tbuckley/cabot-search huggingface dataset:
Abstract 18356: Autologous Intracoronary Stem Cell Therapy is Safe and Feasible for Children With Dilated Cardiomyopathy: A Randomised Controlled Cross-Over Pilot Study
Authors: E. Sian Pincott, Deborah Ridout, Margaret Brocklesby, Angus McEwan, Vivek Muthurangu, Michael Burch
Journal: Circulation (2013)

Meta-analysis of adult stem cell therapy studies post myocardial infarction has shown moderate &amp; sustained improvement of function. Positive results have also been seen in adult dilated cardiomyopathy (DCM) &amp; chronic ischaemic heart failure. The place of stem cells in pediatric heart failure is unknown. This randomised, blind, crossover placebo controlled trial sought to evaluate the potential use of stem cells in the management of pediatric heart failure &amp; is the first of its kind within the pediatric population. Methods &amp; results: Ten children (mean age 7.2y, range 2.2-14.1y, 6 male) with DCM were recruited from Heart Failure clinic. Patient profiles on study entry: NYHA/Ross class 3-4, ejection fraction (EF) on MRI mean 40% (range 30-48%). On enrolment patients were randomised to receive stem cell or placebo intracoronary injection &amp; MRI, with cross-over of intervention at 6 months &amp; final MRI assessment at 1 year. Bone marrow processing was performed using standard techniques. The mononuclear cells, obtained within 1.5 hours of aspiration, were divided to provide 1ml for coronary injection &amp; 1ml for phenotyping. Intracoronary injections &amp; MRI were performed under the same anaesthetic. Mononuclear cell count mean was 51.7 x 106/ml (range 11.8-115.1 x 106/ml). Nine patients completed the protocol, the tenth patient had Duchenne Muscular Dystrophy (DMD) &amp; did not undergo general anaesthesia, this data was excluded from the group analysis and is presented separately. There were no withdrawals, morbidity or mortality. Primary end point, freedom from death or transplant, was achieved in all patients. Secondary end points, indexed end diastolic volume (EDV) 6 months post cell infusion for n=9, was reduced in 7 &amp; unchanged in 2 (P=0.01 for comparison of means), end systolic volume (ESV) decreased in 6 following cell injection. (P=0.05 for comparison of means). EDV increased in 5 patients following placebo. EF did not change significantly. EDV reduced in all patients with an injected cell count &gt;34.2 x 106. Conclusion: This pilot study demonstrates that intracoronary injection of autologous stem cells is safe &amp; feasible in children. Encouraging data on EDV were generated, larger scale studies will be required to measure clinical effect.
Abstract 18402: Outcomes of Pacing in Patients With Cardiac Amyloidosis - A Single Center Experience
Authors: Jo Jo Hai, Tracy L Webster, Grace Lin, Angela Dispenzieri, Martha Grogan, Peter A Brady
Journal: Circulation (2013)

