tbuckley/cabot-search huggingface dataset:
Abstract 4141396: Activation of the Wnt Signaling Pathway Links Atrial Myopathy to Atrial Fibrillation in Lamin A/C Heart Disease
Authors: Asia Owais, Hanna Chen, Yining Chen, Arvind Sridhar, Miles Barney, Abhinaya Baskaran, Jaime DeSantiago, Mahmud Arif, Dawood Darbar
Journal: Circulation (2024)

Objective: Pathogenic variants in LMNA are associated with early-onset atrial fibrillation (EOAF) but the pathophysiological mechanisms by which atrial myopathy leads to AF are poorly understood. Here, we investigated electrophysiologic (EP) and epigenetic mechanisms by which a heterozygous pathogenic LMNA -S143P mutation causes EOAF utilizing mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs) generated from a large Caucasian kindred with a strong cardiac phenotype. Hypothesis: Atrial myopathy due to the LMNA -S143P mutation, creates an arrhythmogenic substrate for AF by causing ion channel and chromatin remodeling. Approach: We performed clinical phenotyping and genetic testing of the proband and family members. hiPSC-aCMs generated from family members and CRISPR-corrected isogenic control (CRISPR-GC) were characterized by optical voltage mapping, calcium transient measurements, and whole-cell patch clamp analysis. Transcriptomic and epigenetic analysis was performed by RNA-sequencing (seq) and assay for transposase-accessible chromatin followed by sequencing (ATAC-seq). Results: The proband presented with EOAF at 35 years. Cardiac MRI and transthoracic echocardiogram revealed an atrial myopathy and low voltage electrograms but preserved left ventricular ejection fraction (56%). Cascade screening of the LMNA -S143P kindred confirmed co-segregation of the variant with AF, conduction disease, and dilated cardiomyopathy (Fig. A) . EP analysis showed that the LMNA -S143P hiPSC-aCMs exhibited heterogeneity of action potential duration (APD)( Fig. B ) ; decreased Na + current (Fig. C) and delayed after-depolarizations (Fig. D) . Integrated analysis of RNA and ATAC-seq revealed significant enrichment of genes associated with Wnt signaling pathway, cytoskeletal remodeling and activation of calcium signaling ( Fig. E-I ) Congruently, we found high enrichment of CAMK2 kinase as well as TCF and NFAT transcription factors associated with Wnt signaling ( Fig. F-G ) . Conclusion: Our results suggest that cytoskeletal remodeling and triggered calcium release mediated by NFAT and CAMK2 respectively create an arrhythmogenic substrate for atrial myopathy and AF highlighting their therapeutic potential.
Abstract 4141238: HIV, Longitudinal Blood Pressure Trajectory, and Preclinical Echocardiographic Measures of Cardiovascular Disease in Tanzania: A Comparative Prospective Cohort Study
Authors: Nicholas Roberts, Grace Ruselu, Godfrey Kisigo, Megan Willkens, Cody Cichowitz, Bernard Desderius, Myung Hee Lee, Robert Peck
Journal: Circulation (2024)

Background: Longitudinal blood pressure (BP) trajectories are associated with cardiovascular disease (CVD) but have not been characterized in a sub-Saharan African (SSA) cohort. We identified distinct BP trajectories and evaluated their association with HIV and preclinical CVD. Research question: Is HIV associated with lower or higher BP trajectory in SSA? Is BP trajectory associated with preclinical CVD, and does HIV change the association? Methods: Our longitudinal cohort study included 437 people with HIV (PWH) and 473 HIV-uninfected adults recruited from public HIV clinics in Mwanza, Tanzania. Echocardiography was performed in 772 participants. Group-based multi-trajectory modeling identified trajectories based jointly on systolic and diastolic BP. Multivariable multinomial logistic regression determined the association between HIV and BP trajectory group. Multivariable linear regression evaluated the association between BP trajectory group and echocardiographic measurements, including average E/e’, left atrial volume index (LAVI), and left ventricular mass index (LVMI). Results: The mean age was 36 years and 68% (N = 623) were female. Four BP trajectories were identified (Figure 1), numbered from group 1 (lowest BP) to group 4 (highest BP). Compared to BP trajectory group 2, PWH had higher odds of being classified to group 1 (aOR: 1.71; 95% CI: 0.97-3.02) and lower odds of being classified to group 3 (aOR: 0.51, 95% CI: 0.36-0.71) and group 4 (aOR: 0.45, 95% CI: 0.29-0.71). Participants in group 4 had significantly higher average E/e’, LAVI, and LVMI compared to group 2 (Figure 2). The association between BP trajectory and preclinical CVD did not differ by HIV status. HIV was associated with higher LAVI and LVMI after adjusting for age, sex, traditional CVD risk factors, and BP trajectory. Conclusion: BP trajectory and HIV were independently associated with preclinical CVD. Integrating CVD prevention with routine HIV care is urgently needed in HIV clinics across SSA.
Abstract 4140702: Sex Differences Revealed by Single Cell Transcriptome Analysis of Peripheral Blood Mononuclear Cells in Single Ventricle/Hypoplastic Left Heart Patients
Authors: Huiqi Qu, Kayleigh Ostberg, Diana Slater, Fengxiang Wang, James Snyder, Cuiping Hou, John Connolly, Michael March, Joseph Glessner, Charlly Kao, Hakon Hakonarson
Journal: Circulation (2024)

