Description: Background— Chronic kidney disease (CKD) promotes the development of atherosclerosis and increases the risk of cardiovascular disease. The aim of the present study was to compare the coronary plaque characteristics of patients with and without CKD using optical coherence tomography. Methods and Results— We identified 463 nonculprit plaques from 287 patients from the Massachusetts General Hospital (MGH) optical coherence tomography registry. CKD was defined as estimated glomerular filtration rate 〈60 mL/min per 1.73 m 2 . A total of 402 plaques (250 patients) were in the non-CKD group and 61 plaques (37 patients) were in the CKD group. Compared with non-CKD plaques, plaques with CKD had a larger lipid index (mean lipid arc x lipid length, 1248.4±782.8 mm° [non-CKD] versus 1716.1±1116.2 mm° [CKD]; P =0.003). Fibrous cap thickness was not significantly different between the groups. Calcification (34.8% [non-CKD] versus 50.8% [CKD]; P =0.041), cholesterol crystals (11.2% [non-CKD] versus 23.0% [CKD]; P =0.048), and plaque disruption (5.5% [non-CKD] versus 13.1% [CKD]; P =0.049) were more frequently observed in the CKD group. In the multivariate linear regression model, a lower estimated glomerular filtration rate and diabetes mellitus were independent risk factors for a larger lipid index. Conclusions— Compared with non-CKD patients, the patients with CKD had a larger lipid index with a higher prevalence of calcium, cholesterol crystals, and plaque disruption. The multivariate linear regression model demonstrated that a lower estimated glomerular filtration rate was an independent risk factor for a larger lipid index. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01110538.

Description: Although the role of IL-7 and IL-7R has been implicated in the pathogenesis of rheumatoid arthritis (RA), the majority of the studies have focused on the effect of IL-7/IL-7R in T cell development and function. Our novel data, however, document that patients with RA and greater disease activity have higher levels of IL-7, IL-7R, and TNF-α in RA monocytes, suggesting a feedback regulation between IL-7/IL-7R and TNF-α cascades in myeloid cells that is linked to chronic disease progression. Investigations into the involved mechanism showed that IL-7 is a novel and potent chemoattractant that attracts IL-7R + monocytes through activation of the PI3K/AKT1 and ERK pathways at similar concentrations of IL-7 detected in RA synovial fluid. To determine whether ligation of IL-7 to IL-7R is a potential target for RA treatment and to identify their mechanism of action, collagen-induced arthritis (CIA) was therapeutically treated with anti–IL-7 Ab or IgG control. Anti–IL-7 Ab treatment significantly reduces CIA monocyte recruitment and osteoclast differentiation as well as potent joint monocyte chemoattractants and bone erosion markers, suggesting that both direct and indirect pathways might contribute to the observed effect. We also demonstrate that reduction in joint MIP-2 levels is responsible for suppressed vascularization detected in mice treated with anti–IL-7 Ab compared with the control group. To our knowledge, we show for the first time that expression of IL-7/IL-7R in myeloid cells is strongly correlated with RA disease activity and that ligation of IL-7 to IL-7R contributes to monocyte homing, differentiation of osteoclasts, and vascularization in the CIA effector phase.

Description: A deficiency in bone morphogenetic protein receptor type 2 (BMPR2) signaling is a central contributor in the pathogenesis of pulmonary arterial hypertension (PAH). We have recently shown that endothelial-specific Bmpr2 deletion by a novel L1Cre line resulted in pulmonary hypertension. SMAD1 is one of the canonical signal transducers of the BMPR2 pathway, and its reduced activity has been shown to be associated with PAH. To determine whether SMAD1 is an important downstream mediator of BMPR2 signaling in the pathogenesis of PAH, we analyzed pulmonary hypertension phenotypes in Smad1 -conditional knockout mice by deleting the Smad1 gene either in endothelial cells or in smooth muscle cells using L1Cre or Tagln -Cre mouse lines, respectively. A significant number of the L1Cre(+); Smad1 (14/35) and Tagln -Cre(+); Smad1 (4/33) mutant mice showed elevated pulmonary pressure, right ventricular hypertrophy, and a thickening of pulmonary arterioles. A pulmonary endothelial cell line in which the Bmpr2 gene deletion can be induced by 4-hydroxy tamoxifen was established. SMAD1 phosphorylation in Bmpr2 -deficient cells was markedly reduced by BMP4 but unaffected by BMP7. The sensitivity of SMAD2 phosphorylation by transforming growth factor-β1 was enhanced in the Bmpr2 -deficient cells, and the inhibitory effect of transforming growth factor-β1–mediated SMAD2 phosphorylation by BMP4 was impaired in the Bmpr2 -deficient cells. Furthermore, transcript levels of several known transforming growth factor-β downstream genes implicated in pulmonary hypertension were elevated in the Bmpr2 -deficient cells. Taken together, these data suggest that SMAD1 is a critical mediator of BMPR2 signaling pertinent to PAH, and that an impaired balance between BMP4 and transforming growth factor-β1 may account for the pathogenesis of PAH.

