tbuckley/cabot-search huggingface dataset:
Abstract 19286: Rhythm Results Following Surgical Ablation- How Should it Be Reported?
Authors: Niv Ad, Sharon Hunt, Linda Henry
Journal: Circulation (2012)

Background: The improved understanding of the pathophysiology of atrial fibrillation (AF) and the non-pharmacological approaches to treat AF provided higher success. There is a lack of uniformity and agreement in the best way to report rhythm outcomes. The study purpose is to explore the impact of longitudinal follow up on understanding the ongoing atrial arrhythmia burden compared with the static time points recommended by the Heart Rhythm Society (HRS) guidelines Methods: All patients undergoing AF surgical ablation at our institution (n=690) are followed prospectively thru our AF registry. Rhythm verified by EKG and 24 hour holter. Patients selected for this study had to be at risk for failure at least 2 years following the procedure (n=464). The HRS definition of failure determined rhythm. Rhythm is reported per HRS guidelines/ “longitudinal rate (LR)” defined as the need for additional interventions to keep patients in SR (ablations and cardioversions). Results: Per HRS guidelines, patients in SR at discharge was 388/464 (84%) ; 6 months 359/400 (90%) with 281/370 (76%) off antiarrhythmic drugs (AAD) ; 12 months 356/397 (90%) with 312/386 (81%) off AAD, 24 months 268/307 (87%) with 231/301 (77%) off AAD. Success per LR at 6 months 315/400 (79%), 12 months 299/397 (75%) patients and 24 months 217/301 (71%). The freedom from AF and interventions was lower at each period compared to the HRS rate. Of the patients off AAD, 12% (n=26) required an intervention suggesting that only pharmacological methods were required to maintain SR not captured per LR (Figure). Conclusion: Surgical ablation for AF results in acceptable rhythm outcomes over time. Reporting of rhythm status only at static time points does not provide the continuous burden of atrial arrhythmia and need for follow-up pharmacological and non-pharmacological interventions. We recommend patients should be followed using the two methodologies to improve understanding of the rhythm results following ablation for AF.
Abstract 19684: The Deficiency of β-Arrestin 2 Attenuates Abdominal Aortic Aneurysm Formation in Mice
Authors: Darshini Trivedi, Charles Loftin, Robert Langenbach
Journal: Circulation (2012)

β-arrestin 2 (βarr2 ) is a multifunctional scaffolding protein that participates in the regulation of numerous signaling pathways by coupling with G-protein coupled receptors, such as the angiotensin II (AngII) receptor AT1a. The aim of the current study was to examine the role βarr2 in AngII-induced abdominal aortic aneurysm (AAA) formation in mice. Male Apoe-/-/βarr2+/+ and Apoe-/-/βarr2-/- mice were infused with AngII (1000 ng/kg/day) or saline (vehicle) for 28 days and analyzed for AAA incidence and severity. AngII induced a 61.8% incidence (21 of 34) of AAAs in Apoe-/-/βarr2+/+ mice, as compared to 9.5% (2 of 21) in Apoe-/-/βarr2-/- mice, indicating the importance of βarr2 in AAA formation. To investigate the mechanisms by which βarr2 contributes to AAAs, we determined the effect of βarr2 deficiency on the expression of the inflammatory mediator cyclooxygenase 2 (COX-2) that we have previously shown to be a key contributor to AngII-induced AAA pathology. AngII induced abundant COX-2 expression in the abdominal aortas of Apoe-/-/βarr2+/+ mice, whereas COX-2 expression was significantly attenuated in the aortas of Apoe-/-/βarr2-/- mice (P&lt;0.05), indicating that βarr2 is involved in the induction of COX-2 in response to AngII. An extensively studied pathway triggered by the βarr2-AT1a complex is ERK1/2 activation, and pERK1/2-mediated signaling has been independently shown to be important in AAA development. Indeed, activated ERK1/2 was observed in the abdominal aortas of Apoe-/-/βarr2+/+ mice, but not in the abdominal aortas of Apoe-/-/βarr2-/- mice. To determine if ERK1/2 activation was a mechanism for βarr2-AT1a-induced COX-2 expression, Apoe-/-/βarr2+/+ mice were treated with the ERK1/2 inhibitor, CI1040 (100mg/kg), together with AngII and examined for COX-2 expression. ERK1/2 inhibition markedly decreased AngII-induced COX-2 expression in the abdominal aortas of Apoe-/-/βarr2+/+ mice (P&lt;0.05) to a level that was equivalent to the COX-2 expression observed in Apoe-/-/βarr2-/- mice. Thus, βarr2 may contribute to AAA formation by activating the ERK1/2-COX-2 pathway. These studies have important implications for the design of therapeutics that target βarr2-mediated signaling for the treatment of AAAs.
