tbuckley/cabot-search huggingface dataset:
Abstract 19817: Influence of the Purkinje Conduction System on the Ekg: A Modeling Study
Authors: Shankarjee Krishnamoorthi, Olujimi Ajijola, Luigi E Perotti, William S Klug, Alan Garfinkel, Daniel B Ennis
Journal: Circulation (2012)

Introduction - Computational modeling of cardiac electrophysiology (EP) is important for exploring the mechanisms that underlie fatal arrhythmias. Methods are limited for anatomically mapping the Purkinje conduction system (PCS) in whole hearts, and incorrect definition of the PCS geometry and/or conduction velocity leads to incorrectly modeled activation wavefronts, fractioned QRS, and T-wave inversion. The objective of this study was to design a PCS that resulted in the best simulated six-lead electrocardiogram (ECG), while maintaining consistency with known anatomy. Methods - Diffusion tensor (DT) MRI was used to define gross anatomy and fiber orientations, combined with a cell model to build a finite element model of rabbit cardiac EP, from which the six-lead ECG was simulated. An in vivo six-lead rabbit ECG served as a reference for the computed ECG. The number and distribution of Purkinje-muscle junctions (PMJ) and the conduction velocity in RV, LV, and septal branches were varied. Whole-heart activation wavefronts and the resultant ECG were compared to the normal rabbit ECG. Parameters assessed included activation wavefront timing and QRS/T-wave morphology in a six-lead ECG. Results - Forty combinations of PCS geometry and conduction speed were implemented. Increasing the density (from 34 to 399), uniformly distributing the PMJs, and a PCS with branches for earlier septal activation (3.0m/s) and a faster Purkinje conduction speed in the LV (3.0m/s) compared to the RV (2.1m/s) was necessary to produce the correct activation sequence, eliminate QRS fractionations, and produce the best T-wave morphology. The figure shows the comparison of the ECG output from V3 for three different iterations. Conclusion - The reported Purkinje conduction speed is 0.8-2m/s, but a heterogeneous Purkinje conduction speed distribution combined with a high PMJ density is needed to produce computationally accurate ECGs.
Abstract 18248: Should We Refrain to Perform TAVI Procedures in Patients with a Mitral Regurgitation? Insights from the FRANCE 2 Registry
Authors: Eric van belle, Francis Juthier, Andre Vincentelli, Bernard Iung, Helene Eltchaninoff, Marc Laskar, Jean Fajadet, Alain Leguerrier, Martine Gilard, Carlo Banfi, Pascal Leprince, Alain Prat, Emmanuel Teiger
Journal: Circulation (2012)

Background: The presence of mitral regurgitation (MR) is an independent predictor of mortality after conventional aortic valve replacement for aortic stenosis. The predictive value of pre-procedural MR on clinical outcome after TAVI is unknown. Methods: 3,195 consecutive patients were enrolled between January 2010 and October 2011 in 33 centres. MR was graded according to pre-procedural transthoracic echocardiography (TTE) as none/trivial (=0), mild (=1), moderate (=2), moderate-to-severe (=3), or severe (=4). The mean age was 82±7 years; 49% were female and mean logistic EuroSCORE was 21.9±14.3. Balloon (BE) and self-expendable (SE) devices were implanted in 66.9% and 33.1% of patients, respectively. Approaches were transarterial (transfemoral: 74.6%; subclavian: 5.8%), transapical (17.8%), and transaortic (1.8%). Results: Pre-procedural TTE showed no MR in 32% of cases, a grade 1 MR in 46% of cases, a grade 2 MR in 20% of cases and a grade 3-4 in 2% of cases. Procedural success rate was 96.9%. Actuarial 1 year mortality was 19.5%. By univariate analysis, pre-procedural MR grade≥2, MR