bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 122: Compression-Induced Ventilation Volumes Decrease with Chest Compression Depth and Prolonged CPR
Authors: Ordelman Simone , Aelen Paul , van Berkom Paul , Noordergraaf Gerrit J
Published: July 2021

Introduction:
Compression-induced ventilation may aid gas exchange during CPR. We hypothesized that the amount of gas moving in and out of the lungs depends on chest compression depth.

Methods:
VF was induced in five female, anesthetized and intubated pigs of about 30 kg. After 30 seconds of non-intervention time, chest compressions were started and maintained at a rate of 100 compressions per minute. Every two minutes chest compression depth was altered, resulting in 14 minutes of CPR with a depth sequence of 4 cm, 3 cm, 4 cm, 5 cm, 5.5 cm, 5 cm and 4 cm. Ventilations were performed manually with a bag-valve device 10 times per minute during continuous chest compressions by a dedicated expert. Airway flow was measured at the end of the endotracheal tube. Compression-induced ventilation was determined from the periods between the manual ventilations. The average compression-induced minute ventilation volume was determined over the last minute of each two minute period of CPR at each specific chest compression depth.

Results:
The compression-induced ventilation volume in the first period of CPR at 4 cm of depth was 1.6 ± 0.9 L/min (about 4% of total ventilation volume). The figure shows how the compression-induced ventilation volume decreases with increasing chest compression depth, relative to this initial value. CPR with a chest compression depth of 4 cm was performed three times in each pig, and the corresponding compression-induced ventilation volumes decreased with time. This suggested that there might be just a time effect (e.g. atelectasis). However, the final compression depth of 4 cm resulted in larger compression-induced ventilation volumes than the preceding 5 cm and 5.5 cm compression depths, indicating that the decreased volume over time could not purely be a time effect, but must also be an effect of the depth.

Conclusion:
In conclusion, compression-induced ventilation volume appears to decrease with deeper chest compressions as well as with prolonged CPR.
Abstract 12236: Redistribution of Gsk-3β to Cardiac Intercalated Discs in Arrhythmogenic Cardiomyopathy
Authors: Asimaki Angeliki , Chelko Stephen , Judge Daniel P , Kleber Andre G , Saffitz Jeffrey E
Published: July 2021

Reduced signal at intercalated discs (IDs) and nuclear accumulation of the desmosomal protein plakoglobin (γ-catenin) in arrhythmogenic cardiomyopathy (ACM) have been linked to suppression of canonical Wnt/β-catenin signaling. In a chemical screen in a zebrafish model of ACM, we found that SB216763, annotated as an inhibitor of glycogen synthase kinase-3β (GSK-3β), prevents heart failure and reduces mortality. It also prevents arrhythmias and myocyte injury and apoptosis in cultured neonatal rat ventricular myocytes (NRVM) and intact mouse hearts expressing ACM mutations in 3 different desmosomal genes. Given the role of GSK-3β in the canonical Wnt/β-catenin pathway, we further examined GSK-3β in ACM pathogenesis. To determine if GSK-3β is redistributed in ACM, we immunostained myocardium from 11 patients who met diagnostic criteria, including 8 with desmosomal gene mutations. GSK-3β immunoreactive signal accumulated at ventricular myocyte IDs in the hearts of all patients with ACM but not in control hearts or samples from patients with end-stage ischemic, dilated or hypertrophic cardiomyopathies (n=5 for each) or cardiac sarcoidosis (n=10). The GSK-3β binding partner adenomatous polyposis coli (APC) also localized to cell-cell junctions in ACM hearts only, consistent with the presence of the GSK-3β/axin/APC complex at IDs in ACM. GSK-3β and APC also showed marked junctional localization in NRVM expressing mutant forms of plakoglobin (2057del2) or plakophilin2 (1851del123), and in the hearts of adult mice expressing 2057del2 plakoglobin and a cardiac myocyte-specific Dsg2 knock-in mouse, but not in normal controls cells or tissues. GSK-3β and APC distributions were normalized by SB216763 in these in vitro and in vivo models of ACM. Immunoblotting showed no apparent change in the total cellular content of GSK-3β in the presence of ACM-causing desmosomal gene mutations. However, in addition to restoring the normal cytoplasmic localization of the GSK-3β/APC complex, SB216763 also decreased the total cellular content of the active (non-phospho) form of GSK-3β in all 4 experimental models. These observations suggest a role for GSK-3β distribution in the ACM disease mechanism independent of the specific underlying desmosomal mutation.
Abstract 12274: A Regional Pharmacoinvasive PCI Strategy Incorporating Bleeding Avoidance Strategies
Authors: Chava Sreedivya , Raza Samreen R , El-Haddad Mohamed , Priest Jeff , Ashikaga Takamura , Dauerman Harold L
Published: July 2021

Background:
Pharmacoinvasive Therapy (PIT) is a potential treatment for STEMI patients who are not able to achieve primary PCI within guideline recommended time limits. The risk of bleeding complications with PIT has not been studied in the setting of routine use of bleeding avoidance strategies (BAS).

Methods:
We analyzed a contemporary multicenter registry (2009-2013) of consecutive patients undergoing PCI as part of a 10 hospital regional algorithm involving 1 PCI center and 9 transfer centers: PIT for hospitals > 60 minutes (N=140) and Primary PCI if < 60 minutes travel time to PCI center (N=346). We compared the risk of HORIZONS Major Bleeding for patients undergoing PIT vs Primary PCI in the setting of routine use of BAS and determined the independent predictors of major bleeding in the entire cohort.

