bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13775: Increased Atherosclerosis in the Lack of IkBNS in LDL Receptor-deficient Mice is Associated With Increased Interleukin-6 Production by Macrophages
Authors: Akita Koji , Isoda Kikuo , Sato-Okabayashi Yayoi , Ishii Yuko , Shimada Kazunori , Daida Hiroyuki
Published: April 2024

Background:
IκBNS is a nuclear IκB protein which regulates nuclear factor-κB dependent interleukin (IL) -6 production. Although IL-6 is an important biomarker for cardiovascular diseases, the role of IκBNS in the development of atherosclerosis is poorly understood.

Methods and Results:
Mice that lacked IκBNS (IκBNS-/-) were crossed with LDL receptor-deficient (LDLr-/-) mice and formation of atherosclerotic lesion was analyzed after 16 weeks consumption of a high-fat diet. When compared with single LDLr-/- mice (n=6), the surface atherosclerotic lesions in aortas were significantly increased in IκBNS-/-LDLr-/- mice (n=6) (22.7 ± 3.0% vs. 6.2 ± 1.4 %; p <0.001)(Figure). Immunostaining revealed significant increase in both Mac-3-positive (1.6-fold, p <0.05) and α-SMA-positive (3.6-fold, p <0.01) lesions in IκBNS-/-LDLr-/- mice compared with LDLr-/- mice. Furthermore, IL-6 expression (2.2-fold, p<0.001), and percent phospho-STAT3-positive cell (1.9-fold, p<0.05) were increased in IκBNS-/-LDLr-/- mice, indicating IκBNS deficiency promoted proliferation of both macrophage and smooth muscle cells via the IL-6-Stat3 signaling pathway. Then, we studied the function of macrophages. After LPS stimulation, the mRNA levels of both IL-6 (2.4-fold, p<0.001) and IL-18 (1.4-fold, p<0.05) were increased in the macrophages from IκBNS-/-LDLr-/- mice compared with LDLr-/- mice. Moreover, ELISA experiments revealed IκBNS-/-LDLr-/- macrophages produce much higher level of IL-6 in culture supernatants compared with LDL-/- macrophages (1.9-fold, p<0.01).

Conclusions:
The present study shows that IκBNS gene deficiency in atherogenic mice led to the increase of IL-6 production and the development of atherosclerosis.
Abstract 13826: Patient Characteristics and Prognosis of OCT Verified Calcified Nodules in Acute Coronary Syndrome
Authors: Nishiguchi Tsuyoshi , Tanaka Atsushi , Taruya Akira , Hikimoto Shigetoshi , Morimoto Junko , Mori Kazuya , Asae Yoshinori , Higashioka Daisuke , Tamaki Tetsuya , Aoki Hiroshi , Teraguchi Ikuko , Kameyama Takeyoshi , Okouchi Keishi , Shiono Yasutsugu , Orii Makoto , Kuroi Akio , Yamaguchi Tomoyuki , Yamano Takashi , Matsuo Yoshiki , Ino Yasushi , Kubo Takashi , Hozumi Takeshi , Akasaka Takashi
Published: April 2024

Backgrounds:
Pathological studies have shown that calcified nodule (CN) is one of important causes for acute coronary syndrome (ACS). Optical coherence tomography (OCT) is able to identify CN in vivo. No data, however, is available for prognosis of CN.

Purpose:
The purpose of this study was to investigate the prognosis of CN.

Methods:
This study consisted of 492 patients with ACS on native coronary artery who underwent pre-PCI OCT to explore the culprit artery. Patients were divided into a CN group and a non-CN group according to OCT findings. The OCT criterion of CN was defined when fibrous cap disruption was detected over a calcified plaque characterized by protruding calcification, superficial calcium, and the presence of substantive calcium proximal and/or distal to the lesion. The primary end-point was overall survival. The secondary end-point was composite of major adverse cardiac events (MACE) including cardiac death, non-fetal myocardial infarction (MI), and unstable angina pectoris (uAP).

Results:
The prevalence of OCT-CN was 4.5% (n=22). Patients with CN were significantly older (CN: 75.4±9.0 vs. non-CN: 66.7±11.3, p<0.01), and more likely to female (CN: 50% vs. non-CN: 23%, p<0.01). Compared with non-CN patients, hypertension (CN: 95% vs. non-CN: 71%, p<0.01), and hemodialysis (CN: 18% vs. non-CN: 3%, p<0.01) were more common in CN. Mean follow-up period was 25.4 (range 1-60) month. During the period, cardiac death occurred in 19 (CN: 1, non-CN: 18), non-cardiac death in 15 (CN: 3, non-CN: 12), non-fatal MI in 7 non-CNs, and uAP in 11 non-CNs. Kaplan-Meier curve showed significantly low overall survival in CN (Figure A, p<0.05), while MACE were similar in both groups (Figure B, p=0.42).

Conclusions:
The prevalence of OCT-CN was 4.5%. Patients with CN were older, and had more co-morbidities including hypertension and kidney dysfunction. The overall survival was significantly poor in patients with CN, although the MACE free survival were similar between groups.
Abstract 13828: Fibroblast Growth Factor-23 Induces Cellular Senescence in Human Mesenchymal Stem Cells From Skeletal Muscle Independently of Klotho Pathway
Authors: Sato Chisato , Iso Yoshitaka , Mizukami Takuya , Sasai Masahiro , Sekiya Ichiro , Miyazaki Akira , Suzuki Hiroshi
Published: April 2024

Introduction:
Mesenchymal stem cells (MSCs) in skeletal muscle represent a distinct cell population from satellite cells (StCs), and the functional impairment have shown to be associated with ectopic fat formation in muscle tissues. Muscle wasting and/or degeneration are prevalent in heart failure and chronic kidney disease. However, it remains unknown whether such disease condition influences the MSC function and fate. Thus, aim of this study was to investigate effects of fibroblast growth factor (FGF)-23 and angiotensin (ANG)-II, neurohumoral factors related to pathophysiology of cardio-renal syndrome (CRS), on the MSCs in culture system.

