Role of prostaglandin D2 receptors in the pathogenesis of abdominal aortic aneurysm formation.

Prostaglandin D2 (PGD2) released from immune cells or other cell types activates its receptors, D prostanoid receptor (DP)1 and 2 (DP1 and DP2), to promote inflammatory responses in allergic and lung diseases. Prostaglandin-mediated inflammation may also contribute to vascular diseases such as abdominal aortic aneurysm (AAA). However, the role of DP receptors in the pathogenesis of AAA has not been systematically investigated. In the present study, DP1-deficient mice and pharmacological inhibitors of either DP1 or DP2 were tested in two distinct mouse models of AAA formation: angiotensin II (AngII) infusion and calcium chloride (CaCl2) application. DP1-deficient mice [both heterozygous (DP1+/-) and homozygous (DP1-/-)] were protected against CaCl2-induced AAA formation, in conjunction with decreased matrix metallopeptidase (MMP) activity and adventitial inflammatory cell infiltration. In the AngII infusion model, DP1+/- mice, but not DP1-/- mice, exhibited reduced AAA formation. Interestingly, compensatory up-regulation of the DP2 receptor was detected in DP1-/- mice in response to AngII infusion, suggesting a potential role for DP2 receptors in AAA. Treatment with selective antagonists of DP1 (laropiprant) or DP2 (fevipiprant) protected against AAA formation, in conjunction with reduced elastin degradation and aortic inflammatory responses. In conclusion, PGD2 signaling contributes to AAA formation in mice, suggesting that antagonists of DP receptors, which have been extensively tested in allergic and lung diseases, may be promising candidates to ameliorate AAA.

Impact of IVUS-Derived Vessel Size on Midterm Outcomes After Stent Implantation in Femoropopliteal Lesions.

Purpose: To identify intravascular ultrasound (IVUS) findings that predict midterm stent patency in femoropopliteal (FP) lesions. Materials and Methods: A retrospective analysis was undertaken of 335 de novo FP lesions in 274 consecutive patients (mean age 72.4±8.2 years; 210 men) who had IVUS assessment before and after successful stent implantation. The mean lesion length was 13.2±9.8 cm. The primary outcome was primary patency at 24 months, defined as freedom from major adverse limb event (MALE) and in-stent restenosis (ISR). MALE was defined as major amputation or any target lesion revascularization (TLR). ISR was defined by a peak systolic velocity ratio >2.4 by duplex ultrasonography. Logistic regression analyses were performed to identify independent predictors of stent patency at 24 months; the results are presented as the odds ratio (OR) and 95% confidence interval (CI). Receiver operator characteristic (ROC) curve analysis was performed to determine the optimal threshold for prediction of stent patency at 24 months. Results: Over the 24-month follow-up, 18 (7%) patients died and 43 (15%) of 286 lesions were responsible for MALE (42 TLRs and 1 major amputation). Primary patency was estimated at 82.5% (95% CI 78.1% to 86.9%) at 12 months and 73.2% (95% CI 67.9% to 78.5%) at 24 months. Multivariable analysis revealed that longer lesion length (OR 0.89, 95% CI 0.82 to 0.97, p<0.01) was an independent predictor of declining patency, while cilostazol use (OR 3.45, 95% CI 1.10 to 10.78, p=0.03) and increasing distal reference external elastic membrane (EEM) area (OR 1.18, 95% CI 1.02 to 1.37, p=0.03) were associated with midterm stent patency. ROC curve analysis identified a distal reference EEM area of 29.0 mm2 as the optimal cut-point for prediction of 24-month stent patency (area under the ROC curve 0.764). Kaplan-Meier estimates of 24-month primary patency were 83.7% (95% CI 78.3% to 89.2%) in lesions with a distal EEM area >29.0 mm2 vs 53.1% (95% CI 42.9% to 63.3%) in those with a distal EEM area ≤29.0 mm2 (p<0.001). Conclusion: In FP lesions with a larger distal vessel area estimated with IVUS, stent implantation can be considered as a reasonable treatment option, with the likelihood of acceptable midterm results.

Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b.

