tbuckley/cabot-search huggingface dataset:
Abstract 17335: Novel Functional Genomic Studies in Scn1bb Variant Associated With Brugada Syndrome and the Ameliorative Effect of Acacetin
Authors: Hector Barajas-Martinez, Jose M Di Diego, Bence Patocskai, Virag Borbath, Gui-Rong Li Li, Alexander Burashnikov, Dan Hu, Charles N Antzelevitch
Journal: Circulation (2023)

Background: Brugada syndrome (BrS) is a channelopathy associated with the development of life-threatening ventricular tachycardia and fibrillation (VT/VF). At present, pharmacological approaches to therapy are very limited. Objective: To evaluate the effect of an SCN1Bb variant and the effects of acacetin in experimental models of BrS. Methods: We evaluated the effect of acacetin in: 1) HEK293 cells expressing Kv4.3+ KChIP2 and Nav1.5+ SCN1B using patch clamp techniques (22 O C), 2) canine ventricular epicardial myocytes 3) coronary-perfused canine right (RV) preparations and 4) Langendorff-perfused canine whole-heart models of BrS in which the sodium channel blocker ajmaline or the calcium channel blocker verapamil, together with the transient outward current agonist NS5806 were used to provoke the arrhythmic phenotype. Results: Co-expression of SCN5A -WT+ KCND3-WT with KChIP2 + SCN1Bb -R214Q (variant associated with 3 cases of BrS and 1 case of sudden infant death (SIDS)), resulted in a 210% increase in total charge of the transient outward potassium current (I to ) as well as a 56.5% reduction in sodium channel current (I Na ) when compared to SCN1Bb-WT . In the absence of the mutation, acacetin inhibited I to with an IC 50 of 7.2±1.0 μM (n=3) in HEK cells, similar to the value obtained in native epicardial myocytes (6 μM). In the presence of the SCB1Bb mutant, IC 50 was dramatically reduced to 2.6±1 μM (n=5, p&lt;0.05) Mean ±SEM. In the wedge and whole-heart models of BrS, acacetin dose-dependently reduced the epicardial action potential notch recorded from the RV or RVOT. Acacetin (5-10 μM) totally suppressed the electrocardiographic and arrhythmic manifestation of BrS, regardless of the pharmacologic model used to induce the arrhythmic phenotype. All repolarization defects were reversed, resulting in marked diminution of J waves leading to total suppression of VT/VF. Conclusions: Our findings demonstrate the ability of an SCN1Bb variant to dramatically shift the balance of current in the early phases of the RV epicardial action potential by reducing I Na as well as augmenting I to , thus predisposing to the development of the BrS phenotype. Our observations also hold promise for acacetin as a safe and effective pharmacologic treatment for BrS and some cases of SIDS.
Abstract 19063: An Updated Meta-Analysis Comparing Left Bundle Branch Area Pacing and Biventricular Pacing for Cardiac Resynchronization Therapy
Authors: Sisir Siddamsetti, Hammam Shereef, Jesse Galuk, Atul Bhatia, Jasbir Sra
Journal: Circulation (2023)

Introduction: Left bundle branch area pacing (LBBAP) is a type of conduction system pacing that has been considered as an alternative to biventricular pacing (BVP) in patients requiring cardiac resynchronization therapy (CRT). Hypothesis: We performed a meta-analysis comparing the clinical and echocardiographic outcomes between LBBAP and BVP in patients requiring CRT. Methods: We performed a systematic literature review in Embase, PubMed, and SCOPUS for all the related articles until November 2022. The literature search yielded 44 publications, of which 6 studies fulfilled the inclusion criteria. The Inverse Variance random effects model was used for continuous variables to calculate Mean Difference (MD) and 95% confidence intervals (CI) and Mantel- Haenszel random effects model was used for dichotomous variables to calculate odds ratio (OR) and 95% confidence intervals (CI). Outcomes analyzed were changed in left ventricle ejection fraction (LVEF), left ventricle end-diastolic dimension (LVEDD), NYHA class, and QRS duration and patients with the echocardiographic response (as defined as LVEF improvement &gt;5%) and heart failure hospitalizations. Results: Over a mean follow up of 8+/-2 months, LBBAP when compared to BVP resulted in significant difference in LVEF improvement (MD = 5.78 % (95% CI [4.75%, 6.80%], P&lt;0.00001), QRS duration reduction (MD = -24.77 ms) (95% CI [-32.78, -16.77], P&lt;0.00001), NYHA class reduction (MD = -0.43, 95% CI [-0.78, -0.08], P=0.02) and number of patients with echocardiographic response (OR = 2.94, 95% CI [1.40-6.14], P=0.004) at follow up. There was no significant difference in LVEDD reduction (MD = -0.5 mm, 95% CI [-3.36, 2.37], P=0.73) and HF hospitalization rates (OR = 0.42, 95% CI [0.11-1.61], P=0.21) between the 2 groups. Conclusions: LBBAP is an effective alternative to BVP in patients with an indication for CRT.
Abstract 19218: Prognosis of Apical Hypertrophic Cardiomyopathy in Patients With Implantable Cardioverter Defibrillators
Authors: Yusuke Kondo, Miyo Nakano, Masahiro Nakano, Takatsugu Kajiyama, Yoshio Kobayashi
Journal: Circulation (2023)

