bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4116298: Once Weekly Utreglutide (GL0034), a Glucagon-like Peptide-1 Receptor Agonist, at 4 × 450 µg Doses Reduces Blood Pressure, Lipids, and Body Weight in Post-menopausal Females: A Phase I Study
Authors: Thennati Rajamannar , Burade Vinod , Natarajan Muthukumaran , Shahi Pradeep , Nagaraja Ravishankara , Agrawal Sudeep , Duvauchelle Thierry , Pratley Richard , Thorens Bernard , Vilsboll Tina
Published: November 2024

Background:
Utreglutide (GL0034), a novel, once weekly glucagon-like peptide-1 receptor agonist (GLP-1RA), previously demonstrated significant reductions in body weight (BW) after a single dose ascending study in individuals with obesity
.
BW reductions after pharmacological treatment of obesity with GLP-1RA is associated with blood pressure (BP) lowering effects.

Aim:
This phase I study assessed the safety, tolerability, and cardio-metabolic effects of utreglutide after multiple ascending doses in post-menopausal female volunteers with overweight and obesity.

Methods:
In this randomized, double-blind, placebo-controlled study 12 post-menopausal female volunteers with overweight/obesity, aged 18 to 65 years old with a body mass index (BMI) ≥26 kg/m
2
were randomized (9:3) to subcutaneous utreglutide fixed doses (4 × 450 µg); or placebo once weekly for four weeks. Safety, tolerability, and key cardio-metabolic parameters were assessed. Biomarker measurements included oral glucose tolerance test (OGTT) insulin and glucose area under the curve (AUC), systolic- and diastolic BP, lipid profile (triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL), creatinine, potassium, BW and leptin.

Results:
Utreglutide was generally well tolerated and related adverse effects were mainly gastrointestinal with dose-dependent nausea, vomiting and decreased appetite. Reductions in OGTT AUCs of insulin (
p
<0.05) and glucose (
p
<0.01) were noted on Day 23 after four weeks treatment with Utreglutide. This was accompanied by a decrease (
p
<0.001) in mean systolic and diastolic BP on Day 23 from baseline (BL). On Day 23, significant reductions in TC (
p
<0.01), LDL (
p
<0.05) and non-HDL (
p
<0.05) were observed. BW reduction versus BL (
p
<0.001) was 2.0 kg and 1.8 kg respectively on Day 29 and End of Study (EoS). Leptin levels significantly reduced from BL on Day 23 (
p<
0.01) and EoS (
p
<0.001). No significant changes were observed for TG, creatinine and potassium (Table).

Conclusions:
Once weekly utreglutide dosing for four weeks at a dose of 450 µg in post-menopausal females with overweight and obesity, demonstrated clinically relevant reductions of systolic and diastolic BP. This was associated with improved performance of OGTT AUC of insulin and glucose, lipids, BW and leptin with an overall good tolerability and with potential to demonstrate cardio-metabolic benefits.
Abstract 4116844: Simplifying Cardiology Research Abstracts: Assessing ChatGPT's Readability and Comprehensibility for Non-Medical Audiences
Authors: Malkani Kabir , Zhang Ruina , Falk Zachary , Tawde Prianca , Hughes Ryan , Parker Melissa , Collins Griffin , Maizes Danielle , Zhao Alexander , Kini Vinay
Published: November 2024

Background:
Artificial Intelligence (AI)-powered chatbots like ChatGPT are increasingly used in academic medical settings to help with tasks such as evidence synthesis and manuscript drafting. They have shown potential in simplifying complex medical texts for non-medical audiences like patients and journalists. However, less is known about whether simplified texts may exclude important information or be of interest to patients or other non-medically-trained people such as journalists.

Objective:
This study aims to assess ChatGPT's capacity to simplify cardiology research abstracts by eliminating jargon and enhancing universal comprehension.

Methods:
We analyzed all abstracts and scientific statements published from July to November 2023 in
Circulation
(n=113). These abstracts were processed through ChatGPT with the prompt: "Please rewrite the following text to be comprehensible at a 5th-grade reading level. Retain all original information and exclude nothing". We assessed the readability of both original and simplified texts using Flesch-Kincaid Grade Level (FKGL) and Reading Ease (FKRE) scores. Additionally, a panel of five physicians and five laypeople evaluated these texts for completeness, accuracy, and understandability.

Results:
ChatGPT transformation or abstracts reduced the required reading level from a college graduate to 8-9th grade by both FKGL (18.3 to 8.6; p<.001) and FKRE (14.6 to 68.5; p<.001). The physician panel generally found that the simplified abstracts retained all essential information without introducing errors. Both physicians and laypeople found the simplified texts more comprehensible. Laypeople appreciated the ease of understanding but did not strongly express a desire for more such simplified texts, and some still worried about the simplified abstracts missing important details.

Conclusion:
ChatGPT simplifies medical research abstracts to a level understandable by those with less than a high school education without excluding important information. This approach may be useful to communicate new research findings to patients and other non-medically-trained people.
Abstract 4116949: Specialized Pericyte Subtypes in the Pulmonary Capillary
Authors: Klouda Tim , Kim Yunhye , Baek Han-Seong , Bhaumik Mantu , Liu Yu , Liu Tiffany , Que Jianwen , Wu Joseph , Raby Benjamin , Dejesus Vinicio , Yuan Ke
Published: November 2024

Introduction:
Lung pericytes (PCs) are mural cells in close contact with endothelial cells (ECs) in the microvasculature. A significant challenge in investigating PC biology is largely due to the absence of a unique cell marker, making it difficult to distinguish them from other mural cell populations. The identification of such a marker would allow investigators to describe the role of PCs in various diseases including pulmonary arterial hypertension.

Hypothesis:
We hypothesize that HIG1 hypoxia-inducible domain family member 1B (
Higd1b
) is exclusively expressed in lung PCs, which contributes to hypoxia (Hx)-induced vascular remodeling.