Grade=1 and MR Grade=0 were associated with a 1 year mortality rate of 24.0%, 20.1% and 15.8%, respectively (p=0.002). By multivariate analysis, 4 independent baseline characteristics were associated with preprocedural MR: a higer Logistic EuroSCORE (p=0.0001), a lower ejection fraction (p=0.0002), a higher NYHA class (p=0.0007), and female gender (p=0.001). By multivariate Cox analysis, independent predictors of one-year mortality were: logistic EuroSCORE (p=0.0001), NYHA class (p=0.0001) and transapical approach (p=0.0005). The presence of preprocedural MR was not significantly associated with 1-year mortality (p=0.31). Results did not differ when analyses were restricted only to BE or only to SE devices. Conclusion: A mild (grade1) or a moderate (grade 2) MR preprocedural is associated with a higher 1-year mortality after TAVI. However, since preprocedural MR is associated with a higher NYHA class or a higher logistic Euroscore, pre-procedural MR is not an independent predictor of mortality. These findings suggest that, in itself, the presence of a mild or a moderate MR should not refrain from performing TAVI and should not impact the type of valve to be used
Abstract 18330: Asymmetric Dimethylarginine, a Biomarker for the Effects of Drug Therapy in Pulmonary Hypertension
Authors: Nika Skoro-Sajer, Stefan Aschauer, Gerald Hlavin, Michael Wolzt, Roela Sadushi-Kolici, Irene Lang
Journal: Circulation (2012)

Rationale: Pulmonary hypertension (PH) is characterized by high morbidity and mortality, requiring aggressive treatment. Asymmetric dimethylarginine (ADMA), a potent endogenous nitric oxide synthase inhibitor, is increased in PH, and associated with unfavorable outcome. We hypothesized that ADMA may serve as a biomarker to monitor disease progression under pulmonary arterial hypertension (PAH)-specific treatment. Methods: ADMA plasma levels were measured at baseline and at least after 24 weeks of treatment in consecutive patients (pts) under PAH-targeted treatments (endothelin receptor antagonists (bosentan, ambrisentan), phosophodiesterase-V inhibitors (sildenafil), high dose calcium channel blockers (diltiazem) and prostanoids (subcutaneous treprostinil)). Therapy “responders” were defined by decrease of pulmonary vascular resistance (PVR) of at least 200dynes.cm-1.s-5, 6-minute walking distance &gt;380m, and improvement of WHO by one class and were compared with “non-responders”. Results: 51 consecutive patients (44 pts with PAH; 23 pts with idiopathic PAH, 8 pts with PAH associated (APAH) with congenital heart disease (CHD), 2 APAH pts with HIV, 4 APAH pts with connective tissue diseases (CTD), 5 pts with portopulmonary hypertension, 2 PAH patient with hepatitis C) and 7 patients with PH due to lung disease/hypoxia) were enrolled in this study. According to our definition; there were 16 non-responders, and 23 responders to treatments. 11 patients showed no change. ADMA plasma levels did not change significantly under treatment in the whole group. However, there was a significant drop of ADMA in responder group (p&lt;0.0001), Furthermore, ADMA change in “responders” and “non-responders” was significantly different (p=0.003). The decrease of ADMA correlated with the decrease of PVR (r=0.56, p&lt;0.0001), and with the decrease of mean pulmonary arterial pressure (r=0.44, p=0.001). Furthermore, the difference of ADMA correlated with the increase of cardiac index (r=-0.38, p=0.005) and mixed venous saturation (r=-0.3, p=0.03). Conclusions: ADMA parallels the hemodynamic benefit of PAH-specific treatment in patients with PH of various etiologies. ADMA can serve as a biomarker for the effect of PAH-specific treatments.
