bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4120480: HIV-Nef extracellular vesicles utilize the novel Btk-NFκB-MerTK signaling axis to impair macrophage efferocytosis and promote atherosclerosis: A multiomics study
Authors: Chelvanambi Sarvesh , Decano Julius L , Nakamura Yuto , Yangihara Yoshihiro , Jule Amelie , Delwarde Constance , Bartoli-Leonard Francesca , Jha prabhash , Lupieri Adrien , Enomoto Takashi , Matamalas Joan , Mukai Shin , Pestana Diego , Ge Rile , Perez katelyn , Kasai Taku , Kuraoka Shiori , Silva Monteiro Gabriel , Tabas Ira , Ho Sui Shannan , Sonawane Abhijeet , Singh Sasha , Aikawa Elena , Aikawa Masanori
Published: November 2024

Background:
People living with HIV (PLWH) on anti-retroviral therapy remain at risk for cardiovascular diseases, including atherosclerosis. We hypothesized that persistent viral protein (HIV-Nef) in extracellular vesicles (EVs) modulate macrophage heterogeneity to impair atheroprotective efferocytosis to accelerate cardiovascular disease.

Methods and Results:
Macrophage heterogeneity was characterized in human primary macrophages (50,931 cells; 4 donors) stimulated with EVs engineered to contain HIV-Nef by simultaneous scRNAseq and scATACseq. Among 16 clusters (Fig.1A), two inflammatory Nef dominant clusters were characterized using gene set enrichment analysis. Gene regulatory network analysis of scRNAseq (pySCENIC) and transcription factor footprinting analysis of sc-ATACseq (ChromVar) suggest elevated NFκB activation in these clusters. Whole cell and sub-cellular compartmentalized proteomics of nucleus, cytosol, cell surface and secreted EVs indicate changes in immune response related biological pathways. Network analysis of our multi-omics data predicts Bruton Tyrosine Kinase (Btk) signaling as a potential contributor to Nef induced macrophage dysregulation. Pathway enrichment analysis of these multiomics dataset suggest Nef influences atheroprotective efferocytosis through the Btk-NFκB signaling axis. Spectral flow cytometry, high content imaging and multiplexed qPCR showed reduction in key effector of efferocytosis, MerTK. Btk inhibition using siRNA, reversible and irreversible Btk inhibitors restored MerTK expression and rescued efferocytosis. Importantly, CRISPRa based overexpression of MerTK in human primary macrophages rescued Nef impaired efferocytosis. Injection of HIV-Nef EVs into male and female C57BL6/J mice impaired efferocytosis of peritoneal and bone marrow derived macrophages which was rescued with Btk inhibition
in vivo
. Critically, injection of HIV-Nef EV into male and female Ldlr
-/-
enhanced atherogenesis with larger aortic wall thickness and necrotic core (Fig.1B).

Conclusion:
Persistent Nef in EV in PLWH may modulate macrophage heterogeneity to impair efferocytosis. These findings may help develop novel atheroprotective therapies by restoring macrophage efferocytosis.
Abstract 4120657: A Personal Risk Assessment Device in Patients with Chest Pain
Authors: Shvilkin Alexei , Zlatic Natasa , Atanasoski Vladimir , Grujovic-Zdolsek Sanja , Popovic-Maneski Lana , Miletic Marjan , Vukcevic Vladan
Published: November 2024

Introduction:
Early prehospital chest pain assessment improves acute coronary syndrome (ACS) outcomes and can reduce unnecessary Emergency Room (ER) visits but requires medical personnel and electrocardiographic (ECG) equipment.

Objective:
To evaluate the feasibility of a personal credit-card sized chest pain self-assessment device (HeartBeam, Santa Clara, CA, USA) in diagnosing ACS.

Methods:
ACS risk was estimated by serial likelihood ratio analysis of 3 components: pre-existing coronary heart disease (CHD) risk (pre-calculated based on pooled ASCVD equation), chest pain characteristics (interactive proprietary questionnaire), and integrated near-orthogonal 3-lead self-recorded vectorcardiogram (VCG) with optional comparison to baseline using portable handheld HeartBeam recorder. Final ACS risk was graded High/Intermediate/Low by the cloud-based proprietary algorithm. High risk was considered positive for ACS.

Results:
184 ER patients with chest pain (Age 57 +/- 7years, 90 Male, 43 (23%) ACS) comprised learning (n=96) and test (n=88) sets. ACS sensitivity was 28/28 (100%) in learning and 15/16 (94%) in test set with specificity of 43% and 42% respectively. In the subset of patients with pain-free portable VCG recorded 9 months later used as a “reverse baseline” (n=110) sensitivity was 17/17 (100%) and 11/12 (92%), specificity 54% and 58% in learning and test set, respectively (p>0.1 with no baseline). Single patient missed by the analysis had known coronary disease with usual anginal episode resulting in minor troponin leak. In “reverse baseline” analysis 41/110 (37%) patients were classified as Low risk compared to 18/184 (10%) without baseline (p<0.001), all negative for ACS.

Based on the analysis of CHD risk factors, chest pain characteristics, and 12-lead ECG, a consensus of 3-member ER chest pain unit physicians panel had sensitivity/specificity of 94/54% for the whole and 93/48% for the “reverse baseline” groups (p>0.1 with HeartBeam device).