Methods and Results:
MSCs were isolated from human skeletal muscle and cultured with appropriate growth medium. Gene expression analysis demonstrated the enhanced expression of FGF receptors and ANG-II type 1 receptor in the MSCs as compared with the human StCs. Klotho gene was not detected in the two progenitors. The cultured MSCs and StCs were treated with FGF-23 (10ng/ml) and ANG-II (100 nM) for 48 hours. Cell proliferation assay revealed significant decreased cell number in the MSCs treated with FGF-23 but not ANG-II than in the controls (58 % of the controls, p< 0.05). The neurohumoral factors did not affect the cell counts of the StCs. The FGF-23 treated MSCs exhibited the senescent phenotype, as judged by senescence-associated β-galactosidase assay (%senescent cells: 46.5± 11.7 % in the FGF-23 vs. 35.8± 5.8% in the controls, p< 0.05), cell morphology, and increased expression of p53 and p21 in western blot analysis. FGF-23 also augmented intracellular oxidative stress in the MSCs. The mechanisms responsible for the accumulation of reactive oxygen species (ROS) were attributable to increased NADPH oxidase and decreased MnSOD expression in the cells. In histological study, p53-positive senescent MSCs were detected in adipose infiltration area of degenerated gastrocunemius muscle tissues from a CRS patient.

Conclusions:
Results of this study indicate that FGF-23 induces premature senescence in human MSCs from skeletal muscle via promoting ROS/p53/p21 pathway in klotho-independent action. Interaction of the MSCs with FGF-23 may play a key role in muscle wasting in patients with CRS.
Abstract 13907: Transplantation of Brown Adipose Tissue Inhibits Atherosclerosis in Apoe Deficient Mice via Activation of Fgf-21/adiponectin Axis
Authors: Kikai Masakazu , Terada Kensuke , Yamamoto Keita , Motoyama Shinichiro , Wada Naotoshi , Wakana Noriyuki , Yamada Hiroyuki
Published: April 2024

[Background]
Brown adipose tissue (BAT), a key nonshivering thermogenic tissue, has been recently identified as an endocrine organ to regulate metabolic homeostasis. Experimental BAT transplantation has been reported to improve glucose tolerance and insulin sensitivity; however, the beneficial effect of BAT transplantation on atherogenesis remains undefined.

[Method and Result]
Interscapular BAT was harvested from 12-week-old mice (C57BL/6) and transplanted into the visceral cavity in 12-week-old recipient apoE-/- mice. After 3 months of high-cholesterol diet, atherosclerosis development was evaluated. BAT transplanted mice showed a modest, but significant, decrease in body weight and increase in mean blood pressure compared with sham control mice (4.7%, 12%, respectively, P<0.05). Food intake and lipid profile except for triglyceride level did not differ between the 2 groups. Oil-red-O staining of entire aorta showed a significant decrease in atherosclerotic lesion area in BAT transplanted mice by 19.7 % compared with sham control mice (P<0.05). Histomorphological analysis of transplanted BAT graft showed a similar appearance as white adipose tissue rather than brown adipose tissue. Consistently, mRNA expression levels of brown adipose tissue-related genes such as UCP-1 and PGC-1α were markedly decreased compared with those in endogenous BAT. Interestingly, transplanted BAT graft showed a significantly increased mRNA expression level of fibroblast growth factor-21 (FGF-21), while its expression level in liver was comparable between the 2 groups. The serum concentration of FGF-21 was also increased in BAT transplanted mice (49%, P<0.05), accompanied by the higher concentration of circulating adiponectin (36%, P<0.05). Serum concentration of adiponectin was negatively correlated with the percentage of plaque area (r=-0.44, P<0.05), suggesting that transplanted BAT graft exerts atheroprotective effect via activation of FGF-21/adiponectin axis.

[Conclusion]
Our findings demonstrated for the first time that BAT transplantation reduces atherosclerosis development, and phenotypic modulation of BAT graft could be a potential therapeutic strategy for preventing atherosclerotic diseases.
Abstract 13940: Risk Stratification of Future Left Ventricular Dysfunction in Patients With Indications for Right Ventricular Pacing Owing to Bradycardia
Authors: Ooka Junichi , Tanaka Hidekazu , Hatani Yutaka , Hatazawa Keiko , Dokuni Kumiko , Matsuzoe Hiroki , Shimoura Hiroyuki , Sano Hiroyuki , Motoji Yoshiki , Mochizuki Yasuhide , Ryo Keiko , Matsumoto Kensuke , Hirata Ken-ichi
Published: April 2024

Background:
Although right ventricular (RV) pacing is the only effective treatment for patients with symptomatic atrioventricular block, it creates left ventricular (LV) mechanical dyssynchrony, which can induce LV dysfunction and heart failure. Current criterion for consideration of cardiac resynchronization therapy (CRT) is LV ejection fraction (LVEF) ≤35%, but indication for CRT in patients required for RV pacing with LVEF >35% remains uncertain.

Methods:
We studied 35 consecutive patients with LVEF of 51±9% (all≥35%) who had undergone implantable cardioverter-defibrillator implantation (RV pacing <5%). Echocardiography was performed at baseline and during RV pacing. LV dyssynchrony was determined by the anteroseptal-to-posterior wall delay from mid-LV short-axis view using two-dimensional speckle-tracking radial strain (≥130ms as significant). Patients were divided into two groups based on baseline LVEF: preserved LVEF≥50% (n=19) and mildly reduced LVEF of 35-50% (n=16).

