bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5445: Tissue Kallikrein Deficiency Impairs Circulating Proangiogenic Cells Invasive Capacity
Authors: Spinetti Gaia , Fortunato Orazio , Cordella Daniela , Alhenc-Gelas Francois , Ritcher Christine , Vincent Marie-Pascale , Tonolo Giancarlo , Cherchi Sara , Emanueli Costanza , Madeddu Paolo R 
Published: April 2024

Background: Circulating proangiogenic cells (PACs) express the serine protease tissue kallikrein (K1), which favours invasion through metalloproteinases activation.
Aim: To determine whether inherited or disease-induced K1 deficiency alters PACs migration and proangiogenic capacity, and whether K1-deficient PACs transduction with wild type or polymorphic variant (R53H) K1 can rescue functional defects.

Methods & Results: Wild type (WT, n=8) or K1-knockout mice (K1KO, n=7) lineage negative (Lin-) bone marrow mononuclear cells (BMMNC) were used in migration assays or differentiated into PACs. K1KO Lin-BMMNC showed defective migration to SDF-1
α
compared to WT (fold increase vs vehicle 2.2, p=N.S and 5.8, p<0.05 vs vehicle and K1KO, respectively, n=3). Similarly impaired was K1KO PACs migration (n=3, p<0.05 vs WT). Further, K1KO PACs were unable to promote endothelial cell (EC) networking in vitro (p<0.05). Adenovirus-mediated K1 transduction rescued both defects in K1KO PACs (n=3, p<0.05 vs Ad.Null). Next, we studied type 2 diabetic patients and age-matched healthy controls circulating PACs (n<6 per group). Diabetic PACs showed reduced migration and proangiogenic potential (−1.8 and 2.0 fold vs controls, p<0.05) and lower K1 protein (−56.6 %, p<0.05), but normal K1 mRNA abundance, pointing at a post-transcriptional defect. K1 overexpression increased healthy PACs migration and EC networking (p<0.01 vs Ad.Null), but could not revert diabetic PACs liabilities (p±N.S. vs Ad.Null). We then verified if K1 increases PACs invasive capacity. K1-PACs invaded matrix more efficiently (2.5-fold increase, p<0.01 vs Null-PACs). In contrast, the polymorphic variant R53H, which encodes for an enzymatic defective K1 form, did not improve invasion. Moreover, K1-PACs failed to invade the matrix when regular collagen was substituted with glycated one.

Conclusions: Inherited or diabetes-induced K1 deficit hampers PACs invasive and proangiogenic capacities, with K1 gene therapy being able to restore those functions except in diabetes. Diabetes could interfere with K1 enzymatic activity and make extracellular matrix impenetrable to PACs. Alternatively, additional migratory machinery deficit may overwhelm benefits of K1 overexpression.
Abstract 5492: Risk of Major Adverse Cardiovascular Events in Patients on Clopidogrel and Proton Pump Inhibitors: A Meta-analysis
Authors: Singh Mukesh , Singh Sarabjeet , Molnar Janos , Arora Rohit 
Published: April 2024

Background: The anti-platelet properties of clopidogrel are thought to be activated by cytochrome P450 2C19. This isoenzyme is potently inhibited by the most commonly prescribed proton pump inhibitors (PPIs) and therefore may interfere with clopidogrel activation and its anti-platelet effects. However, recently published studies have yielded mixed results, leaving the question unanswered. Hence a meta-analysis was performed to evaluate the potential impact of PPIs on the effectiveness of clopidogrel to prevent major adverse cardiovascular events (MACE).
Methods: A systematic review of literature revealed 5 studies involving 29749 patients. End points analyzed were major adverse cardiovascular events (acute myocardial infarction, repeat revascularization, death due to cardiac causes. Combined relative risks (RR) across all the studies and the 95% confidence intervals were computed using the Mantel-Haenszel fixed-effect model. A two-sided alpha error < 0.05 was considered to be statistically significant.
Results: There were no significant differences in patient demographics between both groups. Compared with patients on clopidogrel without PPI, the risk of MACE was significantly higher in patients taking clopidogrel with PPI (RR: 1.65, CI: 1.55 – 1.76; p=0.000).
Conclusions: The present meta-analysis suggests that combinig PPI with clopidogrel increases risk of MACE and it may be a class effect.
Abstract 5575: Ca2+/Redox-Sensitive Tyrosine Kinase PYK2 Promotes Atherogenesis Through OxLDL/ROS/p21-Dependent Premature Senescence in Endothelium
Authors: Katsume Asako , Okigaki Mitsuhiko , Matsui Akihiro , ji shen Che , Yamaguchi Shinihiro , Kishita Eigo , Yamada Hiroyuki , Matsubara Hiroaki 
Published: April 2024

