tbuckley/cabot-search huggingface dataset:
Abstract 19164: Products of Murine Cytochrome P450 Cyp2j Locus Regulate Pulmonary Vascular Response to Alveolar Hypoxia
Authors: Guo Ling Zhou, Arkadi Beloiartsev, Binglan Yu, David M Baron, Weihua Zhou, Rasma Niedra, Naifang Lu, Warren M Zapol, Brian Seed, Kenneth D Bloch
Journal: Circulation (2012)

Epoxyeicosatrienoic acids (EETs) are eicosanoids with potent vasoactive effects. Multiple cytochrome P450 enzymes, including CYP2J2, synthesize EETs in humans. However, genetic analysis of the contributions of CYP2J2 to physiologic processes in humans has been confounded by the allelic expansion in rodents: mice have 8 Cyp2j genes that encode epoxygenases similar to CYP2J2. To investigate the role of CYP2J2, we created mice bearing a 626 kb deletion spanning the murine Cyp2j locus using a combination of homologous and site-directed recombination strategies. Two bacterial artificial chromosomes (BACs) covering the 2 ends of murine Cyp2j locus were modified to allow an integrase-mediated site-specific recombination event to fuse the BACs and form a deletion replica that could be propagated in E. coli. The replica was introduced into mouse ES cells to ultimately enable generation of Cyp2j-null mice (Cyp2j-/-). RT-MLPA (Multiplex Ligation-independent Probe Amplification) revealed that the 8 Cyp2j genes were expressed in wild-type (WT) but not in Cyp2j-/- mice. A mouse strain in which the Cyp2j locus deletion was complemented by transgenic delivery of BAC sequences encoding human CYP2J2 was also created (Cyp2j-/-tg). Systemic and pulmonary hemodynamic parameters did not differ in anesthetized WT, Cyp2j-/-, and Cyp2j-/-tg mice at baseline. Hypoxic pulmonary vasoconstriction (HPV) was monitored by measuring left pulmonary vascular resistance (LPVR) and systemic arterial oxygenation (PaO2) before and during left main stem bronchial occlusion (LMBO). LMBO did not alter systemic arterial pressure in any genotype. LMBO increased LPVR 2.0- and 2.3-fold in WT and Cyp2j-/-tg mice, respectively, due to HPV (P&lt;0.05 for both). LMBO did not change LPVR in Cyp2j-/- mice. During LMBO, PaO2 was greater in WT and Cyp2j-/-tg mice than in Cyp2j-/- mice (P&lt;0.05 for both) demonstrating that Cyp2j deficiency impairs matching of ventilation with perfusion (V/Q). Administration of MS-PPOH, a selective inhibitor of CYP450 epoxygenase, to WT mice also blocked the ability of LMBO to increase LPVR. These data suggest that products of Cyp2j epoxygenase activity contribute to the pulmonary vasoconstriction produced by alveolar hypoxia and preservation of V/Q matching.
