bluuebunny/crossref_metadata_2025 huggingface dataset:
2009 Dickinson W. Richards Memorial Lecture—Improving Survival From Out-of-Hospital Cardiac Arrest
Authors: Kern Karl
Published: April 2024

A renewed understanding of resuscitation physiology has led to several bold new approaches to basic life support (BLS) and advanced cardiovascular life support (ACLS), as well as a recognition that aggressive postresuscitation care can have a major impact on long-term outcome. Concepts initially tested in basic and translational resuscitation research laboratories have within the past several years been piloted in a number of rural and urban communities. Several of these newer approaches to BLS, ACLS, and postresuscitation care have dramatically increased historical survival rates around the world. These include the following:

Hands-only BLS CPR
. The survival rate for witnessed ventricular fibrillation in Tokyo increased from 11% to 19% when lay bystander rescuers performed chest compression– only or “hands-only” BLS as compared with chest compressions and mouth-to-mouth breathing. The American Heart Association endorsed “hands-only” BLS for encouraging more bystander CPR in March 2008.

New ACLS algorithm emphasizing uninterrupted chest compressions
. The initial report of the use of this newly revised ACLS approach came from rural Wisconsin. The rate of 1-year survival from witnessed ventricular fibrillation cardiac arrest tripled, from 15% to 48%. A follow-up report 3 years later showed a persistent benefit, with a 3-year survival rate of 40%. In Phoenix, Arizona, introduction of this revised ALCS algorithm increased the rate of survival to hospital discharge with ventricular fibrillation cardiac arrest from 12% to 28%.

Postresuscitation care
. Postresucitation care is the next great opportunity to improve long-term outcome among victims of out-of-hospital cardiac arrest. In Norway, the rate of 1-year survival among those resuscitated from out-of-hospital cardiac arrest increased from 26% to 56% after formalization of the postresuscitation care, with emphasis on providing mild therapeutic hypothermia and early catheterization and percutaneous coronary intervention where indicated. Case series reported in the literature suggest this approach can produce long-term survival rates of 70% among those initially resuscitated, with 80% of such long-term survivors being neurologically intact.

The near future holds more real promise for improving the outcome of those suffering cardiac arrest than ever before. Now is the time to move forward and provide improved care to all victims of sudden cardiac death.
Sirt1 Limits Endothelial Notch Signaling During Blood Vessel Growth Through NICD Deacetylation
Authors: Potente Michael
Published: April 2024

Abstract #3056

Michael Potente, Virginia Guarani, Inst for Cardiovascular Regeneration, Frankfurt, Germany; Gianluca Deflorian, IFOM, the FIRC Inst of Molecular Oncology, Milan, Italy; Raul Mostoslavsky, The MGH Cancer Ctr-Harvard Medical Sch, Boston, MA; Ralf Brandes, Inst for Cardiovascular Physiology, Frankfurt, Germany; Marina Mione, IFOM, the FIRC Inst of Molecular Oncology, Milan, Italy; Holger Gerhardt, Vascular Biology Lab, London, United Kingdom; Andreas M Zeiher, Dept of Cardiology, Frankfurt, Germany; Stefanie Dimmeler, Inst for Cardiovascular Regeneration, Frankfurt, Germany

Michael Potente, 2009 Finalist and Presenting Author
Cardiac Fibroblasts Are Essential for the Adaptive Response of the Heart to Pressure Overload
Authors: Takeda Norifumi
Published: April 2024

Abstract #3058

Norifumi Takeda, Ichiro Manabe, Yuichi Uchino, The Univ of Tokyo, Tokyo, Japan; Takayuki Shindo, Shinshu Univ Graduate Sch of Med, Matsumoto, Japan; Motoaki Sano, Keio Univ Sch of Med, Tokyo, Japan; Kinya Otsu, Osaka Univ Graduate Sch of Med, Suita, Japan; Paige Snider, Simon J Conway, Indiana Univ of Med, Indianapolis, IN; Ryozo Nagai, The Univ of Tokyo, Tokyo, Japan

Norifumi Takeda, 2009 Finalist and Presenting Author
Cardiomyocyte Protein Kinase G Activation by Phosphodiesterase-5 Inhibition Suppresses Canonical Transient Receptor Potential (TRPC) Channel 6 Expression/Activity and Cardiac Hypertrophy Signaling
Authors: Koitabashi Norimichi
Published: April 2024

Abstract #3087

Norimichi Koitabashi, Takeshi Aiba, John Hopkins Medical Inst, Baltimore, MD; Geoffrey G Hesketh, Univ of Cambridge, Cambridge, United Kingdom; Manling Zhang, Gordon F Tomaselli, David A Kass, John Hopkins Medical Inst, Baltimore, MD

Norimichi Koitabashi, 2009 Finalist and Presenting Author
Multipotent Mesenchymal Stem Cells Contribute to Vascular Remodeling in Patients With Chronic Thromboembolic Pulmonary Hypertension
Authors: Firth Amy L
Published: April 2024

Abstract #2365

Amy L Firth, Weijuan Yao, Aiko Ogawa, Michael M Madani, Grace L Lin, Jason X-J Yuan, Univ of California, San Diego, La Jolla, CA

Amy L Firth, 2009 Finalist and Presenting Author
Stromal Cell–Derived Factor-1
α
Activation of Tissue Engineered Endothelial Progenitor Stem Cell Matrix Enhances Ventricular Function After Myocardial Infarction by Inducing Neovasculogenesis
Authors: Frederick John R
Published: April 2024

Abstract #4221

John R Frederick, J. Raymond Fitzpatrick III, Ryan C McCormick, David A Harris, Ah-Young Kim, Jeffrey R Muenzer, Ashwin Murthy, Univ of Pennsylvania Sch of Med, Philadelphia, PA; Philip F Hsiao, Alisha D Prystowsky, Univ of Pennsylvania, Philadelphia, PA; Maximilian J Smith, Jeffrey Cohen, Pavan Atluri, Y. Joseph Woo, Univ of Pennsylvania Sch of Med, Philadelphia, PA

John R Frederick, 2009 Finalist and Presenting Author
Leptin and Soluble Leptin Receptor Levels in Plasma and Risk of Type 2 Diabetes in US Women: A Prospective Study
Authors: Sun Qi
Published: April 2024

