tbuckley/cabot-search huggingface dataset:
Abstract 19166: Major Gap Exists Between Races in Applying Published Guidelines for Primary Prevention of Sudden Cardiac Death; An ESCAPE Database Analysis
Authors: Emad F Aziz, Chaithanya K Pamidimukala, Joseph Bastawrose, Balaji Pratap, Urvi Pai, Jonathan Kahn, Haitem Muafa, Eun Sik Cho, Ian Lizardo, Neville Jadeja, Anthony Awad, Alexandre M Benjo, Fahad Javed, Eyal Herzog
Journal: Circulation (2012)

Background: We have developed a novel ESCAPE pathway and registry to monitor, evaluate and guide physician’s referral for patients who meet class I indication of ICD implantation. Methods: All heart failure (HF) patients admitted to an inner city hospital and presented to our imaging laboratories with LVEF ≤35% and met Class I criteria for an Implantable ICD were prospectively followed and included in this study. Number of implanted devices and patient outcome of death and HF readmissions were assessed at 24-month and compared between the races. Results: A total of 1087 enrolled in this registry including 472 (43%) African Americans (AA) and 205 (19%) Hispanics (H). AA patients had a mean age of 64 ± 15 years, 75% with hypertension, 33% diabetics, and 30% with coronary artery disease. At the end of the follow-up period, only 88 (22%) AA and 42 (25%) H patients underwent ICD implantation; yet 183 (38%) AA patients and 61 (29%) H Patients had adverse outcomes. These included 99 (20%) deaths and 109 (23%) HF readmissions for AA, patients and 31 (16%) deaths and 35 (17%) HF readmissions for H patients (Figure). Conclusions: This real world prospective study reveals the significant gap and underutilization of ICD among special race eligible patients who carry a worse outcome.
Abstract 18768: Comparison of Displacement-Based and Radial Uniformity Ratio Estimate Dyssynchrony Metrics in Serial Echocardiography of Post-Infarct Mice
Authors: Dan Lin, Yaqin Xu, Brent A French, John A Hossack
Journal: Circulation (2012)

Background: Many of the existing dyssynchrony metrics rely on myocardial strain measurements, including circumferential uniformity ratio estimate (CURE) and related metrics such as RURE. Since strain is a derivative of displacement, amplification of noise in strain calculations due to noisy displacement data is common, thus compromising strain-based dyssynchrony metrics. We propose a novel displacement-based dyssynchrony metric, called Dyskinesia Index (DI), that is sensitive and consistent in detecting left ventricular (LV) dyssynchrony, particularly dyskinesia. Methods: Long-axis (LA) cines of 7 C57BL/6 mice were captured with a 30MHz ultrasound transducer. Baseline (B) data were acquired prior to myocardial infarction (MI) induced by a 1-hr occlusion of the LAD followed by reperfusion. Thereafter, cines were acquired at 2, 4, 7, 14 and 28 days post-MI. Displacements were quantified using speckle tracking on the LA cines. DI was determined using Fourier analysis of radial displacement distributed along the endocardial wall, and is the square root of the ratio of the zero-order power term to the sum of zero-order and a scaled first order power terms. Results: In Fig. 1, DI is compared to RURE at B and at 5 time-points post-MI. DI values at B are consistently close to 1 (0.96±0.01), and decrease significantly early after MI due to dyskinesia, reaching a minimum at D4 (0.64±0.08). After the first week, motion in the infarct zone becomes more akinetic due to scar formation and DI values partially recover to a plateau late after MI. ANOVA reveals significant differences between B and all post-MI time-points (p &lt; 0.05). In contrast, RURE is less sensitive to dyskinesia at D4 and post-MI estimates are only significant from B for after D4 (p &lt; 0.05). Conclusion: Strain-based measures of dyssynchrony are error-susceptible without proper filtering of displacement data. DI has been shown to work well in ultrasound B-mode images, where image artifacts can degrade displacement data.