OBJECTIVE: Copper (Cu) is essential micronutrient, and its dysregulation is implicated in aortic aneurysm (AA) development. The Cu exporter ATP7A (copper-transporting P-type ATPase/Menkes ATPase) delivers Cu via the Cu chaperone Atox1 (antioxidant 1) to secretory Cu enzymes, such as lysyl oxidase, and excludes excess Cu. Lysyl oxidase is shown to protect against AA formation. However, the role and mechanism of ATP7A in AA pathogenesis remain unknown. Approach and Results: Here, we show that Cu chelator markedly inhibited Ang II (angiotensin II)-induced abdominal AA (AAA) in which ATP7A expression was markedly downregulated. Transgenic ATP7A overexpression prevented Ang II-induced AAA formation. Conversely, Cu transport dysfunctional ATP7Amut/+/ApoE-/- mice exhibited robust AAA formation and dissection, excess aortic Cu accumulation as assessed by X-ray fluorescence microscopy, and reduced lysyl oxidase activity. In contrast, AAA formation was not observed in Atox1-/-/ApoE-/- mice, suggesting that decreased lysyl oxidase activity, which depends on both ATP7A and Atox1, was not sufficient to develop AAA. Bone marrow transplantation suggested importance of ATP7A in vascular cells, not bone marrow cells, in AAA development. MicroRNA (miR) array identified miR-125b as a highly upregulated miR in AAA from ATP7Amut/+/ApoE-/- mice. Furthermore, miR-125b target genes (histone methyltransferase Suv39h1 and the NF-κB negative regulator TNFAIP3 [tumor necrosis factor alpha induced protein 3]) were downregulated, which resulted in increased proinflammatory cytokine expression, aortic macrophage recruitment, MMP (matrix metalloproteinase)-2/9 activity, elastin fragmentation, and vascular smooth muscle cell loss in ATP7Amut/+/ApoE-/- mice and reversed by locked nucleic acid-anti-miR-125b infusion. CONCLUSIONS: ATP7A downregulation/dysfunction promotes AAA formation via upregulating miR-125b, which augments proinflammatory signaling in a Cu-dependent manner. Thus, ATP7A is a potential therapeutic target for inflammatory vascular disease.

A single high-fat meal provokes pathological erythrocyte remodeling and increases myeloperoxidase levels: implications for acute coronary syndrome.

High-fat meal (HFM) consumption can produce acute lipemia and trigger myocardial infarction in patients with atherosclerosis, but the mechanisms are poorly understood. Erythrocytes (red blood cells, RBCs) intimately interact with inflammatory cells and blood vessels and play a complex role in regulating vascular function. Chronic high-fat feeding in mice induces pathological RBC remodeling, suggesting a novel link between HFM, RBCs, and vascular dysfunction. However, whether acute HFM can induce RBC remodeling in humans is unknown. Ten healthy individuals were subjected to biochemical testing and assessment of endothelial-dependent flow-mediated dilation (FMD) before and after a single HFM or iso-caloric meal (ICM). Following the HFM, triglyceride, cholesterol, and free fatty acid levels were all significantly increased, in conjunction with impaired post-prandial FMD. Additionally, peripheral blood smears demonstrated microcytes, remodeled RBCs, and fatty monocytes. Increased intracellular ROS and nitration of protein band 3 was detected in RBCs following the HFM. The HFM elevated plasma and RBC-bound myeloperoxidase (MPO), which was associated with impaired FMD and oxidation of HDL. Monocytic cells exposed to lipid in vitro released MPO, while porcine coronary arteries exposed to fatty acids ex vivo took up MPO. We demonstrate in humans that a single HFM induces pathological RBC remodeling and concurrently elevates MPO, which can potentially enter the blood vessel wall to trigger oxidative stress and destabilize vulnerable plaques. These novel findings may have implications for the short-term risk of HFM consumption and alimentary lipemia in patients with atherosclerosis.

Atherosclerotic Component of the Yellow Segment After Drug-Eluting Stent Implantation on Coronary Angioscopy　- An Ex-Vivo Validation Study.

