bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16605: Peripheral Blood-Derived Myeloid Subtypes Are Associated With Cardiac Allograft Vasculopathy
Authors: Holzhauser Luise , Schroeder Allison , Arnold Kathryn A , Imamura Teruhiko , Nguyen Ann , Chung Ben , Narang Nikhil , Rodgers Daniel , Jeevanandam Valluvan , Murks Catherine , Riley Tiana , Powers JoDel , Sarswat Nitasha , Kalantari Sara , Raikhelkar Jayant , Sayer Gabriel , Kim Gene H , Uriel Nir , Alenghat Francis J
Published: April 2024

Introduction:
The evidence for innate immunity’s role in cardiac allograft rejection does not necessarily extend to cardiac allograft vasculopathy (CAV), and predictors of CAV remain elusive. We hypothesize that circulating monocytes and their derived macrophage subtypes, as well as associated inflammatory and angiogenesis markers, correlate with CAV.

Methods:
49 consecutive heart transplant recipients over 2 years post-transplant were enrolled. Peripheral blood mononuclear cells were isolated, with monocytes stained and measured by flow cytometry for classical (CD14
++
/CD16
-
), intermediate (CD14
++
/CD16
+
), and nonclassical (CD14
lo
/CD16
++
) subtypes. Monocytes were cultured into macrophages, driven by M-CSF, and assayed for polarization markers CD86 and CD206. Serum concentrations of multiple factors including IL8, IL6, TNFα, angiopoietin-2, and VEGF-A were measured by immunoassay. CAV was assessed by angiogram and intravascular ultrasound (IVUS).

Results:
22 patients had no significant CAV (Stanford class I-II) while 27 had significant CAV by angiogram or IVUS (class III-IV). Other than time since transplant (77±13 vs 135±12 months), baseline characteristics of the two groups were similar. There were no differences between monocyte subgroups in isolation, but when combined with derived macrophage polarization, patients with CAV tended toward lower M2 (CD206
+
) macrophage production (0.18±0.04%) than those without CAV (0.35±0.11%). The CAV monocyte/macrophage profile was distinct from that of a reference native CAD population. IL8 was higher late post-transplant (>7.5 years) compared to early post-transplant (1.8±0.3 vs 1.0±0.1 pg/ml). There was also higher expression of angiopoietin-2 with time after transplant and with CAV.

Conclusions:
The reduced ability of CAV patients to generate regulatory M2 macrophages and their higher circulating IL8 and angiopoietin-2, both linked to inflammatory macrophage signatures, support a model in which pro-inflammatory myeloid phenotypes are connected to development of CAV, and notably, these circulating monocyte and macrophage subtypes differ from those of native CAD. These cell-based and paired circulating markers could be useful to differentiate high vs. low CAV risk phenotypes.
Abstract 16615: A Rare
MEGF8
Variant is Involved in the Genetic Risk for Transposition of the Great Arteries
Authors: Moreau de Bellaing Anne , Williams Kylia , Li Sally , Bais Abha S , Young Cullen B , Lo Cecilia W
Published: April 2024

Introduction:
Transposition of the great arteries (TGA) is one of the most common neonatal heart defects with a prevalence of 0.2 per 1,000 live births. Although some studies have suggested laterality genes and environmental factors are involved, the pathogenesis of this outflow defect is still unclear. The majority of TGA are sporadic, arguing for a polygenic etiology.

Methods:
Whole exome sequencing (WES) analysis was conducted on 104 unrelated subjects with isolated or complex TGA. Variants in 20 human and mouse genes previously reported with TGA were recovered using frequency filter of 1%. These were compared to those on 120,000 subjects of the Genome Aggregation Database (GnomAD).

Results:
Among variants recovered in the 20 selected genes, we observed 14 (13.5%) patients with rare variants in
MEGF8
. Four patients shared the same
MEGF8
rare variant (0.26% in GnomAD) causing missense of a conserved amino acid (p.Val2502Ile). This variant is significantly overrepresented in the TGA cohort (OR=7.6,
p
=0.002).
MEGF8
encodes a type I transmembrane protein shown to play a role in laterality specification in zebrafish and mice. It also has been shown to negatively regulate Hedgehog (Hh) signaling. Interestingly, recessive
MEGF8
mutations are associated with Carpenter’s syndrome characterized by multiple congenital malformations and skeletal dysplasia. Unlike Carpenter’s mutations mostly distributed at the MEGF8 protein N-terminus, the variant we highlight is at the C-terminal extremity. Also of note, all TGA patients were heterozygous, except for one patient with cleft palate who had compound heterozygous
MEGF8
mutations. Interestingly, 10 of the TGA patients also had rare variants in at least one other TGA-associated gene, supporting a complex genetic model of disease for TGA. Using fibroblasts from TGA patients with this variant and also
Megf8
mutant mice with TGA, we are assaying Hh signaling pathway to confirm its role in TGA pathogenesis.

Conclusions:
We identified
MEGF8
as a gene significantly associated with TGA, especially a rare variant localized at the C-terminus. The co-occurrence of rare variants in other laterality genes supports a multigenic etiology for TGA and points to the involvement of laterality defects in TGA pathogenesis.
Abstract 16619: Acute Aortic Dissection With No Ascending Involvement: Is Entry Tear Location in the Arch Different From Entry Tear Location in the Descending?
Authors: de Beaufort Hector , Peterson Mark D , O’Gara Patrick , Bismuth Jean , Shalhub Sherene , Tolva Valerio , Taylor Bradley S , Eckstein Hans-Henning , Suzuki Toru , Hutchison Stuart , Montgomery Daniel G , Coselli Joseph S , Evangelista Arturo , Nienaber Christoph A , Eagle Kim A , Isselbacher Eric M , Trimarchi Santi
Published: April 2024

Introduction:
Optimal management of acute aortic dissections (AD) with entry tear in the arch without ascending involvement (arch B AD) is not discussed in clinical guidelines. This study aims to better define this type of AD.

