bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16852: Inhibition of Hypoxia-Inducible Factor Prolyl Hydroxylase Reduces Infarct Size and Improves Cardiac Function in a Rat Model of Myocardial Ischemia Reperfusion Injury
Authors: Signore Pierre , Wei Zhihua , Fung Cyra , Russell Loren , Arend Michael , Flippin Lee , Walkinshaw Gail , del Balzo Ughetta
Published: April 2024

Hypoxia-inducible factor (HIF) has been shown to have cardioprotective effects when stabilized prior to a cardiac ischemic event. In the present studies, we investigated the cardioprotective effects of HIF stabilization post-ischemia, at the time of reperfusion, using the HIF prolyl-hydroxylase inhibitor (HIF-PHI) FG-6515. In a first study, the left coronary artery was temporarily ligated in rats to induce myocardial infarction (MI). After 30 minutes of ischemia, the ligature was removed, the myocardium was reperfused and FG-6515 (2, 6 or 20 mg/kg) or vehicle was administered once intravenously. Twenty-four hours after reperfusion, heart sections were stained with triphenyl tetrazolium chloride to measure infarct size as a percentage of the area at risk (AAR). FG-6515 given at reperfusion significantly decreased infarct size in a dose dependent manner (Table 1) and induced non-significant decreases in serum cardiac troponin I. In a second study using the same MI procedure, FG-6515 (20 mg/kg) was administered either once at reperfusion or 3 times (at reperfusion, 24 and 48 hours post-reperfusion). In addition, an MI group and a sham group received vehicle. Twenty-eight days after reperfusion, a Millar catheter was inserted in the left ventricle to measure cardiac function. FG-6515 significantly improved ejection fraction (EF), end-systolic volume (ESV) and relaxation time constant (RT). Three administrations of FG-6515 at daily intervals for the first 48 hours after reperfusion were more efficacious than a single administration (Table 2). In conclusion, these data support the use of HIF-PHI at reperfusion to limit infarct size and improve cardiac function after MI.
Abstract 16875: Measurement of Atherosclerotic Inflammation with FDG-PET Imaging Improves Cardiovascular Risk Stratification
Authors: Figueroa Amparo L , Abdelbaky Amr , Corsini Erin M , Lawler Meredith A , Gurm Gagandeep , Uthamalingam Shanmugam , Subramanian Sharath , Vijayakumar Jayanthi , Brady Thomas J , Hoffmann Udo , Tawakol Ahmed
Published: April 2024

Background:
FDG uptake correlates with cardiovascular (CV) events. Here we test the hypothesis that aortic inflammation measured with FDG-PET-CT imaging provides added value to Framingham risk score (FRS).

Methods:
We screened consecutive clinical data (n= 6,109) for patients with no prior CVD, active cancer, or chronic inflammatory conditions who had clinical follow-up data for up to 5 years after an index FDG-PET. From the 229 (median age[IQR],60[47,68], 38% males) meeting these criteria, 42 had CV events (incident ischemic stroke, TIA, ACS, carotid or coronary revascularization) and 187 did not during the follow-up. FRS 10 year % probability of CHD was calculated. FDG uptake was measured (ascending aorta) and reported as target-to-background ratio (TBR) while blinded to clinical data. Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) were used to compare FRS with and without TBR for CV event prediction.

Results:
Patients in the highest TBR tertile were substantially more likely to experience CV events (HR[95%CI], 4.85[1.89,12], p=0.001) compared to the lowest tertile after adjusting for FRS, BMI, statin, and diabetes. Further, addition of TBR (tertiles) to FRS variables resulted in an improvement in patient net reclassification, (NRI[95% CI]=26.89%[10%, 47%) across risk categories (<10, 10-20, >20) compared to their initially calculated risk. Adding TBR (tertiles) to FRS variables further improved discrimination of CV risk, (IDI=5.56%[0.27%, 11%]).

Conclusions:
FDG-PET measured aortic plaque inflammation improves risk discrimination and reclassification. These preliminary data support prospective follow-up studies to evaluate imaging plaque inflammation for CVD risk assessment.
Abstract 16896: Kinin-Mediated Recruitment of Circulating Endothelial Supporting Cells is Impaired in Patients with CAD or Diabetes: Impact on Endothelial Healing
Authors: Kraenkel Nicolle , Kuschnerus Kira , Mueller Maja , Speer Timo , Briand Sylvie , Bader Michael , Madeddu Paolo , Alhenc-Gelas Francois , Luescher Thomas F , Landmesser Ulf
Published: April 2024

Purpose:
We have investigated the role of vascular-derived kinins for the recruitment of angiogenic monocytes and circulating angiogenic progenitor cells (CPC) to the vessel wall, and the functionality of this mechanism during coronary artery disease (CAD) and type 2 diabetes mellitus (T2D).

Methods:
Expression of the kinin B2 receptor (B2R) on peripheral blood mononuclear cell (PBMC) subsets of CAD patients with or without T2D, and age- matched healthy subjects (HS) was assessed by flow cytometry. Adhesion to an endothelial monolayer and subsequent healing of a scratch gap in the endothelium was studied in vitro. In vivo, recruitment of systemically injected human PBMC to injured carotid endothelium was assessed in a mouse model. B2R blockade by icatibant or B2R deficient bone marrow cells (B2R-/- BMC) were used in those analyses to verify the relevance of the B2R.

