tbuckley/cabot-search huggingface dataset:
Abstract 13533: Impact of Cola Drinking on the Cardiorenal Axis in Rats
Authors: Matilde Otero-Losada, Hernán Gómez Llambí, Angélica Müller, Graciela Ottaviano, Gabriel Cao, Giuseppe Ambrosio, José Milei
Journal: Circulation (2015)

Introduction. The cardiorenal syndrome is a constellation of interactive cardiac and renal risk factors. We reported that chronic cola drinking induces metabolic syndrome and pro-oxidative metabolism in rats. Hypothesis . To evaluate whether chronic cola drinking affects cardiorenal integrity in relation with oxidative metabolism and local inflammation in rats. Methods. Male Wistar rats drank ad libitum regular cola (C, n=12) or water (W, n=12). Measures/recordings: body weight (weekly), nutritional data (twice a week); at 0 mo and 6 mo: plasma glucose, cholesterol fractions, TG, uric acid, creatinine (enzymocolorimetry), coenzyme Q-10 (RP-HPLC-ED), SBP (plethysmography), echocardiograms (awake rats). At 6 mo euthanasia was performed. The heart and kidneys were excised and processed for histopathology and immunohistochemical IL-6 and TNFα staining. Glomerulosclerosis and histopathology score were semiquantitatively evaluated. ANOVA, Bonferroni t-test, Pearson r, p&lt;0.05 significant. Results. Compared with W, C rats showed: I). overweight (8%, p&lt;0.05), hyperglycemia (11%, p&lt;0.05), hypertriglyceridemia (2-fold, p&lt;0.001), higher atherogenic index in plasma (2-fold, p&lt;0.01), lower Q 10 levels (-55%, p&lt;0.05); II). higher LV diastolic diameter (+9%, p&lt;0.05) and volumes (diastolic 26%, p&lt;0.01; systolic 24%, p&lt;0.05), posterior wall thinning (-8%, p&lt;0.05) and larger cardiac output (24%, p&lt;0.05); III). glomerulosclerosis (21%, p&lt;0.05), higher histopathological score (13%, p&lt;0.05), IL-6 (7-fold, p&lt;0.001) and TNFα (4-fold, p&lt;0.001) expression; IV). Left ventricle dimensions were strongly correlated with IL-6 (74%, r=0.86, p&lt;0.001) and TNFα (52%, r=0.72, p&lt;0.001). Controlling for either or both TG and Q 10 reduced the strength of correlations or nearly abolished them. Conclusions . Cardiac remodeling was associated with increased pro-inflammatory cytokines and renal damage. Cardiorenal association was highly dependent on hypertriglyceridemia and Q10 level. Hypertriglyceridemic lipotoxicity in a context of defective antioxidant and anti-inflammatory protection due to low Q10 level might be involved in the cardiorenal syndrome induced by chronic cola drinking in rats.
Abstract 12947: Clarithromycin Prevents Progression &amp; Rupture of Aortic Aneurysm
Authors: Wataru Uchida, Aika Yamawaki-Ogata, Hideki Oshima, Akihiko Usui, Yuji Narita
Journal: Circulation (2016)

Introduction: The pathogenesis of aortic aneurysm (AA) is mainly characterized by chronic inflammation in the aortic wall with accumulation of macrophages and degradation of extracellular matrix (ECM) with increased matrix metalloproteinases (MMP), particularly MMP-2 &amp; -9, resulting in the degradation of collagen, elastin fragmentation and smooth muscle cell apoptosis. Meanwhile, clarithromycin (CAM) is well-known potent antibiotic, otherwise, CAM has been reported to have multiple biologic effects, such as alteration of inflammatory factors including MMP-2 &amp; -9. In this study, we investigated the effects of clarithromycin on induced AA in mice. Methods: Male aged apolipoprotein E deficient (ApoE-/-) mice were infused 1000 ng/kg/min Angiotensin II for 28 days to induce AA. In the CAM-treated group (CAM group: n=13), the mice were dosed with CAM (100 mg/kg/day) by the gastric tube every day. In the control group (CONT; n=13), saline was administrated. Echo-aortography was performed every week to measure aortic diameters. The aneurysm induced aorta was removed and evaluated. Elastica van-Gieson stain was performed for evaluation of ECM in the aortic wall. The elastin content of the aorta were measured. Infiltrations of inflammatory macrophages were evaluated by immunofluorescence staining against CD 206 &amp; F4/80. Gelatin zymography was performed to evaluate MMP-2 &amp; -9 activities in aortic tissues. Results: Echo-aortography showed the aortic diameters were significantly attenuated in CAM group. The incidence of AA in CONT was 100%, which was significantly decreased to 23% in CAM group. No ruptured death was observed in CAM group in contrast to 5 ruptured deaths in CONT (Log Rank test, p=0.01). CAM significantly suppressed degradation of aortic elastin (56.3% &amp; 16.5%, p&lt;0.001) &amp; decreased infiltration of inflammatory macrophages (5.3% &amp; 16.0%, p=0.005). CAM significantly attenuated MMP-2 (0.15 &amp; 0.56, p&lt;0.001) &amp; MMP-9 activities (0.12 &amp; 0.60, p&lt;0.001) respectively. Conclusions: CAM prevented the development of AA &amp; rupture through suppression of inflammatory macrophages infiltration, decreased MMP-2 &amp; -9, &amp; preserved elastin content.
Abstract 18760: Homeostatic Intracellular Repair Response (HIR <sup>2</sup> ) is Affected by Glycemic Control in Diabetics Undergoing Cardiac Surgery
Authors: David Sengstock, Salik Jahania, Allen Andres, Bruce R Ito, Roberta A Gottlieb, Robert M Mentzer
Journal: Circulation (2013)