Methods:
Presentation, management, and in-hospital mortality of patients with arch B AD enrolled in the International Registry of Acute Aortic Dissection were analyzed and compared to a control group of Stanford type B AD (TBAD) with entry tear in the descending aorta.

Results:
Patients with arch B AD (n=156) and TBAD (n=222) were not significantly different concerning demographics, except age, which was higher in TBAD patients (60±14 vs 64±14 years; p=0.024). Medical history, including hypertension, diabetes, bicuspid aortic valve, Marfan disease, renal insufficiency and COPD, was similar for both groups. On preoperative imaging, arch B AD patients had a larger median arch diameter (3.7 vs 3.5 cm; p=0.007) and smaller descending diameter (3.6 vs. 4.4 cm; p<0.001). The two groups were not different concerning preoperative complications such as shock, aortic rupture or neurological complications, except descending diameter >5.5 cm, which was less frequently seen for arch B AD (2.6% vs 13.5%; p<0.001). Arch B AD was more frequently treated with open surgery (19.9% vs. 10.8%; p=0.013) and less frequently managed medically (47.4% vs. 61.4%; p=0.007), while the frequency of endovascular treatment was similar (26.3% vs. 26.0%; P=0.953). The overall in-hospital mortality was higher for arch B AD (17.3% vs. 12.6%; p=0.196). This difference was driven primarily by those receiving open surgery (32.3% mortality for arch B AD vs. 16.7%; p=0.226), while mortality was similar after endovascular treatment (9.8% vs. 8.6%; p=1.0), and medical management (13.5% vs. 14.1%; p=1.0).

Conclusions:
Arch B AD is more frequently treated aggressively with open surgery, but associated mortality rates are high. A more conservative approach with either endovascular treatment or medical management may be preferable. In this respect, arch B AD may be comparable to TBAD.
Abstract 16633: Aspirin Ingestion and Omega-3 Fatty Acids Interact: The Framingham Heart Study
Authors: Block Robert C , Shearer Greg C , Tu Xin , Mousa Shaker A , Brenna J T , Tintle Nathan
Published: April 2024

Introduction:
Aspirin can reduce cardiovascular disease (CVD) events. While eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been associated with CVD benefits, we find this benefit on platelet function, lysolipids, and HDL cholesterol is non-linear when aspirin is taken. EPA and DHA are substrates for cyclooxygenase, while aspirin is a suicide inhibitor of this enzyme.

Hypotheses:
Aspirin’s CVD effects depend on the abundance of EPA and DHA in tissue, as indicated by red blood cell membrane concentrations (Omega-3 Index or Index).

Methods:
We included adults recruited in 1971 into the Offspring Cohort of the Framingham Heart Study and attended their 8
th
exam (N=2,500 after excluding those missing an Index or had CVD); stratified into those who were and were not taking aspirin. The lowest Index quintile (<4.2%) was used as the comparison. Primary analyses related incident events by date of event (or censoring) to quintiles of the Index after adjusting for numerous demographic and medical history covariates. Secondary analyses explored both linear and quadratic risk patterns across quintiles. All analyses used 2-sided tests and the 0.05 significance level.

Results:
Those not taking aspirin had a hazard ratio (HR) for total CVD of 0.45 (95% CI 0.23-0.89) and total stroke of 0.27 (0.08-0.9) when their Index was 4.2-4.9%. Those who were taking aspirin with the same Index had a HR for total CVD of 2.12 (1.08-4.13) and total stroke of 2.67 (0.89-8.03). These HRs were not statistically significant (HR crossed 1; ≥0.05) for other Index quintiles (4.9-5.7%, 5.7-6.8%, and >6.8%). The
p
-value for the linear trend test was 0.029 for total CVD and 0.009 for total stroke in those taking aspirin and ≥0.05 for those not taking aspirin when assessing all of the Index quintiles. The
p
-value for total quadratic fit was 0.29 for total CVD and 0.04 for total stroke in those taking aspirin and ≥0.05 for those not taking aspirin when assessing all of the Index quintiles.

Conclusions:
Overall, a low to moderate EPA and DHA red blood cell level was associated with opposite outcomes in those who were or were not taking aspirin. A low to moderate Omega-3 Index may adversely affect the benefits of aspirin ingestion, which is potentially of great importance for individuals at high risk for CVD events.
Abstract 16650: EDEM3 Modulates the Plasma Triglyceride Level via Its Regulation of LRP1 Expression
Authors: Xu Yu-Xin , Peloso Gina , Nagai Taylor H , Deik Amy , Clish Clary , Rader Dan , Kathiresan Sekar
Published: April 2024

Population genetic studies have provided abundant insight about the development of diseases in all kinds, which has been validated to be instrumental to prioritize biological research and molecular targets for therapeutic intervention. Here we show another example of endoplasmic reticulum (ER) - degradation alpha -mannosidase like protein 3 (EDEM3) in this aspect. We first used a population genetic approach to highlight a variant in the coding region of EDEM3 that is significantly associated with lower blood triglyceride level in a cohort with >30,000 individuals worldwide. Our functional analysis show that the deletion of EDEM3 gene induced a strong uptake of very low-density lipoprotein (VLDL), but not LDL, as a result of up-regulated expression of low-density lipoprotein receptor (LDLR) - related protein 1 (LRP1). We found that the deletion of EDEM3 gene increased more mannose-containing glycoproteins on cell surface, but without altering the sensitivity of cells to ER stress. Our pathway analyses demonstrate that the gene deletion up-regulated the pathways for RNA and ER protein processing and transport, while down-regulated the metabolic pathways, which may help to maintain a normal response to ER stress, and facilitate the processing and transport of the mannose-containing glycoproteins including LRP1 to cell surface. Lipid metabolite analyses reveal a cellular accumulation of TG under EDEM3 deficiency, in particular those with shorter carbon-chains, a profile largely opposite to the one of the plasma from individuals carrying the EDEM3 missense mutation, suggesting that the data from our functional analysis are consistent with the phenotype of genetic perturbation of EDEM3. Thus, our study identifies EDEM3 as a regulator of plasma TG, and targeted inhibition of EDEM3 expression may provide opportunity for plasma TG lowering.
Abstract 16654: The Role of Glycolytic ATP Generation in the Restoration of Vascular Endothelial Barrier Function
Authors: Gajwani Priyanka , Wang Li , Chaturvedi Pallavi , Krantz Sarah , Malik Asrar , Karginov Andrei , Rehman Jalees
Published: April 2024

