bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10210: Automating Risk Assessment of Acute Kidney Injury for Patients Undergoing Percutaneous Coronary Intervention
Authors: Huang Chenxi , Murugiah Karthik , Annapureddy Amarnath , Schulz Wade , Masoudi Frederick A , Rumsfeld John , Mortazavi Bobak , Krumholz Harlan M
Published: March 2022

Background:
The risk of acute kidney injury (AKI) for percutaneous coronary intervention (PCI) can inform decision-making and mitigation. However, risk assessment is hampered by the burden of manually abstracting and inputting data required by the established model developed on registry data. Accordingly, there is a need to develop AKI models that use automatically extracted electronic health records (EHR) data and evaluate their performance in comparison to the contemporary registry model.

Methods:
We used EHR data for PCIs performed at Yale New Haven Hospital (YNHH) and the linked local National Cardiovascular Data Registry (NCDR) CathPCI data to develop and compare the EHR models with the NCDR model. AKI was defined as an increase of ≥0.3 mg/dL or 50% in serum creatinine. To maximize interoperability across systems and usability at the point of care, we only considered structured EHR readily extractable before PCI, and implemented simple but universal data preprocessing. Longitudinal data was aggregated into 24h, 7d and 14d prior to PCI. We used Lasso regression and gradient descent boosting (GDB) to train the models and tested their capacity to approximate the NCDR model predictions and predict AKI independently. We evaluated performance via cross-validation by c-statistic, calibration slope, and predictive range defined by event rate difference in the lowest and highest risk deciles. We used paired t tests for model comparison.

Results:
The cohort included 9,202 PCIs from December 2012 to November 2019 at YNHH for 8,445 patients and had a mean age of 67.0±12.0 years with 27.6% females and 798 (8.7%) AKIs. Evaluated on the same test sets, the EHR models approximating the NCDR model predictions achieved similar performance to that model (all p>0.05). Further, the EHR model employing GDB to independently predict AKI achieved slightly better performance than the NCDR model in c-statistic (0.84 vs 0.83, p=0.02) and predictive range (41.2% vs 39.5%, p=0.13) with similar calibration (slope 0.98 vs 0.99).

Conclusion:
The automatically extracted EHR data produced models with similar performance to the registry model. These models can automate AKI risk assessment for PCI, alleviating provider burden and increase uptake of risk assessment.
Abstract 10214: Stress Testing Prior to Abdominal Aortic Aneurysm Repair: What is Our Return on Investment?
Authors: Columbo Jesse , Ponukumati Aravind S , Henkin Stanislav , Scali Salvatore T , Creager Mark A , Powell Richard J , Stone David
Published: March 2022

Introduction:
The use of stress testing prior to abdominal aortic aneurysm (AAA) repair is highly variable. We examined the financial implications of this variation and its impact on postoperative cardiac events.

Methods:
We studied patients who underwent elective endovascular (EVAR) or open AAA repair at Vascular Quality Initiative participating centers from 2015–2019. We grouped centers into quintiles by their frequency of preoperative stress testing. We calculated rates of major adverse cardiovascular events (MACE), a composite of in-hospital myocardial infarction, stroke, heart failure, or death, for each quintile. We applied the charges for electrocardiographic, echocardiographic, and nuclear stress tests at our institution in 2019 to the study population to calculate expected charges per 1,000 patients.

Results:
We studied 27,978 patients who underwent EVAR (mean age: 73.5 ±8.5 years, 81.7% male) and 4,481 who underwent open AAA repair (mean age: 69.5 ±8.1 years, 75.1% male). Stratifying by quintile, stress test frequency ranged from 13.0% to 68.6% (mean: 37.9%) among EVAR patients and 15.9% to 85.0% (mean: 52.8%) among open AAA repair (Figure). The rate of MACE was 1.4% after EVAR and 10.2% after open AAA repair. MACE after EVAR increased with the frequency of stress testing and was 0.9% at 1
st
quintile centers vs 1.7% at 5
th
quintile centers (p-trend=0.033). There was no association between MACE and stress testing for open AAA repair (p-trend=0.192). The estimated charges for stress testing prior to EVAR was $125,806 per 1,000 patients at 1
st
quintile centers, and $664,975 at 5
th
quintile centers, while charges prior to open AAA repair were $153,861 per 1,000 patients at 1
st
quintile centers, and $825,473 at 5
th
quintile centers.

Conclusions:
More frequent stress testing is associated with high cost without a reduction in MACE. This lack of return on investment highlights the need for more judicious stress test use prior to AAA surgery.
Abstract 10216: Sinus Node Dysfunction After Pulmonary Thromboendarterectomy Surgery
Authors: Vanam Sai , Munir Muhammad , Darden Douglas , Barat Masihullah , Keyt Lucas , Long Tanner , Feld Gregory K , Hsu Jonathan C , Birgersdotter-green Ulrika , Ho Gordon , Krummen David , Raissi Farshad , Fernandes Timothy , Poch David , Kim Nick , Papamatheakis Demosthenes G , Kerr Kim , Pretorius Victor , Madani Michael M , Han Frederick , Hoffmayer Kurt S
Published: March 2022

Background:
Pulmonary Thromboendarterectomy (PTE) is a specialized cardiac surgery for treating chronic thromboembolic pulmonary hypertension (CTEPH). Sinus node dysfunction is seen in this population as patients often require epicardial pacing after cardiac surgeries. We aimed to define the incidence, predictors, and outcomes of sinus node dysfunction after PTE surgery.

Hypothesis:
We hypothesized that sinus node dysfunction requiring epicardial pacing is common after PTE surgery.

Methods:
We reviewed the charts of 883 consecutive patients who were referred to University of California San Diego for PTE. Demographics, lab results and imaging were extracted from chart review. Predictors and outcomes were analyzed using multivariate backward logistic regression model or independent samples T test respectively.

