-8 assay in human umbilical vein endothelial cells, which showed that hypoxic conditions reduced cell viability. Treatment with uric acid caused a further reduction in cell viability, while ascorbic acid improved viability. Using Western blot analysis, we observed that uric acid reduced endothelial nitric oxide synthase phosphorylation during hypoxic conditions. Serum uric acid level is associated with peripheral vascular endothelial function in patients with low-risk hypertension and uric acid could directly impair endothelial function under hypoxic conditions. These results are relevant to the interventional studies examining the cardiovascular protective effect of hypouricemic agents.

Background: Although magnesium deficiency induces left ventricular dysfunction, it is not known whether both systolic and diastolic functions are altered to the same extent. In this study, we investigated the effects of theophylline on left ventricular function in rats fed a normal diet or a magnesium-deficient diet for 1 month, and determined whether K201, a multi-channel blocker, modulated the effects of theophylline., Methods: Theophylline was infused at 5 mg/kg/min for 15 min in 6 control rats and 6 magnesium-deficient rats, and hemodynamic measurements were performed. In another 6 magnesium-deficient rats, K201 was infused at 0.1 mg/kg/min for 15 min simultaneously with theophylline., Results: Theophylline induced persistent increases in heart rate, peak positive first derivative of left ventricular pressure (+dP/dt), and a transient increase in left ventricular end-diastolic pressure (LVEDP), but did not affect left ventricular systolic pressure (LVSP) and peak negative first derivative of left ventricular pressure (-dP/dt) in the control rats. In contrast, in the magnesium-deficient rats, there was a persistent decrease in LVSP and a persistent increase in -dP/dt after theophylline infusion, although increases in heart rate, +dP/dt and LVEDP were similar to those in the control rats. When K201 was infused along with theophylline in the magnesium-deficient rats, both the decrease in LVSP and increase in -dP/dt were suppressed., Conclusions: Theophylline impaired left ventricular function in the magnesium-deficient rats, and this was improved by K201. K201 may provide new insights regarding future strategies for heart failure treatment.

A narrow and calcified sinotubular junction (STJ) represents a risk for ascending aortic dissection after balloon-expandable transcatheter aortic valve implantation (TAVI). The aim of this study was to assess computed tomography (CT)-based aortic root morphology in patients with aortic stenosis (AS), and to evaluate the feasibility of a two-step inflation technique that we devised for TAVI using the SAPIEN 3 in patients with a narrow and calcified STJ. We retrospectively analyzed the STJ diameter (STJD) as well the as aortic annulus diameter (AAD) and STJ calcification using CT imaging in 412 patients undergoing TAVI. We defined a "narrow STJ" as a minimum STJD that was smaller than the diameter corresponding to a 10% oversized annulus area, and a "calcified STJ" as an STJ calcification angle > 90°. A "narrow and calcified STJ" was identified in 54 patients (13.1%) of patients. Among them, we performed TAVI using the two-step inflation technique with SAPIEN 3 in 20 patients and compared with 11 patients that underwent the conventional inflation procedure. Two-step inflation was successfully performed without ascending aortic dissection in all 20 patients. The effective orifice area index at discharge in these 20 patients was similar to that in 11 patients who underwent the conventional inflation procedure for a "narrow and calcified STJ" [1.40 (1.20-1.51) vs. 1.33 (1.18-1.41) cm 2 /m 2 , p = 0.23]. Although further assessment is required, the two-step inflation technique with the SAPIEN 3 is feasible for a narrow and calcified STJ.

