bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 8887: Impact of Event Rate Assumptions on the Conclusions of Non-Inferiority Coronary Stent Trials
Authors: Simonato Dos Santos Matheus , Ben-Yehuda Ori , Vincent Flavien , Zhang Zixuan , Redfors Bjorn
Published: April 2024

Background:
Non-inferiority trials are increasingly common in assessing novel therapies. The outcome and interpretation of non-inferiority trials depends on the magnitude of the non-inferiority margin, whether a relative or absolute non-inferiority margin is used, and may be affected by imprecision in event rate estimation.

Methods:
We performed a systematic review of randomized non-inferiority coronary stent trials published within the past 5 years as a case study. For non-inferiority endpoints with absolute margins, the assumed corresponding relative margin was defined as the ratio of the absolute margin and the assumed event rate, and the observed corresponding relative margin as the ratio between the absolute margin and the observed event rate in the control arm.

Results:
A total of 58 trials, encompassing 106,989 patients, were identified and analyzed. The event rate in the control arms were overestimated by a median of 28% [2%-74%]. The majority of non-inferiority trials used absolute rather than relative margins (55/58; 94.8%). Due to overestimation, absolute non-inferiority margins became more permissive than originally assumed (observed relative non-inferiority margin 1.62 [1.50-1.80] versus assumed relative non-inferiority margin 1.47 [1.39-1.55], p<0.001). Among trial comparisons that met non-inferiority with an absolute non-inferiority margin, 17/50 (34%) would not have met non-inferiority with a corresponding assumed relative non-inferiority margin.

Conclusions:
Assumed event rates are often overestimated in non-inferiority coronary stent trials. Because most of these trials use absolute margins to define non-inferiority, such overestimation results in excessively permissive non-inferiority margins.
Abstract 9009: Management of Renin-Angiotensin-Aldosterone System Blockade in Patients Admitted in Hospital With Confirmed Coronavirus Disease (COVID-19) Infection: The McGill RAAS-COVID-19 Randomized Controlled Trial
Authors: Sharma Abhinav , Elharram Malik , Ni Jiayi , Afilalo Jonathan , Flannery, RN Alexandria , Ezekowitz Justin , Cheng Matthew P , Ambrosy Andrew P , ZANNAD Faiez , Brophy Jay , Giannetti Nadia , Bessissow Amal , Kronfli Nadine , Marelli Ariane J , Aziz Haya , AlQahtani Mohammad , Aflaki Mona , Craig Morgan , Lopes Renato D , Ferreira Joao P
Published: April 2024

Background:
More data is needed on the cardiovascular impact of discontinuing versus continuing renin-angiotensin aldosterone system inhibitors (RAASi) among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection (COVID-19).

Methods:
The McGill RAAS-COVID-19 trial was a randomized, open label trial in adult patients hospitalized with COVID-19, who were previously treated with RAASi (angiotensin converting enzyme inhibitors [ACEi]/angiotensin receptor blocker [ARB]) (NCT04508985; 10/2020-03/2021). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]). All analyses were conducted using the intention-to-treat principle.

Results:
Overall, 21 participants were randomized to discontinue RAASi and 25 to continue. Patients’ mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a similar mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); p= 0.60), but the negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.7 [95% CI 1.1 to 2.6]; p=0.03). Particularly, RAASi discontinuation increased brain natriuretic peptide (BNP) levels (% change from baseline: +16.7% vs. -27.5%; p= 0.02) and increased the incidence of acute heart failure (33% vs. 4.2%, p=0.03).

Conclusion:
Discontinuation of RAASi increased BNP levels and risk of acute heart failure in participants hospitalized with COVID-19; where possible, RAASi should be continued.
Abstract 9051: Gender Differences and Aging on Beta-Adrenergic Receptor Subtypes Expression and Function in Murine Left Ventricular Myocytes
Authors: Cheng Che Ping , Chen Zhe , Cao Jing , Sun Xiaoqiang , Zhou Peng , Zhao David , Herrington David M , Kitzman Dalane W , Cheng Heng
Published: April 2024

Background:
Sex-specific modulation of β-adrenergic receptor (AR) stimulation plays a pivotal role in cardiac function and in the manifestation of heart disease, including aging. However, the sex and age influences on 3 cardiac β-AR subtypes have not been systematically evaluated. Their effects on β
1
-AR have yielded mixed results. Virtually no previous studies have examined sex and age-related changes on the functional cardiac β
3
-AR. We hypothesized that sex differences exist in aging-induced changes in myocyte β
1
- and β
3
-AR. Aged males may exhibit a greater selective β
1
-AR downregulation with a more pronounced decline of β-AR reserve.

Methods:
LV myocytes were obtained from young (Y) (6 mo) and aged (A) (24 mo) (6/group) male (M) and female (F) wild-type mice. We simultaneously compared LV myocyte protein levels of β
1
-, β
2
-, and β
3
-AR, and the responses of cell contractile function (dL/dt
max
) to β-AR subtype stimulation by random exposure of myocytes to isoproterenol (ISO) (10
-8
M) or a selective β
1
-, β
2
-, or β
3
-agonist, Norepinephrine (NE, 10
-7
M), Zinterol (ZIN,10
-5
M) and BRL-37,344 (BRL,10
-8
M), respectively.

