tbuckley/cabot-search huggingface dataset:
Abstract 13352: The Impact of Machine Learning Models in Reducing Variants of Uncertain Significance in Individuals From Underrepresented Populations Who Are Undergoing Genetic Testing for Heritable Heart Conditions
Authors: Ana Morales, Britt Johnson, Flavia Facio, Yi-Lee Ting, Matteo Vatta, Laure Fresard, Dianalee McKnight, Yuya Kobayashi, Jason Reuter, Swaroop Aradhya, Keith Nykamp, Alexandre Colavin
Journal: Circulation (2023)

Introduction: Many missense variants remain categorized as variants of uncertain significance (VUS) due to limited evidence. VUS are at the core of disparities, as underrepresented individuals tend to receive more VUS. To improve variant classification (VC) across race, ethnicity and ancestry (REA) groups, we developed machine learning (ML) models by leveraging genomic datasets. For this study, we evaluated the impact of ML-informed VC for cardiomyopathy, arrhythmia, lipidemia, aortopathy, hereditary hemorrhagic telangiectasia, and pulmonary hypertension genes. Research Question: What is the utility of ML models for cardiovascular disease panel testing VC across REA groups? Methods: From 1/1/2022 to 5/22/2023, ML algorithms that leveraged SpliceAI, gnomAD, AlphaFold and others were validated. ML evidence that met a negative or positive predictive value &gt;80% was incorporated into Sherloc, an ACMG/AMP-based VC framework. At least 1 validated model was available for 225 genes. Analyses of &gt;20,000 patients were performed from random sampling of 20,000 patients with extrapolation. Measurement error was less than 2% variation by bootstrapping. VCs impacted by ML were evaluated, stratified by REA. Results: Out of 113,206 (32% were from an underrepresent group) US-based individuals that underwent panel genetic testing, ~65,900 (58%) had ML evidence applied to at least 1 variant. ML contributed to classifying at least 1 benign/likely benign (B/LB) variant in ~33,200 (29%) and at least 1 pathogenic/likely pathogenic (P/LP) variant in ~2,700 (2.4%) individuals. A higher percentage of Asian (43%), Black (42%), and Hispanic (37%) individuals had an ML-dependent definitive VC (P/LP or B/LB) relative to White (28%) individuals by a one-tailed, two-sample proportion test (p&lt;2.0x10 -58 ). Conclusions: ML modeling demonstrated utility in cardiology diagnostic gene panel testing. Among individuals who had at least 1 variant with ML evidence applied, 54% resulted in definitive classifications. Additionally, ML appears to provide more definitive VCs for underrepresented individuals. ML can assess factors in ways that are agnostic to population ancestry and, when appropriately incorporated into VC, can narrow the VUS gap rates across REA groups.
Abstract 15123: Adult Human Cardiomyocyte Mechanics in Osteogenesis Imperfecta
Authors: Benjamin W Lee, Matthew Caporizzo, Yingxian Chen, Kenneth Bedi, Benjamin Prosser, Kenneth B Margulies, Alexia Vite
Journal: Circulation (2023)

