bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10893: Dietary Nitrate Supplementation With Beetroot Juice Enhances Cardiac Autophagy Markers AMBRA-1 (Activating Molecule in Beclin-1-regulated Autophagy) and ATG-5 (Autophagy-related Gene 5): Protective Role Against Doxorubicin Cardiotoxicity
Authors: Yin Chang , Rehman Shabina , Kukreja Rakesh C , Xi Lei
Published: April 2024

Background:
Beetroot juice (BRJ) is a dietary supplement containing high levels of nitrate and other nutrients. We previously reported that oral intake of BRJ protects against cardiotoxicity of doxorubicin (DOX) - a widely used anticancer drug. BRJ diminished cell injury (indicated by significantly lower serum levels of cardiac troponin I) and ventricular dysfunction caused by DOX. However, it remains unknown if BRJ modulates cardiac autophagy - a critical endogenous cellular quality control and damaged organelles removal mechanism, particularly under DOX-induced cardiototoxic stress. Therefore, the current study is designed to determine if cardioprotective dose of BRJ affects cardiac autophagy.

Methods:
Adult male CF-1 mice were divided into 4 groups (n=3-4/group) to receive: 1) Saline (0.2 ml, IP); 2) DOX (15 mg/kg, IP); 3) BRJ (10 g BRJ extract per liter of drinking water provided for 13 days); and 4) BRJ+DOX (BRJ for 7 days before DOX injection on Day 8 and throughout the 5-day post-DOX period. On Day 13, heart tissue samples were collected for determining the key autophagy markers with real-time PCR or Western blots.

Results:
Cardiac protein expression of AMBRA-1 (Fig. A) and ATG-5 (Fig. C) was significantly enhanced by BRJ with or without DOX co-treatment (P<0.05). Interestingly, BRJ intake also significantly augmented mRNA levels of AMBRA-1 (Fig. B) and ATG-5 (Fig. D) in BRJ+DOX group. Furthermore, the ratio of LC3B-II/LC3B-I, another hallmark for autophagy was decreased in DOX group, but restored in BRJ+DOX group to the level of Saline control group.

Conclusions:
BRJ intake significantly upregulates several key molecular markers of cardiac autophagy such as AMBRA-1 and ATG-5, which may contribute to BRJ-induced protection against DOX cardiotoxicity. The autophagy-related novel molecular mechanisms revealed in this study may provide a new rationale for potential use of BRJ as a safe nutraceutical therapy in reducing cardiotoxicity caused by DOX chemotherapy.
Abstract 11013: Predictive Role of Late Gadolinium Enhancement on Cardiac Magnetic Resonance in Hypertrophic Cardiomyopathy: An Updated Meta-Analysis
Authors: Yao Jialu , Zhou Yafeng , Yang Xiangjun , Qian Xiaodong
Published: April 2024

Background:
Myocardial fibrosis detected by late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) is currently used to predict adverse cardiovascular events in patients with hypertrophic cardiomyopathy (HCM). However, controversies remain about its prediction value of sudden cardiac death (SCD).

Objective:
The aim of this study was to perform an updated meta-analysis of the prediction value of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) for future events and death in hypertrophic cardiomyopathy (HCM).

Methods:
We searched PubMed and Web of Science for clinical trials that investigated the prognosis indexes of LGE in HCM patients. The outcomes of interest comprised all-cause mortality, cardiac death, SCD, aborted SCD and heart failure death. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the role of LGE CMR in the risk stratification of HCM.

Results:
Seven studies were retrieved from 393 citations for the analysis, and in total, 3423 patients (mean age: 52.3 years; median follow up: 37.7 months) were included in the analysis. After synthesizing data, the meta-analysis showed that LGE by CMR was associated with SCD/Aborted SCD (OR=2.921, 95%CI=1.760-4.848; P<0.001) and all cause mortality (OR=1.715, 95%CI=1.013-2.901; P=0.044), and showed a trend toward significance of predicting cardiac death (OR=2.174, 95%CI=1.000-4.727; P=0.05). However, we did not observe a correlation between LGE and heart failure death (OR=2.066, 95%CI=0.788-5.416; P=0.14).

Conclusions:
LGE by CMR exhibited a substantial prognostic value in SCD events prediction. Significant associations were found between LGE and SCD, and all cause mortality. Moreover, LGE displayed a trend toward significance on cardiac death but not on heart failure death. Myocardial fibrosis assessed by LGE is effective in SCD risk stratification in patients with HCM.
Abstract 11081: Crucial Role of Thrombin Activatable Fibrinolysis Inhibitor in the Pathogenesis of Chronic Thromboembolic Pulmonary Hypertension
Authors: Satoh Taijyu , Satoh Kimio , Yaoita Nobuhiro , Kikuchi Nobuhiro , Omura Junichi , Kurosawa Ryo , Nogi Masamichi , Otsuki Tomohiro , Kozu Katsuya , Numano Kazuhiko , Suzuki Kota , Sunamura Shinichiro , Tatebe Shunsuke , Aoki Tatsuo , Sugimura Koichiro , Shimokawa Hiroaki
Published: April 2024

Background:
Chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease; however, its pathogenesis still remains to be elucidated. We tested our hypothesis that thrombin activatable fibrinolysis inhibitor (TAFI) plays a crucial role in the pathogenesis of CTEPH as it regulates fibrinolysis, reduces plasmin production, and prolongs clot lysis time.

