bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17350: Altered PDE5 Targeting in Pathologic Hearts . Switching From NO-cGMP to ANP/BNP-cGMP
Authors: Zhang Manling , Takimoto Eiki , Lee Dong I , Santos Celio X , Hsu Steven , Bedja Djahida , Yuan Yuan , Eaton Philip , Shah Ajay , Kass David
Published: April 2024

Background:
cGMP degrading phosphodiesterase 5 (PDE5) resides at Z-band of adult cardiac myocyte and regulates cell physiology in a compartmentalized manner. Under physiological condition, it hydrolyzes cGMP derived from endothelial nitric oxide synthase (eNOS) but not from natriuretic peptide (NP). In hypertrophied hearts, however, PDE5 localization becomes diffuse though its expression and activity increases. We tested the hypothesis that PDE5 alters its targeting to NP-cGMP from eNOS -cGMP via diffusing its localization in pathological hearts where NP is up-regulated and eNOS is dys-regulated.

Methods and Results:
While acute administration of PDE5 inhibitor (sildenafil, 100µg/kg/min for 5min) does not affect ANP(10µg) -stimulated myocardial cGMP level in control mouse hearts, it significantly increased ANP-cGMP in hearts exposed to 1wk pressure overload (TAC). We further tested this hypothesis by examining the impact of PDE5 over-expression on TAC response of eNOS null hearts (eNOS KO). eNOS KO animals were crossed with cardiac myocyte specific PDE5 over-expressor (PDE5-TG), and animals were subject to 1week TAC at 2 months of age. eNOS KO alone showed ameliorated hypertrophic response, associated with reduced myocardial superoxide level, while PDE5 TG alone revealed exacerbated response, as reported. Importantly, PDE5 over-expressed eNOS KO hearts (PDE5TG-eNOSKO) revealed significantly exacerbated cardiac remodeling (chamber dilation and increase in heart weight) and impaired cardiac function compared to eNOS KO hearts, though myocardial superoxide level remained low. Cardiac fetal gene expression (ANP), calcineurin activity (RCAN-1 expression) and transient receptor potential cation channel 6(TRPC6) expression were all significantly higher in PDE5TG-eNOSKO than eNOS KO.

Conclusion:
These results suggest that increased NP-cGMP in cardiac hypertrophy/failure might be targeted by PDE5 via altered localization of the enzyme. Myocyte PDE5 regulation of NP-cGMP plays a pivotal role in the pathogenesis of remodeling independently of myocardial superoxide level. Sildenafil may enhance ANP/BNP activated cGMP pathway in heart failure patients to exert its cardiac protective effect.
Abstract 17371: Benefits and Risks of Catheter Ablation of Atrial Fibrillation in Elderly Patients (75 Years or Older)
Authors: Nademanee Koonlawee , Amnueypol Montawatt , Lee Francis , Schwab Mark
Published: April 2024

Published reports of atrial fibrillation (AF) treatment by catheter ablation (CA) included typically relatively young healthy individuals, but long-term outcomes of CA in elderly patients (PTs) remain unclear. We thus carried out the following study aiming to determine: 1) Safety and efficacy of CA in elderly PTs in maintaining sinus rhythm; 2) Risks of discontinuation of anti-coagulation in patients who remained in sinus rhythm (SR) after the ablation.

Methods:
We evaluated 302 elderly AF PTs (> 75 years old); 246 PTs (mean age = 80) underwent CA guided by complex fractionated atrial electrogram (CFAE); 85 were paroxysmal AF, 46 persistent AF and 115 long-lasting AF. The remaining 56 patients (mean age = 79) declined the procedure. The clinical end points were SR, stroke, death and major bleeding. Warfarin was discontinued if sinus rhythm was maintained or AF burden < 5% with no AF episodes was > 12 hours.

Results:
After a mean follow-up of 3 + 6 years including multiple ablations, 196 Patients (79 %) remained in SR. The annual death rate was 4% vs. 10% in PTs who stayed in SR vs. those remained in AF after ablations respectively (p < 0.001); interestingly, the annual death rate was also at 11% in patients who declined ablation. We were able to discontinue warfarin in 164 patients (70%) who had a stroke rate only 1.08 per 100 person -year compared to 2.62 per 100 person-year in patients who continued to have AF and stayed on coumadin (p <0.01). Patients with CHADS score > 2, who stayed in SR and stopped warfarin, had a stroke rate of 2 per 100 person-year compared to 0.98 for those with CHADS score 1. Major complications were groin bleeding (n= 9 [4%]), 2 patients had stroke (1 intracranial hemorrhage leading to death at home) and 2 patients had hemopericardium.

Conclusions:
Our data suggest that elderly PTs with AF benefit from AF substrate ablation which is safe and effective in maintain SR. Warfarin could be safely discontinued after SR is maintained post ablation. Our data suggest that SR after CA is associated with lower mortality and stroke risks.
Abstract 17391: Effect of Advanced Heart Failure Care on the Risk of Early Readmission
Authors: Patel Snehalkumar A , Koelling Todd M
Published: April 2024

Introduction:
Risk adjusted rates of 30-day readmission (30DR) for heart failure (HF) have been publicly reported since 2008 and are included in the Medicare Shared Savings Program for Accountable Care Organizations. Whether the risk represented by HF patients followed in Advanced Heart Failure Programs (AHFP) offering LVAD and heart transplantation (HTX) services is adequately adjusted using the CMS model is unknown. To examine this issue, we sought to compare readmission risk and comorbidity distributions in patients under evaluation for LVAD or HTX and in patients followed by the AHFP at our institution.

Methods:
We collected data on patients discharged from the University of Michigan Hospital with a HF DRG from July, 2008 to November, 2010. Data collection included comorbidities used in the CMS risk model and laboratory values. LVAD and HTX evaluation status and discharging service type were determined. Patients < 19 years old and those expiring in the hospital were excluded from the analysis.