Abstract #897

Qi Sun, Rob M. van Dam, Harvard Sch of Public Health, Boston, MA; James B. Meigs, Massachusetts General Hosp, Boston, MA; Oscar H. Franco, Univ of Warwick, Coventry, United Kingdom; Christos S. Mantzoros, Beth Israel Deaconess Medical Ctr, Harvard Medical Sch, Boston, MA; Frank B. Hu, Harvard Sch of Public Health, Boston, MA

Qi Sun, 2009 Finalist and Presenting Author
Elevated Levels of the Wnt Antagonist DKK1 and RANKL in the Bone Marrow Environment Link Chronic Heart Failure With Osteoporosis
Authors: Leistner David M.
Published: April 2024

Abstract #2369

David M. Leistner, Florian H. Seeger, Birgit Assmus, Jörg Honold, Ulrich Fischer-Rasokat, Thomas Trepels, Mahir Karakas, Univ Hosp of Frankfurt, Frankfurt am Main, Germany; Tino Röxe, Stefanie Dimmeler, Ctr of Molecular Med, Goethe Univ Frankfurt, Frankfurt am Main, Germany; Andreas M. Zeiher, Univ Hosp of Frankfurt, Frankfurt am Main, Germany

David M. Leistner, 2009 Finalist and Presenting Author
Heart Failure With Preserved Ejection Fraction: Do Abnormalities in Oxygen Utilization Contribute to Exercise Intolerance?
Authors: Bhella Paul S
Published: April 2024

Abstract #2372

Paul S Bhella, Katja Heinicke, Jeffery L Hastings, Anand Prasad, Shigeki Shibata, Ronald Haller, Benjamin D Levine, Univ of Texas-Southwestern, Dallas, TX

Paul S Bhella, 2009 Finalist and Presenting Author
Abstract 4755: Serial Changes in Coronary Vessel Remodeling During Plaque Progression Are Related to Alterations in Plaque Composition as Seen on Integrated Backscatter Intravascular Ultrasound
Authors: Inaba Shinji , Okayama Hideki , Funada Jun-ichi , Hashida Hidetoshi , Hiasa Go , Sumimoto Takumi , Takata Yasunori , Inoue Katsuji , Ogimoto Akiyoshi , Ohtsuka Tomoaki , Higaki Jitsuo
Published: April 2024

Background:
Studies have demonstrated that coronary arteries with initial atherosclerosis show outward (positive) remodeling in order to maintain luminal diameter. However, serial changes in coronary vessel remodeling and its relation to alterations in plaque composition have not been investigated. Recently, assessment of plaque composition has become possible using an integrated backscatter intravascular ultrasound system (IB-IVUS). Using IB-IVUS, we examined whether the progression of coronary vessel remodeling is associated with changes in plaque components.

Methods:
One hundred sixty non-culprit, intermediate lesions were identified in 88 patients. Seventy-eight plaques demonstrated plaque progression at follow up examination and were included in this study. Plaque progression was defined as a >5% increase in plaque volume. A total of 20 IB-IVUS images were recorded at 0.5 mm intervals along a 10 mm length of plaque. Total vessel volume (TVV) on conventional IVUS, total lipid volume (TLV) and total fibrous volume (TFV) on IB-IVUS were measured at each site. Six months later, a follow up IVUS examination was performed of the same coronary segment imaged at baseline. Serial changes in vessel remodeling (vessel remodeling index: VRI) were calculated as TVV at follow up examination/TVV at baseline examination. Progressive plaques were divided into two groups (compensation: 52 plaques, C-group VRI>1; no compensation or shrinkage: 26 plaques, S-group VRI≤1).

Results:
TLV and TFV at baseline examination were not significantly different between the two groups. However, ΔTLV (TLV at follow up examination - TLV at baseline examination) in the C-group was significantly higher compared to the S-group (10.0±8.6 vs. 2.7±7.0 mm
3
, P<0.01). Conversely, ΔTFV (TFV at follow up examination - TFV at baseline examination) in the C-group was significantly lower compared to the S-group (2.9±5.6 vs. 6.5±3.9 mm
3
, P<0.01). The VRI positively correlated with ΔTLV (r=0.34, P<0.01), but not with ΔTFV.

Conclusions:
Serial changes in coronary vessel remodeling are associated with alterations in the lipid component of progressively enlarging plaques.
Abstract 4854: Acute Systemic Inflammation Increases Central Blood Pressure and Pulse Wave Velocity in Healthy Subjects
Authors: Jae Sae Young , Heffernan Kevin , Woods Jeffrey , Vieira Victoria , Martin Stephen , Pence Brandt , Fernhall Bo
Published: April 2024

Objective.
Acute systemic inflammation or infection transiently increases risk of cardiovascular events, but the underlying mechanisms are not fully understood. Although observational studies suggest that inflammation is associated with arterial stiffness and blood pressure, the causal relationship of this is not clear. We tested the hypothesis that induced acute inflammation causes an increase in blood pressure and arterial stiffness.

Methods.
Using a randomized double blind sham placebo-controlled cross over design, nineteen healthy subjects (male 10, female 9; age 24±4 yrs) were injected with an influenza vaccine (0.5m/L) as a model to generate systemic inflammation, and a sham vaccine (normal saline). C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-a) were measured as a markers of inflammation. Central aortic blood pressure was measured by radial artery tonometry and a generalized transfer function. Carotid-radial pulse wave velocity (PWV) was measured using applanation tonometry. These variables were measured at baseline 24 hours and 48 hours after each vaccination.

Results.
The influenza vaccination caused a significant increase in CRP (1.42±0.6 at baseline, 2.81±1.0 after 24 hours, 5.0±1.3mg/L after 48 hours, p<0.05) and IL-6 (1.12±0.3, 2.56±0.4, 2.26±0.6, p<0.05) but not TNF-a compared with sham placebo. Brachial artery systolic blood pressure was not significantly increased after an influenza vaccination (115.9±9.9, 118.8±10.9, 118.3±10.2mmHg, NS). However, central systolic blood pressure (98.0±7.4, 104.5±10.8, 100.7±8.4mmHg, p<0.05) and PWV (7.8±0.9, 8.6±1.5, 8.7±1.3m/s, p<0.05) were significantly increased after an influenza vaccination but not sham vaccination.

