tbuckley/cabot-search huggingface dataset:
Abstract 18714: Predictors of Incident Abdominal Aortic Aneurysm in The Elderly: Insights from the Southern Community Cohort Study
Authors: Eiman Jahangir, Loren Lipworth, Michael T Mumma, Todd L Edwards, William J Blot, Uchechukwu K Sampson
Journal: Circulation (2012)

Background: Abdominal aortic aneurysm (AAA) is a leading cause of death in the United States, with high prevalence in the elderly population. We sought additional insight into the incidence and predictors of AAA among elderly persons with documented lifestyle and socioeconomic characteristics. Methods: Among 11,013 elderly (≥ 65 years) participants in the Southern Community Cohort Study who were also Medicare recipients from 1999-2008, we calculated age-adjusted incidence rates (IR) of AAA. We assessed the predictors of incident AAA using Cox proportional hazards regression analysis, adjusting for demographic, lifestyle, socioeconomic factors, and medical history. Participants with prevalent AAA at baseline were excluded from this analysis. Results: Overall, 198 incident AAA cases were identified during the study period. Age-adjusted IR (per 100,000) were 528, 1267, 247 and 590 among black men, white men, black women and white women, respectively. After adjusting for known risk factors, women had lower risk for AAA compared with men (Hazard ratio (HR) 0.59, 95% CI 0.43-0.81; Table) and blacks had lower risk compared with whites (HR 0.42, 95% CI 0.31-0.59). Smoking remained the strongest risk factor overall (former: HR 2.14, 95% CI 1.40-3.30; current: HR 5.09, 95% CI 3.25-7.95), and this association was most pronounced among women. Hypertension and myocardial infarction or coronary artery bypass surgery were each positively associated with AAA incidence among men (respective HR 1.84, 95% CI 1.13-2.99 and 1.68, 95% CI 1.06-2.66). Interestingly, the presence of diabetes mellitus (DM) was inversely associated with incident AAA (overall HR 0.68, 95% CI 0.47-0.99). Conclusion: Smoking and HTN were independent predictors of increased risk of incident AAA in this cohort, while female sex, black race, and DM confers protective effects. The underlying mechanism(s) for these protective effects remain incompletely understood and warrant further evaluation.
Abstract 18695: Role of Autophagy in Amyloidogenic Light Chain Induced Cardiac Toxicity
Authors: Jian Guan, Shikha Mishra, Jianru Shi, Francesca Lavatelli, Paola Rognoni, Guy Las, Giampaolo Merlini, Lawreen H Connors, David C Seldin, Calum A MacRae, Orian Shirihai, Ronglih Liao
Journal: Circulation (2012)

AL amyloid cardiomyopathy is characterized by the deposition of amyloid fibers from monoclonal immunoglobulin light chain proteins (AL-LC) in the heart. We and others have shown that AL-LC directly results in cardiac toxicity; however, the mechanisms underlying this toxicity remain to be determined. Morphological examinations of hearts from patients with AL amyloid cardiomyopathy reveal increased double membrane autophagosome-like structures and mitochondrial deformation. Using isolated adult rat cardiomyocytes, we therefore examined whether dysregulated autophagy mediates the development of AL-LC induced cardiac toxicity. Methods and Results: Autophagy is a dynamic process and autophagic flux is, hence, determined by measurement of LC3-II protein expression in the absence and presence of lysosome inhibitors (E64d and pepstatin A). The autophagic substrate, polyubiquitin-binding protein (p62), was also examined via immunoblotting. We found that LC3-II expression increased in the absence but decreased in the presence of lysosome inhibitors in cardiomyocytes exposed to AL-LC relative to vehicle control. Moreover, p62 expression was increased in AL-LC treated cardiomyocytes, suggesting that AL-LC resulted in impaired clearance of autophagosomes in cardiomyocytes. To define the causal relationship between dysregulated autophagic clearance and AL-LC induced cardiac toxicity, we determined the functional consequences of autophagic inhibition by treatment with 3MA (3-Methyladenine, PI3K inhibitor), or autophagic activation by treatment with rapamycin (mTOR inhibitor). Inhibition of autophagy led to worsen of AL-LC induced cardiac toxicity whereas activation of autophagy protected cardiomyocytes against AL-LC induced cardiac toxicity, as measured by ROS production and cell death. Conclusion: Our data demonstrate that AL-LC directly results in impaired autophagic clearance in cardiomyocytes, contributing to the development of amyloid cardiac toxicity and cardiomyopathy. Therapies aimed at modulation of cellular autophagy may provide new treatment approaches for patients with AL amyloid cardiomyopathy.
