bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11113: A Novel ATF4 Dependent ER-Stress Induced Transcriptional Unit Within the CHAC1 Promoter
Authors: Crawford Rebecca R , Prescott Eugenia T , Mungrue Imran N
Published: July 2021

A systems genetics screen of transcriptome wide RNA co-expression in a population of human cell cultures can broadly define novel functional gene-gene relationships. Using this method, we predicted a role for the human gene, CHAC1, within the ER-stress pathway functionally linked to ATF4. Targeted cell culture and genetic perturbations refined a role for CHAC1 as an ER-stress gene regulated by ATF4. ATF4 siRNAs blocked induction of CHAC1 mRNA by ER-stress, and ATF4 over-expression induced CHAC1 mRNA expression. ATF4 is an important gene involved in ER-stress and apoptotic signaling, and we demonstrated the pro-apoptotic potential for CHAC1. ATF4 plays important roles in osteoblast development, metabolic disease and atherosclerosis. Herein a direct transcriptional link between ATF4 and the CHAC1 promoter by ATF4 is defined in the setting of ER-stress. We cloned the CHAC1 promoter upstream of luciferase reporter system to define functional elements by deletion analysis. A highly conserved bipartite DNA element dubbed the ATF/CRE and ACM were the major regulators of basal CHAC1 expression, induction by ER-stress agonists or ATF4 co-expression. We compared the CHAC1 promoter -luciferase reporter to well-characterized ATF4 target genes CHOP and ASNS, using parallel luciferase assays. Notably, the CHAC1 promoter-reporter was induced to the highest extent following ATF4 co-expression compared to CHOP and ASNS promoters. Using a novel Immunoblot-EMSA assay we determined binding of ATF4 and ATF3, but not CHOP to CHAC1 ATF/CRE and ACM oligos. We also used the CHip method to query binding of ATF3 and ATF4 at the CHAC1 promoter under control and ER-stress conditions. We noted significant binding of ATF3 to the CHAC1 promoter under control and ER-stress treatment. Interestingly, we noted a dramatic increase in ATF4 occupancy at the CHAC1 promoter accompanying ER-stress. The ATF4 responsive ATF/CRE and ACM of the CHAC1 promoter represent a novel target for ATF4, and may reveal important contributions to disease processes involving ATF4. These data also implicate CHAC1 as an important target gene of ATF4, which may mediate important biological effects in the setting of ER-stress, and might have implications for cardiovascular and metabolic disease.
Abstract 11127: Let-7 Family MicroRNAs Expression in Subcutaneous Skin Negatively Correlate With Severity of Pulmonary Hypertension in Patients With Systemic Scleroderma
Authors: Izumiya Yasuhiro , Kimura Yuichi , Onoue Yoshiro , Hanatani Shinsuke , Araki Satoshi , Ogawa Hisao
Published: July 2021

Introduction:
MicroRNAs (miRNAs) have been shown to play an important role in various cardiovascular diseases. However, its roles in the pathogenesis of connective tissue disease-associated pulmonary hypertension (PH) are not clear.

Hypothesis:
In patents with systemic scleroderma (SSc), subcutaneous miRNAs expression profiles are different depending on the presence or absence of PH.

Methods and Results:
Data of 16 SSc patients who underwent subcutaneous tissue biopsy were available for retrospective analysis. To determine the changes in subcutaneous miRNAs expression profiles in SSc-associated PH, a mixture of equal amount of subcutaneous miRNAs from 6 PH or 6 non-PH were prepared. We performed miRNA PCR array analysis, and the miRNA expression was comprehensively compared between PH and non-PH group. We found that 591 miRNAs were upregulated, and 57 miRNAs were downregulated in PH group (Figure). Among them, only miRNAs which showed a Ct value less than 35 were considered for further analysis. When a 1.5-fold difference was considered meaningful, 32 miRNAs were upregulated, and 14 miRNAs were down regulated in PH group. Interestingly, 5 out of 14 downregulated miRNAs belong to let-7 family (let-7a, -7b, -7d, -7f, -7g). We validated the results by quantitative real-time PCR with specific primer for each miRNAs individually and found that 4 let-7 family members (let-7a, -7d, -7f, -7g) were significantly downregulated in 6 PH compared with those in 10 non-PH skin. The expression level of let-7d was negatively correlated with pulmonary arterial pressure measured by echocardiography.

Conclusions:
The expression level of let-7 family microRNAs in subcutaneous skin are lower in patients with SSc with PH than those without PH. Let-7 family microRNAs expression in subcutaneous skin negatively correlate with severity of PH in patients with SSc. Subcutaneous miRNA could be a useful marker to identify the presence and severity of PH in patients with SSc.
Abstract 11212: Left Atrial Volume Index Predicts Recurrence of Stroke in Patients With Non-Sustained Atrial Tachycardia
Authors: Chung Hyemoon , Min Pil-Ki , Yoon Young Won , Lee Byoung-Kwon , Hong Bum-Kee , Rim Se-Joong , Kwon Hyuck Moon , Choi Eui-Young , Kim Jong-Youn
Published: July 2021

Introduction:
NSAT is known to appear more frequently in patients with paroxysmal AF. Additionally enlarged LA is considered to be an independent risk factor for newly diagnosed AF. We investigated the relationship between non-sustained atrial tachycardia (NSAT) and stroke recurrence and the risk factors that may predict stroke recurrence in stroke patients where 24-hour Holter monitoring documented NSAT without paroxysmal AF.

Hypothesis:
We hypothesized that those patients who presented with NSAT and enlarged LA would have a higher incidence of stroke recurrence.

Methods:
214 patients (102 males, mean 70±11 years) with acute ischemic stroke and NSAT were subject to 24-hour Holter monitoring. During follow-up patients were assessed for stroke recurrence and echocardiographic parameters.