BACKGROUND: Coronary angioscopy (CAS) is used to comprehensively evaluate vascular responses after drug-eluting stent (DES) implantation. This study sought to evaluate the capability of CAS for evaluating DES strut coverage grade and color grade of the intima compared with histological images in coronary autopsy specimens. Methods and Results: A total of 23 DES extracted from 11 autopsy hearts were imaged by CAS. All stent segments were graded as white or yellow according to the luminal surface color, and thrombus was evaluated according to a previous report. Neointimal coverage over the DES was graded as 0 (stent struts fully visible) to grade 3 (stent struts fully embedded and invisible). Of 76 segments, neointimal coverage was graded as 0 in 35 (46%), 1 in 22 (29%), 2 in 8 (11%), and 3 in 11 (14%). The neointimal thickness increased significantly with increasing neointimal coverage grade on angioscopy. Neointimal color was graded as white in 40 (53%) and yellow in 36 segments (47%). Histological analysis revealed that yellow neointima contained fibroatheroma, foam cells accumulation or superficial calcium deposition. A thrombus was identified in 13 segments. Thrombi adherent around the stent strut were partly intimal erythrocyte accumulation around the strut. CONCLUSIONS: In-stent yellow segment had atherosclerotic components. CAS could evaluate vascular status comprehensively after DES implantation.

Remote Effects of Transplanted Perivascular Adipose Tissue on Endothelial Function and Atherosclerosis.

PURPOSE: Perivascular adipose tissue (PVAT) surrounds the arterial adventitia and plays an important role in vascular homeostasis. PVAT expands in obesity, and inflamed PVAT can locally promote endothelial dysfunction and atherosclerosis. Here, using adipose tissue transplantation, we tested the hypothesis that expansion of PVAT can also remotely exacerbate vascular disease. METHODS: Fifty milligrams of abdominal aortic PVAT was isolated from high-fat diet (HFD)-fed wild-type mice and transplanted onto the abdominal aorta of lean LDL receptor knockout mice. Subcutaneous and visceral adipose tissues were used as controls. After HFD feeding for 10 weeks, body weight, glucose/insulin sensitivity, and lipid levels were measured. Adipocytokine gene expression was assessed in the transplanted adipose tissues, and the thoracic aorta was harvested to quantify atherosclerotic lesions by Oil-Red O staining and to assess vasorelaxation by wire myography. RESULTS: PVAT transplantation did not influence body weight, fat composition, lipid levels, or glucose/insulin sensitivity. However, as compared with controls, transplantation of PVAT onto the abdominal aorta increased thoracic aortic atherosclerosis. Furthermore, PVAT transplantation onto the abdominal aorta inhibited endothelium-dependent relaxation in the thoracic aorta. MCP-1 and TNF-α expression was elevated, while adiponectin expression was reduced, in the transplanted PVAT tissue, suggesting augmented inflammation as a potential mechanism for the remote vascular effects of transplanted PVAT. CONCLUSIONS: These data suggest that PVAT expansion and inflammation in obesity can remotely induce endothelial dysfunction and augment atherosclerosis. Identifying the underlying mechanisms may lead to novel approaches for risk assessment and treatment of obesity-related vascular disease.

Impact of analysis interval size on the quality of optical frequency domain imaging assessments of stent implantation for lesions of the superficial femoral artery.

OBJECTIVES: This study aimed to investigate the influence of analysis interval size on optical frequency domain imaging (OFDI) assessment of stent therapy for lesions of the superficial femoral artery (SFA). BACKGROUND: No consensus or validating data are available with respect to the methodology of intravascular imaging analysis for the peripheral arteries. METHODS: OFDI was performed for 30 SFA lesions, during endovascular therapy and at the 6-month follow-up. Initially, lumen and stent borders were traced at 1-mm axial intervals. Volumes were calculated using a PC-based software, and the volume index (VI) was defined as the volume divided by the stent length. Two additional OFDI analyses were performed using 2-mm and 5-mm intervals, thereby reducing the number of cross-sectional image frames analyzed. RESULTS: The mean stent length was 89.7 ± 35.2 mm. The mean difference in baseline minimum lumen area (MLA) was 0.4 mm2 between MLA values from the 1-mm and 2-mm interval analyses, and 2.2 mm2 between MLA values from the 1-mm and 5-mm interval analyses. In volumetric analysis, there were excellent correlations and good agreements for stent, lumen, and neointimal VI measurements obtained on the basis of different analysis intervals. CONCLUSIONS: Using large intervals in OFDI analyses of SFA lesions resulted in few differences in measurement variability of volumetric parameters. However, planar analysis for MLA assessment can be susceptible to high variability when large intervals are applied. © 2016 Wiley Periodicals, Inc.