Abstract 18739: Autophagy Regulates Vascular Smooth Muscle Cell Synthetic Phenotype Transition and Resistance to Oxidative Stress
Authors: Joshua K Salabei, Timothy D Cummins, Aruni Bhatnagar, Bradford G Hill
Journal: Circulation (2012)

Arterial lesions due to atherosclerosis and restenosis are characterized by heightened oxidative stress and the transformation of vascular smooth muscle cells (VSMCs) to a synthetic phenotype. However, it is not known how synthetic VSMCs (sVSMCs) respond to the stress encountered in advanced vascular lesions. Our previous studies show that electrophilic stress caused by lipid peroxidation products promotes autophagy and endoplasmic reticulum stress. In this study, we tested the hypothesis that conversion to the synthetic phenotype primes VSMCs to survive under conditions of high oxidative stress. Synthetic VSMCs, elicited by exposure to platelet-derived growth factor-BB (PDGF-BB), maintained lower levels of endogenous protein-aldehyde adducts and demonstrated a heightened ability (2.5-fold; p&lt;0.05) to remove proteins modified by the lipid peroxidation product 4-hydroxy- trans -2-nonenal (HNE) than contractile VSMC (cVSMC). Moreover, HNE detoxification in sVSMCs was enhanced; the primary pathway of HNE detoxification—aldehyde dehydrogenase-mediated oxidation to 4-hydroxynonenoic acid—was increased by 30% and glutathione conjugation was increased by 50% (p&lt;0.05). The sVSMCs showed a 20% increase in viability compared with cVSMCs when challenged with HNE (p&lt;0.05). This resistance to stress in sVSMCs was found to be due primarily to robust induction of the autophagic program. PDGF-BB exposure increased autophagic flux (&gt;2-fold vs. untreated cells; p&lt;0.05), as assessed by quantifying GFP-microtubule-associated protein 1 light chain 3 (LC3) puncta as well as electron microscopy and LC3II abundance. Blockade of autophagy by spautin-1 or 3-methyladenine prevented the PDGF-BB-induced decreases in expression and abundance of calponin and α-SM-actin, suggesting that autophagy is required for VSMC phenotype conversion. Inhibiting autophagy also prevented removal of HNE-damaged proteins and prevented PDGF-induced increases in NAD + - and glutathione-linked HNE detoxification (p&lt;0.05). Collectively, these results show that PDGF-BB induces autophagy in VSMCs, which is required for conversion of VSMCs to the synthetic phenotype and for resistance to the oxidative stress characteristic of vascular lesions.