Abstract 17966: The Roles of S-Phase Kinase-Associated Protein-2 and Mitochondrial Dysfunction in the Aging-Related Endothelial Progenitor Cell-Cycle Retardation
Authors: Yih-Jer Wu, Hsueh-Hsiao Wang, Kuo-Tung Shu, Wen-Ting Liu, Yau-Huei Wei, Hung-I Yeh
Journal: Circulation (2011)

Background Deceleration of cell-cycle progression is a prominent feature of cellular senescence. S-phase kinase-associated protein-2 (Skp2) is a subunit of SCF Skp2 ubiquitin ligase responsible for ubiquitination and subsequent degradation of many cell-cycle regulators, such as cyclin-dependent kinase inhibitors p27 Kip1 and p21 Cip1 , and therefore is a key mediator for G1-S progression. However, it remains poorly understood whether Skp2 regulation and mitochondrial dysfunction are associated with endothelial progenitor cell (EPC) senescence. Materials and Methods In vitro EPC senescence was induced by serial passages. Bone marrow mononuclear cells from bone marrows (BM-MNC) of young (3 months) and old (24 months) rats were served as in vivo model of aging. Results Senescent EPC had a significantly longer cell doubling time, along with a typical increase of senescence-associated β-galactosidase (SA-βGal) activity and the enhanced expression of aging-related proteins, such as p21 Cip1 and p16 INK4a . In line with a slow-down of S-phase entry, aging EPC demonstrated a graded downregulation of Skp2 expression. Compared with young EPC, old EPC demonstrated a more elongated mitochondrial network along with a reduction of ATP production. Mitochondrial fission protein Fis-1 was found to be remarkably reduced in old EPC and silencing Fis-1 in young EPC resulted in an elongated mitochondrial network and a reduced ATP level similar to those of old EPC. However, Skp2 levels were not affected by Fis-1 silence, suggesting a mitochondria-independent regulation. Surprisingly, adenovirus-mediated Skp2 expression significantly reversed SA-βGal activity and almost completely rescued old EPC proliferation back to the level of young EPC, though Fis-1 levels and ATP production were not affected. Bone marrow blood from old rats had significantly reduced CD34 + /KDR + cells. Importantly, Skp2 expression in BM-MNC from old rats was also able to reverse SA-βGal activity and cell proliferation. Conclusion Skp2 downregulation and mitochondrial dysfunction develop with EPC senescence. Skp2 expression reverses SA-βGal and cell proliferation in old EPC and in old rat BM-MNC. Skp2 is at least one of the important factors that may rejuvenate senescent EPC.
Abstract 18314: Dysfunction of Junctional NCX Following JPH2 Knockdown Alters Spatial Properties of Ca <sup>2+</sup> Sparks and Contributes to Arrhythmogenesis in Mice
Authors: Wei Wang, Sayali Dixit, Qiongling Wang, Ralph J van Oort, Alejandro Garbino, Andrew P Landstrom, Michael J Ackerman, Xander H Wehrens
Journal: Circulation (2011)

Background. Na + /Ca 2+ exchanger (NCX) is essential in tuning intracellular Ca 2+ and the development of heart failure (HF). We reported that loss of Junctophilin 2 (JPH2) in adult mouse hearts leads to reduced NCX activity in addition to hyperactive RyR2s and more arrhythmogenic Ca 2+ waves. NCX has been found to co-localize with RyR2 recently. However, what is the physiological significance of junctional NCX and whether the reduced junctional NCX activity following JPH2 knockdown contributes to the arrhythmogenesis is still unknown. Hypothesis. Dysfunction of Junctional NCX in response to JPH2 knockdown alters spatial properties of Ca 2+ sparks and contributes to arrhythmogenesis. Methods. Tamoxifen-treated MCM and MCM-shJPH2 (KD) mice were studied. Contractile function was measured by echocardiography. Open probability of single RyR2 was evaluated by lipid bilayer. Ca 2+ spark were assessed with confocal microscopy. NCX activity was measured by exponential fitting of the declining phase of caffeine-induced Ca 2+ transient. Results. JPH2 knockdown increased spark size (MCM: 2.55 ± 0.14; KD: 4.25 ± 0.16, P &lt; 0.001), suggesting an increased occurrence of proarrhythmic macrosparks. Cardiac Contractile function (EF% ) is negatively correlated with Ca 2+ spark size (n = 8, P &lt; 0.05). Increased Open probability of RyR2 (MCM: 0.038 ± 0.018 KD: 0.274 ± 0.142, P &lt; 0.01) is unlikely the reason for the ~70% increase in spark size, since it is not observed in 3 other mouse models with hyperactive RyR2s but normal JPH2 levels (RyR2:S2814D, mdx and FKBP12.6 -/- ). Loss of JPH2 also slows Ca 2+ efflux via NCX by ~50% (MCM: 2.70 ± 0.23 vs. KD: 5.11 ± 0.61 s, P &lt; 0.01) without altering NCX expression level. Spark size and NCX activity are negatively correlated (n = 8 mice, P &lt; 0.05), and partial inhibition (~30%) of NCX with 1 mM Cd 2+ significantly increased spark size by 14.0 ± 2.8% (n = 8, P &lt;0.05) in wt mice. Conclusion. For the first time we showed that reduced NCX activity increases spatial properties of Ca 2+ sparks and thus arrhythmogenesis. Since reduced JPH2 is associated with HF and NCX plays more important role in human than in murine, reduced junctional NCX activity following loss of JPH2 could be a novel mechanism underlying the development of HF and associated ventricular arrhythmias.