Results:
In HS PBMC, B2R was low expressed (<1000MFI) on CD14hi inflammatory monocytes and highest in angiogenic Tie2+ or KDR+ monocytes and in KDR+ or CXCR4+ angiogenic CPCs (2517 to 7516MFI; P<0.05 vs. CD14hi). Recruitment of healthy CXCR4+ CPC to the endothelium was blocked by B2R inhibition in vitro (-67% vs. vehicle, P<0.05) and in vivo (-58% vs. vehicle; P<0.05), while adhesion of CD14hi monocytes was unchanged, indicating a critical role of B2R for vascular homing of CPCs, but not of CD14hi monocytes. Kinin receptor expression on CXCR4+ PC was reduced in CAD patients with or without T2D (-75% vs. H; P<0.05). Endothelial recruitment of CXCR4+ PC from T2D patients was markedly impaired and not regulated by the B2R. In vitro, endothelial gap closure was, partially mediated by the B2R during adhesion of healthy PBMC, which was lost in patients with T2D PBMC. Adenoviral B2R overexpression increased in vitro endothelial healing, while silencing of B2R abolished the recruitment and acceleration of gap closure by healthy CPC. In vivo endothelial healing was impaired in B2R-/- derived BMC that were transplanted in mice with endothelial injury (24.7% vs. 36.1%, P<0.05).

Conclusions:
We newly describe that vascular kinins recruit endothelial-supportive circulating cells to the vessel wall via B2R on the circulating cell. The loss of B2R on those cells might contribute to the loss of endothelial function in T2D.
Abstract 16903: Predictors of Major Bleeding Risk: Insights from the Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF)
Authors: Goodman Shaun G , Wojdyla Daniel M , White Harvey D , Piccini Jonathan P , Paolini John F , Nessel Christopher C , Mahaffey Kenneth W , Patel Manesh R , Becker Richard C , Halperin Jonathan L , Hacke Werner , Singer Daniel E , Hankey Graeme J , Breithardt Gunter , Fox Keith A , Califf Robert M
Published: April 2024

Background:
AF is associated with increased ischemic stroke risk. Oral anticoagulation reduces this risk, but there is often suboptimal use of stroke prophylaxis among AF patients, which may be due to challenges in risk stratification for bleeding.

Methods:
We investigated factors associated with bleeding in 14,264 pts with nonvalvular AF randomized to rivaroxaban or dose-adjusted warfarin in ROCKET AF. Endpoints of interest were ISTH-defined major bleeding events, intracranial and fatal bleeding. Cox proportional hazards modeling was used to identify factors associated with major bleeding.

Results:
Over a median follow-up of 1.94 yrs, a major bleed occurred in 395 (5.55%; 3.60 per 100-pt yrs) pts assigned rivaroxaban and 386 (5.42%; 3.45 per 100-pt yrs) assigned warfarin (HR 1.04, 95% CI 0.90, 1.20). Intracranial (0.49% vs. 0.74% per yr; p=0.019) and fatal bleeding (0.24% vs. 0.48% per yr; p=0.003) were lower with rivaroxaban. Pts (n=781) with a major bleed were more likely to be older (median 75 vs. 73 yrs), smokers (40 vs. 33%), and with lower baseline calculated CrCl (median 63 vs. 68 mL/min); less likely to be female (34 vs. 40%) and have a prior stroke/TIA (46 vs. 53%) (all p<0.002) compared with those without a major bleed (n=13,455). Increased age, male sex, BMI, history of diabetes and COPD, and decreased calculated CrCl were independent predictors of increased risk for major bleeding (C-index=0.62). No significant interaction was identified between predictors of bleeding and components of major bleeding.

Conclusions:
Major bleeding rates were similar with rivaroxaban or warfarin; however, intracranial and fatal bleeding was significantly lower with rivaroxaban. Older age, male sex, prior diabetes, increased BMI, lower diastolic BP, and reduced renal function at baseline were independently associated with major bleeding. Careful assessment of bleeding risk in patients with AF is required to support clinical decision making for stroke prevention therapy.
Abstract 16942: Maternal Hypertension and Low Birth Weight: Do Socio-Economic and Racial/Ethnic Disparities Matter?
Authors: Sergeev Alexander V , Nyirati Christina M
Published: April 2024

Background:
Maternal hypertension (HTN) can increase risk for low birth weight (LBW, weight< 2,500 grams), a compelling, unsolved health problem. Identification of high risk groups for HTN-related LBW is essential to designing evidence-based interventions addressing vulnerable populations. We hypothesized that selected disparities contribute to HTN-related LBW.

Methods:
A case-control study of 114,298 births in the year 2010 in Ohio was conducted. Comprehensive Ohio birth data were obtained from Ohio Department of Health. Maternal HTN status was classified as: pre-pregnancy HTN, gestational HTN, or non-hypertensive. Mothers utilizing Medicaid or the Federal Special Supplemental Nutrition Program for Women, Infants and Children were considered of low socio-economic status (SES). Adjusted odds ratios (OR) for LBW in relation to mother's HTN status, race, ethnicity, and SES were obtained using multivariable logistic regression (SAS software), adjusting for known confounders - gestational age, mother's age, pre-pregnancy or gestational diabetes, pre-pregnancy and pregnancy smoking status, and plurality.

Results:
Maternal pre-pregnancy HTN and gestational HTN were associated with a statistically significant increase in LBW risk (adjusted OR 1.286, 95% CI 1.061-1.560, p<0.05, and adjusted OR 1.588, 95% CI 1.417-1.780, p<0.01, respectively). Adjusted for HTN status and confounders, African American and Asian mothers had a statistically significantly higher risk of delivering a LBW infant than Caucasian mothers (adjusted OR 1.931, 95% CI 1.763-2.115, p<0.01, and adjusted OR 1.780, 95% CI 1.522-2.083, p<0.01, respectively), and Hispanic ethnicity was associated with lower risk of LBW (adjusted OR 0.750, 95% CI 0.615-0.915, p<0.01). When adjusted for confounders, effect of low SES on LBW was only borderline significant (adjusted OR 1.081, 95% CI 0.990-1.180, p=0.08).