Abstract 19264: Regression of Atherosclerosis is Characterized by Molecular Re-programming of the Transcriptome: Insights into the Identification of New Therapeutic Targets Against Cardiovascular Disease
Authors: Jonathan E Feig, Yuliya Vengrenyuk, Chaowei Wu, Constantin Aliferis, Alexander Statnikov, Michael J Garabedian, Oscar Puig, Edward A Fisher
Journal: Circulation (2012)

Atherosclerosis is the leading underlying cause of strokes and myocardial infarctions worldwide. We reported a mouse model of atherosclerosis regression that involves transplanting an atherosclerotic aortic arch into a normolipidemic mouse. The CD68+ cell population (predominantly macrophages) in the regressing plaques exhibited migratory behavior. To identify pathways and factors responsible for the beneficial changes in macrophage content and phenotype in the regressing plaques, we performed microarray analysis on RNA purified from laser captured CD68+ plaque cells isolated from atherosclerosis progression and regression environments. This yielded two major findings. First, genes associated with the contractile apparatus (such as titin, actinin and myopalladin) that are responsible for cellular movement were differentially up-regulated under regression conditions (by 3-4 fold) with members of the cadherin family (serves in adhesion functions) being significantly down-regulated by 2-3 fold. Both changes are consistent with the macrophage migratory behavior we observed in the regression environment. Secondly, the most highly up-regulated gene under regression conditions was arginase I (~8 fold), a classical marker of the M2 alternatively activated macrophage. Further examination revealed that regression was characterized by macrophages displaying other M2 markers, such as CD163, C-lectin receptor, mannose receptor, and Fizz-1, consistent with a less inflammatory state in the regression environment. In addition, we applied recently introduced local causal pathway discovery methods to the microarray data that revealed that vinculin and ApoCII, known factors in cell adhesion and lipid metabolism, respectively, may be important regulators in the pathophysiology of atherosclerosis regression. Ultimately, the insights gained from the regression model and the different modes of global analyses should lead to new therapeutic targets against cardiovascular disease.
Abstract 18661: Endothelial Effects of High-Density Lipoprotein (HDL) Remain Impaired Following Dalcetrapib Treatment in Patients with Coronary Artery Disease or Risk Equivalent
Authors: Meliana Riwanto, John Deanfield, Jasmin Manz, Lucia Rohrer, Gabriela Suchankova, David Kallend, Arnold von Eckardstein, Thomas F Lúscher, Ulf Landmesser
Journal: Circulation (2012)

Introduction: As low HDL-Cholesterol levels are associated with an increased cardiovascular risk at least in epidemiology, raising HDL-Cholesterol is being examined as a potentially important therapeutic strategy. However, vascular effects of HDL have recently been found to be highly heterogeneous and benefits may be lost, at least partially, in patients with coronary artery disease (CAD). We therefore studied in patients with CAD or CAD-risk equivalent the effect of the CETP inhibitor dalcetrapib as compared to placebo on HDL function. Methods: HDL was isolated by sequential ultracentrifugation from patients randomized to treatment with dalcetrapib (600 mg/day; n=25) or placebo (n=25) at baseline, 12 and 36 weeks, and from healthy subjects. The effect of HDL on endothelial nitric oxide (NO) production was measured by ESR spectroscopy and on endothelial pro-inflammatory and pro-apoptotic activation determined by VCAM-1 and active caspase-3 expression assays, respectively. Results: There was no significant improvement in the capacity of HDL to stimulate endothelial NO production following dalcetrapib treatment or placebo in patients with CAD or risk equivalents, that remained impaired as compared to HDL-Healthy. HDL isolated from the dalcetrapib group showed an increase in the capacity to reduce endothelial VCAM-1 activation (9.0±6.3% at 12 weeks, 9.7±6.7% at 36 weeks, vs. 5.3±4.5% at baseline; p&lt;0.05); but remained significantly impaired (HDL-Healthy: 15.2±6.5%; p&lt;0.05). There was also an increase of the capacity of this HDL to reduce active endothelial caspase-3 expression (12.1±8.7% at 36 weeks vs. 6.9±9.9% at baseline; p&lt;0.05); however, these endothelial anti-apoptotic capacities remained largely impaired as compared to healthy subjects (18.9±6.6%; p&lt;0.05). Conclusions: Despite a significant increase in HDL-C levels (+31% at 36 weeks), dalcetrapib treatment did not restore the potential anti-atherosclerotic properties of HDL on the endothelium as found in the healthy controls. This finding may contribute, at least in part, to the lack of benefit on endothelial function seen in dal-VESSEL trial and demonstrates the importance of measuring not just HDL-C plasma levels but also its vascular impact when assessing novel treatments.