Background: Bone marrow-derived progenitor cells likely contribute to both endothelial- and smooth muscle cell-dependent healing responses in stent-injured vessel sites. This study aimed to assess mobilization of progenitor cells and vessel healing after zotarolimus-eluting (ZES) and everolimus-eluting (EES) stents., Methods and Results: In 63 patients undergoing coronary stent implantation, we measured circulating CD34 + CD133 + CD45low cells and serum levels of biomarkers relevant to stem cell mobilization. In 31 patients of them, we assessed vessel healing within the stented segment using optical coherence tomography (OCT) imaging. The CD34 + CD133 + CD45low cells increased 68 ± 59% 7 days after bare metal stent (BMS), 10 ± 53% after ZES ( P  < 0.01 vs BMS), 3 ± 49% after EES ( P  < 0.001 vs BMS), compared with baseline. Percent change in CD34 + CD133 + CD45low cells was positively correlated with that in stromal cell-derived factor (SDF)-1α ( R  = 0.29, P  = 0.034). Percentage of uncovered struts was higher in the EES group (14.4 ± 17.3%), compared with the BMS (0.7 ± 1.3, P  < 0.01) and ZES (0.4 ± 0.5, P  < 0.01) groups. The change in CD34 + CD133 + CD45low cells showed positive correlation with OCT-quantified mean neointimal area ( R  = 0.48, P < 0.01). Finally, circulating mononuclear cells obtained from 5 healthy volunteers were isolated to determine the effect of sirolimus, zotarolimus and everolimus on vascular cell differentiation. The differentiation of mononuclear cells into endothelial-like cells was dose-dependently suppressed by sirolimus, zotarolimus, and everolimus., Conclusions: Mobilization of progenitor cells was suppressed, and differentiation of mononuclear cells into endothelial-like cells was inhibited, in association with increased number of uncovered stent struts, even after second generation drug-eluting stenting. These data suggest that new approaches are necessary to enhance stent healing.

Background: The alarmin family member myeloid-related protein (MRP)-14 (S100A9), which has been identified by platelet transcriptional profiling as an acute myocardial infarction gene, regulates vascular inflammation and thrombosis. Elevated plasma levels of MRP-8/14 (S100A8/A9) heterodimer predict first and recurrent cardiovascular events. The aim of this study was to elucidate pathophysiological roles of MRP-8/14 in acute coronary syndrome (ACS)., Methods and Results: In 38 consecutive ACS patients, the MRP-8/14 level in coronary artery blood obtained at thrombus aspiration was higher in 23 patients, in whom aspirated thrombus was confirmed, compared to the 15 patients, in whom it was absent [4.86 (1.95, 8.29) vs 2.94 (1.31, 4.44), P=0.017]. The MRP-8/14 level was correlated with myeloperoxidase (MPO) level (R 2 =0.52), but not with soluble P-selectin level (R 2 =0.0002) in the coronary artery blood. Immunohistochemistry of the aspirated thrombus exhibited that expression of MRP8/14 was co-localized with leukocytes positive for activated Mac-1. Finally, in cultured human umbilical vein endothelial cells, MRP-8/14 increased tissue factor expression., Conclusions: Our findings indicate that MRP-8/14 concentration increases in coronary artery blood in association with thrombus formation in ACS, co-localizes with leukocytes, and is associated with leukocyte activation. MRP-8/14 is positioned as a unique biomarker at the interface of inflammation and thrombosis in ACS., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Epicardial adipose tissue (EAT) releases both adiponectin and TNFα, and these two adipokines play important roles in heart diseases such as coronary arterial disease. The aim of the present study was to clarify whether fatty acid (FA) profiles in EAT are linked to the serum concentration of these adipokines. The relationships between serum adipokine levels and FA profiles in patients undergoing cardiovascular surgery were analyzed., Methods: Patients ( n  = 21) undergoing cardiovascular surgery (11 males, 70.4 ± 9.0 years, BMI 26.0 ± 5.1 kg/m 2 ) were included. EAT samples were taken. We measured clinical biochemical data and FA profiles in venous blood and EAT samples using gas chromatography. Serum adiponectin and TNFα concentrations were also measured., Results: The adiponectin and TNFα levels were not correlated with any fatty acid concentration in serum lipids. In contrast, there was a positive correlation between the serum adiponectin level and epicardial level of nervonic acid (C24:1ω9, r  = 0.525, P  = 0.025). In multiple regression analysis, adiponectin showed a positive association with the epicardial C24:1ω9 concentration after controlling for age and BMI, or TG, non-HDL-C, and BNP. The serum TNFα concentration was negatively correlated with the epicardial C18:3ω3, C12:0 and C18:0 content. In multiple regression analysis, the serum TNFα concentration showed a positive association with the epicardial C18:3ω3 level (β = - 0.575, P  = 0.015)., Conclusions: These results suggest that there is a close relationship between epicardial FA profiles and serum levels of adiponectin and TNFα. Dietary therapy to target FA profiles may be helpful to modulate inflammation.

