bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Gene Expression in Macrophages From Human Atherosclerotic Plaques Shows Convergence on Pathways Implicated by Genome-Wide Association Study Risk Variants
Authors: Chai Joshua T. , Ruparelia Neil , Goel Anuj , Kyriakou Theodosios , Biasiolli Luca , Edgar Laurienne , Handa Ashok , Farrall Martin , Watkins Hugh , Choudhury Robin P. 
Published: October 2018

Objective—
Plaque macrophages are intricately involved in atherogenesis and plaque destabilization. We sought to identify functional pathways in human plaque macrophages that are differentially regulated in respect of (1) plaque stability and (2) lipid content. We hypothesized that differentially regulated macrophage gene sets would relate to genome-wide association study variants associated with risk of acute complications of atherosclerosis.

Approach and Results—

Forty patients underwent carotid magnetic resonance imaging for lipid quantification before endarterectomy. Carotid plaque macrophages were procured by laser capture microdissection from (1) lipid core and (2) cap region, in 12 recently symptomatic and 12 asymptomatic carotid plaques. Applying gene set enrichment analysis, a number of gene sets were found to selectively upregulate in symptomatic plaque macrophages, which corresponded to 7 functional pathways: inflammation, lipid metabolism, hypoxic response, cell proliferation, apoptosis, antigen presentation, and cellular energetics. Predicted upstream regulators included
IL-1β
,
TNF-α
, and
NF-κB
. In vivo lipid quantification by magnetic resonance imaging correlated most strongly with the upregulation of genes of the
IFN
/
STAT1
pathways. Cross-interrogation of gene set enrichment analysis and meta-analysis gene set enrichment of variant associations showed lipid metabolism pathways, driven by genes coding for
APOE
and
ABCA1/G1
coincided with known risk-associated SNPs (single nucleotide polymorphisms) from genome-wide association studies.

Conclusions—
Macrophages from recently symptomatic carotid plaques show differential regulation of functional gene pathways. There were additional quantitative relationships between plaque lipid content and key gene sets. The data show a plausible mechanism by which known genome-wide association study risk variants for atherosclerotic complications could be linked to (1) a relevant cellular process, in (2) the key cell type of atherosclerosis, in (3) a human disease-relevant setting.
Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis
Authors: Shi Dan , Qi Man , Zhou Liping , Li Xiang , Ni Le , Li Changming , Yuan Tianyou , Wang Yunqian , Chen Yongli , Hu Chaoyue , Liang Dandan , Li Li , Liu Yi , Li Jun , Chen Yi-Han 
Published: October 2018

Objective—
Mitochondria are the important yet most underutilized target for cardio-cerebrovascular function integrity and disorders. The Tom (translocases of outer membrane) complex are the critical determinant of mitochondrial homeostasis for making organs acclimate physiological and pathological insults; however, their roles in the vascular system remain unknown.

Approach and Results—

A combination of studies in the vascular-specific transgenic zebrafish and genetically engineered mice was conducted. Vascular casting and imaging, endothelial angiogenesis, and mitochondrial protein import were performed to dissect potential mechanisms. A loss-of-function genetic screening in zebrafish identified that selective inactivation of the
tomm7
(translocase of outer mitochondrial membrane 7) gene, which encodes a small subunit of the Tom complex, specially impaired cerebrovascular network formation. Ablation of the ortholog
Tomm7
in mice recapitulated cerebrovascular abnormalities. Restoration of the cerebrovascular anomaly by an endothelial-specific transgenesis of
tomm7
further indicated a defect in endothelial function. Mechanistically, Tomm7 deficit in endothelial cells induced an increased import of Rac1 (Ras-related C3 botulinum toxin substrate 1) protein into mitochondria and facilitated the mitochondrial Rac1-coupled redox signaling, which incurred angiogenic impairment that underlies cerebrovascular network malformation.

