tbuckley/cabot-search huggingface dataset:
Abstract 18304: Dimerization with the Prostacyclin Receptor Triggers Thromboxane Receptor Relocation to Lipid Rafts
Authors: Salam Ibrahim, Emer Smyth
Journal: Circulation (2011)

Membrane rafts are liquid-ordered microdomains characterized by high levels of sphingolipids, cholesterol and saturated phospholipids. Prostacyclin (PGI2) effects its anti-thrombotic, anti-proliferative and vasodilator actions via a Gs coupled receptor, IP, opposing those of thromboxane A2 (TxA2) via TP, a Gq coupled receptor. IP is raft localized but the relevance is ill-defined. We reported a TP signaling shift to IP-like function through IP-TP heterodimerzation. In the present study, we examined IP and TP membrane localization and explored the importance of raft integrity to receptor dimerization and function. COS-7 cells were co-transfected with IP and/or TP. Gs activation was examined by measuring cAMP stimulation with cicaprost (PGI2 analog) or U46619 (TxA2 analog). Membrane localization was examined by measuring bioluminesence resonance energy transfer (BRET) from IP or TP fused to renilla luciferase (rLuc) to a raft-associated fluorophore, DiIC16. IP was localized in rafts, identified as saturable BRET from rLucIP to DiIC16. By comparison, rLucTP transfer was shallow and inefficient, similar to the non-raft associated ß2-adrenoreceptor, consistent with raft exclusion. Interestingly, the rLucTP BRET curve was strongly left-shifted, readily saturable and indistinguishable from rLucIP alone, when rLucTP-cells were cotransfected with untagged IP. This indicated IP-triggered relocation of TP to lipid rafts. Disruption of rafts by cholesterol depletion (2-hydroxypropyl-β-cyclodextrin; 20mM, 1hr) reduced cicaprost-stimulated cAMP in IP transfected cells (48.49±9.18 % inhibition) as well as cicaprost- and U46619-stimulated cAMP in IP-TP co-transfected cells (51.18+10.47 and 52.78+6.83 % inhibition) consistent with IPTP heterodimer function in rafts. Our data confirm IP localization to, and TP exclusion from, membrane rafts. IP function alone and as part of the IPTP heterodimer was at least partially dependent on raft integrity. Further, the shift in TP signaling to the cAMP pathway likely follows its relocation to rafts as the IPTP heterodimer. These data highlight the intricate cellular mechanisms through which IP can limit the cardiovascular effects of TP activation contributing to cardiovascular homeostasis and disease.
Abstract 8823: Abnormal Cardiac Innervation in Ventricular Fibrillation Patients with and Without Brugada Syndrome
Authors: Yukiko Nakano, Noboru Oda, Kazuyoshi Suenari, Yuko Makita, Kenta Kajihara, Akinori Sairaku, Takenori Tokuyama, Chikaaki Motoda, Mai Fujiwara, Iwasaki Toshitaka, Yoshikazu Watanabe, Ryo Yamazato, Hiroomi Sumida, Yasuki Kihara
Journal: Circulation (2011)

Abnormal cardiac innervation in patients with ventricular fibrillation (VF) has been reported. We investigated autonomic function in 48 successfully resuscitated VF patients using heart rate variability (HRV) as measured by Holter ECG and 123 I-metaiodobenzylguanidine ( 123 I-MIBG) scintigraphy. Eight patients were excluded because of hypertrophic cardiomyopathy (N = 2), arrhythmogenic right ventricular cardiomyopathy (N = 3), catecholamine-sensitive ventricular tachycardia (N = 1), and long QT syndrome (N = 2). Patients who could not discontinue internal remedies (N = 5) were also excluded. Fifteen patients (42 ± 14 years, 15 males) were diagnosed with Brugada syndrome (BS), and the remaining 20 patients (47 ± 6 years, 8 males) were diagnosed with idiopathic VF (IVF). QTc time was longer in the IVF patients than in the BS patients (450.1 ± 10.1 ms vs. 389.4 ± 21.0 ms, P &lt; 0.05). RMS40 was lower in the BS patients than in the IVF patients (13.9 ± 2.2 mV vs. 20.9 ± 3.6 mV, P &lt; 0.05). Parameters of HRV were similar in both groups, but abnormal circadian variations of HRV were observed in 53.3% of BS patients and 13.3% of IVF patients. The washout ratio was higher in the IVF patients than in the BS patients (36.3 ± 4.3 vs. 26.0 ± 2.1). The 123 I-MIBG uptake was increased in lateral regions in BS patients. Regionally reduced 123 I-MIBG uptake was observed with many variations in all patients, but no significant difference was observed between groups. These results demonstrated impairment of sympathetic innervation or enhanced activity of the sympathetic nervous system in patients with VF, particularly indicating sympathetic hypertonia in IVF and imbalance of circadian HRV in BS. These findings may have an impact on the arrhythmogenesis of such patients.
