bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9900: Implantation of Adipose-Derived Regenerative Cells Enhances Lymphangiogenesis and Improves Secondary Lymphedema
Authors: Shimizu Yuuki , Shintani Satoshi , Shibata Rei , Izumi Yusuke , Ogura Yasuhiro , Ishii Masakazu , Murohara Toyoaki
Published: April 2024

Introduction:
Secondary lymphedema often occurs as a complication of surgery or radiotherapy for cancer. Although it deteriorates patient's quality of life, there are few therapeutic options. We previously reported that implantation of adipose-derived regenerative cells (ADRCs) augmented neovascularization. Accordingly, we tested our hypothesis that ADRCs implantation promotes lymphangiogenesis and improves secondary lymphedema.

Methods:
ADRCs and bone-marrow mononuclear cells (BM-MNCs) were isolated from C57BL/6J or GFP-transgenic mice. We established a modified model of mouse tail lymphedema, and mice were randomly divided into four groups (ADRCs implantation (2×10
6
/mouse), BM-MNCs implantation(2×10
6
/mouse), recombinant VEGF-C injection(4μ g/mouse), or PBS injection). Real time RT-PCR and ELISA were performed at postoperative day 5. Four weeks after implantation, tail diameter was measured and histological analysis was performed to detect new lymphatic vessels using ant-LYVE-1 antibody. In vitro study, we performed migration and proliferation assay of human lymphatic endothelial cells (hLECs), which were stimulated by ADRCs conditioned medium (ADRC-CM). In addition, we measured phosphorylated eNOS and Erk, which have been shown to play an important role in promoting migration and proliferation of hLECs.

Results:
Expression of VEGF-C mRNA at the edematous tissue and plasma VEGF-C levels were greater in the ADRC group compared to the PBS group (p<0.05). Lymphedema was significantly improved in ADRCs group to the level similar to VEGF-C or BM-MNCs groups at 4 weeks after cell therapy (p<0.001, vs PBS group). Moreover, lymphatic capillary density in the edematous tissue was greater in the ADRC group than in the PBS group (p<0.000005). Only few GFP positive cells were incorporated into new lymphatic vessels, and most of LECs constructing lymph vessels were negative for anti-GFP-FITC mAb. In vitro, we confirmed that ADRC-CM contained VEGF-C protein. Treatment of hLECs stimulated migration and proliferation of hLECs, and which was accompanied by increased phosphorylation of eNOS and Erk.

Conclusions:
The implantation of ADRCs seemed to be a novel strategy for therapeutic lymphangiogenesis in secondary lymphedema.
Abstract 9904: Ability of Comprehensive Assessment of Strain Dyssynchrony Index by Speckle Tracking Imaging to Predict Long-Term Outcome After Cardiac Resynchronization Therapy in Patients with Heart Failure
Authors: Tatsumi Kazuhiro , Tanaka Hidekazu , Miyoshi Tatsuya , Hiraishi Mana , Kaneko Akihiro , Tsuji Takayuki , Ryo Keiko , Fukuda Yuko , Matsumoto Kensuke , Yoshida Akihiro , Kawai Hiroya , Hirata Ken-ichi
Published: April 2024

Background:
We previously reported that a combined assessment of radial, circumferential, and longitudinal strain dyssynchrony index (SDI) can further enhance the ability of the method to predict left ventricular reverse remodeling short-term after cardiac resynchronization therapy (CRT).

Hypothesis:
SDI can predict long-term outcome after CRT in patients with heart failure (HF).

Methods:
We studied 64 HF patients who underwent CRT. SDI was calculated as the average difference between peak and end-systolic strain from 6-segment for radial and circumferential SDIs and 18-segment for longitudinal SDI using two-dimensional speckle-tracking strain. On the basis of our previous observations, pre-defined cutoff for significant dyssynchrony and residual myocardial contractility was radial SDI ≥6.5%, circumferential SDI ≥3.2%, and longitudinal SDI ≥3.6%. The pre-defined principal outcome variable was the combined endpoint of death from worsening HF and re-hospitalization for deteriorating HF. Long-term follow-up after CRT was tracked over 3.5 years.

Results:
The primary endpoint of a pre-specified clinical event occurred in 15 patients (23%). Patients with significant radial, circumferential, and longitudinal SDIs were associated with favorable long-term outcome after CRT (p<0.001, <0.005, and <0.01 vs. patients without significant SDIs, respectively). Furthermore, long-term outcome after CRT in patients with positivity 3 of 3 types of SDIs was better than that in patients with positivity either 1 or none of 3SDIs (p<0.005 and <0.001). Cardiovascular event-free rate in patients with positivity 3 of 3 SDIs was also higher than that in patients with positivity none of 3SDIs (100% vs. 30%, p<0.001).

Conclusions:
SDIs can successfully predict long-term outcome after CRT in HF patients. Moreover, the combined approach leads to more accurate prediction than using individual parameters, and these observations may have clinical implications in CRT patients.
Abstract 9908: Acute Hemodynamic Improvement During Dual Sites Pacing Study Does Not Predict the Late Hemodynamic and Functional Status by Cardiac Re-synchronization Therapy in Patients with a Right Ventricular Type Systemic Ventricle
Authors: Sakaguchi Heima , Miyazaki Aya , Yamamoto Tetsuya , Komori Akiko , Matsuoka Michio , Ohuchi Hideo
Published: April 2024

Background:
Cardiac resynchronization therapy (CRT) has shown a reduced mortality as well as functional improvements in patients with refractory heart failure. However, data on CRT in patients with congenital heart disease (CHD) are limited.

Objectives:
This study aims to clarify the efficacy of CRT in CHD patients with various hemodynamic settings, especially a morphology of the systemic ventricle (SV).

Methods:
The study population consisted of 17 CHD patients (mean 22 ± 12.7 years old) who had been treated with CRT since 2006. We divided the patients into 3 groups based on types of the hemodymamics and the type of SV, i.e., 7 patients with left ventricle SV (sLV), 6 with right ventricle SV (sRV) after a biventricular repair, and 4 with the unbalanced SV single ventricular physiology (sBV). We evaluated the acute effect of CRT on hemodynamics and SV function before the device implantation and also assessed chronic (≥ 6 months) impact of CRT on the late outcome, including plasma brain natriuretic peptide level (BNP: pg/ml) and New York Heart Association (NYHA) functional class.

