bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 24032: Exercise Instigates Apoptosis-inducing Factor Nuclear Translocation and Myocyte Death in Arrhythmogenic Cardiomyopathy
Authors: Chelko Stephen P , Keceli Gizem , Andersen Peter , Amat-Codina Nuria , Agrimi Jacopo , Bedja Djahida , Stahlberg Marcus , Halushka Marc , James Cynthia A , Calkins Hugh , Judge Daniel P , Paolocci Nazareno
Published: March 2022

Exercise increases disease penetrance in arrhythmogenic cardiomyopathy (ACM). Yet, how exercise contributes to disease pathogenesis is unclear. Mitochondria potentiate reactive oxygen species (ROS) generation during exercise that are scavenged by antioxidants, such as thioredoxin-2 (Trx2). Here we tested if deficits in Trx2-based ROS buffering act as substrates for exercise-induced cardiac apoptosis in ACM. Homozygote
Desmoglein-2
mutant mice (
Dsg2
mut/mut
) model ACM features, thus WT and
Dsg2
mut/mut
mice were enrolled in a 10 week swimming protocol to evaluate survival and post-effort cardiac function, ROS production by EPR, and mitochondrial ROS-gating protein levels. Survival rate after swimming was 91% (20/22) in WT, but only 60% (15/25) in
Dsg2
mut/mut
mice (p=0.008). Of the survivors,
Dsg2
mut/mut
mice displayed cardiac dysfunction (Ejection Fraction 57±4
vs
84±0.4% in WT; n≥14/cohort, P<0.001) and increased bouts of non-sustained VT. Swimming augmented ROS emission in
Dsg2
mut/mut
right ventricles (RV) than in WT (25±3
vs
15±1 Gauss/total protein [G/tp]; P<0.05) and amplified ROS release from
Dsg2
mut/mut
left ventricles (LV) (39±5 G/tp
vs
mutant RV; P<0.05). Isolated mutant mitochondria showed reduced NADH generation and peroxiredoxin-3, Trx2 and Trx2 reductase (Trx2R) protein levels, with impaired Trx2R activity (all P<0.05
vs
WT in RV&LV). When mitochondria bound, Apoptosis-Inducing Factor (AIF) acts as a NADH oxidoreductase, yet upon oxidation, AIF translocates to the nucleus and initiates apoptosis. After exercise,
Dsg2
mut/mut
hearts displayed marked AIF nuclear and chromatin-bound protein levels and increased AIF immunostained nuclei
vs
WT. Additionally, direct H
2
O
2
exposure or Trx2 inhibition (by auranofin) in
Dsg2
mut/mut
embryonic stem-cell derived myocytes elevated AIF-nuclear translocation and apoptosis (via AnnexinV/PI FaCS analysis). Our study reveals a novel causal link between exercise-evoked cardiac redox imbalance and aberrant AIF-Trx2 signaling in ACM, which was associated with increased apoptosis, propensity of arrhythmias and sudden cardiac death. These findings offer a new targetable mechanism for preventing one of the most cited, yet poorly understood, pathological phenotypes (apoptosis) in ACM.
Abstract 24033: Regional Assessment of Pyruvate Metabolism in the Remodeled Heart Using Dynamic Nuclear Polarization Carbon13 Magnetic Resonance
Authors: Pilla James J , Gade Terence , Mizsei Gabor , Butler Norman , Saito Yoshiaki , Imai Akito , Okamoto Keitaro , Gade Christopher L , Pilla Gabrielle , Zsido Jerry , Gorman Joseph H , Gorman Robert C
Published: March 2022

Introduction:
After infarction compensated remodeling of the left ventricular (LV) may be followed by adverse remodeling leading to heart failure. The mechanism of adverse remodeling maybe linked to the elevated wall stress in the dysfunctional myocardium adjacent to the infarct (border zone BZ). We hypothesize that increased BZ stress results in altered metabolism which could drive the transition from compensated to adverse remodeling. To evaluate BZ and remote metabolism we compared the regional uptake and intracellular conversion of 1-13C-pyruvate using hyperpolarized (HP)
13
C MR.

Methods:
An established pre-clinical posterolateral infarct model of LV remodeling was used to investigate region metabolism. To accurately measure regional metabolism, we developed implantable carbon-tuned surface coils placed on the epicardium over the BZ and remote regions (Fig. Top). A coronary catheter was placed for direct injection of the HP substrate to maximize deliver and eliminate cavity blood pool signal. MR was performed at 6-weeks post infarct with a spectra acquired every 1.5s for each region simultaneously during HP infusion under physiologic and DOB stress conditions. The resulting spectra from each coil were analyzed to measure lactate, alanine, bicarb, and total flux.

Results:
Under physiologic (Pre-DOB) conditions the percent difference between remote and BZ lactate, alanine, and total flux was only slightly elevated in the remote region whereas bicarb flux was greater in BZ compared to remote (Fig. Bottom). DOB stress produced an increase in remote metabolite flux compared to BZ with lactate, alanine and total flux reaching significance and bicarb flux shifting from greater in BZ Pre-DOB to greater in remote.

Conclusion:
These findings demonstrate an impaired metabolic response to pharmacologic stress in BZ myocardium which may provide a mechanism for the established association of mechanical stress and adverse cardiac remodeling following infarct.
Abstract 24035: Human iPSC-Derived Endothelial Cells Predict Predilection to Atherogenesis by Endothelial Proinflammatory Activation
Authors: Paik David T , Kim Youngkyun , Rhee June-Wha , Yi Hyoju , Mishra Ridhima , Wu Joseph C
Published: March 2022

Introduction:
Coronary artery disease (CAD), the direct outcome of atherosclerosis, is the leading cause of death in the United States. Previous studies demonstrated that impaired function of aldehyde dehydrogenase 2 (ALDH2), a key enzyme for alcohol metabolism, is linked to increased susceptibility to CAD. A single-nucleotide polymorphism that generates E487K mutation (ALDH2*2) reduces enzymatic activity of ALDH2 to less than 40% of the wild type (WT) and is present in ~560 million people. However, it remains unclear how ALDH2 regulates atherosclerotic progression.

