bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11596: Amyloidogenic Medin Induces Endothelial Cell Prothrombotic Activation
Authors: Karamanova Nina , Truran Seth , Davies Hannah , Madine Jillian , Migrino Raymond Q
Published: March 2022

Background:
Vascular aging is characterized by acquisition of a pro-inflammatory and prothrombotic vascular phenotype independent of cardiovascular metabolic risk factors through still unknown mechanisms. Medin is an amyloidogenic peptide formed as a cleavage product of milk fat globule EGF factor 8 protein. It accumulates in the vasculature with aging and is one of the most common yet poorly understood human amyloid proteins. Cerebrovascular medin was shown to be strongly associated with vascular dementia and Alzheimer’s disease. It was shown to induce endothelial pro-inflammatory activation and endothelial dysfunction. We aim to test the hypothesis that medin induces prothrombotic activation in endothelial cells.

Methods:
Recombinant medin was expressed in Lemo 21 (DE3 cells) and purified. Human umbilical vein endothelial cells (HUVECs) were exposed to either vehicle or medin (5 μM, a dose found to be physiologically relevant in human tissue) for 20 hours. Cell lysates were measured for protein content of tissue factor (TF, receptor and cofactor for factor VII and initiates coagulation), plasminogen activator inhibitor-1 (PAI-1, inhibits plasminogen activators that promote fibrinolysis) and thrombomodulin (cell surface glycoprotein that inhibits procoagulant function of thrombin) using standard Western blot and compared.

Results:
See Figure. Physiologic dose of medin induced increased endothelial cell protein expression of TF, PAI-1 and reduced expression of thrombomodulin.

Conclusions:
Medin induces prothrombotic activation in human endothelial cells and may be a key novel mediator in the development of vascular aging phenotype.
Abstract 11599: Elevated Interleukin-6 and
TMPRSS6
Genotype Are Associated with Worse Cardiovascular Outcomes
Authors: Barrows Ian , Amdur Richard
Published: March 2022

Introduction:
Elevated levels of plasma interleukin-6 (IL-6) and impaired iron homeostasis are associated with cardiovascular disease. IL-6 and matriptase-2, which is encoded by the
TMPRSS6
gene, help regulate iron homeostasis. A nonsynonymous V736A substitution (rs855791) reduces the ability of matriptase-2 to inhibit hepcidin transcription, leading to iron-deficiency anemia that is refractory to iron administration. We assessed the hypothesis that patients with chronic kidney disease and elevated IL-6 and the rs855791 genotype have poorer cardiovascular outcomes.

Methods:
We used the clinical, genetic and biomarker data from 3031 Chronic Renal Insufficiency Cohort (CRIC) study participants with follow-up over 10 years. The genotype data was extracted from genome-wide association studies. The primary outcome of interest was all-cause mortality and a composite of myocardial infarction (MI), stroke, congestive heart failure (CHF) and peripheral arterial disease (PAD). We used a separate logistic regression model for each outcome, with covariates for genotype and IL-6 quintile, and the genotype x IL-6 interaction. These models were adjusted for the Pooled Cohort Equation 10-year atherosclerotic cardiovascular disease probability estimate, race, BMI, baseline eGFR and baseline albuminuria.

Results:
Among the study participants, 1569 (52%) and 1122 (37%) were homozygous for GG and AA alleles, and 1122 (37%) were heterozygous (AG). The rs855791 genotype and plasma level of IL-6 were significantly associated with lower hemoglobin levels, all-cause mortality and cardiovascular outcomes. In the adjusted model that included the rs855791 genotype, IL-6 remained significantly associated with all-cause mortality (1.36 (1.26-1.45), p<0.001) and the CVD composite (1.27 (1.19-1.36), p<0.001). The interaction of IL-6 quintile x rs855791 genotype was not significantly associated with outcomes.

Conclusion:
In conclusion, elevated plasma levels of IL-6 and the rs855791 genotype are both independently associated with anemia, all cause mortality and cardiovascular outcomes in patients with kidney disease.
Abstract 11607: Protein Citrullination Landscape of Human Coronary Atherosclerosis
Authors: Stachowicz Aneta , Mao Chunhong , Hixson James , Jackson Fannie R , Vander Heide Richard , Van Eyk Jennifer E , Herrington David M , Fert-Bober Justyna P
Published: March 2022

Introduction:
Recently, an irreversible enzymatic post-translational modification, citrullination, has been shown to be present in the cardiovascular system (e.g. aorta). Citrullination, in which arginine is converted to citrulline, can alter protein structure and function, and produce autoantigens

Hypothesis:
Emerging evidence suggest a potential role for autoimmunity in the pathogenesis of atherosclerosis. However, it remains unknown whether of post-translational citrullination of arterial proteins contributes to local inflammatory processes that initiate or accelerate the atherosclerotic process. The aim of this study was to investigate changes in protein citrullination in human left anterior descending (LAD) coronary artery specimens with and without early atherosclerosis obtained from autopsied young adults with no clinical manifestations of coronary disease.

Methods:
Segments of the mid-LAD from 74 autopsied individuals (age range:15-55 yrs., 75% male, 67% White) were graded by a pathologist for percent of surface area involved with fatty streaks (FS) or fibrous plaque (FP). The frozen samples were homogenized and digested with Lys-C for subsequent proteomic mass-spectrometry using a data-independent acquisition (DIA) proteomic strategy with a hyper-citrullinated spectral library approach and our published CitFinder software.

Results:
We found 133 differentially expressed proteins (FDR<0.05) between control, FS and FP groups. Among them, 19 citrullinated proteins with 26 modified amino acid residues were identified. Citrullinated peptides from fibrinogen alpha chain (R84) and transgelin (R146) were upregulated in FP samples in comparison to FS and normal samples. Similarly, the citrullination site (R269) on alpha-enolase was significantly increased in the FP samples compared to normal. Interestingly, citrullination (R110) on myosin light polypeptide 6 was downregulated in FP samples.

