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High Throughput Screening for Colorectal Cancer Specific Compounds.
Xie J, Wang C, Gore JC
(2016) Comb Chem High Throughput Screen 19: 180-8
MeSH Terms: Antineoplastic Agents, Apoptosis, Cardiac Glycosides, Cardiotonic Agents, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Glioma, High-Throughput Screening Assays, Humans, Hypolipidemic Agents, Structure-Activity Relationship
Show Abstract · Added February 6, 2016
The development of new anti-cancer therapeutic agents is necessary to improve antitumor efficacy and reduce toxicities. Here we report using a systematic anticancer drug screening approach we developed previously, to concurrently screen colon and glioma cancer cell lines for 2000 compounds with known bioactivity and 1920 compounds with unknown activity. The hits specific to each tumor cell line were then selected, and further tested with the same cells transfected with EGFP (Enhanced Green Fluorescent Protein) alone. By comparing the percentage of signal reduction from the same cells transfected with the sensor-conjugated reporter system; hits preferably causing apoptosis were identified. Among the known lead compounds, many cardiac glycosides used as cardiotonic drugs were found to effectively and specifically kill colon cancer cells, while statins (hypolipidemic agents) used as cholesterol lowering drugs were relatively more effective in killing glioma cells.
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14 MeSH Terms
Catecholamine-resistant hypotension and myocardial performance following patent ductus arteriosus ligation.
Noori S, McNamara P, Jain A, Lavoie PM, Wickremasinghe A, Merritt TA, Solomon T, Sekar K, Attridge JT, Swanson JR, Gillam-Krakauer M, Reese J, Poindexter BB, Brook M, Auchus RJ, Clyman RI, PDA Ligation/Hypotension Trial Investigators
(2015) J Perinatol 35: 123-7
MeSH Terms: Cardiac Surgical Procedures, Cardiotonic Agents, Catecholamines, Dobutamine, Dopamine, Drug Resistance, Ductus Arteriosus, Patent, Echocardiography, Female, Humans, Hypotension, Infant, Newborn, Infant, Premature, Ligation, Male, Postoperative Complications, Treatment Outcome
Show Abstract · Added April 9, 2015
OBJECTIVE - We performed a multicenter study of preterm infants, who were about to undergo patent ductus arteriosus ligation, to determine whether echocardiographic indices of impaired myocardial performance were associated with subsequent development of catecholamine-resistant hypotension following ligation.
STUDY DESIGN - A standardized treatment approach for hypotension was followed at each center. Infants were considered to have catecholamine-resistant hypotension if their dopamine infusion was > 15 μg kg(-1)min(-1). Echocardiograms and cortisol measurements were obtained between 6 and 14 h after the ligation (prior to the presence of catecholamine-resistant hypotension).
RESULT - Forty-five infants were enrolled, 10 received catecholamines (6 were catecholamine-responsive and 4 developed catecholamine-resistant hypotension). Catecholamine-resistant hypotension was not associated with decreased preload, shortening fraction or ventricular output. Infants with catecholamine-resistant hypotension had significantly lower levels of systemic vascular resistance and postoperative cortisol concentration.
CONCLUSION - We speculate that low cortisol levels and impaired vascular tone may have a more important role than impaired cardiac performance in post-ligation catecholamine-resistant hypotension.
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17 MeSH Terms
Does renal dysfunction and method of bridging support influence heart transplant graft survival?
Haglund NA, Feurer ID, Dwyer JP, Stulak JM, DiSalvo TG, Keebler ME, Schlendorf KH, Wigger MA, Maltais S
(2014) Ann Thorac Surg 98: 835-41
MeSH Terms: Adolescent, Adult, Aged, Cardiotonic Agents, Female, Graft Survival, Heart Failure, Heart Transplantation, Heart-Assist Devices, Humans, Male, Middle Aged, Preoperative Care, Renal Insufficiency, Retrospective Studies, Risk Factors, Severity of Illness Index, Young Adult
Show Abstract · Added October 28, 2014
BACKGROUND - Renal insufficiency is common in status 1B patients supported with inotropes or a continuous flow left ventricular device (CF-LVAD) as a bridge to heart transplantation. We evaluated the association of renal function and inotrope versus CF-LVAD support on posttransplant graft survival in status 1B patients.