Hypothesis:
Recent studies suggest a critical role of ALDH2 in plaque development and endothelial activation. Therefore, we hypothesize that endothelial cells of ALDH2*2 carriers possess greater susceptibility to proinflammatory activation, whereby endothelial cells recruit immune cells, leading to increased risk of atherogenesis.

Methods:
To study the patient-specific effects of ALDH2*2 mutation on endothelial proinflammatory activation, we generated and characterized iPSC-derived endothelial cells (iPSC-ECs) from 5 WT subjects and 5 ALDH2*2 carriers. We exposed the iPSC-ECs to pro-inflammatory conditions and assessed the level of endothelial proinflammatory activation by gene expression analysis and monocyte adhesion assay.

Results:
Our preliminary data show ALDH2*2-iPSC-ECs exhibit impaired ALDH2 function resulting in metabolic dysregulation compared to WT. Presence of ALDH2*2 mutation resulted in enhanced inflammatory response in the iPSC-ECs when treated with proinflammatory cytokines such as TNFα and IL-1β, as evidenced by up-regulation of cell adhesion molecules and augmented adherence to monocytes. The ALDH2*2-iPSC-ECs also exhibited an increased basal expression of vascular endothelial growth factor receptor 1 (FLT1) gene, which was further augmented upon inflammatory stimulation. FLT1 is a receptor for vascular endothelial growth factor ligands, playing a critical role in endothelial homeostasis and biology.

Conclusion:
Taken together, we elucidate the effects of impaired ALDH2 function on increased susceptibility to atherogenesis by endothelial proinflammatory activation using patient-derived iPSC-ECs.
Abstract 24043: Cytosolic RBFox1 in Cardiac Fibrosis Regulation
Authors: GAO Chen , Hsiao Yun-Hua Esther , Ren Shuxun , Xiao Xinshu (Grace) , Xing Yi , Wang Yibin
Published: March 2022

RBFox1 is known to be an RNA splicing regulator with enriched expression in cardiac muscle. Loss of RBFox1 expression is a molecular hallmark associated with pathological hypertrophy and heart failure. However, much of our current knowledge about RBFox1 focuses on nuclear RBFox1 with a major impact on global alternative splicing changes in the diseased heart. Yet, RBFox1 gene also generates a cytosolic isoform through alternative splicing (RBFox1c), but the specific function of RBFox1c in heart has not been characterized.

RBFox1c expression is significantly repressed in the mouse failing heart and hypertrophic cardiomyocytes. We performed RNA-seq combined with GO and IPA analysis to determine the impact of RBFox1c expression in culture. Among the genes suppressed specifically by RBFox1c but not the nucleus RBFox1 are groups of pro-inflammatory genes. Both Motif enrichment analysis and de novo motif discovery identified significant enrichment of RBFox1 binding motif in the 3’UTRs of the RBFox1c regulated genes. Using CLIP analysis followed by RT-PCR, we observed RBFox1c, but not nuclear RBFox1 specifically interacted with targeted inflammatory gene 3’UTR. In the cardiac specific RBFox1 knockout mice, enhanced cardiac fibrosis was observed following TAC, associated with elevated expression of RBFox1c dependent inflammatory genes. In contrast, cardiac specific expression of RBFox1c significantly reduced cardiac fibrosis and inflammatory gene expression following TAC, associated with improved ejection fraction and reduced hypertrophic marker gene expression. Further, we tested the effect of RBFox1c expression on cardiac fibrosis response using NRVM conditioned media. We showed the conditioned media from the hypertrophic cardiomyocytes potently induce fibroblast proliferation. However, RBFox1c expression can suppress phenylephrine and isoproterenol induced fibroblasts proliferation.

RBFox1 regulates cardiac transcriptome reprogramming at two post-transcriptional steps. The RBFox1 nuclei isoform regulates global RNA splicing reprogramming in heart, while the RBFox1c regulates inflammatory gene expression and fibrotic remodeling potentially through potential interaction with their 3’UTR and targeted RNA degradation.
Abstract 24056: Longitudinal Evaluation of the Associations between Severe Hypertriglyceridemia and Cardiovascular Features
Authors: Gidanian Samuel D , Chaudhari Uddhav , Newcomb Jennifer D , Mhaskar Rahul D , Hansen Barbara C
Published: March 2022

Introduction:
For at least 35 years the associations between insulin resistance, hyperinsulinemia, hypertriglyceridemia and hypertension have been described. Nevertheless, the existence of an independent association between hypertriglyceridemia (HTG) and cardiovascular diseases (CVD) remains controversial. This may be due to the insufficiency of longitudinal study data that include severe elevations of TG. The purpose of this study was to characterize the associations between systolic blood pressure and various cardiovascular features under different degrees of naturally-occurring HTG severity and to determine the independent effect of severe HTG.

Methods:
We characterized TG in a large cohort of longitudinally studied nonhuman primates (n=227; 164 males) maintained for their lifetimes under constant environmental and dietary conditions. The TG ranged from normal TG levels <100 mg/dl, to mild HTG 100-200 mg/dl, high HTG 200-500 mg/dl, very high 500-1000 mg/dl and severe >1000 mg/dl. The Kruskal Wallis H test was applied, as the data samples were not normally distributed.

Results:
Severe hypertriglyceridemia was statistically significantly related to systolic blood pressure and was significantly higher (p<0.0001) at the severe HTG levels of 500-1000 mg/dl and ≥1000 mg compared to all other TG levels. Diastolic blood pressure and mean arterial blood pressure were not significantly different among the normal to severe HTG groups. HDL cholesterol was significantly lower (p<0.0001) at all levels of HTG (TG 100-200, 200-500, 500-1000 and ≥1000mg/dl) compared to normal TG <100 mg/dl, and was not related to the severity of the HTG, a finding similar to the relationship with body weight. By contrast, LDL cholesterol was significantly higher (p<0.05) in monkeys with severe HTG >500-1000 mg/dl, as was systolic blood pressure.

