bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4119078: Adjunctive pulmonary artery catheter for patients with cardiogenic shock treated with impella: a meta-analysis
Authors: Barbosa Lucas , Araujo Beatriz , Aziri Buena , Begic Edin
Published: November 2024

Introduction:
The efficacy and safety of use and impact of pulmonary artery catheter (PAC) in patients with cardiogenic shock (CS) treated with Impella remains unclear. The use of PAC in conjunction with Impella for patients with CS might be associated with improved clinical outcomes and increased safety compared to the use of Impella alone. We aimed to perform a systematic review and meta-analysis comparing Impella with versus without PAC for patients with CS.

Methods:
We systematically searched PubMed, Embase, and Cochrane databases for studies comparing PAC use in patients with CS treated with Impella. We pooled odds ratios (OR) with 95% confidence intervals (CI) applying random-effects model. We used R version 4.3.2 for statistical analyses.

Results:
We included two observational studies comprising 11,463 patients, of whom 6,058 (53%) had PAC. Compared with no PAC, the use of PAC was associated with a significantly lower in short-term mortality rates (37% vs. 42%; OR 0.83; 95% CI 0.77-0.90; p<0.01; Figure 1A). There was no significant difference in the incidence of arrhythmias 59% vs. 63%; OR 1.14; 95% CI 0.92-1.41 p=0.44; Figure 1B) or renal complications between groups (47% vs. 50%; OR 1.08; 95% CI 1.00-1.17; p=0.06; Figure 1C).

Conclusions:
In patients with CS, adjunctive PAC to Impella is associated with lower mortality rates, but no significant difference in arrhythmias and renal complications. Randomized controlled trials are warranted to further validate this results.
Abstract 4119094: Claims-Based versus Registry-Reported Stroke Events in the NCDR Left Atrial Appendage Occlusion Registry
Authors: Faridi Kamil , Freeman James , Wang Yongfei , Pereira Lucy , Zimmerman Sarah , Friedman Daniel , Sharma Richa , Higgins Angela , Mortazavi Bobak , Ross Joseph , Krumholz Harlan , Yeh Robert , Curtis Jeptha
Published: November 2024

Background:
Administrative claims data are increasingly used for post-marketing surveillance of drugs and medical devices, though data reliability remains uncertain. Given their associated morbidity and mortality, stroke events are particularly important to monitor for cardiovascular therapies such as transcatheter left atrial appendage occlusion (LAAO). However, there are limited data comparing stroke events in contemporary claims data to events reported in large nationwide registries with comprehensive data collection.

Aim:
To compare stroke events in Medicare claims data with adjudicated registry-reported events in the National Cardiovascular Data Registry Left Atrial Appendage Occlusion (LAAO) Registry.

Methods:
LAAO Registry data were linked with 2016-2022 Medicare inpatient claims. Primary diagnosis ICD-10 codes from inpatient hospitalizations were compared to adjudicated registry-reported ischemic and hemorrhagic stroke events occurring after discharge with up to two years of follow-up. In multiple secondary analyses, primary and secondary diagnosis codes were counted as events in claims data and patients with prior history of stroke were also excluded.

Results:
The cohort included 71,043 adults ≥65 years old in the LAAO Registry with inpatient Medicare data. Following LAAO hospitalization discharge, there were 1405 claims-based and 1308 registry-reported total stroke events. Sensitivity and positive predictive value (PPV) of claims for identifying registry-reported events were 60.8% and 50.5% for ischemic stroke (kappa statistic 0.55), 42.7% and 50.5% for hemorrhagic stroke (kappa 0.46), and 58.1% and 54.1% for all stroke (kappa 0.55), respectively. Inclusion of secondary diagnosis codes improved sensitivity of claims (70.3% for ischemic stroke, 53.9% for hemorrhagic stroke and 67.0% for all stroke), but PPV decreased (44.8% for ischemic stroke, 34.8% for hemorrhagic stroke and 47.8% for all stroke). Specificity and negative predictive values of claims data were >98% for all stroke types. Findings were similar after excluding patients with prior history of stroke (
Table
).

Conclusions:
Among Medicare patients in the LAAO Registry, administrative claims data had moderate agreement with adjudicated registry-reported stroke events. Claims data may not reliably capture all stroke events in real-world practice, and additional event ascertainment methods may be needed to ensure accurate assessment of stroke in post-marketing surveillance efforts.
Abstract 4119129: PREDICTING 30-DAY ALL-CAUSE READMISSION AFTER STROKE: THE APPLICATION OF MACHINE LEARNING TO LINKED REGISTRY DATA
Authors: Hailat Raed , de los Campos Gustavo , Thompson Mike , Nickles Adrienne , Oostema John , Reeves Mathew
Published: November 2024

Background:
Thirty-day readmission following hospital discharge for stroke is an important quality measure for US hospitals. Current US prediction models for post stroke readmission based on electronic medical records from single healthcare systems or hospitals have modest discrimination (AUC range 0.64 - 0.74).

Aim:
To develop 30-day all-cause readmission prediction model using a machine learning (ML) based method trained on linked stroke registry and administrative claims data.

Methods:
Using probabilistic linking, we matched acute stroke (ICD-10 I61-I63) discharges from 31 hospitals participating in the Michigan Acute Stroke registry between 2016-2020 to multipayer administrative claims data provided by the Michigan Value Collaborative for Medicare and Blue Cross Blue Shield of Michigan commercial beneficiaries. Stroke registry data included patient demographics, clinical characteristics, past medical history, and treatments. Claims data was used to identify readmissions within 30 days of discharge. We used multivariable LASSO logistic regression- a simple ML technique to predict 30-day all-cause-readmission and evaluated the prediction accuracy using a hospital-split internal validation scheme to generate hospital-specific and pooled AUC estimates with 95% confidence intervals (Figure 1).