Conclusions:
Adjusted for demographic and clinical confounders, maternal HTN increases risk of LBW. Independently from HTN, racial/ethnic and SES disparities contribute to risk of LBW. Epidemiological phenomenon of Hispanic paradox extends its effect to the HTN-related LBW issue. Effect of low SES on HTN-related LBW may be partially attributed to racial disparities.
Abstract 16969: Plaque Attenuation Pattern Assessment to Predict Advanced Atherosclerotic Lesions in Coronary CT Angiography
Authors: Maurovich-Horvat Pal , Schlett Christopher , Alkadhi Hatem , Kriegel Matthias , Nakano Masataka , Otsuka Fumiyuki , Stolzmann Paul , Scheffel Hans , Ferencik Maros , Virmani Renu , Hoffmann Udo
Published: April 2024

Introduction:
We sought to determine the accuracy of qualitative assessment of attenuation patterns of non-calcified plaque by CT to differentiate between early and advanced atherosclerotic lesions as defined by histology.

Methods:
Overall 611 histological sections from 21 coronary arteries were studied. The coronaries were filled with iodinated methylcellulose and scanned with CT (GE, CT 750HD). Histological sections with an increment of 1.5 mm were prepared and matched with cross-sectional CT images. The images were read randomly for the presence of non-calcified (NP), mixed (MP), calcified plaque (CP). The NCP-s and the non-calcified portion of MP-s were further assessed for the pattern of plaque attenuation and classified as homogenous (HP) or heterogeneous. Plaques that appeared heterogeneous were further stratified into those with and without napkin-ring sign (NRS and non-NRS).

Results:
No plaque was detected in 134 (21.9%), NCP in 254 (41.6%), MP in 191 (31.3%), and CP in 32 (5.2%) CT cross-sections. Among NCP components we identified HP in 207 (46.5%), non-NRS plaque in 200 (44.9%) and NRS plaque in 38 (8.6%) cross sections. The absence of plaque had excellent sensitivity and negative predictive value [99.3% (95% CI: 95.9-99.9%) and 99.3% (95% CI: 95.9-100.0%); respectively]. The specificities of NCP and MP to identify advanced lesions were moderate (58.1%, 95% CI: 53.4-62.7% and 71.9%, 95% CI 67.4-76.0%, respectively), similarly to the homogenous and heterogeneous plaques (42.8%, 95% CI: 37.4-48.2% and 57.2%, 95% CI: 51.8-62.6%, respectively). In contrast, the specificity of NRS plaque to identify advanced lesions was excellent (98.9%, 95% CI: 97.4-99.6%). The overall diagnostic performance of the attenuation pattern analysis to identify advanced lesions was better than that of the conventional plaque scheme (area under the curve 0.761 vs. 0.678, respectively; p=0.0012).

Conclusions:
The CT finding of NRS is highly specific for the presence of advanced atherosclerotic plaque. The assessment of the plaque attenuation pattern has significantly higher accuracy to identify advanced plaques than the conventional CT plaque scheme. The validity of these findings needs to be demonstrated in vivo.
Abstract 17040: Selective Inhibition of Myocardial NADPH Oxidase with a Dominant-Negative Mutant of p67
phox
Attenuates Angiotensin II-Induced Cardiac Hypertrophy in Adult Transgenic Mice
Authors: Zhao Qiong , Zhao Guiqing , Zhang Chongxu , Xu Xianyao , Varadarajan Sudhahar , Urao Norifumi , Fukai Masuko , Fukai Tohru , Xiao Lei
Published: April 2024

Angiotensin (Ang) II infusion not only induces hypertrophy and fibrosis in mouse heart, but also causes hypertension and inflammation in vivo. Thus, the precise mechanisms of Ang II-induced cardiac hypertrophy are unclear. Recently, selective inhibition of Ang II receptor in vivo was reported to attenuate the increase of expression of myocardial NADPH oxidase (NOX) subunits including p67
phox
in heart failure rats. To study the endogenous “cardiac” NOX role in vivo, we created a transgenic (Tg) mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NOX subunit p67
phox
that prevented NOX activity. Age- and body weight (BW)-matched male Tg or WT C57BL/6 mice (12-14 weeks) were infused with either PBS or Ang II (0.7 mg/kg/day) for 2 weeks by an osmotic mini-pump. Echocardiography (echo) was then performed to determine the following parameters: left ventricular myocardial area (LVMA); LV wall thickness at end diastole; LV internal dimension at end diastole (IDd), LV end-diastolic volume (EDV), LV ejection fraction (EF), and LV mass. Mice were divided into 4 groups (6-8 mice/group) including WT-PBS, WT-Ang, Tg-PBS & Tg-Ang. The LVEDV, LVIDd & BW were similar between the PBS and Ang groups in both WT and Tg mice. The LVEF (mean 49-52%) was not statistically different among all groups. The WT-Ang mice showed significant increase in LVMA, LV mass & wall thickness indicating LV hypertrophy compared to WT-PBS. In contrast, Tg-Ang showed no significant difference in LVMA, LV mass & wall thickness vs. Tg-PBS, suggesting Ang-induced LV hypertrophy was inhibited in Tg mice (Table 1). Our echo data were confirmed by our results of heart weight (HW)/BW ratio and myocardium reactive oxygen species (ROS) measurement, showing the attenuation of the increase of both HW/BW ratio and ROS in TG-Ang mice vs. WT-Ang mice. In summary, our results showed that selective inhibition of myocardial NOX/p67
phox
attenuates Ang II-Induced cardiac hypertrophy in Tg mice.
Abstract 17095: Caveolin-1 Mediates Cellular Protective Effects of a High-Molecular Weight Polyethylene Glycol-Based Copolymer, PEG 15-20 During Hypoxia-Reoxygenation in Cardiac Myocytes
Authors: Malhotra Ricky , Theccanat Tiju , Akhter Shahab A
Published: April 2024