Description: Background and Purpose— Diffusion-weighted image fluid-attenuated inversion recovery (FLAIR) mismatch has been considered to represent ischemic lesion age. However, the inter-rater agreement of diffusion-weighted image FLAIR mismatch is low. We hypothesized that color-coded images would increase its inter-rater agreement. Methods— Patients with ischemic stroke 〈24 hours of a clear onset were retrospectively studied. FLAIR signal change was rated as negative, subtle, or obvious on conventional and color-coded FLAIR images based on visual inspection. Inter-rater agreement was evaluated using and percent agreement. The predictive value of diffusion-weighted image FLAIR mismatch for identification of patients 〈4.5 hours of symptom onset was evaluated. Results— One hundred and thirteen patients were enrolled. The inter-rater agreement of FLAIR signal change improved from 69.9% ( k =0.538) with conventional images to 85.8% ( k =0.754) with color-coded images ( P =0.004). Discrepantly rated patients on conventional, but not on color-coded images, had a higher prevalence of cardioembolic stroke ( P =0.02) and cortical infarction ( P =0.04). The positive predictive value for patients 〈4.5 hours of onset was 85.3% and 71.9% with conventional and 95.7% and 82.1% with color-coded images, by each rater. Conclusions— Color-coded FLAIR images increased the inter-rater agreement of diffusion-weighted image FLAIR recovery mismatch and may ultimately help identify unknown-onset stroke patients appropriate for thrombolysis.

Description: Background and Purpose— Good collateral flow is an important predictor for favorable responses to recanalization therapy and successful outcomes after acute ischemic stroke. Magnetic resonance perfusion–weighted imaging (MRP) is widely used in patients with stroke. However, it is unclear whether the perfusion parameters and thresholds would predict collateral status. The present study evaluated the relationship between hypoperfusion severity and collateral status to develop a predictive model for good collaterals using MRP parameters. Methods— Patients who were eligible for recanalization therapy that underwent both serial diffusion-weighted imaging and serial MRP were enrolled into the study. A collateral flow map derived from MRP source data was generated through automatic postprocessing. Hypoperfusion severity, presented as proportions of every 2-s T max strata to the entire hypoperfusion volume ( T max≥2 s), was compared between patients with good and poor collaterals. Prediction models for good collaterals were developed with each T max strata proportion and cerebral blood volumes. Results— Among 66 patients, 53 showed good collaterals based on MRP-based collateral grading. Although no difference was noted in delays within 16 s, more severe T max delays ( T max 16–18 s , T max 18–22 s , T max 22–24 s , and T max 〉24 s ) were associated with poor collaterals. The probability equation model using T max strata proportion demonstrated high predictive power in a receiver operating characteristic analysis (area under the curve=0.9303; 95% confidence interval, 0.8682–0.9924). The probability score was negatively correlated with the volume of infarct growth ( P =0.030). Conclusions— Collateral status is associated with more severe T max delays than previously defined. The present T max severity–weighted model can determine good collaterals and subsequent infarct growth.

