bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4141327: Alternate Day Fasting Attenuates Arterial Thrombotic Risk via Increasing Indole-3-propionic acid
Authors: Feng Ruijia , Yang Wenchao , Peng Guiyan , Feng Weiqi , Long Ting , Li Zilun , Chang Guangqi , Huang Kan
Published: November 2024

Background:
Arterial thrombotic disease has long been a crucial worldwide health concern. Metabolic disorders have been validated to enhance platelet reactivity, thereby augmenting the thrombotic risk. Recent investigations have highlighted the metabolic improving effect of alternate day fasting (ADF). However, its impact on thrombosis remains unclear.

Hypothesis:
We hypothesize that ADF may reduce arterial thrombotic risk through its metabolic modulatory effect.

Aims:
To investigate the effects of ADF on thrombogenesis and unravel its underlying mechanisms.

Methods:
Thirty male C57BL/6J mice fed with high fat diet (HFD) for 6 weeks were randomly allocated into 3 groups: HFD, ADF, or pair feeding, for another 6 weeks dietary intervention, while mice fed standard laboratory diet were set as control.
In vivo
carotid artery ferric chloride injury model and multiple
ex vivo
platelet function assays were utilized to assess the impacts of ADF on thrombogenesis and platelet reactivity. Fecal microbiota transplantation was performed to further explore the causal relationship between gut microbiota and ADF-mediating effects on thrombosis. Moreover, fecal metagenomic and plasma untargeted metabolomics analyses were conducted to identify the alterations of gut microbiota composition and metabolite profiles under ADF intervention.

Results:
Our study demonstrated that ADF ameliorated HFD-induced heightened platelet reactivity and thrombotic tendency in mice on a gut microbiota dependent manner. Indole-3 propionic acid (IPA), a gut microbiota-derived metabolite, was enriched under ADF and further identified as a crucial factor mediating the anti-thrombotic effect of ADF. Supplementation of IPA impeded platelet activation via suppressing intraplatelet Rho-GTPase cycle and its downstream signals, thereby alleviating thrombotic formation without affecting hemostasis. Of note, we demonstrated that plasma IPA was remarkably decreased in patients with acute arterial thrombotic events, which also exhibited a significant negative association with platelet reactivity.

Conclusions:
Our study uncovers the protective effect of ADF on thrombogenesis, providing mechanistic insights and a potential therapeutic strategy for arterial thrombotic diseases.
Abstract 4141331: The HCM-causing Mutation R495Q in Cardiac Myosin Binding Protein C Causes Contractile Changes in Human Engineered Heart Tissue that is Ameliorated by Chronic Mavacamten Treatment
Authors: Ross Anthony , De Lange Willem , Gauchan Angeela , Farrell Emily , Ralphe J Carter
Published: November 2024

Background:
About 45% of identified HCM-causing mutations are in cardiac myosin binding protein C (cMyBP-C). One prevalent missense mutation is R495Q, which is in a positively charged pocket and alters the predicted electrostatic properties of the C3 domain. Many known HCM-causing mutations cause hypercontractility, likely through promoting the disordered relaxed state (DRX), in which myosin heads are more likely to bind to actin to generate contractile force, relative to the super relaxed state (SRX) in which myosin heads fold back on myosin tails. Mavacamten (MAVA), an FDA-approved drug for HCM patients with left ventricular outflow obstruction, is proposed to reduce DRX:SRX toward normal by inhibiting the myosin ATPase. It is unclear if all HCM-causing mutations act via this mechanism.

Question:
What is the contractile phenotypic timeline of
MYBPC3
R495Q in human iPSC-engineered heart tissue (EHT) and can chronic MAVA ameliorate this phenotype?

Aim:
Define the phenotype progression in EHTs homozygous for the R495Q mutation (QQ), compared to isogenic controls (RR). We will use this timeline, combined with pharmacologic intervention to gain mechanistic insight into the pathogenesis of the R495Q mutation.

Methods:
3D EHTs were generated from CRISPR/Cas-9 edited QQ and RR human iPSC cardiomyocytes. We used capillary immunoassay to quantify cMyBP-C expression and immunocytochemistry to determine protein localization. Contractile function of EHTs was assessed weekly (weeks 1-6) with chronic treatment of MAVA (100nM) starting at day 8 of EHT culture.

Results:
QQ EHTs express normal cMyBP-C protein levels with appropriate incorporation into the sarcomere, yet at day 8 show increased twitch force (TF) and fast relaxation (Fig A-B). At day 36, QQs have normalized TF and
slow
relaxation. Importantly, MAVA normalizes relaxation time (Fig C,D).

Conclusion:
These data suggest that R495Q presents with an early hypercontractile phenotype. With prolonged time in culture, TF is reduced, and relaxation time slows. Chronic administration of MAVA quickened relaxation, but reduced total force compared to untreated normal EHT, suggesting that caution may be warranted to ensure that systolic function isn’t impaired.
Abstract 4141332: Gut Microbiota Dysbiosis Contributes to the Development of Diabetic Cardiomyopathy
Authors: Zhang Chaoyue , Shi Yunke , Shi Ao , Cai Hongyan
Published: November 2024

Background:
Diabetic cardiomyopathy (DCM) is one of the most serious complications of diabetes mellitus (DM). However, studies exploring the roles of gut microbiome in DM and cardiovascular disease remain limited.

Hypothesis:
Gut microbiota dysbiosis is associated with the development of DCM.

Methods:
We collected fecal and serum samples from 18 DCM patients and 13 matched control subjects for metagenomic and metabolomic analysis. Fecal microbiota transplantation (FMT) with samples from both groups was performed on the pseudo-germ-free (PGF) rats. Then, we analyzed rat gut microbiota by 16S rDNA sequencing, and examined cardiac parameters and blood glucose indicators of PGF rats. Serum and myocardium metabolomic analysis was performed on DCM rats and compared with human samples.

