bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10751: Pericardial Injection of Micronized Matrix Biomaterial Improves Post-Infarct Cardiac Function and Modulates Fibroblast Activity to Enhance Repair
Authors: Vasanthan Vishnu , belke darrell , Teng Guoqi , Fatehi Hassanabad Ali , Dundas Jameson , Turnbull Jeannine , Deniset Justin , Fedak Paul W
Published: March 2022

Introduction:
Injection of micronized biomaterials into the pericardial space leverages bioinductive properties to enhance post-infarct cardiac repair. This less invasive, potentially bedside, approach enables early intervention. Micronized porcine small intestinal submucosal extracellular matrix (SIS-ECM) contains fibroblast growth factor 2 (FGF2) which reduce fibrosis and increase vasculogenesis.

Hypothesis:
Pericardial delivery of micronized SIS-ECM improves post-infarct cardiac function. It promotes a proangiogenic and antifibrotic fibroblast phenotype.

Methods:
Mice received coronary ligation (infarct) through an undisrupted pericardium followed by pericardial delivery of micronized SIS-ECM or saline control. Pressure-volume loops were at 28 days. Myocardial isolectin stain assessed small vessel density on confocal microscopy.

Mouse 3T3 cell line fibroblasts in 3D collagen matrices were exposed to biomaterial-conditioned media or media control. Multiplex analyzed paracrine activity. Collagen gel contraction and MMP2 production assessed profibrotic phenotype. FGF2 inhibitor elucidated mechanism.

Results:
Mice receiving micronized SIS-ECM had lower ventricular stiffness (0.23±0.03 vs 0.39±0.05 mmHg/uL; p=0.01), higher ejection fraction (34.7±2.5 vs 26.9±2.8%; p<0.05) and higher stroke work (1510±138 vs 1066±152 μL/mmHg; p=0.04). The SIS-ECM group had higher normalized border zone isolectin mean fluorescence (0.82±0.04 vs 0.58±0.06; p=0.01).

Micronized SIS-ECM attenuated collagen gel contraction (26±6 vs 56±5%; p=0.01) and MMP2 release (66±2 vs 83±3 ng/mL; p<0.01). Micronized SIS-ECM increased fibroblast VEGF production (904±79 vs 628±25; pg/mL). FGF2 inhibitor negated biomaterial effects, increasing gel contraction (27.3±5.3 vs 11.0±0.5%; p=0.04; inhibitor vs no inhibitor) and MMP-2 release (141±8 vs 100±6 ng/mL; p=0.02).

Conclusions:
Pericardial injection of micronized SIS-ECM attenuates profibrotic fibroblast activity, increases release of angiogenic VEGF protein, increases vasculogenesis on isolectin staining, and preserves post-infarct cardiac function. This less invasive strategy facilitates early intervention to attenuate maladaptive post-infarct structural remodeling.
Abstract 10765: Plasma Cell-Free DNA Predicts Survival and Maps Tissue-Specific Sources of Injury in Pulmonary Arterial Hypertension
Authors: Brusca Samuel B , Elinoff Jason M , Zou Yvette , Jang Moon K , Kong Hyesik , Demirkale Cumhur Y , Sun Junfeng , Seifuddin Fayaz , Pirooznia Mehdi , Valantine Hannah A , Tanba Carl , Chaturvedi Abhishek , Kanwar Manreet , Benza Raymond L , Preston Ioana R , agborenoh sean , Solomon Michael A
Published: March 2022

Background:
Cell-free DNA (cfDNA) is a non-invasive marker of tissue injury. Although being incrementally used as a clinical biomarker, its significance in pulmonary arterial hypertension (PAH) is unknown.

Methods:
Plasma cfDNA was isolated in two independent PAH cohorts (A, n=48; B, n=161) and healthy controls (n=48). Clinical variables and survival status were collected for Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL 2.0) scores and outcome determinations. Total cfDNA levels were compared amongst controls and PAH patients and also used to predict transplant-free survival. A subset of samples from cohort B (n=96) and controls (n=16) were subjected to bisulfite sequencing and methylation analysis to quantify tissue-specific sources of cfDNA.

Results:
Median (IQR) cfDNA concentrations were higher in cohort A PAH patients (exploratory cohort) compared to controls and increased according to REVEAL 2.0 risk group: controls 13.7 (10.8-18.8) vs low risk 14.4 (10.0-19.9) vs medium risk 14.6 (11.3-28.2) vs high risk 31.5 (17.2-45.6) ng/ml (P<0.01). cfDNA analysis in cohort B (validation cohort) demonstrated a similar cfDNA pattern: controls 13.7 (10.8-18.8) vs low risk 24.3 (16.0-57.9) vs medium risk 50.4 (29.4-70.9) vs high risk 51.5 (34.0-110.5) ng/ml (P<0.0001). cfDNA tertiles (Log-Rank; P=0.0001) and REVEAL 2.0 risk group (Log-Rank; P<0.0001) similarly predicted transplant-free survival, and the addition of cfDNA to REVEAL 2.0 improved model performance (AUC 0.64 to 0.70; P<0.05). Tissue-specific methylation analysis revealed increased cfDNA originating from vascular endothelium, cardiac myocytes, monocytes, erythrocyte progenitors, neutrophils, natural killer cells, and adipocytes (all P<0.005), but not colon, head/neck, liver, bladder, or kidney. With the exception of natural killer cells, cfDNA from enriched tissues also differentiated PAH patients of varying REVEAL 2.0 risk.