Introduction:
Acute Lung Injury (ALI) is characterized by endothelial barrier dysfunction of the lung vasculature, leading to disassembly of endothelial adherens junctions, increased vascular permeability and fluid accumulation in the lungs. Little is known about the bioenergetics of the barrier disruption and repair processes. The glycolysis regulatory enzyme PFKFB3 has recently been identified as a key mediator of endothelial glucose metabolism and could thus serve as a potential mediator of barrier repair.

Methods and Results:
To quantitatively measure metabolic changes in response to an inflammatory stimulus, we performed a Seahorse bioenergetic flux assay using human lung microvascular endothelial cells (HLMVECs). Glycolysis, as measured by the extracellular acidification rate, increased acutely by 36% (from 9.1 to 12.4 mpH/min) following treatment with the inflammatory mediator TNFα. This upregulation was abolished in the presence of PFK15, a specific inhibitor of PFKFB3. PFKFB3 activity was also necessary for barrier restoration of HLMVECs following injury, as measured by a transendothelial electrical resistance (TER) assay (p<0.0001). Live cell microscopy of endothelial cells expressing the ATP biosensor Perceval HR revealed that ATP is generated at cell junctions following TNFα treatment. Additionally, controlled translocation of PFKFB3 to the plasma membrane resulted in enhanced barrier restoration after injury, both in terms of the extent of barrier integrity as well as the rate of recovery (p<0.0001). Finally, PFKFB3 was pharmacologically inhibited
in vivo
following lung injury with the bacterial toxin LPS in mice. This inhibition resulted in significantly impaired recovery of lung vascular barrier function as measured by an Evans blue albumin (EBA) permeability assay (p<0.001). Endothelial cell-specific overexpression of PFKFB3 in mice by liposomal delivery resulted in an enhanced rate of recovery from LPS mediated injury. Lung vascular leakiness decreased from 29.0 to 18.3 ng EBA/g body weight at two days following the LPS injury (p<0.001), thus achieving pre-injury levels of barrier function.

Conclusions:
Glycolytic ATP generation regulated by PFKFB3 is essential for restoration of the endothelial barrier after inflammatory injury. A better understanding of the endothelial barrier bioenergetics could allow for the development of novel therapeutic approaches which enhance barrier function in severe diseases such as acute lung injury.
Abstract 16658: Patient Selection for Long-Term Secondary Prevention With Ticagrelor: Insights From PEGASUS-TIMI 54
Authors: Bonaca Marc P , Storey Robert F , Bhatt Deepak L , Steg P. Gabriel , Cohen Marc , Im KyungAh P , Johanson Per , Braunwald Eugene P , Sabatine Marc S
Published: April 2024

Introduction:
Long-term treatment with ticagrelor 60 mg added to ASA reduces ischemic risk but increases bleeding in patients with prior MI.

Hypothesis:
Clinical characteristics predicting bleeding and ischemic risk respectively applied in PEGASUS-TIMI 54 (NCT01225562) will identify subgroups who derive greater benefit with lower risk

Methods:
Predictors of bleeding (anemia at baseline, prior hospitalization for bleeding) and subgroups associated with greater ischemic risk reduction were merged into a selection algorithm. Efficacy (PEP - CV death, MI or stroke), safety (TIMI major bleeding) and net outcomes (CV death, MI, stroke, ICH or fatal bleeding) of ticagrelor 60 mg were evaluated by risk group.

Results:
Patients (N=13938) were divided into 4 groups first by the presence of a bleeding predictor (High Bleeding Risk - HBR, N=2703, 19%) and then the remainder (Low Bleeding Risk - LBR, N=11235, 81%) divided by the number of ischemic risk factors. In those with HBR, ticagrelor did not reduce the PEP (ARD 0.0%) but did increase bleeding by 2.2%. Of those with LBR, 22% had only 0 or 1 ischemic risk indicators, and in this subgroup ticagrelor reduced PEP by 0.5%, but increased bleeding by 1.0%. The remaining 59% of patients had no bleeding risk indicators and at least 2 ischemic risk indicators, and in this subgroup ticagrelor significantly reduced the risk of the PEP by 1.9% (P=0.0024, NNT 52) and only increased bleeding by 1.0% (P<0.0001, NNH 102). In this latter subgroup, ticagrelor significantly reduced CV death (HR 0.66, 95% CI 0.50 - 87, p=0.0034, ARR 1.2%) and all-cause mortality (HR 0.75, 95% CI 0.61 - 0.95, p=0.018, ARR 1.1%) and the net outcomes (HR 0.80, 95% CI 0.68 - 0.93, p=0.0031, ARR 1.9%).

Conclusions:
A patient selection strategy first identifying those at low bleeding risk and then stratifying according to number of ischemic high-risk features identifies a population that derives significant ischemic benefit with reductions in all-cause mortality and net outcomes.
Abstract 16662: Microvesicle Release During Exercise-Induced Cardiovascular Stress in Young Adult Hypertension
Authors: Ayers Lisa , Lewandowski Adam J , Huckstep Odaro J , Williamson Wilby , Ferry Berne , Leeson Paul
Published: April 2024

Introduction:
Microvesicles are elevated in the circulation during cardiac stress; a response that is blunted in those with cardiovascular disease. Microvesicles play both activating and regulatory roles in the pathogenesis of hypertension, and their release is believed to be a protective mechanism during cardiac stress.