The distribution of calcified nodule and plaque rupture in patients with peripheral artery disease: an intravascular ultrasound analysis.

In addition to plaque rupture (PR), calcified nodule (CN) may also have the potential to develop into arterial thrombus in the peripheral arteries. This study evaluated the distribution of plaque ruptures and calcified nodules in the peripheral arteries and their impact on the outcome of endovascular therapy (EVT). Consecutive 159 patients who underwent EVT with intravascular ultrasound guidance were enrolled. The position of CNs and PRs were assigned to any of common iliac artery, external iliac artery, common femoral artery, and superficial femoral artery. Forty-six (29%) patients had calcified nodule and twenty-eight (18%) patients had plaque rupture somewhere in the lower limb arteries. Although calcified nodules were evenly distributed throughout the length of the arteries plaque ruptures were predominantly located in the proximal segment of the iliofemoral arteries. Stent expansion ratio was significantly smaller in the target arteries with calcified nodules than in those with plaque rupture. Multivariate logistic regression analysis identified hemodialysis as an independent clinical predictor of calcified nodule (odds ratio 8.15, 95% confidence interval 1.73-38.3; P = 0.008). CN definitely affects incomplete stent deployment in the peripheral artery contributing to adverse events, on the other hand, PR has more acceptable outcomes after stent implantation. In the clinical setting, it is important that we realize the features of peripheral artery disease and its patient characteristics which having CNs and PRs to make a strategy for revascularization.

Impact of thermodilution-derived coronary blood flow patterns after percutaneous coronary intervention on mid-term left ventricular remodeling in patients with ST elevation myocardial infarction.

We recently reported the coronary thermodilution curve can be evaluated by analyzing the thermodilution curve obtained from a pressure sensor/thermistor-tipped guidewire, and presence of a bimodal-shaped thermodilution curve following primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction (STEMI) patients was associated with worse outcomes. This study evaluated whether the bimodal-shaped thermodilution curve predicts left ventricular (LV) remodeling after STEMI. The coronary thermodilution curve patterns were evaluated for 75 patients treated by pPCI for their first STEMI using a pressure sensor/thermistor-tipped guidewire, and classified into the three groups according to the thermodilution curve shape: narrow unimodal (n = 39), wide unimodal (n = 26), and bimodal pattern (n = 10). Echocardiography was performed at baseline and 6 months after STEMI. LV remodeling was defined as a >20 % increase in LV end-diastolic volumes (LVEDV). LVEDV at 6-month follow-up was greater in the bimodal group than in the other groups (p < 0.001). The prevalence of LV remodeling was highest in the bimodal group than in the narrow and wide unimodal groups (60, 12, and 15 %, respectively; p = 0.003). Multivariate analysis revealed a bimodal-shaped thermodilution curve as an independent predictor of the prevalence of LV remodeling. A bimodal-shaped thermodilution curve is associated with LV remodeling after STEMI. This easily assessable coronary thermodilution curve pattern is useful to predict mid-term LV remodeling for STEMI patients at the catheterization laboratory.

Intravascular Ultrasound-Derived Stent Dimensions as Predictors of Angiographic Restenosis Following Nitinol Stent Implantation in the Superficial Femoral Artery.