Results:
In all patients, the SV volume (ml/m2) (139 ± 41 to 117 ± 36) and BNP (353 ± 396 to 112 ± 102) decreased (p < 0.01 for both) with the improvement of NYHA functional class (2.1 ± 0.7 to 1.9 ± 0.8,
p
=0.04) 6 months after the CRT. Among the 3 groups, the sRV group did not show a late SV volume reduction despite the shortening of QRS width (198 ± 28 to 136 ± 19 ms,
p
=0.0005) and increase in SV peak dP/dt (
p
=0.02) at the acute study, while the other 2 groups showed the acute and late hemodynamic improvement with the late SV volume reduction.

Conclusions:
The CRT improves late hemodynamic and functional status in sLV and sBV CHD patients with a dyssynchronized SV. However, an acute effect of CRT cannot guarantee the long-term benefit in sRV patients.
Abstract 9921: Angiotensin II Receptor Blocker Improves Exercise Capacity and Mitochondrial Function of Skeletal Muscle via Inhibiting Oxidative Stress in High Fat Diet-Induced Diabetic Mice
Authors: Takada Shingo , Kinugawa Shintaro , Yokota Takashi , Suga Tadashi , Takahashi Masashige , Fukushima Arata , Homma Tsuneaki , Mochamad Sobirin A , Ono Taisuke , Masaki Yoshihiro , Kadoguchi Tomoyasu , Okita Koichi , Tsutsui Hiroyuki
Published: April 2024

Background
We have previously reported that the exercise capacity is reduced and mitochondrial function is impaired in high fat diet (HFD)-induced diabetic mice, which is due to NAD(P)H oxidase-induced oxidative stress. NAD(P)H oxidase can be activated by angiotensin II.

Hypothesis
We thus hypothesized that angiotensin II receptor blocker can ameliorate the reduced exercise capacity in diabetic mice.

Methods
C57BL/6J mice were fed on normal diet (ND) or HFD, and each group of mice was divided into 2 groups of the treatment with or without olmesartan (OLM, 3mg/kg/day) in the drinking water. Four groups of mice, ND (n=10), ND+OLM (n=10), HFD (n=15), and HFD+OLM (n=15), were studied. After 8 weeks, treadmill tests were performed to determine the work and oxygen uptake (VO
2
). ADP-dependent (state 3) respiration in mitochondria was determined, and NAD(P)H oxidase activity and superoxide production by lucigenin chemiluminescence method were measured in isolated skeletal muscle.

Results
HFD significantly increased body weight, adipose tissue weight, plasma glucose and insulin compared to ND, and OLM did not affect these parameters in either group. The work and peak VO
2
were significantly reduced in HFD compared to ND (work; 14±1 vs 28±2 J, peak VO
2
; 111±2 vs 145±3 mL/kg/min), and these reductions were ameliorated in HFD+OLM (work; 18±1 J, peak VO
2
; 122±3 mL/kg/min). State 3 respiration was significantly decreased, and NAD(P)H oxidase activity and superoxide production were significantly increased in HFD compared with ND (state 3 respiration; 58±3 vs 39±3 nmol/min/mg protein, NAD(P)H oxidase activity; 403±70 vs 1771±326 RLU/min/100µg protein, superoxide; 61±11 vs 181±27 RLU/min/mg), which was attenuated by OLM (state 3 respiration; 56±3 nmol/min/mg protein, NAD(P)H oxidase activity; 646±51 RLU/min/100µg protein, superoxide; 81±20 RLU/min/mg). There were no such effects by OLM in ND mice.

Conclusions
Olmesartan ameliorated the reduced aerobic capacity in HFD-induced diabetic mice via the improvement of impaired mitochondrial function and attenuation of oxidative stress in the skeletal muscle. The improvement of aerobic capacity by angiotensin II receptor blocker may have a clinical impact in the treatment of patients with diabetes mellitus.
Abstract 9945: Concomitant Early Repolarization Increases Occurrences of Ventricular Fibrillation in Patients with Acute Myocardial Infarctions
Authors: Naruse Yoshihisa , Tada Hiroshi , Harimura Yoshie , Hayashi Mayu , Takeyasu Noriyuki , Sato Akira , Sekiguchi Yukio , Yoshida Kentaro , Aonuma Kazutaka
Published: April 2024

Background:
Previous studies demonstrated that there is an increased prevalence of electrocardiographic early repolarization among patients with a history of idiopathic ventricular fibrillation (VF). Early repolarization is also associated with life threatening ventricular tachyarrhythmias in patients with chronic coronary artery disease. However, no studies have clarified whether or not there is an association between electrocardiographic early repolarization and the VF occurrences after the onset of acute myocardial infarction (AMI).

Methods:
This study included 220 consecutive patients with AMIs (69±11 years; 57 females) in whom 12-lead ECGs before the AMI onset could be evaluated. The patients were classified based on the VF occurrence within 48 hours after the AMI onset. Sustained VF was defined as that lasting longer than 30 seconds or that required electrical cardioversion. Early repolarization was electrocardiographically defined as an elevation of the QRS-ST junction of >0.1 mV from baseline in at least 2 inferior or lateral leads, manifested as QRS slurring or notching.

Results:
Twenty-one (10%) patients experienced an episode of VF within 48 hours of AMI onset. Compared to the patients without VF, the VF patients had a higher prevalence of early repolarization (p<0.001) and male gender (p<0.05), a shorter duration from onset to admission (p<0.05), and a greater number of diseased coronary arteries (p<0.05) and Killip class (p<0.001). A multivariate analysis revealed that early repolarization (odds ratio [OR]=6.45; 95% confidence interval [CI]= 2.07-20.40; p<0.01), a time from onset to admission less than 180 minutes (OR=3.54; 95% CI=1.08-11.53; p<0.05), and a Killip class greater than I (OR=11.43; 95% CI=3.22-40.59; p<0.001) were independent predictors of VF occurrences.

