tbuckley/cabot-search huggingface dataset:
Abstract 8965: C1q/TNF-Related Protein-3, a Newly Identified Adipokine, is a Novel Anti-Apoptotic, Pro-Angiogenic, and Cardioprotective Molecule in the Ischemic Mouse Heart
Authors: Yang Sun, Wei Yi, Wayne Bond Lau, Yuexing Yuan, Qijun Zheng, Xiaoliang Wang, Yajing Wang, Xiying Shang, Erhe Gao, Walter J Koch, Xin-Liang Ma
Journal: Circulation (2011)

Obesity/diabetes adversely affects ischemic heart remodeling via incompletely understood mechanisms. Adipocytes produce various adipokines. Delineating these adipokines’ cardiovascular profiles is critical in advancing our knowledge regarding how obesity/diabetes may cause cardiovascular damage. C1q/TNF-related protein-3 (CTRP3) is a newly identified adipokine exerting beneficial metabolic regulation. However, the cardiovascular actions of this novel adipokine remain unknown. The current study determined whether CTRP3 may regulate post-ischemic cardiac remodeling and cardiac dysfunction, and, if so, sought to elucidate the involved underlying mechanisms. Male adult mice were subjected to MI, and treated with saline or CTRP3 via peritoneally implanted osmotic-pumps for 2 weeks. Plasma CTRP3 levels were significantly reduced 4 hours after MI, and remained at low level until 1 week after MI. Supplementation of CTRP3 (beginning 4 hours after MI) at a dose (0.25 μg/g/day) restoring physiological CTRP3 levels in MI animals improved survival rate (P&lt;0.05), rescued cardiac function (determined by echocardiograph and left ventricular catheterization, P&lt;0.01), attenuated cardiomyocyte apoptosis within infarct border zones (determined by TUNEL staining and caspase 3 activation, P&lt;0.01), increased revascularization (evidenced by CD31 and α-SMA immunostaining, P&lt;0.01), and dramatically reduced interstitial fibrosis (41% reduction vs. vehicle group, P&lt;0.01). In vivo CTRP3 administration had no significant effect upon AMPK phosphorylation, but significantly increased Akt phosphorylation, and increased HIF-1α and VEGF expression. Surprisingly, treatment of HUVECs in vitro with CTRP3 failed to increase tube formation. However, pre-conditioned medium from CTRP3-treated cardiomyocytes significantly enhanced HUVEC tube formation, an effect that was blocked by either pre-treatment of cardiomyocytes with a PI3K inhibitor, or pre-treatment of HUVECs with a VEGF inhibitor. Our results demonstrate for the first time that CTRP3 is a novel anti-apoptotic, pro-angiogenic, and cardioprotective adipokine in the ischemic mouse heart, via facilitation of cardiomyocyte-endothelium communication.
