tbuckley/cabot-search huggingface dataset:
Abstract 4143368: Glycosphingolipid-Mediated Peripheral Immune Cell Inflammatory Activation Impairs Cardiomyocyte Function in Hypoplastic Left Heart Syndrome
Authors: Mary Turner, Ashley Pietra, Praveen Ramaswamy, Anastacia Garcia
Journal: Circulation (2024)

Introduction: Hypoplastic Left Heart Syndrome (HLHS) is the leading indication for heart transplant and the most common cause of cardiovascular death in infants, yet our understanding of the immunologic alterations in HLHS is inadequate. In this study we aimed to (1) assess whether peripheral blood immune cells (PBMCs) from HLHS patients display a pro-inflammatory phenotype, (2) identify specific factors associated with inflammation in HLHS, and (3) investigate the interaction between HLHS PBMCs and cardiomyocytes. Methods: PBMCs were isolated from whole blood by density gradient centrifugation and gene expression changes were assessed using next-generation RNA-sequencing. Mass-spectrometry was used to quantify PBMC lipid species. Healthy PBMCs were cultured with liposomes containing 10μM lactosylceramide (LacCer) and conditioned media (CM) was collected. Cytokine arrays were used to quantify LacCer-mediated inflammatory changes. Cardiomyocytes were treated with CM and mitochondrial bioenergetics were assessed using the Seahorse Bioanalyzer. Results: PBMCs from HLHS patients display significant enrichment of pathways associated with immune cell activation, and cytokine signaling that are suggestive of a pro-inflammatory phenotype. Glycosphingolipids (GSLs) are one of the most abundant glycolipids in humans and play an important role in immune cell signaling and function. We identified that the GSL, LacCer, is significantly enriched in HLHS PBMCs and that exogenous LacCer treatment of healthy PBMCs induces secretion of proinflammatory mediators (e.g., VCAM1, IL-8, CD14). Additionally, in vitro assays determined that CM from healthy PBMCs treated with LacCer is sufficient to promote mitochondrial dysfunction in primary cardiomyocytes. Conclusions: These data suggest that immune cells in HLHS display a pro-inflammatory phenotype that is mediated, at least in part, by increased LacCer. Further, these data provide insight into LacCer’s role in paracrine-mediated crosstalk between immune cells and cardiomyocytes in the setting of HLHS. This suggests a novel role for LacCer-rich PBMCs to potentiate progressive cardiac dysfunction in HLHS and provide an avenue for therapeutic intervention in this vulnerable population.
Abstract 4143314: Veteran Affairs Lipid Optimization Reimagined Quality Improvement Program (VALOR-QI) – A Dual Process Approach to Lipid Management in Patients with Atherosclerotic Cardiovascular Disease (ASCVD) at the Long Beach VA
Authors: Kenny Vu, Sayana Lee
Journal: Circulation (2024)

Objectives: Improve clinical pathways to impact atherosclerotic cardiovascular disease (ASCVD) management of Veterans through a Learning Healthcare System model of quality improvement designed to improve the management of dyslipidemia among those with high-risk ASCVD. Methodology: Long Beach VA (LBVA) is one of 50 VA sites participating in a national quality improvement initiative called the VALOR QI: VA Lipid Optimization Reimagined Quality Improvement Project. VALOR-QI is a collaborative project between the U.S. Department of Veterans Affairs (VA) and the American Heart Association (AHA) with the goal of positively impacting Veterans’ cardiovascular (CV) health. As part of the program, VA sites work with an AHA QI Consultant develop and deploy a local quality improvement plan to help overcome site specific barriers preventing Veterans from achieving optimal cholesterol levels. At the LBVA, patients with LDL-C&gt;70 and an ASCVD diagnosis are screened from a list generated by the health care provider. If a patient meets criteria, the health coach approaches the patient and begins working with them once a month over the phone or in person. During these meetings medication compliance and refills are reviewed, lifestyle goals or progress are reevaluated, and patients are reminded of upcoming appointments and labs. Results: Since October 2022, the LBVA VALOR-QI program has directly interacted with 277 patients who have a high ASCVD risk and LDL-C&gt;70. Of those 277 patients, 84 patients (30%) have reached an LDL-C&lt;70. As of June 2024, 16 patients have maintained their LDL-C&lt;70 for more than 6 months. Patients that have participated since October 2022 have seen a 59% improvement in LDL-C and 50% of those patients have reached goal. The VALOR-QI program collaborates with 8 different primary care or heart failure clinics and some clinics have experienced up to 53% of patients reaching LDL-C&lt;70. Conclusions: The VALOR-QI program at the LBVA has demonstrated the effectiveness of a dual process approach of 1) active health coaching – working directly with patients on lifestyle changes, medication management, and healthcare reminders and 2) collaborating with patients’ providers on intensifying medication or referring to pharmacy or cholesterol clinics.