Results:
Of 19,382 linked stroke discharges, 2,724 (14.1%) were readmitted within 30-days. Readmitted patients were older, more likely to be male, black, and have higher stroke severity (NIHSS >5). Registry hospitals were either primary (64%) or comprehensive (26%) stroke centers. Hospital-specific 30-day readmission ranged between 9.9%-23.1% (
P
<.001) with an average of 14.1% (95% CI:13.6%-14.5%) (Figure 2). Hospital specific AUC estimates ranged between 0.60-0.80 with a pooled AUC of 0.68 (95% CI:0.65-0.70) (Figure 2).

Conclusions:
ML prediction model fitted to linked registry data can be used to predict hospital-specific and statewide readmissions post stroke.
Abstract 4119260: Anomalous Origin Of Left Circumflex Artery From Right Pulmonary Artery Resulting In Heart Failure: A Rare Vascular Steal Phenomenon
Authors: Chander Yogesh , Bhardwaj Rajeev , Nandal Rajesh , Mittal Saurav , Pruthi Taniya , Singh Subeg
Published: November 2024

Background:
Anomalous origin of coronary arteries from the pulmonary artery usually presents at a younger age. However, we encountered a case of a 62-year-old female with an anomalous origin of the left circumflex (LCx) artery from the right pulmonary artery.

Case summary:
A 62-year-old female presented with complaints of dyspnea and angina on exertion for 1 month and had paroxysmal nocturnal dyspnea for the last 4-5 days. She also had an episode of ventricular tachycardia which required DC cardioversion. She had diabetes mellitus type 2 and hypertension. ECG showed diffuse horizontal ST segment depression in precordial, and limb leads and ST segment elevation in aVR suggesting subendocardial ischemia. The echocardiogram showed hypokinesia in basal, mid-inferior and inferolateral segments and LVEF of 42%. There was a marked reduction in global longitudinal strain (average GLPS of -9.2%). Her coronary angiogram revealed extensive collaterals to the left circumflex artery (from the left anterior descending artery and right coronary artery). The left circumflex artery was arising from the pulmonary artery. Exact localization of origin was done by simultaneous contrast injections in the right pulmonary artery and LAD. The anomalous origin of LCx from the right pulmonary artery was hooked using a Tiger catheter.

The patient was advised for surgical management; however, the patient has opted for medical therapy.

Conclusion:
The anomalous origin of coronary arteries from pulmonary arteries is usually detected in childhood e.g. ALCAPA and is associated with other congenital heart diseases. Anomalous origin of LCx from the right pulmonary artery is a rare variant. It can result in a steal phenomenon which may result in angina, heart failure and risk of sudden cardiac arrest.
Abstract 4119262: Anti-atherosclerotic Potential of M2 Macrophage-Derived Exosomes by Promoting Cholesterol Efflux of Foam Cell-Like Vascular Smooth Muscle Cells via the PPARγ-LXRα-ABCA1/ ABCG1 Pathway
Authors: wang shuo , lv yunhui , cui yongchun
Published: November 2024

Background:
Impediment in the excretion of lipid deposits within SMC-derived foam cells (SMC-FCs) is one of the reasons for the continuous expansion of the plaque necrotic core. This study aims to explore the effect and underlying mechanimsm of exosomes secreted by M2 macrophage (M2-exos) on SMC-FCs lipid metabolism and plaque stability.

Methods:
First, immunofluorescence was used to detect the expression levels of CD45 (a recognized differentially expressed molecule of myeloid and SMC-FCs) and the key proteins of cholesterol efflux pathway, ABCA1 and ABCG1, in human early and late plaques. Exosomes derived from M0 and M2 macrophages were purified by sucrose density gradient centrifugation, and characterized based on specific morphology and surface markers. Western blot, Oil red O staining and cell total cholesterol assay were used to assess the effects of M2-exos on the lipid mechanism of SMC-FCs. RNA-seq was used to detect the miRNA profiles of M2-exos. Quantitative real-time PCR was used to identify candidate miRNAs. The dual-luciferase reporting system was utilized to assess the regulatory effect of candidate miRNA on target gene. Then, the effect of M2-exos on the progression and stability of plaques in ApoE
-/-
mice was evaluated using Oil red O, H&E, Masson, Movat and immunohistochemistry.

Results:
Immunofluorescence revealed that compared with early plaques, VSMC-FCs (CD45
-
) were significantly increased in late plaques, and the expression levels of ABCG1 and ABCA1 were marked lower than those in macrophage-derived foam cells (CD45
+
). Purified M2-exos treatment significantly promoted the cholesterol efflux of SMC-FCs in vitro. In high-fat-fed ApoE
-/-
mice, M2-exos significantly reduced the VSMC-FCs, delayed the progression of plaques, decreased necrotic core area and enhanced plaque stability. MiRNA profiling and comprehensive analysis of signaling pathways showed that M2-exos were rich in miR-7683-3p, which played a key role in regulating SMC-FCs lipid metabolism through PPARγ-LXRα-ABCA1/ABCG1 pathway. Dual-luciferase reporting assay showed that miR-7683-3p can specifically bind to the promoter region of homeobox genes A1(HoxA1), an inhibitor of PPARγ-LXRα-ABCA1/ABCG1 pathway.

