bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4147122: Automated quantification of amyloid burden in cardiac amyloidosis
Authors: Greco Francesco , Aimo Alberto , Musetti Veronica , Celi Alessandra , Polito Syria , Castiglione Vincenzo , Vergaro Giuseppe , Emdin Michele , Pucci Angela
Published: November 2024

Background:
Cardiac amyloidosis (CA) involves the accumulation of amyloid fibrils in the extracellular cardiac spaces, increasing the extracellular volume (ECV) and correlating with poorer outcomes. Accurate quantification of cardiac amyloid is prognostically valuable but challenging with current manual methods using Congo-Red (CR)-stained tissue. We developed a digital pathology pipeline for automated quantification of cardiac amyloid on CR-stained endomyocardial biopsies (EMBs).

Methods:
We analyzed 20 consecutive left ventricular EMBs with CA (AL, n=12; ATTR, n=8) and 10 EMBs with cardiac hypertrophy (CH) and CA excluded. Amyloid was semi-quantitatively assessed as focal, multi-focal or diffuse by a cardiac pathologist. Polarized light images were converted into negative images using MATLAB to obtain bright field images, normalized using modified Reinhard normalization, and imported into QPath software. Images underwent color deconvolution to isolate the negative of the apple-green color. An intensity threshold on the amyloid channel detected positive pixels. Total tissue area was calculated by intensity threshold of the bright field image.

Results:
Standardized staining and image acquisition using automated machines and fully closed polarizer filters resulted in consistent histological staining. Residual staining variabilities were removed by applying a modified Reinhard normalization, equalizing the median of the image channels in the L*a*b color space. Conversion of dark field polarized images to negative allowed for the use of standard color deconvolution algorithms to isolate the negative apple-green channel and to use thresholding to quantify positive pixel. Amyloid quantification showed significantly higher amyloid percentages in positive controls (mean 6.21%) compared to negative controls (mean 2.29%) with a 0.05 threshold. The method was applied to six independent acquisition of the same section to assess reproducibility. The variation coefficient of the percentage of amyloid-positive pixels in the replicates was 11.6%, confirming method reproducibility.

Conclusions:
A digital pathology pipeline quantifying amyloid birefringence areas and, in most cases, differentiated it from collagen birefringence. Automated amyloid quantification simplifies EMB sample analysis and provides valuable information for risk prediction.
Abstract 4147141: Relationship Between CVH and Survival in the Acoramidis Treated Participants Within ATTRibute-CM
Authors: Alexander Kevin , Davis Margot , Ambardekar Amrut , Nativi-Nicolau Jose , Shah Keyur , Hanna Mazen , Gibbs Simon , Tamby Jean-Francois , Siddhanti Suresh , Whang John , Fox Jonathan , Du Jing , Cheng Richard
Published: November 2024

Background:
Acoramidis is a novel, potent, investigational, transthyretin (TTR) stabilizer under development for the treatment of TTR amyloidosis that results in near-complete (≥90%) TTR stabilization. In a phase 3 study, ATTRibute-CM, acoramidis demonstrated improved clinical outcomes in participants with transthyretin amyloid cardiomyopathy (ATTR-CM), including a 50% reduction in the risk of CVH compared to placebo over 30 months. The study also demonstrated that cardiovascular hospitalization (CVH) during the study predicted a higher subsequent mortality in participants with ATTR-CM.

Hypothesis:
CVH portends a higher risk of mortality in participants with ATTR-CM. Since acoramidis reduces CVH, it can improve the prognosis of participants with ATTR-CM.

Aim:
To evaluate the relationship between CVH and survival in the acoramidis group within ATTRibute-CM.

Methods:
In this post-hoc analysis, the relationship between those with or without CVH and survival was analyzed within the acoramidis treatment group using the Kaplan-Meier (KM) estimator method.

Results:
Demographics and baseline disease characteristics were mostly comparable between acoramidis-treated participants with and without CVH, although participants with CVH had a higher baseline NT-proBNP and lower eGFR. At Month 30, in acoramidis-treated participants, those without any CVH (n=300) had a higher survival [86.8% (95% CI = 82.2, 90.3)] versus 62.4% (95% CI = 52.6, 70.7) in those who had any CVH (n=109); p<0.0001 from log-rank test (Figure).

Conclusion:
In the ATTRibute-CM study, pts without any CVH receiving acoramidis have a higher survival rate. CVHs remain a powerful predictor of mortality. This reinforces the importance of an effective therapy that reduces CVH and in turn may improve survival in patients with ATTR-CM.
Abstract 4147159: Feasibility of Cine Magnetic Resonance Fingerprinting for Combined Assessment of Cardiac Structure, Function and Tissue Characteristics in Cardiomyopathy.
Authors: Akula Navya , Okyere Robert , Eastman Jason , Li Shou , Pollard Jordan , Hamilton Jesse , Imran Rashid
Published: November 2024

Introduction:
Cardiac Magnetic Resonance has emerged as the non-invasive standard for assessment of cardiac structure, function and tissue characteristics in patients with suspected cardiomyopathy. However, there are several well-known barriers. Cine magnetic resonance fingerprinting (MRF) is a novel imaging technique that streamlines ‘all-in-one’ assessment of myocardial function and tissue characteristics. It allows for simultaneous quantitative assessment of biventricular size and systolic function, T
1
, T
2
maps and synthetic late gadolinium enhancement (LGE) imaging. This model compensates for various confounding factors, including arrhythmias, slice profile imperfections, inversion pulse efficiency and B1+ inhomogeneities to generate accurate and reproducible measurements.

Hypothesis:
Cine MRF can be used as an “all-in-one” imaging platform for diagnosis of various cardiomyopathy phenotypes.

