bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13904: Associations of the Ankle Brachial Index With Functional Decline According to Presence or Absence of Diabetes
Authors: Gold Matthew E , Tian Lu , Criqui Michael H , Ferrucci Luigi , Guralnik Jack , KIBBE Melina R , Li Lingyu , Sufit Robert , Zhao Lihui , McDermott Mary M , Polonsky Tamar S
Published: April 2024

Introduction:
Among patients with peripheral artery disease (PAD), there is an inverse association between the ABI and the risk of functional decline. Whether the association is consistent for adults with vs without diabetes is unknown.

Methods:
Adults with PAD (ABI<0.90) were identified from vascular labs and outpatient clinics from 4 Chicago-area hospitals in a pooled analysis of 4 observational studies. Every 6-12 months participants completed the six-minute walk (6MW) and were asked about mobility loss (becoming unable to walk up and down a flight of stairs or walk ¼ mile without help). Mixed-effects linear regression analysis with a subject-specific random intercept was used to calculated annual change in 6MW, stratified by diabetes status. Cox proportional hazards models were used to estimate the risk of mobility loss, a decline in 6MW ≥20m or having to stop during the 6MW, per unit increment of ABI (1 unit=0.15). Analyses were adjusted for age, sex, race, study cohort and comorbidities.

Results:
Among 1,135 patients with PAD, 409 (36%) had diabetes. Mean ABI was similar between groups (0.64 with diabetes, 0.65 without diabetes, p=0.4). Compared to those without diabetes, those with diabetes were older (71.4 vs 68.6, p<0.001) and had a higher BMI (30.5 kg/m
2
vs 27.3 kg/m
2
). Mean follow-up was 3.3 years. At baseline those with diabetes had a shorter 6MW distance (320.2m vs 356.1m, p<0.001) and over follow-up had a faster rate of annual decline (-20m vs -14.5m, p<0.001). Among adults without diabetes the ABI was associated with stopping during the 6MW, mobility loss and a decline in 6MW ≥20m (Table); among adults with diabetes ABI was only associated with stopping during the 6MW.

Conclusions:
Among adults with PAD, those with diabetes had worse functional capacity at baseline and faster decline than those without diabetes. Lower ABI values were associated with faster functional decline among adults with PAD, but this association was less consistent among adults with diabetes.
Abstract 13939: Triiodothyronine and Dexamethasone Enhances Electrophysiological Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Wang Lili , Wada Yuko , Ballan Nimer , Schmeckpeper Jeffrey , Gepstein Lior , Knollmann Bjorn C
Published: April 2024

Background:
Human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) technology opens new avenues for disease modeling and drug development. However, hiPSC-CMs remain functionally immature, which hinders their utility as a model of human cardiomyocytes.

Objective:
To improve the electrophysiological maturation of hiPSC-CMs.

Methods and Results:
Day 16
th
hiPSC-CMs were treated with vehicle or 100 nmol/L triiodothyronine (T3) and 1 μmol/L Dexamethasone (Dex) for 14 days. On day 30
th
, hiPSC-CMs were dissociated and replated as cell sheets or single cells. Optical mapping and patch-clamp technique were used to examine the electrophysiological properties of vehicle- and T3+Dex-treated hiPSC-CMs. T3+Dex-treated hiPSC-CMs had a slower spontaneous beating rate (vehicle 17 ± 0.8
vs
. T3+Dex 12 ± 0.8 beats/min,
P
< 0.01), more hyperpolarized resting membrane potential (vehicle -65.04 ± 1.20
vs.
T3+Dex -72.00 ± 1.10 mV,
P
< 0.01), faster maximal upstroke velocity (vehicle 86.08 ± 8.12
vs.
T3+Dex 131.78 ± 8.49 mV/ms,
P
< 0.01), and shorter action potential duration at 90% repolarization (APD
90
, vehicle 550.44 ± 39.54
vs.
T3+Dex 418.59 ± 21.58 ms,
P
< 0.01) compared to the vehicle. Changes in spontaneous activity and AP were mediated by decreasing the funny current (I
f
, vehicle -12.20 ± 2.15
vs.
T3+Dex -6.98 ± 0.89 pA/pF at -120 mV,
P
< 0.05) and increasing the inward rectifier potassium current (I
K1
, vehicle -4.62 ± 0.59 pA/pF
vs
. T3+Dex -18.79 ± 1.98 pA/pF at -120 mV,
P
< 0.01), the sodium current (I
Na
, vehicle -9.8 ± 1.86
vs.
T3+Dex -44.9 ± 7.10 pA/pF at -30 mV,
P
< 0.01), and the rapidly and slowly activating delayed rectifier potassium currents (I
Kr
, 0.81 ± 0.07 vs. T3+Dex: 1.35 ± 0.19 pA/pF at 20 mV, P < 0.01; I
Ks
, vehicle 0.38 ± 0.06
vs.
T3+Dex 0.72 ± 0.17 pA/pF at 40 mV,
P
< 0.05). Furthermore, T3+Dex-treated hiPSC-CM cell sheets (hiPSC-CCSs) exhibited a faster conduction velocity and shorter APD than the vehicle. Inhibition of I
K1
by 100 μM BaCl
2
significantly slowed conduction velocity and prolonged APD in T3+Dex-treated hiPSC-CCSs but had no effect in the vehicle group, demonstrating the important role of I
K1
for conduction velocity and APD.

Conclusion:
T3+Dex treatment is an effective approach to rapidly enhance electrophysiological maturation of hiPSC-CMs.
Abstract 13940: Whole Mount Confocal Microscopy of Mouse Aortic Valve Leaflet Innervation
Authors: Chaparro Daniel , Hutcheson Joshua
Published: April 2024

Introduction:
Within the aortic valve leaflets (AVLs) reside a heterogeneous cell population holistically referred to as valve interstitial cells (VICs). These cells maintain the highly organized trilaminar extracellular matrix (ECM) structure in the AVL and are involved in the pathological progression of aortic valve disease (AVD). Various cell types have been reported in the AVL, including an understudied subpopulation of neurons. Since the mid-2000s, little has been done to report the possible role these neurons have in tissue homeostasis. Typically, imbedded sections of tissue chosen from specific areas of the valves are used to visualize immunoreactivity of these proteins. These sections usually come from the belly region or annular sections of the valve and seldom depict the entire leaflet anatomy.

