bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4142220: Recovery of Anthracycline-Induced Cardiomyopathy- A Contemporary Cohort Study
Authors: Itzhaki Ben Zadok Osnat , Simitsis Panagiotis , Nohria Anju
Published: November 2024

Background:
There are limited data regarding left ventricular ejection fraction (LVEF) recovery rates among patients with anthracycline-induced cardiomyopathy (AIC).

Aims:
To assess the rate of LVEF recovery and its predictors in a contemporary and heterogenous cohort of patients with AIC.

Methods:
A retrospective cohort study of adult patients with new onset cardiomyopathy determined to be secondary to anthracyclines after a comprehensive work-up for potential etiologies within Massachusetts General Brigham between 2010 and 2023. LVEF recovery was defined as an absolute LVEF increase of ≥10% from LVEF at detection of AIC to a final LVEF ≥50%. Time to LVEF recovery within the first 3 years post-diagnosis was assessed using Cox proportional hazards regression analysis with all-cause death/mechanical circulatory support/heart transplant as competing risks based on the Fine-Gray method. Non-fatal cardiovascular (CV) events included acute decompensated heart failure, acute coronary syndrome and malignant arrhythmias requiring admission.

Results:
The cohort included 167 patients with AIC. The median age at anthracycline exposure was 60 (Q1, Q3: 48, 69) years, 53% (n=88) were females and majority had lymphoma (n=92, 55%) and breast cancer (n=39, 23%). The median time from first anthracycline exposure to detection of AIC was 631 (Q1, Q3: 219, 3569) days and median LVEF was 38 (Q1, Q3: 29, 45) %. A total of 42% (n=70) were managed by dedicated cardio-oncologists and neurohormonal therapy was prescribed in 86% (n=144). LVEF recovered in 38% (n=63) at a median time of 349 (Q1:Q3: 137, 691) days from AIC detection. Statin use was associated with a higher likelihood of recovery (HR=2.162, 95%CI:1.207-3.875, p=0.009), while age>60 at time of anthracycline exposure, non-white race, longer duration between anthracycline exposure and detection of AIC, increased LV end-diastolic diameter, and lymphoma vs. other cancers had lower adjusted odds of LVEF recovery. Patients with recovered LVEF were less likely to experience CV events during follow-up (HR=0.455; CI 0.22-0.95, p=0.036). LVEF recovery, as a time-dependent variable, was not associated with all-cause or cardiovascular death.

Conclusion:
In a contemporary cohort of patients with AIC, 38% experienced LVEF recovery and lack of recovery was associated with a higher burden of CV events requiring admission. Routine screening for AIC may improve the likelihood of recovery and improve outcomes.
Abstract 4142224: Efficacy of Inferior Vena Cava-Pulmonary Artery Bypass for Right Ventricular Dysfunction under Left Ventricular Assist Device Support: An in vitro study using a biventricular circulation system
Authors: Uchida Kanami , Hattori Kaoru , Inafuku Hitoshi , Jumpei Takada , Furukawa Kojiro , Iwasaki Kiyotaka
Published: November 2024

Introduction:
Right heart failure under the support of a left ventricular assist device (LVAD) presents a life-threatening condition characterized by organ edema and limited LVAD support. Implementing an inferior vena cava-pulmonary artery (IVC-PA) bypass graft may mitigate these complications by reducing central venous pressure (CVP) and improving LVAD support efficiency. This study aimed to elucidate an adequate graft diameter for an IVC-PA bypass in terms of CVP reduction during LVAD-assisted circulation using an in vitro biventricular pulsatile circulatory system.

Methods:
We developed a biventricular pulsatile circulation system capable of providing circulatory assistance via an LVAD (centrifugal pump) connected to the apex of a left ventricular model （Fig）. A representative condition of cardiogenic shock was produced by adjusting LV systolic pressure, aortic pressure, and CVP to 80 mmHg, 80/40 mmHg, and 7.5 mmHg, respectively. A right heart failure model was produced by adjusting LV systolic pressure, aortic pressure, and CVP to 45 mmHg, 70 mmHg, and 16 mmHg, respectively, under LVAD support at 1700 rpm. Then, an adequate IVC-PA bypass diameter was investigated in terms of reducing CVP and increasing bypass flow support among 4mm and 18 mm with 2mm interval. The diameters of PA and IVC, and systolic PA pressure were set to 19 mm, 19 mm, and 18 mmHg, respectively. Elastic LV and RV models were driven by pneumatic positive and negative pressures.

Results:
We found a linearly increasing trend of bypass flow and a decreasing trend of CVP with increasing bypass diameters from 4 to 12 mm. When applying the bypass graft over 12mm diameter, bypass flow and CVP plateaued at 3.4 L/min and 7.5 mmHg, respectively (Fig).

Conclusion:
Our sophisticated in vitro biventricular circulation study suggests that in scenarios of right heart failure under LVAD support, implementing a bypass graft from the IVC to the PA is effective for decreasing CVP and reducing right ventricular preload. This study indicates that the optimal bypass diameter for reducing CVP is 12 mm when the diameters of the IVC and PA are 19 mm. These findings encouraged us to evaluate the efficacy in in vivo clinical settings.
Abstract 4142228: The Association Between Sodium-glucose Cotransporter-2 Inhibitors and Major Adverse Cardiac Events in Tafamidis-treated Transthyretin Amyloid Cardiomyopathy: A Real-World Analysis
Authors: Chi Kuan Yu , Borkowski Pawel , Osabutey Anita , Varrias Dimitrios , Song Junmin , Chiang Cho Han , Chang Yu-Cheng , Lee Pei Lun , Chang Yu , Madan Shivank , Patel Snehal
Published: November 2024

Background:
In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), residual mortality remains high despite the use of tafamidis.

Research Question:
What is the impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on tafamidis-treated ATTR-CM?

Aims:
We aimed to examine if SGLT2i were associated with additional benefits in this population.

