bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11005: Activation of Hypothalamic Mineralocorticoid Receptor-Independent Epithelial Sodium Channels Leads to Salt-Sensitive Hypertension in Mouse Model of Metabolic Syndrome
Authors: Kunita-Takanezawa Mutsumi , Ito Koji , Kishi Takuya , Hirooka Yoshitaka
Published: July 2021

Introduction and Hypothesis:
Metabolic syndrome (MetS) is often associated with salt-sensitive hypertension. In genetic salt-sensitive hypertensive models, activation of the hypothalamic mineralocorticoid receptor (MR)-epithelial sodium channel (ENaC) pathway has been established as a major worsening factor. However, in MetS, contribution of the hypothalamic MR-ENaC pathway to salt-sensitive hypertension remains unknown. Therefore, we determined whether the hypothalamic MR-ENaC pathway activation leads to salt-sensitive hypertension in MetS.

Methods and Results:
Diet-induced obesity (DIO) was achieved in male C57BL/6 mice by feeding them a high-fat diet from 4 weeks of age. Mice fed a normal diet served as controls (CON). Mice at 12 weeks of age were given tap water with regular salt (RS) or 1% NaCl (high salt; HS) for 8 weeks. HS led to increased systolic blood pressure only in DIO-mice, and not in CON-mice (DIO-HS: 122±3 mmHg vs DIO-RS: 107±2 mmHg, CON-HS: 109±2 mmHg vs CON-RS: 105±1 mmHg, n=6/group, p<0.05). In DIO-mice, 24-h urinary norepinephrine excretion after salt loading was significantly higher than that before salt loading (244±18 ng/day vs 371±29 ng/day, n=6 in each, p<0.05). HS-induced hypertension was significantly prevented by intracerebroventricular infusion of the ENaC blocker benzamil (Ben), but not the MR blocker spironolactone (Spl; DIO-HS-Vehicle 122±1 mmHg, DIO-HS-Ben 108±1 mmHg, DIO-HS-Spl 119±1 mmHg, n=6 in each, p<0.05). Expression of hypothalamic serum and glucocorticoid-regulated kinase (SGK) 1, a marker of MR activity, did not differ between in CON-mice and DIO-mice. However, the SGK1 phosphorylation level was greater in DIO-mice than in CON-mice, suggesting MR-independent SGK1 activation. Water intake and urinary sodium excretion did not differ between in DIO-HS-Vehicle and DIO-HS-Ben. Interestingly, salt loading-induced plasma arginine vasopressin (AVP) secretion was significantly prevented in DIO-HS-Ben.

Conclusions:
These findings suggest that salt-induced hypertension in DIO-mice results from MR-independent hypothalamic SGK1-ENaC activation with systemic AVP secretion. Hypothalamic ENaC could be a novel therapeutic target in salt-induced hypertension of MetS.
Abstract 11043: Lipoprotein(a) Cholesterol but not Lipoprotein (a) Mass is Significantly Correlated With Angiographic Coronary Artery Disease and Major Adverse Events
Authors: Baudhuin Linnea , Bryant Sandra , Spears Grant , Hartman Stacy , Somers Virend , Berger Peter , McConnell Joseph , Jaffe Allan
Published: July 2021

Introduction:
Elevated plasma levels of lipoprotein(a) [Lp(a)] are associated with increased risk for coronary artery disease (CAD), but the strength of the association and whether it is independent of other risk factors remains controversial. Differences in prospective studies may be partially explained by variability in methods used to measure Lp(a).

Methods:
We utilized two different analytical methods (electrophoretic and immunologic) to measure Lp(a) and determine the predictive value of Llp(a) in assessing angiographic coronary artery disease (CAD) and association with major adverse events in 500 patients.

Results:
In univariate analyses, median Lp(a) cholesterol and Lp(a) mass were significantly associated with angiographic CAD. In a multivariable model, Lp(a) cholesterol remained a significant correlate of CAD (OR 1.61, 95% CI 1.13-2.31, P = 0.009) while Lp(a) mass was not (OR 1.18, 95% CI 0.95-1.47, P = 0.14). Additionally, on multivariable analysis, the presence of a detectable amount of Lp(a) cholesterol (> or =2.5 mg/dL) was more strongly correlated with CAD than HDL cholesterol < 40 mg/dL, and, along withLp(a) cholesterol, was strongly correlated with major adverse events (OR 2.08 95% CI 1.22-3.56, P = 0.007 and OR 1.22, 95% CI 1.05-1.42, P = 0.012, respectively).

Conclusions:
Lp(a) cholesterol measured electrophoretically is independently correlated with angiographic CAD and presence of major adverse events, and may be used as an alternative or supplement to Lp(a) mass analysis.
Abstract 11105: Obesity Accelerates T Cell Senescence in Visceral Adipose Tissue
Authors: Shirakawa Kohsuke , Shinmura Ken , Endo Jin , Kataoka Masaharu , Yamamoto Tsunehisa , Katsumata Yoshinori , Anzai Atsushi , Isobe Sarasa , Yoshida Naohiro , Fukuda Keiichi , Sano Motoaki
Published: July 2021

Background:
Age-related changes in the immune function, particularly T-cell immune-senescence likely contribute to the nature of chronic inflammation associated with ageing-related diseases. Recently, it becomes clear that T-cell immune-senescence is not due to dysregulation of the whole T cell population, but rather the accumulation of senescence-associated T-cells. The senescence-associated T-cells are memory phenotype (MP) T-cells that constitutively express programmed cell death 1 (PD-1) on their surface.

Purpose:
Obesity predisposes to a lower age of onset of ageing-related diseases. We examined whether obesity accelerates T-cell senescence in visceral adipose tissue (VAT), and if so, how this impacts on VAT inflammation and glucose metabolism.

