bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1841: Stromal Cell Derived Factor-1 Increases Capillary Density But Does Not Contribute To Cardiomyocyte Replacement After Experimental Myocardial Infarction
Authors: Loffredo Francesco , Segers Vincent F , MacGillivray Catherine , Lee Richard T 
Published: July 2021

Background. The mechanisms by which regenerative therapies improve cardiac function are incompletely defined. Numerous laboratories have demonstrated that the stem cell chemoattractant Stromal cell derived factor-1 (SDF-1) improves cardiac function after myocardial infarction (MI). This study used a genetic fate-mapping approach to ask the question: Is the beneficial effect of SDF-1 delivery due to cardiomyocyte regeneration, increased capillary density, or both?
Methods. We used a genetic fate-mapping system that allows “pulse-chase” studies of cardiomyocyte turnover in mice. We crossed an inducible cardiomyocyte-specific Mer-Cre-Mer transgenic mouse with Z/EG reporter mice. Using a high-efficiency 4-OH-tamoxifen protocol, we then induced Cre recombination and expression of GFP in cardiomyocytes only. SDF-1(S4V), a protease-resistant form of SDF-1, was delivered with nanofibers after coronary ligation.
Results. The percentage of pulse-labeled GFP+ cardiomyocytes was 81±4% (n=6) in sham-operated mice, as anticipated with this system. GFP+ cardiomyocytes were 60±5% and 69±4% (n=11) respectively at MI border and MI remote areas of the control nanofiber group, consistent with our previous study and suggesting a significant stem/precursor cell contribution to cardiomyocyte replacement after injury (P<0.0001). GFP+ cardiomyocytes were 65±9% and 76±6% (n=10) respectively at MI border and MI remote areas of the SDF-1(S4V)-RAD group (p=ns vs nanofiber control group), indicating no significantly increase in cardiomyocyte refreshment attributable to SDF-1. However, capillary density increased from 204.7 ± 10.1/mm2 in the nanofiber control group to 308.9 ± 21.9/mm2 in SDF-1(S4V)-RAD + nanofiber group (p =0.0003).
Conclusion. Using genetic “pulse-chase” fate mapping, these data indicate that the stem cell chemoattractant SDF-1 does not induce measurable adult mammalian cardiomyocyte replacement by stem/precursor cells following injury. However, SDF-1 significantly increases myocardial capillary density, suggesting that increased angiogenesis but not cardiogenesis is responsible for the beneficial effects of SDF-1 on cardiac function.
Abstract 3734: Differential Platelet Proteome Analysis Following Specific Activation Of Glycoprotein VI
Authors: Schulz Christian , Leuschen Nina V , Fröhlich Thomas , Lorenz Michael , Arnold Georg J , Massberg Steffen 
Published: July 2021

Background: Platelets play a key role in haemostasis and in the pathophysiology of various diseases including arterial thrombosis. Glycoprotein (GP)VI, the major platelet collagen receptor, mediates platelet activation and firm adhesion to collagen structures exposed at sites of vascular injury. Here, we determined the effects of specific activation of GPVI on the human platelet proteome by two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry.
Methods and Results: Platelets from healthy human donors were isolated and purified. Platelets were stimulated with an activating monoclonal antibody specific for GPVI, or control IgG. Platelet proteins were subjected to 2D-DIGE with extensive software-assisted image analysis. Subsequent identification of the differentially abundant proteins was carried out by MALDI TOF/TOF MS and LC ESI-MS/MS. We identified 8 differentially regulated proteins associated with cell signaling, metabolism, organization and rearrangement of the cytoskeleton, and membrane trafficking. Differentially abundant proteins included pleckstrin, beta-centractin, src substrate cortactin, charged multivesicular body protein 3, aldose reductase and protein disulfide isomerase-associated 3 precursor.
Conclusion: Specific platelet activation via GPVI results in the differential regulation of several proteins. The results provide further insight into the mechanisms that underlie platelet activation through the GPVI receptor, which may help to identify novel pharmacological targets.
Abstract 5270: Crystal Structure of Nkx2.5 Homeodomain in Complex with Anf-242 Motif
Authors: Nam Hyun-Joo , Genis Caroli , Scone Peyton , Kasahara Hideko 
Published: July 2021