Background: Single ventricle (SV) and hypoplastic left heart syndrome (HLHS) present significant sex differences in terms of surgical outcomes and long-term prognosis between male and female patients. Peripheral blood mononuclear cells (PBMCs) drive tissue damage and cardiac dysfunction, contributing to the sex-specific clinical outcomes. Aims: We used single-cell RNA sequencing (scRNA-seq) to assess gene expression profiles in PBMCs, aiming to gain insights into sex effects and identify new biomarkers for assessing disease prognosis. Methods: We studied PBMCs from 32 cases with SV/HLHS. The experiments were conducted in 3 independent batches (9 females/11 males; 2 females/6 males; 2 females/2 males), using 10X Chromium Single Cell Gene Expression assay (10x Genomics, Single Cell 3' v3). Sequencing was performed using the Illumina NovaSeq6000. The data analysis was conducted using the Seurat R package, employing SCTransform for data normalizing and scaling (Satija, Farrell et al. 2015, Butler, Hoffman et al. 2018). To mitigate batch effects, the 3 batches were analyzed separately. Results: 42 genes were consistently identified of differential expression (DE) (|log 2 FC|≥0.25, P adj&lt;0.05) in each of the 3 batches, including 38 upregulated (6 on ChrX) and 4 downregulated genes in females. Notably, 3 autosome genes were also identified of DE in SV/HLHS cases compared to controls: PPP1R15A upregulated in cases has lower expression in females; EVL and CLEC2D downregulated in cases have higher expression in females. The expression of these 3 genes is more significant in naïve CD4 + T cells, CD14 + Monocytes, NK cells, and naïve B cells. Conclusion: PPP1R15A mediates cellular stress responses and apoptosis (Blais, Filipenko et al. 2004). EVL negatively regulates cell migration (Lambrechts, Kwiatkowski et al. 2000). CLEC2D mediates immune sensing of cell death through the recognition of histone sequences (Lai, Cruz et al. 2020). The expression changes in females may mitigate inflammation and immune dysregulation in SV/HLHS patients. The significance of these genes as prognostic markers and potential targets for therapeutic intervention in SV/HLHS management warrants further research.
Abstract 4141617: Evaluating the Cellular and Molecular Effects of Biological Sex in Porcine RV Failure
Authors: Ryan Moon, Johannes Weiblen, Felipe Kazmirczak, Kurt Prins
Journal: Circulation (2024)

