tbuckley/cabot-search huggingface dataset:
Abstract 11535: Persistent Qt Prolongation After Doxorubicin Administration at Doses Similar to Adjuvant Breast Cancer Therapy in African Green Monkeys
Authors: George Bodziock, Giselle C Melendez
Journal: Circulation (2021)

Introduction: Cancer patients undergoing doxorubicin (Dox)-based chemotherapy often experience cardiac repolarization abnormalities, including electrocardiography (ECG)-derived QT and corrected QT (QTc) interval prolongation, which increases the risk for life-threatening arrhythmias such as torsades de pointes. We have previously reported that African Green monkeys exhibit CMR-derived myocardial fibrosis long-term after receiving Dox at doses similar to those experienced by women treated for breast cancer. Here, we sought to determine if QT/QTc prolongation persists after treatment cessation and its association with myocardial fibrosis. Methods: Five female African Green AGMs (AGMs) aged 13±1 years received Dox (30 - 60 mg/m 2 / biweekly IV, total cumulative dose: 240 mg/m 2 ) and underwent 12-lead ECG and CMR imaging with pre- and post-contrast T1 maps from which extracellular volume (ECV) was calculated, before and 15 weeks after the final dose of Dox treatment. A blinded paired and correlation analysis was performed on ECG-derived heart rate (HR), QRS, QT, QTc interval durations and ECV. Results: After Dox, all monkeys exhibited increased QT (BL: 323.2 ± 27.4 ms vs. Post-Dox: 366.4 ± 18.7 ms, p=0.002) and QTc (BL: 440.2 ± 22.8 ms vs. Post-Dox: 500.8 ± 22.0 ms, p=0.009) intervals, without any significant changes in HR or QRS duration (p=0.92 and p=0.47 respectively). Longer QTc intervals were associated with increases in ECV ( r =0.58, p=0.05) (Figure). Conclusions: AGMs that received Dox - in a fashion similar to adjuvant anthracycline chemotherapy for breast cancer- exhibited longer QT and QTc intervals associated with myocardial fibrosis. Our study suggests this may not be solely due to transient ion channel disruption from Dox but rather from persistent changes in the electrophysiological properties of cardiomyocytes and the extracellular matrix. Future longitudinal studies are needed to determine the clinical significance of these findings.
Abstract 10181: The Effect of Immune Checkpoint Inhibitors for Cancer on Blood Pressure
Authors: Zsofia D Drobni, Thomas Mayrhofer, Amna Zafar, Vineet Raghu, Hannah K Gilman, Sarah Hartmann, Thiago Quinaglia, Julia Karady, Carlos Gongora, Leyre Zubiri, Pal Maurovich-Horvat, Kerry Reynolds, Tomas G Neilan
Journal: Circulation (2021)

Introduction: Immune checkpoint inhibitors (ICIs) treat an expanding range of cancers and the use of ICIs has been associated with an increase in atherosclerotic cardiovascular disease (ASCVD) events. The mechanisms involved in the increase in ASCVD with ICIs are incompletely understood. These same immune checkpoints targeted for cancer also regulate vascular function, yet there are no data testing the effect of ICIs on blood pressure. Hypothesis: Based on basic data on the role of these immune checkpoints in vascular function, we hypothesize that the use of ICIs would increase systolic and diastolic blood pressure. Methods: This was a single academic medical center study of 8,724 patients treated with an ICI. The primary analysis evaluated whether exposure to ICIs was associated with changes in blood pressure using repeated measures multivariate mixed linear regression models. The secondary analysis evaluated the effect of changes in blood pressure on all cause mortality using Cox proportional hazard models. Results: Of the 8,724 patients, 4,812 (55.2%) had a diagnosis of hypertension at ICI start. The average blood pressure at ICI start was 128.3±18.1/72.5±10.1mmHg. Among the entire cohort, there was a decrease of 2.9 mmHg in systolic blood pressure (95% CI: 2.70-3.02) after starting an ICI, and a drop of 1.6 mmHg (95% CI: 1.52-1.70) in diastolic blood pressure (adjusted, p&lt;0.001 for both) (Figure 1). The effect of an ICI on blood pressure was independent of the development of any toxicity associated with an ICI. Patients who had an increase of ≥20 mmHg in systolic blood pressure after starting ICI had a lower risk of all-cause death (HR 0.74, 95% CI: 0.63-0.86) compared to patients with no or less than ≥20 mmHg increase. Conclusions: Among a large cohort of patients, ICI therapy is associated with a drop in systolic and diastolic blood pressure. However, patients who had an increase of at least ≥20 mmHg in systolic blood pressure had lower risk of all-cause death.
Response by Abrahami et al to letter regarding article ‘Proton pump inhibitors and risk of colorectal cancer’
Authors: Devin Abrahami, Laurent Azoulay
Journal: Gut (2021)

