bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4141580: Prognostic value of blood cellular indices for 30-day mortality in patients with acute pulmonary embolism. Study from the RIETE Registry.
Authors: Siddiqui Fakiha , Tafur Alfonso , Kantarcioglu Bulent , García-Ortega Alberto , CIAMMAICHELLA Maurizio Maria , MARCHENA Pablo Javier , Gavin Olga , MUNERA Adriana , Fareed Jawed , Monreal Manuel , Group RIETE
Published: November 2024

Introduction:
Diagnostic and prognostic value of blood cellular indices (CI) has been reported to predict the adverse outcome in various diseases including pulmonary embolism (PE). We have recently reported neutrophil to lymphocyte ratio (NLR) as the best predictive marker for short-term mortality in acute PE patients compared to platetet to lymphocyte ratio (PLR) and systemic immune inflammation index (SII). This study was designed to compare the prognostic value of NLR with other cellular indices such as neutrophil to monocyte ratio (NMR) and monocyte to lymphocyte ratio (MLR) predicting 30-day mortality outcome in patients with acute PE.

Methods:
This study include 5084 patients from the RIETE Registry to evaluate the association between NLR, NMR and MLR with the 30-day mortality in PE patients. Receiver operating curve (ROC) analysis was used to define the optimal cutoff values for the ratio’s. Degree of association were analyzed by univariate chi-square and multivariate logistic regression model with all the clinically relevant variables , however, to avoid multicollinearity, ratios were modeled separately.

Result:
In the cohort of 5084 patients, 49 % were male and 51% were female with the median age 71-years. Thirty-day mortality rate was 4.5%. Following ROC analysis, NLR >7.0, NMR >11.0 and MLR >0.5 were considered as the optimal cutoff for 30-day mortality. Degree of association between cellular indices and 30-day mortality were presented in table 1, elevated level of NLR, NMR, and MLR at baseline were associated with risk of death at 30-day. In both the adjusted (with clinically relevant variables) and unadjusted model, patients with elevated NLR >7.0 showed the finest association with mortality compared to NMR and MLR (figure 1).

Conclusion:
Blood cellular indices is considered as a reliable and measurable prognostic marker for 30-day mortality in PE patients, however, elevated NLR at baseline supercede NMR and MLR. Further studies are obligatory to investigate the potential mechanisms by which the NLR, NMR, and MLR relates with PE outcomes to improve patient management.
Abstract 4141585: Lipoprotein(a) and risk of cardiovascular disease events: an analysis in a large US national database
Authors: MacDougall Diane , McGowan Mary , Hu Xingdi , Boatwright Wess , Stern Theresa , Hartsuff Bonnie , Wilemon Katherine
Published: November 2024

Introduction/Background:
Despite increasing awareness of lipoprotein(a) [Lp(a)] as an independent, genetically determined, causal risk driver of atherosclerotic cardiovascular disease (ASCVD), Lp(a) screening occurs infrequently, and nationwide, comprehensive data characterizing the risk of elevated Lp(a) are lacking.

Aims:
To evaluate the association of Lp(a) level with cardiovascular disease (CVD) events in individuals with and without pre-existing ASCVD using real-world data from the Family Heart Database
TM
.

Methods:
Observational, retrospective cohort study using longitudinal data in over 324 million individuals from 2012-2021. Selection criteria included individuals ≥18 years with ≥1 Lp(a) test measured in nmol/L during May 1, 2013 to December 31, 2020, and ≥1 medical claim pre- and post-index date (date of earliest Lp[a] test). Lp(a) levels were categorized by percentile (<20th, 20
th
to 80
th
, and >80
th
). Elevated Lp(a) was defined as >80
th
percentile (>140 nmol/L). Multivariable Cox Proportional Hazards model analyses compared a group with Lp(a) <20
th
percentile [<10 nmol/L] and no ASCVD to five other groups that differed by pre-index ASCVD status (Yes/No) and category of Lp(a) level.

Results:
A total of 392,835 individuals were included: mean (SD) age 59 (13.6) years, 55% female, and 43.0% with pre-index ASCVD. Elevated Lp(a) was most prevalent in women and Black individuals. Mean/median follow-up duration was 3.0/2.5 years. In individuals without pre-index ASCVD, those with Lp(a) >140 nmol/L had an adjusted 12% increased risk of CVD events (p<0.0001) versus those with Lp(a) <10 nmol/L. Compared to individuals with no pre-index ASCVD and Lp(a) <10 nmol/L, individuals with pre-index ASCVD and Lp(a) >140 nmol/L had the highest CVD event risk: adjusted HR = 3.25, 95% CI 3.11, 3.41, P<0.0001.

Conclusions:
In one of largest analyses of US individuals with Lp(a) levels to date, elevated Lp(a) consistently predict the increased risk of future CVD events in individuals with and without pre-index ASCVD. These findings highlight the substantial unmet need for Lp(a) screening to support risk stratification and subsequent care.
Abstract 4141589: Race, neighborhood poverty, and all-cause mortality in heart failure with preserved ejection fraction
Authors: Khodneva Yulia , Arora Pankaj , Nordberg Megan , Hearld Larry , Cherrington Andrea
Published: November 2024

Background:
Race and neighborhood socioeconomic disadvantage are linked to worse health outcomes in heart failure, but studies have not specifically focused on patients with heart failure with preserved ejection fraction (HFpEF).

Research Question:
Is race associated with all-cause mortality among patients with HFpEF and does the area-level poverty moderate this association?

