bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4132149: Elevated Levels of Plasma Mitochondrial DNA Damage-Associated Molecular Patterns (DAMPS) in Humans and Dogs with Heart Failure and Reduced Ejection Fraction
Authors: Sabbah Hani , Gupta Ramesh , Szekely Kristina , Kalabat Sean , Lanfear David
Published: November 2024

Background:
Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with increased inflammatory response that contributes to progressive worsening of the HF state. Potential endogenous triggers of this process include damage-associated molecular patterns (DAMPs). DAMPs originate from within cells following tissue stress or injury and activate pattern recognition receptors of the immune system, triggering an inflammatory response. Mitochondria are the major cell organelles that release DAMPs into the circulation. Chronic HF is associated with multi-organ mitochondrial dysfunction and cell injury and death.

Purpose:
The present study sought to quantify differences in mitochondrial DNA (mtDNA) DAMPs in the setting of HFrEF in humans and dogs compared to normal humans and dogs.

Methods:
Plasma samples were obtained from 9 HFrEF patients with left ventricular ejection fraction (LVEF) ≤35% and 9 age-matched healthy subjects, and from 6 dogs with coronary microembolization-induced HF (LVEF ≤35%) and 6 normal dogs. DNA fragments were isolated from 1 ml of plasma using a commercially available kit. Quantitative PCR and specifically designed primers were used to measure the amount of DNA in plasma from
COX1
(cytochrome c oxidase subunit 1),
ND1
(NADH dehydrogenase subunit 1) and
ND6
(NADH dehydrogenase subunit 6) using an Applied Biosystems 7500 Fast-PCR unit. The relative abundances of plasma mtDNA DAMPs were expressed as threshold cycles (C
T
).

Results:
Compared to normal human subjects, mtDNA DAMPs levels of
COX1
,
ND1
and
ND6
in plasma of HFrEF patients was 4-fold, 9-fold and 8-fold greater, respectively. Similarly, compared to normal dogs, mtDNA DAMPs levels of
COX1
,
ND1
and
ND6
in plasma of HFrEF dogs was increased 48-fold, 12-fold and 4-fold, respectively.

Conclusions:
These findings indicate a marked increase of mtDNA DAMPs in plasma of humans and dogs with HFrEF. The increase of mtDNA DAMPs is consistent with the elevated systemic inflammatory state of HFrEF. The results underscore mitochondrial abnormalities as integral players in the progressive worsening of HFrEF.
Abstract 4132249: Preoperative identification of respiratory viral genomes in the trachea but not in the nasopharynx is a risk factor for postoperative pulmonary hypertension in patients with congenital cardiac communications
Authors: ABUD KELLY CRISTINA DE OLIVEIRA , Vilas Boas Lucy , Maeda Nair , Souza Maria , Carvalho Eloisa , Lopes Antonio
Published: November 2024

Introduction:
Pulmonary vascular remodeling is a key determinant of outcomes in patients undergoing surgery for congenital cardiac communications (CCCs). Respiratory epithelial cells infected by viruses express cytokines and growth factors with potential impact on airway and vascular remodeling.

Hypothesis:
Preoperative exposure to respiratory viruses renders CCC patients susceptible to postoperative pulmonary hypertension.

Aims:
To investigate if asymptomatic patients carrying respiratory viral genomes (RVGs) in the airways are at risk for pulmonary hypertension following cardiac surgery. To analyze the role of postoperative inflammatory reaction.

Methods:
The study comprised patients with unrestrictive CCCs undergoing surgery under cardiopulmonary bypass (CPB). In the absence of any signs of recent infection, RVGs were searched for in nasopharyngeal aspirates 2-3 days before surgery, and in tracheal aspirates collected in the operating room (RT-PCR, panel for 19 viruses). Serum levels of 36 inflammatory proteins were measured by chemiluminescence preoperatively and 4 hours post CPB. Pulmonary/systemic mean arterial pressure ratio (PAP/SAP) computed during the first 12 hours postoperatively (invasive assessment) was defined as the study outcome. A cutoff level was set at 0.40.

Results:
Sixty patients were enrolled (age 11 [7-16] months, median with interquartile range). Preoperative PAP/SAP was 0.78 (0.63-0.88). RVGs were present in nasopharyngeal and tracheal aspirates in 64% and 38% of patients, respectively. The presence of RVGs in tracheal aspirates was associated with an upward shift of postoperative PAP/SAP curve (p=0.006). The same was not observed for positive tests in nasopharyngeal aspirates (p=0.343). Of all factors analyzed as possible predictors of postoperative PAP/SAP >0.40, only preoperative peripheral oxygen saturation and the presence of RVGs in the trachea were selected at multivariate analysis (respective OR with 95% CI, 0.40 [0.23-0.72] and 4.42 [1.17-16.78]. Heightened post-CPB levels of interleukin-1 receptor antagonist and chemokines MIF and MCP-1 were found to increase the risk of having a PAP/SAP >0.40 in RVG carriers (respective OR with 95% CI, 2.04 [1.09-3.81], 2.34 [1.15-4.74] and 2.18 [1.07-4.43].

Conclusion:
The observed relation of postoperative hemodynamics to respiratory viruses and post-CPB inflammatory reaction may have pathophysiological and therapeutic implications in pulmonary hypertension associated with congenital heart disease.
Abstract 4132341: Systematic Examination of the AHA PREVENT Equations
Authors: Krishnan Vaishnavi , Huang Xiaoning , Ndumele Chiadi , Rangaswami Janani , Coresh Josef , Perak Amanda , Shah Nilay , Lloyd-Jones Donald , Khan Sadiya
Published: November 2024

Background:
The novel AHA Predicting Risk of CVD Events (PREVENT) equations newly incorporate predictors (estimated glomerular filtration rate [eGFR]) and outcomes (heart failure [HF]) relevant to the novel construct of cardiovascular-kidney-metabolic (CKM) syndrome.

