bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Exome Data Question the Pathogenicity of Genetic Variants Previously Associated With Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Jabbari Javad , Jabbari Reza , Nielsen Morten W. , Holst Anders G. , Nielsen Jonas B. , Haunsø Stig , Tfelt-Hansen Jacob , Svendsen Jesper H. , Olesen Morten S. 
Published: September 2013

Background—

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal, rare hereditary disease with an estimated prevalence of 1:10 000. The genetic variants that cause CPVT are usually highly penetrant. To date, about 189 variants in 5 genes (
RYR2, CASQ2, CALM1, TRND
, and
KCNJ2
) have been associated with CPVT pathogenesis.

Methods and Results—

The Exome Sequencing Project database (ESP; n= 6503) was systematically searched for previously published missense and nonsense CPVT–associated variants reported in several comprehensive reviews and in 2 databases: The Human Gene Mutation Database and The Inherited Arrhythmias Database. We used 4 different prediction tools to assess all missense variants previously associated with CPVT and compared the prediction of protein damage between CPVT-associated variants identified in the ESP and those variants not identified in the ESP. We identified 11% of the variants previously associated with CPVT in the ESP population. In the literature, 57% of these variants were reported as novel disease-causing variants absent in the healthy control subjects. These putative CPVT variants were identified in 41 out of 6131 subjects in the ESP population, corresponding to a prevalence of CPVT of up to 1:150. Using an agreement of ≥3, in silico prediction tools showed a significantly higher frequency of damaging variants among the CPVT-associated variants not identified in the ESP database (83%) compared with those variants identified in the ESP (50%;
P
=0.021).

Conclusions—
We identified a substantial overrepresentation of CPVT-associated variants in a large exome database, suggesting that these variants are not necessarily the monogenic cause of CPVT.
Outcome and Impact of Surgery in Paradoxical Low-Flow, Low-Gradient Severe Aortic Stenosis and Preserved Left Ventricular Ejection Fraction
Authors: Mohty Dania , Magne Julien , Deltreuil Mathieu , Aboyans Victor , Echahidi Najmeddine , Cassat Claude , Pibarot Philippe , Laskar Marc , Virot Patrice 
Published: September 2013

Background—
The clinical relevance and management of paradoxical low-flow, low-gradient aortic stenosis (LFLG-AS) with preserved left ventricular ejection fraction remain debated. The aim of this study is to determine the features and outcome of LFLG-AS assessed using cardiac catheterization.

Methods and Results—

Between 2000 and 2010, 768 patients with preserved left ventricular ejection fraction (>50%) and severe AS (valve area ≤1cm
2
) without other valvular disease underwent cardiac catheterization. Mean age was 74±8 years, 42% were women, and 46% had associated coronary artery disease. The prevalence of LFLG (indexed left ventricular stroke volume <35 mL/m
2
and mean gradient <40 mm Hg), normal flow high gradient, normal flow low gradient, and low flow high gradient were 13%, 50%, 22%, and 15%, respectively. Compared with patients with normal flow high gradient, those with LFLG were significantly older, with significantly reduced systemic arterial compliance and vascular resistances and increased valvulo-arterial impedance (all
P
<0.05). Ten-year survival was reduced in LFLG-AS (32±9%) compared with normal flow high gradient (66±4%;
P
=0.0002). After adjustment for other risk factors, LFLG-AS was independently associated with reduced long-term survival (hazard ratio, 1.85; 95% confidence interval, 1.08–3.07;
P
=0.02). However, despite higher operative mortality, patients with LFLG-AS undergoing aortic valve replacement seemed to have better long-term survival than those managed conservatively (5-year survival rate: 63±6% versus 38±15%;
P
=0.007; hazard ratio, 0.23; 95% confidence interval, 0.09–0.59;
P
=0.002).

Conclusions—
This large cardiac catheterization–based study reports that the LFLG-AS entity is not rare and is associated with worse outcome whether treated medically or surgically. However, these patients may have better long-term survival if treated surgically. Further prospective studies are needed to confirm this finding.
Primary Arterial Switch Operation as a Strategy for Total Correction of Taussig–Bing Anomaly
Authors: Hayes Denise A. , Jones Sophie , Quaegebeur Jan M. , Richmond Marc E. , Andrews Howard F. , Glickstein Julie S. , Chen Jonathan M. , Bacha Emile , Liberman Leonardo 
Published: September 2013

Background—
Studies of the arterial switch operation for Taussig–Bing anomaly demonstrate significant rates of reintervention and mortality, particularly after initial palliation to delay complete repair. We aimed to describe the long-term outcomes of our 21-year practice of single-stage arterial switch operation for all patients with Taussig–Bing anomaly.

