tbuckley/cabot-search huggingface dataset:
Abstract 10351: Validity and Relevance of Clinical Worsening as a Composite Endpoint in Pulmonary Arterial Hypertension Trials
Authors: Vicky Mai, Elodie Tremblay, Camille Gosselin, Annie Christine Lajoie, Lacasse Yves, Jean-Christophe Lega, Sebastien Bonnet, Steeve Provencher
Journal: Circulation (2021)

Background: Clinical worsening (CW) is commonly used as an endpoint in pulmonary arterial hypertension (PAH) trials. The use of composite endpoints is based on the assumption that each component is interchangeable. Objectives: We aimed to assess the trial-level surrogacy of CW for predicting overall mortality (considered adequate when coefficient of determination R 2 trial &gt;0.70) in PAH trials. We also assessed whether the various CW components were similar in terms of: 1) frequency of occurrence; 2) treatment-related relative risk (RR) reduction and; 3) importance to patients. Methods: We searched MEDLINE, Embase, and the Cochrane Library (01/1990-12/2020) for RCTs evaluating the effects of PAH treatment on CW. The R 2 trial between the RR for CW and mortality (including after censoring) was analysed by regression analysis. The frequency of occurrence of the CW components, as well as the RR reduction of the CW components and those considered of critical, major and mild-to-moderate importance determined through a web-based survey on 257 PAH patients were assessed. Results: From 4,778 references, we included 35 studies (7,744 pts). The effects of PAH-specific therapies on CW modestly correlated with mortality (R 2 trial 0.32). Most of the CW defining-events were PAH-related hospitalizations (30.5%) and symptomatic progressions (48.0%), whereas deaths (14.1%), treatment escalations (6.8%) and transplantations or atrial septostomies (0.6%) were unusual. The RR across components differed by &gt;0.4 in 20/35 studies (57%). Furthermore, the composite endpoints combined components of both critical to moderate importance to patients in 31/35 studies (89%). The pooled treatment effects only became significant when endpoints of major (RR 0.67;95%CI 0.60-0.74;p&lt;0.01) and moderate (RR 0.61;0.52-0.70;p&lt;0.01) importance to patients were added to critical outcomes (RR 1.02;95%CI 0.78-1.32;p=0.91). Consistently, 8/12 (67%) trials with documented decreases in CW were no longer significant when outcomes of moderate importance to patients were excluded. Conclusion: CW is not a surrogate outcome for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy and importance to patients and are thus not interchangeable.
Abstract MP247: Mitochondrial Complex V Is Regulated By GRK2 In The Heart
Authors: Kimberly Ferrero, Jessica M Pfleger, Kurt Chuprun, Eric Barr, Erhe Gao, Walter J Koch
Journal: Circulation Research (2021)

The GPCR kinase GRK2 is highly expressed the heart; importantly, during cardiac injury or heart failure (HF) both levels and activity of GRK2 increase. The role of GRK2 during HF is canonically studied upstream of β-adrenergic desensitization. However, GRK2 has a large interactome and noncanonical functions for this kinase are being uncovered. We have discovered that in the heart, GRK2 translocates to mitochondria ( mtGRK2 ) following injury and is associated with negative effects on cardiac metabolism. Thus, we have sought to identify the mechanism(s) by which GRK2 can regulate mitochondrial function. We hypothesize that mtGRK2 interacts with proteins which regulate bioenergetics and substrate utilization, and this never-before-described role may partially explain the altered mitochondrial phenotype seen following cardiac injury or HF. Stress-induced mitochondrial translocation of GRK2 was validated in neonatal rat ventricular myocytes, murine heart tissue and a cardiac-derived cell line. Consequently, the GRK2 interactome was mapped basally and under stress conditions in vitro, in vivo , and with tagged recombinant peptides. GRK2-interacting proteins were isolated via immunoprecipitation and analyzed via liquid chromatography-mass spectroscopy (LCMS). Proteomics analysis (IPA; Qiagen) identified mtGRK2 interacting proteins which were also involved in mitochondrial dysfunction. Excitingly, Complexes I, II, IV and V (ATP synthase) of the electron transport chain (ETC) were identified in the subset of mtGRK2-dysfunction partners. Several mtGRK2-ETC interactions were increased following stress, particularly those in Complex V. We further established that mtGRK2 phosphorylates some of the subunits of Complex V, particularly the ATP synthase barrel which is critical for ATP production in the heart. Specific amino acid residues on these subunits have been identified using PTM-LCMS and are currently being validated in a murine model of myocardial infarction. To support these data, we have also determined that alterations in either the levels or kinase activity of GRK2 appear to alter the enzymatic activity of Complex V in vitro , thus altering ATP production. In summary, the phosphorylation of the ATP synthesis machinery by mtGRK2 may be regulating some of the phenotypic effects of injured or failing hearts such as increased ROS production and reduced fatty acid metabolism. Research is ongoing in our lab to elucidate the novel role of GRK2 in regulating mitochondrial bioenergetics and cell death, thus uncovering an exciting, druggable novel target for rescuing cardiac function in patients with injured and/or failing hearts.
Abstract 13321: Identifying Mitral Valve Prolapse at Risk for Ventricular Arrhythmias and Myocardial Fibrosis From 12-lead ECGs Using Deep Learning
Authors: Geoffrey H Tison, Sean Abreau, Lisa Lim, Joshua Barrios, Gene Hu, Thuy Nguyen, Shalini Dixit, gregory nah, Yoo Jin Lee, Francesca N Delling
Journal: Circulation (2021)