Abstract 19144: New Ischemic Stroke and Outcomes with Vorapaxar vs. Placebo: Results from TRA 2°P-TIMI 50 Trial
Authors: Marc P Bonaca, Benjamin M Scirica, Eugene Braunwald, Stephen D Wiviott, Shinya Goto, Dennis Nilsen, Vernon Bonarjee, Sabina A Murphy, David A Morrow
Journal: Circulation (2012)

Vorapaxar is a potent platelet inhibitor that reduces thrombotic events in stable patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD); however, this benefit is offset by increased bleeding including intracranial hemorrhage particularly in patients with established cerebrovascular disease (CVD). We investigated the outcomes in patients with MI or PAD experiencing a first ischemic stroke on vorapaxar. METHODS: The TRA2P-TIMI 50 trial was a randomized, double-blind, placebo controlled trial of vorapaxar 2.5 mg daily in 26,449 patients with established atherosclerotic vascular disease. Patients were stratified at randomization by their qualifying atherosclerotic condition (MI, PAD, or CVD). After two years, the Data and Safety Monitoring Board recommended discontinuation of study treatment in those with prior stroke or incident stroke. We evaluated the risk of new ischemic stroke outcomes with vorapaxar in 20,170 patients with MI or PAD but no history of CVD. RESULTS: In patients with MI or PAD and no history of CVD, vorapaxar significantly reduced ischemic stroke (HR 0.57, 95% CI 0.43 - 0.75, p&lt;0.001)(Figure A). Overall there were numerically fewer hemorrhagic conversions in patients treated with vorapaxar who suffered a first ischemic stroke. The risk of hemorrhagic conversion (HR 1.19, 95% CI 0.49 - 2.91, p=0.70) or death (HR 1.09, 95% CI 0.57 - 2.07, p=0.79) during follow up was not significantly increased with vorapaxar. Although hemorrohagic stroke was increased (HR 2.78, 95% CI 1.00- 7.73, p=0.049) overall stroke was significantly reduced (HR 0.68, 95% CI 0.52 - 0.8, p=0.005) with vorapaxar (Figure B). CONCLUSIONS: Vorapaxar reduces thrombotic events including ischemic stroke in stable patients with MI or PAD. There is no significant increase in the risk of hemorrhagic conversion or death in MI or PAD patients who experience a first ischemic stroke on vorapaxar. Hemorrhagic stroke is increased but all stroke is reduced.