METHODS - The Scientific Registry for Transplant Recipients database was analyzed for posttransplant survival in status 1B patients bridged with inotropes or CF-LVAD who underwent transplantation between 2003 and 2012. Pretransplant renal function was measured by estimating glomerular filtration rate (GFR) and was stratified as less than 45 mL · min(-1) · 1.73 m(-2), 45 to 59, and 60 or greater. Univariate Kaplan-Meier and multivariate Cox regression models were used to evaluate the main effects of GFR strata and inotropes versus CF-LVAD, and the interaction effect of GFR strata by CF-LVAD, on graft survival.
RESULTS - This study included 4,158 status 1B patients (74% male, aged 53 ± 12 years). Of those, 659 patients had a CF-LVAD (HeartMate-II [Thoratec, Pleasanton, CA], n = 638; HVAD [HeartWare, Framingham, MA], n = 21), and 3,530 were receiving inotropes (31 CF-LVAD patients were also receiving inotropes). Kaplan-Meier analyses demonstrated reduced graft survival (p = 0.022) in patients with pretransplant GFR less than 45 versus GFR 45 to 59 (p = 0.062) and versus GFR 60 or greater (p = 0.007), and no effect of inotrope versus CF-LVAD support on graft survival (p = 0.402). Multivariate analysis demonstrated that, after adjusting for the main effects of GFR stratum, CF-LVAD, and inotropes, status 1B patients bridged with a CF-LVAD and GFR in the lowest stratum had reduced graft survival (interaction effect p = 0.040).
CONCLUSIONS - Pretransplant renal insufficiency was associated with reduced posttransplant graft survival in status 1B patients. This risk is increased for patients bridged with a CF-LVAD (versus inotropes) who have GFR in the lowest stratum.
Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms
Are peripherally inserted central catheters associated with increased risk of adverse events in status 1B patients awaiting transplantation on continuous intravenous milrinone?
Haglund NA, Cox ZL, Lee JT, Song Y, Keebler ME, DiSalvo TG, Maltais S, Lenihan DJ, Wigger MA
(2014) J Card Fail 20: 630-7
MeSH Terms: Academic Medical Centers, Cardiotonic Agents, Catheter-Related Infections, Catheterization, Central Venous, Catheterization, Peripheral, Female, Heart Failure, Heart Transplantation, Heart-Assist Devices, Hemorrhage, Humans, Infusions, Intravenous, Intensive Care Units, Male, Middle Aged, Milrinone, Regression Analysis, Retrospective Studies, Tennessee, Venous Thromboembolism, Waiting Lists
Show Abstract · Added February 19, 2015
BACKGROUND - Peripherally inserted central catheters (PICCs) are used to deliver continuous intravenous (IV) milrinone in stage D heart failure (HF) patients awaiting heart transplantation (HT).
METHODS - We retrospectively analyzed PICC adverse events (AEs) and associated cost in 129 status 1B patients from 2005 to 2012. End points were HT, left ventricular assist device (LVAD), and death. Regression analysis was used to identify AE risk factors.
RESULTS - Fifty-three PICC AEs occurred in 35 patients (27%), consisting of 48 infections, 4 thromboses, and 1 bleeding event. Median duration of PICC support was 63 (interquartile range [IQR] 34-131) days, and median time to first PICC infection was 44 (IQR 14-76) days. Among PICC infections, 9% required defibrillator removal and 30% were inactivated on the HT list for a mean of 23 ± 17 days. Rate of HT, LVAD, or death was similar between groups (P > .05). Regression analysis found that a double lumen PICC was associated with a shorter time to first PICC infection (hazard ratio 7.59, 95% CI 1.97-29.23; P = .003). Median cost per PICC infection was $10,704 (IQR $7,401-$26,083).
CONCLUSIONS - PICC infections were the most frequent AEs. PICCs with >1 lumen were associated with increased risk of infection. PICC AEs accounted for increased intensive care unit admissions, HT list inactivations, and overall cost.
Copyright © 2014 Elsevier Inc. All rights reserved.
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21 MeSH Terms
HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox-dependent phospholamban oligomerization.