Results:
LV dyssynchrony in patients with mildly reduced LVEF was significantly worsened during RV pacing compared to that in patients with preserved LVEF (from 86.0±103.9ms to 214.6±132.1ms vs. from 21.7±29.0ms to 65.6±90.9ms, p=0.01). Furthermore, the prevalence of significant LV dyssynchrony during RV pacing in patients with mildly reduced LVEF was significantly higher than that in patients with preserved LVEF (68% vs. 16%, p<0.01). LVEF in patients with mildly reduced LVEF was also significantly worsened during RV pacing compared to that in patients with preserved LVEF (from 42.8±4.6% to 37.6±6.8% vs. from 58.3±5.7% to 57.9±6.9%, p<0.01).

Conclusions:
The amount of RV pacing-induced LV dysfunction may be associated with baseline LV function. Thus, these adverse effects in patients with mildly reduced LVEF of 35-50% and indications for RV pacing owing to bradycardia can be prevented by CRT.
Abstract 13943: Time to Target Temperature and Outcome After Out-of-Hospital Cardiac Arrest
Authors: Della Mattia Alessio , Pellis Tommaso , Gregori Dario , Nielsen Niklas , Campanile Vincenzo , Peratoner Alberto , Brunetti Iole , Pelosi Paolo , Kjaergaard Jesper , Hassager Christian
Published: April 2024

Background:
We studied in the association between time to target temperature (TTT) and outcome in patients enrolled in the Target Temperature Management (TTM-Trial) after out of hospital cardiac arrest (OHCA).

Methods:
The TTM-Trial is a randomized study that investigated temperature management at 33 or 36°C for 24 hours (h) in 950 patients. We defined TTT as the time from return of spontaneous circulation (ROSC) to a bladder temperature <34°C or <36.5°C.

Results:
Target temperature after ROSC was achieved in a median time of 5.3h and 2.9h, respectively in the 33°C and 36°C group. In patients randomized at 33°C a shorter TTT was associated with worse survival (Log-rank <0.0001) and TTT was a predictor of survival with a hazard ratio (HR) for mortality of 0.68 (95%CI 0.56-0.81). There was a linear relationship between TTT and log relative hazard of mortality (P= 0.29). After multivariate analysis TTT had a HR for mortality of 0.81 (95%CI 0.67-0.98). In addition, TTT was a predictor of poor neurological outcome with an odds ratio (OR) of 0.63 (95%CI 0.48-0.83) with a linear relationship between TTT and log odds of poor neurological outcome (P= 0.38). After adjustment for confounders, TTT was not any longer an independent predictor of poor neurological outcome (OR 0.87, 95%CI 0.64-1.18).

In patients randomized at 36°C, TTT was not associated with survival and after adjustment for confounders TTT was no longer an independent predictor of survival (HR 0.81, 95%CI 0.46-1.43) and of poor neurological outcome (OR 1.05, 95%CI 0.54-2.03).

Conclusions:
A faster TTT in patients cooled at 33°C was associated with increased mortality and was a predictor of mortality and poor neurological outcome. TTT remained an independent predictor of mortality after multivariate analysis.
Abstract 13954: Myocardial T1 Mapping at 3 T: Reference Values and Influencing Factors
Authors: Zhao Lei , Li Song-Nan , Wang Lu , Lin Hui , Wen Song-Nan , Ning Man , Ma Xiao-Hai , Yu Rong-Hui , Long De-Yong , Tang Ri-Bo , Sang Cai-Hua , Jiang Chen-Xi , Du Xin , Dong Jian-Zeng , Fan Zhan-Ming , Ma Chang-Sheng
Published: April 2024

Introduction:
T1 mapping is a robust application to provide quantitative measurement reflecting myocardial properties. Knowledge of normal values for quantitative cardiovascular magnetic resonance (CMR) is crucial to distinguish normal from disease.

Hypothesis:
T1 mapping methods provide information of myocardial properties, in normal cohort, whether there is difference of myocardial tissue characterization in different gender, age remained unclear.

Methods:
40 healthy volunteers (27 females; mean age 46±13 years) underwent left-ventricular (LV) T1 mapping in 3 short-axis slices at 3 T. For T1 mapping, a validated modified Look-Locker inversion recovery sequence was used before and after injection of gadolinium contrast. T1 relaxation times were quantified for each slice and extracellular volume (ECV) fraction was calculated. The association between the T1 mapping parameters and potential influencing factors were determined using a Pearson correlation.

Results:
Mean global LV pre-contrast T1 times were 1267.3±39.0ms, post-contrast T1 times were 572.4±53.2ms, ECV were 27.2±2.7%. There were differences of T1 (pre-/post-contrast) times and ECV in different LV level: 1258.8 ms/578.7 ms/26% (base), 1267.8 ms/ 575.6 ms/ 26.5% (mid-ventricle), 1293.5 ms/564.5 ms/29.4% (apex). There were no significant differences of myocardium T1 times between male and females (all P> 0.05), but ECV was slightly higher in women than men (P <0.05). There was negative correlation between global LV ECV fraction and hematocrit (R=-0.65, P<0.01), no correlation between age and T1 mapping parameters were found (all P > 0.05).

Conclusion:
Myocardial T1 reference values for the specific CMR setting are provided. T1 mapping parameters show no gender and age differences in normal individuals.
Abstract 13955: Small Conductance Ca2+-activated K+ Current is Upregulated via the Phospholylation of CaMKII in Cardiac Hypertrophy
Authors: Mizukami Kazuya , Yokoshiki Hisashi , Mitsuyama Hirofumi , Watanabe Masaya , Tenma Taro , Kamada Rui , Takada Shingo , Tsutsui Hiroyuki
Published: April 2024

Background:
Left ventricular hypertrophy is associated with increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca2+-activated K+ (SK) channel is involved in the pathogenesis of ventricular arrhythmias in heart failure. We have recently reported that the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) is increased in hypertensive cardiac hypertrophy.

Objective:
The aim of this study is to test the hypothesis that SK channels activity is increased via the CaMKII-dependent pathway in hypertensive cardiac hypertrophy.

