bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12577: Pulmonary Endothelial Sulfatase-1 is Regulated by NEDD9 and Increased in Pulmonary Arterial Hypertension
Authors: Samokhin Andriy , Yefang Wang , Wertheim Bradley M , Alba George A , Arons Elena , Maron Bradley
Published: April 2024

Introduction:
Oxidation of the scaffolding protein NEDD9 by aldosterone (ALDO) increases NEDD9 bioactivity in human pulmonary artery endothelial cells (HPAECs), leading to pulmonary arterial hypertension (PAH). In tumor cells, oxidizing conditions alter Sulfatase-1 (SULF-1) activity. In turn, SULF-1 catalyzes 6-O-sulfate removal from heparan sulfate proteoglycans that releases cytokines implicated in the pathogenesis of PAH.

Hypothesis:
NEDD9 regulates SULF-1 expression in HPAECs, which is associated with pulmonary arterial remodeling in PAH.

Methods:
HPAECs were treated with ALDO (10
-7
mol/L) for 24 hr and then untransfected (Un-Tx) or transfected with siRNA against NEDD9, and cell lysates were used to isolate mRNA for RNA-Seq. Separately, SULF1 expression was measured by immunoblot in HPAECs transfected with si-NEDD9 or scrambled control siRNA. Paraffin-embedded lung specimens from donor controls (N=5), patients with PAH (N=5), or the monocrotaline (MCT) (inflammatory) and SU-5416/hypoxia (angioproliferative) experimental rat models of PAH were analyzed by immunofluorescence to quantify SULF1, NEDD9, and endothelial PECAM-1.

Results:
In ALDO-treated HPAECs, si-NEDD9 decreased SULF1 mRNA quantity vs. Un-Tx (logFC -6.39, N=3, P<0.001, FDR<0.001). Transfection with si-NEDD9 also decreased SULF1 protein compared to si-Scr (14 ± 2.0 vs. 2.7 ± 1.0 arb. units, N=3, P<0.01)
in vitro
. In remodeled pulmonary arterioles from MCT-PAH and SU-5416/hypoxia-PAH, SULF1 was increased by 5.6-fold (P<0.01) and 6.6-fold (P<0.01), respectively, and correlated strongly with NEDD9 protein (r=0.91, N=9, P<0.001). The translational relevance of these data was assessed next: compared to donor controls, pulmonary endothelial SULF1 was increased in remodeled pulmonary arterioles from PAH patients
in situ
(0.03 ± 0.01 vs. 0.14 ± 0.03 arb. units, P<0.05).

Conclusions:
SULF1 is regulated by the scaffolding protein NEDD9 in HPAECs
in vitro
, and remodeled pulmonary arterioles from two experimental PAH models and PAH patients express increased NEDD9-SULF1. Identifying the molecular mechanism(s) regulating NEDD9-dependent regulation of SULF1 may have important implications for therapeutic target discovery to prevent vascular remodeling in PAH.
Abstract 12591: Mitochondrial Dysfunction and Reticulocytes Maturation: Contribution to the Pathogenesis of Pulmonary Hypertension
Authors: Niihori Maki , James Joel , Valuparampil Varghes Mathews , Rafikov Ruslan , Rafikova Olga
Published: April 2024

Introduction:
Sugen/Hypoxia treated rats and idiopathic pulmonary arterial hypertension (PAH) patients have increased circulating levels of cell-free heme (CFH). However, the mechanisms responsible for the elevated CFH and its pathogenic role are not fully identified.

Hypothesis:
Mitochondrial energy plays a critical role in the maturation of the red blood cell precursors, reticulocytes (RTC). We propose that incomplete RTC maturation due to mitochondrial dysfunction (MD) could increase RTC fragility and rupture, elevate the plasma CFH and promote PAH.

Methods:
The rat model of severe MD induced by NFU1
G206C
mutation is associated with spontaneous PAH phenotype. This model was used to study erythropoiesis activation, total/immature RTC count, and plasma CFH levels. FITC-dextran extravasation was analyzed in fresh transversely cut pulmonary slices 24h after FITC-dextran injection (60 mg/kg. i.v.) by ChemiDoc MP Imaging System. The effects of free heme
in vitro
were evaluated using pulmonary arterial smooth muscle cells (PASMCs) isolated from NFU1
G206C
and WT rats.

Results:
NFU1
G206C
rats had increased erythropoietin levels and significantly higher total and immature RTC counts compared to WTs. In contrast, NFU1
G206C
rats with a restored mitochondrial function, achieved by a chronic supplementation with lipoic acid (LA,1.7 mM orally), had normalized total/immature RTC counts (WT/NFU1
G206C
/NFU1
G206C
+LA for total and immature RTC: 2.5±0.2%/4.4±0.3%/3.4±0.3%, p<0.002 and 2.2±0.4%/9.8±1.9%/0.8±0.2%, p<0.001, N=8-12). These changes corresponded to the significantly elevated plasma CFH levels and elevated extravasation of FITC-dextral in the lungs in untreated NFU1
G206C
rats, suggesting the disruptive effect of CFH on the pulmonary endothelial barrier. Finally, the exposure of PASMC isolated from NFU1
G206C
rats to heme (50μM) significantly increased the proliferation rate ~1.5 and ~2.9 folds compared to untreated NFU1
G206C
or WT PASMC.

Conclusions:
We conclude that MD mediates activation of erythropoiesis coupled with an impaired RTC maturation. These effects promote an increase in circulating CFH, disruption of endothelial barrier, and elevated rate of PASMC proliferation, contributing to the PAH pathobiology.
Abstract 12597: Phenotypic Drug Screen Reveals That Lacidipine, a Calcium Channel Blocker, Enhances the Vascular Lumen Formation
Authors: Nawrot Dorota , Yildiz Ozer Lutfiye , Al Haj Zen Ayman
Published: April 2024

Background:
Vascular lumen formation is a critical process of angiogenesis towards establishing a functional circulatory system capable of delivering oxygen and nutrients to tissues. Targeting lumen formation is required for the development of efficient therapeutic angiogenesis.

