tbuckley/cabot-search huggingface dataset:
Abstract 13447: Superior Vena Cava Isolation From the Right Atrial Posterior Wall: A Case Series
Authors: Carola Gianni, Sanghamitra Mohanty, Chintan Trivedi, Rong Bai, Amin Al-Ahmad, J D Burkhardt, G J Gallinghouse, Patrick M Hranitzky, Rodney P Horton, Javier E Sanchez, Luigi Di Biase, Andrea Natale
Journal: Circulation (2016)

Introduction: Superior vena cava (SVC) isolation is a common ablation strategy to address non-pulmonary vein triggers in patients with paroxysmal and non-paroxysmal AF. SVC isolation with circumferential ablation might be difficult to achieve because of the phrenic nerve (PN) location in its anterolateral aspect. Hypothesis: It is possible to isolate the SVC sparing its anterolateral aspect given the presence of preferential conduction from the posterior wall of the right atrium (RA) to the SVC. Methods: Consecutive patients in which SVC isolation ablating in the RA posterior wall. RF ablation was started in the septal aspect of the SVC-RA junction and it was continued posteriorly-inferiorly in sites of early activation (relative to the SVC) until electrical isolation was obtained. The distance between the SVC-RA junction and the site of SVC isolation was measured with 3D electro-anatomical mapping. Results: 85 patients were included in the analysis. 27% were females, with a mean age of 66 ± 10 years, 21% had paroxysmal AF, 42% persistent AF, 36% longstanding persistent AF. The procedure was a repeat ablation in 58% of the cases, with a mean procedure time of 124 ± 38 minutes. Acute SVC isolation was achieved in 98%. Mean distance of isolation from the SVC-RA junction was 19.9 ± 5.1 mm (range 10.2-32.1 mm). At follow-up, we observed 2 (2%) transient PN injuries. After this, we began performing PN mapping in the PW, which precluded complete SVC isolation in 1 case (see Figure 2). Conclusions: SVC isolation can be achieved without circumferential ablation by targeting sites with early activation (relative to the SVC) in the RA posterior wall.
Abstract 12532: Cellular and Cardiac Microtissue Assays of iPSC-derived Myocytes With the Hypertrophic Cardiomyopathy Mutation in MYH7-Val606Met
Authors: Calvin C Sheng, John T Hinson, Anant Chopra, Christopher S Chen, Jonathan Seidman, Christine Seidman
Journal: Circulation (2015)

Introduction: Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease affecting 1 in 500 people and is the leading cause of sudden cardiac death in young adults. Mutations in β-myosin heavy chain ( MYH7 ) account for one-third of cases, but the underlying pathogenesis remains unclear. In this study, we investigated myocytes derived from CRISPR-Cas9-engineered isogenic induced pluripotent stem cell cardiomyocytes (iPSC-CMs) with a missense mutation Val606Met by single-cell and microtissue functional assays. Hypothesis: We hypothesize that iPSC-CMs with Val606Met will recapitulate features of HCM in single cell and microtissue assays, such as changes in contractile function and hypertrophic signaling. Methods &amp; Results: Val606Met mutations in MYH7 (VM/+, VM/VM) were introduced by targeting an iPSC line using CRISPR-Cas9. Transfected iPSCs were isolated by FACS to detect green fluorescent protein, clones were expanded, and mutational events were confirmed by Sanger sequencing. Mutant iPSCs, like isogenic wildtype control iPSCs, were differentiated into cardiomyocytes with &gt;90% efficiency. Microtissue studies of mutant iPSC-CMs exhibited increases in contractility (WT=2.96±0.23μN, VM/+ = 3.51±0.34μN, VM/VM = 4.63±0.51; R 2 = 0.963). Mutant iPSC-CMs also showed evidence of altered signaling by increases in spontaneous beating rate (WT &lt; VM/+ &lt; VM/VM; R 2 =0.946), cell size (compared to WT, ~20% increases in both VM/+, p=0.04 and VM/VM, p=0.038), and sarcomere content (compared to WT, ~20% increases in both VM/+, p=4e-06 and VM/VM, p=0.11). These changes are supported by activated expression in myocytes of hypertrophic genes such as NPPA , NPPB , and ACTA2 as well as transcriptional up-regulation of TGF-β. Conclusions: Isogenic iPSC-CMs with MYH7 variant Val606Met created by CRISPR-Cas9 recapitulate features of HCM in vitro . Our data confirms Val606Met as a pathogenic mutation that causes increased contractility in cardiac microtissues and myocyte hypertrophy. We speculate that increased myocyte-derived TGF-β signaling may contribute to the HCM phenotype. This approach could also be used for better understanding of genotype-phenotype correlations in HCM.