Conclusions:
These data represent the most comprehensive interrogation of citrullinated proteins in human arterial samples to-date and suggest a possible association between this modification of several key proteins involved in tight junction, vascular smooth muscle contraction and inflammation and early atherosclerosis.
Abstract 11613: Prognostic Implication of Early Drop in Systolic Blood Pressure During the First 48 Hours in Patients with Acute Heart Failure from REALITY-AHF Registry
Authors: Dotare Taishi , Maeda Daichi , Sunayama Tsutomu , Iso Takashi , Kida Keisuke , Kitai Takeshi , Kagiyama Nobuyuki , Yamaguchi Tetsuo , OKUMURA TAKAHIRO , Mizuno Atsushi , Oishi Shogo , INUZUKA YASUTAKA , Akiyama Eiichi , Suzuki Satoshi , Yamamoto Masayoshi , Minamino Tohru , Matsue Yuya
Published: March 2022

Background:
Although it has been suggested that excessive drop in systolic blood pressure (SBP) in the acute phase of acute heart failure potentially has a negative impact on prognosis, the association between changes in SBP during acute phase and prognosis has yet to be clarified.

Methods and Results:
This is the sub-analysis of REALITY-AHF (Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure) study, which was a prospective, multicenter, observational registry which registered patients with acute heart failure admitted through emergency department (ED). Peak drop in SBP was defined as the difference between the baseline SBP values and the lowest values during the first 48 hours of hospitalization. After ED arrival, SBP was measured at the time of admission, 90 minutes, 6 hours, 24 hours, and 48 hours of ED admission. Patients were divided into three groups according to the value of peak SBP drop . A total of 1,656 patients were included in our study. Patients with greater peak SBP drop group was associated with higher baseline SBP and vasodilator use after admission. Cox proportional hazard analysis demonstrated greater peak SBP drop (per 10mmHg decrease) was independently associated with 180-day (hazard ratio, 1.12; 95% confidence interval, 1.01–1.23; P=0.027) and 1-year (hazard ratio, 1.12; 95% confidence interval, 1.03–1.21; P=0.006) mortality even after adjustment for confounding factors including baseline SBP (Figure).

Conclusions:
Early drop in SBP during first 48 hours of hospitalization was associated with all-cause mortality in patients with acute heart failure.
Abstract 11614: Investigating Outcomes in Patients with Pulmonary Hypertension Diagnosed with Covid-19 in a Tertiary Pulmonary Hypertension Referral Center
Authors: DeSalvo Jennifer , Franco Veronica , Benza Raymond L , Daniels Curt , Kittel Debra , Alexander Amy , Homsy Elie , Lastinger Lauren , Rajpal Saurabh
Published: March 2022

Introduction:
Preexisting endothelial dysfunction and effects of selective pulmonary vasodilator therapy are postulated to prevent vascular remodeling and decrease morbidity and mortality in pulmonary arterial hypertension (PAH) patients with COVID-19. However, research on outcomes in PAH patients with COVID-19 is limited. We studied morbidity and mortality from COVID-19 in a tertiary PAH referral center.

Methods:
Of 596 clinic patients on at least one PAH specific medication, 27 patients were diagnosed with COVID-19 between March 2020 and January 2021. Retrospectively evaluated outcomes included mortality, hospitalization, intensive care unit admission (ICU), mechanical ventilation (MV), extracorporeal membrane oxygenation (ECMO), lung transplant, and hospital readmission within 30 days.

Results:
Of 27 PAH patients with COVID-19 (mean age=60 years; 74% female; 96% non-Hispanic; 74% White), 15 (56%) were hospitalized, 7 (26%) died, and 1 (4%) underwent ECMO followed by lung transplant. Hospitalized patients, compared to non-hospitalized patients, had higher mean age (64 vs 56 years), number of patients on IV prostacyclin (20% vs 0%), mean REVEAL 2.0 score (8.4 vs 6.5), and moderate-severe RV dysfunction (6, 40% vs 3, 25%). There was no difference in NYHA FC and mean pulmonary arterial pressure (45 mm Hg vs 43.7 mm Hg) between hospitalized and non-hospitalized patients. Complications during hospitalization included worsened hypoxemia (13, 87%), cardiac ischemia (4, 15%), new or worsening arrhythmias (3, 11%), and acute kidney injury (AKI) (6, 22%). Four patients (27%) required ICU admission and MV. Of these, 2 (50%) had new or worsening arrhythmias and all 4 (100%) had AKI. Of 15 patients hospitalized, 5 (19%) were readmitted to the hospital within 30 days. The 7 patients who died during hospitalization, compared to 8 who survived, had increased rates of ICU admission and MV (43% vs 12.5%) and higher REVEAL 2.0 scores (10.1 vs 6.9).

Conclusion:
COVID-19 in hospitalized PAH patients was associated with high rates of multi-organ complications, mortality, ICU admission, and hospital re-admission. Advanced age, IV prostacyclin therapy, higher REVEAL score, moderate to severe RV dysfunction, and AKI were associated with adverse outcomes.
Abstract 11616: Seizures in Infants with Congenital Heart Disease
Authors: Aly Safwat , Aly Hany , Mohamed Mohamed A
Published: March 2022

Background:
Infants with congenital heart disease (CHD) may have an increased risk to develop seizures during hospitalization.

Objectives:
to examine the association of CHD with non-epileptic, non-traumatic seizures in hospitalized infants up to one year of age.

