tbuckley/cabot-search huggingface dataset:
Abstract 11016: Bag3 Regulates Contractility and Ca Homeostasis in Adult Mouse Ventricular Myocytes
Authors: Arthur M Feldman, JuFang Wang, Jianliang Song, Xue-Qian Zhang, Douglas D Tilley, Erhe Gao, Walter J Koch, Jennifer Gordon, Kamel Khalili, Joseph Y Cheung
Journal: Circulation (2015)

Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations are associated with familial dilated cardiomyopathy and reduced BAG3 expression was observed in murine transverse aortic constriction and porcine myocardial infarction models. BAG3 is expressed in the sarcolemma and t-tubules in adult myocytes. To simulate reduced BAG3 expression in disease states, we downregulated BAG3 in adult myocytes by shRNA (shBAG3). Despite ~50% reduction in BAG3 by shRNA, expression of α-subunit of L-type Ca channel, SR Ca-ATPase, Na/Ca exchanger, α1- and α2-subunits of Na-K-ATPase, and ryanodine receptor was unchanged. At baseline, BAG3 downregulation had no effect on myocyte contraction and [Ca]i dynamics. After isoproterenol, BAG3 downregulation resulted in reduced myocyte contraction amplitudes, shortening and re-lengthening velocities, lower systolic [Ca]i and [Ca]i transient amplitudes, and prolongation in both APD50 and APD90. L-type Ca current (ICa) and sarcoplasmic reticulum (SR) Ca content but not Na/Ca exchange current or SR Ca uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyrl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes. On the other hand, BAG3 overexpression resulted in enhanced myocyte contractility after isoproterenol. In addition, BAG3 overexpression rescued the depressed contraction amplitudes in myocytes overexpressing the HIV protein Tat, and improved myocardial contractility in Tg26 (HIV-1 transgenic) mice. We conclude: (1) BAG3 modulates myocyte contraction, Ca dynamics and action potential duration by regulating ion channels and provides a novel paradigm for contractile dysfunction and increased arrhythmia risks in familial dilated cardiomyopathy; (2) BAG3 is a therapeutic target for cardiomyopathy including HIV-associated cardiomyopathy.
Abstract 11483: Possible Criteria to Prospectively Define and Characterize Myocardial Denervation in Ischemic Patients With Ventricular Tachycardia (VT) Using I123-Meta-iodobenzylguanidine-defined (I123-MIBG)
Authors: Mohammed Abdulghani, John Duell, Mark Smith, Wengen Chen, Kiddy L Ume, Tamunoinemi Bob-Manuel, Vincent See, Hasan Imanli, Anastasios Saliaris, Stephen Shorofsky, Vasken Dilsizian, Timm Dickfeld
Journal: Circulation (2015)

Introduction: Cardiac innervation is a critical component in ventricular arrhythmogenesis. However, a clear definition and electrophysiological characterization of denervation zone (DZ), transitional innervation zone (TZ) and normal innervation zone (NZ) does not exist, which allow a standardized use for clinical trials and image-guided treatment/ablation. Method: 15 patients with ischemic VT undergoing VT ablation underwent pre-procedural sympathetic innervation imaging using I123-MIBG SPECT. Sequential short axis I123-MIBG images were visually classified by 2 experienced cardiac nuclear radiologists into zones of DZ, TZ, and NZ. ROC curves were used to identify the best cut-offs of normalized voxel-based signal intensities. After reconstruction and integration of 3D innervation maps with high-density electrophysiological maps, voltage and signal characteristics were determined. Result: All patients demonstrated areas of denervation, TZ and normal innervation. Innervation defects were localized in the inferior (100%), lateral (73%), septal (60%), apical (20%) and anterior wall (6%). Normalized MIBG uptake in areas of denervation was 25% (Q1-Q3 15.3-31.7%) [min-max 4-50%], increased to 40% (Q1-Q3 30.2-43.6%) [14-72%] in the TZ (p=0.05) and was highest in normal myocardium (NZ): 67% (Q1-Q3 52.2-71.4%) [39-100%] (p&lt;0.001). ROC curve- defined best cut-offs for DZ, TZ and NZ were &lt;31%, 31-47 and &gt;47%. Local electrograms in denervated myocardium (n=1487) were abnormal (83%), fractionated (10%), normal (4%) and with diastolic potentials (3%). In the TZ (n=611) signals were abnormal (82%), fractioned (14%), normal (3%) and with diastolic potentials (1%). Bipolar voltages of 1.5mV were equally commonly in denervated (35%, 36%, and 29%, p&gt;0.05) and transition zone (35%, 35%, and 30%, p&gt;0.05). Conclusion: Denervated, transitional and normally innervated myocardium was best defined by &lt;31, 31-47% and &gt;47% tracer uptake, which provides for the first time quantitative cut-offs for future diagnostic and therapeutic trials. As voltage/signal characteristics were unable to predict innervation categories, cardiac imaging remains the critical modality to assess myocardial innervation characteristics.