Results:
In Y mice, no sex differences were found in myocyte protein levels of β
1
- (YM: 0.73 vs YF: 0.74), β
2
- (0.28 vs 0.29) and β
3
-AR (0.19 vs 0.17). Consistently, there were similarly significant increases in dL/dt
max
in responses to ISO (YM: 73%, 209.5 vs121.1; YF: 72%, 210.7 vs122.5 μm/s), NE (48% vs 45%), ZIN (18% vs 20%) and decrease after BRL (8.1% vs 7.9%). Compared with sex-matched Y, in both AM and AF, aging caused a ~58% significant increase in β
3
(AM: 0.30 vs AF: 0.27) and slightly reduced β
2
(11% vs 6%) (P=NS). Aging caused ~30% decline in basal cell contractility. No sex differences in dL/dt
max
of aging myocyte response to ZIN (increased AM: 17% vs AF: 20%), and BRL (decreased 19% vs 21%). However, in AM, β
1
decreased 33% (0.48) which was significantly greater than that in AF (26%, 0.55). Versus AF, in AM, ISO caused significantly less increase in dL/dt
max
(34% vs 48%) accompanied by attenuated NE-mediated increase in dL/dt
max
(17% vs 26%).

Conclusions:
Aging is associated with LV myocyte β
1
-AR downregulation and β
3
-AR upregulation. Sex affects age-related β
1
-AR downregulation, with males exhibiting a more profound decrease with increasing age.
Abstract 9094: Intensive Lifestyle Medicine for Primary & Secondary Prevention for Cardiovascular Risk Reduction in Patients With Diabetes
Authors: Jafri S. Hammad , Imran Tasnim F , Freeman Andrew M , Ornish Dean , Wu Wen-chih
Published: April 2024

Introduction:
Cardiovascular disease (CVD) carries significant morbidity and mortality, especially for patients with diabetes. Intensive Cardiac rehabilitation (ICR) has proven benefits for patients with CVD through a high fiber low fat diet, peer support, exercise and stress reduction; which may help in diabetes management. However, outcomes of ICR in patients with diabetes with and without CVD are unknown.

Hypothesis:
ICR can improve outcomes in diabetic patients with or without CVD.

Methods:
We conducted a retrospective cohort study of 4793 diabetic patients who were offered ICR at 46 CR centers across USA from January 2016 to December 2020. Five ICR centers in Hawaii had patients enrolled with diabetes without any CVD as Hawaii is the only state in US which has approved ICR for diabetic patients without CVD for primary prevention. ICR sessions are 4-hours long, twice weekly for 9-weeks of lifestyle modification aiming at high fiber low fat diet, peer support, exercise and stress reduction. Diabetic patients were divided into two groups: CVD group (known CVD) - 3723 patients (78%) and Non-CVD group (without CVD) - 1070 patients (22%). Primary endpoints were change in HbA1C, LDL and BP. Secondary outcomes were change in BMI, triglycerides, cholesterol, HDL, dietary fat intake, dietary fiber intake, depression scores (CESD) and exercise minutes per week. We used t tests to compare variables pre and post ICR.

Results:
The mean age of patients was 66.5 ± 0.2 years, 43% were females and 44% were white. ICR completion rate & number of ICR sessions was higher in Non-CVD group (Non-CVD: 60.11 ± 27.16 vs. CVD: 55.67 ± 33.15, p<0.01). Primary (HBA1c, BP, LDL) and secondary outcomes improved in both groups Pre and Post ICR as shown in
table.

Conclusions:
Significant improvement in diabetes & ICR outcomes were achieved for both groups after completing ICR. Although long term outcomes are unknown, diabetic patients should continue to participate in ICR for further risk reduction.
Abstract 9105: Eliminated Male Advantages in Cardiopulmonary Exercise Testing Performance after Fontan Operation Indicates a Central Mechanism of Decreased Exercise Performance in a Single Ventricle Physiology
Authors: Tsuda Takeshi , Kernizan Daphney , D'Aloisio Gina
Published: April 2024

Background:
Fontan patients have significantly diminished exercise performance compared with healthy peers. Sex differences in exercise performance after Fontan operation have not been well characterized.

Methods:
We retrospectively analyzed cardiopulmonary exercise testing (CPET) of Fontan and age-matched control adolescents. Data were analyzed via one-way analysis of variance (ANOVA) and are shown as mean ± standard deviation.

Results:
We studied 36 Fontan patients (male 18/female 18) and 65 age-matched controls (male 32/female 33). When compared between Fontan and controls, peak values of heart rate (HR), oxygen consumption (VO2), and work rate (WR), ventilator anaerobic threshold (VAT), and oxygen uptake efficiency slope (OUES) were significantly lower in Fontan than in controls in both sexes. In controls, significant sex differences were noted in peak values of VO2, oxygen pulse (OP), WR, VAT, heart rate dependency (αHR/αWR), OUES, and ventilatory efficiency (αVE/αVCO2) whereas no such sex differences were detected in Fontan patients (Table). Significant sex differences noted in correlations between weight and peak VO2 and between αHR/αWR and peak VO2 in controls were not appreciated in Fontan patients (Figure), suggesting that single ventricle physiology abolished some key male advantages in exercise performance under biventricular physiology including body mass (skeletal muscle mass) effects and stroke volume reserve.

Conclusion:
Disappearance of male advantages in CPET performance in Fontan patients indicates a limitation of systemic ventricular filling due to the absence of sub-pulmonary ventricle as a central determinant of low exercise performance.
Abstract 9117: Heart Failure E-learning Training for Low Income Countries is Effective and Feasible: A Pilot Study
Authors: Alizadeh Faraz , Ngoga Gedeon , Klassen Sheila L , Habineza Adrien , Karema Nadine , Karera Innocent , Ng'ang'a Mwihaki L , DUSABEYEZU Symaque , Viateur Kalisa , Emmanuel Dushimimana , Park Paul , Mpanumusingo Egide , Bukhman Gene , Cubaka Vincent , Kwan Gene F
Published: April 2024

Introduction:
Heart failure (HF) is a burden in low income countries (LICs). However, HF care is complex and skilled providers in LICs are limited. E-learning (EL) could offer access to specialized HF training, but little is known about its feasibility in rural LICs. We describe the design and pilot study of an EL HF module.