Conclusion:
M2-exos exerted an obvious atherosclerotic protective effect, and the underlying mechanism was closely related to MiR-7683-3p, which targeted the 3’UTR of HoxA1 mRNA and activated the PPARγ-LXRα-ABCA1/ABCG1 mediated cholesterol efflux in SMC-FCs.
Abstract 4119428: Monosialoganglioside-containing nanoliposomes protect against acute and chronic ischemic stroke injury
Authors: Ahmad Saif , Contreras Jessica , Weissig Volkmar , Lozoya Maria , Davis Tracy , Karamanova Nina , Snider Justin , Ducruet Andrew , Migrino Raymond
Published: November 2024

Background:
Stroke remains a leading cause of mortality and disability. The narrow temporal window and limited availability of, and eligibility for thrombolytic therapy or endovascular thrombectomy are major therapeutic limitations in treating stroke. Neuroprotective therapies that could be given early to replace or augment these existing therapies are needed to improve stroke outcomes. We showed that monosialoganglioside (GM1) containing nanoliposomes composed of phosphatidylcholine, cholesterol and GM1 (70/25/5% molar ratios, NLGM1) protect against hypoxic injury likely through Nrf2-dependent upregulation of antoxidant enzymes.

Aims:
To test if post-occlusion NLGM1 treatment could reduce 1) acute stroke injury following middle cerebral artery occlusion (MCAO) and 2) chronic injury following photothrombotic (PT) stroke injury.

Methods:
20 week old C57BL/6 mice underwent MCAO for 60 minutes and then injected with saline or NLGM1 (1 or 2 mg IV) prior to reperfusion. Neurologic deficit score and brain infarct % area were measured the next day. Separately, mice underwent PT injury followed by injection of saline or NLGM1 (1 or 2 mg immediately and 2 hours post-injury) and cognitive/behavior tests done 1-90 days post injury.

Results:
Following MCAO, there was reduced neurologic impairment, infarct volume and brain edema with NLGM1 versus saline control (Fig. 1). Following PT injury, there was reduced neurologic, cognitive and motor impairment from Day 2-90 post-injury with NLGM1 versus saline control (Fig. 2). In both stroke models, there was no difference in efficacy between 1 and 2 mg NLGM1 doses.

Conclusions:
Treatment of mice with NLGM1 following MCAO or PT stroke injury resulted in improved structural (infarct size, edema) and functional (cognitive, behavior, motor) outcomes in the acute (MCAO) and chronic (PT) timeframes. NLGM1 is a potential novel therapeutic agent for stroke.
Abstract 4119472: Predictors of Sudden Cardiac Death in Patients with Atrial Fibrillation and No Apparent Risk Factor of Sudden Cardiac Death
Authors: Chang Sheng Nan , Chen Jien-Jiun , Huang Pang-Shuo , Chiu Fu-chun , Wu Cho-Kai , Tsai Chia-Ti
Published: November 2024

Background:
Atrial fibrillation (AF) is associated with sudden cardiac death (SCD). It is known that AF is associated with multiple traditional risk factors of SCD, such as coronary artery disease (CAD), history of myocardial infarction (MI), left ventricular hypertrophy (LVH) and low left ventricular ejection fraction (LVEF). However, AF per se could predispose SCD not mediated by these cardiovascular risk factors, and predictors of SCD in AF patients without these apparent SCD risk factors are unknown.

Methods:
Using the NTUH iMED database, AF patients without apparent SCD risk factors were longitudinal followed up from Jan. 2010 to Dec. 2021. The primary outcome was implantation of implantable cardioverter defibrillator (ICD) due to SCD. Cox regression was used to identify the predictors of SCD.

Results:
A total of 11250 AF patients without cardiovascular SCD risk factors and LVEF ≥55 % were longitudinally followed up. We first found CHA2DS2-VASc score did not predict SCD event. We found male gender (hazard ratio [HR ] 1.71 [1.05-2.78 ], p =0.032), hyperthyroidism (HR 3.50 [1.40-8.77 ], p=0.007）and paroxysmal AF (PAF)(HR 2.86 [1.63-5.04 ], p<0.001）were associated with higher SCD risks. We created a AFSCD score using these parameters. We found SCD risk incrementally increased with increasing AFSCD score (p <0.001 for trend). Patients with highest score (5 points) had more than 3-fold SCD risk compared with those with 0-point score (1.18 % person-year vs 0.36 %, p<0.001). The C statistic of AFSCD score was significantly higher than CHA2DS2-VASc score (0.64 [0.57-0.70] vs 0.40 [0.33-0.48], p <0.01).

Conclusions:
Male gender, hyperthyroid AF and PAF were predictors of incident SCD in AF patients and AFSCD scoring scheme based on these risk factors could possibly be implemented in clinical practice.
Abstract 4120270: Risk Factors for Catastrophic Complications Requiring Emergent Extracorporeal Life Support in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Fisher Bryant , Wang Yisi , Thoma Floyd , Shetty Neha , Yoon Pyongsoo , Bonatti Johannes , Kaczorowski David , Serna-Gallegos Derek , West David , Sultan Ibrahim , Morell Victor , Chu Danny
Published: November 2024

Background:
Transcatheter Aortic Valve Replacement (TAVR) is often performed in the cardiology catheterization suite. Although rare, instances of annular rupture, cardiac arrest, and coronary occlusion may occur requiring institution of emergent extracorporeal life support (ECLS). This study aims to examine the risk factors for complications requiring ECLS during TAVR procedures to identify patients who may benefit from having procedures performed in hybrid operating rooms.

Methods:
Data from the Transcatheter Valve Therapy registry for our institution was obtained on patients (n=4908) who underwent TAVR between November 2012 and July 2023. Univariable logistic regression was performed to compare relevant covariates in those requiring intraoperative ECLS (n=23) to the rest of the patient cohort (n=4885). All-cause mortality during the follow-up period was compared to assess the impact of emergent intraoperative ECLS.

