bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4125719: Efficacy of Prodromal Symptom Assessment in Prognostic Stratification of Acute Myocarditis
Authors: Kawai Yoshiki , Jimba Takahiro , Kohsaka Shun , Maejima Yasuhiro , Hiruma Takashi , Hosoya Yumiko , Yonetsu Taishi , Yamamoto Takeshi , Takayama Morimasa
Published: November 2024

Introduction:
The outcomes of acute myocarditis are heterogeneous and can lead to clinically significant consequences. However, the patient characteristics associated with adverse outcomes at presentation are not fully understood.

Objection:
To investigate the association between the presence or absence of prodromal symptoms and in-hospital mortality in patients admitted with acute myocarditis.

Methods:
We analyzed multicenter data registry (Tokyo CCU Network Database, comprising 76 institutions in the Tokyo metropolitan area). The study included 261 cases with acute myocarditis from January 2017 to December 2020, among which 260 required hospitalization from the emergency department. Patients were grouped based on the presence or absence of prodromal symptoms prior to hospitalization. Prodromal symptoms include the following: (a) chest pain; (b) dyspnea; (c) fever; (d) ful-like symptoms; and (e) others.The primary outcome was in-hospital death.

Results:
Among the 261 patients with acute myocarditis, 187 patients (71.6%) exhibited prodromal symptoms, and 74 patients (28.3%) did not. The primary outcome occurred in 19 patients (25.6%) without prodromal symptoms and in 20 patients (10.6%) with prodromal symptoms (hazard ratio, 2.87; 95% CI, 1.34 to 6.13; P=0.004, Figure 1A). A multivariable-adjusted Cox regression analysis confirmed that the absence of prodromal symptoms was an independent predictor of poor prognosis, even after adjusting for age, sex and the history of diabetes and hypertension. Notably, this trend was pronounced among patients with Killip classes 2-4, revealing higher in-hospital mortality rate in the patients without prodromal symptoms compared to those with prodromal symptoms (48.6% vs 11.7%; P < 0.001, Figure 1B).

Conclusions:
This study demonstrates that the absence of prodromal symptoms in patients with acute myocarditis is an independent predictor of poor prognosis, especially for patients presented with Killip classes 2-4.
Abstract 4125938: Novel Surgical Model of Thoracic Aortic Aneurysm Mediated by Vasa Vasorum Inhibition
Authors: Fisher Bryant , Richards Tara , Hill Jennifer , Lee Yoojin , Gleason Thomas , Phillippi Julie
Published: November 2024

Objective:
The adventitial layer of the aorta contains the network of microvessels known as vasa vasorum. Previous work by our team revealed deficient vasa vasorum associated with medial hypoxia and upregulated adventitial thrombospondin-1 (TSP-1), an anti-angiogenic molecule, in human aortic aneurysm. We hypothesize that heightened TSP-1 in the ascending thoracic aorta induces aneurysmal degeneration through its anti-angiogenic effects on the vasa vasorum. We tested this hypothesis in a rabbit model via peri-adventitial delivery of ABT-510, a thrombospondin peptide mimetic.

Methods:
The ascending aorta was exposed in New Zealand White rabbits (n=16) and treated with ABT-510 proximally and a vehicle control distally. Echocardiography was undertaken immediately prior to the procedure and 14 days post-operatively. Adventitial vasa vasorum were quantified from H&E-stained sections. Elastin and collagen organization were assessed with Verhoeff-Van Gieson (VVG) and pentachrome staining as well as multiphoton microscopy. Immunodetection of Hypoxyprobe™ and alpha smooth muscle actin (αSMA) were also undertaken to identify hypoxia and smooth muscle cell content, respectively.

Results:
Echocardiography revealed an increase in aortic diameter over 14 days with ABT-510 treatment compared with control (42.27% ± 5.54 vs 20.99% ± 4.10, p=0.004). Histological analysis showed decreased vasa vasorum count (44.7 ± 9.19 vs 85.8 ± 12.89, p=0.048) and decreased vasa vasorum indexed cumulative area (0.013 ± 0.0037 vs 0.021 ± 0.0050 µm
2
/ µm
2
adventitial area, p=0.019). Immunodetection of Hypoxyprobe™ showed evidence of increased hypoxia. VVG, pentachrome, and immunodetection of αSMA showed decreased elastin content, increased deposition of ground substance, and areas of smooth muscle cell loss
.
Multiphoton microscopy demonstrated fragmented elastin fiber microarchitecture and decreased collagen content
(Fig 1).

Conclusions:
Our study findings demonstrate a novel, clinically relevant model for thoracic aortic aneurysm through vasa vasorum inhibition that recapitulates features of cystic medial degeneration. This translational model could enable development of targeted, pro-regenerative therapies that restore perfusion to the aortic wall.
Abstract 4125992: Eicosapentaenoic Acid (EPA) Increases Expression of Nrf2-mediated Antioxidant Response Element and Heme Oxygenase-1 in Cytokine-Activated Endothelial Cells
Authors: Sherratt Samuel , Libby Peter , Dunbar Richard , Bhatt Deepak , Mason Preston
Published: November 2024

Background:
Endothelial cell (EC) nuclear factor erythroid 2-related factor (Nrf2) translocates to the nucleus during inflammation to mediate transcription of genes in the antioxidant response elements (ARE). An ARE regulates mRNA encoding HMOX-1, thioredoxin (TXN), and NAD(P)H quinone oxidoreductase-1 (NQO1), among others. Parkinson disease protein 7 (PARK7) and p62 work independently to prevent Keap1-mediated degradation of Nrf2 during oxidative stress. Eicosapentaenoic acid (EPA) administered as icosapent ethyl reduced CV events (REDUCE-IT). We tested the effects of EPA on ARE protein expression in ECs from multiple tissues during cytokine challenge.