Methods:
We utilized single-cell RNA sequence (scRNA-seq) databases, spatial transcriptomics, and RNAscope from human and murine lungs to identify a PC-specific cell marker and compare the gene expression between PC subtypes. We utilized Cre-LoxP and CRISPR technology to construct a novel tamoxifen-inducible
Higd1b-CreERT2
knock-in mouse model and performed lineage-tracing studies to describe the role of PC subtypes in Hx-induced pulmonary hypertension (PH).

Results:
ScRNA-seq analysis from the lungs of humans and mice identified
Higd1b
as a specific gene marker for PCs whose expression is absent in other mural cell populations. Validation with a reporter mouse line
Higd1b-CreERT2::R26-tdT
confirmed Higd1b-Cre+ cells specifically label PCs and no other mural cells (
Fig 1A
). Lineage tracing in the Hx-induced murine model of PH demonstrated the accumulation of PCs in the muscularized distal arterioles (
Fig 1B
). Through scRNA-seq and immunofluorescence validation, we identified two
HIGD1B
+ PC subtypes that exist in the pulmonary capillary: Type 1 PCs, which are quiescent in the capillaries, and Type 2 PCs exhibit multipotent cell-like properties and accumulate in the arterioles after exposure to Hx. Furthermore, we found Type 2 PCs transited into SMC-like cells via the upregulation of Vimentin, contributing to vascular remodeling in Hx-induced PH.

Conclusion:
We identified
Higd1b
as a unique marker for PCs and generated a novel
Higd1b-CreERT2
mouse that specifically labels PCs in the lungs. The discovery of PC-subtype specialization advances our understanding of lung pericyte biology and PC’s contribution to capillary remodeling under pathological conditions.
Abstract 4117085: Frequency and Patterns of Paroxysmal Supraventricular Tachycardia Episodes Among Patients Opting For Acute Drug Treatment: Analysis of the NODE-303 Open-Label Etripamil Trial
Authors: Desai Nihar , Ip James , Hu Derek , Noseworthy Peter , Parody Maria Lenor , Pokorney Sean , Rafii Farhad , Singh Narendra , Stambler Bruce , Shardonofsky Silvia , Bharucha David , Camm A. John
Published: November 2024

Background:
Etripamil nasal spray (NS) is a fast acting, self-administered calcium channel blocker in development for the termination of AV-nodal-dependent supraventricular tachycardia (SVT). Prior randomized, placebo-controlled and open-label studies have demonstrated favorable safety and efficacy of etripamil in converting paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm (SR) self-administered without direct medical supervision.

Research Question/Hypothesis:
To assess patterns and annualized PSVT episode frequency among patients opting to self-administer acute treatment with etripamil.

Methods:
NODE-303 was an event-driven, multi-center, open-label Phase 3 study, conducted in North and South America to evaluate the safety and efficacy of etripamil in patients with documented PSVT over multiple episodes. Test dosing was not performed prior to at-home use. Enrolled patients, upon perceiving symptoms of PSVT: applied an ambulatory ECG monitor, performed a previously trained vagal maneuver and, if symptoms persisted, self-administered etripamil NS 70 mg. During the study, the protocol was amended to allow a repeat dose (70 mg) if symptoms persisted 10 min after the first dose. Each patient could self-treat up to 4 episodes.

Results:
Of 1,116 enrolled patients, 503 (45.1%) treated ≥1 perceived PSVT episode (safety population). Etripamil achieved conversion to SR in 60% of patients by 30 minutes and 70% by 60 minutes. A total of 220, 118, 62, and 103 patients completed the study with 1, 2, 3, and 4 etripamil-treated perceived episodes of PSVT, respectively, with an average time on study of 440 days. Among these patients, the average number of annualized etripamil-treated PSVT episodes was 3.2 (standard deviation 3.8). Annualized use: etripamil was self-administered for 0-2 PSVT episodes per year, 2-6 episodes, 6-12 episodes, and >12 episodes, in 54%, 32%, 10%, and 4% of patients, respectively
(Figure).

Conclusions:
This analysis aimed to assess the annualized use of etripamil NS in a real-world setting, by analyzing how often patients would self-administer the drug for PSVT episodes. Of patients that self-administered etripamil (n=503), the majority treated >1 episode and the annualized frequency of episodes treated with etripamil was 3.2 episodes/yr.
Abstract 4117180: Hyperkalemia-Related Hospitalization Associated with Short-Term vs. Long-Term Outpatient SZC Therapy Among RAASi Users: The GALVANIZE Outcome study
Authors: Colman Ellen , Agiro Abiy , Mu Fan , Cook Erin , Greatsinger Alexandra , Smith Jess , Reichert Emily , Malhotra Arun , Kumar Neela , Rhee Connie
Published: November 2024

Introduction:
Patients receiving renin-angiotensin-aldosterone system inhibitors (RAASi) are at increased risk of developing hyperkalemia (HK). Sodium zirconium cyclosilicate (SZC) is used to treat HK, but the impact of duration of SZC on healthcare resource utilization (HRU) in RAASi users is unknown. The GALVANIZE Outcome study compared HK-related HRU among RAASi users between long-term and short-term SZC users.

Methods:
Adults with ≥1 outpatient prescription for SZC (index date) and ≥1 RAASi prescription spanning the index date were identified from a large US insurance claims database (7/2018-12/2022) and were stratified based on duration of SZC use. Long-term SZC users (>90 days) and short-term SZC users (≤30 days) were exactly and propensity score matched on key baseline characteristics. Rates of HK-related hospitalizations or emergency department (ED) visits, HK-related ED visits, and HK-related hospitalizations were compared during follow-up from index to the earliest of 6 months post-index, end of data availability, other potassium binder use, or re-initiation of SZC post-discontinuation.

