tbuckley/cabot-search huggingface dataset:
Abstract 18692: Survival From Sudden Cardiac Arrest in Women Compared to Men
Authors: Eloi Marijon, Carmen Teodorescu, Florence Dumas, Kyndaron Reinier, Hazrije Mustafic, Audrey Evanado, Kumar Narayanan, Wulfran Bougouin, Lionel Lamhaut, Daniel Jost, Gilbert Pochmalicki, Adriana Huertas Vazquez, Eric Stecker, Katherine Jerger, Harpriya Chugh, Karen Gunson, Jonathan Jui, David S Celermajer, Xavier Jouven, Sumeet Chugh
Journal: Circulation (2013)

Introduction: There is controversy regarding comparative survival from sudden cardiac arrest (SCA) between the sexes that needs further investigation. Hypothesis: Women present with a better outcome after resuscitation for SCA, compared to men. Methods: Female and male SCA cases aged 15-75 years were pooled and compared from 2 large community-based SCA programs across the Atlantic, a Northwestern US metro region and the Greater Paris, France metro area. We compared incidence, characteristics, and outcome (return of spontaneous circulation, ROSC). Results: Of the 7,357 SCA cases, 1783 (24.8%) were female, an incidence of 22.8 (95% CI 22.6-23.0) per 100,000 per year. Compared to men, the overall relative risk of SCA in women was 0.46 (95% CI 0.40-0.54) in US and 0.32 (95% CI 0.31-0.33) in France. Women were older (mean age 57.5±13 vs. 56.3±12, P&lt;0.001), with higher rates of diabetes (40.4 vs. 35.6%, P=0.02) and hypertension (59.0 vs. 53.0%, P=0.006), lower proportion witnessed (63.9 vs. 70.0%, P&lt;0.001), with less bystander cardiopulmonary resuscitation (29.0 vs. 32.3%, P&lt;0.01), and lower proportion of ventricular fibrillation (28.7 vs. 42.4%, P&lt;0.001). Response times were not statistically different in women compared to men (P=0.25). Proportion of ROSC was similar in both sexes (27.82 vs. 27.85%, P=0.98). After adjustment for confounding factors, women were associated with better outcome (OR 1.54, 95% CI 1.30-1.82, P&lt;0.001): 1.35 (95% CI 1.10-1.69, P=0.006) in US, and 1.72 (95% CI 1.28-2.32, P&lt;0.001) in France. Conclusions: SCD in women has distinct characteristics and outcome compared to SCD in men. Our results suggest higher propensity for survival in women compared to men that warrants further investigation.
Abstract 18710: Improvements in Glycemic Control in Type 2 Diabetes Do Not Lead to Reductions in Circulating Cardiac Troponin
Authors: Brendan M Everett, Nancy R Cook, Paul M Ridker, Aruna D Pradhan
Journal: Circulation (2013)

Objective: Concentrations of cardiac troponin T, when measured with a high-sensitivity assay (hsTnT), have emerged as a strong marker of cardiovascular mortality, and are frequently elevated in patients with type 2 diabetes. Whether glycemic control affects concentrations of this marker is unknown. Methods and Results: We measured hsTnT in patients from the LANCET trial, a 14 week, 2x2 factorial, randomized, placebo-controlled trial of insulin glargine and metformin in early type 2 diabetes. Baseline and 14-week follow up samples were available from 438 participants. At baseline, 408 out of 438 (93.2%) had detectable circulating hsTnT, while 59 (13.5%) had hsTnT levels above the established upper reference limit (≥ 14 ng/L). At baseline, the median (IQR) HbA1c was 6.9% (6.3-7.7%) with no significant differences by treatment group. Statistically significant