bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4146532: Human Induced Pluripotent stem Cell Derived Nanovesicles for Cardiomyocyte Protection
Authors: Geng Xiaoxiao , Wei Yuhua , Zhang Jianyi , Ye Lei
Published: November 2024

Introduction:
It is well-known that reactive oxygen species (ROS) play important roles in myocardial ischemia reperfusion (I/R) injury. Exosomes have shown great potential and application in mitigating I/R induced cell and tissue damage. However, the clinical translation of exosomes
has been
limited by deficiencies in the yield of exosomes from cultured cells. Instead, nanovesicles (NVs), products manufactured directly from cells, can be easily scaled-up which facilitates translation into clinic.

Methods:
NVs were manufactured from human induced pluripotent stem cells (hiPSCs) using an extruder and with a 0.2-μm filter membrane. The size and number of hiPSCs derived NVs (hiPSC-NVs) were measured by a Nanosight, and morphology of NVs were visualized with an electron microscope. The potency of hiPSC-NVs on protection of hiPSCs derived cardiomyocytes (hiPSC-CMs) against hypoxia and H
2
O
2
were assessed in culture and in a mouse model of I/R injury. Proteomic analysis was performed to identify proteins that have ROS scavenger properties in hiPSC-NVs.

Results:
About 9,500 NVs can be manufactured per one hiPSC. hiPSC-NVs starting 6.25x10
8
/mL concentration effectively reduced lactate dehydrogenase leakage and apoptosis in hiPSC-CMs cultured in HBSS for 24 h in a hypoxia incubator, and protected cultured hiPSC-CMs from 200 µM H
2
O
2
induced damage. When hiPSC-NVs or 0.9% NaCl was intramyocardially injected into C57BL mice hearts after cardiac I/R, measurements of cardiac function and infarct size conducted 4 weeks later were significantly better in the hiPSC-NV treatment group and were accompanied by increases in recipient mouse CM survival. Notably, proteomic analyses indicated that compared to hiPSCs, hiPSC-NVs were enriched in numerous proteins that scavenge ROS, including NUDT2, PRDX2, PRDX4, PRDX5, PRDX6, and GSR. Thus, through all these proteins in NV cargos, hiPSC-NVs exert CM protection activity against ROS injury after I/R.

Conclusions:
The use of hiPSCs as parental cells for manufacturing NVs, can easily scale-up production, and have great potential for cardiac protection after I/R.
Abstract 4146568: Hemodynamics of Acute Type B Aortic Dissections with 4D Flow MRI
Authors: Cebull Hannah , NAEEM MUHAMMAD , Liu Minliang , Dong Hai , Gleason Rudolph , Elefteriades John , Piccinelli Marina , Oshinski John , Leshnower Bradley
Published: November 2024

Background:
Type B aortic dissections (TBAD) develop from a tear in the intimal layer of the aorta, distal to the left subclavian artery. This tear separates the aorta into true (TL) and false lumens (FL), increasing the risk of dilation and rupture. In cases of surgical intervention, treatment for type B aortic dissections (TBAD) after the acute phase (> 14 days) is associated with worse outcomes. Identification of those patients who will experience aortic growth could identify patients who would benefit from early intervention. This study aims to characterize blood flow for risk stratification using 4D flow MRI. We identified possible markers of interest: entry tear velocity, pulse wave velocity (PWV), and wall shear stress (WSS).

Methods:
TBAD patients (n = 7; 3 F) from Emory University Hospital were enrolled. We acquired 4D flow MRI during the acute phase (3T Prisma Fit; Siemens Healthcare). We created image-derived 3D models of lumens and measured velocity at entry tears. We estimated PWV using cross correlation of waveforms at perpendicular, evenly-spaced planes throughout the true lumens. We estimated WSS throughout the false lumen using a previously developed method (Matlab, Ansys EnSight). Growth rates were measured from at follow up computed tomography exams.

Results:
Three of the patients (P2, P3, P7) did not grow, while P1, P4-P6 grew 2.1, 1.2, 5.3, and 2 mm/month, respectively. Peak entry tear velocities were higher in growth (143 cm/s) than non-growth (90 cm/s) cases, with P5 having the highest (180 cm/s). Forward flow was greatest in the distal end of FL near visceral branches (growth = 17.1, non-growth = 11.0 ml/cycle). Pulse wave velocity measurements between growth and non-growth were similar (4.5 and 3.5 m/s). Both averages were lower than PWV for non-dissected aortas. Regions of high vorticity and WSS can be observed in the true and FL near tears, but no trends were found between growth and non-growth cases.

Conclusion:
We anticipate stronger trends as enrollment continues, but our preliminary findings demonstrate the first MRI study to enroll acute TBAD subjects and identify markers of interest.

Sources of Funding:
This study is supported by NIH R01HL155537 and the National Center for Advancing Translational Sciences under Award Numbers UL1TR002378 and TL1R002382.
Abstract 4146618: Differential Impact of Left Atrial Volume on Post-Ablation Recurrence Rates in Patients with Normal and Reduced Left Atrial Ejection Fraction: A DECAAF II Subanalysis
Authors: Bsoul Mayana , Liu Yingshuo , Assaf Ala' , bidaoui ghassan , Jia Yishi , Younes Hadi , Feng Han , Mekhael Mario , Tirado Polo Francisco , Lim Chanho , Hui Yanpei , Hassan Abboud , Rao Swati , Pandey Amitabh , Kreidieh Omar , donnellan eoin , Marrouche Nassir
Published: November 2024

Background:
The left atrial volume (LAV) has been known to be positively correlated with the atrial fibrillation (AF) recurrence rates after catheter ablation (CA) but negatively correlated with the left ventricular ejection fraction (LVEF). We hypothesized that LAV plays different roles for patients with normal LVEF (LVEF ≥ 50%) and those with lower LVEF (LVEF < 50%).

