bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9673: Mesenchymal Stem Cells Modulate Inflammatory Responses in Murine Heart by Inhibition of the TNF System
Authors: Martire Alessandra , Belema Bedada Fikru , Uchida Shizuka , Poeling Joechen , Wietelmann Astrid , Krueger Markus , Kubin Thomas , Szibor Marten , Warnecke Henning , Braun Thomas
Published: April 2024

Mesenchymal stem cells have been used to treat numerous different clinical conditions, although the mechanisms by which pathogenetic processes are affected are still poorly understood. We have recently demonstrated the homing of murine long-term renewing adult bone marrow-derived multipotent mesenchymal stem cells (BM-MASCs) to diseased tissues and postulated that BM-MASCs might modulate inflammatory reactions. We here show that administration of BM-MASCs modulates adverse cardiac remodeling inhibiting the TNF system in a transgenic mouse model of cardiac-specific expression of MCP-1-induced inflammatory dilative cardiomyopathy. Four-months old MCP-1 mice were analyzed before and after 4-week administration of MASCs, Etanercept (Amgen), Pentoxifylline (Sanofi-Aventis), or NaCl (sham). MRI, Histological (Masson's thricromic), immunofluorescent (CD45 and Collagen VI antibodies, and Lectin from Bandeiraera Simplicifolia), Western blot (sTNFR-I, TNF-β, Phosphorylated-nuclear factor k (NFkBp65), and Collagen VI), SILAC-base mass spectrometry, cytokine arrays, Mission shRNA system (NM_011609.2-1538s1c1, NM_011609.2-996s1c1, and NM_011609.2-1652s1c1), and survival analysis were performed. Our results show that administration of BM-MASCs to MCP-1 mice significantly reduced cardiac accumulation of infiltrating cells and fibrosis, improved capillary density and function, and extended lifespan. Comprehensive analysis of the secretome of MASCs unveiled the release of soluble tumor necrosis factor receptor I (sTNFR-I), which significantly suppressed activation of the NFκBp65 signaling pathway in MCP-1 hearts in vivo. Administration of TNFRI-knock-down BM-MASCs yielded no positive effects demonstrating the requirement of sTNFR-I for BM-MASCs-mediated improvement of inflammatory dilative cardiomyopathy. Substitution of BM-MASCs by recombinant soluble TNFR recapitulated several effects of BM-MASCs including lifespan expansion. We conclude that BM-MASCs suppress local inflammatory processes by release of numerous signaling molecules including sTNFR-I, which makes them useful tools for various clinical applications.
Abstract 9677: Fatty Acid-Binding Protein 4 is a Novel Predictor of Cardiovascular Events in End-Stage Renal Disease
Authors: Furuhashi Masato , Hayashi Manabu , Nishitani Takahiro , Ishimura Shutaro , Ota Hideki , Koyama Masayuki , Okazaki Yusuke , Tanaka Marenao , Yoshida Hideaki , Miura Tetsuji
Published: April 2024

[Background]
Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages and plays important roles in the regulation of insulin sensitivity and the development of atherosclerosis. Recently, FABP4 was found to be secreted from adipocytes. However, little is known about the impact of serum FABP4 concentrations on development of cardiovascular diseases. Here we tested the hypothesis that serum FABP level predicts prognosis of patients with end-stage renal disease (ESRD), a group at high risk for atherosclerosis-associated morbidity and mortality.

[Methods & Results]
Biochemical markers including FABP4 were determined in 61 ESRD patients on chronic hemodialysis (HD) and 61 age-, gender- and body mass index (BMI)-matched controls. Serum FABP4 level in females (404.2 ± 30.5 ng/ml) was significantly higher than that in males (315.8 ± 30.0 ng/ml), and the levels in ESRD patients were approximately 20-times higher than those in controls. FABP4 level was decreased by 57.2% after HD and was positively correlated with blood pressure, BMI, and levels of lipids and insulin. Multiple regression analysis indicated that HD duration, BMI, and triglycerides level were independent determinants of serum FABP4 level. Kaplan-Meier survival curves showed that ESRD patients with higher FABP4 levels had higher cardiovascular mortality during the 7-year follow-up period. Cox proportional hazard regression analysis revealed that logarithmically transformed FABP4 level was an independent predictor of cardiovascular death adjusted for age, gender, and HD duration (hazard ratio, 4.89; 95% CI, 1.33-20.23).

[Conclusions]
Present findings suggest that FABP4 level, being related to adiposity and metabolic disorders, is a novel predictor of cardiovascular mortality in ESRD.
Abstract 9678: Long Term Results of Aortic Valve and Root Replacement in 1045 Patients Over Thirty-Three Years. A Single-Centre Experience
Authors: Pacini Davide , Pantaleo Antonio , Berretta Paolo , Di Marco Luca , Leone Alessandro , Pilato Emanuele , Marinelli Giuseppe , Di Bartolomeo Roberto
Published: April 2024

Introduction.
Aortic root replacement using composite graft represents the treatment of choice for a large variety of aortic root diseases. The aim of the current study is to evaluate the long-term results of this procedure.

Methods.
Between 1978 and 2010, 1045 patients aged 58.7±13.6 years (834 males) underwent aortic root composite graft replacement: 95 (9.1%) underwent Bentall operation, 926 (88.6%) were operated following the “button technique”, whereas 24 (2.3%) underwent Cabrol technique. Six-hundred thirty five patients (62.3%) had annuloaortic ectasia and 162 (15.5%) aortic dissection.