associations with baseline natural logarithm transformed hsTnT were noted for age (ρ=0.09, P&lt;0.05), but not fasting glucose, HbA1c, body mass index, interleukin-6, or high-sensitivity C-reactive protein (each P&gt;0.26). After 14 weeks of randomly allocated therapy, we observed a significant reduction in HbA1c in all treatment groups except placebo (Figure). In models adjusted for baseline hsTnT and baseline antihyperglycemic therapy we observed no over all change in hsTnT by random treatment allocation (P=0.92) and no individual treatment group differences relative to placebo (Figure; each P≥0.37). Conclusions: These data suggest that aggressive glucose control with insulin glargine, metformin, or the combination does not alter concentrations of circulating cardiac troponin T. Our findings are concordant with the results of large randomized controlled trials showing that glycemic control alone may not suffice to substantively lower cardiovascular risk. (Clinicaltrials.gov Identifier: NCT00366301 )
Abstract 12854: Parenchymal Lung Injuries Related to Standard Cardiopulmonary Resuscitation
Authors: Kyoung-Chul Cha, Sung Oh Hwang, Hyung Il Kim, Oh Hyun Kim, Yong Sung Cha, Hyun Kim, Kang Hyun Lee
Journal: Circulation (2016)

Purpose: Little is known about parenchymal lung injuries after external chest compressions during cardiopulmonary resuscitation (CPR). We analysed chest CT scan to evaluate parenchymal lung injury and its clinical significance in patients who received standard CPR and were resuscitated from cardiac arrest. Materials and Methods: We enrolled non-traumatic out-of-hospital cardiac arrest patients older than 18 years old who had been admitted to the ED in cardiac arrest and successfully resuscitated after CPR. Chest CT was obtained immediately after return of spontaneous circulation (ROSC). To allocate the area of lung contusion, we divided both hemithoraces into upper, middle, and lower parts longitudinally and each part was subdivided into 4 regions (anteromedial, anterolateral, posteromedial, and posterolateral) except the lower part of the left lung. Finally, both lungs were divided into 23 regions. To stratify the severity of lung contusion, each region was scored depending on the area of lung contusion (ALC) with 1 = ALC&lt;1/3 of a region, 2 = 1/3≤ALC&lt;2/3 of a region and 3=ALC≥2/3 of a region. Oxygenation index (OI: PaO 2 /FiO 2 ) was measured at the time of ROSC, 24hr, 48hr, 72hr, and 1 week after cardiac arrest. Acute lung injury (ALI) was defined as OI below 300. Results: Ninety-one patients were enrolled. Lung contusion was developed in 37 patients (40.7%) and median lung contusion score was 15 (0-15). Lung contusion was not associated with hospital mortality (p=0.318), development of ALI (p=0.515), or the length of ICU stay (p=0.203). The OI at the time of ROSC was lower in patients with lung contusion score &gt; 23 than in patients with lung contusion score≤23 (164±93 vs. 278±122, p=0.008). However, the OI at 24hrs, 72hrs, and 1 week after ROSC was not different between patients with lung contusion score &gt; 23 and patients with lung contusion score≤23 (p=0.240, 0.698, 0.446, and 0.168, respectively) Conclusion: Extensive lung contusion is associated with a lower oxygenation index at the time of ROSC, but did not affect the resuscitation outcome.
