bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13079: Synergistic Effect of Human Cardiac Stem Cells and Bone Marrow Mesenchymal Stem Cells to Reduce Infarct Size and Restore Cardiac Function
Authors: Williams Adam R , Hatzistergos Konstantinos E , Carvalho Decio , Suncion Viky , McCall Fred , Mather Jacques P , Morales Azorides R , Sussman Mark A , Da Silva Jose , Heldman Alan W , Hare Joshua M
Published: April 2024

Adam R Williams, 2011 Finalist and Presenting Author
Abstract 8169: Relationship Between the Ratio of Serum Eicosapentaenoic Acid to Arachidonic Acid and the Risk of Death: the Hisayama Study
Authors: Ninomiya Toshiharu , Doi Yasufumi , Kiyohara Yutaka
Published: April 2024

Background:
Recent evidence emerged to imply that greater intakes of omega-3 fatty acids reduce the risk of atherosclerotic disease. Some epidemiological studies suggested that a ratio of serum eicosapentaenoic acid to arachidonic acid (EPA/AA) is a possible good biomarker of risk for cardiovascular disease and death, but this issue has not been fully evaluated. We assessed the hypothesis that subjects with lower EPA/AA levels would be at increased risk of death from any causes and cardiovascular causes.

Methods:
We followed a total of 3,103 community-dwelling Japanese individuals aged 40 years or older, without history of cardiovascular disease, and with available EPA/AA data, for 5 years, and examined the relationship between EPA/AA levels and the risk of death from any and cardiovascular causes by using the Cox proportional hazards model.

Results:
The median value of EPA/AA levels in the study population was 0.41 (interquartile range, 0.29-0.59). During the follow-up, 191 subjects died in total, 48 of which were deceased from cardiovascular causes. The mortality rate from any causes increased gradually with lower EPA/AA levels: The risk of death from any causes increased significantly with EPA/AA levels of <0.25, 0.25-0.49, 0.5-0.74, and ≥0.75, being 23.5, 11.8, 12.8, and 11.5 per 1,000 person-years, respectively (p for trend =0.01). Likewise, there was an increasing trend in the mortality rate from cardiovascular causes with lower EPA/AA levels: 4.9, 4.0, 2.2, and 1.6 per 1,000 person-years for EPA/AA levels of <0.25, 0.25-0.49, 0.5-0.74, and ≥0.75, respectively (p for trend =0.03). After adjusting for potential confounding factors: namely, age, sex, hypertension, diabetes, total cholesterol, use of lipid-modifying agents, body mass index, smoking habits, and alcohol intake, subjects with EPA/AA level of <0.25 had a 2.04-fold (95% confidence interval [CI], 1.18-3.41) and 2.90-fold (95% CI, 0.78-10.77) greater risk of deaths from any causes and cardiovascular causes, as compared to those with EPA/AA level of ≥0.75.

Conclusions:
Our findings suggest that lower EPA/AA level is associated with a greater risk of death in the general Japanese population.
Abstract 8198: Serum Heat Shock Protein 60 Level Predicts Cardiac Events in Chronic Heart Failure Patients with Preserved Left Ventricular Systolic Function
Authors: Niizeki Takeshi , Kaneko Kazuyoshi , Sasaki Toshiki , Omi Koki , Sugawara Shigeo , Kubota Isao
Published: April 2024

Background:
More than 40% of patients hospitalized with chronic heart failure (CHF) have preserved left ventricular ejection fraction (LVEF) and are at high risk for cardiac events. Heat shock protein 60 (Hsp60) are induced by a variety of stressors including infection, anoxia, oxidative stress, and inflammation and have a protective role against stress-induced cardiomyocyte injury. Recently, it has been reported that Hsp60 exists in the circulation and serum Hsp60 levels are positively associated with serum TNF-α level, interleukin-6 level, and an important proinflammatory cytokines. CHF is characterized by systemic abnormalities and the myocardium is continually exposed to various stressors, such as anoxia, ischemia, inflammation, and free radicals. We have been reported that serum Hsp60 level was related to severity of CHF and associated with a high risk for adverse cardiac events in CHF patients. The purpose of this study was to examine whether Hsp60 is useful to determine the prognosis of CHF patients with preserved LVEF.

Methods and Results:
Serum Hsp60 level was measured in 141 CHF patients with preserved LVEF and 62 control subjects by the competitive enzyme-linked immunosorbent assay. Patients were prospectively followed with endpoints of cardiac death or re-hospitalization for worsening CHF during a median follow-up period of 786 days. Serum Hsp60 level was increased with advancing NYHA functional class (P < 0.0001). There were 45 cardiac events during follow-up period (31%). Serum Hsp60 level was significantly higher in patients with cardiac events than those in event free patients. Kaplan-Meier analysis clearly demonstrated that the high Hsp60 group had a significantly higher incidence of cardiac events than the low Hsp60 group (P < 0.0001). Patients were divided into 3 groups based upon Hsp60 level, and the highest 3
rd
tertile was associated with the highest risk of cardiac events (6.27-fold compared to the 1
st
tertile). In the multivariate Cox analysis, Hsp60 level was an independent risk factor for cardiac events (hazard ratio 3.51, 95% confidence interval 1.46-5.01, P = 0.0031).

Conclusion:
Serum Hsp60 level is an independent and powerful prognostic factor and may be useful for risk stratification of CHF patients with preserved LVEF.
Abstract 8301: Clopidogrel Plus Aspirin is Cost-Effective for Stroke Prevention in Patients with Atrial Fibrillation in Whom Warfarin is Unsuitable
Authors: Coleman Craig I , Straznitskas Andrew D , Sobieraj Diana M , Kluger Jeffrey
Published: April 2024

Introduction:
Updated guidelines for atrial fibrillation (AF) now recommend clopidogrel plus aspirin as an alternative stroke prevention strategy in patients whom warfarin is unsuitable.