Result:
A total of 1412 patients admitted for HF were analyzed in this sample (30DR 27%). Patients under evaluation for LVAD or HTX trended to have higher 30DR compared to other patients (34.5% vs 26.4%, p=0.06). Predicted probability of readmission for the AHFP team (n=407) was higher than other services (0.230±0.002 vs 0.218±0.002, p<0.001), but 30DR was similar for the two groups (27.8% vs 26.8%, p=0.70). Logistic regression analysis, controlling for variables included in the CMS risk model and laboratory values, demonstrated that patients under evaluation for LVAD or HTX were more likely to experience 30DR (OR 1.76, 95% CI 1.10-2.82, p=0.018) while patients treated on the AHFP service were less likely to experience 30DR (OR 0.74, 95% CI 0.55-0.99, p=0.047).

Conclusion:
HF patients treated in our AHFP have higher predicted probability of readmission compared to those admitted to general cardiology or medicine services. Patients under evaluation for LVAD or HTX have a higher risk of readmission, and when controlling for these patients, our AHFP service demonstrated a reduced risk of early readmission compared to other services. Further study is needed to determine what elements of care provided through the AHFP are responsible for this reduced readmission risk.
Abstract 17412: Comparative Study of Factor Eight Inhibitor Bypass Activity and Recombinant Activated Factor VII in Refractory Post-Cardiopulmonary Bypass Bleeding
Authors: Rao Vidya K , Bartlett Blake , Soran David , Oakes Daryl , Hill Charles , Lobato Robert , Klanjac Mark , Mora-Mangano Christina , van der Starre Pieter
Published: April 2024

Introduction.
Profuse post-CPB bleeding occurs in up to 29% of cardiac surgical patients. Studies have shown rFVIIa to be a useful rescue procoagulant in bleeding refractory to conventional hemostatic measures. Recently, FEIBA, available for <30% the cost of rFVIIa, has also been utilized in this setting. While efficacious, both compounds have been associated with thromboembolic events. This retrospective cohort study compares FEIBA and rFVIIa in treating refractory post-CPB bleeding.

Methods.
We reviewed records of all adult cardiac surgical patients who received FEIBA or rFVIIa from January 1, 2005 to September 30, 2010. Primary outcomes included total numbers of thromboembolic events in the first 30 post-operative days. Secondary outcomes included 30-day mortality, transfusion requirements prior to and after FEIBA or rFVIIa administration, and number of reoperations for excessive bleeding.

Results.
Of 2619 cases performed during the study period, 107 patients received FEIBA, and 61 received rFVIIa. There were no significant demographic differences between the cohorts, but patients in the rFVIIa group had significantly longer CPB times (305 v. 244 min) and were more frequently undergoing reoperations (56% v. 35%). There were no differences in the number of thrombembolic events, 30-day mortality, re-operations for bleeding, or overall transfusion requirements with the exception of platelets (FEIBA 1.7 v. rFVIIa 3.1). The most common thrombotic events in the FEIBA and rFVIIa cohorts were pulmonary embolism (5.6%) and stroke (6.6%), respectively.

Discussion.
This study contains the largest case series of FEIBA utilization in cardiac surgical patients to date, and suggests that FEIBA and rFVIIa may have similar efficacy and safety profiles when used for refractory post-CPB bleeding. FEIBA may represent an economically viable alternative to rFVIIa in this setting. Further studies are required to define the roles of these procoagulants in cardiac surgery.
Abstract 17420: Simvastatin Induces Cardiac Autophagy Through PTEN Activation
Authors: Lee Pam , Andres Allen , Huang Chengqun , Ratliff Eric , Gottlieb Roberta
Published: April 2024

Background:
Statins are a widely prescribed class of cholesterol-lowering drugs that inhibit HMG-CoA reductase, the rate-limiting step of cholesterol biosynthesis. Statins have been shown to be cardioprotective; however, the mechanism of this protection remains unclear. Autophagy is a housekeeping function that allows for the clearance of protein aggregates or dysfunctional organelles in order to maintain cellular homeostasis. We have shown that autophagy is required for cardioprotection. Recent studies have demonstrated that statins are able to induce autophagy. Therefore, we sought to explore the regulation of autophagy by statins in the heart.

Methods:
Simvastatin (Sigma) was diluted in DMSO, and added at 1μ M to C2C12 myotubes, or administered to FVB/N mice at doses ranging from 5 to 40 mg/kg via IP. Protein extracts from hearts and cells were prepared for western blot analysis. ROS production in cells was determined via FACS with H2-DCFDA.

Results:
Preliminary studies indicated that simvastatin induced autophagy in C2C12 cells, as assessed by increased conversion of LC3I to LC3II. Parallel studies in mice also showed a dose-dependent increase in LC3II/I ratio in hearts. We next investigated the effect of simvastatin upon the Akt/mTOR pathway, which suppresses autophagy. Concurrent with the increase in LC3II, simvastatin decreased Akt/mTOR activity, reflected by decreased phosphorylation of S6 and Akt. We observed an increase in PTEN, a well-recognized negative regulator of Akt. Moreover, we observed that cells treated with simvastatin produced less ROS, which are known to negatively regulate PTEN phosphatase activity. Mevalonate is a component of the cholesterol biosynthetic pathway downstream of HMG-CoA. Addition of mevalonate to statin-treated cells restored Akt and S6 activation to basal levels, thus indicating that cholesterol may mediate simvastatin's effects on Akt/mTOR.