Abstract 4143326: Multicomponent Digital Therapies to Promote Healthy Eating and Physical Activity and Reduce Risk Factors for Cardiovascular Disease in Older Adults: A Pilot Study
Authors: Marysol Cacciata, Dion Candelaria, Andrew Thomas Reyes, Reimund Serafica, Janett Hildebrand, Axel Sta. Maria, Jung-Ah Lee, Anna Stromberg, Lorraine Evangelista
Journal: Circulation (2024)

Background: Digital health technologies can promote healthy lifestyle behaviors. They can help patients identify, treat, and self-care for chronic illnesses, promote healthy aging, and minimize disparities through primary prevention. However, there is limited research on the efficacy of these systems in promoting healthy eating and physical activity and improving clinical outcomes among older adults at risk for cardiovascular disease. Aims: This pilot study aimed to (1) evaluate the feasibility of the study protocol for indicators of process (e.g., recruitment, consent, retention rates, engagement), resources (e.g., participant adherence, data collection time), and program safety (e.g., number of adverse events); and (2) compare changes in eating patterns, physical activity, and clinical outcomes (weight, blood pressure, lipid profile, and hemoglobin A1C [HbA1C]) between participants randomized to Get FIT vs. Get FIT+ at baseline (pre-intervention) and 12 weeks (post-intervention). Methods: Fifty-four older adults (65.6 ± 5.8 years, 61% females, 61% married, 50% Asians, 6% Whites, 33% Hispanics, 11% Blacks) were randomized to Get FIT (n=24), which included one in-person behavioral counseling session on healthy eating and exercise, a participant handbook, an activity tracker (Fitbit Charge), and access to a nutrition app (MyFitnessPal) for 12 weeks, or Get Fit+ (n=30), which included weekly personalized text messages to motivate and encourage participants to meet their weekly goals in addition to all the other components offered to participants in Get FIT . Results: All feasibility metrics were highly satisfactory, with consent and retention rates being 100% at 12 weeks. Both groups increased moderate to vigorous physical activity levels and decreased calorie intake over time. Participants in Get FIT+ showed a 6% reduction in weight compared to less than 1% in the Get FIT group . All participants showed improvements in blood pressure levels, lipid profiles, and HbA1C, but improvements in HDL cholesterol and triglyceride levels were more prominent in the Get FIT+ group. Conclusion: Our findings suggest that the Get FIT+ intervention may help encourage healthy eating and physical activity among older adults while lowering their cardiometabolic risk. A large randomized clinical trial is needed to evaluate the efficacy of multicomponent digital health therapies in older adults at risk for cardiovascular disease.
