tbuckley/cabot-search huggingface dataset:
Abstract 4142133: Variant-enhancer-gene mapping at the 9p21 locus in smooth muscle cells reveals new enhancer-gene pairs and mechanistic insights for coronary artery disease
Authors: Markus Ramste, Chad Weldy, Quanyi Zhao, Amanda Ranta, Daniel Li, Disha Sharma, Joao Monteiro, Matthew Worssam, Dulguun Amgalan, Guyu Qin, Trieu Nguyen, Juyong Kim, Jesse Engreitz, Themistocles Assimes, Chong Park, Thomas Quertermous
Journal: Circulation (2024)

The majority of variants identified by genome-wide association studies (GWAS) that influence coronary artery disease (CAD) risk reside in noncoding regions of the genome, making it challenging to link them with the genes they regulate. The 9p21.3 locus is the most impactful genetic risk locus for CAD. Due to the complexity of this locus, the causal genes and molecular mechanisms are poorly understood. Enhancers are cell type specific, and vascular smooth muscle cells (SMC) are known to have the highest heritable risk for CAD and play a major role in the atherosclerotic plaque formation. Here, we report efforts to systematically map SMC specific enhancers to neighboring genes within the 9p21.3 locus by implementing single cell CRISPRi enhancer screens and validating single causal variants in these enhancers. First, we intersected CAD GWAS loci with human coronary artery SMC (HCASMC) ATAC-seq and H3K27ac ChIP-seq datasets to focus on the disease relevant SNPs. This analysis identified 27 SNPs in 11 enhancers, that we targeted with CRISPRi machinery and analyzed at 5- and 10-days post transduction. As target genes in the locus are lowly expressed, we employed the targeted Perturb-seq (TAP-seq) approach for library generation and sequencing. We identified several enhancer-gene -pairs, including a strong enhancer-gene connection to both CDKN2A and CDKN2B . Additionally, we identified multiple enhancer regions that control MTAP expression, with smaller but significant effects. We followed up with individual validation of enhancer-gene pairs through qPCR. Furthermore, these results are consistent with chromosomal interaction data obtained from our previous HiChIP. Notably, enhancers 5 and 6 were strong regulators of CDNK2B and CDKN2A expression, so we investigated how variants in these enhancers might directly disrupt transcription factor (TF) binding. By using luciferase enhancer assays, CHIPseq and phenotypic in vitro assays we linked this variation with TFs that drive vascular calcification in SMCs. Our results identify new variant to gene links and suggest how the genetic risk in 9p21 is mediated in the vascular wall, providing mechanistic understanding of vascular calcification and genetic risk of CAD and suggesting a novel mechanism of how 9p21.3 mediates disease risk.
Abstract 4142890: Risk of Life-Threatening Ventricular Arrhythmias in Newly Diagnosed Non-Ischemic Heart Disease – A Meta-Analysis
Authors: Eloi Marijon, Pamela Aidelsburger, Claude elayi, Rui Providencia, Kumar Narayanan, Olivier Piot, Giancarlo Casolo, Marco Metra, Serge Boveda, David Duncker
Journal: Circulation (2024)

Background and Aims: In patients with non-ischemic cardiomyopathy (NICM), conditions such as peripartum cardiomyopathy or myocarditis may resolve, and an increase in left ventricular ejection fraction (LVEF) may occur within the first months of initiating guideline-directed medical therapy before considering an implantable cardioverter defibrillator (ICD). However, patients are at increased risk for sudden cardiac death (SCD) during this period, and a wearable cardioverter defibrillator (WCD) may help mitigate this transient risk. In this meta-analysis, we sought to assess the risk for appropriate shocks delivered by the WCD in patients with NICM in this vulnerable period. Methods: A systematic literature search was conducted in Medline, Embase, and Cochrane Library to identify studies reporting the use of WCD in patients with newly diagnosed NICM before April 2024. Two independent reviewers selected studies based on predefined inclusion and exclusion criteria. The study types considered included randomized and non-randomized controlled trials, prospective and retrospective cohort studies, registry data, and case series. Publications in languages other than English, German, or French were excluded. Studies with mixed populations (including patients with ischemic heart disease) were included if separate results were reported for each indication. Data on appropriate shocks, inappropriate shocks, WCD wear time, final device implantation, and deaths were extracted. Mean incidence rates for different outcomes were calculated for each subtype of NICM. Results: Forty-four studies were included. The mean incidence rate (per 1,000 patients) for appropriate shocks was 12 in dilated cardiomyopathy, 16 in myocarditis, 43 in peripartum cardiomyopathy, 19 in Takotsubo syndrome, and 13 in other genetic/congenital heart conditions. Inappropriate shocks were rare (&lt;1% of patients). Finally, 1277 patients (35%) received an ICD across all studies. Conclusion: Patients with NICM face a significant risk of SCD during the waiting period before deciding if patient qualifies for an ICD implantation. Additional efforts are needed to refine identification methods and enhance strategies to manage at-risk patients during this critical period.
Abstract 4142152: Different Determinants of Thrombotic Events in Transthyretin Cardiac Amyloidosis versus Other Left Ventricular Hypertrophy Phenotypes
Authors: Benay Ozbay, Corey Rearick, Bharadwaj Satyavolu, Prem Soman, Timothy Wong, Abdullah Azhar, William Katz, Leyla Elif Sade
Journal: Circulation (2024)