Methods:
An interdisciplinary team from Partners In Health adapted an existing classroom based HF curriculum for an online, self-guided, asynchronous EL format. We emphasized design features promoting user engagement (clinical cases, animations, interactions) and functionality (download for offline viewing). Due to paucity of EL data in LICs, an introduction to Heart Failure pilot module was used to evaluate implementation.In phase 1, we evaluated usability among 7 experienced HF providers in Rwanda, Malawi, and Liberia. In phase 2, we assessed the ability of 19 novice providers in Rwanda to learn concepts using EL (
Figure 1)
. Pre and posttests, post-course surveys, and semi-structured group interviews were used for evaluation. Results from phase 1 informed changes piloted in phase 2.

Results:
Providers from both phases improved test scores with a significant change among novices (
Figure 1
).
Figure 2
summarizes key findings identified in surveys and focus group analyses.

Discussion:
An EL module teaching basic HF concepts is feasible and shows early signs of effectiveness in rural LICs. EL training modules may benefit from interactive content, reliable internet, and a simple interface. EL may facilitate HF training for both novice and experienced providers through decentralized programs like the Package of Essential Noncommunicable Disease Plus (PEN-Plus).
Abstract 9129: Effect of Cardiovascular Risk Factors on Hypertensive Disorders of Pregnancy: A Mendelian Randomization Study
Authors: Ardissino Maddalena , Millar Ophelia , Reddy Rohin , Lazzari Laura , Patel Kiran , Ryan David , Gill Dipender , Johnson Mark , Ng Fu Siong
Published: April 2024

Introduction:
Cardiovascular risk factors have been associated with adverse maternal and fetal outcomes, including risk of hypertensive disorders of pregnancy such as pre-eclampsia (PE) and low fetal birth weight. However, it is difficult to establish causal relationships from retrospective evidence due to risk of confounding. We applied Mendelian randomization to explore the role of traditional cardiovascular risk factors in determining maternal and fetal outcomes of pregnancy.

Methods:
Summary statistics were used to perform a 2-sample Mendelian randomization study to investigate the association of genetically-predicted systolic blood pressure (SBP), body mass index (BMI), glycated haemoglobin A1C (HbA1C), low-density lipoprotein cholesterol (LDL-C), and smoking with the primary outcome of pre-eclampsia or eclampsia in 1,689 cases and 52,576 controls of Finnish ancestry, and secondary outcome of birth weight of the first child of 145,558 European women from the UK Biobank.

Results:
There was a significant association between PE and both genetically-predicted SBP (OR per mmHg increase: 1.05,95%CI 1.01-1.10, p=0.030) and genetically-predicted BMI (OR per kg/m
2
increase: 0.24 95%CI 1.07-1.90 p=0.017). Genetically-predicted SBP was associated with lower birth weight (OR per mmHg increase: 0.98, 95%CI 0.97-0.98 p<0.001), whereas genetically-predicted HbA1C was associated with higher birth weight (OR per mmol/mol increase: 1.31 95%CI 1.11-1.56 p=0.002).

Conclusion:
Our results suggest a causal association between some cardiovascular risk factors, specifically hypertension, obesity and HbA1C, with adverse maternal and fetal outcomes, such as pre-eclampsia and low fetal birth weight. No causal association was found for LDL-C and smoking.The results provide insight into the genetic and pathophysiological basis of pre-eclampsia and identify important targets for pre-pregnancy counselling and optimization to improve maternal and fetal outcomes.
Abstract 9154: Sex Differences in Mortality from Covid-19 Pandemic: Are Men Vulnerable and Women Protected. Why?
Authors: Soomro Khalida , Soomro Muhammad Ali
Published: April 2024

The epidemiological studies shows that compared to women, men infected with the novel COVID-19 have more severe and threatening disease and have a higher mortality globally. The population which is under real panic comprises older men. The reason could be linked to sex chromosome genes and sex hormones with differential regulation of immune responses between the sexes.

Objectives of Study:
We need to recognize the phenotypical differences in severe case manifestations of COVID-19 in men and women as a fundamental step to understand the effects of this health emergency.

Study Design/Methodological/Approach:
The study was designed upon factors that are the major cause of gender inequality of infection. The statistical data was collected from the official record of COVID-19 Emergency Centre established in OJHA Centre Dow University Karachi.

Results:
It was found that, the mortality rate is very high in men. Less deaths of patients younger than 40 years even in past coronavirus leading to severe acute respiratory SARS-CoV, were found to infect more men than women. This may be due to not required enhanced response to infections on reproductive function in young men population, enhanced immune reactivity along with changes in immune cells during aging and pleiotropic nature of many genes.

Conclusion:
Evidence from this study tells us that sex is an important driver of risk of mortality and response to the COVID-19 pandemic. Age distribution is related with increased mortality rate among men, especially the older age men. Further research is warranted to investigate hormonal, inflammatory, immunologic, and phenotypical differences in severe COVID-19 disease presentations.
Abstract 9196: Innocuous Levels of Pulmonary Thrombosis Protect Against Inflammatory Lung Injury via Endothelial Arachidonate 15-Lipoxygenase and Hypoxia-Inducible Factor 1α
Authors: Evans Colin E , Zhang Xianming , Machireddy Narsa , Zhao Youyang
Published: April 2024

Introduction:
Sepsis patients commonly suffer from lung thrombosis and sepsis-induced acute lung injury (ALI), but clinical trials of anti-coagulants in sepsis and ALI have failed, and the impact of varying severities of lung thrombosis on ALI is unknown.

Hypothesis:
Pulmonary thrombosis regulates the severity of sepsis-induced ALI through modulation of pulmonary endothelial cell (EC) viability. In this study, we aimed to determine the impact of varying levels of lung thrombosis on ALI and to delineate the underlying mechanisms.

