bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4142830: High Prevalence of Cardiovascular-Kidney-Metabolic Syndrome and Lack of Sex Disparities in Youth Referred for Hypertension Disorders: A SUPERHERO Analysis
Authors: South Andrew , Baker-Smith Carissa , Campbell Jessica , Harry Giya , Laisure John , Murphy Margaret , Onugha Elizabeth , Pudupakkam Ashna , Riar Sandeep , Siddiqui Sahar , Walsh Michael , Vincent Carol
Published: November 2024

Background:
Given the increasingly high prevalence of adverse cardiovascular (CV) health in adults and its relationship with numerous organ systems, an AHA Presidential Advisory recently defined CV-kidney-metabolic (CKM) syndrome. However, CKM syndrome prevalence and presence of sex disparities are unknown in youth with hypertension disorders.

Methods:
Cross-sectional descriptive and inferential analysis of baseline data from 7 sites in the Study of the Epidemiology of Pediatric Hypertension (SUPERHERO), a retrospective Registry of electronic health record data using standardized biomedical informatics scripts and validated by manual record review. Inclusion criteria were youth <19 years old who received care from subspecialists for hypertension disorders from 1/1/2016–12/31/2023 defined by ICD-10 codes. Exclusion criteria were kidney failure on dialysis, kidney transplantation, or pregnancy by ICD-10 codes. We defined CKM syndrome as Stage 2, Stage 1, Stage 0, or Unclassified using ICD-10 codes and recorded BP and BMI (Figure 1). We reported mean (
SD
) and
n
(%) and used directed acyclic graph-informed generalized linear models.

Results:
Of 9,356 participants, mean age was 12.8 years (
SD
4.5) and 38% were female. CKM syndrome prevalence was 85% (20% Stage 1, 65% Stage 2), and 7% were Unclassified. Table 1 describes the various health conditions by CKM syndrome staging. Among the 8,726 participants with known staging, female sex was not associated with worse CKM syndrome (RR 1.04, 95% CL 0.95–1.14).

Discussion:
In this novel study of youth with hypertension disorders, CKM syndrome was common (85% at baseline) but there were no sex differences. Ongoing SUPERHERO steps are improving CKM syndrome case definition. Future analyses will investigate CKM syndrome’s relationship with social determinants of health and outcomes. Presence of CKM syndrome could inform innovative primordial and primary preventative interventions, and hypertension treatment, in youth to greatly improve CV health across the life course.
Abstract 4142835: Remote Patient Monitoring and Excess Readmission Rates for Cardiovascular Conditions at Hospitals in the United States
Authors: Pedroso Camargos Aline , Lin Zhenqiu , Ross Joseph , Khera Rohan
Published: November 2024

Background:
Heart failure (HF) and acute myocardial infarction (AMI) have been a key focus of health policy initiatives targeting hospital readmission risk, but after initial improvements, progress has slowed. Digital remote patient monitoring (RPM) tools have been recognized as potential strategies for enabling better patient outcomes by tracking healthcare outside clinical settings. We evaluated patterns of RPM service use at US hospitals and their association with post-discharge outcomes for HF and AMI.

Methods:
We used the 2022 American Hospital Association (AHA) Annual Survey data to identify US hospitals offering RPM services and the nature of these services (post-discharge, chronic care, others), overall and across different hospital groups (based on bed size, location, ownership, teaching status, and region). We linked these with hospitals’ benchmarked risk-standardized relative performance on readmissions (excess readmission ratio [ERR]) from CMS Hospital Quality Report (2019-2022) to examine the association between RPM services at hospitals and lower than expected HF and AMI readmission rates (ERR<1), accounting for hospital characteristics in multivariable logistic regression.

Results:
The study included 2,255 hospitals in the AHA Survey with paired readmission performance data. Of these, 55.7% offered RPM services: 41.7% for monitoring post-discharge care, 47.4% for chronic care management, and 40.2% for other RPM services. RPM service availability was highest at hospitals with bedsize ≥500 (81.1%) and those in the Northeast (73.6%). RPM services were also more frequently available at urban vs rural (57.5% vs 29.7%) and teaching vs non-teaching (86.4% vs 52.5%) hospitals
(A)
. Hospitals with RPM services compared with those without RPM services were more likely to have an ERR<1 for HF (OR 1.24, 95% CI 1.03-1.49) but not for AMI (OR 1.20, 95% CI 0.95-1.51). However, availability of RPM services targeted explicitly at post-hospitalization monitoring was associated with greater likelihood of having an ERR<1 for both HF (OR 1.33 95% CI 1.10-1.60) and AMI (OR 1.29, 95% CI 1.02-1.62)
(B)
.

Conclusions:
Large, urban, and teaching hospitals more frequently invested in RPM services, which was associated with lower-than-expected readmission rates for HF and AMI, especially when RPM specifically targeted post-discharge care. There is a need to rigorously evaluate the nature of services that enable the best post-discharge outcomes for each condition.
Abstract 4142839: Modulating the Intestinal Mycobiome Mitigates Pulmonary Arterial Hypertension Severity
Authors: Kremer Benjamin , Ngo Elizabeth , Prisco Sasha
Published: November 2024

Introduction:
Inflammation is a key driver in the development of pulmonary arterial hypertension (PAH). Recent studies have indicated that modulating the intestinal microbiome may be an innovative approach to mitigate systemic inflammation in PAH. The gut microbiome is a complex ecosystem consisting of trillions of organisms, 0.1% of which are fungi. The role of fungal species, or intestinal mycobiome, is undefined in PAH and is understudied in all diseases. We investigated whether the use of fluconazole, a broad-spectrum antifungal, affects the pulmonary vasculature in the monocrotaline (MCT) rat model.