Abstract 17970: Metabolic Support of Mitochondrial Complex I with Yeast Ndi1 Evokes Significant Cardioprotection in the i <i>n vivo</i> Rat Model of Acute Myocardial Infarction
Authors: Karin Przyklenk, Peter Whittaker, Joseph Wider, Vishnu V Undyala, Roberta A Gottlieb, Robert M Mentzer
Journal: Circulation (2011)

Lethal myocardial ischemia-reperfusion injury has been attributed in part to mitochondrial respiratory dysfunction (including damage to Complex I) and the resultant excessive production of reactive oxygen species. Recent evidence has shown that Ndi1 (the single-subunit protein that serves as the surrogate for Complex I in yeast), transduced by addition of the TAT-conjugated protein to culture media and buffer, can preserve mitochondrial function and attenuate ischemia-reperfusion injury in isolated cardiomyocytes and isolated buffer-perfused hearts. However, the in vivo efficacy of this novel metabolic strategy to salvage ischemic-reperfused myocardium has, to date, not been explored. To address this issue, TAT-conjugated Ndi1 and TAT-conjugated placebo control protein were synthesized using a cell-free (non-bacterial) system. After confirming the identity of the proteins by immunoblotting, rats were randomly assigned to receive intraperitoneal injection of either TAT-Ndi1 or TAT-placebo. Two hours post-treatment, all animals underwent 45 min coronary artery occlusion followed by 2 hours of reperfusion. Infarct size was delineated by tetrazolium staining and normalized to the volume of at-risk myocardium (the primary determinant of infarct size in this model), with all analysis conducted in a blinded manner. Risk region was comparable in the two cohorts, averaging 28-32% of the total left ventricular weight (p=ns). Pre-ischemic administration of TAT-Ndi1 was, however, associated with profound cardioprotection: infarct size in TAT-Ndi1-treated rats was 25+7%* of the myocardium at risk, significantly smaller than the value of 63+5% seen in the TAT-placebo control group (mean + SEM; *p&lt;0.01 versus control). These results provide the first in vivo evidence that yeast Ndi1 can provide metabolic support to ischemic-reperfused myocardium and reduce myocardial infarct size. Moreover, these data suggest that metabolic support of mitochondrial proteins may provide a novel molecular strategy to protect the human heart against planned ischemia-reperfusion events.