Background: Calcium/redox-sensitive tyrosine kinase PYK2 plays crucial roles in cell migration. Analysis of PYK2-deficient macrophages has been reported that their directional migration was impaired due to dysfunction of PI3K, small GTPase Rho, and Ca (2+)-mobilization. Since monocyte/macrophage plays crucial role in atherogenesis, we newly generated the PYK2-knock-out mice and investigated the role of PYK2 in atherogenesis.
Methods: PYK2−/− mice (P-KO) were crossbred with ApoE−/− mice (E-KO), and PYK2−/−/ApoE−/− double knockout (D-KO) mice were established. Four-week-old mice were fed with high-fat-diet for 8 weeks, and the thoracic aorta and aortic root were histologically analyzed. Then we studied the mechanisms of their difference in atherogenesis.
Results: At the 8th week, atherosclerotic area of thoracic aorta in D-KO was less than E-KO (~54%, P<0.01, n=15, respectively). Numbers of infiltrating macrophage in D-KO mice was also reduced (~52%, P<0.01, n=15). We also verified that no significant difference in atherosclerotic area between E-KO recipient with D-KO bone marrow and D-KO recipient with E-KO bone marrow (n=6). At the 7th day, in E-KO aorta, we detected the senescence-associated-beta-gal staining area, however in D-KO aorta there is no area stained with SA-beta-gal. The expression of p21 was significantly increased in E-KO aorta at the 7th day, but in D-KO aorta there is no increase in p21 expression. In primary-cultured endothelial cells (ECs), Lysophosphatidylcholine (LPC) induced p21 expression in WT was significantly higher than that in P-KO. And we studied that these results were caused by ROS and JNK dependent pathway. The stained area with SA-beta-gal and the expression of p21 was impaired by intra peritoneal injection with JNK inhibitor (SA600125). The stained area with 8OHDG in E-KO was higher than that in D-KO, and the number of the stained endothelial cells with DCF in WT was much higher than that in P-KO. The expression of VCAM-1 and MCP-1 in E-KO was significantly increased than that in D-KO.
Conclusion: PYK2 promotes atherogenesis by inducing ROS/p21-dependent premature senescence and cytokine induction in endothelium
Abstract 5682: Novel Role of Copper Transporters CTR1 and ATP7A in PDGF-induced Vascular Smooth Muscle Cell Migration and Vascular Remodeling
Authors: Ashino Takashi , Urao Norifumi , Oshikawa Jin , Wang Huan , Huo Yuqing , McKinney Ronal D , Ushio-Fukai Masuko , Fukai Tohru 
Published: April 2024