Methods and Results:
We used normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Whole cell membrane current was recorded in isolated ventricular myocyte by the patch-clamp method, and apamin-sensitive K+ current (IKAS), inhibited by apamin (100 nM), a blocker of SK channel, was evaluated. IKAS at 40 mV was present in SHR, whereas it was hardly detectable in WKY (0.579±0.046 pA/pF vs 0.022±0.062 pA/pF, both n=6, p<0.05). IKAS was almost completely abolished by 1 μM KN-93, an inhibitor of CaMKII, in SHR. Optical recordings of action potential in left ventricular anterior wall revealed that apamin prolonged the late phase of repolarization only in SHR (APD90 113.07±3.62 vs 124.95±3.62 msec, both n=4, p<0.05, and APD50 37.53±4.21 vs 50.48±4.21 msec, both n=4, p<0.05). Western blot analysis of SK channel protein isoform demonstrated that SK2 was significantly increased in SHR compared to WKY (SK2/GAPDH 0.66±0.07 vs 0.40±0.02, both n=6, p<0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHR (pCaMKII/GAPDH 0.80±0.06 vs 0.58±0.06, both n=6, p<0.05) despite comparable total amount of CaMKII between groups.

Conclusion:
SK channels are upregulated via the enhanced activation of CaMKII in hypertensive cardiac hypertrophy.
Abstract 13981: Predictive Value of Local Prolonged Electro-Mechanical Interval in the Concealed Stage of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
Authors: Mast Thomas P , Teske Arco J , Te Riele Anneline S , Groeneweg Judith A , Tichnell Crystal , Murray Brittney , Tandri Harikrishna , van der Heijden Jeroen F , Velthuis Birgitta K , Loh Peter , Doevendans Pieter A , Dooijes D , van Veen Toon A , de Bakker Jaques M , Abraham Ted P , James Cynthia A , Calkins Hugh , Hauer Richard N , Cramer Maarten J
Published: April 2024

Introduction:
The concealed stage of ARVD/C is associated with increased risk of life-threatening arrhythmias. However, presymptomatic arrhythmic risk stratification of ARVD/C mutation carriers is challenging. Activation delay is a hallmark of arrhythmogenesis. Deformation imaging may unmask activation delay in the absence of ECG and structural abnormalities.

Methods:
From the merged transatlantic ARVD/C database three groups were compared 1) mutation-positive definite ARVD/C patients (n=108), 2) asymptomatic mutation carriers (AMC) not fulfilling Task-Force criteria (TFC) and without history of ventricular arrhythmias (n=35) and 3) healthy controls (n=50). All underwent echocardiographic deformation imaging and ECG according to TFC. As a surrogate for local activation delay the electro-mechanical interval (EMI) was measured, defined as time between first ECG-detected deflection and local onset of shortening. Arrhythmic outcome (PVC count, VT) of AMC was correlated to EMI and ECG TFC.

Results:
EMI was prolonged in all RV segments in ARVD/C patients. In AMC prolonged EMI was detected in the subtricuspid area in 17/35 subjects, Terminal Activation Duration ≥ 55ms was the only TFC-defined ECG abnormality found in this group (9/35). After a mean follow-up of 3.1±2.7 years 11/35 subjects experienced an increase in ventricular arrhythmia burden. Prolonged subtricuspid EMI was the only parameter significantly correlated to ventricular arrhythmias during follow-up (Figure 1).

Conclusions:
Deformation imaging reveals activation delay in all ARVD/C patients. In AMC prolonged EMI in the subtricuspid area is often detected without any additional abnormalities. Prolonged EMI is a new parameter unmasking activation delay in early ARVD/C stages and may contribute to risk stratification.
Abstract 14051: Changes in Medical Therapy and Lifestyle After Anatomical Versus Functional Testing for Coronary Artery Disease: The PROMISE Trial (PROspective Multicenter Imaging Study for Evaluation of Chest Pain)
Authors: Ladapo Joseph A , Hoffmann Udo , Lee Kerry L , Coles Adrian , Huang Megan , Mark Daniel B , Dolor Rowena L , Pelberg Robert A , Budoff Matthew , Sigurdsson Gardar , Severance Harry W , Douglas Pamela S
Published: April 2024

Introduction:
Diagnostic testing may represent a “teachable moment” for patients newly presenting with symptoms suggestive of CAD and requiring further evaluation, and may influence risk factor management, independent of test results. However, little is known about changes in medications and lifestyle after anatomical versus functional testing.

Hypothesis:
Patients assigned to coronary CTA will report greater use of preventive medications and lifestyle practices.

Methods:
We randomly assigned 10,003 symptomatic patients (53% women; mean age 61 yrs) to anatomical testing with CTA or functional testing (exercise ECG, nuclear stress, or stress echocardiography). We assessed use of preventive medications (aspirin, statin, beta blocker, and ACEi/ARB) and lifestyle practices (heart healthy diet, regular exercise, smoking, and obese/overweight status [BMI>25]) at 60 days. Chi-square tests assessed between-group changes (initiation or discontinuation). Multivariable logistic regression models assessed the association between testing strategy and prevalence of medication use or lifestyle practices.

Results:
There were no differences in medications or lifestyle practices at baseline. At 60 days, the CTA strategy was associated with a higher proportion of patients newly initiating aspirin (11.6% vs 7.6%), statin (12.7% vs 6.2%), and beta blockers (8.2% vs 5.4%), compared to functional testing (p<0.0001 for each). The CTA strategy was also associated with a higher incidence of weight loss among obese/overweight patients (2.8% vs 2.4%), but the difference was not significant (p=0.051). Overall prevalences of aspirin (aOR=1.55), statin (aOR=2.04), and beta blocker (aOR=1.32) use were higher after CTA (p<0.001 for each). Eating a healthy diet (54.7% vs 50.8%) was increased after CTA (aOR=1.13 p=0.004), whereas obese/overweight status was reduced (aOR=0.79 p=0.047). Exercise and smoking cessation increased similarly in both arms. Benefits of CTA for statin use and weight loss persisted after adjusting for test results.