Hypothesis:
Whole mount immunofluorescence microscopy allows us to map the 3D localization of these neuroendocrine markers throughout the entire aortic valve.

Methods:
Here, we gathered high resolution confocal microscopy images in whole mount mouse aortic valve tissues of various neuroendocrine markers such as tyrosine hydroxylase, protein gene product 9.5, and calcitonin gene related peptide.

Results:
We note that neuroendocrine markers mainly localize near the free edge on the ventricular surface of AVL tissue. We do not see the long dendritic neurons seen in the mitral and tricuspid valves, instead these markers are present in cells of varying morphologies throughout.

Conclusions:
The data gathered in this study aids our future efforts in determining mechanosensitive neural regulation of aortic valve leaflet mechanics and ECM remodeling. Future experiments will assess neuromodulation of valve rigidity under mechanical strain.
Abstract 13941: RNA-Sequencing Reveals a Distinct Transcriptomic Signature for Giant Cell Myocarditis and Identifies Novel Druggable Targets
Authors: Qin Juan , Amancherla Kaushik , Moslehi Javid
Published: April 2024

Introduction:
Giant cell myocarditis (GCM) is a rare inflammatory heart muscle disease that is often rapidly progressive and carries a poor prognosis. The pathogenesis of GCM is incompletely understood, but is thought to be autoimmune in nature. An improved mechanistic understanding of GCM is critical for identifying novel therapeutic targets and improving survival.

Hypothesis:
We hypothesized that GCM exhibits a distinct transcriptomic profile. By querying database of drug-gene interactions, novel drug targets could be identified.

Methods:
We performed RNA-seq utilizing FFPE tissues.

Results:
Demographics and clinical characteristics of the groups are highlighted in Panel A. Principal component analysis (B) based on complete expression profiles and unsupervised hierarchical cluster analysis of significant differentially expressed genes identified a distinct transcriptomic profile for GCM (C). Consistent with shared histological features, overlap is noted between rejection and lymphocytic myocarditis. Pathway enrichment analysis (D) in GCM showed that upregulated pathways were enriched for neutrophil degranulation, multiple cytokine signaling pathways, and phagocytosis, while downregulated pathways included those involved in muscle contraction and cardiac conduction. The most significantly upregulated genes play roles in innate and adaptive immune responses (E). Querying the Drug Gene Interaction Database (DGIdb) identified several novel biologically-plausible therapeutic targets (F).

Conclusions:
To our knowledge, this is the first study using RNA-seq to interrogate the transcriptomic profile of GCM. Our results demonstrate that GCM has a gene expression profile that mirrors clinical and histopathological features of GCM, and is distinct from the transcriptomic profiles seen in other healthy and inflammatory cardiac diseases. By querying a drug-gene interaction database, several novel drug targets were identified.
Abstract 13956: Nalfurafine, an Orally Active, G Protein-Biased Kappa Opioid Receptor Agonist, Increases the Diuretic Response to Loop and Thiazide Diuretics and Limits Electrolyte Losses
Authors: Meariman Jacob , Sutphen Jane , Gao Juan , Kapusta Daniel R
Published: April 2024

Nalfurafine, a G protein-biased kappa opioid receptor (KOR) agonist that produces analgesia and is devoid of CNS adverse effects, is used in Japan to treat pruritis in dialysis patients. Our lab has shown that in rats, IV nalfurafine produces a marked diuresis, antinatriuresis, antikaliuresis, and decrease in blood pressure. Here, we examined the cardiovascular and renal responses to IV and oral nalfurafine in combination with furosemide or hydrochlorothiazide (HCTZ). We hypothesized that combining nalfurafine with these diuretics would increase urine output, given its distinct mechanism of vasopressin inhibition, and limit electrolyte loss. Following chronic catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion, and after stabilization, were administered an IV bolus diuretic alone or in combination with nalfurafine. Mean arterial pressure (MAP), heart rate (HR), and urine output were recorded for 90-min. In a separate study, rats were placed in metabolic cages, and following 2-hour acclimation, were administered drug in a volume load (20 cc/kg) via oral gavage. Hourly urine samples were then collected for five hours. When compared to diuretic treatment alone, IV co-administration with nalfurafine significantly increased total urine output to furosemide and HCTZ while reducing the amount of sodium and potassium excreted (Table 1). Notably, MAP was reduced with nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral co-administration of nalfurafine significantly increased the urine output to HCTZ and reduced the amount of sodium and potassium excreted, whereas combination with furosemide only limited the amount of sodium excreted (Table 1). Together, these findings demonstrate that nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, which may offer a new approach to treat several cardiovascular conditions.
Abstract 13957: Predicting In-Hospital Mortality Among Patients Hospitalized With Heart Failure Using a Convolutional Neural Network and Transfer Learning on a Single Admission Chest X-Ray
Authors: Hidalgo-Goto David , Dhingra Lovedeep , Sangha Veer , Oikonomou Evangelos K , Khera Rohan
Published: April 2024

Background:
Early identification of mortality risk among patients hospitalized with heart failure (HF) is critical for therapeutic decisions. Early warning systems have relied on large datasets with frequent outcomes. We evaluate the use of transfer learning to use a single chest x-ray obtained at presentation in a small sample of HF hospitalizations to predict in-hospital mortality.

Methods:
In MIMIC-IV - a publicly available electronic health record dataset of consecutive hospitalizations from the ED or those requiring ≥1 day of ICU stay during 2008-2019 - we identified all hospitalizations with a primary diagnosis of HF. We combined this with chest x-rays (CXRs) drawn from the MIMIC-CXR dataset with available radiographic labels. We evaluated the risk of mortality based on CXR using a convolutional neural network (CNN) based on the Efficient Net B3 architecture. We compared 2 strategies - (1) training on primary HF hospitalizations directly for mortality risk (direct learning), or (2) pre-training the model on a non-mortality radiographic label, before training for mortality (transfer learning) (Fig A).