Abstract 11807: Phenotyping Family History of Coronary Heart Disease to Inform Risk Assessment for Cardiovascular Events in MESA
Authors: Jaideep Patel, Mahmoud Al Rifai, Pradeep Patel, Maren Scheuner, Steven J Shea, Roger S Blumenthal, Khurram Nasir, Michael J Blaha, John W McEvoy
Journal: Circulation (2016)

Introduction: The relationships between various family history (FH) of coronary heart disease (CHD) phenotypes and cardiovascular disease (CVD) events have not been fully explored. Hypothesis: The association between FH and CVD will differ by, 1) FH at any age vs. premature FH in a parent, sibling, or child, and 2) familial risk score strata (weak, moderate, or strong; see Table for details). Methods: We ascertained CVD events (CHD, angina, stroke, peripheral arterial disease [PAD], and heart failure [HF]) over a median of 10.1 years. Multivariable Cox models examined the association of FH with CVD events (individual and composite). The C-statistic assessed the prognostic impact of FH for predicting CVD when added to traditional RFs. Results: Of 6192 adults [mean (±SD) age 62±10 years, 48% men, 40% white] with information on FH, 36% reported any FH. Those with strong familial risk (n=1240) were more likely to be diabetic, overweight, smoke, or take medication for hypertension and dyslipidemia. Overall, 741 CVD events occurred. Compared to no FH, any FH was associated with incident CHD, angina, and composite CVD in adjusted models [hazard ratio (95% CI)]: 1.4 (1.1-1.8), 1.6 (1.2-2.1), and 1.3 (1.1-1.5), respectively]. Nearly identical results were obtained for premature FH ( Table ). Compared to weak familial risk, strong risk was also associated with CHD, angina and CVD. However, there was no association between FH of any type and stroke, PAD, or HF. FH status (any or premature) and familial risk score improved discrimination of CVD (p =0.0005, p=0.005, and p=0.001, respectively). Familial risk score provided marginal discrimination over and above premature FH status (C statistic from 0.742 to 0.744, p=0.051). Conclusion: The association between FH and CVD risk differs depending on the number of affected family members, suggesting the value of detailed FH information to refine risk assessment. The predictive value of FH of CHD for non-coronary events is limited.
