bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5522: Improvement of Angiotensin-II-Induced Vascular Dysfunction and Oxidative Stress by the Organic Nitrate Pentaerithrityl Tetranitrate Depends on Heme Oxygenase-1-Induction
Authors: Wenzel Philip , Schuhmacher Swenja , Schulz Eberhard , Oelze Matthias , Kamuf Jens , Gori Tommaso , Hortmann Marcus , Bhatnagar Aruni , Daiber Andreas , Münzel Thomas 
Published: April 2024

Objective: Pentaerithrityl tetranitrate (PETN)-treatment is devoid of nitrate tolerance which has been attributed to the induction of the antioxidant enzyme heme oxygenase-1 (HO-1). With the present study we tested, whether chronic treatment with PETN can improve angiotensin-II (AT-II)-induced vascular oxidative stress and dysfunction.
Methods and Results: In contrast to isosorbide mononitrate (ISMN, 75mg/kg/d/7d), co-treatment with PETN (15mg/kg/d/7d) improved impaired endothelial and smooth muscle function and normalized vascular and cardiac ROS production (mitochondria, NADPH oxidase activity and uncoupled endothelial nitric oxide synthase [eNOS]) as assessed by dihydroethidine (DHE)-staining, lucigenin-enhanced chemiluminescence and quantitative HPLC of DHE-oxidation products in AT-II (1mg/kg/d/7d) treated rats. The antioxidant features of PETN were recapulated in spontaneously hypertensive rats. In addition to increase in HO-1 protein expression, PETN but not ISMN augmented aortic protein levels of the tetrahydrobiopterin-synthesizing enzymes GTP-cyclohydrolase-I and dihydrofolate reductase in AT-II-treated rats, thereby preventing eNOS uncoupling. In AT-II-treated (0.1mg/kg/d/7d) HO-1+/− mice, PETN failed to be antioxidant, whereas HO-1 induction by hemin (25mg/kg) mimicked the PETN effect in AT-II-treated HO-1+/+ mice.
Conclusions: PETN improves AT-II-induced vascular oxidative stress and dysfunction via induction of HO-1. Thus, PETN is the first organic nitrate to be beneficial in an experimental model of arterial hypertension.
Abstract 5608: Recognition of Abnormal Glucose Metabolism and Its Impact on Treatment in Patients With Acute Myocardial Infarction in Germany: Results of the SWEETHEART Registry
Authors: Gitt Anselm K , Towae Frank , Juenger Claus , Zeymer Uwe , Zahn Ralf , Senges Jochen 
Published: April 2024

Background: Recent reports from epidemiological studies demonstrated a high prevalence of undiagnosed diabetes in patients with coronary artery disease. These findings led to joint guidelines by the ESC and the EASD on diabetes, pre-diabetes and cardiovascular disease.
Methods: Since 2007, 1,773 consecutive patients with STEMI or NSTEMI were enrolled into the MI-registry SWEETHEART to document patients’ characteristics and treatment in clinical practice with special emphasis on the identification of abnormal glucose metabolism. In patients with previously unknown diabetes, oral glucose tolerance test was performed at day 4 after the acute MI. We examined the prevalence of abnormal glucose metabolism and its impact on treatment in clinical practice.
Results: Out of 1,773 consecutive patients with MI, 919 (52.3%) presented with STEMI and 837 (47.7%) with NSTEMI. Diabetes was already known in 33.0% of patients. Oral glucose tolerance tests identified another 16.1% of patients with manifest diabetes and 22.4% with impaired fasting glucose or impaired glucose tolerance (pre-diabetes). Only 28.5% of the MI population had no signs of abnormal glucose tolerance. Medical treatment for secondary prevention at discharge was quite well according to guidelines for antiplatelet therapy, betablockers, statins, ACE-inhibitors and ARB for all patients. Nevertheless, only 61.1% of patients with newly diagnosed diabetes did receive treatment for diabetes at discharge, in whom 74.0% only received diet.
Conclusion: There was a high prevalence of newly diagnosed diabetes and pre-diabetes in consecutive patients with myocardial infarction in Germany. Despite new guidelines by the ESC and the EASD with clear recommendations for early and aggressive therapy of diabetes in patients with cardiovascular disease, 40% of myocardial infarction patients with newly diagnosed diabetes did not receive diet or an antidiabetic treatment at discharge.
Abstract 5631: Isolation of a Resident and Dynamic Oct4+ Stem Cell Population From Adult Skin
Authors: Limbourg Anne , Lozanovski Vladimir , Schnabel Sabine , Templin Christian , Napp L C , Drexler Helmut , Limbourg Florian P 
Published: April 2024

