tbuckley/cabot-search huggingface dataset:
Abstract 18508: Exposure of Adipocytes to High Mobility Group Box 1 Impairs Insulin Signaling via RAGE, While Stimulating Monocyte Recruitment Through TLR2
Authors: Yan Chen, Guangping Li, Yanxia Liu, Kevin Jon Williams, Ming-Lin Liu
Journal: Circulation (2013)

Background: Smokers show increased prevalence of insulin resistance for glucose and type 2 diabetes mellitus (T2DM). The underlying mechanisms, however, remain poorly understood. Tobacco smoke exposure increases tissue expression of high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) that activates innate immunity. We recently reported that exposure of human macrophages to tobacco smoke extract (TSE) provokes the release of HMGB1 in two forms: as a soluble molecule and carried on membrane microvesicles (MV). Both soluble recombinant HMGB1 (rHMGB1) and MV-associated HMGB1 on TSE-induced MVs (TSE-MVs) mediate crucial crosstalk with adipocytes by impairing insulin signaling and by recruiting monocytes to the adipocytes - GOAL- To identify the receptors on adipocytes that mediate the effects of HMGB1 on insulin signaling and monocyte recruitment. Methods: Cultured 3T3-L1 adipocytes were incubated for 24h with rHMGB1 or TSE-MVs, in the absence or presence of neutralizing antibodies against different receptors, followed by assays of signaling responses to insulin and chemoattraction of monocytes across a Boyden chamber. Results: Exposure of adipocytes to rHMGB1 or TSE-MVs impaired insulin-induced phosphorylations of IRS1 (Tyr612) and AKT (Ser473) and induced MCP1 secretion and hence monocyte transmigration and adherence to the cultured adipocytes. Neutralizing antibodies against RAGE, but not TLR2, improved insulin signaling in adipocytes exposed to rHMGB1 or TSE-MVs. In contrast, neutralizing antibodies against TLR2, but not RAGE, attenuated the induction of MCP1 secretion, and hence inhibited monocyte transmigration and adherence to cultured adipocytes exposed to rHMGB1 or TSE-MV. Conclusion: Our results indicate that soluble and MV-associated HMGB1 that is released from macrophages exposed to tobacco smoke mediates harmful macrophage-adipocyte crosstalk through two pathways: via adipocyte RAGE to impair insulin signaling, and via adipocyte TLR2 to induce MCP1 secretion and monocyte recruitment. These pathways may contribute to insulin resistance for glucose and the development of T2DM in individuals exposed to tobacco smoke.
Abstract 12188: Combined Effect of BMI and Renal Function on Long-term Clinical Outcomes in the Elderly Following Percutaneous Coronary Intervention
Authors: Ryo Naito, Katsumi Miyauchi, Jun Shitara, Hirohisa Endo, Hideki Wada, Shinichiro Doi, Hirokazu Konishi, Shuta Tsuboi, Manabu Ogita, Tomotaka Dohi, Takatoshi Kasai, Hiroshi Tamura, Shinya Okazaki, Kikuo Isoda, Hiroyuki Daida
Journal: Circulation (2015)

Introduction: Accompanied by aging society, percutaneous coronary intervention (PCI) has been widely performed in the elderly for the past few decades. However, a paucity of data examining clinical features and outcomes is available. Previously, low body mass index (BMI) and renal insufficiency were demonstrated to be negative predictors in patients with coronary artery disease. However, the effect of BMI and renal insufficiency on clinical outcome in elderly following PCI was not fully examined. Methods: We analyzed data of patients with the age of 70 to 85 following PCI in Juntendo University (Tokyo, Japan) from 1985 to 2010. Cox regression analysis was performed to assess an effect of combination with BMI less than 22 and eGFR less than 60 on all-cause mortality that was evaluated at 3-year after the index PCI. Results: Of 3824 patients, 1019 patients with the age of between 70 and 85 were examined. Mean age, BMI and eGFR were 75.2, 23.3 and 59.6, respectively. The population was divided into 3 groups according to the value of BMI and eGFR (BMI &lt; 22 and eGFR &lt; 60; high risk, BMI &lt; 22 or eGFR &lt; 60; intermediate risk, BMI ≥ 22 and eGFR ≥ 60; low risk). The higher incidence of all-cause mortality was observed in accordance with the greater risk determined by BMI and eGFR (P for trend &lt; 0.0001) (Figure 1). Kaplan-Meier estimation for all-cause mortality was significantly different between the three groups (Figure 2). In multivariable Cox regression analysis including traditional coronary risk factors, combined effect of BMI and eGFR was associated with all-cause mortality. Conclusions: Combination of BMI and eGFR was independently associated with all-cause mortality in the elderly following PCI.
