bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6147: A Tissue Stem Cell Niche Regulates Bicuspid Aortic Valve Disease
Authors: Rajamannan Nalini M 
Published: July 2021

Bicuspid aortic valve disease is the most common congenital cardiac malformation and indication for surgery for aortic valve patients. The age of onset for the development of stenosis is earlier in bicuspid aortic valves than tricuspid aortic valves. Understanding the cellular mechanisms of this valve lesion, will help to develop novel approaches towards slowing disease progression. This study hypothesizes that bicuspid aortic valve disease develops secondary to a tissue stem cell niche to activate a cross-talk mechanism which induces Notch1 cleavage and Lrp5 mediated bone formation specific to the bicuspid aortic valve. Human ex vivo bicuspid valves versus control aortic valves were tested for Notch1 expression by RTPCR, Western Blot and Immunohistochemistry. eNOS null bicuspid mice: control (n=20), cholesterol (n=20), cholesterol + Atorvastatin (n=20), were tested for the development of aortic stenosis by Visual Sonics Echo, Immunohistochemistry for Notch1, Wnt, Lrp5, Osteocalcin, PCNA and RTPCR for Notch1, Lrp5, Cbfa1, Osteocalcin. In vitro studies were performed to characterize Wnt secretion from aortic valve endothelial cells and gene expression for Notch1, Lp5 and osteocalcin from the valve myofibroblast cells. This study characterizes the secretion of Wnt3a (>300-fold, p<0.01) from aortic valve endothelium in the presence of abnormal nitric oxide regulation and lipids as measured by eNOS enzymatic activity and tissue nitrite levels. Osteoblastogenesis in the adjacent myofibroblast cell is activated via Notch1 cleavage(p<0.001) and upregulation of the Wnt3a/Lrp5 receptor. Human ex vivo valves express Notch1 cleavage as compared to normal valves from heart transplant(p<0.01). Cholesterol treated eNOS mice develop severe stenosis with cleavage of Notch1, increase in Lrp5, Wnt3a, cyclin, Cbfa1, and Osteopontin,(3-fold increase(p<0.01) which was not present in the controls and normalized in the statin treated valves. Targeting the Notch1/Wnt3a/Lrp5 pathway in bicuspid valvular calcification presents a novel approach towards treating this disease. The importance of this cross talk mechanism is demonstrated in three models of aortic valve disease and will have important clinical implications.
This research has received full or partial funding support from the American Heart Association, AHA National Center.
Abstract 6171: High-dose Epoprostenol Therapy Reverses Pulmonary Hypertension by Inducing Pulmonary Artery Smooth Muscle Cell Apoptosis in Patients with Idiopathic Pulmonary Arterial Hypertension
Authors: Akagi Satoshi , Nakamura Kazufumi , Matsubara Hiromi , Nagase Satoshi , Morita Hiroshi , Kusano Kengo , Ohe Tohru 
Published: July 2021