Results:
Linear Discriminant Analysis Effect Size (
p
＜0.05, LDA≥2.0) of the metagenomics data identified 11 gut microbiota, which can be used as the DCM patient’s biomarkers. After FMT, compared to control-PGF rats, DCM-PGF rats showed significant differences in the composition of gut microbiota (α-diversity, simpson
p
=0.015, shannon
p
=0.011; β-diversity p= 0.005). Moreover, DCM-PGF rats had higher fasting blood glucose levels (
p
=0.036), intraperitoneal glucose tolerance test showed higher blood glucose levels at 15 and 30 minutes (
p
=0.000, 0.030), left ventricular (LV) end systolic diameter was larger (
p
=0.009), diastolic and systolic LV anterior wall thickness, and systolic LV posterior wall thickness were thicker (
p
=0.011, 0.035, 0.036), fibrosis area was larger (
p
=0.022). When comparing metabolic profiles of serum of DCM patients, serum of DCM rats and the myocardium of DCM model with the corresponding controls, we identified 2 shared differential metabolites:
Hydroxybutyric acid
and
15,16-DiHODE
. Spearman correlation analysis of these two metabolites with differential gut microbiota species in DCM patients
vs.
control subjects showed that
Hydroxybutyric acid
and
15,16-DiHODE
are strongly correlated with 7 species (
p
＜0.05, r＞|0.5|) and with 23 species (
p
＜0.05, r＞|0.5|) respectively.

Conclusions:
Our study found that DCM patients have their characteristic altered gut microbiota and serum metabolites, which may be responsible for the development of DCM. Gut microbiota is expected to be a potential target for therapeutic intervention in DCM.
Abstract 4141338: Independent positive associations of coronary calcium density and volume with incident cardiovascular events in the 75-and-older population: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Liu Hairong , Mok Yejin , Shah Amil , Chen Lin , Budoff Matthew , Blaha Michael , Matsushita Kuni
Published: November 2024

Background:
Coronary artery calcium (CAC) is usually quantified by Agatston score, integrating both its density and area. Importantly, several studies have reported different prognostic implications between calcium density and volume, with the former inversely associated with cardiovascular disease (CVD) events suggesting predominantly “stable/healed” plaque and the latter better representation of total plaque burden. However, those studies predominantly involved middle-aged populations, with limited data on very older adults, and used estimated CAC density.

Aim:
To examine the independent association of directly measured CAC density and volume with incident CVD events among the 75-and-older population.

Methods:
We included 1,456 participants aged >75 from ARIC visit 7 (2018-2019) with CAC data (mean age 80.4 [SD 4.2] years, 58.2% female, 18.2% Black). We assessed CAC maximum peak density (the highest density across all calcified plaque[s] in each participant) and volume. We ran multivariable Cox models with composite CVD (myocardial infarction, stroke, and heart failure) as the outcome. Mean peak CAC density(the average of the highest HU in every plaque in each participant) were used to check the pattern consistency.

Results:
During a median follow-up of 2.9 years, there were 122 CVD events. After adjusting for traditional CVD risk factors, both CAC density and volume were positively associated with CVD (e.g., hazard ratio for the highest (Q4) vs. the lowest (Q1) quartile 3.73 [95%CI 2.02-6.90] and 4.33 [2.44-7.66], respectively) (Model 1 in
Table
). When we further adjusted for each other, the associations were attenuated but remained significant (Model 2 in
Table
). The patterns were largely similar when we explored mean peak density.

Conclusions:
Unlike results in previous studies with middle-aged adults and estimated CAC density, both directly measured CAC density and volume were positively and independently associated with increased CVD risk in the 75-and-older population.
Abstract 4141340: Fbxo44 Alleviates Heart Aging and Mitochondrial Calcium Overload Injury by Modulating RyR2-Related Pathway
Authors: Yang Jian , Zhang Chengzhi , Zhang Jing
Published: November 2024

Background:
Cardiac aging is a continuous pathological process. Imbalances in mitochondrial calcium homeostasis are prevalent in the aging myocardium. Fbxo44 is a member of the F-box family that has been shown to be involved in a variety of diseases. Here, we report an aging-associated mechanism in cardiomyocytes in which Fbxo44 disrupts mitochondrial calcium homeostasis by promoting phosphorylation of the calcium release channel protein RyR2.

Hypothesis:
Fbxo44 regulates cardiac aging through the RyR2-related pathway.

Methods:
The doxorubicin was used to established the animal models of cardiac aging in Cardiac myocyte-specific Fbxo44 knockout (CKO) and control mice. The age-related proteins and positive stained area were used to assess the senescence phenotypes. Cardiac function of mice was assessed using Doppler ultrasound. Expression levels of Fbxo44 and p-RyR2 were evaluated through Western blotting. Fbxo44 was knocked down using adenovirus in H9C2 cells, followed by the addition of doxorubicin to induce cellular senescence. The cell model was analyzed for senescence-related phenotypes by β-galactosidase staining and western blotting. Confocal laser scanning microscopy was employed to assess the expression of the Rhod-2 probe and RyR2 fluorescence. Western blotting was performed to detect the levels of Fbxo44 and phosphorylation of RyR2.

Results:
Myocardial tissue-specific knockdown of Fbxo44 resulted in improved cardiac function compared to the control group, along with a significant reduction in the degree of senescence and expression of associated pathway proteins. In the cellular model, down-regulation of Fbxo44 significantly reduced the proportion of positive β-galactosidase staining and decreased the expression of senescence markers and related pathway proteins. Furthermore, inhibition of Fbxo44 mitigated mitochondrial calcium damage, accompanied by a decrease in RyR2 fluorescence intensity.

