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Aim To evaluate the ability of the DrugSorb™-AntiThrombotic Removal (ATR) haemoadsorption device utilizing porous polymer bead sorbent technology to remove three commonly used antithrombotic drugs from whole blood. Methods and results We... more
Aim To evaluate the ability of the DrugSorb™-AntiThrombotic Removal (ATR) haemoadsorption device utilizing porous polymer bead sorbent technology to remove three commonly used antithrombotic drugs from whole blood. Methods and results We evaluated the removal of apixaban, rivaroxaban, and ticagrelor by the DrugSorb-ATR haemoadsorption device in a benchtop clinical scale model using bovine whole blood. Blood spiked at clinically relevant concentrations of an antithrombotic agent was continuously circulated through a 300-mL DrugSorb-ATR haemoadsorption device at a flow rate of 300 mL/min. Drug concentration was monitored over 6 h to evaluate drug removal. Results were compared with a control circuit without the haemoadsorption device. Removal rates at 30, 60, 120, and 360 minutes were: apixaban: 81.5%, 96.3%, 99.3% >99.8%; rivaroxaban: 80.7%, 95.1%, 98.9%, >99.5%; ticagrelor: 62.5%; 75%, 86.6%, >95% (all P <0.0001 vs. control). Blood pH and haematological parameters were n...
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Aim: The guideline for coronary artery revascularization replaces the 2011 coronary artery bypass graft surgery and the 2011 and 2015 percutaneous coronary intervention guidelines, providing a patient-centric approach to guide clinicians... more
Aim: The guideline for coronary artery revascularization replaces the 2011 coronary artery bypass graft surgery and the 2011 and 2015 percutaneous coronary intervention guidelines, providing a patient-centric approach to guide clinicians in the treatment of patients with significant coronary artery disease undergoing coronary revascularization as well as the supporting documentation to encourage their use. Methods: A comprehensive literature search was conducted from May 2019 to September 2019, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, CINHL Complete, and other relevant databases. Additional relevant studies, published through May 2021, were also considered. Structure: Coronary artery disease remains a leading cause of morbidity and mortality globally. Coronary revascularization is an important therapeutic option when managing patients with coronary artery disease. The...
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Syndecan-4 is one of the principal heparan sulfate-carrying proteins on the cell surface. Unlike other members of syndecan family, syndecan-4 mediates phosphatidylinositol 4,5-bisphosphate 2 (PIP(2))-dependent PKC-alpha activation, and... more
Syndecan-4 is one of the principal heparan sulfate-carrying proteins on the cell surface. Unlike other members of syndecan family, syndecan-4 mediates phosphatidylinositol 4,5-bisphosphate 2 (PIP(2))-dependent PKC-alpha activation, and overexpression of syndecan-4 in vitro results in enhanced FGF2 signaling. The present study was designed to test the functional effect of increased syndecan-4 expression in endothelial cells in transgenic mice. Several transgenic mice lines expressing syndecan-4 cDNA under control of human endothelial nitric oxide (NO) synthase (eNOS) promoter were generated. Exogenous syndecan-4 was mainly expressed in the heart, brain, and lungs. In particular, the heart demonstrated the greatest increase in the ratio of transgenic-to-native syndecan-4 gene expression. Vessels from the eNOS-syndecan-4 mice demonstrated more pronounced vasodilation to FGF2 but not to VEGF-A(165), sodium nitroprusside, and A 23187 compared with wild-type mice. To elucidate the mechani...
