tbuckley/cabot-search huggingface dataset:
Abstract 18204: Activation of the Pro-Hypertrophic Calcineurin/Nfat-Pathway Mediates Atrio-Ventricular Conduction Disturbances in Cardiac Sodium Channelopathy
Authors: Mathilde Rivaud, Rianne Wolswinkel, Antonius Baartscheer, Inge van der Made, Harold V van Rijen, Connie R Bezzina, Esther E Creemers, Carol Ann Remme
Journal: Circulation (2013)

Introduction: SCN5A mutations have been associated with progressive atrio-ventricular conduction disturbances and development of cardiac structural abnormalities. In transgenic Scn5a-1798insD+/- mice, intracellular sodium and calcium concentrations are increased, setting the stage for potential activation of calcium-dependent signaling pathways. Here we investigated the impact of the pro-hypertrophic calcineurin/Nfat signaling pathway on atrio-ventricular (AV) conduction in Scn5a-1798insD+/- mice. Methods and Results: Aged (12-18 months old) Scn5a-1798insD+/- (MUT) mice developed cardiac hypertrophy (increased heart weight and Anf mRNA levels) and progressive AV-conduction abnormalities on surface ECG. Isolated Langendorff-perfused aged MUT hearts showed profound AV-delay and AV-block at high right atrial stimulation frequencies (basic cycle length 90-120 ms). To study the contribution of the calcineurin/Nfat signaling pathway to the AV-conduction phenotype, adult (age 3-5 months) wild-type (WT) and MUT mice were subjected to 2 weeks of transverse aortic constriction (TAC). WT and MUT mice showed similar hypertrophic responses to TAC. However, MUT-TAC mice displayed increased PR-interval on surface ECG and a higher incidence of sudden death. Furthermore, isolated MUT-TAC hearts showed AV-block and significantly prolonged AV-delay as compared to WT-TAC or sham hearts. Atrial and His-ventricular conduction was unaffected in MUT-TAC hearts, indicating that conduction delay occurred within the AV-nodal region. Since Nfatc2 is a well-described downstream effector of the calcineurin pathway, adult MUT mice were crossed with mice lacking Nfatc2 (Nfatc2-KO). In MUT/Nfatc2-KO hearts, AV-delay after TAC was attenuated as compared to MUT-TAC, indicating rescue of the AV-conduction disturbances by Nfatc2 deficiency. Conclusions: Scn5a-1798insD+/- mice develop profound atrio-ventricular conduction disturbances with increased age and after activation of the calcium-dependent pro-hypertrophic calcineurin/Nfat-pathway. These findings indicate that cardiac hypertrophy may modulate disease severity in cardiac sodium channelopathy.
Abstract 18153: Gene-Smoking Interactions in CHD Risk - Analyses of the CARDIoGRAMplusC4D Data in 60,000 CHD Cases and 80,000 Controls
Authors: Danish Saleheen, Robin Young, Jane Ferguson, Weankee Ho, Wei Zhao, Daniel J Rader, Nilesh Samani, John Danesh, Muredach Reilly
Journal: Circulation (2013)

Background: Tobacco use is one of the most important avoidable causes of coronary heart disease (CHD). GWAS have discovered variants that lead separately to CHD and smoking behaviour; however no large scale studies exist that have investigated the interaction of sequence variants and tobacco use on CHD. Objective: To investigate gene-smoking interaction in CHD at known genetic loci related to CHD (n=45) and smoking (n=5) behavior. Methods: Studies participating in the CARDIoGRAMplusC4D consortium (n=37) with available genetic data (GWAS and/or CARDIOMETABOCHIP) and information on smoking exposure were invited to participate. For all genetic variants, each participating study was asked to provide effect estimates and standard errors in relation to CHD separately in current smokers, ever smokers and never smokers. Within each study, beta(s) were quantitatively compared between (i) current smokers vs. never smokers, and (ii) ever smokers vs. never smokers. Study specific interaction beta(s) and se(s) were calculated, which were pooled across using a fixed-effects meta-analysis. Interaction analyses were declared to be significant at a P-value of &lt; 1.0x10-3 (Bonferroni correction for 50 tests). Results: Genetic data and information on smoking exposure was available on 60,919 CHD cases and 80,243 controls from 29 studies. Of the 45 CHD loci investigated, the reported CHD SNP at the ADAMTS7 locus had differential CHD association in non-smokers compared to ever smokers (P-value of interaction: 7.1 x 10-5). Multiple additional variants at the ADAMTS7 locus were observed to have similar gene-smoking interactions on CHD risk. Of the 5 smoking loci, variants at the CHRNA5 locus were found associated with CHD risk at GWAS levels of significance (P-value: 4x10-8). The reported lead variant for smoking behavior at CHRNA5 was associated with CHD only in “ever” or “current smokers” but not in “never-smokers” (P-value of interaction: 1x10-3). Conclusions: We report a novel association of the CHRNA5 locus with CHD and provide novel evidence for interaction effects of smoking behavior at the ADAMTS7 and CHRNA5 loci in relation to CHD. These findings are likely to provide novel biological and therapeutic insights into the etiology, risk and prevention of CHD.
Abstract 18168: Plasma Free Fatty Acids, Fatty Acid-Binding Protein 4, and Mortality in Older Adults in the Cardiovascular Health Study
Authors: Michael D Miedema, Marlena Maziarz, Mary Lou Biggs, Susan J Zieman, Jorge R Kizer, Joachim H Ix, Dariush Mozaffarian, Russell Tracy, Bruce M Psaty, David Siscovick, Kenneth J Mukamal, Luc Djousse
Journal: Circulation (2013)