We thank Chen Dong et al 1 for their interest in our study on the use of proton pump inhibitors (PPIs) and colorectal cancer incidence.2 We have responded to their comments as follows.

While there may be some differences between PPI and histamine-2 receptor antagonist (H2RA) users, these two drug classes are used across similar indications in the real-world setting.3 Thus, the use of H2RAs as an active comparator provides a clinically meaningful comparison for physicians deciding whether to treat patients with gastric disorders with a PPI or H2RA. This is certainly a better approach than comparing PPI users to non-users. Furthermore, we included all approved and off-label indications for acid suppressant drug use in our propensity score models to minimise residual confounding by disease severity. After applying propensity score weights, our population was well balanced on all …
Abstract MP224: IL-10 Protects The Heart From Late Phage Cardiac Inflammation Associated With Intestinal Permeability Following Transaortic Constriction
Authors: Sumanta K Goswami, Prabhat Ranjan, Suresh Verma
Journal: Circulation Research (2021)

Introduction: Impaired intestinal permeability is known to augment cardiac dysfunction. Though the cardioprotective role of IL-10 is known in early phase cardiac inflammation, following transaortic constriction (TAC), its role in alleviating late phase cardiac inflammation associated with intestinal permeability is not known. Hypothesis: We hypothesized that IL-10 reduces late-phase cardiac inflammation by minimizing intestinal permeability and systemic reduction of pathogen-associated molecular pattern (PAMP), which ultimately improve cardiac function. Methods: WT and IL-10 KO mice (n=6 in each group) were subjected to TAC or sham surgery, and echocardiography was performed to evaluate cardiac function for up to 56 days. Heart and intestine were collected to evaluate inflammation (RT-qPCR), immune cell infiltration (flow cytometry), and intestinal permeability (WB and immunohistochemistry). Blood was collected to quantify the level of peptidoglycan (PGN, a PAMP) and other bacterial metabolites. The effect of PGN on mitochondrial function was evaluated in neonatal rat ventricular myocyte (NRVM). Results: Cardiac functions were significantly reduced in IL10-KO mice, following TAC till 56 days. Furthermore, exacerbated inflammation was observed both at early phase (within 14 days) and late phase (around 56 days) in IL-10 KO TAC mice as compare to the WT counterpart. Interestingly, early cardiac inflammation coincided with immune cell infiltration into the intestine of IL-10 KO mice following TAC. Enhanced inflammatory immune cells homing to the intestine following TAC led to gut dysbiosis (16S RNA sequencing) which ultimately caused impaired gut wall permeability in the IL-10 KO mice as compared to the WT mice. Further, plasma PGN level was significantly increased in IL-10 KO mice following TAC. Finally, our cardiotoxicity array in neonatal rat cardiomyocytes following PGN treatment showed altered expression of proteins which are involved in the regulation of mitochondrial function and cardiac contractility. Conclusion: IL-10 plays an important role in limiting late phase cardiac inflammation by reducing intestinal permeability and systemic increase in PGN which induce inflammation and mitochondrial dysfunction in cardiac muscle.
Abstract 10461: Totum-854 Lowers Blood Pressure in L-NAME-Induced Arterial Hypertension in Mice and in Spontaneous Hypertensive Rat Model
Authors: Gaetan Bolea, Doriane Ripoche, Gregory MEYER, Florian Le Joubioux, Arnaud Michaux, Yolanda F OTERO, Sébastien PELTIER, Pascal SIRVENT, Cyril REBOUL
Journal: Circulation (2021)