PURPOSE: To identify intravascular ultrasound (IVUS) measurements that can predict angiographic in-stent restenosis (ISR) following nitinol stent implantation in superficial femoral artery (SFA) lesions. METHODS: A retrospective review was conducted of 97 patients (mean age 72.9±8.9 years; 63 men) who underwent IVUS examination during endovascular treatment of 112 de novo SFA lesions between July 2012 and December 2014. Self-expanding bare stents were implanted in 46 lesions and paclitaxel-eluting stents in 39 lesions. Six months after stenting, follow-up angiography was conducted to assess stent patency. The primary endpoint was angiographic ISR determined by quantitative vascular angiography analysis at the 6-month follow-up. Variables associated with restenosis were sought in multivariate analysis; the results are presented as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: At follow-up, 27 (31.8%) angiographic ISR lesions were recorded. The lesions treated with uncoated stents were more prevalent in the ISR group compared with the no restenosis group (74.1% vs 44.8%, p=0.02). Lesion length was longer (154.4±79.5 vs 109.0±89.3 mm, p=0.03) and postprocedure minimum stent area (MSA) measured by IVUS was smaller (13.9±2.8 vs 16.3±1.6 mm(2), p<0.001) in the ISR group. Multivariate analysis revealed that bare stent use (OR 7.11, 95% CI 1.70 to 29.80, p<0.01) and longer lesion length (OR 1.08, 95% CI 1.01 to 1.16, p=0.04) were predictors of ISR, while increasing postprocedure MSA (OR 0.58, 95% CI 0.41 to 0.82, p<0.01) was associated with lower risk of ISR. Receiver operating characteristic analysis identified a MSA of 15.5 mm(2) as the optimal cutpoint below which the incidence of restenosis increased (area under the curve 0.769). CONCLUSION: Postprocedure MSA can predict ISR in SFA lesions, which suggests that adequate stent enlargement during angioplasty might be required for superior patency.

Impact of intravascular ultrasound findings on long-term patency after self-expanding nitinol stent implantation in the iliac artery lesion.

Although intravascular ultrasound (IVUS) predictors of stent patency for the coronary artery lesion have been established, little is known about IVUS predictors of stent patency for the aorto-iliac artery lesion. We analyzed 154 lesions of 122 patients who underwent stent implantation for iliac artery lesions. Quantitative and qualitative IVUS analyses were performed for pre- and post-procedural IVUS imaging in all lesions. Target lesion revascularization (TLR) was defined as clinically driven revascularization with >50 % angiographic stenosis of the target lesion. The mean follow-up period was 39 ± 16 months. TLRs were performed in 13 lesions (8.4 %). Post-procedural minimum stent area (MSA) was significantly smaller in the TLR group compared to the no-TLR group (16.0 ± 5.8 vs. 25.6 ± 8.5 mm(2), p < 0.001). Stent edge dissection was frequently observed in the TLR group compared to the no-TLR group (53.8 vs. 24.1 %, p = 0.04). Multivariate analysis revealed that post-procedural MSA (OR = 0.76, p < 0.01) and stent edge dissection (OR = 10.4, p < 0.01) were independent IVUS predictors of TLR. Receiver-operating characteristic analysis identified post-procedural MSA <17.8 mm(2) as the optimal cut-point for the prediction of TLR (AUC = 0.846). Post-procedural MSA and stent edge dissection could predict long-term stent patency in the iliac artery lesion. Our results propose that adequate stent enlargement without edge dissection might be important to reduce TLR in the iliac artery lesion.

Impact of spotty calcification on long-term prediction of future revascularization: a prospective three-vessel intravascular ultrasound study.

To date, there are no prospective studies on the relationship between plaque characteristics identified by 40 MHz IVUS and future adverse events. This prospective study evaluated the relationship between plaque morphology in nonculprit nonsignificant lesions, determined by 40 MHz IVUS, and long-term clinical outcomes. Consecutively, 45 patients who underwent 3-vessel intravascular ultrasound (IVUS) examinations were prospectively enrolled. Qualitative and quantitative IVUS analyses including scoring of echogenicity for assessment of plaque characterization were performed for each nonsignificant nonculprit lesion. The number, the length, the location (superficial or deep), and maximum arc were measured for each calcium deposit within plaques. Spotty calcification was defined as calcium deposits <90° and <6 mm in length. Primary end point was defined as nonsignificant nonculprit lesion-related revascularization (NNLR) during 6 years of follow-up. A total of 163 nonsignificant nonculprit lesions with mild to moderate stenosis were identified on baseline 3-vessel IVUS. Of those 163 lesions, six lesions required NNLR during the follow-up period. There were no differences in quantitative IVUS parameters including remodeling index, plaque burden, and echogenicity between lesions requiring and not requiring NNLR. However, deep spotty calcification was more frequently identified in lesions requiring NNLR than in those not requiring NNLR (33 vs. 8 %, P = 0.02). Spotty calcium deposits identified by 40 MHz IVUS predicted the need for NNLR during a 6-year follow-up period. This finding suggests that deep spotty calcium may be a surrogate marker for plaque progression and the subsequent need for revascularization in the future.