Abstract 12376: Analysis of Novel Target Molecules of Nobiletin, a Potent Therapeutic Agent Against Heart Failure
Authors: Yoichi Sunagawa, Shintaro Ogawahara, Masafumi Funamoto, Ryoga Sakurai, Kehima Hieda, Yasufumi Katanasaka, Tomohiro Asakawa, Toshiyuki Kan, Akira Murakami, Hiromichi Wada, Akira Murakami, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation (2015)

Introduction: Maladaptive hypertrophy is being recognized as a critical event during the development of heart failure. We screened some natural compounds and found that nobiletin, contained in Citrus depressa , prevented the development of heart failure in rats with myocardial infarction. However, the target molecule of nobiletin in cardiomyocytes is still unclear. Hypothesis: To solve this problem, we attempted to identify novel nobiletin-binding proteins by a proteomics approach and investigate its functional mechanism in mice. Methods and Results: Nobiletin-binding proteins were purified from rat heart using biotin-conjugated nobiletin or biotin alone and identified by LC-LC/MS-MS. One of them, nobiletin-binding protein 1 (NBP1) which related to cellular metabolic pathway, physically bound to biotin-conjugated nobiletin by pull-down assay. Nobiletin also activated enzyme activity of NBP1 in vitro . In cardiomyocyte, knockdown of NBP1 failed to nobiletin-mediated anti-hypertrophic effect, and overexpression of NBP1 inhibited phenylephrine-induced ANF and ET-1 promoter activities and cardiomyocyte hypertrophy. TG mice carrying NBP1 gene under the CAG promoter and WT mice were subjected to sham or transarotic constriction (TAC). After 8 weeks, NBP1-TG mice resisted pressure-overload induced cardiac hypertrophy and systolic dysfunction compared to WT mice without affecting blood pressure. The quantitative mRNA analysis showed that TAC-induced ANF, BNP, and β-MHC gene transcriptions were reduced in left ventricle of NBP1-TG mice compared to those of WT mice. Conclusions: Proteomics analysis on molecular targets of nobiletin is useful to delineate nobiletin-mediated signaling pathways and anti-hypertrophic effect in cardiomyocytes. These finding suggest that nobiletin inhibits cardiomyocyte hypertrophy and the development of heart failure through the functional regulation of NBP1 activity. A natural compound, Nobiletin, might be a candidate for heart failure agent in human.