Research Interests: Physiology, Biology, Microcirculation, Medicine, Transgenic Mice, and 15 moreSignal Transduction, Humans, Mice, Nitric oxide, Animals, Vascular endothelium, Medical Physiology, Fibroblast Growth Factor, Proteoglycans, Nitric Oxide Synthase, Coronary Circulation, Gene Expression Regulation, ENOS, Vascular endothelial growth factors, and Nitric oxide synthase type II
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Hypothermia-induced changes in endothelial cell (EC) morphology and function after organ storage may influence the initial outcome and development of transplant-associated coronary artery disease. Human saphenous vein ECs were incubated... more
Hypothermia-induced changes in endothelial cell (EC) morphology and function after organ storage may influence the initial outcome and development of transplant-associated coronary artery disease. Human saphenous vein ECs were incubated with saline (NaCl), University of Wisconsin (UW), and histidine-tryptophan-ketoglutarate (HTK) solution, with and without protein additives, at 4 degrees C and 37 degrees C. After 6 hours, ECs were recultivated for 24 and 48 hours with culture medium (reperfusion). Mitochondrial activity, adenosine triphosphate concentration, cell count, and inflammatory responses were analyzed. Cold preservation did not affect the mitochondrial activity of ECs and allowed a complete regeneration of the metabolic turnover after reperfusion. However, under normothermic conditions the metabolism of the cells was influenced by time and type of preservation solution. While both the mitochondrial activity and cell count did not change after treatment with NaCl and culture medium, the metabolic turnover of cells treated with HTK and UW solution significantly increased (twofold) and decreased (twofold, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), respectively, after reperfusion. The endothelial reactivity remained unchanged after treatment with NaCl and HTK. The addition of serum proteins significantly improved mitochondrial activity of cells treated with warm NaCl and HTK (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). The UW-treated cells burned out through a significant up-regulation of the ATP concentration resulting in a complete metabolic regression after reperfusion and induction of apoptosis. Normothermic preservation in UW prevented regeneration of ECs, while treatment with HKT solution did not irreversibly affect mitochondrial activity of ECs and allowed complete regeneration of metabolism and function. Serum proteins improved the preservation effect of HTK and NaCl.
Research Interests: Cardiology, Andrology, Cell Adhesion, Cryopreservation, Apoptosis, and 15 moreEnergy Metabolism, Adenosine, Glucose, Endothelial Cells, Glutathione, Anesthesia, Clinical Sciences, Endothelial cell, DDC, Cell Survival, Allopurinol, Blood Proteins, Adenosine Triphosphate, Cell count, and Cardiovascular medicine and haematology
Research Interests: Microcirculation, Oxidative Stress, Apoptosis, Medicine, Blood Pressure, and 15 moreAnimals, Heart rate, Clinical Sciences, Coronary Angiography, Myocardium, Coronary Circulation, Myocardial Perfusion Imaging, Naproxen, Celecoxib, Coronary artery, Myocardial Ischemia, Cardiovascular medicine and haematology, Inflammation Mediators, collateral circulation, and Cyclooxygenase
Background Diabetes mellitus (DM) is an independent risk factor for complications following cardiac surgery. We examined peripheral gene expression and clinical responses to cardiopulmonary bypass (CPB) in patients with and without DM.... more
Background Diabetes mellitus (DM) is an independent risk factor for complications following cardiac surgery. We examined peripheral gene expression and clinical responses to cardiopulmonary bypass (CPB) in patients with and without DM. Methods Skeletal muscle was harvested from non-DM (n = 5) and insulin-treated DM (n = 5) patients before and after CPB. Oligonucleotide microarrays of 12,625 genes were performed on matched samples. Postoperative weight gain, systemic vascular resistance (SVR), temperature, and vasopressor requirements were determined. Nonparametric correlation analyses were used to examine clinical and gene expression relationships. Results Mean CPB duration was 77.5 ± 4.0 minutes. Compared to pre-CPB, peripheral tissue post-CPB revealed 626 up-regulated and 348 down-regulated genes in non-DM vs 420 up-regulated and 473 down-regulated genes in DM patients (p < .001). Mean percent weight gain was 4.5 ± 1.4%. Expression of TR3, a nuclear receptor that mediates vascular endothelial cell function, was shown to negatively correlate with percent weight gain. When compared to non-DM, patients with DM had greater weight gain (1.8% ± 0.56 vs 7.3 ± 2.0%, non-DM vs DM, p = .03), which correlated with lower levels of TR3 expression (post/pre-CPB ratio 7.6 ± 3.3 vs 1.7 ± 0.3, non-DM vs DM; Spearman's rank correlation r = -.68, p = .03). SVR, temperature, and vasopressor requirements were not significantly different in non-DM and DM. Conclusions The gene expression profile following CPB is quantitatively and qualitatively different in diabetic patients. Clinical correlation suggests that differential TR3 expression is associated with postoperative weight gain, likely due to vascular endothelial dysfunction and tissue edema. These results have possible implications for the design of tailored operative strategies for diabetic patients undergoing CPB.