Results:
The PIT patients had a median travel time of 103±49 minutes and were more frequently female, had a higher incidence of renal failure and less cardiogenic shock than the primary PCI group. BAS was routine and similar in both groups (Table). Rates of death, stroke, ischemic and major bleeding outcomes were similar among the two groups, and length of stay was shorter in the PIT group. Multivariate logistic models indicated that two independent predictors of major bleeding were cardiac arrest (OR=3.89, 95% CI: 1.2-12.1, p=0.02) and bailout GPI utilization (OR=3.23, 95% CI 1.2-9.9, p =0.03). The PIT strategy in conjunction with BAS did not predict major bleeding (OR=2.1, 95% CI: 0.85-5.44, p=0.11).

Conclusions:
We report the largest study of BAS in conjunction with a regional STEMI strategy of PIT: PIT is associated with low rates of bleeding and thrombotic complications. Bleeding and ischemic rates were similar to the primary PCI strategy. PIT in conjunction with BAS is not an independent predictor of bleeding risk in a regional STEMI population.
Abstract 12279: Novel and Reliable Method to Screen for Drug Cardiac Toxicity Using Human Induced Pluripotent Stem Cell Derived Cardiomyocytes (hiPS-CM)
Authors: Mohamed Tamer M , Ellinger Bernhard , Stankovikj Vera , Wiesinger Adriana , Guan Kaomei , Neyses Ludwig , Oceandy Delvac , Gul Sheraz , Cartwright Elizabeth J
Published: July 2021

Unexpected cardiotoxicity underlies high rates of attrition during drug development, posing a multi-billion dollar burden on the pharmaceutical industry. Over reliance on the use of animals and materials derived from animals in preclinical assays to predict the cardiotoxic effect of new drugs in humans has contributed to this problem. The drug responses in human cardiomyocytes compared to animal-derived primary cardiomyocytes (CM) for
in vitro
assays is not always the same. Here, we describe a combination of human pluripotent stem cell-derived cardiomyocytes (hiPS-CM) and high content analysis confocal microscopy as a potential solution for this major setback in drug development.

Initially human skin fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSCs) by lentiviral transduction and utilization of the following combination of transcription factors: Oct3/4, Sox2, c-Myc and Klf4. The human pluripotent stem cell phenotype of the generated hIPSCs was confirmed. hiPSCs were differentiated into cardiomyocytes and the cardiac cell phenotype was confirmed by immunofluorescence and RT-PCR analysis of cardiac markers i.e. αMHC, cTNT, NKX2.5 and connexin 43. Seventeen known cardiotoxic compounds, as well as controls, were applied to the cells in 384 well format at a dose of 10μM for 48 hours. Then hiPSC-CM underwent confocal microscopy high content analysis to simultaneously evaluate the cell mitochondrial transmembrane potential (using TMRM dye), and plasma membrane permeability (using TOTO-3 dye). All known cardiotoxins showed a significant decrease in mitochondrial transmembrane potential ranging from 74% to 95% and an increase in plasma membrane permeability ranging from 67-327 fold in comparison to the controls. These results showed 100% prediction rate of cardiotoxicity of known cardiotoxins by hiPS-CM. This was compared to only 12% general cytotoxicity prediction rate when these compounds tested on A549 and ACHN cancer cell lines.

In conclusion, combining two state of the art technologies 1) hiPSC-CM and 2) confocal microscopy high content analysis, we were able to provide a reliable high throughput method to assess cardiotoxicity of compounds.
Abstract 12308: Assessment of Liver Fibrosis Using Magnetic Resonance Elastography in Children Who Undergo the Fontan Procedure and Intracardiac Repair
Authors: Sugimoto Masaya , Oka Hideharu , Kajihama Aya , Nakau Kouichi , Azuma Hiroshi
Published: July 2021

Background:
The incidence of late complications related to the liver such as fibrosis/cirrhosis is increasing in patients who have undergone the Fontan procedure and may contribute to morbidity and mortality. Recently, magnetic resonance elastography (MRE), a novel evaluation technique of liver fibrosis, has been attracting attention. However, few reports have described the use of MRE for evaluating liver fibrosis in children with congenital heart disease (CHD).

Methods:
Thirty-two children were examined and divided into 4 groups: 12 children with CHD who underwent intracardiac repair (ICR; median age, 13.0 years); 10 with CHD who underwent the Fontan procedure (Fontan; 15.3 years); 8 who were included in the control group (control; 15.8 years); and 2 children with cirrhosis (cirrhosis; 16.3 years). The liver stiffness (LS) was estimated by MRE. LS was measured 3 times consecutively, and the mean value was considered for further analysis. Central venous pressure (CVP) and cardiac index (C.I.) were determined by cardiac catheterization. The levels of cardiac biomarkers (NTproBNP and PIIIP) were determined at the same time.

Results:
Among the 4 groups, no significant differences were observed in age, C.I., and NTproBNP levels. The PIIIP levels in the cirrhosis group were significantly higher than those in the control, but no significant difference in PIIIP levels was found among the other groups (p < 0.01). LS in the Fontan and cirrhosis group was significantly higher than that in the control group (5.6, 15.3 vs. 2.4 kPa, respectively; Fig. 1). Furthermore, there was a strong correlation between LS and CVP (r = 0.802; Fig. 2).

Conclusions:
This study showed that LS is a direct function of CVP, which should be considered when assessing the degree of liver fibrosis in children with CHD. In particular, in the case of children who undergo the Fontan procedure, the highly sensitive MRE can be used to evaluate liver fibrosis and help detect LS earlier than cardiac biomarkers do.
Abstract 12310: Detection of Transient Left Ventricular Apical Hypertrophy During Recovery From Takotsubo Cardiomyopathy by Serial Echocardiography
Authors: Hashimoto Go , Suzuki Makoto , Yoshikawa Hisao , Otsuka Takenori , Isekame Yukiko , Shiba Masanori , Iijima Raisuke , Hara Hidehiko , Nakamura Masato , Sugi Kaoru
Published: July 2021

Introduction:
Takotsubo cardiomyopathy (TTC) is characterized by a transient systolic dysfunction of the left ventricle. A few case was reported about left ventricular apical hypertrophy (APH) during recovery from TTC. The purpose of this study was to investigate the incidence of transient APH and the differences in clinical characteristics in TTC patients.

