tbuckley/cabot-search huggingface dataset:
Abstract 18960: Ciliary Neurotrophic Factor Increases the Angiogenic Properties of Human Pluripotent Stem Cell Derived Neuropilin-1+ CD34+ Nascent Endothelial Cells Via a JAK2 Dependent Pathway
Authors: Jennifer K Lang, Fraser J Sim, Thomas R Cimato
Journal: Circulation (2012)

Pluripotent stem cells are a model to identify novel regulators of angiogenesis. Previously, we showed that Neuropilin-1 (NRP1) CD34- cells were vascular precursors. Subsequently, genomic analysis revealed that NRP1+ CD34+ cells had transcript content consistent with nascent endothelium, and unique growth factor receptors that may be exploited to modulate their angiogenic properties. The objectives of our study was to verify that NRP1+ CD34+ cells form endothelium, and determine the function of the Ciliary Neurotrophic Factor (CNTF) Receptor and its downstream kinase Jak2 in angiogenesis. Methods and Results: Human induced pluripotent stem cells (hiPSCs) were differentiated as embyroid bodies and NRP1+ CD34+ nascent endothelial cells were sorted. NRP1+ CD34+ cells readily formed sheets of endothelium expressing VE-Cadherin, CD146, PECAM, and eNOS, absorbed acetylated LDL, and formed tubule networks in Matrigel. These features confirmed their endothelial properties. Here we show that CNTF promotes angiogenic sprouting of NRP1+ CD34+ cells via a Jak2 dependent mechanism. RT-PCR analysis of NRP1+ CD34+ transcripts showed a significant (&gt; 5 fold) increase in the growth factor receptor CNTFR, and the downstream signaling partners Jak2, Stat5A and Stat6 versus undifferentiated hiPSCs. CNTF increased the length of endothelial tubules in Matrigel 44±7.3% vs. no CNTF (p≤0.05), while inhibition of JAK2 in the presence of CNTF blocked the effect of CNTF. Conclusions: NRP1+ CD34+ cells derived from human pluripotent stem cells readily form endothelium, and their angiogenic properties can be augmented by activation of a novel CNTFR-Jak2 mediated pathway. Collectively, the findings confirm that NRP1+ CD34+ cells are a nascent endothelial cell, and identify a novel growth factor signaling pathway involved in angiogenesis, suggesting a role for CNTF in promotion of angiogenesis in therapy for vascular diseases.
Abstract 333: Sudden Death Expertise Center: A Sudden Cardiac Arrest (SCA) Registry
Authors: Lionel Lamhaut, Wulfran Bougouin, Thomas Loeb, Francois Revaux, Olivier Varenne, Eloi Marijon, Pierre Carli, Xavier Jouven
Journal: Circulation (2012)

Introduction - Knowledge of the epidemiology of the SCA is scarce, requiring collaboration of Emergency Medical Services and Intensive Care Units. Thus we developed a Sudden Death Expertise Center which first step was to develop a exhaustive register. Methods - We considered cases from a large ongoing population-based register, conducted in Paris and suburbs (population of 6.6 millions). Using multiple-source and central adjudication, we prospectively enrolled all out-of-hospital cardiac arrests since May 2011. Sources are fire departments (BLS), Mobile intensive care ambulance (ALS) and hospital services (Emergency, Intensive Care, Cardiology). Completeness is ascertained through informatic queries in some hospitals. Results - Over the first 8 months, we reported 2,214 out-of-hospital cardiac arrests, including 1449 with resuscitation attempted and 1193 with presumed cardiac cause (Figure 1). Among them, mean age was 64.5 years, and they occurred at home in 826 case (72.2%). Initial shockable rhythm was reported in 186 cases (16.2%), and 375 patients (31%) were admitted to hospital. Coronary angiography was performed in 198 patients (53%) and therapeutic hypothermia was applied in 192 patients (51%). Survival at discharge was 3,1% considering all OHCA, and 5,7% for SCA when the resuscitation was attempted. Completeness of the registry was 93%. Conclusion - This registry allow a better understanding of epidemiology of SCA. The next step is the establishment of a multidisciplinary approach to improve survival, through prevention (education programs), treatments (AED programs), and familial screening.
Abstract 8808: Early Repolarization Syndrome: Valsalva Maneuver in Familial Screening
Authors: Jean Baptiste Gourraud, Solena Le Scouarnec, Frederic Sacher, Stephanie Chatel, Pascal Chavernac, Philippe Mabo, Richard Redon, Jean Jacques Schott, Herve Lemarec, Michel Haissaguerre, Vincent Probst
Journal: Circulation (2011)

