bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15630: Direct Renin Inhibition With Aliskiren Improves Ischemia-Induced Neovascularization
Authors: Desjarlais Michel , Dussault Sylvie , Dhahri Wahiba , Rivard Alain
Published: July 2021

Background:
The activation of the renin-angiotensin system is associated with impaired formation of new blood vessels (neovascularization) in response to ischemia. Aliskiren is the only direct renin inhibitor that is clinically used as an orally active antihypertensive drug. Here we tested the hypothesis that aliskiren might improve neovascularization following ischemia.

Methods and Results:
C57BL/6 mice were treated with a high dose of aliskiren (50 mg/kg), a low dose of aliskiren (10 mg/kg), or drinking water only. After two weeks of treatment, hindlimb ischemia was surgically induced by femoral artery removal. Treatment with aliskiren led to a significantly faster rate of blood flow recovery after hindlimb ischemia (Laser Doppler). Interestingly the lower dose of aliskiren, which did not reduce blood pressure, provided similar improvement of blood flow recuperation compared to the higher dose of aliskiren. At day 21 after surgery, Doppler flow ratios were significantly improved in mice treated with aliskiren (0.69+/-0.07 vs. 0.52+/-0.03; p<0.05). This was associated with an increased expression of angiogenic factors in ischemic muscles, including VEGF and eNOS. Endothelial progenitor cells (EPCs) have been shown to have an important role in postnatal neovascularisation. We found that aliskiren significantly increased the number of bone marrow EPCs at day 7 after ischemia (172+/-7% increase; p<0.05). Moreover, the adhesive properties of EPCs were significantly improved in mice treated with aliskiren (175+/-5% increase; p<0.05). In vitro, aliskiren improves cellular migration and tubule formation in HUVECs. This is associated with an increased expression of nitric oxide (DAF staining), and a significant reduction of oxidative stress levels (DHE staining). Importantly, the antioxidant and angiogenic properties of aliskiren in HUVECs are abolished following treatment with the NOS inhibitor L-NAME.

Conclusions:
Direct renin inhibition with aliskiren leads to improved ischemia-induced neovascularization that is not dependant on blood pressure lowering. The mechanisms involve beneficial effects of aliskiren on NO and angiogenic pathways in ischemic tissues, together with an increase in the number and the functional activity of EPCs.
Abstract 15650: Nutritional Support With Medium Chain Fatty Acids During Extracorporeal Membrane Oxygenation in Infant Swine Model
Authors: Kajimoto Masaki , Ledee Dolena R , Isern Nancy G , Des Rosiers Christine , Portman Michael A
Published: July 2021

Background:
Extracorporeal membrane oxygenation (ECMO) is the most frequently used mechanical circulatory support in children with cardiopulmonary failure. Nutritional energy support as well as inotropic support is important to recover cardiac function during ECMO. Fatty acids (FAs) are major myocardial energy source for citric acid cycle (CAC). Medium-chain FAs (MCFAs) are easily uptaken into cell and mitochondria without membrane transporters. Our previous animal study suggested that MCFAs can potentially use for myocardial energy metabolism as the best accessible substrates during ECMO. Even-numbered MCFAs enter into CAC via acetyl-CoA, while odd-numbered MCFAs are anaplerotic for the CAC as propionyl-CoA in addition to acetyl-CoA. This study assessed whether odd- or even-numbered MCFAs product efficient energy during a short-term ECMO.

Methods:
Fifteen male Yorkshire pigs (26-45 days old) with 8-hour ECMO were received either normal saline, heptanoate (odd-numbered MCFA) or octanoate (even-numbered MCFA) at 2.3 μmol/kg body wt/min as MCFAs systemically during ECMO (n = 5 per group). The 13-Carbon (
13
C) labeled substrates ([2-
13
C]lactate, [5,6,7-
13
C
3
]heptanoate and [U-
13
C
6
]leucine) as metabolic markers were infused into coronary artery for the final hour before left ventricular tissue extraction. Extracted left ventricular tissues were analyzed for the
13
C-labeled and absolute concentrations of metabolites by nuclear magnetic resonance and gas chromatography-mass spectrometry.

Results:
There were no adverse events in any groups during experiments. Octanoate produced markedly high citrate concentration, indicating the conjugation of CAC, and led to high [ATP]/[ADP] ratio compared with other groups (6.2 ± 0.6, 6.0 ± 0.6 and 7.8 ± 0.5 in normal saline, heptanoate and octanoate, P < 0.05). Octanoate strongly increased the CAC metabolism through anaplerotic pathway from propionyl-CoA, but not heptanoate. Lactate oxidation and protein synthesis ratio from leucine were not different among 3 groups.

Conclusions:
Even-numbered MCFAs was superior energy source for CAC than odd-numbered MCFAs in normal heart supported with ECMO. These results support that nutritional therapy with even-numbered MCFAs facilitates weaning from ECMO.
Abstract 15675: Bone Marrow Derived Ixmyelocel-T From Patients With Severe Ischemic Dilated Cardiomyopathy Display Robust Anti-Inflammatory and Pro-Angiogenic Properties
Authors: Ledford Kelly J , Remmers Ann E , Tubo Ross
Published: July 2021

Ixmyelocel-T, an expanded autologous multicellular therapy cultured from BMMNCs consisting of regenerative MSCs and M2-like macrophages, has shown clinical promise in the treatment of ischemic DCM. However the quality of BM-derived cell therapies from patients with severe heart failure is unclear as reports suggest they are dysfunctional due to advanced age and the systemic disease state. We hypothesized that ixmyelocel-T generated from ischemic DCM patients BMMNCs would consist of expanded MSCs and M2 macrophages, and produce anti-inflammatory and angiogenic factors useful for cardiac repair.