Methods:
Human brain, pulmonary and vascular ECs were treated with IL-6 (12 ng/mL) for 2 hours and then incubated with EPA (40 µM) for 24 h. Global proteomic analysis performed by LC-MS measured relative protein expression. Significant (p<0.05) changes between treatment groups >1-fold were analyzed by differential enrichment analysis of proteomics data (DEP) and included in gene set enrichment analyses (GSEA). Significantly modulated pathways within the Gene Ontology (GO) database were identified as those with an adjusted-p value <0.05.

Results:
Proteomic analysis revealed that EPA significantly modulated ≥600 proteins in ECs distinct from IL-6 challenge alone. In EC, EPA significantly modulated the “cellular response to oxidative stress” pathway (GO: 0034599) relative to IL-6 alone. Within this GO pathway, EPA increased levels of catalase (1.2-fold, 1.1-fold, 1.1-fold) and mitochondrial glutathione reductase (1.1-fold, 1.1-fold, 1.1-fold) in brain, pulmonary, and vascular ECs, respectively. We also observed a consistent increase in brain, pulmonary, and vascular ECs of p62 (1.3-fold, 1.2-fold, and 1.2-fold, respectively), and ARE members HMOX-1 (1.5-fold, 1.7-fold, and 2.1-fold, respectively), and NQO1 (1.1-fold, 1.2-fold, and 1.3-fold, respectively). TXN was increased in pulmonary and vascular ECs (1.1-fold and 1.2-fold, respectively) with EPA. Mitochondrial TXN (also called TXN2) increased in brain ECs with EPA 1.1-fold. EPA also significantly increased levels of PARK7 1.1-fold.

Conclusions:
During inflammation, EPA enhanced expression of cytoprotective proteins in the ARE, notably HMOX-1, along with its regulators, in ECs from multiple tissues. Augmented endogenous antioxidant pathways may contribute to EPA’s clinical benefits.
Abstract 4126262: The impact of angiotensin receptor neprilysin inhibitors on the elderly population with heart failure and reduced ejection fraction: data from the real world
Authors: Balaguer German jorge , CORTES GARCIA MARCELINO , Rodriguez Lopez Carlos , Romero Otero Jose Maria , Esteban Chapel Jose Antonio , Nieto Roca Luis , Taibo Urquia Mikel , Pello Lazaro Ana Maria , Tunon Jose
Published: November 2024

Heart failure (HF) remains a disease of increasing prevalence and morbidity. Validation of new lines of therapy in the elderly are required due to the progressive ageing of the world's population and scarce evidence in elderly patients with HF with reduced ejection fraction (HFrEF). The purpose of our study is to analyse the effect of Angiotensin Receptor–Neprilysin Inhibitors (ARNI) in this subgroup of patients. We conducted a single-centre, real-world observational study.

We consecutively enrolled all patients aged ≥75 years diagnosed with HFrEF (defined as an ejection fraction <40%) and theorical indication for treatment with ARNI from November 2019 to January 2021. The main outcomes analysed were all cause mortality and admission due to HF. In order to avoid potential confounding factors, we performed a propensity-score (PS) matched analysis. Patients matching was performed in a 1:1 ratio with the nearest neighbour method.

A total of 364 patients were recruited (total population). The mean age was 84.1 years of which 67% were male. 81% were hypertensive and 33.5% diabetic. The main cause of ventricular dysfunction was ischemic with 50.2%. At inclusion 55.8% were in NYHA functional class II and the mean LVEF was 29.8%. After PS matching, we selected 184 patients (study population), 92 with ARNI. As compared with non ARNI group, the ARNI patients showed higher use of mineralocorticoid receptor antagonists (MRA) (59.8% vs 43.5%, p< 0.05) and SGLT2 inhibitors (40.2% vs 6%, p<0.05). Other treatments were otherwise similar in both groups. There were not significant differences in relation with age, etiology or comorbidities between ARNI group and non-ARNI group. During a median follow-up of 39 months, total mortality was 31.5% (58 patients). After a Cox logistic regression analysis, ARNI therapy was shown to be an independent protective variable with respect to total mortality [HR 0.6 (0.4-1), p 0.05]. The figure shows the Kaplan-Meier survival curves for total mortality in patients with and without ARNI treatment.

In summary, treatment of HFrEF remains a significant challenge in managing HF patients, especially in the elderly. According to our data, treatment with ARNI in elderly patients with HFrEF was associated with a lower rate of all-cause mortality. Our data show us that ARNI therapy could improve prognosis in the elderly with HFrEF in a real-world study.
Abstract 4126304: A Cardiac Targeting Peptide Linked to miRNA106a Targets and Suppresses Genes Known to Cause Heart Failure: Reversing Heart Failure at the Source
Authors: Lu Ming , Deng Claire , Taskintuna Kaan , Ahern Gerard , Yurko Ray , Islam Kazi , Zahid Maliha , Gallicano Ian
Published: November 2024

Background:
About one in five adults at age 40 will develop heart failure (HF) during their lifetime. Risk factors for HF (e.g., hypertension, etc.) alter cardiomyocytes structure and function resulting in HF. At the cellular level, these changes consist of mis/over-expression of genes that regulate cardiac identity (e.g., CamK2d, PKC, etc). The current paradigm for treating HF is pharmacological intervention or surgery; however, with few exceptions, the condition worsens with time. We are proposing a paradigm-shift for treating HF from a drug-centric system to a molecular approach that would reverse hypertrophy and adverse remodeling.

Methods:
A cardiac targeting peptide (CTP) was generated and linked by disulfide bond to miRNA106a, which was then introduced into a HF mouse model to measure its ability to reverse multiple heart failure parameters. CTP-miRNA106a was also introduced into a human cardiac cell line, followed by multiple analyses including Western Blot, qPCR, FACS, immunofluorescence all used to identify mechanism(s) utilized by CTP-miRNA106a to reverse HF characteristics.