Abstract 17987: Association of Cardiovascular Events and Apolipoprotein CIII - A Systematic Review and Meta-Analysis
Authors: Moritz Wyler von Ballmoos, Bernhard Haring
Journal: Circulation (2011)

BACKGROUND: Apolipoprotein CIII (apoCIII) is an 8.8-kDa apolipoprotein peptide found on HDL, VLDL and LDL. OBJECTIVE: To systematically review current evidence on the association of blood apoCIII level with cardiovascular events, and to evaluate whether the current literature suggests a dose-response relationship for this association. DATA SOURCES : MEDLINE, EMBASE, BIOSIS, CINAHL, Clinicaltrials.gov, grey-literature sources, contact with investigators, and reference lists of studies, without language restrictions. STUDY SELECTION: Publications were selected if they investigated the association between blood apoCIII level and coronary heart disease, myocardial infarction, stroke, or sudden death from stroke or myocardial infarction. Data including study and patient characteristics, apoCIII level, and outcomes were extracted independently by two investigators. DATA SYNTHESIS AND RESULTS: 10 studies (6 case-control, 4 cohort studies) with a total of 1469 cases of cardiovascular events met inclusion criteria. Four studies compared apoCIII levels and showed higher blood levels in subjects with a cardiovascular event. The other six studies calculated adjusted estimates of relative risks of 1.82-3.88 (total apoCIII), 2.25-8.87 (non-HDL apoCIII), and 0.64-2.57 (HDL apoCIII) for cardiovascular events. Random-effects meta-analyses were performed with summarized dose-response data where applicable. All studies showed a positive, significant association of apoCIII with cardiovascular disease. Risk estimates demonstrate a monotonous, graded increase in risk of cardiovascular disease with increasing levels of apoCIII and are beyond what could reasonably be explained by residual confounding alone. CONCLUSION: The current body of literature includes several methodologically sound studies that together provide consistent evidence for an independent association of cardiovascular events with blood apoCIII level. Available data suggest that apoCIII is an independent risk factor for cardiovascular events. Further data is needed in order to determine the significance of the location and amount of apoCIII on specific lipoproteins in cardiovascular risk management.
Abstract 214: Drivers of In-Hospital Cardiac Arrest Survival Rates: A Risk-Adjusted Model
Authors: Raina M Merchant, Robert A Berg, Peter W Groeneveld, Lin Yang, Lance B Becker, David A Asch, Paul S Chan
Journal: Circulation (2012)

Background Cardiac arrest in hospitalized patients is common and often fatal. Factors which predict which patients will survive arrest to discharge or die in the hospital are unknown. This gap in our understanding precludes hospitals from characterizing their relative in-hospital cardiac arrest (IHCA) outcome rates relative to other hospitals and identifying their individual needs for quality improvement. Methods Using data from the Get With the Guidelines-Registry, years 2000-2010, we identified patients with IHCA. Excluded were patients &lt;18 or &gt;110 years of age, arrests in hospital visitors or employees, and events with missing variables. A regression model was used to identify predictors of survival rates across hospitals. The sequential model included demographics ( age, race, gender), then pre-arrest comorbidities, and then intra-arrest factors (e.g. initial rhythm, in-place interventions, arrest: etiology, location, time). The outcome measure was survival to discharge. Unadjusted and risk-adjusted survival rates per hospital were calculated. Results We evaluated 136,663 IHCA at 588 hospitals. IHCA survival to discharge rates varied across hospitals; unadjusted: median: 0.19 (IQR 0.14-0.24); adjusted: median 0.18 (IQR 0.16-0.21). The regression model showed several predictors explained some but not all of the variability in outcomes (c-statistic =0.74). Several predictors of variability in survival outcomes included age 41-65 (OR 1.5; 95% CI 1.5-1.6, p&lt;.01), female sex (OR 1.1; 95% CI 1.0-1.1 p&lt;.01), black race (OR 0.83; 95% CI 0.79-0.87, p&lt;.01), prior arrhythmia (OR 1.25; 95% CI 1.2-1.3, p&lt;.01), cardiac arrest etiology (OR 1.2; 95% CI 1.2-1.3, p&lt;.01), toxicologic arrest etiology (OR 2.4,95% CI 2.1-2.8, p&lt;0.01), monitored bed status (OR 1.7; 95%CI 1.6-1.8, p&lt;.01), and pre-arrest anti-arrhythmic drugs (OR 1.2; 95% CI 1.2-1.3, p&lt;.01). Conclusion There is significant variability in IHCA outcomes across hospitals although not all explained by patient level risk-adjustment of available variables. Further research is needed to investigate additional drives (e.g. hospital structure and process measures, patient level variables in other datasets) of this variability in order to develop valid comparisons of outcomes across hospitals.