Background: Intravenous epoprostenol has been shown to improve long-term survival in patients with idiopathic pulmonary arterial hypertension (IPAH). Although most experts believe that the appropriate dose range of epoprostenol is between 25 and 40 ng/kg/min, the optimal dose has not been determined. In the present study, we investigated the hemodynamic change induced by high-dose epoprostenol therapy in IPAH patients, and we determined by experiments the reason why high-dose epoprostenol improves hemodynamics.
Methods: We evaluated hemodynamics in 16 IPAH patients (11 females and 5 males, mean epoprostenol dosage was 100.7±35.4 ng/kg/min) treated with high-dose epoprostenol. Lung tissues obtained from 2 IPAH patients and one non-PAH patient were assessed by terminal dUTP nick end-labeling (TUNEL) assays. We examined the induction of apoptosis by epoprostenol in cultured PAH-pulmonary artery smooth muscle cells (PASMCs) and non-PAH-PASMCs. To assess the apoptosis in cultured PASMCs, we performed TUNEL assay, caspase-3,-7 assays and transmission electron microscopy. We also examined the expression of survivin by immunocytochemical analysis.
Results: Compared with the baseline state, there were significant reductions in mean pulmonary artery pressure (26%) and pulmonary vascular resistance (66%). Hemodynamic improvements in the present study were superior to those in previous studies. Apoptotic cells were detected in lung tissues obtained from IPAH patients treated with high-dose epoprostenol. TUNEL-positive and caspase-3,-7-active cells were observed in cultured PAH-PASMCs treated with epoprostenol at a high concentration. Condensation of chromatin along the nuclear membrane and fragmentation of the nucleus were observed by transmission electron microscopy. Epoprostenol at a high concentration significantly induced apoptosis in cultured PAH-PASMCs compared with that in non-PAH-PASMCs (7.69% versus 1.92%; P<0.01). Immunocytochemical analysis revealed that epoprostenol suppressed expression of survivin in cultured PAH-PASMCs.
Conclusions: The results of the present study showed that high-dose epoprostenol therapy reverses pulmonary hypertension by induction of PASMCs apoptosis.
Abstract 3213: Acarbose, an
α
-glucosidase Inhibitor, Reduces Myocardial Infarct Size in Rabbits via Stimulation of GLP-1 Receptors, Opening Mitochondrial KATP Channels, and Preventing Hydroxyl Radical Production
Authors: Minatoguchi Shinya , Ushikoshi Hiroaki , Bao Narantuya , Kobayashi Hiroyuki , Yasuda Shinji , Iwasa Masamitsu , Sumi Shouhei , Zhang Zengi , Nishigaki Kazuhiko , Takemura Genzou , Fujiwara Takako , Fujiwara Hisayoshi 
Published: July 2021

Background: Acarbose, an anti-diabetic drug, is an α– glucosidase inhibitor that can inhibit glucose absorption in the intestine. A recent large-scale clinical trial, STOP-NIDDM, showed that acarbose reduces the risk of myocardial infarction. We examined whether acarbose reduces myocardial infarct size and investigated its mechanisms.
Methods and Results: Rabbits were fed with one of four diets in this study: normal chow, 30 mg acarbose/100 g chow, 8 g sucrose/100 g chow, or 30 mg acarbose plus 8 g sucrose/100 g chow for 7 days. Rabbits were assigned randomly to one of eight groups: control (n=10), acarbose (n=10), sucrose (n=10), acarbose+sucrose (n=10), acarbose+i.v. 5-hydroxydecanoate (5HD, a mitochondrial KATP channel blocker, 5 mg/kg) (n=10), 5HD (i.v. 5 mg/kg, n=10), acarbose+exendin(9 –39) (n=10, a Glucagon-Like Peptide-1(GLP-1) receptor blocker, 3 nmol/l) (45.4±1.2%) and exendin(9 –39)(n=10). Rabbits then underwent 30 min of coronary occlusion followed by 48 h reperfusion. Postprandial blood glucose levels were highest in the sucrose group and higher in the control groups, but decreased in the acarbose and sucrose+acarbose groups. The infarct size as a percentage of the left ventricular area at risk was reduced significantly in the acarbose (19.4±2.3%) and sucrose+acarbose groups (19.0±5.6%) as compared with the sucrose (47.4±4.2%) and control groups (42.8±5.4%). The infarct size-reducing effect of acarbose was abolished by 5HD (43.4±4.7%) and exendin(9 –39) (45.4±1.2%). The 5HD and exendin(9 –39) by itself did not affect the infarct size. Myocardial interstitial 2,5-DHBA levels, an indicator of hydroxyl radicals, increased during reperfusion after 30 min of ischemia but this increase was inhibited in the acarbose group.
Conclusions: Acarbose reduces myocardial infarct size via stimulation of GLP-1 receptors, opening mitochondrial KATP channels, and preventing hydroxyl radical production.
Abstract 6214: Comparison of Adiponectin Levels in Healthy Americans and Japanese: Results from Framingham and Fukuoka
Authors: Koga Tsunehisa , Furusyo Norihiro , Ai Masumi , Otokozawa Seiko , Asztalos Bela F , White Charles C , Banjaw Serkalem D , Cupples L A , Nakajima Katsuyuki , Schaefer Ernst J , Hayashi Jun 
Published: July 2021

