tbuckley/cabot-search huggingface dataset:
Abstract 12412: In Silico Evaluation of Dosing Regimens to Accommodate Coadministration of Mavacamten With Strong Inhibitors of Cytochrome P450 3A4 and Moderate Inhibitors of Cytochrome P450 2C19 in Patients With Obstructive Hypertrophic Cardiomyopathy
Authors: Samira Merali, Haden Bunn, Caroline Sychterz, Manting Chiang, Shilpa puli, Amy J Sehnert, Bindu Murthy, Joga Gobburu
Journal: Circulation (2023)

Background: Mavacamten is primarily metabolized by cytochrome P450 enzymes CYP2C19 and CYP3A4 and coadministration with strong CYP3A4 or moderate CYP2C19 inhibitors is contraindicated in patients with obstructive hypertrophic cardiomyopathy (HCM) in the US prescribing information (USPI). Aim: To assess the safety and efficacy of accommodating coadministration of mavacamten with strong CYP3A4 and moderate CYP2C19 inhibitors via simulations. Methods: Simulations of 5000 virtual patients with obstructive HCM uniformly distributed by CYP2C19 metabolizer phenotypes were performed using population pharmacokinetic and pharmacodynamic models. The USPI posology and variations were simulated to evaluate if short term (1 week) and long term (chronic) coadministration of CYP3A4 or CYP2C19 inhibitors could be accommodated. Analogous to USPI posology development, comparisons were made by evaluating proportions of patients with left ventricular ejection fraction [LVEF] &lt; 50% (safety) and Valsalva left ventricular outflow tract gradient [VLVOTg] &lt; 30 mmHg (efficacy). Results: When initiating mavacamten with a CYP3A4 inhibitor, a posology using 2.5 mg starting dose, with coadministration stopped if LVEF &lt; 50% at 2.5 mg, resulted in a similar peak proportion of CYP2C19 poor metabolizers with LVEF &lt; 50% (5.7%) and LVEF &lt; 40% (0.9%) compared to the USPI (2.7% and 0.3% respectively; Table ). When initiating mavacamten with a CYP2C19 inhibitor, a 2.5 mg starting dose resulted in a similar peak proportion of LVEF &lt; 50% in CYP2C19 ultrarapid metabolizers to USPI. Optimal efficacy was achieved; in some patients, this was delayed owing to dose reduction. Interruption of mavacamten during short term administration of inhibitors transiently increased VLVOTg for the duration of interruption, with no effect on LVEF. Conclusion: Coadministration of mavacamten with CYP3A4 or CYP2C19 inhibitors could be accommodated within the titration scheme with dose interruption or down titration.
Abstract 12422: Does a Jump in the Atrioventricular Conduction Curve Really Indicate a Switch From Fast Pathway to Slow Pathway Conduction?
Authors: Youhua Zhang
Journal: Circulation (2023)

Introduction: A jump in the atrioventricular (AV) conduction curve (aka, a discontinuous curve) remains the current clinical criterion for diagnosing dual pathway AV nodal electrophysiology. However, it has never been proven that a jump in the AV conduction curve indicating a transition from fast pathway (FP) to slow pathway (SP) conduction, as it has been assumed. Hypothesis: A jump in the AV conduction curve may not reflect the transition from FP to SP conduction, as assumed it does by the current clinical criterion. Methods: Eighty-one experimental records from rabbit AV nodal preparations containing the following data were analyzed. 1. had at least one AV conduction curve, and 2. had intracellular action potential recordings from AV nodal fibers and/or recording of His electrogram alternans (a validated new index of dual pathway conduction). Results: There were 11 (13%) of 81 preparations showing a jump in the AV conduction curve. In these preparations, the transition from FP to SP conduction was smooth. The jumps always occurred after the FP to SP transition at a much shorter prematurity (Figure). On average, the FP-SP transition occurred at prematurity of 196±39ms versus the jump at 117±9ms (P&lt;0.001). Complex intranodal/nodal-atrial reentries were detected after the FP to SP transition. The jumps were always associated with and most likely caused by the intranodal/nodal-atrial reentry and its subsequent conduction to the His bundle, rather than a direct conduction by the premature beat itself. Conclusions: The transition from FP to SP conduction does not produce a jump in the AV conduction curve. A jump in the AV conduction curve is likely caused by induction of intranodal/nodal-atrial reentry by the premature beat and the subsequent conduction of the reentrant beat to the His bundle, rather than a direct conduction by the premature beat itself. Thus, a jump in the AV conduction curve as the current clinical criterion of dual pathway conduction should be invalidated.
Abstract 12348: Targeted Degradation of Topoisomerase 2b by Dexrazoxane for Prevention of Doxorubicin-Induced Cardiotoxicity: Dose and Time Course Study in Human
Authors: Hui-Ming Chang, Jinn-Yuan Hsu, Jim Chen, Edward T Yeh
Journal: Circulation (2023)