Conclusions:
The robust induction of autophagy in heart after statin treatment is associated with decreased Akt/mTOR, as well as increased PTEN. Statin-induced autophagy may underlie the cardioprotective effects of statins.
Abstract 17423: A Novel in vitro Platform of Perfused Human Microtissues for the Study of Neovascularization
Authors: Moya Monica L , Hsu Yu-Hsiang , Hughes Christopher C , Lee Abraham P , George Steven C
Published: April 2024

Understanding the process of vascular network formation and remodeling is key to designing effective strategies for the treatment of ischemic vascular diseases. Much of our current understanding of the neovascularization process is limited to in vivo studies, which require extrapolation of results to human, or in vitro models that lack the dynamic feature of perfusion. In this work we report the development of an in vitro model system of metabolically active microtissues that exchange nutrients and waste through perfused capillaries. For such design, a device consisting of 2 fluidic channels on either side of a central tissue channel, containing fibroblasts seeded in a fibrin matrix (Fig 1A), was microfabricated in polydimethylsiloxane. To study vasculogenic-like processes, ECs were co-seeded with the fibroblasts in the tissue channel. The devices were grown at 5% oxygen tension and formation of perfused vessel networks was encouraged by mechanical (pressure gradients, interstitial flow) and chemical stimuli (hypoxia and nutrient deprivation). Vessel network formation was observed within a week of culture and as early as day 1. Perfusion of the network was confirmed at day 18. Fluorescent dextran (70kDa) introduced on one end of one of the fluidic channel (Fig 1B-C) was shown to reach the other side of the device by traveling through the capillaries of the microtissues as evidence by the presence of dextran in the tissue channel and the absence of dextran in the fluidic channel. (Fig 1D) Anastomosis of vessels in the tissue channel with the fluidic channels was verified by tracking movement of fluorescent 1µm beads introduced into the fluidic channel and through patent capillaries (20-105 µm/s) in the tissue channel. Confocal microscopy of devices stained for CD31 (EC marker) and DAPI (nuclear marker) showed the extensive vessel network (Fig 1E) and further demonstrated the presence of capillary lumens containing microbeads (Fig 1F).
Abstract 17427: A Unique “Cellular Fibrillation” Status in Mouse Ventricular Myocytes
Authors: Xie Lai-Hua , Wen Hairuo , Zhao Zhenghang , Fefelova Nadezhda , Allen Charelle
Published: April 2024

Different intracellular calcium (Ca
i
) wave patterns have been observed in cardiac myocytes. However, their mechanisms and corresponding electrophysiological properties remain unclear. In the present study, we have generated various patterns of Ca
i
waves in isolated mouse ventricular myocytes under highly-activated Ca
i
cycling states, such as high external Ca concentration or in the present of -adrenergic stimulation (i.e. isoproterenol and Bay K8644). Our results revealed at least three distinct types of Ca wave dynamics: I) slow propagating planar waves; II) Repetitive single spiral waves; III) Multiple spiral/micro waves, in which average Ca
i
level remained high. All waves were completely blocked by tetracaine (1 mM), suggesting RyR leaking is the original source for the waves. Simultaneous recording of membrane potential under current-clamp mode revealed that these complex Ca
i
wave dynamics have several functional consequences. The cell exhibited individual or oscillatory EADs and/or DADs under the conditions with type I or type II Ca
i
waves. Interestingly, a unique “cellular fibrillation” status was associated with type III Ca
i
waves. Under this condition, the cell maintained a high Ca
i
level and a depolarized membrane potential (~ -20 mV) and thus lost its excitability and contractility. We also found that in the same cell, the Ca waves can be converted from one type to another by changing the Ca handling conditions. The multiple spiral/micro waves (type III) were transformed into slow-propagating, planar waves (type I) by a Ca/Na-free Tyrode's solution or by Gadolinium (Gd
3+
), a nonselective TRPC channel blocker; but not by nifedipine (L-type Ca channel blocker), SEA0400 (Na-Ca exchange blocker) or TTX (Na channel blocker). Hyperpolarizing the cell membrane by external injection of an outward current also transformed type III to type I Ca waves, suggesting the facilitating role of membrane current in the generation of the cellular fibrillation status. Termination of the cellular fibrillation by blocking TRPC channel activity may provide new opportunities for the treatment of clinical ventricular fibrillation.
Abstract 17437: Ultra Fast Brightfield and Fluorescence Imaging of Micron Size Objects for Research in Microbubble-Ultrasound Mediated Therapeutics
Authors: Chen Xucai , Wang Jianjun , Villanueva Flordeliza
Published: April 2024

Background:
Ultrasound (US)-assisted therapies such as US-induced microbubble (MB) destruction have potential to enhance thrombolysis and drug or gene delivery for cardiovascular disease. Visualization of US-MB-cell interactions, which occur in nano-second time scale due to the physics of US, should yield insights into therapeutically relevant MB dynamics, and improve design of US-MB-mediated therapies. We present a high speed brightfield and fluorescence imaging system that allows unique
in vitro
and
in vivo
microscopic observations of MB acoustic behavior.

Methods:
Our integrated system includes a custom multi-frame camera and software control (Cordin Co), customized modular microscope and laser system, US generator, and combined US and optical imaging chamber for
in vitro
and
in vivo
MB observations. The camera system, based on a rotating mirror design, contains 64 digital CCD cameras (1392 x 1040 pixels) and acquires 128 image frames. A strobe light triggered from the timing board is used for the brightfield light source. A fast pulse capable Cyan-488 optically pumped semiconductor laser system is used for fluorescence imaging. A custom fiber optics alignment system delivers laser light through the microscope.

Results:
The system images at up to 25 million frames per second (Mfps). Fig 1A shows selected frames of fluorescent beads (1, 2, 4 um), proving the concept of ultra-fast fluorescent imaging, and demonstrating the potential for
in vivo
intravital microscopy of vibrating fluorescent MB in the microcirculation. Fig 1B shows selected brightfield frames of US-induced MB vibration, fluid jets, and invagination of thrombus (block arrow).

