tbuckley/cabot-search huggingface dataset:
Abstract 4146149: Influence of Hypertension on Cardiovascular Injury of Short-term Particulate Air Pollution Exposure in Mice
Authors: Lexiao Jin, Matthew Junard, Gabriel Bonvillain, Sarah Barnett, Alexis Miller, Gregg Shirk, Anna Gumpert, Richa Singhal, Daniel Conklin
Journal: Circulation (2024)

Background: The WHO estimates that air pollution causes 7 million premature deaths or about 1 in 8 global deaths. Epidemiological studies indicate that 60-70% of the premature mortality attributed to air pollution are cardiovascular deaths especially in those with pre-existing conditions such as hypertension and heart failure. The underlying pathophysiological mechanisms by which exposures to air pollution worsen cardiovascular disease are unclear. Hypothesis: We hypothesized that the cardiovascular toxicity of particulate air pollution (PM 2.5 ) exposure would be enhanced in the setting of hypertension. Methods: To test this, we combined air pollution exposure with a hypertension model (angiotensin II, 2.5 mg/kg bwt/day: ANGII osmotic pump) where normotensive and hypertensive male wildtype (WT, C57BL/6J) mice were exposed to filtered air or concentrated ambient PM 2.5 (CAP) for 3 weeks. To understand how combined hypertension and CAP exposure may alter cardiac remodeling, fibrosis and gene transcription (bulk RNAseq) were quantified. Results: Mice with ANGII-infusion developed hypertension (non-invasive tail cuff) that was significantly elevated by CAP exposure. Hypertensive mice also developed cardiac hypertrophy (heart weight/tibia length ratio, mg/mm) independent of exposure [hypertensive: WT+Air, 9.6±0.4; WT+CAP, 10.3±0.4; normotensive groups: WT+Air, 8.3±0.3; WT+CAP, 7.4±0.1). CAP exposure had no effect on differential gene transcription in normotensive mice, yet CAP exposure significantly induced 996 differentially expressed genes (DEG) in hypertensive mice (332 up, 664 down). Gene Ontogeny (GO) analysis found dysregulated gene clusters (&gt;40 genes) primarily for cardiac and striated muscle development and differentiation. Increased genes included caspase 12 ( Casp12 ) and catechol- O -methyltransferase ( Comt) genes that likely reflect enhanced apoptosis and sympathetic input. Downregulated genes included 2 collagen genes ( Col5a3 and Col6a3 ) and death inducer-obliterator 1 ( Dido1 ) -- reflecting dysregulated cardiac remodeling. Conclusions: Hypertension enhanced the susceptibility of short-term air pollution exposure to worsen cardiovascular effects especially cardiac remodeling. This study reveals potential genetic mechanisms by which air pollution hastens cardiac dysregulation and promotes heart failure – a serious, globally relevant cardiovascular health risk of particulate air pollution.
Abstract 4146283: Infrequent Cognitive Assessments in CABG Trials (from 2005-2023) Highlight Need for Improved Strategies for Cognitive Screening post-coronary bypass grafting (CABG) surgery
Authors: Shantanu Srivatsa, Sajeevan Sujanthan, Stephanie Ninode Rivera, Ruth Masterson Creber, Richard Swartz
Journal: Circulation (2024)

Objective: The incidence of cognitive decline following coronary artery bypass grafting (CABG) is well-documented, significantly impacting patient morbidity, mortality, and quality of life. We conducted a systematic review that examines cognitive outcomes in CABG randomized controlled trials (RCTs) to identify which cognitive assessments were used, their administration frequency, attrition rates, and their effectiveness in detecting perioperative cognitive changes in control groups. Methods: We conducted a search of MEDLINE, EMBASE, Cochrane Library, and PsycINFO for CABG RCTs that included cognitive assessments, from January 2005 to December 2023. Descriptive statistics were used to summarize the frequency, domains, and attrition rates of each cognitive task. For tasks assessed both pre- and post-operatively in at least three RCTs, control group scores and standard deviations were reported. Results: Out of 3337 screened studies, 2163 were CABG RCTs, and only 69 (3.2%) included cognitive evaluations (Figure 1). These trials involved 15,839 subjects (79% male, mean age 64.4, median follow-up time 90 days) and used 145 unique cognitive tasks. The Trailmaking Test Part B (40/69; 58.0%) and Part A (38/69; 55.0%) were the most frequently used. Only 7 tasks had means and standard deviations reported before and after surgery in more than three RCTs, and none detected significant pre- to post-operative changes. Attrition rates averaged 19.3%, with a wide range from 0% to 62%. Figure 2 demonstrates the decline in cognitive assessments in CABG trials over the years, with a sharp decline after 2014. Trials that assessed cogntion after 2014 tended to favor screening tasks (MMSE/MoCA) alone. Conclusion: Cognitive assessments are infrequent in CABG trials, and existing tests fail to consistently detect cognitive changes. To effectively evaluate and address cognitive impact after CABG, new assessment strategies that are resilient to attrition and practical for use in diverse trial settings are needed.
Abstract 4146267: Causal Relationship of Obesity with Chronic Kidney Disease and Diabetic Nephropathy: A Meta-Analysis of Mendelian Randomization Studies
Authors: Kesha Doshi, Preet Doshi, Diksha Sanjana Pasnoor, Brian Brereton, Sambasiva Rao Mettela, Vijaya Rupa Konakanchi, CHAITANYA KALAPALA, Naga Pratyusha Cheruvu, Kesar Prajapati, Rupak Desai
Journal: Circulation (2024)