Objective:
To evaluate the cost-effectiveness of clopidogrel plus aspirin compared to aspirin alone for stroke prevention in patients with nonvalvular AF (NVAF).

Methods:
A Markov model was conducted from the societal prospective using data from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE)-A trial and other published studies of anticoagulation. Drug cost was estimated using the average wholesale price and the cost of complications and adverse events was based on values from the Healthcare Cost and Utilization Project and CMS reimbursement rates. The base-case analysis evaluated patients aged 65 years with NVAF, a CHADS
2
score of 2 and a low risk for major bleeding. Patients received clopidogrel 75 mg daily plus aspirin (recommended dose of aspirin: 75-100 mg daily) or aspirin alone. Patients were followed for up to 35 years. Outcomes included quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Costs were inflated to 2011US$ using the Consumer Price Index for Medical Care. Future costs and QALYs were discounted at a rate of 3% annually.

Results:
Quality-adjusted life expectancy and therapy-related costs were 9.37 QALYs and $88,751 with clopidogrel plus aspirin and 9.01 QALYs and $79,057 with aspirin alone. The ICER for clopidogrel plus aspirin was $26,928/QALY. Upon one-way sensitivity analysis, using a willingness-to-pay (WTP) threshold of $50,000/QALY, clopidogrel plus aspirin was no longer cost-effective when CHADS
2
score was ≤1, major bleeding risk with aspirin was ≥2.50%/patient-year and the relative risk reduction for ischemic stroke with clopidogrel plus aspirin vs. aspirin alone was <25%. Monte Carlo simulation demonstrated that clopidogrel plus aspirin was cost-effective in 55% and 73% of 10,000 iterations, assuming WTP thresholds of $50,000 and $100,000/QALY.

Conclusion:
Clopidogrel plus aspirin appears cost-effective compared to aspirin alone for stroke prevention in patients with NVAF who have at least a CHADS
2
of 2 and a low risk of bleeding.
Abstract 8321: Reduced Estimated Glomerular Filtration Rate Levels to Predict Mortality Depend on Presence of Hypertension or Diabetes
Authors: Tsuji Hisako
Published: April 2024

BACKGROUND:
The current staging system of chronic kidney disease based on estimated glomerular filtration rate (eGFR) led to a marked increase in number of subjects to target for intervention and better methods for identifying those at high risk of adverse outcomes is needed. Hypertension (HT) and diabetes (DM) are the leading causes of end-stage renal disease and effect of reduced eGFR on mortality may be different among subjects with HT or DM. We examined effect of reduced eGFR on all-cause mortality according to presence or absence of HT and DM.

METHODS:
We studied 16,461 subjects (mean age 54±13 years, men 26%) who had the annual health examination offered to adult citizens of Moriguchi city, Osaka, Japan in 1997. The new equation for eGFR based on inulin renal clearance for Japanese was applied. The relative risks (RR) were calculated for mortality of each group according to eGFR levels of <30 mL/min/1.73m
2
(group 1), 30-44 mL/min/1.73m
2
(group 2) and 45-59 mL/min/1.73m
2
(group 3), relative to the highest eGFR group (>60 mL/min/1.73m
2
; group 4), using proportional hazards regression analyses adjusted for age, sex, smoking, drinking, hypercholesterolemia, and history of cardiovascular disease, separately in DM subjects (with DM), HT only subjects (with HT without DM) and control subjects (no HT or DM).

RESULTS:
Reduced eGFR <60 mL/min/1.73m
2
was observed in 13.5%. During a mean follow-up of 11.0±3.0 years (median 12.2 years), there were 1,208 deaths. In DM subjects, the RRs were significantly higher in group 3 (HR=1.65, 95% CI=1.12 to 2.42), group 2 (HR=2.03, 95% CI=1.04 to 3.97), and group 1 (HR=8.86, 95% CI=4.28 to 18.31), compared to group 4. In HT only subjects, the RRs were significantly higher in group 2 (HR=1.91, 95% CI=1.32 to 2.78) and group 1 (HR=3.42, 95% CI=1.86 to 6.28). In control subjects, the RR was significantly higher only in group 1 (HR=2.98, 95% CI=1.39 to 6.39). (figure).

CONCLUSIONS:
Reduced eGFR level to predict mortality depended on presence of HT or DM.
Abstract 8407: The T-peak to T-end Interval Independently Predicts Both Ventricular Tachyarrhythmia and Death in Patients with Cardiomyopathy and an Implanted Defibrillator
Authors: Morin Daniel P , Saad Marc N , Shams Omar F , Owen J S , Xue Joel Q , Abi-Samra Freddy M , Khatib Sammy , Nelson-Twakor Onajefe S , Milani Richard V
Published: April 2024

Background:
The heart rate-corrected T wave peak to T end interval (Tpe
c
), an electrocardiographic (ECG) index of dispersion of ventricular repolarization, has been proposed as an indicator for arrhythmic risk. The real-world clinical value of Tpe
c
for risk stratification is unclear.

Methods:
We evaluated 327 patients (75% M, LVEF 23±7%) with LVEF <=35% and an ICD. Clinical data and ECGs were analyzed at baseline. Follow up for appropriate ICD therapy and death was conducted via device interrogation and the Social Security Death Index.

Results:
During device clinic follow-up of 17±12 months, 59 (18%) patients had appropriate ICD therapy, and during mortality follow-up of 30±13 months, 67 (21%) patients died. Tpe
c
predicted ICD therapy, death, and the combination of appropriate ICD therapy or death (p<0.01 for each endpoint; see Figures stratified by tertiles of Tpe
c
: T1, T2, T3). On multivariable analysis correcting for other predictors including demographics, clinical data, medication use, and ECG parameters, Tpe
c
remained predictive of ICD therapy (HR per 10 ms increase: 1.16, p=0.02), all-cause mortality (HR per 10 ms: 1.14, p=0.03), and the combined endpoint of ICD therapy or death (HR per 10 ms: 1.16, p<0.01).

