tbuckley/cabot-search huggingface dataset:
Abstract 16157: Impaired Branched Chain Amino Acid Metabolism in Porcine Right Atrial Dysfunction
Authors: Jacob Sternbach
Journal: Circulation (2023)

Background: Right atrial (RA) dysfunction is prevalent and an early predictor of mortality in pulmonary arterial hypertension (PAH). At present, the underlying pathobiology of RA dysfunction is not well defined, and thus approaches are needed to delineate potential therapeutic pathways to hopefully improve outcomes in PAH. Methods: Surgical pulmonary artery banding induced right ventricular and right atrial dysfunction in male piglets. 6 weeks post-banding, cardiovascular magnetic resonance imaging quantified cardiac structure/function. Right atrial and ventricular tissue was subjected to quantitative proteomics and targeted metabolomics. Results: PAB piglets had decreased RA ejection fraction (RAEF) and increased RA end-systolic volume. Pathway analysis revealed proteins responsible for branched chain amino acid (BCAA) degradation, including MCEE (Methylmalonyl CoA Epimerase), DLD (Dihydrolipoamide Dehydrogenase), HIBADH (3-hydroxyisobutyrate Dehydrogenase), ACAT1 (Acetyl-CoA Acetyltransferase 1), and IVD (Isovaleryl-CoA Dehydrogenase), were reduced in PAB RAs, which was not observed in RV tissue. Targeted metabolomics analysis demonstrated BCAAs were elevated in the RA of PAB piglets and BCAA levels were strongly and inversely associated with RAEF. Conclusions: Deranged BCAA metabolism is uniquely observed in the dysfunctional RA, which offers a new therapeutic target for this important clinical problem.
Abstract 15506: Pattern of Use of Anakinra for Patients With Kawasaki Disease versus Multisystem Inflammatory Syndrome in Children Associated With COVID-19
Authors: Michael A Portman, Ashraf S Harahsheh, Geetha Raghuveer, Balasubramanian Sundraram, Aishwarya Venkataraman, Marco Yamazaki-Naksahimada, Susan Park, Mona El Ganzoury, Audrey Dionne, Deepika Thacker, Arthur J Chang, Nadine Choueiter, Elizabeth A Braunlin, William Orr, Kimberly E McHugh, Pedrom Farid, Cedric Manlhiot, Brian W McCrindle
Journal: Circulation (2023)

Background/Aims: Anakinra (interleukin-1 blocker) has emerged as a potential adjunctive therapy for treating resistant acute Kawasaki disease (KD) and those with evolving aneurysms, and has been used as both primary and adjunct therapy for treating Multisystem Inflammatory Syndrome in Children (MIS-C), both in the absence of randomized trials. We sought to determine patterns of use, adverse events and evidence of benefit. Methods: The International KD Registry contemporaneously enrolled 727 patients with KD (site diagnosis confirmed by AHA criteria) and 1476 with MIS-C (site diagnosis confirmed by CDC criteria) from 39 sites in 7 countries from 01/2020 to 01/2023. Data collected included demographics, clinical features and presentation, management, laboratory values, and outcomes. Results: Anakinra was used at 22 (56%) sites for 11 (1.5%) KD patients (median duration 21 days) and 257 (17.4%) MIS-C patients (8 days; 11% discharged on anakinra). For KD, anakinra was used for treatment resistance for 5 sites, evolving aneurysms 3, macrophage activation syndrome (MAS) 1 and not-specified for 2. For MIS-C, anakinra use was determined by protocol for 3 sites, on a case-by-case basis for 10, reserved for treatment failure for 3 and not-specified for 6 sites. Reported indications for use (may be multiple) included routine use for ICU patients for 34% of treated MIS-C patients, worsening/persistent lab abnormalities 28%, critical decompensation (primarily cardiac) 21%, persistent/recurrent fever 21%, treatment failure 9%, coronary artery abnormalities 8%, and cytokine storm/MAS for 4%. Adverse events in treated MIS-C patients were noted for 23 (9%) and included neutropenia in 9, transaminitis 8, injection site pain/rash 4 and one each with anemia and thrombocytopenia. Extreme patient heterogeneity and confounding by indication precluded a formal analysis of impact on outcomes, although sites reported evidence of clinical improvement relevant to reported indications for all but one patient. Conclusions: Greater anakinra use for MIS-C vs KD likely reflects greater perceived indication, primarily greater clinical and inflammatory severity. Subjective evidence of benefit and a low prevalence of adverse events suggest an ongoing role for anakinra.
