tbuckley/cabot-search huggingface dataset:
Abstract 11843: Population Effects of Clinical, Laboratory, and Genetic Risk Factors for Incident CAD: A Cohort Study in the UK Biobank
Authors: Christopher S Marnell, Romit Bhattacharya, Seyedeh M Zekevat, Mark Trinder, Michael Honigberg, Gina Peloso, Pradeep Natarajan
Journal: Circulation (2021)

Background: Modifiable clinical risk factors are estimated to account for the majority of population attributable risk (PAR) for first myocardial infarction (MI). Hypothesis: Novel biomarkers and genetic factors additionally contribute to the risk for first MI. Methods: We determined incident coronary artery disease (CAD), defined as first-time MI or revascularization, in the UK Biobank. Exposures included laboratory (ApoB/A1, lipoprotein(a) [Lp(a)], C reactive protein [CRP]), genetic (CAD polygenic risk score [PRS], heterozygous familial hypercholesterolemia [HeFH]), and clinical (waist/hip ratio, hypertension, diabetes, diet, exercise, smoking, Townsend deprivation index) risk factors. We fitted multivariable logistic regression models with clinical risk factors alone, then added CAD PRS, HeFH, CRP and Lp(a). Results: Among 98 387 participants, 5 408 had incident CAD (5.5%). Compared to a model with clinical risk factors alone (PAR 82.3%, 95% CI 77.6-86.9%), adding novel biomarkers (Lp(a), CRP) and genetic risk raised total PAR to 89.0% (95% CI 86.4-91.5%). Novel risk factors Lp(a) &gt; 125 nmol/L (OR 1.22, PAR 2.5%), CRP &gt; 2.0 mg/L (OR 1.22, PAR 8.0%), HeFH (OR 1.52, PAR 0.1%), and high CAD PRS (OR 2.48 for top vs lowest decile, PAR 37.4%) were significantly associated with incident CAD controlling for clinical risk factors. In combination with novel risk factors, smoking (OR 1.25 for current + former vs never, PAR 11.3%), ApoB/A1 ratio (OR 1.60 for top vs lowest quintile, PAR 16.6%), hypertension (OR 2.17, PAR 31.9%), waist-to-hip ratio (OR 1.21 for top vs lowest tertile, PAR 13.3%), diabetes (OR 1.59, PAR 5.6%), diet (OR 1.42, PAR 7.8%), exercise (OR 1.12, PAR 7.1%) and Townsend index (OR 1.34 for top vs lowest decile, PAR 8.6%) were significantly associated with incident CAD at α=0.05. Conclusions: The novel cardiovascular risk factors Lp(a), CRP, CAD PRS, and HeFH contribute significant risk for first-time CAD, with PAR for CAD PRS exceeding conventional risk factors.
Abstract 11229: Clinical and Genetic Atrial Fibrillation Risk and Discrimination of Cardioembolic from Non-Cardioembolic Stroke
Authors: Lu Weng, Shaan Khurshid, Sophia Gunn, Emelia J Benjamin, Patrick T Ellinor, Ludovic Trinquart, Kathryn Lunetta, Christopher D Anderson, Steven A Lubitz
Journal: Circulation (2021)

Introduction: Prior studies demonstrate correlation between atrial fibrillation (AF) polygenic risk score (PRS) and ischemic stroke, especially cardioembolic (CE) stroke, suggesting shared genetic components. In this study, we hypothesized that an AF PRS can discriminate CE from non-CE strokes. Methods: We evaluated AF and stroke risk in 26,145 individuals of European descent from the NINDS Stroke Genetics Network (SiGN) with study-adjudicated TOAST subtypes. AF genetic risk was estimated using two newly derived PRS (LDpred-funct and sBayesR) and two previously validated PRS (pruning and thresholding and LDpred). A clinical risk score (CRS) was derived within separate individuals in UK Biobank utilizing components of the Cohorts for Aging and Genomic Research in Epidemiology (CHARGE-AF) model available in SiGN. We regressed each AF PRS on AF status and separately CE stroke in logistic regression models adjusted for CRS, imputation group, and the first 10 principal components. We calculated discrimination of AF and CE stroke, and compared across models using 2000-iteration bootstrapping and pairwise Z-testing. We also assessed category-free reclassification of CE stroke risk with the addition of PRS to a) CRS, and b) a modified CHA 2 DS 2 -VASc score including all available score components. Results: Each AF PRS was significantly associated with AF and CE stroke after adjustment for the CRS. Addition of any AF PRS significantly improved model discrimination as compared to the CRS alone, and LDpred discriminated both AF and CE better than other PRSs ( Figure ; P &lt;0.005). Adding LDpred PRS to CRS resulted in appropriate reclassification of CE stroke risk compared to the CRS or the modified CHA 2 DS 2 -VASc score alone ( Figure ). Conclusions: Addition of AF polygenic risk to clinical risk factors improves discrimination of CE from non-CE strokes, as well as reclassification of stroke subtype. AF polygenic risk may be a useful biomarker for identifying AF-related strokes.