Results:
The patients requiring ECLS experienced significantly higher all-cause mortality (69.6% versus 28.8%, p<0.001) with median follow up of 2 years
(Table 1)
. Female sex (p=0.013) and smaller annulus size (p=0.007) were significant independent risk factors for complications requiring emergent intraoperative ECLS based on univariable logistic regression
(Table 2).
Patients requiring ECLS had significantly smaller annulus sizes (21.0-23.2 mm) compared to the uncomplicated cohort (22.0-25.8 mm). Of the patients requiring ECLS, 11 cases (47.8%) were due to annular/ventricular rupture while 4 cases (17.4%) resulted from valve embolization. Of note, valve type (self-expanding versus balloon expandable), annular calcification, and porcelain aorta were not found to be significant risk factors.

Conclusions:
In this large volume single-center retrospective cohort study, female sex and smaller aortic annular size significantly increased the risk of complications necessitating ECLS support during TAVR procedures. Our study represents the first to identify independent risk factors for catastrophic complications during TAVR procedures. Patients with these high-risk profiles should have their TAVR procedures performed in the hybrid operating room with cardiopulmonary bypass on immediate standby.
Abstract 4120680: Language AI Chat BOTs as Pioneers in Cardiovascular Diagnosis? A Retrospective Analysis on Real-Time Patients in a Tertiary Care Centre
Authors: Naeem Azka , Baqir Syed Mujtaba , Khan Omair , Jana Kundan , Mohsin Fizza , sajid fatima , Aung oo , kaur Avleen , Wong Victor , SHETTY VIJAY , Slobodyanyuk Kseniya
Published: November 2024

GPT-3 and GPT-4, show promise in assisting healthcare professionals with clinical questions. Their performance in real-time clinical scenarios, particularly with cardiovascular symptoms, remains underexplored. This study aims to evaluate their precision and reliability compared to physicians.

Hypothesis:
We hypothesize that board-certified emergency department attendings at Maimonides Medical Center exhibit higher accuracy and reliability than GPT-3.5 and GPT-4 in generating differential diagnoses based on history and physical examination for patients presenting to the emergency department.

Methods:
Patient data from Maimonides Medical Center's emergency department, collected from January 1, 2023, to April 30, 2023, was analyzed. Demographics, symptoms, medical history, and discharge diagnoses recorded by emergency room attendings were examined. ChatGPT-3.5 and GPT-4 generated differential diagnoses, which were compared with those by attending physicians. Accuracy was determined by comparing each rater's diagnoses with discharge diagnosis, calculating the proportion of correctly identified cases. Precision was assessed using Cohen's kappa coefficient and Intraclass Correlation Coefficient to measure agreement between raters.

Results:
Patient demographics showed mean age of 49.12 years, with 57.3% males and 42.7% females. Chief complaints included fever/sepsis (24.7%), gastrointestinal issues (17.7%), and cardiovascular problems (16.4%). Diagnostic accuracy against discharge diagnoses was highest for Chat GPT-4 (85.5%), followed by Chat GPT-3.5 (84.6%) and ED attendings (83%). Cohen’s kappa demonstrated moderate agreement (0.7) between AI models, with lower agreement observed for ED attendings. Stratified analysis revealed higher accuracy for gastrointestinal complaints with Chat GPT-4 (87.5%) and cardiovascular complaints with Chat GPT-3.5 (81.34%).

Conclusion:
Our study demonstrates that Chat GPT-4 and GPT-3.5 exhibit comparable diagnostic accuracy to attendings, highlighting their potential to aid decision-making in dynamic clinical settings. The stratified analysis revealed comparable reliability and precision of the AI chat bots for cardiovascular complaints which represents a significant proportion of the high risk patients presenting to the emergency department. This study contributes to integrating AI models into medical practice, enhancing efficiency and effectiveness in clinical decision-making
Abstract 4120687: Multi-Omics Insights into Recovery from Acute Fulminant Myocarditis Treated with Ruxolitinib
Authors: Qin Juan , Aras Mandar , Song Evelyn , Padmanabhan Arun , Connolly Andrew , Zhou Lylybell , O'Brien Connor , Moslehi Javid
Published: November 2024

Background:
There are currently no approved medical therapies for acute fulminant myocarditis (AFM). Janus kinase (JAK) inhibitors target the JAK-STAT signaling pathway, which is crucial in immune activation. We report the first use of ruxolitinib, a JAK inhibitor, for treatment of AFM. Multi-omics single-cell technologies, including RNA-seq, T-/B-cell receptor seq, and CITE-seq, were employed to analyze immune profiles pre- and post-ruxolitinib treatment.

Results:
A 20-year-old female presented with AFM with cardiogenic shock and was supported by VA-ECMO and impella CP. Endomyocardial biopsy showed lymphocytic myocarditis. The patient received pulsed steroids and was listed for orthotopic heart transplant. Due to deteriorating conditions, ruxolitinib (10 mg BID) was added with immediate improvement in cardiac and inflammatory biomarkers and hemodynamics. ECMO was decannulated on day 6 and impella CP was removed on day 8. Repeat TTE on day 9 showed normalization of cardiac function (LVEF 58%, increased from 10%). She was discharged on ruxolitinib and is doing well in follow-up. Multi-omics single-cell technologies were employed on PBMCs collected at four time points: prior to ruxolitinib treatment (but after treatment with corticosteroids), and post-ruxolitinib treatment on day 5, day 8, and 2-months. At baseline, prior to treatment, scRNA-Seq and CITE-seq analysis revealed upregulated JAK-STAT signaling in pathogenic immune cells such as NK cells, CCR2
+
/CCR5
+
/HLA-DR
+
monocytes and activated T cells. Ruxolitinib treatment significantly decreased these pathogenic immune cells, with inhibition of STAT1/STAT3 signaling. Ruxolitinib also significantly decreased key cytotoxic genes PRF1, GZMB, and TBX21 in T and NK cells. TCR sequencing revealed clonal expansions of activated T cells with high levels of pro-inflammatory genes (IL2/IL6/IFNg) at baseline which were dramatically reduced post-treatment with ruxolitinib. Longitudinal data indicated normalization of naive T and B cell levels and clonal diversity, mirroring her clinical improvement.

