tbuckley/cabot-search huggingface dataset:
Abstract 18248: Reduced β-catenin Expression in Mouse Cardiomyocytes Increases Matrix Metalloproteinase Activation and Apoptosis, Producing Greater Post-Infarction Ventricular Dysfunction
Authors: Kaustabh Singh, Anton Mihic, Kota Hatta, Saeid Amini-Nik, Jun Wu, Shu-Hong Li, Lu Sun, Benjamin A Alman, Keith R Brunt, Richard D Weisel, Ren-Ke Li
Journal: Circulation (2013)

Introduction: The loss of beating cardiomyocytes after myocardial infarction (MI) is followed by detrimental remodelling involving activation of matrix metalloproteinases (MMPs), which can lead to heart failure. β-catenin, a member of the cadherin family, is found at cell-cell junctions and can increase cell survival and promote tissue repair via canonical Wnt signaling. However, its role in the heart has not been characterized. We sought to determine whether β-catenin is important in cardiac remodelling after MI. Hypothesis: β-catenin signaling in cardiomyocytes mediates cell death and matrix remodelling and contributes to post-infarction ventricular dysfunction. Methods/Results: The role of β-catenin in cardiomyocytes was evaluated with transgenic mice harboring a floxed mutation for β-catenin driven by a muscle creatine kinase-Cre promoter. Mutant and wild-type (WT) mice were subjected to coronary artery ligation to induce MI, and cardiac function was evaluated by echocardiography. The β-catenin null mice exhibited a 16% decrease in ejection fraction compared to WT controls (69.2±0.9 vs. 59.6±1.0, p&lt;0.05, n=7). Histology revealed greater cardiac thinning and dilatation in the null mice. Histological analysis demonstrated increased β-catenin protein expression in the nuclei of WT myocardium following ligation. TUNEL staining revealed 50% greater apoptosis in the border region of the infarcted myocardium of the null mice (p&lt;0.05). Both WT and null mice had a 4-fold increase in the protein level of the apoptotic markers caspase3 and cleaved parp in the infarct scar compared to the remote region (p&lt;0.05, n=4), which was similar between groups. Gel zymography (to assess MMP2 activity) demonstrated a 60% increase in MMP2 activation within the infarct region (p&lt;0.05, n=4), and Western blot showed a 75% decrease in tissue inhibitor of metalloproteinase 3 (TIMP3) protein levels within the remote region of the null mice (p&lt;0.05, n=4). Conclusion: The exaggerated ventricular dysfunction in the null mice following injury was due to the depletion of β-catenin in cardiomyocytes. Our data suggest that β-catenin is necessary for the modulation of MMP2 and cell apoptosis to prevent detrimental remodelling and heart failure following MI.
Abstract 11676: Importance of Longitudinal Dyssynchrony in Low Flow Low Gradient Severe Aortic Stenosis Patients Undergoing Dobutamine Stress Echocardiography. A Multicenter Study (on behalf of the HAVEC group)
Authors: Joao L Cavalcante, Antonia Delgado-Montero, Abdelaziz Dahou, Luis Caballero, Shasank Rijal, John Gorcsan III, Jean-Luc Monin, Philippe Pibarot, Patrizio Lancellotti
Journal: Circulation (2015)

Introduction: Patients with reduced left ventricular ejection fraction (LVEF), low-flow low-gradient aortic stenosis (LFLG AS) represent a challenging cohort with high morbidity and mortality. Low-dose dobutamine stress echocardiogram (DSE) is recommended for assessment of flow reserve (FR, defined as ≥ 20% increase in stroke volume) which is prognostically important. Hypothesis: Presence of longitudinal dyssynchrony (LD) is independently associated with no FR during DSE. Methods: 185 LFLG AS patients from 4 different institutions who underwent DSE between 1997 through 2013 were studied. Baseline LD, transverse dyssynchrony and strain analysis were performed using vendor-independent 2D CPA TomTec software using DICOM images from apical 2 and 4-chamber and feasible in 97% of patients (N=179). Multivariate logistic regression analysis of predictors of no FR was performed. Results: The mean age was 74 ± 9 yrs; LVEF 30 ± 10%; indexed AV area 0.44 ± 0.1 cm2/m2; mean AV gradient 24 ± 7 mmHg; mean QRS width 126 ± 32 msec and 28% of the cohort had a QRS width ≥ 130 msec. LD, pre-defined as maximum opposite wall delay ≥ 130 msec, was present in 83% (149/179) of study cohort, whereas FR on DSE was present in 54%. Coronary artery disease was more common in those without FR. Although baseline LVEF was not different according to FR status (p=0.23), greater LV stroke volume index (p=0.001) and longitudinal strain (p=0.004) were seen in those without FR. LD was more prevalent in patients without FR (90% vs 77%, p=0.02). On multivariate analysis (Figure 1), presence of LD (HR=4.58, p=0.01) was an independent predictor of no FR despite several adjustments. Conclusions: LD is very prevalent in patients with LFLG AS undergoing DSE. Quantification of LD provides important insights as LD is independently associated with no FR. Whether LD improves after valvular intervention and whether its correction confers a better prognosis to these patients remains to be studied.