Methods and Results:
In the lung of CTEPH patients, perivascular expression of TAFI in small pulmonary arteries (PA) was enhanced. In mice
in vivo
, chronic exposure to hypoxia (O
2
10%, 3 weeks) caused TAFI up-regulation in the lung. We then newly developed TAFI- overexpressing mice (Tg), in which chronic hypoxia increased right ventricular systolic pressure (RVSP) and caused RV hypertrophy and PA remodeling to a greater extent than in littermate controls (all P<0.05, n=8 each). Moreover, Tg mice (n=19) showed a significantly reduced long-term survival under hypoxia compared with controls (n=22) (63 vs. 95%, P<0.01). To evaluate the role of TAFI for inflammatory cell recruitment, we performed bone marrow reconstitution with GFP
+
cells, which demonstrated increased recruitment of GFP
+
cells in Tg mice compared with controls by 3D imaging. In experiments with pulmonary artery smooth muscle cells (Tg-PASMCs)
in vitro
, cell proliferation was significantly increased in Tg-PASMCs compared with controls (2.8 vs. 1.8-fold, n=8 each, P<0.01). Hypoxia (2% O
2
) significantly increased TAFI expression and secretion from PASMCs. Furthermore, Tg-PASMCs showed significantly enhanced p38 activity and secretion of inflammatory cytokines/chemokines and growth factors compared with controls. Conditioned medium from Tg-PASMCs promoted cell proliferation compared with controls (1.3- vs. 1.1-fold, n=8 each, P<0.05). Human recombinant TAFI (100 nM) also promoted proliferation of PASMCs from CTEPH patients compared with vehicle controls (1.21- vs. 0.97-fold, n=8 each, P<0.01). Finally, plasma levels of activated TAFI were significantly increased in CTEPH patients (n=32) compared with healthy controls (n=13) (8.7-fold, P<0.01).

Conclusions:
These results indicate that TAFI plays a crucial role in the pathogenesis of CTEPH, suggesting that it is a novel therapeutic target for CTEPH.
Abstract 11141: Left Ventricular Global Longitudinal Strain in Patients With Heart Failure With Preserved Ejection Fraction: Outcomes Following an Acute Heart Failure Hospitalization
Authors: Buggey Jonathan , Alenezi Fawaz , Yoon Hyun Ju , Phelan Matthew , DeVore Adam D , Khouri Michel G , Schulte Phillip J , Velazquez Eric J
Published: April 2024

Objectives:
To assess the association between abnormal left ventricular global longitudinal strain (LV GLS) and outcomes in patients hospitalized with acute heart failure with preserved ejection fraction (HFpEF).

Methods:
Patients discharged alive from Duke University Medical Center between 2007 and 2010 following admission for acute HFpEF who had an echocardiogram with left ventricular ejection fraction ≥50% during the admission comprised the analysis cohort. We performed 2-dimensional, speckle-tracking analysis and stratified the cohort by LV GLS as normal (≤-16%) or abnormal (>-16%). Cox proportional hazards models assessed the association between continuous LV GLS and outcomes.

Results:
We identified 545 consecutive patients with measurable LV GLS. The median LV GLS was -12.6% (25
th
-75
th
percentile, -15.5% to -10.6%) and 424 (78%) had abnormal LV GLS. Patients with abnormal LV GLS had higher levels of NT-proBNP (2548 vs. 1522 pg/mL, p=0.02) compared to those with normal LV GLS. There was no statistically significant association between LV GLS and mortality through 5 years (adjusted HR 1.02 per 1% increase; 95% CI: 0.98 to 1.06; p=0.33) or mortality and hospitalization (adjusted HR 1.02 per 1% increase; 95% CI: 0.99 to1.06; p=0.25) (
Figure
). A similar trend was seen between LV GLS and mortality and hospitalizations at 30 days (adjusted HR 1.08 per 1% increase; 95% CI: 1.00 to1.16; p=0.06) and 1 year (adjusted HR 1.04 per 1% increase; 95% CI: 1.00 to1.09; p=0.08).

Conclusions:
Using a cutoff value for LV GLS of -16%, a high prevalence of patients with acute HFpEF have abnormal LV GLS suggesting covert myocardial systolic dysfunction. However, LV GLS was not associated with mortality after accounting for traditional risk factors. Further studies are necessary to understand the role for LV GLS in routine clinical practice for HFpEF patients.
Abstract 11416: The “Natural History” of Intra-operative Pulmonary Artery Stents: A 20-year Perspective
Authors: Zampi Jeffrey D , Loccoh Emefah , Armstrong Aimee K , Yu Sunkyung , Lowery Ray , Rocchini Albert , Hirsch-Romano Jennifer C
Published: April 2024

Background:
Branch pulmonary artery (PA) stenoses are typically treated with catheter-based percutaneous therapies or surgical arterioplasty. Intra-operative (intra-op) PA stent placement is an alternative strategy. In this study, we sought to describe our 20-year experience with intra-op PA stent placement and to evaluate long-term patient outcomes, specifically the need and risk factors for re-intervention.

Methods:
We performed a retrospective review of all intra-op PA stents placed at our institution from 1994-2013. Patient and stent characteristics and outcome data were collected. Risk factors associated with re-intervention were identified using univariate cox regression analysis.

Results:
Eighty-one PA stents were placed in 68 patients, mostly to treat proximal PA stenoses (85%). Stent implantation was acutely successful in 67 patients (98.5%) with a procedural complication rate of 4.4%. Stents capable of being dilated to large diameters (“adult-size”) were used in 97% of patients. At hospital discharge, 93% of patients had no or mild residual PA stenosis by echocardiogram. During a median follow-up period of 6 years (interquartile range 0.9-12.7), 31 patients (46%) underwent PA re-intervention with a median time to first re-intervention of 2.5 years. Risk factors for re-intervention included age < 18 months (Hazard ratio [HR] 3.26, p=0.002) and body surface area < 0.47 m2 (HR 3.47, p=0.001) at the time of stent implantation, and the presence of multiple aorto-pulmonary collaterals in patients with tetralogy of Fallot (HR 3.19, p=0.02).

Conclusions:
Intra-op PA stent implantation is technically feasible with low procedural complications. It offers several advantages over transcatheter stenting, including the ability to implant adult-size stents in small patients while avoiding injury to percutaneous vessels, to position and flare stents to facilitate future percutaneous stent re-dilation, and to access the PAs directly, which shortens procedural time and eliminates radiation exposure. It also may prevent re-stenosis from scar tissue caused by patch arterioplasty. A future direct comparison of intra-op PA stenting to catheter-based stenting and surgical arterioplasty for PA stenosis is necessary.
Abstract 11457: Surveillance of Perioperative Myocardial Injury With Cardiac Troponins Influences Medical Management at the Time of Hospital Discharge
Authors: Zakharova Marina , Mazzulla Francesca , Rector Thomas , McFalls Edward O , Yannopoulos Demetris , Brilakis Emmanouil , Garcia Santiago
Published: April 2024

Background:
Current AHA/ACC guidelines recommend against the use of cardiac troponins (cTn) for the surveillance of perioperative myocardial injury (PMI) in asymptomatic patients. We hypothesized that surveillance of PMI with cTnI would lead to initiation or intensification of medical therapies for coronary artery disease (CAD).