Method:
Out of 843 patients from the DECAAF II trial, 674 patients with baseline LAV and LVEF data were included. Among these, 506 patients were characterized as having normal LVEF, while 168 patients had lower LVEF. For each group, the effect of LAV was studied against the AF recurrence through the Cox model, adjusting for age, sex, baseline LA fibrosis, and comorbidities, including coronary artery disease (CAD), hypertension (HTN), congestive heart failure (CHF), diabetes (DM), and hyperlipidemia (HLD). Patients were further divided into high and low LAV groups and compared performance after CA through the Kaplan-Meier curves and log-rank tests.

Result:
From Cox models, in the high LVEF group, LAV was identified as a significant predictor of the AF recurrence, with a hazard ratio (HR) of 1.009 (95% CI: 1.006-1.013, p < 0.001) for each unit of increase (Table 1a). In the low LVEF group, LAV was not associated with AF recurrence (Table 1b). As in Figure 1, among lower LVEF patients, high LAV and low LAV provide similar AF recurrence rates. However, low LAV patients with normal LVEF have the lowest AF recurrence rate, while high LAV and normal LVEF patients have the highest AF recurrence rates after CA (p < 0.001).

Conclusion:
The study found that baseline left atrial volume (LAV) is a strong predictor of AF recurrence after CA for patients with normal LVEF but not for patients with lower LVEF. Patients with large LAV and normal LVEF have even worse outcomes compared to those with large LAV and lower LVEF.
Abstract 4146669: Impacts of left ventricle–mitral annulus orifice area mismatch annuloplasty for advanced severe degenerative mitral regurgitation
Authors: Chen Ming , Yue Zhang , Fan Pengning , chen zhe , Zheng Yidan , Tong Fuqiang , zhai haoyang , Liu Yuqi , Qian Xingyu , rao zhenqi , Zhu Da , Pan Xiangbin , Dong Nianguo , Xu Li , Li Fei
Published: November 2024

Background:
In advanced severe degenerative mitral regurgitation (asDMR, i.e., C2 to D stage DMR), an overt deterioration of the mitral valve (MV) apparatus and left ventricular (LV) enlargement are typically observed. The negative impacts of a mismatch between the left ventricular end-systolic dimension (LVESD) and MV ring size on mitral regurgitation (MR) recurrence have been established in secondary MR, while its impacts on asDMR prognosis remains unknown.

Hypothesis:
LVESD/MV ring size ratio may impact on asDMR prognosis.

Goals:
To verify the impact and to reveal its side effects.

Methods:
We retrospectively analyzed patients diagnosed with asDMR who underwent mitral valve repair and annuloplasty from 2008 to 2019. Patients were followed up to April 2024. Primary outcomes included 10-year moderate or severe mitral stenosis (MS), recurrent MR, and death. Prosthetic orifice areas (POA) were obtained from official instructions. LVESD/POA was introduced as a novel parameter to identify LV-MV mismatch and non-mismatch.

Results:
A total of 450 eligible patients were enrolled. During the follow-up of 5.8 ± 2.3 years, 60 recurrent MRs, 71 MSs, and 46 deaths were observed. At 3rd, 5th, and 10th years after surgery, rates of freedom from recurrent MR were 98.1%, 92.4%, and 65.4%, respectively; rates of freedom from MS rates were 99.0%, 94.9%, and 59.4%, respectively; survival rates were 97.8%, 94.9%, and 69.6%, respectively. In multivariable Cox regression analysis, only a larger LVESD/POA ratio (HR: 3.50; 95% CI: 1.98-6.16; p < 0.001) was associated with recurrent MR. ROC curve determined an optimal LVESD/POA cutoff value of 11.52 mm/m
2
(AUC = 0.88, p < 0.001) for recurrent MR prediction. In subgroup analysis, mismatch group (LVESD/POA > 11.52 mm/m
2
) had higher cumulative recurrent MR rate (log-rank p < 0.001), MS rate (log-rank p < 0.001), and survival rate (log-rank p < 0.001). In mismatch group, ring cohort exhibited higher cumulative MS rate (log-rank p = 0.027) and higher cumulative recurrent MR rate (log-rank p = 0.013). However, in the non-mismatch group, the cumulative MS and MR rates were comparable between the ring and band cohorts (log-rank p = 0.53).

Conclusion:
LV-MV mismatch annuloplasty increases the risks of recurrent MR, MS, and death. LVESD/POA ratio effectively predicts recurrent MR in asDMR. In patients with significant LV dilation, a posterior band may be preferable to a complete ring for downsized annuloplasty.
Abstract 4146671: Validation of Xenon (Xe)-Liposomal Cerebroprotection for Ischemic Stroke
Authors: Yin Xing , Wu Jean , Moody Melanie , Aronowski Jaroslaw , McPherson David , Savitz Sean , Booher Keith , Huang Shaoling
Published: November 2024

Background:
Xe-liposome therapy has shown cerebroprotection in adult stroke animals. This study aims to validate the Xe therapeutic effect by MRI in adult rats and the therapeutic effect in an aged animal.

Method:
A 2-hour MCAO was induced in adult rodents. The MCAO animals were then divided into two groups: one receiving no treatment and the other receiving Xe-liposomal treatment (3 doses within 2-6 hours after stroke followed by 1 dose per day). Diffusion-weighted MRI conducted at 2, 6, and 24 hours post-MCAO, were analyzed by our image center. For aged rats (14 rats, 74 weeks old, male and female), MCAO (1.5 hours) was induced and then divided into two groups: stroke without treatment (n=5) and stroke with Xe-liposome treatment (n=9) and given 3 doses at day one and once per day for following days. Neurological function was tested by Limb placement and rotarod, and infarct volumes were measured two days post-stroke/treatment.

Results:
MRI (Fig.) demonstrated that infarct volume growth ratio was lower in the Xe-treated animals than those without treatment, indicating a protective effect of Xe against ischemic injury. MCAO induced 25% ± 5.4% infarct volume in the aged animals. Xe- reduced the infarct size to 6.7% ± 3.4%. Xe treatment demonstrated improved neurological functional recovery in these aged stroke animals.