BMMNCs were obtained from 55-80 year old ischemic DCM patients, with LVEF < 35% and NYHA Class III or IV, enrolled in the phase 2b clinical IXCELL-DCM trial. The BMMNCs were either used in experiments or expanded in a closed bioreactor system for 12 days to generate ixmyelocel-T (n = 13). FACS revealed a 50 ± 5% fold expansion in CD90+ MSC and a 96 ± 39% fold expansion in CD14+ M2-like macrophages in ixmyelocel-T. Cytokine arrays revealed ixmyelocel-T secreted more regulatory and trophic factors compared to BMMNCs. Specifically, ixmyelocel-T secreted significantly more Flt-3L, GM-CSF, IL-10, IL-13, IL-1ra, IL-2, IL-3, IL-5, MCP-1, CCL18, TGF-β, angiopoietin-2, IL-8, TIMP-1, TIMP-2, and VEGF compared to BMMNCs. ELISA analysis confirmed that ixmyelocel-T secreted significantly higher levels of IL-10 (2092 ± 183 vs 130 ± 17 pg/mL, p < 0.001) and IL-1ra (12241 ± 2806 vs 1857 ± 564, p < 0.001) after LPS challenge. Ixmyelocel-T had higher gene expression of the anti-inflammatory and pro-angiogenic markers HMOX1, CCL18, FGF2, IGF1, PGF, SDF-1α, Ang-1, Ang-2 and lower levels of the pro-inflammatory markers TNFα, IL-1β, IFN[[Unable to Display Character: ɣ]], IL-12 compared to BMMNCs after LPS challenge. Additionally, co-culture of ixmyelocel-T with HUVECs resulted in significant wound healing in an in vitro scratch assay compared to BMMNCs (56 ± 4 vs 39 ± 8%, p < 0.001).

This data suggests that the process used to generate ixmyelocel-T is ideal for the therapeutic expansion of BMMNCs from patients with severe cardiac diseases. Ixmyelocel-T retains a regenerative, anti-inflammatory, and pro-angiogenic profile which holds promise for treatment in advanced cardiac diseases where treatment options are limited.
Abstract 15680: Sinus Node Dysfunction in Associated With Higher Symptom Burden and Increased Risk of Progression to Permanent Atrial Fibrillation: Results From ORBIT-AF Registry
Authors: Jackson Larry R , Kim Sung Hee , Piccini Jonathan P , Gersh Bernard J , Naccarelli Gerald V , Reiffel James A , Freeman James , Thomas Laine , Chang Paul , Fonarow Gregg C , Go Alan S , Mahaffey Kenneth W , Peterson Eric D , Kowey Peter R
Published: July 2021

Background:
Patients with sinus node dysfunction (SND) are at increased risk of atrial tachyarrhythmias, including atrial fibrillation (AF). Whether the presence of SND is also associated with worse outcomes among those with AF has not been well described.

Methods:
The ORBIT-AF registry enrolled patients with AF from a range of clinical practices across the US. SND was defined clinically, based on the presence of sinus bradycardia, severe sinus bradycardia, sinus arrest, sinoatrial exit block, or features of tachycardia-bradycardia syndrome. Descriptive statistics and multivariable logistic regression analysis were used to describe treatment patterns and outcomes for patients with and without SND and AF.

Results:
Overall, 1,710 (17.7%) patients had SND at enrollment. Patients with SND had lower left-ventricular ejection fractions, higher CHA
2
DS
2
-VASc risk scores, and more prior cerebrovascular events. Patients with SND had more severe symptoms (EHRA class IV: 17.5% vs. 13.9%; p=0.007) and poorer quality of life (median AFEQT 77.5 vs. 81.1; p=0.008) as compared to those without. SND patients were more frequently treated with oral anticoagulants (79.2% vs. 75.9%, p=0.004) and had more often received interventional therapy for AF (16.1% vs. 10.5%, p<0.0001). There were no differences in the current AF management strategy between patients with SND and those without [rate control (69.7% vs. 67.7%), rhythm control (30.0% vs. 32.0%); P=0.11]. After adjustment, significantly more patients with SND had progressed from paroxysmal AF at baseline to persistent or permanent AF at any follow-up or persistent AF at baseline to permanent AF at any follow-up than those without (OR 1.23, 95% CI 1.01-1.49, p=0.035).

Conclusion:
Sinus node dysfunction is associated worse symptoms, lower quality of life, and higher risk of progression to permanent AF. However, SND is not associated with increased risk of all-cause hospitalization, incident stroke, or all-cause death.
Abstract 15687: Loss of Tribbles 3 (TRIB3) Attenuates Pressure-Overload Induced Myocardial Hypertrophy
Authors: Abdelwahid Eltyeb , Wu Rongxue , Rines Amy K , Ardehali Hossein
Published: July 2021

Introduction:
Tribbles 3 (TRIB3) is a pseudokinase that regulates several biological functions such as cell proliferation and differentiation through its role in cellular metabolism. TRIB3 expression is modulated by various signals such as endoplasmic reticulum (ER) stress, nutrient availability, and insulin. The exact function of TRIB3 in the heart is largely unknown. We hypothesized that loss of TRIB3 protects against cardiac hypertrophy through its role in the regulation of cellular metabolism.

Results:
To elucidate the role of TRIB3 loss in the heart, we generated TRIB3 knock-out (KO) mice. The animals were then subjected to transverse aortic constriction (TAC) and sham-surgery control. In the sham operation groups, there was no hypertrophy in both TRIB3-/- and Wild type (WT) age matched control mice. WT mice subjected to TAC (WT-TAC) showed cardiac hypertrophy evidenced by increased heart weight/body weight, increased left ventricular wall thickness and increased cardiomyocyte cross-sectional area. These hypertrophic findings were significantly reduced in TRIB3 KO-TAC hearts (P<0.05). Echocardiographic analysis revealed increased diastolic interventricular septum wall (IVSd), increased left ventricular wall posterior wall thickness (LVPWd) and decreased fractional shortening (FS) in WT-TAC mice, however these changes were significantly blocked in TRIB3 KO-TAC group suggesting that TAC-induced left ventricular hypertrophy and dysfunction was attenuated in TRIB3 KO mice (P<0.05). The blunted response to hypertrophy seen in TRIB3 KO-TAC group was further demonstrated by the significant decrease in mRNA expression of myocardial hypertrophic markers (ANP, BNP and MHC) in TRIB3 KO-TAC hypertrophied left ventricles compared to WT-TAC control subjects (P<0.05). Furthermore, our data indicated increased TRIB3 expression in the WT-TAC hypertrophied left ventricles compared to WT-Sham group (P<0.05).

