bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16472: Deciphering a Mechanistic Link Between Enhanced Late Sodium Current and Triggered Atrial Fibrillation Using Patient-specific and Gene-corrected Induced Pluripotent Stem Cell-derived Atrial Cardiomyocytes
Authors: HONG Liang , Ly Olivia T , Chen Hanna , Sridhar Arvind , Zhang Meihong , Lambers Erin , Chalazan Brandon , Youn Seock-Won , Maienschein-Cline Mark , Feferman Leonid , Ong Sang-Ging , Wu Joseph C , Rehman Jalees , Darbar Dawood
Published: May 2021

Introduction:
Gain-of-function mutations in
SCN5A,
which encodes the cardiac sodium channel, have been linked with familial atrial fibrillation (AF). However, the mechanistic link between the late sodium current (I
Na,L
) and triggered arrhythmia remains unclear.

Hypothesis:
To characterize the electrophysiological (EP) phenotype of gain-of-function AF-linked SCN5A mutations, elucidate the underlying cellular mechanisms using patient-specific and gene-corrected (GC) induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs).

Methods:
We generated iPSC-aCMs from two families carrying SCN5A mutations (E428K and N470K) and control subjects. Whole-cell patch clamp and multi-electrode arrays were recorded to assess the EP phenotypes of the atrial iPSC-CMs. We corrected the E428K iPSC-aCMs using CRISPR/Cas9 gene editing approach (isogenic control).

Results:
The
SCN5A
mutation lines displayed abnormal EP properties including increased beating frequency and irregularity with triggered beats characteristic of AF (
Fig. 1
). E428K iPSC-aCMs displayed spontaneous arrhythmogenic activity with beat-to-beat irregularity (
Fig. 1 A-D
) with the prolonged APD (
Fig. 1 E-H
) associated with enhanced I
Na,L
(
Fig. 1 I-L
). In contrast, expression of
SCN5A
-E428K in heterologous expression system failed to show enhanced I
Na,L
. The gene-corrected E428K iPSC-aCMs normalized the aberrant EP phenotype. Gene expression profiling revealed differential expression of calcium and potassium channel homeostasis and nitric oxide mediated signal transduction which could result in EP remodeling of atrial CMs.

Conclusions:
Patient-specific and gene-corrected iPSC-aCMs exhibited striking
ex-vivo
EP phenotype of an AF-causing
SCN5A
gain-of-function mutation that produced minimal changes
in-vitro
. We established a mechanistic link between enhanced I
Na,L
, ion channel remodeling and nitric oxide signaling pathways, and triggered AF.
Abstract 16482: Cardiac Remodeling During Pregnancy With Challenge: A Prologue of Pathological Remodeling
Authors: Yang Yijun , Kurian Justin , Schena Giana , Johnson Jaslyn , KUBO Hajime , Kang Chunya , Lucchese Anna Maria , Eaton Deborah , Khan Mohsin , Mohsin Sadia , Houser Steven R
Published: May 2021

Introduction:
Life-style changes in the past decades have led to an increased incidence of metabolic syndrome (MetS), obesity and hypertension in women of childbearing age. These comorbidities are known to predispose individuals to adverse cardiovascular events. There is also evidence that cardiovascular complications during pregnancy may link to future heart diseases. During normal pregnancy, the heart undergoes physiological hypertrophy without fibrosis or fetal gene activation. However, recent study showed extremely obese women have increased cardiac hypertrophy and more frequent diastolic dysfunction at term. The objective of this research was to determine if MetS modifies the cardiac remodeling that takes place during pregnancy.

Hypothesis:
MetS during pregnancy induces pathological rather than physiological cardiac remodeling.

Methods and Results:
We performed long-term feeding of high fat (45%kcal) diet (HFD) in C57BL/6J female mice to establish a model of MetS, which showed increased body weight, impaired glucose tolerance and dyslipidemia compared to normal chow, resembling the features of human MetS. After pregnancy, HFD fed mice showed higher heart weight and ECHO-derived LV mass compared with Ctrl. Pregnant mice with MetS had signs of pathological cardiac remodeling, such as cardiomyocyte hypertrophy, fetal gene activation and interstitial fibrosis. At the transcriptome level, pregnancy in HFD fed mice lead to distinct gene expression patterns compared to normal pregnancy, with enrichment in genes involved in cardiac hypertrophy, oxidative stress and fibroblast activation that likely underly the adverse remodeling. Moreover, when animals were stressed with Angiotensin/phenylephrine infusion, MetS postpartum hearts had more severe cardiac hypertrophy, with overt concentric remodeling and increased fibrosis accumulation compared with nulliparous females

Conclusions:
MetS can induce maladaptive cardiac remodeling during pregnancy and exacerbate pathological remodeling in the postpartum heart.
Abstract 16487: Variation in Provider Practice Patterns Across Clinical Settings for Medicare Beneficiaries Undergoing Endovascular Femoropopliteal Artery Revascularization
Authors: Raja Aishwarya , Choi Eunhee , Shen Changyu , zhao tianyi , Wadhera Rishi , Yeh Robert W , Secemsky Eric A
Published: May 2021

Introduction:
After CMS established bundled payments for outpatient peripheral vascular intervention (PVI) in 2008, a large proportion of PVIs shifted to outpatient settings, including ambulatory surgery centers (ASCs) and office-based laboratories (OBLs). Little is known about these free-standing procedural centers, such as their proximity to tertiary care hospitals and the characteristics of patients being treated.

Methods:
Medicare fee-for-service beneficiaries ≥66 years undergoing femoropopliteal artery PVI from 4/1/15-12/31/17 in outpatient settings were identified in the CMS Carrier file linked to institutional outpatient files. The exposure was treatment at an ASC/OBL versus an outpatient hospital. An area deprivation index of ≤15th percentile identified those who reside in regions of lower socioeconomic status (SES). The primary business address of each ASC/OBL was identified using the National Provider Identifier. The address of the closest tertiary care hospital was identified in the Medicare Hospital database and distances were calculated using a Google Maps API platform.