Aims: This Short Communication aims to identify the difference between the prognoses of apical and other types of hypertrophic cardiomyopathy (HCM) in patients with implantable cardioverter defibrillators (ICDs). Methods: We retrospectively analysed the database of our ICD clinic. All patients were implanted with ICDs from October 2006 to August 2017. We classified patients with HCM based on left ventricular (LV) outflow tract obstruction (LVOTO) and midventricular obstruction (MVO), in addition to apical HCM and other non-obstructive HCM types. Patient backgrounds, incidences of appropriate ICD therapies, hospitalizations for heart failure, electrical storms, and total deaths were examined. Results: A total of 64 consecutive Japanese patients with HCM and ICDs were enrolled in this study. The mean follow-up period was 86 ± 24 months, the mean age was 65 ± 14 years, and 83% of the patients were male. The LV ejection fraction was 56 ± 14%, the LV max wall-thickness was 19 ± 7 mm, 9.0% had LV apical aneurysms, and the HCM Risk-SCD was 4.4 ± 2.1. We classified the patients into two groups: 14 patients with apical HCM and 50 patients with other types of HCM. During the follow-up periods, there was no significant difference in the incidence of electrical storm, hospitalization for heart failure, and death between the 2 groups (p=0.11, p=0.60, p=0.39, respectively). Appropriate therapies occurred in 6 of 14 (43%) patients with apical HCM patients and 5 of 50 (10%) patients with other types of HCM (p=0.010). Conclusions: Compared with patients with other types of HCM, patients with apical HCM have a comparative prognosis, and treatment of ventricular arrhythmias should be strongly considered.
Abstract 17330: Demographic Factors Associated With Disparity in Radial Artery Usage in Coronary Artery Bypass Graft Surgery: Insights From the National Inpatient Sample
Authors: Qianyun Luo, Renxi Li, Stephen Huddleston
Journal: Circulation (2023)

Introduction: The choice of graft for revascularization in coronary artery bypass grafting (CABG) impacts surgical outcomes. While both radial artery (RA) and greater saphenous vein (GSV) are options for secondary conduits to the left internal mammary artery (LIMA), RA graft usage is associated with better patency and better long-term survival benefit. However, equity of RA conduit usage in CABG is unknown. This study aimed to examine demographic factors associated with disparity of RA grafting among patients undergoing CABG. Methods: The National Inpatient Sample (NIS) was used to extract patients received who underwent CABG between Q4 2015-2020 based on ICD10-PCS. Patients less than the age of 40 were excluded for congenital heart defects. Preoperative variables include sex, age, race and ethnicity, socioeconomic status (SES), Elixhauser comorbidities, and hospital characteristics. The rate of RA usage with respect to race, sex, and SES was compared, respectively, while all preoperative variables besides the variable of interest were adjusted by multivariable analysis. Results: There were 56,318 CABG cases identified in the NIS with 11,708 RA and 44,610 GSV grafting. African American race (aOR 0.78, p&lt;0.01), Hispanic race (aOR 0.83, p&lt;0.01), female sex (aOR 0.53, p&lt;0.01), and lower income (0-25 percentile, aOR 0.78, p&lt;0.01; 25-50 percentile, aOR 0.95, p=0.04) were independently associated with lower rates of RA grafting usage among patients who underwent CABG. Conclusion: This study reveals disparities in RA graft usage for CABG, including racial minorities, women, and economically disadvantaged groups who were less likely to receive RA. These findings highlight the need for healthcare equity in choosing the optimal graft conduit in CABG.
Abstract 17355: Mitochondrial Calcium Uptake Regulates Lung Alveolar Epithelial Regeneration by Connecting Mitochondrial Metabolism With Epigenetic Changes
Authors: Mir Ali, Xiaoying Zhang, Dhanendra Tomar, John W Elrod, Ying Tian
Journal: Circulation (2023)