Conclusions:
The present study demonstrated that TRIB3 expression is promoted in hypertrophied hearts. TRIB3 deletion suppresses cardiac pressure overload-induced hypertrophy. Thus, TRIB3 is a novel target that plays a role in cardiac hypertrophy and maladaptation following pressure overload.
Abstract 15714: Prediction of Sudden Cardiac Death With Automated High-Throughput Analysis of T-Wave Heterogeneity in Standard 12-Lead Electrocardiogram
Authors: Kenttä Tuomas , Nearing Bruce D , Porthan Kimmo , Tikkanen Jani T , Viitasalo Matti , Nieminen Markku S , Salomaa Veikko , Oikarinen Lasse , Huikuri Heikki V , Verrier Richard L
Published: July 2021

Introduction:
Noninvasive identification of patients at risk for sudden cardiac death (SCD) remains a major clinical challenge. Abnormal ventricular repolarization is associated with increased risk of lethal ventricular arrhythmias and SCD.

Hypothesis:
We investigated the hypothesis that spatial repolarization heterogeneity can identify patients at risk for SCD in general population.

Methods:
Spatial R-, J- and T-wave heterogeneities (RWH, JWH and TWH, respectively) were automatically analyzed with second central moment technique from standard digital 12-lead ECGs in 5618 adults (46% men; age 50.9±12.5 yrs.) who took part in Health 2000 Study, an epidemiological survey representative of the entire Finnish adult population. During average follow-up of 7.7±1.4 years, a total of 72 SCDs occurred. Thresholds of RWH, JWH and TWH were based on optimal cutoff points from ROC curves.

Results:
Increased RWH, JWH and TWH (Fig.1) in left precordial leads (V4-V6) were univariately associated with SCD (P<0.001, each). When adjusted with clinical risk markers (age, gender, BMI, systolic blood pressure, cholesterol, heart rate, left ventricular hypertrophy, QRS duration, arterial hypertension, diabetes, coronary heart disease and previous myocardial infarction) JWH and TWH remained as independent predictors of SCD. Increased TWH (≥102μV) was associated with a 1.9-fold adjusted relative risk (95% confidence interval [CI]: 1.2 - 3.1; P=0.011) and increased JWH (≥123μV) with a 2.0-fold adjusted relative risk for SCD (95% CI: 1.2 - 3.3; P=0.004). When both TWH and JWH were above threshold, the adjusted relative risk for SCD was 3.2-fold (95% CI: 1.7 - 6.2; P<0.001). When all heterogeneity measures (RWH, JWH and TWH) were above threshold, the risk for SCD was 3.7-fold (95% CI: 1.6 - 8.6; P=0.003).

Conclusions:
Automated measurement of spatial J- and T-wave heterogeneity enables analysis of high patient volumes and is able to stratify SCD risk in general population.
Abstract 15721: Coronary Artery Calcium Scoring Effectively Stratifies Long-Term Mortality Risk in Smokers and Non-Smokers
Authors: Lebeis Taylor A , Sandesara Pratik , Knapper Joseph , Blaha Michael J , Berman Daniel S , Quyyumi Arshed , Budoff Matthew J , Min James K , Giambrone Ashley E , Callister Tracy Q , Shaw Leslee J
Published: July 2021

Background:
Cigarette smoking is a known risk factor for coronary heart disease (CHD). Studies have shown earlier onset and higher burden of coronary artery calcium (CAC) in smokers compared to non-smokers. However, little long-term follow-up data exists on the potential interaction between cigarette smoking and CAC for the prediction of important clinical outcomes.

Hypothesis:
In the setting of cigarette smoking, CAC scoring should accurately predict clinical outcomes.

Methods:
A total of 9,785 (mean age 53±10 years) consecutive asymptomatic individuals, free of known CHD, underwent computed tomography to estimate CAC for cardiovascular risk assessment. CHD risk factors were prospectively obtained by patient interview. Unadjusted and risk-factor adjusted Cox proportional hazard modeling was used to estimate time to all-cause mortality (mean follow-up=13.7 years) by CAC subsets.

Results:
3,833 patients (39.2%) were current smokers. Smokers were less likely than non-smokers to have a CAC score of 0 (42.7% vs 54.3%). For smokers and non-smokers, survival rates ranged from 60 to 94% and 73 to 97% by CAC subsets, respectively (see Figure, p<0.0001). Compared to CAC=0, adjusted hazard ratios for CAC scores of 1-10, 11-100, 101-399, 400-999, and ≤ 1000 were 1.8, 2.3, 2.7, 4.1, and 5.4 (p<0.0001) among smokers; and 1.4, 2.2, 4.1, 5.6, and 7.6 among non-smokers (interaction p<0.0001). Higher adjusted mortality was observed for CAC scores <400 among smokers as compared to non-smokers. The relative hazards for CAC scores of 400-999 (p=0.052) and ≥1,000 (p=0.14) were similar by smoking status.

Conclusion:
CAC scoring effectively stratifies long-term all-cause mortality risk in both smokers and non-smokers. However, smokers are at substantially higher risk and excess mortality is noted for smoking patients with CAC scores <400. High risk CAC scores of 400 or higher carry a high mortality hazard for smokers and non-smokers.
Abstract 15759: Arrhythmic Risk Stratification in Patients With Idiopathic Dilated Cardiomyopathy and No Conventional Indications for Implantable Cardiac Defibrillator
Authors: Merlo Marco , Pirozzi Fabrizio , Stolfo Davide , Gianluca D’Angelo , Alonge Marco , Gigli Marta , Barbati Giulia , Zecchin Massimo , Sinagra Gianfranco
Published: July 2021

Background:
Primary prevention of major ventricular arrhythmias (MVA) in patients with idiopathic dilated cardiomyopathy (IDCM) is primarily based on left ventricular ejection fraction (LVEF) assessment. Nonetheless, unexpected MVA still affect patients considered at low-risk (LR), attesting the limitation of the current risk stratification.