Conclusions:
Downregulation of Fbxo44 regulates mitochondrial calcium overload and cardiac senescence via RyR2-related pathways.
Abstract 4141344: Leadless Pacemaker vs. Transvenous Pacemaker in End Stage Kidney Disease: Insights from the Nationwide Readmission Database
Authors: Shtembari Jurgen , Kansakar Sajog , Naeem Azka , Moskovits Norbert , Shrestha Dhan , Biswas Monodeep , Basyal Binaya , Shantha Ghanshyam , Storey James , Katz Daniel
Published: November 2024

Background:
Leadless pacemakers offer a safe and effective alternative pacing strategy, crucial for patients with end-stage renal disease (ESRD) overcoming vascular access isues. However, there is limited data available on their use in this population.

Methods:
We utilized the Nationwide Readmission Database to extract data on all adult patients with ESRD who received either traditional transvenous or leadless pacemaker implantation from 2016 to 2021. We then compared in-hospital mortality, in-hospital complications, healthcare resource utilization, and 30-day readmission rates between these two groups.

Results:
A total of 6,384 patients (81.2%) were included in the transvenous pacemaker cohort, while 1,481 patients (18.8%) were in the leadless pacemaker cohort. In ESRD patients, leadless pacemaker implantation was associated with higher in-hospital complications compared to transvenous pacemakers, including cardiac complications (aOR 4.12, CI 1.70-9.98, p<0.01), vascular complications (aOR 3.6, CI 1.40-9.26, p=0.01), and the need for blood transfusions (aOR 1.85, CI 1.32-2.60, p<0.01). There was no difference between the cohorts in terms of in-hospital mortality and 30-day readmission rates. However, the median length of stay was longer for leadless pacemaker implantation (5 days vs. 4 days, p<0.01), and the total hospitalization charges were higher ($139,826 vs. $93,919, p<0.01).

Conclusion:
In conclusion, while LPM implantation in ESRD patients was associated with higher in-hospital complications and healthcare resource utilization compared to TVPM, there was no significant difference in in-hospital mortality and 30-day readmission rates. Further research is needed to understand the nature of these complications and optimize outcomes for ESRD patients undergoing LPM implantation.
Abstract 4141350: Endothelial-Mesenchymal Transition Mediated by Mechanical Stress Prompts Atrial Fibrogenesis
Authors: Cui Chang , Qin Huiyuan , ZHU YUE , ZHANG YIKE , Shen Youmei , Liu Hailei , Chen Minglong
Published: November 2024

Background:
Atrial fibrosis is crucial in developing atrial fibrillation (AF). Elevated atrial pressure may significantly mediate atrial fibrosis, yet its underlying mechanisms remain unclear.

Methods:
Patients with AF who underwent radiofrequency ablation were recruited. Clinical data, including high-density mapping and imaging information, was analyzed. Multivariate regression analysis was performed to identify risk factors for low-voltage areas in the atrium. The CS-CREM mouse model, an autonomic AF model, was previously developed by our research group. Millar pressure catheters were used to measure left ventricular, right ventricular, and right atrial pressures in CS-CREM mice. Single-nucleus sequencing was employed to map the single-cell transcriptomes of atrial samples in CS-CREM and wild-type mice at different disease stages. Human primary atrial endocardial endothelial cells (ACCE) and HUVEC cell lines were subjected to mechanical stretch using the Flexcell tension system, followed by in vitro validation experiments. Mg101, a calpain inhibitor, was administered to CS-CREM mice for in vivo validation experiments.

Results:
Elevated atrial pressure in AF patients was identified as a significant risk factor for atrial fibrosis. Atrial pressure-related indices were linearly correlated with atrial fibrosis. Compared to wild-type mice, CS-CREM heterozygous mice exhibited significantly higher atrial pressure and aggravated atrial fibrosis. Single-nucleus sequencing revealed that atrial endocardial endothelial cells in CS-CREM mice underwent endothelial-mesenchymal transition (EnMT) into fibroblasts, with mechanical stress protein Flna being a critical regulatory protein. In vitro experiments demonstrated mechanical stretch-induced EnMT in ACCE and HUVEC cell lines. Mechanical stretch-activated mechanosensitive receptors on ACCE cell membranes led to increased intracellular calcium levels and calpain activation, which cleaved Flna into Flna 90. Flna 90 facilitated the nuclear translocation of transcription factor Smad3/7 and TGF-β, promoting the expressions of EnMT genes. This EnMT process was reversible with Mg101. In vivo experiments showed that Mg101 reduced the incidence of AF and mitigated atrial fibrosis in CS-CREM mice.

Conclusion:
Mechanical stress induces cleaved Flna 90 from Flna in atrial endocardial endothelial cells, thus assisting transcription factors Smad3/7 and TGF-β in nuclear translocation, regulating EnMT and mediating atrial fibrosis.
Abstract 4141357: Diagnostic and prognostic value of quantitative stress perfusion CMR in the non-invasive assessment of cardiac allograft vasculopathy
Authors: Bisaccia Giandomenico , Leo Isabella , Licordari Roberto , La Vecchia Giulia , Perotto Maria , Procopio Maria Cristina , Miaris Nikolaos , Torella Daniele , Ricci Fabrizio , GALLINA SABINA , Kellman Peter , Wong Joyce , Bucciarelli-Ducci Chiara
Published: November 2024

Background:
Cardiac allograft vasculopathy (CAV) is a rapidly progressive form of coronary atherosclerosis limiting long-term survival after heart transplantation.

Objectives:
We evaluated the diagnostic and prognostic yield of quantitative stress cardiovascular magnetic resonance (CMR) perfusion for CAV detection in heart transplant recipients.