Aims:
We sought to characterize the intrinsic properties of the PREVENT equations by simulating different risk profiles across the age and CKM risk spectrum.

Methods:
We applied the PREVENT base equations to estimate 10-year predicted risk for total CVD, which includes atherosclerotic CVD and HF. First, we calculated risk estimates for a hypothetical individual varying age from 30-79 years with an average risk factor profile (mean population risk factor levels based on National Health and Nutrition Examination Survey 2011-2020 data without diabetes, not on anti-hypertensive or statin medication, and who does not smoke). Second, we examined at which age a hypothetical individual would exceed the previously defined intermediate risk threshold ≥7.5% established by national guidelines. Lastly, we examined the differences in predicted risk with or without diabetes and/or Stage 3 CKD (defined as eGFR 44.5 mL/min/1.73m
2
).

Results:
For hypothetical individuals aged 30-79 years with average risk factor levels, predicted 10-year CVD risk is shown in the figure for females (Panel A) and males (Panel B). The predicted risk would exceed the intermediate risk threshold at age 68 years if female and 63 years if male. If the individual had Stage 3 CKD, the predicted risk would exceed the intermediate risk threshold at 60 if female and 55 years if male. If the individual had diabetes, the predicted risk would exceed the intermediate risk threshold at 59 if female and 52 years if male. If both diabetes and Stage 3 CKD were present, the predicted risk would exceed the intermediate risk threshold at age 42 years if female and 35 years if male.

Conclusions:
The PREVENT equations enable more granular differentiation of risk among individuals with varying CKM profiles. Understanding risk estimates across the spectrum of age and CKM can support interpretability among clinicians and patients.
Abstract 4132351: Soluble Urokinase Plasminogen Activator Receptor Levels Predict Incident Cardio-Kidney-Metabolic Disease Risk
Authors: Yadalam Adithya , Liu Chang , Sun Yan , Quyyumi Arshed
Published: November 2024

Introduction:
Given the rising global incidence of cardio-kidney-metabolic (CKM) syndrome, there is an urgent need for novel risk prediction strategies for CKM disease.

Hypothesis:
As soluble urokinase plasminogen activator receptor (suPAR) levels have been associated with the development of cardio-kidney disease, we hypothesized that elevated suPAR levels would predict incident CKM disease risk.

Methods:
A total of 25,596 UK Biobank participants without CKM disease at enrollment were analyzed for the association of suPAR levels and incident CKM disease. CKM disease was defined as the first occurrence of CVD (heart failure, atrial fibrillation/flutter, coronary heart disease, stroke, and peripheral artery disease), chronic kidney disease (CKD), or metabolic disease (type 2 diabetes mellitus and obesity). Incident CVD, CKD, and metabolic disease were also analyzed separately as secondary outcomes. Kaplan-Meier analysis was performed to visualize the association between suPAR levels and the primary composite CKM outcome. Competing-risk regression, while accounting for competing non-CKM disease death, was performed to examine the association between suPAR levels and the primary composite CKM outcome. Models were adjusted for demographics, traditional risk factors, and CRP levels.

Results:
The mean age was 56.0 (SD 8.3) years, 44% were male, and 94% were White. suPAR levels were associated with a significantly higher rate of composite CKM events (P<0.001) (Figure 1). During a median follow-up of 13.5 [IQR 1.7] years, 5,012 (20.0%) composite CKM events, 3,599 (8.3%) incident CVD events, 863 (3.4%) incident CKD events, and 1,397 (4.7%) incident metabolic disease events occurred. suPAR levels (per SD) significantly predicted the primary composite CKM outcome (sHR 1.23, 95% CI 1.19-1.27) after adjustment. suPAR levels (per SD) also significantly predicted incident CVD (sHR 1.24, 95% CI 1.19-1.29), incident CKD (sHR 1.41, 95% CI 1.30-1.53), and incident metabolic disease (sHR 1.17, 95% CI 1.10-1.24) after adjustment.

Conclusion(s):
In this large, longitudinal cohort study of UKB participants, plasma suPAR levels were a significant predictor of CKM disease risk, independent of demographics, traditional risk factors, and CRP levels.
Abstract 4132657: Age-related Differences in Peak Oxygen Uptake in Patients with Multimorbidity Undergoing Cardiac Rehabilitation
Authors: Gomes Pauline , Miller Sophie , Chacin-Suarez Audry , Olson Thomas
Published: November 2024

Background:
Cardiac rehabilitation (CR) patients demonstrate a high burden of chronic conditions (CC). Both multimorbidity (MM; ≥2 coexisting CC) and aging negatively impact functional capacity, whereas CR improves performance. Age-related difference in cardiorespiratory fitness (CRF, peak oxygen uptake (VO
2
)) in CR patients with MM has not been studied.

Hypothesis:
We hypothesized improvement in CRF will be attenuated by MM with increasing age in CR patients.

Aims:
We aimed to identify age-related differences in CRF improvement in CR patients with MM.

Methods:
Patients ≥18 yrs old who attended ≥1 CR sessions from 1999-2017 and completed cardiopulmonary exercise stress test before and after CR were included. The prevalence of CC was assessed using Rochester Epidemiology Project records-linkage system. Age categories included: Younger (18-49 yrs), Midlife (50-64 yrs) and Older (≥65 yrs). CRF categories included: <0%, 0-8% and >8%. Analysis included Kruskal-Wallis and Chi-squared.

