bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12757: Impact of Social Vulnerability on Cardio-Oncology Mortality in the United States
Authors: Ganatra Sarju , Dani Sourbha , Kumar Ashish , Khan Safi U , Neilan Tomas , Thavendiranathan Paaladinesh , Barac Ana , Hermann Joerg , Leja Monika , Deswal Anita M , Fradley Michael , Liu Jennifer , Ky Bonnie , Sadler Diego B , Asnani Aarti , Baldassarre Lauren A , Gupta Dipti , Yang Eric , Guha Avirup , Brown Sherry-Ann , Wadhera Rishi , Kazi Dhruv S , Stevens Jennifer P , Hayek Salim , Baron Suzanne J , Nasir Khurram , Nohria Anju
Published: April 2024

Introduction:
Racial and social disparities affect cancer and CVD-related mortality. The relationship between social vulnerability and concomitant cancer and CVD (cardio-oncology) related mortality remains understudied.

Methods:
We used the CDC Wide-Ranging OnLine Data for Epidemiologic Research (WONDER) database to determine the association between deaths attributed to the presence of concomitant CVD and cancer (ICD-10 codes I00-I09, I11, I13, I20-I51 and C00-C96), and the county-level social-vulnerability index (SVI). SVI measures a community’s vulnerability based on socioeconomic status, household composition, disability, minority status, language, and transportation. We aggregated counties by SVI quartiles (1st: most favorable = 0.00 to 0.25; 4th: least favorable = 0.75 to 1.00) and compared age-adjusted mortality rates (AAMRs) across SVI quartiles.

Results:
Between 2014 and 2018, the AAMR due to concomitant cancer and CVD was 47.75 (95% CI, 47.66- 47.85) per 100,000 person-years with higher mortality in areas with a higher SVI (Figure). Similarly, CVD and cancer-related mortality was also significantly greater in counties with the highest SVI [(CVD: 1.287 (95% CI 1.284-1.290); Cancer: 1.087 (95% CI 1.084-1.091)]. Moreover, the proportional increase in cardio-oncology mortality between the highest and lowest SVI counties was greater than that observed for CVD or cancer-associated mortality alone (p<0.001). This difference was most striking in adults < 45 years, females, Asian and Pacific Islanders, and Hispanics.

Conclusion:
A graded increase in cardio-oncology mortality is observed in counties with higher social vulnerability. The incremental impact of SVI was greater for cardio-oncology mortality than for cancer or CVD mortality alone, particularly in certain demographic groups. These findings highlight the need for targeted resource allocation and public health interventions to address social inequities in cardio-oncology.
Abstract 12763: High Innate Aerobic Capacity Protects Against Angiotensin II-Induced Hypertension and Vascular Remodeling
Authors: Stevenson Mark D , Canugovi Chandrika , Vendrov Aleksandr E , Koch Lauren G , Britton Steven , Runge Marschall , Madamanchi Nageswara R
Published: April 2024

Low aerobic capacity is associated with increased cardiovascular morbidity and mortality. A heterogeneous rat population selectively bred to segregate genes that sustain innate aerobic exercise capacity, low capacity runners (LCR) show impaired cardiac function in old age and premature death versus high capacity runners (HCR). Here we investigated whether high innate aerobic capacity offers early protection against cardiovascular disease by examining the hypertensive response of 7-month-old LCR and HCR rats to angiotensin II (Ang II, 150 μg/kg/min for 14 days). LCR and HCR rats showed no difference in basal blood pressure (105 mmHg) or vessel wall morphology, but in LCRs the mean arterial blood pressure increased to 145 mmHg versus 125 mmHg in HCRs. Congruently, LCR rats had increased aortic medial thickness and fibrosis. Aortic cytosolic and mitochondrial superoxide levels were also significantly increased in LCRs. Vascular reactivity experiments revealed impaired endothelium-dependent and -independent relaxation of mesenteric arteries of LCRs. Ang II infusion significantly increased the infiltration of macrophages into the aortic adventitia of LCRs as determined by CD68 and Mac-3 staining. Gene expression analysis by qPCR showed that markers of classically-activated macrophages CD86 and TNF-α were unchanged in rat strains but markers of alternatively-activated macrophages CD163 and Arg-1 were upregulated only in LCRs. Plasma IL-6, RANTES, CCL2 and Ang II and aortic VCAM1 levels were elevated only in LCRs whereas no difference in eNOS levels was observed between the rat strains. Aortic sections of LCRs showed increased senescence in adventitia whereas vascular smooth muscle cells (VSMC) isolated from LCR rats were more susceptible to Ang II-induced senescence. LCRs also showed increased cardiac hypertrophy and fibrosis. These data support the “outside-in” hypothesis, in which vascular inflammation initiated in adventitia progresses inwards to media and intima, causing VSMC and endothelial dysfunction, and that fibroblasts play a critical role in Ang II-induced hypertension and vascular remodeling under low innate aerobic capacity conditions, whereas high innate aerobic capacity is potentially protective against hypertension.
Abstract 12779: Up-Regulation of the Renal Sodium Transporters is Associated With Increased CD81 in Preeclampsia Rats and Patients
Authors: Yu Yanting , Zhu Gangyi , Wang Ping , Wang Zhiyin , Liu Dan , Ren Zhiyun , hu yali , Wang Xiaoyan
Published: April 2024

Introduction:
the abnormalities of placental CD81 play an important role in preeclampsia (PE), a disorder that links to the impaired placentation in the early stages of pregnancy and the subsequent systemic endothelial cell activation.

Hypothesis:
up-regulation of the renal sodium transporters is associated with increased CD81 in preeclampsia rats and patients

Methods:
we examined the renal protein abundance of CD81 and sodium transporters, channels and pump along nephron in rat model with lipopolysaccharide (LPS) -induced PE. A single ultra-low dose of LPS (0.5ug/kg) (PE) or vehicle(control group,CTL) were applied to female SD rats( age: 8-12 wks, n=4/group) on gestational day 5 (GD5) by intraperitoneal injection.