We sought to identify the clinical predictors of MVA in patients with IDCM and no conventional indications for implantable cardioverter defibrillator (ICD).

Methods:
In this retrospective, case-control study, among 922 patients enrolled in the Heart Muscle Disease Registry of Trieste from 1988 to 2013, we analyzed 414 IDCM patients considered at LR according to the following criteria: LVEF≥36% and no previous episodes of MVA (sustained ventricular tachycardia/non-fatal ventricular fibrillation (SVT/VF), appropriate ICD intervention and sudden cardiac death (SD)). Data were recorded at the last available medical examination before the index event. Patients were optimally treated at the time of index evaluation (87% and 84% of ACE-inhibitors/sartans and beta-blockers, respectively).

Results:
Over a median follow-up of 43 (IQR 16-116) months, 45 patients (11 % of patients at LR; 31% of the all MVA in whole IDCM population) experienced MVA. The mean age at the time of event was 51±14 years. They were characterized by a previous history of syncope in 10 patients (22%), LVEF of 42±6% with a normal value (>50%) in 10 patients (22%), significant LV dilation (VTDi>90ml/m
2
) in 16 patients (35%) and left bundle branch block 12 patients (27%). Independent risk factors for MVA in LR subgroup were previous history of syncope (OR 3.41, 1.45-8.03, p=0.004), larger left ventricular dilation (OR 2.62, 1.72-3.99, p<0.0001) and longer duration of disease (OR 1.39, 1.42-2.63, p<0.0001).

Conclusions:
in a large cohort of IDCM patients nearly one-third of the MVA occurred in a population apparently at LR of events. History of syncope, larger LV dilatation and significant duration of disease emerged as strong predictors of MVA and should be considered in the arrhythmic risk stratification of patients without conventional criteria for SD primary protection.
Abstract 15776: Determination of Maximum Isotherm to Achieve Conduction Block During Cryoablation
Authors: Kaszala Karoly , Huizar Jose F , Tan Alex , Ellenbogen Kenneth A
Published: July 2021

Introduction:
Thermal characteristics of cryoablation to achieve myocardial conduction block is not well understood. In this study we evaluated the maximum isotherm during cryoablation to achieve conduction block.

Methods:
Anesthetized, ventilated canines (n=9) underwent thoracotomy. In in-situ RV outflow tract, blind alley (BA) that conducted to and from the RV only via an isthmus (IS) was created by cut and sew method by making a surgical incision. Cryoablation (7Fr, 8 mm tip FreezorMax3, Medtronic) was performed (4 -6 min per lesion) from the endocardium at the IS. Epicardial temperature was monitored by a thermal camera (FLIR, Danderyd, Sweden). Conduction block was assessed by pacing and recording from inside the BA and from the LV. Acute and chronic block was defined as bidirectional block through the IS at 15 min and 180 min, respectively. Ablation was continued until acute block was achieved and observation continued for 180 min.

Results:
Ten preparations were studied. Acute block was achieved in all preparations. IS temperature was ≤ -10C in all samples with chronic block (4/8, p=0.028) and >-10C without chronic block (4/8). Chronic block was not assessed in two due to delay in achieving acute block. Ablation data is summarized in the Table.

Conclusion:
We presented a novel in-vivo large animal model that allows in-situ assessment of temperature changes and conduction. Tissue cooling below -10C is required during cryoablation to achieve prolonged (180 min) conduction block.
Abstract 15777: Association Between Sleep Disordered Breathing, Obstructive Sleep Apnea and Incident Cancer: A Systematic Review and Meta-Analysis
Authors: Palamaner Subash Shantha Ghanshyam , Kumar Anita A , Cheskin Lawrence J , Pancholy Samir B
Published: July 2021

Introduction:
Sleep disordered breathing (SDB) and obstructive sleep apnea (OSA) increase risk for multiple morbidities such as cardiovascular events, diabetes mellitus, and hypertension. Association between SDB and incident cancer is unclear and studies that assessed this association have yielded conflicting results.

Hypothesis:
We systematically reviewed the literature and pooled available evidence that has associated SDP and incident cancer.

Methods:
Medline, Embase, Cochrane central library, and electronic databases were searched for relevant studies. Studies were included if: 1) they studied patients with SDB, and 2) reported rates of incident cancer. We excluded studies that reported cancers involving head and neck as we suspected reverse causation, since head and neck cancers can lead to SDP. Data were pooled using a random-effects model.

Results:
From 3522 retrieved citations, 7 observational studies were included in the review. Of these, 4 studies, representing 48,152 patients with SDB and 87,849 patients without SDB, were included in the meta-analysis. In total 6931 incident cancer cases were reported (2813 in SDB group and 4118 in non-SDB group). In the pooled analysis, patients with SDB experienced higher odds of incident cancer (OR: 1.30, 95% CI: 1.06 - 1.60, P = 0.01, I
2
: 75%, 4 included studies) compared to those without SDB. Data from 2 studies that assessed patients with OSA, showed that OSA increased risk for incident cancer at 5 years follow-up (OR: 1.90, 95% CI: 1.46 - 2.45, P < 0.001, I
2
: 0%) and 8 years follow-up (OR: 1.54, 95% CI: 1.25 - 1.88, P < 0.001, I
2
: 0%). Also, cancer risk (OR: 1.28, 95% CI: 1.09 - 1.51, P = 0.003, I
2
: 21%, 2 studies) and cancer mortality (OR: 1.84, 95% CI: 1.32 - 2.56, P = 0.003, I
2
: 0%, 2 studies) was significant only in patients with severe OSA [apnea-hypopnea index (AHI) > 30] and not in patients with mild to moderate OSA (AHI < 30). Factors namely; obesity, type of cancer, age and gender did not account for between study heterogeneity.