Ischemic heart disease is the primary etiology for the development of heart failure. We recently demonstrated that PEG 15-20 protects cardiac myocytes from hypoxia-reoxygenatiion (H-R)-induced cell death and preserves ventricular function. In the present study we investigated our hypothesis that PEG 15-20 exerts its beneficial effect by stabilizing sarcolemmal lipid rafts particularly by its effect on Caveolin-1 (Cav-1). Cav-1 alongwith Cav-3, the principal structural components of caveolar domains are abundantly expressed in the myocardium and implicated in the pathogenesis of ischemic injury. Cardiac myocytes were exposed to 30 minutes of hypoxia (2% O
2
, 5% CO
2
, 93% N
2
) followed by 3 hours of reoxygenation (5% CO
2
, 95% air) with cells treated with 5% PEG 15-20 during reoxygenation. Adenoviral-mediated knockdown of Cav-1 in cardiac myocytes by RNA interference reversed the anti-apoptotic effect of PEG 15-20 both in terms of caspase 3 activity (6.7±1.2 vs. 3.8±0.76 fluorometric units/mg protein) and TUNEL staining (38±7 vs. 17±3 apoptotic cells). Cav-1 knockdown also abrogated the decrease in oxidative stress mediated by PEG 15-20 during H-R as measured by superoxide radical generation (4.3±0.65 vs. 1.4±0.32 nmoles/min/mg protein with PEG 15-20 alone). Further Cav-1 knockdown mitigated the increased pro-survival phosphorylation of Akt, GSK-3β and ERK1/2 observed with PEG15-20 during H-R. Importantly maintenance of cardiac myocyte β-adrenergic signaling that is critical for myocardial function that was observed with PEG 15-20 treatment during H-R in cardiac myocytes was also reversed with knockdown of Cav-1(16±1.8 vs. 28±2.6 pmol cAMP/mL with PEG 15-20 alone). Finally, confocal microscopy revealed that PEG 15-20 mediated preservation of sarcolemmal lipid-raft architecture during H-R was abolished in cells deficient in Cav-1as seen by increased lipid raft coalescence. These studies demonstrate that PEG 15-20 primarily exerts its cardiac-specific pro-survival and anti-apoptotic effects during H-R by binding and stabilizing Cav-1 in the caveolar domains. Therapeutic strategies to augment maintenance of lipid raft micro architecture in the cardiac sarcolemmal membrane may improve survival after ischemic injuries.
Abstract 17276: Cyclophilin D is Required for Mitophagy-Regulating Parkin Translocation to Mitochondria
Authors: Quarato Giovanni , Huang Chengqun , Gottlieb Roberta A
Published: April 2024

INTRODUCTION
Cyclophilin D (CyD), encoded by the
Ppif
gene, is a mitochondrial protein that regulates the Mitochondria Permeability Transition Pore (MPTP) and is necessary for the removal of damaged mitochondria via autophagy in cardiac cells.

Ppif
-/-

mice show an increase in the mitochondrial calcium retention capacity and a desensitization of MPTP opening. These features are associated with protection against ischemia/reperfusion injury. However recent finding show that CyD is involved in different physiological pathways important for cell homeostasis.

HYPOTHESIS
We tested the hypothesis that the CyD mediates mitochondrial removal by controlling Parkin translocation to the mitochondrial outer membrane.

METHODS
Cardiac mitochondria were isolated from wild type and

Ppif
-/-

young (2 months) and old (20 months) mice according to standard protocol using a sucrose based buffer.

RESULTS
Western Blot analysis of total heart tissue lysate showed a 1.8 fold increase in the microtubule-associated protein1 light chain 3 (LC3) and a 2.2 fold increase in the total Parkin protein levels in the

Ppif
-/-

young mice compared to age matched wild type mice. Parkin in the mitochondrial fraction was 2.0 fold less in the samples from young and old

Ppif
-/-

mice compared to age-matched wild type mice. The diminished activity in the Parkin-dependent mitophagy results in accumulation of defective mitochondria, leading to metabolic reprogramming followed by pathological hypertrophy. While young

Ppif
-/-

mice show normal phenotype, old mice develop cardiac hypertrophy with elevated HW/BW ratio and ANF compared to age-matched wild type mice.

CONCLUSIONS
The decrease in the Parkin-dependent mitophagy machinery activity observed in the

Ppif
-/-

mice describe for the first time the requirement for CyD in the Parkin-dependent mitophagy and give a further explanation for the cardiac hypertrophic phenotype in old

Ppif
-/-

mice.
Abstract 17328: Frequency of Consumption of French Fries Is a Strong Predictor of Plasma Trans-Fatty Acids in Persons with Type 2 Diabetes
Authors: Schwenke Dawn C , Foreyt John P , Miller Edgar R , Reeves Rebecca , Vitolins Mara ,   Biomarkers of Oxidative Stress Subgroup
Published: April 2024

Trans
-fatty acids (TFA) increase cardiovascular disease risk. However, relative contribution of foods to plasma TFA concentrations is unknown in persons with type 2 diabetes. We investigated how seven food sources of TFA (French fries, doughnuts, biscuits, nondairy creamer, chips, pretzels, and margarine on bread) were related to plasma 18-carbon TFA. Our population included persons randomized into Look AHEAD at two clinics (Baltimore, n=92; Houston, n=177) who participated in an ancillary study of oxidative stress and completed the Look AHEAD Food Frequency Questionnaire (LAFFQ). Look AHEAD is a multi-center controlled trial of lifestyle intervention for weight loss in overweight or obese adults (aged 45-75) with type 2 diabetes. Representation of women (57%) and minorities (18.6% AA, 8.2% Hispanic, 4.1% other race/ethnicity) was similar to Look AHEAD. TFA were measured before intervention in plasma collected between December 2002 and April 2004. Nutrients and eating frequency of food sources of TFA were determined from LAFFQ before intervention. In models with single sources of TFA adjusted for age, sex, race/ethnicity, clinic, sampling time, and plasma total fatty acid concentration, eating frequency of French fries (p<0.01) and doughnuts (p=0.03) and margarine on bread (p=0.02) were significant predictors of log-transformed fasting plasma TFA (model R-square = 0.49 to 0.50) whereas eating frequency of biscuits, nondairy creamer, chips, and pretzels were not. Results were similar after further adjusting for body mass index, total dietary fat, dietary saturated fat, total calories, physical activity, serum insulin, and statin use. In a similarly adjusted model also mutually adjusting for all seven TFA sources (model R-square = 0.54), French fries was the only TFA food source that remained significantly associated with plasma log-transformed TFA (p<0.005). Compared with ≤ once per month (lowest tertile), eating French fries ≥ twice per week (highest tertile) was associated with about 10% increase in log-transformed fasting plasma TFA. These results both emphasize the importance of continued efforts to reduce TFA in French fries and suggest frequency of eating French fries as a useful measure of modifiable TFA exposure.
Abstract 17361: An Optimized Human Apyrase Substantially Decreases Infarct Size Without Bleeding Time Prolongation after Coronary Fibrinolysis in Dogs and Coronary Ligation and Release in Mice
Authors: Abendschein Dana , Moeckel Douglas , Sun Xiaofeng , Nguyen Annie , Jeong Soonseog , Robson Simon , Chen Ridong
Published: April 2024