Results:
Among 1,586 matched pairs, the mean age was 65.5 years, 41.0% of patients were female, and most patients had any stage chronic kidney disease (91.9%), hypertension (90.8%), and diabetes (73.4%). Also, 30.0% of patients had heart failure. The most used RAASi therapies at index were angiotensin-converting enzyme inhibitors (57.3%) and angiotensin-receptor blockers (56.3%). Patients with long-term SZC use had a 44% lower rate of HK-related hospitalizations or ED visits, a 41% lower rate of HK-related hospitalizations and a 52% lower rate of HK-related ED visits than patients with short-term SZC use during follow-up (all p<0.01; Figure 1).

Conclusions:
Among patients with RAASi and SZC therapy use, long-term SZC use was associated with significantly lower rates of HK-related HRU compared to matched patients with short-term SZC use.

Funding:
AstraZeneca
Abstract 4117731: Interleukin-1 Blockade in Patients With ST-Segment Elevation Myocardial Infarction Across the Spectrum of Coronary Artery Disease Complexity.
Authors: Denicolai Martin , Morello Matteo , Golino Michele , Corna Giuliana , Del Buono Marco , Agatiello Carla , Van Tassell Benjamin , Abbate Antonio
Published: November 2024

Background:
Patients with ST-segment elevation myocardial infarction (STEMI) and complex coronary artery disease (CAD) face a poor prognosis, including increased heart failure (HF) risk. Interleukin-1 (IL-1) blockade with Anakinra inhibits the acute inflammatory response and prevent HF after STEMI, but data on its effects based on CAD complexity are lacking.

Aims:
To assess the effects of Anakinra in patients with STEMI, across the spectrum of CAD complexity.

Methods:
We performed a pooled secondary analysis of 139 patients with STEMI from three randomized clinical trials (VCUART studies) comparing Anakinra (N=84) versus placebo (N=55). Multivessel CAD was defined as the presence of at least one ≥70% stenosis in a non-culprit vessel of >2.5 mm diameter, not stented during index coronary intervention. The SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery), SYNTAX II and Gensini scores were calculated, and patients were divided by the median. We evaluated a composite endpoint of new-onset HF, HF hospitalization, or all-cause death at 1-year follow-up using Kaplan-Meier survival curves, Cox regression analysis for Hazard Ratios, and calculated interactions between groups.

Results:
We included 139 patients with STEMI, 85 (61%) with single vessel CAD and 54 (39%) with multivessel CAD. According to the spectrum of CAD complexity, 60 (43%) presented a SYNTAX score >9, 59 (42%) a SYNTAX II score >24 and 65 (47%) a Gensini score >32. New-onset HF, HF hospitalization, or all-cause death occurred in a total of 23 patients: 7 among the 84 subjects in the Anakinra group and 16 within the 55 patients in the placebo group. We found no statistically significant interactions between CAD complexity and allocation to Anakinra or placebo for the composite endpoint (Figure).

Conclusions:
Among patients with STEMI, IL-1 blockade with Anakinra significantly reduced the risk of new-onset HF, HF hospitalization, or all-cause death compared to placebo, regardless of the number of vessels affected and the spectrum of CAD complexity.
Abstract 4117883: Long noncoding RNAs and machine learning to improve cardiovascular outcomes of COVID-19
Authors: Karaduzovic-Hadziabdic Kanita , Adilović Muhamed , Zhang Lu , Lumley Andrew , Shah Pranay , Shoaib Muhammad , Satagopam Venkata , Srivastava Prashant , Emanueli Costanza , Greco Simona , Padro Teresa , Domingo Pedro , Lustrek Mitja , Scholz Markus , Rosolowski Maciej , Jordan Marko , Benczik Bettina , Agg Bence , Ferdinandy Peter , Baker Andrew , Fagherazzi Guy , Ollert Markus , Michel Joanna , Sanchez Gabriel , Firat Hueseyin , Brandenburger Timo , Martelli Fabio , Badimon Lina , Devaux Yvan
Published: November 2024

Introduction/Background:
Cardiovascular symptoms appear in a high proportion of patients in the few months following a severe SARS-CoV-2 infection. Non-invasive methods to predict disease severity could help personalizing healthcare and reducing the occurrence of these symptoms.

Research Questions/Hypothesis:
We hypothesized that blood long noncoding RNAs (lncRNAs) and machine learning (ML) could help predict COVID-19 severity.

Goals/Aims:
To develop a model based on lncRNAs and ML for predicting COVID-19 severity.

Methods/Approach:
Expression data of 2906 lncRNAs were obtained by targeted sequencing in plasma samples collected at baseline from four independent cohorts, totaling 564 COVID-19 patients. Patients were aged 18+ and were recruited from 2020 to 2023 in the PrediCOVID cohort (n=162; Luxembourg), the COVID19_OMICS-COVIRNA cohort (n=100, Italy), the TOCOVID cohort (n=233, Spain), and the MiRCOVID cohort (n=69, Germany). The study complied with the Declaration of Helsinki. Cohorts were approved by ethics committees and patients signed an informed consent.

Results/Data:
After data curation and pre-processing, 463 complete datasets were included in further analysis, representing 101 severe patients (in-hospital death or ICU admission) and 362 stable patients (no hospital admission or hospital admission but not ICU). Feature selection with Boruta, a random forest-based method, identified age and five lncRNAs (LINC01088-201, FGDP-AS1, LINC01088-209, AKAP13, and a novel lncRNA) associated with disease severity, which were used to build predictive models using six ML algorithms. A naïve Bayes model based on age and five lncRNAs predicted disease severity with an AUC of 0.875 [0.868-0.881] and an accuracy of 0.783 [0.775-0.791].

