bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13444: Complete Left-Sided Reverse Remodeling in Cardiac Resynchronization Therapy and Clinical Implications: a MADIT-CRT Long-term Follow-up Sub-study
Authors: Mathias Andrew M , Solomon Scott D , Moss Arthur J , Knappe Dorit , Pouleur Anne-Catherine , Zareba Wojciech , Klein Helmut , Kuperstein Rafael , Klempfner Robert , Goldenberg Ilan , Kutyifa Valentina
Published: July 2021

Background:
Left ventricular and left atrial remodeling (defined as a reduction in left ventricular end-systolic volume [LVESV] and left atrial volume [LAV] respectively) have both been shown to be associated with better clinical outcome in patients with cardiac resynchronization therapy (CRT). However, a portion of CRT patients exhibit discordant remodeling (e.g. improvement in LVESV but not in LAV or vice versa). Whether combined assessment of LA and LV remodeling predicts clinical outcome is unknown.

Objectives:
We aimed to evaluate the predictive value of a combined assessment of LAV and LVESV change in CRT patients with left bundle branch block (LBBB) enrolled in MADIT-CRT. We hypothesized that combined assessment better predicts outcome than LAV or LVESV reduction alone.

Methods:
The study population comprised 533 CRT-D LBBB patients assigned to lesser remodeling (below median LAV and LVESV change), discordant remodeling (above median change in only LAV or LVESV), or complete left-sided remodeling (above median change in both LAV and LVESV). The end point was heart failure (HF) during follow-up.

Results:
At 1-year follow-up, 206 patients had lesser remodeling, 115 had discordant remodeling and 212 had complete left-sided remodeling. Patients with complete left-sided remodeling had less HF than those with discordant remodeling or lesser remodeling (Figure, p=0.002). Multivariate analysis confirmed that complete left-sided remodeling is associated with lower risk of HF than discordant remodeling and discordant remodeling is better than lesser remodeling (HR=0.62 per each group, 95% CI: 0.44-0.86, p = 0.004).

Conclusions:
A combined assessment of LAV and LVESV reduction predicts HF in CRT patients with LBBB. Patients with complete left-sided remodeling had a significantly lower risk of HF during long-term follow-up.
Abstract 13502: Glucagon-like Peptide-1 Directly Promotes Angiogenesis via PKA/AMPK-dependent Autophagy in Endothelial Cells
Authors: Monij Akio , Bando Yasuko K , Aoyama Morihiko , Kawase Haruya , Mitsui Toko , Shimizu Atsuya , Murohara Toyoaki
Published: July 2021

Introduction:
We recently reported the impact of glucagon-like peptide-1 (GLP-1) on myocardial remodeling observed in type 2 diabetic mice (T2DM) via cyclic-AMP-dependent activation of autophagy in myocardium; however, it remains unclear whether GLP-1 may modulates capillary formation in heart.

Hypothesis/AIM:
We thus evaluated the impact of GLP-1 on angiogenesis and its link to endothelial autophagy.

Methods:
T2DM was treated with Ex4 (24 nmole/kg/day for 4 weeks). Cardiac capillary density was measured by immunohistology. Cultured HUVECs were used for in vitro experiments. Changes in activities of autophagy (LC3-turnover assay and protein levels of p62 and Beclin1), and angiogenesis (tube formation assay and Akt/AMPK/eNOS activity), were evaluated.[[Unable to Display Character:  ]] Role of PKA was assessed by CREB phosphorylation and RNA interference (siRNA for catalytic subunit of PKA). Effect of autophagy was assessed by use of pharmacological inhibitor 3MA and siRNA of autophagy-related gene (ATG) 5 , ATG7, and p62.

Results:
Immunohistochemical analyses revealed that T2DM exhibited reduced cardiac capillary density, which was reversed by Ex-4 with concomitant amelioration of systemic diabetic condition. Ex-4 treated heart exhibited increase in myocardial cyclic AMP concentration. We thus observed direct impact of Ex-4 and cyclic AMP elevation on HUVECs, in which GLP-1 receptor expression was confirmed by immunoblot and QPCR. In vitro angiogenesis assay revealed that Ex-4 and PKA enhancers (10 μM forskolin and 1 mM 8-bromo-cyclic AMP) facilitated angiogenesis and autophagy in HUVECs. The PKA/AMPK/eNOS phosphorylation levels of Ex-4-treated HUVECs were elevated. Of note, each Akt activity remains unchanged. PKA inhibitors (H89, RP-cAMP, siRNA) abrogated the increase in phosphorylation of AMPK/eNOS axis induced by Ex-4 in HUVECs. Tube formation assay revealed that Ex-4 and PKA enhancers augmented in vitro angiogenesis, which were abrogated by inhibition of autophagy and AMPK using pharmacological inhibitors (3MA and compound C) and siRNA for autophagy-related gene (ATG) 5 , ATG7, p62, and catalytic subunit of AMPK. [[Unable to Display Character:  ]]

Conclusions:
GLP-1 directly promoted angiogenesis via the PKA/AMPK-dependent autophagic activation.
Abstract 13535: The Synergistic Effects of Incretin-related Drugs for the Treatment of Pulmonary Arterial Hypertension
Authors: Hosokawa Susumu , Haraguchi Go , Maejima Yasuhiro , Doi Shozaburo , Isobe Mitsuaki
Published: July 2021

Introduction:
A growing body of evidence suggests that inflammation plays a crucial role in the development of pulmonary arterial hypertension (PAH). Dipeptidyl peptidase-4 (DPP-4; also known as CD26), a protease which degrades incretin hormones such as glucagon-like peptide-1 (GLP-1), modulates inflammatory processes by regulating activity of T cells through co-stimulatory pathway.

Hypothesis:
Incretin-related drugs, including both DPP-4 inhibitors and GLP-1 receptor agonists, suppress the progression of PAH by attenuating inflammatory response of PA.

