bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13036: Relations of Metabolically Healthy and Unhealthy Obesity and to Digital Vascular Function in Three Community-based Cohorts: A Meta-Analysis
Authors: Brant Luisa C , Wang Na , Ojeda Francisco M , LaValley Michael , Barreto Sandhi M , Benjamin Emelia J , Mitchell Gary F , Vasan Ramachandran S , Palmisano Joseph N , Munzel Thomas , Blankenberg Stefan , Wild Philip S , Zeller Tanja , Ribeiro Antonio L , Schnabel Renate B , Hamburg Naomi M
Published: April 2024

Introduction:
Obesity and metabolic risk factors induce microvascular dysfunction, a marker of early vascular disease that predicts cardiovascular events. Whether obese individuals with a metabolically healthy profile have impaired microvascular function remains unclear.

Objectives:
The aim of this study was to evaluate the relation of obesity phenotypes stratified by metabolic status to microvascular function.

Methods:
We meta-analyzed aggregate data from 3 large cohorts (Brazilian Longitudinal Study of Adult Health, the Framingham Heart Study and the Gutenberg Heart Study; N= 16830 participants, age range 19-90, 48.7% women). Regression slopes between cardiovascular risk factors and microvascular function, measured by peripheral arterial tonometry (PAT), were calculated for each cohort. Individuals were classified as normal-weight, overweight or obese by body mass index (BMI) and further stratified by healthy or unhealthy metabolic status based on metabolic syndrome defined by the ATP-III criteria.

Results:
Male sex, BMI and the presence of metabolic risk factors were associated with more impaired PAT measures (
P
<0.0001 for baseline pulse amplitude,
P
<0.01 for PAT ratio). There was stepwise impairment of vascular measures from normal weight to obesity in both metabolic status strata (all
P
<0.0001). Metabolically healthy obese had more impaired vascular function than metabolically healthy normal-weight individuals (baseline pulse amplitude 6.12±0.017 vs. 5.61±0.010; PAT ratio 0.58±0.008 vs. 0.76±0.005, respectively, all
P
<0.0001). Within the same BMI category, metabolically healthy individuals had better vascular function than their metabolically unhealthy counterparts (all
P
<0.0001).

Conclusion:
Metabolically healthy obese individuals have impaired microvascular function, though the degree of impairment is less marked than in metabolically unhealthy obese individuals. Our findings suggest that obesity is detrimental to vascular health irrespective of metabolic status.
Abstract 13040: Repeated Social Defeat Stress Enhances Neutrophil Extracellular Traps Formation in vivo and in vitro: Implication in the Exaggerated Atherosclerosis in Chronic Social Stress-exposed Apoe
-/-
Mice
Authors: Yamamoto Keita , Yamada Hiroyuki , Terada Kensuke , Motoyama Shinichiro , Wada Naotoshi , Saburi Makoto , Kikai Masakazu , Wakana Noriyuki , Matoba Satoaki
Published: April 2024

Introduction:
Neutrophil extracellular traps (NETs) has been reported to promote atherosclerosis through induction of NETosis, a new type of neutrophil cell death; however, the role of NETosis in psychosocial stress-induced atherosclerosis remains undefined.

Methods and Results:
Eight-week-old male apoE
-/-
mice were exposed to the repeated social defeat (RSD) by housing with a larger CD-1 mice in a shared home cage with a clear perforated divider. They were repeatedly subjected to vigorous physical contact for 5-10 min each day on 10 consecutive days. Control mice were housed in the same gage without physical contact. After 6 weeks of high-cholesterol diet feeding, atherosclerotic lesion area of the aortic root was significantly increased in RSD mice compared with control mice (19.4% vs 13.9%,
P
< 0.05). There was no significant difference in body weight, food intake, mean blood pressure, and lipid profile between the 2 groups. Although both of Ly6G-positive and Mac3-positive area in immunofluorescent staining were comparable between the 2 groups, Ly6G-positive area in RSD mice was much strongly co-localized with MPO (16.4% vs. 6.6%;
P
< 0.05) and H3Cit (15.1% vs. 9.0%;
P
< 0.05), suggesting the augmented NETosis in RSD mice. Consistently, serum IL-1β level was markedly higher in RSD mice (2.9-fold;
P
< 0.05). The percentages of circulating neutrophils (Ly6G
+
CD11b
+
F4/80
-
CD11c
-
) were significantly increased in RSD mice compared with control mice (27.1% vs. 13.0%;
P
< 0.05), whereas the fractions of circulating inflammatory monocytes (Lin
-
CD11b
+
Ly6C
+
) and bone marrow (BM) monocyte-lineage progenitor cells were equivalent between the 2 groups. To further examine the NETs formation of individual neutrophils in vitro, BM neutrophils (Ly6G
+
) were isolated by flow cytometry and stimulated by PMA for 4 hr. The percentages of MPO- and H3Cit-positive cells were significantly increased by 2.5-fold in RSD mice compared with control mice (
P
< 0.01).

Conclusions:
Our findings demonstrated for the first time that RSD promotes NETs formation in BM neutrophils as well as in atherosclerotic lesions, which precede high-cholesterol diet-induced monocytosis, suggesting that NETosis could be a new therapeutic target in psychosocial stress-induced atherosclerosis.
Abstract 13056: Endoplasmic Reticulum-Resident Protein TXNDC5 Augments Myocardial Fibrosis by Facilitating Extracellular Matrix Protein Folding in Cardiac Fibroblasts
Authors: Chen Chao-Ling , Shi Yin-Chun , Zhang Yan , Mellor Rebecca L , Kanter Evelyn M , Fang Yun , Hung Chen-Ting , Nong Jing-Yi , Yamada Kathryn A , Nerbonne Jeanne M , Yang Kai-Chien
Published: April 2024

Introduction:
Cardiac fibrosis plays a critical role in fostering heart failure (HF). Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited. Exploiting RNA sequencing data from human failing heart and co-expression gene network analysis, we identified thioredoxin domain containing 5 (TXNDC5), a cardiac fibroblast (CF)-enriched endoplasmic reticulum (ER) protein, as a potential novel mediator of cardiac fibrosis. The goal of this study was to test this hypothesis directly.

