Novel treatment system using endoscopic ultrasound-guided high-intensity focused ultrasound: A proof-of-concept study.

AIM: High-intensity focused ultrasound (HIFU) is a novel minimally invasive local treatment of solid tumors. Endoscopic ultrasound-guided HIFU (EUS-HIFU) using mechanical effects would have potential benefits, including precise detection of target lesions and enhance drug delivery. The aim of this study is to develop EUS-HIFU device and to prove our concept in porcine model using a locally injected phase change nano droplet (PCND) as the sensitizer. METHOD: A phospholipid PCND contained volatile perfluoro-carbon liquids. The prototype HIFU apparatus comprised a small (20 × 20 mm) transducer with center frequency of 2.1 MHz, attachable to a linear EUS transducer. Under general anesthetic, a single porcine received EUS-guided injection of PCND. The HIFU transducer was placed laparotomically in the stomach, and the liver was ablated through the gastric wall. RESULTS: PCND was injected successfully and a distinct lesion was generated at the HIFU transducer focus only in injected areas that received HIFU exposure at 4.7 kW/cm2 at a duty cycle of 5 % (mean temporal intensity, 0.245 kW/cm2) for 30 s. The generated lesions were mechanically fractionated in macroscopic view. CONCLUSION: The concept of transluminal HIFU ablation using novel EUS-HIFU system was proved in a porcine animal model. This novel treatment system has great potential for future cancer treatment although further investigation in more animals and different organs are warranted.

Persistent Myocardial Production of Follistatin-like 1 Is Associated With Left Ventricular Adverse Remodeling in Patients With Myocardial Infarction: Myocardial production of FSTL1 in AMI patients.

BACKGROUND: Although animal studies showed that Follistatin-like 1 (FSTL1) exerts cardioprotective effects against ischemic injury, little is known in humans. We examined whether FSTL1 is secreted in an infarcted myocardium and whether its production is associated with left ventricular (LV) remodeling in survivors of acute myocardial infarction. METHODS AND RESULTS: FSTL1 levels were measured by enzyme-linked immunosorbent assay in plasma collected from the aortic root and the anterior interventricular vein in 93 patients with anterior acute myocardial infarction. Measurement of FSTL1 levels and left ventriculography were repeated during the early phase (2 weeks) and the chronic phase (6 months) after MI. A persistent increment in FSTL1 levels from the aortic root to the anterior interventricular vein, reflecting FSTL1 production in the infarcted myocardium at both the early and chronic phases, was seen in 22 patients (24%). A linear regression analysis revealed that a persistent transmyocardial increment in FSTL1 levels was significantly associated with percent changes in LV end-diastolic volume index, LV end-systolic volume index, and LV ejection fraction from the early to the chronic phase (r = 0.44, 0.51, and -0.43, respectively, all P < .001). CONCLUSIONS: The persistent production of FSTL1 in the infarcted myocardium was associated with adverse LV remodeling in survivors of acute myocardial infarction.

Pulmonary Vascular Resistance Is Associated With Brachial-Ankle Pulse-Wave Velocity and Adverse Clinical Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The precise mechanisms underlying the high prevalence of pulmonary hypertension (PH) with increased pulmonary vascular resistance (PVR) in heart failure with preserved ejection fraction (HFpEF) remain largely unknown. Measurements of brachial-ankle pulse wave velocity (baPWV) have been shown to be useful for risk assessment in HF patients. Thus, this study sought to define the association of PVR with baPWV and clinical outcomes in HFpEF. METHODS AND RESULTS: Patients with HFpEF (n = 198) had measurements of baPWV and PVR by right heart catheterization, and were prospectively followed-up for <96 months or until the occurrence of a composite of all-cause death, hospitalization with worsening HF, and nonfatal acute coronary syndrome. RESULTS: Multivariate logistic analysis showed that baPWV was independently associated with PH with increased PVR (P < .001). During the follow-up period, 46 clinical events occurred. Multivariate Cox proportional hazards analysis showed that PH with increased PVR was a significant predictor of adverse outcomes after adjustment for conventional risk factors (HR 1.96, 95% CI 1.03-3.76, P = .04). CONCLUSIONS: PH with increased PVR was associated with increased baPWV and adverse clinical outcomes in HFpEF. Thus, increased arterial stiffness may contribute to increased risk predictability of PVR for patients with HFpEF.