Methods:
Sprague Dawley rats were injected monocrotaline to induce PAH

(N=80). After 14 days from PAH induction, these rats were treated with alogliptin, a DPP-4 inhibitor (M+A, N=20), liraglutide, a GLP-1 receptor agonist (M+L, N=20), both of these drugs (M+A+L, N=20), or vehicle

(M, N=20).

Results:
A significant increase of survival was observed on days 30

after PAH induction both in the M+A and M+L compared to the M (M+A: 45%* vs. M+L: 60%* vs. M: 5%, *
p
<0.05). Both alogliptin and liraglutide markedly improved right ventricular pressure (M+A: 33±4.1mmHg*

vs. M+L: 26±1.9mmHg* vs. M: 85.9±1.2mmHg, *
p
<0.05). mRNA levels of both CD28 and CD86, co-stimulators of T cells, significantly decreased

and the level of caveolin-1 markedly increased in lung tissues of the M+A compared to those in the M. mRNA levels of both Tissue Factor (TF) and PAI-1 significantly decreased in lung tissues of the M+L than those in the M. Consistently, survival of rats in the M+A+L was the highest (65%) among all of the groups of PAH rats. Coimmunoprecipitation assays revealed that CD26 in T cells physically interacted with caveolin-1 in rat

pulmonary vascular smooth muscle cells (rPASMCs). Immunoblot analyses showed that alogliptin suppressed caveolin-1 phosphorylation in rPASMCs. Furthermore, reporter gene assays demonstrated that alogliptin significantly inhibited the transcriptional activity of NF-κB.

Conclusions:
These results suggest that DPP-4 inhibition and stimulation of GLP-1 receptors synergistically mediate salutary effects on monocrotaline-induced PAH by modulating T cell activity and TF-associated signaling pathway. Thus, incretin-related drugs have a potential

as a novel therapeutic tool for PAH.
Abstract 13581: Combined Assessment of N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity Troponin T Levels Improves the Prediction of Future Admission for Heart Failure in Outpatients with Hypertension and Preserved Left Ventricular Ejection Fraction
Authors: Matsui Shigeru , Ishii Junnichi , Takahashi Hiroshi , Okuyama Ryuunosuke , Kawai Hideki , Muramatsu Takashi , Naruse Hiroyuki , Motoyama Sadako , Izawa Hideo , Ozaki Yukio
Published: July 2021

Background:
Hypertension is one of the most prevalent cardiovascular diseases and one of the most important causes of heart failure (HF) with preserved left ventricular ejection fraction (LVEF). We prospectively investigated the incremental predictive value of a combination of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), and galectin-3 for HF admission in outpatients with hypertension.

Methods:
Baseline serum NT-proBNP, hsTnT, and galectin-3 levels were measured in 443 outpatients (mean age, 69.4 years) with hypertension and LVEF ≥ 50%. Using tissue Doppler echocardiography, E/e’ ratio was calculated. Among these patients, 34% had a history of cardiovascular disease, and 46% had a history of diabetes.

Results:
Galectin-3 levels significantly (p < 0.0001) correlated with E/e’ ratio (r = 0.21) and estimated glomerular filtration rate (eGFR; r = –0.78). During a mean follow-up period of 899 days, there were 40 (9%) HF admissions. Using multivariate Cox regression analysis including 10 clinical, biochemical, and echocardiographic variables, increased NT-proBNP (relative risk, 2.88 per 10-fold increment, p = 0.007) and hsTnT (4.30 per 10-fold increment, p = 0.004) levels, but not ga1ectin-3 levels, were shown to be independent predictors of HF admission. When patients were stratified into four groups according to NT-proBNP levels ≥ a median value of 193.7 pg/mL and/or hsTnT levels ≥ a median value of 14 pg/mL, HF admission rates were 1.1%, 2.1%, 4.3%, and 20%, respectively (p < 0.0001). Furthermore, when NT-proBNP and hsTnT levels were combined, the predictive values for HF admission were increased, as shown by the C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI; Table 1).

Conclusions:
The combined assessment of NT-proBNP and hsTnT levels can improve the prediction of HF admission in outpatients with hypertension.
Abstract 13659: Development of a TransAtlantic Cardiovascular risk Calculator for Rheumatoid Arthritis (ATACC-RA)
Authors: Semb Anne Grete ,   ATACC-RA consortium (1 2 3 4 5 6 7 8)* 9 10 11 1213
Published: July 2021

Introduction:
Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease (CVD), which is not accurately predicted by risk calculators designed for the general population.

Hypothesis:
To develop a RA specific CVD risk calculator.

Methods:
The study population included RA patient cohorts from 8 centres in 7 countries. In all cases, data had been collected prospectively on CV outcomes (MI, revascularization, angina, stroke, TIA, PAD and CV death). At baseline RA characteristics (duration, seropositivity, disease activity (DAS28) and CRP/ESR) were collected in addition to traditional CV risk factors. Cox models stratified by centre were used to develop a CVD risk calculator considering traditional CV risk factors and RA characteristics. Model performance was assessed using measures of discrimination and calibration.

Results:
In total 3176 RA patients who did not have prior CVD were included (mean age: 55 [SD: 14] years, 73% female). During a mean follow-up of 7.8 years (24733 person years), 314 had a CVD event. The multivariable risk score modelling revealed 2 models including either seropositivity or DAS28 along with age, sex, current smoking, presence of hypertension, and ratio of total cholesterol to high-density lipoprotein (table). Both 10-fold cross validation and multiple imputation analyses confirmed these findings with little change to the estimated coefficients. Both models demonstrated good discrimination (c-statistic: 0.76 and 0.74) and calibration (observed/predicted ratio: 1.00; 95% confidence interval: 0.89, 1.12). The ATACC-RA (mean: 11.5%, SD 14.1%) showed significantly improved discrimination compared to either Framingham (c-statistic: 0.71, p<0.001) or SCORE (c-statistic: 0.72, p<0.001) risk algorithms.