Abstract 4143390: HEMODYNAMIC AND CLINICAL IMPACT OF OBESITY IN GROUP 1 PULMONARY HYPERTENSION
Authors: Revati Varma, Adel Kabbara Allababidi, Yogesh Reddy
Journal: Circulation (2024)

Introduction: Obesity is rising in prevalence worldwide and co-exists in patients with group 1 pulmonary hypertension (PH). Clinical and hemodynamic implications of having obesity in group 1 PH remain unknown. Hypothesis . We hypothesized that obese patients with group 1 PH would exhibit worse hemodynamic parameters including higher right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) compared to non-obese patients. Aims: To compare hemodynamic parameters obtained from right heart catheterization (RHC) and echo among group 1 PH with and without obesity. Methods: We evaluated a cohort of patients with group 1 PH who underwent RHC at Mayo Clinic Rochester between 2002 to 2021 with diagnosis adjudicated by detailed chart review and initiation of pulmonary vasodilator therapy. Patients with a mean pulmonary artery pressure (mPAP) ≥ 25 mm who were clinically diagnosed with WHO Group 1 PH and recommended pulmonary vasodilator therapy initiation were included. Results: Of 822 participants with group 1 PH, obesity was common, present in 325 patients (40%). There was no difference in survival among patients with and without obesity (HR 1.15; 95% CI 0.95-1.38; p=.15). Obese patients had higher RAP (12.8 ± 6.8 vs 10.4 ± 6.5 mm of Hg, p&lt;.0001) and cardiac output (5.2 ± 2.2 vs 4.5 ± 1.8 L/min, p&lt;.0001) compared to non-obese group (Table 1). Despite having group 1 PH, pulmonary capillary wedge pressure (PCWP) was higher with obesity (13.8 ± 6.3 vs 12.2 ± 6.5 mm of Hg, p=.001) compared to those without obesity. Along with higher PCWP, there was less pulmonary vascular disease severity with obese group 1 PH, with higher pulmonary artery compliance (PAC, 1.65 ± 1.06 vs 1.38 ± 0.84 mL/mm of Hg, p=.0002) and lower pulmonary vascular resistance (PVR, 7.9 ± 5.2 vs 9.4 ± 7.7 Wood Units, p=.0007). After accounting for age, gender, diabetes mellitus and systemic hypertension, the RAP, cardiac output, PAC and PCWP remained significantly higher, and PVR remained lower in obese patients (p&lt;0.05 for all). Conclusions: Comorbid obesity is associated with higher biventricular filling pressures, higher cardiac output and lower pulmonary vascular disease severity in otherwise clinically diagnosed group 1 PH. These findings call for further study of whether targeting obesity with novel weight loss drugs such as glucagon like peptide 1 receptor agonists or other drugs can lower biventricular filling pressures and associated pulmonary hypertension in group 1 PH with obesity.
Abstract 4143335: Prenatal Dibutyl Phthalate Exposure Dysregulates Fetal-Placental Vascular Function and Spatial Transcriptomic Profile
Authors: Xinran Yang, Aastha Mamidi, Andre Chavez, Dilen Kadlec, Zelieann Craig, Chi Zhou
Journal: Circulation (2024)

Introduction: Fetal vascular dysfunction during pregnancy has long-term adverse effects on the cardiovascular health of the offspring. Prenatal exposure to dibutyl phthalate (DBP), is associated with adverse pregnancy/fetal outcomes and cardiovascular diseases in the offspring. To date, the impact of DBP exposure on fetal vascular function during pregnancies is unclear. Hypothesis: Environmentally relevant low-dosage DBP exposure during pregnancy differentially dysregulates fetal placental vascular function. Methods: Adult female CD-1 mice (10-12wks) were treated with vehicle (CT) or DBP at 0.1 μg/kg/day (DBP0.1) daily 30days before pregnancy through gestational day (GD) 18.5. Fetal-placental blood flow was measured non-invasively using a high-frequency ultrasound (Vevo3100, n=6-8dams/group). Spatial transcriptomic sequencing was performed using Visium (10xGenomics)&amp;NovaSeq (Illumina) with GD18.5 placentas (n=3/fetal sex/group). Bioinformatic analysis was performed with SpaceRanger, Suerat and IPA software. Spatial gene expression validation and lipid disposition were performed with IHC and Oil Red O staining (n=6-8 litter/group). Results: DBP0.1 increased the fetal umbilical-placental velocity time integral (7.9±0.6mm vs. 6.5±0.8mm) at GD18.5. DBP0.1 decreased placental efficiency with more dramatic changes seen in female fetuses. Spatial transcriptomic analysis obtained 20,161 spatial-linked units from placentas from CT and DBP0.1 placentas (median: 140k reads&amp;6,174 genes per unit). Bioinformatic analysis revealed 15 distinct clusters of units that were annotated to 10 different cell types (based on gene expression profiles) that precisely mapped to corresponding placental morphological structures. We identified vascular endothelial cells (ECs-1 [microvasculature]&amp;ECs-2 [larger vasculature]) 2 populations in the fetal placental labyrinth. Pseudo-bulk analysis showed that DBP0.1 dysregulated 40 and 6 genes in ECs-1 from female and male placentas, respectively, but did not affect gene expression in ECs-2. Further, DBP0.1 dysregulates lipid metabolism-associated pathways only in female but not in male ECs-1. This is consistent with our Oil Red O data showing prenatal DBP0.1 exposure significantly decreased lipid disposition in the fetal labyrinth of female, but not in male placentas. Conclusions: Prenatal DBP0.1 exposure dysregulates fetal-placental blood flow velocity, placental efficiency, placental spatial transcriptomic profile and lipid disposition.
Abstract 4143194: Clinical predictors of right ventricular contractile depression among patients with pulmonary hypertension
Authors: Yoo Jin Kim, Ilton Cubero Salazar, Vivek Jani, Paul Hassoun, Ryan Tedford, Steven Hsu
Journal: Circulation (2024)

Background: Right ventricular (RV) dysfunction in patients with pulmonary hypertension (PH) leads to drastically worse clinical outcomes. It remains difficult to find the best clinical correlates of intrinsic RV contractile dysfunction given the load dependent nature of these measures. Here, we evaluate which clinical indices may identify poor RV myocyte contractility among PH patients. Methods: Single-center cohort study of 14 patients with PH (10 with group 1 pulmonary arterial hypertension, 4 with group 2 secondary to heart failure). Clinical evaluation included transthoracic echocardiogram and RV pressure-volume loops measured at rest and during supine bike exercise. Myocyte mechanics were measured using frozen, permeabilized RV myocardium samples. Poor RV myocyte contractility was defined as &gt;2 standard deviations below the mean of normal controls. Results: Among 14 PH subjects, we identified 6 and 8 patients with normal and depressed RV myocyte function, respectively. By area under the receiver operator curve (AUROC) analysis, we found that common clinical measures did not capture those with reduced RV myocyte contractile function: TAPSE (AUROC 0.70, P- value 0.26), RAP (AUROC 0.58, P- value 0.61), RAP/PCWP (AUROC 0.50, P- value &gt;0.99), and PAPi (AUROC 0.52, P -value 0.90) (Figure 1A). We next investigated more sensitive methods of detecting RV dysfunction, such as RV contractile reserve measured during exercise. Changes in RV contractility and RV dilation during exercise were worse in those with poor RV myocyte contractility (Figure 1B). Using AUROC analysis, these measures of RV contractile reserve post-exercise were better able to identify those with intrinsic poor RV myocyte contractility: RV contractile reserve (AUROC 0.94, P -value &lt;0.01) and RV exercise dilation (AUROC 0.85, P -value 0.03) (Figure 1C). Conclusion: Measures of RV contractile reserve are better than commonly obtained clinical measures of resting RV dysfunction at identifying underlying RV myocyte contractile weakness.