Results:
The SBP (101±1.6 vs 116±0.8 mmHg, p<0.001, tail-cuff, BP-98A, Softron, Japan) and urine albumin (1885±35 vs 3550±157.8 ug, p<0.001) were higher in PE than CTL while there were no differences in BW, fetus number/weight and serum creatinine and cholesterol concentrations (GD18) between the 2 groups. The renal protein abundances of NKCC2 (168±14 vs 100±13, % of control,P=0.02,immunoblotting) and NCC (161±16 vs 100±13, P=0.04) , among the 8 sodium transport proteins checked, were greater in PE group than in CTL group along with the increase in renal protein abundances of CD81 in PE group relative to CTL group. The protein expressions of MCP-1, IL-6, TNF-a were similar between the 2 groups. CD81 were located in thick ascending limbs of Henle’s loop and distal convoluted tubules and co-immunoprecipitated with NKCC2 and NCC in rat homogenates. CD81 was not altered in placenta, serum, liver in the LPS-PE model indicated that the increase of CD81 is kidney-specific. In PE patients , urinary exosome CD81 was also increased along with increases of NKCC2 and NCC. Furthermore, the increases of CD81 and NCC were confirmed in cultured mouse distal convoluted tubule cells (DCT) stimulated by LPS for 24 hrs at different concentrations. The knockdown of CD81 by siRNA for 48 hrs had no effects on NCC but blocked the increase of NCC induced by LPS for 24 hr.

Conclusions:
inhibition and decrease of renal CD81 may reverse the increases of renal sodium transporters, therefore improve the hypertension in preeclampsia.
Abstract 12780: TBX20 Improves Contractility and Mitochondrial Function During Direct Cardiac Reprogramming From Human Fibroblasts
Authors: Zhou Yang , Tang Yawen , Lu Rui , Zhang Jianyi
Published: April 2024

Background:
Direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as one of the promising strategies to remuscularize the injured myocardium. Yet, it is still insufficient to generate functional induced cardiomyocytes (iCMs) from human fibroblasts using conventional reprogramming cocktails, such as our previously published combination consisting of MEF2C, GATA4, TBX5 and microRNA miR-133 (MGT133). We thus sought to identify potential missing factors for human direct reprogramming.

Methods and Results:
By comparing the transcriptome differences between human iCMs and functional cardiomyocytes (CMs), we identified T-box transcription factor TBX20 as the top CM gene that is not activated by MGT133. TBX20 is required for normal heart development and cardiac function in adult CMs but its role on cardiac reprogramming remains undefined. Here, we found that transduction of MGT133+TBX20 in human cardiac fibroblasts resulted in enhanced reprogramming featured with significant activation of contractile proteins, such as αActinin (38.31±2.54% vs 23.30±1.32%,
P <
0.0001) and cardiac troponin I (79.65±1.47% vs 48.42±1.88%,
P
< 0.0001) when compared with MGT133+EV control transduction. Meanwhile, iCMs produced with MGT133+TBX20 more frequently demonstrated beating in co-culture with pluripotent stem cell derived CMs (32.50±4.61% vs 2.29±1.52%,
P
< 0.0001). Furthermore, addition of TBX20 led to increased mitochondrial amount determined by MitoTracker staining (~3.1 fold,
P
< 0.0001) and qPCR amplification of mitochondrial genome copy number (~2.9 fold,
P
< 0.0001). TBX20-transduced iCMs also showed higher mitochondrial respiration, suggesting TBX20 as a potent activator on metabolic maturation of iCMs. Mechanistically, TBX20 directly bound on the enhancers of under-expressed cardiac genes, such as
MYBPC3
,
MYH7
and
KCNH2
, to activate gene expression. We also found that TBX20’s binding on MGT-regulated cardiac loci could further boost activation of contractile genes, such as
ACTC1
,
SCN5A
and
MYOM2,
for cardiac fate conversion.

Conclusions:
Our findings demonstrate that TBX20 promotes cardiac cell fate conversion and enhances functional acquisition of iCMs by direct targeting contractility genes.
Abstract 13005: The Prognostic Role of Systemic Arterial Pulsatility Index in Surgical Aortic Valve Replacement
Authors: Shah Kajal P , Betz Yaqub , Strickling Jarred , Ondigi Olivia , Mwansa Hunter , Zhuo David , Shisler David , Philips Steven , Sodhi Nishtha , Abuannadi Mohammad , Kwon Younghoon , Bergin James D , Bilchick Kenneth C , Mazimba Sula
Published: April 2024

Introduction:
Ventricular-arterial coupling (VAC) dynamics reflect the interaction between myocardial and vascular functions and are known to influence cardiac outcomes. Systemic arterial pulsatility index (SAPi = [systemic systolic pressure-systemic diastolic pressure]/pulmonary capillary wedge pressure) is a metric of VAC, incorporating pulse pressure and left ventricular filling pressure. We hypothesized that SAPi would be associated with adverse outcomes in patients undergoing surgical aortic valve replacement (SAVR) and or concomitant coronary artery bypass graft surgery (CABG).

Methods:
This was a retrospective analysis of patients who underwent SAVR +/- CABG at a tertiary academic center from 2008 to 2016. SAPi was calculated using right heart catheterization hemodynamics prior to surgery. Logistic regression model was used to evaluate the relationship between SAPi and mortality.

Results:
Among 133 patients (mean age 73.4, 43% female) who underwent SAVR, 37 (28%) underwent concomitant CABG. The median SAPi was 4.3 (IQR 2.76-6.40). Patients with SAPi > 4.3 had a lower risk of mortality during the mean follow up of 6.9 years (OR 0.39 95% CI 0.18-0.85). Increasing SAPi was associated with a lower risk of mortality (OR 0.88 per unit increase in SAPi, 95% CI 0.76-0.99). A receiver operator characteristic curve is shown in Figure 1 with SAPI as a continuous variable adjusted for age. Area under the curve was 0.64 (95% CI 0.533-0.743).