High levels of stromal cell-derived factor-1α predict short-term progression of renal dysfunction in patients with coronary artery disease.

BACKGROUND: Stromal cell-derived factor-1α (SDF-1α) is an inflammatory chemokine that plays a critical role in cardiovascular disease. Although persistent inflammation causes renal dysfunction, it remains unclear whether SDF-1α is related to progression of chronic kidney disease. This study examined whether high levels of SDF-1α are associated with future declines in renal function in patients with coronary artery disease (CAD). METHODS: Plasma levels of SDF-1α in the peripheral blood were measured by enzyme-linked immunosorbent assay in 344 patients with CAD. All patients were followed for 24 months or until the occurrence of renal dysfunction, defined as ≥ 25% decrease in estimated glomerular filtration rate (eGFR) from baseline. RESULTS: During the follow-up period, 36 patients developed renal dysfunction. Multivariate logistic regression analysis showed that high plasma levels of SDF-1α were significantly associated with progression of renal dysfunction (odds ratio 1.65; 95% confidence intervals 1.07-2.35, p = 0.03). In addition, high plasma levels of SDF-1α had a significant incremental effect on the predictive value of known risk factors for renal dysfunction in analyses using net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.58 [0.07-1.02], p < 0.01; and IDI 0.030 [0.001-0.085], p = 0.02). CONCLUSION: High plasma levels of SDF-1α were associated with the short-term decline of eGFR in patients with CAD. Thus, SDF-1α may be useful for predicting the progression of renal dysfunction in patients with CAD.

Centralization of extruded medial meniscus delays cartilage degeneration in rats.

BACKGROUND: Meniscus extrusion often observed in knee osteoarthritis has a strong correlation with the progression of cartilage degeneration and symptom in the patients. We recently reported a novel procedure "arthroscopic centralization" in which the capsule was sutured to the edge of the tibial plateau to reduce meniscus extrusion in the human knee. However, there is no animal model to study the efficacy of this procedure. The purposes of this study were [1] to establish a model of centralization for the extruded medial meniscus in a rat model; and [2] to investigate the chondroprotective effect of this procedure. METHODS: Medial meniscus extrusion was induced by the release of the anterior synovial capsule and the transection of the meniscotibial ligament. Centralization was performed by the pulled-out suture technique. Alternatively, control rats had only the medial meniscus extrusion surgery. Medial meniscus extrusion was evaluated by micro-CT and macroscopic findings. Cartilage degeneration of the medial tibial plateau was evaluated macroscopically and histologically. RESULTS: By micro-CT analysis, the medial meniscus extrusion was significantly improved in the centralization group in comparison to the extrusion group throughout the study. Both macroscopically and histologically, the cartilage lesion of the medial tibial plateau was prevented in the centralization group but was apparent in the control group. CONCLUSIONS: We developed medial meniscus extrusion in a rat model, and centralization of the extruded medial meniscus by the pull-out suture technique improved the medial meniscus extrusion and delayed cartilage degeneration, though the effect was limited. Centralization is a promising treatment to prevent the progression of osteoarthritis.

Lack of phospholipase A2 receptor increases susceptibility to cardiac rupture after myocardial infarction.