Sivakumaran V, Stanley BA, Tocchetti CG, Ballin JD, Caceres V, Zhou L, Keceli G, Rainer PP, Lee DI, Huke S, Ziolo MT, Kranias EG, Toscano JP, Wilson GM, O'Rourke B, Kass DA, Mahaney JE, Paolocci N
(2013) Antioxid Redox Signal 19: 1185-97
MeSH Terms: Adenosine Triphosphate, Animals, Antioxidants, Calcium, Calcium Signaling, Calcium-Binding Proteins, Cardiotonic Agents, Cyclic AMP-Dependent Protein Kinases, Disulfides, Heart Ventricles, In Vitro Techniques, Mice, Mice, Knockout, Microsomes, Myocytes, Cardiac, Nitrogen Oxides, Oxidation-Reduction, Phosphorylation, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Stability, Sarcoplasmic Reticulum, Sarcoplasmic Reticulum Calcium-Transporting ATPases
Show Abstract · Added May 27, 2014
AIMS - Nitroxyl (HNO) interacts with thiols to act as a redox-sensitive modulator of protein function. It enhances sarcoplasmic reticular Ca(2+) uptake and myofilament Ca(2+) sensitivity, improving cardiac contractility. This activity has led to clinical testing of HNO donors for heart failure. Here we tested whether HNO alters the inhibitory interaction between phospholamban (PLN) and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in a redox-dependent manner, improving Ca(2+) handling in isolated myocytes/hearts.
RESULTS - Ventriculocytes, sarcoplasmic reticulum (SR) vesicles, and whole hearts were isolated from control (wildtype [WT]) or PLN knockout (pln(-/-)) mice. Compared to WT, pln(-/-) myocytes displayed enhanced resting sarcomere shortening, peak Ca(2+) transient, and blunted β-adrenergic responsiveness. HNO stimulated shortening, relaxation, and Ca(2+) transient in WT cardiomyocytes, and evoked positive inotropy/lusitropy in intact hearts. These changes were markedly blunted in pln(-/-) cells/hearts. HNO enhanced SR Ca(2+) uptake in WT but not pln(-/-) SR-vesicles. Spectroscopic studies in insect cell microsomes expressing SERCA2a±PLN showed that HNO increased Ca(2+)-dependent SERCA2a conformational flexibility but only when PLN was present. In cardiomyocytes, HNO achieved this effect by stabilizing PLN in an oligomeric disulfide bond-dependent configuration, decreasing the amount of free inhibitory monomeric PLN available.
INNOVATION - HNO-dependent redox changes in myocyte PLN oligomerization relieve PLN inhibition of SERCA2a.
CONCLUSIONS - PLN plays a central role in HNO-induced enhancement of SERCA2a activity, leading to increased inotropy/lusitropy in intact myocytes and hearts. PLN remains physically associated with SERCA2a; however, less monomeric PLN is available resulting in decreased inhibition of the enzyme. These findings offer new avenues to improve Ca(2+) handling in failing hearts.
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25 MeSH Terms
Adenosine A2B receptors on cardiac stem cell antigen (Sca)-1-positive stromal cells play a protective role in myocardial infarction.
Ryzhov S, Zhang Q, Biaggioni I, Feoktistov I
(2013) Am J Pathol 183: 665-72
MeSH Terms: Animals, Antigens, Ly, Cardiotonic Agents, Heart Function Tests, Membrane Proteins, Mesenchymal Stem Cell Transplantation, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Infarction, Myocardium, Platelet Endothelial Cell Adhesion Molecule-1, Receptor, Adenosine A2B, Signal Transduction, Stromal Cells, Survival Analysis
Show Abstract · Added May 29, 2014
Transplantation of mesenchymal stem-like cells to the heart is known to improve cardiac recovery in animal models of myocardial infarction (MI). Because stimulation of A2B adenosine receptors on mouse cardiac stem cell antigen (Sca)-1(+)CD31(-) mesenchymal stem-like cells significantly up-regulates their secretion of pro-angiogenic factors, we hypothesized that ablation of the A2B receptor signaling in these cells would reduce their ability to improve vascularization of the infarct area seen after transplantation. Wild-type (WT) C57BL/6 mice underwent permanent left coronary artery ligation and received intramyocardial injections of Sca-1(+)CD31(-) cells generated from WT or A2B receptor knockout (A2BKO) mice or the same volume of cell-free saline. Only 12% to 16% of injected cells remained in the ventricles 1 week later; there was no significant difference between WT and A2BKO cell survival. Transplantation of WT, but not A2BKO, cells significantly reduced both post-MI decline in cardiac function and adverse remodeling compared with that seen in control hearts. Morphological analysis conducted 4 weeks after MI revealed significantly increased vascularization of the infarct areas and reduced myocardial scarring in animals treated with WT, but not with A2BKO, cells compared with control. Thus, our study demonstrated that the A2B receptor signaling linked to up-regulation of pro-angiogenic factors in cardiac Sca-1(+)CD31(-) stromal cells is essential for overall improvement of cardiac recovery seen after their transplantation to the injured heart.
Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Elevation of plasma milrinone concentrations in stage D heart failure associated with renal dysfunction.