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Research Interests: Endocrinology, Immunohistochemistry, Oxidative Stress, Medicine, Comorbidity, and 15 moreHumans, Internal Medicine, Hemodynamics, Animals, Hypercholesterolemia, Heart, Clinical Sciences, HDL, Celecoxib, Myocardial Ischemia, epoprostenol, Left Ventricular, Cx, Cardiovascular medicine and haematology, and Cyclooxygenase
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Research Interests: Medicine, Adhesion, Wine, Collagen, Animals, and 15 moreMale, Ethanol, Hypercholesterolemia, Fibrosis, Clinical Sciences, Time Factors, Swine, Alcoholic Beverages, Pericardium, Thoracic and cardiovascular surgery, Heart Diseases, Reoperation, Myocardial Ischemia, Cardiovascular medicine and haematology, and Inflammation Mediators
Aprotinin is a naturally occurring serine protease inhibitor that is being used with increasing frequency in cardiac surgery and beyond to reduce blood loss and the need for perioperative blood transfusion. Through inhibition of serine... more
Aprotinin is a naturally occurring serine protease inhibitor that is being used with increasing frequency in cardiac surgery and beyond to reduce blood loss and the need for perioperative blood transfusion. Through inhibition of serine proteases such as plasmin, aprotinin significantly reduces fibrinolysis, thereby aiding hemostasis during surgical procedures. In addition, aprotinin interacts with other factors in the coagulation and fibrinolytic cascade, creating a hemostatic balance, without increasing the risk of thrombosis. These proven benefits are supplemented by the anti-inflammatory properties of aprotinin, which may help curb some of the deleterious effects of cardiopulmonary bypass. This article will review the discovery of aprotinin, its mechanism of action, dosing and adverse effects, and highlight the major recent trials demonstrating its efficacy.
Research Interests: Medicine, Cardiac Surgery, Therapeutic drug monitoring, Humans, Animals, and 11 moreExpert, Public health systems and services research, Hemostasis, Drug Costs, Fibrinolysis, Aprotinin, Cardiopulmonary bypass, Clinical Trials as Topic, Perioperative, plasmin, and Cardiovascular medicine and haematology
Research Interests: Endocrinology, Inflammation, Diet, Cardiovascular disease, Glucose Metabolism, and 15 moreDiabetes mellitus, Cholesterol, Animals, Heart, Dietary Supplements, C reactive protein, Endothelial Function, Glucose Transport, Body Mass, Biological markers, Coronary Artery Disease, Glucose Tolerance Test, Gene Expression Regulation, Coronary artery, and Glucose tolerance
Research Interests: Endocrinology, Medicine, Energy Metabolism, Signal Transduction, Internal Medicine, and 15 moreMetformin, Insulin, Animals, Male, Phosphorylation, Clinical Sciences, Myocardium, Swine, Oral Hypoglycemic Agents, Coronary Circulation, Insulin Receptor, Myocardial Ischemia, Metabolic Syndrome X, Phosphatidylinositol 3-KINASE, and Cardiovascular medicine and haematology
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Introduction Neurocognitive decline (NCD) is a common complication in cardiac surgical patients. Its pathophysiology remains unknown; leading to significant morbidity particularly in the elderly. We studied the inflammatory response and... more
Introduction Neurocognitive decline (NCD) is a common complication in cardiac surgical patients. Its pathophysiology remains unknown; leading to significant morbidity particularly in the elderly. We studied the inflammatory response and CRP in relation to NCD following cardiopulmonary bypass and correlated this to a marker of axonal central nervous system (CNS) injury. Methods Prospective cohort of 43 low-risk patients undergoing CABG and/or valve procedures using cardiopulmonary bypass were administered a neurocognitive battery preoperatively, postoperatively at day 4 and at 3 months. Battery consisted of eight validated assessments covering memory, executive function, naming, attention, fluency, and premorbid intelligence. Following published STS Consensus Statement, NCD was defined as one standard deviation from baseline on ≥ 25% of tasks. CRP, interleukin-1β (IL-1β), IL-6, and IL-10 were quantified from serum with high sensitivity immunoassay and fold-change(FC) calculated between preoperative/postoperative samples at 6 hrs. Increase of serum tau protein after surgery (dichotomous) was used as a marker of axonal CNS damage. Results Cohort had an NCD rate of 45% (mean age 72 ± 3.6 years). Baseline characteristics and known predictors of NCD such as age, education level, and perioperative temperature were not significantly different between patients with/without NCD. Patients with NCD had a significantly higher increase of CRP, IL-1β and IL-10 compared to those without NCD, as described in the Table below. Serum tau protein increase was significantly correlated to NCD. Conclusions Increased CRP and inflammatory response perioperatively is associated with NCD in patients following cardiopulmonary bypass. Inflammation plays a key role in NCD pathophysiology, likely via axonal CNS injury, and could become a target for prevention. Table Neurocognitive Decline in Relation to Inflammatory Markers and Axonal CNS Injury
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Despite tremendous success of growth factor therapy in animal models, clinical trials have demonstrated minimal success. Vascular endothelial growth factors are perhaps the most potent inducers of angiogenesis in these animal models. This... more
Despite tremendous success of growth factor therapy in animal models, clinical trials have demonstrated minimal success. Vascular endothelial growth factors are perhaps the most potent inducers of angiogenesis in these animal models. This review outlines the biology of vascular endothelial growth factors in the context of myocardial angiogenesis with an emphasis on its effects on the endothelium. It also provides an overview of delivery strategies and summarises the preclinical and clinical evidence relating to exogenous growth factor delivery for myocardial angiogenesis with an emphasis on the key future challenges.