Conclusion:
In patients with left ventricular systolic dysfunction and an implanted ICD, Tpe
c
independently predicts both ventricular tachyarrhythmia and overall mortality.
Abstract 8419: Impact of Abdominal Obesity and Physical Inactivity on the Relationship Between Systemic Hypertension and Risk of Coronary Heart Disease in Apparently Healthy Men and Women
Authors: Rheaume Caroline , Arsenault Benoit J , Després Jean-Pierre , Amos Dorcely , Wareham Nicholas J , Khaw Kay-Tee , Boekholdt Matthijs
Published: April 2024

Background
Individuals with systemic hypertension (HT) are at increased of future coronary heart disease (CHD). Physical inactivity and abdominal obesity may increase the risk of HT and impact on the relationship of HT and CHD risk. Therefore, the objective of the present study was to test the hypothesis that active individuals with smaller waist circumference (WC) will have lower blood pressure (BP) than inactive individuals with higher WC in a large population-based sample of individuals representative of a contemporary European population. Our second objective was to determine the respective contributions of WC and HT to CHD risk.

Methods and Results
A total of 9580 men and 12250 women aged 45 to 79 years residing in Norfolk, United Kingdom participated in a prospective, population-based study with a 11.4-year follow-up. During follow-up, 2191 CHD events were recorded. Physical activity was evaluated using a validated lifestyle questionnaire that takes into account both leisure-time and work-related physical activity. WC was measured at the smallest circumference between the ribs and iliac crest with a D-loop non-stretch fibreglass tape. BP was measured by using a non-invasive oscillometric device in sitting position. Within each physical activity category, a consistent relationship was observed between increasing WC tertiles and increasing systolic (SBP) and diastolic BP. Within each WC tertile, inactive individuals had higher SBP than active individuals (P for trend <0.001). After adjusting for traditional CHD risk factors, compared to individuals with both low WC and BP, those with high BP and high WC were at increased CHD risk (Hazard ratio (HR) =3.32 [95% CI, 2.25-4.89] and 3.11 [1.98-4.87] respectively in men and women). In individuals with normal BP, those in the top WC tertile were at increased CHD risk compared to those in the bottom WC tertile (HR=2.78 [1.66-4.66] and 2.23 [1.18-4.20] respectively in men and women).

Conclusion
In this population-based study, elevated WC and HT have an independent and additive impact on CHD risk. Targeting elevated abdominal obesity by increasing physical activity levels may reduce the increased CHD risk associated with elevated BP in primary prevention.
Abstract 8420: Critical Role of CIKS/Act1 In Lipopolysaccharide (LPS)-Induced Cardiac Dysfunction i
n vivo
And Cardiomyocyte Contractility
in vitro
Authors: Valente Anthony J , Prabhu Sumanth D , Siebenlist Ulrich , Chandrasekar Bysani
Published: April 2024

The innate immune system and inflammatory cytokines are critical in the initiation and perpetuation of tissue injury. Toll-like receptor (TLR)4 recognizes bacterial LPS, and is currently known to signal via distinct MyD88-dependent and MyD88-independent (TRAM-dependent) pathways to activate NF-κB and AP-1, and induce proinflammatory cytokines such as interleukin (IL)-18. Since the adapter molecule CIKS (connection to IκB kinase and stress-activated protein kinases; also known as Act1 or traf3ip2) lies upstream of IKK and JNK, and since both TLR4 and CIKS contain
TIR
(Toll/Interleukin-1 receptor)
domains
, we hypothesized that CIKS can interact with TLR4, and contribute independently to LPS-induced contractile depression. Treatment with LPS inhibited adult mouse cardiomyocyte contractility by 54% (IonOptix), an effect partially reversed by MyD88 or TRAM knockdown. Significantly, CIKS knockdown also reversed LPS-induced contractile depression. Using GST pull-down and reciprocal immunoprecipitation/immunoblotting, we found that TLR4 can physically associate with CIKS, and this association is enhanced by LPS. LPS upregulates CIKS protein expression, and CIKS knockdown inhibited LPS-induced IKK/NF-κB and JNK/AP-1 activation, IL-18 expression, and contractile depression. LPS-mediated contractile depression was reversed by IL-18 neutralizing Ab and IL-18 binding protein (IL-18BP, a natural inhibitor of IL-18). These results were confirmed in cardiomyocytes isolated from TLR4-mutant, CIKS null, IL-18 null and IL-18BP Tg mice. Notably, systemic LPS administration reduced cardiac ejection fraction by 43% at 6 h in wild type mice, and this effect was markedly attenuated in TLR4-mutant, CIKS and IL-18 null, and IL-18BP Tg mice. These novel observations identify a TLR4/CIKS pathway in NF-κB and AP-1 activation in cardiomyocytes, and appears to be distinct from the well-characterized MyD88 and TRAM-dependent LPS/TLR4 signaling. These data also show that LPS induces contractile dysfunction in part via CIKS-mediated IKK/NF-κB and JNK/AP-1-dependent IL-18 expression. These data identify CIKS as a novel therapeutic target in conditions of innate immune activation and inflammation such as myocardial injury and congestive heart failure.
Abstract 8510: Regulation of Microrna-155 of the Atherosclerotic Inflammatory Responses by Targeting Map3k10
Authors: Yan Hui , Chen Ting , Zhu Jianhua , Zhang Li , Li Zhoubin , Yang Lin
Published: April 2024

Objectives and Aims:
There are increasing evidence that many miRNAs play important roles in cell proliferation, apoptosis and differentiation which accompany immno-inflammatory responses, and as all know that immuno-inflammation is thought to be a major contributor to atherogenesis.This study aims to investigate the potential role of microRNA on the atherosclerosis (AS) immuno-inflammatory mechanism.