Conclusions—
Tomm7 drives brain angiogenesis and cerebrovascular network formation through modulating mitochondrial Rac1 signaling within the endothelium.
SR-BI (Scavenger Receptor Class B Type 1) Is Critical in Maintaining Normal T-Cell Development and Enhancing Thymic Regeneration
Authors: Zheng Zhong , Ai Junting , Guo Ling , Ye Xiang , Bondada Subbarao , Howatt Deborah , Daugherty Alan , Li Xiang-An 
Published: October 2018

Objective—
Continuous T-cell production from thymus is essential in replenishing naïve T-cell pool and maintaining optimal T-cell functions. However, the underlying mechanisms regulating the T-cell development in thymus remains largely unknown.

Approach and Results—
We identified SR-BI (scavenger receptor class B type 1), an HDL (high-density lipoprotein) receptor, as a novel modulator in T-cell development. We found that SR-BI deficiency in mice led to reduced thymus size and decreased T-cell production, which was accompanied by narrowed peripheral naïve T-cell pool. Further investigation revealed that SR-BI deficiency impaired progenitor thymic homing, causing a dramatic reduction in the percentage of earliest thymic progenitors, but did not affect other downstream T-cell developmental steps inside the thymus. As a result of the impaired progenitor thymic homing, SR-BI-deficient mice displayed delayed thymic regeneration postirradiation. Using a variety of experimental approaches, we revealed that the impaired T-cell development in SR-BI-deficient mice was not caused by hematopoietic SR-BI deficiency or SR-BI deficiency-induced hypercholesterolemia, but mainly attributed to the SR-BI deficiency in adrenal glands, as adrenal-specific SR-BI-deficient mice exhibited similar defects in T-cell development and thymic regeneration with SR-BI-deficient mice.

Conclusions—
This study demonstrates that SR-BI deficiency impaired T-cell development and delayed thymic regeneration by affecting progenitor thymic homing in mice, elucidating a previously unrecognized link between SR-BI and adaptive immunity.
Randomized Controlled Trial of Surgical Versus Catheter Ablation for Paroxysmal and Early Persistent Atrial Fibrillation
Authors: Adiyaman Ahmet , Buist Thomas J. , Beukema Rypko J. , Smit Jaap Jan J. , Delnoy Peter Paul H.M. , Hemels Martin E.W. , Sie Hauw T. , Ramdat Misier Anand R. , Elvan Arif 
Published: October 2018

Background:
Current guidelines recommend both percutaneous catheter ablation (CA) and surgical ablation in the treatment of atrial fibrillation, with different levels of evidence. No direct comparison has been made between minimally invasive thoracoscopic pulmonary vein isolation with left atrial appendage ligation (surgical MIPI) versus percutaneous CA comprising of pulmonary vein isolation as primary treatment of atrial fibrillation. We, therefore, conducted a randomized controlled trial comparing the safety and efficacy of these 2 treatment modalities.

Methods:
Eighty patients were enrolled in the study and underwent implantable loop recorder implantation. Twenty-eight patients did not reach randomization criteria. A total of 52 patients with symptomatic paroxysmal or early persistent atrial fibrillation were randomized, 26 to CA and 26 to surgical MIPI. The primary end point was defined as freedom of atrial tachyarrhythmias, without the use of antiarrhythmic drugs. The safety end point was freedom of complications.

Results:

Median age was 57 years (range, 37–75), and 78% were men. Paroxysmal atrial fibrillation was present in 74%. Follow-up duration was ≥2 years in all patients. CA was noninferior to MIPI in terms of single-procedure arrhythmia-free survival after 2 years of follow-up (56.0% versus 29.2%; HR, 0.56; 95% CI, 0.26–1.20; log-rank
P
=0.059). Procedure-related major adverse events occurred significantly more often in MIPI than CA (20.8% versus 0%;
P
=0.029).