Conclusions.
These findings show that an acute inflammation caused a temporary increase in central blood pressure and arterial stiffness. This offers insight regarding the noted increased risk of cardiovascular events associated with acute systemic inflammation.

This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).
Abstract 4873: Superiority of Polymer-free Cerivastatin-eluting Stent Over Polymer-based Paclitaxel-eluting Stent for Neointimal Inhibition and Vasomotor Function Preservation in Rabbit Iliac Arteries
Authors: Pendyala Lakshmana , Li Jinsheng , Yin Xinhua , Goodchild Traci , Geva Sara , Chen Jack , Chronos Nicolas , Hou Dongming
Published: April 2024

Objectives:
The present study was designed to evaluate and compare endothelial function and vascular biological responses following implantation of a novel, non-polymeric cerivastatin-eluting stent (CES) versus polymer-based paclitaxel-eluting stent (PES) in a rabbit iliac artery model.

Methods
:
In vitro,
human aortic and coronary smooth muscle cells (hASMC & hCSMC), as well as aortic and coronary endothelial cells (hAEC & hCEC), were cultured; and IC50 curves were determined for cerivastatin (CER).
In vivo
PES (n=6), CES (n=12), and polymer-free sol-gel only (sol-gel, n=12) stents were implanted in 15 rabbits. Vasomotor function was investigated at 28 days by infusion of acetylcholine (Ach) and nitroglycerin (NTG). Animals were terminated for histopathological analyses.

Results:
CER was cytotoxic to hASMC and hCSMC (IC50s of 10
−6
M and 10
−5
M, respectively), although such cytotoxic effects were not observed for hAEC and hCEC at maximal study dose. PES-associated vasodilation response to endothelial-dependent Ach was significantly suppressed at both proximal and distal adjacent arterial segments, as compared to CES and sol-gel. Furthermore, microscopically, the percent area stenosis was higher for PES (25±3%) compared to both CES and sol-gel (15±6% and 16±7%,
p
< 0.05, respectively). Medial area was lower for PES (0.3±0.04 mm
2
) than CES and sol-gel (0.5±0.03 and 0.4±0.04 mm
2
,
p
<0.001, respectively). Additionally, re-endothelialization scores were comparable among groups (
P
=NS); but profound fibrin deposition was clearly evidenced in PES (
p
< 0.05 vs. others).

Conclusions:
CER elicits a differential effect on hSMC compared to hEC
in vitro.
In contrast to PES, a novel bioabsorbable sol-gel coated CES demonstrated superior neointimal inhibition and less vessel toxicity, as well as preservation of vasomotor function in the rabbit iliac model.
Abstract 4884: Identification of Hetero-multimeric P2X Receptor Which Regulates Vascular Tone in Rat Arterial Smooth Muscle
Authors: Sugihara Megumi , Morita Hiromitsu , Matsuda Miho , Kajioka Shunichi , Ito Yushi , Abe Kihachiro , Hirata Masato
Published: April 2024

Background: ATP is one of important vasoactive substances and is released from sympathetic nerve terminal, endothelial cells and other cells surrounding smooth muscle cells. Ionotropic P2X channel is one of the representative receptors, and only homomeric P2X
1
has been thought to be the functional molecular architecture in vascular smooth muscle cells for a long time. However, some inconsistencies exist between native P2X
1
-like and cloned P2X
1
channels.

Methods: Male rats aged 10 –11w were used. P2X channel current was measured in smooth muscle cells isolated from aorta, cerebral or mesenteric artery using patch-clamp technique. RT-PCR and Western blot analyses were employed for detecting their messenger RNAs and proteins, and their interaction in combination with an immunoprecipitation method.

Results: Application of ATP (≥100nM) elicited dual phase, fast and slow, desensitizing inward current by whole cell recording. The ATP-induced current also showed rebound current, which is a typical feature specific to cloned P2X
1/5
channel. I-V relationship of the current was that of inward-rectifying, and reversal potential was around 0mV, close to the equivalent potential of non-selective cation channel in spite of various intracellular chloride ion concentration. Sensitivity of several ATP analogs is as follows; 2-methylthio ATP>BzATP>ATP>
α
,
β
-methylene ATP>ATP
γ
S. The channel conductance was 10.5±0.1pS by a single channel recording. The current was blocked by several P2X and P2 receptor antagonists, TNP-ATP, suramin and PPADS, and their 50% inhibitory concentrations (IC
50
) were similar to those of cloned P2X
1/5
channel (1.0, 0.5 and 0.6
μ
M, respectively; n=3~5). RT-PCR and Western blot analysis revealed highly expression of both P2X
1
and P2X
5
channels in extracts from arteries examined, and both channel proteins were found to be complexed as assessed by an immunoprecipitation method.

Conclusion: Our results indicate that hetero-multimeric P2X
1/5
channel, but not only P2X
1
, is functionally expressed in arterial smooth muscle, and may play an important role in vascular tone regulation.
Abstract 4885: Folic Acid Modulates eNOS Phosphorylation Status/Activity via Phosphoinositide 3-Kinase-Dependent and Independent Pathways
Authors: Taylor Sarah , Lang Derek
Published: April 2024

