tbuckley/cabot-search huggingface dataset:
Abstract 8654: Low In-Treatment HDL Cholesterol Levels Strongly Predict New Heart Failure in Hypertensive Patients: The LIFE Study
Authors: Peter Okin, Darcy A Hille, Kristian Wachtell, Sverre E Kjeldsen, Lars H Lindholm, Björn Dahlöf, Richard B Devereux
Journal: Circulation (2011)

Background: Although low HDL levels predict incident heart failure (HF) in a population-based study, whether low HDL is associated with increased risk of new HF in hypertensive patients is unclear. Methods: Incident HF was examined in relation to in-treatment HDL levels in 8445 hypertensive patients with no history of HF with baseline HDL levels randomly assigned to losartan- or atenolol-based treatment. In-treatment HDL at each year of testing was categorized into the lowest quartile vs upper 3 quartiles according to baseline HDL levels or examined as a continuous variable with hazard ratios calculated for each SD of the baseline mean lower HDL (0.44 mmol/l). Results: During 4.7±1.1 years follow-up, there were 264 new HF hospitalizations (3.1%). In univariate Cox analyses, compared with HDL ≥1.21 mmol/l, in-treatment HDL &lt;1.21 was associated with a 117% greater risk of new HF. In parallel analyses which used in-treatment HDL as a continuos variable, each 1 SD lower HDL was associated with a 45% higher HF risk. In multivariate Cox analyses adjusting for randomized treatment, age, sex, body mass index, prevalent and history of atrial fibrillation and diabetes, history of MI, ischemic heart disease, stroke, peripheral vascular disease, smoking status, baseline serum creatinine, glucose, urine albumin/creatinine ratio as standard risk factors and for incident MI, in-treatment diastolic and systolic pressure, heart rate, QRS duration, Cornell product and Sokolow-Lyon voltage criteria for left ventricular hypertrophy and non-HDL cholesterol levels as time-varying covariates, the lowest quartile of in-treatment HDL remained associated with a 102% greater risk and, in alternative analyses, each 1 SD lower HDL treated as a continuous variable with a 38% higher risk of incident HF. Conclusions: Lower in-treatment HDL is an independent predictor of new HF in hypertensive patients, even after adjusting for other potential risk factors and treatment effects.
Abstract 290: Endothelial Dysfunction in a Rat Model of Asphyxia-Induced Cardiac Arrest
Authors: Thomas T Troelsen, Asger Granfeldt, Else Tønnesen, Ulf Simonsen
Journal: Circulation (2012)

Background: Altered vasoreactivity and elevated markers of endothelial activation are found following cardiac arrest (CA) and resuscitation. However, it is unknown whether the described altered vasoreactivity reflects influence from humoral factors, affection of the underlying smooth muscle or a change in the endothelium itself. Furthermore, it is unknown how the inflammatory markers correlate to endothelial function. The aim of the present study was to assess endothelial function and the relation to plasma markers of inflammation and adhesion, CA and resuscitation. Methods: Male Sprague Dawley rats underwent 5 min. of asphyxia-induced CA and subsequent resuscitation. After return of spontaneous circulation (ROSC) animals were euthanized after 30 min. or 2 hrs. Sham operated animals were used as controls. At the end of the experiment blood was drawn and analyzed for IL-1β, IL-6, IL-10, TNF-α, ICAM-1, VCAM-1, VEGF-α, vWF and sP-Selectin. Segments of the Left coronary artery (LCA) and mesenteric resistance arteries were mounted in microvascular myographs. Concentration-response curves for acetylcholine (ACH), NS309, and sodium nitroprusside where obtained. Results: LCA-segments exhibited an impaired vasodilation to ACH after 30 min. of ROSC as CA animals dilated to a max of 66 ± 2 vs. 94 ± 8% in the sham group (Mean ± SE; P=0.0014). After 2 hrs. of ROSC vasoreactivity was comparable to sham groups for all drugs tested. The mesenteric arteries exhibited a larger response to NS309 after 2 hrs. of ROSC compared to 2 hr. sham (logEC50 ± SE: 0.43 ± 0.05 vs. 1.85 ± 0.23 µM; P&lt;0,001). Levels of sP-selectin, vWF and sVCAM-1 were elevated in both CA groups vs. sham groups, with no correlation to vasoreactivity. Conclusion: Endothelium-dependent ACH-induced nitric oxide (NO)-mediated vasodilation was blunted in LCA segments in the early post-resuscitation phase, NS309-induced endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilation was enhanced in mesenteric resistance arteries in the intermediate post-resuscitation phase. There was no relation of vasoreactivity to plasma markers of adhesion and inflammation. The altered vascular reactivity may explain impaired coronary flow and hypotension in the restitution phase after cardiac arrest.
Abstract 18627: Cellular Encapsulation of Mesenchymal Stem Cells Enhances Cardiac Repair in a Rat Model of Myocardial Infarction
Authors: Rebecca D Levit, Natalia Landazuri, Edward A Phelps, Milton E Brown, Andres Garcia, Michael E Davis, Gigi Joseph, Long Robert, Collin J Weber, Susan A Safley, Jonathan D Suever, Alicia N Lyle, W. Robert Taylor
Journal: Circulation (2012)