Conclusions:
Xe-liposomal treatment reduces ischemic core growth in adult rats and has a therapeutic effect in aged stroke animals. These results support further development of Xe-based therapies for stroke.
Abstract 4146678: Artificial Intelligence-enhanced Interpretation of Single-lead Electrocardiogram in Normal Sinus Rhythm to Detect and Predict Atrial Fibrillation and Flutter
Authors: Aminorroaya Arya , Dhingra Lovedeep , Pedroso Camargos Aline , Oikonomou Evangelos , Khera Rohan
Published: November 2024

Background:
Portable ECG devices can help identify symptomatic atrial fibrillation/flutter (AF) episodes outside healthcare settings. However, most individuals remain undiagnosed due to the transient and often asymptomatic nature of AF. Here, we developed an AI-ECG model to detect concomitant paroxysmal AF and predict its future risk using lead I ECG recordings in normal sinus rhythm (NSR), with special adaptation for noisy acquisition on portable devices.

Methods:
The model was developed using 1.6 million ECGs at Yale (2000-2015). ECGs in NSR associated with an ECG with AF rhythm from 30 days before to any time after were considered NSR with concomitant AF. A convolutional neural network was trained using lead I ECG to detect concomitant AF among NSR ECGs, augmented using random Gaussian noise during training to make them resilient to noisy acquisition on portable devices. We evaluated the model's probability as a predictor for incident AF (defined by AF ECGs or clinical diagnosis), in (1) a separate set of individuals in a temporally distinct population at Yale (2016-2023) and (2) the UK Biobank (UKB) (2014-2021), excluding those without a history of AF. We constructed age- and sex-adjusted Cox proportional hazards models with model probability as a key independent variable.

Results:
The AI-ECG model achieved an AUROC of 0.821 (95% CI, 0.818-0.824) for detecting concomitant AF based on a single-lead ECG in NSR with a sensitivity of 75%, a specificity of 75%, a PPV of 28%, and an NPV of 96%. In the predictive assessment, 312,533 individuals (52 [IQR, 32-66] years, 54% women) at Yale, and 41,711 individuals (65 [59-71] years, 52% women) in UKB had no known AF. In these groups, 3.1% at Yale and 1.4% in UKB had incident AF over median follow-ups of 3.1 [1.6-4.5] years and 3.0 [2.1-4.5] years, respectively. AI-ECG had high discrimination for future AF risk (Harrell’s C-statistic, 0.77 in Yale and 0.68 in UKB). After accounting for age and sex, a positive AI-ECG was associated with a 2-fold higher hazard of AF (adjusted HR: 1.93 [1.84-2.02] in Yale and 2.34 [1.98-2.76] in UKB).

Conclusion:
We developed an AI-ECG model capable of detecting concomitant paroxysmal AF and predicting incident AF using a single-lead ECG noted to be in NSR. With the growing availability and accessibility of portable ECGs, this model enables a scalable screening and risk stratification strategy for AF, especially in older adults at increased risk of stroke, in the community.
Abstract 4146679: Effects of Daily Muscle Stretching in Peripheral Artery Disease Patients
Authors: Lanka Santh Prakash , Alsabbagh Yaman , Nussbaum Sam , Martenson Matthew , Maraj Joshua , Liu Xiuwen , Rodriguez Cesar , Ade Carl , PROCTOR DAVID , Farres Sam , hakaim albert , Delp Judy
Published: November 2024

Introduction:
Peripheral artery disease (PAD), an atherosclerotic disease of the peripheral arteries, also results in microvascular dysfunction. PAD patients are recommended to undergo supervised walking and medical management; however, compliance with supervised walking programs is limited due to inconvenience and pain, necessitating alternative non-pharmacological interventions. We have shown that daily muscle stretching improved microvascular function in aged rats. This prompted us to study the effect of daily muscle stretching on microvascular function of the calf muscles in PAD patients.

Methods:
A randomized, single-blinded study was conducted on 24 PAD patients. Patients were assigned to either stretching or placebo stretching using a dorsiflexion splint
(Image 1)
for 30 min/day, 5 days/wk for 4 wks. Calf muscle oxygen saturation (smO
2
) was recorded using near-infrared spectroscopy during the six-minute walking test (6MWT) before (Visit 1) and after (Visit 2) stretching or placebo stretching. The percentage decrease in smO
2
(from baseline) at minute 1 (Δ1) and minute 2 (Δ2) of the 6MWT was determined. Two-way ANOVA was used to compare Δ1 and Δ2 between the stretching and placebo stretching groups.

Results:
The mean age of the patients was 74.1±11.4 yrs with 52% (13/23) males. There was no significant difference in the changes in smO
2
during the 6MWT at either minute 1 (Δ1: 44.1±7.3% vs 27.1±7.0%, p=0.12) or minute 2 (Δ2: 78.7±8.2% vs 58.1±7.9%, p=0.08) between the stretching group and placebo stretching group at Visit 1. In contrast, at Visit 2, there was a significantly greater change in smO
2
at minute 2 (D2: 83.1±8.2% vs 51.3±7.9%, p=0.008) in the stretching group compared to the placebo stretching group with a trend towards a statistically greater change in smO
2
at minute 1 (Δ1: 39.0±7.3% vs 20.4±7.0%, p=0.06)
(Image 2).