Methods:
ICD diagnostic codes for HFpEF were used to identify patients with first hospitalizations for HFpEF in University of Alabama in Birmingham (UAB) Medicine EHR data from 2017-2023. Demographics, comorbidities, and laboratory data were extracted at admission. Patient zip codes were merged with Census zip code poverty data. All-cause mortality was ascertained in the EHR. Multivariable-adjusted Cox proportional hazard models examined the association between race and all-cause mortality and interaction between race and zip-level poverty ratio, dichotomized at the median.

Results:
Between 2017-2023, 14,043 adults had a first hospitalization for HFpEF at UAB; 37% were African American (AA), 58% white, 4.5% from other race/ethnicities. Half resided in high poverty areas (19% of area residents with income below the median poverty level). Compared to whites, AA adults with HFpEF were more likely to be younger, women, reside in high-poverty areas, and have hypertension, diabetes, obesity, worse kidney function and higher brain-natriuretic peptide at admission (Table). Over a median follow-up of 2.7 years [IQR: 0.9-4.9 years], there were 3,747 deaths; 2146 (26.2%) among whites, 1447 (27.8%) among AAs, and 154 (24.3%) among other ethnicities. AA adults had increased all-cause mortality compared to whites, with an adjusted HR 1.14 [95% CI: 1.06-1.23, p=0.001]. The race* poverty interaction p-value was 0.02, indicating that the association between race and all-cause mortality was significantly more pronounced among those residing in higher poverty areas (Table). This was not observed for AA adults in lower poverty areas or for other ethnicities.

Conclusion:
In this study, AA patients with HFpEF, residing in high poverty areas, had higher all-cause mortality rates compared to white patients. No racial differences in mortality were observed in lower poverty areas.
Abstract 4141603: Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases as Biomarkers in Duchenne Muscular Dystrophy Cardiomyopathy
Authors: Starnes Joseph , Campbell Michael , Gambetta Katheryn , Hor Kan , Husain Nazia , Li Jennifer , Raucci Frank , Soriano Brian , Spurney Christopher , Dayan Jonathan , Markham Larry , Soslow Jonathan
Published: November 2024

Introduction/Background:
Cardiomyopathy is the leading cause of death in patients with Duchenne muscular dystrophy (DMD), but existing biomarkers are poor indicators of cardiomyopathy onset and progression. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate collagen turnover and have previously been associated with DMD cardiomyopathy through their role in fibrosis.

Hypothesis:
We hypothesized that MMPs/TIMPs would correlate with cardiac magnetic resonance (CMR) measures of cardiomyopathy.

Aims:
We aimed to assess the relationship between circulating MMPs/TIMPs and CMR measures of cardiomyopathy.

Methods:
Patients with DMD were prospectively enrolled in a multi-center observational study with CMR, quantitative muscle testing (QMT), and bloodwork. CMR included measurement of left ventricular ejection fraction (LVEF), late gadolinium enhancement (LGE) global severity score (GSS), LGE using full-width half-maximum (FWHM), and global circumferential strain (Ecc) using tagged images. Spearman’s rank test was used to assess correlation between CMR measurements and MMPs. Wilcoxon rank-sum tests were used to compare MMPs by binary categories.

Results:
A total of 166 patients were included (mean age 14.4 years, 83% white/11.9% Black/10.8% Hispanic). MMP1 and the MMP1/TIMP1 ratio correlated negatively with LVEF and positively LGE GSS (Table 1). MMP7 correlated positively with LGE GSS and Ecc. Patients with LGE had higher MMP1, MMP7, and MMP1/TIMP1 (Figure 1). Similarly, patients with reduced LVEF had higher MMP1 and MMP1/TIMP1, although not MMP7. MMP7 and MMP1/TIMP1 were also negatively correlated with total QMT.

Conclusions:
Multiple MMPs and TIMPs associate with DMD cardiomyopathy severity and may serve as biomarkers of DMD cardiac disease progression.
Abstract 4141605: Genetic Determinant for Prognosis of Dilated Cardiomyopathy: The role of NAV3 in Cardiac Fibrosis
Authors: Wang Min , Wang Li , Ghazal Rachad , Seal Mayah , Nguyen Thanh Thanh , McNamara Dennis , Barlera Simona , Pileggi Silvana , Mestroni Luisa , Merlo Marco , sinagra Gianfranco , Pinet Florence , Krejci Jan , Liu Duan , Weinshilboum Richard , Pereira Naveen
Published: November 2024

Background:
Dilated Cardiomyopathy (DCM) is a major cause of heart failure (HF) and carries a high mortality rate. Drug treatment response for DCM-related HF patients is highly variable, with some patients having no response. A pharmacogenomic approach, genome-wide association study (GWAS) followed by biologically functional validation, can potentially identify genetic determinants of prognosis in DCM and might provide insight into novel biology of DCM pharmacotherapy.

Methods:
A GWAS was performed using DNA from 686 patients with recent onset DCM who were on standard HF therapy using change in left ventricular ejection fraction (LVEF) at a median of 6 months after initial diagnosis. Cultured human cardiac fibroblasts (HCFs) were used to functionally validate the GWAS findings
in vitro
. RNA-seq followed by pathway analysis after NAV3 knock-down (KD) using siRNA in HCFs were performed to explore potential biological mechanisms.

Results:
A genetic variant, rs11105445(G>A), identified from the GWAS, mapping to the neuron navigator 3 (NAV3) gene (rs11105445, p=2.37E-07; beta 2.74 ± 0.53) was associated with improvement in LVEF. Functional genomic experiments demonstrated that, both in LV tissue and in cultured fibroblasts, the minor allele A was associated with decreased transcription of NAV3 (pvalue: 0.0335 and 0.0432) suggesting that ↓NAV3 expression might be associated with improvement in LVEF. TGF-β1 can induce HCF transdifferentiation into myofibroblasts and we demonstrate that it also increases NAV3 expression. NAV3 KD which mimics the GWAS variant significantly suppressed TGF-β1 induced HCF transdifferentiation demonstrated by decreased expression of α-smooth muscle actin (ACTA2) and collagen I (COL1A1). RNA-seq after NAV3 KD followed by pathway analysis suggested that NAV3 exerted its effect by regulating ECM and cell cycle processes, especially G1/S transition. We demonstrate that NAV3 KD suppressed TGF-β1 induced G1/S arrest by regulating CDK4, CDK6 and INK4B (cyclin-dependent kinase inhibitor 2B/P15, CDK4 inhibitor).