Rebecca D Levit, 2012 Finalist and Presenting Author
Abstract 19206: Pressure Overload Induced Heart Failure Reduces Endogenous Hydrogen Sulfide (H2S) and Mitochondrial Respiratory Function but is Rescued by a Novel H2S Sulfide Donor
Authors: Kazuhisa Kondo, Shashi Bhushan, Adrienne L King, Gabriel Gorjon, Gabriel Gorjon, David J Lefer
Journal: Circulation (2012)

Introduction: Sustained hypertension induces cardiac hypertrophy and dysfunction with increased generation of reactive oxygen species (ROS) by the mitochondria and other cellular sources. Hydrogen sulfide (H2S) is a potent signaling molecule that has been shown to attenuate oxidant-mediated cardiac injury. We investigated the effects of hypertension-induced heart failure on endogenous H2S production, mitochondrial function, and left ventricular performance. Methods: Transverse aortic constriction (TAC) was performed in male, C57BL/6J mice (n=15-20 per group). Mice received a novel, orally active H2S donor (SG-1002 at 20 mg/kg/day) delivered in the diet at 1 week prior to TAC. Follow-up echocardiography was performed up to 6 weeks. H2S and the stable metabolite - sulfane sulfur - were measured. Additionally, 8-isoprostane levels in the heart and myocardial mitochondrial respiratory function were also assessed following TAC. Results: Control and SG-1002 treated mice exhibited equivalent hypertrophy (VEH; 1.35 mm vs. SG-1002; 1.34 mm) at 6 weeks following TAC, but SG-1002 mice exhibited significantly improved cardiac function (EF; 69% vs. 47%, p &lt; 0.001). Interestingly, control mice exhibited significantly lower H2S and sulfane sulfur levels in the blood and heart compared to sham mice at 6 weeks following TAC. Treatment with SG-1002 partially rescued H2S and sulfane sulfur levels in the blood and heart. Control mice exhibited higher 8-isoprostane levels in the heart compared to sham or SG-1002 treated mice at 6 weeks following TAC. At 6 weeks following TAC, myocardial mitochondrial respiratory function was also reduced, but rescued by SG-1002 diet. Conclusion: Our results indicate that pressure overload induced hypertrophy attenuates endogenous H2S bioavailability as a result of increased oxidative stress and mitochondrial dysfunction. Restoring endogenous H2S with an oral H2S donor may be a potential treatment in the setting of hypertensive heart failure.
Abstract 9383: Selective Tissue Factor/Factor VIIa Inhibitor ER-410660 and its Prodrug E5539 Have an Anti-Venous Thrombotic Effect with Low Risk of Bleeding
Authors: Tadashi Nagakura
Journal: Circulation (2011)