Conclusions:
Development of an RA-specific CVD risk calculator is feasible by pooling resources from many centres. Further development including external validation is underway.
Abstract 13680: Impact of Estimated Glomerular Filtration Rate and Proteinuria on Contrast-induced Nephropathy in Patients With Cardiac Catheterization
Authors: Saito Yoshihiko , Watanabe Makoto , Aonuma Kazutaka , Hirayama Atsushi , Tamaki Nagara , Tsutsui Hiroyuki , Murohara Toyoaki , Ogawa Hisao , Akasaka Takashi , Yoshimura Michihiro , Satoh Akira , Takayama Tadateru , Sakakibara Mamoru , Suzuki Susumu , Ishigami Kenichi
Published: July 2021

Background:
Contrast induced nephropathy (CIN) has been a subject of concern to cardiologists in recent year because CIN is associated with increased morbidity, mortality, and healthcare expense. Incidence and risks of contrast induced nephropathy (CIN) after cardiac catheterization are not clear in Japan.

Objective:
The aim of this study is to investigate the pre-procedural predictors of CIN.

Methods:
This study, named the study for CIN after cardiac catheterization in Japan (the CINC-J study), is a multicenter cohort study, which examined 1021 patients undergoing cardiac catheterization from 29 hospitals in all over Japan. We divided into 4 groups on the basis of estimated glomerular filtration rate (eGFR: >60 ml•min-1•1.73m-2 = Normal, 45 to 60 = Mild, 30 to 45 = Moderate, <30 = Severe). CIN was defined as an increase in serum creatinine level of 0.5mg/dl or 25% from 48 to 72 hours after contrast-medium injection.

Results:
The incidence of CIN was significantly higher in patients with proteinuria than those without proteinuria (13.6% vs. 2.8%, p<0.001). In patients without proteinuria, the incidence of CIN was not increased with reducing eGFR, however, in patients with proteinuria, the incidence of CIN was significantly increased with reducing eGFR as shown in the figure. Multivariate-logistic-regression analysis revealed that proteinuria (hazard ratio=3.77; 95% CI: 1.54 to 9.10), contrast volume/eGFR (hazard ratio=1.29; 95% CI: 1.01 to 1.62), Ca antagonist (hazard ratio=3.46; 95% CI: 1.36 to 9.94) were independent predictors of CIN.

Conclusions:
Proteinuria is the strongest predictor for CIN after cardiac catheterization.
Abstract 13699: A True World Picture - Surgical Revision After Percutaneous Mitral Valve Repair With the Mitraclip Device
Authors: Hirnle Grzegorz , Seeburger Joerg , Borger Michael A , Garbade Jens , Misfeld Martin , Mohr Freidrich W
Published: July 2021

Background:
Transcatheter mitral valve (MV) repair is of increasing interest facing however questionable mid term results. We herein report MV reference center experience of 18 patients who underwent MV surgery after failed percutaneous MV repair with MitraClip device (Evalve, Menlo Park, CA).

Methods:
Between June 2010 and October 2013, a total of 141 patients with severe mitral regurgitation (MR) underwent MitraClip procedure at Heart Center Leipzig. 11 patients (7.8%) needed surgical treatment for failed MV repair with the MitraClip device. For the same reasons we admitted 7 patients who underwent MitraClip procedure in other cardiac surgery centers. Mean EuroScore II of the patients was 23,51 (5,17-60,14).

Results:
From the group of 18 patients undergoing surgical treatment after MitraClip repair, 14 patients (77.7%) received one or more clip-implants and 4 patients (22.2%) suffered from failed MitraClip implantation. All patient were symptomatic (n=9, 50% - NYHA III; n=9, 50% - NYHA IV).

The primary indications for surgery were: partial clip detachment (n=11, 61.1%), failed MitraClip implantation (n=4, 22.2%), recurrent MR greater than moderate (2+) (n=3, 16.6%), acute mitral valve endocarditis (n=1, 5.5%), mitral ring and clip detachment (n=1, 5.5%). 13 patients (72.2%) underwent MV replacement, 3 patients (16.6%) received left-ventricular assist device (LVAD), 2 patients (11.1%) underwent MV repair.

One-month mortality reached 27,8% (n=5), and the overall mortality reached 50% (n=9).

Conclusions:
MV repair was feasible in only 2 cases (11.1%). Despite the high operative risk, surgical treatment after percutaneous MV repair failure with the MitraClip device is an option to be considered.
Abstract 13701: Impact of Stent Platform on Longitudinal Stent Deformation: an in vivo 3-dimensional Optical Coherence Tomography Study
Authors: Yamada Ryotaro , Kume Teruyoshi , Fukuhara Kenzo , Koyama Terumasa , Higa Tomitaka , Neishi Yoji , Okura Hiroyuki
Published: July 2021

Introduction:
Recently, longitudinal coronary stent deformation has been highlighted as a possible cause of drug-eluting stent failure. Although bench tests and in-vivo studies have demonstrated difference in longitudinal stent strength among the stents with different platforms, its clinical impact is still unknown. The aim of this study was to investigate the longitudinal deformation of the everolimus-eluting stents (EES) with different stent platforms by using 3-dimensional frequency domain optical coherence tomography (3D FD-OCT).

Methods:
Fifty-nine lesions treated with EES (Xience Prime (CoCr-EES): n=28, Promus element (PtCr-EES): n=31) were studied. Stent length was measured by 3D FD-OCT. Percent longitudinal stent shortening (%SS) was defined as the longitudinally shortened stent length standardized by nominal stent length. Longitudinal stent deformation was defined as %SS >10%.

Results:
Patients’ and procedural characteristics were similar between CoCr- and PtCr-EES. There was no difference in mean %SS between PtCr-EES and CoCr-EES (3.1±6.5 vs. 0.9±5.6%, p=0.197). However, incidence of longitudinal stent deformation was significantly higher in PtCr-EES than in CoCr-EES (16.1% vs 0%, p=0.026) (Figure).

