bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3491: Endo-Epicardial Dissociation of Electrical Activity Increases During the Development of the Substrate for Atrial Fibrillation in the Goat
Authors: Eckstein Jens , Maesen Bart , Verheule Sander , Allessie Maurits , Schotten Ulrich 
Published: July 2021

Background: The high incidence of transmural conduction of fibrillation waves (breakthroughs) in a complex substrate for atrial fibrillation (AF) implies the presence of electrical dissociation between the subepicardial layer (Epi) and the endocardial bundle network (Endo). The presence of this Endo/Epi dissociation (EED) in remodeled atria and its role in the progressive stabilization of AF over time has not been studied yet.
Methods: We developed a mapping tool for synchronous Endo/Epi mapping (spatial resolution 1.6mm) with 90 exactly opposing electrode pairs (open chest experiment). We included 3 groups of goats: C = Control (acute AF induced by 50Hz burst pacing, n=7), 3wk = 3weeks AF (n=7) and 6mo = 6months AF (n=7). Dissociated activity was postulated when either activation times differed by more than 12ms vertically or 8ms horizontally (indicating a local conduction velocity < 20cm/s) or local direction of propagation between Endo and Epi differed by more than 90 degrees. To monitor AF stability, repetitive in-vivo cardioversion experiments with class 1C drugs were performed in 6 of the 6mo goats at 2,6,10 and 14wk AF.
Results: Applying the time criterion, EED increased from 15±4% (C) to 22±11% (3wk) and 35±13% (6mo, p=0.002 vs. C). Also the differences in the direction of propagation significantly contributed to EED. Using the combined criterion, EED increased from 38±5% (C) to 46±10% (3wk) and 53±11% (6mo, p=0.007 vs. C). Dissociation within the epicardial and the endocardial layer (time criterion) increased to a comparable extent (19±8% vs. 27±14% vs. 37± 7%, p<0.001 C vs. 6mo). Mean Endo/Epi activation time differences were close to 0ms in all three groups (−1.0±15ms vs. −0.8±16ms vs. −0.3±20ms), ruling out preferential conduction from Endo to Epi or vice versa. Success rate of cardioversion experiments decreased from 83% (2w) to 33% (6wk) to 16% (10wk) to 0% (14wk) indicating increasing stability of AF over time.
Conclusion: During AF, pronounced EED occurs. EED (like dissociation within Endo and Epi) increases over time, contributing to the progressive stabilization of AF. Enhanced EED might explain the high incidence of transmural conduction (breakthroughs) in a complex substrate for AF.
Abstract 3501: Calmodulin Kinase II Activation of Mutant Ryanodine Channels Promotes Ectopic Activity and Atrial Fibrillation
Authors: Chelu Mihail G , Sood Subeena , Wang Sufen , Sarma Satyam , van Oort Ralph J , Skapura Darlene G , Anderson Mark E , Dobrev Dobromir , Valderrabano Miguel , Wehrens Xander H 
Published: July 2021

Some individuals with mutations in the cardiac ryanodine receptor gene (RyR2) develop stress-induced atrial fibrillation (AF), but the underlying mechanisms are unknown. This study explored the molecular basis of AF susceptibility in mice heterozygous for the human arrhythmia-linked RyR2 mutation R176Q (RQ mice). AF inducibility was assessed with atrial burst pacing in WT (n=34), RQ mice (n=43) and RQ mice crossed with transgenic mice expressing the CaMKII-inhibitory peptide AC3I (RQxAC3I, n=6) or the inactive analog AC3C (RQxAC3C, n=9). Dual voltage (RH237) and calcium (Rhod-2 AM) optical mapping was applied to monitor simultaneous Ca2+ and membrane-voltage changes. Ca2+ fluorescence (Fluo-4 AM) was used to study SR Ca2+ release. Expression/phosphorylation of CaMKII and RyR2 were determined by immunostaining in mice and human atrial biopsies from sinus rhythm (SR) (n=7) and chronic AF (n=7) patients. Atrial burst pacing-induced AF was more common in RQ (55%) than in WT mice (11%*; *P<0.05) and was associated with ~50% higher CaMKII-dependent RyR2 phopshorylation (Ser2814 site). Expression and phosphorylation (Thr287) of CaMKIId were increased in AF patients by 63%* and 40%*, respectively, and CaMKII-phopshorylation of RyR2 at Ser2814 was 80%* higher in AF than in SR patients. Genetic inhibition of CaMKII reduced AF incidence in RQxAC3I (16%*), but not in RQxAC3C mice (62%). Optical mapping revealed more atrial burst pacing-induced ectopic beats (and re-entry) in RQ than WT atria (296 vs.19* ectopic beats, 120 ms cycle length) that were depressed by CaMKII inhibiton with KN-93 (1 μM). [Ca2+]i release by 10 mM local caffeine puffs (an index of SR Ca2+ content) were similar in RQ and WT mice (4.59±0.42 vs 4.04±0.41 [a.u.], respectively), whereas SR Ca2+ leak defined as tetracaine (5 μM)-sensitive decrease in diastolic [Ca2+]i was higher in RQ than in WT mice (% of SR Ca2+ content: 10.2±0.9 vs 7.7±0.8*). CaMKII inhibition with KN-93 suppressed SR Ca2+ leak. High rate-associated CaMKII activation promotes AF inducibility in mice with a stress-induced arrhythmia-linked R176Q mutation in RyR2. Inhibition of CaMKII may be a viable drug target for effective AF therapy.
This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).
Abstract 3665: Aggf1 Is Essential for Embryonic and Pathological Angiogenesis
Authors: Zhang Teng , He Ping , Wang Qing 
Published: July 2021