Methods:
We conducted a retrospective, propensity score-matched cohort study using aggregate data from the TriNetX Global Collaborative Network database. We included adult patients with ATTR-CM, through the identification of tafamidis prescription, between May 1
st
, 2019 and Nov 1
st
, 2023. SGLT2i users were defined as having SGLT2i prescriptions on the day of tafamidis initiation. SGLT2i nonusers had no records of SGLT2i during the same period. Index date was set as the date of tafamidis initiation. The primary endpoint was major adverse cardiac events (MACE), defined as a composite of any death, hospitalization for heart failure (HF), or cardiac arrest/ventricular tachycardia/fibrillation. Secondary endpoints were individual MACE. We set pneumonia and gastrointestinal bleeding as falsification endpoints. Differences in baseline characteristics between SGLT2i users and non-users were compared using standardized mean differences (SMDs) after propensity score matching. The outcomes were compared within 2 years of index date between SGLT2i users and non-users.

Results:
Of 4,995 tafamidis-treated ATTR-CM, 468 SGLT2i users were matched with 468 nonusers (mean age: 76.5 vs 76.3; females: 21.0% vs 18.5%; mean ejection fraction: 47.9% vs 47.8%). Important covariates were also balanced between two arms. The use of SGLT2i was associated with a significantly lower risk of MACE (HR, 0.72; 95% CI, 0.57 to 0.92), primarily driven by reductions in hospitalization for HF (HR, 0.69; 95% CI, 0.51 to 0.93) and all-cause mortality (HR, 0.70; 95% CI, 0.50 to 0.98) (Figure). There was no difference in prespecified falsification endpoints between two arms (Figure).

Conclusions:
In this retrospective database analysis, SGLT2i use in patients with tafamidis-treated ATTR-CM was associated with a significant reduction in MACE. This association warrants further investigation in prospective trials.
Abstract 4142236: Safety and Efficacy of Early Aspirin Versus Aspirin Plus Low Molecular Weight Heparin in Patients with Ischemic Stroke and Immobility: A Multi-National Database Study
Authors: Nareddy Suhas , Chang Kyle , Hambach Bryce , Prucnal Christiana , Hernandez Elvin , Sovory Lisa
Published: November 2024

Background:
Early aspirin is standard of care after acute ischemic stroke (AIS). There is increased incidence of venous thromboembolism (VTE) in patients with AIS and reduced mobility, but thromboprophylaxis with low molecular weight heparin (LMWH) must be weighed against the risk of bleeding. We compared safety and efficacy of early aspirin with or without LMWH in AIS and reduced mobility.

Methods:
Patients with AIS and Modified Rankin Scale of 4-5 were identified in the TriNetX Research Database. Patients were categorized as either aspirin alone or aspirin plus LMWH within 72 hours of AIS. We excluded patients receiving any other anticoagulant, thrombolytic agents, or with history of long-term anticoagulation or atrial fibrillation. Bivariable analysis was performed with chi-square and independent
t
-tests. Cohorts were then 1:1 propensity score-matched by 26 relevant covariables including demographics, comorbidities, and medications. Outcomes were all-cause mortality, VTE, intracranial hemorrhage, and extracranial hemorrhage at 30 and 90 days.

Results:
We included 2,572 patients in each cohort. Mean age and SD was 71±13, and 48% were male. There was no significant difference in all-cause mortality in patients treated with aspirin alone versus aspirin plus LMWH at 30 days (RR=1.1, 95% CI: 0.91-1.3) or 90 days (RR=1.2, 95% CI: 0.98-1.3). Similarly, the risks of VTE and intracranial or extracranial hemorrhage were not significantly different at either timepoint.

Conclusions:
In patients with AIS and reduced mobility, the early addition of LMWH to aspirin may have similar risks of bleeding, all-cause mortality, and VTE.
Abstract 4142237: Atrial Arrhythmia Ablation in Myotonic Muscular Dystrophy Patients: A Single Institution Experience
Authors: Austin Melissa , Supple Gregory , Carrell Samuel , Elman Lauren , Nazarian Saman
Published: November 2024

Introduction:
Atrial fibrillation (AF) and atrial flutter (AFL) are commonly observed cardiac manifestations of myotonic muscular dystrophy (MMD). However, there is sparse data available describing the safety and efficacy of atrial ablation procedures in this population.

Goals/Aims:
This study aims to describe the safety and efficacy of AF or AFL ablation procedures in a cohort of MMD patients at a large, academic institution.

Methods/Approach:
All MMD patients who underwent AF or AFL ablations at a single institution between 2019 and 2023 were identified and analyzed using summary statistics.

Results/Data:
Between January 2019 and December 2023, ten patients with MMD underwent either AF or AFL ablation. Of these ten patients, 8/10 had type 1 MMD, 2/10 had type 2 MMD, and 3/10 were female. Median age at time of AF/AFL diagnosis was 34 years [IQR: 26, 48] and median age at time of ablation was 40 years [IQR: 30, 52]. All patients were on direct oral anticoagulants for >3 weeks prior to and post ablation, 7/10 were on rate control medications and 5/10 were on rhythm control medications (2 class Ic, 3 class III). Indications for ablation included inappropriate ICD shocks in 3 patients, tachycardia-induced cardiomyopathy in 3 patients, arrhythmia-related symptoms in 3 patients, and patient preference in 1 patient. During the study period, 6/10 patients had cavotricuspid isthmus (CTI) AFL ablations, 2/10 patients had pulmonary vein isolation (PVI) ablations for AF, and 2/10 patients had simultaneous CTI and PVI ablations. No procedural complications were observed, though complications in the post-procedural period included aspiration pneumonia in 1 patient, aspiration and agitation necessitating prolonged intubation in 1 patient, and altered mental status prompting close observation and ultimately a negative stroke work-up in 1 patient. The majority of patients (7/10) had recurrent AF/AFL at a median 39 days post-ablation [IQR: 18, 270]. Four patients underwent a second AF or AFL ablation.