Background: We previously reported that HIR 2 is activated in the human heart during cardiac surgery. The mechanism underlying HIR 2 is adaptive autophagy, a beneficial stress response to ischemia, hypoxia, and nutritional depletion. It is a process that eliminates damaged mitochondria and protein aggregates. Preclinical studies in animal models have shown that HIR 2 is impaired in the setting metabolic syndrome. To confirm our previous clinical findings and test the hypothesis that HIR 2 is altered in patients with Type II diabetes (T2DM), autophagy was examined in heart tissue obtained from a cohort of patients with and without the disease. Methods: Biopsies of the right atrium were obtained before initiation and after weaning from cardiopulmonary bypass in 19 patients undergoing conventional cardiac surgery. The Society of Thoracic Surgeons’ database was used to identify individuals with T2DM (n=8). HbA1c was used as a measure of diabetic control. Autophagy was measured by immunoblotting for Beclin-1, LC3, Atg5-12, and p62, and normalized to actin levels. The pre-post difference in p62 (Δp62) was used to assess autophagic flux. Results: Consistent with previously observed, heart surgery was associated with a significant reduction (all p &lt; 0.01) in Beclin-1 (1.18 ± 0.18 vs. 1.73 ± 0.24), Atg5-12 (0.74 ± 0.10 ± vs.1.11 ± 0.14), and p62 (0.89 ± 0.11 vs. 1.51 ± 0.20), but not LC3. As shown below, depletion of p62 during surgery significantly correlated with Atg5-12 and Beclin-1 across all patients. Notably, in diabetics there was a decrease in the magnitude of the cardiac HIR 2 response (Δp62) as a function of glycemic control (HbA1c). Conclusion: These results confirm our previous findings indicating a robust activation of HIR 2 in patients undergoing cardiac surgery. Importantly, in patients with T2DM this adaptive response appears to be substantially blunted, and may explain, in part, the increased morbidity and mortality associated with this at-risk patient population.
Abstract 18762: The Association Between Atrial Fibrillation and Sudden Cardiac Death is Confounded by Clinical History of Congestive Heart Failure
Authors: Kyndaron Reinier, Eloi Marijon, Audrey Uy-Evanado, Carmen Teodorescu, Harpriya Chugh, Karen Gunson, Jonathan Jui, Sumeet S Chugh
Journal: Circulation (2013)