Abstract 12136: Detection of Sub-Clinical Left Ventricular Dysfunction in COVID-19 Patients
Authors: Muhammad Khalid, Sathwika Thodeti, Brandon Mikolich, J Ronald Mikolich
Journal: Circulation (2021)

Introduction: Abnormalities of left ventricular (LV) strain have been shown to occur prior to impairment of global left ventricular function, measured by global LV ejection fraction (EF). Although first described in patients receiving cardiotoxic chemotherapy, impairment of LV strain prior to a decrease in EF has also been shown in many other disease states which affect LV function. This study was designed to assess impairment of LV strain in post COVID-19 patients with normal EF using cardiac MRI MyoStrain Fast-SENC (strain encoded) pulse sequences. Methods: An institutional cardiac imaging database was queried for all patients with documented COVID-19 test positivity and a normal LVEF &gt;= 55% who underwent measurement of global longitudinal strain (GLS), global circumferential strain (GCS), and regional longitudinal and circumferential strain using cardiac MRI Fast-SENC pulse sequences. Global and regional strain measurements were compared to a cohort of healthy volunteers who also underwent CMR Fast-SENC imaging. Abnormal myocardial strain was defined as a value &gt;-17%. Results: Of 50 COVID-19 patients in the cardiac imaging database who underwent CMR Fast-SENC imaging, 40 had a normal LVEF, constituting the study cohort. Mean GLS and GCS for the study cohort were -16.40% and -15.45% and for healthy volunteers were -19.71% and -20.93% respectively; both comparisons were statistically significant with an unpaired t-test (p&lt;0.01). Furthermore, the prevalence of abnormal LV strain in COVID-19 patients with normal LVEF was 77.78%. Conclusions: These data suggest that impairment of LV strain (longitudinal and circumferential) occurs in COVID-19 patients who have a normal LVEF. Whether a decrease in GLS and/or GCS precede a decrease in LVEF, is beyond the scope of this study. However, the ability to evaluate progression of LV strain abnormalities with CMR may help identify changes in LV function before the onset of a reduction in LVEF and development of heart failure. The ability to identify and quantify abnormal left ventricular GLS and GCS with cardiac MRI also opens the door to assess any benefit of therapy, including anti-inflammatory agents, anti-viral drugs and steroids.
Lysophospholipid Mediators in Health and Disease
Authors: Kuniyuki Kano, Junken Aoki, Timothy Hla
Journal: Annual Review of Pathology Mechanisms of Disease (2021)

Lysophospholipids, exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are produced by the metabolism and perturbation of biological membranes. Both molecules are established extracellular lipid mediators that signal via specific G protein-coupled receptors in vertebrates. This widespread signaling axis regulates the development, physiological functions, and pathological processes of all organ systems. Indeed, recent research into LPA and S1P has revealed their important roles in cellular stress signaling, inflammation, resolution, and host defense responses. In this review, we focus on how LPA regulates fibrosis, neuropathic pain, abnormal angiogenesis, endometriosis, and disorders of neuroectodermal development such as hydrocephalus and alopecia. In addition, we discuss how S1P controls collective behavior, apoptotic cell clearance, and immunosurveillance of cancers. Advances in lysophospholipid research have led to new therapeutics in autoimmune diseases, with many more in earlier stages of development for a wide variety of diseases, such as fibrotic disorders, vascular diseases, and cancer.