Results:
Overall, 60% (n=533) of patients required epicardial pacing for an average of 3.9 +/- 2.2 days. Strongest predictors of epicardial pacing were coronary artery disease (OR 2.6, p=<0.01) and tobacco abuse (OR 2.1, p=0.01). Of the patients who required epicardial pacing, only 1% (n=4) required permanent pacemaker placement. Patients who required epicardial pacing had significantly longer post-operative length of stays (12.9 days vs 11.3 days, p=<0.01) and ventilator days (2.3 days vs 1.8 days, p=0.02).

Conclusions:
The majority of patients undergoing PTE for chronic thromboembolic pulmonary hypertension develop sinus node dysfunction requiring temporary epicardial pacing. The mechanism of sinus node dysfunction appears transient as the average pacing requirement is 3.9 +/- 2.2 days, and ultimately only 1% (n=4) require permanent pacemaker placement. Patients who required epicardial pacing had significantly longer post-operative length of stay and ventilator days.
Abstract 10222: Demographic and Clinical Characteristics of Patients Enrolled in a Non-Academic Multidisciplinary Cardio-Obstetrics Program
Authors: Shaw Kirsten , Wagner MD William , Sidebottom Abbey , Baechler Courtney , Hayes Joy , Benson Gretchen A , Okeson Brynn , Guenther Alena , Saxena Retu
Published: March 2022

Introduction:
Pregnancy in women with cardiovascular disease (CVD) is associated with significant morbidity and mortality. The CARPREG2 and the modified World Health Organization (mWHO) classification have been developed to predict cardiac complications. Most cardio-obstetric (CVOB) clinics are conducted through academic institutions; we describe the demographic and clinical characteristics of patients enrolled in a non-academic multidisciplinary CVOB specialty program after its inception in 2018/2019. We compared this with pregnant women seen in cardiology consultation in 2016/2017 prior to the program’s inception.

Hypothesis:
Women seen by the CVOB program will have higher risk scores compared to pre-program controls.

Methods:
A retrospective chart review was conducted of 113 patients who received care from the CVOB program in 2018/2019 as well as 338 pregnant women seen by cardiology in 2016/2017. Data on demographics, CVD risk and comorbidities were collected.

Results:
The CVOB patients had higher mWHO score (
>
II-III) at 57% vs.17% and higher CARPREG2 scores (
>
2) 51% vs 28%. The CVOB patients were more racially diverse (34% nonwhite vs 24%). The CVOB group had higher rates of valvular heart disease (27% vs 8%) and hypertension (19% vs 12%). The use of antiplatelets and antihypertensives in the CVOB group was higher during pregnancy.

Conclusions:
Women in the CVOB program were at significantly increased CVD risk and were more racially diverse compared to pregnant women referred for cardiology consultation.
Abstract 10223: Tissue-Entrapped Extracellular Vesicles Modulate Divergent Mechanisms of Cardiovascular Calcification
Authors: Blaser Mark C , Buffolo Fabrizio , Halu Arda , Schlotter Florian , Higashi Hideyuki , Pantano Rubino Lorena , Saddic Louis A , Atkins Samantha , Rogers Maximillian , Pham Tan , Vromman Amelie , Shvartz Eugenia , Sukhova Galina K , MONTICONE Silvia , camussi giovanni. , Body Simon C , Kaneko Tsuyoshi , Muehlschlegel J Daniel D , Singh Sasha A , Aikawa Masanori , Aikawa Elena
Published: March 2022

Introduction:
Fewer than 50% of patients develop vascular and valvular calcification, implying differential pathogenesis. Tissue-entrapped extracellular vesicles (EVs) are implicated in mineralization but their contents and functions are unstudied. We investigated entrapped EV cargoes in human cardiovascular disease.

Methods:
Human carotid endarterectomy specimens and stenotic aortic valves were obtained from 53 patients. Disease stage-specific proteomics was performed on whole tissue (non-diseased/fibrotic/calcified areas). Tissue EVs were enriched by gradient fractionation then underwent proteomics and miRNA-seq. miR targets were predicted by TargetScan, pathway analyses utilized BioCarta/KEGG/Reactome, and protein-protein interaction networks employed STRING.

Results:
Disease progression drove significant convergence (p<0.0001) of atherosclerotic plaque and valve proteomes (2,318 proteins). 548 and 158 proteins were exclusively altered (q<0.05) by disease in plaques or valves, respectively. Vesicular GO terms increased 2.2x (p<0.01) amongst proteins altered by disease in both tissues (202). Proteomics found 24 EV markers in the low-density fractions of plaques and valves, confirmed by electron microscopy and nanoparticle tracking. EV omics quantified 1,104 proteins and 123 miR cargoes. Networks of proteins and miR targets shared by plaque and valve EVs revealed common regulation of Rho GTPase and MAPK signaling. 179 proteins and 5 miRs were altered between plaque and valve EVs (q<0.05); multi-omics integration found that EVs modulated cellular contraction and p53-mediated transcriptional regulation in plaques and valves, respectively.

Conclusions:
This first comparative proteomics study of human valves and arteries finds shared EV functionality in both diseases. Using novel means to examine tissue EV molecular cargoes, we also reveal critical divergent tissue-specific roles for EVs in mediating cardiovascular disease.
Abstract 10224: What Are the Effects of a Gradual Taste Adaptation Approach in Patients with Heart Failure and Family Caregivers?
Authors: Chung Misook L , Lennie Terry A , Miller Jennifer , Moser Debra K
Published: March 2022

Introduction:
Adherence to the sodium-restricted diet (SRD) remains poor due to multiple barriers. We developed a dyadic intervention, a gradual taste adaptation to SRD to improve adherence to the SRD by overcoming sensory and family barriers. The purpose was to determine the efficacy of the gradual taste adaptation approach on dietary sodium intake, preferences for salty food, and enjoyment of SRD.

Hypothesis:
There will be a greater decline in dietary sodium intake and preference for salty food and an increase in the enjoyment of SRD at 4 and 12 months in dyads receiving the intervention compared to the dyads receiving usual care.