Results:
Of 622 patients, 75.4% were male. Mean age: 62.9±11.2 yrs; Younger (n=70) age: 42.7±6.8 yrs, 67.1% male; Midlife (n=283) age: 58.3±4.3 yrs, 78.8% male; Older (n=269) age: 73.0±5.2 yrs, 74.0% male. BMI was 29.9±5.4 kg/m
2
(Younger: 30.0±6.7, Midlife: 30.4±5.6, Older: 29.3±4.7; p<.05). Median (Q1, Q3) no. of CR sessions attended was 33(22, 35), with lower attendance in the Younger group: 25(16,34) vs Midlife: 33(20,35) and Older: 34 (29,35), p<.05. Overall, percent change in peak VO
2
was 11.5±21.6% (Younger: 18.8±22.8%, Midlife: 11.6±19.5%, Older: 9.4±23.1%; p<.01). The median number of CC was 7(5,8) with significant differences across groups: Younger: 5(3,7), Midlife: 6(5,8), Older: 7(6,9), p<.01. Number of CC increased with age across all CRF categories (p<.01, Fig. 1). However, there was no difference in number of CC within age groups across categories of CRF, Table 1.

Conclusions:
Our results suggest that MM increases with age in patients attending CR; however, within a given age group, improvement in CRF does not appear dependent on MM. The impact of age appears to have a greater impact than MM on CRF improvement. Individualized treatment plans should focus on the impact of age-related disparities on CRF improvement among CR patients with MM.
Abstract 4132742: Fractional flow reserve guided complete revascularization versus Culprit-only percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction and multivessel coronary artery disease. A meta-analysis of randomized controlled trials
Authors: OBI OGECHUKWU
Published: November 2024

Background:
Data comparing the efficacy and safety of fractional flow reserve (FFR)-guided complete revascularization (CR) to culprit-only percutaneous coronary artery intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease are limited.

Method:
Pubmed, Embase and Cochrane were searched for randomized controlled trails (RCTs) comparing FFR-guided CR to Culprit-only PCI in patients with STEMI and multivessel CAD. A meta-analysis was performed on primary outcomes of major adverse cardiac events (MACE) and all-cause mortality. Heterogeneity was examined with I
2
statistics. A random-effects model was used for outcomes with high heterogeneity.

Results:
We included 4 RCTs with 3173 patients comparing FFR-guided CR with culprit-only PCI in patients with STEMI and multivessel coronary artery diseases. The pooled results of the 4 RCTs showed that MACE (RR=0.66; 95% CI [0.45, 0.99]; p=0.01; 16.8% vs 24.1%), PCI revascularization (RR=0.50; 95% CI [0.37, 0.67]; p<0.00001; 13.1% vs 24.9%) and unplanned revascularization (RR=0.66; 95% CI [0.44, 0.99]; p=0.04; 8.7% vs 12.9%) were significantly reduced in the FFR-guided complete revascularization group compared to culprit-only PCI group.

However, all-cause mortality (RR=1.09; 95% CI [0.84, 1.42]; p=0.53; 7.2% vs 6.0%), stroke (RR=1.02; 95% CI [0.38, 2.75]; p =0.97; 2.0% vs 1.8%), major bleeding (RR=0.95; 95% CI [0.54, 1.67]; p=0.87; 1.7% vs 1.7%), death from cardiovascular causes (RR=0.82; 95% CI [0.55, 1.21]; p=0.31; 3.1% vs 3.4%), MI (RR=1.09; 95% CI [0.60, 1.95]; p=0.78; 6.7% vs 6.4%), rehospitalization for HF (RR=0.72; 95% CI [0.44, 1.15]; p=0.17; 3.4% vs 5.3%), death from any cause or MI (RR=1.02; 95% CI [0.61, 1.71]; p=0.95; 14.9% vs 13.6%), any stent thrombosis (RR=1.42; 95% CI [0.35, 5.72]; p=0.62; 2.2% vs 1.4%), contrast induced nephropathy (RR=0.25; 95% CI [0.02, 2.79]; p=0.26), and CABG revascularization (RR=1.25; 95% CI [0.30, 5.15]; p=0.76) were not statistically different between groups.

Conclusion:
Our meta-analysis suggests that FFR-guided CR is safe and has superior efficacy to Culprit-only PCI in patients with ST-segment elevation myocardial infarction and multivessel coronary artery disease with significantly lowered incidence of MACE, PCI revascularization as well as unplanned or urgent revascularization. However, FFR-guided CR showed no beneficial effect on all-cause mortality, stroke, major bleeding and myocardial infarction.
Abstract 4132752: The immune checkpoint landscape in human atherosclerosis: influence of lipid lowering and type 2 diabetes
Authors: Barcia Duran Jose Gabriel , Das Dayasagar , Gildea Michael , Amadori Letizia , Gourvest Morgane , Kaur Ravneet , Eberhardt Natalia , Smyrnis Panagiotis , Cilhoroz Burak , sajja swathy , Rahman Karishma , Fernandez Dawn , Faries Peter , Narula Navneet , Vanguri Rami , Goldberg Ira , Fisher Edward , Berger Jeffrey , Moore Kathryn , Giannarelli Chiara
Published: November 2024