Conclusions:
In conclusion, much of the association between triglyceride levels and cardiovascular features, including blood pressure, may be principally determined by the severely elevated triglyceride levels, possibly highlighting the importance of longitudinal within subject evaluation of such associations for break points in the interactions of these features.
Abstract 24061: Targeting Trpv4 Channels Protects Heart From Pathological Remodeling Following Myocardial Infarction
Authors: Adapala Ravi K , Minasyan Ashot , Kanugula Anantha K , Cappelli Holly C , Paruchuri Sailaja , Meszaros Gary J , Thodeti Charles K
Published: March 2022

Heart failure is one of the leading causes of death which is often characterized by pathological fibrosis. Cardiac remodeling following myocadial infarction is a multiphase reparative process which involves replacement of damaged tissue with physiological (reparative) fibrosis to form scar that limit the expansion of the infarct. Myofibroblasts are critical mediator of this reparative fibrosis, however, hyperactivation of these cells can cause pathological fibrosis leading to heart failure. We have previously demonstrated that the mechanosensitive ion channel TRPV4 (transient receptor potential vanilloid channel 4) regulates cardiac fibroblast differentiation into myofibroblasts. However, the physiological or translational significance of TRPV4 in cardiac remodeling following MI is unknown. To explore this, we have induced MI (permanent LAD ligation) in WT and TRPV4KO mice and measured cardiac function for 8 weeks. Separately, WT mice were given an orally active TRPV4 antagonist GSK2193874, immediately after MI surgery and followed for 5 weeks. 2D-echocardiography revealed that the cardiac function (ejection fraction and fractional shortening) is preserved post-MI in both TRPV4KO and GSK2193874-treated WT mice compared to either WT or vehicle treated mice. Further, we found reduced cardiac fibrosis at infarcted and remote zones in TRPV4KO and GSK2193874-treated WT mice compared to their MI counter parts. Furthermore, TRPV4KO hearts exhibited decreased cardiomyocyte apoptosis (TUNEL assay) and increased capillary density (CD31 staining) post-MI compared to WT hearts. Our results thus suggest that targeting TRPV4 protects heart from myocardial infarction-induced damage by preserving cardiac structure and function via reduced myocyte apoptosis, diminished fibrosis and increased revascularization, and identifies TRPV4 as a novel therapeutic target for heart failure.
Abstract 24063: Heart Fields Are Induced by Coordinated Activity of Wnt and Bmp Signaling and Identified by CD184 and EphA2 in PSC-Derived Organoids
Authors: Andersen Peter , Jimenez-Cyrus Dennisse , Chelko Stephen P , Kannan Suraj , Tampakakis Emmanouil , Saberi Amir , Murphy Sean , Miyamoto Matthew , Kwon Chulan
Published: March 2022

Over the past few decades, major advances have been made in identifying the origins of cardiac cells from developing embryos. In particular, the discovery of the first heart field (FHF) and the second heart field (SHF), led us to understand how diverse lineages and different anatomical structures of the heart arise during cardiogenesis. However, it remains unknown how the two heart fields are specified and segregated, a fundamental step toward understanding heart formation and developing pluripotent stem cell (PSC)-based therapeutic strategies. Here, we generated 3D organoids with mouse PSCs that harbor green and red fluorescent protein (GFP and RFP) reporters under the control of the FHF marker
Hcn4
and the SHF marker
Tbx1
, respectively. We demonstrate how GFP+ cells and RFP+ cells appear from two distinct areas of mesodermal cells and develop in a complementary fashion, similar to the in vivo process. Consistently, these populations exhibit a high degree of similarities with FHF/SHF cells isolated from early embryos, determined by RNA-sequencing analysis. Through a series of bioinformatics approaches, we found that Bmp and Wnt are among the most differentially regulated pathways in the two populations. Importantly, an increased activity of Bmp or Wnt signaling resulted in selective induction of GFP+ or RFP+ cells from mesodermal cells, enabling us to generate heart field-specific cells from PSCs. We further found that FHF/SHF cells can be distinguished and isolated by the surface proteins CD184 and EphA2. This study provides fundamental insights into understanding the specification of two cardiac origins that enable generation of chamber-specific populations for studying heart field/chamber-specific heart disease in cell culture.
Abstract 24075: Heart Failure Induced Upregulations of MicroRNAs in the Human Sinoatrial Node Associated with Pacemaker Dysfunction
Authors: Li Ning , Petkova Maria , Hansen Brian J , Ssekayombya Prosper S , Yanni Joseph , Biesiadecki Brandon J , Kilic Ahmet , Mohler Peter J , Janssen Paul M , Davis Jonathan P , Accornero Federica , Boyett Mark R , Dobrzynski Halina , Fedorov Vadim V
Published: March 2022

Background:
Heart failure (HF), a leading cause of morbidity and mortality, involves significant dysfunction of the sinoatrial node (SAN). MicroRNAs (miRs) are abundant, non-coding RNAs that ultimately regulate protein expression at the post-transcriptional level and have been implicated in HF. However, nothing is known about the distribution and expression of miRs in the human SAN as well as their roles in regulating pacemaker channels and SAN dysfunction (SND) in HF.