While evidence suggests that folic acid can improve endothelial function through the regulation of endothelial nitric oxide synthase (eNOS), the exact mechanism(s) involved in this process remain elusive. Given that the phosphorylation status of eNOS can play a significant role in modifying its activity, the present study investigated the effect of folic acid on the phosphorylation of eNOS at important regulatory sites. Cultured porcine aortic endothelial cells (PAEC) were exposed to folic acid (0 –50
μ
M for 24 hours) in the absence or presence of phosphoinositide 3-kinase (PI3K) inhibition (wortmannin 100nM or LY294002 10
μ
M for 30 minutes before folic acid). The phosphorylation status of eNOS as well as total eNOS protein levels were then determined by western blotting. In other experiments similarly treated PAEC were subsequently exposed to calcimycin (10
μ
M for 30 minutes) before being lysed. The cGMP content of the cell lysates was then measured by ELISA to provide an index of eNOS activity. Exposure of PAEC to folic acid promoted significant (p<0.05) concentration-dependent dephosphorylation of eNOS at Ser116 and Thr495 (negative regulatory sites) and increased phosphorylation at Ser635 and Ser1177 (positive regulatory sites). In the presence of PI3K inhibition the observed folic acid-induced changes in phosphorylation at Ser116, Ser635 and Ser1177, but not Thr495 (a regulatory site well known to be independent of PI3K control), were prevented. Importantly, the expression of total eNOS protein was not affected by any of the treatments outlined above. The folic acid-induced change in eNOS phosphorylation status was accompanied by increased eNOS activity (as measured by calcimycin-induced cGMP production). Again this increase in eNOS activity was prevented by the presence of PI3K inhibition. In conclusion, these data would suggest that exposure of PAEC to folic acid modulates eNOS phosphorylation status/activity via both PI3K-dependent and independent pathways. Such changes may underlie the beneficial effect of folic acid on endothelial function described by many previous studies.
Abstract 4894: Risk Factors for Hypertension Incidence in Type 1 Diabetes: The Pittsburgh Epidemiology of Diabetes Complications Study
Authors: Costacou Tina , Orchard Trevor J
Published: April 2024

Recent analyses of the DCCT/EDIC demonstrated that hyperglycemia and intensive insulin therapy are associated with incident hypertension. We assessed this hypothesis in a population based cohort study of individuals with type 1 diabetes mellitus. Participants of the Pittsburgh Epidemiology of Diabetes Complications Study, a prospective cohort of childhood onset type 1 diabetes (at baseline, mean age was 28 years and mean diabetes duration 19 years), free of hypertension at baseline, were selected for study (n = 510). Hypertension incidence was defined as systolic blood pressure >140 mmHg, or diastolic blood pressure >90 mmHg, or use of medication for the treatment of high blood pressure in two consecutive study visits. Intensive insulin therapy (IIT) was defined as ≥3 injections (or pump) and ≥4 glucose tests daily. Predictors of hypertension incidence were examined using multivariable Cox proportional hazard models with backward elimination. During 18 years of follow-up, 200 (39.2%) incident cases of hypertension occurred. At study entry, incident cases were more likely to be older, have longer diabetes duration, higher levels of body mass index, HbA1, blood pressure, pulse, non-HDL cholesterol, albumin excretion rate and inflammatory markers and lower HDL cholesterol and were more likely to have had a diagnosis of confirmed distal symmetric polyneuropathy, microalbuminuria, and overt nephropathy compared to non-cases. Cases were also less likely to practice IIT. In multivariable models, significant independent predictors of hypertension incidence consisted of HbA1 (HR = 1.16, 95% CI = 1.05–1.30), IIT (HR = 0.46, 95% CI = 0.19 –1.13, p = 0.09), insulin dose per weight (HR = 0.56, 95% CI = 0.30 –1.04), systolic blood pressure (HR = 1.05, 95% CI = 1.03–1.06), pulse (HR = 1.02, 95% CI = 1.00 –1.03), albumin excretion rate (HR = 1.28 –1.17–1.39) and presence of proliferative retinopathy (HR = 1.48, 95% CI = 1.03–2.13) and coronary artery disease (HR = 1.83, 95% CI = 0.95–3.55). In conclusion, hyperglycemia is a risk factor for the development of hypertension among individuals with long-standing type 1 diabetes. Moreover, as reported in DCCT, IIT is inversely related with hypertension incidence.
Abstract 4900: Left Ventricular Hypertrophy by Electrocardiography in the African-American Study of Kidney Disease and Hypertension
Authors: Razzouk Louai , Peterson Gail E , Wright Jackson T , Phillips Robert A , De Backer Tine L , Baran David A , Kendrick Cynthia , Greene Tom , Esquitin Ricardo , Aneja Ashish , Muntner Paul , Farkouh Michael E
Published: April 2024

Purpose:
Electrocardiogram (ECG) criteria for left ventricular hypertrophy (LVH) have low sensitivity in the general population though a high rate of ECG LVH has been consistently reported in African-Americans (AA). The purpose of the current study was to evaluate the value of ECG criteria among AA with hypertensive kidney disease, a population with a high burden of LVH.

Methods:
AA with hypertensive kidney disease (n = 645) were evaluated for LVH on echocardiography and ECG as part of the African-American Study of Kidney Disease and Hypertension (AASK) cohort. ECGs were read by two cardiologists at an independent core laboratory using the two Sokolow-Lyon criteria and the Cornell criteria. LVH on echocardiography was defined as left ventricular mass index >49.2 and >46.7 g/m
2.7
in men and women respectively, and was used as the gold standard.

Results:
The mean age of the patients was 60.1 years (SD = 10.1), 39.2% were women and 12.9% had diabetes. All patients had hypertensive kidney disease with a mean serum creatinine of 2.30 mg/dL (SD = 1.39). Sixty-nine percent of the population had LVH on echocardiogram, while 35% had LVH by any of the ECG criteria; 15% had LVH by Sokolow-Lyon-1 (S in V
1
+ R in V
5
or V
6
whichever is larger > 35 mm
or
R in V
5
or V
6
>25mm), 16% by Sokolow-Lyon-2 (R in aVL > = 11 mm) and 20% by Cornell criteria (S in V
3
+ R in aVL >28 mm in men, and S in V
3
+ R in aVL > 20 mm in women). LVH by ECG in AA had low sensitivity by any of the criteria, while specificity was higher (Table

). The NPV were low and PPV were higher regardless of the ECG criteria applied, and the kappa statistic indicated poor agreement between ECG- and echocardiogram-defined LVH.