Abstract 18607: High-Risk, Multi-Vessel Coronary Intervention Guided by Viability-Imaging and Supported by Awake-ECMO in Patients With Severe Ischemic Cardiomyopathy is Feasible, Safe, and Efficacious
Authors: Jörn Tongers, Christian KÜhn, Georg Berding, Frank Bengel, Holger Ahrens, Philipp Röntgen, Katharina Hupa, Christian Hagl, Axel Haverich, Johann Bauersachs, Bernhard Schieffer
Journal: Circulation (2013)

Background: The burden of end-stage coronary artery disease is rising and its care is complicated by cardiac failure and hospitalization. Recruitment of ischemic but viable myocardium is warranted to balance risk and benefit. Mechanical support enables high-risk coronary interventions despite severe LV-dysfunction. We aimed to develop a therapeutic algorithm of viability guided, awake-ECMO supported revascularization to stabilize therapy-refractory patients. Methods/Results: In this single-center study, consecutive patients (n=5, 61±9 yrs, all male) were prospectively enrolled (baseline: EF/echo study 15±4%; EF/SPECT-CT 17±5%). Myocardial perfusion SPECT-CT and viability 18-fluordesoxy-glucose (FDG)-PET imaging was performed. Veno-arterial ECMO (rate 3050±495 rpm, flow 2.8±1.0 l/min) was inserted in awake patients. Targeted by viability pattern, complex interventional revascularization was performed (2.8±1.1 vessels/patient, 3.0±1.5 stents/patient) without complications. Because no procedure/ECMO-related complications occurred, patients were discharged 5-7 days after PCI. During follow-up cardiac function improved significantly (ΔBNP: -42±15 %, p=ns; EF/echo: follow-up 26±7 %, ΔEF +11±7% vs. baseline, p&lt;0.05; EF/SPECT-CT 29±7%, ΔEF +11±6% vs. baseline, p&lt;0.05). This observation was associated with a clinical improvement (NYHA: 2.2±0.8; 6-minute walk: 242±76m; workload: max. 69±24W, VO 2 max. 9±2 ml/(min*kg), O 2 -pulse 8±2 ml/beat). Reflecting the recruitment of hibernating myocardium, perfusion defect score (SRS) was 27±15, LV-perfusion/metabolism mismatch 37±15%, and extent of scar 20±25%. Following revascularization, the perfusion defect score decreased (SRS: follow-up 21±14, p&lt;0.05); 50 of 85 myocardial segments showed significant improvement. All patient reported freedom from acute events for 172±61 days. Conclusion: We developed a novel algorithm of high-risk, multi-vessel coronary intervention guided by perfusion/viability-imaging and supported by transient awake-ECMO in fragile patients. This interdisciplinary strategy was safe, feasible, and efficacious in recruiting hibernating myocardium, and improving formerly unstable patients.
Abstract 18668: Is Functional Capacity a Reliable Predictor in Pre-Operative Cardiac Risk Stratification?