Results:
TXNDC5 mRNA and protein were highly upregulated in human failing heart and in the left ventricle (LV) from a mouse model of isoproterenol (ISO)-induced HF. Cardiac TXNDC5 expression showed strong positive correlation with that of ECM protein genes. TXNDC5 increased in CF upon transforming growth factor β (TGFβ) stimulation. Knocking down TXNDC5 in CF abrogated TGFβ-induced ECM protein upregulation and myofibroblast transformation independent of SMAD3 activity. Forced expression of TXNDC5 triggered activation of CF and increased ECM protein production. Further experiments revealed that TXNDC5, a protein disulfide isomerase, facilitated proper ECM protein folding; depletion of TXNDC5 led to ECM protein misfolding and degradation through ER-associated degradation (ERAD) pathway. In addition, TGFβ-induced TXNDC5 upregulation in CF was dependent on increased ER stress and activating transcription factor 6 (ATF6)-mediated regulation. Knocking out TXNDC5 by CRISPR/Cas9 genome editing showed cardioprotective effects including reduced cardiac fibrosis (by 36%), preserved LV contractility (post-ISO LV ejection fraction in WT 40.1±2.6 vs KO 57.5±5.1,
P
<0.001) and improved survival in mice with ISO-induced HF.

Conclusion:
ER resident protein TXNDC5 promotes cardiac fibrosis by increasing CF activity and ECM production through facilitating ECM protein folding. Genetic deletion of TXNDC5 protects against β agonist-induced cardiac fibrosis and LV dysfunction. Targeting TXNDC5, therefore, could be a novel approach to mitigate excessive ECM accumulation and fibrosis formation during HF.
Abstract 13061: Right Atrial Strain Combined With Ve/vco
2
in Early Detection of Systemic Sclerosis Pulmonary Vascular Involvement
Authors: Giubertoni Ailia , Gravellone Miriam , Zanaboni Jacopo , Piccinino Cristina , Marino Paolo N
Published: April 2024

Introduction:
Systemic sclerosis (SSc) is at risk of developing pulmonary vasculopathy (PV) leading to pulmonary arterial hypertension (PAH), right heart failure and death. Early detection of this life-limiting complication may allow timely therapy and improve patients’ survival. Nevertheless, standard non-invasive screening tests are not fully adequate to identify milder degrees of vascular disease and right heart catheterization is reserved to hemodynamic confirmation. An integrating strategy including reliable specific echocardiographic and CPET parameters may identify “pre-clinic” PV and better characterize patients that warrant further attention.

Hypothesis:
The aim of this study was to test the value of right atrial (RA) two-dimensional strain echocardiography (2D-STE) combined with VE/VCO2 slope in the early detection of PV in SSc patients.

Methods:
We recruited 57 asymptomatic, consecutive, SSc patients without previous diagnosis of PAH, referred to our specialized out-patients clinic from April 2015 to March 2016. Six patients were excluded because unsuitable for CPET. The remaining 51 patients (48 female and 3 male - mean age 61±11years) had normal resting pulmonary function, chest X-ray, BNP, blood routine test and standard echo parameters. RA 2D STE was assessed by averaging all segments in dedicated 4-chamber view. During an incremental CPET we analyzed: minute ventilation, workload, peak oxygen uptake, oxygen pulse, anaerobic threshold, ventilatory reserve and VE/VCO2 slope. We also studied 11 matched controls.

Results:
Despite normal standard CPET parameters, we found that SSc patients had higher VE/VCO2 slope (mean 31,4±5,1 vs. 24,3±3,7; p <0.001) and lower RA strain (mean 21,4±9.0% vs. 27,5±6.0%; p=0,01) than controls. Moreover, VE/VCO2 slope, but not traditional parameters as BNP, RA area, PAPs and TAPSE, showed a significant correlation with RA strain (r=-0.32 p< 0.002). In particular, patients with VE/VCO2 slope >34 had lower strain than patients with VE/VCO2 slope ≤34 (mean 15,6±3,8% vs. 23,8±9,5%; p<0,001).

Conclusions:
In asymptomatic SSc patients, combined approach with VE/VCO2 slope and RA strain could unmask milder forms of PV, improve SSc patients’ characterization and minimize diagnosis delay.
Abstract 13064: The Long-term Cardiac Rehabilitation Improves the Prognosis of Patients With Cardiovascular Disease: The Large Cohort Study of Cardiac Rehabilitation in Tokyo (CART Study)
Authors: Nakayama Atsuko , Nagayama Masatoshi , Komuro Issei , Tomoike Hitonobu
Published: April 2024

Introduction:
The effects of comprehensive cardiac rehabilitation (CR) were already reported, but the most of the rehabilitation programs are consisted of short periods and the studies of continuous exercise training in a long time are not sufficient. Otherwise, many patients with cardiovascular disease clinically need sustained CR.
Propose:
The aim of this study is to prove the effects of the long-term CR and find the suitable candidates to be recommended participating in a rehabilitation program in the maintenance phase.

Methods:
We conducted a prospective cohort study on 10,275 patients receiving CR without dropout the CR program in Sakakibara Heart Institute in Tokyo from January 2003 to August 2015. The patients who had CR in the acute phase were classified into Phase l group who needs hospitalization and the patients after acute phase who had CR more than once a week for less than 150 days were classified into Phase ll group. The patients who had CR more than once a week for more than 150 days were classified into Phase lll group. Phase ll and lll groups underwent cardiopulmonary exercise testing (CPX) at intervals of 3 months. The rate of major adverse cardiac events (MACE: composite of cardiac death, acute coronary syndrome and cerebral infarction), the rate of mortality and the result of CPX in the three groups were compared. The sub-analysis was performed on each disease which composed of stable angina pectoris, acute coronary syndrome, heart failure, post CABG, post heart valve surgery, and large vessel disease.