Introduction: Lung disease is the third leading cause of death and expanding. The endogenous regeneration of lung alveolar epithelium is severely compromised with age and chronic lung disease resulting in deaths after infections such as COVID-19. Mammalian lung alveolar epithelium consists of: alveolar epithelial type 1 and type 2 cells (AT1 and AT2). Stem/progenitor AT2 cells trans-differentiate into the gas exchanging AT1 cells in response to injury and regenerate the lost alveolar epithelium. Molecular mechanism of AT2-to-AT1 cell differentiation is unknown and its identification is critical for therapeutic development. Mitochondrial calcium controls fundamental cellular processes such as ATP production, metabolism, cell death etc. Dysregulation of mitochondrial calcium is implicated in diabetes, heart failure and neurodegeneration. Mitochondrial calcium uptake 1 (MICU1) negatively regulates mitochondrial calcium uptake which affects downstream signaling such as metabolite bioavailability and epigenetics. Results: We have identified a remarkable increase in MICU1 expression and a decrease in mitochondrial calcium uptake in AT2 cells during AT2-to-AT1 cell differentiation in adult mice after bacterial lung infection injury. Micu1 knockout in AT2 cells resulted in mitochondrial calcium overload, reduced AT2-to-AT1 cell differentiation and impaired lung regeneration after lung injury in mice. MICU1-dependent mitochondrial calcium regulated the citric acid cycle metabolite, α-ketoglutarate in AT2 cells. The metabolite, α-ketoglutarate, also functions as a signaling molecule and alters cellular epigenetics by activating Jumonji C domain containing histone lysine demethylases. Micu1 knockout AT2 cells exhibited α-ketoglutarate downregulation and the epigenetic change of H3K9 hypermethylation. Pharmacological inhibition of Jumonji histone demethylase in mouse AT2 cells increased H3K9me3 level and completely blocked AT2-to-AT1 cell differentiation in vitro. Conclusions: Overall, the results suggest that MICU1-mediated mitochondrial calcium uptake plays a key role in AT2-to-AT1 cell differentiation and lung alveolar epithelial regeneration by linking mitochondrial metabolism with epigenetics.
Abstract 17351: Structural Racism and 3-month Postpartum Blood Pressure in a Mulitethnic Prospective Cohort
Authors: Teresa Janevic, Alison Lee, Frances Howell, Micki Burdock, Sarah Nowlin, Sheela Maru, Natalie Boychuk, Oluwadamilola Oshewa, Maria Monterroso, Katharine McCarthy, Alva Rodriguez, Camila Cabrera, Jennifer Lewey, Elizabeth Howell, Lisa Levine
Journal: Circulation (2023)

Introduction: Postpartum hypertension is a leading cause of racial inequities in maternal morbidity and mortality. Research Question: Is racial-economic segregation, a proxy for structural racism, associated with differences in postpartum blood pressure (BP) in Black, Hispanic and Asian (“Global Majority”) birthing people? Methods: We used data (n=369) from the coronaVirus Impact on Birth Equity (VIBE) Study, a prospective cohort in Philadelphia and New York City, 2022-2023. We measured racial-economic segregation by the Index of the Concentration of Extremes (ICE) using zipcode. Participants completed the Gendered Racial Microagressions (GRM) in Obstetrics Scale, and reported postpartum BPs through a text-messaging platform for 90 days. We used mixed-effects linear regression with repeated measures to estimate associations between ICE and postpartum systolic and diastolic BP (SBP, DBP). We adjusted for prepregnancy BMI, race-ethnicity, age, parity, and prepregnancy hypertension. We tested effect modification by hypertensive disorders of pregnancy (HDP) and GRM. Results: Participants were 10.3% Asian, 38.0% non-Hispanic Black, 38.2% Hispanic, and 13.6% other; 26.0% had HDP, 70.7% lived in high concentration poor, Black neighborhoods (highest quartile of ICE), and 37.6% experienced GRM. People in poor, Black neighborhoods had a higher 90-day postpartum mean SBP (120.6 mmHg) than those in other neighborhoods (116.4 mmHg, difference (β)=4.2, 95% confidence interval(CI)=1.7, 6.8; adjusted difference (aβ) = 2.1, 95% CI=0, 4.2). DBP did not differ (73.8 vs. 73.1 mmHg, β =0.8, 95%CI=-1.1, 2.6; aβ=0.1, 95% CI=-1.9, 1.6). Associations did not vary by HDP but were heightened for participants in poor, Black neighborhoods who experienced GRM vs. those in other neighborhoods who did not experience GRM (SBP: β = 6.2, 95%CI= 2.8, 9.6; aβ = 4.2, 95%CI = 1.3, 7.1; DBP: β = 2.1, 95%CI= 0.5, 4.7; aβ = 1.1, 95%CI = -1.3, 3.6). Conclusions: Racial-economic segregation is associated with higher postpartum BP over a 90-day period in Global Majority people, and further heightened in those who experienced GRM. Interventions to disrupt structural racism, including segregation, and eliminate GRM in obstetric care may improve postpartum health inequities.
Abstract 19210: Interpretation of Deep Learning Model That Identifies Regional Myocardial Dysfunction From the Surface Ecg
Authors: Rayan A Ansari, neal bhatia, James Tooley, Vyom Thakkar, Jessica Torres, Jagteshwar Tung, Mahmood Alhusseini, Paul L Clopton, Reza Sameni, Gari Clifford, Euan A Ashley, Marco V Perez, Matei Zaharia, Sanjiv M Narayan, Albert J Rogers
Journal: Circulation (2023)