Methods:
Forty seven TTC patients were enrolled in this study. Patients were divided into two groups as N-APH group which did not show APH like findings in the process of wall motion recovery and T-APH group which showed transient APH findings. Cardiac complications were defined as cardiac death, pump failure, sustained ventricular tachycardia or ventricular fibrillation and advanced atrioventricular block.

Results:
Twelve of 47 (25.5%) TTC patients demonstrate typical APH findings during recovery from wall motion abnormality. Finally, this APH findings disappeared and left ventricular morphology recovered to normal structure. There is no significant difference between two groups in clinical characteristics (table). Incidence of cardiac complication showed significantly lower in T-APH group than that in N-APH group (P< 0.005).

Conclusions:
Transient left ventricular APH were observed in 25.5% in TCC patient by serial echocardiographic observation. Incidence of cardiac complications in T-APH group is significantly lower than that in N-APH group. Detection of T-APH is useful as a prognostic indicator in patients with TTC.
Abstract 12412: Imaging the PM/AICD Patient; Does the Diagnostic Value Justify the Risk?
Authors: Samar Huma Y , Yamrozik June , Williams Ronald , Doyle Mark , Biederman Robert
Published: July 2021

Background:
MR imaging is infrequently performed on patients with implanted pacemakers/AICDs. When the risk justifies the end, however, consideration to perform 'high-risk’ scanning can be made on a case-by-case basis but typically with trepidation. This raises a critically important question: "Is the MRI scan adding valuable and irrefutable information to warrant such risk?

Methods:
84 patients with implanted devices (13AICD,10 AICD/PM,5 retained leads, 6 REVO and 50 dual chamber PM.) were imaged via MRI/CMR (1.5T GE, Milwaukee, WI) over 3 years in a single institution. Specific criteria were followed for all patients to objectively define whether final diagnosis by MRI imaging enhanced patient care. A checklist of 3 questions was answered following scan interpretation by both the technologist and performing MRI physician(s):

1)

Did the diagnosis change?

2)

Did the MRI provide additional information to the existing diagnosis?

3)

Did patient management change?

If ‘Yes’ was answered to any of the above questions, it was considered that the MRI scan was of value to patient diagnosis and/or therapy.

Results:
All patients completed the procedure with no death, VT/VF, power-on-reset or adverse events. Average MRI study time: 20±55min. The device was interrogated pre and post MRI by EP/cardiologist to determine changes in impedance, amplitude or threshold. No clinically meaningful changes occurred, no post-procedure revisions to generator/lead or parameters were required.

Conclusion:
The use of PM/AICD imaging in MRI remains controversial. Our study shows that MR imaging in carefully selected patients under the supervision of experienced physicians is not only safe but extremely beneficial, substantially adding value and often irrefutable information to patient diagnosis and management. PM/AICDs when imaged properly are safe and no longer 'forbidden’ in the MRI environment. Moreover there is frequently marked life-altering and life-saving information obtained.
Abstract 12422: Evaluation of RV and LV Mass by CMR and Comparison to Recipient Heart Following Heart Transplant; The First-Ever CMR Human Autopsy Study
Authors: Reddy Sahadev T , Farber Nicholas , Doyle Mark , Rayarao Geetha , Thompson Diane , Williams Ronald B , Yamrozik June A , Murali Srinivas , Biederman Robert W
Published: July 2021

Introduction:
CMR is considered the ‘gold standard’ for noninvasive LV and RV mass quantitation. This concept is predominantly based on GRE sequences yet never validated in humans undermining its credibility. SSFP offers superior image contrast potentially redefining the CMR gold standard for mass.

Objective:
To establish correlations between SSFP-CMR LV and RV mass vs. pathology mass using Htx pts.

Methods:
Over 3 years, 68 pts were evaluated including 48 HTx explants obtained immediately from the OR upon HTx. They were prepared (removed PM/AICD and/or LV/RVAD) and scanned
ex vivo
via SSFP for CMR LV/RV mass (1.5T GE, WI). Via an
A
utomatic
T
hresholding program for segmentation with
M
anual
T
rimming (ATMT) of extraneous cardiac tissue a 3D LV model was generated. The weight of total heart
including
papillary and trabeculae for LV and RV was measured via high-fidelity scale. Correlations were between 3D CMR vs. pathology with B-A plots. A separate cohort of 20 non-Htx pts underwent
in vivo
validation.

Results:
Of 48 Htx pts, 3 (6%) were excluded due to poor images (peri-surgical destruction) leaving 45 (94%) for analysis. Correlations: 1) Total CMR 3D mass (448±116g) vs. total pathology mass (444±118g; r=0.99, p<.001); 2) 3D CMR-LV mass (297±95g) vs. pathology-LV mass (308±96g; r =0.95, p<.001) 3) 3D CMR-RV mass (152±44g) vs pathology-RV mass (132±41g; r = 0.76, p<.001). The equation y = 1.01x - 6.6b regressed the LV (r = 0.95). Avg bias between CMR and pathology for total, LV and RV mass was +4.4g. For the validation cohort LVEDV r=0.99; LVESV r= 0.99.

Conclusions:
SSFP-CMR accurately defines total cardiac, LV and RV mass as compared to explanted hearts (despite variable surgical removal of instrumentation). Thus, while GRE was the original ‘gold standard’ for LV mass, SSFP, despite its universal acceptance as the ‘
de facto
gold standard is now formally validated in a first-ever human autopsy study. Further, the regression equation now
includes
, not
excludes
papillary and trabecular mass.
Abstract 12425: Sirt2 Mediated-Deacetylation Regulates Cellular Iron Homeostasis
Authors: Yang Xiaoyan , Vassilopoulos Athanassios , Park Seong-Hoon , Gius David , Ardehali Hossein
Published: July 2021

Background:
Sirtuins (SIRTs) are NAD+-dependent deacetylases and critical regulators of energy metabolism and response to oxidative stress in the heart. Iron is essential for these processes but is toxic when present in excess. Thus, SIRTs may regulate iron levels to ensure adequate supply of this element for their biological functions. SIRT2 is among the least characterized SIRTs and is mainly present in the cytoplasm. We hypothesized that SIRT2 might be required for cellular iron homeostasis.