Results.
Overall in-hospital mortality was 5.3% (55/1045). Independent risk factors for in-hospital mortality at logistic regression analysis were age (p=0.051,OR=3.2), preoperative NYHA class III-IV (p=0.015,OR=5.9), aortic dissection (p=0.059,OR=3.6) and Cabrol technique (p=0.065,OR=2.2). Overall actuarial survival at 5, 10, and 20 years was 84.1%±1.3%, 65.5%±2.6%, and 40.7%±4.6%, respectively. Multivariate analysis revealed preoperative EF<50% (p=0.057, OR=3.1), postoperative neurologic complications (p=0.013, OR=6.1) and postoperative pulmonary complications (p=0.046, OR=3.9) to be significant predictors of late death. Freedom from thromboembolism, freedom from bleeding complications, and freedom from endocarditis was 93.7%±2.6%, 90.3%±3.1%, and 98.4%±1% at 20 years, respectively. Freedom from aortic reoperation was 91.8%±2.1% at 20 years, and was significantly lower in patients with aortic dissection.

Conclusions.
Aortic root replacement for aortic root aneurysms can be performed with low morbidity and mortality and with satisfactory long-term results. Few late serious complications were related to the need for long-term anticoagulation or a prosthetic valve. Reoperation on the proximal or in the distal aorta was most commonly performed in patients with aortic dissection.
Abstract 9819: Comparison of Optical Coherence Tomography and Histopathology Findings Following Paclitaxel-Coating Balloon in Porcine In-Stent Stenosis Model
Authors: Sumida Arihiro , Nikanorov Alexander , Shinke Toshiro , Li Jinsheng , Singh Jaipal , King Spencer , Chronos Nicolas , Hou Dongming
Published: April 2024

Background:
Paclitaxel-Coating balloon (PCB) has shown efficacy for treatment of coronary artery disease. Optical coherence tomography (OCT) is a promising endovascular imaging devise and has been reported to have a high correlation with histomorphometric measurement. However, the association of in-stent stenosis (ISR) by OCT and histopathology response is still not fully addressed. The current study was designed to compare the OCT and histopathological findings following PCB treatment in a porcine ISR model.

Materials and Methods:
Thirty-two coronary arteries (LAD: n=12, LCX: n=11, RCA: n=9) of 24 Yorkshire pigs were assigned to two (2) groups randomly. PCB (SeQuent, length 20mm, n=16) or non-coating balloon (NCB, length 20mm n=16) were inflated for 60 seconds with B:A 1.2:1 followed by BMS (length 12mm) implantation (S/A 1.5:1) within the target region. At 28 days, animals underwent OCT and histopathology evaluation.

Results:
There were no significant differences between groups among parameters measured by OCT. The thickness of neointimal hyperplasia on stent strut and the percent of ISR were 585 ± 277 μ m, 46.8 ± 19.0 % for PCB, and 661 ± 237 μ m, 52.4 ± 15.3 % for NCB (p=NS, respectively). However, inflammation (PEB: 3.40 ± 0.84, NCB: 2.27 ± 1.18, p=0.003) and fibrin deposition scores (PCB: 2.31 ± 0.93, NCB: 0.81 ± 0.86, p<0.001) were significantly higher in PCB compared to NCB. The OCT ISR% was positively correlated with inflammation score (PCB: r=0.62, and NCB: r=0.85; p<0.05 respectively). Interestingly, fibrin deposition score only in PCB was negatively correlated with the OCT ISR% (r=-0.68, p=0.005). OCT also showed an uncovered (33.3%) and insufficient non-uniformed neointima (13.3%) in PCB group (p=0.008 vs NCB).

Conclusions:
OCT can be used as a valuable imaging tool to evaluate vessel wall histopathological changes in vivo. The higher inflammation and fibrin deposition scores in PCB may indicate a delayed healing response in the current experimental setting.
Abstract 9842: Bone Morphogenetic Protein-2 Decreases MicroRNA 30b-c to Promote Vascular Smooth Muscle Cell Calcification
Authors: Balderman Joshua A , Lee Hae-Young , Loscalzo Joseph , Leopold Jane A
Published: April 2024

Bone morphogenetic protein-2 (BMP2) initiates vascular smooth muscle cell (SMC) calcification by upregulating expression of the osteoblast transcription factor Runx2. MicroRNAs (miRs) are negative regulators of gene expression; however, the role of miRs in regulating Runx2 expression remains unknown. Accordingly, we treated human coronary artery SMC with BMP-2 (100 ng/ml), and confirmed a 13-fold (p<0.01) increase in Runx2 mRNA levels at 4 h and a 1.7-fold (p<0.02) increase in protein at 24 h. A miR microarray revealed that BMP2 decreased miR-30 family expression 5.1-fold (p<0.01), and real-time PCR verified this finding: BMP2 decreased expression of miR-30b by 4.4-fold (p<0.01) and miR-30c by 3.4-fold (p<0.01). Downregulation of miR-30b-c by transfection of SMC with anti-miR-30b-c increased Runx2 protein by 1.9-fold (p<0.01) or 3.0-fold (p<0.01), respectively. By contrast, forced expression of miR-30b-c by transfection with pre-miR-30b-c attenuated BMP2-induced expression of Runx2 (1 ± 0 vs. 0.6 ± 0.3 vs. 0.5 ± 0.2 arb units, p <0.02). Next, we cotransfected COS7 cells with a luciferase reporter plasmid containing the Runx2 3' untranslated region (UTR) and pre-miR-30b-c. In this assay system, forced expression of miR-30b-c decreased luminosity (1.0 ± 0 vs. 0.6 ± 0.1 vs. 0.6 ± 0.1 fl. units, p<0.04) indicating that miR-30b-c bind to the Runx2 3'-UTR to modulate expression. Downregulation of miR-30b-c also increased expression of the Runx2-dependent calcification protein osteocalcin (1.0 ± 0 vs. 1.7 ± 0.5 vs. 2.2 ± 0.4 arb. units, p<0.03). Von Kossa staining of SMC transfected with anti-miR-30b-c for 14 d revealed that SMC calcification was increased by 1.7-fold (p<0.03) or 1.8-fold (p<0.03) while forced expression of miR-30b-c prevented calcification (1.2 ± 0 vs. 0.9 ± 0.1 vs. 0.9 ± 0.1 arb units, p<0.01). In BMP2-treated SMC, downregulation of miR-30b or miR-30c increased calcification 1.7± 0.3-fold (p<0.03) or 2.3 ± 0.7-fold (p<0.03) while forced expression of miR-30b-c prevented calcification (0.9 ± 0.1 vs. 1.0 ± 0.1 vs. 1.0 ± 0.1 arb units, p<0.01). These data demonstrate that miR-30b-c regulate Runx2 expression to influence SMC mineralization, and suggest that strategies to regulate expression of these miRNA may limit vascular calcification.
Abstract 9851: Tenascin-C Deficiency Promotes Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function in Chronic Pressure-Overload
Authors: Song Lei , Wang Lai , Arias Ana , Chaux Aurelio , Shah Prediman K , Sharifi Behrooz G
Published: April 2024