Hypothesis:
We hypothesised that microvesicle release during exercise-induced cardiac stress differs in young adults with and without hypertension.

Methods:
Microvesicle release was measured in 106 participants (79 normotensive, 27 hypertensive). Blood samples were obtained during maximal exercise testing at three time-points: before, immediately post and following 20 minutes recovery. The level of microvesicle procoagulant activity was determined in all participants. Microvesicles were phenotyped by flow cytometry in a subset of participants.

Results:
Exercise was associated with a significant elevation in the total procoagulant activity of microvesicles (p<0.001) and this increase was significantly higher in the normotensive group than the hypertensives (median(IQR) +0.7(0.0-2.1) vs -0.1(-0.4-0.4), p=0.001). Circulating procoagulant, platelet, endothelial, leucocyte, granulocyte and monocyte-derived microvesicles were shown to be elevated during exercise (p<0.05). The elevation in endothelial and leucocyte microvesicle levels returned to baseline within 20 minutes recovery. The significant elevation in procoagulant, platelet, granulocyte and monocyte-derived microvesicles was only seen in the normotensive participants, not in those with hypertension. Furthermore, amongst the normotensive participants, those with a blunted release of platelet microvesicles had higher peak diastolic blood pressures (86.8±8.4 vs 73.5±14.5, p=0.028) during exercise and increased global arterial stiffness measured at rest by the cardio-ankle vascular index (CAVI: 6.1±0.6 vs 5.4±0.5, p=0.022).

Conclusions:
In young adult hypertension there is a blunted release of microvesicles during exercise-induced cardiac stress. Normotensive young adults with a blunted platelet microvesicle release demonstrate early markers of future hypertension risk with greater peripheral resistance and arterial stiffness.
Abstract 16692: Clinical Outcomes of Ambulatory Heart Failure Patients Managed With an Intra-Aortic Balloon Pump Prior to Left Ventricular Assist Device Implantation
Authors: Ternus Bradley , Behfar Atta , Schirger John , Maltais Simon , Barsness Gregory , Stulak John , Jentzer Jacob
Published: April 2024

Introduction:
Patients at increased risk of complications following LVAD placement are admitted to the hospital for hemodynamic optimization prior to LVAD implantation, which can include adjustment of medical therapy and/or placement of an IABP.

Hypothesis:
Prior to LVAD placement patients treated with an IABP during hemodynamic optimization will have similar outcomes despite worse baseline characteristics compared with patients treated medically.

Methods:
This single-center study included 199 non-inotrope dependent patients who underwent durable LVAD implantation between January 1
st
, 2007 and April 10
th
2017. Hemodynamic data was collected retrospectively. Patients who received an IABP were compared to those who did not. Stage 2 or 3 acute kidney injury, right ventricular failure, and 30 day mortality was compared between patients with and without and IABP.

Results:
The mean age was 62.7 and 82.9% were male; 72 (36.2%) received an IABP. Baseline characteristics between groups were similar. Patients treated with an IABP had worse INTERMACS profiles and worse baseline hemodynamic parameters. The incidence of the primary composite endpoint was similar between patients who had an IABP and those who did not (23.6% vs 19.7%; p=0.517), as were each of the individual endpoints: stage 2 or 3 acute kidney injury (18.1% vs 14.2%; p=0.472), right ventricular failure (13.9% vs 13.4%; p=0.796), and 30 day mortality (6.9 % vs 3.2%; p=0.226). Patients treated with an IABP had greater relative reductions in mean right atrial pressure (-24.1% vs -5.9%; p=0.044), pulmonary artery systolic (-11.7% vs +3.3%; p=<0.001), diastolic (-17.0% vs +12.0%; p=0.015), and mean pressures (-15.2% vs 0.5%; p=<0.001).

Conclusions:
Despite worse hemodynamic parameters and INTERMACS profile at baseline, ambulatory heart failure patients who received an IABP prior to LVAD implantation did not have an increased incident of stage 2 or 3 acute kidney injury, right ventricular failure, or 30 day mortality, and had more favorable reductions in right atrial and pulmonary artery pressures. These results suggest that the use of the IABP prior to LVAD implantation in non-inotrope dependent patients with poor baseline hemodynamics may mitigate the risk of postoperative complications.
Abstract 16704: Treating Children Like Little Adults: Pediatrician Communication About High Blood Pressure Includes Diminution and Targeting Children With High Systolic Blood Pressures Exceeding Adult Thresholds
Authors: Bismar Nora , Brady Tammy M , Turer Christy B
Published: April 2024

Introduction:
High blood pressure (BP) in children is under recognized by pediatric providers. Our aim was to describe and determine factors associated with provider communication of high BP during visits with a child with an elevated BP.

Hypothesis:
Few providers will communicate that BP is high.

Methods:
Cross-sectional analysis of video/audio-recorded well-child visits of 6–12-year-olds with overweight/obesity recruited from academic and private clinics (2014–15). Elevated BP and hypertension (HTN) were identified by applying contemporary pediatric HTN thresholds to EHR-stored BP data. Systolic BP (SBP) exceeding the adult threshold of ≥120 mmHg also was determined. Recorded visits were transcribed/analyzed. Two independent reviewers used transcript data to identify BP communication and establish communication themes. Chi-square was used to test if SBP elevation ≥120 mmHg is associated with communication of high BP in children.