NKX2.5 is a homeodomain (HD) containing transcription factor preferentially expressed in cardiomyocytes. Mutations in the NKX2.5 gene have been identified in patients with congenital heart disease, suggesting its critical roles in cardiac development and maturation. NKX2.5 is reported to regulate transcription of atrial natriuretic factor (ANF), potentially through direct binding to -242 bp proximal promoter region (ANF-242). ANF-242 contains two palidromic NKX2.5 binding sites, and occupation of both sites by NKX2.5 has been reported. In addition, physical interaction between NKX2.5 proteins has been suggested to facilitate DNA binding through domains outside of the HD. However, detailed crystal structure of NKX2.5 protein is currently not available. The HD of human NKX2.5 (aa 138–197; C193S) with the oxidizable Cys193 substituted with Ser was co-crystallized with 19bp double stranded DNA including ANF-242 region. This mutant was reported to have the same DNA binding characteristics as the wild type. The crystal structure was determined at 1.8 Å resolution with final R-working and R-free values of 0.234 and 0.278, respectively. Consistent with previous studies, two molecules of NKX2.5 HD are bound to ANF-242 region without physical interaction between the two proteins. Column purification demonstrated that NKX2.5 behaves as dimers in solution in a concentration dependent manner. These results suggest that dimeric NKX2.5 HD in solution may change conformation upon DNA binding. Among various NK class proteins, the three-dimensional structure has only been determined in the HD of Drosophila vnd/NK2 (ventral nervous system defective proteins) using NMR. When the two HDs are compared, NKX2.5 HD shows extended DNA contacts to a total of 8 base pairs. Most of the residues of HD implicated in pathology of mutants are involved in DNA binding and structural stabilization. The structure of NKX2.5 HD with ANF-242 shows that the HD occupies two binding sites of ANF-242 without physical interaction between themselves. This high resolution crystal structure of NKX2.5 protein provides a detailed picture of protein and DNA interactions, which allows us to predict DNA binding of mutants identified in human patients.
This research has received full or partial funding support from the American Heart Association, AHA Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).
Abstract 5440: Klf2 Inhibits Hif-1α Expression and Function in the Endothelium
Authors: Kawanami Daiji , Lin Zhiyong , Mahabaleshwar Ganapati , Atkins G. B , Hamik Anne , Haldar Saptarsi , Maemura Koji , Lingrel Jerry , Jain Mukesh 
Published: July 2021