Abstract 18718: Differential Effects of Nebivolol and Metoprolol on Oxidative Stress Markers and Circulating Progenitor Cells
Authors: Joseph Poole, Robert Neuman, Nino Kavtaradze, Alanna Morris, Jose Binongo, Ali Khan, Salman Sher, Arshed Quyyumi
Journal: Circulation (2013)

Background: Unlike traditional beta-blockers, nebivolol activates nitric oxide (NO) release via partial agonist activity at beta-2/3 receptors. We hypothesized that this property of nebivolol compared to metoprolol would improve oxidative stress (OS) and mobilize progenitor cells (PCs) that are known to be enhanced by NO, and ultimately contribute to improved vascular health. Methods: Thirty-two hypertensive subjects (age 54±10 years, 57% male, 83% African American) were randomized in a double-blind, cross-over study to receive either nebivolol or metoprolol for 3 months each. Of the 32 subjects randomized, 30 subjects successfully completed the trial. Two subjects did not complete the study due to serious adverse events. Nebivolol was titrated from 5mg to 20mg daily (mean 12mg) and metoprolol XL from 50mg to 200mg daily (mean 123mg). All other hypertensive therapy was kept constant. Measurements were made at baseline and on each drug after 3 and 6 months. OS was estimated from plasma levels of glutathione that reflects increased oxidative stress at lower levels. Circulating PCs were measured using flow cytometry for CD34+ and CD34+/CD133+ positive cells in mononuclear cell pools (CD45med). Arterial stiffness was measured as pulse wave velocity and augmentation index using the Sphygmacor device. Results: Compared to baseline, both nebivolol and metoprolol significantly and equally lowered systolic and diastolic BP (p&lt;0.01). Nebivolol, but not metoprolol significantly increased the glutathione level (from 1.08 to 1.50μM; p=0.04). Both nebivolol and metoprolol significantly increased circulating numbers of CD34+/CD133+ PCs compared to baseline by 28% and 18%, respectively (p=0.02, for both). Neither nebivolol nor metoprolol significantly changed indices of arterial stiffness. Conclusion: Beta adrenergic antagonists increase circulating levels of PCs indicating improved regenerative capacity. Nebivolol, but not metoprolol, reduces oxidative stress, measured as plasma glutathione. The lack of translation of these effects on arterial stiffness may be secondary to the short duration of therapy in a treated population.
Abstract 186: NHE-1 Inhibition Reduces Rigor and Hypercontracture in Isolated Cardiomyocytes During Ischemia and Reperfusion
Authors: Sathya Velmurugan, Jeejabai Radhakrishnan, Alvin Baetiong, Raúl J Gazmuri
Journal: Circulation (2013)

Background: During ischemia, anaerobic metabolism prompts intracellular acidosis with activation of the sodium hydrogen exchanger isoform-1 (NHE-1), resulting in intracellular Na+ overload consequent to reductions in Na+-K- ATPase activity. The Na+ excess prompts Ca2+ entry through the sodium-calcium exchanger, leading to Ca+ overload. Ca+ overload, predisposes cells to hypercontracture upon reoxygenation. NHE-1 inhibition reduces Na+ overload and the subsequent Ca+ overload. We developed a programmable system to model ischemia and reperfusion by dynamically blending O2, CO2, and N2 and used it to model changes in gas tension at the tissue levels during ischemia and reperfusion. We validated the model by comparing the effects of reoxygenation with and without the NHE-1 inhibitor zoniporide in isolated adult rat cardiomyocytes. Methods: The set-up included: (i) a programmable dynamic gas blender developed by us, (ii) equilibration of ischemic buffer with anoxic gas mixture at 3-5 LPM and perfusion within an imaging chamber at 2.5 ml/min, (iii) a glass reservoir and stainless steel tubing to avoid gas diffusion, (iv) an acrylic hood, constantly flushed with anoxic gas mixture, covering the chamber on the stage of the microscope, and (v) an O2 microelectrode to continuously monitor PO2 in the chamber. The set-up resulted in PO2 of 0 mmHg during ischemia. The cells were subjected to 15 min of baseline stabilization, 45 min of ischemia, and 120 min of reperfusion. Zoniporide (at a final concentration of 3 μM) was administered starting at 10 min of ischemia and was maintained throughout reperfusion. Results: Zoniporide significantly attenuated development of rigor and subsequent hypercontracture (P=0.001, Gehan Breslow survival analysis). Conclusion: The newly develop system reproduced at the cell level effects of ischemia and reperfusion. These effects were attenuated by NHE-1 inhibition as it has been reported in isolated organs and in the in situ heart.