Conclusion:
Ablation of AF/AFL can be performed safely in MMD patients. However, anesthesia related complications and early recurrences of atrial arrhythmias warrant close consideration during evaluation for atrial ablation.
Abstract 4142242: Phenylacetylglutamine accelerated endothelial senescence and early-stage atherosclerosis formation by modulating cholesterol synthesis
Authors: Huang Rong , Jiang Xueying , Hou Siyu , Li Jie
Published: November 2024

Background:
Early-onset acute coronary syndrome (EO-ACS) poses a significant health burden, necessitating a deeper understanding of its underlying mechanisms. Dysfunction or loss of endothelial cells is an early detectable change and contributes to the onset of atherosclerosis. This study aimed to investigate the role of PAGln, in early-onset ACS, endothelial dysfunction, and atherosclerosis progression.

Results:
Plasma metabolic signatures were measured with untargeted metabolomics in patients with EO-ACS and control subjects. The potential role of PAGln and PAGly,
a homologous metabolite of PAGln,
in atherosclerosis was evaluated in ApoE
−/−
mice through PAGln or PAGly supplementation via i.p. injection. Various functional experiments involving PAGln treatment were performed on HUVECs or HAECs to unravel the underlying mechanism.

Methods:
Elevated levels of circulating PAGln were found to be increased in patients with EO-ACS and positively associated with endothelial chemokine levels. PAGln and PAGly treatment were observed to promote the initiation of atherosclerotic lesion formation in the early-stage and accelerate endothelial senescence. In vitro experiments demonstrated that increased cholesterol synthesis in endothelial cells mediated PAGln-induced endothelial senescence. Conversely, inhibition of cholesterol synthesis alleviated PAGln-induced acceleration of endothelial senescence and delayed the natural aging process of endothelial cells.

Conclusion:
This study further provide evidence to the detrimental impact of elevated PAGln levels on cardiovascular dysfunction, thus offering valuable insights into the mechanisms underlying early-onset ACS and endothelial senescence.
Abstract 4142245: Eosinophilic Myocarditis and Duodenitis: A Unique Manifestation of Hypereosinophilic Syndrome
Authors: Sweeting Alexander , Atalay Michael , Agarwal Saurabh , Hulten Edward , Patel Yash
Published: November 2024

Description of Case:
This case presents a 23-year-old man with history of sickle cell disease and allogeneic peripheral blood stem cell transplantation (SCT) who presented with symptoms of acute substernal chest pain, shortness of breath, abdominal pain, and vomiting.

Methods:
Performed a comprehensive retrospective analysis of one patient's medical history, clinical presentation, diagnostic assessment, therapeutic intervention, and clinical outcome.

Results:
Physical exam was remarkable for euvolemia. Electrocardiogram demonstrated sinus rhythm. Laboratory studies revealed a complete blood count significant for eosinophilia of 14,800. Troponins and BNP were elevated at 31 ng/mL and 98 pg/ml respectively. Echocardiogram showed normal biventricular systolic function. CT abdomen/pelvis with contrast showed findings suggestive of esophagitis and duodenal thickening. Biopsy of the duodenum revealed an increased number of eosinophils with scattered lymphocytes and plasma cells. Infectious work-up including stool ova and parasite, tryptase, vitamin B12, uric acid, and IgE were unremarkable. BCR-ABL, CHIC-2 deletion, and peripheral flow cytometry were negative. C-reactive protein was elevated.

Cardiac MRI (CMR) findings demonstrated late gadolinium enhancement (LGE) of the mid-inferior segment of the left ventricle with moderate hypokinesis. Patient was treated with a short course of steroids. Repeat CMR 10 weeks later showed resolving LGE in the mid-inferior segment of the left ventricle.

Discussion:
CMR and duodenal biopsy demonstrated findings consistent with rare manifestation of HES with muti-organ inflammation as evident by left ventricular LGE, duodenal biopsy, and peripheral eosinophilia. Initial management involves prompt initiation of immunosuppressive therapy to mitigate eosinophilic infiltration and end-organ damage. Diagnostic modalities such as tissue biopsy, advanced imaging, and laboratory testing play crucial roles in confirming the diagnosis. Follow-up CMR can help follow the response treatment and rule-out confounding disease processes, as seen in our case. In conclusion, HES is a rare disorder with variable presentations. Eosinophilic myocarditis, a life-threatening sequala of HES, should be considered as a differential in patients that develop heart failure symptoms and eosinophilia after SCT.
Abstract 4142259: The Increase Of High Sensitive Troponin Post Percutaneous Coronary Intervention Is Associated With An Increase Of The Index Of Microcirculatory Resistance
Authors: Maksud Danilo Maksud , Jallad Pedro , Alves Bruno , Calderon Jean Carlos , GODINHO ROGER , Pileggi Brunna , Lopes Neuza , Gowdak Luis Henrique , Abizaid Alexandre , CAMPOS CARLOS
Published: November 2024

Background:
A reduction or delay in myocardial flow and perfusion, despite recanalization of the epicardial coronary arteries, is a well-known phenomenon. However, the association between microvascular resistance and troponin levels following elective percutaneous coronary intervention (PCI) is not well established.

Objective:
The present study aimed to assess the angiographic-derived index of microcirculatory resistance (AMR) in patients undergoing elective PCI and its relationship with high-sensitivity troponin (hsT) values post-procedure.

Methods:
Between June 2021 and December 2023, patients who underwent elective PCI were considered for inclusion. Patients with successful PCI outcomes were selected for the IMR analysis using AngioPlus Core (Shanghai Pulse Medical Technology Inc); individuals with branch occlusion were excluded. All patients had hsT collected at least twice in the first 24 hours after PCI.

