bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4142370: KDM2B Antagonizes Trimethylamine N-Oxide-Induced Calcific Aortic Valve Disease by Suppressing Nox4 via JunD Demethylation
Authors: Xu minhui , Li Jiaying , Lin Ying-wen , Duan Xiaolin , Li Shunyi , Xian Gaopeng , Xu Dingli , Zeng Qingchun
Published: November 2024

Background and Objective:
Calcific aortic valve disease (CAVD) is a debilitating condition characterized by excessive oxidative stress and inflammation. Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been implicated in CAVD pathogenesis. Lysine-specific demethylase 2B (KDM2B) possesses antioxidant properties. This study aimed to investigate the protective role of KDM2B against TMAO-mediated CAVD and explores the underlying mechanisms. We hypothesized that KDM2B mitigates TMAO-induced inflammatory and osteogenic response of valve interstitial cells (AVICs) by reconstructing intracellular oxidative balance.

Methods and Results:
KDM2B expression was diminished in calcified aortic valves and TMAO-treated valve interstitial cells (AVICs) compared to healthy controls, as confirmed by western blot, qPCR, immunohistochemistry (IHC), and immunofluorescence. KDM2B silencing via siRNA exacerbated TMAO-induced inflammation and osteogenic response in AVICs, while KDM2B overexpression (Ad-KDM2B) mitigated these effects. RT-qPCR array identified NADPH Oxidase 4 (Nox4) as a key KDM2B-regulated oxidizing gene. Ad-KDM2B significantly downregulated Nox4 mRNA expression in AVICs. Chromatin immunoprecipitation with qPCR (Chip-qPCR) revealed enhanced JunD binding to the Nox4 promoter upon KDM2B overexpression. KDM2B promoted JunD expression by demethylating H3K4me3, thereby suppressing Nox4 transcription. Western blot, along with alkaline phosphatase and Alizarin Red staining, demonstrated that Nox4 overexpression abolished the protective effects of KDM2B overexpression. In vivo, adeno-associated virus-mediated KDM2B overexpression significantly attenuated aortic valve lesions in mice fed a high-fat, choline diet (HFCD).

Conclusion:
KDM2B protects against TMAO-induced CAVD by regulating oxidative stress. It achieves this by decreasing H3K4me3 on JunD, thereby preventing Nox4 transcription. KDM2B represents a potential therapeutic target for CAVD.
Abstract 4142374: The Impacts of Achieved Blood Pressure During the First 12 hours on Clinical Outcomes in Patients with Out-of-hospital Cardiac Arrest
Authors: Chang Chen-Hsi , Lin Shih-Neng , Huang Chin-Chou
Published: November 2024

Background:
Out-of-hospital cardiac arrest (OHCA) typically results in low survival rates and undesirable neurological outcome. There is a significant correlation between mean arterial pressure (MAP) levels after the return of spontaneous circulation (ROSC) and the outcomes of OHCA patients, yet the optimal blood pressure target remains unclear. This study explores how achieved blood pressure within the initial 12 hours after ROSC impacts the clinical outcomes of OHCA patients.

Methods:
We conducted a retrospective analysis of patients who experienced OHCA and achieved ROSC. Patients were divided into three tertiles based on the distribution of patient numbers, with each tertile defined as follows: MAP < 80 mmHg, 80 mmHg ≤ MAP < 95 mmHg, and MAP ≥ 95 mmHg. MAP levels were measured within the first 12 hours. Mortality and cerebral performance category (CPC) were utilized in the study to assess the clinical outcomes at 30 days post-OHCA event.

Results:
A total of 231 non-traumatic OHCA patients who survived for 12 hours after ROSC were enrolled. Among the three tertiles (n = 77 in each), significant difference in mortality and CPC score were found between tertile 1 and the remaining two tertiles, but no notable difference were observed between tertile 2 and 3. Higher MAP level, specifically target MAP ≥ 80 mmHg (hazard ratio [HR]: 0.960, 95% confidence interval [CI]: 0.949-0.971, P < 0.001) was associated with lower 30-day mortality. Additionally, a higher MAP level with target MAP ≥ 80 mmHg within the first 12 hours was correlated with better neurological outcomes (odd ratio [OR]: 0.370, 95% CI: 0.147-0.935, P = 0.035).

Conclusions:
MAP levels within the initial 12 hours after ROSC is a practical predictor of 30-day mortality and neurological outcomes among OHCA patients. Maintaining MAP levels above 80mmHg exhibits strong correlation with short-term outcomes improvement in the early post-arrest period.
Abstract 4142387: Sodium-Glucose Cotransporter-2 Inhibitors In Children With Left Ventricular Systolic Dysfunction
Authors: Newland David , Law Yuk , Albers Erin , Ali Reda , Friedland-Little Joshua , Hartje-Dunn Christina , Kemna Mariska , Knorr Lisa , Nemeth Thomas , Spencer Kathryn , Wisotzkey Bethany , Hong Borah
Published: November 2024

Introduction:
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are proven to reduce risk of cardiovascular death and hospitalization for heart failure (HF) in adults with reduced or preserved ejection fraction (EF). There are limited data on SGLT2i use in pediatric HF.

Hypothesis:
Addition of SGLT2i to standard HF medical therapy in children with left ventricular (LV) systolic dysfunction is associated with improved clinical outcomes.

Methods:
Single-center observational analysis of 65 pediatric patients (≤ 21 years old) with LV systolic dysfunction (n=44 dilated cardiomyopathy; n=21 repaired biventricular congenital heart disease) who had SGLT2i added to standard HF medical therapy since January 2020. Patients must have received SGLT2i for minimum of 3 months to be included. Patients with single ventricular physiology or already supported by a ventricular assist device (VAD) were excluded.