Conclusion:
Daily stretching of the calf muscles for 4 weeks is associated with increased oxygen extraction by the calf muscles during walking.
Abstract 4146686: Carvedilol Exerts Evolutionarily Conserved Cardioprotective Effects via Autophagy Modulation and Energetics Restoration
Authors: Boukhalfa Asma , SHIN PEI-TSZ , Meola Dawn , Showers Annie , Yu Ada , Upshaw Jenica , London Cheryl , Jaffe Iris , Pulakat Lakshmi , Yang Vicky , Chen Howard
Published: November 2024

Carvedilol (CAR) is an FDA-approved adrenergic blocker commonly given to cardiovascular disease patients. Interestingly, CAR also shows anti-cancer potential in reducing cancer-specific mortality in breast cancer patients. To advance CAR usage in cardio-oncology, we hypothesize that elucidating the molecular mechanism of the energy sensing and homeostasis pathways underlying CAR’s cardioprotective capabilities can enhance its clinical translation.

Canine cardiac slices were generated from 3 euthanized pet dogs free of cardiovascular disease. CAR pretreatment (1μM, 4 hrs) with or without a 24-hr exposure to 5μM of cardiotoxic doxorubicin (DOX) was performed. Murine slices from 5 C57Bl6 mice with the same treatments as above was also performed. Direct tissue imaging on IVIS Spectrum was carried out to assess apoptosis by Annexin V staining, autophagy with autophagy detecting nanoparticle (ADN) developed in-house, and DOX retention in tissue by the inherent DOX fluorescence. Tissue was analyzed by histological staining of apoptosis and Western blot of autophagy and energy sensing pathways. Energetics quantified by Seahorse assay was performed in isolated mitochondria from cardiac slices in rat cardiomyoblasts (H9C2 cells) and human iPSC-induced cardiomyocytes (iCells).

In both canine and murine cardiac slices, autophagy was significantly reduced (p<0.05) by DOX while apoptosis was significantly increased (p<0.05), both of which were reversed by CAR. CAR did not change DOX fluorescence in tissue. Western blot of autophagy biomarkers LC3, p62 and Beclin-1 confirmed that autophagy impaired by DOX was restored by CAR. The beneficial autophagy restoration by CAR was modulated by a significantly increased phosphorylation of AMP kinase (AMPK), a key energy sensing pathway that activates autophagy via significantly reducing mTOR (p<0.0001). In mitochondria isolated from cardiac slices, basal respiration and ATP production that were significantly impaired by DOX were rescued (p<0.0001) by CAR. Similar rescue of basal respiration and ATP production by CAR was seen in murine and human cardiomyocytes, suggesting that CAR exerts a direct protective effect on the at-risk cardiomyocytes during DOX stress.

We demonstrated for the first time in human, canine, and murine that CAR targets the AMPK pathway to activate autophagy, reduce cardiomyocyte apoptosis, and restore mitochondrial energetics, thus with immense translational potential in cardioprotection.
Abstract 4146692: Cardiovascular Health Declines During Young Adulthood – An Electronic Health Record Study of >75,000,000 Individuals
Authors: Ortiz Robin , Heffron Sean
Published: November 2024

Background:
Young adulthood (YA, 19–39 years) is the life stage of greatest increase in cardiovascular (CV) risk and decline in CV health (CVH). Cosmos is a database of Electronic Health Record (EHR) data from all Epic EHR sites – including >250 million patients. Previous observations of CVH in YA have been limited to small, epidemiological cohort studies.

Purpose:
The current study aimed to be the first to use Cosmos to describe CVH in a nationally representative, extremely large, cohort of YAs.

Methods:
The AHA Life’s Essential 8 framework for CVH includes target metrics for health behaviors (nicotine exposure, diet, physical activity (PA), and sleep) and clinical factors (BMI, non-HDL-C, glucose, and blood pressure (BP)). We aimed to trend the proportion meeting “ideal” (highest score) for available CVH metrics (smoking, systolic BP (SBP), non-HDL, BMI, hemoglobin A1c, PA) across the young adulthood (from 19 to 39 years), by extracting available Cosmos data spanning May, 2022 to April, 2024.

Results:
The total sample included 76,216,126 YA (54% White, 15% Black, 4% Asian, 14% Hispanic; 54% female) of age 19-39 years. CVH available data varied: 2, 3.5, and 4.3 million for non-HDL, PA, and A1c, respectively; 28.8, 47.8, and 66.6 million for BMI, SBP, and smoking, respectively. Overall, ideal CVH metrics were more common than poor (Table), except for BMI. However, prevalence of ideal CVH decreased with increasing age (Figure). A notable exception was the proportion reporting PA 6+ days/week, which was low and stable by age. Additional analysis showed a greater proportion reported PA 4+ (vs. 6+) days/week, potentially increasing by age (34.2% at 22-24y, ~42% at 31-39y, 44.6% at 19-21y).

Conclusion:
Among the largest group of YAs ever assessed, we found persistent declines in most CVH metrics with age. Within the context of analyses from much smaller cohorts, these findings support investigating interventions to effectively stem the decline in CVH in this at-risk group.
Abstract 4146697: Computational Pipeline for Right Ventricular Hemodynamic Analysis from Pressure-Volume Loop Generation
Authors: Moon Gyeongtae , Jani Vivek , Tedford Ryan , Hassoun Paul , Hsu Steven
Published: November 2024

Introduction:
In patients with pulmonary hypertension (PH), right ventricular (RV) dysfunction is a key discriminator of clinical outcomes, However, current clinical indices of RV function are poor. The gold standard for evaluating RV function is the invasive pressure-volume (PV) loop, which is not acquired routinely clinically. Moreover, there is no streamlined pipeline for estimating PV loop derived from waveforms obtained by standard chart review. Here, we present a new semi-automated pipeline for single beat estimation of PV loops and load-independent RV contractile indices from clinically obtained waveforms from routine right heart catheterization.

Methods:
RV pressure waveforms were obtained from PH patients (n=24) (
Figure 1A
). Waveform reports were digitized using computer vision techniques and subsequently averaged for single-beat analysis. P
isovol
was calculated using a piece-wise sinusoidal fit. End-systolic (ESP) and end-diastolic pressures (EDP) were estimated using the square of the second derivative of the waveform. The end-diastolic pressure-volume relationship (EDPVR) was calculated by fitting an exponential function. Ejection was estimated using a cubic spline between (ESV, ESP) and (EDV, Pressure[dP/dt
max
]). Clinically relevant RV functional parameters Ees (end systolic elastance) and Ea (effective arterial elastance) were obtained as previously described.