Conclusions:
SAPi, a hemodynamic marker of VAC, was associated with mortality in patients undergoing SAVR +/- CABG. SAPi may have potential utility in pre-operative risk stratification of patients undergoing SAVR +/- CABG.
Abstract 13034: Endothelial Exosomal miR-24 Predicts Cerebrovascular Events in COVID-19 Patients
Authors: Gambardella Jessica , Jankauskas Stanislovas , Wang Xujun , COPPOLA ANTONIETTA , Izzo Raffaele , annunziata anna , fiorentino giuseppe , Matarese Alessandro , Trimarco Bruno , Santulli Gaetano
Published: April 2024

Introduction:
Neuropilin-1 has been recently identified as a co-factor needed for the entry of SARS-CoV-2 in host cells and has been linked to neurologic symptoms of COVID-19 (Science 2020). Emerging evidence indicates that exosomal microRNAs (miRNAs) are involved in a number of physiologic and pathologic processes. However, to our knowledge, exosomal miRNAs have not been hitherto investigated in COVID-19.

Hypothesis:
Since we have recently demonstrated that miR-24 targets the 3’UTR of the gene encoding for Neuropilin-1 and this miRNA is expressed in human brain endothelial cells, we hypothesized an association between plasma levels of CD31
+
extracellular vesicles (EVs) enriched in miR-24 and the risk of cerebrovascular manifestations in patients hospitalized for COVID-19.

Methods and Results:
We obtained plasma from >300 COVID-19 patients; as control COVID-19 negative populations, we obtained plasma from healthy donors and patients hospitalized for cerebrovascular disorders. CD31
+
EVs were isolated from plasma on hospital admission, and miR-24 levels were quantified. When comparing patients with
vs
without cerebrovascular disorders, we found that plasma levels of CD31
+
EV miR-24 were significantly different between these populations. We did not find any significant difference among groups when assessing circulating free levels of miR-24. Using a multiple regression analysis, adjusting for age, hypertension, and diabetes, the association between EV miR-24 and cerebrovascular complications in COVID-19 patients was confirmed (P<0.05).

Conclusions:
This is the first study showing a significant association between EV non-coding RNAs and clinical outcome in COVID-19 patients. Our results are relevant for basic researchers, because we identified an unprecedented significant association between EV miR-24 and cerebrovascular disorders, which could be helpful to better understand the molecular mechanisms underlying the pathophysiology of cerebrovascular events in COVID-19, as well as for clinicians, inasmuch as this association may help healthcare professionals in identifying COVID-19 patients who are at high risk of developing cerebrovascular disease.
Abstract 13044: Hemodynamic Changes In Neonates Born To Mothers With Graves’ Disease
Authors: Ishikawa Takamichi , Uchiyama Hiroki
Published: April 2024

Purpose:
Cardiac insufficiency is a major morbidity in neonatal hyperthyroidism. It is therefore important to assess the hemodynamics in neonates born to mothers with Graves’ disease (GD). This study prospectively evaluated the hemodynamic changes in neonates born to mothers with GD.

Methods:
The subjects of this study were neonates born to mothers with GD who became pregnant between April 2006 and May 2018 and visited Hamamatsu University Hospital. This study included two groups: neonates born to mothers consistently negative for thyroid-stimulating hormone (TSH) receptor antibody (TRAb) in the third trimester of pregnancy, and neonates born to mothers with at least one positive TRAb assay in the third trimester of pregnancy. The serum levels of TSH, free triiodothyronine (FT3), free thyroxine (FT4), and N-terminal-pro-B-type natriuretic peptide (NT-proBNP), the cardiac output, and cardiac index (CI) evaluated by echocardiography were compared between the two groups at several postnatal points (day of delivery and 5, 10, and 30 days of life).

Results:
Overall, 80 newborns were enrolled. Thirty-six neonates were born to mothers with GD who were positive for TRAb, and 44 were born to mother negative for TRAb. During the study period, four newborns (11.1%) in the TRAb-positive group required treatment with ATD for overt neonatal hyperthyroidism. Eight newborns (22.2%) in the TRAb-positive group were diagnosed with subclinical hyperthyroidism based on findings of laboratory tests in the absence of any clinical symptoms. One neonate in the TRAb-positive group had subclinical hypothyroidism at birth, but there were no symptoms, so no treatment was required. The TRAb-positive newborns had higher FT4 levels and CI on Day 5 (both p < 0.05) and higher FT3 (p < 0.05) and FT4 levels (p < 0.01) and CI (p < 0.01) but lower TSH levels (p < 0.05) on Day 10 than the TRAb-negative newborns. The TRAb-positive newborns had significantly higher NT-proBNP levels on Days 5 (median 752 vs. 563 pg/mL, p = 0.034) and 10 (median 789 vs. 552 pg/mL, p = 0.002) than the TRAb-negative newborns.

Conclusions:
Hemodynamic changes in neonates born to TRAb-positive mothers with GD resulted in a higher CI and NT-proBNP levels than in those with TRAb-negative mothers from postnatal days 5 to 10.
Abstract 13046: ALDH2-Mediated 4-HNE Contributes the Pathogenesis of Pulmonary Arterial Hypertension in Atherosclerotic Mice
Authors: Chou Yen-Hung , Lee Yi-Nan , Hsin-I Lee , Hsieh Chin-Ling , Su Cheng-Huang , Yeh Hung-I , Wu Yih-jer
Published: April 2024

Introduction:
A high residual mortality for patients with pulmonary arterial hypertension (PAH) in this PAH-targeted therapy era implies the existence of untargeted pathways. High fat diet-fed
ApoE
knockout mice were found to develop PAH phenotype. Monocrotaline (MCT)-induced PAH rats also express high levels of 4-hydroxynenonal (4-HNE), a lipid peroxidation related aldehyde, in pulmonary vessels. Aldehyde dehydrogenase-2 (ALDH2), an important enzyme responsible for the removal of 4-HNE, is functionally defective near 50% of East Asians. Whether 4-HNE and its cognate detox enzyme ALDH2 participate in lipid dysregulation-induced PAH remains poorly understood.