Methods:
We conducted a retrospective analysis of the U.S. National Inpatient Sample dataset (2015-2018). We used the international classification of disease-10
th
version to identify infants with different types of CHD. We included infants up to one year of age. We excluded infants <35 week gestational age, infants with central nervous system or with major congenital anomalies, common trisomy or genetic disorders. We used chi square testing to examine the association of subtypes of CHD with seizures excluding post traumatic and epileptic seizures. We calculated mortality in infants with CHD who developed seizures versus those who did not have seizures.

Results:
There was 12,023,781 infants in the weighted sample who met our inclusion criteria. Of them, 48.7% were females, 46.7% were Caucasians, 195,685 (1.63%) were identified with a CHD and 20,565 (0.17%) suffered at least one episode of seizure during hospitalization. Seizures occurred in 4225 (2.2%) of infants with any type of CHD compared to 16,340 (0.14%) in infants with no CHD, odds ratios for seizures is 15.6 (CI: 15.2-16.5,
p
<0.001). The association of seizures with subtypes of CHD is shown in table-1. Among infants with CHD, 2205 infants expired during hospitalization. Mortality was higher in infants with CHD who suffered seizures (8.5%) vs. those who did not have seizures (1.0%), OR 9.6 (8.5-10.8,
p
<0.001).

Conclusion:
Infants with CHD have a higher chance to experience seizure episodes during their hospitalization and those who have seizures have higher chances of mortality during hospitalization. Further analysis is required to understand the pathological correlation between seizures and CHD and its impact on long term developmental outcomes.
Abstract 11630: Comparing Outcomes Between Robotic Assisted versus Manual Percutaneous Coronary Intervention - A Meta-Analysis of 2,203 Patients
Authors: Gupta Rahul , malik aaqib , Aedma Surya K , Aronow Wilbert S , Vyas Apurva , Mehta Sanjay , Combs William G , Patel Nainesh
Published: March 2022

Introduction:
Robotics in percutaneous coronary intervention (R-PCI) has been one such area of advancement where potential benefits may include reduction in radiation exposure, improved outcomes and reduced rate of adverse events. Robotic assistance may offer many potential benefits to both the operator and the patient. Limited data exist about the benefits of R-PCI vs. conventional manual PCI (M-PCI).

Hypothesis:
The aim for our meta-analysis is to evaluate the procedural measures and clinical outcomes between R-PCI and M-PCI.

Methods:
A comprehensive literature search was performed in PubMed, Embase, and Cochrane to identify relevant clinical studies. Summary effects were calculated using a DerSimonian and Laird random effects model as odds ratio with 95% confidence intervals for all the clinical endpoints. All studies adhering to the inclusion criteria of direct comparisons between R-PCI and M-PCI were evaluated.

Results:
Seven studies with a total of 2,230 patients were identified. There was significant decrease in the chest-level operator radiation exposure (OR= -442.32; 95% CI = -675.88 to -208.76), fluoroscopy time (OR = -1.46; 95% CI -2.92 to 0.00) and amount of contrast used (OR= -18.28; 95% CI -24.16 to -12.41) in the robotic group as compared to the manual group. PCI time (OR = 2.41; 95% CI -3.95 to 8.76) and procedural success rate (OR 1.26; CI 0.19-8.22) was not statistically different between the two groups. In terms of clinical outcomes, there was no difference between R-PCI and M-PCI in terms of major adverse cardiac events (OR 0.90; CI 0.45-1.79), all-cause mortality (OR 0.95; CI 0.21-4.30), and myocardial infarction (OR 0.88; CI 0.41-1.89).

Conclusions:
Robotic PCI is associated with reduced operator radiation exposure, fluoroscopy time and amount of contrast used. While there is a significant reduction in the procedural characteristics with robotic PCI, the clinical outcomes are not different compared to manual PCI. Use of robotics in PCI appears to be safe and potentially favorable to the patients, in addition to its benefits of improved ergonomics. More randomized studies looking at the use of R-PCI, especially in complex lesions, are needed before consideration for widespread implementation.
Abstract 11634: Sympathetic Neural Overdrive, Endothelial Dysfunction and Aortic Stiffness in Coronavirus Disease 2019 Survivors: A Short-Term Study of Cardiovascular Sequelae
Authors: Faria Diego , Testa Laura , Moll-Bernardes Renata , Moniz Camila , Rodrigues Erika , Costa-Neto Abel , Sousa Andrea , Rodrigues Amanda , Oliveira Patricia , Alves Maria Janieire , Santos Gabriel , Salemi Vera , Pimenta Ruan , Paixão Camila , Santos Beatriz , Rondon Maria U , Craighead Daniel , Rossman Matthew , Consolim-Colombo Fernanda M , Irigoyen Maria C , Martinez-Lemus Luis A , Padilla Jaume , Seals Douglas R , Negrao Carlos E , Sales Allan
Published: March 2022

Introduction:
Coronavirus disease 2019 (COVID-19) has become one of the more dramatic health problems in the century. This disease has enormous consequence for the health care worldwide. In addition to high mortality rate, patients recovered from COVID-19 present short and long-term cardiovascular sequelae including chest pain, myocardial dysfunction, arrhythmia, dyspnea, breathlessness, postural tachycardia syndrome, and thrombotic complications. The explanations for these clinical manifestations are still uncertain but can involve a constellation of physiological alterations.

Hypothesis:
To test if COVID-19 survivors have augmented sympathetic outflow, diminished endothelial function, elevated aortic stiffness, and reduced physical capacity compared to healthy individuals.

Methods:
Nineteen COVID-19 survivors [age: 47.0±2.3 years, BMI: 30.1±1.2 Kg/m
2
] and eighteen well-matched healthy controls (age: 44.0±2.0 years, BMI: 28.4 ±1.2 Kg.m
2
] were included in study. COVID-19 survivors were evaluated within 6 months of original diagnosis by RT-PCR. Muscle sympathetic nerve activity (MSNA) from fibular nerve (Microneurography), brachial artery flow-mediated dilation (BAFMD; Doppler-Ultrasound), carotid-femoral pulse wave velocity (cf-PWV; Complior), beat-to-beat blood pressure (Peripheral BP; Finometer), heart rate (HR; Electrocardiography) and peak oxygen uptake (VO
2peak
, Cardiopulmonary exercise testing) were measured in both groups.