Background: Thrombotic events (TE) are more frequent in cardiac amyloidosis (CA) as compared to other phenotypes of left ventricular hypertrophy (LVH) the absence of regional wall motion abnormalities. Aim: We sought to investigate the determinants of TE in patients with transthyretin cardiac amyloidosis (ATTR-CA). Method: Among subjects referred to our CA center those with LVH (interventricular septum thickness ≥ 1.2 cm) were included consecutively. Patients with hypertrophic obstructive cardiomyopathy, light chain CA or mitral valve disease were excluded. All subjects underwent echocardiography with speckle tracking imaging, Tc-99m pyrophosphate scintigraphy, serum and urine immune electrophoresis as per the registry protocol. Cardiac magnetic resonance imaging and endomyocardial biopsy were performed for diagnosis as needed. Control group consisted of subjects with non-amyloidosis LVH. Patients were followed-up over 5 years for TE (ischemic stroke, peripheral emboli, intracardiac thrombus). Results: In all, 149 ATTR-CA and 133 LVH patients (24 non-obstructive hypertrophic cardiomyopathy, 18 aortic stenosis, 91 hypertensive cardiomyopathy) were studied. Maximal LA volume index (LAVImax) did not increase significantly with atrial fibrillation (AF) in the ATTR-CA group, unlike in the LVH group. In the ATTR-CA group left atrial reservoir strain (LASr) was significantly reduced (10.2±4.8 vs 16.1±8.1, p&lt;0.001) and LA stiffness (LASr/E/e’) significantly increased (2.4±1.6 vs 1.3±1.0, p&lt;0.001) as compared to the LVH group. CHA 2 DS 2 -VASc was similar in both groups. (p=0.376). The comparison of patients with and without TE is presented in the table (Figure 1). In the ATTR-CA group, a higher percentage of patients (74%) were in or developed new AF versus the LVH group (55%) (p&lt;0.001). In the LVH group, AF (hazard ratio (HR): 10, 95% confidence interval (CI), 2.4-42.2, p=0.024) and CHA 2 DS 2 -VASc (HR: 3.6, 95% CI, 1.52-8.48, p=034) were the independent determinants of TE. Whereas, in the ATTR-CA group LASr (HR: 0.85, 95% CI, 0.74-0.97, p=0.021) and LA stiffness (HR: 1.54, 95% CI, 1.18-1.99, p=0.001) emerged as independent determinants of TE among relevant covariates (AF, CHA 2 DS 2 -VASc, LAVImax), (Figure 2). Conclusion: In ATTR-CA LA remodeling is associated with TE irrespective of AF or CHA 2 DS 2 -VASc. Whereas AF and CHA 2 DS 2 -VASc are the main determinants of TE in other LVH phenotypes. These findings have potential implications to develop empirical anticoagulation strategies.
Abstract 4142863: Patient and Clinician Perceptions of Barriers to and Facilitators of Equitable Oral Anticoagulation in Atrial Fibrillation: A National Qualitative Study
Authors: Utibe Essien, Taylor Boyer, Nicole Beyer, Kristina Hruska, Keri Rodriguez, Terrence Litam, Valerie Nguyen, Jasmyn Tang, Alison Hamilton, Leslie Hausmann
Journal: Circulation (2024)