Acute Embolic Cerebral Infarction and Coronary Artery Embolism in a Patient with Atrial Fibrillation Caused by Similar Thrombi.

Although atrial fibrillation (AF) is one of the most frequent causes of ischemic stroke, coronary artery embolism (CE) from AF is rare, and 2.9% of all myocardial infarctions are caused by CE. We present a case of an 87-year-old female patient who suffered ischemic stroke and myocardial infarction at the same time and received intracranial and coronary thrombectomy. Pathological investigation revealed that thrombi were similar and both infarctions were considered as cardioembolism.

Tissue Characterization of In-Stent Neointima Using Optical Coherence Tomography in the Late Phase After Bare-Metal Stent Implantation--An Ex Vivo Validation Study.

BACKGROUND: We performed an ex vivo study to investigate optical coherence tomography (OCT) imaging for differentiating several types of neointimal tissue during the later phases after bare-metal stent (BMS) implantation as compared with histologic results. METHODS AND RESULTS: OCT imaging was performed in 6 autopsy hearts for 10 BMS with implant duration >4 years. OCT qualitative neointimal tissue characterization was based on tissue structure and classified as homogeneous pattern, heterogeneous pattern with visible struts, or heterogeneous pattern with invisible struts. Corresponding histological analyses of each 2-mm cross-section of the entire BMS were performed. Of 81 cross-sections, histological analysis revealed that the homogeneous pattern of neointima on OCT (n=39) contained smooth muscle cells with collagen, indicating high neointimal maturity. The heterogeneous patterns with visible struts (n=35) contained different tissues, including a proteoglycan-rich myxomatous matrix or dense calcified plate deposition. The heterogeneous patterns with invisible struts (n=7) included neointimal lipid/necrotic core formation, accumulation of foam cells, or microcalcification scattering. Of the 66 cross-sections containing large microvessels within the neointima on histology, only 6 (9%) were visualized by OCT. CONCLUSIONS: The present study confirmed the potential use of OCT in differentiating several types of neointima after BMS implantation. The image interpretation of OCT, based on visualization of stent struts, enables identification of several types of neointimal tissues, including in-stent fibroatheroma formation, more accurately.

Effect of bare-metal nitinol stent implantation and paclitaxel-eluting nitinol stent implantation on vascular response in the superficial femoral artery lesion assessed on intravascular ultrasound.

BACKGROUND: Although previous intravascular ultrasound (IVUS) studies reported that the drug-eluting stent (DES) has successfully decreased in-stent restenosis (ISR) by inhibiting neointimal hyperplasia (NIH) in the coronary artery lesion, no IVUS data for vascular response after DES implantation in the superficial femoral artery (SFA) have been published. METHODS AND RESULTS: We retrospectively analyzed 38 de novo SFA lesions from 32 patients who underwent endovascular therapy (EVT) with self-expanding bare-metal nitinol stent (25 lesions; BMS group) or self-expanding paclitaxel-eluting nitinol stents (13 lesions; PES group). At 6 months after EVT, follow-up IVUS was done to evaluate NIH. Serial IVUS volumetric analysis was done after stent deployment and at follow-up. Mean stent, lumen and neointimal areas were calculated as the volume divided by the stent length. The primary endpoint of this study was mean late lumen loss at 6-month follow-up. The mean follow-up period was 189±39 days. Mean neointimal area was smaller in the PES group compared to the BMS group (3.3±1.0mm(2) vs. 10.2±4.1mm(2), P<0.001). Mean late lumen loss was significantly lower in the PES group compared to the BMS group (-2.3±3.7mm(2) vs. 2.1±4.7mm(2), P<0.05). CONCLUSIONS: EVT with DES in SFA lesions might decrease NIH associated with ISR in short-term follow-up.