Although measurement of right ventricular ejection fraction (RVEF) may be relevant for evaluation of therapeutic efficacy and/or prognosis in patients with pulmonary hypertension, RVEF obtained by echocardiography has limited accuracy. In contrast, radionuclide and/or magnetic resonance imaging can measure RVEF more reliably. In this study, we investigated the relationship between RVEF measured by radionuclide angiography and the echocardiographic parameters that are recommended by the American Society of Echocardiography as representative of right heart function. There were 23 study participants with pulmonary hypertension who underwent radionuclide angiography and 2-dimensional and Doppler echocardiography (n = 30 measurements). RVEF measured by radionuclide angiography correlated with right ventricular Tei index (RV Tei index) measured by Doppler echocardiography (r = -0.601, P < 0.0005). Receiver operating characteristic curve analysis showed that an RV Tei index cut-off value of 0.371 was the best of predictor of RVEF ≤35% (area under the curve = 0.768, sensitivity = 0.857, selectivity = 0.667). Multiple regression analysis showed that RVEF was correlated with the RV Tei index, and this association was independent of other echocardiographic right ventricular function parameters (r = -0.644, P < 0.005). The RV Tei index measured by Doppler echocardiography may be an acceptable surrogate marker of RVEF in patients with pulmonary hypertension.

Background: Type 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD). SGLT2 inhibitors are known to not only decrease plasma glucose levels, but also favorably modulate a wide range of metabolic and hemodynamic disorders related to CV pathways. Although some experimental studies revealed a beneficial effect of SGLT2 inhibitors on atherosclerosis, there is a paucity of clinical data showing that they can slow the progression of atherosclerosis in patients with T2DM. Therefore, the EMBLEM trial was designed to investigate whether empagliflozin treatment can improve endothelial function, which plays a pivotal role in the pathogenesis of atherosclerosis, in patients with T2DM and established CVD., Methods: The EMBLEM trial is an ongoing, prospective, multicenter, placebo-controlled double-blind randomized, investigator-initiated clinical trial in Japan. A total of 110 participants with T2DM (HbA1c range 6.0-10.0%) and with established CVD will be randomized (1:1) to receive either empagliflozin 10 mg once daily or a placebo. The primary endpoint of the trial is change in the reactive hyperemia (RH)-peripheral arterial tonometry-derived RH index at 24 weeks from baseline. For comparison of treatment effects between the treatment groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for the following allocation factors: HbA1c (<7.0 or ≥7.0%), age (<65 or ≥65 years), systolic blood pressure (<140 or ≥140 mmHg), and current smoking status (nonsmoker or smoker). Key secondary endpoints include the change from baseline for other vascular-related markers such as arterial stiffness, sympathetic nervous activity, and parameters of cardiac and renal function. Importantly, serious adverse effects independently on the causal relationship to the trial drugs and protocol will be also evaluated throughout the trial period., Discussion: EMBLEM is the first trial to assess the effect of empagliflozin on endothelial function in patients with T2DM and established CVD. Additionally, mechanisms associating empagliflozin-mediated actions with endothelial function and other CV markers will be evaluated. Thus, the trial is designed to elucidate potential mechanisms by which empagliflozin protects CV systems and improves CV outcomes. Trial registration Unique Trial Number, UMIN000024502 ( https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000028197 ).