Conclusion:
Decreased expression of NAV3 is associated with myocardial recovery in DCM, most likely due to its role in suppressing HCF differentiation by regulating TGF-β1 induced G1/S arrest. The role of NAV3 as a novel therapeutic target in DCM needs to be explored.
Abstract 4141618: Endothelium dependent and non-dependent effects of age and blood pressure on the progression of arterial stiffness in hypertension
Authors: Nakano Hiroki , Tomiyama Hirofumi , Shiina Kazuki , Kani Junya , Fujii Masatsune , Matsumoto Chisa , Yamashina Akira , Satomi Kazuhiro
Published: November 2024

Background:
Endothelial dysfunction affects arterial stiffness. While age and blood pressure are major determinants for the progression of arterial stiffness and both also affect endothelial dysfunction, it has not been clarified whether these factors affect arterial stiffness directly or mediated by endothelial dysfunction.

Methods:
Flow-mediated vasodilatation in Japan (FMD-J) study was a multicenter prospective observational study to examine the clinical significance of FMD in the management of cardiovascular diseases and their risk factors. In this study, FMD and brachial-ankle pulse wave velocity (baPWV), a marker of arterial stiffness, were repeatedly measured three times {i.e., baseline, 1.5 year’s and 3 years’ follow-up (1.5fol and 3fol)} in 617 subjects under anti-hypertensive medication.

Results:
In cross-sectional assessment at baseline, at 1.5fol and at 3fol, multiple linear regression analyses adjusted with covariates demonstrated that age and systolic blood pressure (SBP) were independently associated with baPWV. During the study period, baPWV was increased significantly (from 1621 ± 295 to 1626 ± 294 cm/s, P<0.001). The study participants were divided into two groups by the median of age or by that of SBP at baseline. The baPWV at 3fol was higher in age over median and in SBP over median as compared to the group of those under median (1537 ± 278 vs. 1714 ± 282, P<0.001, 1593 ± 297 vs. 1656 ± 288, P<0.001). In multivariate longitudinal assessments, age and SBP at baseline were significantly associated with baPWV at 1.5fol (beta 0.412, P<0.001 and beta 0.216, P<0.001) and that at 3fol (beta 0.424, P<0.001 and beta 0.115, P= 0.002), but not with FMD. Multivariate mediation analyses demonstrated that age and SBP at baseline were directly associated with baPWV at baseline, at 1.5fol and at 3fol, but no significate mediated effect of FMD was conformed at each study period.

Conclusion:
In subjects under anti-hypertensive medication, the progression of arterial stiffness may be accelerated along with age and also along with the elevation of SBP. In there, age and blood pressure may directly affect the progression of arterial stiffness without mediating endothelial dysfunction.
Abstract 4141626: A closed-loop system based on piezoelectric thin-film sensors and photothermal nanomaterials enables precise renal denervation for the treatment of hypertension
Authors: Liu Chengzhe , Zhou Liping , Yu Lilei
Published: November 2024

Background:
Since renal sympathetic nerves play a crucial role in the pathogenesis of hypertension, renal denervation (RDN) has emerged as a new solution for hypertensive patients, especially those with refractory hypertension. However, clinical trials have shown inconsistent results with current RDN techniques. This may be attributed to the short duration of effects induced by nerve fiber regeneration after ablation and the lack of measures to localize and assess efficacy.

Hypothesis:
In this study, we attempted to construct a sustainable closed-loop RDN system and overcome these limitations.

Methods:
We designed a new closed-loop RDN system containing a monitoring module with piezoelectric thin-film sensor (PTFS) and an intervention module with Pd nanopartical shell (PdNPS)-mediated photothermal nerve ablation. The feasibility and safety of this closed-loop system was explored in canine models of acute and chronic renal sympathetic nerve stimulation simulating hypertension, respectively.

Results:
In vivo
experiments showed that PTFS on the surface of the renal artery enabled monitoring and collection of arterial pulsations and blood pressure. The self-monitoring function based on PTFS can guide PdNPS to maximize RDN. During the treatment window of 90-120s, PdNPS could maintain an ablation temperature of 58-62°C under NIR irradiation to inhibit renal sympathetic nerve activity and function. In the hypertension simulation model, the increase in blood pressure was 54.65% lower in the PdNPS group compared to the control group (p<0.05). Histologic testing showed that PdNPS ablation resulted in necrosis and degeneration of the renal sympathetic nerves, whereas the renal arteries were structurally intact and functioned normally. In addition, the increase in blood pressure after 1 month was 52.84% lower in the PdNPS group compared with the sham group (p<0.05), suggesting microinjection of PdNPS photothermal ablation is sustainably effective.

Conclusion:
This novel closed-loop system has the potential for safe and effective RDN, which would provide a new therapeutic strategy for refractory hypertension and even chronic diseases of the autonomic nervous system.
Abstract 4141631: Abdominal Circumference and Coronary Calcium Score in a Healthy Nonobese Brazilian Cohort: ELSA-Brasil Cohort Analysis
Authors: Correa Fabiano Ronaldo , Bosco Mendes Thiago , Romero-Nunez Carlos , Generoso Giuliano , Staniak Henrique , Foppa Murilo , Santos Raul , Lotufo Paulo , Bensenor Isabela , Bittencourt Marcio
Published: November 2024

Introduction:
Obesity increases coronary artery disease (CAD) risk and is highly associated with diabetes. Although body mass index (BMI) is more frequently used as an objective assessment of obesity, abdominal circumference (AC) is often overlooked as a risk factor, especially in nonobese individuals. We examined the association between AC and coronary artery calcium score (CAC), a marker of subclinical CAD.