Conclusions:
cfDNA is elevated in PAH patients, correlates with disease severity and predicts worse survival. Methylation analysis of cfDNA in PAH patients is consistent with prevailing paradigms of disease pathogenesis. Thus, cfDNA may add prognostic power to PAH risk assessment and provide insight into disease progression.
Abstract 10767: Therapeutic Effects of Clustered Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells for Chronic Hind Limb Ischemia
Authors: Yokota Junki , Kawamura Takuji , Miyake Keisuke , Harada Akima , Shibuya Takashi , Miyagawa Shigeru
Published: March 2022

Introduction:
Human induced pluripotent stem cell-derived mesenchymal stem cell (iPS-MSC) is a promising cell source of regeneration therapy for hind limb ischemia (HLI). To date, we have already demonstrated the clustered cell administration has better therapeutic effects for HLI than single-cell administration using autologous myoblast cells. In this study, we administered clustered iPS-MSCs into the chronic HLI mouse and evaluated the regeneration effect.

Methods:
Human iPS cells were cultured in a serum-free medium containing the transforming growth factor-β pathway inhibitor SB431542 for the differentiation to MSC
in vitro
. These iPS-MSCs were expanded to form cell patches (10
6
cells/sheet). These iPS-MSC patches were mechanically fragmented and were then administered into HLI mice as clustered cells (CC group, n=10). As control groups, non-clustered single iPS-MSC (SC, n=12) or Hanks’ balanced salt solution (HBSS, n=9) were administered. HLI was induced to the NOD/Shi-scid mouse by resecting the femoral artery and vein. The mice of which blood perfusion, being evaluated with Laser Doppler Perfusion Imaging (LDPI) at day 7, was under 40 % as compared with contralateral leg were included in the further study as the “chronic HLI model”. Serial change of LDPI and histological change of leg muscles were analyzed regarding angiogenesis and skeletal muscle regeneration.

Results:
Blood perfusion was significantly improved in CC (56.16±20.03%) as compared with HBSS (34.09±12.80%, P=0.0140) and SC (29.04±6.770%, P=0.0010) at day 14. Also, histological analysis showed the number of CD31
+
endothelial cells is significantly larger in CC (353.6±59.97/mm
2
) as compared with HBSS (126.2±22.85/mm
2
, P=0.0004) and SC (103.6±23.81/mm
2
, P=0.0001). The mean diameter of skeletal muscle cells is significantly larger in CC (42.28±4.113μm) as compared with SC (29.02±2.535μm, P=0.0001) and HBSS (29.61±3.103μm, P=0.0007).

Conclusions:
The clustered iPS-MSC significantly augmented angiogenesis and muscle regeneration in chronic HLI as compared with single-cell administration.
Abstract 10769: Osteoprotegerin and Incident Heart Failure: The Atherosclerosis Risk in Communities Study
Authors: Kamimura Daisuke , Buckley Leo , Dorbala Pranav , Claggett Brian , Yu Bing , Coresh Josef , Matsushita Kuni , Chang Patricia , Hoogeveen Ron C , Ballantyne Christie M , Hall Michael E , Shah Amil M
Published: March 2022

Background:
Osteoprotegerin (OPG), a protein involved in bone metabolism, is associated with cardiac fibrosis and remodeling in animal models. Circulating OPG levels correlate with left ventricular mass index and plasma brain natriuretic peptide levels in humans, but the association with incident heart failure (HF) is not known.

Methods:
Among 10,261 participants in the community-based Atherosclerosis Risk in Communities (ARIC) Study free of prevalent HF at study Visit 3, we investigated the association of plasma OPG levels at Visit 3 with incident HF hospitalization post-Visit 3 using multivariable Cox proportional hazard models. OPG was measured using a high-throughput DNA aptamer-based proteomic platform (Somalogic, Boulder, CO), and relative fluorescence unit values were log2 transformed. All models adjusted for age, sex, race, study field center, body mass index, hypertension, diabetes, estimated glomerular filtration rate, smoking status, prevalent coronary artery disease, and atrial fibrillation.

Results:
Mean age was 60±6 years, 54% were women, and 20% of participants were Black. Higher OPG levels were associated with older age, female gender, Black race, and higher prevalence of hypertension, diabetes, and smoking (all p <0.001). Over a median of 15.0 years follow-up (interquartile range: 13-15), there were 1301 incident HF hospitalizations. In multivariable models, higher serum OPG levels were associated with greater risk of incident HF (hazard ratio per 1 SD increase: 1.20 [95% confidence interval, 1.13-1.27]; Figure). This association persisted after further adjustment for NT-proBNP (HR 1.19 [95% CI 1.12-1.26], p<.001).

Conclusion:
In this large community-based cohort, higher plasma OPG levels were significantly associated with incident HF hospitalization, independent of traditional cardiovascular risk factors and NT-proBNP. Further studies are warranted to clarify whether OPG could be a new therapeutic target for HF prevention.
Abstract 10774: A Single Center Study Investigating the Relationship Between Atrial Fibrillation and Sleep Apnea Testing
Authors: Latif Zara , Modest Anna , Tieu Hieu , Tung Patricia
Published: March 2022

Introduction:
Sleep apnea is recognized as a predictor of incident atrial fibrillation (AF); it has been associated with decreased response to antiarrhythmic drugs, and higher rates of AF recurrence after cardioversion and catheter ablation. However, it is not known whether widespread screening for sleep apnea in patients with AF affects arrhythmia outcomes.

Objective:
to evaluate the effect of universal sleep apnea screening on AF outcomes.

Methods:
We conducted a prospective study of all patients referred to electrophysiology clinic at our center for management of AF and referred for sleep apnea testing between March 2018 and March 2021. Screening was performed using home sleep testing (HST) and polysomnography (PSG). Patients were assessed for progression of AF as defined by any of the following: change from paroxysmal to persistent AF, change in antiarrhythmic drug, ablation, or cardioversion.

Results:
Among 321 patients evaluated for atrial fibrillation, 78% (251) of patients were tested for sleep apnea with HST or PSG. Of these, 6% (16) had no sleep apnea, 83% (208) had either obstructive or mixed apnea, and 11% (27) were inconclusive. Among those with sleep apnea, 56% (116) had OSA, 42% (87) had mixed apnea, and 2% (5) had pure central apnea.As the time from AF diagnosis to sleep apnea testing increased, the risk of AF progression also increased (p <0.0001). This effect was observed even when stratified by obstructive versus mixed apnea(OSA p= 0.04, mixed p=0.0005).