Conclusions:
Ruxolitinib significantly modulates immune profiles and disrupts pathogenic signaling in AFM. This first reported use of ruxolitinib in AFM, coupled with our multi-omics analysis, highlights profound immune reprogramming and supports targeted immune modulation for rapid recovery, underscoring ruxolitinib’s therapeutic efficacy.
Abstract 4120749: GPR39 Orchestrates the Myogenic Response in Coronary Autoregulation
Authors: Le Dai-Trang , Kajimoto Masaki , Zhao Yan , Kaul Sanjiv
Published: November 2024

Background:
Coronary autoregulation is the ability of a normal heart to maintain constant coronary blood flow (CBF) over a wide range of coronary driving pressures (CDPs) provided cardiac work remains constant. It is based on the myogenic response, the molecular mechanism of which is unknown. We recently described the presence of a G-protein coupled receptor (GPR39) in the vascular smooth muscle cells (VSMCs) of coronary arterioles in the mouse heart. We showed that endogenous eicosanoids, the vasoconstrictor 15-hydroxyeicosatetraenoic acid (15-HETE) and the vasodilator 14,15-epoxyeicosatrienoic acid (14,15 EET). act through this receptor to maintain coronary vascular tone.

Hypothesis:
We, therefore, hypothesized that GPR39 is the molecular switch responsible for the coronary myogenic response and autoregulation.

Methods:
We studied 6 anesthetized dogs at baseline and after administration of VC-108, a specific, potent GPR39 antagonist. Both during baseline and drug administration multiple coronary stenoses were created on the left anterior descending coronary artery (LAD). At each stage, heart rate, mean aortic pressure, distal LAD pressure, and right atrial pressure (RAP) were measured, as was CBF. Stenosis severity was defined by the CDP (LAD pressure minus RAP).

Results:
Mean basal coronary hyperemic response was 3.0 in all anesthetized animals indicating normal vasomotor function. Systemic hemodynamics did not differ between baseline and drug stages. Figure 1 is an example from a single dog where, at baseline, CBF remained constant over a CDP of 40-90 mm Hg indicating intact autoregulation. As expected, CBF declined when CDP fell below the autoregulatory range. After VC-108 administration CBF correlated linearly with CDP, indicating abolishment of the myogenic response. Baseline CDP vs. CBF data from all 6 animals within the autoregulatory range is depicted in Figure 2. No relation is noted between the two indicating intact autoregulation. In contrast, CDP vs. CBF relation is linear in all animals after VC108 is administered over the entire range of CDP’s measured, indicating abolishment of autoregulation (Figure 3).

Conclusions:
Our results indicate that GPR39 is a potential molecular switch for the regulation of the myogenic response underlying coronary autoregulation. Pharmacological blockage of GPR39 abolishes the myogenic tone. These novel findings set the stage for development of novel pharmacological agents for treatment of coronary artery disease.
Abstract 4120830: A Curious Case of Clozapine Carditis with Cardiac Convalescence
Authors: Maamari Dimitri , Koshti Vivek , Yaros Katarina , Berbarie Rafic
Published: November 2024

Case Presentation:
Clozapine is an antipsychotic used in treatment-resistant schizophrenia. Its use has been limited by adverse events, rarely including myocarditis. Here, we describe a rare case of clozapine-induced myocarditis and the improvement of cardiac function with avoidance of clozapine for one week and initiation of guideline-directed medical therapy (GDMT).

A 29-year-old man with schizophrenia on risperidone and paroxetine was admitted with schizophrenia decompensation and suicidal ideations. He was transitioned to clozapine with improvement in his psychiatric symptoms. Thirteen days after starting clozapine, he developed nausea, vomiting, tachycardia, and low-grade fever. He had leukocytosis but it was thought to be, in part, secondary to methylprednisolone before rituximab infusions for his multiple sclerosis. An electrocardiogram revealed sinus tachycardia, and troponin, which was taken in the setting of clozapine therapy, was 6.

Four days later, his fever and tachycardia with chills and dyspnea persisted; troponin was in the forties and increased to 235 within a few hours. Over the next 36 hours, troponin peaked at 3,600. C-reactive protein and erythrocyte sedimentation rates were elevated at 20.5 and 51, compared to 1.8 and 3 respectively upon initiation of symptoms a few days earlier. A respiratory viral panel, blood and urine cultures, human immunodeficiency virus, and an autoimmune workup were unrevealing. Clozapine was held. A transthoracic echocardiogram revealed a reduced systolic function with a left ventricular ejection fraction (LVEF) of 40%. A cardiac magnetic resonance imaging revealed acute myocarditis with LVEF 24%. He was started on GDMT and a repeat echocardiogram six days later revealed normalization of systolic function with LVEF 56% with clinical improvement. His last dose of clozapine was seven days earlier. He was discharged on GDMT and clozapine was added to his allergy list.

