bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9889: A Potent Flavonoid Luteolin Protects Against the Angiotensin II-Induced Cardiac Remodeling
Authors: Nakayama Atsuko , Morita Hiroyuki , Nagai Ryozo
Published: April 2024

Background:
Luteolin is a food-derived flavonoid and its antioxidant, anti-inflammatory, and antifibrotic functions are reported. However, the effects of luteolin on the cardiac remodeling remain to be clarified.

Methods:
Five-week-old male rats were divided into 3 subgroups; 1) Ang II+Luteolin- rats which fed with normal diet for 3 weeks and then infused with angiotensin II (Ang II; 0.7 mg/kg/min) for 1 week with an osmotic mini-pump, 2) Ang II+Luteolin+ rats which fed with 0.035% luteolin-mixed diet for 3 weeks and then infused with Ang II for 1 week with an osmotic mini-pump, 3) Control rats which fed with normal diet for 3 weeks and then received the sham operation. The effect of oral luteolin administration on the cardiac remodeling was evaluated by echocardiography, histopathology and Real-time PCR technique. In vitro, cultured human cardiac fibroblasts (HCFs) were pretreated with luteolin or PBS before the stimulation with Ang II. The influence of luteolin pretreatment on the expression levels of related genes and the phosphorylation of c-JUN NH2-terminal protein kinase (JNK1) and extracellular signal-regulated kinase 1/2 (ERK1/2) were evaluated.

Results:
Systolic blood pressure was higher in both Ang II+Luteolin- rats and Ang II+Luteolin+ rats, compared with control rats. Echocardiography revealed accelerated cardiac concentric remodeling in Ang II+Luteolin- rats, but not in Ang II+Luteolin+ rats. Left ventricular weight was lower in Ang II+Luteolin+ rats than that in Ang II+Luteolin- rats (p=0.031). Histopathologic studies showed less prominent interstitial fibrosis in the ventricles of Ang II+Luteolin+ rats than in those of Ang II+Luteolin- rats. Cardiac gene expression levels of atrial natriuretic peptides and transforming growth factor-β1 (TGF-β1) were significantly suppressed in Ang II+Luteolin+ rats, compared with Ang II+Luteolin- rats. In cultured HCFs, luteolin pretreatment significantly inhibited the Ang II-induced upregulation of phosphorylated JNK1 and phosphorylated ERK1/2.

Conclusion:
Oral administration of luteolin has a protective role against Ang II-induced cardiac remodeling through suppression of the Ang II-TGF-β1 signaling pathway, which can be related to suppression of JNK1 and ERK1/2 pathways.
Abstract 9917: Electrical Coupling and Action Potential Properties of Transplanted Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Comparison with Fetal Cardiomyocytes
Authors: Halbach Marcel , Peinkofer Gabriel , Baumgartner Sven , Maaβ Martina , Krausgrill Benjamin , Ladage Dennis , Fatima Azra , Saric Tomo , Hescheler Júrgen , Múller-Ehmsen Jochen
Published: April 2024

A functional integration and maturation of transplanted cardiomyocytes prevents arrhythmias and enhances synergistic contractions of transplanted and host tissue. We compared electrical coupling and action potential (AP) properties of transplanted induced pluripotent stem cell-derived cardiomyocytes (iPSCM), which are regarded as promising cell type for cell therapy, and fetal cardiomyocytes (FCM).

Methods:
Murine iPSCM expressing eGFP and a puromycin resistance under control of the α-MHC promoter, were purified by antibiotic selection and dissociated at day 16 of differentiation. FCM from transgenic mice expressing eGFP under control of the α-actin promoter were isolated at day 13.5-15.5 p.c. IPSCM and FCM were injected into adult mouse hearts (2 injections, ∼500,000 cells per site). 6-12 days after transplantation, recipients were sacrificed and viable ventricular tissue slices (thickness: 150 μ m) were prepared. Slices were focally stimulated by a unipolar electrode placed in host tissue. AP recordings were performed by glass microelectrodes in transplanted cells, which could be identified by their green fluorescence, and in neighboring host tissue within the slices.

Results:
Coupling of iPSCM and FCM to host tissue could be clearly demonstrated, 74% of iPSCM and 85% of FCM were coupled. Some transplanted iPSCM and FCM had no conduction blocks even at high stimulation frequencies up to 8 Hz, while others had blocks at lower frequencies. The delay between stimulus and AP upstroke was significantly longer in iPSCM (35.34±8.79 ms) than in FCM (19.84±3.77 ms). In host tissue, the delay was 6.96±1.0 ms. IPSCM had immature AP properties at all time points, while FCM matured and possessed comparable AP properties as host cardiomyocytes after 12 days.

Conclusions:
IPSCM and FCM are able to integrate electrically into host tissue, but conduction blocks and decelerations occur. The quality of integration is higher in FCM than in iPSCM. AP properties of transplanted iPSCM differ considerably from those of host cardiomyocytes up to day 12 after transplantation, while FCM mature to an adult electrophysiological phenotype.
Abstract 9923: Cardiac Rehabilitation Reduces Levels of Oxidized LDL
Authors: TAKASHIMA Akira , Ise Takayuki , Akaike Masashi , Ueta Yuka , Iwase Takashi , Hara Tomoya , Kadota Muneyuki , Ota Rie , Ogasawara Kozue , Niki Toshiyuki , Hocchi Junko , Yamaguchi Koji , Taketani Yoshio , Yamada Hirotsugu , Soeki Takeshi , Wakatsuki Tetsuzo , Sata Masataka
Published: April 2024

Background:
Oxidized LDLs have been shown to play an important role in atherosclerosis progression. However, no established methods are available for effectively reducing oxidized LDL levels. Comprehensive cardiac rehabilitation (CR) with exercise training prevents atherosclerosis progression. The purpose of the current study was to examine whether CR reduces oxidized LDL levels.