Conclusion:
HeartBeam chest pain self-assessment device provides accurate ACS detection comparable to expert ER physicians using 12 lead ECG. The presence of baseline recording reduces the number of false positive results. If confirmed in larger studies, it can be used to facilitate outpatient chest pain assessment and triage by remote physicians and patients themselves.
Abstract 4120741: Estrogen Regulates Abdominal Aortic Aneurysm Tregs via CD45
+
Fibroblast-derived IL-33
Authors: Hu Wangling , Li Jingyong , Zhai Luna , Chen Zhuo , Xia Ni , Tang Tingting , Nie Shaofang , Min Zhang , Jiao Jiao , Lv Bingjie , Yang Fen , Lu Yuzhi , zha Lingfeng , Gu Muyang , Hu Xia jun , Wen Shuang , Li Dan , Hu Desheng , Zhang Li , Wang Weiming , hu jiong , Shi Guo-Ping , cheng xiang
Published: November 2024

Background:
Sexual dimorphisms manifest during the progression of abdominal aortic aneurysm (AAA). Regulatory T cells (Tregs) are a subset of T cells characterized by their immunosuppressive and tissue-repairing functions, therefore playing a protective role in AAA.

Aims:
We aim to elucidate the mechanism underlying sexual dimorphism in Tregs presented in AAA aortas, which is significant for unraveling the pathogenesis of AAA and developing gender-specific therapeutic approaches.

Methods and Results:
AAA mice were induced by receiving porcine pancreatic elastase. By flow cytometry, we observed that ovariectomy (OVX) increased the ratio of Tregs in female mice, while estrogen led to a decrease in aortic Tregs. Additionally, compared to littermate controls, estrogen receptor α (ERα) KO mice exhibited an increase in Treg ratio. Similar results were observed for the ST2
+
Treg ratio. IL-33, as an alarming molecule, can promote the maintenance of ST2
+
Tregs in tissues. Western blot revealed lower IL-33 expression levels in female mice than in male mice. By analyzing the IL-33 expression profiles of various cells in AAA tissue, we found that IL-33 mainly originates from fibroblasts. We found two subpopulations of fibroblasts, CD45
+
and CD45
-
fibroblasts. Immunofluorescence on the aortas verified the presence of cells co-expressing CD45 and PDGFRα in AAA fragments. Furthermore, IL-33 expression only showed gender differences in CD45
+
fibroblasts. Adoptive transfer of CD45.1
+
mouse bone marrow macrophages into CD45.2
+
mice revealed that aortic CD45.1
+
cells could regain the PDGFRα phenotype, with a lower proportion of female PDGFRα
+
cells in CD45.2
-
CD45.1
+
cells than in male mice. Lyz2(cre/+); Rosa26(tdtomato/+) mice showed the presence of lyz2-tdtomato
+
cells expressing PDGFRα in the aortic adventitia after AAA induction. This suggests that CD45
+
fibroblasts are partially derived from bone marrow macrophages, which can migrate to aneurysms and acquire a PDGFRα phenotype.

Conclusions:
Female sex hormones negatively regulate CD45
+
fibroblast formation and IL-33 secretion between female and male mice during AAA. This resulted in reduced Treg function in female mice compared to male mice.
Abstract 4120763: Predicting Disease Risk Among Variants in Cardiomyopathy-Associated Genes Across Diverse Genetic Ancestries
Authors: Wolfe Rachel , Gurumoorthi Manasa , Chahal Anwar , Sharaf Dabbagh Ghaith , Landstrom Andrew
Published: November 2024

Background:
Many cases of cardiomyopathy (CM) are genetically inherited, and the expansion of broad genomic sequencing has opened the door for predicting those at risk for developing disease. However, genetic tools that help determine variant pathogenicity employ genetic data from predominantly European genetic ancestries. Understanding the full diversity of genetic variants in cardiomyopathy genes is central to identifying which variants will cause disease.

Hypothesis:
Participants of non-European genetic ancestry will have a higher burden of cardiomyopathy gene variants with "VUS" designation in ClinVar but will have equivalent/less penetrance of clinical cardiomyopathy compared to a European ancestry group.

Methods:
Participants in the AllofUs database with exome sequencing (ES) were queried and a cohort of 230,013 participants were retained after sample quality control filters. Participant genetic ancestry was based on the designated ancestry group determined via AllofUs as previously described (1). Participants were queried for variants in genes with definitive or moderate evidence of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic cardiomyopathy (ACM) in ClinGen. Variants were filtered by ClinVar status (1* and above P/LP, 1* and above B/LB, and VUS). Participant CM disease status was determined via ICD-9/10 code.

Results:
For each ancestry group, prevalence of cardiomyopathy ranged from 0.34% in the Latino/admixed American ancestry group to 1.09% in the African group, with an average prevalence of 0.91% across all groups. The European group had a statistically significant lower percentage of ClinVar VUS variants at 26%, while all other non-European ancestry groups had a combined VUS prevalence rate of 35% (****p<0.0001). The penetrance of CM in participants with CM VUS variants was lower in combined non-European ancestry groups (0.84%) than European ancestry (1.02%) (*p=0.0156).

Conclusion:
Prevalence of ClinVar VUS variants varies across different genetic ancestry groups, with European ancestry having a lower burden of VUS variants compared to non-European groups. However, non-European ancestry groups with increased burden of VUS variants have lower disease penetrance.

Citations:
(1) The All of Us Research Program Genomics Investigators. Genomic data in the All of Us Research Program.
Nature
627
, 340–346 (2024). https://doi.org/10.1038/s41586-023-06957-x
Abstract 4120805: Comparison of Thermodilution and Doppler Flow Velocity Derived Indexes of Coronary Physiology using Intracoronary Adenosine in Patients with Angina and Unobstructed Coronary Arteries (ANOCA)
Authors: Lauinger Louisa , Hubert Astrid , Seitz Andreas , Bekeredjian Raffi , McChord Johanna , Ong Peter
Published: November 2024

Introduction:
Patients with angina but unobstructed coronaries (ANOCA) represent a diagnostic and therapeutic challenge. Current Guidelines recommend invasive testing using acetylcholine and adenosine for evaluation of coronary vasomotor disorders. However, there is a broad variability among the different measurement techniques.

Purpose:
To assess the differences of bolus thermodilution versus Doppler flow velocity derived indexes of coronary physiology using intracoronary adenosine in patients with ANOCA.