Objective:
Perform a drug screen to identify compounds regulating the vascular lumen formation using a novel 2D angiogenesis assay that mimics the lumen formation of blood vessels and suitable for high throughput applications.

Methods and Results:
First, we optimized the phenotypic angiogenesis assay that captures the cellular process of lumen formation. Human Umbilical Vein Endothelial Cells (HUVEC) were seeded on Matrigel-coated wells. A mixture of matrix gel was added on top of adhered HUVEC. HUVECs form luminized vascular-like structures in 48 hours. To identify modulators of lumen formation, we conducted a high content screen of a library containing 150 FDA-approved cardiovascular drugs. The screening resulted in five calcium channel blockers being able to increase the lumen area compared to controls. Lacidipine was selected for further mechanistic studies. We found the cells in the luminal space stained positively for activated caspase-3 at 24 hours using immunofluorescence. Pharmacological inhibition of RAC1 or caspase activity abolished the Lacidipine-enhancing effect on lumen formation, suggesting the involvement of apoptosis and cell polarization. Next, we found that the addition of ML7, an MLCK inhibitor, enhances the lumen formation by inducing apoptosis. In contrast, the addition of the ROCK inhibitor GSK429286 or blebbistatin, an inhibitor of non-muscle myosin II ATPase, did not affect the lumen formation. Using a Ca2+ biosensor imaging, Lacipidine reduces the intracellular Ca2+ oscillations amplitude in the migrating cells at the early stage (6 hours), whereas Lacidipine blocked these Ca2+ oscillations completely at the late stages (24-48 hours).

Conclusions:
This study highlights a novel high throughput phenotypic assay to evaluate vascular lumen formation. Our findings suggest that calcium signaling plays a vital role during lumen morphogenesis, and calcium channel blockers could be used for more efficient angiogenesis-mediated therapies.
Abstract 12600: Racial and Ethnic Disparities in the Management of Acute Myocardial Infarction Complicated by Cardiogenic Shock
Authors: Shankar Aditi , Patolla Sri Harsha , Sundaragiri Pranathi R , Vallabhajosyula Saraschandra
Published: April 2024

Background:
We sought to evaluate the impact of race/ethnicity on the in-hospital outcomes of acute myocardial infarction-cardiogenic shock (AMI-CS) in contemporary practice.

Methods:
This is a retrospective cohort study of AMI-CS admissions from the National inpatient Sample (2012-2017). Race was classified as White, Black and, Others (Hispanic, Asian/Pacific Islander, Native Americans). The primary outcome was in-hospital mortality, and secondary outcomes included use of invasive cardiac procedures, length of hospital stay and discharge disposition. Multivariate logistic regression and univariate analysis were used to analyze trends and outcomes.

Results:
We identified 203,905 (5.8%) AMI-CS admissions, of which 70.4% were White, 8.1% were Black and 15.7% of Other race. Black admissions were more often female, with lower socio-economic status, had higher comorbidities, and higher rates of non-ST-segment-elevation AMI-CS, cardiac arrest, and multi-organ failure. Black and Other races had lower rates of coronary angiography (69.3% vs 73.6% vs 75.3%), percutaneous coronary intervention (48.6% vs 54.8% vs 52.7%), coronary artery bypass grafting (15.1% vs 16.6% vs 19.7%) and mechanical circulatory devices (42.8% vs 43.7% vs 48.3%) compared to White races (all
p
<0.001). Unadjusted in-hospital mortality was comparable for White (33.3%) and Black (33.8%) and lower for Other race (32.1%). After multivariable regression, the mortality for Black (odds ratio [OR] 0.85 [95% confidence interval {CI} 0.82-0.88];
p
<0.001) and Other race (OR 0.97 [95% CI 0.94-1.00];
p=
0.02) was lower than White race. Admissions of Black race had longer hospital stay, and lower rates of discharges to home.

Conclusion:
Contrary to previous studies, this contemporary study of racial disparities in AMI-CS noted Black and Other races had lower in-hospital mortality despite lower rates of cardiac procedures compared to White admissions.
Abstract 12618: Feasibility of Non-Contrast Optical Coherence Tomography Imaging in Coronary Arteries
Authors: Kang Dong , Nam Hyeong Soo , Kim Sunwon , Yoo Hongki , Kim Jin Won
Published: April 2024

Background/Objectives:
Contemporary high-resolution intracoronary optical coherence tomography (OCT) requires injection of flushing media for image acquisition to avoid signal attenuation by red blood cells. There is a growing need for an alternative flushing media other than iodine contrast to reduce the risk of renal dysfunction. To address this issue, we investigated the safety and feasibility of pentastarch solution as a flushing media for OCT image acquisition and compared with the contrast media flushed images.

Methods/Results:
We prospectively enrolled 12 patients with 15 coronary lesions (12 stented lesions and 3 non-culprit lesions). Paired OCT images were obtained by manual injection of iodine contrast (average 12 mL), followed by pentastarch (average 18-20 mL). A total of 30 runs were analyzed and each OCT pullback was assessed on a frame-by-frame basis by automated customized pixel-wise comparison algorithm. The number of clear image segments (CIS) and pre-specified quantitative measurements were compared between the paired OCT images. Image quality as assessed by proportion of CIS showed no significant difference between the contrast media and pentastarch (98.5% vs. 97.5%; p=0.850). Quantitative measurements including minimal lumen area, mean lumen area, and pixel-wise blood flushing capability correlated well between the paired image segments (p<0.001) (Figure). There were no clinically relevant complications associated with OCT imaging with pentastarch administration such as anaphylactic reaction, life-threatening arrhythmia, heart failure, or acute renal deterioration.