Abstract 11625: Role of Wnts and Secreted Frizzled-Related Protein-1 in Atrial Fibroblast Pathophysiology During Atrial Fibrotic Remodeling
Authors: Sirirat Surinkaew, Kristin Dawson, Xiao- Y Qi, Yiguo Sun, Hai Huang, Yu Chen, Patrice Naud, Stanley Nattel
Journal: Circulation (2015)

Introduction: Left atrial (LA) fibroblasts (FBs) respond differentially vs left ventricular (LV) to fibrotic stimuli underlying LA selective fibrosis and atrial fibrillation (AF) in contexts like heart failure (HF). The most differentially expressed gene between LA and LV FBs (28 fold greater in LA) is secreted frizzled-related protein-1 (sFRP1), an endogenous Wnt antagonist. However, the role of sFRP1 and Wnt signaling in FB pathophysiology is unknown. Methods: HF-related LA remodeling was induced in dogs by ventricular tachypacing (VTP 240 bpm). mRNA and protein were quantified in freshly isolated FBs by qPCR (19 Wnt ligands) and immunoblot. Recombinant Wnt and sFRP1 proteins were used to assess effects on FBs; lentivirus-transferred small interfering RNA (siRNA) to knock down sFRP1. Results: AF duration, collagen1 and fibronectin expression increased at 1 and 2 wk VTP, paralleling LA fibrosis. Wnt2 and Wnt5a showed high FB expression. Wnt2 increased in LA FBs at 2 wks (4.8 fold) but did not change in LV (Fig A). Wnt5a decreased quickly in LA and LV (at 12 hrs, -8.9 and -2.9 fold) and remained decreased in LA up to 2 wks (Fig B). sFRP1 decreased at 12 and 24 hrs (-3.9 and -5.4 fold). Treatment of LA FBs with Wnt2 or Wnt5a increased cell size, collagen1 (1.7 and 1.8 fold) and fibronectin (31 and 2.1 fold) expression, and decreased sFRP1 mRNA (by 95% and 54%) (Fig C). Recombinant sFRP1 decreased fibronectin expression (-2.4 fold). Moreover, sFRP1 KD (85% reduction) increased Wnt2 and Wnt5a expression by 4.1 and 7.5 fold (Fig D), suggesting mutual negative interaction between sFRP1 and Wnt signaling in regulating ECM protein secretion. Conclusions: A variety of Wnt ligands are strongly and dynamically expressed in LA. Wnt2 and Wnt5a show countervailing changes during LA fibrosis development in HF, and negatively interact with sFRP1. Our results indicate complex regulation of atrial FB function by the Wnt system, which may provide novel therapeutic targets for AF-substrate prevention.