Introduction:
Early coronary reperfusion by percutaneous coronary intervention or pharmacologic fibrinolysis attenuates myocardial infarction, but thrombotic reocclusion and reperfusion injury limit the benefits of intervention. Standard-of-care conjunctive agents including aspirin, heparin and clopidogrel increase bleeding, and have unproven benefit in attenuating reperfusion injury.

Objectives:
This study tested whether an optimized human recombinant apyrase (APT102), which degrades circulating ATP and ADP causing inhibition of platelet activation and generation of cardioprotective adenosine, will more effectively and safely decrease infarction.

Methods:
Conscious dogs had coronary thrombotic occlusion induced by electrical current and fibrinolysis with IV rt-PA (Activase, 1 mg/kg) an average of 91min after ischemia; while anesthetized C57BL/6J mice had coronary ligation followed by release of ligation after 60 min. Animals received either clopidogrel (4-10 mg/kg, PO) or IV APT102 (1.0 mg/kg) 45-50 min after ischemia with heparin and aspirin, or saline as the control in dogs and mice, respectively. Bleeding times were measured serially by precision cuts to the inner lip for dogs and by immersing the incised tip of the tail in saline for mice. Ischemic ‘risk’ zone (Evan's blue perfusion) and infarcted myocardial tissue (TTC staining) were quantified after 24 h by planimetry of transverse heart sections.

Results:
Reocclusion occurred in all clopidogrel-treated dogs (n=6), but was universally prevented in dogs given APT102 (n=6, p<0.05). All groups had similar ischemic risk zones, but infarction as a percent of the risk zone was 23 ±4% for clopidogrel-treated compared to 3 ± 2% for APT102-treated dogs (p<0.05). Infarction was decreased by 50% in mice given APT102, but was not affected by clopidogrel pretreatment. Bleeding times were increased significantly by clopidogrel compared with APT102. In mice given APT102 after clopidogrel, the bleeding time prolongation was decreased significantly.

Conclusions:
APT102 prevents reocclusion and decreases infarct size after coronary fibrinolysis and/or reperfusion without increasing bleeding. APT102 warrants further study as a conjunctive agent to optimize reperfusion therapy.
Abstract 17362: Regulation of Oxidative Stress and Apoptotic Signaling in Cardiac Myocytes by G Protein-Coupled Receptor Kinase-2: The Role of NADPH Oxidases
Authors: Malhotra Ricky , Theccanat Tiju , Akhter Shahab A
Published: April 2024

Oxidative stress due to generation of reactive oxygen species (ROS) is an important mechanism of cardiac myocyte death following ischemia-reperfusion (I-R) injury and can lead to heart failure. NADPH oxidases (Nox) are major cellular enzymatic sources for superoxide (O
2
) radical production and Nox2 and Nox4 are the two predominant isoforms expressed in the heart. The mechanisms by which these Nox isoforms are regulated in the heart after various stresses are unclear. G protein-coupled receptor kinase-2 (GRK2) is a critical regulator of β-adrenergic signaling and cardiac function. We hypothesized that GRK2 may play a role in regulating cardiac myocyte oxidative stress and apoptosis. Cardiac myocytes were exposed to 3 hours of hypoxia (2% O
2
, 5% CO
2
, 93% N
2
) followed by 3 hours of reoxygenation (5% CO
2
, 95% air). Hypoxia-reoxygenation (H-R) led to significant 3.5-fold upregulation of GRK2 activity as well as ROS production (4.7±0.7 vs 1.1±0.4 nmoles/min/mg protein) and apoptosis measured by caspase-3 activity (6.2±1.5 vs 1.8±0.6 fluorimetric units/mg protein) compared to normoxic controls. Interestingly, 4-fold overexpression of GRK2 by adenoviral infection led to an identical 3-fold increase in ROS production under basal conditions (3.5±1.2 vs 1.3±0.5 nmoles/min/mg protein with null vector controls) which was completely inhibited by pre-treatment with 10μM apocyanin, a Nox inhibitor. Inhibition of GRK2 by adenoviral-mediated expression of βARKct led to a significant reduction in ROS production and caspase 3 activity following H-R which was similar to that observed by knocking down Nox4. Immunoprecipitated Nox4 demonstrated a strong total serine phosphorylation under H-R conditions. Finally, confocal imaging of Nox4 and GRK2 in cardiac myocytes exposed to H-R demonstrated a primarily peri-nuclear co-localization that was absent under control normoxic conditions. These data provide evidence that GRK2 may be an important regulator of oxidative stress via NADPH oxidases in cardiac myocytes. Further investigation of this novel interaction between GRK2 and Nox4 will provide additional insight into the potential role of GRK2 as a regulator of oxidative stress and apoptotic signaling in the heart.
Abstract 17399: Nuclear Plakoglobin Mediates Differentiation of Cardiac Progenitor Cells to Adipocytes in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Lombardi Raffaella , Cabreira Maria de Graca , Willerson James T , Marian Ali J
Published: April 2024