Abstract 18341: Prospective, Multicenter Study on the Incidence of New Embolic Cerebral Lesions following Pulmonary Vein Isolation Using Laserballoon Ablation
Authors: Erik Wissner, Andreas Metzner, Petr Neuzil, Jan Petru, Reddy Vivek, Jan Skoda, Lucia Sediva, Bas Schoonderwoerd, Peter Rausch, Roland R Tilz, Feifan Ouyang, Karl-Heinz Kuck
Journal: Circulation (2012)

Background: Silent cerebral embolism following catheter ablation for atrial fibrillation (AF) has recently been described and its incidence varies depending on the intraprocedural anticoagulation strategy chosen or the ablation technology used. Its incidence following laserballoon ablation for AF is currently unknown. This multicenter, prospective study reports on the number of new lesions on postprocedural cerebral MRI following pulmonary vein isolation using laser-, cryo- or radiofrequency (RF) ablation. Methods: Each patient underwent cerebral MRI before catheter ablation for AF. Target ACT during the procedure was ≥ 300 s. Pulmonary vein isolation was performed using laserballoon (group 1), cryoballoon (group 2) or irrigated RF (group 3) ablation. Following the procedure all patients underwent repeat cerebral MRI. Results: Of a total of 72 patients (age: 63±9 years, 75% paroxysmal AF), 6/44 (13.6%) in group 1, 0/11 (0%) in group 2 and 3/17 (17.6%) in group 3 demonstrated new cerebral lesions on postprocedural MRI. Two patients with lesions in group 1 necessitated RF touch-up ablation, one of whom experienced diplopia with complete remission within days. No other gross abnormal neurological findings were detected in the remaining patients. Follow-up MRIs in those patients with lesions are currently underway. Conclusions: Laserballoon-based catheter ablation of AF demonstrates a similar safety profile regarding the rate of cerebral lesions than established ablation technologies.
Abstract 18244: The Association Between South Asian Ethnicity and Long-term Survival Among Patients Undergoing Coronary Artery Bypass Grafting
Authors: Billie-Jean Martin, Colleen M Norris, Danielle A Southern, Hude Quan, David B Ross, Imtiaz S Ali, Merill L Knudtson, Kevin Bainey
Journal: Circulation (2012)

Introduction: South Asians (SA) have a high burden of coronary artery disease (CAD) often requiring coronary artery bypass grafting (CABG). However, CABG outcomes in this population have not been explored. The objective of this study was to assess the survival of patients of SA descent undergoing CABG in a large, well described Canadian cohort. Methods: All patients who underwent CABG between 1996 and 2010 were identified from the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease registry. Ethnicity was determined using the Nam Pehchan surname software. Differences in long-term survival were compared between SA and European (EC) patients using adjusted and then unadjusted cox proportional hazards models. SA subjects were then matched 1:1 with EC counterparts using a non-parsimonious propensity model to balance groups; models were then re-run with the matched cohort. Results: Of the 20608 patients undergoing CABG, 608 were SA. SA patients were younger (63.8 vs 65.8 years) and had a higher prevalence of diabetes (39.5 vs 27.7%), but a lower prevalence of smoking (13.3 vs 25.3%) than EC patients (all p&lt;0.001). There were 5382 deaths long-term with a median follow-up of 7.2 years. Ninety-one deaths occurred in SA patients, 5291 in the EC patients. Kaplan-Meier survival analysis demonstrated a lower incidence of death in the SA patients (log rank, p&lt;0.0001) (Figure). In the unadjusted Cox PH model, SA ethnicity was associated with reduced mortality (Hazard Ratio 0.53, 95% CI 0.43, 0.66), an association that persisted in the adjusted model (HR 0.63, 95%CI 0.51, 0.78). All SA subjects were matched to EC counterparts. In the matched cohort SA ethnicity remained associated with reduced mortality (HR 0.68, 95%CI 0.52, 0.90). Conclusion: In a large prospective Canadian registry, SA undergoing CABG appear to have improved long-term survival compared to EC patients. The reasons behind this striking difference in mortality deserve further exploration.