Methods and results:
The miRNA transcriptome was verified by TaqMan Real-time PCR assay with thoracic aorta sample from western-type diet fed APOE knockdown mice and plasma sample from coronary artery disease(CAD)patients.miR-155, miR-146a, miR-9 were aberrantly upregulated in APOE knockdown mice and miR-155, miR-146a, miR-29a were dysregulted in patients with CAD. In particular, miR-155 level was the most significantly elevated both in AS mice and in CAD patients relative to normol control. Moreover, we showed that miR-155 is part of a negative feedback loop, which down-modulates inflammatory cytokine production , lipid uptake and decreases atherosclerosis progression in the oxLDL-treated human monocytic cell line THP-1 and atherosclerotic model mice.(figure) Bioinformatics analysis suggested that mitogen-activated protein kinase kinase kinase 10(MAP3K10) maybe a potential target of miR-155, this was also confirmed by a luciferase reporter assay. Significantly, we suggested an additional explanation for the mechanism of miR-155 mediate immuno-inflammatory response and MAPK pathway by targeting mitogen-activated protein kinase kinase kinase 10.

Conclusions:
miR-155 contributes to prevent AS development and progression and may be involved in the posttranscriptional regulation of the immno-inflammatory response and MAPK pathway by targeting MAP3K10
Abstract 8525: Adipose-Derived Mesenchymal Stem Cell Protects Kidneys Against Ischemia-Reperfusion Injury Through Suppressing Oxidative Stress and Inflammatory Reaction
Authors: Chen Yung-Lung , Tsai Tzu-Hsien , Chua Sarah , Yip Hon-Kan
Published: April 2024

Background:
Reactive oxygen species are important mediators exerting toxic effects on various organs during ischemia-reperfusion (IR) injury. We hypothesized that adipose-derived mesenchymal stem cells (ADMSCs) protect the kidney against oxidative stress and inflammatory stimuli in rat during renal IR injury.

Methods:
Adult male Sprague-Dawley (SD) rats (n=24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus immediate intra-renal administration of 1.0 × 10
6
autologous ADMSCs, followed by intravenous ADMSCs at 6h and 24h after IR). The duration of ischemia was 1h, followed by 72 hours of reperfusion before the animals were sacrificed.

Results:
Serum creatinine and blood urea-nitrogen levels and the degree of histological abnormalities were markedly lower in group 3 than in group 2 (all p<0.03). The mRNA expressions of inflammatory, oxidative stress, and apoptotic biomarkers were lower, whereas the anti-inflammatory, anti-oxidative, and anti-apoptotic biomarkers were higher in group 3 than in group 2 (all p<0.03). Immunofluorescent staining showed a higher number of CD31+, von Willebrand Factor+, and heme oxygenase (HO)-1+ cells in group 3 than in group 2 (all p<0.05). Western blot showed notably higher NAD(P)H quinone oxidoreductase 1 and HO-1 activities, two indicators of anti-oxidative capacity, in group 3 than those in group 2 (all p<0.04). Immunohistochemical staining showed higher glutathione peroxidase and glutathione reductase activities in group 3 than in group 2 (all p<0.02).

Conclusion:
ADMSC therapy minimized kidney damage after IR injury through suppressing oxidative stress and inflammatory response (The possible mechanisms of ADMSC therapy in protecting kidney from IR injury are schematically presented in the following figure).
Abstract 8528: Functional Outcome 5 Years After Massive Pulmonary Embolism Treated with Percutaneous Mechanical Thrombectomy or Pharmacologic Therapy
Authors: Pelliccia Francesco , Speciale Giulio , Pasceri Vincenzo , Pristipino Christian , Roncella Adriana , Irini Diego , Arrivi Alessio , Tanzilli Gaetano , Mangieri Enrico , Mercuro Giuseppe , Gaudio Carlo
Published: April 2024

Introduction.
Percutaneous mechanical thrombectomy (PMT) has emerged as an effective treatment in patients with massive pumonary embolism (PE). The long-term functional outcome, i.e. development of chronic thromboembolic pulmonary hypertension (CTEPH), after PMT as compared to conventional therapy is unknown.

Hypothesis.
Are follow-up data on 5-year outcome different among survivors of massive PE treated either with PMT or drug therapy only?

Methods.
We studied 85 survivors of massive PE (defined as mean pulmonary arterial pressure (PAP)>25 mm Hg and Miller index>20/34) from 3 tertiary centers between January 2004 and December 2007. At referral, 52 patients (49±18 years) had thrombolitics and/or heparin (Gr.A), whereas 33 patients (43±13 years) underwent PMT (Angiojet, Possis Medical, Minneapolis, MN) because of relative or absolute contraindications to thrombolytics and/or heparin (Gr.B). All patients were evaluated at 6-month intervals over a 5-year follow-up period after discharge.

Results.
While in-hospital, Gr.A showed significant improvement in functional class (from 3.6±1.2 to 2.3±1.1, p<0.001) and increase in oxygen saturation (from 77±21 to 94±19%, p<0.001). In Gr.B, PMT resulted in immediate angiographic improvement in 22/23 patients, with a rapid amelioration in functional class (from 3.3±0.9 to 2.1±0.7, p<0.001) and an increase in oxygen saturation (from 71±15 to 92±17%, p<0.001). At discharge, peak systolic PAP resulted significantly (p<0.001) decreased in both Gr.A (from 57±28 to 35±22 mm Hg) and Gr.B (from 65±31 to 31±19 mm Hg). The clinical improvement was maintained during the follow-up in both groups, and after 5 years a peak systolic PAP>50 mm Hg was recorded in 6/52 Gr.A patients and 2/33 Gr.B patients (12 vs. 6%).