Methods:
We assessed inflammatory lung injury in mouse models of pulmonary thrombosis combined with sepsis-induced lung injury and thrombocytopenia. We also used RNA sequencing and nanoparticle-mediated EC-targeted gene editing to delineate and target thrombosis-induced EC signaling pathways.

Results:
In wild type mice, excessive increases in lung thrombosis worsened ALI, but the induction of a mild and innocuous level of lung thrombosis instead reduced ALI and mortality. We then showed that this mild level of lung thrombosis increases the expression of multiple factors that regulate cell survival, including arachidonate 15-lipoxygenase (Alox15) and hypoxia-inducible factor (HIF) 1α in ECs. Next, we used nanoparticle-mediated EC gene editing to show that the protective impact of mild lung thrombosis on ALI is dependent upon EC-specific Alox15 and HIF1α. From a therapeutic perspective, the mild level of lung thrombosis could be induced up to 8 hours after sepsis and still maintain its protective impact on ALI. Furthermore, the induction of mild lung thrombosis completely prevented thrombocytopenia-induced increases and ALI and mortality.

Conclusions:
Mild levels of lung thrombosis protect against inflammatory lung injury via EC Alox15 and HIF1α. Promoting lung EC survival through Alox15 or HIF1α signaling represents a promising therapeutic strategy against ALI.
Abstract 9214: β-arrestin-biased Receptor CXCR7 in Cardiomyocytes Acts on Cell Survival and Inhibits Post-Infarction Remodeling
Authors: Ishizuka Masato , Harada Mutsuo , Nomura Seitaro , Ko Toshiyuki , Bujo Satoshi , Guo Jiaxi , Zhai Bowen , Kishikawa Risa , TOKO Haruhiro , Komuro Issei
Published: April 2024

Introduction:
Seven transmembrane receptors (7TMRs) play various important roles in the heart in which β-arrestin-biased agonism has been recently reported to be cardioprotective. Chemokine receptor CXCR7 is a 7TMR expressed in the heart and binds not to G protein but only to β-arrestin, serving as a β-arrestin-biased receptor. The expression levels of CXCL12, the ligand of CXCR7, are increased in myocardial infarction (MI) but the role of CXCL12/CXCR7 in MI remains elusive.

Hypothesis:
CXCR7 protects the heart from myocardial infarction as a β-arrestin-biased receptor.

Methods and Results:
First, we performed bulk RNA sequencing (RNAseq) in murine hearts and found
Cxcr7
to be the most abundantly expressed 7TMR. We next used single-cell RNAseq and demonstrated that
Cxcr7
was strongly expressed in cardiomyocytes and fibroblasts but not in the other type of cells. Second, we generated cardiomyocyte-specific
Cxcr7
knockout (cKO) mice and induced MI by left anterior descending artery ligation.
Cxcr7
cKO mice showed significantly exacerbated cardiac dilation and dysfunction at 4 weeks after MI compared to controls. In contrast, fibroblast-specific knockout mice showed no such difference. Third, we revealed that CXCL12 recruited β-arrestin to CXCR7 in CXCR7 expressing cells. We stimulated cultured neonatal rat ventricular myocytes with CXCL12 and induced cell death by oxygen glucose deprivation. ERK was activated and cell death was suppressed by CXCR7 stimulation. In the border zone of mouse infarcted hearts,
Cxcr7
expression was increased and ERK was activated, which was attenuated in
Cxcr7
cKO hearts. Finally,
CXCR7
expression was also increased in human failing hearts, suggesting CXCR7 is also associated with human heart failure.

Conclusion:
CXCR7 is predominantly expressed in cardiomyocytes, acts on cell survival through ERK activation, and inhibits post-infarction remodeling. CXCR7 may be a new therapeutic target for MI.
Abstract 9294: Prognosis of Atrial Fibrillation in Low Gradient Aortic Stenosis
Authors: Kolluri Nikhil , Oguz Didem , Scott Christopher , Crestanello Juan A , Pislaru Sorin , Thaden Jeremy J , Nkomo Vuyisile T
Published: April 2024

Introduction:
A significant portion of patients with aortic stenosis (AS) have low-gradient AS (LGAS) defined as aortic valve area ≤ 1.0 cm
2
and a trans-aortic mean systolic gradient and peak velocity < 40 mmHg and < 4 m/s, respectively. LGAS has been shown previously to have worse mortality compared to high-gradient AS (HGAS). Etiologies for LGAS include diastolic dysfunction, heart failure, other significant valvular disease, and atrial fibrillation (AF). AF is associated with worse outcomes compared to sinus rhythm (SR) in HGAS. AF is common in LGAS, but whether AF is associated with worse outcomes versus SR in LGAS has not been elucidated.

Hypothesis:
We hypothesize that AF is associated with higher mortality compared to SR in patients with LGAS.

Methods:
We retrospectively identified and reviewed charts of patients who were diagnosed with LGAS on transthoracic echocardiogram (TTE) from 2010-2020 at Mayo Clinic. Patient were classified according to rhythm at the time of TTE and history of AF was ascertained among those in SR. Patents were divided into 3 groups; SR without history of AF (group 1), SR with history of AF (group 2), and AF during TTE (group 3). Primary endpoints of overall mortality and cardiac mortality were ascertained.

Results:
A total of 3400 patients were included: n=2036 in group 1, n=519 in group 2, and n=845 in group 3. After adjusting for age, sex, and the Charlson index, group 2 and group 3 patient had significantly higher overall mortality (HR 1.22 and HR 1.52, respectively, p<0.0001 for both) and cardiac mortality (HR 1.37 and HR 2.05, respectively, p<0.0001 for both),
Figure
.