Results:
The average age of patients was 66±14 years and the average follow-up period was 5.1±3.0 years. The patients were divided into three groups (Phase l: n=5178, Phase ll: n=3902, and Phase lll: n=1195). The average rehabilitation period of Phase lll group was 1.8±2.0 years. The risks of MACE and death were extremely lower in Phase lll group compared to that in Phase ll group, especially in patients with heart failure (MACE: HR0.59, p=0.022, and death: HR0.83, p=0.023). The improved peak VÒ
2
of Phase lll group with heart failure significantly paralleled till 4.4 years by multilevel modeling.

Conclusions:
The long-term cardiac rehabilitation for patients with cardiovascular disease improves the MACE, mortality and peak VÒ
2
.
Abstract 13093: An Imbalance in Cardiomyocyte Glucocorticoid and Mineralocorticoid Receptor Signaling Leads to Heart Failure
Authors: Oakley Robert H , Cruz-Topete Diana , Foley Julie F , Myers Page H , He Bo , Murphy Elizabeth , Chambon Pierre , Willis Monte S , Cidlowski John A
Published: April 2024

Stress is increasingly associated with adverse cardiac outcomes; however the mechanisms underlying these effects are poorly understood. Glucocorticoids are primary stress hormones that regulate cell and tissue homeostasis through two closely related nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Cardiomyocytes express both these receptors but little is known concerning their coordinated actions in heart physiology and whether an imbalance in their signaling contributes to cardiac disease. Here, we show that patients with failing hearts have a disparity in the relative levels of GR and MR compared to non-failing donor hearts. To examine the
in vivo
function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioMRKO mice exhibited normal heart function whereas the cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction. Surprisingly, the cardioGRMRdKO mice were protected from the cardiac disease observed for the cardioGRKO mice. At a molecular level, pathological gene changes present in the GR deficient hearts were also found in the double knockout hearts whereas specific cardioprotective gene changes were detected only in hearts from the cardioGRMRdKO mice. Re-installation of MR into the cardioGRMRdKO hearts by adeno-associated virus gene delivery reversed these cardioprotective gene changes and resulted in cardiac dysfunction. These findings reveal critical gene-regulatory roles for both GR and MR in the heart and suggest that an imbalance in these two signaling pathways leads to heart disease. Therapies designed to modulate cardiomyocyte glucocorticoid signaling to favor more GR and less MR activity may provide new approaches for treating the failing heart.
Abstract 13096: Mechanisms Underlying Associations Between Optimism, Hostility, and Cardiovascular Risk
Authors: Salmoirago-Blotcher Elena , Hovey Kathleen , Andrews Christopher , Allison Matthew , Brunner Robert L , Denburg Natalie L , Eaton Charles , Garcia Lorena , Sealy-Jefferson Shawnita , Zaslavsky Oleg , Kang Joseph , Post Stephen G , Tindle Hilary A , Wassertheil-Smoller Sylvia
Published: April 2024

Introduction:
Optimism has been associated with reduced cardiovascular (CV) risk, while cynical hostility has been linked with worse CV risk. The pathophysiological mechanism(s) underlying these associations are largely unexplored. We sought to examine associations between optimism, hostility, and heart rate variability (HRV).

Hypothesis:
Greater optimism will be associated with higher HRV, while greater hostility will be associated with lower HRV.

Methods:
Participants (n=3,372) enrolled in the Myocardial Ischemia and Migraine Study, a Women’s Health Initiative (WHI) ancillary study, underwent a 24-hour ambulatory ECG monitoring (AECG) 3 years after WHI enrollment. Optimism (Life Orientation Test-Revised), cynical hostility (Cook-Medley questionnaire), demographics, and CV risk factors were assessed at baseline. HRV measures included standard deviation of all analyzed N-N intervals (SDNN); standard deviation of average N-N interval over 5 min (SDANN); and average heart rate (HR). Multivariable linear regression models examined the relationship between optimism, hostility and HRV indices adjusted for demographics and coronary risk factors.

Results:
After excluding women with previous CV disease, missing data, and AECG <12 hours, 2655 were included in the analysis. At baseline, more optimistic women were more likely to be younger, white, educated, non-smokers, physically active, and to have lower systolic blood pressure (SBP). More hostile women were more likely to be older, Hispanic or African American, less educated, diabetic, obese, smokers, and to have high cholesterol and high SBP. We found a significant inverse association between hostility and HRV (SDANN: adjusted β= -0.54; 95% CI -0.97, -0.11; SDNN: -0.49; 95% CI -0.93, -0.05). Optimism was not associated with HRV indices (SDANN: adjusted β= 0.10; 95% CI -0.25, 0.44; SDNN: 0.03; 95% CI -0.32, 0.39). Average HR was not associated with optimism or hostility.

Conclusions:
A worse autonomic balance may play a role in the physiopathology of unfavorable CV outcomes observed among women with higher cynical hostility. The lack of association between HRV and optimism suggests that other (behavioral?) factors may play a role in the protective association between optimism and CV outcomes.
Abstract 13112: Benefit of Early Discharge Among Patients With Low-risk Pulmonary Embolism: Focus on Net Clinical Impact
Authors: Wang Li , Baser Onur , Wells Phil , Peacock W. F , Coleman Craig , Fermann Gregory J , Schein Jeff , Crivera Concetta
Published: April 2024

Introduction:
Clinical guidelines recommend early discharge of patients with Low Risk Pulmonary Embolism (LRPE). With increasing awareness of the risks of hospital acquired complications (HAC), we sought to measure the overall impact of early discharge of LRPE patients on clinical outcomes and costs within the Veterans Health Administration.

