tbuckley/cabot-search huggingface dataset:
Abstract 4139829: New Insights in Non-syndromic Mitral Valve Dystrophy: Role of Inflammation and Macrophages
Authors: Benjamin Le Vely, Constance Delwarde, claire toquet, Pascal Aumond, Emilie Charon, Séverine Remy, Ignacio Anegon, Solena Le Scouarnec, Jean-Jacques Schott, Thierry Le Tourneau, Elvira Mass, Jean Merot, Romain Capoulade
Journal: Circulation (2024)

Background: Myxomatous mitral valve dystrophy (MVD) is the first cause of mitral valve prolapse (MVP), a common disease affecting 2 to 3 % of the population. The first causal mutation in the FLNA gene (FLNA-P637Q), was associated with MVD in 2007. Recently, the FlnA-P637Q KI rat model was generated and phenotyped. Using multimodality imaging, MVD was diagnosed as early as 3 weeks (D21) and signature of chemotaxis and immune cell migration was described at the transcriptomic level. Aims: This study aims to delineate the contribution of macrophages recruitment and activation to the pathophysiology of MVD. Methods: New-born (D0), two days (D2) and seven days (D7) KI and WT animals were phenotyped. Anatomopathological score was used to assed MV morphological alterations. MV cell proportions were analyzed by flow cytometry (D7 and D21), and molecular phenotyping was done by bulk RNAseq (D7). WT and KI MVs were dissociated for valvular interstitial cells (VICs) primary culture and subsequent in vitro studies. Results: At D21, a 2-fold increased proportion of myeloid cells in KI MV compared to WT was detected by flow cytometry (13% vs 7%, p&lt;0.05). Interestingly, although no morphological differences were seen after birth (D0 and D2; p&gt;0.05), MV remodeling, characteristic of MVD, was observed and quantified at D7 (histological score: 7 in KI vs 4 in WT; p&lt;0.001). Consistently, transcriptomic data of D7-MV revealed enrichment of GO-Terms (p&lt;0.05) related to morphogenesis and development, cytoskeleton and extracellular matrix, and cellular activation and differentiation. Chemotaxis and cytokine related pathways were also enriched (p&lt;0.05), but no difference in myeloid cell proportions was seen by flow cytometry at D7 (7% in WT and KI, p&gt;0.05). Furthermore, monocytes adhesion assay showed an increased monocytes adhesion to KI-VICs compared to WT-VICs (p&lt;0.01). This could be partly mediated by ICAM1 over-expression observed in KI-VICs (p&lt;0.05). Of note, TNFa pro-inflammatory stimulation exacerbated ICAM1 expression in KI-VICs and monocytes adhesion. Conclusion: At seven days, the FLNA-KI rats model display MVD associated to a pro-inflammatory signature without increase in macrophage proportion, as observed at later stages. In vitro, KI-VICs have a higher expression of adhesion molecule ICAM1 and are more susceptible to inflammatory stimuli. This results in increased adhesion of monocytes to VICs.
Abstract 4139265: APOL1 Kidney Disease Risk Variants Are Causal in Obesity
Authors: Andrew Kearney, JOHNSON YANG, Esther Liu, Jiayi Kong, Matthew Wright, Jennie Lin
Journal: Circulation (2024)