Methods:
Patients who received orthotopic heart transplants and underwent stress CMR for CAV assessment were included in the study and followed up for almost 2 years (median 1.8; IQR 0.9,2.7). The diagnostic accuracy of qualitative and quantitative stress CMR was assessed by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), using invasive or CT coronary angiography as the reference for CAV detection. The area under the curve (AUC) was compared for qualitative and quantitative stress CMR. Adjusted hazard ratios for major adverse cardiac events (MACE), including death and unplanned cardiac hospitalizations were derived in all patients. The global myocardial perfusion reserve index (MPRi) was obtained by normalization to the rate-pressure product.

Results:
In a cohort of 60 patients, n=18 (30%) had significant CAV (grade 2 or 3), and n=11 (18.3%) experienced MACE. At the Youden index threshold of 2.1, the myocardial perfusion reserve index (MPRi) demonstrated a sensitivity of 85.7%, a specificity of 70.3%, a PPV of 52.2%, and an NPV of 92.9%. The MPRi was significantly more accurate than visual assessment (p < 0.001) in identifying underlying CAV (Figure 1) and it was an independent predictor of MACE (HR:0.26;95%CI:0.07,0.93; log-rank p=0.022; Figure 2), while the visual presence of inducible myocardial perfusion defect did not (HR:2.23;95%CI:0.57,8.66; p=0.2).

Conclusions:
In patients with previous heart transplantation, quantitative stress CMR perfusion has incremental diagnostic and prognostic value over qualitative stress CMR for the non-invasive detection of CAV.
Abstract 4141366: Teamwork Makes the Dream Work: Self-care and Depressive Symptoms in Rural Heart Failure Dyads
Authors: Graven Lucinda , Abbott Laurie , Ledermann Thomas , Howren M. Bryant , Grant Joan
Published: November 2024

Introduction:
Managing heart failure (HF) in the home is stressful and complex for rural dyads who experience unique challenges and barriers to optimal HF self-care (SC). Innovative, tailored, dyadic problem-solving interventions are needed which support teamwork in managing HF SC problems in the home to enhance dyadic HF SC and reduce depressive symptoms.

Research Question:
Will participation in a 3-month dyadic, telephone-based problem-solving intervention focused on dyadic HF SC problems experienced in the home improve patient and care partner-contributed HF SC and reduce depressive symptoms in rural dyads living with HF?

Methods:
Using a dyadic single-group repeated-measures design, 41 rural dyads (patient-informal care partner) living with HF participated in 8 telephone sessions with a registered nurse to identify and develop management strategies for dyadic HF SC problems experienced in the home. Data were collected at baseline and 5-, 9-, and 13-weeks post baseline using the Self-care of HF Index (SCHFI), Caregiver Contribution to the SCHFI, and the Center for Epidemiological Studies – Depression Scale. HF patients were mostly female (59%), married (66.7%) Caucasians (69.2%), with 2-3 comorbidities (53.8%) and Class 2 NYHA HF (69.2%). Care partners were primarily female (58.5%), married (75.6%) Caucasians (70.7%), and spouses of the HF patient (68.3%), with 0-1 comorbidities (58.6%), and had been providing care for ≥ 5 years (46.3%). Descriptive statistics were used to examine dyad characteristics and outcome variables at each time point. Changes in patients' and care partners’ outcomes were analyzed using dyadic Growth Curve Modeling within the Multilevel Modeling framework.

Results:
Across time, patient scores improved for depressive symptoms (
b
= -1.81,
p
= .002) and SC maintenance (
b
= 2.29,
p
< .001). SC confidence increased in both patients (
b
= 2.51,
p
< .001) and care partners (
b
= 2.26,
p
= .01). Increases in patient SC management across time was noted but non-significant (
b
= 1.46,
p
= .133 for patients;
b
= 0.60,
p
= .561 for care partners).

Conclusions:
Problem-solving interventions in rural dyads living with HF may be helpful in addressing HF SC issues and depressive symptoms in the home, especially in HF patients. However, more research is needed to examine this promising intervention in a larger clinical trial.
Abstract 4141392: The LDL-C Lowering Effect and Patient Out-of-Pocket Cost Among Patients Who Received Inclisiran Treatment at Outpatient Clinics
Authors: Desai Nihar , Van Hise Nicholas , Niu Xiaoli , Ghera Elizabeth , Brown Alan
Published: November 2024

Introduction:
Inclisiran is a novel small interfering RNA indicated to reduce LDL-C as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH). It is administered subcutaneously initially, again at 3 months, and then every six months by an HCP. Subsequent doses may be administered within three months after the scheduled dose without restarting a new dose schedule. Few studies have investigated out of pocket (OOP) costs for patients receiving inclisiran. Metro Infusion Center (MIC) is one of the largest infusion centers across the US with over 200 centers in 38 states.

Objective:
To describe the real-world changes in LDL-C levels and OOP costs associated with inclisiran use at MICs.

Methods:
Patient charts for those who initiated inclisiran between March 1, 2022 and November 30, 2022 and who received ≥2 doses were reviewed retrospectively. Patient characteristics at initiation were collected and patients were followed until February 2024. Study outcomes included changes in LDL-C levels from baseline and OOP cost by payer type. The incidence of adverse events (AEs) was extracted from the chart if documented.

Results:
A total of 534 patients who initiated inclisiran received ≥2 doses. Mean (SD) age was 70.2 (10.3) years and 50% were male. The majority of patients (81%) were covered by Medicare. A total of 479 (90%) patients had a history of ASCVD and 55 (10%) had HeFH. Prior PCSK9i use was reported in 35% of patients, and 54% had concurrent statin therapy. Among 274 patients with LDL-C measurements, mean (SD) baseline LDL-C was 147.2 (59.7) mg/dL. After initiating inclisiran, the average reduction in LDL-C from baseline was 47%. The average OOP costs for the initial dose was $37 ($0-$2950) for Medicare insured patients and $115 ($0-$1300) for patients covered by commercial insurance. Among patients insured by Medicare, 96% paid $0 OOP for both doses. A total of 24 (4%) patients reported an AE, and half discontinued treatment. The most commonly reported AEs were muscle weakness and joint pain in 5 patients.