Abstract 11669: Pulse Pressure and Risk of Cardiovascular Events in Patients With Atherothrombosis: Findings From the REACH Registry
Authors: Senthil Selvaraj, Philippe Steg, Yedid Elbez, Emmanuel Sorbets, Laurent J Feldman, Kim Eagle, E. Magnus Ohman, Jacques Blacher, Deepak Bhatt
Journal: Circulation (2015)

Background: Pulse pressure (PP) provides valuable prognostic information in specific populations, but few studies have assessed its prognostic value on cardiovascular outcomes in a broad, worldwide population. Hypothesis: PP is associated with adverse outcomes independent of mean arterial pressure. Methods: We examined participants from the REACH (Reduction of Atherothrombosis for Continued Health) registry, an international study of individuals with atherothrombotic disease or risk factors for its development. We excluded those with incomplete four-year follow-up or PP data (final N=45,087). Univariable and multivariable regression analyses (using stepwise modeling) were performed to determine the association between PP and cardiovascular outcomes, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, cardiovascular hospitalization, and a combined outcome. Model 1 covariates included sex, age, smoking status, hyperlipidemia, diabetes mellitus, aspirin use, statin use. Model 2 further adjusted for history of atherothrombosis. Model 3 additionally adjusted for blood pressure medications. Model 4 finally adjusted for mean arterial pressure. Results: The mean age of the cohort was 68±10 years, 35% were female, and 81% were treated for hypertension. The mean blood pressure was 138±19/79±11 mmHg (mean PP of 49±16 mmHg). On univariable analysis, increasing PP quartile was associated with worse outcomes (p&lt;0.05 for all comparisons). The Figure displays hazard ratios per 10 mmHg increase in PP, and shows an increased risk of the combined outcome. Similar findings were demonstrated for non-fatal myocardial infarction and cardiovascular hospitalization (p&lt;0.01). Conclusions: In a large international cohort of high-risk individuals, PP, a readily available hemodynamic parameter, is associated with multiple adverse cardiovascular outcomes and provides prognostic utility beyond that of mean arterial pressure.
Abstract 11868: Intracardiac Pressures Measured Using an Implantable Hemodynamic Monitor: Relationship to Mortality in Patients With Chronic Heart Failure
Authors: Stephanie El Hajj, Tom D Bennett, Michael R Zile, Fred J Kueffer, Catalin F Baicu, William T Abraham, Robert C Bourge, Lynne Stevenson
Journal: Circulation (2016)

Introduction: The use of implantable hemodynamic monitor (IHM)-derived pressure to facilitate management of chronic heart failure (CHF) has been shown to decrease ventricular filling pressures and reduce heart failure hospitalizations. However, whether IHM-derived pressures predict mortality rate is unknown. Hypothesis: Determine whether IHM-derived baseline estimated pulmonary artery diastolic pressure (ePAD) and change from baseline ePAD were independent predictors of all-cause mortality in patients with CHF. Methods: A retrospective analysis used data from three studies in CHF patients with an IHM (n=790). Baseline ePAD, mean of daily median ePAD from 0-14 days after IHM implantation, was related to mortality using a multivariable model including baseline and demographic data. Change in ePAD defined from baseline to 6 month and from baseline to 14 days prior to death or exit from study were related to mortality. Area under the pressure vs time curve (AUC) during 180 days prior to death or exit from study was related to mortality. Results: Baseline ePAD, independent of other covariates, was a significant predictor of mortality (Chi-square=36.7, HR=1.067, 95% CI=1.047, 1.089, p&lt;0.0001) (Fig. A). Change in ePAD was a predictor of mortality. There was a significant relationship between change in ePAD from baseline to 6 months and mortality (HR=1.074, 95% CI=1.048, 1.100, p=0008). Change in ePAD = 3, 4, or 5 mmHg from baseline to 6 months was associated with a change in mortality risk of 23.8%, 32.9%, or 42.8% respectively (Fig. B). Change in ePAD from baseline to 14 days prior to death or exit from study was higher in patients that died 3.0±8 vs 1.7±10 mmHg, p=0.003). AUC in the 180 days prior to death or exit from study was higher in the patients that died (185±668 vs 17±482 mmHg.days, p=0.006). Conclusions: Implantable hemodynamic monitor -derived baseline ePAD and change from baseline ePAD were independent predictors of mortality in CHF patients.