Methods:
A total of 162 patients (61.1% women, mean age 63±28 years) with ANOCA (no epicardial stenosis >50%, FFR >0.80) were enrolled between 2018 and 2023. All patients underwent wire-based assessment of coronary flow reserve (CFR) and microvascular resistance (MR) using adenosine in the left anterior descending artery. The bolus thermodilution technique was applied in 46 patients (CFR/IMR, CFRThermo) and the Doppler technique in another 116 patients (CFR/HMR, CFRDoppler). All measurements were performed according to a standardised protocol. The commonly applied cut-offs for CFR (<2.5), HMR (>2.5) and IMR (>25) were used.

Results:
The study population was characterized by the following risk factors: arterial hypertension (63%), hypercholesterolemia (62%), positive family history for cardiovascular disease (36%), diabetes (16%) and smoking (10%). The frequency of an abnormal CFR <2.5 was 36%. There was a significant difference between the frequency of an abnormal CFR among patients with CFRThermo (8/46, 17.4%) and patients with CFRDoppler (50/116, 43.1%, p=0.002). Moreover, the median CFR was higher in the CFRThermo group compared to the CFRDoppler group (3.5 [IQR2.8] vs. 2.6 [IQR 0.9], p<0.0005) with a much larger interquartile range in the former (Figure 1). Assessment of MR revealed an abnormal result in 20% of cases which was more often observed with the thermodilution (IMR >25 in 39.1%, median 22.5 [IQR 17.0]) compared to the Doppler technique (HMR >2.5 in 12.1%, median 1.7 [IQR 0.7], p<0.0005). Multivariable analysis revealed arterial hypertension (OR 4.04, CI 1.88 – 8.77, p<0.0005) and female sex (2.12, 1.04 - 4.34, p=0.04) as independent predictors for an abnormal CFR.

Conclusion:
Comparison of thermodilution and Doppler derived indexes of coronary physiology in patients with ANOCA reveals marked differences among the different measurement techniques. The results are important for the endotype classification and subsequent patient management.
Abstract 4120957: Endovascular Thrombectomy Versus Medical Management for Acute Ischemic Stroke with Large Infarct: An Updated Meta-Analysis of Randomized Controlled Trials
Authors: Jain Hritvik , Odat Ramez , Goyal Aman , Jain Jyoti , Jenil Franco Ancy , Patel Nandan , Shah Janhvi , Jha Jagriti , Passey Siddhant , Gole Shrey
Published: November 2024

Background:
Endovascular therapy (EVT) has revolutionized the treatment of acute ischemic stroke due to large vessel occlusions. Despite the increasing evidence for EVT, its efficacy remains understudied in patients with acute ischemic stroke with large infarcts. Patients with large-volume ischemic strokes are excluded from major randomized controlled trials (RCTs) despite contributing up to 25% of all acute ischemic strokes.

Aim:
This study aimed to compare clinical outcomes with endovascular thrombectomy versus medical management in patients with acute ischemic stroke with large infarct.

Methods:
We conducted a systematic literature review on PubMed, Embase, Scopus and Cochrane Library from inception to 15th May 2024 for RCTs. The inverse-variance random-effects model was used to pool odds ratio (OR) and risk ratio (RR) with 95% confidence intervals. The statistical significance was set at p<0.05.

Results:
6 RCTs with 1887 patients (945: EVT and 942: medical management) were included. The mean age in both EVT and medical management groups was 70 ± 11.4 years. EVT was associated with a better modified Rankin Score (mRS) at 90 days [OR: 1.68; 95% CI: 1.38, 2.04; p<0.00001], mRS at 90 days (0-2) [OR: 2.47; 95% CI: 1.87, 3.27; p<0.00001], mRS at 90 days (0-3) [OR: 1.96; 95% CI: 1.56, 2.46; p<0.00001], and early neurological improvement [RR: 2.35; 95% CI: 1.79, 3.10; p<0.00001] compared to medical management. EVT was also associated with a higher risk of symptomatic intracranial hemorrhage [RR: 1.71; 95% CI: 1.09, 2.66; p=0.02]. The 90-day mortality [RR: 0.86; 95% CI: 0.72, 1.02; p=0.08] was comparable between the two groups.

Conclusion:
Patients with acute ischemic stroke with large infarct had superior functional outcomes with EVT as compared to medical management alone. However, EVT was associated with higher risks of symptomatic intracranial hemorrhage, with comparable 90-day mortality risk. Further large RCTs are warranted to evaluate the outcomes with EVT in acute ischemic stroke with large infarct.
Abstract 4120966: Outcomes Following Balloon Angioplasty with Drug Coated Versus Uncoated Balloons in Patients with Coronary In-Stent Restenosis: A Systematic Review and Meta-Analysis
Authors: Rehman Mohammad , Khalid Burhan , Khan Muhammad Haris , Waseem Muhammad , Rehman Nohela , Abideen Zain Ul , Jamil Muhamamd , Hamza Muhammad , Nasir Malaika , Afridi Abdullah , Masood Simel , Shahram Hamza , Saeed Sajeel , Haider Tehseen , Basit Jawad , Akbar Usman , Iftikhar Ahmad
Published: November 2024

Background

The development of in-stent restenosis (ISR) has emerged as a substantial barrier to interventional treatment for coronary heart disease. Drug-coated balloon (DCB) is an efficacious interventional technique for the management of ISR. This meta-analysis compares the efficacy of DCB in the treatment of ISR with that of an uncoated balloon (UCB).

Methods

We comprehensively searched literature on MEDLINE, Embase, Cochrane, and clinicaltrials.gov using MeSH terms and relevant keywords for “Balloon Angioplasty” and “in-stent Restenosis” from inception to June 1, 2024, followed by a meta-analysis of all randomized controlled trials (RCTs) to assess both strategies for treatment of ISR. Random effects model was used to aggregate the risk ratios (RR) for dichotomous and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI).