Introduction: Atrial fibrillation (AF) is a common arrhythmia associated with ischemic stroke. Prior work shows that stroke-reducing oral anticoagulant (OAC) therapy is less commonly prescribed in minoritized racial/ethnic groups, but the drivers of these disparities are unclear. Hypothesis: We hypothesized that clinicians and patients would provide key themes to inform disparities in OAC prescribing. Goals/Aims: To identify barriers to and facilitators of equitable OAC prescribing. Methods: Using data from a cohort of patients with incident AF in the Veterans Health Administration (VA) from 2018-2021, we identified VA medical centers (N=21) with high vs. low rates of OAC prescribing and racial disparities (&gt;10%) in prescribing. From these sites, we recruited 30 clinicians (PCPs, cardiologists, pharmacists) and 33 patients with AF (67% Black or Hispanic). We conducted 1:1 semi-structured interviews from 6/1/23-3/1/24. A primary and secondary analyst co-coded 20% of the interviews using negotiated consensus before coding the remaining interviews independently. Themes related to patient and structural-level barriers to and facilitators of equitable OAC use were identified using thematic analysis. Results: Clinicians identified patient-level barriers including knowledge of someone who had a negative anticoagulation experience, mistrust of the health system, and concerns about bleeding risk and side effects. Patients raised concerns about the OAC regimen or distrust of medications and a lack of information about OACs. Structural-level barriers identified by clinicians included perceptions that patients’ adverse social circumstances (e.g., homelessness) interfere with medication use, care fragmentation between VA and non-VA clinics, and AF care not being a top VA priority. Patients also identified distance to VA and poor coordination of care as barriers. All clinicians noted comfort prescribing OACs as a facilitator of equitable prescribing. Other facilitators included strong collaboration between clinicians and anticoagulation clinics, patient-clinician trust, and Veterans learning about the benefits of OAC. Conclusion: Clinicians and diverse patients with AF in VA identified several barriers to equitable prescribing of OAC, including adverse social determinants of health and care fragmentation. Strengthening physician-pharmacist collaboration, building trust with patients, and enhancing AF education are actionable strategies for eliminating disparities in OAC use.
Abstract 4142056: Impact of Obstructive Sleep Apnea on In-Hospital Outcomes of Adults with Hypertrophic Cardiomyopathy
Authors: Nicholas Roma, Spandan Desai, Megan Pattoli, Lindsey Magid, Vikas Yellapu, Jamshid Shirani
Journal: Circulation (2024)

Background: Obstructive sleep apnea (OSA) has been reported in a sizable proportion of adults with hypertrophic cardiomyopathy (HCM) and has been associated with higher incidence of adverse outcomes including arrhythmias (atrial fibrillation, non-sustained ventricular tachycardia) and sudden cardiac death when untreated. We aimed to evaluate the impact of OSA on in-hospital outcomes of patients with HCM. Methods: National Inpatient Sample 2016-2020 was queried to identify admissions for HCM patients with (HCM+OSA) and without (HCM-OSA) OSA. In-hospital outcomes were compared with use of logistic regression. Results: From 2016-2020, 271,085 adults with HCM were admitted to hospital of whom 45,135 (16.6%) were identified to also have OSA. Age was similar between both groups. (Table) Comorbidities (diabetes, coronary artery disease, hyperlipidemia, and chronic kidney disease) were more prevalent among HCM+OSA [Table]. Additionally, HCM+OSA more often had the obstructive phenotype (43.8 vs. 42.87%, p&lt;0.001), heart Failure with preserved ejection fraction (37.75 vs. 27.01%, p&lt;0.001), and paroxysmal atrial fibrillation (24.65 vs. 19.76%, p&lt;0.001) and more frequently underwent septal reduction therapy [surgical myectomy (2.61 vs. 2.09%) or alcohol septal ablation (0.94 vs. 0.76%), both p&lt;0.001)]. In-hospital outcomes such as overall mortality, need for intensive care unit admission, mechanical ventilation, mechanical circulatory support and use of vasopressors did not differ among patients with HCM and with or without SH [Table]. Conclusion: In this study, 1 in ~6 adults with HCM admitted to hospital also had OSA. OSA in HCM was associated with higher prevalence of comorbid conditions and the obstructive phenotype and thus higher rates of septal reduction therapy. However, presence of OSA did not impact in-hospital outcomes of HCM in this study.
Abstract 4142894: Multimorbidity Trajectories Across the Lifespan in Patients with Congenital Heart Disease
Authors: Chao Li, Aihua Liu, Solomon Bendayan, Liming Guo, Judith Therrien, Archer Yang, Robyn Tamblyn, Jay Brophy, Yue Li, Ariane Marelli
Journal: Circulation (2024)