Background: Inferior biphasic or inverted T waves have been described on a standard 12-lead ECG in some, but not all patients with malignant mitral valve prolapse (MVP). In contrast, complex ventricular ectopy (ComVE) is associated with myocardial fibrosis and increased mortality in MVP and may represent a better marker of arrhythmic risk. We hypothesize that an ECG-based machine-learning model can identify MVP with ComVE and/or myocardial fibrosis on cardiac magnetic resonance (CMR) imaging within a large ECG database beyond traditional ECG criteria. Methods: A deep convolutional neural network (DNN) was trained to detect ComVE using 12 leads in 6,916 ECGs from 569 MVP patients evaluated at the University of California San Francisco (UCSF) between 2012 and 2020. A DNN was also trained using 87 UCSF MVP patients with available contrast CMR to detect late gadolinium enhancement (LGE). Results: The prevalence of ComVE was 160/569 or 28% (20 or 3% with cardiac arrest or sudden arrhythmic death). The area under the curve (AUC) of the DNN to detect ComVE was 0.81 (95% CI, 0.78-0.84) (Figure). AUC remained high even after excluding patients with moderate-severe mitral regurgitation (MR) [0.80 (95% CI, 0.77-0.83)], or with bileaflet MVP [0.81 (95% CI, 0.76-0.85)]. The top ECG segments able to discriminate ComVE vs no ComVE were related to ventricular depolarization and repolarization (early-mid ST and QRS fromV1, V3, and III). LGE in the papillary muscles or basal inferolateral wall was present in 22 of 87 (25%) with available CMR. The AUC for detection of LGE was 0.75 (95% CI, 0.68-0.82). Conclusions: A deep-learning model can detect MVP at risk for ventricular arrhythmias and fibrosis from standard 12-lead ECGs, and can identify novel ECG correlates of arrhythmic risk regardless of leaflet involvement or mitral regurgitation severity. ECG-based deep-learning may help select, within a large echocardiographic database, those MVP patients requiring closer follow-up and/or a CMR.
Abstract 11983: Prolonged Coronary Arterial Phase and Recurrent Ischemia Are Hallmarks of Repeat Heart Failure and Sudden Cardiac Death in Patient With Dilated Cardiomyopathy and Patent Coronary Arteries an Angiographic and Machine Learning Analysis
Authors: Thach N Nguyen, Thanh N Huynh, Thoa Le, Minh Anh Le, Thu Q Nguyen, Chuong T Le, Nguyet Nguyen, Loc Vu, Minh H Le, Dung T Ho, Gianluca Rigatelli, Ernest Talarico, Marco Zuin, Hung N Pham, Thinh Cao, Nghia T Nguyen Thuong
Journal: Circulation (2021)