Methods:
A total of 158 patients with HF and caregiver dyads were randomly assigned to either the intervention (n=79 dyads) or a usual care control group (n=79 dyads). The 12-week intervention was delivered remotely using video conferencing. Outcomes were measured at 4 and 12 months for dyads, including dietary sodium intake using 24-hour urinary sodium excretion and self-reports on preference for salty food and enjoyment of SRD. Repeated measures ANOVA was used to determine intervention effects.

Results:
There was no difference in patients’ dietary sodium intake at baseline between the groups. Compared to the control group, patients in intervention significantly reduced dietary sodium intake and greater enjoyment of SRD. Sodium was reduced by 1,144 mg sodium at 4 months and 960 mg at 12 months while ratings of enjoyment of SRD increased at 4 and at 12 months (Figure 1). The intervention was not effective in decreasing the preference for salty food. There were also no significant intervention outcomes effects for caregivers.

Conclusions:
An innovative approach of gradual taste adaptation demonstrated significant short and long-term effects on reducing dietary sodium intake and enjoyment of SRD for patients. The intervention has the potential to expand the application to individuals who need to follow a SRD.
Abstract 10225: Vasopressor Use and 60-Day Outcomes Among Covid-19 Patients in the Intensive Care Unit
Authors: Kerlos Mina M , Gill Ahmad , Ruge Max , Du-Fay-de-Lavallaz Jeanne M , Gomez Joanne , Santos Volgman Annabelle , Williams Kim A , Rao Anupama , Marinescu Karolina , Suboc Tisha Marie
Published: March 2022

Introduction:
Vasopressor use has been associated with higher mortality rates in patients with COVID-19, the association between the maximum number of concurrent vasopressors with mortality has not yet been studied.

Methods:
A retrospective cohort study was conducted on patients admitted with COVID-19 to the intensive care unit (ICU) at Rush University System for Health in Illinois between March and October 2020. Multivariable logistic regression, adjusted for age, BMI, history of CAD and diabetes, was used to determine if an increasing number of vasopressors is associated with higher 60-day mortality.

Results:
A total of 637 patients met the inclusion criteria. Composite 60-day mortality was 28.6%. Of the 637 patients who met inclusion criteria, 338 (53.1%) required the support of at least one vasopressor. When compared to patients with no vasopressor requirement, those who required 1 (adjusted OR [aOR] 3.27, p<0.01), 2 (aOR 4.71, p<0.01), 3 (aOR 26.2, p<0.01), and 4 or 5 (aOR 106.38, p<0.01) vasopressor(s) were at increased risk of 60-day mortality (Figure 1). Additionally, the incidence of mechanical ventilation, venous thromboembolism, ventricular arrhythmia, and new renal replacement therapy increased with additional vasopressor requirement (p < 0.001 for each outcome; Table 1). There was no statistical difference in the incidence of MACE between the groups (p = 0.139).

Conclusion:
In this cohort, each additional vasopressor added was associated with escalating 60-day mortality. Identifying these high-risk patients can help determine prognostic outcomes and guide decision-making.

.
Abstract 10227: High-Sensitive Magnetic Particle Imaging of Intraplaque Hemorrhage for Identification of Unstable Atherosclerotic Plaques
Authors: Tong Wei , Hui Hui , Zhang Yingqian , Tian Jie , Chen Yundai
Published: March 2022

Introduction:
Intraplaque hemorrhage (IPH), which is believed to arise from immature neovessels, drives atherosclerosis progression and is an imaging predictor of stroke and myocardial infarction. However, detection of IPH using magnetic resonance imaging (MRI) might be limited due to false signals from varied plaque components. Magnetic particle imaging (MPI) is a novel tomographic method that directly images the magnetization of ferromagnetic particles.

Aims:
To test whether MPI can image IPH for detecting unstable plaques and exploring the mechanism of IPH.

Methods:
The tandem stenosis (TS) mouse model was used to establish unstable plaques with IPH. The intervention agent used for reducing IPH was 4-ABAH. TS ApoE
-/-
mice and human carotid endarterectomy samples were scanned with MPI and computed tomography. IPH was confirmed by fat-suppressed T1-weighted MRI and Prussian blue staining. Plaque specimens were analyzed histologically.

Results:
Human carotid samples exhibited endogenous MPI signals, which were related to IPH. Hemosiderin was likely the source of MPI signals. Seven weeks post-TS, unstable plaques in the right carotid artery showed endogenous MPI signals, which were three-fold greater compared with stable plaques in the brachiocephalic artery or normal arterial wall (P < 0.05). From the temporal points, MPI signals in unstable plaques increased from 3.05 ± 1.45 (4 weeks) to 7.29 ± 4.47 (7 weeks) and reduced to 2.59 ± 0.84 (11 weeks) (P < 0.05), while intraplaque neovessel densities showed no difference. Compared with 4 or 7 weeks post-TS, intraplaque neovessels at 11 weeks revealed a more mature phenotype indicated by increased neovessel lumen areas and VE-cadherin (endothelial junction marker) expressions (P < 0.05). Administered 4-ABAH attenuated MPI signals in unstable plaques (9.38 ± 6.75
vs.
3.11 ± 1.25, P < 0.05) and downregulated vWF (endothelial damage marker) expressions (P < 0.05) without affecting neovessel densities or lumen areas.

Conclusions:
MPI allows
ex vivo
IPH imaging in human carotid tissues,
in vivo
IPH monitoring and unstable plaque detection in ApoE
-/-
mice. MPI-detected IPH is likely associated with endothelial barrier function. As a result, MPI is a promising method for detecting unstable plaques in patients.
Abstract 10228: Efficacy and Safety of Catheter Ablation in Patients with Atrial Fibrillation and Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis
Authors: Siddiqui Muhammad U , Junarta Joey , Ahmed Adnan , Pasha Ahmed K , Alvarez Rene , Frisch Daniel R
Published: March 2022

Background:
Catheter ablation for atrial fibrillation is a proven alternative to pharmacologic rhythm control in patients with heart failure with reduced ejection fraction (HFrEF). Whether outcomes differ in patients with heart failure with preserved ejection fraction (HFpEF) is of interest.