Conclusion:
These real-world data demonstrate significant LDL-C reductions within 1 year in patients who initiated inclisiran, which is consistent with the ORION clinical development program. Most patients were covered by Medicare, nearly all of whom had $0 for OOP costs compared with average costs of $115 for initial dose for commercially insured patients.
Abstract 4141398: Relationship between Gut Microbial Butyrate and Hypertension
Authors: Das Pritha , Reczek Sebastian , Hogue Taylor , Cook Marc , Hampton-Marcell Jarrad
Published: November 2024

Background:
Hypertension is the most common cardiovascular disease risk factor of which African Americans have a greater burden. Gut microbial production of short chain fatty acids (SCFA) has been associated with blood pressure status in animals, with limited evidence in humans. The complex and diverse gut microbial ecosystem contributes to synthesizing the SCFA butyrate. Aim: The goal of the study is to determine if butyrate production in the gut is associated with hypertension and how the microbial composition differs in normal and hypertensive participants.

Methods:
Fecal samples from 20 participants diagnosed with normal (n = 10) or high (n = 10) blood pressure were sequenced via the 16S rRNA gene. Inference-based modeling generated functional (PICRUSt2) and metabolic (MICOM) models of microbial communities focusing on carbohydrate fermentation pathways. Supervised learning was conducted to identify significant (p < 0.05) differences in predicted functional genes and microbial communities.

Results:
Microbial dominance was inversely correlated with increasing systolic blood pressure (Pearson, p < 0.05, R = -0.44); however, no significant correlation was measured for beta diversity between the two groups. More importantly, inference modeling showed differences in microbial function and metabolism between groups. Functional pathways associated with carbohydrate fermentation were significantly (ANOVA, p < 0.05) lower for hypertensive compared to normal participants. Carbohydrate fermentation accounted for only 8.05% of the predicted functions of the identified pathways. Within this subset, pyruvate fermentation to isobutanol was the most abundant pathway (12.6%), followed by starch degradation (9.6%) and glycolysis III (9.34%). Additionally, metabolic flux models revealed
Catenibacterium, Subdoligranulum
, and
Roseburia
were predicted as butyrate producers.
Catenibacterium
and
Subdoligranulum
produced 51% and 44% butyrate, respectively, in the normal group. In contrast, a different distribution was observed in the hypertensive group, with
Catenibacterium
accounting for 97% and
Roseburia
contributing 3% of the butyrate production.

Conclusion:
Our preliminary investigation elucidates the potential relationship between SCFA producers (as well as butyrate producers) and blood pressure status among minority participants, providing insights into how gut microbiota may influence or be influenced by blood pressure.
Abstract 4141400: Inhibition of Chylomicron Uptake Stimulates Treg Accumulation
Authors: Wei Zihan
Published: November 2024

Introduction:
Chylomicrons are major lipid fuel for cells. They contain dietary triglycerides, cholesterols, and apolipoproteins. In the intestine, apolipoprotein C-III (apoC-III) is produced during fat feeding, and secreted onto chylomicrons. ApoC-III is a key regulator of chylomicron hydrolysis and clearance through its inhibitory effects on lipoprotein lipase (LPL) and low-density lipoprotein receptor (LDLr) in multiple tissues. In humans, genetic polymorphisms in apoC-III are directly tied to plasma triglyceride levels and cardiovascular disease risk. As a result, apoC-III is a major drug target with antisense therapies already in clinical trials. Though plasma chylomicrons and the lipids they carry are well-known instigators of cardiovascular disease, they also deliver necessary lipid fuels to organs and cells that require energy. As an important regression factor in cardiovascular diseases, regulatory CD4+ Foxp3+T cells (Tregs) are a highly oxidative lymphocyte subset, and Tregs heavily rely on fatty acids to fuel their differentiation, proliferation, and anti-inflammatory functions.

Hypothesis:
Though Tregs rely on FA for ATP generation, few studies consider how Tregs encounter their lipid fuel and whether this process is regulated. We hypothesized that chylomicrons deliver triglyceride to Tregs, and that apoC-III would regulate this process through receptor inhibition.

Methods:
We used purified chylomicrons and albumin-bound fatty acid, Seahorse metabolic flux analysis of Tregs, and
in vivo
functional assays of inflammatory bowel disease. Finally, we asked whether these processes may be at play during atherosclerosis, where both Tregs and chylomicron lipids are critical factors.

Results:
Our studies reveal: CD4+Foxp3+Tregs endocytose chylomicrons lipids (both FFA and cholesterol); oxidative phosphorylation in Tregs is stimulated by lipids in apoC-III containing chylomicrons; these events can be targeted to change Treg accumulation and suppressive function in the gut and the aorta. We find that the inhibition of chylomicron uptake by Tregs also coincides with an increase in Treg accumulation at sites of inflammation, and a decrease in their expression of apoptotic markers.

Conclusions:
These data suggest a link between chylomicron lipid metabolism and apoptosis in anti-inflammatory Tregs. Further research will be conducted to reveal the mechanism of Treg chylomicron uptake and how regulation of this pathway alters Treg metabolism and apoptosis.
Abstract 4141410: Coronary Calcified Plaque Number and Risk of Incident Cardiovascular Disease in the 75-and-Older Population: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Zou Siyu , Liu Hairong , Mok Yejin , Gami Abhishek , Chen Lin , Budoff Matthew , Blaha Michael , Matsushita Kunihiro
Published: November 2024

Background:
The Agatston score is established as the clinical measure of coronary artery calcium. However, prognostic implications of the overall number and location of calcified plaques remain unknown in the 75-and-older population.

