tbuckley/cabot-search huggingface dataset:
Abstract 4141331: The HCM-causing Mutation R495Q in Cardiac Myosin Binding Protein C Causes Contractile Changes in Human Engineered Heart Tissue that is Ameliorated by Chronic Mavacamten Treatment
Authors: Anthony Ross, Willem De Lange, Angeela Gauchan, Emily Farrell, J Carter Ralphe
Journal: Circulation (2024)

Background: About 45% of identified HCM-causing mutations are in cardiac myosin binding protein C (cMyBP-C). One prevalent missense mutation is R495Q, which is in a positively charged pocket and alters the predicted electrostatic properties of the C3 domain. Many known HCM-causing mutations cause hypercontractility, likely through promoting the disordered relaxed state (DRX), in which myosin heads are more likely to bind to actin to generate contractile force, relative to the super relaxed state (SRX) in which myosin heads fold back on myosin tails. Mavacamten (MAVA), an FDA-approved drug for HCM patients with left ventricular outflow obstruction, is proposed to reduce DRX:SRX toward normal by inhibiting the myosin ATPase. It is unclear if all HCM-causing mutations act via this mechanism. Question: What is the contractile phenotypic timeline of MYBPC3 R495Q in human iPSC-engineered heart tissue (EHT) and can chronic MAVA ameliorate this phenotype? Aim: Define the phenotype progression in EHTs homozygous for the R495Q mutation (QQ), compared to isogenic controls (RR). We will use this timeline, combined with pharmacologic intervention to gain mechanistic insight into the pathogenesis of the R495Q mutation. Methods: 3D EHTs were generated from CRISPR/Cas-9 edited QQ and RR human iPSC cardiomyocytes. We used capillary immunoassay to quantify cMyBP-C expression and immunocytochemistry to determine protein localization. Contractile function of EHTs was assessed weekly (weeks 1-6) with chronic treatment of MAVA (100nM) starting at day 8 of EHT culture. Results: QQ EHTs express normal cMyBP-C protein levels with appropriate incorporation into the sarcomere, yet at day 8 show increased twitch force (TF) and fast relaxation (Fig A-B). At day 36, QQs have normalized TF and slow relaxation. Importantly, MAVA normalizes relaxation time (Fig C,D). Conclusion: These data suggest that R495Q presents with an early hypercontractile phenotype. With prolonged time in culture, TF is reduced, and relaxation time slows. Chronic administration of MAVA quickened relaxation, but reduced total force compared to untreated normal EHT, suggesting that caution may be warranted to ensure that systolic function isn’t impaired.
Abstract 4141348: High-intensity Interval Training Improves Cardiac Function and Increases Expression of Genes Promoting Cardiomyocyte Proliferation in Myocardial-infarcted Mice
Authors: BING BO, THANH NGUYEN, Yuji Nakada, Jianyi Zhang
Journal: Circulation (2024)

Background: Previous studies in exercise-based therapies for heart failure patients have demonstrated significant improvements in symptoms and overall quality of care. However, several questions regarding exercise intensity and training modalities are yet to be answered. Also, whether and how high-intensity training (HIIT) may improve cardiac function following acute myocardial infarction (MI) has not been examined. Research Question: HIIT improves cardiac function in mice undergoing myocardial infarction. Approach: Mice were familiarized with treadmill running for five days before MI (LAD ligation); then, mice resumed HIIT following MI (MI+HIIT group). Each session of HIIT intervention in mice includes treadmill running at 90%-100% of the maximal running speed and following 30s of passive recovery, 15 sessions per day, three days per week (one exercise day followed by one rest day) for six weeks. Cardiac function was measured via ultrasound and compared among the MI+HIIT, MI mice without HIIT (MI-only), mice underwent sham operation (Sham), mice underwent HIIT without MI (HIIT-only), and control mice underwent none of these intervention (CON) groups. Cardiac cell proliferation was quantified via EdU immunohistochemistry. Cardiac Bulk-RNA sequencing data was generated to identify signaling mechanisms potentially impacted by HIIT and analyzed via the Deseq2 package and pathway enrichment analysis. Result: MI+MIIT mice showed significantly higher ejection fraction, fraction shortening, and cardiomyocyte EdU signal compared to the MI-only group. Pathway enrichment analysis showed that signaling pathways known for regulating cardiac regeneration, including PI3k-Akt, MAPK, Hippo, and TGFb, were significantly enriched. Also, expressions of growth factors promoting cardiomyocyte proliferation, including POSTN, FSTL1, and FST, were increased in MI+MIIT hearts. Conclusion: HIIT improved cardiac function in mice after MI; also, HIIT may promote regulators of heart regeneration and cardiomyocyte proliferation.
Abstract 4141340: Fbxo44 Alleviates Heart Aging and Mitochondrial Calcium Overload Injury by Modulating RyR2-Related Pathway
Authors: Jian Yang, Chengzhi Zhang, Jing Zhang
Journal: Circulation (2024)