Conclusions:
Among patients with suspected CAD, anatomical testing is associated with greater favorable changes in preventive medical and lifestyle practices. This may represent a long term benefit of a CTA testing strategy.
Abstract 14059: High Serum Erythropoietin Levels and the Development of Heart Failure in the General Population
Authors: Grote Beverborg Niels , van der Wal Haye H , Klip IJsbrand T , Voors Adriaan A , de Boer Rudolph A , van Gilst Wiek H , van Veldhuisen Dirk J , Gansevoort Ron T , Hillege Hans L , van der Harst Pim , Bakker Stephan J , van der Meer Peter
Published: April 2024

Aims:
In patients with heart failure (HF), serum erythropoietin (EPO) levels are elevated and associated with disease severity and outcome. Clinical trials with erythropoiesis-stimulating agents in HF and chronic kidney disease showed more adverse events. Whether endogenous EPO levels are prospectively associated with the development of HF or cardiovascular events in the general population is unknown.

Methods and results:
Serum EPO levels were measured at baseline in 6,686 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Mean age (±SD) was 53±12 years, 49.8% were male, and median (IQR) EPO level was 7.7 (5.9-10.2) IU/L. During a median follow-up of 8.3 (7.7-8.8) years, 209 (3.1%) subjects were newly diagnosed with HF, 97 (1.5%) died of a cardiovascular cause and 386 (6.0%) subjects had a non-fatal cardiovascular event (277 cardiac events and 93 strokes). Each doubling of EPO level was multivariably associated with new onset HF (HR: 1.41, 95% CI: 1.14-1.76, P=0.002). EPO levels showed interaction with urinary albumin excretion (P=0.002) and were only associated with HF in subjects with microalbuminuria (HR: 1.53, 95% CI: 1.21-1.92, P<0.001, Figure 1). Also, EPO levels were only independently associated with HF of ischemic origin (HR: 1.58, 95% CI: 1.14-2.20, P=0.006), not with HF of other etiologies. There was an independent association of EPO levels with stroke in women (HR: 1.82, 95% CI: 1.24-2.65, P=0.002), but not in men. No association was observed for EPO levels with other cardiovascular events or cardiovascular mortality.

Conclusion:
High serum EPO levels are independently associated with an increased risk of new onset HF in subjects with microalbuminuria. The interaction between EPO and microalbuminuria might be indicative for a role of the vascular endothelium in the mechanism linking EPO to HF. However, more research is needed to understand this association.
Abstract 14086: Investigation of Inflammatory Markers and Cardiac Events Following Discontinuation of Interleukin-1 Receptor Antagonist in NSTE-ACS Patients
Authors: Rothman Alexander M , Morton Allison , Greenwood John , Gunn Julian , Chase Alex , Clarke Bernard , Hall Alistair , Fox Keith , Foley Claire , Banya Winston , Wang Duolao , Flather Marcus , Crossman David C
Published: April 2024

Background:
The ILA HEART study demonstrated that administration of IL-1 receptor antagonist (IL-1ra) for 14 days after onset of NSTE-ACS reduced high sensitivity C-reactive protein (hsCRP) at 7 and 14 days, however day 30 hsCRP and 1 year MACE were both increased.

Objectives:
To analyze the inflammatory effect of withdrawal of IL-1ra following effective suppression of hsCRP in the context of NSTE-ACS.

Methods and Results:
Mixed-model analysis was performed with log hsCRP as dependent variable, day 1 hsCRP as covariate, treatment, day, and treatment/day interaction as fixed effects, and patient as random effect. Mixed-model analysis (Table 1) demonstrates increased hsCRP in the IL-1ra group at day 30 (vrs day 14 IL-1ra, p<0.0001 and vrs day 30 placebo, p=0.0196). Analysis of achieved hsCRP at day 14 demonstrates suppression of hsCRP with IL-1ra in each tertile (Fig 1A). In contrast to the placebo group, withdrawal of IL-1ra results in loss of hsCRP suppression. Within the IL-1ra group hsCRP was higher in patients suffering MACE events (Fig 1B).

Conclusions:
Inhibition of IL-1 for 14 days after NSTE-ACS temporarily suppresses CRP. It seems likely that anti-IL-1 therapy will need to be continued for longer after NSTE-ACS.
Abstract 14105: Apoptosis Inhibitor of Macrophage Activates Inflammatory Response After Acute Myocardial Infarction
Authors: Nishikido Toshiyuki , Shiraki Aya , Oyama Jun-ichi , Node Koichi
Published: April 2024

Introduction:
The persistent inflammation response after myocardial infarction increases myocardial injury, and causes heart failure due to cardiac dysfunction and remodeling. TLR-4 was activated by the recognition of not only pathogen-associated molecular patterns but also endogenous ligands and it serves as a proinflammatory function in circumstances involving myocardial tissue injury. Whereas, it was reported the apoptosis inhibitor of macrophage (AIM) provoke an efflux of saturated free fatty acid, one of the TLR-4 ligands, due to lipolysis, which causes the chronic inflammation via TLR-4 pathway in adipose tissue.

Hypothesis:
This study investigated the hypothesis that AIM activates a proinflammatory response after myocardial infarction.

Methods:
The ligation of the left anterior descending coronary artery to induced myocardial infarction was performed on both AIM-deficient (AIM-/-) mice and wild-type mice. After 3 days, the inflammation responses were assessed in TLR-4/NFkB activation pathway. And infarct size/area-at-risk was measured by staining with Evans blue and triphenyltetrazolium chloride. In addition, the left ventricular remodeling was examined after 28 days.