Conclusions:
Intracoronary OCT using pentastarch is safe and technically feasible without affecting the optical signal intensity and overall image quality. Non-contrast imaging with pentastarch significantly reduces the obligatory iodine contrast load, therefore, could be considered as a promising strategy in high-risk patients for renal impairment.
Abstract 12627: Effects Of Lipid Control On Coronary Calcification
Authors: Alam Mustafa , Savinova Olga V
Published: April 2024

Introduction:
Lipid lowering drugs are some of the most prescribed medications to control coronary artery disease (CAD). The long-term lipid lowering effects on coronary artery calcium (CAC) progression remain a subject of controversy with inconclusive results from multiple literature reviews. The purpose of this meta-analysis is to elucidate the relationship between lipid control and CAC progression.

Methods:
A computerized search of MEDLINE was conducted using the search terms “coronary”, “calcification”, “statin”, and “lipid lowering.” Studies were included if they measured mean value changes from baseline in coronary calcium using cardiac computed tomography. Data were extracted from the articles using the Cochrane method. RevMan 5.4 was used to aggregate the studies and report statistics.

Results:
A total of 13 studies were included with a total of 6671 patients. LDL reduction amongst the studies was significant as compared to placebo or lower dose lipid lowering therapy (standardized mean difference [SMD]: -0.71; 95% CI: -0.79, -0.64; p<0.00001). A small increase in CAC was not statistically significant (standardized mean difference [SMD]: 0.10; 95% CI: 0.02, 0.17; p=0.19).

Conclusions:
Lipid lowering therapy shows efficacy in LDL reduction however, it does not lead to coronary calcium reduction. Further studies are needed to elucidate the long-term effects of lipid powering on CAC and the prognostic value of CAC in CAD parents receiving optimal therapy.
Abstract 12634: Impact of New-Onset Atrial Fibrillation (NOAF) versus Pre-Existing Atrial Fibrillation on Outcomes After Transcatheter Aortic Valve Replacement/Implantation (TAVR/TAVI)
Authors: Nso Nso , EMMANUEL KELECHI , Iluyomade Adedapo , Ayinde Hakeem
Published: April 2024

Background:
Aortic stenosis patients who undergo Transcatheter Aortic Valve Replacement/Transcatheter Aortic Valve Implantation (TAVR/TAVI) experience a high incidence of pre-existing atrial fibrillation and new-onset atrial fibrillation (NOAF) post-operatively. We aim to update current evidence concerning the incidence of 30-day mortality, stroke, acute kidney injury, length of stay, and early/late bleeding in TAVR/TAVI with NOAF or pre-existing atrial fibrillation (preAF).

Methods:
We searched Pubmed, Google Scholar, JSTOR, Cochrane Library and Web of Science for studies published between January 2012 and December 2020 that reported the association between NOAF/preAF and clinical complications after TAVR/TAVI. Relevant studies were included in our systematic review and meta-analysis. Our primary clinical outcomes included 30-day mortality, stroke, early bleeding, and late bleeding. The secondary clinical outcomes included acute kidney injury and extended length of stay.

Results:
We included 15 studies based on 158,220 TAVI/TAVR adult patients (>18 years of age) with NOAF or preAF. Compared to patients in sinus rhythm, TAVR/TAVI patients who developed NOAF had higher risk of 30-day mortality, acute kidney injury, early bleeding events, extended length of stay and stroke (OR: 3.18 [95% CI 1.58, 6.40]) (OR: 3.83 [95% CI 1.18, 12.42]) (OR: 1.70 [95% CI 1.05, 2.74]) (OR: 13.96 [95% CI, 6.41, 30.40]) (OR: 2.51 [95% CI 1.59, 3.97], respectively). Compared to patients in sinus rhythm, TAVR/TAVI patients with pre-AF had higher risk of acute kidney injury and early bleeding episodes (OR: 2.43 [95% CI 1.10, 5.35]) (OR: 17.41 [95% CI 6.49, 46.68], respectively). Pre-AF was not associated with an increase in 30-day mortality, late bleeding, stroke, and length of stay after TAVR/TAVI.

Conclusions:
The findings of our meta-analysis showed that atrial fibrillation (AF) was associated with higher risk of all primary and secondary outcomes. Specifically, NOAF but not pre-AF was associated with higher risk of 30-day mortality, stroke, and extended length of stay in TAVR/TAVI patients.
Abstract 12635: Mitochondria-Targeted NOX4 Overexpression Causes Restrictive Diastolic Dysfunction in a “Two-Hit” Mouse Model of HFpEF
Authors: Lozhkin Andrey , Vendrov Aleksandr E , Runge Marschall S , Madamanchi Nageswara R
Published: April 2024

Heart failure with preserved ejection fraction (HFpEF) prevalence increases with age. However, the pathophysiologic mechanisms of HFpEF are unknown and no specific treatment is available. NOX4 NADPH oxidase levels, particularly in mitochondria, increase with age and induce mitochondrial dysfunction. We previously showed that diastolic dysfunction patients’ hearts had higher NOX4, ROS levels and mitochondrial damage whereas mice with mitochondria-targeted NOX4 overexpression (
Nox4
TG) had impaired mitochondrial function and pronounced diastolic dysfunction. Here we investigated the effects of increased mitochondrial NOX4 levels on the pathophysiology of HFpEF using
Nox4
TG mice in a “two-hit” model.

The “two-hit” mouse HFpEF model is a combination of metabolic stress from high-fat diet and dysregulation of NO after treatment with L-NAME. Compared to wild-type,
Nox4
TG mice had significantly lower ATP-linked and maximal oxygen consumption rates in ventricular cardiomyocytes and showed a trend towards reduced exercise tolerance. Echocardiography analysis showed that both strains in “two-hit” model had increased E/E' versus controls, whereas
Nox4
TG mice had significantly prolonged isovolumic relaxation and mitral valve deceleration time. In addition, NOX4 overexpression significantly reduced cardiac output, suggesting restrictive diastolic dysfunction. MCP1 expression was significantly higher in left ventricle (LV) lysates and the percentage of CD11b
+
cells was higher in LV sections of
Nox4
TG mice. Myocardium flow cytometry analysis showed higher percentage of Ly6C
hi
macrophages with elevated TNFα expression in
Nox4
TG mice. TGFβ1 and osteopontin expression was also higher in the LV lysates. Picrosirius red and collagen I staining showed increased interstitial fibrosis in
Nox4
TG mice as in LV sections of patients with diastolic dysfunction. Congruently, percentage of periostin
+
and ACTA2
+
cells was significantly higher in
Nox4
TG mice, recapitulating findings in human LV sections.