Conclusions:
In LGAS, AF is a significant prognostic indicator of overall mortality and cardiac mortality. LAGS associated with AF may need different management strategies given the higher mortality associated with the presence of AF.
Abstract 9295: Ertugliflozin Has Favorable Effects on Kidney Outcomes in Patients With Baseline Evidence of Heart Failure in VERTIS CV
Authors: Cherney David , Consentino Francesco , Dagogo-Jack Samuel , McGuire Darren K , Pratley Richard E , Frederich Robert , Maldonado Mario , Liu Chih-Chin , Cannon Christopher P
Published: April 2024

Background:
Data from VERTIS CV (NCT01986881) were analyzed to study the effect of ertugliflozin on kidney outcomes in patients with and without baseline evidence of HF.

Methods:
Patients with type 2 diabetes mellitus and ASCVD were randomized (1:1:1) to ertugliflozin 5 or 15 mg (both doses pooled for analyses) or placebo. Subgroups were defined by baseline history of HF or a pre-randomization left ventricular ejection fraction (EF) ≤45%. eGFR over time, total 5-year eGFR slopes and Cox proportional hazards for time to first event of a kidney composite of sustained ≥40% decrease from baseline eGFR, chronic kidney replacement therapy, or kidney death were assessed.

Results:
At baseline, 2439 (29.6%) had a history of HF or EF ≤45% (HF) and 5807 (70.4%) had no evidence of HF (no HF). Compared with placebo, ertugliflozin treatment resulted in a slower rate of eGFR decline in both subgroups; total placebo-adjusted 5-year eGFR slope (mL/min/1.73 m
2
/year [95% CI]): 0.96 (0.67, 1.24) and 0.95 (0.76, 1,14) for the HF and no HF subgroups, respectively (Figure 1). The HF subgroup had a higher event rate for the composite kidney outcome than the no HF subgroup. Hazard ratios (95% CI) for ertugliflozin for reducing the risk of the composite kidney outcome did not differ significantly across the two subgroups; 0.53 (0.33, 0.84) and 0.76 (0.53, 1.08) for the HF and no HF subgroups, respectively (
P
interaction
=0.22) (Figure 2).

Conclusion:
In VERTIS CV, patients with HF at baseline had a notably faster rate of eGFR decline that is unlikely to be explained by the slightly lower baseline eGFR in that group. The effects of ertugliflozin on kidney outcomes did not differ between the two groups stratified by baseline HF.
Abstract 9316: Role of Bile Acids in Calcific Aortic Valve Stenosis
Authors: Atefi Negar , Surendran Arun , Raabe Michael , Jassal Davinder S , Shah Ashish H , Ravandi Amir
Published: April 2024

Introduction:
Calcific aortic valve stenosis (CAVS) is the most common valvular pathology seen in the Western world. Patients with symptomatic CAVS have a poor prognosis with the only therapy being valvular intervention. There is currently no known mechanism and therefore medical therapy for controlling the progression of CAVS. Our recent metabolomics analysis of human aortic valve tissue identified bile acid biosynthesis as a potential mitigator of valvular stenosis. In this study, utilizing a targeted metabolomics approach, we investigated the role of valvular and plasma bile acids in the degree of severity and the rate of progression of CAVS.

Methods:
Human aortic valves from 102 patients who underwent AVR surgery were collected. Bile acid profiling (80 bile acids) of valvular tissues along with 19 plasma samples was carried out by a targeted mass spectrometry approach. The explanted aortic valves were graded from mild, moderate, and severe categories based on mean pressure gradient (MPG) and valvular calcification score by transthoracic echocardiography. CAVS progression was determined in a subset of our cohort (N=49), categorizing patients as “fast” and “slow” progressors based on echocardiography measures of the peak jet velocity.

Results:
Bile acids nordeoxycholic acid, norcholic acid, and glycodeoxycholic acid were significantly altered (p<0.05) across CAVS severity stages based on MPG. Similarly, six bile acids namely nordeoxycholic acid, norcholic acid, 3β,7α-diOH-5-cholestenoic acid, 3β-OH-5-cholestenoic acid, glycolithocholic acid, and glycoallocholic acid were significantly altered (p<0.05) based on valvular calcification scores. Taurodeoxycholic acid showed a significant difference (p<0.05) between the slow and fast progressors. Additionally, valvular tissue levels of these bile acids correlate with plasma levels.

Conclusions:
In this report, we present a potential novel mechanistic pathway correlating bile acids with the pathogenesis of CAVS. Our goal is to validate these findings in a large cohort of patients with CAVS. Given that bile acid modulating therapies are already used in clinical practice, this represents a potential novel therapeutic target to prevent or delay the progression of CAVS.
Abstract 9327: Risk Factors for Adverse Outcomes in Term Infants With Congenital Heart Disease and Necrotizing Enterocolitis
Authors: Bakas Anna M , Moynihan Katie , Przybylski Robert , Braudis Nancy , Farr Bethany , Modi Biren P , Mills Kimberly I , Nathan Meena , Levy Philip T
Published: April 2024

Introduction:
Infants with congenital heart disease (CHD) are at increased risk of developing necrotizing enterocolitis (NEC), with mortality rates up to 57%. The aim of this study was to investigate pre-NEC factors associated with adverse outcomes in term infants with CHD-NEC.

Methods:
We performed a 20-year (2000-2020) single-institution retrospective cohort study in term infants (>37 weeks) <6 months of age admitted to the Boston Children’s Hospital Cardiac Intensive Care Unit with CHD-NEC (Bell’s stage
>
2). The primary outcome was a composite of in-hospital mortality and post-NEC morbidity (extracorporeal life support or surgical NEC). Predictors included baseline admission patient characteristics, cardiac diagnosis and intervention, feeding regimen, and severity of illness, as measured with the pediatric sequential organ failure assessment (pSOFA) score.