Hepatocyte-specific disruption of soluble epoxide hydrolase attenuates abdominal aortic aneurysm formation: novel role of the liver in aneurysm pathogenesis.

Introduction: Inflammation is a key pathogenic feature of abdominal aortic aneurysm (AAA). Soluble epoxide hydrolase (sEH) is a pro-inflammatory enzyme that converts cytochrome P450-derived epoxides of fatty acids to the corresponding diols, and pharmacological inhibition of sEH prevented AAA formation. Both cytochrome P450 enzymes and sEH are highly expressed in the liver. Here, we investigated the role of hepatic sEH in AAA using a selective pharmacological inhibitor of sEH and hepatocyte-specific Ephx2 (which encodes sEH gene) knockout (KO) mice in two models of AAA [angiotensin II (AngII) infusion and calcium chloride (CaCl 2 ) application]. Methods and results: sEH expression and activity were strikingly higher in mouse liver compared with aorta and further increased the context of AAA, in conjunction with elevated expression of the transcription factor Sp1 and the epigenetic regulator Jarid1b, which have been reported to positively regulate sEH expression. Pharmacological sEH inhibition, or liver-specific sEH disruption, achieved by crossing sEH floxed mice with albumin-cre mice, prevented AAA formation in both models, concomitant with reduced expression of hepatic sEH as well as complement factor 3 (C3) and serum amyloid A (SAA), liver-derived factors linked to AAA formation. Moreover, sEH antagonism markedly reduced C3 and SAA protein accumulation in the aortic wall. Co-incubation of liver ex vivo with aneurysm-prone aorta resulted in induction of sEH in the liver, concomitant with upregulation of Sp1, Jarid1b, C3 and SAA gene expression, suggesting that the aneurysm-prone aorta secretes factors that activate sEH and downstream inflammatory signaling in the liver. Using an unbiased proteomic approach, we identified a number of dysregulated proteins [ e.g., plastin-2, galectin-3 (gal-3), cathepsin S] released by aneurysm-prone aorta as potential candidate mediators of hepatic sEH induction. Conclusion: We provide the first direct evidence of the liver's role in orchestrating AAA via the enzyme sEH. These findings not only provide novel insight into AAA pathogenesis, but they have potentially important implications with regard to developing effective medical therapies for AAA.

Clinical utility of reticulocyte hemoglobin equivalent in patients with heart failure.

Anemia and iron deficiency (ID) are common in patients with heart failure (HF) and intravenous (IV) administration of iron to patients hospitalized for decompensated HF with ID improves outcome. The diagnosis of ID in routine practice is based on serum ferritin and transferrin saturation (TSAT) but both have limitations; alternatives should be considered. Reticulocyte hemoglobin equivalent (Ret-He) reflects iron content in reticulocytes but its clinical utility in patients with HF remains uncertain. We prospectively enrolled 142 patients hospitalized for decompensated HF. Sixty five percent had ID as defined in current international guidelines. Ret-He was directly correlated with serum iron and ferritin concentrations and with TSAT. There was a poor relationship between quartile of Ret-He and HF hospitalization or death but increases or decreases in Ret-He between admission and discharge were associated with a worse outcome. The clinical utility of Ret-He for identifying ID and predicting response to IV iron and prognosis for patients with HF requires further investigation.

Comparison of preventive effect on cardiovascular events with different statins. -The CIRCLE study-.