Immune checkpoint inhibitor (ICI) therapies substantially increase the risk of atherosclerotic cardiovascular events in cancer survivors. Here, we mapped the expression of immune checkpoints (ICs) within human atherosclerotic plaques, unraveling an intricate local network of immune cell-cell interactions in the context of relevant comorbidities like dyslipidemia and diabetes. Our findings identified a population of mature, regulatory
CCR7
+
FSCN1
+
dendritic cells as pivotal orchestrators of IC-mediated signaling within human and murine plaques, a function akin to their role in tumor environments. In clinical cohorts, type 2 diabetes diminished
CCR7
+
FSCN1
+
dendritic cells within atherosclerotic plaques and dampened interactions steered by PD-1 or CTLA4 consistently across immune cell subpopulations. This effect was also present and further decreased by lipid lowering in the circulation, where CD86–CTLA4 was among the most prominent IC pairs signaling between regulatory T cells and myeloid populations including
CCR7
+
FSCN1
+
dendritic cells. These findings underline the vulnerability of atherosclerotic plaques to cancer immunotherapies and underscore the critical impact of cardiometabolic disease and lipid-lowering strategies on the atherosclerotic IC landscape, offering a framework toward the reshaping of clinical approaches.
Abstract 4132875: Living Address Environmental Biotope Affects the Risk of Coronary Obstruction and Myocardial Ischemia Detected by Coronary Computed Tomography
Authors: De Potter Tom , Motoc Andreea , Verachtert Els , Koppen Gudrun , Hooyberghs Hans , Tanaka Kaoru , Belsack Dries , fierens frans , Tsugu Toshimitsu , Nawrot Tim , CLAEYS Marc , Cosyns Bernard , Argacha François
Published: November 2024

Background:
Several studies reported positive associations between air and noise pollution exposure and coronary artery calcification, but environmental effects on coronary obstruction and flow remain largely unknown.

Hypothesis:
Distance to road and airport, air pollution, and residential green space are linked to coronary artery obstruction and myocardial ischemia. Low CV-risk patients develop coronary obstruction due to environmental factors, while high-risk patients are more prone to develop myocardial ischemia.

Methods:
Consecutive patients screened by coronary CT angiography for stable chest pain between 01/01/2019 and 31/12/2020 were included in a registry. Distance to airport and major road, and exposure to PM2.5, NO
2
and normalized difference vegetation index (NDVI) were modelled at patients’ living address. Risk of obstructive coronary artery disease (OCAD, stenosis ≥50%) and abnormal fractional flow reserve (FFR
CT
<80%) was assessed using propensity score (PS)-adjusted logistic regression. Subgroup analysis was performed according to gender and Framingham CV-risk categories.

Results:
We enrolled 2620 patients, including 420 (16%) FFR
CT
analyses. OCAD was reported in 518 (20%) patients and abnormal FFR
CT
in 276 (11%). People with OCAD lived closer to the airport (10.841 [7.869-19.022] km vs. 12.297 [8.691-22.843] km, p<0.001). Distance to airport decreased OCAD risk (OR 0.983, 95%CI 0.974-0.992, per 1 km) in univariate analysis, with the association present in male, female, and low-risk patients. After PS-adjustment, a trend of association was present between airport distance and abnormal FFR
CT
risk (OR 0.986, 95%CI 0.969-1.003, per 1 km). Road distance tended to decrease OCAD risk in univariate and PS-adjusted analysis, in the general (OR 0.928, 95%CI 0.808-1.309; and OR 0.928, 95%CI 0.840-1.021, per 1 km) and high-risk population. NO
2
exposure tended to increase OCAD risk in univariate analysis (OR 1.012, 95%CI 0.997-1.027, per 1 µg/m
3
), with the association only present in female patients, and disappearance after PS-adjustment. PM2.5 exposure showed no associations, while NDVI tended to increase OCAD risk in low-risk patients after PS-adjustment.

Conclusion:
Residential distance to airport is the major risk component compared to other urban exposome factors studied in this epidemiological observation. Green space tends to exert a cardioprotective effect in low-risk patients, whereas living close to major road worsens the risk in high-risk patients
Abstract 4132968: CCR5 modulation enhances M-MDSCs functionality in early atherosclerosis
Authors: Sagar Komal , Akhtar Shamima , Roy Ambuj , Hote Milind , Sharma Alpana
Published: November 2024

Background:
The role of immune suppressive microenvironment, promulgated by the presence of Myeloid Derived Suppressor Cells (MDSC) have been the major focus of research delineating the underlying mechanisms of cardiovascular diseases (CVD). CCR5, a chemokine receptor, has been associated with both immunosuppressive and inflammatory phenotypes, however, the possible role of CCR5 pertaining to MDSCs in the development of atherosclerosis has not been elucidated yet. Therefore, we investigated the therapeutic potential of CCR5 modulation in early atherosclerosis progression.

Methods:
CCR5 receptor-ligand expression was studied with flow cytometry, real time PCR and immunocytochemistry in 65 individuals (25 Healthy controls, 20 young hypercholesterolemic individuals, and 20 stable [Coronary Artery Disease] CAD patients). To induce atherosclerosis, mice were fed high fat diet (HFD) for 6 weeks following partial ligation of left carotid artery in C57BL6 mice. MDSCs phenotype and functionality were assessed using CCR5 inhibitor
in vitro
(10
-8
M) and
in vivo
(i.p 3ng/day for 15 days)
.
M-MDSCs phenotype switch, atherosclerotic lesion development and plaque phenotype was studied
in vivo
.

Results:
We observed CCR5 elevation on Monocytic-MDSCs in the early phase of atherosclerosis. M-MDSCs displayed an intermediate phenotype with expression of both pro and anti-inflammatory mediators in early atherosclerosis, a similar trend was observed in inflammatory cytokines stimulated M-MDSCs (
in vitro
). Notably, DAPTA treatment shifted phenotype of M-MDSCs to anti-inflammatory profile with elevated expression of IL-10 and reduced expression of IFNγ, IL4, and IL22. Further, CCR5 modulation expanded IL10+M-MDSC
in vivo
. Additionally, DAPTA reduced the migratory potential, reduced cholesterol uptake and improved the functionality (suppression of T cell) of M-MDSCs. Blocking CCR5 with DAPTA led to the formation of stable plaque in HFD-fed mice.