Methods:
The Cardiac Remote Ischemic Preconditioning Prior to Elective Vascular Surgery (CRIPES, NCT 01558596) is an ongoing prospective, randomized, sham-controlled phase 2 trial using remote ischemic preconditioning prior to elective vascular procedures. The primary efficacy end-point is the proportion with and magnitude of postoperative increases in cTnI. Cardiac troponins, measured before and after surgery, were available to treating clinicians. Increases above ≥ 0.01 μg/L in the perioperative period were considered clinically significant. Intensification of medical therapy was defined as initiation of aspirin (ASA) or initiation/increases in the dose of angiotensin-converting-enzyme inhibitors (ACEI)/angiotensin-receptor blockers, statins, or beta-blockers.

Results:
Between June 2011 and April 2015, a total of 185 patients (mean age 68±7, 100% male) were enrolled in the trial. A total of 28 patients (15%) had significant increases in cTnI after vascular surgery and 38 (20.5%) had their medical therapies intensified in the perioperative period. Baseline utilization of medical therapies was high: ASA 86%, statins 75%, beta-blockers 65%, ACEI 48%. The most frequent change in medical therapy in the perioperative period was initiation of ASA (9%). Among patients with substantial increases in cTnI 11 (39%) had intensification of medical therapy versus 27 (17%) in patients with no or smaller increases in cTnI (p=0.02). Using logistic regression analysis to control for subject’s age, history of CAD, CHF, diabetes, high-risk surgery, and revised cardiac risk index, a cTnI increase > 0.01 μg/L remained associated with intensification of medical therapy (odds ratio: 3.2, 95% CI: 1.3-8.3. p=0.014).

Conclusions:
Among patients undergoing vascular surgery, surveillance of cTn in the perioperative period has value, by altering the clinician’s decisions to either initiate or intensify medical therapies for CAD.
Abstract 11498: MicroRNA 140 Regulates Disease Phenotype in Experimental Pulmonary Arterial Hypertension And Identifies Smurf1 as a Novel Therapeutic Target
Authors: Rothman Alexander M , Arnold Nadine D , Pickworth Josephine A , Iremonger James , Ciuclan Loredana , Allen Robert , Guth-Gundel Sabine , Southwood Mark , Morrell Nicholas W , Francis Sheila E , Rowlands David , Lawrie Allan
Published: April 2024

Rationale:
Clinical therapies for the treatment of pulmonary arterial hypertension (PAH) target vasoconstriction. However, the proliferative pulmonary vascular remodelling that drives disease persists contributing to significant patient morbidity and mortality. MicroRNA (miR) are short non-coding RNA that mediate post-transcriptional regulation of mRNA targets. We hypothesise that dysregulation of miR leads to de-repression of cellular targets central to disease pathogenesis.

Objective:
To identify dysregulated circulating miR in patients with PAH, determine their phenotypic effect using in vitro and in vivo models and identify key mechanistic regulators that may represent novel therapeutic targets.

Methods and Results:
Expression of miR-140 was reduced in whole blood samples from patients with PAH and the monocrotaline (Mct) and Sugen5416 plus Hypoxia (SuHx) rat models of PAH. Reduced expression of miR-140 at the time of diagnosis identified patients with adverse clinical outcome. Network and pathway analysis identified key regulators of TGFß and PDGF signalling as miR-140 targets. Transfection with miR-140 inhibitor resulted in increased proliferation and migration of PASMC and de-repression of key targets. Nebulised delivery of miR-140 mimic prevented the development of PAH in the Mct rat model and attenuated progression of established PAH in the Mct and SuHx rat models. SMAD Specific E3 Ubiquitin Protein Ligase 1 (SMURF1) mRNA and protein was decreased in the lungs of miR-140 mimic treated animals. Levels of SMURF1 protein correlated inversely with miR-140. Direct regulation of SMURF1 by miR-140 was demonstrated in vitro by 3’UTR luciferase activity. Both miR-140 mimic and SMURF1 siRNA increased BMP response element activity identifying SMURF1 as a key negative regulator of BMP signalling in PASMC. Genetic ablation of SMURF1 in C57BL6 mice conferred allele dependent protection from SuHx induced PAH. Finally, whole blood mRNA and pulmonary vascular immunoreactivity of SMURF1 was increased in patients with PAH.

Conclusions:
These studies suggest that miR-140 and SMURF1 are key regulators of BMP signaling and disease pathology in PAH and highlight SMURF1 as a potential novel therapeutic target.
Abstract 11575: Comparative Effectiveness of Generic Atorvastatin and Lipitor® in Patients Hospitalized With an Acute Coronary Syndrome
Authors: Jackevicius Cynthia , Tu Jack , Krumholz Harlan , Austin Peter , Ross Joseph , Stukel Therese , Koh Maria , Chong Alice , Ko Dennis
Published: April 2024

Introduction:
After generic atorvastatin became available in Canada in June 2010, Ontario’s public prescription benefit program mandated universal substitution of Lipitor® to generic atorvastatin to reduce expenditures. Although generic medications are approved based on bioequivalence with brand-name medications, there remains substantial concern about their clinical effectiveness and safety. This policy change afforded a unique opportunity to compare clinical outcomes between patients with acute coronary syndrome (ACS) prescribed generic atorvastatin and Lipitor®.

Methods:
We assembled a population-based cohort of patients ≥65 years, discharged alive after an ACS hospitalization between 2008-2012, who were prescribed generic atorvastatin or Lipitor® within 7 days of discharge. Propensity score-matching on demographics, comorbidities, medical and invasive treatment, and physician and hospital characteristics was used to adjust for confounding. The primary outcome was death or recurrent ACS hospitalization at 1-year. Secondary outcomes included hospitalization for heart failure, stroke, new-onset diabetes, rhabdomyolysis, and renal failure.