Results:
Of 1,155 providers who performed ≥1 PVI in an ASC/OBL, the average distance to the nearest hospital was 1.5±2.2 miles. There was a weak correlation between the proportion of procedures performed at ASCs/OBLs and the distance to the nearest hospital (Figure). Among 686 providers who performed procedures in both ASCs/OBLs and outpatient hospitals, patients treated in ASCs/OBLs had a higher burden of comorbidities and were more often Black, dually-enrolled in Medicare/Medicaid, and residing in lower SES regions.

Conclusions:
ASCs/OBLs are geographically close to tertiary care centers, with little correlation between the proportion of procedures performed and the distance to the nearest hospital. The heterogeneity of patient characteristics across outpatient settings underscores the need for better measures of quality and appropriateness of PVI procedures.
Abstract 16489: Comparison of Severity of Illness at Presentation and Outcomes for Patients With Acute Cardiovascular Syndromes Before and During Covid-19 Pandemic
Authors: Sanina Cristina , Gabr Mohamed , DiBiase Luigi , Wiley Jose M , Garcia Mario J
Published: May 2021

Introduction:
The New York Governor Andrew M. Cuomo’s executive order N202.25 on March 7, 2020, canceled all elective, semi-urgent procedures, including cardiovascular interventions such as coronary angiography and angioplasty due to SARS- Cov2 (COVID 19) pandemic. New York City was devastated by COVID 19 infection carrying the highest incidence, prevalence, and mortality rates in the US. Importantly, a 4. 4.83-fold increase in death rate at home was reported. We hypothesized that the COVID19 surge postponed the patient's decision to seek medical attention leading to an increase in cardiovascular-related hospital mortality.

Methods:
We conducted a retrospective observational study examining the incidence, prevalence, complication rate, and mortality from cardiovascular diseases in hospitalized patients during COVID 19 surge. We performed a patient chart review of a cohort with acute cardiovascular events (STEMI, NSTEMI, Stroke, CHF) during the COVID 19 surge who were hospitalized at Montefiore Medical Center between March 7, 2020, and April 21, 2020, and compared it to a similar cohort from the preceding year (March 7, 2019 and April 21, 2019).

Results:
During the dates (March 7- April 21, 2020), there was a significant decrease in NSTEMI, stroke, and CHF admissions (P<0.05). (Figure 1) Respectively, fewer cardiac catheterization procedures were performed for patients presenting with NSTEMI, UA, and shock. There was no difference in the number of STEMI admissions. Troponin T levels at presentation were significantly higher (P<0.05), and increased prevalence of wall motion abnormalities and LVEF < 50% (P<0.05). Mortality for HF asdmissions was 20% in 2020 compared to 0.02% in 2019.

Conclusions:
Montefiore Medical Center admitted and treated significantly fewer patients with acute cardiovascular syndromes during the COVID19 surge. Non-COVID patients presented with delayed MI. All HF patients (COVID+Non-COVID) carried a significantly higher mortality rate.
Abstract 16493: Comparison of Left Ventricular Volumes and Ejection Fraction Measured by Non-contrast 2 Dimensional, Contrast 2 Dimensional and 3 Dimensional Transthoracic Echocardiography in Patients With Heart Failure During One Examination, to Measurements by Cardiovascular Magnetic Resonance Imaging
Authors: Rosenthal Allison , Lee Katherine C , Padiyar Shaefali , Uribe Bliss , Liu Shizhen , Cochran JD , Green Theresa , mobasseri sara , Flueckiger Peter , Rangarajan Vibhav , Sayegh Hassan S , Vannan Mani A
Published: May 2021

Introduction:
Non-contrast 2D TTE (2D NC TTE) is done in patients with HF to assess LV EDV and ESV and EF. 2D contrast and 3D TTE (2D C TTE, 3D TTE) are also done.

Hypothesis:
There are no distinct cut-offs for LV volumes for 2D C TTE or 3D TTE volumes. And, it is not known which of these measurements should be reported. The relative differences in these measurements, and their relative accuracy, compared to CMR is unknown.

Methods:
This is an observational, retrospective analysis of 239 HF patients who had 2D NC, 2D C, 3D TTE, and CMR. We measured bi-plane LV EDV and ESV, ml), and EF (%) in the 2D NC and C TTEs, and 3D LV EDV and ESV were measured in one TTE.

Results:
Data from 35 of the 239 patients are shown. 2D NC LV volumes were significantly smaller than 2D C volumes (EDV: 189±80 Vs. 227±86 and ESV: 133±68 Vs. 158±77, p<0.001 for both). 2D NC TTE volumes were significantly smaller than 3D TTE volumes (EDV: 189±80 Vs. 206±85 and ESV: 133±68 Vs. 154±70). But,
only
2D C EDV was significantly smaller than 3D TTE (227±86 Vs. 206±85, p<0.01), ESV was not significantly different between the two. Compared to CMR, 2D C TTE did not show any significant differences in volumes because contrast was able to identify the compacted myocardial edge. In 3D TTE, only EDV was significantly smaller than CMR (p<0.01) but not 3D TTE ESV, because there is a bigger separation of trabeculated and compacted myocardial edges in ED which is less so in systole. 2D NC TTE EDV and ESV were both significantly smaller (p<0.001) than CMR because the trabeculated myocardial edge is used to measure these. There were no significant differences in EF between the three TTE methods. Figure 1 shows an example.

Conclusions:
In HF, 2D NC is smaller than 2D C TTE LV volumes, the latter being larger and comparable to CMR. Thus, there is a need to identify specific cut-offs for contrast TTE LV volumes to classify LV size. 3D TTE volumes are comparable to CMR, but smaller than 2D C TTE volumes. Contrast 3D TTE may prove to be most comparable to CMR when this becomes available.
Abstract 16497: Intensive Cardiac Rehabilitation and Traditional Cardiac Rehabilitation are Markedly Underutilized: Results From a Medicare Sample Analysis
Authors: Husaini Mustafa , Deych Elena , RACETTE Susan B , Rich Michael W , Joynt Maddox Karen E , Peterson Linda R
Published: May 2021

Introduction:
Cardiac rehabilitation (CR) is proven to improve cardiovascular outcomes in patients with heart disease. Intensive cardiac rehabilitation (ICR) was developed to enhance CR by adding sessions focused on nutrition, education, and stress management. ICR improves adiposity, lipid profiles, and exercise capacity vs. CR and has been Medicare-approved since 2010. Little is known about national utilization rates of ICR in the Medicare population or baseline characteristics associated with its use.