Abstract 18743: Bayesian Comparative Analysis for Prevention of Stroke and Net Clinical Benefit of Novel Oral Anticoagulants in Non-Valvular Atrial Fibrillation
Authors: Christopher Lang, Rohit Arora
Journal: Circulation (2012)

Background: The recent emergence of novel oral anticoagulants dabigatran, rivaroxaban and apixaban for prevention of stroke and systemic embolization in atrial fibrillation are attractive alternatives to warfarin. Despite this, the differences in efficacy and bleeding events between these medications remains unclear. To compare differential benefit, we performed a Bayesian analysis comparing the efficacy and safety parameters of the 3 novel agents. Methods: Using data from the 3 major trials investigating the novel oral anticoagulants, we conducted a Bayesian analysis using null prior probabilities, which is particularly suited to indirect comparisons. The primary endpoints of stroke and systemic embolization were assessed, along with safety endpoints of major bleeding. A Bayesian analysis was performed on each group, defining probabilities of benefit for the posterior probability. From this data, net clinical benefit calculations were performed and posterior probabilities were obtained. Results: Posterior probabilities for stroke and systemic embolization indicate the apixaban, rivaroxaban and dabigatran have an 87.3%, 88.7%, and 66.3% probability of benefit over warfarin, respectively. Major bleeding events were found to have a 98.6%, 88.0% and 55.0% probability of benefit over warfarin. Net clinical benefit analysis indicates benefit with apixaban and rivaroxaban that was greater than dabigatran. Conclusions: Using Bayesian analytic techniques, all of the novel oral anticoagulants were found to be non-inferior to warfarin. However, the effectiveness in prevention of stroke suggests that both apixaban and rivaroxaban significantly outperform dabigatran. Net clinic benefit and safety endpoints support the use of apixaban as opposed to rivaroxaban and dabigatran. While more data emerges investigating the differential benefit of these new medications, Bayesian techniques offer novel comparative statistics which can guide clinical decision making.
Abstract 186: Baseline ECG Predictors of 90-Day Survival in Wearable Cardioverter-Defibrillator Patients Experiencing a Sudden Cardiac Arrest
Authors: Darshak Karia, Nicole R Bianco, Chingping Wan, Jo Ann M Glad, Steven J Szymkiewicz
Journal: Circulation (2012)

Purpose: Factors affecting survival after SCA resuscitation continues to be an active area of investigation. The current wearable cardioverter defibrillator (WCD) records ECG periodically. The objective of this study was to determine whether there are any basic ECG differences in patients (pts) that died &lt;90d after first shock versus those that were alive 90d post-shock. We analyzed ECGs at baseline (Base), one week prior to SCA (1WK), and immediately prior to first shock for ventricular tachyarrhythmias VT/VF (pre-S). Methods: 100 sequential WCD pts (68% male, age 59 ± 16 years) shocked for VT/VF between November 2009 and June 2011 were retrospectively analyzed. Heart rate, QRS duration, QRS amplitude, corrected QT duration (QTc), ectopic activity and rhythm were manually measured at Base, 1WK, and pre-S. The WCD has four non-adhesive ECG electrodes, and measurements were made on both the side-to-side (ss) and front-to-back (fb) leads. Only pts wearing the WCD ≥1 week were included for analysis. Results: 77 pts survived ≥90 days post shock (68% male, age 58 ± 16 years), and 23 pts died &lt;90 days after first shock (70% male, age 63 ± 13 years). Those pts that died &lt;90 days after first shock had a longer QTc and a shorter QRS amplitude at Base than those surviving ≥90 days post-shock (Table 1)(p≤0.05). Conclusions: The WCD provides an opportunity to monitor ECG rhythms in at-risk pts prior to defibrillation. Similar to studies of overall mortality, this small study suggests that QT duration and QRS amplitude may be important predictive markers of survival post-SCA.
