tbuckley/cabot-search huggingface dataset:
Abstract 15494: Physiological Investigation of the C57bl6 Mouse Aorta Reveals a Critical Role for Voltage Gated Calcium Channel Activity in Spontaneous Arterial Ageing
Authors: Sofie De Moudt, Jhana O Hendrickx, Dorien G De Munck, Arthur J Leloup, Wim Martinet, Guido De Meyer, Paul Fransen
Journal: Circulation (2020)

Introduction: Arterial stiffness (AS) has gained much recognition as a hallmark and independent predictor of cardiovascular (CV) events. Although generally assumed to be an adaptive response to increased blood pressure (BP), AS precedes hypertension in at least two experimental mouse models, thus revealing an incomplete understanding of AS pathophysiology. Methods: The current study presents the longitudinal CV characterization of spontaneously ageing C57Bl6 mice (2, 4, 6, 9, 12 and 24-month old) (male, n&gt;8). In vivo analysis of peripheral BP (Coda), aortic pulse wave velocity (aPWV, Vevo2100), and echocardiography (Vevo2100) was combined with ex vivo aortic studies of isometric reactivity (organ baths) and AS measurements in the Rodent Oscillatory Tension set-up for Arterial Compliance (ROTSAC). (Data are presented as mean ± SEM.) Results: In vivo and ex vivo characterisation confirms that aortic stiffness precedes peripheral BP alterations in spontaneously ageing C57Bl6 mice, with significantly and gradually increasing aPWV (Fig.A) and isobaric Peterson modulus (Ep) (Fig.B) from 6-month of age onward. Thereafter, cardiac hypertrophy was observed at 9-months of age (Fig.C), and peripheral BP measurement reveals elevated pulse pressure at 24-months (30% increase vs. all other ages) (Fig.D). Ex vivo investigation of the thoracic aorta shows increased contractions to phenylephrine (PE) in old (6-24 month) vs. young (2-4 month) mice (Fig.E,F) with an increased contribution of voltage-gated calcium channel (VGCC) (Fig.G,H) with age. Remarkably, no differences were observed on endothelial function, meaning that all changes occur on the level of the vascular smooth muscle cell (VSMC). Conclusions: Physiological ageing of VSMC results in high PE contractions, increased VGCC activity, and the development of significant arterial stiffening by 6-months of age. AS thereby precedes the development of peripheral BP alterations by 18 months.
Loss of Aurora Kinase Signaling Allows Lung Cancer Cells to Adopt Endoreplication and Form Polyploid Giant Cancer Cells That Resist Antimitotic Drugs
Authors: Vural Tagal, Michael G. Roth
Journal: Cancer Research (2020)

Abstract Polyploid giant cancer cells (PGCC) are common in tumors and have been associated with resistance to cancer therapy, tumor relapse, malignancy, immunosuppression, metastasis, cancer stem cell production, and modulation of the tumor microenvironment. However, the molecular mechanisms that cause these cells to form are not yet known. In this study, we discover that Aurora kinases are synergistic determinants of a switch from the proliferative cell cycle to polyploid growth and multinucleation in lung cancer cell lines. When Aurora kinases were inhibited together, lung cancer cells uniformly grew into multinucleated PGCCs. These cells adopted an endoreplication in which the genome replicates, mitosis is omitted, and cells grow in size. Consequently, such cells continued to safely grow in the presence of antimitotic agents. These PGCC re-entered the proliferative cell cycle and grew in cell number when treatment was terminated. Thus, PGCC formation might represent a fundamental cellular response to Aurora kinase inhibitors and contributes to therapy resistance or tumor relapse. Significance: These findings provide a novel insight about how cancer cells respond to Aurora kinase inhibitors and identify a new mechanism responsible for resistance to these agents and other antimitotic drugs.
Abstract 17238: Taper With Caution: A Case Report of Treatment Response of a Patient With Cardiac Sarcoidosis to Tapering of Steroid Therapy and Initiation of Methotrexate
Authors: GAURANGA MAHALWAR, HANAD BASHIR, Jeffery Courson, Anas Alameh
Journal: Circulation (2020)