Methods:
Medline, Scopus, and Cochrane Central Register of Controlled Trials were systematically searched to identify relevant studies. We extracted or calculated a risk ratio (RR) and 95% confidence intervals (CI) from each study. Primary outcomes of interest include atrial arrythmia recurrence and repeat ablation. Harm outcomes of interest include all-cause mortality, all-cause hospitalizations, cardiovascular hospitalizations, stroke/transient ischemic attack, and cardiac tamponade.

Results:
We included 7 observational studies comprising 2,525 patients with HFpEF who underwent catheter ablation for atrial fibrillation. There were no significant differences in primary and harm outcomes when comparing catheter ablation for atrial fibrillation in patients with HFpEF to patients with no heart failure. Similarly, there were no significant differences in outcomes when comparing catheter ablation for patients with HFpEF to HFrEF. The certainty in these estimates was low.

Conclusions:
Non-randomized studies suggest that catheter ablation for atrial fibrillation in patients with HFpEF is associated with similar arrythmia free survival and safety profile when compared to patients with HFrEF and without heart failure. This suggests that patients with AF and HFpEF may benefit equally from catheter ablation as those with AF and HFrEF.
Abstract 10230: Sestrin2 Plays an Essential Role in Regulating the Unfolded Protein Response During Cardiac Ischemia/Reperfusion and Preventing Excessive Myocardial Apoptosis
Authors: Li Xuan , Wang Zhen , do Carmo Jussara , Da Silva Alexandre A , Mouton Alan , Omoto Ana C , Hall John E
Published: March 2022

Introduction:
Cardiac ischemia/reperfusion (I/R) alters cellular redox and calcium homeostasis, causing protein-folding errors in the endoplasmic reticulum (ER) which activates the unfolded protein response (UPR). Although appropriate UPR is an adaptive response of the cell, excessive and prolonged UPR can cause cellular apoptosis and aggravate I/R injury. We showed that Sestrin2 (Sesn2) regulates AMP-activated protein kinase (AMPK) activity and acts as an endogenous inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) to modulate protein synthesis and autophagy in the heart.

Hypothesis:
We hypothesized that Sesn2 regulates activation of UPR and maintains ER homeostasis as a protective response during myocardial I/R.

Methods:
Ligation and release of the left anterior descending coronary artery (LAD) was performed in wild-type (WT) C57BL/6J and cardiac specific Sesn2 knock out (KO) mice to induce myocardial I/R injury (45’ ischemia with different time of reperfusion).

Results:
I/R induced UPR in a time-dependent manner, reaching its peak 6 hours post reperfusion, and returning to normal values after 24 hours of reperfusion in WT mice. Pharmacological inhibition of the UPR by 4-phenylbutyrate (100mg/kg, i.p.) after reperfusion attenuated myocardial infarction size and restored systolic function. Conversely, genetic ablation of cardiac-specific Sesn2 was associated with increased myocardial infarction of 49.4%, and decreased systolic function of 22.9%, compared to WT mice. Molecular analysis showed that cardiac Sesn2 deficiency resulted in greater and prolonged activation of the UPR, and increased myocardial apoptosis compared to WT mice. Furthermore, activation of mTORC1 pathway after I/R was more pronounced and prolonged in cardiac-specific Sesn2 KO hearts, whereas AMPK activity post reperfusion was similar in both groups. Inhibiting mTORC1 with rapamycin (3mg/kg, i.p.) after I/R reduced myocardial apoptosis in a similar fashion in WT and cardiac-specific Sesn2 KO mice.

Conclusions:
During I/R, regulation of mTORC1 signaling pathway by Sesn2 may be a key factor for maintaining ER homeostasis and reducing I/R-induced apoptosis and cardiac injury.
Abstract 10231: Parp1-Pkm2 Axis Mediates Right Ventricular Failure Associated with Pulmonary Arterial Hypertension
Authors: Shimauchi Tsukasa , Wu Wenhui , Grobs Yann , Omura Junichi , Tremblay Eve , Martineau Sandra , Yokokawa Tetsuro , Shimauchi Kana , Nadeau Valerie , Breuils Bonnet Sandra , Orcholski Mark , Paulin Roxane , Potus Francois , BOUCHERAT Olivier , Provencher Steeve , Bonnet Sebastien
Published: March 2022

Introduction:
Right ventricular (RV) function is the poor prognosis factor in pulmonary arterial hypertension (PAH) patients. Inflammation, oxidative DNA damage, and glycolysis are key triggering pathways that induce cardiomyocytes (CM) dysfunction. Oxidative DNA damage-dependent Poly (ADP ribose) Polymerase 1 (PARP1) activation was documented to promote glycolysis and inflammation through nuclear retention of Pyruvate Kinase Muscle isozyme 2 (PKM2). Despite PARP1/PKM2 axis is involved in many pathologies, their role in RV failure (RVF) remains unclear. We hypothesized that sustained PARP1 activation induces nuclear PKM2 localization, cardiac inflammation, and myocytes apoptosis resulting in transition from compensated (cRV) to decompensated RV (dRV).

Methods and Results:
We found that PARP1/PKM2 expression/activity (IF, WB) is upregulated in dRV patients (died of RVF, n=11) compared to cRV patients (CI>2.2, n=12) and control donors (n=19). Similar findings were seen in two rat models of RVF (monocrotaline, PA banding).
In vitro
, we confirmed that oxidative DNA damage (ET-1+H
2
O
2
) as well as inflammatory stress (ET-1+LPS) induced nuclear expression of PARP1/PKM2 (IF, WB) leading to inflammation (NF-κB nuclear translocation) and CM death (TUNEL). These effects were prevented by treatment with PARP1 inhibitor (ABT-888, Olaparib) or enforced cytosolic retention of PKM2 (TEPP-46, DASA-58). Cardiomyocytes isolated from neonatal
Parp1
deficient mice were resistant to myocyte dysfunction (PKM2 nuclear upregulation, NF-κB nuclear translocation, TUNEL) induced by oxidative DNA damage (ET-1+H
2
O
2
).
In vivo
, Olaparib (10mg/kg) as well as TEPP-46 (25mg/kg) prevented RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis) induced by PAB in rats (n=8~12 per group). Moreover, we confirmed that global
Parp1
loss-of-function confers protection against PAB induced-RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis, n=10 per group). (All p<0.05)