Discussion:
Myocarditis is a serious and rare adverse event to clozapine therapy. Symptoms are non-specific and delays in diagnosis may lead to myocardial damage and fatal arrhythmias. In light of the patient’s presentation, unrevealing workup, and improvement with avoidance of clozapine, we believe that the individual had clozapine-induced myocarditis. It is important to highlight the occurrence of this rare outcome to consider this toxicity and initiate treatment in time.
Abstract 4121042: Novel genetic risk loci of arterial stiffness in Asian ancestry individuals
Authors: Chen Bangwei , Zeng Shengyin , Zhao Zhiguang , ruan lei , Zhang Jiangguo , Zhu Shida , Zhang Cuntai , LI TAO
Published: November 2024

Background:
Arterial stiffness serves as an independent predictor of cardiovascular disease risk. Pulse-wave velocity (PWV) is a non-invasive measurement of arterial stiffness. However, the genetic risk variants associated with arterial stiffness in the Asian ancestry population remain largely unknown. This lack of knowledge hinders the development of targeted preventive and treatment strategies.

Hypothesis:
Arterial stiffness is associated with genotyped SNP loci that have genetic relationships with metabolic syndrome phenotypes.

Methods:
For PWV, we performed genome-wide association study and gene-based genetic association study in 912 individuals from the Tongji-BGI research cardiovascular health (TORCH) cohort. We then used linkage disequilibrium score regression to estimate pairwise genetic correlations between arterial stiffness, blood pressure, lipids, and diabetes.

Results:
Eleven risk loci associated with arterial stiffness were discovered at genome-wide significance (
P
< 5 × 10
−8
), including three in intronic (rs978453410 mapping to
PPP2R5E;
rs146270927 mapping to
ECI1;
rs189517402 mapping to
CNN2
).
UBE2U
and
ECI1
were identified as the PWV-associated genes by gene-based analysis. Genetic correlation analyses revealed inter-related of PWV with systolic blood pressure, mean arterial pressure, total cholesterol and diabetes.

Conclusions:
This research firstly identified eleven novel genetic variants associated with arterial stiffness in Asian ancestry individuals. Further research aimed at reducing arterial stiffness may benefit from the identification of SNPs and genes like ECI1, which is related to the oxidation of unsaturated fatty acids in the mitochondria.
Abstract 4121198: Structural Network Alterations After Cardiopulmonary Bypass In a Juvenile Porcine Model
Authors: Furuta Akihisa , Kobayashi Kumi , Kobayashi Kei , Agaronyan Artur , Wang Paul , Tu Tsang-Wei , Lin Stephen , Ishibashi Nobuyuki
Published: November 2024

Background:
Cardiopulmonary bypass (CPB) can trigger inflammatory and oxidative stresses in the developing brain. Clinical studies showed altered brain network structure in children after infant cardiac surgery. However, the impact of CPB on structural connectivity remains poorly understood. This study aims to determine the effects of CPB on structural connectivity and underlying cellular events using a juvenile porcine model.

Methods:
CPB (150 min total) was performed on 2-week-old Yorkshire piglets. High-resolution diffusion tensor imaging (DTI) and neurite orientation dispersion and density (NODDI) imaging were performed 4 weeks post-CPB in a total of 12 animals (Control; n=7, CPB; n=5). Structural connectivity assay together with histological analysis was conducted to assess the brain network organization.

Results:
Our network analysis (Image 1) revealed a CPB-induced reduction of structural connections in particular nodes, such as in the anterior prefrontal cortex (APC), primary somatosensory cortex, substantia nigra (SN), and globus pallidus (GP). In contrast, there was an increase in the premotor cortex (PreMC), primary motor cortex (PriMC), dorsal posterior cingulate cortex (DPCC), and somatosensory cortex (SAC). Three-dimensional images were generated based on these altered nodes, and tractography was generated to indicate changed fiber tracking (Image 2). We found reduced network connections between the basal ganglia and frontal cortex, and increased connections between the motor and posterior region. DTI and NODDI indicated that microstructures of the superior corona radiata (SCR), internal capsule (PLIC), and anterior prefrontal (AP-WM), motor (PreM-/PriM-WM), and somatosensory white matter (SA-WM) were significantly altered after CPB (Image 3). While Iba1+ microglia was activated across all brain regions after CPB (P<.05), CPB-induced oligodendrocyte immatureness was identified in the WMs involved in APC-SN and APC-GP pathways (P<.05). Notably, CPB increased the number of mature oligodendrocytes in motor and SA-WMs (P<.05) where structural connections were increased after CPB. In addition, we found SN dopaminergic neuron injury after CPB (P<.05).

Conclusion:
CPB altered structural network organization in the developing brain. Spatial differences in oligodendrocyte responses and susceptibility of specific subpopulations of neurons may contribute to the unique connectivity alterations observed after CPB.
Abstract 4121516: Efficacy of Sentinel Cerebral Embolic Protection Device in Transcatheter Aortic Valve Replacement: A Meta-Analysis of Randomized Controlled Trials and Propensity Score Matched Studies
Authors: Jain Hritvik , Odat Ramez , Pervez Neha , Dey Debankur , Goyal Aman , Jain Jyoti , Ahmed Mushood , Patel Nandan , Jenil Franco Ancy , Shah Janhvi , Jha Jagriti , Passey Siddhant
Published: November 2024

Background:
Transcatheter aortic valve replacement (TAVR) is frequently associated with stroke due to debris embolization. Although the risk of stroke with the newer-generation devices is lower, stroke still represents a significant cause of mortality and morbidity after TAVR. The Sentinel cerebral embolic protection (CEP) device (Boston Scientific) is a dual embolic filter device designed to capture debris dislodged during TAVR. The current literature concerning the efficacy of Sentinel CEP in the reduction of stroke in patients undergoing TAVR is limited and inconsistent.

Aim:
This meta-analysis aimed to compare clinical outcomes with Sentinel CEP device in patients undergoing TAVR.