Introduction: Osteogenesis imperfecta (OI) is an extracellular matrix (ECM) disorder characterized by defects in collagen 1 transport or synthesis. While reduced collagen in OI hearts have been associated with reduced myocardial stiffness and left ventricular remodeling, its consequences on cardiomyocyte (CM) function have not been studied. Here we explore the tissue-level and CM-level properties of a heart from a deceased organ donor with OI Type I (heterozygous c.1821+1G&gt;A mutation in COL1A1). Methods: The OI heart and non-failing (Control) hearts were obtained at the time of organ donation and arrested using ice-cold cardioplegia. Portions of the left ventricle were flash frozen or fixed for molecular assays. Trabeculae were dissected and passive mechanics assessed. The left anterior descending artery was cannulated and perfused with collagenase to isolate single CMs, which were then cultured on physiologic (10 kPa) or pathologic (50 kPa) stiffness substrates. CM contractility was assessed after 24 or 48 hours of culture. Results: Immunoblot and histology confirmed approximately 50% reduction of collagen 1 in OI vs. Control. Trabecular stretch demonstrated low stiffness at the tissue level. Isolated CMs from the OI heart were hypercontractile relative to non-failing controls after 24 hours of culture regardless of culture stiffness. In response to 48 hours of culture, OI CMs demonstrated an exaggerated stiffness-dependent reduction in contractility (sarcomere shortening on 50 kPa substrate- Controls: 0.10±0.01 μm vs. OI: 0.04±0.07 μm, p&lt;0.01) suggesting that OI CMs may have an impaired stress response. Levels of detyrosinated tubulin, known to be responsive to ECM stiffness, were 30% reduced in OI. Conclusions: These data confirm CM level adaptations to reduced ECM stiffness that extend our understanding of OI in the heart and suggests that CMs adapted to a constitutively low stiffness environment may be less able to respond to increased external loads.
Abstract 11647: Effectiveness of Micro Continuing Medical Education at Improving Clinician Knowledge Related to the Management of Degenerative Mitral Regurgitation
Authors: Margaret Harris, Julie Schrand, Joy Marko
Journal: Circulation (2023)

Introduction: We sought to determine the impact of online CME consisting of micro-chapters on clinician knowledge related to the diagnosis and treatment of DMR. Methods: The educational initiative consisted of a collection of six online video-based micro-CME chapters, presented by 3 experts, allowing learners to choose the chapters for participation. The education effects were assessed using a repeated pairs pre-assessment/post-assessment study design, where individual participants served as their own control. McNemar’s tests (P&lt;.05) determined statistical significance overall in level of mastery of the content (made at least 1 more decision correctly or improved confidence in their correct decisions from pre- to post-education). At the question level, a paired-analysis confidence-based assessment (CBA) measured changes in competence and confidence in learners’ pre/post responses to identify learners who are correct and confidence (mastery), correct but not confident (doubt), incorrect or confident (uninformed), and incorrect but confident (misinformed). 1 question was asked per micro chapter. Results: Data from 115 cardiologists and 51 primary care physicians (PCPs) who completed the pre/post questions were included in the analysis. Improvements in percentage of correct decisions answered confidently were seen from pre- to post. Overall, 77% of cardiologists and 75% of PCPs improved their knowledge ( P &lt; .001). Further results highlight the percentage of correct decisions answered confidently before and after education, percent improvement from pre- to post-education, and percent increase in mastery/decrease uninformed for cardiologists and PCPs, respectively, organized by learning objective (Table). Conclusion: This study demonstrates the success of an online CME activity with micro chapters on improving knowledge of related to the diagnosis and management of DMR. Additional gaps were identified for future educational targets.
Abstract 14871: Mitral Valve Involvement in Systemic Sclerosis, Post COVID-19 Infection
Authors: Lu Xu, Albert Avany, Magrian Munetsi, Ashok Khanna
Journal: Circulation (2023)

Introduction: We report a case of mitral valve regurgitation as cardiac involvement of systemic sclerosis (SSc) in a 52-year-old woman post COVID-19 infection. Case Description: 52-year-old female presented with new-onset, progressive dyspnea, dryness and thickness of the skin, intermittent palpitations, and weight loss 3 months after recovered from COVID-19. Initial laboratory studies showed low hemoglobin levels and elevated pro-BNP, troponin-T, hs-CRP and ESR. An autoimmune panel was ordered and revealed positive antinuclear antibodies (ANA) and positive scleroderma related antibodies (anti-RNA polymerase III). Chest radiography and Chest CT without contrast both showed septal and bronchial wall thickening. A transthoracic echocardiogram was performed and showed a severely dilated left atrium and mildly thickened mitral valve leaflets with severe mitral regurgitation. A transesophageal echocardiogram revealed a thickened anterior mitral leaflet and restricted mobility of the posterior leaflet with mitral regurgitation being moderate in severity. These findings were consistent with the reported changes seen on echocardiogram and in autopsies in patients with SSc. The diagnosis of SSc in this patient was made and the patient was started on mycophenolate. Conclusions: This case highlights the possible mechanisms through which COVID-19 may trigger the development of autoimmune and inflammatory reactions which, in our case, lead to the development of mitral regurgitation as a sequela of SSc. Imagine 1. Imagine 2.
Abstract 15426: Stress-Induced Transcriptomic Shift in Human iPSC-Derived Cardiomyocytes Carrying Hypertrophic Cardiomyopathy Associated MYH7 G256E Mutation
Authors: Paul Heinrich, Soah Lee, Alison S Vander Roest, Brock Roberts, Daniel Bernstein, Sean M Wu
Journal: Circulation (2023)