Abstract 18298: Niferidile, New Class III Antiarrhythmic Agent: Study of Electrophysiological Effects Aad Efficacy in Patients with Supraventricular Arrhythmias
Authors: Nikolay Y Mironov, Yulia A Yuricheva, Sergey P Golitsyn, Sergey F Sokolov, Eugeniy B Maykov, Nikolay B Shlevkov, Yuriy V Mareev, Leonid V Rosenstraukh, Eugeniy I Chazov
Journal: Circulation (2012)

Background. Niferidile (Nf) is a new potassium channel blocker that inhibits transient outward and delayed rectifier currents. Preclinical studies showed that Nf increases effective refractory periods (ERP) in atria more than in ventricles. High affinity of Nf to atrial myocardium should contribute to high efficacy in supraventricular arrhythmias and to low risk of ventricular proarrhythmia. Objectives. To evaluate electrophysiological effects and antiarrhytmic efficacy of Nf in patients with paroxysmal supraventricular tachycardia (PSVT). Materials and methods. Effects of Nf (administered 20µg/kg intravenously) were studied in 28 patients (16 males) with PSVT (14 orthodromic tachycardia in WPW syndrome, 10 AV-nodal reentrant tachycardia, 4 orthodromic tachycardia due to concealed bypass tract) during endocardial electrophysiological study. Termination of sustained paroxysms of PSVT by Nf could be investigated in 23 patients and prevention of reinduction of PSVT - in 25 patients. Results. Nf terminated PSVT in 78.26% and prevented reinduction in 84% of patients. Nf increased ERP of right atrium (by 22.25%; p&lt;0.01), left atrium (by 22.45%; p&lt;0.01), right ventricle (by 12.03%; p&lt;0.05) and accessory pathways (anterogradely by 23.64% [p&lt;0.01]; retrogradely by 29.43% [p&lt;0.001]). Nf did not affect sinus node and atrioventricular conduction. Nf significantly increased relative refractory period of His-Purkinje system (by 34.71%; p&lt;0.01). Nf prolonged QT (by 24.5%; p&lt;0.01) and QTc (by 20.11%; p&lt;0.05) intervals. One patient developed short runs of torsade de pointes shortly after injection of drug. Conclusion. Prolongation of ERP, predominantly in atria and accessory pathways, and RRP in His-Purkinje system are main electrophysiological effects of Nf. New drug demonstrated high antiarrhythmic efficacy and good safety profile in patients with PSVT.
Abstract 18351: Prevalence, Clinical Significance and Relevance to Screening of Electrocardiographic Abnormalities in Hypertrophic Cardiomyopathy <i>Versus</i> Athlete's Heart
Authors: Chiara Calore, Paola Melacini, Antonio Pelliccia, Cianfrocca Cinzia, Maurizio Schiavon, Di Paolo Fernando M, Bovolato Francesca, Quattrini Filippo M, Cristina Basso, Gateano Thiene, Sabino Iliceto, Domenico Corrado
Journal: Circulation (2012)

Background: Hypertrophic cardiomyopathy is often in the differential diagnosis with athlete’s heart due to the partial overlap of ECG and echocardiographic abnormalities. This study assessed the prevalence, clinical significance and relevance to athletic screening of ECG abnormalities in hypertrophic cardiomyopathy (HCM) patients versus highly trained athletes. Methods: We compared the ECG tracings of 247 HCM patients (73% males, mean age 39±14 years) with those of 133 highly trained athletes with augmented left ventricular (LV) mass (87% males, mean age 27±6 years), with the same age range (15-65 years) Based on the ECG findings, HCM patients and athletes were grouped as normal ECG (Group 1), isolated increase of QRS voltage (Group 2) and abnormal ECG showing ≥1 non-voltage criteria, including atrial enlargement, QRS left axis deviation, ST-segment or T-wave abnormalities, pathologic Q waves, and complete bundle branch block, regardless of QRS amplitude (Group 3). Results: Group 1 ECG was found in 11/247 (4%) HCM patients vs 69/133 (52%) athletes (P&lt;0.001); Group 2 ECG in 6 (2%) vs 53 (40%) (P&lt;0.001) and Group 3 ECG in 230 (93%) vs 11 (8%) (P&lt;0.001). Compared with HCM patients from Group 3, those from Group 1 and 2 had a lower maximal LV wall thickness (16±2 and 18±3 mm vs 21±5 mm; P=0.01) and a lower rate of either defibrillator implants (0 vs 17%) or major arrhythmic events (0 vs 6%) during a follow-up of 8±6 years. Combined voltage and non-voltage ECG abnormalities (Group 2 and 3) showed a sensitivity of 96% and a specificity of 52% for HCM, whereas non-voltage criteria alone (Group 3) increased the specificity to 92% (P&lt;0.001) and reduced the sensitivity to 93% (P=0.35). Conclusions: The ECG abnormalities of HCM and athlete’s heart overlap marginally. Unlike athletes, among HCM patients the ECG pattern of isolated increase of QRS voltages is uncommon and associated with a mild phenotype similarly to normal ECG. Interpreting as normal an isolated increase of QRS voltages almost doubles the ECG specificity, without significantly reducing sensitivity for HCM.