Introduction: Hypoxia-inducible factor 1 (HIF-1) is a central regulator of the hypoxic response in many cell types. In endothelial cells, HIF-1 induces the expression of key pro-angiogenic factors such as vascular endothelial growth factor (VEGF) to induce new blood vessel formation. Recent studies have identified Kruppel-like Factor 2 (KLF2) as a potent inhibitor of angiogenesis. However, the role of KLF2 in regulating the expression and function of HIF-1 has not been evaluated.
Hypothesis: KLF2 inhibits HIF-1α expression and function.
Methods and Results: Adenoviral overexpression of KLF2 in human umbilical vein endothelial cells (HUVECs) inhibited hypoxia-induced expression of HIF-1α, VEGF secretion, and matrigel tube formation. Conversely, siRNA-mediated knockdown of KLF2 in HUVECs increased HIF-1α expression and VEGF secretion. Consistent with this observation, KLF2−/− mouse embryonic fibroblasts (MEFs) showed accelerated HIF-1α accumulation in response to hypoxia and a marked induction of VEGF secretion (90.4±7.4 pg/ml in KLF2+/+ versus 234.6±6.1 pg/ml in KLF2−/−, p<0.01). From a mechanistic standpoint, KLF2-mediated reduction of HIF-1α level was attenuated by three distinct proteasome inhibitors (MG132, ALLN, or lactacystin), demonstrating that KLF2 mediated reduction of HIF-1α protein was proteasome-dependent. In addition, KLF2 maintained its ability to inhibit HIF-1α protein levels in VHL−/− cells, thermo-sensitive E1 deficient cells, and p53−/− cells. Finally, co-immunoprecipitation experiments revealed that KLF2 overexpression disrupted the interaction between HIF-1α and its chaperone Hsp90, suggesting that KLF2 promotes degradation of HIF-1α by affecting its folding and maturation.
Conclusions: These observations identify KLF2 as a novel inhibitor of HIF-1α expression and function through a VHL/p53 independent but proteasome dependent pathway. As such, KLF2 may be a target for modulating the angiogenic response in disease states.
Abstract 5441: The Roles for MicroRNA-221 and IGF-1 Signaling in Regulation of High Glucose-Induced Endothelial Dysfunction and Apoptosis
Authors: Li Yangxin , Song Yao-Hua , Li Fan , McNamara Kate , Geng Yong-Jian 
Published: July 2021

Persistent hyperglycemia represents a major metabolic complication of diabetes, which may cause endothelial cell dysfunction and apoptosis. microRNAs are novel biomarkers, modulators and therapeutic targets for disease. The microRNA miR-221 is expressed in human umbilical vein endothelial cells (HUVEC). Insulin-like growth factor 1 (IGF-1) is an important survival factor for multiple cell types. This study was to investigate whether high glucose (HG) induces endothelial dysfunction and apoptosis through altering the microRNA expression and IGF-1 signaling. The mirVana qRT-PCR miRNA detection assay showed that exposure to glucose for 24 h dose-dependently (up to 25 mM) increased miR-221 expression by 2.6 ± 0.5 folds (p<0.05). HG treatment decreased c-kit protein expression (58 ± 7 % decrease vs. control at 48 h) assessed by flow cytometry. The treated HUVEC had a reduced capacity for wound healing responded to stem cell factor (SCF, the ligand of c-kit). SCF-induced HUVEC migration potential was also reduced significantly by exposure to high dose of glucose. As estimated by prediction algorithms, c-kit, but not IGF-1, was identified as the target of miR-221. Transfection of HUVEC with 2′-O-methyl antisense inhibitory oligonucleotide (AMO-221) downregulation of miR-221 led to attenuation of the glucose’s effect on the c-kit expression, SCF-induced migration and wound healing in HUVEC. Prolonged glucose exposure (25 mM, 96 h) induced apoptosis of HUVEC assessed by Death ELISA (O.D. values = 0.49 ± 0.06 in glucose group vs. 0.12 ± 0.07 in control, p<0.01). Addition of IGF-1 (30 ng/ml) blocked the glucose-induced apoptosis, whereas AMO-221 did not attenuate the apoptosis. In addition, the anti-apoptotic effects of IGF-1 was attenuated by PI3 kinase inhibitor LY294002 (15 uM) (IGF-1 + glucose + PI3 kinase inhibitor vs. IGF-1 + glucose = 0.45 ± 0.07 vs. 0.15 ± 0.05 O.D. values). Our data demonstrate that downregulation of miR-221 attenuates HG-induced reduction of c-kit, wound healing and migration of HUVEC, and enhanced IGF-1 signaling prevents HG-induced apoptosis. Thus, reducing miR-221 expression and activating IGF-1 signaling pathway may be a useful strategy to prevent diabetic-induced endothelial dysfunction and apoptosis.
This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).
Abstract 5517: A Novel Tissue Engineered Skeletal Muscle Screening Platform to Assess the Myotoxic Potential of Statins
Authors: Tiburcy Malte , Christalla Peter , Eschenhagen Thomas , Zimmermann Wolfram H 
Published: July 2021

Our study had two objectives:

to develop a novel tissue engineered skeletal muscle drug screening platform and

to assess myotoxicity of various statins and identify underlying mechanisms.