Methods:
Adult patients with ≥1 inpatient diagnosis for PE (index date) between 10/2011- 6/2015 and continuous enrollment for ≥12 months pre- and 3 months post-index date were included. PE risk stratification was done using the simplified Pulmonary Embolism Stratification Index (sPESI). Propensity score matching (PSM) was used to compare 90-day PE-related outcomes, HAC, healthcare utilization and costs among short versus long length of stay (LOS) LRPE patients. We defined short LOS as ≤2 days, adverse PE events (APE) as recurrent deep vein thrombosis, major bleed, or death, and net clinical benefit as 1 minus the combined rate of APE and HAC.

Results:
Among 6,746 PE patients, 95.4% were male, 67.7% were white, 22.0% were African American, and 1,918 had a LRPE. Among LRPE patients, only 688 (35.9%) had short LOS. After PSM, 784 LRPE patients were evaluated. There were no differences in APE, but short LOS had fewer HAC (1.5% vs. 13.3%; p<0.0001) and bacterial pneumonias (5.9% vs. 11.7%, p<0.005). Net clinical benefit was higher for short LOS patients (86.9% vs. 78.3%, p=0.0013). Among long LOS, the number of HAC (52) exceeded APE (14 recurrent DVT, 5 bleeds). Short LOS had lower inpatient costs ($2,164 vs. $5,100; p<0.0001) and lower total costs ($9,056 vs. $12,544; p<0.0001) versus long LOS.

Conclusions:
LRPE patients with short LOS had better net clinical outcomes at lower costs than those with long LOS. Providers should deploy risk stratification strategies and consider early discharge for LRPE patients.
Abstract 13151: Can Depth of Chest Compressions Be Estimated From Compression-Induced Artifacts in the Thoracic Impedance or ECG Signal?
Authors: Liu Chenguang , Jorgenson Dawn , Gehman Stacy , Tadipatri Vijay Aditya
Published: April 2024

Objective:
To explore the feasibility of estimating chest compression depth (CD) by analyzing the compression-induced artifacts in the thoracic impedance (TI) or ECG signals from out-of-hospital cardiac arrest (OHCA) patients who receive manual CPR.

Methods:
Data from 641 OHCA patients was recorded by Philips MRx defibrillators with Q-CPR meters in 2011 and 2012. For each of the 94,566 extracted segments (6 seconds long) with chest compressions, the CD from the Q-CPR meter and the peak-peak value of TI signal (PPV-TI) were obtained. Univariate linear regression was performed between PPV-TI and CD for the whole population and the coefficient of determination (
R
2
) was calculated. Linear regression was also performed in each of the individual patients who received at least 5 minutes of chest compressions (n=450). A subset of segments (n=608) were analyzed from asystolic patients (n=215), where the signals in the ECG were assumed to be compression-induced artifacts. In these segments, the CD and the peak-peak value of ECG signal (PPV-ECG) were obtained and linear regression was performed.

Results:
CD was 47 ± 11 mm (mean ± standard deviation). The
R
2
between PPV-TI and CD was 0.05 (Figure 1A). For the segments with the 5% smallest PPV-TI, 18% of the compressions were deeper than 50 mm. The mean of
R
2
between PPV-TI and CD in individual patients was 0.25 (Figure 1B), and 35.3% of the patients had an
R
2
value smaller than 0.1. The
R
2
between PPV-ECG and CD was 0.001 (Figure 1C).

Conclusions:
The linear correlation between PPV-TI and CD was low for the entire population. There was almost no correlation between PPV-ECG and CD. These results suggest that it is unreliable to estimate compression depth from the compression-induced artifacts in either the TI or ECG signal. Within individual patients, the
R
2
of PPV-TI varied and was below 0.1 in >35% of the patients, which suggests that estimating the trend of compression depth from the change of TI is not feasible in many patients.
Abstract 13175: Outcomes of Heart Failure (HF) Patients Admitted to the Intensive Care Unit (ICU): Impact of Early or Late ICU Admission
Authors: Lee Douglas S , Ross Heather J , Stelfox Thomas H , Fowler Robert A , Scales Damon C , Mak Susanna , Farkouh Michael E , Wunsch Hannah , Wang Xuesong , Tu Jack V , Stukel Therese A , Austin Peter C
Published: April 2024

Background:
Little is known about the outcomes of HF patients who are admitted to an ICU. We examined the outcomes of HF patients who were admitted to directly to the ICU (early) or admitted to the ICU after initial ward admission (late), compared to non-ICU admitted patients.

Methods:
We examined 118,595 HF patients (ICD-10 code I50) in Ontario, Canada, who were hospitalized from 2003-2012 using the Canadian Institute for Health Information Discharge Abstract Database. We examined the association of ICU admission and timing with: a) 30-day mortality using multiple Cox regression with time-varying covariates, and b) 30-day hospital readmissions using repeated events analysis approach of Prentice, Williams and Peterson.

Results:
Of the cohort, 24,119 (20%) were admitted to an ICU during the hospital stay, of whom 84% were admitted early (median age 76 years, 54% men) and 16% were admitted later (age 77 years, 53% men). 30-day mortality was higher in early and late ICU compared to no ICU: 13%, 27%, 10.5% (p <.001). Multivariable-adjusted hazard ratios (HR) were: 1.65 (95%CI; 1.58-1.73) for early ICU (p<.001) and 4.59 (95%CI; 4.31-4.89) for late ICU (p<.001) vs. no ICU (referent). All-cause 30-day readmissions were also highest among late ICU, followed by early ICU, and lowest in non-ICU patients: 24.3, 22.9, 21.7 readmissions per 100 person-months (all p <.001). Multivariable-adjusted repeated events analysis demonstrated a progressively increasing HRs for all-cause readmission: 1.07 (95%CI; 1.04-1.11) for early ICU (p<.001) and 1.13 (95%CI; 1.04-1.22) for late ICU (p<.01) vs. no ICU (referent). Median in-hospital costs were $16,553 for late ICU, $8587 for early ICU, and $7296 for non-ICU admitted patients (p <.001).