Platelet-derived growth factor (PDGF) stimulates vascular smooth muscle cell (VSMC) migration primary through the PDGF receptor-beta (PDGFR), which contributes to vascular remodeling in vivo. Previous study shows that copper chelation inhibits neointimal formation in response to injury. However, underlying mechanisms remain unknown. Intracellular copper levels are tightly regulated by the copper importer CTR1 which localizes at plasma membrane (PM) and the copper exporter ATP7A which traffics between trans-Golgi network (TGN) to PM. Here we show that both CTR1 and ATP7A are expressed in cultured VSMC. Co-immunoprecipitation assay shows that ATP7A binds to PDGFR basally and PDGF stimulation rapidly promotes their association within 5 min, which is prevented by knockdown of CTR1 with siRNA (85%). Proteomic analysis in caveolae/lipid raft (C/LR) fraction reveals that ATP7A is localized in C/LR where PDGFR is found. PDGF stimulation promotes recruitment of ATP7A to C/LR fraction, which is inhibited by CTR1 siRNA (95%). Furthermore, inductively coupled plasma mass spectrometry (ICP-MS) shows that C/LR contains high amount of copper (139.7 (C/LR) vs. 17.9 (non-C/LR) ppb/mg proteins). In response to wound injury or PDGF stimulation, ATP7A translocates from TGN to PM at the leading edge where it colocalizes with PDGFR and the LR marker cholera toxin subunit B in actively migrating VSMCs, which is prevented by CTR1 siRNA or C/LR disruptor methyl-beta cyclodextrin. Note that this ATP7A translocation is associated with decrease in copper levels in C/LR, suggesting increase in copper efflux in C/LR during active VSMC migration. Functionally, PDGF-induced VSMC migration is significantly inhibited by knockdown of CTR1 or ATP7A with siRNAs (84% and 68%, respectively) as well as treatment with cell permeable copper chelator TTM (50.2%) and cell impermeable copper chelator BCS (39.1%). Moreover, ATP7A expression is dramatically increased in the neointima in a mouse wire injury model. In summary, CTR1-dependent translocation of the copper exporter ATP7A to C/LR and its binding to PDGFR plays an important role in PDGF-induced VSMC migration, which may contributes to vascular remodeling in response to injury and development of atherosclerosis.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).
Abstract 18297: Peri-stent Contrast Staining After Drug-eluting Balloon Angioplasty for Treatment of Coronary In-stent Restenosis
Authors: Otsuji Hideaki , Kadota Kazushige , Goto Tsuyoshi , Kato Harumi , Yamamoto Hiroyuki , Oka Naoki , Fuku Yasushi , Tanaka Hiroyuki , Tada Tsuyoshi , Habara Seiji , Shigemoto Yoshikazu , Hasegawa Daiji , Ootsuru Suguru , Saito Naoki , Hayakawa Yuki , Miyake Kohshi , Yusuke Hyodo , Ozaki Masatomo , Kubo Shunsuke , Ichinohe Tahei , Mitsudo Kazuaki 
Published: April 2024

Background: Peri-stent contrast staining (PSS) induced by sirolimus-eluting stent (SES) implantation has been reported and the PSS rate was about 2%. It is said that PSS is an abnormal vessel reaction and is related to stent thrombosis. However, it remains unknown whether PSS arises after drug-eluting balloon (DEB) angioplasty. We report on PSS which arose after DEB angioplasty in the in-stent restenosis (ISR) lesion in relation to previously deployed stents.
Methods: From September 2008 to October 2011, 378 consecutive patients with 453 lesions (42 de novo and 411 ISR) underwent DEB angioplasty in our hospital. The 411 ISR lesions were classified according to the previously deployed stent: SES, 182; paclitaxel-eluting stent (PES), 61; zotarolimus-eluting stent (ZES), 54; everolimus-eluting stent (EES), 34; biolimus-eluting stent (BES), 16; bare metal stent (BMS), 64. All patients underwent midterm follow-up coronary angiography (f/u CAG) at 6 months after DEB angioplasty, and those without restenosis underwent late f/u CAG at 12 months after midterm f/u.
Results: The PSS rates were as follows: overall 3.3% (15/153); de novo, 0% (0/42); SES, 4.40% (8/182); PES, 6.56% (4/61); ZES, 1.85% (1/54); EES, 0% (0/34); BES, 0% (0/16); BMS, 3.13% (2/64). There were no significant differences between each PSS lesion, between first (SES and PES) and second (ZES, EES, and BES) generation drug-eluting stents, and between de novo lesions and each generation group of drug-eluting stent. Stent thrombosis has not occurred.
Conclusion: PSS can arise after DEB angioplasty for ISR. Compared with the previous report on PSS after SES implantation, PSS occurred more frequently after DEB angioplasty than after SES implantation. With respect to stent thrombosis, long-term follow-up of patients with PSS after DEB angioplasty is necessary.
Abstract 19523: Catheter-Based Renal Denervation for the Treatment of Patients with Drug-Resistant Hypertension: EnligHTN I: Three-Month Data of a First in Man Study Using a Multi-Electrode Radiofrequency Ablation Catheter
Authors: Papademetriou Vasilios , Worthley Stephen G , Tsioufis Costas , Worthley Matthew , Chew Derek , Sinhal Ajay , Meredith Ian , Malaiapan Yuvaraj 
Published: April 2024