Abstract 4143312: Impact of Angiotensin Receptor Neprilysin Inhibitor on Chronic Heart Failure with Reduced Ejection Fraction in Adult Congenital Heart Disease Patients: A Systematic Review and Meta-analysis
Authors: Bibhuti Das, Shriprasad Deshpande, Lazaros Nikolaidis, Jaime Hernandez-Montfort, Jianli Niu
Journal: Circulation (2024)

Background: Heart failure (HF) in adults have benefitted significantly from addition of angiotensin receptor-neprilysin inhibitor (ARNI). However, limited data exist on the efficacy and safety of ARNI in adults with congenital heart disease (ACHD) related HF. Methods: We conducted a comprehensive search of 3 major databases- PubMed, Scopus, and Embase, and collected articles published the use of ARNI for HF in ACHD patients who were already receiving angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), beta-blockers, and mineralocorticoid antagonists. We excluded articles on acute decompensated HF and HF with preserved ejection fraction. The primary outcome was the change in NYHA functional class (FC). Additionally, we evaluated the safety and tolerability of ARNI by studying adverse effects such as hypotension, elevated serum creatinine (Cr), and potassium (K + ). A pooled effect size was calculated based on mean differences (MD) or log odds ratio (LogOR). Results: Our meta-analysis included 14 studies with a total of 305 patients, aged 25 to 84 (median 42 years) ( Table ). Among 305 ACHD patients, 70% had systemic RV, 27% had systemic LV, and 3% were Fontan patients with unknown ventricular morphology. When ARNI replaced ACEIs/ARBs and was added to remaining therapies, the pooled analysis indicated that ARNI significantly improved NYHA FC (LogOR: 0.67, 95% confidence interval (CI) 0.15-1.19, p=0.01) ( Figure 1A ). However, there was no significant change in ventricular function (logOR: 0.37, 95% CI 0.45-0.42, p=0.38). Notably, ARNI use led to a significant decrease in systolic blood pressure (MD=0.49, 95% CI -0.70 to -0.29, p=0.00) ( Figure 1B ), and elevated Cr levels (MD = 0.30, 95% CI 0.10-0.45, p=0.00) ( Figure 1C ). No significant change in K + level (MD=0.0, 95% CI -0.61 to 0.61; p=0.99) ( Figure 1D ). Eighteen patients (6%) discontinued ARNI due to side effects. Conclusion: Our meta-analysis found that ARNI replacement for ACEIs/ARBs improved NYHA FC in most ACHD HF patients across a heterogeneous group of ACHD HF patients consisting of single ventricle, systemic- RV and LV. However, there was no significant change in ventricular function or natriuretic peptide levels. Hypotension and increased serum Cr are more frequent with ARNI use, warranting close monitoring. Future research is needed to assess composite outcomes, including hospitalizations and mortality in ACHD HF patients after adding ARNI to conventional therapy.
Abstract 4143176: Association Between Frailty Testing through Gait Speed and Mortality in CRT Patients: Report for a Multidisciplinary CRT Clinic
Authors: Aritra Paul, Joe Demian, Niraj Varma, J. Emanuel Finet, Arshneel Kochar, Feras Bader, Oussama Wazni, Wilson Tang, John Rickard
Journal: Circulation (2024)

Background: Identifying predictors of mortality in CRT patients remains an active area of investigation. Objective: To establish a relationship between gait speed (GS) and mortality in heart failure patients with CRT. Hypothesis: Patients with slower gait speeds have worse survival rates after CRT implantation. Methods: This retrospective study included 504 patients who underwent CRT implantation at our institution between 2017-2022. All patients were followed up with a multidisciplinary team, including electrophysiology and heart failure physicians about 6 months after CRT implantation, where frailty was assessed. We used GS as a measure of frailty and divided patients into 2 groups: GS: &lt;1 m/s (n=177) and ≥ 1 m/s (n=327). The primary endpoint was a composite of left ventricular assist device implantation, transplant, or death at 2 years post-CRT. Data was collected retrospectively from electronic medical records. Results: The study population was 65.7% male, with a mean age of 69.1 years, with majority of the devices being CRT-D (79.6%). Response was defined as an improvement in LVEF &gt;5% with reduction in LVESV&gt;10%; anybody not meeting this definition was classified as a non-responder. Responder and non-responder rates among GS&lt; 1 m/s and GS &gt; 1 m/s were 53.8% vs 66.4%; and 35.1% vs 26.2%, respectively. The median (IQR) GS was 1.15 m/s (0.91-1.37 m/s). 52 (10.3%) patients had a composite outcome within 2 years follow up. Non-parametric univariate analysis revealed that lower GS was significantly associated higher composite outcome rates (median GS 0.8 vs 1.18 m/s; p&lt;0.001). Multivariate cox regression also revealed GS&lt;1 m/s to be an independent predictor of our composite outcome [HR- 4.33 (2.20-8.86); p&lt;0.001] (Table 1), with survival graphs showing patients with GS&lt;1m/s having worse 2-year survival (Figure 1). Conclusion: Frailty testing using GS post-CRT implantation is a strong predictor of mortality in CRT patients.