Objectives: This study was designed to elucidate differences in effects of 2 beta blockers, bisoprolol and carvedilol, in patients with chronic heart failure., Background: Although the beta blockers bisoprolol and carvedilol are commonly used in patients with chronic heart failure, differences in the efficacy and safety of these medications have not been established in this patient population., Methods: Patients with chronic systolic heart failure, defined as ≤45% ejection fraction, who had received intensive medical therapy with the exception of beta blockers, were randomly assigned to receive either bisoprolol or carvedilol for 24weeks., Results: A total of 67 patients were enrolled in the study (bisoprolol: 38 patients, carvedilol: 29 patients). No difference was observed in the improvement of NYHA class, ejection fraction, or N-terminal pro-brain-type natriuretic peptide level between groups. In contrast, the level of high sensitivity troponin T decreased in the bisoprolol group [-4.1±0.9 to -4.5±0.8 log (ng/ml), P=0.003], but did not change in the carvedilol group [-4.4±1.1 to -4.6±0.8 log (ng/ml), P=0.161]. Forced expiratory volume in the first second increased in the bisoprolol group [2.26±0.70 to 2.40±0.70 (L), P=0.014], but did not change in the carvedilol group [2.53±0.71 to 2.59±0.78 (L), P=0.127]., Conclusion: Bisoprolol might be superior to carvedilol in providing protection from myocardial injury and preserving pulmonary function in patients with chronic systolic heart failure., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Experimental ischemia-reperfusion models have shown that 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, have cardioprotective effects. SAMIT (Statin Acute Myocardial Infarction Trial) is a multicenter prospective open randomized trial, designed to evaluate the effects of statin treatment from the earliest stage on cardioprotection in patients with acute myocardial infarction (AMI). Patients were randomly assigned to receive atorvastatin (initial dose of 40 mg at admission followed by the maintenance dose of 10 mg/day for 30 days) or not (control), and then immediately underwent percutaneous coronary intervention (PCI) for the culprit lesion. The primary endpoints were infarct size and left ventricular function. The secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) and various biomarkers. There were no significant differences in baseline characteristics between 2 groups of the statin treatment group and the control group. The left ventricular ejection fraction increased at 6 months after the onset of AMI, compared with the baseline level in the atorvastatin group (P < 0.05), while it did not change in the control group. Although there were no significant differences in the MACCE, the changes in the levels of angiopoietin-like protein 2 (ANGPTL2) (P < 0.05), and glyceraldehyde-derived advanced glycation end-products, (TAGE) (P < 0.01) were suppressed at 2 weeks in the atorvastatin group, compared with the control group. Statin therapy started early after the onset reduced the levels of ANGPTL2 and TAGE, and thus, might have cardioprotective effects in patients with AMI.

Although exercise oscillatory ventilation has emerged as a potent independent risk factor for adverse prognosis in heart failure, it is not well known whether cardiac rehabilitation can improve oscillatory ventilation. In this study, we investigated the magnitude of oscillations in ventilation before and after cardiac rehabilitation in chronic heart failure patients with exercise oscillatory ventilation. Cardiac rehabilitation (5-month program) was performed in 26 patients with chronic heart failure who showed an oscillatory ventilation pattern during cardiopulmonary exercise testing (CPX). After the 5-month rehabilitation program was completed, the patients again underwent CPX. To determine the magnitude of oscillations in ventilation, the amplitude and cycle length of the oscillations were calculated and compared with several other parameters, including biomarkers that have established prognostic value in heart failure. At baseline before cardiac rehabilitation, both oscillation amplitude (R = 0.625, P < 0.01) and cycle length (R = 0.469, P < 0.05) were positively correlated with the slope of minute ventilation vs. carbon dioxide production. Plasma BNP levels were positively correlated with amplitude (R = 0.615, P < 0.01) but not cycle length (R = 0.371). Cardiac rehabilitation decreased oscillation amplitude (P < 0.01) but failed to change cycle length. The change in amplitude was positively correlated with the change in BNP levels (R = 0.760, P < 0.01). Multiple regression analysis showed that only the change in amplitude was an independent predictor of the change in BNP levels (R = 0.717, P < 0.01). A 5-month cardiac rehabilitation program improves exercise oscillatory ventilation in chronic heart failure patients by reducing the oscillation amplitude. This effect is associated with a reduction of plasma BNP levels, potentially contributing to an improvement of heart failure.

Overall stent performance should be characterized by geometric luminal gain acquisition, neointimal coverage of the stent struts, and stabilization of the underlying inflammatory neoatheroma. The aim of this study was to compare the performance of zotarolimus-eluting stent (ZES), everolimus-eluting stent (EES) and bare metal stent (BMS) using optical coherence tomography (OCT) and coronary angioscopy. For 36 stented coronary lesions (BMS, 12 lesions; ZES, 11 lesions; EES, 13 lesions) in 27 patients, we calculated neointimal area and uncovered stent strut rate based on OCT findings at 10 months after stent placement. The grades of neointimal coverage and yellow color, both of which were classified from 0 to 3, were also assessed by coronary angioscopy. The plaque area of the ZES lesions was larger than that of the EES lesions (P < 0.05) but smaller than that of the BMS lesions (P < 0.05). The OCT-based uncovered rate of the ZES lesions was less than that of the EES lesions (P < 0.01), but similar to that of the BMS lesions. The stent coverage grade by angioscopy was higher in the ZES lesions than in the EES lesions (P < 0.05), but similar to the BMS lesions. The yellow grade was less in the ZES lesions than in the EES lesions (P < 0.01), but similar to the BMS lesions. ZES might be better than BMS in terms of neointimal thickening, and better than EES in terms of neointimal coverage as well as prevention of neoatheroma formation. ZES may have superior performance compared with EES.