Methods:
We analyzed data from 2184 asymptomatic nonobese individuals (BMI 18 - 30 kg/m
2
) without prior cardiovascular disease (CVD) from the ELSA-Brasil cohort. The association of standardized AC and CAC incidence was examined by multivariable logistic regression models. Models were adjusted for age, sex, race, premature family history of CVD, tobacco use, physical activity, hypertension, triglycerides, LDL, statin use, diabetes, and interaction between diabetes and AC. CAC incidence was defined by initial CAC = 0 and repeated CAC > 0 and were performed between 2010-2018.

Results:
The mean age was 48±8, 60% were female, and 67.2% were white. CAC incidence was 15% (327/2184) and the mean CAC interval in years was 5.2±1. AC was significantly associated with CAC incidence across all models (Model 1 OR = 1.53, 95% CI: 1.24-1.89, p<0.001; Model 2 OR = 1.49, 95% CI: 1.20-1.85, p<0.001; Model 3 OR = 1.46, 95% CI: 1.16-1.83, p=0.001). Diabetes mellitus status did not significantly alter the risk estimates.

Conclusions:
Abdominal circumference is an independent risk factor for the incidence of subclinical CAD assessed by CAC in nonobese asymptomatic individuals without prior CVD, after adjusting for classical risk factors. This finding suggests that AC may serve as a subtle clinical marker of residual risk factors, potentially indicating the importance of visceral fat in this population.
Abstract 4141659: Uncovering Sex Bias in Machine Learning Algorithms for Detecting Acute Myocardial Infarction using Electrocardiographic Data
Authors: Kandikonda Yasoda Sai Ram , Goyal Abhinav , Zegre-Hemsey Jessica , Kumar Lekshmi , Wright David , Van Assen Marly , Wawira Judy , Suba Sukardi , Carey Mary , bold delgersuren , Ding Cheng , Fedorov Alex , Lu Jiaying , Yan Runze , Hu Xiao , Xiao Ran
Published: November 2024

Introduction:
Acute myocardial infarction (AMI) is a life-threatening manifestation of cardiovascular disease so timely detection and intervention are crucial for improving patient outcomes. Increasingly, machine learning (ML) algorithms are being leveraged to analyze 12-lead electrocardiograms (ECGs) to optimize early and accurate triage for AMI. However, the potential inherent sex bias within these data-driven algorithms remains insufficiently explored. This study aims to uncover potential sex bias in ML algorithms through a systematic and well-controlled investigation.

Methods:
Utilizing a public ECG dataset (PTBXL) with cardiologist annotations of AMI and non-AMI classes, we conducted sex-based resampling to obtain datasets with varying male-to-female sample ratio from 0.5 to 1.5, keeping the AMI to non-AMI ratio constant at 1:2 for each sex group. We evaluated the performance of ML models derived from these datasets on ECGs from male and female subgroups. The process was repeated 30 times with random subsampling. The area under the precision-recall curve (AUCPR) was used as the performance metric because it is robust to class imbalance issues.

Results:
The models consistently performed better on the male subgroup, even as the number of female samples increased. At a male-to-female ratio of 0.5 (male: 2394; female: 4788), the mean AUCPR for males was 0.626 ± 0.03, compared to 0.573 ± 0.02 for females. This trend persisted at a balanced ratio of 1.0 (4788 samples each), with an AUCPR of 0.651 ± 0.02 for males and 0.592 ± 0.02 for females. At a ratio of 1.5 (male: 7182; female: 4788), the AUCPR for males was 0.667 ± 0.02, versus 0.598 ± 0.02 for females. All comparisons were statistically significant (p < 0.05, two-sample Student t-tests).

Discussion:
Despite an increased number of female samples, the consistently better performance of the model to detect AMI in males suggests a potential bias in the model. We hypothesize that this bias may be related to inherent differences in the distribution of ECG patterns between male and female subgroups. Our findings indicate that simply balancing the dataset by increasing the female sample size is insufficient to mitigate bias. Addressing disparities in healthcare data requires more nuanced strategies beyond data balancing. Future work should explore alternative approaches to overcome sex bias in the application of ML algorithms in the interpretation of ECGs in patients with suspected AMI.
Abstract 4141673: Immunologic Insights: Activated and Exhausted Circulating T-Cell Phenotype in Hypoplastic Left Heart Syndrome (HLHS)
Authors: Kumah Yvonne , Garcia Anastacia , Abbott Jordan , Lang Julie , Nakano Stephanie
Published: November 2024

Background:
While staged surgical palliation for infants born with hypoplastic left heart syndrome (HLHS) has enabled many patients to survive a previously fatal condition, there is now a growing population of HLHS children and young adults who experience significant co-morbidities and mortality secondary to their palliated physiology. Abnormalities of the immune system, including T-cell lymphopenia, have been documented in HLHS patients. However, the impact of altered T-cell homeostasis remains ill-defined.

Hypothesis:
Both intrinsic and acquired alterations in T-cell sub-populations results in T-cell activation/exhaustion and a pro-inflammatory phenotype.

Methods:
Peripheral T-cell sub-populations and activation/inhibition markers were quantified in HLHS (n=32, median age 1.65 years, range 0-13.2 years) and healthy, pediatric controls (n=14, median age 4.55 years, range 0.2-15.1 years) by mass cytometry (Helios Cytometry Time Of Flight, CyTOF). Comparison between HLHS and controls was performed by unpaired t-test or Mann-Whitney, based on normality.