Background: Cardiac aging is a continuous pathological process. Imbalances in mitochondrial calcium homeostasis are prevalent in the aging myocardium. Fbxo44 is a member of the F-box family that has been shown to be involved in a variety of diseases. Here, we report an aging-associated mechanism in cardiomyocytes in which Fbxo44 disrupts mitochondrial calcium homeostasis by promoting phosphorylation of the calcium release channel protein RyR2. Hypothesis: Fbxo44 regulates cardiac aging through the RyR2-related pathway. Methods: The doxorubicin was used to established the animal models of cardiac aging in Cardiac myocyte-specific Fbxo44 knockout (CKO) and control mice. The age-related proteins and positive stained area were used to assess the senescence phenotypes. Cardiac function of mice was assessed using Doppler ultrasound. Expression levels of Fbxo44 and p-RyR2 were evaluated through Western blotting. Fbxo44 was knocked down using adenovirus in H9C2 cells, followed by the addition of doxorubicin to induce cellular senescence. The cell model was analyzed for senescence-related phenotypes by β-galactosidase staining and western blotting. Confocal laser scanning microscopy was employed to assess the expression of the Rhod-2 probe and RyR2 fluorescence. Western blotting was performed to detect the levels of Fbxo44 and phosphorylation of RyR2. Results: Myocardial tissue-specific knockdown of Fbxo44 resulted in improved cardiac function compared to the control group, along with a significant reduction in the degree of senescence and expression of associated pathway proteins. In the cellular model, down-regulation of Fbxo44 significantly reduced the proportion of positive β-galactosidase staining and decreased the expression of senescence markers and related pathway proteins. Furthermore, inhibition of Fbxo44 mitigated mitochondrial calcium damage, accompanied by a decrease in RyR2 fluorescence intensity. Conclusions: Downregulation of Fbxo44 regulates mitochondrial calcium overload and cardiac senescence via RyR2-related pathways.
Abstract 4140963: Major Adverse Cardiovascular Events in Patients with Chronic Atrial and Intestinal Dysrhythmia Syndrome: A Nationwide Analysis
Authors: Jamal Perry, Adarsh Balaji, Sherlon Sinclair, Mustafa Ozbay, Charles poluyi, Esther Duodu, Emmanuel Ukenenye, Oluwasegun Akinti, Anna Nevolina, Henry Aiwuyo, Moshe Gunsburg
Journal: Circulation (2024)