Methods and Results:
We measured the levels of malondialdehyde-modified LDL (MDA-LDL), a marker of oxidized LDL, in 118 patients who were enrolled for a 6-month CR program. Peak VO
2
and MDA-LDL levels were examined before and at 6 months after enrolment in 55 patients who completed the CR program (CR group) and in 63 patients who failed to continue the CR program (non-CR group). At 6 months, the peak VO
2
in the CR group was significantly higher than the baseline value (1131 ± 364 to 1327 ± 442 ml/min, p < 0.01). At 6 months, the MDA-LDL level was significantly lower than the baseline value in the CR group (111 ± 43 to 89 ± 25 U/l, p < 0.05) but this difference was not significant in the non-CR group. The increase in peak VO
2
was inversely correlated with the decrease in the MDA-LDL level (r = -0.40, p < 0.01). This correlation was observed even in patients who had not just started statin therapy.

Conclusion:
The CR program significantly reduced oxidized LDL levels in association with increase in exercise capacity. Thus, CR may exert an anti-atherosclerotic effect through reduction of oxidized LDLs.
Abstract 9936: Cardiac Magnetic Resonance Factors Associated With Successful Univentricular to Biventricular Conversion in Small Left Hearts
Authors: Banka Puja , Schaetzle Barbara , Emani Sitaram , Del Nido Pedro , Geva Tal , Powell Andrew J
Published: April 2024

Background:
In patients (pts) with small left heart structures, the decision to attempt conversion from a univentricular to biventricular (BiV) circulation has profound consequences, but preoperative factors predicting success are not well established. We sought to identify cardiac magnetic resonance imaging (CMR) parameters associated with successful BiV conversion.

Methods:
All pts with hypoplastic left heart structures and univentricular physiology who underwent CMR prior to an attempted BiV conversion were retrospectively identified. Subjects were divided into 2 anatomic groups: 1) right-dominant atrioventricular canal defect (AVC), and 2) small left heart structures without an AVC defect (SLH). Successful BiV conversion was defined as a BiV circulation at latest follow-up.

Results:
In the SLH group, there were 20 pts who underwent BiV conversion at a median age of 38.5 months (0-82) and 15 (75%) were successful with a median follow-up of 12 months (0-64). Pts with successful BiV conversion had a higher median left ventricular end-diastolic volume (LVEDV) (61 vs. 27 ml/m
2
, p=0.006), higher median LV/RV stroke volume ratio (0.9 vs. 0.2, p=0.004), and a trend towards higher median mitral/tricuspid inflow ratio (1.1 vs. 0.7, p=0.08). LVEDV ≥30 ml/m
2
was associated with higher percentage of successful conversion (88 vs. 25%, p=0.02); 3 of the 4 pts with LVEDV <30 ml/m
2
were unsuccessful. Late gadolinium enhancement (LGE) consistent with endocardial fibroelastosis (EFE) was present in 15 pts (75%) and was not associated with failed conversion (p=0.56), although 14 pts (93%) underwent EFE resection either before or after CMR. In the AVC group, there were 10 pts who underwent BiV conversion at a median age of 6.5 months (2-75) and all were successful. Minimum values were LVEDV 22ml/m
2
, LV/RV stroke volume ratio 0.2, and mitral/tricuspid area ratio 0.3. None had LGE.

Conclusion:
In SLH pts, CMR derived LVEDV and LV/RV stroke volume ratio but not LGE are associated with successful BiV conversion. In AVC pts, the high rate of successful BiV conversion precluded discriminant analysis, but the range of CMR parameters permitting success is provided. These data aid in the interpretation of CMR results in pts being considered for a BiV conversion.
Abstract 9940: Novel Function of the P2y/cysteinyl-leukotriene Receptor Gpr17 in Recruitment of Circulating and Resident Myofibroblast Progenitors Following Acute Myocardial Infarction
Authors: Cosentino Simona , Castiglioni Laura , Nobili Elena , Colazzo Francesca , Tremoli Elena , Rosa Patrizia , Abbracchio Maria Pia , Sironi Luigi , Pesce Maurizio
Published: April 2024

Background
- GPR17 is a G
i
-coupled dual receptor activated by uracil-nucleotides and cysteinyl-leukotrienes, families of signaling molecules massively released into hypoxic tissues. In the normal heart GPR17 expression has been reported, while its role during ischemia is totally unknown.

Aims and Results
- To investigate GPR17 expression in mice hearts, before or after myocardial infarction (MI) induction, immunofluorescence was set up. In non ischemic hearts, GPR17 protein was confined into small cell groups localized between myocytes. These cells expressed the stem cell antigen-1 (Sca-1). At 24, 48 and 72 hrs post-MI, cell clusters expressing GPR17 were found to infiltrate the MI border zone and penetrate into the ischemic area. They expressed Sca-1, the myofibroblast/mesenchymal marker CD44 and the hematopoietic lineage marker CD45. Interestingly, not all cells expressing GPR17 also expressed CD45, suggesting a dual origin of GPR17
+
cells recruited after MI. A flow-sorting experiment was performed to separate Sca-1
+
/CD45
+
from Sca-1
+
/CD45
-
cells at 48 hrs post-MI. RT-PCR showed that both cellular populations expressed GPR17, thus confirming their dual origin. A clonogenic Sca-1
+
cell line was derived from non-ischemic hearts. In addition to CD44, these cells expressed mesenchymal markers CD29 and CD105, but not endothelial and hematopoietic markers, and showed a side population phenotype. Sca-1
+
cells expressed GPR17 RNA/protein and were able to differentiate into cardiac lineage cells and myofibroblasts in culture. To investigate GPR17 functions, Sca-1
+
cells were treated with receptor agonists UDP-Glucose (10nM) and LTD
4
(100nM). These ligands did not rescue cells from hypoxia-induced apoptosis. By contrast, they enhanced CSCs migratory activity (3.1±0.8 and 1.7±0.2, folds
vs.
control;
P
< .05 paired t-test). Finally, addition of GPR17 antagonists montelukast and cangrelor abolished this migratory effect.