Abstract 8563: Chronic Administration of Oral Vasopressin Type 2 Receptor Blocker, Tolvaptan Exerts Both Myocardial And Renal Protective Effects in Rats with Hypertensive Heart Failure
Authors: Hanako Morooka, Yoshitaka Iwanaga, Toru Takase, Yasumitsu Akahoshi, Yodo Tamaki, Yoshimasa Nakano, Hiroyuki Fujiki, Shunichi Miyazaki
Journal: Circulation (2011)

Background: During the diuretic therapy in heart failure (HF), the greatest concerns include additional activation of the neurohormonal cascade and renal injury. Although the recent clinical trials have shown the efficacy of the oral vasopressin (AVP) type 2 receptors (V2R) blocker, tolvaptan, the long-term effects on the myocardium and kidney in HF patients are not clear. Therefore, we tested chronic tolvaptan administration in rat hypertensive HF model and examined the chronic effects both on myocardium and kidney. Methods and Results: Dahl salt-sensitive hypertensive rats were given 8% high salt diet from 6 weeks of age. Not only circulating AVP level, but also myocardial AVP and V1a receptor (V1aR) expressions, and renal V1aR, V2R and aquaporin 2 (AQP2) expressions were significantly activated during the transition to HF (18-21 weeks of age). They were chronically treated with tolvaptan (30mg/kg/day) (Tolv group: n=21) or vehicle (n=22) from the LV hypertrophic stage (11 weeks of age) until 21 weeks. Chronic tolvaptan treatment persistently increased urine volume (94% increase) and decreased urine osmolality (43% decrease). Although there was no difference in blood pressure between the two groups, the survival rate in Tolv group was improved at 21 weeks of age from 45.5% to 81.0% (log rank test: p&lt;0.01). At HF stage, LV fractional shortening was preserved (40.2% vs. 27.5%; p&lt;0.05) and lung congestion was suppressed in Tolv group. Serum AVP level and plasma renin activity were not changed and mRNA levels of ANP, endothelin-1 (ET-1), AVP and V1aR in LV were significantly decreased in Tolv group. In contrast, renal histopathologic damage (glomerulosclerosis and tubulointerstitial fibrosis) was ameliorated, and renal function (creatinine clearance and sodium excretion) was improved in Tolv group at HF stage. Concomitantly, not only activation of AQP2, but also those of V2R, V1aR and ET-1 in kidney were significantly suppressed (p &lt;0.05 in all). Conclusions: These results indicate chronic tolvaptan treatment has beneficial effects by preventing the progressions of both LV dysfunction and renal injury in hypertensive rats with HF. The underlying mechanism may be related to the prevention of local (myocardial and renal) neurohumoral activation.