Introduction: Early repolarization (ER) has been recently linked with idiopathic ventricular fibrillation. In spite of a frequent familial past history of SCD, ER identification in relatives is limited by variability of the ER over the time and with the variation of autonomic tone and heart rate. The aim of the study was to test the ability of valsalva maneuver (VM) to identify larges families affected by early repolarization syndrome (ERS). Methods: We have screened relatives of 2 families in which SCD occurred with ERS. Patients were considered to be affected in the presence of a positive deflection on the S wave in two consecutive leads and at least a 1 mm amplitude above baseline. A VM was performed in relatives to increase or reveal ER. Comparison between heart rate and J wave amplitude before and after VM was performed with a paired Student's t-test. Results: In the first family, 4 SCD occured whose one with an ER pattern. We identified 25 other ER out of 82 available ECG (prevalence 34%). In the second family, 4 SCD occurred whose one with an ER pattern. We identified 17 other ER out of 29 available ECG (prevalence 58%). In those families, ER is transmitted with an autosomal dominant trait through respectively 5 and 4 generations. VM was performed for 80 relatives. It increased ER amplitude in 17/20 (85%) affected patients and revealed ER in 17/60 (28%) patients unaffected at rest. VM succeeded in unmasking pattern for 5/11 (45%) expected carrier of ER previously considered as unaffected. Heart rate at rest was 75 ± 13 bpm and decreased of 3,9 ± 7,9 bpm (p&lt;0,001) during the test without any differences between groups. Conclusion: Malignant forms of ER can be transmitted as an autosomal dominant trait in large families. VM could be helpful to unmask ER for familial screening of relatives. Further investigations are required to assess prognosis of VM.
Abstract 9717: Hypertension-Induced Atrial Remodeling Promotes Atrial Fibrillation Stabilization Upon Tachyarrhythmia Onset
Authors: Yuki Iwasaki, Patrice Naud, Yanfen Shi, Ange Maguy, Kyoichi Mizuno, Jean-Claude Tardif, Stanley Nattel
Journal: Circulation (2011)

Background: Hypertension (HT) is a major risk factor for atrial fibrillation (AF) but the underlying mechanisms are poorly understood. We hypothesized that HT produces an AF-stabilizing influence that favors faster progresion of spontaneous AF-maintenance when atrial tachyarrhythmia (AT) begins. Methods: HT was induced in dogs (n=6) by left nephrectomy and right renal artery constriction (1K1C). Sham operated dogs with the same surgery but no nephrectomy or artery constriction (n=5) were controls. Beginning 28 days from surgery, AT-pacing (ATP, 600 bpm) was started for 7 days. Serial atrial ERP measurement and AF induction was performed at days 7, 14, 28, 29, 30, 32 and 35 from surgery. Final open chest EPS was performed at day 36. Results: Systolic blood pressure (SBP) of HT dogs increased beginning at day 7 post 1K1C surgery (baseline 128±4 mm Hg; 7-d 183±6*, 28-d 176±10* mmHg; * p&lt;0.01 vs. baseline). SBP of sham dogs remained constant (baseline 133±4 mm Hg; 7-d 128±3, 28-d 126±6 mmHg). Mean AF duration (10 Hz burst pacing induced) increased marginally in HT dogs pre-ATP (Figure), but substantially after 1 and 2 days ATP vs control. At open-chest EPS, there were no differences in AF vulnerability to premature extrastimuli (HT, 69±5% vs. Sham, 70±11%; p=NS), AF duration (HT, 1501±273 sec vs. Sham, 1458±342 sec; p=NS) or regional ERP heterogeneity. HT dogs showed increased atrial conduction heterogeneity (heterogeneity index in HT, 2.01±0.10 vs. sham, 1.50±0.08; p&lt;0.01), associated with significant downregulation of connexin (Cx) 43 expression (by 57% + , + p&lt;0.05) but no change in Cx40 expression. Heart to body weight ratio increased in HT (9.7±0.4 vs. 8.5±0.2 + ), reflecting LVH. Conclusions: HT alone produces modest AF promotion, but changes caused by HT accelerate AF stabilization once initiated, increasing vulnerability to prolonged AF. The AF-promoting effects of hypertension are related to conduction abnormalities, possibly caused by connexin downregulation.
Abstract 9748: Exercise Oscillatory Breathing and NT-pro-BNP Levels in Stable Heart Failure Provide the Strongest Prediction of Cardiac Outcome when Combining Biomarkers with Cardiopulmonary Exercise Testing
Authors: Marco Guazzi, Patrizia Boracchi, Marco Vicenzi, Ross Arena, Giuseppe Reina
Journal: Circulation (2011)