The “extrinsic coagulation pathway” is activated by complex formation between tissue factor (TF) and factor VIIa (FVIIa). The onset of thrombosis is associated with the specific expression of TF. Compounds that inhibit the TF/FVIIa complex might therefore have therapeutic and/or prophylactic uses for diseases associated with thrombus formation. TF/FVIIa inhibitors might also reduce the risk of bleeding as they leave the intrinsic pathway intact and so maintain normal hemostasis. We assessed this hypothesis using a series of triazolone derivatives that acted as potent and selective TF/FVIIa inhibitors. Based on human intravenous pharmacokinetic data from a microdosing study, we identified ER-410660 as a candidate for prodrug formation to improve oral availability. ER-410660 showed potent and selective inhibition of the TF/FVIIa complex with an IC 50 of 5.7 nM. The compound selectively prolonged the prothrombin time (PT) in human, rhesus monkey, and rat plasma (a 50% increase of PT was obtained at 2.0, 1.7, and 19 μM, respectively). Intravenous (iv) administration of ER-410660 dose-dependently inhibited thrombin generation caused by TF-injection in the rhesus monkey with an ED 50 of 40 (95% CI, 25-55) μg/kg. ER-410660 (iv) reduced venous thrombus weights in a TF-administered stasis-induced venous thrombosis model in rats with an ED 50 of 0.18 (95% CI, 0.11-0.25) mg/kg. The anti-hemostatic effect of ER-410660 (iv) was evaluated in a rat tail-cut model. The total bleeding time was doubled at 7.1 (95% CI, 6.1-11) mg/kg, which was 39-fold higher than the ED 50 value in the rat venous thrombosis model. E5539, an orally available form of ER-410660, was discovered by prodrug formation. Oral E5539 at doses of 3, 10, and 30 mg/kg reduced plasma thrombin-antithrombin (TAT) complex levels elevated by TF-injection in a dose-dependent manner. The TAT level was reduced to 50% of the control at an ED 50 value of 12 (95% CI, 8.0-17) mg/kg. These proof-of-concept studies in animal models suggest that selective TF/FVIIa inhibitors such as ER-410660 and its prodrug E5539 could act as novel anticoagulants with a low risk of bleeding.
Abstract 9959: An Intensive Lifestyle Modification Program Reduces the Number of Component Factors in Subjects With Metabolic Syndrome
Authors: Sammy Chan, Emma Hardwick, Kay McQueen, Minetaro Naruki-Van Velzen, Cindy Kam, Susanne Burns, Gregory Bondy, Minette Walker, Jiri Frohlich, Andrew Ignaszewski
Journal: Circulation (2012)

The prevalence of obesity is increasing. Among subjects with obesity, those with metabolic syndrome represent a high risk subset for development of cardiovascular disease. We initiated an intensive lifestyle modification program targeting subjects with Metabolic Syndrome. The program is based on an expanded chronic care model with a multidisciplinary team. The program duration is 18 months with initial active 12 months of intervention and 6 months of passive follow up afterwards. In the intervention phase there are prescribed individual counselling and group visits and exercise sessions. The central themes of the program are collaborative goal setting between subjects and care team, stress management, motivation enhancement for behaviour change, self management support and prevention of relapse. We have previously reported the aggregate results. We now report results pertaining to individual changes. Paired data after the one year intervention phase were available for 346 subjects (age 55±10y, female 59%); 37 subjects (age 55±10y, female 51%) who registered but did not participate in the program (≤ 4 sessions) formed the control group. We determined the number of metabolic syndrome components (IDF 2006 worldwide definition) for each subjects at entry into program and at 1 year. At one year, majority of subjects who actively participated in the program (53% active, 38% control, Table) had at least one less Metabolic Syndrome criteria whereas majority of control subjects has same number of Metabolic Syndrome criteria (36% active, 54% control, Table). Chi square analysis showed a significant difference between active and control groups in the proportion of subjects who had less, same or more number of Metabolic Syndrome criteria from entry to one year (Chi-square=6.85, df 2, p=0.038). We conclude that a multidisciplinary intensive lifestyle modification program can significantly reduce the number of Metabolic Syndrome criteria in obese community living subjects.
Abstract 9103: Rivaroxaban Use is Associated with Reduced Risk of Myocardial Infarction-Insights from a Meta-analysis and Trial Sequential Analysis of Randomized Clinical Trials
Authors: Saurav Chatterjee, Abhishek Sharma, Ken Uchino, Giuseppe Biondi-Zoccai, Edgar Lichstein, Debabrata Mukherjee
Journal: Circulation (2012)