Results:
Bio-distribution studies showed CTP delivered its miRNA106a cargo specifically to the heart within 30 mins, followed by clearance of CTP from the heart to the kidneys and liver by 3-5hrs post systemic drug injection. MiRNA106a persisted in cardiomyocytes until day 7 (latest tested time-point). CTP-miRNA106a reversed Ang2/Iso induced hypertrophy in 90% of the experimental mice (
Fig1
). We also identified two potential HF intracellular signaling mechanisms (PLCb1/PKC/IP3 and NfkB) targeted by CTP-miRNA106a that could benefit both types of HF, HFrEF and HFpEF. PLCβ1 is a direct target for miRNA106a while the Nfkb pathway is indirectly targeted by decreased Camk2d (an miRNA106a target) signaling to IκBα. NfkB activity is quelled by miRNA106a.

Conclusions:
Our approach utilizes the function of miRNA106a to downregulate genes involved in cardiac hypertrophy and inflammation through the PLCb1 and CamKIId/Nfkb pathways. Most importantly, using a CTP-miRNA106a, we show delivery of miRNA106a cargo is specific to cardiomyocytes both
in vitro
and
in vivo
and that once delivered, many HF parameters including hypertrophy are reversed.
Abstract 4127792: Age-stratified Monogenic and Polygenic Contributions for Atrial Fibrillation in the
All of Us
Research Program
Authors: Chen Zhanlin , Gordon Adam , Webster Gregory
Published: November 2024

Background:
Rare and common genetic variation both contribute to atrial fibrillation (AF), but the effects may not be uniform across ages. The
All of Us
Research Program contains whole-genome sequencing of 100,574 adult participants with electronic health records.

Hypothesis:
Rare genetic variants are associated with early-onset AF; common genetic variants are associated with late-onset AF.

Aims:
To quantify the diagnostic yield provided by rare and common genetic variation in AF across age.

Methods:
The clinical, monogenic, and polygenic contributions to AF were assessed in a cross-sectional group of participants in the NIH-funded
All of Us
Research Program, stratified by three age groups: <45 years (n=22,290), 45-60 years (n= 26,805), >60 years (n=51,659). Variant discovery was performed for pathogenic or likely pathogenic (P/LP) variants among 145 candidate cardiac genes with dominant inheritance for cardiomyopathy and arrhythmia. A previously established polygenic risk score (PRS) was calculated. After adjusting for known clinical factors, multivariable analysis quantified the associations between monogenic and polygenic factors versus AF status in each age group.

Results:
There were 100,574 participants: 7,811 with AF and 92,763 without AF. The presence of ≥1 P/LP variant(s) were associated with AF across all age groups, with stronger associations in the age <45 group (OR 2.3 [95% CI 1.4-4.1]) compared older groups (OR 1.5 [95% CI 1.1-2.1] in age 45-60, and OR 1.4 [95% CI 1.2-1.7] in age >60). In contrast, PRS was not associated with AF in participants <45 years (OR 1.02 [95% CI 0.88-1.17]) but was associated with AF in the older groups: OR 1.54 [95% CI 1.31-1.80] in age 45-60 and OR 1.49 [95% CI 1.40-1.59] for age >60. Overall, clinical risk factors are highly associated with AF (AUC 0.84 [0.83-0.85]); adding polygenic and monogenic factors contribute only marginal improvement (AUC 0.86 [0.85-0.87]).

Conclusion:
In this cross-sectional dataset, monogenic and polygenic factors have opposite associations with AF. Monogenic variants are associated with early-onset AF, whereas PRS has no association with AF at younger ages. Clinical risk factors continue to explain the majority of the variation in AF status.
Abstract 4128590: Identical Twins, Non-Identical Results: Genetic Testing for Cardiomyopathy
Authors: Newman Noah , Garcia Mariana , Singh Abhishek , Coyne Robert , Bhatt Kunal , Burke Michael
Published: November 2024

Case:
A 58-year-old male (Twin A) with no medical history presented with syncope while playing paddle ball. TTE showed LVEF 15-20%. Cardiac MRI (CMR) identified transmural late gadolinium enhancement (LGE) in the inferolateral wall of the LV, but angiography showed non-obstructive CAD. Four years later, his monozygotic twin (Twin B), also with no medical history, suffered cardiac arrest while playing paddle ball. TTE showed LVEF 5-10%. CMR revealed inferolateral LGE (Figure 1) with angiography showing non-obstructive CAD. Genetic testing was performed by different companies. Twin A was found to be heterozygous for myosin light chain kinase 3 (
MYLK3
) p.R380H (c.1139C>A), a variant of uncertain significance (VUS). While rare (gnomAD allele frequency 2.7e
-4
),
MYLK3
p.R380H is not conserved across species, exchanges amino acids with similar biochemical properties, and is predicted to be benign by
in silico
pathogenicity tools. Notably,
MYLK3
was not sequenced in Twin B, who was instead found to be heterozygous for desmoplakin (
DSP
) p.R1002W (c.3004C>T).
DSP
p.R1002W is highly conserved, exchanges amino acids with dissimilar properties, and is very rare (gnomAD allele frequency 2.8e
-5
).
In silico
testing yielded conflicting results with some tools predicting it to be damaging to protein function. Interestingly, the variant was present in both twins but was classified differently by each company: likely benign for Twin A (and therefore not reported) and VUS for Twin B. First degree relatives are advised to undergo clinical screening and cascade genetic testing for
DSP
p.R1002W.