Conclusions.
PMT is an effective alternative to pharmacologic treatment for PE, and is associated with a lower tendency to develop CTEPH over 5 years.
Abstract 8558: Mechanical Stretch Induces the Apoptosis Regulator Puma in Vascular Smooth Muscle Cells
Authors: Shyu Kou-Gi , Cheng Wen-Pin , Wang Bao-Wei
Published: April 2024

Aims
The expression of PUMA (p53-upregulated modulator of apoptosis), an apoptosis regulated gene, increases during endoplasmic reticulum (ER) stress. How mechanical cyclic stretch affects the regulation of PUMA in vascular smooth muscle cells (VSMCs) during apoptosis is not fully understood. We aimed to test the hypothesis that cyclical stretch enhances PUMA expression in VSMCs undergoing apoptosis.

Methods and results
Human VSMCs grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles/min. An in vivo model of aorta-caval shunt in adult rats was used to investigate PUMA expression. Cyclic stretch significantly enhanced PUMA protein and mRNA expression after 18 h of stretch. Addition of c-jun N-terminal kinase (JNK) inhibitor SP600125 and interferon-γ (IFN-γ) antibody 30 min before stretch inhibited the induction of PUMA protein. Gel shift assay showed that DNA-binding activity of Interferon Regulatory Factor-1 (IRF-1) increased after stretch. SP600125, JNK siRNA and IFN-γ antibody abolished the binding activity induced by stretch. Stretch increased while PUMA-Mut plasmid, SP600125, and IRF-1 antibody abolished the promoter activity. Cyclic stretch significantly increased the interferon-γsecretion from VSMCs at 1 h and remained elevated for 6 h. Both conditioned media from stretched VSMCs and exogenous administration of IFN-γrecombinant protein to the non-stretched VSMCs increased PUMA protein expression similar to that seen after stretch. Cells in the sub-G1 fraction stained with propidium iodide and caspase 3 activity was elevated after stretch for 18 h and addition of interferon-γ. Addition of PUMA and JNK siRNA abolished the induction of sub-G1 and caspase 3 activity induced by stretch. The increases of TUNEL-positive nuclei in VSMCs induced by stretch were significantly reversed by PUMA and JNK siRNA. An in vivo model of aorta-caval shunt in adult rats also demonstrated the increased PUMA protein expression in the aorta.

Conclusion
Cyclic stretch enhanced PUMA expression in cultured human VSMCs. The stretch-induced PUMA is mediated by IFN-γ,JNK and IRF-1 pathway. These findings suggest that PUMA plays a role in stretch-induced VSMC apoptosis.
Abstract 8566: Regression Pattern of Aortic Lesion after Endovascular Stent-graft Implantation in Patients with Complicated Acute Aortic Syndrome
Authors: Choe Hyunmin , Jang Woo-Ik , Kim Chang Young , Doh Joon Hyung , Kwak Jae-Jin , Namgung June , Lee Sung Yun , Lee Won Ro
Published: April 2024

Background:
Endovascular aortic repair (EVAR) using stent-graft has been appropriate and valid treatment in selected patients with complicated or progressive acute aortic syndrome (AAS). However, there is few data about regression or change of aortic lesions after EVAR.

Methods and Results:
From January 2007 to May 2010, 29 patients who underwent EVAR due to complicated or progressive AAS were enrolled. The underlying aortic syndrome included an intramural hematoma (IMH, n = 15), penetrating atherosclerotic ulcer in aortic aneurysm (PAU in AA, n = 9) and Stanford type B aortic dissection (AD, n = 5). We analyzed the changes in maximal diameter of aorta, minimal diameter of inner lumen and maximal thickness or lumen size of hematoma, aneurysm and dissection before and after EVAR using 64-multidetector computed tomography (MDCT). Then, we defined > 75% of shrinkage in maximal thickness or size of pathologic lesions after EVAR as complete, 25-75% as partial and < 25% as no regression. The follow-up 64-MDCT data was obtained from 12-month after EVAR (mean 10.8 ± 1.1 months), and the rate of follow-up 64-MDCT was 89.7%. Lesion characteristics and changes after EVAR were described in Table.

Conclusion:
EVAR in complicated or progressive AAS lesions promotes the regression of the main aortic disease through stabilizing further evolution of underlying pathology and maintaining inner luminal space. Also, EVAR achieves the high rate of complete regression in patients with IMH.
Abstract 8608: Oxidized Low Density Lipoprotein Synergizes with Toll-Like Receptor 4 Agonist to Induce the Inflammatory and Osteogenic Responses in Human Aortic Valve Interstitial Cells
Authors: Zeng Qingchun , Ao Lihua , Zhai Yufeng , Fullerton David A , Meng Xianzhong
Published: April 2024

The inflammatory and osteogenic responses of aortic valve interstitial cells (AVICs) play an important role in the progression of calcific aortic valve stenosis. We found that stimulation of TLR4 induces the expression of inflammatory and osteogenic mediators in human HAVICs, indicating a role for TLR4 in the pathogenesis and progression of this cardiovascular disease. In patients with aortic valve stenosis, valvular tissue exhibits increased levels of oxidized LDL (oxLDL), and oxLDL induces the secretion of pro-inflammatory cytokines in monocytes and macrophages. However, it remains unclear whether oxLDL modulates the inflammatory and osteogenic responses in valvular cells. We tested the
hypothesis
that oxLDL augments the inflammatory and osteogenic responses to TLR4 stimulation in human AVICs. The
purposes
of this study were to determine: 1) whether oxLDL induces IL-6, ICAM-1 and BMP-2 in human AVICs, 2) whether oxLDL synergizes with TLR4 agonist endotoxin to augment the production of inflammatory and osteogenic mediators and 3) the mechanism by which oxLDL exerts an effect.