Results:
In the 7,863 matched pairs (15,726 patients) of ACS patients, mean age was 76.9 years, 56.3% were male, 87.6% had a myocardial infarction and 12% had unstable angina, and all patients had complete follow-up. At 1-year, 17.7% of those prescribed generic atorvastatin and 17.7% prescribed Lipitor® experienced death or recurrent ACS (HR:1.00, 95%CI 0.93-1.08, p=0.94). Pre-specified subgroup analyses by age, sex, diabetes, atorvastatin dose, admission diagnosis, or generic product also found no difference between groups. No significant differences in secondary outcomes, including side effects, between treatment groups were observed.

Conclusions:
Among older adults discharged alive after ACS hospitalization, we found no significant difference in cardiovascular outcomes or side effects in patients prescribed generic atorvastatin compared with those prescribed Lipitor® at 1 year. Our findings support the use of generic atorvastatin in ACS, which could lead to substantial cost saving for patients and healthcare plans without diminishing population clinical effectiveness.
Abstract 11602: Direct Evidence That Vascular Endothelial Protection Leads to aa Reduction of Heart Failure
Authors: Maupoint Julie , Martinet Jérémie , Gomez Elodie , Bouhzam Najime , Besnier Marie , Henry Jean-Paul , Boyer Olivier , Mulder Paul , Richard Vincent
Published: April 2024

Introduction:
Heart failure (HF) induces endothelial dysfunction, and especially decreases nitric oxide (NO) production, but the direct link between endothelial dysfunction and aggravation of HF is unknown. We previously reported a new treatment of endothelial dysfunction, based on inhibition of protein tyrosine phosphatase 1B (PTP1B), which both increases NO production and reduces cardiac dysfunction in HF. However the exact role of
endothelial
PTP1B in these effects is unknown.

Hypothesis:
Specific endothelial deletion of PTP1B reduces HF by limiting endothelial dysfunction

Methods:
Endothelial deletion of PTP1B was obtained by crossing LoxP-PTP1B mice with mice expressing Cre recombinase under the control of the endothelial promoter Tie2. Since this Tie2-Cre approach is known to also induce gene extinction in hematopoietic cells, Tie2Cre(+)PTP1Bf/f mice were also lethally irradiated and reinjected with bone marrow from wild type (WT; CD45.1) mice, in order to obtain a specific deletion of endothelial PTP1B (endoPTP1B-/- mice). All mice were then subjected to 4 months of myocardial infarction (MI) in order to induce HF, or to sham surgery

Results:
Vascular function evaluated
ex vivo
in mesenteric arteries (arteriograph) showed that in WT mice, HF markedly impaired endothelium-dependent, flow-mediated dilatation (sham: 40±4%; HF: 5±5; p<0.001). This HF-induced endothelial dysfunction was less marked in Tie2Cre(+)PTP1Bf/f (MI: 30±5; p<0.001 vs. WT) and in endoPTP1B-/- mice (35±6%). This improved response in endoPTP1B-/- mice were abolished by a NO-synthase inhibitor, suggesting a restored NO production.

Evaluation of cardiac function by echocardiography showed that in WT, MI decreased left ventricular fractional shortening (sham: 49±2; HF: 12±1%; p<0.001) and which was improved in Tie2Cre(+)PTP1Bf/f (26±1%; p<0.01 vs. WT), and in endoPTP1B-/- mice (29±1%; p<0.01 vs. WT). In parallel, endothelial PTP1B deficiency was associated with an increased survival.

Conclusions:
Endothelial PTP1B deficiency induced an improvement of endothelial function but especially improved cardiac function. These results provide a direct demonstration of the beneficial effect of endothelial protection in HF.
Abstract 11619: Basal Septal Hypertrophy in Severe Aortic Stenosis is Associated With Worse Left Ventricular Diastolic Function but Has Not Impact on the Postoperative Transvalvular Pressure Gradients
Authors: Alexandru Dragos , Petillo Florentina , Pollack Simcha , Reichek Nathaniel , Barasch Eddy
Published: April 2024

Background:
Basal septal hypertrophy (BSH) is found in 1.5 %-18% of the general population associated with hypertension. Its significance in severe aortic stenosis (AS) is uncertain. Hypothesis: In AS, BSH may adversely affects LV diastolic function and increases transvalvular gradients after valve replacement (AVR).

Methods:
Between 2011-2014, 6012 pts with AS of some degree underwent echocardiography. Severe AS was present in 255 with a septal buldge and normal EF, of whom 30 had BSH (AS+/BSH+). 106 were AS+/BSH-. Controls included 119 AS-/BSH+ pts. 38 with AS+/BSH+ with any EF underwent AVR. BSH was defined as BS diastolic diameter ≥ 15 mm and BS >2 mm thicker than mid septum in PSLAX view in multiple images. Inter and intraobserver reliability were calculated (ICC, n = 20). One-way ANCOVA, Fisher’s exact test and multivariate logistic regression controlled for age, sex and BSA were used as appropriate.

Results:
ICC = 0.99 for BS and 0.80 for mid septum. AS+/BSH+ pts were older than AS+/BSH-, more were females and their diastolic function was worse despite similar transvalvular gradients, AVAi, LV mass index (table), and similar medical histories. After controlling for prosthetic valve type and size and stroke volumes, BSH did not affect post AVR transvalvular gradients. In adjusted logistic regression models, BSH was associated with E/A (OR = 2.6, CL s:1.32 and 5.29, p =0.006, AUC = 0.85) and showed a trend toward association with LA area index ( OR = 1.14, CLs,1.14 and 0.99, p = 0.06, AUC = 0.77). Conclusions: 1. Using rigorous criteria,< 4% of pts with severe AS have BSH. 2. AS+/BSH+ have Doppler evidence of higher LV filling pressures despite similar stenosis severity and LV mass than AS +/BSH- pts, so that BSH may be a marker of worse diastolic function. 3. BSH does not affect post AVR transvalvular pressure gradients. 4. Larger prospective studies are warranted to validate these findings and compare outcomes of AS pts with and without BSH.
Abstract 11625: Role of Wnts and Secreted Frizzled-Related Protein-1 in Atrial Fibroblast Pathophysiology During Atrial Fibrotic Remodeling
Authors: Surinkaew Sirirat , Dawson Kristin , Qi Xiao- Y , Sun Yiguo , Huang Hai , Chen Yu , Naud Patrice , Nattel Stanley
Published: April 2024