Conclusions:
Incidence of longitudinal stent deformation was different between EESs with different stent platforms. Stent material, stent design and/or stent delivery balloon may affect longitudinal stent deformation.
Abstract 13725: Oxidative Stress Accelerates Senescence and Reduces Life Span but Does Not Alter Cardioprotection in Mice Over-expressing H11kinase/hsp22
Authors: Morin Didier , Long Romain , Laure Lydie , Depre Christophe , Vatner Stephen F , Vatner Dorothy E , Derumeaux Geneviève , Berdeaux Alain , Ghaleh Bijan
Published: July 2021

H11 kinase/Hsp22 (H11K) is a small heat shock protein which provides powerful cardioprotection, i.e., reduction by 80% of infarct size expressed as a fraction of area at risk following 45 min coronary occlusion/4 hr reperfusion when over-expressed in a cardiac-specific transgenic (TG) mouse model. The goal of this investigation was to determine if these protective mechanisms would also enhance longevity and be effective in protecting from age-related myocardial dysfunction. Surprisingly, TG mice showed a reduction of 48% in their mean life span as compared to wild type (WT). The mechanism of premature death was most likely cardiac as left ventricular ejection fraction was reduced in one year old TG mice (49% vs 74% in WT, p<0.01), left ventricular cavity was dilated and cardiac hypertrophy was increased by 58%, all compatible with severe dilated cardiomyopathy. At the molecular level, hearts from TG mice showed a significant increase in reactive oxygen species, oxidized/reduced glutathione ratio, NADPH and xanthine oxidase activities, Nox2 expression associated with an increase in p16, p19 mRNA, β-galactosidase positive cells and telomerase activity. Subgroups of WT and TG mice were also treated with the antioxidant tempol (100 mg/kg/d) from weaning to their sacrifice. Chronic tempol treatment abolished oxidative stress, reduced cardiac hypertrophy, extended life span (+31%) and prevented aging markers (p16, p19 mRNA, β-galactosidase positive cells) in TG mice. The marked reduction in infarct size with ischemia/reperfusion noted above, observed in 10-12 weeks old mice, remained unchanged after tempol in TG mice and was not abolished with aging. Thus, this is the first demonstration that the mechanisms mediating reduced longevity such as increased oxidative stress do not reduce cardioprotection in H11K TG mice, and conversely, the mechanisms mediating powerful cardioprotection against ischemic stress are ineffective in maintaining normal cardiac function with aging.
Abstract 13773: A Novel Immunoglobulin G Autoantibody Against a Cryptic Epitope in Low Density Lipoprotein Induces Macrophage Tumour Necrosis Factor Release
Authors: Khamis Ramzi , Woollard Kevin , Boyle Joseph J , Chang Shang-Hung , Hyde Gareth , Johns Michael , Haskard Dorian O
Published: July 2021

Introduction/Objective:
Although IgG autoantibodies reacting with modified LDL have been associated with cardiovascular events, there is controversy as to whether such antibodies can be pathogenic. We set out to generate monoclonal autoantibodies reacting with LDL for further mechanistic studies.

Methods/Results:
We fused LDL receptor deficient (Ldlr-/-) mouse splenocytes with Sp2/0 myeloma cells, and screened hybridoma supernatants for reactivity with LDL. We selected a monoclonal IgG2b antibody, designated LO9. Variable heavy and light chain sequencing revealed somatic mutations indicative of LO9 being part of an acquired immune response. LO9 showed greater binding to unmanipulated solid phase human LDL than to Cu++ oxidised-LDL or malondialdehyde-conjugated LDL. LO9 did not react with LDL captured by immobilised anti-apoB, and binding to solid phase LDL was not inhibited by fluid phase LDL. Expression of the LO9 epitope on adherent LDL was increased by activated macrophage supernatant and this was inhibited by pepstatin A. Together, these observations suggest that LO9 reacts with a cryptic epitope in LDL unmasked by adhesion and/or the action of macrophage-derived enzyme(s). LO9 epitope expression in vivo was confirmed by immunohistochemical staining of human and mouse atherosclerosis. Following intra-venous injection of LO9 labelled with VivoTag-S 750-MAL, fluorescence molecular tomography imaging showed LO9 uptake in the aortic arch of Ldlr-/- but not wild-type animals. Confocal microscopy confirmed that LO9 localised in atherosclerotic regions beneath endothelium and in the vicinity of macrophages. In functional in vitro assays, addition of macrophages to LO9 bound to adherent LDL led to significant TNF release, an effect that was blocked by inhibition of Fc gamma receptors, and which was not seen when macrophages were incubated with adherent LDL alone.

Conclusions:
We believe LO9 is the first example of an IgG autoantibody that reacts with a cryptic epitope in LDL, revealed by adherence and/or by macrophage-derived enzyme(s). Binding of LO9-like IgG antibodies to LDL trapped on arterial matrix could lead to promotion of atherosclerosis via ligation of macrophage Fc gamma receptors and release of TNF and other inflammatory mediators.
Abstract 13785: Left Ventricular Contractile Entropy in 99mTc-Sestamibi SPECT is a Novel Prognostic Predictor in Patients with Non-ischemic Dilated Cardiomyopathy
Authors: Kano Naoaki , Okumura Takahiro , Sawamura Akinori , Watanabe Naoki , Mori Hiroaki , Fukaya Kenji , Morimoto Ryota , Hirashiki Akihiro , Bando Yasuko , Murohara Toyoaki
Published: July 2021

Background:
It has been reported that mechanical dispersion of myocardial contraction is increased in failing myocardium. However little is known about the association between contractile entropy evaluated by myocardial scintigraphy and prognosis in patients with non-ischemic dilated cardiomyopathy (NIDCM).

Purpose:
We aimed to investigate the prognostic value of contractile entropy in patients with NIDCM.