Results:
Median age at SGLT2i initiation was 11.2 years (range 2 months to 21 years), 54% were female, and 46% were started on SGLT2i (89% dapagliflozin; 11% empagliflozin) during an inpatient hospitalization. Median daily SGLT2i dose received was 5 mg or 0.14 (IQR 0.11-0.17) mg/kg/day. Sixty percent had a HF hospitalization within the prior year preceding SGLT2i start. Chronic HF medications at latest follow-up included sacubitril/valsartan (82%) or ACE inhibitor (6%), beta-blocker (83%), and mineralocorticoid receptor antagonist (77%). Median follow-up was 16.2 months (IQR 8.1-27.1). Median LVEF increased significantly from 35% (IQR 27-41) to 41% (IQR 32-52) and B-type natriuretic peptide (BNP) decreased from 300 pg/mL (IQR 84-728) to 86 pg/mL (IQR 18-308) (both p<0.01). There was a significant difference in NYHA/Ross Class from baseline (I: 12%; II: 62%; III: 20%; IV: 6%) to latest follow-up (I: 35%; II: 49%; III: 6%; IV: 9%) (p<0.01) with 32% improved, 62% unchanged, and 6% worsened. HF hospitalization occurred for 20% of the patients at median time of 7.9 months (IQR 3.2-16.5) after SGLT2i initiation. Eleven percent of the cohort were listed for transplant, died, or underwent VAD implant at latest follow up.

Conclusion:
Long-term use of SGLT2i in addition to standard HF medications in children with LV systolic dysfunction is associated with significant improvement in LVEF, BNP, and NYHA/Ross class. Use of SGLT2i in pediatric HF is evolving and further larger scale studies should be supported to determine efficacy.
Abstract 4142394: HDL/ApoA1 inhibits macrophage ferroptosis via upregulating NRF2/SLC7A11/GSH pathway
Authors: Luo Yonghong , Yi Yuting , Deng Yongjie , Peng Daoquan
Published: November 2024

Background:
Ferroptosis is a novel type of programmed cell death characterized by excessive lipid peroxides and iron overload inside the cell. SLC7A11/GSH is one of the most important anti-ferroptotic pathways. Macrophage ferroptosis contributes to the progression of atherosclerosis. HDL exerts anti-atherosclerotic effects primarily by promoting cholesterol efflux. Whether HDL also inhibits macrophage ferroptosis is unknown.

Research Questions:
This research was aimed to explore the effects and mechanisms of HDL on macrophage ferroptosis.

Methods:
Macrophage ferroptosis was detected in plaques from patients with coronary artery disease. In vitro, macrophage was induced ferroptosis by multiple inducers and then the cells were treated with either vehicle or HDL or ApoA1. Ferroptosis was measured by detecting multiple ferroptosis markers (lipid peroxide, LDH release, ROS production, and cellular ferrous ion level).

Results:
Compared to controls, iron, lipid peroxide and macrophages were co-localized and significantly increased in coronary plaques, suggesting increased macrophage ferroptosis in atherosclerosis. In mouse macrophages, ferroptosis-inducers increased ferroptosis significantly, which was inhibited by HDL and ferroptosis inhibitors, but not neither by inhibitors of apoptosis, necroptosis, or autophagy. ApoA1, the main apolipoprotein on HDL, may account for HDL’s anti-ferroptotic effect. Mechanically, ApoA1 upregulated System Xc- (encoded by SLC7A11), an amino acid antiporter that exchanges intracellular glutamate and extracellular cysteine, thus elevating intracellular GSH and reducing ferroptosis. We further elucidated that ApoA1 activated NRF2, the transcription factor of SLC7A11, by promoting its nuclear translocation.

Conclusion:
Our results imply that HDL/ApoA1 inhibits macrophage ferroptosis via upregulating NRF2/SLC7A11/GSH pathway, enriching the regulation and mechanisms of HDL/ApoA1’s anti-atherosclerotic effects.
Abstract 4142403: Temporal Trends And Procedural Safety of Mitral Valve Transcatheter Edge to Edge Repair (M-TEER) in Patients with Previous Coronary Artery Bypass Grafts (CABG). Insight From The National Inpatient Database
Authors: Ahmed asmaa , Eisa Mahmoud , Mohamed Mohamed , Takla Andrew , Osama Muhammad , Arora Sahej , Feitell Scott
Published: November 2024

Introduction:
M-TEER is a minimally invasive procedure for selected patients with symptomatic mitral regurgitation. Data about the safety of the procedure among post-CABG patients is limited.

Methodology:
We used the Nationwide Inpatient Sample data between January 2016 and December 2020 to identify M-TEER hospitalizations with history of CABG. Baseline characterestics including demographic data and comorbidities were identified. Primary outcomes were in-hospital all-cause mortality and net all cardiac periprocedural complications defined as a composite of acute myocardial infarction, pacemaker placement, cardiac tamponade, pericardiocentesis, pericardiotomy, pericarditis, and hemopericardium.

Results:
48,835 cases of M-TEER were identified during the study period, of whom 9,655 (19.78%) had prior CABG. Patients with prior CABG undergoing M-TEER were older (76 vs. 75 years, p <0.0001), more likely to be males (72% vs. 49%, p=0.0002), and with more comorbidities. During the study years, the number of M-TEER in post-CABG patients was increasing (2145 in 2016 vs. 2682 in 2020) with however downtrend in the percentage of periprocedural complications (11% in 2016 vs. 8% in 2020). On adjusted analysis, there was no significant difference in in-hospital mortality between the two cohorts [aOR 0.85, 95 % CI(0.85-1.32), p =0.47], however, post-CABG patients had lower odds of net all periprocedural cardiac complications [ aOR 0.72 ,95% CI (0.59-0.87), p=0.001] compared to the other group. Results remained the same on subgroup analysis for men and women, There was no significant difference in mortality between the two cohorts for both men and women [aOR 0.67, 95% CI (0.38- 1.2), p=0.18], [aOR 1.15,95% CI (0.59- 2.23), p=0.66] respecetively. Men and women with prior CABG had lower odds of net all periprocedural cardiac complications compared to the men [aOR 0.59,95% CI (0.47- 0.74), p<0.001] and women [aOR 0.71,95% CI (0.52- 0.98), p=0.04] in the other cohort.