Background: Obesity-which develops from environmental and biological factors-is disproportionately more prevalent among individuals of African ancestry. Part of this difference may be due to DNA variants specific to African ancestry. Recent observational studies have reported an association between obesity and the common APOL1 G1 and G2 DNA variants, specific to individuals of sub-Saharan African ancestry. Compared to the G0 major allele, the G1 and G2 risk variants (RV) are known to increase the risk of kidney disease in African-ancestry patients and have been extensively studied in the renal context. However, no functional validation has established whether the APOL1 RV are also causal in obesity. The aim of this study is to address the hypothesis that APOL1 RV are causal in the pathogenesis of obesity independent of kidney disease. Methods: Because APOL1 expression is primate-specific, we leveraged transgenic G0 and APOL1-RV mice (n = 58), which were fed standard chow or high-fat diet (HFD) for 16 weeks. The mice underwent measurements of body mass, body composition by Echo-MRI, and tail cuff BP. Blood, urine, kidneys, perigonadal adipose tissue (AT), and bone-marrow derived macrophages (BMDMs) were examined for cardiometabolic traits. Results: Concordant with single-cell RNA-seq data of human AT (GSE176067) revealing APOL1 expression in multiple cell types, robust APOL1 protein expression was detected in AT of the APOL1 transgenic mice. Although no differences in body mass were seen among males, female APOL1-RV mice had higher body mass than G0 females in both the standard chow (p = 0.01) and HFD groups (p = 0.04). Both male and female mice on standard chow did not exhibit genotype-specific differences in body composition, but G0 female mice on HFD had significantly higher lean:fat mass ratio than female APOL1-RV mice (7.7 vs. 3.8, p = 0.04). In addition, female APOL1-RV mice on standard chow had significantly higher systolic BP than G0 females (129.5 vs. 107.6 mmHg, p = 0.04), while female APOL1-RV mice on HFD had more albuminuria than G0 females (43.4 vs. 22.7 mg/g, p = 0.01). Although qPCR assays of kidney and AT were unrevealing, APOL1-RV BMDMs modeling inflamed AT macrophages of obesity expressed significantly higher levels of Tnf than G0 when stimulated with interferon-γ. Conclusion: This is the first study to report a causal link between APOL1 kidney disease variants and obesity, seen more prominently in female transgenic mice.
Abstract 4140309: Developing a Community-Informed Service Delivery Model to Increase Uptake of Rheumatic Heart Disease Primary Prevention
Authors: McCall Miller, Lisa Vaughn, miriam nakitto, Jafesi Pulle, Rachel Sarnacki, Sarah de Loizaga, Andrea Beaton, Joselyn Rwebembera
Journal: Circulation (2024)

Introduction: Primary prevention of rheumatic heart disease (RHD) is aimed at timely diagnosis and treatment of superficial group A Streptococcal infections, most commonly Strep sore throat. However, uptake and delivery of primary prevention in RHD-endemic regions is suboptimal. Development of scalable and sustainable models is urgently needed. Community co-design is an important aspect of development, aimed at ensuring approaches are culturally and contextually appropriate and reach the highest number of community members. Aim: Utilize a community-based participatory research (CBPR) approach to co-develop a model for RHD primary prevention in Uganda. Methods: Group Level Assessment (GLA) was used to evaluate the community’s priorities and provide insights around sore throat in the community to identify potential interventions. Personas, or potential user archetypes, were then developed to capture the behaviors and characteristics of diverse future users of primary prevention in the district. Finally, these personas were used in community co-design workshops to identify barriers and facilitators to potential interventions, generate creative solutions to overcome identified barriers, and prioritize implementation models for testing. The final list of implementation strategies was taken by workshop participants to the broader community for additional validation and feedback. Results: The GLA sessions identified six key priorities: 1) Desire for formal treatment; 2) Lack of access to resources and long distances; 3) Competing traditional methods of treatment; 4) Strong influence of community leaders; 5) Importance of mothers as caregivers; and 6) Need for sore throat awareness and education. Five personas were created including: Hands-on Caregiver, Restricted Caregiver, Removed Family Decision Maker, Helpful Neighbor, and Influential Leader. Design workshops identified the highest rated interventions as train village health teams to diagnose, conduct outreach screening events, and designate a sore throat focal person at health facilities. Participants then proposed potential practical applications of these interventions. Conclusion: CBPR identified novel implementation strategies for an RHD primary prevention program in Uganda. Next steps include evaluation of the acceptability, feasibility, and uptake of these strategies via a planned implementation trial, and improved primary prevention in an RHD-endemic country.
Abstract 4138953: Salivary Tumor Necrosis Factor-Alpha, Plasma Omega-3 Fatty Acid Index and Coronary Artery Plaque
Authors: Ralph Daher, Bushra Ahmad, Abdulaziz Malik, Abdulhamied Alfaddagh, Francine Welty
Journal: Circulation (2024)