Abstract 12604: Potassium-dependence of Arrhythmias due to the <i>SCN5A</i> Variant R222Q
Authors: Laura Daniel, Tao Yang, Dan Roden
Journal: Circulation (2016)

Background: R222Q is a charge-neutralizing mutation in domain I/S4 voltage sensor of the cardiac sodium channel. Mutation carriers display very frequent ectopy and dilated cardiomyopathy (DCM). To probe mechanisms for the ectopy, DCM, and the relationship between the two, we have generated mice carrying humanized wild-type (H) or mutant (RQ) channels. Methods and results: RQ/RQ pups are viable but typically die by 7 days postnatally, so the data reported here compare RQ/H and H/H. Consistent with previous heterologous expression studies, RQ/H myocytes displayed hyperpolarizing shifts in both inactivation (V 1/2 : -107.1±1.2 mV vs -94.7±1.3, p&lt;0.01) and activation (V 1/2 : -70.1±1.3 mV vs -53.8±1.6, p&lt;0.01) resulting in increased window current. RQ/H myocytes also displayed accelerated I Na fast inactivation (1.5±0.1 ms vs 2.1±0.2 at -40 mV, p&lt;0.01), recovery from inactivation, and unusually short action potential duration (APD 90 : 12.6±1.3 ms vs 29.1±1, p&lt;0.01). However, at 3 and 6 months RQ/H mice exhibited only infrequent ectopy. Surface ECGs and echocardiograms were normal. Previous reports have identified an outward pore current with DCM-associated SCN5A voltage sensor domain mutations, and in analogous SCN4A mutations associated with hypokalemic periodic paralysis. Decreasing [K + ] o from 4 to 2 mM increased R222Q-associated pore current from 11.9±2.0 pA/pF to 19.1±2.1 at +40 mV (p&lt;0.05); there was minimal pore current in H/H myocytes at either potassium concentration. Decreasing [K + ] o also elicited afterdepolarizations in 9/14 RQ/H myocytes compared to 0/10 H/H. With Langendorff perfusion of 2 mM [K + ] o , ectopy was present in 0.2±0.6% of beats in H/H hearts but was markedly enhanced to 24.3±9.6% in RQ/H (n=6-9; P&lt;0.05). Conclusion: Despite striking I Na dysfunction, RQ/H mice displayed minimal ectopy. The lack of DCM in the absence of frequent ectopy supports the hypothesis that frequent ectopy causes the DCM in human mutation carriers. Hypokalemia increased pore current in R222Q myocytes, and was highly arrhythmogenic in vitro and ex vivo . We speculate that frequent ectopy in human mutation carriers could be responsive to potassium supplements, and this in turn could prevent or ameliorate the DCM phenotype.
Abstract 18577: Survival Benefits of Transcatheter Mitral Valve Repair is Comparable to Surgery, but Superior to Conservative Treatment in High Risk Patients
Authors: Martin J Swaans, Annelies L Bakker, Arash Alipour, Frank D Eefting, Benno W Rensing, Jan A van der Heyden, Martijn C Post
Journal: Circulation (2013)

Objective: Up to 50% of patients with symptomatic severe mitral valve regurgitation (MR) are denied for surgery due to high perioperative risk. Transcatheter repair using MitraClip might be a good alternative. We compared mortality outcome between MitraClip, surgery and conservative treatment in high risk patients. Methods: Consecutive patients treated with the MitraClip system were included. Comparator surgical and conservative treated patients were identified retrospectively and consented to compare survival. Surgical risk was based on logistic EuroSCORE or the presence of relevant risk factors, judged by the heart team. Results: Mean follow-up time was 3.8±0.2 years. 251 patients were included of whom 59 were treated conservatively, 139 treated with MitraClip and 53 underwent surgery. Logistic EuroSCORE was higher in MitraClip (23.9±16.1) than in surgical (14.2±8.9) and conservative (18.7±13.2, P&lt;0.0001) treated patients. MitraClip patients (74.6±9.4) were older than those in the surgical (70.2±9.5) and conservative (71.7±9.6, P=0.009) groups. Majority of patients had functional MR. LVEF was better in surgery group (43.9±14.4%), with similar values for MitraClip (36.8±15.3%) and conservative treated subjects (34.5±16.5%, P=0.003). PHT (sPAP &gt;31mmHg) was more prevalent in MitraClip than in conservative and surgery patients. Incidence of other risk factors did not differ. The mortality rates were 23,0%, 45,3%, and 67,8% for Mitraclip, high risk surgery and conservative treatment, respectively. However due to the retrospective character of the comparator groups, the Mitraclip group had a shorter follow-up time. After weighting for propensity score and controlling for age, COPD and PHT both MitraClip (HR=0.50 95%CI [0.28 - 0.88], p=0.02) and surgical group (HR=0.53 95%CI [0.32 - 0.89], p=0.02) showed better survival than the conservative group. MitraClip and surgical groups did not differ (HR=1.06 95%CI [0.60 - 1.88], p=0.84). Conclusion: Despite higher logistic EuroSCORE, high risk patients with severe symptomatic MR treated with the MitraClip have similar mortality outcomes compared to those treated surgically, both showing survival benefit compared to conservative treatment.