A 70-year-old man underwent stent implantation for right coronary artery (RCA) lesions with a bare metal stent (BMS) and two sirolimus-eluting stents (SES). However, as both the BMS and SES stented sites developed restenosis after 13 months, he underwent target lesion revascularization using directional coronary atherectomy (DCA). On histopathology, the restenosis lesion at the SES-deployed site showed greater inflammation and less re-endothelialization than that at the BMS-deployed site. Three months later, the SES-deployed site developed a second restenosis, in which paclitaxel-eluting stents (PES) were implanted (PES-in-SES), while the BMS-deployed site was restenosis free. Five years later, restenosis was absent in these RCA lesions. However, by optical coherence tomography and/or coronary angioscopy, the PES-in-SES site in the RCA showed poor neointimal coverage over the stent struts and yellowish neointima, suggesting lipid-rich neoatheroma formation, whereas at the BMS site appropriate white neointima formation was observed. Drug-eluting stents still have problems of persistent inflammation, inappropriate neointima formation, and neoatherosclerosis. Although we are now in the era of second generation DESs in which better stent performance would be promising, we should remember that we are obliged to continue to follow-up all patients in whom first generation DESs such as SES or PES have been placed.

Background and Aims: Heparin/protamine micro/nanoparticles (LH/P-MPs) were recently developed as low-molecular weight, biodegradable carriers for adipose-derived stromal cells (ADSCs). These particles can be used for a locally delivered stem cell therapy that promotes angiogenesis. LH/P-MPs bind to the cell surface of ADSCs and promote cell-to-cell interaction and aggregation of ADSCs. Cultured ADSC/LH/P-MP aggregates remain viable. Here, we examined the ability of these aggregates to rescue limb loss in a mouse model of hindlimb ischemia., Methods: Unilateral hindlimb ischemia was induced in adult male BALB/c mice by ligation of the iliac artery and hindlimb vein. For allotransplantation of ADSCs from the same inbred strain, we injected ADSC alone or ADSC/LH/P-MP aggregates or control medium (sham-treated) directly into the ischemic muscles. Ischemic limb blood perfusion, vessel density, and vessel area were recorded. The extent of ischemic limb necrosis or limb loss was assessed on postoperative days 2, 7, and 14., Results: Compared with the sham-treatment control, treatment with ADSCs alone showed modest effects on blood perfusion recovery and increased the number of α-SMA-positive vessels. Response to ADSC/LH/P-MP aggregates was significantly greater than ADSCs alone for every endpoint. ADSC/LH/P-MP aggregates more effectively prevented the loss of ischemic hindlimbs than ADSCs alone or the sham-treatment., Conclusion: The LH/P-MPs augmented the effects of ADSCs on angiogenesis and reversal of limb ischemia. Use of ADSC/LH/P-MP aggregates offers a novel and convenient treatment method and potentially represents a promising new therapeutic approach to inducing angiogenesis in ischemic diseases., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: The impact of obstructive sleep apnoea on heart failure with preserved ejection fraction is unknown., Methods: Fifty-eight patients who had heart failure with a left ventricular ejection fraction; ≥50% underwent a sleep study. Brain natriuretic peptide (BNP) levels were determined at enrolment and at one, six, 12 and 36 months after enrolment., Results: Obstructive sleep apnoea was found in 39 patients (67%), and they were all subsequently treated with continuous positive airway pressure. Echocardiography at admission showed that E/E' tended to be higher in the 39 patients with, than in the 19 patients without, obstructive sleep apnoea (15.0±3.6 vs 12.1±1.9, respectively, P=0.05). The median BNP levels at enrolment were similar in patients with and without obstructive sleep apnoea [median (interquartile range): 444 (233-752) vs 316 (218-703) pg/ml]. Although BNP levels decreased over time in both groups, the reduction was less pronounced in patients with obstructive sleep apnoea (P<0.05). Consequently, BNP levels were higher in patients with sleep apnoea at six months, [221 (137-324) vs 76 (38-96) pg/ml, P<0.05], 12 months [123 (98-197) vs 52 (38-76) pg/ml, P<0.05] and 36 months [115 (64-174) vs 56 (25-74) pg/ml, P<0.05]., Conclusion: Obstructive sleep apnoea, even when treated appropriately, may worsen long-term cardiac function and outcomes in patients who have heart failure with preserved ejection fraction., (Copyright © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