RATIONALE: Recent evidence indicates that the biological effects of secretory phospholipase A2 (sPLA2) cannot be fully explained by its catalytic activity. A cell surface receptor for sPLA2 (PLA2 receptor 1 [PLA2R]) and its high-affinity ligands (including sPLA2-IB, sPLA2-IIE, and sPLA2-X) are expressed in the infarcted myocardium. OBJECTIVE: This study asked whether PLA2R might play a pathogenic role in myocardial infarction (MI) using mice lacking PLA2R (PLA2R(-/-)). METHODS AND RESULTS: MI was induced by permanent ligation of the left coronary artery. PLA2R(-/-) mice exhibited higher rates of cardiac rupture after MI compared with PLA2R wild-type (PLA2R(+/+)) mice (46% versus 21%, respectively; P=0.015). PLA2R(-/-) mice had a 31% decrease in collagen content and a 45% decrease in the number of α-smooth muscle actin-positive fibroblasts in the infarcted region compared with PLA2R(+/+) mice. PLA2R was primarily found in myofibroblasts in the infarcted region. PLA2R(-/-) myofibroblasts were impaired in collagen-dependent migration, proliferation, and activation of focal adhesion kinase in response to sPLA2-IB. Binding of sPLA2-IB to PLA2R promoted migration and proliferation of myofibroblasts through functional interaction with integrin ß1, independent of the catalytic activity of sPLA2-IB. In rescue experiments, the injection of PLA2R(+/+) myofibroblasts into the infarcted myocardium prevented post-MI cardiac rupture and reversed the decrease in collagen content in the infarcted region in PLA2R(-/-) mice. CONCLUSIONS: PLA2R deficiency increased the susceptibility to post-MI cardiac rupture through impaired healing of the infarcted region. This might be partly explained by a reduction in integrin ß1-mediated migratory and proliferative responses of PLA2R(-/-) myofibroblasts.

Deficiency of phospholipase A2 receptor exacerbates ovalbumin-induced lung inflammation.

Secretory phospholipase A2 (sPLA2) plays a critical role in the genesis of lung inflammation through proinflammatory eicosanoids. A previous in vitro experiment showed a possible role of cell surface receptor for sPLA2 (PLA2R) in the clearance of extracellular sPLA2. PLA2R and groups IB and X sPLA2 are expressed in the lung. This study examined a pathogenic role of PLA2R in airway inflammation using PLA2R-deficient (PLA2R(-/-)) mice. Airway inflammation was induced by immunosensitization with OVA. Compared with wild-type (PLA2R(+/+)) mice, PLA2R(-/-) mice had a significantly greater infiltration of inflammatory cells around the airways, higher levels of groups IB and X sPLA2, eicosanoids, and Th2 cytokines, and higher numbers of eosinophils and neutrophils in bronchoalveolar lavage fluid after OVA treatment. In PLA2R(-/-) mice, intratracheally instilled [(125)I]-labeled sPLA2-IB was cleared much more slowly from bronchoalveolar lavage fluid compared with PLA2R(+/+) mice. The degradation of the instilled [(125)I]-labeled sPLA2-IB, as assessed by trichloroacetic acid-soluble radioactivity in bronchoalveolar lavage fluid after instillation, was lower in PLA2R(-/-) mice than in PLA2R(+/+) mice. In conclusion, PLA2R deficiency increased sPLA2-IB and -X levels in the lung through their impaired clearance from the lung, leading to exaggeration of lung inflammation induced by OVA treatment in a murine model.

Echolucency of carotid plaque is useful for assessment of residual cardiovascular risk in patients with chronic coronary artery disease who achieve LDL-C goals on statin therapy.

BACKGROUND: Ultrasound assessment of either intima-media thickness (IMT) or plaque echolucency of the carotid artery provides prognostic information on coronary events. This study examined the hypothesis that IMT and plaque echolucency of the carotid artery may remain useful for prediction of coronary events in patients with coronary artery disease (CAD) after achievement of LDL-C goals on statin therapy. METHODS AND RESULTS: Ultrasound assessment of carotid maximum IMT (maxIMT) and plaque echolucency with integrated backscatter (IBS) analysis was performed in 357 chronic CAD patients with LDL-C <100mg/dl on statin therapy. All patients were prospectively followed up until the occurrence of one of the following coronary events: cardiac death, non-fatal myocardial infarction, or unstable angina pectoris requiring unplanned revascularization. During a mean follow-up of 32±18 months, 33 coronary events occurred. On multivariate Cox proportional hazards analysis, plaque echolucency (lower IBS value) was a significant predictor of coronary events (HR, 0.44; 95% CI: 0.29-0.73; P=0.009), whereas maxIMT was not. The addition of plaque echolucency to traditional risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI; NRI, 0.59; P=0.0013; and IDI, 0.075; P=0.0009). CONCLUSIONS: Measurement of echolucency of the carotid artery was useful for assessment of residual coronary risk in CAD patients after LDL-C goal attainment on statin treatment.