Background: Plasma free fatty acids (FFA) are important in energy homeostasis and fatty acid-binding protein 4 (FABP4) is a key cytoplasmic chaperone of fatty acids. While both FFA and FABP4 have been associated with cardiovascular risk factors and cardiovascular events, limited and inconsistent data are available on the relation of these biomarkers with cardiovascular and total mortality. Methods and Results: We studied 4,707 participants with plasma FFA and FABP4 measured at baseline (1992-1993) in the Cardiovascular Health Study. The mean age of the participants was 75 (range 64-98) and 58.3% were women. Over a median follow-up of 11.8 years, 3,555 of the participants died. Cox proportional hazard models were used to estimate hazard ratios (HR) for mortality. After adjustment for age, sex, race, clinic, education, body-mass index, cystatin c, albumin, physical activity, alcohol intake, smoking, hormone replacement therapy in women, self-reported health status, systolic blood pressure, LDL cholesterol, HDL cholesterol, hypertensive medication, and lipid-lowering medication, FFA (HR: 1.14, 95% CI 1.09-1.18 per SD [0.2 mEq/L] higher FFA) but not FABP4 (HR: 1.04 (95% CI: 0.98-1.09 per SD [18.9 ng/mL] higher FABP4) levels were associated with total mortality. In a cause-specific mortality analysis, higher concentrations of FFA were associated with a greater risk of death due to cardiovascular and certain non-cardiovascular causes (Table 1). Conclusion: In a cohort of community-dwelling older individuals, elevated plasma concentrations of FFA (but not FABP4) were associated with cardiovascular and non-cardiovascular mortality.
Abstract 18179: Prognostic Markers of Left Ventricular Dysfunction in Patients With Newly Recognized Cardiomyopathy and Atrial Fibrillation
Authors: Shalin J Patel, Sachin Shah, Alena Goldman, Mark E Josephson, Peter J Zimetbaum
Journal: Circulation (2013)

INTRODUCTION: Tachycardia-induced cardiomyopathy (TIC) is confirmed with the improvement in ventricular function following restoration of sinus rhythm or control of ventricular rate. We sought to identify characteristics which could predict recovery of left ventricular dysfunction (LVD) in patients who present with newly recognized cardiomyopathy and atrial fibrillation (AF). METHODS: 114 consecutive patients presenting for cardioversion to our institution with newly recognized LVD defined as LVEF ≤ 45% and AF were identified. Patients with known cardiomyopathy, without admission ECG or follow up echocardiogram were excluded. QRS duration from admission ECG was used as a binary variable (≥ 125 ms or &lt; 125 ms) while LVEDD from admission echocardiogram was used as a binary variable (≥ 5.6 cm or &lt; 5.6 cm). The outcome was a binary variable, resolution of cardiomyopathy (LVEF ≥ 45%) or persistence of cardiomyopathy (LVEF ≤ 45%). The outcome was analyzed with logistic regression model using STATA. The outcomes were adjusted for age, gender, obstructive sleep apnea, coronary artery disease, diabetes mellitus, hypertension, excessive alcohol ingestion, tobacco, beta blockers, ACE inhibitors and aldosterone antagonist. RESULTS: 92 patients met the inclusion and exclusion criteria. Possible TIC was diagnosed in 65 patients who had recovery of LVD. Mean QRS duration in patients with possible TIC was 101 +/- 18 ms while LVEDD was 5.21 +/- 0.67 cm. In patients with persistent LVD, mean QRS duration was 120 +/- 27 ms while LVEDD was 5.61 +/- 1.0 cm. Normal QRS duration (&lt; 125 ms) on admission ECG was associated with a significantly higher incidence of LV functional recovery (adjusted odds ratio: 4.02; 95% CI: 1.21 - 13.33, p = 0.023). Normal LVEDD (&lt;5.6 cm) on presentation was also associated with a significantly higher incidence of LV function recovery (adjusted odds ratio: 3.75; 95% CI: 1.43 - 9.85, p = 0.007). Next Step/Future: Normal QRS duration on admission ECG and LVEDD on admission echocardiogram in patients presenting with newly diagnosed AF and cardiomyopathy serve as good markers of LV function recovery. If confirmed by larger prospective series, QRS duration and LVEDD on presentation can be used as prognostic markers in patients with new onset AF and cardiomyopathy.
Abstract 11340: The Plasma Membrane Calcium ATPase 4 Signaling in Cardiac Fibroblasts Mediates Cardiomyocyte Hypertrophy <i>(Best of Basic Science Abstract)</i>
Authors: Tamer M Mohamed, Riham AbouLeisa, Nicholas Stafford, Min Zi, Sukhpal Prehar, Florence Baudoin, Elizabeth Cartwright, Ludwig Neyses, Delvac Oceandy
Journal: Circulation (2015)