Abstract 19745: Brugada, Long QT and Cardiac Conduction Disease Overlap Syndrome Associated with the SCN5A-E1784K Mutation: Clinical Phenotype, Genetic Background and Potential Therapy
Authors: Dan Hu, Christian Veltmann, Hector Barajas-Martinez, Ryan Pfeiffer, Luiz Belardinelli, Gerhard Strupp, Theano Papavassiliu, Martin Borggrefe, Christian Wolpert, Rainer Schimpf, Charles Antzelevitch
Journal: Circulation (2012)

INTRODUCTION: Phenotypic overlap of type 3 long QT syndrome (LQT3), Brugada syndrome (BrS) and cardiac conduction disease (CCD) is observed with some SCN5A mutations. SCN5A -E1784K is the most common mutation associated with LQT3 and BrS. The present study examines the genotype-phenotype relationship in a 76 member European family carrying the SCN5A -E1784K mutation and the common polymorphism SCN5A -H558R. METHODS: Clinical work-up and genetic analysis were performed following informed consent. Functional characterization was achieved by expression of the SCN5A variants in TSA201 cells. Peak (I Na,P ) or late (I Na,L ) sodium channel current was recorded using whole cell patch-clamp techniques. RESULTS: A total of 35 family members (19 male and 16 female, mean age 29.8 ± 15.9 years) were evaluated. Thirteen patients died prior to initiation of the study. Twenty-eight family members refused genetic screening. Of the 35 genotyped family members, 17 were positive for the E1784K mutation in SCN5A (Table 1). All 17 displayed LQT intervals and either BrS or prolonged PR (as a surrogate of CCD). The presence of H558R did not significantly alter the phenotype of carriers positive for E1784K. Fourteen patients positive for E1784K underwent ICD implantation; 4 developed VF and received appropriate defibrillation shocks during a follow-up period of 8±3 months. Co-expression of SCN5A -E1784K and SCN5A -WT reduced I Na,P to 70.03% of WT, shifted steady-state inactivation by -11.03mV and increased INa,L from 0.14% to 1.86% of I Na,P . Similar changes were observed when E1784K was co-expressed with H558R. Ranolazine (10 µM) reduced INa,L of E1784K+WT by 65% without significantly affecting INa,P. CONCLUSION: We demonstrate strong genotype-phenotype correlation and complete penetrance for LQTS and BrS/CCD in a large family harboring the E1784K missense mutation in SCN5A. Ranolazine, by virtue of its ability to suppress I Na,L , may be an effective therapy for these cases of LQT3.
Abstract 19269: Impact of Recommedations of Guidelines in Patients with Atrial Fibrillation Submitted for Coronary Stenting
Authors: Maria Mutuberria, Antonia Sambola, Eduard Bosch, Garcia Del Blanco Bruno, F Alfonso, Angel Cequier, Hector Bueno, Oriol Rodriguez, Javier Zueco, Javier Zueco, Nadia Llavero, David Garcia Dorado
Journal: Circulation (2012)

Objetive: to assess the impact of dual antiplatelet therapy (DAT) with clopidogrel and ASA vs. DAT with warfarin (triple therapy: TT) in patients with nonvalvular AF submitted to coronary stenting and the impact of CHADS2 and CHA2DS2VASc scores. Methods: a retrospective multicenter study was conducted from 2007 to 2011 to identify patients with nonvalvular AF who undergoing PCI with stenting. Patients basic characteristics, CHADS2 score, CHA2DS2VASc score, PCI details, antithrombotic therapy at discharge and its duration were recorded. Follow-up was 1 year. All bleeding events, stroke, thromboembolism, death, acute myocardial infarction or target revascularization were recorded. Results: We identified 489 patients with AF (74.8% male, 73.11±8 years); 307 (62.8%) received TT and 182 (37.2%) received DAT. Duration of DAT and TT was: 5.15±4 and 4.49±2.85 months, respectively. Baseline characteristics were similar in both groups, except for a higher rate of previous stroke (9.6% vs 16.8%, p=0.018) and previous PCI (44.5 % vs 25.4%, p=0.0001) in TT group. Patients treated with TT showed a trend to a higher rate of CHADS2 score ≥2 (64.8% vs 35.2%, p=0.17) and for CHA2DS2VASc ≥2 (64.3% vs 35.2%, p=0.25). Major bleeding and cardiovascular death were more frequent in patients with TT (6.7% vs 1.7%, p=0.01; 7% vs 2.9%, p=0.042, respectively). Stroke rate was more frequent in patients with DAT (5.7% VS 1.3%, p=0.008). In these patients CHADS score was median 2 (range 1-4) and CHA2DS2VASc median 4.5 (range 3-5). 44 patients (9.2%) died during follow-up.13 (29.2%) of them had had a bleeding event; 3 of them had CHADS2=1. Multivariate analysis identified as independent predictors for cardiovascular death: previous stroke (OR 5.7; 95% CI 0.9-34.6, p=0.05), drug eluting stent (OR:0.35; 95% CI 0.13-0.96, p=0.03) and TT (OR 0.35; 0.12-1.00, p=0.05). CHADS2 and CHA2DS2VASc scores were not predictors (OR 1.86: 95% CI 0.93-1.77, p=0.076; OR 1.32; 95% CI 0.92-1.89, p=0.123, respectively). Conclusions: In patients with nonvalvular AF who undergo PCI with stenting, the decisions of treatment with DAT or TT is not always influenced by CHADS or CHA2DS2VASc. There is a high incidence of bleeding with TT and a high incidence of stroke with DAT.