Together, our data show that mitochondrial dysfunction leads to restrictive diastolic dysfunction through inflammation and fibrosis, suggesting that preserving mitochondrial function in aging is a potential therapeutic strategy for HFpEF.
Abstract 12640: Automated Pre-Operative Frailty Assessment in CABG: The Electronic Frailty Index
Authors: Crespo Eric , Davis Jared , Bordelon Rachel , Callahan Kate , Pajewski Nicolas M , Rangel Maria O , Zhao David X , Richardson Karl
Published: April 2024

Introduction:
Frailty results in decreased capacity to respond to physiologic stress, increasing risk of adverse outcomes following surgery. There is no standard tool for quantifying frailty in the pre-operative setting; available screening tools are resource intensive and typically focus on comorbidity. Many patients who undergo Coronary Artery Bypass Grafting (CABG) are medically frail. The electronic Frailty Index (eFI), based on the theory of deficit accumulation, is an automated score embedded in the electronic health record (EHR) at our institution that integrates 54 deficits assessing outpatient vital signs and labs, comorbidity, polypharmacy, and functional status. This study aims to assess the clinical utility of the eFI in preoperative risk stratification among patients who underwent CABG.

Methods:
Single institution, retrospective cohort study of patients that underwent CABG from January 2017 to July 2020. Exclusion criteria included patients with insufficient pre-operative EHR data for the eFI, INR >1.5, total bilirubin >2, and CABG >5 days after admission. Outcomes included length of stay (LOS) and discharge destination (home vs acute care facility). Patients’ eFI score prior to surgery was classified as fit (0-0.10), pre-frail (>0.10-0.21), or frail (>0.21). Data were analyzed using multivariable linear regression and area under the curve.

Results:
414 patients, mean age = 68.7 (SD 7.4) years, underwent CABG, with 49.3% categorized at pre-frail and 30.2% as frail. Both mean LOS (fit 7.0 days, pre-frail 7.3 days, frail 9.7 days) and the likelihood of being discharged to an acute care facility (fit 21.6%, pre-frail 19.6%, frail 34.1%) were increased for patients classified as frail. The eFI was the only variable we considered that was associated with LOS (p=0.006), while both age (p<0.001) and the eFI (p=0.005) were associated with discharge location. Adding the eFI to a classifier based on age and sex improved the AUC from 0.627 to 0.671 for LOS < 6 days vs >6 days, and from 0.675 to 0.695 for discharge destination.

Conclusions:
The eFI was a strong predictor of LOS and discharge to an acute care facility after CABG. Automated tools such as the eFI should be considered preoperatively when discussing potential revascularization options.
Abstract 12645: National Trends, Predictors and Outcomes of Inpatient Palliative Care Use in Cardiac Arrest Complicating Acute Myocardial Infarction
Authors: Patlolla Sri , Kanwar Ardaas , Vallabhajosyula Saraschandra
Published: April 2024

Introduction:
Multi-disciplinary care with integration of the palliative care services (PCS) in acutely ill cardiac patients is known to improve resource utilization and overall patient care. However, there are limited data on the role of PCS in the care of acute myocardial infarction (AMI) patients with cardiac arrest (CA).

Methods:
We used the National Inpatient Sample (2000-2017) to identify adult AMI admissions with concomitant CA. We evaluated temporal trends and predictors of PCS use, and in-hospital mortality, length of stay, and discharge disposition in AMI-CA admissions with and without PCS use. A propensity matching analysis using 1:1 nearest neighbor matching was performed between cohorts with and without PCS use to derive a propensity-matched sample with standardized differences <5% for all baseline characteristics.

Results:
During the study period, there were a total of 584,263 AMI-CA admissions, of which 26,919 (4.6%) received PCS. PCS use increased from <1% in 2000 to 11.5% by 2017. AMI-CA admissions that received PCS were on an average older (70.1 ± 13.0 vs 66.7 ± 13.5), had greater comorbidity with higher rates of cardiogenic shock (44.5% vs 26.6%) and non-cardiac organ failure (80.6% vs 41.6%)(all p<0.001). Admissions receiving PCS had lower rates of angiography (48.6% vs 63.3%) and percutaneous coronary intervention (37.4% vs 46.9%) use (p<0.001). Older age, greater comorbidity, and acute organ failure were independently associated with PCS use. In-hospital mortality was higher in the PCS cohort (84.6% vs 42.9%, adjusted odds ratio 3.62 [95% CI 3.48-3.76]; p<0.001). Similar findings were seen in the propensity-matched cohort with higher in-hospital mortality for AMI-CA admissions receiving PCS (84.7% vs 66.2%, p<0.001) The PCS cohort had higher do-not-resuscitate status use (47.6% vs. 3.7%), shorter hospital stays (4 vs 5 days), and more frequent skilled nursing facility discharges (73.6% vs. 20.4%); p<0.001.

Conclusions:
Despite an increase in PCS use in AMI-CA, it remains significantly underutilized, highlighting the need to further integrate PCS specialists into the care of high-risk conditions such as cardiac arrest to deliver holistic patient care.
Abstract 12650: Clinical Outcomes of Fractional Flow Reserve (FFR) versus Instantaneous Wave-Free Ratio (IFR) versus Coronary Angiography (CAG) Guided Cardiovascular Procedures, Including PCI (Percutaneous Coronary Intervention) and CABG (Coronary Artery Bypass Grafting): A Systematic Review and Meta-Analysis
Authors: Nso Nso , Choudhary Khushal , Enoru Sostanie , Marmur Jonathan D
Published: April 2024

Background:
Recent evidence from two systematic reviews and meta-analysis advocates the superiority of fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) guided PCI (percutaneous coronary intervention) and CABG (Coronary Artery Bypass Grafting) in improving the clinical outcomes of CAD (coronary artery disease) patients. We aimed to expand this evidence and comparatively analyze the efficacy/safety of FFR-guided, iFR-oriented, and CAG (coronary angiography)-guided PCI/CABG.

