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P ulmonary arterial hypertension (PAH) is a life-threatening disease characterized by elevated pulmonary artery pressure caused by increased pulmonary vascular resistance, ultimately leading to right heart failure and death.1 A combination of vasoconstriction, and vascular wall remodeling, which includes excessive extracellular matrix (ECM) deposition, and smooth muscle cell hyperplasia leads to occlusion of the small pulmonary arteries.2 Therapeutic options for the clinical management of PAH are limited, and the disease remains essentially untreatable, underscoring the need for a better understanding of the pathogenic mechanisms at play that give rise to increased pulmonary vascular resistance. 3 In this regard, 1 key area of interest is to clarify the causes and nature of the pulmonary vascular remodeling associated with PAH.To date, most studies that have explored vascular remodeling in pulmonary hypertension (PH) have focused on increased cell proliferation and apoptosis resistance as an underlying cause of medial hypertrophy and neointimal formation. Regulation of pulmonary artery smooth muscle cell (PASMC) proliferation, apoptosis, and contraction has received much attention, with potassium and calcium channels, growth factors (including transforming growth factor-β, © 2014 American Heart Association, Inc. Objective-Pulmonary vascular remodeling, the pathological hallmark of pulmonary arterial hypertension, is attributed to proliferation, apoptosis resistance, and migration of vascular cells. A role of dysregulated matrix cross-linking and stability as a pathogenic mechanism has received little attention. We aimed to assess whether matrix cross-linking enzymes played a causal role in experimental pulmonary hypertension (PH). Approach and Results-All 5 lysyl oxidases were detected in concentric and plexiform vascular lesions of patients with idiopathic pulmonary arterial hypertension. Lox, LoxL1, LoxL2, and LoxL4 expression was elevated in lungs of patients with idiopathic pulmonary arterial hypertension, whereas LoxL2 and LoxL3 expression was elevated in laser-capture microdissected vascular lesions. Lox expression was hypoxia-responsive in pulmonary artery smooth muscle cells and adventitial fibroblasts, whereas LoxL1 and LoxL2 expression was hypoxia-responsive in adventitial fibroblasts. Lox expression was increased in lungs from hypoxia-exposed mice and in lungs and pulmonary artery smooth muscle cells of monocrotaline-treated rats, which developed PH. Pulmonary hypertensive mice exhibited increased muscularization and perturbed matrix structures in vessel walls of small pulmonary arteries. Hypoxia exposure led to increased collagen crosslinking, by dihydroxylysinonorleucine and hydroxylysinonorleucine cross-links. Administration of the lysyl oxidase inhibitor β-aminopropionitrile attenuated the effect of hypoxia, limiting perturbations to right ventricular systolic pressure, right ventricular hypertrophy, and vessel muscularization and normalizing collagen cross-linking and vessel matrix architecture....

Rationale: Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood. Objectives: To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD. Methods: Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-b) was preemptively blocked in mice exposed to hyperoxia using TGFb-neutralizing antibodies. Lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxl1 promoters fused upstream of the firefly luciferase gene. Measurements and Main Results: mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygeninjured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-b signaling drove aberrant lox, but not loxl1 or loxl2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells. Conclusions: Lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-b signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD.

ObjectiveTo determine the safety and efficacy of aerobic exercise on activities of daily living in the subacute phase after stroke.DesignMulticentre, randomised controlled, endpoint blinded trial.SettingSeven inpatient rehabilitation sites in Germany (2013-17).Participants200 adults with subacute stroke (days 5-45 after stroke) with a median National Institutes of Health stroke scale (NIHSS, range 0-42 points, higher values indicating more severe strokes) score of 8 (interquartile range 5-12) were randomly assigned (1:1) to aerobic physical fitness training (n=105) or relaxation sessions (n=95, control group) in addition to standard care.InterventionParticipants received either aerobic, bodyweight supported, treadmill based physical fitness training or relaxation sessions, each for 25 minutes, five times weekly for four weeks, in addition to standard rehabilitation therapy. Investigators and endpoint assessors were masked to treatment assignment.Main outcome measuresThe primary outcomes were change in maximal walking speed (m/s) in the 10 m walking test and change in Barthel index scores (range 0-100 points, higher scores indicating less disability) three months after stroke compared with baseline. Safety outcomes were recurrent cardiovascular events, including stroke, hospital readmissions, and death within three months after stroke. Efficacy was tested with analysis of covariance for each primary outcome in the full analysis set. Multiple imputation was used to account for missing values.ResultsCompared with relaxation, aerobic physical fitness training did not result in a significantly higher mean change in maximal walking speed (adjusted treatment effect 0.1 m/s (95% confidence interval 0.0 to 0.2 m/s), P=0.23) or mean change in Barthel index score (0 (−5 to 5), P=0.99) at three months after stroke. A higher rate of serious adverse events was observed in the aerobic group compared with relaxation group (incidence rate ratio 1.81, 95% confidence interval 0.97 to 3.36).ConclusionsAmong moderately to severely affected adults with subacute stroke, aerobic bodyweight supported, treadmill based physical fitness training was not superior to relaxation sessions for maximal walking speed and Barthel index score but did suggest higher rates of adverse events. These results do not appear to support the use of aerobic bodyweight supported fitness training in people with subacute stroke to improve activities of daily living or maximal walking speed and should be considered in future guidelines.Trial registrationClinicalTrials.gov NCT01953549.