Abstract 13500: An Improved Reporter Identifies Ruxolitinib as a Potent and Cardioprotective CaMKII Inhibitor
Authors: Oscar E Reyes Gaido, Nikoleta Pavlaki, Jonathan Granger, Olurotimi O Mesubi, Bian Liu, Brian L Lin, Alan Long, David Walker, Joshua Mayourian, Kate L Schole, Chantelle E Terrillion, Lubika J Nkashama, Mohit M Hulsurkar, Lauren E Dorn, Kimberly M Ferrero, Richard L Huganir, Frank U Muller, Xander H Wehrens, Jun O Liu, Elizabeth Luczak, Vassilios J Bezzerides, Mark E Anderson
Journal: Circulation (2023)

Background: Ca 2+ /Calmodulin-dependent protein kinase II (CaMKII) hyperactivity is an established driver of cardiac arrhythmias. Despite proven benefits of CaMKII inhibition in numerous preclinical arrhythmia models, translation of CaMKII antagonists into humans has remained unsuccessful, and today, there are no clinically approved CaMKII inhibitors. Our ability to identify potent CaMKII inhibitors has been hamstrung by a lack of a CaMKII biosensor with sufficient sensitivity for high throughput drug discovery. Research question: We hypothesized that development of a CaMKII biosensor with high throughput capabilities would enable identification of CaMKII inhibitors capable of preventing arrhythmias. Methods: To address this problem, we engineered and validated a new genetically encoded CaMKII biosensor: CaMKAR (CaMKII Activity Reporter). CaMKAR enjoys a dynamic range of 227 ± 11.1 %, seconds-scale kinetics, robust specificity, and dual in cellulo and in vitro functionality. This makes CaMKAR the fastest and most sensitive CaMKII biosensor to date and the first that is amenable for in cellulo drug screening. Results: Using CaMKAR, we carried out a drug repurposing screen (4,475 compounds in clinical use) in human cells. This yielded five previously unrecognized CaMKII inhibitors: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib (false discovery-adjusted p&lt;3 x 10 -5 ). Stand out among these, ruxolitinib, an FDA-approved Janus kinase inhibitor, blocked CaMKII kinase activity with an inhibitory constant of 23.5 ± 2.2 nM. In patient-derived cardiomyocytes, ruxolitinib ameliorated arrhythmogenic Ca 2+ release events (p&lt;0.0001), and in mice, ruxolitinib prevented catecholaminergic polymorphic ventricular tachycardia (p&lt;0.01) and rescued pre-existing atrial fibrillation (p&lt;0.0001). Conclusion: Our work presents three impactful Conclusions: 1) Our biosensor, CaMKAR, provides the highest CaMKII activity reporting performance to date. 2) Long sought-after CaMKII inhibitors already exist within the human pharmacopeia. 3) Our results demonstrate that ruxolitinib—a drug already in human use—is a cardioprotective CaMKII inhibitor and a suitable candidate for cardiovascular repurposing.