Introduction: Hypertrophic cardiomyopathy (HCM) is a monogenic disorder caused by heterozygous (HET) mutations in sarcomere genes such as MYH7. Recently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying HET HCM mutations have shed new insights into the molecular mechanisms of HCM. However, it remains unclear whether the cellular phenotypes of low penetrant mutations such as MYH7 G256E and others, can be adequately elucidated. Hypothesis: We hypothesize that the incorporation of cellular stressors can enhance the manifestation of pathogenic HCM phenotypes in low penetrant MYH7 mutations. Methods: We generated HET and homozygous (HOM) hiPSC-lines for mutation G256E in the MYH7 locus, which is associated with HCM. We performed single-cell RNA sequencing (scRNAseq) with CellPlex technology on wildtype (WT), HET, and HOM iPSC-CMs at day 30 and 60 of cardiac differentiation to establish baseline cellular transcriptional phenotype. We then treated day 30 hiPSC-CMs with 1μM isoproterenol treatment for 5 days or glucose starvation for 10 days and performed scRNAseq to assess their transcriptional shift. Additional Digital Droplet PCR studies were performed to investigate the MYH7 mutant allele expression. Results: In day 30 iPSC-CMs we detected a large clone-to-clone and batch-to-batch variability transcriptionally that obscured the identification of a consistent mutant phenotype in HET MYH G256E vs WT hiPSC lines. These phenotypes correlated with a 1:1 ratio of mutant vs WT allele expression. Implementation of long-term culture or treatment with isoproterenol or glucose starvation led to enhanced hypertrophic and oxidative phosphorylation gene expression in HET hiPSC-CMs. Intriguingly, the expression of MYH6 increased in MYH7-mutant hiPSC-CMs. Conclusions: The application of cellular stressors can enhance the manifestation of hypertrophic phenotypes in HET MYH G256E hiPSC-CMs and suggests a potential mechanism for the variable penetrance of MYH7 mutations in HCM patients.
Abstract 14651: Noncoding RNA Drug, TY1, Attenuates Cardiac Fibrosis in Two Mouse Models of Systemic Sclerosis
Authors: Xaviar M Jones, Alessandra Ciullo, Thassio Mesquita, Mario Fournier, Weixin Liu, Liang Li, Ahmed G Ibrahim, Eduardo Marban
Journal: Circulation (2023)