Conclusions:
We demonstrated for the first time that PARP1/PKM2 axis is a critical signal pathway RV decompensation. Targeting PARP1/PKM2 axis may represent a promising avenue for tackling maladaptive RV remodeling and pulmonary circulation, simultaneously.
Abstract 10240: Key Pathomechanisms of Cardiomyopathy Due to TTN Truncation
Authors: Fomin Andrey , Gaertner Anna , Cyganek Lukas , Tiburcy Malte , von Frieling-Salewsky Marion , Zimmermann Wolfram H , Milting Hendrik , Linke Wolfgang A
Published: March 2022

Introduction:
Heterozygous truncating variants in
TTN
(TTNtv) coding for titin cause dilated cardiomyopathy (DCM) but the underlying pathomechanisms are unclear and disease management remains uncertain. Here, we aim to elucidate the key pathomechanisms of TTNtv-DCM.

Hypothesis:
Stable expression of truncated titin proteins and titin haploinsufficiency characterize TTNtv-DCM and represent potential targets for therapy.

Methods and Results:
We studied left ventricular tissues from 14 nonfailing donor hearts and 113 endstage failing DCM patients and identified a TTNtv in 22 DCM patients (19.5%) by next generation sequencing. Using titin protein gel electrophoresis and western blot we demonstrate, for the first time, titin haploinsufficiency in TTNtv-DCM hearts. Strikingly, all 21 adult TTNtv-DCM hearts of our cohort showed stable expression of truncated titin proteins. Expression was variable, up to one-half of the total titin protein pool, and negatively correlated to patient age at heart transplantation. Truncated titin proteins were not detected in sarcomeres but were present in intracellular aggregates. Deregulated ubiquitin-dependent protein quality control was apparent. Next, we produced human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), comparing wildtype controls to cells with a patient-derived, prototypical A-band TTNtv or a CRISPR/Cas9-edited M-band TTNtv. TTNtv hiPSC-CMs showed reduced wildtype titin expression and contained truncated titin proteins, whose proportion increased upon inhibition of proteasomal activity. In engineered heart muscle generated from hiPSC-CMs, depressed contractility caused by TTNtv could be reversed by correction of the mutation using CRISPR/Cas9, thereby eliminating truncated titin proteins and raising wildtype titin content. Functional improvement also occurred when titin protein content was increased by proteasome inhibition.

Conclusions:
Our study reveals the major pathomechanisms of TTNtv-DCM, which include titin haploinsufficiency as a life-long condition and truncated titin protein enrichment with aggregate formation, along with aberrant protein quality control. Results can be exploited for new therapies of TTNtv cardiomyopathies.
Abstract 10241: Single-Cell RNA-Sequencing Reveals Hyperacute NK Cell and Monocyte Cell States Correlating with Poor Neurological Outcomes After Cardiac Arrest
Authors: Tamura Tomoyoshi , Cheng Changde , Weissman Alexandra , Pinilla-Vera Mayra , Merriam Louis , Varon Jack , Saliba Sam , Hou Peter , Seethala Raghu , Lawler Patrick R , Oldham William M ,   Immunology of Cardiac Arrest Network (I-CAN), Choi Jiyoung , Ikeda Kohei , Hayashida Kei , Tesfaigzi Yohannes , Berg Katherine , Bohula Erin , Morrow David , Baron Rebecca , Donnino Michael , Ichinose Fumito , Chen Xiang , Kim Edy
Published: March 2022

Background:
Lymphopenia and elevated cytokine levels suggest a role for the systemic immune response after cardiac arrest (CA). However, little is known about the phenotypes and interactions of immune cells after CA. This study aimed to investigate the immunological network after CA and identify cell states correlating with poor neurological outcomes.

Methods:
Peripheral mononuclear blood cells of 11 post-out-of-hospital CA patients and 3 healthy subjects were analyzed by single-cell RNA-sequencing (scRNA-seq), with validation by flow cytometry, bulk RNA-seq of sorted cell subsets, plasma levels of cytokines, and the murine model of CA. Good and poor neurological outcomes at hospital discharge were defined by Cerebral Performance Category 1-2 and 3-5, respectively.

Results:
The scRNA-seq analysis of 96,179 cells revealed 6 major cell lineages with several subclusters. At 6h post-CA, cells of patients with good outcomes co-clustered with healthy subjects, while patients with poor outcomes formed distinct transcriptomic clusters. This distinction was lost by 48h post-CA. At 6h post-CA, we identified pro-inflammatory and hypoxia-responsive Tim-3
+
NK cell and Nectin-2
+
monocyte cell states specific to poor outcomes. In a validation cohort of post-CA patients, Tim-3
+
NK cells and Nectin-2
+
monocyte cell states were validated by flow cytometry. Bulk RNA-seq analysis of these sorted cells reproduced the transcriptomic profile determined by scRNA-seq. Interactome analysis identified NK cell-monocyte axes in poor outcomes, including IFNG-IFNGR2. Measurement of plasma cytokine levels revealed increased IFNγ levels at 6h post-CA that were associated with poor outcomes, but both poor and good outcomes had similarIFNγ levels by 48h. A murine model of CA demonstrated that IFNγ drives poor outcomes and mortality after CA.