Methods and results:
Human AVICs isolated from normal aortic valve were treated with TLR4 agonist endotoxin (0.1 μg/ml), oxLDL (20 µg/ml) or endotoxin plus oxLDL for 48 h. Endotoxin alone induced the production of IL-6, ICAM-1 and BMP-2 in human AVICs. OxLDL alone had no effect on IL-6 secretion and cellular ICAM-1 protein levels, while it induced a slight increase in cellular BMP-2 protein levels. Surprisingly, cells exposed to oxLDL and endotoxin produced markedly higher levels of IL-6 (3.4 folds), ICAM-1 (4.0 folds) and BMP-2 (3.5 folds) than cells expose to endotoxin alone. Similarly, oxLDL enhanced endotoxin-induced activation of Notch1. Inhibition of Notch1 reduced IL-6, ICAM-1, BMP-2 levels in cells treated with oxLDL and endotoxin. Further, Notch1 ligand Jagged1 also augments the inflammatory and osteogenic responses to endotoxin.

Conclusions:
The Notch1 pathway augments TLR4-mediated inflammatory and osteogenic responses in human AVICs, and oxLDL synergizes with endotoxin to induce these responses through modulation of Notch1 activation. Thus, a synergy between oxLDL and TLR4 agonist may promote the progression of calcific aortic valve stenosis.
Abstract 8642: A Randomized Controlled Trial of Physician Alerts to Prevent Symptomatic Venous Thromboembolism after Hospital Discharge
Authors: Piazza Gregory , Anderson Frederick A , Ortel Thomas L , Cox Michael J , Rosenberg David J , Rahimian Shahram , Pendergast William J , McLaren Gordon D , Welker James A , Akus Jan J , Stevens Scott M , Elliott C. G , Freeman Andrew L , Patton William F , Dabbagh Ousama , Wyman Allison , Huang Wei , Rao Amanda F , Goldhaber Samuel Z
Published: April 2024

Introduction:
Many patients develop venous thromboembolism (VTE) in the months following hospitalization for medical illness.

Hypothesis:
We assessed the hypothesis that a VTE prophylaxis alert from a hospital staff member to the Attending Physician prior to patient discharge from the hospital will reduce the incidence of symptomatic VTE after discharge.

Methods:
We enrolled hospitalized Medical Service patients in a large multicenter randomized controlled trial using a validated point score system to identify those at high risk for symptomatic VTE who were not ordered to receive VTE prophylaxis after discharge.

Results:
Among 2,513 eligible patients randomized from 18 study sites, 1,252 were assigned to the intervention group, and 1,261 were assigned to the control group. Patients in the intervention group were more than twice as likely to receive VTE prophylaxis at discharge as controls (22.0% versus 9.7%, p<0.0001). Symptomatic VTE at 90 days (99.9% follow-up) occurred in 4.5% of patients in the intervention group compared with 4.0% of controls (hazard ratio, 1.12; 95% confidence interval, 0.74 to 1.69). Rates of death at 90 days and major bleeding at 30 days in the intervention group were similar to that of the control group. In an on-treatment analysis, we observed a nearly one-third reduction in 90-day mortality among at-risk medical patients whose physicians were alerted and in whom discharge prophylaxis was prescribed compared with those in whom the alert recommendation was not followed and compared with those for whom an alert was not issued and prophylaxis was not ordered after hospital discharge.

Conclusion:
We observed no difference in the rate of symptomatic VTE in patients assigned to the alert group compared with controls. The physician alert doubled the rate of VTE prophylaxis ordered at the time of hospital discharge. Further Quality Improvement initiatives to improve VTE prevention after hospital discharge are warranted.
Abstract 8807: Cardiac Resynchronization Therapy Reduces Mortality and Hospitalization in Patients with Minimal Heart Failure: Specific Evidence on Asymptomatic (NYHA I) Patients
Authors: Roukoz Henri , Moss Arthur J , Anand Inder , Adabag Selcuk
Published: April 2024

Background:
Recent clinical trials suggest that cardiac resynchronization therapy (CRT) improves left ventricular function and clinical outcomes in patients with mild (New York Heart Association (NYHA) I-II) heart failure (HF). However, no individual trial had sufficient number of asymptomatic (NYHA I) patients to assess the CRT effect in this group. We tested the hypothesis that CRT benefits asymptomatic HF patients.

Methods:
We performed a meta-analysis of randomized clinical trials comparing CRT vs. implantable cardioverter defibrillator (ICD) in patients with NYHA class I-II HF.

Results:
We identified 5 trials (acronyms: RAFT (n=1438), MADIT-CRT (n=1820), REVERSE (n=610), MIRACLE-ICD II (n=186), CONTAK-CD (n=263) including 4,317 patients with NYHA class I-II HF. Average age of patients was 65 years, and 80% were male. Mean weighted follow-up was 2.4 years (range 6 to 40 months). CRT patients had a significantly greater improvement in ejection fraction (+5.9% vs. +2.2%, p<0.001). CRT was associated with significantly lower mortality and HF hospitalization among NYHA class II patients (RR=0.73; 95% CI (0.64-0.83), p<0.001) (Table). In asymptomatic (NYHA I) patients, HF hospitalization risk was lower (RR=0.57; 95% CI (0.34-0.97), p=0.04) with CRT, however, there was no difference in mortality (Table). Twelve asymptomatic (NYHA I) HF patients needed to be treated to prevent 1 hospitalization.