Background and Purpose-Fluid-attenuated inversion recovery hyperintense vessels (FHV) are frequently observed on magnetic resonance imaging in acute stroke patients with proximal vessel occlusion. Whether FHV can serve as a surrogate for the collateral status and predict functional outcome of patients is still a matter of debate. Methods-Acute ischemic stroke patients with M1-middle cerebral artery occlusion who received magnetic resonance imaging before endovascular treatment in 3 hospitals in Germany between January 2007 and June 2016 were eligible. Quantification of FHV was performed using an FHV-Alberta Stroke Program Early CT Score (ASPECTS) rating system. Functional outcome was evaluated with the modified Rankin Scale 3 months after stroke. Collateral status of patients was graded on baseline angiography using the American Society of Interventional and Therapeutic Neuroradiology grading system. Odds for good outcome (modified Rankin Scale score, 0-2) were determined using logistic regression analyses.

ObjectiveTo determine the role of circulating microvesicles (MV) on long-term cardiovascular outcomes after stroke, we measured them in first-ever stroke patients with a three-year follow-up.MethodsIn the PROSpective Cohort with Incident Stroke Berlin (PROSCIS-B), patients with first-ever ischemic stroke were followed for 3 years. The primary combined endpoint consisted of recurrent stroke, myocardial infarction, and all-cause mortality. Citrate-blood levels of endothelial MV (EMV), leukocyte-derived MV (LMV), monocytic MV (MMV), and platelet-derived MV (PMV) were measured using flow cytometry. Kaplan-Meier curves and adjusted Cox proportional hazards models were used to estimate the effect of MV levels on the combined endpoint.ResultsFive hundred seventy-one patients were recruited (median age 69 years; 39% female; median NIHSS 2, interquartile range 1–4) and 95 endpoints occurred. Patients with levels of EMV [adjusted hazard ratio (HR) = 2.5, 95% confidence interval (CI) 1.2–4.9] or LMV (HR = 3.1, 95% CI 1.4–6.8) in the highest quartile were more likely to experience an event than participants with lower levels using the lowest quartile as reference category. The association was less pronounced for PMV (HR = 1.7, 95% CI 0.9–3.2) and absent for MMV (HR = 1.1, 95% CI 0.6–1.8).ConclusionHigh levels of EMV and LMV after stroke were associated with worse cardiovascular outcome within 3 years. These results reinforce that endothelial dysfunction and vascular inflammation affect the long-term prognosis after stroke. EMV and LMV might play a role in risk prediction for stroke patients.Study registrationclinicaltrials.gov/ct2/show/NCT01363856. UID: NCT01363856.Classification of evidenceThis study provides Class II evidence of the impact of MV levels on subsequent stroke, myocardial infarction or all-cause mortality in survivors of mild stroke.

BackgroundGiven the rising number of strokes worldwide, and the large number of individuals left with disabilities after stroke, novel strategies to reduce disability, increase functions in the motor and the cognitive domains, and improve quality of life are of major importance. Physical activity is a promising intervention to address these challenges but, as yet, there is no study demonstrating definite outcomes. Our objective is to assess whether additional treatment in the form of physical fitness-based training for patients early after stroke will provide benefits in terms of functional outcomes, in particular gait speed and the Barthel Index (co-primary outcome measures) reflecting activities of daily living (ADL). We will gather secondary functional outcomes as well as mechanistic parameters in an exploratory approach.Methods/DesignOur phase III randomised controlled trial will recruit 215 adults with moderate to severe limitations of walking and ADL 5 to 45 days after stroke onset. Participants will be stratified for the prognostic variables of “centre”, “age”, and “stroke severity”, and randomly assigned to one of two groups. The interventional group receives physical fitness training delivered as supported or unsupported treadmill training (cardiovascular active aerobic training; five times per week, over 4 weeks; each session 50 minutes; total of 20 additional physical fitness training sessions) in addition to standard rehabilitation treatment. The control intervention consists of relaxation sessions (non-cardiovascular active; five times per week week, over 4 weeks; each session 50 minutes) in addition to standard rehabilitation treatment. Co-primary efficacy endpoints will be gait speed (in m/s, 10 m walk) and the Barthel Index (100 points total) at 3 months post-stroke, compared to baseline measurements. Secondary outcomes include standard measures of quality of life, sleep and mood, cognition, arm function, maximal oxygen uptake, and cardiovascular risk factors including blood pressure, pulse, waist-to-hip ratio, markers of inflammation, immunity and the insulin-glucose pathway, lipid profile, and others.DiscussionThe goal of this endpoint-blinded, phase III randomised controlled trial is to provide evidence to guide post-stroke physical fitness-based rehabilitation programmes, and to elucidate the mechanisms underlying this intervention.Trial registrationRegistered in ClinicalTrials.gov with the Identifier NCT01953549.