Results:
MSNA was higher in COVID-19 survivors compared to controls (33.0±1.0 vs. 22.0±1.0 bursts/min,
p
=0.001). Both BAFMD and VO
2peak
were lower in COVID-19 survivors compared to controls (4.6±0.7 vs. 8.2 ±0.8%,
p
=0.005 and 22.2±1.5 vs. 29.7±1.6 mL/Kg/min
p
=0.001, respectively). Although COVID-19 survivors had greater cf-PWV than controls (8.6±0.5 m/s vs. 7.4±0.4 m/s,
p
=0.03), BP and HR were not different between groups.

Conclusions:
Our study revealed that patients recently recovered from COVID-19 have abnormal neurovascular control, vascular alterations and reduced physical capacity. These findings strongly indicate the need of further long-term investigations to uncover cardiovascular sequelae provoked by COVID-19.
Abstract 11637: Decline in Stroke Mortality in the United States, 1975-2019: Impact of Obesity Among Women and Men
Authors: Ananth Cande V , Brandt Justin S , Keyes Katherine M , Graham Hillary L , Kostis John B , Kostis William J
Published: March 2022

Introduction:
The extent to which shifting age distributions, changes in stroke subtypes, and increases in obesity rates have impacted stroke mortality remain uncertain.

Hypothesis:
We hypothesize strong age and period effects on trends in stroke mortality, with obesity playing an important role in these trends.

Methods:
We designed a sequential time series analysis of 4,060,259 stroke deaths among women and men aged 18-84 years in the US, 1975-2019. The US annual mortality data, and US mid-year population data were accessed from Our World in Data and the CDC. Mortality rates were examined for overall stroke, and ischemic and hemorrhagic strokes. Trends in stroke mortality based on changes in the distribution of age, period, and birth cohorts (APC) were evaluated from Poisson models. We also aimed to quantify how much of the temporal increase in obesity rates explain the variance in stroke mortality trends.

Results:
Age-standardized stroke mortality declined for women (87.5 [95% confidence interval , CI, 86.8, 88.1] per 100,000 in 1975 to 30.9 [95% CI, 30.6, 31.2] in 2019) and men (112.1 [95% CI, 111.3, 113.0] per 100,000 in 1975 to 38.7 [95% CI, 38.3, 39.0] in 2019). In an APC analysis, stroke mortality increased sharply with advancing age (Figure). Ischemic and hemorrhagic strokes declined by period. There was a cohort effect for ischemic, but not hemorrhagic stroke. In 2019, the rate ratio (RR) of mortality for men versus women was 1.30 (95% CI, 1.27, 1.33) for ischemic stroke and 1.12 (95% CI, 1.09, 1.15) for hemorrhagic stroke. Increasing rates of obesity accounted for 86% and 80% of the temporal decline in stroke mortality rates among women and men, respectively.

Conclusions:
In the US, mortality rates from stroke have declined over the last 45 years. While men are more likely to die from stroke, the gender difference has narrowed for ischemic stroke, but widened for hemorrhagic strokes. Obesity appears to have contributed substantially to the decline in stroke mortality.
Abstract 11640: Longitudinal Changes in Ventricular Torsion in Adolescents with Single-Ventricle Anatomy: Long Term Follow Up
Authors: Aly Safwat , Mertens Luc L , Friedberg Mark K , Grosse-Wortmann Lars , Dragulescu Andreea
Published: March 2022

Background:
Ventricular torsion is important in assessment of the systolic and diastolic function especially in single ventricle (SV) but is poorly studied.

Objective:
We aimed to a) examine serial changes in SV torsion, and b) examine its association with CMR data and exercise performance.

Methods:
We retrospectively studied SV patients after Fontan completion. Speckle-tracking echocardiography was used to evaluate serial changes in ventricular mechanics; strain, torsion, and untwist. CMR volumetric data and cardiopulmonary exercise data closest to echocardiograms were obtained. The most recent follow up echocardiographic and CMR data were compared to data before Fontan.

Results:
45 SV patients (27 LV, 12 RV, and 6 co dominant) were studied. Demographics, echocardiographic, CMR, and exercise data are shown in table 1. Mean time at follow up echo from time of Fontan was 12.8 (10.6-16.6) years. Follow up echocardiograms showed reduced global longitudinal strain [-17.5(-6.5 to-19.5) vs -19.8 (-12 to -23%), p=0.01], circumferential strain [-15.7 (-8.4 to - 20.7) vs [-18.9 (-11.2 to -25.0), p=0.009], reduced torsion [5.5°/cm (-6.1 to 17.8) vs 8.1°/cm (-9.7 to18.5) vs, p=0.03], decreased apical rotation [6.5°/cm (-11.3 to 18.1) vs 5.1°/cm (-21.2 to 19.7), p=0.02] with no significant change in basal rotation compared to the echo at time of Fontan. Single RV had lower net torsion compared to single LV [2.7°/cm (-2.5.1 to 13.1) vs 6.1°/cm (-6.3 to 19.5) vs, p=0.03]. Mean interval between echocardiograms and exercise testing and CMR were 3.5±2.2 and 5.6±1.8 months respectively. Torsion and untwist rates correlated with peak oxygen consumption (r=0.64, -0.41, p=0.01, 0.04 respectively) but did not correlate with ventricular volumes or ejection fractions.