Conclusion:
CRT decreases all-cause mortality, reduces HF hospitalizations, and improves left ventricular ejection fraction in asymptomatic and mildly symptomatic HF patients. These are the first data on CRT effects specifically in asymptomatic (NYHA I) HF patients.
Abstract 8910: Clinical Use, Diagnostic Efficiency and Impact on Patient Management of Cardiovascular Magnetic Resonance
Authors: von Knobelsdorff-Brenkenhoff Florian , Bublak Angelika , El-Mahmoud Sana , Wassmuth Ralf , Opitz Christian , Schulz-Menger Jeanette
Published: April 2024

Objectives:
To evaluate the clinical use, diagnostic efficiency and impact on patient management of cardiovascular magnetic resonance (CMR).

Methods
: Data of the individual patient and procedural information of 2598 consecutive clinically indicated CMR exams were collected. For a representative subgroup of 250 exams, an external blinded reviewer evaluated the need for diagnostic tests and hospitalization before and after CMR and assessed the impact of CMR on patient management.

Results:
Table 1 lists the subjects' characteristics and procedural information of all studies. CMR was used in a large variety of indications, with inflammatory (29.4 %) and ischemic (26.2 %) heart disease as the most frequent. All moderate adverse events (0.5 %) were associated with stress medication or contrast media. In the subgroup analysis, CMR ruled out a suspected disease in 63.1%, confirmed a suspected or known disease in 27.8% or detected an unexpected new pathology in 7.2 %. The clinical question was answered completely or partial in 88.4 % and 11.2 %, respectively. CMR reduced the amount of ordered diagnostic tests by 65.7 % and led to an altered diagnostic strategy in the individual patient in 92.4 %. Heart catheterization was cancelled in almost every third patient following CMR (11 / 36), and newly ordered after CMR in additional 6% (12 / 214). In 23.6 %, CMR led to a strategic change between in- or outpatient treatment.

Conclusions:
CMR is safe, robust and versatile. It influences the indication for hospital admission, the choice and extent of individual downstream diagnostic testing, and the determination of the final diagnosis.
Abstract 8987: Prostacyclin Reduction Upregulates Tissue Factor and Predisposes COX-2 Knockout Mice to Thrombosis
Authors: Barbieri Silvia S , Gianellini Sara , Amadio Patriza , Zacchi Elena , Howe Louise R , Weksler Babette B , Mussoni Luciana , Tremoli Elena
Published: April 2024

Selective inhibitors of cyclooxygenase-2 (COX-2) increase the risk of myocardial infarction and athero-thrombotic events, but the mechanisms responsible for these effects are not fully understood. To assess the role of COX-2 in arterial thrombosis, a well-studied model of ferric chloride-induced carotid artery injury was applied to COX-2 knockout (COX-2KO) mice and data were compared with those obtained in wild-type (WT) mice. We found that thrombus formation was significantly greater in COX-2-null compared to WT mice. We then explored the role of platelets in this model. Platelets isolated from blood of COX-2KO mice showed enhanced aggregation responses to collagen and ADP together with greater thromboxane production than WT platelets. Interestingly, cyclooxygenase-1 and thromboxane synthase protein levels were similar in both animal groups. In cross-transfusion experiments, we found that platelets from COX-2KO mice behaved similarly to WT platelets in terms of in vivo thrombus formation. Importantly, we observed that the activity of tissue factor (TF), initiator of blood coagulation, was elevated both in concentrated microparticles derived from plasma and in leukocytes or in the carotid arteries of COX-2KO mice. Furthermore, the arterial wall of COX-2KO mice expressed higher levels of TF mRNA compared to WT animals, and these levels correlated with both reduced prostacyclin synthase mRNA levels and decreased prostacyclin production. In addition, treatment with CA10441, a prostacyclin receptor (IP) antagonist, increased TF activity in WT mice. Conversely, carbaprostacyclin, a stable IP agonist, reduced TF activity in COX-2KO mice. Overall, these findings reveal for the first time that the propensity to thrombosis observed in association with COX-2 inhibition is consequent to the impairment in the generation of prostacyclin by vascular endothelium, which in turn results in increased TF expression and activity.
Abstract 90: Circadian Variation in Out-of-Hospital Cardiac Arrests in a Nationwide Japanese Patient Population: A Difference Between Survivors and Nonsurvivors
Authors: Tsukada Takehiro , Ikeda Takanori , Mera Hisaaki , Yoshino Hideaki , Matsuda Takeaki , Yamaguchi Yoshihiro , Yonemoto Naohiro , Nonogi Hiroshi , Kimura Takeshi , Nagao Ken
Published: April 2024

Background:
It is well known that acute cardiovascular events and sudden cardiac death occur most frequently in the morning. This study aimed to determine whether there is a difference of circadian variation between survivors and nonsurvivors in the presentation of all-Japan cohort of patients with out-of-hospital cardiac arrests.

Methods:
We referred a database of a prospective, nationwide, population-based registry of out-of-hospital cardiac arrests that is conducted by the Fire and Disaster Management Agency of Japan between April 2006 and December 2009. The records are based on the standardized Utstein style. Patients who had sudden collapse witnessed by family members, friends, or bystanders of the public and who received cardiopulmonary resuscitation (CPR) in accordance with protocol of guideline 2005 were enrolled. We categorized patients into two groups: survivors for 30 days and more after cardiac arrest and nonsurvivors who died of cardiac arrest. We assessed the incidence of the cardiac arrest as hourly data (i.e., circadian variation).