Abstract 17470: NF-κB Activation Down Stream of Tuber Sclerosis Complex -mTOR Signaling pathway is Suppressed in Doxorubicin-Induced Cardiotoxicity
Authors: Rimpy Dhingra, Joseph W Gordon, Hongying Gang, Lorrie A Kirshenbaum
Journal: Circulation (2011)

The signaling networks that coordinate cell survival and cell death are poorly defined in the heart. The mammalian target of rapamycin (mTOR) is a highly conserved serine threonine kinase centrally involved in vital processes including growth, proliferation, and gene transcription. However, mTOR's role in regulating cell survival under normal or disease conditions has not been undetermined. Previously we established a cytoprotective role for the cellular factor NF-κB in ventricular myocytes. Notably, we demonstrated that NF-κB activation was necessary and sufficient for basal cell survival and suppressing mitochondrial perturbations during hypoxic injury. Herein, we provide new compelling evidence that activation of IKK-NF-κB signaling pathway down-stream of mTOR suppresses mitochondrial perturbations and cell death during metabolic stress imposed by nutrient deprivation or hypoxia. In contrast to wild type cells, constitutive activation of mTOR in tuber sclerosis complex (TSC) 2 -/- cells displayed marked increased mTOR targets p-P70S6, p-4EBP-1 and S6 protein. Interestingly, a significant increase in nuclear NF-κB activity and NF-κB gene transcription was also observed in TSC 2 -/- cells. Interestingly, in in vivo and in vitro models of Doxorubicin (Dox) -induced cardiotoxicity we observed a marked reduction in mTOR and NF-κB activity. However, basal NF-κB activity and cell viability were significantly reduced upon mTOR inactivation following metabolic stress or hypoxia. Moreover, basal Bnip3 gene transcription and cell death were significantly increased in cells treated with DOX and defective for mTOR activity. IKKβ- mediated activation of NF-κB restored mTOR activity and suppressed cell death induced by Bnip3 in DOX treated cells. To our knowledge our data provide the first direct evidence that operationally links mTOR and cell survival via IKKβ-NF-κB mediated repression of Bnip3.
Abstract 18126: Attenuations in Serum Albumin Over Time Powerfully Predict an Amplified Risk of Death in Chronic Heart Failure
Authors: Richard Jabbour, Syed Husain, Nabeela Zaman, Nay Aung, Hua Zen Ling, Resham Baruah, Graham Cole, Charlotte Manisty, Antony Barron, Jamil Mayet, Darrel Francis, Martin Thomas, Simon Woldman, Darlington O Okonko
Journal: Circulation (2011)

Background: Worsening heart failure is typically accompanied by diffuse inflammation, plasma volume expansion, diminished nutritional status and blunted liver biosynthetic function due to hepatic congestion. Because attenuations in serum albumin over time reliably reflects these derangements, we hypothesized that it would be predictive of death in patients (pts) with chronic heart failure (CHF) and that its prognostic power would supercede that of static single measures of albumin at baseline. Methods: We analysed the relation of serum albumin on first consultation and over time with mortality in 246 outpatients with CHF (mean [±SD] age 68±12y, LVEF 29±8%, albumin 42±5 g/L, 48% NYHA class &gt;2, 55% ischemic). Results: On initial consultation, 12 (5%) pts had an albumin &lt; 35g/L. Over a median (±IQR) follow-up of 13±18 months, 51 (21%) pts died, 132 (54%) pts had a fall in albumin, and 46 (19%) pts harboured attenuations &gt; 6g/L. On Cox proportional hazards analyses, a lower albumin at baseline predicted increased mortality (HR 0.89, CI 0.84 - 0.94, χ 2 :18, P&lt;0.0001) independently of all covariates. However, a falling albumin over time (unadjusted HR 0.89, CI 0.84 - 0.92, χ 2 53, P&lt;0.0001) was even more predictive (Difference in ROC AUC for baseline vs Δalbumin 0.16, P&lt;0.001) and did so independently of baseline albumin, NYHA class and changes in urea and hemoglobin (Δalbumin adjusted HR 0.84, CI 0.81 - 0.88, χ 2 54, P&lt;0.0001). A reduction in albumin &gt; 6 g/L optimally predicted death (ROC AUC 0.82, CI 0.76 - 0.86, P&lt;0.0001, Fig A) and conferred a 6-fold escalated risk of mortality (HR 6.42, CI: 3.67 - 11.22, P&lt;0.0001, Fig B). In incremental prognostic analyses, the addition of Δalbumin to the strongest 4 variable model dramatically augmented the χ 2 value (Fig C). Conclusions: Attenuations in serum albumin over time strongly correlate to an enhanced risk of death in chronic heart failure and could be utilised to further refine risk stratification.