Authors: Vijaiganesh Nagarajan, Likhitesh Jaikumar, Meghana Halkar, Prashant Sharma, Anbazhagan Prabhakaran, Roop Kaw
Journal: Circulation (2013)

Introduction: Functional capacity has been used both in guidelines and clinical practice as an important predictor of adverse events in pre-operative cardiac risk stratification. It is measured in metabolic equivalents (METs). Current guidelines advise that patients can proceed with surgery if the functional capacity is more than 4 METs with no further investigations. But it is unclear whether a history of good functional capacity is reliable predictor. Methods: In this retrospective study, we reviewed 614 patients who were evaluated in our pre-operative clinic (IMPACT clinic) and had stress test within 90 days of evaluation. Functional capacity in METs and stress test results were obtained from electronic records. Patients have been divided into ‘good’ and ‘poor’ functional capacity (FC) groups based on patients’ capacity to do more than 4 METs. Revised cardiac risk index (RCRI) was calculated using clinical risk factors. Patients were divided into risk groups based on RCRI. We used chi-square test to compare functional capacity and stress test results. Results: 84% of patients underwent intermediate risk surgery. 82% of patients had functional capacity of more than 4 METS. 24.8% of patients with ‘poor FC’ had reversible ischemia in stress test, but 14.3% with ‘good FC’ had reversible ischemia as well (p=0.023). When patients with intermediate (1-2 risk factors) and high risk groups (≥ 3 risk factors) are considered, reversible ischemia was present in 12.9% and 22.5% of patients respectively even if they had good functional capacity (&gt; 4 METs). This shows very high number of patients with good functional capacity may have reversible ischemia. Conclusion: Functional capacity by history may not be a reliable predictor in pre-operative cardiac risk assessment as lot of patients may have undiagnosed cardiac ischemia. This may be more relevant in patients with multiple clinical risk factors. Further studies are warranted before final conclusions can be made.
Abstract 183: Appropriate Prolongation of Therapeutic Hypothermia Reduces Myocardial Damage After Prolong Cardiac Arrest
Authors: Min-Shan Tsai, Chien-Hua Huang, Chia-Ying Tsai, Hsaio-Ju Cheng, Wei-Tien Chang, Wen-Jone Chen
Journal: Circulation (2013)

Background: Therapeutic hypothermia improves myocardial dysfunction and survival in cardiac arrest survivors. However, whether the duration of hypothermia should be prolonged in according to the duration of cardiac arrest to mitigate excess myocardial damage has not been clarified. Hypothesis: Appropriate prolongation of therapeutic hypothermia can mitigates excess myocardial damage after prolong cardiac arrest. Methods: The animals were equally randomized to NormoT(normothermia), 5H1, 5H2, 7H1, 7H2 and 7H4 groups. VF was induced and untreated for 5 minutes (NormoT, 5H1, 5H2) or 7 minutes (7H1, 7H2, 7H4), followed by 1 minutes of CPR, and then one electric shock of 5 J. Therapeutic hypothermia was initiated at simultaneously at the start of CPR with intravenous administration of 4°C saline and fan. After ROSC, hypothermia was maintained for 1hour (5H1, 7H1), 2 hours (5H2, 7H2) and 4 hours (7H4), respectively. Results: The plasma Troponin-I and FABP concentration at 2 nd hour following ROSC was significantly lower in the 5H2 and 7H4 groups than in the other groups (except the 7H2 group) (Figure). At 4 th hour after ROSC, The 5H2 and 7H4 groups showed less myocytolysis and apoptosis (Tunel staining) in the myocardium when compared with the other groups. Six out of 12 animals in both the 5H2 and 7H4 groups survived 72 hours after ROSC, whereas only 3 out of 12 animals in the 5H1 and 7H2 groups, and only 1 out of 12 animals in the 7H1 and NormoT groups. At the 72 nd hour, the 5H2 and 7H4 groups showed less myocardial fibrosis when compared with the groups. Conclusion: Appropriate prolongation of therapeutic hypothermia can mitigates excess myocardial damage in prolong cardiac arrest.