Abstract 18272: Aggravation of Myofibroblast Arrhythmogeneicity by Mechanical Stress
Authors: Teddy Grand, Nicolò Salvarani, Stephan Rohr
Journal: Circulation (2012)

INTRODUCTION: Owing to their modest membrane polarization, cardiac myofibroblasts (MFBs) induce arrhythmogenic slow conduction and ectopic activity by causing partial depolarization of electrotonically coupled cardiomyocytes (CMCs) in-vitro. We hypothesize that mechanical stress may aggravate this condition by activation of stretch activated channels (SACs) in MFBs that accentuate MFB depolarization. METHODS: The effects of acutely blocking SACs with streptomycin (SM) on single MFB and CMC membrane polarization (Vm) were assessed by patch clamp. Modulation of impulse conduction velocity (θ) by SM and by stretch was investigated in strands of neonatal rat ventricular CMCs or CMCs coated with MFBs using optical recording techniques. For stretch experiments, cell strands were cultured on silicon membranes. RESULTS: Whereas SM (50 µmol/L) had no effect on Vm of CMCs (control: -75.1±2.62mV; SM: -75.3±2.59mV, n=8 each), it caused MFBs to hyperpolarize from -33.7 ± 11.2 mV to -37.7±11.4 mV (n=8) suggesting the presence of active SACs in MFBs under control conditions. In accordance with these findings, SM exerted no effects on θ in CMC cell strands (control: 335.4±23.3 cm/sec; SM: 328.0±19.8 cm/sec; n=36 each; n.s.) but increased θ from 173.8±68.2 cm/sec to 224.9±63.3 cm/sec (n=54 each; p&lt;0.0001) in CMC-MFB strands. Direct proof for the modulation of θ by MFB-SACs was obtained by subjecting cell strands to acute length changes. In CMC-only strands, θ was positively correlated with strand length (8% relaxation: 323.6±19.1 cm/s; control: 332.6±22.8 cm/s; 10% stretch: 340.6±22.7 cm/s; n=14) which is likely explained by changes in cell geometry. In contrast, θ of hybrid CMC-MFB strands decreased with increasing strand length (8% relaxation: 270.8±36.9; control: 248.4±48.1 cm/s; 10% stretch: 237.6±40.1, n=5) suggesting that stretch caused activation of SACs in MFBs that ultimately led to partial depolarization of coupled CMCs. CONCLUSION: The results demonstrate that acute stretch differentially affects θ depending on the cellular composition of cardiac tissue. Slowing of conduction is observed only in presence of MFBs which suggests that arrhythmogenic consequences of mechanical stress may be aggravated by MFBs in fibrotically remodelled myocardia.