Introduction: Arterial Hypertension (AHT) is a major cause of premature death worldwide. We have developed Totum-854 (T-854), a polyphenol-rich botanical composition to reduce the risk of developing AHT. We assessed the chronic effect of T-854 on preventing the development of L-NAME-induced AHT in mice, and the acute effect on blood pressure in spontaneous hypertensive rats (SHR). Methods: 12-week-old C57Bl6/J mice were divided into Control, L-NAME, and L-NAME + T-854 group. L-NAME (100 mg/kg/day) was dissolved in drinking water. Mice received either T-854 (450 mg/kg) or vehicle by gavage once a day for three weeks . The arterial pressure was assessed using the CODA® Tail-Cuff System every week for three weeks. 12-week-old SHR rats received a dose of vehicle or T-854 (1250mg/kg) per os with a 48h-wash-out interval between two gavages, in random order. Arterial pressure was recorded during 24h post-gavage with a radio-telemetry device (HD-S10, DSI) directly implanted into the abdominal aorta. Results: In mice, L-NAME increased systolic (SBP; from 105±3 to 130±1 mmHg, p&lt;0.0001), diastolic (DBP; from 77±3 to 97±2 mmHg, p&lt;0.0001) and mean (MBP; from 86±3 to 108±2 mmHg, p&lt;0.0001) blood pressure along the 3 weeks of treatment. Interestingly, in T-854-supplemented mice, SBP was significantly reduced from the first week of supplementation, and DBP and MBP from the second week of supplementation. After three weeks, T-854 lowered the SBP by 16% (p&lt;0.0001), the DBP by 20% (p&lt;0.05) and the MBP by 18 % (p&lt;0.01), in comparison to L-NAME mice. In the SHR study, SBP and DBP were reduced during 24h recording after T-854 gavage in comparison to vehicle, with a 24h-AUC decreased by 108 ± 87.8 and 84.4 ± 69.3 mmHg.h, respectively. Conclusions: In conclusion, T-854 appears as an efficient strategy to prevent AHT and this effect was confirmed in two different preclinical models: L-NAME-induced AHT in mice and SHR rats.
Abstract 13915: Unsupervised Machine Learning Algorithm Identifies People From the General Population at Risk of Heart Failure Based on Speckle Tracking Patterns: The Copenhagen City Heart Study
Authors: Jakob Oeystein Simonsen, Kristoffer G Skaarup, Daniel Modin, Kasper Djernæs, Mats Lassen, Niklas D Johansen, Sergio S Martinez, Brian L Claggett, Jacob Marott, Peter G Jorgensen, Gorm Jensen, Peter Schnohr, Rasmus Mogelvang, Tor Biering-Sørensen
Journal: Circulation (2021)

Background: Peak global longitudinal strain (Peak-GLS) is recognized as a powerful predictor of heart failure (HF). However, the entire strain curve remain undiscovered and therefore important prognostic information regarding HF might be lost. Hypothesis: We hypothesized that analysis of the strain curve using unsupervised machine learning (uML) would reveal novel ventricular deformation patterns capable of predicting incident HF independently of Peak-GLS. Methods: Longitudinal strain curves from 3,767 subjects from the general population without prevalent HF were analyzed using uML. Results: Mean age was 56 years and 43% were male. During a median follow-up of 5.3 years, 94 subjects (2.5%) developed HF. The uML algorithm generated a hierarchical clustering tree (HCT)(Figure 1a) resulting in 9 different clusters with mean strain curves (figure 1b and 1c). Figure 1a summarizes the mean age, IRHF and number of subjects in each cluster. In multivariable Cox regression cluster 3 was significantly associated with reduced incidence of HF when compared to cluster 2 [HR 0.13, 95%CI: 0.04;0.41, P&lt;0.001]. Cluster 4 was also significantly associated with reduced incidence of HF compared to cluster 2 [HR 0.21, 95%CI: 0.08;0.57, P=0.002]. Cluster 2 was associated with increased incidence of HF compared to cluster 3 and 4 even though cluster 2 displayed healthier clinical baseline characteristics as well as higher EF and Peak-GLS. The mean strain curve of cluster 2 had an increased absolute peak value, more rapid decline during systole, faster increase during diastole and a larger diastolic curvature compared to the mean strain curves of cluster 3 and cluster 4. Conclusion: uML was capable of identifying a cluster (cluster 2) exhibiting a deformation pattern associated with increased risk of HF despite having higher EF and peak-GLS. The deformation patterns of cluster 2 was characterized by a faster contraction, faster relaxation and a higher deacceleration after early filling.
Abstract 13258: Transcriptomic Remodeling of Brugada Syndrome Arises During <i>in vitro</i> Cardiac Development
Authors: Bastien Cimarosti, Robin Canac, Virginie Forest, Aurore Girardeau, Nathalie Gaborit, Patricia Lemarchand, Richard Redon, Guillaume Lamirault
Journal: Circulation (2021)