Background: Oral inflammation is thought to affect systemic atherosclerosis, but the mechanisms are unclear. Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that has been implicated in coronary plaque rupture as well as periodontitis by mediating periodontal destruction and inflammation. Blood levels of the omega-3 fatty acids have been inversely associated with systemic inflammation and coronary plaque volume, but their impact on oral inflammation requires further study. Objective: To examine the relationship between salivary levels of TNF-α, plasma levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and coronary plaque. Methods: Salivary TNF-α was measured in gingival crevicular fluid in 199 patients with clinical coronary artery disease on statin therapy. Fatty, fibrous and noncalcified coronary plaque volumes were measured using coronary CT angiography. The plasma omega-3 fatty acid index was the sum of EPA and DHA of total plasma fatty acids. Linear regression estimated the association between TNF-α, omega-3 fatty acid index and coronary plaque volumes. Results: Mean age was 62.7±7.5 years; mean LDL-C was 78.2±28.9 mg/dL, and median triglyceride was 119 [80.5,165.0] mg/dL. Higher salivary TNF-α was independently associated with a lower plasma omega-3 fatty acid index (Table 1). Moreover, higher salivary TNF-α was independently associated with higher fatty, fibrous, and noncalcified plaque volumes after adjustment for age, sex, BMI, triglyceride, LDL-C, diabetes status, diastolic blood pressure, albumin-to-creatinine ratio, and estimated glomerular filtration rate (Table 2). Conclusions: The inverse relationship between salivary TNF-α and the plasma omega-3 fatty acid index and direct relationship with fatty plaque suggests that maintaining high blood levels of omega-3 fatty acids may be beneficial in lowering oral inflammation and amount of fatty plaque, thus, potentially decreasing risk for acute coronary syndromes.
Abstract 4139937: Plant-Based Diet and All-Cause and Cause-Specific Mortality among Patients with Cardiovascular Disease: A Population-Based Cohort Study
Authors: Xiaohui Liu, Xuzhi Wan, Pan Zhuang, Yu Zhang, Jingjing Jiao
Journal: Circulation (2024)

Background: The role of plant-based diet in preventing premature death among patients with cardiovascular disease (CVD) remained unknown. To explore the relationship of plant-based dietary patterns with all-cause and cause-specific mortality among patients with CVD. Methods: A sum of 10,841 participants with CVD at baseline were followed up in the UK Biobank. We constructed three types of plant-based diet indexes [an overall plant-based diet index (PDI), a healthy PDI (hPDI), and an unhealthy PDI (uPDI)] by assigning different weights to various food groups from web-based 24-h dietary recall questionnaires. The national death registry documented primary causes of death. The Cox proportional hazards regression models were utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality. Results: Over a median of 11.3-year follow-up, 1,275 death cases were ascertained. After multivariable adjustment, PDI had a negative correlation with all-cause mortality [HR T3vsT1 : 0.81 (0.70-0.94), P trend =0.005] and CVD mortality [HR T3vsT1 : 0.78 (0.61-0.99), P trend =0.040], while uPDI displayed a positive correlation with all-cause mortality [HR T3vsT1 : 1.33 (1.16-1.53), P trend &lt;0.001] and CVD and cancer mortality. Additionally, in mediation analyses, serum concentration of C-reactive protein (CRP) accounted for 6.2%, 4.0%, and 5.1% of the relationship between uPDI and all-cause, CVD, and cancer mortality, respectively. No significant associations were detected between hPDI and mortality. Conclusions: Among patients with CVD, stronger adherence to PDI correlated with reduced all-cause and CVD mortality rates. Conversely, adherence to uPDI showed an association with increased mortality, possibly attributable to elevated levels of circulating CRP. Our findings support dietary guidelines that recommend limiting the consumption of unhealthy plant-based foods.
Abstract 4139471: Engineering Human-Induced Pluripotent Stem Cells Overexpressing Ferritin for In Vivo Graft Tracking via Magnetic Resonance Imaging
Authors: Yura Son, Pengsheng Li, Dakota Ortega, Huiliang Qiu, Hannah Prachyl, Ming Yang, Wuqiang Zhu
Journal: Circulation (2024)