Background:
Tenascin-C (TnC) is a matricellular protein that is generally expressed during embryogenesis and in pathological settings; however, little is known about the role of TnC in maladaptive LV remodeling in response to chronic pressure-induced hypertrophy.

Methods:
Aortic constriction was performed in TnC null mice and control wild type mice (all mice in C57BL6 background). The aorta between the celiac and superior mesenteric arteries was constricted by tying a silk ligature against a 28-gauge needle for to yield a~33% narrowing of the aortic luminal diameter when the needle is removed. The LV size and function was assessed by two-dimensional guided M-mode echocardiography. Aortic blood pressure proximal to the constriction site was calculated by adding the pressure gradient across the constriction (measured by pulse Doppler) to the post-constriction blood pressure measured in the tail using a special cuff. LV mass was measured after euthanizing the mice at one month and histology was used to estimate myocardial fibrosis.

Results:
Before aortic constriction, LV size, EF and shortening fraction were similar in TnC null and wild type control mice. One month after constriction, the LV end diastolic diameter was larger in TnC null compared to wild type control mice (4.6 ± 0.5 vs 3.7 ± 0.2; p<0.001), the LVEF was lower in TnC null compared to wild type control mice (47.3 ± 10.7 vs. 60.7 ± 3.8; p<0.001), the fractional LV shortening was lower in TnC null compared to wild type control mice (24.2 ± 5.9 vs. 31.9 ± 2.6; p<0.001), the heart weight in mg/gram of body weight was higher in TnC null compared to wild type control mice (6.9 ± 1 vs. 5.1 ± 0.1; p<0.05). Collagen staining revealed that LV fibrosis was abundant in TnC null mice whereas it was scant in wild type control mice. There were no significant differences in the calculated proximal aortic blood pressure, the pressure gradient across the constriction, or the tail blood pressure or total body weight between the two groups of mice.

Conclusions:
TnC gene deletion is associated with maladptive LV remodeling, reduced LV systolic function and increased LV fibrosis in response to chronic pressure overload identifying a potentially beneficial role for TnC in myocardial response to pressure overload.
Abstract 9868: Coronary Artery Calcium Predicts Coronary Heart Disease Events Even at the Extremes of Age: The Multi-Ethnic Study of Atherosclerosis
Authors: Tota-Maharaj Rajesh , Blaha Michael J , Blankstein Ron , Shaw Leslee J , Blumenthal Roger S , Budoff Matthew J , Nasir Khurram
Published: April 2024

CAC testing to refine risk prediction is utilized in intermediate-risk asymptomatic patients, largely excluding elderly and young patients who are typically classified as high- or low-risk due to the influence of age in risk-scoring algorithms. The clinical utility of CAC in predicting coronary heart disease (CHD) events in patients at extremes of age remains to be explored.

Methods:
The MESA cohort was followed up for a median of 5.8 years. The primary endpoint of CHD events was assessed in the following age groups: 45-54, 55-64, 65-74, and 75-84 years. Cox regression analysis was employed to determine the interplay of CAC and aging in predicting CHD events after adjusting for demographic factors, traditional risk factors, and medication use.

Results:
Of 6,809 participants, 278 (4%) CHD events were noted. The prevalence of CAC=0 was 75% in the 45-54 age group, decreasing progressively with increasing age (75-84 yr=19%, p<0.0001). Conversely, CAC >100 increased from 6% in the 45-54 age group to 51% in the elderly. After adjusting for age, demographic and cardiovascular risk factors, CAC>100 predicted a significantly increased CHD event rate compared to CAC=0 in both the young and elderly (45-54: HR 8.29 [95% CI 2.84-24.16], 75-84: HR 8.34 [95% CI 2.11-36.92]). Increasing age group was associated with a statistically significant increased risk of CHD events, compared to the 45-54 year old group, even after adjusting for risk factors and CAC (HR [95% CI], 55-64 yr: 1.71[1.06-2.74], 65-74 yr: 1.75 [1.10-2.79], 75-84 yr: 1.95 [1.17-3.25]).

Conclusions:
Greater CAC burden was associated with increased CHD events in all age groups, adding incremental prognostic value in both young and elderly patients. Young individuals with CAC>100 had a higher CHD event rate compared to older individuals with no CAC. Increasing age was independently associated with higher event rates, confirming that atherosclerotic burden cannot completely explain the association of aging with CHD events.
Abstract 9871: Utility of Electronic Health Records in Predicting 30-Day Readmission After Heart Failure Hospitalization
Authors: Schmidt Philip H , Kansal Preeti , Wozniak Gregory , Christensen Keri , Klein Liviu , Pang Peter S , Barsuk Jeffrey H , Williams Mark V , Kitt Stephanie , Sama Danny , Farmer Steven A , Gheorghiade Mihai , Bonow Robert O
Published: April 2024

Introduction:
Hospitalizations for heart failure (HF) represent a growing healthcare burden and are a major focus for quality improvement and payment reform. Prior studies have evaluated predictors of readmission after hospitalization for HF, but few have examined consecutive patients at a single medical center using electronic health records (EHRs).