Abstract 132: The Effect of Social Determinants on Cardiac Arrest and Pre-Arrest Care Patterns
Authors: Meghan Dillan, Kristen Curtis, Lance D Wilson, Joseph S Piktel
Journal: Circulation (2023)

Background: More than 300,000 people experience out-of-hospital cardiac arrest (OHCA) and only 11% of patients survive to discharge, calling for a focus on prevention. Understanding the impact of social determinants of health (SDOH) on OHCA, including access to care pre-cardiac arrest (CA) can improve outcomes. Aims: To 1) determine the incidence of CA in a large national database across demographics and 2) characterize the CA patient population’s access to care pre-arrest based on SDOH. Hypothesis: SDOH will have a significant effect on CA incidence and access to pre-arrest care. Methods: Observational retrospective cohort study using Epic Cosmos, a large deidentified electronic health database with 186 million patients. IRB approval was not required. Inclusion criteria was ED visit for CA (ICD-10-CM: I46). Patient demographics included age, gender, race, ethnicity, social vulnerability index (SVI, a composite measure with greater SVI representing more adverse SDOH). The primary outcome was CA incidence between demographic groups, reported as odds ratios (ORs). The secondary outcome was incidence of prior visits within 30 days within each demographic group. Significance was determined using Chi-squared analysis. Results: There were 201,846 ED visits for CA between April 20, 2020, and April 19, 2023 (0.11% incidence). For all ages, the odds of CA were greater in the highest SVI quartile compared to the lowest (OR 1.84, p&lt;0.001). Black patients had higher odds of CA than White patients (OR 1.65, p&lt;0.001). In the cohort of patients with an ED visit for cardiac arrest, 9.1% had a prior ED visit within 30 days, and 9.1% and 6.0% had an office or specialty care visit, respectively. Patients with a higher SVI had a greater incidence of ED visits (10.2% vs. 7.8%, p&lt;0.001), but a lower incidence of office visits (8.1% vs. 9.9%, p&lt;0.001) and specialty visits (5.2% vs. 6.8%, p&lt;0.001) pre-arrest. Similarly, Black patients had more ED visits (11.6% vs. 8.6%, p&lt;0.001) than White patients, but less office visits (8.5% vs. 9.8%, p&lt;0.001) and specialty visits (5.6% vs. 6.5%, p&lt;0.001). Conclusions: The SDOH have a significant impact on the risk of CA and s pre-arrest care patterns. Targeting interventions to address community and individual SDOH can lead to prevention of OHCA.
Abstract 14597: Beyond Sex Bias: The Uncharted Role of Rage Signaling in Pulmonary Arterial Hypertension
Authors: Odunayo S Lawal, Maki Niihori, Nolan McClain, Joel James, Ruslan Rafikov, Olga Rafikova
Journal: Circulation (2023)

Background: Pulmonary arterial hypertension (PAH) is a life-threatening disease that initiates in response to pulmonary artery endothelial cells (PAEC) damage followed by inadequate repair. The Receptor for Advanced Glycation Endproducts (RAGE) triggered upon the damage, plays a crucial role in vascular regeneration. However, its specific impact on PAH remains incompletely explored. Hypothesis: In this study, we investigated the sex-specific outcome of RAGE deletion on PAEC homeostasis. Methods: The effect of the global RAGE knockout (KO) on pulmonary hemodynamics, cardiac and endothelial function was studied disaggregated by sex in WT and RAGE KO rats. Endothelial integrity was evaluated via the expression of endothelial junction proteins, the activity of barrier disruptive signaling pathways, and in vivo pulmonary vascular permeability assay. To understand the significance of diminished RAGE signaling in male PAH, we measured membrane RAGE levels in untreated and Sugen/Hypoxia treated rats of both sexes and examined the publicly available single-cell transcriptomic profiles of human PAECs. Results: Male but not female RAGE KO rats developed a spontaneous PAH characterized by a significant increase in the right ventricle (RV) systolic pressure and RV hypertrophy. The PAH phenotype in males corresponded with a male-specific decrease in the expression of CD31 (WT vs. RAGE KO: 1.0 ± 0.07 vs. 0.1 ± 0.02, p &lt;0001, N=6), activation of p38/RhoA signaling axis (p-p38 in WT vs. RAGE KO: 1.0 ± 0.2 vs. 3.2 ± 0.6, p=0.01, N=4), significant PAEC cytoskeletal rearrangement, and increased FITC-dextran extravasation, while female RAGE KOs remained unaffected. We also discovered that Sugen/Hypoxia treatment induced a substantial loss of membrane RAGE, specifically in males. Additionally, human PAEC transcriptomic data revealed that RAGE is expressed primarily in young females but not in males or older females. Conclusions: We conclude that the male sex associates with a reduced RAGE expression and signaling in PAEC, which is further diminished in PAH. The disruption in RAGE signaling, in turn, impairs the pulmonary endothelial barrier, instigates spontaneous PAH, and may contribute to the more severe phenotype observed in male PAH patients.