The transcription factor Oct3/4 is a critical regulator of pluripotency in embryonic stem cells and induced pluripotent stem (iPS) cells and iPS generation requires re-activation of endogenous Oct4 expression. Since Oct4 might be a critical regulator of somatic stem cell pluripotency we have employed a genetic, bona-fide reporter strategy to determine the temporo-spatial expression of Oct4 in adulte mice.
RESULTS: Postnatal Oct4 expression was determined in transgenic Oct4::eGFP reporter mice by flow cytometry, for hearts and skin the response to injury was also evaluated (n=9 –28). The fidelity of the Oct4-GFP reporter strain was confirmed by immunofluorescence confocal microscopy and by RT-PCR. No GFP+ cells were detected in bone marrow or spleen, nor in the atria or ventricles of the myocardium under baseline and post-ischemic conditions. Importantly, Oct4+ cells resided in skin, where levels increased postnatally over time until puberty and returned to low levels in the adult (Oct4+/500.000 cells: puberty 400±268; adult 53±23). Furthermore, the Oct4+ cell pool increased robustly after wound injury (289±156, n=9, p<0.05) even in remote skin areas. In situ analysis revealed the existence of GFP+ niches associated with distinct regions of hair follicle. Oct4+ cells after FACS-sorting revealed a phenotype of c-kit lo, sca-1 +, CXCR4 lo, alpha6 integrin lo, beta1 integrin -, and expressed by qRT low levels of Oct4, Sox2, Klf4, and high levels of c-myc, factors involved in iPS induction. The differentiation potential of Oct4+ skin cells was evaluated by transplanting dual reporter cells (GFP+; lacZ+) into nude mice following hindlimb ischemia and analysis of contribution to tissue lineages. 4 weeks after transplantation, LacZ+ cells contributed to muscle cells, adipose tissue and vascular structures.
CONCLUSION: Genetic reporter studies reveal no evidence for Oct4+ cells in bone marrow or heart but, unexpectedly, show persistence of resident Oct4+ stem cells in adult skin, which contribute to mesodermal cell lineage after transplantation. These findings suggest adult skin as an important source for regenerative cell therapy.
Abstract 5675: Local Gene Silencing of TLR4 Expression
in vivo
Improves Vein Graft Patency in Mice
Authors: Karper Jacco , de Vries Margreet , van den Brand Ben , Niessen Hans , Hoeffer Imo , Quax Paul 
Published: April 2024

Introduction: Patency of vein grafts is limited by vascular remodelling processes such as neointima formation and accelerated atherosclerosis. Toll Like Receptor 4 (TLR4) is associated with neointima formation and atherosclerosis.
Hypothesis: We hypothesize that TLR4 can serve as a local therapeutic target against vein graft disease.

Methods: In human saphenous veins (huSV) immunohistochemical staining for TLR4 was performed on cross-sections of either directly harvested huSV (n=6),
in vitro
perfused huSV (n=6) and coronary graft huSV derived at autopsy (n=5). Mouse venous bypass grafting was performed in Balb/c mice (n=8) and in TLR4 deficient (C3H/Hej) mice (n=7) using a venous interposition model in the carotid artery. Five lentiviral TLR4 shRNAs were created and validated for local TLR4 gene silencing by measurement of murine TLR4/MD2 expression by FACS analysis and the best vector was selected for
in vivo
analysis. To test the effect of local TLR4 deficiency on vein graft disease virus was administered in pluronic gel and lubricated around vein grafts after vein grafting in APOE3*Leiden mice fed a high cholesterolemic diet.

Results: A marked induction of focal TLR4 expression was observed in HuSV, reperfused ex vivo with whole blood under pulsatile arterial pressure. Moreover, TLR4 was abundantly present in the neointima formed in autopsy grafts and preexisting intimal lesions in directly harvested huSV. Vein grafts in C3H/Hej mice had 48±12% less vessel wall thickening (p=0.04) than Balb/c controls, 28 days after surgery. Hypercholesterolemic APOE3*Leiden mice showed massive vein graft disease due to neointima formation and accelerated atherosclerosis after vein grafting. Local gene silencing of TLR4 led to a significant reduction of vessel wall thickening (38±10%, n=10, p=0.03) in the graft segment and superior graft patency (p=0.013) as compared to the control. In conclusion, the upregulation of TLR4 expression in huSV during remodelling, the reduced vein graft thickening in TLR deficient C3H/Hej mice and reduction of vessel wall thickening after local interfering in the TLR4 pathway indicate the potential of TLR4 as a local therapeutic target against vein graft disease to increase graft patency.
Abstract 5687: Identification of HGF as a Novel Vascular ADAM Metalloprotease Substrate by Phage Display
Authors: Higuchi Sadaharu , Kimura Keita , Takaguri Akira , Hinoki Akinari , Eguchi Kunie , Frank Gerald D , Eguchi Satoru 
Published: April 2024