Conclusions:
LVH by ECG had low sensitivity in this cohort of AA with hypertensive kidney disease. These results are consistent with previous findings from Caucasian and AA populations without chronic kidney disease.
Abstract 4914: Extracellular SOD-derived H
2
O
2
Promotes VEGF Signaling via Oxidative Inactivation of Protein Tyrosine Phosphatases Localized in Caveolae/Lipid Rafts
Authors: Oshikawa Jin , Kaplan Nihal , Razvi Masooma , Urao Norifumi , McKinney Ronald , Fukai Tohru , Ushio-Fukai Masuko
Published: April 2024

Reactive oxygen species (ROS), in particular, H
2
O
2
, is essential for full activation of VEGF receptor2 (VEGER2) signaling involved in endothelial cell (EC) proliferation and migration. Extracellular superoxide dismutase (ecSOD) is a major extracellular antioxidant enzyme in the vasculature that converts superoxide to H
2
O
2
. It is secreted and anchored to the endothelial surface through binding to the heparan sulfate proteoglycan (HSPG), which binds to VEGFR2 to facilitate its signaling. Mice lacking ecSOD show impaired postnatal angiogenesis. However, underling mechanism remains unknown. Here we show that adenovirus-mediated ecSOD overexpression in cultured medium in ECs enhances VEGF-induced tyrosine phosphorylation of VEGFR2 (VEGFR2-pY) (2.9-fold). This ecSOD-induced effect is prevented by short-term pretreatment with catalase which scavenges extracellular H
2
O
2
. Of note, either exogenous H
2
O
2
or mutant ecSOD lacking heparin binding domain (ecSOD-deltaHBD) has no effect on VEGF-induced VEGFR2-pY, suggesting that H
2
O
2
needs to be produced close to VEGFR2 for its activation. Mechanistically, VEGFR2 as well as protein tyrosine phosphatases (PTPs) PTP1B and DEP1, which negatively regulate VEGFR2, but can be inactivated by ROS, are colocalized in caveolae/lipid rafts. VEGF-induced VEGFR2-pY in these microdomains is enhanced by ecSOD (2.3-fold), which is associated with oxidation of PTP1B and DEP1, and decrease in PTPs activity (48.9%) in caveolae/lipid rafts. PTPs inhibitor orthovanadate; or siRNAs for PTP1B and DEP1; or disruption of caveolae/lipid rafts by methyl-b-cyclodextrin enhances VEGF-induced VEGFR2-pY, which prevents ecSOD-induced effect. Functionally, ecSOD significantly promotes VEGF-stimulated EC migration (1.7-fold) and proliferation (1.4-fold). In vivo, adenovirus ecSOD injection into adductor muscle improves blood flow recovery and increases capillary formation after hindlimb ischemia, while mutant ecSOD-deltaHBD has no effects. In summary, H
2
O
2
produced proximity to VEGFR2 by ecSOD inactivates PTPs in caveolae/lipid rafts via oxidation, thereby promoting VEGF-induced VEGFR2-pY and angiogenesis. Thus, ecSOD is important therapeutic target for angiogenesis-dependent cardiovascular diseases.

This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).
Abstract 4918: Cytochrome P450 4F2 Transgenic Mice Increase 20-hete and Blood Pressure by Oxidative Stress
Authors: Liu Xiaoliang , Wu Jingjing , Liu Hong , Zhao Yanyan
Published: April 2024

Cytochrome P450 4F2 (CYP4F2) is a primary enzyme that converts arachidonic acid (AA) to 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoconstrictive and natriuretic metabolite that regulates human blood pressure. We recently established a
CYP4F2
transgenic mouse model using mouse kidney androgen-regulated protein (KAP) promoter, which demonstrated increased 20-HETE production and elevated blood pressure. The present study aims to elucidate the relationship between oxidative stress and 20-HETE in the development of hypertension. The level of oxidative stress was evaluated by measuring malondialdehyde (MDA), a marker of lipid peroxidation, and superoxide dismutase (SOD), a major antioxidative parameter. Plasma MDA was significantly higher in transgenic mice than in wild-type controls (
P
<0.05), which was consistent with the level of 20-HETE. Plasma SOD activity was decreased in transgenic mice compared with wild-type controls (
P
<0.05). Kidney homogenate also showed increased MDA and decreased SOD activity. In addition, treatment of 5
α
-dihydrotestosterone (DHT) strongly induced the synthesis of 20-HETE, and hence enhanced the MDA production and impaired the SOD activity. These results indicate that 20-HETE overproduction in
CYP4F2
transgenic mice suffered higher level of oxidative stress. Oxidative stress may possibly be involved in the pathogenesis of 20-HETE-mediated hypertension.
Abstract 4926: Tyrosine Kinase Inhibitors Are Potent Pulmonary Vasodilators in Rats
Authors: Abe Kohtaro , Ito Masako , Gerthoffer William T , Fagan Karen A , McMurtry Ivan F , Oka Masahiko
Published: April 2024

Background: The pathogenesis of pulmonary arterial hypertension (PAH) includes vascular remodeling and vasoconstriction. Tyrosine kinase inhibitors have recently been reported promising for the treatment of PAH. Their therapeutic effects are postulated to be due to inhibition of cell growth-related kinases, such as platelet-derived growth factor receptor, and subsequent attenuation of vascular remodeling. Nothing, however, has been considered regarding their potential vasodilatory activity. This study examined whether tyrosine kinase inhibitors might acutely induce pulmonary vasodilation.

Methods and Results: In isolated extra-lobar pulmonary arteries from normal adult rats, imatinib, sorafenib, and nilotinib concentration-dependently reversed U46619-induced contractions (see figure

). Nitro-L-arginine did not reduce their relaxant potency. Imatinib (30 uM) reduced phosphorylation of MYPT-1 in U46619-treated arterial rings. Imatinib (50 mg/kg, ip) acutely and preferentially lowered high right ventricular systolic pressure (from 96 ± 11 to 67 ± 7 mmHg, a 29 % reduction) compared to systemic arterial pressure (from 98 ± 3 to 89 ± 5 mmHg, a 10 % reduction) in SUGEN 5416 (VEGF receptor inhibitor; 20 mg/kg, sc) plus chronic hypoxia-exposed severe pulmonary hypertensive rats.

Conclusion: Tyrosine kinase inhibitors have potent, Ca2+ desensitization-dependent pulmonary vasodilator activity, which could be involved in their long-term beneficial effect against PAH.
Abstract 4945: Eptifibatide is Non-inferior to Abciximab in Acute Coronary Syndromes: Results From the Swedish Coronary Angiography and Angioplasty Registry (SCAAR)
Authors: Akerblom Axel , James Stefan K , Koutouzis Michael , Lagerqvist Bo , Stenestrand Ulf , Svennblad Bodil , Oldgren Jonas
Published: April 2024

Introduction: Glycoprotein IIb/IIIa inhibitors are recommended by international guidelines with high level of evidence in patients with Acute Coronary Syndromes (ACS) undergoing treatment with percutaneous coronary interventions. No prospective randomized trial comparing abciximab and eptifibatide has been published.