Methods and Results—

A retrospective study was performed, and 43 patients with Taussig–Bing anomaly were identified between 1990 and 2011. Median age at arterial switch operation was 7 (range, 2–192) days, and median operative weight was 3.2 (1.4–6.2) kg. Aortic arch obstruction was present in 30 patients (70%). Hospital mortality was 7% (n=3). Follow-up was available for 37 hospital survivors at a mean of 8.1 (±6.3) years. Late mortality was 2% (n=1). At follow-up, all patients were in New York Heart Association functional class I. Freedom from transcatheter or surgical reintervention was 73% at 1 year, 64% at 5 years, and 60% at 10 years. Eleven patients underwent 13 catheter reinterventions on the pulmonary arteries (n=8) or aortic arch (n=5). Seven patients underwent 11 reoperations, including relief of right ventricular outflow tract obstruction (n=5), pulmonary arterioplasty (n=3), recoarctation repair (n=2), and tricuspid valve repair (n=1). By multivariate analysis, a preoperative aortic valve annulus
z
score of ≤−2.5 was associated with reintervention (hazard ratio, 7.66 [95% confidence interval, 1.29–45.6],
P
=0.03).

Conclusions—
Although reintervention is common, primary correction of Taussig–Bing anomaly with arterial switch operation can be achieved in all patients with low mortality and good long-term outcomes.
Impact of Wall Thickness and Saccular Geometry on the Computational Wall Stress of Descending Thoracic Aortic Aneurysms
Authors: Shang Eric K. , Nathan Derek P. , Sprinkle Shanna R. , Fairman Ronald M. , Bavaria Joseph E. , Gorman Robert C. , Gorman Joseph H. , Jackson Benjamin M. 
Published: September 2013

Background—
Wall stress calculated using finite element analysis has been used to predict rupture risk of aortic aneurysms. Prior models often assume uniform aortic wall thickness and fusiform geometry. We examined the effects of including local wall thickness, intraluminal thrombus, calcifications, and saccular geometry on peak wall stress (PWS) in finite element analysis of descending thoracic aortic aneurysms.

Methods and Results—

Computed tomographic angiography of descending thoracic aortic aneurysms (n=10 total, 5 fusiform and 5 saccular) underwent 3-dimensional reconstruction with custom algorithms. For each aneurysm, an initial model was constructed with uniform wall thickness. Experimental models explored the addition of variable wall thickness, calcifications, and intraluminal thrombus. Each model was loaded with 120 mm Hg pressure, and von Mises PWS was computed. The mean PWS of uniform wall thickness models was 410±111 kPa. The imposition of variable wall thickness increased PWS (481±126 kPa,
P
<0.001). Although the addition of calcifications was not statistically significant (506±126 kPa,
P
=0.07), the addition of intraluminal thrombus to variable wall thickness (359±86 kPa,
P
≤0.001) reduced PWS. A final model incorporating all features also reduced PWS (368±88 kPa,
P
<0.001). Saccular geometry did not increase diameter-normalized stress in the final model (77±7 versus 67±12 kPa/cm,
P
=0.22).

Conclusions—
Incorporation of local wall thickness can significantly increase PWS in finite element analysis models of thoracic aortic aneurysms. Incorporating variable wall thickness, intraluminal thrombus, and calcifications significantly impacts computed PWS of thoracic aneurysms; sophisticated models may, therefore, be more accurate in assessing rupture risk. Saccular aneurysms did not demonstrate a significantly higher normalized PWS than fusiform aneurysms.
KLF4 Regulates Abdominal Aortic Aneurysm Morphology and Deletion Attenuates Aneurysm Formation
Authors: Salmon Morgan , Johnston William F. , Woo Andrew , Pope Nicolas H. , Su Gang , Upchurch Gilbert R. , Owens Gary K. , Ailawadi Gorav 
Published: September 2013

Background—
KLF4 mediates inflammatory responses after vascular injury/disease; however, the role of KLF4 in abdominal aortic aneurysms (AAAs) remains unknown. The goals of the present study were to (1) determine the role of KLF4 in experimental AAA; and (2) determine the effect of KLF4 on smooth muscle (SM) cells in AAAs.