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an enigmatic disease characterized by fibro-fatty infiltration of the myocardium, particularly in the right ventricle. Molecular basis of adipocytic replacement of cardiac myocyte is not fully known. We have implicated suppression of the canonical Wnt signaling in the second heart field cardiac progenitors by nuclear plakoglobin (PG), a desmosome protein, in the pathogenesis of ARVC. However, the direct role of PG in a phenotypic switch from myogenesis to adipogenesis remains unestablished. To delineate the direct role of PG in adipogenesis in ARVC, we over-expressed and deleted PG in cardiac myocyte lineage in vivo. We also expressed a truncated PG, known to cause ARVC in humans, in the heart, as a control. Over-expression of wild type (WT) and mutant PG led to their nuclear localization. The WT but not the mutant PG also incorporated into desmosomes. The mutant PG exhibited reduced binding affinity to other desmosome proteins and predominantly was localized to cytosol and nucleus but not the membrane. Over-expression of WT and mutant PG led to excess adipocytes in the heart, cardiac dysfunction and premature death. FACS sorted c-Kit+/Sca1+ cells isolated from the hearts of transgenic PG mice showed increased adipogenesis and mRNA levels of adipogenic markers KLF15, BMP-7, IGFBP-5 and Wnt5B but decreased level of CTGF, an inhibitor of adipogenesis. Treatment with BIO, a known activator of the canonical Wnt signaling, reversed enhanced adipogenesis, in a dose-dependent manner. In contrast to the over-expressors, c-Kit+/Lin-/Flk- cells isolated from 12-day PG-null embryos showed suppressed adipogenesis and increased levels of canonical Wnt signaling markers, leading to embryonic lethality. These findings establish the direct role of nuclear PG in mediating transdifferentiation of cardiac progenitors cells to adipocytes in ARVC, a phenotypic switch that is induced by suppression of the canonical Wnt signaling and rescued upon activation of the canonical Wnt signaling.
Abstract 174: Cardiotoxic Neighborhoods: Marked Variations in Domiciles of Victims of Cardiac Arrest Within a Large Urban Area
Authors: Allan Katherine S , Ray Joel G , Gozdyra Peter , Kiss Alex , Morrison Laurie J , Buick Jason E , Zhan Cathy , Guttman Matthew , Dorian Paul
Published: April 2024

Introduction:
Out of hospital cardiac arrest (OHCA) incidence rates may vary across regions. Prior studies measured OHCA variability by the location of the OHCA, rather than the victim's place of residence, thereby omitting potentially important demographic predictors of OHCA.

Objectives:
To measure variability of OHCA rates by residential address within a large urban centre, and the characteristics of persons living in areas that are associated with a higher rate of OHCA.

Methods:
We included 5656 adults aged 20+ y who experienced an OHCA in Toronto, Canada from 2006-2010. Each OHCA patient's home address was spatially mapped to 1 of 527 census tracts (CT). In order to assess variability we conducted (1) point cluster analysis using SatScan software, which identified areas with significantly higher counts of OHCA; (2) Poisson regression models were used to assess the OHCA relative risk (RR) by CT (after adjusting for age and sex); (3) We assessed the relationship between OHCA rates and socioeconomic (SES) variables within each CT.

Results:
Incidence of OHCA varied widely by CT (Figure 1). Adjustment for age and sex did not alter this variation. Cluster analysis identified 4 geographically distinct areas where there was higher risk of OHCA compared to adjacent CTs. With respect to SES variables, CTs with a higher median household income had a lower risk of OHCA (RR 0.98 per $10000 increase in income, 99% CI 0.95-1.00), as did CTs with higher education status (RR 0.996 per 1% increase in education, 99% CI 0.992-0.999). CTs with a higher percentage of South Asians (SA) were not at higher risk of OHCA (RR 1.003 per 1% increase in SA population, 99% CI 0.997-1.009), but those with a higher percentage of Afro-Caribbeans (AC) were (RR 1.007 per 1% increase in AC population, 99% CI 1.002-1.013).

Conclusions:
The risk of OHCA varies by the features of one's place of residence. Further study is required to investigate possible causes for these variations.
Abstract 17409: Effects of Statin Therapy by Sex in a Meta-Analysis of Individual Patient Data from 169 139 Patients in the Cholesterol Treatment Trialists' Collaboration Study
Authors: Fulcher Jordan , Barnes Elizabeth , Simes John , Kirby Adrienne , Keech Anthony C ,   Cholesterol Treatment Trialists' Collaboration
Published: April 2024

Background:
Statins have been shown to reduce cardiovascular risk and mortality, but the extent of their efficacy in women has been controversial.

Objective:
Using individual patient data, we aimed to assess statin efficacy overall and by sex.

Methods:
We analysed data from 26 randomised controlled trials assessing the effects of either statin vs. control or high dose statin vs. low dose statin on a series of prespecified CVD outcomes. Effects of statins on mortality and cardiovascular endpoints were expressed as the hazard ratio (HR, 95% CI for overall population/99% CI for subgroups) associated with a 1.0 mmol/L reduction of blood LDL-cholesterol achieved at 1 year.

Results:
Of 169 138 participants, 45 495 (27%) were female. Statin treatment significantly reduced the overall population risk for each CVD endpoint. Major coronary and major vascular events were significantly reduced overall and in both men and women, though the reductions with statin therapy were somewhat smaller in women (neither
P
for interaction reached the 1% level of significance). Death from CVD and all-cause mortality were significantly reduced overall and in men, but again the treatment-by-sex interaction tests were not significant at the 1% level. Numbers needed to treat to prevent a major vascular event for each 1.0 mmol/L LDL-cholesterol reduction with statin therapy for men and women, respectively, were 20 and 30 in secondary prevention, and 51 and 127 in primary prevention. There was no treatment effect on noncardiovascular death, cancer incidence or cancer death overall and in either sex.