Abstract 12060: The Extent of Myocardial Injury as a New Criterion
Authors: Kaixi Ren, Jon Lomasney, Rishi K Arora, Gangjian Qin, Steven E Johnson, Mazen Albaghadai, Chad R Haney, Emily A Waters, Xingyao He, Daocheng Zhu, Jeffrey J Goldberger, Ming Zhao
Journal: Circulation (2016)

Introduction: In acute coronary syndromes (ACS), infarct size is a primary criterion for gauging the pathological state of the post-ischemic heart and subsequent prognosis. However, early adverse outcomes may be noted even with small to moderate infarcts, suggesting that there are other contributing factors to the negative prognosis. Hypothesis: We hypothesize that the extent of injured myocardium, which may be significantly larger than the infarct zone, can be noninvasively assessed using membrane phospholipid reorganization as a molecular marker. Methods: The studies were conducted in a rat model of preconditioned myocardial ischemia and reperfusion. The area of injured myocardium was positively delineated by the uptake of 99m Tc-duramycin, which detects phosphatidylethanolamine as a marker for cellular injury. Quantitative ex vivo studies (n = 8) were first conducted to determine the relationship among the area-at-risk, infarct size and myocardial injury, followed by in vivo radionuclide imaging studies (n = 6), with cross-validation using histopathology. Results: We demonstrated 1) that the extent of myocardial injury can be detected noninvasively; 2) the size of injured myocardium can extend substantially outside the infarct zone (Figure 1); and 3) the injured-but-noninfarct tissue, which was missed by conventional infarct measurement, contained significant pathological changes, including apoptosis in vulnerable cells, inflammation and denervation. Conclusions: “Global myocardial injury, or GMI” is a novel clinical concept which defines the full extent of myocardium that sustained injury both in and outside the infarct zone. Our data demonstrate the feasibility to conspicuously delineate this region of cardiac injury, thus providing an opportunity to better characterize its roles in cardiac impairment and prognosis following ACS.
Abstract 12087: KCa3.1 Channels Support Resting Potential and Proliferative Function During Store-Operated Ca <sup>2+</sup> -Entry in c-kit <sup>+</sup> Endogenous Cardiac Stem Cells
Authors: Patrick Vigneault, Patrice Naud, Darryl R Davis, Stanley Nattel
Journal: Circulation (2015)

Introduction: Adult hearts contain c-kit + endogenous cardiac stem cells (eCSCs). Cultured eCSCs express a wide range of ion channels, but cell culture is known to affect phenotype. Here we defined ion currents in freshly isolated c-kit + eCSCs and their potential functional role. Methods: eCSCs isolated from healthy and heart failure (HF, ventricular tachypacing X 2 wks) dog hearts were magnetically purified with c-kit antibodies. Ion currents and membrane potential were recorded with patch clamp. Results: Contrary to cultured c-kit + eCSCs, ion currents were barely detectable with Ca 2+ i buffered (Fig A). Free Ca 2+ i activated prominent I KCa3.1 (TRAM34 sensitive, Fig B) in 82% of cells. I KCa3.1 was reduced in eCSCs isolated from HF dogs (Fig C), along with corresponding KCNN4 mRNA (Fig D). Under perforated patch to maintain spontaneous physiological [Ca 2+ ] i , eCSCs had a membrane potential (V mem ) of -73±10 mV. Ca 2+ i depletion with nominally 0 mM [Ca 2+ ] o strongly depolarized the membrane. After passive Ca 2+ i depletion, store-operated channel (SOC) mediated Ca 2+ entry (SOCE) caused a robust V mem hyperpolarization (from -21±4 to -79±7 mV, p&lt;0.001). The SOCE effect on V mem was substantially reduced by both 2-APB (SOC inhibitor) and TRAM34 (Fig E). Inhibiting KCa3.1 (TRAM34, 0.1 μM) or SOCs (2-APB, 50 μM) in culture decreased c-kit + eCSCs proliferation by 21% (p&lt;0.05) and 55% (p&lt;0.001) respectively. Conclusions: In contrast to cultured eCSCs, voltage-dependent ion currents are virtually absent from freshly isolated c-kit + eCSCs. I KCa3.1 is prominent and maintains V mem in the face of substantial Ca 2+ entry from SOCs. This Ca 2+ entry would normally depolarize the cell, reduce the gradient for Ca 2+ entry and turn off the Ca 2+ signal. We hypothesize that the Ca 2+ -mediated KCa3.1 K + -conductance increase is necessary to maintain V mem in the face of the Ca 2+ entry that activates eCSC proliferation, and that KCa3.1 channels may therefore play an important role in eCSC function.