Conclusions:
HF patients who are admitted to the ICU are sicker and experience increased risk of 30-day readmissions and death. Late ICU admissions were associated with the highest risk of death and readmission, and incurred substantially higher costs of care.
Abstract 13202: Cellular Iron Regulates Mitochondrial Dynamics Through the RNA-Binding Protein Tristetraprolin (TTP)
Authors: Shapiro Jason S , Chang Hsiang-Chun , Sato Tatsuya , Jiang Xinghang , Wilsbacher Lisa D , Ardehali Hossein
Published: April 2024

Background:
Iron is a critical molecule for normal cellular and physiologic processes including mitochondrial energy production. Previous work in our lab has established the RNA-binding protein TTP as a protein whose expression is induced by iron deprivation. TTP functions by binding to AU-rich elements in the 3’UTR of mRNAs and promotes their degradation. Many of the targets of TTP encode metabolically active proteins that function in pathways requiring iron. Recently, we have identified Mitofusin 1 (MFN1), a critical component of the mitochondrial fusion machinery, as a novel target of TTP. Published reports have shown MFN1/2 double knockout mice develop spontaneous cardiomyopathy. Conversely, under conditions of ROS induced cellular stress, MFN1 knockout in cardiomyocytes has been associated with protection from cell death. We hypothesize that the level of MFN1 closely matches the metabolic demands of the cell and, therefore, induction of TTP by low iron reduces the level of MFN1 to fragment the mitochondria and limit the cell’s ability to proliferate during conditions of iron insufficiency.

Results:
Twenty-four hours of iron chelation using either desferoxamine (DFO) or 2-2, bipyridyl (BPD) induced TTP expression at both the mRNA and protein levels in a dose-dependent manner.
In silico
analysis of the MFN1 3’UTR revealed four conserved AU-rich elements. Basal levels of MFN1 were increased in TTP KO cells indicating TTP actively targets MFN1 mRNA. Additionally, iron chelation decreased MFN1 mRNA expression in WT but not TTP KO cells. Confocal imaging of mitochondria showed profound fragmentation in WT cells exposed DFO that was abrogated in TTP KO cells. Functionally, iron chelation induced complete growth arrest in WT cells that was partially escaped by TTP KO cells. The increase in proliferation was accompanied by higher rates of cell death in TTP KO cells.

Conclusions:
Our studies show that TTP expression is upregulated under conditions of iron deficiency and in turn represses the expression of the mitochondrial fusion protein MFN1 to alter mitochondrial dynamics. By remodeling the mitochondria under conditions of iron deprivation we propose a critical role for TTP in coordinating growth arrest to protect metabolically active cells from cell death.
Abstract 13223: Influence of Troponin Elevation on Short- And Long-Term Mortality in Severe Sepsis and Septic Shock
Authors: Vallabhajosyula Saraschandra , Jentzer Jacob C , Geske Jeffrey B , Kashani Kianoush B , Gajic Ognjen , Kashyap Rahul
Published: April 2024

Background:
Troponin-T (TnT) elevation is common in severe sepsis and septic shock, but the impact on mortality and other clinical outcomes remains uncertain.

Methods:
This was a retrospective review of adult patients with severe sepsis and septic shock admitted to all the intensive care units (ICU) at Mayo Clinic, Rochester from January 2012 to December 2014. Patients with congenital heart disease or pre-existing moderate or greater valvular disease were excluded. TnT elevation was defined as initial TnT ≥0.1 ng/mL or rise in 3- and 6-hour TnT ≥0.03 ng/mL. Primary outcomes included ICU, hospital, 28-day and 1-year mortality and secondary outcomes were need for and duration of non-invasive ventilation or invasive mechanical ventilation, ICU readmission, and ICU and hospital length of stay. Two-tailed
p
<0.05 was considered statistically significant.

Results:
During this three-year period, TnT was measured in 372/765 patients (49%) with septic shock with TnT elevation noted in 329/372 (88%) patients. In patients with and without TnT elevation, initial TnT was 0.14±0.26 vs. 0.14±0.02 ng/mL,
p
=0.57 and peak TnT was 0.20±0.36 vs. 0.08±0.11 ng/mL,
p
<0.001. Severity of illness scores, laboratory values, vasopressor use, clinical parameters and medications were similar between patients with and without TnT elevation, except that patients with TnT elevation were older and had more frequent history of coronary atherosclerosis, chronic kidney disease, heart failure and atrial fibrillation (all
p
<0.05). There was no significant difference in ICU mortality [43 (13%) vs. 8 (19%),
p
=0.34] and hospital mortality [75 (23%) vs. 12 (28%),
p
=0.45] between patients with and without TnT elevation. Long-term follow-up of 220/329 (67%) patients showed no significant difference in 28-day mortality [97/216 (45%) vs. 1/4 (25%);
p
=0.63] or 1-year mortality [163/216 (75%) vs. 4/4 (100%);
p
=0.58]. There was no significant difference in any of the secondary outcomes between patients with and without elevated TnT (all
p
>0.05). There was no difference in mortality with increasing quartiles of peak TnT.