Results:
In HLHS subjects, circulating CD4
+
and CD8
+
populations are significantly decreased (p<0.001) compared to control. The proportions of CD4
+
HLA-DR
+
(p<0.05) and CD8
+
EOMES
+
(p<0.01) T cells are increased in HLHS. HLHS CD8
+
TC1
+
populations are increased (p<0.05) while HLHS CD8
+
TC2
+
(p<0.05) populations are decreased compared to controls. Notably, there is an increase in CD4
+
regulatory T cells in HLHS subjects (p<0.001).

Conclusions:
Immunoprofiling of peripheral T-cell populations suggests that abnormalities extend beyond a decrease in T-cell numbers: HLHS T cells demonstrate an activated and exhausted phenotype, which may impact development of co-morbidities in this population. Additional investigations are required to delineate the functional consequences of this unique HLHS immunophenotype.
Abstract 4141686: Chromatin Remodeling Drives Immune-Fibroblast Cell Communication in Heart Failure
Authors: Alexanian Michael , Padmanabhan Arun , Nishino Tomohiro , Travers Joshua , Ye Lin , Angelo Pelonero , Lee Clara , Sadagopan Nandhini , Huang Yu , Auclair Kirsten , Zhu Ada , An Yuqian , Ekstrand Christina , Martinez Cassandra , Gonzalez Teran Barbara , Flanigan Will , Kee-Seon Kim Charis , Conradson Devon , Gardner Zachary , Li Li , Costa Mauro , Jain Rajan , Charo Israel , Combes Alexis , Haldar Saptarsi , Pollard Katherine , Vagnozzi Ronald , McKinsey Timothy , Przytycki Pawel , Srivastava Deepak
Published: November 2024

Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator
Brd4
in infiltrating
Cx3cr1
-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy
in vivo
in
Cx3cr1
-positive cells identified a large enhancer proximal to
Interleukin-1 beta
(
Il1b)
, and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controls expression of
Il1b
in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor
MEOX1
, resulting in a profibrotic response in human cardiac fibroblasts.
In vivo
, antibody-mediated IL1B neutralization improved cardiac function and tissue fibrosis in heart failure. Mechanistically, systemic IL1B inhibition or targeted
Il1b
deletion in
Cx3cr1
-positive cells prevented stress-induced expression of
MEOX1
and inhibited fibroblast activation. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides mechanistic insights into how inflammation drives profibrotic cell states and presents new therapeutic strategies for heart disease and other chronic inflammatory disorders featuring maladaptive tissue remodeling.
Abstract 4141687: Optimal Duration of Ambulatory Monitoring for Detecting Non-Sustained Ventricular Tachycardia (NSVT) in Pediatric and Adult Congenital Heart Disease Patients
Authors: El Assaad Iqbal , Dakik Lama , E'mar Abdel Rahman , Heilbronner Alison , Aziz Peter , Patel Akash
Published: November 2024

Background:
The frequency and clinical significance of non-sustained ventricular tachycardia (NSVT) detected on ambulatory monitors in pediatric and congenital heart disease (CHD) patients has not been thoroughly investigated. We sought to examine the prevalence of NSVT, analyze the presence of associated cardiovascular disease, and describe changes in management.

Methods:
We performed a retrospective cohort study of all patients evaluated in cardiology clinic at Cleveland Clinic who were found to have NSVT on ambulatory Zio monitors (2017 and 2023). Kaplan Meier curves and Cox proportional hazards model were performed to analyze time to NSVT detection and factors associated with detection.

Results:
Among 2805 patients, 172 (mean age 29 ± 14, 51% male) had NSVT yielding a prevalence of 6% and a mean monitoring duration of 7.5 ± 5.5 days. Cardiac diagnoses were as follows: 98 (57 %) CHD, 44 (26%) structurally normal hearts, 14 (8%) cardiomyopathy, 10 (6%) connective tissue disorder, and 6 (3%) channelopathy. Monitoring indications included symptoms (97, 56%), history of arrhythmias (34, 20%), screening (36, 21%) and others (5, 3%). Mean day of NSVT detection was 4.3 ± 3.7 years without significant difference amongst the various underlying cardiac diagnoses (p = 0.2). Of the patients who had a repeat ambulatory monitor, 39/113 (34%) were found to have NSVT. Management changes were made in 56 (32%) patients: medication change in 46, EP study in 1, implantable loop recorder placement in 4, and ICD placement in 5. Five patients died during the study period with only 1 suspected sudden cardiac death. The likelihood of NSVT detection increased with longer monitoring duration with only 55% of cases detected at 2 days (Figure 1). In a multivariable model, monitoring duration (HR 0.8, 95% CI: 0.77-0.84, p < 0.001) but not underlying diagnosis, age, monitor indication, or single ventricle status, was associated with likelihood of NSVT detection.

Conclusions:
NSVT is not an uncommon arrhythmia in pediatric and CHD patients with increasing prevalence with longer monitoring duration regardless of underlying cardiac etiology. Although medical management changes based on monitor findings were frequent, sudden death was rare.
Abstract 4141690: Bisphosphonate therapy improves bone deficits but worsens arterial calcification in
Mgp
-null mice
Authors: Soheili Fariborz , Heydarikhorneh Niloufar , Rotstein Benjamin , Chen Hsiao-huei , Stewart Alexandre
Published: November 2024

Background:
Arterial calcification often occurs with bone mineral loss in osteoporosis, for which bisphosphonates are a standard therapy. Mice lacking the matrix GLA protein (Mgp) exhibit lethal arterial calcification and cranial bone formation deficits causing dental malocclusion. Mgp not only binds to hydroxyapatite but also inhibits the bone morphogenic protein activation of Runx2 transcription factor, which drives the osteogenic conversion of arterial smooth muscle cells (SMCs). Prior studies showed bisphosphate therapy ameliorates warfarin-induced arterial calcification in rats. This study investigated whether bisphosphonate (Alendronate,ALN) treatment could address bone deficits and arterial calcification in Mgp-null mice.