Methods and Results:
Compared with
ApoE
knockout mice fed with normal chow, those with Piagen diet developed hypercholesterolemia, higher right ventricular systolic pressure (RVSP), and higher Fulton index (RV hypertrophy). Atherosclerotic plaques were widely distributed in the entire major arteries as well as pulmonary arteries. The lung tissue of Paigen diet-fed mice had higher levels of ALDH2 protein but lower levels of ALDH2 enzymatic activity, which was negatively associated with serum 4-HNE levels. Importantly, lung ALDH2 activities were negatively (R= -0.829, P=0.041), and serum 4-HNE levels positively (R=0.936, P=0.006) associated with RVSP. This data suggests that, in our model, ALDH2 expression may be upregulated to counteract but still exhausted by the high levels of lipid peroxidation products, such as 4-HNE.

Conclusions:
This data suggests that lipid dysregulation related 4-HNE/ALDH2 imbalance, at least in part, participates in PAH development and may potentially serve as a novel PAH target, particularly for East Asian people.
Abstract 13062: The Effect of Empagliflozin on Contractile Reserve in Heart Failure: Prespecified Sub-Study of a Randomized, Double-Blind, and Placebo-Controlled Trial
Authors: Jensen Jesper , Omar Massar , Mulham Ali , Frederiksen Peter H , Kistorp Caroline , Tuxen Christian , Andersen Camilla , Larsen Julie H , Ersbøll Mads K , Kober Lars , Gustafsson Finn , Forman Julie L , Moller Jacob E , Schou Morten
Published: April 2024

Introduction:
Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve cardiac structure but most studies suggest no change in left ventricular (LV) systolic function at rest. Whether SGLT2 inhibitors improve LV contractile reserve is unknown. We investigated the effect of empagliflozin on LV contractile reserve in patients with heart failure (HF) and reduced ejection fraction (HFrEF).

Methods:
Prespecified sub-study of the Empire HF trial, a double-blind, placebo-controlled, and randomized trial. Patients with LV ejection fraction (LVEF) ≤40% on guideline-directed HF therapy were randomized (1:1) to empagliflozin 10 mg or placebo for 12 weeks. The treatment effect on contractile reserve was assessed by low dose dobutamine stress echocardiography.

Results:
In total, 120 patients were included. The mean age was 68 (SD 10) years, 83% were male, and the mean LVEF was 38 (SD 10) %. Respectively 60 (100%) and 59 (98%) patients in the empagliflozin and placebo groups completed stress echocardiography. No statistically significant effect of empagliflozin was observed for the contractile reserve assessed by LV-GLS [adjusted mean absolute change, empagliflozin versus placebo, 0.7% (95% CI -0.5 to 2.0, P=0.25)] or LVEF [adjusted mean absolute change, empagliflozin versus placebo, 2.2% (95% CI -1.4 to 5.8, P=0.22)] from baseline to 12 weeks. LV-GLS contractile reserve was associated with accelerometer-measured daily activity level [coefficient, -24 accelerometer counts (95% CI -46 to -1.8, P=0.03)] as opposed to LVEF contractile reserve [coefficient, -2.9 accelerometer counts (95% CI -10 to 4.5, P=0.43)].

Conclusions:
Empagliflozin for 12 weeks added to guideline-directed HF therapy did not improve LV contractile reserve in patients with HFrEF.
Registration:
NCT03198585. https://www.clinicaltrials.gov/ct2/show/NCT03198585?term=Empire+HF&draw=2&rank=1
Abstract 13064: Sex-Related Differences in Chest Pain and Asymptomatic Myocardial Ischemia Experienced During Exercise Stress Echocardiogram
Authors: Patel Nikhil , Brooks Jeremy , Sokolsky Mark , Upadhya Bharathi , Pu Min , Stacey Brandon
Published: April 2024

Background:
Coronary artery disease (CAD) continues to account for significant morbidity and mortality for both men and women. Women present with greater variability in symptoms from coronary artery disease than men. This study seeks to describe the potential differences between men and women in the association between stress test-related chest pain and obstructive CAD.

Methods:
Patients with an exercise stress test who underwent a coronary angiogram from September 2013 to January 2019 were included in our analyses. The patients’ clinical characteristics, symptoms, coronary angiography and ECGs were analyzed to determine the relationship between ischemia, chest pain, and obstructive coronary artery disease (CAD; stenosis > 70%). T-tests and chi-square tests described differences in continuous and categorical variables, respectively. Logistic regression was used to adjust for demographic, imaging, and stress testing factors.

Results:
A total of 368 patients were included in our analyses: 297 patients had a positive stress echocardiogram or ECG; 71 patients had negative stress tests but continued to have persistent symptoms. The study population had a mean age of 63 years and included 29% female, 11% African-American, and 61% obstructive CAD. In those with obstructive CAD, only 39% of women experienced chest pain during stress (p>0.2), but in men, 48% experienced stress test related chest pain (p<0.001). Adjusting for baseline demographics in sex-stratified models, echo-based ischemia and ECG-based ischemia were significantly associated with obstructive CAD in women, but stress-test related chest pain was not (p=0.02; p<0.001; p>0.2, respectively). In men, echo-based ischemia, ECG-based ischemia, and stress-test related chest pain all associated with obstructive CAD (p<0.001; p<0.001; p=0.008, respectively). These changes persisted with adjustment for stress test performance (METS, heart rate achieved) as well as baseline left ventricular ejection fraction.

Conclusion:
In women, stress test-related chest pain during stress testing was not associated with obstructive CAD. Further studies are needed to understand the role, significance, and management of potential myocardial ischemia without chest pain in women.
Abstract 13067: Recapitulating Long QT Syndrome Phenotype in Induced Pluripotent Stem Cells-Derived Cardiomyocytes Using CRISPR/Cas9 Technology
Authors: Ge Ning , LIU MIN , Krawczyk Janusz , mcinerney veronica , Galvin Joseph , Ward Deirdre , McGorrian Catherine , O'Brien Timothy , Shen Sanbing , Prendiville Terence W
Published: April 2024

Introduction:
Long QT syndrome (LQTS) is an inherited arrhythmia syndrome with a hallmark of QT prolongation secondary to delayed repolarization of cardiomyocytes (CM) on 12-lead ECG.