Conclusions:
In clinical CA, transcriptomic analysis at single-cell resolution revealed hyperacute cell states of NK cells and monocytes associated with poor neurological outcomes. These hyperacute cell states interact by IFNγ-IFNγR2 axis, which is pathogenic in the murine model of CA. The immunophenotypes that distinguish patients with poor or good neurological outcomes are present at 6h but are no longer detectable by 48h post-CA.
Abstract 10247: Establishing a Therapeutically Modifiable ROS/RNS-Beta 1 Adrenergic Receptor Desensitization and Internalization Axis in Aging Coronary Microvessels
Authors: Tracy Evan P , Dukes Michaela , Rowe Gabrielle , Beare Jason , Leblanc Amanda
Published: March 2022

Introduction:
Coronary Microvascular Disease (CMD) causes hyperconstriction, reduced perfusion, and chronic angina in aging. We previously showed increased coronary microvascular ROS and reduced NO/glutathione in aging rats correlating with reduced β1 Adrenergic receptor (β1ADR) dilation. Adipose Stromal Vascular Fraction (SVF) therapy reverses oxidative stress in CMD to improve β1ADR function. Our objective is to elucidate a mechanism for SVF’s recovery of β1ADR function in pursuit of a cell therapy to treat CMD.

Hypothesis:
β1ADR dilation is reduced in aging due to ROS-mediated receptor desensitization & internalization, reversible by inhibition of GRK2/dynamin & SVF antioxidation.

Methods:
Rat coronary microvessels were isolated from young (YC, 3-6 months), old (OC, 24 months), and old + SVF injection (OSVF, 24 months). RNAseq (n = 3 per group) and immunofluorescence (n ≥ 5 per group) were used to analyze pro/antioxidant gene & protein expression. Using pressure myography, dilation to isoproterenol was evaluated at baseline and with ROS (hydrogen peroxide and menadione) or RNS (sodium nitroprusside, SNP) +/- inhibitors of receptor desensitization (GRK2 via paroxetine) and internalization (dynamin via dynasore). Significance was set at p < .05 utilizing Two-Way Repeated Measures ANOVA with Holm-Sidak post-hoc analysis.

Results:
Aging (n = 16) reduced dilation to isoproterenol, reversed to youthful (n = 17) levels by SVF (n = 16). In YC/OSVF, ROS (n = 10 & 6) attenuated dilation reversed by dynasore (n = 8) and paroxetine (n = 7). In OC, SNP (n = 7), dynasore (n = 10), and paroxetine (n = 5) restored dilation. Aging increased prooxidant genetic (xanthine oxidase) and protein (NOX4) expression and increased antioxidant genetic (catalase) but not protein expression. SVF reduced prooxidant genetic (dynamin related protein 1) and protein (NOX4) expression with increased antioxidant genetic (glutathione synthetase) and protein (SOD2) expression.

Conclusion:
ROS in aging causes β1ADR dysfunction via desensitization & internalization, as their inhibition preserves β1ADR function. We name this interaction the
ROS/RNS-
β1ADR Desensitization & Internalization Axis
, which was therapeutically modulated by SVF antioxidation to restore β1ADR function.
Abstract 10249: Association of Eligibility for a Sodium-Glucose Co-Transporter 2 Inhibitor and Cardiovascular Outcomes in Patients with Atrial Fibrillation
Authors: Oraii Alireza , Healey Jeff S , Fonguh Sylvanus , Wang Jia , Pandey Arjun K , Conen David , Connolly Stuart J , McIntyre William F
Published: March 2022

Introduction:
Heart failure (HF) is the leading cause of death in patients with atrial fibrillation (AF). Although sodium-glucose co-transporter 2 inhibitors (SGLT2i) reduce HF in a broad range of populations, they have not been studied specifically in patients with AF.

Objective:
We aimed to determine the proportion of AF patients who are eligible for an SGLT2i based on co-morbidities, and compare their risk of cardiovascular outcomes to ineligible patients.

Methods:
We pooled data from two randomized controlled trials (RCTs) of AF patients (RE-LY and ACTIVE-W). Among patients assigned to the anticoagulation arms, those meeting the inclusion criteria from at least one of the large Phase 3 SGLT2i RCTs were included in the “SGLT2i-eligible” and the others in the “SGLT2i-ineligible” group. Eligibility indications were diabetes mellitus + cardiovascular disease (DM+CVD), HF with reduced ejection fraction (HFrEF), and renal disease. We examined a primary outcome of cardiovascular death and hospitalization for HF, and compared study outcomes between SGLT2i-eligible and ineligible groups.

Results:
A total of 21485 AF patients (mean age: 71.2±8.8, 36.1% women, Median CHA
2
DS
2
-VASc Score = 3, IQR 2-4) met inclusion. The proportion of AF patients eligible for treatment with an SGLT2i was 23.6%, with 8.9%, 22.6%, 9.1% being eligible for Empagliflozin, Dapagliflozin, and Canagliflozin, respectively. Renal disease (17.6%) was the most common eligibility indication, followed by DM+CVD (9.0%) and HFrEF (5.3%). After a median follow-up of 1.9 years, the incidence of cardiovascular death/hospitalization for HF (10.9% vs. 6.3%, p<0.001), cardiovascular death (5.2% vs. 2.4%, p<0.001), hospitalization for HF (6.8% vs. 4.2%, p<0.001), hospitalization for AF (6.7% vs. 5.4%, p<0.001), and thromboembolic events (4.9% vs. 3.9%, p=0.003) was significantly higher in the SGLT2i-eligible than the ineligible group.

Conclusion:
The majority of AF patients are not eligible for an SGLT2i. Although these patients are lower-risk than eligible patients, they still have high rates of cardiovascular events. RCTs are needed to test the efficacy of SGLT2is in AF patients.
Abstract 10250: Unique Lived Experiences of Partners of Individuals Living with Single Ventricle Congenital Heart Disease -A Pilot Investigation
Authors: Well Andrew , Taylor Kate , Ulack Chris , Carberry Kathleen , Colucci Jose , Stewart Eileen , Affolter Jeremy T , Wallace Scott , Teisberg Elizabeth , Fraser Charles D , Mery Carlos M
Published: March 2022

Introduction:
With advances in care, an increasing number of individuals with single-ventricle congenital heart disease (SVCHD) are surviving into adulthood. Partners of individuals with chronic illness have unique experiences and challenges. This pilot qualitative research study explores the lived experiences of partners of individuals with SVCHD.