Goals:
We aim to assess the accuracy of cine MRF compared to standard MRI for volumetric analysis and parametric tissue mapping. Further explore diagnostic yield of simulated images with synthetic scar imaging using MRF in comparison to standard LGE imaging.

Method:
Feasibility study. N= 8; 3 healthy volunteers and 5 patients with reduced ejection fraction (defined as EF <50%) were scanned using 1.5 T MRI. Cine MRF was acquired using retrospective ECG gating (25 cardiac phases, spatial resolution of 1.6x1.6x8.0 mm). Slice duration (10.7s breathhold + 10s pause) of total ~4 minutes for 12 short-axis slices. MRF data were processed using a self-supervised deep learning (Deep Image Prior) reconstruction. Synthetic cine images were derived analytically from the maps. Post-contrast cine MRF maps were used to calculate synthetic PSIR LGE images.Volumetric analysis by 2 individual Level II/III readers. Bland-Altman analysis was used. Further comparative qualitative assessment of standard LGE to cine MRF derived synthetic LGE was performed.

Results:
Volumetric analysis using standard vs Cine MRF showed high agreement. Cine MRF parametric mapping correlated with standard T1/T2 mapping techniques with expected difference in reference ranges. Qualitative assessment of synthetic LGE images derived from cine MRF allowed for detection or exclusion fibrosis/scar that correlated with standard LGE imaging.

Conclusion:
Cine MRF holds promise as a single ‘all-in-one’ platform for assessment of myocardial structure, function and tissue characteristics in patients with cardiomyopathy.
Abstract 4147168: Left Atrial Remodeling By Cardiac MRI In Mitral Stenosis Patients Pre- and Post- Balloon Mitral Valvuloplasty
Authors: Mishriky Mary , Romeih Soha , Gergis Michael , Shaker Kerolos , Elborae Ahmed , Hassan Ahmed , Samaan Amir , Doss Ramy , Mohamed Hesham , Kandil Hossam , Abdelhamid Magdy
Published: November 2024

Background:
Mitral stenosis (MS) is associated with adverse left atrial (LA) structural changes. Mechanical relief of this obstruction via balloon mitral valvuloplasty (BMV) may be associated with LA reverse remodelling.

Objective:
To study LA and RV remodelling in isolated severe rheumatic MS patients before and 9-12 months after successful BMV.

Methods:
We included 49 patients with isolated severe rheumatic MS in sinus rhythm who underwent successful BMV. CMR was done at baseline and 9-12 months post BMV. Thirty age- and gender- matched healthy controls were included for comparison. Indexed LA volumes (V
max
, V
min
,&V
pre-A
) were obtained from CMR cine images. LA phasic functions were evaluated using both volumetric and deformation indices. Deformation analysis including LA strain (global, passive,&active strain)&strain rate (SRs, SRe, and SRa ) measurements were performed using specialized MASS (R) software for CMR feature tracking.

Results:
At baseline, there was significant impairment of LA volumes and functions in severe MS patients compared to healthy controls. Following BMV, there was statistically significant reduction in all LA indexed volumes compared to baseline (p-value <0.001 for all). There was significant improvement in LA phasic functions; Reservoir, conduit and pump functions as shown in Table. Higher mean gradient (MG) at baseline correlated significantly with passive strain and passive SR. Strain indices of reservoir and pump functions have normalized, however, the LA volumes and volumetric functions still remained significantly impaired compared to healthy controls.

RV volumes, EF and RV free wall GLS were normal at baseline. Post BMV, both RV ESVi and RV EF showed significant improvement.

Conclusion:
Significant MS is associated with marked LA structural&functional changes detected by CMR. Successful BMV results in reverse LA remodelling with reduction in LA volumes and improvement in LA functions and strain indices, This reverse remodelling was evident at 9-12 months post procedure. Longer term follow-up studies are needed to assess whether improvement in LA volumetric functions and strain indices are sustained or not.
Abstract 4147229: Guideline-directed medical therapy improves cell viability in an iPSC-derived cardiomyocyte hypoxia injury model
Authors: Li Jiwen , Ikeda Gentaro , Tzng Eileen , Inoue Hiroyuki , Koike-Ieki Mariko , Yang Phillip
Published: November 2024

Introduction:
Beta blockers, renin-angiotensin-aldosterone antagonists, and mineralocorticoid antagonists are mainstays of current guideline-directed medical therapy (GDMT) in heart failure with reduced ejection fraction. They have been shown to reduce morbidity and mortality in heart failure patients, reverse remodeling, and improve left ventricular ejection fraction (LVEF) in landmark human clinical trials. GDMT has been hypothesized to interact and have protective effects in bioenergetics in cardiac injury by reducing cardiac workload and energy demand. We have previously used a human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCM) injury model to provide an in vitro validation of bioenergetics through measurement of cell viability and proliferation, intracellular measurement of ATP, contractility, and respiratory function. The application of GDMT in this in vitro model has not been previously assessed.

Methods:
Highly pure iCMs were differentiated from a healthy, human monoclonal iPSC line using CHIR99021 followed by C59 to modulate Wnt pathway activity. Upon spontaneous contractility, iCMs were replated for purification. Prior to hypoxia exposure, iCMs were treated with either 5uM metoprolol, 5uM losartan, 5uM spironolactone, or a control for 24 hours. To mimic in vivo ischemia, iCM are placed in a glucose deprived media (GDM) in a hypoxia inductor chamber with <1% oxygen-containing mixed gas in a 37°C incubator for 18 hours. A second iCM group is similarly treated in GDM for 18 hours in a normoxic setting. Cell viability and proliferation was then studied using MTT assay.