Methods:
The human SAN was isolated and cryopreserved from failing hearts with implantable pacemakers (n=5) or non-diseased donor hearts (n=3) that were cardioplegically arrested in the surgery room. Utilizing immunohistochemistry, the intact 3D intramural SAN structure was precisely identified as the fibrotic region around the SAN artery containing Connexin43-negative pacemaker cardiomyocytes (Figure). Small biopsies from the central SAN compartment were used to characterize the expression pattern of 14 miRs and their associated pacemaker channels. Ingenuity software (Qiagen) was used to predict the relationship between miRs and their targeted mRNA of SAN ion channels

Results:
Out of 14 studied miRs, 3 miRs (mir-370-3p miR-133-3a and miR-1) were significantly upregulated in SAN, but not in atria, during HF. We found that mir-370-3p was predominantly expressed in the human SAN, but not atria. Whereas, both miR-133-3a and miR-1 were highly expressed in atria vs SAN. All three miRs were predicted to regulate pacemaker HCN1 and/or HCN4 channel expression. RT-PCR showed that HCN1 and HCN4 mRNA were downregulated in the HF SAN.

Conclusions:
This is the first study to explore the miRs profiles in healthy and diseased human SAN with SND. We demonstrate that miR-370, miR-133a and miR-1, thought to regulate SAN pacemaker HCN channel expression, are selectively upregulated in human HF SAN. We propose that understanding the function of miRs in human SAN might lead to novel SND treatments.
Abstract 10010: Long-Term Prognostic Value of the Combination of Ahead Score and a Systemic Inflammation-Nutrition Index in Patients Admitted for Acute Decompensated Heart Failure
Authors: Yamada Takahisa , Watanabe Tetsuya , Morita Takashi , Kawasaki Masato , Kikuchi Atsushi , Kawai Tsutomu , Seo Masahiro , Nakamura Jun , Kayama Kiyomi , UEDA KUMPEI , Sakamoto Daisuke , Tamura Yuto , Fujita Takeshi , Kogame Takehiro , Nishigaki Keisuke , Fukuda Yuto , Kokubu Yuki , Fukunami Masatake
Published: March 2022

Backgrounds:
Comorbidities are strongly associated with poor clinical outcome in heart failure patients (pts). AHEAD (A: atrial fibrillation; H: hemoglobin; E: elderly; A: abnormal renal parameters; D: diabetes mellitus) score has been related to clinical outcomes in acute decompensated heart failure (ADHF) pts. On the other hand, systemic inflammation plays a critical role in the outcomes of heart failure and malnutrition is also associated with poor outcome in heart failure pts. It has been recently reported that advanced lung cancer inflammation index (ALI), which is calculated as body mass index х serum albumin / neutrophil to lymphocyte ratio (NLR), is an independent prognostic marker in several types of cancer. We sought to investigate the prognostic value of the combination of AHEAD score and ALI in pts admitted for ADHF.

Methods and Results:
We studied 260 pts admitted for ADHF and discharged with survival. At the discharge, we evaluated AHEAD score (range 0-5, atrial fibrillation, hemoglobin <13 mg/dL for men and 12 mg/dL for women, age >70 years, creatinine >130 μmol/L, and diabetes mellitus) and measured ALI. The study endpoint was cardiovascular-renal poor outcome (CVR), defined as cardiovascular death and the development of end-stage renal disease requiring renal replacement therapy. During a follow-up period of 5.1±4.2 years, 77 pts had CVR. At multivariate Cox analysis, AHEAD score and ALI were significantly associated with CVR, independently of prior heart failure hospitalization, systolic blood pressure and serum sodium level. Pts with both high AHEAD score (≥3 determined by ROC analysis: AUC 0.651[0.582-0.719]) and low ALI (<35.8: AUC 0.7171[0.648-0.786]) had a higher risk of mortality than those with either and none of them (59% vs 28% vs 15%, p<0.0001, respectively).

Conclusion:
The combination of AHEAD score and ALI would be useful for stratifying patients at risk for cardiovascular-renal poor outcome in ADHF pts.
Abstract 10012: The Relationship Between Mitral Valve Regurgitation and Left Atrial Enlargement on the Risk of Stroke and Systemic Embolism in Japanese Atrial Fibrillation Patients: The Fushimi Af Registry
Authors: DOI KOSUKE , Ishigami Kenjiro , Ikeda Syuhei , Hamatani Yasuhiro , Ide Yuya , Fujino Akiko , ISHII MITSURU , Iguchi Moritake , Ogawa Hisashi , Masunaga Nobutoyo , Wada Hiromichi , Hasegawa Koji , Abe Mitsuru , Akao Masaharu
Published: March 2022

Background:
We previously reported that left atrial enlargement (LAE) was an independent predictor of stroke/systemic embolism (SE) in Japanese atrial fibrillation (AF) patients. Mitral regurgitation (MR) likely accompanies LAE; it sometimes causes LAE and conversely LAE can cause secondary MR. However, the relationship between MR and LAE on the risk of stroke/SE is unknown.

Purpose:
The aim of this study is to investigate the impact of LAE on stroke/SE in AF patients with or without MR.

Method:
The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, which is a typical urban district of Japan. We started to enroll patients from March 2011, and follow-up data were available for 4,472 patients by the end of October 2020. In the entire cohort, echocardiography data were available for 3,622 patients. 131 AF patients with rheumatic mitral stenosis or prosthetic valve and 63 patients without data of left atrial diameter (LAD) were excluded. We divided eligible 3,428 patients in MR group (n=393) and non-MR group (n=3,035). We compared clinical characteristics and rates of stroke/SE between patients with LAE (LAD > 45mm) and without LAE (Non-LAE) in each group.

Result:
In both MR and non-MR groups, patients with LAE were, as compared with non-LAE, more in body weight, more often persistent/permanent type, more likely to have chronic kidney disease. LAE group was older, more likely have heart failure, hypertension, diabetes mellitus and more often received oral anticoagulant in non-MR group, but not in MR group. During the median follow-up of 1,804 days, the incidence rate of stroke/SE was higher in LAE than non-LAE in non-MR group (2.13 vs. 1.08 per 100 person-years, respectively, log rank p<0.001), but it was comparable between LAE and non-LAE groups in MR group (1.23 vs. 1.82 per 100 person-years, respectively, log rank p=0.41).