Results:
HFD-induced obesity causes the phenotypic changes in CD4+ T-cells similar to those observed during chronological aging process, marked by a progress increase in the number of PD-1+ MP CD4+ T-cells highly resembling senescence-associated T cells. Unique features of adipose tissue PD-1+ MP CD4+ T-cells include; expression of myeloid lineage gene, attenuated TCR-mediated proliferation, a decreased ability to produce T-cell specific lymphokines on TCR stimulation, highly biased secretin of OPN, and a rise in the levels of DNA damage response markers as well as the cyclin-dependent kinase inhibitors. The PD-1+ MP CD4+ T-cells stimulated macrophage infiltration and promoted M1 macrophage polarization, while reducing regulatory T-cells in VAT. HFD-dependent conversion of naïve T cells to PD-1+ MP T-cells in VAT depends on macrophages and B cells. Immunological depletion of PD-1+ T-cells attenuated adipose inflammation and improved insulin resistance in diet-induced obese mice, while adoptive transfer of PD-1+ MP CD4+ T-cells in VAT induced adipose inflammation and insulin resistance in non-obese mice. Analysis of human tissue suggested that a similar process may also occur in human. Interestingly, T2DM patients had more abundant PD-1+ T-cells in omental adipose tissue than non-DM patients independently BMI and age.

Conclusion:
Increased visceral adiposity accelerates T-cell senescence and this, in turn, leads to chronic VAT inflammation and abnormal glucose metabolism.
Abstract 11159: Prolonged QRS Duration Predicts Outcomes in Heart Failure With Preserved Ejection Fraction
Authors: Joseph Jacob , Claggett Brian L , Anand Inder S , Fleg Jerome L , Huynh Thao , Desai Akshay S , Solomon Scott D , O’Meara Eileen , McKinlay Sonja , Pitt Bertram , Pfeffer Marc A , Lewis Eldrin F
Published: July 2021

Introduction:
QRS widening on the surface electrocardiogram (ECG) is a marker of disease progression in heart failure (HF) with reduced ejection fraction. We hypothesized that prolonged QRS duration would similarly identify patients with HF with preserved ejection fraction (HFPEF) at high risk for cardiovascular (CV) events.

Methods:
We examined the relationship of baseline QRS duration to primary outcome [composite of CV death, aborted cardiac arrest, or HF hospitalization (HFH)] and HFH alone in TOPCAT, a multicenter, randomized, placebo-controlled trial of spironolactone in HFPEF. QRS duration was analyzed as a dichotomous variable (≥ 120 ms or < 120 ms). Multivariable analyses were conducted including variables that were significantly associated with QRS duration ≥ 120 ms (Table 1). Analyses were conducted in the entire study cohort as well as in separate analyses for only subjects enrolled from the Americas or from Russia/Georgia independently.

Results:
QRS duration was known in 3426 of 3445 TOPCAT patients. Compared to those with QRS duration < 120ms, 613 (17.9%) subjects had a QRS duration ≥ 120 ms and were older (72.9 years vs. 67.8 years; p < 0.0001) and more likely to be men (62% vs. 45%; p<0.0001). A QRS duration ≥ 120 ms was independently associated with an increased risk of primary outcome and HFH in the entire study cohort and in the subset of patients enrolled in the Americas but was of borderline statistical significance in Russia/Georgia (Table 1). No statistical interaction was observed between treatment with spironolactone and QRS duration (p value for interaction= 0.33).

Conclusions:
QRS duration identifies HFPEF subjects at a higher risk of adverse clinical outcomes; spironolactone had a similar effect on outcomes independent of QRS duration. This easily obtainable marker may be an important component of risk stratification in this syndrome.
Abstract 11546: Role of Natural Autoantibodies Among Ugandans With Rheumatic Heart Disease and HIV
Authors: Huck Daniel M , Okello Emmy , Mirembe Grace , Ssinabulya Isaac , Zidar David A , Silverman Gregg J , Getu Lelise , Nowacki Amy S , Calabrese Leonard H , Salata Robert A , Longenecker Chris T
Published: July 2021

Introduction:
Rheumatic heart disease (RHD) and HIV are prevalent diseases in sub-Saharan Africa associated with distinct immune dysregulatory abnormalities, but little is known about their potential interrelationships. Among naturally arising autoantibodies to oxidation-associated neo-determinants studied in other clinical populations, higher levels of IgM anti-phosphorylcholine (PC) correlate with protection from atherosclerotic CV and inflammatory diseases, while higher levels of IgG anti-malondialdehyde (MDA) instead correlate with greater autoimmune disease activity. The objective of this study was to assess the prevalence of natural autoantibodies among patients with and without RHD in Uganda, and to determine whether the levels of these natural autoantibodies among patients with RHD are affected by HIV status.

Methods:
In this cross-sectional study, we grouped patients according to RHD and HIV status. The three control groups (RHD- HIV-, RHD- HIV+, RHD+ HIV-) were age-matched to the RHD+ HIV+ participants. All participants underwent echocardiography, HIV testing, and venous blood draw. IgM anti-PC and IgG anti-MDA were measured from frozen serum using ELISA.

Results:
Overall, we enrolled 220 participants; 21 with both RHD and HIV. Ages ranged from 10 to 60 years, most being female (64%). After adjusting for age and gender, HIV infection and RHD were each associated with low IgM anti-PC (HIV: p<.0001 and RHD: p=.01). The figure shows median levels of IgM anti-PC by group. A significant HIV*RHD interaction was identified for IgG anti-MDA (p=.049) such that HIV infection was associated with increased IgG anti-MDA in participants without RHD, whereas it was associated with decreased IgG anti-MDA in participants with RHD.

Conclusions:
This is the first study of natural autoantibody responses in patients with RHD. HIV appears to alter natural autoantibody levels potentially increasing risk for atherosclerosis and impacting the pathogenesis of RHD.
Abstract 11563: Proteomic Analysis of Adult Congenital Heart Disease Associated Pulmonary Hypertension
Authors: Li Li , Xiong Changming , Hu Enci , Huang Shian , Liu Chao , Wang Hongyue , Duan Xuejing , Zhao Ranxu , He Jianguo
Published: July 2021

Introduction:
Pulmonary arterial hypertension (PAH) is a relative common complication in patients with congenital heart disease (CHD), affecting both disease progression and prognosis. The pathogenic mechanisms that lead to “irreversible” PAH are therefore poorly understood in subjects with CHD.