Conclusion:
Increased expression of CCR5 coupled with inflammatory cytokine secretion by regulatory cells lead to dysfunctional M-MDSCs in CVD risk factor population. Possibly this dysfunctionality contributes to the development and progression of CVD including atherosclerosis. Our findings show targeting of CCR5 with DAPTA reduces atherogenesis, increases plaque stabilization and corrects phenotypic alterations in immune suppressive M-MDSCs. The functionality and phenotype of M-MDSCs in atherosclerosis, may be ameliorated by targeting CCR5.
Abstract 4133122: Integrative Metabolomic Analysis of Triglyceride-Independent Lipoprotein Lipase Pathway Mechanisms for Coronary Artery Disease
Authors: Dron Jacqueline , Xue Liying , Koyama Satoshi , Schuermans Art , Lee Jiwoo , Honigberg Michael , Hornsby Whitney , Peloso Gina , Natarajan Pradeep
Published: November 2024

Background:
Strong genetic evidence supports the associations between key genes in triglyceride (TG) metabolism via the lipoprotein lipase (LPL) pathway (i.e.,
LPL
,
APOC3
, and
ANGPTL3
) and coronary artery disease (CAD). Given sparse human genetic or clinical trial evidence for other TG-modulating pathways, it is unclear if CAD risk reduction is due to reductions in TG levels alone or a secondary mechanism of action.

Aim:
To determine if there are TG-independent mechanisms of CAD risk reduction specific to the LPL pathway using genomics and metabolomics.

Methods:
We assessed the genetic effects of LPL pathway genes (67, 46, and 17 SNPs for
LPL
,
APOC3
, and
ANGPTL3
, respectively) and non-LPL pathway genes (3462 SNPs) for TG levels and 168 metabolites. We identified metabolites with associated effects that were greater than the associated effects with TG levels for LPL pathway genes and showed heterogeneity compared to the effects for non-LPL pathway genes. Cox proportional-hazards models were used to evaluate the association of candidate metabolites measured at baseline with incident CAD in participants of the UK Biobank. Models were adjusted for age, sex, TG levels, BMI, prevalent type 2 diabetes, statin, and ten PCs of genetic ancestry.

Results:
Among 233,719 UK Biobank participants free of prevalent CAD and with metabolite measurements, the mean (SD) age was 57.1 (8.0) years, 105,111 (45.0%) were male, and all self-reported as white. Over a median (IQR) follow-up of 11.2 (10.5-11.9) years, there were 7992 (3.4%) incident CAD cases. There were 30, 6, and 93 metabolites with significantly greater genetic effects for
LPL
,
APOC3
, and
ANGPTL3
than what was observed with TG levels, respectively. Among 20 metabolites with heterogeneity for ≥2 LPL pathway genes compared to non-LPL pathway genes, multi-variable Cox regression revealed 19 significantly associated with CAD (P<3x10
-4
).

Conclusion:
LPL pathway genes have convergent and distinct impacts across metabolites. While
LPL
and
ANGPTL3
have large genetic effects on VLDL metrics,
APOC3
may have genetic effects beyond lipoprotein metabolism that impact CAD risk. The extent to which these metabolites influence CAD risk beyond TG alterations requires further study.
Abstract 4133161: Variation in Prevalence, Treatment, and Outcomes in Heart Failure with Improved Ejection Fraction by Race and Ethnicity
Authors: Chang Alex , Lee Keane , Parikh Rishi , Ambrosy Andrew , Tan Thida , Hamilton Steven , Pabon Porras Maria , Vardeny Orly , Ku Ivy , Vasti Elena , Sandhu Alexander , Go Alan , Adatya Sirtaz , Bhatt Ankeet
Published: November 2024

Background:
Racial and ethnic disparities exist in heart failure with reduced ejection fraction (HFrEF), but little is known about how race and ethnicity relate to patients with HF with improved EF (HFimpEF).

Research Question:
Do the epidemiology, treatment, and outcomes vary by race and ethnicity in patients with HFimpEF?

Aim:
To describe the relationship between race and ethnicity and HFimpEF within a large, integrated health care delivery system.

Methods:
We identified adults aged ≥18 years with incident HFrEF (LVEF≤40%) from 2013-2018 within Kaiser Permanente Northern California. HFimpEF was defined as LVEF>40% within 12 months after incident HFrEF. Self-reported race and ethnicity were classified as non-Hispanic White, non-Hispanic Black, Asian American/Native Hawaiian/Pacific Islander (AANHPI), Hispanic, and other. Incidence rates of worsening HF (WHF) events (i.e., HF hospitalization, ED visit, or urgent outpatient WHF visits) or all-cause death were compared across patients with HFimpEF and persistent HFrEF using Cox proportional hazard models adjusted for age, sex, and LVEF at incident HFrEF, stratified by race and ethnicity.

Results:
Among 12,639 adults with incident HFrEF, 7,562 (59.8%) were White, 1,481 (11.7%) were AANHPI, 1,385 (11.0%) were Black, and 1,537 (12.2%) identified as Hispanic. Rates of HFimpEF following incident HFrEF was lowest among Black patients (26%), but similar among other race and ethnicities (36%, 34%, 30%, and 30% for AANHPI, White, Hispanic, and other, respectively, chi-squared p<0.01). Medication use was similar across groups at time of HFimpEF, but generally declined thereafter
(Panel A)
. Among patients with HFimpEF, Black and Hispanic patients had significantly higher crude rates of WHF or death compared to White patients (34 and 30 compared to 23 per 100 person-years, p<0.01 for each). Despite these differences in absolute rates, relative associations between HFimpEF (vs. persistent HFrEF) and WHF or death remained similar across all race and ethnicities (AANHPI: aHR=0.52 [95%CI 0.42-0.65], Black: aHR=0.70 [95%CI 0.56-0.87], Hispanic: aHR=0.60 [95%CI 0.49-0.73], White: aHR=0.53 [95%CI 0.48-0.58], p
interaction
=0.13)
(Panel B)
.