Activation of a metalloprotease, ADAM17, and subsequent EGF receptor transactivation via proteolytic cleavage of its pro-ligand has been implicated in vascular remodeling induced by angiotensin II (AngII). The known substrates of ADAM17 include proHB-EGF and proTNF-alpha. However, whether other unidentified ADAM17 substrates are involved in AngII-induced vascular remodeling remains unanswered. To search for such substrates, we made a rat aortic cDNA phage library that has a hexa-histidine tag. After Ni-NTA agarose binding, the library phage was incubated with recombinant ADAM17 and only the cleaved phages were rescued and amplified (bio-panning). Upon repeating the panning 3 times, we obtained about 4000 phage colonies which potentially displayed ADAM17 substrates. From 128 colonies, we identified 71 candidate proteins in 88 readable sequences. Among these proteins, eleven proteins were known as ADAM17 substrates including (amphiregulin, Notch etc.) while six proteins were other protease substrates indicating strong reliability and provability of the technique. Among the novel substrate candidates, we focused on hepatocyte growth factor (HGF), a multifunctional growth factor with a proteolytic mechanism of activation. Upon transfection with a shedding assay vector encoding proHGF with its N terminus fused with ALP, the ALP activity in the condition medium was significantly reduced in ADAM17-null MEF cells compared to the control MEF cells. Moreover, the reduction was rescued with adenovirus vector encoding ADAM17. In rat VSMCs transfected with the assay vector, AngII markedly enhanced the ALP activity in the conditioned medium that was completely blocked with a MMP/ADAM inhibitor, BiPS. Also, AngII stimulated secretion of HGF-alpha in VSMCs. Recombinant HGF markedly stimulated ERK1/2 activity via the Met receptor in VSMCs. It also stimulated proliferation of VSMCs. In conclusion, we have established a novel phage display system for identification of a protease substrate with high probability. HGF was identified as a novel ADAM17 substrate potentially involved in vascular remodeling induced by AngII.
This research has received full or partial funding support from the American Heart Association, National Center.
Abstract 5821: The Effect of Spironolactone on Biomarkers of Inflammation and Extracellular Remodelling in Early Chronic Kidney Disease
Authors: Edwards Nicola C , Kirkwood Helen , Cramb Robert , Hutchinson Colin A , Steeds Richard P , Ferro Charles J , Townend John N 
Published: April 2024

Introduction Early stage chronic kidney disease (CKD) is associated with major abnormalities of arterial and ventricular stiffness and function and with a high rate of adverse cardiovascular events. We have previously demonstrated that in this high risk group, significant reductions in LV mass and markers of arterial stiffness occurred after 40 weeks of treatment with the aldosterone antagonist, spironolactone. We hypothesized that serological markers of collagen turnover, inflammation and ventricular stress might also be improved with this treatment.
Methods 112 patients participating in the double blind randomized controlled trial investigating the effect of spironolactone in early CKD had serum biomarkers of

collagen turnover; amino-terminal propeptide of procollagen type III (PNIIIP),

inflammation; high sensitivity C-Reactive Protein (hsCRP), and

ventricular stress- N-terminal Pro Beta- Natriuretic Peptide (BNP) measured. Patients had stage 2 and 3 CKD, were on ACE Inhibitor or ARB therapy, with controlled hypertension (<130/85mmHg) and no history of cardiovascular disease or diabetes. Samples were measured at baseline and after 40 weeks of blinded treatment with either spironolactone 25mg once a day or matching placebo.

Results PNIIIP levels were unchanged with spironolactone but increased significantly in the placebo group (0.06
μ
g/L±0.70 vs 0.46
μ
g/L±0.82, p<0.01). There was no difference in median hsCRP levels (0.01mg/L (IQR 1.63) vs. 0.08mg/L (IQR 2.76), p =NS). Spironolactone resulted in significant reduction in median BNP levels (−0.4pg/L (IQR 70.9) vs. 9.3pg/L (IQR 54.7), p<0.01). All baseline biomarkers were positively correlated; PNIIIP with hsCRP (
r
= 0.24, p<0.05) PNIIIP and BNP (
r
= 0.27, p<0.01), hsCRP and BNP (
r
= 0.39, p<0.01).