Conclusion:
The presence of early repolarization increases the risk of VF occurrences within 48 hours after the AMI onset.
Abstract 9966: Right Ventricular Myocardial Strain Evaluated by Two-Dimensional Echocardiographic Speckle Tracking is Strongly Associated with Right Ventricular Contractile Function by Magnetic Resonance Imaging
Authors: Kato Shingo , Kusakawa Yuka , Ishii Nao , Muto Kazuhiro , Nakachi Tatsuya , Okusu Yasuo , Nakagawa Tsuyoshi , Fukui Kazuki , Uchino Kazuaki , Kimura Kazuo , Umemura Satoshi
Published: April 2024

Purpose:
Although the evaluation of right ventricular (RV) function is clinically important in patients with cardiovascular disease, accurate assessment is difficult due to the complexity of anatomy. Two-dimensional speckle tracking echocardiography (2D-STE) permits non-invasive measurement of regional and global RV myocardial strain. The purposes of this study were to investigate the relationship between RV myocardial strain by 2D-STE and RV ejection fraction (RVEF) by magnetic resonance imaging (MRI), and to determine whether RV strain measurement by 2D-STE can detect patients with pulmonary hypertension (PH).

Methods:
Fifty-two patients (mean age: 66 ± 10) with cardiovascular disease (ischemic heart disease, n= 10, cardiomyopathy, n= 7, valvular heart disease, n= 19, idiopathic pulmonary hypertension, n= 5, others, n= 11) were studied. RV free wall (RVFW) was divided into three segments on four chamber view (base, mid and apex). Regional and global longitudinal strain of RVFW was measured by using 2D-STE. Cine MRI was acquired in 23 patients by using 1.5T MR scanner, and RVEF was calculated by tracing endocardial border of RV on short axis slices. Right heart catheterization (RHC) was performed in 35 patients, and PH was defined as mean pulmonary arterial pressure (PAP) ≥25mmHg.

Results:
The global longitudinal strain of RVFW showed the strongest negative relation with RVEF by cine MRI (r = -0.82, P<0.001). Both regional and global RV longitudinal strains were significantly decreased in patients with PH in comparison to those without (base:-24.1 ± 7.7 vs -17.9 ± 7.3, p=0.02; mid: -22.7 ± 6.0 vs -14.7 ± 6.3, p<0.001; apex: -22.7 ± 5.4 vs -15.7 ± 7.2, p=0.002; global: -22.8 ± 5.5 vs -17.1 ± 6.5, p=0.009). RV longitudinal strain at mid level demonstrates highest correlation with mean PAP by RHC (r=0.71, p<0.001). The area under the ROC curve (AUC) of RV longitudinal strain at mid for the detection of patients with PH was 0.83 (95%CI; 0.69 to 0.98).

Conclusions:
RV global longitudinal strain measured by 2D-STE correlates well with RVEF assessed by cine MRI. RV longitudinal strain at mid can detect patients with PH with AUC of 0.83. 2D-STE allows for non-invasive assessment of myocardial strain of RVFW, which is closely related to RV contractile function and PAP.
Abstract 9968: Radiofrequency Catheter Ablation for Persistent Atrial Fibrillation Improves Sleep-Disordered Breathing
Authors: Naruse Yoshihisa , Tada Hiroshi , Satoh Makoto , Yanagihara Mariko , Tsuneoka Hidekazu , Hirata Yumi , Machino Takeshi , Yamasaki Hiro , Igarashi Miyako , Kuroki Kenji , Ito Yoko , Sekiguchi Yukio , Aonuma Kazutaka
Published: April 2024

Background:
Recent studies have suggested an emerging link between sleep apnea and atrial fibrillation (AF). Radiofrequency catheter ablation is becoming an effective therapeutic option for drug-refractory AF. However, the effect of radiofrequency catheter ablation on sleep-disordered breathing has not been sufficiently clarified.

Methods:
This study included 19 patients (18 men and 1 woman; 62±6 years) with sleep apnea syndrome who underwent radiofrequency catheter ablation for drug refractory, persistent AF. The standard overnight polysomnographic evaluation was performed before and 1 week after the ablation in all patients. The total duration and number of episodes of central or obstructive sleep apnea or hypopnea were analyzed and compared.

Results:
Among 19 patients, all patients predominantly had obstructive apnea (obstructive apnea index, median 13.8, IQR (interquartile range) 7.1-20.9; central apnea index, 0.2, IQR 0.0-0.5; p<0.001). One week after the ablation, the number of apnea hypopnea index (21, [IQR 12-39] to 10, [IQR 6-24]; p=0.001) and obstructive type of apnea (14, [IQR 7-21] to 7, [IQR 2-16]; p=0.002) were significantly reduced. Median % change of apnea hypopnea index was 42% (IQR 22-60). In 9 (47%) patients, the severity of sleep-disorder breathing improved after the ablation. Furthermore, the sleep-disorder breathing was normalized after the ablation in 2 (11%) patients. In 3 patients who did not maintain sinus rhythm after the ablation, the apnea hypopnea index did not improve, and there was a significant correlation between rhythm control after radiofrequency catheter ablation and % change of apnea hypopnea index (rs=0.63, p=0.004). Body weight (70.8±11.3 to 69.6±10.9 [kg], p<0.001), plasma N-terminal pro B-type natriuretic peptide level (384, [IQR 237-610] to 106 [66-166] [pg/ml], p=0.001), left atrial volume (65±22 to 56±17 [ml], p=0.048), and estimate pulmonary capillary wedge pressure (13±4 to 11±3 [mmHg], p=0.006) were also reduced significantly after the ablation.

Conclusions:
In patients with sleep apnea syndrome and persistent AF, to restore sinus rhythm by radiofrequency catheter ablation significantly improves obstructive sleep apnea.
Abstract 9973: Mitral Regurgitation with Mechanical Dyssynchrony as a Substrate Associated with Long-Term Survival After Cardiac Resynchronization Therapy
Authors: Onishi Tetsuari , Onishi Toshinari , Oyenuga Olusegun A , Haberman Stephanie C , Saba Samir , Gorcsan John
Published: April 2024

Background:
Mechanisms for mitral regurgitation (MR) in patients with left ventricular (LV) dysfunction are complex. Cardiac resynchronization therapy (CRT) may improve MR. However, effects are variable and the influence of mechanical dyssynchrony on MR and its association with long-term outcome is unclear.