Conclusions
- The present results indicate a role of dual GPR17 receptor in early homing of Sca-1
+
cardiac stem cells-derived and circulatory stem cells-derived myofibroblasts into the infarcted myocardium. These findings have implications for the pharmacologic control of heart remodeling at early times after infarction.
Abstract 9969: Genotype-phenotype Correlations According to Clinical and Echocardiographic Characteristics in Hypertrophic Cardiomyopathy
Authors: Henri Christine , Garceau Patrick , Robb Laura , Lavoie Joël , Mercier Lise-Andrée , Romeo Philippe , Phillips Michael S , Renaud Yannick , Barahona-Dussault Catherine , Fillion Isabelle , L'Allier Philippe , Marcotte FranÇois , Talajic Mario
Published: April 2024

Background:
Many mutations among genes encoding sarcomeric proteins have been identified in hypertrophic cardiomyopathy (HCM). Data on specific genotype-phenotype correlations are limited and highly variable.

Methods:
Identified mutations in genes TNNI3 (troponin I), TNNT2 (troponin T), MYBPC3 (myosin-binding protein C) and MYH7 (myosin heavy chain) were screened in 284 patients at the Cardiovascular Genetic Clinic of the Montreal Heart Institute. Mutations were identified in 113 patients (40%) and 84 patients (74%) were included for analysis. Five cardiac transplant recipients without previous echocardiographic images available were analysed according to clinical characteristics only. We excluded 16 patients without HCM phenotype and 13 patients with follow-up outside of our center.

Results:
MYH7 (40%) and MYBPC3 (40%) mutations were the most common. Only one patient was identified with a TNNI3 (1%) mutation and was excluded. Patients with MYH7 mutations were younger at diagnosis and presented more often with a familial history of sudden cardiac death (76%) and defibrillator implantation (59%). Patients with MYH7 mutations were also more likely to progress to “burn-out” HCM (27%) and cardiac transplantation (18%). Significant mitral insufficiency was more prevalent in patients with MYBPC3 mutations (33%). Patients with TNNT2 (18%) mutations showed an increased probability of having a significant resting and provocable left outflow tract obstruction (47%) with systolic anterior movement of the mitral valve (53%) leading to septal myomectomy (27%). Genotype did not affect septal morphology with an overall predominance of the midseptal form (73% overall).

Conclusion:
This retrospective study suggests that TNNT2 mutations are associated with obstructive HCM while MYH7 mutations are related with arrhythmic complications. Moreover, septal morphologies do not appear to be influenced by any specific gene mutation.
Abstract 9983: Low Heart Rate Variability and the Risk of Sudden Cardiac Death in the General Population: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Chen Lin Y , Lopez Faye L , Prineas Ronald , Soliman Elsayed Z , Adabag Selcuk , Whitsel Eric A , Alonso Alvaro
Published: April 2024

Background
Low heart rate variability (HRV) is associated with an increased risk of sudden cardiac death (SCD) in post-myocardial infarction and heart failure patients. However, it is unclear whether low HRV is associated with an increased risk of SCD in the general population. We sought to determine whether low HRV predicts risk of SCD in the ARIC study, a large US population-based cohort study.

Methods
We included 14,071 subjects (aged 45-64 years, 55% female, 27% black) enrolled 1987-89, and followed through 2001. Measures of HRV (RR interval, standard deviation of all normal RR intervals [SDNN], root mean square of successive differences [r-MSSD], low frequency power [LF], and high frequency power [HF]) were obtained from 2-minute rhythm strips at baseline. SCD was physician-adjudicated and was defined as death from a sudden, pulseless condition from a cardiac origin in a previously stable individual. We used Cox proportional hazards models to assess association between HRV measures and SCD. We also assessed interactions by sex and race.

Results
During follow-up (median 13.0 yrs), there were 264 SCD cases. Compared with the lowest tertile, the highest tertile of RR, SDNN, and LF were significantly associated with a lower risk of SCD (Table 1). Greater r-MSSD and HF were also non-significantly associated with a lower risk of SCD. In addition, there was an interaction between SDNN and sex (P for interaction=0.004): Hazard ratios (95% CI) of SCD in the highest tertile compared with the lowest tertile in women and men were 0.41 (0.21-0.80), P=0.009 and 0.96 (0.66-1.40), P=0.83, respectively. We did not find an interaction by race.

Conclusions
Low HRV is associated with an increased risk of SCD in the general population. Before low HRV can be used as a marker for the risk stratification of SCD in the general population, additional studies to validate this novel association and to define the role of HRV in risk stratification of SCD in the general population are warranted.
Abstract 18028: [18F]-fluorodeoxyglucose is a Stronger Correlate of Intraplaque Inflammatory Burden in Human Carotid Plaque Than C-Reactive Protein: A Sub-Study of the Canadian Atherosclerosis Imaging Network (CAIN)
Authors: Cocker Myra S , Spence J David , Hammond Robert , Mc Ardle Brian , Bernick Jordan , deKemp Rob , Lum Cheemun , Youssef George , Yerofeyeva Yulia , Karavardanyan Tigran , Adeeko Adebayo , Hill Andrew , Nagpal Sudhir , Stotts Grant , Renaud Jennifer , Kelly Cathy , Brennan Joanne , Garrard Linda , Alturkustani Murad , Hammond Laura , DaSilva Jean , Tardif Jean-Claude , Beanlands Rob
Published: April 2024

Background and Purpose:
Inflammation triggers and contributes to the progression of atherosclerosis. C-reactive protein (CRP), a circulating marker of inflammation, is a putative risk factor for cardiovascular disease, but this is not borne out in Mendelian randomization studies. Inflammation in carotid arteries can be imaged with hybrid [18F]-fluorodeoxyglucose (18FDG) positron emission tomography (PET) computed tomography (CT) imaging.

In this investigation, circulating levels of CRP and 18FDG uptake in carotid vasculature were directly compared with intraplaque inflammatory burden, using macrophage-specific CD68 immunohistology.