Introduction:
Left atrial (LA) fibroblasts (FBs) respond differentially vs left ventricular (LV) to fibrotic stimuli underlying LA selective fibrosis and atrial fibrillation (AF) in contexts like heart failure (HF). The most differentially expressed gene between LA and LV FBs (28 fold greater in LA) is secreted frizzled-related protein-1 (sFRP1), an endogenous Wnt antagonist. However, the role of sFRP1 and Wnt signaling in FB pathophysiology is unknown.

Methods:
HF-related LA remodeling was induced in dogs by ventricular tachypacing (VTP 240 bpm). mRNA and protein were quantified in freshly isolated FBs by qPCR (19 Wnt ligands) and immunoblot. Recombinant Wnt and sFRP1 proteins were used to assess effects on FBs; lentivirus-transferred small interfering RNA (siRNA) to knock down sFRP1.

Results:
AF duration, collagen1 and fibronectin expression increased at 1 and 2 wk VTP, paralleling LA fibrosis. Wnt2 and Wnt5a showed high FB expression. Wnt2 increased in LA FBs at 2 wks (4.8 fold) but did not change in LV (Fig A). Wnt5a decreased quickly in LA and LV (at 12 hrs, -8.9 and -2.9 fold) and remained decreased in LA up to 2 wks (Fig B). sFRP1 decreased at 12 and 24 hrs (-3.9 and -5.4 fold). Treatment of LA FBs with Wnt2 or Wnt5a increased cell size, collagen1 (1.7 and 1.8 fold) and fibronectin (31 and 2.1 fold) expression, and decreased sFRP1 mRNA (by 95% and 54%) (Fig C). Recombinant sFRP1 decreased fibronectin expression (-2.4 fold). Moreover, sFRP1 KD (85% reduction) increased Wnt2 and Wnt5a expression by 4.1 and 7.5 fold (Fig D), suggesting mutual negative interaction between sFRP1 and Wnt signaling in regulating ECM protein secretion.

Conclusions:
A variety of Wnt ligands are strongly and dynamically expressed in LA. Wnt2 and Wnt5a show countervailing changes during LA fibrosis development in HF, and negatively interact with sFRP1. Our results indicate complex regulation of atrial FB function by the Wnt system, which may provide novel therapeutic targets for AF-substrate prevention.
Abstract 11907: The Association of Life’s Simple 7 Health Metrics and Incident Non-Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis
Authors: Ogunmoroti Oluseye , Allen Norrina B , Michos Erin D , Rundek Tatjana , Rana Jamal , Blankstein Ron , Blumenthal Roger S , Cushman Mary , Blaha Michael J , Veledar Emir , Nasir Khurram
Published: April 2024

Introduction:
The American Heart Association (AHA) introduced the Life’s Simple 7 (LS7) health metrics to assess and promote cardiovascular health and wellness. Favorable LS7 status is associated with reduced risk of cardiovascular and all-cause mortality. We assessed the association between the LS7 health metrics and non-cardiovascular disease (non-CVD).

Methods:
6,814 participants (mean age 62 ±10 years, females 53%) from the Multi-Ethnic Study of Atherosclerosis (MESA) were followed for a median of 10.2 years. Each component of the LS7 metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure and blood glucose) was categorized into 3 according to AHA criteria and assigned points, ideal (2), intermediate (1) and poor (0). The LS7 health index, created from the metrics, was categorized into 3 levels based on total number of points achieved, ideal (11-14), intermediate (9-10) and poor (0-8). Cox proportional hazard ratios and incidence rate per 1000 person-years were calculated for hospital ICD-9 diagnoses of cancer, chronic kidney disease (CKD), pneumonia, chronic obstructive pulmonary disease (COPD), dementia and hip fracture. Analyses were adjusted for age, race/ethnicity, and socioeconomic status.

Results:
Overall all non-CVD event rates were lower with improving LS7 health status (Figure 1). In multivariable adjusted models (Table 1), with the poor category of the LS7 health index as reference, individuals in the ideal category had a lower hazard for non-CVD events, 21% lower for cancer (95% CI 0.64-0.98), 62% lower for CKD (95% CI 0.27-0.53), 45% lower for pneumonia (95% CI 0.39-0.78) and 48% lower for COPD (95% CI 0.31-0.85).

Conclusion:
The LS7 health index may identify vulnerability for multiple chronic conditions beyond CVD. These results suggest the implications of achieving the AHA’s national goal of ideal LS7 health metrics are favorable, as it will reduce the burden of many diseases as well as health care costs.
Abstract 11928: An Interaction Between The Time Delay And Pharmacologic Pre-treatment. Effect On Myocardial Perfusion And Infarct Size
Authors: Prech Marek , Bartela Ewa , Janus Magdalena , Araszkiewicz Aleksander , Jeremicz Igor , Kutrowska Aleksandra , Pyda Malgorzata
Published: April 2024

Introduction:
Primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion in STEMI patients. However, optimal adjunctive pharmacotherapy is still under investigation.

Hypothesis:
To assess the effect of triple pharmacologic therapy on myocardial perfusion and infarct size in relation to different time delays.

Methods:
We studied 309 consecutive STEMI patients admitted within 12 hours from symptom onset with: (1) chest pain persisting for >30min, (2) ST-segment elevation >1mm in ≥ 2 contiguous leads, (4) pre-treatment with 600mg of clopidogrel, 300mg of aspirin and 5000U of intravenous heparin. Group I (n=90) comprised patients transferred immediately to cathlab, group II (n=219) consisted of patients transferred via local hospitals (staged transfer). Results of TIMI flow prior to PCI and post-PCI, ST-segment resolution, troponin T level and MBG were analyzed in relation to time delay to intervention.