Conclusions:
Patients with prior CABG do not have amore dverse peri-procedural outcomes compared to other M-TEER patients. Despite the higher prevalence of comorbidities, our study suggests the overall safety of M-TEER in this subset of patients
Abstract 4142415: Higher t-PA Doses are Associated with Reduced In-Hospital Mortality in Pulmonary Embolism Patients Undergoing Catheter-Directed Thrombolysis
Authors: Hinkamp Colin , Liu Jason , Nardi Matthew , Postalian Alexander , Nair Ajith , Segar Matthew
Published: November 2024

Background:
Pulmonary embolism (PE) is a leading cause of cardiovascular death and preventable hospital mortality in the US. High-risk acute PE has a 30% mortality rate, despite new treatments like catheter-directed thrombolytics (CDT). CDT has shown to improve right ventricle/left ventricle (RV/LV) diameter ratio compared to anticoagulation alone, but the optimal t-PA dose is uncertain. Traditional dosing is 10-24 mg over 12-24 hours, but clinical trials have showed similar RV/LV diameter ratio reductions with lower doses and shorter infusions. No prospective data has shown a mortality benefit.

Hypothesis:
Higher t-PA doses will improve in-hospital mortality, length of stay (LOS), pulmonary artery (PA) pressure reduction, and cardiac biomarker reduction in patients receiving CDT for acute PE.

Methods:
We retrospectively analyzed patients who presented with PE and underwent CDT at a single center, tertiary hospital. Patients were stratified by t-PA dose (<24mg vs ≥24mg). Outcomes were compared using adjusted linear or logistic regression models.

Results:
Among 133 patients, 105 (80%) received t-PA ≥24mg. Patients who received higher doses of t-PA were younger (61 vs. 71 years, p=0.02), more likely to have bilateral PE (93% vs 77%; p=0.03) and had higher BMI (35 vs 30.5; p=0.04) and PA pressure (51 vs 40.5 mmHg; p=0.003) at baseline. In unadjusted analysis, no significant difference in in-hospital mortality was observed with t-PA ≥24mg (3.8% vs. 16.4%, p=0.08). However, in the adjusted analysis, a significantly lower risk in-hospital mortality rate was observed with t-PA ≥ 24mg (OR 0.15, 95%CI 0.02-0.97, p=0.046) (Table). No significant differences were observed in BNP reduction, PA pressure change, or LOS (Table).

Conclusion:
In acute PE patients undergoing CDT, t-PA dosing ≥24mg was associated with reduced in-hospital mortality. Prospective randomized controlled trials are needed to further define optimal dosing protocols.
Abstract 4142436: The HeartPlus Clinic Project: Multidisciplinary Treatment for Patients with Stimulant-Associated Cardiomyopathy
Authors: Tran Thu , Azari Soraya , Johnson Elizabeth , Jimenez Shirin
Published: November 2024

Background:
Stimulant-associated cardiomyopathy is an increasingly common cause of non-ischemic cardiomyopathy. Unfortunately, the last decade has seen dramatically higher rates of hospitalization for heart failure related to stimulant use. There are currently no Food and Drug Administration-approved medications for stimulant use disorder treatment (SUD). However, contingency management is a behavioral treatment that has been shown to be effective for SUD. In partnership with UC San Francisco, we developed a heart failure-addiction medicine co-management clinic (HeartPlus) to offer guideline-directed medical therapy in conjunction with contingency management to treat stimulant-associated cardiomyopathy over twelve weeks. The most common stimulant of abuse was methamphetamine.

Methods:
Our retrospective chart review assessed the feasibility of an Addiction Medicine and Heart Failure Cardiology co-management clinic at UC Davis. The clinic combined contingency management including point of care urine drug testing, as well as guideline-directed medical therapy for heart failure. We evaluated how many patients attended HeartPlus clinic at least once, how many completed the twelve-week program, and of those patients who completed the program, how many had improvement in self-reported symptoms as assessed by Kansas City Cardiomyopathy Questionaire (KCCQ-12) and left ventricular systolic function as assessed by echocardiogram.

Results:
A total of 39 patients were referred to HeartPlus Clinic. Of those referred, 25 patients attended the initial visit, and 7 patients successfully completed the 12-week program. Of the 7 patients who completed the program, 4 patients had improvement in left ventricular ejection fraction by at least ten percentage points. All 7 patients demonstrated improvement in KCCQ-12 scores by at least ten points (generally accepted as moderate improvement).

Conclusions:
The HeartPlus Clinic is a feasible treatment intervention for patients with stimulant-associated cardiomyopathy. For those patients who completed the program, they reported encouraging improvement in heart failure symptoms and four of seven demonstrated significant improvement in left ventricular systolic function. At an average cost of $74 per participant, this twelve-week multidisciplinary program is a promising area for future efforts to treat this growing population of disproportionately young patients.
Abstract 4142443: Multi-Omics Integration of Clinical Risk Factors, Polygenic Risk Score, and Proteomics to Predict Abdominal Aortic Aneurysm in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Li Aixin , Pankow Jim , Matsushita Kuni , Norby Faye , Hoogeveen Ron , Guan Weihua , Lutsey Pamela , Boerwinkle Eric , Coresh Joe , Folsom Aaron , Tang Weihong
Published: November 2024

Introduction:
Abdominal aortic aneurysm (AAA) is a significant cause of morbidity and mortality in older adults. The AAA screening guidelines from the Society of Vascular Surgery include risk factors such as sex, age, smoking, and family history. This study explored whether integration of a polygenic risk score (PRS) and proteomics with clinical data could improve AAA prediction in the ARIC Study.