Conclusion:
We developed a ML model including age and five lncRNAs predicting COVID-19 severity. This model could help improve patients’ management and cardiovascular outcomes.
Abstract 4118076: Right Innominate Artery Endovascular Intervention Via Single Radial Access and Use Of Embolic Protection
Authors: El-Shaer Ahmed , Radaideh Qais , Deisz McKayla , Dakar Leonel , Shaik Abdullah , Shafqat Areez , Abdul Jabbar Ali , Lodhi Muhammad Noraiz , Mahfood Haddad Toufik
Published: November 2024

Introduction:
The occurrence of innominate artery stenosis is less prevalent compared to subclavian artery disease. Small studies suggest up to 8% of individuals initially diagnosed with suspected subclavian steal syndrome may present with innominate artery lesions. Deployment of an embolic protection filter within the internal carotid artery during percutaneous intervention of the innominate artery presents a solution to mitigate embolism.

Case:
A 70-year-old female with a history of peripheral vascular disease presented with claudication in both arms, manifested as pain in both arms. Her left subclavian was stented months prior to presentation. An aortogram revealed severe stenosis of the innominate artery (Figure 1). Since multiple attempts to cross the lesion antegrade from the femoral access site were unsuccessful, we proceeded with the successful deployment of an embolic protection filter in the right internal carotid artery via our right radial artery access site (Figure 2). Using the right radial artery, we passed a long run-through guidewire into the distal abdominal aorta. Due to severe aortic tortuosity, we were unable to snare the wire from the aorta. Therefore, we upsized the radial sheath to 7 French over both wires (runthrough and bare). Using a support catheter, we exchanged the runthrough wire for a Glidewire Advantage. We advanced an 8 x 29mm balloon expandable stent to the area of innominate stenosis and deployed it (Figure 3). We postdilated the stent with a 14mm balloon. Angiography demonstrated adequate expansion. On follow up, the patient was without claudication and had triphasic flow in the innominate and left subclavian arteries.

Discussion:
Treating innominate artery stenosis via radial access employing a sole entry point for both embolic protection and treatment administration offers a substitute where additional access is infeasible. Modern embolic protection techniques are superior due to their flexibility and ease of use. In this case, placing the embolic protection device in the carotid artery was mandatory through the sole radial access to prevent trapping the filter behind the innominate artery stent. We were able to perform both the embolic device placement and the stenting with the same radial access.

Conclusion:
Endovascular intervention of innominate artery stenosis via radial access, utilizing a single radial access for both embolic protection and treatment delivery, presents an alternative when femoral access is not feasible.
Abstract 4118084: Targeting Monoamine Oxidase B in Dystrophic
mdx
Hearts Dampens Inflammation and Fibrosis
Authors: Venegas Francisca , Gasparella Francesca , Sanchez Rodriguez Ricardo , Fontana Francesca , Vitiello Libero , Canton Marcella
Published: November 2024

Background:
Cardiomyopathy is a major cause of death for Duchenne muscular dystrophy (DMD) patients. Current treatments cannot prevent cardiac tissue remodeling. Oxidative stress, inflammation and fibrosis are early events in DMD, preceding heart dysfunction. Monoamine Oxidase B (MAOB), which forms H
2
O
2
by oxidizing amines, is overactivated in inflammatory conditions and overcomes cell antioxidant defenses, thus altering redox homeostasis and eliciting harmful effects. We showed that targeting MAOB with inhibitors (iMAOB) improves skeletal muscle function in dystrophic mice by lowering oxidative stress, and reduces inflammation in murine models of sepsis and arthritis by dampening NF-kB, a redox-sensitive transcription factor.

Aim:
We explore the therapeutic potential of iMAOB to alleviate cardiomyopathy using dystrophin-deficient
mdx
mice. We hypothesize that iMAOB treatment could dampen oxidative stress, inflammation and fibrosis in dystrophic
mdx
hearts by modulating the phenotype of cells that are crucial in cardiac remodeling.

Methods:
Three-month-old
mdx
mice, that already show signs of fibrosis but no cardiac dysfunction, were orally treated with iMAOB or vehicle for one month (n≥ 6). Heart ventricular mononucleated cells were obtained by enzymatic digestion. Myeloid, endothelial and fibroblast cells were isolated by cell sorting by FACS and analysed by RT-PCR. Oxidative stress, inflammation and fibrosis were measured in whole tissue by immunohistochemistry.

Results:
The expression of proinflammatory and profibrotic genes was markedly increased in myeloid [Interleukin (Il)-1b, Il-6, Tgf-b and Spp1, the gene coding for osteopontin], endothelial [Il-1b, Il-6, mmp2 and nos3] and cardiac fibroblast cells [Tgf-b, Spp1, Timp1 and Col1] isolated from
mdx
hearts, as compared to wild type mice. All these genes were significantly dampened by iMAOB treatment. In parallel, once again iMAOB treatment blunted the increase in oxidative stress, inflammation and fibrosis observed in
mdx
cardiac sections. Of notice, the differences were not linked to changes in the percentage of the various cell types, as they were unmodified amongst wild type,
mdx
and iMAOB-treated
mdx
hearts.

Conclusions:
We show that iMAOB can positively affect the phenotype of cells that are important in cardiac tissue remodeling. Our data suggest that iMAOB can be a viable therapeutic tool in DMD cardiomyopathy. As iMAOB are already in clinical use, such approach could be easily translated to patients.
Abstract 4118341: Outcomes of Heart Failure with Preserved Ejection Fraction Patients With Concurrent Opioid Use: Insights From the National Inpatient Sample
Authors: Younes Ahmed , Maraey Ahmed , Elzanaty Ahmed
Published: November 2024

Background:
Opioid use has increased significantly in the past few decades, impacting cardiac and non-cardiac patients. As heart failure with preserved ejection fraction (HFpEF) comprises half of all heart failure cases, understanding its management and effect on outcomes is crucial. This study aims to evaluate the outcomes of chronic opioid therapy on HFpEF patients.

Methods:
Studying the National Inpatient Sample (2016-2020), we identified adult HFpEF patients using the appropriate ICD-10 codes -after excluding patients with end-stage renal disease (ESRD)- and compared outcomes between chronic opioid users and non-users. Multivariate logistic and linear regression analyses were performed, adjusting for multiple patient and hospital confounders. The primary outcome was all-cause in-hospital mortality while secondary outcomes included acute kidney injury/hemodialysis (AKI/HD), cardiogenic shock, cardiac arrest, mechanical ventilation, length of stay, and total charges.