Background: Despite there being a significant association between obesity and chronic kidney disease (CKD) there is a paucity of evidence on the causal role of obesity in the development of CKD. Hence, this meta-analysis aims to elucidate a causal relationship between body mass index (BMI) and the risks of CKD and diabetic nephropathy (DN) using Mendelian randomization studies. Method: We searched PubMed/Medline and Google Scholar for the Mendelian Randomization studies evaluating the association of BMI with the occurrence of CKD/renal failure and DN until May 2024. The inverse-variance weighted method was employed for the meta-analysis. The random effects models and I2 statistics were used for pooled odds ratio (OR) and heterogeneity assessment. Leave-one-out sensitivity analyses were also performed to assess the robustness of the findings Result: Our search rendered a total of 81 studies which were screened thoroughly. From those, 8 studies, all with a unique instrumental variable database were selected. Out of these 6 studies consisted of cases from European Ancestry and remaining 2 from east asian ancestry. According to our meta-analysis, increased genetically predicted BMI was significantly associated with increased risk of CKD (OR 1.40, 95 % CI: 1.26-1.55, I2= 66.74 %, P &lt; 0.02) and DN (OR 2.00, 95 % CI: 1.15-3.50, I2= 87.15 %, P&lt;0.01). In addition, leave-one-out sensitivity analysis showed that the effect size did not change substantially by removal of any particular study in MR studies. Conclusion: The meta-analysis provides robust evidence supporting a causal relationship between higher BMI and increased risks of CKD and DN. These findings underscore the importance of managing BMI as a modifiable risk factor to mitigate the risk of developing CKD and DN. Further studies should explore the underlying mechanisms and evaluate the impact of BMI management on the progression of CKD and DN.
Abstract 4146244: Late Gadolinium Enhancement-Derived Heart Digital Twins Non-Invasively Predict Ventricular Tachycardia Risk in Duchenne Muscular Dystrophy
Authors: Justin Tso, Adityo Prakosa, Kelly Zhang, Eugene Kholmovski, Nestor Vasquez, Lisa Yanek, Brian Beckman, Genila Bibat, Mary Yep, Lisa Dellefave-Castillo, Chet Villa, Naomi Kertesz, Elizabeth McNally, Kathryn Wagner, Hugh Calkins, Doris Leung, Linda Cripe, Andreas Barth, Natalia Trayanova
Journal: Circulation (2024)

Introduction: Patients with Duchenne muscular dystrophy (DMD) universally develop dilated cardiomyopathy. Characteristic left ventricular (LV) fibrosis and decreased LV systolic function can increase the likelihood of fatal ventricular arrhythmias (VA). However, the benefits of ICD therapy in DMD remain uncertain, and there are no established VA risk stratification methods to guide clinical decision making. Here, we developed a digital twin approach that uses standard-of-care late-gadolinium enhanced cardiac magnetic resonance (LGE CMR) imaging alone to non-invasively screen for VA risk in DMD. Methods: Thirty-nine DMD patients from three centers with LGE CMR and Ziopatch monitoring were included, with fast nonsustained VT (NSVT; &gt;170 BPM) as the primary clinical outcome (positive control). From short-axis 2D LGE CMR, we constructed 3D computational models of the LV with patient-specific fibrosis distribution (Fig A). These models were separated into positive and negative groups by performing unsupervised clustering on regional substrate percentages (Fig B). DMD-specific EP properties were then assigned to the 3D models, and a rapid pacing protocol was used to assess in silico VT inducibility (Fig C). Patients were predicted to have VA if they tested positive with both clustering and simulation methods. Tests were performed blinded to clinical outcome, cohort positivity rate, and covariates such as ejection fraction. Results: Five patients were observed to have fast NSVT. Our approach achieved 80% (4/5) sensitivity, 79.4% (27/34) specificity, and 79.5% (31/39) accuracy in predicting these events. The sole false negative patient had lower LGE CMR resolution relative to the rest of the cohort (p &lt; 0.01). While extensive LGE was present in all patients, the positive cluster showed higher inferolateral, apical, and total fibrosis burden (p &lt; 0.01) compared to the negative cluster. Without using simulation, specificity and accuracy decreased to 58.8% and 64.1%. Conclusion: LGE-derived digital twin models show strong potential for screening for VA risk in DMD patients. Future application of these models may help define optimal indications for ICD implantation in DMD.
Abstract 4146171: LDL-C Lowering with Evolocumab and Arterial Aneurysms: Long-Term Analysis from the FOURIER Trial
Authors: Prakriti Gaba, Andre Zimerman, Michelle O'Donoghue, Robert Giugliano, Sabina Murphy, Julia Kuder, Maria Laura Monsalvo, Jose Flores-Arredondo, Dan Atar, Anthony Keech, Marc Sabatine, Nicholas Marston, Brian Bergmark
Journal: Circulation (2024)