Conclusion:
In long term follow up post Fontan, SV torsion is decreased due to decreased apical rotation, worse in single RV, and is associated with decreased exercise capacity.
Abstract 11641: Targeted Intrathecal Nos1 Inhibition Rescues Pulmonary Hypertension and Right Ventricular Failure in Rats by Reducing Neuroinflammation, Apoptosis and Sympathoexcitation
Authors: Razee Asif , Banerjee Somanshu , HONG JASON , Umar Soban
Published: March 2022

Introduction:

Pulmonary hypertension (PH) is associated with aberrant sympathoexcitation leading to RV failure (RVF), arrhythmias and death. NOS1 is known to induce neuroinflammation, nitrosative stress and apoptosis in neural tissue. In spinal cord, NOS1 is activated by afferent signaling via Ca
2+
influx through activated NMDAR in dorsal horn by increased glutamate release via K
+
channels.

Hypothesis:
Cardiopulmonary afferent signaling in PH-RVF leads to NOS1-mediated neuroinflammation, nitrosative stress and apoptosis in thoracic spinal cord (TSC) resulting in aberrant sympathoexcitation. Targeted intrathecal NOS1-inhibition may rescue PH and RVF.

Methods:
Male rats received s.c. Monocrotaline (MCT, 60mg/kg, n=8, 4wk) or Sugen (SuHx, 20mg/kg, n=8, 3wk hypoxia+2wk normoxia). Controls received PBS (n=8). A group of MCT-rats received either daily intrathecal specific NOS1-inhibitor S-Methyl-L-thiocitrulline (SMTC; 0.5mg/kg, n=7) or PBS (n=7) from day 14-28. Echo and RV cath were performed. TSC and RV RNASeq, RT-qPCR, NOS1 activity, NOS1 immunolocalization, microglia+astrocyte quantification and TUNEL were performed. Plasma catecholamines were measured by ELISA. Values are mean±SD.

Results:
Rats developed severe PH-RVF (Increased RVSP, Fulton-index, decreased RVFAC; p<0.01). TSC transcriptome showed common genes and pathways linked to neuroinflammation, nitrosative stress and apoptosis and identified NOS1 as one of the top-most upregulated genes (MCT
/
SuHx:8 fold; p<0.05) in TSC but not lumbar. We found significantly increased microglia+astrocyte activation, NMDAR-1, Kv3.4, CX3CL1, nitrosative stress markers AP1B1, AP1M1 and pro-apoptotic p53, TGFβ1 expression in TSC. We
observed increased NOS1 activity, its colocalization with microglia+astrocyte, apoptosis and norepi/epi in both models.
SMTC
decreased RVSP, Fulton-index, RVID
d
, pulmonary vascular wall thickness, increased RVFAC by reducing TSC NOS1 activity, CX3CL1/TGF
β
1, microglia/astrocyte activation, apoptosis and plasma norepi/epi (p<0.05). RV transcriptome demonstrated that SMTC decreased pro-fibrotic, pro-apoptotic, SNS & RAAS related and pro-inflammatory RV gene expression profile.

Conclusions:
Intrathecal NOS1 inhibition rescues PH and RVF.
Abstract 11643: ACTN4 Regulates HLA-DPA1-Related Pulmonary Endothelial Pathophenotypes in Pulmonary Arterial Hypertension Through Allele-Specific Binding to Functional SNP rs9277336
Authors: Hafeez Neha , Sun Wei , Jiang Danli , Wu Ting , Kirillova Anna , Li Gang , Chan Stephen Y
Published: March 2022

Introduction:
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary arterial pressure and vascular resistance. This vascular injury promotes immune dysregulation, further worsening the vasculopathy. A genome-wide association study identified a single nucleotide polymorphism (SNP) associated with PAH risk (rs2856830) at Human Leukocyte Antigen DPA1 (HLA-DPA1) locus, a gene known to be involved in adaptive immunity. However, little is known about the mechanism underlying this clinical association.

Hypothesis:
Allele-specific binding of transcription factors to a disease-associated functional SNP (fSNP) controls HLA-DPA1 expression, driving pulmonary vascular cell dysfunction and PAH.

Methods:
Oligonucleotides containing alleles of rs2856830 and eight SNPs in linkage disequilibrium (LD) were subjected to electrophoretic mobility shift assays (EMSA) to identify fSNPs characterized by allele-imbalanced binding to human pulmonary arterial endothelial cells (PAEC) nuclear proteins. SNP genotyping was done using blood from PAH (n=134) and control patients (n=131) at UPMC. Transcriptomics, angiogenesis, and migration were assessed in siRNA mediated HLA-DPA1 and Alpha Actinin 4 (ACTN4) knockdown (KD) in PAECs.

Results:
Through EMSA, rs9277336 (LD r
2
=0.87) was identified as a fSNP in HLA-DPA1 locus. SNP pulldown and immunoblotting confirmed allele-specific binding of nuclear ACTN4 protein to rs9277336 risk allele A (3.26 ± 0.49, p=0.001). SNP genotyping revealed a 2.04 ± 0.67 fold enrichment of risk allele A in PAH patients (χ
2
test, p=0.025). ACTN4 KD in cultured human PAECs decreased HLA-DPA1 transcript (0.30 ± 0.10, p<0.001)
.
Transcriptomics revealed overlap of several cell structure and immune system-related pathways by HLA-DPA1 and ACTN4 KD. HLA-DPA1 and ACTN4 KD affected PAH associated pathophenotypes, including angiogenesis and migration.