Results:
During a mean follow-up period of 36±34 months, the recurrence rate of stroke was 11.8% (25 of 214). Those patients with recurrence had a larger LA diameter (34.73±5.04 vs. 40.64±3.45mm, p<0.001), LA volume index (LAVI, 22.56±5.86vs. 33.81±7.80 ml/m
2
, p<0.001and increased E/E’ (12.27±4.86 vs. 14.49±4.38, p=0.032) compared to patients without recurrence (n=189). A Kaplan-Meier survival rate was significantly lower in patients with enlarged LA size (LAVI>28 mm
3
/m
2
) compared with patients without enlarged LA size (LAVI≤28 mm
3
/m
2
) (p<0.001 by log-rank test). Cox regression analysis revealed that left atrial volume index hazard ratio (HR: 1.148, 95% CI: 1.092-1.206, p<0.001) was an independent predictor for stroke recurrence in patients with NSAT. Areas under the Receiver Operating Characteristics (ROC) curve of LAVI for recurrence of stroke was 0.876 (95% CI: 0.791-0.960, p<0.001).

Conclusions:
In patients with acute ischemic stroke and NSAT, increased LAVI predicts an increased risk of stroke recurrence. This study supports the potential use of anticoagulants in stroke patients with NSAT and increased LAVI without documented AF to reduce recurrent stroke.
Abstract 11217: A New Treatment for Diastolic Heart Failure: Trabecular Cutting
Authors: Halaney David L , Acevedo Pedro J , Pérez William , Feldman Marc D
Published: July 2021

Background:
Heart failure with preserved ejection fraction remains a leading cause of hospitalization, without development of new medications and operative procedures to treat these patients. We hypothesize that trabeculae carneae serve an important role in modulating LV diastolic compliance, and during hypertrophy of the myocardium, trabeculae contribute to abnormal compliance.

Methods and Results:
Eight
ex vivo
human hearts from patients with LV diastolic dysfunction were perfused at 37[[Unable to Display Character: ⁰]]C and had a balloon inserted into the LV through the mitral annulus. Diastolic LV pressure-volume compliance curves were measured at baseline and following trabecular cutting. LV compliance improved significantly (n=6, p<0.001), but not in the control hearts without trabecular cutting (n=2, p=0.85). The figure shows aggregate data from the six hearts before and after trabecular cutting. To determine if trabeculae serve a similar role in all mammals, 28 hearts from 10 species were obtained. We demonstrate significant relationships between circumferential wall stress and the number of trabeculae in these species, particularly trabeculae which attach nets of trabeculae to the ventricle walls (p=0.02, n=733) and trabeculae located at the apex and free wall (p=0.02, n=602). The percent of LV cardiac titin of the stiff isoform (%N2B), a determinate of LV diastolic compliance, also demonstrated a significant relationship with the number of trabeculae with the same anatomic subsets (p=0.04, n=597; and p=0.02, n=488, respectively).

Conclusions:
We demonstrate for the first time that rather than being an embryologic remnant, trabeculae carneae serve an important role in the maintenance of passive LV diastolic compliance, and can contribute to LV diastolic dysfunction. A new procedure, cutting trabeculae, is proposed to improve LV diastolic compliance.
Abstract 11288: Breast Arterial Calcifications and Their Association With Cardiovascular Disease in the Prospect Cohort
Authors: Hendriks Eva J , Beulens Joline W , Mali Willem P , van der Graaf Yolanda , de Jong Pim A , van der Schouw Yvonne T
Published: July 2021

Introduction:
Breast arterial calcifications (BAC) are a type of medial arterial calcification observed at mammography. They are more prevalent among diabetes patients and thought to be associated with increased cardiovascular risk, but high quality longitudinal studies are scarce. We aimed to investigate the association of BAC with risk of different types of cardiovascular outcomes.

Methods:
We performed a series of case-cohort studies nested within the PROSPECT-EPIC cohort, including a random subcohort (n = 1672), and incident cases of coronary heart disease (n=1050), stroke (n=399) peripheral artery disease (n=257), cardiovascular mortality (n=250), and type 2 diabetes (n=526). At baseline BAC was scored as absent, mild, moderate or severe by experienced radiologists. The average follow-up time was 12.0(±1.9) years. We calculated hazard ratios(HRs) using Cox proportional hazards models, adapted to the case-cohort design through Prentice-weighting and adjusting for traditional cardiovascular risk factors.

Results:
Of the women in the sub cohort with mammograms available (n=1540), 133 women (8.6%) had BAC in at least one breast. Grade was scored as mild in 75 women (4.9%), moderate in 39 women (2.5%) and severe in 19 women (1.2%). BAC presence was borderline significantly (0.05<p<0.10) associated with risk of coronary heart disease, stroke and cardiovascular mortality, with adjusted HR estimates ranging from 1.42 to 1.58. Much larger effect sizes were found for women with the most severe grade of BAC, as they had a HR of 3.43 (95% CI 1.85-6.37) for coronary heart disease, a HR of 3.19 (95% CI 1.52-6.72) for stroke, a HR of 2.92 (95%CI 1.02-8.35) for peripheral artery disease and a HR of 3.55 (95%CI 1.48-8.52) for cardiovascular mortality compared to women without BAC.