Methods:
Mgp-null mice were subjected to various doses of Alendronate therapy starting at weaning or postnatal day 3. Dental malocclusion severity was assessed by incisor trimming frequency. Arterial calcification was quantified by Alizarin red staining and µ-CT.

Results:
In Mgp-null mice, susceptibility to aortic artery calcification was not uniform but varied by location, with calcification highest at the proximal aorta. Of note, recurring nodes of calcification were found to correspond to branch points of vertebral arteries, with internodal regions showing less calcification. Alendronate therapy started at 3 weeks of age ameliorated dental malocclusion in Mgp-null mice of both sexes and improved but did not normalize body weight gain in males and females. However, no improvement in arterial calcification was observed at 7 weeks. Similarly, Alendronate therapy at lower doses from postnatal day 3 for 5 weeks ameliorated dental malocclusion and improved but did not normalize body weight gain in both sexes, while at higher doses, Alendronate prevented incisor development and caused growth retardation in both wild type and Mgp-null mice. However, Alendronate accelerated the appearance of Runx2 in SMCs of the aorta and worsened internodal arterial calcification in Mgp-null mice in a dose-dependent fashion, but not in Mgp-hemizygous or wild type mice.

Conclusion:
Our study reveals an important dichotomy in Mgp's function in bone and arteries. The bone deficits in Mgp-null mice, highlighted by incisor malocclusion, could be rescued by bisphosphonate treatment, whereas the arterial calcification could not. Thus, Mgp performs an essential function to prevent arterial calcification that cannot be restored by bisphosphonate therapy.
Abstract 4141693: EPA/DHA Supplementation Modulates Monocyte Subpopulations in a 15-Lipoxygenase-dependent Fashion
Authors: Zeng Haihan , Alcaide Pilar , Rowan Sheldon , Lamon-Fava Stefania
Published: November 2024

Background:
Atherosclerosis is a chronic inflammatory disease driven by the defective resolution of inflammation. Alterations in monocyte/macrophage subtypes in the atherosclerotic plaque, particularly a shift towards inflammatory subtypes, contribute to chronic inflammation and the progression of atherosclerosis. Previous studies have documented a protective effect of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on atherosclerosis, but the specific impact of specialized pro-resolving lipid mediators (SPMs) derived from EPA and DHA on modulating monocyte populations remains unclear.

Hypothesis:
We tested the hypothesis that EPA/DHA supplementation would alter the monocyte landscape toward a pro-resolving phenotype in LDL receptor knockout (

Ldlr
-/-

) atheroprone mice, and that this effect would be blunted by the deletion of the 15-lipoxygenase gene (
15Lox
), which is responsible for the synthesis of most SPMs.

Methods:

Ldlr
-/-
/15Lox
+/+

single knockout (SKO, n=48) and

Ldlr
-/-
/15Lox
-/-

double knockout (DKO, n=48) male and female mice were randomized to four diet groups (n=12/group): 1) low-fat diet (LFD, 4% fat and 0.02% cholesterol); 2) LFD + 1% EPA/DHA (w/w); 3) high-fat diet (HFD, 20% fat and 0.2% cholesterol); and 4) HFD + 1% EPA/DHA (w/w). The diet interventions lasted for 16 weeks. At the end of the study, mice were euthanized, fresh splenocytes were harvested, and flow cytometry was performed using the markers CD11b, Ly6G, and Ly6C to profile pro-inflammatory and pro-resolution monocytes.

Results:
EPA/DHA supplementation did not affect the spleen monocyte landscape in either SKO or DKO mice fed the LFD. However, in SKO mice fed the HFD, the proportion of pro-inflammatory monocytes (CD11b
+
Ly6C
hi
) was significantly lower in the EPA/DHA supplementation group (19±6% versus 12±7%, mean±SD,
p=0.03
), with a trend toward higher resolving monocytes (CD11b
+
Ly6C
low
, 80±6% versus 87±7%;
p=0.12
). Strikingly, EPA/DHA supplementation did not significantly change pro-inflammatory monocytes (14±5% versus 13±6%,
p=0.84)
or resolving monocytes (85±5% versus 86±6%,
p=0.95
) in DKO mice fed the HFD.

Conclusions:
Our results suggest that EPA/DHA supplementation exerts immune modulatory effects that are dependent on the expression of
15Lox
. Ongoing work is focused on assessing the impact of these effects on atherosclerosis plaque burden.
Abstract 4141701: Legacy Effects of Supervised Exercise Training on Body Composition and Cardiorespiratory Fitness in STRRIDE-Prediabetes
Authors: Ross Leanna , Sudnick Alyssa , Collins Katherine , Counts Julie , Huffman Kim , Kraus William
Published: November 2024

Background:
While exercise training elicits substantial health benefits, too few individuals adopt exercise as a health maintenance strategy. Thus, determining if a relatively modest duration of exercise training can lead to sustained benefits years later (legacy effects) is clinically important. The STRRIDE I Reunion revealed legacy effects for cardiorespiratory fitness (CRF) and cardiometabolic risk factors 10 years after exercise intervention. In an older cohort at greater risk of disease development, the STRRIDE-PD Reunion study aims to determine whether prior exercise training–with or without weight loss–elicits legacy health effects.