Results:
A total of 330 patients were included into the analysis. Compared with baseline, there was an increase in AMR in 89.6% of the patients, from 174.9 pre-PCI to 256.2 post-PCI (p< 0.001, Figures 1A-C). The higher the hsT peak after PCI, the greater the delta IMR (p = 0.004, Figure 1D) and the post-PCI IMR (p < 0.001, Figure 1E). There was a positive and significant correlation between the absolute values of hsT peak and delta IMR (p < 0.001, Figure 1F).

Conclusion:
In patients who underwent elective successful PCI, the increase in hsT is closely related to increase in the index of microcirculatory resistance during the procedure.
Abstract 4142268: Calcium channel blocker-induced prescribing cascades: Signal detection using high-throughput sequence symmetry analysis
Authors: Kulkarni Priyanka , Ndai Asinamai , Smith Kayla , Keshwani Shailina , Choi Jae , Luvera Michael , Hunter Julia , Galvan Rebecca , Beachy Tanner , Molk Matthew , Wright Shannon , Calvet Marianna , Pepine Carl , Schmidt Stephan , Vouri Scott , Morris Earl , Smith Steven
Published: November 2024

Background:
Dihydropyridine calcium channel blockers (DHCCBs) are effective first-line therapy for hypertension but can cause adverse effects (AEs) leading to the prescription of a new drug, i.e., a ‘prescribing cascade.’

Aim:
To identify potential DHCCB-induced prescribing cascades using high throughput sequence symmetry analysis (HTSSA).

Methods:
Using claims from 5% (2011-15) and 15% (2016-20) samples of Medicare fee-for-service beneficiaries, we identified new DHCCB users aged
>
66 y with continuous enrollment
>
360 days pre- and
>
180 days post-CCB initiation. We screened for the initiation of 446 other ‘marker’ drug classes (based on WHO Anatomical Therapeutic Classification level 4 codes) within
+
90 days of DHCCB initiation. Adjusted sequence ratios (aSRs), representing proportions of DHCCB initiators starting the marker class after vs. those starting before DHCCB were calculated, with 95% CIs >1 considered significant; for significant signals, the number needed to harm (NNTH) was also calculated. Independent clinical reviewers classified signals as potential prescribing cascades or not based on biological plausibility.

Results: We identified 388,862 DHCCB initiators (mean
+
SD age 77
+
7.5 years; 62% female and 92% with hypertension). Of the 446 marker classes assessed, we identified 82 signals that warranted further exploration (aSR > 1). After clinical review, 29 (35.36%) signals were classified as potential prescribing cascades (Figure 1). The top 3 potential prescribing cascades ranked by aSR were other systemic hemostatics (aSR 2.99 [1.10-8.16]), other nasal preparations (aSR 1.99 [1.47-2.70]), and drugs used in erectile dysfunction (aSR 1.85 [1.27-2.70]). Other clinically relevant signals included electrolyte solutions (NNTH 216, aSR 1.35), osmotically acting laxatives (NNTH 710, aSR 1.13), and sulfonamides (NNTH 104, aSR 1.50).

Conclusion:
HTSSA is a novel approach to identify DHCCB-induced potential prescribing cascades. Using this method, we identified known and underrecognized AEs of CCBs in this nationally-representative Medicare cohort. More research is needed to evaluate clinical outcomes attributed to these prescribing cascades.
Abstract 4142273: Pharmacosurveillance study of FDA Adverse Event Reporting System (FAERS) events of Tirzepatide and Semaglutide
Authors: Logvinsky Ilana , Barlas Sait , Maddineni Gautam , Wood Malissa , Delibasic Maja
Published: November 2024

Background:
GLP-1 Receptor Agonists have become widely used for treating Diabetes Mellitus Type 2 and weight loss in patients across the United States. However, new data reports increasing cases of pancreatitis, acute kidney injury, increased Hba1c, and thyroid malignancy.

Research question:
Like many medications, GLP-1 receptor antagonists have a risk of side effects. The question is which medication, Semaglutide or Tirzepatide, has the highest risk of developing the above mentioned side effects.

Goals:
Using the FAERS database to calculate the reporting odds ratio (ROR) for the risk of pancreatitis, acute kidney injury, increased HgA1c, and thyroid malignancy.

Methods:
The FDA's FAERS system gathers information on adverse events and medication errors. The data shows that both Semaglutide and Tirzepatide have been linked to pancreatitis, acute kidney injury, elevation in HbA1c, and various types of thyroid malignancies. For consistent analysis, this data covers the period from 2022 to 2024 for both drugs.

Results:
January 2022- March 2024 data showed that Semaglutide and Tirzepatide had 11584 AE and 29453 AE, respectively. Semaglutide had a higher risk of developing pancreatitis, elevation of HbA1c, and thyroid malignancy compared to Tirzepatide (ROR 2.62, 95% CI 2.21-3.10) (ROR 1.72, 95% CI 1.38 to 2.15), (ROR 4.32, 95%CI 2.66 to 7.01) respectively. However, Semaglutide had 72% fewer reported cases of AKI than Semaglutide (ROR 0.28, 95% CI= 0.20 to 0.37).

Conclusion:
Lately, the popularity of GLP-1 Agonists is soaring mainly due to their role in facilitating weight loss and providing additional cardiovascular benefits. To the best of our knowledge, this is the first study comparing the likelihood of these four AEs with Semaglutideand Tirzepatide, using the FAERS Database. Being the newer agent, Tirzepatide is significantly less strongly associated with three AEs than AKI. Additional studies are needed to investigate further the epidemiology and pathophysiology of AKI with Tirzepatide use. In the meantime, Tirzepatide should be the drug of choice in patients who are at high risk for pancreatitis, thyroid cancer, and poorly controlled DM. Semaglutide might be considered in chronic kidney disease patients.
Abstract 4142283: Opposing Responses to Oxygen in the Rabbit Ductus Arteriosus and Fetal Pulmonary Arteries: Proteomic Analysis Reveals Significant Metabolic Differences
Authors: Bentley Rachel , Prins Kurt , Martin Ashley , Emon Isaac , Hindmarch Charles , Archer Stephen
Published: November 2024