Background: Cardiac amyloidosis (CA) is associated with sinus node dysfunction (SND) and conduction system disease (CSD) yet data on pacing indications and outcomes is scarce. Methods: Retrospective review of patients (pts) with CA who had device implantation due to pacing indication at our institution. Results: At total of 51 (mean age 67.2±9.2 years, 90.2% male) pts with immunoglobulin light chain (n=27, 52.9%), hereditary transthyretin (n=7, 13.7%) and wild-type transthyretin (n=17, 33.3%) CA were included. Indication for pacing was exercise intolerance (n=16, 31.4%), syncope (n=16, 31.4%), congestive heart failure (n=5, 9.8%) and palpitation (n=2, 3.9%) with SND (n=23, 45.1%), CSD (17=33.3%) and uncontrolled atrial fibrillation (n=11, 21.6%). 16 (31.4%) pts received defibrillators (ICD) for primary prevention, of whom 8 (15.7%) had left ventricular ejection fraction (LVEF) ≤35%. Atrial (P wave: 1.7±1.2mV, threshold: 1.1±0.5mV/0.5±0.2ms) and right ventricular (RV) (R wave: 7.9±3.8mV, threshold: 0.8±0.4mV/0.4±0.1ms) lead parameters were satisfactory at implantation. During follow-up (mean 36.6±33.6 months), 26 (51%) pts reported symptomatic improvement (SI). Syncope was the only predictor of SI (OR 16.4, 95%CI 1.8-145.2, p=0.01) while exercise intolerance was not (OR 0.09, 95%CI 0.02-0.44, p=0.003). First-time life-threatening ventricular arrhythmias (VA) occurred in 6 (11.8%) pts, 3 (5.9%) had ICD implanted for LVEF ≤35%, 3 (5.9%) without ICD and LVEF ≥35%. Syncope was not predictive of first-time VA. RV lead noise led to inappropriate ICD shocks in 1 patient. Atrial lead sensing failure occurred in 6 (11.8%) and loss of capture in 5 (9.8%). Conclusion: Device implantation in patients with cardiac amyloidosis is safe but atrial lead failure is common. Syncope usually improves with pacing whereas other factors should be considered in those presented with exercise intolerance. Selection of pts who need pacing for prophylactic ICD implantation is challenging as neither left ventricular ejection fraction nor syncope are predictive of arrhythmic events.
Role of LRP1 in Protecting the Vasculature
Authors: Dudley Strickland
Journal: Circulation (2012)

Since the early studies of Russell Ross, numerous investigators have confirmed that inflammation is a driving force behind chronic diseases such as atherosclerosis, and key to this process is the recruitment and activation of macrophages. Our studies reveal that the LDL receptor-related protein (LRP1) plays an important role in macrophage biology by regulating the adhesive properties of the integrin α M ß 2 . LRP1 is a large endocytic and signaling receptor that is widely expressed and mediates the endocytosis and subsequent degradation of several ligands. Deletion of the Lrp1 gene is lethal in mice, and genome wide association studies reveal that the Lrp1 gene represents a susceptibility locus for migraine, for elevated plasma lipids, and for coronary heart disease. LRP1 is abundantly expressed in macrophages where it functions to protect the vasculature from the development of disease. By employing macrophage specific knockout mice (macLRP1-/- mice) we discovered that LRP1 expressed in these cells protects the vasculature from excessive remodeling upon injury by regulating the TGFß signaling pathway and by influencing vascular smooth muscle cell (SMC) recruitment into the developing neo-intima. It is well established that an important contribution to cardiovascular diseases is the transdifferentiation of SMC. Under normal physiological conditions, SMC are fully differentiated and in a contractile phenotype. However, under pathological conditions SMC switch to a proliferative and migratory phenotype and contribute to lesion development in atherosclerosis and/or neo-intima formation. Significant effort is underway to define molecular mechanisms regulating SMC transdifferentiation, and substantial evidence suggests an important role for the LDL receptor related protein 1 (LRP1) in this process by modulating the PDGF signaling pathway. Our data in SMC LRP1 deficient mice (smLRP1-/-) reveal that LRP1 modulates SMC transdifferentiation and regulates pathways relevant to neo-intima and aneurysm formation.
Abstract 18175: Cytoglobin-Defiencient Mice Develop Maladaptive Cardiac Remodeling After Ischemia-Reperfusion Injury Due to Alterations in NF-kB Signaling
Authors: Diana C Canseco, Erika Von Grote, Sarvjeet Singh, Beverly A Rothermel, Pradeep P Mammen
Journal: Circulation (2013)