Abstract 12008: Increased Circulating Endothelial Microparticles in the Acute Phase of Kawasaki Disease
Authors: Hideyuki Nakaoka, Keiichi Hirono, Asami Takasaki, Nariaki Miyao, Keijiro Ibuki, Kazuyoshi Saito, Sayaka Ozawa, Fukiko Ichida
Journal: Circulation (2015)

Introduction: Kawasaki disease(KD) is a typically acute inflammatory syndrome that takes the form of systemic vasculitis. The acute inflammation and subsequent reparative process may lead to lasting changes in arterial structure even in the convalescence of KD including increased endothelial dysfunction. Endothelial microparticles(EMPs) are vesicles formed by the cell membrane after endothelial activation. EMPs typically contain microRNAs(miRs). MiRs can affect mRNA degradation and translation. EMPs may transfer information from the parent cell to various target cells by direct cell-to-cell contact or alternatively through secretion of soluble mediators and effectors. Methods: We enrolled 35 patients (aged 3 months to 14 years, 21 male, 14 female), 35 controls. KD patients were divided into two subgroups; coronary artery lesion (CAL, Zsocre&gt;2.5, n=5) and no coronary lesion (NCAL, Zscore≦2.5, n=30). Blood samples were collected at the time of diagnosis before the initiation of IVIG treatment, then immediately after the first IVIG infusion and at 2-4 weeks after disease onset. EMPs were measured by using flow cytometry, and we performed miR expression profiling by using microarrays(Affymetrix® GeneChip® miRNA 4.0). Results: The percentage counts of EMPs were 2.90±1.26% in KD children before initial treatment, which were significantly higher (P&lt;0.005) than those of controls (0.09±0.08%). The highest percentage count of EMPs (5.47%) was observed in the patient with CAL before initial treatment. In the patients with acute phase of KD with CAL, miR-320a (Fold change 22.66), miR-320b (Fold change 17.52) and miR-320c (Fold change 11.78) which were extracted from EMPs were up-regulated, while miR-550a (Fold change -4.81) and miR-3613-3p (Fold change -5.51) were down-regulated in comparison with those in convalescent phase. These 5 miRs were normalized after treatment. Conclusions: These results suggested that EMPs could serve as a sensitive marker of the severity of endothelial dysfunction and vasculitis in patients with KD. Moreover, miR-320 may have a pivotal role of vasculitis and the development of CAL during acute phase of KD.
Abstract 12304: Activation of the Exosome Biogenesis Pathway in Cardiomyocytes by Overexpression of Hsp20 Improves Cardiac Function and Angiogenesis in Diabetic Mice
Authors: Hiatao Gu, Xiaohong Wang, Wei Huang, Yigang Wang, Guo-Chang Fan
Journal: Circulation (2015)

Background: Exosomes derived from cardiomycytes are able to affect endothelial cell growth. Increased Hsp20 levels in myocytes have been shown to promote cardiac angiogenesis. Given that diabetic hearts exhibit severe microvascular rarefaction and impaired angiogenesis, we asked whether overexpression of Hsp20 could attenuate diabetes-triggered cardiac adverse remodeling, and if so, whether Hsp20-mediated cardioprotection is associated with the activation of exosome biogenesis/release. Methods and Results: 2-mon old male wild-type (WT) mice and transgenic (TG) mice with heart-specific overexpression of Hsp20 (10-fold) underwent daily peritoneal injection of streptozotocin (STZ, 50μg/g) for 5 days to induce diabetic condition (&gt;300mg/dl). Control mice were received injections of citrate buffer. 3-month later, we observed that the left ventricular ejection fraction (EF) and fractional shortening (FS) were reduced by 43% and 35%, respectively, in STZ-injected WT mice, compare to controls. However, STZ-induced cardiac dysfunction was significantly attenuated in Hsp20-TG mice, compared to WTs. The wheat germ agglutinin (WGA) staining displayed that the size of cardiomyocytes was significantly increased in STZ-WT hearts, but not in STZ-Hsp20TG samples, compared to controls. Similarly, STZ could greatly induce myocardial fibrosis and apoptosis in WT hearts, but not significant in Hsp20-TGs. In addition, the density of myocardial blood vessels, measured by Isolectin IB4 staining, was decreased to a greater degree in STZ-WTs than STZ-TGs. Mechanistically, we observed that Hsp20 interacted with Tsg101, an initiator of exosome biogenesis in cells. As a result, the levels of Tsg101, Rab11a/b and Rab35, factors known to participate in exosome biogenesis/release, were significantly increased in Hsp20TG hearts, compared to WTs. Accordingly, blockade of exosome generation with GW4869 (2.5μg/g), a specific inhibitor of exosome biogenesis, offset cardio-protective effects observed in STZ-treated Hsp20-TG mice. Conclusions: This study indicates that overexpression of Hsp20 protects mouse hearts against diabetes-induced cardiac adverse remodeling via activation of exosome biogenesis/release in cardiomyocytes, at least in part.