Conclusions:
Sleep apnea was present in the vast majority of patients with AF. Of those with sleep apnea, almost half had mixed central and obstructive sleep apnea. Duration of greater than 24 months from atrial fibrillation diagnosis to sleep apnea testing was associated with higher rates of AF progression. Thus, early, universal screening for sleep apnea may improve outcomes in patients with AF.

Table I.
The relationship between time from AF diagnosis to sleep apnea (SA) testing on AF outcomes.
Abstract 10782: Optimization of Preservation Solution and Temperature of Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Patch for Regenerative Therapy
Authors: Iseoka Hiroko , Miyagawa Shigeru , Kawamura Takuji , Matsuura Ryohei , Sawa Yoshiki
Published: March 2022

Background:
Regenerative therapy for heart failure is being practical as a new treatment. Since cell products contain living cells, it is important to apply the storage method according to the characteristics of the product in order to maintain its structure and function. A lot of studies have been done on suitable storage solutions for organs, and organ storage solutions may also be effective for cell product preservation, especially tissues with three-dimensional structures. In this study, we investigated the optimal storage conditions for human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) patches.

Methods and Results:
We evaluated the properties of iPSC-CM patches after storage in cell culture buffer solution (BS), intracellular fluid type organ preservation solution A (PSA), and extracellular fluid type organ preservation solution B (PSB) and under room temperature or 4°C. Although the patches maintained their sheet-like morphology up to 120hrs , the sarcomere structure was disrupted, and the viability decreased over time after 48hrs of storage in BS at room temperature. Myocardial contraction/relaxation velocity and cytokine production after reculture of the stored patches showed a significant decrease after 96hrs of storage in BS at room temperature. We tested whether PSA and PSB improve the preservation of the patches compared to the BS in 48hrs storage. As a result, contraction velocity after reculture was comparable for PSA (17.1±4.4 μm/sec), PSB (10.0±0.9 μm/sec) and BS (12.9±1.4μm/sec). However, cell viability after storage was significantly decreased in PSA (13.9±19.9%) and PSB (68.4±26.1%) compared to BS (90.6±4.1%). Although sarcomere structure was maintained in BS, it was disrupted in PSA and PSB. No improvement was observed in contraction velocity, cell viability and sarcomere structure in PSA at 4°C compared to BS at room temperature.

Conclusions:
The iPSC-CM patches maintained their structure and function for up to 48 hrs under storage conditions in BS at room temperature. The buffer solution, intracellular or extracellular fluid type organ preservation solution have different ionic balances, suggesting that the optimal storage conditions differ according to tissue structure and cell type.
Abstract 10807: Pace-Capture versus No Pace-Capture Guided Ablation for Atrial Fibrillation: Systematic Review and Meta-Analysis
Authors: Shah Kuldeep , Shah Siddharth , Turagam Mohit K , Bhardwaj Rahul , Contractor Tahmeed , Mandapati Ravi , Natale Andrea , Lakkireddy Dhanunjaya , Garg Jalaj
Published: March 2022

Introduction:
Radiofrequency catheter ablation through circumferential lesions around pulmonary veins (PVs) ostia has been shown to be effective for treating atrial fibrillation. Arrhythmia recurrence has largely been due to recovery of conduction between PVs and left atrium.

Hypothesis:
To determine the efficacy of unexcitability to pacing along the ablation line as an endpoint of the PV isolation procedure.

Methods:
Electronic searches on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from the inception through June 7, 2021was performed. Statistical analysis was performed using
meta-package
for R version 4.0 and Rstudio version 1.2. The primary outcome was recurrent atrial arrhythmias. Secondary outcomes were procedure time (minutes), fluoroscopic time (minutes), and procedural complications.

Results:
Three eligible studies consisting of 338 patients (Pace-capture group - 168 and No Pace-capture group - 170) were included in the meta-analysis. There was a statistically significant reduction of recurrent atrial arrhythmias in the Pace-capture group vs. No Pace-capture (21% versus 31%, RR 0.68; 95% CI 0.47 - 0.98; p = 0.04). Procedure duration was significantly longer in the pace group {mean difference (MD) 16, 95% CI 6.96-25.05, p<0.001}; however, fluoroscopy times were not different (MD 2.24, 95% CI -0.27-4.75, p=0.08). No difference in procedural-related complications was noted between the two groups (RR 0.33, 95% CI 0.05-2.10; P=0.24).

Conclusions:
The endpoint of unexcitability along the ablation line was associated with a reduction in recurrent atrial arrhythmia after PV isolation, but as expected, it did prolong procedure time by ~16 min
Abstract 10808: Prognostic Significance of Obstructive Coronary Artery Disease in Patients Admitted with Acute Decompensated Heart Failure: The ARIC Study Community Surveillance
Authors: Chunawala Zainali , Qamar Arman , Arora Sameer , Pandey Ambarish , Fudim Marat , Vaduganathan Muthiah , Mentz Robert J , Caughey Melissa
Published: March 2022

Background:
Coronary artery disease (CAD) is a common cause of heart failure (HF). Whether the extent of coronary artery stenosis differs by HF type or prognosis for patients admitted with acute decompensated heart failure (ADHF) is uncertain.

Methods:
The Atherosclerosis Risk in Communities (ARIC) study conducted hospital surveillance of adjudicated HF in 4 US areas from 2005-2014. Medical histories were abstracted from the hospital record. Obstructive CAD was defined as > 49% stenosis in the left main coronary artery or >74% stenosis in the other major coronary arteries. Associations between obstructive CAD and 28-day mortality were analyzed separately for heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), adjusting for age, race, sex, year of admission, and coronary revascularization procedures. All analyses were weighted by the inverse of the sampling probability.