Results:
Among 1,557,344 HFpEF patients, 21,655 (1.4%) were on opioids chronically. Inpatient mortality was not significantly different between patients who were on opioids and those who were not. (adjusted odds ratio [aOR] 1.01, 95% CI 0.85 - 1.2, p=0.89). There was a non-significant increased risk of cardiogenic shock (aOR 1.14, 95% CI 0.87 - 1.5, p=0.35) and cardiac arrest (aOR 1.05, 95% CI 0.8 - 1.36, p=0.74) in patients on chronic opioids. Chronic opioids were associated with increased risk of AKI/HD (aOR 1.12, 95% CI 1.04 - 1.2, p=0.002) and mechanical ventilation (aOR 1.29, 95% CI 1.16 - 1.43, p< 0.001). Opioid use was also associated with longer hospital stay (adjusted MD [aMD] 1.07 days, 95% CI 0.75 - 1.39, p<0.001) and a non-significant increase in total charges (aMD $2,593, 95% CI -$2,044 - $7,229, p=0.27).

Conclusions:
While chronic opioid use in hospitalized HFpEF patients did not significantly impact in-hospital mortality, it was associated with increased risk of other adverse events and longer hospital stay. Further research is needed to understand the impact of chronic opioid use on HFpEF patients.
Abstract 4118360: Lipocalin10 is Critical for Macrophage Efferocytosis to Repair Myocardial Ischemia/Reperfusion Injury
Authors: Zhang Yu , Wang Xiaohong , Zhu Ruiyao , Sakabe Masahide , Chowdhury Debabrata , Li Zhixin , Chen Jing , Huang Wei , Xin Mei , Fan Guo-Chang
Published: November 2024

Introduction:
Efficient clearance of dead/dying cells by macrophages (MΦs) (termed efferocytosis) is critical for timely repairing the injured heart after ischemia/reperfusion (I/R). Prior work by us and others shows that Lipocalin 10 (Lcn10), a secreted protein of lipocalin family, can regulate MΦ polarization and is greatly downregulated in cardiac tissue of patients with heart failure. However, the potential role of Lcn10 in MΦ efferocytosis during cardiac I/R has never been investigated.

Methods:
Wild-type (WT) and Lcn10-knockout (KO) mice were subjected to 45 minutes of ischemia
via
the ligation of left anterior descending artery (LAD) followed by reperfusion. Cardiac function was measured by echocardiography. Flow cytometry was utilized to assess MΦ efferocytosis. Bone marrow-derived MΦs (BMDMs) were used to test efferocytosis
in vitro
and dissect mechanism. Dead cells were prepared by treating red-dye-labelled H9C2 cells with H
2
O
2
(1mM, 2h).

Results:
After co-culturing BMDMs with dead H9C2 cells for 2h, we observed a 25% reduction of efferocytosis in Lcn10-KO BMDMs, compared to WTs. Using Lcn10-KO
mCherry
mouse model (cardiomyocyte-specific overexpression of mCherry in Lcn10-KO background), we consistently found that cardiac MΦs in Lcn10-KO mice taken up fewer dead mCherry-myocytes at 4 days post-I/R surgery, leading to an increased accumulation of cardiac dead cells, higher serum levels of troponin I, greater myocardial fibrosis, and dramatically impaired cardiac function, compared to WT
mCherry
controls. In contrast, pre-treatment of BMDMs with recombinant Lcn10 protein (rLcn10) enhanced efferocytosis by 50%. Mechanistically, RNA-seq analysis revealed that many efferocytosis-related genes were dysregulated (
e.g.,
downregulation of
Id
1,
Id
3,
Itga
8,
Itga
v,
Cd
44,
Cx3cr
1,
Msr
1, and upregulation of
Sirp
α) in Lcn10-KO BMDMs, compared to WTs. Interestingly, most of these dysregulated genes are controlled by transcription factors Id1/3. Further studies showed that rLcn10 interacted with Cd44 and activated the expression of its downstream Id1/3, leading to enhanced MΦ efferocytosis. Importantly, rLcn10-mediated efferocytosis was greatly impaired by pre-treatment of MΦs with either anti-CD44 blocking antibody (KM201, 10µg/ml) or Id1/3 inhibitor (AGX51, 25µM).

Conclusion:
Our data indicate that Lcn10 is essential for MΦ efficient efferocytosis to repair I/R-induced cardiac damage though affecting the Cd44-Id1/3 signaling and its related MΦ surface receptors.
Abstract 4118415: Device Dislodgement and Embolization associated with a New Leadless Pacemaker
Authors: Bahbah Ali , Sengupta Jay , Witt Dawn , Zishiri Edwin , Zakaib John , Abdelhadi Raed , Hauser Robert
Published: November 2024

Background:
Leadless pacemakers (LP) avoid the pocket and lead-related complications of transvenous pacing. A potential complication of LPs is dislodgement and/or embolization (D/E) during or after implant. No D/E occurred in the original 725-patient Micra™ VR clinical trial. However, in the 526-patient LEADLESS II-phase 2 trial, the rate of dislodgement for 200 Aveir™ VR LPs was 1.5%. Thus, there appears to be a significant difference in D/E rates between these LPs that have different fixation mechanisms and insertion tools.

Aims:
We aimed to determine if the Aveir VR LP has continued to exhibit D/E since it was approved by the Food and Drug Administration (FDA) in April 2022.

Methods:
We queried the FDA's Manufacturers and User Facility Device Experience (MAUDE) database for Aveir D/E that occurred in the U.S. and were reported by the manufacturer from April 2022-December 2023. The number of Aveir VR implants in the U. S. was obtained from the manufacturer's publicly available product performance report. D/E outside the U.S. were excluded.