Methods and Results—
KLF4 expression progressively increased at days 3, 7, and 14 after aortic elastase perfusion in C57BL/6 mice. Separately, loss of a KLF4 allele conferred AAA protection using ERTCre+ KLF4 flx/wt mice in the elastase AAA model. In a third set of experiments, SM-specific loss of 1 and 2 KLF4 alleles resulted in progressively greater protection using novel transgenic mice (MYHCre+ flx/flx, flx/wt, and wt/wt) in the elastase AAA model compared with control. Elastin degradation, MAC2, and cytokine production (MCP1, tumor necrosis factor-α, and interleukin-23) were significantly attenuated, whereas α-actin staining was increased in KLF4 knockout mice versus controls. Results were verified in global KLF4 and SM-specific knockout mice using an angiotensin II model of aneurysm formation. KLF4 inhibition with siRNA attenuated downregulation of SM gene expression in vitro, whereas in vivo studies demonstrated that KLF4 binds to promoters of SM genes by chromatin immunoprecipitation analysis. Finally, human aortic aneurysms demonstrated significantly higher KLF4 expression that was localized to SM cells.

Conclusions—
KLF4 plays a critical role in aortic aneurysm formation via effects on SM cells. These results suggest that KLF4 regulates SM cell phenotypic switching and could be a potential therapeutic target for AAA disease.
Correlates of Saphenous Vein Graft Hyperplasia and Occlusion 1 Year After Coronary Artery Bypass Grafting
Authors: Une Dai , Kulik Alexander , Voisine Pierre , Le May Michel , Ruel Marc 
Published: September 2013

Background—
Intimal hyperplasia of saphenous vein grafts (SVGs) can lead to subsequent graft atherosclerosis and occlusion after coronary artery bypass grafting (CABG). This study examined whether patient characteristics, anatomic factors, and medications are associated with SVG intimal hyperplasia and occlusion after CABG.

Methods and Results—

We performed a post hoc analysis of the Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) trial, where 322 grafts were assessed by angiography and 90 grafts were examined by intravascular ultrasound at 1 year after CABG. We assessed the following correlates for intimal hyperplasia and occlusion: patient characteristics, discharge medications, target vessel characteristics, and SVG diameter. At 1 year, the SVG mean intimal area was 4.3±2.1 mm
2
, and the occlusion rate was 6.2% (13/209). Independent correlates of hyperplasia were larger SVG diameter (1.9±0.2 mm
2
/mm;
P
<0.001), hypertension (0.7±0.3 mm
2
;
P
=0.03), and grafting to the right coronary territory (0.6±0.3 mm
2
;
P
=0.03), whereas statin (−0.8±0.3 mm
2
;
P
=0.01) and β-blocker use (−1.0±0.4 mm
2
;
P
=0.03) were associated with less hyperplasia. Low target vessel quality was an independent correlate of SVG occlusion (odds ratio, 5.2±3.1;
P
<0.01).

Conclusions—
Hypertension, SVG diameter, grafting to the right coronary artery, and low quality of the target vessel correlate with the development of SVG hyperplasia or occlusion by 1 year after CABG, whereas β-blockers and statins are associated with less SVG disease. These new findings further our understanding of SVG remodeling after bypass surgery and may guide future research to help prevent post-CABG SVG disease.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00228423
Load Dependency of Right Ventricular Performance Is a Major Factor to be Considered in Decision Making Before Ventricular Assist Device Implantation
Authors: Dandel Michael , Potapov Evgenij , Krabatsch Thomas , Stepanenko Alexander , Löw Alexandra , Vierecke Juliane , Knosalla Christoph , Hetzer Roland 
Published: September 2013

Background—
Left ventricular assist devices (LVADs) provide better outcome than biventricular devices, but it is a challenge to predict the impact of LV mechanical unloading on postoperative right ventricular (RV) function preoperatively. We assessed the load dependency in RV performance before and after LVAD implantation aiming to improve preoperative decision making.