Abstract 11081: Crucial Role of Thrombin Activatable Fibrinolysis Inhibitor in the Pathogenesis of Chronic Thromboembolic Pulmonary Hypertension
Authors: Taijyu Satoh, Kimio Satoh, Nobuhiro Yaoita, Nobuhiro Kikuchi, Junichi Omura, Ryo Kurosawa, Masamichi Nogi, Tomohiro Otsuki, Katsuya Kozu, Kazuhiko Numano, Kota Suzuki, Shinichiro Sunamura, Shunsuke Tatebe, Tatsuo Aoki, Koichiro Sugimura, Hiroaki Shimokawa
Journal: Circulation (2015)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease; however, its pathogenesis still remains to be elucidated. We tested our hypothesis that thrombin activatable fibrinolysis inhibitor (TAFI) plays a crucial role in the pathogenesis of CTEPH as it regulates fibrinolysis, reduces plasmin production, and prolongs clot lysis time. Methods and Results: In the lung of CTEPH patients, perivascular expression of TAFI in small pulmonary arteries (PA) was enhanced. In mice in vivo , chronic exposure to hypoxia (O 2 10%, 3 weeks) caused TAFI up-regulation in the lung. We then newly developed TAFI- overexpressing mice (Tg), in which chronic hypoxia increased right ventricular systolic pressure (RVSP) and caused RV hypertrophy and PA remodeling to a greater extent than in littermate controls (all P&lt;0.05, n=8 each). Moreover, Tg mice (n=19) showed a significantly reduced long-term survival under hypoxia compared with controls (n=22) (63 vs. 95%, P&lt;0.01). To evaluate the role of TAFI for inflammatory cell recruitment, we performed bone marrow reconstitution with GFP + cells, which demonstrated increased recruitment of GFP + cells in Tg mice compared with controls by 3D imaging. In experiments with pulmonary artery smooth muscle cells (Tg-PASMCs) in vitro , cell proliferation was significantly increased in Tg-PASMCs compared with controls (2.8 vs. 1.8-fold, n=8 each, P&lt;0.01). Hypoxia (2% O 2 ) significantly increased TAFI expression and secretion from PASMCs. Furthermore, Tg-PASMCs showed significantly enhanced p38 activity and secretion of inflammatory cytokines/chemokines and growth factors compared with controls. Conditioned medium from Tg-PASMCs promoted cell proliferation compared with controls (1.3- vs. 1.1-fold, n=8 each, P&lt;0.05). Human recombinant TAFI (100 nM) also promoted proliferation of PASMCs from CTEPH patients compared with vehicle controls (1.21- vs. 0.97-fold, n=8 each, P&lt;0.01). Finally, plasma levels of activated TAFI were significantly increased in CTEPH patients (n=32) compared with healthy controls (n=13) (8.7-fold, P&lt;0.01). Conclusions: These results indicate that TAFI plays a crucial role in the pathogenesis of CTEPH, suggesting that it is a novel therapeutic target for CTEPH.
Abstract 18172: Nicotine Accelerates the Expansion of Abdominal Aortic Aneurysms via a Matricellular Protein, Periostin
Authors: Junya Azuma, Rei Otsu, Yoshiaki Taniyama, Masaaki Iwabayashi, Ryuichi Morishita
Journal: Circulation (2013)

Abdominal aortic aneurysms (AAA) are more closely associated with cigarette smoking than any other tobacco-related disease except lung cancer. Periostin (PN) is a matricellular protein that is induced by mechanostress and regulates organ remodeling. Our previous study has shown that PN was significantly unregulated in early remodeling phase of AAAs and its ablation contributed to reduce AAA growth induced by angiotension ll (Angll). The purpose of the present study was to investigate the effect of nicotine on PN and its potential role in AAA disease progression. PN-knockout (KO) mice were originally generated in our lab and crossed with ApoE-KO mice to establish ApoE/PN-double knockout (dKO) mice. Ang II (1.0 mg/kg/min) for 28 days or nicotine (7.0 mg/kg/min) for 42 days was administrated via osmotic minipumps for 24 &gt;-wk-old male mice. Growth of AAAs was serially monitored by ultrasound imaging. The systolic blood pressure(BP)measured by tail cuff method was equivalent between ApoE-KO and ApoE/PN-dKO mice at baseline (101.4±7.3 vs 107.6±8.3mmHg, ns). The BP response to Ang II or nicotine in ApoE/PN-dKO mice was also similar to that in ApoE-KO mice throughout the observation period (data not shown). In Ang II treated mice, the expansion rate of the aortic diameter (AD) was decreased significantly in ApoE/PN-DKO mice (n=10) over ApoE-KO mice (n=12) from day7 to 28day (239.3±43.4% vs 144.4±8.5% at day 28, p&lt;0.05). Moreover the incidence of rupture and hematoma was significantly reduced in ApoE/PN-DKO mice at day 28 (60.0% vs 16.7% at day 28, p&lt;0.05). In nicotine treated mice, the expansion rate of the AD was also diminished in ApoE/PN-DKO mice (n=5) over ApoE-KO mice (n=10) at day 42 (156.1±9.6 vs 113.9±4.0% at day 42, p&lt;0.05). However no rupture or hematoma was observed in this treatment group. The present study investigated the effect of nicotine on PN and their potential role in progressing AAAs. AngII had more potential induction of AAA rupture than nicotine in ApoE KO mice. Although the mechanism to develop AAA would be partially different between AngII and nicotine, the ablation of PN limited the AAA expansion in both AAA model. Antagonists against PN would lead to new therapeutic targets on a molecular basis to limit AAA progression related to cigarette smoking.