Conclusion:
The incidence rate of stroke/SE was higher in LAE than non-LAE in non-MR group, but not in MR group.
Abstract 10016: Potential of Stress T1 Mapping for Detection of Microvascular Dysfunction Without Contrast Agents
Authors: Kosuge Hisanori , Hachiya Shoko , Fujita Yasuhiro , Hida Satoshi , Chikamori Taishiro
Published: March 2022

Introduction:
Ischemia of hypertrophic myocardium due to microvascular dysfunction is related to worse prognosis in hypertrophic cardiomyopathy (HCM). Stress T1 mapping is a novel cardiac magnetic resonance (CMR) method without contrast agents to be able to assess myocardial blood flow.

Hypothesis:
We assessed the hypothesis that stress T1 mapping can detect microvascular dysfunction in HCM patients.

Methods:
Forty-one consecutive subjects without history of coronary artery disease (mean age : 60±3 years, 25 HCM patients, 10 concentric left ventricular hypertrophy (LVH) patients and 6 control subjects) underwent CMR at 3T including cine imaging, rest and adenosine stress T1 mapping, and late gadolinium enhancement (LGE). Native and stress T1 values were measured as an averaged T1 values in the septum of 3 short-axis slices of base-to-apex left ventricle myocardium and T1 reactivity (ΔT1) was calculated as follows: ΔT1 (%) = (T1stress - T1rest)/T1rest х 100. Thirteen HCM patients underwent phase-contrast imaging of coronary sinus flow during rest and adenosine stress to assess coronary flow reserve (CFR).

Results:
Native T1 values in HCM patients (1271±12ms) showed no significant differences compared with LVH (1225±13ms, p=0.0877) and control subjects (1243±8ms, p=0.534), but ΔT1 in HCM patients (4.00±0.36%) was significantly lower than that in control subjects (5.97±0.41%, p=0.0272), but not in LVH patients (4.95±0.29%, p=0.265, Figure 1). In HCM patients, native T1 values and ΔT1 showed no significant differences between LGE-positive (n=19) and LGE-negative (n=6) groups (native T1: 1274±15ms vs. 1260±20ms, p=0.632, ΔT1: 4.55±0.79% vs. 3.82±0.41%, p=0.394). A moderate positive correlation between ΔT1 and CFR was seen (β=0.697, p=0.0398).

Conclusions:
T1 reactivity (ΔT1) was reduced in HCM patients compared to control subjects. Stress T1 mapping is a promising CMR method for the assessment of microvascular dysfunction without contrast agents.
Abstract 10024: Single-Cell Transcriptomic Profiling of Immune Cell Phenotype Modulation in Murine Abdominal Aortic Aneurysm
Authors: Yuan Zhen , Song Shen , Yuan Tan , Min Xinjia , Cai Zhejun
Published: March 2022

Background:
Abdominal aortic aneurysm (AAA) is recently recognized as an autoimmune-induced vascular disease. Nonetheless, the inflammatory cellular heterogeneity and specialty within the aortic wall have not been fully identified.

Methods:
Infrarenal abdominal aortas of WT mice were perfused with PBS or elastase to simulate sham or AAA models. The aortas were harvested 14 days after surgery and digested for single-cell preparation. The cell pellet was mixed with CD45 microbeads, and proceeded with magnetic separation to isolate CD45 positive immune cell suspension. The cell suspension was loaded into Chromium microfluidic chips with 3’ chemistry and barcoded with 10х Chromium Controller (10X Genomics). All downstream single-cell analyses were performed using the CellRanger, Seurat, or clusterProliler R package.

Results:
Based on the filtered gene expression matrix, 18 clusters were identified in the final datasets. Enrichment analysis was performed to finger out the specific biological behaviors, such as inflammatory cytokine secretions and promotion of cell proliferation, in each clusters of immune cells. According to the highly expressed cell markers and biological behaviors, we divided each clusters of immune cells into macrophages, dendritic cells (DCs), T or B lymphocytes. It was shown in the t-SNE plot that the cellular quantity of CD45 positive immune cells, especially macrophages and DCs, were prominently altered in the AAA group. The refined subtypes of each kinds of inflammatory cells were distinguished and identified by limiting essential cell markers and increase dimensionality resolution. The specific marker-based analysis showed that the cell count difference of resident macrophages and monocyte-derived DCs (moDCs) are most noticeable between the AAA and the sham group, which might suggest these cells have eventful influence in aneurysm development.

Conclusions:
The integrated data exhibited the distinctive heterogeneity of CD45 positive immune cells within elastase-induced AAA samples. Some of these cells, such as resident macrophages and moDCs, may play an essential role through several pathways in the pathogenesis of AAA formation according to our scRNA-sequencing result.
Abstract 10026: Higher Odds of Major Adverse Cardiovascular and Cerebrovascular Events in Hospitalized Cancer Patients with Hypertensive Crisis: A Nationwide Population-Based Study
Authors: Jain Akhil , Srikanth Sashwath , Yar Khan Nibras , Shenwai Priya , Chintalapalli Patta Harika Varma , Rida Taherunnisa , Asfeen Ummul , Gandhi Zainab J , Desai Rupak
Published: March 2022

Background:
Cancer patients have an increased risk of new-onset hypertension. Burden, comorbidities, and outcomes of hypertensive crisis (HTNcrisis) in prior and current cancer patients remain undefined.

Methods:
The National Inpatient Sample (2015 October-2017) was used to identify cancer patients (current+prior cancer) and sub-grouped into HTNcrisis vs. non-HTNcrisis to compare demographics, comorbidities, and outcomes (MACCE-major adverse cardiovascular and cerebrovascular events: all-cause mortality, acute myocardial infarction, cardiac arrest & stroke).