Hypothesis:
Fluconazole administration will alter PAH severity in a preclinical PAH model.

Methods:
Three groups of male Sprague-Dawley rats were investigated: Control, MCT-vehicle (MCT-V), and MCT-fluconazole. MCT was given once subcutaneously at 60 mg/kg. Two weeks after MCT injection, MCT-fluconazole rats were administered fluconazole 20 mg/kg daily via oral gavage for ten days. Echocardiography and invasive hemodynamics defined right ventricular (RV) function and PAH severity. The pulmonary vasculature was evaluated histologically. RV hypertrophy was assessed by weight and cardiomyocyte area. Treadmill exercise testing assessed functional capacity.

Results:
MCT-fluconazole rats had significantly decreased PAH disease severity with a significant reduction in RV systolic pressure (A), effective arterial elastance (B), and percent pulmonary medial wall thickness (C) compared to MCT-V. Rats administered fluconazole had augmented RV function with increased percent RV free wall thickness change (D), RV ejection fraction (E) and RV-pulmonary arterial coupling (F). Compared to MCT-V, MCT-fluconazole rats had diminished RV hypertrophy with a reduction in Fulton index (
p
<0.05), RV/body weight (
p
<0.05), and cardiomyocyte area (
p
<0.0001). Although MCT-fluconazole rats ran for a similar amount of time compared to MCT-V (6.5±2.6 and 5.2±3.4 seconds, respectively), they had significantly lower respiratory exchange ratios (G) and a trend towards higher maximum oxygen consumption (H)
.

Conclusion:
Modulating the intestinal mycobiome may be a novel approach to diminish PAH severity.
Abstract 4142841: Relationship Between Amino Acid Metabolomics in Patients with Acute Ischemic Stroke Undergoing Intervention
Authors: Tantry Udaya , Bliden Kevin , Singh Sahib , Raghavakurup Lekshmi Narayan , Le Anne , Stude Taylor , Khare Pratik , Zhang Xiwen , Gurbel Paul , Ashley William
Published: November 2024

Background:
Emerging data reveal the importance of metabolomics in identifying specific amino acids and their metabolites as markers of hypercoagulability and stroke. Hypercoagulability, measured by a global hemostasis assay, is associated with thrombotic risk in patients with acute ischemic stroke (AIS).

Hypothesis:
AIS Patients undergoing coronary intervention compared to healthy controls (HC) exhibit dysregulated amino acid metabolomics that is associated with coagulation.

Methods:
Serum samples were collected from HC and AIS patients during the intervention. Untargeted metabolomics was performed using a Thermo-Scientific Q Exactive Plus Orbitrap mass spectrometer with Vanquish Horizon Binary UPLC. Metabolomics results were normalized relative to control subjects and compared to patients with AIS. Whole blood samples were used for the TEG assay, and the results were compared between patients with AIS and HC. Hypercoagulability was defined as platelet-fibrin clot strength (P-FCS)
>
66.5 mm.

Results:
AIS patients undergoing interventional procedures (n=12) and HC (n=17) were included. Among AIS patients, 50% were black, 67% were male, and 67% were obese. AIS patients vs. controls had elevated levels of P-FCS (67±3mm vs. 62±2mm) and a higher prevalence of hypercoagulability (83% vs. 0%) (p<0.05 for both). Compared to HC, patients with AIS had negative correlation with histidine (his), glutamine (Glu), arginine, lysine (Lys), asparagine (ASP), homoarginine (Harg), ornithine (orn), valine (Val), homocysteine (Hcyc), anthranilate (Ant), serotonin (Ser), tryptophan (Trp), proline (Prl), alanine (Ala), and beta-alanine (Bala). They positively correlated with kynurenine (Kyn), xanthine (Xan), and xanthosine (Xanth) (P<0.05 for all, Figur ).

Conclusions:
This hypothesis-generating study of untargeted metabolomics revealed that patients with AIS at the time of intervention were characterized by significant hypercoagulability and dysregulation of amino acids associated with coagulation. Further studies are planned to analyze the relationship between these amino acids and AIS risk and to identify them as novel prognostic risk factors.
Abstract 4142846: Endothelial Copper Uptake Transporter CTR1 Senses Disturbed Flow to Promote Atherosclerosis through Cuproptosis
Authors: Varadarajan Sudhahar , Xiao Zhen , Das Archita , Ash Dipankar , Yadav Shikha , Chatterjee Barun , McMenamin Malgorzata , Kelley Stephanie , Rao Jianghong , Kaplan Jack , Ushio-Fukai Masuko , Fukai Tohru
Published: November 2024

Background:
Endothelial cells (ECs) utilize molecular mechanosensors that are critical for sensing disturbed flow (DF) to promote atherosclerosis. Copper (Cu), an essential micronutrient, is increased in human atherosclerotic plaques, while Cu chelation inhibits atherosclerosis in mice. “Cuproptosis” is a recently recognized form of programmed cell death which is driven by Cu-dependent mitochondrial protein aggregation and mitochondrial dysfunction; however, its role in atherosclerosis remains unknown.