Results:
The median time interval between the onset of symptoms and pharmacologic pre-treatment was comparable in both groups, but the delay between pharmacologic pre-treatment and angiography was twice longer in cases of staged transfer. Despite a longer delay to intervention, higher rates of pre-angiography total ST-segment resolution (STSR) and TIMI flow 3 at initial angiography were observed in those patients. Differences in the rate of total STSR, TIMI flow 3 and MBG were no longer observed post PCI. Similarly, the peak troponin level was comparable in both groups - table.

Conclusions:
1. Pre-hospital treatment with a combination of antiplatelet and antithrombotic agents improves myocardial perfusion.

2. Longer transfer delay paradoxically allows for the amplification of pharmacologic pre-treatment before mechanical reperfusion.
Abstract 11934: Resuscitation by Transfusion With Hemoglobin Vesicles in Trauma Hemorrhagic Shock / Coagulopathy Rabbits
Authors: Hagisawa Kohsuke , Kinoshita Manabu
Published: April 2024

Introduction:
We have developed Hemoglobin vesicle (HbV) as an artificial substitute for Red blood cells (RBC).

Hypothesis:
To evaluate the efficacy of HbV for alternative treatment of massive transfusion protocol (MTP) in traumatic hemorrhagic shock / coagulopathy rabbits.

Methods:
Hemorrhagic shock / thrombocytopenia were induced in rabbits by repeated blood withdrawal (total 400ml) and isovolemic transfusion of autologous washed RBC. Liver penetrating injury led lethal oozing hemorrhage. Balloon compression and Platelet rich plasma (PRP) administration stopped bleeding. Thereafter, allogenic RBC transfusion, HbV or 5% Albumin was administered to the animals (n=30). Acute prognosis was compared among them for 24 hr. Hemodynamic and hematologic parameters were periodically recorded for first 1hr.

Results:
In anemic and thrombocytopenic rabbits (Hb < 6.0 g/dl, platelets < 40,000 /μL, mean arterial pressure (MAP) < 50 mmHg), liver penetrating injury caused additional bleeding and animals suffered class IV shock (Hb < 5.0 g/dl, MAP < 40 mmHg). PRP administration restored platelets ≧ 70,000 /μL, which stopped bleeding within 40 min. Subsequent administration of HbV as well as RBC transfusion regained MAP more than 50 mmHg, and they rescued 70 % animals from liver hemorrhage, although rabbits receiving 5% albumin showed 10% survival in the first 24 hours. HbV administration did not affect the coagulation parameters as well as RBC transfusion.

Conclusions:
HbV may be effectively instead of RBCs for acute hemorrhagic shock and trauma induced coagulopathy.
Abstract 11966: Rhythm Changes Following Defibrillation During Resuscitation in Out-of-hospital Cardiac Arrest
Authors: Li Yongqin , Gong Yushun , He Mi , Quan Weilun
Published: April 2024

Introduction:
In the treatment of cardiac arrest, immediate resumption of chest compressions is recommended after delivery of defibrillation. However, it is unclear what the optimal timing is to determine presence of an organized rhythm after shock delivery. The purpose of this study was to investigate the dynamic rhythm changes after defibrillation during resuscitation.

Methods:
A total of 581 shocks from 264 out-of-hospital cardiac arrest patients with ventricular fibrillation (VF) as the first recorded rhythm were included in this study. Post shock rhythms were analyzed every10 seconds after each shock up to 120 seconds. We determined the presence of VF, asystole (AS) and organized rhythm (OR) at each time point.

Results:
Ten seconds after shock delivery, VF had been terminated in 70.4% cases (N=409). However, 53.5% of these non-VF rhythms were AS (N=219). Rhythm changes occurred in half of all cases (N=274, 47.2%) during the 2 minutes after shock delivery (Figure 1) and 88.3% of these changes occurred within 60 seconds. Of those initially in AS, 62 (28.3%) evolved into OR within 32.4±24.6 seconds and 117 (53.4%) returned to VF after 31.3±19.9 seconds. Of those with OR (N=190), 89 (46.8%) returned to VF 40.2±28.2 seconds later and 6 degenerated to AS (3.2%) after 48.3±41.7 seconds. VF was recurred in 50.4% (N=206) non-VF rhythms but there were no post-shock rhythm changes in patients remaining in VF (N=172) after shock delivery.

Conclusion:
Post-shock rhythms are very volatile in the first minute after shock delivery. Given the large percentage of post-shock rhythm changes, chest compressions should resume for at least 60 seconds immediately after a shock before rhythm and pulse are checked. Technology displaying cardiac rhythm during chest compressions could help to decide whether chest compressions should be stopped for a pulse check at that time.
Abstract 12012: Relation Between Colchicine and Epicardial Adipose Tissue Volume Surrounding Left Atrium in Atrial Fibrillation Recurrence After Ablation
Authors: Egami Yasuyuki , Nishino Masami , Shutta Ryu , Makino Nomuhiko , Tanouchi Jun
Published: April 2024

Background:
Immediate recurrence of atrial fibrillation (AF) after AF ablation was related with inflammatory process. Colchicine treatment after AF ablation can reduce AF recurrence by suppression of such inflammatory reactions. The epicardial adipose tissue (EAT) has been shown to release activated pro-inflammatory cytokines and to associate with the development of AF. However, it is unclear whether colchicine treatment affects recurrence of AF according to EAT volume of left atrium (LA-EAT volume). The purpose of this study was to evaluate the relation between reduction of AF recurrence by colchicine treatment after AF ablation and LA-EAT volume.

Methods:
One hundred twenty two consecutive AF patients who underwent AF ablation and in whom multi-detector computed tomography was performed before ablation were included. Colchicine was prescribed to patients who approved colchicine treatment and was started at 0.5 mg/day for 2 weeks after AF ablation. We divided the study patients into larger LA-EAT group and smaller LA-EAT group according to the median (22.4 cm3) of LA-EAT volume. LA-EAT volume was obtained by semi-automatically tracing axial images from the bifurcation of the pulmonary artery to the coronary sinus and EAT was recognized using threshold attenuation values of -50 to -200 HU. In each group, we compared incidences of AF recurrence (AF > 30 sec) in 3 months and 12 months after ablation between colchicine group and non-colchicine group.