Discussion:
The presentation described is consistent with arrhythmogenic cardiomyopathy (ACM) and the family history strongly supports a genetic etiology.
DSP
is a causal gene for ACM with unique clinical features that are strikingly similar to those observed herein. The differences in genes tested and variant adjudication between companies has left diagnostic uncertainty; hence, definitive pathogenicity cannot be attributed to either variant without cosegregation analysis, which is ongoing. In summary, this case illustrates the challenges of variant interpretation, and the impact that this can have on genetic counseling and family screening.
Abstract 4129036: Air pollution and Cardiovascular Disease Incidence in a Pooled Analysis of 6 U.S. Cohorts
Authors: Leiser Claire , Quraishi Sabah , Biggs Mary Lou , Hart Jaime , Sandler Dale , Whitsel Eric , White Alexandra , Young Michael T , Szpiro Adam , Spalt Elizabeth , Kaufman Joel
Published: November 2024

Introduction/Background:
Long term air pollution is associated with cardiovascular disease (CVD) incidence, however the effects at low levels in the US are unknown.

Research Questions/Hypothesis:
To assess the effect of long-term exposure to ambient air pollution CVD incidence (myocardial infarction [MI], stroke, and all CVD) in a pooled analysis of epidemiological cohorts.

Materials and Methods:
We harmonized data from six cohorts (Cardiovascular Health Study, Nurses’ Health Study II, Multi-Ethnic Study of Atherosclerosis, and Reasons for Geographic And Racial Differences in Stroke Study, Sister Study, and Women’s Health Initiative) with both CVD incidence data and extensive covariate information. We predicted time-varying two-year average concentrations of particulate matter <2.5 microns (PM
2.5
) and nitrogen dioxide (NO
2
) from 1990-2019 at participant residential addresses using validated regionalized spatio-temporal models, combining spatio-temporal universal kriging and partial least squares regression with inputs from monitoring data from regulatory and researcher-deployed networks, satellite remote-sensing data and chemical transport modeling. Cox proportional hazards regression models adjusted for individual and area-level information, including smoking status, socio-economic factors, anthropometry, blood pressure, cholesterol, and other clinical variables.

Results:
Our analysis included over 300,000 participants and 10,229 incident CVD events. The median residential concentration of PM
2.5
was 10.1 µg/m
3
and NO
2
was 9.3 ppb. A 5 µg/m
3
increase in PM
2.5
was not significantly associated with a higher hazard ratio for all outcomes: 1.03 (95%CI: 0.96, 1.10) for CVD incidence, 1.03 (95%CI 0.93, 1.15) for MI, and 1.00 (95%CI 0.90, 1.10) for stroke. We found that a 10ppb increase in NO
2
was associated with a 1.06 (95%CI: 1.01, 1.11) higher hazard ratio for CVD, 1.07 (95%CI: 1.01, 1.11) for MI, and 1.02 (95%CI 0.96, 1.09) for stroke.

Conclusions:
In this analysis of a large, pooled cohort with excellent exposure, outcome, and covariate information, we found an association of NO
2
exposure—considered a surrogate for traffic-related air pollution—with CVD incidence and MI. Associations with particulate matter were not statistically significant, but could not exclude a small increased risk. We are extending this analysis to include 6 additional cohorts and an additional 700,000 participants to allow for generation of a highly resolved concentration-response function.
Abstract 4129182: Transendocardial Stem Cell Therapy Improves Cardiac Parameters in Chronic Ischemic Heart Failure: A Meta-analysis of Randomized Controlled Trials
Authors: Al-Sawalha Ibrahim , Al-Bdour Mohammad , ABU SALIH ABDEL QADER , Al-Shimi Rula , Al-Slehat Mohammad , Batarseh Suhel , Jaloudi Nebras , Almansi Amjad
Published: November 2024

Introduction:
Despite recent advances in therapy, chronic ischemic heart failure remains a significant cause of morbidity and mortality worldwide. Stem cell (SC) therapy has recently emerged as a potential therapeutic approach, yet its efficacy remains debatable. We aimed to systematically review and meta-analyze the current evidence to evaluate its effectiveness.

Methods:
A comprehensive literature search was conducted across the following databases: PubMed, Embase, and Cochrane, from inspection to April 2024. We identified RCTs with a blinded study design, done on patients diagnosed with chronic ischemic HFrEF, and utilized mesenchymal stem cells as an intervention in comparison to placebo/sham intervention using percutaneous endomyocardial catheter systems. Meta-analysis was conducted using RevMan v5.4 to calculate the odds ratio (OR) at 95% confidence intervals (CI) and a p-value of 0.05. I
2
was indicated for the assessment of heterogeneity. Sensitivity analysis was done in case of heterogeneity between studies.

Results:
A total of twenty studies were included in our meta-analysis. The overall change in left ventricular end-systolic volume (LVESV) and stress SPECT significantly favored the stem cell group (pooled effect size -7.59, 95% CI [-12.28 to -2.89], P=0.002), and (pooled effect size -5.33, 95% CI [-6.73 to -3.93], P=0.00001), respectively. Initially, the change in left ventricular end-diastolic volume (LVEDV) did not favor either group. However, sensitivity analysis which excluded one study at a time, reduced heterogeneity (P=0.01, I
2
=54%) and showed a significant effect favoring the stem cell group (pooled effect size -3.87, 95% CI [-6.77 to -0.97], P=0.009). However, the overall changes in left ventricular ejection fraction (LVEF) did not favor either of the two groups (pooled effect size 0.08, 95% CI [-0.1 to 0.26], P=0.39). Similarly, the overall change in myocardial oxygen consumption (MVO2) did not favor either group (pooled effect size 0.66, 95% CI [-0.1 to 1.32], P=0.05).

Conclusion:
Transendocardial SC therapy demonstrates promising results by significantly improving specific cardiac parameters. While the therapy shows potential, particularly after sensitivity adjustments, its impact on other critical measures like LVEF and MVO2 remains inconclusive. These findings highlight the need for further investigation to fully understand and enhance the therapeutic potential of stem cell interventions in heart failure management.
Abstract 4129397: Cardiovascular Risk Models Using Large-Scale Physical Examination Data
Authors: Fei Jintao , Ding Shuhan , Li Minghui , Yuan Yifang , Luo Jiangying , Wang Guoxin , Zhao Jun , Cao Xuyang , Gao Minyu , Yao Yang , Zhang Ping , Xu Zhaoji , Liu Mingxue , Wu Xinyue , Wang Ding
Published: November 2024

Background:
Physical examination (PE) data offer more potential key risk factors that can enhance the development of risk models. Additionally, the latest CVD risk model, PREVENT, developed from an American population, necessitates validation within China.