Methods:
Over a median follow-up of 24 years from ARIC visit 2 (1990-92) baseline, we identified 487 clinical AAA cases among 9,373 ARIC participants (7,397 Whites and 1,976 Blacks) through hospital discharge diagnoses or death certificates. We selected AAA-associated clinical risk factors based on literature and our expertise, including age, gender, race, field center, smoking status, smoking pack-years, waist girth, BMI, levels of total and HDL cholesterols, hypertension, diabetes, and eGFR. We calculated the PRS[WT1] based on SNP dosage in ARIC and the latest genome-wide association study for AAA, which reported 141 independent associations from 14 discovery cohorts (PMID: 37845353). ARIC used SOMAscan v4 to measure 4,955 plasma proteins at baseline, of which 24 were significantly associated with clinical AAA (p < 1x10^-5) independent of the clinical risk factors. The prediction equation for AAA risk was constructed in 3 Cox regression models: 1) clinical risk factors measured at baseline, 2) model 1 variables plus PRS, and 3) model 2 variables plus the 24 AAA-associated proteins identified through proteomics analysis. We used the area under the curve (AUC) to evaluate the prediction performance of these models for AAA risk.

Results:
Participants in the top quintile of PRS showed significantly higher AAA risk compared to the lowest quintile (HR 1.41, 95% CI: 1.03 – 1.85) after adjustment for clinical risk factors. Adding the PRS to clinical risk factors did not improve the AUC: 0.890 (95% CI: 0.869 - 0.945) in model 1 vs 0.891 (95% CI: 0.853 - 0.961) in model 2. Further adding the 24 AAA-associated proteins substantially improved the performance of the prediction model [AL2] (AUC=0.950, 95% CI: 0.939 - 0.986 in model 3), with 289 AAA events in the top quintile of predicted risk compared to 12 in the lowest quintile.

Conclusion:
A proteomics-integrated approach that combined clinical risk factors and proteomics data enhanced AAA risk prediction and has the potential to improve risk stratification and early intervention for AAA.
Abstract 4142452: LDL-C variability was affected by lipid-lowering strategies and associated with adverse cardiovascular outcomes
Authors: Kim Dong-Eon , Hong Sung-jin , Bangalore Sripal , Yun Kyeong Ho , Lee Sang-Hyup , Lee Yong-Joon , Lee Seung-Jun , Ahn Chul-Min , Kim Jung-Sun , Kim Byeong-Keuk , Ko Young-Guk , Choi Donghoon , Jang Yangsoo , Hong Bum , Hong Myeong-Ki
Published: November 2024

Background:
Prior studies have shown an independent association between visit-to-visit variability in low-density lipoprotein cholesterol (LDL-C) and adverse cardiovascular (CV) events and that this variability can be reduced by high-intensity statins (HIS). However, it is not known whether LDL-C variability can be reduced by moderate-intensity statin (MIS) plus ezetimibe combination or by a treat-to-target strategy (TTS).

Hypothesis:
We aimed to evaluate whether visit-to-visit variability in LDL-C is affected by lipid-lowering strategies and its association with CV outcomes in patients treated with HIS or MIS plus ezetimibe or statins with a target LDL-C levels of 50 to 70 mg/dL (TTS).

Methods:
Data from the RACING and LODESTAR trial in patients with atherosclerotic disease, LDL-C variability was evaluated from 3 months after randomization. In the RACING trial, MIS plus ezetimibe combination therapy was compared with HIS monotherapy. In the LODESTAR trial, TTS with a target LDL-C level of 50 to 70 mg/dL by titration of the statin intensity was compared with HIS strategy. LDL-C variability was compared according to these lipid-lowering strategies. The primary endpoint was a composite of death, myocardial infarction, stroke, or coronary revascularization.

Results:
Among the 6800 patients included, when compared with patients randomized to HIS, LDL-C variability was similar in the group randomized to MIS plus ezetimibe combination (SD 8.92±7.15 vs 9.17±7.34, P=0.325) but higher in those randomized to TTS (SD 8.9±7.2 vs 10.6±7.7, P=0.001). There was a linear association between LDL-C variability and primary endpoint (Figure 1). The variability in LDL-C (by SD) was a predictor of primary endpoint (HR 1.024; 95% CI 1.014 to 1.035; P<0.001) even after adjustment for lipid-lowering strategy and mean LDL-C.

Conclusions:
Compared with HIS therapy, visit-to-visit variability in LDL-C was not increased in the MIS plus ezetimibe combination therapy, but was increased in the TTS. Even in those treated with MIS plus ezetimibe or HIS or statins with a target LDL-C levels of 50 to 70 mg/dL, increased LDL-C variability was significantly associated with higher risk of adverse CV outcome.
Abstract 4142467: Geographic and Temporal Trends in Stroke Mortality among Major Racial and Ethnic Populations in the United States, 2000-2019
Authors: Forde Allana , Strassle Paula , Dwyer-Lindgren Laura , Li Zhuochen , Kendrick Parkes , Mokdad Ali , Mensah George , Perez-Stable Eliseo
Published: November 2024

Background:
Despite profound disparities in stroke mortality, there is limited research on geographic variation across and within US racial and ethnic populations.

Research Question/Hypothesis:
Do geographic trends in stroke mortality vary across and within racial and ethnic populations living in the US? We hypothesized that changes in county-level stroke mortality would vary across and within racial and ethnic groups.

Methods:
We applied validated small-area estimation methods to US National Vital Statistics System death certificates to estimate stroke mortality rates by county (N=3110) and race and ethnicity (American Indian or Alaska Native [AIAN], Asian, Black, Hispanic or Latino [Latino], and White) from 2000-19. Mortality estimates were corrected for race and ethnicity misclassification on death certificates and age-standardized to the 2010 Census.