Background: Befitted from advances in medical care, patients with congenital heart disease (CHD) now survive to adulthood but face elevated risks of both cardiac and non-cardiac complications. Understanding the trajectories of comorbidity development over a patient's lifespan is cornerstone to optimize care expected to improve long-term health outcomes. Research Aim: This study aims to investigate the temporal sequences and evolution of comorbidities in CHD patients across their lifespan. We hypothesize that multimorbidity trajectories in CHD patients are linked to CHD lesion severity and age at onset of specific comorbidities. Methods: Using the Quebec CHD database which comprised data in outpatient visits, hospitalization records and vital status from 1983 to 2017, we designed a longitudinal cohort study evaluating the development of 39 comorbidities coded using ICD-9/10. Temporal sequences were mapped using median age of onset. Associations between disease pairs were quantified by hazard ratios from Cox proportional hazard models adjusting for age, sex, genetic syndrome, competing risks of death, and taking into account the time-varying nature of the predictor diseases. Results: The cohort included 9,764 individuals with severe and 127,729 with non-severe CHD lesions. In severe CHD patients, most comorbidities developed between ages 25 and 40. Comorbidity progression began with childhood cardiovascular diseases, followed by systemic diseases such as diabetes, liver and kidney diseases, and advanced to heart failure and dementia in middle adulthood. In addition, mental disorders emerged in early adulthood and were associated with subsequent development of kidney diseases and dementia. Different trajectories were observed in non-severe CHD patients with 2-3 decades later disease onsets and non-differential onsets between cardiovascular and systemic complications (Figure). Conclusions: Distinct multimorbidity trajectories were observed in CHD patients by CHD lesion severity. In patients with severe CHD lesions, early systemic diseases significantly influenced subsequent complications. These findings highlight the need for well-timed surveillance guidelines and interventions to improve health outcomes.
Abstract 4142898: Marine N-3 Fatty Acids Improve Carotid Atherosclerosis in Diabetic Patients
Authors: Jingjing Jiao, Yu Zhang, Pan Zhuang, Xiaohui Liu, Xuzhi Wan
Journal: Circulation (2024)

Introduction: It remains uncertain whether dietary supplementation of marine n-3 polyunsaturated fatty acids (PUFAs) improves atherosclerosis and lipoprotein subclasses in patients with type 2 diabetes (T2D). In addition, whether the anti-atherosclerotic effect of n-3 PUFA supplementation is modified by genetics remains unclear. Research Questions: We aim to evaluate the effects of marine n-3 PUFA on atherosclerotic plaque risk in Chinese T2D patients; assess changes in NMR-derived lipoprotein subclasses and their mediating effects and explore potential interactions between marine n-3 PUFA supplementation and genetics. Methods: In this 14-month double-blind, randomized controlled trial (RCT), 415 patients with T2D were randomly assigned to receive high-dose (3.0g/day) or low-dose (1.5g/day) marine n-3 PUFAs or placebo (refined olive oil). The primary outcome was the prevalence of carotid artery plaques assessed by ultrasound. Secondary outcomes included changes in NMR-derived lipoprotein subclasses and their mediation effects on carotid plaque. Genetic interactions with n-3 PUFA supplementation were also analyzed. Results: There were 383 participants (92.3%) completed the 14-month intervention and 358 patients (86.3%) completed carotid ultrasound exams. Fish oil supplementation was significantly associated with reduced prevalence of carotid plaques (P=0.023). Compared to the placebo group, the adjusted odds ratio (95% CI) was 0.41 (0.19-0.88) for the high-dose group and 0.86 (0.42-1.79) for the low-dose group. High-dose fish oil intervention significantly reduced remnant cholesterol, LDL-1-triglycerides (TG), HDL-4-TG, and HDL-3-TG, which largely mediated the anti-atherosclerotic effects. Additionally, the anti-atherosclerotic effect on carotid plaques was most prominent among patients with low genetic risk of remnant cholesterol and LDL. Variants of ELOVL2 (rs2295602, rs4711171 and rs3734398) significantly modified the protective effects of high-dose marine n-3 PUFAs on carotid plaques. Conclusions: Long-term supplementation with high-dose marine n-3 PUFAs was associated with a reduced risk of carotid artery plaques among T2D patients, potentially mediated by improvements in lipoprotein subclasses, particularly remnant cholesterol and TG-rich particles. Our findings support the use of high-dose dietary n-3 PUFA supplements for atherosclerosis protection and also highlight the potential for personalized n-3 PUFA treatment based on genetic risk.
Abstract 4142998: Optimizing Transcatheter Aortic Valve Design to Mitigate Subclinical Leaflet Thrombosis
Authors: Dong Qiu, Ali Azadani
Journal: Circulation (2024)