Introduction: Chronic Atrial and Intestinal Dysrhythmia Syndrome (CAIDS) is a rare but intriguing pathology caused by simultaneous arrhythmias impacting both the cardiovascular and gastrointestinal systems. Due to the rarity of the condition, the research remains largely unexplored. As such, the primary focus of this study is to unravel cardiovascular risk within this syndrome. Hypothesis: Patients hospitalized with CAIDS experience a high burden of major adverse cardiovascular events (MACE). Aim: While there is no well-understood etiology for this condition, We aim to analyze data on MACE in patients with CAID to gain insight into their cardiovascular risk. Methods: We queried the National Inpatient Sample (NIS) between 2016 and 2020, searching for adult patients hospitalized for CAIDS using ICD-10 codes. The primary outcomes were MACE and inpatient mortality. Propensity scores were used to match patients with CAIDS who experienced MACE and those who did not. Multivariate and univariate logistic regressions were applied for outcomes, adjusting for age and gender. A p-value of &lt;0.05 was considered significant. Stata 18 was used for analysis. Results: The mean age of the cohort experiencing CAIDS was 76.42 years (95% CI: 75.30-77.54), with a slightly higher proportion of males (63.64%) compared to females (36.36%). The average length of stay for patients with CAIDS was 8.37 days (95% CI: 7.60-9.14). The in-hospital mortality rate for patients with CAIDS was 3.39% (OR 1.02, p = 0.965, 95% CI: 0.51-2.00). Additionally, 3.12% of patients with CAIDS experienced cardiac arrest (OR 3.87, p &lt; 0.001, 95% CI: 1.87-7.99). STEMI was observed in 1.30% of patients with CAIDS (OR 2.65, p = 0.068, 95% CI: 0.93-7.54). Cardiogenic shock was present in 0.52% of patients with CAIDS (OR 12.66, p &lt; 0.05, 95% CI: 1.14-139.94). Heart failure occurred in 36.88% of patients with CAIDS (OR 4.16, p &lt; 0.001, 95% CI: 3.09-5.60), and stroke was present in 10.65% (OR 2.89, p &lt; 0.001, 95% CI: 1.96-4.26). Dilated Cardiomyopathy occurred in 5.2% (OR 5.7, p &lt; 0.001, 95% CI: 3.06 -10.68) Conclusion: Patients with CAIDS face significant risks, with elevated rates of MACE such as cardiac arrest, cardiogenic shock, dilated cardiomyopathy, heart failure, and stroke, although STEMI and in-hospital mortality were not statistically significant.This underscores the critical importance of vigilance in monitoring and managing these patients to mitigate such outcomes.
Abstract 4141691: Uncovering the Mechanisms by Which SGLT-2 Inhibitors Improve Cardiovascular Outcomes: A Proteomic Analysis
Authors: Jad Hamze, Dwight Harris, Christopher Stone, Mark Broadwin, Meghamsh Kanuparthy, Sharif Sabe, Ruhul Abid, Frank Sellke
Journal: Circulation (2024)

Introduction: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to improve cardiovascular outcomes, as evidenced by their inclusion as a preferred treatment option in the ACC/AHA/HFSA guidelines for heart failure management. However, the mechanisms underlying these benefits are not well-understood. The goal of this study is to address this gap through high-sensitivity proteomic analyses to characterize the specific molecular pathways affected by SGLT-2 inhibitor canagliflozin (CAN) administration in a large animal model of coronary artery disease and metabolic syndrome. Methods: Twenty-one six-week-old Yorkshire swine were fed a high-fat diet for induction of metabolic syndrome, after which chronic myocardial ischemia was induced by placing an ameroid constrictor around the left circumflex coronary artery. Two weeks later, the swine either received no drug (CON n=11) or 300mg of CAN daily (n=10). Treatment lasted for five weeks, after which myocardial tissue from both ischemic and non-ischemic regions was collected and sent for proteomic analysis. Results: Proteomic analysis identified a total of 2855 common proteins between ischemic and nonischemic CAN groups. The CAN ischemic group had 124 upregulated and 111 downregulated proteins as compared to CON; pathway analysis applied to this data yielded upregulation of oxidative phosphorylation and respiratory electron transport, as well as downregulation of glycolysis and the pentose phosphate pathway. The CAN nonischemic group had 121 upregulated and 25 down regulated proteins as compared to the CON group. Pathway analysis showed that of the up- and downregulated proteins, significant alterations included upregulation of oxidative phosphorylation and downregulation of gluconeogenesis and glycolysis. Conclusion: CAN treatment in both ischemic and nonischemic myocardial tissue upregulates oxidative phosphorylation and downregulates glycolysis in a clinically relevant large animal model. These changes ameliorate metabolic derangement in the ischemic myocardium and provide further mechanistic insights into the molecular function of SGLT-2 inhibitors in ischemic heart disease.
Abstract 4141299: Cannabis Use and Cardiovascular Crisis: A Meta-Analytical Evaluation of Stroke and Myocardial Infarction Risk
Authors: Vibhor Agrawal, Vinay Suresh, Debankur Dey, Rishu Raj, Anmol Kaur, Adeeb Ali Mohammad, Priyansha Singh
Journal: Circulation (2024)