Methods:
Nineteen prospectively recruited patients (66 ± 11 years, 15 male) scheduled for carotid endarterectomy underwent 18FDG-PET and CT angiography of carotids. CRP levels were assessed. Maximum 18FDG uptake in both internal carotids was quantified and normalized to blood (tissue:blood ratio, TBR). Following endarterectomy, excised plaque was fixed, sectioned and immunostained for CD68. CD68 expression was quantified.

Results:
Carotid endarterectomy was performed in 19 patients; one received a 2
nd
carotid endarterectomy due to bilateral disease. The direct burden of inflammation, as quantified by CD68 immunohistology, correlated with maximum 18FDG uptake (r=0.716, p<0.001). There was no evidence of a correlation between CRP and CD68 (r=0.159, p=0.50), nor with maximum 18FDG uptake (r=0.238, p=0.31). Furthermore, 18FDG and CRP are different correlations where FDG is more strongly correlated with CD68 than CRP (p=0.02, Hoteling Williams test).

Conclusion:
18FDG uptake is more strongly related to the extent of inflammatory burden within high-risk carotid plaque than CRP. CRP may not be an accurate criterion for assessing vulnerable carotid plaque (based on histopathology nor 18FDG uptake). Prospective outcomes-based trials are needed to establish 18FDG as a direct biomarker of vulnerable carotid plaque.
Abstract 18073: Traditional Lipid and Advanced Lipoprotein Associations With Subclinical Atherosclerosis of Persons Living With and Without HIV: The Multicenter AIDS Cohort Study (MACS)
Authors: Zikusoka Michelle , Deal Jennifer , Jacobson Lisa P , Palella Frank J , Budoff Matthew , Witt Mallory D , Kingsley Lawrence A , Brown Todd , Post Wendy S
Published: April 2024

Background:
HIV infection is associated with coronary artery disease (CAD). We previously observed that HIV-infected (HIV+) men had a higher prevalence of non-calcified plaque than uninfected (HIV-) men. We tested associations between lipids and plaque composition and differences by HIV status.

Methods:
We performed non-contrast (n=613) and contrast coronary (n= 464) CT scans to measure coronary calcium (CAC), total plaque (TP), non-calcified plaque (NCP), calcified plaque (CP), mixed plaque (MP) and stenosis greater than 50%. Traditional lipid and advanced lipoprotein measures with nuclear magnetic resonance (NMR) were determined using blood samples in HIV+ and HIV- men who have sex with men (MSM) age 40-70 years. Separate logistic regression models were used to estimate associations between presence of plaque and each lipid variable, adjusting for age, race, CAD risk factors, and use of cholesterol medications. Effect modification by HIV was tested with interaction terms.

Results:
HIV+ men had lower LDL particle concentrations (LDL-p), but higher small LDL-p and smaller LDL-p size. HIV+ men had higher medium HDL-p and lower total, large and small HDL-p and traditional HDL concentrations. They had higher total and large VLDL-chylomicron (CHY), medium VLDL, VLDL particle size, NMR VLDL-CHY-TG concentrations and higher traditional TG (p<0.05). Increased LDL-p and small LDL-p were both associated with the presence of CAC, any plaque (TP), NCP, CP, and MP (all p< 0.03; OR per SD 1.27- 1.41). Large HDL-p and HDL were inversely associated with presence of TP, NCP and MP (all p<0.05; OR per SD 0.67-0.79). Increased VLDL-CHY, small VLDL-p, small LDL-p and traditional TG were associated with stenosis greater than 50% (all p<0.02; OR per SD 1.49-1.57). Cholesterol medication use was positively associated with presence of CAC, TPS, MP, and CP, but not NCP. There were no significant interactions by HIV status for these outcomes.

Conclusions:
Most plaque subtypes are associated with LDL and HDL particles. Cholesterol medication use is associated with calcified plaque but not NCP. VLDL and TG particles were associated with stenosis > 50%. HIV+ men have higher concentrations of atherogenic lipid particles than HIV- men, which may explain some of the increased risk for CAD.
Abstract 18106: Short- and Long-Term Outcomes of Patients With Type A Acute Aortic Dissection and Cardiogenic Shock: Contemporary Results From the International Registry of Acute Aortic Dissection (IRAD)
Authors: Bossone Eduardo , Pyeritz Reed E , Braverman Alan C , Peterson Mark D , Ehrlich Marek P , O’Gara Patrick , Suzuki Toru , Trimarchi Santi , Gilon Dan , Greason Kevin , Desai Nimesh D , Montgomery Daniel G , Isselbacher Eric M , Nienaber Christoph A , Eagle Kim A
Published: April 2024

Background:
Shock is a highly dreaded complication of type A acute aortic dissection (TAAAD). However, few data exist on its incidence and association with prognosis.

Methods:
We evaluated 2704 TAAAD patients [mean age 61.4 ± 14.5, (67.6%) male] from the International Registry of Acute Aortic Dissection.

Results:
Shock was present at arrival in 407 (15.1%) TAAAD patients. These patients demonstrated no difference in age (61.5 ± 15.2 with shock vs. 61.4 ± 14.4 years without; p=0.873), but were more likely to have history of hypertension (83.1% vs. 73.0%; p<0.001), atherosclerosis (36.5% vs. 21.7%, p<0.001) and diabetes (12.3% vs. 7.0%, p=0.001) than patients without shock. They had more surgical management (90.9% vs. 86.0%; p=0.007). In-hospital complications such as hypotension (49.8% vs. 28.6%; p<0.001), coma (11.4% vs. 5.8%; p<0.001), tamponade (33.6% vs. 18.2%; p<0.001) and myocardial ischemia/infarction (19.7% vs. 13.7%; p=0.006) were more common among shock patients. Overall in-hospital mortality (30.2% vs. 23.9%; p=0.007) and mortality by management (surgical: 24.6% vs. 19.1%; p=0.015; medical: 88.9% vs. 53.3%, p<0.001) were higher among shock patients. Independent predictors of in-hospital mortality in shock patients are displayed in Table 1. Among hospital survivors, Kaplan-Meier estimates of follow-up mortality were similar between groups (p=0.609).