Introduction:
The ductus arteriosus (DA) is a fetal vessel connecting the pulmonary artery (PA) and aorta, diverting oxygenated blood away from the developing lungs to the systemic circulation. Following the first breath, the DA rapidly constricts in response to increased arterial oxygen (O
2
) which simultaneously induces relaxation of small resistance pulmonary arteries (rPA). These changes, vital for adaptation to neonatal life, separate the pulmonary and systemic circulations (DA vasoconstriction) and enable adequate perfusion of newly ventilated lungs (PA vasodilation). The underlying mechanism of these opposite O
2
responses is not fully understood. A failure of either vessel to appropriately respond to O
2
results in clinical complications, notably persistent ductus arteriosus or persistent pulmonary hypertension of the newborn. To examine the underlying differences in these fetal vessels, we performed proteomics on fetal rabbit DA and rPA.

Methods:
DA and rPA were isolated from male (n=4) and female (n=4) term (30 days gestation) fetal New Zealand white rabbits (protocol #2021-2122). Extracted protein was labelled with TMTpro mass tag labeling. Following HPLC fractionation, samples were run on the ThermoFisher Orbitrap Eclipse Mass Spectrometer. Analysis was completed using ThermoFisher Proteome Discoverer software and DESeq2.

Results:
There were 3103 significantly, differentially expressed proteins between the DA and PA(Benjamini Hochberg adjusted p<0.05), 232 of which were ±1.5-fold differentially expressed (
Figure 1
). Using KEGG pathway analysis the most significantly DA enriched pathway is “Starch and sucrose metabolism” (map00500) and the most significantly rPA enriched pathway is “Sulfur Metabolism” (map00920). There was also rPA enrichment of other metabolic pathways including “Fatty Acid Degradation” (map00071), “Pyruvate Metabolism” (map00620), and “Glycolysis/Gluconeogenesis” (map00010).

Conclusions:
This analysis reveals unique mitochondrial metabolic pathways that may contribute to the opposing tissue responses of these specialized blood vessels to O
2
. Exploration of these pathways may identify potential therapeutic targets and inform future investigations of differential O
2
sensing in DA and rPA.
Abstract 4142289: Abatacept Drug-Induced Loeffler Endocarditis: A Manifestation of Hypereosinophilic Syndrome
Authors: Sweeting Alexander , Atalay Michael , Agarwal Saurabh , Hulten Edward , Patel Yash
Published: November 2024

Description of Case:
This case presents a 32-year-old woman with history of rheumatoid arthritis who presented with symptoms of worsening dyspnea on exertion, fatigue, and stable angina five weeks after starting abatacept.

Methods:
Performed a comprehensive retrospective analysis of one patient's medical history, clinical presentation, diagnostic assessment, therapeutic intervention, and clinical outcome.

Results:
Physical exam was remarkable for signs of volume overload. Electrocardiogram showed sinus tachycardia and diffuse nonspecific T-wave inversions. Laboratory studies revealed a complete blood count significant for eosinophilia of 26,000, representing 79.5% of the differential. Troponins were negative. A brain natriuretic peptide was 903 pg/ml. Echocardiogram findings included mild reduction in biventricular systolic function with wall motion abnormality seen at the apex. Cardiac MRI (CMR) demonstrated mild biventricular systolic dysfunction, left ventricular intracavitary filling defect consistent with thrombi, and diffuse biventricular subendocardial late gadolinium enhancement (LGE) consistent with fibrosis. Abatacept was stopped with resolution of eosinophilia. Patient was treated with a short course of steroids and initiated on warfarin for left ventricular thrombi. Repeat CMR four months later showed resolution of left ventricular thrombi and biventricular dysfunction, with persistence of diffuse subendocardial fibrosis in both left and right ventricles.

Discussion:
CMR demonstrates findings consistent with Loeffler Endocarditis as evident by ventricular intracavitary filling defects and diffuse biventricular subendocardial late gadolinium enhancement. Initial management of involves prompt discontinuation of the suspected offending drug. Corticosteroids may be employed to mitigate eosinophilic infiltrate and myocardial inflammation. Diagnostic modalities such as cardiac imaging, endomyocardial biopsy, and laboratory testing play crucial roles in confirming the diagnosis and assessing severity. Follow-up CMR can help follow the response to cessation of the offending agent and rule-out confounding disease processes, as seen in this case. In conclusion, abatacept-induced eosinophilic endocarditis is a rare phenomenon that is poorly understood. Drug-induced eosinophilic endocarditis should be considered as a differential in patients that develop heart failure symptoms and eosinophilia after initiating abatacept.
Abstract 4142305: Demand Ischemia Predicts Worse Cardiovascular Outcomes in Patients With Nonocclusive Coronary Disease Admitted for Nonsevere Sepsis
Authors: Adeyemi Boluwaduro , Harb Ahmad , Fatunmbi Oluwafunmbi , Khabsa Mariam , Ishola Folake , Ezenna Chidubem , Alugba Gabriel , Desai Raj
Published: November 2024

Background:
Demand ischemia is typically ascribed little importance but likely indicates an elevated cardiovascular risk that is more significant than current convention dictates, despite the absence of plaque rupture.

Hypothesis:
Demand ischemia likely predicts worse 3-month cardiovascular outcomes in patients with nonocclusive CAD admitted for nonsevere sepsis.

Methods:
We conducted a retrospective cohort study using data from the National Readmissions Database 2017 to 2020 to evaluate whether demand ischemia predicts increased risk of 3-month readmission with adverse cardiovascular outcomes in patients with nonocclusive CAD admitted for nonsevere sepsis. The outcomes of interest were 3-month readmissions with acute heart failure, ventricular tachyarrhythmia, cardiogenic shock, STEMI, acute respiratory failure, AKI and vasopressor use. Multivariate analysis was employed to derive adjusted odds ratios (OR) after accounting for age, Charlson comorbidity index, household income, hospital location and size, hypertension, diabetes mellitus, hyperlipidemia, CHF, atrial fibrillation/flutter, CKD, tobacco use, anemia, malnutrition, obesity, OSA and OHS.