Results:
There were 3604 hospitalizations with a primary diagnosis of HF (mean age 70.8 years, 48% women) who had a corresponding CXR, of whom 87 (2.4%) died in the hospital. There were 102,551 hospitalizations without a diagnosis of HF with a CXR. The CNN model developed on HF data (60% training, 20% validation, 20% test) led to modest predictive performance (AUROC 0.67) for mortality (Fig B). In the second model that was pre-trained on identifying pleural effusion on CXRs in the absence of a HF diagnosis, and was tuned on the HF data for mortality, was associated with a large predictive gain (AUROC 0.80) (Fig B).

Conclusion:
A single CXR can accurately classify the mortality risk of patients with HF with high model discrimination. Transfer learning allows the use of unstructured data inputs in predictive models for small datasets and few inputs.
Abstract 13964: A Microtubule-Connexin-43 Feed-Forward Loop Suppresses Arrhythmias in Duchenne Muscular Dystrophy Mice
Authors: Nouet Julie , Himelman Eric , Lillo Mauricio , Alexander Chong , Wehrens Xander H , Rodney George G , Xie Lai-hua , Shirokova Natalia , Contreras Jorge E , Fraidenraich Diego
Published: April 2024

Dilated cardiomyopathy is the leading cause of death in patients with Duchenne muscular dystrophy (DMD), a lethal neuromuscular disorder that affects 1 in 5,000 males. We identified pathological remodeling of gap-junction protein Connexin-43 (Cx43) is a strong contributor towards DMD-related cardiomyopathy, which occurs primarily through a reduction in post-translational phosphorylation of Cx43 serine residues 325/328/330. We hypothesized that the organization of the microtubules (MTs) regulates the phospho-status of Cx43, and that the phospho-status of Cx43 regulates the organization of the MTs. To study a potential regulation of Cx43 by MTs, we delivered colchicine (Colch), a MT-regulator that reduces oxidative stress and corrects MT organization, into the DMD mouse model (mdx) and in Cx43-phosphorylation-deficient mdx mice (mdxS3A). We found that, while Colch treatment prevented the formation and aberrant activity of remodeled Cx43 in the hearts of mdx mice, it did not prevent aberrant activities in the hearts of mdxS3A mice. Thereby, Colch treatment did not prevent severe cardiac conduction in Isoproterenol-stressed mdxS3A mice, while it protected against Isoproterenol-induced arrhythmias in mdx mice. To study a potential regulation of MTs by Cx43, we evaluated the MT cytoskeleton in Cx43-phospho-mimicking mdx mice (mdxS3E). We found that the MT organization of mdxS3E isolated cardiomyocytes resembled that of wild-type. Lastly, to assess the potency of S3E in rescuing fibrosis in severe models of DMD-cardiomyopathy, we studied mdxS3E mice with partial absence of utrophin (utr). We found that S3E conferred protection against fibrosis in mdxutr(+/-)S3E relative to mdxutr(+/-) mice. In sum, Cx43-triplet phosphorylation depends on proper organization of the MT cytoskeleton, and the organization of the MT cytoskeleton depends on Cx43-triplet phosphorylation. This dual dependency creates a feed-forward mechanistic loop, which is disrupted in DMD-cardiomyopathy leading to MT disarray, arrhythmias and long-term fibrosis. The pathology is prevented either by forcing corrections in the MTs with Colch or in Cx43 with S3E. Thus, the impactful intersection between MTs and Cx43 can be harnessed for future cardiovascular disease studies.
Abstract 13965: Natural Language Processing of Hospitalization Discharge Summary to Predict 1-year Post-Discharge Mortality Among Patients With Acute Heart Failure
Authors: Rosand Benjamin , Radev Dragomir , Krumholz Harlan M , Khera Rohan
Published: April 2024

Background:
Patients hospitalized with heart failure (HF) have over 20% risk post-discharge 1-year mortality. Current risk models rely on multiple structured clinical data elements including vitals, diagnoses, laboratory tests and medications to predict mortality and have modest performance (AUROC 0.70-0.74). However, clinical notes, which capture the assessment of patients and their prognosis have had a limited role in predictive models, due to challenges with engineering features from the unstructured text.

Methods:
We identified all primary HF hospitalizations for consecutive patients at Yale, between 2013-2019, and linked to the Connecticut death index to assess 1-year post-discharge deaths. The discharge summaries for these hospitalizations were split into training and validation sets (80% and 10%), and a 10% independent test set. We used the interpretable term frequency-inverse document frequency NLP model to assess the probability of 1-year death, evaluated against observed events, presented as Kaplan-Meier Curves, and interpreted using a word importance plot.

Results:
There were 6702 discharge summaries for HF hospitalization survivors. Their mean age was 78 (SD 15) years, 50% were women, with a 1-year mortality of 21%. The NLP model on discharge summaries had high discrimination for 1-year death in the independent test set, AUROC 0.78 (Figure A), with high positive and negative predictive role (F1 score, 0.73). Moreover, the model identified prognosis over the course of the post-discharge year (Fig B), reflecting prognostic cues outside of the immediate post-discharge period. Word tokens of chronic, severe, end organ disease, represented most frequent predictors of mortality (Fig C).

Conclusions:
An NLP model exceeded the performance of the best models based on structured data. Risk-prediction using unstructured clinical notes could reduce the burden of data collection for risk prediction and adjustment while maintaining interpretability.
Abstract 14102: National Trends and Disparities in Hospitalization for Hypertensive Emergencies Among Medicare Beneficiaries, 1999-2019
Authors: Lu Yuan , wang yun , Spatz Erica S , Onuma Oyere K , Nasir Khurram , Rodriguez Fatima , Watson Karol E , Krumholz Harlan M
Published: April 2024

Introduction:
In the last two decades, hypertension control in the U.S. population has worsened, and there are widening disparities. Less is known, however, about trends in hospitalizations related to hypertensive emergencies.