Methods:
We prospectively studied 138 consecutive CRT patients with NYHA class III/IV heart failure, QRS width ≥120ms, and ejection fraction (EF) ≤35%. Quantitative echocardiography was performed before CRT and 1.5±2 months after CRT. Baseline dyssynchrony was assessed as interventricular mechanical delay (IVMD) > 40ms, tissue Doppler opposing wall delay (OWD) > 65ms, Yu Index > 32ms, and speckle tracking radial strain delay >130ms. MR was quantified by vena contracta width and jet area, and severity expressed as a grade from 1 to 4. Long-term outcome events were pre-specified as death, transplant or left ventricular assist device over 4 years.

Results:
Of 138 CRT patients aged 66±12 yrs with EF 24±7%, 74 patients (54%) had no significant baseline MR (≤grade 1+), and 64 patients (46%) had significant baseline MR: n=35 grade 2+, n=20 grade 3+, and n=9 grade 4+. At baseline, There are significant differences in EF (p<0.01) and MR severity (<0.0001) between patients with and without significant MR. Dyssynchrony at baseline by all indices were statistically associated with MR reduction (all p<0.03). Among patients with significant MR at baseline, speckle-tracking radial dyssynchrony was significantly associated with long-term event free survival.

Conclusion:
The co-existence of baseline dyssynchrony by radial strain in patients with significant MR was associated with a more favorable long term survival after CRT. Patients with significant MR who lacked dyssynchrony had the least favorable outcome. These observations have mechanistic and clinical implications.
Abstract 9974: Inadequate Lipid Target Achievement Among US Treated Adults with Dyslipidemia
Authors: Wong Nathan D , Wong Kalina , Phan Amy , Marrett Elizabeth , Ramey Dena R , Neff David R
Published: April 2024

Background:
Despite available medications for dyslipidemia, many treated persons still have suboptimal lipid levels. We examined the extent of residual dyslipidemia in U.S. adults.

Methods:
We studied a sample of 2679 U.S. adults aged 18 and over from the National Health and Nutrition Examination Survey 2007-2008, of which 1473 (55%) were defined to have dyslipidemia, based on modified 2004 National Cholesterol Education Program - Adult Treatment Panel III Update and 2006 American Heart Association/American College of Cardiology cutpoints for LDL-C along with the Framingham risk score for cardiovascular disease or if on pharmacologic treatment. Of these, 669 (45.4%) were on pharmacologic treatment. Among this group, we examined the proportions of individuals who still had LDL-C not at goal, low HDL-C, and/or elevated triglycerides.Results were projected to represent the U.S. adult population in millions.

Results:
In this cohort treated for dyslipidemia, mean (SD) age was 61.2 (12.1) years, and 49.8% were male. Over half (55.0%) were of non-Hispanic white, 24.8% Hispanic and 16.1% African American race. Only 17.6% of subjects on treatment for dyslipidemia were at recommended levels for all three lipids (LDL-C, HDL-C, and triglycerides). LDL-C remained above goal for 63% of subjects, 28% had low HDL-C, and 42% had elevated triglycerides. Two lipid abnormalities were identified in 27.5% of subjects and 12% had all three lipid parameters not at recommended levels (figure).

Conclusion:
Despite widely available treatments for dyslipidemia, many persons remain not at LDL-C goal and/or at recommended levels for other lipids, indicating opportunities for more intensive combination lipid-lowering treatment and efforts to improve adherence.
Abstract 9989: Integration of Genetics with Metabolomics Identifies a Novel Gene Associated with Risk of Incident Cardiovascular Events:
TRAF3IP2
Authors: Shah Asad A , Craig Damian M , Haynes Carol , Bain James , Stevens Robert , Hughes G C , Newby L K , Hauser Elizabeth R , Kraus William E , Newgard Christopher B , Gregory Simon G , Shah Svati H
Published: April 2024

Background:
Despite strong heritability, the genetic architecture of cardiovascular (CV) disease remains incompletely characterized. Plasma metabolite concentrations are heritable and have been associated with risk of CV events. We sought to identify novel genes for CV event risk using metabolic profiles as intermediate phenotypes.

Methods:
From a genome-wide association study of multiple metabolites performed in the KORA population, we selected a single nucleotide polymorphism (SNP;
rs174399
, located in the intronic region of TRAF3IP2) strongly associated with short-chain dicarboxylacylcarnitine levels (metabolites that predict CV events). We genotyped this SNP in 3404 patients presenting for cardiac catheterization who also had quantification of 60 metabolites using mass-spectroscopy. Association between the SNP and short-chain dicarboxylacylcarnitine levels was tested using linear regression. Its association with CV events (death/MI) over a median of 5.4 years follow-up was tested using multivariable Cox proportional hazards regression adjusted for 11 clinical variables.

Results:
The association of
rs174399
(T/C) with levels of the short-chain dicarboxylacylcarnitine C5-DC validated in our cohort (dominant P=0.01; additive P=0.03), but the association with C6-DC was not (dominant P=0.11; additive P=0.19).
Rs174399
was also associated with values of a principal components analysis-derived metabolic factor consisting of multiple short-chain dicarboxylacylcarnitines (dominant P=0.01; additive P=0.08). The minor allele, C, was associated with higher concentrations of both C5-DC and values of the short-chain dicarboxylacylcarnitine factor. It was also associated with greater risk of death or MI (HR 1.17, [1.05-1.31], P=0.006) and death alone (HR 1.15 [1.02-1.30], P=0.03).