Introduction: We present a case of a patient with systemic sarcoidosis with cardiac involvement who presented with palpitations and was noted to be in non-sustained ventricular tachycardia (NSVT) after being tapered down the prednisone dose and being started on methotrexate. Clinical Course: 49-year-old female presented with symptoms of palpitations for 10 day prior to presentation with associated lightheadedness. Her past medical history included cardiac sarcoidosis, atrial tachycardia and complete heart block with a pacemaker placement. Upon checking her remote pacemaker interrogation during the current admission she was found to have recurrent episodes of non-sustained ventricular tachycardia. Patient was diagnosed with sarcoidosis 4 months prior to presentation and was started on 50 mg of prednisone which was tapered down to 30 mg 2 months prior to patient’s presentation due to weight gain along with initiation of methotrexate therapy .Patient was started on amiodarone 200 mg daily with a loading dose of 400 TID while admitted. Her prednisone was increased temporarily and weekly methotrexate was continued. The patient was found to have resolution of symptoms and did not have recurrence of arrhythmia on telemetry. She was upgraded to ICD placement during the same admission and was discharged with follow up. Conclusions: Ventricular tachycardia (VT) resulting from myocardial inflammation is the most common arrhythmia in cardiac sarcoidosis (CS), found in up to 23% of the patients. Antiarrhythmic drugs such as amiodarone are standard treatment for VT in patients with CS. However, corticosteroid therapy has shown to be beneficial for ventricular arrhythmias (VA) as demonstrated in some studies while even worsening ventricular arrhythmias in minority of the patients. In our patient, the tapering of the prednisone dose despite introduction of methotrexate resulted in the recurrence of ventricular tachycardia which eventually resolved with the re-administration of the original dose of prednisone. This indicates that more definitive immunosuppression therapy guidelines are required for patients with CS.
Abstract 13837: Fibronectin is Essential for Cardiac Stem Cell Response Following Myocardial Infarction
Authors: Mathias H Konstandin, Haruhiro Toko, Pearl Quijada, Mercedes Quintana, Mirko Volkers, Shabana Din, Natalie Gude, Mark A Sussman
Journal: Circulation (2012)

Background: Cardiac Progenitor Cells (CPCs) show promise in early clinical trials for treatment of heart failure despite limited mechanistic knowledge of the endogenous regenerative response follow...
Abstract 13454: Relationship Between Brain-type Natriuretic Peptide and Serum Growth Factors in Infants With Single Ventricle Heart Disease and Shunt- or Ductal-dependent Pulmonary Blood Flow
Authors: Monique M Gardner, Jen Faerber, Tamar J Preminger, Catherine M Avitabile, Somya Shankar, Susan Schachtner, Andrew C Glatz, Chitra Ravishankar, David J Goldberg
Journal: Circulation (2020)

Introduction: For infants with shunt- or ductal-dependent single-ventricle heart disease (SD-SVHD), poor growth is common and associated with morbidity and impaired neurodevelopmental outcome. While attention has focused on nutrition to promote weight gain, little is known about the contribution of heart failure to diminished growth. Methods: A prospective observational pilot study was performed to assess the relationship between heart failure, assessed by brain natriuretic peptide (BNP), and growth factors [insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3)] at 4 visits: 1) prior to discharge from neonatal intervention, 2) immediately prior to stage 2 palliation, 3) prior to discharge after stage 2 palliation, and 4) 3-6 months after stage 2 discharge. IGF-1 Z-scores were generated by the analysis lab using reference data. The relationship between log-transformed BNP and growth factors was analyzed using pairwise correlations at each visit and modeled over time with a linear mixed-effects model. Correlations were considered statistically significant using a p-value &lt;0.10, given the exploratory nature of the study. Results: The study included 38 infants (66% male, 68% hypoplastic left heart syndrome). Median BNP was elevated at Visit 1 and decreased over time [287 pg/dL (IQR 147, 794), 85 pg/dL (52, 183), 90 pg/dL (70, 138), and 47 pg/dL (43, 135)]. Median IGF Z-score was &lt;0 at each visit but increased over time [-0.9 (IQR -1.1, 0.1), -0.7 (-1.2, 0.1), -0.5 (-1.2, 0), and -0.2 (-0.8, 0)]. Inverse correlations were noted between log BNP and IGF-1 Z-score at Visit 1 (r = -0.45, p=0.06) and Visit 3 (r = -0.50, p=0.02), and between log BNP and IFGBP-3 at Visit 1 (r = -0.44, p=0.06) and Visit 2 (r = -0.34, p=0.08). There was a small effect of log BNP on IGF-1 Z-score over all time periods (coefficient: -0.23, 95% CI: -0.49, 0.024, p=0.07). Conclusions: This pilot study demonstrates an inverse correlation between BNP and growth factors, suggesting that the heart failure state associated with this physiology may play a mechanistic role in impaired growth. Further work directed at therapies that target the underlying heart failure state might help to optimize the potential for growth in this vulnerable patient population.
Tauopathy-associated tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model
Authors: Sanjib Guha, Sarah Fischer, Gail V. W. Johnson, Keith Nehrke
Journal: Molecular Neurodegeneration (2020)