Aims: N-terminal-pro brian natiruretic peptide (NT-pro-BNP) and cardiopulmonary exercise testing (CPET)-derived variables are gold standards for assessing prognosis in heart failure (HF) patients. We sought to refine the prediction of cardiac-related events by performing a combined analysis of NT-pro-BNP with markers of ventilatory inefficiency during exercise. Methods and Results: 260 patients with stable CHF underwent measurement of plasma NT-pro-BNP levels prior to, at peak exercise and 1 minute recovery phase during a CPET evaluation with determination of peak oxygen uptake (VO2), ventilation to CO2 production (VE/VCO2) slope and exercise periodic breathing (EPB). Blood samples were drawn for standard measurements and for hormonal determinations both at rest and at peak exercise. Results: After a median follow-up period of 20.6 months, there were 54 cardiac-related deaths. Univariate analysis showed that, among the 6 variables of interest including plasma NT-pro-BNP at rest, at peak exercise and 1 minute recovery, peak VO2, VE/VCO2 slope and EPB. NT-pro-BNP was the strongest independent predictor of cardiac death with equivalent prognostic power and strong correlation among rest, peak exercise and 1 minute recovery. Thus, only NT-pro-BNP at rest was considered (Harrel C: 0.783; CI: 0.722-0.844) followed by VE/VCO2 slope (Harrel C: 0.720; CI: 0.646-0.794), EPB (Harrel C: 0.685; CI: 0.619-0.751), and peak VO2 (Harrel C: 0.618; CI: 0.533-0.704). At bivariate stepwise analysis, among various combinations, NT-pro-BNP at rest along with EPB emerged as the strongest prognostic one (Harrel C: 0.800; CI: 0.737-0.862) to estimate the two-years incidence of cardiac death. Conclusions: In the refinement for robust predictors of outcome in HF patients, high NT-pro-BNP levels together with EPB led to the most powerful definition. VE/VCO2 slope and peak VO2 did not provide any further prognostic adjunct. A biomarker/CPET approach seems very promising to warrant the continuous implementation in the prognostic work-up of HF patients.
Abstract 291: A Targeted Approach to Community Consultation for an Exception from Informed Consent Study: More Support than Willingness to Participate
Authors: Eugene Vu, Kathy Arnold, Tony Carnevale, Denise Griffiths, Dana Zive, Aarzoo Sidhu, Terri Schmidt, Mohamud Daya
Journal: Circulation (2012)

Objectives: Community consultation (CC) is a key part of research conducted under the FDA Exception from Informed Consent (EFIC) framework. The best practices to achieve CC remain uncertain. We report results from a targeted approach that surveyed at-risk members of a health maintenance organization. Methods: The Resuscitation Outcomes Consortium (ROC) Amiodarone, Lidocaine, or Placebo Study (ALPS) is being conducted under EFIC. As part of the CC effort, we designed a survey with the Kaiser Permanente Northwest Center for Health Research. Surveys were mailed to 2,000 Kaiser members between the ages of 48-78 residing in a 3 county region served by participating EMS agencies. The age group was considered representative of the population-at-risk for out-of-hospital cardiac arrest (OHCA). The survey described ROC-ALPS and the opt-out option. Respondents were asked if the study was important to do, whether the benefits justified doing it under EFIC and if they would be willing to be enrolled in the study. Responses were recorded using a 5-point Likert scale. Demographic information collected included age, gender and race. Descriptive statistics were used to tabulate responses to survey questions. Pearson chi- square test was used for sub-group analyses. Results: Of the 2,000 mailed surveys, 1951 were delivered and 337 returned (17.2% response rate). Respondents were 48.8% male with a mean age of 63.1 years. Most respondents were white (89.3%) and representative of the study community. A majority (88.3%) of respondents agreed that EFIC research is important, and 73.9% felt that the benefits justify this method of research. Fewer respondents (53.1%) expressed a willingness to be enrolled in ROC-ALPS. There were no gender differences in question response. More respondents under the age of 65 expressed a willingness to be enrolled in the study. (p=0.002). However, those ≥ 65 were more likely to agree that the benefits justify the risk in EFIC studies. (p =0.029) Conclusions: A majority of at-risk HMO community member respondents expressed support for EFIC research and more than half expressed a willingness to be enrolled in the ROC randomized placebo control ALPS study. The response rate was low and differences were identified between respondents in relation to age.
Abstract 339: Impact of Left Ventricular Dilatation on Characteristics of Ventricular Fibrillation and ICD Shock Success
Authors: Judith L Bonnes, Jeroen Jaspers Focks, Sjoerd W Westra, Marc A Brouwer, Joep L Smeets
Journal: Circulation (2012)