Results

The search strategy retrieved 2330 studies. Duplicates and irrelevant articles were removed and data from seven RCTs (1,408 patients) was extracted. The mean age ranged from 64 to 74 years. The mean clinical follow-up ranged from 1 to 10 years. DCB was found to be superior to UCB at latest follow up in terms of target lesion revascularization (TLR) (RR 0.34, 95% CI 0.19-0.58; p 0.0001; I2 79%), major adverse cardiovascular events (MACE) (RR 0.41, 95% CI 0.23-0.73; p 0.003; I2 84%), late lumen loss (LLL) (MD -0.46 mm, 95% CI -0.64- -0.28]; p <0.00001; I2 64%), and target vessel revascularization (TVR) (RR 0.45, 95% CI 0.29-0.70; p 0.0003; I2 67%). The two groups were comparable at latest follow up in terms of mortality (RR 0.87, 95% CI 0.65-1.16; p 0.35; I2 0%), cardiac death (RR 0.89, 95% CI 0.66-1.19; p 0.43; I2 0%), myocardial infarction (MI) (RR 0.70, 95% CI 0.39-1.24; p 0.22; I2 28%) and stent thrombosis (RR 0.22, 95% CI 0.04-1.10; p 0.06; I2 46%).

Conclusion

DCB showed promising results in the treatment of patients with coronary ISR. DCB outperformed UCB in significantly reducing TLR, MACE, LLL and TVR risks. The risk of mortality, cardiac death, MI, and stent thrombosis was similar between DCB and UCB.
Abstract 4121039: Refining the American Heart Association Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) equations using depression and anxiety disorder
Authors: Nakada Shinya
Published: November 2024

Background:
Growing evidence has suggested associations of common mental health conditions including depression and anxiety disorder with CVD, but no studies have examined their incremental predictive values in PREVENT (AHA Predicting Risk of CVD EVENTs).

Research questions:
Does including anxiety and/or depression improve the PREVENT predictive performance?

Aims:
We used a range of measures of anxiety and depression and combinations to examine whether these conditions improved the prediction performance of PREVENT.

Methods:
New risk prediction models were developed and internally validated using 60% and 40% of the UK Biobank cohort data, respectively. Mental health predictors included: depressive symptom score based on the four-item Patient Health Questionnaire and self-reported and record-based anxiety and depression diagnoses before baseline. CVD events were ascertained through hospital admission and death certificate data after baseline. The Cox proportional hazards models were used to calculate coefficients and 95% confidence intervals. The incremental predictive values were examined by adding the mental health predictors to the PREVENT predictors based on Harrell’s C-indices, sensitivity, specificity, positive and negative predictive values, and net reclassification improvement indices (NRIs).

Results:
Of the 502,366 UK Biobank participants, 195,489 were included in the derivation set and 130,326 were included in the validation set. In the validation set, the inclusion of each mental health measure produced an increase in C-index and higher sensitivity, specificity, and positive and negative predictive values compared with the PREVENT equations, with the greatest improvements for depressive symptom score. Depressive symptom score produced the greatest improvements in net reclassification overall (NRI 0.84, 95% CI 0.46–1.20) and this was further improved by adding recorded anxiety and depression (NRI 0.89, 95% CI 0.52–1.24). In addition, depressive symptom score showed better discrimination and NRI in both female and male validation sets.

Conclusions:
Our findings suggest that including depressive symptom score in PREVENT could improve the prediction of CVD with low cost and without invasive procedures.
Abstract 4121148: A functional survey of postnatal heart maturation with
in vivo
Perturb-seq in spatial and temporal resolution
Authors: Wang Haofei , Dong Yanhan , Shi Huitong , Colon Marazzano , Liu Xingyan , Farber Gregory , Qian Yunzhe , Anthony Nicholas , Qian Li , Liu Jiandong
Published: November 2024

Background:
Cardiomyocyte maturation is a crucial process that involves intricate molecular and structural changes necessary for more vigorous and efficient heart function after birth. Understanding the regulatory mechanisms of this process is essential for leveraging these insights to develop advanced therapies for heart disease. Despite recent advancements, the limitations of current
in vivo
genetic and single-cell approaches - such as the low throughput of
in vivo
genetics, lack of spatial information in single-cell RNA-seq, and, most importantly, the lack of high-throughput combined use of both approaches - hinder the construction of a comprehensive regulatory network of cardiomyocyte maturation.

Methods:
Here, we established an experimental pipeline combining time-course single-nucleus RNA sequencing and spatial transcriptomics with our optimized
in vivo
Perturb-seq platform to establish the regulatory network underlying heart maturation.

Results:
Our current study has generated a postnatal murine heart atlas with 67,000 nuclei from postnatal heart. Temporal analysis of the cardiomyocyte transcriptome dynamics identifies Ankrd1+ cardiomyocyte as a transient state between proliferative and matured cardiomyocytes. We constructed a regulatory network consisting of 35 known and novel regulators for cardiomyocyte maturation. Our analysis of postnatal cardiomyocyte interactome elucidated signaling pathways’ stage-specific contribution to cardiomyocyte maturation. With the spatial transcriptomic data, we further identified signaling pathways that played unique roles in the maturation of chamber-specific cardiomyocytes. Using fixed RNA
in vivo
Perturb-seq established in this study, we have validated 21 novel regulators of postnatal cardiomyocyte maturation out of 53 candidate regulators from previous temporal and spatial analyses.