Conclusions:
Integrating genetics with metabolomics in a large CV study, we have identified a novel gene that predicts risk of CV events. This gene which encodes TRAF3 interacting protein 2, a protein involved in regulating responses to cytokines by members of the Rel/NF-kappaB transcription factor family, may serve as a good biological candidate to mediate CV risk through a metabolic pathway reported on by short-chain dicarboxylacylcarnitines.
Abstract 18252: Washing of Stored Red Cells Prevents Transfusion Related Acute Lung Injury but not Transfusion Associated Coagulopathy
Authors: Patel Nishith N , Lin Hua , Abidoye Aderoye , Wiltshire Michael , Cardigan Rebecca , Britchford Kristina , Verheyden Veerle , Angelini Gianni D , Murphy Gavin J
Published: April 2024

Objective To determine if washing of old Red Blood Cell (RBC) units prior to transfusion will prevent transfusion mediated organ dysfunction in our large animal experimental model. Method Adult White-Landrace pigs (50-70kg, n=32) were randomized to either sham procedure or to receive an allogeneic transfusion of 1-, 14- or washed 14-day RBCs. Endpoints included characterization of the RBC storage lesion, serial functional and biochemical measures of lung and renal injury, assessment of platelet function using platelet aggregometry, platelet activation using FACS and coagulation using ROTEM. All pigs were recovered for 24 hours prior to organ harvest.

Results Transfused pigs received 1000mls of cross-matched allogenic leucodepleted RBC stored in SAG-M preservative for either 1 or 14 days. Accumulation of toxic metabolites within the supernatant as well as cellular changes showed considerable homology to those measured in SAG-M stored human RBC units. Transfusion of allogeneic porcine RBCs was associated with 24hr RBC survivals of greater than 75% and sustained increases in haematocrit irrespective of age of unit. Despite enhancing oxygen delivery, transfusion of 14-day old RBCs decreased tissue oxygen unloading, caused significant hypoxia and pulmonary hypertension. This was associated with plasma platelet depletion with sequestration into lung parenchyma, platelet dysfunction with decreased aggregation in response to ADP stimulation, coagulopathy and inflammation with increased P-selectin expression in circulating platelets. Washing of aged RBC units prior to transfusion ameliorated TRALI and inflammation, but had no effect on transfusion induced coagulopathy and platelet dysfunction. Data are summarised below.

Conclusion Washing of aged RBC units prevents TRALI and should be evaluated in a randomized controlled in patients undergoing cardiac surgery. RBC transfusion mediated coagulopathy is a novel finding which is not affected by washing.
Abstract 18282: Atrial Fibrillation Independently Increases Risk of All-Cause Mortality: The Honolulu Heart Program
Authors: Rivera Kahealanik K
Published: April 2024

Introduction:
Atrial fibrillation (AF) increases cardiovascular and cerebrovascular mortality. However, there are few studies examining the natural history of AF in Asian populations in the US.
Objective:
To determine the long-term effect of AF detected in mid-life and late-life on all-cause mortality in a population of Japanese-American men.

Methods:
The Honolulu Heart Program prospective cohort included Japanese-American males (born 1900-1919) living on O`ahu, Hawai`i in 1965. Analyses included 6,860 and 2,675 participants with electrocardiograms from mid-life and late-life, followed over 36 years and 13 years, respectively. Mid-life AF was defined as having fibrillation or flutter at any of the 3 mid-life exams (ages 45-68 years old) and late-life AF was defined as having fibrillation or flutter at any of 2 late-life exams (ages 71-94 years old). The primary outcome was all-cause mortality.

Results:
AF prevalence was 0.74% and 4.36% in mid-life and late-life, respectively, and increased significantly with age (p<0.05), up to 12% in nonagenarians. After adjustment for multiple potential confounders, AF was an independent predictor of mortality in mid-life (RR=1.37, 95% CI=1.03-1.82, p=0.033) and late-life (RR=1.44, 95% CI=1.13-1.83, p=0.003). This relationship remained significant even in those without prevalent coronary heart disease, left ventricular hypertrophy, heart failure, and rheumatic heart disease in both mid-life (RR=1.45, 95% CI=1.04-2.02, p=0.029) and late-life (RR=1.51, 95% CI=1.13-2.02, p=0.005).

Conclusions:
In conclusion, atrial fibrillation was a significant independent predictor of all-cause mortality in both mid-life and late-life, including previously healthy participants.
Abstract 18290: Sense of Coherence in Adolescents with Congenital Heart Disease: Development, Antecedents, and Outcomes
Authors: Apers Silke , Luyckx Koen , Goossens Eva , Rassart Jessica , Moons Philip
Published: April 2024

Sense of coherence (SOC), a construct that reflects psychological and behavioral resilience, is found to promote health and quality of life (QOL). The development of a strong SOC in adolescents with congenital heart disease (CHD) can explain the relatively good QOL in afflicted patients. We investigated the development of SOC over time; and tested the hypothesis that developmental classes differ regarding antecedents (sex; age; disease complexity; perceived parenting) and outcomes (QOL; perceived health; depressive symptoms).

Methods:
We assessed 429 adolescents with CHD (mean age 16y; 53% boys) at three points in time (nine month intervals), recruited at a university hospital. Inclusion criteria were: confirmed CHD; aged 14-18y; last cardiac consult ≤5y ago; and being able to read and write Dutch. Exclusion criteria were: cognitive and/or physical limitations inhibiting filling out questionnaires; and prior heart transplantation. We measured SOC (SOC-13); perceived parenting (subscale of Parental Regulation Scale-Youth Self-Report; Psychological Control Scale-Youth Self-Report; Child Report of Parent Behavior Inventory); QOL (linear analog scale); perceived health (PedsQL); and depressive symptoms (CESD-20). Latent class growth analysis was used to identify developmental classes of SOC. Based on model fit tests, a solution with three classes was selected. Chi-square and multivariate tests were used to examine inter-class differences.

Results:
Class 1 (33% of the sample) was labeled Consistently High SOC; Class 2 (49%) Intermediate and Decreasing SOC; and Class 3 (18%) Chronically Low SOC. Significantly more boys than girls belonged to class 1. No significant age or disease complexity differences were found at time 1. Perceived parenting is a significant antecendent, with class 1 scoring highest on parental responsiveness and regulation, and class 3 scoring highest on psychological control at time 1. In terms of outcomes, class 1 scored highest on QOL and perceived health and class 3 scored highest on depressive symptoms at time 3.