Conclusion Treatment with spironolactone prevents deterioration of or improves biomarkers of collagen synthesis and of ventricular stress in CKD. These data support the hypothesis that deleterious effects of aldosterone on extracellular remodeling can be attenuated by spironolactone in CKD as has been observed in clinical outcome studies of heart failure. The association of all biomarkers suggests a complicated interplay of collagen turnover, inflammation and myocyte stretch.
Abstract 18252: Washing of Stored Red Cells Prevents Transfusion Related Acute Lung Injury but not Transfusion Associated Coagulopathy
Authors: Patel Nishith N , Lin Hua , Abidoye Aderoye , Wiltshire Michael , Cardigan Rebecca , Britchford Kristina , Verheyden Veerle , Angelini Gianni D , Murphy Gavin J 
Published: April 2024

Objective To determine if washing of old Red Blood Cell (RBC) units prior to transfusion will prevent transfusion mediated organ dysfunction in our large animal experimental model. Method Adult White-Landrace pigs (50-70kg, n=32) were randomized to either sham procedure or to receive an allogeneic transfusion of 1-, 14- or washed 14-day RBCs. Endpoints included characterization of the RBC storage lesion, serial functional and biochemical measures of lung and renal injury, assessment of platelet function using platelet aggregometry, platelet activation using FACS and coagulation using ROTEM. All pigs were recovered for 24 hours prior to organ harvest.
Results Transfused pigs received 1000mls of cross-matched allogenic leucodepleted RBC stored in SAG-M preservative for either 1 or 14 days. Accumulation of toxic metabolites within the supernatant as well as cellular changes showed considerable homology to those measured in SAG-M stored human RBC units. Transfusion of allogeneic porcine RBCs was associated with 24hr RBC survivals of greater than 75% and sustained increases in haematocrit irrespective of age of unit. Despite enhancing oxygen delivery, transfusion of 14-day old RBCs decreased tissue oxygen unloading, caused significant hypoxia and pulmonary hypertension. This was associated with plasma platelet depletion with sequestration into lung parenchyma, platelet dysfunction with decreased aggregation in response to ADP stimulation, coagulopathy and inflammation with increased P-selectin expression in circulating platelets. Washing of aged RBC units prior to transfusion ameliorated TRALI and inflammation, but had no effect on transfusion induced coagulopathy and platelet dysfunction. Data are summarised below.
Conclusion Washing of aged RBC units prevents TRALI and should be evaluated in a randomized controlled in patients undergoing cardiac surgery. RBC transfusion mediated coagulopathy is a novel finding which is not affected by washing.
Abstract 18401: P53 Silenced, Apoptosis Resistant, Endothelial Progenitor Stem Cells (EPC) Improve Collateral Circulation Post Femoral Artery Occlusion in Diabetic Mice
Authors: Young Mary , Chou Cyril , Sen Sabyasachi 
Published: April 2024

Literature shows that EPCs contribute to increased collateral vessel formation following vaso-occlusion. However diabetes reduces EPC number and reduces collateral vessel formation. We cultured human EPCs and exposed them to 5.5 mM (equivalent to 99mg%) and 20mM (equivalent to 360mg%, HG) glucose, which resulted in significant EPC death within 48hrs. We noted HG exposure was associated with up-regulation of P53 and its downstream genes such as P21, PUMA and Caspase-3. We hypothesized that EPC reduction in hyperglycemia is secondary to up-regulation of P53. We obtained mouse EPCs from P53 null mice and observed that p53 KO EPCs are more resistant to cell death in HG. P53 null EPCs evolved into mature mouse EC (MEC) and retained endothelial properties. Next, we used Lenti and Adenovirus mediated si-RNA methods to silence P53 (long and short term respectively) in human EPCs and P53 silenced EPc showed better survival in HG. We developed femoral artery occlusion model to mimic peripheral vascular disease in diabetic animals. We used streptozotocin induced type 1 diabetic or Leptin resistant type 2 diabetic mouse model. We delivered saline, P53 WT and P53 null mouse EPCs intra-muscularly around the femoral occlusion in these mouse models (n=7 in each group) and counted CD31+ve number of capillaries in a 20x microscopic field. Highest number was noted in the group that received P53null EPCs. We also quantified increased vessel formation by laser doppler assay of the ischemic and contralateral hind limbs upto 2 weeks and conducted qRT-PCR and western blot of key endothelial genes such as eNOS, p-eNOS, VEGF-A, PECAM-1 and vWF from both quadriceps in all groups of mice.
Summary: Transplantation of P53 null EPCs in hyperglycemic mice with femoral occlusion demonstrate better collateral vessel formation post femoral artery occlusion setting compared to WT-EPC transplanted group. Preliminary results from transplantation of p53 silenced human CD34+ cells also indicate increased vessel formation compared to non p53 silenced hCD34+ cell in NOD-SCID diabetic mice.
Conclusion: This finding indicates towards possible therapeutic benefit in transplanting P53 silenced human EPC or CD34+ cells to prevent peripheral vascular disease in patients with diabetes.
Abstract 18571: Stroke and Outcomes in Patients with Acute Type A Aortic Dissection
Authors: Bossone Eduardo , Harris Kevin M , Suzuki Toru , Fattori Rossella , Hutchison Stuart , Ehrlich Marek P , Pyeritz Reed E , Steg P. Gabriel , Greason Kevin , Evangelista Arturo , Voehringer Matthias , Montgomery Daniel G , Isselbacher Eric M , Nienaber Christoph A , Eagle Kim A 
Published: April 2024