Conclusions:
Shock occurred in 15.1% of patients with TAAAD and was associated with increased in-hospital morbidity and mortality, but not long-term mortality.
Abstract 18111: Engineered Cell Therapy With Embryonic Stem Cell-Derived Cardiomyocytes Encapsulated in Injectable Nanomatrix Gel Enhanced Engraftment and Promoted Cardiac Repair in Experimental Myocardial Infarction
Authors: Ban Kiwon , Park Hun-Jun , Kim Sangsung , Cho Kyu-Won , Hwang Jung Wook , Cha Ho Jin , Andukuri Adinarayana , Jun Ho-Wook , Yoon Young-sup
Published: April 2024

Background:
A significant barrier to the therapeutic use of stem cells is poor cell engraftment in vivo. To overcome this hurdle, studies have attempted to engineer stem cells using biomaterials. Particularly, injectable self-assembling nanomatrix gel has emerged as a highly promising biomaterial by providing a natural extracellular matrix-like microenvironment. Here, we evaluate the therapeutic potential of cardiomyocytes (CMs) derived from mouse embryonic stem cells (mESCs) encapsulated with injectable nanomatrix gel consisting of peptide amphiphiles incorporating cell adhesive ligand RGDS (PA-RGDS) on experimental myocardial infarction (MI).

Methods and results:
First, we examined the survival of CMs on RGDS. We cultured rat neonatal CMs on PA-RGDS for 7 days and found that higher than 90% of the CMs remained alive with well-defined CM structures as determined by live/dead and immuno stainings. Next, to test if PA-RGDS can increase the retention of CMs in the heart, we intramyocardially injected DiI (fluorescent probe)-labeled CMs into the uninjured hearts with or without PA-RGDS. Flow cytometry analysis with enzymatically digested heart tissues harvested at day 7 showed a ~3 fold higher rate of mESC-CM engraftment in the mice receiving CMs with PA-RGDS compared to those receiving only mESC-CMs (11.3% ± 0.4 vs 4.4% ± 0.2). Finally, we investigated the therapeutic effects of mESC-CMs with PA-RGDS on the MI in comparison with PBS control, CM alone, and PA-RGDS alone. Weekly echocardiography demonstrated that three groups (CM, PA-RGDS and CM+PA-RGDS) showed higher ejection fractions than the PBS group at week 2. However, in the CM or PA-RGDS alone groups, cardiac function was dramatically reduced between 3-4 weeks. In contrast, the CM+PA-RGDS group maintained cardiac function for up to 12 weeks. Confocal microscopic examination showed that injected CMs in PA-RGDS engrafted robustly in myocardium, formed clusters, integrated into host myocardium, and expressed representative CM proteins such as cTNT and MHC6/7.

Conclusions:
This study demonstrated that implantation of ESC-derived CMs encapsulated with PA-RGDS improves cell retention and cardiac function post-MI. This engineered cell therapy can develop into a novel option for treating MI.
Abstract 18124: Skeletal Muscle Proteomic Signature in Pulmonary Arterial Hypertension
Authors: Pflieger Aude , Potus François , Malenfant Simon , Breuils-Bonnet Sandra , Bonnet Sebastien , Provencher Steeve
Published: April 2024

Introduction:
Most pulmonary arterial hypertension (PAH) patients exhibit severe dyspnea and fatigue resulting in restricted exercise capabilities and poor quality of life. Numerous observations suggest that exercise limitation in PAH is not solely due to cardio-pulmonary impairment, but that other determinants such as skeletal muscle abnormalities are involved. In order to better understand the origins of exercise limitation in PAH, we studied the proteomic signature of skeletal muscle impairment in PAH.

Methods and results:
Muscle proteins from 4 idiopathic PAH patients and 4 matched controls were extracted following quadriceps muscle biopsy. Fractioned peptides were then tagged using an isobaric Tags for Relative and Absolute Quantitation (iTRAQ, ABsciex) specific for each patient. Tagged peptides were then mixed, fractioned, identified and quantified using mass spectrometry quantitative method. Over 900 proteins were identified using iTRAQ analysis, among them, 9 were under-expressed and 7 were over-expressed in all iPAH patient quadriceps. More than 75% of the under-expressed proteins are involved in oxidative metabolism and most other highlighted proteins play a role in myogenesis. In addition, structural differences between control and PAH skeletal muscles were explored by electronic microscopy. PAH skeletal muscles had decreased mitochondrial density and impaired mitochondrial structure resulting in abnormal metabolism. Finally, PAH skeletal muscles had impaired micro-vessels structure and decreased in their density.

Conclusions:
Proteomic data allowed us to highlight proteins that could be responsible for exercise limitation in PAH. Taken together with electronic microscopy experiments, these data suggest that as shown in both the lungs and the right ventricle (RV), impairment of oxidative metabolism is also present in skeletal muscles of PAH patients. Similarly to the RV, metabolism unbalanced is associated with abnormal mitochondria and micro-vessels. In addition to shedding light on exercise limitation in PAH, this study might lead to the discovery of an early and less invasive diagnostic method for PAH.
Abstract 18139: Genetic Deficiency of Traf-1 Attenuates Diet-Induced Adipose Tissue Inflammation by Limiting the Pool of Circulating and Splenic Monocytes in Mice
Authors: Wolf Dennis , Anto Michel Nathaly , Hergeth Sonja , Stachon Peter , Bode Christoph , Zirlik Andreas
Published: April 2024

Background:
Accumulation of inflammatory leukocytes, such as of macrophages, is a prerequisite of adipose tissue inflammation during the metabolic syndrome. We recently reported that genetic deficiency of Tumor necrosis factor receptor-associated factor (TRAF) -1 attenuated inflammatory cell recruitment in atherosclerosis. Here, we tested the hypothesis that TRAF-1 deficiency modulates adipose tissue inflammation in a model of diet-induced obesity (DIO) in mice.