Abstract 206: Intravenous Lipidic Oxygen Microparticles Improve Arterial Oxygen Content and Cerebral Oxygen Delivery During CCC-Only CPR
Authors: John Kheir, Lindsay Thomson, Lauren Danforth, Julie Cronin, Catherine Dowling, Jennifer Elder, Luis Velazquez, Vinay Nadkarni, Robert Berg, Francis McGowan
Journal: Circulation (2012)

Background: Although the effectiveness of CCC-only CPR is well-established, the benefits of adjuncts to further improve systemic oxygen delivery merit study. Oxygen gas can be encapsulated within injectable microparticles, or lipidic oxygen microparticles (LOMs), which transfer oxygen rapidly to the bloodstream within seconds of intravenous injection. The purpose of this study was to determine whether LOMs increase arterial oxyhemoglobin concentration, oxygen delivery and affect ROSC in a porcine model of experimentally-induced VF employing CCC-only CPR. Methods: Yorkshire swine (30 kg) were sedated with Ketamine and Xylazine for tracheal intubation and placement of femoral venous and arterial catheters. VF was induced and animals were immediately extubated and treated as shown in Fig 1A. CPR depth, rate, and leaning was guided in all animals with real time feedback from the monitor/defibrillator. Animals with shock-refractory VF were randomized to treatment with standard ACLS therapy with (n=5) or without (n=3) intravenous LOMs (Fig 1A). Results: Relative to controls, animals treated with LOMs in addition to standard ACLS therapy exhibited a significantly increased arterial oxyhemoglobin saturation during LOM administration (P&lt;0.0001, 2 way ANOVA, Fig 1B), a higher cerebral NIRS during LOM administration (P&lt;0.0001, linear regression, Fig 1C), a higher diastolic blood pressure during LOM administration (P&lt;0.0001, linear regression, Fig 1D), and a trend towards increased incidence of ROSC (P=0.36, Fig 1E). CPR quality (depth and rate) was similar between groups (P=1.00). Conclusion: LOMs may increase arterial oxygen content, cerebral oxygen delivery during CCC-only CPR, and may be a useful adjunctive therapy in non intubated patients with out-of-hospital cardiac arrest.
