bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Randomized Multicenter Trial Comparing the Efficacy of Simvastatin and Fluvastatin
Authors: Illingworth D.R. , Stein E.A. , Knopp R.H. , Hunninghake D.B. , Davidson M.H. , Dujovne C.A. , Miller V.T. , Tobert J.A. , Laskarzewski P.M. , Isaacsohn J.L. , Bacon S.P. , Tate A.C. 
Published: November 2007

Background: Inhibitors of hydroxymethylglutaryl co-enzyme A reductase are widely used for the treatment of hypercholesterolemia. Physicians and third-party payers need an accurate measure of their relative potency and hypolipidemic efficacy. We have therefore compared simvastatin against fluvastatin, the newest member of this class. Methods and Results: One hundred fifty-eight hypercholesterolemic patients in seven United States lipid clinics participated in this balanced double-blind incomplete block study. After a placebo-diet run-in period, patients received treatment with active drug for three con secutive 5-week periods, with measurement of lipids in a NHLBI-CDC standardized central laboratory at the end of each period. Each patient was randomly assigned to three of the fol lowing five treatments: simvastatin 5 mg, 10 mg, and 20 mg and fluvastatin 20 mg and 40 mg. The mean percent reductions in low density lipoprotein cholesterol from baaeline were 21, 27, 32, 16, and 23 respectively. The simvastatin/fluvastatin milligram potency ratio was 6.8 (95% CI, 5.3-9.3). At the same 20 mg dosage, simvastatin produced an effect on LDL cholesterol approximately double that of fluvastatin and resulted in 46% of patients achieving their National Cholesterol Education Program low density lipoprotein cholesterol target levels, compared to 12% for fluvastatin. Conclusions. Fluvastatin at its maximal dose of 40 mg daily is approximately equivalent to simvastatin 5 mg daily. Higher doses of simvastatin are considerably more effective in the treatment of primary hypercholesterolemia.
Differences in the Effects of d- and dl-Sotalol on Isolated Human Ventricular Muscle: Electromechanical Activity After Beta-Adrenoceptor Stimulation
Authors: Lathrop David A. , Varró András , Nánási Péter P. , Bódi Ilona , Takyi Eric , Pankucsi Csaba 
Published: November 2007

Background: The racemate of sotalol ( dl-sotalol) and its dextrorotatory isomer ( d-sotalol) are equally effective in increasing isolated cardiac action potential durations. dl-Sotalol, however, is reported to be more effective than d-sotalol in increasing ventricular effective refractoriness following coronary artery occlusion. These differences are attributed to the beta-adrenergic blocking properties of dl-sotalol. We wished to determine if in isolated human ventricular muscle preparations the effects of 30 μM d- and dl-sotalol could be modified by preexposure to 1 μM isoproterenol. Methods and Results: Microelectrodes were used to record action potential duration (APD) in the presence and absence of isoproterenol during continuous pacing. Preparations were obtained from explanted hearts of transplant recipients suffering idiopathic cardiomyopathies. Without isoproterenol, APD measured at 90% of repolarization (APD90) was signiticantly increased by both d- and dl-sotalol (352.0 ± 17.7 to 418.0 ± 23.8 ms, P < .05; and 339.2 ± 17.0 to 405.0 ± 25.3 ms, P < .05; respectively). Isoproterenol alone, prior to sotalol exposure, tended to shorten APD90 in the two groups first exposed to this beta-aclenoceptor agonist and subsequently exposed to either d-sotalol or dl-sotalol (317.5 ± 16.5 to 286.2 ± 28.8 ms and 288.0 ± 16.2 to 254.0 ± 15.0 ms, respectively). dl-Sotalol signiticantly increased APD90 from its baseline value after isoproterenol (288.0 ± 16.2 to 359.0 ± 25.1 ms, P < .005) while d-sotalol did not (317.5 ± 16.5 to 316.2 ± 28.5 ms, NS). Conclusions: The beta-adrenergic blocking properties of dl-sotalol may be important in determining antiarrhythmic efficacy when tonic sympathetic nervous activity is high.
Amiodarone Therapy After Previous Sotalol-induced Torsade de Pointes: Analysis of QT Dispersion to Predict Proarrhythmia
Authors: van de Loo Andreas , Klingenheben Thomas , Hohnloser Stefan H. 
Published: November 2007