Hypothesis:
The aim of this study was to apply proteomics to discover protein regulations in the lungs of irreversible PAH patients, which could lead to generation of new hypotheses concerning signaling pathways and elucidating the pathophysiology of irreversible PAH.

Methods:
Label-free liquid chromatography tandem mass spectrometry was used to compare protein profiles in surgical samples of lungs from 4 patients with irreversible CHD-PAH, 4 reversible CHD-PAH and 4 control subjects.

Result:
A total of 133 proteins were differently expressed. The majority of differential expressed proteins were associated with cytoskeleton remodeling, integrin-mediated cell adhesion and migration, endothelial cell contacts, blood coagulation and HDL-mediated reverse cholesterol transport. Novel findings included increased expression of filamin A and caveolin-1 and decreased expression of glutathione S-transferase (GST) family. Filamin A, a major isoform of the filamin family which is a family of cytoskeletal proteins that have been implicated as critical mediators of organ development and cell signaling and migration. In the present study, the density and cellular location of filamin A immunoreactivity was accordant with caveolin-1. The results were confirmed by Western blot and immunohistochemistry. In reversible CHD-PAH and control lung tissue, filamin A and caveolin-1 were prominent in endothelium of pulmonary arteriole. In irreversible CHD-PAH lung tissue, they were prominent in the vascular smooth muscle cell.

Conclusions:
Label-free proteomics identified differences in the expression of several proteins in the CHD-PAH lung, many of which are relevant to the cell proliferation, differentiation and migration. Increased expression of filamin A and caveolin-1 may be pertinent to the proliferation and migration of vascular smooth muscle cell. Decreased expression of GST indicated impaired anti-oxidative function in irreversible CHD-PAH.
Abstract 11564: A Key Role of PGC-1α Co-transcription Factor, but not HIF1α Transcription Factor, in Production of Vascular Endothelial Growth Factor (VEGF) by a Novel Angiogenic Agent COA-Cl in Cultured Human Fibroblasts
Authors: Okamoto Ryuji , Igarashi Junsuke , Yamashita Tetsuo , Hashimoto Takeshi , Karita Sakiko , Shoji Kazuyo , Kubota Yasuo , Takata Maki , Yamaguchi Fuminori , Tokuda Masaaki , Sakakibara Norikazu , Tsukamoto Ikuko , Konishi Ryoji , Hirano Katsuya
Published: July 2021

We have recently demonstrated a potent angiogenic effect of a newly developed adenosine-like agent termed COA-Cl (Figure). COA-Cl exerts tube forming activity in human umbilical vein endothelial cells in the presence of normal human dermal fibroblasts (NHDF). We thus hypothesized that COA-Cl induces production of VEGF, a key promoter of angiogenesis, from fibroblasts. The present study addressed this hypothesis and elucidated the mechanism underlying COA-Cl-induced VEGF production. ELISA revealed that COA-Cl (100 μM, 48 h) promoted secretion of VEGF into culture medium of NHDF from 16±15 to 274±52 pg/mL (p<0.01). COA-Cl also up-regulated the expression of VEGF mRNA by 2.1±0.3 fold (RT-PCR, p<0.05). Two transcriptional regulatory proteins have been identified as major activators of VEGF gene: HIF1α, a transcription factor associated with hypoxic insult, and PGC-1α, a co-transcription factor associated with metabolic stress that activates a transcription factor ERRα. Immunoblot and RT-PCR analyses revealed that COA-Cl (100 μM) markedly upregulated the expression of PGC-1α protein (2.1±0.3 fold) and mRNA (4.2±0.5 fold) (p<0.05, respectively). In contrast, COA-Cl had no effect on the expression of HIF1α protein/mRNA in both hypoxia (1% O
2
for 3h) and normoxia (20% O
2
). Silencing PGC-1α gene by siRNA attenuated the ability of COA-Cl to promote VEGF secretion. HIF1α gene silencing was without effect. When PGC-1α and ERRα were co-transfected in COS-7 cells, COA-Cl (100 μM) upregulated expression of the endogenous VEGF mRNA (2.2±0.3 fold p<0.05 vs. vehicle). COA-Cl had no effect in COS-7 cells transfected with HIF1α. Together, these results demonstrate the ability of COA-Cl to induce VEGF gene expression and protein secretion in fibroblasts. The co-transcription factor PGC-1α, in concert with ERRα, plays a key role in the COA-Cl-induced VEGF production, potentially representing a novel means to induce therapeutic angiogenesis.
Abstract 11569: Activation of cAMP/CREB/PGC-1α Pathway Plays a Key Role for a Novel Adenosine-like Angiogenic Agent COA-Cl to Induce Production of Vascular Endothelial Growth Factor (VEGF) in Cultured Human Fibroblasts
Authors: Okamoto Ryuji , Igarashi Junsuke , Hashimoto Takeshi , Yamashita Tetsuo , Shoji Kazuyo , Kubota Yasuo , Sakakibara Norikazu , Tsukamoto Ikuko , Konishi Ryoji , Hirano Katsuya
Published: July 2021