Introduction: Right ventricular failure (RVF) presents a significant challenge in the management of pulmonary arterial hypertension. It is well known that there are sexually dimorphic responses in RVF as females generally exhibit superior RV function when compared to males. However, the mechanisms underlying these differences are understudied. Moreover, studies of sex differences in RV remodeling/function in large animal models are lacking. To address these two knowledge gaps, we evaluated the cellular, molecular, and functional impacts of pulmonary artery banding in male and female piglets. Methods: 4-week-old male and female piglets underwent surgical pulmonary artery banding (PAB) to induce right ventricular dysfunction. Cardiac MRI was conducted six weeks post-banding to quantify changes in cardiac structure/function, volume, and mass. Super resolution confocal microscopy evaluated cardiomyocyte hypertrophy, transverse tubule architecture, and nuclear morphology and polyploidy. Proteomics evaluated RV mitochondrial enrichments. RV tissue was subjected to metabolomic/lipidomic analysis to probe metabolic function. Results: Despite having the same right ventricular ejection fraction, PAB-females had greater relative RV hypertrophy and dilation as assessed by cardiac MRI ( A-E ). Histologically, PAB-females had a nearly two-fold increase in RV cardiomyocyte cross sectional area as compared to PAB-males ( F-H ). Analysis of myocyte nuclear structure demonstrated both PAB males and females exhibited nuclear remodeling and hypertrophy, but the change in nuclear size was greater in females. Proteomic analysis revealed distinct mitochondrial signatures as fatty acid oxidation, oxidative phosphorylation, and mitochondrial ribosomal proteins were downregulated in PAB-males, but predominantly upregulated in PAB-females ( I-L ). Metabolomic/lipidomic profiling revealed divergent responses between PAB males and females as females had less accumulation of amino acids and acylcarnitines than males ( M-N ). Finally, both PAB males and females showed t-tubule derangements, but the relative change in t-tubule organization was greater in females than males ( O-P ). Conclusion: Male and female piglets exhibit differential cellular and molecular responses to PAB, with females having greater hypertrophic response, less metabolic/energetic derangements, and more impairment in t-tubule structure.
Abstract 4141423: Bridging the Divide: Evaluating Outcomes Between the Sexes for Transcatheter Aortic Valve Replacement
Authors: Aleyah Hattab, Siddharth Bhayani, Azmer Khan, David Tiu, Daniel Tiu, Laura Navarro, Pranati Sreepathy, Manoj Ambalavanan, Swetha Kalagara, Mariam Ismail, Kayla Torres, Bayan Hammad, Jesse Balami, Edward Salem, Zachary Natsheh, Suhas Seshadri, Andrew Carlson, Julia Yu, Trang Dau, Victor Qiao, Manisha Singam, Romani Wahba, Samer Habeel, Farrah Nasrollahi, Helena Dickens, Carlos Dohse, Khalil Ibrahim, Mayank Kansal, Adhir Shroff
Journal: Circulation (2024)

Introduction: Sex-related short-term outcomes following transcatheter aortic valve replacement (TAVR) are known. There is less data comparing the long-term differences in outcomes between sexes. Studies suggest women are less likely to be referred for TAVR and have higher mortality. This study investigated the differences between genders and races on outcomes in the following 6 and 12 months post-TAVR. Questions: Are there differences in outcomes between males and females who undergo TAVR? Are there differences in outcomes between females of different races undergoing TAVR? Methods: We performed a retrospective cohort study among 252 patients undergoing TAVR between 2018 and 2023 at a major academic medical center in Chicago, Illinois. Primary outcomes included composite major adverse cardiac events (MACE) (CVA, MI and/or CVA) and all-cause death. Outcomes were analyzed at 6 and 12 months following TAVR. T and Chi square tests were used to analyze continuous/categorical variables respectively. Results: Among the 252 patients studied, 27.4% were female, 27.5% white, 47.8% black, 10.1% Hispanic/Latino, 14.45% other. Average age of females and males were 77 ± 1 years and 75 ± 0.74 years (p=0.2967), respectively. Males were more likely to be former smokers (p=0.000) and to drink more than 8 alcoholic beverages per week (p=0.023). No significant differences were seen between genders for MACE, all-cause death, CVA or MI at 6 or 12 months (Table 1). There were also no significant differences were found between females of different races for MACE, all-cause death, CVA, or MI at 6 or 12 months. There was a significant difference by race for development of conduction abnormalities found at 6-month follow-up (p=0.02). Conclusion: This study shows females appeared to have similar outcomes at 6 and 12 months following TAVR when compared to males. However, the possible causes leading to increased development of conduction abnormalities found at 6 months follow up between female racial groups needs to be further studied.
Abstract 4140909: In vitro model of restrictive cardiomyopathy using engineered heart tissue reflecting impaired relaxation
Authors: Moyu Hasegawa, Kenji Miki, Takuji Kawamura, Masaru Tsuchida, Kunio Kashino, Hidekazu Ishida, Shigeru Miyagawa
Journal: Circulation (2024)