Conclusions:
SDB and OSA are associated with incident cancer. Though our study did not support the role of obesity in this association, strong mechanistic link exists, associating SDB, obesity and cancer. Future studies should assess the association between SDB and organ specific cancers.
Abstract 15833: LRP1 is a Novel Receptor of Bmper and Required for Pathological Angiogenesis
Authors: Li Xi , Pi Xinchun
Published: July 2021

Low density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional member of the LDL receptor family, impacting a variety of biological processes such as lipid metabolism, endocytosis and signal transduction. However, the role of LRP1 in endothelium was almost unknown. Until recently we discovered that LRP1 is a novel regulator of bone morphogenetic protein (Bmp) signaling through its association with the extracellular modulator-Bmper (Bmp-binding endothelial cell precursor-derived regulator) and regulates zebrafish vascular development. Here we studied the functional roles of LRP1 in mammalian system by performing cell culture studies with endothelial cells (ECs) and analyzing angiogenic defects in oxygen-induced retinopathy model with LRP1flox/flox;Tie2-Cre+/- mice (EC-LRP1 KO). In MECs, we observed that the activation of Src, ERK and tyrosine phosphorylation of multiple proteins were induced by Bmper and this activation was LRP1-dependent since LRP1 knockdown inhibited their activation. However, this Bmper-induced activation was not blocked by Bmp4 neutralized antibody, which suggests that LRP1 is required for Bmp4-independent signaling for Bmper. These data also indicate that Bmper and LRP1 is a novel ligand receptor pair. Moreover, we observed that LRP1 protein was induced in response to 1% hypoxia in both mouse ECs (MECs) and human retinal microvascular endothelial cells, suggesting that LRP1 is required for hypoxia induced endothelial function. In hypoxia condition, EC-LRP1 KO mice resulted in accelerated angiogenesis in retinal endothelial cells, similar to the pattern of Bmper deleted mice. Therefore, we identify that the Bmper/LRP1 signaling is a novel signaling pathway in endothelial cells and their activity regulates angiogenic responses during oxygen-induced retinopathy. This study provides mechanistic insights for angiogenesis-related pathophysiologic conditions.
Abstract 15850: Desmin Expression is Abnormal in Myofibers of the Gastrocnemius of Patients With Peripheral Arterial Disease and is Associated With Impaired Mitochondrial Respiration and Reduced Muscle Strength
Authors: Koutakis Panagiotis , Casale George P , Kim Julian Kyung-So , Miserlis Dimitrios , Zhu Zhen , Papoutsi Evlampia , Ha Duy M , Swanson Stanley A , Carpenter Lauren A , Myers Sara A , Johanning Jason M , Pipinos Iraklis I
Published: July 2021

Introduction:
Patients with peripheral arterial disease (PAD) develop a myopathy in their ischemic limbs which is characterized by myofiber degeneration, mitochondrial dysfunction and decreased muscle force production. Desmin, a cytoskeletal protein of the myofiber, is central to maintenance of the structure, shape and function of the myofiber and its organelles especially the mitochondria.

Hypothesis:
We hypothesized that desmin expression in myofibers of the gastrocnemius of PAD patients is abnormal and correlates with decreased mitochondrial respiration and reduced muscle strength.

Methods and Results:
We quantified desmin protein and gene transcripts in myofibers of gastrocnemius biopsies from 30 PAD patients and 29 controls and determined their association with myofiber morphology, mitochondrial respiration and calf muscle strength. Compared to control, desmin protein and gene transcripts were increased in myofibers of PAD gastrocnemius. Increased expression was associated with a diffuse appearance of the protein, suggesting a loss of its normally filamentous structure. These changes in desmin correlated with altered myofiber morphology, decreased mitochondrial respiration and reduced calf muscle strength.

Conclusions:
Desmin expression and organization are abnormal in myofibers of the gastrocnemius of patients with PAD and these changes correlate with decreased mitochondrial function and reduced muscle strength.
Abstract 15869: Off-Pump Coronary Artery Bypass Grafting is Associated With Higher Rate of Percutaneous Coronary Intervention at 8-Year Follow-Up
Authors: Barili Fabio , Rosato Stefano , D’Errigo Paola , Parolari Alessandro , Menicanti Lorenzo , Seccareccia Fulvia
Published: July 2021

Introduction:
The debate on the advantages and limitations of off-pump (OPCAB) vs on pump CABG has not still arrived to a conclusion and concerns still exist on graft patency. This study was designed to compare the impact on mortality and morbidity of OPCAB and on-pump CABG, with a specific focus on mid-term need for percutaneous cardiac intervention (PCI).

Methods:
The PRIORITY project was designed to evaluate the mid-long term outcomes of 2 large prospective multicenter cohort studies on CABG conducted between 2002-2004 and 2007-2008. Data on isolated CABG performed both on-pump and off-pump were derived from clinical dataset and linked to 2 administrative datasets. Time-to event analyses were performed in a competing risk framework to evaluate the potential role of surgical techniques on outcomes.

Results:
The population consisted of 11020 patients who underwent isolated CABG (27.2% OPCAB). Several risk factor but surgical technique independently affected in-hospital mortality. The incidence of postoperative PCI was significantly higher in OPCAB group (p<0.05) and the multivariate logistic regression demonstrated that on-pump CABG was the only factor that protects from PCI after surgery (OR 0.61). Although unadjusted long-term survival was significantly worst for OPCAB (Log-rank p-value 0.00), the adjustment for factors found significant in the univariate analysis did not confirm OPCAB as a risk factor for mortality (hazard ratio was 0.96 ± 0.05, p-value 0.407). On the contrary, the significantly better cumulative incidence function of hospitalization for PCI at follow-up (Gray test p-value 0.00) in the on-pump group was confirmed even by the adjustment for confounding factors (p-value 0.00, adjusted hazard ratio 0.70 ± 0.07) and hence OPCAB was demonstrated to be an independent risk factor for PCI with an hazard that is 42% higher than on-pump CABG.