Introduction: Atrial fibrillation / flutter (AF) has been associated with overall cardiac mortality, and recent studies have reported an association with sudden cardiac death (SCD). Since AF and SCD share many of the same risk factors, we hypothesized that this association could potentially be explained by other clinical predictors, especially a clinical diagnosis of congestive heart failure (CHF). Methods: In an ongoing prospective case-control study of SCD in a metro region of the Northwestern US (pop. approx. 1 million), cases of SCD were ascertained from the region’s EMS system, medical examiner, and hospitals and adjudicated by systematic review of arrest circumstances and medical records. SCD cases age ≥18 (2002-2012) with physician records and a cardiac evaluation by ECG or echocardiogram were compared to control subjects with coronary artery disease (CAD) from the same geographic region. AF was defined by physician-documented medical history or from a pre-arrest ECG or echocardiogram. Results: Case subjects (n=935, age 71 ± 13 yrs, 64% male) were more likely than control subjects (n=679, age 66 ± 12 yrs, 66% male) to have a history of myocardial infarction (41% vs. 34%, p=0.004), CHF) (45% vs. 18%, p&lt;0.0001), cerebrovascular accident (CVA) (22% vs. 10%, p&lt;0.0001), and diabetes (41% vs. 32%, p=0.0004), but less likely to have documented hyperlipidemia (54% vs. 82%, p&lt;0.0001). Among all subjects, cases were significantly more likely to have a history of AF than controls (29% vs. 18%, p&lt;0.0001). However, AF was strongly associated with a history of CHF: AF was prevalent in 44% of subjects with CHF and 15% of subjects without CHF (p&lt;0.0001). In multivariable models, AF was significantly associated with SCD when adjusting for age, gender, history of MI, hypertension, CVA, diabetes, and dyslipidemia (p=0.01), but when CHF was added to the model, the AF-SCD association was no longer significant (OR 1.05, 95% CI 0.8 - 1.4, p=0.74). In this model, CHF remained a significant predictor of SCD risk (OR 3.5, 95% CI 2.6 - 4.5). Conclusions: In this population-based study, the AF-SCD association appears to be driven by a clinical history of CHF. These findings have potential implications for clinical and mechanistic approaches to AF and SCD.
Abstract 13427: Treatment With a Direct Thrombin Inhibitor Interrupts the Progression of Obesity-Associated Pathologies in Mice Fed a High Fat Diet <i>(Best of Basic Science Abstract)</i>
Authors: Anna K Kopec, Nikita Joshi, Holly Cline-Fedewa, Kurt J Williams, Rance Nault, Tim R Zacharewski, Ashley Goss, Joanne van Ryn, James P Luyendyk
Journal: Circulation (2015)

Obesity is accompanied by activation of the coagulation cascade in humans and in experimental settings of diet-induced obesity. Genetic and pharmacologic interference with thrombin proteolytic activity has previously been shown to attenuate obesity-associated pathologies, including non-alcoholic fatty liver disease (NAFLD). In this study we sought to determine if intervention with the thrombin inhibitor, dabigatran etexilate (DE), can slow the progression of NAFLD and obesity when administered after onset of disease. Wild-type C57BL/6J mice were fed a control diet (AIN-93M, 10% calories from soybean oil) or a high fat diet (HFD, 60% calories from lard and soybean oil) for 3 months and then switched to identical diets containing 7.5 mg/g DE (AIN-93M+DE and HFD+DE) for an additional 2 months (intervention groups). Additional groups of mice were fed DE-containing diets for all 5 months (prophylactic groups). Terminal plasma DE levels were comparable (~330 ng/ml) in mice fed AIN-93M+DE and HFD+DE. Therapeutic intervention with DE prevented excess body weight gain, marked by no further increase in body fat mass, in HFD-fed mice. DE treatment elicited a selective reduction in micro-, but not macro-vesicular, hepatocellular steatosis in mice with established HFD-induced obesity. In addition, DE treatment prevented progression of liver injury (i.e., serum alanine aminotransferase levels) in HFD-fed mice. HFD-induced hyperglycemia was significantly attenuated in DE-treated mice, suggesting improved insulin sensitivity. DE treatment did not significantly affect these parameters in AIN-93M-fed mice. Analysis of inflammatory cytokines linked to metabolic inflammation revealed a robust increase in plasma KC/Gro, a neutrophil chemokine related to adiposity and insulin resistance, in HFD-fed mice. Notably, both prophylaxis and intervention with DE dramatically reduced plasma KC/Gro levels. Overall, the data suggest that DE can halt the progression of diet-induced obesity and NAFLD in mice fed a HFD. Moreover, the results suggest that thrombin-mediated chemokine induction contributes to HFD induction of obesity and liver disease in mice.
Abstract 13764: Development of <i>in vitro</i> Drug-Induced Cardiotoxicity Assay by Using Three-Dimensional Cardiac Tissues Derived From Human Induced Pluripotent Stem Cells
Authors: Maki Takeda, Shigeru Miyagawa, Satsuki Fukushima, Atsuhiro Saito, Emiko Ito, Ryohei Matsuura, Akima Harada, Noriko Oda, Yuto Amano, Michiya Matsusaki, Mitsuru Akashi
Journal: Circulation (2015)