Abstract 19334: Exposure to Diesel Exhaust Emissions Markedly Induce Systemic Lipid Peroxidation and the Development of Dysfunctional Prooxidative and Proinflammatory HDL
Authors: Fen Yin, Akeem Lawal, Jerry Ricks, Julie Richman, Tim Larson, Mohamad Navab, Michael Rosenfeld, Jesus Araujo
Journal: Circulation (2012)

Rationale: Exposure to ambient particulate matter is associated with increased cardiovascular ischemic events and enhanced atherosclerosis, likely due in part to the promotion of systemic pro-oxidant and pro-inflammatory effects. Objective: The purpose of this study was to test our hypothesis that air pollutants may induce oxidative modifications of plasma lipoproteins resulting in alteration of the anti-oxidant and anti-inflammatory properties of high-density lipoproteins (HDL). Methods and Results: We exposed ApoE-/- and C57BL/6 wild-type male mice to diesel exhaust (DE) emissions at 200-300 µg PM2.5/m3 for two weeks, filtered air (FA) for two weeks or DE for two weeks, followed by FA for one week (DE+FA). HDL anti-oxidant capacity was assessed by a DCF-based cell fluorescence assay that evaluate the ability of HDL to inhibit LDL oxidation, determined by the level of fluorescence intensity. In the ApoE-/- background, DE and DE+FA mice significantly impaired the HDL anti-oxidant capacity in comparison with FA mice (p&lt;0.001), as judged by almost a doubling in the level of DCF fluorescence and by a promotion rather than inhibition of oxidation. Decreased HDL anti-oxidant properties was accompanied by reduced anti-inflammatory capacity, as determined by a monocyte chemotaxis assay. The HDL anti-oxidant dysfunction correlated with decreased paraoxonase enzymatic activity, increased levels of plasma 8-isoprostanes, 12-HETE, and 13-HODE as well as liver malondialdehyde and 5-HETE levels (p&lt; 0.05), with subsequent up-regulation of hepatic anti-oxidant genes, activation of unfolded protein response and the 5-lipoxygenase pathway. Moreover, while DE led to enhanced lipid peroxidation in the bronchoalveolar lavage fluid of both ApoE-/- and C57BL/6J mice, there were no effects of DE exposure on systemic lipid peroxidation or HDL functionality in the latter. Conclusions: DE emissions induced systemic pro-oxidant effects that led to the development of dysfunctional HDL in hyperlipidemic ApoE-/- mice, which might be one of the mechanisms how air pollution contributes to enhanced atherosclerosis.
Abstract 19283: Low Density Lipoprotein Cholesterol is Associated with the Extent of Noncalcified and Soft Lipid Rich Coronary Plaque but Not Coronary Calcium in Apparently Healthy Individuals from High Risk Families
Authors: Brian G Kral, Lewis C Becker, Lisa R Yanek, Dhananjay Vaidya, Rehan Qayyum, Taryn F Moy, Elliot K Fishman, Diane M Becker
Journal: Circulation (2012)

Background: Low density lipoprotein cholesterol (LDL-C) is strongly associated with CAD events. Calcified coronary plaque (CCP) is a proxy of overall plaque burden but the relationship between LDL-C and CCP has been inconsistent. LDL-C likely plays a more putative role in the early stages of atherogenesis including the formation and progression of noncalcified coronary plaque (NCP), especially lipid rich plaque (LRP), than later processes of vascular remodeling with CCP. Thus, we examined the association of LDL-C levels with the extent and relative volumes of NCP in apparently healthy individuals from families with premature CAD. Methods: Participants in GeneSTAR (N=561; mean age 51±10 years; 58% female, 37% AA) were screened for CAD risk factors and for coronary plaque using 256 multidetector dual-source CT angiography. Segmental CCP volumes (mm3) were measured using standard techniques and volumes of NCP and LRP defined as &lt;30 HU were quantified (mm3) using an automated well-validated method. All plaque volumes were log transformed as log(plaque+0.05). Controlling for age, sex, and race, multivariate GEE regression analyses for the association of CAD risk factors, including LDL-C, hypertension, diabetes, and smoking, as well as statin medication use, were performed separately for transformed NCP, CCP, and LRP. Results: The prevalence of any coronary plaque was 45.6%. Multivariate regression demonstrated that LDL-C was significantly associated with the volume of NCP (p=0.02) and LRP (p=0.01) but not CCP (p=0.23). All other risk factors and statin use were significantly associated with all three plaque volumes. Additionally LDL-C was the only risk factor associated with the relative ratio of noncalcified to calcified plaque volume (p=0.02), consistent with a more putative role of LDL-C in earlier stages of plaque development and progression. Conclusion: This is the first study to show that LDL-C is more strongly associated with noncalcified and lipid-rich coronary plaque volumes than with the extent of coronary calcification in high-risk apparently healthy individuals. These findings suggest that early preventive therapies to lower LDL-C may have the greatest benefit prior to the detection of significant CCP.