Abstract 11885: Neuromuscular Blockade Requirement is Associated With Good Neurologic Outcome in Cardiac Arrest Survivors Treated With Targeted Temperature Management
Authors: Dong Hun Lee, Byung Kook Lee, Kyung Woon Jeung, Yong Il Min
Journal: Circulation (2016)

Introduction: The optimal method for neuromuscular blockade (NMB) in post-resuscitation care has not been fully elucidated. We aimed to examine the association of NMB use with neurologic outcome and lactate clearance in cardiac arrest survivors treated with targeted temperature management (TTM). Methods: This retrospective observational study included consecutive adult cardiac arrest survivors treated with TTM from 2012 to 2015. NMB use was categorized into 3 groups: no NMB, bolus NMB (intermittent bolus use), and continuous NMB (continuous infusion). The serum lactate was obtained on admission and at 12 h, 24 h, and 48 h after admission. The primary outcome was poor neurologic outcome at hospital discharge. The secondary outcome was lactate clearance. Results: A total of 309 patients were included, and 206 (66.7%) were discharged with poor neurologic outcomes. No NMB, bolus NMB, and continuous NMB groups included 93, 119, and 97 patients, respectively. No NMB, bolus NMB, and continuous NMB use was associated with poor neurologic outcomes in 81/93 (87.1%), 78/119 (65.5%), and 47/97 (48.5%), respectively ( p &lt; 0.001). Multivariate analysis revealed that older age (odd ratio [OR] 1.038, 95% confidence interval [CI] 1.015-1.061, p = 0.001), shockable rhythm (OR 0.273, 95% CI 0.125-0.599, p =0.001), cardiac etiology (OR 0.262, 95% CI 0.115-0.599, p =0.001), longer downtime (OR 1.051, 95% CI 1.026-1.076, p &lt;0.001), high Glasgow coma scale (OR 0.550, 95% CI 0.416-0.728, p &lt;0.001), and continuous NMB (OR 0.317, 95% CI 0.124-0.815, p =0.017) compared to no NMB use were associated with poor neurologic outcomes. Serum lactate level ( p = 0.658) and lactate clearance ( p = 0.440) were not different among NMB groups. The serum lactate level decreased significantly over time ( p &lt;0.001), and was different between good and poor neurologic outcomes ( p &lt;0.001), while lactate clearance was not different ( p = 0.701). Conclusions: Continuous NMB use, rather than no NMB use, was associated with good neurologic outcome at discharge in cardiac arrest survivors treated with TTM. The method of NMB was not associated with serum lactate level and lactate clearance.
Abstract 18250: Tafazzin-Knockdown Mice: Heart Mitochondrial Structure and Function
Authors: Junhwas Kim, Hisashi Fujioka, Bernard Tandler, Charles Hoppel
Journal: Circulation (2013)

Barth syndrome is a genetic disorder with mutations in the tafazzin gene resulting in cardiomyopathy, hypotonia, growth delays, and cyclic neutropenia. Mitochondria have been examined for functional defects in Barth syndrome and defects found in oxidative phosphorylation, a decreased content and abnormal composition of cardiolipin, and an increased content of monolysocardiolipin. Consequently, mitochondrial dysfunction resulting from the cardiolipin abnormality has been posited as the primary cause for pathology in Barth syndrome. However, the mechanisms that link cardiolipin abnormality, mitochondrial dysfunction, and the various pathological conditions in Barth syndrome are still unknown. We studied isolated heart subsarcolemmal and interfibrillar mitochondria from tafazzin knockdown mice to examine the role of cardiolipin in mitochondrial dysfunction. In the knockdown mice, the cristae assume the shape of Florence flasks, so we designate them as “florentine”. They have a narrow tubular neck connected directly to the boundary membrane_these are the crista junctions, which in these organelles are of exaggerated length. In mitochondria from tafazzin knockdown mice, the yield of mitochondrial protein is similar to wild type, but the content of cardiolipin decreased by 50 %, monolysocardiolipin increased 25-fold, and unsaturated acyl chains increased. In both mitochondrial populations, state-3 respiration using glutamate plus malate, succinate (+rotenone), and acetylcarnitine plus malate was similar to wild type mice. However, state-3 respiration was decreased with palmitoylcarnitine plus malate (both @-25%;p&lt;0.05) and pyruvate plus malate (subsarcolemmal -25%, p&lt;0.05; interfibrillar -14%, p NS), localizing defects to these separate processes, not the oxidative side of oxidative phosphorylation. Mitochondria from knockdown mice did not generate increased reactive oxygen species. Despite a 50 % decrease in cardiolipin content there is only a mild selective defect in mitochondrial function in this mouse model. However, this change in cardiolipin might be involved in the morphological and perhaps physiological alteration of crista junctions.