Introduction: Renal denervation has emerged as a novel approach for the treatment of patients with drug-resistant hypertension. To-date studies in humans have been done using a single-tip electrode radiofrequency ablation catheter to achieve circumferential sympathetic fiber interruption through the renal artery wall. We investigated the safety and efficacy of a multi-electrode catheter ablation system developed by St Jude Medical (EnligHTN).
Methods and results: The EnligHTN catheter has 4 electrodes attached on a basket mounted at the tip of the catheter. The basket is collapsed and can be expanded via an external mechanism once the catheter is placed in the desired location of the renal artery. The electrodes can then be activated sequentially to achieve the desired lesion pattern. In preclinical studies, in large animal models we found that using a predetermined algorithm, transmural lesions can be placed strategically in the renal artery so to achieve optimal renal denervation. In the present study we assessed the efficacy and safety of the EnligHTN catheter in 46 patients with drug resistant hypertension (av. age 60±10years, 33% women, BMI 32kg/m², 20% with CAD, 59% with hyperlipidemia , 33% with type II DM and 30% with sleep apnea). Patients were on an avg. of 4±0.6 antihypertensive medications at baseline. Bilateral renal nerve ablation was done using the femoral percutaneous approach. On av. 7.7±0.8 lesions were created in the right renal artery and 7.4±1.4 lesions in the left renal artery. The median procedure time was 34 minutes. At one month there was a 28/10 mmHg (n=46) reduction in BP (p<0.001) and at three months a 35/14mmHg (n=24) reduction (baseline BP of 176±16). There was no significant change in serum creatinine or eGFR. There were no significant procedure related complications. Small hematomas were noted in 4 patients, vasovagal reaction in 3 and transient bradycardia in 1.
Conclusions: In conclusion this data indicates that the EnligHTN ablation system is safe and effective. Sympathetic renal denervation can substantially improve BP control in patients with drug resistant hypertension.
Abstract 19581: Embryonic Lethality of Mice Deficient for IRF2BP2: An Essential Ischemia-Inducible Transcriptional Coactivator of VEGFA
Authors: Ho Tiffany V , Yap Nida , Almontashiri Naif , Stewart Alexandre F 
Published: April 2024

Background - VEGF (vascular endothelial growth factor) is a master regulator of angiogenesis is a major player in ischemic heart disease. In 2010, we found that IRF2BP2 (interferon regulatory factor-2 binding protein-2) coactivates VEGFA expression in muscle. IRF2BP2 protein levels show a 7-fold increase is ischemic muscle whereas its mRNA expression is not increased, indicating that IRF2BP2 is translational repressed in normoxic tissues and becomes translationally derepressed during ischemia.
Methods - To characterize the mechanisms repressing translation of IRF2BP2 mRNA in normoxic conditions and enabling derepression during ischemia, luciferase reporter plasmids were transiently transfected in cultured cells. In addition, we generated transgenic mice with targeted deletion of the IRF2BP2 gene and others with a floxed IRF2BP2 allele enabling tissue specific ablation by Cre-transgene expression.
Results - In the 3’UTR of IRF2BP2 mRNA, microRNAs miR-17 and -20a were found to differentially regulate translation. A common 9 nucleotide deletion polymorphism (rs3045215) disrupted the miRNA target sequence in IRF2BP2 mRNA and associated with coronary artery disease risk in the Ottawa Heart Genomics study (p<0.0045). The RNA binding protein Staufen-1 (Stau1) binds to the 3’UTR of IRF2BP2 mRNA and inhibits its translation. Stau1 levels increased during C2C12 skeletal muscle differentiation, coincident with the downregulation of IRF2BP2 protein levels. Of interest, IRF2BP2 knockout mice died during embryonic development. Out of 11 litters from hemizygous matings, 42 offspring were born: 15 wild type (35.7%), 25 hemizygous (59.5%), and 2 homozygous null (4.8%) mice, deviating from the expected Mendelian ratio of 25% wild type:50% hemizygous: 25% null. The 2 surviving IRF2BP2 null mice displayed severe growth retardation. We are currently characterizing the phenotype of embryonic lethality in these mice.
Conclusion - Translational derepression enables expression of IRF2BP2 protein in ischemic tissues, an emerging mechanism of gene regulation. Our data show the IRF2BP2 gene is critical for mouse development. These transgenic models will enable the elucidation of IRF2BP2 function in angiogenesis and the response to ischemia.
Abstract 19603: Disruption of βPDGF Receptor-Dependent PI3k and Plcγ Signaling Protects from Hypoxia-Induced Pulmonary Hypertension
Authors: Ten Freyhaus Henrik , Janssen Wiebke , Leuchs Maike , Zierden Mario , Berghausen Eva , Vantler Marius , Caglayan Evren , Schermuly Ralph T , Tallquist Michelle D , Rosenkranz Stephan 
Published: April 2024