Cox ZL, Calcutt MW, Morrison TB, Akers WS, Davis MB, Lenihan DJ
(2013) J Cardiovasc Pharmacol Ther 18: 433-8
MeSH Terms: Adult, Aged, Cardiac Catheterization, Cardiotonic Agents, Creatinine, Defibrillators, Implantable, Female, Heart Failure, Hemodynamics, Humans, Kidney Diseases, Male, Middle Aged, Milrinone, Renal Dialysis, Retrospective Studies, Severity of Illness Index, Tachycardia, Ventricular
Show Abstract · Added May 27, 2014
PURPOSE - To determine steady state milrinone concentrations in patients with stage D heart failure (HF) with and without renal dysfunction
METHODS - We retrospectively identified patients with stage D HF at a single medical center on continuous milrinonein fusion at the time of plasma collection for entry into a research registry database. Milrinone was prescribed and titrated to improve hemodynamic and clinical status by a cardiologist. Plasma samples were obtained at steady state milrinone concentrations. Patients were stratified by creatinine clearance (CrCl) into 4 groups: group 1 (CrCl >60 mL/min), group 2 (CrCl 60-30 mL/min), group 3 (CrCl <30 mL/min), and group 4 (intermittent hemodialysis). Retrospective chart review was performed to quantify the post milrinone hemodynamic changes by cardiac catheterization and electrophysiologic changes by implantable cardiac defibrillator (ICD) interrogation.
RESULTS - A total of 29 patients were identified: group 1 (n=14), group 2 (n=10), group 3(n=3), and group 4 (n = 2). The mean infusion rate (0.391+0.08 mg/kg/min) did not differ between groups (P=0.14). The mean milrinone concentration was 451+243 ng/mL in group 1, 591+293 ng/mL in group 2, 1575+962 ng/mL in group 3, and 6252+4409 ng/mL in group 4 (P<0.05 compared to groups 1). There was no difference in post milrinone hemodynamic improvements between the groups (P=0.41). The ICD interrogation revealed limited comparisons, but 6 of the 8 post milrinone ventricular tachycardia episodes requiring defibrillation occurred in group 4 patients.
CONCLUSION - Patients with stage D HF having severe renal dysfunction have elevated milrinone concentrations. Future studies of milrinone concentrations are warranted to investigate the potential risk of life-threatening arrhythmias and potential dosing regimens in renal dysfunction.
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18 MeSH Terms
Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments.
Huke S, Venkataraman R, Faggioni M, Bennuri S, Hwang HS, Baudenbacher F, Knollmann BC
(2013) Circ Res 112: 1334-44
MeSH Terms: Adenosine Triphosphate, Adenylate Kinase, Animals, Arrhythmias, Cardiac, Calcium, Cardiomyopathy, Hypertrophic, Cardiotonic Agents, Connexin 43, Disease Models, Animal, Disease Susceptibility, Electrocardiography, Energy Metabolism, Female, Gap Junctions, Heterocyclic Compounds, 4 or More Rings, Male, Mice, Mice, Inbred Strains, Mice, Transgenic, Myofibrils, Quinolines, Thiadiazines
Show Abstract · Added May 27, 2014
RATIONALE - The Ca(2+) sensitivity of the myofilaments is increased in hypertrophic cardiomyopathy and other heart diseases and may contribute to a higher risk for sudden cardiac death. Ca(2+) sensitization increases susceptibility to reentrant ventricular tachycardia in animal models, but the underlying mechanism is unknown.
OBJECTIVE - To investigate how myofilament Ca(2+) sensitization creates reentrant arrhythmia susceptibility.
METHODS AND RESULTS - Using hypertrophic cardiomyopathy mouse models (troponinT-I79N) and a Ca(2+) sensitizing drug (EMD57033), here we identify focal energy deprivation as a direct consequence of myofilament Ca(2+) sensitization. To detect ATP depletion and thus energy deprivation, we measured accumulation of dephosphorylated Connexin 43 (Cx43) isoform P0 and AMP kinase activation by Western blotting and immunostaining. No differences were detected between groups at baseline, but regional accumulation of Connexin 43 isoform P0 occurred within minutes in all Ca(2+)-sensitized hearts, in vivo after isoproterenol challenge and in isolated hearts after rapid pacing. Lucifer yellow dye spread demonstrated reduced gap junctional coupling in areas with Connexin 43 isoform P0 accumulation. Optical mapping revealed that selectively the transverse conduction velocity was slowed and anisotropy increased. Myofilament Ca(2+) desensitization with blebbistatin prevented focal energy deprivation, transverse conduction velocity slowing, and the reentrant ventricular arrhythmias.