Abstract 8768: Involvement of Rho-Kinase Activation in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stents in Patients with Coronary Artery Disease
Authors: Kentaro Aizawa, Satoshi Yasuda, Jun Takahashi, Toru Takii, Yoku Kikuchi, Ryuji Tsuburaya, Yoshitaka Ito, Kenta Ito, Masaharu Nakayama, Morihiko Takeda, Hiroaki Shimokawa
Journal: Circulation (2011)

Background: We have previously demonstrated that activation of Rho-kinase, the effector of the small GTP-binding protein Rho, plays a central role in the pathogenesis of coronary vasospasm in pigs and humans and coronary hyperconstricting responses following drug-eluting stent (DES) implantation in pigs. In this study, we further examined whether Rho-kinase activation is also involved in the DES-induced coronary hyperconstricting responses in humans. Methods: We examined 25 patients with coronary artery disease who underwent coronary intervention with either DES (n=16, sirolimus/paclitaxel 15/1, M/F 10/6, 69 ± 11[SD] years) or bare-metal stents (BMS, n=9, M/F 7/2, 70 ± 8 years). We examined coronary vasoconstricting responses to intracoronary (IC) acetylcholoine (ACh) before and after the intracoronary treatment with a Rho-kinase inhibitor, fasudil (300 μ g/min for 15 min). We evaluated coronary vasomotor responses by quantitative coronary angiography (QCA) and coronary vascular structure by optical coherence tomography (OCT). Results: QCA showed that the coronary vasoconstricing responses to ACh were significantly enhanced in the DES group compared with the BMS group at both the proximal (BMS -13.0 ± 10.7% vs. DES -24.7 ± 14.2[SD] %, P&lt;0.05) and the distal segments (BMS -24.4 ± 12.2%, DES -42.8 ± 14.8%, P&lt;0.01). Importantly, fasudil markedly attenuated the enhanced vasoconstricting responses to ACh in the DES group (proximal -10.2 ± 11.3%, distal -14.2 ± 10.2% vs. before fasudil, both P&lt;0.01). In contrast, coronary vasodilator responses to intracoronary isosorbide dinitrate were comparable between the 2 groups. Although OCT showed a variable degree of intimal thickening at the segments adjacent to DES, there was no significant correlation between intimal thickness and coronary vasoconstriction to ACh. Conclusion: These results indicate that Rho-kinase activation is substantially involved in the pathogenesis of the DES-induced coronary hyperconstricting responses in patients with CAD as well, suggesting the therapeutic importance of Rho-kinase pathway.