COA-Cl is a recently developed pro-angiogenic agent (Figure) that promotes tube forming activity of human umbilical vein endothelial cells that are co-cultured with fibroblasts. Recently, a metabolic stress-related co-transcription factor termed PGC-1α was identified as a novel activator of VEGF gene, a key regulator of angiogenesis. In skeletal muscle, the cAMP/CREB signaling pathway plays a central role in inducing PGC-1α expression. We therefore hypothesized that COA-Cl induces PGC-1α to promote VEGF production by elevating cAMP and activating CREB in fibroblasts. COA-Cl (100 μM for 48 h) augmented VEGF secretion into culture medium of normal human dermal fibroblasts from below the level of detection to 54±4 pg/mL (ELISA, p<0.01 vs. basal). This enhancement of VEGF secretion was associated with up-regulation of mRNA encoding VEGF and PGC-1α (RT-PCR, 2.1±0.3 and 9.9±0.8 fold, p<0.05, respectively). Induction of PGC-1α expression by COA-Cl was attenuated by 49±4% (p<0.01 vs. COA-Cl alone) by H-89 (100 μM), an inhibitor of PKA. Conversely, forskolin (25 μM), a direct stimulator of adenylyl cyclase that increases cAMP, increased VEGF production (423±20 pg/mL, p<0.01 vs. basal) and expression of mRNA encoding both VEGF and PGC-1α. COA-Cl induced an increase in cAMP content (ELISA) and phosphorylation of CREB at Ser133 (immunoblot), a PKA site associated with an increased transcriptional activity of CREB, in a time- and dose-dependent manner (4.4±0.3 and 2.3±0.2 fold at 100 μM COA-Cl for 20 min, p<0.05, respectively). In COS-7 fibroblast-like cells, COA-Cl elevated luciferase activity of transfected reporter construct driven by CRE, which is regulated by cAMP/CREB (2.4±0.1 fold at 200 μM COA-Cl for 24 h). Collectively, our results demonstrate that COA-Cl elevates cAMP and activates CREB in human fibroblasts to induce PGC-1α expression, thereby promoting VEGF transcription and secretion, potentially identifying a novel way to induce therapeutic angiogenesis.
Abstract 11593: Thrombus Formation Under Flow is Inhibited by the Mechanosensitive Cation Channel Blockers GsMTx-4 Peptide and Gadolinium Chloride
Authors: Ilkan Zeki , Wright Joy R , Francescut Lorenza , Goodall Alison H , Mahaut-Smith Martyn P
Published: July 2021

Introduction:
Ion channels contribute significantly to platelet physiology, including control of Ca
2+
as a second messenger. Although there is a clear link between platelet activation and shear stress, no study has examined the functional relevance of mechanosensitive (MS) ion channels in platelets or their precursors, megakaryocytes.

Hypothesis:
Human platelets express MS cation channels such as Piezo1, which contribute to platelet function and the development of thrombosis.

Methods:
Thrombus formation and [Ca
2+
]
i
(intracellular Ca
2+
) responses were studied by confocal microscopy using the indicators DiOC
6
and Fluo-3, respectively, under physiological levels of shear stress in a parallel-plate flow chamber. Aggregation and [Ca
2+
]
i
responses to collagen and thrombin in washed human platelets were assessed by light transmission aggregometry and Fura-2 ratiometric measurements. GsMTx-4 (2.5μM) and gadolinium chloride (GdCl
3
) (30μM) were used as MS cation channel inhibitors, targeting Piezo1 and TRPC6 in platelets. Piezo1 mRNA and protein expression were studied in platelets and the megakaryocytic cell line Meg-01.

Results:
Both inhibitors significantly inhibited thrombus formation on a collagen surface under normal arterial shear rate (average thrombus volume was reduced from 48132.7±7739.4μm
3
to 13478.9±2744.8μm
3
by GdCl
3
(n=6, P<0.01) and to 25125.9±6433.5μm
3
(n=6, P<0.05) by GsMTx-4). GsMTx-4 also caused a reduction in thrombin-induced platelet aggregation (to 53.6±14.0% of control, n=4, P<0.05), however GdCl
3
did not affect platelet shape change or aggregation under static conditions. Pre-treatment with either GsMTx-4 or GdCl
3
did not reduce calcium influx in response to TRPC6 stimulation with 60μM OAG, suggesting a MS role for Piezo1, which was found at the mRNA transcript and protein level in platelets and Meg-01 cells. Meg-01 cells showed shear rate-dependent increases in [Ca
2+
]
i
levels; at a shear rate of 3989.2s
-1
, F/F
0
increased to 1.38±0.05 from 1.00±0.00 baseline (n=53 cells, P<0.0001), a response which was diminished by GsMTx-4, and by chelation of extracellular Ca
2+
by EGTA.

Conclusions:
We provide evidence for the first time for a functional contribution of MS cation channels in platelet physiology and thrombosis.
Abstract 11597: Voluntary and Occupational Physical Activity Have Different Effects on Mortality
Authors: Bahls Martin , Baumeister Sebastian , Völzke Henry , Gläser Sven , Leitzmann Michael , Felix Stephan B , Dörr Marcus
Published: July 2021

Introduction:
Animal studies suggest oppositional effects for voluntary and involuntary physical activity (PA). To assess this in humans, we used distinct domains of PA (sports, leisure time, work) as well as physical fitness and associated these variables with all-cause, cardiovascular (CVD) and cancer mortality in a large population-based cohort.

Methods:
Data of 2,925 participants from the Study of Health in Pomerania (SHIP-1) were used [median age: 48 (interquartile range (IQR): 35, 62) years (y), 52% [[female symbol]]]. All-cause and cause-specific mortality was determined after a median follow-up of 7.0 y (IQR: 5.6 - 6.2). A Sports index (SI), Leisure Time index (LTI) and Work index (WI) were assessed using a modified Baecke questionnaire. Maximal oxygen consumption (VO2peak), oxygen consumption at the anaerobic threshold (VO2@AT), and maximal work load (Wmax) were measured on a bicycle ergometer during symptom-limited cardiopulmonary exercise testing (CPET). Cox models were adjusted for sex, age, smoking, alcohol consumption, years of schooling, income, and body mass index.