Abstract 9027: A Novel Polymorphism Arg146 of the Natriuretic Peptide Receptor-3 Gene Results in a Significant Reduction in Protein Expression Due to Accelerated Degradation
Authors: Naveen Pereira, Lin Dong, Linda Pelleymounter, Irene Moon, Gail Stilling, Bruce Eckloff, Eric Wieben, Vivien Yee, Margaret Redfield, John Burnett, Richard Weinshilboum
Journal: Circulation (2012)

Background: The primary role of natriuretic peptide receptor 3 (NPR3) is clearance of natriuretic peptides. Genetic variation in NPR3 has been associated with blood pressure regulation and obesity. Despite its importance, variation in NPR3 characterizing coding single nucleotide polymorphisms (SNPs) has not been addressed by resequencing the gene. Objective: We set out to identify and functionally characterize common variation in NPR3 in 3 ethnic groups. DNA samples from such subjects are studied because common genetic variation needs to be defined initially in “normal” individuals prior to studying drug effect and response. Also, rare variants identified by sequencing are enriched in complex disease traits. Methods and Results: DNA samples from 96 European-American, 96 African-American, and 96 Han Chinese-American healthy subjects were used to resequence NPR3. There were 105 polymorphisms identified of which 50 were novel, including 8 nonsynonymous (ns) SNPs of which 7 were novel. Expression constructs for the nsSNPs were created and HEK-293 cells were transfected with constructs for wild type (WT) and the variants. Recombinant proteins were analyzed by quantitative Western blot analysis. A significant reduction in NPR3 immunoreactive protein (60% or less of WT) was observed for the following variants Cys3, Arg146, Val499, and Ser477+Asp521. The Arg146 novel polymorphism resulted in the least protein expression (20% of WT). After treatment of WT and Arg146 cells with proteasome (MG132) and autophagy (3MA) inhibtors, it was determined that autophagy and not proteasomes plays an important role in the degradation of the Arg 146 variant protein. Modeling based on the NPR3 x-ray crystallography structure confirmed that the Arg146 variant were not compatible with WT conformation and could result in protein misfolding or instability. Conclusions: Multiple novel polymorphisms of NPR3 were identified in 3 ethnic groups. There were 4 variant receptors that displayed a significant decrease in NPR3 protein quantity, Arg146 being the variant with the least expression. Degradation of the variant Arg146 was mediated predominantly by autophagy. This SNP could have a significant effect on the metabolism of natriuretic peptides with clinical implications.
Abstract 8622: Transmural Dispersion of Repolarization in Febrile Children with Kawasaki Disease
Authors: Tadayoshi Hata, Masayuki Fujino, Marina Kuriki, Kayo Horio, Yumi Omeki, Hidetoshi Uchida, Yoshihiko Eryu, Hiroko Boda, Masafumi Miyata, Toshio Yamazaki
Journal: Circulation (2011)

Introduction: The instability of myocardial repolarization is generally mediated by myocardial failure. We assessed the hypothesis that transmural dispersion of repolarization is increased in the inflamed myocardium in patients with acute-phase Kawasaki disease. Method: Consecutive 25 infants (M:F = 15:10 ) with Kawasaki disease aged 2.6 ± 2.2 years and 25 age-matched control infants were included. RR interval, QT interval and Tp-e time (CM5 lead) were calculated using analysis software (Acqknowledge Ver. 3.9, Biopac Systems Inc. CA, USA). Tp-e time was corrected by Fridericia equation (Tp-eC). These parameters were compared in the acute phase (6.9 ± 3.0 days after onset) and recovery phase (23.0 ± 13.3 days after onset) or control. The relationship between Tp-e/QT, Tp-eC and C reactive protein, body temperature on admission were evaluated by regression analysis. Results: 1) The Tp-e/QT in the acute phase were significantly higher than that in the recovery phase (Mean ± SD: 0.248 ± 0.055 vs 0.215 ± 0.022, p&lt;0.05 ) and control group (0.220 ± 0.025, p&lt;0.005). 2) The Tp-eC in the acute phase was significantly higher than that in the recovery phase (89.99 ± 16.86 vs 82.11 ± 7.45, p&lt;0.05) and control group (80.02 ± 10.46, p&lt;0.01). 3) In acute phase, significant positive correlation was observed between Tp-e/QT and C reactive protein or body temperature (r = 0.677 and 0.672, respectively). Further, between Tp-eC and C reactive protein or body temperature (r = 0.482 and 0.583, respectively). Conclusions: Transmural dispersion of repolarization assessed by Tp-e/QT and Tp-eC was increased in the acute phase of Kawasaki disease, which exhibits the sub-clinical lability of ventricular repolarization. These repolarization properties of the myocardium were considered a useful indicator to assess arrhythmogenesis in patients with Kawasaki disease.