Backgroud: AGGF1 is a newly identified angiogenic factor associated with vascular disease Klippel-Trenaunay syndrome. AGGF1 has been shown to promote angiogenesis as potently as VEGF in a chicken embryo angiogenesis assay; however, the physiological role of AGGF1 is unknown.
Methods and Results: We explored the physiological function of AGGF1 in vivo by employing the gene-trapping strategy in mice. AGGF1−/− mice died by E8.5, suggesting that AGGF1 is essential for embryogenesis. AGGF1 heterozygosity resulted in 31% embryonic lethality. Further macroscopic analysis of embryos at different stages revealed growth retardation and defective vascular development in AGGF1+/− embryos. The major vascular phenotypes included failed development of large vessels and interconnected yolk sac vasculature. Interestingly, decreased phosphorylation of VEGFR2 (Tyr951) was detected in AGGF1+/− embryos compared to the wild type littermate controls, suggesting that AGGF1 may function through VEGFR2-mediated signaling during angiogenesis. Moreover, vascular pathologies of various internal organs were detected in older AGGF1+/− mice. Hemorrhages were frequently noted in brain, spleen and lung, and a chronic inflammatory change was readily detected in lungs in AGGF1+/− mice compared to the littermate controls. Permeability assay further revealed increased vascular permeability in old AGGF1+/− mice (50 – 60 weeks) compared to age- and sex-matched wild-type controls. A tumor angiogenesis model induced by two melanoma cell lines was employed to further assess the angiogenic function of AGGF1 in vivo. Tumor growth was significantly inhibited in AGGF1+/− mice. Histological examinations of the tumor sections revealed markedly reduced microvessel formation in tumors grown in AGGF1+/− mice. Moreover, vascular density quantified after PECAM1 immunostaining showed significant reduction in tumors grown in AGGF1+/− mice.
Conclusions: AGGF1 is an important regulator for embryonic angiogenesis and vascular integrity. AGGF1 is also involved in tumor growth and pathological angiogenesis. These results provide for the first time the in vivo experimental evidence that AGGF1 is a potent angiogenic factor essential for both embryonic and pathological angiogenesis.
Abstract 3730: Celecoxib Does Not Deteriorate Antiplatelet Effects of Aspirin and Clopidogrel in Healthy Volunteers
Authors: Lee Wonjae , Kwon Dong-A , Cho Hyun-Ju , Suh Jung-Won , Choi Su-Yeon , Kim Sang-Hyun , Kim Chul-Ho , Oh Byung-Hee , Park Young-Bae , Kim Hyo-Soo 
Published: July 2021