Heart disease continues to be the leading cause of death globally, even with the development and implementation of numerous pharmacological and surgical treatments. Transplanting cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) shows potential for repairing heart damage. However, tracking and quantifying these cells after transplantation in large animals remains challenging. This study aimed to develop a hiPSC line that overexpresses ferritin heavy chain (FHC) to enable tracking of transplanted hiPSC-CMs via magnetic resonance imaging (MRI). Using the CRISPR/dCas9 activation system, we increased FHC expression in hiPSCs and hiPSC-CMs. Both mRNA and protein levels of FHC were significantly elevated following transfection. Cell viability was unaffected by iron chloride concentrations between 0 μM and 2000 μM. hiPSCs and hiPSC-CMs overexpressing FHC (hiPSC-FHC OE and hiPSC-CM-FHC OE ) showed enhanced iron chloride uptake without changes in their electrophysiological properties compared to control hiPSC-CMs. Additionally, hiPSC-CM-FHCOE cells provided strong contrast and lower T 2 * values, indicating their effectiveness for cardiac MRI. When hiPSC-CM-FHCOE cells were injected into mouse hearts and imaged three days later, MRI revealed distinct signals from these cells with lower T 2 * values and rapid signal decay. Overall, endogenous FHC labeling in hiPSC-CMs could significantly improve the precision of cardiac MRI, marking a crucial advancement in assessing the success of hiPSC-CM transplantation in large animal models and enhancing cardiac regenerative therapies.
Abstract 4139454: Patients with Atrial Fibrillation who Maintain Sinus Rhythm post Ablation Demonstrate Improved Left Atrial Blood Flow and Volume
Authors: David Dushfunian, Justin Baraboo, Anthony Maroun, Maurice Pradella, Daniel Lee, Philip Greenland, Rod Passman, Daniel Kim, Michael Markl
Journal: Circulation (2024)

Introduction: Atrial Fibrillation (AF) incidence increased by 30% over the past 20 years with 1 of 7 strokes attributed to AF. While catheter ablation (CA) is valuable at decreasing AF burden, its long-term effect on stroke risk is unknown. 4D flow MRI studies of AF patients have found reduced peak velocities and increased blood stasis in the left atrium (LA) and LA appendage (LAA), indicating AF-associated atrial flow impairment and increased thromboembolism risk. Aim: To explore, using 4D flow MRI, pre vs post-CA LA and LAA hemodynamics and volumes in patients with and without AF recurrence. Methods: We enrolled 60 AF patients who had baseline (pre-CA) and follow-up (post-CA) 4D-flow MRI scans. Success was defined as no recurrent AF &gt; 30 sec on intermittent monitoring after a 3-month blanking period. 4D flow data analysis included pre-processing and LA/LAA manual 3D segmentation. The segmentations were used to calculate LA and LAA volumes as well as peak velocity and blood stasis (Figure 1). Results: Of the 60 patients (61.1 ± 12.3 years, 73% male), forty-five maintained SR while 15 had AF recurrence post-CA. One LAA was excluded from the analysis due to the presence of an artifact. Mean LA stasis significantly decreased for both groups post-CA (success: 46 ± 17% to 41 ± 11% and failure: 40 ± 13% to 37 ± 12%, p &lt;0.05). However, only the success group’s LAA peak velocity (36 ± 0.15 cm/s to 41.5 ± 0.09 cm/s, p &lt;0.05) and LA volume (101 ± 39 ml to 89 ± 28 ml, p &lt;0.05) changed significantly (Figure 2 A-C). Further, the change in LA stasis was strongly correlated (r=0.48, p &lt;0.01) with the change in LA volume only in the success group (Figure 2D). Conclusions: Our results reinforce that SR maintenance post-CA is key for improved LA flow and geometry, indicating that reverse remodeling is taking place. The LAA velocity change in those with successful CA may confer reduced thrombotic risk, since thrombus formation is linked to a reduced LAA velocity.
Abstract 4138981: Indication and electrical performance of conventional, resynchronisation and conduction system pacing in Transthyretin Amyloid Cardiomyopathy (ATTR-CM)
Authors: Stephan Dobner, Serlha Tawo, Fabian Wieser, Christoph Graeni, Andreas Haeberlin
Journal: Circulation (2024)