Conclusions:
Our functional analysis identified ACTN4 as a novel regulator to disease-associated gene HLA-DPA1, affecting the endothelial pathophenotypes in PAH. The allele-specific binding to fSNP rs9277336 provides a mechanistic explanation for the clinical association between HLA-DPA1 locus and PAH outcomes.
Abstract 11645: Use of an Electronic Health Record to Identify Implantable Cardiac Rhythm Device Lead Failure
Authors: Brock Jonathan , Bundy Richa , Rosenthal Gary , Rodgers Larisa , Bhave Prashant
Published: March 2022

Introduction:
Electronic health records (EHR) offer the potential to facilitate research examining the real-world effectiveness and safety of medical interventions. However, few studies have used EHR data to evaluate medical devices. This study sought to devise a method using current procedural terminology (CPT) and international classification of disease (ICD) codes captured in EHR data to identify patients with implantable cardiac rhythm device lead failures.

Hypothesis:
CPT and ICD diagnosis codes within an EHR can be used to correctly identify implantable cardiac rhythm device lead failures.

Methods:
Study data were extracted from the EHR of a large North Carolina health system. Patients who had implantable cardiac rhythm devices implanted during January 2013 to December 2018 were identified using predetermined CPT codes. Patients were followed longitudinally to identify those undergoing subsequent lead insertions or removals through December 2019. Medical records were reviewed to determine reasons for the re-insertion or removal and identify true lead failures. Random forest modeling was used to develop an algorithm for predicting true lead failure using CPT and ICD codes for mechanical breakdown or cardiac device complication. Patients with potential lead failure were split into two cohorts: 60% for model training and 40% for testing.

Results:
A total of 4,148 encounters with billed CPT codes for implantable cardiac rhythm devices were initially identified. After applying study exclusion criteria, 2,390 patients met study inclusion criteria. Of those, 175 patients had a subsequent insertion indicating a potential lead failure. A total of 31 patients were found to have true lead failures. A random forest algorithm predicted true lead failures with good discrimination, achieving an AUROC (area under receiver operating curve) of 0.908. The model accurately detected 66% of true lead failure cases in the testing dataset.

Conclusions:
Applying a specific combination of CPT and diagnosis codes to a cohort of patients undergoing subsequent implantable cardiac rhythm device procedures following an index insertion can correctly identify patients with lead failure with strong accuracy and moderate sensitivity.
Abstract 11656: Chagas Disease Reactivation After Heart Transplant in an Endemic Country
Authors: Salazar Lukas , Medina Ramon , Vasquez Juan Felipe F , Ramirez John , López Mónica , Rodriguez Maria J
Published: March 2022

Introduction:
Chagas disease (CD) is a common cause of advanced heart failure in Colombia and the third cause of heart transplant in our center. For transplanted patients the immunomodulatory therapy is crucial, but it makes them susceptible to CD reactivation. Fiorelli
et al
showed a frequency of reactivation of 40% based in histological diagnosis; also, Gray
et al
reported a frequency of 61% using quantitative PCR. The estimation of this phenomenon in our population is essential to improve its management.

Methods:
We performed a retrospective cohort study of patients with heart transplant due to chagasic cardiomyopathy. The primary outcome was the prevalence of CD reactivation. Secondary outcomes included the description of clinical manifestations, immunomodulatory therapies used and the time elapsed since the transplant until the reactivation. Reactivation was defined as a positive RT-PCR for T.cruzi after heart transplant or a compatible endomyocardial biopsy. The RT-PCR test was performed if clinical deterioration, ventricular disfunction, or either randomly according to physician criteria.

Results:
Fifteen patients were included in the analysis. The age at the moment of the transplant was 54 YO (IQR 43-56), 67% were men. CD reactivation was diagnosed in the 67% of patients (Figure 1a). The median of the time to CD reactivation after the transplant is 12 months (95%-CI:3,16-20,8) (Figure 1b). The mortality during follow-up was 0% and the longest follow-up time was 11 years.The most frequently used drugs in patients with reactivation were cyclosporine, tacrolimus and corticosteroids. All of the patients with reactivation received benznidazole.

Conclusions:
There is a high prevalence of CD reactivation in heart transplanted patients due to Chagasic cardiomyopathy, especially during the first year. Protocols for screening these condition are necessary for an adequate care of these patients. Cualitative RT-PCR test and myocardial biopsy should be considered.
Abstract 11664: Contractile Reserve is Impaired in Patients After Fontan Operation and Predicts Exercise Performance on Exercise Stress Echocardiography
Authors: Bhatt Shivani M , Faerber Jennifer , Wang Yan , DeCost Grace , Mai Anh Duc , McBride Michael W , Paridon Stephen , Goldberg David , Mercer-rosa Laura M
Published: March 2022

Introduction:
Exercise capacity is diminished in Fontan patients. There is limited understanding of their contractile reserve, or ventricular response to exercise. We sought to evaluate contractile reserve in Fontan patients and its association with exercise performance using exercise stress echocardiography.

Methods:
Single center prospective study of Fontan patients (n=56) and healthy controls (n=11) presenting for cardiopulmonary exercise test and rest/peak exercise research echocardiograms. Contractile reserve was defined as the change in the systemic ventricle’s global longitudinal strain (GLS), free wall strain (FWS) and global circumferential strain (GCS) (and strain rates) from rest to peak exercise. Fontan fenestration mean gradient was obtained by Doppler interrogation. Exercise outcomes included percent predicted maximum oxygen consumption (%mVO2), maximum work and oxygen pulse.

Results:
Fontan patients were 14.5 ± 4.4 years old at testing and (58%) males. There was a fenestration in 33 patients. Exercise parameters in Fontan patients were abnormal with reduced %mVO2 of 75.5 ± 21.5%. Most strain parameters were lower in Fontan patients than controls at rest and peak exercise. There was a significant increase in fenestration gradient from rest to peak exercise. GLS, GCS strain and GLS, GCS and FWS rates increased significantly from rest to peak exercise in both groups, but the magnitude of increase was significantly less in Fontan patients compared to controls, indicating reduced contractile reserve. An increase in FWS rate at peak exercise was independently associated with better %mVO2 and oxygen pulse in Fontan patients.