Results:
A total of 5115 patients admitted with ADHF underwent coronary angiography during the hospital visit (mean age = 72, 45% women, 28% Black, 30% HFpEF). Obstructive CAD was more prevalent with HFrEF (
Figure 1
), whether at the left main coronary artery (16% vs 12%), left anterior descending artery (50% vs 35%), left circumflex artery (42% vs 34%), right coronary artery (45% vs 34%), or multiple coronary vessels (47% vs 34%). A similar proportion of patients with obstructive CAD underwent revascularization, irrespective of HF type (HFrEF: 55%, HFpEF: 61%). After adjustments, obstructive CAD (in any vessel) was associated with higher 28-day mortality, both for HFrEF (OR: 3.21; CI: 1.91 - 5.97) and HFpEF (OR: 3.62; 95% CI: 1.43 - 9.18) with no significant interaction by HF type (
P
-interaction = 0.9).

Conclusion:
Patients hospitalized with ADHF and coexisting obstructive CAD are at greater risk of short-term mortality, irrespective of the HF type, warranting the need for effective interventions as well as secondary preventive measures in this population.
Abstract 10819: Eosinophilic Myocarditis Due to Idiopathic Hypereosinophilic Syndrome
Authors: Bourdillon Paul M , Macheret Fima , Xu Haodong , Chhieng David C , Li Song
Published: March 2022

Background:
Idiopathic Hypereosinophilic Syndrome (iHES) is a rare disease with varied clinical presentations including acute heart failure.

Case:
A 44-year-old man who had been treated for asthma 9 months ago was admitted with worsening exertional dyspnea. EKG demonstrated sinus tachycardia with anterolateral ST depressions. Labs revealed troponin-I 44.95 ng/ml, BNP 405 pg/mL, and white blood cell count 21.2k with 50% eosinophils. Transthoracic echocardiogram showed normal left ventricular size with globally reduced ejection fraction (30-35%). Coronary angiography found normal coronary arteries. An extensive infectious and auto-immune workup was unrevealing, and bone marrow biopsy was negative for monoclonal proliferation (Fig 1A). He received 1 gram of IV methylprednisolone for 2 days lowering eosinophil count to zero and was discharged on heart failure GDMT. Two weeks later, he was readmitted from clinic for ventricular tachycardia (VT) near 120bpm (Fig 1B). Cardiac MRI and endomyocardial biopsy confirmed active eosinophilic myocarditis (Fig 1C/D). Patient was diagnosed with iHES and treated with IV methylprednisolone (500mg BID x 3 days) with an oral prednisone taper. Amiodarone and lidocaine infusions were temporarily needed to suppress his VT and an ICD was placed. After clinical stabilization and immunology consultation, an interleukin-5 inhibitor was used for further treatment of iHES.

Discussion:
Only 6% of patients with iHES present with cardiac symptoms, however one in five eventually develop cardiac manifestations that are often rapidly progressive. Prompt treatment with glucocorticoids is indicated for severe presentations, and subsequent use of targeted therapies can dramatically reduce morbidity and mortality. Recognition of severe peripheral eosinophilia should prompt a broad hematologic, infectious, and auto-immune workup to guide treatment and prevent end-organ damage.
Abstract 10822: Lower EPA/AA Ratio is Associated with a Higher Prevalence of Vulnerable Characteristics in Non-Culprit Coronary Plaques in Statin-Treated Patients with Coronary Artery Disease
Authors: Asakura Kiyoshi , Minami Yoshiyasu , Kinoshita Daisuke , Nagata Takako , Katamine Masahiro , Katsura Aritomo , Hashimoto Takuya , KAMEDA RYO , Meguro Kentaro , Shimohama Takao , Ako Junya
Published: March 2022

Introduction:
Low eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio is associated with an increased risk of cardiovascular events in patients with coronary artery disease (CAD). However, the association between EPA/AA ratio and the characteristics of non-culprit coronary plaque in statin-treated patients with CAD remains to be elucidated.

Hypothesis:
Lower EPA/AA ratio is associated with a higher prevalence of vulnerable characteristics in non-culprit coronary plaque in statin-treated patients with CAD.

Methods:
A total of 367 consecutive stain-treated patients with stable coronary disease, who underwent percutaneous coronary intervention for the culprit lesion and optical coherence tomography (OCT) imaging of a non-culprit plaque in a culprit vessel were included. The characteristics of non-culprit plaque assessed by OCT were compared between the lower EPA/AA group (EPA/AA <0.4, n=255) and the higher EPA/AA group (EPA/AA ≥0.4, n=112).

Results:
The prevalence of lipid-rich plaque (58.8 vs. 42.0%, p=0.004) and plaque with macrophage (56.1 vs. 32.1%, p<0.001) was significantly higher in the lower EPA/AA group than in the higher EPA/AA group (Panel A). The lower EPA/AA was independently associated with the presence of lipid-rich plaque (Odds ratio [OR], 1.837; 95% confidence interval [CI]: 1.130-3.004, p=0.015) and plaque with macrophage (OR, 2.764; 95% CI: 1.672-4.639, p<0.001) (Panel B).

Conclusions:
Lower EPA/AA ratio was associated with a higher prevalence of vulnerable characteristics in non-culprit plaque. The present results may partly explain the impact of low EPA/AA ratio on the increased incidence of recurrent events in patients with CAD.
Abstract 10826: Lineage Specific Integrin Alpha V Augmentation Promotes Tgf-β Induced Integrin-FAK-Akt
thr308
Signaling Pathway
Authors: Nakamura Ken , Yokoyama Nobu , Pedroza Albert J , Dalal Alex R , Uchida Tetsuro , Fischbein Michael P
Published: March 2022

Introduction:
Marfan syndrome (MFS) patients classically develop focal aortic root aneurysms. Aortic root smooth muscle cells (SMCs) develop predominately from second heart field (SHF), whereas ascending aorta/arch SMCs originate from cardiac neural crest (CNC). We previously demonstrated induced pluripotent stem cell (iPSC)-derived SHF SMCs overexpress integrin αV (ITGAV). Therefore, we hypothesize that ITGAV promotes SHF SMC proliferation, contributing to thoracic aortic root aneurysm development.