Results:
The metoprolol, losartan, and spironolactone treatment groups significantly improved cell viability after hypoxic injury when compared to the control treatment groups. Metoprolol treatment had the highest cell viability after hypoxic injury (46%), followed by spironolactone (23%) and losartan (22%), compared to control (13%). In the normoxic group, metoprolol, losartan, and spironolactone treatment showed no significant difference in viability compared to the control group.

Conclusion:
iPSC-derived iCMs treated with GDMT improved cell viability after hypoxic injury. The iPSC hypoxia-injury model appears to be a promising in vitro platform for studying the effects of GDMT on cellular bioenergetics.
Abstract 4147236: Healing Hearts Mending Minds: Battling Anxiety and Depression in adults with congenital heart disease.
Authors: Alberts Adam , Chowdhury Devyani
Published: November 2024

Background/Introduction:
Adults with congenital heart disease have higher rates of anxiety, depression, and suicide, compared to those without congenital heart disease. A variety of factors contribute to psychological distress among adults with CHD, including functional impairment, neurocognitive deficits, the increasing concerns for reinterventions, body image due to surgical scars or body insecurity. However, screening and targeted treatment is still lacking.

Methods/Approach:
96 unique patients were seen in ACHD clinic. Each was screened for anxiety and depression using the PHQ-4. Based on the results and clinical findings, 1 of 4 clinical pathways were pursued: 1 negative screening; no consult with a psychologist was recommended; 2 positive PHQ-4 with telehealth follow-up with an in-practice psychologist; 3 PHQ-4 positive with an in-practice psychologist consult during their outpatient visit; 4 already established relationship with a psychologist.

Results/Data:
Of the unique 96 patients seen in ACHD clinic 6 were excluded for severe developmental delays. Of the remaining 90 patients, 7% (n = 6) had an established relationship with a psychologist. The 84 that did not have an established relationship with a psychologist were screened for anxiety and depression. 49%, ( n = 44) were either seen in clinic by the psychologists and 22%, (n=20) followed up with an outpatient visit. The remaining 22% (n = 20) were screened and had a negative phq-4 with no clinically significant signs of anxiety or depression at that visit.

Conclusions:
Adults living with CHD have and will continue to encounter unique challenges that extend beyond the physical realm, often grappling with psychological distress that affects their overall well-being and quality of life. While depression has been a focal point in general cardiac research, elevated anxiety levels are equally significant and warrant attention. Within this study, anxiety and depression requiring mental health follow-up was underdiagnosed and undertreated in 76% of the population. Underpinning the need for routine screening for psychological and QOL impairments, as well as ntegration of mental health professionals within ACHD programs.
Abstract 4147238: Targeting Current Delivery During Atrial Fibrillation Ablation May Improve Ablation Success
Authors: Murphy Rachel , Adewumi Joseph , Cerbin Lucasz , Sabzwari Syed Rafay Ali , Ashur Carmel , Saqi Bilal , Varela Daniel , Grubb Alex , Padalia Kishan , Barrett Christopher , Garg Lohit , Tumolo Alexis , Von Alvensleben Johannes , Aleong Ryan , Varosy Paul , Rosenberg Michael , Tzou Wendy , Zipse Matthew , Sandhu Amneet
Published: November 2024

Background:
Contemporary power-controlled radiofrequency (RF) ablation prioritizes power, force, and time. However, variables such as impedance and current also greatly impact ablation lesion formation. The appropriate current values to target at various pulmonary vein (PV) regions are not well established.

Objective:
To characterize 1) the range of current (mA) delivery with standard ablation and impedance (ohms) values at PV ostia, and 2) the impact of maximum current achieved on freedom from atrial fibrillation (AF) at one year.

Methods:
One hundred fifteen consecutive paroxysmal AF patients at our institution between 2020-2021 undergoing first-time RF PV isolation were retrospectively analyzed. Baseline impedance (ohms), impedance drop, power, force, and time were compiled and separated by ostial PV site (CARTO®). Current was calculated based on Power=current x resistance. Calculated current was then compared in a small cohort of patients with the displayed current on the Smart Ablate® system.

Results:
Of all patients, 27 patients had atrial fibrillation recurrence within one year. Calculated current was lower than the displayed Smart Ablate® current but had reliable correlation. Baseline impedance was higher in the roof and posterior wall compared to anterior/inferior regions. There was a statistically significant difference in the mean maximum current achieved between patients with AF recurrence vs those without in the regions of the left posterior wall (543 mA vs 564 mA, p = 0.049), left roof (556 mA vs 575 mA, p = 0.043), and right roof (559 mA vs 578 mA, p = 0.042).

Conclusion:
Current delivery during RF ablation is dependent on baseline impedance and the impedance drop achieved. We noted significant differences in delivered current in those with and without AF recurrence at the left posterior wall/roof and right roof. Titrating ablation parameters to achieve effective current delivery may be a promising intraprocedural strategy for AF ablation success.
Abstract 4147247: A Deep Learning Topic Analysis Approach for Enhancing Risk Assessment in Heart Failure Using Unstructured Clinical Notes
Authors: Adejumo Philip , Pedroso Camargos Aline , Khera Rohan
Published: November 2024

Background:
Assessing clinical complexity in heart failure (HF) patients is essential for effective resource allocation. Despite notable limitations, CMS currently uses administrative claims to estimate complexity and determine provider payments. Unstructured clinical notes contain valuable patient information that can enhance risk assessment. We introduce a novel deep-learning approach that identifies clinically significant features from notes to improve risk assessment in HF.