Introduction: Recent genetic data suggest that abnormal cardiac development participate to the pathogenesis of Brugada Syndrome (BrS), a rare inherited arrhythmia responsible for sudden cardiac death in young adults. In vitro cardiac differentiation of human induced pluripotent stem cells (hiPSCs) mimics cardiac development at the cellular level up to a prenatal stage. Objective: This study aims at defining whether BrS impairs cardiac differentiation of hiPSCs. Methods &amp; Results: Transcriptomic kinetics (daily bulk 3’RNA-seq from day 0 to day 30 of in vitro cardiac differentiation) were generated in triplicate for 2 control hiPSC lines and 2 BrS-patient hiPSC lines. First, global analysis unveiled that BrS and control kinetics start to diverge as early as day 8, coinciding with the emergence of beating cells. The 500 most differentially expressed genes between BrS and control kinetics revealed 7 main distinct expression profiles. Interestingly, in one of the clusters (Cluster 2), enriched in genes involved in ventricular development ( e.g. IRX4 , NKX2-5 ), the expression levels were higher in BrS as compared to control, starting at day 8. Inversely, another cluster (Cluster 4), enriched in genes involved in atrial development ( e.g. TBX18 , PITX2 ), displayed an opposite expression profile. Cell-type annotation of single-cell RNA-seq data obtained at day 30 of cardiac differentiation for 1 control (n=2; 11,499 cells) and 1 BrS hiPSCs line (n=2; 12,142 cells) confirmed this ventricular-to-atrial imbalance with an average ventricular-to-atrial cell number ratio of 0.97 and 8.27 for control and BrS lines, respectively. Conclusion: This first transcriptomic kinetic study supports the hypothesis of an early developmental defect in BrS. Altogether, our data show that BrS hiPSCs are more prone to ventricular specification as compared to control cells. This suggests that an abnormal cell fate during cardiac differentiation may participate to BrS pathogeny.
Abstract 13466: In Experimental Pad miR29a Modulates Perfusion Recovery and ADAM12 Expression Through Direct Interaction With ADAM12 mRNA
Authors: Victor Lamin, Thomas Wong, Joseph Verry, Isaac Eigner-Bybee, Ayotunde O Dokun
Journal: Circulation (2021)