Abstract 17863: Analysis of Social Determinants of Health, Burden of Treatment and Quality of Life in Patients With Heart Failure With Preserved and Reduced Ejection Fraction, a Single Center Study With Six Months Follow Up
Authors: Kenneth Johan, Chee Yao Lim, Pinal Patel, Inderpreet Singh, Israel Duran Santibanez, Jeffrey Evans, Jorge Gutierrez, Favour Markson, Betina Sinanova, Ammar Vohra, Laverne YIP, Aditya Bhaskaran, Harsh Sura, vidya menon
Journal: Circulation (2023)

Introduction: Heart failure (HF) is a chronic debilitating disease with immense burden on the patient’s life. This study aims to investigate the clinical characteristics, social determinants of health (SDOH), burden of treatment (BoT), and quality of life (QoL) of patients with heart failure with preserved and reduced ejection fraction (HFpEF and HFrEF). Methods: Data from 191 patients (63 HFpEF, 128 HFrEF) were collected from February 2022 to March 2023. Validated questionnaires including SDoH, BoT and QoL were filled by the patient on admission and in 6 months as a follow up. Descriptive statistics were used to compare the demographic and clinical characteristics of HFpEF and HFrEF patients. Inferential statistics, including logistic regression, were used to analyze the associations between SDOH, BoT, QoL, and 30-day readmission rates. Results: Distribution between both groups is similar to the general population. HFpEF patients experienced more interpersonal challenges and reported greater difficulty with self-care and usual activities. HFrEF patients had higher rates of substances, alcohol, and tobacco use. Regarding readmission, HFpEF patients with medication difficulties and HFrEF patients with difficulty accessing healthcare services were more likely to be readmitted. Both HFrEF and HFpEF patients showed significant improvement in SDOH, QoL and BoT in the follow up data (Table 1). Conclusions: The study findings highlight the distinct clinical characteristics, SDOH, BoT, and QoL factors associated with HFpEF and HFrEF. These findings can contribute to targeted interventions and improved patient care. Moreover, the study emphasizes the importance of addressing social and personal factors influencing HF outcomes, aiming to reduce healthcare disparities and improve patient well-being. The results have implications for healthcare providers, policymakers, and researchers in improving the management and outcomes of heart failure patients.
Abstract 14288: α1-Antichymotrypsin Complex (SERPINA3) is an Independent Predictor of Long-Term All-Cause Mortality, but Did Not Predict CVD Events
Authors: Dennis W Nilsen, Volker Poenitz, Reidun Aarsetoey, Thor Ueland, Pal Aukrust, Annika Michelsen, Trygve Brugger-Andersen, Harry Staines, Heidi Grundt
Journal: Circulation (2023)

Introduction: SERPINA3 is an acute phase protein triggered by inflammation. It inhibits neutrophil cathepsin which cleaves protease-activated receptor 4 (PAR-4) via a thrombin-independent pathway, and mast cell chymase which mediates the production of angiotensin-II via an ACE-independent pathway. SERPINA3 is upregulated after an acute myocardial infarction (MI), but data on its long-term prognostic value in MI patients are scarce. Aim: To assess the utility of SERPINA3 as a prognostic marker in patients hospitalized for chest pain of suspected coronary origin. Methods: A total of 871 consecutive patients were included (ClinicalTrials.gov Identifier: NCT00521976). Stepwise Cox regression models, applying continuous log e -transformed values, were fitted for each of the biomarkers with all-cause mortality and cardiac death within median 24-months (mo) and all-cause mortality within median 7 years (y) as the dependent variables, adding an analysis of 