Conclusions:
Troponin elevation is associated with older age and higher comorbidity burden, but does not predict mortality in patients with severe sepsis and septic shock.
Abstract 13280: Localized Hydrogen Peroxide Production and Differential Activation of Redox-sensitive Transcription Factors Involved in Atherogenesis
Authors: Steinhorn Benjamin , Belousov Vselovod , Michel Thomas
Published: April 2024

Reactive oxygen species modulate key physiological responses, yet ROS are also implicated in vascular disease states. At low concentrations, the stable ROS hydrogen peroxide (H
2
O
2
)

activates eNOS and enhances vascular barrier function. Yet at higher concentrations, vascular ROS lead to oxidative stress, increase permeability and promote atherosclerosis. The molecular events underlying the transition from “physiological” to “pathological” ROS in the endothelium are incompletely understood. Laminar shear stress activates “atheroprotective” redox-modulated transcription factors whereas turbulent/oscillatory flow activates “atherogenic” transcription factors that are sensitive to cellular redox state. In these studies, we constructed differentially-targeted HyPer biosensors for H
2
O
2
to identify the intracellular organelles and pathways responsible for dynamic mechanochemical regulation of endothelial H
2
O
2
metabolism. We discovered that laminar (physiological) shear stress increases H
2
O
2
in the endothelial cell nucleus much more than in the cytosol. By contrast, oscillatory (pathological) shear increases H
2
O
2
in the cytosol significantly more than in the nucleus. We next generated H
2
O
2
in specific subcellular locales in endothelial cells using recombinant constructs expressing a D-amino acid oxidase (DAAO) that robustly generates H
2
O
2
upon addition of D-alanine to the cells. By transfecting a series of differentially targeted DAAO constructs into endothelial cells, we discovered that generation of H
2
O
2
in distinct subcellular compartments differentially modulates transcriptional activation. Generation of H
2
O
2
by DAAO expressed in the endothelial cell nucleus led to enhanced transcription of Nrf2-modulated genes, whereas generation of H
2
O
2
by DAAO targeted to the cytosol instead activated NF-κB-regulated genes. This differential transcriptional response regulated by H
2
O
2
generated in distinct subcellular locales provides new insights into the roles of ROS and eNOS in mechanochemical coupling. Taken together, these findings have important implications for our understanding of flow-responsive genes in the normal blood vessel as well as in disease states associated with disordered blood flow and oxidative stress.
Abstract 13293: Instability of the Mechanosensory Domain of Platelet Glycoprotein GPIbα Underlies the Pathophysiology of Bernard-Soulier Syndrome
Authors: Zhang Xiaoqin , Liu Lanbo , Tao Yue , Mo Xi , Li Renhao
Published: April 2024

Glycoprotein (GP)Ib-IX complex is a highly expressed receptor complex on the platelet surface and plays a critical role in platelet activation and clearance. It consists of GPIbα, GPIbβ and GPIX subunits, with GPIbα containing the ligand-binding domain for von Willebrand factor (VWF) and other hemostatically important proteins. Bernard-Soulier syndrome (BSS), a rare hereditary bleeding disorder, is characterized by the abnormally low expression of functional GPIbα on the platelet surface. Previous studies of GPIb-IX expression in platelets and transfected Chinese hamster ovary (CHO) cells have showed that efficient surface expression of GPIbα requires its coexpression and proper assembly with GPIbβ and GPIX. However, the molecular basis underlying the fast degradation and low surface expression of GPIbα in the absence of GPIbβ and GPIX has remained unclear. Since the recently identified mechanosensory domain of GPIbα is not stable in isolation, we tested here whether it plays a role in influencing GPIbα expression in transfected CHO cells. Removal of this domain produced the first GPIbα variant (GPIbαΔ417-483) that could express alone in the plasma membrane at a level comparable to that of GPIbα in the wild-type GPIb-IX complex. Further analysis of mutational effects on GPIbα expression detected by flow cytometry and Western blot suggests that in the absence of GPIbβ and GPIX residues 461-483 confer GPIbα the vulnerability to degradation and low surface expression in transfected CHO cells. The underlying reason is being explored, but it is not due to the heightened exposure of the ADAM17 cleavage site because surface expression levels of various GPIbα variants in transfected CHO M2 cells, which lack a functional ADAM17, was very similar to those in wild-type CHO cells. In conclusion, we have identified for the first time high-expressing GPIba variants that retain native VWF-binding activity and intracellular signaling sequence, which will help to shed important insights on BSS pathogenesis and GPIb-IX structure-function.
Abstract 13306: Advanced Care Planning in Persons Who Die From Heart Disease
Authors: Goebel Joy R , Korosteleva Olga , Ortega Elizabeth A , Manning Timothy , Lodebo Yemisrach T
Published: April 2024

Introduction:
The unpredictable trajectory of persons dying from cardiovascular disease (CVD) may make planning for future care challenging. In order to target quality improvement (QI) efforts, it is necessary to identify factors associated with advanced care planning (ACPing) in CVD.

Methods:
The Health Retirement Survey (a nationally representative sample) provided data for a secondary data analysis of 1304 individuals’ ≥65 years of age that died of CVD from 2002-2012. Proxies of decedents reported ACPing activities (identifying a durable power of attorney for health care [DPOA_HC], completing a living will, or engaging in a conversation about care preferences at end of life (EoL). Demographic and clinical factors were also recorded.

Results:
Proxies reported 78% of decedents engaged in some level of ACPing (60% had a DPOA_HC, 56.5% had a conversation about EoL treatment preferences, and 47.3% completed a living will). In bivariate analysis, being older, female, Caucasian, widowed, dying at home/hospice/other, having higher income or education, and more symptoms were associated with any type of ACPing (chi-squared test p-value ranges between <0.000 and 0.028). In the multivariate regression model, older age (OR=1.026, 95%CI [1.002, 1.052], p=0.037), Caucasian race (OR=1.754, 95%CI [1.126, 2.735], p=0.013), more education (‘high school grad’: OR=1.723, 95%CI [1.151, 2.580], p=0.008; ‘some college’: OR=2.659, 95% CI [1.451, 4.871], p=0.002; ‘college grad’: OR=3.404, 95%CI [1.710, 6.774], p<0.000), higher income (‘$10,001-$88,000’: OR=1.670, 95%CI [1.000, 2.791], p=0.050; ‘>$88,000’: OR=2.012, 95%CI [1.150,3.520], p=0.014), and more symptom burden (OR=1.350, 95%CI [1.217, 1.498], p<0.000) were associated with any type of ACPing.