Abstract 230: Epidemiology and Outcomes of Emergency Medical Services-Assessed Out-of-Hospital Cardiac Arrest in Korea: A Nationwide Observational Study from 2006 to 2010
Authors: Sang Do Shin, Young Sun Ro, Kyoung Jun Song, Eui Jung Lee, Ki Ok Ahn
Journal: Circulation (2012)

Background The goal of this study is to better understand the epidemiologic features and the patient-community-emergency medical service (EMS)-hospital factors affecting outcomes of out-of-hospital cardiac arrest (OHCA). Methods and Results This study was performed in an EMS system with a single-tiered basic-to-intermediate service level and approximately 900 destination hospitals for eligible OHCA cases. A nationwide OHCA database including demographic, Utstein, EMS, and hospital factors and outcomes was constructed using EMS run sheets of eligible cases transported by 119 EMS ambulances and followed by medical record review for 2006 to 2010. Cases with unknown outcome were excluded. The primary end points were survival to discharge. The epidemiologic characteristics of OHCA were described and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for main outcome, adjusting for potential predictors. There were 97,291 EMS-assessed OHCAs excluding 14,798 cases because the medical records were not available (N=10,626) and the survival outcomes were unknown (N=4,172). Of these, 73,826 (75.9%) OHCAs were resuscitation attempted by EMS. The survival to discharge was 3.0% for EMS-assessed (3.3% for cardiac origin vs. 2.3% for non-cardiac origin), 3.6% for EMS-treated (4.0% for cardiac vs. 2.7% for non-cardiac), and 20.9% for cardiac origin with shockable rhythm. The drowning, intoxication, and asphyxia induced OHCAs had statistically better survival rates than cardiac origin. The odds for survival to discharge are significantly lower for elderly, asystole as primary ECG, OHCA with cardiac origin occurred in winter or 6PM to midnight, un-witnessed, no bystander cardiopulmonary resuscitation, OHCA with longer EMS response, and being transported to lower level of ED. Conclusions In this nationwide cohort study from 2006 to 2010, the standardized incidence rate increased 46.3 in 2006 to 52.0 per 100,000 person-years for EMS-assessed OHCA and overall survival rate was 3.0%. Potential factors for poor outcome were systemically identified in individual, community, EMS, and hospital chain.
Abstract 19480: Non-Calcified Coronary Plaque (NCCP) Burden &amp; its Correlation with Left Ventricular Mass (LVM) in Diabetic vs Non-Diabetic Patients
Authors: Atif N Khan, Faisal Khosa, Jian kang, Zehra Malik, Ali F Jon, Faraze Niazi, Melvin E Clouse
Journal: Circulation (2012)

Determine Non-Calcified Coronary Plaque (NCCP) burden &amp; its correlation with Left Ventricular Mass (LVM) in Diabetic vs Non-diabetic patients. Methods : IRB approved, retrospective review of 190 patients imaged with 320-row MDCTA [89 Diabetics (mean age 62.5 ± 8.73 Yrs &amp; BMI 31.49 ± 5.13) &amp; 101 Non-diabetic (mean age 61.15±14.6 Yrs &amp; BMI 27.47 ± 5.47)]. Measurements were taken for plaque subtypes and total plaque burden (TPB) using Vitrea 5.2. RCA, LM, LAD and LCX were analyzed to quantify fatty, fibrous and calcified plaque in mm 3 . LVM was calculated from left ventricular inner diameter (LVID), posterior wall thickness (PWD) and Septal wall thickness (SWT) measured in diastolic phase from 4 and 2 chamber views using ASE formula. STATA was used for analyses. Results: TPB &amp; LVM for diabetic vs. non-diabetic were: RCA: 10.00±3.80 mm 3 