Methods:
iPSCs from MFS patients (n=2) and healthy control (n=1) were differentiated into SHF and CNC SMCs. ITGAV-pFAK-pAkt
Thr308
levels were detected with western blot and ELISA at baseline and following recombinant TGF-β (2ng/ml) and/or an ITGAV antagonist (GLPG0187, 10nM) for 24 hours. Cell proliferation was measured with quantitative BrdU assay.

Results:
Baseline ITGAV-pFAK-pAkt
Thr308
activation were significantly elevated in MFS SHF lines (n=5 experimental replicates) compared to MFS CNC (n=5) or control SHF (n=4, p<0.05). Addition of recombinant TGF-β to SMC differentiation media further enhanced pFAK-pAkt
Thr308
levels in MFS SHF. Treatment with GLPG0187 reduced pFAK-pAkt
Thr308
in MFS SHF and CNC, confirming ITGAV-mediated signaling promotes pathologic FAK- Akt
Thr308
activation. SMCs from MFS SHF (n=6) had increased proliferation compared to other SMCs (p<0.01 vs MFS CNC and control SHF) which was reversed to the same level as control SHF (p=0.132) with GLPG0187 treatment.

Conclusions:
The integrin-FAK-Akt
Thr308
signaling pathway is activated in iPSC SMCs from MFS patients specifically from the SHF lineage, which is further exacerbated by TGF-β. Mechanistically, this pathway promotes SMC proliferation
in vitro
. ITGAV blockade via GLPG0187 may be a promising therapeutic approach for MFS aneurysmal growth.
Abstract 10828: Stem-Cell Therapy for Abdominal Aortic Aneurysms in Swine
Authors: Zilberman Brian , Ghobrial Gaby , Emery Robert , De Leo Nicholas , Zhu Clara , Platoff Rebecca , Zhang Ping , Ostrovsky Olga , Hunter Krystal , Krishnadoss Vaishali , Iman Noshadi , Brown Spencer , Carpenter Jeffrey P
Published: March 2022

Introduction:
The current treatment paradigm of abdominal aortic aneurysms (AAA) focuses on observing patients until their disease reaches certain thresholds for intervention, with no preceding treatment available. There is an opportunity to develop drug or cell-based therapies to prevent further aneurysmal growth and decrease the risk of a highly morbid rupture. A previously validated acute AAA swine model was treated directly with gelfoam containing human adipose-derived stem cells (h-ADSCs).

Methods:
Male Yorkshire swine (n=16) received periadventitial injections (type 1 collagenase and porcine pancreatic elastase) into a 4 cm segment of infrarenal aorta. Experimental group (n=7) received gel foam soaked with 10 million h-ADSCs and control group (n=9) media-soaked gel foam. Aortic diameters (AD) were monitored at post-operative day (POD) 7 and 14 using ultrasound with euthanasia on POD 21. Suprarenal (control) and infrarenal aortas (experimental) were harvested for PCR, mechanical tensiometry testing, histopathological analyses as well as immunohistochemistry (IHC). Each animal served as their own control. Groups were compared with paired t-tests and Mann Whitney U tests.

Results:
Twelve animals survived until POD 21. Stem cell treated AAAs, unlike controls, demonstrated no growth (-1.6 ± 8.8% vs. 34.8 ± 13.7%, p<0.001), and had greater medial thickness (682.7 ± 149.1 um vs. 321.7 ± 194.0 um, p<0.001), and greater areas of elastin (5.33 ± 1.49% vs. 2.57 ± 2.25%, p<0.0001), smooth muscle (55.8 ±6.59% vs. 24.0 ± 6.84%, p<0.001), collagen 1 (p=.014), and VEGF (p=.009) than untreated controls. MMP9 mRNA expression in stem cell AAA specimens was downregulated 0.501 (±0.464) fold compared to control segments from those same animals (p= 0.025). Though tensiometry data displayed greater strength within the stem cell AAA rings, this did not reach statistical significance (p=.15).

Conclusion:
Stem cell therapy prevents the development of aortic aneurysms in a swine model. Stem cell treated swine with induced AAAs show more normal gross features, histologic, and biochemical properties compared to untreated controls with induced AAAs. Further investigation is merited as a possible translatable therapy for aneurysmal disease.
Abstract 10833: 30-Day Readmissions After Primary Percutaneous Coronary Intervention in Nonagenarians: A Nationwide Analysis from the United States
Authors: Ismayl Mahmoud , Machanahalli Balakrishna Akshay , Walters Ryan , Pajjuru Venkata Siva Kumar , Aboeata Ahmed S
Published: March 2022

Objective:
To assess 30-day readmission rates and mortality at readmission in nonagenarians following primary percutaneous coronary intervention (pPCI) for ST elevation myocardial infarction (STEMI).

Background:
There is limited contemporary data exploring the 30-day readmission rates and mortality in nonagenarians (age greater than 90 years) with STEMI following pPCI when compared to no pPCI.

Methods:
We utilized the National Readmissions Database (NRD) from 2010 to 2018 to identify nonagenarians hospitalized with STEMI. We divided the total cohort into two groups based on pPCI status. We analyzed 30-day readmission rates, mortality at the time of readmission, and causes of readmissions in both study cohorts.

Results:
Between 2010-2018, an estimated 37,363 STEMI hospitalizations were identified in nonagenarians, of which 12,062 (32.3%) included pPCI and 25,301 (67.7%) had no pPCI. Compared to pPCI cohort, no pPCI had more women (69.8% vs 36.7%), higher elixhauser comorbidity index (13% vs 8%), palliative care consultation (12.6% vs 3.4%), and nursing home placement (48% vs 33.3%) (all p<0.01). Overall, 30-day readmission rates were higher in pPCI cohort compared with no pPCI (22.1% vs 16.2%; p<0.01). However, the in-hospital mortality rates at 30-day readmission were significantly lower in pPCI cohort compared with no pPCI (7.0% vs 14.3%; p<0.01). Heart failure is the most common cause of 30-day readmissions in both cohorts, followed by acute myocardial infarction (MI) and gastrointestinal hemorrhage. Recurrent MI rates were significantly lower in pPCI cohort compared with no pPCI (12.3% vs 18.4%; p<0.01).