Results:
Here we show that the Cu uptake transporter CTR1, which mainly localizes in the plasma membrane and caveolae/lipid rafts (C/LR), functions as a novel mechanosensor for DF to promote cuproptosis and atherosclerosis. Using X-ray fluorescence and ICP-MS analysis, we found that Cu, but not Fe and Zn levels, were increased in DF-exposed EC layers in the aortic arch of high fat diet-induced atherosclerotic (ApoE-KO) mice (2.3-fold) and cultured human aortic ECs (1.73-fold). Notably, DF vs. laminar flow (LF) increased mitochondrial Cu (1.6-fold) in ECs and induced mitochondrial dysfunction and cell death. These responses were rescued by mitochondrial-targeted Cu-depleting nanoparticle (mitoCDN) or CTR1siRNA. Functionally, the partial carotid ligation model revealed that EC-Ctr1 KO mice (by 70%) or mitoCDN (i.v.)(by 58%) reduced DF-induced atherosclerotic lesions in ApoE-KO mice, suggesting that DF-induced mitochondrial Cu promotes atherosclerosis through CTR1. Importantly, DF induced cuproptosis-related responses (increased DLAT aggregation, reduced DLAT lipoylation (47%) and Fe-S cluster proteins vs. LF), thereby increasing proteotoxic stress and decreasing mitochondrial respiration. All of these DF-induced responses were blocked by mitoCDN or CTR1siRNA. To address how DF increased mitochondrial Cu via CTR1, we performed subcellular fractionation and colocalization analysis and found that DF promoted mitochondrial Cu transporter SLC25A3 translocation to the plasma membrane (C/LR)(10.2-fold) and its association with CTR1 (2.8-fold), which were blocked by the disruption of C/LR using methyl-beta cyclodextrin. Furthermore, CTR1siRNA prevented DF-induced SLC25A3 translocation to plasma membrane.

Conclusion:
Endothelial CTR1 functions as a novel DF “mechanosensor” to increase mitochondrial Cu levels via recruiting mitochondrial SLC25A3 to plasma membrane C/LR where it binds to CTR1, leading to cuproptosis, which contributes to atherosclerosis.
Abstract 4142847:
Dnmt3a
modifies the anti-inflammatory effect of the IL-6 classical pathway in macrophages to change the atherosclerosis burden.
Authors: Nakao Tetsushi , Rentz Thiago , McConkey Marie , Williams Jason , Chen Mengyu , Vromman Amelie , Janini Gomes Mariana , Moscavitch Samuel , Tobar Santiago , Sausen Grasiele , Shvartz Eugenia , Folco Eduardo , Ebert Benjamin , Libby Peter
Published: November 2024

Background:
Clonal hematopoiesis of indeterminate potential (CHIP) can contribute to cardiovascular risk. The Interleukin-6 receptor (IL6R) polymorphism (D358A) modifies the risk of coronary artery diseases among CHIP carriers in human cohorts. However, the effects of the IL6R D358A on IL-6 pathways are discordant with the canonical expectation, that the classical IL-6 signaling pathway is anti-inflammatory while the trans-signaling pathway is pro-inflammatory.

Hypothesis:
DNMT3A, the most frequent driver gene for CHIP, changes the inflammatory consequence of IL-6 classical signaling from anti-inflammatory to pro-inflammatory to worsen atherosclerosis.

Method:
We investigated if an anti-IL6R antibody modifies atherosclerosis associated with myeloid
Dnmt3a
deficiency
in vivo
.
Ldlr
-/-
mice were transplanted with 10% bone marrow cells from
Dnmt3a
-/-
mice/90% of wild-type (WT) cells compared with 100% WT transfer. After engraftment, mice consumed a high-fat diet, and received an anti-IL6R antibody for 10 weeks to assess aortic root atherosclerosis vs. control antibody treatment. We also investigated the differences between IL-6 classical- vs trans-signaling pathways and whether
Dnmt3a
deficiency in bone marrow-derived macrophages (BMDM) modifies the IL-6 pathways. RNA-seq was performed in BMDM stimulated with IL-6, which activates the classical IL-6 pathway, or IL-6/IL6R conjugate, which activates trans-signaling. We further compared IL-6 vs control stimulation between
Dnmt3a
-/-
and WT BMDM using RNA-seq, and the major finding was replicated by quantitative PCR. In addition, IL-1β was quantified in the conditioned medium.

Result:
Anti-IL6R antibody treatment reduced atherosclerosis in the mice with myeloid
Dnmt3a
deficiency. IL4R expression rose significantly in BMDM stimulated by IL-6 compared to IL-6/IL6R conjugate. IL4R induction by IL-6, but not the IL-6/IL6R conjugate, fell significantly in

Dnmt3a
-/-

BMDM compared to WT. IL-1β secretion declined with IL-6 stimulation and was higher in IL6R deficient BMDM, but IL-6 stimulation and deletion of
IL6R
did not affect IL-1β secretion in
Dnmt3a
-/-
BMDMs.