Methods:
We utilized PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework and extracted randomized controlled trials/ observational (retrospective/prospective studies) concerning FFR/iFR/CAG-guided PCI/CABG on 05/27/2021. We explored JSTOR, PubMed/Medline, Cochrane Library, EMBASE, Google Scholar, CINAHL, and Scopus to identify and track the articles of interest published from January 2005 until December 2020. We constructed forest plots and funnel plots to investigate several clinical endpoints related to FFR/iFR/CAG-oriented cardiovascular interventions.

Results:
The meta-analysis results indicated higher potential of FFR-guided PCI/CABG to minimize all-cause mortality (OR: 0.73, 95% CI 0.56, 0.94) (p=0.01), cardiovascular death (OR: 0.73, 95% CI 0.43, 1.24) (p=0.25), hospitalization (for heart failure, unstable angina, or chest pain) (OR: 0.73, 95% CI 0.42, 1.27), MACE (OR: 0.65, 95% CI 0.51, 0.82) (p=0.0005), bleeding (OR: 0.72, 95% CI 0.24, 2.09), MI (OR: 0.85, 95% CI 0.73, 0.99), and unplanned revascularization (OR: 0.61, 95% CI 0.40, 0.94) (p=0.03) compared to CAG-guided cardiovascular procedures. The results also proved non-inferiority of iFR-guided PCI/CABG to FFR-guided PCI/CABG (OR: 0.66, 95% CI 0.40, 1.11) (OR: 1.03, 95% CI 0.84, 1.27) (OR: 0.42, 95% CI 0.11, 1.62) (OR: 0.55, 95% CI 0.15, 2.05).

Conclusion:
The findings of this systematic review/meta-analysis increase the scope of replacing CAG-guided PCI/CABG with FFR/iFR-guided procedures to improve patient outcomes. Future studies should strengthen current evidence concerning FFR/iFR-guided cardiovascular interventions to enhance their utilization across wider subsets of patients with coronary artery disease.
Abstract 12656: Atrial Speckle Tracking Echocardiography for Detecting Atrial Fibrillation in Cryptogenic Stroke: A Meta-Analysis
Authors: Hassib Mohab , Barssoum Kiro , Chowdhury Medhat , Mannumbeth Renjithlal Sarath Lal , Abumoawad Abdelrhman , Hamilton Steven , Elkhouly Ahmed , Haq Muhammad , Bchech George , Bhat Vivek , Victor Varun , Kumar Ashish
Published: April 2024

Introduction:
Cryptogenic stroke (CS) accounts for approximately twenty-five percent of ischemic stroke cases with atrial fibrillation (AF) accounting for thirty percent of CS cases. We aimed to investigate the utility of atrial speckle tracking (STE) in identifying patients at high risk of AF after CS and potentially guiding patients who will benefit from long term rhythm monitoring devices.

Methods:
Cochrane Library, MEDLINE, and EMBASE were searched for relevant studies. We included studies that examined patients with new CS without a history of AF, and further examined LA strain parameters (peak and/or reservoir strain). Continuous data were pooled as a mean difference (MD) comparing patients who developed AF versus(vs) no AF. We used inverse variance method with Paule-Mandel estimator for tau2 and Hartung-Knapp adjustment, for random effect analysis. Hazard ratios were pooled using a similar statistical method. I2 was used to assess heterogeneity.

Results:
Eleven observational studies met our criteria, and included 2834 patients with new CS. Of those, 377 patients developed AF on follow up and 2457 patients did not develop AF. The AF group vs no AF had significantly reduced LA reservoir strain (LARS) [MD: -8.95; 95% CI: -11.33, -6.57) I2= 85%, p<0.001] at presentation. Further, a higher LARS was associated with a significantly lower incidence of AF after CS[HR: 0.93; 95%CI:0.89, 0.97)I2=0%].

Conclusion:
Atrial reservoir strain is significantly lower in patients who developed AF after CS and a lower value is predictive of AF. More studies are needed to validate this data.
Abstract 12672: A New Genetic Model Organism for Primate-Specific Cardiac Function and Disease
Authors: Chang Stephen , Krasnow Mark
Published: April 2024

Introduction:
Due to differences in cardiac structure and function, it has become increasingly clear that many aspects of cardiovascular disease are not well modeled in mice. This has spurred a search for new model organisms with the practical advantages of mice but that more closely mimic human biology. This study examines mouse lemur (Microcebus species) - the world’s smallest, most prolific, and among the most abundant non-human primates - and the cheapest and easiest to maintain, as such a model.

Methods:
This study characterizes the normal cardiac anatomy and histology, and baseline values for heart rate, cholesterol, and cardiac waveform by ECG (a point-of-care blood assay and a portable 3-lead monitoring device were used to screen ~400 animals). It also describes the development of a whole genome and single cell RNA-sequencing and analysis pipeline for Microcebus murinus.

Results:
Transcriptomic analysis identified 6000 cardiac cells, including all major and many minor cardiac cell types, including several exceedingly rare cell types. The lipid profiles of these animals more closely resembled that of humans, with an average LDL level of 81 mg/dL, with several obese animals having values >200. 20 naturally-occurring ECG variants were identified, all resembling known human ECG variants including 8 major cardiac arrhythmias. The screen uncovered the first cases of heart disease in lemurs. One is atrial fibrillation; Another is sick sinus syndrome (SSS), whose human familial form arises from mutations in ion channel genes, HCN4 or SCN5A. Both arrythmias show familial clustering, with the SSS pedigree exhibiting an autosomal dominant inheritance pattern. SNP/variant analysis revealed 30 million variants in the SSS animals, and ongoing work has narrowed these to just a handful of high impact, functional variants in SCN5A, suggesting that the underlying mouse lemur SSS disease gene and causative mutation are the same as in humans.

