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: 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: 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: 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.

Description: Background— The pathophysiological basis for the association between metabolic syndrome (MetS) and coronary artery disease is not well understood. We sought to characterize coronary plaques in patients with MetS by using optical coherence tomography. Methods and Results— We identified 451 coronary plaques from 171 subjects who underwent optical coherence tomographic imaging in 3 coronary arteries. Subjects were divided into 3 groups: diabetes mellitus (DM, n=77), MetS (n=35), and a control group (C group, n=59) without DM or MetS. Optical coherence tomographic analysis included the presence of lipid-rich plaque, maximum lipid arc, lipid-core length, lipid index (LI), fibrous cap thickness, and thin-cap fibroatheroma. We defined LI as mean lipid arc multiplied by lipid-core length. Lipid-core length and LI were significantly greater in DM and MetS than in C group (lipid-core length: 7.7±4.0 and 7.0±3.8 versus 5.5±2.4 mm; P 〈0.001 and P =0.012, and LI: 1164±716 and 1086±693 versus 796±417 mm; P 〈0.001 and P =0.008). Maximum lipid arc was significantly greater in DM than in C group, whereas no significant difference was observed between MetS and C group (196±45°, 187±42° versus 176±52°; P =0.002 and P =0.182). Fibrous cap thickness and thin-cap fibroatheroma showed no significant difference among the 3 groups. In multivariate analysis, DM and MetS were independently associated with LI, whereas only acute coronary syndrome was the independent predictor for thin-cap fibroatheroma. Conclusions— Compared with control subjects, coronary plaques in MetS contain larger lipid. However, the MetS criteria used in this study could not distinguish the vulnerable features such as thin-cap fibroatheroma, suggesting the necessity of complementary information to identify patients at high risk for cardiovascular events.

Description: Objective— Allogeneic transplantation of human embryonic stem cell (hESC) derivatives has the potential to elicit the patient’s immune response and lead to graft rejection. Although hESCs and their derivatives have been shown to have advantageous immune properties in vitro, such observations could not be determined experimentally in vivo because of ethical and technical constraints. However, the generation of humanized mice (hu-mice) harboring a human immune system has provided a tool to perform in vivo immunologic studies of human cells and tissues. Using this model, we sought to examine the therapeutic potential of hESC-derived endothelial cells, human embryonic fibroblasts, and cord blood–derived endothelial progenitor cells in a human immune system environment. Approach and Results— All cell types transplanted in hu-mice showed significantly reduced cell survival during the first 14 days post-transplantation compared with that observed in immunodeficient mice. During this period, no observable therapeutic effects were detected in the hindlimb ischemic mouse models. After this point, the cells demonstrated improved survival and contributed to a long-term improvement in blood perfusion. All cell types showed reduced therapeutic efficacy in hu-mice compared with NOD scid IL2 receptor gamma chain knockout mice. Interestingly, the eventual improvement in blood flow caused by the hESC-derived endothelial cells in hu-mice was not much lower than that observed in NOD scid IL2 receptor gamma chain knockout mice. Conclusions— These findings suggest that hESC derivatives may be considered a good source for cell therapy and that hu-mice could be used as a preclinical in vivo animal model for the evaluation of therapeutic efficacy to predict the outcomes of human clinical trials.

Description: Background— Recent studies have reported development of neoatherosclerosis (NA) inside the stents several years after stent implantation. The aim of this study was to determine the predictors for NA using optical coherence tomography. Methods and Results— From a total of 1080 patients who underwent optical coherence tomography, we identified 179 stents in 151 patients in which the mean neointimal thickness was 〉100 µm. The presence of lipid-laden neointima or calcification inside the stents was defined as NA in the present study. Patient characteristics, stent type, and time since stent implantation (stent age) were compared between stents with or without NA. Univariable and multivariable logistic regression analyses were used to assess the independent predictors. In univariate analysis, stent age ≥48 months (Odds ratio [OR], 4.48; [95% CI 2.68-9.65]; P 〈0.001), drug-eluting stents (OR, 2.66; [95% CI, 1.38–5.16]; P =0.004), age ≥65 years (OR, 1.91; [95% CI, 1.05–3.44]; P =0.032), current smoking (OR, 2.30; [95% CI, 1.10–4.82]; P =0.024), chronic kidney disease (OR, 4.17; [95% CI, 1.42–12.23]; P =0.009), and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockade use (OR, 0.42; [95% CI, 0.22–0.80]; P =0.008) were significant predictors. In multivariate analysis, stent age ≥48 months, all subtypes of drug-eluting stent, current smoking, chronic kidney disease, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockade use remained independent predictors for NA. Conclusions— In addition to the stent type and the stent age, patient characteristics, including current smoking, chronic kidney disease, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockade, were associated with the presence of NA. This result may support the importance of secondary prevention after stent implantation.