Results:
A total of 156 subjects died due to all-cause, 53 due to CVD and 50 due to cancer after follow-up. After adjustment, SI [hazard ratio (HR) per SD: 0.27; 95%-confidence interval (CI): 0.13; 0.55] and LTI (HR per SD: 0.34; 95%-CI: 0.15; 0.77) were associated with a reduced risk of all-cause mortality. WI was not associated with all-cause mortality. SI was associated with reduced risk of CVD mortality (HR: 0.26; 95%-CI: 0.07; 0.96). All CPET measures were significantly related to reduced risk of all-cause and cancer mortality (VO2peak - all-cause HR per SD: 0.007; 95%-CI: 0.001; 0.057 and cancer HR per SD: 0.011; 95%-CI: 0.005; 0.210; VO2@AT - all-cause HR per SD: 0.047; 95%-CI: 0.001; 0.028 and cancer HR per SD: 0.052; 95%-CI: 0.004; 0.073; Wmax - all-cause HR per SD: 0.012; 95%-CI: 0.002; 0.074 and cancer HR per SD: 0.01; 95%-CI: 0.0007; 0.166).

Conclusion:
Voluntary PA was associated with a reduced risk for all-cause and CVD mortality, while occupational PA was not. Exercise capacity was inversely related to all-cause and cancer mortality. Our results indicate that the benefits of PA may be limited to voluntary PA. Thus, questionnaires need to differentiate between voluntary and occupational PA.
Abstract 11601: Identifying Patients at High Risk for Poor Global Outcome After Left Ventricular Assist Device for Destination Therapy: Results From the INTERMACS Registry
Authors: Arnold Suzanne V , Jones Philip G , Allen Larry A , Cohen David J , Fendler Timothy J , Holtz Jonathan E , Aggarwal Sanjeev , Spertus John A
Published: July 2021

Introduction:
LVAD for destination therapy (DT-LVAD) improves survival and quality of life (QOL) for many, but not all, patients with end-stage heart failure who are ineligible for transplantation. To aid in decision-making and help calibrate patients’ expectations of recovery, we evaluated the frequency and predictors of poor global outcome using a composite measure that integrates QOL with mortality.

Methods:
Within the INTERMACS national registry, QOL was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ-OS). Poor outcome was defined as death or an average KCCQ-OS <45 over the year following LVAD (i.e., continued NYHA IV symptoms despite LVAD). Inverse propensity weighting was used to adjust for loss to follow-up. Predictors of poor outcome were assessed using logistic regression with 18 demographic and clinical factors, with parameter estimates penalized to minimize the effect of over-fitting. Validation was conducted using bootstrap methods.

Results:
Among 1487 patients who underwent DT-LVAD, 30% had a poor outcome, with death in 23% and very poor QOL in 7%. Higher BMI (OR 1.12 per 5kg/m2, 95% CI 1.02-1.24), older age (OR 1.23 per 10y, 95% CI 1.08-1.40), and pre-implant poor QOL (OR 1.10 per 10pt lower KCCQ-OS, 95% CI 1.02-1.18) were significant predictors of poor global outcome, with trends for a history of cancer (OR 1.39, 95% CI 0.96-2.01) and INTERMACS profile 1-2 (i.e., critically ill with heart failure; OR 1.27, 95% CI 0.97-1.65). The model had moderate discrimination (c-index=0.64, validated=0.62), good calibration, and identified 10% of patients with a ≥40% risk of poor outcome. At 1 year, 33% of these high risk patients were dead and an additional 15% had very poor QOL.

Conclusions:
Nearly one-third of patients have poor outcomes over the year after DT-LVAD. We developed a simple predictive model that can identify patients’ risk for a poor global outcome after DT-LVAD to enable more realistic expectations of outcomes for individual patients.
Abstract 11653: The Qualitative Grading of Aortic Valve Calcification in Severe Aortic Stenosis is Weakly Associated With Aortic Valve Weight and is Gender Dependent
Authors: Alexandru Dragos , Petillo Florentina , Pollack Simcha , Reichek Nathaniel , Barasch Eddy
Published: July 2021

Background:
In severe aortic stenosis (AS), qualitative estimation of aortic valve calcification (AVC) burden by echocardiography has diagnostic and prognostic value. Hypothesis: there is a weak association between a qualitative calcium score (QCS) by TEE and AV weight in severe AS.

Methods:
Between 2010-2014, of 719 pts who underwent surgical AVR for isolated severe AS, QCS was feasible in 483 (67%): mean age 76.7 ± 9.5 yrs, 59% males, EF 56 ±12%, AVAi 0.35 ±0.09 cm2/m2, AVW 2.45 ± 0.09 g, QCS 3.5± 0.57, 11% bicuspid valves . AVC was determined using short- and long-axis views and graded as mild (1) localized, small, nondense calcifications to severe (4) extensive thickening and calcification of all cusps. TEEs were done on the day of surgery and excised valves were weighed. Independent t-test, Fisher’s exact test, analysis of variance, and Pearson correlation were done as appropriate.

Results:
Intraclass correlations for intra and interobserver variability were 0.76 and 0.53 , respectively.The association between indices of AS severity and AVC burden, is stronger for AVW than for QCS (table).19 pts had QCS = 2, 183 = 3 and 280 = 4. A QCS of 2 to 4 corresponded to an AVW of 1 to 6 g. The correlation between QCS and AVW was 0.11, p=.01, and 0.09, p =.04 when controlling for age, sex and BSA. QCS-AVW association was gender dependent : for females (196), who had a lower severity of stenosis, r=0.23, p=0.001, for males (286), r=0.02, p=.68 with p =.02 for the difference. Conclusions: 1. In severe AS, QCS by TEE has limited reliability with no relationship with AVW in males and a weak one in females. 2. The utilization of QCS in severe AS even when employing TEE is weakly associated with total AVC burden and should probably be replaced by quantitative objective non- echocardiographic methods.
Abstract 11665: Oral Triiodothyronine Supplementation Decreases Time to Extubation After Pediatric Open Heart Surgery in Indonesia
Authors: Marwali Eva M , Budiwardhana Novik , Prakoso Radityo , Fakhri Dicky , Boom Cindy E , Djer Mulyadi M , Sastroasmoro Sudigdo , Portman Michael A
Published: July 2021

Background:
In Indonesia, children with congenital heart disease (CHD) usually present later for corrective surgery than in developed countries. These children show chronic malnutrition associated with low thyroid hormone levels, which decline further immediately after open-heart surgery.