Conclusions:
The results establish the mouse lemur as the first systematic, high-throughput primate genetic model for cardiovascular physiology and disease, and reveal human-like cardiac cell types and diseases. The approach uncovered naturally-occurring cardiac diseases that have not been found in mice.
Abstract 12676: Hypertrophic Cardiomyopathy in Infants of Diabetic Mothers is Associated With Significantly Worse In-Hospital Outcomes: A Multicenter Analysis
Authors: Collins Ronnie T , Bond Elizabeth G , Bolin Elijah H
Published: April 2024

Introduction:
Hypertrophic cardiomyopathy (HCM) is a known complication among infants of diabetic mothers (IDMs). Ventricular outflow tract obstruction is common in these newborns, often necessitating therapy with beta-blockers. Because of relatively small sample sizes, the in-hospital outcomes of IDMs with HCM are unknown.

Hypothesis:
HCM in IDM is associated with increased in-hospital mortality.

Methods:
We performed an analysis of all newborns with a diagnostic code for IDM admitted from 2004 to 2020 to one of the 49 children’s hospitals in the Pediatric Hospital Information System. Those with a diagnostic code for HCM were assigned to the HCM, and those without were assigned to the comparison group (No-HCM). Outcomes of interest included vasopressor use, cardiac arrest, use of extracorporeal membrane oxygenation (ECMO), length of stay, mechanical ventilation, and in-hospital mortality. Standard statistical techniques were used to assess differences between groups.

Results:
There were 37,085 IDMs (55% male) in the study cohort, 677 (1.8%) with a diagnosis of HCM. Prematurity was more common in No-HCM (43% versus 33%, p<0.001), and birthweight was lower in No-HCM (3.3 kg [IQR: 2.5-3.9] versus 4.0 kg [IQR: 3.4-4.6], p<0.001). HCM was twice as common in Black IDMs (3.1%) compared to White IDMs (1.6%)(p<0.001). As shown in the Table, HCM was associated with all study outcomes of interest.

Conclusions:
HCM is diagnosed twice as often in Black IDMs as White IDMs. HCM in IDMs is associated with multiple negative, in-hospital outcomes, including mortality. Further investigation is needed to determine if specific management strategies can ameliorate these negative outcomes.
Abstract 12677: Multidimensional Sleep Health is Associated With Cardiometabolic Health in a Nationally Representative Sample of US Adults
Authors: Makarem Nour , Alcantara Carmela , Musick Sydney , Quesada Odayme , Chen Ziyu , Tehranifar Parisa
Published: April 2024

Introduction:
Sleep characteristics have been independently linked to cardiometabolic health, but sleep dimensions do not occur in isolation. Multidimensional sleep health predicts CVD mortality; however, associations with cardiometabolic health have not been evaluated.

Hypothesis:
Favorable multidimensional sleep health would be related to lower odds for hypertension (HTN), type 2 diabetes (T2D), obesity, and central adiposity.

Methods:
Participants were 4,559 adults aged ≥20 y from the 2017-18 National Health and Nutrition Examination Survey. A multidimensional sleep health score was computed from self-reported sleep duration, timing/regularity, and latency, snoring habits, and daytime sleepiness (Table); scores of 0-1, 2-3, and 4-5 indicated poor, moderate, and ideal sleep health, respectively. Survey-weighted linear and logistic models examined associations of multidimensional sleep health with blood pressure (BP), fasting glucose, anthropometric measures, and odds of cardiometabolic disease.

Results:
Ideal vs. poor sleep health was related to 66%, 58%, 73%, and 69% lower odds of HTN, T2D, obesity, and central adiposity, respectively (Table), and a linear trend was detected across the gradients of sleep health. In linear models, those with ideal and moderate vs. poor sleep health had lower BP, fasting glucose, BMI, and waist size. When sleep dimensions were examined separately, never/rare snoring, not having difficulty falling asleep, and never/rare daytime sleepiness were related to up to 46%, 51%, 58%, and 54% lower odds of HTN, T2D, obesity, and central adiposity, respectively (p<0.05). Sufficient sleep duration (7-9 h vs. <7 h or ≥9 h) was related to 29% lower odds for HTN (OR (95%CI): 0.71 (0.56-0.92)).

Conclusions:
Poor sleep health was associated with prevalent HTN, T2D, obesity, and central adiposity in US adults. Prospective studies are needed to decipher the role of sleep health in lowering CVD risk and extending healthspan.
Abstract 12681: Implication of Aurora Kinase B in Pulmonary Arterial Hypertension
Authors: Sauvaget Melanie , Lemay Sarah-eve , Breuils Bonnet Sandra , Orcholski Mark , Mkannez Ghada , Schimauchi Kana , Paulin Roxane , Potus François , BOUCHERAT Olivier , Bonnet Sebastien
Published: April 2024

Objective:
Pulmonary arterial hypertension (PAH) is a vascular disease characterized by a progressive remodelling of pulmonary arteries (PAs). This leads to an elevation in PA pressure and resistance, leading to right heart failure and death. Nowadays, it is recognized that PA smooth muscle cells (PASMCs) are key actors in the histopathological changes in PAH. As seen in cancer cells, PASMCs exhibit a pro-proliferative and anti-apoptotic cancer-like phenotype, sustained by an important metabolic switch known as Warburg effect. Aurora kinase B (AURKB) is strongly involved in cell proliferation, apoptosis and metabolism by controlling cell cycle activation and mitochondrial functions. Previous research has shown that AURKB is overexpressed in various human cancers and its inhibition repressed tumor progression both in vivo and in vitro, suggesting that it could be a novel therapeutic target in PAH. We thus hypothesized that AURKB is upregulated in PAH and contributes to PAH-PASMCs proliferation and resistance to apoptosis, inhibition of which may reverse PA remodeling.