Conclusion:
These data suggest that DNMT3A tonically limits the IL-6 classical pathway to limit atherogenesis in an IL-4 signaling-dependent manner. These findings promote understanding of the CHIP-atherosclerosis association and inform the development of management strategies for CVD risk in CHIP carriers.
Abstract 4142850: SGK1 inhibition attenuated left ventricular thickening and diastolic dysfunction in a mouse model of Heart Failure with Preserved Ejection Fraction
Authors: Bapat Aneesh , Pradhananga Sabindra , Srinivasan Dinesh , Sager Philip , Ellinor Patrick
Published: November 2024

Background:
Heart failure with preserved ejection fraction (HFpEF) is growing in prevalence and expected to become the dominant form of heart failure in the future. Given its significant burden, it is important that novel therapeutic options are explored to identify potential drug targets. Serum and glucocorticoid regulated kinase 1 (SGK1) is a PI3-kinase-dependent kinase and lies downstream of insulin signaling pathways.

Hypothesis:
Given the association between HFpEF and insulin resistance, we hypothesized that SGK1 activation is involved in HFpEF pathogenesis, and that SGK1 inhibition may have therapeutic potential.

Methods:
In this study, we utilized a mouse model of HFpEF, derived by combining obesity and increased afterload.C57BL6/J mice (age 10 weeks) were either fed with control chow and control water (CTL, N=5) or high fat diet (HFD) and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 0.5g/L in drinking water) (HFpEF, N=8) or HFD chow with an incorporated SGK1 inhibitor as well as L-NAME in drinking water (SGK1I, N=6). After treatment for 15 weeks, the mice underwent tail-cuff blood pressure measurements as well as transthoracic echocardiography (TTE) to assess cardiac structural parameters, systolic function, and diastolic function.

Results:
After 15 weeks of treatment, the two groups of mice fed HFD had increased body weight and higher systolic and diastolic tail-cuff BPs than the control group. There were no differences in LV chamber size or systolic function as determined by LVEF or fractional shortening. The HFpEF group had significantly higher diastolic posterior wall thickness (HFpEF: 1.2±0.06, CTL: 1.08±0.04 mm p=0.001), but these differences were attenuated in the SGK1I group (1.09±0.05, p=NS compared to CTL). HFpEF mice, when compared to controls, had a significantly lower early diastolic mitral annular septal tissue velocity (e’) (CTL:37.5±3.2; HFpEF: 24.8±4.2; p=0.002), as well as a significantly higher ratio of E/e’ (CTL: 23±1.2; HFpEF 32.4±6.6; p=0.01). Treatment with SGK1I mitigated HFD+L-NAME induced diastolic dysfunction (e’: 31±8.1; E/e’ 28±4.6; p=NS compared to control for both).

Conclusions:
SGK1 inhibition attenuated left ventricular thickening and diastolic dysfunction in mice treated with HFD and L-NAME. Further investigation is warranted to determine the underlying mechanisms and assess for translational promise.
Abstract 4142867: Dysregulated AP-1 Expression in Monocyte in Recurrent In-Stent Restenosis: Insights from Human Coronary Artery Blood Single-Cell Sequencing
Authors: yu miao , jiang yu , Tan Fangshun , Qian Hai-Yan , Yang WeiXian
Published: November 2024

Aims:
Recurrent in-stent restenosis (RISR) refers to a second event of ISR after successful revascularization procedures of an initial ISR lesion. However, due to its unclear pathogenesis, effective treatment methods are lacking in clinical practice. Therefore, this study aims to investigate the potential mechanisms underlying RISR pathogenesis from an immunological perspective using single-cell RNA sequencing (scRNA-seq), to provide theoretical support for clinical interventions.

Methods:
Single-cell RNA sequencing was conducted to profile coronary blood mononuclear cells (CBMCs) obtained from 10 patients with recurrent in-stent restenosis (RISR) and 10 control individuals without ISR one year after stent implantation. The potential pathogenic pathway was identified through comprehensive bioinformatics analyses and further validated at the cellular level by isolating monocytes via flow cytometry from the coronary blood of patients in the RISR validation cohort (n=8).

Results:
RISR altered the proportion of monocyte subtypes, including an increasing trend in FCGR3A+ Monos and a decrease in MHC-II+ Monos. And a marked elevation of activator protein-1 (AP-1) complex within monocytes was identified as key contributor to the unique transcript profile observed in RISR. Evidence at both the RNA and protein levels demonstrated that in RISR patients, CCL5 secreted by T cells can specifically interact with CCR1 of monocytes, thereby upregulating the p38 MAPK/AP-1/inflammatory cytokine axis. Furthermore, co-culture experiments revealed that these monocytes with heightened expression of inflammatory cytokines can indeed promote the proliferation and migration of endothelial cells (EC) and smooth muscle cells (SMC), thus contributing to the occurrence and progression of RISR.

Conclusion:
Our study provides the first depiction of immunological landscape in the coronary blood of RISR patients. The upregulation of the CCR1/p38 MAPK/AP-1/cytokine axis in monocytes is a critical mechanism that facilitates RISR. Our study fills the gap in the understanding of RISR pathogenesis and holds significant implications for guiding clinical interventions.
Abstract 4142895: Artificial Intelligence for Clinical Risk Stratification: Expert Based Risk Scores versus Online Open Source Generative Pre-Trained Transformers
Authors: Veshtaj Marinela , Omar Alaa , Alam Loba , Kim Ga Hee , Pinney Sean , Argulian Edgar
Published: November 2024

Background:
We explored the potential of cutting-edge open-label artificial intelligence, particularly the unique cognitive capabilities it offers, in modern clinical practice. Our study evaluated the efficacy of online open-source generative pre-trained transformers (ChatGPT) in predicting cardiovascular risk in patients with heart failure and preserved ejection fraction, comparing its performance with expert-based clinical stratification.