Conclusion:
We have developed a high speed camera system for fluorescence and brightfield imaging at 25 Mfps. This system should enable unique visualization of interactions between US, MB, and cells
in vitro
and
in vivo,
and ultimately help to optimize novel US-MB mediated therapies for cardiac disease.
Abstract 17446: Intra-arrest Hypothermia Protection Requires Endothelial Nitric Oxide Synthase
Authors: Vitzthum Lucas , Orbelyan Gerasim , Costakis James , Vanden Hoek Terry L , Beiser David
Published: April 2024

Introduction:
Intra-arrest hypothermia (IH), cooling the body to 30 - 32°C during cardiac arrest, has previously been shown as protective in a mouse model of cardiac arrest. Hypothermia has also been shown to protect cultured cardiomyocytes exposed to simulated ischemia/reperfusion (I/R) in a nitric oxide synthase-dependent manner. However, the effect of IH on NOS signaling in whole animal models of cardiac arrest has not been studied. We hypothesized that mice deficient in endothelial NOS (NOS3) would not be protected by IH following cardiac arrest. Furthermore, we hypothesized that IH would alter NOS3 signaling in WT mouse hearts.

METHODS:
Adult NOS3
-/-
(B6.129P2-Nos3tm1Unc/J, n = 30) and WT (C57Bl/6J, n = 24) mice underwent 8 min of cardiac arrest. At 6 min, mice were randomized to normothermia (NT, 37°C) or IH (30°C) followed by re-warming to 37°C at 60 min post-ROSC. Animals were hemodynamically monitored for 2 h and then neurologically scored at regular intervals up to 48 h. In separated experiments, cardiac NOS3 signaling was evaluated in similarly randomized mice at the end of the arrest period.

RESULTS:
In NOS3-/- mice, IH and NT groups had similar 48 h neurologically-intact survival rates (20 % vs. 0%, p=0.80). By contrast survival rates were significantly higher in IH vs. NT treated WT mice (47% vs. 0%, p=0.03). After 8 min of arrest heart p-NOS3(Ser1177) was significantly lower in NT relative to sham controls (p<0.05) and IH treated WT mice (p<0.05). Also during arrest, phosphorylation of the metabolically-sensitive AMP activated protein kinase p-AMPK(Thr172) was similarly increased (p<0.05) following arrest in both IH and NT groups. Cardiac p-Akt(Ser474/Thr308) content was unchanged at 8 min of arrest (p>0.05) in both groups.

CONCLUSIONS:
Loss of NOS3 abrogates IH protection following cardiac arrest. Maintenance of cardiac NOS3 phosphorylation during cardiac arrest may play an important role in determining survival in this model. Such maintenance of phosphorylation appears to be independent of upstream kinase phosphorylation.
Abstract 17451: Dense Genotyping of Candidate Gene Loci Identifies Variants Associated with Oxidized Ldl Serum Levels
Authors: Karakas Mahir , Baumert Jens , Thorand Barbara , Meisinger Christa , Rottbauer Wolfgang , Illig Thomas , Koenig Wolfgang
Published: April 2024

Background:
Oxidized low-density lipoprotein (oxLDL) as a marker of oxidative stress has been proposed to play an important role in the development of atherosclerosis. OxLDL consists of a number of heterogeneously modified particles, including apoB, phospholipids, LDL-cholesterol, and unsaturated fatty acids. Serum levels of oxLDL are known to be heritable, but the degree of heritability has not been established yet.

Methods:
We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from oxLDL candidate genes selected on known biology of oxLDL metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs. 1,332 men and women from a randomly drawn subsample of the baseline examination of the MONICA/KORA Augsburg Cohort Study, conducted between 1984 and 1995, with measurements of oxLDL (Mercodia assay) and genotyping by the 50K IBC Chip comprised the study population. Linear regression analysis with adjustment for age, sex and survey was applied to assess the associations between gene variants and oxLDL levels. Statistical significance was defined as 5.0e-6 accounting for multiple testing.

Results:
Eight SNPs showed a statistically significant association with ox-LDL and were located at chromosome 2 in the APOB gene with
rs676210
having the strongest association (p value = 4.13e-12). All eight SNPs had minor allele frequencies above 20% showing a substantial gene variation.

Conclusions:
In summary, we identified variants in the APOB gene that are associated with levels of oxLDL in the general population. These findings may not only enhance our understanding of oxidative pathways and lipid metabolism and function, but may also pave the way for novel research avenues.
Abstract 17475: High Throughput Screening and Diagnosis of Structural Heart Defects in Newborn Mice Using High Resolution Micro-Computed Tomography
Authors: Kim Andrew J , Francis Richard , Ramirez Ricardo , Liu Xiaoqin , Chen Guozhen , Tobita Kimimasa , Lo Cecilia W
Published: April 2024

Background:
We are conducting a high-throughput chemical mutagenesis screen in mice to recover mutations causing congenital heart defects (CHD) using fetal echocardiography. Mutant fetuses identified to have cardiac defects by ultrasound screening must be further examined by time-consuming necropsy and histological analysis to confirm the CHD. We hypothesize post-mortem micro-CT may be used as a high throughput secondary screening tool for phenotyping CHD in fetal/newborn mice.

Methods:
Formalin fixed fetuses and neonatal mice were soaked with iodine for soft tissue visualization. Micro-CT scanning was carried out at 15 or 45μ m using the Siemens Inveon with a custom 12-pup cradle. Micro-CT diagnoses of suspected CHD were validated using episcopic fluorescence image capture (EFIC), a 3D high resolution histological imaging technique that provides registered image stacks suitable for digital resectioning in any imaging plane (Figure).

Results.
We micro-CT scanned 938 newborn mice and 58 late term fetuses and found a spectrum of CHD. This included ventricular septal defects (VSDs; 14.7%, n=146), endocardial cushion defects (0.9%, n=9), transposition of the great arteries (TGA; 1.2%, n=12), double outlet right ventricle (DORV; 2.2%, n=22), pulmonary atresia (PA; 0.1%, n=1), tricuspid atresia (0.5%, n=5), right aortic arch (RAA; 0.3%, n=3), interrupted aortic arch (0.2%; n=2), and dextrocardia (0.5%; n=5). Subsequent necropsy/EFIC imaging of 45 pups confirmed all RAA diagnoses (100%; n=3), 91% of the VSD (n=29/32), 90% of the TGA/DORV/PA (n=9/10) and 100% of the dextrocardia (n=5/5). We had false positive rate of 6% (n=2) for VSD and 10% (n=1) for TGA/DORV, while a false negative rate of 3% (n=1) was observed for VSD.