Methods:
Forty-seven patients (38 male, 55.1 years) with NIDCM were performed gated 99mTc-sestamibi myocardial perfusion SPECT (GMPS) and endomyocardial biopsy. Entropy was automatically calculated as a result of contractile phase analysis for each myocardial sampling point from GMPS, and it reflects a dispersion of global mechanical contraction. All patients were allocated into two groups based on the median of entropy; HE-group: entropy≥0.61 and LE-group: entropy<0.61. All patients were followed up at the mean of 2.8 years.

Results:
The mean QRS duration, left ventricular ejection fraction (LVEF) and plasma brain natriuretic peptide (BNP) levels were 114 msec, 35% and 225 pg/mL, respectively. Although there were no significant differences in QRS duration and plasma BNP levels between the two groups, LVEF was lower in the HE-group than in the LE-group (31.1% vs 39.8%, p=0.002). In Kaplan-Meier survival analysis, cardiac event rate was significantly higher in the HE-group (Figure). Cox proportional hazard analysis revealed that the HE-group was a significant determinant of cardiac events (Hazard Ratio: 7.66; 95%CI: 0.070-2.532; p=0.033). The mRNA expression level of sarcoplasmic endoplasmic reticulum Ca2+ ATPase (SERCA2a) in biopsy specimens was significantly lower in the LE-group (p=0.015).

Conclusion:
Contractile entropy, reflecting an impairment of global left ventricular contraction, might be useful to predict a poor prognosis in patients with NIDCM.
Abstract 13801: The p.Leu167del Mutation in APOE Gene causes Autosomal Dominant Hypercholesterolemia by Down-Regulation of LDL Receptor Expression in Hepatocytes
Authors: Cenarro Ana , Martín César , Stef Marianne , de Castro-Orós Isabel , Etxebarria Aitor , Palacios Lourdes , Mateo-Gallego Rocío , Ostolaza Helena , Tejedor Teresa , Civeira Fernando
Published: July 2021

Introduction:
The p.Leu167del mutation in APOE gene has been associated to different hyperlipidemias. However, the frequency of this mutation in autosomal dominant hypercholesterolemia and the mechanism of this association is not known.

Objectives:
To establish the frequency of p.Leu167del mutation in APOE gene in subjects with clinical diagnosis of Autosomal Dominant Hypercholesterolemia (ADH) non-dependent of LDLR, APOB nor PCSK9 genes, and to investigate the mechanism by which this mutation associates to ADH.

Methods:
We selected 288 unrelated subjects with ADH non-dependent of LDLR, APOB nor PCSK9 genes, and 220 unrelated normolipidemic subjects (control group). All available family members of mutation carrier subjects were also studied. Exon 4 of APOE gene was sequenced in all subjects.

VLDL and LDL were isolated from p.Leu167del carriers and E3/E3 control subjects by ultracentrifugation. Quantification of lipoprotein uptake in HepG2 and THP-1 cells and LDL receptor membrane-expression in HepG2 cells were carried out by flow cytometry.

Results:
In the ADH group, 9 unrelated subjects (3.1%) were carriers of the p.Leu167del mutation in APOE gene and none in the control group. Eleven family members were carriers of the mutation, 7 with isolated hypercholesterolemia and 4 with mixed hyperlipidemia. A clear co-segregation of p.Leu167del mutation with elevated plasma cholesterol levels in the families was found.

VLDL isolated from p.Leu167del mutation carriers had a significantly higher uptake by HepG2 and THP-1 cells compared to VLDL isolated from E3/E3 subjects (p<0.01). When increasing incubation times of HepG2 cells with VLDL from p.Leu167del carriers, the LDL receptor expression in surface membrane diminished, in contrast with the VLDL from E3/E3 subjects. When pre-incubating HepG2 cells with VLDL from p.Leu167del mutation carriers, the percentage of LDL internalisation was significantly lower than when incubating with VLDL from E3/E3 subject (p<0.01).

Conclusion:
The p.Leu167del mutation in APOE gene is associated to ADH in 3.1% of studied subjects. The mechanism of this association is higher uptake of VLDL, down regulation of the LDLR expression and decrease of LDL internalisation in hepatocytes.
Abstract 13846: The Relationship of Platelet Function Measurements with Bleeding Outcomes During Long-term Treatment with Dual Antiplatelet Therapy in Medically Managed NSTE-ACS Patients
Authors: Cornel Jan H , Ohman E. M , Neely Benjamin , Jakubowski Joseph A , Bhatt Deepak L , White Harvey D , Ardissino Diego , Fox Keith A , Prabhakaran Dorairaj , Armstrong Paul W , Erlinge David , Gurbel Paul A , Roe Matthew T
Published: July 2021

Introduction:
The relationship of low “on-treatment” platelet reactivity to longitudinal risks of major bleeding following acute coronary syndromes (ACS) has not been clearly delineated.

Methods:
We analyzed 2428 patients with non-ST-elevation ACS (NSTE ACS) from the TRILOGY ACS trial who were managed without revascularization and had platelet reactivity measurements (P2Y12 reaction units [PRUs]) collected in a platelet function substudy. Patients received aspirin + prasugrel (10 mg/d; 5 mg/d for those ≥75 y or <75 y and <60 kg) or clopidogrel (75 mg/d). Non-CABG severe/moderate GUSTO bleeding and non-CABG TIMI major/minor bleeding were ascertained through 30 months. Contal’s method was used to investigate whether a PRU cut point could distinguish high vs low bleeding risk. Multivariable Cox proportional hazard models were used to evaluate the association between PRU and time to first bleed.

Results:
Through 30 months, there were 27 GUSTO severe/moderate bleeds and 37 TIMI major/minor bleeds, with gastrointestinal bleeding the most common. Baseline characteristics were stratified by tertiles of PRU values at 5 d, and significant differences were seen across tertiles (Table). Unadjusted bleeding rates appeared highest among those in the lowest PRU tertile but no reliable PRU cut point was found that significantly distinguished bleeding risk. Unadjusted analyses showed continuous measures of PRUs were not associated with GUSTO (HR=1.00, 95% CI: 0.96-1.04) or TIMI bleeding (HR=1.03, 95% CI: 0.99-1.06). This relationship did not change after multivariable adjustment.