Conclusions:
BAC presence is modestly associated with cardiovascular disease, with an approximately 3-fold increased risk for the severest grade of BAC, independent of traditional risk factors. This indicates a possible contribution of a medial, non-atherosclerotic pathway to cardiovascular disease events. Whether BAC is a marker of medial arterial calcification in different vascular beds needs to be further investigated.
Abstract 11302: Sevoflurane Pre-Conditioning Effectively Ameliorates Diabetic Myocardial Ischemia/Reperfusion Injury via Differential Regulation of p38 and ERK
Authors: Zhao Jianli , Li Jingjing , Li Rui , Jiao Liyuan , Zhang Yanqing , Wang Lili , Yuan Yuexing , Lau Wayne Bond , Ma Xin , Wang Yajing
Published: July 2021

Diabetes (DB) significantly exacerbates myocardial ischemia/reperfusion (MI/R) injury. Unfortunately, conventional pre-conditioning (PreCon) provides diminished cardioprotection during DB, due partially to impaired AMP-activated protein kinase (AMPK) signaling. The current study investigated whether PreCon by inhaled anesthetic sevoflurane (SF-PreCon) remains protective in DB, and if so, to dissect the involved mechanisms. Non-diabetic (ND) or high-fat diet-induced DB mice were subjected to MI/R and randomized into control and SF-PreCon (3 cycles of 15 minute-exposures to 2% sevoflurane prior to MI) groups. As expected, SF-PreCon significantly reduced MI/R injury in ND mice. Importantly, SF-PreCon also significantly reduced MI/R injury in DB mice, as evidenced by reduced apoptosis (-23.1±1.6, P<0.01), decreased infarct size (-21.2±2.3%, P<0.01), and augmented cardiac function (+24±3.0%, P<0.01). To determine the role of AMPK in SF-PreCon-mediated cardioprotection, the effect of SF-PreCon upon MI/R injury was determined in cardiac specific AMPKα2 dominant negative overexpression mice (AMPK-DN). We demonstrate SF-PreCon remained cardioprotective in AMPK-DN mice. To explore the responsible molecular mechanisms, multiple cell-survival signaling molecules were screened. Interestingly, SF-PreCon differentially regulated mitogen-activated protein kinase (MAPK) family members in the MI/R heart. In ND mice, SF-PreCon dramatically reduced (-81±7.2%) MI/R-induced activation of p38, a pro-death MAPK, without significantly altering ERK and JNK. In DB and AMPK-DN mice, the inhibitory effect of SF-PreCon upon p38 activation was significantly blunted (DB: -8±2.1%) or virtually abolished (AMPK-DN). However, SF-PreCon significantly increased (P<0.05) phosphorylation of ERK1/2, a pro-survival MAPK. Collectively, we demonstrate SF-PreCon protected the heart via AMPK-dependent inhibition of pro-death MAPK in ND mice. However, SF-PreCon exerts its cardioprotective actions via AMPK-independent activation of pro-survival MAPK in DB mice. These results suggest SF-PreCon may be a superior intervention over conventional PreCon in DB patients, where AMPK signaling is impaired.
Abstract 11322: Detection of Subclinical Left Ventricular Systolic Dysfunction by Real-Time 3D Speckle Tracking Echocardiography in Patients With Myocardial Bridge of Left Anterior Descending Coronary Artery
Authors: Sun Jing Ping , Wang Dian , Yang Xing Sheng , Lee Alex Pui-Wai , Ma Gengshan , Liu Nai Feng , Yu Cheuk-Man
Published: July 2021

Background:
To understand the impact of myocardial bridge (MB) on left ventricle (LV) function, we evaluate the myocardial function in patients with MB of the left anterior descending coronary artery (LAD), using real-time 3-dimensional speckle tracking echocardiography (RT3D-STE).

Methods:
The LAD MB was diagnosed by coronary angiography in 82 patients. According to the percentage of systolic compression (SC), patients were divided into 3 groups: SC <50% defined as Group I (n=24), SC 50%-75% as Group II (n=28), and SC >75% as Group III (n=30). Thirty age and gender matched normal subjects were studied as controls. The traditional echocardiography was performed, and LV deformation was estimated by RT3D-STE.

Results:
The LV ejection fraction was normal in patients with LAD MB. However, the peak longitudinal (LS) and area strain (AS) of the LAD territory were significantly reduced in Group II and III when compared with controls and Group I (p<0.05). The peak circumferential (CS) and radial strain (RS) were significantly reduced only in Group III (p<0.05) (Table). Furthermore, the amplitude of strain variables were significantly reduced in patients with symptom than those without (AS: 17.7±6.4 vs. 25.3±8.4%; LS:-13.0±1.9 vs. -16.2±2.5%; CS:-15.4±3.3 vs. 18.9±3.0 %; RS: 36.6±3.8 vs. 49.4±2.7%; all p<0.0001). The severity of LAD compression correlated the best with with AS at LAD territory (r=–0.90, p<0.0001), although it was also significant in conventional strain variables (LS: r =–0.79, CS: r =–0.69, RS: r =–0.64, all p <0.0001).

Conclusions:
Despite apparently normal ejection fraction, myocardial strain is abnormal in the LAD territory which had MB. Such abnormality is more pronounced in patients with progressively more severe MB and in those with symptoms. Furthermore, the area strain by RT3D-STE appeared to be most accurate in detection of subclinical systolic dysfunction in patients with LAD MB than conventional 2D strain parameters.
Abstract 11403: T-Wave Area as an Additional Predictor of Volumetric and Clinical Response to Cardiac Resynchronization Therapy
Authors: Engels Elien B , Vegh Eszter M , van Deursen Caroline J , Vernooy Kevin , Singh Jagmeet P , Prinzen Frits W
Published: July 2021

Purpose:
Chronic heart failure (HF) patients with a left ventricular (LV) conduction delay, mostly due to left bundle branch block (LBBB), derive benefit from cardiac resynchronization therapy (CRT). However, approximately 30% of patients do not improve clinically after CRT. We investigated whether T-wave analysis can improve patient selection.

Methods:
The study population comprised 335 CRT recipients with baseline 12-lead electrocardiogram recordings. Echocardiographic response after 6-months CRT was defined as a ≥ 5% increase in LV ejection fraction (LVEF). Patients were assessed for HF hospitalization and death separately, as well as both combined with heart transplantation and LVAD implantation (HTLD) at 3 years follow-up. T-wave area was determined in vectorcardiograms (VCGs), constructed from digital 12-lead ECGs using an adapted Kors method.