Abstract 11025: Insertable Cardiac Monitors Reveal Progression of 1 <sup>st</sup> Degree AV-block to Higher Grade Block Requiring Pacemaker Implant
Authors: Thorsten Lewalter, Guido Rieger, Lorenza Mangoni
Journal: Circulation (2015)

Introduction: In the past, 1 st degree AV-block has generally been considered a benign condition. A few recent studies have shown that 1 st degree AV-block is associated with an increased risk for heart failure, pacemaker (IPG) implantation, and death. We investigated the outcomes of patients who received an insertable cardiac monitor (ICM) (Medtronic Reveal XT ® ) within the scope of the INSIGHT XT study and had 1 st degree AV-block at baseline. Methods: The observational, international, multicenter INSIGHT XT study prospectively enrolled 1003 patients implanted with an ICM for arrhythmia diagnosis, irrespective of the clinical indication. This analysis includes 37 patients (3.7%) who had documented 1 st degree AV-block at enrollment. Patients with known concurrent higher grade block at enrollment were excluded. Results: The indication for ICM implantation was syncope or pre-syncope in 54.1%, cryptogenic stroke in 18.9%, AF with rhythm control intervention in 21.6%, and unexplained palpitations or symptoms in 5.4%. The mean age was 68±14 years and 75.7% were male. Concurrent bundle branch block (BBB) was present in 8.1%. The median follow-up time was 12.2 months (IQR: 3.9-15.9). Fifteen patients (40.5%) received an IPG during the follow-up, and in 93.3% of the cases the implant was needed to treat a progression of the conduction disease. In addition, one patient died due to sinus arrest 86 days after enrollment; one patient developed transient 3 rd degree AV block but did not receive an IPG. Conclusions: The ICM revealed progression of 1 st degree AV-block to a higher grade block warranting an IPG in 40.5% patients. This finding supports the conclusion that 1 st degree AV-block is not benign in all patients. Further studies may reveal patient subgroups which are at high risk for developing higher grade AV block and may warrant a preventive IPG implantation.