Results:
A child had an elevated BP at 34 of 100 visits; 30 were valid recordings with 23 providers. Of these encounters, mean age was 8.7 years (y); 37% were overweight, 63%, obese; 37%, Black, and 47%, Latino. At the visit, 53% had elevated BPs (of which, 38% met diagnostic criteria for elevated BP and 0% for HTN); 47% had HTN-level BPs (29% met criteria for elevated BP and 43% for HTN); 37% had SBP ≥120 mmHg. Major themes for how pediatricians communicate about BP included: direct, unclear, minimize and absent. Communication of high BP was direct in 17% of visits, unclear, 17%, minimize, 13%, and absent, 67%. Exemplifying direct communication, a pediatrician said, ‘
Your BP’s a little bit high
[avg. SBP 134]
. 120 is the highest we want for her age
[11 y].’ An example of ’unclear’ was, ‘
The biggest reason I worry about this
[obesity]
is you can start having adult problems like high BP
,’ (8 y, BP 115/76, 93%). A quote illustrating ’minimize’ was, ‘
BP is a bit high. He’s just nervous
,’ (8 y, BP 114/75, 91%). Exceeding the adult elevated-BP threshold was associated with direct communication, which occurred in 80% of visits with SBP ≥120, vs. 20% with <120 (
P
=.047).

Conclusions:
During well-child visits, most overweight children with high BP receive no communication that BP is high. Of those who do, communication commonly is unclear or dismissive, and more likely when SBP exceeds the adult high-BP threshold.
Abstract 16713: Defining the Tbx5-Dependent miRNA Regulatory Networks of Atrial Fibrillation
Authors: Lazarevic Sonja , Nadadur Rangarajan D , Gadek Margaret , Shen Kaitlyn M , Perez-Cervantes Carlos , Laforest Brigitte , Yang Xinan H , Weber Christopher R , Moskowitz Ivan P
Published: April 2024

Atrial fibrillation (AF) is the most commonly diagnosed arrhythmic disorder, characterized by random electrical activity in the heart. Complications of AF include stroke and heart failure, which makes understanding the molecular mechanism underlying this conduction defect imperative. The
Tbx5
locus has been implicated by genome wide association studies (GWAS) to have an increased risk for AF. Our lab has previously demonstrated the absence of this transcription factor leads to spontaneous and sustained AF, which corroborates the importance of
Tbx5
in the maintenance of cardiac rhythm. While
Tbx5
is known to drive the network for cardiac rhythm, the downstream regulatory components need to be further characterized, including the downstream miRNAs. The components involved in cardiac rhythm are dose sensitive, therefore small perturbations in gene expression can lead to arrhythmias. Maintaining stable levels of gene expression can be regulated with miRNAs, which provide a negative feedback in dose sensitive pathways.

Tbx5
-deficient mice developed spontaneous, sustained AF; in order to further interrogate the TBX5-dependent pathway that led to AF, we transcriptionally profiled small RNAs from the left atrium of
Tbx5
-deficient mice. The most downregulated TBX5-dependent miRNA was miR10b. In concordance with previous publications, our miR10b mimic and inhibitor experiments in HL-1 cardiomyocytes demonstrate that miR10b negatively regulates
Tbx5
expression. Therefore, we hypothesized that miR10b was crucial in the maintenance of atrial rhythm. Cellular electrophysiology studies with the overexpression of miR10b in HL-1 cardiomyocytes led to the elongation of atrial action potentials, similar to the phenotype we saw in the
Tbx5
-deficient atrial tissue. Using whole mouse electrophysiology, we found that the mir10b removal in the hearts leads to increased AF susceptibility. Thus, providing evidence that mirR10b is crucial for the maintenance of normal cardiac conduction. In order to identify other miRNAs essential for cardiac conduction, we examined the other TBX5-dependent miRNAs in a high-throughput calcium screen. Further defining the miRNAs can provide a better understanding of the regulatory mechanisms crucial for cardiac conduction.
Abstract 16729: Pressure Adjusted Heart Rate as a Predictor Ofadverse Outcomesafter Left Ventricular Assist Device Implantation
Authors: Ternus Bradley , Behfar Atta , Schirger John , Maltais Simon , Barsness Gregory , Stulak John , Jentzer Jacob
Published: April 2024

Introduction:
Baseline hemodynamic parameters have been shown to predict postoperative outcomes such as right ventricular failure (RVF) in LVAD patients. The pressure adjusted heart rate (PaHR) is a hemodynamic parameter that has not been reported in LVAD recipients.

Hypothesis:
Patients with an elevated PaHR at baseline will have an increased risk of adverse outcomes following LVAD implantation.

Methods:
Historical cohort study of 273 patients with preoperative invasive hemodynamic assessment before durable LVAD implantation from January 1
st
, 2007 to April 10
th
2017. Baseline patient characteristics and hemodynamic parameters were assessed. The primary endpoint was a composite of 30 day mortality, stage 3 acute kidney injury (AKI), and postoperative RVF. Univariate analysis was used to identify predictors of the composite endpoint, which were entered into stepwise backwards multivariate logistic regression to determine independent predictors of the composite outcome.

Results:
The mean age was 59 and 79% of the patients were male. The median INTERMACS profile was 4 and 166 (60%) of LVADs placed were as destination therapy. The primary composite endpoint was reached by 74 (27%) patient, including 30-day mortality in 13 (5%), severe AKI in 48 (18%) and RVF in 53 (19%). Univariate predictors of the composite endpoint (p <0.05) included atrial fibrillation, INTERMACS profile, home inotropes, preoperative IABP, admission creatinine, baseline Vasoactive-Inotropic Score, mean right atrial pressure (mRAP), mRAP/wedge, mean arterial pressure/mRAP, mean pulmonary artery pressure/mRAP, right ventricular stroke work index (RVSWi), pulmonary artery pulsatility index, and the PaHR. Logistic regression identified PaHR (OR 0.96, 95% CI 0.93-0.99, p=.026), RVSWi (OR 1.002, 95% CI 1.001-1.004, p=.002), home inotropes (OR 0.46, 95% CI 0.22-0.94, p=.034), atrial fibrillation (OR 0.48, 95% CI 0.26-0.88, p=.019) and admission creatinine (OR 0.51, 95% CI 0.34-0.77, p=0.002) as predictors of the composite endpoint.