Methods:
Retrospectively, we included 772 patients presenting with heart failure symptoms (mean age: 69±6 years, 56% female, mean ejection fraction: 61±5%, all >50%). They were followed for a median of 3.9 years for occurrences of death and hospitalization due to heart failure (HF). A script incorporating 12 variables (see Figure 1) was generated and submitted to the ChatGPT website, utilizing the returned score. Additionally, the H2FPEF score was computed as per guidelines. We then compared the predictive capabilities of both models for outcomes.

Results:
During follow-up, 17 patients died, 52 were hospitalized, and 67 experienced the combined outcome. The average ChatGPT score stood at 6.1±1.7, whereas the mean H2FPEF score was 3.1±1.5, exhibiting a modest correlation (r=0.51, p<0.001). Receiver-operator characteristic curve analysis suggested thresholds of ChatGPT of 6 and H2FPEF of 3 [AE1] for predicting the combined outcome, with comparable accuracy (AUC: 0.71 vs 0.72, all p<0.001). Both models similarly accounted for patients' comorbidities, exercise capacity, and baseline and post-exercise diastolic function. Survival curves illustrated the discriminative power of both H2FPEF and ChatGPT scores in predicting death, HF hospitalization, and the combined outcome. While the agreement between the two classifications was modest (Kappa 0.4, p=0.032), ChatGPT facilitated the reclassification of high-risk patients identified by H2FPEF.

Conclusions:
Open-source large language models such as ChatGPT can contribute to existing methods for predicting cardiac risk, offering the potential for significant cost and expertise savings. Future research endeavors should explore broader applications in diagnosis and management, always prioritizing rigorous ethical and equitable considerations.
Abstract 4142898: Marine N-3 Fatty Acids Improve Carotid Atherosclerosis in Diabetic Patients
Authors: Jiao Jingjing , Zhang Yu , Zhuang Pan , Liu Xiaohui , Wan Xuzhi
Published: November 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 4142908: Pulsatile perfusion attenuates kidney injury during ECMO
Authors: Shen Xueyang
Published: November 2024

Background:
Extracorporeal membrane oxygenation(ECMO) is a critical intervention for treating critically ill patients, Kidney injury is a common occurrence during ECMO therapy, and studies indicate that Veno-Arterial ECMO (VA-ECMO) is linked to more severe kidney damage compared to Veno-Venous ECMO (VV-ECMO). This study aims to compare the impact of VV-ECMO and VA-ECMO on the kidneys and explore their potential underlying mechanisms.

Methods:
Based on our prior research, we established rat models for both VV-ECMO and VA-ECMO. Subsequently, we conducted a comparative analysis to assess the impact of VV-ECMO and VA-ECMO on renal injury. This analysis involved the examination of various data points such as blood urea nitrogen (BUN), creatinine (CR), cystatin C, and Kidney Injury Molecule-1 (KIM-1). Histopathological analysis using HE staining was performed to evaluate the extent of pathological damage. Additionally, we placed particular emphasis on monitoring the pulsatility index in both groups.Furthermore, we employed RNA-Seq on both the VV-ECMO and VA-ECMO rat groups to investigate potential underlying mechanisms.

Results:
The study demonstrated lower levels of renal injury indicators (e.g., BUN, CR, cystatin C, KIM-1) in the VV-ECMO group compared to the VA-ECMO group. Furthermore, HE staining revealed less severe pathological damage in the VV-ECMO group. VV-ECMO also displayed a higher pulsatility index. Transcriptomic analysis highlighted differentially expressed genes between the VV-ECMO and VA-ECMO groups, primarily associated with angiotensin II. Concurrently, the omics data indicated a milder inflammatory response in the VV-ECMO group. We further validated the more pronounced inflammatory response of VA-ECMO through Western blot and RT-PCR experiments. This suggests that VA-ECMO might activate angiotensin II, inducing inflammation due to the absence of cardiac pulsation.

Conclusion:
Compared to VA-ECMO, VV-ECMO demonstrates a more favorable effect in mitigating renal injury. The potential mechanism may involve the rhythmic cardiac pulsation provided by VV-ECMO, effectively suppressing angiotensin II and thereby reducing inflammatory responses. This study offers crucial insights for developing rational strategies in the clinical selection of combined cardiopulmonary support systems.
Abstract 4142966: Bullying Behavior in Children with Congenital Heart Disease: Key Findings From The National Survey of Children’s Health
Authors: Modi Hitakshi , Jani Sagar , O'Connor Mario , Patt Hannock , Lamari-Fisher Alexandra , Van Diest Heather , Mery Carlos , Fraser Charles , Well Andrew
Published: November 2024

Background:
Bullying can negatively impact children’s mental health and well-being. Research shows a higher prevalence of being bullied in those with chronic disease. Data on bullying behavior (being bullied as well as bullying others) in children with congenital heart disease (CHD) is limited.

