Description: Background and Purpose— We aimed to generate rigorous graphical and statistical reference data based on volumetric measurements for assessing the relative severity of white matter hyperintensities (WMHs) in patients with stroke. Methods— We prospectively mapped WMHs from 2699 patients with first-ever ischemic stroke (mean age=66.8±13.0 years) enrolled consecutively from 11 nationwide stroke centers, from patient (fluid-attenuated-inversion-recovery) MRIs onto a standard brain template set. Using multivariable analyses, we assessed the impact of major (age/hypertension) and minor risk factors on WMH variability. Results— We have produced a large reference data library showing the location and quantity of WMHs as topographical frequency-volume maps. This easy-to-use graphical reference data set allows the quantitative estimation of the severity of WMH as a percentile rank score. For all patients (median age=69 years), multivariable analysis showed that age, hypertension, atrial fibrillation, and left ventricular hypertrophy were independently associated with increasing WMH (0–9.4%, median=0.6%, of the measured brain volume). For younger (≤69) hypertensives (n=819), age and left ventricular hypertrophy were positively associated with WMH. For older (≥70) hypertensives (n=944), age and cholesterol had positive relationships with WMH, whereas diabetes mellitus, hyperlipidemia, and atrial fibrillation had negative relationships with WMH. For younger nonhypertensives (n=578), age and diabetes mellitus were positively related to WMH. For older nonhypertensives (n=328), only age was positively associated with WMH. Conclusions— We have generated a novel graphical WMH grading (Kim statistical WMH scoring) system, correlated to risk factors and adjusted for age/hypertension. Further studies are required to confirm whether the combined data set allows grading of WMH burden in individual patients and a tailored patient-specific interpretation in ischemic stroke-related clinical practice.

Description: Background and Purpose— An urgent need exists to develop therapies for stroke that have high efficacy, long therapeutic time windows, and acceptable toxicity. We undertook preclinical investigations of a novel therapeutic approach involving supplementation with carnosine, an endogenous pleiotropic dipeptide. Methods— Efficacy and safety of carnosine treatment was evaluated in rat models of permanent or transient middle cerebral artery occlusion. Mechanistic studies used primary neuronal/astrocytic cultures and ex vivo brain homogenates. Results— Intravenous treatment with carnosine exhibited robust cerebroprotection in a dose-dependent manner, with long clinically relevant therapeutic time windows of 6 hours and 9 hours in transient and permanent models, respectively. Histological outcomes and functional improvements including motor and sensory deficits were sustained on 14th day poststroke onset. In safety and tolerability assessments, carnosine did not exhibit any evidence of adverse effects or toxicity. Moreover, histological evaluation of organs, complete blood count, coagulation tests, and the serum chemistry did not reveal any abnormalities. In primary neuronal cell cultures and ex vivo brain homogenates, carnosine exhibited robust antiexcitotoxic, antioxidant, and mitochondria protecting activity. Conclusions— In both permanent and transient ischemic models, carnosine treatment exhibited significant cerebroprotection against histological and functional damage, with wide therapeutic and clinically relevant time windows. Carnosine was well tolerated and exhibited no toxicity. Mechanistic data show that it influences multiple deleterious processes. Taken together, our data suggest that this endogenous pleiotropic dipeptide is a strong candidate for further development as a stroke treatment.

Description: Background— The most frequent complications associated with implantable cardioverter-defibrillators (ICDs) involve the transvenous leads. A subcutaneous implantable cardioverter-defibrillator (S-ICD) has been developed as an alternative system. This study evaluated the safety and effectiveness of the S-ICD System (Cameron Health/Boston Scientific) for the treatment of life-threatening ventricular arrhythmias (ventricular tachycardia/ventricular fibrillation). Methods and Results— This prospective, nonrandomized, multicenter trial included adult patients with a standard indication for an ICD, who neither required pacing nor had documented pace-terminable ventricular tachycardia. The primary safety end point was the 180-day S-ICD System complication-free rate compared with a prespecified performance goal of 79%. The primary effectiveness end point was the induced ventricular fibrillation conversion rate compared with a prespecified performance goal of 88%, with success defined as 2 consecutive ventricular fibrillation conversions of 4 attempts. Detection and conversion of spontaneous episodes were also evaluated. Device implantation was attempted in 321 of 330 enrolled patients, and 314 patients underwent successful implantation. The cohort was followed for a mean duration of 11 months. The study population was 74% male with a mean age of 52±16 years and mean left ventricular ejection fraction of 36±16%. A previous transvenous ICD had been implanted in 13%. Both primary end points were met: The 180-day system complication-free rate was 99%, and sensitivity analysis of the acute ventricular fibrillation conversion rate was 〉90% in the entire cohort. There were 38 discrete spontaneous episodes of ventricular tachycardia/ventricular fibrillation recorded in 21 patients (6.7%), all of which successfully converted. Forty-one patients (13.1%) received an inappropriate shock. Conclusions— The findings support the efficacy and safety of the S-ICD System for the treatment of life-threatening ventricular arrhythmias. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01064076.