Abstract 19328: Postnatal Formation of Myocardial Laminar-Sheet Architecture in New Born Pig Hearts
Authors: Junjie Chen, Lei Zhang, Huiying Zhang, Gregory M Lanza, Samuel A Wickline
Journal: Circulation (2012)

Myocardial fiber and laminar sheet architecture is a critical determinant of coordinated cardiac contractile function. We hypothesized that myofiber and sheets may reorganize after birth to accommodate programmed perinatal adaptations of cardiac function. Isolated fixed pig hearts at postnatal day 1, day 5, day 14, and adulthood (n = 5 for each group) were acquired for diffusion-weighted magnetic resonance imaging to determine cardiomyocyte fiber angle and sheet structure in the left ventricular free wall using previously reported methods. Finally, hearts were prepared for histology analysis of sheet architecture. A progressive increase in left ventricular wall thickness occurred from day 1 (4.8±0.2 mm) to adulthood (22±4 mm, p &lt; 0.05). However, the transmural distribution of helix angle (fiber architecture) was comparable at all ages (p = N.S.). In contrast, fractional anisotropy decreased progressively from day 1 (0.71±0.05) to adulthood (0.28 ±0.29, p &lt; 0.05), which was caused by increased cross-fiber water diffusivity (0.25 ± 0.04 μm2/ms at day 1 vs. 0.55±0.05 μm2/ms at day 5, p &lt; 0.05). The expected laminar sheet cleavage (white spaces) was not detectable at day 1, but became visually appreciable after day 5 (Figure ). In summary, the helical myofiber architecture appeared well developed at birth but unchanged thereafter. However, the higher order laminar sheet architecture did not emerge until after birth. The postnatal formation of laminar sheets appears to play a critical role in physiological remodeling of new born hearts to accommodate the an abrupt increase of left ventricular workload after the closing of patent ductus arteriosus and foramen ovale, which bypassed the right ventricular output to systemic circulation in prenatal hearts. .
Abstract 19654: Absence of Cardiovascular Implantable Electronic Device Infection in Remote Implantations Demonstrated by Fluorine-18 Positron Emission Tomography
Authors: Hiroko Beck, Olurotimi Mesubi, Mark Smith, Anastasios Saliaris, Vincent See, Kelechi Ogu-Esuala, Vasken Dilsizian, Omar Shams, Steven Shorofsky, Timm Dickfeld
Journal: Circulation (2012)

Background: Cardiovascular implantable electronic device (CIED) infection can be very challenging and unnecessary device extraction can expose the patient to significant morbidity and mortality. Recent publications suggests that fluorine-18 ( 18 F-FDG) positron emission tomography (PET) has a high sensitivity and specificity to differentiate pocket and/or lead infections from non-infected devices older than 6 months. However, control groups were small (n≤10 patients) and the prevalence of increased 18 F-FDG uptake in not-infected CIED patients is unknown. Method: All patients with remote (&gt;6month) ICD implantation and no clinical/laboratory evidence of infection undergoing 18FDG-PET in preparation for VT ablation from 2006 to 2011 were identified in a single tertiary center. Semi-quantiative ssessment of 18 F-FDG uptake was assessed in 4 sites (generator pocked, innominate vein, superior vena cava (SVC), and intracardiac space (right atrium/ventricle). using a semi-quantitative score assessing .Uptake was categorized in none (score = 0), mild (≤thoracic background activity[t1] ; score = 1), moderate (&gt;thoracic background activity; score = 2), and severe hypermetabolism (very intense uptake; score = 3). Results: 65 contiguous patients were enrolled in this study. 18FDG PET signal uptake scores were 0 in 0%, 0%, 0%, 0% for generator pocket, innominate vein, SVC and intracardiac position, respectively. Resulting semiquantitative scores were 0.0±0.0 in (locations) and 0.1±0. Conclusion This as far as we know largest series on 18FDG PET scans in patients with remote device implantation demonstrates no incidence of increased tracer uptake in non-infected patients localized in ¼ This supports a potential use of 18 F-FDG PET/CT in differentiating patients with CIED infection from chronic implant changes, providing a new potentially new path in management of CIED infection.
