Enhanced Biocompatibility of NiTi (Nitinol) Via Surface Treatment and Alloying

It is projected that by 2020, there will be 138 million Americans over 45, the age at which the increased incidence of heart diseases is documented. Many will require stents. This multi-billion dollar industry, with over 2 million patients worldwide, 15% of whom use Nitinol stents have experienced a decline in sales recently, due in part to thrombosis. It is a sudden blood clot that forms inside stents. As a result, the Food and Drug Administration and American Heart Association are calling for a new generation of stents, new designs and different alloys that are more adaptable to the arteries. The future of Nitinol therefore depends on a better understanding of the mechanisms by which Nitinol surfaces can be rendered stable and inert. In this investigation, binary and ternary Nitinol alloys were prepared and subjected to various surface treatments such as electropolishing (EP), magnetoelectropolishing (MEP) and water boiling & passivation (W&P). In vitro corrosion tests were conducted on Nitinol alloys in accordance with ASTM F 2129-08. The metal ions released into the electrolyte during corrosion tests were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). Biocompatibility was assessed by observing the growth of human umbilical vein endothelial cells (HUVEC) on the surface of Nitinol alloys. Static and dynamic immersion tests were performed by immersing the Nitinol alloys in cell culture media and measuring the amount of metal ions released in solution. Sulforhodamine B (SRB) assays were performed to elucidate the effect of metal ions on the growth of HUVEC cells. The surfaces of the alloys were studied using Scanning Electron Microscopy (SEM) and X-ray Photoelectron Spectroscopy (XPS) respectively. Finally, wettability and surface energy were measured by Contact Angle Meter, whereas surface roughness was measured by Atomic Force Microscopy (AFM). All the surface treated alloys exhibited high resistance to corrosion when compared with untreated alloys. SRB assays revealed that Ni and Cu ions exhibited greater toxicity than Cr, Ta and Ti ions on HUVEC cells. EP and MEP alloys possessed relatively smooth surfaces and some were composed of nickel oxides instead of elemental nickel as determined by XPS. MEP exhibited lowest surface energy and lowest surface roughness.

Determinants and Outcomes of Stroke Following Percutaneous Coronary Intervention by Indication

© 2016 American Heart Association, Inc.

Prior Antithrombotic Use is Associated with Favorable Mortality and Functional Outcomes in Acute Ischemic Stroke

Sources of Funding The GWTG-Stroke program is currently supported in part by a charitable contribution from Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership and the American Heart Association Pharmaceutical Roundtable. GWTG-Stroke has been funded in the past through support from Boehringer-Ingelheim and Merck. These funding agencies did not participate in design or analysis, manuscript preparation, or approval of this study.

Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice

This work was supported by the National Institutes of Health (Grant Nos. R01DK093587 and R01DK101379 [to YX], R01DK092605 to [QT], R01DK078056 [to MM]), the Klarman Family Foundation (to YX), the Naman Family Fund for Basic Research (to YX), Curtis Hankamer Basic Research Fund (to YX), American Diabetes Association (Grant Nos. 7-13-JF-61 [to QW] and 1-15-BS-184 [to QT]), American Heart Association postdoctoral fellowship (to PX), Wellcome Trust (Grant No. WT098012 [to LKH]), and Biotechnology and Biological Sciences Research Council (Grant No. BB/K001418/1 [to LKH]). The anxiety tests (e.g., open-field test, light-dark test, elevated plus maze test) were performed in the Mouse Neurobehavior Core, Baylor College of Medicine, which was supported by National Institutes of Health Grant No. P30HD024064. PX and YH were involved in experimental design and most of the procedures, data acquisition and analyses, and writing the manuscript. XC assisted in the electrophysiological recordings; LV-T assisted in the histology study; XY, KS, CW, YY, AH, LZ, and GS assisted in surgical procedures and production of study mice. MGM, QW, QT, and LKH were involved in study design and writing the manuscript. YX is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors report no biomedical financial interests or potential conflicts of interest.