Results:
In 2019, age-standardized county-level stroke mortality rates per 100,000 ranged from 10.9 to 170.6 among AIAN, 11.8 to 96.9 among Asian, 17.4 to 179.7 among Black, 6.5 to 114.3 among Latino, and 14.5 to 139.7 among White populations. Despite stroke mortality declining nationally among all racial and ethnic populations, there were counties where mortality increased (AIAN: 15/474; Asian: 46/667; Black: 11/1488; Latino: 154/1478; White: 46/3051),
Fig
. Among these counties, median absolute increases were 3.5 (IQR 1.9-5.3; max: 26.8) among AIAN, 4.1 (1.1-5.4; max: 12.2) among Asian, 7.1 (1.0-10.2; max: 52.5) among Black, 2.4 (1.3-4.6; max: 18.3) among Latino, and 5.6 (1.9-12.3; max: 47.5) among White populations. Increased stroke mortality largely occurred in the Carolinas, Florida, and Georgia (72.4% of counties with increases) for all racial and ethnic groups except AIAN, which were mostly in Oklahoma (n=9). Geographic and temporal trends also varied across stroke type.

Conclusions:
Stroke mortality increased in over 200 counties nationally, with differential effects by race and ethnicity. Most increases occurred in the lower South Atlantic states. These findings underscore the importance of understanding drivers of stroke mortality disparities, as well as creating prevention and treatment strategies that target populations and places at high risk.
Abstract 4142480: BMI trajectories from childhood to midlife are associated with cardiovascular morbidity and mortality
Authors: Tian Jing , Blizzard Leigh , Cleland Verity , Bazzano Lydia , Daniels Stephen , Dwyer Terence , Jacobs David , Juonala Markus , Magnussen Costan , Raitakari Olli , Sinaiko Alan , Steinberger Julia , Urbina Elaine , Whitaker Kara , Woo Jessica , Venn Alison
Published: November 2024

Background:
Few studies have examined associations of BMI trajectories from childhood with CVD events.

Aims:
To describe BMI trajectories from childhood to midlife and their associations with CVD morbidity and mortality.

Methods:
Data were from the International Childhood Cardiovascular Cohort Consortium of 7 cohorts from Australia, Finland, and the USA. Participants (n=21,410) had ≥2 measures of height and weight prior to CVD events, including ≥1 in childhood (3-19 years) and ≥1 in adulthood (≥20 years). Age-sex-standardised BMI-z scores in childhood were estimated using WHO Child Growth Standards, and in adulthood using the internal reference. Group-based trajectory modelling identified BMI-z score trajectories. Outcomes were physician-adjudicated fatal and non-fatal CVD events in adulthood. Cox proportional hazards models estimated the risk of CVD outcomes, adjusted for mean age and calendar year at childhood visits, sex, race, cohort, and childhood smoking, accounting for competing risk.

Results:
Six trajectories were identified, differing by attained adult BMI category: persistently low (10.3%, adult normal weight), persistently average (35.1%, normal/overweight), moderately high decreasing (29.2%, overweight), high decreasing (12.1%, class I obesity), moderately high increasing (8.7%, class II/III obesity) and persistently high (4.6%, class III obesity). Over a median follow-up of 38.1 years, 98 fatal CVD events occurred among 20,821 participants and 388 fatal or nonfatal CVD events occurred among 18,069 participants with available covariates. Compared to the persistently average trajectory, high decreasing, moderately high increasing and persistently high trajectories were associated with higher risks of fatal CVD events (adjusted hazard ratios [aHRs]: 1.88-4.16, all p<0.05) and fatal or nonfatal CVD events (aHRs: 1.76-3.27, all p<0.05). A higher risk of fatal and nonfatal CVD events was found for the moderately high decreasing trajectory (aHR: 1.33, 95% CI: 1.02-1.74).

Conclusions:
BMI z-score trajectories that started moderately high or high in childhood, even if with z-score decrease over time, were associated with overweight and obesity in adulthood and increased risks of CVD morbidity and mortality.
Abstract 4142483: An Integrated Germline and Somatic Genomic Model Improves Risk Prediction for Coronary Artery Disease
Authors: Kim Min Seo , Yang Xiong , Uddin Md Mesbah , Nakao Tetsushi , Cho So Mi Jemma , Koyama Satoshi , Zhu Xinyu , Xu Tingfeng , Reeskamp Laurens Frans , Zhang Rufan , Liu Zhaoqi , A Yunga , Ellinor Patrick , Natarajan Pradeep , Wang Minxian , Fahed Akl
Published: November 2024

Background:
Multiple germline and somatic genomic drivers are associated with coronary artery disease (CAD), but their combined effects have not been thoroughly investigated.

Hypothesis:
An integrated model using all available information from single DNA biopsy including germline and somatic drivers improves CAD risk prediction.

Methods:
Based on whole genome sequencing data from UK Biobank, we curated familial hypercholesterolemia variants, clonal hematopoiesis of indeterminate potential, and leukocyte telomere length to calculate CAD polygenic risk score (PRS), proteome PRS, and metabolome PRS. An integrated genomic model (IGM) was developed by incorporating the six germline and somatic drivers for CAD.

Results:
Among 391,536 participants from UK Biobank (mean age 56.5 years; 53.8% women), 28,346 participants (7.2%) underwent incident CAD over a median follow-up of 12.3 years. The IGM showed better performance in predicting CAD risk (C-statistic 0.734, 95% CI 0.731 to 0.736) compared to the pooled cohort equations (PCE)(C-statistic 0.725, 95% CI 0.723 to 0.728). Addition of IGM to PCE further improved prediction accuracy (C-statistic 0.750, 95% CI 0.748 to 0.753) and resulted in a net reclassification improvement of 3.7% at risk threshold of 7.5%. IGM holistically captured CAD genetic risk, identifying individuals at high risk for CAD who do not have a single high-risk genomic factor but whose overall genomic profile places them at significant risk.

Conclusions:
We developed a state-of-the-art genomic model that integrates all available DNA information from a single biopsy. By accounting for the cumulative effects of multiple genomic drivers, IGM identifies high-risk individuals who might be overlooked by genomic risk models that rely on a single genetic factor.
Abstract 4142500: Intrauterine Tobacco Smoke Exposure Affects Cardiac Geometry and Function in Infants
Authors: Harada Kenji , Harada Yukiko , Hatakeyama-Sasaki Miho , Nakamoto Yuichi , Toyono Manatomo
Published: November 2024

Background:
Environmental tobacco smoke (ETS) exposure is associated with increased risk of cardiovascular events, however, there is little information on when cardiovascular functional changes begin to occur. The purpose of this study is to assess blood pressure and cardiac function in infants exposed to ETS .