Introduction: Systemic sclerosis (SSc) is a connective tissue disease characterized by inflammation and fibrosis of the skin and vital organs. The disease has no specific treatment options and a high mortality (~30% at 3 years). We have previously demonstrated anti-fibrotic and anti-inflammatory properties of EV-YF1, a small Y RNA abundant in extracellular vesicles secreted by cardiosphere-derived cells (CDCs). Here we describe the therapeutic bioactivity of a shorter, engineered derivative, TY1. Methods: 5-7-week-old female C57BL/6J wild type mice (n=100 total) were injected with phosphate-buffered saline (PBS; WT) or 100 μL bleomycin (1 mg/ml) subcutaneously every other day for 3 weeks. Animals then received either vehicle (formulation only, in PBS), TY1, or scrambled TY1 (as an RNA control) via oral gavage. Endpoints include exercise capacity, lung weight, systolic and diastolic function by echocardiography, and histologic quantification of fibrosis in heart and skin. To confirm the antifibrotic findings in an inflammation-independent model, 4-6-week-old Tight-skin (tsk-1) mice (n=18 total) received oral TY1, scramble or vehicle for 4 weeks. Results: Diastolic dysfunction was evident in bleomycin mice, but was normalized by TY1 ingestion (E/E’ ratios in WT: 18.91, vehicle: 32.29, scramble: 36.19, TY1: 20.65 p &lt;0.0001). Likewise, lung congestion and exercise intolerance were ameliorated by TY1 ingestion (p&lt;0.0001). In both models (bleomycin-induced and tsk-1), skin and cardiac fibrosis were greater in vehicle or scramble groups than in WT, but were normalized by TY1 after 4 weeks (p &lt;0.001). Conclusions: These results demonstrate the therapeutic bioactivity of a bioinspired new chemical entity in two complementary mouse models of SSc. Thus, TY1 merits investigation as a potential novel therapeutic for SSc.
Abstract 13721: Coronary Artery Calcium for Risk Stratification Among Persons With Very-High High-Density Lipoprotein Cholesterol
Authors: Alexander C Razavi, Anurag Mehta, Matthew J Budoff, Eugenia Gianos, Nathan Wong, Viola Vaccarino, Marly Van Assen, Carlo N De, Alan Rozanski, Michael Miedema, John A Rumberger, Martin B Mortensen, Leslee J Shaw, Khurram Nasir, Roger S Blumenthal, Anand Rohatgi, Arshed A Quyyumi, Laurence Sperling, Seamus P Whelton, Michael J Blaha, Daniel Berman, Omar Dzaye
Journal: Circulation (2023)

Introduction: Persons with very-high high-density lipoprotein-cholesterol (HDL-C) may experience an increased mortality risk. However, the predictors of mortality among those with very-high HDL-C remain unknown. Hypothesis: Compared to traditional risk factors, coronary artery calcium (CAC) will more strongly stratify risk among individuals with very-high HDL-C. Aims: Among individuals with very-high HDL-C, to 1) calculate crude all-cause mortality rates across the burden of traditional risk factors and CAC, and 2) identify independent risk factors associated with all-cause mortality. Methods: There were 335 primary prevention patients from the CAC Consortium who had very-high HDL-C ( &gt; 80 mg/dL in men, &gt; 100 mg/dL in women) and available information on traditional CVD risk factors. Crude all-cause mortality rates were calculated per 1,000 person-years. Multivariable Cox proportional hazards regression assessed the association of traditional risk factors and CAC with mortality. Results: The mean age was 58.6 years old, 51.0% were women, 51.3% had prevalent CAC, and the median HDL-C was 100 mg/dL. There were 20 deaths (6.0%) over a median follow-up of 10.5 years, 7 (2.1%) of which were attributable to CVD. There was a stepwise higher crude mortality rate per 1,000 person-years across increasing CAC burden ( Central Illustration ). Independent of traditional risk factors, each 100 Agatston Unit increase in CAC score was associated with a 7% higher hazard of all-cause mortality (HR: 1.07, 95% CI: 1.01-1.12) and individuals with CAC &gt; 1000 experienced a 5.75-fold higher hazard of mortality when compared to CAC=0 (HR: 5.75, 95% CI: 1.26-26.24). Beyond age, no traditional risk factor was associated with mortality in multivariable analyses. Conclusion: Measurement of CAC on non-contrast cardiac computed tomography may facilitate risk assessment among individuals with very-high HDL-C.
Abstract 15205: miR-132 Inhibition Improves Myocardial Strain in a Large Animal Model of Chronic Adverse Remodeling
Authors: Sandor Batkai, Celina Genschel, Janika Viereck, Steffen Rump, Denise Traxler, Mariann Gyongyosi, Thomas Thum
Journal: Circulation (2023)