Results:
PV loops, Ees, and Ea were derived from 24 patients. Single-beat validation data were acquired by applying single-beat estimation to data collected from a standard pressure catheter. A representative pressure waveform and resulting PV loop estimate are shown in
Figures 1A
and
B
, respectively. The Bland-Altman analysis (
Figure 1C
) reported moderate to good agreement between two datasets, with a bias of -0.03 mmHg/mL (95% CI: -0.28, 0.21 mmHg/mL) and 0.08 mmHg/mL (95% CI: -0.29 to 0.45 mmHg/mL) for Ea and Ees, respectively.

Conclusion:
We have developed a novel and robust computational pipeline tool for digitization and single-beat analysis of RV pressure waveforms from an image of RV pressure waveform. Results from this pipeline were consistent with the single-beat validation data.
Abstract 4146706: Amyloidogenic Medin Induces Prothrombotic Activation in Human Brain Microvascular Endothelial Cells
Authors: Morrow Kaleb , Karamanova Nina , Nabaty Natalie , Maerivoet Alana , Madine Jillian , Li Ming , Migrino Raymond
Published: November 2024

Background:
The endothelium plays a major role in preventing thrombosis. Aging leads to a hypercoagulable state with increased procoagulant factors without accompanying rise in anticoagulant factors, shifting the balance to a prothrombotic profile. This increases the risk for conditions such as stroke or myocardial infarction. The mediator/s of this change remains unknown. Medin is a 50 amino acid cleavage product of MFGE8, accumulates in the vasculature with aging and is the most common human amyloid. Vascular medin burden is increased in vascular dementia, Alzheimer’s disease and aortic aneurysms. Medin was shown to induce endothelial and smooth muscle dysfunction and endothelial pro-inflammatory activation. Its role in aging-associated prothrombotic activation is unknown.

Aim:
To determine the effect of medin on human brain microvascular endothelial cells (HBMVECs) expression and function of thrombomodulin (a transmembrane glycoprotein that is a major anticoagulant through its interaction with thrombin leading to activation of protein C and S which in turn degrades factors Va and VIIIa) and HBMVEC expression of plasminogen activator inhibitor-1 (PAI-1) and tissue factor (major procoagulant proteins).

Methods:
Primary HBMVECs (passages 6-8) were exposed for 20 hours to physiologic doses of recombinant human medin (1 or 5 uM) and gene and protein expression of thrombomodulin, PAI-1 and tissue factor were measured using rtPCR or Western blot, respectively. In separate experiments, assessment of thrombomodulin function was determined by exposing HBMVECs for 20 hours to medin, after which human protein C (0.2 uM) and α-thrombin (10 nM) were added for 1 hour and amount of activated protein C in media was measured using ELISA.

Results:
Physiologic dose of medin (5 uM) given to HBMVECs resulted in reduced gene and protein expression of thrombomodulin (Fig. 1), increased gene and protein expression of PAI-1 (Fig. 2), and modest increased protein, but not gene expression of tissue factor (Fig. 3). Medin exposure also reduced HBMVEC ability to convert protein C to activated protein C in the presence of thrombin.

Conclusions:
Medin reduced HBMVEC production of anticoagulant protein thrombomodulin and increased protein expression of procoagulant proteins PAI-1 and tissue factor. Medin is a potential novel mediator of aging-associated hypercoagulability and could be a promising target in thrombotic diseases such as stroke.
Abstract 4146712: Prediction of Thrombosis in Coronary Artery Aneurysms Following Kawasaki Disease Using a Deep Learning Survival Approach
Authors: Manlhiot Cedric , Dionne Audrey , Portman Michael , Dahdah Nagib , Carr Michael , Khare Manaswitha , Harahsheh Ashraf , Tierney Seda , Khoury Michael , Raghuveer Geetha , Harris Kevin , Norozi Kambiz , Giglia Therese , Lang Sean , Mawad Wadi , McCrindle Brian
Published: November 2024

Background:
Prediction of thrombosis of coronary artery (CA) aneurysms in children with Kawasaki disease (KD) is challenging both because risk is determined by the interplay of complex anatomical, physiological and pharmacological factors and because of the rarity of events.

Methods:
We used data from 483 patients with at least one giant CA aneurysm (z>10) and enrolled in the International Kawasaki Disease Registry to train and evaluate the performance of a deep learning survival (DeepSurv) algorithm predicting CA thrombosis over time. Outcomes were predicted separately for each CA branch. Each patient’s total follow-up duration was divided into epochs; new epochs were created with any new echocardiogram, change in thromboprophylaxis (either antiplatelet or anticoagulation) or outcome. Data (absolute aneurysm size, z-score and architecture) from the most recent echocardiogram were used at the start of each new epoch. Censoring was done on the last day of the epoch or date of last follow-up for the last epoch. Three-fold cross-validation was used to estimate model performance. SHAP analysis was used to calculate variable importance.

Results:
Average duration of follow-up was 4.2 years per patient; 87 (18%) patients had thrombosis during the follow-up period. The prediction model for thrombosis identified a high-risk group of epochs (28%). The high-risk epochs had a substantially greater incidence rate (5.1; 95%CI: 3.8-6.7) vs. 0.5 (95%CI: 0.4-0.7) events/100 patient-years, p<0.001) and rate ratio (9.8; 95%CI: 6.3-15.4, p<0.001). SHAP analysis identified critical features in predicting thrombosis, including larger aneurysm size, irregular aneurysm shape, recent change in thromboprophylaxis and, for those events diagnosed in the acute phase of the disease, immunosuppression and degree of inflammation. Events missed by the prediction algorithm were most often associated with rapid changes in CA aneurysm size during the acute phase of KD.