Methods:
We identified all individuals with hospitalizations for HF in a large, diverse health system and defined CMS HF comorbidities using ICD codes. In parallel, we extracted clinical notes from these encounters to determine information relevant to the same conditions using a novel natural language processing-based topic modeling approach. We digitized all notes into a vector space using a previously trained embedding model (NV-embed) with learned contextual word associations. We projected the descriptions of CMS ICD-code-based risk factor categories into the embedding and used cosine similarity to identify whether notes provided additional information. We used logistic regression models for 30-day readmission and 30-day and 1-year mortality to evaluate the predictive performance of the approaches.

Results:
We identified 40,604 HF hospitalizations, with 30-day and 1-year mortality rates of 6.4% and 18.2%, and 30-day readmission rate of 23.3%. Clinical notes of those with vs without a code-based comorbidity had the information identifiable on topics (cosine similarity, 0.73 vs 0.57). Among those without coded conditions, notes varied substantially in information corresponding to the topic (range of coefficient of variation, 0.21-0.50). Models using note-defined topics as predictors consistently outperformed those using CMS risk scores, with higher AUROCs for 30-day mortality (0.81 vs 0.63), 1-year mortality (0.85 vs 0.64), and 30-day readmissions (0.78 vs 0.59). The average net reclassification index was 0.37, indicating improved risk stratification using information from notes vs structured CMS risk scores.

Conclusion:
A novel deep-learning approach applied to unstructured clinical notes more accurately identifies conditions of interest, with the models based on these features significantly outperforming the current CMS risk-adjustment models for post-hospitalization events. This has important implications for defining the next generation of tools for hospital profiling for HF care.
Abstract 4147256: The Effect of Obesity on Outcomes of Mechanical Circulatory Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock: Insight from the National Inpatient Sample Database
Authors: Gbegbaje Oghenetejiri , Ezenna Chidubem , Alugba Gabriel , Nelson Favour , Okorare Ovie , Okey-Ndeche Uzoma , Patel Dipal , Saint Croix Garly , Goldsweig Andrew
Published: November 2024

Introduction:
Studies suggest a complex relationship between body mass index (BMI) and percutaneous coronary intervention (PCI) outcomes. However, the effect of obesity on in-hospital outcomes of PCI with mechanical circulatory support (MCS) for acute myocardial infarction complicated by cardiogenic shock (AMICS) has not been established.

Objective:
To characterize outcomes of PCI with MCS for AMICS in patients with and without obesity.

Methods:
In the National Inpatient Sample (NIS) 2016-2020, we identified patients with AMICS treated with MCS with obesity (BMI 30.0-39.9) or normal BMI (20.0-24.9). The primary outcome was in-hospital mortality. Secondary outcomes included cardiac arrest, stroke, acute kidney injury, bleeding, acute respiratory failure, palliative consults, hospital length of stay (LOS), and total charges. Multivariate logistic regression models adjusted for baseline characteristics and estimated odds ratios (ORs) with 95% confidence intervals (CIs).

Results:
5270 patients met study criteria (4870 obese). Obese and normal weight patients had a mean age of 69.8 vs. 63.5 years and male sex 78.1% vs. 71.3%. Obese patients had more hypertension, diabetes, dyslipidemia, and previous myocardial infarction (Table 1A). There was no difference in mortality [OR 0.84, CI (0.41-1.71), P=0.623] or the secondary outcomes (Table 1B). Normal weight was associated with longer LOS (13.0 vs. 8.5 days) and higher charges ($325,926.3 vs. $294,629.1).

Conclusion:
There were no significant differences in in-hospital mortality or secondary outcomes between obese and normal-weight AMICS patients treated with PCI and MCS. PCI with MCS may be performed safely in AMICS patients with and without obesity.
Abstract 4147279: The Role of Left Atrial Compliance in the Stroke Volume Response to Exercise in HFpEF
Authors: Tovar Carlos , Huang Le , Wakeham Denis , Brazile Tiffany , Hearon Christopher , Macnamara James , Levine Benjamin , Sarma Satyam
Published: November 2024

Background:
Left atrial (LA) dysfunction is common in heart failure with preserved ejection fraction (HFpEF), but the extent to which LA dysfunction impacts cardiac performance during exercise is unknown. Given the importance of the LA for ventricular filling, we assessed the relationship between LA compliance (LAc) at rest and during exercise and exercise stroke volume (SV) generation.

Methods:
We studied 50 adults with HFpEF during rest and upright cycle exercise (20W). LA volumes were calculated from two-dimensional, 4-chamber and 2-chamber echocardiographic views during both stages. LA pressures were derived from v-wave maximal amplitudes of corresponding pulmonary capillary wedge pressure tracings. LAc was calculated as LA volume divided by LA pressures (mL/mmHg).

Results:
LA volume increased by 3.5
+
1.4mL (p<0.01), LA compliance decreased by 4.2
+
5.3 mL/mmHg (p<0.001), and SV increased by 28.9
+
13.4mL (p<0.001) from rest to 20W exercise. Resting LAc was not associated with changes in SV (R
2
=0.01, p=0.47). LAc at 20W was statistically associated, albeit weakly, with changes in SV (p<0.04, R
2
=0.11). Only 2 patients improved/increased LAc and there was no relationships between LA compliance changes and SV changes during rest and exercise (p=0.93).

Conclusions:
LAc decreased with exercise in patients with HFpEF. LAc measured at 20W had a weak relationship with SV response but changes in LAc did not discriminate for individual SV responses. These findings suggest that LAc does not contribute to SV generation during exercise in patients with HFpEF.
Abstract 4147291: Examination of pre-mRNA from cardiomyocytes at single-cell resolution from post-infarcted mouse hearts
Authors: Ravindran Sriram , Rau Christoph
Published: November 2024

Background:
RNA-seq provides a powerful tool to dissect cellular heterogeneity in diseased hearts. It generates reads from both mature RNA and pre-mRNA. Traditionally, only mature RNA transcripts are considered for analysis, but studying both species of transcripts from single-cell RNA-seq of cardiomyocytes in post-infarcted hearts can reveal novel insights into the dynamic transcriptional changes and regulatory mechanisms that occur during heart repair and regeneration

Research question:
Do nascent transcriptional events from pre-mRNA forecast the biological processes in failing hearts better than the mRNA and unravel the complexity of cardiomyocyte diversity?