Background: MicroRNAs (miRNAs) are transcriptional regulators and essential drivers of heart failure (HF). The miR-132 is necessary and sufficient to progress adverse cardiac remodeling. The strong effects are exhibited by, amongst others, cardiomyocyte hypertrophy and calcium signaling impairment. Treatments directly targeting the roots of the disease are scarce, but miR-132 inhibition by CDR132L, a rationally designed synthetic oligonucleotide, significantly improves cardiac dysfunction in HF early after myocardial infarction (MI). Rational: The aim of the current study was to gain further data on myocardial function and efficacy of CDR132L by analyzing left ventricular (LV) and atrial (LA) wall motion by serial cardiac magnetic resonance (cMRI) strain imaging in a clinically relevant large animal (pig) model of chronic HF. Methods and Results: Mangalica pigs (n=15) were randomized 1-month post-MI, initiated by left anterior descending artery occlusion followed by reperfusion as a chronic model of post-MI HF. Animals received CDR132L over 5 months by monthly intravenous treatments with 5 mg/kg. LV and LA strain parameters were deteriorated after MI over time but significantly ameliorated by CDR132L treatment, compared to placebo. Strain parameters showed significant correlations with pharmacodynamic measures such as left-ventricular ejection fraction, NT-proBNP and cardiac interstitial fibrosis in remodeling hearts 6 months post-MI. Conclusions: LV and LA motion and contractility were improved by repeated dosing of CDR132L with monthly frequency in a large animal model of chronic post-MI HF. The results highlight the translational value and usability of MRI-based cardiac strain imaging in HF drug development and support further clinical development of CDR132L.
Abstract 13693: Left Atrial Sarcoma Mimicking Myxoma in Embolic Stroke
Authors: Abdul Moiz Qureshi, Haris Manan, Taylor Goulding Avedisian, Christopher Malozzi, Bassam Omar
Journal: Circulation (2023)

Background: Myxomas cause about 0.5% of strokes. Cardiac sarcomas are rare, may mimic myxomas, and are also associated with stroke. Imaging can provide clues to diagnosis. Case: A 53-year-old woman with diabetes, hypertension and prior strokes was admitted with new left hemiparesis. Computed tomography (CT) of the head revealed large middle cerebral artery infarct with petechial hemorrhages. Transthoracic echocardiogram (TTE; panel A) revealed large left atrial (LA) mass suspicious for myxoma protruding through the mitral valve. CT of the chest (panel B) revealed hilar adenopathy and LA mass concerning for myxoma or thrombus with stalk attachment to the right pulmonary vein (PV). Decision-making: Following heart team meeting decision was to remove the mass surgically given its embolic potential. Intraoperative transesophageal echocardiogram (TEE; panel C) revealed a large LA mass with multiple papillary protrusions and attachment via a stalk to the right lower PV. The mass was successfully removed and the patient recovered and was discharged. Follow up pathology returned as cardiac sarcoma. Conclusion: Pulmonary vein intimal sarcomas are rare tumors with poor prognosis, presenting early with chest pain, dyspnea and hemoptysis, or late with stroke. They can mimic myxomas and are therefore often diagnosed post-operatively. Preoperative diagnosis however is imperative to plan treatment and for prognostication. TEE and cardiac magnetic resonance imaging are the modalities of choice to diagnose sarcomas and evaluate extent of cardiac structure involvement.
Abstract 15424: Phase-to-Phase Short Phenomenon in a Left Ventricular Assist Device: Navigating Through Clinical and Ethical Challenges
Authors: Cesar J Benites Moya, Sam J Apple, Adhya Mehta, sheetal vasundara mathai, Diego Barzallo Zeas, Sandhya Murthy
Journal: Circulation (2023)