Methods and Results:
Iron content was significantly lower in SIRT2-/- mouse embryonic fibroblasts (MEFs) compared to SIRT2+/+ MEFs (non-heme iron: 0.073 vs. 0.060 nmol/μg protein, p=0.02). Gene expression of ferroportin-1 (FPN1), the major cellular iron exporter, was significantly increased in SIRT2-/- MEFs. Similarly, silencing SIRT2 in HepG2 cells decreased cellular iron levels and increased FPN1 expression, indicating that enhanced FPN1 in SIRT2 knockout or knockdown condition increases iron export and reduces cellular iron. To investigate the underlying mechanism, we focused our studies on nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a known regulator of FPN1. Our results demonstrated that Nrf2 is upregulated and translocates into the nucleus in SIRT2-/- MEFs and knocking down Nrf2 in SIRT2-/- MEFs reverses iron deficiency and FPN1 expression. Furthermore, Nrf2 is acetylated by P300/CBP and can be deacetylated by SIRT2. Finally, to confirm the role of SIRT2 in iron regulation, cellular heme and non-heme iron in the heart (major iron-consuming organ) and liver (major iron-storage organ) were measured in wild type (WT) and SIRT2-/- mice. Heme and non-heme iron content were significantly decreased in SIRT2-/- mouse livers compared to WT livers (heme: 2.25 vs. 1.65 nmol/mg protein, p=0.002; non-heme iron: 0.073 vs. 0.064 nmol/μg protein, p=0.03). Furthermore, heme levels were also significant decreased in the heart, while non-heme iron was not significantly altered.

Conclusions:
Our results suggest that SIRT2 regulates cellular iron homeostasis by deacetylating NRF2 and altering iron export through FPN1.
Abstract 12519: Regulation of Cardiac Fibroblast Phenotype by Scleraxis
Authors: Bagchi Rushita , Roche Patricia , Schweitzer Ronen , Czubryt Michael P
Published: July 2021

Cardiac fibroblasts constitute the primary extracellular matrix synthesis machinery in the myocardium. Activation of fibroblasts into a hyper-synthetic and contractile phenotype potentiates fibrosis, impairs cardiac function and contributes to heart failure. Our laboratory previously reported that the transcription factor scleraxis regulates human cardiac collagen Iα2 expression and has shown its up-regulation in the post-infarct scar. Here we demonstrate a novel regulatory role for scleraxis in governing cardiac fibroblast function and phenoconversion. Cell contractility assays using collagen gels demonstrated the abrogation of pro-fibrotic TGF-β-mediated contractility of myofibroblasts in response to scleraxis knockdown. The de novo expression of α-smooth muscle actin (αSMA) and its incorporation into stress fibers is a key feature of myofibroblasts - key causative cells of fibrosis. Scleraxis over-expression in isolated primary cardiac fibroblasts induced αSMA gene expression and stress fiber formation, and rescued the αSMA loss observed in cardiac fibroblasts from scleraxis null mice. Luciferase reporter assays demonstrated a significant transactivation of the αSMA gene promoter by scleraxis. Mutation analysis revealed that scleraxis interacts with two E-boxes within the αSMA promoter, a finding confirmed by chromatin immunoprecipitation of scleraxis in primary cardiac fibroblasts. An increase in scleraxis binding to the αSMA promoter was observed in cardiac myofibroblasts compared to fibroblasts, and also in response to TGF-β, further supporting a direct role of scleraxis in regulation of myofibroblast αSMA expression and its contractile phenotype. Gel shift assays also confirmed the direct interaction of scleraxis with E-boxes within the αSMA gene promoter. Our data indicates that scleraxis plays a required role in cardiac fibroblast phenotype and contractile function. Taken in context with our finding that scleraxis regulates expression of multiple extracellular matrix components, including fibrillar collagens, our data reveals that scleraxis exerts broad and potent pro-fibrotic effects on cardiac fibroblast form and function, and may thus represent a novel target for fibrosis therapy.
Abstract 12555: The Dual PPAR-α/γ Agonist Aleglitazar Enhances Arteriogenesis, Angiogenesis and Endothelial Function
Authors: Werner Christian , Schirmer Stephan H , Pavlickova Valerie , Böhm Michael , Laufs Ulrich
Published: July 2021

Objective:
Peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists modify lipid and glucose metabolism. The aim of the study was to characterize the effects of the dual PPAR-α/γ agonist aleglitazar on endothelial function, neoangiogenesis and arteriogenesis in mice and on human endothelial progenitor cells (EPC).

Methods and Results:
Male C57Bl/6 wild-type (WT, normal chow) and apolipoprotein E-deficient (apoE-/-) mice on Western-type diet (WTD) were treated with aleglitazar (10 mg/kg i.p.) or vehicle by daily injection.

Hindlimb ischemia was induced by right femoral artery ligation (FAL). ApoE-/- mice on WTD treated with aleglitazar before FAL were characterized by an improvement of endothelial-dependent laser Doppler perfusion (right/left foot ratio 0.40±0.03) 1 week after FAL compared to controls (R/L foot ratio 0.24±0.01; p<0.001). Collateral-dependent perfusion measured under conditions of maximal vasodilatation 1 week after FAL using fluorescent microspheres was impaired in apoE-/- on WTD compared to WT mice (R/L leg ratio in WT 78±13 vs. apoE-/- 56±6; p<0.001) and was normalized by aleglitazar treatment.