Objectives:
(1) Determine predictors of 30 day readmission in patients with a HF discharge diagnosis and (2) evaluate relationship between 30 day readmission and 1 year mortality using the Social Security Death Index.

Methods:
We analyzed outcomes of 1,417 consecutive patients with a primary discharge diagnosis of HF for years 2008 and 2009 in an urban, tertiary-care hospital using a unique EHR system integrating inpatient and outpatient data. Outcomes included 30 day all-cause hospital readmissions and all-cause mortality from 30 days to 1 year.

Results:
The 30-day readmission rate was 24.8%. Factors associated with readmission included weight, BNP, creatinine, and BUN at both admission and discharge, as well as systolic blood pressure and ejection fraction (Table). Readmitted patients had higher BNP, creatinine, and BUN at the time of discharge compared to corresponding admission data in patients not readmitted (p <0.01). Age, gender, and length of stay (7.3±7.5 vs 7.3±7.6 days, respectively) did not differ between the 2 groups. Readmitted patients were less likely to have hypertension, but other comorbidities did not differ between the 2 groups. Readmission within 30 days was not associated with all-cause mortality at 30, 60, 90, 180 days or 1-year post-discharge.

Conclusion:
Patients with HF at risk for 30 day readmission are readily identified by EHR data during the index hospitalization. Real time utilization of EHRs provides potential to detect patients who may benefit most from targeted interventions at discharge to reduce rehospitalization. Short-term readmissions are not related to long-term mortality.
Abstract 9896: Reduction of Endoplasmic Reticulum Stress Prevent Neointima Formation After Vascular Injury
Authors: Ishimura Shutaro , Furuhashi Masato , Ota Hideki , Yamashita Tomohisa , Koyama Masayuki , Okazaki Yusuke , Tanaka Marenao , Mita Tomohiro , Fuseya Takahiro , Yoshida Hideaki , Miura Tetsuji
Published: April 2024

[Background]
Restenosis after percutaneous coronary intervention is still a major obstacle in treatment of coronary artery disease. The endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) is a predominant feature in pathological processes in several types of tissues. However, little is known about the link between ER stress and vascular diseases. In this study, we investigated involvement of ER stress in neointima hyperplasia after vascular injury.

[Methods & Results]
The femoral artery of 7-8-week male mice was subjected to wire-induced vascular injury. After 4 weeks, immunohistological analysis showed that ER stress markers, including phosphorylation of eukaryotic initiation factor 2α (eIF2α) and inositol-requiring enzyme-1 (IRE1), protein disulfide isomerase (PDI), glucose-regulated protein 94 (GRP94), and C/EBP homologous protein (CHOP) were up-regulated in hyperplastic neointima in injured regions. Treatment with 4-phenylbutyrate (PBA) and tauroursodeoxycholic acid (TUDCA), chemical chaperones, significantly reduced intima/media ratio by 46.6% and 70.9%, respectively, compared with the control. In the second series of experiments, the involvement of ER stress in cell proliferation was examined in human coronary artery smooth muscle cell (CASMC). Stimulation of CASMCs with platelet-derived growth factor (PDGF) led to activation of the UPR, which was indicated by a phosphorylation of IRE1 and eIF2α and an induction of GRP78 and PDI proteins, and the UPR was accompanied by phosphorylation of extracellular signal-regulated kinase (ERK). Elevation of mRNA levels of GRP94, GRP78, PDI, and spliced form of X-box binding protein 1 after PDGF treatment was confirmed by quantitative RT-PCR. PBA significantly suppressed PDGF-induced elevation of protein and mRNA levels of the ER stress markers and inhibited proliferation of CASMC by 62.9%.

[Conclusions]
Our findings suggest that ER stress plays a significant role of neointima hyperplasia after vascular injury and that reduction of ER stress might be a novel strategy against post-angioplasty restenosis.
Abstract 9913: Different Impacts of Body Fat Composition and Computed-Tomography-Determined Visceral Fat on Left Ventricular Mass, Geometry and Left Atrial Structural Alteration
Authors: Lai Yau-Huei , Yun Chun-Ho , Wu Yih-Jer , Kuo Jen-Yuan , Yeh Hung-I , Tsai Cheng-Ho , Hung Chung-Lieh
Published: April 2024

Background
The adverse effects of body fat distribution on left ventricular (LV) mass and geometry has recently been recognized. Excessive visceral fat deposition, specifically those surrounding the heart and central aorta, was associated with adverse cardiovascular events. We sought to examine the impact of body fat composition and visceral adipose tissue on cardiac structure and geometry.

Methods
We studied 1,063 subjects (age: 49.5±10.5, 39.4% female) without angina or heart failure symptoms. Cardiac structures and LV geometry parameters including LV mass index (LVMI), relative wall thickness (RWT) and mass-to-volume ratio were all determined by echocardiography. Body fat composition (both fat and fat-free mass) was assessed by Tanita foot-to-foot bioimpedance analysis. A subgroup of 361 subjects further underwent multidetector computed tomography (MDCT) for three-dimensional, volume-based epicardial adipose tissue (EAT) and thoracic peri-aortic adipose tissue (TAT) quantification.

Results
Both fat and fat-free mass were positively related to LV mass (β coef: 0.42 & 0.31, both p<0.001) after multivariate adjustment for age, gender, blood pressure and medical histories. However, only fat mass (β coef: 0.15, p<0.001) contributed independently to concentric remodeling (RWT>0.42). For each standard-deviation increase of EAT and TAT volume, there was an observed increase of LVMI (β coef: 0.14 & 0.15, both p<0.05) after multivariate adjustment. In addition, left atrial dimension was also positively related to both EAT and TAT even after adjusting for severity of mitral regurgitation (β coef: 0.16 & 0.12, both p<0.05).