Background: Polymorphic ventricular tachycardia of the torsade de pointes type represents, potentially, the most dangerous side effect of antiarrhythmic drugs that prolong ventricular repolarization. Much effort has been devoted to the identification of the degree of drug-asso ciated QT prolongation that might predict the occurrence of torsade de pointes. However, there is still no general agreement as to which level of QT prolongation might be the harbinger of torsade and which may simply represent the manifestation of the class III antiarrhythmic effect of a given compound. Methods and Results: A 70-year-old woman who had survived an episode of cardiac arrest outside of a hospital was treated with dl-sotalol (320 mg/d). After 8 days of therapy, she devel oped two episodes of hemodynamically unstable torsade de pointes. Sotalol was withdrawn and after extensive diagnostic work, therapy with amiodarone was instituted. Despite the fact that the degree of QT prolongation observed during amiodarone therapy was comparable to that observed during sotalol exposure, the patient tolerated amiodarone and is now free of recurrent ventricular tachyarrhythmias over a follow-up period of I year. Analysis of QT dis persion in the surface electrocardiograph revealed a marked increase during sotalol therapy but not during amiodarone administration (77 vs 47 ms). During drug-free control, QT dis persion was 43 ms. Conclusions: These findings emphasize the potential usefulness of determination of QT dis persion from the surface ECG to assess disparity in ventricular recovery, which is known to favor the occurrence of torsade de pointes. These observations need to be corroborated in large prospective trials. Finally, this case report further emphasizes the low arrhythmogenic potential of amiodarone—an unexplained paradox, the understanding of which might provide insights for the development of newer antifibrillatory compounds.
Cerivastatin, a New Potent Synthetic HMG Co-A Reductase Inhibitor: Effect of 0.2 mg Daily in Subjects With Primary Hypercholesterolemia
Authors: Stein E. , Sprecher D. , Allenby K.S. , Tosiello R.L. , Whalen E. , Ripa S.R. 
Published: November 2007

Background: Reduction of serum cholesterol, most notably low-density lipoprotein choles terol is associated with reductions in cardiovascular morbidity and mortality. Statins have been shown to effectively reduce low-density lipoprotein cholesterol via inhibition of the hydroxymethyl-coenzyme A (HMG-CoA) reductase. Cerivastatin is the most potent HMG- CoA reductase inhibitor currently under study in the United States. Methods and Results: A parallel group, randomized, placebo-controlled, double-blind, mul ticenter study was conducted to compare the efficacy and safety of three different dosing reg imens of 0.2 mg/day of cerivastatin, a new HMG-CoA reductase inhibitor, in patients with hypercholesterolemia. After a 10-week diet-placebo lead-in period, 319 patients with low- density lipoprotein cholesterol >160 mg/dL were randomized to 4 weeks of treatment with one of the following regimens: cerivastatin 0.1 mg twice daily, cerivastatin 0.2 mg once daily with the evening meal, cerivastatin 0.2 mg once daily at bedtime or placebo. All three active treatment groups produced statistically significant ( P < .05) changes compared to baseline and placebo in total cholesterol (0.1 mg twice daily -18.9%; 0.2 mg once daily with the evening meal: -21.9%; 0.2 mg once daily at bedtime: -22.1%; placebo: 0.0%), low-density lipoprotein cholesterol (0.1 mg twice daily: -25.7%; 0.2 mg once daily with the evening meal: -29.4%; 0.2 mg once daily at bedtime: -30.4%; placebo: 1.4%) and high-density lipoprotein cholesterol (0.1 mg twice daily: 5.3%; 0.2 mg once daily with the evening meal: 2.3%; 0.2 mg once daily at bedtime: 3.2%; placebo: -1.2%). Triglycerides, compared to baseline and placebo, were also reduced by all active treatments (0.1 mg twice daily: -11.6% [ P = .05]; 0.2 mg once daily with the evening meal: -11.6% [ P = .05]; and 0.2 mg at bed time: -10.9% [ P = .07]). The percentage change in total cholesterol and low-density lipopro tein cholesterol after 4 weeks of therapy for the once-daily cerivastatin groups was statisti cally significantly greater ( P < .05) than the cerivastatin twice daily regimen. A treatment response was seen by 1 week of therapy and was maximal by 3 weeks. The drug was well tolerated in all three dosing regimens and resulted in no significant increase in biochemical or clinical side effects compared to placebo. Conclusion: Cerivastatin is a novel, highly potent, well-tolerated HMG-CoA reductase inhibitor that produces low-density lipoprotein cholesterol reductions of approximately 30% when administered at 0.2 mg once a day in the evenings.
d-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Epicardial or Endocardial Cells of the Canine Ventricle
Authors: Sicouri Serge , Moro Sandra , Elizari Marcelo V. 
Published: November 2007