Pediatric refractory chronic immune thrombocytopenia: Identification, patients' characteristics, and outcome
Authors: Thomas Pincez, Helder Fernandes, Mony Fahd, Marlène Pasquet, Wadih Abou Chahla, Jérome Granel, Stéphane Ducassou, Caroline Thomas, Nathalie Garnier, Eric Jeziorski, Sophie Bayart, Pascal Chastagner, Nathalie Cheikh, Corinne Guitton, Catherine Paillard, Julien Lejeune, Frédéric Millot, Valérie Li‐Thiao Te, Coralie Mallebranche, Isabelle Pellier, Martin Castelle, Corinne Armari‐Alla, Liana Carausu, Christophe Piguet, Joy Benadiba, Claire Pluchart, Jean‐Louis Stephan, Marianna Deparis, Claire Briandet, Eric Doré, Aude Marie‐Cardine, Vincent Barlogis, Guy Leverger, Sébastien Héritier, Nathalie Aladjidi, Thierry Leblanc
Journal: American Journal of Hematology (2024)

Refractory chronic immune thrombocytopenia (r-cITP) is one of the most challenging situations in chronic immune thrombocytopenia (cITP). Pediatric r-cITP is inconsistently defined in literature, contributing to the scarcity of data. Moreover, no evidence is available to guide the choice of treatment. We compared seven definitions of r-cITP including five pediatric definitions in 886 patients with cITP (median [min-max] follow-up 5.3 [1.0-29.3] years). The pediatric definitions identified overlapping groups of various sizes (4%-20%) but with similar characteristics (higher proportion of immunopathological manifestations [IM] and systemic lupus erythematosus [SLE]), suggesting that they adequately captured the population of interest. Based on the 79 patients with r-cITP (median follow-up 3.1 [0-18.2] years) according to the CEREVANCE definition (≥3 second-line treatments), we showed that r-cITP occurred at a rate of 1.15% new patients per year and did not plateau over time. In multivariate analysis, older age was associated with r-cITP. One patient (1%) experienced two grade five bleeding events after meeting r-cITP criteria and while not receiving second-line treatment. The cumulative incidence of continuous complete remission (CCR) at 2 years after r-cITP diagnosis was 9%. In this analysis, splenectomy was associated with a higher cumulative incidence of CCR (hazard ratio: 5.43, 95% confidence interval: 1.48-19.84, p = 7.8 × 10
Abstract 11870: The -174 G&gt;C Interleukin-6 Gene Polymorphism is Associated With Angiographic Progression of Non-culprit Coronary Plaques in a Mid-term Period
Authors: Nikolaos Anousakis-Vlachochristou, Dimitrios Klettas, Konstantinos Melidis, Zeta Azilazian, Maria Asimomiti, Antonios Karanasos, Anastasios Spanos, Eleftherios Tsiamis, Konstantinos Toutouzas, Petros Nihoyannopoulos, Dimitris Tousoulis
Journal: Circulation (2016)

Hypothesis: Inflammation is the key process underlying the course of CAD. Interleukin-6 (IL-6) is an upstream key regulator of inflammation. Single nucleotide polymorphisms (SNPs) of inflammatory genes, reportedly influence the outcomes of CAD patients. We sought to evaluate the impact of -174 G&gt;C IL-6 SNP in patients with established CAD. Methods: We examined previous angiographies of patients with a PCI history, who were prospectively re-investigated for stable/unstable angina after &gt;12 months. We defined progression of CAD by qCA as the emergence of a new culprit lesion. We genotyped patients to their Mendelian randomization group of -174 G&gt;C IL-6 SNP (rs1800795). The probability for CAD progression was evaluated with the Kaplan-Meier and Cox model analysis including age, hypertension, family history, dyslipidemia and diabetes. Results: A total of 157 patients were included with