Methods:
Partners of SVCHD patients ≥18 years were recruited and participated in Experience Group (EG) sessions and 1:1 interviews. EG sessions are lightly moderated groups that bring together individuals with similar experiences and place them as the experts to discuss lived experiences. Formal qualitative coding was performed to identify salient themes.

Results:
A total of 6 partners, 4 male, 4 married and all partners of someone of the opposite sex, participated. Themes identified included uncertainty of their partners future health and mortality, becoming a lay SVCHD specialist, balancing multiple roles, and providing positivity and optimism.(Table) Participants expressed a steep learning curve initially, which transforms into a strong understanding of the condition. Over time they took on the advocacy role as a repository of medical history and navigating the health system, which is often a role of parents of younger SVCHD patients. They struggled with taking on the role of primary medical caregiver of their partner while managing greater responsibility at home, and changes to their role as a spouse and a parent. Despite the uncertainties, participants described many facets of championing positivity and optimism for the future for their partner.

Conclusions:
In this first of its kind pilot study, partners of individuals with SVCHD expressed unique challenges and experiences in their lives. There is a tacit need to design strategies to help partners of SVCHD patients cope with those challenges. Further larger-scale research is required to better understand the experiences of this unique population.
Abstract 10251: Intracranial Aneurysms in Sickle Cell Adults Screened by Mra
Authors: Gomes Padilha Igor , Forté Stéphanie , Letourneau-guillon Laurent , Soulieres Denis , NELSON KRISTOFF , Belair Manon , Raymond Jean , Guilbert François
Published: March 2022

Introduction:
Sickle cell disease(SCD) is the most common genetic disease globally. It is an autosomal recessive disease that affects the β-globin chain which most often presents with anemia and vaso-occlusive symptoms. This condition includes multiples genotypes/phenotypes, the most common of which is HbSS (homozygosity for Hemoglobin S); others are compound heterozygosity with HbC variant (HbSC) and HbS-β-thalassemia (HbSβ+/HbSβ0). Stroke occurs in up to 25% of SCD patients and MRI screening is already recommended by the American Society of Hematology. Small case series have shown a higher prevalence of intracranial aneurysms (ICAN) in SCD, and MR angiography (MRA) may therefore be of benefit for the detection of arterial pathology.

Hypothesis:
There is an increased prevalence of ICAN in adults with SCD; Frequency of anevrysms is associated with SCD genotype and age.

Methods:
Adult patients from the SCD clinic of our institution were screened with 3T brain MR complemented with MRA in order to accurately determine the prevalence of ICAN.

Results:
Our study included 245 asymptomatic SCD adults (369 MRIs). Median age was 32; 52% were women. The overall prevalence of ICAN was 0.11 (0.95 CI 0.07-0.15). All aneurysms were saccular ≤ 10 mm. Forty-four aneurysms were detected in 27 patients with a third presenting with multiple aneurysms. Genotype subgroup analysis revealed a higher prevalence of ICAN in SS/Sb0 (0.17; 0.95 CI 0.11-0.25) compared to the SC/Sb+ (0.06; 0.95 CI 0.02-0.11) (p = 0.007). An association between age and ICAN was also statistically significant (p = 0.03) with stratification revealing a higher prevalence of ICAN for >30 years old, 0.15 (0.95 CI 0.09-0.21). In addition, in patients aged 18-30, the prevalence was 0.06 (0.95 CI 0.26-0.12).

Conclusions:
This is the largest cohort of SCD adults screened specifically with MRA. We confirm with higher confidence the increased prevalence of ICAN in this population which is in the range of other established indications for aneurysm screening such as Familial Intracranial Aneurysm and Autosomal Dominant Polycystic Kidney Disease. This knowledge could therefore impact the existing screening guidelines for SCD patients via systematic inclusion of an MRA sequence in the recommended imaging protocol.
Abstract 10252: State Wide Pregnancy Outcomes for Adolescents and Adults with Single-Ventricle Congenital Heart Disease - A 14 Year Review
Authors: Well Andrew , Ilangovan Sruthi , Mercado Amelia , Dawson Catherine , Mizrahi Michelle , Patt Hanoch , Johnson Gregory , Fraser Charles D , Mery Carlos M , Beckerman Ziv
Published: March 2022

Introduction:
With advances in care, survival into adulthood of single-ventricle (SV) palliation is more frequent. Fertility and family planning in this setting is complex. In the general population, maternal mortality is 0.02%, post-partum hemorrhage (PPH) is 3.1% and pre-eclampsia is 7.5%. There are limited data on outcomes of pregnancies of women with SV physiology. This study reviews deliveries of SV mothers in Texas over the past 14 years.

Methods:
This is a retrospective review of the Texas Inpatient Discharge Dataset, an administrative dataset containing most hospital discharges. All discharges of females≥15 years old between 1/1/2006-12/31/2019 were reviewed. ICD-9/10 diagnosis codes consistent with Hypoplastic Left Heart Syndrome (HLHS), Double Inlet Ventricle (DIV)/Common Ventricle (CV), and Hypoplastic Right Heart Syndrome (HRHS)/Tricuspid Atresia (TA) were included. Pregnancy-related discharges were identified by ICD-9/10 codes. Descriptive and univariate statistics were utilized.

Results:
A total of 56 pregnancy-related discharges were identified, with 40 (71.4%) deliveries (Table). One (2.5%) was a twin gestation and 4(10%) had fetal demise. Number of annual deliveries increased from 0 in 2006 to 8 in 2019. Median gestational age was 37[IQR: 33.25-38] weeks, 7 (17.5%) had fetal anomalies and 7(17.5%) had poor fetal growth. Twelve (30%) underwent C-Section. Median length of stay was 3.5[2-5] days, 3(7.5%) mothers had PPH, 2(5%) required ventilator support, and there were no in-hospital mortalities.