Introduction: Cardiac wall motion abnormalities (WMA) are key prognostic indicators for major cardiovascular events and mortality, yet they are poorly detected by current ECG screening tools such as Q waves. Deep learning (DL) models have improved analysis of complex data and novel tools may provide interpretation of these models. Hypothesis: ECG features beyond the Q wave may be identified by analyzing an ECG-trained DL model to improve WMA detection over standard ECG measurements. Methods: We developed a DL neural network using 36,964 unique patients (62.9±16.9 years, 47% female, 58% white) labeled by natural language processing of echocardiography reports within 60 days. To understand how the CNN model identifies WMAs from the ECG input, we implemented Shapley Additive exPlanations (SHAP) and DeepExplainer on R-wave aligned beats over 300ms surrounding the QRS complexes to identify hot-spots across the ECG. We then retrained classifiers on 60mg windows of the ECG to identify which timepoints produced the greatest performance (ablation method). Results: Probing the CNN revealed that ECG regions throughout the QRS and T-waves identified WMA. Analysis output shows that such ECG regions arose throughout the QRS and T-waves, and not just at early regions corresponding to Q waves (Panel A) . An aggregate view of the ECG reports summarizes the most discriminatory ECG regions for all patients (Panel B) . Stepwise analysis of limited windows within aligned ECG beats also confirmed this analysis (Panel C) . We found that the highest performance window was 60-120ms (AUC 0.814), containing most of the QRS, with the lowest performance in the window of 0-60 ms (AUC 0.699) and 0.20-0.80ms (AUC 0.707). Conclusions: The DL model show promise in accurately detecting WMAs and provides key insights into critical ECG regions for WMA detection beyond the Q wave. Further analysis of WMA detection with these expanded regions is needed.
Abstract 17305: Diet-Induced Obesity Drives Phospholamban Acetylation and Promotes Cardiomyocyte Calcium Reuptake Into the Sarcoplasmic Reticulum
Authors: Bellina Mushala, Ellen Cho, Michael Stoner, Iain Scott, Seth L Robia, Janet R Manning
Journal: Circulation (2023)

Background: The rising incidence of obesity and metabolic syndrome in the US has profound implications for the pathology of heart disease in coming years. Excessive fat and sugar intake is linked to elevated acetyl-CoA, which in turn is linked to protein acetylation. Although an increasing body of work has determined that non-nuclear lysine acetylation can alter the activity and stability of key proteins involved in cardiac health, the impact of acetylation on calcium handling sarcoplasmic reticulum (SR) proteins, particularly the SERCA2a regulator phospholamban, remains poorly understood. Hypothesis: Metabolic dysregulation and obesity lead to the acetylation of phospholamban, relieving its inhibition on SERCA2a and increasing calcium uptake into the SR. APPROACH: C57BL/6J Mice were subjected to high fat diet-induced obesity (DIO). Left ventricle (LV) tissue was collected and analyzed using immunoblotting and acetylation was quantified by immunoprecipitation with acetyl-lysine antibodies. Human LV tissue from control and diabetic patients was similarly processed and evaluated. Adult ventricular cardiomyocytes were isolated from DIO and control mice, and DIO cells were incubated in media containing excess lipid substrates (1% Lipid Mix 1, Millipore Sigma) and acutely administered HDAC activator ITSA-1 to promote deacetylation. Changes in stimulated calcium dynamics were assessed using Fura-2AM and Fluo-4AM imaging. Results: Phospholamban acetylation significantly increased in LV tissue from both DIO mice (p=0.003) and human diabetic patients (p=0.034) compared to their respective controls. Primary cardiomyocytes isolated from DIO mice and incubated for 24hrs in a high-fat environment exhibited increased calcium transient amplitude and reuptake time (tau) into the SR, while incubation with pan HDAC activators significantly reduced these parameters (p=0.0004, and p=0.003 respectively). Conclusions: Obesity increases the acetylation of phospholamban and enhances the reuptake of calcium into the SR, while deacetylation reverses these effects. These data directly tie nutritive status to a novel phospholamban post-translational modification that may directly impact myocardial calcium handling and contractile function.
Abstract 19066: God Fixed It! A Case of Mitral Valve Prolapse
Authors: Gayatri Bondi, Shwetha Gopal, Jerel M Zoltick
Journal: Circulation (2023)