Methods:
A total of 224 infants aged 4 months, 78 infants who have been exposed to tobacco smoking since intrauterine life and 146 controls without ETS exposure, underwent echocardiographic study. Left atrial anteroposterior diameter, left ventricular end-diastolic volume, ejection fraction, mass, and mass-to-volume ratio were measured. Transmitral peak flow velocities during early and late diastole and mitral annular myocardial velocities during early and late diastole were measured. Left atrial systolic force was calculated. Isovolumic relaxation time and tissue Doppler-derived myocardial performance index were assessed. Effective arterial elastance was estimated by end-systolic pressure/stroke volume index. End-systolic elastance was calculated by a modified single-beat method.

Results:
Body mass index was similar between the 2 groups (p >0.05). Systolic and diastolic blood pressures were significantly higher in ETS-exposed infants with than in controls (112 ± 10 vs. 109 ± 9 and 63 ± 8 vs 60 ± 8 mmHg, respectively, p <0.05). Compared with controls, left atrial size, left ventricular mass, and mitral annular myocardial velocities during late diastole were significantly higher (1.6 ± 0.16 vs. 1.4 ± 0.20 cm, 13.7 ± 3.1 vs. 12.6 ± 2.9 g, and 8.4 ± 2.2 vs. 7.6 ± 2.0 cm/sec, respectively, p < 0.05) in infants exposed to ETS. Ejection fraction, isovolumic relaxation time, myocardial performance index, end-systolic elastance, and effective arterial elastance did not differ between the 2 groups.

Conclusions:
The present study indicates that tobacco smoke exposure can adversely affect blood pressure, cardiac geometry, and function even in early infancy. Passive smoking may contribute to the increased prevalence of cardiovascular diseases in later life.
Abstract 4142506: Comparative Proteomic Analysis of Myocarditis: COVID-19 mRNA Vaccination vs. Pre-Pandemic Viral Etiologies
Authors: Jang Eunsom , Kim Euisoon , Jung Mi-Hyang , Kim In-Cheol , Kim Jong-Seo , Youn Jong-Chan
Published: November 2024

Introduction:
Myocarditis has been reported after mRNA-based COVID-19 vaccination, but the immune mechanisms remain unclear. This study aimed to identify the proteome-based immunopathogenesis of post-vaccination myocarditis compared to viral myocarditis in the pre-COVID-19 era.

Methods:
Proteomic analysis of right ventricle (RV) biopsy specimens was performed in myocarditis patients (pre-pandemic viral myocarditis: n=3, post-vaccination myocarditis: n=3) and controls (normal endomyocardial biopsy specimens of heart transplant recipients, n=4) using mass spectrometry. Differentially expressed proteins were analyzed with CIBERSORTx, Gene Ontology (GO) analysis, and Ingenuity Pathway Analysis (IPA). To examine the relationship between the SARS-CoV-2 spike protein and post-vaccination myocarditis, immunohistochemistry (IHC), mass spectrometry analysis of spike protein, and activation-induced marker (AIM) assay in T cells from RV samples were conducted.

Results:
In the proteomic analysis, 6,861 proteins were identified. Post-vaccination myocarditis showed increased extracellular matrix formation and cardiac fibrosis. Both pre-pandemic and post-vaccination myocarditis had elevated pro-inflammatory cytokine activities. However, post-vaccination myocarditis exhibited higher expression of interferon-alpha (IFNα) and pattern recognition receptor activation, including TLR3 and TLR7. Pre-pandemic myocarditis showed higher activation of the complement system, neutrophils, and NK cells, whereas post-vaccination myocarditis showed increased Th2 cell activation and classical macrophage activation. Spike protein and related T-cell activation were not detected.

Conclusion:
The immune activation in myocarditis after COVID-19 mRNA vaccination may be triggered by the mRNA in the vaccine via an IFNα-driven immune response, leading to autoimmune-like features. Further studies are necessary to validate whether these proteins correlate with clinical characteristics.
Abstract 4142540: Using Three-Dimensional Strain Deformation Imaging To Quantify Replacement Fibrosis In Hypertrophic Cardiomyopathy
Authors: pang kunjing , Wang Rong , song lei
Published: November 2024

Background:
Three-dimensional speckle tracking deformation STE (3D-STE) can overcome some limitations of 2D imaging. This study aims to verify the feasibility of using 3D-STE to quantify replacement fibrosis against enhanced cardiac magnetic resonance imaging (CMR-LGE).

Method:
3D-STE and the extent of LGE (%LGE) were prospectively measured in a large cohort of HCM patients, with an interval ≦ of 72 hours.

Results:
511 HCM patients (age 49.0 ± 14.3 years; 66.5% male) were enrolled. Three-dimensional global longitudinal strain (GLS-3D) moderately correlated with GLS-2D (r=0.622, p=0.000). GLS-3D showed the strongest correlation with %LGE (r = 0.699, p < 0.001). A quadratic model (R2=0.448, p=0.000) for the relationship between GLS-3D and %LGE performed better than a linear model. GLS-3D (OR = 0.632, p < 0.001) was independently associated with extensive LGE (%LGE≧15%). GLS-3D exhibited the highest area under the curve (AUC 0.894, p < 0.001) for detecting extensive LGE With a cutoff of -15.25%, sensitivity 87.3%, specificity 78.3%.