Conclusions:
This study demonstrated that OPCAB did not affect short and long-term mortality. Nonetheless, it was a risk factor for re-hospitalization for PCI.
Abstract 15876: The Safety of Transesophageal Echocardiography in Patients With Gastroesophageal Varices
Authors: Alnabki Ziad , Rawasia Wasiq F , Dryden Gerald , Usmani Ali , Stoddard Marcus F
Published: July 2021

Introduction:
The presence of gastroesophageal varices (GEV) is considered a relative contraindication to performing Trans esophageal echocardiography (TEE) however; the safety of TEE in patients with GEV is unknown.

Hypothesis:
Bleeding complications related to TEE in patients with GEV are dependent on the severity of the GEV.

Methods:
55 patients (G1) with GEV undergoing clinically indicated TEE were studied. Each patient was matched by age and gender to a control subject (C). GEV were graded using esophagogastroduodenoscopy (EGD). There were 39 males and 16 females in either group. Complications related to TEE were defined as upper gastrointestinal (GI) bleed, decline in hemoglobin by more than 2 g/dl, esophageal perforation, aspiration, respiratory compromise requiring intubation and/or need for sedative reversal agents that occurred within 48 hours of the procedure.

Results:
In G1 grade 1, grade 2, and grade 3 GEV were present in 21, 24, and 12 patients, respectively. Of the 12 patients with grade 3 GEV, one patient had GI bleed.

TEE findings included vegetation in 8 patients of G1 and in — patients of C and thrombus in 3 patients of G1 and 3 patients of C.

Conclusions:
TEE appears safe in patient with grade 1 or 2 GEV. However, caution should be advised when performing TEE in patients with grade 3 GEV. TEE showed significant findings of vegetation or thromus in at least 20% of the patients with GEV.
Abstract 15890: Hornerin, a Multifunctional Protein Critical to Non-VEGF-Mediated Angiogenesis, Plays a Determining Role in Neovascularization of the Infarct Post-mi
Authors: Dasa Siva Sai Krishna , Gutknecht Michael , Seaman Marc , French Brent A , Kelly Kimberly A
Published: July 2021

Introduction:
Pathological angiogenesis is a hallmark of cancer and other ischemic/inflammatory diseases including remodeling after myocardial infarction (MI) and diabetic retinopathy. Inhibitors of vascular endothelial growth factor (VEGF) signaling have been tested for efficacy against various cancers in clinical trials, but have proven only moderately succesful. To identify factors other than VEGF involved in angiogenesis, we biopaned a phage display library against HUVECs in combination with negative selection against VEGF-mediated signaling. A separate phage display screen was carried out in vivo against the infarct border zone in mice at Day 4 post-MI.

Methods:
One of the few phage clones in common between the two screens bound to endothelium in the infarct zone at Day 4 post-MI in the mouse model. The molecular binding target of this clone was identified as hornerin (Hrnr) by means of a phage-based proteomics approach. Hornerin belongs to the S100 family, and like other proteins in this family, is relevant in wound-healing post-MI. To study its function post-MI, we performed knock-down studies using siRNA specific for Hrnr. Further, in an effort to identify the potential mechanism of hornerin-induced neovascularization, we performed in vitro proliferation and apoptosis studies using human microvasculature endothelial cells (HMVECs).

Results:
siRNA-mediated knock-down of Hrnr in post-MI mice prevented neovessel formation and further in vitro studies showed that Hrnr protected endothelial cells against ROS-induced apoptosis through activation of NF-kB (Fig. 1).

Conclusions:
Inhibitors of Hrnr hold promise as an alternative anti-angiogenic therapy for various diseases including cancer and diabetic retinopathy. The upregulation of hornerin might also serve as therapy to protect endothelial cells against oxidative stress in the healing infarct after MI.
Abstract 15915: Gender Matters in the Risk for Sudden Death in Young Competitive Athletes
Authors: Ahluwalia Aneesha , Haas Tammy S , Garberich Ross F , Maron Barry J
Published: July 2021

Background:
Sudden deaths in young competitive athletes are highly visible and tragic events, which receive much public visibility. However, little is known regarding the specific impact of gender on these events.

Methods and Results:
The U.S. National Registry of Sudden Death in Athletes was accessed to identify the causes, frequency and epidemiology of sudden deaths in U.S. competitive athletes by gender. A total of 2,408 deaths (2155 male; 253 female) were identified in athletes engaged in 41 diverse organized sports from 1980 to 2011. Most sudden deaths occurred with physical exertion during competition/training (66%), and were predominantly due to cardiovascular disease (54%). In high school and college athletes, accounting for participation rates, the ratio of male to female deaths was 5.4:1. Males were somewhat older than females (19±6 vs. 17.8±6; P=0.003), and were more commonly black (30% vs. 17%; P<0.001). Of the male athletes, the highest rate of cardiovascular sudden death was in blacks (65% vs. 49% in whites; P<0.001). The most frequent sports were football (n=725) and basketball (n=437) in males, and basketball (n=47) and cross country/track (n=41) in females. Most common cardiovascular cause of death was hypertrophic cardiomyopathy (HCM), which accounted for a greater proportion of confirmed cardiovascular deaths in males (47%) vs. females (14%; P<0.001); a 19:1 male:female ratio in high school and college athletes. In contrast, females experienced greater frequency of death due to congenital coronary artery anomalies (30% vs. 14%; P<0.001), arrhythmogenic right ventricular dysplasia (12% vs. 4%; P=0.018), and long-QT syndrome (7% vs. 1%; P<0.001). Blunt trauma, including commotio cordis, occurred more frequently in males (24% vs. 15% in females; P=0.001).