Conclusion:
A deep learning survival approach can be used to combine multiple dimensions of risk into a comprehensive, time-dependent, prediction model for thrombosis. This model identified a group of situations for which patients may be at substantially higher risk of developing a clot and where enhanced thromboprophylaxis should be considered. Particular attention should be paid to patients with large, irregular aneurysms, especially in hyperinflammatory contexts and when changing thromboprophylaxis regimen.
Abstract 4146742:
Outstanding Research Award in Pediatric Cardiology:
Association of rurality with long-term survival after congenital heart surgery
Authors: Yang Yanxu , Huang Eugene , Knight Jessica , Oster Matthew , Kochilas Lazaros
Published: November 2024

Objective:
Disparities in health outcomes exist between metro and non-metro areas for many medical conditions, but this issue has not been examined within the context of congenital heart disease (CHD). This study aims to determine the association of metro vs. non-metro residence status with long-term survival after congenital heart surgery (CHS).

Methods:
This retrospective cohort study included patients from the Pediatric Cardiac Care Consortium who had initial CHS between 1990 and 2003. Outcomes were tracked using the National Death Index through 2022. Analysis was restricted to counties where PCCC patients resided. Based on the description of Rural-Urban Continuum Codes (RUCCs), we categorized counties in metro and non-metro areas per the 1993 and 2003 RUCCs, including two subgroups (adjacent to a metro area and not adjacent to a metro area). Kaplan-Meier survival estimates were plotted to compare long-term survival in patients living in metro vs non-metro areas. Comparison of survival length between areas was performed by fitting semiparametric accelerated failure time models with adjustment for covariates.

Results:
Among 28,504 patients (47.0% female), 19,772 (69.4%) resided in metro areas. Patients living in non-metro areas experienced an absolute lower 30-year survival following discharge post initial CHS vs. patients living in metro areas (86.5 vs. 88.4%, log-rank p=0.015) (Figure) with a 22% reduction in median survival time [adjusted time ratio (aTR): 0.78; 95%CI 0.64-0.94] after adjustment for sex, birth era, CHD severity, and chromosomal abnormality. Additional adjustment for neighborhood socioeconomic status (nSES) attenuated the association’s magnitude (aTR: 0.91; 95% CI: 0.74-1.13). Subgroup analysis indicated that decreased survival time was significant only for those living in non-metro and not adjacent to metro areas (aTR: 0.73; 95% CI: 0.57-0.93).

Conclusion:
In this large multicenter study, non-metro residency, particularly in areas not adjacent to metro areas, was associated with reduced median survival time, an attenuated effect explained by nSES differences. Targeted interventions are needed to reduce disparities and improve outcomes post-CHS.
Abstract 4146754: The Prognostic Value of Dobutamine Stress Echocardiography in Liver Pre-Transplant Evaluation
Authors: Lu Jim , Ferraro Richard , Su Amanda , Osgueritchian Ryan , Hays Allison , Gurakar A. , Mukherjee Monica
Published: November 2024

Background:
Dobutamine stress echocardiography (DSE) is a frequently used tool in cardiovascular (CV) risk assessment of liver transplantation (LT) candidates. Its prognostic value compared to traditional cardiac risk stratification remains unclear.

Research Question:
How does the prognostic value of pre-transplant DSE in LT candidates compare to the revised cardiac risk index (RCRI)?

Aim:
Compare DSE’s prognostic value to RCRI in LT patients and analyze post-transplant CV outcomes.

Methods:
This single-center study included adult patients undergoing pre-transplant DSE as part of LT evaluation from 2008-2021. DSE were categorized as positive, negative, or inadequate. Primary outcomes were post-operative ischemic cardiac events and mortality, with secondary outcome of transplant delays from inadequate DSE. Mann-Whitney U and Fischer’s exact tests compared variables; logistic regression assessed RCRI and DSE for 30-day mortality and cardiac events.

Results:
Of 981 LT candidates, 644 (66%) had pre-transplant DSE with minimum 2-year follow-up. Average age was 57 ± 7 years, with 33% women. Four and eleven patients experienced cardiac events and mortality <30 days post-transplant, none of whom had positive pre-LT DSE. Six DSE exhibited inducible ischemia, with one revealing obstructive coronary artery disease on invasive assessment. DSE was inadequate in 113 patients (18%), with 34 (30%) undergoing further cardiac evaluation on average 33.8 days later (Table 2). Logistic regression showed a c-statistic of 0.52 for RCRI>1 (p-value 0.50), 0.51 for DSE (p-value 0.82), and 0.52 for RCRI>1 and DSE combined (p-value 0.80) in predicting 30-day mortality and cardiac events.

Conclusion:
Our study demonstrates limited prognostic value of DSE above RCRI score alone for predicting post-transplant mortality. Inadequate DSE was frequent and extended LT wait times. Further research is necessary to define clinically relevant subgroups and refine CV risk assessment in LT candidates.
Abstract 4146832: Cardiac Fibroblast Atlas Reveals Myofibroblast Activation After Myocardial Infarction
Authors: Lu John , Januszyk Michael , Longaker Michael
Published: November 2024

Introduction:
After a myocardial infarction (MI), cardiac fibroblasts are activated to deposit extracellular matrix that while prevents acute cardiac rupture in the short-term, causes long-term diastolic and systolic dysfunction. Despite the clinical burden of cardiac fibrosis, especially after MI, the molecular mechanisms driving cardiac fibroblasts to produce excessive scar tissue are unknown. To study MI scar formation, we sought to characterize the molecular drivers of cardiac fibroblast activation by creating a comprehensive single-cell transcriptomic atlas of cardiac fibroblasts after MI.