Methods:
A 5% sample of Medicare claims data from 2012 to 2015 was used to identify beneficiaries with a qualifying indication for CR/ICR (MI, CABG, valve surgery, PCI, heart transplant, heart failure, stable angina) and to quantify utilization of CR or ICR within 1 year of the index qualifying diagnosis.

Results:
From 2012-2015, there were 111,432 qualifying events in 107,261 Medicare beneficiaries. On average in this 5% sample, 15.6% of eligible beneficiaries (n = 17,422) completed at least 1 session of CR and only 0.1% (n = 108) completed at least 1 session of ICR. Rates of CR and ICR use (combined) increased by 2.95% to only 17.55% (Figure). The number of ICR centers (14 to 29 centers) increased over these 3 years. Those who attended CR or ICR were younger, more likely to be male and white, and have higher median income compared with eligible beneficiaries who did not attend. While participants that attended CR lived closer to the center (CR 5.5 miles; ICR 7.2 miles; p=0.01), there were no differences between CR and ICR enrollees with respect to age, sex, race, discharge location, median income, dual enrollment (Medicare + Medicaid), or number of comorbidities.

Conclusions:
Although the number of ICR centers has increased, CR and ICR remain markedly underutilized and ICR is not yet widely available. Continued research is needed to understand the barriers to program development, patient participation.
Abstract 16534: Pulmonary Artery Tapering Pattern on Chest CT-Angiogram Predicts Phenotype of Pulmonary Hypertension
Authors: Azeem Ali Ahsan A , Laurenzo Scott A , Dhingra Ravi , Runo James R , Deano Roderick C , Francois Christopher J , Raza Farhan
Published: May 2021

Introduction:
Non-invasive methods to identify phenotype of pulmonary hypertension (PH) are essential to improve the diagnostic algorithm of PH.

Hypothesis:
Delayed tapering of pulmonary artery (PA) is a signature of pre-capillary PH, while in post-capillary PH, the PA tapers rapidly. This differential tapering pattern of PA can be detected on a chest CT-angiogram (CTA), and quantified as a ratio of main PA diameter to PA branch diameter (right or left) at 5.0 cm length after the PA bifurcation.

Methods:
We identified 30 subjects with chest CTA and PH confirmed with invasive right heart catheterization (RHC). We identified 3 PH phenotypes: 1. “PVD” (pulmonary vascular disease) = Pre-capillary PH (n=10, PVR>3.0 WU, PAWP <15mmHg), 2. “Mixed” = pre- and post-capillary PH (n=10, PVR>3.0 WU, PAWP >15mmHg), and 3. “PVH” (pulmonary venous hypertension) = post-capillary PH (n=10, PVR<3.0 Woods units [WU], PAWP >15mmHg).

Results:
The results are summarized in Table. Additional results are expressed as comparison among the three groups in order: PVD vs Mixed vs PVH (mean±SD, % or n, as appropriate). CTA-chest findings: RV basal diameter (mm)= 51.1±8.4 vs 51.0±5.4 vs 38.1±13.9, left ventricular (LV) basal diameter (mm)= 32.1±7.2 vs 31.6±13.3 vs 56.6±15.2*, PA:Ao ratio= 1.1±0.1 vs 1.1±0.2 vs 1.0±0.1. Echo findings: tricuspid annular plane systolic excursion (TAPSE, mm)= 16±3 vs 19±4 vs 22±10*. We performed ROC to identify predictive ability of PA:RPA-5 and PA:LPA-5 to predict PVR>3 WU. The AUC for PA:RPA-5 = 0.859 (p=0.03) and for PA:LPA-5 = 0.812 (p=0.01); with optimal cut-off for both parameters (PA:RPA-5 and PA:LPA-5) was 1.85. Among the overall cohort, the patients with PA:RPA<1.85, 15/16 had PVR>3 and 11/16 were on PH meds.

Conclusion:
Pattern of PA tapering quantified with PA:RPA-5 or PA:LPA-5 can reliably identify elevated PVR (>3.0 WU). Pre-capillary PH imprints a signature morphological mark on the pattern of PA dilation that can be identified with a CTA-thorax.
Abstract 16535: Mental and Behavioral Health Disorders Among Patients With Acute Myocardial Infarction in the United States
Authors: Sreenivasan Jayakumar , Khan Mohammad S , Khan Safi U , Aronow Wilbert S , Panza Julio A , Levine Glenn N , Commodore-Mensah Yvonne , Blumenthal Roger S , Michos Erin D
Published: May 2021

Background:
Mental and behavioral health disorders (MBD) are associated with an increased risk of cardiovascular disease and with worse long-term outcomes after myocardial infarction (MI).

Hypothesis:
We hypothesized the prevalence of MBD among patients with acute MI is rising over time.

Methods:
Using National Inpatient Sample Database, we assessed temporal trends in the prevalence of MBD and in-hospital outcomes among patients hospitalized for acute MI in the US from 2008-2017. We used multiple logistic regression for in-hospital outcomes and examined yearly trends and estimated annual percent change (APC) in odds of MBD among MI patients.

Results:
We included a total of 6,117,804 patients with MI (ST elevation MI 30.4%) with a mean age of 67.2±0.04 and 39% females. Psychoactive substance use disorder (PSD) (24.9%) was the most common behavioral health disorder, and major depression (6.2%) and anxiety disorders (6.0%) were the most common mental health disorders, followed by bipolar disorder (0.9%), schizophrenia/psychotic disorders (0.8%) and post-traumatic stress disorder (PTSD) (0.3%). Between 2008 to 2018, the prevalence of PSD (23.7-25.0%, APC +0.6%), major depression (4.7-7.4%, APC +6.2%), anxiety disorders (3.2-8.9%, APC +13.5%), PTSD (0.2-0.6%, +12.5%) and bipolar disorder (0.7-1.0%, APC +4.0%) significantly increased over the time period. Major depression, bipolar disorder or schizophrenia/psychotic disorders were associated with a lower likelihood of coronary revascularization, although a co-diagnosis of MBD was associated with a lower risk of in-hospital mortality.