Abstract 19060: An Anti-Viral Drug with Properties of Selective Inhibition of Adenylyl Cyclase Type 5 Reduces Infarct Size More when Delivered after than Before Reperfusion
Authors: Claudio Bravo, Seonghun Yoon, Raymond K Kudej, Rong Tian, Stephen Kolwicz, Bruno Buchholz, Ricardo Gelpi, Ishikawua Yoshiro, Kosaku Iwatsubo, Dorothy E Vatner, Lin Yan, Stephen F Vatner
Journal: Circulation (2012)

There are at least two reasons why very few of the discoveries from genetically engineered mice have been translated to the clinics: 1.Most therapy requires delivery of a drug, since it is difficult to change a gene in patients; 2. Most cardioprotective agents require pretreatment before coronary artery (CA) reperfusion (R), but patients with myocardial infarction are rarely seen before CAR. We studied the drug 9-beta-D-arabinofuranosyladenine (Ara-Ade), previously used and FDA approved as an antiviral drug, because it has a structure resembling adenosine, but demonstrates selective adenylyl cyclase isoform type 5 (AC5) inhibition properties, i.e., it inhibits responses to beta-adrenergic receptor stimulation much greater in AC5 transgenic (Tg) mice than wild type, but not more in AC6 Tg and not at all in AC5 knockout, both in vitro and in vivo. We examined its ability to reduce infarct size (measured with TTC) after 30 min CA occlusion (CAO) and 24 hr CAR in mice. Surprisingly, infarct size, expressed as a fraction of the area at risk was lower, p&lt;0.05, when the drug was delivered at CAR (16%), than when given before either CAO or CAR (21%) compared to vehicle (36%). p Ara-Ade also reduced infarct size in chronically instrumented conscious pigs, when delivered after CAR. In this model instantaneous measurements of coronary blood flow demonstrated that post reperfusion coronary hyperemia and reactive hyperemia, following a 15 sec CAO, were attenuated, consistent with isolated heart studies showing reduced coronary flow recovery after ischemia. Thus, a novel drug that inhibits AC5 induces even more cardioprotection when delivered after CAR than before, making it potentially more useful the clinical setting, where patients with myocardial infarction require CAR immediately after arriving at the hospital. It is conceivable that the mechanism, in part, involves protection of CAR damage, since the magnitude of coronary hyperemia after CAR has been related to CAR reperfusion damage.
Abstract 96: Favorable Survival of In-Hospital Compared with Out-of-Hospital Refractory Cardiac Arrest Patients Treated with Extracorporeal Membrane Oxygenation: An Italian Tertiary Care Center Experience
Authors: Leonello Avalli, Gianluca Greco, Fabio Sangalli, Lucia Galbiati, Margherita Trabucchi, Francesco Formica, Cristina Costa, Giuseppe Ristagno, Roberto Fumagalli
Journal: Circulation (2011)

Objective: Extracorporeal membrane oxygenation (ECMO) support has been suggested to improve survival in patients with refractory in- and out-of-hospital cardiac arrest (IHCA, OHCA). Aim of the present study was to report our experience on the use of ECMO in adult patients with refractory IHCA and OHCA. We have further examined outcome differences between IHCA and OHCA and factors accounting for such differences. Methods: Forty-two patients (31 males) with refractory cardiac arrest, 24 IHCA and 18 OHCA, were enrolled in this single centre, retrospective, observational study, from January 2006 to December 2010. Results: There was significant difference in the time of no-flow (duration of untreated cardiac arrest) between the OHCA and IHCA patients (p&lt;0.001). The time of low flow (duration of CPR prior to ECMO) was also significantly longer in the OHCA group compared with the IHCA one (77 mins vs 55 mins, p&lt;0.001). ECMO implantation was successful in 38 (90%) of the 42 patients. ECMO support was positioned: 3 times (8%) in the operating room, 6 (16%) in the cardiac surgery intensive care unit, 21 (55%) in the emergency department, 5 (13%) in the catheterization laboratory and 3 (8%) in general ward. A total of 14 IHCA (58%) and 3 OHCA (16%) patients were weaned from ECMO (p&lt;0.05). 11 IHCA (46%) and 1 OHCA (5% p&lt;0.05) were discharged from intensive care unit (ICU). Among IHCA patients, 10 were alive at 6 months, 9 of whom (38%) with good neurological outcome. Among OHCA patients weaned from ECMO, one was alive at six months with good neurological outcome (5%, p&lt;0.05 vs IHCA). Conclusions: ECMO support should be considered as a resuscitation alternative in selected patients. More specifically, patients with witnessed IHCA have more benefits from ECMO treatment compared to those who experience an out-of-hospital cardiac arrest.