Objectives:
To test the hypothesis that oral triiodothyronine (T3) supplementation improves clinical outcome indexed by time to extubation (TTE) after aortic cross-clamp release.

Methods:
The study was a single center, randomized, double blind, and placebo controlled trial in children with CHD younger than 2 years of age undergoing open-heart surgery. Oral T3 or placebo was administered every 6 hours for 60 hours. TTE served as the primary endpoint. Hemodynamics, echocardiography parameters, inotropic score, fluid balance, diuresis, and sepsis complication were serially recorded and evaluated as secondary endpoints

Results:
A total of 78 patients were allocated to T3 group and 74 patients to the control group. Oral T3 prevented the declination in serum T3 noted in control group. The T3 group had a shorter time to extubation than placebo with a mean (SD) 25.99(24.30) and 40.71(56.29) hours, respectively and a hazard ratio for chance of extubation (95% CI) 1.49 (1.06-2.11), p=0.02. The median (IQ) cardiac index increased significantly after surgery in T3 (day 1 vs. day 2, 3.28 (2.46 - 4.46) to. 3.65 (2.65 - 4.77) L/min/m2, p=0.01), but not in the placebo group. More diuresis and a significantly more negative fluid balance (p=0.03) were found in T3 group during the first 72 hours post surgery. No difference in the use of inotropic agents or loop diuretics. Sepsis was significantly lower in T3 group with incidence (%) of sepsis in T3 and placebo group 1(1) vs. 10(13) patients, (p=0.004), respectively. Otherwise there was no difference in adverse events including arrhythmia.

Conclusion:
Oral T3 supplementation is safe and provides multiple clinical benefits in an extremely vulnerable population of children in a developing country. Any reduction in TTE could improve sparse resources by increasing ventilator and ICU availability.
Abstract 11668: High Resolution Magnetocardiography as a Novel Noninvasive Tool to Distinguish Between Benign and Malignant Early Repolarization Pattern
Authors: Iwakami Naotsugu , Aiba Takeshi , Takaki Hiroshi , Kamakura Tsukasa , Wada Mitsuru , Ishibashi Kohei , Nakajima Ikutaro , Miyamoto Koji , Inoue Yuko Y , Okamura Hideo , Nagase Satoshi , Noda Takashi , Kusano Kengo , Yasuda Satoshi , Ogawa Hisao , Sugimachi Masaru , Kamakura Shiro
Published: July 2021

Introduction:
Most of the early repolarization patterns (ERP) in electrocardiography (ECG) are benign but some of them are associated with ventricular fibrillation (VF).

We evaluated whether or not a high spatio-temporal resolution magnetocardiography (MCG) could non-invasively detect malignant types of ERP.

Methods:
Sixty four-channel MCG, standard 12-lead ECG, and signal averaged ECG (SAECG) were recorded in 120 patients with inferolateral ERP in ECG without any major structural heart diseases; 13 of them had a history of VF (VF(+)-group) and the remaining 107 had no VF (VF(-)-group). We evaluated the following novel MCG indexes: MCG-QRS (msec), root mean square of terminal 40 msec magnetic field (MCG-RMS) (msec), and the duration under 10% of maximal amplitude (MCG-LAS) (msec) of the highest amplitude channel.

Results:
The amplitude and distribution of the J-wave, ST-T morphology in ECG, parameters of SAECG were not significantly different, whereas MCG-QRS and MCG-LAS were significantly longer and MCG-RMS was smaller in ERP-VF(+) compared with ERP-VF(-) group (107(SD=24) vs 84(13) msec, P<0.01, 8(22) vs 22(11) msec, P<0.01, 0.10(0.08) vs 0.28(0.19) msec, P<0.01, respectively). In the multivariate logistic regression model, only MCG-QRS remained significant among the MCG indexes and the existing predictors (odds ratio (OR) 1.08, 95%CI 1.01 to1.17). The predictive ability of VF was significantly higher using MCG-QRS when the c-statistic was compared with that of the existing ECG measure (0.82 vs 0.56, P<0.01, Figure). When cut-offs were set by the least squares method at MCG-QRS 100 msec, MCG-RMS 0.24 msec, MCG-LAS 27 msec, corresponding ORs were calculated as 12.7, 95%CI 3.6 to 45.0, 6.1, 95%CI 1.7 to 21.2, 6.2, 95%CI 1.8 to 20.8, respectively.

Conclusions:
MCG-QRS >100 msec was a simple and effective criterion for prediction of high risk ERP subjects, thus MCG analysis is an useful screening tool to detect malignant ERP out of the numerous benign ones.
Abstract 11714: Allogeneic Cardiosphere-Derived Cells Administered at the Time of Reperfusion Only Improve Ejection Fraction When Infused to Ischemic as well as Remote Myocardial Regions in Swine With Acute Myocardial Infarction
Authors: Suzuki Gen , Weil Brian R , Young Rebeccah F , Fallavollita James A , Canty John M
Published: July 2021

Introduction:
While intracoronary infusion of cardiosphere-derived cells (CDCs) to myocardial infarcts using the stop-flow technique reduces scar volume, ejection fraction (EF) remains unchanged.

Hypothesis:
We hypothesized that this may relate to ineffective treatment of myocyte loss in normally-perfused remote regions which could negatively impact EF. We therefore compared CDC infusion to the entire heart with conventional regional infusion to the infarct-related artery.