Hypothesis:
Studying LQTS in an induced pluripotent stem cell (iPSC)-derived CM model allows for patient-specific phenotype characterization
in vitro
. We report such a strategy (fig. A) in a patient with LQT type 3 (ECG QTc 503 msec) who harbored a heterozygous pathogenic variant in
SCN5A
(c.1231G>A), and in a healthy control for comparison (ECG QTc 388 msec).

Methods:
IPSCs were generated from patient and control dermal fibroblasts using a non-integrational Sendai reprogramming method. The patient’s
SCN5A
(c.1231G>A) variant was edited into the healthy control using CRISPR/Cas9 technology. CM were subsequently differentiated and beating CM clusters were seeded onto Maestro CytoView multi-electrode array plates. Serial corrected field potential duration (FPD) measurements (n=12), equivalent to QTc values on ECG, were recorded on days 24 to 39 of CM differentiation per sample. CM were exposed to varying concentrations of Nifedipine and Sotalol through cell culture media exchange. Paired t-tests (non-parametric) were utilized for p<0.05.

Results:
Reprogrammed iPSCs displayed pluripotency characteristics (fig.B). IPSC-derived CMs had confirmed cardiac lineage (fig. C). Prolonged FPD values, corrected for beating rate, were observed in both the LQT3 patient-derived iPSC-CMs (p<0.0001) and the genetically induced LQT3 iPSC-CMs (p<0.0001) compared to control (fig. D & E). Nifedipine and sotalol altered FPD in a dose-dependent response (fig. F & G).

Conclusions:
An iPSC-derived CM model reliably recapitulates the phenotype of LQTS. Induced LQT3 iPSC-CMs genetically edited from a healthy control accurately recapitulate the LQT3 disease phenotype. Drug effects on CM repolarization were demonstrable in the iPSC-CM model.
Abstract 13089: Reperfusion Injury is Reduced by Antagonism of NLRP3's Caspase-1
Authors: Cohen Michael V , Yang Xi-Ming , Tuckey Amanda N , Audia Jonathon , Downey James M
Published: April 2024

VX-765, inhibitor of caspases-1, 3 and 4, at reperfusion reduces infarction in isolated rat hearts by 50% after ischemia/reperfusion (I/R). It was assumed cardioprotection by this pharmaceutical-grade drug was the result of inhibition of caspase-1 (cas-1) activation by the NLRP3 inflammasome which would trigger lethal pyroptosis. However, there has been no direct proof of that hypothesis. To test which, if any, caspase was responsible for protection, we measured infarct size after 50-min global ischemia/2-h reperfusion in isolated wild type (WT) mouse hearts and hearts from mice in which cas-1 had been genetically deleted (offspring of breeders from Jackson Labs genotyped to confirm mutation). Infarct size was measured objectively by Image J analysis of tetrazolium-stained heart slices using the same threshold settings for all hearts. No gender difference in infarct size was found in WT hearts (see figure) so genders were mixed, especially in the in the knockout (KO) groups. Because Krebs perfusate lacks blood-borne esterases required to convert pro-drug VX-765 to its active metabolite, VRT-043198 (VRT), we employed VRT in our model. Infarct size in hearts reperfused with buffer containing 180 nM VRT was halved to 43.7±4.8% of ventricular mass (p<0.001 vs either cohort of WT hearts). Infarct size in cas-1 KO mice averaged 42.2±5.1% (pNS vs VRT). To eliminate possibility of a protected phenotype unrelated to cas-1, cas-1 KO mice were treated with 180 nM VRT. There was no further change in infarct size (44.0±4.3%) confirming cas-1 is VRT’s only target. NLRC4 also activates cas-1, but NLRC4 KO mice exposed to I/R were not protected (89.2±1.2% infarction), whereas inhibition of NLRP3 with MCC950 resulted in modest protection (65.5±5.3% infarction). These results strongly support NLRP3 as the source of the lethal cas-1. VX-765 at reperfusion is a promising adjunct intervention to decrease infarct size in patients treated for ST-segment elevation myocardial infarction.
Abstract 13099: Correlation of Lipoprotein(a) Levels With Coronary Plaque Morphological Features and Vulnerability: An Optical Coherence Tomography Study
Authors: Xiaopeng Chu , Chongying JIN
Published: April 2024

Introduction:
High lipoprotein(a) level is a potential independent risk factor for coronary artery disease (CAD). However, the relationship between the Lp(a) value and the morphological characteristics of plaque defined by optical coherence tomography (OCT) has not been completely clarified so far. Meanwhile, no evidence has been raised for a clear cut-off value of Lp(a) for preventing the process of CAD.

Hypothesis:
Based on the biological properties of Lp(a), We assessed the hypothesis that the Lp(a) levels may relate to the vulnerable features of lipid plaque defined by OCT.

Methods:
420 CAD patients who had undergone OCT scan to at least 1 main coronary vessel during 2013-2018 were enrolled. Patients were first stratified into 3 levels according to the values of Lp(a) at admission: Lp(a)<30 mg/dl (Group A), 30-60 mg/dl(Group B), and >60 mg/dl(Group C). After enrolled the cases with Lp(a) >60mg/dl, we chose cases of the other 2 groups matching according to traditional risk factors of CAD to our current analysis. OCT pullbacks of the target vessels were collected and analyzed at every 0.4 mm by 2 independent observers blinded to the clinical data and angiographies with QIVUS software.

Results:
A total of 90 cases were enrolled into the current study, with 30 cases in each group. Lipid plaque in Group B and Group C had a thinner minimum fibrous cap thickness, wider maximum lipid arc, longer lipid length, and greater lipid index than Group A. The Lp(a) levels significantly correlated with lipid length (r=0.283), the maximum arc of lipid(r=0.293), lipid index(r=0.357), and inversely correlated with minimum fibrous cap thickness (r =-0.403). Multivariate analysis demonstrated that the Lp(a) level was independently associated with TCFA (odds ratio 1.035, 95% confidence interval 1.014-1.057). In addition, the ROC curve analysis results (AUC =0.694, p < 0.001) indicated the Lp(a) is a good diagnostic indicator for detecting TCFA, and the optimal cut-off was 33.65 mg/dl.