Methods:
We conducted serial cross-sectional analysis of Medicare fee-for-service beneficiaries aged 65 years or older between 1999 and 2019 using Medicare denominator and inpatient files. We evaluated trends in national hospitalization rates for hypertensive emergencies, overall and by demographic and geographic subgroups.

Results:
The sample consisted of 397,238 individual Medicare fee-for-service beneficiaries. From 1999 through 2019, the annual hospitalization rates for hypertensive emergencies increased significantly from 51.5 to 125.9 per 100,000 beneficiary-years; this increase was most pronounced among the following subgroups: adults ≥85 years (66.8 to 274.1), females (64.9 to 160.1), Blacks (144.4 to 369.5), and Medicare-Medicaid insured (dual eligible, 93.1 to 270.0). Across all subgroups, Black adults had the highest hospitalization rate in 2019, and there was a significant increase in the differences in hospitalizations between Blacks and Whites from 1999 to 2019. Marked geographic variation was also present, with the highest hospitalization rates in the South (so-called “Stroke Belt”). Among 3,143 counties and county-equivalents included in the study, less than 1% of counties either had no change (n=7) or decreased (n=20) hospitalization rates since 1999.

Conclusions:
Among Medicare fee-for-service beneficiaries aged 65 years or older, hospitalization rates for hypertensive emergencies increased substantially and significantly from 1999 to 2019. Black adults had the largest increase in hospitalization rates across age, sex, race, and dual-eligible strata. There was significant national variation, with the highest rates generally in the South.
Abstract 14118: Racial Disparities In The Incidence And Outcomes Of Peripartum Cardiomyopathy Complicated By Cardiogenic Shock
Authors: Olanipekun Titilope , Abe Temidayo , Effoe Valery S , Fatuyi Micheal , Egbuche Obiora
Published: April 2024

Introduction:
There is limited data on racial disparities in the outcomes of PPCM complicated by cardiogenic shock

Methods:
We identified 5,838 patients hospitalized with the PPCM and CS from the 2007 to 2018 National Inpatient Sample, of which 2214 (38%) were White, 3006 (51.4%) Black, and 618 (11%) Hispanic. Cochrane Armitage test and multivariable logistic regression were used to assess the temporal trends in the incidence of CS among patients with PPCM stratified by the racial group stated above. In addition, we compared in-hospital mortality, systemic thromboembolism, mechanical circulatory support (MCS) use (intra-aortic balloon pump, temporal ventricular assist device, extracorporeal membrane oxygenation), heart transplant referral in Blacks and Hispanics compared to Whites using multivariable logistic regression.

Results:
The mean age of the study sample was 34 +/- 8. An increase was noted in the incidence of CS in PPCM among all racial groups from 2007 to 2018 (Whites; 0.8% to 4.1%, Blacks; 0.3% to 8.5%, Hispanics; 2.4% to 2.9%, P < 0.0001 for all). After adjusting for confound variables at baseline, the adjusted odds ratio for in-hospitality remained significantly higher in Hispanics and Blacks than whites. MCS and heart transplant referral were lower in Blacks than Whites (Table 1). Most significant factors associated in-hospital mortality among patients with PPCM and CS included baseline chronic kidney disease, chronic hemodialysis, and mechanical circulatory support use

Conclusions:
We found an incidence rate of 2.1% for CS in PPCM. Though there was an upward trend in the incidence across all ethnicities during the study period, the increase was most striking among African Americans. Hispanics and African Americans were more likely to die and less likely to be referred for heart transplant compared to Whites. African Americans were more likely to be treated with MCS compared to Whites.
Abstract 14158: Cardiac Leaflet Enhancement (CARLEN) Treats Functional Mitral Regurgitation While Preserving the Native Valve Dynamics
Authors: Sreerangathama Suresh Kirthana , Xu Dongyang , He Qi , Nambiar Hirschel , Padala Muralidhar
Published: April 2024

Introduction:
Interventional repair of functional mitral regurgitation (FMR) is rapidly replacing traditional surgical correction as surgery is contraindicated in most FMR patients. Current treatments reduce FMR acutely but unfavorably alter mitral valve (MV) geometry resulting in MR recurrence over time and are restricted to use in specific anatomies. We developed a new focal leaflet augmentation approach (
Fig. 1A
) that augments a single leaflet to correct FMR without the disturbing MV dynamics.

Hypothesis:
We hypothesize that Cardiac leaflet enhancing (CARLEN) implant can effectively correct regurgitation in different geometries seen clinically in FMR patients.

Methods:
CARLEN was laser cut from a thin sheet of nitinol and shape set to form a 3D structure with two arms that grasp the leaflet and a balloon like section that enables leaflet enhancement (
Fig. 1B
). A trans-septal delivery system was developed and the feasibility of deployment was tested in a swine model (
Fig. 2
). CARLEN functionality was tested and compared to Edge-to-Edge repair (EE) in an in-vitro left heart simulator with an isolated pig MV (n=6) in different valve geometries seen in FMR patients: a) Annular dilation (AD) alone (aFMR), b) AD+asymmetric tethering (iFMR), and c) AD+symmetric tethering (dFMR).

Results:
CARLEN consistently and significantly decreased FMR in all geometries (aFMR: 14.79±3.11% vs 6.79±1.90%; iFMR: 20.52±2% vs 6.64±2.16%; dFMR: 21.93±7.2% vs 7.12±2.83%, p<0.05). However, significant reduction after EE was seen only in iFMR and dFMR (
Fig. 3
). CARLEN did not perturb leaflet kinematics whereas leaflet mobility was significantly decreased after EE (
Fig. 4
) in all geometries.

