tbuckley/cabot-search huggingface dataset:
Abstract 15509: Circulating Ceramides Predict Fatal and All Incident Major Adverse Cardiovascular Events: A Prospective Analysis of the FINRISK 2002 Cohort
Authors: Aki S Havulinna, Marko Sysi-Aho, Reini Hurme, Reijo Laaksonen, Veikko Salomaa
Journal: Circulation (2015)

Introduction: Ceramides are molecular lipids assumed to play a role in apoptosis, inflammation, obesity and insulin resistance. A recent study reported that certain ceramides were associated with fatal outcome among patients with CHD. Hypothesis: We hypothesized that ceramides are associated with incident cardiovascular (CVD) outcomes among apparently healthy individuals over and above the traditional risk factors. Methods: FINRISK 2002 is a population-based risk factor survey, which recruited 8,798 men and women aged 25-74 years. The participation rate was 65.5%. The cohort was followed up through 31 Dec, 2011, for incident CVD events and through 31 Dec, 2012, for deaths. Our primary outcome was major adverse cardiovascular events (MACE, n= 471). Secondary analyses were carried out for fatal MACE (n=137). Four circulating ceramides (Cer d18:1/16:0, Cer d18:1/18:0, Cer d18:1/24:0, and Cer d18:1/24:1) were determined from frozen samples using mass spectrometry. We used Cox proportional hazard models with age as the time scale to determine associations of the ceramides with incident outcomes. All models were stratified by sex and the full models were adjusted for geographic region, total and HDL-cholesterol, systolic blood pressure, blood pressure medication, BMI, smoking and diabetes. The predictive ability of the ceramides was assessed by estimating the 10-year absolute risk of MACE and comparing the full models with and without ceramides. The predictions were done using 10-fold cross-validated Weibull proportional hazard models. Results: When considered one by one, three out of the four ceramides were significantly associated with the risk of incident MACE in the fully adjusted Cox models. Ceramide score, formed as a linear combination of the four ceramides had a hazard ratio (HR) of 1.75 (p=0.005) in the full model. C-statistics did not change significantly but the net reclassification improvement among persons with intermediate risk was significant 6.2% (2.6 - 9.7%). The association of the ceramide score with fatal MACE was even stronger than with all MACE: HR=2.31 (p=0.02). Conclusions: These results show the potential of lipidomics profiling in producing new insights in the pathogenesis of CVD and suggesting new therapeutic targets.
Abstract 14702: Evaluation of Inflammation in Carotid Disease by New Imaging Modalities: Implications From 18-FDG PET/CT and Microwave Radiometry
Authors: Iosif Koutagiar, Konstantinos Toutouzas, Georgios Benetos, Alexandros Georgakopoulos, Emmanouil Athanasiadis, Sofoklis Trachanellis, Nikolaos Patelis, Konstantinos Filis, Nikos Bessias, George Spyrou, Dimitrios Tousoulis, Constantinos Anagnostopoulos
Journal: Circulation (2015)

Background and Purpose: Nowadays, 18F fludeoxyglycose Positron Emmision Tomography/computed tomography (18F-FDG PET/CT) is the leading modality for tracing inflammation within atherosclerotic plaques in vivo, but patients’ exposure to radiation, costs and availability limit its widespread use. We hypothesize that microwave radiometry (MWR), a safe noninvasive method allowing in vivo estimation of atherosclerotic process by measuring temperatures of tissues could be an accurate alternative tool for assessing lesional inflammation. Therefore, the aim of the present study was to investigate the relationship between temperature differences and FDG uptake assessed by MWR and 18F-FDG PET/CT respectively, in patients with significant carotid disease. Methods: Consecutive patients, scheduled for carotid endarterectomy due to significant carotid artery (CA) stenosis, underwent 18F-FDG PET/CT and MWR. PET/CT images were acquired 90 min after FDG injection. FDG uptake was measured as maximal standardized uptake value (SUVmax) in consecutive axial slices starting at the bifurcation and extending 2 cm superiorly and 2 cm inferiorly. During MWR evaluation, ΔΤ (maximal temperature across the carotid artery minus minimum) was calculated over the respective carotid segments. Results: In total, 44 CAs from 22 patients (18 male) were studied. There was a significant positive correlation between ΔT and SUVmax values in the operated arteries and also between the same parameters in all 44 vessels (R=0.44, p=0.05 and R=0.44, p=0.005, respectively). Operated and non-operated CAs demonstrated similar ΔT and SUVmax values (0.57±0.19 vs 0.59±0.17 °C, p=0.67 and 2.18±0.44 vs 2.28±0.41, p=0.48 respectively). In addition, there was no correlation between the degree of angiographic stenosis and ΔT values (R=0.07, p=0.65) or between lesional SUV measurements and the percentage of luminal stenosis (R=0.10, p=0.55). Conclusions: There is a significant correlation between FDG uptake and thermal heterogeneity, indicating that MWR is a promising marker of plaque inflammation. Moreover, there is discrepancy between stenosis severity and inflammation intensity assessed by FDG uptake and MWR, highlighting the diversity of processes involved in CA atherosclerosis.
Abstract 14612: Does the Open Smooth Antrum of the Left Atrial Appendage Serve as a Nidus for Thrombus Formation in Patients With Atrial Fibrillation and Surgical Appendage Clip i <i>n situ</i> ?
Authors: Sanghamitra Mohanty, Chintan Trivedi, Carola Gianni, Mahmut F Gunes, Yalcin Gokoglan, Rong Bai, John David Burkhardt, Javier Sanchez, Patrick Hranitzky, G. J Gallinghouse, Amin Al-Ahmad, Rodney Horton, Richard Hongo, Steven Hao, Salwa Beheiry, Luigi Di Biase, Andrea Natale
Journal: Circulation (2015)