Conclusions:
Among NSTE-ACS patients managed without revascularization and receiving dual antiplatelet therapy, PRU values were not significantly associated with long-term bleeding risk. The relatively small number of bleeding events accrued limited study power, but these results suggest that low “on-treatment” platelet reactivity does not independently predict post-ACS bleeding risk.
Abstract 13944: Early Initiation of Remote Monitoring in CIED Patients is Associated with Reduced Mortality
Authors: Mittal Suneet , Piccini Jonathan , Avi Fischer , Snell Jeff , Dalal Nirav , Varma Niraj
Published: July 2021

Introduction:
Remote monitoring (RM) of cardiac implantable electronic devices (CIED) has been associated with reduced mortality. However, the relationship between the time from device implantation to initiation of RM and survival is unknown.

Hypothesis:
Following CIED implantation, early (within 91 days) initiation of remote monitoring will result in improved survival as compared to later initiation.

Methods:
Patients implanted with a St. Jude Medical
™
CIED (2008-2011) that participated in RM were included and data collected through Nov 2012. Patients enrolled in a clinical study were excluded. Age, gender, device type, and surveillance duration were ascertained using device tracking data. Weekly RM service utilization was determined from Merlin.net
™
. The index time was set as the time of first RM transmission (RM
1
). The all-cause mortality incidence rate (MIR) was evaluated for each device type among patients with early (≤ 91 days) or late (> 91 days, ≤ 52 weeks) time from device implant to RM
1
. All-cause survival was prospectively compared for each device type among patients with early or late time to RM
1
using Cox proportional hazards with gender as a covariate and stratification on age.

Results:
We evaluated 105,285 RM patients (71 ± 13 years, 64% male) with a PM (n= 46,758, 44%), ICD (n= 31,697, 30%), or CRT device (n= 26,830, 26%). The median time to RM
1
was 8 [4, 19] weeks. In comparison to patients with late RM
1
(median: 24 weeks), patients with early RM
1
(median 4 weeks) had lower MIR (4,114 vs 4,924 per 100k-pt-yrs, p< 0.001) and greater survival (adjusted HR: 1.27 [CI: 1.22-1.32], p< 0.001). This relationship held across each of the device types (Table.)

Conclusion:
Our data show that survival is higher in patients who have a shorter time between device implant and remote monitoring initiation, across all CIED device types. These data suggest RM should be initiated as soon as possible following device implantation.
Abstract 13993: Impact of Prasugrel Pretreatment and Timing of Coronary Artery Bypass Grafting on Clinical Outcomes of Patients With Non-ST-Segment Elevation Myocardial Infarction: From the Accoast Study
Authors: Dudek Dariusz , Widimsky Petr , Bolognese Leonardo , Goldstein Patrick , Hamm Christian , Tanguay Jean-Francois , LeNarz LeRoy , Miller Debra L , Brown Eileen , ten Berg Jurrien M , Montalescot Gilles ,   for the ACCOAST Investigators
Published: July 2021

Objectives:
We evaluated the impact of prasugrel pretreatment and timing of coronary artery bypass grafting (CABG) on clinical outcomes of patients with non-ST-segment elevation myocardial infarction (NSTEMI) undergoing CABG based on data from ACCOAST.

Methods:
We evaluated the impact of troponin, prasugrel pretreatment and CABG timing on clinical outcomes of NSTEMI patients undergoing CABG through 30 days from ACCOAST.

Results:
CABG patients versus PCI or medically managed patients were more often male, diabetic, had peripheral arterial disease and a higher GRACE score. By randomization assignment, 157 patients received a 30-mg loading-dose of prasugrel before CABG; 157 patients did not. CABG patients were grouped by tertiles of time from randomization to CABG; baseline characteristics in the Table. Patients in the lowest tertile had significantly more events (cardiovascular death, MI, stroke, urgent revascularization or glycoprotein IIb/IIIa bailout) and all TIMI major bleeds than those in the other 2 groups (p<0.045, p<0.002 respectively), but the patients in the higher 2 groups were not significantly different from each other. No difference was detected in all cause death among the 3 groups (p>0.39). A multivariate model evaluated 5 possible predictors of the composite endpoint of all cause death, MI, stroke and TIMI major bleeding. Time from randomization to CABG (HR 0.84 for each 1 hour of delay), left main disease presence (HR 1.76), and region of enrollment (Eastern Europe vs other, HR 3.83) were significant predictors but not prasugrel pretreatment or baseline troponin level ≥3xULN.

Conclusions:
In this group of high-risk patients presenting with NSTEMI, early surgical revascularization carried an increased risk of bleeding and ischemic complications, without impact on all-cause mortality. No impact of baseline troponin or prasugrel pretreatment (important factors influencing time of CABG) on clinical outcomes was confirmed.
Abstract 14046: Heparin Alone is Not Enough. Gp IIb/IIIa Inhibitors Improve Outcome in Patients With Primary PCI for STEMI Treated With Heparin. Results of the Prospective ALKK-Registry
Authors: Zeymer Uwe , Hochadel Matthias , Gitt Anselm , Andresen Dietrich , Zahn Ralf
Published: July 2021

Background:
There is still debate about the optimal antithrombotic therapy in patients undergoing primary PCI. Earlier randomized trials have shown a benefit of GP IIb/IIIa inhibitors in patients treated with heparin, with the highest benefit in high risk patients. Most recent trials did not support the earlier data. Therefore we evaluated the impact of GP IIb/IIIa inhibitors on outcome in patients with primary PCI for STEMI in real life in a large number of patients.

Methods:
We used the data of the ongoing prospective ALKK-PCI registry and included patients with PCI for STEMI < 24 h duration treated with heparin in 40 centres. We excluded patients who were treated with bivalirudin.