Abstract Background A defining pathological hallmark of the progressive neurodegenerative disorder Alzheimer’s disease (AD) is the accumulation of misfolded tau with abnormal post-translational modifications (PTMs). These include phosphorylation at Threonine 231 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is recognized to play a central role in pathogenesis of AD, the precise mechanisms by which these abnormal PTMs contribute to the neural toxicity of tau is unclear. Methods Human 0N4R tau (wild type) was expressed in touch receptor neurons of the genetic model organism C. elegans through single-copy gene insertion. Defined mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 genome editing. These mutations included T231E, to mimic phosphorylation of a commonly observed pathological epitope, and K274/281Q, to mimic disease-associated lysine acetylation – collectively referred as “PTM-mimetics” – as well as a T231A phosphoablation mutant. Stereotypical touch response assays were used to assess behavioral defects in the transgenic strains as a function of age. Genetically-encoded fluorescent biosensors were expressed in touch neurons and used to measure neuronal morphology, mitochondrial morphology, mitophagy, and macro autophagy. Results Unlike existing tau overexpression models, C. elegans single-copy expression of tau did not elicit overt pathological phenotypes at baseline. However, strains expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited reduced touch sensation and neuronal morphological abnormalities that increased with age. In addition, the PTM-mimetic mutants lacked the ability to engage neuronal mitophagy in response to mitochondrial stress. Conclusions Limiting the expression of tau results in a genetic model where modifications that mimic pathologic tauopathy-associated PTMs contribute to cryptic, stress-inducible phenotypes that evolve with age. These findings and their relationship to mitochondrial stress provides a new perspective into the pathogenic mechanisms underlying AD.
Abstract 15418: An Arrhythmogenic Isolated Septal Aneurysm
Authors: Bina Kviatkovsky, Michael P Cinelli, Samer Saouma, Philippe Akhrass, Marcin Kowalski, Rina Shah, Soad Bekheit
Journal: Circulation (2020)

Background: Septal infarct due to isolated occlusion of a perforator branch is extremely rare. Few reported cases only describe either the EKG findings, imaging abnormalities or revascularization techniques. Objective: We report a case of an isolated septal aneurysm (ISA) caused by the acute occlusion of the second septal perforator presenting with recurrent ventricular fibrillation (VF). Results: A 63 year old woman presented to the hospital with chest pain. EKG showed an ST segment elevation localized to lead V3 (Fig1A), troponin 18.23. Angiogram showed an isolated 95% tubular stenosis of large second septal branch of LAD (Fig1B). No revascularization was performed. The patient subsequently had cardiac arrest (VF) requiring cardioversion. Repeat angiogram was unchanged. Echo showed isolated mid septal dyskinetic segment (Fig1C). LVEF was 60%. The patient was discharged with an external defibrillator. Repeat echo showed unchanged EF but presence of the isolated dyskinetic segment. An electrophysiologic study (EPS) showed VF induced with 2 extra stimuli at 250 ms with a drive cycle of 600 ms (Fig1D). An ICD was implanted for prevention of SCD. Conclusion: We describe the first case of an arrhythmogenic ISA in the presence of normal LVEF. The interventricular septum is composed of right and left ventricular endocardium. Experiments have shown that acute septal ischemia produces trans-septal asymmetry in expression of membrane ion channels and action potentials in local conduction velocity and gradients. This results in trans-mural heterogeneity of tissue excitability, a substrate for transmural re-entry and ventricular tachyarrhythmias, in septal infarction. This also explains the persistence of enhanced arrhythmogenicity in our patient during the initial and chronic phases of ischemia. ISA is rare but potentially arrhythmogenic. ISA with preserved LVEF, EPS for arrhythmogenicity and ICD for secondary prevention of SCD should be considered in such cases.
In Vivo Microbial Coevolution Favors Host Protection and Plastic Downregulation of Immunity
Authors: Suzanne A Ford, Kayla C King
Journal: Molecular Biology and Evolution (2020)