Abstract 19526: Fractional Flow Reserved Derived from Computed Tomographic Angiography (FFRCT) to Discriminate Individuals with versus without Ischemia: Results from the DeFACTO Trial (Determination of Fractional Flow Reserve by Anatomic Computed TOmographic Angiography)
Authors: James K Min, Daniel Berman, Leslee J Shaw, Laura Mauri, Bon-Kwon Koo, Carlos van Mieghem, Andrejs Erglis, Jonathon Leipsic
Journal: Circulation (2012)

Background Non-invasive fractional flow reserve (FFR) derived from coronary computed tomographic (CT) angiography (FFRCT) is a novel method that employs computational fluid dynamics to diagnose coronary lesions that cause ischemia. To date, the per-patient diagnostic performance of FFRCT versus obstructive CAD by CT (&gt;50% stenosis) to discriminate ischemia has been inadequately studied. Methods A total of 407 vessels were evaluated in 252 patients from 17 centers in 4 countries who underwent CT, FFRCT, invasive coronary angiography and invasive FFR. The area under the receiver operator characteristics curve (AUC) for detecting abnormal FFR on a per-patient basis was examined considering: (1) all vessels interrogated by FFR (n=252 patients), (2) only vessels &gt;2 mm interrogated by FFR (n=149 patients); 3) a decision rule which included all vessels interrogated by FFR, as well as vessels with maximal stenosis 90% which were considered negative and positive, respectively, for ischemia (n=252 patients); and 4) a decision rule for &gt;2 mm vessels (n=229 patients). Per-patient AUCs were compared for FFRCT alone, CT stenosis &gt;50% alone, and the combination of FFRCT and CT stenosis &gt;50%. FFRCT was superior to CT stenosis for discrimination of individuals with ischemia (AUC 0.81 vs. 0.69, p2 mm vessels (AUC 0.82 vs. 0.74, p=0.0007), when employing the decision rule (0.83 vs. 0.67, p2 mm vessels (0.92 vs. 0.68, p&lt;0.0001). The combination of FFRCT and CT stenosis was similarly superior to CT stenosis alone when considering all vessels interrogated by FFR (0.81 vs. 0.69, p2 mm vessels (0.82 vs. 0.74, p&lt;0.001), when applying the decision rule (0.83 vs. 0.67, p2 mm vessels (AUC 0.91 vs. 0.68, p&lt;0.0001). In contrast, no added discrimination was noted when CT stenosis was added to FFRCT, as compared to FFRCT alone (p=NS). Conclusion FFRCT improves discrimination for identification of individuals who manifest ischemia. The addition of CT stenosis findings to FFRCT does not improve discrimination of individuals with ischemia.