Introduction: Atrial fibrillation (AF) is a significant risk factor for embolic stroke originating from the left atrial appendage (LAA). LAA occlusion is recommended in patients that are not amenable to anticoagulation therapy because of elevated CHADS 2 or CHA 2 DS 2 -VASC score. We assessed the risk of stroke off anticoagulants in AF patients following LAA occlusion with appendage clip device. Methods: One hundred eighty-five AF patients (age 66±13, males 69%, CHADS 2 2.6± 0.8, CHA 2 DS 2 -VASC 3.5± 1.2) that received surgical left atrial appendage occlusion device (clip) were included in this analysis. Transesophageal echocardiogram (TEE) was performed at the end of the procedure to evaluate successful closure of the antrum of the LAA and was repeated at 1 and 6-month post-procedure. Patients remained on oral anticoagulants for 1-month post-procedure after which it was discontinued. All patients were monitored for thrombo-embolic complications for at least 1 year by TEE, clinic visits at 3-month intervals and phone calls by our research staffs. Result: The follow-up TEE revealed the LAA clip to be stable without any secondary displacement. No LAA thrombus was detected. Interestingly, in 177 (95.6%) patients, TEE revealed the proximal part of the smooth antrum of the LAA neck below the clip, to be still open. At the end of the 24±3 months of follow-up, no stroke or transient ischemic attack (TIA) or other neurological events were observed in the study population (0 of 155, 0%). Conclusions: In patients with AF in whom oral anticoagulation is deemed unsuitable because of high CHADS 2 or CHA 2 DS 2 -VASC score, left atrial appendage closure with surgical clip device seems to be safe and effective in preventing stroke. It is relatively common to find incomplete obliteration of the LAA with the surgical clip with the proximal portion of the smooth antrum still remaining open as the clip is typically seen to be placed higher up in the LAA neck. However, presence of the open smooth-antrum did not increase the risk of stroke even after discontinuation of anticoagulants.
Abstract 14682: Impact of Life-Style Change on the Arrhythmia Status in Patients With Long-Standing Persistent Atrial Fibrillation
Authors: Sanghamitra Mohanty, Prasant Mohanty, Chintan Trivedi, Carola Gianni, Mahmut F Gunes, Yalcin Gokoglan, Amin Al-Ahmad, John David Burkhardt, Javier Sanchez, Rodney Horton, Patrick Hranitzky, G. J Gallinghouse, Steven Hao, Richard Hongo, Luigi Di Biase, Andrea Natale
Journal: Circulation (2015)