Conclusions
While both fat and fat-free mass exert their independent effect on ventricular mass increase, only fat mass had independent impact on ventricular geometry. Our data also suggested that epicardial adipose tissue may further impact LA dimension, possibly mediated by impeding ventricular diastolic filling.
Abstract 9918: The ATP-Binding Cassette Transporter ABCG2 Protects Against Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure by Promoting Angiogenesis and Antioxidant Response
Authors: Higashikuni Yasutomi , Nagai Ryozo , Sata Masataka
Published: April 2024

Background:
ATP-binding cassette transporter subfamily G member 2 (ABCG2), originally identified in cancer cells, was shown to be expressed in various normal organs, including the heart, and was suggested to regulate several tissue defense mechanisms via modulation of survival and function of ABCG2-expressing cells. However, its role in pressure overload-induced cardiac hypertrophy remains unknown.

Methods and Results:
Immunohistochemistry demonstrated that ABCG2 was mainly expressed in endothelial cells of microvessels in the heart. Pressure overload was induced in 8- to 12-week-old wild-type (WT) and Abcg2 knock-out (KO) mice by transverse aortic constriction (TAC). In the absence of pressure overload, cardiac function and morphology did not differ between WT and KO mice. In WT mice, ABCG2 mRNA expression was increased about 3 times at 4 days and 28 days after TAC compared with that before surgery. At 28 days after TAC, mortality due to heart failure was higher in KO mice than in WT mice (KO mice, 53.2%, n=62, versus WT mice, 21.2%, n=33, p=0.002). Most of dead KO mice died at 4 days after TAC. KO mice showed exaggerated concentric hypertrophy at 4 days after TAC, and exacerbated ventricular remodeling and impaired systolic function at 28 days after TAC compared with WT mice. At 4 days after TAC, impaired angiogenesis and exaggerated oxidative stress in myocardium were found in KO mice compared with those in WT mice, although expression levels of angiogenesis-related and antioxidant genes were comparable or higher in KO mice than in WT mice. In vitro experiments demonstrated that inhibition of ABCG2 led to impaired survival of human microvascular endothelial cells from the heart (HMVEC-Cs) under oxidative stress. In addition, ABCG2 inhibition resulted in impaired migration and tube formation of HMVEC-Cs even under normal condition. Moreover, ABCG2 regulated extracellular concentrations of glutathione, an important endogenous antioxidant, in HMVEC-Cs under external stimuli.

Conclusions:
ABCG2 protects against pressure overload-induced cardiac hypertrophy and subsequent heart failure by promoting angiogenesis and antioxidant response. ABCG2 may be of interest for a therapeutic target to improve clinical outcomes of hypertrophic heart disease.
Abstract 9923: Circulating Pregnancy-Associated Plasma Protein Levels Reflect Plaque Instability and Predict the No-Reflow Phenomenon After Percutaneous Coronary Intervention
Authors: Daidoji Hyuma , Takahashi Hiroki , Otaki Yoichiro , Funayama Akira , Tamura Harutoshi , Arimoto Takanori , Shishido Tetsuro , Miyashita Takehiko , Miyamoto Takuya , Watanabe Tetsu , Kubota Isao
Published: April 2024

Background and Aims
Because coronary no-reflow phenomenon during percutaneous coronary intervention (PCI) is associated with a poor prognosis, it is clinically important to stratify high risk coronary no-reflow patients. Previous study reported that plasma pregnancy-associated plasma protein (PAPP-A) level was a marker of adverse outcome such as cardiac death and myocardial infarction in both acute coronary syndrome (ACS) and non-ACS patients. In the present study, we examined whether serum PAPP-A level could predict incidence of coronary no-reflow during PCI.

Results
Consecutive 85 patients (ACS, n=37; non-ACS, n=48; mean age 69 ± 11 years old) who were underwent PCI with integrated backscatter intravascular ultrasound (IB-IVUS) were prospectively enrolled. No-reflow, including transient filter no-reflow by using distal protection devices, was observed in 18 (21%) patients. Plasma PAPP-A levels were significantly higher in no-reflow patients compared with normal-reflow patients (8.25 ± 2.28 vs. 6.27 ± 1.54 ng/ml, P<0.001). To predict coronary no-reflow, a receiver operating characteristic (ROC) analysis determined a cut-off plasma PAPP-A value as 7.68 ng/ml (sensitivity of 62%, specificity of 82%, area under curve 0.76). The multivariate logistic regression analysis showed that plasma PAPP-A was an independent predictor of the no-reflow phenomenon (odds ratio 2.27; 95% confidence interval, 1.123-4.602; P = 0.023). Since plasma PAPP-A levels were not correlated (r=0.009, p=0.94) with culprit plaque percentage of lipid volume analyzed by IB-IVUS, they might be associated with not lipid plaque volume but plaque instability.

Conclusion
Plasma PAPP-A levels is a useful biomarker to stratify high risk coronary no-reflow patients during PCI. Plasma PAPP-A cut-off values determined by present study could help our approach for predicting high risk coronary no-reflow patients.
Abstract 9926: Molecular Imaging of the Pro-angiogenic Paracrine Effects of Stem Cell Therapy
Authors: Ryu Jae Choon , Yue Qi , Carr Chard , Belcik Todd , Xie Aris , Davidson Brian , Zhao Yan , Woda Juliana M , Ting Anthony E , Lindner Jonathan R
Published: April 2024

Background:
Pro-angiogenic stem cells are a promising therapy for patients with severe coronary or peripheral vascular disease. Mechanisms by which cell therapy promotes vascular remodeling remain unclear. We applied contrast-enhanced ultrasound (CEU) molecular imaging to test whether cell therapy acts in a paracrine fashion by promoting recruitment of pro-angiogenic (CX3CR-1
hi
) monocytes.