Introduction: Many patients with dilated cardiomyopathy (DilCM) and patent coronary arteries came to emergency room with shortness of breath, chest discomfort, elevated troponin level. Many similar DilCM patients did not. Why? Hypothesis: In DilCM and patent coronary arteries, could the combination of coronary slow flow and ischemia is a predictor of recurrent heart failure (HF) and sudden cardiac death (SCD)? Methods: Patients with DilCM underwent coronary angiography and were enrolled if the coronary arteries were patent. In a new dynamic angiographic technique, contrast was injected until the index coronary artery was completely opacified. Then the manual injection stopped. At this moment, the blood in “white” color moved in, displacing the black contrast. The shape and movement of the blood flow could be clearly analyzed above a background of black contrast. The first study measurement was the arterial phase (AP) which was calculated by visual angiographic assessment and artificial intelligence program (Machine Learning algorithms). The AP was defined as the duration from the entry of blood until all the contrast was cleared from the distal index artery. The second study factor was the series of troponin levels. The patients were followed up for (1) recurrent HF hospitalization, (2) aborted ventricular tachycardia by defibrillator (ICD) and (3) SCD. Results: 40 patients with DilCM were enrolled (ejection fraction (EF) averaged 34%) and followed up for 3 years. In 35 DilCM patients, the AP phase was extremely prolonged at 120 frames or 8 seconds compared with 1.56 seconds of historical controls. The results showed: Group A (5 patients): No prolonged AP, no Ischemia: so no HF admission, no death if on guideline-directed medical therapy (GDMT), 3 patients had EF recovered &gt;50%. Group B (25 patients): Prolonged AP and No ischemia: rare hospitalization, ICD shock, no death if compliant with GDMT. Group C (10 patients) Prolonged AP and ischemia: recurrent HF, ICD shocks and 6 SCD Conclusions: In patients with DilCM, prolonged AP and recurrent ischemia were the markers of recurrent HF and SCD. The patients with only prolonged AP were at medium risk and stable if on GDMT. Patients with normal AP without ischemia were at low risk and the EF could recover to normal with GDMT.
Abstract 13722: Co-Existing Cardiac Arrhythmia is Associated With Increased Inpatient Mortality in Hospitalized Patients With Systemic Sclerosis: Analysis of the National Inpatient Sample
Authors: Mavi M Rivera Pavon, Ayesha Abbasi, Sami Shoura, Abhishek Dutta, Dua Ashfaq, Mukunthan Murthi, Alejandro Viilafranca, Sandhya-Shri Kannayiram, Emmanuel Akuna, Ziad Sad Aldeen
Journal: Circulation (2021)

Introduction: Arrhythmias are the most frequent cardiac complications in patients with Systemic Sclerosis (SS). Although associated with high mortality and poor prognosis, hospitalization outcomes for SS patients with arrhythmias are yet to be elucidated. This study aims to determine the burden of cardiac arrhythmias in hospitalized patients with SS. Hypothesis: Co-existing arrhythmia increases mortality and morbidity in hospitalized SS patients. Methods: We searched the National Inpatient Sample (NIS) 2016-2017 databases to identify systemic sclerosis hospitalizations with and without arrhythmia. Using STATA 17 software, we applied multivariate logistic and linear regression to adjust for confounders. The primary outcome was inpatient mortality. Secondary outcomes were mean length of stay (LOS), mean total hospital charge (THC), odds of stroke, heart failure (HF), cardiogenic shock, and cardiac arrest. Results: There were over 71 million discharges in the 2016-2017 NIS database. Out of 63,155 SS hospitalizations, 13,994 (22.1%) had a diagnosis of arrhythmia. SS hospitalizations with arrhythmias had higher inpatient mortality (OR 1.63, CI 1.32-2.01, p&lt;0.001), risk of cardiogenic shock (OR 1.81, CI 1.20-2.73 p=0.005), and cardiac arrest (OR 1.81, CI 1.20-2.73), p=0.005) compared to those without arrhythmias. There was no statistically significant difference in the rates for stroke (OR 1.64, CI 0.75-3.59, p=0.2) and HF (OR 1.15, CI 0.98-1.36, p=0.08) between the two groups. SS and arrhythmia patients had increased adjusted mean LOS by 0.85 days (7 days versus 5 days, p&lt;0.001). Patients with SS and arrhythmias incurred higher adjusted THC than those without arrhythmias (85,184 USD versus 64,152 USD, p&lt;0.001). Conclusion: Hospitalized patients with SS and arrhythmias have increased odds of inpatient mortality, cardiogenic shock, and cardiac arrest compared to those without arrhythmias. Still, the rates of stroke and HF are similar in both groups.
Abstract 14302: Noninvasive Detection of Cardiotoxicity Induced by Chemotherapeutic
Authors: Humayra Afrin, Md Nurulhuda, Tamanna Islam, Md Nurunnabi
Journal: Circulation (2021)