It has been suggested that n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against cardiovascular diseases, and EPA/arachidonic acid (AA) and DHA/AA ratios in serum are potential risk markers for coronary artery disease (CAD). The purpose of this study was to clarify the clinical significance of the difference in the EPA/AA ratio and the DHA/AA ratio in patients with CAD. In 369 patients with confirmed or suspected CAD who underwent diagnostic coronary angiography, we measured serum levels of EPA, DHA and AA and calculated the EPA/AA and DHA/AA ratios. The EPA/AA ratio was significantly lower in patients with acute coronary syndrome (ACS) than in patients with chronic CAD or chest pain syndrome (0.27±0.19 vs. 0.44±0.20, respectively; P<0.01), whereas the DHA/AA ratio was similar in the two groups (0.78±0.27 vs. 0.79±0.37). Multiple logistic regression analyses using various biomarkers related to coronary risk discriminated ACS from other disease entities and demonstrated that the EPA/AA ratio (odds ratio: 0.0012, 95% confidence interval: 0.00-0.16, P<0.01) but not the DHA/AA ratio (odds ratio: 1.05, 95% confidence interval: 0.98-1.12) was a significant independent predictive factor. Our findings suggest that the EPA/AA ratio might be more closely associated with the pathophysiology of CAD, especially with that of ACS, than the DHA/AA ratio. Our findings suggest that interventions with EPA agents or supplemental EPA intake, compared with DHA agents or supplemental DHA, may confer greater benefit for plaque stabilization to prevent the onset of ACS in patients with CAD.

It has been shown that segmentation in the short-germ insects proceeds by a two-step mechanism. The anterior region is simultaneously segmented in a manner similar to that in Drosophila, which is apparently unique to insects, and the rest of the posterior region is segmented sequentially by a mechanism involving a segmentation clock, which is derived from the common ancestor of arthropods. In order to propose the evolutionary scenario of insect segmentation, we examined segmentation in the jumping bristletail, the basalmost extant insect. Using probes for engrailed-family genes for in situ hybridization, we found no sign of simultaneous segmentation in the anterior region of the jumping bristletail embryos. All segments except the anteriormost segment are formed sequentially. This condition shown in the jumping bristletail embryos may represent the primitive pattern of insect segmentation. The intercalating formation of the intercalary segment is assumed to be a synapomorphic trait shared among all insects after the branching of the jumping bristletail.

Expression of the gene encoding the S100 calcium-modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been established. Here, using multiple models of vascular injury, we found that time to arterial thrombotic occlusion was markedly prolonged in Mrp14⁻/⁻ mice. We observed that MRP-14 and MRP-8/MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets from WT mice and that thrombus formation was reduced in whole blood from Mrp14⁻/⁻ mice. Infusion of WT platelets, purified MRP-14, or purified MRP-8/MRP-14 heterodimers into Mrp14⁻/⁻ mice decreased the time to carotid artery occlusion after injury, indicating that platelet-derived MRP-14 directly regulates thrombosis. In contrast, infusion of purified MRP-14 into mice deficient for both MRP-14 and CD36 failed to reduce carotid occlusion times, indicating that CD36 is required for MRP-14-dependent thrombosis. Our data identify a molecular pathway of thrombosis that involves platelet MRP-14 and CD36 and suggest that targeting MRP-14 has potential for treating atherothrombotic disorders, including MI and stroke.