Conclusions:
Our studies showed micro-CT has a low false negative CHD detection rate, thus making it a valuable secondary imaging tool for enhancing the diagnosis of structural heart defects in large-scale mutagenesis screens.
Abstract 17477: Role of NADPH Oxidase Subunit p67
phox
in Regulation of Pressure-Overload-Induced Cardiac Hypertrophic Oxidative Stress and Antioxidant Gene Expression
Authors: Zhang Chongxu , Zhao Guiqing , Xu Xianyao , Zhao Qiong , Deng Jing , Xiao Lei
Published: April 2024

We had reported a transgenic (Tg) mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NADPH oxidase (NOX) subunit p67
phox
that inhibits NOX activity. We showed that transverse aortic constriction (TAC)-induced cardiac hypertrophy was significantly attenuated in the Tg mice, but not in wild type (WT) mice. Since TAC had been reported to increase mouse myocardial reactive oxygen species (ROS) level, we thus tested if the myocardial ROS contributed to the above difference between WT and Tg. Age (10-12 weeks)-, body weight (BW)-matched Tg and WT C57BL/6 male mice were subjected to TAC or sham operation. Cardiac hypertrophy were confirmed 4-week post-TAC by echocardiography, heart weight/BW ratio, and fetal gene expression. Freshly isolated hearts were perfused and the left ventricle (LV) ROS level was determined using chemiluminescence method. Surprisingly, we found that the WT-TAC mouse heart showed consistently decreased ROS level (42±2% ↓, p<0.01, n=4) vs. WT-sham; whereas there is no difference among the WT-sham, Tg-sham and Tg-TAC groups (n=6). This finding was different from the previous reports showing the increased ROS in WT-TAC heart. Next, we screened the LV expression profile of various antioxidant proteins. We found that the mRNA expression of SOD3 (3.0-fold↑) and thioredoxin1 (Trx1, 3.8-fold↑) was significantly increased (p<0.05) in WT-TAC mice vs. WT-sham by qRT-PCR; whereas there is no difference among the WT-sham, Tg-sham and Tg-TAC groups. The increased SOD3 and Trx1 mRNA expression was confirmed by Western blotting for protein expression (3.0-fold↑). In contrast, the expression of other antioxidants including SOD1, SOD2, catalase, Trx2, Nrf2, NQO1 and glutaredoxin were not changed in WT-TAC heart. The selectively increased expression of SOD3 and Trx1 may contribute to the decreased ROS level detected in WT-TAC heart. Unlike WT-TAC, the ROS, SOD3 and Trx1 levels in Tg heart were not increased by TAC vs. sham, suggesting the critical role of p67
phox
in regulation of TAC-induced myocardial ROS generation and antioxidants expression. In summary, our data show that NOX/p67
phox
regulates pressure-overload-induced cardiac oxidative stress and myocardial expression of antioxidants SOD3 and Trx1.
Abstract 17487: S-Nitroso Human Serum Albumin (S-NO-HSA) Attenuates Pulmonary Hypertension, Improves Right Ventricular-Arterial Coupling and Reduces Oxidative Stress in a Chronic Right Ventricle Volume Overload Model
Authors: Rungatscher Alessio , Hallström Seth , Morjan Mohammed , Linardi Daniele , Gasser Harald , Podesser Bruno K , Luciani Giovanni Battista , Mazzucco Alessandro , Faggian Giuseppe
Published: April 2024

BACKGROUND
The study was aimed to examine the acute overall hemodynamic and oxidative stress effects to intravenous S-NO-HSA infusion in a model of chronic left-to-right shunt-induced pulmonary arterial hypertension and right ventricle failure.

METHODS AND RESULTS
Fifty male Wistar rats underwent surgical creation of aorto-caval fistula (Qp/Qs> 2.0) After 10 weeks they were randomly treated with S-NO-HSA (0.5 υmol/kg/h) (n. 20) or human serum albumin (HSA) (n. 25) infusion for 60 minutes. Right ventricular contractility, right ventriculo-vascular coupling and ventricular interdependence were assessed in vivo ad different preloads by biventricular conductance catheters prior and after 60 minutes infusion. Heart and lung biopsies were obtained to determine oxidative stress by reduced to oxidized glutathione (GSH/GSSG) ratio and high energy phosphates content. S-NO-HSA compared to HSA infusion resulted in a significant reduction in right ventricular afterload expressed by effective pulmonary arterial elastance (Ea) (0.49 +/- 0.3 versus 1.2 +/- 0.2 mmHg/ml; P = 0.0005). S-NO-HSA significantly improve right ventricular diastolic function (slope of end-diastolic pressure-volume relations) but not contractility (slope of preload recruitable stroke work), whereas a significant increase in the efficiency of ventricular-vascular coupling (ratio of end-systolic to pulmonary arterial elastances: Ees/Ea) occurred after S-NO-HSA but not HSA infusion (from 0.35 +/- 0.17 to 0.94 +/- 0.21; P = 0.005 and from 0.37 +/- 0.11 to 0.43 +/- 0.19; P = 0.1 respectively) with significant increase in left ventricular stroke volume (56 +/- 4 vs 9 +/- 5 %; P = 0.0013). S-NO-HSA compared to HSA treatment significantly improved ATP and PCr right ventricle myocardial content (13.9 +/- 1.1 vs. 7.0 +/- 1.8 and 5.9 +/- 3.3 vs. 1.9 +/- 0.6 micromol/g protein; P = 0.01) and increase tissue GSH/GSSG ratio (P = 0.001).