Abstract Microbiota can protect their hosts from infection. The short timescales in which microbes can evolve presents the possibility that “protective microbes” can take-over from the immune system of longer-lived hosts in the coevolutionary race against pathogens. Here, we found that coevolution between a protective bacterium (Enterococcus faecalis) and a virulent pathogen (Staphylococcus aureus) within an animal population (Caenorhabditis elegans) resulted in more disease suppression than when the protective bacterium adapted to uninfected hosts. At the same time, more protective E. faecalis populations became costlier to harbor and altered the expression of 134 host genes. Many of these genes appear to be related to the mechanism of protection, reactive oxygen species production. Crucially, more protective E. faecalis populations downregulated a key immune gene, , known to be effective against S. aureus infection. These results suggest that a microbial line of defense is favored by microbial coevolution and may cause hosts to plastically divest of their own immunity.
Abstract 17245: The Ipad Project: Enhancing Patient-Family Communication During COVID-19 Visitor Restrictions
Authors: Mollie Kettle, Kelly Kester, Amanda Ornell, Ashley Dobbins, Sara Floyd, Annie Jaeger, Kristen Cossaart, Krista Williams, Meredith Wilkinson, Jill Engel, Bradi B Granger
Journal: Circulation (2020)

Introduction: As patients, hospitals and scientific communities are struck by rapidly evolving effects of the COVID-19 pandemic, new approaches to achieving high quality care and communication in the context of “restricted visitation” are emerging. The evidence for optimal communication strategies in the context of restrictive visitation is lacking in the literature. Methods: We used a rapid-cycle quality improvement approach to design and evaluate high quality, effective communication with families in the context of visitor restrictions in two cardiothoracic ICUs in an academic health system. The effectiveness of video chat, assessment of loved-ones’ awareness, understanding and inclusion in the plan of care, and the engagement of the healthcare team in communication of decisions were each defined using validated response scales. To evaluate the effectiveness of communication using video chat, six questions were included from two subscales using a visual analogue scale. To evaluate the inclusion in healthcare decisions, three items were included using Likert scales and binary or open-ended narratives. Results: Overall, 92 adult patients contributed complete data for analysis. Communication with the ICU team met expectations (Always-95.3%), with expected frequency (Always - 91.9%), and duration (Always - 97.7%), and quality, including having questions answered (Always - 96.5%) and seeing (visualizing) members of the healthcare team when requested (Always - 82.6%). Patient and families reported high levels of “presence” on a validated scale reflecting the quality, sensitivity and responsiveness of the providers to critical conversations. In 96.3% of cases, patients and family reported feeling “that I had the impression that I was actively participating” and that “the other person reacted to my presence.” Conclusion: The COVID-19 pandemic introduced opportunities for rapid innovation due to the need for fully restrictive visitation. This case demonstrates that teamwork, collaboration and creative engagement of people and resources across clinical, administrative and academic partners can efficiently improve patient-provider communication in rapid-cycle timeframes.
Ticagrelor or Prasugrel for Platelet Inhibition in Acute Coronary Syndrome Patients
Authors: Katharina Mayer, Dario Bongiovanni, Vincent Karschin, Dirk Sibbing, Dominick J. Angiolillo, Heribert Schunkert, Karl-Ludwig Laugwitz, Stefanie Schüpke, Adnan Kastrati, Isabell Bernlochner
Journal: Journal of the American College of Cardiology (2020)
Abstract 14390: The Cardiac Myosin Inhibitor, Ck-3772271, Attenuates Cardiac Fibrosis and Diastolic Dysfunction in the Dahl/salt Sensitive Rat Model of Heart Failure With Preserved Ejection Fraction
Authors: Xihui Xu, Darren T Hwee, James J Hartman, Jingying Wang, Yangsong Wu, Claire McHugh, Eva R Chin, Fady I Malik, Bradley P Morgan
Journal: Circulation (2020)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is characterized by underlying contractile dysfunction and progressive myocardial fibrosis and stiffness. CK-3772271 (CK-271) is a novel small molecule cardiac myosin inhibitor that reduces cardiac myosin ATPase activity and reduces cardiac contractility in unloaded isolated cardiomyocytes in vitro and in healthy rats and dogs in vivo . The effect of chronic CK-271 treatment on cardiac function and morphology was evaluated in the Dahl/Salt Sensitive (DSS) rat hypertension model of HFpEF. Methods: DSS male rats were fed either a control low salt (LS, 0.3% NaCl) or high salt (HS, 4% NaCl) diet to induce a hypertension-driven HFpEF disease phenotype. 6 weeks after HS diet treatment, DSS rats were randomized into two sub-groups: continued HS diet or a HS diet formulated with CK-271 (100 ppm) for an additional 6 weeks. Body mass, systolic blood pressure, and cardiac function were measured longitudinally. After 12 weeks of HS treatment, hearts were collected to assess cardiac fibrosis. Results: HS diet treatment increased systolic blood pressure (LS:132.2 ± 4.7 mm Hg vs. HS: 163.5 ± 4.0 mm Hg, mean ± SEM, p&lt; 0.001) and caused cardiac hypercontractility as evidenced by an increase in the end-systolic pressure-volume relationship (LS: 0.8 ± 0.17 vs. HS: 2.1 ± 0.46 mm Hg/ml). HS diet also increased isovolumic relaxation time (IVRT) (LS: 16.8 ± 0.6 vs. HS: 22.8 ± 0.6 ms, p&lt;0.0001), left atrial area (LS: 30.3 ± 0.8 vs. HS: 42.5 ± 2.2 mm 2 , p&lt;0.0001) and cardiac fibrosis (LS: 3.4 ± 0.4 vs. HS: 5.0 ± 0.6 %). 6 weeks of CK-271 treatment reduced fractional shortening (HS: 53.8 ± 1.4 vs. HS+CK-271: 42.7 ± 1.0 %, p&lt;0.0001) and reduced HS diet-induced diastolic dysfunction, including IVRT (HS: 22.8 ± 0.6 vs. HS+CK-271: 19.5 ± 0.5 ms, p&lt;0.0001) and left atrial area (HS: 42.5 ± 2.2 vs. HS+CK-271: 35.4 ± 0.8 mm 2 , p&lt;0.0001). Furthermore CK-271 reduced the development of cardiac fibrosis (HS: 5.0 ± 0.6 vs. HS+CK-271: 3.5 ± 0.3 %, p&lt;0.05) induced by HS diet. Conclusion: The small molecule cardiac myosin inhibitor, CK-3772271, attenuated the development of cardiac hypercontractility, diastolic dysfunction and fibrosis in the DSS rat model of HFpEF. Cardiac myosin inhibition may be a novel approach to mitigate the development of HFpEF.
Diagnostic performance of congestion score index evaluated from chest radiography for acute heart failure in the emergency department: A retrospective analysis from the PARADISE cohort
Authors: Masatake Kobayashi, Amine Douair, Kevin Duarte, Déborah Jaeger, Gaetan Giacomin, Adrien Bassand, Victor Jeangeorges, Laure Abensur Vuillaume, Gregoire Preud'homme, Olivier Huttin, Faiez Zannad, Patrick Rossignol, Tahar Chouihed, Nicolas Girerd
Journal: PLoS Medicine (2020)