Objectives:
This study aimed to develop CVD risk models based on large-scale PE records and compare them with PREVENT model in Chinese adults.

Methods:
Data were collected from a China national database (2016-2024), including 929682 participants aged 30-79 years without previous CVD (Table I). The variables covered demographics, comorbidities, and PE items, resulting in 59 features as input. The endpoint events were defined as total CVD and its subtypes, ASCVD and heart failure (HF). Sex-specific survival analysis was developed based on age-scale, utilizing Cox Proportional Hazards and Random Survival Forests (RSF). Feature importance was assessed using the average minimal depth in RSF. The performance was evaluated by the Harrell C-statistic in the validation set.

Results:
The results showed that our RSF model achieved the best performance in total CVD, with the highest C-index of 0.82 (Table II). The top 15 predictive risk factors for each gender are presented in Figure 1. Additionally, validation of the PREVENT model in our Chinese population dataset showed its great generalizability, particularly for HF events.

Conclusions:
Overall, this research underscores the importance of leveraging large-scale PE data and advanced modeling techniques to improve CVD risk prediction. Beyond traditional risk factors, greater emphasis should be placed on more demographic characteristics, comorbidities, urinalysis, and ECG features.
Abstract 4129523: MicroRNA-1282 Rescues Diabetic Limb Ischemia Via a SERF2-Protein Aggregation Pathway
Authors: Sachan Madhur , Rawal Shruti , Wu Winona , Zhai Ming , Wara Akm , Vaz Camila , Bektik Emre , Cheng Henry , Perez-Cremades Daniel , Ryan Terence , Goodney Philip , Creager Mark , Sabatine Marc , Bonaca Marc , Feinberg Mark
Published: November 2024

Introduction:
Patients with diabetes are at higher risk of chronic limb-threatening ischemia (CLTI), a severe form of peripheral artery disease (PAD) causing restricted blood flow to the lower limbs due, in part, to impaired angiogenesis. However, the role of microRNAs (miRNAs) in diabetic CLTI remains poorly understood. By integrating plasma miRNA sequencing data from PAD patients with diabetes with a diabetic CLTI mouse model, we have recently identified the conserved miRNA miR-1282 that is in cis-antisense orientation to SERF2, a gene associated with amyloid aggregation. Therefore, we hypothesize that miR-1282 orchestrates endothelial angiogenesis and proteostasis during diabetic CLTI.

Methods:
Using miR-1282 overexpression or SERF2 knockdown studies, we characterized mouse orthologs of human miR-1282 and SERF2 for angiogenesis, apoptosis, protein aggregation, and oxidative stress in diabetic mouse skeletal muscle endothelial cells (ECs). In vivo, miR-1282 mimics were delivered intramuscularly to assess their impact on blood flow recovery, angiogenesis, and protein aggregation. Mechanistic insights in ECs were gained via RNA-seq, predictive algorithms, and proteomic analyses.

Results:
miR-1282 inhibited the expression of its cis-antisense target SERF2 by 98%. miR-1282 is a hypoxia-induced endothelial-enriched miRNA, and its expression was inversely correlated with SERF2 expression. miR-1282 levels were markedly reduced after femoral artery ligation (FAL) in diabetic db/db mice. Overexpression of miR-1282 or SERF2 knockdown enhanced angiogenesis and reduced protein aggregation, apoptosis, and oxidative stress in both normal and hypoxic conditions in vitro. Delivery of miR-1282 mimics in db/db mice improved blood flow recovery by 108% and angiogenesis by 98%, and reduced protein aggregation by 48% and tissue necrosis. Coupling RNA-seq profiling and prediction algorithms of ECs upon miR-1282 overexpression or SERF2 knockdown revealed EREG, BAG5, CASP3, ARG1, and HSP90AA1 as potential downstream regulators. Pathway enrichment analysis implicated inhibition of endothelial apoptosis, ER stress, and protein stability among the most dysregulated processes.

Conclusion:
A novel mouse ortholog of human miR-1282 augments endothelial functions and diminishes protein aggregation in diabetic CLTI via suppression of its cis-antisense target SERF2. These findings uncover new potential therapeutic targets in treating diabetic CLTI.
Abstract 4130641: The Role of Oxidized Phospholipids in Triggering Trained Immunity and Accelerating Atherosclerotic Plaque Inflammation during Cholesterol Cycling
Authors: Li Zhixing , La Forest Maxwell , Weinstock Ada , Scolaro Bianca , Fortounas Konstantinos , Krautter Franziska , Laskou Maria , Obieta Amaia , Nacher Espuig Maria , Xu Chenxi , Witztum Joseph , Fisher Edward
Published: November 2024

Introduction:
Oxidized phospholipids (OxPL) derived from LDL play a crucial role in the development and progression of atherosclerosis by promoting chronic inflammation and formation of foam cells. The natural antibody E06, binding to OxPL, diminishes macrophage uptake of OxLDL in vitro and decreases atherosclerosis progression in vivo. In our prior work using a model of plasma cholesterol cycling (high-low-high), resulting in atherosclerotic plaque Progression (P)-Regression (PR)-re-Progression (PRP), respectively, we observed accelerated plaque inflammation in the PRP group relative to mice with non-cycling high cholesterol.

Hypothesis:
OxPL promotes plaque inflammation in the cholesterol cycling model via trained immunity and that the E06 antibody will mitigate this process.