Conclusions:
We have not only created a single-cell-resolution temporal and spatial atlas during postnatal heart development but also established an
in vivo
Perturb-seq platform to allow the functional interrogation of key regulatory genes in a physiologically relevant context. Importantly, the proposed working model unlocks new possibilities for research, no longer limiting to a single gene or pathway, but allowing for the exploration of a network of genes. This high-resolution, high-throughput
in vivo
mapping and screening platform has the potential to revolutionize the way we study organogenesis and disease progression in the heart.
Abstract 4121234: Macrophage activation in aorticorenal ganglion as a potential trigger to induce renal sympathetic overactivation-related ventricular arrhythmias after acute myocardial infarction
Authors: Lian Wenxi , Hu Wenfeng , Zhang Dongze
Published: November 2024

Background:
Ischemia-related ventricular arrhythmia is the leading cause of death in patients after acute myocardial infarction (AMI). Although the therapeutic potential of renal denervation (RDN) for ventricular arrhythmias has been reported, RDN-induced adverse complications partially limit its use in the clinic. Since neuroinflammation has recently emerged as a key factor for sympathetic overactivation in the central and peripheral nervous systems, this study aims to test if macrophage activation in renal sympathetic postganglionic (RSP) neurons located in the aorticorenal ganglion (ARG) contributes to renal sympathetic overactivation-related ventricular arrhythmogenesis post-AMI.

Methods and Results:
AMI was induced by surgical ligation of the left anterior descending artery in rats. Data from immunofluorescence staining showed that the expression of Iba1, TNF-α, and IL-1β was increased in ARGs at 3 days post-AMI rats compared with sham rats, suggesting that macrophage activation and neuroinflammation occurred in the ARG at an early stage after AMI. Direct recording of renal sympathetic nerve activity (RSNA) found that the RSNA was much higher in the 3 days post-AMI rats than in sham rats. To validate the contribution of macrophage activation to AMI-elevated RSNA, we depleted macrophages in ARGs by local microinjection of clodronate liposomes (CL) into ARGs. Immunofluorescence staining data showed that microinjection of CL into ARGs attenuated the AMI-induced macrophage activation (Iba1) and neuroinflammation (TNF-α and IL-1β) in ARGs. Flow cytometry data also confirmed that macrophage depletion in ARGs reduced the AMI-elevated macrophage infiltration in ARGs, which was accompanied by a significant decrease in RSNA in CL-treated AMI rats. To test the ventricular arrhythmogenesis post-AMI, we measured ventricular tachycardia/fibrillation (VT/VF) from 24-hour telemetry ECG recording in conscious rats. Our data showed that macrophage depletion in ARGs alleviated AMI-induced ventricular arrhythmogenesis, as evidenced by a significant reduction in the occurrence of VT/VF in CL-treated AMI rats.

Conclusion:
These data suggest that macrophage activation and neuroinflammation in the ARG might be critical factors responsible for the renal sympathetic overactivation-related ventricular arrhythmia post-AMI. Inhibiting macrophage activation and neuroinflammation in the ARG could be an effective strategy to achieve the antiarrhythmic effect of RDN after AMI.
Abstract 4121348: Impairments in Left Atrioventricular Coupling Underpins Reductions in Skeletal Muscle Mass and Function in Ageing Older Adults
Authors: Xie Alex Yufei , Tan Glades , Leng Shuang , ZHAO XIAODAN , Zhong Liang , Lim Wee Shiong , Lee Gina , Tan Ru , Gao Fei , Koh Angela
Published: November 2024

Background:
Age-related cardiovascular disease (CVD) may manifest with changes in left ventricular (LV) systolic or left atrial (LA) dysfunction. Alterations in functional performance between the LV and LA chambers characterized by LA-LV coupling may be a sensitive marker representative of impairments in global cardiac performance, compared to either chamber alone. The increasing relevance of skeletal muscle function towards cardiac health in ageing, motivated our current work that investigated associations between skeletal muscle function and LA-LV coupling.

Aim
: Using advanced cardiac magnetic resonance (CMR) that characterizes cardiac volumetric parameters and strain functions, we determined the association between handgrip strength (HGS) and appendicular lean mass (ALM) with left atrioventricular coupling index (LACI).

Methods:
Community older adults without CVD underwent simultaneous assessment of HGS by hand dynamometer, height-square adjusted ALM by bio-impedance, and LA phasic function (namely reservoir, conduit, booster strain) as well as LA and LV volumetric parameters by CMR feature tracking. LACI is defined as the ratio of the ratio of LA to LV end-diastolic volumes. We performed linear regression and multivariable logistic regression to examine the relationship between HGS/ALM and LACI.

Results:
Among 251 study participants (mean age: 71 ± 9.1 years, female 44.7%), 149 (59%) had impaired LACI. HGS was linearly associated with LACI (β=-0.004, p=0.003) and LVEDV (β=1.62, p<0.0001), and ALM was linearly associated with LA volume (β=0.55, p=0.018) and LVEDV (β=3.45, p<0.0001) (Figure.1). Participants with impaired LACI (> 25%) had lower HGS (mean=22.8 ± 7.1 kg vs 26.1 ± 6.4 kg, p= 0.0002), lower ALM (16.4 ± 4.2 kg/m2 vs 17.7 ± 3.8 kg/m2, p=0.014), higher LA volume (36.8 ± 15.2 ml vs 22.0 ± 5.5 ml, p < 0.0001) and lower LV end-diastolic volume (101.0 ± 24.2 ml vs 111.9 ± 27.3 ml, p = 0.0011). The association between impaired LA-LV coupling and lower HGS (β=-0.0647, 95%CI -0.0255, -0.1040, p=0.001) and lower ALM (β=-0.0776, 95%CI -0.0107, -0.1444, p=0.011) persisted after adjusting for age.