Results:
Logistic regression models indicated repolarization variables as good predictors of CRT response. The VCG-derived T-wave area predicted CRT response (odds ratio (OR) per 10 μVs increase 1.172 (p < 0.001)), even better than QRS-wave area (OR = 1.116 (p = 0.001)). T-wave area had especially predictive value in LBBB patients (OR = 2.77 in LBBB vs. 1.09 in non-LBBB). This predictive value persisted after adjustment for multiple covariates, such as gender, ischemia, age, hypertension, coronary artery bypass graft, and the usage of diuretics and beta-blockers. The table depicts that patients with large T-wave area showed a larger increase in LVEF and a lower occurrence of the end-points HF hospitalization, death and HTLD, as compared to those with a small T-wave area, the difference being significant for LBBB patients.

Conclusions:
In patients with LBBB morphology of the QRS complex, a larger baseline T-wave area is an important additional predictor of both volumetric and long-term clinical response following CRT.
Abstract 11405: The Association of Co-Morbid Symptoms of Depression and Anxiety With All-Cause Mortality in Patients With Heart Failure
Authors: Alhurani Abdullah , Dekker Rebecca , Abed Mona , Khalil Amani , Lee Kyoung Suk , Mudd-Martin Gia , Biddle Martha , Lennie Terry , Moser Debra K
Published: July 2021

Introduction:
Depression or anxiety are associated with survival in heart failure (HF); however, whether co-morbid symptoms of anxiety and depression are associated with survival in patients with HF is unknown.

Hypothesis:
Co-morbid symptoms of depression and anxiety are more strongly associated with all-cause mortality in patients with HF compared to those with anxiety or depression alone.

Methods:
A total of 1,260 HF patients participated and were followed for mortality outcomes for 12 months. The Patient Health Questionnaire (PHQ-9) and Brief Symptom Inventory-anxiety subscale (BSI) were used to measure symptoms of depression and anxiety. Cox regression analysis was used to determine whether co-morbid symptoms of depression and anxiety independently predicted all-cause mortality controlling for age,gender, ethnicity, and NYHA class. Depression and anxiety were treated first as continuous level variables, then as categorical variables using standard published cut points. Patients were divided into four groups based on the presence of anxiety and depression symptoms: 1) neither anxiety nor depression, 2) depression alone, 3) anxiety alone, and 4) co-morbid depression and anxiety

Results:
When entered as continuous variables, the interaction between anxiety and depression (HR 1.02; 95% CI: 1.01-1.03; p = 0.002) was a significant predictor of all-cause mortality. When entered as a categorical variable, co-morbid symptoms of depression and anxiety (versus the other three groups) independently predicted all-cause mortality (HR 2.59; 95% CI: 1.49-4.49; p = 0.001).

Conclusions:
To improve mortality outcomes in patient with HF, attention must be paid by healthcare providers to the assessment and management of co-morbid symptoms of depression and anxiety.
Abstract 11437: Circulating Anti-Elastin Antibody and Arterial Disease Characteristics: Association With Arterial Stiffness and Atherosclerosis
Authors: Lee Seung-Hyun , Shin Kihyuk , Park Sungha , Kang Seok-Min , Lee Seung-Hyo , Lee Sang-Hak
Published: July 2021

Objectives:
Elastin is a major structural protein of arteries and elastin derived peptide is known to be related to arterial change. We previously reported a novel assay for anti-aortic elastin antibody, but its clinical implication has not been clearly shown. The aim of this study was to check if anti-aortic elastin antibody titers may reflect the risk of coronary artery disease (CAD) or its detail characteristics.

Methods:
This study included 174 CAD patients and 171 age-, sex-matched control subjects. In all subjects, anti-aortic elastin antibody titer was quantified by ELISA. Parameters of arterial stiffness including augmentation index (AI) and heart to femoral pulse wave velocity (hfPWV) were measured non-invasively. In patients with CAD, clinical and angiographic characteristics were evaluated. Associations between anti-aortic elastin and vascular characteristics were identified by linear regression analysis.

Results:
Median blood level of anti-aortic elastin was significantly lower in the CAD group than that of the control group (197 a.u. vs. 63 a.u., p<0.001). Levels of anti-aortic elastin were significantly lower in males, subjects with hypertension, diabetes mellitus, hyperlipidemia, or hfPWV (Figure). However, the levels were not dependent of atherothrombotic events or angiographic severity of CAD (Figure). In multivariate analysis, male (β=-0.38, p<0.001), diabetes mellitus (β=-0.62, p<0.001), hyperlipidemia (β=-0.29, p<0.001), and AI (β=-0.006, p=0.02) were finally identified as determinants for anti-aortic elastin levels (Table).

Conclusions:
Taken together, lower levels of anti-aortic elastin are related to CAD. The association between antibody titer and CAD is linked to arterial stiffness rather than advancement of atherosclerosis.
Abstract 11446: Systemic Administration of Mitochondria Alleviates 100% Oxygen-Induced Acute Respiratory Distress Syndrome in Rats
Authors: Yip Hon Kan , Tsai Tzu -Hsien , Leu Steve , Chua Sarah
Published: July 2021

Background:
We tested the hypothesis that mitochondria-replacement therapy ameliorated 100% oxygen-induced rat acute respiratory distress syndrome (ARDS).