Background and Objectives: Adiponectin is an adipocytokine with insulin-sensitizing and anti-atherosclerotic effects. Serum adiponectin levels have been reported to be negatively correlated with body weight and waist circumference (WC). Low plasma adiponectin levels are known to predispose to the development of insulin resistance and type 2 diabetes mellitus. Adiponectin levels may vary according to ethnic group. The aim of this study was to investigate potential differences in plasma adiponectin levels between Japanese and Americans.
Methods: Subjects consisted of 2,060 healthy American male and female participants in exam 6 of the Framingham Offspring Study (mean age 57.0 ± 9.0 years, 57.4 ± 10.5 years, respectively), and 1131 healthy Japanese male and female participants in the Fukuoka Study (mean age 56.3 ± 5.5 years, 55.6 ± 5.4 years, respectively). Frozen plasma samples (at −80 degree C) from both studies were shipped to Tufts University, Boston. Plasma concentrations of direct LDL-C, fasting plasma glucose and adiponectin were measured using the same assay kits on the same machine (Hitachi 911) by the same staff. Anthropometric measurements including weight, height, body mass index (BMI) and WC, were also used in the analysis.

Results: Plasma adiponectin levels were significantly and inversely correlated with BMI, WC, glucose, insulin, triglycerides, and systolic and diastolic blood pressure. Moreover adiponectin levels were significantly and positively correlated with HDL-C in both populations. Mean BMI and WC of Japanese men and women were significantly lower (23.8 kg/m
2
and 22.1 kg/m
2
, 86.0 cm and 78.7 cm, respectively) than in US men and women (28.2 kg/m
2
and 27.0 kg/m
2
, 100.4 cm and 92.8 cm, respectively) (all p<0.05). However, mean adiponectin levels (± SD) in Japanese men and women were significantly lower (9.3 ± 4.5 micro g/mL and 14.7 ± 7.3 micro g/mL, respectively) than in US men and women (10.3 ± 5.2 micro g/mL and 16.3 ± 7.7 micro g/mL, respectively)(p<0.05).

Conclusion: Our data indicate a substantially lower prevalence of adiposity, but not higher adiponectin levels, in a healthy Japanese population as compared to an American population. The data indicate that population specific norms may have to be used for different ethnic groups.
Abstract P109: Alteration in Intracellular Calcium During Cardiac Arrest
Authors: Takeda Satoshi , Yoshida Hiroshi , Ogawa Takeki 
Published: July 2021