Conclusion:
MBD are common among patients with acute MI and there was a concerning increase in the prevalence of PSD, major depression, bipolar disorder, anxiety disorders and PTSD. Focused mental and behavioral health interventions and health care policy changes are warranted to address the increasing burden of comorbid MBD among acute MI.
Abstract 16539: Heart Failure With Mid-Range or Improved Ejection Fraction Improves Cardiovascular Outcomes
Authors: Cefalu Matthew , Devgun Jasneet , Kennedy Samuel , Slivnick Jeremy , Garrett Zachary , Smith Sakima A
Published: May 2021

Heart failure with improved ejection fraction (HFiEF) is a unique and developing clinical entity among the heart failure (HF) spectrum. Prior studies suggest the characteristics, therapy, and prognosis of HFiEF are distinctive from HF with reduced ejection fraction (HFrEF) or mid-range ejection fraction (HFmrEF). We hypothesized that patients diagnosed with acute HF who later progressed to HFiEF would have improved cardiovascular outcomes compared to HFrEF. Our retrospective study included 295 adult patients with no prior history of HF at The Ohio State University diagnosed with acute HF. We defined HFrEF as a persistent ejection fraction < 40%, HFmrEF as persistent ejection fraction 40-49%, and HFiEF as improvement from baseline ejection fraction by > 5%. Nearly 74% of patients were found to have HFiEF while 12% and 14% were classified as HFrEF and HFmrEF respectively. Using a log-rank test, the time to first cardiovascular rehospitalization was significantly longer in HFiEF compared to HFrEF or HFmrEF (p=0.0192, Figure 1). Multivariable analysis, controlled for age and gender, indicated HFiEF had a trend towards significance as an independent predictor for time to cardiovascular hospitalization (p=0.053). Notably amyloid HF, valvular HF, and ischemic HF were all significant independent predictors. Survival analysis demonstrated that HFmrEF had significantly longer survival on log-rank test compared to HFrEF (p=0.0367). Multivariable analysis shows significantly lower hazard of mortality for those with HFmrEF (HR 0.57, 95% CI [0.36-0.92], p=0.017). Our exciting data indicates the progression to HFiEF after the diagnosis of acute HF is associated with reduced cardiovascular rehospitalization, and HFmrEF is associated with increased survival. These data have implications in patient surveillance and risk stratification as well as defining the natural history of HFiEF and HFmrEF as unique entities.
Abstract 16543: Severe Thrombocytopenia is Common in Adults Undergoing Venoarterial Extracorporeal Membrane Oxygenation and is Predictive of Hemorrhage
Authors: Kohs Tia C , Raghunathan Vikram , Liu Patricia , Amirsoltani Ramin , Oakes Michael , McCarty Owen J , Olson Sven , Zonies David , Shatzel Joseph J
Published: May 2021

Introduction:
Extracorporeal membrane oxygenation (ECMO) is used to provide circulatory support and facilitate gas exchange via cardiopulmonary bypass. The relationship between ECMO and the incidence of severe thrombocytopenia (platelet count <50 x 10
9
/L) and subsequent clinical consequences are ill defined. We aimed to identify the risk factors for the development of thrombocytopenia and its clinical implications.

Methods:
This is a single-center retrospective cohort study of adults who received venoarterial (VA) ECMO. We examined consecutive platelet counts while on ECMO. Univariate logistic regression was used to determine if mean platelet count, platelet count range, or severe thrombocytopenia were predictors of overall survival, hemorrhage and thrombosis. A multivariate logistic regression model was used to identify factors that contribute to the development of the aforementioned patient outcomes.

Results:
In our cohort, 33 patients were included with a mean age of 55 years and duration of ECMO of 5.9 days. All patients received heparin, 33.3% received antiplatelet therapy and 45.5% developed severe thrombocytopenia. In univariate, analysis the development of severe thrombocytopenia increased the odds of major bleeding by 450% (OR 5.500, 95% CI 1.219 - 24.813,
P
-value 0.027), and the odds of surviving hospitalization decreased 84.1% (OR 0.159, 95% CI 0.033 - 0.773,
P
-value 0.023). Multivariate logistic regression controlling for additional clinical variables found no significant association between the development of severe thrombocytopenia and rates of thrombosis, hemorrhage, or overall survival. Platelet count decreased over time while on ECMO.

Conclusions:
Nearly half of the patients requiring VA-ECMO developed severe thrombocytopenia, which was associated with an increased risk of hemorrhage and in-hospital mortality. Additional studies are required to clarify the clinical implications of severe thrombocytopenia in ECMO patients.
Abstract 16544: Small Rna-sequencing Analysis of Circulating Proinflammatory Microrna Following Murine Myocardial Ischemia/reperfusion Injury
Authors: Yang Yang , Wang Sheng , Suen Andrew , Shimada Briana K , Zou Lin , Chao Wei
Published: May 2021

Introduction:
Transient myocardial ischemic/reperfusion injury (I/R) leads to cellular RNA release into extracellular (ex) space. Ex-RNAs and certain uridine-rich miRNAs activate innate immune response via TLR7-MyD88 pathway. Systemic administration of RNase reduces myocardial inflammation and infarct size after I/R, suggesting a pivotal role of ex-RNA in I/R injury. However, the nature of plasma RNAs and their biological functions in inflammation are not well understood.

Hypothesis:
Multiple plasma miRNAs are elevated in response to myocardial I/R injury and some are proinflammatory.

Methods:
Myocardial I/R injury was created in C57BL/6 mice by thoracotomy and 45 min of left anterior descending (LAD) ligation followed by 4 h of reperfusion. Sham mice underwent same procedure without LAD ligation. Plasma RNA was extracted using Trizol LS with Cel-miR-39 as spiked-in and quantified by RNA Quant-it kits. The plasma RNA was used to create cDNA libraries for small RNA sequencing (Norgen, Canada). Three abundant miRNAs that were differentially expressed between sham and I/R groups were tested for their proinflammatory effect.