Methods/Results:
Using Western blot (WB), we demonstrated a FOXM1-dependent upregulation of AURKB in PASMCs isolated from PAH patients compared to controls (p<0.05 ; n=8-14). Similar results were found in the monocrotaline (MCT) and sugen-hypoxia (Su/Hx) rat models (p<0.05 ; n=11-22). In vitro, we found that pharmacological inhibition of AURKB significantly decreases PAH-PASMC proliferation (EdU incorporation, Ki67 labeling) as well as resistance to apoptosis (Annexin V assay) (p<0.05 ; n=6). We also demonstrated that inhibition of AURKB decreases pro-survival factors such as Survivin and PLK1 and increases apoptosis and cell cycle arrest factors including P21, P27, and P53 (WB; p<0.05 ; n=6). As expected, inhibition of AURKB in PAH-PASMCs was associated with a dose-dependent decrease of phosphohistone H3 expression, a well-known target of AURKB (p<0.05 ; n=6). The therapeutic potential of Barasertib, a clinically available and specific AURKB inhibitor, is currently investigated in both MCT and Su/Hx models.

Conclusion:
Our preliminary data suggests the contribution of AURKB in PA remodeling and the great potential of using AURKB inhibitors to reverse PAH development.
Abstract 12686: Frailty is Associated With Perioperative Major Adverse Cardiovascular Events After Non-Cardiac Surgery
Authors: Siddiqui Emaad , Banco Darcy , Berger Jeffrey , Smilowitz Nathaniel
Published: April 2024

Introduction:
Frailty is increasingly recognized for its association with adverse outcomes after surgery, but its excess risks have not been characterized in large representative cohorts. We investigated the prevalence of frailty and the associated incidence of major adverse cardiovascular events (MACE) among those hospitalized for non-cardiac surgery.

Methods:
Adults aged ≥45 years hospitalized for non-cardiac surgery between 2004-2014 were identified from the Healthcare Cost and Utilization Project’s National Inpatient Sample. A validated Hospital Frailty Risk Score (HFRS) based on International Classification of Diseases codes was used to classify patients as low (<5), medium (5-15), or high (>15) frailty risk. The primary outcome was MACE, defined as in-hospital mortality, myocardial infarction, and cardiac arrest. Multivariable logistic regression was used to estimate the adjusted odds of MACE by HFRS.

Results:
A total of 55,349,978 hospitalizations were identified, of which 81%, 18%, and 1% had low, medium, and high HFRS, respectively. Patients with higher HFRS had a greater burden of cardiovascular risk factors and comorbidities (Table). MACE occurred during 2.5% of all hospitalizations and was more common in patients with higher HFRS (high: 8.4%, medium: 7.4%, low: 1.3%, p<0.001). Compared to low HFRS, medium (adjusted odds ratio [aOR] 2.34, 95% CI 2.31-2.38) and high (aOR 2.49, 95% CI 2.42-2.56) HFRS were associated with greater odds of MACE. The association between high (versus low) HFRS and MACE was consistent across age groups (aOR 4.26 [95% CI 3.96 - 4.57] for ages 45-64, aOR 2.64 [95% CI 2.51 - 2.79] for ages 65-74, and aOR 2.80 [95% CI 2.72 - 2.89] for ages ≥75).

Conclusion:
Higher frailty scores are associated with increased risks of MACE overall and within age subgroups. Implementation of HFRS as a standardized, electronic health record-based screening tool may identify frail surgical inpatients at risk for adverse perioperative outcomes.
Abstract 12760: Association of Machine Learning-Derived Measures of Body Fat Distribution in >40,000 Individuals With Cardiometabolic Diseases
Authors: Agrawal Saaket , Klarqvist Marcus D , Diamant Nathaniel , Ellinor Patrick T , Mehta Nehal N , Philippakis Anthony , Ng Kenney , Batra Puneet , Khera Amit V
Published: April 2024

Background:
Obesity is defined based on body-mass index (BMI), a proxy for overall adiposity. However, for any given BMI, individuals vary substantially in fat distribution. The clinical implications of this variability are not fully understood.

Methods:
We studied MRI imaging data of 40,032 UK Biobank participants. Using previously quantified visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volume in up to 9,041 to train convolutional neural networks, we quantified these depots in the remainder of the participants. We derived new metrics for each adipose depot - fully independent of BMI - by quantifying deviation from values predicted by BMI (e.g. VAT adjusted for BMI, VATadjBMI) and determined associations with cardiometabolic diseases.

Results:
Machine learning models based on two-dimensional projection images enabled near-perfect estimation of VAT, ASAT, and GFAT, with r
2
in a holdout testing dataset >0.97 for each. Using the newly derived measures of local adiposity - residualized based on BMI - we note marked heterogeneity in associations with cardiometabolic diseases. Taking presence of type 2 diabetes as an example, VATadjBMI was associated with significantly increased risk (odds ratio per standard deviation increase (OR/SD) 1.49; 95%CI: 1.43-1.55), while ASATadjBMI was largely neutral (OR/SD 1.08; 95%CI: 1.03-1.14) and GFATadjBMI conferred protection (OR/SD 0.75; 95%CI: 0.71-0.79). Similar patterns were observed for coronary artery disease.

Conclusions:
For any given BMI, measures of local adiposity have variable and divergent associations with cardiometabolic diseases.
Abstract 12767: Accuracy of Trans-Thoracic Echocardiography vs. Cardiac Magnetic Resonance for Assessment of Ventricular Aneurysms in Patients With Chagas Disease
Authors: Medina Ramon , Manrique Frida T , Vargas Vergara Diana , González Russi Lorena , Forero Julian , Fajardo Jorge , Diaztagle Juan José , Brugada Josep , Olaya Alejandro , Díaz Andrés , Medina Hector M.
Published: April 2024

Introduction:
Chagas disease is highly prevalent in Latin America and, due to migration, this condition is being diagnosed more frequently in developed countries. Trans-thoracic echocardiogram (TTE) is routinely used to evaluate these patients, in whom ventricular aneurysms (VA) are common. We aim to compare the accuracy of TTE vs. cardiac magnetic resonance imaging (CMR) as the gold standard for diagnosing VA.