Introduction: There has been recent evidence to suggest an increased risk of myocardial infarction (MI) with the use of the direct thrombin inhibitor, dabigatran etexilate-approved in the US for prevention of stroke in non-valvular atrial fibrillation. Hypothesis: We systematically evaluated the risk of MI associated with use of the other drug, recently approved for the same indication-rivaroxaban, an oral factor Xa inhibitor. Methods: We searched PubMed, CINAHL, Cochrane CENTRAL, Scopus, and the Web of Science. Randomized controlled trials of rivaroxaban that reported on myocardial infarction as clinical outcomes. The fixed-effects Mantel-Haenszel (M-H) test was used to evaluate the effect of rivaroxaban on MI, in the absence of heterogeneity. Trial sequential analysis (TSA) was performed to ensure validity of our findings. Results: Seven trials were selected (N=45,566), including 1 study of stroke prophylaxis in atrial fibrillation, 2 in acute coronary syndrome, and 4 of short-term prophylaxis of deep venous thrombosis. Control arms included warfarin, enoxaparin, or placebo administration. Rivaroxaban was associated with a significantly lower risk of MI than that seen with agents used in the control group; OR, 0.82; 95% CI, 0.72-0.93; P=0.002). No heterogeneity was noted in the risk (I2=0%; P=0.82), TSA reinforced validity of our findings. Conclusions: Rivaroxaban is associated with a significantly lower risk of MI in a broad spectrum of patients when tested against different controls. We recommend the use of rivaroxaban over dabigatran for nonvalvular AF particularly in patients at high risk of acute coronary events.
Abstract 314: Outcomes of Patients with Cardiac Arrest Treated with Therapeutic Hypothermia: Insights on Etiology and Initial Rhythm
Authors: Brian T Kalish, Kathleen R Avery, Carol D Pierce, Annmarie Chase, Robert Fine, Alison Forni, Karen M Griswold, Galen V Henderson, Beth Anne Hirning, Peter C Hou, Kyller G Michael, Anthony F Massaro, David A Morrow, Raghu R Seethala, Peter H Stone, Stefan Strojwas, Paul M Szumita, Benjamin M Scirica
Journal: Circulation (2012)

Background: Therapeutic hypothermia (TH) improves neurological outcomes and reduces mortality in patients successfully resuscitated after VT/VF cardiac arrest (CA). Outcomes according to the clinical scenarios leading to the CA and initial rhythm, though, vary significantly. Methods: We report a single center experience that recommended TH for all patients who were comatose after CA, regardless of etiology or initial rhythm. Patients were categorized according to clinical scenario surrounding CA and initial rhythm. Good neurologic recovery was defined as a cerebral performance category of 1/2 (no deficit to moderate disability). All outcomes were assessed at discharge. Results A total of 135 patients with CA received TH of whom 79 cases (58%) had cardiac etiology (27 [20%] were STEMI and 52 [39%] other cardiac etiologies) and 56 (42%) non-cardiac. Patients with a cardiac cause of CA were more likely to survive until discharge than non-cardiac (51% vs. 23%, p=0.002) and have better neurologic recovery (41% vs. 8%, p&lt;0.001). VT/VF was the most common initial rhythm (50%), followed by PEA (30%), asystole (19%), and bradycardia (2%). Patients presenting with VT/VF were most likely to survive at discharge and have better neurologic recovery compared to non-shockable rhythms (p&lt;0.001 for both). (Figure) Conclusion: Cardiac etiologies, in particular VT/VF, were the most common cause of CA in patients undergoing TH. PTs with VT/VF had the best survival and neurologic outcomes. Further research into the optimal treatment of CA from non-cardiac etiology or non-shockable rhythms is needed.
Abstract 18928: Cardiac Soluble Guanylate Cyclase Protects Against Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice
Authors: Sara Vandenwijngaert, Melissa Swinnen, Peter Pokreisz, Hilde Gillijns, Ellen Caluwé, Jozef Bartunek, Kenneth D Bloch, Stefan P Janssens
Journal: Circulation (2012)