Description: LPSs are widely used to stimulate TLR4, but their effects on ion channels in immune cells are poorly known. In THP-1 cells and human blood monocytes treated with LPS, inwardly rectifying K + channel current (I Kir,LPS ) newly emerged at 1 h, peaked at 4 h (–119 ± 8.6 pA/pF), and decayed afterward (–32 ± 6.7 pA/pF at 24 h). Whereas both the Kir2.1 and Kir2.2 mRNAs and proteins were observed, single-channel conductance (38 pS) of I Kir,LPS and small interfering RNA–induced knockdown commonly indicated Kir2.2 than Kir2.1. LPS-induced cytokine release and store-operated Ca 2+ entry were commonly decreased by ML-133, a Kir2 inhibitor. Immunoblot, confocal microscopy, and the effects of vesicular trafficking inhibitors commonly suggested plasma membrane translocation of Kir2.2 by LPS. Both I Kir,LPS and membrane translocation of Kir2.2 were inhibited by GF109203X (protein kinase C [PKC] inhibitor) or by transfection with small interfering RNA–specific PKC. Interestingly, pharmacological activation of PKC by PMA induced both Kir2.1 and Kir2.2 currents. The spontaneously decayed I Kir,LPS at 24 h was recovered by PI3K inhibitors but further suppressed by an inhibitor of phosphatidylinositol(3,4,5)-trisphosphate (PIP 3 ) phosphatase (phosphatase and tensin homolog). However, I Kir,LPS at 24 h was not affected by Akt inhibitors, suggesting that the decreased phosphatidylinositol(4,5)-bisphosphate availability, that is, conversion into PIP 3 by PI3K, per se accounts for the decay of I Kir,LPS . Taken together, to our knowledge these data are the first demonstrations that I Kir is newly induced by TLR4 stimulation via PKC-dependent membrane trafficking of Kir2.2, and that conversion of phosphatidylinositol(4,5)-bisphosphate to PIP 3 modulates Kir2.2. The augmentation of Ca 2+ influx and cytokine release suggests a physiological role for Kir2.2 in TLR4-stimulated monocytes.

Description: Background— Optical coherence tomography (OCT) was recently introduced to optimize percutaneous coronary intervention. However, the exact incidence and significance of poststent OCT findings are unknown. Methods and Results— A total of 900 lesions treated with 1001 stents in 786 patients who had postprocedure OCT imaging were analyzed to evaluate the incidence of poststent OCT findings and to identify the OCT predictors for device-oriented clinical end points, including cardiac death, target vessel–related myocardial infarction, target lesion revascularization, and stent thrombosis. Patients were followed up to 1 year. Stent edge dissection was detected in 28.7% of lesions, and incomplete stent apposition was detected in 39.1% of lesions. The incidences of smooth protrusion, disrupted fibrous tissue protrusion, and irregular protrusion were 92.9%, 61.0%, and 53.8%, respectively. Small minimal stent area, defined as a lesion with minimal stent area 〈5.0 mm 2 in a drug-eluting stent or 〈5.6 mm 2 in a bare metal stent, was observed in 40.4% of lesions. One-year device-oriented clinical end points occurred in 33 patients (4.5%). Following adjustment, irregular protrusion and small minimal stent area were independent OCT predictors of 1-year device-oriented clinical end points ( P =0.003 and P =0.012, respectively). Conclusions— Abnormal poststent OCT findings were frequent. Irregular protrusion and small minimal stent area were independent predictors of 1-year device-oriented clinical end points, which were primarily driven by target lesion revascularization.

Description: Our aim was to examine the impact of TLR5 ligation in rheumatoid arthritis (RA) and experimental arthritis pathology. Studies were conducted to investigate the role of TLR5 ligation on RA and mouse myeloid cell chemotaxis or osteoclast formation, and in addition, to uncover the significance of TNF-α function in TLR5-mediated pathogenesis. Next, the in vivo mechanism of action was determined in collagen-induced arthritis (CIA) and local joint TLR5 ligation models. Last, to evaluate the importance of TLR5 function in RA, we used anti-TLR5 Ab therapy in CIA mice. We show that TLR5 agonist, flagellin, can promote monocyte infiltration and osteoclast maturation directly through myeloid TLR5 ligation and indirectly via TNF-α production from RA and mouse cells. These two identified TLR5 functions are potentiated by TNF-α, because inhibition of both pathways can more strongly impair RA synovial fluid–driven monocyte migration and osteoclast differentiation compared with each factor alone. In preclinical studies, flagellin postonset treatment in CIA and local TLR5 ligation in vivo provoke homing and osteoclastic development of myeloid cells, which are associated with the TNF-α cascade. Conversely, CIA joint inflammation and bone erosion are alleviated when TLR5 function is blocked. We found that TLR5 and TNF-α pathways are interconnected, because TNF-α is produced by TLR5 ligation in RA myeloid cells, and anti–TNF-α therapy can markedly suppress TLR5 expression in RA monocytes. Our novel findings demonstrate that a direct and an indirect mechanism are involved in TLR5-driven RA inflammation and bone destruction.