Conclusions:
The development of SOC seems to be determined by sex and perceived parenting, and impacts on QOL, perceived health, and depressive symptoms. Enhancing SOC can be an important goal for interventions.
Abstract 18309: Familial Atrial Fibrillation - Common Atrial Fibrillation Susceptibility Alleles and Response to Catheter Ablation
Authors: Bollmann Andreas , Ueberham Laura , Lehmann Helge Immo , Hindricks Gerhard , Arya Arash , Adams Volker , Husser Daniela
Published: April 2024

Background:
Familial atrial fibrillation (AF) is common but AF-causing rare genetic variants are infrequently found supporting the multigenetic nature of this arrhythmia. On the other hand, genome-wide association studies have identified common AF susceptibility alleles, but their possible relation with familial AF is unknown. The aim of this study was to compare familial and sporadic AF with respect to common alleles on chromosomes 1q21 (rs13376333), 4q25 (rs10033464 and rs2200733) and 16q22 (rs7193343) and rhythm outcome after radiofrequency catheter ablation (CA).

Methods:
A total of 393 patients (mean age 59 +/- 10 years, 68 % males, 38 % persistent AF), who underwent CA were studied. The family history of AF was considered positive if at least one of the first-degree family members had AF based on patient's interviews, chart and ECG reviews. Genotypes were determined using real-time polymerase chain reaction and fluorescence resonance energy transfer. AF recurrence > 30 sec was detected using serial 7-day Holter ECG recordings after a blanking period between 3 and 12 months after radiofrequency CA.

Results:
Familial AF was found in 14.2 % and was associated with the absence of structural heart disease (OR 1.888, 95 % CI 1.017 - 3.505, p=0.042) and age (OR 0.964, 95 % CI 0.938 - 0.991, p=0.009). In familial AF, minor allele frequency of AF risk alleles on chromosomes 1q21 (40.0 % vs. 32.8 %) and 4q25 (rs10033464: 26.4 % vs. 11.0 % and rs2200733: 39.4 % vs. 27.2 %) tended to be higher compared with non-familial AF. Using a dominant genetic model, rs2200733 on chromosome 4q25 showed the strongest association with familial AF (OR 2.222, 95 % CI 1.015 - 4.865, p=0.042). AF recurrence was observed in 27.6 % of non-familial AF and in 30.9 % of familial AF patients (p=0.621).

Conclusion:
This study, for the first time, shows a dominant modulating function of a common AF susceptibility allele on chromosome 4q25 also in familial AF. Ablation outcome is comparable in familial and non-familial AF highlighting the role of the pulmonary veins in AF development.
Abstract 18331: Systemic Administration of Allogenic Fetal Membrane-derived MSC Ameliorates Experimental Autoimmune Myocarditis via Suppression of Th1/Th17 Immunity
Authors: Yamahara Kenichi , Ohshima Makiko , Ishikane Ken , Harada Kazuhiko , Tsuda Hidetoshi , Otani Kentaro , Kodama Makoto , Kangawa Kenji , Ikeda Tomoaki
Published: April 2024

Background:
We have reported that systemic administration of autologous bone marrow or allogenic fetal membrane (FM)-derived mesenchymal stem cells (MSCs) similarly attenuated experimental autoimmune myocarditis (EAM) (JMCC 42:88-97 2007, 49:753-61 2010). Since rat EAM is a T-helper (Th) cell-mediated autoimmune disease, and recent evidence has indicated that MSCs exert an immunosuppressive effect on Th cell activity, we focused on Th cell differentiation in allogenic FM-MSC administered EAM rats.

Methods and Results:
EAM was induced in Lewis rats by injecting porcine cardiac myosin (day 0). Allogenic FM-MSCs, obtained from major histocompatibility complex mismatched ACI rats, were intravenously injected (5×10[[Unable to Display Character: ⁵]] cells/rat) on day 7, 10, or 14 (MSCd7, MSCd10, or MSCd14 groups, respectively). At day 21, echocardiography confirmed that reduced ejection fraction in the untreated EAM group (63±2%) was significantly improved in the MSCd10 and MSCd14 groups (74±1 and 75±2%, respectively, P<0.01). CD68 immunostaining revealed that prominent macrophage infiltration in the myocardium of the EAM group (1466±93 cells/mm²) was significantly decreased in the MSCd10 group (958±139 cells/mm², P<0.05). To evaluate Th cell differentiation, flow cytometry was performed to determine the percentage of interferon (IFN)-γ positive Th1 and interleukin (IL)-17 positive Th17 cells in peripheral CD4-positive Th cells. The percentage of Th1 cells at day 16 was significantly lower in the MSCd10 (1.3±0.2%) and MSCd14 (1.6±0.3%) groups compared to the EAM group (2.4±0.3%, P<0.05), as was the percentage of Th17 cells in the MSCd10 group (1.9±0.5%) compared to the EAM group (2.2±0.9%, P<0.05). In addition, human CD4+ Th cells co-cultured with human FM-MSCs exhibited reduced Th1 and Th17 cell differentiation and proliferation, with increased expression of immunosuppressive molecules including indoleamine 2,3-dioxygenase 2 and IL-6 in co-cultured FM-MSCs.

Conclusion:
Our findings demonstrate the protective effects of intravenously administered FM-MSCs in EAM due to profound suppression of Th1/Th17 cells and provide a new perspective for the treatment of acute myocarditis.
Abstract 18341: Prospective, Multicenter Study on the Incidence of New Embolic Cerebral Lesions following Pulmonary Vein Isolation Using Laserballoon Ablation
Authors: Wissner Erik , Metzner Andreas , Neuzil Petr , Petru Jan , Vivek Reddy , Skoda Jan , Sediva Lucia , Schoonderwoerd Bas , Rausch Peter , Tilz Roland R , Ouyang Feifan , Kuck Karl-Heinz
Published: April 2024

Background:
Silent cerebral embolism following catheter ablation for atrial fibrillation (AF) has recently been described and its incidence varies depending on the intraprocedural anticoagulation strategy chosen or the ablation technology used. Its incidence following laserballoon ablation for AF is currently unknown. This multicenter, prospective study reports on the number of new lesions on postprocedural cerebral MRI following pulmonary vein isolation using laser-, cryo- or radiofrequency (RF) ablation.