Results:
AIM-/- mice showed significantly smaller infarct size compared with wild-type mice given similar area at risk (20.8±0.6% vs. 27.8±1.9%, p=0.02). In AIM-/- mice with reduction of plasma free fatty acid, IRAK4 in TLR-4/NFkB pathway and NFkB activity were decreased on myocardium (p=0.02, 0.03 vs. wild-type, respectively). Moreover, there was the reduction of myeloperoxidase activity and iNOS in the inflammation response (p<0.01, p=0.03, respectively). We found that the NFkB DNA-binding activation via TLR-4, neutrophil infiltration, and inflammatory mediator were decreased in AIM-/- mice compared with wild-type mice after 3days. And, the heart weight to body weight ratio, myocardial fibrosis of AIM-/- mice were decreased, and a survival rate improved after 28 days (p<0.01).

Conclusions:
AIM-/- mice demonstrated less inflammation response and smaller infarction size after myocardial infarction, suggesting AIM may activate a proinflammatory of TLR-4 after myocardial infarction.
Abstract 14126: Safety and Efficacy of Anti-thrombotic Therapy After PCI in Octogenarians With Atrial Fibrillation: A Multi-center Study
Authors: Otsuki Hisao , Yamaguchi Junichi , Arashi Hiroyuki , Jujo Kentaro , Kamishima Kazuho , Nakao Masashi , Shimazaki Kensuke , Hata Takehiro , Kkuchi Yasuhiro , Ogawa Hiroshi , Hagiwara Nobuhisa
Published: April 2024

The purpose of the present study was to clarify the safety and efficacy of oral anticoagulation (OAC) in addition to dual antiplatelet therapy (DAPT) in octogenarians with atrial fibrillation (AF) undergoing PCI. Method and Result: We examined consecutive 360 AF patients registered at 8 medical centers who took DAPT or OAC + DAPT at the time of PCI. Octogenarians (n=77) were compared with those of younger patients (n=283). In octogenarians, acute coronary syndrome (octogenarians vs. younger patients = 54.6% vs. 37.4%) was more common and diabetes (32.5% vs. 45.6%) and usage of drug-eluting stent (58.4% vs. 73.1%) were less common (P<0.01, respectively). There was a significant difference in CHADS2 score (2.9±1.0 vs. 2.2±1.3, P<0.01) and no statistical difference HAS-BLED score (2.4±0.7 vs. 2.2±0.8). At 1-year, major adverse cerebro-cardiovascular events (MACCE) was significantly higher in octogenarians than in younger patients (16.9% vs. 3.9% P<0.01) and bleeding complications (defined as TIMI minor plus major) were similar (7.8% vs. 5.6% P=0.48). In octogenarians, there was a trend in lower cumulative incidence of MACCE in OAC+DAPT patients (n=44) compared to DAPT patients (n=33; 13.6% vs. 21.2% p=0.06), however, there was an excess risk of bleeding complications (13.6% vs. 0%, p=0.008).

Conclusion:
Octogenarians with AF undergoing PCI showed poor prognosis and were at high risk of bleeding, especially in patients who took OAC + DAPT. “Tailor-made” treatment strategies should be considered in this high-risk subset.
Abstract 14133: Angiotensin II-induced Vascular Fibrosis was Prevented by Caveolin-1 Deficient Mice
Authors: Kawai Tatsuo , Forrester Steven J , Elliot Katherine J , Eguchi Satoru , Rizzo Victor
Published: April 2024

Introduction:
We have recently reported that caveolin-1 (Cav1) enriched membrane microdomains in vascular smooth muscle cells (VSMC) mediates a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation, which is linked to vascular remodeling induced by AngII.

Hypothesis:
We have tested our hypothesis that Cav1, a major structural protein of caveolae, plays a critical role in AngII-mediated vascular remodeling via regulation of ADAM17 and EGFR.

Methods:
In vivo: 8 week old male Cav1-/- and control Cav+/+ wild-type mice (WT) were infused with AngII (1 μg/kg/min) for 2 weeks to induce vascular remodeling and hypertension.

In vitro: Rat aortic VSMCs were cultured and stimulated with 100 nM AngII.

Results:
Upon AngII infusion, histological assessments demonstrated medial hypertrophy and perivascular fibrosis of coronary and renal arteries in WT mice compared to sham-operated mice. The AngII-infused WT mice also showed a phenotype of cardiac hypertrophy with increased HW/BW ratio (mg/g: 8.0±0.6 vs 5.7±0.7 p<0.01) compared with sham-operated WT control. In contrast, vascular remodeling but not cardiac hypertrophy were attenuated in Cav1-/- mice with AngII infusion; HW/BW ratio (8.6±0.5 vs 6.4±0.2 p<0.05) compared to sham-operated mice. However, AngII induced similar levels of hypertension in both WT and Cav1-/- mice as assessed by telemetry (MAP mmHg: 142±9 vs 154±20). AngII infusion in WT mice enhanced ADAM17 and phospho-Tyr EGFR staining in heart and kidney vasculature, whereas AngII-infused Cav1-/- mice showed diminished ADAM17 and phospho-Tyr EGFR staining within the vasculature. In addition, IHC analyses revealed reduced vascular ER stress in heart and kidney samples of AngII-infused Cav1-/- mice compared to WT mice. In cultured rat VSMC, Cav1 silencing attenuated induction and activation of ADAM17 by AngII.

Conclusions:
These data suggest that Cav1, and presumably caveolae microdomains, plays a critical role in vascular fibrosis via vascular induction of ADAM17 and activation of EGFR independent of blood pressure or cardiac hypertrophy regulation.
Abstract 14136: Right Ventricle Speckle Tracking Analysis During Maximal Exercise in Heart Failure Patients: Possible Indicator of Impaired Ventilatory Efficiency Rather Than Overall Exercise Performance?
Authors: Donghi Valeria , Carbone Francesco , Labate Valentina , Generati Greta , Pellegrino Marta , Bandera Francesco , Alfonzetti Eleonora , Guazzi Marco
Published: April 2024

Background:
Speckle tracking (ST) analysis is a reliable methodology that allow to quantify myocardial functional properties better than traditional echo parameters.