Methods:
We utilized transgenic "E06 mice" that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter on the Ldlr−/− background. Both E06 mice and Ldlr-/- mice were subjected to high cholesterol diets (HCD) and categorized into three groups in the cholesterol cycling model: Baseline Progression (P), PR and PRP. Plaque regression was induced by ApoB-ASO injection, which significantly lowered cholesterol levels by inhibiting LDL production.

Results:
As before, Ldlr-/- mice in the PRP group exhibited accelerated plaque inflammation post-regression shown by CD68 staining on aortic roots. Notably, this acceleration was significantly inhibited in the E06 mice, highlighting the protective effects of E06 against plaque re-progression. Additionally, flow cytometry of peripheral blood exhibited reduced total monocytes and Ly6Chi-monocytes (thought to become inflammatory macrophages in plaques), alongside increased Ly6Clo-monocytes (thought to become inflammation resolving macrophages in plaques) among E06 mice in the PRP group compared to Ldlr-/- mice. Ex-vivo stimulation of bone marrow cells with the inflammatory stimulus LPS demonstrated higher IL-6 levels in supernatant in Ldlr-/- mice versus E06 mice in the PRP group, suggesting OXPL-induced trained immunity in bone marrow precursors of monocytes and macrophages is involved.

Conclusion:
The acceleration of plaque inflammation in cholesterol cycling model was significantly inhibited in the E06 mice. These results provide insight into the increased risk of cardiovascular disease in individuals with intermittent adherence to statins who undergo cholesterol cycling.
Abstract 4131409: Systemic Review and Meta-analysis of Global Longitudinal Strain Changes after Angiotensin Receptor Nephrilysin Inhibitor Initiation in Patients with Heart Failure
Authors: Carter Kristen , Gupta Soumya , Correa Ashish , Mahmood Kiran , Fox Arieh
Published: November 2024

Angiotensin Receptor Nephrilysin Inhibitors (ARNi) have been established as a beneficial medication in patients with heart failure (HF). This class of medications has been shown to decrease HF hospitalizations and has been included as one of the pillars in guideline directed medical therapy. Recently, left ventricular (LV) global longitudinal strain (GLS) measurements on echocardiograms have become more common and provide a more precise measurement of LV function than ejection fraction. GLS is now being used as a more intricate way of monitoring improvement in the function of the myocardium, especially in patients with heart failure. This meta-analysis was conducted to determine if treatment with ARNi in HF patients significantly improves myocardial functioning measured by LV GLS.

A meta-analysis of 9 studies including observational studies and randomized controlled trials found in a Pubmed search was performed and included patients with heart failure who were initiated on an ARNi for guideline directed medical therapy and had LV GLS measurements taken on an echocardiogram before and after ARNi initiation. The study included patients with heart failure with reduced ejection fraction. Studies were excluded if the patient population did not have a diagnosis of HF and if LV GLS measurements were not available before and after treatment with ARNi. This analysis was performed to determine if initiation of ARNi in patients with HF led to a significant improvement in LV GLS on echocardiography and therefore a significant improvement in myocardial function.

There were 9 studies included in the analysis and 879 patients with HF who were treated with ARNi or a control. The change in LV GLS at the conclusion of the study period was measured in both treatment and control groups and the mean difference between the two groups was -1.61 with a 95% confidence interval of (-2.23, -0.98) (p <0.00001). This indicates that the ARNi treatment groups had a significant improvement in GLS compared to the control groups.

ARNi initiation was found to significantly improve LV GLS and therefore myocardial function in patients with HF with reduced ejection fraction. LV GLS is a precise measurement of myocardial function. Using this form of measurement in echocardiograms can aid in determining the effect different treatments have directly on myocardial function.
Abstract 4131412: Effects of Angiotensin Converting Enzyme Inhibition And Afterload Reduction in Single Ventricle Patients Prior To Fontan: Not What You Might Think
Authors: Fogel Mark , Giner Cassie , Jones Andrea , Ramirez Suarez Karen , Medina Maria , Partington Sara , Vaiyani Danish , Harris Matthew , Whitehead Kevin , Biko David
Published: November 2024

Introduction:
Pts with single ventricle (SV) after bidirectional Glenn (BDG) are placed on angiotensin converting enzyme inhibitors (ACEI) to reduce afterload, improve ventricular performance and allow for decreased systemic to pulmonary collateral flow (APC). No large scale data exists to support ACEI use in BDG pts to accomplish this. We hypothesized that ACEI may not perform as predicted.

Goals:
To determine if ACEI use in BDG pts decreases APC and improves ventricular function.

Methods:
Single center retrospective study of all BDG pts who underwent cardiac magnetic resonance (CMR) from 2010 to present. Demographics, medication, ventricular function and flow data were collected. Pts included were >1 year old and on ACEI for >3 months prior to CMR. Wilcoxon and Fisher Exact tests were used. Significance P<0.05

Results:
Of the 320 BDG pts (median 2.8 years old) studied, 137 (43%) were treated with ACEI. See table for all data. There was no difference in age, sex, medications (except for ACEI) or body surface area (BSA) between both groups. APC as a % of aortic flow and APC/BSA were not different between those treated with ACEI compared to those who were not, whether right (RV) or left ventricle (LV) dominant.

There was no correlation of APC with time on ACEI or ACEI dosage.

Ejection fraction (EF) was lower and end-diastolic volume (EDV) was higher in BDG on ACEI for the entire group and RVs. Although LV EDV was higher with those on ACEI, LV EF was the same for those on ACEI and those who weren’t (graph). APC as a % of aortic flow and APC/BSA positively correlated with EDV (rho 0.25-0.34, P<.001). There was no difference in atrioventricular valve regurgitation between those on ACEI and those who were not (median 5 vs 6% respectively). As a surrogate for cerebral blood flow (CBF), superior vena caval (SVC) flow was lower for those on ACEI compared to those who were not.