Abstract 4143199: The Multi-omic, Multi-tissue Response to Acute Endurance and Resistance Exercise: Results from the Molecular Transducers of Physical Activity Consortium
Authors: Daniel Katz, Christopher Jin, Gregory Smith, Natalie Clark, Gayatri Iyer, Hasmik Keshishian, Patrick Hart, James Sanford, Zidong Zhang, Yongchao Ge, Jeremy Robbins, Jacob Barber, Samuel Montalvo, David Jimenez-Morales, Malene Lindholm, Jimmy Zhen, Byron Jaeger, Lauren Sparks, Tyler Sagendorf, Gina Many, Nikolai Vetr, Archana Raja, David Amar, Fang-Chi Hsu, Michael Miller, Ashley Xia, Jerome Fleg, Russell Tracy, Robert Gerszten, Joshua Adkins, Martin Walsh, Stuart Sealfon, Bret Goodpaster, Scott Trappe, Charles Burant, Steven Carr, Kevin Smith, Michael Snyder, Stephen Montgomery, Euan Ashley, Matthew Wheeler, MoTrPAC Study Group .
Journal: Circulation (2024)

Introduction: Exercise is critical to cardiovascular health. However, the underlying molecular mechanisms are not well described. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) seeks to create a detailed molecular map of the response to exercise. Described here is the first human cohort of MoTrPAC, enrolled prior to the COVID-19 shutdown (N=175). Methods: Healthy, sedentary adults were randomized to an 8-exercise circuit of resistance exercise (RE, N=73), a 40 minute submaximal endurance exercise bout (EE, N=65), or to non-exercising control (N=37). Blood, muscle, and adipose tissue were sampled at 4-7 time points relative to exercise, depending on tissue/modality. Samples were deep phenotyped across multiple omic domains including chromatin accessibility, transcriptomics, proteomics, phosphoproteomics, and metabolomics. Results: The cohort was 72% female, with a mean±sd age of 41±15 years and BMI of 27.1±4.0 kg/m2. Exercise affected over 34,000 molecular features in ≥1 tissue/time point including a high proportion of transcriptomic and phosphoproteomic features (Figure A). Molecular signatures were compared between EE and RE: enrichment analysis of muscle phosphoproteomics showed a greater activation of MAP kinases in RE compared to EE at all time points. To identify plausible exerkines (secreted molecules signaling an acute exercise bout), differentially abundant features in any sampled tissue cells were compared to temporally-matched cognate protein levels in plasma, yielding 110 features. A known exerkine, CX3CL1 (fractalkine) was identified, in addition to novel candidates, such as cellular communication network factor 1 (CCN1), a secreted extracellular matrix protein linked to plasma triglyceride levels, which showed increased abundance early post exercise (Figure B). Network analysis across tissues and omes identified novel transcription factor “hubs” as candidate master regulators of exercise response. Conclusions: These first MoTrPAC data represent an unparalleled multi-tissue, multi-omic, multi-time point, multi-modality map of acute exercise, enhancing our understanding of the molecular transducers that may link exercise and cardiovascular health.