Results:
Active or prior cancer diagnosis had 9,279,536 admissions, of which 70,530 had HTNcrisis (0.8%). HTNcrisis arm more often included older (74 vs. 71 years), black (22.5 vs. 11.0%), female (58.5% vs. 50.7%), Medicare enrollees (77.2% vs. 67.9%) vs. non-HTNcrisis
(Table 1)
. HTNcrisis arm had higher rates of hyperlipidemia, smoking, diabetes, renal failure, CHF, prior TIA/stroke, prior CABG vs non-HTNcrisis. Cancer with HTNcrisis had higher rate and odds of MACCE (9.7% vs.19.6%, OR:1.92, 95CI:1.88-1.96), higher rate of AMI (7.6% vs 3.3%), arrhythmia (29.8% vs 27.2%), stroke (10.8% vs 3.0%) with comparable healthcare resource utilization (p<0.001). Of the HTNcrisis cohort, patients with an active cancer diagnosis with prior history of treated cancer (4.9%) had higher all-cause mortality compared to patients with either currently active cancer (4.0%) or prior cancer (2.1%) (p<0.001).

Conclusion:
Cancer patients with HTNcrisis often included elderly, black, and female compared to those without. HTNcrisis admissions had two times higher odds of MACCE including higher rates of AMI, arrhythmia and stroke. Among HTNcrisis admissions, patients currently diagnosed with active cancer along with prior history experienced a higher burden of inpatient deaths compared to admissions either with current or prior cancer.
Abstract 10030: A Novel Multi-Target Drug Prevents Cancer Therapy-Induced Hypertension and Renal Damage
Authors: Imig John D , Jankiewicz Wojciech K
Published: March 2022

Introduction:
Cardiovascular and kidney damage is associated with cancer therapeutics and has resulted in the clinical specialties of cardio-oncology and nephro-oncolgy.

Hypothesis:
Investigate a multi-target soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibitor, PTUPB, on cardiovascular and kidney damage that occurs during cancer therapy with sorafenib.

Method:
Rats were given were administered sorafenib and administered high salt diet for 8 weeks. The study included three experimental groups (n=4-8/group); (1) control group, (2) vehicle group treated with sorafenib (20mg/kg/d), and (3) PTUPB-treated group consisting of rats which were initially treated with sorafenib for 4 weeks and subsequently co-administered PTUPB (10mg/kg/d) from weeks 4 to 8. Blood pressure was measured, and urine collected every two weeks. Plasma and kidney tissue were collected at the end of the treatment period. Additional experiments were conducted in isolated glomeruli and mesangial cell cultures.

Results:
After 4 weeks, sorafenib-treated rats developed hypertension (177±9 mmHg) and sorafenib resulted in a further elevation in blood pressure at week 8 (205±10 mmHg). PTUPB treatment attenuated the sorafenib-induced blood pressure elevation. After 4 weeks, sorafenib rats developed pronounced proteinuria (9.0±2 Pr/Cr), which intensified significantly (32.0±4 Pr/Cr) by the end of week 8. PTUPB mitigated sorafenib-induced proteinuria and PTUPB reduced proteinuria by 75%. Kidney histopathology revealed glomerular injury, and glomerular nephrin loss in sorafenib rats. PTUPB treatment reduced glomerular injury by 30 to 70% as well as restored glomerular nephrin expression levels. Consistent with renoprotective action, PTUPB reduced sorafenib-induced renal oxidative stress as indicated by 26% lower MDA content. In isolated glomeruli, PTUPB treatment decreased angiotensin II induced glomerular permeability. Sorafenib induced glomerular mesangial cell death was also prevented by PTUPB treatment.

Conclusion:
Our data demonstrate that PTUPB decreased hypertension and kidney injury associated with the cancer therapeutic sorafenib.
Abstract 10031: Gaps in Medical Therapy for Patients with Heart Failure and Reduced Ejection Fraction (HFrEF) in a Large, Diverse, Electronically Identified Cohort
Authors: Mukhopadhyay Amrita , Reynolds Harmony , Phillips Lawrence M , Nagler Arielle , Horwitz Leora , Katz Stuart D , Blecker Saul
Published: March 2022

Background:
National registries reveal significant gaps in medical therapy for patients with heart failure and reduced ejection fraction (HFrEF), but may not completely capture the population eligible for therapy. We developed an electronic health record-based algorithm to identify eligible HFrEF patients, and used this to assess prescribing in a large, diverse, urban health system.

Methods:
In this cross-sectional study of NYU Langone Health outpatients (>350 sites) with EF≤40% on echocardiogram and clinic visit from 3/1/2019-2/29/2020, we assessed contraindication to and prescription of the following: beta-blocker (BB), angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI), and mineralocorticoid receptor antagonist (MRA).

Results:
We electronically identified 2,732 patients for analysis. Among those eligible for each medication class, 84.8% and 79.7% were appropriately prescribed BB and ACE-I/ARB/ARNI, respectively, while only 23.9% and 22.7% were appropriately prescribed MRA and ARNI, respectively. In adjusted models (Table), younger age, cardiology visit, and lower EF were associated with increased prescribing. Medicaid insurance was associated with increased prescribing of ARNI and Black race with prescribing of MRA.

Conclusions:
We observed significant gaps in MRA and ARNI therapy for HFrEF patients. Medicaid insurance was associated with increased ARNI use, possibly due to lack of prior authorization requirements under New York State Medicaid policy. Our findings support system- and policy-level interventions to increase use of these life-saving therapies.
Abstract 10034: Trends, Predictors, and Outcomes After Transcatheter Aortic Valve Implantation in Patients with Baseline Right Bundle Branch Block, from National Inpatient Sample
Authors: Zahid Salman , Khan Muhammmad , Ullah Waqas , Khan Muhammad U , Khan Muhammad Atif , UBAID AAMER , Pendela Satish , Tanveer Ud Din Mian , Muhammadzai Hamza , Depta Jeremiah , Balla Sudarshan
Published: March 2022

Introduction:
Contemporary data on the outcomes after Transcatheter Aortic Valve Implantation (TAVI) in patients with a baseline right bundle branch block (RBBB) remains limited.