Results:
Among patients with nonocclusive CAD admitted for nonsevere sepsis, 717,110 did not have demand ischemia, compared to 25,728 patients who did. In patients with demand ischemia, our results showed significantly increased risk of 3-month readmission with acute heart failure (OR 2.10, P < 0.0005, CI 2.00 – 2.19), ventricular tachyarrhythmia (OR 2.51, P < 0.0500, CI 1.19 – 5.34), cardiogenic shock (OR 1.66, P < 0.0005, CI 1.45 - 1.90), acute respiratory failure (OR 1.97, P < 0.0005, CI 1.89 – 2.05), AKI (OR 1.48, P < 0.0005, CI 1.42 – 1.54) and vasopressor use (OR 1.52, P < 0.0005, CI 1.31 – 1.78) There were no cases of 3-month readmissions with STEMI, possibly due to coding.

Conclusion:
Our results indicate that despite being considered a relatively benign diagnosis, demand ischemia is likely actually a marker for meaningfully elevated cardiovascular risk. Further studies will be needed to support this idea and to identify interventions that mitigate the risk.
Abstract 4142317: β-hydroxybutyrate attenuates abdominal aortic aneurysm formation via BHB-mediated epigenetic modification of CTPS1 expression
Authors: FANG LIXIN , Chen Yuanwei , Yang Fan , Luo Jianfang
Published: November 2024

Background:
Ketone body β-hydroxybutyrate (BHB), a lipid metabolic intermediate, is known as protective functions in cardiovascular diseases. We had reported that BHB attenuated chronic kidney disease through anti-inflammation. Abdominal aortic aneurysm (AAA) is a devastating cardiovascular disease without effective medication treatment. It is unclear whether BHB attenuates AAA formation and the potential molecular mechanism.

Methods:
Exogenous supplementation of BHB, and systemic HMGCS2(the key enzyme for the synthesis of BHB) knockout mice were employed to observe the effect of BHB on AAA with angiotensin II (Ang II)-induced in ApoE knockout/CaPO4-induced in C57BL/6J mice. Ultrasonography, histology and immunohistochemistry, Gelatine zymography were used to evaluate the formation of AAA. Bioinformatics analysis, small interfering RNA, pathway inhibitor, DNA pulldown and CUT&RUN were used to explore the potential mechanisms.

Results:
Clinically, we found that AAA patients showed low expression of BHB in serum and in aortic tissue compared with healthy human subject. Exogenous supplementation of BHB exhibited a reduced maximal diameter of AAA, alleviated vascular elastin degradation, and decreased the gathering of extracellular matrix proteins (MMPs) in Ang II-induced ApoE knockout mice and CaPO4-induced C57BL/6J mice through decreasing the expression of inflammasome and MMPs in both macrophage and vascular smooth muscle cells (VSMCs). Conversely, HMGCS2 knockout mice significantly increased maximal diameter and deteriorated elastic fiber degradation of abdominal aorta. Furthermore, BHB attenuated Ang II+LPS-stimulated inflammasome and LPS-stimulated MMPs expression through PI3/AKT dependent mechanism, while the suppressive effects of BHB were reversed by LY294002 (PI3-kinase inhibitor). The top 10 most differentially upregulated mRNAs were identified by transcriptomics on the aorta, of these, Cytidine triphosphate synthase 1(CTPS1) was closely related to PI3K/AKT signaling pathway. We found that BHB significantly increased the expression of CTPS1, which CTPS1 siRNA could diminished the inhibition of BHB on inflammasome and MMPs in vivo and in vitro. Finally, we found that BHB regulated CTPS1 expression by enhancing local β-hydroxybutyrylation of H3K9 at the promoter of CTPS1 gene.

Conclusion:
BHB attenuated AAA formation via BHB-mediated epigenetic modification of CTPS1 expression which activated PI3K/AKT signaling pathway in macrophages and VSMCs.
Abstract 4142331: Metabolomic Signature of Mitochondrial Dysfunction After Subacute Air Pollution Exposure: An Animal-to-Human Translational Study
Authors: Lin Yan , Ramanathan Gajalakshmi , Lu Xinchen , Gupta Rajat , Yin Fen , Fiehn Oliver , Zhang Junfeng , Zhu Yifang , Qiu Xinghua , Araujo Jesus
Published: November 2024

Introduction:
Exposure to air pollution is among the leading risk factors for cardiovascular diseases. This animal-to-human translational study aims to identify metabolomic signatures connecting subacute air pollution exposure with early mechanisms mediating chronic cardiovascular disease development.

Methods:
We studied ApoE
-/-
mice exposed to diesel exhaust (DE) or filtered air (FA) for 2 weeks and 26 healthy adults who traveled from Los Angeles (average PM
2.5
levels = 14.4 µg/m
3
) to Beijing (average PM
2.5
levels = 67.6 µg/m
3
) for 10 weeks. We previously reported increased systemic lipid peroxidation, inhibited paraoxonase 1 activity, without changes in HDL or total cholesterol levels in both animals and humans after air pollution exposure. In this study, we profiled plasma metabolomics using multiple analytical platforms and identified 547 metabolites in animals, and 1357 metabolites in humans with confirmed structure or putative chemical ID. We conducted enrichment analysis using ChemRICH algorithm and characterized molecular signature of common metabolic pathways affected by air pollution in both animals and humans.