Abstract 13142: Characteristics of Decremental Accessory Pathways in Children
Authors: Allison Hill, Michael Silka, Yaniv Bar-Cohen
Journal: Circulation (2015)

Introduction: While decremental retrograde accessory pathways (DAPs) classically present clinically as permanent junctional reciprocating tachycardia (PJRT), they may be diagnosed unexpectedly during electrophysiology study (EPS). Although DAPs associated with PJRT have been studied, information about other variants of DAPs in children is limited. Methods: We retrospectively studied patients 0 - 21 years of age with retrograde DAPs who underwent EPS between 2005 and 2014. Decrement was defined as rate-dependent prolongation of the local ventriculo-atrial (VA) time by &gt; 30 ms during ventricular extrastimulus or rapid ventricular pacing. Clinical presentation, electrophysiologic properties and ablation outcomes of patients with DAPs were compared to an age-matched cohort of patients with non-decremental accessory pathways. In addition, a sub-analysis examined patients with DAPs depending on whether clinical PJRT was diagnosed prior to the EPS. Results: A total of 29 patients with DAPs and 83 controls were included [mean age at time of EPS 10.3 ± 5.7 years and 10.7 ± 5.2 years, respectively (p = NS)]. Compared to controls, DAPs were more likely to be associated with syncope [6/29 (21%) vs 3/83 (4%), p = 0.01], ventricular dysfunction [6/29 (21%) vs 4/83 (5%), p = 0.04], and treatment with antiarrhythmic medications [20/29 (69%) vs 39/83 (47%) p = 0.04]. In addition, DAPs were more likely to be right-sided [20/29 (69%) vs. 24/83 (29%), p &lt; 0.01] and septal [19/29 (66%) vs 17/83 (21%), p &lt; 0.01]. DAPs and their age-matched controls had similar rates of acute ablation success [26/29 (90%) vs 77/83 (93%), p = NS] and recurrence [2/29 (7%) vs 4/83 (5%), p = NS]. There were no major procedural complications in either group. Of the patients with DAPs, only 12 (41%) had clinical PJRT, and these patients had more syncope [6/12 (50%) vs 0/17 (0%), p &lt; 0.01], slower ORT (mean cycle length 383 ± 89 ms vs 323 ± 60 ms, p = 0.04), and longer maximum VA times (mean 283 ± 116 ms vs 208 ± 42 ms, p = 0.01) compared to those with DAPs without clinical PJRT. Conclusions: The majority of pediatric patients with DAPs do not present with clinical PJRT. DAPs in general are typically associated with more severe symptoms, but ablation outcomes are similar to age-matched controls with non-decremental pathways.