Conclusion:
BDG pts treated with ACEI did

not

demonstrate decreased APC or improved ventricular performance. There is a suggestion that ventricular performance

may be worse

on ACEI. CBF is decreased in BDG on ACEI using SVC flow as a surrogate. This suggests that ACEI use in SV pts at the BDG stage is

not

indicated and should be discouraged.
Abstract 4131674: ADP-Ribosylation In a Mouse Model of Atherosclerosis: a Potential Novel Link Between Dyslipidemia and Inflammation in Cardiovascular Disease
Authors: Delwarde Constance , Pestana Diego , Kasai Taku , Kuraoka Shiori , Nakamura Yuto , Okada Takeshi , Decano Julius , Chelvanambi Sarvesh , Ge Rile , Mlynarchik Andrew , Perez katelyn , Campedelli Alesandra , Sonawane Abhijeet , Aikawa Elena , Singh Sasha , Aikawa Masanori
Published: November 2024

Background:
Inflammation and lipid accumulation are major features of atherosclerosis, a leading cause of death and morbidity worldwide. Our previous study recognized ADP-ribosylation, a post-translational modification, as a novel regulator of macrophage activation. We also have established mass spectrometry-based ADP-ribosylation proteomics. Using this technology, we evaluated the completely uncharacterized role of ADP-ribosylation in atherogenesis. We hypothesized that ADP-ribosylated proteins circulate from liver, accumulate in aorta and promote atherogenesis.

Methods and Results:
We harvested the aorta, liver, and plasma of LDL receptor-deficient (
Ldlr
-/-
) mice that were on a regular chow or high-fat diet for 3 or 6 months (n=40/condition). To increase ADP-ribosyl peptide signals in the aorta, we applied our novel recently optimized ion mobility mass spectrometry strategy to generate ADP-ribosylation proteomics data. We analyzed 160 mice aortas and identified 3 APOA1 and 3 APOE ADP-ribosylated peptides in both the aorta and the liver (Fig. A). In addition, these peptides were differentially abundant in the aorta of HFD-fed mice, compared to controls (i.e, APOA1 ARPALEDLR peptide relative abundance (Fig. B)).

Using the same mouse plasma, we then validated the presence of ADP-ribosylated APOA1 and ADP-ribosylated APOE in HDL and chylomicron/VLDL/LDL fractions (Western blot), respectively. This finding indicates that classical apolipoproteins circulate as ADP-ribosylated forms, representing a completely novel class of modified apolipoproteins. Immunohistochemistry confirmed the enrichment of aortic lesions in macrophages and ADP-ribosylation signal (5-fold increase, p=0.0006).

Conclusions:
This work provides the first
in vivo
evidence that ADP-ribosylation occurs in atherosclerotic lesions, which may originate from the liver via circulating blood (Fig. C). Future studies will examine whether ADP-ribosylation of apolipoproteins, specifically APOA1, alters anti-atherogenic functions of HDL.
Abstract 4131815: The Prevalence of Normal Coronary Arteries as Determined by a Coronary Artery Calcium Score of Zero Amongst Subjects with Diabetes Mellitus
Authors: Phan Jonathan , Kinninger April , Roy Sion , Krishnan Srikanth , Bhandari Mrinal , Schwarzman Logan , Budoff Matthew
Published: November 2024

Background:
The CDC reports that in 2021, 11.6% of the American population had diabetes mellitus (DM). Past literature has shown diabetes to be a significant risk factor for the development of atherosclerotic cardiovascular disease (ASCVD).

Research Question/Goal:
Using data obtained through Computed Tomography Angiography (CTA), we aim to distinguish the risk factors associated with a coronary artery calcium (CAC) score of zero in subjects with DM and to identify the prevalence of non-calcified plaque in individuals with this score.

Methods:
We performed a retrospective study of patients with DM, who underwent CAC and CTA screenings from October 2004 to January 2024 at our center in Torrance, California to examine CTA outcomes in those with CAC Score of zero and greater than zero.

Results:
Among the cohort of 2,763 subjects with DM, the average age was 63.8±12.2 years, 62% male. Within this cohort, 465 (17%) subjects had a CAC Score of zero compared to 2,298 subjects with a CAC Score greater than zero with a median score of 428 (Interquartile range (IQR) 91-1267). DM subjects with CAC Score of zero were significantly younger (53.0±13.9 versus 66.0±10.6: p<0.001), were more likely to be female and had significantly lower rates of hypertension (57% versus 76%: p<0.001), and hyperlipidemia (63% versus 76%: p<0.001). In DM subjects with CAC Score of zero, 133 (29%) had a total plaque severity score of 1 or greater (median 1, IQR 1-2) while 332 (71%) had normal coronaries on CTA.

Conclusions:
A significant percentage of subjects with DM were determined to have a CAC score of zero. Subjects with normal coronary arteries were more likely to be younger, female, and/or absent of other chronic diseases such as hypertension and hyperlipidemia. Although age and sex are nonmodifiable risk factors of ASCVD, limiting the comorbid conditions associated with DM may be beneficial in preventing ASCVD in individuals with diabetes.
Abstract 4132152: Cardiovascular Procedures for Hospitalized Patients with Hypertrophic Cardiomyopathy requiring Valvular Heart Repair/Replacement or Coronary Artery Revascularizations: A Risk-Stratified Analysis of a Large National Database
Authors: Shoar Saeed , Ali Khaled , Abdelrazek Ahmed , Ahmad Elham , Asadi Sadegh , Sharma Samin
Published: November 2024

Background:
Hypertrophic cardiomyopathy (HCM) is associated with increased mortality mainly due to sudden cardiac arrest. However, it is not clear how HCM affects in-hospital mortality among patients hospitalized due to other cardiovascular conditions requiring intervention.

Methods:
National Inpatient Sample (NIS) database was queried from 2016 to 2020 to identify hospitalized patients with a diagnosis of HCM. Patients with HCM were stratified based on their concomitant cardiovascular conditions necessitating interventions.