Impact of Hemoglobin Levels and Anemia on Mortality in Acute Stroke : Analysis of UK Regional Registry Data, Systematic Review, and Meta‐Analysis

Funding Sources The NNUH Stroke and TIA Register is maintained by the NNUH NHS Foundation Trust Stroke Services and data management for this study is supported by the NNUH Research and Development Department through Research Capability Funds.

Computational Methods for Identifying Hypertrophic Cardiomyopathy using 12-lead ECG

Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease where the heart muscle is partially thickened and blood flow is - potentially fatally - obstructed. It is one of the leading causes of sudden cardiac death in young people. Electrocardiography (ECG) and Echocardiography (Echo) are the standard tests for identifying HCM and other cardiac abnormalities. The American Heart Association has recommended using a pre-participation questionnaire for young athletes instead of ECG or Echo tests due to considerations of cost and time involved in interpreting the results of these tests by an expert cardiologist. Initially we set out to develop a classifier for automated prediction of young athletes’ heart conditions based on the answers to the questionnaire. Classification results and further in-depth analysis using computational and statistical methods indicated significant shortcomings of the questionnaire in predicting cardiac abnormalities. Automated methods for analyzing ECG signals can help reduce cost and save time in the pre-participation screening process by detecting HCM and other cardiac abnormalities. Therefore, the main goal of this dissertation work is to identify HCM through computational analysis of 12-lead ECG. ECG signals recorded on one or two leads have been analyzed in the past for classifying individual heartbeats into different types of arrhythmia as annotated primarily in the MIT-BIH database. In contrast, we classify complete sequences of 12-lead ECGs to assign patients into two groups: HCM vs. non-HCM. The challenges and issues we address include missing ECG waves in one or more leads and the dimensionality of a large feature-set. We address these by proposing imputation and feature-selection methods. We develop heartbeat-classifiers by employing Random Forests and Support Vector Machines, and propose a method to classify full 12-lead ECGs based on the proportion of heartbeats classified as HCM. The results from our experiments show that the classifiers developed using our methods perform well in identifying HCM. Thus the two contributions of this thesis are the utilization of computational and statistical methods for discovering shortcomings in a current screening procedure and the development of methods to identify HCM through computational analysis of 12-lead ECG signals.

Mitral Valve Surgery for Rheumatic Lesions in Young Patients

BACKGROUND: The appropriateness of rheumatic mitral valve repair remains controversial due to the risks of recurrent mitral dysfunction and need for reoperation. The aims of this study were to determine the overall short- and long-term outcomes of pediatric rheumatic mitral valve surgery in our center. METHODS: Single-center, observational, retrospective study that analyzed the results of rheumatic mitral valve surgery in young patients, consecutively operated by the same team, between 1999 and 2014. RESULTS: We included 116 patients (mean age = 12.6 ± 3.5 years), of which 66 (57%) were females. A total of 116 primary surgical interventions and 22 reoperations were performed. Primary valve repair was possible in 86 (74%) patients and valve replacement occurred in 30 (26%). Sixty percent of the patients were followed up beyond three months after surgery (median follow-up time = 9.2 months [minimum = 10 days; maximum = 15 years]). Long-term clinical outcomes were favorable, with most patients in New York Heart Association functional class I (89.6%) and in sinus rhythm (85%). Freedom from reoperation for primary valve repair at six months, five years, and ten years was 96.4% ± 0.25%, 72% ± 0.72%, and 44.7% ± 1.34%, respectively. Freedom from reoperation for primary valve replacement at six months, five years, and ten years was 100%, 91.7% ± 0.86%, and 91.7% ± 0.86%, respectively. Mitral stenosis as the primary lesion dictated early reintervention. CONCLUSIONS: Despite the greater rate of reoperation, especially when the primary lesion was mitral stenosis, rheumatic mitral valve repair provides similar clinical outcomes as compared with replacement, with the advantage of avoiding anticoagulation.