Methods: Engineered skeletal muscle tissue (SMT) was generated from adult rat skeletal myoblasts, rat fibroblasts (1.25x106 cells/SMT), matrigel, and collagen. Reconstitution-mixtures (450 μl) were poured into circular moulds yielding ring-shaped constructs after 5 days. SMTs were cultured for additional 10 days on stretch devices and treated with increasing concentrations of statins or vehicle for the last 5 culture days. Force of contraction (FOC) was measured and SMTs subjected to either immune fluorescence (IF), HE-staining or Western blotting (WB).
Results: SMTs displayed differentiated muscle bundles (actin-IF and HE) and elicited tetanic contractions with maximal force at 60 Hz (1.3±0.2 mN; n=5). Carbachol (1 μM) induced a reversible block of muscle contraction which was antagonized by pancuronium (10 μM) indicating the presence and functionality of nicotinergic acetylcholine receptors. Statin treatment caused a concentration-dependent decrease in FOC in the following order of potency (EC50): cerivastatin (10 nM), simvastatin (100 nM), atorvastatin (350 nM), pravastatin (1860 nM; n=6–8/group and concentration). Contractile failure was paralleled by sarcomere breakdown and apoptosis (IF and WB: reduced actin, increased caspase 3). To assess the mechanism of statin myotoxicity, we investigated the protective effects of mevalonic acid (MEV, 100 μM), farnesyl-pyrophosphate (F-PP, 10 μM), squalene (S, 10 μM), and geranyl-geranyl-pyrophophate (G-PP, 10 μM) in the presence of maximally toxic cerivastatin concentrations (1 μM; complete contractile failure). MEV prevented cerivastatin toxicity completely (FOC: 102.3±16% of vehicle; n=7). GG-PP partially prevented cerivastatin-induced contractile failure (FOC: 53.3±14% of vehicle; n=4). S and F-PP had no protective effect (n=4/group).
Conclusion: SMT can be used to identify and compare statin myotoxicity in vitro and may be useful to dissect its underlying mechanisms. In addition, our data suggests that statin myotoxicity is at least in part independent of cholesterol depletion.
Abstract 2095: Health Policy: Can an Open Access Model for Intravenous Diuretics in an Outpatient Heart Failure Disease Management Program Reduce Hospital Costs?
Authors: Steen Dylan L , Reed Valerie , Roxas Gwendolyn , Fonseca Maria , Lopez Barbara , Hebert Kathy 
Published: July 2021