Description: Background— Recoarctation after the Norwood procedure increases risk for mortality. The Single Ventricle Reconstruction (SVR) trial randomized subjects with a single right ventricle undergoing a Norwood procedure to a modified Blalock-Taussig shunt or a right ventricle–pulmonary artery shunt. We sought to determine the incidence of recoarctation, risk factors, and outcomes in the SVR trial. Methods and Results— Recoarctation was defined by intervention, either catheter based or surgical. Univariate analysis and multivariable Cox proportional hazard models were performed with adjustment for center. Of the 549 SVR subjects, 97 (18%) underwent 131 interventions (92 balloon aortoplasty, 39 surgical) for recoarctation at a median age of 4.9 months (range, 1.1–10.5 months). Intervention typically occurred at pre–stage II catheterization (n=71, 54%) or at stage II surgery (n=38, 29%). In multivariable analysis, recoarctation was associated with the shunt type in place at the end of the Norwood procedure (hazard ratio, 2.0 for right ventricle–pulmonary artery shunt versus modified Blalock-Taussig shunt; P =0.02), and Norwood discharge peak echo-Doppler arch gradient (hazard ratio, 1.07 per 1 mm Hg; P 〈0.01). Subjects with recoarctation demonstrated comorbidities at pre–stage II evaluation, including higher pulmonary arterial pressures (15.4±3.0 versus 14.5±3.5 mm Hg; P =0.05), higher pulmonary vascular resistance (2.6±1.6 versus 2.0±1.0 Wood units·m 2 ; P =0.04), and increased echocardiographic volumes (end-diastolic volume, 126±39 versus 112±33 mL/BSA 1.3 , where BSA is body surface area; P =0.02). There was no difference in 12-month postrandomization transplantation-free survival between those with and without recoarctation ( P =0.14). Conclusions— Recoarctation is common after Norwood and contributes to pre–stage II comorbidities. Although with intervention there is no associated increase in 1-year transplantation/mortality, further evaluation is warranted to evaluate the effects of associated morbidities. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00115934.

Description: Background and Purpose— We investigated whether the brachial-ankle pulse wave velocity (baPWV) has prognostic value for predicting functional outcome after acute cerebral infarction and whether the prognostic value differs between stroke subtypes. Methods— We included 1091 consecutive patients with first-ever acute cerebral infarction who underwent baPWV measurements. Stroke subtypes were classified using the Trial of Org 10172 in Acute Stroke Treatment classification. Poor functional outcomes were defined as modified Rankin Scale score 〉2 at 3 months after stroke onset. Results— We noted that 181 (16.59%) patients had a poor functional outcome. In multivariate logistic regression, patients in the highest tertile of baPWV (〉22.25 m/s) were found to be at increased risk for poor functional outcome (adjusted odds ratio, 1.88; 95% confidence interval, 1.06–3.40) compared with those in the lowest tertile (〈17.55 m/s). No significant interaction between baPWV and stroke subtype was noted. Receiver operating characteristic curve analysis indicated that the addition of baPWV to the prediction model significantly improved the discrimination ability for poor functional outcome. Conclusions— baPWV has an independent prognostic value for predicting functional outcome after acute cerebral infarction. The prognostic value did not differ according to the stroke subtype.

Description: Background and Purpose— Occlusive radiation vasculopathy (ORV) predisposes head-and-neck cancer survivors to ischemic strokes. Methods— We analyzed the digital subtraction angiography acquired in 96 patients who had first-ever transient ischemic attack or ischemic strokes attributed to ORV. Another age-matched 115 patients who had no radiotherapy but symptomatic high-grade (〉70%) carotid stenoses were enrolled as referent subjects. Digital subtraction angiography was performed within 2 months from stroke onset and delineated carotid and vertebrobasilar circulations from aortic arch up to intracranial branches. Two reviewers blinded to group assignment recorded all vascular lesions, collateral status, and infarct pattern. Results— ORV patients had less atherosclerotic risk factors at presentation. In referent patients, high-grade stenoses were mostly focal at the proximal internal carotid artery. In contrast, high-grade ORV lesions diffusely involved the common carotid artery and internal carotid artery and were more frequently bilateral (54% versus 22%), tandem (23% versus 10%), associated with complete occlusion in one or both carotid arteries (30% versus 9%), vertebral artery (VA) steno-occlusions (28% versus 16%), and external carotid artery stenosis (19% versus 5%) (all P 〈0.05). With comparable rates of vascular anomaly, ORV patients showed more established collateral circulations through leptomeningeal arteries, anterior communicating artery, posterior communicating artery, suboccipital/costocervical artery, and retrograde flow in ophthalmic artery. In terms of infarct topography, the frequencies of cortical or subcortical watershed infarcts were similar in both groups. Conclusions— ORV angiographic features and corresponding collaterals are distinct from atherosclerotic patterns at initial stroke presentation. Clinical decompensation, despite more extensive collateralization, may precipitate stroke in ORV.