Background: After stent-related vascular injury, an inflammatory response triggers the mobilization of bone marrow-derived stem cells, including both endothelial and smooth muscle progenitors, leading to re-endothelialization as well as restenosis. It has been postulated that neutrophil-released matrix metalloproteinase-9 (MMP-9) induces stem cell mobilization., Aim: To elucidate the mechanistic link between inflammation and stem cell mobilization after coronary stenting., Methods: In 31 patients undergoing coronary stenting, we serially measured activated Mac-1 on the surface of neutrophils and active MMP-9 levels in the coronary sinus blood plasma, and the number of circulating CD34-positive cells in the peripheral blood., Results: After bare-metal stent implantation (n=21), significant increases in the numbers of CD34-positive cells (maximum on post-procedure day 7, P<0.001), activated Mac-1 (at 48 h, P<0.001), and active MMP-9 levels (at 24h, P<0.001) were observed. However, these changes were absent after sirolimus-eluting stent implantation (n=10). In overall patients, the numbers of CD34-positive cells on day 7 (R=0.58, P<0.01) and activated Mac-1 at 48 h (R=0.58, P<0.01) were both correlated with active MMP-9 levels at 24h. Stimulation of activated Mac-1 on the surface of isolated human neutrophils produced active MMP-9 release in vitro., Conclusions: These results suggest that stent-induced activation of Mac-1 on the surface of neutrophils might trigger their MMP-9 release, possibly leading to the mobilization of bone marrow-derived stem cells. These reactions were substantially inhibited by sirolimus-eluting stents., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The cellular and molecular processes that control vascular injury responses after percutaneous coronary intervention involve a complex interplay among vascular cells and progenitor cells that control arterial remodeling, neointimal proliferation, and re-endothelialization. Drug-eluting stents (DES) improve the efficacy of percutaneous coronary intervention by modulating vascular inflammation and preventing neointimal proliferation and restenosis. Although positive effects of DES reduce inflammation and restenosis, negative effects delay re-endothelialization and impair endothelial function. Delayed re-endothelialization and impaired endothelial function are linked to stent thrombosis and adverse clinical outcomes after DES use. Compared with bare-metal stents, DES also differentially modulate mobilization, homing, and differentiation of vascular progenitor cells involved in re-endothelialization and neointimal proliferation. The effects of DES on vascular inflammation and repair directly impact clinical outcomes with these devices and dictate requirements for extended-duration dual antiplatelet therapy., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Down-regulation of the forkhead transcription factor Foxp1 by integrin engagement controls monocyte differentiation in vitro. To determine whether Foxp1 plays a critical role in monocyte differentiation and macrophage functions in vivo, we generated transgenic mice (macFoxp1tg) overexpressing human FOXP1 in monocyte/macrophage lineage cells using the CD68 promoter. Circulating blood monocytes from macFoxp1tg mice have reduced expression of the receptor for macrophage colony-stimulating factor (c-Fms/M-CSFR), impaired migratory capacity, and diminished accumulation as splenic macrophages. Macrophage functions, including cytokine production, phagocytosis, and respiratory burst were globally impaired in macFoxp1tg compared with wild-type cells. Osteoclastogenesis and bone resorption activity were also attenuated in macFoxp1tg mice. In models of chemical and bacterial peritonitis, macFoxp1tg mice exhibited reduced macrophage accumulation, bacterial clearance, and survival. Enforced overexpression of c-Fms/M-CSFR reversed the cytokine production and phagocytosis defects in macFoxp1tg macrophages, indicating that repression of c-fms/M-CSFR is likely the dominant mechanism responsible for Foxp1 action in monocyte differentiation and macrophage function. Taken together, these observations identify down-regulation of Foxp1 as critical for monocyte differentiation and macrophage functions in vivo.

Background: Using a transcriptional profiling approach, we recently identified myeloid-related protein 8/14 (MRP-8/14) to be expressed by platelets during acute myocardial infarction (MI). Elevated concentrations of MRP-8/14 are associated with a higher risk for future cardiovascular events in apparently healthy individuals but have not been assessed with respect to prognosis in patients with acute coronary syndrome., Methods: We performed a nested case-control study (n = 237 case-control pairs) among patients enrolled in the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial (mean follow-up 24 months) to investigate the risk of cardiovascular death or MI associated with MRP-8/14 measured at 30 days after an acute coronary syndrome., Results: Patients with cardiovascular death or MI after 30 days (cases) had higher median [25th, 75th percentile] MRP-8/14 levels than patients who remained free of recurrent events (5.6 [2.8, 13.5] mg/L vs 4.0 [1.9, 10.1] mg/L, P = .020). The risk of a recurrent cardiovascular event increased with each increasing quartile of MRP-8/14 (P-trend = 0.007) such that patients with the highest levels had a 2.0-fold increased odds (95% CI 1.1-3.6, P = .029) of a recurrent event after adjusting for standard risk indicators, randomized treatment, and C-reactive protein. Patients with elevated levels of MRP-8/14 and high-sensitivity C-reactive protein showed significantly increased risk of cardiovascular death or MI compared with patients with the lowest levels of both markers (adjusted odds ratio 2.1, 95% CI 1.2-3.8)., Conclusions: Myeloid-related protein 8/14 may be a useful biomarker of platelet and inflammatory disease activity in atherothrombosis and may serve as a novel target for therapeutic intervention.