Background: Vascular remodeling is critical during the pathogenesis of pulmonary hypertension (PH). Growth factors, such as platelet-derived growth factor (PDGF), appear to be involved in these processes. With pharmacological inhibitors, we demonstrated previously that phosphatidyl inositol-3 kinase (PI3K) and phospholipase Cγ (PLCγ) are the critical mediators of βPDGF receptor (βPDGFR)-dependent proliferation and migration in pulmonary arterial smooth muscle cells (PASMC). Whereas expression data and data with the tyrosine kinase inhibitor imatinib suggest a role for PDGF in PH, data from genetic models is lacking.
Methods and results: We utilized βPDGFR F3/F3 (“F3”) mice that were generated by introducing point mutations of the PI3K and PLCγ binding sites into the βPDGFR locus by gene targeting. We isolated PASMC from F3 and wild-type (WT) mice. Co-immunoprecipitation experiments after PDGF treatment showed that PI3K and PLCγ did not bind to the activated F3 receptor, whereas overall phosphorylation and binding of RasGap and SHP-2 were unaffected. In line with these observations, PDGF-mediated phosphorylation of Akt and Erk 1/2 was inhibited in F3-PASMC compared to WT. To address, if cellular responses were altered, we analyzed βPDGFR-dependent proliferation (as BrdU incorporation) and migration (modified Boyden chamber). These experiments revealed that these responses were essentially completely blocked in F3-PASMC compared to WT. To analyze the development and severity of PH in vivo, we exposed F3 and WT mice to hypoxia for 3 weeks. Following this treatment, right ventricular systolic pressure (RVSP) was measured by right heart catheterization, and right ventricular (RV) hypertrophy was assessed as RV weight/left ventricular + septal weight (RV/LV+S). These analyses revealed that RVSP and RV/LV+S were significantly reduced in F3 compared to WT mice.
Conclusions: These data show that disruption of βPDGFR-dependent PI3K and PLCγ signaling blocks PDGF-dependent proliferation and migration of PASMC in vitro and protects from the development of hypoxia-induced PH in vivo. Consequently, these data support a critical role of PDGF during the pathogenesis of PH.
Abstract 19648: Exposure to Ionized Medical Radiation after Heart Transplant is Associated with Higher Risk of Malignancies
Authors: Uriel Nir , Pak Sang-Woo , Morrison Kerry , Garan Arthur R , Yuzefpolskaya Melana , Colombo Paolo C , Restaino Susan W , Einstein Andrew , Takayama Hiroo , Mancini Donna M , Naka Yoshifumi , Jorde Ulrich P 
Published: April 2024