Hypothesis: We hypothesized that eptifibatide is non-inferior to abciximab.

Methods: We included all ACS patients in Sweden undergoing percutaneous coronary interventions receiving either eptifibatide or abciximab during 2004 to 2006 from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). The primary endpoint was death and myocardial (re-)infarction during one year follow-up with adjustment for baseline differences with a multivariable logistic regression analysis including propensity score. The pre-specified non-inferiority margin was set to 1.29.

Results: ACS patients were stratified in two treatment groups (eptifibatide n=3703 and abciximab n=10252) which showed similar baseline characteristics with mean age of 65 years, female representation of 27% and diabetes in 20.5% respectively 19.4%. The eptifibatide cohort had a lower proportion of ST-elevation myocardial infarctions (45.8% vs. 67.6%). The combined endpoint occurred in 543 (14.7%) and 1607 (15.7 %) of eptifibatide and abciximab treated patients respectively. The unadjusted odds ratio (95 %CI) for eptifibatide versus abciximab was 0.92 [0.83 – 1.03]. Multivariable adjustment (n=13882) showed non-inferiority with an odds ratio of 1.07 [0.95 – 1.19]. In patients with ST-elevation myocardial infarctions the non-inferiority remained with adjusted odds ratio of 1.03 [0.89 – 1.20] (n=8598).

Conclusions: This large scale registry study shows that eptifibatide is non-inferior to abciximab as adjunctive therapy in invasively managed ACS patients with respect to death or myocardial infarction during one year, justifying its broad use in clinical practice.
Abstract 4946: Comparison of Prasugel With Clopidogrel on Platelet Function in Coronary Artery Disease Patients With Type 2 Diabetes Mellitus - Third Optimizing Anti-Platelet Therapy in Diabetes MellitUS (OPTIMUS-3)
Authors: Angiolillo Dominick J , Badimon Juan , Saucedo Jorge F , Frelinger Andrew L , Michelson Alan D , Jakubowski Joseph A , Zhu Baojin , Ojeh Clement K , Baker Brian , Effron Mark B
Published: April 2024

Introduction:
Type 2 diabetes mellitus (T2DM) patients (pts) have decreased response to clopidogrel (Clop) compared to non-diabetic patients. Prasugrel (Pras) has shown to be more efficacious than Clop in reducing thrombotic cardiovascular events in T2DM pts with acute coronary syndrome undergoing percutaneous coronary interventions. However, the pharmacodynamic effects of Pras compared to Clop in T2DM have not been fully explored. The OPTIMUS-3 study evaluated pharmacodynamic responses of Pras compared with Clop in coronary artery disease (CAD) pts with T2DM.

Methods:
A total of 35 CAD pts with T2DM on chronic aspirin were randomized to Pras 60 mg loading dose (LD)/10 mg maintenance dose (MD) or Clop 600 mg LD/150 mg MD for 1 week in a double-blind cross-over design with a 2 week washout period between study drugs. Platelet function was assessed by the VerifyNow P2Y12 (VN-P2Y
12
) assay, light transmission aggregometry (LTA) following 5 and 20
μ
M ADP, and phosphorylation of vasodilator stimulated phosphoprotein (VASP), at baseline, 1 hr, 4 hr and 24 hr post LD, and 6 – 8 days post-MD. The primary comparison of inhibition of platelet aggregation (IPA) at 4 hours after LD between 60 mg Pras and 600 mg Clop was assessed by VN-P2Y
12
.

Results:
Significantly greater IPA by VN-P2Y
12
at 4 hr post LD was achieved by Pras vs. Clop (89.3 % vs. 27.7%, p<0.0001). Significantly greater IPA was also observed at 1 hr and 24 hr post LD and 7 days post-MD (Figure

). Similar results were obtained when platelet function was assessed by VN-P2Y
12
Reaction Units, LTA and VASP.

Conclusion:
In CAD pts with T2DM, Pras is associated with significantly greater inhibition of platelet function than high LD and MD regimens of Clop.
Abstract 4953: Del-1, a New Beta2-integrin Ligand, Which Inhibits Mobilization, Adhesion and Homing of Progensitor Cells
Authors: Chavakis Emmanouil , Hain Andreas , Orlandi Alessia , Carmona Guillaume , Quertermous Thomas , Chavakis Triantafyllos , Dimmeler Stefanie
Published: April 2024

Progenitor cells (PC) are recruited to ischemic tissues and improve neovascularization. Beta2-integrins are essential for adhesion and homing of PC to ischemic tissues. Developmental Endothelial Locus-1 (Del-1) is an extracellular matrix protein that binds alphaVbeta3-and beta2-integrins and is up-regulated during ischemia. Therefore, we investigated the role of Del-1 for angiogenesis and homing functions of PC. Del-1-deficient mice (Del-1−/−) displayed a significantly increased angiogenic response in ischemic muscles in comparison to the wild type (WT) mice in the model of hind limb ischemia. However, when we assessed the role of Del-1 in HUVEC in vitro, silencing of Del-1 by siRNA did not affect angiogenic sprouting. Moreover, the ischemic muscles of Del-1−/− mice displayed a higher infiltration with CD45+ cells than WT mice, suggesting that Del-1-deficiency may induce activation of homing of PC and inflammatory cells to ischemic tissues. Interestingly, in adhesion assays human endothelial progenitor cells (EPC) and murine Lin- PC bound to Del-1 via beta2-integrins, but not via the alphaVbeta3-integrins. Furthermore, soluble Del-1 significantly inhibited the adhesion of EPC to HUVEC monolayers and to the major beta2-integrin-ligand, ICAM-1. Moreover, WT murine bone marrow (BM) mononuclear cells displayed higher adhesion rates on Del-1-deficient murine lung endothelial cells (LEC) than on WT LEC. In order to investigate the role of Del-1 for in vivo homing of PC, we intravenously injected murine fluorescence-labeled WT Lin- BM PC in WT and Del-1−/− mice 2 days after the induction of hind limb ischemia. Interestingly, the homing of injected Lin- cells to ischemic muscles was significantly increased in Del-1−/− in comparison to WT mice (200±30 % increase). Moreover, Del-1−/− mice displayed a significantly increased GCSF-induced mobilization of Sca1+ cKit+ PC in the peripheral blood in comparison to WT mice. Taken together, Del-1 is a new beta2-integrin ligand, which blocks PC mobilization and beta2-integrin-dependent adhesion and homing of PC to ischemic tissues. It is conceivable, that endogenous Del-1 may reduce ischemia-induced neovascularization through an inhibitory effect on the beta2-integrins of PC and inflammatory cells.
Abstract 5031: A Novel Ultrasound-based Wall Shear Stress Biomarker (Echo Particle Image Velocimetry) to Generate Hemodynamic Vascular Profiles in Carotid Arteries: Clinical Studies on 16 Healthy Subjects
Authors: Zhang Fuxing , Gates Phillip E , Strain W D , Mazzaro Luciano , Barker Alex J , Fulford Jonathan , Shore Angela C , Bellenger Nick G , Lanning Craig , Shandas Robin
Published: April 2024