Research Question:
Do children with CHD bully and get bullied more than those without?

Methods:
National Survey of Children’s Health (NSCH) 2022 data were utilized. Children aged 6-17 years were included. Three groups were created: bully, bullied by others, and not involved. Descriptive, univariate, and multivariable multinomial analyses were utilized.

Results:
A total of 32,984 children were included with 15,857(48%) female; 21,222(64%) Non-Hispanic White; and 803(2%) with CHD. Bullies were found to be 1,136(3%) and 3,566(11%) as being bullied. Children with CHD were more likely to bully(OR=1.53(95%CI:1.2-2.2), p<0.001) and be bullied(OR=1.66(95%CI:1.2-1.8), p<0.001) than those without. Autism, depression, anxiety, and developmental concerns were significantly associated with bullying and being bullied.(Table 1) In multivariable multinomial analysis, CHD was no longer significantly associated with bullying(aOR:0.92(95%CI:0.65-1.29),p=0.644) or being bullied(aOR:0.98(95%CI:0.80-1.24),p=0.983). Other factors including autism, depression, anxiety, and developmental concerns remained significantly associated with both bullying and being bullied.(Table 2)

Conclusion:
In a large national sample, CHD was not independently associated with bullying or being bullied. However, the presence of comorbidities common in CHD (e.g. developmental concerns) was significantly associated with bullying and being bullied. This suggests that CHD itself is not directly a significant factor, but its common comorbidities are. Additional work is needed to understand bullying and design interventions focused on comorbidities to effectively address and mitigate bullying in children with CHD.
Abstract 4142971: Lower Resilience is Associated with Increased Risk of Heart Failure Hospitalizations and Cardiovascular Death in High-Risk Heart Failure
Authors: Farooqui Naba , Steiger Kyle , Killian Jill , Smith Jamie , Redfield Margaret , Dunlay Shannon
Published: November 2024

Introduction:
Psychological resilience is the ability to adapt to significant adversity. Higher resilience has been associated with better quality of life in HF, but its association with outcomes is not known. Herein, we characterize resilience and its association with outcomes in HF.

Research Questions/Hypothesis:
Greater resilience is associated with better health status and outcomes in high-risk HF.

Methods:
In a prospective study, adult residents of 11 counties in Southeastern Minnesota with HF who had been hospitalized with decompensated HF or ventricular arrhythmia (“high-risk HF”) in the preceding 1 year were mailed a survey that included questionnaires to assess resilience (Connor Davidson resilience scale, CD-RISC2), health status (KCCQ-12), and other psychosocial constructs in March 2022. Patients were divided into tertiles by resilience scores, and association with outcomes (survival and hospitalization) were examined using Cox proportional hazard regression and Andersen-Gill models, respectively.

Results:
Among 649 respondents (mean age 76 ± 11.5 years, 40% women, 64.3% HFpEF), patients with greater resilience were older (
p=0.015
), had lower BMI (
p=0.003
) and were more often retired or employed (vs disabled or unemployed,
p<0.001
). Greater resilience was moderately correlated with better health status (r=0.33), social support (r=0.27), and health literacy (r=-0.30); and lower treatment burden (r=-0.42), symptom burden (r=-0.41), and fewer depressive symptoms (r=-0.41) (
p<0.001 for all
). At 1-year follow up, patients with the lowest resilience (lowest tertile) were at a significantly increased risk for HF hospitalizations (adjusted HR 2.09, 95% CI 1.06-4.11) and CV mortality (adjusted HR 1.90, 95% CI 1.01-2.57) compared to those with highest resilience. There was no statistically significant association of resilience with risks of all-cause mortality or all-cause hospitalizations after adjustment (
Figures 1A-D
).

Conclusion:
Higher resilience is associated with better health status and psychosocial profile. Patients with low resilience are at increased risk for HF hospitalizations and CV mortality. Impact of resilience on long term outcomes and response to interventions must be tested in future studies.
Abstract 4142984: Sex Differences in Atrial Fibrillation: Insights from Metabolomics and Transcriptomics
Authors: Qian Ningjing , Jin Junyan , Gao Ying , Wang Yaping
Published: November 2024

Background:
Patients with atrial fibrillation (AF) show different prevalence, complications and prognosis between sexes, which increases the difficulties of risk stratification and therapy strategy management. However, the underlying reasons remain unclear.

Hypothesis:
Plasma metabolites might contribute to sex differences in AF.

Methods:
Plasma samples of male and female patients with AF were collected and performed with metabolomics analysis. Transcriptomics data of atrial tissue from GEO database was analyzed based on a sex stratification. Metabolomics and transcriptomics data were further integratedly analyzed to explore the association among metabolites, atrial remodeling and AF. The related different expressed genes were validated by qPCR.