BACKGROUND: Although statins vary in their effectiveness in lowering low-density lipoprotein cholesterol (LDL-C) and increasing high-density lipoprotein cholesterol (HDL-C) levels, there is little evidence that the degree of these changes can explain cardiac risk reduction in Japan. Our objective was to compare the efficacy of statins on serum lipid levels and to explore the association between those changes and cardiac events in patients after percutaneous coronary intervention (PCI). METHODS AND RESULTS: The 743 consecutive patients who underwent PCI from 2001 to 2008 were retrospectively investigated. Treatment with either atorvastatin or pitavastatin significantly reduced LDL-C compared with pravastatin or no statin. In contrast, only pitavastatin treatment significantly increased HDL-C (13.4 ± 22.9%, P=0.01 vs. no statin). Each statin significantly prevented major adverse cardiac events (MACE) compared with no statin, and pitavastatin was the most effective of all. Multivariate-adjusted analysis revealed that percent changes of both LDL-C and HDL-C independently predicted the incidence of MACE (hazard ratio [HR]: 1.015; 95% confidence interval [CI]: 1.010-1.020, HR: 0.988; 95%CI: 0.981-0.996, respectively). This relationship was preserved in patients with a baseline HDL-C level ≤ 45 mg/dl, but not HDL-C level > 45 mg/ml. CONCLUSIONS: The extent of changes in LDL-C and HDL-C with statin treatment would independently alter the risk of cardiac events in Japanese patients for secondary prevention. Statins with varying lipid-modifying ability might provide differing prognosis in patients after PCI.

Anemia has an impact on prognosis in heart failure with preserved ejection fraction with mild chronic kidney disease.

BACKGROUND: Anemia and chronic kidney disease (CKD) are common in patients with heart failure with preserved left ventricular fraction (HFpEF). However, it is entirely unknown about the impact of anemia on prognosis in HFpEF patients with CKD. In this study, we investigated the impact of anemia on prognosis and the optimal hemoglobin (Hb) levels to predict prognosis in HFpEF patients with CKD. METHODS AND RESULTS: We prospectively examined 523 consecutive HFpEF patients enrolled in Japanese heart failure syndrome with preserved ejection fraction registry. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL /min/1.73 m2. The prevalence rate of anemia was 78% in HFpEF patients with CKD by using the World Health Organization criteria. Kaplan-Meier analysis for all-cause mortality and heart failure rehospitalization demonstrated that anemic patients had poor prognosis compared with non-anemic patients in HFpEF patients with CKD, but not those without CKD. According to the degree of CKD, anemia affected prognosis in HFpEF patients with mild CKD (45 ≤ eGFR < 60), but not those with moderate to severe CKD (15 ≤ eGFR < 45). Additionally, multivariate analysis revealed that anemia and Hb levels were independent predictors of composite outcomes in HFpEF patients with mild CKD, but not those with moderate to severe CKD. Finally, survival classification and regression tree analysis showed that the optimal Hb levels to predict composite outcomes were 10.7 g/dL in those with mild CKD. CONCLUSIONS: Anemia has an impact on prognosis in HFpEF patients, especially among those with mild CKD.

Mechanisms of gradual pressure drop in angiographically normal left anterior descending and right coronary artery: Insights from wave intensity analysis.

BACKGROUND: This study evaluated the mechanism of decline in coronary pressure from the proximal to the distal part of the coronary arteries in the left anterior descending (LAD) versus the right coronary artery (RCA) from the insight of coronary hemodynamics using wave intensity analysis (WIA). METHODS: Twelve patients with angiographically normal LAD and RCA were prospectively enrolled. Distal coronary pressure, mean aortic pressure, and average peak velocity were measured at 4 different positions: 9, 6, 3, and 0 cm distal from each coronary ostium. RESULTS: The distal-to-proximal coronary pressure ratio during maximum hyperemia gradually decreased in proportion to the distance from the ostium (0.92±0.03 and 0.98±0.03 at 9 cm distal to the LAD and RCA ostium). WIA showed the dominant forward-traveling compression wave gradually decreased and the backward-traveling suction wave gradually decreased in proportion to the decrease in coronary pressure through the length of the non-diseased LAD but not the RCA. CONCLUSIONS: The pushing wave and suction wave intensities on WIA were diminished in proportion to the distance from the ostium of the LAD despite the wave intensity not changing across the length of the RCA, which may lead to gradual intracoronary pressure drop in the angiographically normal LAD.