Methods and Results:
Adult-Male SD rats (n=24) were equally categorized into group 1 (controls, room air inhalation), group 2 (ARDS: induced by inhalation of 100% oxygen for 48 hrs), and group 3 [ARDS + mitochondrial transfusion (1400 μg/each rat) from intra-venous administration 6 h after ARDS induction]. By 72 h after ARDS induction, the oxygen saturation (O
2
-Sat) was significantly lower in group 3 and more significantly lower in group 2 than in group 1, whereas pulmonary artery systolic-blood pressure showed a reversed pattern of O
2
-Sat among three groups (all p<0.001). H&E stain for lung crowded score showed an identical pattern of O
2
-Sat and number of alveolar sacs and lung weight exhibited an opposite pattern of O
2
-Sat among the three groups. The protein expressions of apoptotic (mitochondrial Bax, cleaved caspase 3 & PARP), fibrotic (Smad5, TGF-β), ROS (NOX-1, NOX-2, NOX-4), oxidative stress (oxidized protein), DNA- & mitochondrial-damaged (γ-H2AX, Ki-67; cytosolic cytochrome-c) and inflammatory (TNF-α, MMP-9, NF-κB) biomarkers, and IHC/IF microscopic findings of inflammatory (CD14+, CD68+), DNA-damaged (γ-H2AX+, Ki-67+) cells exhibited an opposite pattern, whereas the protein expressions of anti-apoptotic (Smad1/3, BMP-2) markers exhibited an identical pattern of O
2
-Sat among three groups (all p<0.001). The anti-oxidant (HO-2, NQO-1), mitochondrial-preserved (mitochondrial cytochrome-c) biomarkers, and cellular levels of anti-oxidants (HO-1, NQO-1, GR, GPx) were significantly higher in group 2 and more significantly higher in group 3 than in group 1 (all p<0.0001).

Conclusions:
Mitochondria therapy protects against 100% oxygen-induced ARDS.

Key words:
mitochondrial replacement, acute lung injury, inflammation, oxidative stress, DNA and mitochondrial damage
Abstract 11521: Prognostic Value of Left Atrial Function in Normal Exercise Stress Echocardiography
Authors: Tsutsui Rayji S , Kusunose Kenya , Popovic Zoran B , Thomas James D
Published: July 2021

Background:
The association between poor left atrial (LA) function and adverse outcomes in subjects following an acute myocardial infarction is recognized. On the other hand, prognostic value of LA function in low risk subjects is not well characterized. The purpose of this study was to assess the prognostic value of LA function in subjects who have exercise stress echocardiography negative for ischemia.

Methods:
Subjects who underwent exercise stress echocardiography for exclusion of coronary artery disease (CAD) between January to April 2010 were included. Subjects were excluded if they were in atrial fibrillation/flutter at the time of exercise, left ventricular ejection fraction (LVEF) < 45%, moderate or severe valvular disease, echocardiographic evidence of exercise-induced myocardial ischemia, or had known CAD. Maximum metabolic equivalents (METs), LA total strain (analyzed offline with Siemens Syngo VVI), LV E/e’, LA volume index (LAVI) were measured for all subjects. Diagnosis of major adverse cardiac events (MACE: myocardial infarction, coronary revascularization, cardiovascular mortality) and coronary artery disease (CAD: angina, unstable angina) were recorded.

Results:
Of 672 subjects identified, 486 subjects remained after exclusion. The mean follow up time was 51.6 ± 1.2 months, and the mean LVEF was 56 ± 5%. Following the index stress test, 25 (5%) subjects had MACE and 35 (7%) subjects had CAD. With MACE, maximum METs was a strong prognostic factor, with worse outcome when METs < 9 (median = 9). None of the echocardiographic parameters reached statistical significance. For CAD, none of the variables reached statistical significance including METs.

Conclusions:
In subjects who have negative exercise stress test for ischemia, reduced METs was strongly associated with adverse outcomes. In this low risk population, none of the tested LA echocardiographic parameters appeared to be associated with adverse outcomes.
Abstract 11598: Increased Advanced Glycation End-Products Accelerate the Progress of Left Ventricular Hypertrophy Under Condition of Elevated Oxidative Stress or Insulin Resistance in Patients With Hypertension
Authors: Akihiro Aoyama , Takashi Masuda , Misao Ogura , Ryosuke Shimizu , Michitaka Kato , Daisuke Kamekawa , Yumi Kamada , Shinya Tanaka , Kentaro Kamiya , Nobuaki Hamazaki , Emi Maekawa , Minako Tojo Y , Junya Ako
Published: July 2021

Background:
Elevated oxidative stress or insulin resistance has been shown to promote the production of advanced glycation end-products (AGEs) in patients with hypertension (HT). Because AGEs enhance left ventricular hypertrophy (LVH) via the activation of nuclear factor-kappa B, it is considered that increased AGEs contribute to LVH in HT patients. The aim of this study was to investigate the effect of increased AGEs on LVH in them.

Methods:
Eighty five HT patients aged 65 ± 9 years were prospectively followed up for a year, whose blood pressure was controlled under 140/90mmHg. We assessed patients’ glucose and lipid metabolism and neurohumoral factors including plasma noradrenaline and renin activity as clinical characteristics.

We measured serum malondialdehyde-modified LDL-cholesterol (MDA-LDL) and plasma pentosidine as parameters of oxidative stress and AGEs, respectively. Homeostasis model assessment ratio (HOMA-R), estimate glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) were assessed as parameters of insulin resistance, renal function and LVH, respectively. All parameters were assessed before and after one-year observation period. We examined the change in each parameter from baseline to the value measured after the observation period ([[Unable to Display Character: ⊿]]MDA-LDL, [[Unable to Display Character: ⊿]]pentosidine, [[Unable to Display Character: ⊿]]HOMA-R and [[Unable to Display Character: ⊿]]LVMI). We divided patients into two groups based on the median of baseline pentosidine: high AGEs and low AGEs groups. We compared baseline values between the two groups. We analyzed the relationships among [[Unable to Display Character: ⊿]]MDA-LDL, [[Unable to Display Character: ⊿]]HOMA-R, [[Unable to Display Character: ⊿]]Pentosidine and [[Unable to Display Character: ⊿]]LVMI, and performed stepwise multiple regression analysis using parameters of clinical characteristics and AGEs to detect the predictors for the LVH progress after one year.