Introduction: Arterial aneurysms, particularly abdominal aortic aneurysms (AAA), are life-threatening conditions. Human genetic studies and preclinical mouse models have supported LDL-C reduction through PCSK9i as a strategy to slow the progression of arterial aneurysms. Aims: To investigate the rates of arterial aneurysm events among patients randomized to the PCSK9i evolocumab vs. placebo. Methods: In FOURIER, 27,564 patients with stable ASCVD and LDL-C ≥70 or non-HDL-C ≥100 mg/dL on statins were randomized to evolocumab vs. placebo and followed for a median of 2.2 years. 6,635 patients entered the open-label extension period and received evolocumab for 5 years, irrespective of initial assignment. The primary endpoint of this analysis was any aneurysm event, defined as diagnosis, progression, or intervention related to an arterial aneurysm. Adverse events were reported by the local site and potential aneurysm events were centrally identified by blinded investigators. Procedure-related pseudoaneurysms were excluded. A Cox model, adjusted for randomization stratification factors and an indicator for inclusion in the open-label cohort, was used to compare randomized groups throughout the two trial periods. Results: A total of 236 patients had aneurysm events (58% AAA) during follow-up. Patients who had aneurysm events were older (median age 67 vs. 63 yrs), more likely to be male (86% vs. 75%) and have a history of PAD (21% vs. 13%). Patients randomized to evolocumab had significantly lower rates of aneurysm events during follow-up (HR 0.77 [0.59–0.99]; p=0.041) ( Figure ). The association between randomization to evolocumab and fewer aneurysm events was consistent for both AAA (HR 0.78 [0.56–1.09]) and non-AAA (HR 0.81 [0.55–1.18]). Conclusion: In patients with stable ASCVD on optimized statin therapy, early initiation of long-term evolocumab was associated with fewer arterial aneurysm events compared with delayed initiation. These data support earlier intensive LDL-C reduction with PCSK9i as a promising strategy to prevent the formation and progression of arterial aneurysms, including AAA.
Abstract 4146208: Blood protein mediators of association between smoking and abdominal aortic aneurysm: exploration integrating human proteomic and genomic data
Authors: Shuai Yuan, Samuel Khodursky, Jiawei Geng, Pranav Sharma, Joshua Spin, Philip Tsao, Michael Levin, Scott Damrauer
Journal: Circulation (2024)