Introduction: Doxorubicin is known to induce cardiotoxicity through topoisomerase 2b (Top2b), whereas doxorubicin poisons topoisomerase 2a (Top2a) to kill cancer cells. When Top2b was genetically deleted in the cardiomyocytes of adult mice, doxorubicin-induced cardiomyopathy was prevented. Pharmacological degradation of Top2b by dexrazoxane can also prevent doxorubicin-induced cardiotoxicity in mice. However, it is not known whether dexrazoxane can induce degradation of Top2b in human. Hypothesis: Targeted degradation of Top2b by dexrazoxane can be achieved in humans. Methods: Top2b protein level in peripheral blood mononuclear cells (PBMC) were assessed serially after intravenous dexrazoxane infusion in human volunteers. The effectiveness of dexrazoxane on Top2b degradation and the time course of Top2b degradation were determined. Blood was drawn before dexrazoxane infusion, hourly after infusion up to 12 hours, at 24 hours, and at 48 hours. PBMCs were isolated using SepMate tube and fractionated into nuclear and cytosolic fractions. The nuclear fractions were used in Western blot analysis. Immunoblotting was carried out with rabbit anti-Top2b, anti-Top2a, or anti-Lamin B1 antibodies, followed by Peroxidase AffiniPure goat anti-rabbit IgG. The ratio of the intensity of the Top2b and Lamin B1 bands were normalized by setting the pre-ratio to 1. Results: One hour after dexrazoxane infusion, Top2b level in leukocytes was reduced to 14%-21% of baseline. Dexrazoxane-induced degradation of Top2b persisted for up to 12 hours and returned to baseline 24 hours after dexrazoxane infusion. Importantly, Top2a level did not vary significantly following dexrazoxane infusion. There were no serious adverse reactions in all participants. Conclusions: Human PBMC can be used as a surrogate to follow Top2b degradation. Degradation of Top2b can be achieved with dexrazoxane dose as low as 100 mg/M 2 (one-fifth of the current FDA recommended dose when used in conjunction with doxorubicin). Thus, early dexrazoxane followed by delayed-administration of doxorubicin can be studied as a new strategy to prevent doxorubicin-induced cardiotoxicity by depleting Top2b. Moreover, dexrazoxane did not affect Top2a, thus preserving doxorubicin’s efficacy.
Abstract 12464: Family Caregiving Support and Sleep Duration Among African American Family Caregivers
Authors: Elliane Irani, Stephanie Griggs, Heba Aldossary, Carolyn H Still, Ronald L Hickman
Journal: Circulation (2023)

Background: African Americans family caregivers are at risk for poor sleep health and cardiovascular disease. Psychological health (i.e., depressive symptoms) and social determinants of health (i.e., social interactions) are associated with sleep health (i.e., sleep duration) and are important contextual drivers of cardiovascular health. Recently, the American Heart Association recognized sleep duration as a component of cardiovascular health. However, there is limited literature on psychological and social determinants of sleep duration among African American family caregivers. Aim: The purpose of this cross-sectional study was to examine the contribution of depressive symptoms and family caregiving support to sleep duration among African American family caregivers. We hypothesized that higher levels of depressive symptoms and lower levels of family caregiving support would be associated with shorter sleep duration. Methods: African American family caregivers ( n = 55) of adults with chronic illness were recruited through community-engaged strategies. Demographic, depressive symptoms, family caregiving support, and sleep duration data were based on self-report measures, whereas body mass index (BMI) data were based on objective height and weight assessments. Hierarchical linear regression was used to determine the contributions of depressive symptoms and family caregiving support on sleep duration, controlling for age, gender, and BMI. Results: On average, participants were 60.67 years old (SD = 12.04) and had a BMI of 34.61 (SD = 7.55). The majority self-identified as female (87.3%). Mean self-reported sleep duration was 5.87 hours (SD = 1.35) per night, which is below the recommended sleep duration of 7-9 hours for adults. In the final model, lower levels of family caregiving support were associated with shorter sleep duration ( b = -.46, p = .046), controlling for caregivers’ age, gender, BMI, and depressive symptoms. Conclusion: Family caregiving support is a modifiable target to promote sleep and cardiovascular health equity for African American family caregivers. Multilevel interventions may optimize the support that caregivers receive from other family members and friends as well as professional and community-based sources.
Abstract 12461: Early Use of Tocilizumab Following Cytokine Release Syndrome During CAR-T Therapy for Multiple Myeloma May Be Associated With Fewer Short and Long Term Adverse Cardiovascular Events
Authors: Sophia Golec, Brunna Pileggi, Erin Moshier, Ariel Peleg, Adriana Rossi, GAGAN SAHNI
Journal: Circulation (2023)