Conclusions:
Percutaneous pulmonary vein isolation was noninferior to MIPI in terms of efficacy and resulted in less complications.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00703157.
Loss-of-Function
ABCC8
Mutations in Pulmonary Arterial Hypertension
Authors: Bohnen Michael S. , Ma Lijiang , Zhu Na , Qi Hongjian , McClenaghan Conor , Gonzaga-Jauregui Claudia , Dewey Frederick E. , Overton John D. , Reid Jeffrey G. , Shuldiner Alan R. , Baras Aris , Sampson Kevin J. , Bleda Marta , Hadinnapola Charaka , Haimel Matthias , Bogaard Harm J. , Church Colin , Coghlan Gerry , Corris Paul A. , Eyries Mélanie , Gibbs J. Simon R. , Girerd Barbara , Houweling Arjan C. , Humbert Marc , Guignabert Christophe , Kiely David G. , Lawrie Allan , MacKenzie Ross Rob V. , Martin Jennifer M. , Montani David , Peacock Andrew J. , Pepke-Zaba Joanna , Soubrier Florent , Suntharalingam Jay , Toshner Mark , Treacy Carmen M. , Trembath Richard C. , Vonk Noordegraaf Anton , Wharton John , Wilkins Martin R. , Wort Stephen J. , Yates Katherine , Gräf Stefan , Morrell Nicholas W. , Krishnan Usha , Rosenzweig Erika B. , Shen Yufeng , Nichols Colin G. , Kass Robert S. , Chung Wendy K. 
Published: October 2018

Background:

In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in
KCNK3
, was identified as a genetic cause and pharmacological target.

Methods:
Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis.

Results:

We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in
ABCC8
in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in
ABCC8
and identified 11 additional heterozygous predicted damaging
ABCC8
variants.
ABCC8
encodes SUR1 (sulfonylurea receptor 1)—a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all
ABCC8
variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide.

Conclusions:

Novel and rare missense variants in
ABCC8
are associated with PAH. Identified
ABCC8
mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.
Cystatin C for Risk Stratification in Patients After an Acute Coronary Syndrome
Authors: Correa Simon , Morrow David A. , Braunwald Eugene , Davies Richard Y. , Goodrich Erica L. , Murphy Sabina A. , Cannon Christopher P. , O'Donoghue Michelle L. 
Published: October 2018

Background
Cystatin C (Cys‐C) is a marker of renal function that has shown prognostic value for cardiovascular risk stratification across different patient populations. The incremental value of Cys‐C beyond established cardiac and renal biomarkers remains incompletely explored.

Methods and Results

SOLID
‐
TIMI
52 (Stabilization of Plaques Using Darapladib‐Thrombolysis in Myocardial Infarction 52;
www.clinicaltrials.gov
, NCT01000727) randomized patients ≤30 days post–acute coronary syndrome were treated with darapladib or placebo. The association between Cys‐C and long‐term risk (median follow‐up 2.5 years) was assessed in 4965 individuals with adjustments made for clinical variables and other risk markers (eg, estimated glomerular filtration rate, high‐sensitivity troponin I, brain‐type natriuretic peptide, and fibroblast growth factor‐23). The prespecified outcome of interest was cardiovascular death (CVD) or heart failure hospitalization. Cys‐C was strongly correlated with creatinine (
r
=0.60) and estimated glomerular filtration rate (
r
=−0.68), moderately correlated with fibroblast growth factor‐23 (
r
=0.39), and weakly correlated with brain‐type natriuretic peptide (
r
=0.28) and high‐sensitivity troponin I (
r
=0.06) (all
P
<0.0001). After multivariate adjustment, increasing concentration of Cys‐C (per
SD
of log‐transformed Cys‐C) was significantly associated with a 28% higher hazard of CVD or heart failure hospitalization (hazard ratio [
HR
] 1.28, 95% confidence interval [
CI
] 1.12‐1.46,
P
<0.001), including CVD (
HR
1.24, 95%
CI
1.04‐1.47,
P
=0.01) and heart failure hospitalization (
HR
1.42, 95%
CI
1.19‐1.69,
P
<0.001). Cys‐C was also associated with a higher hazard of CVD, myocardial infarction, or stroke (
HR
1.15, 95%
CI
1.04‐1.28,
P
<0.01), including myocardial infarction (
HR
1.17, 95%
CI
1.02‐1.33,
P
=0.02). The addition of Cys‐C to a fully adjusted model without estimated glomerular filtration rate improved the C‐statistic from 0.80 to 0.81 (
P
=0.03) for CVD or heart failure hospitalization. In contrast, the addition of estimated glomerular filtration rate to a fully adjusted model without Cys‐C failed to improve model discrimination (
P
=0.17).