Background: Celecoxib, cyclooxygenase (COX)-2 inhibitor, has been reported to inhibit neointimal hyperplasia in animal studies and to reduce restenosis after coronary stenting in COREA-TAXUS clinical trial. The main concern is that celecoxib would increase thrombogenecity by inhibiting the synthesis of prostacyclin in endothelial cells. However, it is not known whether the administration of celecoxib would weaken antiplatelet effects of aspirin and clopidogrel which are used after stenting.
Methods: We recruited healthy volunteers (n=40) and randomized them into five subgroups. Each subject received the medication for 6 days and blood samples were taken day 0 and 7. Celecoxib 200mg twice a day, and/or aspirin 100mg daily, and/or clopidogrel 75 mg daily was administered. We compared platelet function by using light transmittance aggregometry and arachidonic acid metabolite assay among subgroups.
Results: Celecoxib single treatment did not significantly affect platelet aggregation. Dual asprin and Plavix treatment inhibited platelet aggregation by 53%, which was not affected by addition of celecoxib showing 52% inhibition (t-test: p = 0.873). The changes of prostacyclin level did not differ among each treatment group (ANOVA: p=0.193). Although statistically not significant, celecoxib seems to lower the thromboxane level further when added to antiplatelet agents.
Conclusion: Celecoxib treatment did not interfere with antiplatelet effect of aspirin or clopidogrel, suggesting that celecoxib as anti-restenosis agent would be administered safely during coverage of dual antiplatelet therapy in patients with coronary stenting without increasing thrombogenecity.
Abstract 3933: Local Cytokine Release is Increased in Less Mature Collateral Arteries and Reflects Collateral Arterial Oxygen Pressure in Man
Authors: Schirmer Stephan H , van Royen Niels , Moerland Perry D , Fledderus Joost O , Baan Jan , Henriques José P , van der Schaaf René J , Vis Marije M , Piek Jan J 
Published: July 2021

Background: The molecular background of the maturation of the human collateral circulation in response to coronary narrowings is poorly understood, particularly because of the complexity to evaluate coronary collateral growth in-vivo. Local sampling of collateral blood in patients could provide valuable insights in this process. We sought to determine metabolic parameters and plasma cytokine profiles in the human coronary collateral circulation in relation to collateral maturation.
Methods and Results: We used a Proxis® proximal embolic protection device (St. Jude Medical) to perform blood sampling directly from the coronary collateral circulation in 60 patients with non-total (n=25) or total coronary occlusions (n=35). Coronary collateral flow index (CFI) was assessed by intracoronary pressure measurements. Oxygenation and lactate content was measured as well as 30 cytokines potentially involved in collateral artery growth, using a custom-made multiplex assay. Oxygen gradient between systemic and collateral arterial correlated inversely with CFI (R=−0.63, p<0.001). No rise in lactate or change in pH was found in collateral blood. Locally increased plasma levels were found for bFGF, Eotaxin, MIF, MCP-1, VEGF and TGFbeta, while SCF was significantly decreased. The highest cytokine gradients were found in patients with the least developed collateral circulation. The majority of cytokines correlated more strongly with pO2 extraction across the collateral bed than with CFI.
Conclusion: Upregulation of cytokines at the site of coronary collateralization and in collateral vessels with enhanced oxygen gradient between systemic and collateral arterial blood demonstrate increased inflammatory activity in arteries where oxygen delivery is insufficient. Less pronounced cytokine gradients in collateral arteries in CTOs indicate reduced arteriogenic activity in these vessels. Determining oxygen gradient may be a more sensitive tool for the assessment of the functional capacity of the collateral circulation in patients than measurements of CFI.
Abstract 5391: Combined Ablation of Junctin and Triadin is Associated with Leaky Ryanodine Receptors and Depressed Cardiac Contractile Function
Authors: Han Peidong , Zhou Xiaoyang , Zhao Wen , Chen Guoli , Chen Shan , Figueira Sarah , Fan Guochang , Allen Paul D , Kranias Evangelia G 
Published: July 2021

Junctin (JCN) and triadin (TRD) share similar structures and they both function to anchor calsequestrin (CSQ) to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR) quaternary Ca-release complex. In failing human hearts, JCN and TRD protein levels are markedly decreased, implicating alterations in SR Ca-cycling and contractility. To address the role of combined JCN and TRD down-regulation in cardiac function, we generated and characterized a murine model deficient in both JCN and TRD. The double-knockout (DKO) mice presented lower body weight, poor fertility, and an apparent cardiac hypertrophy. In addition, deficiency of both JCN/TRD was associated with decreased peak Ca transient amplitude (34%), prolonged transient decay time (48%) and reduced caffeine-induced SR Ca-release. This depressed contractility was also confirmed at the intact organ (Langendorff perfusion) and whole animal (by echocardiography and catheterization) levels. Furthermore, examination of the properties of Ca sparks, which are informative of ryanodine receptor (RyR) gating , revealed increased frequency in the DKO myocytes, which indicated a larger opening probability of RyR. These findings suggest that the combined JCN/TRD-deficiency is associated with leaky RyR and depressed cardiac Ca-cycling, which may contribute to the progression of heart failure.
This research has received full or partial funding support from the American Heart Association, AHA National Center.