Conclusion:
Reduced HGS and ALM among community-dwelling older adults was associated with impaired LA-LV coupling suggestive of underlying early-stage LA remodelling and impairments in left atrioventricular compliance. Detection of reduced HGS and ALM in community cohorts may prompt early identification of older adults at risk of dysfunctional cardiac aging.
Abstract 4121454: Machine-extractable Markers in Chest Radiograph to Predict Cardiovascular Risk in Screening Population
Authors: Du Richard , Chowdhury Debajyoti , Hung Yui Chi , Du Mike , Tsougenis Efstratios , Fang Xin Hao Benjamin
Published: November 2024

Introduction:
Recent research has shown that AI is able to assess biological aging and cardiovascular disease (CVD) risk using chest radiographs. However, the lack of explainability of such deep learning algorithms hinders clinical utility and adoption. This motivates the current study which searches for and tests the use of machine extractable quantitative features in chest radiographs to predict CVD risk in population screening.

Method:
Chest radiograph measurements characterizing cardiomediastinal geometry, aortic calcification and tortuosity were handpicked for development of a segmentation-based feature extraction algorithm. The algorithm was applied on the PLCO lung screening dataset for analysis. The association between measurement-based imaging features, clinical characteristics (age, sex, BMI, smoking status, hypertension, diabetes, liver disease) with CVD mortality and 10-year major adverse cardiovascular events (MACE) were analysed by using proportional hazard regression, with feature selection done by LASSO.

Result:
Of 29,453 eligible subjects, 5693 subjects from a single study centre were used for fitting of all models. The median follow-up time was 19 years. A total of 32 imaging features were extracted and analysed. For both 10-year MACE and CVD mortality, model using imaging features, age, and sex performed similarly to model using conventional risk factors, and a deep learning chest radiograph CVD risk model. Two imaging features, mediastinal width at valve-level [HR 1.36 (1.23-1.50)] and maximal lateral displacement of descending aorta [HR 1.29 (1.18-1.42)] were found to be prognostic. To the best of our knowledge, these features have not been reported previously.

Conclusion:
Quantitative imaging features can predict CVD risk in chest radiograph similar to deep learning models while providing feature interpretability and explainability. Two novel imaging features prognostic of CVD risk were found and shown to be complementary to conventional risk factors.
Abstract 4121530: Comparison of Drug-Coated Balloon Versus Drug-Eluting Stents in Acute Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis
Authors: Jain Hritvik , Odat Ramez , Goyal Aman , Pervez Neha , Jain Jyoti , Patel Nandan , Fatima Eeshal , Jenil Franco Ancy , Shah Janhvi , Jha Jagriti , Passey Siddhant
Published: November 2024

Background:
Percutaneous coronary intervention (PCI) is the preferred revascularization strategy for acute myocardial infarction (AMI). Drug-eluting stents (DES) are linked to higher risks of stent restenosis and stent thrombosis when implanted for AMI. Drug-coated balloons (DCB) provide a high concentration of anti-proliferative drugs over the target lesion without using the polymeric stent structures. The current literature comparing DCB to DES for AMI PCI is limited.

Methods:
A systematic literature search was performed on the major electronic databases for studies comparing DCB to DES for AMI PCI. Mean difference (MD) and odds ratio (OR) with their corresponding 95% confidence intervals were pooled using a random-effects model, and a p-value of <0.05 was considered statistically significant.

Results:
A total of 8 studies with 1401 AMI patients were included (545: DCB and 856: DES). The pooled analysis demonstrated that DCB was associated with significantly lower mean lumen diameter on follow-up [MD: -0.26; 95% CI: -0.47, -0.05; p=0.02] compared to DES. However, there was no statistically significant difference in mean in-stent late lumen loss [MD: 0.07; 95% CI: -0.03, 0.18], cardiovascular mortality [OR: 0.90; 95% CI: 0.35, 2.34], all-cause mortality [OR: 0.80; 95% CI: 0.25, 2.63], myocardial infarction [OR: 0.94; 95% CI: 0.36, 2.45], major adverse cardiovascular events [OR: 0.97; 95% CI: 0.47, 2.00], target lesion revascularization [OR: 1.59; 95% CI: 0.52, 4.87], and stent thrombosis [OR: 0.48; 95% CI: 0.05, 4.94].

Conclusion:
In patients with AMI, PCI using DCB leads to a significant reduction in the minimum lumen diameter on follow-up compared to DES. No statistically significant difference was noted in mean in-stent late lumen loss, cardiovascular mortality, all-cause mortality, myocardial infarction, major adverse cardiovascular events, target vessel revascularization, and stent thrombosis. Further trials are warranted to confirm these findings.
Abstract 4121568: The Influence of Cardiovascular Health on Atherosclerotic Cardiovascular Disease Progression and Life Expectancy Among Individuals with Type 2 Diabetes
Authors: Wei Yanxia , Liu Xianbao , Wang Jianan
Published: November 2024

Objective:
This study aims to evaluate whether cardiovascular health (CVH) plays a similar role in the transition from a healthy state to atherosclerotic cardiovascular disease (ASCVD) and subsequent mortality rates in diabetic patients compared to those without diabetes. It also evaluates the effectiveness of CVH in reducing diabetes-related ASCVD risks and enhancing ASCVD-free life expectancy.

Research design and methods:
This cohort study included 176,669 adults from the UK Biobank, among whom 10,109 (22.3%) were diagnosed with type 2 diabetes mellitus (T2DM). CVH was assessed using the Life's Essential 8 score, encompassing diet, physical activity, smoking, sleep, BMI, blood lipids, blood glucose, and blood pressure. CVH scores were categorized into low, moderate, and high levels based on their distribution among diabetic patients. The main outcomes were the transitions from no ASCVD to the onset of ASCVD and then to mortality, as well as the ASCVD-free life expectancy.