Background: Despite its class III antiarrhythmic actions, experimental and clinical studies have shown that d-sotalol can also be proarrhythmic; a recent clinical trial that evaluated d- sotalol in postmyocardial patients (SWORD) had to be prematurely interrupted because of the excess mortality in the treated group. Previous studies have demonstrated the existence of a marked heterogeneity across the ventricular wall; epicardial, endocardial, and M cells have been shown to display distinct electrophysiologic characteristics and pharmacologic behav ior. The present study was designed to test the hypothesis that M cells are the primary target for the class III actions of d-sotalol in canine ventricular myocardium and may contribute to its proarrhythmic effects. Methods and Results: We used standard microelectrode techniques to record transmem brane activity from endocardial, epicardial, midmyocardial, and transmural strips isolated from the canine left ventricle. d-Sotalol (100 μM, 60 minutes of exposure, [K+]o = 4 mM) prolongs the action potential in the three cell types, but more so in M than epicardial or endo cardial cells, especially at the slower rates. At a basic cycle length of 2000 ms, action poten tial duration after 90% repolarization increases from 199 ± 20 to 247.5 ± 28 ms in epi cardium (n = 10), from 212 ± 26 to 274 ± 27 ms in endocardium (n = 11), and from 309 ± 65 to 533 ± 207 ms in M cells (n = 13). d-Sotalol produces a marked steepening of action potential duration-rate relationships of M cells and an upward shift of restitution of action potential duration curves, more accentuated in M cells. Early afterdepolarizations were observed at slow rates (basic cycle lengths > 1000 ms) in 7 of 13 M cell preparations (54%) but not in endocardial or epicardial preparations. A sudden acceleration of the rate could also induce a transient prolongation of the action potential and early afterdepolarization activity. Conclusion: In canine ventricular tissues, d-sotalol manifests its class III effects preferen tially in the M cells, leading to the development of early afterdepolarizations and a marked increase in transmural dispersion of repolarization. The data suggest an important role of M cells in the proarrhythmic effects of the drug.
Estradiol, Administered Acutely, Protects Ischemic Myocardium in Both Female and Male Rabbits
Authors: Hale Sharon L. , Birnbaum Yochai , Kloner Robert A. 
Published: November 2007

Background: The benefits of chronic administration of estrogen to postmenopausal women are well documented; however, the acute effects of exogenous estradiol on myocardium after coronary artery occlusion and reperfusion in male and female animal models are unknown. We tested the influence of acute pretreatment with estradiol on the development of myocar dial necrosis in two protocols, studying intact anesthetized female and male rabbits. Methods and Results: 17β-estradiol (1 mg) was given 15 minutes before coronary artery occlusion in the treated groups (n = 10 females, 10 males); control rabbits (n = 11 females, 10 males) received water. All rabbits underwent 30 minutes of coronary artery occlusion and 4 hours of reperfusion. Myocardial blood flow was similar between groups at 10 minutes after treatment and during coronary artery occlusion and reperfusion. Thus estradiol did not increase blood flow. Heart rate and systemic pressure were also similar between groups. Estradiol levels during coronary artery occlusion were 1-8 pg/mL in untreated female and male rabbits and 66 ± 28 (male) and 352 ± 273 (female) in treated rabbits. Although the size of the ischemic risk zones was similar in both groups in both protocols, estradiol-treated rab bits of both sexes developed significantly less necrosis. Infarct size as a percent of the risk region was 10 ± 1% in female estradiol-treated rabbits compared with 23 ± 5% in controls ( P < .03) and 16 ± 4% in estradiol-treated male rabbits compared with 31 ± 5% in control males (P = .03). Although male rabbits had larger infarcts than female rabbits, sex was not a significant covariate for infarct size. Conclusions: Estradiol exerts a protective effect on ischemic myocardium that is not associ ated with an increase in myocardial blood flow or alteration in hemodynamics. This study shows that acute administration of estrogen before coronary artery occlusion reduces infarct size in both male and female rabbits.
Role of Oxidative Stress in Amiodarone-induced Toxicity
Authors: Sarma Jonnalagedda S. M. , Pei Hong , Venkataraman K. 
Published: November 2007