Introduction: Cardiac toxicity is one of the most common side effects of many anticancer drugs. Heart damage due to chemotherapy-induced cardiotoxicity can increase the risk of death from cardiac-related causes and reduce quality of life. Hypothesis: We hypothesize that Vascular Cell Adhesion Molecule 1 (VCAM1), a biomarker overly expressed within heart when a someone treated with doxorubicin (DOX) due to induction of inflammation within the epithelial cells. In this study we aimed to develop a Vcam1 peptide-based imaging nanoprobe to detect and visualize the cardiotoxicity induced by DOX. Method: PLGA-VCAM1-RhB nanoprobe was synthesized using oil in water emulsion method. Size, zeta potential and stability of the probe was measured both in PBS, and PBS with 10% FBS. For in-vitro study Human Cardiomyocyte Cell (HCM) were treated with 0.5μM of DOX for different time period (24 , 48 and 72 hr) to create the inflammation. Toxicity was confirmed by MTT, live dead assay, western blotting, and morphological changes. For in-vivo study 5 mg/kg DOX was injected via tail vain once a week for 3 weeks. After one week of the last dose 100 μg of PLGA-VCAM1-RhB and RhB was injected via tail vain and images were taken at 4 hour of post administration. Results: The nanoprobe was found to be stable both in PBS and in 10% FBS solution. Selective binding and higher accumulation of nanoprobe was detected in DOX treated cell compared to the untreated cell and accumulation content was directly proportional to the duration of treatment. In in-vivo study we found higher fluorescent signal in the DOX treatment group than control (RhB and healthy). We also confirmed the results, by measuring the fluorescence intensity of homogenized cardiac tissue by UV-spectrophotometry. Conclusion: VCAM1-linked nanoprobe was able to detect Vcam1 expression in inflamed cardiac muscle cell. Hence, we can conclude that Vcam1 is overexpressed in DOX induced cardiotoxicity and our nanoprobe is a potential tool to visualize the damaged area of heart in real time.Abbreviation: PLGA - poly(lactic-co-glycolic acid), RhB- Rhodamine B
The 2021 Medicare Advantage Hospice Carve-In
Authors: Claire K. Ankuda, R. Sean Morrison, Melissa D. Aldridge
Journal: JAMA (2021)

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Abstract 12101: Clinical Implications of Integrating Polygenic Risk Into Established Cardiovascular Disease Risk Scores
Authors: Fernando Riveros-Mckay, Saskia Selzam, Priyanka Seth, Rachel Moore, William A Tarran, Jack W O'Sullivan, Euan A Ashley, Gilean McVean, Vincent Plagnol, Peter Donnelly, Michael E Weale
Journal: Circulation (2021)

Risk-guided intervention in the US, informed by the pooled cohort equations (PCE) risk calculator, is the accepted practice for prevention of atherosclerotic cardiovascular disease (ASCVD). We recently showed that a polygenic risk score (PRS, summarising common genetic risk) can be integrated with PCE into an integrated risk tool (IRT) and we validated its utility across multiple contexts including sex, age, genetic ancestry and self-identified ethnicity (Weale et al 2021). The addition of PRS is always beneficial, but its contribution varies by context. When meta-analysed across multiple cohorts, the PRS is more predictive in men (odds ratio per standard deviation, ORsd=1.57) than women (ORsd=1.46). Across ethnicities, the group with the lowest effect size is African American (ORsd=1.14 in men, ORsd=1.11 in women), a result that predominantly reflects a lack of available training samples. The availability of a CVD IRT has practical clinical implications. Because the IRT substantially spreads the risk scores in a given patient stratum, the inclusion of genetic factors can result in some individuals crossing actionable risk thresholds in both directions. Using UK Biobank, a large UK population cohort aged 45-64 with extensive medical and genetic information, we show that the rates of up/down classification are 7.8%/4.2% in younger men (40-54yo), 1.9%/11.6% in older men (55-69yo), 1.0%/0.2% in younger women, and 6.5%/6.6% in older women. This implies a tendency to under-treat in younger and over-treat in older individuals under current guidelines. Model discrimination (Harrell’s C, a measure of area-under-the-curve for survival data) is also greatest in the younger (C=0.751/0.732 in men/women) vs older (C=0.666/0.697 in men/women) age group. Given the increased up-classification and discrimination in the younger group, the addition of genetics provides an opportunity for earlier intervention in those most at risk.
Abstract 10661: Association Between Blood Transfusion and Mortality During Hospitalization for Acute Decompensated Heart Failure
Authors: Laura Methvin, Stephen Kearing, Cassandra Brugger, Emma Hanlon, Pablo Martinez-Camblor, Shayne Dodge, Lauren Gilstrap
Journal: Circulation (2021)