Results:
Metabolomics analysis showed 155 higher-level metabolites and 408 lower-level metabolites in female patients with AF compared to male patients. And a total of 41 annotated metabolites were further identified. Especially, plasma level of phenylalanine was significantly lower in female patients with AF compared with male patients (FC 0.79,
p
<0.05) while plasma levels of phenylalanine derived-metabolites, including 3,4-dihydroxyphenylacetic acid and 4-hydroxybenzoic acid were significantly higher in female patients with AF compared with male patients (FC 1.71,
p
<0.05; FC 2.29,
p
<0.05). KEGG pathway analysis also showed differential metabolites were enriched in phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism pathways. Transcriptomics analysis of left atrium suggested that atrial remodeling in males with AF was prone to be enriched in metabolic pathways while that in females was strongly enriched in inflammation related pathways. Moreover, related genes responded to phenylalanine and phenylalanine derived-metabolites such as NRF2, GPX4 were both significantly unregulated in left atrium of AF patients compared to those of sinus rhythm (SR) patients in males (FC 3.96,
p
<0.01; FC 2.20,
p
<0.05) while were not significantly altered between AF and SR patients in females (both
p
>0.05).

Conclusion:
This study highlights sex differences of plasma metabolites in patients with AF and their association with differential transcriptomic signature of left atrium. The findings provide new insights into understanding sex differences in AF and identify several specific metabolites, which underscores the importance of taking sex differences into consideration during decision making in clinical practice.
Abstract 4143019: Fetuses with Congenital Heart Disease and Placental Malperfusion Have Adverse Outcomes and
De Novo
Variants in Key Placental Developmental Pathways
Authors: Josowitz Rebecca , Woyciechowski Stacy , Linn Rebecca , Rychik Jack , Gaynor J , Rajagopalan Ramakrishnan , Spinner Nancy
Published: November 2024

Background:
Placental malperfusion (PMP), and perturbation of shared developmental pathways between the fetal heart and placenta, may play a role in the development and outcomes of congenital heart disease (CHD). We hypothesize that genomic variation in pathways involved in vascular or placental development underlie PMP in CHD, which in turn impacts outcomes.

Methods:
Fetuses were diagnosed prenatally with structural CHD in our Fetal Heart Program. Maternal characteristics, neonatal biometrics, genomic diagnoses, and outcomes data were reviewed. Placentas with PMP met pathological criteria according to the Amsterdam Placental Workshop classification for maternal or fetal vascular malperfusion, or placental weight <10% for gestational age. All probands (and available parents) underwent genome sequencing and rare, predicted deleterious exonic or putative splicing single nucleotide variants and small insertion deletions were identified from whole genome sequencing data.
De novo
variants were identified from trios (n = 252) and pathway enrichment analysis was performed. T-tests/Mann-Whitney or Chi-squared/Fishers exact tests were performed with p-value < 0.05 considered significant.

Results:
Of 299 fetuses with CHD, 51% had evidence of PMP (n=153). There were no significant differences in baseline characteristics or CHD subtype of those with or without PMP. Non-syndromic fetuses with PMP (n=118) had decreased birth weight (3335g vs 3000g; p<0.001), length (49cm vs 48cm; p<0.001), head circumference (34cm vs 33cm; p<0.001), longer index hospitalization (15d vs 21d; p=0.02), and a trend towards increased mortality (6% vs 12.7%; p=0.08). The burden of vascular developmental pathway or
de novo
variants (34% vs 39%) was similar between groups and not associated with adverse outcomes. Genes with
de novo
variants were significantly enriched in cardiac developmental pathways in all CHD fetuses, however those with PMP demonstrated distinct enrichment in Notch signaling (
NOTCH1, NOTCH3, DLL4, SMAD6, VIM, TIE1
) and collagen/extracellular matrix biosynthesis (
COL4A4, FN1, MMP2
), genes critical for trophoblast and placental vascular development.

Conclusion:
CHD fetuses with PMP have impaired fetal growth, longer hospital length of stay, and a trend towards increased mortality. In CHD fetuses with PMP, rare, deleterious
de novo
variants were significantly enriched in several key placental developmental pathways, which may represent key mechanisms underlying PMP in CHD.
Abstract 4143064: Dynamic expression poly(A) binding protein N1 coordinate cardiac growth during development and disease.
Authors: Chorghade Sandip , Seimetz Joe , Natua Subhashis , Zhang Bo , Misra Chaitali , Wehrens Xander , Chen Jiwang , Kalsotra Auinash
Published: November 2024

The nuclear poly(A) binding protein (PABPN1) is a ubiquitously expressed, evolutionarily conserved protein that actively involved in 3’-poly(A) tail elongation and alternative polyadenylation (ApA). Here we report that PABPN1 protein expression is post-transcriptionally silenced during postnatal heart development especially in cardiomyocytes but re-expressed during heart failure. Combining single-molecule RNA imaging and nucleo-cytoplasmic fractionations, we demonstrate that PABPN1 silencing in healthy cardiomyocytes occurs through a drastic shift in its mRNA localization: the mRNA is cytoplasmic in neonatal cardiomyocytes but remain incompletely spliced, nuclear speckle-detained, and thus translation-inaccessible in adult cardiomyocytes. Surprisingly during cardiac disease, the stored Pabpn1 mRNA undergoes splicing and transported to cytoplasm for translation. Importantly, cardiomyocyte-specific conditional loss- and gain-of-function studies revealed that persistent expression of PABPN1 in the mouse myocardium provokes major structural and functional abnormalities, resulting in heart failure and death. Using nanopore-based direct RNA and high-resolution illumina sequencing, we identified widespread changes in ApA and poly(A) tail lengths of cardiac transcripts during disease contributing significantly to their expression. Taken together, these results indicate that developmental silencing of PABPN1 through its regulated mRNA splicing and localization is critical for function of the heart while its persistence expression is essential for cardiomyopathy progression.
Abstract 4143098: Development and characterization of an ex vivo human precision-cut lung slice (hPCLS) system for target validation for pulmonary arterial hypertension
Authors: Kim Haejin , Jain Dhawal , Akram Muzaffar , Zhou Willa , Provencher Steeve , Lemay Sarah-Eve , Bonnet Sebastien , Potus Francois , Montesinos Monica , Lu Min , Goodwin Bryan
Published: November 2024