Abstract 11422: Aligned Nanofibrillar Collagen Scaffold Guide Therapeutic Lymphangiogenic Repair in Secondary Lymphedema
Authors: Stanley G Rockson
Journal: Circulation (2015)

Background: As a mechanical adjunct to therapeutic lymphatic repair in acquired lymphedema, we have investigated the applicability of guided lymphatic regeneration, through the introduction of a biological scaffold consisting of aligned collagen fibrils. These fibrils provide for cell attachment, alignment, and migration. Methods: We refined a large animal model using minipigs (n=16). We resected the inguinal and popliteal lymphatic system and irradiated the groin area to reproduce the conditions encountered in human cancer-related lymphedema. We assessed the status of lymphedema by detecting interstitial fluid accumulation through bioimpedance, the number of major lymphatic collectors by contrast-enhanced CT, and presence of lymphatic dermal backflow by contrast-enhanced MRI. Results: Three months after lymphatic resection and irradiation, animal subjects were randomized to: (1) scaffolds only, (2) scaffolds impregnated with VEGF-C, and (3) VEGF-C-scaffolds with additional transplantation of autologous lymph node fragments. The control group (4) did not receive any treatment. Seven animals out of 16 developed chronic lymphedema by the pre-defined bioimpedance threshold. The number of lymphatic collectors, as determined by CT, correlated with bioimpedance data. In group 1, there was slight improvement of bioimpedance ratios. In groups 2 and 4 (control), lymphedema persisted. In group 3 lymphedema was reversed in all subjects at post-Rx time-point 6 months. Macroscopic analysis of collectors in the implantation area after intradermal injection of blue dye showed newly developed lymphatic collectors aligned in the direction of the implanted collagen scaffolds. Conclusions: In this porcine acquired lymphedema model, implantation of aligned nanofibrillar collagen scaffolds facilitates the ingrowth of lymphatics across the treatment field. Moreover, simultaneous transplantation of autologous lymph node fragments improves lymphatic regeneration. The biocompatibility of these surgical approaches suggests their potential as an effective treatment option for the human disease.
Abstract 18169: Identifying Early Changes in Myocardial Microstructure via Ultrasound in Hypertensive Heart Disease
Authors: Pranoti Hiremath, Michael Bauer, Hui-Wen Cheng, Kazumasa Unno, Ravi Patel, Bethany Harvey, Ronglih Liao, Susan Cheng
Journal: Circulation (2013)

BACKGROUND: The transition from healthy myocardium to hypertensive heart disease is characterized by a series of poorly understood changes in myocardial tissue microstructure. Incremental alterations in the orientation and deformation of myocardial fibers can now be assessed using advanced techniques in ultrasonic image analysis. METHODS: We used a modified approach to non-invasively assess left ventricular (LV) myocardial microstructure, based on sonographic signal intensity analysis of the inferolateral pericardium (viewed in the parasternal long-axis view of B-mode echocardiographic images). We defined the transmission intensity (TI), an indirect measure of the intensity reflection coefficient at the myocardial-pericardial interface, as 1 - (P/256) where P is the 25th percentile value of pericardial signal intensity on a 256 scale. We determined the extent to which TI is able to differentiate between normal myocardium and hypertensive heart disease in a mouse model and in humans. RESULTS: As shown in the Figure, 7-week echocardiographic measurements of TI were significantly different between groups of mice that underwent fixed aortic banding (n=3) versus sham procedure (n=3) at baseline. Similarly, measurements of TI were significantly different between individuals with uncomplicated essential hypertension (N=30, age 54±3 yrs, 47% women) and healthy controls (N=28, age 53±9 yrs, 60% women). Although there was a trend in higher relative wall thickness in hypertensive individuals compared to controls (P=0.09), there was no difference between these groups in LV mass (P=0.67) or LV wall thickness (P=0.26). CONCLUSION: Based on sonographic signal intensity analysis, the TI is an accessible, non-invasive measure that appears to differentiate normal LV microstructure from myocardium exposed to chronic afterload stress. The TI may be a particularly sensitive measure of myocardial changes that occur early in the course of disease progression.