Abstract 12085: In Vivo Performance of a Novel Permanently Implanted Left Atrial Pressure Monitoring System
Authors: Leor Perl, David Meerkin, Yair Levi, Dedi Erdheim, Oren Goldstein, William T Abraham
Journal: Circulation (2016)

Introduction: Heart failure (HF) is a prevalent and burdensome chronic disease, with a characteristic high rate of hospital admissions. Left ventricular filling pressure is the earliest, most objective sign of impending HF exacerbation. Previous implantable devices, positioned in the pulmonary artery, have shown good safety and clinical efficacy. The Vectorious Left Atrial Pressure (V-LAP) monitoring system is a robust, miniature, battery-less sensor. It uses advanced application-specific integrated circuit (ASIC)-based technologies, enabling left-sided daily pressure readings with a wirelessly connected external unit. Our aim was to examine the safety and the functionality of the device in animal subjects. Methods: Using a dedicated repositionable delivery system, through a standard transseptal approach, adult sheep were implanted with a V-LAP device. Aspirin (325mg) and clopidogrel (750mg) were given prior to the procedure, the latter continued (225mg daily) during follow-up. An external wearable belt was used to remotely power the implant, interrogate the bi-directional digital data from the sensor, and transmit detailed wireless left atrial pressure waveforms to a web-based database. Results: The device was implanted in 10 animals, and was able to communicate well with the external belt, at depths of up to 30 cm in the thorax, for periods of up to 100 days, generating accurate and precise waveforms, with high temporal resolution. No peri-implant thrombotic events were observed (figure). There were no device-related complications. Conclusions: Using an advanced, left sided, intracardiac monitoring system, safety and feasibility were demonstrated with good functionality in animals, as evidenced by high resolution pressure wave outputs. Data in human subjects will determine whether the V-LAP is a safe and an effective monitoring system of hemodynamic data in heart failure patients, thus reducing readmission, morbidity and mortality rates.