Introduction ICD testing offers a unique setting to study VF characteristics under controlled conditions in humans. Recently, it was observed that myocardial substrate (infarction) affects VF characteristics and shock success in animals. To further study the effect of myocardial pathology on VF, we investigated the association between left ventricular (LV) dilatation and characteristics of induced VF and we determined the impact of dilatation on the success of the first ICD shock. Methods Patients who underwent Medtronic ICD implantation with defibrillation testing between 2005-2011 were included. VF frequency characteristics were analyzed using intracardiac recordings of 4 seconds of induced VF before shock delivery (15 joule) and were compared between patients with normal-mildly and moderate-severely dilated LVs. Multivariate linear regression was performed to associate LV dilatation with the respective VF characteristics. Results Patients with moderate-severely dilated LVs tended to have a lower first shock success during testing. In addition, the fundamental frequency of VF was lower and the organization index was higher (Table). The fundamental frequency was independently associated with LV dilatation (β -0.28; p=0.007), amiodarone use (β -0.48; p&lt;0.001) and history of myocardial infarction (MI) (β -0.20; p=0.048). The organization index was independently associated with LV dilatation (β 0.04; p=0.030) and history of MI (β -0.05; p=0.003). The median frequency was not associated with any of the tested variables. Conclusions Characteristics of induced VF depend on LV dilatation: VF is slower and more regular in dilated LVs. Interestingly, ischemic etiology of cardiac disease and amiodarone also affect VF characteristics. ICD shock success was slightly lower in patients with dilated LVs. To improve future resuscitation strategies, further research is needed to evaluate the interaction between clinical characteristics, VF and shock success.
Abstract 9259: Upregulation of Cardiac Urotensin II (UII) Exacerbates UII Stimulation-Induced Negative Modulation on Myocyte Contractile Function and Ca <sup>2+</sup> Current in Streptozotocin-Induced Diabetic Rats
Authors: Heng-Jie Cheng, Peng Zhou, Weixin Zhao, Nadeem Wajih, Qing-Hua Han, William C Little, Che Ping Cheng
Journal: Circulation (2011)

Background. Urotensin II (U-II), a somatostatin-like peptide is a potent vasoconstrictor. It has been implicated in metabolic regulation. In diabetes mellitus (DM) patients, circulating UII levels are increased. Recent evidence suggests that UII plays a significant role in DM and its complications, such as diabetic cardiomyopathy. However, the mechanisms are unclear. Whether UII alters cardiac contractile behavior in DM is unknown. We tested the hypothesis that DM causes upregulation of myocyte UII and its receptors (UT). This may exacerbate UII stimulation-induced negative modulation on myocyte function and Ca 2+ current and contribute to the progression of left ventricular (LV) dysfunction in DM. Methods. We compared LV myocyte UII and UT expression, myocyte contractile, and L-type Ca 2+ current (I Ca,L ) responses to UII stimulation in 8 rats at 6 weeks after receiving streptozotocin (STZ, 35 mg/kg, ip) and 8 age-matched normal control (C) rats. Results. Compared with controls, STZ-treated rats (DM rats) had more than 4-fold elevated blood glucose levels (DM: 569 vs C: 108 mg/dl) and reduced body weight followed by cardiomyocyte systolic and diastolic dysfunction with significant decreases in the peak velocity of myocyte shortening (dL/dt max ) (28%, DM: 88.4 ± 5.2 vs C:122.7 ± 4.8 μm/s), relengthening (dR/dt max ) (21%, -73.1 ± 4.9 vs -92.9 ± 6.0 μm/s), and I Ca,L (23%, 6.1 ± 0.2 vs 7.9 ± 0.3 pA/pF). Compared to normal myocytes, in DM myocytes, both UII (26%, DM: 0.58 vs C: 0.46) and UT (20%, 0.91 vs 0.76) mRNA and protein levels were significantly increased. Importantly, these changes were associated with enhanced UII-mediated negative modulation on myocyte contraction, relaxation, and I Ca,L . Compared to normal myocytes, in DM myocytes, superfusion UII (10 -5 M) caused significantly greater decreases in dL/dt max (DM: 24% vs C:11%) and dR/dt max (28% vs 14%) accompanied by significantly larger reductions in I Ca,L (19% vs 9.8%) ( P &lt;0.01). Conclusions. STZ-induced DM causes upregulation of cardiac UII system, which enhances inhibition of cardiomyocyte contraction, relaxation, and I Ca,L and, thus, may play an important role in the development and progression of diabetic cardiomyopathy.
Abstract 207: Postresuscitation Care and Outcomes of Out-of-Hospital Cardiac Arrest in Korea: A Nationwide Propensity Score Matching Analysis
Authors: Joo Yeong Kim, Sang Do Shin, Young Sun Ro, Kyoung Jun Song, Eui Jung Lee, Chang Bae Park, Seung Sik Hwang
Journal: Circulation (2012)