Abstract 19434: Early Ischemic Preconditioning Requires Akt- and PKA-Mediated Activation of eNOS via Serine <sup>1176</sup> Phosphorylation
Authors: Changjun Yang, M.A. Hassan Talukder, Saradhadevi Varadharaj, Murugesan Velayutham, Jay L Zweier
Journal: Circulation (2012)

Aims: The role of endothelial nitric oxide synthase (eNOS)/NO signaling is well-documented in late preconditioning or postconditioning; however, the role of eNOS and its activation in early IPC remains controversial and poorly defined. This study investigates the role of eNOS in early IPC and what signaling pathways and molecular interactions regulate eNOS activation during early IPC. Methods and Results: Rat hearts were subjected to 30-min global ischemia and reperfusion (I/R) with or without IPC (3 cycles 5-min I and 5-min R) in the presence or absence of the NOS inhibitor, L-NAME, PI 3 K inhibitor, LY294002/LY, or PKA inhibitor, H89, during IPC induction. IPC improved postischemic contractile function and reduced infarction compared to I/R with this abrogated by NOS inhibition. eNOS Ser1176 , Akt Ser473 , and PKA Thr197 phosphorylation was increased following IPC. I/R decreased eNOS Ser1176 phosphorylation, while IPC increased it. Mass spectroscopy confirmed eNOS Ser1176 phosphorylation and quantative western blots showed that ∼24 % modification of eNOS Ser1176 was present following induction of early IPC. Immunoprecipitation demonstrated eNOS, Akt and PKA complexation. Immunohistology showed that IPC induced Akt and PKA phosphorylation in cardiomyocytes and endothelial cells. With eNOS activation, IPC increased NO production as measured by EPR spin trapping and fluorescence microscopy. LY or H89 not only greatly decreased Akt Ser473 or PKA Thr197 phosphorylation, respectively; but also abolished IPC-induced preservation of eNOS and eNOS Ser1176 phosphorylation as well as subsequent cardioprotection. Conclusion: Thus, Akt- and PKA-mediated eNOS activation, with phosphorylation near the C-terminus, is critical for early IPC-induced cardioprotection with eNOS-derived NO serving a critical role.
Abstract 9111: Augmented Cardiac Formation of Oxidatively-Induced Carbonylated Proteins Accompanies the Increased Functional Severity of Post-Myocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus
Authors: Kathleen E Dennis, Oghenerukevwe Odiete, Salisha Hill, Kristie L Rose, Michael F Hill
Journal: Circulation (2012)

Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher cardiovascular mortality than those without DM. We have previously shown that after MI, type 1 DM is associated with accentuated myocardial oxidative stress (OS) and concomitant worsening of left ventricular (LV) function. However, the precise mechanisms whereby type 1 DM-enhanced OS adversely affects HF after MI remain obscure. As carbonylation of proteins is an irreversible post-translational modification induced only by OS that often leads to the loss of function, we analyzed protein-bound carbonyls in the viable LV myocardium of MI and DM + MI rats in relation to residual LV function at 4 weeks post-MI. Type 1 DM was induced in male Sprague-Dawley rats by a single injection of streptozotocin (65 mg/kg i.p.). Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by left coronary artery ligation. Residual LV function was assessed by echocardiography. Carbonylated proteins were detected through oxyblot analysis, and identified by mass spectrometry. Mortality following induction of MI was higher among the DM + MI group compared to the MI group (47% vs. 33%, respectively). Compared with MI rats, DM + MI rats exhibited significantly greater LV systolic dysfunction as well as elevated wet to dry weight ratios of the lungs (Table), indicating an increased functional severity of HF among the DM + MI group. No difference in the weight of myocardial scar caused by the infarction was observed between the MI and DM + MI groups (Table). Protein carbonyl content in cardiac tissue and isolated mitochondria of DM + MI rats was 20% and 48% higher, respectively, than in MI rats (n=4/group). Anti-oxidative enzymes and fatty acid utilization proteins were the predominant carbonylated proteins identified. The findings of this in vivo study implicate protein carbonylation as part of the molecular pathophysiology of aggravated HF in the type 1 diabetic post-infarction heart.