Conclusion:
GLS-3D is the most strongly correlated with %LGE among all strain parameters, demonstrating potential as a surrogate marker for LGE in HCM.
Abstract 4142541: Chronic heart failure associates with activation and clonal expansion of T cells with predicted autoreactive capacity
Authors: Abplanalp Wesley , Merten Maximilian , Rasper Tina , Cremer Sebastian , John David , Speer Thimoteus , Leistner David , Hoffmann Jedrzej , Bonig Halvard , Knosalla Christoph , Potapov Evgenij , Sarapki Tamim , Mustafic Emina , Berkowitsch Alexander , Zeiher Andreas , Dimmeler Stefanie
Published: November 2024

Background:
Chronic heart failure (HF) is characterized by adverse remodeling and persistent inflammation, leading to impaired heart function and poor prognosis. While the acute immune response post-myocardial infarction (MI) is well-studied, the role of the immune system in chronic HF remains unclear. This study aims to elucidate the response of T cells to HF.

Methods and Results:
In a cohort of 188 HF patients and healthy controls (HC), flow cytometry of peripheral blood revealed an increase in T cell memory/effector cells (HF=65%, HC=53% activated T cells) and a reduction in naïve T cells in HF patients. Additionally, antigen-presenting cells (APCs) displayed a higher immune stimulatory profile (e.g., HLA-DR, ICAM-1, TREM-1). Immune secretome analysis supported the chronic inflammatory state with significantly elevated serum levels of sICAM-1, IL6, and TNFRI in HF patients.

Phenotyping of peripheral blood T cells showed a decline in T central memory cells (TCM) and an increase in CD4+ Th17 and CD8+ T effector memory cells in HF patients compared to healthy controls. This decline in TCM cells and the increased expression of the homing marker CCR5 on T cell subsets were associated with poor prognosis in HF. T cell receptor (TCR) sequencing revealed reduced TCR diversity (p=0.03) and clonal expansion in circulating and cardiac T cells of HF patients. Epitope prediction modeling identified 22 unique human-derived epitopes specific to HF, suggesting potential autoreactivity.

Single-cell RNA sequencing (scRNA-seq) of CD45+ sorted cardiac and circulating cells confirmed clonal TCR expansion in the heart and blood of HF patients. Post-MI mouse models demonstrated an accumulation of pro-inflammatory Th17 T cells in the heart at days 14, 28, and 48, with later time points showing more pronounced pro-inflammatory profiles.

Conclusion:
Chronic HF is associated with persistent T cell activation and clonal expansion, potentially contributing to adverse remodeling and poor prognosis through autoimmune mechanisms. These findings provide insights for therapeutic cardio-immunological interventions targeting T cell responses in HF.
Abstract 4142554: Prevalently carried HLA allele associates with inflammation and poor prognosis in HF patients via co-stimulatory and MHC-II enhanceosome regulation
Authors: Abplanalp Wesley , Merten Maximilian , Cremer Sebastian , Rasper Tina , Mustafic Emina , Ruz Jurado Mariano , John David , Puntmann Valentina , Nagel Eike , Krishnan Jaya , Guzik Tomasz , Siedlinski Mateusz , Zeiher Andreas , Dimmeler Stefanie
Published: November 2024

Background:
Cardiovascular diseases, including chronic heart failure with reduced ejection fraction (HFrEF), pose a substantial global health burden, emphasizing the need for better understanding of their genetic and immune-related mechanisms. While the immune system, particularly human leukocyte antigens (HLAs), has garnered attention in cardiovascular research, their specific role in HFrEF remains unclear. This study aims to explore the association between HLA alleles and cardiovascular risk in HFrEF, focusing on disease progression, prognosis, and underlying mechanisms.

Methods and Results:
Ninety-six chronic HFrEF patients underwent four-digit HLA typing analysis in a case-control study. Analysis of HLA alleles revealed the HLA-DR2 family (mostly HLA-DRB5*0101) carried by 14 patients (15.1%). HLA-DR2 showed the highest significant association with mortality. Additional cohort analysis confirmed elevated cardiac injury markers, including Troponin T, in HLA-DR2 carriers, independent of renal function. Multivariate analysis revealed a higher incidence of myocardial infarction in DRB5 carriers, while non-carriers had higher associations with stroke, CKD, and hyperuricemia. Analysis of 3000 plasma proteins from 30,000 UK participants also showed increased inflammatory (TIMD4,CD80) and CV risk associated (IGFBP7) markers were strongly elevated in HLA-DR2 subjects.

Mechanistic insights were obtained through CITE-seq analysis of immune cells from HLA-DR2 carriers and non-carriers, revealing enhanced antigen presentation and pro-inflammatory gene expression in carriers. Functional experiments confirmed that silencing HLA-DRB5 in macrophages reduced antigen presentation and T cell activation. HLA-DR2 carriers also exhibited greater T cell activation and polarization, with HLA-DR2 (specifically HLA-DRB5*0101 allele) silencing in dendritic cells diminishing T cell invasion potential into cardiac organoids.

Conclusions:
This study associates HLA-DR2 alleles, specifically HLA-DRB5*0101, with prognosis in chronic heart failure and myocardial injury, indicating an increased risk for cardiovascular pathology in carriers. These findings underscore the potential of HLA typing for enhancing risk stratification and informing targeted therapies in HFrEF. Further research is warranted to explore targeted treatments for HLA-DRB5 carriers, offering potential avenues for precision medicine in managing heart failure.
Abstract 4142559: The effect of blood pressure monitoring program based on intelligent wearable devices on the compliance of nursing guidelines for intravenous thrombolysis in acute ischemic stroke
Authors: Chang Hong , Li Suai , Zhao Jie , Liu Mengrao , tian siying , Wang Yuxin , Yang Ting
Published: November 2024

Introduction:
It is recommended that blood pressure (BP) in patients with acute ischemic stroke should be monitored closely before and until 24 hours after thrombolysis. This study aimed to develop a BP monitoring protocol for acute ischemic stroke patients using smart wearable devices and investigate its feasibility and effectiveness.