vs 8.69±4.2 mm 3 , p = 0.029; LM 16.66±5.24 mm 3 vs 13.74±4.58 mm 3 ,p = &lt;0.001, LAD: 7.41±2.67 mm 3 vs 6.55±2.72 mm 3 , p = 0.034; LCX: 9.69±2.93 mm 3 vs 8.30±2.76 mm 3 ,p = 0.002 &amp; LVM: 175.29 ± 53.8 vs 173.92 ± 71.6 gm, p = 0.0881 respectively Diabetic had significantly ↑ TPB in all arteries compared to non-diabetics. Diabetics had significantly ↑ fibrous and fatty plaque in LM, LAD &amp; LCX and fatty plaque only in RCA. Calcified plaque volume and LVM were same in both groups (Table 1). Adjusting for demographic and clinical variables, linear regression showed no difference in TPB in all vessels. In sub analyses LAD had significantly ↑ fibrous (p = 0.050), fatty (p =0.042) and calcified plaque (p = 0.031) whereas LM had ↑ fibrous (p =0.039) and LCX had ↑ calcified plaque (p =0.039) in diabetics. Linear regression showed significantly ↑ PWT (p =0.017), LVID (p =&lt;0.001) and LVM (p =&lt;0.001) in diabetics. Conclusion: Diabetes is associated with higher non-calcified plaque burden with increase in LVM which may provide a reason for increased risk of adverse cardiac events in diabetics. Timely screening and appropriate medical therapy may reduce coronary events in this specific group.
Abstract 211: Poor AED Availability Despite Improved AED Dissemination: A Challenge for Public Access Defibrillation
Authors: Carolina Malta Hansen, Mads Wissenberg, Peter Weeke, Martin H Ruwald, Morten Lamberts, Freddy Lippert, Gunnar H Gislason, Soren L Nielsen, Lars Kober, Christian Torp-Pedersen, Fredrik Folke
Journal: Circulation (2012)

Background Strategic AED placement and availability are paramount for successful public access defibrillation (PAD). However, analyses of AED coverage in relation to location and incidence of cardiac arrest in community settings are limited. We assessed AED placement and coverage according to workday, weekends and hour of day in relation to out-of-hospital cardiac arrests (OHCAs) in public. Methods All OHCAs in public places from 1994-2011 and all publicly available AEDs in Copenhagen, Denmark, were geographically located. OHCA high-risk areas were defined as those with ≥1 arrest every 2 years, within a 100-meter radius. All OHCAs occurring within a 100-meter radius were counted as well as the number of AEDs in these areas. AEDs available for PAD were registered in a nationwide network with the following information: location, time and weekday availability. Results A total of 2151 OHCAs occurred in public locations. The mean age was 61.7 (SD±17.7) years (74.8% males). High-risk areas accounted for 1.1% (n=112) of the city and 16.5% (n=360) of all arrests. A significant proportion of arrests occurred on weekends and between 6 p.m. and 8 a.m (65.8%). The number of AEDs increased from 36 in 2007 to 555 by the end of 2011. Of these, 5.8% (n=32) covered 44.6% of the high-risk areas and 96.2%, 31.9% and 9.7% were available all weekdays during daytime, evening and nighttime, respectively. On weekends 29.4%, 17.7% and 9.2% of all AEDs were available in daytime, evening and nighttime, respectively. Only 18.8% (n=6) AEDs in high-risk areas had 24-hour and all-week availability. Conclusion Despite a large increase in public AEDs, the coverage of OHCA high-risk areas remains insufficient. Further, only 18.8% of AEDs in OHCA high-risk areas were available at all times although 65.8% of arrests occurred outside working hours. Hence, a much greater proportion of AEDs should offer 24-hour and all-week availability to cover the actual incidence of cardiac arrest.