Abstract 12890: Relaxin Reverses Profibrotic and Inflammatory Atrial Remodeling in a Human Tachyarrhythmia Model
Authors: Alicja Bukowska, Philipp Bornfleth, Ingo Kutschka, Andreas Goette
Journal: Circulation (2015)

Introduction: Atrial fibrosis is a critical substrate in the initiation and maintenance of atrial fibrillation (AF). Deposition of atrial collagen has been well documented in patients with AF. The accumulation of collagens results from transcriptional activation of collagens genes in the response to bioactive peptides, cytokines and oxidative stress. The present study addresses the therapeutic potential of relaxin in human atrial tissue. Hypothesis: Relaxin reverses atrial remodeling in tachyarrhythmia. Methods: Right atrial appendages were obtained from 28 patients undergoing heart surgery for coronary artery bypass graft or mitral/aortic valve replacement. Tissue samples were sliced into 350μm and cultivated for up to 24h in the presence of relaxin in the concentration range from 10nM to 1μM (n=15). To resemble AF, the tissue slices were stimulated in the electrical field at 4 Hz (vs.0.6 Hz) up to 24h without and with the presence of 0.1 μM (n=6), or 1 μM (n=7) relaxin. Then, atrial tissue was examined at the transcriptional and protein level. Results: Relaxin diminished the transcriptional expression of molecules associated with atrial fibrosis like: collagen 3 (0.1μM: 0.83±0.06; 1μM: 0.68±0.07; p&lt;0.01), CTGF, TGF-ß1, and TGFßR2. Moreover, relaxin reduced basal expression of inflammatory molecules like ICAM-1 and IL-8. To assess the therapeutic potential of relaxin in tachyarrhythmia, tissue slices were exposed to electrical field. Relaxin prevented the pacing-dependent increase in the expression of collagen3 (0.1μM: 1.2±0.2; 1μM: 1.0±0.2; p&lt;0.05 vs 4Hz: 2.2±0.4) CTGF (0.1μM: 1.1±0.2; 1μM: 1.2±0.2; p&lt;0.05 vs 4Hz: 2.2±0.3), TGF-ß1 (0.1μM: 1.1±0.2; 1μM: 0.9±0.1; p&lt;0.05 vs 4Hz: 2.2±0.4). Similarly effects achieved relaxin on the expression of inflammatory molecules. Of note, relaxin prevented the pacing-dependent activation of NF-κB transcription factor and MAP kinases. However, relaxin did not influence the pacing-induced phosphorylation of SMAD2. Conclusions: Relaxin reverses atrial remodeling in a human tachyarrhythmia model. We demonstrated that relaxin abolishes the expression of pro-fibrotic and pro-inflammatory and prevents via NF-kB inhibition the pacing-dependent pro-fibrotic and pro-inflammatory responses.