1) all-cause mortality or MI, and 2) all-cause mortality or MI or stroke at 7 y follow up (FU). The hazard ratio (HR) (95% CI) was assessed in a univariate and multivariable model, adjusting for traditional clinical cardiovascular risk factors, adding BNP, hsCRP, TnT. Results: Plasma samples from 847 patients were available. At 24 mo FU, 138 (15.8%) patients had died, of which 86 were cardiac deaths. The univariate analysis showed a positive, significant association between SERPINA3 and total death [HR 1.42 (95% 1.19-1.68), p =0.000], but was not significant for cardiac death. Associations after multivariable adjustment were statistically non-significant. At 7 y FU, 332 (38.1%) patients had died. After adjustment, SERPINA3 was independently associated with all-cause mortality [HR 1.14 (95% CI, 1.02-1.28), p=0.022], but not for MI (n=203), and stroke (n=55), respectively, and remained essentially unaffected for all-cause mortality or MI combined (n=404) [HR 1.12 (95% CI, 1.01-1.24), p=0.031], slightly weakened when stroke also was added (n=422) [HR 1.10 (95% CI, 1.00-1.22), p=0.060]. Conclusions: SERPINA3 predicts long-term all-cause mortality, but had no prognostic bearing on short-term cardiac death. Introducing non-fatal CVD events during long-term FU did not improve its prognostic value.
Abstract 17489: Bupropion Poisoning: Extracorporeal Membrane Oxygenation as a Rescue Strategy
Authors: Avtandil Kochiashvili, Jevin Yabut, Bethany Kwarta, Jason A Gluck
Journal: Circulation (2023)

Introduction: Bupropion is a commonly prescribed antidepressant. Although generally well-tolerated, bupropion overdose can lead to severe cardiovascular and neurological toxicity. We present a case of cardiogenic shock and status epilepticus as a result of bupropion intoxication. Case Presentation: A 29-year-old female with history of depression and borderline personality disorder presented to the emergency department unresponsive after ingesting large quantities of bupropion, alprazolam and lisdexamfetamine. Vital signs were unremarkable and physical exam revealed pupil asymmetry. CT head was unremarkable. Urine toxicology was positive for amphetamines and benzodiazepines, with a blood alcohol level of 104. QTc was 522. Patient received versed for status epilepticus and was placed on mechanical ventilation. She developed sustained ventricular tachycardia and hypotension, unresponsive to bicarbonate and amiodarone. The patient was placed on venoarterial extracorporeal membrane oxygenation (VA ECMO) to provide hemodynamic support while eliminating bupropion from circulation. Following repeated episodes of VT, the patient was successfully cardioverted and started on amiodarone. TTE demonstrated left ventricular ejection fraction (LVEF) of &lt;30%. Notably, lipid emulsion therapy was not administered as patient stabilized with ECMO support. After 48 hours of electrical stability, she was weaned off ECMO and inotropes and transitioned to guideline-directed medical therapy. Repeat TTE demonstrated LVEF of 60% on day 12. Mental status improved and patient was admitted to psychiatry with outpatient cardiology follow-up. Discussion: Bupropion overdose can cause prolonged QTc, ventricular arrhythmias, and seizures. Cardiotoxicity results from inhibition of gap junction ion channels, compromising conduction and contractility. Various approaches, including ECMO and lipid emulsion therapy, have been effectively employed in such cases. This case demonstrates that ECMO can serve as a hemodynamic bridge during the elimination of bupropion while augmenting its clearance via increased flow, underscoring the benefits of mechanical circulatory support in cases of intoxication affecting cardiac contractility and conduction.