Methods:
A comprehensive systematic literature search was performed on PubMed, Embase, Cochrane Library and Clinicaltrial.gov from inception until 1st May 2024 to retrieve randomized controlled trials (RCTs) and propensity-matched studies comparing TAVR with and without the Sentinel CEP device. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using the DerSimonian-Laird random-effects model, with a p-value of <0.05 considered statistically significant.

Results:
6 studies with a total of 25,130 patients undergoing TAVR (12608: Sentinel CEP device; 12522: Without Sentinel CEP device) were included in this meta-analysis. The use of the Sentinel CEP device in TAVR was associated with a statistically significant lower risk of acute kidney injury [OR: 0.89; 95% CI: 0.81, 0.97; p=0.01]. The use of Sentinel CEP device in TAVR was associated with a statistically insignificant trend towards reduction in stroke [OR: 0.80; 95% CI: 0.58, 1.10; p=0.18], all-cause mortality [OR: 0.74; 95% CI: 0.51, 1.07; p=0.11], and major vascular complications [OR: 0.74; 95% CI: 0.46, 1.19; p=0.21].

Conclusion:
The use of the Sentinel CEP device in patients undergoing TAVR does not lead to a statistically significant reduction in stroke, all-cause mortality, and major vascular complications; however, the risk of acute kidney injury is lower. Large, multicentric RCTs are warranted to corroborate the findings of this meta-analysis.
Abstract 4121527: Empagliflozin Improves Mitochondrial Biogenesis in Pulmonary Arterial Hypertension
Authors: Yoshida Keimei , Toth Eszter , Duijvelaar Erik , Neep Beau , Agarwal Stuti , Pan Xiaoke , Sanada Takayuki , Yoshida Yu , Aman Jurjan , Dejesus Vinicio , Handoko Louis , Abe Kohtaro , Sun Xiao-Qing , Bogaard Harm
Published: November 2024

Background:
Pulmonary arterial hypertension (PAH) is a devastating disease characterized by endothelial proliferation and progressive pulmonary vascular (PV) remodeling. Empagliflozin (EMPA), a sodium glucose cotransporter 2 (SGLT2) inhibitor, benefits heart failure patients, potentially mediated by improved mitochondrial function. This study aimed to explore the impact of EMPA in PAH.

Methods and Results:
Immunohistochemistry of pulmonary arteries revealed the expression of SGLT2 in the intima of PAH patients. Microvascular endothelial cells (MVECs) were isolated from lungs of control subjects (CTRL) and PAH patients and found intense expression of SGLT2 in PAH MVECs. Western blot showed significantly higher expression of SGLT2, while PGC-1α, a transcriptional coactivator known as a master regulator of mitochondrial biogenesis, was lower in PAH MVECs compared to CTRL (Image 1). PAH MVECs were treated with EMPA (1 μM) and observed a significant increase of PGC-1α and BMPR2-pSmad1/5/9. Similarly, knockdown of SGLT2 using siRNA resulted in enhanced expression of PGC-1α. Moreover, Seahorse analysis revealed increased oxygen consumption rate and reduced extracellular acidification rate by EMPA, suggesting that EMPA improved mitochondrial respiration. In addition, EMPA attenuated reactive oxygen species and proliferation of PAH MVECs, as revealed by MitoTracker analysis and MTT assay respectively.

For the in vivo study, Sprague-Dawley rats (120-180 gram) were injected with SU5416 (Week-0) and exposed to hypoxia for 3 weeks followed by normoxia. After randomization at Week-4, rats were treated with EMPA (300 mg/kg in chow, n=12) or placebo (PLAC, n=12). Catheterization and histological analysis were performed at Week-8. EMPA decreased PV resistance index (0.21±0.02 vs. 0.37±0.05 mmHg/mL/min/mm
2
, p=0.01), ameliorated intima thickening (21.0±7.5 vs. 40.0±7.8%, p<0.01) and vessel occlusion (Image 2).

We further conducted a single-center, open-label, single-arm interventional proof-of-concept study to assess the tolerability of 12 weeks of treatment with 10mg of EMPA as add-on therapy in eight patients with a prior PAH diagnosis. There were no treatment related adverse events during the study time course.

Conclusions:
EMPA directly improved mitochondrial biogenesis and attenuated proliferation of MVECs from PAH patients and reversed PV remodeling in experimental PAH. EMPA treatment was feasible in patients with PAH. EMPA may serve as a new therapeutic option for PAH.
Abstract 4121555: Integrated Polygenic Score Stratifies Risk of Peripheral Artery Disease and Major Adverse Limb Events
Authors: Flores Alyssa Monica , Ruan Yunfeng , Misra Anika , Selvaraj Margaret , Bellomo Tiffany , Eagleton Matthew , Rosenfield Kenneth , Hornsby Whitney , Patel Aniruddh , Natarajan Pradeep
Published: November 2024

Background:
Peripheral artery disease (PAD) is a heritable atherosclerotic condition. With growing knowledge of the genetic basis for PAD and related risk factors, there is opportunity to identify high-risk individuals for prevention and potentially intervention based on polygenic background.

Aims:
To develop and validate an integrated genome-wide polygenic score for PAD (GPS
PAD
), evaluate association of polygenic risk with major adverse limb events (MALE), and compare predictive performance in diverse ancestral populations to previously published polygenic scores.

Methods:
We developed GPS
PAD
by integrating genetic association summary statistics for PAD and related traits stratified by ancestry. GPS
PAD
was trained in a sample of 96,239 European individuals from the UK Biobank, and validated in multi-ancestry cohorts, including a holdout validation UK Biobank dataset (N=304,294), and external All of Us (AoU; N=237,173) and Mass General Brigham Biobank datasets (N=37,017). GPS
PAD
performance was benchmarked against previously published polygenic scores and clinical risk factors.