Aim:
Execute an exon-intron analysis on cardiomyocyte single-cell RNAseq data obtained from post-infarcted mouse hearts

Methods:
Cardiomyocytes from mice (n=4) post-LAD ligation were isolated and single-cell RNAseq was performed using MegaKit v.2 (Parse Biosciences) on a NovaSeq 6000. Data was analyzed via the
Parse
pipeline and
Seurat v5
. Pre-mRNA reference was built with
AGAT
. Gene set enrichment was done using
fgsea
. Sham mice without ligation (n=4) served as controls

Results
: We analyzed at least 70K cells for each transcript type and compared their enrichment profiles for post-infarcted hearts to sham. Infarction resulted in enrichment for biological processes predominantly for development and fatty acid metabolism, especially from pre-mRNA mapping (mRNA vs pre-mRNA;
p=
4.2 x 10
-18
vs 4.8 x 10
-32
). At the level of individual clusters, cardiomyocyte heterogeneity was revealed with cells enriched for distinct processes. Common to both types of transcripts were terms enriched for cell death (mRNA vs pre-mRNA;

p=7.6 x 10
-3
vs 4.2 x 10
-3
)

, tissue remodeling (

p=4.3 x 10
-4
vs 9.6 x 10
-4
)

, and respiratory&metabolic activity (

p=8.9 x 10
-5
vs 7.2 x 10
-8
).

However, compared to mRNA, the pre-mRNA had more cell clusters enriched for terms related to increased protein production activity (
p
=

7 x 10
-4

), activation of key signaling pathways (
p
=8.5 x 10
-4
), and defense response (
p
=2.1 x 10
-6
). These additional processes show adaptive mechanisms that promisingly forecast cardiomyocyte repair and could be visualized by mapping pre-mRNA

Conclusion:
Examining pre-mRNA offers a realistic view of stressed cardiomyocytes’ transcriptional dynamics. This study could identify new biomarkers to predict the onset of heart failure. Further insights into transitioning cells could aid in developing therapies for regeneration
Abstract 4147293: The GLP1 Receptor Agonist Semaglutide Ameliorates Myocardial Ischemia-Reperfusion Injury in a Porcine Model Mediated by the RISK and SAFE Molecular Pathways
Authors: Santosgallego Carlos , Vahl Torsten , Ishikawa Kiyotake , Picatoste Botija Maria Belen , Nazar Nijas , Adiya Nisna , Shajahan Shehanaz , Sanz Javier , Badimon Juan
Published: November 2024

Introduction:
GLP1 receptor agonists (GLP1RA) improves outcomes by reducing event rates of myocardial infarction (MI). Whether GLP1RA also reduce MI size by ameliorating myocardial ischemia-reperfusion (I/R) injury remains incompletely understood. The main cardioprotective pathways to induce myocardial salvage are RISK (activation of Akt) and SAFE (activation of STAT3). We hypothesized that semaglutide increases myocardial salvage, reduces myocardial infarction (MI) size, improves left ventricular (LV) systolic function, and decreases apoptosis and oxidative stress in a porcine model of I/R mediated via activation of both RISK and SAFE pathways

Methods:
Myocardial I/R injury was induced in Yorkshire pigs by balloon occlusion of the proximal LAD for 60 min, followed by reperfusion. Animals randomly received semaglutide 0.5mg the day before I/R (to mimick patients on chronic GLP1RA), or saline for controls (n=6/group). Animals were evaluated at 1-day post-MI with cardiac MRI, 3D-echo, histology (apoptosis and oxidative stress) and molecular biology (activation of RISK and SAFE). To mechanistically study the effect of each molecular pathway, two additional groups were treated with GLP1RA+wortmannin (inhibitor of RISK) and GLP1RA+AG490 (inhibitor of SAFE)

Results:
Despite similar of myocardium at risk in both groups (42.8±2.2% vs 42.2±2.7%, p=NS), semaglutide significantly reduced LGE-determined MI size (33.1±2.3% vs 41.1±2.8% of LV, p<0.01), resulting in larger salvaged myocardium (23.2±6.4% vs 4.1±3.9% of AAR, p<0.01), and improved LV systolic function (MRI-determined LVEF 42.6±3.2% vs 34.4±5.4%, p<0.01). Semaglutide reduced apoptosis (19.3±5.1% vs 40.4±9.1% of TUNEL+ cells, p<0.01) and oxidative stress (12.7±4.7% vs 38.2±9.5% of 8-hydroxydoexyguanosine+ cells, p<0.01). Semaglutide increased the phosphorylation of both Akt and STAT3 (ie semaglutide activated RISK and SAFE). Importantly, these cardioprotective effects of semaglutide were mediated via RISK and SAFE activation because both the inhibition of RISK (with wortmannin) and SAFE (with AG490) pathways abrogated these GLP1RA-induced benefits on I/R injury (Figure)

Conclusions:
The GLP1RA semaglutide increases myocardial salvage, reduces MI size, improves LV systolic function, and decreases apoptosis and oxidative stress in a porcine model of I-R mediated via activation of both RISK and SAFE pathways. This mechanism might explain part of the cardiovascular benefits of semagutide in large clinical trials
Abstract 4147295: Outcomes after Acute Thoracic Aortic Dissection in Children and Young Adults ≤30 years of age
Authors: Jones Edward , Yetman Angela , Prakash Siddharth , Cecchi Alana , Braverman Alan , Tierney Seda , Jeremy Richmond , Steele Jeremy , Espahbodi Nadia , Milewicz Dianna , MORRIS Shaine
Published: November 2024

Background:
Thoracic aortic dissection (TAD) is rare in patients under 30 years of age, and is associated with high morbidity and mortality. There is limited published data on factors impacting survival and long-term outcomes after TAD in younger patients.