Conclusions:
Our current study indicates that CAD patients with higher Lp(a) level(>30 mg/dl) exhibited a higher prevalence of TCFA and had more other typical vulnerable characteristics defined by OCT. New Lp(a) lowering therapy could aim at a level of < 33.65mg/dl for stabilizing coronary plaque.
Abstract 13105: Coronary CT Angiography Predicts Major Adverse Events in Dialysis Dependent End-Stage Renal Disease Patients
Authors: Cho Geoffrey W , Quesada Carlos G , Ghanem Ahmed K , Arasheben Audelia , Dailing Christopher , Budoff Matthew J , Karlsberg Ronald P
Published: April 2024

Introduction:
Coronary atherosclerosis is prevalent in the end-stage renal disease population. Cardiovascular complications are the primary cause of morbidity and mortality in this group due to advanced CAD. Coronary CT angiography (CTA) in this population is challenging due to their severe coronary atherosclerosis, often with dense calcifications that limit diagnostic specificity and sensitivity. We characterized the CAD-RADS Classification of 62 ESRD patients on chronic dialysis to assess whether CAD-RADS stratification correlates the severity of disease to major adverse cardiac events.

Methods:
62 patients (mean 69 years; range 41-95 years; 59% male) underwent coronary CTA. All patients were on dialysis (83% HD, 10% PD, 7% transition between PD-HD). Average creatinine was 3.9 mg/dL. 38% of patients had history of revascularization either via CABG or PCI. CAD-RADS, coronary artery calcium score (CAC), and other parameters (diabetes mellitus, creatinine, LVEF) were investigated as predictors of cardiac events.

Results:
Of the 62 patients in this study, 42 patients had significant CAD (CAD-RADS 3 or greater). Average CAC score was 1999.8 Agatston Units (AU). 46 patients (74%) had interpretable CT angiograms. Higher CAC-score moderately correlated with higher CAD-RADS in patients with CAD (R = 0.58, 95% CI, 0.38-0.73, p<0.0001). Analysis revealed that higher CAD-RADS score (>4) is a significant predictor for the presence of major adverse cardiac events (ACS Odds-Ratio 4.03, 95% CI, 1.33-10.68, 61.7% vs 28.5%, p<0.012). In addition, patients with CAD-RADS 4 or greater (including N-scores due to severe calcification), also trended towards higher mortality (Mortality Odds-Ratio 2.0, 95% CI, 0.70-5.57, 52.9% vs 35.7%, p<0.20). Higher CAD-RADS, especially scores >4, had higher incidence of heart failure and decreased cardiac function (LVEF 60.5% vs 47.2%, p<0.003).

Conclusions:
CAD-RADS classification can be determined in a significant portion of ESRD patients on dialysis, even in the setting of high CAC scores. Higher CAD-RADS scores demonstrated increased incidence of major adverse cardiac events, including heart failure and ACS. This study suggests that cardiac CTA in Dialysis-Dependent-ESRD patients is feasible and prognostic.
Abstract 13111: Circulating Extracellular Microvesicles: Mediators of Altitude-Related Vascular Inflammation
Authors: Brewster Madden , Bain Anthony R , Pacheco Garcia Vinicius P , DeSouza Noah M , Tymko Michael , Ainslie Philip N , Desouza Christopher
Published: April 2024

Ascent to high altitude can adversely affect cardio- and cerebrovascular health, particularly in those with pre-existing disease. Pathologic vascular responses to acute and subacute high altitude exposure include, endothelial dysfunction, cerebral and pulmonary edema as well as pulmonary hypertension. Changes in vascular endothelial cell function, most notably the induction of a proinflammatory endothelial phenotype, is thought to be an underlying factor. Endothelial inflammation can induce cerebral edema in stroke and promote pulmonary edema. The mechanisms underlying high-altitude related vascular inflammation remain unclear. The vascular endothelium is significantly influenced by circulating cell-derived microvesicles (MVs). MVs are small (100-1000 nm) membrane vesicles that are released by various cell types (e.g. endothelial, platelets, leukocytes) in response to a myriad of physiologic and pathologic stimuli including hypoxia. Circulating MVs have emerged as biomarkers and mediators of endothelial inflammation. We tested the hypothesis that ascent to high altitude induces a proinflammatory circulating MV phenotype. Ten healthy adults (8 M/2 F; age: 28
+
2 yr
)
residing at sea level (Kelowna, BC, Canada) were studied prior to and 4-6 days after ascending to high altitude (Cerro de Pasco, Peru; 4300 m). Circulating MVs were isolated, enumerated and collected from plasma by flow cytometry. Human umbilical vein endothelial cells were cultured and treated with MVs collected from each subject at sea level and altitude. Circulating MVs were significantly higher at altitude vs sea level (26637
+
3315 vs19388
+
1699 MV/μL). Altitude-related MVs induced higher (~25%; P<0.05) release of interleukin (IL)-6 (63.9±3.9 vs 53.3±3.6 pg/mL) and IL-8 (140.2±3.6 vs 120.7±3.8 pg/mL) compared with MVs harvested at sea level. Although intracellular expression of total NF-κB p65 (83.4
+
6.7 vs 90.2
+
6.9 AU) was not significantly affected, high altitude-MVs resulted in ~55% higher (P<0.05) cell expression of p-NF-κB p65 (active NF-κB: 129.6
+
19.8 vs 90.7
+
10.5 AU) than sea level-MVs. Circulating extracellular MVs increase at high altitude and induce endothelial inflammation, potentially contributing to altitude-related vascular pathologies.
Abstract 13118: Sex Disparities in Hemodynamics and Outcomes Among Women Undergoing Contemporary Transcatheter Aortic Valve Replacement
Authors: Medranda Giorgio A , Rogers Toby , Case Brian C , Zhang Cheng , Shea Corey , Satler Lowell F , Ben-Dor ITSIK , Waksman Ron
Published: April 2024

Introduction:
Several studies have demonstrated worse outcomes following transcatheter aortic valve replacement (TAVR) in women compared to men using early transcatheter heart valves (THV). Different THV designs impact hemodynamics in patients with small annuli and women constitute the majority of these patients.