CONCLUSIONS - Myofilament Ca(2+) sensitization rapidly leads to focal energy deprivation and reduced intercellular coupling during conditions that raise arrhythmia susceptibility. This is a novel proarrhythmic mechanism that can increase arrhythmia susceptibility in structurally normal hearts within minutes and may, therefore, contribute to sudden cardiac death in diseases with increased myofilament Ca(2+) sensitivity.
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22 MeSH Terms
Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials.
Holtkamp FA, de Zeeuw D, de Graeff PA, Laverman GD, Berl T, Remuzzi G, Packham D, Lewis JB, Parving HH, Lambers Heerspink HJ
(2011) Eur Heart J 32: 1493-9
MeSH Terms: Aged, Albuminuria, Amlodipine, Angiotensin Receptor Antagonists, Biphenyl Compounds, Blood Pressure, Calcium Channel Blockers, Cardiotonic Agents, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Diabetic Nephropathies, Female, Heart Failure, Humans, Hypertension, Irbesartan, Losartan, Male, Middle Aged, Myocardial Infarction, Randomized Controlled Trials as Topic, Retrospective Studies, Risk Factors, Stroke, Tetrazoles, Treatment Outcome
Show Abstract · Added December 10, 2013
AIMS - The long-term cardioprotective effect of angiotensin receptor blockers (ARBs) is associated with the short-term lowering of its primary target blood pressure, but also with the lowering of albuminuria. Since the individual blood pressure and albuminuria response to an ARB varies between and within an individual, we tested whether the variability and discordance in systolic blood pressure (SBP) and albuminuria response to ARB therapy are associated with its long-term effect on cardiovascular outcomes.
METHODS AND RESULTS - The combined data of the RENAAL and IDNT trials were used. We first investigated the extent of variability and discordance in SBP and albuminuria response (baseline to 6 months). Subsequently, we assessed the combined impact of residual Month 6 SBP and albuminuria level with cardiovascular outcome. In ARB-treated patients, 421 patients (34.5%) either had a reduction in SBP but no reduction in albuminuria, or vice versa, indicating substantial discordance in response in these parameters. The initial reduction in SBP and albuminuria independently correlated with cardiovascular protection: HR per 5 mmHg SBP reduction 0.97 (95% CI 0.94-0.99) and HR per decrement log albuminuria 0.87 (95% CI 0.76-0.99). Across all SBP categories at Month 6, a progressively lower cardiovascular risk was observed with a lower albuminuria level. This was particularly evident in patients who reached the guideline recommended SBP target of ≤130 mmHg.
CONCLUSION - The SBP and albuminuria response to ARB therapy is variable and discordant. Therapies intervening in the renin-angiotensin-aldosterone system with the aim of improving cardiovascular outcomes may therefore require a dual approach targeting both blood pressure and albuminuria.
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26 MeSH Terms
Mechanisms of anthracycline cardiotoxicity and strategies to decrease cardiac damage.
Geisberg CA, Sawyer DB
(2010) Curr Hypertens Rep 12: 404-10
MeSH Terms: Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, Animals, Anthracyclines, Antibiotics, Antineoplastic, Antineoplastic Protocols, Cardiotonic Agents, Cardiotoxins, Cell Death, Heart Diseases, Humans, Models, Animal, Neoplasms, Oxidative Stress, Risk Factors, Sarcomeres, Time
Show Abstract · Added March 5, 2014
Anthracyclines are common chemotherapeutic agents used to treat many different types of cancer. Unfortunately, the use of anthracyclines is limited by their cardiotoxic effects, which may become manifest as late as 20 years from initial exposure. Studies in cells and animals suggest that the mechanism of anthracycline-induced cardiotoxicity (AIC) is multifactorial. Anthracyclines induce multiple forms of cellular injury by free radical production. In addition, anthracyclines alter nucleic acid biology by intercalation into DNA and modulate intracellular signaling, leading to cell death and the disruption of homeostatic processes such as sarcomere maintenance. In an effort to decrease AIC, many strategies have been tested, but no specific therapies are universally acknowledged to prevent or treat anthracycline-induced cardiac dysfunction. Newer imaging modalities and cardiac biomarkers may be useful in improving early detection of cardiac injury and dysfunction. As long as there is no cardiac-specific therapy for AIC, evidence suggests that high-risk patients will benefit from prophylactic treatment with neurohormonal blockade by angiotensin-converting enzyme inhibitors and beta-adrenergic receptor blockers.
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17 MeSH Terms