Conclusion:
In nonagenarians with STEMI, pPCI during index hospitalization is associated with slightly higher 30-day readmissions but significantly lower mortality at the time of readmission. Given the remarkable mortality benefit with pPCI, further research is necessary to risk stratify and optimize readmission rates following STEMI in nonagenarians.
Abstract 10838: Impact of Diabetes on Soluble Fms-Like Tyrosine Kinase-1 and Cardiovascular Events in Patients with Suspected or Known Coronary Artery Disease: The EXCEED-J Study
Authors: Wada Hiromichi , Shinozaki Tsuyoshi , Suzuki Masahiro , Sakagami Satoru , Funada Junichi , Matsuda Morihiro , Shimizu Masatoshi , Takenaka Takashi , Morita Yukiko , Yonezawa Kazuya , Matsubara Hiromi , Ono Yujiro , Nakamura Toshihiro , Fujimoto Kazuteru , Ninomiya Akiyo , Kato Toru , Unoki Takashi , Takagi Daisuke , Wada Kyohma , Iguchi Moritake , Kotani Kazuhiko , Abe Mitsuru , Akao Masaharu , Hasegawa Koji
Published: March 2022

Background:
Whether diabetes mellitus (DM) modifies the relationship between soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, and cardiovascular (CV) events in patients with suspected or known coronary artery disease (CAD) are unclear.

Methods:
Using data from a multicenter, prospective cohort of 3255 patients with suspected or known CAD undergoing elective coronary angiography, we assessed the impact of DM on the prognostic values of sFlt-1 and other biomarkers. Heparin-free fasting serum levels of sFlt-1, VEGF, placental growth factor, cystatin C, N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), and high-sensitivity C-reactive protein (hs-CRP) were measured in 1281 DM and 1974 non-DM patients enrolled in the EXCEED-J study. The primary outcome was 3-point major adverse CV events (3P-MACE) defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, CV death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization.

Results:
After adjusting for potential clinical confounders, serum levels of sFlt-1, NT-proBNP, hs-cTnI and cystatin C, but not other biomarkers, were significantly associated with 3P-MACE in the entire cohort. These associations were still significant for sFlt-1, NT-proBNP, and hs-cTnI, but not for cystatin C, in non-DM patients. In contrast, NT-proBNP, hs-cTnI and cystatin C, but not sFlt-1, were significantly associated with 3P-MACE in DM patients. The sFlt-1 level was also significantly associated with all-cause death and CV death in the entire cohort and in non-DM patients, but not in DM patients. It was not significantly associated with 5P-MACE in the entire cohort, non-DM patients, or DM patients. Furthermore, sFlt-1 provided an incremental prognostic information for 3P-MACE and CV death to the model with potential clinical confounders in non-DM patients, but not in DM patients.

Conclusions:
Serum levels of sFlt-1 were independently associated with 3P-MACE and CV death in patients with suspected or known CAD. These associations were attenuated in DM patients.
Abstract 10840: Direct Admission versus Inter-Hospital Transfer of Hospitalized Patients with Acute Myocardial Infarction in China: Findings from the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome Project
Authors: Hu Danqing , Hao Yongchen , Liu Jun , Yang Na , Huo Yong , Smith Sidney C , Ge Junbo , Fonarow Gregg , Morgan Louise , Ma Chang-Sheng , Yaling Han , Zhao Dong , Liu Jing ,   CCC-ACS Investigators
Published: March 2022

Introduction:
Although percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for AMI, a substantial proportion of patients initially arrive at non-PCI hospitals. The impact of direct admission to a PCI-capable hospital and inter-hospital transfer on prognosis of AMI with relatively long ischemia time in real-world practice is still debated. We aimed to compare the in-hospital outcomes associated with direct admission versus inter-hospital transfer of hospitalized patients with AMI in China.

Methods:
From November 2014 to December 2019, 94,623 patients with AMI were enrolled from 159 tertiary hospitals and 82 secondary hospitals in 30 provinces in China in the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome (CCC-ACS) Project. Patients were divided into those directly admitted or inter-hospital transferred to a PCI hospital. Associations of direct admission versus inter-hospital transfer with in-hospital major adverse cardiovascular events (MACE) were examined by multivariable Cox regression, propensity score matching (PSM), and inverse probability of treatment weighting (IPTW) analysis.

Results:
Among the 94,623 patients, 53,653 (56.7%) were directly admitted to PCI hospitals, and 40,970 (43.3%) were inter-hospital transferred. Compared with inter-hospital transfer, direct admission was associated with a shorter time from symptom onset to reperfusion (6.0h vs.9.8h for STEMI and 54.4h vs.83.3h for NSTEMI), and higher rates of reperfusion for STEMI (63.4% vs. 50.7%) and timely PCI for NSTEMI (41.1% vs. 34.7%). No significant associations were found between direct admission relative to inter-hospital transfer and the risk of in-hospital MACE in Cox regression (HRs [95%CIs] were 1.17 [0.95-1.42] for STEMI and 0.81 [0.55-1.19] for NSTEMI), in PSM (1.17 [0.94-1.45] for STEMI and 0.79 [0.49-1.27] for NSTEMI), and in IPTW analysis (1.22 [0.95-1.58] for STEMI and 0.87 [0.55-1.37] for NSTEMI).