Objective Evidence on the increase cancer risk due to medical radiation is mounting. Heart transplant (OHT) patients are at high risk for cancer due to immunosuppression medications. In this study we shout to determine the correlation between the cumulative ionized medical radiations after OHT to the development of cancer.
Methods: Adult Patients transplanted between 1999-2010 without history of cancer in a large medical center were included in this analysis. Medical tests that expose the patients to radiation (i.e X-ray, Computer Tomography (CT), nuclear test and cardiac catheterization) were collected from the hospital database, and the amount of radiation was calculated based on a look up tables specified for our institution. The prevalence of cancer was recorded from electronical medical records.
Results: 891 patients were enrolled to the study. Age 52.3±13.0 years old, 677 (75.9%) were male. The mean follow up time post OHT was 6.9±3.3 years and 76 (8.5%) patients developed de-novo malignancy. Prostate cancer was the most common 20%, followed by lung 17% and hematologic malignancies 13%. The mean time for development of malignancy was 5.2±3.4 years. Patients that developed cancer were exposed to significantly more ionizing radiation 68.0 ± 65.9 mSv vs 54.4 ± 45.9 mSV (p=0.026) respectively. Cumulative radiation exposure was the only variable associated with the development of de-novo cancer in a multivariable regression model (for every increase of 10mSv the chance of cancer increase by 5.1% P=0.046). Patients in the higher tertile of radiation exposure had 40% more chance to develop cancer (Figure).
Conclusion High frequency of early post OHT malignancy was reported. There was a strong association between the amounts of medical ionizing radiation to the frequency of post OHT malignancy. This is the first study to report actual cancer percentage in relate to radiation exposure. Minimized the amount of radiation post OHT may reduce the frequency of cancer.
Abstract 226: Neuromuscular Blockade in Post--Cardiac Arrest: Practice Patterns and Association with Outcome Measures
Authors: Salciccioli Justin D , Cocchi Michael N , Rittenberger Jon C , Peberdy Mary Ann , Abella Benjamin S , Gaieski David F , Ornato Joseph P , Callaway Clifton , Clore John N , Gautam Shiva , Donnino Michael W 
Published: April 2024

Introduction: Neuromuscular blockade (NMB) may improve outcomes in acute respiratory distress syndrome. In post-cardiac arrest (CA) patients receiving therapeutic hypothermia (TH) NMB is sometimes used to prevent shivering. Whether NMB improves outcomes from CA is unknown.
Objective: To assess the association between NMB and outcomes from CA.

Methods: A
post-hoc
analysis of a prospective multicenter observational study of adult CA from 6/2011 to 3/2012. Inclusion criteria were: adult (> 18 years), out-of-hospital CA, return of spontaneous circulation (ROSC), comatose following ROSC. Traumatic CA were excluded. Patient characteristics, vital signs, laboratory data and discharge data were recorded. The exposure of interest was NMB within 24hrs of ROSC. The primary outcome was in-hospital survival. Secondary outcomes were neurological status (Modified Rankin [MR]), oxygenation (PaO
2
:FiO
2
), and lactate clearance. We used simple descriptive statistics to describe the study population, Chi-square for unadjusted tests, and multivariable (age, downtime, rhythm, SOFA score) logistic regression or linear mixed-models for the relationship between NMB and outcomes.

Results: 111 patients were analyzed. The median age was 63 years (IQR: 50 - 75) and 41% were female. TH was completed in 97% and overall survival was 47%. 60% received any NMB within 12hrs of ROSC and 69% received any NMB within 24hrs of ROSC. With 12hrs of sustained NMB, the crude survival rate was 15/21 (71%) compared to 37/90 (41%) without 12hrs of NMB (p = 0.01). With 24hrs of sustained NMB, the crude survival rate was 14/18 (78%) compared to 38/93 (41%) in patients without sustained NMB (p = 0.004). There was a trend toward improved neurologic outcome with NMB: MR 0 - 2: 44% vs. 23% (p = 0.05). After multivariable adjustment, NMB was not associated with survival (adjusted OR: 3.35, 95% CI: 0.83 - 13.57, p = 0.09; H-L goodness-of-fit: p = 0.95). Sustained NMB improved lactate clearance over 24hrs (adjusted p = 0.03). There was no effect of NMB on PaO
2
:FiO
2
(p = 0.5).

Conclusion: In post-CA early NMB is common. Early, sustained NMB is associated with improved lactate clearance and a trend in improved survival, but no effect was observed on PaO
2
:FiO
2
ratio.