CTNI-16. TROTABRESIB (CC-90010, BMS-986378), A REVERSIBLE, POTENT ORAL BROMODOMAIN AND EXTRATERMINAL INHIBITOR (BETi) IN PATIENTS WITH HIGH-GRADE GLIOMAS: A PHASE 1 OPEN-LABEL ‘WINDOW OF OPPORTUNITY’ STUDY
Authors: Michael Vogelbaum, Juan Manuel Sepulveda, David Reardon, Bishoy Hanna, Ellen Filvaroff, Ida Aronchik, Barbara Amoroso, Marlene Zuraek, Tania Sanchez-Perez, Cristina Mendez, Zariana Nikolova, Victor Moreno
Journal: Neuro-Oncology (2021)

Abstract Trotabresib is a potent, reversible oral BETi with antitumor activity in patients with advanced malignancies (Moreno et al. ESMO 2020. Abstract 5270). The CC-90010-GBM-001 study (NCT04047303) enrolled patients with progressive or recurrent astrocytoma or recurrent glioblastoma scheduled for salvage resection. Patients were treated with trotabresib 30 mg daily for 4 days before surgery, then trotabresib 45 mg daily 4 days on/24 days off after recovery. Primary objectives were trotabresib tumor tissue concentration and plasma pharmacokinetics (PK). Secondary and exploratory objectives included safety, antitumor activity, cerebrospinal fluid concentration, and pharmacodynamics (PD). Twenty patients were enrolled; blood PK, blood PD, and tumor PD data were available for 14, 12, and 11 patients, respectively. Geometric mean peak trotabresib plasma concentration on day 4 was 1.92 μM; median time to peak concentration was 1.5 hours. At the time of resection, geometric mean trotabresib concentrations in plasma and brain tumor tissue were 1.01 and 0.68 μM, respectively. Blood CCR1 mRNA was reduced ≥ 50% from baseline after dose 4. Blood HEXIM1 mRNA increased at 72–96 hours following first dose, and at the time of surgery the percentage increase was related to plasma trotabresib concentration. Tumor HEXIM1 RNA increased in 10 of 11 patients. Eighteen patients (90%) had ≥ 1 treatment-related adverse event (TRAE). Nine patients (45%) had grade 3/4 TRAEs, most frequently thrombocytopenia (5 patients [25%]). Only 1 patient had serious TRAEs (hemiparesis and lethargy). Two patients died of intracranial hemorrhage unrelated to study drug. Of 16 patients evaluable for antitumor response, 7 had stable disease per RANO criteria, with 3 ongoing beyond data cutoff at cycles 4–11. Median progression-free survival was 1.9 months (95% CI, 1.4–3.3). Overall, trotabresib showed good tumor tissue penetration, with PD signals of response, and was well tolerated. A study of trotabresib + temozolomide in first-line glioblastoma is ongoing (NCT04324840).