Results:
We identified 82 patients with CHD-NEC from 3933 admissions (prevalence, 2.1%), including 54 (66%) duct dependent and 55 (67%) with NEC post cardiac surgery. Twenty-seven (33%) met the primary outcome, (in-hospital mortality in 14 (17%) with 9 (64%) attributed to NEC). In univariate analysis, pre-NEC factors significantly associated with the primary outcome included female sex, fetal growth restriction, systolic dysfunction, older age and weight at NEC (
Table
). Feeding regimen (formula, caloric density), genetic conditions, APGARs, race, cardiac lesion, outflow tract z-score or STAT category had no impact on outcome. In multivariable analysis, peri-NEC pSOFA, lower weight and older age at NEC diagnosis remained significantly associated with the primary outcome
(Table)
.

Conclusions:
Radiologically-proven NEC occurred in 2% of term infants with CHD, with death and adverse post-NEC outcomes in more than one-third. Lower weight and older age at diagnosis were associated with adverse outcomes informing risk-triage and prognostic counseling for families.
Abstract 9337: Right Ventricular's Strain Behavior in Patients Treated With Chemotherapy / Radiotherapy in a Patient Cohort
Authors: Canahuate Grisel , Taveras Hiraldo Amparo , Rivera Eleana , Perez Saray , arias miguel
Published: April 2024

Introduction:
Is well known the usefulness of left ventricle (LV) longitudinal global strain (GLS) in patients receiving antineoplastic therapy but studies suggested a similar behavior of the right ventricle (RV) free wall longitudinal strain (FWLS). Still, many controversies exists that limit its evaluation, so this study is a contribution to this need for practicality.

Objective:
To assess the behavior and usefulness of RV FWLS in patients treated with chemotherapy and / or radiotherapy and its relationship with LV GLS.

Method:
A data collection protocol of demographic variables and personal history was applied to patients diagnosed with cancer treated with chemotherapy and/or radiotherapy who underwent an echocardiogram with strain at our center from November 2020 to March 2021. Echocardiogram performed accordingly with American Society of Echocardiography guidelines standards, including a LV GLS and a RV FWLS. The data was analyzed in the SPSS.

Results:
A total of 84 patients collected. Women 89%, mean age 59 ±11 years, 73% breast cancer. Hypertension 54%, 27% obesity, 23% dyslipidemia, 19% were diabetic and 11% smokers. Received concomitantly chemotherapy and radiotherapy 46% and 48% treatment was more than a year ago. Echocardiographic findings: mean LV ejection fraction (EF) 64±7 %, with LV GLS being reduced in 82% (44% being less than -15%). Similarly, 74% of RV FWLS was reduced, but only 15% of the S wave of the RV by tissue Doppler was abnormal, 7% of TAPSE was reduced, and 6% of fractional area change (FAC). The Pearson correlation coefficient between LV GLS and RV FWLS was 0.463 with a p value of <.001.

Conclusion:
Our study suggests that RV FWLS has a similar behavior as LV GLS and is a better predictor of RV dysfunction than conventional parameters and should be incorporated in echocardiographic evaluation of patients receiving antineoplastic therapy.
Abstract 9362: A Quality Improvement Project to Optimize TEE Orders and Reduce Hospitalization Cost at a Large Volume Academic Hospital
Authors: Modi Malak , Sultan Ali , Dawson Desiree , Douglass Kendall , Modi Kalgi A
Published: April 2024

Introduction:
Appropriate use criteria (AUC) for indication of transesophageal echocardiography (TEE) were revised in 2011.

Aim:
To evaluate the appropriateness of TEEs ordered at Ochsner LSU Health Shreveport based on 2011 AUC guidelines and take necessary steps to optimize the TEE workflow and reduce hospitalization cost.

Method:
A retrospective analysis of the TEE case requests received by the echocardiography lab at Ochsner LSU Health Shreveport between March 1, 2020 and August 31, 2020 was carried out. Each TEE case request was classified as appropriate (A), inappropriate (I) or uncertain (U) based on the 2011 AUC guideline. TEE case requests were divided based on the ordering specialty as well as indications.

Result:
Among the total 372 case requests for TEE,189 (50.80%) were ordered by cardiologists and 183 (49.20%) were ordered by non-cardiologists. Out of the 189 orders by cardiologists, 184 (97.35%) were appropriate and 5 (2.65%) were inappropriate. Cardiologists ordered 123 TEEs for Atrial fibrillation/flutter evaluation/management, 33 for valvular evaluation, 10 for evaluation of mass/vegetation, 3 for atrial mass evaluation, 10 for CVA workup and 10 for other reasons. Among the total 183 TEE orders placed by non-cardiologists, 125 (68.31%) were appropriate and 58 (31.69%) were inappropriate. Specialty-wise, Neurology placed 78 TEE orders (54-A, 24-I), Hospital Medicine placed 59 orders (38-A, 21-I) while other specialties placed 46 orders (33-A, 13-I). Most common indications for TEE requests by non-cardiologists were for CVA workup (62-A, 30-I) and infective endocarditis workup (21-A, 13-I).