Abstract 12526: Snf1-related Kinase Improves Cardiac Mitochondrial Efficiency by Decreasing Mitochondrial Uncoupling
Authors: Amy K Rines, Hsiang-Chun Chang, Rongxue Wu, Tatsuya Sato, Arineh Khechaduri, Jason S Shapiro, Meng Shang, Michael A Burke, Xinghang Jiang, Chunlei Chen, Tenley A Rawlings, Gary D Lopaschuk, Paul T Schumacker, E. D Abel, Hossein Ardehali
Journal: Circulation (2016)

Introduction: Ischemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in cardiac tissue death. Snf1-related Kinase (SNRK) is a serine/threonine kinase with sequence similarity to AMP-activated protein kinase, but its function is unknown. We found that SNRK is increased in hearts from patients with ischemic cardiomyopathy, and our gene array data suggested that SNRK alters metabolic genes. Here, we assessed the hypothesis that SNRK improves cardiac metabolic efficiency and mitochondrial uncoupling, and protects against ischemia/reperfusion (I/R) injury. Results: Cardiac-specific SNRK transgenic (TG) mice displayed decreased glycolysis, glucose oxidation, and palmitate oxidation compared to wild type littermate controls in perfused working hearts. However, cardiac power, contractility, ATP, and triglyceride and glycogen stores were maintained, while oxygen consumption was reduced, demonstrating that SNRK TG mice have increased cardiac metabolic efficiency. Consistent with improved cardiac metabolic efficiency, SNRK TG mice exhibited decreased infarct size after I/R. Mitochondria from SNRK TG mice also had reduced respiration, and increased respiratory control ratio and mitochondrial membrane potential, indicating reduced mitochondrial uncoupling. Uncoupling protein 3 (UCP3) levels were also decreased. Conversely, hearts from heterozygous SNRK knockout mice had increased glucose and palmitate oxidation and UCP3. SNRK knockdown in cardiac cells decreased mitochondrial efficiency, which was abolished with UCP3 knockdown. To determine the mechanism for the regulation of UCP3 by SNRK, we performed yeast two-hybrid assay, and identified tribbles homolog 3 (Trib3) to bind to SNRK. Furthermore, Trib3 enabled downregulation of UCP3 by downregulating the expression of PPARα. Conclusions: Our results demonstrate that overexpression of SNRK decreases cardiac metabolic substrate usage and oxygen consumption but maintains cardiac function and enhanced mitochondrial coupling. We also identify a binding partner of SNRK, Trib3, which is upregulated by SNRK in mice and mediates the regulation of PPARα and UCP3 by SNRK.
Abstract 12601: <i>O</i> -Glycosylation of ApoB100 is Associated With Enhanced Sphingomyelinase Activity and Atherogenicity of Human Electronegative LDL
Authors: Liang-Yin Ke, Hua-Chen Chan, Chih-Chieh Chen, Jonathan Lu, Gopal K. Marathe, Chih-Sheng Chu, Hsiu-Chuan Chan, Chung-Ya Wang, Shi-Hui Law, Yi-Ching Tung, Thomas M McIntyre, Jeng-Hsien Yen, Chu-Huang Chen
Journal: Circulation (2015)

Background: Among the 5 (L1-L5) chromatographically resolved subfractions of human LDL, L5 is the most electronegative and atherogenic. L5’s atherogenicity may be attributed in part to its high ceramide content. Because ceramides can be converted from sphingomyelins by sphingomyelinase (SMase), we examined whether L5 has SMase-like properties. Methods and Results: The total lipid extract of L5 was as capable as L5 in inducing arterial endothelial cell (EC) apoptosis. LC/MS E analysis confirmed that L5 had a significantly greater ceramide content in the lipid extract than L1 (n=4; P &lt;0.01). On Amplex Red SMase assays, L5 but not L1 exhibited a strong SMase-like activity (n=12). ECs treated with L5 increased intracellular ceramide concentrations; the associated cytotoxicity was significantly attenuated by SMase inhibitor desipramine. To identify the putative region of LDL with SMase activities, we compared human apolipoprotein B100 (apoB100) with Bacillus cereus , Leptospira interrogans , and Staphylococcus aureus SMases in amino acid sequences. The predicted catalytic site of human apoB-100 with activities similar to the bacterial SMases comprised N 2035 , E 2079 , F 2081 , N 2084 , E 2140 , N 2251 , D 2253 , D 2312 , and H 2366 in the α2 region. Post-translational analysis with LC/MS E and ProteinLynx Global SERVER (PLGS) revealed exclusive O -glycosylation of the amino acid residues S 1732 , S 1959 , S 2378 , S 2408 and S 2429 in the α2 region. Conclusions: The structural uniqueness of the α2 region of apoB-100 characterized by specific O -glycosylation may underlie L5’s atherogenicity through enhanced SMase activity and ceramide overproduction. Modifying this region may curtail L5’s atherogenicity.