Background Congestion score index (CSI), a semiquantitative evaluation of congestion on chest radiography (CXR), is associated with outcome in patients with heart failure (HF). However, its diagnostic value in patients admitted for acute dyspnea has yet to be evaluated. Methods and findings The diagnostic value of CSI for acute HF (AHF; adjudicated from patients’ discharge files) was studied in the Pathway of dyspneic patients in Emergency (PARADISE) cohort, including patients aged 18 years or older admitted for acute dyspnea in the emergency department (ED) of the Nancy University Hospital (France) between January 1, 2015 and December 31, 2015. CSI (ranging from 0 to 3) was evaluated using a semiquantitative method on CXR in consecutive patients admitted for acute dyspnea in the ED. Results were validated in independent cohorts ( N = 224). Of 1,333 patients, mean (standard deviation [SD]) age was 72.0 (18.5) years, 686 (51.5%) were men, and mean (SD) CSI was 1.42 (0.79). Patients with higher CSI had more cardiovascular comorbidities, more severe congestion, higher b-type natriuretic peptide (BNP), poorer renal function, and more respiratory acidosis. AHF was diagnosed in 289 (21.7%) patients. CSI was significantly associated with AHF diagnosis (adjusted odds ratio [OR] for 0.1 unit CSI increase 1.19, 95% CI 1.16–1.22, p &lt; 0.001) after adjustment for clinical-based diagnostic score including age, comorbidity burden, dyspnea, and clinical congestion. The diagnostic accuracy of CSI for AHF was &gt;0.80, whether alone (area under the receiver operating characteristic curve [AUROC] 0.84, 95% CI 0.82–0.86) or in addition to the clinical model (AUROC 0.87, 95% CI 0.85–0.90). CSI improved diagnostic accuracy on top of clinical variables (net reclassification improvement [NRI] = 94.9%) and clinical variables plus BNP (NRI = 55.0%). Similar diagnostic accuracy was observed in the validation cohorts (AUROC 0.75, 95% CI 0.68–0.82). The key limitation of our derivation cohort was its single-center and retrospective nature, which was counterbalanced by the validation in the independent cohorts. Conclusions In this study, we observed that a systematic semiquantified assessment of radiographic pulmonary congestion showed high diagnostic value for AHF in dyspneic patients. Better use of CXR may provide an inexpensive, widely, and readily available method for AHF triage in the ED.