Safety and Efficacy of Azacitidine with Venetoclax for Newly Diagnosed Intensive Chemotherapy Ineligible, and Relapsed or Refractory Acute Myeloid Leukemia in Arab Population: A Single-Center, Retrospective Study
Authors: Mohammmad Alwadi, Jude Howaidi, Abdullah M Alrajhi, Adel Alnakhli, Mohammed A. Marei, Imran K. Tailor, Fouad H. Alnajjar, Syed Y. Altaf, Mohammed S. Alnoamani, Kamal Alzahrani, Hassan Alshehri, Ibraheem H. Motabi, Syed Ziauddin A Zaidi, Nawal F Alshehry, Mansour Alfayez
Journal: Blood (2021)
Abstract P338: Myopeptide Improves Contractile Mechanics In A Mouse Model Of Heart Failure Expressing Phosphoablated Cardiac Myosin Binding Protein-C
Authors: Rohit Singh, Sakthivel Sadayappan
Journal: Circulation Research (2021)

Rationale: Normal heart function depends on cardiac myosin binding protein-C (cMyBP-C) phosphorylation. Its decrease is associated with heart failure (HF) by inhibiting actomyosin interactions. In absence of cMyBP-C phosphorylation, the protein is bound to myosin S2, but released when phosphorylated, allowing myosin to form cross-bridges with actin. Challenging cMyBP-C/myosin S2 interaction by myopeptide (the first 126 amino acids of myosin S2) could promote actomyosin interaction in vitro , but its ability to improve contractility in HF remains untested. Objective: To test contractile function in skinned papillary fibers of a cMyBP-C dephosphorylated mouse model using myopeptide. Methods and Results: To mimic constitutive phosphoablation, a knock-in mouse model was established to express cMyBP-C in which serines 273, 282 and 302 were mutated to alanine (cMyBP-C AAA ). Western blotting revealed 50% and 100% of cMyBP-C AAA in het and homo mouse hearts, respectively. Echocardiography showed a decreased percentage of ejection fraction (28%, p&lt;0.01) and fractional shortening (30%, p&lt; 0.05) in both het and homo cMyBP-C AAA mice at 3 months of age, compared to knock-in negative controls. These mice also developed diastolic dysfunction with elevated ratio of E/A and E/e’ waves. Next, pCa-force measurements using skinned papillary fibers determined that maximal force (F max ) and rate of cross-bridge formation ( k tr ) were decreased in the cMyBP-C AAA groups, compared to the control. However, administration of dose-dependent myopeptide increased F max and k tr in wild-type and cMyBP-C AAA permeabilized skinned papillary fibers without affecting myofilament Ca 2+ sensitivity. Conclusions: Myopeptide can increase contractile force and rate of cross-bridge formation by releasing cMyBP-C/myosin S2 and promoting actomyosin formation of cross-bridges, thus validating its therapeutic potential.
Abstract 11948: A Standardized Method to Isolate and Purify Cardiomyocytes from Individual Mouse Hearts Irrespective of Postnatal Age
Authors: Amy M Nicks, Sara R Holman, Andrea Y Chan, Ching-ho J Pang, Michael Tsang, Nawazish Naqvi, Ahsan Husain, Ming Li, David T Humphreys, Nicola J Smith, Siiri E Iismaa, Robert M Graham
Journal: Circulation (2021)

Rational: Primary cardiomyocytes (CMs) are invaluable for understanding postnatal heart development and elucidating disease mechanisms in genetic and pharmacological models, however, a method to obtain freshly purified CMs at any postnatal age, without the need for different age-dependent isolation procedures and cell culture, is lacking. Objective: To develop a standardized method that allows rapid isolation and purification of CMs in high yield and viability from individual neonatal, infant, and adult mice. Methods and Results: Using a novel in situ aortic cannulation procedure optimized to allow cannulation of even the very small vessel of neonates [postnatal day 0-2 (P0-2)], hearts of C57BL/6J mice were subjected to Langendorff retrograde perfusion and enzymatic digestion. After subsequent tissue disaggregation and filtration, CMs were isolated in high yield (1.55-2.2 x 10 6 CMs/heart) and viability (~78%). The larger size of infant (P10 and P13) and adult (P70), but not neonatal CMs, compared to non-myocytes, allowed their further enrichment by differential centrifugation, before purification at the bench by bead-based immunomagnetic cell separation. This involved depletion of endothelial cells (for infant and adult preparations) or non-myocytes (neonatal preparations). Together, these procedures resulted in highly purified CMs (~95%) from hearts of all ages within 1 hour. Moreover, in situ fixation immediately after tissue digestion via coronary perfusion, preserved the cytoarchitecture of isolated CMs (~94% rod-shaped CMs at all postnatal ages), allowing capture of spindle-shaped neonatal cells undergoing mitosis, as well as enabling accurate quantitation of CM area and nucleation state. RNA-sequencing of CMs purified from one P2 male and female heart per litter (n=4 litters) showed distinct clustering by litters rather than by sexes; a finding consistent with cardiac size and shape being indistinguishable between P2 male (n=6) and female (n=6) hearts as determined by micro-computed tomography (X-ray 3D imaging). Conclusion: The procedures developed here provide a universal protocol for the rapid purification of high-quality CMs from individual hearts at any postnatal age, even those of neonates.