Background: Conduction system disease, atrial and ventricular arrhythmias may require pacemaker or ICD implantation in transthyretin amyloid cardiomyopathy (ATTR-CM). The optimal pacing mode in ATTR-CM patients remains unknown. Objective: To assess how availability of cardiac resynchronization and conduction system pacing influenced pacemaker indications and to compare early electrical performance of conventional, resynchronisation and conduction system pacing in ATTR-CM. Methods and Results: 67 of 250 (26.8%) patients presenting with ATTR-CM between June 2019 and February 2023 received a pacemaker [HA1] and were included in this retrospective analysis. Pacemaker implantation occurred in 25 patients (37.3%) prior to, and in 42 (62.7%) after ATTR-CM diagnosis. Implantation of conventional single- (VVI) or dual-chamber (DDD) pacemakers was more common (n=17/25, 68%) in undiagnosed ATTR-CM, while physiological pacing systems (CRT/ CSP) were preferably implanted in patients (n=24/42; 57.1%) after diagnosis. Sick sinus syndrome (11/35; 31.4% vs. 6/32; 18.8%) and higher degree AV-block (20/35; 57.1% vs. 9/32; 28.1%) were more common indications for VVI/DDD compared to CRT/CSP pacemakers, with pursuit of a pace/ablate strategy (12/32; 37.5%) and heart failure (5/32; 15.6%) contributing significantly to implantation of CRT/CSP. QRS width was significantly lower with CSP [122ms (IQR: 120-139)], compared to CRT [155ms (IQR: 141-160); p=0.005] or VVI/DDD [160ms (IQR: 144-180)], with the latter resulting in a significant increase in QRS width compared to intrinsic QRS [from 138 (IQR: 123-150) (p&lt;0.001)]. LV/LBBAP pacing capture thresholds (0.4ms pulse width) were significantly lower after CSP [0.75V (IQR: 0.5-1.2)] compared to CRT [1.3V (IQR: 1.0-1.6); p=0.049]. RA and RV lead performance were comparable between all pacing systems (p&gt;0.05). Conclusions: Pacing indications are changing with earlier diagnosis of ATTR-CM. CSP may offer improved electrical performance and resynchronization, the effect of conduction system pacing on clinical outcomes should be further explored.
Abstract 4138948: Identifying atrial fibrillation symptom clusters and examining associations with major adverse cardiovascular events following catheter ablation
Authors: Meghan Reading, Danielle Scharp, Yihong Zhao, Mollie Hobensack, Liesbet Van Bulck, Alexander Volodarskiy, David Slotwiner
Journal: Circulation (2024)

Introduction: Atrial fibrillation (AF) is associated with a heavy burden of symptoms that frequently co-occur. Patterns of co-occurring symptoms and improvements after AF treatments are poorly understood. Disentangling AF symptoms can support better clinical management. Objective: This study aims to (1) identify co-occurring symptoms, or clusters, of patients undergoing catheter ablation for AF and (2) determine associations between symptom clusters and post-ablation AF-related major adverse cardiovascular events (MACE). Methods: We conducted a retrospective secondary analysis of electronic health record (EHR) data for adults who underwent catheter ablation for treatment of AF at one academic medical center from 2010-2020. We used a natural language processing algorithm developed by our team (F-score=0.81) to extract ten symptoms from clinical notes: anxiety, chest pain, dizziness, dyspnea, edema, fatigue, malaise, palpitations, syncope, and weakness. To conduct symptom clustering, we used an unsupervised machine learning approach, Ward’s hierarchical agglomerative clustering, to identify subgroups of patients representing different clusters. The composite AF-related MACE variable included AF-specific ED visit, AF-specific hospitalization, stroke, and/or death within one year post-ablation documented in EHRs. We used logistic regression models to examine associations between the six symptom clusters and the AF-related MACE outcome, adjusting for age, sex, and race. Results: The mean age of the sample (n=1,292) was 65.5 (standard deviation 12.6) years, 35% were female, and 58% were White. We identified six distinct clusters from notes (n=13,416), labeled using the most prevalent symptoms in each cluster: generally symptomatic, dyspnea and edema, chest pain, anxiety, asymptomatic, and fatigue and palpitations. One-third (n= 372; 29%) had an AF-related MACE within one year of ablation. The prevalence of symptom clusters within the sample and associations with MACE are shown in Table 1 . Conclusions: AF patients’ pre-ablation symptoms vary widely and correlate with post-ablation MACE. It is possible symptom clusters signify latent biological differences with implications for the clinical care of AF.