Abstract 17460: Sildenafil Upregulates Pgc1α and Mitochondrial Function in Advanced Cardiac Hypertrophy Independently of Rgs2 or Leucine-Zipper Function of Pkg1α
Authors: Guangshuo Zhu, Manling Zhang, Nina Kaludercic, Djahida Bedja, Dongik Lee, Hideyuki Sasaki, Yuan Yuan, Norimichi Koitabashi, Nazareno Paolocci, Michael E Mendelsohn, David Kass, Eiki Takimoto
Journal: Circulation (2011)

Enhanced cGMP-PKG signaling by PDE5 inhibitor, sildenafil (SIL), ameliorates cardiac mal-adaptive hypertrophy/remodeling. Although Gq inhibition via PKG-RGS2 activation is an essential mechanism for the early stage anti-hypertrophy under pressure-overload (TAC) in mice, the mechanism for the advanced disease stage remains unknown. Impaired mitochondrial respiration was observed in advanced stage dilative 9wk TAC hearts, associated with down-regulation of PGC1α and reduced mitochondrial biogenesis (mt cytochrome b/ b-actin DNA), but not in 1-3 wk TAC hearts. Delayed SIL treatment (100mg/kg/day) initiated after hypertrophy establishment (1-3 wk TAC) inhibited progression of remodeling up to 9wks, which was associated with restored PGC1α expression and preserved mitochondrial function, but not with RGS2 activation. RGS2 null (KO) mice or PKG1α leucine zipper mutant knock-in (LZM) mice harboring disrupted RGS2-PKG interaction develop exacerbated early hypertrophy (1wk TAC) which is unresponsive to SIL, whereas SIL initiated after 1wk ameliorated long term (up to 7wk) progression of cardiac remodeling and function, with restored PGC1α expression, mitochondrial biogenesis and improved mitochondrial respiration assessed in cardiac fibers when palmitoyl carnitine (state3 O2 consumption, nmol/min/mg dry fiber, RGS2KO TAC: SIL 13.52±1.68 vs veh 8.47±0.87; LZM TAC: SIL 14.04±1.06 vs veh 8.79±1.27) or glutamate/malate(RGS2KO TAC: SIL 18.69±2.78 vs veh 9.58±0.78; LZM TAC: SIL 15.81±1.66 vs veh 9.68±1.16) was used as substrate. In rat neonatal cardiac myocytes (RNCM), 72hr exposure to phenylephrine (Gq agonist, 20µM) down-regulated PGC1α and impaired mitochondrial respiration, both of which were normalized by SIL co-treatment (1µM). Over-expression of PKG up-regulated PGC1α in RNCM, increasing mitochondrial respiration, whereas this was not observed when PGC1α was silenced. These results suggest enhancing cGMP-PKG signaling by SIL improves cardiac energetics by restoring myocyte PGC1α and thereby ameliorates remodeling progression in advanced stage of pressure-overload hypertrophy, which is independently of RGS2 or LZ function of PKGIa.
Abstract 18388: Is Pregnancy Associated with an Increased Risk of Arrhythmias and Disease Progression in Arrhythmogenic Right Ventricular Cardiomyopathy?