Introduction:
Hemodynamic vascular profiling using Wall Shear Stress (WSS) may allow prediction of plaque progression and/or rupture in carotid arteries. However, there is no easy-to-use method to accurately measure WSS and develop carotid vascular profiles clinically. We previously described
in vitro
and
in vivo
validation of a novel contrast-enhanced ultrasound-based velocimetry technique (Echo PIV) that can generate high-resolution spatially-and temporally-resolved velocity vector and WSS maps of complex vascular flows. Here, we evaluate the utility of Echo PIV to generate baseline vascular profiles of normal carotid hemodynamics.

Methods:
Echo PIV was used to obtain high resolution (temporal resolution: 0.7 ms; spatial resolution: 0.4 mm) velocity vector, flow rate, and WSS maps of carotid hemodynamics, as well as internal diameter, and curvature of the internal carotid sinus (ICS).

Results:
Regression analysis found that mean WSS was inversely related to common carotid artery (CCA) diameter (r=−0.88, P<0.0001; Figure

) at the CCA and to mean curvature (r=−0.92, P<0.01) at the ICS. At the CCA, there was a strong association between peak WSS and peak velocity (r=0.82, P<0.001), but not between mean WSS and peak velocity (r=0.17, P=0.52). No association was found between mean blood flow and mean WSS at CCA (r=0.15, P=0.57), or at ICA (r=−0.28, P=0.50).

Conclusions:
Echo PIV can generate vascular profiles of human carotid arteries that include WSS, blood flow and vessel morphology, and appears to hold promise as a simple-to-obtain biomarker for evaluating vascular plaque vulnerability.
Abstract 5039: Globular and Full-length Adiponectin Induce NO-Dependent Vasodilation in Resistance Arteries of ZL but Not ZDF Rats
Authors: Schmid Peter M , Resch Markus , Birner Christoph , Stoelcker Benjamin , Pietrzyk Gabriela , Fredersdorf-Hahn Sabine , Buechler Christa , Riegger Günter A , Luchner Andreas , Endemann Dierk H
Published: April 2024

Adiponectin increases NO-production in endothelial cell cultures and is reduced in the circulation of obese and diabetic patients, but it is not known whether adiponectin has a functional effect on small resistance arteries. In order to address this question, we assessed the direct vasodilatory response of mesenteric resistance arteries of Zucker diabetic fatty (ZDF) rat and the Zucker lean (ZL) rats to globular (gAd) and full-length adiponectin (fAd) in a small vessel myograph after precontraction with norepinephrine. Serum adiponectin levels measured by ELISA were significantly higher in ZL than in ZDF rats (ZL 4.0±0.1
μ
g/l vs ZDF 2.9±0.2
μ
g/l; p<0.001). Both gAd and fAd induced a relevant dose dependent vasodilation in ZL, but not ZDF rats (max. vasodilation to gAd: ZL 21.0±0.9% vs ZDF 2.9±0.9%; p<0.001. max. vasodilation to fAd: ZL 23.8±1.2% vs ZDF 1.4±1.1%; p<0.001). This vasodilatory effect in ZL rats could totally be blunted by preincubation with L-NAME (p<0.001) indicating that it is exclusively mediated by NO. ZDF rats showed a significantly lower endothelium-dependent vasodilation response to acetylcholine (max. vasodilation: ZL 96.7±5.5% vs ZDF 60.1±6.0%; p<0.001). The additional administration of low dose gAd or fAd could not improve the vasodilatory response to ACh. The gene expressions of AdipoR1 and AdipoR2 quantified by real-time RT-PCR were not significantly different in both animal models, AdipoR2 only tended to be higher expressed in ZDF rats (ZL 0.62±0.03 vs ZDF 0.68±0.06; p=0.061). But AdipoR1 was significantly more abundant expressed than AdipoR2 in resistance arteries of both ZL and ZDF rats (ZL: 1.06±0.04 vs 0.62±0.03; p<0.001. ZDF: 1.06±0.08 vs 0.68±0.06; p<0.001). In conclusion, we showed that adiponectin exerts a relevant NO-mediated vasodilation in resistance arteries of normal control rats. Reduced adiponectin serum levels and a blunted response to adiponectin in diabetic animals may contribute to endothelial dysfunction and thus play a role in the pathogenesis of atherosclerosis. In diabetes mellitus, adiponectin receptors are not downregulated in resistance arteries indicating a dysfunction downstream of the receptors.
Abstract 5057: CXCR4 Antagonist AMD3100 Preserves Cardiac Function After Myocardial Infarction (MI) via CXCR4 Dependent and Independent Pathways
Authors: Jujo Kentaro , Hamada Hiromichi , Seguchi Haruki , Thorne Tina , Klyachko Ekaterina , Renault Marie-Ange , Losordo Douglas W
Published: April 2024

Background:
Recent studies have been shown that CXCR4 antagonist AMD3100 rapidly mobilizes stem/progenitor cells from BM and prior studies suggested a potential therapeutic effect in MI. This study was performed to explore the mechanisms of this effect in a mouse ischemia reperfusion (IR) injury model.