Conclusion:
Focal leaflet enhancement with CARLEN can effectively correct regurgitation in all clinically relevant valve geometries associated with FMR, potentially expanding the opportunity for transcatheter repair to a larger patient population.
Abstract 14166: Epigenetic Biomarkers Correlate With Post-stroke Long-term Memory Recovery
Authors: Guo Wei , Yin Xing , Claypool Jonathan , Moody Melanie , Aronowski Jaroslaw , Savitz Sean , McPherson David , booher keith , Huang Shaoling
Published: April 2024

Introduction:
Epigenetic markers including 5-metylcytosine (5mC) can reflect disease severity and treatment effect. Stroke is a multifactorial disease causing aberrant DNA methylation (DNAm) and memory damage.

Hypothesis:
Models built for 5mC biomarker panel signatures may be useful for quantitative prediction of post-stroke long-term memory recovery in response to treatment.

Methods:
Stroke was induced with a middle cerebral artery occlusion (MCAO)(18 rats: sham(6), stroke(6), and stroke with treatment (6)). Xe-liposomes were intravenously administrated repetitively for 3 days after MCAO. At day 35, memory was assessed and scaled using a novel objective recognition test. Brain hippocampus and cortex tissue samples were prepared for whole-genome bisulfite sequencing (WGBS) to generate quantitative DNA methylation datasets in response to repetitive intermittent Xe administration. The resulting WGBS data were evaluated and quantitatively associated with memory recovery.

Results:
A post-stroke long-term memory outcome model was generated with scaled data using the following inputs: (1) good recovery, (2) moderate recovery, (3) edge, (4) light damage, and (5) severe damage. Differential DNAm 5mC analysis was performed comparing MCAO affected hemisphere with sham and Xe-treated samples. Initial 5mC differential analysis identified 6,175 (Cortex), and 9,037 (Hippocampus) CpG sites that were different between groups. Subsequently the LASSO algorithm was applied and selected 22 CpG sites that correlated with the long-term memory recovery scale. PCA analysis using the 22 CpGs demonstrated separation of memory outcomes. We have also built a predictive linear regression model of the 22 CpGs to assess memory loss or recovery in response to treatment. Analysis showed 7 out of 22 CpGs are conserved in humans (orthologs) for 30 bp regions.

Conclusions:
Epigenetic 5mC marker panels have the potential for quantitating post-stroke memory damages/recovery.
Abstract 14170: Incremental Value of Magnetic Resonance-Based Ventricular and Atrial Strain in Predicting Ventricular Arrhythmia
Authors: Nakata Kei , Cirillo Julia , Paskavitz Amanda , Rodriguez Jennifer , Sadhwani Trishna , Yankama Tuyen , Waks Jonathan W , Manning Warren J , Ngo Long H , Kramer Daniel B , Nezafat Reza
Published: April 2024

Introduction:
Only a small subset of patients with primary prevention ICDs, for whom left ventricular ejection fraction (LVEF) is emphasized in current guidelines, receive appropriate ICD therapy.

Objectives:
To study the incremental value of cardiovascular MR (CMR)-derived right and left ventricular and left atrial strain measured using feature tracking in predicting ventricular arrhythmia in patients eligible for implantable cardioverter-defibrillator (ICD) primary prevention of ventricular arrhythmia.

Methods:
The study included patients who met the current clinical guideline to receive an ICD for primary prevention of SCD. CMR imaging was performed on either a 1.5 or a 3T scanner, including standard evaluation of LV function and structure, LV/RV/LA strains, LGE. Outcomes were comprised of 1) unstable VT/VF >30sesonds, 2) appropriate ICD therapy; shock or anti-tachycardia pacing for VT/VF, or 3) SCD. The primary outcome was a composite endpoint of any of the above three outcomes.

Results:
A total of 239 patients were included and the average age was 57±14 years old. Patients with outcomes had slightly lower RV global longitudinal strain (GLS). Univariate Cox proportional hazards regression showed that every standard deviation increase in RV GLS was associated with a 73% increase in risk (p< 0.01). The baseline multivariable Cox’s proportional hazards regression model with a standardized clinical risk score, standardized LVEF, LGE had an AUC of 0.64. The best performing model, which included standardized LV and RV GLS, significantly improved prognosis compared with the baseline model, with an AUC of 0.72 and a categorical free NRI of 0.88 (p=0.04). Model 1 indicated an increased risk of 77% for every standard deviation increase in RV GLS (p< 0.01) and a decreased risk of 49% for every standard deviation increase in LV GLS (p= 0.02). Kaplan-Meier curves could be stratified using the selected thresholds; LV GCS ≥ 5.3 and RV GLS ≥ -10.8, respectively (p=0.02, p<0.01).
Abstract 14174: Utilization of a Standardized Aseptic Technique to Prevent Cardiovascular Implantable Electronic Device Infections
Authors: Al-zakhari Rana , Aljammali Safa , Nunez Garcia Arismendy , Rednam Chandra , Isber Ryan , Isber Nidal
Published: April 2024

Introduction:
The use of cardiovascular implantable electronic devices (CIED) (pacemaker, implantable cardiac defibrillators (ICD) and cardiac resynchronization therapy (CRT) systems) has had a significant impact in reducing mobility and mortality. However, these devices can be associated with a significant risk of infections. We present our experience showing a low incidence of infection and describe a standardized aseptic technique during CIED implantation that explains its effectiveness in the prevention of infection.

Methods:
A retrospective observational cohort study, with a concomitant cross-sectional cohort conducted at Richmond University Hospital in Staten Island New York. The department of electrophysiology has utilized a standardized aseptic technique for CIED implantations. We reviewed all data by a single operator at a single center from July 2006 to July 2016. Skin and pocket cultures were taken from fifty patients in a pilot study to determine its effectiveness at achieving complete sterilization of the surgical site which is consisted of the sequential use of antiseptics at all stages of the device implant. Tyrx Antibiotic pouch was not used during the procedure.

Results:
χ
2
test was used and a p-value of <0.05 was considered statistically significant. 1811 cases were identified and included in the analysis. There were 612(34%) generator changes and 1198 primary implants (66%), 47% of the devices were pacemakers, whereas 33% and 17% were ICD and Biventricular Defibrillators, respectively. There was only one infection identified with a rate of 0.05 within one week of the procedure. Fifty patients underwent wound cultures at the time of the procedure, all revealed no growth after 5 days.