Background: Cannabis is among the most widely used psychotropic substances globally. With its increasing prevalence, questions have arisen regarding its potential impact on cardiovascular and cerebrovascular health. While multiple studies have explored the association between cannabis use and the risk of cardiovascular and cerebrovascular diseases, findings across these studies have been inconsistent, necessitating a comprehensive evaluation to elucidate the true nature of this relationship. Aim: This meta-analysis aims to investigate the association between cannabis use and the risk of myocardial infarction (MI) and stroke. Methods: A systematic search was conducted in relevant electronic databases, including PubMed, EMBASE, and SCOPUS, from inception to April 2024. Inclusion criteria comprised observational studies evaluating the association between cannabis use and events such as MI and stroke. Two reviewers independently screened studies, extracted data, and assessed quality. A random-effects meta-analysis was performed to estimate pooled ORs and 95% CIs. Heterogeneity was assessed using I 2 statistic. Results: Our meta-analysis included data from 26 studies, with a total population of 72,551,926 individuals of whom 69.5% were female. Among these, 7,832,105 individuals (2.1%) were identified as cannabis users, with 41.2% being female. Cannabis users exhibited significantly higher odds of experiencing MI (OR= 1.38, 95%CI: 1.14-1.68) and stroke (OR= 1.43, 95%CI: 1.08-1.89) compared to non-users. When considering stroke subtypes, while the odds of ischemic stroke among cannabis users showed a trend toward elevation (OR= 1.60, 95%CI: 0.91-2.81), the difference was non-significant. Similarly, the odds of hemorrhagic stroke among cannabis users did not reach statistical significance when compared to non-users, (OR= 1.98, 95%CI: 0.80-4.88). Conclusions: Our analysis reveals a significant increase in the odds of both MI and stroke in cannabis users. Notably, we observed a comparable yet increased trend in both ischemic and hemorrhagic stroke subtypes. Further research is crucial to delineate these associations and understand the underlying mechanisms.
Abstract 4140776: Pre-Existing Atrial Fibrillation and Mortality in Left Ventricular Assist Device Recipients
Authors: Beatriz Castillo Rodriguez, Lakshmi Uppalapati, Patrick Lynch, Alexandra Maloof, Anish Badjatiya, Matthew Segar, Joanna Molina Razavi, Abdi Rasekh, Mohammad Saeed, Mehdi Razavi, Andrew Civitello, Selby Oberton, Leo Simpson, Lola Xie, Ajith Nair, Mihail Chelu
Journal: Circulation (2024)

Introduction: Left Ventricular Assist Devices (LVADs) revolutionized the care of patients with advanced heart failure (AHF). Among AHF patients, atrial fibrillation (AF) is a common arrhythmia. Despite its prevalence, the impact of pre-existing AF on outcomes in post-LVAD recipients is poorly understood. Hypothesis: LVAD recipients with preexisting AF have higher all-cause mortality. Methods: This is a single-center, retrospective review of 573 LVAD recipients. Patients with LVADs implanted elsewhere, implants prior to 2011, implantation of an unconventional LVAD (e.g. artificial heart), and those with insufficient records were excluded. Univariate descriptive statistics and multivariate logistic&amp;linear regression analyses of patient all-cause mortality, as appropriate, were performed using STATA. Significance was determined at alpha &lt; 0.05. Results: Pre-implant AF was seen in 54% of LVAD recipients. Participants with AF were more likely to be male and older. They had higher rates of hyperlipidemia, prior stroke or TIA, prior CABG, pre-existing ICD at time of implant, and pre-LVAD sustained VT (Table 1). After a median follow-up time of approximately 2 years, 57% of patients died, 22% were transplanted, 9% were explanted, and 12% were lost to follow up. Irrespective of incidence of pre-LVAD AF, worse survival was seen in ischemic cardiomyopathy (HR 2.0 [1.5-2.7]), RV failure necessitating RVAD (HR 2.6 [1.9-3.6]), and pre-LVAD ICD shocks (HR 1.3 [1.0-1.7]). Pre-LVAD AF was associated with increased mortality (61% vs 47%, p= 0.001). This finding remained significant on multivariate analysis while controlling for other comorbidities (Table 2). Additionally, presence of AF was significantly associated with an increased occurrence of both post-implant VT (63% vs 43%, p &lt;0.001) and post-implant RV failure necessitating RVAD (19% vs 10%, p&lt; 0.001). Conclusions: A history of prior AF is associated with worse survival and higher incidence of complications following LVAD placement when compared to LVAD recipients without prior AF. This association is maintained even when controlling for possible confounders. However, this study is limited by its retrospective design, and further prospective randomized studies would better determine the impact of pre-implant AF on survival in LVAD recipients.
Abstract 4141066: Multimodal Data-Based Longitudinal Prognostic Model for Predicting Atrial Fibrillation Recurrence after Catheter Ablation in Patients with Patent Foramen Ovale and Paroxysmal Atrial Fibrillation
Authors: Shoupeng Duan, Daijiao Wang
Journal: Circulation (2024)