Background: Chimeric antigen receptor-T cell (CAR-T) therapies have recently been approved for multiple myeloma (MM). Patients with MM have a higher burden of cardiovascular (CV) disease compared to other hematologic malignancies due to higher prevalence of CV risk factors, potentially cardiotoxic therapies and older age. Retrospective studies of CAR-T therapy in other hematologic malignancies demonstrated a 20-30% CV event rate following higher grades of cytokine release syndrome (CRS). Early use of the interleukin-6 antagonist, tocilizumab, to reverse CRS has been reported to lower rates of major adverse CV events (MACE). Hypothesis: At our institution, tocilizumab is usually administered as early as grade 1 CRS. We hypothesized that our patients would have lower rates of CV toxicity compared to studies where tocilizumab was administered late or not at all. Methods: We conducted a retrospective chart review of adult patients undergoing CAR-T therapy for MM between 2017 and 2023. The primary outcome was MACE (composite of myocardial injury, new heart failure, stroke, new arrhythmias and CV death) over a median period of 12 months. A Kaplan-Meier curve was used to analyze probability of developing MACE. Results: Of the 145 patients studied, the demographics included median age of 61, male (61%), prior anthracycline use (25%), and carfilzomib use (47%) within 1 year. CV co-morbidities included 57% with hypertension, 35% hyperlipidemia, 23% diabetes mellitus type 2, 17% coronary artery disease, and 14% left ventricular dysfunction. CRS occurred in 121 (83%) patients, of which 99 had grade 1 (82%), 19 (16%) had grade 2 and 3 (2%) had grade 3. Of those with CRS, 108 (89%) received tocilizumab, on average within the first day of CRS. Within 1 year of CAR-T therapy, 14 patients (10%) experienced MACE. The Kaplan-Meier estimates for incidence of MACE were 6% at 30 days, 8% at 6 months and 11% at 12 months. Conclusion: The occurrence of MACE in MM patients following CAR-T therapy with early administration of tocilizumab was lower compared to previously published retrospective studies of CAR-T therapy for other hematologic malignancies despite high CV burden. Further prospective studies are needed to validate these findings.
Abstract 12450: Mystifying Masquerade: Renal Cell Carcinoma Associated Arteriovenous Fistula Presenting as High-Output Heart Failure
Authors: Jaswanth Rao Jasti, Thabuna Sivaprakasam, Muhammad Hamza Saad Shaukat, Randall Lamfers, Orvar Jonsson
Journal: Circulation (2023)

Case Presentation: 59 year-old woman with CKD stage 3b and hypertension presented with 3 months of progressive dyspnea, abdominal distension, bilateral lower extremity edema, and a 60-pound weight gain. Physical exam noted diffuse anasarca, with stable hemodynamics on room air. EKG revealed low voltage leads and chest X-ray demonstrated an enlarged cardiac silhouette. CT abdomen was remarkable for significant ascites, body wall edema, and a suspicious large right renal mass. Diagnostic paracentesis indicated cardiac ascites. Echocardiogram showed preserved ejection fraction, moderate pericardial effusion and an enlarged right side of the heart. Right heart catheterization confirmed high-output heart failure (HOHF). A suspected renal mass-related arteriovenous fistula (AVF) was confirmed through inferior vena caval and renal venogram blood gas sampling, indicating arteriovenous shunting within the renal mass. Hepatic venogram excluded portal hypertension. MRI abdomen confirmed a large necrotic right renal mass consistent with renal cell carcinoma (RCC). Symptoms significantly improved after nephrectomy, with aggressive diuresis, and therapeutic paracenteses leading to an 80-pound weight loss. Postoperative echocardiography illustrated decrease in pericardial effusion and right ventricular size. Cardiac MRI and stress test were unremarkable prior to planned immunotherapy for stage III RCC. Discussion: AVF and HOHF associated with malignancy are unusual presentations. RCC is the most prevalent underlying malignancy linked with AVF and is hypothesized to be a result of hypervascularity caused by a VHL gene mutation. The most often utilized imaging modalities for detecting a tumor-related AVF are contrast enhanced CT or MRI. When imaging is inconclusive, a venogram with blood gas sample, as observed in our case, may be considered to establish an RCC-associated AVF.
Abstract 12426: Effect of Presenting Size on Sex Differences in Ascending Aortic Growth Rate
Authors: Siavash Zamirpour, Marko T Boskovski, James P Pirruccello, William A Pace, Alan E Hubbard, JOSEPH LEACH, Liang Ge, Elaine E Tseng
Journal: Circulation (2023)