Abstract 12893: Early- and Delayed-Afterdepolarizations as Cellular Promoter of Ventricular Fibrillation in Hypertrophic Cardiomyopathy
Authors: Lorenzo Santini, Raffaele Coppini, CHIARA ZOCCHI, Cecilia Ferrantini, Iacopo Olivotto, Elisabetta Cerbai
Journal: Circulation (2021)

Introduction: Hypertrophic cardiomyopathy (HCM) represents the main cause of sudden cardiac death (SCD) due to ventricular fibrillation in young adults. Recent data suggest that enhanced cellular automaticity as early- and delayed-afterdepolarizations (EADs and DADs) could represent a major trigger of arrhythmogenesis in HCM. Hypothesis: To deeper understand the cellular mechanisms of arrhythmogenesis and to establish an arrhythmic rysk stratification in HCM patients, we performed a translational and retrospective study in 61 HCM patients who underwent surgical interventricular-septum myectomy to relieve refractory obstruction-related symptoms, combining a clinical follow-up study with in vitro assessment of ventricular myocyte arrhythmogenicity. Methods: At the time of surgery, fresh ventricular tissue was collected and used to isolate single ventricular cardiomyocytes, which were then used to perform patch clamp experiments, to assess the occurrence of EADs and DADs. HCM patients were followed up for a median time of 8 years, monitoring the occurrence of non-sustained ventricular tachycardia (NSVT) or life-threatening arrhytmic events (LAE, including sustained VT and VF). Results: Our data show that EADs occurred in 36% of patients (22/61) and were correlated to a prolongation of action potential duration (due to larger I Nal and I CaL density), while DADs occurred in 27% of patients and were associated to an impairment of Ca 2+ handling. During follow up, NSVT events occurred in 19/62 patients, while LAE occurred in 4/62 patients (combined occurrence 37%). Moreover, patients with NSVT/LAE were more likely to show specific "pro-arrhythmic" ECG-patterns. The occurrence of NSVT/ LAE was strongly associated with the presence of DADs in cells but not with the presence of EADs. Interestingly, the occurrence of DADs in cells was also associated with the presence of "proarrhythmic" ECG-patterns. Conclusions: The presence of cellular triggers as DADs, related with changes of ion channels and intracellular calcium homeostasis, appear to be necessary for arrhythmia generation in HCM. Such pro-arrhythmic changes seem to be linked with specific alterations at ECG level, that might be used as clinical arrhythmia predictors in HCM patients.
Abstract 11636: Association Between Troponin Elevation and Adverse Outcomes: Effects of Cardiac, Non-Cardiac, Acute Coronary Syndrome and Non-Acute Coronary Syndrome Causes
Authors: Miguel Rodriguez Guerra, Alaa Omar, Jeirym Miranda, Arundhati Dileep, Alvaro Garcia, Nisha Ali, Preeti Jadhav, Eduard Sklyar, Timothy Vittorio, Jonathan N Bella
Journal: Circulation (2021)

Introduction: The role of high sensitivity troponin (HsTn) is clear in patients with acute coronary syndrome (ACS), however, its role in non-ACS positive HsTn is not. Accordingly, we studied the heterogeneity of outcomes as related to cardiac and non-cardiac causes of positive HsTn. Methods and Results: Retrospectively, 288 consecutive patients [60±17 years, 143 (49%) females, EF:59±14%] who had HsTn measured to exclude ACS were included and followed for a median of 4.9 months. Compared to negative HsTn, patients with positive HsTn were older (64±15 vs 57±16 year), with worse EF (55±16 vs 65±8%), left atrial volume index (43±15 vs 26±11 ml/m 2 , all p&lt;0.001), E/e’ ratio (11.6±5.5 vs 9.4±2.7, p=0.002) Tricuspid regurgitation velocity (TRV, 2.8±0.5 vs 2.6±0.4, p=0.015). and pro-BNP (4625±12657 vs 166±228 pg/ml, p=0.003). Survival curves (figure 1) showed that composite of mortality and rehospitalization were not different between both groups at follow-up (p=0.789). Patients with positive HsTn were classified according to the cause of HsTn rise non-cardiac, cardiac non-coronary, coronary non-ACS, and ACS, figure 1). Admission and follow-up HsTn were highest in the non-cardiac group and comparable to the ACS group. Furthermore, the worst EF and diastolic dysfunction were found in ACS and cardiac non-coronary groups, while. Survival curves suggested that the composite outcomes were worst in non-cardiac and cardiac non coronary groups, best in coronary non-ACS group and intermediate in the ACS groups (p=0.05). Conclusion: Stratifying causes of HsTn elevation differentiated phenotypes of cardiac function and risk. Patients with non-cardiac or cardiac non-coronary causes had worse outcomes than ACS, while patients with non-ACS coronary causes approach the negative HsTn in terms of outcomes which may explain the lack of significant difference in composite outcomes between positive and negative admission HsTn.