Hypothesis:
We hypothesized that women represent the majority of patients with small annuli resulting in worse hemodynamics.

Methods:
We examined patients with symptomatic severe aortic stenosis who underwent TAVR using contemporary THVs across all surgical risk categories. We compared baseline characteristics, procedural details, in-hospital outcomes, and hemodynamics (30-day) according to sex. We then performed a secondary analysis focusing on the female patients, dichotomizing them based on aortic annular area above or below 430mm
2
.

Results:
Included were a total of 869 patients who underwent TAVR using a contemporary THV. The majority of patients with an annular area <430mm
2
were female (82.5%) and most with an annular area >430mm
2
were male (76.8%). Females saw a trend towards higher 30-day (1.5% vs. 0.6%; p=0.313) and 1-year (4.1% vs. 2.7%; p=0.265) mortality. Females with an annular area <430mm
2
who received an self-expanding THV saw lower mean gradients at 30 days compared to those who received a balloon-expandable THV (8.0mmHg vs. 13.8mmHg; p<0.001) which resulted in lower rates of moderate patient prosthesis mismatch (PPM) (21.2% vs. 73.6%; p<0.001). A similar trend was seen in females with an annular area >430mm
2
who received a self-expanding THV (9.3mmHg vs. 11.5mmHg; p<0.001) which resulted in lower rates of moderate PPM as well (24.5% vs. 59.2%; p<0.001). Conversely, female patients who received a self-expanding THV saw higher rates of permanent pacemaker implantation regardless of annular size.

Conclusions:
Female patients undergoing contemporary TAVR saw numerically higher short-term mortality which could be, a result of higher rates of PPM. These findings were more pronounced in the subset of females with small aortic annuli, where those who received a self-expanding THV demonstrated superior hemodynamics but at the cost of increased rates of permanent pacemaker implantation.
Abstract 13125: The Role of FXR1 and Cellular Senescence in Vascular Pathology
Authors: Corbett Cali , St Paul Amanda , Leigh Tani , Kelemen Sheri E , Okune Rachel Okune , Autieri Michael
Published: April 2024

Introduction:
Despite the advent of stents, intimal hyperplasia subsequent to vascular interventional procedures remains a major obstacle to success. Vascular smooth muscle cells (VSMC) play a critical role in the development and pathogenesis of intimal hyperplasia indicative of restenosis; therefore regulation of gene expression in VSMC represents a logical intervention point to attenuate this syndrome. FXR1 is a muscle-enhanced RNA binding protein and expression is increased in injured human and mouse arteries. We have shown that modulation of FXR1 levels affects abundance and stability of inflammatory transcripts in VSMC, suggesting that FXR1 is a negative regulator of inflammation. This drives our hypothesis that FXR1 is involved in mitigating vascular disease and acts as a crucial regulator of inflammatory and proliferative mRNA in VSMC.

Approach/Results:
Because FXR1 expression is increased in injured arteries, we have developed a novel VSMC-specific conditional knockout mouse (FXR1
VSMC/VSMC
). In a carotid artery ligation model of intimal hyperplasia, FXR1
VSMC/VSMC
mice have significantly reduced neointima formation (p<0.001) post-ligation compared to several controls. To determine the mechanism of these effects, we knocked down FXR1 in human VSMC by siRNA and observed decreased proliferation (p<0.05) as well as an increase in beta galactosidase (p<0.05) and gamma H2AX (p<0.01) staining compared with controls, indicative of senescence. Senescent cells exhibit phenotypic changes called the senescence associated secretory phenotype (SASP) with characteristic gene expression leading to increased inflammation in the tissue microenvironment. RNA sequencing demonstrated a decrease in abundance of cell cycle control genes. This was validated by actinomycin D RNA stability assays, and further qPCR analysis showed an increase in abundance of SASP-related mRNA with FXR1 depletion. VSMC knockout of FXR1 via Cre adenovirus in mouse cells validated these results.

Summary & Conclusions:
Our results are the first to suggest that in addition to destabilization of inflammatory transcripts, FXR1 may stabilize cell cycle related genes in VSMC, and absence of FXR1 leads to induction of a senescent phenotype and reduction of intimal hyperplasia.
Abstract 13126: Sudden Cardiac Arrest in Asian Americans: Prospective Evaluation in Two US Communities
Authors: Chugh Harpriya , Sargsyan Arayik , Uy-Evanado Audrey , Klebe Damon , Sorenson Chad , Dizon Bernadine , NAKAMURA Kotoka , Norby Faye L , Salvucci Angelo , Jui Jonathan , Chugh Sumeet S , Reinier Kyndaron
Published: April 2024

Background:
There is a lack of data on epidemiology of sudden cardiac arrest (SCA) in the Asian-American community. We have recently reported lower annual incidence of SCA in Asian compared to White non-Hispanic residents of Ventura County, CA. However, the generalizability of these findings has not been evaluated.

Hypothesis:
We hypothesized that these trends are observed in other US communities.

Methods:
An epidemiologic assessment of SCA was performed and compared in Ventura County, CA (2018 Pop 848,112; study period 2015-2021) and Multnomah County, OR (2010 Pop 712,036; study period 2002-2014). All out-of-hospital SCA cases with likely cardiac etiology and resuscitation attempted by emergency medical services (EMS) were prospectively ascertained. We calculated race-specific annual age-adjusted SCA incidence using the US standard population and compared incidence and resuscitation outcomes between Asians and Whites in both counties.

Results:
A total of 2084 SCA cases were identified in VC (65% male; mean age 71 ± 16 y) and 4149 in MC (69% male; mean age 63 ±18 y). Asian and White SCA cases were similar by age and sex in both counties (p=0.08). In VC, annual age adjusted incidence per 100,000 was 29.4 in Asians and 36.8 in Whites (p=0.02). In MC, annual age adjusted incidence per 100,000 was 22.8 in Asians and 31.1 in Whites (p=0.002). No significant differences were observed in bystander CPR provision or 911 call response time (p>0.23), but Asians were less likely than Whites to present with shockable rhythm (VF/VT) in both locations (VC 10% vs 26%, p<0.001; MC 36% vs 44%, p=0.07). Survival to hospital discharge following SCA was similar in Asian and White residents in VC (Asians 8.4%, Whites 12%, p=0.25) and MC (Asians 11.9%, Whites 14.1%, p=0.52).