Results:
Myocardial I/R led to a marked increase in plasma troponin (392.1±324.6
vs.
17.9±9.9ng/ml, P<0.05) and RNA levels (163±129 vs. 81±40 ng/ml) as compared with sham mice (
Fig. A
). Plasma RNA-Seq revealed miRNA was the predominate biotype constituting of 85.7% and 79.2% of plasma RNA in sham and I/R mice, respectively (
Fig. B
). We validated three miRNA expressions using qRT-PCR and found miR191-5p, miR125a-5p, and miR125b-5p were substantially increased (
Fig. C
). When incubated with macrophage cultures, miR125a-5p and miR-125b-5p, but not miR-191-5p, induced a dose-dependent response in CXCL-2 and IL-6 productions (
Fig. D
).

Conclusions:
Myocardial I/R injury results in an increase in multiple miRNAs in plasma. miR125a-5p and miR125b-5p, but not miR-191-5p, are pro-inflammatory in macrophages.
Abstract 16549: Trimethylamine N-Oxide-Derived Endothelial Microvesicles Induce a Dysfunctional Endothelial Cell Phenotype
Authors: Garcia Vinicius , Brewster L. Madden , Stockelman Kelly A , Fandl Hannah K , Rahaman Clay , Maly Lukas , Greiner Jared J , Davy Kevin P , Desouza Christopher
Published: May 2021

Introduction:
Gut microbiota-generated increases in trimethylamine N-oxide (TMAO) has been linked to atherosclerosis and major adverse cardiovascular events. Experimental and clinical studies suggest that TMAO impairs endothelial cell function resulting in a proatherogenic endothelial phenotype. Endothelial microvesicles (EMVs) are anucleate vesicles shed constitutively by the endothelium aiding in cell-to-cell communication, activate repair or defense mechanisms, and/or stimulate immune responses. Under pathologic conditions, however, EMVs are released in greater number and their functional phenotype is more likely to evoke dysfunctional cellular effects. The experimental aims of this study were to determine: 1) if TMAO stimulates EMV release from endothelial cells
in vitro
; and 2) the effects of TMAO-generated EMVs on endothelial cell inflammation, apoptosis, autophagy and nitric oxide (NO) production.

Methods:
Human umbilical vein endothelial cells (HUVECs) were treated with TMAO (100 μmol) for 24 h. EMVs released into the supernatant from cells treated with TMAO or vehicle were isolated and quantified by flow cytometry. Fresh HUVECs were treated with either TMAO-derived or control EMVs for 24 h.

Results:
EMV release was significantly higher in cells treated with TMAO compared with control (55±3 vs 28±3 EMV/μL). TMAO-generated EMVs induced significantly higher release of interleukin (IL)-6 (33.9±2.6 vs 20.2±1.3 pg/mL) and IL-8 (45.4±2.6 vs 33.1±1.6 pg/mL) and active NF-κB p65 (Ser536) (17.4±1.3 vs 7.7±1.0 AU) expression than control EMVs. TMAO EMVs significantly increased cell expression of apoptotic proteins caspase-9 (198.5±19.4 vs 119.7±11.2 AU) and active caspase-3 (17.7±2.8 vs 11.3±0.7 AU) and markedly depressed eNOS activity (10.6±0.9 vs 6.9±0.6 AU) and NO production (7.7±0.4 vs 5.5±0.6 μmol/L). In addition, cell autophagy was dysregulated by TMAO EMVs; cell expression of Beclin-1 (53.8±6.4 vs 36.6±3.6 AU), p62 (34.0±0.8 vs 16.9±1.2 AU) and LC3BII/LC3BI (15.0±0.1 vs 7.5±0.8 AU) were significantly elevated in cells treated with TMAO vs control EMVs.

Conclusions:
TMAO-generated EMVs adversely affect major functional characteristics of endothelial cells potentially contributing to the proatherogenic profile of TMAO.
Abstract 16552: Chromosomal Microarray Abnormalities in More Than 1300 Patients With Congenital Heart Disease Provide Novel Clinical and Etiological Insights
Authors: Landis Benjamin J , Elmore Lindsey R , Geddes Gabrielle C , Lin Jiuann-huey I , Yatsenko Svetlana A , Lo Cecilia W , Bleyl Steven B , Border William L , Wechsler Stephanie B , Murali Chaya N , Lalani Seema R , Hinton Robert B , Garg Vidu , McBride Kim L , Hodge Jennelle C , Ware Stephanie M
Published: May 2021

Introduction:
The genetic basis of congenital heart disease (CHD) is incompletely understood. Approximately 10-20% of infants with CHD have abnormal chromosome microarray (CMA) results, however, the spectrum of genomic and phenotypic abnormalities remains incompletely characterized.

Methods:
All study patients had abnormal CMA on clinical testing and abnormal cardiac findings on echocardiogram, as identified at 9 pediatric cardiac centers. Clinical genetic testing results, diagnoses, and echocardiogram reports for detailed cardiac phenotyping were collected. CMA results were denoted as abnormal for any reported findings that included copy number variants (CNVs) and/or regions of homozygosity. Cardiac classification was performed with minor modification to National Birth Defect Prevention Study methods. Recurrent CNVs were identified algorithmically. Functional enrichment analysis of genes predicted to be intolerant of loss-of-function (LOF) in CNVs and genes located in monogenic CNVs was performed using ToppGene.

Results:
The study included 1369 patients. Genetic syndromes highly associated with CHD such as Trisomy 21, Turner syndrome, and 22q11.2 deletion syndrome among others were identified in 401 patients and elucidated less recognized cardiac phenotypes in these groups. Analyzing genes known to be causative of CHD in the remaining patients (N=968) showed enrichment in CNVs < 5 megabases (N=51; 7%). Common recurrent loci included duplications in 15q13.2-13.3 (N=16 patients) and 16p11.13 (N=12; 8 with left-sided cardiac lesion), and deletions in 15q11.2 (N=14; 6 with total anomalous pulmonary venous return) and 2q13 (N=10; 8 with conotruncal defect). Genes predicted to be intolerant of LOF (495 genes) or located in monogenic CNVs (137 genes) were enriched for neuronal processes.