Methods:
Unilateral hindlimb ischemia was produced in 52 mice by iliac artery ligation. One day later, the proximal hindlimb received either: (1) IM injection of 1×10
6
multipotent adult progenitor cells (MAPC), (2) sham saline injection, or (3) no therapy. At Day3, 7, and 21 CEU perfusion imaging and molecular imaging of CX3CR-1 and P-selectin were performed. In 8 separate mice, intravital microscopy of TNF-a-treated cremaster muscle was performed 3 days after injection of either 5×10
5
MAPCs or saline.

Results:
Arterial ligation resulted in a 70% reduction in limb muscle blood flow to 0.20±0.06 ml/min/g. MAPC therapy produced a more rapid and complete recovery of flow (0.61±0.06 ml/min/g at day 21, ≈25% higher than both control groups, p<0.05). Signal for CX3CR-1 was significantly (p<0.05) higher vs control groups at all 3 study intervals (Figure),corroborated by a marked increase in tissue monocytes on Mac-2 immunohistology. P-selectin signal was also significantly higher in the MAPC-treated mice at days 3 and 7 (Figure). Intravital microscopy which showed that MAPCs migrated to a perivascular location and produced a 50% increase in leukocyte rolling flux fraction.

Conclusions:
In chronic limb ischemia, MAPCs migrate to a perivascular location and promote the sustained recruitment of pro-angiogenic monocytes, in part through effects on endothelial adhesion molecule expression. These results suggest that cell therapy can act to promote vascular remodeling through inflammatory pathways
Abstract 18243: Transplantation of Mesenchymal Cells Rejuvenated by Delivery of Telomerase and Myocardin Genes Promotes Revascularization and Tissue Repair in Ischemic Hindlimbs of Apolipoprotein-e-null Mice
Authors: Madonna Rosalinda , Gao Shanshan , Gao Song , Shelat Harnath S , De Caterina Raffaele , Willerson James T , Geng Yong-Jian
Published: April 2024

Background and Objective:
In adult bone marrow and other tissues the number and function of stem cells decline with aging. Myocardin (MyC) and telomerase (TeM), two nuclear proteins, may synergize to prevent senescence and to promote cardiovascular myogenesis. This study analyzed the impact of enhanced expression of MyC and TeM on survival, growth, and differentiation of mesenchymal stem cells (MSC) from old bone marrow and adipose tissues, as well as the therapeutic efficacy of transplantation of TeM
+
/McC
+
MSCs in murine hindlimbs with ischemic injury.

Methods and Results:
MSCs from adipose or bone marrow tissues of young (one month) and old (12 months old) male C57BL/6J and apolipoprotein E deficient (ApoE
−/−
) mice were efficiently transduced or co-transduced with the 3
rd
generation lentiviral vectors carrying the cDNAs coding for TeM-YFP (yellow fluorescence protein) or MyC-V5 epitope fusion proteins. Transduction with TeM, and to a less extent, MyC, but not empty vectors (mock), elevated MSC viability and BrdU uptake (p<0.05 vs mock controls, at flow cytometry). Colony formation increased in the transduced cells, while apoptosis in response to Fas stimulation was inhibited (Table). Endogenous MyC, cardiac and smooth muscle α-actin occurred in the cells with MyC/TeM cDNA delivery (at immunoblotting). Doppler ultrasound imaging and immunohistochemistry showed marked improvement of blood flow (Figure A, B) and arteriogenesis (Figure C) in the ischemic hindlimbs of ApoE
−/−
mice transplanted with the TeM
+
/MyC
+
transduced MSCs.

Conclusions:
The simultaneous delivery of the TeM and MyC genes resuscitates MSCs from old adipose and bone marrow tissues by increasing their capacity of survival, proliferation, and differentiation. TeM
+
/MyC
+
MSCs possess the potential of repairing ischemic tissues and, when transplanted into the ischemic hindlimb, improve revascularization.
Abstract 18254: Provisional Side Branch Stenting for 1.1.1 Distal Left Main Percutaneous Coronary Intervention
Authors: van Rothem Jérome , Lefevre Thierry , Garot Philippe , Carrié Didier , Morice Marie-Claude , Louvard Yves
Published: April 2024

Objective:
To evaluate the impact of bifurcation characteristics on long-term clinical outcome after distal left main (LM) percutaneous coronary intervention (PCI) with a provisional side-branch (SB) stenting strategy.

Background:
Provisional SB stenting provides good results for patients with distal LM undergoing PCI. It is the preferred strategy in cases where a single ostium is involved (LAD or LCX). This strategy has never been specifically evaluated in more complex lesions involving the two side branches (medina 1.1.1).

Methods:
Individual data of patients with distal LM lesions included in the French Taxus, Friend, Lemax and large centers registries and treated with a provisional SB stenting strategy were analysed.

Results:
A total of 454 patients were included, 199 (43.8%) with a 1.1.1 bifurcation and 255 patients (56.2%) with any other type of bifurcation. Patients with a medina 1.1.1 had a higher Syntax score (28±10.2 vs. 21.9±8.7; p<0.0001) and were treated with a higher rate of SB stenting (45.7% vs. 14.5%; p<0.0001) compared to other lesion types. At multivariate logistic regression analysis, after adjustment for patient and procedure confounders, a medina class 1.1.1 emerged as a predictor of 36 months’ MACE (odd ratio: 2.332, 95% confidence interval 1.416 to 3.3841; p=0.001) and death (odd ratio: 3,689, 95% confidence interval 1.658 to 8.205).