Table 1.

Hemodynamic parameters from echocardiography and catheterization
Abstract 5417: Inducible 20S β Subunit LMP-2 is Down-Regulated in db/db Mouse Hearts with Diabetic Cardiomyopathy
Authors: Zu Lingyun , Bedja Djahida , Becker Lewis C , Cai Zheqing P 
Published: July 2021

Background: The ubiquitin-proteasome system (UPS) plays an important role in cell growth, differentiation, and survival. Low molecular mass polypeptide (LMP)-2 is an inducible 20S beta subunit and its role in diabetic cardiomyopathy has not been previously studied. We investigated the hypothesis that LMP-2 is down-regulated in diabetic hearts and is involved in diabetic cardiomyopathy.
Methods: db/db mice and control db/+ littermates were studied at 20 weeks of age. Cardiac function was measured by echocardiography. Chymotryptic-like activity of the 20S proteasome was analyzed by fluorogenic assay using the substrate Suc-LLVY-aminomethycoumarin (-AMC).
Results: db/db mice had a severe increase in blood glucose and a decrease in heart weight compared with db/+ mice (135±6 vs. 168±7 mg, n = 4, p < 0.01). Left ventricular function was decreased with a lower fractional shortening in db/db mice (48.7±3.2 vs. 60.7±0.4 %, n = 4, p < 0.05). LMP-2 was constitutively expressed in both db/+ and db/db mouse hearts, but its level was severely depressed in the db/db hearts (78±11 vs. 245±18 AU, n = 4, p < 0.01). Consistent with the change in LMP-2, chymotryptic-like activity was also significantly down-regulated in these diabetic hearts (3286±112 vs. 3598±52 AU, n = 3, p < 0.05). Furthermore, the role of LMP-2 in regulating 20S proteasome function and cardiac mass was determined in LMP-2 knockout and wildtype mice. Chymotryptic-like activity was significantly decreased in LMP-2 knockout mouse hearts (11156±360 vs. 18280±454 AU, n = 4, p < 0.01), and cardiac atrophy was found in these knockout mice (147±7.1 vs 178±10.5 mg, n=10; p < 0.01). Taken together, these results suggest that LMP-2 is necessary for normal proteasome function in the heart and its down-regulation may contribute to the development of diabetic cardiomyopathy.
Abstract 5554: Runx2 Represses TGFβ/Smad-Mediated Connective Tissue Growth Factor Gene Expression in Vascular Smooth Muscle Cells
Authors: Ohyama Yoshiaki , Tanaka Toru , Shimizu Takehisa , Sato Hiroko , Koitabashi Norimichi , Doi Hiroshi , Iso Tatsuya , Arai Masashi , Kurabayashi Masahiko 
Published: July 2021

[Background] Runx2, a key transcription factor for osteoblastic differentiation, is expressed in calcified atherosclerotic plaques. We recently reported that Runx2 represses vascular smooth muscle cells (VSMC) differentiation and promotes its osteogenic differentiation. Connective tissue growth factor (CTGF) has been implicated in the progression to vulnerable plaque by inducing mononuclear cell chemotaxis and VSMC apoptosis despite of its potent stimulatory effect on synthesis of extracellular matrix. In this study, we investigated the regulatory mechanism of CTGF gene expression by Runx2 in VSMC.
[Methods and Results] RT-PCR analyses showed that adenovirally overexpressed Runx2 significantly repressed the basal expression of the CTGF gene in human aortic SMCs (HASMCs). Consistent with this, knockdown of the Runx2 expression in HASMCs by small interfering RNA (siRNA) increased CTGF mRNA levels. Luciferase assays showed that Runx2 reduced the transcriptional activity of the CTGF promoter. Transfection of a series of 5′-deletion constructs revealed that Runx2 inhibited CTGF expression through the sequence element located at 5′ untranslated region of CTGF mRNA. We next examined the effects of Runx2 on the TGFβ-induced CTGF expression. Runx2 overexpression significantly attenuated the TGFβ-mediated induction of CTGF expression in HASMCs, and knockdown of Runx2 by siRNA enhanced the induction of CTGF expression in response to TGFβ. Runx2 repressed TGFβ-induced CTGF promoter activity through the sequence containing Smad binding element (SBE), and luciferase assay using SBE-specific mutation construct showed that Runx2 repressed CTGF promoter activity in an SBE-dependent manner. Overexpression of Runx2 significantly reduced TGFβ and Smad3-mediated luciferase activity of 4xSBE-tkLuc, which contains four copies of SBE. Co-immunoprecipitation showed that Runx2 formed a complex with Smad4.
[Conclusion] These data demonstrate that Runx2 represses basal and TGFβ-induced CTGF gene expression in VSMC, and thus suggest that besides the potential for inducing vascular calcification, Runx2 may affect plaque stability by modulating extracellular matrix synthesis through inhibiting CTGF gene expression and TGFβ signaling.
Abstract 645: Effect of Stun Gun Discharges on Pacemaker Function
Authors: Khaja Azamuddin , Govindarajan Gurushankar , McDaniel Wayne , Flaker Greg 
Published: July 2021