Abstract 18452: Microtubule Motors Coordinate mRNA Export and Transport to Direct Local Translation in the Cardiomyocyte
Authors: Emily A Scarborough, Rani M Randell, Maria C Vogel, Benjamin L Prosser
Journal: Circulation (2023)

Introduction: The post-mitotic cardiomyocyte (CM) must maintain proteostasis while also preserving the ability to remodel, particularly during times of cardiac growth. How the CM couples transcription and translation in space and time for normal maintenance of the cell is understudied, and thus it is also unclear how these programs are co-opted to enable hypertrophy. Our lab’s previous work has indicated the necessity of microtubules (MTs) and kinesin-1 in proper localization of transcripts, translation and growth of the CM, yet the molecular mechanisms that direct specific mRNAs to subcellular regions for local translation remain opaque. Research Questions: We hypothesize that changes to MT PTMs are sufficient to alter the subcellular localization of motors, mRNA and translation. We additionally postulate that changes to the MT network during initial cardiac growth facilitate mRNA transport and translation. Methods/Approach: To visualize mRNA and protein localization in CMs, we couple immunofluorescence (IF) and smFISH. To measure translation, we methionine-deplete and use methionine-analogues and click chemistry. To measure cell size, we use live cell imaging of a membrane dye. Results: We find that the CM contains at least three subdomains for mRNA localization and local translation, and that some transcripts require proper localization for translation. Nearly any change to the MT detyrosination or tyrosination status is sufficient to mislocalize motors and mRNA. We observe mRNA accumulation at the nuclear short axis when detyrosinated tubulin is increased at the nuclear poles using taxol. This mRNA accumulation is accompanied by dynactin1 and kinesin-1 accumulation as well as nucleoporin relocalization. Taxol treatment in neonatal rat CMs results in a similarly asymmetric mRNA and nucleoporin localization, concomitant with an increase in width along this mRNA axis. Conclusions: A precise balance of dynein/dynactin1 and kinesin-1 in the CM is necessary for mRNA localization, which is at least partly established by MT PTMs. Stabilizing the MT network reveals a role for dynein/dynactin1 and nucleoporins in mRNA export and transport. We propose that perturbed mRNA export/localization may alter downstream translation to direct the growth of the CM.
Abstract 14816: PCSK9 Inhibitors Modify Plaque and Reduce Plaque Progression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Ana E Lima, Gustavo Vilas Boas, Andre L Carvalho Ferreira, Maria Benitez Gonzalez, Camila Guida
Journal: Circulation (2023)

Introduction: Elevated coronary plaque burden and high-risk plaque characteristics, such as thin fibrous cap, are associated with an increased risk of adverse cardiovascular events. However, there is limited evidence on the effect of PCSK9 inhibitors (PCSK9i) on changes to plaque burden and composition. Hypothesis: We aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of standard lipid-lowering therapy with vs. without PCSK9i on plaque burden and phenotype. Methods: We searched PubMed, Embase and Cochrane Central for studies that performed serial intravascular imaging comparing patients with vs. without PCKS9i therapy. Two reviewers independently performed study selection, data extraction and assessment of bias. All outcomes were continuous; thus, we computed pooled mean difference (MD) or standardized mean difference (SMD) with 95% confidence intervals (CI). Random-effects models were used. Statistical analysis was performed using Review Manager 5.4.1. Results: We included 1,696 patients from 6 RCTs. The mean follow-up ranged from 36 to 76 weeks. Mean age ranged from 58.4 to 61.8 years; 1,246 (65%) were male; and 368 (21.6%) had previous myocardial infarction. Percent atheroma volume (MD -1.05%; 95% CI -1.32, -0.77%; p&lt;0.001), total atheroma volume (MD -6.33 mm 3 ; 95% CI -10.01,-2.66 mm 3 ; p&lt;0.001), and total lipid index (SMD -0.58; 95% CI -0.90,-0.26; p&lt;0.001) were significantly reduced in patients treated with PCSK9i. The minimum fibrous cap thickness (SMD 0.59; 95% CI 0.26,0.93; p&lt;0.001) was also significantly improved in patients randomized to PCSK9i. Conclusions: Our findings suggests that PCSK9i reduce progression of coronary atherosclerosis and stabilizes plaque, as evidence by favorable changes in percent atheroma volume, total atheroma volume, lipid index of the plaque, and minimal fibrous cap thickness.