Conclusion:
In this observational study, patients with Medina 1.1.1 LM lesions have worse baseline characteristics and clinical outcome compared to other lesion types. Even after adjustment for data confounders Medina 1.1.1 remained associated with a worse outcome suggesting that Medina 1.1.1 is by itself a risk factor.
Abstract 18278: The Prognostic Value Of WFDC2, a New Biomarker for Heart Failure
Authors: de Boer Rudolf A , Cao Qi , Postmus Douwe , Damman Kevin , Voors Adriaan A , Jaarsma Tiny , van Veldhuisen Dirk J , Hillege Hans L , Silljé Herman H
Published: April 2024

Aim
s:

Identification of plasma biomarkers that help to stratify heart failure (HF) patients may help to improve treatment. We investigated the prognostic value of WAP four-disulfide core domain protein 2 (WFDC2, also termed HE4), a biomarker not previously described in HF.

Methods:
Data of 567 patients participating in the Coordinating study evaluating outcomes of Advising and Counselling in Heart failure (COACH) study were analysed. Patients had been hospitalized for HF and were followed for 18 months. Several plasma biomarker levels were determined using an ELISA platform. The primary endpoint of this study was a composite of all-cause mortality and HF hospitalization.

Results:
Mean age was 71±11 years, 62% were males, mean LVEF was 33±14%, and mean eGFR was 54±20 mL/minute. WFDC2 was identified as a biomarker that showed strong correlation with HF severity, according to NYHA functional class and BNP levels (
P
< 0.001). WFDC2 also showed a strong positive correlation with GDF15 (
P
<0.001). In addition, WFDC2 levels correlated with kidney function (BUN, creatinine, and eGFR; all
P
<0.001). Cox regression analysis revealed that a doubling of WFDC2 levels was associated with a hazard ratio (HR) of 1.73 (1.53-1.95) for the primary outcome (
P
<0.001). After correction for age, gender, BNP and eGFR the HR was 1.46 (1.23-1.72) (
P
<0.001) and after additional adjustment for GDF15 the HR lowered to 1.30 (1.07-1.59) (
P
=0.009). The AUC in the ROC curve analysis increased from 0.7123 to 0.7375 when WFDC2 was included to the clinical model (
P
=0.068). The IDI and NRI metrics for reclassification showed highly significant improvements when WFDC2 was added to the clinical model (NRI=0.12,
P
<0.001) and this remained significant after inclusion of BNP to this model.

Conclusion:

WFDC2 plasma levels are correlated with markers of HF severity, show prognostic value, and improve risk assessment in HF.
Abstract 18332: Clinical Parameters Associated with the Development of the Coronary Collateral Circulation in Patients with a Chronic Total Occlusion
Authors: van der Hoeven Nina W , Teunissen Paul F , Delewi Ronak , Schirmer Stephan H , Traupe Tobias , van der Pouw-Kraan Tineke , Tijssen Jan P , Piek Jan J , Werner Gerard S , Seiler Christian , van Royen Niels
Published: April 2024

A well-developed collateral circulation provides a survival benefit in patients with obstructive coronary artery disease. Studies aiming to detect clinical parameters associated with collateral circulation show controversial results and have only been assessed in studies using angiographic assessment of the collateral circulation and mainly in patients with non-occlusive lesions. Here we assess the correlation of clinical parameters with intracoronary derived collateral flow index (CFI) a unique group of patients with a chronic total occlusion (CTO) in which was measured directly upon opening of the CTO. Data from 295 patients (Bern, Switzerland, Amsterdam, the Netherlands and Jena, Germany) were pooled. Clinical parameters and lab values were collected before the procedure. CFI was calculated from the occlusive pressure distal from the coronary lesion (Pd), the aortic pressure (Pao) and central venous pressure (CVP). Multivariate analysis was performed to assess the correlation between collateral formation and clinical parameters. The mean CFI was 0.39 ± 0.14. After multivariate analysis, β-blockers, hypertension and duration of AP were positively associated with a well-developed collateral circulation (respectively B=0.07, SE=0.03, p=0.02, B=0.040, SE=0.02, p=0.042 and B=0.001, SE=0.000, p=0.02). Furthermore, high serum leukocytes, prior MI and high diastolic blood pressure were negatively associated with a well-developed collateral circulation (respectively B=-0.01, SE=0.005, p=0.03, B=-0.04, SE=0.02, p=0.03 and B=-0.002, SE=0.001, p=0.011). In a unique cohort of CTO patients we show that high serum leukocytes and high diastolic blood pressure are associated with a poorly developed collateral circulation. Interestingly, the use of β-blockers is positively associated with a well developed collateral circulation, shedding new light on the potential mode of action of this drug in patients with angina pectoris.
Abstract 18348: Total Mast Cell Numbers in Human Carotid Atherosclerotic Plaques and Tryptase Plasma Levels are Predictive for Future Cardiovascular Events
Authors: Willems Sanne , Vink Aryan , Quax Paul , de Borst Gert-Jan , de Vries Jean-Paul , van de Weg Sander M , Moll Frans L , de Kleijn Dominique P , Hoefer Imo E , Pasterkamp Gerard
Published: April 2024

Mast cells (MCs) are inflammatory cells known to contribute to the pathogenesis of atherosclerotic disease. Experimental studies have revealed that MCs might be involved in the progression of atherosclerosis by inducing intraplaque neovascularization.

OBJECTIVE:
This study was designed to assess total MC numbers and relate the score to neovascularization in human atherosclerotic plaques. In addition we related the presence of plaque MCs with the occurrence of adverse cardiovascular events during follow-up.