Abstract 18778: Myocardial Gene Therapy by Adeno-HSPA12B Administration Induces Angiogenesis and Prevents Ventricular Dysfunction Following Acute Myocardial Infarction in Type I Diabetic Rats
Authors: Mahesh Thirunavukkarasu, Sumanth C Suresh, Vaithinathan Selvaraju, Juan A Sanchez, Nilanjana Maulik
Journal: Circulation (2012)

Introduction: Molecular chaperones/heat shock proteins (HSPs) are important regulators of angiogenesis. HSPA12B, a member of HSP70 sub-family 12 predominantly expressed in endothelial cells is required for angiogenesis. In the present study we examined the effects of overexpressing HSPA12B on angiogenesis and myocardial function by intramyocardial administration of adenovirus encoding HSPA12B (Ad. HSPA12B) in a myocardial infarction (MI) model in streptozotocin induced Type I diabetic rats. Methods: The rats were divided into 6 groups. 1) Control Sham (CS), 2) CMI+Ad.LacZ (CLZMI), 3) CMI+Ad.HSPA12B (CMI-HSPA12B), 4) Diabetic Sham (DS), 5) DMI+Ad.LacZ (DLZMI), 6) DMI+Ad.HSPA12B (DMI-HSPA12B). Following left anterior descending coronary artery ligation Ad.LacZ or Ad.HSPA12B was injected at 4 border zone sites to either CLZMI/DLZMI or CMI-HSPA12B /DMI-HSPA12B group. Results: We observed increases in capillary (2245±37.2 (n=4) vs 1732±102.5 (n=3); p&lt;0.05) &amp; arteriolar (19±0.5 (n=3) vs 14±0.5 (n=6); p&lt;0.05) density (counts/mm2) in the DMI-HSPA12B compared to the DLZMI group. Formalin-fixed mid-ventricular tissue sections stained with Picrosirius red, exhibited a 44% decrease in collagen deposition in DMI-HSPA12B compared to DLZMI hearts. Echocardiography at 30 days revealed decreased left ventricular inner diameter (systole) (6.3±0.3 vs. 8.5±0.3 (n=6); p&lt;0.05) &amp; increased ejection fraction (51±0.6 vs. 32±0.9 (n=6); p&lt;0.05) &amp; fractional shortening (27±0.4 6 vs. 16±0.5 6 (n=6); p&lt;0.05) in the DMI-HSPA12B compared to DLMI group. Western blot analysis showed increased expression of HSPA12B (1.4 fold) and VEGF (1.4 fold) 4 days after HSPA12B gene delivery in the DMI-HSPA12B group compared to the DLZMI group. Conclusion: Targeted delivery of HSPA12B induced angiogenesis and improved hemodynamic function in a rat model. Our novel approach may be a viable therapeutic modality in the treatment of diabetes related cardiac failure by stabilizing the myocardium, promoting neovascularization &amp; augmenting protective as well as regenerative responses in ischemic rat myocardium.
Abstract 18754: Prognostic Evaluation of Catalytic Iron in Patients with Acute Coronary Syndromes: Observations from OPUS-TIMI 16
Authors: Dylan L Steen, Christopher P Cannon, Suhas Lele, Mohan Rajapurkar, Banibrata Mukhopadhyay, Benjamin M Scirica, David A Morrow
Journal: Circulation (2012)

BACKGROUND: The potential of iron to generate reactive oxygen species (ROS) has motivated a long-standing interest in whether excess iron is causally linked to atherosclerotic heart disease. Catalytic iron, or “free” iron, is the circulating store of iron that is not bound to transferrin or ferritin and is available to generate ROS that may have deleterious vascular effects. METHODS: We investigated the association of catalytic iron with clinical outcomes in 1701 patients with UA, NSTEMI, or STEMI who were followed for a median of 10 months. All endpoints were adjudicated by a blinded Clinical Endpoints Committee. RESULTS: The median catalytic iron level was significantly higher in those who died, 0.45μmol/L (0.37, 0.57), compared with survivors 0.37μmol/L (0.31, 0.46), p= 0.016. Catalytic iron was associated with a step-wise increased risk of death, with the highest quartile at an almost 4-fold risk compared to baseline (HR 3.94, p=0.035), which persisted after adjustment for age, diabetes, prior MI, prior CHF, ST deviation, CrCl, BNP, and Killip class (adjHR 3.89, p=0.038, FIGURE). There was no association between catalytic iron and risk of myocardial infarction, recurrent ischemia, heart failure, or bleeding. CONCLUSION: Increasing catalytic iron levels were associated with all-cause mortality. Our findings suggest that catalytic iron is not likely to add to currently available tools as a routine clinical biomarker for risk stratification of ischemic events, but its association with mortality is intriguing and leaves open the question of whether cardiovascular therapeutics aimed at catalytic iron may have utility.