Results:
Baseline LVMI was significantly higher in the high AGEs group than in the low AGEs group (P<0.05). [[Unable to Display Character: ⊿]]Pentosidine was positively correlated with [[Unable to Display Character: ⊿]]MDA-LDL (r=0.34, P<0.01),[[Unable to Display Character: ⊿]]HOMA-R (r=0.37, P<0.01) and [[Unable to Display Character: ⊿]]LVMI (r=0.39, P<0.05). Multiple regression analysis detected pentosidine as a significant independent predictor for the LVH progress (β=0.407, P=0.005) (R2=0.315).

Conclusion:
Increased AGEs accelerated the LVH progress under condition of elevated oxidative stress or insulin resistance in HT patients.
Abstract 11607: Novel Assay for Detection of LDL Transcytosis Across Coronary Endothelium Reveals an Unexpected Role for SR-B1
Authors: Armstrong Susan M , Sugiyama Michael G , Levy Andrew , Neculai Dante , Roufaiel Mark , Bolz Steffen-Sebastian , Cybulsky Myron , Heit Bryan , Lee Warren L
Published: July 2021

Introduction:
Retention of LDL beneath the arterial endothelium initiates an inflammatory response culminating in atherosclerosis. How LDL crosses the endothelium to enter the arterial wall remains unknown. While LDL could conceivably pass between endothelial cells (paracellularly) or through them (transcytosis), electron microscopy studies in animals revealed LDL in intracellular vesicles and none at intercellular junctions. This, combined with the absence of endothelial injury or intercellular gaps in early atherosclerosis, suggests that transcytosis is the major route. However, technical challenges with studying transcytosis have made confirming and extending these findings difficult. We developed and validated a novel assay for measuring the transcytosis of native LDL across live human coronary artery endothelium in vitro. Using this assay, we propose to elucidate the regulation of LDL transcytosis and have identified a novel role for SR-B1.

Methods and Results:
Experiments were performed using primary human coronary artery endothelial monolayers. Transcytosis was quantified in single live cells in real time using total internal reflectance fluorescence microscopy. Transcytosis of LDL was saturable and inhibited by excess unlabeled LDL. By fluorescence microscopy we found that DiI-LDL colocalized significantly with scavenger receptor, class B, type 1 (SR-B1). Unexpectedly, overexpression of SR-BI resulted in increased LDL transcytosis, while knockdown of SR-BI by siRNA inhibited transcytosis. Excess HDL, the canonical SR-B1 ligand, also decreased LDL transcytosis. To confirm the occurrence of transcytosis in an intact vessel, we perfused murine aortas ex vivo with both LDL and dextran of a smaller molecular radius. We observed the accumulation of subendothelial LDL without dextran, indicating that transcytosis of LDL occurs in intact vessels.

Conclusions:
The accumulation of LDL in the subendothelial intima is the first step of atherosclerosis yet little is known about how it occurs. Our data suggests that transcytosis of LDL is an important contributor, particularly in the early stages of the disease. By identifying the mechanisms of transcytosis, our work could have important implications for its pathogenesis and therapy.
Abstract 11637: Physical Activity and Atrial Fibrillation: Results From the Multi-ethnic Study of Atherosclerosis (MESA)
Authors: Bapat Aneesh , Nazarian Saman , Alonso Alvaro , Zhang Yiyi , Post Wendy , Guallar Eliseo , Soliman Elsayed Z , Heckbert Susan , Lima Joao , Bertoni Alain
Published: July 2021

Introduction:
Prior studies have raised the question of whether an association exists between physical activity (PA) and atrial fibrillation (AF), with mixed results. We sought to use the Multi-Ethnic Study of Atherosclerosis (MESA) database to examine the association between PA and AF in a diverse population without clinically recognized prevalent cardiovascular disease (CVD).

Hypothesis:
Increased exercise will have a protective influence on AF incidence.

Methods:
MESA participants (N=5793) with a completed baseline PA survey and complete covariate data were included. Incident AF events were determined based on hospital discharge ICD-9 codes and Medicare inpatient claims. Total intentional exercise (TIE), defined as a sum of walking for exercise, dance/sport, and conditioning, was used as our independent variable of interest. The MESA population was stratified based on whether they reported participation in any vigorous physical activity (VPA), which was defined as “heavy effort” expended in household chores, lawn/yard/garden/farm work, conditioning activities, and occupational/volunteering work. Cox models, adjusted for demographics and CVD risk factors, were used to determine hazard ratios (HR) for incident AF based on total intentional exercise (TIE) for the subgroups. We performed similar analyses using TIE as a categorical variable stratified into tertiles.

Results:
During a mean follow-up of 7.7±1.9 years, 199 AF cases occurred. In the overall MESA population, TIE alone was not associated with incident AF. However, within the group that reported any VPA (N=1866), there was a statistically significant protective influence of increasing TIE on incident AF (HR=0.658, p=0.014). Additionally, among the same group, the top tertile of TIE was associated with a significantly lower risk of incident AF compared with the group with no TIE (HR=0.48, p=0.048).

Conclusions:
TIE was associated with a lower risk of incident AF among those that participated in any VPA, and this protective influence was most notable among those that performed the most TIE. Perhaps as importantly, no subgroup of participants demonstrated an increased risk of incident AF with TIE. These results re-emphasize the beneficial role of exercise for cardiovascular health.
Abstract 11662: Obesity Does Not Increase Venous Thromboembolism in Hospitalized Medical Patients Upon Multivariate Analysis
Authors: Fontaine Gabriel V , Vigil Emily , Wohlt Paul , Collingridge David , Lloyd James F , Woller Scott C
Published: July 2021

Introduction:
Obesity increases the risk of venous thromboembolism (VTE) in hospitalized medical patients. Standard chemoprophylaxis in these patients may be suboptimal, potentially leading to increased VTE. The objective of this study was to compare the rate of VTE in obese (body mass index [BMI] ≤30 kg/m
2
) medical patients receiving standard VTE prophylaxis with rates in non-obese patients (BMI 17-29.9 kg/m
2
).

Hypothesis:
Obese patients will suffer from a higher incidence of VTE within 90 days of hospitalization.