Background - The chemotherapeutic use of doxorubicin (DOX) is limited by cardiotoxicity. Growing evidence suggests a protective role for cyclic guanosine monophosphate (cGMP) in pathological LV remodeling. We therefore tested the hypothesis that reduced cGMP bioavailability in cardiac myocytes worsens myocardial dysfunction in mice after chronic DOX treatment. Methods and Results - We generated mice with an inducible (Tet-Off) cardiac myocyte-specific expression of a dominant-negative soluble guanylate cyclase (dnsGC) mutant, which inhibits sGC signaling selectively in the heart. Cardiac cGMP levels, measured using an enzyme immunoassay, were lower in dnsGC mice (n=10) than in WT littermates (n=20) 5 minutes after administration of the NO-donor GSNO (1mg/kg) (0.99±0.34 vs 1.85±0.17 nmol/mg protein, respectively, P&lt;0.05). At baseline, transthoracic echocardiography (TTE) demonstrated similar LV dimensions and function in dnsGC and WT (data not shown). Heart to body weight ratio was also comparable (HW/BW; 4.3±0.2 mg/g in dnsGC, n=13, vs 3.9±0.1 mg/g in WT, n=21). After 12 weeks DOX (2 mg/kg weekly), LV function was significantly reduced and LV diameters significantly enlarged as compared to saline-treated WT (Table). The impact of DOX on cardiac function and dimensions was more marked in dnsGC than in WT (P&lt;0.05 for both, Table). Survival was similarly impaired in DOX-treated dnsGC (67%, n=30) and WT (59%, n=24) compared with saline-treated WT (100%, n=25). HW/BW was similar in DOX-treated dnsGC and WT (4.3±0.1 vs 4.2±0.1 mg/g), as was the % bromodeoxyuridine (BrdU)-positive cardiac myocytes or cardiac progenitor cells (0.8±0.4%, n=7 vs 1.6±0.7%, n=9, respectively, P=NS). Conclusions - Reduced myocardial cGMP results in increased LV dysfunction and dilatation in doxorubicin-treated mice. Stimulation of sGC activity in cardiac myocytes may represent a promising therapeutic approach for doxorubicin cardiotoxicity.
Abstract 223: Kynurenine Pathway Activation Following Resuscitation from Cardiac Arrest: An Experimental and Clinical Investigation---from a Rat and a Pig Model to a Preliminary Clinical Validation
Authors: Giuseppe Ristagno, Laura Brunelli, Micheal Fries, Francesca Fumagalli, Renzo Bagnati, Roberta Pastorelli, Roberto Latini
Journal: Circulation (2012)