Introduction: Tasers are electronic controlled devices used by law enforcement to temporarily incapacitate individuals. They generate high voltage, low current repetitive pulsed waveforms which may adversely affect implanted pacemakers.
Methods: A single chamber Medtronic bipolar lead was placed under fluoroscopic guidance in the RV apex of 4 pigs and connected to an Adapta generator placed in pre-pectoral pocket. After anesthesia, multiple stun gun shocks were fired every 3 minutes with Taser X-26, Taser M-26 and Stinger S-200. Intracardiac electrograms were continuously recorded during the taser discharges by placing the wand over the pacemaker pocket.

Results: The taser did not produce any effects on the native rhythm which is easily seen underlying the distinctive noise signature from the taser shock (Fig-1A

). The Adapta device used for this testing has atrial tachycardia detection capability, explaining the atrial sense markers appearing with the taser noise. Figure 1B

was recorded when the pig was 100% paced and the stun gun fired. The reversion pacing, observed in this strip, is functionally asynchronous from the native rhythm the entire time that the taser noise is present and goes away as soon as the taser noise is removed.

Conclusions: Stun Gun discharges,

were recognized by the pulse generator and sensed as either high rate atrial or ventricular activity depending on which vector is more in line with the electric field created by the two taser electrodes,

did not affect the native rhythm,

did not conduct down the lead systems to cause any extra systoles,

and had no effect on paced rhythm. The use of these devices appears safe in victims with this type of pulse generator.
Abstract 698: Late Enhancement in Isolated Noncompaction Left Ventricle is Related to Repetitive Ventricular Arrhythmias
Authors: Almeida Ana G , Marques João S , Guilherme Pereira , Dias Nuno C , varela Manuel G , Sargento Luis M , David Cláudio , Lopes Mário G 
Published: July 2021

Isolated noncompaction left ventricle (INLV), an unclassified cardiomyopathy, is associated to an ominous prognosis due to arrhythmias, embolism and heart failure. We hypothesized that, in patients with INLV, the presence of late enhancement (LE), assessed by cardiovascular magnetic resonance (CMR) could be related to repetitive ventricular arrhythmias, which are determinants of sudden death.
Methods: 22 consecutive patients (pts), aged 35±11 years-old, 11 men) with INLV, were included. Diagnosis was established by echocardiography and CMR using accepted criteria. All underwent complete CMR LV assessment using a 17-segments model:

SSFP short-axis LV volumes and ejection fraction;

SSFP 2, 3, 4-chambers for noncompaction segmental distribution;

LV segmental LE (segmented inversion-recovery fast gradient-echo sequence, 10–15 mn after 0.2mmol/kg of Gd-DTP);

the number of segments with LE was assessed. A 24 hours-Holter monitoring was obtained in less than two-weeks interval and the number of repetitive ventricular arrhythmias was assessed (pairs, triplets, ventricular tachycardia).
Results: Non-compaction was present in 212 segments, involving mainly the inferior, posterior and lateral walls, but all walls were involved in different patients. LE was detected in 242 segments (8±2 per patient), present in all non-compaction segments and in 30 morphologically normal segments. Fibrosis was visible in the non-compacted layer (all segments) and in the more internal layer of the compacted myocardium (161 segments, 67%). LV end-diastolic volume was 128±22ml/m2) and there was LV dilatation and reduced ejection fraction in 14 patients. Repetitive ventricular arrhythmias were present in all patients, varying from 3 to 155 episodes in the Holter monitoring. There was a correlation between the number of ventricular arrhythmias the number of non-compaction segments (r=0.43, 0,04) and the number of LE present segments (r=0.65, p=0.001). No correlation was found with LV end-diastolic volumes or ejection fraction.
Conclusions: CMR late enhancement is a frequent finding in isolated non-compaction LV and is significantly associated to complex ventricular arrhythmias. Further study should address the prognostic meaning of LE in this condition