In-stent restenosis is inhibited in a bare metal stent implanted distal to a sirolimus-eluting stent to treat a long de novo coronary lesion with small distal vessel diameter.

OBJECTIVES: This study examined whether sirolimus-eluting stent (SES) implantation exerts an antiproliferative action on a bare metal stent (BMS) placed distally in the same coronary artery. BACKGROUND: Diffusion of sirolimus into flowing coronary blood may cause accumulation of this drug in the coronary bed beyond the distal edge of an SES. METHODS: We analyzed data from 115 consecutive patients with ischemic heart disease who were treated with two overlapping stents without a gap in the same coronary artery for a long de novo lesion. The distal stent was a 2.25 mm BMS in all patients, and the proximal stent was an SES in 73 patients (SES-BMS group) and a BMS in 42 patients (BMS-BMS group). Quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) were performed at stent implantation and 8 months later. RESULTS: Clinical and procedural variables were comparable between the two groups. QCA and IVUS showed that the SES-BMS group had less luminal late loss and a lower percent of in-stent volume obstruction in the distal BMS compared with the BMS-BMS group. Furthermore, compared with the BMS-BMS group, the SES-BMS group had less in-stent restenosis (23.3 vs. 54.8%, P < 0.0005) and target lesion revascularization (21.9 vs. 50.0%, P < 0.005). CONCLUSIONS: SES implantation just proximal to a BMS inhibits neointimal proliferation in the BMS, when both stents are implanted in the same coronary artery to treat a de novo lesion.

Contrast-enhanced ultrasound imaging of carotid plaque neovascularization is useful for identifying high-risk patients with coronary artery disease.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) in the carotid artery has potential as a technique for imaging plaque neovascularization. This study examined whether CEUS could provide information on the severity and instability of coronary artery disease (CAD). METHODS AND RESULTS: A total of 304 patients with CAD and carotid plaque underwent CEUS examination of the carotid artery. Intraplaque neovascularization was identified on the basis of microbubbles within the plaque and graded as: G0, not visible; G1, moderate; or G2, extensive microbubbles. The complexity and extent of the coronary lesions were assessed angiographically. A higher grade of CEUS-assessed plaque neovascularization of the carotid artery was associated significantly with greater complexity (ρ=0.48 by Spearman's rank correlation test) and extent (ρ=0.51) of coronary lesions. G2 plaque neovascularization was a risk for acute coronary syndrome, independent of traditional risk factors (odds ratio 1.91, 95% confidence interval 1.04-3.53, P<0.01). Subgroup analysis showed that carotid CEUS-assessed neovascularization regressed in 12 (46%) of 26 plaques in patients during 6 months of statin treatment, whereas regression occurred in 2 (14%) of 14 plaques in patients not taking a statin (P=0.04, Chi-square test). CONCLUSIONS: CEUS examination of the carotid artery may provide valuable information on the severity and instability of CAD and also the efficacy of antiatherosclerotic treatment.

Group X secretory PLA2 in neutrophils plays a pathogenic role in abdominal aortic aneurysms in mice.