Results:
A total of 411,562 patients were registered nationwide and 92,492 patients had cardiogenic out-of-hospital cardiac arrests witnessed by bystanders. Of the patients, 1,817 patients were excluded because exact time of collapse or certain age was not determined. Finally, 90,675 patients were enrolled for assessment. Of the patients, 9,681 patients (10.7%) were successfully resuscitated and survived and 80,994 patients (89.3%) died. Survivors had a large single circadian rhythm in the morning (8:00-9:00). Men had more apparent circadian variation than women in the survivors. In contrast, nonsurvivors had a circadian rhythm with two zeniths in the morning (8:00-9:00) and evening (18:00-19:00). No difference of gender was found in the nonsurvivors.

Conclusions:
There exists a different circadian variation of out-of-hospital cardiac arrests between survivors and nonsurvivors, particularly in men. In emergency cardiovascular care, the management in the evening is also important to improve the survival rate.
Abstract 9013: Myeloperoxidase is Critically Linked to the Development of Diastolic Heart Failure Following Pressure Overload
Authors: Deuschl Florian , Klinke Anna , Friedrichs Kai , Weinberger Florian , Lau Denise , Rudolph Volker , Rudolph Tanja , Geerts Birgit , Geisler Anne , Adam Matti , Zeller Tanja , Ojeda-Echevarria Francisco , Blankenberg Stefan , Eschenhagen Thomas , Baldus Stephan
Published: April 2024

Background:
Plasma levels of the leukocyte derived enzyme myeloperoxidase (MPO) are elevated in patients with heart failure (HF). We have shown previously that MPO promotes vasoconstriction, leukocyte recruitment and myocardial fibrosis - suggesting that MPO may be mechanistically linked to the pathophysiology of HF. Here we assessed whether MPO is modulating systolic and diastolic myocardial performance in a pressure overload model.

Methods and Results:
C57Bl/6-Wild-type (WT) and MPO-deficient (Mpo-/-) mice were subjected to mild transverse aortic constriction (TAC, Δp max: 50 ±10 mmHg). After 6 weeks, echocardiography revealed significantly reduced left ventricular (LV) ejection fraction (EF) in TAC-treated animals as compared to sham operated controls. In vivo hemodynamic assessment of left ventricular function using pressure-volume loops revealed an upward shift of enddiastolic pressure volume relation (EDPVR) in both TAC groups as compared to sham animals (p< 0.001). Of note WT-TAC revealed a significantly higher upward shift than Mpo-/- TAC (3.18 ±0.74 mmHg/µl vs. 1.17 ±0.17 mmHg/µl; n=8; p=0.02). Enddiastolic pressure was higher in WT-TAC as compared to Mpo-/- TAC (6.23 ±1.88 mmHg vs. 2.82 ±0.33 mmHg; n=8; p = 0.05). In WT-TAC heart weight and lung weight normalized on tibia length was significantly increased as compared to Mpo-/- TAC mice (15.21 ±0.67 mg/mm vs. 12.65 ±0.79 mg/mm; n=10; p<0.02; respectively 20.15 ±2.65 mg/mm vs. 10.78 ±1.00 mg/mm; n=10; p=0.006). mRNA of matrix metalloproteinase 9 was increased in WT-TAC mice compared to Mpo-/- TAC (2.58 ±0,84 vs. 0,95 ±0,15, n=11; p=0,06). In accordance with this experimental observations MPO plasma levels of 5,000 patients enrolled in the Gutenberg Health Study were associated with left ventricular hypertrophy (median (IQR): 310pmol/l (240/384) vs. 297pmol/l (237/369); p=0.034).

Conclusions:
The current data reveal that MPO is critically linked to impaired diastolic compliance during pressure overload. This suggests that leukocyte activation in general and MPO release in particular is not only a prognostic marker in heart failure but evolves as an important pathophysiological link and potential pharmacological target in this disease.
Abstract 9107: Pim-1 Kinase Increases Non-Random Chromatid Segregation in Cardiac Progenitor Cells
Authors: Sundararaman Balaji , Avitabile Daniele , Konstandin Mathias , Gude Natalie , Cottage Christopher T , Sussman Mark A
Published: April 2024

Rationale:
A cell has DNA strands of different replication ages because DNA replication is semi-conservative. Double-stranded DNA molecules possess one DNA strand that is one generation older than the other. Non-sister chromatids containing newly synthesized DNA and ‘old’ DNA strands are non-randomly partitioned between mother and daughter cells. Stem cells are presumed to non-randomly segregate chromatids to determine cell fate of daughter cells, although experimental evidence is lacking. Resident cardiac progenitor cells (CPC) present in the adult heart have been used for cell-based treatment of myocardial damage but the factors determining the stemness and lineage commitment of these cells are poorly understood. Cardio protective kinase Pim-1 increases asymmetric cell division in vivo, proliferation and commitment of CPCs after adaptive transfer in pathological injury model but its role in non-random segregation is unknown.

Objective:
Establish role of Pim-1 on non-random chromatid segregation and correlate with daughter cell fate determination in cardiac progenitor cells.

Methods and Results:
Non-random segregation was tracked by incorporation of bromodeoxyuridine (BrdU), a thymidine analogue labeling newly synthesized DNA strands. For label retention assay, cells were labeled for many generations and blocked in second cytokinesis during chase in BrdU free media. Two daughter nuclei within a cell body had different BrdU intensity. Density measurements showed that 4.6% of CPCs outside the 95% confidence interval for equal BrdU intensity between daughter nuclei indicating non-random segregation of BrdU labeled chromatids. Genetic engineering of CPCs to express Pim-1 kinase greatly enhanced non-random segregation (12.6% vs 5.6% GFP expressing cells). Non-random segregation was further confirmed by asymmetric BrdU segregation in anaphase cells from second mitotic shake off during chase.

Conclusions:
CPCs non-randomly segregate chromatids as demonstrated by selective segregation of BrdU labeled chromatids which is twofold increased in cells overexpressing Pim-1 kinase.

Future Directions:
The relationship of non-random chromatid segregation to identity of stem cells fate remains to be determined.