Background: Aggressive life-style changes by reversing obesity reportedly cause significant decrease in arrhythmia burden and symptom severity, thereby reducing or eliminating the need for arrhythmia medications in AF patients. However, these observations were documented in populations comprised primarily of paroxysmal and persistent AF patients. This study investigated the impact of lifestyle changes on AF status and quality of life (QoL) in long-standing persistent (LSPAF) patients. Methods: Fifty-two LSPAF patients [age 64±10 years, 71% male, weight 256 (IQR 216 -342) lb.] were included in this prospective analysis. Subjects that volunteered to try weight-loss interventions undertook aggressive diet and exercise measures for 1 year while remaining on anti-arrhythmic drugs. They received Individualized diet menus prepared by experienced nutritionists to achieve targeted weight loss and were prescribed moderate-intensity exercise; 150 minutes/week of brisk walking (15 minutes a mile) or bicycling slower than 10 miles per hour. At the beginning and end of the intervention period, body weight was measured; arrhythmia status was evaluated by ECG, Holter and Atrial Fibrillation Symptom Severity (AFSS) survey and QoL was assessed by SF-36 survey. A scoring algorithm with two summary measures, PCS and MCS was prepared for QoL analysis. Results: After 1-year of intervention, significant reduction in body weight (median -54 (IQR -42 to -120) lb., p&lt;0.001) was observed. Also, the PCS and MCS scores demonstrated substantial improvement with a change from baseline of 8.4±3 (p=0.013) and 12.8±8.2 (p &lt;0.02) respectively. However, no such impact was observed on the AF symptoms. Two (3.8%) and 3(5.8%) patients were asymptomatic, 18(34.6%) and 15(28.8%) had mild, 28(53.8%) and 31(56.9%) had moderate, and 4(7.7%) and 3(5.8%) patients experienced severe symptoms, pre- and post-intervention respectively (p=0.85). Similarly, very little change in AF burden was observed at the end of the intervention. All patients underwent catheter ablation for AF, eventually. Conclusions: In LSPAF patients, aggressive life-style changes lead to considerable weight-loss and improvement in quality of life. However, substantial weight loss does not alter the AF status.
Abstract 15426: Inflammasome-induced Signalling Mechanisms via Microparticles
Authors: Philipp Pfeifer, Jansen Felix, Sebastian Zimmer, Katharina Schild, Eike Latz, Bernardo Franklin, Georg Nickenig, Nikos Werner
Journal: Circulation (2015)

Introduction: The inflammasome, a multi-protein signaling platform, has been shown to be an important mediator in the development of atherogenesis. Microparticles (MPs) are small membrane vesicles, which are released from apoptotic cells. Whether inflammasome activation leads to the release of MPs by vascular cells is unknown. Hypothesis: Inflammasome-activation in vascular cells leads to microparticle release. These microparticles contain components of the inflammasome and exert functional effects on other vascular cells. Methods: EMP (endothelial microparticles) and MMP (monocytic microparticles) were quantified by flow cytometry using TruCount tubes. Inflammasome-activation was investigated by IL-1β ELISA and immunoblotting. The latter was also used to determine EMP content. Viability Assay was performed to test cell-viability and Scratch assay to examine effects of EMP on migration and proliferation of vascular cells. Results: Human coronary artery endothelial cells (HCAEC) and monocytes were primed with LPS and subsequently stimulated with either ATP or Nigericin, two established inflammasome activators. MP release was quantified by flow cytometry using TruCount tubes. Stimulation of HCAEC and monocytes with both Nigericin and ATP resulted in a time-dependent release of MPs. Inflammasome-activation in HCAEC was confirmed by the release of IL-1β into the cell supernatant and immunoblotting against Caspase-1. Immunoblotting also showed that inflammasom-activated HCAEC and the associated EMP contain pro-Caspase-1, active Caspase-1 and NALP-3. Inoculation of HCAEC with EMP, derived from HCAEC stimulated with Nigericin, lead to a rapid and significant cell death and reduced cell migration/ proliferation shown by Viability Assay and Scratch Assay, respectively. Conclusions: We show for the first time that Nigericin and ATP, two established inflammasome activators, lead to inflammasome activation and release of microparticles by vascular cells. Furthermore, we could demonstrate that these microparticles contain pro-Caspase-1, mature-Caspase-1 and NALP-3 and that they cause cell death accompanied with reduced cell migration and proliferation.
Abstract 14665: The Impact of Glomerular Filtration Rates on the In-Hospital Outcomes of Patients Undergoing Transcatheter Aortic Valve Replacement: Insights of the Healthcare Cost and Utilization Project’s National Inpatient Sample
Authors: Fabio V Lima, Tzyy Y Yen, Luis Gruberg
Journal: Circulation (2015)