Purpose:
We considered a heart failure reduced ejection fraction (HFrEF) population with the aim to investigate how a 2D ST analysis on right ventricle at peak exercise could help to stratify different cardiopulmonary exercise testing (CPET) functional phenotypes.

Methods:
36 HFrEF patients (mean age 69±12; male 69%; NYHA I-II-III-IV 19-17-25-5 %) underwent a maximal CPET evaluation combined with Echo-Doppler and off-line ST analysis. Study population was divided in two groups according to median value of 2D right ventricle longitudinal strain at peak exercise (Group A RVLG at peak < -16 vs Group B ≥ -16). In all patients we performed rest and peak 2D left atrium (LA LG), left and right ventricle longitudinal (LV LG, RV LG) strain, considering RV free-wall LG strain and RV LG global strain.

Results:
The table reports main echo and CPET results in the two groups of patients. Despite similar left ventricle function and RVLG at rest, Group B showed nonsignificant differences in exercise performance (peak VO2) but more impaired ventilation (increased VE/VCO2 slope and reduced PetCO2), associated with more advanced RV reserve limitation and lower LA LG strain at peak exercise.

Conclusions:
In HFrEF patients, a worse RV disease negatively influence the exercise gas exchange phenotype and RV strain analysis performed at peak exercise is of additive value in the identification of patients with impaired ventilatory efficiency.
Abstract 14147: The Non-Linear Relationship of Pulse Pressure to Mortality at the 22 year Follow-Up of the Systolic Hypertension in the Elderly Program
Authors: Kostis John B , Wang Fei , Kostis William J , Amaratunga Dhammika , Pantazopoulos John S , Cabrera Javier , Messerli Franz H
Published: April 2024

Introduction:
An association of pulse pressure (PP) with mortality has been reported. However, scant data are available on long-term follow-up in placebo controlled clinical trials and on the shape of the relationship between PP and all-cause and cardiovascular (CV) death.

Hypothesis:
We examined the relationship between PP with mortality at 22 years in the placebo and active treatment groups of the Systolic Hypertension in the Elderly Program (SHEP).

Methods:
SHEP enrolled participants aged 60 and older (mean 72) with isolated systolic hypertension (systolic blood pressure 160 mm Hg or higher and diastolic blood pressure below 90 mm Hg). The relationship between all-cause and CV mortality with baseline PP was examined in 4,211 SHEP participants.

Results:
A J curve relationship of mortality and PP was observed for all-cause death in an unadjusted analysis: linear term p<0.0001, quadratic term (green) p=0.01743 and tricubic (red). In this analysis highest risk was at a PP of 118 mm Hg (left figure). When the analysis was adjusted for age, gender, co-morbidities and risk factors for CV disease, the non-linear relationship was markedly attenuated with the quadratic term not statistically significant (right figure). Age (p<0.0001) and female gender (p=0.0215) were significant predictors of mortality. The effects on CV mortality were similar to those of all-cause mortality.

Conclusions:
In patients with isolated systolic hypertension, there is a non-linear (quadratic) relationship between PP and all-cause and CV mortality at 22 years of follow-up. This relationship is primarily mediated by age, gender, co-morbidities and CV risk factors and is attenuated after adjustment.
Abstract 14155: Haemodynamic Changes After Aortic Valve Replacement in Bicuspid Aortic Valve Disease Differ With Prosthesis Type
Authors: Bissell Malenka M , Loudon Margaret , Stoll Victoria , Orchard Elizabeth , Neubauer Stefan , Myerson Saul G
Published: April 2024

Introduction:
Bicuspid aortic valve disease (BAV) is associated with dilatation of the proximal aorta and abnormal flow patterns, particularly increased helical flow and changes in the aortic wall shear stress. We assess the effect of different types of aortic valve replacement (AVR) on aortic flow patterns.

Hypothesis:
Aortic valve replacement in bicuspid aortic valve disease normalises ascending aortic flow patterns.

Methods:
We prospectively enrolled 87 participants: 27 BAV patients with prior AVR (10 mechanical, 8 bioprosthetic, 9 Ross procedure), 30 BAV patients with a native aortic valve and 30 healthy volunteers. All underwent 4D flow cardiovascular magnetic resonance.

Results:
The majority of patients with mechanical AVR or Ross showed a normalised flow pattern (70% and 67% respectively) with near normal rotational flow values (7.4±1.2 and 10.6±3.5 mm
2
/s respectively; normal range -5 to +11 mm
2
/s). They also showed reduced in-plane wall shear stress compared to native BAV (0.13±0.04 N/m
2
for mechanical AVR vs. 0.37±0.05 N/m
2
for native BAV, p<0.05). In contrast, all subjects with bioprosthetic AVR showed abnormal flow patterns (mainly marked right-handed helical flow), with similar rotational flow values to native BAV (20.7±3.3 mm
2
/s and 25.9±3.1 mm
2
/s respectively, p>0.05) and similar wall shear stress pattern. Data before and after AVR (n=16) supported these findings: mechanical AVR showed a significant reduction in rotational flow (29.3±5.3 to 7.9±1.2 mm
2
/s, p<0.05) and in-plane wall shear stress (0.45±0.07 to 0.20±0.04 N/m
2
, p<0.05), whereas these remained unchanged in the bioprosthetic AVR group.

Conclusions:
Abnormal flow patterns in BAV are significantly reduced after mechanical AVR or Ross procedure, but remain similar after bioprosthetic AVR. This is the first insight indicating that the type of valve replacement may influence post-operative aortic flow patterns, and could have important implications for future aortic growth.
Abstract 14167: Clinical Characteristics of Subjects With Different Levels of Systemic Erythrocyte-bound Apolipoprotein B
Authors: de Vries Marijke A , Klop Boudewijn , van der Meulen Noëlle , van de Geijn Gert-Jan M , Prinzen Lenneke , van der Zwan Ellen , Birnie Erwin , Castro Cabezas Manuel
Published: April 2024

Introduction:
The level of apolipoprotein (apo) B-containing lipoproteins in plasma is positively associated with cardiovascular risk. We have previously demonstrated that apo B bound to circulating erythrocytes (ery-apoB) may protect against atherosclerosis. We evaluated the clinical characteristics of subjects with different levels of ery-apoB.