AIM: A cytosolic free calcium is an important regulator of cardiac metabolism and contractility, and an increased [Ca2+]i has been implicated in irreversible cell injury and contractile dysfunction. We investigated intracellular calcium ([Ca2+]i) dynamics during cardiac arrest, especially in pulseless electrical activity (PEA) and asystole.
METHODS: Rat hearts (n=18) were perfused with a Langendorff system and loaded with Fura-2/AM, as a [Ca2+]i marker, and BCECF/AM, as a pHi marker. Surface fluorescence of the heart was recorded with an intracellular ion analyzer. A latex balloon was inserted into the left ventricle to monitor left ventricular pressure. Sustained normo-thermic cardiac arrest was induced for 20 min by clamping the aortic cannula.
RESULTS: After clamping (cardiac arrest), the left ventricular developed pressure decreased significantly, from 84.3±11 mmHg to 3.88±0.7 mmHg (p<0.01) at 2min. The rhythm was PEA in all cases in this period, followed by asystole. The amplitude of the [Ca2+]i transient (0.30±0.03) was maintained at 2 min, but further significant increases were observed in both systolic (1.14±0.04, p<0.01) and diastolic levels of [Ca2+]i (0.84±0.04, p<0.05), when compared with pre-arrest levels. The [Ca2+]i transient disappeared 4.7±0.6 min. The diastolic [Ca2+]i increased gradually after 5 min to 20 min. This diastolic [Ca2+]i increase was parallel with the increase in left ventricular end diastolic pressure (indicated ischemic contracture). The pHi increased (to 7.6±1.0) immediately after clamping. Thereafter pHi decreased rapidly and remained steady (at pH 6.6±0.6).
CONCLUSIONS: The change in the [Ca2+]i-pressure relationship rather than change in the amplitude of the [Ca2+]i transient was the main contributor in the early cardiac arrest phase. The diastolic [Ca2+]i increase might induce irreversible cell injury in the late cardiac arrest phase.
Abstract P118: Influence of a Sulfide Donor on Resuscitability and Neurological Outcome in a Porcine Model of Prolonged Cardiac Arrest
Authors: Derwall Matthias , Cizen Aysegül , Loewer Celine , Westerkamp Maren , Schnorrenberger Nora , Deike-Glindemann Jan , Fries Michael 
Published: July 2021

Introduction: Hydrogen sulfide (H2S) protects vital organs and promotes survival in ischemia-reperfusion injury.
Hypothesis: H2S increases resuscitability and neurological outcome in a porcine model of cardiac arrest (CA).
Methods: 16 pigs were instrumented with an arterial line and a pulmonary artery catheter to measure mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP) and pulmonary capillary wedge pressure (PCWCP) before CA was electrically induced and left untreated for 10 minutes. One minute after starting cardiopulmonary resuscitation (CPR), animals were randomized to intravenous bolus injection of 1mg/kg of a liquid donor of H2S (Na2S; IK-1001, Ikaria, Clinton, NJ), followed by continuous infusion of 1mg/kg/h for two hours or placebo. After a total of 6 minutes of CPR defibrilation was attempted. Surviving animals were assessed for neurological outcome on four postoperative days using a neurological deficit score (NDS).
Results: In both groups 50% of the animals could be initially resuscitated. Hemodynamic variables did not differ at baseline (i.e. before CA). However, H2S treated animals showed significantly lower MAP, MPAP and PCWP 60 minutes post CPR. PCWP remained significantly lower after 2, 3 and 4 hours. Two animals in the H2S group died before day four. Furthermore, H2S animals performed worse on the NDS at all time points after CPR (Time point - H2S vs. Placebo: +1 − 79 vs. 84/+2 − 74 vs. 89/+3 − 72 vs. 88/+4 71 vs. 88).
Conclusion: In this pilot study, H2S at a dose of 1 mg/kg did not improve resuscitability and worsened post CPR hemodynamics and neurological outcome.
Abstract P156: Health Care Professionals in Emergency Services and Hospitals Hesitate to Do CPR Because of Fear of Harming The Patient
Authors: Rosengren Ewa , Mäkinen Marja , Ponzer Sari , Kurola Jouni , Axelsson Christer , Kurland Lisa , Aune Solveig , Niemi-Murola Leila , Sopanen Marja , Christensen Erika , odegaard silje , Castrén Maaret 
Published: July 2021