Vitamins Reverse Endothelial Dysfunction Through Regulation of eNOS and NAD(P)H Oxidase Activities

Antioxidant vitamins C and E have protective properties in genetic hypertension associated with enhanced oxidative stress. This study investigated whether vitamins C and/or E modulate vascular function by regulating enzymatic activities of endothelial nitric oxide synthase (eNOS) and NAD(P)H oxidase using thoracic aortas of 20- to 22-week-old male spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar-Kyoto rats (WKY). SHR aortas had impaired relaxant responses to acetylcholine but not to sodium nitroprusside, despite an 2-fold increase in eNOS activity and NO release. The levels of superoxide anion (O2 ), a potent NO scavenger, and NAD(P)H oxidase activity were also 2-fold higher in SHR aortas. Mechanical but not pharmacological inactivation of endothelium (by rubbing and 100 mol/L L-NAME, respectively) significantly abrogated O2 in both strains. Treatments of SHR aortas with NAD(P)H oxidase inhibitors, namely diphenyleneiodinium and apocynin, significantly diminished O2 production. The incubation of SHR aortas with different concentrations of vitamin C (10 to 100 mol/L) and specifically with high concentrations of vitamin E (100 mol/L) improved endothelial function, reduced superoxide production as well as NAD(P)H oxidase activity, and increased eNOS activity and NO generation in SHR aortas to the levels observed in vitamin C- and E-treated WKY aortas. Our results reveal endothelial NAD(P)H oxidase as the major source of vascular O2 in SHR and also show that vitamins C and E are critical in normalizing genetic endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities.

Molecular Characterization and Localization of the NAD(P)H Oxidase Components gp91-phox and p22-phox in Endothelial Cells

The production of reactive oxygen species (ROS) within endothelial cells may have several effects, including alterations in the activity of paracrine factors, gene expression, apoptosis, and cellular injury. Recent studies indicate that a phagocyte-type NAD(P)H oxidase is a major source of endothelial ROS. In contrast to the high-output phagocytic oxidase, the endothelial enzyme has much lower biochemical activity and a different substrate specificity (NADH.NADPH). In the present study, we (1) cloned and characterized the cDNA and predicted amino acid structures of the 2 major subunits of rat coronary microvascular endothelial cell NAD(P)H oxidase, gp91-phox and p22-phox; (2) undertook a detailed comparison with phagocytic NADPH oxidase sequences; and (3) studied the subcellular location of these subunits in endothelial cells. Although these studies revealed an overall high degree of homology (.90%) between the endothelial and phagocytic oxidase subunits, the endothelial gp91-phox sequence has potentially important differences in a putative NADPH-binding domain and in putative glycosylation sites. In addition, the subcellular location of the endothelial gp91-phox and p22-phox subunits is significantly different from that reported for the neutrophil oxidase, in that they are predominantly intracellular and collocated in the vicinity of the endoplasmic reticulum. This first detailed characterization of gp91-phox and p22-phox structure and location in endothelial cells provides new data that may account, in part, for the differences in function between the phagocytic and endothelial NAD(P)H oxidases.

Impact of Routine Fractional Flow Reserve Evaluation During Coronary Angiography on Management Strategy and Clinical Outcome: One-Year Results of the POST-IT.

Penetration of fractional flow reserve (FFR) in clinical practice varies extensively, and the applicability of results from randomized trials is understudied. We describe the extent to which the information gained from routine FFR affects patient management strategy and clinical outcome. METHODS AND RESULTS: Nonselected patients undergoing coronary angiography, in which at least 1 lesion was interrogated by FFR, were prospectively enrolled in a multicenter registry. FFR-driven change in management strategy (medical therapy, revascularization, or additional stress imaging) was assessed per-lesion and per-patient, and the agreement between final and initial strategies was recorded. Cardiovascular death, myocardial infarction, or unplanned revascularization (MACE) at 1 year was recorded. A total of 1293 lesions were evaluated in 918 patients (mean FFR, 0.81±0.1). Management plan changed in 406 patients (44.2%) and 584 lesions (45.2%). One-year MACE was 6.9%; patients in whom all lesions were deferred had a lower MACE rate (5.3%) than those with at least 1 lesion revascularized (7.3%) or left untreated despite FFR≤0.80 (13.6%; log-rank P=0.014). At the lesion level, deferral of those with an FFR≤0.80 was associated with a 3.1-fold increase in the hazard of cardiovascular death/myocardial infarction/target lesion revascularization (P=0.012). Independent predictors of target lesion revascularization in the deferred lesions were proximal location of the lesion, B2/C type and FFR. CONCLUSIONS: Routine FFR assessment of coronary lesions safely changes management strategy in almost half of the cases. Also, it accurately identifies patients and lesions with a low likelihood of events, in which revascularization can be safely deferred, as opposed to those at high risk when ischemic lesions are left untreated, thus confirming results from randomized trials.