Results:
Forty-two patients received colchicine. In larger LA-EAT group (> 22.4 cm3) (n=60) incidence of AF recurrence in colchicine group showed lower tendency in 12 months after ablation (10.5% vs. 34.2%, p=0.06) while in smaller LA-EAT group (< 22.4 cm3) (n=62), incidence of AF recurrence was similar between colchicine group and non-colchicine group (Table).

Conclusion:
Colchicine treatment after AF ablation may reduce mid-term AF recurrence in AF patients with larger LA-EAT volume.
Abstract 12040: JAK-STAT Signalling and the Atrial Fibrillation-Promoting Fibrotic Substrate: Pathogenic Role and Possible Therapeutic Target
Authors: Chen Yu , Surinkaew Sirirat , Qi Xiao- Y , Huang Hai , Gillis Marc- A , Duval Francine , Shi Yan- F , Naud Patrice , Tardif Jean- C , Dobrev Dobromir , Nattel Stanley
Published: April 2024

Introduction:
Left atrial (LA) fibrosis is an important feature of the atrial fibrillation (AF) substrate. The JAK-STAT system, activated by platelet derived growth factor (PDGF), contributes to cardiac remodeling but its role in AF is unknown. Here, we investigated the participation of the JAK-STAT system in LA fibrosis development.

Methods:
Heart failure (HF) was induced in dogs by ventricular tachypacing (VTP, 240 bpm) and in mice subjected to myocardial infarction (MI). Protein and mRNA expression were measured in freshly isolated LA fibroblasts (FBs) by Western blot and qPCR. Mice received S3I-201,a selective STAT3 inhibitor, or vehicle control (CTL) by osmotic minipump for 2 weeks post MI.

Results:
HF dogs developed progressive LA-selective fibrosis and AF susceptibility beginning at 1 wk VTP. HF increased JAK2 mRNA expression in LA FBs from 1 wk VTP (1.4-1.5 fold**, **P<0.01). Phosphorylated JAK2 and STAT3 protein increased in HF atrial tissue by 2.5** and 2.9* fold (*p<0.05) respectively. Upstream signalling through PDGF was also enhanced by HF: PDGF A/C/D upregulated by 2.2-3.5*** fold (***p<0.001); PDGFR β upregulated by 2.3** fold. PDGF stimulation of CTL dog LA FBs increased TGFβ1, TGFβ receptor 2, STAT3, collagen 1α1 and collagen 3α1 expression (by 1.2-2.3 fold***). These effects were abolished by S3I-201 in a dose dependent manner (by 79%*** at 100 μM). In vivo S3I-201 treatment (Figure) decreased LA fibrosis (by 60%***), LA dimension at end systole (by 11%*) and P wave duration (by 31%***). MI-induced LV dilation and contractile dysfunction were not affected by S3I-201.

Conclusions:
HF activates the LA JAK-STAT system via enhanced PDGF signalling. JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine FBs in vitro and attenuates LA fibrosis and electrical remodeling post MI in mice. These results suggest that the JAK/STAT pathway plays an important role in LA fibrogenesis and is a potential target for LA fibrosis prevention in man.
Abstract 12108: Long-term Increased Inpatient and Outpatient Visits Associated With Cardiovascular Events: A Large Real World Study
Authors: Fox Kathleen M , Wang Li , Quek Ruben G , Gandra Shravanthi R , Li Lu , Baser Onur
Published: April 2024

Introduction:
This study evaluated the burden to patients and the healthcare system associated with a new cardiovascular event (CVEs) up to 3 years after a new CVE among high-risk hyperlipidemia patients. Hypothesis: High-risk hyperlipidemia patients with new CVEs have long-term clinical burden.

Methods:
Using the IMS LifeLink PharMetrics Plus claims database, this retrospective cohort study included high CV risk hyperlipidemia patients with and without a new CVE between 01/01/2006 and 06/30/2012. CVEs included primary inpatient claims for myocardial infarction, unstable angina, ischemic stroke, transient ischemic attack, revascularization and heart failure. Patients were stratified into two CV risk cohorts: history of cardiovascular disease (CVD) and coronary heart disease risk equivalent (CHD RE) [See table for definitions]. Propensity score matching was applied to compare the burden among patients with and without a new CVE, from 1 month through 3 years post-CVE date.

Results:
Total 21,482 patients were included in the history of CVD and 181,228 in the CHD RE cohort. During the 31-365 days post-new CVE, the mean inpatient length of stay was significantly longer for patients with a new CVE than for those without (history of CVD: 6.61 vs. 2.06 days; CHD RE: 3.20 vs. 0.70 days, both p<0.0001). This trend was sustained through 3 years post-new CVE for both cohorts. In both cohorts, significantly more inpatient, outpatient and pharmacy visits per patient per month were observed between patients with and without a new CVE during month 1 and years 1, 2 and 3 post new CVE (Table). Conclusions: High-risk hyperlipidemia patients with new CVEs had significantly higher burden of hospitalizations and healthcare visits compared to matched patients without new CVEs, evident in the 1st month and sustained through 3 years post-CVE. Interventions used to prevent the occurrence of CVEs may alleviate the long-term clinical burden among high-risk hyperlipidemia patients in the US.
Abstract 12117: Screening for Metabolic Risk in Adolescent Blood Donors
Authors: Eason Stephen , Gore Odette , Ayers Colby , Goudar Shankar , Sayers Merlyn H
Published: April 2024

Introduction:
Cardiometabolic risk factors such as elevated blood pressure, total cholesterol and glycated hemoglobin (HbA1C) in adolescents persist into adulthood and are associated with increased risk for cardiovascular disease and diabetes. These risks are increased when multiple risk factors are present. High school blood drives are a unique opportunity to provide screening for cardiometabolic risk factors at low cost and minimum inconvenience to participants.