Methods:
We analyzed National Inpatient Sample (NIS) data from the year 2011 to 2018.

Results:
Of the patients who underwent TAVI, 3472 (1.6%) had baseline right bundle branch block and 212467 (98.4%) did not. The patients who had baseline RBBB were older at 83 years [Interquartile range (IQR), 77-87] vs 82 [75-87]) and had higher male gender representation (66.7 % vs 52.2%) (p<0.01 for all). Rates of permanent pacemaker implantation was significantly higher in the RBBB group compared to no RBBB group (30.5% vs 10.80%, p<0.01). Median Cost of care ($53206 vs $48429) and length of stay (5 vs 4 days) were considerably higher for patients with RBBB when compared to the comparison group (p<0.01 for all). Logistic regression analysis showed that age greater 75 [OR] 1.26 [95% CI 1.21-1.31], male sex [OR] 1.12 [95% CI 1.09-1.15] , atrial fibrillation [OR] 1.29 [95% CI 1.07-1.57], coronary artery disease [OR] 1.07 [95% CI 1.04-1.11] diabetes [OR] 1.07 [95% CI 1.02-1.12], hypertension [OR] 1.10 [95% CI 1.05-1.15] obesity [OR] 1.10 [95% CI 1.05- 1.1.16] and renal failure (OR, 1.12 [CI, 1.09-1.15] were significant predictors of PPM implantation post TAVI in patients with a RBBB at baseline.

Conclusions:
In conclusion we report that RBBB is associated with increased pacemaker implantation after TAVI. Factors like age greater than 75, male gender, coronary artery disease, diabetes, hypertension, obesity, and renal failure are associated with higher incidence of PPM implantation.
Abstract 10037: Cerebral Embolic Protection During Transcatheter Aortic Valve Implantation: Updated Systemic Review and Meta-Analysis
Authors: Zahid Salman , UBAID AAMER , Khan Muhammad Atif , Tanveer Ud Din Mian , Muhammadzai Hamza Zahid Ullah , Khan Muhammmad , Uddin Muhammad Faisal , Ullah Waqas , Khan Muhammad U , Adil Abid Nawaz Khan , Baqi Abdul , Abbas Sakina , Inayat Arslan , Salman Fnu , Depta Jeremiah
Published: March 2022

Introduction:
In patient undergoing transcatheter aortic valve implantation (TAVI), stroke remains a potentially devastating complication associated with significant morbidity and mortality.

Hypothesis:
To reduce the risk of stroke, cerebral protection devices (CPD) were developed to prevent debris from embolizing to the brain during TAVI.The data on the safety and efficacy of cerebral protection devices (CPD) remains limited.

Methods:
We performed a systemic review and meta-analysis to determine the safety and efficacy of CPD in TAVI. The MEDLINE (PubMed, Ovid) and Cochrane databases were queried with various combinations of medical subject headings to identify relevant articles. Statistical analysis was performed using a random-effects model to calculate unadjusted odds ratio (OR).

Results:
Using a pooled analysis, CPD was associated with a significant reduction in major adverse cardiovascular events (MACE) (OR 0.69, 95% CI 0.50-0.96, p=0.03) and stroke (OR 0.61, 95% CI 0.42-0.90, p=0.08) in patients undergoing TAVI. Similarly, on MRI volume per lesion were lower for patients with CPD use (SMD -0.79 [-1.30,-0.28], p<0.01). No significant difference were observed in mortality (OR 0.97, 95% CI 0.60-1.55, p=0.88), acute kidney injury (OR 0.75, 95% CI 0.42-1.37, p=0.68), bleeding (OR 0.93, 95% CI 0.52-1.65, p=0.80) or vascular complications (OR 0.90, 95% CI 0.62-1.31, p=0.6) for patients undergoing TAVI with CPD.

Conclusions:
In conclusion, CPD device use in TAVI is associated with a reduction of MACE and stroke compared with patients undergoing TAVI without CPD.
Abstract 10047: Ethnic-Specific Trends in Long-Term Post-Stroke Recurrence and Mortality Over 13 Years
Authors: Chen Chen , He Kevin , Shi Xu , Shafie-Khorassani Fatema , Morgenstern Lewis B , Lisabeth Lynda D
Published: March 2022

Introduction:
Estimating trends in long-term outcomes after stroke is important for long-term planning of health resources. Data on trends in long-term post-stroke outcomes are not available among Hispanics. Whether race-ethnic disparities exist and how trends in these outcomes have changed over time comparing non-Hispanic Whites (NHWs) with Mexican Americans (MAs) are also unknown. Thus, we aimed to estimate ethnic-specific trends in risk of 5-year all-cause mortality and recurrence after initial stroke in MAs and NHWs.

Methods:
We included 3308 patients who had first-ever ischemic stroke ascertained between January 1, 2000 and December 31, 2012 from the Brain Attack Surveillance in Corpus Christi (BASIC) project in Texas. Data on recurrent stroke and death were available through December 31, 2017. Fine-Gray subdistribution hazard models including covariates and an interaction term between calendar year and ethnicity were used to calculate 5-year cumulative incidence of recurrence and death in both ethnic groups in each year.

Results:
Among the 3308 index stroke patients, 402 (12.15%) recurrences and 1420 (37.61%) deaths were observed during the 5-year follow-up. Adjusted 5-year cumulative incidence of recurrence among MAs declined from 15.76% to 11.28%. Among NHWs, a slight decline from 12.49% to 10.46% was observed. An ethnic disparity in 5-year recurrence was not apparent in 2000 (risk difference 3.27%, [95% CI, -10.41, 9.10]) or during the study duration (Figure). The greatest ethnic disparity in 5-year mortality risk was observed in 2000 but disappeared in 2012, which was driven by the increasing trend in MAs from 23.11% in 2000 to 24.28% in 2012 and the decreasing trend in NHWs from 31.09% to 27.19% accordingly.