Group X secretory PLA(2) (sPLA(2)-X) is expressed in neutrophils and plays a role in the pathogenesis of neutrophil-mediated tissue inflammation and injury. This study tested the hypothesis that sPLA(2)-X in neutrophils may contribute to the pathogenesis of abdominal aortic aneurysms (AAA) using sPLA(2)-X(-/-) mice. AAA was created by application of CaCl(2) to external surface of aorta. As a result, the aortas of sPLA(2)-X(-/-) mice had smaller diameters (percent increase from baseline; 24.8 ± 3.5% vs. 49.9 ± 9.1%, respectively; P < 0.01), a reduced grade of elastin degradation, and lower activities of elastase and gelatinase (26% and 19% lower, respectively) after CaCl(2) treatment compared with sPLA(2)-X(+/+) mice. In sPLA(2)-X(+/+) mice, immunofluorescence microscopic images showed that the immunoreactivity of sPLA(2)-X was detected only in neutrophils within aortic walls 3 days, 1, 2, and 6 wk after CaCl(2) treatment, whereas the immunoreactivity was not detected in macrophages or mast cells in aortic walls. sPLA(2)-X immunoreactivity also was colocalized in cells expressing matrix metalloproteinase (MMP)-9. Neutrophils isolated from sPLA(2)-X(-/-) mice had lower activities of elastase, gelatinase, and MMP-9 in response to stimuli compared with sPLA(2)-X(+/+) mice. The attenuated release of elastase and gelatinase from sPLA(2)-X(-/-) neutrophils was reversed by exogenous addition of mouse sPLA(2)-X protein. The adoptive transfer of sPLA(2)-X(+/+) neutrophils days 0 and 3 after CaCl(2) treatment reversed aortic diameters and elastin degradation grades in the lethally irradiated sPLA(2)-X(+/+) mice reconstituted with sPLA(2)-X(-/-) bone marrow to an extent similar to that seen in sPLA(2)-X(+/+) mice. In conclusion, sPLA(2)-X in neutrophils plays a pathogenic role in AAA in a mice model.

Disruption of group IVA cytosolic phospholipase A(2) attenuates myocardial ischemia-reperfusion injury partly through inhibition of TNF-α-mediated pathway.

Group IVA cytosolic phospholipase A(2) (cPLA(2)α), which preferentially cleaves arachidonic acid from phospholipids, plays a role in apoptosis and tissue injury. Downstream signals in response to tumor necrosis factor (TNF)-α, a mediator of myocardial ischemia-reperfusion (I/R) injury, involve cPLA(2)α activation. This study examined the potential role of cPLA(2)α and its mechanistic link with TNF-α in myocardial I/R injury using cPLA(2)α knockout (cPLA(2)α(-/-)) mice. Myocardial I/R was created with 10-wk-old male mice by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. As a result, compared with wild-type (cPLA(2)α(+/+)) mice, cPLA(2)α(-/-) mice had a 47% decrease in myocardial infarct size, preservation of echocardiographic left ventricle (LV) function (%fractional shortening: 14 vs. 21%, respectively), and lower content of leukotriene B(4) and thromboxane B(2) (62 and 50% lower, respectively) in the ischemic myocardium after I/R. Treatment with the TNF-α inhibitor (soluble TNF receptor II/IgG1 Fc fusion protein, sTNFR:Fc) decreased myocardial I/R injury and LV dysfunction in cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) mice. sTNFR:Fc also suppressed cPLA(2)α phosphorylation in the ischemic myocardium after I/R of cPLA(2)α(+/+) mice. Similarly, sTNFR:Fc exerted protective effects against hypoxia-reoxygenation (H/R)-induced injury in the cultured cardiomyocytes from cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) cardiomyocytes. H/R and TNF-α induced cPLA(2)α phosphorylation in cPLA(2)α(+/+) cardiomyocytes, which was reversible by sTNFR:Fc. In cPLA(2)α(-/-) cardiomyocytes, TNF-α induced apoptosis and release of arachidonic acid to a lesser extent than in cPLA(2)α(+/+) cardiomyocytes. In conclusion, disruption of cPLA(2)α attenuates myocardial I/R injury partly through inhibition of TNF-α-mediated pathways.