Background: Clinical studies on atrial fibrillation (AF) recurrence after catheter ablation in patients diagnosed with patent foramen ovale (PFO) and paroxysmal AF (PAF) are scarce. Here, we aimed to develop a nomogram model utilizing multimodal data for the risk stratification of AF recurrence following catheter ablation in individuals diagnosed with PFO and new-onset PAF. Methods: Patients with PFO and PAF who underwent catheter ablation at our hospital from January 2018 to June 2020 were consecutively enrolled. The identification of potential risk factors was conducted using the regression method known as least absolute shrinkage and selection operator. Subsequently, multivariate COX regression analysis was conducted to determine the independent risk factors, after which a nomogram scoring system was developed. The nomogram's performance was assessed via various statistical measures, including receiver operating characteristic curve analysis, calibration curve, and decision curve analysis (DCA). Results: The dataset was partitioned into the development cohort (n=102) and the validation cohort (n=43) using a 7:3 ratio. The constructed nomogram included four clinical variables: age, diabetes mellitus, lipoprotein (a), and right ventricular diameter. The area under the curve values of the development and validation cohorts at 1, 2, and 3 years post-catheter ablation were 0.911, 0.812, and 0.786 and 0.842, 0.761, and 0.785, respectively. Additionally, the nomogram demonstrated a significant correlation between the predicted and actual outcomes in the development and validation cohorts, indicating its excellent calibration. Lastly, the DCA findings suggested that the model had notable clinical applicability in predicting the likelihood of AF recurrence within 1, 2, and 3 years after catheter ablation. Conclusion: The incorporation of multimodal data in a nomogram visualization tool facilitates the concise representation of multimodal data, thereby enhancing the comprehension of the clinical status of patients with PFO and PAF following catheter ablation and providing accurate risk stratification at 1, 2, and 3 years post-treatment. Trial registration: This trial was registered in the Chinese Clinical Trial Registry (ChiCTR2300072320).
Abstract 4141341: Association of Polygenic Risk Scores with Aortic Valve Calcium: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Seamus Whelton, Jie YAO, Clary Clish, Alexis Wood, Kent Taylor, Michael Blaha, Natalie Marrero, George Thanassoulis, Wendy Post, Xiuqing Guo, Jerome Rotter
Journal: Circulation (2024)

Background: Aortic valve calcification (AVC) is the primary underlying process leading to aortic stenosis. Whether polygenic risk scores (PRS) are associated with AVC beyond traditional atherosclerotic cardiovascular disease risk factors (ASCVD) is unknown. Methods: This study included 6,812 Multi-Ethnic Study of Atherosclerosis participants who had AVC measured via CT at Visit 1 and single-nucleotide polymorphism (SNP) genotype data. Using previously published PRS for coronary artery disease (CAD), coronary artery calcium (CAC), and ASCVD risk factors we calculated a weighted PRS for each participant that was standardized within each ancestry group. The cross-sectional association of the individual PRS with AVC &gt;0 was examined using multivariable logistic regression modeling with Bonferroni correction. Results: The mean age was 62 years old, 53% were women, and 913 (13.4%) of participants had AVC &gt;0 at baseline. The PRS for CAD (HR 1.17, 95% CI 1.07-1.26), SBP (HR 1.13, 95% CI 1.04-1.24), LDL-C (HR 1.16, 95% CI 1.07-1.26), and lipoprotein(a) [Lp(a)] (HR 1.11, 95% CI 1.02-1.20) were significantly associated with AVC, while the other PRS including CAC (HR 1.02, 95% CI 0.94-1.10) and CRP (HR 0.97, 95% CI 0.89-1.05) were not (Table). In sex stratified analyses, the PRS for CAD, LDL-C, and Lp(a) were significantly associated with AVC &gt;0 for both women and men (p&lt;0.05), while the SBP PRS for women was HR 1.14, 95% CI 0.99-1.32 and for men was HR 1.11, 95% CI 0.99-1.25. Conclusions: Our results further confirm the role of atherogenic lipids in the pathogenesis of AVC and suggest that SBP may also be an important risk factor for AVC, while also suggesting that inflammation may not be an independent risk factor for AVC &gt;0. Additionally, the lack of association for the CAC PRS with AVC &gt;0 demonstrates that significant differences exist in the calcification pathways for AVC and CAC.