Background:
Translating therapeutic target biology from in vitro culture systems and animal models to humans remains a significant challenge in drug discovery. Recently, human precision-cut lung slices (hPCLS) have emerged as an innovative ex vivo model to better understand the pathophysiology of pulmonary disease. Given the difficulty in acquiring lung tissue from patients with pulmonary arterial hypertension (PAH), we aimed to develop a hPCLS culture system from healthy donors that replicates the PAH phenotype.

Methods:
Cryopreserved hPCLS from several healthy donors were obtained from AnaBios. Viability of the hPCLS was assessed using the lactate dehydrogenase (LDH) assay on cultured media. The hPCLS were cultured for seven days with growth factor (GF) cocktails containing various combinations of EGF, FGF, endothelin-1 (ET-1), PDGF-β, activin A, and TGF-β for 7 days to induce PAH-like phenotypes. The stimulated hPCLS were analyzed using RNA sequencing (RNA-seq). Histological analysis assessed pulmonary arterial (PA) medial wall thickness. RNA-seq data from human lungs with and without PAH served as a reference. Gene expression patterns were compared across key disease-associated pathways and processes. The effects of α5β1 integrin inhibition were investigated using the antibody M200 in the PAH-like hPCLS system.

Results:
LDH activity remained low across all treatment groups over the seven-day period, indicating no tissue toxicity. Histological analysis with H&E and EVG staining showed increased medial wall thickness and elastin deposition in pulmonary arteries stimulated by GFs. RNA-seq analyses revealed gene expression changes in response to several GFs that were consistent with the reference PAH dataset. Key gene sets related to extracellular matrix formation, integrin signaling, proliferation, senescence, and growth factor signaling showed similarities between several GFs and human PAH. Moreover, treatment with the α5β1 antibody, M200, in GF-stimulated hPCLS demonstrated modulation of PAH-like phenotypes.

Conclusions:
We successfully established a novel ex vivo model using hPCLS from healthy donors that mimics PAH characteristics when stimulated by GFs (ET-1, FGF, PDGF-β, and EGF). This model also demonstrated that α5β1 inhibition reduced PAH-like phenotypes. This hPCLS model, in conjunction with tissue from PAH patients, could be a valuable tool for evaluating new therapies, enhancing the translation from preclinical studies to human applications.
Abstract 4143120: Efficacy of Sacubitril-Valsartan Compared with Angiotensin-Converting Enzyme Inhibitor or Angiotensin-Receptor Blocker for Preventing Atrial Fibrillation Recurrence After Catheter Ablation: A Systematic Review and Meta-Analysis
Authors: BEZERRA FERNANDO , Rocha Dantas Clara , Sobreira Luis , Kendi Tsuchiya Sano Vitor , de Oliveira Macena Lobo Artur , Cardoso Jorge , Kelly Francinny , A de Moraes Francisco Cezar , Colombo Fernanda
Published: November 2024

Introduction:
In patients who have undergone catheter ablation due to atrial fibrillation (AF), recurrence of this condition can occur. The effect of Sacubitril/Valsartan (S/V) on preventing atrial fibrillation recurrence compared to Angiotensin-Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Blocker (ARB) is not established. This meta-analysis aims to establish the best therapeutic choice for preventing AF recurrence after catheter ablation.

Method:
A systematic search was conducted in PubMed, Embase, and Cochrane databases for randomized clinical trial (RCT) and observational studies comparing the use of S/V with ACEI/ARB in patients who underwent catheter ablation. Results were presented as mean differences (MD) with a 95% confidence interval (CI). Heterogeneity was assessed by I2, and outcomes were expressed as relative risks (RR), using R software version 4.2.3.

Results:
Three randomized clinical trials and one cohort study, comprising 642 patients with 319 patients in the S/V group and 323 in the control group, were included. Follow-up ranged from 6 to 36 months, with mean ages ranging from 58.9 to 65.8 years. A significant reduction in persistent AF occurrence was demonstrated favoring the S/V group (RR: 0.54; 95% CI: 0.41 to 0.70; P=0.000004; I2: 80%) compared to the ACEI/ARB group. The analysis also showed a significant reduction in Left Atrial Volume Index (LAVI) (MD: -5.33; 95% CI: -8.76 to -1.90; P=0.002; I2: 57%) in the S/V group compared to ACEI/ARB. There was no significant difference in left ventricular ejection fraction (LVEF) with S/V use (MD: 1.23; 95% CI: -0.12 to 2.60; P=0.076; I2: 0%) compared to ACEI/ARB.

Conclusion:
This meta-analysis demonstrated the efficacy of S/V in reducing the incidence of AF in patients undergoing catheter ablation compared to the use of ACEI/ARB. However, more randomized clinical trials are needed for a comprehensive evaluation of its efficacy in reducing AF recurrence in post-catheter ablation patients in clinical practice.