Abstract 18738: The Cdkn2a/2b Tumour Suppressor Locus is a Hot Spot for Genome Instability in Mouse Cardiac Progenitor Cells
Authors: Michela Noseda, Adam J De Smith, Thomas Leja, Pulivarthi H Rao, Marta S Abreu paiva, Farah Al-Beidh, Alex I Blakemore, Michael D Schneider
Journal: Circulation (2012)

Among the cells with best cardiac potential, autologous heart cells present the fewest regulatory issues, and therapeutic trials are on-going. Existing work has largely relied on purified but potentially heterogeneous populations. As ES, iPS and cardiosphere-derived cells all are known to accumulate genomic aberrations, we analyzed genome integrity in clonally derived mouse Lin-/Sca-1+/side population (SP) cardiac progenitor cells (CPCs), which stably express cardiogenic transcription factors for ≥ 35 passages. DNA content analysis showed progressive aneuploidy, with &gt;90% of clones abnormal by passage 11. By multicolour spectral karyotyping (SKY), even those with normal DNA content had aberrations, though no recurrent anomalies were seen; genome instability was not contingent on clonal isolation per se or Hoechst 33342. High-resolution array CGH (aCGH) was performed on 15 clones, using 1 million probe arrays. Numerous aberrations were found, most 100-fold below the limits of SKY. Interestingly, copy number variation did not explain the observed differences in cardiac transcription factors. After passage 10, recurrent deletions were seen in Cdkn2a/2b, encoding the tumour suppressors p16Ink4a, p15Ink4b, and p19ARF. QPCR confirmed this in &gt;80% of clones. Integrity of Cdkn2a/2b through passage 10 indicates its deletion is not required for clonal growth. Because genome instability has been ascribed to hyperoxic stress in ambient (21%) [O2], we derived and propagated clones in physiological (2 or 7%) [O2]. Reduced [O2] increased (&gt;3x) and accelerated (2x) clone formation, reduced aneuplody, reduced chromosomal aberrations, but did not prevent loss of Cdkn2a/2b. Low [O2] also enabled generating clones readily from Lin-/Sca1+/SP- CPCs, for which the cloning efficiency was previously reported as &lt; 0.1%. Thus, genomic instability of propagated CPCs was demonstrated, including recurrent deletion of Cdkn2a/2b. Reduced [O2] conferred partial protection from genomic instability. Clonal analysis unveiled heterogeneities in genome structure that could be obscured in a mixed population. These data highlight the need to develop bioprocesses that optimize genomic stability.