Methods:
We performed TTE and CMR the same day in a prospective cohort of Chagas disease patients and no history of coronary artery disease. We classified VA′s according to their location and the apical ones were subclassified as follows: Microaneurysms (limited to the segment AHA-17), macroaneurysms (with extension to all apical segments), and giant aneurysms (with extension to midventricular segments).

Results:
A total of 79 patients were included. Of these, 57% were women with a median age of 60 years old (IQR 51-69) and a prevalence of VA of 24%. TTE had an overall sensitivity for VA of 47% (95% CI: 24 - 69%), specificity of 98% (95% CI: 95 -100%), positive predictive value of 90% (95% CI: 71 - 100%) and negative predictive value of 86% (95% CI: 77 - 93%) compared to CMR. Of notice, the TTE sensitivity for giant aneurysms was 100% (95% CI: 100 - 100%), for macroaneurysms was 54% (95% CI: 25 - 83%), and 0% (95% CI: 0 - 0%) for microaneurysms.

Conclusions:
The TTE sensitivity for VA in Chagas disease patients is limited and proportional to the size of the defect. Of notice, the specificity and positive predictive values are high. In patients with Chagas disease, CMR may be needed during the course of disease for optimal left ventricular wall characterization.
Abstract 12769: Neutrophil
Peptidylarginine Deiminase 4
is Essential for Detrimental Age-Related Cardiac Remodeling in Mice
Authors: Van Bruggen Stijn , Martinod Kimberly , Witsch Thilo , Frederix Liesbeth , Carai Paolo , Van wauwe Jore
Published: April 2024

During a period of chronic inflammation, such as in aging, neutrophils have a decreased threshold for activation. Neutrophils express
peptidylarginine deiminase 4
(
PAD4
), an enzyme which converts arginine residues to citrulline, resulting in chromatin decondensation and formation of neutrophil extracellular traps (NETs). These NETs have been shown to be prothrombotic and proinflammatory. However, their specific contribution to cardiac remodeling remains elusive.

We hypothesized that during chronic inflammation, neutrophil PAD4, via NETs, promotes cardiac damage and resultant tissue fibrosis.

We therefore generated neutrophil-specific
PAD4
knockout mice (PAD4
fl/fl
MRP8Cre
+
), confirmed they have a NET defect, and assessed the effect of this deletion on cardiac tissue during natural aging. These mice, as well as PAD4
fl/fl
(WT) littermate controls, were aged for two years, after which cardiac function, remodeling-related gene expression, and tissue remodeling were measured. Young and healthy (YH) controls (8-12 weeks old) were assessed in parallel.

We saw that systolic function, via ejection fraction (EF), in old WT mice (53±10%, n = 24) was significantly decreased as compared to old PAD4
fl/fl
MRP8Cre
+
(67±7%, n = 14, P = 0.002). Which in turn was not different from the YH group (67±6%, n = 11, P = 0.86). In addition, old WT mice had a deterioration in diastolic function (E/A) (1.21±0.17) as compared to old PAD4
fl/fl
MRP8Cre
+
(1.38±0.21, P = 0.0326), while there was no difference with the YH group (1.50±0.23, P = 0.48). Histological examination revealed that collagen deposition in the heart tissue was negatively correlated to systolic function. Analysis of cardiac gene expression shows a significant downregulation of CCL12, CCN2, CCL3, Col1α3, and MMP13, and upregulation of Col3α1 and TIMP4 in old PAD4
fl/fl
MRP8Cre
+
mice compared to old WT mice.

In conclusion, lack of PAD4 in neutrophils results in healthy cardiac aging, due to the absence of increased collagen deposition in the heart muscle. This can be explained by reduced production of pro-inflammatory cytokines by the heart, resulting in less immune cell recruitment and activation, and a decrease in growth factor expression, inhibiting downstream fibroblast proliferation and collagen deposition.
Abstract 12770: Using the Socioecological Model to Explore Barriers to Healthcare Provision in Rural Communities in the Philippines
Authors: Evangelista Lorraine S , Lorenzo Elizabeth
Published: April 2024

Background:
Basic healthcare in the Philippines is provided via rural healthcare clinics (RHC) located in barangays and supervised by provincial health centers. These RHC are the cornerstone of the country's public health system and were designed to promote and prevent disease through basic healthcare services and education. However, RHC became nonfunctional during the COVID pandemic leaving the community without the resources necessary to address the acute problems associated with COVID and chronic conditions. Given the crucial role of RHC in disease prevention and control, identifying barriers to providing its services and programs is warranted.

Aims:
The purpose of this qualitative study was to explore multilevel barriers to the provision of healthcare services and education in RHC.

Methods:
We used a qualitative approach and the socioecological model as a framework to investigate the multilevel barriers affecting resource access at RHC. Four public health nurses and fifteen community healthcare workers (CHW) from five RHC across the country participated in individual interviews and group discussions. Traditional content analysis was used to examine the data.

Results:
Findings revealed barriers at the individual (insufficient motivation, incorrect beliefs), interpersonal (insufficient ability of CHW to provide services, and lack of training, unrealistic expectations, and lack of supervision and monitoring of CHW), organizational (excessive workload for CHW, lack of resources, inadequacy of evaluation and monitoring of CHW), community (lack of trust in CHW by people, lack of motivation to seek healthcare, continued belief in traditional healers), and policy (lack of financial support for RHC, lack of an organized system to meet community needs) levels.

Conclusion:
Examining individual, interpersonal, community, and policy level determinants that affect RHC can inform community-based health promotion interventions for the country's rural communities. Given the multidimensional barriers identified, it is recommended that a comprehensive program be developed and implemented in collaboration with licensed healthcare providers, CHW, district and regional healthcare department representatives, and healthcare policymakers.