Description: Background and Purpose— Several stroke risk scores for prediction of functional outcome have been developed, but rarely validated in Asian populations. We assessed the validity of the iScore, recently developed from Canadian stroke population, in an Asian stroke population from Korea. Methods— We applied the iScore to 4061 eligible participants with acute ischemic stroke in the nationwide multicenter stroke registry in Korea. The main outcome was poor functional outcome defined as having a modified Rankin Scale 3 to 6 at 3 months after stroke onset. The secondary outcome was death at 3 months. C-statistics were calculated to assess performance of the iScore. Results— Poor functional outcome was found in 1496 patients (36.8%), whereas death at 3 months occurred in 294 patients (7.2%). C-statistics were 0.819 (95% confidence interval, 0.805–0.833) for poor functional outcome and 0.861 (95% confidence interval, 0.840–0.883) for death. Overall, there was a high correlation between observed and expected outcomes for poor functional outcome (Pearson correlation coefficient, r =0.990) and for death ( r =0.969) according to risk score. Conclusions— The iScore reliably predicts poor functional outcome or death at 3 months after stroke in Korean patients.

Description: Objective— Velocity-vector imaging (VVI) represents a valuable new method for noninvasive quantification of vascular properties associated with aging. The purpose of this study was to assess the correlations between VVI parameters and histological changes with aging. Approach and Results— Fourteen mongrel dogs were classified as either young (n=7; age, 1–2 years; female; weighing 22–29 kg) or senescent (n=7; age, 8–12 years; female; weighing 36–45 kg). The short-axis image of the descending thoracic aorta was obtained for VVI analysis with transesophageal echocardiography. The location of the image was identified using fluoroscopic guidance, and the aortic tissue was extracted. After dividing the aortic wall into 6 segments, both regional and segmental tissue collagen and elastin contents were quantified and correlated with the aortic elastic properties. In the regional analysis, the M-mode–derived aortic dimensions and elastic moduli except for intima-media thickness were not significantly different between the groups, whereas the VVI-derived aortic area and fractional area changes showed more dilated and stiffer aorta in senescent dogs. Also, fractional area change was significantly correlated with the tissue collagen content unlike the M-mode–derived elastic moduli. In the segmental analysis, the radial velocity, circumferential strain, and strain rates of VVI were more reduced in senescent dogs than young dogs, and the radial velocity and circumferential strain showed independent associations with the collagen content of the corresponding aortic wall. Conclusions— VVI was a feasible method for direct quantification of aortic elastic properties with a significant histological correlation.

Description: Background and Purpose— Asiatic acid (AA) has been shown to attenuate cerebral infarction in a mouse model of focal ischemia and shows promise as a neuroprotective stroke therapy. To facilitate translation of these findings to clinical studies, we determined pharmacokinetics, a dose–response relationship, the therapeutic time window, and efficacy using multiple stroke models. We also explored potential mechanisms of action. Methods— Escalating doses of intravenous AA were administered and serum concentrations were measured at multiple time points for the pharmacokinetic studies. Subsequently, a dose–response relationship was determined followed by administration at different intervals after the onset of ischemia to establish a therapeutic time window for neuroprotection. Outcome measurements included both histological and behavioral. Mitochondrial function and matrix metalloproteinase activity in controls and treated rats were also determined. Results— The pharmacokinetic studies showed that AA (75 mg/kg) has a half-life of 2.0 hours. AA significantly decreased infarct volume and improved neurological outcome even when administration was at time points up to 12 hours after the onset of ischemia. Infarct volume was also significantly decreased in female rats and spontaneously hypertensive rats. AA attenuated mitochondrial dysfunction and reduced matrix metalloproteinase-9 induction. Conclusions— Our study shows AA is effective against multiple models of focal ischemia, has a long therapeutic time window, and is also effective in females and hypertensive animals. AA may mediate neuroprotection by protecting mitochondria and inhibiting matrix metalloproteinase-9 induction and activation. Taken together these data suggest that AA is an excellent candidate for development as a stroke therapy.