Hypotheses:
Those who completed vigorous intensity training will have maintained CRF to the greatest extent, while those who completed a high amount of training will have maintained body composition to the greatest extent.

Methods:
In STRRIDE-PD, sedentary adults (45-75 y) with prediabetes and overweight/obesity were randomized to one of four 6-month aerobic training groups: 1) low amount/moderate intensity (LM); 2) high amount/moderate intensity (HM); 3) high amount/vigorous intensity (HV); or 4) LM plus diet/weight loss (LMD). Waist circumference (WC), body composition via BODPOD, and CRF (relative peak VO
2
) were measured at baseline, post-intervention, and Reunion (10 y). Change scores were calculated as Reunion value minus baseline. Two-tailed
t
-tests determined within-group significance (p<0.05). ANCOVA with baseline values assessed among-group effects.

Results:
Seventy-three participants (71.3±7.2 y; 64% women; 78% White) returned for the STRRIDE-PD Reunion study. Compared to baseline, all groups either maintained (HM and LMD) or significantly reduced (HV and LM) WC and total body mass. LM, LMD, and HV experienced significant reductions in fat free mass. All groups showed a significant decrease in CRF, ranging from ~10% (LM, LMD, and HV) to 16% (HM). Magnitudes of change were not different among groups.

Conclusion:
All groups exhibited legacy effects for WC, fat mass, and body mass. Although LM and HV significantly reduced WC and body mass compared to baseline, these changes were coupled with fat free mass reductions. Contrary to STRRIDE I, vigorous intensity participants did not maintain CRF to a greater extent than moderate intensity. These STRRIDE-PD specific findings may indicate aging-related skeletal muscle loss and an accelerated CRF decline for older individuals at increased risk for cardiometabolic disease.
Abstract 4141705: Volume of Physical Activity and Coronary Artery Calcium - ELSA-Brasil Cohort Analysis
Authors: Correa Fabiano Ronaldo , Generoso Giuliano , Staniak Henrique , Foppa Murilo , Lotufo Paulo , Bensenor Isabela , Bittencourt Marcio
Published: November 2024

Introduction:
Current guidelines recommend 500-1000 metabolic equivalent minutes per week (METs-min/wk) of physical activity (PA) to reduce cardiovascular (CVD) risk. Interestingly, studies (DeFina 2019, Aengevaeren 2017) have found an association between high PA and subclinical coronary artery atherosclerosis (CAD) cross-sectionally by coronary artery calcium score (CAC). However, Shuval et al (2024) did not find this association. We aim to investigate the association between PA and CAC in the ELSA-Brasil cohort.

Methods:
We analyzed cross-sectionally data of 2711 asymptomatic statin-free individuals without prior CVD or inflammatory disease from the ELSA-Brasil cohort. PA and CAC were examined by unadjusted and adjusted (age, sex, race) regression. PA and CAC were used as both continuous (log-transformation) and categorical variables to evaluate the results' robustness. For visual illustration, raw data, unadjusted, and adjusted regressions were plotted.

Results:
The mean age was 50±8, 53% (1433/2711) were female, 15% (387/2577) and 61% (1573/2577) were black and white, respectively. CAC = 0, CAC 1 – 100, and greater than 100 in

2001/2711 (73.8%), 485/2711 (17.9%), and 225/2711 (8.3%), respectively. PA (METs-min/wk) 0 – 500, 500 – 1000, and higher than 1000 in 66.3% (1797/2711), 13.8% (367/2711), and 16.2% (441/2711), respectively. In unadjusted regression (similar using categorical or continuous both CAC and PD), PA was associated with CAC (OR = 1.06, 95% CI: 1.02-1.10, p=0.005) but this association was not found when adjusted to age, sex, and race (table, graphic).

Conclusions:
A high volume of physical activity was not associated with CAC after adjustment for age, sex, and race in relatively young asymptomatic statin-free individuals from the ELSA-Brasil cohort without prior CVD.
Abstract 4141726: Ceramides produced by gut bacteria
Bacteroides thetaiotaomicron
causally induce aortic perivascular adipose tissue-endothelial cell senescence in aged host
Authors: Shabanian Khatereh , Pugin Benoit , Constancias Florentin , Shabanian Taraneh , Gergely Karsai , Menni Cristina , Hornemann Thorsten , Hermann Matthias , Paneni Francesco , RUSCHITZKA FRANK , Saeedi Soheil
Published: November 2024

Introduction:
Specific ceramides play a crucial role in cellular senescence by upregulating the SASP in the vasculature, leading to atherosclerosis in the aging population. Gut microbiota is emerging as a regulator of circulating ceramides in the host. However, it remains unknown what/how gut bacteria causally regulate ceramide-induced perivascular adipose tissue (PVAT) and endothelial cell (EC) senescence in aging.

Methods:
To address the knowledge gap in gut-derived ceramides and their regulation of (peri)vascular aging, we performed high-throughput multi-omics (fecal shotgun metagenomics and plasma LC-MS/MS lipidomics) coupled with bacterial colonization, senescence, and cell-cell interaction studies.

Results:
Our metagenomic and plasma lipidomic studies on human (TwinsUK Aging Cohort, n=900; Aging Heart Zurich Cohort, n>800) and mouse (>24
vs.
3 months, n=6) aging cohorts pinpointed a higher abundance of

Bacteroides thetaiotaomicron (B. theta)

harboring the serine palmitoyltransferase (
SPT
) gene, synthesizing deleterious ceramides C18:1/16:0 and C18:1/18:0 in old hosts. Importantly, plasma levels of the ceramides were positively associated with major adverse cardiovascular events (MACE) in atherosclerotic CVD patients within the Aging Heart Zurich Cohort (n=105).