Abstract 12422: Influence of Polypharmacy on the Efficacy And Safety Of Dabigatran Versus Warfarin for the Treatment of Acute Venous Thromboembolism: A Pooled Analysis of RE-COVER <sup>®</sup> and RE-COVER II <sup>™</sup>
Authors: Samuel Z Goldhaber, Henry Eriksson, Ajay Kakkar, Sebastian M Schellong, Martin Feuring, Mandy Fraessdorf, Joerg Kreuzer, Sam Schulman
Journal: Circulation (2015)

Background: Polypharmacy in patients treated for acute venous thromboembolism (VTE) has been associated with increased bleeding risk during warfarin (W) treatment. Polypharmacy is common in patients with VTE, who are likely to carry a greater burden of comorbidity, and may itself indicate increased VTE risk. In RE-COVER ® and RE-COVER II ™ , dabigatran etexilate (DE) showed similar efficacy and lower bleeding vs W. Objective: To evaluate the impact of polypharmacy on the efficacy/safety of DE vs W, we conducted a pooled post-hoc analysis of RE-COVER ® /RE-COVER II ™ subgroups taking ≤3 or &gt;3 concomitant medications (con-meds) at baseline. Methods: Patients with acute VTE, initially on parenteral anticoagulation, were randomized to W (parallel initiation; target INR range 2.0–3.0) or DE 150 mg bid for 6 months. The efficacy endpoint was recurrent, symptomatic VTE/VTE-related death at the end of post-treatment follow-up (6 months + 30 days). Safety endpoints were centrally adjudicated major bleeding events (MBEs), composite of MBEs or clinically relevant non-major bleeding (MBEs/CRBEs), and any bleeds during the 6-month oral-only treatment period (DE or W alone, double-dummy). Results: 2553 patients received DE and 2554 W; both groups had similar proportions taking con-meds: ≤3, 47.5% and 48.3%; &gt;3, 52.5% and 51.7% for DE and W, respectively. VTE/VTE-related deaths occurred at low rates (Graph), with no statistically significant differences between treatments. Irrespective of number of con-meds, rates of MBEs, MBE/CRBEs, and any bleeds were lower with DE vs W, and statistically significant for MBE/CRBEs and any bleeds. With both treatments, more con-meds generally corresponded with greater risks of bleeds and a slightly greater risk of VTE/VTE-related deaths. Conclusion: Polypharmacy was an indicator of increased bleeding risk with both anticoagulants; however, irrespective of number of con-meds, safety outcomes were better with DE and efficacy was similar to W.
Abstract 12040: JAK-STAT Signalling and the Atrial Fibrillation-Promoting Fibrotic Substrate: Pathogenic Role and Possible Therapeutic Target
Authors: Yu Chen, Sirirat Surinkaew, Xiao- Y Qi, Hai Huang, Marc- A Gillis, Francine Duval, Yan- F Shi, Patrice Naud, Jean- C Tardif, Dobromir Dobrev, Stanley Nattel
Journal: Circulation (2015)

Introduction: Left atrial (LA) fibrosis is an important feature of the atrial fibrillation (AF) substrate. The JAK-STAT system, activated by platelet derived growth factor (PDGF), contributes to cardiac remodeling but its role in AF is unknown. Here, we investigated the participation of the JAK-STAT system in LA fibrosis development. Methods: Heart failure (HF) was induced in dogs by ventricular tachypacing (VTP, 240 bpm) and in mice subjected to myocardial infarction (MI). Protein and mRNA expression were measured in freshly isolated LA fibroblasts (FBs) by Western blot and qPCR. Mice received S3I-201,a selective STAT3 inhibitor, or vehicle control (CTL) by osmotic minipump for 2 weeks post MI. Results: HF dogs developed progressive LA-selective fibrosis and AF susceptibility beginning at 1 wk VTP. HF increased JAK2 mRNA expression in LA FBs from 1 wk VTP (1.4-1.5 fold**, **P&lt;0.01). Phosphorylated JAK2 and STAT3 protein increased in HF atrial tissue by 2.5** and 2.9* fold (*p&lt;0.05) respectively. Upstream signalling through PDGF was also enhanced by HF: PDGF A/C/D upregulated by 2.2-3.5*** fold (***p&lt;0.001); PDGFR β upregulated by 2.3** fold. PDGF stimulation of CTL dog LA FBs increased TGFβ1, TGFβ receptor 2, STAT3, collagen 1α1 and collagen 3α1 expression (by 1.2-2.3 fold***). These effects were abolished by S3I-201 in a dose dependent manner (by 79%*** at 100 μM). In vivo S3I-201 treatment (Figure) decreased LA fibrosis (by 60%***), LA dimension at end systole (by 11%*) and P wave duration (by 31%***). MI-induced LV dilation and contractile dysfunction were not affected by S3I-201. Conclusions: HF activates the LA JAK-STAT system via enhanced PDGF signalling. JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine FBs in vitro and attenuates LA fibrosis and electrical remodeling post MI in mice. These results suggest that the JAK/STAT pathway plays an important role in LA fibrogenesis and is a potential target for LA fibrosis prevention in man.