Methods and Results:
To test the association of TRAFs and adipose tissue inflammation we screened for expression of different TRAFs in mouse adipose tissue after 20 weeks of feeding with a high fat (HFD) or a control diet. HFD induced up-regulation of TRAF-1, -3, -5, -6, and -7 mRNA. Interestingly, the amplitude of gene regulation was highest for TRAF-1 (4.9-fold, n=8 per group, p=0.002). Also, in human subcutaneous tissue TRAF-1 gene expression correlated with body mass index of donors (r=0.94, p=0.019). To test functional relevance of our findings, WT or TRAF-1-/- mice consumed HFD for 12 weeks (n ≥ 10 mice per group). Interestingly, TRAF-1-/- mice gained less weight during DIO (119 ± 7.5 % vs. 41 ± 3.7 % of starting body weight for WT and TRAF-1-/-, respectively). Accordingly, total body weight, weight of visceral and cardiac fat pads was decreased in TRAF-1-/- mice. Moreover, TRAF-1-/- mice demonstrated lower glucose levels after starving and during weight-adapted intraperitoneal glucose and insulin tolerance tests, suggesting functional involvement of TRAF-1 in insulin and glucose signaling. Finally, inflammatory cell recruitment was impaired in TRAF-1-/- mice with reduced numbers of adipose tissue macrophages. Functionally, circulating and splenic, but not bone marrow monocytes were lowered in TRAF-1-/- mice, proposing that TRAF-1 modulates monocyte mobilization during inflammation.

Conclusion:
We present the novel finding that TRAF-1 is regulated in obese murine and human adipose tissue. Genetic deficiency of TRAF-1 attenuates adipose tissue inflammation in mice by limiting monocyte recruitment. These findings identify TRAF-1 as a potent mediator at the interface of cardiovascular and metabolic disease.
Abstract 18172: Nicotine Accelerates the Expansion of Abdominal Aortic Aneurysms via a Matricellular Protein, Periostin
Authors: Azuma Junya , Otsu Rei , Taniyama Yoshiaki , Iwabayashi Masaaki , Morishita Ryuichi
Published: April 2024

Abdominal aortic aneurysms (AAA) are more closely associated with cigarette smoking than any other tobacco-related disease except lung cancer. Periostin (PN) is a matricellular protein that is induced by mechanostress and regulates organ remodeling. Our previous study has shown that PN was significantly unregulated in early remodeling phase of AAAs and its ablation contributed to reduce AAA growth induced by angiotension ll (Angll). The purpose of the present study was to investigate the effect of nicotine on PN and its potential role in AAA disease progression.

PN-knockout (KO) mice were originally generated in our lab and crossed with ApoE-KO mice to establish ApoE/PN-double knockout (dKO) mice. Ang II (1.0 mg/kg/min) for 28 days or nicotine (7.0 mg/kg/min) for 42 days was administrated via osmotic minipumps for 24 >-wk-old male mice. Growth of AAAs was serially monitored by ultrasound imaging. The systolic blood pressure(BP)measured by tail cuff method was equivalent between ApoE-KO and ApoE/PN-dKO mice at baseline (101.4±7.3 vs 107.6±8.3mmHg, ns).

The BP response to Ang II or nicotine in ApoE/PN-dKO mice was also similar to that in ApoE-KO mice throughout the observation period (data not shown). In Ang II treated mice, the expansion rate of the aortic diameter (AD) was decreased significantly in ApoE/PN-DKO mice (n=10) over ApoE-KO mice (n=12) from day7 to 28day (239.3±43.4% vs 144.4±8.5% at day 28, p<0.05). Moreover the incidence of rupture and hematoma was significantly reduced in ApoE/PN-DKO mice at day 28 (60.0% vs 16.7% at day 28, p<0.05). In nicotine treated mice, the expansion rate of the AD was also diminished in ApoE/PN-DKO mice (n=5) over ApoE-KO mice (n=10) at day 42 (156.1±9.6 vs 113.9±4.0% at day 42, p<0.05). However no rupture or hematoma was observed in this treatment group.

The present study investigated the effect of nicotine on PN and their potential role in progressing AAAs. AngII had more potential induction of AAA rupture than nicotine in ApoE KO mice. Although the mechanism to develop AAA would be partially different between AngII and nicotine, the ablation of PN limited the AAA expansion in both AAA model. Antagonists against PN would lead to new therapeutic targets on a molecular basis to limit AAA progression related to cigarette smoking.
Abstract 18187: Medicare Readmission Penalties: Worsening Cardiovascular Disease Outcome Disparities in a Low-Income Metropolitan Area?
Authors: Williams Kim A , Javed Arshad A , Horton Amy M
Published: April 2024

Background:
Over 2,000 hospitals will reportedly forfeit more than $280 million in Medicare funds over the next year due to readmission penalties (RP) stimulated by the Affordable Care Act. Because key factors like socioeconomic status are not accounted for, it is suspected that RPs would target many safety-net hospitals that treat low-income patients with higher readmission rates, due to poor access to follow-up and medications.
Objective:
To evaluate the disparities between the RPs of poorer urban/inner-city hospitals (the Detroit Metropolitan Area, DMA) in comparison with those within the state of Michigan (MI), but outside of DMA.

Methods:
We analyzed the published Medicare RPs for 2013, which was based on 30-day readmission rates from 2008-2011 for congestive heart failure, pneumonia and acute myocardial infarction, attributing penalties ranging from 0 to 1% of all Medicare payments for 2013. We removed data from hospitals known to not serve patients with these illnesses (i.e., surgical or dedicated cancer hospitals).

Results:
Out of the 93 hospitals in the state of MI fitting these criteria, 5 were within the city of Detroit, 12 within the Detroit Medicare Region and 17 within the Detroit/Dearborn Region, which serves a similar population. No RP (0%) was given to 45 of 76 non-DMA hospitals, but to none of the 17 DMA hospitals (p < 0.0001). The maximum penalty (1%) was received by 29% of DMA hospitals, compared with 22% of non-DMA hospitals. The average penalty in the DMA hospitals was 0.68%, but only 0.15% in non-DMA MI hospitals (p < 0.001).