Conclusions:
HFimpEF is common within 12 months after incident HFrEF, and HF medication adherence declines in the years following. HFimpEF is associated with improved clinical outcomes across race and ethnicity, but occurs less frequently in Black patients despite similar HF medical therapy use.
Abstract 4134267: Effects of GLP-1 Receptor Agonists and SGLT2 Inhibitors on In-Hospital Mortality and 30-Day Readmission in Type 2 Diabetic Patients with Acute Coronary Syndrome
Authors: AL-Nasseri Abraheim , Kazi Usman , Reed Hunter , Ho Huy , Patel Aakash , Nerella Nishant , Pasupuleti Suman
Published: November 2024

Background:
The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose cotransporter 2 inhibitors (SGLT2is) on reducing cardiovascular events in heart failure patients are well-established; however, less is known about their effects after a myocardial infarction. This study aims to investigate the effects of GLP-1RAs and SGLT2is on in-hospital mortality and 30-day readmission in type 2 diabetic patients with/without heart failure who were hospitalized for acute coronary syndrome (ACS).

Methods:
We conducted a multicenter retrospective cohort on type 2 diabetic patients who were admitted to the hospital for ACS from 01/01/2020 to 01/31/2024 across 16 West Florida hospitals. Patients receiving a GLP-1RA alone, SGLT2i alone, or both were compared to those taking neither. Chi-square and binary logistic regression were used to predict the clinical outcomes of in-hospital mortality, all-cause readmission within 30 days, and cardiac readmission within 30 days.

Results:
Among 7,481 type 2 diabetics with ACS, 392 (5.24%) were taking GLP-1RA monotherapy, 577 (7.71%) were taking SGLT2i monotherapy, 144 (1.92%) were taking both, and 6,362 (85.12%) were taking neither. The likelihood of in-hospital mortality was similar among patients on neither medication compared to patients on both (χ
2
= 0.06,
p
= 0.802), GLP-1RA monotherapy (χ
2
= 0.61,
p
= 0.435), and SGLT2i monotherapy (χ
2
= 0.002,
p
= 0.968). The odds of all-cause readmission within 30 days was similar among patients on neither medication compared to patients on both (χ
2
= 0.0004,
p
= 0.983), GLP-1RAs monotherapy (χ
2
= 0.07,
p
= 0.791), and SGLT2i monotherapy (χ
2
= 3.10,
p
= 0.078). The likelihood of cardiac readmission within 30 days was similar among patients on neither medication compared to patients on both medications (χ
2
= 1.63,
p
= 0.202), GLP-1RA monotherapy (χ
2
= 0.95,
p
= 0.329), and SGLT2i monotherapy (χ
2
= 0.94,
p
= 0.332).

Conclusion:
Our study found no significant differences in the odds of in-hospital mortality or 30-day readmission among type 2 diabetics with ACS who were taking GLP-1RAs, SGLT2is, or both, when compared to those taking neither. These findings further support the outcomes discovered in the EMPACT-MI trial.
Abstract 4134272: Association of depression symptoms with cardiovascular health stratified by military status: Insights from 2013-2020 National Health and Nutrition Examination Survey
Authors: Lim Arum , Benjasirisan Chitchanok , Botchway Marian , Alhabodal Ashwag , Baptiste Diana , Koirala Binu
Published: November 2024

Introduction:
Emerging evidence supports the mind-heart-body connection, yet less attention has been given to examining the relationship in specific populations. Veterans have a higher risk for mental and cardiovascular problems and have unique social determinants of health (SDoH), such as healthcare access, than civilians. This study aims to examine how depression and SDoH are associated with cardiovascular health (CVH) and if associations differ by military status.

Hypotheses:
1) Depression symptoms and SDoH will be associated with CVH. 2) The associations will differ between people who served in the US military and those who did not.

Methods:
A cross-sectional analysis was conducted using data from the 2013 to 2020 National Health and Nutrition Examination Survey. Individuals were aged ≥ 20 years without cardiovascular disease and current pregnancy. Patient Health Questionnaire-9 was used to assess depression symptoms and dichotomized into no symptoms (<5) and mild-to-severe symptoms (≥5). The Life's Essential 8 quantified CVH, with scores from 0-100. SDoH included age, gender, race/ethnicity, marital status, education, employment, financial status, health insurance, and healthcare access. Sample weights were applied in multiple linear regression analyses.

Results:
Among 6498 participants, 92% were civilians (mean age: 45 years; 51% female), and 8% were veterans (mean age: 56 years; 10% female). In both groups, 23% had depression symptoms. The mean CVH was 72 in civilians and 69 in veterans. In adjusted models, individuals with depression symptoms had 4 points lower CVH scores than those without (95% CI: -5.11, -2.84). This trend was similar in civilians but insignificant in veterans. Lower CVH was significantly associated with age, being non-Hispanic Black and other races people, lower education, and lower financial status. The associations were preserved after being stratified by military status.

Conclusions:
Depression symptoms and SDoH were associated with lower CVH. However, there was no significant evidence that military status moderated the associations of depression and SDoH with CVH. Examining the intersection between depressive symptoms and SDoH may be useful when assessing CVH.
Abstract 4134277: Impairment of Vascular Endothelial Function by Inhalation of Smoke or Aerosol from Tobacco and Marijuana Products is Dependent on Vagus Nerve Input from the Airway
Authors: Wang Xiaoyin , Cheung Christian , Goyal Natasha , punnati chaitanya , Abdelaal Shadi , Derakhshandeh Ronak , Springer Matthew
Published: November 2024

Background:
Smoke or vaporizer aerosol from different tobacco or marijuana products can cause vascular endothelial dysfunction in humans and rodents. Mechanisms of acute smoke-induced endothelial dysfunction are complex and remain ambiguous. We reported that endothelial functional impairment by tobacco smoke is dependent on intact vagus nerves, leading us to hypothesize that endothelial function impaired by smoke/aerosol from tobacco or marijuana relies on vagal input from the airway.