Objective:
Genetic and clinical findings associated with TAD in patients aged 30 and younger were analyzed to identify predictors of long-term post-dissection outcomes.

Methods:
This retrospective cohort study included patients from the Collaborative for Longitudinal Aortic Research in the Young and the Montalcino Aortic Consortium. Any patient with a type A or type B TAD that occurred at the age of 30 or younger was included.

Results:
A total of 62 patients were included (53% male). Median age at first TAD was 23.9 years (IQR 18.0-27.0) with range of 3.0 to 30.8 years; 40 (65%) were type A and 22 (35%) were type B dissections. All patients carried a genetic diagnosis, as this is required for both registries, with the highest proportion carrying
TGFBR2
or
ACTA2
pathogenic variants (PVs, Figure 1A).

Median post-TAD follow-up was 7.8 years (IQR 2.1-11.9). Overall survival was 85% [76-95%], 83% [74-93%], and 75% [64-88%] at 1, 5, and 10 years, respectively. Freedom from death or additional aortic event was 79% [69-90%], 72% [61-86%], and 55% [42-72%] at 1, 5, and 10 years and was lower for individuals with TGFβ pathway (
SMAD3
,
TGFB2
,
TGFBR1
,
TGFBR2
) PVs compared to PVs in smooth muscle (
ACTA2
,
MYLK
,
PRKG1
) or extracellular matrix genes (
COL3A1
,
FBN1
) (p=0.12) (Figure 1B).

In univariable Cox regression analysis, only aortic rupture at the time of initial TAD (HR 3.0 [1.2-7.6], p=0.018) and type A dissection (HR 3.9 [1.1-13.2], p=0.029) were significant predictors of death or additional aortic event (Table 1).

Conclusion:
TAD in young patients causes significant morbidity and mortality. Long-term outcomes may vary by dissection type, presence of aortic rupture, and mutated gene.
Abstract 4147312: Retrospective Analysis of Patients with Intermediate-Risk Pulmonary Embolism: Demographics, Management, and Outcomes from a Large Academic Referral Center
Authors: McKay Kelly , Ferrante Monica , Jensen William , Howard Frances , Elwing Jean , Louis Louis , Ahmad Saad , Bennett Suzanne , Ramser Evan , ARROYO JOSE
Published: November 2024

Introduction:
Risk stratification and treatment for pulmonary embolism (PE) have evolved significantly in recent years. It is proposed that patients with intermediate-risk PE, including low and high intermediate-risk categories, may benefit from percutaneous interventions in addition to heparin monotherapy. With the increasing availability of catheter-directed therapy (CDT) and percutaneous mechanical thrombectomy (PMT), more information is needed to optimize these resources.

Methods:
We retrospectively analyzed data from an institutional pulmonary embolism response team (PERT) registry (n=591) from 2018 to 2022. Patients were stratified as intermediate-low and intermediate-high risk based on European Society of Cardiology guidelines. Survival time was recorded from the initial PERT consult to the last clinical encounter. Survival events were defined as 1) death within 90 days, or 2) a composite endpoint including death, cardiac arrest, ECMO or vasopressor use, or death within 90 days. Cox proportional hazards and Kaplan-Meier methods estimated the risk of 90-day all-cause mortality and the composite endpoint.

Results:
We studied 211 intermediate-risk patients, including intermediate-low (n=112, 53.1%) and intermediate-high risk (n=99, 46.9%). The sample was predominantly female (51.2%) with a mean age of 64.8 years (SD 15.6). Median PESI scores were 103 and 100 for intermediate-low and high risk, respectively. Among patients, 27% had active cancer, and 17% had recent surgery or hospitalization within 30 days prior. A history of PE and DVT was present in 8% and 11% of patients, respectively. Interventions included heparin monotherapy (n=164, 77.7%), CDT (n=27, 12.8%), and PMT (n=20, 9.5%). Within 90 days, 29 patients (13.7%) expired, and 43 patients (20.4%) met the composite endpoint. Active cancer and baseline oxygen requirement were linked to a higher likelihood of meeting the composite endpoint. CDT and PMT were associated with better 90-day survival (log-rank p = 0.024) and a lower probability of meeting the clinical endpoint (log-rank p = 0.052) compared to heparin monotherapy, with no significant difference between CDT and PMT.

Conclusion:
In intermediate-risk PE patients, CDT or PMT were associated with better 90-day survival and showed a trend towards a lower likelihood of meeting the composite outcome.
Abstract 4147328: Adverse Social Determinants of Health in a Low-Income Population Hospitalized with Heart Failure
Authors: Rizvi Syed Kazim , Lokesh Nidhish , Dhruve Ritika , Miller James , Keshvani Neil , Pandey Ambarish
Published: November 2024

Background:
Heart failure (HF) is a leading cause of hospitalization and readmission. Understanding the burden and impact of social determinants of health (SDOH) among HF patients at safety-net hospitals is critical for improving outcomes.