Abstract 19703: Real-Time Microscopic Assessment of Ischemia-Reperfusion with Intravital Autofluorescence Imaging
Authors: Hsueh-Han Lu, Wei-Tien Chang, Yao-Ming Wu, Ian Liau
Journal: Circulation (2012)

Background: Real-time microscopic characterization of ischemia and reperfusion (IR) in vivo is essential to improve our understanding of the underlying pathogenesis of IR injury, but histopathological examination post reperfusion remains a common means to assess IR. The mitochondrial flavoprotein switches between non-fluorescent and fluorescent state as it undergoes redox change. We herein sought to visualize IR microscopically in a real-time and label-free manner in vivo based on the autofluorescence of this intrinsic indicator. Methods: Intravital autofluorescence microscopy was employed to image hepatic IR in vivo on a rat model. Time-lapse autofluorescence images of the liver tissue and time-varying intensity of the autofluorescence were recorded continuously on liver subject to short and long durations of ischemia. FITC-dextran was injected intravenously to highlight sinusoids with circulating blood. Results: The autofluorescence decreased by ~30% immediately after ischemia, but restored gradually after reperfusion. The recovery rate depended strongly on the duration of ischemia: the intensity restored to the baseline within 10 min for 20-min ischemia whereas the recovery was significantly slower (&gt; 30 min) for 60-min ischemic time. Results of complementary experiments on cultured hepatocytes in vitro including (1) emission spectral measurements, (2) autofluorescence imaging on cells undergoing simulated IR, and (3) inhibitory assay all support strongly that the autofluorescence change observed during IR is associated with hypoxia-reoxygneartion of tissue. The intravital imaging further revealed that the retarded autofluorescence recovery is associated with delayed reoxygenation that was caused by impaired microcirculation. Conclusions: Our work demonstrates that the autofluorescence of mitochondrial flavoprotein is a sensitive endogenous indicator that enables visualization of the hypoxia-reoxygenation of tissues associated with IR at the microscopic level in real time. This approach should be extendible to investigate IR of other vital organs.
Abstract 253: Effect of First-Degree Heart Block on Left Ventricular Filling and Hemodynamics
Authors: Amar P Jadhav, Nadish Garg, Rahul Shekhar, Marius Petruc, John Fresen, Kul Aggarwal
Journal: Circulation (2011)

Background: First degree heart block (FHB) is considered a benign electrographic finding. However, recent studies have suggested that FHB is associated with excess mortality. In another study PR interval greater than 220msec was associated with increased rate of heart failure hospitalizations. So far, very little is known about the effect of FHB on left ventricular (LV) filling and hemodynamic. Objective: To evaluate the hemodynamic effects and LV filling in patients with FHB Methods: This was retrospective chart review of 133 patients with and without FHB. The patients were identified from our electrocardiography (EKG) database. All the patients that had both echocardiogram and EKG in 2010 were included for the study. FHB was confirmed with the ekg tracing on the echocardiogram. For LV filling we calculated mitral inflow velocity time integral (MV VTI), by tracing the mitral inflow pulse wave doppler tracing using the standard software. The data was analyzed using the R version 2.12 statistical package. Linear regression analysis was preformed to study the effect of FHB on LV filling. Several linear models were fitted to the data using the PR interval and HR as predictor variables. Results: The patients were divided in two groups, PR interval less than and greater than 220. In the patients with PR interval less than 220msec (n=65), LV filling (MV VTI) was noticed to progressively decrease with increase in PR interval (P&lt;0.02) and was unaffected by heart rate (P=0.4). However, in patients with PR interval greater than 220 msec (n=66), LV filling progressively decreased with increase PR interval (P&lt;0.03) and increase in heart rate (P&lt;0.02). Interestingly, it appears that for lower heart rates HR-50 beats per minute ( BPM), increase in PR interval resulted a greater reduction in LV filling as compared to higher heart rate (HR-70 BPM) Conclusion: LV filling is adversely affected with increase in PR interval and heart rate. In addition, it appears that lower heart (&lt;50 BPM) in patients with PR interval &gt;260 msec results in more pronounced reduction of LV filling. Patients with PR intervals &gt;220msec might benefit from higher heart rates which needs to be further evaluated.