Methods:
We used Sprague-Dawley rats at 10-12 weeks of age (n=8/group; 4M+4F). Rats were anesthetized by ketamine/xylazine and exposed to one session of exposure to smoke/aerosol of tobacco (Marlboro Red) or marijuana (~10% THC) cigarettes, e-cigarettes (JUUL), or IQOS (American HeatSticks). Exposure was pulsatile (10 cycles of 5s 2x/min for 5 min via nosecone). Endothelial function was assessed as flow-mediated dilation (FMD) in the femoral artery pre- (baseline) and post-exposure. Surgical bilateral cervical vagotomy was performed in the anesthetized rats post-baseline FMD (before exposure). Sham surgical procedures were carried out without severing vagus nerves. We used paired Student
t
tests to compare FMD values in each group pre- and post-exposure. Significance was
P
<.05.

Results:
FMD was decreased from pre- to post-exposure in all exposed sham groups as expected, whereas the impairment of FMD by smoke/aerosol exposure was completely abrogated in all vagotomized groups (Figure), with no apparent effect of sex. The pre- vs. post-exposure FMD values (mean±SD) in exposed sham groups were 16.0±3.0% vs. 6.7±3.1% for tobacco cigarettes, 13.1±2.3% vs. 5.0±2.3% for JUUL, 14.3±3.0% vs. 6.0±2.2% for IQOS, and 16.2±4.9% vs. 7.1±3.6% for marijuana. For exposed vagotomized groups, pre- vs. post-exposure FMD values were 13.3±3.7% vs. 12.6±3.7% for tobacco cigarettes, 12.8±2.6% vs. 13.0±3.2% for JUUL, 13.9±2.2% vs. 13.3±2.7% for IQOS, and 14.4±4.2% vs. 15.1±5.0% for marijuana. Heart rate was increased and respiratory rate was decreased in vagotomized groups as expected.

Conclusions:
Inhaling smoke or aerosol causes vascular endothelial impairment via a common mechanism involving vagal stimulation from the airway.
Abstract 4134572: Assessing Sex Differences in the Relationship Between Social Isolation and Incident Atherosclerotic Cardiovascular Disease and Death Using Data from the U.S. Health and Retirement Study
Authors: Graves Claire , Eisenberg-Guyot Jerzy , Varghese Ashwini , Dodson John
Published: November 2024

Background:
Inadequate social connection has been associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and mortality. There are insufficient and conflicting data on whether sex differences play a role in this relationship. Therefore, we sought to further examine the relationship between sex, social isolation, and these subsequent events.

Methods:
We analyzed Health and Retirement Study (HRS) and RAND data collected biennially from 8,987 individuals enrolled from 2004-2020 who completed at least 1 Leave Behind Questionnaire (LBQ). Social isolation was determined from LBQ data using a previously validated 6-item scale where scores of 3 or greater indicated social isolation. Development of ASCVD was classified as new self-reported myocardial infarction or stroke at any follow-up assessment. Mortality was determined with RAND longitudinal data, which was available for all individuals. We examined the incidence of ASCVD in socially isolated and not socially isolated individuals using a cumulative incidence function accounting for the competing risk of death.

Results:
Mean age at baseline LBQ survey was 55.7 years and 43% of the sample were male. In the sample, 23% identified as Black, 63% identified as White, and 13% identified as Other. Social isolation was present in 1,653 (18%) individuals at their baseline survey. ASCVD developed in 484 (5%) participants, and 593 (7%) participants died over the study’s follow-up period. Cumulative incidence analysis showed no significant difference in ASCVD incidence between socially isolated and non-socially isolated groups for either sex (male p-value: 0.15; female: 0.09) (Figure). However, the incidence of death was significantly increased for both socially isolated sexes (male p-value: <0.001; female: <0.001).

Conclusion:
While socially isolated participants were not at significantly increased risk of incident ASCVD, they were at significantly increased risk of mortality, irrespective of sex. This highlights the need for continued public health initiatives that foster social connection to enhance the well-being of the general population. The study is limited by reliance on self-report for ASCVD, which may underestimate disease incidence.
Abstract 4134695: The Effect and Mechanism of Histone Lactylation In Pathological Cardiac Hypertrophy Induced by Pressure Overload
Authors: Chen Miao , Wang Zhen , Xu Hongfei
Published: November 2024

Introduction:
Cardiac hypertrophy is characterized by significant metabolic changes, notably an increase in glycolysis. Histone lactylation, a post-translational modification influenced by the glycolytic state of cells, plays a crucial role in regulating gene transcription. However, the relationship between histone lactylation and cardiac hypertrophy remains unclear.

Research Questions:
This study aims to elucidate the effects and underlying mechanisms of histone lactylation in the progression of cardiac hypertrophy induced by pressure overload.