Objective: To assess the importance of the interaction between leukocyte integrin Mac-1 (a Mb 2) and platelet glycoprotein (GP) Ib-a for leukocyte recruitment after vascular injury and the effect of the neutralization of the Mac-1-GPIba interaction on cell proliferation and the neointimal hyperplasia triggered by the vascular injury., Methods: A peptide called M2 or anti-M2 antibody was developed to block the Mac-1-GPIba interaction. This peptide was injected and compared to a control-peptide in C57B1/6J mice submitted to vascular injury of the femoral artery with a guide wire. One, five or 28 days after the vascular injury, the femoral arteries were removed for morphometric and immunohistochemical analyses., Results: The blocking of the Mac-1-GPIba interaction promoted a statistically significant reduction in the number of leukocytes in the neointimal layer on the first day after the vascular injury (control: 7.9+/-5.0% of the cell total versus anti-M2: 2.0+/-1.6%, p=0.021), as well as determined a statistically significant decrease in leukocyte accumulation in the neointimal layer on days 5 and 28 (control: 42.3+/-12.9% versus anti-M2: 24.6+/-10.8%, p=0.047 and control: 7.9+/-3.0% versus anti-M2: 3.3+/-1.3%, p=0.012; respectively). Cell proliferation in the neointimal layer of the vessel five days post-injury was reduced with the blocking of the Mac-1-GPIba interaction (control: 5.0+/-2.9% of the cell total versus anti-M2: 1.8+/-0.5%; p=0.043), along with a significant decrease in cell proliferation in the vessel neointimal layer 28 days post-injury (control: 3.8+/-1.7% versus anti-M2: 2.0+/-1.2%; p=0.047). The blocking of the Mac-1-GPIba interaction also determined a statistically significant decrease of the intimal thickening 28 days post-injury (control: 10,395+/-3,549 microm(2) versus anti-M2: 4,561+/-4,915 microm(2); p=0.012)., Conclusion: Leukocyte recruitment after a vascular injury depends on the Mac-1-GPIba interaction and the neutralization of this interaction inhibits cell proliferation and neointimal formation.

A 47-year-old woman was referred to our hospital because of cardiomegaly and pericardial effusion. She complained of a cough. Computed tomography, echocardiography, and magnetic resonance imaging showed a mass on the pericardium. Exploratory surgery revealed a solid tumor invading the pericardium over the aortic arch and main pulmonary artery. Histological examination indicated primary malignant pericardial mesothelioma. After 58 Gy radiation, the size of the tumor was temporarily reduced and the patient's symptoms disappeared. However, the tumor enlarged and her symptoms reappeared 7 months after temporary improvement. Eighteen months after the development of cough, the patient died suddenly.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced, in part, from NADPH oxidase in response to host invasion and tissue injury. Defects in NADPH oxidase impair host defense; however, the role of ROS and RNS in the response to tissue injury is not known. We addressed this issue by subjecting leukocyte oxidase (Nox2)-deficient (Nox2-/-) mice to arterial injury. Femoral artery injury was associated with increased Nox2 expression, ROS/RNS production, and oxidative protein and lipid modification in wild-type mice. In Nox2-/- mice, RNS-mediated protein oxidation, as monitored by protein nitrotyrosine content, was significantly diminished. This was accompanied by reduced neointimal proliferation, as monitored by intimal thickness and intimal/medial ratio, in Nox2-/- compared to wild-type mice. In addition, Nox2 deficiency led to reduced cellular proliferation and leukocyte accumulation. These data indicate that Nox2-mediated oxidant production has a requisite role in the response to tissue injury., (Copyright 2004 The National Academy of Sciencs of the USA)