Background: The clinical usefulness of amiodarone for the treatment of cardiac arrhythmias is limited by multiorgan toxicity, especially pulmonary and hepatic. There are conflicting reports in the literature regarding the role of free radicals in the initiation of amiodarone- induced toxicity. We evaluated the possible oxidative stress in a chronic model that is known to manifest pulmonary toxicity. Methods and Results: A group of 20 Fischer-344 rats were injected with 60 mg/kg/day of amiodarone for 21 days. A control group of 20 animals received only saline injections. The alveolar macrophages obtained by lung lavage were incubated with hydroethidine and opsonized green fluorescent zymosan particles to measure oxidative and phagocytic activities by flow cytometry. Malondialdehyde levels were measured to assess the extent of lipid per oxidation in lung, liver, spleen, kidney, and heart. Total phospholipid levels in all the col lected tissues and distribution of phospholipid classes in the lung and the liver were mea sured. The levels of amiodarone and its metabolite desethylamiodarone in serum and all collected tissues were measured by high-performance liquid chromatography. The phago cytic activity of the macrophages from treated animals was decreased by 18-22% ( P < .03) compared to controls; however, the oxidative activities of control and treated groups were not significantly different. The tissue malondialdehyde levels were not significantly different except in the spleen where they increased after amiodarone treatment (18.2 ± 1.1 vs 23.7 ± 2.8 μM/g tissue, P < .0001). Malondyaldehyde levels were not significantly different when normalized to lipid phosphorous content. Lung, liver, and spleen showed significantly higher phospholipid levels in the treated group. The tissue amiodarone and desethylamiodarone lev els in the treated group were highest in spleen followed by lung, liver, kidney, and heart. Conclusions: The results show that amiodarone-induced pulmonary and hepatic toxicity is not directly mediated by oxidative stress; however, increased lipid peroxidation in the spleen, although secondary to phospholipidosis, may be physiologically significant.
Nisoldipine Cardioplegia in the Isolated Rabbit Heart
Authors: Açikel Ünal , Hazan Eyüp , Sariosmanoglu Nejat , Çatalyürek Hüdai , Silistreli Erdem , Güner Gül , Saydam Nurten , Tunçok Yeşim , Güven Hülya , Karabay Özalp , Oto Oztekin 
Published: November 2007

Background: The metabolic and hemodynamic effects of nisoldipine supplementation in cardioplegia after ischemic injury were investigated in 13 isolated rabbit hearts. Group 1 con sisted of 6 hearts, which received St. Thomas II cardioplegic solution. In group 2, nisoldipine was added to the cardioplegic solution at a concentration of 0.1 mg/kg in 7 hearts. Methods: The explanted hearts were suspended from Langendorff apparatus and were per fused with Krebs-Henseleit solution. Left ventricular pressure, heart rate, malondialdehyde, glutathione peroxidase, glutathione reductase, reduced glutathione, oxidized glutathione, cre atine kinase MB, (CK-MB), aspartate transaminase, and lactate dehydrogenase (LDH) were measured before and after 60 minutes of ischemia. Peak generated pressure after ischemia was significantly higher in group 2 versus group I while end-diastolic pressure was signifi cantly lower in group 2 after ischemic arrest ( P < .05). Results: Malondialdehyde levels were lower in group 2 ( P < .05). Glutathione peroxidase and glutathione reductase levels were significantly higher in group 2 ( P < .05). The only enzymatic significant difference was observed between the preischemic and postischemic levels of aspartate transaminase in group 2 ( P < .05). Conclusions: These findings show beneficial effects of nisoldipine cardioplegia, although its use as a cardioplegic additive is not yet possible. We believe, however, the effects of oral nisoldipine before cardiac surgery can be studied in a clinical setting.
Therapeutic Concentrations of Heparin Augment Platelet Activation at the Time of Coronary Angiography
Authors: Naqvi Tasneem Z. , Shah Prediman K. , Ivey Pamela A. , Molloy Mia D. , Linn Patricia , Linker-Israeli Mariana , Cercek Bojan , Kaul Sanjay 
Published: November 2007