Introduction: In vitro drug-induced cardiotoxicity assay is a critical step in drug discovery for clinical use. Use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is promising for this purpose; however, dissociated single iPSC-CMs are concerned by their functionality, while generation of artificial cardiac tissue by iPSC-CMs mimicking native cardiac tissue has not been established for the cardiotoxicity assay. We hypothesized that three-dimensional (3D) cardiac tissues derived from human iPSC-CMs (3D-hiPSC-CMs) may be used for in vitro drug-induced cardiotoxicity assay. Methods and Results: Single hiPSC-CMs coated with fibronectin and gelatin nanofilms were cultured in a cell culture insert to generate 3D-hiPSC-CMs. Histologically, the 3D-hiPSC-CMs formed thick multilayers dependent upon the number of seeded cells. In addition, the 3D-hiPSC-CMs exhibited sarcomere structure in the myocytes and extracellular matrix proteins, such as fibronectin, laminins or collagen type I/III. Electrophysiologically, synchronous extracellular electrical potentials were recorded in the entire 3D-hiPSC-CMs. Addition of cytotoxic doxorubicin at 2 uM induced release of lactate dehydrogenase (LDH), while that at 1 uM induced reduction of cell viability as assessed by WST assay. In contrast, addition of E-4031, hERG type potassium channel blocker, failed to induce cytotoxicity in the 3D-hiPSC-CMs by LDH and WST assay. Instead, E-4031 at 30 nM induced significant decrease in peak Ca2+ transient (80±4 vs 61±10 /min), beating rate (81±4 vs 77±7 /min), contraction velocity (9.2±1.9 vs 6.7±1.9 um/sec) and relaxation velocity (7.8±1.5 vs 3.3±0.8 um/sec). On the other hand, addition of Isoproterenol at 100 nM induced significant increase in peak Ca2+ transient (80±4.1 vs 96±8.0 /min), and beating rate (81±4.0 vs 115±11 /min), but failed to induce significant increase in contraction velocity (9.2±1.9 vs 11.4±1.4 um/sec) or relaxation velocity (7.8±1.5 vs 11±0.6 um/sec). Conclusions: The 3D-hiPSC-CMs exhibited doxorubicin-sensitive cytotoxicity and hERG channel blocker/isoproterenol-sensitive electrical activity in vitro, indicating its usefulness for drug-induced cardiotoxicity assay or drug screening system for drug discovery.
Abstract 13475: Acute Hemodynamic Effects of Large Capacity Intra-aortic Balloon Counterpulsation Pumps in Patients With Advanced Heart Failure
Authors: Lyanne Buiten, Vikram Paruchuri, Kevin Morine, Ryan O'Kelly, Duc Thinh Pham, Michael Kiernan, Jeffrey Shih, Carey Kimmelstiel, David DeNofrio, Richard H Karas, Navin K Kapur
Journal: Circulation (2015)

Over 40,000 intra-aortic balloon counterpulsation pumps (IABPs) are implanted in the United States annually. We explored the hemodynamic effect of large capacity (50cc) IABPs in patients with advanced heart failure. Methods: We conducted a prospective, observational study in 10 consecutive patients with Stage D, NYHA Class 3 or 4, non-ischemic heart failure referred for non-emergent IABP placement. Left ventricular (LV) hemodynamics were recorded for 10 minutes using a conductance catheter (CD Leycom; Figure) before and after activation of a 50cc IABP (Maquet Inc). Next, the 50cc IABP was halted for 10 minutes and a 10cc gas-extension tube inserted into the driveline to reduce the displacement volume to 40cc. LV hemodynamics were again recorded for 10 minutes before and after 40cc-IABP activation. Results: Mean age of the study population was 58±14 with an LV ejection fraction of 15±8%. The 50cc IABP reduced LV stroke work (LVSW: 1666±760 vs 1260±774 mmHg x mL, p&lt;0.01), end-systolic pressure (LVESP: 89±24 vs 75±23 mmHg, p&lt;0.05), and dP/dt max (868±225 vs 744±220 mmHg/sec, p&lt;0.01). The IABP with 40cc of volume displacement reduced LVSW (1717±814 vs 1424±703, p&lt;0.05), LVESP (94±19 vs 84±20, p&lt;0.05), and dP/dt max (890±171 vs 810±179, p&lt;0.01). Both 50cc and 40cc settings increased aortic diastolic pressures and reduced systolic pressures to similar degrees. Neither 50cc nor 40cc of volume displacement altered arterial elastance, LV volumes, or end-diastolic pressures (Figure). No hemodynamic differences between 50cc and 40cc of volume displacement were observed. Conclusions: This is the first study of large capacity IABPs using conductance catheters in patients with advanced heart failure. Both 50cc and 40cc volume displacement balloons reduced LV stroke work primarily by reducing LV end-systolic pressure with minimal effect on LV volumes. The clinical utility of IABPs in heart failure requires further study.
Abstract 13731: Activation of Focal Adhesion Kinase Leads to the Development and Progression of Abdominal Aortic Aneurysm in Mice
Authors: Takasuke Harada, Koichi Yoshimura, Osamu Yamashita, Koshiro Ueda, Noriyasu Morikage, Kimikazu Hamano
Journal: Circulation (2015)