Background: Heart failure (HF) is the most frequent discharge diagnosis for patients older than 65 and one of the most expensive diseases to treat for CMS. Patients with early symptoms of decompensated HF may need access to IV diuretics when oral medications used in a sliding scale dosage are no longer effective. Indigent patients without access to a private physician are at particular risk of having to use the emergency room (ER) for this reason. This model results in more costs and potential admissions. We sought to reduce ER use and improve quality of care and service to indigent patients followed in a Heart Failure Disease Management Program (HFDMP).
Methods: Grant funding was procured to provide free furosemide IVP, potassium and metolazone for patients enrolled in a HFDMP at Jackson Memorial Hospital. The HFDM program consist of intense patient education using DVD’s in both English and Spanish, written material, log books for weight, activity, blood pressure and diuretic use. Patients are instructed to weight daily and add an additional oral dose of furosemide at home for weight gain of greater than 2 pounds. For weight gain of greater than 5 pounds unresponsive to oral therapy, patients were given access to the clinic without an appointment for “walk-in” IVP furosemide, potassium and metolazone.
Results: 173 new patients were enrolled into program in 3 months (10/07 through 12/31/07). Of these, 115 visits for IVP furosemide were recorded from 54 patients. 16 patients used it multiple times (range 2–11). Average ER cost for all CHF patient seen and discharged after diuresis at JMH is $25,692. Therefore, an estimated cost savings of 115 avoidable ER visits is $2,954,586. In the last three quarters of 2007, of all CHF patients seen in the ER, 96.6% are admitted. The average inpatient cost for a primary diagnosis of CHF was $26,404.05 (LOS 5.25 days). The average for a CHF patient seen and discharged from the ER was $5,295 (LOS <48hrs). All monetary values are Billed Charges.
Conclusion: An open access IVP furosemide program is cost effective alternative to ER and inpatient treatment for CHF patients requiring diuresis.
Abstract 2140: Infrequent Need for Pacing Following Implantable Cardioverter-Defibrillator Shocks: Analysis of the Sudden Cardiac Death in Heart Failure Trial
Authors: Prutkin Jordan M , Poole Jeanne E , Johnson George , Anderson Jill , Mark Daniel B , Lee Kerry L , Bardy Gust H 
Published: July 2021

Background: Implantable cardioverter-defibrillators (ICD) are routinely programmed to pace after a shock to prevent possible asystole. In those with no prior history of bradycardia, there is little data regarding the prevalence and characteristics of those who use post-shock pacing (PSP).
Methods: We analyzed the occurrence of pacing within the first nine beats after the first successful ICD shock for ventricular tachycardia (VT) or ventricular fibrillation (VF) in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). All ICDs were single lead with the first PSP delivered at 1400msec and all subsequent stimuli delivered at 1200msec. We excluded patients with pacing during pre-shock rhythms and those who had pacing rates different than the protocol default rate of 50bpm (1200 msec).
Results: There were 2521 patients enrolled in SCD-HeFT, of which 811 received an ICD. A total of 153 shock events were examined; 36 (23.5%) had at least one of the first nine beats paced post-shock, though only 4 (2.5%) had greater than 4 out of the 9 beats paced. No subjects needed pacing for all nine beats and only 8 (5.2%) paced for greater than 5 seconds. There were no differences in age, gender, etiology of cardiomyopathy, or NYHA class between those with PSP or not. The prevailing heart rate pre-shock was predictive of PSP; the mean cycle length of the baseline rhythm pre-shock was longer (slower rate) for those who used PSP (735 ± 228msec vs. 624 ± 158msec, P=0.001). More often, VF (vs. VT) was the rhythm shocked in those using PSP (P=0.015). A trend also was seen toward increased frequency of PSP in those receiving 30J shocks (16 of 49) versus ≤20J shocks (20 of 104, P=0.068).
Conclusion: Patients infrequently require multiple paced beats post-shock for VT or VF. Patients using PSP have a slower baseline heart rate and are more likely to have VF as the shocked rhythm. While 1 or 2 paced beats out of the first nine occurred occasionally, these patients also had rapid return of their native rhythm for which the hemodynamic contribution of 1 or 2 paced beats is unclear. These data suggest that for most patients receiving a primary prevention ICD programmed for shock-only therapy, the need for PSP is limited. PSP use may reflect convention and the assumption that minor post-shock pauses are detrimental.
Abstract 2141: Lead Extraction in Pediatric and Congenital Heart Disease Patients
Authors: Atallah Joseph , Berul Charles I , Alexander Mark E , Triedman John K , Walsh Edward P , Cecchin Frank 
Published: July 2021