Cytoglobin ( Cygb ) is a stress-responsive hemoprotein expressed in cardiomyocytes. Data from our laboratory indicate Cygb is able to translocate to the nucleus under stress and one mechanism by which it is able to exert its cytoprotective effect is by serving as a repressor of p53 transcriptional activity. In a model of ischemia-reperfusion (IR), Cygb transcript levels within wild-type hearts peak 2 days post-IR injury. We hypothesize that Cygb modulates cardiac remodeling following IR injury by effecting redox sensitive signaling pathyways (p53, NF-κB, etc). To test our hypothesis, we generated mice with cardiac-specific deletion of Cygb ( Cygb+/- ). These mice are viable with normal cardiac function under baseline conditions [ECHO: FS(%) 70±0.05 vs 72±0.05, Cygb+/- vs control (Ctrl); p=NS, n=12]. However, Cygb+/- mice develop worse cardiac remodeling 1 month post-IR injury [FS(%) 35±0.05 vs 59±0.05, p&lt;0.005, n=8; %Fibrosis of LV 40 vs 20, p&lt;0.05, n=4; Cygb+/- vs Ctrl] with evidence of increased cardiomyocyte cell death (TUNEL 8.0±0.5 vs 2.0±0.5 cells per unit area, Cygb+/- vs Ctrl; p&lt;0.05, n=4). In vitro assays utilizing small interference RNA targeting Cygb also support the importance of Cygb in maintaining cardiomyocyte viability under hypoxic conditions (%Viability 47.34±0.05 vs 57.14±0.05, hypoxic si Cygb H9C2 vs hypoxic Ctrl siRNA H9C2 cells; p&lt;0.05, n=6). A transcriptome analysis of the NF-κB signaling pathway (60 genes including IL-6, Myd88, CSF2, and TLR3) revealed a global downregulation in expression of NF-κB target genes in hypoxic H9C2 cells and IR-injured Cygb+/- hearts. Utilizing in vitro assays (Luc assays, etc) NF-κB activity in si Cygb H9C2 cells was decreased in a p53-dependent manner. This data was confirmed by demonstrating decreased NF-κB activity in 2 day post-IR injured Cygb +/- hearts. Collectively, our data suggests Cygb modulates cardiac remodeling post-IR injury by affecting NF-κB signaling via a p53-dependent mechanism.
Abstract 18426: The Role of /SUMO-1 in Cardiac Oxidative Stress and Hypertrophy
Authors: Ahyoung Lee, Dongtak Jeong, Shinichi Mitsuyama, Changwon Kho, Roger J Hajjar
Journal: Circulation (2013)

Background: Small ubiquitin-like modifier type 1 (SUMO-1) has been shown to have a critical role in the dysfunction of the cardiac isoform of the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) in the setting of heart failure. In cardiac hypertrophy the role of SUMO-1 has not been defined and our study’s goals were to examine the effects of modulating SUMO-1 on the hypertrophic response in vitro and in vivo and to examine whether oxidative stress (during cardiac hypertrophy) is abrogated by SUMO-1 gene transfer. Results: In mice undergoing trans-aortic constriction (TAC), SUMO-1 levels increased slightly during the compensated stage of hypertrophy and then dropped sharply following the transition to heart failure. In isolated cardiomyocytes, SUMO-1 gene transfer inhibited hypertrophic responses in the presence of phenylephrine. AAV9 (adeno-associated vector type 9) gene transfer of SUMO-1 prevented the heart from hypertrophying following TAC and prevented the development of left ventricular dysfunction. Furthermore, SUMO-1 gene transfer blocked the negative effects of H2O2 on SERCA2a activity in cardiac myocytes, while in vivo indices of oxidative stress were decreased by SUMO-1 in cardiac hypertrophy and heart failure. Conclusion: The results of this study indicate that post-translational modifications of SERCA2a caused by the toxic environment of the hypertrophied and failing myocardium can be prevented by the expression of SUMO-1.
Abstract 99: A Modified Dispatch Protocol Based on a Layperson’s Description of Breathing Styles of Sudden Cardiac Arrest Victims Is Effective in the Performance of Bystander Cardiopulmonary Resuscitation
Authors: Hidetada Fukushima, Kazuo Okuchi, Tadahiko Seki, Yasuyuki Kawai, Kazunobu Norimoto, Yasuyuki Urizono, Michiaki Hata, Kenji Nishio
Journal: Circulation (2012)