Conclusion:
RPs reduce Medicare payments to inner-city hospitals more than other hospitals in the state of MI. This may have the unintended consequence of further reducing access care from safety-net hospitals due to a) lack of funding for programs that can reduce recurrent illness post-discharge, b) incentives to stiffen criteria for admission to patients needing care, or c) resulting hospital closures.
Abstract 18263: Poor Handgrip Strength and Outcomes in Heart Failure. The Atlanta Cardiomyopathy Consortium
Authors: Deka Anjan , Li Song , Marti Catherine N , Snell Gail , Caltabiano Nina , Cole Robert , Gupta Divya , Laskar Sonjoy , Smith Andrew L , Butler Javed , Kalogeropoulos Andreas P , Georgiopoulou Vasiliki V
Published: April 2024

Background:
Handgrip strength test quantifies the amount of static force that the hand can squeeze around a dynamometer and is associated with increased mortality in middle-aged and older adults, and in patients with chronic diseases. The prognostic role of handgrip strength in heart failure (HF) has not been fully investigated.

Methods:
A hydraulic hand dynamometer was used to measure handgrip strength in 317 outpatients with HF enrolled in The Atlanta Cardiomyopathy Consortium (TACC) cohort study. Patients repeated the test 3 times in each hand and the average from both hands was used. We defined poor handgrip strength based on age- and gender-specific normative data. We evaluated the association between poor handgrip strength and major clinical event (death, heart transplant, left ventricular assist device) and healthcare resource utilization.

Results:
Baseline patient characteristics are presented in Table 1; 228 patients (71.9%) had poor handgrip strength. Total follow-up was 911 patient-years; 55 patients (17.4%) experienced a major clinical event. There was a total of 836 all-cause hospitalizations with an average length of stay of 4.7 days. Poor handgrip strength was not significantly associated with major clinical events (hazard ratio (HR) 1,19; 95% CI: 0.64 to 2,21; P=0.59). However, patients with poor strength had 42% higher hospitalization rate (95% CI: 1.3% to 98%; P=0.042) and spent 85% (95% CI: 10% to 210%; P=0.020) more days in the hospital. Average length of stay among patients with poor handgrip strength was 4.9 days vs. 4.2 days in those with preserved strength.

Conclusion:
Poor handgrip strength is highly prevalent among HF patients and is associated with higher healthcare resource utilization and length of stay.
Abstract 18268: Development of First Patient-Specific Computational Model to Analyze Wall Stress in Ascending Thoracic Aortic Aneurysms
Authors: Ge Liang , Wisneski Andrew D , Hope Michael D , Chitsaz Sam , Guccione Julius M , Barocas Victor , Tseng Elaine E
Published: April 2024

Background:
Ascending thoracic aortic aneurysms (aTAA) can rupture or dissect and rapidly become a lethal cardiovascular emergency. Peak aTAA wall stress may be a better predictor of rupture risk than diameter. However,
in vivo
models have never been validated and require zero-stress geometry, regional material properties, and residual stress. The goal of this study was to develop the first patient-specific computational models of aTAAs associated with bicuspid vs. tricuspid aortic valve using surgical specimens to accurately determine wall stress magnitudes.

Methods:
High-resolution micro-computed tomography of aTAA surgical specimens was used to construct zero-stress geometry. Bi-axial stretch testing of aTAAs in 4 quadrants provided stress-strain data to describe regional mechanical properties. Opening angle was used to determine residual stress. Finite element analyses were performed with LS-DYNA.

Results:
Elevated wall stress was seen in pockets in the anatomic left and right regions of bicuspid aTAA, primarily towards the sino-tubular junction, and in the left face of the inner lumen of the tricuspid aTAA more distally (Figure 1). Magnitudes of peak and mean wall stresses were similar between the bicuspid and tricuspid aTAAs.

Conclusions:
Wall stress magnitudes were relatively similar for these two aTAAs from bicuspid and tricuspid valve patients. Maximal wall stress areas may indicate sites more prone to rupture. Development of patient-specific aTAA models from surgical specimens is essential to determine true wall stress and to validate any
in vivo
-derived models. Such understanding is required to uncover the relationship between wall stress and rupture risk.
Abstract 18286: Relative Prognostic Impact of Various Measures of Right Atrial Pressures on Survival in Patients With End Stage Renal Disease on Hemodialysis: Results From a Prospective Cohort of 442 Patients
Authors: Aftab Waqas , Motabar Ali , Varadarajan Padmini , Pai Ramdas G
Published: April 2024

Background:
End stage renal disease (ESRD) patients on hemodialysis (HD) are prone to heart failure (HF) because of volume excess leading to poor functioning, atrial remodeling, pulmonary hypertension (PHTN) and high mortality. Right atrial pressure (RAP) estimate helps in achieving euvolemic status or optimal dry weight. There is limited data on the best measure of RAP in this population. We compared relative prognostic values of clinically assessed jugular venous pressure (RAP-JVP), RAP estimate recommended by ASE (RAP-ASE) and a visual estimate by an expert reader from combination of inferior vena caval (IVC) and hepatic vein size, hepatic congestion and hepatic vein flow (RAP-EXP).

Methods:
442 patients who underwent pre-renal transplant evaluation at our cardiology clinic were prospectively followed. Assessment of RAP by CE as elevated JVP, echo evaluation of RAP-ASE and RAP-EXP were performed on same pre or post dialysis day within a hour of each other. Quantitative evaluation of minimum (IVC min), maximum (IVC max) IVC diameters along with collapse (IV max-IVC min/IVC max) was computed following ASE guidelines independently. Logistic regression and Cox proportional hazard ratio were performed for outcomes assessment.