Methods:
We analyzed data from 1,746 participants in the ARIC study who underwent non-contrast cardiac-gated chest computed tomography (CT) at visit 7 (2018-19) and were free of cardiovascular disease (CVD) at baseline. In addition to quantifying the Agatston score, we also interpreted the total number of calcified plaques and their location (proximal [before the first major branch] vs. distal [after the first major branch]) in each coronary artery. Multivariable Cox proportional hazards models were used to quantify the association of calcified plaque number with CVD events (adjudicated myocardial infarction, stroke, and heart failure). Participants with zero plaque were treated as a reference, and those with at least one plaque were divided into quartiles of plaque number.

Results:
During a median follow-up time of 2.8 (interquartile interval 2.4-3.3) years, there were 114 (6.5%) CVD events. After adjusting for traditional CVD risk factors, there was a dose-response relationship between overall calcified plaque number and CVD events (Model 1 in Table), with a hazard ratio of 8.17 (95% CI 2.44, 27.39) in plaque number ≥ 25 (Q4) vs. 0 (no plaques). The association remained statistically significant even after further adjusting for Agatston score (Model 2). When we analyzed proximal and distal plaques separately, the association was more evident in the proximal distribution (e.g., hazard ratio of Q4 vs. no plaques 3.95 (1.42, 11.00) for proximal vs. 1.38 (0.67, 2.85) for distal in Model 2).

Conclusion:
Calcified coronary plaque number, especially in proximal arteries, was associated with incident CVD events beyond the traditional risk factors and the Agatston score in the 75-and-older population. Our findings suggest the possibility to further optimize the use of cardiac CT beyond the Agatston score for predicting CVD events in this population.
Abstract 4141412: Regulation of Vascular Smooth Muscle Cell Phenotype and Metabolic Profile by CD70
Authors: Pandey Arvind , Das Apabrita , Waldeck-Weiermair Markus , Yadav Shambhu , Oldham William , Michel Thomas , Loscalzo Joseph
Published: November 2024

Introduction:
We recently identified the tumor necrosis superfamily member CD70 as a novel regulator of redox homeostasis and mitochondrial function in endothelial cells. Whether CD70 exerts a regulatory role on metabolism and cellular function in vascular smooth muscle cells (VSMCs) is unknown.

Methods:
Human aortic VSMCs (AoVSMCs) were transfected with control or CD70-directed siRNA (n = 5-6). Metabolic function was assessed by Seahorse assay. Hydrogen peroxide, calcium, ATP, and NADH/NAD
+
ratio were assayed in live cells with fluorescent biosensors. Semi-quantitative proteomics were performed using liquid chromatography-tandem mass spectrometry. VSMC phenotype was evaluated by scratch assay and collagen gel contraction assay. VSMC function was assessed in control versus global CD70 knockout mice using wire myography.

Results:
CD70 knockdown significantly altered cellular metabolic profile, decreasing oxidative phosphorylation and glycolysis (Fig. 1A). This was accompanied by mitochondrial network dispersion, reduced mitochondrial membrane potential and impaired glucose-dependent ATP production (Fig. 1B-C). Markers for mitochondrial fusion and biogenesis, including the key regulator PGC1-alpha, were reduced (Fig. 1D-E). Cellular redox balance shifted towards an oxidized state with decreased NADH/NAD
+
ratio (Fig. 1F) and enhanced intracellular hydrogen peroxide generation. Proteomic analysis using intensity-based absolute quantification and a false discovery rate of 5% revealed that CD70 knockdown led to activation of pro-oxidative proteins, alteration in proteins involved in mitochondrial dynamics, and decreased expression of contractile proteins, all with significant p values. CD70 knockdown reduced VSMC contractile function (Fig. 1G) and intracellular calcium flux; migratory capacity increased. CD70 knockout mice had reduced aortic contractile reserve (Fig. 1H).

Conclusions:
CD70 has a previously unknown homeostatic role in maintaining VSMC metabolic and contractile function. Loss of CD70 disrupts mitochondrial networks and alters VSMC metabolism to promote phenotypic switching from a contractile to a migratory state. These results identify CD70 as a potential new target for regulating VSMC pathobiology.
Abstract 4141413: Impact of diabetes mellitus on bifurcation percutaneous coronary intervention: Insights from the PROGRESS-BIFURCATION registry
Authors: Strepkos Dimitrios , Carvalho Pedro , Rempakos Athanasios , Alexandrou Michaella , Mutlu Deniz , Krestyaninov Oleg , Khelimskii Dmitrii , Kultursay Barkin , karagoz ali , Yildirim Ufuk , soylu korhan , Uluganyan Mahmut , Mastrodemos Olga , Rangan Bavana , Jalli Sandeep , Al-Ogaili Ahmed , Voudris Konstantinos , Sandoval Yader , Burke M Nicholas , Brilakis Emmanouil
Published: November 2024

Background:
The impact of diabetes mellitus (DM) on short and long-term outcomes following bifurcation percutaneous coronary intervention (PCI) has received limited study.

Methods:
We examined the procedural characteristics and outcomes of 1,224 bifurcation PCIs (1,076 patients) performed at five centers between 2013-2024 from the Prospective Global Registry for the Study of Bifurcation Lesion Interventions (PROGRESS-BIFURCATION, NCT05100992).