Introduction: Current guidelines recommend ascending aortic surveillance at 6-24 month intervals regardless of sex. However, emerging evidence suggests that ascending aortic growth is faster in women than men. It is unknown whether this difference is affected by presenting aortic size. Objective: To characterize aortic growth by sex and presenting size. Methods: The study population consisted of all adults receiving repeated chest computed tomography and/or magnetic resonance imaging at our institution 1994-2022, excluding type A dissections. A custom text processing algorithm was implemented to extract ascending aortic dimensions from radiology reports. Patient-level aortic growth rates were determined by linear regression. Patient-level growth rates were linearly regressed on the interaction of sex and presenting size &lt;4.5 vs 4.5-4.9/5.0-5.4/≥5.5cm, controlling for presenting age. Surveillance intervals at 6, 12, and 24 months were simulated by linear interpolation at the patient level. Results: Ascending aortic dimensions were extracted from 7194 scans across 1998 patients (676 [34%] female). Mean (SD) aortic growth was 0.12 (2.0) mm/yr in women and 0.0 (2.0) in men. Excess growth rate in women compared to men was 0.45 mm/yr (95% CI, -0.07 to 0.98, p=0.09) at 4.5-4.9cm, 1.26 mm/yr (0.35-2.17, p=0.007) at 5.0-5.4cm, and 0.83 mm/yr (-0.44 to 2.11, p=0.20) at ≥5.5cm. For surveillance intervals of 6, 12, and 24 months, 25% of women presenting at 4.5-4.9cm would reach 5.5cm after 3, 2, and 1 scan(s), respectively, compared to 11, 6, and 3 scans in men. For presentation at 5.0-5.4cm, 25% of women would reach 5.5cm after one six-month scan, compared to 10, 5, and 3 scan(s) in men for intervals of 6-, 12-, and 24-months. Conclusions: While others have reported faster aortic growth with larger size overall, we observed this trend only in larger-presenting women compared to larger-presenting men. Our findings suggest a role for sex- and size-specific aortic surveillance.
Abstract 12479: <b> <i>Cardiovascular Stroke Nursing Best Abstract Award:</i> </b> Sex Differences in Relationships Between Inflammation and Symptoms in Persons With Heart Failure
Authors: Brittany Butts, Erica Davis, Alanna A Morris, Sandra B Dunbar
Journal: Circulation (2023)

Background: Heart failure (HF) is a complex syndrome involving interplay of pathologic processes, such as inflammation and myocardial remodeling. Sex differences in cardiac remodeling and function are linked to differences in inflammation. Female hearts show a pro-inflammatory shift and increased cytokine expression with aging not seen in male hearts. Yet, sex is not often considered in HF interventions. Previous studies suggest sex may moderate the relationship between inflammation and symptoms in cardiometabolic disease, but the relationship in HF is unknown. Purpose: To examine sex differences in inflammation and symptoms in Black adults living with HF. Methods: Black adults living with HF (N=41) were enrolled in this pilot study. Physical symptoms were measured with PROMIS Dyspnea, Heart Failure Somatic Perception Scale (HFSPS), and Multidimensional Fatigue Inventory (MFI). Mood symptoms were measured with Center for Epidemiological Studies Depression Scale (CESD), State-Trait Anxiety Inventory (STAI), and Perceived Stress Scale (PSS). Inflammatory biomarkers were measured via multiplex immunoassay. Xanthine oxidase (XO) activity, an indicator of oxidative stress, was measured via ELISA. Pearson correlations were stratified by sex. Results: The mean age was 57 ± 11 years, and 66% were female. Dyspnea was positively associated with XO activity in both groups. Among females, dyspnea was positively associated with matrix metalloproteinase (MMP)-12 (r=.519, p=.033), interleukin (IL)-6 (p=.564, p=.018), [C-C motif chemokine ligand(CCL)-3, (r=.509, p=.037), and CCL-11 (r=.520, p=.032). HFSPS was positively associated with XO activity among females only (r=.445, p=.014). CCL-11 was positively associated with MFI (r=.616, p=.008), PSS (p=.0537, r=.032), STAI (r=.714, p=.001), and CESD (r=.635, p=.008) symptoms among females but not males. Conclusions: While physical symptoms were associated with similar inflammatory pathways, fatigue and mood symptoms were associated with inflammation among females only. Women may be more vulnerable to inflammation-induced mood changes and fatigue. Further work is needed to better understand how sex modulates the relationship between inflammation and symptoms in persons with HF.
Abstract 12317: UBC9 Alleviates Diabetic Cardiomyopathy via the Modulation of Mitophagy
Authors: Hanlin Wu, Ting Zhou, Jing Wang, Yuxin Bu, Zheming Yang, Chenghui Yan, Dan Liu, Yaling Han
Journal: Circulation (2023)