Conclusion:
83% of all the TEE orders (309 out of 372) were appropriate. 97% (184 from 189) of the TEE orders by cardiologists were appropriate compared to 68% (125 from 183) orders by non-cardiologists. Following this result, medical providers were educated about the correct indications of TEE by educational presentation as well as distributing posters and pocket cards. Plan is to also evaluate the appropriateness of TEE orders post intervention phase. We believe that educating the physician providers can optimize the appropriate TEE requests, avoid unnecessary invasive procedures and reduce the hospitalization cost.
Abstract 9370: Myocardial Tissue Characterization of Pediatric Patients With Duchenne Muscular Dystrophy
Authors: Sunthankar Sudeep , George-Durrett Kristen , Crum Kim , Markham Larry W , Soslow Jonathan H
Published: April 2024

Introduction:
Cardiomyopathy (CM) is the leading cause of death in Duchenne muscular dystrophy (DMD). Cardiac magnetic resonance (CMR) parametric mapping sequences, Native T1, T2, and extracellular volume (ECV), can offer insights into disease pathophysiology. The objective of this abstract was to leverage parametric mapping sequences to define the tissue characteristics of DMD CM progression. We hypothesized DMD subjects could be categorized based on fibrosis, myocardial edema, and fat infiltration.

Methods:
DMD patients (n=52; median 12.1 years) underwent CMR including T1, T2, and ECV at the base, mid, and apex. Categories were defined as normal, early fibrosis (normal ECV, high T1, normal T2), fibrosis (high ECV, normal or high T1, normal T2), edema (normal or high ECV, normal or high T1, high T2), fat (normal ECV, low T1, high T2) or fibrofatty (high ECV, normal or low T1, high T2). Statistical analysis included Chi-square, Wilcoxon rank sum, Wilcoxon signed rank, and Spearman’s rho.

Results:
Median left ventricular ejection fraction (LVEF) was 59% and 15 (29%) had LVEF < 55%; 18 subjects (35%) had normal LVEF and no late gadolinium enhancement. These subjects were younger (10.2 years [8.4,11.6] vs 14.7 [11.5,17.8], p<0.001). Native T1 was elevated in at least one slice in 42 (81%). Patients with high T2 at any slice (n=13) were older (p=0.009) and had lower LVEF (p=0.009) compared with normal T2 (n=39). The most common stratifications (Figure 1) were early fibrosis (n=14) and fibrosis (n=21). Of the 13 with high T2, 9 were categorized as edema, 2 as fibrofatty, and 2 as fat. T2 at the base, mid, and apex increased from first to second CMR (all p<0.05) and T2 at mid and apex correlated with age (rho=0.2 and rho=0.38, p<0.05).

Conclusion:
Myocardial fibrosis is common in DMD. CM progresses with age and higher T2 suggesting fatty/fibrofatty infiltration. CMR parametric mapping sequences offer insights into disease pathophysiology, which should drive therapeutic innovation.
Abstract 9390: Mechanical Circulatory Support and Outcomes in Women versus Men
Authors: Pristera Nicole , Il'Giovine Zachary , Zheng Weili , Bakhtadze Beka , Cho Leslie
Published: April 2024

Introduction:
There has been a substantial increase in the use of temporary mechanical circulatory support (MCS) in cardiac intensive care, particularly driven by Impella and veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Sex-specific data in patients with MCS are limited. We report our single-center experience on characteristics and outcomes of women versus men supported with MCS.

Methods:
This was a retrospective study of all patients receiving Impella CP, 5.0, or 5.5 and/or VA-ECMO in our cardiac intensive care unit from January 1, 2019 to December 31, 2020. Primary outcomes were death and major MCS-associated complications, including bleeding, neurologic, and limb events as defined by the Extracorporeal Life Support Organization.

Results:
167 adult patients were included (22% female). Baseline characteristics between women and men were significantly different (Table). Non-acute myocardial infarction cardiogenic shock was the leading indication for MCS in both sexes. Impella CP was used most frequently in women, with only 3 (8.1%) women receiving Impella 5.0/5.5. In contrast, 50 (38.5%) men had Impella 5.0/5.5. VA-ECMO use was also lower in women (14.6% versus 33.1%, p=0.04). There was a trend toward higher bleeding, neurologic, and limb events in women, not statistically significant (35.1% vs 30.8%, p=0.61; 8.1% vs 2.3%, p=0.09; 21.6% vs 12.3%, p=0.15). In-hospital mortality was similar between women and men (43.2% vs 41.5%, p=0.85). Among survivors, women and men were equally likely to be discharged home (47.6% vs 57.9%, p=0.4).

Conclusions:
There were notable differences in baseline characteristics and device selection among women and men requiring MCS. There was a trend toward higher major complication rates in women, not reaching statistical significance likely due to small sample size with low number of events. Larger studies are needed to further explore sex-specific risk factor profiles and outcomes in the MCS population.
Abstract 9393: A Genetic Risk Score to Predict Peripheral Artery Disease and Acute Limb Ischemia in Patients With Cardiometabolic Disease
Authors: Patel Siddharth M , Marston Nicholas A , Melloni Giorgio E , Kamanu Frederick K , Roselli Carolina , Antman Elliott M , Bhatt Deepak L , Braunwald Eugene , Cannon Christopher P , Odonoghue Michelle L , Giugliano Robert P , Mosenzon Ofri , Scirica Benjamin M , Lubitz Steven A , Ellinor Patrick T , Bonaca Marc P , Sabatine Marc S , Ruff Christian T
Published: April 2024

Introduction:
GWAS have identified SNPs associated with an increased risk of peripheral artery disease (PAD). We sought to compare the performance of a genetic risk score (GRS) comprised of these SNPs with established clinical risk factors to predict PAD and acute limb ischemia (ALI) across five RCTs in cardiometabolic disease. Given high prevalence of coronary artery disease (CAD) in patients with PAD, we also evaluated the performance of the GRS for incident myocardial infarction (MI).

Methods:
Pts from the ENGAGE AF-TIMI 48, SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, and FOURIER trials were included in this analysis. ALI and MI were adjudicated by a blinded CEC comprised of vascular medicine specialists and cardiologists. A previously validated GRS (
Nature Medicine
2019) of 19 SNPs associated with PAD was calculated for each pt. ORs for PAD were calculated across genetic risk groups. HRs adjusted for clinical risk factors were calculated for ALI and incident MI.