Conclusions:
Both men and women benefit from reductions in major coronary and vascular events with statin therapy. The numbers needed to treat are higher for primary prevention, especially in women. Although mortality reductions are not independently significant in women, the balance of evidence supports routine statin therapy for individuals at risk of either sex.
Abstract 17594: Brain Microglial Cytokines are Critical for Renin-Angiotensin-Aldoterone-System(RAAS)-Induced Neurogenic Hypertension
Authors: Shi Peng , Grobe Justin L , Desland Fiona A , Rodriguez Vermali , Shan Zhiying , Richards Elaine M , Raizada Mohan K , Sumners Colin
Published: April 2024

Purpose:
Our previous studies have established that activation of microglial cells and production of proinflammatory cytokines (PIC) within the PVN are two critical events in the establishment of chronic angiotensin (Ang) II-induced neurogenic hypertension. These have led us to hypothesize that brain microglial cells are a primary target of Ang II, initiating a sequence of cellular and physiological events resulting in sympathetic nervous system activation and hypertension.

Methods:
Microglial cells from the hypothalamus of Sprague-Dawley rats were established in primary culture. Their phenotype was confirmed by the presence of IBa1 immunoreactivity and high levels of CD11b mRNA, markers for microglia. They were used to determine the effects of, Ang II, prorenin and aldosterone (ALDO) on cytokine production. Neurogenic hypertensive mice were generated using decoxycorticosterone acetate (DOCA)-salt model (DOCA 50 mg s.c., 0.15 M NaCl in drinking water for 3 weeks). The PVN was dissected to determine PIC expression at the end of the protocol.

Results:
Treatment of cultures with Ang II (100 nM) or ALDO (1 nM) for 24 hr increased the expression of PIC mRNAs, e.g. for tumor necrosis factor (TNF)α. Ang II and ALDO elicited respective 2- and 3-fold increases (P<0.05). More strikingly, we found that prorenin (20 nM, 24 hr) elicited highly significant 300- and 400-fold increases in the expression of TNFα and interleukin (IL)-1β mRNAs, respectively (P<0.05). These effects of prorenin were associated with respective 16- and 14-fold increases in NFκb1 and NFκbia mRNA levels, which are two subunits of the transcription factor NFκb complex. We previously demonstrated that DOCA mice exhibit a similar hypertensive phenotype as double transgenic hypertensive sRA mice, which display increased levels of PIC and activation of microglia in the PVN. Consistently, DOCA-salt mice exhibit respective 1.5, 1.08 and 1.09 fold increases in the expression of mRNAs for IL-1β, TNFα and IL-6 in the PVN compared to control mice (n=3-4).

Conclusion:
These data indicate that brain microglial cells are the primary target of RAAS components in promoting PIC production, which in turn contribute to hypertension development.
Abstract 17767: Geometric Differences in the Mitral Apparatus Between Ischemic Cardiomyopathy and Lone Atrial Fibrillation with Significant Mitral Regurgitation: A Real-Time Three-Dimensional Echocardiography Study
Authors: Izumo Masaki , Saitoh Takeji , Fukuoka Yoko , Tanaka Jun , Gurudevan Swaminatha V , Tolstrup Kirsten , Siegel Robert J , Shiota Takahiro
Published: April 2024

Introduction:
Real-time three-dimensional transesophageal echocardiography (3D TEE) is a new technique that allows superior visualization of the mitral annulus and leaflet to two-dimensional TEE. We sought to elucidate the geometric differences in the mitral apparatus between lone atrial fibrillation (AF) and ischemic cardiomyopathy (ICM) with significant MR by 3D TEE.

Methods:
This study consisted of 20 patients (pts) with ischemic MR and 20 pts with functional MR due to lone AF. The severity of MR was evaluated on a basis of vena contract width (VCW). 3D TEE images were evaluated with dedicated mitral valve quantification software (Figure). Mitral annular anteroposterior (AP) and commissure-commissure (CC) diameters, AP-CC diameter ratio, area, and height which corresponds to annular saddle-shape depth (Figure) were analyzed at mid-systole. Tenting height, and tenting volume were also determined. Additionally, coaptation length (overlap length of the anterior and posterior leaflet) was measured in three locations; medial (CLm), central (CLc) and lateral (CLl).

Results:
No difference in VCW was found between lone AF pts and ischemic MR pts. Lone AF pts had greater AP (38 ± 5.0 vs. 30 ± 4.6 mm) and CC diameters (39 ± 4.9 vs. 33 ± 4.2 mm), AP-CC diameter ratio (0.99 ± 0.08 vs. 0.90 ± 0.06), and mitral annular area (12 ± 2.7 vs. 8.7 ± 2.2 cm
2
) and smaller annular height (2.1 ± 0.8 vs. 4.3 ± 1.7 mm) than ischemic MR pts (all p<0.001). Although tenting volume was similar (2.8 ± 2.0 vs. 3.2 ± 1.6 ml, p=ns), tenting height was smaller in lone AF pts than ischemic MR pts (6.9 ± 3.2 vs. 9.0 ± 2.4 mm, p<0.05). CLc was smaller in lone AF pts than ischemic MR pts (3.1 ± 0.5, 3.5 ± 0.9 mm, p<0.05), whereas there were no differences in CLm and CLl between the two groups.

Conclusion:
3D TEE clarified geometric differences in the mitral apparatus between ischemic MR and functional MR in lone AF pts.
Abstract 17826: Frequency and Pattern of Left Ventricular Dysfunction in Potential Heart Transplant Donors
Authors: Mohamedali Burhan , Zelinger Allan
Published: April 2024

Cardiac transplantation is a recognized treatment for patients with end stage cardiomyopathy. However, the scarcity of donor hearts remains a limiting factor. In addition, some potential donor hearts may be rejected due to cardiac dysfunction reported on diagnostic imaging by echocardiography or cardiac catheterization.