Conclusions:
As the number of patients with SV surviving into adulthood increases, accurate counseling on risks of pregnancy is required. While these data cannot evaluate the outcomes for the delivered baby, they suggest favorable short-term outcomes for mothers with no in-hospital mortalities. Further research is needed to both understand outcomes for the delivered babies as well as potential longer-term sequelae for mothers.
Abstract 10258: Do Statins Impact Long-term Mortality Peripheral Artery Disease Patients Who Have End Stage Renal Disease?
Authors: Ranka Sagar , Chan Wan Chi , Tadros Peter , Wiley Mark A , Hockstad Eric , gupta Kamal
Published: March 2022

Introduction:
Statins have shown mortality benefit in peripheral artery disease (PAD), their impact in end-stage renal disease (ESRD) patients with PAD is not well studied.

Hypothesis:
Does statin utilization have any impact on mortality in ESRD patients with PAD?

Methods:
We included ESRD Medicare beneficiaries from the United states Renal Database (Jan 1
st
2006 to May 31
st
2017) with PAD within 6 months of incident dialysis. Medicare part D claims were used to determine STU during the follow-up period. Fractional polynomial regression across varying % of STU was generated to predict 2-year mortality.

Results:
Out of 45,424 ESRD patients with PAD, 62.3% received no statins while the rest had at least some duration of STU. ST was bimodally distributed, with median utilization of 0% (IQR= 0-90%). Mortality was 41.7% over a median follow-up of 472 days. Univariate association of STU on mortality yielded odds ratio (OR) of 0.99 (95% CI = 0.992-0.993; p<0.001). Model 1 including baseline demographics and comorbidities (age, sex, body mass index, hypertension, coronary artery disease, stroke, smoking, diabetes, and heart failure) an AUC of 0.65. The addition of STU (Model 2) resulted in only minimal improvement in the AUC (0.65 vs 0.67; p<0.01).

Conclusions:
Statin utilization in ESRD patients is associated with only borderline statistically significant reduction in mortality (≈0.1%) of unclear clinical implications
Abstract 10268: Establishment of a Hypoimmunogenic Human Induced Pluripotent Stem Cell Line Which Allows
in Vivo
Tracing of Ventricular Cardiomyocytes
Authors: Ottele Lina , Heinrich Paul , Lahm Harald , Dzilic Elda , Doppler Stefanie , Lange Ruediger , Krane Markus , Dressen Martina
Published: March 2022

Introduction:
In recent years, human induced pluripotent stem cells (hiPSCs) have emerged as a promising source for cardiac cell therapy. However, immune rejection and insufficient methods for cell fate tracing compromise the assessment of graft efficiency and survival. Hence, we sought to establish a hiPSC line for regenerative therapies which combines hypoimmunogenic and
in vivo
traceable features.

Methods:
A hiPSC line was modified using CRISPR/Cas9 technology to first insert a
tdTomato
reporter into the
MLC2v
gene and in a second step to replace exons 2 and 3 of the
B2M
gene with a neomycin resistance cassette, designated B2M-KO. MHC-I surface expression was evaluated by flow cytometry analysis. The immune response of cytotoxic CD8+ T cells and natural killer (NK) cells against the B2M-KO and wild-type hiPSCs was evaluated with a lactate dehydrogenase-based cytotoxicity assay. Immunocytochemistry and qRT-PCR expression analyses were performed to study the cardiomyogenic capacity of
B2M-KO
hiPSCs during directed cardiac differentiation.

Results:
The homozygous disruption of the
B2M
gene was confirmed by qRT-PCR and flow cytometry. However, mRNA expression of essential cardiac transcription factors (
NKX2.5, TBX5
) and important structural genes (
MLC2a, MLC2v
) during cardiac differentiation was not affected. By contrast, CD8+ T cell-mediated cytotoxicity against
B2M
-deficient hiPSCs was dramatically reduced compared to wild-type hiPSCs (p<0.002) while NK cell-dependent lysis remained unaffected. The
tdTomato
fluorescence in differentiating
B2M
-deficient hiPSCs was generally detectable around day 20 of the directed cardiac differentiation protocol and increased over time. These cells concomitantly also showed expression of
MLC2v
. Finally, immunocytochemistry confirmed expression of MLC2a, MLC2v and α-ACTININ similar to unedited cells after 30 days of cardiac differentiation.

Conclusions:
Genetic manipulation of MHC-I surface expression is an efficient strategy to reduce T cell-mediated immune rejection, yet unable to decrease NK cell-mediated cytotoxicity. The generated B2M-KO hiPSC line exhibits hypoimmunogenic properties and allows post-transplantational
in vivo
tracking of ventricular cardiomyocytes.
Abstract 10269: Direct Oral Anticoagulation Therapy vs Vitamin K Antagonist in Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review and Meta-Analysis
Authors: El Iskandarani Mahmoud , Al Tamari Ahmad , Khalid Muhammad , Paul Timir K
Published: March 2022

Introduction:
The use of direct oral anticoagulation therapy (DOAC) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) has recently increased, despite the scarce evidence to support their use in this condition. Our systematic review and meta-analysis aim to summarize the available data on the safety and effectiveness of DOAC.

Hypothesis:
DOAC is a safe and effective alternative anticoagulation therapy in CTEPH.

Methods:
Unrestricted search of the PubMed, EMBASE, and Cochrane databases from inception till May 1, 2021, for studies comparing DOAC with Vitamin K antagonist (VKA) in CTEPH patients. Relevant data were extracted and analyzed using Revman 5.3 software. Odds Ratio (OR) and 95% Confidence interval (CI) were calculated using the random-effects model.

Results:
A total of 3 observational studies were included examining 1,630 patients with CTEPH (386 DOAC vs 1,244 VKA). The most used DOAC was Rivaroxaban (79% of that population). There was no difference between DOAC and VKA in the incidence of recurrent venous thromboembolism OR 1.35 (95% CI 0.40-4.52), major bleeding OR 0.60 (95% CI 0.33-1.10), and clinically relevant non-major bleeding OR 1.42 (95% CI 0.86-2.33).

Conclusions:
DOAC is probably non-inferior to VKA in CTEPH patients. Since rivaroxaban is the most used DOAC in the included cohort, the safety, and efficacy of other DOAC remain unclear. Our findings need further validation with randomized clinical trials.