Conclusions:
Female athletes have a 5-fold lower risk for sudden death, compared to males, and were almost 20-times less likely to die of HCM. Black males had the highest rate of sudden death due to cardiovascular disease, with HCM most common.
Abstract 15934: Refractory Cardiogenic Shock in a Patient With Hypertrophic Obstructive Cardiomyopathy and Mitral Regurgitation Necessitating Intra-Aortic Balloon Pump Use
Authors: Mahata Indrajeet , Faulx Michael , kola Snigdha , Singh Sweta
Published: July 2021

Introduction:
Hypertrophic obstructive cardiomyopathy (HOCM) is a genetic disease due to a mutation in cardiac muscle protein resulting in left ventricular wall and septal hypertrophy. The presence of systolic anterior motion (SAM) of the mitral valve leads to dynamic left ventricular outflow tract (LVOT) obstruction. With increasing SAM of the anterior mitral leaflet there is resultant loss of coaptation leading to mitral regurgitation (MR). MR has been associated with HOCM but severe MR physiology causing refractory cardiogenic shock and requiring the use of afterload reduction through intra-aortic balloon pump (IABP) is rare and seems paradoxical to the conventional therapy for HOCM.

Case summary:
This is a case of 71year old female with HOCM, presenting with worsening shortness of breath. She had pulmonary vascular congestion on Chest X-ray and her Transthoracic Echocardiography demonstrated significant LVOT obstruction with moderate MR. She was being evaluated for myomectomy while being treated medically with beta blocker therapy for HOCM. She decompensated with acute respiratory failure from pulmonary edema, her blood pressure and oxygen saturation dropped. She was intubated. Swan- ganz catheter reading suggested wedge pressures of 22 and elevated pulmonary pressures. MvO2 was 32% and this was suggestive of cardiogenic shock. The Trans-esophageal echocardiogram (TEE) showed normal EF with severe concentric LVH and a moderate to severe (3+) MR due to restricted leaflet motion with regurgitant orifice area being 2.5cm2. At that point her MR was the dominant physiology behind her acute decompensation and cardiogenic shock and hence an IABP was placed for reducing afterload that helped in stabilizing her. Subsequently her wedge pressure and MvO2 improved, she was weaned off the IABP and extubated. The patient is being evaluated for myomectomy and mitral valve repair.

Conclusion:
This case illustrates complex hemodynamics and a challenging management due to competing MR and HOCM physiologies, too much central volume to offset HOCM may worsen MR and pulmonary edema while too much afterload reduction might worsen the HOCM. The use of IABP in a HOCM patient though seems paradoxical but was necessary in this setting to deal with complex physiologies.
Abstract 15952: Feasibility and Safety of Balloon Expandable Transcatheter Aortic Valve Implantation With Moderate or No Predilatation
Authors: Abramowitz Yigal , Jilaihawi Hasan , Chakravarty Tarun , Nakamura Mamoo , Cheng Wen , Dhoble Abhijeet , Castellanos Jorge , Kashif Mohammad , Takahashi Nobuyuki , Doctor Niraj , Gheorghiu Mitch , Makkar Raj R
Published: July 2021

Background:
Aortic valve preparation by performing balloon aortic valvuloplasty (BAV) has so far been considered mandatory during transcatheter aortic valve replacement (TAVR) procedures. We hypothesized that performing TAVR without predilatation (PD) could potentially reduce BAV complications during TAVR (e.g. stroke or conduction disorders), while yielding similar hemodynamic and clinical outcome. There is limited data on the safety of TAVR with moderate or with no PD and previous publications addressing this issue are mainly of self-expandable valves.

Methods & Results:
Between September 2012 and January 2014, 95 patients underwent direct balloon expandable TAVR (no PD group) and 255 patients had moderate PD before valve deployment (mean balloon width-15mm; moderate PD group). The Transfemoral approach was used in 79% of patients. Device success was similar between groups (no PD -97%, moderate PD -95%; p=0.44), post procedural mean aortic valve gradients were 6.8 and 6mmHG. There was significantly less initial perivalvular leak (PVL) in the no PD group: 82%, 17%, 1%, 0% versus 66%, 23%, 9%, 2% for no/trace, mild, moderate and severe PVL respectively (p<0.01). Postdilatation was performed in 5.3% of the patients in the no PD group compared to 8.2% in the moderate PD group (p=0.34). Thirty-day mortality and stroke rates were 2.1% and 2.1% in the no PD group compared to 3.5 and 2.4 in the moderate PD group (Table). Fewer permanent pacemaker implantations were needed in the no PD group (2.1% vs. 7.8%; p=0.048). All other in-hospital complications were similar between groups.

Conclusions:
TAVR with moderate or no PD is feasible and safe. The no PD approach was associated with lower rates of permanent pacemaker implantation and less PVL without affecting procedural success.
Abstract 15985: Liver Transplantation Does Not Reverse Cirrhotic Cardiomyopathy
Authors: Ibrahim Ahmed , Schuster Andres , Sonny Abraham , Cywinski Jacek B , Jaber Wael A
Published: July 2021

Background:
Cirrhotic cardiomyopathy (CCM), a frequent finding in patients with end stage liver disease (ESLD), presents with diastolic dysfunction (DD), hyperdynamic state, and prolonged corrected QT interval (QTc). Liver transplantation (LT) is thought to be the only treatment for CCM. The aim of our study is to assess the reversibility of CCM after LT.

Methods:
We retrospectively assessed the data of 82 patients collected from the Cleveland Clinic LT database between the years 2007 to 2008 that had an echocardiogram (TTE) and an EKG pre and post-LT. The clinical characteristics were obtained from the electronic record and all EKG and TTE were analyzed by 2 independent observers in the standard manner. The frequency of CCM criteria in ESLD patients was compared with 74 matched controls with no history of liver disease.

Results:
The median age of patients was 57 years (IQR 19 to 72), 72% were males and 85% were Caucasian. The median time between LT and post-LT testing was 4 years (IQR 0.1 to 6). Compared to controls, patients with ESLD had a longer QTc (449 ±25 vs. 430 ±23 msec; p<0.001) and higher cardiac output (CO) (5.9 ±1.8 vs. 4.8 ±1.1 L/min; p=0.001), left atrial (LA) volume index (33 ±10 vs. 25 ±7 ml/m
2
; p<0.001), left ventricular (LV) end diastolic volume index (60±14 vs. 49±12 ml/m
2
; p=0.001 and mitral valve inflow velocity (E) (85 ±23 vs. 75 ±20 cm/sec; p=0.003).