Conclusions:
The majority of individuals dying of CVD participate in ACPing. QI efforts to improve ACPing should target non-Caucasian individuals with less education, less income, younger age, and lower symptom burden.
Abstract 13419: Linear Fractional Shortening on Echocardiography (Echo)- A Novel Index of Right Ventricular Systolic Dysfunction as Validated by Cardiac Magnetic Resonance (CMR)
Authors: Srinivasan Aparna , Kim Jiwon , Rusli Melissa , Feher Attila , Geevarghese Alexi , Di Franco Antonino , Khan Saadat A , Shah Tara , Rozenstrauch Meenakshi , Khalique Omar , Devereux Richard B , Weinsaft Jonathan W
Published: April 2024

Introduction:
Among pts with LV systolic dysfunction (LV
dys
), biventricular (LV and RV) dysfunction (BiV
dys
) impacts outcomes. Echo linear indices are widely used to assess LV
dys
but performance for RV
dys
is unknown.

Methods:
The population comprised LV and BiV
dys
pts (gender, BSA matched) undergoing echo and CMR within 2 weeks: Echo included standard RV indices (fractional area change [FAC], TAPSE, S’) and linear fractional shortening (FS) in parasternal (RV outflow tract [RV
OT
]) and apical 4 chamber views (width [RV
WD
], length [RV
LG
]). CMR was the reference for volumetric LV & RV
dys
(EF<50%): Linear echo cutoffs were first established in a derivation cohort; then tested in a validation cohort.

Results:
168 pts (67% M, 57±15 yo) underwent echo and CMR (3±3 days); BiV
dys
pts had lower RVEF (36±9 vs 58±6%) and LVEF (28±12 vs 37±9%, both p<0.001) on CMR. On echo, FAC (47±9 vs 28±11), TAPSE (1.9±0.4 vs 1.5±0.3) and S’ (11.4±2.3 vs 9.9±2.6, all p<0.001) were lower with BiV
dys
, as were all linear FS indices (RV
OT
32±8 vs 17±10
Abstract 13422: Novel Calcium Therapy for Preserving Cardiac Conduction During Myocardial Inflammation
Authors: George Sharon , Calhoun Patrick , Gourdie Robert , Smyth James , Poelzing Steven
Published: April 2024

Introduction:
Diseases like ischemia, myocarditis and heart failure are associated with myocardial inflammation and elevated cytokines such as Tumor Necrosis Factor α (TNFα). TNFα modulates gap junctional coupling (GJC) which may then alter cardiac conduction velocity (CV) . Yet, the relationship between TNFα and GJC is controversial. TNFα also modulates extracellular edema, and edema slows CV via an alternative mode of intercellular communication called ephaptic coupling (EpC). However, the relationship between TNFα, CV, GJC, and EpC remains poorly understood.

Hypothesis:
TNFα modulates cardiac conduction velocity (CV) by altering EpC.

Methods:
CV was quantified from optically mapped guinea pig ventricles. The width of the candidate cardiac ephapse called the perinexus (WP) was measured by transmission electron microscopy. Connexin43 (Cx43) expression, phosphorylation and distribution around the myocyte was determined by western blotting and confocal immunofluorescence.

Results:
TNFα anisotropically slowed conduction at 90 minutes relative to time controls (0.21±0.01 vs 0.24±0.01m/s). While TNFα increased WP and reduced EpC (24.2±1.12 vs 18.6±0.86 nm), TNFα did not significantly modify total Cx43 expression or phosphorylation, although Cx43 localization at the intercalated disc was reduced relative to time controls (81% vs 86%). Physiologically elevating calcium concentration in the presence of TNFα (TNFα + 2.5mM calcium) restored CV to time control values within 15 mins and further improved conduction above time control values at 90 mins. This CV increase correlated with restoration of WP to control values at both 0 and 90 mins. Interestingly, at 90 mins, TNFα + 2.5mM calcium also increased total Cx43 expression as well as intercalated disc localization relative to 90mins of TNFα alone(86%).

Conclusions:
TNFα reduces CV by increasing WP and redistributing Cx43. With TNFα, 2.5mM calcium acutely (15 mins) improves CV presumably by increasing EpC, and over 90 mins, improves CV above control values possibly by the increase in both EpC and GJC . Taken together, the data suggests that physiologic ionic modulation could be an effective therapy to prevent cardiac arrhythmias.
Abstract 13427: The Presence of Fragmented QRS predicts Mortality and Appropriate Shocks in ICD Recipients
Authors: Vandenberk Bert , Robyns Tomas , Floré Vincent , Garweg Christophe , Ector Joris , Willems Rik
Published: April 2024

Introduction:
QRS fragmentation (fQRS) on the 12-lead electrocardiogram (ECG) has been shown to reflect inhomogeneous activation of the ventricles by the presence of myocardial infarction or scarring. Presence of fQRS has been shown to be a predictor of mortality and sudden cardiac death, however data in ICD recipients are scarce.

Methods:
All ICD recipients in our hospital with ischemic (ICM) or non-ischemic cardiomyopathy were included in this single-center retrospective registry. Electrocardiograms before implant were analyzed for the presence of fQRS according to the criteria defined by Das in 2006 and 2008. Endpoints were appropriate ICD shocks (AS) and all-cause mortality. Kaplan-Meier and multivariate Cox regression analyses with demographic, clinical and electrocardiographic variables were performed.