Introduction: To increase survival from out-of-hospital cardiac arrests (OHCAs), the current guideline for resuscitation emphasizes the role of dispatcher-assisted bystander cardiopulmomary resuscitation (CPR). However, previous studies show that identification of OHCAs by dispatchers is unsatisfactory. Since the callers tend to recognize agonal respiration as a sign of life and perceive as various breathing styles, the current two-question protocol asking the callers whether the unresponsive victim is breathing normally or not is insufficient for the dispatchers to identify OHCA. The aim of this study is to verify a modified protocol for dispatcher-assisted bystander CPR based on the layperson’s description of sudden OHCA breathing styles. Method: “Not breathing”, “weak breathing”, “unusual breathing or snoring”, and “breathing or not breathing cannot be determined” were identified as the typical layperson descriptions of sudden OHCA breathing styles, based on analysis of dispatcher records from 2007 to 2009 in Nara prefecture, Japan. According to the modified dispatch protocol, dispatchers were to provide CPR instruction when the callers report those key breathing styles. The protocol was implemented in four fire departments which covered an area including 840,000 residents. All data were collected prospectively, using Utstein Style guidelines. Results: This protocol was carried out for 82 cases of layperson-witnessed OHCA during August to December 2011. Dispatchers instructed CPR for 59 cases of OHCA (71.9%) and callers performed bystander CPR in 41 cases (50.0%). Compared to data from August to December 2010, both the performance of dispatch instruction and dispatcher-assisted bystander CPR significantly improved with the modified dispatch protocol. Conclusion: A modified dispatch protocol based on the layperson’s description of breathing styles of victims experiencing sudden OHCA significantly improved the performance of bystander CPR.
Abstract 17610: Noninvasive Assessment with N-Benzyl-N-[11C]Methyl-2-(7-Methyl-8-oxo-2-Phenyl-7,8-Dihydro-9H-Purin-9-yl)Acetamide ([11C]DAC) Delineates Dynamic Interaction Between Brain and Heart as Well as Local Denervation Status After Cardiac Injury in Rats
Authors: Sho Okada, Kenichi Odaka, Rong Ming-Zhang, Hiroyuki Tadokoro, Joji Yui, Hidekatsu Wakizaka, Lin Xie, Yoshio Uchino, Kazunori Kawamura, Katsushi Kumata, Issei Komuro, Tohru Minamino, Yoshio Kobayashi
Journal: Circulation (2012)

Sho Okada, 2012 Finalist and Presenting Author
Abstract 13170: Microvascular Notch Signaling is Upregulated in Response to Vascular Engothelial Growth Factor and Chronic Myocardial Ischemia
Authors: Antonio D Lassaletta, Nassrene Y Elmadhun, Thomas A Burgess, Michael P Robich, Louis M Chu, Frank W Sellke
Journal: Circulation (2012)

Antonio D Lassaletta, 2012 Finalist and Presenting Author
Abstract 9977: Prognostic Value of Coronary Artery Calcium and Epicardial Adipose Tissue Assessed by Noncontract Computed Tomography
Authors: Eiji Kunita, Hideya Yamamoto, Hiroto Ustunomiya, Toshiharu Oka, Yoji Urabe, Toshiro Kitagawa, Hiroshi Tsushima, Ryo Yamazato, Yasuyuki Tomohiro, Yasuki Kihara
Journal: Circulation (2012)