Abstract 19088: Differential Mobilization of Progenitor Cells in Smoker and Non-smoker Patients with Acute Myocardial Infarction : Insights from the Bonami Biology Sub-study
Authors: Guillaume Lamirault, Sophie Susen, Virginie Forest, Caroline Hemont, Angelo Parini, Philippe Le Corvoisier, Christophe Piot, Marie-Jeanne Richard, Béatrice Delasalle, Hélène Rouard, Catherine Sportouch, Virginie Persoons, Eric Van Belle, Eric Van Belle, Jérôme Roncalli, Patricia Lemarchand
Journal: Circulation (2012)

Introduction: Although autologous bone marrow cell (BMC) therapy has emerged as a promising option to treat acute myocardial infarction (AMI), randomized trials reported mixed results. This may be explained in part by great variability in the functionality of BMCs retrieved from patients with risk factors of atherosclerosis. Hypothesis: We hypothesized that active smoking may alter bone marrow-derived progenitor cells number and functionality in patients with AMI. The aim of the current study was to investigate the characteristics of BMCs in active smokers and non-smokers with AMI and their potential impact on BMC therapy efficacy. Methods: We compared progenitor cells in bone marrow and blood samples from 54 active smokers and 47 non-smokers with AMI enrolled in the BONAMI cell therapy trial. Results: White bone marrow cell number per microliter and CD45dimCD34+ cell number were higher in active smokers (p=0.001, p=0.03, respectively). In marked contrast, in active smokers there was a decrease of both bone marrow and blood endothelial progenitor CD45dimCD34+KDR+ cells (EPCs) expressed as their percentage per 10 5 WC (p=0.005, p=0.04, respectively). Importantly, a multivariate linear regression analysis including CV risk factors that were significantly different between non- and active smokers, confirmed the association between active smoking and a lower EPC number per 10 5 WC in both blood (p=0.04) and bone marrow (p=0.04) Furthermore, in non-smokers not receiving BMC therapy, there were positive correlations between circulating EPC levels and the decrease in infarction defect size (p=0.02) and viability improvement (p=0.02) measured by SPECT at 3 month post-MI. This association was not observed in active smokers and in patients receiving BMC therapy. Conclusion: These data suggest that circulating EPCs play an important role in cardiac repair post-MI in non-smokers but not in active smokers. This discrepancy may be explained by a lack of activation of the endothelial cell lineage, and of blood mobilization of EPCs in active smokers after AMI. Future studies are warranted to understand critical features of progenitor cell preparations and of patients with AMI that are predictive of a favorable response to cell transfer.
Abstract 8378: Novel System for the Molecular Imaging of Atherosclerotic Plaque with <sup>68</sup> Ga-DOTA-ApoA-I Mimetic Peptide (-FAMP)
Authors: Eiji Yahiro, Yoshinari Uehara, Koki Hasegawa, Emi Kawachi, Tsuneo Yano, Yasuyoshi Watanabe, Shin-ichiro Miura, Keijiro Saku
Journal: Circulation (2011)

Cardiovascular disease is the leading cause of death, and atherosclerosis is a chronic, progressive disease with a long asymptomatic phase. Currently, most diagnostic modalities for atherosclerosis imaging can not provide information on the biology and metabolism of plaque, which could help to identify the stage of the disease. PET has the potential to provide information on the extent and activity of atherosclerotic plaque. We have previously described FAMP, a novel apoA-I mimetic 24-amino acid peptide, which may be able to remove cholesterol via specific ATP-binding cassette transporter A1. In this study, we investigated the potential of FAMP to image developing plaque lesions in vivo. FAMP was modified with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with 68 Ga for noninvasive PET in a familial hypercholesterolemic rabbit (WHHL) with atherosclerotic lesions in the presence or absence of aortic stenting. The uptake of 68 Ga-DOTA-FAMP in the atherosclerotic region in WHHL rabbit was visible on small-animal PET images. Aortic atherosclerotic plaque showed a high uptake of 68 Ga-DOTA-FAMP in WHHL rabbit (Fig.B), but not in normal (JW) (Fig.A) rabbit in both in vivo and in vitro imaging. Furthermore, 68 Ga-DOTA-FAMP also showed strong uptake in aortic-stenting lesion in Planar Positron Imaging System (Fig.C). In conclusion, we demonstrated that 68 Ga-DOTA-FAMP is a promising candidate tracer for PET imaging of atherosclerotic plaque. Detection of these plaques which are prone to rupture could be clinically important for the prevention of cardiac events.