Usefulness of a collateral channel dilator for antegrade treatment of chronic total occlusion of a coronary artery.

OBJECTIVES: The aim of this study was to clarify the effectiveness of a collateral channel dilator microcatheter in antegrade percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) of a coronary artery. BACKGROUND: The Corsair microcatheter, which was originally developed as a collateral channel dilator, has been reported to be useful for retrograde CTO-PCI. METHODS: We compared the success rate of the Corsair microcatheter collateral channel dilator for antegrade CTO-PCI with a previously available microcatheter. We analyzed the data from 27 patients (32 CTOs) using the FinecrossMG (Finecross group) and the data from 31 patients (34 CTOs) using the Corsair (Corsair group). RESULTS: There were no significant differences in the clinical or lesion characteristics between the 2 groups. The success rate for crossing the CTO by the microcatheter was 62.5% in the Finecross group and 85.3% in the Corsair group (P < 0.05). After the Corsair crossed the CTO, a 2-mm diameter balloon catheter crossed the lesion in all the cases, but it crossed the lesion in only 17 of 20 cases in the Finecross group (85.0%, P < 0.05). The number of balloon catheters used for predilation was significantly less in the Corsair group compared with the Finecross group (P < 0.05). CONCLUSIONS: The success rate for crossing of the microcatheters and the balloon catheters through the occlusion in antegrade CTO-PCI was better with the Corsair than with the FinecrossMG. In addition, the use of the Corsair reduced the number of balloon catheters used for predilation in antegrade CTO-PCI.

Early improvement in carotid plaque echogenicity by acarbose in patients with acute coronary syndromes.

BACKGROUND: The resolution of hyperglycemia is associated with suppression of in-hospital cardiac complications in patients with acute coronary syndromes (ACS). This study evaluated carotid artery plaque echolucency using ultrasound in patients with ACS and type 2 diabetes mellitus (DM) to determine whether acarbose, an α-glucosidase inhibitor, may rapidly stabilize unstable atherosclerotic plaques. METHODS AND RESULTS: ACS patients with type 2 DM and carotid plaques (n=44) were randomly assigned to treatment with acarbose (150 or 300 mg/day, n=22) or a control group (no acarbose, n=22). Acarbose treatment was initiated within 5 days after the onset of ACS. Unstable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) before, and at 2 weeks, 1 and 6 months after the initiation of treatment. An increase in the IBS value reflected an increase in carotid plaque echogenicity. As results, the IBS value of echolucent carotid plaques showed a significant increase at 1 month and a further increase at 6 months after treatment in the acarbose group, but there was minimal change in the control group. The increase in IBS values was significantly correlated with a decrease in C-reactive protein levels. CONCLUSIONS: Acarbose rapidly improved carotid plaque echolucency within 1 month of therapy in patients with ACS and type 2 DM.

Inhibition of secretory phospholipase A2 activity attenuates acute cardiogenic pulmonary edema induced by isoproterenol infusion in mice after myocardial infarction.

Several types of secretory phospholipase A2 (sPLA2) are expressed in lung tissue, yielding various eicosanoids that might cause pulmonary edema. This study examined whether inhibition of sPLA2 activity attenuates acute cardiogenic pulmonary edema in mice. Acute cardiogenic pulmonary edema was induced in C57BL/6J male mice by an increase in heart rate with continuous intravenous infusion of isoproterenol (ISP) (10 mg/kg/h) at 2 weeks after the creation of myocardial infarction by left coronary artery ligation. Just before ISP infusion, a single intraperitoneal injection of 100 mg/kg LY374388, a prodrug of LY329722 that inhibits sPLA2 activity, or vehicle was administered. The ISP infusion after myocardial infarction induced interstitial and alveolar edema on lung histology. Furthermore, it increased the lung-to-body weight ratio, pulmonary vascular permeability evaluated by the Evans blue extravasation method, lung activity of sPLA2, and lung content of thromboxane A2 and leukotriene B4. These changes were significantly attenuated by LY374388 treatment. In Kaplan-Meier analysis, the survival rate during the ISP infusion after myocardial infarction was significantly higher in LY374388- than in vehicle-treated mice. Similar results were obtained with another inhibitor of sPLA2 activity, para-bromophenacyl bromide. In conclusion, inhibition of sPLA2 activity suppressed acute cardiogenic pulmonary edema.