Conclusions:
There was no significant difference in the risk of in-hospital MACE between directly admitted and transferred patients with AMI in China. Therefore, when direct admission is not feasible, timely transfer to PCI-capable hospitals maybe an alternative in real-world practice.
Abstract 10841: Clinical Significance of Left Atrial Function Estimated by Two Dimensional Speckle Tracking Echocardiography for Diagnosis of Concomitant Transthyretin Amyloid Cardiomyopathy in Patients with Aortic Stenosis
Authors: Oike Fumi , Usuku Hiroki , Yamamoto Eiichiro , Takashio Seiji , Ishii Masanobu , Sueta Daisuke , Hanatani Shinsuke , Araki Satoshi , Soejima Hirofumi , Matsushita Kenichi , Tsujita Kenichi
Published: March 2022

Background:
Aortic stenosis (AS) and transthyretin amyloid cardiomyopathy (ATTR-CM) are common in the elderly. We evaluated the usefulness of two-dimensional (2D) speckle strain imaging to diagnose concomitant ATTR-CM in patients with AS.

Methods and Results:
We analyzed 72 consecutive patients with moderate to severe AS who underwent
99m
Tc-pyrophosphate (PYP) scintigraphy, a useful modality for diagnosis of ATTR-CM, at Kumamoto University Hospital from January 2012 to September 2020. There were no significant differences in the baseline clinical characteristics or conventional echocardiographic findings between the
99m
Tc-PYP scintigraphy-positive and -negative groups. In 2D speckle strain imaging of the left ventricle, the relative apical longitudinal strain (LS) index [apical LS/ (basal LS + mid LS)] was significantly higher in the
99m
Tc-PYP scintigraphy-positive than -negative group (p<0.05). In 2D speckle strain imaging of the left atrium (LA), the peak longitudinal strain rate (LSR) and the late LSR were significantly lower in the
99m
Tc-PYP scintigraphy-positive than -negative group (peak LSR:0.36±0.14 vs. 0.55±0.20, p<0.05 and late LSR:0.26±0.25 vs. 0.52±0.29, p<0.05, respectively). In the receiver-operating-characteristic analysis, the peak LSR in the LA was the most effective echocardiographic parameter for
99m
Tc-PYP scintigraphy positivity (area-under-the-curve, 0.79). Multivariable logistic analysis using two forced inclusion models identified the peak LSR in the LA was more significant factor of
99m
Tc-PYP scintigraphy positivity in patients with AS.

Conclusion:
The peak LSR in the LA may be a useful predictor of the presence of ATTR-CM in patients with AS.
Abstract 10850: Investigating the Role of a Cardiac Enhancer in the Development of Heart Failure
Authors: Htet Myo , Arvanitis Marios , Lin Brian , Gangrade Harshi , Tampakakis Emmanouil
Published: March 2022

Introduction:
Alpha actinin-2 (ACTN2) is a major cytoskeletal protein that plays a critical role in maintaining the structural and functional integrity of the sarcomere.
ACTN2
mutations, although rare, have been shown to be associated with various types of cardiomyopathy. Using genome-wide association and multi-omic approaches, we recently identified non-coding variants that showed a strong association with heart failure (HF). Two of the variants are within an evolutionary conserved transcriptional enhancer region that regulates the
ACTN2
gene in human stem cell derived cardiomyocytes (hPSC-CMs). However, the role of cardiac enhancers in the development of HF remains unknown, therefore we used engineered heart tissues (EHT) from hPSC-CMs to investigate the effects of the ACTN2 enhancer.

Methods:
We used hPSC-CMs and performed morphologic and functional analyses by immunostaining, calcium transient measurements and quantitative assays such as western blotting, proteomics, qPCR and single cell transcriptomics. Next, we utilized CRISPR interference (CRISPRi) and chromatin immunoprecipitation (ChIP) to analyze the transcriptional regulation of the
ACTN2
enhancer. Finally, we measured force generation using EHTs.

Results:
We first engineered hPSC-CMs carrying an
ACTN2
enhancer deletion. This resulted in decreased
ACTN2
gene and protein expression, and cardiomyocytes developed myofibrillar disarray, hypertrophy, lower beating rates and suppressed calcium transients. Moreover, EHTs demonstrated reduced mechanical force. Using CRISPRi and ChIP we found that the transcription factor MEF2c binds a short DNA sequence containing an enhancer variant to regulate
ACTN2
expression. Single cell RNA-Seq analysis of hPSC-CMs treated with isoproterenol to model the hyperadrenergic state observed in HF, revealed the induction of pathways involved in protein quality control, actin fragmentation and apoptosis. We have also recently developed a mouse model to address the effect of the enhancer
in vivo
.

Conclusions:
Our study confirms that a conserved and clinically relevant enhancer region can effectively regulate
ACTN2
, and variants within that region can have detrimental consequences on CMs which can contribute to HF.
Abstract 10853: Emergency Activations for Chest Pain and Ventricular Arrhythmias Related to Regional Covid-19 Across the US
Authors: Aung Sidney , Vittinghoff Eric , nah gregory , Lin Anthony , Joyce Sean , Mann N. Clay , Marcus Gregory M
Published: March 2022

Introduction:
Localized studies have reported a decline in myocardial infarctions during the coronavirus disease 2019 (COVID-19) pandemic. The mechanisms underlying these observations remain unknown, but evidence that patients may avoid healthcare facilities for fear of COVID-19 infection has heightened concern that true rates of myocardial infarctions have been under-ascertained and left untreated.

Methods:
We analyzed data from the National Emergency Medical Services Information System (NEMSIS) and incident COVID-19 infections across the United States between January 1, 2020 to April 30, 2020. Grouping events by US Census Division, multivariable adjusted negative binomial regression models were utilized to estimate the relationship between COVID-19 and EMS activations for chest pain, non-ST-elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI), cardiac arrests, and ventricular arrhythmias.

Results:
After multivariable adjustment, increasing rates of COVID-19 were associated with a reduction in EMS activations for chest pain (RR 0.67, 95% CI 0.63-0.70, p < 0.001) and NSTEMIs (RR 0.16, 95% CI, 0.10-0.26; p < 0.001). Simultaneously, increasing COVID-19 was associated with a significant increase in EMS activations for cardiac arrests (RR 1.51, 95% CI 1.36-1.68, p < 0.001), ventricular fibrillation (RR 1.47, 95% CI 1.23-1.77, p < 0.001), and ventricular tachycardia (VT) episodes (RR 1.34, 95% CI 1.16-1.56, p < 0.001). These statistically significant relationships were consistently observed within each of the 9 US Census Divisions alone.