Background Mitral Valve prolapse (MVP) occurs in 1.2 to 3% of the population. Myxomatous degeneration is the most common cause of MVP in the United States. Clinical features range from asymptomatic to serious complications such as heart failure, endocarditis, arrhythmias, and sudden cardiac death. Patients with MVP may develop severe mitral regurgitation (MR) requiring surgery. We present a unique case of severe MR in a patient with MVP. Case A 67-year-old male with a history of Dysautonomia and Parkinson’s disease presented to the cardiology clinic with complaints of exertional dyspnea, lightheadedness, and palpitation. Transthoracic echo was obtained as part of the workup revealing ejection fraction&gt;55%, Myxomatous Mitral Valve with significant prolapse of the posterior leaflet which was partially flail causing severe MR, regurgitant volume of 149 cc, and percentage of 69%. Cardiac catheterization showed normal coronaries. A transesophageal echo to evaluate the MR and surgical repair of the mitral valve was offered, but the patient refused surgery. He was later lost to follow-up. After 4 years, he presented to the clinic with some exertional dyspnea. Repeat echo revealed moderately calcified posterior leaflet with less mobility causing only moderate MR. His MR continued to improve, an echo after 5 years revealed increasing calcific changes involving posterior leaflet and chordal attachment, causing mild MR and mitral stenosis. Discussion Isolated MVP can develop degenerative MR in up to 25%, and 0.4 to 1.9% can suffer sudden cardiac death. Surgery is recommended for severe symptomatic MVP with MR and it is considered fatal if left unrepaired. In this case, the patient refused surgery and had an unusual natural history of valve calcification leading to decreased mobility, reduced prolapse, and converting severe MR into mild. To our knowledge, this is the first case in literature where there is a self-correction of MVP due to the calcification of the valve leaflet.
Abstract 17309: Assessing the Effect of Corticosteroid Taper Rate and Repeat Pet Imaging on Cardiovascular Outcomes Among a Homogenously Treated Cohort of Patients With Suspected Cardiac Sarcoidosis
Authors: Chaitanya Rojulpote, Abhijit Bhattaru, Sarah Adams, John Salas, Shivaraj Patil, Mahesh K Vidula, Paco E Bravo
Journal: Circulation (2023)

Introduction: Serial positron emission tomography (PET) imaging is utilized to monitor disease activity and treatment response in patients with suspected cardiac sarcoidosis (CS). However, there is no data available on the cardiovascular outcomes associated with corticosteroid taper rates and timing of repeat PET imaging in patients with CS. Methods: We identified 70 patients with suspected CS (Age: 56.3 ± 9, 31% female, LVEF 45.6 ± 13.6, median follow-up time: 6.3 months [4-7.6]) who were treatment naïve and displayed inflammation on baseline FDG-PET, subsequently started on a moderate-dose of prednisone only (i.e., 30-40 mg/day), and had a diagnostic follow-up PET. Patients were divided into two groups based on median follow-up time between PET scans; early (&lt;6.3 months, n=35) or delayed (≥6.3 months, n=35) surveillance imaging. Corticosteroid taper was captured by measuring weekly changes in prednisone from treatment initiation to follow-up PET. Major adverse cardiovascular events (MACE) were defined as sustained ventricular tachycardia/ventricular fibrillation (VT/VF), heart failure (HF) admission, and death. Results: In this homogenously treated cohort, overall, we observed no significant difference in MACE between early vs delayed imaging groups (p=0.117, Figure 1A). Furthermore, there were no significant differences in corticosteroid taper rates between early and delayed groups (-0.927 ± 1.15 vs -0.618 ± 0.58, p=0.163). As such, we observed no difference in MACE associated with taper rate (p=0.647, Figure 1B). Conclusion: Patients with suspected CS undergoing repeat PET imaging had similar adverse cardiovascular outcomes despite variations in follow-up time and taper rates of prednisone. We suggest to adopt an early imaging strategy to allow for timely optimization of immunosuppression and clinical surveillance.