Plasma membrane calcium ATPase 4 (PMCA4) is a ubiquitously expressed Ca 2+ pump that is important in mediating molecular signaling in the heart. Here we show a novel role of PMCA4 in cardiac fibroblasts in controlling cardiac hypertrophy. We generated three PMCA4 knockout mouse strains: i) PMCA4 global knockout (PMCA4 -/- ); ii) PMCA4 cardiomyocyte-specific knockout (PMCA4 cko ); iii) PMCA4 fibroblast-specific knockout (PMCA4 fko ). Following transverse aortic constriction (TAC) for 5 weeks, PMCA4 -/- and PMCA4 fko mice displayed a significantly reduced hypertrophy compared to control mice. In contrast, the PMCA4 cardiac specific knockout (PMCA4 cko ) mice did not show any protective effect following TAC, prompting us to hypothesise that the protective effect might be due to PMCA4 ablation in fibroblasts. Microarray analysis revealed a ~100 fold upregulation of secreted frizzled-related protein 2 (sFRP2) in PMCA4 -/- fibroblasts, which was further confirmed by qRT-PCR and Western blot. sFRP2 is a potent inhibitor of the Wnt/β-catenin pathway. We then cultured wild type (WT) cardiomyocytes with conditioned medium from either PMCA4 -/- or WT fibroblasts. In response to phenylephrine stimulation, cardiomyocytes cultured in PMCA4 -/- fibroblast–conditioned medium displayed 88% less hypertrophy than those cultured in WT fibroblast–conditioned medium (P&lt;0.01). Mechanistically, PMCA4 -/- fibroblasts showed a significant elevation in NFκB activity, a transcription factor that regulates sFRP2 expression. Inhibition of NFκB activity significantly reduced the sFRP2 expression in PMCA4 -/- fibroblasts to a level comparable to WT expression. A chemical library screen identified a novel PMCA4 inhibitor, aurintricarboxylic acid (ATA). ATA treatment enhanced sFRP2 expression in the mouse heart. Importantly, ATA inhibited and reversed TAC-induced cardiac hypertrophy in mice, demonstrating its efficacy in both preventive and therapeutic strategies. In conclusion, PMCA4-mediated signaling in cardiac fibroblasts plays a key role in controlling cardiac hypertrophy. Cardiac fibroblasts lacking PMCA4 produce higher levels of sFRP2, which protects the neighbouring cardiomyocytes. Finally, PMCA4 is a potential target for cardiac hypertrophy treatment.
Abstract 11496: Differences in Bystander Cardiopulmonary Resuscitation and First Responder Defibrillation Narrowed to Similar Levels in Urban and Non-urban Out-of-Hospital Cardiac Arrest Patients Following a Quality Improvement Program in North Carolina
Authors: Kristian Kragholm, Carolina Malta Hansen, Matthew Dupre, Benjamin Strauss, Clark Tyson, Lisa Monk, David Pearson, R. Darrell Nelson, Emil L. Fosbol, Monique Anderson, James G. Jollis, Thomas Rea, Bryan McNally, Christopher B. Granger
Journal: Circulation (2015)