CONCLUSIONS:
S-NO-HSA reduces pulmonary hypertension and improves right ventricular diastolic function and right ventricular-arterial coupling with a positive effect on ventricular interdependence. This results in an increased energetic reserve of the heart and reduction of oxidative stress.
Abstract 175: Effects of Dispatcher-Assisted Cardiopulmonary Resuscitation Recommended in the 2005 AHA Guidelines for CPR
Authors: Nishikawa Kei , Nagao Ken , Tachibana Eizo , Yagi Tukasa , Yonemoto Naohiro , Takayama Morimasa , Hiroshi Nonogi Hiroshi , Shirai Shinichi , Kimura Takeshi
Published: April 2024

BACKGROUND
The AHA 2010 guidelines for cardiopulmonary resuscitation (CPR) recommended that dispatchers should assertively provide compression-only CPR instructions to untrained rescuers. However, it is unclear whether dispatcher-instructed CPR recommended in the AHA 2005 guidelines can improve survival.

METHODS
We compared the effects of dispatcher-instructed CPR recommended in the 2005 CPR guidelines with those recommended in the 2000 CPR guidelines from the data of the All-Japan Utstein Registry, a prospective, nationwide, observational registry. The study endpoints were return of spontaneous circulation (ROSC) on hospital arrival and 30-day favorable neurological outcome after cardiac arrest.

RESULTS
Of the 58,448 adult patients with bystander-witnessed out-of-hospital cardiac arrest due to presumed cardiac etiology in the year 2005, 2008 and 2009, 23,165 who received instructions in CPR given by dispatchers over the telephone were included; 17,282 received the instructions of CPR recommended in the 2005 guidelines, and 5,883 received in the 2000 guidelines. The performance of dispatcher-instructed CPR (chest compression plus mouth-to-mouth ventilation or chest compression only) of the 2005 guidelines group showed a higher proportion than that of the 2000 guidelines group (42% vs.33%, p<0.0001), especially those with compression-only CPR (33% vs.18%, p<0.0001). The 2005 guidelines group had significantly higher rates of ROSC and favorable neurological outcome than the 2000 guidelines group in the whole cohort (ROSC; 12.2% vs. 8.4%, p<0.001, favorable neurological outcome; 5.3% vs. 2.9%, p<0.001), and in the subgroups of patients who received compression-only CPR (ROSC; 13.0% vs. 8.6%, p<0.001, favorable neurological outcome; 6.0% vs. 2.6%, p<0.001). The adjusted odds ratios after dispatcher-instructed CPR recommended in the 2005 guidelines was 1.56 (95% CI, 1.37-1.72) for ROSC and 2.17 (95% CI, 1.79-2.65) for favorable neurological outcome.

CONCLUSION
Dispatcher-instructed CPR recommended in the 2005 guidelines improved ROSC and favorable neurological outcome in adult patients with bystander-witnessed out-of-hospital cardiac arrest due to presumed cardiac etiology.
Abstract 17540: The CC Variant of Locus 9p21 Increases Coronary Disease Risk with High Values of Hs-CRP
Authors: Palma dos Reis Roberto , Silva Bruno , Cafe Hugo , Freitas Sonia , Ornelas Ilidio , Guerra Graca , Freitas Ana I , Brehm Antonio , Mendonca Maria I
Published: April 2024

Recent genomic wide association studies have identified several
loci
associated with coronary artery disease (CAD) risk. Among them, SNP rs 1333049 in the
locus
9p21 (variant CC) has demonstrated a solid association with CAD which has been replicated in several populations, namely ours. High sensibility C-reactive protein (hs-CRP) has also been associated with inflammatory activity and atherosclerosis. An eventual interaction among these two atherosclerotic markers is unknown.

Aim:
To explore the interaction between this homozygous genetic variant (CC) and hs-CRP plasmatic levels in the emergence of CAD.

Methods:
Case-control study with 1561 participants, 695 consecutive coronary patients (mean age 53.9±8.9 years, 78.8% male) and 838 controls without apparent CAD (mean age 52.0±11.4 years, 71% male) selected in order not to present significant differences in sex and age. The G/C variants were studied blindly using a combined technique of PCR and TaqMan. Hardy-Weinberg distribution was analyzed. The CAD risk was investigated by univariate analysis and the OR and 95% confidence intervals were calculated. hs-CRP values were distributed by quartiles and the highest one, considered as the risk, was evaluated. To determine the interaction between CC genotype and elevated hs-CRP values we used a 4x2 table approach, as well as synergy measurements in additive (SI) and multiplicative (SIM) models. Finally, the risk excess (RERI) and the attributable proportion (AP) due to the interaction were calculated.

Results:
The CC variant was significantly associated with CAD risk in the whole population (OR=1.32; p=0.011). The presence of this genetic variant with normal hs-CRP values presented a smaller risk (OR=1.28) when compared to the association with the elevated hs-CRP values in the highest quartile (OR=1.7; p=0.007; SI=1.63; SIM=1.15; RERI=0.27).

Conclusion:
The present study demonstrates that the CC variant of the 9p21
locus
globally increases the risk of CAD. This risk can be further increased in the presence of elevated hs-CRP values, as shown by the addictive and multiplicative interaction. This concept allows us to foresee the possibility of genetic risk factors management through the control of associated conditions, whenever possible.
Abstract 17600: Lipid Phosphate Phosphatase 3 Negatively Regulates Smooth Muscle Cell Phenotypic Modulation and Limits Neotimal Hyperplasia
Authors: Panchatcharam Manikandan , Miriyala Sumitra , Salous Abdelghaffar , Wheeler Jessica , Dong Anping , Sunkara Manjula , Escalante-Alcalde Diana , Morris Andrew J , Smyth Susan S
Published: April 2024

Rationale:
A common SNP in
PPAP2b
associates with risk of coronary artery disease (CAD). PPAP2b encodes the lipid phosphate phosphatases (LPP) 3 that degrades and thereby may attenuate lysophosphatidic acid (LPA) responsiveness of cells. However, a pathophysiologic role for LPP3 in vascular cells remains to be established.