Conclusions:
The consortium provides the largest data set of abnormal clinical CMA results in patients with detailed CHD phenotyping to our knowledge. The findings provide novel understanding of CHD phenotypes, a roadmap of recurrent loci, and pathways and candidate genes in CNV-associated CHD. The consortium’s data will lead to improved genetic understanding and clinical care of patients with CHD.
Abstract 16571: An Appraisal on Prognostic Value of Left Atrial Strain in Exercise Echocardiography
Authors: Ye Zi , Miranda William , Kane Garvan , McCully Robert B , Oh Jae K
Published: May 2021

Introduction:
Diastolic dysfunction impairs exercise capacity and has prognostic value in exercise echocardiography. We aimed to assess whether left atrial strain (LAS), which is reduced with worsening in diastolic function, is associated with all-cause death or heart failure hospitalization in patients undergoing treadmill echocardiography.

Methods:
We performed 2D-speckle tracking analysis of LAS in 1636 consecutive patients (mean age 64±13 and 59% men) who underwent treadmill echocardiography between 1/2013 and 1/2014. We used the 2016 ASE recommendation to define diastolic function and elevated LV filling pressure.

Results:
Of 1636 study subjects, 95% had LV ejection fraction ≥ 50%. Diastolic function was normal in 44% of patients and abnormal in the remaining (23% grade I, 9% grade II, 1% grade III, and 23% indeterminate). During a mean follow-up of 5.5±1.8 years, 210 patients (12.8%) experienced the composite outcome (157 death and 88 heart failure hospitalization). Lower LASreseroivr, LASbooster and LA emptying fraction (LAEF) were all associated with increased risk for the adverse outcome independent of age, sex, clinical and echocardiographic parameters, and after further adjustment for diastolic function (abnormal vs. normal) (all p≤0.001). The association of LASbooster with the outcome attenuated in a model with LASreservoir or LAEF (both p>0.1). Adding LASreservoir to clinical and echocardiographic parameters provided incremental prognostic value (continuous net reclassification improvement=0.09, p=0.04), but not LAEF or LASbooster. Patients with LASreservoir <34.2% (lowest tertile) had more than doubled risk for death or heart failure hospitalization than those with LASreservoir ≥34.2% after multivariable adjustment in the entire cohort (adjusted hazard ratio 2.2, 95%CI: 1.53 - 3.23), as well as in those with normal stress test (n=1217, adjusted HR, 3.53, 95%CI: 2.29 - 5.53) or those without elevated resting LV filling pressure (n=1466, adjusted HR: 2.08, 95%CI: 1.46 - 2.96).

Conclusions:
LASreservoir provides independent prognostic information in patients undergoing exercise echocardiography.
Abstract 16572: Single-Cell Transcriptomics Revealed Distinct B Cell Activation and Repression States in Obese Adipose Tissue
Authors: Matz Alyssa J , Qu Lili , Li Chuan , Vella Anthony , Zhou Beiyan
Published: May 2021

Obesity increases risk of several disease states including type-2 diabetes, arthritis, and cardiovascular disease. B cell dysfunction within visceral adipose tissue (AT) has been demonstrated to be a driving force towards insulin resistance, but the AT B cells (ATBs) responsible have not been well identified or characterized. We sought to elucidate the cellular changes occurring in ATBs during obesity that will confer obesity’s comorbidities using the single cell RNA sequencing technique. Consistent with previous studies, we observed a significant change in the B cell compartment composition in obese AT compared to the control lean ATBs. As expected, the majority of lean ATBs were naïve cells, characterized by several factors including moderate expression of transcription factor Pax5 and low BCR activation. Further cell function annotation identified two distinct states with increased proportions of obese ATBs, which were revealed by differential gene expression analysis to be either activated towards antibody producing or in a state of repression. The first state was characterized by an upregulation of several genes in B cell receptor (BCR) signaling and subsequent transcription factors such as Blk, Cd19, Pax5, Slamf7, and Cr2, suggesting activation. Such activation status is concomitant with high Ighm and increasing Ighd levels in the same cell population. Interestingly, we also observed a distinct B subtype that was also enriched in obese ATBs. These ATBs displayed low immunoglobulin production, low BCR associated proteins, low transcription factors, and high Pdcd1lg2, mouse homolog to human PD-L2, the programmed cell death ligand used in B cell repression. Further characterization of these newly identified ATB states under healthy or obese conditions suggested a significant change in B cell polarized action in obesity. The impact of these diversified ATB on other immune cells and the adipocyte actions and their cell-cell interaction will be further analyzed using our original bioinformatic programs. A high resolution of ATBs action in obesity will provide critical information to develop new therapeutic/prevention strategies against obesity induced health risk.
Abstract 16583: Beta Blocker Administration Within 30 Days Post-Left Ventricular Assist Device Significantly Decreases 1-Year Mortality in a Multi-institutional Retrospective Cohort Study
Authors: Derbala Mohamed H , Rivas-Lasarte Mercedes , Kumar Salil , Ferrall Joel , Cefalu Matthew , Guo Aaron , Mohammad Somayya , Sims Daniel B , Smith Sakima A
Published: May 2021

Introduction:
The utilization of beta blockers (BB) post LVAD implantation is controversial, especially in the setting of right ventricular failure. There is limited evidence-based data regarding the survival benefits of BB post LVAD implantation

Hypothesis:
We hypothesized that BB use would not be associated with increased mortality

Methods:
We performed a dual-center retrospective study of 487 patients from Ohio State University & Montefiore Medical Center who received a continuous-flow durable LVAD bet. Jan 2006 through Dec 2016. A survival analysis was done to determine if patients had increased 1 year mortality depending on whether they received BB within 30 days post LVAD, after 30 days & up to 1 year post LVAD, or did not receive BB. Multivariate analysis of predictors of post LVAD mortality was conducted.