Conclusion:
The rate of CIED infection in our population was 0.05% and it remained low across all high-risk groups. Our technique that was used on all patients, proved its ability to achieve complete surgical site sterility. This result suggests that the use of a standardized asepsis strategy can potentially decrease the risk of CIED infections without the use of Tyrx antibiotic pouch. However, given the lack of a control group our results should be validated on a randomized control study.
Abstract 14189: Isolated Tricuspid Valve Surgery Repair versus Replacement for Infective Endocarditis: A Nationwide Analysis
Authors: Bansal Agam , Gad Mohamed , Cremer Paul , Jaber Wael A , Menon Venu , wassif heba
Published: April 2024

Introduction:
Incidence of right-sided infective endocarditis (IE) is on rise secondary to opioid epidemic, and increasing use of cardiac devices, central catheters, or AV fistulas. We aimed to compare outcomes of isolated tricuspid valve (TV) repair versus replacement and determine the predictors of mortality after isolated TV surgery for hospitalizations with IE.

Methods:
We utilized nationwide readmission database (NRD) to identify hospitalizations for IE that underwent isolated TV repair or replacement in 2018. Hospitalizations with concomitant or previous cardiac surgery were excluded. Multivariate logistic regression analysis was performed to determine predictors of mortality after isolated TV surgery for IE.

Results:
1463 hospitalizations were identified for IE undergoing either isolated TV repair (n=531, 36.3%) or replacement (n=932, 63.7%). 106 (11.3%) underwent mechanical TV replacement. Patients undergoing TV replacement had increased risk of acute kidney injury (aOR: 1.45 (1.03-2.03), p=0.03) and pacemaker implantation (aOR: 7.03 (3.95-13.45), p<0.001), however there were no significant differences in in-hospital mortality (aOR: 0.80 (0.35-1.83), p=0.59) (Table). Independent predictors of mortality for TV replacement were advanced liver disease (ALD) (5.31 (1.62-17.67), p=0.005), and acute heart failure (3.48 (1.02-18.14), p=0.044) and for TV repair were ALD (5.72 (1.31-24.90), p=0.017), and age (1.07 (1.02-1.14), p=0.026). However, predisposing conditions (drug use, infection of cardiac prosthesis, or vascular device), micro-organisms, and mechanical TV replacement were not associated with mortality in patients undergoing surgery.

Conclusions:
Our study reinforces that TV repair should be preferred over replacement for right sided IE when feasible, and adds to existing literature that it is the patient’s co-morbidities rather than the predisposing factors or microbiology that is associated with increased mortality.
Abstract 14192: Accuracy Improvement In The Fully Automated Assessment Of Right Ventricular Function Using Artificial Intelligence
Authors: Wang Shuo , Chauhan Daksh , Patel Hena , Amir-Khalili Alborz , Sojoudi Alireza , Kawaji Keigo , Singh Amita , Landeras Lius , Mor-Avi Victor , Amit Patel R
Published: April 2024

Introduction:
The use of deep learning (DL) contouring algorithms to automatically calculate right ventricular ejection fraction (RVEF) is challenging due to the highly variable right ventricular (RV) geometry. The robustness of a DL algorithm to quantify RVEF using cardiac magnetic resonance (CMR) is highly dependent on the quality of the dataset used to train and cross-validate the algorithm. Using an insufficiently heterogeneous dataset to cross-validate a DL algorithm during development may poorly affect its performance when deployed in a clinical environment with diverse disease states and variable image quality. This study was designed to test the hypothesis that using a heterogeneous CMR dataset with a wide range of RV pathology during the cross-validation phase of DL algorithm development would result in more accurate quantification of RV function.

Methods:
We identified 100 CMR exams in which the RV function could not be accurately quantified using a commercially available DL algorithm (DL1), resulting in errors >5%. We then used a new algorithm that was developed while including images from a greater diversity of disease states and acquisition techniques during the cross-validation phase (DL2). RVEF was measured automatically using both DL1 and DL2 (Figure A) and compared to measurements made in a core laboratory (Core).

Results:
DL2-RVEF correlated highly with Core-RVEF (r=0.87), whereas DL1-RVEF correlated only modestly (r=0.42) (Figure B). DL2 also resulted in a smaller RVEF error than DL1 when compared to Core-RVEF (Figure C). For DL1, the percentages of smaller errors were considerably lower with no cases with <5% error, while errors >10% were noted in 35% of cases. In contrast, for DL2, 70% of cases were within 5% error, while only 10% of cases showed errors >10%.

Conclusions:
The use of a diverse dataset during the cross-validation phase of DL algorithm development resulted in a considerable improvement in the accuracy of the automated analysis of RVEF.
Abstract 14203: Implications of Atrial Fibrillation on Clinical Outcomes of Patients With Heart Failure With Preserved Ejection Fraction
Authors: Shafi Irfan , Alhusain Rashid , Awadelkarim Abdalaziz , Tidwell Chad , Mumm Tyler , Mishra Tushar , Ali Mohammed , Manmohan Singh , AFONSO Luis , Kottam Anupama
Published: April 2024

Background:
Atrial fibrillation and heart failure with preserved ejection fraction(HFpEF) are closely interrelated, and atrial fibrillation confer poor prognosis in HFpEF patients.

Objective:
We sought to study outcomes and implications of atrial fibrillation among patients hospitalized with HFpEF.

Methods:
Patients with a principal discharge diagnosis of HFpEF between 2016 and 2018 were identified in the National Readmissions Database. Among those, patients with and without a secondary diagnosis of atrial fibrillation were categorized. HFpEF hospitalizations with atrial fibrillation were matched 1:1 fashion to HFpEF without atrial fibrillation using age, sex, and Charlson comorbidity index.