Introduction: Preliminary studies showed that 41,4 % of nurses in a Finnish hospital hesitate to perform defibrillation because of fear of injuring the patient and 22,9% because the patient might die and the nurse would feel guilty. Of 80 paramedics in Oslo 39 % stated that deep compressions could result in serious patient injury. These attitudes can result in bad quality CPR starting with a delay.
Hypothesis: We assessed the hypothesis that it is common among health care professionals to feel that CPR might harm the patient, to hesitate to do compressions and to hesitate to defibrillate.
Methods: Valid questionnaires were send to nurses working in Kuopio University hospital in Finland, Uppsala Akademiska sjukhuset, Sahlgrenska hospital, Göteborg and Södersjukhuset, Stockholm in Sweden and to paramedics working in Vantaa and Kuopio in Finland, Århus in Denmark and Gothenburg in Sweden. All together 811 nurses and 216 paramedics answered the questions about background data and attitudes towards resuscitation, defibrillation and guidelines.
Results: Of paramedics 60% felt that deep compressions could injure the patient and 32% felt the harm caused is bigger than the benefit of compressions. When arriving to the patient 21.5% prioritize intubation and infusion over everything else. Of the nurses 16% hesitate to start CPR because of anxiety, 26% did not feel competent to defibrillate and 21% hesitate to defibrillate because they fear to harm the patient. Still 54.2% had had CPR training at their hospital during the last six months. Nurses that hesitate to start resuscitation felt significantly more often that only doctors should defibrillate. This will delaye defibrillation and lives will be lost.
Conclusion: Major changes has to be done in training programs for CPR to ensure better confidence in performing the different tasks involved in resuscitation. Today too many health care professionals feel that CPR might do more harm than good.
Abstract 352: Juvenile Doxorubicin Treatment Impairs Recovery and Promotes Apoptosis in Adult Hearts via failure of up-regulation of Mcl-1 after Myocardial Infarction
Authors: Huang Chengqun , Quinsay Melissa N , Kim Lucy , Kubli Dieter A , Gustafsson Åsa B 
Published: July 2021

The anthracycline doxorubicin (DOX) is an effective chemotherapeutic agent used to treat pediatric cancers. However, it is associated with cardiotoxicity which can manifest many years after the initial exposure. Very little is known about the mechanisms of this late-onset cardiotoxicity. To understand this problem, we have developed a model of pediatric DOX cardiotoxicity where mouse pups were injected with 4 low doses of DOX or saline at 5, 10, 15, and 20 days of age. After completion of treatment, all mice were healthy and had normal cardiac function as adults. However, when mice were subjected to myocardial infarction (MI), DOX treated mice developed severe cardiac fibrosis and had increased mortality compared to saline treated mice (67% vs. 20%), suggesting that these hearts do not tolerate stress well. Assessment of infarct size revealed that infarct size was greater in DOX-treated hearts compared to saline. Anthracyclines are known to affect the Bcl-2 family proteins which are also important regulators of cell death in the heart. We found that Mcl-1, an anti-apoptotic Bcl-2 protein, is expressed in the heart and localizes to the mitochondria. Overexpression of Mcl-1 in HL-1 myocytes reduced simulated I/R-mediated cell death (58±8% vs. 26±7%, n=3, p<0.05), suggesting that Mcl-1 promotes survival of cardiac cells in response to stress. Immunostaining analysis of Mcl-1 expression in mouse hearts revealed that Mcl-1 was significantly increased in myocytes in the border zone after acute MI. Myocytes with enhanced Mcl-1 expression were negative for apoptosis as assessed by TUNEL staining, whereas cells with reduced Mcl-1 expression were TUNEL positive. Since anthracyclines have been shown to reduce Mcl-1 expression in cancer cells, we investigated whether juvenile DOX treatment would suppress Mcl-1 expression in adult heart in response to stress. We found that cardiac myocytes in the border zone of DOX treated hearts failed to upregulate Mcl-1 in response to MI which likely impaired recovery and contributed to increased injury and mortality. These studies suggest upregulation of Mcl-1 is an important salvage response after MI and that juvenile DOX treatment affects Mcl-1 expression in adulthood resulting in a heart that is more susceptible to stress.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).
Abstract 412: Pentaerithrityltetranitrate Does Not Deteriorate Endothelial Dysfunction In Patients With Coronary Artery Disease. A Prospective, Randomized, Double-blind, Placebo-controlled, Monocentric Clinical Trial (PENTA)
Authors: Schiewe Robert , Schnorbus Boris , Ostad Mir Abolfazl , Medler Christoph , Wenzel Philip , Daiber Andreas , Münzel Thomas , Warnholtz Ascan 
Published: July 2021