Conclusions:
Fontan patients have abnormal response to exercise with reduced contractile reserve compared to controls. Greater contractile reserve is associated with better exercise performance in these patients. Therapies aimed at increasing contractile reserve after the Fontan may improve exercise performance.
Abstract 11665: Does the Benefit of Secondary Prevention Implantable Cardioverter-Defibrillators Vary Based on the Estimated Proportional Risk of Sudden Death?
Authors: Kelly Molly E , Bilchick Kenneth C , Dardas Todd F , Shadman Ramin , Chatterjee Neal A , Levy Wayne C
Published: March 2022

Introduction:
The Seattle Proportional Risk Model (SPRM) is a validated model developed in systolic heart failure patients without implantable cardioverter-defibrillators (ICDs) to estimate the proportion of all-cause mortality (ACM) due to sudden death. This study aims to ascertain if SPRM has utility in risk stratification for secondary prevention ICD.

Methods:
The AVID (Antiarrhythmics Versus Implantable Defibrillators) trial was a multicenter, randomized clinical trial in which 1,016 patients presenting with ventricular fibrillation or sustained, symptomatic ventricular tachycardia were randomized to ICD or antiarrhythmic (AA) drug therapy. Using routine clinical variables, we applied the SPRM to patient-level data (n=995 with complete data) and assessed if the ICD benefit for ACM varied with SPRM-predicted probability of sudden death.

Results:
SPRM was predictive of sudden death vs. non-sudden death in patients without an ICD (logistic regression p=0.005). The ICD hazard ratio for ACM was 0.59. ICD survival benefit varied with SPRM for ACM (p=0.013) with benefit (ICD HR≤0.80) seen in patients with SPRM>40%. ICD benefit trended higher in patients with a history of heart failure (HF) vs no HF (HR=0.52 vs. 0.81, interaction p=0.13) (Figure 1). In comparison to the AA group, patients with either HF or SPRM>51% (median) had a meaningful ICD benefit (HR=0.60, p=0.017), and patients with both HF and SPRM>51% had the greatest ICD benefit (HR=0.38, p<0.001). There was no ICD benefit if no HF and SPRM<51% (HR=1.17).

Conclusions:
In a population of patients with VF or sustained VT, secondary prevention ICDs decreased ACM by 41%. ICD survival benefit varied with SPRM-predicted proportion of sudden death, and trended higher in patients with HF. SPRM may therefore provide a useful tool for risk stratifying patients for secondary prevention ICD.

Figure 1:
Survival benefit for ICD therapy varies with SPRM-estimated proportion of sudden death, and HF versus no HF.
Abstract 11666: Who Could Return To Their Former Lifestyle In Comatose Survivors Of Cardiac Arrest With Asystole?
Authors: Kagawa Eisuke , Kato Masaya , Oda Noboru , Nagai Michiaki , Dote Keigo
Published: March 2022

Introduction:
In patients with initial shockable rhythms had favor outcomes than those with non-shockable rhythms, and those of asystole had worst outcomes.

Purpose:
The purpose of the study is to investigate the predictors of favorable outcomes in specific in the asystole rhythms.

Method:
Patients who were resuscitated after out-of-hospital cardiac arrest and were underwent targeted temperature management were enrolled in this study. Patients were divided into 3 groups according to initial recorded rhythms after indexed cardiac arrest. Favorable outcomes were defined as cerebral performance category of 1 or 2 after 90 days of indexed cardiac arrest. The logistic regression analysis was performed to assesses independent predictor of favorable outcomes.

Results:
Among the 305 study patients, 57 (19%) patients had initially recorded asystole rhythms, 149 (49%) patients had shockable rhythms, and 99 (32%) patients had pulseless electrical activity (PEA). The patients of PEA were elder (median 62 y [interquartile range 49 y - 72 y], 65 [57 - 75], and 62 [49 - 74], P = 0.03 in the patients of shockable, PEA, and asystole), the rate of male was higher in the shockable (86%, 58%, and 72%, P < 0.001), the time interval from collapse to return of spontaneous circulation (ROSC) were longer in the asystole (28 min [17 - 48], 37 [24 - 53], and 46 [39 - 61], P < 0.001), and the lactate of hospital arrival were higher in the asystole (10.1 mmol/l [6.1 mmol/l - 13.6 mmol/l], 12.0 [8.6 - 15.4], and 13.3 [9.6 - 18.3], P = 0.002). The rate of acute coronary syndrome as the cause of arrest were similar between the groups (45%, 34%, and 28%, P = 0.06). The rate of favorable outcome was 53%, 21%, and 12% (P < 0.001), respectively. The time interval from collapse to ROSC were independently associated with favorable outcomes in the patients of all initial recorded rhythms.

Conclusions:
The cardiac arrest patients who were witnessed arrest or shorter interval from collapse to ROSC with initial recorded asystole rhythms had favor outcomes than those not. We could not find specific predictors in the patients with asystole.
Abstract 11671: Inpatient Cardiac Rehabilitation After Hospitalization for Acute Decompensated Heart Failure is Associated With Reduced Cardiovascular Events
Authors: Enzan Nobuyuki , Matsushima Shouji , Ide Tomomi , Kaku Hidetaka , Tohyama Takeshi , Funakoshi Kouta , Higo Taiki , Tsutsui Hiroyuki
Published: March 2022

Introduction:
The effects of cardiac rehabilitation during acute decompensated heart failure (HF) hospitalization remain to be elucidated. This study sought to determine whether inpatient cardiac rehabilitation after HF hospitalization could improve outcomes in HF patients.

Methods:
We analyzed HF patients enrolled in the Japanese Registry Of Acute Decompensated Heart Failure (JROAD-HF), a national database of HF. Eligible patients were divided into two groups according to the inpatient cardiac rehabilitation. The primary outcome was the composite of cardiovascular death or re-hospitalization due to cardiovascular event after discharge. The secondary outcomes were cardiovascular death and re-hospitalization due to cardiovascular event.