Results:
During the 21 months, 55 of 3,139 (1.75%) Aveir VR implants exhibited D/E. More D/E (34;61.8%) occurred during implant, with 18 (52.9%) of these happening after release of the device from the tether mode. Fourteen (41.2%) of the intra-procedural D/E occurred when the device prematurely released from the delivery catheter, and two dislodged during cardiopulmonary resuscitation (CPR). D/E occurred in 21 patients (38.2%) after implant and were signified by loss of pacing or inability to interrogate the device. Four (19%) out of those 21 patients presented with symptomatic bradycardia. The dislodged devices commonly embolized to the pulmonary artery and right atrium/vena cava. LP retrieval was successful in 49 (89%) cases. Thirty-two patients (58.1%) received a new LP, 5 patients were transitioned to a transvenous system, and a replacement device was not specified for 17 (31%) patients. One patient died during implantation due to ventricular fibrillation (VF) not related to D/E.

Conclusions:
Fixation issues and premature separation of the device from the delivery catheter appear to be responsible for most of these D/E. Studies are needed to determine if impedance or another metric is associated with adequate Aveir fixation. The manufacturer should address the premature separation problem with Aveir. Success of D/E retrieval may be related to tools specific for Aveir. Further studies are needed to compare between the two LPs.
Abstract 4118444: Right Ventricular Contractile Reserve and Right Ventricular-Pulmonary Arterial Coupling Are Impaired in Long-Term Survivors of Childhood Cancers
Authors: Ho Chung Sum Samuel , Shi Julia Z. , Cheuk Daniel KL , Cheng Frankie WT , Wong Wilfred HS , Chan Yuk-ting , Cheung Yiu-Fai
Published: November 2024

Background:
Childhood cancer survivors are at risk of right ventricular (RV) dysfunction in relation to cardiac toxicity due to chemotherapy and radiation therapy. This study tested the hypothesis that RV contractile reserve and RV-pulmonary arterial (PA) coupling are altered in long-term survivors of childhood cancers.

Methods:
Thirty survivors (60% men) aged 24.3 ± 5.2 years at 15.3 ± 6.3 years after completion of chemotherapy and thirty healthy control subjects (47% men) were studied. Resting and submaximal supine bicycle stress echocardiography was performed for assessment of RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), left ventricular (LV) and RV longitudinal strain, mitral and tricuspid annular velocities and myocardial acceleration during isovolumic contraction (IVA). The slope of the RV force-frequency relationship was derived from the change in IVA with the change in heart rate during exercise (△IVA/△heart rate), while RV-PA coupling was determined by the ratio between TAPSE and pulmonary arterial acceleration time indexed to RV ejection time (PAATi).

Results:
At rest, tricuspid annular systolic velocity and RV systolic strain were significantly lower in survivors (
P
< 0.05 for both), while RV FAC, TAPSE and IVA were similar between the two groups (
P
> 0.05 for all). During submaximal exercise testing, all RV systolic functional indices were significantly lower in survivors than controls (
P
< 0.05 for all). The slope of the RV force-frequency relationship was significantly flatter in survivors compared to controls (0.038 ± 0.002 vs 0.059 ± 0.003 m/sec
2
beats/min,
P
< 0.001). For RV-PA coupling, TAPSE/PAATi was similar between survivors and controls at baseline but became significantly lower in survivors during submaximal exercise (
P
= 0.002).

Conclusions:
The RV contractile reserve and RV-PA coupling are impaired during exercise in long-term survivors of childhood cancers. Future studies aimed at determining the clinical and prognostic significance of these impairments are warranted.
Abstract 4118451: A Real-world Evaluation of Longitudinal Healthcare Expenses in a Health System Registry of Type-2 Diabetes Mellitus and Cardiovascular Disease Enabled by the 21
st
Century Cures Act
Authors: Dhingra Lovedeep , Aminorroaya Arya , Pedroso Camargos Aline , Rajpura Jigar , Mehanna Sherif , TONNU-MIHARA IVY , Khera Rohan
Published: November 2024

Background:
An evaluation of the longitudinal burden of healthcare expenses in type-2 diabetes mellitus (T2DM) is limited to self-selected cohorts and claims-based or self-reported spending. Leveraging the 21
st
Century Cures Act rule that made reporting hospital-level service prices mandatory, we demonstrate healthcare spending in T2DM with and without cardiovascular disease in a diverse multisite EHR-based T2DM cohort.

Methods:
Patients with T2DM seeking regular care (≥ 1 visit/2 years) across 5 hospitals and a large outpatient network (2013-2023) in the Yale New Haven Health System (YNHHS). Cohorts were defined by the presence of atherosclerotic cardiovascular disease (ASCVD) and/or heart failure (HF) before or up to 1 year after the T2DM diagnosis. We used the YNHHS chargemaster file to extract Medicare and insurance-negotiated cash prices. We linked census data using residential zip codes to estimate household income, used multivariable logistic regression to identify factors associated with financial hardship (health expenses >20% of income), and evaluated expenses during the last year of life. All values were inflation-adjusted to 2023 US$.

Results:
Overall, 106881 patients with T2DM followed for 5.4 years (3.1-7.5) had 147919 hospitalizations, representing $3.41B in expected healthcare expenses. 8% of patients with T2DM without ASCVD/HF, 14% with ASCVD, 23% with HF, and 28% with ASCVD and HF had a financial obligation for healthcare above the threshold for financial hardship. Compared with White patients, Black and Hispanic patients were more likely, and Asians were less likely to have financial hardship (OR: Black, 1.81 [1.73-1.91]; Hispanic, 1.39 [1.31-1.48]; Asian, 0.46 [0.37-0.57]), after accounting for age, sex, and comorbidities. Comorbid HF at baseline portended 2x higher odds of financial hardship (OR: HF, 2.20 [2.00-2.42]; ASCVD and HF, 1.98 [1.84-2.14]) compared with T2DM alone. Care in the last year of life represented 72-80% of overall health expenses, with 55-61% of patients at risk for financial hardship across cohorts.