METHODS AND RESULTS:
In the current study atherosclerotic plaques of 270 patients suffering from carotid artery stenosis, were stained for the presence of MCs (MC tryptase), macrophages (CD68), neutrophils (CD66) and microvessels (CD34). Furthermore, during a follow-up of 3 years, cardiovascular related endpoints were assessed in all patients. Counting of mast cells revealed a surprising high number of MCs that were present in plaques (165 ± 10 MC per plaque). We equally divided the patient cohort into a group with low (n=126) and high (n=127) total MC numbers. High MC numbers were associated with high microvessel density 6,0 [4,3-9,0] versus 10,7 [6,5-14,2] vessels per hotspot (P<0.001). Patients with high plaque MC numbers showed significantly more cardiovascular events during follow up (35 [28%] versus 54 [43%] events (P<0.05)). Macrophage and neutrophil presence did not show this association with the occurrence of cardiovascular events. In addition, in 80 patients (1:1 event versus no event) MC tryptase and chymase have been measured in plasma. Patients with high plasma tryptase showed significantly more cardiovascular events (11 [28%] versus 24 [60%] events (P<0.01)). Plasma chymase levels did not show predictive value in our cohort.

CONCLUSIONS:
MCs are highly prevalent in carotid atherosclerotic lesions and associated with plaque neovessel density. Total intraplaque MC numbers and MC plasma tryptase levels are predictive for future cardiovascular events. These data support the view that MCs could play an important role in progression of atherosclerotic disease.
Abstract 18398: Long-term Surgical Outcome of Mitral Valve Repair for Degenerative Mitral Regurgitation with Chronic Atrial Fibrillation: The Impact of Maze Procedure on Long-term Survival and Cardiac Function
Authors: Murashita Takashi , Okada Yukikatsu , Fukunaga Naoto , Konishi Yasunobu , Koyama Tadaaki
Published: April 2024

Introduction: It is unclear whether maze procedure for atrial fibrillation (AF) would positively affect long-term survival, stroke and cardiac function. The aim of this study is to investigate the long-term surgical outcomes of mitral valve repair for degenerative mitral regurgitation with chronic AF and to determine the impact of concomitant maze procedures on long-term survival, cardiac events, stroke and cardiac function, comparing the outcomes of patients who underwent maze procedure and patients who did not undergo maze procedure.

Methods: We retrospectively investigated 159 patients who underwent mitral valve repair for degenerative mitral regurgitation with chronic AF between 1991 and 2010. The mean age was 63.1±10.5 years old. We started Cox-maze IV procedure in 2002. As a result, 65 patients underwent concomitant maze procedure (maze(+) group) and 94 patients did not undergo maze procedure (maze(-) group). Follow-up was completed in 156 patients (98.1%). The median follow-up duration was 7.6 years (max 21 years).

Results: There was one operative death (0.63%). The survival rate was significantly better in the maze(+) group than maze(-) group (5-year survival; 100% vs 85.2±4.0%, p<0.001). The actual freedom from atrial fibrillation in the maze(+) group was 86.4±4.5% at 1 year and 81.1±5.6% at 5 years. The actual freedom from cardiac events (cardiac death, cardiac-related re-admission and re-operation) was not different between the maze(+) group and maze(-) group (5-year freedom rate; 81.6±5.9% vs 88.9±3.5%, p=0.113). The rate of freedom from stroke was better in the maze(+) group than maze (-) group (5-year freedom rate; 92.1±3.9% vs 82.6±4.2%), though the difference of them was not statistically significant (Log-rank p=0.081). The latest NYHA functional class was worse in the patients who did not covert to sinus rhythm (AF group) than who did (SR group)(1.4±0.5 vs 1.1±0.3, p<0.001). The systolic and diastolic diameter of left ventricle gradually enlarged in AF group, which became significant difference during the long-term period.

Conclusions: Maze procedure can improve long-term survival, rate of freedom from stroke and cardiac function in the patients with degenerative mitral regurgitation with chronic atrial fibrillation.
Abstract 18427: Dysregulation of the miR143/145 Cluster and Mir133a During Progression of Vein Graft Neointima Formation
Authors: McDonald Robert A , White Katie M , Robertson Keith E , Hu Jia , Lu Ruifaug , George Sarah J , Wan Son , Baker Andrew H
Published: April 2024

Background:
The late failure of autologus human saphenous vein bypass grafts due to neointimal formation carries a major clinical burden. Therefore, identifying novel strategies to prevent neointimal formation is desirable. The principal cell type responsible for the neointimal lesion are smooth muscle cells (SMC), which are activated in response to injury leading to accelerated rates of proliferation and migration. MicroRNAs (miRs) are small non-coding RNAs that play an important role in modulating vascular phenotypes through regulation of gene expression.

Methods and results:
We undertook a microarray profiling approach to identify miRs which may be modulated during the development of neointimal lesions in the setting of vein graft disease. Profiling experiments revealed several miRs (miR133a, miR143 and miR145) which have been previously implicated in SMC de-differentiation and activation. These results were validated by q-PCR which demonstrated that miR-133a and miR-143 were down-regulated 4-5 fold and miR-145 was down regulated between 7-11 fold in the human saphenous vein ex vivo culture model and the porcine interposition model of vein graft neoinitma formation (both models, n=6). Treatment of isolated SMC harvested from human saphenous veins with TGF-β
1
(10ng/ml), to induce differentiation to a more quiescent and contractile phenotype, up-regulated miR-145 by 2.2+0.2 fold (n=3) but miR-133a levels were unaffected
.
A wounding assay was utilised to determine whether miR levels were elevated during SMC migration. Following quiescence, SMC were subjected to multiple scratch wounds and placed in serum to induce migration for a period of 16 hours. Quantification of miR-145 levels in migrating SMC revealed a 5-fold reduction in miR-145 levels following induction of migration.

Conclusion:
These results suggest that the miR-143/145 cluster plays an important role in the dedifferentiation of SMCs during neointimal formation following vein grafting. We also demonstrate that TGF-β
1,
an established modulator of SMC differentiation and proliferation, increased miR-143/145 levels suggesting that elevation of miR-143/145 in vein grafts may prevent SMC de-differentiation and elevated rates of SMC proliferation and migration.