Conclusions:
Taken together, these data suggest that individuals are commonly delaying or avoiding care for myocardial infarction in areas with more COVID-19, leading to lethal consequences. Interventions aimed at reinforcing the need to seek appropriate care for suspected myocardial infarctions, even in the context of heightened infectious disease risks, should be pursued.
Abstract 10860: Cardiotoxicity as an Adverse Effect of Immunomodulatory Drugs and Proteasome Inhibitors in Multiple Myeloma: A Meta-Analysis of Randomized Clinical Trials
Authors: Das Avash , Roy Bhaskar , Dasgupta Subhajit , Gong Yan , Shah Urvi A , Cheng Richard K , Fradley Michael G , Guha Avirup
Published: March 2022

Introduction:
Combination therapy of Immunomodulatory drugs (iMiDs) (Thalidomide, Lenalidomide, Pomalidomide) and Proteasome Inhibitors (PIs) (Bortezomib, Carfilzomib, Ixazomib) constitutes the backbone of treatment in MM patients. Cardiotoxic side-effect profile of iMiDs is not well-documented. Although Carfilzomib has been associated with cardiotoxicity, whether its adverse effects also mirror the class-specific cardiotoxic profile of PI remain obscure. Proper assessment of cardiotoxicity due to treatment reagents is necessary for optimal patient management. In this pairwise meta-analysis, we explored direct cardiotoxicity with iMiDs and PIs use in patients with multiple myeloma (MM).

Hypothesis:
Treatment with iMiDs and PIs in MM patients leads to independent cardiotoxicity that is associated with individual class of drugs.

Methods:
Published randomized control trials (RCTs) were searched up to May 2021 reporting cardiotoxicity (cumulative reported events of ischemia, arrhythmia, failure, stenosis) in MM patients (newly diagnoses and/or relapsed) treated with iMiD and/or PI. Studies, where iMiD or PI were used atop the chemotherapy vs placebo or no additional drugs (control) in the other arm, were included. The primary outcome was presence of cardiotoxicity after follow-up. Meta-analysis was performed using frequentist’s approach to estimate odds ratio (OR).

Results:
Eighteen RCTs including 8,479 MM patients were included in this analysis. Eleven studies compared iMiDs and seven studies compared PIs with control. CTACE high-grade (≥ grade 3) cardiotoxic events were increased with iMiDs in comparison to their control counterpart (OR 2.05; 95% CI 1.30-3.26). Cardiotoxicity was also noted more frequently with PI use when compared to the control group (OR 1.47; 95% CI 1.19-1.82). Similar difference was observed between high-grade cardiotoxic complication between these groups. There was no evidence of publication bias among studies.

Conclusions:
Our results showed iMiDs and PIs are independently associated with cardiotoxicity, which may warrant increased awareness among treating physicians and close monitoring of patients. The adverse cardiac event profile with these drugs require further investigation in future studies.
Abstract 10865: Elucidating the Variant-to-Function Relationship for LIPA, a Risk Locus of Coronary Artery Diseases
Authors: Li Fang , Flynn Elise , Xue Chenyi , Meng Yujiao , Wang Ziyi , Wu Xun , Li Sufang , Cui Jian , Shi Jianting , Chirikjian Margot K. , Zhu Yizhou , Rozenblyum Annie , Shan Sophie , Razani Babak , Westerterp Marit , Bauer Robert , Jin Fulai , Suh Yousin , Lappalainen Tuuli , Zhang Hanrui
Published: March 2022

Introduction:
Genome-wide association studies revealed a robust association between genetic variants at the
LIPA
(lysosomal acid lipase) locus and coronary artery diseases (CAD). eQTL studies support that the risk alleles of
LIPA
CAD variants are associated with higher LIPA mRNA and enzyme activity in human monocytes, but not other blood or vascular cells, suggesting that increased myeloid
LIPA
may confer CAD risk. Herein, we aim to establish the causality of the variant-to-function relationship for the
LIPA
locus and elucidate how increased myeloid
LIPA
impact atherosclerosis in vivo.

Hypothesis:
We hypothesized that causal variants in
LIPA
lead to increased
LIPA
expression and enzyme activity in macrophages and myeloid-specific overexpression of
Lipa
promotes atherosclerosis.

Results:
We first confirmed that in human monocyte-derived macrophages, LIPA mRNA, protein and enzyme activity are higher in the risk allele carriers of CAD variants. High-resolution HiC revealed an intronic enhancer region showing strong interaction with the
LIPA
promoter. Within the enhancer region, both rs1320496 and rs1412445 had independent association with CAD and their risk alleles led to increased enhancer activity measured by luciferase assay. Risk allele of rs1320496 also demonstrated increased binding for PU.1, a myeloid-specific transcription factor. To establish how increased myeloid
LIPA
impact atherosclerosis, we generated myeloid-specific
Lipa
overexpression mice (

Lipa
Tg
, Ldlr

-/-
).

Lipa
Tg

significantly increased atherosclerotic lesion size without affecting plasma cholesterol level. scRNA-seq analysis showed that

Lipa
Tg

led to reduced lipid-enriched yet increased inflammatory macrophage subsets, and upregulation of genes in chemokine signaling. This is further confirmed by reduced neutral lipid accumulation in both plaque and peritoneal macrophages in

Lipa
Tg

mice. Mechanistically,

Lipa
Tg

led to reduced expression of modified-LDL receptors, increased expression of inflammatory chemokines, and increased circulating IL18 and CXCL2 that likely drive immune cells infiltration during atherosclerosis.

Conclusions:
We for the first time established that
LIPA
risks alleles drive increased myeloid
LIPA
and aggravate atherosclerosis.