Background: Coronary artery calcium (CAC) and epicardial adipose tissue volume (EATV) as assessed by noncontrast computed tomography (NCT) have demonstrated to be associated with adverse cardiac outcomes. However, it is not well known whether the simultaneous evaluation of CAC and EATV has value in prediction of future cardiac events (CEs). Methods: We studied 712 patients (65 ± 11 years, 61% men) referred for NCT, and assessed CAC and EATV. CAC score was measured using Agatston method. Patients were initially assigned to two groups: low (&lt;100 ml) or high (≥100 ml) EATV. Patients were followed up as to the occurrence of CEs (cardiac death, myocardial infarction, unstable angina requiring hospitalization, and late coronary revascularization). Results: During a 3.8 ± 1.4 years follow-up period, 44 CEs were documented. The prevalence of CAC (93% vs. 62%, p &lt; 0.001) and high EATV (77% vs. 54%, p = 0.002) were significantly higher in patients with CEs than in those without. In Cox regression analysis, CAC (hazard ratio [HR] 5.44, 95% confidence interval [CI] 1.85-23.4, p = 0.001) and high EATV (HR 2.34, 95% CI 1.16-5.14, p = 0.017) were independent predictors of CEs after adjustment of age, gender, and traditional cardiovascular risk factors. Kaplan-Meier event-free survival curves amongst 4 groups divided by absence or presence of CAC and low or high EATV for CEs are shown in Figure. The CE rates were highest in the high EATV group with CAC compared to other groups. Furthermore, when analyzed in groups with CAC, high EATV was associated with CEs even after adjustment of CAC scores (HR 2.25, 95% CI 1.07-5.17, p = 0.031). In contrast, there was no significant difference in adjusted HRs between low and high EATV groups without CAC. Conclusions: The high EATV and the presence of CAC were independent predictors of CEs. Notably, the measurement of EATV in patients with CAC was useful to predict CEs in the near to medium term. The simultaneous evaluation of CAC and EATV can improve prediction of future CEs.
Abstract 18657: Fibulin-4 Deficiency Alters Collagen Regulation in the Aortic Wall
Authors: Christina L Papke, Lea-Jeanne Ringuette, Yoshito Yamashiro, Jun Tsunezumi, Mitsuo Yamauchi, Elaine Davis, Hiromi Yanagisawa
Journal: Circulation (2013)

Thoracic aortic aneurysms/dissections (TAAD) are a major cause of mortality each year in the U.S. Disruption of fibulin-4 (fbln4), an extracellular matrix component, leads to TAAD in human and mouse models. Fbln4 plays an essential role in elastic fiber assembly: our recent data suggest a role for proliferation in the aortic wall that may be independent of elastic fiber defects. Roles for Fbln4 beyond elastic fiber assembly have been suggested but not previously investigated. We hypothesize that Fbln4 loss alters the aortic wall microenvironment to promote localized cell proliferation, in part through altered collagen synthesis and maturation. Smooth muscle-specific Fbln4 deficient (SMKO) ascending aortas show increased BrdU+ cells at P30 (p&lt;.05) localized throughout the aortic wall but mainly near the medial/adventitial border, irrespective of elastic fiber disruption. Smooth muscle actin inducible Cre mice show intact elastic fibers but a similar pattern of BrdU+ cells. Fbln4 loss also alters synthesis of collagen isoforms, leading to increased Type VIII mRNA (p&lt;.05) and Type I protein expression. Electron microscopy, second harmonic generation images, and molecular analysis of collagen cross-linking revealed highly irregular collagen fiber bundle size, collagen fiber disorganization, and decreased mature cross-links (p&lt;.05). Our data demonstrate a proliferative phenotype and previously uncharacterized collagen defect in Fbln4 deficient mice. Altered collagen isoforms and maturity are known to influence cell proliferation: future work will determine the precise identity of the proliferating cells and specific mechanisms by which collagen defects drive the proliferative phenotype. Increased understanding of the molecular mechanisms driving TAAD will ultimately lead to more effective treatments to delay or prevent onset of disease.
Abstract 9753: Highly Electronegative LDL is Elevated in Patients With Acute Myocardial Infarction and Triggers Platelet Activation and Aggregation
Authors: Hua-Chen Chan, Liang-Yin Ke, Chin-Sheng Chu, An-Sheng Lee, Ming-Yi Shen, Miguel A Cruz Cruz, Kai-Hung Cheng, Hsiu-Chuan Chan, Wen-Ter Lai, Jeng-Hsien Yen, Tatsuya Sawamura, Sheng-Hsiung Sheu Sheu, Chu-Huang Chen
Journal: Circulation (2012)