Methods:
Ery-apoB was measured by flow cytometry in subjects with (n=177) and without (n=208) cardiovascular disease (CVD), and expressed as mean fluorescent intensity in arbitrary units (au). The number of criteria for metabolic syndrome as outlined by the NCEP was scored. Carotid intima media thickness (cIMT) was measured using B-mode ultrasound. Data are given as median (IQR).

Results:
Ery-apoB was lower in patients with CVD than in controls (0.80 (0.40-1.40) and 0.90 (0.46-1.79) au, respectively, p=0.039). Ery-apoB was inversely associated with cIMT, waist circumference, plasma triglycerides, C-reactive protein and complement C3, and was positively associated with HDL-cholesterol. Ery-apoB was similar in men and women. The number of criteria for the metabolic syndrome was closely associated with ery-apoB, in a dose-depending manner. Median ery-apoB decreased with increasing number of metabolic syndrome criteria (Kruskall Wallis test, p=0.02). Furthermore, ery-apoB was almost 3-fold higher in subjects with blood group O than in subjects with a non-O blood group (1.40 (0.75-2.15) and 0.50 (0.10-0.95) au, respectively, p<0.001). No correlation between ery-apoB and plasma apo B was found, and ery-apoB was unrelated to statin use. Discontinuation of statin use did not affect ery-apoB (n=54).

Conclusion:
Apo B bound to circulating erythrocytes is associated with several characteristics of the metabolic syndrome, inflammation and ABO blood group. These data provide novel insight into the mechanisms involved in the binding of atherogenic lipoproteins to erythrocytes.
Abstract 14173: Pharmacologic and Activated Fibroblast-Specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury
Authors: Travers Joshua G , Kamal Fadia A , Nieman Michelle L , Blaxall Burns C
Published: April 2024

Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are largely responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transition to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately results in pathologic G protein-coupled receptor kinase 2 (GRK2)-mediated β-adrenergic receptor downregulation. We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast differentiation, interstitial fibrosis and the overall progression of heart failure.

To investigate this hypothesis, mice were subjected to ischemia/reperfusion injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein for 4 weeks. Animals receiving vehicle demonstrated severe cardiac dilatation and deterioration in overall cardiac function as measured by percent fractional shortening and ejection fraction. Remarkably, mice treated with gallein exhibited nearly complete preservation of cardiac function, along with reduced scar formation and fibrotic marker expression, suggesting a direct effect within the cardiac fibroblasts. To further explore possible mechanisms, activated fibroblast-restricted GRK2 knockout mice (GRK2fl x PeriostinMCM) were subjected to 4 weeks of ischemia/reperfusion injury. These animals displayed preserved myocardial function and reduced eccentric hypertrophy and collagen deposition compared to GRK2fl littermate controls. Finally, systemic Gβγ-GRK2 inhibition by gallein may not confer further protection over activated fibroblast-specific GRK2 ablation alone.

In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression. We believe this fibroblast-targeted approach will lead to the refinement of existing targets and compounds, and possibly the generation of novel therapeutics for the treatment of heart failure.
Abstract 14184: Patients With Coronary Artery Disease and Bilateral Carotid Inflammation Show Higher One Year Rate of Cardiovascular Events
Authors: Benetos Georgios , Toutouzas Konstantinos , Drakopoulou Maria , Mitropoulou Fotini , Barampoutis Nikolaos , Koutagiar Iosif , Davlouros Periklis , Tsiamis Eleftherios , Siores Elias , Tousoulis Dimitrios
Published: April 2024

Background:
Inflammation is an essential characteristic of vulnerable atherosclerotic plaque. Although its prognostic value during invasive assessment has been documented, the clinical significance of its routine evaluation is still under dispute. Microwave radiometry (MWR) allows the rapid, in vivo, noninvasive assessment of the internal temperature of carotid arteries, reflecting local inflammation. The aim of the present study was to evaluate the prognostic role of carotid atherosclerotic plaque temperatures in patients with documented coronary artery disease (CAD).

Methods:
Consecutive patients with significant CAD as documented by coronary angiography were included in the study. All patients underwent evaluation of both carotid arteries by 1) ultrasound and 2) microwave radiometry (MWR). During ultrasound study maximum carotid plaque thickness was assessed in all carotids. Temperature difference (ΔT) by MWR was defined as maximal temperature along the carotid artery minus minimum. ΔT ≥0.90°C was assigned as high ΔT. Major cardiovascular event (MACE) was defined as death, stroke, myocardial infarction or revascularization. All patients were followed-up clinically for one year.

Results:
In total 192 patients were included in the study. At baseline thirty patients (15.6%) had high ΔT temperatures (≥0.90°C) in both carotid arteries. Max plaque thickness was slightly higher in this group (2.75±1.34 vs 2.27±1.03, p=0.07). MACE was 23.3% in the group with bilateral high ΔT and 4.3% in non-high ΔT group (p<0.001). By multivariate logistic regression analysis, ΔT was an independent predictor for MACE, when adjusted for sex, age contemporary risk factors, number of vessels with significant stenosis and maximum carotid plaque thickness (OR: 6.10, 95% CI 1.56-23.80, p=0.001). In Kaplan-Meier plots patients with bilateral high ΔT showed higher event and mortality rates, compared with patients in non-high ΔT group (log-rank p=0.001 for both comparisons).

Conclusion:
The presence of bilateral high carotid artery temperatures as assessed by MWR has implications in short term prognosis of patients with CAD. A long term study is warranted to establish the prognostic impact of MWR in this high-risk population.