Abstract 10282: Biventricular Shape Markers in Repaired Tetralogy of Fallot Associate with Pulmonary Valve Replacement Better Than Standard Clinical Indices
Authors: Sachin Govil, Charlene Mauger, Sanjeet Hegde, James C Perry, Alistair A Young, Jeffrey H Omens, Andrew D McCulloch
Journal: Circulation (2021)

Introduction: Current indications for pulmonary valve replacement (PVR) in repaired tetralogy of Fallot (rTOF) rely on global ventricular measurements but are inconsistently applied, lead to mixed outcomes, and are widely debated. Hypothesis: We aimed to test the hypothesis that specific regional markers of biventricular shape can discriminate differences in ventricular remodeling between rTOF patients that were and were not designated for follow-up PVR better than standard clinical indices. Methods: In this cross-sectional retrospective study, biventricular shape models were fit to CMR images from 84 rTOF patients. A statistical atlas of end-diastolic shape was constructed using principal component analysis. Multivariate regression was used to quantify shape marker and clinical index associations with subsequent intervention status (PVR, n=48 vs. No-PVR, n=36) while accounting for confounders. Clustering analysis was then used to test the ability of statistically significant shape markers and clinical indices to discriminate PVR status as evaluated by Matthews correlation coefficient (MCC). Geometric strain analysis was also conducted to assess shape marker associations with systolic function. Results: PVR status correlated with shape markers associated with RV apical dilation and LV dilation (p&lt;0.001), RV basal bulging and LV conicity (p&lt;0.02), and pulmonary valve dilation (p&lt;0.002). PVR status also correlated with RV EF (p&lt;0.03) and non-significantly correlated with LV ESVi (p&lt;0.06). Clustering analysis revealed that shape markers discriminated PVR status better than clinical indices (MCC=0.49 and MCC=0.28, respectively). These shape markers were also significantly associated with RV and LV radial strain. Conclusions: Biventricular shape markers discriminated PVR status better than standard and current use clinical indices for PVR. These specific, regional features of cardiac morphology can provide mechanistic insight into adaptive vs. maladaptive types of ventricular remodeling that provide the foundation for clinical decision-making but may be overlooked when relying solely on global ventricular measurements.
Large-scale integration of the plasma proteome with genetics and disease
Authors: Egil Ferkingstad, Patrick Sulem, Bjarni A. Atlason, Gardar Sveinbjornsson, Magnus I. Magnusson, Edda L. Styrmisdottir, Kristbjorg Gunnarsdottir, Agnar Helgason, Asmundur Oddsson, Bjarni V. Halldorsson, Brynjar O. Jensson, Florian Zink, Gisli H. Halldorsson, Gisli Masson, Gudny A. Arnadottir, Hildigunnur Katrinardottir, Kristinn Juliusson, Magnus K. Magnusson, Olafur Th. Magnusson, Run Fridriksdottir, Saedis Saevarsdottir, Sigurjon A. Gudjonsson, Simon N. Stacey, Solvi Rognvaldsson, Thjodbjorg Eiriksdottir, Thorunn A. Olafsdottir, Valgerdur Steinthorsdottir, Vinicius Tragante, Magnus O. Ulfarsson, Hreinn Stefansson, Ingileif Jonsdottir, Hilma Holm, Thorunn Rafnar, Pall Melsted, Jona Saemundsdottir, Gudmundur L. Norddahl, Sigrun H. Lund, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Kari Stefansson
Journal: Nature Genetics (2021)