Conclusion:
A digital individualized expense-linked registry of patients enabled by recent US price transparency rules defined that annually, one-fifth of patients with T2DM and cardiovascular disease had healthcare events exceeding 20% of their annual income, and vulnerable racial/ethnic minorities were at high risk for financial toxicity.
Abstract 4118724: Validity of a NYHA Classification Guide with Six Minute Walk Test Outcomes
Authors: Prasun Marilyn , Stamp Kelly , Rathman Lisa , McCoy Thomas
Published: November 2024

Background:
The New York Heart Association (NYHA) classification is a subjective tool that is commonly used in clinical practice to assess symptoms and functional capacity of patients with heart failure (HF). Correct assignment of NYHA is essential to facilitate evidence-based management.

Research Question:
What is the validity of the CLASS-HF Guide compared to the 6-minute walk test (6MWT)?

Purpose:
To examine the validity of the new investigator-developed CLASS-HF guide to assist in appropriate assignment of NYHA Class relative to the 6MWT.

Methods:
A multi-site, cross-sectional study in three cardiology clinical sites (two specializing in HF) recruited 103 patients in various classes and stages of HF. Providers assigned patients their NYHA Classification using the CLASS-HF guide. Patients then performed the 6MWT with test staff blinded to the assigned NYHA class. Exertion, dyspnea, and walk distance were captured post-test. The validity of the guide-assisted classification was then examined for convergent validity with 6MWT outcomes. Data analysis was performed with correlations, ANOVA, and multivariable regression.

Results:
Of the 103 total participants, 65.1% were male, 18.4% were non-White, with an average age of 66.0 ± 15.5 years old. A little less than one-third (30.1%) had HFpEF (LVEF ≥ 50%). Provider-assigned NYHA Class was 22.3% I, 38.8% II, 35.0% III and 3.9% IV. The average distance walked during the 6MWT by class was: 367.1 ± 85.6 m for I, 343.7 ± 104.7 m for II, 261.6 ± 73.9 m for III, and 184.6 ± 114.0 m for IV. Convergent validity of NYHA class with Borg exertion (Spearman’s
r
= .546,
p
< .001) and dyspnea (
r
= .504,
p
< .001) was strong. A statistically significant inverse correlation was found between NYHA assigned class and meters walked during the 6MWT (
r
= -.469,
p
< .001), with significant mean differences (ANOVA
F
(3,99) = 10.72,
p
< .001) in distance walked for: NYHA Class I vs. III (
md
= 105.5 m), I vs. IV (
md
= 182.6 m), II vs. III (
md
= 82.1 m), II vs. IV (
md
= 159.2 m). Increasing NYHA class remained significantly associated with lower 6MWT distance (
F
(3,90)=5.22,
p
= .002) in multivariable regression (Adj.
R
-squared= .575) controlling for age, sex, race/ethnicity, diagnosis, site, Borg exertion and dyspnea, and 6MWT stopping/pausing.

Conclusion:
Validity evidence was found for NYHA class assignment after use of the CLASS-HF guide with respect to 6MWT distance and post-test perceived exertion and dyspnea.
Abstract 4118735: Interpretable deep learning translation of GWAS findings for drug repurposing in Atrial Fibrillation
Authors: Tonegawa-Kuji Reina , Xu JIelin , Dou LIjun , Hou Yuan , Barnard John , Chung Mina , Cheng Feixiong
Published: November 2024

Introduction:
Translating human genetic findings, such as genome-wide association studies (GWAS) to pathobiology and the discovery of therapeutic target remains a major challenge for Atrial Fibrillation (AF). We previously published a network topology-based deep learning framework to identify disease-associated genes (NETTAG).

Hypothesis:
By using a deep learning framework, we can efficiently identify AF risk genes, druggable targets, and candidates of repurposable drugs.

Aims:
To identify potential AF related genes and repurposable drug candidates using our deep learning framework.

Methods:
First, we collected the reported quantitative trait loci (QTLs) for AF from human heart tissues. Then, we identified the overlaps between the QTLs and the previously reported 150 AF GWAS loci in the latest meta-analysis. We previously built a comprehensive human protein-protein interactome using 18 publicly available databases, containing 351,444 unique PPIs and 17,706 proteins. Using the human protein-protein interactome and the overlaps between AF GWAS hits and QTLs, we prioritized genes and defined the genes with the top 1 % predicted score as AF risk genes (afRGs) using the NETTAG. Then, we assembled drugs from the Drugbank database relating 2,938 FDA-approved drugs or clinically investigated molecules. Using network proximity approaches to evaluate the closest distance between afRGs and a drug’s targets within the human protein-protein interactome, we computationally predicted drugs for AF using Z scores <-2.0.

Results:
We first collected the overlaps between AF GWAS hits and QTLs, which constituted 27 expression and 12 splicing QTLs. Via NETTAG, we identified 176 afRGs. Among the 176 predicted afRGs, 12 proteins (gene products of afRGs) have been identified as known drug targets with FDA-approved medicines. In total, 1,275 targets have been widely investigated as therapeutic targets for treating AF. Using the closest-based network proximity approach, we computationally identified 49 candidate drugs. These included drugs both reportedly potentially treating AF, such as Pioglitazone (Z=2.29), Telmisartan (Z=-2.52), Sildenafil (Z=-2.86), and those have never been reported before, such as Balsalazide (Z=-2.32).

Conclusion:
Using a deep learning methodology that utilized GWAS and QTL findings, we identified risk genes and repurposing drug candidates for AF.
Abstract 4118882: Decompensated Heart Failure Secondary to a Non-Coronary Sinus of Valsalva to Right Atrium Fistula: A Case Report
Authors: Hasan Muhammad , LaVoie Melanie
Published: November 2024

Introduction:
Sinus of Valsalva aneurysm (SVA) accounts for 3.5% of all congenital cardiac anomalies. Rupture occurs in 35% of cases and can lead to life-threatening fistulas, predominantly involving the right ventricle or right atrium.