Methods:
In a single-center retrospective cohort study, patients admitted to all medical units between November 2007 and November 2013 were evaluated for eligibility if they received an initial dose of VTE prophylaxis within 48 hours of admission. Appropriate prophylaxis was heparin 5000 units subcutaneously (SQ) every 8 to 12 hours or enoxaparin 30 mg SQ twice daily or 40 mg SQ once daily. Exclusion criteria included hypercoagulable states, therapeutic anticoagulation, and admission for trauma or surgery. The primary outcome was 90 day VTE defined as deep vein thrombosis or pulmonary embolism using ICD-9 codes. Secondary outcomes included in-hospital VTE, 30 day VTE, and 90 day mortality. Univariate and multivariate analyses were used in calculating p-values and odds ratios (OR) for the primary outcome.

Results:
There were 17,525 patients eligible for inclusion. The final cohort included 4,237 obese patients and 4,990 non-obese patients (median BMI 36 and 25 kg/m
2
, respectively). Obesity increased the risk of in-hospital VTE (5.6% vs. 4.4%; p=0.01), 30 day VTE (5.7% vs. 4.6%; p=0.013), and 90 day VTE (5.9% vs. 4.8%; p=0.028) on univariate analysis. However, using multiple logistic regression, obesity was not an independent predictor of 90 day VTE (OR 1.0; p=0.83). Variables which independently increased 90 day VTE were Charlson Comorbidity Index (OR 1.09; p=0.003), prior VTE (OR 36.35; p<0.001), congestive heart failure (OR 1.33; p=0.017), and surgery in 90 days following admission (OR 1.56; p=0.004). Mortality was lower at 90 days in obese patients (3.3% vs. 6.3% non-obese; p<0.001)

Conclusions:
The incidence of VTE at 90 days in hospitalized medical patients is significant, but it is uncertain if obesity independently contributes to this.
Abstract 11694: The Gut Hormone Obestatin Induces Nitric Oxide-Dependent Vasodilation and Inhibits Endothelin-1 Activity in Obese Patients
Authors: Schinzari Francesca , Tesauro Manfredi , Adamo Angelo , Paolucci Alessandra , Rovella Valentina , Di Daniele Nicola , Mores Nadia , Campia Umberto , Cardillo Carmine
Published: July 2021

Obese patients have vascular dysfunction related to impaired nitric oxide (NO)-dependent vasodilation and increased endothelin (ET)-1 activity. Obestatin is a gastrointestinal peptide with favorable metabolic actions linked to obesity and diabetes; it has also been shown to exert cardiovascular benefits in experimental models by producing vascular relaxation via specific activation of endothelium-dependent NO signaling. Here we tested the hypothesis that obestatin might have advantageous impacts on the NO pathway and the ET-1 system in patients with central obesity. To this purpose, forearm blood flow responses to intra-arterial infusion of graded doses of exogenous obestatin (0.2; 0.4; 0.8; 1,6; 3.2 nmol/min, each dose given for 5 min) were assessed in lean subjects (n=5) and in patients with central obesity (n=14), during the concurrent infusion of saline and after NO inhibition by L-NMMA (4 μmol/min for 15 min). In another group of obese patients (n=10), vascular responses to selective blockade of ET
A
receptors (BQ-123, 10 nmol/min for 60 min) were measured in the absence and the presence of obestatin (0.8 nmol/min). In lean subjects, before NO synthase inhibition obestatin resulted in a progressive increase in forearm flow (60% at the highest dose; P<0.001 vs. baseline); obestatin-induced vasodilation, however, was completely abolished by L-NMMA (P<0.001 vs. saline). Similarly, in obese patients obestatin induced a significant vasodilation (45%; P<0.001 vs. baseline), which was blunted by L-NMMA (16%; P<0.01 vs. saline). Before obestatin, in obese patients ET
A
receptor blockade resulted in a marked vasodilation (39% flow increase at 60 min; P<0.001 vs. baseline), which was totally abrogated in the presence of obestatin (P<0.001 vs. absence). In conclusion, obestatin produces vasorelaxation in healthy humans via specific activation of endothelium-dependent NO signaling. This beneficial effect of obestatin is preserved in obese arteries, where it is associated with inhibition of ET-1 signaling. These actions of obestatin, therefore, may be important in the normal regulation of vascular function and are clearly relevant to obesity, a condition characterized by increased prevalence of hypertension and cardiovascular complications.
Abstract 11726: Novel Non-Invasive Method to Estimate Myocardial Mass at Risk Calculated From Cardiac Computed Tomography Data: Validation Study Using Angiographic Myocardial Jeopardy Scores in Patients With Single Vessel Disease
Authors: IDE Seiko , Sumitsuji Satoru , Yokoi Kensuke , Yoshida Masatoki , Mizote Isamu , Awata Masaki , Yamasaki Keita , Tachibana Kouichi , Nanto Shinsuke , Sakata Yasushi
Published: July 2021

Background:
The myocardial mass at risk (MMAR), representing volume of myocardium distal to culprit lesion, is one of important factors for predicting adverse cardiac event in ischemic heart disease. However, current non-invasive cardiac imaging fails to quantify MMAR in patients with stable coronary artery disease. We have developed a new software calculating MMAR of any designated coronary artery by reconstructing the 3-dimensional-volume-data of cardiac computed tomography (CCT). The novel index, ratio of MMAR to whole left ventricular volume (%LV-MMAR), calculated with this software would be appealing to obtain MMAR objectively.

This study aims to compare the %LV-MMAR with Bypass Angioplasty Revascularization Investigation (BARI) and modified Albert Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) scores, both of which are invasive angiographic methods widely used to estimate MMAR, in patients with single-vessel disease.

