Beschreibung: Background and Purpose— Mismatch in lesion visibility between diffusion-weighted image and fluid-attenuated inversion recovery image (DWI–FLAIR mismatch) has been proposed as a biomarker for the estimation of ischemic lesion age. The actual onset in some patients with unclear-onset stroke (UnCOS) may be close to the first-found abnormal time. We hypothesized that patients with UnCOS within a particular time window might have a similar DWI–FLAIR mismatch profile with patients with clear-onset stroke (COS). Methods— Patients who underwent MRI within 6 hours from first-found abnormal time were recruited retrospectively. Clinical characteristics and the proportion of DWI–FLAIR and perfusion-weighted image–DWI mismatch in each time window were compared between UnCOS and COS. Results— The final analysis included 259 patients (114 with UnCOS and 145 with COS). Patients with UnCOS were older and had more severe stroke at baseline. Risk factors, stroke subtypes, and perfusion-weighted image–DWI mismatch did not differ between the 2 groups. The proportion of patients with DWI–FLAIR mismatch in UnCOS did not differ from COS within 2 hours of first-found abnormal time (50.0% versus 51.5%; P =0.92), but it was significantly lower in UnCOS than in COS at 2 to 3 hours (16.1% versus 44.4%; P =0.02), 3 to 4 hours (13.8% versus 36.4%; P =0.04), and 4 to 5 hours (5.6% versus 29.6%; P =0.05). Conclusions— The proportion of DWI–FLAIR mismatch in UnCOS within the first 2 hours from first-found abnormal time was similar with COS, but it sharply decreased beyond 2 hours. These data suggest that patients with UnCOS within 2 hours of symptom detection may be good candidates for multimodal imaging-based thrombolysis.

Beschreibung: 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.

Beschreibung: Background and Purpose— Diagnosis of Moyamoya disease (MMD) is based on the characteristic angiographic findings. However, differentiating MMD from intracranial atherosclerotic disease (ICAD) is difficult. We compared vessel wall imaging findings on high-resolution magnetic resonance imaging between MMD and ICAD. Methods— High-resolution magnetic resonance imaging was performed on 32 patients with angiographically proven MMD and 16 patients with acute infarcts because of ICAD. Bilateral internal carotid arteries and steno-occlusive middle cerebral artery were analyzed for wall enhancement and remodeling. Results— Enhancement patterns and distribution were different. Most patients with MMD (90.6%) showed concentric enhancement on distal internal carotid arteries and middle cerebral arteries, whereas focal eccentric enhancement was observed on the symptomatic segment in ICAD. MMD was characterized by middle cerebral artery shrinkage; the remodeling index and wall area were lower in MMD than in ICAD (remodeling index, 0.19±0.11 versus 1.00±0.43; wall area, 0.32±0.22 versus 6.00±2.72; P 〈0.001). Conclusions— MMD was characterized by concentric enhancement on bilateral distal internal carotid arteries and shrinkage of middle cerebral artery, regardless of symptoms.

Beschreibung: 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.

Beschreibung: 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.

Beschreibung: Background— Patients with acute coronary syndrome (ACS) have a higher incidence of recurrent ischemic events. The aim of this study was to compare the plaque characteristics of nonculprit lesions between ACS and non-ACS patients using optical coherence tomography (OCT) imaging. Methods and Results— Patients who had 3-vessel OCT imaging were selected from the Massachusetts General Hospital (MGH) OCT Registry. MGH registry is a multicenter registry of patients undergoing OCT. The prevalence and characteristics of nonculprit plaques were compared between ACS and non-ACS patients. A total of 248 nonculprit plaques were found in 104 patients: 45 plaques in 17 ACS patients and 203 plaques in 87 non-ACS patients. Compared with plaques of non-ACS patients, plaques of ACS patients had a wider lipid arc (147.3 ± 29.5° versus 116.2 ± 33.7°, P 〈0.001), a longer lipid length (10.7 ± 5.9 mm versus 7.0 ± 3.7 mm, P =0.002), a larger lipid volume index [averaged lipid arc x lipid length] (1605.5 ± 1013.1 versus 853.4 ± 570.8, P 〈0.001), and a thinner fibrous cap (70.2 ± 20.2 µm versus 103.3 ± 46.8 µm, P 〈0.001). Moreover, thin-cap fibroatheroma (64.7% versus 14.9%, P 〈0.001), macrophage (82.4% versus 37.9%, P =0.001), and thrombus (29.4% versus 1.1%, P 〈0.001) were more frequent in ACS patients. Although the prevalence of microchannel did not differ between the groups, the closest distance from the lumen to microchannel was shorter in ACS subjects than in non-ACS (104.6 ± 67.0 µm versus 198.3 ± 133.0 µm, P =0.027). Conclusions— Nonculprit lesions in patients with ACS have more vulnerable plaque characteristics compared with those with non-ACS. Neovascularization was more frequently located close to the lumen in patients with ACS.

Beschreibung: 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.

Beschreibung: 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.

Beschreibung: 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.

Beschreibung: Background and Purpose— Recent randomized clinical trials (RCTs) have evaluated the benefit of new oral anticoagulants in reducing the risk of vascular events and bleeding complications in patients with atrial fibrillation (AF). However, abundant and strict enrollment criteria may limit the validity and applicability of results of RCTs to clinical practice. We estimated the eligibility for participation in RCTs of an unselected group of patients with AF. In addition, we compared features favoring new oral anticoagulant use between patients with versus without stroke. Randomized Evaluation of Long-Term Anticoagulation Therapy Methods— We applied enrollment criteria of 4 RCTs (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) to 695 patients with AF taking warfarin, prospectively and consecutively collected at a university medical center; 500 patients with and 195 patients without stroke. Time in therapeutic range and bleeding risk scheme (anticoagulation and risk factors in atrial fibrillation) were also measured. Results— The proportions of patients fulfilling the trial enrollment criteria varied, ranging from 39% to 72.8%, depending on the differences in indications/contraindications among studies and presence/absence of stroke. The main reasons for ineligibility for RCTs were hemorrhagic risk (anticoagulation and risk factors in atrial fibrillation [ATRIA] score) (10.8%–40.5%) and planned cardioversion (5.1%–7.7%) for nonstroke patients, and a low creatinine clearance (5.6%–9.2%) and higher risk of bleeding (15.2%–20.8%) for patients with stroke. When compared with nonstroke patients, patients with stroke showed a lower time in therapeutic range (54.4±42.8% versus 65.4±34.9%, especially with severe disability) and a high hemorrhagic risk (ATRIA score) (3.06±2.30 versus 2.18±2.16) ( P 〈0.05 in both cases). Conclusions— Patients enrolled in RCTs are partly representative of patients with AF in clinical practice. When time in therapeutic range and bleeding tendency with warfarin use were considered, the use of new oral anticoagulants was preferred in patients with stroke than in nonstroke patients, but they were more likely to be excluded in RCTs.