Introduction: Subclinical leaflet thrombosis is an increasingly recognized complication in patients undergoing transcatheter aortic valve replacement (TAVR). Patients with hypoattenuated leaflet thickening (HALT) and reduced leaflet motion (RELM) have a higher incidence of strokes and transient ischemic attacks. Early clinical data suggested that HALT is more common in supra-annular than intra-annular transcatheter aortic valves (TAVs). It was postulated that intra-annular TAVs have a larger neo-sinus volume and are potentially at a higher risk of blood flow stagnation in the neo-sinus region than supra-annular devices. However, recent clinical data obtained from the Evolut Low-Risk trial and the PARTNER 3 Cardiac CT sub-study showed that the incidence of HALT was comparable between supra-annular Evolut R (30.9%) and intra-annular SAPIEN 3 (28%) devices at one year. Hypothesis: We hypothesized that TAV leaflet design plays a vital role in the initiation and growth of leaflet thrombosis. Aim: The study aimed to optimize the leaflet and frame geometry of TAVs to mitigate the risk of subclinical leaflet thrombosis using an interactive parametric design platform that streamlines the engineering design process. Methods: We developed an automated computational framework to optimize the design of TAV leaflets in ANSYS Workbench, aiming to minimize (i) blood stasis on the surface of the TAV leaflets and (ii) the peak stress experienced by the tissue. Seven design variables were defined to modify the leaflet geometry and valve position (Figure 1). Results: The design platform revealed a complex response of the design variables, underscoring the importance of numerical optimization to obtain an optimal valve geometry. A considerable reduction in the blood stasis and maximum in-plane principal stress (31%) was observed in comparison to commercially available TAVs. Conclusions: The simulation results revealed that the leaflet geometry plays a vital role in the degree of blood stasis on the surface of the TAV leaflets and the stress experienced by the tissue. The optimized TAV design could reduce the risk of subclinical leaflet thrombosis in patients undergoing TAVR.
Abstract 4142037: Age Differences in Patients with Ischemia and Nonobstructive Coronary Arteries
Authors: Spyridon Kostantinis, Gabriel Garcia Castro, Nida Latif, Natasha Cigarroa, Steffne Kunnirickal, Natalija Odanovic, Samit Shah
Journal: Circulation (2024)

Introduction: Ischemia and nonobstructive coronary arteries (INOCA) is increasingly recognized and encompasses vasomotor disorders such as coronary microvascular dysfunction (CMD) and vasospastic angina (VA). The prevalence of atherosclerotic coronary artery disease increases with age, but the age at the time of diagnosis in patients with INOCA is not well described. Methods: From 2017 to 2024, 221 patients with INOCA underwent invasive coronary physiologic assessment including vasoreactivity testing with acetylcholine provocation, guidewire-based assessment of coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and fractional flow reserve (FFR). Age cut-off of 60 years was selected to create two groups of adequate size. Results: Mean age was 57.7 ± 10.8 years and 158 (71.5%) were females. Older INOCA patients (&gt;60 years old) had higher rates of hypertension and obstructive sleep apnea, but similar rates of hyperlipidemia, diabetes, depression, anxiety, and active smoking compared to younger patients (&lt;60 years old). There were significant differences in medical therapy at baseline with older patients being more likely to receive statin (69.7% vs 54.9%, p=0.024), ACEi/ARB (35.4% vs. 22.1%, p=0.029), or β-blockers (50.5% vs. 35.3%, p=0.022). Increasing age was associated with progressive decrease in CFR (rho=-0.21; R 2 = 0.04; p&lt;0.001), and a progressive increase in IMR (rho=0.35; R 2 = 0.12; p=0.002) (Figure 1). Older INOCA patients had higher rates of CMD (38.4% vs. 21.3%; p=0.005), and myocardial bridging was more frequent in younger patients (14.8% vs. 5.1%; p=0.015) (Figure 2). Conclusion: In our study sample, increasing age was associated with a reduction in CFR and increase in IMR. Older INOCA patients were more likely to have CMD and less likely to have myocardial bridging compared to younger patients.