Abstract 19323: Disruption of Adenylyl Cyclase Type 5, a Novel Target for Obesity, Diabetes and Diabetic Cardiomyopathy
Authors: David Ho, Lin Yan, Xin Zhao, Claudio Bravo, William Stanley, Dorothy E Vatner, Jeffrey Pessin, Stephen F Vatner
Journal: Circulation (2012)

We have previously reported that an adenylyl cyclase type 5 (AC5) deficient mouse model (AC5 knock out, KO) lives one-third longer than wild type (WT) mice. Despite greater daily food intake the AC5KO mice weigh less than WT mice and are protected against cardiac stress. In addition, the AC5KO mice have the same molecular signature of caloric restriction, the most common effective intervention to increase healthy longevity.. Since caloric restriction improves metabolic profiles and protects against insulin resistance, obesity and diabetes, we placed 6-8 week old male AC5KO mice and their corresponding wild type littermates (WTL) controls on a 35.5% high fat diet (HFD) for 100 days. At sacrifice, fat deposits were reduced 36% in AC5KO and cholesterol levels were reduced from 131±9.9 mg/dl to 105±3.1 mg/dl, p&lt;0.05. Indirect calorimetry demonstrated that the AC5KO mice had a 16.7% increase in oxygen consumption during the light cycle (p&lt;0.01) and 29.2% increase during the dark cycle (p&lt;0.01) compared to WTL on HFD, suggesting enhanced metabolic rate as the mechanism for decreased adiposity and body weight. AC5KO mice also displayed improved glucose tolerance with a 32% reduction in area under the curve concomitant with a 111% increase in whole body insulin sensitivity (insulin tolerance test). In parallel, conscious non-stressed euglycemic-hyperinsulinemic clamp studies confirmed the marked enhancement of glucose homeostasis and insulin sensitivity in the AC5KO mice. Moreover, WTL developed reduced cardiac function consistent with diabetic cardiomyopathy following high fat diet feeding (e.g., left ventricular (LV) ejection fraction fell from 71±2% to 53±2%) whereas AC5 KO mice had better preserved LV ejection fraction (61±3%). In addition, AC5 KO mice showed 33% decrease in cardiac fibrosis and 40% decrease in apoptosis compared to WTL on HFD. Thus, reduction of AC5 protects against obesity, diabetes and diabetic cardiomyopathy, suggesting that AC5 is a potential novel therapeutic target for the treatment of obesity, diabetes and associated cardiomyopathy.
Abstract 19295: Genetic Deletion of E2F1 Protects Myocardium from Ischemic Injury by Upregulating Angiogenic Growth Factors
Authors: Min Wu, Junlan Zhou, Min Cheng, Chan Boriboun, Dauren Biyashev, Hong Wang, Raj Kishore, Douglas Losordo, Gangjian Qin
Journal: Circulation (2012)

Background : The E2F family of transcription factors, with eight members identified, are involved in the regulation of a variety of cellular functions, including cell growth, differentiation, metabolism, and survival; however, the specific roles of individual members in the cardiovascular system have not been carefully characterized. Here, we investigated the potential role of E2F1 in cardiac neovascularization. Methods and Results : Myocardial infarction (MI) was induced in WT and E2F1 -/- mice. Compared to observations in WT mice, cardiac function, capillary density, and endothelial-cell (EC) proliferation were greater (P&lt;0.01), infarct sizes were smaller (P&lt;0.01), apoptotic ECs were less common (P&lt;0.01); border-zone levels of vascular endothelial-cell growth factor (VEGF) (P&lt;0.05) and placental growth factor (PlGF) (P&lt;0.01) were higher; and border-zone p53 levels were lower (P&lt;0.01); in E2F1 -/- mice. Blockade of VEGF receptor 2 (VEGFR2) signaling with the selective inhibitor SU5416 or with the VEGFR2-blocking antibody DC101 abolished the differences between E2F1 -/- mice and WT mice in cardiac function, infarct size, capillary density, EC proliferation, and EC apoptosis. Hypoxia-induced VEGF and PlGF upregulation was significantly greater in E2F1 -/- than in WT cardiac fibroblasts, and E2F1 overexpression suppressed PlGF upregulation in both WT and p53 -/- cells; however, VEGF upregulation was suppressed only in WT cells. E2F1 interacted with and stabilized p53 under hypoxic conditions, and both E2F1:p53 binding and the E2F1-induced suppression of VEGF promoter activity were absent in cells that expressed an N-terminally truncated E2F1 mutant. Conclusions : E2F1 limits cardiac neovascularization and functional recovery after MI by suppressing VEGF and PlGF upregulation through p53-dependent and -independent mechanisms, respectively.