Results:
Data pertinent to 278,995 admission cases with HCM was analyzed. Of this, 15,035 cases had concomitant non-ST elevation MI (NSTEMI), and 1,230 cases had ST-elevation MI (STEMI). Additionally, 15,100 cases were diagnosed with aortic valve diseases (AVD), 33,580 had concomitant mitral valve diseases (MVD), 5,580 cases had tricuspid valve diseases (TVD), and 16,815 cases had pulmonary valve diseases (PVD). Cardiovascular procedures were more common among HCM patients with concomitant STEMI (43.5%) followed by HCM patients with AVD (17.1%) and HCM patients with NSTEMI (16.9%). Stratification of mortality rate based on cardiovascular procedures and the underlying indication revealed CABG to have the highest mortality rate for HCM patients with STEMI (25%), followed by PCI for HCM patients with STEMI and HFrEF (12.5%). HCM patients with NSTEMI undergoing revascularization had higher mortality when PCI was performed for HFrEF cases and when CABG was performed for HFpEF cases. For HCM patients with AVD requiring repair or replacement, TAVR was superior to SAVR if performed in patients with HFpEF but was inferior among HFrEF subgroup in terms of in-hospital mortality. For subgroup of HCM patients with MVD, transcatheter replacement was associated with a lower mortality than surgical repair regardless of concomitant heart failure. Data was insufficient for HCM patients with concomitant TVD or PVD undergoing repair or replacement procedures.

Conclusions:
Among hospitalized patients with HCM, concomitant HFrEF but not HFpEF is associated with a significantly higher mortality rate regardless of the underlying cardiovascular conditions requiring revascularization or heart valvular repair. A more comprehensive preoperative risk assessment could delineate the ideal procedures for HCM patients with certain comorbidities and specific need.
Abstract 4132159: Dietary Intake of Niacin and Risk of Cardiovascular Mortality in The Golestan Cohort Study
Authors: Yazdanpanah Mohammad Hosein , Sharafkhah Maryam , Poustchi Hossein , Etemadi Arash , Kamangar Farin , Abnet Christian , Roger Veronique , Malekzadeh Reza , Hashemian Maryam
Published: November 2024

Introduction:
Recent studies have linked niacin metabolism with vascular inflammation and cardiovascular disease (CVD); however, the association is still inconclusive regarding dietary intake, and the findings may not be generalizable to various populations. In this longitudinal study within a Middle Eastern population, we aimed to assess the relationship between dietary intake of B vitamins, including niacin, and the risk of CVD mortality.

Methods:
Our study utilized data from the Golestan Cohort Study, which has tracked 50,045 participants aged 40-75 years since 2004. We excluded subjects who reported extreme total energy intake or had a positive history of cancer, CVD, or diabetes at baseline. Vitamin B intake estimations including thiamin, riboflavin, niacin, pyridoxamine, folate, and cobalamin intake were derived from the baseline food frequency questionnaire, noting that supplement use was uncommon in this cohort. To adjust for calorie intakes, we employed the nutrient density method. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for cardiovascular mortality, using the lowest quintile of intake as the reference group for vitamins and adjusting for potential confounders.

Results:
We analyzed 42,456 subjects with a mean age of 51.5 ± 8.7 years at baseline. During 579,339 person-years of follow-up (median: 14.1 years), 3,065 CVD deaths were recorded. The median dietary intake of niacin was 25.3 mg/d (Recommended Dietary Allowance = 14-16 mg/d). We observed significant associations between niacin intake (HR
Q5 vs. Q1
= 1.13, 95% CI = 1.01-1.26, P
trend
<0.05) and CVD mortality. When niacin was modeled as a continuous linear variable, it was associated with a greater risk of CVD mortality (HR = 1.05, 95% CI = 1.01-1.09) per 2 mg/1000Kcal/d increase. None of the other B vitamin intakes evaluated were associated with CVD mortality in this population.

Conclusion:
These findings suggest that among B vitamins, only dietary niacin intake was positively associated with CVD mortality. Further confirmation in larger studies is needed.
Abstract 4132223: Mavacamten in adolescent patients with symptomatic obstructive hypertrophic cardiomyopathy: design of the Phase 3 SCOUT-HCM trial
Authors: Rossano Joseph , Canter Charles , Wolf Cordula , Favatella Nick , Lockman Jeff , puli Shilpa , Javidialsaadi Atefeh , Dyme Joshua , Crevar Christina , Mital Seema
Published: November 2024

Background:
While most current treatments can improve symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), they may be poorly tolerated and do not target the underlying pathophysiology. Mavacamten is the first and only cardiac myosin inhibitor approved for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive HCM but has not been evaluated in a pediatric age group. SCOUT-HCM (Study of MavaCamten in AdOlescents with Symptomatic ObstrUcTive HCM; NCT06253221) will evaluate the efficacy, safety, and pharmacokinetics of mavacamten in adolescents with symptomatic obstructive HCM.

Methods:
SCOUT-HCM is a randomized, double-blind, placebo-controlled, international phase 3 clinical trial that will enroll 40 adolescents (age 12 to <18 years) with obstructive HCM (
Figure
). Patients will receive mavacamten or placebo during the first 28 weeks, followed by a 28-week double-blind active treatment period. Inclusion criteria include a diagnosis of HCM with presence of symptoms and left ventricular outflow tract (LVOT) obstruction. Patients with HCM phenocopies, LVEF <50% at rest in the past 6 months, planned escalation in HCM therapy or upcoming intervention (eg, major cardiac surgery) will be excluded. The primary endpoint is change in Valsalva LVOT gradient from baseline to week 28. Key secondary endpoints include other echocardiographic parameters, safety, pharmacokinetics, and exercise capacity.

Conclusions:
SCOUT-HCM is the first randomized controlled trial evaluating a targeted myosin inhibitor in adolescents with symptomatic obstructive HCM. The results will inform the utility of mavacamten in adolescent patients with symptomatic obstructive HCM.