Results:
Baseline patient characteristics: age 57± 11 years, men 64%, DM in 68 %, CAD 30%, EF 61± 11%. Elevated RAP-JVP was noticed in 15% and RAP-EXP was high in 30% of the patients. Quantitatively, IVC max was 1.39± 0.55 cm, IVC min 0.87± 0.62 cm and mean IVC collapse 44± 29%. 14% patients had IV max of ≥ 2cm. IVC size, collapse or RAP-ASE group were not predictive of survival. However RAP-JVP (HR 2.15, 95 % CI 1.09-4.12, P = 0.03) and RAP-EXP (HR 2.25, 95 % CI of 1.21- 4.20, P = 0.01) were significant predictors of higher mortality on univariable analysis and after adjusting for age, gender, smoking, HTN, DM, LVEF and duration of dialysis. RAP-JVP and RAP-EXP better correlated with each other and HF by, left atrial pressure and PHTN than RAP-ASE.

Conclusions:
1) Clinically estimated JVP and an expert assessment of RAP are equally predictive of survival in patients on HD. 2) Echo assessment of RAP by ASE guidelines is twice as sensitive as CE and its use may help achieve euvolemic status in ESRD patients.
Abstract 18288: Flow Shear Stress and Osmotic Stretch Both Enhance Intracellular Ca2+ in PASMC From Patients With Idiopathic Pulmonary Arterial Hypertension
Authors: Song Shanshan , Yamamura Hisao , Makino Ayako , Yuan Jason X.-J.
Published: April 2024

Idiopathic pulmonary arterial hypertension (IPAH) is a fatal and progressive disease which is attributed to elevated pulmonary arterial pressure and pulmonary vascular resistance due in part to sustained pulmonary vasoconstriction and vascular remodeling. Pulmonary arterial smooth muscle cells (PASMC) are normally shielded from exposure to shear stress and sense small flow shear through transmural interstitial flow driven by transvascular pressure differential. However, in the context of endothelial injury or enhanced vascular permeability caused by increased pulmonary arterial pressure, PASMC are exposed to shear stress or to enhanced transmural interstitial flow. The decreased extracellular osmotic pressure caused by enhanced vascular permeability will exert osmotic stretch on PASMC. Both shear stress and osmotic stretch increase cytosolic Ca2+ concentration ([Ca2+]cyt). An increase in [Ca2+]cyt in PASMC is a major trigger for vasoconstriction and a key stimulus for cell proliferation, which contribute to vascular remodeling. We show here that flow shear stress and osmotic stretch induced increased [Ca2+]cyt in PASMC from patients with IPAH compared with control. Flow shear induced enhanced transient and plateau [Ca2+]cyt and larger Ca2+ oscillation amplitude in IPAH PASMC than in control. Expression of TRPM7, a Ca2+ channel implicated in response to shear stress, is increased in IPAH PASMC. TRPM7 blockers 2-APB and SK&F96365 inhibited flow shear-induced enhanced [Ca2+]cyt in control and IPAH PASMC, and the TRPM7 agonist bradykinin induced enhanced [Ca2+]cyt in IPAH PASMC than in control. Osmotic stretch also induced a transient increase in [Ca2+]cyt in IPAH PASMC, but not in control. La3+, an inhibitor of TPRM3, a Ca2+ channel important for responses to osmotic stress, completely inhibited osmotic stretch-induced increase in [Ca2+]cyt in IPAH PASMC. Furthermore, the TRPM3 agonist PregS induced a transient increase in [Ca2+]cyt in IPAH PASMC but not in control. These results demonstrate that flow shear stress and osmotic stretch induce enhancement of [Ca2+]cyt in IPAH PASMC through the Ca2+ channels, TRPM7 and TRPM3, and that mechanical sensitive channels TRPM7 and TRPM3 play a critical role in PAH by modulating [Ca2+]cyt homeostasis.
Abstract 18290: Mitochondrial-Targeted Overexpression of Transcriptionally Inactive STAT3 in the Heart Reduces Infarct Size and Improves Contractile Recovery Following Ischemia and Reperfusion
Authors: Szczepanek Karol , Xu Aijun , Hu Ying , Chen Qun , Lesnefsky Edward J
Published: April 2024

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that drives expression of antiapoptotic and antioxidant genes. STAT3 contributes a crucial role in protection against ischemia (ISC)-reperfusion (REP) injury. STAT3 is also found in the mitochondria, where it modulates the activity of the electron transport chain (ETC) and the permeability transition pore. We have previously shown that transgenic mice overexpressing mitochondrial-targeted, transcriptionally inactive STAT3 in cardiomyocytes (MLS-STAT3E mice) exhibit a persistent, partial blockade of electron transfer through complex I that uniquely does not lead to tissue dysfunction at baseline yet increases mitochondrial ischemic tolerance. MLS-STAT3E protects complex I against ischemic damage, attenuates reactive oxygen species (ROS) production from the ETC and inhibits cytochrome c release during ISC. The direct contribution of non-transcriptional, mitochondria-localized STAT3 to protection during ISC-REP remains to be established. We hypothesize that the enhanced mitochondrial tolerance seen in MLS-STAT3E mice will decrease cardiac injury during ISC-REP. In the isolated buffer-perfused heart model of ISC-REP, non-transgenic littermate (WT) hearts subjected to 35 min of ISC and 60 min of REP exhibit an infarct size of 34 ± 2% (n=10) of the left ventricle (LV) risk area. MLS-STAT3E hearts are more resistant to ISC-REP injury with a decreased infarct size (23 ± 5%; P<0.05, n=10). Contractile recovery, expressed as a percent of LV developed pressure before ISC, is improved in MLS-STAT3E mice compared to WT (10 ± 2% WT vs. 21 ± 3% MLS-STAT3E; P<0.05, n=10). Mitochondria isolated after ISC-REP show MLS-STAT3E-mediated attenuation of ROS release. These results suggest that the partial and persistent blockade of complex I present in MLS-STAT3E decreases ISC-REP injury. Our data implicates STAT3 as a mediator of cardioprotection not only via canonical action as a transcription factor, but also as a modulator of ETC activity directly in the mitochondria.