Conclusions:
The PaHR is a readily available, novel hemodynamic parameter, that when elevated on baseline hemodynamic assessment can predict those patients at increased risk of postoperative adverse outcomes after durable LVAD implantation.
Abstract 16732: Differential Association of Various Cardiac Hemodynamic Parameters With Renal Dysfunction in End-Stage Heart Failure Patients
Authors: Melvinsdottir Inga M , Hess Timothy M , Dhingra Ravi
Published: April 2024

Introduction:
Decreased cardiac output is often thought to be the main determinant of renal dysfunction in patients with heart failure. However, large cohort studies are lacking to show these correlations in patients with end stage heart failure.

Methods:
We selected all adult patients between 2007-2016 who were listed for heart transplant (n=11,030) after excluding those on life support, inotropes, nitric oxide, total artificial heart, percutaneous mechanical or ECMO support, dialysis dependent, biventricular or only right ventricular assist device support and with prior heart or kidney transplant using the United Network for Organ Sharing database. We evaluated associations between renal function and three hemodynamic parameters: 1) cardiac index (CI), 2) mean pulmonary artery pressure (mPA) and 3) pulmonary vascular resistance (PVR) using robust regression models.

Results:
Average age of patients was 53.5±12.3 years (23% females) with mean estimated glomerular filtration rate (eGFR) of 71.7±26.2 mL/min/1.73m
2
. Nearly half (49%) of the patients had left ventricular assist devices (LVAD) with mPA pressure of 26.2±9.9 mmHg and average CI of 2.4±0.7. There was an inverse correlation between mPA pressure and eGFR (p<0.001) however no association between CI and eGFR (p=0.853); or between PVR and eGFR (p=0.989). After multivariate adjustment, mPA pressure was inversely correlated with eGFR (p<0.001). Subgroup analysis of individuals with LVADs (N=5,417) showed similar results with significant inverse relations between mPA and eGFR (p= 0.008) and no significant correlation between PVR or CI and eGFR (p>0.2 for both). Analysis restricted to individuals with low CI (< 1.8 L/min/m
2
) and PVR < 4 Woods Units (n=8376) also showed inverse linear correlation between mPA pressures up to 45 mmHg and eGFR (p<0.001).

Conclusions:
Among patients with end stage heart failure, higher mPA pressure and not the lower cardiac index are cross-sectionally related to lower eGFR values.
Abstract 16745: Incremental Prognostic Value of Get With the Guidelines Heart Failure Risk Score and Comorbidity in Patients Admitted for Acute Decompensated Heart Failure: Insights From Osaka Prefectural Acute Heart Failure Registry (OPAR)
Authors: Kayama Kiyomi , Yamada Takahisa , Morita Takashi , Furukawa Yoshiro , Tamaki Syunsuke , Iwasaki Yusuke , Kawasaki Masato , Kikuchi Atsushi , Kawai Tsutomu , Seo Masahiro , Abe Makoto , Nakamura Jun , Yamamoto Kyoko , Kawahira Masatugu , Tanabe Kazuya , Fukunami Masatake
Published: April 2024

Background:
The Get With the Guidelines-Heart Failure (GWTG-HF) risk score was recently developed to predict in-hospital mortality in patients (pts) admitted with acute decompensated heart failure (ADHF). On the other hand, comorbidity is also associated with poor clinical outcome in HF patients. However, there is no information available on the prognostic value of combining GWTG-HF risk score and comorbidity in patients admitted for ADHF.

Methods:
We prospectively studied 396 ADHF patients with survival discharge. GWTG risk score consists of 7 admission variables (blood urea nitrogen, systolic blood pressure, age, sodium, heart rate, race, and lung disease). Comorbidity was measured with the Age-adjusted Charlson comorbidity index (ACCI) which is commonly used for the evaluation of the comorbid condition which is weighted and scored, with additional points added for age. The endpoint was all-cause death (ACD).

Results:
During a follow-up period of 2.2±1.4 years, 114 patients had ACD. At multivariate Cox analysis, GWTG-HF risk score (p<0.0001) and ACCI (p=0.0077) were significantly and independently associated with ACD, after the adjustment with sex, NYHA class, history of worsening heart failure hospitalization, LVEF, eGFR and plasma BNP level at the discharge. Patients with both higher GWTG-HF risk score (>39 by ROC analysis, AUC 0.714 [95%CI 0.667-0.758]) and higher CCI (>5 by ROC analysis, AUC 0.653 [95%CI 0.604-0.700]) had a significantly increased risk of ACD than either or none of them (46% vs 28% vs 7%, p<0.0001). Adjusted hazard ratio in patients with both higher GWTG-HF risk score and ACCI was 9.4 (95%CI 4.3-20.6), which was two-fold of that in patients with either of them (4.5[95%CI 2.0-10.1]).

Conclusions:
GWTG-HF risk score and comorbidity had an prognostic incremental value in patients admitted for ADHF.
Abstract 16747: High Incidence of Congenital Heart Defects in a Dominant Mouse Forward Genetic Screen Using Fetal Echocardiography
Authors: Tan Tuantuan , Wang Michael , Radomile Caleb W , Ho Sebastian Elliot , William Devine , Liu Xiaoqin , Laura Reinholdt , Wu Yijen , Meyer Lauren Elizabeth , Lo Cecilia W
Published: April 2024

Introduction:
Congenital heart disease (CHD) is largely sporadic and suggested to be largely mediated by non-Mendelian or complex genetics. We previously showed the efficacy of mouse mutagenesis in recovering recessive mutations causing CHD. Here we hypothesize the complex genetics of human CHD can be modeled in mice using a sensitized mutagenesis screen for dominant mutations causing CHD.

Methods:
C57BL/6J mice were mutagenized using ethylnirosourea, then mated with C57BL/6J mice to generate G1 males that were further mated to females harboring heterozygous “driver” mutation (
Kif7, Anks6, Sap130
) that can cause CHD when in homozygosity. The G2 fetuses generated by each G1 male were considered a pedigree and were ultrasound scanned (US) at E13.5-19.5 using a 40 MHz transducer with the Vevo2100 ultrasound system.