Abstract 19601: Absence of Adverse Cardiovascular Risk Factors for Over 35 Years is Associated with Better Health-Related Quality of Life at Older Ages: The Chicago Healthy Aging Study (CHAS)
Authors: Norrina B Allen, Thanh Huyen T Vu, Amber Pirzada, Daniel Garside, Martha Daviglus
Journal: Circulation (2012)

Background: Absence of adverse cardiovascular (CV) risk factors (RF) or having a favorable CV RF profile during middle-age is associated with better health-related quality of life at older ages. However, the impact of having no adverse CV RFs throughout middle- and older-age remains unknown. Objective: To examine the impact of remaining free of all adverse CV RFs for over 35 years on health-related quality of life among participants of the Chicago Health Aging Study (CHAS). Methods: The CHAS study conducted physical examinations at baseline (1967-1973) and follow-up (2007-2010). Absence of adverse CV RF profile was defined as having all the following: blood pressure &lt;140/&lt;90 mm Hg and not taking antihypertensive medication, serum cholesterol level &lt;240 mg/dL and not taking cholesterol-lowering medication, BMI &lt;30, no diabetes and not currently smoking. Health-related quality of life was measured at follow-up using the SF-36. We compared the SF-36 component scores (range 0-100, higher scores associated with better health-related quality of life) for individuals who continued to remain free of adverse CV RF profile in older age (i.e. from baseline to follow-up) vs. those with elevated levels of CV risk factors at baseline and/or at follow-up using linear regression models adjusted for age, sex, race, and highest educational attainment. Results: Among 1395 CHAS participants 8.8% (123) remained free of adverse CV risk factors for over 35 years from middle to older-age. Individuals who continued to have no adverse CV risk factors were more likely to be white (95.3% vs 87.4%; p&lt;0.01) and have a graduate school education (35% vs 19%; P&lt;0.001). Also, they had higher (better) adjusted physical component scores (54.0 vs 51.7; P=0.005), general health scores (77.0 vs 72.9; P=0.008), and physical functioning scores (99.5 vs 94.1; P=0.003) compared to those with adverse RFs. No differences were observed for the mental component score or the pain index, mental health index, role-emotional, role-physical, social functioning or vitality subscales. Conclusions: Remaining free of adverse cardiovascular risk factors for over 35 years from middle to older-age is associated with better physical quality of life at older ages.
Abstract 17828: Preconditioning of Mice with a Prolyl Hydroxylase Inhibitor, Dimethyloxalylglycine, Prevents Skin Flap Necrosis
Authors: Mitsuru Takaku, Shuhei Tomita, Hirotsugu Kurobe, Akira Ushiyama, Ichiro Hashimoto, Hideki Nakanishi, Toshiaki Tamaki
Journal: Circulation (2011)

Background- Local skin flaps often present with flap necrosis caused by critical disturbance of blood supply. Because hypoxia-inducible factor 1 (HIF-1) has a pivotal role in ischemic vascular responses, we assessed the hypothesis that preoperative stabilization of HIFs using prolyl hydroxylases (PHD) inhibitor contributes to improvement of skin flap survival. Methods and Results- Mice with ischemic skin flap on the dorsum were treated with PHD inhibitor dimethyloxalylglycine (DMOG) 48hr prior to operation by intraperitoneal administration. Immunoblot assay revealed sustained up-regulation of HIF-1α protein at pre- and postoperative states in the skin. Survival area of flap and the number of CD31 positive vessels at proximal part of flaps in DMOG-treated mice were significantly increased at day seven (20.6±4.9% vs. 55.5±13.2%; P&lt;0.001 and 11.3±1.7 vs. 17.3±3.3; P&lt;0.05). Serum vascular endothelial growth factor (VEGF) protein at the time of operation and its receptor Flk-1 protein at proximal part of flap on day one were significantly increased in DMOG-treated mice. Furthermore, flow cytometric analysis revealed a marked induction of circulating endothelial progenitor cells (EPCs) in DMOG-treated mice on day one (0.75±0.01% vs. 1.49±0.11% of CD45 gated CD34/CD133 positive cells; P&lt;0.005). Of interest, flow cytometric bromodeoxyuridine (BrdU)/DNA analysis showed a marked induction of proliferative progenitor cells in bone marrow 48hr after DMOG treatment. In addition, TUNEL staining at distal part of flaps revealed significantly decreasing apoptotic cells accompanied by increasing protein level of hexokinase II and decreasing Bax protein expression in DMOG-treated mice. HIF-1α heterozygous-null mice showed the reduction of flap survival areas, decreasing the number of circulating EPCs, and increasing the number of apoptotic cells, but these mutant mice with DMOG pretreatment demonstrated complete recovery of these parameters. Conclusion- These findings indicate that prevention of flap necrosis by pretreatment of DMOG is due to enhancement of both anti-apoptotic effects and angiogenesis at the flap region via HIF-1 functions, and that pretreatment of DMOG could be a potential therapeutic strategy for prevention of flap necrosis.