Results:
Overall the baseline characteristics bet. the 3 groups were similar (Table 1). BB utilization within 30 days post LVAD was associated with a drastic decrease in 1 year mortality (p <0.001; Fig.1). Multivariate analysis shows that no BB use (HR 3.36, p <0.001), age ≥70 (HR 2.73, p = 0.005) & pre LVAD creatinine ≥1.5 mg/dl (HR 1.86, p = 0.022) were significant independent predictors of mortality (Table 2).

Conclusions:
The early use of BB significantly improves 1 year survival post LVAD. Notably these results are from Midwest and East Coast Medical Centers to improve generalizability.
Abstract 16594: Disruption of Caveolae-Confined Phosphorylation of Ryanodine Receptors Promotes Ca
2+
Handling Abnormalities and Arrhythmogenesis in Mouse Atrial Myocytes
Authors: Medvedev Roman , Lang Di , Glukhov Alexey
Published: May 2021

Rationale:
Chronic atrial fibrillation has been linked to ectopic triggered activity driven by delayed afterdepolarizations in response to sarcoplasmic reticulum Ca
2+
leak from certain areas in atria. These activities were associated with hyperphosphorylated ryanodine receptors (RyRs), while the underlying mechanisms remain uncertain. Here, we hypothesized that mouse atria have areas with lower transversal-axial tubule system (TATS) organization, where phosphorylation of RyRs is mainly confines by caveolae nanodomains and might be firstly disturbed in disease conditions.

Methods and results:
In wild type (WT) mouse intact atria stained with RH-237, we found that myocytes located in the intercaval region (ICR, between the superior vena cava and atrioventricular junction and between the crista terminalis and interatrial septum) have a significantly less density of TATS than right atrial appendage (RAA) myocytes: 5.7±0.4% in ICR vs. 13.4±0.9% in RAA, P<0.01. Also an elevated frequency of spontaneous Ca
2+
sparks was observed in myocytes isolated from ICR vs. RAA (12.5±2.6 vs. 1.5±0.3 sparks/μm/s, P<0.01). ICR myocytes isolated from mice with a cardiac-specific knockout of the main structural protein of caveolae, caveolin-3, showed significant increase of Ca
2+
sparks frequency as compared to WT (27.3±4.1 sparks/μm/s, P<0.01). Immunofluorescence staining of RyRs, phosphorylated at protein kinase A/ Ca
2+
/calmodulin-dependent protein kinase-II phosphorylation sites: Ser
2808
-RyR and Ser
2814
-RyR, showed predominant subsarcolemmal localization, with a high co-localization with caveolin-3, in ICR and RAA cells. Myocytes isolated from caveolin-3 knockout mice showed extension of both Ser
2808-
RyR and Ser
2808-
RyR to whole-cell wide striated pattern in ICR, but not RAA. This redistribution was associated with development of delayed afterdepolarizations in ICR but not RAA cells.

Conclusions:
Our findings demonstrate that in ICR in mouse atria, caveolae form functional, spatially-confined cAMP nanodomains and control localized RyR phosphorylation. Disruption of caveolae structures, seen in various pathologies, may lead to hyperphosphorylation of RyRs promoting Ca
2+
handling abnormalities and arrhythmogenic triggered activity.
Abstract 16599: Impact of Race and Ethnicity on Long Term Outcomes Post Percutaneous Coronary Intervention With Drug Eluting Stents
Authors: Roumeliotis Anastasios , Claessen Bimmer E , Sartori Samantha , Cao Davide , Koh Won-Joon , Nicolas Johny , Qiu Hanbo , Chandiramani Rishi , Chiarito Mauro , Goel Ridhima , Sweeny Joseph , Barman Nitin , Krishnan Prakash , Kini Annapoorna , Sharma Samin K , Dangas George , Mehran Roxana
Published: May 2021

Introduction:
Cardiovascular disease is the leading cause of mortality worldwide, irrespective of race/ethnicity. Previous studies reported that minority patients with ACS have distinct clinical, genetic and socioeconomic backgrounds that may affect clinical outcomes.

Hypothesis:
To investigate post percutaneous coronary intervention (PCI) outcomes according to race/ethnicity in a contemporary ACS population.

Methods:
We included consecutive patients undergoing drug-eluting stent implantation for STEMI, non-STEMI or unstable angina (UA) between 2012-2017. The study population was stratified into Caucasian, African American, Hispanic and Asian. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE) defined as a composite of death, spontaneous myocardial infarction or stroke at 1 year.

Results:
Of the 6800 patients included, 3377 (49.7%) were Caucasian, 1408 (20.7%) Hispanic, 1156 (17.0%) Asian and 859 (12.6%) African American. Caucasians were the oldest, Hispanics and Asians had the highest prevalence of diabetes mellitus (DM) and African Americans had more insulin dependent DM and chronic kidney disease. Hispanics and African Americans had the highest STEMI rate, while Asians were more likely to present with UA, have private insurance and be discharged on aspirin and clopidogrel. Compared to Caucasians, Asians had a lower rate of MACCE at 1 year (3.9% vs. 7.1%; p<0.01) whereas Hispanics (6.2% vs. 7.1%; p-value=0.17) and African Americans (8.0% vs. 7.1%; p-value=0.38) had comparable outcomes. Differences were driven by fewer deaths in the Hispanic (2.1% vs. 4.2%; p<0.01) and Asian (1.7% vs. 4.2%; p<0.01) subgroups. Findings remained unchanged after adjusting for potential confounders [Figure].