Methods:
We generated a comprehensive transcriptomic atlas of cardiac fibroblasts by integrating all single cell RNA sequencing (scRNA-seq) datasets of mouse post-MI samples that are publicly available on the NIH GEO and EBI ArrayExpress databases. We screened 104 total datasets, identifying 26 datasets that met inclusion criteria, which collectively include transcriptomic data from 125 mouse samples (85 MI / 19 sham MI / 1 IR / 1 sham IR / 19 healthy). Transcriptomic data were processed, integrated, and analyzed using Seurat and Harmony. Pseudotime analysis was performed using Monocle3.

Results:
To construct our comprehensive cardiac fibroblast atlas, we integrated scRNA-seq data from nearly 700,000 mouse cells from 125 mouse samples across 26 datasets (Fig. 1A). Using this integrated all-cells atlas, we computationally isolated over 171,000 cardiac fibroblasts. Sub-clustering of the cardiac fibroblasts revealed that there are nine subpopulations. Specifically, we identify that one of these subpopulations, which we term myofibroblasts, expands from ~1% to ~40% of all fibroblasts after MI (Fig. 1B). These myofibroblasts are characterized by increased production of extracellular matrix proteins (e.g., Col1a1, Cthrc1) relative to other fibroblast subpopulations (Fig. 1C). Pseudotime analysis reveals that increased pseudotime is correlated with increased expression of Cthrc1 (Fig. 1D).

Conclusion:
Our comprehensive single-cell atlas of cardiac fibroblasts after MI reveals a myofibroblast subpopulation that emerges after MI to deposit extracellular matrix to cause tissue fibrosis.
Abstract 4146850: Expectant Management versus Ibuprofen Treatment for Preterm Infants with PDA: A Meta-Analysis of Randomized Controlled Trials
Authors: Joseph Meghna , Murali Krishna Mrinal , Ezenna Chidubem , Kutty Shelby
Published: November 2024

Introduction:
Ibuprofen is used to induce closure of patent ductus arteriosus (PDA) in preterm infants due to its fewer side effects compared to other nonsteroidal anti-inflammatory drugs. However, ibuprofen treatment has not improved survival or decreased morbidity in this population.

Objective:
To compare expectant management vs. ibuprofen treatment in preterm infants with PDA.

Methods:
We systematically searched PubMed, Scopus, and Cochrane Central databases for studies comparing expectant management versus treatment with ibuprofen in preterm infants with PDA. Outcomes of interest included all-cause mortality, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), sepsis, surgical or transcatheter PDA ligation, cystic periventricular leukomalacia (CPL), pulmonary hemorrhage, impaired renal function, composite outcome of BPD or death, duration of ventilator support and duration of supplemental oxygen therapy. Random effects models were used to generate risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). Heterogeneity was assessed using I
2
statistics. Analysis followed the PRISMA guideline.

Results:
The meta-analysis consisted of 5 randomized controlled trials including 1,536 infants. All-cause mortality, BPD, NEC, IVH, ROP, sepsis, PDA ligation, pulmonary hemorrhage, composite of BPD or death, duration of ventilator support and duration of supplemental oxygen therapy did not show any significant differences between the groups. CPL (RR 0.50; 95%CI 0.27-0.92; p=0.02) and impaired renal function (RR 0.64; 95%CI 0.51-0.81; p<0.001) were significantly lower with expectant management.

Conclusion:
In preterm infants with PDA, expectant management did not show any difference in all-cause mortality and adverse clinical outcomes compared with ibuprofen treatment. However, there was a lower risk of CPL and impaired renal function with expectant management.
Abstract 4146871: Comparative Analysis of Transcatheter Mitral Valve Replacement versus Redo-Surgical Mitral Valve Replacement: A Systematic Review and Meta Analysis
Authors: Shaukat Muhammad Talha , Rehman Wania , Rehman Aqeeb Ur , Mohsin Aleenah , Rahman Saad Ur , Imran Hafiz , Qureshi Muhammad Ahmad , Abbott Jinnette , Ehsan Afshin , Sellke Frank
Published: November 2024

Background:
Transcatheter mitral valve replacement (TMVR) has emerged as a promising alternative to conventional redo-surgical intervention in patients presenting with mitral valve prosthesis failure. We conducted a meta-analysis to delineate efficacy and safety of transcatheter mitral valve replacement (TMVR), encompassing both valve-in-valve (ViV) and valve-in-ring (ViR) procedures, compared to redo-surgical mitral valve replacement (SMVR).

Aim:
The primary aim of our meta-analysis was to investigate the early clinical outcomes following either ViV/ViR TMVR or SMVR.

Methods:
PubMed/MEDLINE, Cochrane Library, and clinicaltrials.gov were systematically searched according to predefined inclusion and exclusion criteria. Several efficacy and safety outcomes were pooled and reported as risk ratios (RRs) with 95% confidence intervals (CIs).

Results:
Fourteen retrospective cohort studies (patients=18,519) were evaluated in this analysis. Compared with redo-SMVR for mitral valve prosthesis failure, TMVR exhibited lower in-hospital mortality (OR=0.69; 95% CI 0.56–0.86; p<0.01). Moreover, stroke (OR=0.46; 95% CI 0.31–0.68; p=0.05), renal dysfunction (OR=0.49; 95% CI 0.38–0.63; p<0.01), need for pacemaker implantation (OR=0.28; 95% CI 0.23–0.34; p<0.01), major cardiac complications (OR=0.43; 95% CI 0.32–0.59; p<0.01), length of ICU stay (OR=-2.11; 95% CI -2.82 - -1.39; p< 0.01), and need for exploration for bleeding (OR=0.23; 95% CI 0.17–0.30; p<0.01) also revealed significant improvements in the TMVR cohort. To minimize heterogeneity, we performed subgroup analysis for in-hospital mortality, which remained significant (OR=0.42; 95% CI 0.34–0.51; P< 0.01) on propensity matching. Conversely, paravalvular leak (OR=22.12; 95% CI 2.81-174.16; p=0.003) generated results favoring SMVR. There was negligible and nonsignificant difference in mean mitral valve gradient (MD: -0.01; 95% CI: −0.57 to 0.5; P =0.97), 30-day mortality (OR: 0.86; 95% CI: 0.48–1.53; P = 0.60), and 1-year mortality (OR: 1.05; 95% CI: 0.68–1.61; P = 0.83) between the two groups.