Introduction: Differences in care and outcomes between non-urban versus urban out-of-hospital cardiac arrest cases have previously been shown. Therefore, we examined temporal changes in bystander and first responder interventions, direct transport to PCI center and outcomes in non-urban versus urban arrests during Heart Rescue initiatives to improve regional systems of care and outcomes during 2010-2014 in North Carolina. Hypothesis: Differences in bystander and first responder interventions, direct transport to PCI center, and outcomes have narrowed over time between non-urban and urban cases. Methods: From the Cardiac Arrest Registry to Enhance Survival, we identified non-emergency medical service witnessed cases from 16 counties (catchment population 3,143,809) in North Carolina with complete case capture during 2010-2014. We used geospatial information on arrest location and US Census classification to categorize urban areas with ≥50,000 versus non-urban with &lt;50,000 people. Results: Of 7,885 patients, 21.1% of the arrests (n=1667) occurred in non-urban areas and 78.9% (n=6218) occurred in urban areas. Bystander cardiopulmonary resuscitation (CPR), first responder defibrillation and outcomes improved in both groups, but most substantially in non-urban cases (Figure). Overall, bystander defibrillation was 2.9% in non-urban versus 8% in urban cases (P&lt;0.01) and did not change over time. Similarly, no change was seen over time in proportion taken directly to PCI centers (overall 54.2% versus 97.4%, respectively). Conclusions: Differences in bystander CPR and first responder defibrillation substantially narrowed to similar levels between non-urban and urban cases following Heart Rescue quality improvement program during 2010-2014 in North Carolina. Significant differences in bystander defibrillation and direct transport to PCI center remained and represent future target areas to potentially further reduce differences in outcomes.
Abstract 18185: Regression of Severe Left Ventricular Hypertrophy After Transcatheter Valve Replacement for Aortic Stenosis: Impact on Clinical Outcomes in PARTNER Cohort A
Authors: Brian R Lindman, William Stewart, Philippe Pibarot, Rebecca T Hahn, Neil J Weissman, Thomas C McAndrew, Wilson Y Szeto, Raj Makkar, D. Craig Miller, Vasilis Babaliaros, Samir Kapadia, Bruce Bowers, Kevin L Greason, Martin B Leon, Maurice Sarano, Richard B Devereux, Catherine M Otto, Pamela S Douglas
Journal: Circulation (2013)

Background: Left ventricular (LV) mass regression after aortic valve replacement (AVR) for aortic stenosis (AS) is a favorable effect of LV unloading, but its relationship to improved clinical outcomes is unclear. We examined the effect on clinical outcomes after transcatheter AVR (TAVR) of: 1) amount of LV mass index (LVMi) regression; and 2) persistent severe LV hypertrophy (LVH). Methods: Of 2115 patients with symptomatic AS at high surgical risk receiving TAVR in the PARTNER randomized trial or continued access registry, 462 (55% women) who had severe LVH (LVMi ≥149 g/m 2 men, ≥122 g/m 2 women, by ASE criteria) at baseline (BL) and LVMi measured 6 mo post-TAVR were included in our analysis. The effect of LVMi regression was evaluated by comparing outcomes in patients with greater vs. lesser decrease (dichotomized by median % change) in LVMi between BL and 6 mo, and in those without vs. with persistent severe LVH 6 mo post-TAVR. Cox PH models evaluated rates of all-cause mortality (6-12 mo), rehospitalizations (through 1 yr), and the composite of these two outcomes. Results: LVMi decreased from 173±32 (BL) to 121±25 g/m 2 (6 mo) (p&lt;0.001) in those with greater LVMi regression, and from 164±30 (BL) to 158±34 g/m 2 (6 mo) (p&lt;0.001) in those with lesser LVMi regression. Patients with greater vs. lesser LVMi regression had similar baseline clinical characteristics, a lower rate of rehospitalization (10.5% vs. 19.9%, p=0.006) and lower rate of the composite endpoint of death or rehospitalization (13.2% vs. 21.4%, p=0.02), but a similar rate of death (4.9% vs. 4.8%, p=0.86). Persistent severe LVH at 6 mo post-TAVR was present in 54% (58% of whom were women). Patients without vs. with persistent severe LVH had similar baseline clinical characteristics, a lower rate of rehospitalization (11.9% vs. 18.1%, p=0.053) and lower rate of the composite endpoint of death or rehospitalization (13.3% vs. 20.7%, p=0.03), but a similar rate of death (3.9% vs. 5.7%, p=0.42). Similar results were obtained when including patients with moderate or severe LVH. Conclusions: In high-risk patients with severe AS and severe LVH undergoing TAVR, greater LV mass regression and resolution of initially severe LVH at 6 months are associated with a lower rate of death or repeat hospitalization.
Abstract 11673: Neuroprotective Mechanisms of Mefenamic Acid in an <i>in vitro</i> Model of Stroke
Authors: Parto S Khansari, Sonali S Shaligram, Roshanak Rahimian, Robert F Halliwell
Journal: Circulation (2016)