Methods and Results—

Laboratory, echocardiography, and right heart catheterization data collected from 205 patients before LVAD implantation were tested for relationship with postoperative RV function. Comparing patients with different time-course of RV function after LVAD implantation, we found significant differences (
P
<0.01) in preoperative RV end-diastolic short-/long-axis and long-axis/length-area ratios, tricuspid annulus peak systolic velocity, RV peak longitudinal global systolic strain rate, systolic pressure gradient between RV and right atrium (Δ
P
RV−RA
), tricuspid regurgitation velocity-time integral, and pulmonary arterial pressure between patients with and without postoperative RV failure. High predictive values for postoperative RV failure were found for end-diastolic short-/long-axis ratio ≥0.6, tricuspid annulus peak systolic velocity <8 cm/s, and peak systolic longitudinal strain rate <0.6/s in patients with maximum Δ
P
RV−RA
<35 mm Hg. These parameters also seemed predictive for RV failure in patients with tricuspid regurgitation grade >2 and pulmonary arterial pressure <50 mm Hg. End-diastolic short-/long-axis ratio <0.6, tricuspid annulus peak systolic velocity ≥8 cm/s, and peak systolic longitudinal strain rate ≥0.6 in patients with maximum Δ
P
RV−RA
≥35 mm Hg showed high predictive values for postoperative freedom from RV failure. The RV load adaptation index seemed particularly predictive for RV function after LVAD implantation.

Conclusions—
RV geometry and velocity of contraction before LVAD implantation become more predictive for postoperative RV function and can improve decision making before VAD implantation if preoperative RV pressure load and tricuspid regurgitation are also considered.
Full Prescription Coverage Versus Usual Prescription Coverage After Coronary Artery Bypass Graft Surgery
Authors: Kulik Alexander , Desai Nihar R. , Shrank William H. , Antman Elliott M. , Glynn Robert J. , Levin Raisa , Reisman Lonny , Brennan Troyen , Choudhry Niteesh K. 
Published: September 2013

Background—
Eliminating out-of-pocket costs for patients after myocardial infarction (MI) improves adherence to preventive therapies and reduces clinical events. Because adherence to medical therapy is low among patients treated with coronary artery bypass graft surgery (CABG), we evaluated the impact of providing full prescription coverage to this patient subgroup.

Methods and Results—

The MI Free Rx Event and Economic Evaluation (FREEE) trial randomly assigned 5855 patients with MI to full prescription coverage or usual formulary coverage for all statins, β-blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers. We assessed the impact of full prescription coverage on adherence, clinical outcomes, and healthcare costs using adjusted models among the 1052 patients who underwent CABG at the index hospitalization and 4803 who did not. CABG patients were older and had more comorbid illness (
P
<0.01). After MI, CABG patients were significantly more likely to receive β-blockers and statins but were less likely to receive angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy (
P
<0.01). Receiving full drug coverage increased rates of adherence to all preventative medications after CABG (all
P
<0.05). Full coverage was also associated with nonsignificant reductions in the rate of major vascular events or revascularization for patients treated with CABG (hazard ratio, 0.91; 95% confidence interval, 0.66–1.25) or without CABG (hazard ratio, 0.93; 95% confidence interval, 0.82–1.06), with no interaction noted (
P
int
=NS). After CABG, full prescription coverage significantly reduced patient out-of-pocket spending for drugs (
P
=0.001) without increasing overall health expenditures (
P
=NS).

Conclusions—
Eliminating drug copayments after MI provides consistent benefits to patients treated with or without CABG, leading to increased medication adherence, trends toward improved clinical outcomes, and reduced patient out-of-pocket expenses.
Reproducible Porcine Model of Thoracic Aortic Aneurysm
Authors: Eckhouse Shaina R. , Logdon Christina B. , Oelsen J. Marshall , Patel Risha K. , Rice Allison D. , Stroud Robert E. , Wince W. Benjamin , Mukherjee Rupak , Spinale Francis G. , Ikonomidis John S. , Jones Jeffrey A. 
Published: September 2013

Background—
Thoracic aortic aneurysms (TAAs) develop secondary to abnormal aortic extracellular matrix remodeling, resulting in a weakened and dilated aortic wall that progressed to rupture if left unattended. Currently, no diagnostic/prognostic tests are available for the detection of TAA disease. This is largely driven by the lack of a large animal model, which would permit longitudinal/mechanistic studies. Accordingly, the objective of the present study was to establish a reproducible porcine model of aortic dilatation, which recapitulates the structural and biochemical changes observed during human TAA development.

Methods and Results—

Descending TAAs were induced in Yorkshire pigs (20–25 kg; n=7) through intra-adventitial injections of collagenase (5 mL, 0.35 mg/mL) and periadventitial application of crystalline CaCl
2
(0.5 g). Three weeks after TAA induction, aortas were harvested and tissue was collected for biochemical and histological measurements. A subset of animals underwent MRI preoperatively and at terminal surgery. Results were compared with sham-operated controls (n=6). Three weeks after TAA induction, aortic luminal area increased by 38±13% (
P
=0.018 versus control). Aortic structural changes included elastic lamellar degradation and decreased collagen content. The protein abundance of matrix metalloproteinases 3, 8, 9, and 12 increased in TAA tissue homogenates, whereas tissue inhibitors of metalloproteinases 1 and 4 decreased.