Neoangiogenesis was measured in-vivo by subcutaneously implanting discs covered with cell-impermeable filters. The vascularized area of the discs was quantified after 14 days by perfusion of the animals with space-filling fluorescent microspheres. Aleglitazar increased neoangiogenesis in WT mice by 178±18% compared to vehicle (p<0.05).

Endothelium-dependent relaxation of aortic rings was impaired in apoE-/- mice on WTD for 6 weeks (relaxation to 52±5% of max. contraction) compared to WT animals (relaxation to 18±5% of max. contraction) (p<0.001). Aleglitazar treatment improved endothelial function (relaxation to 39±5% of max. contraction; p<0.05).

In parallel, number and function of EPC were improved in mice. Studies in human EPC showed that 1) aleglitazar’s effects were mediated by both PPAR-α and -γ signalling and Akt and 2) migration and colony forming units were up-regulated by aleglitazar in cultivated EPC from CAD patients.

Conclusion:
The study provides evidence for beneficial effects of the dual PPAR-α/γ agonist aleglitazar on vascular function in addition to or mediated by its metabolic actions.
Abstract 12566: Receptor for Activated Protein Kinase C1 Competes With GATA4 for p300 and Represses Hypertrophic Responses in Cardiomyocyte
Authors: Suzuki Hidetoshi , Sunagawa Yoichi , Katanasaka Yasufumi , Wada Hiromichi , Hasegawa Koji , Morimoto Tatsuya
Published: July 2021

Introduction:
The zinc finger protein GATA4 is one factor involved in transcriptional regulation during myocardial cell hypertrophy, and forms a complex with an intrinsic histone acetyltransferase (HAT), p300. HAT activity of p300 is required for acetylation and the transcriptional activity of GATA4, as well as for cardiomyocyte hypertrophy and the development of heart failure
in vivo
. We recently identified Receptor for Activated Protein Kinase C1 (RACK1), a multi-functional scaffold protein, as a novel GATA4-binding partner, and revealed that RACK1 regulates the p300/GATA4-dependent transcriptional pathway and hypertrophic responses in cardiomyocytes. However, the molecular mechanism by which RACK1 suppresses p300/GATA4-dependent gene transcription remains unknown.

Hypothesis:
We hypothesized that RACK1 reduces the phenylephrine (PE)-induced increase of the interaction between GATA4 and p300 in cardiacmyocytes.

Methods and Results:
To examine the effect of RACK on the binding activity of p300 to GATA4, expression plasmids encoding these proteins were used to co-transfect HEK293 cells. Nuclear extracts from these cells were subjected to immunoprecipitation, followed by Western blotting. Overexpression of RACK1 inhibited p300-induced GATA4 acetylation and the association with p300/GATA4. Based on chromatin immunoprecipitation and reporter assays, RACK1 inhibited not only p300-induced DNA binding activity of GATA4 on atrial natriuretic factors (ANF) and endothelin-1 (ET-1) promoters but also p300/GATA4-induced ANF and ET-1 promoter activities. In cultured neonatal rat ventricular cardiomyocytes, overexpression of RACK1 significantly inhibited PE-induced GATA4 acetylation, activation of ANF and ET-1 promoters, and myocardial cell hypertrophy. Also, PE decreased binding between GATA4 and RACK1. Finally, PE stimulation increased tyrosine phosphorylation of RACK1. This phosphorylation was inhibited by a tyrosine kinase inhibitor, Dasatinib.

Conclusions:
The findings demonstrated that RACK1 disrupted the p300/GATA4 complex and inhibited hypertrophic responses in cardiomyocytes. Tyrosine phosphorylation of RACK1 may trigger the dissociation of RACK1 from p300/GATA4.
Abstract 12576: Impact of Insulin Resistance on Left Ventricular Remodeling in Patients With a First-Time ST Elevation Acute Myocardial Infarction Without Overt Diabetes Mellitus
Authors: Iwahashi Noriaki , Gohbara Masaomi , Kataoka shunsuke , Akiyama Eiichi , Maejima Nobuhiko , Tsukahara KEngo , Hibi Kiyoshi , Kosuge Masami , Ebina Toshiaki , Umemura Satoshi , Kimura Kazuo
Published: July 2021

Backgrounds:
Insulin resistance (IR) has been reported to be associated with worse prognosis in patients with coronary artery disease. However, the role of IR in patients with acute myocardial infarction(AMI) remains unclear. Therefore, we explored the impact of IR on left ventricular remodeling (LVR) after ST elevation AMI (STEMI) without overt DM.

Methods:
One hundred seventy patients with a first-time ST elevation AMI (STEMI) who underwent reperfusion within 12 hours were enrolled in this study. Patients had no history of diabetes mellitus prior to their first STEMI. We examined echocardiography results 24 hours after PCI and 12 months later. We measured global longitudinal strain using 3D speckle tracking echocardiography (4D LV Analysis, TOMTEC, Germany). We calculated 3D global longitudinal strain(3D-GLS) as the parameter of accurate systolic function free from tethering effect. Infarct size was defined using Tc99m-sestamibi as the area of <50% uptake at 2 weeks. We checked HOMA-R at 2 weeks. The absolute difference of the LV end-diastolic volume (ΔLVEDV) after 12 months was calculated as a parameter of LVR. We excluded the patients with CKD (eGFR <30ml/min/1.73m2) and the high fasting glucose level (>140mg/dl).

Results:
Infarct size (r2=0.30, p=0.03) and HOMA-R (r2=0.50, p=0.018) had a good association with ΔLVEDV. There was a significant relationship between HOMA-R andΔLVEDV (r2=0.096, p=0.0007). Multiple regression analysis showed that HOMA-R was the strongest predictor of ΔLVEDV, followed by 3D-GLS (Table).