Methods:
160 stroke patients in the emergency department of a designated advanced stroke center from were recruited from March to September 2023 (Fig.1). The intervention group received the BP monitoring protocol using smart wearable devices, while the control group received traditional bedside BP monitoring using standalone devices. Process evaluation indicators included feasibility, fidelity, and stakeholder acceptability. Outcome evaluation indicators included adherence to BP monitoring guidelines, time from admission to intravenous thrombolysis, National Institutes of Health Stroke Scale scores, modified Rankin Scale scores, and the incidence of symptomatic intracranial hemorrhage.

Results:
The implementation rate of BP monitoring guidelines from before intravenous thrombolysis to 24 hours after thrombolysis in the experimental group was 90.00 (87.50, 95.00) %, and that in the control group was 87.50 (82.50, 92.50) % (Table 1). The results of the process evaluation showed that the feasibility and intervention fidelity of this study were good. Interviews with stakeholders (11 nurses and 11 patients) revealed that the implementation of the intervention protocol was beneficial in improving nursing efficiency and timely detection of disease changes, but the protocol needed further improvement.

Conclusion:
The BP monitoring protocol for stroke patients undergoing intravenous thrombolysis based on smart wearable devices is scientifically sound and feasible. It can enhance adherence to BP monitoring guidelines and promote the implementation of evidence-based nursing practices.
Abstract 4142561: A 10-year longitudinal cohort study of lipid variability, cognitive decline, and dementia in 9846 community-dwelling older adults
Authors: Zhou Zhen , Moran Chris , Murray Anne , Zoungas Sophia , Nelson Mark , Talic Stella , Wolfe Rory , Ryan Joanne
Published: November 2024

Background:
Lipid metabolism in older adults is affected by various factors including biological ageing, functional decline, reduced physiological reserve, and nutrient intake. The dysregulation of lipid metabolism has been suggested to adversely impact brain health. This study aims to investigate the association between year-to-year lipid variability and subsequent risk of cognitive decline and dementia in older adults.

Methods:
ASPREE was a randomized trial of aspirin and extended into an observational study, ASPREE-XT with a maximum follow-up of 11 years. Included in this study were participants who had cholesterol values measured at baseline, and first three-year annual visits. Only those who initiated or discontinued lipid-lowering therapy during the measurement period were excluded as this study aims to explore change in lipid levels unrelated to changes in treatment. Year-to-year variability in total cholesterol (TC), Low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), and triglycerides was quantified using variability independent of the mean (VIM). Associations with incident dementia and cognitive impairment-no dementia (CIND) were analysed using multivariable Cox proportional-hazards models. Linear mixed model was used for assessing the association with changes in different cognitive function domains including global, memory, processing speed, verbal fluency, and a composite over 11 years.

Results:
The analysis included 9,846 individuals. Baseline characteristics are shown in
Table 1
. 509 incident dementia and 1,760 CIND events were recorded over a median follow-up of 5.8- and 5.4-years post-variability assessment. The HRs (95%CI) comparing the highest vs. lowest quartiles of TC and LDL-C variability, were 1.60 (1.23-2.08) and 1.48 (1.15-1.91) for dementia, and 1.23 (1.08-1.41) and 1.27 (1.11-1.46) for CIND. Restricted cubic splines revealed a monotonic increased risk of dementia with higher TC and LDL-c variability (
Fig 1
). TC and LDL-C variability were also associated with a faster decline in global cognition, episodic memory, psychomotor speed, and the composite score (all p<0.001). No strong evidence was found for an association between HDL-C and triglycerides variability with dementia and cognitive change.

Conclusions:
Tracking the variability of TC and LDL-C measured annually may serve as a novel biomarker for higher risk of incident dementia and cognitive decline in older adults.
Abstract 4142573: Validation of Wrist-Worn Body Impedance Analysis Technology for Cardiovascular Disease Risk Management
Authors: Deery Adrian , Francey Jonathan , Diven Jordan , McKenna Stacey , Easlea Holly , Horigan Geraldine , Price Ruth , Sanchez Terrones Benjamin
Published: November 2024

Background:
Chronic hypohydration and heightened adiposity are established contributors to CVD risk that are modified by lifestyle behaviours. However, traditional monitoring methods require specialised equipment and are impractical for everyday use. Emerging wrist-worn devices with body impedance analysis (BIA) capabilities offer a non-invasive solution for monitoring body composition to aid in CVD risk self-management.

Aims:
To validate the accuracy of a wrist-worn BIA device and associated algorithms in measuring body fat percentage (BFP) and total body water (TBW) relative to gold standard measurements.

Methods:
This cross-sectional, single-centre study recruited healthy participants with diverse demographic and anthropometric characteristics for a single time-point investigation at the Human Interventions Studies Unit, Ulster University. Two-minute BIA recordings were collected from participants on a proprietary wrist-worn device and used to train and validate a predictive BIA algorithm. BFP and TBW metrics were validated against clinical-grade measurements on a GE Lunar DEXA scanner and Impedimed SFB7 device, respectively. Algorithm accuracy was evaluated using the mean absolute error (MAE) between predicted and true values. The R
2
value assessed the predictive model's goodness of fit.

Results:
A total of 130 participants were recruited (44% male, 82% Caucasian, mean age: 39.8±14.8 years, mean BMI: 25.4±5.5 kg/m
2
; Figure 1a), 15 of whom were excluded for failing to adhere to the study protocol. The remaining 115 subjects’ data were divided into training (n=100) and test (n=15) sets. On test data, regression analysis indicated a strong relationship between algorithm-predicted values and true values of BFP (R
2
=0.83; Figure 1b) and TBW (R
2
=0.83; Figure 1c). The algorithm accurately measured BFP and TBW, achieving a MAE of 3.4% for BFP and 2.3 L for TBW relative to gold standard measurements.

Conclusion:
The wrist-worn BIA technology has shown comparable accuracy to gold standard devices in measuring BFP and TBW. These findings suggest that wearable BIA devices could serve as effective, non-invasive tools for body composition monitoring, enabling individuals to better manage their cardiovascular health.