Conclusion:
We observed lower annual incidence of SCA among Asians compared to Whites in these two separate and geographically distinct US communities. Emergency response and outcomes of arrest were similar in Asians and Whites, despite a lower presentation with a shockable rhythm among Asians. Further study is required to determine whether lower SCA incidence in Asians is explained by a lower risk factor burden or other factors.
Abstract 13133: Heterogeneous Uptake of [
99m
Tc]microspheres and
201
Tl in Skeletal Muscles in Porcine Model of Hindlimb Ischemia
Authors: Lee Supum , Gil de Rubio Cruz Pedro , Thorn Stephanie , Liu Zhao , hawley christi , Mamarian Marina , Turlejski Tymoteusz , Meng Ling Jian , Liu Chi , Sinusas Albert
Published: April 2024

Introduction:
There is a need for quantitative methods to evaluate skeletal muscle blood flow in PAD patients. We assessed skeletal muscle blood flow heterogeneity at rest or vasodilator stress using
99m
Tc-microspheres (HSA), that do not cross the capillaries, and
201
Tl, a freely diffusible radiotracer, in a pig hindlimb ischemia model.

Methods:
Following acute right femoral artery ligation, pigs (n=8) were injected with either
201
Tl or HSA at rest (n=2 per tracer) or under adenosine-stress (n=2 per tracer). Ex vivo SPECT/CT imaging was performed on excised ischemic (I) and non-ischemic (NI) gastrocnemius (GM) and soleus (SM) muscles. SPECT images were analyzed for the ischemic/nonischemic (I/NI) activity ratio, tracer heterogeneity as indicated by the coefficient of variance (CV) of signal intensity and image intensity histograms.

Results:
The rest
201
Tl I/N ratio for SM was higher (0.86±0.08) compared to stress (0.64±0.16), with no difference in GM. In contrast, the I/N ratio for HSA was near normal in both muscle groups at rest (GM: 0.80±0.21, SM: 1.06±0.45) although decreased during stress (GM: 0.70±0.04, SM: 0.71±0.12). Rest
201
Tl displayed uniformly low CV in both I (GM: 0.43, SM: 0.43) and NI muscles (GM: 0.37, SM: 0.43). Corresponding CV for stress
201
Tl were similar (I - GM: 0.41, SM: 0.42; NI - GM: 0.41, SM: 0.46). Rest HSA CV were higher in I (GM: 0.92, SM: 1.03) and NI (GM: 0.67, SM: 0.69) muscle, although there was greater heterogeneity in the I muscles assessed with HSA. Stress HSA CV decreased in both I (GM: 0.60, SM: 0.73) and NI (GM: 0.52, SM: 0.51). Figure displays representative count histograms.

Conclusions:
201
Tl displayed less heterogeneity than HSA.
201
Tl appears to be more sensitive at detecting reduced blood flow at rest, due to changes in microcirculation. There was no change in the I/NI ratio during
201
Tl stress due to capillary recruitment, although HSA did demonstrate a decrease in the I/NI ratio with vasodilation, reflecting proximal vascular occlusion.
Abstract 13140: Eicosapentaenoic Acid (EPA) Restores Pulmonary Endothelial Nitric Oxide Bioavailability Following Exposure to Urban Air Pollution Small Particles
Authors: Sherratt Samuel , Dawoud Hazem , Libby Peter , Bhatt Deepak L , Malinski Tadeusz , Mason Preston
Published: April 2024

Introduction:
Air pollution is the fourth leading contributor to global mortality. Cardiovascular (CV) disease accounts for the majority of these deaths, including stroke and myocardial infarction. The omega-3 fatty acid (n3FA) eicosapentaenoic acid (EPA) has vascular benefits that may contribute to reduced events in patients with CV risk (REDUCE-IT). Loss of endothelial cell (EC) nitric oxide (NO) bioavailability can favor thrombosis, vasoconstriction, and inflammation. We measured the effects of EPA on EC function during exposure to urban pollutant small particles (SPs).

Methods:
Pulmonary ECs (PECs) were pretreated with EPA (40 μM) for 2 h before addition of SPs with a diameter range of 1.35 to 30.1 μm from collected urban air (St. Louis, MO) for 2 h (50 μg/mL). Cells were stimulated with calcium ionophore to measure the time-dependent production of nitric oxide (NO) and peroxynitrite (ONOO
–
) using tandem porphyrinic nanosensors; the ratio of NO to ONOO
–
is a measure of NO synthase coupling efficiency. Levels of soluble intercellular adhesion molecule-1 (sICAM-1) were also measured using immunochemistry (ELISA).

Results:
ECs challenged with urban SPs showed a reduction in NO release by 13% compared with control (373 ± 10 vs 428 ± 18 nM). An increase in ONOO
–
release by 52% (262 ± 17 vs 172 ± 14;
p
<0.001) accompanied this drop in NO. The NO/ONOO
–
release ratio thus fell by 43% (1.43 ± 0.09 vs 2.49 ± 0.10;
p
<0.001) following SP exposure. ECs treated with EPA had a greater NO/ONOO
–
release ratio by 31% (
p
<0.01) due to an increase in NO release by 5% and decrease in ONOO
–
release by 20% (
p
<0.01) compared with vehicle. Challenge with the SPs caused a 70% increase in sICAM-1 levels (
p
<0.05), while treatment with EPA attenuated sICAM-1 levels compared with SP alone (60%,
p
<0.05).

Conclusions:
EPA significantly improved pulmonary EC function under conditions of inflammation caused by air pollution particles, including reductions in nitroxidative stress and the adhesion molecule ICAM-1. These effects of EPA in pulmonary tissue challenged with air particulate matter indicate a novel benefit for people exposed to air pollution.