Results:
We US scanned 17,750 fetuses from 487 G1 pedigrees, yielding 123 fetuses with CHD from 90 G1 lines (Table 1A). Interestingly, the overall incidence of CHD (0.69%) is similar to that observed in the previous recessive mutagenesis screen (0.76%) (Table 1A). Surprisingly, no laterality mutants were recovered compared to the 2.2% recovered in the recessive screen (Table 1A). Regardless of the driver mutations, similar spectrum of CHD was observed (Table 1B). Besides VSD, the predominant CHD phenotype observed was double outlet right ventricle and overriding aorta (Fig.1) and atrioventricular septal defect (Table 1B).

Conclusion:
We showed the feasibility of using mice to model dominant mutations causing CHD. The incidence of CHD observed in the dominant screen was similar to that of the recessive screen, indicating the genetics of CHD in mice and human are similar.
Abstract 16758: The Role of Estrogen Receptor Alpha in Preserving Right Ventricular Mitochondrial Respiration in Pressure Overload
Authors: Cheng Tik-Chee , Philip Jennifer L , Kumari Santosh , Tabima Diana M , Hacker Timothy A , Li Rongbo , Sun Xin , Goss Kara , Lahm Tim , Chesler Naomi C
Published: April 2024

Background:
Pulmonary arterial hypertension (PAH) occurs more often in women, but women exhibit better survival. Rodent models of PAH suggest a right ventricular (RV) protective effect of estrogen signaling through estrogen receptor alpha (ERα). While estrogen regulates mitochondrial biogenesis and function, the role of ERα in preserving RV mitochondrial function in the setting of pressure overload is unknown.

Methods:
Estrogen receptor alpha knockout (ERKO) rats were created using a CRISPR/Cas9 system. Male and female ERKO and littermate control (WT) rats underwent pulmonary artery banding (PAB) or sham surgery. After 10 weeks, RV systolic pressure (RVSP) and contractility as measured by dP/dt
max
were recorded by open-chest right heart catheterization. RV hypertrophy was measured by normalizing RV free wall weight to tibia length (TL). Permeabilized muscle fibers from the RV were placed in a high-resolution respirometer in the presence of substrates and inhibitors to measure mitochondrial respiration.

Results:
PAB caused a greater increase in RVSP (Fig. A) and contractility (Fig. B) in the ERKO compared to WT rats. WT and ERKO had comparable degrees of RV hypertrophy (Fig. C). RV muscle fiber respiratory control ratio (RCR) demonstrated a significant positive correlation with RVSP in ERKO rats (Fig. D) not found in WT rats, suggesting that pressure overload is associated with enhanced mitochondrial coupling in the absence of ERα. A decrease in State 4 ADP-depleted respiration in ERKO rats (Fig. E) accounts for the decrease in RCR. PAB did not alter Complex II or Complex IV respiration in either ERKO or WT rats.

Conclusions:
Whereas in the presence of ERα RV adaptation to pressure overload is independent of mitochondrial respiration changes, in the absence of ERα, pressure overload decreased State 4 ADP-depleted respiration, suggesting that ERα regulates RV mechanoenergetic remodeling due to pressure overload.
Abstract 16769: QT Prolongation and Variability Among Patients With Rett Syndrome
Authors: Jutzy Gregory J , Heydemann Peter , Buhrfiend Colleen , Nguyen Hoang H
Published: April 2024

Introduction:
Rett syndrome (RTT) is caused by mutations in the MECP2 genes resulting in various neurological, gastrointestinal, and respiratory symptoms. Prolonged corrected QT interval (QTc) is also reported and thought to be a cause of sudden death in RTT. However, characterization of QTc, its clinical correlation, and association with other clinical features of RTT has been limited. For example, while the incidence of prolonged QTc in RTT varies widely in previous reports, no previous studies have looked at QTc variability, which is an important electrophysiological characteristic affecting both the incidence of prolonged QTc and risk of sudden death.

Hypothesis:
QTc in RTT has a greater variability than QTc in a healthy age-and-gender matched historical control.

Methods:
Retrospective chart review of RTT patients with serial electrocardiograms (ECGs) was performed. Each ECG was manually read by two pediatric cardiologists, and the QTc was calculated using Bazett’s formula. ECGs while a patient was given potentially QTc prolonging medications were excluded. Prolonged QTc was defined as ≥ 460 ms for pre-pubertal and ≥ 480 ms for post-pubertal females. QTc variability, defined as the difference of the maximum and minimum QTc, was calculated for each patient and compared to a healthy age-and-gender matched historical control.

Results:
A total of 30 RTT patients (all females) and 116 ECGs were included in the study. The mean QTc was 442 ms (383—534 ms).Patient age rage was from 1- 45 years. The mean intra-subject variability in QTc in our patient cohort was significantly greater than that of the control cohort (16.5 ms vs. 8.1 ms,
P
< 0.001). Twenty-one patients (70%) had variability greater than 2 standard deviations of the control group. The mean inter-subject variability in QTc was 26.8 ms (1.4 - 42 ms). The incidence of prolonged QTc in our cohort was 60% (18/30). However, the incidence of persistent prolonged QTc was 7% (2/30).

Conclusions:
QTc in RTT has a significantly larger variability than that of healthy controls. Given this QTc variability over time and its assocaition with increased risks of sudden death, serial evaluation of not only QTc but also QTc variability and dispersion should be part of the routine cardiac evaluation of RTT patients.
Abstract 16770: Aortic Stiffness is Negatively Associated With Physical Activity in Children With Congenital Heart Disease
Authors: Lopez Jimmy , Voss Christine , Hemphill Nicole M , Kuan Mimi , Pozas Ana Lucia , Harris Kevin C
Published: April 2024

Introduction:
Aortic stiffness is an important marker of cardiovascular risk and is increased in children with repaired congenital heart disease (CHD). We have observed and reported on this in children with Tetralogy of Fallot (TOF), Coarctation of the Aorta (CoA), Transposition of the Great Arteries (TGA) and Fontan circulation (FON). Physical activity (PA) is a key determinant of optimal vascular health in children. In children with CHD, we know little about the interaction between PA and aortic stiffness.