Post-LT, there was significant increase in LV mass index (LVMI) (107±38 vs 91±24 gm/ m
2
; p=0.002) and prevalence of DD (75% vs. 47%; p<0.001) but no difference in CO, LA and LV volumes. In contrast, there was a significant reduction of QTc (449 ±25 to 440 ±28 msec; p=0.04).

Conclusions:
In our study, patients with ESLD had a higher QTc and CO than matched controls. Post-LT, only QTc showed a significant improvement.
Abstract 16007: Functional Comparison of Human Embryonic Stem Cell- versus Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Rat Ischemic Myocardial Infarction Model
Authors: Chen Wenyi , Riegler Johannes , Matsa Elena , Shen Qi , Wu Haodi , Wang Mike , Gold Joseph D , Wu Joseph
Published: July 2021

Introduction:
Both human embryonic stem cell-derived cardiomyocytes (ESC-CMs) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can serve as an unlimited cell source for cardiac regenerative therapy. However, the functional equivalency of both approaches has not been previously reported. Here we performed head-to-head comparison on the beneficial effects of ESC-CM and iPSC-CMs in restoring cardiac function in a rat myocardial infarction (MI) model.

Methods & Results:
Human ESCs and iPSCs were differentiated into cardiomyocytes using small molecules. FACS analysis confirmed ~85% and ~83% of cells differentiated from ESCs and iPSCs, respectively, were positive for cardiac troponin T, and immunofluorescence staining demonstrated that ESC-CMs and iPSC-CMs have striated sarcomeric structure (Figure A-B). Both ESC-CMs and iPSC-CMs displayed similar maturity for calcium handling (transient amplitude: ΔF/F
0
= 3.8±0.3; time to peak: ~200 ms; 50% transient duration: ~400 ms). qRT-PCR showed that ESC-CMs and iPSC-CMs expressed CASQ2, GJA5, KCNJ2, KCNJ5, MYH6, MYH7, and SCN5A at comparable levels to human fetal heart tissue. Next, ESC-CMs and iPSC-CMs were injected into the left ventricular free wall of infarcted hearts (adult nude rats; n=14, 10, respectively). Cardiac function was assessed by MRI one month post cell injection and the hearts were harvested and stained for human cardiac markers. Both ESC-CMs and iPSC-CMs could engraft in ischemic rat hearts (Figure C). Comprehensive functional analysis with small animal magnetic resonance imaging (MRI), echocardiography, and pressure-volume loop analysis are underway.

Conclusion:
We set out to perform head to head comparison for the first time that iPSC-CMs may facilitate cardiac repair at comparable levels to ESC-CMs. Unlike allogeneic ESC-CM therapy, autologous iPSC-CMs could be used to overcome immune rejection for cardiac cell transplantation in the future.
Abstract 16018: Impaired Intrinsic Myocardial Shortening in Both Two Directions and Compensatory Mechanism to Maintain Left Ventricular Ejection Fraction in Patients With Hypertensive Heart Disease
Authors: Yamada Satoshi , Okada Kazunori , Nishino Hisao , Iwano Hiroyuki , Murai Daisuke , Hayashi Taichi , Nakabachi Masahiro , Ichikawa Ayako , Yokoyama Shinobu , Kaga Sanae , Mikami Taisei , Tsutsui Hiroyuki
Published: July 2021

Background:
Longitudinal myocardial shortening is known to be reduced even if left ventricular (LV) ejection fraction (EF) is preserved in patients with hypertensive heart disease (HHD). However, the compensatory mechanism remains to be elucidated. Thus layer-specific longitudinal and circumferential strain as well as stress-strain relationship was observed in HHD patients.

Methods:
In 46 HHD patients with preserved EF (>50%) and 29 age-matched control subjects, global longitudinal strain (LS) and layer-specific circumferential strain (CS) were measured from the apical 4-chamber view and mid-ventricular short-axis view, respectively, by using speckle tracking echocardiography. LS was measured at innermost LV wall layer, and CS at innermost, midwall, and outermost layers. Layer-specific end-systolic circumferential wall stress (CWS) according to Mirsky’s formula and endocardial meridional wall stress (MWS) were calculated.

Results:
Systolic blood pressure (147±20 mm Hg), interventricular septal thickness (13±2 mm), and LV dimension (48±4 mm) were greater in HHD than controls, whereas EF was comparable (66±8 vs 66±5%). LS was smaller in HHD than controls (-13±3 vs -17±3%, p<0.001) in spite of reduced MWS (520±141 vs 637±164 dyn·mm
-2
, p<0.01), suggesting impaired longitudinal myocardial function in HHD. Similarly, CS was smaller in HHD than controls at outer layer (-6.8±2.2 vs -8.8±2.2%, p<0.01) and at midwall (-11.3±3.4 vs -13.9±3.2%, p<0.01) in spite of reduced CWS (outer: 238±82 vs 336±110 dyn·mm
-2
, p<0.001; mid: 360±107 vs 473±131 dyn·mm
-2
, p<0.001). In contrast, at the innermost layer, both CS (-26±5 vs -25±5%, p=0.41) and CWS (979±153 vs 992±139 dyn·mm
-2
, p=0.72) were comparable between groups. Furthermore, the difference of CS between inner and outer layers significantly correlated with relative wall thickness (r=-0.33, p<0.01). Finally, CS at inner layer significantly correlated with EF (r=-0.43, p<0.001), whereas LS did not.

Conclusions:
In patients with HHD, intrinsic myocardial shortening was impaired both longitudinally and circumferentially. Some compensatory mechanism associated with increased relative wall thickness might work to maintain subendocardial CS, resulting in preserved EF.