Results:
A total of 727 patients (84.9% male, 66.4% ICM, 56% primary prevention) with a mean follow-up of 5.2±4.1 y were included. Annual mortality rate was 3.9%/y and for shocks 9.4%/y. Overall 50.6% of patients had fQRS on the ECG, most frequently localized in the inferior (35.4%), followed by the anterior (21.6%) and lateral leads (11.1%). The presence of fQRS in any region was an independent predictor of mortality (HR 1.535, 95%CI 1.141-2.066), particularly in primary prevention patients (HR 1.927, 95%CI 1.206-3.079). Overall fQRS was not an independent predictor of AS. fQRS in the anterior leads was an independent predictor of mortality (HR 1.550, 95%CI 1.130-2.125), particularly in primary prevention patients (HR 2.625, 95%CI 1.575-4.377). Further, in primary prevention anterior fQRS showed a trend towards independent prediction of AS (p=0.059, HR 1.573, 95%CI 0.984-2.514). The presence of fQRS in the lateral leads was an independent predictor of mortality in primary prevention patients (HR 2.037, 95%CI 1.088-3.814), not in the overall study population. Presence of fQRS in the inferior leads did not show any significant results analyzing the complete follow-up.

Conclusions:
Presence of fQRS on the ECG before ICD implantation could be used as risk stratification tool identifying patients at increased risk of dying, particularly if present in the anterolateral leads and in patients with primary prevention ICD indications.
Abstract 13444: Decreased REM Sleep is Associated With Higher Risk of Incident Atrial Fibrillation
Authors: Christensen Matthew A , Dixit Shalini , Vittinghoff Eric , Mukamal Kenneth J , Redline Susan , Robbins John A , Newman Anne B , Patel Sanjay R , Magnani Jared W , Psaty Bruce M , Heckbert Susan R , Marcus Gregory M
Published: April 2024

Introduction:
Reduced sleep quality, beyond that caused by obstructive sleep apnea (OSA), has recently been associated with the development of obesity, hypertension, stroke, and death. While OSA has been shown to predict AF, it remains unknown if sleep disturbances independent of apnea predict the disease.

Hypothesis:
Reduced sleep quality increases the risk of incident AF independent of OSA

Methods:
We performed a longitudinal analysis in a sub-set of participants in the Cardiovascular Health Study who were co-enrolled in the Sleep Heart Health Study. Sleep duration, efficiency, latency, and architecture were measured at baseline using at-home polysomnography. Severity of OSA was determined using clinical cut-offs with the apnea-hypopnea-index (AHI), also measured by polysomnography. Cox proportional hazards models were used to obtain effect estimates and adjust for OSA severity and other potential confounders including: age, sex, race, site, BMI, smoking, alcohol use, use of sleeping pills, diabetes, HTN, CHD, and CHF.

Results:
Among 1,131 participants with a mean age of 77 ± 4.5 years, 665 (59%) were female, and 647 (60%) had at least mild OSA (AHI > 5). Over a median follow-up of 9.8 years (IQR, 5.5 - 11.7), 259 (23%) developed AF. Decreased REM sleep was associated with increased risk of AF before and after adjustment for OSA and other potential confounders (
Figure
). For every standard deviation decrease in the proportion of sleep spent in REM (SD 6.6%) there was an approximate 23% increase in the risk of AF (adjusted hazard ratio 1.23; 95% CI, 1.05 - 1.44, p = .01).

Conclusions:
Reduced REM sleep was independently associated with greater risk of incident AF among older adults. Aspects of sleep beyond OSA may be involved in the pathogenesis of AF and sleep quality may be an important modifiable risk factor for AF.
Abstract 13472: Aortic Valve Reconstruction Using In-body Tissue-Engineered Collagenous Connective Tissue Membranes,BIOSHEETs, in a 3-month Goat Model
Authors: Okamoto Keitaro , Kawashima Takayuki , Nakayama Yasuhide , Anai Hirohumi , Wada Tomoyuki , Takebayashi Satoshi , Shuto Takashi , Kozaki Satoshi , Miyamoto Shinji
Published: April 2024

Background and Purpose:
Autologous pericardium is widely used for a plastic material in intracardiac structures, pulmonary artery, or aortic valve leaflets. Also in aortic valve reconstruction (AVRec: Ozaki Procedure), inducing excellent clinical results over 6 years, autologous pericardium is used after fixation with glutaraldehyde. In-body tissue architecture (IBTA) based on the tissue encapsulation phenomenon of foreign materials can prepare autologous prosthetic tissues. In this study, we used an IBTA-based collagenous connective tissue sheet (Biosheet) as an aortic valve leaflet material for glutaraldehyde-free AVRec to compare the in vivo valve function and the tissue regeneration with original AVRec in a goat model.

Methods and Results:
AVRec was performed using two materials, glutaraldehyde-fixed autologous pericardium or Biosheets. The Biosheets were prepared by 2-month embedding of the plastic molds in the dorsal subcutaneous spaces of goats, obtained as completely autologous connective tissue with collagen and fibroblasts, and stored in alcohol before implantaion. AVRec procedure: The heart was exposed via a left thoracotomy at the fourth costal bed. Cardiopulmonary bypass was established with aortic and right atrial cannulations. After resection of native aortic valve cusps, the distance between each commissure was measured using a self-developed sizing instrument. Biosheet or autologous pericardium was trimmed with a self-developed template corresponding to the measured value. The annular margin of the leaflets was sutured to each annulus with monofilament sutures. In a Biosheet model, postoperative echocardiography after surgery showed smooth movement of the leaflets with little regurgitation, similar to that in an autologous pericardium model. Three month after Biosheet implantation, the valve leaflets was very smooth and covered partially with a thin neointima, including endothelial cells without thrombus formation. Biosheet was assimilated in an aortic root than autologous pericardium.

Conclusion:
An IBTA-based autologous connective sheet, Biosheet, without glutalaldehyde could be used for an AVRec material with high regeneration performance, suggesting that Biosheets have potential clinical use.