Abstract 8489: Study Modifications &amp; Primary Endpoint Reinterpretations Prior to Food &amp; Drug Administration Approval of High-Risk Cardiovascular Devices
Authors: Sanket S Dhruva, Lucy H Liu, Lisa A Bero, Rita F Redberg
Journal: Circulation (2011)

Introduction: It is known that post-hoc analysis is less reliable and reduces the certainty of research findings. The most rigorous Food &amp; Drug Administration (FDA) review process, for novel and high-risk devices, is called Premarket Approval (PMA). It is unknown to what extent post-hoc analysis is used in PMA applications. Hypothesis: We hypothesized that the PMA review process would involve studies of the highest methodological rigor and that all studies of approved cardiovascular devices would meet their pre-specified primary endpoints. Methods: We examined the Summary of Safety and Effectiveness Data, a document which is intended to present an objective critique of the scientific evidence which the FDA reviews for each device, for all PMA cardiovascular devices approved from 2000 through 2010. Any study modification or post-hoc primary endpoint reinterpretation was recorded by one author and confirmed by at least one additional author. Results: Of the 96 cardiovascular PMAs between 2000-2010 containing a study with at least one primary endpoint, 18 (19%) had some form of study modification or post-hoc primary endpoint reinterpretation. In 10 of these PMAs, a study did not meet at least one pre-specified primary endpoint, but the device was approved on the basis of a post-hoc data review. Pre-specified statistical analyses were changed after study initiation in 3 PMAs. Two PMAs were approved on qualitative merits rather than quantitative data after the FDA deemed the study characteristics no longer applicable at the time of review. Pre-specified controls were changed in 2 PMAs. In 1 PMA each, study design was modified after study initiation, a primary endpoint was redefined after study initiation, or new patients were added to a study after completion of initial enrollment. Conclusions: The most rigorous FDA review process includes numerous forms of study modification and post-hoc primary endpoint reinterpretation. More consistent requirements for pre-specified clinical trial outcomes will help improve the quality and consistency of the approval process and ensure that cardiovascular devices are safe and effective.
Abstract 9923: Cardiac Rehabilitation Reduces Levels of Oxidized LDL
Authors: Akira TAKASHIMA, Takayuki Ise, Masashi Akaike, Yuka Ueta, Takashi Iwase, Tomoya Hara, Muneyuki Kadota, Rie Ota, Kozue Ogasawara, Toshiyuki Niki, Junko Hocchi, Koji Yamaguchi, Yoshio Taketani, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Masataka Sata
Journal: Circulation (2012)

Background: Oxidized LDLs have been shown to play an important role in atherosclerosis progression. However, no established methods are available for effectively reducing oxidized LDL levels. Comprehensive cardiac rehabilitation (CR) with exercise training prevents atherosclerosis progression. The purpose of the current study was to examine whether CR reduces oxidized LDL levels. Methods and Results: We measured the levels of malondialdehyde-modified LDL (MDA-LDL), a marker of oxidized LDL, in 118 patients who were enrolled for a 6-month CR program. Peak VO 2 and MDA-LDL levels were examined before and at 6 months after enrolment in 55 patients who completed the CR program (CR group) and in 63 patients who failed to continue the CR program (non-CR group). At 6 months, the peak VO 2 in the CR group was significantly higher than the baseline value (1131 ± 364 to 1327 ± 442 ml/min, p &lt; 0.01). At 6 months, the MDA-LDL level was significantly lower than the baseline value in the CR group (111 ± 43 to 89 ± 25 U/l, p &lt; 0.05) but this difference was not significant in the non-CR group. The increase in peak VO 2 was inversely correlated with the decrease in the MDA-LDL level (r = -0.40, p &lt; 0.01). This correlation was observed even in patients who had not just started statin therapy. Conclusion: The CR program significantly reduced oxidized LDL levels in association with increase in exercise capacity. Thus, CR may exert an anti-atherosclerotic effect through reduction of oxidized LDLs.
Abstract 85: The Overall Performance Category and Cerebral Performance Category to Assess Neurologically Intact Survival at Discharge from Cardiac Arrest: A Good Estimate of Patients’ Functioning?