Comparative study of bezafibrate and pravastatin in patients with coronary artery disease and high levels of remnant lipoprotein.

BACKGROUND: Remnant lipoproteinemia is a strong risk factor for cardiovascular (CV) diseases. This study examined which of 2 common lipid-lowering drugs (fibrates and statins) is more effective in patients with remnant lipoproteinemia and if lowering remnant lipoprotein levels can reduce CV risk. METHODS AND RESULTS: Remnant lipoprotein levels were measured by an immunoseparation method (remnant-like lipoprotein particles cholesterol: RLP-C) in 274 patients with coronary artery disease and high RLP-C levels (>or=5.0 mg/dl). They were randomly assigned to receive bezafibrate (200-400 mg/day) or pravastatin (10-20 mg/day), and were prospectively followed-up for 1 year or until the occurrence of CV events. Complete follow-up data were obtained in 180 patients. RLP-C levels at 1 year of treatment were reduced more by bezafibrate than pravastatin (37% and 25% from baseline, respectively). During follow-up, bezafibrate-treated patients had 3 CV events, compared with 12 events in pravastatin-treated patients (P<0.01). In multivariate logistic regression analysis, a decrease in RLP-C level was significantly associated with a reduction in CV events after adjustment for treatment group and changes in levels of other lipids. CONCLUSIONS: Bezafibrate therapy decreased RLP-C levels to a greater extent than pravastatin and a decrease in RLP-C level may be associated with a reduction in CV events in patients with high RLP-C levels.

Inhibition of secretory phospholipase A2 activity attenuates lipopolysaccharide-induced acute lung injury in a mouse model.

This study evaluated the hypothesis that LY374388, an inhibitor of secretory phospholipase A(2) (sPLA(2)) activity, may exert a protective effect on lipopolysaccharide (LPS)-induced acute lung injury in male C57BL/6J mice. Intratracheal administration of LPS increased histopathological changes in lung tissue, lung wet to dry ratios, and the bronchoalveolar lavage fluid levels of neutrophil numbers, sPLA(2) activity, leukotriene B(4), and thromboxane B(2). However, a simultaneous intraperitoneal treatment with LY374388 significantly attenuated these LPS-induced changes. Thus, inhibition of sPLA(2) activity significantly attenuated the acute lung injury induced by LPS. sPLA(2) played an important role in the pathogenesis of LPS-induced acute lung injury in mice.

Ultrasound Sub-pixel Motion-tracking Method with Out-of-plane Motion Detection for Precise Vascular Imaging.

Ultrasound vascularity imaging provides important information for differential diagnosis of tumors. Peak-hold (PH) is a useful technique for precisely imaging small vessels by selecting a maximum brightness in each pixel through the frames obtained sequentially. To use PH successfully one needs motion compensation to reduce image blur, but out-of-plane motion cannot be avoided. To address this problem, we developed a sub-pixel motion-tracking method with out-of-plane motion detection (OPMD). It is a combination of the sum of the absolute differences (SAD) method and the Kanade-Lucas-Tomasi method and can be accurately applied to various motions. The value from OPMD (γ) is defined as a statistical value obtained from the distribution of residual values in the SAD procedure with the obtained frames. The value is ideally 0, and the frames having large γ are removed from the PH procedure. The accuracy of the proposed tracking method was found by a simulation study to be approximately 20 µm. We also found, through a phantom experiment, that the value of γ sensitively increased enough to detect out-of-plane motion. Most important, γ begins to increase before tracking errors occur. This suggests that OPMD can be used to predict tracking errors and effectively remove frames from the PH procedure. An in vivo experiment with a rabbit showed that the PH image obtained with motion tracking clearly revealed peripheral vessels that were blurred in the PH image obtained without motion tracking. We also found that the image quality becomes better when OPMD was used to remove frames including out-of-plane motion.