Abstract 11934: Resuscitation by Transfusion With Hemoglobin Vesicles in Trauma Hemorrhagic Shock / Coagulopathy Rabbits
Authors: Kohsuke Hagisawa, Manabu Kinoshita
Journal: Circulation (2015)

Introduction: We have developed Hemoglobin vesicle (HbV) as an artificial substitute for Red blood cells (RBC). Hypothesis: To evaluate the efficacy of HbV for alternative treatment of massive transfusion protocol (MTP) in traumatic hemorrhagic shock / coagulopathy rabbits. Methods: Hemorrhagic shock / thrombocytopenia were induced in rabbits by repeated blood withdrawal (total 400ml) and isovolemic transfusion of autologous washed RBC. Liver penetrating injury led lethal oozing hemorrhage. Balloon compression and Platelet rich plasma (PRP) administration stopped bleeding. Thereafter, allogenic RBC transfusion, HbV or 5% Albumin was administered to the animals (n=30). Acute prognosis was compared among them for 24 hr. Hemodynamic and hematologic parameters were periodically recorded for first 1hr. Results: In anemic and thrombocytopenic rabbits (Hb &lt; 6.0 g/dl, platelets &lt; 40,000 /μL, mean arterial pressure (MAP) &lt; 50 mmHg), liver penetrating injury caused additional bleeding and animals suffered class IV shock (Hb &lt; 5.0 g/dl, MAP &lt; 40 mmHg). PRP administration restored platelets ≧ 70,000 /μL, which stopped bleeding within 40 min. Subsequent administration of HbV as well as RBC transfusion regained MAP more than 50 mmHg, and they rescued 70 % animals from liver hemorrhage, although rabbits receiving 5% albumin showed 10% survival in the first 24 hours. HbV administration did not affect the coagulation parameters as well as RBC transfusion. Conclusions: HbV may be effectively instead of RBCs for acute hemorrhagic shock and trauma induced coagulopathy.
Abstract 14630: Elevated CETP Activity is Associated With Low, Dysfunctional HDL in High Cardiovascular Risk South Asians
Authors: Michelle Melone, Shirya Rashid
Journal: Circulation (2015)

Background and Rationale: Low HDL in South Asians (SA) contribute greatly to their high coronary heart disease (CHD) risk relative to European Caucasians (EC), however, the cause of low HDL in SA is unknown. Here we investigated whether cholesteryl-ester transfer protein (CETP) plays a role in mediating low HDL in SA. Methods: Serum was obtained from metabolically well characterized individuals of SA and EC descent (N=244 and 238, respectively) and measured for CETP activity. HDL lipid and protein contents were quantified and HDL size and particle number were measured via NMR. The capacity of HDL to mediate cholesterol efflux was assessed in J774 macrophages with apoB-depleted patient serum. Results: CETP activity was elevated in SA compared with EC (26.5±0.45 vs. 18.5±0.45 pmol/uL/hr, P&lt; 0.0001). HDL from SA was pro-atherogenic - that is, triglyceride-enriched, cholesteryl ester-depleted, reduced in apoAI and smaller in size than in EC (P&lt; 0.05 for all). SA HDL, moreover, showed a reduced capacity to mediate macrophage cholesterol efflux (by 20%, P&lt; 0.0001), even in a subset of younger SA (&lt;40 years, P&lt;0.01). Composition and size changes in HDL were independent predictors of carotid artery intima-media thickness (IMT) in SA (P&lt; 0.05). Conclusions: We have identified for the first time a mechanism to account for low HDL in SA. Elevated CETP in SA was associated with triglyceride-enriched, cholesteryl ester-depleted HDL, smaller in size and reduced in apoA-I content, producing HDL that is less stable in the circulation and less atheroprotective. This was confirmed with the lower relative capacity of HDL from SA to mediate cellular cholesterol efflux and independent correlation of their HDL compositional changes with carotid IMT.