Results:
In patients with T2DM, high CVH levels were associated with lower ASCVD risk (HR: 0.55, 95% CI: 0.45-0.68 for women; HR: 0.57, 95% CI: 0.50-0.65 for men) and reduced mortality in those with ASCVD (HR: 0.62, 95% CI: 0.39-0.98 for women; HR: 0.62, 95% CI: 0.48-0.79 for men), compared to the low CVH group. No significant difference in CVH's effect on ASCVD and mortality was observed between diabetic and non-diabetic groups. When compared with non-diabetic individuals, no excess risk was observed in incident ASCVD and post-ASCVD mortality among diabetic patients with high CVH. At the age of 40, women with low CVH were expected to live 38.5 years (38.0-39.1) free from ASCVD, which increased to 42.9 years (42.4-43.5) for those with high CVH, while non-diabetic women were predicted to have an ASCVD-free life expectancy of 44.1 years (43.5-44.6). For men at the age of 40, those with low CVH had an ASCVD-free life expectancy of 32.0 years (31.3-32.6), which rose to 37.9 years (37.4-38.6) with high CVH. Non-diabetic men were expected to live 38.3 years (37.7-39.0) free from ASCVD. Notably, life expectancy with ASCVD did not increase with higher CVH levels in both genders.

Conclusions:
Our findings suggest that the American Heart Association’s recommendations for promoting CVH, initially designed for the general population, are also beneficial for individuals with T2DM. Adopting these guidelines can help mitigate ASCVD progression and enhance life expectancy in diabetic patients.
Abstract 4121812: Longitudinal Trajectory-Based Classification of Heart Failure with preserved Ejection Fraction: A Machine Learning Approach
Authors: Romero Erick , Patel Dev , Cadeiras Martin
Published: November 2024

Background:
Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome characterized by heterogeneous pathophysiology and dynamic changes in cardiac structure and function. Current research predominantly focuses on left ventricular ejection fraction (LVEF) or left ventricular structures with predefined categories. This study hypothesized that applying unsupervised methodologies to longitudinal echocardiography will reveal distinct trajectory patterns in cardiac structure and function related to clinical outcomes in HFpEF patients.

Methods:
This retrospective cohort study, conducted at UC Davis Medical Center (2014 to 2022), consisted of adult patients with HFpEF. The inclusion criteria included ICD HF codes, a left ventricular ejection fraction (LVEF) ≥50%, and a Brain natriuretic peptide (BNP) ≥100 pg/ml or N-terminal-pro BNP (NT-proBNP) ≥225 pg/ml. Longitudinal data were analyzed using unsupervised machine learning, including UMAP for dimensionality reduction and Gaussian Mixture Models for clustering. Primary and secondary outcomes included all-cause mortality and changes in BNP levels, respectively.

Results:
The study included 1,626 patients. The cohort had a median age of 69 years, was 57.5% female, and 51.8% white. Three distinct echocardiographic trajectory patterns emerged (p<.05) among the HFpEF cohort. Trajectory #1 (n=568) exhibited a high-stable pattern with the highest mortality rates, Trajectory #2 (n=512) showed a high-decreasing pattern with high mortality rates, and Trajectory #3 (n=546) had a low-increasing pattern with the lowest mortality rates. Trajectories varied significantly in baseline characteristics and longitudinal echocardiographic changes, with Trajectory #3 having a lower baseline left ventricular mass index (p<.001) and a higher mean arterial pressure (
p
=.001) compared to the other trajectories. Kaplan-Meier survival analysis indicated significant differences in survival among the trajectories (
p
=.004).

Conclusion:
The study utilized unsupervised analysis of longitudinal echocardiographic data to identify three distinct HFpEF trajectories, each associated with unique clinical features and outcomes. These findings underscore the heterogeneity of HFpEF and highlight the potential trajectory-based patient stratification to improve targeted intervention strategies. Future validation in larger, multicenter cohorts is warranted to enhance HFpEF management and patient prognosis.
Abstract 4121970: Early to Mid-Gestational Testosterone Excess Sex-specifically Reprograms Cardiac Transcriptome and Metabolome Profiles of Sheep Fetuses
Authors: Alkhatib Bashar , Ramamoorthi Elangovan Venkateswaran , Cho Kevin , Shriver Leah , Patti Gary , Padmanabhan Vasantha , Vyas Arpita
Published: November 2024

Exposure of sheep to excess testosterone (T) from days 30-90 of gestation (term 147 days) perturbs maternal systemic lipidome in late gestation, induces fetal growth restriction and sexually dimorphic perturbation in the cardiac left ventricular (LV) transcriptome in gestational (GD) day 90 fetuses culminating in cardiometabolic dysfunction in adult female offspring. We hypothesized that the detrimental impact of prenatal T excess on fetal cardiac transcriptome is a programmed event that will persist even after cessation of excess T exposure and will be accompanied by changes in fetal metabolome. Pregnant ewes were injected with 100 mg intramuscular T propionate or vehicle (C), twice weekly from GD 30-90. On GD120±5, 30 days after cessation of T treatment fetal weights were recorded, left ventricle (LV) tissue and fetal plasma processed for transcriptomics by RNA sequencing and metabolomics analysis (Female C (FC) n=6, T (FT) n=7; Male C (MC) n=6, T (MT) n=7).
LV transcriptome-based
pathways enrichment analysis revealed 1) downregulation of pathways associated with oxidative phosphorylation, citric acid cycle, pyruvate metabolism; 2) upregulation of TGF-β signaling pathway in T fetuses compared to C (p<0.05, FDR<0.1); 3) selective downregulation of the glycolytic pathway in MT relative to MC as opposed to downregulation of mitochondria-related pathways in FT vs FC (p<0.05, FDR<0.1).
LV lipidomics
analyses found glycerophospholipids and sphingolipids as main class
lipid
metabolites to be enriched in FT relative to FC fetuses (p<0.05, ER>1). Fetal
systemic lipidome
main class metabolites enriched (p<0.05, ER>2) in T vs C fetuses included 1) sphingomyelins in both sexes 2) fatty acyls metabolites only in MT vs MC as opposed to glycerophospholipids only in FT vs FC.
LV polar metabolites
enriched (p<0.05, ER>2) included 1) arginine&proline metabolism pathways in T vs C in both sexes 2) nicotinate and nicotinamide metabolism only in MT vs MC (p<0.05, ER>3), and porphyrin, riboflavin metabolism and N-glycan biosynthesis pathways only in FT vs FC.
Systemic polar metabolites
enriched (p<0.05, ER>2) included 1) D-amino acid metabolism pathways in T vs. C, 2) valine, leucine, and isoleucine pathways only in FT vs FC and glycerophospholipid and sphingolipid metabolism only in MT vs MC. These results suggest persistence of sex-specific perturbation in fetal transcriptome and systemic and cardiac metabolome in late gestational fetuses exposed to prenatal T excess.
Abstract 4122008: Bayesian modeling to forecast mortality due to Ischemic Heart Disease, Stroke, and Peripheral Artery Disease in Brazil until 2040
Authors: Salerno Pedro , Cotton Antoinette , Nascimento Bruno , Chen Zhuo , Tensol Rodrigues Pereira Gabriel , Abizaid Alexandre , Palma Dallan Luis Augusto , Salerno Pedro Rafael , Al-Kindi Sadeer , Petermann-Rocha Fanny , Deo Salil
Published: November 2024