Authors: Ilaria Rigato, Sara Rigato, Alexandros Klavdios Steriotis, Alessandro Zorzi, Cristina Basso, Gateano Thiene, Sabino Iliceto, Domenico Corrado, Barbara Bauce
Journal: Circulation (2012)

BACKGROUND:The risk of pregnancy in women with ARVC is an important clinical issue for which systematic data have not been reported so far. OBJECTIVES: to assess the morbidity and mortality in nulliparous and multiparous women affected by Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). METHODS: The study cohort included 27 women affected by ARVC with one or more live births, for a total of 47 live births. Maternal mortality and morbidity related to ARVC during pregnancy was evaluated with a follow-up programme, consisting of personal and family history, ECG, signal-averaged ECG, 24-h Holter and echocardiogram within three years of their pregnancy. The symptoms considered were dyspnoea, asthenia and palpitations. Moreover in 15 patients with &gt;1 pregrancies, clinical and instrumental findings detected at the time of the first and the second pregnancy were compared. Finally, data of 13 nulliparous ARVC patients (mean age 32,3±5yrs) were correlated to those of 10 multiparous patients with the same age (34,9± 3,3 yrs). RESULTS: No pregnancy-related death occurred. In the 27 patients evaluated within close proximity of their first pregnancy, 4 (14%) showed worsening of arrhythmias during pregnancy. All 4 patients had severe form of the disease. One patient experienced a sustained ventricular tachycardia 50 days after delivery. No patient complained of worsening symptoms. In the 15 patients who had more than one pregnancy, the comparison between the first and the second pregnancy demonstrated worsening of symptoms (P=0,05) and arrhythmias (P=0,03) after the second delivery. Similarly, the comparison between nulliparous and mutiparous ARVC patients demonstrated a significant dilatation of the Right Ventricular Outflow Tract (RVOT1= 21mm/m2; p=0,03) as well as worsening of symptoms (P=0,05) and arrhythmias (p=0,03) after the second pregnancy. CONCLUSIONS: Maternal mortality is not increased in patients with ARVC compared with the general population. During gestation a worsening of arrhythmic pattern is more common in subjects with a severe form of the disease. A second pregnancy seems to be associated with worsening of clinical and instrumental features of the disease. Pre-conception planning and risk assessment are essential.
Abstract 18753: ST Elevation Myocardial Infarction in Hospitalized Patients is Associated with Delayed Recognition, Low Rate of Early Revascularization and High Mortality
Authors: Xuming Dai, Joseph Bumgarner, Andrew Spangler, Sidney Smith, George A Stouffer
Journal: Circulation (2012)

Background ---- Efforts to improve the management of ST segment elevation myocardial infarction (STEMI) have focused on patients whose symptoms begin outside of the hospital. Relatively little is known about STEMI that occurs in patients hospitalized for another condition. Methods ---- In-patient STEMI at a university hospital with primary percutaneous coronary intervention (PCI) center were identified by searching the Discharge Database and Cardiac Catheterization Laboratory Database. The diagnosis of STEMI was confirmed by two cardiologists. Non-normally distributed data are presented as median [25%,75%]. Comparison between groups was done using Mann-Whitney rank sum test for continuous variables and χ 2 for categorical variables. Results - A total of 48 in-patient STEMI cases were identified from 139,410 adult discharges from 2007 to 2011. In comparison with 184 out-patient STEMIs who presented directly to the same hospital during the same time span, in-patient STEMI patients were older (69 ± 13 vs 60 ± 13 years; p &lt; 0.01) and more often female (50% vs 33%; p &lt; 0.01). Symptoms were the reason for the index ECG more often in outpatient STEMIs (99% vs 33%; p &lt; 0.01); for in-patient STEMIs a change in clinical status (60%) and/or changes on telemetry (7%) also precipitated an ECG. The median time between the onset of symptoms or change in clinical status to ECG for in-patient STEMI was much greater than door to ECG time for outpatient STEMI (30 [10, 600] vs 5 [2, 10] minutes; p &lt; 0.001). Coronary angiography (71% vs 97%; p &lt; 0.01) and PCI (56% vs 95%; p &lt; 0.01) were performed less frequently in in-patient STEMI. The median ECG to angiography time (91 [45,197] vs. 34 [24,47] minutes; p &lt; 0.001) and the ECG to first device activation (129 [65,250] vs. 51 [40,70] minutes; p &lt; 0.001) were longer with in-patient STEMI. The in-hospital mortality for the in-patient STEMI group was 39.6% but revascularization within 3 hours from the onset of STEMI related event was associated with lower in-hospital mortality compared to patients who had delayed or no revascularization (15% vs 50%; p = 0.02). Conclusion ---- In-hospital STEMI is associated with atypical clinical presentation, delayed ECG interpretation, low rate of rapid revascularization and high mortality.