Background: Cigarette smoking has been identified as an important risk factor for the development of abdominal aortic aneurysm (AAA) and is known to influence levels of blood proteins. However, protein mediators of the smoking-AAA link remain unexplored. Here, we conducted a two-stage Mendelian randomization (MR) study to comprehensively pinpoint possible protein mediators by leveraging large-scale proteomic and genomic data. Methods: We first assessed the associations between genetically predicted smoking traits (lifetime smoking index, smoking initiation and cigarettes per day) and AAA risk (β total ). We then performed a protein-wide MR analysis to explore circulating proteins associated with smoking traits (β 1 ). Among identified proteins, we established their levels associated with AAA risk (β 2 ). According to directionality (β total vs. β 1 ×β 2 ), pathways were constructed, and corresponding mediation proportions were estimated by (β 1 × β 2 )/ β total ×100%. Genetic instruments for smoking traits were selected by filtering variants at P &lt; 5×10 -8 and r 2 &lt;0.001. Cis variants from encoding gene region ± 1Mb were used as instruments for protein. Summary level data on proteins and AAA were obtained from the deCODE study (N=35,559), Fenland study (N=10,708), and AAAgen consortium (37,214 cases), respectively. MR associations were estimated by the multiplicative random effects inverse variance method and summary-data-based MR method were applicable. We performed colocalization analysis for protein-AAA associations. Multiple testing was controlled with False Discovery Rate. Results: Genetically predicted smoking traits were associated with an increased genetic liability to AAA and genetically predicted levels of 48 proteins. Among 48 smoking-associated proteins, genetically predicted levels of 9 proteins were associated with genetic liability to AAA. Three protein pathways were established. Specifically, genetically predicted levels of WFDC2, MMP12, and SMPD1 mediated approximately 10.0 (1.4-18.6) %, 3.6 (1.7-5.5) %, and 2.2 (95% 0.7-3.7) % of the association between genetically predicted lifetime smoking index and genetic liability to AAA. Colocalization evidence was only observed for the SMPD1-AAA association (PH4=0.98). Conclusions: The study revealed a wide effect of cigarette smoking on blood proteins and suggested three potential pathways linking smoking and AAA, including MMP12 which has long been appreciated as important to AAA formation in model systems.
Abstract 4145568: DOACs versus Aspirin for Secondary Prevention of Stroke after ESUS: An Updated Systematic Review and Meta-analysis of Randomized Clinical Trials
Authors: Izael Da Silva, Ivo Queiroz, Camila Veronica Souza Freire, Marianna Daibes, Lucas Barbosa, Jose Maia, André Evangelista, Diandro Mota
Journal: Circulation (2024)

Background: Embolic stroke of undetermined source (ESUS) is a nonlacunar ischemic stroke with no clear cause, having a 4%-5% annual recurrence rate. The potential benefits of direct oral anticoagulants (DOACs) relative to aspirin in patients with ESUS remain unclear. Objective: We aimed to perform a systematic review and meta-analysis to determine the efficacy of the DOACs in secondary prevention for patients with ESUS compared with aspirin. Methods: MEDLINE, Embase, Cochrane, and ClinicalTrias.gov were searched for RCTs comparing DOACs versus aspirin for secondary stroke prevention after ESUS. We performed a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Review (PRISMA) and Cochrane guidelines. Statistical analysis was performed using R software 4.3.2. A random-effects model was employed to measure mean differences and hazard ratios (HR) with 95% confidence intervals (CI). Results: We included 4 RCTs comprising 13,970 patients. The median age was 67 years (IQR 65.5-68.2), 61% were male, 76% had hypertension, and 51% had diabetes. DOACs were administered to 50% of the participants. No significant difference was found between groups for stroke recurrence [RR 0.95 (95% CI 0.8-1.11) p=0.52; I 2 =0%]. Death from any cause [HR 1.11 (95% CI 0.87-1.42) p=0.38; I 2 =0%], cardiovascular death [HR 1.08 (95% CI 0.61-1.94) p=0.77; I 2 =18%] and myocardial infarction [HR 0.92 (95% CI 0.54-1.54) p=0.76; I 2 =16%] were also similar between groups. However, there was a significant increase in clinically relevant non-major bleeding for patients treated with DOACs [HR 1.53 (95% CI 1.22-1.92) p&lt;0.001; I 2 =9%]. Conclusion: In patients with ESUS, DOACs were not superior to aspirin for the secondary prevention of stroke. However, there was a significant increase in clinically relevant non-major bleeding among patients treated with DOACs. These findings suggest that aspirin remains a viable option for secondary prevention in ESUS patients.
Abstract 4146166: Effect of Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, on Systolic Blood Pressure in Patients with Type 2 Diabetes
Authors: Marquette Hardin, Michael Davies, Amy Carroll, Guillermo Umpierrez
Journal: Circulation (2024)