Background: Transcatheter aortic valve replacement (TAVR) is currently a Class I indication for the treatment of high surgical risk patients with severe symptomatic aortic stenosis. Hypothesis: There is limited data on the impact of chronic kidney disease (CKD) in patients undergoing TAVR. Methods: The Healthcare Cost and Utilization Project’s National Inpatient Sample was screened for hospital admissions of patients undergoing TAVR in 2003-2012. Patients were divided into 3 groups according to glomerular filtration rate (GFR): GFR &gt;60 mL/min/1.73m 2 , GFR 15 to 59 mL/min/1.73m 2 , and GFR &lt;15 mL/min/1.73m 2 . The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), the composite of in-hospital death, acute myocardial infarction (AMI) and acute cerebrovascular accident (CVA). Results: Data on 311 patients that underwent TAVR was available for analysis. Patients with a GFR &gt;60 mL/min/1.73m 2 were younger but there were no significant differences regarding other comorbidities. In hospital outcomes were similar in all three groups (Fig 1). In a multivariable analysis, increased age was a predictor of MACCE in patients with a GFR &lt;15 mL/min/1.73m 2 (OR 1.09, 95% CI 1.01-1.17) and patients with GFR &gt;60 mL/min/1.73m 2 (OR 1.08, 95% CI 1.01-1.16). However, GFR &lt;15 mL/min/1.73m 2 was not an independent predictor of MACCE. Conclusions: In a contemporary database of patients undergoing TAVR, in-hospital outcomes were good, with low mortality and stroke rates. There seemed to be a numerically higher rate of in-hospital MACCE in patients with GFR &lt;15 mL/min or stage 5 CKD; however, a GFR &lt;15 mL/min was not an independent predictor of MACCE but age was a predictor of worse outcome.
Abstract 15498: Partial Band Mitral Annuloplasty Can Preserve Mitral-aortic Valve Dynamic Coupling After Mitral Valve Repair in Comparison With Complete Ring Plasty
Authors: Noriyuki Wakana, Tetsuhiro Yamano, Hiroyuki Watanabe, Michiyo Yamano, Naohiko Nakanishi, Takehiro Ogata, Takeshi Nakamura, Hirokazu Shiraishi, Tomomi Ueyama, Satoaki Matoba, Hiroyuki Yamada, Kiyoshi Doi, Akiyoshi Matsumuro, Takeshi Shirayama, Hitoshi Yaku
Journal: Circulation (2015)

Introduction: The aortic and mitral valves (MV) demonstrate synchronous behavior to facilitate both left ventricular (LV) filling and emptying. Although partial band (PB) mitral annuloplasty is often performed to maintain anterior annulus flexibility, actual advantages remain undefined. The object of this study is to identify the effects of PB annuloplasty compared with complete ring (CR). Methods: We retrospectively evaluated 24 patients who underwent MV repair for degenerative mitral regurgitation. A PB (CG Future band, Medtronic Inc) was used in 13 patients and a CR (Carpentier-Edwards Physio or Physio II ring, Edwards Lifesciences) in 11. Three-dimensional transesophageal echocardiography was performed and 4D-MV Assessment, 2.0 (TomTec Imaging Systems) was used for semiautomatic tracking of mitral annulus (MA). Aortic annulus (AoA) was manually traced frame by frame in transverse plane perpendicular to LV outflow tract at the level of hinge points of sinuses, which was reconstructed from three-dimensional datasets. Results: MA surface and AoA projected areas changed reciprocally throughout cardiac cycle (Fig a and b). The PB orifice area measured in vitro was smaller than CR (4.8±0.9 vs 5.8±1.2 cm2, P&lt;0.05). There was no difference in patients’ body surface area (1.57±0.21 vs 1.67±0.20 m2). However, the MA area in PB constantly tended to be larger than in CR (maximum area: 8.1±2.0 vs 6.7±1.5 cm2, P=0.09, Fig a). In PB, MA surface area change was greater (10.1±6.0% vs 5.9±2.9%, P&lt;0.05: Fig c); consequently, AoA projected area change was much larger than in CR (39.2±11.0% vs 18.4±4.2%, P&lt;0.01: Fig d). Immediately postoperative residual regurgitation was none or of mild degree in all patients, and Doppler transmitral mean pressure gradient tended to be smaller in PB than in CR (2.0±0.4 vs 2.3±0.9 mmHg, P=0.32). Conclusions: PB mitral annuloplasty could preserve mitral-aortic dynamic coupling, which must provide important consideration at the time of MV repair.
Abstract 597: Targeted Deletion of Thioredoxin-Interacting Protein Prevents Cardiac Dysfunction in Response to Pressure Overload
Authors: Jun Yoshioka, Kenichi Imahashi, William A Chutkow, Aurora A Burds, Joseph Gannon, Catherine MacGillivray, P. C Schulze, Elizabeth Murphy, Richard T Lee
Journal: Circulation (2006)