Abstract 18371: Regression of LV Mass After Transcatheter or Surgical Aortic Valve Replacement for Aortic Stenosis in the PARTNER I Trial
Authors: William Stewart, Brian R Lindman, Philippe Pibarot, Neil J Weissman, Rebecca T Hahn, Thomas C McAndrew, Steven A Goldstein, David S Rubenson, Martin B Leon, Susheel Kodali, Michael Mack, Lars Svensson, Vinod H Thourani, Howard C Herrmann, Pamela S Douglas
Journal: Circulation (2013)

Background: Regression of left ventricular hypertrophy (LVH) after aortic valve replacement (AVR) for aortic stenosis is a favorable response to ventricular unloading, but has not been compared in transcatheter (TAVR) vs. surgical AVR (SAVR) vs. medical management (MM). Methods: The PARTNER I trial randomized high risk patients to SAVR vs. TAVR (Cohort A), and inoperable patients to MM vs. TAVR (Cohort B). Patients with echocardiograms at all time points (baseline, 30, 180, and 365 days) after TAVR (A+B; n=197), SAVR (n=96), or MM (n=33) were stratified by gender-specific tertiles of baseline LV mass index (LVMi, g/m 2 ) and change in LVMi over time was evaluated. We used ASE criteria (LVMi ≥122 g/m 2 for women, ≥149 g/m 2 for men) to define severe LVH. Results: Compared to baseline, at 1 year LVMi decreased from 151±40 to 130±33 g/m 2 in TAVR (p&lt;0.001), 155±48 to 131±39 g/m 2 in SAVR (p&lt;0.001), but not in MM (146±40 to 139±33 g/m 2 , p=ns). After TAVR and SAVR, regression of LVMi was significant in the middle and highest tertiles of LVMi (all p&lt;0.005), with similar regression in TAVR as SAVR , mostly occurring by 180 days (Figure). At baseline, 56% of men and 70% of women in the AVR groups had severe LVH; compared to 33% of men and 39% of women at 1 year. MM patients showed a trend toward regression in the highest tertile (p=0.07), but not in the middle or lowest tertile. In the lowest tertile of LVMi, no change in LVMi occurred in either AVR group. Change in LVMi (baseline to 1 year) correlated to change in transvalvular mean gradient (baseline to 30 days) in TAVR (r=0.18, p=0.01), but not in SAVR or MM; there was no correlation with change in valve area in any group. Conclusions: LV mass regression was similar after TAVR or SAVR when baseline LVH was more marked (middle and highest tertiles), although one-third had residual severe LVH at 1 year. LV mass regression shows the end-organ correlates of hemodynamic improvement after both TAVR and SAVR, and requires further study.
Abstract 18388: Novel Study of the Dynamic Changes in Mitral Valve Annular and Leaflet Parameters Under Varying Loading Conditions: A Three-Dimensional Echocardiographic Study
Authors: Mohammed S AlHabdan, Timothy Colen, Berthold Klas, Edythe Tham, Lisa Hornberger, Jeffrey Smallhorn, Nee Scze Khoo
Journal: Circulation (2013)

Background: The impact of changing loading conditions on mitral valve (MV) coaptation is controversial. Previous studies assessed the MV at mid or end-systole only, hence MV dynamic changes throughout systole are poorly understood. We used three-dimensional echocardiography (3DE) to explore dynamic changes in MV annular and leaflet parameters during loading stress and inotropy in an animal model. Methods: In open chest model, 8 pigs and 4 dogs were imaged epicardially. 3DE was performed at baseline, with dobutamine infusion, volume infusion and aortic constriction, with a return to baseline hemodynamics between each intervention. The 3DE datasets were analyzed offline using TomTec semi automated MV software. Leaflet (AL) and annular area (AA) were reported as % change from baseline in 5 systolic intervals (1-5; each representing 20% of systole). ANOVA was performed between each intervention and baseline, at the 5 intervals, with Dunnett’s correction. Results: At baseline, MV peak % change of AL and AA occurred during the 4th and 5th intervals respectively. Compared to baseline, dobutamine infusion % change AL was reduced (-5.9% ± 3.8 vs -9.4% ± 6.1, p&lt;0.01) in the 3rd interval, whilst % change AA was reduced throughout systole. With volume loading, % change AL and AA were significantly reduced during intervals 2 to 5. In contrast, with aortic constriction % change AL (-5.9% ± 3.8 vs -2.4% ± 4.8, p&lt;0.05) and %change AA (-1.6% ± 3.8 vs 1.5% ± 5.7, p&lt;0.05) were increased at the 3rd interval (see Figure). Conclusion: Peak MV annular contraction and leaflet apposition occurs in late systole. MV leaflet coaptation area improves in response to increased contractility and pre-load by increasing annular contraction and reducing unopposed leaflet surface. In contrast, increased afterload has the opposite effect on annular and leaflet size, potentially worsening coaptation. The timing of peak annular contraction and leaflet apposition has implications for the design of future MV studies.