Results:
Diabetes mellitus was present in 394 patients (34.20%). Patients with diabetes were more likely to be female (32.30% vs 21.50%, P <0.001), have greater body mass index (BMI) (32.56 ± 6.38 vs 29.26 ± 5.87, P < 0.001) and more comorbidities such as hypertension, dyslipidemia and heart failure. Diabetic patients had more complex angiographic characteristics, with higher prevalence of left main (LM), proximal left anterior descending and right coronary artery stenoses. The main vessel was more likely to be the LM or the right coronary artery in patients with diabetes. Diabetic patients had lower rates of provisional stenting (64.30% vs 70.40%, P = 0.029), required higher procedure times (89.75 min vs 77.00 min, P = 0.001) and radiation (1.57 Gy vs 1.31 Gy, P = 0.002), and were more likely to need in-hospital repeat PCI (OR: 2.8 CI: 1.07, 7.76, P = 0.039). Diabetes was independently associated with higher MACE during follow-up (HR: 1.94, CI: 1.36, 2.76, P < 0.001). Follow-up MI (HR: 2.32 CI: 1.37, 3.94, P = 0.013) and death (HR: 2.56 CI: 1.51, 4.35, P < 0.001) were higher in diabetic patients after adjusting for confounders.

Conclusions:
Bifurcation PCI in patients with diabetes mellitus was associated with higher risk of in-hospital repeat-PCI, follow-up MI and death compared with non-diabetic patients.
Abstract 4141414: Glycoprotein 130 Antagonism Counteracts Autophagy-Mediated Mitochondrial Metabolic Derangements and Improves Right Ventricle Function in Pulmonary Artery Banded Pigs
Authors: Mendelson Jenna , Sternbach Jacob , Moon Ryan , Hartweck Lynn , Kazmirczak Felipe , Prins Kurt
Published: November 2024

Background:
Right ventricular dysfunction (RVD) is a risk factor for death in PAH, but RV-specific therapies are lacking. We showed inhibition of glycoprotein 130 (GP130) signaling with the small molecule SC144 improved RV function in rodent RVD. However, SC144’s efficacy in a translational large animal model of RVD is untested.

Methods:
Ten 4-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB pigs were randomized into 2 groups (daily injections of SC144 [2 mg/kg, PAB-SC144,
n
=5] or vehicle [PAB-VEH,
n
=5] for 3 weeks). Five pigs of a similar age served as controls. Cardiac MRI quantified RV function, mass, and volume. Mitochondrial morphology was examined from electron micrographs of RV free wall cardiomyocytes. Wheat Germ Agglutinin stained RV cross sections were used to calculate cardiomyocyte remodeling. Lipidomics and metabolomics quantified lipid species and metabolites in whole RV tissue. Quantitative proteomics evaluated RV mitochondrial enrichments.

Results:
SC144 significantly improved RV ejection fraction (CONTROL: 60±4%, PAB-VEH: 23±11%, PAB-SC144: 38±6%) despite identical RV afterload. SC144 normalized RV cardiomyocyte size (CONTROL: 131±54 µm
2
, PAB-VEH 200±70 µm
2
, PAB-SC144: 129±62 µm
2
), mitochondrial dimensions, and cristae morphology. Integrated lipidomics, metabolomics, and proteomics revealed changes in lipid metabolism in PAB pigs, which was counteracted by SC144. In particular, the accumulation of acylcarnitines, the mitochondrial form of fatty acids, and the downregulation of fatty acid oxidation proteins was mitigated by SC144. The improvements in mitochondrial structure, protein regulation, and metabolic activity were likely due to the restoration of autophagy as SC144 mitigated the reduction in numerous autophagy proteins.

Conclusion:
SC144 improves RV function in porcine RV failure, likely by maintaining autophagy, which ultimately preserves mitochondrial fatty acid oxidation.
Abstract 4141423: Bridging the Divide: Evaluating Outcomes Between the Sexes for Transcatheter Aortic Valve Replacement
Authors: Hattab Aleyah , Bhayani Siddharth , Khan Azmer , Tiu David , Tiu Daniel , Navarro Laura , Sreepathy Pranati , Ambalavanan Manoj , Kalagara Swetha , Ismail Mariam , Torres Kayla , Hammad Bayan , Balami Jesse , Salem Edward , Natsheh Zachary , Seshadri Suhas , Carlson Andrew , Yu Julia , Dau Trang , Qiao Victor , Singam Manisha , Wahba Romani , Habeel Samer , Nasrollahi Farrah , Dickens Helena , Dohse Carlos , Ibrahim Khalil , Kansal Mayank , Shroff Adhir
Published: November 2024

Introduction:
Sex-related short-term outcomes following transcatheter aortic valve replacement (TAVR) are known. There is less data comparing the long-term differences in outcomes between sexes. Studies suggest women are less likely to be referred for TAVR and have higher mortality. This study investigated the differences between genders and races on outcomes in the following 6 and 12 months post-TAVR.

Questions:
Are there differences in outcomes between males and females who undergo TAVR? Are there differences in outcomes between females of different races undergoing TAVR?

Methods:
We performed a retrospective cohort study among 252 patients undergoing TAVR between 2018 and 2023 at a major academic medical center in Chicago, Illinois. Primary outcomes included composite major adverse cardiac events (MACE) (CVA, MI and/or CVA) and all-cause death. Outcomes were analyzed at 6 and 12 months following TAVR. T and Chi square tests were used to analyze continuous/categorical variables respectively.

Results:
Among the 252 patients studied, 27.4% were female, 27.5% white, 47.8% black, 10.1% Hispanic/Latino, 14.45% other. Average age of females and males were 77 ± 1 years and 75 ± 0.74 years (p=0.2967), respectively. Males were more likely to be former smokers (p=0.000) and to drink more than 8 alcoholic beverages per week (p=0.023). No significant differences were seen between genders for MACE, all-cause death, CVA or MI at 6 or 12 months (Table 1). There were also no significant differences were found between females of different races for MACE, all-cause death, CVA, or MI at 6 or 12 months. There was a significant difference by race for development of conduction abnormalities found at 6-month follow-up (p=0.02).