Methods:
Each patient underwent cerebral MRI before catheter ablation for AF. Target ACT during the procedure was ≥ 300 s. Pulmonary vein isolation was performed using laserballoon (group 1), cryoballoon (group 2) or irrigated RF (group 3) ablation. Following the procedure all patients underwent repeat cerebral MRI.

Results:
Of a total of 72 patients (age: 63±9 years, 75% paroxysmal AF), 6/44 (13.6%) in group 1, 0/11 (0%) in group 2 and 3/17 (17.6%) in group 3 demonstrated new cerebral lesions on postprocedural MRI. Two patients with lesions in group 1 necessitated RF touch-up ablation, one of whom experienced diplopia with complete remission within days. No other gross abnormal neurological findings were detected in the remaining patients. Follow-up MRIs in those patients with lesions are currently underway.

Conclusions:
Laserballoon-based catheter ablation of AF demonstrates a similar safety profile regarding the rate of cerebral lesions than established ablation technologies.
Abstract 18349: Long-term Results Comparing Recurrent Neurological Event Rates of Three Different Devices for Percutaneous PFO-Closure
Authors: Hornung Marius , Franke Jennifer , Bertog Stefan , Taaffe Margaret , Sievert Horst
Published: April 2024

Background:
Percutaneous patent foramen ovale (PFO)-closure for secondary stroke prevention is discussed controversially, and long-term data comparing different closure devices are very limited.

Methods:
This is a prospective trial comparing procedural complications and long-term results after PFO closure in 660 patients with cryptogenic stroke randomized to three different closure devices (Amplatzer, CardioSEAL-STARflex and Helex occluder, 220 patients per group). The primary endpoint was defined as recurrent cerebral ischemia (stroke, TIA or Amaurosis fugax) or death from neurological cause during 5 year follow-up (including periprocedural events).

Results:
The primary endpoint occured in 25 patients (3.8%; 10 TIAs, 12 strokes and 3 cases of cerebral death). Compared with the Amplatzer (1.4%; 2 strokes, 1 cerebral death), significantly more events (p=0.02) occurred in the CardioSEAL-STARflex group (6%; 6 TIAs, 6 strokes, 1 cerebral death). The event rate in the Helex group was 4% (4 TIAs, 4 stroke, 1 cerebral death). The procedure was complicated by pericardial tamponade requiring surgery in 1 patient (Amplatzer device) and device embolization in 3 patients (all Helex devices). Device-associated thrombus formation was detected in 12 cases (11 CardioSEAL-STARflex, 1 Helex, 0 Amplatzer; p<0.0001), of which 2 required surgery. Complete closure after single device implantation was more common with the Amplatzer device than with the CardioSEAL-STARflex or Helex occluders.

Conclusions:
The periprocedural and long-term neurological event rates are low regardless of the device used. The recurrent neurological event rate was significantly higher after CardioSEAL-STARflex than after Amplatzer or Helex implantation. This has important implications regarding the interpretation of trials comparing PFO closure to medical management.
Abstract 18356: Are Soluble Receptors of Advanced Glycation End Products Associated with Pre-clinical Diastolic Dysfunction in Patients with Diabetes?
Authors: Lancefield Terase F , Wai Bryan , Patel Sheila K , Velkoska Elena , Ord Michelle , Srivastava Piyush M , Burrell Louise M
Published: April 2024

Background:
Pre-clinical diastolic dysfunction is common in diabetes. The parameter, E/e (ratio of the early mitral inflow (E) to septal mitral annular velocity (e) in diastole) is a continuous variable that correlates with increased LV filling pressure. In retrospective studies in diabetes, an E/e >15 predicted mortality and heart failure (HF). The soluble receptor of advanced glycation end products (sRAGE) and the splice variant, endogenous secretory RAGE (esRAGE) have been proposed as biomarkers of systolic HF in diabetes. This prospective study investigated the relationship between sRAGE, esRAGE and pre-clinical diastolic function in patients with diabetes.

Methods:
We recruited 263 patients with diabetes attending for a transthoracic echocardiogram as part of a complications surveillance program. Pre-clinical diastolic dysfunction was defined as an E/e >15. Patients with LVEF <50%, coronary artery disease, history of HF and significant valve pathology were excluded (n =86). Serum levels of sRAGE and esRAGE were measured using an ELISA. Data are presented as mean ±SD for parametric variables and geometric mean (25, 75th quartile) for non-parametric variables.

Results:
Patients with an elevated E/e’ were significantly older (69 ±10 vs. 59 ±13y, p <0.001) and were more likely to have hypertension (97 vs. 75%, p = 0.002) and a reduced eGFR <60ml/min/1.73m2 (47 vs. 14%, p <0.001). Gender, HbA1c and other cardiac risk factors were similar. Levels of sRAGE and esRAGE (geometric mean (25, 75th quartile) are shown below. Serum sRAGE remained significantly associated with an elevated E/e’ after adjustment for age, gender, BMI, diabetes duration, hypertension and renal function (p=0.015).

Conclusions:
Serum levels of sRAGE but not esRAGE are associated with pre-clinical diastolic function assessed in patients with diabetes. Follow up studies are underway to assess if an elevated sRAGE predicts the development of overt HF in this cohort of patients with diabetes.
Abstract 18397: Vitamin D Supplementation Prevents Cardiac Failure; MRC RECORD Trial Analysis, Systematic Review And Meta-analysis
Authors: Ford John A , MacLennan Graeme , Bolland Mark J , Grey Andrew , Avenell Alison
Published: April 2024

Objective
To assess if vitamin D supplementation, compared to no vitamin D, prevents cardiac failure, MI, stroke or any cardiovascular event through analysis of the MRC RECORD trial, systematic review and meta-analysis.