Results:
GPS
PAD
was comprised of 603,595 variants with weights informed by association with PAD and ten PAD risk factors across five ancestry groups. GPS
PAD
had an OR-per SD of 1.63 in the holdout UK Biobank dataset (95% CI 1.60-1.68). GPS
PAD
outperformed previously published scores in non-European subgroups in the UK Biobank and achieved superior cross-population portability in external validation cohorts. GPS
PAD
was associated with incident PAD in the UK Biobank (HR 1.66; 95% CI 1.61-1.71) and achieved improvements in discrimination (ΔC-statistic 0.030) that were nearly equivalent to the additive performances of diabetes (ΔC-statistic 0.029) and smoking (ΔC-statistic 0.034) to the baseline model including age, sex, and 10 principal components of ancestry. Among individuals with prevalent PAD, GPS
PAD
was associated with incident MALE in the UK Biobank (HR 1.48; 95% CI 1.24-1.77). GPS
PAD
consistently identified individuals with PAD at high MALE-risk in the Mass General Brigham Biobank (HR 1.34; 95% CI 1.12-1.60), and AoU (HR 1.33; 95% CI 1.12-1.58).

Conclusions:
These findings contribute a polygenic score for PAD that predicts disease and MALE with cross-cohort performance and transferability to diverse ancestries. Integrated polygenic scores may be used to stratify PAD risk and target more aggressive management, lifestyle modification, and surveillance efforts.
Abstract 4121624: Ambulatory Inotropic Support in Patients with Stage D Heart Failure Does Not Increase ICD Therapies
Authors: Sunthankar Kathryn , Pfaff Jamie , Farber-Eger Eric , Richardson Travis , Wells Quinn , Ooi Henry , Skelton Melanie , Stevenson Lynne , Pedrotty Dawn
Published: November 2024

Background:
Ambulatory inotropic infusions can be used as a palliative therapy (PT) or bridge to advanced therapies in end-stage heart failure (ESHF) patients, many of whom have implantable cardioverter defibrillators (ICDs).

Research Questions:
How often do patients receive ICD therapies after initiation of outpatient inotropic support and how often is defibrillation inactivated?

Methods:
We conducted a retrospective review of all patients discharged from an academic tertiary medical center with a new prescription for inotropic therapy between November 2017 and March 2023. Clinical data, Palliative Care consultation, and ICD interrogations before and after inotrope initiation were extracted from the electronic health record.

Results:
The cohort comprised 45 patients discharged on new inotropic support, including 22 (49%) with intent of PT and 23 (51%) as a bridge to advanced therapies (Figure). Among PT patients, 15 (68%) had an ICD in place with only 4 having ICD therapies deactivated at discharge. Only 2 additional PT patients had a documented discussion regarding ongoing ICD therapies. By 1 year, 4 (18%) PT patients were transitioned to hospice and 13 (59%) had died, with only 1 additional patient having ICD deactivation. Of 28 patients discharged on inotropic infusions with ICD therapies on (both PT and bridge patients), only 4 patients had ICD therapies turned off later and no ICD shocks were reported for the year following initiation of inotropic support.

Conclusion:
In a series of 45 patients initiated on inotropic support for PT or bridge to advanced therapies, the majority (77%) had an active ICD, but therapies were rarely delivered. Notably, there were very few documented discussions regarding ICD therapies in PT patients even with specialty Palliative Care consultation. In patients with ESHF initiated on inotropic support as PT, most patients chose to leave ICD therapies in place. For those patients, there was a low rate of ICD therapies delivered.
Abstract 4122024: Fibroblasts Are the Primary Contributors to a Disrupted Micro-Environment in End-Stage Pediatric Hypertrophic Cardiomyopathy
Authors: Tadros Hanna , Turaga Diwakar , Zhao Yi , Tsai Chang-Ru , Adachi Iki , Li Xiao , Martin James
Published: November 2024

Background:
Hypertrophic cardiomyopathy (HCM) is a relatively rare but debilitating diagnosis in pediatric patients. This represents a vulnerable population who often require heart transplantation. Here, we examine the transcriptome in ventricular tissue to identify underlying cellular processes unique to pediatric HCM (pHCM).

Methods:
We performed single-nucleus RNA sequencing on explanted hearts at transplant in female patients with end-stage pHCM (n=3) and compared findings to pediatric control (n=2) and adult HCM (n=5; Figure 1A-1B).

Results:
We generated 91,682 single-cell transcriptomes from 8 tissue samples. Principal component analysis exhibited the largest source of transcriptional variation separated pHCM and controls (Figure 1C). We identified distinct underlying cellular processes in cardiomyocytes, fibroblasts, endothelial cells, and myeloid cells in pHCM. pHCM was enriched in cardiomyocytes with stressed signatures and pathways associated with hypertrophy (Figure 1D); we noted depletion of tissue-resident macrophages (Figure 1D) and increased vascular remodeling in endothelial cells in pHCM. Fibroblasts exhibited activation signatures and compared to adult HCM, showed heightened fibrotic processes and a unique pro-fibrotic cluster with increased metabolic stress, mitochondrial turnover, and anti-apoptotic properties (Figure 2). In cell-to-cell communication, the differential number and weight of interactions were higher in pHCM compared to controls and fibroblasts had the highest strength of outgoing interactions.

Conclusions:
Our analysis provides the first single-nuclei analysis focused on pHCM. Fibroblast-mediated cellular processes contributed most to the disrupted micro-tissue environment; they had more downstream processes associated with fibrosis and may respond to metabolic stress differently compared to adult HCM. This advances our understanding of the early presentation of pHCM, providing a crucial steppingstone toward improved patient outcomes.