Introduction: Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by ventricular diastolic dysfunction. There is limited research on RCM due to the lack of an in vitro model for diastolic dysfunction. Recently, engineered heart tissue (EHT) has significantly advanced disease modeling and drug discovery as a model reflecting contractile dynamics in vivo. Here, we evaluate the relaxation impairment of EHTs generated from an RCM patient using the Phase-Only Correlation (POC) method. Methods: An iPSC line from a pediatric patient with severe RCM harboring the TNNI3 R170W mutation (R170W-iPSC) was generated. An isogenic iPSC line corrected for the mutation was also established using CRISPR/Cas9 technology. The EHTs were created by casting into pillar system using cardiomyocytes differentiated from iPSCs (Figure 1). Video microscopy was used to track one-dimensional pillar deflection under 1 Hz stimulation. The force generation of EHTs was analyzed with POC method, a template-based image matching technique that estimates displacement between two images with subpixel accuracy by locating the correlation peak. We defined the contractile force and the relaxation force using the force waveform calculated from the pillar deflection (Figure 2a). Results: The calculated force at the maximum pillar deflection, showed no difference between R170W-EHT and Isogenic-EHT (Figure 2b). The time for the pillar deflection to decrease from 100% to 20% during relaxation, the time to relaxation, was significantly longer in R170W-EHT than in Isogenic-EHT (Figure 2c). These findings indicated impaired relaxation of R170W-EHT. Furthermore, the ratio of contractile force to total force was lower and the ratio of relaxation force to total force was higher in R170W-EHT than in Isogenic-ETH (Figure 3a and 3b). In addition, the ratio of relaxation force to contractile force was significantly higher in R170W-EHT (Figure 3c). These data showed that R170W-EHT required greater force to dilate. Conclusions: Our EHT model with POC method reflects the clinical manifestation of RCM with diastolic dysfunction by comparing the contractile and relaxation forces and their ratio in vitro.
Abstract 4140846: Racial Disparities in Low-Density Lipoprotein Cholesterol Control and Lipoprotein(a) Testing Among Young Adult Women with Severe Hyperlipidemia
Authors: Amanda Jowell, So Mi Cho, Christian Andersen, Zhi Yu, Pradeep Natarajan, Michael Honigberg, Colleen Harrington
Journal: Circulation (2024)

Background: Young adult women with severe hyperlipidemia (sHLD), or low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL, are less likely to achieve guideline-recommended LDL-C reduction than their male or older counterparts. Lipoprotein(a) [Lp(a)] can serve as a risk modifier of cardiovascular disease and may have some utility in risk-stratification in young populations. Question: Do LDL-C control and Lp(a) testing differ by race among young adult women? Methods: We used clinical registry data from seven Mass General Brigham hospitals/affiliated practices to identify young women (18-45 years) between 2005-2022 with a qualifying LDL-C ≥190 mg/dL. We used linear mixed models to assess longitudinal differences in LDL-C levels by self-identified race. We compared Lp(a) testing and statin initiation rates of these groups and examined whether LDL-C control differed according to Lp(a) testing. Results: Our study included 4,633 women with sHLD, mean (SD) age 35.7 (7.0) years at qualifying LDL-C and median (IQR) follow up 5.8 (9.4) years. Compared to White women, Black women had persistently higher LDL-C levels during follow-up (coefficient=6.4, p&lt;0.001), and women who reported other/multiple racial categories (Other) had a non-significant trend of persistently higher LDL-C during follow-up (coefficient=2.8, p=0.08) [Figure]. Overall, 255 (5.7%) women recieved Lp(a) testing. Lp(a) testing was positively associated with 50% LDL-C reduction (p&lt;0.001), and 8.8% Asian, 3.8% Black, 4.9% Other and 5.9% White women underwent Lp(a) testing (p=0.04). Mean (SD) age of statin initiation was 39.9 (8.2) years; 51.9% Asian, 65.6% Black, 59.3% Other and 56.2% White women received a statin prescription during follow-up (p&lt;0.001). Conclusions: Young women with sHLD had persistently high LDL-C levels over time, and Black women experienced the highest LDL-C burden. Lp(a) testing was also low across all groups, with the lowest testing rates occurring in Black and Other populations, but was associated with improved LDL-C control. Statin initiation was low across all groups. These data highlight an urgent need for strategies to improve guideline-recommended preventive care in young women at high lifetime risk of cardiovascular disease.
Abstract 4140707: The Examination of Expression Patterns, Underlying Mechanisms, Diagnostic Accuracy, and Potential AI-Driven Drug Development Approaches for Ferroptosis-Related Genes in Heart Failure via Single-Cell and Bulk RNA Sequencing Analyses
Authors: Zeye Liu, Hong Jiang, Fengwen Zhang, Wenbin Ouyang, Shouzheng Wang, Ruibing Xia, Yakun Li, Yi Shi, Xiangbin Pan
Journal: Circulation (2024)