Clinical outcome after first and recurrent hemorrhage in patients with untreated brain arteriovenous malformation

Background and Purpose: The morbidity from spontaneous hemorrhage of untreated brain arteriovenous malformations (AVM) is not well described. Methods: The 241 consecutive AVM patients (mean age 3716 years, 52% women) from the prospective Columbia AVM Databank initially presenting with hemorrhage were evaluated using the Rankin Scale (RS) and the National Institute of Health Stroke Scale (NIHSS). From the 241 AVM patients, 29 (12%) had subsequent intracranial hemorrhage during follow-up. For further comparisons, 84 non-AVM patients with intracerebral hemorrhage from the Northern Manhattan Study (NOMAS) served as a control group. Results: In 241 AVM patients presenting with hemorrhage the median RS was 2 and the median NIHSS was 1 (49% RS 0 to 1, 61% NIHSS 2). The median time between hemorrhage and clinical evaluation was 11 days (mean 219 days). Recurrent AVM hemorrhage during follow-up resulted in no significant increase in morbidity (median RS 2, P0.004; median NIHSS 3, P0.322; time between hemorrhage and study evaluation: median 55 days, mean 657 days). Among AVM-hemorrhage subtypes, parenchymatous AVM hemorrhage was associated with higher stroke morbidity (odds ratio, 2.9; 95% CI, 1.5 to 5.8 for NIHSS 2) than nonparenchymatous hemorrhages. Parenchymatous AVM hemorrhage had a significantly better outcome (median NIHSS 1) than non-AVM related hemorrhage (median NIHSS 12; P0.0001). Conclusions: Hemorrhage, either at initial presentation or during follow-up of untreated AVM patients appears to carry

Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem Cell Trial of Recovery EnhanceMent After Stroke (STEMS) Pilot Randomized, Controlled Trial (ISRCTN 16784092)

Background and Purpose - Loss of motor function is common after stroke and leads to significant chronic disability. Stem cells are capable of self-renewal and of differentiating into multiple cell types, including neurones, glia, and vascular cells. We assessed the safety of granulocyte-colony-stimulating factor (G-CSF) after stroke and its effect on circulating CD34 stem cells. Methods - We performed a 2-center, dose-escalation, double-blind, randomized, placebo-controlled pilot trial (ISRCTN 16784092) of G-CSF (6 blocks of 1 to 10 g/kg SC, 1 or 5 daily doses) in 36 patients with recent ischemic stroke. Circulating CD34 stem cells were measured by flow cytometry; blood counts and measures of safety and functional outcome were also monitored. All measures were made blinded to treatment. Results - Thirty-six patients, whose mean SD age was 768 years and of whom 50% were male, were recruited. G-CSF (5 days of 10 g/kg) increased CD34 count in a dose-dependent manner, from 2.5 to 37.7 at day 5 (area under curve, P0.005). A dose-dependent rise in white cell count (P0.001) was also seen. There was no difference between treatment groups in the number of patients with serious adverse events: G-CSF, 7/24 (29%) versus placebo 3/12 (25%), or in their dependence (modified Rankin Scale, median 4, interquartile range, 3 to 5) at 90 days. Conclusions - ”G-CSF is effective at mobilizing bone marrow CD34 stem cells in patients with recent ischemic stroke. Administration is feasible and appears to be safe and well tolerated. The fate of mobilized cells and their effect on functional outcome remain to be determined. (Stroke. 2006;37:2979-2983.)

The Virtual International Stroke Trials Archive

Background and Purpose - Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. Methods - Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. Results - ”Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on 15 000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 6912 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials. Conclusions - This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning. (Stroke. 2007;38:1905-1910.)