Objective:
To determine the role and mechanisms by which LPP3 regulates vascular SMC responses.

Methods and Results:
Robust expression of LPP3 occurs in experimental atherosclerosis and following arterial injury, where SMC serve as the predominant source. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to carotid ligation injury. Gain- and loss-of-function approaches establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation, ERK activity, Rho activation and migration in response to serum and LPA. These effects are, at least partially, a consequence of LPP3-catalyzed LPA hydrolysis. We did not observe systemic effects of SMC-deletion of LPP3 on either circulating LPA levels or hemodynamic parameters, suggesting that the predominate effects of LPP3 on SMCs are exerted in the local environment by regulating SMC responses.

Conclusions:
These findings implicate LPP3 as an important negative regulator of SMC phenotypic modulation and indicate that changes in LPP3 expression control the development of neointima by limiting SMC proliferation, migration, and vascular inflammation.
Abstract 17605: Gender Differences in Predictors of Risk of Retroperitoneal Bleeding
Authors: Ahmed Bina , Lischke Stefan , Straight Faye , Dauerman Harold L
Published: April 2024

Background:
Retroperitoneal bleeding (RPB) can be a serious complication related to cardiac catheterization via femoral approach. Despite improvement in procedural safety, women undergoing cardiac catheterization remain at a two-fold higher risk of access site bleeding including RPB compared to men. We sought to compare clinical and angiographic predictors of RPB among men and women undergoing cardiac catheterization.

METHODS:
Case-control study design was used to identify cases with documented RPB and matched using age, procedure and gender to define controls. Detailed clinical and femoral angiographic data was collected and analyzed. Safe zone arteriotomy (SZA) was defined as access below inferior epigastric artery and above femoral artery (CFA) bifurcation. Univariate comparisons were made between cases and controls in both genders. Multivariate analysis was performed to identify independent predictors of RPB after adjusting for baseline differences.

RESULTS:
There were significant differences in clinical variables such as BMI and femoral artery anatomy among women with and without RPB (Table). On the other hand among men, BMI or size of CFA was not relevant but non-SZA (high stick) was more likely in men with RPB. On multivariate analysis, BMI trended to be only independent predictor of RPB among women (OR 0.83, 95% CI 0.68-1.0, p=0.05) whereas in men, SZA strongly predicted RPB (OR 0.30, 95 % CI 0.1- 0.3, P< 0.01).

Conclusion:
There are significant gender differences in mediators of RPB risk. The presence of non-modifiable risk factors such as smaller BMI and CFA vessel size in women may explain the persistent increased risk of RPB and access site complications seen in women.
Abstract 17733: PPARdelta Activation Protects Endothelial Function In Diabetic Mice via PI3K/Akt/eNOS Signaling Pathway
Authors: Wong Wing Tak , Tian Xiao Yu , Huang Yu
Published: April 2024

Introduction:
Recent evidence highlights therapeutic potentials of peroxisome proliferator-activated receptor-delta (PPARdelta) agonists to increase insulin sensitivity in diabetes. The significance of PPARdelta in the regulation of vascular function remains unclear.

Hypothesis:
The present study investigates whether PPARdelta activation improves endothelial function in type 2 diabetes.

Methods:
Vascular reactivity of mouse aortae was studied in myograph. Protein expression was detected by Western blotting. Nitric oxide (NO) production was measured by DAF-FM fluorescence using confocal microscopy.

Results:
PPARdelta agonists GW0742 and GW1516 improved endothelium-dependent relaxations in diabetic mouse aortae. PPARdelta agonists prevented high glucose-induced impairment of endothelium-dependent relaxations in aortae of wild type mice, but not in PPARdelta knockout mice. PPARdelta antagonist, PI3K inhibitors, or Akt inhibitor reversed the effect of PPARdelta activation on endothelial function. Western blotting showed an increased phosphorylation of eNOS and Akt upon PPARdelta activation under hyperglycaemia in primary endothelial cells (ECs) from mouse aortae. PPARdelta activation enhanced the NO production in ECs under hyperglycemia. Transient transfection with dominant-negative Akt inhibited the effect of GW1516 in ECs on NO production and eNOS and Akt phosphorylation. Chronic treatment with GW1516 (5 mg/kg/day for one week) improved endothelium-dependent relaxation in db/db mice, and diet-induced obese PPARdelta wild type mice, but not in PPARdelta knockout mice.

Conclusions:
The present study demonstrates an endothelial protective effect of PPARdelta activation in diabetes through PI3K/Akt signaling which increases eNOS activity, suggesting the potential of PPARdelta agonists in the treatment of diabetic vasculopathy.
Abstract 17782: New Generation Drug Eluting Stent Has Increased Vascular Healing by Resolved Postprocedural Incomplete Stent Apposition
Authors: Lee Sang-Rok , Yoon Hye-Eun , Song Min-Ju , Lee Sun-Hwa , Rhee Kyoung-Suk , Chae Jae-Keon , Kim Won-Ho , Ko Jae-Ki
Published: April 2024

Background:
While there are controversies regarding the late clinical impact of post-procedural incomplete stent apposition (PISA) and late incomplete stent apposition (LISA), there has been limited data in the newer generation of drug eluting stent. The aim of this study was to investigate the morphologic change of PISA and incidence of LISA during 1 year follow up.

Methods:
We prospectively enrolled 128 patients who underwent percutaneous coronary intervention (PCI); stable angina (n=30), unstable angina (n=82), and non-ST segment elevation myocardial infarction (n=16) (61.2±10.4 years, 78 male, 194 lesions - 106 left anterior descending artery, 25 left circumflex artery, 63 right coronary artery). The implanted stent was randomly assigned (the proportion of 2:1), zotarolimus eluting stent (group I, n=130, Endeavor Resolute
TM
, Medtronic) or everolimus eluting stent (group II, n=64, Xience
TM
V, Abbott Vascular). Post-PCI and 1 year follow up intravascular ultrasound (IVUS) analysis were performed in all patients.