In vivo
colonization of young mice with
B. theta
(4-weeks) confirmed a marked increase in circulating Cer 18:1/16:0 and 18:1/18:0, accompanied by higher signals of the SASP component IL6 and the proliferative arrest marker p16
INK4a
in aortic PVAT and ECs. These mice also exhibited reduced vasorelaxation responses and angiogenic incompetence.

As a proof of concept, our PVAT-EC co-culture studies demonstrated that addition of the ceramides induces senescence and dysfunction in PVAT by upregulating Notch1 signaling. This upregulation increases IL1β and its downstream IL6, leading to the downregulation of adipocyte function markers UCP1 and adiponectin. The released IL6 also induced a senescence phenotype in ECs, evidenced by increased SA-β-gal activity, DNA damage response (↑ γ-H2A.X), telomere attrition (↓ hTERT), and proliferative arrest (↑ p16
INK4a
&p19
INK4d
).

Conclusion:
This research identifies
B. theta
as a causal contributor to deleterious ceramides in the host circulation, leading to (peri)vascular senescence and dysfunction in aging. Targeting
B. theta
offers a novel microbiome-based approach to decelerate (peri)vascular senescence and extend healthspan, with potential clinical applications.
Abstract 4141732: Small Left Ventricular Chamber Size and Mortality in a General Population
Authors: Leibowitz David , Zwas Donna , Amir Offer , Gotsman Israel
Published: November 2024

Background:
Enlargement of the left ventricle (LV) is well recognized as an important marker of adverse cardiac remodeling and poor prognosis in the setting of known cardiovascular disease as well as in general populations. Previous studies demonstrated increased cardiovascular risk in small subsets of patients with small LV chamber size, however, the prognostic implications of small chamber size in a general population remains unclear. The objective of this study was to examine the prognosis of a small LV chamber in a large cohort of patients undergoing echocardiography.

Methods:
All consecutive subjects that underwent echocardiography examinations recorded in the echocardiography database of a university-affiliated laboratory from 2011 to 2023 were retrieved for analysis. Small chamber size was defined as end-diastolic diameter less than 42 mm for men and 37.8 mm for women as per ASE guidelines. The primary endpoint for the study was all-cause mortality.

Results:
46,529 subjects (mean age 60 ± 19 yrs, 56% males) were included in the study of whom 3,787 had small LV chamber size. Clinical variables associated with small chamber included increasing age and lower BSA. Echocardiographic variables included higher relative wall thickness, and E:e' . On multivariate analysis, the presence of a small LV was significantly associated with mortality (HR 1.43 with 95% CI 1.33-1.54; p <0.001). This finding was significant in both older (over 65) (HR 1.30 95% CI 1.19-1.41; p <0.001) and younger (HR 2.09 95% CI 1.81-2.41; p <0.001) subjects and in both males and females.

Conclusions:
In this retrospective large cohort study, small LV chamber size was significantly associated with mortality in a broad range of patients. Further study is necessary to elucidate the mechanisms for this finding.
Abstract 4141742: HFpEF with resting LVEF >60% exhibit a distinct exercise response and circulating proteome to HFpEF with LVEF <60%
Authors: Xavier Roshan , Ng Sher May , Pan Jiliu , Miller Jack , Mozes Ferenc , Valkovic Ladislav , Rayner Jennifer , Fronheiser Matthew , Rigolli Marzia , Neubauer Stefan , Rider Oliver , Lewis Andrew
Published: November 2024

Introduction:
Heterogeneity in heart failure with preserved ejection fraction (HFpEF) is an important challenge for the development of new medicines for this disease. Clinical trials of SGLT-2 inhibitors and renin-angiotensin inhibition have demonstrated reduced efficacy in patients with higher LVEF. With the advent of myosin modulation, there is renewed focus on those with LVEF >60% as a group that could benefit.

Hypothesis:
Patients with HFpEF and LVEF >60% will have impaired cardiac response to exercise stress and reduced functional capacity compared to HFpEF with LVEF <60% with a distinct circulating proteome.

Methods:
Patients with HFpEF (n=64, mean age 76.6± 5.5) and age-matched controls (n=16, mean age 71.9 ± 6.2) were prospectively enrolled. Assessment of cardiac volumes, function and stress response was performed using real-time cardiovascular magnetic resonance imaging at rest and sub-maximal exercise (35W for 6 minutes). Plasma samples were acquired immediately after exercise for aptamer-based proteomics to detect 7000 circulating proteins. Pathway enrichment analysis of the proteome was performed to compare both HFpEF groups to controls.

Results:
HFpEF patients with high LVEF (> 60%, n=46) had smaller left ventricular volumes (LVEDVi 64.8 ± 14.7 vs 93.6 ± 17.1 ml/m
2
, p<0.001) compared to HFpEF patients with lower LVEF (50-60%, n=18). During exercise, HFpEF patients with high LVEF had attenuated systolic augmentation (LVEF +3.1 ± 4.9 vs +5.5 ± 3.6 %, p=0.03), lower cardiac index (4.5 ± 1.1 vs 5.2 ± 1.3 L/min/m
2
, p=0.06) and lower 6-minute walk distance (348 ± 95 vs 401 ± 76m, p=0.03). When compared to controls, HFpEF patients with high LVEF had a distinct plasma proteomic signature, characterized by altered lipid metabolism pathways whereas those with lower LVEF had perturbed extracellular matrix organisation and inflammatory pathways.

Conclusions:
Patients with HFpEF and LVEF >60% have greater functional impairment, smaller LV cavities, blunted systolic augmentation to exercise and a circulating proteome characterised by altered lipid metabolism pathways. These findings support stratified approaches to this group in future clinical trials and identify potential novel biomarkers to assess treatment response.