Background: Besides its anticoagulant effects, heparin is known to alter platelet (PLT) function. We examined the effects of unfractionated heparin on PLT function in patients with stable coronary artery disease (CAD). Methods and Results: PLT function was evaluated by whole-blood flow cytometry to detect PLT CD62 expression and by impedance aggregometry to assess platelet aggregation (PA) before and after bolus intravenous administration of low-dose heparin (2713 ± 1231 U) in 16 patients undergoing coronary angiography (group 1) and high-dose heparin (7937 ± 2414 U) in 16 patients undergoing coronary angioplasty (group 2). Activated clotting time (ACT) and plasma antifactor-Xa heparin levels also were measured. Heparin increased PLT CD62 expression, which was significantly more pronounced in group 1 patients with plasma heparin levels less than 0.7 U/mL and ACT of 222 ± 52 seconds compared with group 2 patients with heparin levels greater than 0.7 U/mL and ACT of 365 ± 86 seconds (8 ± 9 v -1 ± 4% change in resting PLTs, P = .01, and 11 ± 12 v 1 ± 6% increase in adenosine diphosphate (ADP) [5 μM]-stimulated PLTs, P = .02). Heparin produced a slight increase in PA in group 1 patients (1.4 ± 5.3 ohms) as compared with the group 2 patients, where it significantly suppressed PA (-3.0 ± 5.3 ohms, P < .05 v group 1). A strong and statistically significant negative correlation between change in platelet CD62 expression and heparin concentration was observed in group 1 patients ( r = -.5, P = .05, —ADP; r = —.65, P = .006, +ADP), whereas this relationship was weak and did not reach statistical significance in group 2 patients ( r = -0.4, P = .2, -ADP; r = .11, P = 0.9; +ADP). Conclusion: Bolus administration of intravenous heparin augmented PLT activation in patients at clinically relevant anticoagulant concentrations (<0.7 U/mL). These findings may have implications for optimal dosing strategy for heparin as an antithrombotic agent in clinical situations characterized by platelet-dependent thrombotic events.
Nitric Oxide Alters Human Microvascular Endothelial Cell Response to Cyclic Strain
Authors: Upchurch Gilbert R. , Leopold Jane A. , Welch George N. , Loscalzo Joseph 
Published: November 2007

Background: Nitric oxide (NO), a potent vasodilator and inhibitor of platelet function, is elaborated constitutively by endothelial cells through the oxidation of L-arginine by endo thelial NO synthase. Although several biochemical agonists, such as bradykinin, have been shown to stimulate NO production by the endothelium, the effects of physical factors have been less well characterized. We have previously examined the shear-stress-dependent induction of NO production by the endothelium, and others have examined the effects of transmural pressure on NO production. In the current study, we analyzed the effects of cyclic strain or load in the presence and absence of an NO agonist on endothelial cell proliferation. Methods and Results: Subconfluent human microvascular endothelial cells were grown on deformable culture plates in media containing 10% fetal bovine serum and 1 mM L-arginine, and then subjected to either 0, 11, 18, or 27% cyclic strain at a frequency of 1 Hz. Nitrogen oxides (S-nitrosothiols and free NO) in media were measured by photolysis-chemilumines cence at the end of 24 hours, as were cell number, [3H]thymidine incorporation, and total cell protein. In the absence of an NO agonist, 11 % cyclic strain produced a 73 ± 17% increase in nitrogen oxides compared with control ( P < .05), whereas 18 and 27% cyclic strain produced no significant increase in nitrogen oxides compared with control. However, cells subjected to 27% strain increased cell number (by 98 ± 17%) and [3H]thymidine incor poration (by 16 ± 4%, P < .05) compared with control. In an attempt to examine further the effects of endogenous NO on the cells' proliferative response to increasing levels of cyclic strain, we incubated human microvascular endothelial cells with 1 μM bradykinin and subjected them to 27% cyclic strain. In the presence of bradykinin and 27% cyclic strain, production of nitrogen oxides and endothelial NO synthase activity were increased by 110 ± 37% and 135 ± 7%, respectively ( P < .05 compared with control); however, we observed no significant increase in cell number (5 ± 5%), despite an 86 ± 7% increase in [3H]thymi- dine incorporation (P < .05). Conclusions: These results suggest that endogenous NO production by human microvascu lar endothelial cells regulates their growth response to cyclic strain. Modulation of NO pro duction in vivo in areas of the vasculature that are subjected to increased levels of strain may represent one potential mechanism by which to alter endothelial cell proliferation.