Conclusions:
Insulin resistance was the strongest predictor for the degree of LV remodeling in patients with a first STEM without overt DM.
Abstract 12590: Usefullness of Early Release Peak of Cardiac Biomarkers for Detection of Myocardial Infarction Related to Coronary Revascularization Procedures. A Cardiac Magnetic Resonance Study
Authors: Vieira de Melo Rodrigo M , Oikawa Fernando T , Costa Leandro M , Rezende Paulo C , Scudeler Thiago L , Nomura Cesar H , Villa Alexandre V , Hueb Alexandre C , Hueb Whady , Kalil Filho Roberto
Published: July 2021

Background:
The elevation of troponin (TnI) and creatine kinase-MB (CKMB) after coronary revascularization procedures is frequent, but may not be reliable at identifying a definitive procedure-related myocardial injury. Cardiac magnetic resonance (CMR) is the gold standard in the identification of small areas of myocardial necrosis by late gadolinium enhancement (LGE). The presence of a biomarker early release peak might indicate a nonlethal transient cellular myocardial damage and help to discriminate the patients without procedure-related myocardial lesion. Thus, our objective was to evaluate the amount and pattern of release of biomarkers after coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) compared with the area of new LGE on CMR.

Methods:
Patients with indication for coronary revascularization were included. Measurements of high-sensitivity TnI and CK-MB were obtained before and after the procedures, every 6 hours until 48 hours after PCI, and up to 72 hours after CABG. We evaluated the area under the curve (AUC) and peak release of biomarkers and stratified before and 24 hours after the procedure. CMR was performed before and after procedures with quantification of necrosis by LGE.

Results:
From 150 patients who completed the study, 60 (40%) underwent CABG with cardiopulmonary bypass (CPB), 44 (29.3%) without CPB, and 46 (30.7%) underwent PCI. 130 (86.7%) exhibited release of cardiac biomarkers consistent with myocardial injury, however only 32 (21.3%) had new LGE on CMR. The AUC and peak release of TnI showed a moderate correlation with the mass of new myocardial LGE on CMR (AUC: r = 0.46, P < 0.0001; TnI peak: r = 0.45, P < 0.0001), as well as the AUC and peak release of CKMB (AUC: r = 0.33, P < 0.0001; CK-MB peak: r = 0.35, P <0.0001). Patients without new LGE on CMR had more frequently an early peak release of cardiac biomarkers when compared with those with new LGE: 63 (88.7%) vs. 8 (11.3%), P = 0.004.

Conclusion:
The elevation of cardiac biomarkers after coronary revascularization procedures had a low diagnostic power for the detection of new myocardial areas of infarction identified by LGE on CMR. The early release of biomarkers may be useful to rule out the diagnosis of peri-procedural myocardial infarction.
Abstract 12598: Impact of Obesity, Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease on Systemic Inflammation and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Al Rifai Mahmoud S , Blaha Michael J , Blumenthal Roger S , Silverman Michael G , Nasir Khurram , Budoff Matthew J , Blankstein Ron
Published: July 2021

Introduction:
We sought to characterize the association of three adiposity-related risk factors - obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD) - with the outcomes of increased inflammation and subclinical atherosclerosis.

Methods:
We conducted a cross-sectional analysis of 3976 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with adequate CT imaging to diagnose NAFLD. For the study exposures, obesity was defined as BMI ≥30 kg/m
2
, metabolic syndrome by ATP III criteria, and NAFLD using non-contrast cardiac CT and a liver/spleen attenuation ratio (L/S) 0. In order to assess for a possible gradient-response, adjusted logistic regression was used to examine the association of a stepwise increase in the number of three adiposity-related risk factors with increased inflammation and subclinical atherosclerosis. Additional models were conducted stratifying by gender or ethnicity.

Results:
Mean age of participants was 63 years, 45% were male, 37% were white, 10% Chinese, 30% African American, and 23% Hispanic. NAFLD was associated with an odds ratio for high hs-CRP and CAC>0 of 1.54 (1.27-1.87) and 1.41 (1.15-1.73), respectively, adjusting for obesity, metabolic syndrome and traditional risk factors. There was a positive interaction between female gender and NAFLD in the association with high hs-CRP (p=0.01). There was no interaction by race. Importantly, with increasing number of adiposity-related risk factors, the odds ratios of high hs-CRP and CAC>0 increased in a graded fashion, suggesting a collective association (Figure).

Conclusion:
There is an association between three adiposity-related risk factors - obesity, metabolic syndrome, and NAFLD - with both increased inflammation and subclinical coronary atherosclerosis.
Abstract 12611: Moderate to Severe Acute Kidney Injury Provides the Additional Long-Term Prognostic Information to the Blood Urea Nitrogen to Creatinine Ratio in Patients Admitted With Acute Decompensated Heart Failure
Authors: Yamada Takahisa , Morita Takashi , Furukawa Yoshio , Tamaki Shunsuke , Iwasaki Yusuke , Kawasaki Masato , Kikuchi Atsushi , Kondo Takumi , Kawai Tsutomu , Takahashi Satoshi , Ishimi Masashi , Hakui Hideyuki , Ozaki Tatsuhisa , Satoh Yoshihiro , Seo Masahiro , Fukunami Masatake
Published: July 2021

Backgrounds:
Elevated blood urea nitrogen to creatinine ratio (BUN/Cr), a surrogate for renal neurohumoral activation, is a marker of mortality in patients with heart failure. Acute kidney injury (AKI) during heart failure treatment is also associated with poor outcome in patients admitted with acute decompensated heart failure (ADHF). However, there is little information available on the long-term prognostic significance of AKI, relating to BUN/Cr in ADHF patients.