Authors: Stefanie G Beesems, Kim M Wittebrood, Rob J de Haan, Rudolph W Koster
Journal: Circulation (2012)

Objective- It is known that recovery from neurologic damage takes 6-12 months. However, most studies on out of hospital cardiac arrest (OHCA) use the Overall Performance Category (OPC)/Cerebral Performance Category (CPC) as outcome at discharge from hospital. We studied the neurocognitive functioning and level of independence (LoI) of patients (pts) 6-12 months after OHCA and compared the results with the OPC/CPC at discharge. Materials and methods- The study population comprises all pts (&gt;18 year) who survived 6-12 months after OHCA from mid-2010 to mid-2011. Pts were interviewed by telephone with questionnaires validated for telephonic application. We used a validated cut-off score. Neurocognitive functioning was measured with the Telephonic Interview Cognitive Status (TICS) and LoI with the Modified Rankin Scale (MRS). If needed, the IQ-code was used as proxy-questionnaire to measure the neurocognitive functioning of the pt. Neurological outcome at discharge was assessed from hospital records estimating OPC/CPC (figure). Results- Comparison between OPC at discharge and MRS at 6-12 months is shown in the figure. Of all pts, 93% was classified as having a good outcome (OPC 1-2) at discharge. At 6-12 months only 76% had a good outcome (MRS 0-2). Thirty of the 218 (13%) pts seemed to be cognitively impaired (TICS &lt;31) at 6-12 months while they were classified as having a good outcome (CPC 1-2) at discharge. Conclusion- MRS and other tests 6-12 months after discharge better reflect pts’ functioning at home than OPC/CPC at the moment of discharge. OPC/CPC cannot measure impairments that manifest themselves only in the home environment.
Abstract 196: Does Health Status Influence the Willingness to Provide Informed Consent? Results from a Cardiac Arrest Trial Conducted Under Waiver of Informed Consent
Authors: Ralph Frascone, Joshua Salzman, Demetris Yannopoulos, Brian Mahoney, Robert Swor, Robert Domeier, Marvin Wayne, Tom Aufderheide, Michael Olinger, Sandi Wewerka, David Tupper, Richard Holcomb
Journal: Circulation (2012)

Background Federal regulation 21 § CFR 50.24 allows an initial waiver of informed consent (IC) for treatment of certain medical emergencies but requires the consent process be initiated at the earliest feasible opportunity. In a recent out-of-hospital cardiac arrest (OHCA) trial conducted under 21 § CFR 50.24, data from public records were collected which shed light on whether the willingness to provide subsequent IC was associated with study outcomes. We hypothesized that IC was less likely to be obtained in subjects with significantly compromised health status. Methods A post-hoc analysis was conducted using data from a NIH-funded randomized, controlled OHCA clinical trial comparing active compression decompression CPR plus an impedance threshold device (ACD+ITD) with standard CPR. The primary endpoint was survival to hospital discharge (HD) with favorable neurologic function [Modified Rankin Scale (MRS) score &lt;3]. The status of the consent process was tabulated for all subjects who survived to hospital admission. Unadjusted Fisher’s exact test and associated odds ratios were used to compare the MRS at HD by IC status. Results Among a total study population of 1655 subjects, 457 survivors were admitted to the hospital, and 440 had known HD status (see table). Survival with a MRS≤3 was significantly higher in subjects where IC was given: 35.0% vs 4.1%, p &lt; 0.001. Sixteen of the 17 cases with missing MRS outcomes were in the IC denied group. Even if all were considered to have favorable outcomes, the resulting rate (21.1%) was less than that seen among subjects with IC given (p = 0.015). Conclusion Subjects who denied IC were significantly less likely to have favorable outcome. These findings suggest that some resuscitation trials may unknowingly under-represent those subjects with the worst prognoses in a target study population despite pre-specified inclusion and exclusion criteria, due to the unwillingness or inability of the subjects or their families to provide IC.