Background: Transvenous pacemaker and defibrillator device implant is a rapidly growing practice in pediatric and young adult congenital heart disease. The need for lead extraction is an associated eventuality in certain patients. Although several techniques have emerged in the past few years, the safety and efficacy of lead extraction in the pediatric population remains unknown. We report our experience with lead extraction using simple traction or complex extraction methods.
Methods: Retrospective cohort study of all patients having undergone a lead extraction at Children’s Hospital Boston from 2002 to 2008. Lead extraction was defined as simple if only traction was required and complex if it required the use of an interlocking stylet.
Results: A total of 114 patients underwent 124 lead extraction procedures with a total of 172 extraction attempts. The average age was 17.1 (2.47– 48.23) years at lead implant and 23.0 (6 –52.7) years at lead extraction. Congenital heart disease was present in 57.3% (71/124) of patients. Extraction by simple traction was achieved for 51 leads (mean lead age=3.1 years), while the remaining 121 leads required complex extraction (mean lead age=7.5 years), of which 32 were abandoned. Of the remaining leads 83/89 (93%) were extracted successfully. Only 2/55 (4%) leads >7.5 years of age could be extracted with simple traction. However, 63/99 (64%) leads >1 and <7.5 years of age were a complex extraction. Multivariable logistic regression analysis showed that a younger lead age (OR=0.7, 95% CI 0.6 – 0.9, P<0.01), silicone-type of lead insulation (OR=7.6, 95% CI 1.6 –36.7, P=0.01) and a lead in the atrial position (OR=3.0, 95% CI 1.1– 8.7, P=0.05) were independent predictors of a simple extraction. There was only one major complication consisting of right atrial perforation and tamponade that was controlled with surgical exploration. There was no mortality related to lead extraction procedures.
Conclusion: The majority of leads implanted in pediatric and young adult patients with congenital heart disease can be extracted successfully. Though certain lead characteristics correlated with a simple extraction procedure, the majority of leads >1 year of age will require a complex extraction technique.
Abstract 2161: Left Atrium Reverse Remodeling After Pulmonary Vein Isolation. Will It Be a Predictor for Non-recurrence of Atrial Fibrillation?
Authors: Ishikawa kiyotake , Yoshida Yukihiko , Morita Sumio , Furusawa Kenji , Kanemura Noriyoshi , Yoshida Luke , Hashimoto Tousei , Yamamoto Takashi , Aoyama Yutaka , Takigawa Masateru , Inoue Natsuo , Tatematsu Yasushi , Nanasato Mamoru , Hirayama Haruo 
Published: July 2021

Background: Left atrium (LA) dilation plays an important role in development and persistence of atrial fibrillation (AF). Some cases show structural reverse remodeling of LA after catheter ablation of AF. The aim of this study was to assess the clinical significance of LA reverse remodeling.
Method and Results: Echocardiographic data before and after ablation was obtained in 173 cases who underwent pulmonary vein isolation from January 2006 to April 2008 (74.0% men, 61.0±11 years old; paroxysmal AF 114, persistent AF 34, permanent AF 25). Mean atrial diameter before ablation was 39.0±6.1mm (paroxysmal 37.7±5.6mm, persistent 40.7±5.3mm, and permanent 43.0±6.8mm) and LA reverse remodeling was defined as 10% decrement of LA transverse diameter. Half of the cases were taking anti-arrhythmic drugs after ablation, and AF recurrence occurred in 16.8% (29/173) during mean follow up period of 8.5±6.3 months. Reverse remodeling of LA was seen in 34.1% (59/173) and AF recurrence rate in this group was 11.9% (7/59), whereas 19.3% (22/114) without reverse remodeling (P=0.29). However, limited in patients with LA diameter over 40mm (44.5%; 77/173), 3.2% (1/31) of AF recurrence was seen in those with reverse remodeling, while 21.7% (10/46) without reverse remodeling (P=0.04). LA reverse remodeling was observed significantly frequent in patients without history of hypertension(41.5% without hypertension vs 25.6% with hypertension, P=0.036).
Conclusion: LA reverse remodeling after catheter ablation of AF in dilated LA patient is a simple and useful predictor for non-recurrence of AF. Hypertension could be a disturbance for LA reverse remodeling.