Objective : Active post-resuscitation care (APC) strategy showed improved out-of-hospital cardiac arrest (OHCA) outcomes in well controlled trials. This study aimed to determine whether APC is associated with improved OHCA outcomes in Korea, nationwide level. Methods : We used a national OHCA cohort data composed of hospital and ambulance data, including all EMS-treated OHCA survivors from January 2008 to December 2010. We excluded cases with presumed non-cardiac etiology, those without available hospital outcome data and those with age under 15 years old. The APC group is OHCA patients received coronary reperfusion therapy, therapeutic mild hypothermia, coronary artery bypass surgery (CABG), and pacemaker insertion as well as conservative intensive care (CIC). The primary and secondary outcome was survival to discharge and good neurologic outcome (cerebral performance category (CPC) 1 to 2). We extracted propensity matched sample to contol selection bias. Mutivariable logistic regression analysis was used and we adjusted for potential risk factors to calculate adjusted odds ratios (OR) and 95% confidence intervals (95% CIs). Results : Among 64,155 EMS-assessed OHCA patients with available outcome, 44,794 adults patients with presumed cardiac etiology were collected excluding non-cardiac etiology (n=17,970) and pediatric (n=1,391). Of these, 4,557 patients survived to admission were used for final analysis. 1,599 (35.1%) cases survived to discharge and 499 (11.0%) cases discharged with good neurologic recovery. 695 cases (15.3%) received any APC including mild hypothermia (n=377, 8.3%), reperfusion therapy (n=307, 6.7%), CABG (n=18, 0.4%), and pacemaker insertion (n=61, 1.3%). Survival to discharge rate was higher in APC group than CIC group (58.7% vs. 30.8%, p &lt;0.001). Good neurologic outcome was also higher in APC group than CIC group (27.2% vs. 8.0%, p&lt;0.001). Adjusted ORs of APC versus CIC group was 2.12 (95% CI 1.76-2.55) for survival to discharge and 2.53 (95% CI 1.99-3.21) for good neurologic outcome. For propensity score matched cohort, adjusted ORs for survival to discharge and good neurologic outcome of APC was significantly favor. Conclusions : The APC strategy in Korea increased by year and showed significant improved outcomes.
Abstract 315: Both Systemic and Cerebral Microcirculation Are Reduced During Hypothermia in a Porcine Model
Authors: Linhao Ma, Jiefeng Xu, Xiaoye Lu, Xiaobo Wu, Shijie Sun, Wanchun Tang
Journal: Circulation (2012)

Introduction: Mild hypothermia improves neurological outcomes after cardiac arrest. However, systemic microcirculation is reduced with the reduction of body temperature. We investigated the changes of cerebral (CM) and sublingual microcirculation (SM) during hypothermia in a porcine model during spontaneous circulation and following successful cardiopulmonary resuscitation. Hypothesis: We hypothesized that during spontaneous circulation and following CPR, SM is reduced with the progress of hypothermia. However, CM is preserved in the range of mild hypothermia. Methods: Ten domestic pigs weighing 34±1kg were randomized into spontaneous circulation control or CPR groups. The cerebral cortices were exposed for microcirculation measurement. In CPR group, ventricular fibrillation (VF) was induced and untreated for 5 mins. Defibrillation of 150J was attempted after 5 mins of CPR. Hypothermia was initiated after completion of animal preparation in control group and immediately following successful resuscitation in CPR group. The blood temperature was reduced from 37°C to 35°C, 33°C and 28°C with a cooling blanket. SM and CM was measured at each temperature point with the orthogonal polarization spectral imaging technique. Results: Microcirculatory blood flow index and perfused microvessel density of both SM and CM decreased with the progress of hypothermia in both groups. There was no statistical difference between the two groups. (Table) Conclusion: CM is reduced with the reduction of body temperature during spontaneous circulation and following CPR. The relationship between reduced CM during hypothermia and improved neurological outcomes following hypothermia remains to be investigated.