Conclusion:
This study shows females appeared to have similar outcomes at 6 and 12 months following TAVR when compared to males. However, the possible causes leading to increased development of conduction abnormalities found at 6 months follow up between female racial groups needs to be further studied.
Abstract 4141502: Gender Variations in Atrial Fibrillation Incidence Among the American Indian Population in Northern Arizona
Authors: Vargas Juan , Deora Kunal , yadav ritu , Ashraf Hammad , Forbeck Taylor , Lowis Jaron , Jha Neha , Ashurst John , Nagarakanti Rangadham
Published: November 2024

Introduction:
Atrial fibrillation (AF) is the most common cardiac arrhythmia, with gender disparities in age, comorbidities and anticoagulation (AC) therapy. These differences in American Indians (AI) with AF remain underexplored. We aim to evaluate gender differences in demographics, comorbidities, AC status and direct-oral anticoagulant (DOAC) use among AI patients with AF in rural Northern Arizona.

Methods:
We performed a retrospective analysis of AI patients aged >18 years with AF between January 2022 and October 2023 from a health system with two hospitals in northern arizona. We collected demographic variables, comorbidities, AC status, and calculated CHADS-VASc and HAS-BLED scores. Statistical analysis was conducted using chi-square tests for categorical variables and Mann-Whitney U tests for continuous variables, with statistical significance defined as a p-value ≤ 0.05.

Results:
We identified 490 AI patients with AF, 185 (37.8%) were female, and 305 (62.2%) were male. The mean age was 68.8±16.2 years, with females being older on average compared to males (73±14.5 years vs. 66±16.7 years; p < 0.0001) (Table 1). Hypertension was the most common comorbidity, in 70% (343) of patients. Significant gender differences were observed in Coronary artery disease (CAD) (32.1% males vs. 20.5% females, p = 0.005), diabetes mellitus (71.1% males vs. 60.5% females, p = 0.01), alcohol use (22.6% males vs. 4.9% females, p < 0.0001), and tobacco abuse (11.5% males vs. 2.2% females, p = 0.0002). AC use were higher in females (61.1% vs. 49.8% in males, p = 0.02). DOAC use was more prevalent among females (56.8% vs. 43.9% in males, p = 0.006). The mean CHADS-VASc score was higher in females (4.7±1.6 vs. 3.2±1.8 in males, p < 0.0001), whereas HAS-BLED scores did not differ significantly between genders (2.5±1.1 in females vs. 2.6±1.3 in males, p = 0.53)

Conclusions:
Our study found significant gender differences in this population of AI patients with AF. Females were older, had higher CHAD-VASC scores, and more likely to be anticoagulated with DOACs compared to males. These findings highlight the need for gender-specific strategies to optimize AC in this population. Further research is warranted to explore the underlying reasons for these differences and develop targeted interventions.
Abstract 4141509: Hypocholesterolemic Effect of Dietary Stearic Acid Modulated by Alterations in Bile Acid and Cholesterol Metabolism in Post-Menopausal Women
Authors: Zhang Wen , Galluccio Jean , Matuszek Gregory , Dolnikowski Gregory , Lichtenstein Alice , Matthan Nirupa
Published: November 2024

Background:
Dietary stearic acid (18:0), a saturated fatty acid (SFA) commonly present in Western diets, has an LDL-C lowering effect compared to shorter chain SFAs such as palmitic acid (16:0), and a similar effect compared to oleic acid (18:1). However, the underlying mechanisms remain unclear.

Hypothesis:
We tested the hypothesis that the hypocholesterolemic effect of dietary 18:0 and 18:1 relative to 16:0 is modulated by alterations in cholesterol and bile acid (BA) metabolism.

Methods:
This secondary analysis used archived plasma and fecal samples from a randomized crossover feeding study (N=20 mildly hypercholesteremic postmenopausal women, 64±7 years, BMI 26.4±3.4kg/m
2
). Participants consumed each of 3 isocaloric diets enriched in either 18:0, 16:0 or 18:1 for five weeks with a 2-week washout. Primary (P) and secondary (S) BAs, and their conjugates were measured in fecal, fasting and non-fasting (NF) plasma samples using the Biocrates MxP Quant 500 kit and Quadrupole Time-of-Flight mass spectrometry. Fasting and NF plasma cholesterol synthesis (lathosterol) and absorption (-sitosterol) markerswere quantified using gas chromatography. Mixed-effect and generalized linear mixed models were used to test the difference in outcome measures among diets, with Tukey-Kramer post hoc comparison. Spearman correlation coefficients with FDR adjustment was calculated between BA, cholesterol synthesis/absorption markers, and CVD risk factors.

Results:
Compared to the 16:0 diet, consumption of the 18:0 diet resulted in significantly lower fasting and NF plasma lathosterol (-22%); higher -sitosterol (19%); higher fecal PBAs (31%) and lower fecal SBAs (-17%) concentrations. Plasma PBAs were significantly lower in the fasted state (-34%), but higher in the NF state (21%; 18:0 vs. 16:0). Interestingly, conjugated PBA and SBA concentrations in the NF state were significantly higher after participants consumed the 18:0 compared to the 18:1 diet (all p
<
0.05). Plasma NF PBAs were positively associated with -sitosterol (r=0.56, p
<
0.05), while plasma fasting PBAs were negatively associated with lathosterol (r=-0.58, p
<
0.05). Conjugated PBA and SBA concentrations were negatively associated with LDL-C, hsCRP, E-selectin and insulin concentrations in the fasted but not NF state.

Conclusion:
The favorable effects of 18:0 on CVD risk factors may be modulated, in part, by changes in BA and cholesterol metabolism, with distinct effects in the fasted and NF states.