Introduction: Fenamates are classical non-steroidal anti-inflammatory drugs but they are also modulators of GABA A receptors, activators of potassium channels and antagonists of non-selective cation channels. Previous data from our lab has demonstrated that the fenamate, mefenamic acid (MFA), has neuroprotective effects both in vitro and in vivo . Hypothesis: We hypothesized that the neuroprotective actions of mefenamic acid result from its diverse pharmacological properties. To test this hypothesis, we have investigated four pharmacological properties of MFA, namely cyclooxygenase (COX) inhibition, GABA A receptor modulation, potassium channel activation and reactive oxygen species (ROS) inhibition against glutamate neurotoxicity in vitro . Methods: Neurotoxicity was induced by exposure of embryonic rodent hippocampal neurons, 9 days in vitro, to 10 mins of Na-glutamate (5μM). 24 hours after exposure to Na-glutamate, cell death was quantified by measuring the levels of lactate dehydrogenase (LDH) in the media using a CytoTox-96 non-radioactive assay kit. Generation of ROS was measured using Carboxy-H2DCFDA dye. Results: MFA and the non-fenamate COX inhibitors, ibuprofen, indomethacin and Na-salicylate were examined against glutamate neurotoxicity at 10 or 100μM. Cell death was significantly (p&lt;0.01) reduced by 79%, (100μM) and 65% (100μM) by MFA and Na-salicylate, respectively, but not with ibuprofen and indomethacin. Generation of ROS was also decreased significantly when treated with MFA at 30μM and 100μM by 38% and 36% (p&lt;0.05) respectively.The effects of co-application of MFA with either picrotoxin (a GABA A channel blocker) or bicuculline (a competitive GABA A receptor antagonist) or TEA (a K + channel blocker) were examined. Co-application of MFA (100μM) with picrotoxin (100μM), bicuculline (10μM) or TEA (30mM) all reduced cell death but neuroprotection was not significant. Conclusion: Collectively, these data suggest that COX inhibition and reduction of ROS generation significantly contribute to the neuroprotective actions of MFA against glutamate neurotoxicity. GABA modulation and potassium channel inhibition of MFA may also contribute but they are not the primary mechanism of its neuroprotective actions.
Abstract 18196: Sh2 Domain-Containing 5-Inositol Phosphatase 2 (SHIP2) is an Effector of Lymphatic Dysfunction
Authors: Germaine D Agollah, Eva M Sevick-Muraca
Journal: Circulation (2013)

Background: Discovery of variants responsible for familial lymphatic abnormalities have been limited by candidate gene searches and inaccurate phenotyping that is restricted to overt symptomatic presentation. As a result, the majority of patients do not harbor any of the known genes associated with inherited lymphatic abnormalities. Methods: We employed near-infrared fluorescence lymphatic imaging (NIRFLI) to identify asymptomatic, but abnormal lymphatic phenotypes in a nucleus family with two daughters who were previously diagnosed with congenital and praecox lymphedema. Following DNA collection and whole exome sequencing, we first sought to identify causal variants known to be associated with lymphatic abnormalities and then secondly, to discover new gene variants, through unbiased analysis of rare, damaging SNPs with co-segregation analysis that was based upon NIRFLI phenotyping. Relevancy of variants was tested through functional cell culture studies following siRNA candidate gene knock down in lymphatic endothelial cells (LECs), and following overexpression of WT and mutant candidate gene variants. Results: A damaging mutation in hepatic growth factor (HGF), expressed by blood and lymphatic endothelial cells and ligand to its ubiquitously expressed receptor tyrosine kinase (RTK) cMET was passed to both daughters from the asymptomatic father who showed no abnormal NIRFLI phenotype. Yet the mother, who at time of study was found to have abnormal lymphatics through NIRFLI and minor swelling attributed to minor trauma several years prior, had passed a mutation in SHIP2, encoded by INPPL1 , to her daughters. Extended, asymptomatic family members, who agreed to the NIRFLI procedure and harbored the SHIP2 mutation, also possessed an abnormal lymphatic phenotype. Migration and tubulogenesis in LECs was arrested by SHIP2 knock down, and when compared to WT overexpression, was attenuated following HGF and VEGF-C stimulation with mutant SHIP2. Proximity ligation assay showed intracellular association of SHIP2 with cMET and with VEGFR3 upon HGF and VEGF-C stimulation respectively, consistent with SHIP2 functionality as an RTK adaptor protein. Conclusions: SHIP2 may be an effector of lymphatic dysfunction.