Background: Human LDL can be chromatographically resolved into 5 subfractions. L5, the 5th and most negatively charged subfraction, is capable of inducing atherogenic responses in vitro and in vivo. Platelet activation and aggregation are major events underlying acute thrombosis in myocardial infarction (MI). We examined the relationship between L5 and acute MI and the role of L5 in platelet activation and aggregation. Methods and Results: Plasma L5 concentration ([L5]) was measured and compared between subjects with (1) no risk factors (healthy controls), (2) STEMI, (3) stable coronary artery disease (CAD), and (4) hyperlipidemia (HLP) without CAD. In STEMI subjects, LDL cholesterol (LDL-C) levels were similar to those in CAD and control subjects and lower than those in HLP subjects, but L5/LDL% and [L5] (L5/LDL% × LDL-C) were significantly elevated (Table). L5 from STEMI subjects but not L1 (least electronegative LDL subfraction) induced tissue factor and P-selectin expression in human coronary arterial endothelial cells (ECs) in a concentration-dependent manner; in platelets, L5 increased glycoprotein (GP)IIb/IIIa and P-selectin expression and decreased cAMP production (for all, n=8, P &lt;.01 vs PBS). L5 also increased ADP-stimulated platelet aggregation twofold higher than L1 and induced massive platelet–EC adhesion. Experiments with pharmacologic inhibitors indicated that L5 signals through platelet-activating factor receptor and lectin-like oxidized LDL receptor-1 to reduce cAMP production via Akt and trigger granule release and GPIIb/IIIa activation via PKC-α. Injection of human L5 (5 mg/kg) in C57BL/6 mice twice a week for 6 weeks shortened tail-bleeding time by 43% when compared to L1 (n=3; P &lt;.01) and increased expression of P-selectin and GPIIb/IIIa in mouse platelets. Conclusions: L5 triggers platelet activation and aggregation, as well as adhesion to ECs. The significant elevation of L5 in STEMI strongly suggests L5’s involvement in acute MI.
Abstract 9749: Predictors of Missed Reduction of LV Mass in Unselected Hypertensive Members of the Strong Heart Study
Authors: Giovanni de Simone, Richard B Devereux, Raffaele Izzo, Mary J Roman, Elisa T Lee, Barbara V Howard
Journal: Circulation (2012)

Background: Clinical trials indicate that reduction of hypertensive LV mass is a reachable objective during antihypertensive management. Whether similar results can be achieved in usual clinical contexts also in unselected population-based samples is unclear. Methods: Among 1133 hypertensive participants of the 4 th Strong Heart Study (SHS) exam, 862 (76%, 490 women or 57%) underwent a repeated echocardiogram after 4 yrs (5 th SHS exam) and were analyzed. Variations of at least 5% of the initial values of both systolic blood pressure (SBP) and LV mass index (LVMi) were categorized for analysis. Results: Compared with the 4 th exam, SBP decreased in 41% of participants, increased in 31% and was unchanged in 28%. LV hypertrophy (LVH) was found in 31% at the 4 th -exam (n=265) and in 37% at the 5 th exam (n=312). LVMi did not change from 4 th to 5 th exam, but in men there was a more significant trend to increase (from 42.0±8.9 to 43.8±9.3 g/m 2.7 ) than in women (from 45.3±10.5 to 45.8±11.4 g/m 2.7 , p&lt;0.004 between genders). Percent (%) change of LVMi was positively related to % change of SBP (r=0.18) and followup SBP (r=0.19, both p&lt;0.0001). Participants who decreased LVMi had initial higher LVMi, HDL-cholesterol and uric acid (UA), with lower heart rate, BMI, waist-to-hip ratio (WHR) and urinary albumin/creatinine ratio (UACR, all 0.05&lt;p&lt;0.0001). Lack of decrese in LVMi was not related to any class of meds used at the time of the 4 th exam (diuretics, ACE-i, ARB, Ca ++ channel blockers, other vasodilators, β-blockers). In hierarchical logistic regression, adjusting for older age (p&lt;0.02), sex, initial LVMi and field center, lack of decrease in LVMi was independently associated with initially higher BMI (p&lt;0.0001), WHR (p=0.05), UACR (p&lt;0.001), UA (p&lt;0.004) and to the % change of SBP (p&lt;0.005), without additional independent contribution of glucose status (including diabetes), initial SBP and classes of antihypertensive meds. Conclusions: These results suggest that antihypertensive management does not effectively decrease LV mass in unselected population-based hypertensive subjects. The lack of effect is associated with poor BP control, is predicted by older age, initial central obesity, kidney damage, and is not affected by type of initial antihypertensive therapy.