Methods:
We conducted a prospective, cross-sectional study to identify the prevalence of adverse SDOH among patients hospitalized with acute HF at an urban, safety-net hospital. English or Spanish-speaking patients hospitalized for HF were enrolled between 11/2022-6/2023. We collected data across 5 SDOH domains based on the Healthy People 2030 SDOH Model from the U.S. Department of Health and Human Services. The overall burden of adverse SDOH parameters and their association with hospitalization or emergency room (ER) visits at 90 days was assessed. Multivariate logistic regression models adjusted for selected covariates from the total pool of demographic, clinical, and social covariates using stepwise regression.

Results:
174 individuals were included (mean age 55 y, 73.6% male, 61.5% Black, 20.7% Hispanic). A high adverse SDOH burden was noted, with 60% of patients unemployed, 65% living below 130% of the federal poverty limit, 53% with food insecurity, 49% with low social support, and 40% with housing instability (28% homeless). In multivariate logistic regression (area under the curve (AUC) = 0.80, F1 score = 0.71), increasing comorbidity burden (aOR 4.84, 95% CI 2.04-12.5, p<0.01), being uninsured (aOR 3.57, 95% CI 1.59-8.50, p<0.01), having low social support (aOR 3.06, 95% CI 1.48-6.53, p<0.01), and having dependents (aOR 2.98, 95% CI 1.13-8.38, p=0.03) were associated with increased odds of 90-day readmission or ER visit (
see Table
). Conversely, being employed (aOR 0.22, 95% CI 0.09 – 0.52, p<0.01) and having difficulty paying bills (aOR 0.43, 95% CI 0.20-0.88, p=0.02) were associated with decreased odds of 90-day readmission or ER visit.

Conclusions:
Hospitalized patients with HF at a safety-net hospital have a high burden of adverse SDOH. Adjusted analysis revealed significant associations of SDOH parameters with 90-day readmission or ER visits, highlighting the need for targeted interventions to recognize and improve adverse SDOH.
Abstract 4147331: Myeloid-specific Leptin Signaling Links Insulin Resistance to Salt-Sensitive Hypertension
Authors: Tinich Treiy , Mutchler Ashley , Demirci Mert , Kirabo Annet
Published: November 2024

Background:
Salt-sensitivity of blood pressure (SSBP) has been shown to correlate with insulin resistance, metabolic syndrome, and cardiovascular mortality. Hypertension can often be seen in settings of obesity, leptin resistance, and insulin resistance, though the exact mechanistic interaction of these conditions has yet to be elucidated. Inhibition of the mammalian target of rapamycin (mTOR), a major regulator of both insulin and leptin pathways, promotes symptoms of metabolic syndrome. We have previously shown high sodium environments activate antigen presenting cells (APCs) towards an inflammatory phenotype contributing to the pathogenesis of SSBP. In this study, we investigated whether
in vitro
and
in vivo
high sodium exposure affect leptin and insulin signaling in human monocytes.

Methods:
SSBP was assessed using a modified Weinberger salt-loading and depletion protocol (age was 49.25±1.98, 80% male, screening SBP/DBP was 137.3±4/88.2±2.9). Single cell sequencing was performed on circulating immune cells. In additional experiments, bulk RNA sequencing was performed on monocytes isolated from 11 healthy individuals and were treated i
n vitro
with either normal sodium (150mM) or high sodium(190mM). We analyzed the RNA sequence data and cross-referenced these results with a comprehensive list of genes associated with insulin and leptin signaling using the NIH Gene database and the Harmonizome 3.0 database from Ma’ayan laboratory at Icahn School of Medicine. Pearson correlation was used to analyze the associations. Salt sensitivity index (SSI) is the difference in SL versus SD systolic blood pressure.

Results:
We found an overall downregulation of both insulin and leptin signaling genes. Of note, there was a significant downregulation of genes for leptin (log2FC=-2.5; padj<0.0001), leptin receptor (log2FC=-0.53; padj=0.002), insulin receptor (log2FC=-0.36, padj=0.007), and glucose transporter 1 (log2FC=-0.74; padj=0.001). Although mTOR was not significant (log2FC=-0.07; padj=0.69), proline-rich AKT1 substrate 1, a direct inhibitor of mTOR activity, (log2FC=0.71; padj<0.001), was significantly upregulated. Furthermore, we found an inverse correlation between DAKT1S1 and SSI (r=-0.93; p=0.008).

Conclusions:
Our findings suggest that high salt exposed monocytes have impaired leptin and insulin signaling, which may be a factor to promote insulin and leptin resistance contributing to the development of metabolic syndrome in salt-sensitive hypertension.
Abstract 4147355: Tracking Mood Phenotypes in TIA and Ischemic Stroke Patients Using Smartphone Sensors: Preliminary Results from a Real-World Data Pilot Study
Authors: Zawada Stephanie , Dumitrascu Oana , Ganjizadeh Ali , Hagen Clint , Harahsheh Ehab , Demaerschalk Bart , Erickson Bradley
Published: November 2024

Background:
Although no tests are currently available to predict post-stroke depression (PSD), a risk factor for diminished quality of life and stroke-related death, emerging evidence suggests that ischemic stroke (IS) may induce behavioral changes by damaging connections throughout the brain rather than via localized injury.

Hypothesis:
We sought to determine if active (surveys) and passive (accelerometer, GPS, and other sensors) smartphone data could quantify exploratory behavioral proxies of PSD.

Methods:
Thirty-four adults with a recent IS (n = 12) or transient ischemic attack (TIA) (n = 22) diagnosis were followed for 3 months. Participants used the Beiwe app to complete a weekly Patient Health Questionnaire-8 (PHQ-8) survey and were evaluated every 30 days with the Montgomery-Asberg Depression Rating Scale (MADRS).