Results:
Of the 195,110 HFpEF hospitalizations, 66,584 had HFpEF with a secondary diagnosis of atrial fibrillation. Propensity score-matched comparison between HFpEF with and without atrial fibrillation showed higher in-patient mortality (3.18% vs. 2.58%, P=0.00), Cardiogenic shock (0.62% vs. 0.39%, P=0.00) and bleeding (2.09% vs. 1.08%, P=0.00) as compared with HFpEF without atrial fibrillation. Total charges were higher in HFpEF with atrial fibrillation compared to patients without atrial fibrillation ($ 46018.97 vs. $ 43692.16). The 30 days all-cause readmission rate among patients admitted with HFpEF and survived index hospitalization was 20.14% (95% CI 19.96 - 20.31%).

Conclusion:
In patients with HFpEF presence of atrial fibrillation was associated with higher inpatient mortality.

Figure 1: Patient selection flow diagram

Table 1: Outcomes of HFpEF Patients with and without Atrial Fibrillation in Propensity-Matched Groups.
Abstract 14228: Mechanism of Atrial Fibrillation in an Animal Model of Inflammatory Bowel Disease
Authors: Pelaez Andres F , Varma Disha , Pereira Carlos H , Almeida Jonathas F , Wasserlauf Jeremiah , Keshavarzian Ali , Banach Kathrin
Published: April 2024

Introduction:
Ulcerative colitis (UC) is an
i
nflammatory bowel disease with a relapsing and remitting course. UC has extraintestinal manifestations and UC patients exhibit twice the risk for atrial fibrillation (AF) during acute disease activity. The mechanism of AF due to UC remains to be determined.

Hypothesis:
During acute UC a dysregulation of vagal signaling increases a patients propensity for AF.

Methods:
Mice (male, C57BL/6) were treated with Dextran Sulfate Sodium (DSS: 3%) supplemented drinking water for 7days that disrupts intestinal barrier function and mimics the disease phenotype of acute UC. Changes in atrial electrophysiology were quantified
in vivo
(EKG), on the whole heart (Langendorff configuration) and the cellular level (Fluo-4AM) during peak inflammation (DSS
A
) and remission (DSS
R
).

Results:
DSS
A
mice exhibited an attenuated heart rate (HR) in vivo (CTL: 491 ± 11 bpm, n=10; DSS
A
: 448 ± 11 bpm, n=16; p<0.05) and in excised perfused hearts (Langendorff configuration: CTL: 321 ± 15 bpm, n = 3; DSS
A
: 256 ± 17 bpm, n = 4; p < 0.05). The P-wave duration was prolonged (in vivo, CTL: 25.5 ± 0.6 ms, n=10; DSS
A
: 30.2 ± 0.5 ms, n=16; p < 0.0001) and HR variability time-domain measure RR-corrected SDNN was attenuated (CTL: 11.3 ± 1.1 ms, n=10; DSS
A
: 8.2 ± 0.7 ms, n=16; p < 0.05). The latter is an indicator for an attenuated vagal tone in DSS
A
mice and coincided with an increased sensitivity to the vagal agonist Carbachol in-vivo (CCh 150 ng/g, change in HR: CTL: -3.8 ± 4.4 %, n=6; DSS
A
: -42.2 ± 4.8 %, n=10; p < 0.0001). After burst pacing DSS
A
hearts exhibited a prolonged RR-corrected sinus node recovery time (CTL: 11.2 ± 1.4 ms, n=3; DSS
A
: 25.5 ± 2.1 ms, n=4; p < 0.0001), an increased AF propensity, and prolonged duration of AF episodes (CTL: 0.8 ± 0.17 s, n=3; DSS
A
: 2.4 ± 0.31 s, n=4; p < 0.05) even in the absence of CCh. No changes in atrial myocyte Ca handling properties were determined. After remission HR, P-wave duration, and HRV in DSS
R
returned to control values.

Conclusions:
The data suggests that acute UC increases the risk for AF likely as a consequence of an attenuated sinus rhythm and atrial conduction velocity where vagal stimuli could exacerbate the risk for reentry of excitation. If these changes are the direct consequence of the attenuated vagal tone remains to be determined.
Abstract 14259: Exercise Training Attenuates Activin Type II Receptor Signaling in the Aged Heart
Authors: Shiv Chandra Singh Abhilasha , Yu Andy , Chang Bliss , Li Haobo , Rosenzweig Anthony , Roh Jason D
Published: April 2024

Introduction:
Exercise training (ExT) improves functional capacity in older adults with heart failure (HF). However, the molecular mechanisms by which ExT exerts these benefits are unclear. We previously showed that cardiac activin type II receptor (ActRII) signaling increases in aging and HF, and that ActRII inhibition can improve cardiac exercise capacity in aged C57BL/6 mice, a model of age-related HFpEF. Whether cardiac ActRII signaling is modulated by ExT is unknown.

Hypothesis:
We hypothesized that ExT would attenuate cardiac ActRII signaling in aged mice.

Methods:
A moderate intensity ExT protocol (treadmill running, 10m/min, 10° incline, 45min/day, 8 weeks) was performed in 25month-old (mo) female C57BL/6 mice (OE). Functional (exercise capacity), molecular, and gravimetric assessments of HF were compared to young (YS, 4mo) and old (OS, 27mo) sedentary controls, along with indicators of downstream ActRII signaling (FSTL3 expression, SMAD3 phosphorylation, senescence, apoptosis markers).