Results:
There were no baseline clinical, angiographic, and procedural differences between the two groups. The Post-PCI external elastic membrane (EEM) volume (group I
vs
group II, 377.2±111.8
vs
436.1±219.6 mm
3
,
p
=0.155), Post-PCI lumen volume (208.3±66.1
vs
233.8±112.3 mm
3
,
p
=0.283), 1 year EEM volume (387.4±106.8
vs
436.6±218.3 mm
3
,
p
=0.240), 1 year lumen volume (212.5±64.9
vs
231.9±112.5 mm
3
,
p
=0.395), and 1 year intra-stent neointimal hyperplasia volume (4.8±7.3
vs
5.2±17.6 mm
3
,
p
=0.914) by IVUS analysis were not different between the two groups. There were three LISA (1.5%, two Endeavor, one Xience), and ten PISA (5.2%, five Endeavor, five Xience) that were resolved (40%, three Endeavor, one Xience) or persistent (60%, two Endeavor, four Xience). However, both LISA and PISA did not associated with MACE during 1 year follow up.

Conclusions:
In conclusion, the incidence of both LISA and PISA was very low in new generation drug eluting stent. The morphologic healing or persistence of PISA during 1 year IVUS follow up was observed. Future larger long-term follow up study to clarify the clinical course of LISA and PISA would be needed.
Abstract 17795: Left Atrial Appendage Volume Reflects Severity of Mitral Regargitation: A Three-Dimensional Transesophageal Echocardiography Study
Authors: Fukuoka Yoko , Izumo Masaki , Saitoh Takeji , Kuwahara Eiji , Tanaka Jun , Gurudevan Swaminatha V , Tolstrup Kirsten , Siegel Robert J , Shiota Takahiro
Published: April 2024

Background:
Left atrial (LA) size is well known to reflect volume overload condition such as mitral regurgitation (MR). However, the effects to left atrial appendage (LAA) have not been well defined. LAA structure has multilobed complicated three-dimensional structures. Recent development of real-time 3-dimensional transesophageal echocardiography (RT3D-TEE) has enabled us to examine morphology and determine absolute volumes of LAA without geometrical assumptions. We investigated the relationship between MR severity and LAA volume.

Methods:
Seventy-four patients with MR who underwent RT3D-TEE were studied. All measurements were performed off-line software. Maximal LAA orifice area, depth and volume, and the number of LAA lobes were assessed (Figure). We also measured LAA emptying flow velocity (LAAev) as the average of 3 consecutive cardiac cycles in patients in normal sinus rhythm and 5 consecutive cardiac cycles in patients with atrial fibrillation. MR grade was evaluated by vena contracta width (VCW). In 58 patients, we also determined the maximal LA volume by the Simpson method from apical views by 2-dimensional transthoracic echocardiography. Pulsed Doppler E, tissue Doppler E' and E/E' were also measured.

Results:
Mean LAA orifice area was 5.0±3.8 cm
2
, LAA volume was 11±10 ml, LA volume was 116±57ml, and LAAev was 41±23 cm/sec. Patients with moderate to severe MR had larger LAA orifice area, LAA volume, and LA volume than patients with mild MR (Table). In contrast, there were no relationship between MR severity, the number of LAA lobes and LAAev. 3D derived LAA volume was correlated with VCW significantly (r=0.51, p<0.01).

Conclusion:
LAA volume was associated with MR severity.
Abstract 17797: Protective Role of Angiotensin-(1-7) Receptor Mas on Kidney Fibrosis
Authors: Pinheiro Sergio V , Ferreira Anderson J , Magalhães Júnio A , da Silveira Kátia D , Fauler Beatrix , Assis Natalia S , Lopes Jose Ricardo B , Andrade Marcus Vinicius M , Lisboa Rodolfo , Kitten Gregory T , Santos Sérgio Henrique S , Santos Robson A , Silva Ana Cristina S
Published: April 2024

Angiotensin (Ang) II is involved in inflammatory and fibrotic mechanisms of cardiovascular and renal diseases. Ang-(1-7) counterbalances most of the Ang II pathophysiological effects. However, a protective role for Ang-(1-7) in kidney fibrosis remains speculative. To evaluate the role of Ang-(1-7) receptor Mas on pathophysiological mechanisms of kidney fibrosis we used a distinct genetic background of Mas-knockout mice (FVB/N MasKO). Urine and plasma samples were collected for measuring renal function parameters. Kidneys were harvested for histology, confocal immunofluorescence of matrix proteins, RT-PCR of AT1 receptor and TGF-beta and TUNEL apoptosis. Compared with wild-type controls, MasKO mice have reduced 24h-urine volume (0.75±0.15
vs.
1.51±0.33mL p<0.05) and sodium fractional excretion (1.09±0.21
vs.
2.16±0.45% p<0.05), without changes in osmolal and free-water clearances. The 1.8-fold higher creatinine clearance (7.11±1.25
vs.
3.92±0.48µL.min.g
-1
p<0.05) and the 2.9-fold increase in albuminuria (3.42±0.56
vs.
1.17±0.27µg.g
-1
p<0.05) detected in MasKO mice suggest glomerular hyperfiltration. Histology showed variable degrees of mesagial cells proliferation and segmental glomerulosclerosis, with an increased index of glomerular lesion in MasKO (0.56±0.08
vs.
0.25±0.10 p<0.05). These findings were associated with increased glomerular content of collagens I and IV, fibronectin, Ang II and upregulation of mRNA for AT1 receptor and TGF-beta. TUNEL staining revealed a 2-fold augmentation in fluorescence of apoptotic nuclei from glomerular and tubular cells in MasKO. Our results suggest that Mas receptor may exert protective role on renal fibrosis and apoptosis, possibly counterbalancing Ang II and TGF-beta effects in the kidney.