Methods and Results:
We observed an increase in histone lactylation levels in hypertrophic hearts from both humans and mice. To investigate further, male mice underwent transverse aortic constriction (TAC) to induce cardiac hypertrophy, followed by either an intraperitoneal injection of Oxamate (an LDHA inhibitor) to reduce histone lactylation or sodium lactate to increase it. Reducing histone lactylation protected the hearts from TAC-induced hypertrophy and fibrosis, preserving cardiac function, while increased histone lactylation exacerbated cardiac hypertrophy and fibrosis, impairing cardiac function. Cardiomyocyte-specific deletion of LDHA also led to a reduction in cardiac hypertrophy. In vitro experiments showed that inhibiting histone lactylation reduced the expression of hypertrophic markers and the hypertrophic growth of cardiomyocytes stimulated by phenylephrine. Using co-immunoprecipitation, we confirmed that P300 and GCN5 are the transferases mediating histone lactylation in cardiomyocytes. Mechanistic studies using the CUT&Tag technique revealed lactate-dependent histone modification was enriched at the promoter of TGFB2, activating its transcription. Inhibiting cardiac-specific TGFB2 expression through adeno-associated viral delivery of shRNA reduced TAC-induced cardiac hypertrophy. Furthermore, TGFB2 overexpression induced a hypertrophic phenotype in cardiomyocytes and activated the PI3K/AKT/mTOR pathways. This hypertrophic phenotype, induced by TGFB2 overexpression, was suppressed by inhibitors of PI3K or AKT.

Conclusion:
Our findings reveal a critical role for histone lactylation in the development of pathological cardiac hypertrophy by regulating TGFB2 expression and the PI3K/AKT/mTOR pathway.
Abstract 4134707: Metabolomics Discovery and Epicardial Adipose Tissue : a PROMISE Clinical Trial Substudy
Authors: Regan Jessica , He Caroline , Pagidipati Neha , Clish Clary , Ramaker Megan , Nasir Khurram , Foldyna Borek , Douglas Pamela , Shah Svati
Published: November 2024

Introduction:
Epicardial adipose tissue (EAT) is a metabolically active tissue associated with cardiometabolic disease. EAT likely has local paracrine inflammatory and atherogenic effects on coronary vessels, but the metabolic underpinnings related to systemic metabolic pathways has not been evaluated.

Hypothesis:
We hypothesized that metabolic markers of lipid and fatty acid oxidation will be positively associated with volume of EAT.

Methods:
In a biomarker substudy of the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) clinical trial which randomized participants to computed tomography angiography (CTA) vs. stress testing, we analyzed 1542 participants randomized to the CTA arm with available plasma at baseline. CTA phenotyping of EAT volume indexed to body surface area (cm
3
/m
2
) was determined using a validated deep-learning algorithm. Comprehensive metabolomic profiling was performed on plasma samples using mass spectrometry. Principal components analysis (PCA) was used for dimensionality reduction of 571 named metabolites. Linear regression tested the association of metabolomic factors with EAT. Univariate models were adjusted for multiple comparisons and multivariate models were adjusted for age, race and ethnicity, sex, diabetes, BMI, LDL-C, HDL-C and metabolic syndrome.

Results:
Of 82 PCA-derived metabolomic factors, 16 were associated with EAT in univariate models and nine were associated with EAT in multivariate models (p=0.001-0.046); 116 individual metabolites heavily loaded within these factors were significantly associated with EAT volume in multivariate models (
Figure 1
). This included three linoleic acid derivatives, six cholesterol esters, and glycine that were inversely associated with EAT volume (p<0.04) and 106 metabolites positively associated with EAT volume including di- and triacylcerols, glycerophospholipids, fatty acyls and dimethylguanidino valeric acid (p<0.05).

Conclusions:
Leveraging a large clinical trial of CTA to study metabolomics of EAT, we have identified circulating lipid species associated with EAT independent of BMI and conventional lipids. These findings highlight biomarkers of systemic metabolic dysregulation as risk modifiers and therapeutic targets in cardiometabolic disease prevention and treatment.
Abstract 4134712: Pheochromocytoma-Induced Cardiomyopathy Requiring Mechanical Support with Ejection Fracture Recovery Following Surgical Resection
Authors: Garrison Grant , East Lauren , Wanna Charles , Tallaj Jose , Clarkson Stephen
Published: November 2024

Introduction:
Pheochromocytomas are catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla. The annual incidence is approximately 0.8 per 100,000 persons, though this is an underestimate given a high percentage diagnosed at autopsy. Classically, patients present with episodic headache, sweating, and tachycardia, however, pheochromocytomas can be associated with cardiomyopathy secondary to the catecholamine excess. We present an unusual case of pheochromocytoma-induced cardiogenic shock highlighting an excellent use of mechanical circulatory support with Impella and Extracorporeal Membrane Oxygenation (ECMO) bridging to surgical intervention resulting in left ventricular ejection fraction (LVEF) recovery.

Case Description:
A 49-year-old female with past medical history of asthma initially presented to an outside hospital for palpitations, chest pain, and hypertension. Transthoracic echo (TTE) showed preserved left ventricle ejection fraction (LVEF) while cardiac MRI showed a LVEF of 43% with dilated left ventricle and diffuse global hypokinesis consistent with a dilated cardiomyopathy. She underwent a coronary angiogram demonstrating nonobstructive CAD. She was then discharged with readmission a month later at our hospital for chest tightness, palpitations, vomiting, weakness, and dizziness. Repeat TTE showed a drop in LVEF to 10-15%. She progressed to cardiogenic shock requiring BiPAP and inotrope initiation, with progressive shock and hypotension ultimately requiring Impella 5.5 and venoartrial ECMO. Abdominal imaging was notable for 4.7 x 4.2 cm right adrenal nodule and further workup with serum and urine metanephrines confirmed pheochromocytoma. While supported, the patient underwent right adrenalectomy with subsequent wean of mechanical circulatory support and biventricular recovery on TTE.

Discussion:
Pheochromocytoma-induced heart failure is a rare but potentially life-threatening complication from excess catecholamine effects on the myocardium. Pheochromocytomas should be considered in the evaluation of idiopathic heart failure even in the absence of symptoms related to catecholamine excess. Early detection, pharmacological management, and surgical resection may prevent progression of myocardial remodeling. Mechanical circulatory support can be a valuable adjunct in managing refractory heart failure in these patients by providing temporary hemodynamic stabilization while awaiting definitive tumor resection.