Description of Case A 59-year-old male with an axial continuous-flow left ventricular assist device (CF-LVAD) presented asymptomatically after noticing low-flow alarms. He reported extensive external driveline damage that accumulated over one year. The CF-LVAD was connected to an ungrounded cable and the driveline was repaired by the manufacturer. However, low-flow alarms continued. Log files revealed pump stoppages on all modes of power which was compatible with phase-to-phase short phenomenon (PtPSP). The patient was cannulated in case of emergent need for ECMO and upgraded to UNOS status 1 for heart transplant. Because PtPSP was considered unrepairable, the patient underwent emergent cardiac transplantation. Discussion The CF-LVAD driveline consists of three phases, each of which is formed by two electrical wires, connected to six motor stators. PtPSP causes driveline dysfunction due to a loss of insulation between the three phases owing to multiple breaches of the insulator, causing the pump to lose power when the damaged phases come into contact. Pump stoppages are likely and unpredictable even on batteries or an ungrounded cable. Patients may notice alarms associated with low flow, pump speed drops, or pump arrest. PtPSP is unrepairable, and pump exchange or urgent heart transplantation are the only viable treatment options.This case highlights the ethical complexity of the care of patients with advanced heart failure, whereby subjective treatment decisions often translate to objectively different levels of priority on the heart transplantation waiting list without intrinsic measures of disease severity, which may incentivize more aggressive care. Conclusions: CF-LVAD driveline dysfunction due to PtPSP is a clinically asymptomatic ominous scenario often uncovered by pump-controller alarms. Given the high risk of abrupt pump stoppage, a diagnosis of PtPSP necessitates emergent device exchange or explant with an orthotopic heart transplantation.
Abstract 16282: Incident Heart Failure With Preserved Ejection Fraction in a Cohort of Patients With Biopsy-Proven Non-Alcoholic Fatty Liver Disease
Authors: Kara Wegermann, Carolyn Ahlers, Georgia Sofia Karachaliou, Sandra Au, Kaela Miller, Fouad Chouairi, Anna Mae Diehl, Manal Abdelmalek, Cynthia Moylan, Marat Fudim
Journal: Circulation (2023)

Introduction: Non-alcoholic fatty liver disease (NAFLD) is associated with heart failure with preserved ejection fraction (HFpEF), independent of shared risk factors. The aim of this study was to determine the prevalence, clinical, and echocardiographic (TTE) features of HFpEF in patients with biopsy-proven NAFLD. Methods: We performed a retrospective single-center cohort study of patients with biopsy-proven NAFLD in the Duke NAFLD Biorepository and Clinical Database. Study entry was at the time of liver biopsy and patients were followed until death or 5/1/2023. Clinical and echocardiographic data were abstracted via manual chart review. HFpEF was defined as: at least one TTE characteristic (left atrial volume index ≥ 29 ml/m 2 , septal wall thickness ≥ 1 cm, or evidence of diastolic dysfunction) and signs or symptoms of heart failure (diagnosis of heart failure on problem list, hospitalization for heart failure, elevated NT pro-BNP level, jugular venous distention, use of loop diuretics, pulmonary or peripheral edema, fatigue, or exertional symptoms). Descriptive statistics were evaluated. Results: A total of 742 patients were included in the study. The mean age of the cohort was 50 +/- 12 years, and 83% were White. 95 (13%) had TTE both prior to study entry and during follow up, while 279 patients (38%) had TTE only during follow up. A total of 185 patients met criteria for HFpEF during follow up. After removing patients with TTE evidence of HFpEF prior to study entry, there were 132 cases of incident HFpEF over a mean follow up of 9.1 years, representing 47% of those with TTE after liver biopsy, and 18% of the overall cohort. Considering only TTE criteria, 142 patients had incident HFpEF. During follow up, 12 patients were hospitalized for heart failure. Conclusions: HFpEF is common in patients with NAFLD and a small percentage of patients do not have a chart diagnosis despite meeting echocardiographic criteria, suggesting that HFpEF may be under-recognized. Screening for HFpEF and/or formal care pathways to address early heart failure will be important to prevent morbidity and mortality in this population.