Methods:
Blood pressure (SBP and DPB), total nonfasting cholesterol and HbA1C were measured in volunteer blood donors aged 16-19 years, donating blood between January 2011 and December 2012, through Carter BloodCare in Dallas/Fort Worth, Texas. Cardiometabolic risk factors were classified as elevated (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg, cholesterol ≥ 200 mg/dL, HbA1C ≥ 6.5%) and borderline or elevated (SBP ≥ 120 mmHg and/or DBP ≥ 80 mmHg, cholesterol ≥ 170 mg/dL, HbA1C ≥ 5.7%).

Results:
The study included 24,925 donors (11,590 boys and 13,335 girls), including 8.4% African American, 2.2% Asian, 52.7% Caucasian, 24.9% Hispanic and 11.8% other/unknown. Only 33.6% of the entire cohort had no borderline or elevated risk factors (Table). However, 41.6% of females and 51.8% of males had at least 1 borderline or elevated risk factor. When viewed by ethnicity, 48.2% of Caucasians and 45.1% of African Americans had 1 borderline or elevated risk factor, with almost 25 % of African Americans having 2 or more borderline or elevated risk factors.

Conclusions:
Blood donor screening is confirmed as an opportunity to monitor the prevalence of multiple metabolic risk factors in an ostensibly healthy subset of the population. This scrutiny does identify individuals with multiple risk factors and also reveals ethnic and gender differences.
Abstract 12202: Inhaled Nitric Oxide Improves Artificial Circulation and Clinical Outcomes After Prolonged Cardiac Arrest
Authors: Derwall Matthias , Ebeling Andreas , Brücken Anne , Nix Christoph , Nolte Kay W , Fries Michael
Published: April 2024

Introduction:
Primary survival after cardiac arrest can be improved by optimizing circulation during CPR when using a minimal invasive left ventricular assist device (iCPR).

Hypothesis:
Inhaled nitric oxide may facilitate transpulmonary bloodflow during iCPR and thereby improve the functional outcome following cardiac arrest.

Methods:
Ventricular fibrillation (VF) was electrically induced in 20 anesthetized male pigs. Animals were left untreated for 10 minutes before iCPR was attempted. Subjects received either 20ppm of inhaled nitric oxide (iNO, n = 10) or 0ppm iNO (Control, n = 10), simultaneously started with iCPR until 5 hours following return of spontaneous circulation (ROSC). Animals were weaned from the respirator and followed up for five days using overall performance categories (OPC) and a spatial memory task. On day six, all animals were anesthetized again, and brains harvested for neurohistopathologic evaluation.

Results:
All animals in both groups achieved ROSC. iNO treated animals reached significantly higher iCPR flow during CPR (1.81 ± 0.30 L/min compared to 1.64 ± 0.51, p<0.001), leading to significantly higher coronary perfusion pressure (CPP) values during the 6 minutes of CPR (25 ± 13 vs. 16 ± 6 mmHg, p = 0.002). iNO animals showed significantly lower S-100 serum levels thirty minutes post ROSC (0.26 ± 0.09 vs. 0.38 ± 0.15 ng/mL, p = 0.048), as well as lower blood glucose values 120-360 minutes following ROSC.

Lower S-100 serum levels were reflected by superior clinical outcome of iNO treated animals as estimated with OPC (3 ± 2 vs. 5 ± 1, p = 0.036 on days 3 to 5). While n = 3 iNO treated animals were able to successfully participate in the spatial memory task, none of the controls were able to do so. Neurohistopathological examination of cerebral structures prone to ischemia-reperfusion injury revealed a trend towards less cerebral lesions in Neocortex, Archicortex, and Striatum when animals had been treated with iNO.

Conclusions:
In a model of prolonged cardiac arrest, the administration of 20ppm iNO during and following iCPR improved transpulmonary bloodflow and mitigated post-aggression metabolism, indicated by lower serum glucose levels. These effects translated into improved clinical outcomes in iNO treated animals.
Abstract 12206: Endothelial-derived Mif Contributes to Pulmonary Endothelial Cell Proliferation in Human Pulmonary Arterial Hypertension
Authors: Le Hiress Morane , Tu Ly , Phan Carole , Thuillet Raphaël , Ricard Nicolas , Seferian Andrei , Jutant Etienne-Marie , Fadel Elie , Simonneau Gerald , Huertas Alice , Tamura Yuichi , Humbert Marc , Guignabert Christophe
Published: April 2024

Introduction:
In idiopathic pulmonary arterial hypertension (iPAH), pulmonary-endothelial cells (P-ECs) display phenotypic abnormalities including a greater proliferative response to growth factors and apoptosis resistance; however, the precise underlying mechanisms remain obscure. Excessive MIF (macrophage migration-inhibitory factor) expression during the initial stages of tumor contributes to endothelial proliferation, tumor growth and progression.

Hypothesis:
We therefore hypothesized that MIF could function as a growth/survival factor promoting the altered P-EC phenotype in iPAH and disease progression.

Methods:
We examined the expression and the role of MIF in human lung tissues and in cultured pulmonary endothelial cells of control and idiopathic patients. In addition, two complementary animal models of pulmonary hypertension (PH) have been studied: the monocrotaline (MCT) and SU5416 plus chronic hypoxia (SuHx) rat models.

Results:
In distal pulmonary arteries (PAs) of patients with iPAH, we found a strong immunoreactivity for MIF in the endothelium compared with PAs from control patients. This aberrant endothelial MIF expression is also found in the two experimental models of PH. These
in situ
observations were replicated
in vitro
, with cultures P-ECs from patients with iPAH exhibiting increased MIF expression and release compared with control P-ECs. Decreasing MIF expression and signaling by RNA interference or a specific MIF inhibitor called ISO-1 decreased proliferation and induced apoptosis of iPAH P-ECs. Finally, we found that daily treatment of rats with ISO-1 for 2 weeks started 1 week after a subcutaneous monocrotaline injection partially reverses development of pulmonary hypertension.

Conclusions:
We report here that the pulmonary endothelium of iPAH patients represents a local abnormal source of MIF that could contribute to the hyperproliferative and apoptosis-resistant phenotype of iPAH endothelial cells.