Methods Trial analysis
MRC RECORD was a factorial trial (n=5292) randomising participants to vitamin D3 (800 IU daily) or placebo and calcium or placebo. Primary outcome was low trauma fracture. Three year post-intervention follow up after trial closure resulted in a mean follow up of 6.1 years. Cox proportional hazard model adjusted for age, sex, diabetes, smoking, thiazide use, time since fracture and fracture type, was undertaken to assess time to first MI, stroke, cardiac failure or any cardiovascular event (composite endpoint of cardiac failure, MI and stroke).
Systematic review and meta-analysis
Three databases and conference abstracts were searched for randomised controlled trials of vitamin D or analogues. Inclusion criteria were mean/median age >60 and >1 year follow up. There were no language restrictions. Authors were contacted for unpublished data. Risk of bias was assessed using Cochrane risk of bias tool. Data were pooled in meta-analysis using random effects model.

Results
Trial analysis showed that vitamin D compared with placebo prevented cardiac failure events, but not MI, stroke or any cardiovascular event (table). Meta-analysis included 17 trials (n= 12,440). Nine study authors provided unpublished data. Meta-analysis showed that vitamin D prevented cardiac failure events, but not MI, stroke or any cardiovascular event (table). There was no statistical heterogeneity throughout. Risk of bias was generally low or unclear.

Conclusion
This is the first meta-analysis to assess vitamin D and cardiac failure, and the only meta-analysis to include vitamin D cardiovascular events from the large MRC RECORD trial. Vitamin D supplementation was found to prevent cardiac failure events, but not MI, stroke or any cardiovascular event.
Abstract 18401: P53 Silenced, Apoptosis Resistant, Endothelial Progenitor Stem Cells (EPC) Improve Collateral Circulation Post Femoral Artery Occlusion in Diabetic Mice
Authors: Young Mary , Chou Cyril , Sen Sabyasachi
Published: April 2024

Literature shows that EPCs contribute to increased collateral vessel formation following vaso-occlusion. However diabetes reduces EPC number and reduces collateral vessel formation. We cultured human EPCs and exposed them to 5.5 mM (equivalent to 99mg%) and 20mM (equivalent to 360mg%, HG) glucose, which resulted in significant EPC death within 48hrs. We noted HG exposure was associated with up-regulation of P53 and its downstream genes such as P21, PUMA and Caspase-3. We hypothesized that EPC reduction in hyperglycemia is secondary to up-regulation of P53. We obtained mouse EPCs from P53 null mice and observed that p53 KO EPCs are more resistant to cell death in HG. P53 null EPCs evolved into mature mouse EC (MEC) and retained endothelial properties. Next, we used Lenti and Adenovirus mediated si-RNA methods to silence P53 (long and short term respectively) in human EPCs and P53 silenced EPc showed better survival in HG. We developed femoral artery occlusion model to mimic peripheral vascular disease in diabetic animals. We used streptozotocin induced type 1 diabetic or Leptin resistant type 2 diabetic mouse model. We delivered saline, P53 WT and P53 null mouse EPCs intra-muscularly around the femoral occlusion in these mouse models (n=7 in each group) and counted CD31+ve number of capillaries in a 20x microscopic field. Highest number was noted in the group that received P53null EPCs. We also quantified increased vessel formation by laser doppler assay of the ischemic and contralateral hind limbs upto 2 weeks and conducted qRT-PCR and western blot of key endothelial genes such as eNOS, p-eNOS, VEGF-A, PECAM-1 and vWF from both quadriceps in all groups of mice.

Summary: Transplantation of P53 null EPCs in hyperglycemic mice with femoral occlusion demonstrate better collateral vessel formation post femoral artery occlusion setting compared to WT-EPC transplanted group. Preliminary results from transplantation of p53 silenced human CD34+ cells also indicate increased vessel formation compared to non p53 silenced hCD34+ cell in NOD-SCID diabetic mice.

Conclusion: This finding indicates towards possible therapeutic benefit in transplanting P53 silenced human EPC or CD34+ cells to prevent peripheral vascular disease in patients with diabetes.
Abstract 18415: Beta-trace Protein and Beta-2-microglobulin are Independent Predictors of All-cause and Cardiovascular Mortality in US Adults
Authors: Chrung Ching-Lung , Cheung Bernard M
Published: April 2024

Background:
Beta-trace protein (BTP) and beta-2-microglobulin (B2M) are novel markers of renal dysfunction associated with cardiovascular disease. We evaluated their relationship with all-cause and cardiovascular mortality in a representative sample of US adults.

Methods:
6,642 participants aged 20 or above were included in the Third National Health and Nutrition Examination Survey. They were recruited from 1988 to 1994 and followed up through 2006. Multivariate Cox regression analysis was used, with adjustment for age, race/ethnicity, sex, education, smoking, physical activity, BMI, diabetes, hypertension, hypertriglyceridemia, low HDL, serum uric acid, C-reactive protein, vitamin D, total cholesterol, blood urea nitrogen, hemoglobin, white blood cell count and eGFR.

Results:
The mean (95% CI) serum BTP and B2M levels were 0.581 mg/L (0.571-0.592) and 1.93 mg/L (1.89-1.97) respectively. Within an average 12.1 years follow-up, 2,540 all-cause and 1,157 cardiovascular deaths occurred. The multivariate adjusted hazard ratios comparing the lowest BTP quartile with the highest quartile were 1.43 (95% CI: 1.11-1.83; P-trend=0.007) for all-cause mortality, and 1.53 (95% CI: 1.11-2.11; P-trend<0.001) for cardiovascular mortality. The multivariate adjusted hazard ratios comparing the lowest with the highest B2M quartile were 2.30 (95% CI: 1.68-3.15; P-trend<0.001) for all-cause mortality, and 1.91 (95% CI: 1.03-3.55; P-trend=0.006) for cardiovascular mortality. Similar results were obtained when BTP and B2M were analyzed as continuous variables, in the subgroup with eGFR≥60 (n=4,066), or with further adjustment of LDL in the subgroup with LDL measurements (n=3,099).

Conclusion:
We have identified serum BTP and B2M as novel and significant predictors of all-cause and cardiovascular mortality in the general population.