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Background: In animal models, human bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EV) have beneficial effects in cardiovascular disease (CVD) only when administered via intramyocardial injection. The... more
Background: In animal models, human bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EV) have beneficial effects in cardiovascular disease (CVD) only when administered via intramyocardial injection. The biodistribution of either intravenous (IV) or intramyocardial injection of MSC-EV in the presence of myocardial injury is unknown. Methods: MSC-EV were isolated and labeled with DiD lipid dye. FVB mice underwent left coronary artery ligation followed by either peri-infarct intramyocardial or IV injection of 3*106 or 2*109 particles of DiD-labeled MSC-EV or a DiD-saline control. The heart, lungs, liver, spleen and kidneys were harvested 2 hours post-injection and were submitted for fluorescent molecular tomography imaging. Results: Myocardial uptake of MSC-EV was only visualized after intramyocardial injection of 2*109 MSC-EV particles (p = 0.01), and was not detected after IV injection of MSC-EV (p > 0.9), compared to controls. There was no significantly detec...
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Extensive evidence indicates that small-conductance Ca2+-activated K+ channels (SK channels) help regulate cardiac rhythm and myocardial function in physiological and pathophysiological conditions. This chapter will begin by discussing... more
Extensive evidence indicates that small-conductance Ca2+-activated K+ channels (SK channels) help regulate cardiac rhythm and myocardial function in physiological and pathophysiological conditions. This chapter will begin by discussing the basic physiology of SK channel expression, localization, and activation under normal conditions, before proceeding to address the impact of SK channel dysfunction on a variety of cardiac pathologies including atrial fibrillation (AF), ventricular arrhythmias (VA), cardiac hypertrophy/heart failure (HF) and myocardial ischemia/reperfusion (IR) injury. The critical role of aberrant SK channel regulation will also be discussed to establish unifying mechanisms of SK channel pathology across these different conditions. Several animal model and human tissue experiments suggest that pharmacologic modulation of SK channel function may be beneficial in controlling AF, VA, cardiomyopathy and myocardial IR injury. Therefore, targeting SK channels may represe...
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Swine disease models are essential for mimicry of human metabolic and vascular pathophysiology, thereby enabling high-fidelity translation to human medicine. The worldwide epidemic of obesity, metabolic disease, and diabetes has prompted... more
Swine disease models are essential for mimicry of human metabolic and vascular pathophysiology, thereby enabling high-fidelity translation to human medicine. The worldwide epidemic of obesity, metabolic disease, and diabetes has prompted the focus on these diseases in this review. We highlight the remarkable similarity between Ossabaw miniature swine and humans with metabolic syndrome and atherosclerosis. Although the evidence is strongest for swine models of coronary artery disease, findings are generally applicable to any vascular bed. We discuss the major strengths and weaknesses of swine models. The development of vascular imaging is an example of optimal vascular engineering in swine. Although challenges regarding infrastructure and training of engineers in the use of swine models exist, opportunities are ripe for gene editing, studies of molecular mechanisms, and use of swine in coronary artery imaging and testing of devices that can move quickly to human clinical studies.