Conclusions
Cys‐C is associated with the risk of adverse outcomes in patients after acute coronary syndrome. This relationship is independent of established and novel biomarkers of the cardiorenal axis.
Impact of Ideal Cardiovascular Health in Childhood on the Retinal Microvasculature in Midadulthood: Cardiovascular Risk in Young Finns Study
Authors: Campbell Matthew D. , Laitinen Tomi T. , Hughes Alun , Pahkala Katja , Juonala Markus , Kähönen Mika , Wong Tien Y. , Lehtimäki Terho , Hutri‐Kähönen Nina , Raitakari Olli T. , Tapp Robyn J. 
Published: October 2018

Background

This study examined the association between ideal cardiovascular health (
CVH
) and the retinal microvasculature in midadulthood.

Methods and Results

The Cardiovascular Risk in Young Finns Study included children from 5 Finnish University cities, who were chosen randomly from the national population register. Participants ranged from 12 to 18 years in childhood (1986) and from 37 to 43 years in midadulthood (2011). Ideal
CVH
was defined according to the American Heart Association criteria. Retinal microvascular measures included diameters, lengths, length:diameter ratio, and tortuosity. From childhood to adulthood, fasting plasma glucose and blood pressure were significantly higher in those with impaired fasting glucose or diabetes mellitus. Childhood ideal
CVH
was negatively associated with adult arteriolar tortuosity (β=−0.008; 95% confidence interval [CI], −0.01 to −0.003;
P
=0.001). Improved ideal
CVH
from childhood to adulthood was positively associated with adult arteriolar diameter (β=0.122; 95% CI, 0.01–0.24;
P
=0.033) and negatively associated with adult length:diameter ratio (β=−0.666; 95% CI, −1.25 to −0.08;
P
=0.026). When stratified by glucose metabolism, among those with diabetes mellitus and impaired fasting glucose, there was a negative association between childhood ideal
CVH
and adult venular diameter (diabetes mellitus: β=−2.75; 95%
CI
, −5.46 to −0.04;
P
=0.047; impaired fasting glucose: β=−2.13; 95%
CI,
−4.18 to −0.08;
P
=0.042).

Conclusions

This study is the first to comprehensively examine the impact of
CVH
from childhood to midadulthood on quantitative measures of the retinal microvasculature. Ideal
CVH
in childhood and improvement in
CVH
from childhood to adulthood appears to have a protective effect on the retinal microvasculature in those with, without, and at risk of diabetes mellitus.
Immediate and Delayed Procedural Stroke or Death in Stenting Versus Endarterectomy for Symptomatic Carotid Stenosis
Authors: Müller Mandy D. , von Felten Stefanie , Algra Ale , Becquemin Jean-Pierre , Brown Martin , Bulbulia Richard , Calvet David , Eckstein Hans-Henning , Fraedrich Gustav , Halliday Alison , Hendrikse Jeroen , Gregson John , Howard George , Jansen Olav , Mas Jean-Louis , Brott Thomas G. , Ringleb Peter A. , Bonati Leo H. ,   for the Carotid Stenosis Trialists’ Collaboration
Published: October 2018

Background and Purpose—
Stenting for symptomatic carotid stenosis (carotid artery stenting [CAS]) carries a higher risk of procedural stroke or death than carotid endarterectomy (CEA). It is unclear whether this extra risk is present both on the day of procedure and within 1 to 30 days thereafter and whether clinical risk factors differ between these periods.

Methods—
We analyzed the risk of stroke or death occurring on the day of procedure (immediate procedural events) and within 1 to 30 days thereafter (delayed procedural events) in 4597 individual patients with symptomatic carotid stenosis who underwent CAS (n=2326) or CEA (n=2271) in 4 randomized trials.

Results—

Compared with CEA, patients treated with CAS were at greater risk for immediate procedural events (110 versus 42; 4.7% versus 1.9%; odds ratio, 2.6; 95% CI, 1.9–3.8) but not for delayed procedural events (59 versus 46; 2.5% versus 2.0%; odds ratio, 1.3; 95% CI, 0.9–1.9; interaction
P
=0.006). In patients treated with CAS, age increased the risk for both immediate and delayed events while qualifying event severity only increased the risk of delayed events. In patients treated with CEA, we found no risk factors for immediate events while a higher level of disability at baseline and known history of hypertension were associated with delayed procedural events.