Results:
Between 2008 and 2012 a total of 15061 consecutive patients with PCI for STEMI without cardiogenic shock were included. Of these 8864 (58.9 %) received a GP IIb/IIIa inhibitor. Baseline characteristics, procedural features and in-hospital outcomes are given in the table.

In a multivariate analysis GP IIb/IIIa inhibitors were associated with a reduced mortality (odds ratio 0.81, 95% CI 0.72-0.96).

Conclusion:
In clinical practice GP IIb/IIIa inhibitors are used in more than 50% of the patients with primary PCI for STEMI treated with heparin. The use is associated with an improved mortality without an increase in bleeding complications. This data support the results of randomized clinical trials and questions the use of heparin alone as intravenous antithrombotic agent.
Abstract 14050: The Gut Flora Promotes Endothelial Dysfunction Through Vascular MicroRNA-204-mediated Down-regulation of Endothelial Sirtuin1
Authors: Vikram Ajit , Kim Young-Rae , Kumar Santosh , Jacobs Julia S , Irani Kaikobad
Published: July 2021

The gut flora contributes to development of atherosclerosis. Endothelial dysfunction, one manifestation of which is impaired endothelium-dependent vasorelaxation, accompanies and promotes atherosclerotic vascular disease. Here we show that gut flora impair endothelium-dependent vasorelaxation by remotely up-regulating microRNA-204 (miR-204) which downregulates SIRTUIN1 (SIRT1) in the vascular wall. Microarray analysis in aortas of germ-free mice revealed a set of down-regulated microRNAs, including miR-204, which target SIRT1. Suppression of gut flora in mice with antibiotics in drinking water decreased aortic miR-204, increased aortic SIRT1, and improved endothelium-dependent vasorelaxation, effects that were reversed with discontinuation of antibiotics. In addition, miR-204 mimic impaired endothelium-dependent aortic vasorelaxation ex vivo. Moreover, high-fat diet feeding stimulated aortic miR-204, suppressed SIRT1, and impaired endothelial function, all of which were mitigated by administration of antibiotics, and reversed with stoppage of antibiotics. In contrast, antibiotics did not improve high-fat diet-induced endothelial dysfunction in mice conditionally lacking endothelial SIRT1. In addition, anti-miR-204 delivered systemically prevented high-fat diet-induced endothelial dysfunction and vascular SIRT1 decrease. Finally, serum from mice on antibiotics suppressed miR-204, and increased SIRT1, in endothelial cells, effects that were not observed with serum from mice in which antibiotics were discontinued. Therefore, the gut flora remotely downregulates endothelial SIRT1 through miR-204, leading to impairment of endothelial function.
Abstract 14798: Right Atrial Function as Prognostic factor in Patients with Pulmonary Hypertension
Authors: Fukuda Yuko , Tanaka Hidekazu , Motoji Yoshiki , Ryo Keiko , Matsuzoe Hiroki , Hatazawa Keiko , Hatani Yutaka , Dokuni Kumiko , Toki Hiromi , Shimoura Hiroyuki , Ooka Junichi , Sano Hiroyuki , Sawa Takuma , Mochizuki Yasuhide , Tatsumi Kazuhiro , Matsumoto Kensuke , Emoto Noriaki , Hirata Ken-ichi
Published: July 2021

Background:
The development of right ventricular (RV) dysfunction in patients with pulmonary hypertension (PH) has been associated with adverse outcomes. Right atrial (RA) function could be a prognostic factors as well as RV function, but non-invasive evaluation of RA function is limited. Our objective was thus to test the hypothesis that RA function was associated with hemodynamic parameters of RV performance in PH patients.

Methods:
Eighty PH patients with mean pulmonary artery pressure (PAP) of 40±11mmHg (all≥25mmHg) were recruited in this study. RA function was assessed by using two-dimensional speckle-tracking strain from RV-focused apical 4-chamber view. RA strain was calculated with the reference point set at the P wave, which enabled the recognition of peak negative (RAneg), positive strain (RAposi), and the sum of those values (RAtotal), corresponding to RA contractile, conduit, and reservoir function, respectively. All patients underwent right-heart catheterization for measurement of mean PAP and pulmonary vascular resistance (PVR).

Results:
RAneg (r=0.24 and p=0.03), RAposi (r=0.31 and p=0.01) and RAtotal (r=0.35 and p=0.001) were significantly correlated with mean PAP. In addition, RAposi (r=0.41 and p<0.001) and RAtotal (r=0.44 and p<0.001) were also correlated with PVR.

Conclusions:
Non-invasively assessed RA strains were associated with mean PAP and PVR. RA strain may be of a valuable additive factor for the management of PH patients, and thus have potential clinical applications.
Abstract 14859: IL17 Contribute to the Atherosclerotic Development and the Initiation of Chronic Kidney Disease
Authors: Tanigaito Yusuke , Sato Kayoko , Kitamura Kazutaka , Futase Atsuko , Fukushima Keiko , Uto Kenta , Hagiwara Nobuhisa
Published: July 2021

Introduction:
Recent studies suggested that the atherogenic state correlated with progression of chronic kidney disease (CKD). However, it is not known whether sustained status of chronic inflammation in atherosclerosis is closely linked to the development of CKD.

Hypothesis:
Inflammatory cytokine producing-T cells in the advanced atherosclerosis induced the dysfunction of podocytes.

Methods/Results:
Eighteen-week-old apolipoprotein E-deficient mice (Control) were fed with high-fat diet for 8W (ApoE) and compared to IL17/ApoE-double deficient mice fed with high-fat diet (DKO). Sudan staining of aorta revealed the atherosclerotic lesion was increased in ApoE compared to Control, and inhibited in DKO. Activated IFNγ
+
CD4 T cells (Th1) and IL17
+
CD4 T cells (Th17) were significantly increased in ApoE compared to DKO by FACS. Immunohistochemistry of aortic sinus showed many Th1 and Th17 were infiltrated in the atherosclerotic plaque in ApoE, however, inflammatory infiltrates were inhibited in DKO. Furthermore, the urinary albumin/creatinine ratio was increased significantly in ApoE compared to DKO. Th1 and Th17 were correlated with the urinary albumin/creatinine ratio, and many Th1 and Th17 were observed in the glomeruli. Next, to investigate whether the inflammatory cytokine induced dysfunction of podocytes were involved in proteinuria, we investigated nephrin, podocin, and phosphorylated nephrin in the kidney by Western blots and immunohistochemistry. The decreased phosphorylated neprin in ApoE were recovered in DKO. Finally, we confirmed that the morphological changed of podocytes in ApoE were improved in DKO by electron microscopy.