Results:
Out of 10,473 eligible patients, 3,210 patients underwent cardiac rehabilitation. Propensity score matching yielded 2,635 pairs. The mean age was 77.2 years and 2,927 (55.5%) was male. Ischemic heart disease was accounted for 28.8% and the mean left ventricular ejection fraction was 45.2 ± 17.1. During a mean follow-up of 2.8 years, the cardiac rehabilitation group had a lower incidence rate of the composite of cardiovascular death or re-hospitalization due to cardiovascular event (284.0 vs. 311.7 events per 1000 patient-years; rate ratio [RR] 0.89; 95% confidence interval [CI] 0.83-0.96; P = 0.003), and re-hospitalization due to cardiovascular event (255.4 vs. 283.9 events per 1000 patient-years; RR 0.90; 95% CI 0.83-0.97; P = 0.007) than the no cardiac rehabilitation group. Cardiovascular death was not different between groups (71.0 vs. 75.5 events per 1000 patient-years; RR 0.94; 95% CI 0.83-1.06; P = 0.31). Cubic spline analysis showed that patients with lower Barthel index were benefited by cardiac rehabilitation.

Conclusions:
The implementation of cardiac rehabilitation during HF hospitalization was associated with better long-term outcomes in patients with HF.
Abstract 11672: Limited Improvement in Global Quality of Life Measures After TAVR
Authors: Gjini Petro , Massed Alison , Vesel Tamara , Zhan Yong , Rastegar Hassan , Resor Charles , Weintraub Andrew R , Wessler Benjamin S
Published: March 2022

Introduction:
Transcatheter aortic valve replacement (TAVR) is now the preferred treatment for older adults with symptomatic aortic stenosis (AS). While the goal is often symptom improvement, quality of life (QOL) may be adversely impacted by non-cardiac conditions. We evaluated changes in the global QOL Patient-Reported Outcomes Measurement Information System (PROMIS) Physical survey after TAVR.

Methods:
Single-center prospective study of 204 patients undergoing TAVR from 10/2019 to 6/2021. Subjects completed The Kansas City Cardiomyopathy Questionnaire (KCCQ) and PROMIS Physical surveys pre-TAVR and 30 days post-TAVR, of whom 85 (42%) had complete data on disease-specific and global QOL. A clinically meaningful change in PROMIS was defined as > 5 points. Good disease specific QOL was defined as KCCQ > 75. The correlation between KCCQ and PROMIS was assessed.

Results:
The mean age was 78.9 years and 47% identified as female. The mean pre-TAVR PROMIS Physical and KCCQ scores were 42 (SD 9.4) and 62.6 (SD 22.4), respectively. 30-days post TAVR, the average change in KCCQ was +23.0 (SD 24.9), while the average change in PROMIS Physical score was +3.9 (SD 8.8). There was modest correlation between post-procedure disease-specific and global QOL scores (
Figure 1
, R
2
0.48, p <0.001). At 30 days post-procedure, 69 patients (81.2%) reported good disease-specific QOL, while 36 (42.4%) had a clinically meaningful improvement in global QOL. Of patients with improvement in KCCQ, 33 (47.8%) reported a meaningful improvement in global QOL.

Conclusions:
The majority of patients report good disease-specific QOL after TAVR; however, less than ½ of TAVR treated patients have a clinically meaningful increase in global QOL at 30 days. There is modest correlation between disease-specific (KCCQ) and global (PROMIS) QOL scores following TAVR. Improvement in QOL after TAVR may be limited by conditions unrelated to AS.
Abstract 11677: The Complement Receptor C3aR1 is Required for Immune Cell Recruitment and Formation of Granulation Tissue During Neonatal Mouse Cardiac Regeneration
Authors: Wang Shuoshuo , Natarajan Niranjana , Zhu Anthony , Lee Richard T
Published: March 2022

The adult human heart is unable to regenerate after a major injury, while some vertebrates including neonatal mice heart possess substantial heart regeneration. In a previous multi-species transcriptome study, we identified Complement receptors C5aR1 and C3aR1 as evolutionarily conserved upregulated genes during the early phase of heart regeneration in multiple species. The complement system is a central mechanism in innate immunity, but its role in heart regeneration is unclear. After apical resection in neonatal mice, we administrated Cobra Venom Factor (CVF) to specifically deplete Complement, and the mice failed to regenerate the injured myocardium after three weeks. At 2 days after injury, the size of the sagittal area across post-traumatic granulation tissue was significantly reduced by 62.6% (n=5 each, p<0.05), suggesting that complement is necessary for myocardium regeneration through forming granulation tissue as a transient step. Furthermore, genetic deletion of the C3aR1 receptor (C3aR1-KO mice) phenotypically recapitulated the impaired myocardial regeneration observed in Complement-depleted animals. C3aR1 KO mice possessed significantly reduced number of Itgam
+
(Complement Receptor 3, CD11b) leukocytes, especially CD68
+
cells of pan-monocyte lineage and failed to form granulation tissue at the injured apex. Noteworthy, both resected C3aR1-KO and CVF-treated mice shared a common pattern when compared to control animals: downregulation of cell-cycle regulators (e.g., Cdc20, PCNA-associated factor, Cyclin B2, Mcm5) and DNA-damage responders (Survivin, Rad51, Top2a). Since Cdc20 regulates cell-cycle progression and is tightly associated with cardiomyocytes undergoing complete cytokinesis, this is one candidate downstream effector for the complement response. Our results demonstrate that complement and C3aR1 activation is crucial for neonatal mouse cardiac regeneration by initiating rapid granulation tissue formation through immune cell recruitment.