Methods and Results:
We studied 305 consecutive ADHF patients discharged with survival. We defined high BUN/Cr as top tertile at the admission (>24.0). AKI during ADHF treatment was defined according to AKI Network criteria (stage 1, ≥0.3mg/dl absolute or 1.5- to 2.0-fold relative increase in serum creatinine level (s-Cr); stage 2, >2- to 3-fold increase in s-Cr; stage 3, >3-fold increase in s-Cr or s-Cr≥4.0mg/dl with an acute rise of ≥0.5mg/dl). During a follow-up period of 4.2±3.2 yrs, 69 patients had cardiovascular death (CVD). At multivariate Cox analysis, BUN/Cr (p=0.01) and AKI (p=0.0005) were significantly associated with CVD, independently of age, systolic blood pressure, serum sodium and hemoglobin levels and estimated glomerular filtration rate. Irrespective of high or low BUN/Cr, patients with stage 2 or 3 AKI (adjusted hazard ratio(HR): 6.9 (95%CI 1.5 to 30.4) in high BUN/Cr group, 2.9 (95%CI 1.1 to 7.7) in low BUN/Cr group) had the significant increased CVD risk, compared to patients with no AKI. On the other hand, although patients with stage 1 AKI had the significant increased CVD risk (adjusted HR: 3.8 (95%CI 1.5 to 9.7) in high BUN/Cr group, there was no significant difference in CVD risk between patients with stage 1 AKI (adjusted HR: 0.6 (95%CI 0.3 to 1.2) and no AKI in low BUN/Cr group.

Conclusion:
Moderate to severe AKI during heart failure treatment would provide the additional long-term prognostic information to BUN/Cr in ADHF patients.
Abstract 12640: Urine Albumin-to-Creatinine Ratio Outperforms Other Biomarkers in Predicting Death
Authors: Lahoud Rony , Cho Leslie , Brennan Danielle
Published: July 2021

Background:
Risk stratification plays an important role in evaluating patients with no known cardiovascular disease (CVD). Few studies have investigated the role of high-normal urine albumin-to-creatinine ratio as a predictive tool for mortality (normal range defined as <30 mg/g). Our study aims to measure the relative effectiveness of a high-normal urine albumin-to-creatinine ratio in predicting mortality when compared to traditional biomarkers in a primary prevention population.

Methods:
8123 consecutive primary prevention patients evaluated at the Cleveland Clinic Preventive Cardiology Clinic between January 1996 and September 2012 were included in the analysis. Of this patient cohort, 12% had diabetes while 43% had hypertension. The primary outcome was all-cause mortality.

Results:
A urine albumin-to-creatinine ratio above the median (>6 mg/g) independently predicts a 4.4-fold increase in death at 8 years (Hazard Ratio [95% confidence interval] 4.45 [2.56-7.73], p<0.001). When compared to traditional biomarkers such as hsCRP, homocysteine, fibrinogen and lipids, urine albumin-to-creatinine ratio was a better predictor of mortality with a C-index of 0.72. The urine albumin-to-creatinine ratio also improved the predictive ability of the Framingham risk score components, with an increase in C-index from 0.77 to 0.84, and a Net Reclassification Index (NRI) of 64%.

Conclusions:
The urine albumin-to-creatinine ratio is a reliable predictor of mortality in a primary cardiac prevention population. In an era of rising medical costs, the urine albumin-to-creatinine could be used as a relatively non-costly predictor of mortality in this population.
Abstract 12662: Differences in Journal Impact Factor(IF) Between Initial and Subsequent Publication of Cardiovascular Clinical Trials-An Analysis From the ClinicalTrials.gov Repository
Authors: Bhinder Jasjit , Chatterjee Saurav , Messerli Franz H
Published: July 2021

Introduction:
After publication of the primary outcome of a clinical trial additional data of interest continue to be published -.To achieve high visibility of their findings most authors tend to select journals with a high IF. The IF is often viewed as a measure of journal quality as a whole.

Hypothesis:
We compared IF of journals where the primary outcomes from a clinical trial were published to IF of journals where subsequent papers were published.

Methods:
This was a cross sectional analysis design. We analyzed cardiovascular clinical trials from Clinicaltrials.gov. We did not limit our search by date. We chose clinical trials which had 2 or more published manuscripts in journals with indexed IFs. We queried the Thomson Reuters’ Web of Knowledge to determine the individual IF.

Results:
Our search returned 72 cardiovascular clinical trials from a query of the Clinicaltrials.gov database. The mean IF of the primary index publication from the trials were 27.01 (95% confidence interval-CI 21.96-32.06); while that from subsequent publications from the same trials were 11.72 (95% CI 8.97-14.47). The mean difference in IF of journals publishing the index and subsequent results was 15.28 (95% 2.11-17.96). There was a strong correlation between the initial publication IF and the IF difference with the subsequent manuscript (p<0.001).

Conclusions:
The initial publications of cardiovascular trials consistently occur in journals with an IF higher than in subsequent publications. The higher the journal IF of the initial publication the greater the difference in journal IF between initial and subsequent publications.
Abstract 12667: Serum Brain Natriuretic Peptide Level as a Predictive Factor of Pre-Procedural Thrombi in Atrial Fibrillation
Authors: Kimura Takehiro , Takatsuki Seiji , Kashimura Shin , Katsumata Yoshinori , Nishiyama Takahiko , Nishiyama Nobuhiro , Tanimoto Yoko , Aizawa Yoshiyasu , Fukuda Keiichi
Published: July 2021

Introduction:
A scheduled catheter ablation for atrial fibrillation (AF) can be postponed due to preexisting thrombi in the left atrial appendage (LAA) identified by trans-esophageal echocardiography (TEE). We aimed to elucidate the predictive factor for thrombi formation.

Methods:
A total of 372 AF ablation candidates (male, 312; age, 59.8±10.4 years; CHA2DS2-VASc, 1.3±1.3; paroxysmal, 219) were evaluated. Warfarin was administered in 226 patients and dabigatran in 146 patients. A pre-procedural TEE identified thrombi in 24 patients (6.5%: postponed group). The patient background, pre-procedural blood sample data, transthoracic echocardiography (TTE), and TEE were compared between the performed and postponed groups.