Results:
After 8 weeks of ExT, exercise capacity increased in OE mice by 2.5±9.9% versus -24.1±4.6% in OS mice (p=0.05). ExT did not induce significant changes in cardiac hypertrophy or natriuretic peptide expression in aged mice, but decreased lung weight to body weight ratios (3.8±0.2(YS) vs 7.4±0.7(OS) vs 5.3±0.4(OE) mg/g, p=0.001). Cardiac ActRII signaling increased with aging and was attenuated with ExT (FSTL3/GAPDH: 1.0±0.01(YS) vs. 2.9±0.1(OS) vs. 1.0±0.2(OE) p=0.01; pSMAD3/SMAD3: 0.8±0.2(YS) vs. 1.5±0.04(OS) vs. 1.1±0.1(OE), p=0.1). Moreover, parallel changes occurred in markers of cardiac senescence (p16: 1.0±0.02(YS) vs. 1.6±0.1(OS) vs. .3±0.02(OE), p=0.02) and apoptosis (BAX: 0.8±0.2(YS) vs. 1.8±0.05(OS) vs. 1.1±0.1(OE), p=0.0007; cleaved caspase 3: 0.8±0.01(YS) vs. 2.2±0.01(OS) vs. 1.0±0.02(OE), p=0.0001), which have been shown to be regulated by ActRII signaling.

Conclusions:
These findings suggest aerobic ExT attenuates the cardiac ActRII signaling observed in aged mice and slows the age related decline in exercise capacity. Age-associated pathologies linked to ActRII signaling, including cellular senescence and apoptosis, were similarly modulated by ExT.
Abstract 14268: PKM2 to PKM1 Isoform Switching in Fibroblasts Attenuates Cardiac Dysfunction in Infarcted Mice
Authors: McNally Lindsey A , Mehra Parul , Gibb Andrew , Brittian Kenneth , Gumpert Anna , Dassanayaka Sujith , Jones Steven P , Hill Bradford G
Published: April 2024

Introduction:
The muscle isoform of pyruvate kinase, PKM, has two splice variants, with PKM2 having important roles in cardiomyocytes during development. The goal of this study was to understand the role of PKM2 in the adult failing heart.

Methods:
To determine how PKM2 expression changes after myocardial infarction (MI), wild-type (WT) mice were subjected to permanent coronary ligation followed by measurement of PKM2 abundance and localization by Western blotting and immunofluorescence imaging. To delineate the role of PKM2 in fibroblasts after MI, PKM2

fl/fl

mice were bred with a fibroblast-specific, tamoxifen-inducible Cre driver (Col1a2-CreER; Cre). The Cre
+
and Cre
-
PKM2

fl/fl

mice of both sexes were treated with tamoxifen (i.p. 20 mg/kg/d; 5 d), followed by tamoxifen washout and MI surgery. Four weeks after MI, cardiac function was examined by echocardiography.

Results:
Hearts from infarcted WT mice had 10-fold higher levels of PKM2 compared with sham WT hearts (n=8/gp, p<0.05). Immunofluorescence staining revealed PKM2 localized to areas of replacement fibrosis in infarcted hearts, and immunoblotting of isolated, adult cell populations showed PKM2 expressed in fibroblasts, smooth muscle cells, and endothelial cells, but not in cardiomyocytes. Furthermore, PKM2 levels were higher in cardiac fibroblasts isolated from infarcted mice compared with sham mice (n=3/group; p=0.005). Cardiac fibroblasts isolated from tamoxifen-treated Cre
+
/PKM2

fl/fl

mice had decreased PKM2 expression and increased PKM1 expression. In naïve mice, PKM2 to PKM1 isoform switching did not affect cardiac function for up to 5 wk after tamoxifen administration. Although survival was not different between Cre
-
and Cre
+
PKM2

fl/fl

mice after MI (n=18-20/gp; p=0.6383), PKM2 to PKM1 switching in Cre
+
PKM2

fl/fl

male mice improved cardiac function compared with Cre
-
PKM2

fl/fl

controls (n=7-12/gp), with a 15% improvement in ejection fraction (p=0.03), a decrease in LVIDd (p=0.04), EDV (p=0.04), and ESV (p=0.03), and an increase in LVPWd (p=0.01) and LVPWs (p=0.01); however, in female mice, PKM isoform switching did not improve cardiac function.

Conclusions:
Fibroblast-specific switching of PKM2 to PKM1 prior to MI prevents cardiac functional decline in male mice.
Abstract 14284: "Weeding" Out Wellens' Syndrome
Authors: Asghar Moneeb , Adams Joseph , memon saadia , Chadaga Amar
Published: April 2024

Introduction:
Wellens’ syndrome, most often associated with proximal left anterior descending coronary artery stenosis, is considered highly specific for impending myocardial infarction (MI). Its diagnosis relies on symmetric biphasic or deeply inverted T waves in leads V1-V4, normal precordial R wave progression and normal to slightly elevated cardiac markers. Pseudo-Wellens’ syndrome presents similarly, but in the absence of coronary artery disease (CAD). We present a challenging case of a patient with history of excessive recreational cannabis use and incidental electrocardiogram (ECG) findings concerning for Wellens’ syndrome who ultimately was diagnosed with Pseudo-Wellens’ syndrome. With familiarity of cannabis associated Pseudo-Wellens’ syndrome, unnecessary invasive diagnostic and therapeutic procedures were avoided.

Case:
A 20 year old male without significant past medical history presented for evaluation of vomiting and abdominal pain of 2 days duration. In view of his daily cannabis use, he was diagnosed with cannabis hyperemesis syndrome. An ECG to measure QTc prior to administration of ondansetron demonstrated ST elevation in lead V2. A repeat ECG showed T-wave inversions in leads V2-4. Troponin levels were negative. The patient denied chest pain or shortness of breath. An echocardiogram showed normal cardiac wall motion and an estimated ejection fraction of 55-60%. The diagnosis of Pseudo-Wellens’ syndrome secondary to cannabis use was made and the patient was subsequently discharged home following extensive cannabis cessation counseling.

Discussion:
The definitive treatment of Wellens’ Syndrome relies on cardiac catheterization even in patients without cardiac history or risk factors for CAD. This immediate intervention is required to halt the evolution of MI and is crucial for a positive outcome. In contrast, Pseudo-Wellens’ syndrome occurs in the absence of CAD and has been reported in younger, healthy patients in association with illicit drug use. In the era of increased legalized marijuana use, it is imperative that health care providers are familiar with cannabis induced Pseudo-Wellens’ syndrome as to avoid the potential for inappropriate invasive diagnostic modalities in otherwise healthy individuals.