Reduction in myocardial ischemia/reperfusion injury in group X secretory phospholipase A2-deficient mice.

BACKGROUND: Group X secretory phospholipase A(2) (sPLA(2)-X) has the most potent hydrolyzing activity toward phosphatidylcholine and elicits a marked release of arachidonic acid among several types of sPLA(2). sPLA(2)-X is expressed in neutrophils, but its pathogenic role remains unclear. METHODS AND RESULTS: We generated mice that lack sPLA(2)-X and studied their response to myocardial ischemia/reperfusion. The sPLA(2)-X(-/-) mice had a significant reduction in myocardial infarct size and a decrease in myocardial myeloperoxidase activity compared with sPLA(2)-X(+/+) mice. Myocardial infarct size was also significantly reduced in lethally irradiated sPLA(2)-X(+/+) mice reconstituted with sPLA(2)-X(-/-) bone marrow compared with sPLA(2)-X(+/+) bone marrow. The extent of myocardial ischemia/reperfusion injury was comparable between sPLA(2)-X(-/-) and sPLA(2)-X(+/+) mice in Langendorff experiments using isolated hearts and blood-free perfusion buffer, supporting a potential role of sPLA(2)-X in blood in myocardial ischemia/reperfusion injury. In the infarcted myocardium of sPLA(2)-X(+/+) mice, sPLA(2)-X was released from neutrophils but not myocardial tissues and platelets and was undetectable in the peripheral serum. The sPLA(2)-X(-/-) mice had lower accumulation of neutrophils in ischemic myocardium, and the isolated sPLA(2)-X(-/-) neutrophils had lower release of arachidonic acid and attenuated cytotoxic activities including respiratory burst compared with sPLA(2)-X(+/+) neutrophils. The attenuated functions of sPLA(2)-X(-/-) neutrophils were reversible by the exogenous addition of sPLA(2)-X protein. Furthermore, administration of a sPLA(2) inhibitor reduced myocardial infarct size and suppressed the cytotoxic activity of sPLA(2)-X(+/+) neutrophils. CONCLUSIONS: Myocardial ischemia/reperfusion injury was attenuated in sPLA(2)-X(-/-) mice partly through the suppression of neutrophil cytotoxic activities.

Measurement of the platelet retention rate in a column of collagen-coated beads is useful for the assessment of efficacy of antiplatelet therapy.

INTRODUCTION: A simple, validated method to measure platelet function is unavailable for bedside use. Measurement of platelet retention rate using a column of collagen-coated beads and whole blood is a new, simple assay that reflects platelet aggregation. This study was aimed to examine the utility of this assay to assess efficacy of antiplatelet drug therapy. METHODS: Citrated whole blood (1.5 ml) in a syringe was passed through a polyvinyl tube packed with collagen-coated beads for 40 seconds using a syringe pump. Platelet retention rate in the column was calculated from platelet counts in blood before and after passage. An increase in the retention rate reflects an increase in platelet activity. This new platelet retention assay and the traditional optical aggregometry assay were performed in 331 patients with stable coronary artery disease (CAD). RESULTS: The retention rate was significantly reduced in patients taking dual antiplatelet therapy (aspirin plus clopidogrel or ticlopidine) compared with aspirin alone. There was a significant linear correlation between the platelet retention rate and platelet aggregability measured by the traditional method (r=0.44, p<0.001). In multivariate Cox proportional hazards analysis, higher platelet retention rate was an independent predictor of future cardiovascular events in patients on dual antiplatelet therapy (hazard ratio 3.9, 95% CI 1.6 to 9.5, p=0.003). CONCLUSIONS: Measurement of the platelet retention rate in a column of collagen-coated beads may be useful for monitoring the efficacy of antiplatelet drug therapy in patients with CAD.