Conclusions—
The increased procedural stroke or death risk associated with CAS compared with CEA was caused by an excess of events occurring on the day of procedure. This finding demonstrates the need to enhance the procedural safety of CAS by technical improvements of the procedure and increased operator skill. Higher age increased the risk for both immediate and delayed procedural events in CAS, mechanisms of which remain to be elucidated.

Clinical Trial Registration—

URL:
https://clinicaltrials.gov
. Unique identifier: NCT00190398. URL:
http://www.isrctn.com
. Unique identifier: ISRCTN57874028. URL:
http://www.isrctn.com
. Unique identifier: ISRCTN25337470. URL:
https://clinicaltrials.gov
. Unique identifier: NCT00004732.
Focal Cerebral Arteriopathy of Childhood
Authors: Fullerton Heather J. , Stence Nicholas , Hills Nancy K. , Jiang Bin , Amlie-Lefond Catherine , Bernard Timothy J. , Friedman Neil R. , Ichord Rebecca , Mackay Mark T. , Rafay Mubeen F. , Chabrier Stéphane , Steinlin Maja , Elkind Mitchell S.V. , deVeber Gabrielle A. , Wintermark Max ,   the VIPS Investigators
Published: October 2018

Background and Purpose—
Focal cerebral arteriopathy (FCA)—a common cause of arterial ischemic stroke in previously healthy children—often progresses over days to weeks, increasing the risk of recurrent stroke. We developed a novel severity scoring system designed to quantify FCA progression and correlate with clinical outcomes.

Methods—
The VIPS study (Vascular Effects of Infection in Pediatric Stroke) prospectively enrolled 355 children with arterial ischemic stroke (2010–2014), including 41 with centrally confirmed FCA. Two neuroradiologists independently reviewed FCA cerebrovascular imaging, assigning a graded severity score of zero (no involvement) to 4 (occlusion) to individual arterial segments. The FCA severity score (FCASS) was the unweighted sum. In an iterative process, we modeled scores derived from different combinations of arterial segments to identify the model that optimized correlation with clinical outcome, simplicity, and reliability.

Results—

The optimal FCASS summed scores from 5 arterial segments: supraclinoid internal carotid artery, A1, A2, M1, and M2. The median (interquartile range) baseline FCASS was 4 (2–6). Of 33 children with follow-up imaging, the maximum FCASS (at any time point) was 7 (5–9). Twenty-four (73%) had FCA progression on follow-up with their maximum FCASS at a median of 8 (5–35.5) days poststroke; their median FCASS increase was 4 (2.5–6). FCASS did not correlate with recurrent arterial ischemic stroke. Maximum (but not baseline) FCASS correlated with 1-year pediatric stroke outcome measures (
P
=0.037).

Conclusions—
Our novel scoring system for FCA severity correlates with neurological outcomes in the VIPS cohort and provides a tool for FCA treatment trials under development.
Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke
Authors: Kimberley Teresa J. , Pierce David , Prudente Cecília N. , Francisco Gerard E. , Yozbatiran Nuray , Smith Patricia , Tarver Brent , Engineer Navzer D. , Alexander Dickie David , Kline Danielle K. , Wigginton Jane G. , Cramer Steven C. , Dawson Jesse 
Published: October 2018

Background and Purpose—
We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke.

Methods—
We performed a randomized, multisite, double-blinded, sham-controlled pilot study. All participants were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program. Randomization was to active VNS (n=8) or control VNS (n=9) paired with rehabilitation. Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy.

Results—

All participants completed the course of therapy. There were 3 serious adverse events related to surgery. Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 post–in-clinic therapy (difference, 2.3 points; CI, −1.8 to 6.4;
P
=0.20). At day 90, mean scores increased 9.5 points from baseline with active VNS, and the control scores improved by 3.8 (difference, 5.7 points; CI, −1.4 to 11.5;
P
=0.055). The clinically meaningful response rate of FMA-UE at day 90 was 88% with active VNS and 33% with control VNS (
P
<0.05).

Conclusions—
VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke. A pivotal study of this therapy is justified.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02243020.