Results:
Preliminary analysis of app survey compliance was adequate (86%), and the quantity of data collected was greater for Android than iOS phones. PHQ-8 indicated depression (moderate or severe) in 20% of participants. MADRS highly correlated with the most recent PHQ-8 (
r = 0.92,
95% CI (0.19, 0.99),
P
= 0.028). Several exploratory passive physical activity and social measures showed statistically significant change over time and/or associations with PHQ-8 and MADRS.

Conclusion:
Low-burden smartphone data holds promise for developing novel IS and TIA outcome measures as well as identifying patients most at risk of PSD.
Abstract 4147410: Impact of HIV on In-Hospital Outcomes in STEMI Patients: A Propensity-Matched Analysis from the NIS Database
Authors: Ceban Alexandr , Younas Hafiz Muhammad Waqar , Taha Amro , Khir Fadi , Mubeen Hafiz Khizer , Younas Hafiz Muhammad Umair , Nisar Uzair , Ullah Muhammad Naqib , Asif Nawal , Mahmoud Ammar , Alexei Racovita , Boshkovska Spaseski Maja
Published: November 2024

Introduction:
Advancements in antiretroviral therapy (ART) have significantly increased the lifespan of patients living with HIV over the past decade. Studies have shown higher mortality and morbidity rates following acute coronary syndrome (ACS) in HIV patients, attributed to traditional cardiac risk factors, psychosomatic illness, metabolic effects of ART, and chronic immune activation caused by HIV.

Hypothesis:
We hypothesized that HIV patients presenting with ACS in the form of STEMI would have poorer in-hospital clinical outcomes compared to patients without HIV.

Aims:
We hypothesized that HIV patients presenting with ACS in the form of STEMI would have poorer in-hospital clinical outcomes compared to patients without HIV.

Methods:
We queried the National Inpatient Sample (NIS) Database from 2015-2019 using ICD-10 codes to identify STEMI patients with and without HIV. Propensity matching adjusted for confounders. The primary outcome was in-hospital mortality; secondary outcomes included major bleeding, the need for mechanical circulatory support (MCS), and net adverse clinical events (NACE). STATA was used for statistical analysis.

Results:
A total of 581,859 patients were included in the analysis. Baseline comorbidities are listed in Table 1. STEMI patients with HIV were younger (54±12 vs 63±18 years) and had higher rates of liver disease, renal failure, depression, polysubstance abuse, and a history of MI. After propensity matching, in-hospital mortality was similar between both subgroups (Table 2). No significant differences were found between the subgroups in NACE, need for MCS, and major bleeding.

Conclusion:
Despite being a strong risk factor for CAD, the presence of HIV did not influence in-hospital clinical outcomes in patients presenting with STEMI. This may reflect improved ACS protocols, advancements in ART, and a younger patient cohort. Additional studies are needed to further validate these findings.
Abstract 4147419: EKG Abnormalities and Homozygous Embryonic Lethality in Gene-Targeted Mice Mimicking K1479 Acetylation of the Cardiac Na
+
Channel Na
v
1.5
Authors: Kaesbauer Joseph , Dierdorff Jason , Greiner Alexander , Yoon Jin-Young , Irani Kaikobad , London Barry
Published: November 2024

Introduction:
Na
v
1.5, the predominant Na
+
channel in cardiac myocytes, is encoded by
SCN5A
and is essential for depolarization and impulse propagation in the heart. Loss of function mutations of Na
v
1.5 can lead to tachyarrhythmias, conduction disease and dilated cardiomyopathy by altering channel expression, kinetic properties, and/or membrane trafficking. We previously reported that amino acid K1479 of Na
v
1.5 is acetylated, that K1479 acetylation or mutation to the acetylation mimic glutamine (K1479Q) decreases inward Na
+
current (I
Na
) in heterologous expression systems by decreasing membrane trafficking, that cardiac myocytes from mice lacking the deacetylase Sirt1 (Sirt1
-/-
) are hyperacetylated and have less I
Na
, and that Sirt1
-/-
mice have conduction disease and arrhythmias. Here, we studied the effect of the K1479Q mutation that mimics acetylation
in-vivo
.

Methods:
K1479Q knock-in mice were engineered via CRISPR/Cas9 on a C57BL6 background and backcrossed 4 times with C57BL6 wild type (WT) mice. Na
v
1.5
WT/Q
heterozygous (het) mice were mated, and male (M) and female (F) gene-targeted offspring and littermate controls were studied by electrocardiograms (EKGs) and echocardiograms (Echos) at 3 and 6 months of age. Data is shown as mean±SEM.

Results:
The K1479Q mutation was homozygous (hom) embryonic lethal (Na
v
1.5
WT/Q
x Na
v
1.5
WT/Q
crosses: WT, n=23; Het, n=49; Hom, n=0). On EKG (WT: n = 5M, 3F; Het: n = 6M, 5F), Na
v
1.5
WT/Q
mice had a prolonged PR interval at 3 months (42±1 vs. 36±1 ms, p=0.0003) and at 6 months (46±1 vs. 39±1 ms, p=<0.0001) compared to WT (Figure). Na
v
1.5
WT/Q
mice also showed a prolonged QTc interval (72±1 vs. 65±2 ms, p=0.007) compared to WT controls at 6 months. No significant differences were identified in cardiac size or function between Na
v
1.5
WT/Q
and WT mice at 6 months.

Conclusions:
The K1479Q Na
v
1.5 mutation, which mimics the acetylation post-translational modification at K1479, leads to homozygous embryonic lethality and a heterozygous electrophysiological phenotype as severe as targeted deletion of the channel. These findings suggest that Na
v
1.5-K1479Q and acetylated Na
v
1.5-K1479 do not produce I
Na
in-vivo in cardiac myocytes, in part due to failure to traffic to the surface membrane.