Hypothesis:
There is an inverse association between PA and aortic stiffness in children with TOF, CoA, TGA and FON.

Methods:
We recruited children aged 9-16 years old with TOF, CoA, TGA and FON during routine clinic visits. PA was objectively assessed using an ActiGraph accelerometer over the right hip during waking hours for 7 consecutive days. Daily minutes of moderate-to-vigorous PA and vigorous PA were averaged over at least 3 valid measurement days, using Evenson cut-points. We measured aortic pulse-wave-velocity (PWV) using standard echocardiographic technique. We calculated PWV (cm/s) by dividing the length of the aortic arch by the transit time from the ascending to descending aorta averaged across 6 consecutive cardiac cycles. Nonparametric statistical tests were used to compare aortic PWV and PA data (p<0.05).

Results:
Participants (n=68, 60% male) were 12.6 ± 2.3 years old (n=18 TOF, n=20 CoA, n=12 TGA, n=18 FON). Median daily moderate-to-vigorous PA was 45 (IQR: 34-64) minutes/day and vigorous PA was 11 (6-19) minutes/day. Median aortic PWV was 545 cm/s (409-710), which was significantly higher than for children without CHD (~360 cm/s, p<0.001). Lower aortic PWV values were related to higher levels of PA in terms of moderate-to-vigorous PA and vigorous PA (rho=-0.336, p=0.005 and rho=-0.323, p=0.007 respectively).

Conclusions:
In children with TOF, CoA, TGA and FON, higher levels of PA are associated with better vascular function as measured by aortic PWV. Aortic PWV is elevated in these groups compared to healthy children. The association between PA and vascular function in children with CHD supports the need for care providers to focus on routinely promoting PA in this at risk population.
Abstract 16781: The Association Between Electronic Cigarette Use and Cardiovascular Disease According to Smoking Status: Brfss 2016
Authors: Mirbolouk Hassan , Kianoush Sina , Charkhchi Paniz , Orimoloye Olusola A. , Uddin S M Iftekhar , DeFilippis Andrew P. , Bhatnagar Aruni , Nasir Khurram , Blaha Michael J
Published: April 2024

Background:
E-cigarettes are a consumer product designed to deliver nicotine by heating a liquid produced from tobacco. Usage in the US is growing rapidly and is common among combustible cigarette users (dual use). The impact of E-cigarettes on cardiovascular disease is unknown.

Aim:
A cross-sectional examination of e-cigarette use with self-reported cardiovascular disease, according to smoking status, using the nationally representative health survey - the Behavioral Risk Factor Surveillance System (BRFSS) 2016

Methods:
We included 404,332 BRFSS 2016 participants with information on the history of CVD and e-cigarette use. E-cigarette use was categorized as never (reference), occasional, and daily with daily +occasional e-cigarette users considered current e-cigarette users. The association of e-cigarette use and CVD (defined as self-reported coronary heart disease, myocardial infarction, or stroke) was assessed using multivariable logistic regression models stratified by smoking status (never, former, current [occasional or daily]), adjusted for age, sex and race.

Results:
Of the total population, there were 15,240 e-cigarette users and 85,402 with CVD. Compared to those who never used e-cigarettes, current e-cigarette users had significantly higher odds of having CVD among current smoker groups (occasional smoker: Odds Ratio (OR)= 1.36 (95% CI= 1.06 - 1.76); daily smoker: OR=1.34 (1.12 - 1.62)). Daily use of e-cigarettes among occasional smokers was significantly associated with higher odds of having CVD (OR=1.64 (1.05 - 2.57)).
(Table)
There was no association between e-cigarette use and CVD among never and former smokers.

Strengths and Limitations:
Because of large sample size, we were powered to stratify e-cigarette use by smoking status. However, BRFSSS does contain directly measured risk factors or pack-years of smoking.

Conclusions:
Dual use of e-cigarette and combustible cigarettes is a new pattern of tobacco product use that may be associated with more CVD.
Abstract 16809: Geographic Variations in Discharge Outcomes of Cardiac Arrest From 2011-2015: A Nationwide Analysis
Authors: Chen Laura M , Modi Vivek , Pan Di
Published: April 2024

Objective:
We investigated the discharge outcomes of patients with cardiac arrest across nine hospital divisions in the United States from 2011 to 2015.

Methods:
This is a retrospective analysis based on the 2011-2015 Nationwide Inpatient Sample (NIS) databases. Patients with a primary diagnosis of cardiac arrest and who received CPR were included. Multivariate logistic regression was performed to reveal variations in discharge outcomes over nine hospital divisions (New England (NE), Mid-Atlantic (MA), East North Central (ESC), West North Central, South Atlantic, East South Central, West South Central (WSC), Mountain, and Pacific). Diagnoses were identified with ICD-9 codes. The fourth quartile of 2015 NIS was excluded due to the transition to ICD-10 codes.

Results:
Hospitals in NE had fewer discharges home compared to divisions except in MA and ESC. NE had more discharges to short term hospitals (STH) compared to divisions except Pacific. NE had more discharges to skilled nursing facility (SNF) compared to MA and Pacific divisions. NE had fewer deaths compared to MA, ESC, and Pacific divisions. NE had more palliative care encounters compared to ESC and WSC divisions.

Conclusions:
Discharge outcomes of cardiac arrest patients varied by geography in the United States; NE hospitals had fewer discharges home and deaths, while had more discharges to STH and SNF. They also had higher palliative care encounters.