Results:
Of 51,729 total pts included in this analysis, 5,149 (10%) had PAD at baseline. Pts in the top 20% of GRS had 47% higher odds of having PAD compared with those in the bottom 20% (adj OR 1.47, 95% CI 1.33-1.62; p<0.001). The magnitude of risk for PAD conferred by high GRS was similar to many established clinical risk factors (Figure). A total of 91 ALI events occurred over a median follow-up of 2.4 years. Pts in the top 20% of GRS were at 63% increased risk for ALI compared with those in the bottom 80% (adj HR 1.63, 95% CI 1.04-2.56.; p=0.03), consistent in those with and without PAD (p-interaction 0.85). The PAD GRS was also associated with incident MI (n=2323), with pts in the top 20% of GRS at 42% increased risk compared with the bottom 80% (adj HR 1.42, 95% CI 1.36-1.49; p<0.001).

Conclusions:
A 19-SNP GRS was a strong independent predictor of PAD and ALI in patients with cardiometabolic disease. The PAD GRS also predicted MI, supporting overlapping biological mechanisms for atherosclerosis across vascular beds.
Abstract 9804: Overexpression of Pericyte Hif2a Exacerbates Hypoxia Induced Pulmonary Hypertension and Right Ventricular Hypertrophy
Authors: Kim Hyunbum , Klouda Timothy , Kim Jiwon , Hu Cheng-Jun , Tian Wen , Jiang Xinguo , Stenmark Kurt R , Nicolls Mark , De Jesus Perez Vinicio , Yuan Ke
Published: April 2024

Introduction:
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by abnormally elevated pulmonary pressures and right-sided heart failure. Excessive accumulation of mural cells including pericytes surrounding the pulmonary vascular wall is one of the key pathological features seen in PAH. Whether pericytes contribute to other mural cell lineage and the underlying mechanisms responsible for their behavior are still elusive.

Hypothesis:
To evaluate the novel role of HIF2α signaling in pericytes in the pathogenesis of PAH.

Methods and Results:
NG2-Cre-ER mice are used to generate pericyte selective HIF2α overexpression (HIF2α
NG2-OE
) and HIF2α
NG2-OE
reporter mice (HIF2α
NG2-OE
tdT) via tamoxifen injection for cell lineage identification. Compared to control, HIF2α
NG2-OE
mice in chronic hypoxia have

significantly higher

right ventricular systolic pressure and right ventricular hypertrophy along with increased muscularization and a greater abundance of NG2
+
cells surrounding microvessels. Cellular lineage staining on HIF2α
NG2-OE
tdT reporter mice in chronic hypoxia show that tdT
+
cells accumulate in muscularized arterioles and exhibit significantly high levels of HIF2α protein, which initiates vascular cell proliferation and recruitment of inflammatory cells. Moreover, HIF2a over-expressed human pericytes exhibit greater contractility, impaired capacity to establish endothelial-pericyte communications, and loss of vascular integrity. Importantly, the HIF2a-targeted inhibitor attenuates hypoxia-induced pulmonary hypertension.

Conclusions:
HIF2α signaling in pericytes is a key mediator that contributes to abnormal vascular remodeling. Targeting HIF2α could potentially decrease pericyte migration as well as reducing vascular remodeling, therefore, serve as a potential treatment for certain forms of PH.
Abstract 9817: Krüppel-Like Factor 4 Integrates Immunometabolism of Human Arterial Endothelial Cells
Authors: Xiao Wusheng , Loscalzo Joseph
Published: April 2024

Introduction:
Inflammation and metabolic alterations are two common hallmarks of cardiovascular diseases. Yet, the molecular mechanisms integrating inflammation and cell metabolism remain elusive.

Objective:
We investigated whether Krüppel-like factor 4 (KLF4) serves as a link between cellular glucose metabolism and inflammation in human arterial endothelial cells.

Methods and Results:
Primary human pulmonary artery and aortic endothelial cells (PAEC and AoEC, respectively) were stimulated with tumor necrosis factor α (TNFα) or lipopolysaccharide (LPS). Results from fluorescent microscopy and Seahorse extracellular flux analysis revealed that TNFα and LPS enhanced glucose uptake by 2.2-fold, glycolysis by 2.3-fold, and mitochondrial respiration by 1.6-fold in PAEC and AoEC. The increase in glycolysis correlated with a 2-4-fold upregulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and PFKFB4, two key regulatory enzymes of glycolysis. Silencing
PFKFB3
but not
PFKFB4
entirely prevented TNFα-induced enhancement of glycolysis with a concomitant metabolic shift to mitochondrial respiration. Mechanistically, TNFα and LPS stimulated KLF4 mRNA and protein expression (2-4-fold), which functions as a transcriptional repressor of
PFKFB3
.
KLF4
knockdown potentiated TNFα-induced stimulation of PFKFB3 expression by 1.6-fold and glycolysis by 2.2-fold, effects which were completely prevented by co-silencing of
PFKFB3
. Functionally,
KLF4
silencing exacerbated TNFα-induced vascular cell adhesion molecule 1 (VCAM1) expression (by 2-3-fold), E-selectin secretion (by 2.8-fold), and monocyte adhesion (by 1.6-fold) in PAEC, all of which were attenuated by over 50% when PFKFB3 was inhibited by siRNA or with 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3-PO). By contrast,
KLF4
overexpression-mediated inhibition of inflammation was significantly counteracted in PAEC with co-overexpression of
PFKFB3
.

Conclusion:
These results indicate that KLF4 inhibits inflammation by normalizing PFKFB3-mediated enhancement of glycolysis and that the KLF4-PFKFB3 signaling axis integrates immunometabolism in human arterial endothelial cells.