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ABSTRACT
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Introduction Neurocognitive decline (NCD) is a common complication in cardiac surgical patients. Its pathophysiology remains unknown, leading to significant morbidity particularly in the elderly. We studied the inflammatory response and... more
Introduction Neurocognitive decline (NCD) is a common complication in cardiac surgical patients. Its pathophysiology remains unknown, leading to significant morbidity particularly in the elderly. We studied the inflammatory response and CRP in relation to NCD following cardiopulmonary bypass and correlated this to a marker of axonal central nervous system (CNS) injury. Methods Prospective cohort of 43 low-risk patients undergoing CABG and/or valve procedures using cardiopulmonary bypass were administered a neurocognitive battery preoperatively, postoperatively at day 4, and at 3 months. Battery consisted of eight validated assessments covering memory, executive function, naming, attention, fluency, and premorbid intelligence. Following published STS Consensus Statement, NCD was defined as 1 SD from baseline on $ 25% of tasks. CRP, interleukin (IL)-1b, IL-6, and IL-10 were quantified from serum with high sensitivity immunoassay and fold change (FC) calculated between preoperative/postoperative samples at 6 hours. Increase of serum tau protein after surgery (dichotomous) was used as marker of axonal CNS damage. Results Cohort had an NCD rate of 45% (mean age 72 ± 3.6 years). Baseline characteristics and known predictors of NCD such as age, education level, and perioperative temperature were not significantly different between patients with/without NCD. Patients with NCD had significantly higher increase of CRP, IL-1b, and IL-10 compared to those without NCD as described in the table 9 below. Serum tau protein increase was significantly correlated to NCD. Conclusions Increased CRP and inflammatory response perioperatively is associated with NCD in patients following cardiopulmonary bypass. Inflammation plays a key role in NCD pathophysiology, likely via axonal CNS injury, and could become a target for prevention.
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Objective Cold blood cardioplegia (CBC) has been advocated as an advancement in myocardial protection during cardiopulmonary bypass (CPB) and cardioplegic arrest (CA) leading to decreased postoperative morbidity. Bcl-2, Bad, and caspase 3... more
Objective Cold blood cardioplegia (CBC) has been advocated as an advancement in myocardial protection during cardiopulmonary bypass (CPB) and cardioplegic arrest (CA) leading to decreased postoperative morbidity. Bcl-2, Bad, and caspase 3 are intermediates within the apoptosis cascade, which is activated following ischemia-reperfusion (IR)-induced myocardial injury. We studied the expression and modification of these apoptosis intermediates due to cardioplegia and CPB in humans within cardiac and skeletal muscle. Methods Right atrial and skeletal muscle was harvested from cardiac surgical patients (N = 6) before and after CPB, CBC, and mild hypothermia. Total and modified (cleaved/phosphorylated) caspase 3, Bcl-2, and Bad were measured by quantitative immunoblotting using specific antibodies. Microarray gene expression analysis was carried out using Affymetrix U95 GeneChip following RNA isolation. Activity of terminal caspase 3 was assessed by fluorometric assay. TUNEL assay was performed on atrial sections to identify cells undergoing apoptosis. Two-tailed paired t-test was used for statistical analysis. Results In response to CPB, skeletal muscle samples did not show changes in total or modified apoptosis protein levels in response to CPB. In myocardial tissue, CBC significantly increased phosphorylation or cleavage of Bcl-2, Bad, or caspase 3, while there was no significant change in total protein levels. Bcl-2 (Ser70) and Bad (Ser112) phosphorylation were increased by 2.35 ± 0.40 fold and 1.64 ± 0.25 fold, respectively (p < .05), while caspase 3 activity was increased 1.50 ± 0.14 fold (p < .05) after cardioplegic IR. The number of apoptotic cells in atrial tissue using TUNEL staining was increased following CBC/CA. Microarray analysis did not reveal any significant differential gene expression for the genes studied. Conclusion Cold blood cardioplegic arrest triggers the modification/activation balance of both proapoptotic (caspase 3) and antiapoptotic (phospho-Bad and phospho-Bcl-2) proteins. This change is specific to myocardium as apoptosis cascade is not significantly altered following CPB in peripheral skeletal muscle. Moreover, protein activation rather than total protein levels may be the primary indicator of apoptosis induction in myocardium.