a median follow-up time of 48 months. Genotype distribution was: GG: 30, CC: 55, GC: 72, C variant: 58%, frequencies were in Hardy-Weinberg equilibrium: χ 2 =0.54, p=0.46. Baseline characteristics were evenly distributed. Serum levels of IL-6 differed significantly: CC 5.58±2.52, GG 2.73±1.08, GC 4.04±1.86 mg/L, p&lt;0.001. At 48 months, carriers of IL-6 C allele had 52.8% cumulative probability for progression vs 13.3% G allele, p=0.005. Results were confirmed in multivariate analysis: C allele HR: 5.09, 95% CI (1.55, 16.7), p=0.007, family history HR: 2.46, 95% CI (1.43, 4.23), p=0.001, dyslipidemia HR: 1.47, 95% CI (1.02, 2.11), p=0.041. Conclusions: Patients with established CAD, carrying the -174 C allele of IL-6 gene, had increased risk for progression of non-culprit plaques in a 4-year period. C allele significantly contributed to CAD progression along with family history and dyslipidemia.
Abstract 18257: Use of the TIMI Risk Score in the Emergency Department Discriminates Acute Coronary Syndrome Among Chest Pain Patients With Known Coronary Artery Disease
Authors: Matthew T Crim, Frederick K Korley, Scott A Berkowitz, Mustapha Saheed, Jason Miller, Amy Deutschendorf, Gary Gerstenblith, Peter Hill
Journal: Circulation (2013)

Background: Patients with known coronary artery disease (CAD) presenting to the Emergency Department (ED) with chest pain thought to be of ischemic origin are often admitted to the hospital, yet half or fewer are eventually diagnosed with acute coronary syndrome (ACS). We assessed whether the use of the TIMI risk score, developed for UA/NSTEMI prognostication, applied in the ED and modified to eliminate the “known CAD” variable, could discriminate which of these high-risk patients actually do and do not have ACS. Methods and Results: Chart review was performed on a prospectively defined cohort of 111 patients with known CAD (73% prior PCI, 42% prior CABG) presenting to the ED with chest pain thought to be of ischemic origin, all of whom were admitted to the hospital from December 2012 to April 2013. The composite TIMI risk score and its individual variables were assessed with logistic regression models for their association with ACS as determined by the inpatient attending physician at hospital discharge. ACS was eventually diagnosed in 36 (32.4%) of the patients. Non-ACS patients had a 2.8 day average length of stay and $9,290 average inpatient (post-ED) hospital charges, which is $696,773 for the 75 (67.6%) non-ACS patients. The odds of having ACS increased by 207% (p &lt;0.001) per 1 point increase in TIMI score. TIMI score discriminates ACS and non-ACS with an area under ROC curve (AUC) of 0.794. In a multi-variable model with the individual TIMI variables, elevated troponin (OR 8.00, p 0.002) and ST deviation (OR 8.38, p 0.007) in the ED, and 2 or more prior chest pain episodes (OR 3.89, p 0.061), were most predictive; AUC 0.834. In a multi-variable model with the TIMI variables and each of the CAD risk factors, elevated troponin (OR 6.95, p 0.008) and ST deviation (OR 9.54, p 0.007) in the ED, and 2 or more prior chest pain episodes (OR 3.90, p 0.067) remained most predictive, and diabetes was the most predictive risk factor (OR 2.03, p 0.282); AUC 0.850. Conclusions: A modified TIMI risk score is a valuable tool for discriminating between ACS and non-ACS among patients with known CAD presenting to the ED with chest pain. Application of this risk score, along with other clinical factors, may help avoid short, though potentially unnecessary admissions, and reduce associated costs.