Description: Background From a therapeutic viewpoint, it is important to differentiate the underlying causes of embolism in patients with cryptogenic stroke, such as aortic arch atheroma, patent foramen ovale, and paroxysmal atrial fibrillation. We investigated the clinical and radiological characteristics of these 3 common causes of cryptogenic embolism to develop models for decision making in etiologic workups. Methods and Results A total of 321 consecutive patients with acute infarcts from cryptogenic embolism were included. Patients were divided into 3 groups—aortic arch atheroma (n=40), patent foramen ovale (n=153), and paroxysmal atrial fibrillation (n=128)—based on extensive cardiologic workups. We used a multinomial logistic regression analysis to detect the clinical and diffusion-weighted imaging factors associated with the probability of aortic arch atheroma, patent foramen ovale, and paroxysmal atrial fibrillation. Clinical and radiological features differed among the groups. The patent foramen ovale group had a healthy vascular risk factor profile and showed posterior circulation involvement compared with other groups ( P 〈0.01). In contrast, paroxysmal atrial fibrillation–related strokes had higher initial National Institutes of Health Stroke Scale (NIHSS) scores and larger lesions than the other groups ( P 〈0.001). The aortic arch atheroma group had clinical features similar to those of the paroxysmal atrial fibrillation group but showed small lesions scattered in multiple vascular territories ( P 〈0.001). Multivariate regression analysis revealed that age, initial NIHSS score, lesion size (≥20 mm), multiple (≥3) lesions, and involvement of posterior circulation or multiple vascular territories differentiated the 3 groups (pseudo, R 2 =0.656). The prediction ability of this model was validated in the external validation cohort (n=117, area under the curve 0.78). Conclusions Our data indicate that patients with cryptogenic embolic stroke show distinct clinical and radiological features depending on the underlying causes.

Description: Objective— Experimental evidence suggests that exenatide, a glucagon-like peptide 1 receptor analogue, has significant cardiovascular protective effects in various conditions. We examined whether routine use of exenatide at the time of primary percutaneous coronary intervention would reduce infarct size in patients with ST-segment–elevation myocardial infarction. Approach and Results— Fifty-eight patients with ST-segment–elevation myocardial infarction and thrombolysis in myocardial infarction flow 0 were enrolled in the study and randomly assigned to receive either exenatide or placebo (saline) subcutaneously. Infarct size was assessed by measuring the release of creatine kinase-MB and troponin I during 72 hours and by performing cardiac magnetic resonance imaging at 1 month after infarction. Routine and speckle tracking echocardiography was performed at initial presentation and at 3 days and 6 months after primary percutaneous coronary intervention. The exenatide and control groups had similar results with respect to ischemia time, demographic characteristics, and ejection fraction before primary percutaneous coronary intervention. The releases of creatine kinase-MB and troponin I were significantly reduced in the exenatide group. In 58 patients evaluated with cardiac magnetic resonance, the absolute mass of delayed hyperenhancement was significantly reduced in the exenatide group as compared with the control group (12.8±11.7 versus 26.4±11.6 g; P 〈0.01). At 6 months, the exenatide group showed a significantly lower value of E / E ' with improved strain parameters. No significant adverse effects of exenatide administration were detected. Conclusions— In patients with ST-segment–elevation myocardial infarction, adjunctive exenatide therapy with primary percutaneous coronary intervention was associated with reduction of infarct size and improvement of subclinical left ventricular function.