Clinical trials (inTandem, SOLOIST-WHF, and SCORED) utilizing sotagliflozin (SOTA) have demonstrated glycemic improvements in patients with type 1 diabetes (T1D) and reduced heart failure (HF)-related events and cardiovascular (CV) mortality in patients with type 2 diabetes (T2D). SOTA has been evaluated for changes in cardiometabolic parameters including glycemia, blood pressure, and body weight in 8 double-blind, placebo (PBO)-controlled trials in patients with T2D. The glycemic efficacy of SGLTi including SOTA is attenuated with declining kidney function, but it is not known if the effects of SOTA on blood pressure are impacted as well. The purpose of this post-hoc, patient-level meta-analysis from the Phase 3 studies in patients with T2D was to determine the effect of SOTA on systolic blood pressure (SBP) across a broad range of patients including those with moderate to severe renal impairment. The participants (mean age 63 yrs, BMI 32 kg/m 2 , SBP 133 mmHg, eGFR 74 mL/min/1.73m 2 ) were treated with once-daily SOTA 400 mg (N=1728), SOTA 200 mg (N=728), or PBO (N=1440). Of the 3,896 participants, there were 2,207 patients with a SBP≥ 130 mmHg and 1,120 with a SBP≥ 140 mmHg at baseline despite the use of antihypertensive medications in 81% of patients as well as 271 patients with eGFR &lt; 30, 1,046 with eGFR 30 to &lt; 60, and 2,577 with eGFR ≥ 60 mL/min/1.73m 2 . At 26 weeks, SOTA 200mg and 400mg significantly (p≤ 0.05) reduced SBP in all patients compared to PBO, LS mean difference (95% confidence interval [CI]) -3.5 (-4.7, -2.3) and -3.4 (-4.3, -2.5), respectively, as well as significant reductions in subgroups of patients with SBP≥ 130 mmHg, -2.6 (-4.3, -1.0) and -3.7 (-4.9,-2.5), respectively, and SBP≥ 140 mmHg, -2.5 (-4.9, -0.1) and -3.6 (-5.6, -1.7), respectively. Moreover, reductions in SBP with SOTA were seen in patients regardless of baseline eGFR. (Figure) Despite the known attenuation of glycemic control with SGLTi with declining kidney function, the effects of SOTA on SBP are maintained in patients with T2D regardless of kidney function. Together with improvements in other cardiometabolic parameters shown in both patients with T1D and T2D, SOTA may offer a new therapeutic option for patients with diabetes.
Abstract 4146137: Cell-free DNA Analysis Profiles End-Organ Injury and Predicts Outcomes with Left Ventricular Assist Device Implantation
Authors: Ashley Park, Temesgen Andargie, Tom Hill, Neelam Redekar, Xin Tian, Woojin Park, Hyesik Kong, Isabella Cavagna, Moon Jang, Maria Rodrigo, Keyur Shah, Hannah Valantine, Palak Shah, Sean Agbor-Enoh
Journal: Circulation (2024)

Introduction: Durable left ventricular assist devices (LVADs) improve survival in heart failure but carry high risks of infection, hemocompatibility-related adverse events (HRAE), and death. Current clinical tools use subjective assessments or do not incorporate changes in end-organ injury, limiting their prognostic value with these complications. Plasma cell-free DNA (cfDNA), a potential marker for systemic and tissue-specific injury, holds promise to enhance patient risk stratification and prognosis. Hypothesis: LVAD implantation decreases systemic and end-organ injury, measured by cfDNA. Goal: We aimed to assess changes in global and organ-specific injury patterns with LVAD implantation via cfDNA, and to determine if pre-LVAD cfDNA levels predict post-LVAD complications. Methods: We prospectively recruited 40 LVAD candidates and 40 healthy controls. Pre- and post-LVAD plasma samples were analyzed for nuclear cfDNA (ncfDNA) and mitochondrial cfDNA (mtcfDNA) using digital droplet PCR. Tissue-specific cfDNA levels were measured using bisulfite sequencing and a deconvolution algorithm with a DNA methylation library. Wilcoxon sign-rank tests were used to compare cfDNA levels, and log-rank tests were used to compare outcomes. The clinical outcomes were HRAE-free survival (major bleeding, stroke, device thrombosis, death), and post-LVAD infection. Random forest machine learning analysis ranked tissue-specific cfDNA to identify the tissue patterns of those who develop HRAE and those who develop infection. Results: Prior to LVAD implantation, patients had 4-fold higher ncfDNA and 2-fold higher mtcfDNA compared to healthy controls. After LVAD placement, ncfDNA (18980 vs. 10228 copies/mL, p &lt; .001) and mtcfDNA levels (1051882 vs 579609 copies/mL, p &lt; .001) nearly halved, with significant reductions in innate immune and liver cfDNA (Figure). High pre-LVAD ncfDNA levels were associated with worse HRAE-free survival (p = .035) and infection (p &lt; .001). Tissue sources important in determining HRAEs were distinct from those related to infections. Conclusion: LVAD placement significantly improves systemic and tissue-specific injury, measured by reductions in cfDNA. While pre-LVAD cfDNA levels predict both post-LVAD HRAEs and infections, the cfDNA tissue contributions influencing these outcomes are distinct. Future studies will need to validate these findings and compare cfDNA to other predictors of poor LVAD outcomes.