Purpose: Chronic nitrate therapy remains controversial in patients with coronary artery disease (CAD) due to induction of tolerance and deterioration of endothelial dysfunction. Pentaerithri-tyltetranitrate (PETN) differs from other organic nitrates by the lack of tolerance induction and by antioxidative properties. We hypothesized that treatment with PETN improves endothelial dysfunction in patients with CAD.
Methods: In a prospective, double-blind trial, we randomly assigned 80 patients to double-blind treatment for 8 weeks with oral PETN 80mg t.i.d. (PETN) or placebo (C), respectively. The primary endpoint was the absolute change in flow-mediated dilation of the brachial artery (FMD) from baseline to follow-up. Secondary endpoints were the changes in nitroglycerin-mediated dilation (NMD), peripheral arterial tonometry (EndoPAT2000) index as a marker of endothelial function of small arteries, the augmentation index (AI) as a marker of arterial stiffness and the activity of the PETN bioactivating enzyme aldehydedehydrogenase-2 (ALDH-2) in monocytes from baseline to follow-up. Raw data entry, data monitoring and statistic analysis were independently performed by the coordination centre of clinical trials (KKS), Mainz. The trial was registered as ISRCTN 14741768.
Results: Both treatment groups were comparable regarding age, gender, distribution of cardiovascular risk factors and concomitant medication. There was no difference in the mean (±SD) change in FMD between the two treatment groups (PETN: +1.6±3.3% vs. C: +1.4±4.1% p=0.7). NMD significantly rose after treatment with PETN compared to C (PETN: +3.8±5.5% vs. C: +0.6±4.2% p=0.0036). Mean PAT-Index, AI and ALDH-2 activity remained unchanged in both treatment groups.
Conclusions: The three main findings of our trial are: In contrast to other organic nitrates PETN does not deteriorate endothelial dysfunction (1), does not impair ALDH-2 activity (2) and does not induce cross tolerance to nitroglycerin (3). We conclude that chronic PETN therapy in patients with CAD may be established for symptomatic treatment without adverse effects on endothelial function.
Abstract 1716: Calcium Channel Blockers Reduce the Antiplatelet Effect of Clopidogrel
Authors: Siller-Matula Jolanta , Lang Irene , Christ Guenter , Jilma Bernd 
Published: July 2021

Due to the known CYP3A4 inhibition by calcium channel blockers, we hypothesized that there might be a pharmacodynamic interaction between clopidogrel and dihydropyridines in patients with coronary artery disease (CAD). Clopidogrel is activated by CYP3A4 which also metabolizes calcium channel blockers of the dihydropyridine class.
Methods: Responsiveness to clopidogrel was assessed by the vasodilator stimulated phosphoprotein (VASP) phosphorylation assay and aggregometry in 200 patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). The platelet reactivity index (PRI in the VASP assay, normal range 69–100%) was higher in patients on both clopidogrel and calcium channel blockers (61%) as compared to patients on clopidogrel without calcium channel blockers (48%). The absolute difference was 13% (95%CI: 6 –20%; p = 0.001) and the relative difference approached 21%. A high post-treatment platelet reactivity (PRI > 69%) was seen in 40% of patients with concomitant calcium channel blocker treatment compared to 20% without (X2-test: p = 0.008). Intake of calcium channel blocker remained an independent predictor of high platelet reactivity after adjustment for cardiovascular risk factors. This corresponded to an increased platelet aggregation of similar magnitude (p < 0.05). In vitro incubation with calcium channel blockers (nimodipine, verapamil, amlodipine and diltiazem) did not alter the PRI or the ADP-induced platelet aggregation of patients on clopidogrel, indicating that the interaction occurs in vivo, conceivably at the level of the CYP3A4 cytochrome. Co-administration of calcium channel blockers is associated with a decreased platelet inhibition by clopidogrel.