Conclusions—
These data demonstrate aortic dilatation, aortic medial degeneration, and alterations in matrix metalloproteinase/tissue inhibitors of metalloproteinase abundance, consistent with TAA formation. This study establishes for the first time a large animal model of TAA that recapitulates the hallmarks of human disease and provides a reproducible test bed for examining diagnostic, prognostic, and therapeutic strategies.
Normalization of Postinfarct Biomechanics Using a Novel Tissue-Engineered Angiogenic Construct
Authors: Atluri Pavan , Trubelja Alen , Fairman Alexander S. , Hsiao Philip , MacArthur John W. , Cohen Jeffrey E. , Shudo Yasuhiro , Frederick John R. , Woo Y. Joseph 
Published: September 2013

Background—
Cell-mediated angiogenic therapy for ischemic heart disease has had disappointing results. The lack of clinical translatability may be secondary to cell death and systemic dispersion with cell injection. We propose a novel tissue-engineered therapy, whereby extracellular matrix scaffold seeded with endothelial progenitor cells (EPCs) can overcome these limitations using an environment in which the cells can thrive, enabling an insult-free myocardial cell delivery to normalize myocardial biomechanics.

Methods and Results—

EPCs were isolated from the long bones of Wistar rat bone marrow. The cells were cultured for 7 days in media or seeded at a density of 5×10
6
cells/cm
2
on a collagen/vitronectin matrix. Seeded EPCs underwent ex vivo modification with stromal cell–derived factor-1α (100 ng/mL) to potentiate angiogenic properties and enhance paracrine qualities before construct formation. Scanning electron microscopy and confocal imaging confirmed EPC–matrix adhesion. In vitro vasculogenic potential was assessed by quantifying EPC cell migration and vascular differentiation. There was a marked increase in vasculogenesis in vitro as measured by angiogenesis assay (8 versus 0 vessels/hpf;
P
=0.004). The construct was then implanted onto ischemic myocardium in a rat model of acute myocardial infarction. Confocal microscopy demonstrated a significant migration of EPCs from the construct to the myocardium, suggesting a direct angiogenic effect. Myocardial biomechanical properties were uniaxially quantified by elastic modulus at 5% to 20% strain. Myocardial elasticity normalized after implant of our tissue-engineered construct (239 kPa versus normal=193,
P
=0.1; versus infarct=304 kPa,
P
=0.01).

Conclusions—
We demonstrate restoration and normalization of post–myocardial infarction ventricular biomechanics after therapy with an angiogenic tissue-engineered EPC construct.
Impairment of Heart Rate Recovery After Peak Exercise Predicts Poor Outcome After Pediatric Heart Transplantation
Authors: Giardini Alessandro , Fenton Matthew , Derrick Graham , Burch Michael 
Published: September 2013

Background—
A blunted heart rate recovery (HRR) from peak exercise is associated with adverse outcome in adults with ischemic heart disease. We assessed HRR after pediatric heart transplantation (HTx) and its prognostic use.

Methods and Results—

Between 2004 and 2010 we performed 360 maximal exercise tests (median, 2 tests/patient; range, 1–7) in 128 children (66 men; age at test, 14±3 years) who received HTx (age, 8.5±5.1 years) because of cardiomyopathy (66%) or congenital heart defects (34%). The change in heart rate from peak exercise to 1 minute of recovery was measured as HRR and was expressed as
Z
score calculated from reference data obtained in 160 healthy children. HRR was impaired soon after HTx (average in first 2 years
Z
=−1.9±3.5) but improved afterward (
Z
=+0.52/y), such that HRR
Z
score normalized in most patients by 6 years after HTx (average, 0.6±1.8). A subsequent decline in HRR
Z
score was noted from 6 years after HTx (rate of
Z
=−0.11/y). After 27±15 months from the most recent exercise test, 19 patients died or were re-heart transplantation. For the follow-up after 6 years, HRR
Z
score was the only predictor of death/re-heart transplantation (
P
=0.003). Patients in the lowest quartile of HRR
Z
score had a much higher 5-year event rate (event-free rate, 29% versus 84%; hazard ratio, 7.0;
P
=0.0013).

Conclusions—

HRR is blunted soon after HTx but normalizes at ≈6 years, potentially as a result of parasympathetic reinnervation of the graft, but then declines. This late decline in HRR
Z
score is associated with worse outcome.