Introduction: Limited data exist on the association between blood transfusion (BT) and mortality among patients hospitalized with acute decompensated heart failure (ADHF) and anemia. There is good reason for this clinical equipoise because the benefit of enhanced oxygen delivery to tissues must be balanced with the consequences of additional volume in a hypervolemic state. The aim of this study is to determine the association between BT and short and long-term mortality among patients hospitalized with ADHF and anemia. Methods: Using EMR data from an academic referral hospital, we created a cohort of patients admitted between January 2012 and December 2019 for ADHF and anemia. Patients with ACS or transfusion dependence were excluded. BT was determined using CPT codes. Inverse probability weighting was used to balance patients who did and did not receive BT across relevant demographic, laboratory and clinical variables. We then used logistic regression and Cox proportional hazard modeling to determine the association between BT and in-hospital, 90-day, and 1-year mortality. Results: There were 2,114 patients admitted with ADHF and anemia; 490 (23%) of these patients received BT. BT was associated with 1.5-fold increased risk of in-hospital mortality (95% CI [1.05-2.16], p=0.03). Among those who survived to discharge, there was no difference in 90-day mortality (OR 1.18 [0.88-1.59], p=0.26) or 1-year mortality (OR 1.04 [0.85-1.29], p=0.69) between those who received transfusion and those who did not (Figure 1). Conclusions: Among patients admitted with ADHF and anemia, BT was associated with higher in-hospital mortality. Among those who survived to discharge, in-hospital BT was not associated with any difference in long-term mortality. Additional work is needed to understand ideal transfusion thresholds. Our work suggests the importance of judicious use of BT in patients admitted with ADHF and advises that BT is associated with a worse prognosis during admission.
Trainee involvement in ERCP: new criteria to simplify a complex problem
Authors: Sridhar Sundaram, Aditya Kale
Journal: Endoscopy (2021)

See also: Impact of trainee involvement on the outcome of ERCP procedures: results of a prospective multicenter observational trialEndoscopy 2020; 52(02): 115-122DOI: 10.1055/a-1049-0359 See also: Reply to Sundaram et al.Endoscopy 2021; 53(12): 1289-1289DOI: 10.1055/a-1577-3160
Abstract P323: Impact Of Diminished Pulsatility On Unravelling Of Von Willebrand Factor (VWF) In Patients With Continuous Flow Ventricular Assisted Devices (CF-VADs)
Authors: Khanh T Nguyen, Yi Wang, Guruprasad A Giridharan, Xuanhong Cheng, Palaniappan Sethu
Journal: Circulation Research (2021)

Introduction: Patients implanted with Continuous Flow Ventricular Assisted Devices (CF VADs) exhibit diminished pulsatility and are at a high risk for developing acquired von Willebrand Factor syndrome (AVWS) and non-surgical bleeding. This study aimed to understand how diminished pulsatility due to CF VAD impacts unravelling and patient plasma levels of von Willebrand Factor (vWF). A microfluidic approach was used to study unravelling of vWF under normal pulsatile flow and flow with diminished pulsatility. In addition, vWF levels in CF-VAD patients was measured to determine vWF levels in circulation. Hypothesis: We hypothesized that diminished pulsatility increases vWF unravelling, likely leading to increased vWF degradation and elevated levels of low MW vWF fragments in circulation, this in turn leads to decreased endothelial vWF production in CF-VAD patients. Methods: vWF molecules were immobilized in a microfluidic device and subjected to either normal pulsatile flow or flow with diminished pulsatility (same mean flow). vWF unravelling behavior was observed using total internal reflection fluorescence (TIRF) microscopy. Patient blood samples were collected 1-2 days pre CF-VAD implant and monthly post-implant. Patient plasma vWF levels were measured using an ELISA kit. Results: TIRF imaging showed that vWF molecules undergo unravelling and significantly greater elongation (p&lt;0.05) under diminished pulsatility than with normal physiological pulsatility, despite higher levels of peak shear rates with normal pulsatility ( Fig.1A ). Evaluation of plasma vWF levels in patients (n=9) showed that vWF levels decreased progressively following CF-VAD placement ( Fig.1B ). These results suggest that diminished pulsatility increased unravelling of vWF and exposure of ADAMTS13 binding sites, potentially leading to enhanced cleavage of vWF into low molecular weight (MW) multimers. Review of literature suggests that both low MW multimers and diminished pulsatility cause endothelial dysfunction and decreased endothelial vWF production, which was evident in patient samples. Conclusion: Diminished pulsatility may independently promote vWF degradation and lead to decreased production of vWF, thus contributing to AVWS.