Conclusions:
No apparent ethnic disparity in long-term stroke recurrence was found and long-term survival advantage in MAs presented early in the study gradually disappeared over the 13 years.
Abstract 10053: Outcomes of Transcatheter Aortic Valve Implantation with Baseline First Degree Heart Block (from National Inpatient Sample)
Authors: Zahid Salman , Khan Muhammmad , Ullah Waqas , Salman Fnu , Khan Muhammad Atif , UBAID AAMER , Muhammadzai Hamza , Adil Abid Nawaz Khan , Tanveer Ud Din Mian , Baqi Abdul , Rai Devesh , Fischman David L , Alraies Chadi , Alam Mahboob , baibhav bipul , Rao Mohan , Depta Jeremiah , balla Sudarshan
Published: March 2022

Introduction:
Pacemaker implantation remains a frequent complication in patients undergoing transcatheter aortic valve implantation (TAVI). Outcomes of TAVI with a baseline first degree heart block (HB) remain unknown.

Methods:
The purpose of this study was to evaluate outcomes of TAVI in patients with a baseline first degree HB. We utilized the National Inpatient Sample (NIS) data from the year 2011 to 2018.

Results:
A total of 215,938 weighted hospitalizations for TAVI were included in the analysis. Of the patient undergoing the procedure, 11000 had baseline first degree HB (5.1%) and 204938 (94.9%) patients did not have first degree HB. Patients with first degree HB had higher rates of PPM implantation (17.1% vs. 10.1%, p<0.01). At baseline, age greater than 75 (Odds Ratio [OR], 1.26[confidence interval (CI), 1.10-1.45]), male gender (OR, 1.22[CI, 1.09-1.37]), atrial fibrillation (OR, 2.01[CI, 1.68-2.4]), hypertension (OR, 1.54[CI, 1.27-1.88]) and chronic kidney disease (OR, 1.22[CI, 1.08-1.37]) were significant predictors of PPM implantation in patients undergoing TAVI with a baseline first degree HB. In terms of resource utilization, patients with baseline first degree HB had higher median cost of stay ($ 48083 vs. $ 47081)

Conclusions:
In conclusion we report that PPM implantation rate is higher in patients with first degree HB and that age greater than 75, male sex, hypertension and chronic kidney disease are significant predictors of this adverse event.
Abstract 10061: Association of Frailty with In-Hospital and Long-Term Outcomes Among St-Elevation Myocardial Infarction Patients Receiving Primary PCI
Authors: Hosseini Farshad , Pitcher Ian , Kang Mehima , MacKay Martha , Singer Joel , Lee Terry , Madden Kenneth , CAIRNS John A , Wong Graham C , Fordyce Christopher
Published: March 2022

Introduction:
The impact of frailty on outcomes in a contemporary ST-segment-elevation myocardial infarction (STEMI) population is unclear. This study hypothesized that frail STEMI patients undergoing primary percutaneous coronary intervention (pPCI) have worse in-hospital and 1-year outcomes compared to non-frail STEMI patients.

Methods:
We retrospectively identified 600 STEMI patients who had received pPCI (2013 - 2016). A frailty index (FI) was determined using the health deficit accumulation model (Table 1). Frail patients were defined as those with a FI > 0.25. The composite outcome comprised in-hospital heart failure, cardiogenic shock, re-infarction, major bleeding, stroke and all-cause mortality. A multivariable model adjusting for age and sex was performed.

Results:
Among 600 STEMI patients receiving pPCI, 67 (11.2%) were classified as frail. Compared to non-frail patients, frail patients were older (mean 80.3 vs. 75.8 years, p < 0.001) and had a higher comorbidity burden. After adjustment, baseline frailty was independently associated with delayed reperfusion time, in-hospital all-cause mortality, and higher incidence of the composite outcome (Figure 1). Frailty was also associated with increased 1-year all-cause mortality and cardiovascular rehospitalization.

Conclusions:
Among STEMI patients receiving pPCI, 1 in 10 were frail. Frailty was associated with increased rate of the primary in-hospital composite adverse outcome, delayed reperfusion time and worse long-term outcomes. Efforts to routinely identify frail STEMI patients and to implement best practices to reduce the risk of adverse events in this vulnerable population are warranted.
Abstract 10062: Administrative Data Algorithms Can Identify Patients with Advanced Heart Failure
Authors: Dunlay Shannon M , Glasgow Amy , Blecker Saul , Ngufor Che , Schulte Philip , Redfield Margaret M
Published: March 2022

Introduction:
Advanced or “Stage D” heart failure (Adv HF) patients are at high risk of poor outcomes. However, recognition of Adv HF is limited as diagnostic criteria are complex. Administrative algorithms to identify Adv HF could enable better understanding of who has advanced HF and lead to enhanced therapeutics development, dissemination, and outcomes.

Methods:
In a population-based cohort of all Olmsted County, Minnesota residents with ≥1 HF billing code 2007-2017 (n=9881), we identified all patients with Adv HF (n=753) by applying the gold standard European Society of Cardiology Adv HF criteria via manual medical review by a HF cardiologist. The Adv HF index date was the date the patient first met all ESC criteria. We then developed candidate algorithms to identify Adv HF using only administrative data (billing codes and HF prescriptions or comorbidities known to affect HF outcomes), applied them to the entire HF cohort and assessed their ability to identify patients with Adv HF on or after their Adv HF index date.

Results:
A single hospitalization (Hsp) for HF or ventricular arrhythmias (VA, 2007-2017) identified all patients with Adv HF (sensitivity 100%), but the PPV was low (36.4%). Requiring more Hsp, other signs of Adv HF such as hyponatremia, acute kidney injury, hypotension or high-dose diuretic use decreased the sensitivity but improved specificity and PPV. As Adv HF was relatively uncommon, negative predictive values (NPV) were high regardless of algorithm characteristics.

Conclusions:
Algorithms using administrative data can identify patients with Adv HF with clinically useful accuracy.