Methods:
Between April 2008 and March 2014, patients suspected of effort angina pectoris without history of previous myocardial infarction were assessed with CCT and invasive coronary angiography. Of those, 48 patients who were revealed single-vessel disease (left anterior descending artery (LAD): n=22, left circumflex artery (LCX): n=11 and right coronary artery (RCA): n=15) were included in this study. %LV-MMAR was calculated on the software. BARI and modified APPROACH score were calculated and compared with %LV-MMAR.

Results:
Mean %LV-MMAR was 27.6 [18.2-37.1] %. BARI and APPROACH scores showed a significant correlation (r=0.92, p<0.0001). Also, a significant correlation was observed between %LV-MMAR versus BARI and %LV-MMAR versus APPROACH (r=0.95, p<0.0001 and r=0.9, p<0.0001, respectively). %LV-MMAR showed significant correlation with BARI and APPROACH scores in all vessels; LAD (r=0.95, p<0.0001 and r=0.91, p<0.0001, respectively), LCX (r=0.91, p=0.0001 and r=0.83, p=0.0002, respectively) and RCA (r=0.92, p<0.0001 and r=0.85, p<0.0001, respectively).

Conclusions:
This study revealed %LV-MMAR, calculated from CCT data on novel software, to be a promising index for estimating perfusion territory noninvasively in good agreement with BARI and modified APPROACH score.
Abstract 11738: AMP-Activated Protein Kinase Signaling Mediates the Cardioprotective Effect of Antithrombin Against Myocardial Ischemia and Reperfusion Injury
Authors: Ma Yina , Wang Jinli , Gao Junjie , Yang Hui , Sun Wanqing , Chen Xingchi , Wang Yanqing , Rezaie Alireza R , Li Ji
Published: July 2021

Introduction:
Antithrombin (AT) is an endogenous protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. In addition to its anticoagulant function, AT also exhibits an anti-inflammatory and cardioprotective function when it binds to distinct heparin sulfate proteoglycans (HSPG) on vascular endothelial cells. The energy sensor AMP-activated protein kinase (AMPK) is known to play an important cardioprotective role during myocardial ischemia and reperfusion (I/R).

Hypothesis:
The cardioprotective function of AT may be through activation of AMPK by which modulates the substrate metabolism.

Methods:
The cardioprotective activities of wild-type (WT) AT and its two recombinant derivatives one having high affinity and the other no affinity for heparin were evaluated in an acute
in vivo
regional ischemia/reperfusion (30 min/24 hours) injury model in which the left anterior descending coronary artery (LAD) was occluded and released. The serpin derivatives were given 5 min before reperfusion. Langendroff perfused heart system was used to approach an
ex vivo
global ischemia model.

Results:
AT-WT can activate the protective AMPK signaling pathway in both
in vivo
and
ex vivo
conditions. Blocking AMPK activity by using AMPK kinase dead (KD) transgenic mice, the cardioprotective function of AT against I/R damage was abolished. The AT derivative having high affinity for heparin was more effective in activating AMPK but the derivative lacking any affinity for heparin was inactive in eliciting AMPK-dependent cardioprotective activity. Moreover, the AMPK-dependent activity of AT significantly inhibited I/R-induced inflammatory c-Jun N-terminal protein kinase (JNK) pathway. In the
ex vivo
working heart perfusion system, the further studies revealed that the AMPK activity of AT also modulates cardiac substrate metabolism by increasing glucose oxidation but inhibiting fatty acid oxidation during I/R.

Conclusions:
These results suggest that AT binds to heparin sulfate proteoglycans to invoke a cardioprotective function through triggering cardiac AMPK activation, thereby attenuating JNK inflammatory signaling pathways and modulating substrate metabolism during I/R.
Abstract 11804: The Blood Glucose Concentration at Hospitalization is a Significant Predictor of In-Hospital Death in the Patients With Non-Diabetic Acute Decompensated Heart Failure
Authors: Kawasoe Shin , Kubozono Takuro , Torii Hiroyuki , Yamaguchi Tsuyoshi , Miyata Masaaki , Ohishi Mitsuru
Published: July 2021

Background:
The blood glucose (BG) concentration (BG≧140 mg/dL) at hospitalization is reported to be the short-term prognostic predictor in patients with acute myocardial infarction. However, it’s significance in patients with acute decompensated heart failure (ADHF) has not been elucidated.

Purpose:
To evaluate the prognostic power of BG levels at hospitalization in the patients with ADHF.

Methods:
We analyzed consecutive 517 ADHF patients admitted from January 2007 to December 2013. They were divided into the high BG group (H-BG: BG≧140 mg/dL, n=215) and the low BG group (L-BG: BG<140 mg/dL, n=302) by BG levels in an emergency room. Echocardiographic findings, laboratory data and in-hospital mortality were analyzed.

Results:
In 517 ADHF patients, the mean age, BG levels at hospitalization, left ventricular ejection fraction (LVEF) and B-type natriuretic peptide (BNP) were 79.7±11.8 years, 153.0±75.2 mg/dL, 52.2±15.8% and 831.5±787.9 pg/mL, respectively. There were no significant differences in age, LVEF and BNP level between H-BG and L-BG groups. The mortality rate in H-BG group was significantly higher than that in L-BG group (17.0% vs 8.1%, p=0.0081). In diabetic ADHF patients (n=138), there was no significant difference in the in-hospital mortality rate between H-BG (n=100) and L-BG (n=38) groups (13.2% vs 24.4%, p=0.1116). However, in non-diabetic ADHF patients (n=379), the in-hospital mortality rate was significantly higher in H-BG (n=115) group compared to L-BG (n=264) group (21.2% vs 5.6%, p<0.0001), and the logistic regression analysis revealed that the BG level at hospitalization could predict the in-hospital death (p=0.0381). The Kaplan-Meier survival curve demonstrated poorer prognosis in H-BG group compared to L-BG group in non-diabetic ADHF patients (Figure, p<0.0001).

Conclusion:
The BG concentration at hospitalization is a significant predictor of in-hospital death in ADHF patients without diabetes, but not with diabetes.