Peripheral artery disease (PAD) is caused by atherosclerotic occlusion of vessels outside the heart and most commonly affects vessels of the lower extremities. Angiogenesis is a part of the post ischemic adaption involved in restoring blood flow in PAD. Previously, in a murine hind limb ischemia (HLI) model of PAD, we identified ADAM12 as a key genetic modifier of post-ischemic perfusion recovery. However, less is known about ADAM12 regulation in ischemia. MiRNAs are a class of small, non-coding, single-stranded RNAs that regulate gene expression primarily through transcriptional repression of mRNA. We showed miR29a modulates ADAM12 expression in the setting of type 1 DM and ischemia. However, how miR29a modulates ADAM12 was not known. Moreover, the physiological effects of miR29a modulation in a non-diabetic setting was not known. Here, we demonstrate that AAV-mediated ectopic overexpression of miR29a in ischemic mouse hind limbs impairs post ischemic perfusion recovery and angiogenesis. We further demonstrate that miR29a regulates ADAM12 through direct interaction with ADAM12 mRNA. Treatment of ischemic mouse hind limbs with AAV9 particles containing miR29a (pAV-miR29a) increased miR29a expression (pAV-control vs pAV-miR29a: 3.22 ± 0.36, vs 1.0 ± 0.09, p&lt;0.05, n=5-6,) and decreased ADAM12 mRNA expression (1.0 ± 0.31 vs 0.30 ± 0.08, p&lt;0.05, n=7-10) resulting in decreased angiogenesis (1.0 ± 0.07 vs 0.66 ± 0.04, p&lt;0.05, n=5), and impairment perfusion (week 3 post HLI perfusion, 101.9±5.55 vs 66.13±12.39, p&lt;0.05, n=5-6,).AGO2 miRNA/RNA-immunoprecipitation studies showed levels of miR29a and ADAM12 mRNA in the complex decreased in samples treated with antagomiR29a (4, 40, 400nM) in a dose dependent manner (miR29a: 0.87, 0.68, 0.44, and ADAM12: 0.89, 0.78, 0.67, fold) but was unchanged by control antagomir (miR29a: 0.84, 0.84, 0.87, fold, and ADAM12: 1.11, 1.12, 1.10, fold). Taken together the data shows miR29a suppresses ADAM12 expression by directly binding to its mRNA resulting in impaired angiogenesis and poor perfusion. Hence, elevated levels of miR29a as seen in diabetes likely contributes to vascular pathology and lowering miR29a could be a therapeutic target.
Abstract 14161: Drug Compounds Combination Screening Using Human Induced Pluripotent Stem Cell-Derived Cardiac Tissues
Authors: Michal Landesberg, Yehuda Wexler, Irit Huber, Amira Gepstein, Gil Arbel, Lior Gepstein
Journal: Circulation (2021)

Introduction: The introduction of human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) technology provided an important tool for the field of safety pharmacology (QT screening). This approach has been limited, however, mostly to the assessment of a single drug. We present a large scale EP phenotyping system comprised of hiPSC-derived cardiac cell sheets (hiPSC-CCSs), fluorescent voltage sensors and actuators, and an optical mapping system; with the aim of performing drug combination screening. Methods and Results: hIPSCs-CMs were seeded as hiPSC-CCSs in multi-well plates. Tissues were treated with varying concentrations of drug compounds’ combinations. Optical signals were acquired following loading of the hiPSC-CCSs with voltage-sensitive dyes or expression of genetically-encoded voltage indicator (ArcLight). EP parameters such as conduction velocity (CV) and action potential duration (APD) were extracted. ATX2 (late sodium current activator) and Dofetilide (IKr blocker) were chosen as representative APD prolonging reagents. Example of the effects of 16 different drug doses combinations on APD (% change) prolongation is depicted in Fig.1a. Similarly, examples of the restitution plots obtained at 4 different drug combinations are presented in Fig.1b-c. Notice that drug compound's effect on prolonging APD showed greater effect as compared to the cumulative effect of each drug alone. Figure 1: (a) Percentage of change in APD 80 15 minutes post treatment (b, c) APD 80 per condition before and after treatment, respectively Conclusion: These results highlight the potential of the hiPSC-CCS as a model for combinational drug screening. This may bring a unique value to the fields of safety pharmacology, pathophysiology testing and drug screening applications.
EZH2-Mediated MHC Class II Silencing Drives Immune Evasion in AML with t(16;21) (<i>FUS-ERG)</i>
Authors: Nate J Buteyn, Connor G Burke, Jenny L. Smith, Rhonda E. Ries, Amanda R. Leonti, Timothy I. Shaw, Benjamin J. Huang, Todd A. Alonzo, Scott N. Furlan, Jason E Farrar, Soheil Meshinchi, Timothy Junius Triche
Journal: Blood (2021)
Abstract 13690: Complex Clinical Course of Unsuccessfully Revascularized Right Coronary Artery
Authors: Ana Inashvili, Ruifang Yang, Benjamin Kilpatrick, David Goldgrab, Hector Garza, Mauricio Gomez, Christian Perzanowski, Tehreen Khan, William Bugni, Stephen Mester
Journal: Circulation (2021)