Conclusions:
Among patients undergoing PCI for ACS, Asian race is associated with favorable cardiovascular outcomes compared to Caucasian. No significant differences were observed for Hispanics and African Americans.
Abstract 16602: Mitolamban is a Novel Cardiac-Enriched Mitochondrial Microprotein That Regulates Respiratory Complex III
Authors: Makarewich Catherine A , Munir Amir Z , Bezprozvannaya Svetlana , Gibson Aaron M , Matthews Thomas P , Martin Misty , McAnally John R , Morrison Sean J , Bassel-Duby Rhonda S , Olson Eric N
Published: May 2021

Introduction:
Emerging evidence suggests that many RNA molecules currently annotated as noncoding contain short open reading frames that code for functional small proteins called microproteins. Microproteins play critical roles in a diverse range of essential biological processes. To identify novel cardiac-expressed microproteins, we used a comparative genomics approach and identified mitolamban (Mtlbn) as a highly conserved 47-amino acid transmembrane protein that is abundantly expressed in the heart.

Methods and Results:
Subcellular localization studies showed that Mtlbn localized specifically to the inner mitochondrial membrane. Immunoprecipitations and mass spectrometry analysis indicated that Mtlbn interacted with subunits of complex III of the electron transport chain (ETC) and we observed the presence of Mtlbn in complex III respiratory supercomplexes (SCs) by blue native polyacrylamide gel electrophoresis (BN-PAGE). Cardiac-specific Mtlbn overexpressing transgenic (TG) mice and Mtlbn gene-deleted (knockout, KO) mice were generated to dissect the molecular function of this protein in the heart. Mtlbn TG mice developed cardiomyopathy and died prematurely with histological, biochemical and ultrastructural pathologic features. Metabolomic analysis indicated that hearts from TG mice had signs of increased oxidative stress and mitochondrial dysfunction. While Mtlbn KO mice had normal cardiac function and histological appearance, BN-PAGE analysis of purified mitochondria from KO hearts showed altered complex III composition. Functional assessment of purified heart mitochondria from Mtlbn KO mice revealed a reduction in complex III activity and metabolomic analysis of KO heart tissue indicated an altered metabolite profile consistent with deficiencies in complex III activity.

Conclusions:
Mtlbn is a novel heart-enriched microprotein that localizes to the inner mitochondrial membrane where it interacts with complex III of the ETC. Our data indicate that Mtlbn serves as a critical regulator of mitochondrial ETC activity through a direct role in affecting complex III function.
Abstract 16605: The Effectiveness and Safety of the Esophageal Temperature Monitoring During Catheter Ablation of Atrial Fibrillation
Authors: Ito Miwa , Kanazawa Hisanori , Hoshiyama Tadashi , Kawahara Yusei , Tsujita Kenichi
Published: May 2021

Introduction:
Esophageal injury is known to be a serious complication occurs after catheter ablation (CA) of atrial fibrillation (AF).

Hypothesis:
We investigated the factors associated with the occurrence of EI after CA. Also esophageal temperature monitoring (ETM) can be useful, multiple factors such as patient characteristics and specific strategies for radiofrequency energy delivery also merit consideration.

Methods:
Among 508 patients who underwent CA of AF, endoscopy was performed the next day after CA to examine for EI. The incidence of EI was compared between 200 patients who done ETM (ETM group) and 308 patients who didn’t done ETM (Non-ETM group) during CA. The Shortest Distance between esophagus and posterior left atrium measured on contrast Computed Tomography (SD-CT) was also compared between both groups.

Results:
No differences were observed between both groups in total amount of radiofrequency energy applications. However, EI occurred more frequently in Non-ETM group (8/200 patients; 4.0 % vs 27/308 patients; 8.8 %, p=0.042). There was no significant difference in SD-CT between ETM and Non-ETM group. However, SD-CT in patients with EI was significantly shorter than SD-CT in patients without EI, both in ETM (2.4±0.7 vs 4.3±0.9 mm, p<0.001) and in Non-ETM group (2.5±0.2 vs 4.2±0.9 mm, p=0.017), respectively. Multiple regression analysis revealed that only SD-CT significantly correlated with EI. The area under a receiver operating characteristic curve using ST-CT as a predictive marker in EI patients was 0.968 (p<0.001). When the cut-off value of EI was set at 2.9mm, the sensitivity and specificity for EI diagnosis were 96.6% and 87.5%.

Conclusions:
The use of ETM is absolutely safe and necessary in order to prevent the occurrence of thermal EI.
Abstract 16626: Endothelial Zinc Transporter Zip8 Regulates Ventricular Trabeculation and Compaction
Authors: Jang Jihyun , Li Deqiang
Published: May 2021

Trabeculation and subsequent compaction of the ventricular wall are essential for normal heart morphogenesis. In human, excessive trabeculation and impaired myocardial compaction during earlyheart development lead to left ventricular non compaction (LVNC), a third most common cardiomyopathies after dilated and hypertrophic cardiomyopathies. LVNC is also associated with cardiac arrhythmia and sudden cardiac death. The etiology of LVNC is poorly understood. Recently our group identified that Zip8, a Zinc transporter, implicated in ventricular trabeculation and compaction (JCI, 2018,PMID: 29337306). However, it remains elusive how Zip8 regulates these processes through cellular and molecular mechanisms. We conditionally ablated Zip8 in the endothelial cells, epicardial cells and cardiomyocytes in the developing heart respectively. Strikingly, deletion of Zip8 in the endothelial cellsgave rise to LVNC phenotypes, identical to cardiac phenotypes from the global Zip8 knockouts. Incontrast, hearts with deletions of Zip8 in either epicardium or myocardium developed normally. Further,we found only conditional deletion of Zip8 in the endothelium in the early developing hearts (at E8.5)generated LVNC but not in the late gestation stage (E13.5), suggesting that Zip8 plays critical roles during the initial trabeculation stage. Interestingly, we found that endocardial Zip8 deficiency resulted inthe upregulation of Notch signaling, as evidenced by the increase of intracellular domain of notch protein(NICD) and its downstream target gene, bone morphogenetic protein 10 (BMP10). When the notch signaling is inhibited in the endothelial Zip8 knockout hearts either by DAPI, a γ secretase inhibitor, or by genetic deletion of Rbpj, the LVNC cardiac phenotypes are partially rescued. These results suggest thatZip8 orchestrates myocardial trabeculation and compaction by regulating notch signaling.Collectively, our study provides novel insights into the mechanisms of LVNC, suggesting that genetic mutations in Zip8 or zinc deficiency may contribute to LNVC in humans.