Introduction: Heart failure is a significant concern for public health, particularly among the elderly demographic. In this study, we aimed to investigate the molecular underpinnings of heart failure, focusing on ferroptosis-related genes. Purpose: Our objective was to analyze unicellular RNA sequencing data derived from patients with heart failure and healthy controls. We sought to identify common ferroptosis-related genes and explore their potential as therapeutic targets for heart failure treatment. Methods: We analyzed unicellular RNA sequencing data from 200,615 cells, encompassing samples from four heart failure patients and two healthy controls. Initially, we curated a set of 388 ferroptosis-related genes from the FerrDB Database. Subsequently, we identified commonly shared significant ferroptosis-related genes by intersecting these with genes differentially expressed in the cell clusters using bulk RNAseq data. We also utilized data from the DGIdb to explore potential therapeutic drugs targeting these identified genes. Molecular docking and artificial intelligence-based IC50 prediction were employed to assess the efficacy of these drugs in mitigating heart failure. Results: Among the identified ferroptosis-related genes, ALOX5 and PLIN2 emerged as common candidates, both enriched in monocytes and dendritic cells. Interaction analysis revealed 51 drug categories interacting with ALOX5, along with 10 corresponding transcription factors. These genes exhibited robust discrimination ability in independent datasets, with an AUC of 0.915. Compounds exhibiting the strongest binding affinity with the ALOX5 protein were evaluated, demonstrating an affinity of 10.4 kcal/mol. Furthermore, a compound IC50 prediction system based on 42 machine learning models was developed, showing promising correlation coefficients up to 0.723 (P&lt;0.05). Conclusions: Our research indicates ferroptosis may contribute to heart failure progression via ALOX5 and PLIN2 gene dysregulation in monocytes and dendritic cells, highlighting their therapeutic potential. Our study also emphasizes the value of computational approaches in drug discovery and personalized heart failure treatments.
Abstract 4141413: Impact of diabetes mellitus on bifurcation percutaneous coronary intervention: Insights from the PROGRESS-BIFURCATION registry
Authors: Dimitrios Strepkos, Pedro Carvalho, Athanasios Rempakos, Michaella Alexandrou, Deniz Mutlu, Oleg Krestyaninov, Dmitrii Khelimskii, Barkin Kultursay, ali karagoz, Ufuk Yildirim, korhan soylu, Mahmut Uluganyan, Olga Mastrodemos, Bavana Rangan, Sandeep Jalli, Ahmed Al-Ogaili, Konstantinos Voudris, Yader Sandoval, M Nicholas Burke, Emmanouil Brilakis
Journal: Circulation (2024)

Background: The impact of diabetes mellitus (DM) on short and long-term outcomes following bifurcation percutaneous coronary intervention (PCI) has received limited study. Methods: We examined the procedural characteristics and outcomes of 1,224 bifurcation PCIs (1,076 patients) performed at five centers between 2013-2024 from the Prospective Global Registry for the Study of Bifurcation Lesion Interventions (PROGRESS-BIFURCATION, NCT05100992). Results: Diabetes mellitus was present in 394 patients (34.20%). Patients with diabetes were more likely to be female (32.30% vs 21.50%, P &lt;0.001), have greater body mass index (BMI) (32.56 ± 6.38 vs 29.26 ± 5.87, P &lt; 0.001) and more comorbidities such as hypertension, dyslipidemia and heart failure. Diabetic patients had more complex angiographic characteristics, with higher prevalence of left main (LM), proximal left anterior descending and right coronary artery stenoses. The main vessel was more likely to be the LM or the right coronary artery in patients with diabetes. Diabetic patients had lower rates of provisional stenting (64.30% vs 70.40%, P = 0.029), required higher procedure times (89.75 min vs 77.00 min, P = 0.001) and radiation (1.57 Gy vs 1.31 Gy, P = 0.002), and were more likely to need in-hospital repeat PCI (OR: 2.8 CI: 1.07, 7.76, P = 0.039). Diabetes was independently associated with higher MACE during follow-up (HR: 1.94, CI: 1.36, 2.76, P &lt; 0.001). Follow-up MI (HR: 2.32 CI: 1.37, 3.94, P = 0.013) and death (HR: 2.56 CI: 1.51, 4.35, P &lt; 0.001) were higher in diabetic patients after adjusting for confounders. Conclusions: Bifurcation PCI in patients with diabetes mellitus was associated with higher risk of in-hospital repeat-PCI, follow-up MI and death compared with non-diabetic patients.