Conclusion:
In patients experiencing mitral valve prosthesis failure, TMVR offers an efficacious, safe, and less invasive alternative to SMVR. However, the risk of paravalvular leak requires careful monitoring.
Abstract 4146892: Takotsubo cardiomyopathy with Cirrhosis - Mortality and Outcomes among hospitalised patients in the United States
Authors: Hotwani Priya , Sanka Sujana , Borse Tanvi , Alvarez Andy , Habib Anwer , Alraies M Chadi
Published: November 2024

Background:
Takotsubo cardiomyopathy (TCM) is a unique and reversible heart condition typically triggered by intense emotional or physical stress. Meanwhile, Cirrhosis, a chronic liver disease, is associated with increasing inflammation and oxidative stress, which can potentially worsen cardiovascular problems. In this study, we aimed to study the impact of cirrhosis on outcomes in TCM.

Methods:
A retrospective analysis was performed using the NIS database 2016 -2020 and the International Classification of Diseases, Tenth Revision codes to identify patients > 18 years old with the principal diagnosis of Takotsubo cardiomyopathy. The effect of cirrhosis was studied on in-hospital mortality and secondary outcomes such as cardiogenic shock, ventricular arrhythmia (VA), acute respiratory and acute kidney injury (AKI), as well as resource utilisation. Categorical variables were compared using the chi-square test, and continuous variables were compared using the t-test—multivariable regression analyses adjusted for demographics, hospital-level characteristics, and relevant comorbidities.

Results:
We identified a total of 190,025 patients with TCM. Of these, 3,335 (1.76%) patients had liver cirrhosis, with notably higher prevalence of diabetes (33.6%), CKD (20.7%), anemia (10.2%), and major depressive disorder (25.6%) in the cirrhosis group. A higher incidence of in-hospital mortality (12.9% vs. 6.3%, p<0.001), cardiogenic shock (11.7% vs. 6.5%, p<0.001), AKI (41.4% vs. 22.8%, p<0.001), and ARF (40% vs. 31.6%) was noted in the cirrhosis group. After adjusting for confounding factors, the liver cirrhosis group had higher odds of in-hospital mortality (aOR 1.39, 95% CI 1.1-1.75, p=0.006), AKI (aOR 1.53, 95% CI 1.28-1.82, p<0.001), longer length of stay (11.2 days vs. 6.8 days, p<0.001), and higher total hospitalization charges ($198,786 vs. $99,712, p<0.001). The relationship between cirrhosis and cardiovascular outcomes such as cardiogenic shock (aOR 1.23, 95% CI 0.95-1.58, p=0.116) and VA (aOR 1.01, 95% CI 0.75-1.36, p=0.942) was not statistically significant.

Discussion:
Our study noted that TCM patients with cirrhosis had higher in-hospital mortality and resource utilization. There was no statistically significant relationship between cirrhosis and cardiovascular outcomes suggestive of the adverse consequences to be related to cirrhosis itself rather than TCM.
Abstract 4146928: Inflammation, Adverse Cardiac Remodeling and Post-operative Atrial Fibrillation
Authors: Ofosuhene Bernard , Radu Irina , Orwig Taylor , Vogt Bella , Tran Khanh-Van
Published: November 2024

Background:
Post-operative atrial fibrillation (POAF) is a common and serious complication following cardiac surgery, leading to increased morbidity and healthcare costs. Inflammation, particularly mediated by cytokines like IL-17A, is believed to play a significant role in the pathogenesis of POAF. We aim to investigate the association between blood IL-17A levels and the incidence of POAF.

Hypothesis:
We hypothesize that elevated IL-17A levels in the blood are associated with a higher incidence of POAF in patients undergoing cardiac surgery.

Methods:
Blood samples were collected from 16 patients undergoing open heart surgery. Patients were monitored during the index hospitalization for the surgery. IL-17A levels in the blood were quantified using Olink proteomics, where oligonucleotide-labeled antibodies bind to target proteins, forming a new PCR target sequence by a proximity-dependent DNA polymerization event. Quantitative PCR measured the amplicons, and the Olink NPX Manager Software calculated Normalized Protein Expression Units (NPX) by normalizing the Cq values to interpolate controls. Statistical analysis was performed using Student's t-test to compare clinical variables and IL-17A levels across the two groups.

Results:
Our cohort had an average age of 63.8 ± 4.7 with 14% female participants, an average weight of 83.9 ± 14.6 kg, and an average BMI of 28.8 ± 4.7. The POAF group was slightly older (64.8 ± 3.8 years vs. 62.7 ± 4.6 years) but had a similar BMI compared to those who did not develop AF. Hypertension and hyperlipidemia were present in all POAF patients (100%) compared to 81.8% in those without AF, while anemia was more common in the POAF group (40% vs. 18.2%). IL-17A levels were significantly elevated in the POAF group (0.75 ± 0.10 NPX) compared to the non-POAF group (0.35 ± 0.05 NPX) with a p-value < 0.05. Cardiac function assessments showed non-significant differences in left atrial volume index (LAVI) (46.2 mL/m^2 vs. 36.3 mL/m^2) and left ventricular mass index (LVMI) (114.4 g/m^2 vs. 89.3 g/m^2) in the POAF group. These findings suggest a significant association between elevated IL-17A levels and POAF, with trends of differences in left atrial remodeling between the two groups.

Conclusion:
Elevated blood IL-17A levels are associated with an increased risk of developing POAF. This suggests that IL-17A may serve as a critical biomarker and potential therapeutic target for preventing POAF in patients undergoing cardiac surgery.