Abstract 18181: Real-Time Non-ECG-Gated First-Pass Perfusion MRI Enabling Concurrent Assessment of Myocardial Function and Perfusion Abnormalities
Authors: Behzad Sharif, Reza Arsanjani, Rohan Dharmakumar, Aryeh Shalev, Louise Thomson, Noel Bairey Merz, Daniel S Berman, Debiao Li
Journal: Circulation (2013)

Introduction: Combined assessment of wall motion and perfusion abnormalities from cardiac MRI (CMRI) has been shown to have a high performance for diagnosis of coronary artery disease (CAD). CMRI acquisition, however, is hindered by study length, presence of arrhythmias, and the need for synchronization with cardiac cycle via ECG gating. We developed a new non-ECG-gated CMRI technique capable of simultaneously capturing perfusion and wall motion abnormalities in a single 1-minute scan. Hypothesis: Real-time (non-ECG-gated) CMRI can detect perfusion abnormalities with high image quality and enables assessment of wall motion from the same data. Methods: A novel real-time MRI method was developed for ungated first-pass perfusion (FPP) imaging (continuous T1-weighted scan). Canines (n=5) with reversible ischemia (severe LAD stenosis) were studied using both the real-time and gated (conventional) methods. Six normal subjects and 1 patient (suspected CAD) had stress/rest real-time FFP CMRI. The patient also underwent Rb-82 stress/rest myocardial perfusion PET. Results: The real-time FPP stress/rest human studies were all of high quality. The 6 normal subjects demonstrated normal perfusion and function. In the patient, stress-induced hypoperfusion was observed, corresponding to a reversible defect on PET (Figure). In animals, real-time FPP achieved high contrast-to-noise ratio between hypoperfused/remote territories (real-time: 5.2, gated: 4.8). Wall thickening abnormalities (17 frames/s) were observed in hypoperfused areas. Conclusions: A novel approach to FPP CMRI has been developed that does not use ECG gating. Preliminary results in animals with ischemia and at stress/rest in humans were of high quality and showed expected perfusion findings. The real-time method is an attractive alternative to conventional CMRI with the advantage of simplicity (no gating), speed (concurrent MRI of function and perfusion), and potentially improved reliability.
Abstract 18191: Mitochondrial Regulation of the Hyperproliferative Vascular Smooth Muscle Cell Phenotype
Authors: Joshua K Salabei, Steven P Jones, Aruni Bhatnagar, Bradford G Hill
Journal: Circulation (2013)

Background: During arterial restenosis and atherosclerosis, vascular smooth muscle cells (VSMCs) develop a highly proliferative and synthetic phenotype. Because such phenotypic changes are likely integrated with the energetic state of the cell, we hypothesized that changes in mitochondrial function regulate VSMC plasticity. Methods and Results: Exposure of VSMCs to platelet-derived growth factor (PDGF) promoted loss of the contractile proteins α-smooth muscle actin and calponin and was accompanied by remarkable changes in mitochondrial morphology. Confocal analysis showed that 97% of mitochondria in contractile VSMCs were filamentous; however, synthetic VSMCs showed a mitochondrial pool with &gt;70% fragmented mitochondria (p&lt;0.05). Mitochondrial membrane potential decreased by 86±1% with the attainment of the synthetic phenotype (p&lt;0.01; n=3), but was not associated with mitophagy or decreases in the abundance of key proteins involved in oxidative phosphorylation. Compared with contractile VSMCs, synthetic VSMCs showed a 51±1.9% decrease in the abundance of mitofusin 2 (Mfn2; p&lt;0.001; n=3) with no significant changes in Drp1, Fis1, or Opa1. Analysis of mitochondrial function in intact VSMCs showed a 20±3.7% decrease in glucose oxidation in synthetic cells, which was accompanied by a 17±2.6% increase in fatty acid oxidation (p&lt;0.02; n=3). In permeabilized cells, complex II-mediated respiration was decreased by 20±2% in synthetic VSMCs (p&lt;0.05; n=4). An inhibitor of mitochondrial fragmentation, mdivi1, decreased mitochondrial fragmentation by 50±6% (p&lt;0.001; n=3), abolished the hyperproliferative response to PDGF (p&lt;0.03; n=4), and reversed changes in mitochondrial respiration, yet it did not prevent PDGF-induced losses of contractile proteins. Conclusions: These results indicate that changes in mitochondrial morphology and bioenergetics contribute to the hyperproliferation of synthetic VSMCs, but do not affect the degradation of the contractile proteins. We propose that mitochondrial fragmentation that occurs during transition to the synthetic phenotype regulates mitochondrial substrate selection and bioenergetics and is a therapeutic target for vascular disorders characterized by VSMC hyperproliferation.