We report a series of 34 consecutive adult organ donors whose hearts were evaluated for LV systolic function. The donors suffered acute, fatal brain injury. 11/34 (32%) had LV systolic dysfunction. Predominate apical, basal, mid-cavity, or global dysfunction patterns were characterized. Serial echocardiograms, when available, were examined. The findings are summarized in the table 1.

In our series we noted that serial studies uniformly demonstrated a significant improvement in LV systolic function. Improvement appeared independent of the specific pattern in LV dysfunction or sex. In 27% systolic function completely normalized. No difference between the sex of the donor and the pattern of cardiac dysfunction was seen.

In conclusion, our study noted that greater than 30% of screened potential donor hearts have systolic dysfunction. A variable pattern of dysfunction is seen with Global type noted most frequently. Even in hearts with severe initial dysfunction, considerable improvement in EF occurred. Our findings suggest that an initial examination showing LV dysfunction should not exclude a potential heart donor. Reassessment over time and possibly temporizing organ procurement to permit left ventricular function to improve could increase the pool of hearts available for transplantation. Further research into the mechanism underlying transient LV dysfunction in potential heart donor suffering acute, fatal brain injury is warranted.
Abstract 17894: Factors Associated with Cardiac Rehabilitation Attendance in Patients with Coronary Heart Disease in Europe: Results from EUROASPIRE III Survey
Authors: Kotseva Kornelia , De Bacquer Dirk , Wood David ,   EUROASPIRE III Study Group
Published: April 2024

Objective:
To describe patient characteristics and lifestyle and risk factor management in coronary patients participating in cardiac rehabilitation programme (CRP) compared to those who do not.

Methods:
The EUROASPIRE III survey was conducted in 2006-2007 in 76 centres from 22 European countries. Consecutive patients aged ≤ 80 years with the following diagnoses - coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), acute myocardial infarction, and acute myocardial ischaemia- were identified from hospital records and interviewed and examined at least 6 months after their coronary event.

Results:
A total of 13,935 medical records were reviewed and 8,966 patients interviewed (participation rate 73%). Overall, 44.8% of patients were advised to participate in a CRP and 81.4% of these patients attended at least one session; (36.5% of the whole study population). There were wide variations between countries and diagnostic categories, ranging from 0% in Greece to 85.4% in Lithuania, and from 15.9% in the Ischaemia group to 68.1% in the CABG group. Characteristics associated with participation in a CRP included younger age, male sex, higher educational level, CABG as a recruiting index event and a history of previous PCI or angina pectoris. Those who were smokers at the time of their coronary event were less likely to attend a CRP. Patients participated in a CRP had significantly lower prevalence of smoking, better control of total cholesterol and LDL-cholesterol and higher use of beta-blockers, ACE inhibitors/ARBs and lipid-lowering drugs. There was no association between participation in a CRP, the prevalence of obesity and glucose and blood pressure control.

Conclusions:
Only one third of all coronary patients reported attending a CRP. Although the control of smoking, cholesterol and the use of cardioprotective medication was better in those who attended a CPR many patients had not achieved the lifestyle and risk factor targets. There is an urgent need of comprehensive, multidisciplinary rehabilitation programmes addressing all aspects of the lifestyle, other risk factors and therapeutic management and a health care system which invests in prevention.
Abstract 17982: Krìppel-Like Transcription Factor- 2 Preserves Endothelial Function and Protects Against Pulmonary Hypertension
Authors: Dungey Alison A , Deng Yupu , Yin Jun , Rozowsky Simon , Stewart Duncan J
Published: April 2024

RATIONALE:
Pulmonary Hypertension (PH) is associated with ongoing endothelial cell (EC) dysfunction. Shear-responsive Krüppel-like Transcription Factor- 2 (KLF2) is thought to maintain EC homeostasis and to enhance NO bioavailability by inducing eNOS transcription and decreasing caveolin-1 expression. Thus, we hypothesized that KLF2 expression would be reduced in experimental PH, and KLF2 overexpression would prevent pulmonary arterial (PA) remodeling and preserve EC function in chronic hypoxia (CH)-induced PH.

METHODS:
Lung KLF2 mRNA levels were measured at 1, 3, 7, or 21 days in the CH (10% O2) rat model of PH. Selective gene transfer of KLF2 or empty plasmid to lung ECs was achieved by intravenous injection of jetPEI™ with plasmid DNA (150µg) at day 3 of CH. At 21 days of CH, right ventricular systolic pressure (RVSP), RV hypertrophy, and medial area in PAs with external diameters of <30µm and 30-50µm were assessed. Ex vivo lung functional analyses were performed and eNOS expression was assessed 24 hrs after shKLF2 delivery.

RESULTS:
KLF2 mRNA expression was reduced at 3 days of CH (0.3±0.1;P<0.05; normalized to sham), returning to control levels at 7 and 21 days. Compared with control transfection, KLF2 gene therapy reduced RVSP (69.5 ± 6.5 vs. 46.5 ± 2.6 mmHg; P<0.01; n=11-13) and RV/LV+S weight ratios (0.35 ± 0.02 vs. 0.28 ± 0.01, n=11-13; P<0.05), associated with a 1.3 fold increase in lung eNOS expression (P=0.04), but no change in PA medial area at day 21. Moreover, KLF2 knockdown resulted in increased RVSP in normoxic rats, matched with reduced eNOS expression to 0.60 ± 0.08 fold and a blunted vasodilator response to ACh (-4.68 ± 0.99 vs. -7.17 ± 0.80 ⋔mmHg; P<0.01; n=6), while SNP-induced dilation was unchanged (n=4) compared to transfected controls (RS).

CONCLUSIONS:
These results suggest that KLF2 is protective in the CH model of PH. The mechanism of protection involved maintenance of eNOS expression and endothelial dilatory function, rather than vascular remodeling.