Introduction: Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammation, which contributes to the pathological remodeling of extracellular matrix. Focal adhesion kinase (FAK) is involved in the interactions between cells and extracellular matrix, and has been suggested to regulate the remodeling of extracellular matrix. Hypothesis: We assessed the hypothesis that FAK plays a pivotal role in the development of AAA. Methods and Results: Aortic wall specimens were obtained from patients that underwent aortic surgery (AAA; n=25, non-AAA; n=8). Levels of activated FAK were significantly increased in AAA walls compared with non-AAA walls (2.8 ± 2.3 fold, p&lt;0.05). Activated FAK was localized to macrophages in the outer media and adventitia of AAA walls. We performed a comprehensive analysis of proteins secreted from mouse macrophages in vitro. The FAK inhibitor PF573228 significantly reduced the secretion of monocyte chemoattractant protein-1 and matrix metalloproteinase-9 in macrophages after stimulation with tumor necrosis factor-alpha. Further, we created AAA in C57BL/6 male mice by periaortic application of calcium chloride to investigate the role of FAK activation in vivo. From just after application of calcium chloride, mice were treated daily with PF573228 or vehicle for 6 weeks. Treatment of mice with PF573228 significantly prevented the increase in aortic diameter (PF573228; 0.84 ± 0.08 mm, vehicle; 1.19 ± 0.18 mm, p&lt;0.01). Treatment with PF573228 also reduced inflammatory cell infiltration and disruption of the elastic lamellae. In an additional experiment, PF573228 or vehicle was administered daily from weeks 3 to 6 after application of calcium chloride. Interestingly, delayed treatment with PF573228 significantly inhibited the progression of aneurysmal dilatation (PF573228; 0.88 ± 0.18 mm, vehicle; 1.25 ± 0.27 mm, p&lt;0.05). Conclusions: Our results indicate a critical role for FAK activation in the development and progression of AAA in vivo, indicating that FAK represents a novel therapeutic target for preventing and treating AAA.
Abstract 13428: Unveiling the Predictive Mechanisms of Care-seeking Delay in Patients With Acute Myocardial Infarction
Authors: Polly W. C. Li, Doris S. F. Yu
Journal: Circulation (2015)

Introduction: Despite decades of research has been conducted to examine the phenomenon of care-seeking delay in patients with acute myocardial infarction (AMI), such delay remains the most significant limiting factor for effective disease management. Objectives: This study aimed to develop and test an integrative theoretical model to unveil the predictive mechanism for explaining the care-seeking behaviors of patients who experiencing an attack of AMI. Methods: Based on several major theories which explain the illness behaviors of patients with chronic diseases and the research evidence on the care-seeking behaviors of AMI patients, we hypothesized that AMI patients’ care-seeking decision was determined by two sequential perceptual-cognitive processes and the immediate context of symptom occurrence. A total of 301 patients with a recent AMI were recruited from the cardiac units of three regional hospitals in Hong Kong. Structural equation modeling was used to test the validity of the hypothesized model. Results: The results indicated the decision-making process of AMI patients was driven by two sequential perceptual-cognitive processes, by which a successful action relied on whether the patients could correctly attribute the symptoms to AMI. Such correct symptom attribution depended upon whether they were aware of their own susceptibility to this condition and had a good understanding about the nature of the disease manifestation. A perception of severe illness consequences and the associated negative emotional arousal motivated patients to seek care. The immediate context in which the symptoms occurred also played a role in influencing their decision making, with the favorable roles of lower level of perceived barriers to seek care and positive cues from others in advising care-seeking. This model explained 46% of the variance of care-seeking behaviors with a good data-model fit (χ2 = 38.48, df=30, p=0.72; RMSEA=0.03, NFI=0.96, NNFI=0.98 and CFI=0.99). Conclusions: The integrative theoretical model is valid to explain the care-seeking decisions in AMI patients. This model provides important insights to inform the development of innovative empowerment strategies to enhance appropriate care-seeking decisions and behaviors among AMI patients.