Abstract 21: Elevated Resting Heart Rate Is Associated with Pulseless Electrical Activity Independent of β-Blocker Use
Authors: Carmen Teodorescu, Kyndaron Reinier, Audrey Uy-Evanado, Jo Ayala, Ronald Mariani, Harpriya Chugh, Mohamud Daya, Karen Gunson, Jonathan Jui, Sumeet S Chugh
Journal: Circulation (2011)

Introduction: Higher heart rate (HR) has been associated with increased cardiovascular mortality but mechanisms are poorly understood. Sudden cardiac arrest (SCA) presenting with pulseless electrical activity (PEA) has a significantly higher mortality than ventricular fibrillation/tachycardia (VF/VT). Hypothesis: We investigated the hypothesis that resting HR has a predictive role in subjects with future PEA versus VF/VT. Methods: Cases of out of hospital SCA, age ≥18 years, with resuscitation attempted were identified from an ongoing prospective community-based study in the Northwest US (pop. approx. 1 million). HR was measured from resting 12-lead ECG prior and unrelated to the cardiac arrest. Pearson's chi-square tests and independent samples t -tests were used for comparisons of presenting arrhythmia, arrest circumstances and heart rate. A general linear model was used to identify gender and age differences in heart rate between PEA and VF/VT. Significant predictors of PEA were determined using logistic regression. Results: A total of 913 cases (mean age 65±16 years, 68% male) with resuscitation attempted (2002-2009) presented with VF/VT (45%) or PEA (26%). PEA cases were older, more likely to be female and to arrest at home, whereas VF/VT cases were more likely to be witnessed, to have bystander CPR, return of spontaneous circulation and to survive to hospital discharge. There was no difference in the use of beta-blockers between PEA and VF/VT (p=0.19). PEA cases had higher resting HR compared with VF/VT (81 bpm vs. 74 bpm, p=0.0007, n=322). Males with PEA had higher HR than males with VF/VT (83 bpm vs. 75 bpm, p=0.001), but the difference in HR between PEA vs. VF/VT among females was smaller and borderline significant (78 bpm vs. 72 bpm, p=0.06). Heart rate was a significant predictor of PEA after adjustment for age, gender and circumstances of arrest [OR for a 10-beat per minute increase 1.35; 95% CI (1.17-1.56)]. Heart rate remained a significant predictor of PEA after additional adjustment for beta-blockers [OR 1.36; 95% CI (1.18-1.57)]. Conclusions: Resting HR is a significant predictor of future cardiac arrest manifesting with PEA, independent of beta-blocker use and could, in part, explain the association between higher HR and increased mortality.
Abstract 18786: A Combined Risk Score for Predicting Incident Heart Failure
Authors: Karsten Sydow, Aki S Havulinna, Francisco Ojeda, Renate B Schnabel, Johannes T Neumann, Tanja Zeller, Annika Jagodzinski, Stefan Blankenberg, Veikko Salomaa
Journal: Circulation (2012)

Introduction: Identifying individuals at risk for incident heart failure may open the avenue for early preventive treatment. The aim of the study was to develop a straight-forward and clinically relevant risk score for predicting incident heart failure based on major clinical variables and biomarkers. Methods: Analyses were performed in 8,239 individuals of the population-based prospective FINRISK 1997 study, recruiting men and women aged 25-74 years. During the follow-up of 12 years, we identified 497 cases of incident heart failure. We considered major cardiovascular risk factors as clinical risk factor variables. We performed multivariate model selection via LASSO penalized Cox regression to obtain models predicting 6 and 12 years absolute risk of heart failure. The added value of the biomarkers NTproBNP, BNP, MR-proANP, MR-proADM, Cystatin C, hs Troponin I, MPO and CRP to the model was assessed by C-index and continuous net reclassification index (NRI). Results: Besides age, sex and study region (forced into the model), BMI and pulse pressure were selected for the 6 years heart failure risk model revealing an area under the curve of 0.82. Of all biomarkers tested, NTproBNP, MR-proANP, and BNP provided the strongest significant increase in C-index (0.87, 0.86, 0.85, respectively; p&lt;0.001), followed by MR-proADM and Cystatin C (CI=0.84, p&lt;0.001, p=0.004). Continuous NRIs for natriuretic peptides and MR-proADM were 30% - 35% (p&lt;0.001), whereas Cystatin C showed a NRI of 10.1% (p=0.2). Inclusion of either hs Troponin I or CRP only slightly increased the predictive power of the model. Results for the 12 year model were similar, however, with attenuated NRIs, presumably due to the increased impact of age. MR-proADM was the only biomarker adding predictive information in models already including a natriuretic peptide. Conclusions: In a population based setting, age, sex, study region, BMI, and pulse pressure were the most powerful clinical variables for predicting incident heart failure. Biomarkers, i.e. natriuretic peptides and MR-proADM, significantly increased the predictive value of the basic model. These results will be validated within the European BiomarCaRE consortium to establish a biomarker supplemented European heart failure risk score.