Introduction: Type 2 diabetes is prevalent worldwide. Cardiovascular complications in patients with diabetes include diabetic cardiomyopathy (DCM). Ubiquitin-conjugating enzyme E2 I (UBC9) is the only SUMO-E2 enzyme that plays a key role in cardiomyocytes. Hypothesis: The present study aimed to elucidate the role and mechanism of action of UBC9 in the development of DCM. Methods: We established myocardial-specific UBC9 knockout (UBC9-CKO) and adeno-associated virus-overexpressing mouse models. Additionally, a mouse model of DCM was established using high-fat diet feeding and low-dose streptozotocin injection. This mechanism was explained by the stimulation of cultured cardiomyocytes with palmitic acid. Results: The transcript and protein levels of UBC9 were significantly decreased in the myocardium of patients with DCM. Myocardial-specific UBC9 knockout aggravated cardiac dysfunction, alleviated myocardial fibrosis and hypertrophy, and promoted mitophagy and mitochondrial damage. Meanwhile, UBC9 overexpression exhibited the opposite effects. UBC9 exerted mitochondrial protective effects independent of SUMOylation. UBC9 regulated RUNX2 degradation by directly binding to NEDD4, thus regulating PSEN2 to exert protective effects against mitophagy. Moreover, the effect of UBC9 on mitochondrial function was reversed upon PSEN2 knockdown. Conclusions: UBC9 regulates mitophagy through the NEDD4/RUNX2/PSEN2 pathway and alleviates DCM development by improving myocardial mitochondrial dysfunction. These findings offer novel perspectives on the application of UBC9 as a therapeutic target for DCM.
Abstract 12473: Majority of Technetium-99m Pyrophosphate Scans for the Evaluation of Transthyretin Cardiac Amyloidosis Are Ordered Without Appropriate Paraprotein Evaluation
Authors: Crystal L Yan, Nina Rivera, james hoffman
Journal: Circulation (2023)

Background: Guidelines recommend the use of technetium-99 m pyrophosphate (PYP) scanning after light chain amyloidosis has been ruled out via laboratory testing. Yet lack of execution of this condition significantly hinders the real-world value of PYP scanning to diagnose transthyretin amyloidosis. Objective: The aim of this study was to evaluate the prevalence and consequences of inappropriate PYP scanning at an academic, tertiary care center. Methods: We performed a retrospective study of all PYP scans ordered at our institution from January 2018 to March 2023. Categorical variables were determined as frequencies and percentages. Continuous variables were determined as means and standard deviations. Results: 269 PYP scan orders were identified from 228 distinct patients. Mean age was 67.04 years, 51.2% of patients were female, 66.5% were White, and 47.7% were Hispanic. 52 PYP scans (19.3%) should not have been ordered given positive paraprotein results. 145 PYP scans (53.9%) should not have been ordered given lack of any paraprotein results. Only 9 scans (3.3%) were ordered after negative serum free light chain, serum protein electrophoresis, and serum immunofixation results. Up to seven patients (3.1%) did not receive appropriate paraprotein evaluation prior to tafamidis initiation and thus may have been erroneously treated, representing potential unnecessary healthcare costs to not only the patient, but also the healthcare system. There were no temporal trends for scans performed with zero, three, or positive paraprotein results ( Figure ). Conclusions: Most patients did not undergo complete serum monoclonal protein testing prior to PYP scan ordering. Many patients underwent PYP scanning despite positive serum monoclonal protein test results. Increased awareness and education among physicians regarding paraprotein evaluation prior to PYP scanning is still needed to prevent misdiagnosis, delayed diagnosis, and unnecessary healthcare costs.