Background. Kynurenine pathway (KP) is a major route of the tryptophan catabolism, mainly activated upon several inflammatory stimulation and involved in the pathogenesis of numerous cerebral disorders shock states. In the present study, tryptophan and KP metabolites concentrations were measured in plasma from rats, pigs, and humans resuscitated from cardiac arrest (CA). We hypothesized that the KP would be markedly activated following CA. Methods. Plasma was obtained from: A: 18 rats, subjected to 6 min CA and 6 min CPR; B: 10 pigs, subjected to 10 min CA and 5 min CPR with post-arrest normo- (n=5) or hypothermia treatment (n=5); and C: 3 healthy human volunteers and 5 patients resuscitated from CA, with or without hypothermia. Metabolites were extracted and levels analyzed by mass spectrometry with high performance liquid chromatography. Assessements were available at baseline and hrs and days post-arrest (Figure). The specific KP metabolites were subsequently correlated with specific functional measurements and survival. Results. KP activaction after CA was observed in rats, pigs, and humans. More specifically decreases in tryptophan occurred after resuscitation period and were accompanied by significant increases in its major metabolites, 3-hydroxyanthranilic acid (3-HAA) and kynurenic acid in each species, that persisted up to 3-5 days post-arrest (p&lt;0.01, Figure). In rats, changes in KP metabolites reflected changes in post-resuscitation myocardial dysfunction. In pigs, decreases in tryptophan (r=-0.728, p=0.017) and increases in 3-HAA (r=0.792, p&lt;0.01) were significanlty related to the severity of hippocampal injuries. In humans, post-arrest increases in 3-HAA were inversly related with 72 hr survival (r=-0.94, p=0.18). Conclusions. In this fully translational investigation, the KP was activated early following resuscitation from CA. KP activation might account for the severity of post resuscitation syndrome and ultimately to survival.
Abstract 8948: ST-Segment Elevation in Lead aVR Strongly Predicts 3-Year Adverse Outcomes in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome
Authors: Masami Kosuge, Toshiaki Ebina, Kiyoshi Hibi, Kengo Tsukahara, Noriaki Iwahashi, Nobuhiko Maejima, Mitsuaki Endo, Satoshi Morita, Satoshi Umemura, Kazuo Kimura
Journal: Circulation (2012)

Background: In non-ST-segment elevation acute coronary syndrome (NSTE-ACS), lead aVR is referred to as a “cavity lead” and ST-segment elevation in this lead (ST↑aVR) may reflect global subendocardial ischemia in NSTE-ACS. We evaluated the prognostic value of ST↑aVR on admission ECG in patients with NSTE-ACS. Methods: We studied 548 patients with NSTE-ACS who underwent coronary angiography during initial hospitalization. Patients with bundle branch block and left ventricular hypertrophy were excluded. Patients were divided into the 3 groups according to the degree of ST↑aVR on admission ECG: no ST↑aVR (n=378, G-A); ST↑aVR &lt;1.0 mm (n=98, G-B); and ST↑aVR ≥1.0 mm (n=75, G-C). Troponin T (TnT), hemoglobin (Hb), high-sensitivity C-reactive protein (hsCRP), estimated glomerular filtration rate (eGFR), brain natriuretic peptide (BNP), TIMI risk score, and summed ST-segment depression in other leads were also measured on admission. Results: There were no differences in sex or coronary risk factors except for diabetes mellitus in the 3 groups. In G-A, G-B, and G-C, age was 66±11, 68±11, and 70±11 years; the rates of diabetes mellitus were 29%, 48%, and 51%; Killip ≥2 was 5%, 20%, and 33%; positive TnT was 30%, 45%, and 56%; TIMI risk core was 3±1, 4±1, and 4±2; the levels of Hb were 14±2, 13±2, and 12±2 g/dl; hsCRP was 0.349±1.594, 0.640±1.936, and 0.830±1.740 mg/dl; eGFR was 67±24, 59±28, and 53±27 ml/min/1.73 m 2 ; BNP was 149±248, 385±339, and 445±407 pg/ml; summed ST-segment depression was 2±2, 6±4, and 13±7 mm; the rates of left main or 3-vessel disease were 8%, 44%, and 72%; and major adverse events (death, [re]infarction, urgent revascularization, or congestive heart failure) at 3 years were 15%, 38%, and 55%, respectively (all p&lt;0.01). After adjusting for baseline characteristics, multivariate analysis showed that as compared with no ST↑aVR, the hazard ratios (95% CI) for 3-year adverse events associated with ST↑aVR &lt;1.0 mm and ST↑aVR ≥1.0 mm were 1.71 (1.08-6.69; p=0.030) and 3.29 (1.39-7.76; p=0.007), respectively. Conclusions: In patients with NSTE-ACS, greater ST↑aVR on admission ECG is strongly associated with poorer clinical outcomes at 3 years. Our findings suggest the importance of ST↑aVR in early risk stratification.