Results:
Enrichment analysis of 154 overlap metabolites in animal and human plasma indicated that air pollution caused common metabolic alterations of (1) dicarboxylate acids, (2) acyl-carnitines, (3) tryptophan, (4) pyrimidine, and (5) lysine. Although the metabolomic signatures of tryptophan, pyrimidine, and lysine differ between animals and humans following air pollution exposure, we observed consistent increases in long-chain dicarboxylate acids and medium- to long-chain acyl-carnitines – likely due to mitochondrial dysfunction as evidenced by impaired mitochondrial respiration by a Seahorse assay on livers from the same animals.

Conclusion:
Subacute exposure to air pollution induced common metabolomic signatures of dicarboxylate acids and acyl-carnitines, suggestive of mitochondrial dysfunction.
Abstract 4142346: EPAC2-expressing neurons within the stellate ganglia are responsible for cardiac sympathetic innervation
Authors: WANG Yue-Yi , Liu Xinyu , Chen Yu , Cao Gang , Jiang Hong , Yu Lilei
Published: November 2024

Background:
Neurons located in the stellate ganglia (SG) are responsible for providing sympathetic nerve supply to the heart. This innervation plays a role in cardiac sympathetic overactivity, which can lead to malignant ventricular arrhythmias and chronic cardiac remodeling during disease processes. However, the specifics of how SG contributes to cardiac innervation are still not well understood.

Methods:
We used retrograde neuroanatomical tracing and immunofluorescence assays to confirm the presence of cardiac-innervating neurons, specifically the exchange protein directly activated by cAMP 2 positive (EPAC2+) neurons in the SG. Subsequently, single nucleus RNA sequencing was performed to determine the transcriptional profiles of SG cells, including EPAC2+ neurons. Additionally, we evaluated the physiological function of EPAC2+ neurons in healthy dogs and in an acute myocardial infarction (MI) model induced by occlusion of the left anterior descending artery. To explore the pathological role of EPAC2+ neurons in cardiac remodeling, we used a chronic MI model with neuron-specific adeno-associated virus (AAV).

Results:
We identified EPAC2+ neurons within the SG that specifically innervate the heart. These EPAC2+ neurons exhibited a unique transcriptional profile compared to EPAC- neurons, with a notable enrichment in genes involved in the calcium signaling pathway, including calcium channels and adenylyl cyclases 8 and 9 (AC8 and AC9). Functionally, activation of EPAC2 in the SG led to increased sympathetic activity. Inhibition of EPAC2 specifically reduced SG nerve activity and prevented ventricular arrhythmias following acute myocardial infarction. Moreover, targeted knockdown of EPAC2 in neurons diminished SG hyperactivity, enhanced cardiac function, reduced sympathetic nerve sprouting at the infarct border zones, and decreased ventricular remodeling after MI, while reversing the phosphorylation of MEK1/2 and ERK1/2.

Conclusions:
The results indicate that EPAC2+ neurons in the SG play a crucial role in heart innervation. This research enhances our understanding of cardiac sympathetic innervation and could lead to new therapeutic approaches.
Abstract 4142355: Effect of Testosterone Replacement Therapy on Cardiovascular Outcomes in Males: a meta-analysis of Randomized Controlled Trials
Authors: Paul Teebro , Kaza Rohan , Mamudu Hadii , Thilakaratne Dihan , Kerrigan Jimmy
Published: November 2024

Background:
Available data on the effects of testosterone replacement therapy (TRT) on cardiovascular (CV) events and all-cause mortality have yielded conflicting results. There is scarcity of data from large prospective randomized controlled trials in this regard. The objective of this meta-analysis is to compare all-cause mortality and cardiovascular outcomes in patients with and without TRT.

Methods:
PubMed database and Google Scholars was searched through May 2024 for articles meeting the eligibility criteria. We included randomized controlled trials (RCTs) with a sample size of at least 100 patients and a follow-up of more than 12 months. The end points were all-cause mortality, CV mortality, myocardial infarction (MI), stroke, and any CV event. The Mantel-Haenszel odds ratio (OR) with 95% confidence interval (CI) was computed with Random Effects model and p<0.05 was considered as a level of significance. RevMan 5.4 software was used for the analysis.

Results:
There were twelve studies (n=8,636) comparing CV outcomes and all-cause mortality among patients with hypogonadism treated with TRT (n=4,336) vs control groups (n=4300). There was no significant heterogeneity observed with the outcomes. There was no significant difference in MI (OR 1.11; CI 0.79-1.55), stroke (OR 1.02; CI 0.67-1.53), any CV events (OR 0.94; CI 0.62-1.43), CV mortality (OR 0.88; CI 0.0.66-1.16), and all-cause mortality (OR 0.86; CI 0.49-1.49) between TRT and control groups. Forest plots (Figure 1 and Figure 2) showed MI and any cardiovascular events, respectively.

Conclusion:
There was no significant difference in CV outcomes and all-cause mortality in patients treated with TRT as compared to controls. However, large RCTs with a long-term follow-up are needed to evaluate these findings.
Abstract 4142364: Active Left Atrial Ejection Fraction as a Non-Invasive Prognostic Marker in Left Heart Failure associated Pulmonary Hypertension
Authors: Zhou Di , Xin Li , Liu Zhihong , Lu Minjie
Published: November 2024

Background:
Patients with left heart failure (LHF) associated pulmonary hypertension (PH) exhibit a complex pathophysiological progression and poor prognosis. The current study aims to explore the non-invasive prognostic metrics in this population.

Methods:
In this retrospective study, consecutive patients who diagnosed with LHF associated PH and underwent cardiac magnetic resonance (CMR) imaging between December 2010 and December 2021were included. The endpoint were adverse events, including all-cause death, heart-lung transplantation, or left ventricular assist device implantation.