Objective: Since onset of reperfusion era, ventricular aneurysms have become a rare complication of acute myocardial infarction, with incidence of LV inferior wall aneurysm around 5%. Guidelines recommend an ICD placement for sustained V tach after 48 hours of MI, however management of persistent V tach associated with ventricular aneurysm is uncertain. Case: The patient is a 60 year old male who presents with persistent palpitations, occurring after a mechanical fall. EKG demonstrated slow persistent V tach with HR of 121.Two and a half months prior, the patient suffered from inferior wall STEMI, unsuccessfully reperfused at another institution, secondary to iatrogenically dissected RCA. He presented at our institution 3 weeks after complaining of chest pain and diagnosed with moderate pericardial effusion, as well as large LV inferior wall aneurysm. Pericardial fluid was not large enough to drain. He represented two weeks later, with worsening SOB and tamponade physiology by TTE. A total of 2.5 L of pericardial fluid was drained over several days. CT surgery was consulted, coronary angiography was performed and demonstrated multivessel coronary artery disease. Plan was to follow up as an outpatient for surgery. Medical Decision Making: During his most recent presentation with V tach, the patient did not respond to Amiodarone infusion but underwent successful synchronized cardioversion with 30 J.He underwent CABGX2 and inferior LV endoaneurysmorrhaphy with 4x6 cm bovine pericardial patch. An ICD was implanted before his discharge. Conclusion: This patient’s V tach was likely secondary to LV aneurysm. Per our hypothesis, he would still be prone to develop V tach around the suture lines.Therefore the patient underwent an ICD implantation.
Abstract 11755: Adverse Events of Third Generation Left Ventricular Assist Devices: Insights From the Manufacturer and User Facility Device Experience Database
Authors: Joseph Heaton, Sohrab Singh, Matthew Li, Saraschandra Vallabhajosyula
Journal: Circulation (2021)

Background: Left ventricular assist devices (LVAD) are used frequently to treat end-stage heart failure. The HeartMate 3 (HM-3), the newest LVAD, has limited data on complications. We analyzed the post-marketing surveillance data from the Manufacturer and User Facility Device Experience (MAUDE) database to evaluate complications from the HM-3. Methods: We queried the MAUDE database for device event reports of the HM-3 LVAD from 1/1/2017 to 12/31/2019. We screened event reports for completeness, stratified complications into the device and patient effects, and used descriptive analyses on the compiled reported complications. Results: In this time period, 3,867 device reports met the search criteria, of which 961 identifiable device-specific complications were reported. The most common device events reported were infusion flow disruptions (21.0%), halted pump (9.2%), and material deformation (8.4%). Additionally, 5,676 events affecting patients were also reported in this period. Not counting death, blood loss (21.8%), infection (17.8%), and thrombus (3.3%) were the most commonly reported clinical events. Lastly, 535 deaths were reported, stemming from cerebral vascular accidents (9.7%) and hemorrhage (6.7%). Device events, patient events, with device and patient events associated with death are represented in Figure 1 . Conclusion: Findings from the MAUDE database provide insight into complications and risks of the HM-3 LVAD. Addressing the complications and understanding the risk may improve clinical outcomes for patients with refractory heart failure. Figures 1A, 1B, 1C, 1D
Standardised measurement of coronary inflammation using cardiovascular CT: integration in clinical care as a prognostic medical device
Authors: E K Oikonomou, A S Antonopoulos, D Schottlander, M Marwan, C Mathers, P Tomlins, M Siddique, L V Klüner, C Shirodaria, M C Mavrogiannis, S Thomas, A Fava, J Deanfield, K M Channon, S Neubauer, M Y Desai, S Achenbach, C Antoniades
Journal: Cardiovascular Research (2021)