Biomechanical overload induces left ventricular (LV) hypertrophy and failure, and reactive oxygen species (ROS) play a role in both processes. We previously identified Thioredoxin-Interacting Protein (Txnip) as a mechanically regulated gene that controls cell growth and apoptosis in part through the inhibition of the endogenous dithiol antioxidant thioredoxin. Here we show in mice that Txnip is a critical regulator of the cardiac response to pressure overload, potentially through regulation of myocardium glucose utilization. We generated cardiac-specific and systemic Txnip null mice (Txnip-KO) using Flp/frt and Cre/lox technology. Epitope-mapped monoclonal antibodies demonstrated complete absence of Txnip protein in targeted tissues. Compared with wild-type littermates (WT), Txnip-KO hearts had reduced LV mass (Δ%LV mass/ tibial length from baseline to TAC −50±20%, n=14), myocyte cross-sectional area (−16±6%, n=11, P&lt;0.05), and percent fibrosis area (−54±19%, n=11, P&lt; 0.05) in response to pressure overload by transverse aortic constriction. Echocardiography and catheterization revealed that Txnip-KO hearts had preserved fractional shortening (Δ%FS +41±18% from baseline to TAC, n=17, P&lt;0.05), stroke volume (+43±20%, n=4, P&lt;0.05), and LV developed pressure (dP/dt max: +19±10%; dP/dt min: +64±22%, n=6, P&lt;0.05) after TAC compared with wild-type littermates. Surprisingly, the beneficial effects of Txnip deletion on cardiac performance were not associated with increased myocardial thioredoxin activity or reduced levels of ROS. Since the systemic Txnip-KO mice were hypoglycemic, we measured myocardial 2-deoxyglucose uptake (2-DG) using 31 P NMR spectroscopy. Txnip-KO hearts showed a robust increase in 2-DG uptake in an insulin-independent manner (3.2±0.5-fold over WT, n=6, P&lt;0.01). LV developed pressure was preserved during 2-DG uptake in Txnip-KO hearts (2.3±0.3-fold over WT; n=6, P&lt;0.01). These data demonstrate that deletion of Txnip prevents cardiac dysfunction in response to pressure overload in vivo, but the benefits of Txnip deletion may be due to an unanticipated role in myocardial glucose metabolism rather than inhibition of thioredoxin activity.
Abstract 584: Simultaneous Antagonism of the V2 Receptor with Tolvaptan and Activation of the Natriuretic Peptide A-Receptor with B-Type Natriuretic Peptide: A Novel Strategy to Physiologically Enhance Water and Sodium Excretion Without Adversely Affecting Renal Function in a Canine Model of Congestive Heart Failure
Authors: Lisa C Costello-Boerrigter, Guido Boerrigter, Gail J Harty, John C Burnett
Journal: Circulation (2006)

Background: Water and sodium (Na) retention are hallmarks of congestive heart failure (CHF). While widely employed, conventional diuretics may adversely affect renal function. Therefore, physiological strategies that enhance water and Na excretion while maintaining renal function are a high priority. Arginine vasopressin (AVP) increases water reabsorption after binding to the V2 receptor in the collecting duct (CD). In contrast, B-type natriuretic peptide (BNP) decreases Na reabsorption via activation of the NPR-A receptor also in the CD and at higher doses also in the proximal tubule. We hypothesized that coadministration of the V2-receptor antagonist tolvaptan (TLV) and BNP would mediate a potent diuresis and natriuresis without adversely affecting renal hemodynamics in experimental CHF. We also assessed plasma and urinary excretion of AVP. Methods: Severe CHF was induced in 2 groups of dogs by tachypacing. On day 11 cardiorenal function was assessed. One group received TLV alone (0.1 mg/kg IV bolus; n=6), whereas the other group received infusion of BNP (50 ng/kg/min) in addition to TLV (n=5). Results: Renal hemodynamics were preserved in both groups. TLV alone increased urine flow from 0.07±0.01 to 0.48±0.09 mL/min, while urinary Na excretion (UNaV) remained unchanged. TLV+BNP-50 increased urine flow from 0.17±0.07 to 2.58±0.47 mL/min and UNaV from 1±1 to 77±23 uEq/min while decreasing proximal fractional Na reabsorption (all p&lt;0.05 vs. TLV alone). TLV alone increased plasma aldosterone and distal fractional Na reabsorption, both of which were prevented with BNP-50. In addition, while plasma AVP did not change with TLV or TLV+BNP, urinary AVP excretion markedly increased with TLV+BNP (from 16±5 to 694±196 pg/min) as compared to TLV alone (from 1±1 to 69±23 pg/min). Conclusions: TLV and BNP coadministration enhances aquaresis and natriuresis through proximal and distal tubular actions without changing renal hemodynamics. Further, TLV with BNP uniquely enhances urinary elimination of AVP warranting further study. We conclude from these findings in experimental CHF that simultaneously antagonizing the V2 receptor by TLV and activating the NPR-A receptor with BNP may be a novel and physiologic diuretic and natriuretic strategy in overt CHF.