Results
A total of 174 patients with LHF associated PH were included in the study, and the average age of the population were 53.2 ± 14.9 years. After a median follow-up of 31.9 months, 58 patients experienced adverse events. Pulmonary artery wedge pressure had a moderate correlation with active left atrial ejection fraction (LAEF) (r = -0.397, p = 0.044). Active LAEF had a significant correlation with oxygen consumption at anaerobic threshold (r = 0.769, p < 0.001) and peak oxygen consumption (r = 0.754, p < 0.001). After adjusting for confounders, active LAEF can independently predict adverse events, beyond the echocardiography and other CMR variables under consideration (C-statistic: 0.773). Among HF patients with preserved ejection fraction, those with active LAEF ≤ 8.6% had a 7.046-fold higher risk of experiencing the composite endpoint compared to those with active LAEF > 8.6%.

Conclusions:
Active LAEF is worthy of consideration for evaluating disease severity and predicting prognosis in patients with LHF associated PH. The integration of active LAEF and HF subtypes can further identify patients with different risk profiles.
Abstract 4142380: Random survival forests identify myocardial gene signatures associated with survival in heart failure with preserved ejection fraction
Authors: Kannan Suraj , Knuttsdottir Hildur , Vaishnav Joban , Bader Joel , Kass David , Sharma Kavita , Hahn Virginia
Published: November 2024

Background:
Heart failure with preserved ejection fraction (HFpEF) continues to be poorly understood at the molecular level. While previous studies have identified gene expression signatures unique to HFpEF, genes associated with clinical decompensation have not been determined. Here, we performed exploratory analysis of myocardial RNA-seq data to identify genes associated with event-free survival in HFpEF.

Methods:
We analyzed previously published RNA sequencing data of right ventricular septal endomyocardial biopsies from HFpEF patients (n=41) with paired clinical, echocardiographic, and outcome data (including mortality and heart failure hospitalizations). We constructed random survival forests with forward stepwise regularization (the “variable hunting” method) to determine genes associated with time to first event using a combined end-point of heart failure hospitalization or all-cause death. Selection of candidate forest variables was tested with both random and weighted sampling methods.

Results:
We identified 33 genes that are predictive of survival in HFpEF (Figure 1A). This set includes genes previously implicated in heart failure, including
ADAMTSL2
,
ADRB1
,
BMP6
, and
METRNL
. Patients with HFpEF were categorized into 3 groups (Gene Group) based on their expression of this survival gene signature. Gene Group 1 had the worst survival compared to Gene Groups 2 and 3 (log rank p values 7.85e-5 for Gene Group 1 vs 2, 1.16e-5 for Gene Group 1 vs 3, adjusted for age, sex, and renal function, Figure 1B). Survival was not significantly different between Gene Groups 2 and 3 (adjusted log-rank p value 0.17). Survival forests constructed using these genes outperform those constructed from clinical and hemodynamic parameters alone (out-of-bag C-index 0.894 vs 0.545). Moreover, in survival forests constructed from both gene data and hemodynamic measurements, individual survival genes consistently showed higher variable importance than clinical/hemodynamic parameters (Figure 1C).

Conclusions:
Random survival forests identify myocardial gene signatures that may better model HFpEF prognosis than clinical measurements. Further studies are warranted to validate findings in independent cohorts.
Abstract 4142390: The LAI-OLS registry: Unveiling crucial insights into the challenges of managing LDL cholesterol in Indian patients with CAD
Authors: Mahajan Kunal , Gupta Ashu , Batra Aditya , Rana Vivek , Kumar Mukul , Gawalkar Atit , Bhatia Tanuj , Yadav Rahul , Kumar Dhananjay , Sharma Jai Bharat , Theja Pavan , Yadav Ashwani , dev munish , Himral Surender , Thakur Priyanka , Khandelwal Sakshi , Pratap Akshay , Khan Aziz , Agarwala Rajeev , Puri Raman
Published: November 2024

Background:
The Lipid Association of India (LAI) recommends intensive lipid-lowering therapy (LLT) for patients with established atherosclerotic cardiovascular disease to achieve a target low-density lipoprotein cholesterol (LDL-C) level below 50 mg/dl.

Research Question:
The lack of Indian data on achieving LDL-C goals in patients with coronary artery disease (CAD) is a significant knowledge gap that needs to be addressed.

Aim:
The Lipid Association of India's Optimization of LDL-C in the Stable CAD (LAI-OLS) registry
,
aimed to assess the achievement of the LAI-recommended LDL-C goals in patients with angiographically proven CAD.

Methods:
The LAI-OLS registry enrolled 2431 patients with angiographically proven CAD across ten interventional cardiology centers in Northern India over six months (August 2023- January 2024). Interventional cardiologists (ICs) treated all enrolled patients and collected data at a single visit, including the most recent LDL-C and the LLT in the preceding three months of that LDL-C reading.

Results
The study population had a mean age of 60.6 ± 16.9 years, with a male predominance (80.4%). A substantial proportion of the patients had significant cardiovascular risk factors: 30.7% had diabetes mellitus (DM), 37.9% had hypertension (HTN), 28.6% were obese (BMI
>
25 kg/m2), and 17.1% were current smokers. Notably, 74.1% had a history of acute coronary syndrome, and 77.3% had undergone prior percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Rosuvastatin (65.2%) was the most commonly prescribed statin, followed by atorvastatin (34.2%). High-intensity statin (HIS) therapy (20-40 mg rosuvastatin or 40-80 mg atorvastatin) was used in 71.4% of patients. Other lipid-lowering agents (ezetimibe, bempedoic acid, fibrates) were used in a tiny percentage of patients (1.1%), and no patients were on PCSK9 inhibitors. Despite the extensive use of statin therapy, only 26.2% of patients achieved the LAI-recommended LDL-C goal of <50 mg/dl. While 47.1% achieved an LDL-C below 70 mg/dl, it is noteworthy that a small proportion (2.6%) were not taking any lipid-lowering medication.

Conclusion:
Indian patients with CAD face a high risk due to widespread diabetes, hypertension, and obesity. Despite extensive use of HIS, many fail to meet LDL-C targets. These results highlight the need for early and aggressive combination lipid-lowering therapies, including non-statin drugs, to improve outcomes in this high-risk population.