Background: Stroke is one of the most dreaded complications of type A acute aortic dissection (TA-AAD). However, few data exist on its incidence and association with prognosis.
Methods: We evaluated 2202 TA-AAD patients [pts, mean age 61.9 ± 14.4, 1487 (67.5%) male] from the International Registry of Acute Aortic Dissection (IRAD) to determine the incidence and prognostic influence of stroke in TA-AAD.
Results: Stroke was present at arrival in 132 (6.0%) TA-AAD pts. Stroke pts were older (65±12 vs. 62±15 yrs; p=.002) and more likely to have hypertension (86% vs. 71%; p=.001) or atherosclerosis (29% vs. 22%; p=.042). While chest pain at arrival was less common (70% vs. 82%; p<.001), stroke pts presented more often with syncope (44% vs. 15%; p<.001), shock (14% vs. 7%; p=.005) or pulse deficit (51% vs. 29%; p=<.001). Arch vessels involvement was more frequent among the stroke pts (68% vs. 37%; p<.001). Stroke pts were treated less frequently by surgery (74% vs. 85%; p<.001). Hospital stay was significantly longer in patients presenting with stroke (median 17.9 versus 13.3 days, p<0.001). Stroke patients demonstrated more frequent in-hospital complications (Table) and higher mortality (adjusted OR 1.62, 95% CI .99-2.65, p=.055) Among hospital survivors, mortality at follow-up was similar in pts with and without stroke (adjusted HR 1.15, 95% CI 0.46-2.89, p=.761).
Conclusions: Stroke occurred in greater than 1 of 20 pts with TA-AAD and was associated with increased morbidity and in-hospital, but not long-term mortality. Whether aggressive early intervention will reduce morbidity and improve mortality remains to be evaluated in future studies.
Abstract 186: Baseline ECG Predictors of 90-Day Survival in Wearable Cardioverter-Defibrillator Patients Experiencing a Sudden Cardiac Arrest
Authors: Karia Darshak , Bianco Nicole R , Wan Chingping , Glad Jo Ann M , Szymkiewicz Steven J 
Published: April 2024

Purpose: Factors affecting survival after SCA resuscitation continues to be an active area of investigation. The current wearable cardioverter defibrillator (WCD) records ECG periodically. The objective of this study was to determine whether there are any basic ECG differences in patients (pts) that died <90d after first shock versus those that were alive 90d post-shock. We analyzed ECGs at baseline (Base), one week prior to SCA (1WK), and immediately prior to first shock for ventricular tachyarrhythmias VT/VF (pre-S).
Methods: 100 sequential WCD pts (68% male, age 59 ± 16 years) shocked for VT/VF between November 2009 and June 2011 were retrospectively analyzed. Heart rate, QRS duration, QRS amplitude, corrected QT duration (QTc), ectopic activity and rhythm were manually measured at Base, 1WK, and pre-S. The WCD has four non-adhesive ECG electrodes, and measurements were made on both the side-to-side (ss) and front-to-back (fb) leads. Only pts wearing the WCD ≥1 week were included for analysis.
Results: 77 pts survived ≥90 days post shock (68% male, age 58 ± 16 years), and 23 pts died <90 days after first shock (70% male, age 63 ± 13 years). Those pts that died <90 days after first shock had a longer QTc and a shorter QRS amplitude at Base than those surviving ≥90 days post-shock (Table 1)(p≤0.05).
Conclusions: The WCD provides an opportunity to monitor ECG rhythms in at-risk pts prior to defibrillation. Similar to studies of overall mortality, this small study suggests that QT duration and QRS amplitude may be important predictive markers of survival post-SCA.