Methods:
Swine (n=24) chronically treated with cyclosporine (100 mg/day) underwent a 1-hour LAD occlusion and EF decreased from 60 ± 2% at baseline to 46 ± 2% after reperfusion (p<0.05 vs. baseline). We infused either 10x10^6 intracoronary allogeneic CDCs via stop-flow infusion (regional LAD infusion), 20x10^6 intracoronary allogeneic CDCs to the entire heart under flow (global infusion) or vehicle 30 minutes after reperfusion. Four weeks later we assessed left ventricular function (echo), myocyte proliferation (Ki67), infarct size (TTC), myocyte nuclear density and cell size. Data were compared to vehicle.

Results:
Regional LAD infusion increased wall thickening and reduced scar volume but did not affect EF (Table). In contrast, global infusion increased EF despite an insignificant reduction in infarct volume. This was accompanied by 2-fold increases in myocyte proliferation (Ki67) in border and remote regions which did not change with regional LAD infusion. Global infusion increased myocyte nuclear density by 12% and decreased cell size by 9% while there were no significant changes after regional LAD infusion.

Conclusion:
Although regional LAD infusion reduces scar size and improves regional function, only global infusion improves EF since it effectively stimulates endogenous myocyte regeneration throughout the entire left ventricle. Thus, global infusion may more effectively prevent deleterious post-infarction remodeling than regional administration alone.
Abstract 11722: Excellent Preclinical Results of Honeycomb Microporous Covered Stents for the Treatment of Large and Wide-Necked Cerebral Aneurysms
Authors: Nakayama Yasuhide , Satow Tetsu , Funayama Marina , Moriwaki Takeshi , Tajikawa Tsutomu , Furukoshi Maya , Hamano Eika , Ishii Daizo , Hayashi Masataka , Sugata Sei , Ishibashi-Ueda Hatsue , Takahashi Jun C
Published: July 2021

Background:
We developed covered stents with a microhoneycomb mesh for the treatment of large or giant wide-necked cerebral aneurysms. These aneurysms are extremely difficult to treat and carry high risks, even with the use of clinically available surgical methods or the endovascular technique using coils with the assistance of bare stents. This preclinical study confirmed the excellent performance of our stents in three animal experimental models.

Methods and Results:
The covered stents were prepared by using balloon-expandable stents (CoCr; diameter, 3.5-5.0 mm; length, 16-28 mm) and by dip coating to cover their struts completely with a polyurethane membrane (thickness, 20 μm), followed by laser microprocessing (pore size, approximately 100 μm; opening ratio, approximately 30%).

Model 1: In prepared tortuous canine arteries (n = 12) that simulated the shape of the human internal carotid artery, all stent-mounted delivery catheters could smoothly navigate with little arterial damage.

Model 2: In a prepared canine model (n = 10) of large (over 7 mm), wide-necked (over 4 mm) outer-sidewall aneurysms, at 3 months after stenting, completely endothelialized neointima was formed at the aneurysm openings and the aneurysm sacs were entirely organized.

Model 3: In rabbit branching abdominal aortas, the vascular flow pattern at all the branching arteries remained unchanged for over 1 year, even after performing overlap stenting (n = 5) in addition to single stenting (n = 5). On all the stented luminal surfaces, complete thin neointimal formation with complete endothelialization was observed.

Conclusion:
Our newly developed novel covered stents exhibited excellent preclinical performance in three animal experimental models in terms of stent delivery, aneurysm embolization, and flow maintenance in branching arteries. We highly expect that the stents will be useful as endovascular embolization devices for large and wide-necked aneurysms in humans.
Abstract 11749: Prognostic Value of Left Ventricular Global Longitudinal Strain and Ejection Fraction in Patients With Non-ischemic and Ischemic Heart Disease
Authors: Onishi Tetsuari , Tsukishiro Yasue , Kawai Hiroya
Published: July 2021

Background:
Both Left ventricular (LV) global longitudinal strain (GLS) and LV ejection fraction (LVEF) are useful parameters for assessment of LV function. The aim of this study is to confirm the prognostic value of them in patients with non-ischemic and ischemic heart disease.

Methods:
We studied 179 patients (DCM group: Age 61±15 years, 70 females, LVEF 33±9%) with non-ischemic dilated cardiomyopathy and heart failure symptom, and 97 patients (MI group: Age 66±13 years, 18 females, LVEF 45±7%) who were successfully treated with percutaneous coronary intervention for acute anteroseptal myocardial infarction. Echocardiography was used for LV GLS derived from 2D speckle-tracking method and LVEF with modified Simpson’s method. Outcome was assessed according to death and re-hospitalization with heart failure in the follow-up period.

Results:
40 patients in DCM group and 10 patients in MI group experienced at least one event. In these 2 groups, significant differences in GLS and LVEF were found between patients with and without cardiac events (p<0.05). Kaplan-Meier analysis showed patients with worse GLS had an unfavorable outcome in both DCM and MI groups (p<0.05), but LVEF did not associated with outcome.

Conclusion:
LV GLS has the potential to predict the outcome with higher sensitivity than LVEF in patients with heart disease regardless of ischemic etiology.
Abstract 11761: Association of Red Blood Cell Microparticles With Biomarker-Defined Infarct Size in Acute Myocardial Infarction
Authors: Giannopoulos Georgios , Deftereos Spyridon , Angelidis Christos , Tsiachris Dimitrios , Lekakis John , Stefanadis Christodoulos
Published: July 2021

Background:
Red blood cell microparticles (RBCm) have drawn research attention as to their potential prothrombotic and vasoconstrictive effects in experimental settings. Our group has previously reported elevated RBCm counts in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous intervention (PCI).

Methods:
Circulating microparticles were quantified with flow cytometry in blood samples from consecutive STEMI patients after primary PCI. Creatine kinase myocardial-brain fraction (CK-MB) was measured every 6 hours during the first 3 days and every 12 hours thereafter until discharge. The area under the CK-MB concentration curve (CKMB-AUC), calculated with Simpson’s summing rule, was used as a biochemical measure of infarction size.