Introduction:
Atherosclerotic cardiovascular disease, specifically ischemic heart disease (IHD), stroke, and peripheral artery disease (PAD) together are among the leading causes of cardiovascular mortality in Brazil. As the obesity, hypertension, and diabetes rates in the Brazil continue to increase, projecting mortality rates related to these conditions are important for guiding health policy.

Hypothesis:
We hypothesized that there are differences in the future trends of IHD, stroke and PAD in Brazil.

Aims:
We sought to forecast the trends in IHD, stroke, and PAD in Brazil until 2040 to fill in this important knowledge gap and inform public health policy development.

Methods:
We collected the annual death counts for IHD, stroke, and PAD and the mid-year population estimates in 5-year age brackets (40 – 79 years) between 1990 and 2019 from the Global Burden of Disease. We calculated the annual crude and age-standardized mortality rates (per 100 000 residents) for IHD, stroke and PAD between 1990 and 2019. Using this observed data, we estimated the projected mortality rates for these conditions till 2040 using Bayesian age-period-cohort (BAPC) models.

Results:
Brazil`s population (aged 40-79 years) will increase by 237.5% between 1990 and 2040. Nationally, compared to 2019, the age standardized IHD mortality is projected to reduce by 31.66 % [2019: 131.13, 2040:89.6 (IQR: 65.83, 113.37)] and stroke rates are estimated to reduce by 16.75% [2019: 91.09, 2040: 75.83 (IQR: 51.68, 99.98)]. However, PAD rates are projected to increase by 1.2% in the same period [2019: 1.58, 2040: 1.66 (IQR: 1.24, 2.07)]. The age standardized IHD and stroke mortality rates will reduce in males and females. However, the age standardized PAD rates will increase in females [2019: 1.33, 2040: 1.48 (IQR: 1.06, 1.89), 11.28% difference] and remain reasonably constant among males.

Conclusion:
In Brazil, the age standardized rates for IHD and stroke mortality are projected to decline till 2040. However, PAD related mortality is likely to be an important issue among females. Our findings highlight the need for early and targeted interventions to address these potential cardiovascular health disparities.
Abstract 4122080: Outcomes of Left Atrial Appendage Occlusion With and Without Concurrent Catheter Ablation for Patients at High Bleeding Risk: A Systematic Review and Meta-analysis
Authors: Majumdar Abhigyan , Ayyalu Tanesh , Charles Fred , Huang Ewen Shengyao , Turch Hayley , Martignoni Felipe , Sherif Akil
Published: November 2024

Introduction:
The prevalence of non-valvular atrial fibrillation (NVAF) and stroke-related morbidity is rising. First-line therapy remains rate or rhythm control with anticoagulation, with catheter ablation (CA) also considered in suitable candidates. Left atrial appendage closure (LAAC) is increasingly used due to mounting evidence of non-inferiority compared to anticoagulation. Despite improved pre-procedural planning and patient selection reducing complications, adverse outcomes such as pericardial effusion and device-related thrombus occur in about 5% of patients. This study evaluates the outcomes of LAAC with CA versus standalone LAAC in NVAF patients with contraindications to anticoagulation.

Methods:
We searched PubMed, EMBASE, and Cochrane databases for all cohort studies comparing LAAC with CA to LAAC alone in patients with NVAF. Case series, reviews, and non-English language studies were excluded. The assessed outcomes included device compression rate at implant, device-related thrombosis, pericardial effusion, need for pericardiocentesis, and peri-device leak at 6 weeks. Statistical analysis was performed using Review Manager 5.1.7. Heterogeneity was assessed with I
2
statistics.

Results:
We included 6 studies with 51,545 patients, of whom 1,221 (2.3%) underwent both procedures. LAAC with CA and standalone LAAC cohorts had similar baseline demographics including age (68, 69 years), percentage of women (48%, 46%), CHA2DS2-VASc score (3.6, 3.7), and HAS-BLED score (3.1, 3.2). LAAC with CA was associated with a reduced incidence of device-related thrombosis (OR=0.18; 95% CI= 0.04-0.89; p=0.04) without an increase in pericardial effusion rates (OR=0.85; 95% CI= 0.48-1.51; p=0.59). There were no significant differences in device compression rates at implant (MD=0.34; 95% CI= -0.77-1.45; p=0.55), the need for pericardiocentesis (OR=1.01; 95% CI= 0.30-3.48; p=0.98), or rates of peri-device leak at 6 weeks (OR=0.61; 95% CI= 0.21-1.78; p=0.37).

Conclusion:
Concomitant LAAC with CA may reduce rates of device-related thrombosis compared to standalone LAAC without increasing the risk of pericardial effusion or peri-device leak at 6 weeks. These findings support the consideration of combining these procedures in the management of high-risk NVAF patients unable to tolerate anticoagulation.