Results:
Thu number of patients with hypertension (P=0.040), vascular disease (P<0.001), sleep apnea syndrome (P<0.001), and a TEE performed during AF (P=0.001) were significantly higher in the postponed group. The type of AF (paroxysmal, 11) and anticoagulants (warfarin, 16) did not differ between the groups. The age (P=0.007), CHA2DS2-VASc score (P=0.015), average flow velocity of the LAA measured using TEE (P<0.001), left ventricular ejection fraction (LVEF; P=0.006), size of the left atrium (LA; P=0.001) measured using TTE, and serum brain natriuretic peptide level (BNP; 82.4±81.4 pg/ml vs. 236.7±141.9; P<0.001) were significantly higher in the postponed group. The prothrombin time (P=0.087) and activated clotting time (P=0.178) did not differ. A multivariate analysis adjusted for the confounding factors such as the age, CHA2DS2-VASc score, LAA flow velocity, LA size and LVEF revealed that a serum BNP level of >135 pg/ml was the independent predictive factor for LAA thrombi (odds ratio, 14.178; 95% confidence interval [CI], 2.907 to 69.149; P=0.001). The area under the receiver operating characteristic (ROC) curve (AUC) for predicting a thrombus with the serum BNP level was 0.860 (95% CI: 0.775 to 0.944). The sensitivity and specificity for predicting a thrombus with a BNP value of >135 pg/ml were 81.8% and 83.6%, respectively.

Conclusions:
A serum BNP level of >135 pg/ml might be a noninvasive predictive factor for LAA thrombi in AF patients under anticoagulation therapy with warfarin and dabigatran.
Abstract 12728: Common Variant Near
Hey2
as a Protective Modifier of Ventricular Fibrillation in Brugada Syndrome by Modurating QTc Interval
Authors: Nakano Yukiko , Ochi Hidenori , Toshisige Masaaki , Tokuyama Takehito , Kawazoe Hiroshi , Watanebe Yoshikazu , Matumura Masaya , Tomomori Shunsuke , Kishimoto Shinji , Ikenaga Hiroki , Oda Noboru , Chayama Kazuaki , Kihara Yasuki
Published: July 2021

Introduction:
A recent genome-wide association study (GWAS) identified that three loci,
SCN10A
(rs10428132),
SCN5A
(rs11708996), and one downstream from
HEY2
gene (rs9388451) were associated with Brugada syndrome.

Methods:
We investigated these 3 single nucleotide polymorphisms (SNPs) in 94 Japanese patients diagnosed with Brugada syndrome and 1,978 healthy controls.

Results:
Both rs10428132 at
SCN10A
and rs9388451near
HEY2
were associated with Brugada syndrome [
P
= 6.13 х 10
–14
;odds ratio (OR), 8.0 and P = 8.0 х 10
–4
; OR, 2.5, respectively). However, the C
HEY2
allele was more frequent in Brugada syndrome patients without ventricular fibrillation (VF) than those with VF (53.7% vs. 40%, P = 0.04). This suggests a protective effect of this allele against VF occurrence, which may conflict with previous GWAS findings. The QTc interval was significantly longer in patients with the
HEY2
risk allele than those without it (CC: 422 ± 3.8 vs. CT: 409 ± 4.8 vs. TT: 381 ± 9.5 ms,
P
= 0.0004). The other electrocardiogram parameters were unrelated to the
HEY2
allele. PQ interval was longer in patients with the
SCN10A
risk allele than those without it (CC: 157 ± 2.5 vs. CT: 172 ± 5.3 vs. TT: 172 ± 3.5 ms,
P
= 0.0019), but the
SCN10A
SNP was not associated with clinical severity of Brugada syndrome.

Conclusions:
These results suggest that the
HEY2
SNP may be a prognostic marker for Brugada syndrome, protecting VF occurrence presumably by regulating repolarization current.
Abstract 12749: Impact of Intrastent Yellow Plaque Observed by Coronary Angioscopy at Late Phase After Drug-Eluting Stents Implantation in Clinical Outcome
Authors: Dai Kazuoki , Yamaji Takayuki , Oono Takafumi , Morita Yuuichi , Hashimoto Haruki , Harima Ayako , Ooi Kuniomi , Oka Toshiharu , Nakama Yasuharu , Sairaku Akinori , Nishioka Kenji , Miura Fumiharu , Shimatani Yuji , Inoue Ichiro , Ishihara Masaharu
Published: July 2021

Background:
Previous study showed that number of yellow plaque in a coronary artery was associated with future risk of acute coronary syndrome. However, impact of intrastent yellow plaque has not fully understood.

Purpose:
This study was investigated to assess the association of the grade of intrastent yellow plaque observed by coronary angioscopy at late phase after drug-eluting stents (DES) implantation and clinical outcome.

Methods:
This study consisted of 97 patients tread with DES implantation (39 patients with sirolimus-eluting stents ; 9 patients with paclitaxel-eluting stents; 24 patients with everolimus-eluting stents; 6 patients with zotalolimus-eluting stents; 19 patients with biolimus-eluting stents ). Coronary angioscopy was performed 8 months after DES implantation. The plaque color at stent segment was grade as 0 (white), 1 (light yellow), 2 (yellow), 3 (bright yellow). The maximum color grade of the plaques in stent segment was assessed. We divided these patients into 2 groups (53 patients with yellow plaque grade 2 or 3; 44 patients with yellow plaque grade 0 or 1). We evaluated the incidence of revascularization, such as percutaneous coronary intervention or coronary artery bypass graft.

Results:
Kaplan-Meier curves for 7-year Revascularization free rate are shown in Figure. Revascularization free rate was tend to be higher in patients with yellow grade 0/1 than those with yellow grade 2/3.

Conclusion:
The presence of intrastent yellow plaque at late phase after stent implantation might be associated with the future revascularization in coronary artery disease.