Results:
51 STEMI patients (age 59.8±8.8 years) were enrolled. RBCm concentration was 33740±21169 /μl. The median values [25th-75th percentile] of CKMB-AUC according to RBCm quartile were (from the lower to the upper quartile) 3351 [2550-4060] ng.h.ml-1, 4883 [4179-5348] ng.h.ml-1, 6932 [5464-13229] ng.h.ml-1, and 8784 [7216-12605] ng.h.ml-1, respectively (Kruskal-Wallis p<0.001) (see Figure). In a multivariable regression analysis, RBCm quartile remained associated with CKMB-AUC, after adjustment for total RBC count, age, serum creatinine, presence of diabetes and Killip class on admission (adjusted p<0.001). Conclusions: Erythrocyte microparticles appear to be related to total myocardial damage biomarker output, which is a parameter known to reliably reflect infarct size in patients with STEMI. This finding may be explained by rheologic and vasoactive properties of RBCm (close interaction of the heavily oxidative heme with the endothelium, depletion of NO etc.), which may act deleteriously on coronary vasculature, resulting in increased myocardial damage.
Abstract 11785: The Association of Guideline Adherence of Coronary Revascularization and Clinical Outcomes for Patients With Stable and Complex Coronary Artery Disease
Authors: Rao Chenfei , Zheng Zhe , Hu Shengshou , Zhang Heng
Published: July 2021

Introduction:
Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) gained popularity in China, there are gaps in knowledge about the appropriateness of revascularization procedures and related outcomes of stable and complex coronary artery disease.

Methods:
Using the China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) research network, this prospective study of 3-Vessel Disease (China PEACE-3VD) consecutively enrolled patients with 3-vessel and/or left-main disease diagnosed by elective coronary angiography in 24 large cardiovascular centers in China. We abstracted medical record data for patient characteristics and treatment strategies, the core lab calculated SYNTAX Scores for all patients. We classified the appropriateness of treatment for each patient using 2011 Guideline on Myocardial Revascularization published by European Society of Cardiology and European Association of Cardio-Thoracic Surgery. We compared the 1-year rates of major adverse cardiovascular and cerebral events (MACCE) between patients underwent revascularization with I/IIa and IIb/III indications.

Results:
We consecutively enrolled 3186 patients from participated hospitals. Among them, 20.4% (651) underwent medical therapy, 79.6% (2535) underwent revascularization procedures (PCI: 87.4%, 12.6% CABG) during the index hospitalization. For patients underwent revascularization procedures, 47.9% patients were suitable for both CABG and PCI (has I indication for CABG, and IIa indication for PCI, group A), 52.1% were only suitable for CABG (has I indication for CABG, and IIb/III for PCI, group B). In group A, 95% underwent PCI, 5% underwent CABG, the 1-year MACCE rates of CABG and PCI showed no significant difference (PCI: 4.6%, CABG: 7.7%, adjusted OR=1.21, p=0.81); In group B, 80.4% underwent PCI, 19.6% underwent CABG, the 1-year MACCE rates of CABG is significantly lower than PCI (PCI: 7.5%, CABG: 2.3%, adjusted OR=3.18, p=0.027).

Conclusions:
Using the Guideline on Myocardial Revascularization, we identified certain overuse of PCI for stable and complex coronary artery disease. The inappropriate use of PCI is associated with worse 1-year outcomes than CABG. (NCT01625312)
Abstract 11813: The Impact of Surgical Left Atrial Appendage Amputation/Ligation on Stroke Prevention in Patients Undergoing Off-pump Coronary Artery Bypass Grafting
Authors: Endo Daisuke , Kato Tomoko S , Iwamura Tai , Shimada Akie , Kajimoto Kan , Dohi Shizuyuki , Kuwaki Kenji , Yamamoto Taira , Amano Atsushi
Published: July 2021

Background:
Stroke is a major adverse event in patients developing atrial fibrillation (AF) after cardiac surgery. Left atrial appendage (LAA) closure using devices is expected to prevent stroke and enable patients to be warfarin free; however, problems such as procedure-related adverse events and possible residual flow remain unsolved. Concomitant “surgical” LAA amputation/ligation (LAA-A/L) during off-pump coronary artery bypass grafting (OPCAB) is actively performed in our institution.

Methods:
This is a prospective observational study of 578 consecutive patients (mean age 69 ± 9.8 years, Male 82%) undergoing OPCAB with or without concomitant LAA-A/L from 2011 to 2014. The safety and efficacy of the concomitant procedure, performed on 193 (33%) patients, on preventing early (<30 days) and late postoperative stroke were examined.

Results:
LAA was amputated in 154 patients (80%), and ligated in 39 (20%). Between patients with and without LAA-A/L, no difference was seen in the preoperative characteristics including CHADS2 and CHA2DS2-VASc scores, and no significant differences in their operative time, requirement of blood transfusion, length of ICU and total hospital stay were noted. The incidence of postoperative AF was not different (33% vs. 28%, p=0.18), and early and late stroke incidences were not significantly different between the groups (1.0% vs. 0.8%, p=0.75, 2.2% vs. 2.8% p=0.67, respectively). However, in patients without LAA-A/L, both early and late stroke occurred more frequently in those developing AF (2.8% vs. 0%, p=0.005, 6.2% vs. 1.5%; p=0.017, respectively), while stroke incidence in patients receiving LAA-A/L, was not significantly different between those with and without postoperative AF (0.8% vs. 1.6%, p=0.61, 1.6% vs. 2.5%; p=0.69, respectively). Multivariate logistic regression showed postoperative AF without LAA-A/L as the only independent positive predictor of early (OR: 6.8; 95% CI: 1.11 to 52.60; p=0.04) and late (OR: 3.7; 95% CI: 1.18 to 10.94; p=0.03) stroke.

Conclusions:
Concomitant LAA-A/L with OPCAB is safe and effective for stroke prevention in patients developing postoperative AF. This preventative procedure seems beneficial, since AF is the most common arrhythmia associated with the risk of stroke.