Conclusion:
Recruitments of IFNγ
+
Th1 and IL17
+
Th17 T cells might aggravate atherosclerosis acceleration and induce the initiation of glomerular tissue damage.
Abstract 14866: Hyperglycemia is an Independent Predictor of Left Ventricular Hypertrophy
Authors: Thanikachalam Mohan , Harivanzan Vijaykumar , Sunderarajan Jahnavi , Baliga Ragavendra , Thanikachalam Sadagopan
Published: July 2021

Background:
Diabetes mellitus (DM) is a risk factor for cardiovascular morbidity and mortality. In the current study we examine the association of hyperglycemic with left ventricular hypertrophy (LVH) independent of major correlates of LVH, such as, age, body size, blood pressure (BP) and aortic stiffness.

Methods:
We conducted a population-based, cross-sectional survey in 8,080 South Indians over the age of 20 years. The study included anthropometric, socioeconomic, psychosocial, BP, blood lipids, insulin, HbA1C, glucose tolerance test and carotid-femoral pulse wave velocity (PWV) assessments. Insulin resistance (IR) was defined as the 25% of the population with the highest values for homeostasis model assessment of insulin resistance (HOMA-IR). LV mass and relative wall thickness (RWT) were determined using echocardiography. LVH was defined as LV mass index (LVMI) >109 g/m
2
for men and >89 g/m
2
for women.

Results:
After the exclusion of people with hypertension, 5,841 subjects (mean age 41 years, 59% women) constituted the study sample. The mean LVMI in subjects with normoglycemia (n=3585), pre-DM (impaired fasting and/or post prandial blood sugar; n=1315) and DM (n=888) was 78.5 ± 17.5, 80.7 ± 19.4 and 87.2 ± 20.3, while mean RWT was 0.46 ± 0.09, 0.48 ± 0.09 and 0.51 ± 0.1, respectively (p<0.01). After adjustments for age, sex, BMI, BP, PWV, blood lipids, history of coronary artery disease, socioeconomic and smoking status, and physical activity, when compared to persons with normoglycemia, the odds ratio (95% CI) for LVH in pre-DM and DM men was 1.12 (0.89, 1.42) and 1.37 (1.04, 1.8), respectively; the odds ratio in pre-DM and DM women was 1.07 (0.89, 1.28) and 1.4 (1.08, 1.82), respectively. Among the persons with normoglycemia those with IR the odds ratio for LVH was 1.23 (0.85, 1.78) in men and 1.01 (0.79, 1.30) in women. In the multi-linear regression models HbA1c was independently correlated with LVMI. The correlation coefficients were higher in men (β= 0.07, p <0.001) compared to women (β= 0.037, p = 0.032).

Conclusion:
Hyperglycemia is an independent predictor of LVH in South Asian population. These findings indicate potential adverse myocardial effects of DM independent of associated risk factors, such as obesity, BP and aortic stiffness.
Abstract 14925: Inverse Association between Family History of Premature Coronary Artery Disease and the Risk of Death in Patients with Coronary Artery Disease
Authors: Abdi Ali Ahmed , Shaheen Abdel Aziz , Southern Danielle A , Zhang Mei , Knudston Merril , White James , James Matthew , Wilton Stephen B
Published: July 2021

Background:
Family history (FHx) of premature coronary artery disease (CAD) is an established cardiovascular risk factor. However the impact of FHx on outcomes of patients with CAD is unclear.

Methods & Results:
The Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) Program is an inclusive prospective registry of patients undergoing coronary angiography. Between April 2002 and Mar 2013, 99,667 patients were enrolled. 30,030 (30%) patients reported FHx, defined as a first degree relative with premature CAD (males <55, females <65 years). We investigated the association between FHx and all-cause mortality at 1 year, using multivariable logistic regression, adjusting for clinical characteristics, comorbidities, and the extent of CAD. Patients with normal angiography (15.2%) were excluded.

Compared to those without FHx, those with FHx were younger (60.1 vs 64.0 years, p<0.0001), more likely female (30.5% vs 29.5%; p=0.0018), and were less likely to have previously diagnosed CAD, congestive heart failure, stroke, or chronic kidney disease (all p<0.0001) Conversely, those with FHx were more likely current smokers (31.8% vs 25.3%) and to have hypertension (68.8% vs 65.5%) and dyslipidemia (75.7% vs 68.1%), all p<0.0001). The indication for angiography was an acute coronary syndrome (ACS) in 55% of both groups (p=0.57), and the extent of CAD was similar.

Overall, FHx was associated with reduced 1-year mortality in fully adjusted models (odds ratio [OR] 0.56, 95% CI 0.51 to 0.62). This protective association was present in patients with and without a previous CAD event (OR 0.66 [95% CI 0.60 to 0.78] vs 0.53 [95% CI 0.47 to 0.59], respectively), and in patients with and without an ACS (OR 0.56 [95% CI 0.50 to 0.63] vs 0.56 [95% CI 0.48 to 0.65], respectively). There was slight attenuation of association with age, but FHx remained protective even in those aged 80 or more (OR 0.72, 95% CI 0.57 to 0.90).

Conclusion:
In patients with angiographic CAD, a family history of premature CAD is associated with lower mortality, independent of clinical characteristics, mode of presentation, and extent of disease. Further investigation of potential patient- and system-level mediators of this seemingly paradoxical relationship is required.