Methods and Results:
8- to 12-week-old wild-type (WT) mice were treated with single sc injections of either AMD3100 (5 mg/kg) or saline immediately after IR injury (60 min-LAD occlusion followed by reperfusion). FACS analyses identified a significant increase in the number of circulating EPCs(culture method; Day7: 76.0±23.9 vs 34.6±6.1 cells/uL PB,
p
<0.05) in AMD-treated mice on days 3–7 after IR, and ELISA indicated that AMD increased levels of MMP-9 and soluble Kit ligand in BM(Day 3 MMP-9: 88.6±12.7 vs 53.9±24.5 ug/mL,
p
<0.05; sKitL: 20.4±3.3 vs 13.0±4.1 vs. pg/mL,
p
<0.05). On day 3 after IR histo analyses revealed a lower ratio of infarct area/area at risk (AAR) (15.8±2.2% vs 31.9±9.4,
p
<0.05) in AMD-treated mice. On day 28 AMD-treated mice had greater capillary density in AAR (188.7±52.5 vs 113.5±13.4/HPF,
p
<0.05) and less fibrosis(27.6±10.9 vs 43.3±17.0%,
p
<0.05). 4 wks after IR, echocardiograpy showed better LV function in AMD-treated mice (Day28 LVFS: 38.3±6.1% vs. 28.0±5.0,
p
<0.05). To determine whether favorable effect of AMD on recovery after IR is dependent on CXCR4 expression on BM cells, we induced IR injury in WT mice transplanted with BM from CXCR4 conditional KO donor mice. In BM-transplanted mice, AMD continued to increase EPC mobilization from BM after IR, as well as increasing levels of MMP-9 and sKit ligand in BM(all p<.05). However, the enhanced cardiac functional recovery observed in mice with WT BM was
lost in mice with CXCR4 null BM
. These results indicate that the EPC mobilizing effect of AMD is CXCR4 independent, while the BM CXCR4 is essential for AMD mediated preservation of cardiac function after IR.

Conclusions:
This study provides novel mechanistic insights into the cardioprotective effects of CXCR4 antagonist AMD3100 indicating that MMP-9 and Kit ligand contribute to AMD-induced EPC mobilization independent of CXCR4 but that the receptor is essential for AMD mediated myocardial protection.
Abstract 5077: Inhibition of Smooth Muscle Myosin, a Novel Anti-Hypertensive Strategy
Authors: Shen You-Tang , Chen Li , Zhao Xin , Qian Xiangping , Morgans David J , Vatner Stephen F , Malik Fady I
Published: April 2024

Inhibition of smooth muscle myosin is a novel mechanism to reduce vascular smooth muscle tone and may represent a new antihypertensive class. The goal of this study was to examine the effects of a smooth muscle myosin inhibitor, CK-2018448 (CK-448), in conscious dogs at baseline and in the hypertensive state. Hypertension was induced by wrapping one kidney combined with renal artery stenosis in 5 dogs instrumented with a left ventricular (LV) pressure gauge, Transonic flow probes on the ascending aorta, coronary, renal and iliac arteries, and pressure catheters in the aorta and left atrium. One week after surgery, when the dogs were still normotensive, CK-448 (2– 6 mg/kg, iv bolus) produced dose-dependent decreases in mean arterial pressure (MAP) and total peripheral vascular resistance (TPR) and increases in cardiac output, LV dP/dt and heart rate; the latter were nearly eliminated by autonomic blockade. The changes in TPR and regional vascular resistance after administration of CK-448 (6 mg/kg, iv) were compared with those of the calcium channel blocker, amlodipine (0.5 mg/kg, iv) at doses inducing similar reductions in TPR (Table

). The pattern of regional vasodilation in the kidney and limb was different for the 2 drugs; the greatest vasodilation for amlodipine was in the limb, whereas for CK-448 it was the kidney. When hypertension developed 2– 4 weeks later, baseline MAP rose from 101±4 to 158±7 mmHg and TPR from 27±3 to 100±10 mmHg/L/min. The effect of CK-448 on TPR was more than in the normotensive state and there was a similar preferential renal vasodilation with CK-448, i.e., it increased renal blood flow by 76% (t = 3 min), which was twice the increase in the iliac bed. Thus, the smooth muscle myosin inhibitor and a calcium channel blocker elicited different patterns of regional vasodilation. The renal vasodilation induced by CK-448 could have additional salutary effects in hypertension, which is often accompanied by renal insufficiency.
Abstract 5127: Left Atrial Ejection Fraction (LAEF) is a Novel Marker of Left Atrial Appendage Dysfunction in Acute Stroke Patients
Authors: Nishiyama Satoshi , Watanabe Tetsu , Sasaki Shintaro , Tamura Harutoshi , Takahashi Hiroki , Arimoto Takanori , Shishido Tetsuro , Miyashita Takehiko , Miyamoto Takuya , Nitobe Joji , Kubota Isao
Published: April 2024

Background
Recently, it was reported that left atrial ejection fraction (LAEF) may be as a marker of left atrial dysfunction. However, the feasibility of LAEF remains to be determined. We investigated whether LAEF is a marker of left atrial appendage (LAA) dysfunction which causes cardiogenic embolism in stroke patients.

Methods
We performed trans-thoracic echocardiography (TTE) and trans-esophageal echocardiography (TEE) in 53 consecutive stroke patients (cardiogenic embolism, male/female=14/9, 70±12y; stroke of other sources, male/female =21/9, 66±16y). LAEF was calculated by the biplane area-length method from apical 4- and 2-chamber views at end systolic and diastolic phase. We compared LAEF to LAA peak emptying flow velocity which is an established marker of LAA dysfunction.

Results
LAEF was significantly lower in patients with cardiogenic embolism than in those without it (LAEF, 30.4±11.0 vs. 45.4±14.7, P<0.01). Left atrial dimensions, time and the ratio of the early diastolic trans-mitral inflow velocity (E wave), left atrial volume index (LAVI) and LAEF were significantly correlated with LAA emptying flow velocity. However, only LAEF was significantly correlated with LAA emptying flow velocity in patients with atrial fibrillation (R=0.566, p<0.05). Furthermore, the multivariate logistic regression analysis revealed that only LAEF was an independent predictor of LAA dysfunction in TTE parameters (odds ratio 3.96; 95% confidence interval 1.02–15.27; P<0.05).

Conclusions
LAEF may be a reliable non-invasive maker of LAA dysfunction and predict cardiogenic embolism in stroke patients.