Description of Case:
62-year-old female with hypertension and hypothyroidism presented to the ER with progressively worsening dyspnea over the past week. She also reported worsening lower extremity edema, orthopnea, and paroxysmal nocturnal dyspnea. Chest X-ray showed large pleural effusions. Her ejection fraction was 66% ejection fraction with a fistula between the right sinus of Valsalva and the right atrium on transthoracic echocardiogram (TTE) which was also seen on transesophageal echocardiogram (TEE). Her heart failure was due to the fistula as she had no coronary artery disease on coronary angiogram. She had cardiothoracic surgery for fistula repair. Postoperatively, she developed complete heart block requiring a permanent pacemaker. She had no further complications and was discharged home in good condition.

Discussion:
SVA affects the right sinus (94%), with the non-coronary (5%) and left sinus (1%) being less commonly involved. Aneurysm rupture typically forms a fistula into the right ventricle (60%), right atrium (29%), left atrium (6%), or left ventricle (4%), and rarely into the pericardial cavity (1%). Symptoms vary by rupture size and location. TTE is the initial diagnostic tool but has limited sensitivity (50%) for detecting fistulas, whereas TEE has a 90% sensitivity. Cardiac MRI and CT can further refine diagnoses, and cardiac catheterization assesses coronary arteries preoperatively. Surgical closure with a patch is the primary treatment for ruptured SVA, significantly improving survival rates compared to non-surgical management.
Abstract 4119072: When is the Broken Heart Most Dangerous? Assessing Risk Factors to Predicting Mortality in Takotsubo Cardiomyopathy: Analysis of The National Inpatient Sample 2021
Authors: Ogunniyi Kayode , Awoyemi Toluwalase , Ugwendum Derek , Padda Inderbir , Mahtani Arun , Farid Meena
Published: November 2024

Introduction:
Takotsubo Cardiomyopathy often presents very similarly to acute coronary syndromes (ACS). Although the gravity of the condition is being increasingly recognized, prognostic factors have been hardly established. We applied known near-term ACS mortality risk factors to determine their prognostic value in takotsubo cardiomyopathy.

Methods:
We analyzed the National Inpatient Sample database for 2021. Inclusion criteria were Principal Diagnosis of Takotsubo Syndrome (ICD 10 code "I5181") and age 18 years or more. Different comorbidities, age, and gender were analyzed in these patients, and the primary outcome was inpatient mortality. Univariate logistic regression was used to test the association of each factor with mortality, and multivariate logistic regression was then used to test for independent predictive value. Analyses were performed using STATA/BE 18.0. Significance was set at 0.05.

Results:
9109 admissions for takotsubo syndrome were identified (10.3% males and 89.7% females) with a mean age of 67 years and an inpatient mortality rate of 2.31%. On univariate regression, age (OR 1.04; p=0.013), heart failure (OR 3.2; p<0.001), atrial fibrillation (OR 3.12; p<0.001) and chronic kidney disease (OR 3.54; p<0.001) were significant predictors of mortality while gender(0.389), diabetes(0.132), hypertension (0.052), smoking (0.617), nicotine dependence (0.075), hypercholesterolemia (0.686), obesity (0.728), history of stroke (0.068) and history of myocardial infarction (0.613) were not significantly associated with mortality. On multivariate regression, only heart failure (OR 2.8; p=0.007) and chronic kidney disease (OR 2.34; p=0.032) were independently associated with inpatient mortality.

Conclusion:
Our findings are mostly congruent with the existing literature regarding this condition. Pre-existing heart failure and a history of chronic kidney disease are poor prognostic factors in patients presenting with Takotsubo cardiomyopathy. Further large-scale studies are required to validate our findings.
Abstract 4119073: Zaza: A New Etiology of an Acquired Brugada-Pattern ECG
Authors: Bayar-Masood Taimur , Tony-Onugu Nwando , KHAN AIMEN , Shaikh Shawn , Keller Ethan
Published: November 2024

Introduction:
Tianeptine, an unregulated supplement, adds a new problem to the ever-growing drug epidemic. We describe a case of Tianeptine overdose presenting with acute agitation and an acquired Brugada-pattern ECG.

Case Description:
A 26-year-old male presented with acute agitation after bystanders witnessed the patient ingest 15 capsules of “Zaza Silver”. Initial ECG showed a type I Brugada pattern with coved ST-elevations in V1 and prolonged QRS and QTc. Previous ECGs on record were negative for evidence of a hereditary Brugada pattern. His urine toxicology was positive for THC. Troponins, echocardiogram and CT head were unremarkable. The patient was treated with Diazepam and a sodium bicarbonate drip with close monitoring of arterial blood pH, maintaining a goal between 7.50-7.55. After resolution of his symptoms and ECG findings, he was discharged home.

Discussion:
Patients with a Brugada pattern ECG are at increased risk of fatal arrhythmias. Classified as both inherited and acquired, this unregulated supplement presents a new etiology of an acquired Brugada-pattern ECG. Tianeptine is a non-FDA approved tricyclic antidepressant that is marketed as a supplement under the brand name “Zaza” at gas stations and convenience stores. Currently approved for the treatment of depression in Europe, it is solely distributed in the US as an unregulated health supplement. We hypothesize that Tianeptiene’s Tricyclic Antidepressant properties can affect the myocardial voltage-gated sodium channels leading to the Brugada pattern on EKG with a similar mechanism as has been previously described in cases of Tricyclic Antidepressant overdoses. Early identification of EKG findings, coupled with a detailed history can be instrumental in early diagnosis and critical treatment with bicarbonate therapy. This case also demonstrates the dangers of the non-FDA marketing of tianeptine and underscores the urgent need to regulate such supplements.