bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Nociceptin Has Vasodilator Activity in the Pulmonary Vascular Bed of the Rat
Authors: Nossaman Bobby D. , Champion Hunter C. , Kaye Alan David , Anwar Mohammad , Chang Jian Feng  , Kadowitz Philip J.
Published: November 2007

Background: Recent studies have shown that the newly discovered endogenous opioid-like peptide, nociceptin, has vasodilator activity in the peripheral vascular bed. However, little if anything is known about the effects of the peptide in the pulmonary vascular bed. There fore, responses to nociceptin in the pulmonary vascular bed were investigated and com pared with responses in the hindlimb and systemic vascular beds of the rat.

Methods and Results: Responses to nociceptin were investigated in the pulmonary and hindquarters vascular beds in the rat under constant flow conditions and were compared with decreases in systemic vascular resistance. Under conditions of constant flow, injections of nociceptin in doses of 3-30 nM induced dose-related decreases in pulmonary arterial per fusion pressure when baseline tone was increased to a high steady level with U46619. Pul monary vasodilator responses to nociceptin were not modified by the opioid receptor antagonist naloxone, and the newly discovered ligand was 10-fold less potent than adreno medullin in decreasing pulmonary vascular resistance when decreases in pulmonary hind quarters and systemic vascular resistances were compared, nociceptin was significantly more potent in decreasing hindquarters and systemic vascular resistance than in reducing pulmonary vascular rcsistance.

Conclusions: The results of the present study indicate that nociceptin decreases pulmonary vascular resistance by a natoxone-insensitive mechanism, and that the peptide is less potent in decreasing pulmonary vascular resistance than in decreasing systemic vascular resistance in the rat.
Efficacy of Nicardipine for Long-Term Therapy of Chronic Stable Angina
Authors: Deedwania Prakash C. , Safford Robert E. , de Wood Marcus , Costello Dennis , Goldsmith Steven
Published: November 2007

Background: Although angina is a chronic disease, most clinical trials evaluating antiangi nal therapy are of a few weeks or months in duration.

Methods and Results: To evaluate the effects of nicardipine, a second-generation dihydro pyridine calcium channel blocker, as long-term therapy, patients with chronic stable angina were treated for 1 year with open-label nicardipine. Anginal symptoms were controlled with 20 mg tid in 24%, 30 mg tid in 34%, and 40 mg tid in 42%. Of 72 patients completing the 1-year trial, only 14 (19%) had required the addition of long-acting nitrates for control of symptoms. The remaining 57 patients, who had anginal symptoms controlled with nicar dipine alone, were continued into the 3-week, double-blind period and were randomized to continue their usual dose of nicardipine or placebo. Throughout the 1-year, open-label treatment period, the number of anginal episodes and exercise parameters of angina were significantly reduced with nicardipine.

Conclusions: During the double-blind period, the patients who continued on nicardipine had significantly greater exercise time and time to onset of angina than patients who were randomized to placebo. The exercise parameters in the patients randomized to placebo were improved over baseline after 1 year of therapy; however, the improvement with nicar dipine was significantly greater.
Modification of the ATP-Induced Increase in [Ca2+]i by Copper and Zinc in Rat Cardiomyocytes
Authors: Musat Sorin , Wang Xi , Dhalla Naranjan S.
Published: November 2007

Background: It is generally accepted that the plasma membrane of mammalian ventricular myocytes regulates the cytosolic concentration of Ca2+. In this study we investigated the effects of some P2-purinoceptor antagonists and metals such as copper and zinc on the ade nosine triphosphate (ATP)-induced increase in intracellular concentration of free Ca2+ ([Ca2+]i).

Methods and Results: Cardiomyocytes were isolated from adult male Sprague-Dawley rats loaded with Fura-2, and fluorescence measurements were performed by employing stirred cell suspensions at room temperature. ATP (50 μM) increased [Ca2+]i over the basal value, 10 μM ryanodine pretreatment partially attenuated the ATP-evoked increase in [Ca2+]i, and 10 μM cibacron blue or verapamil virtually abolished it. The ATP-induced increase in [Ca 2+]i was not observed in Ca2+- or Mg2+-free buffers. Incubation of cells with ZnCl2 pro duced a significant depression of the ATP-induced increase in [Ca2+]i; 25 μM Zn2+ decreased the peak response to approximately 50% of the control value. The ATP-induced increase in [Ca2+]i, was inhibited by low concentrations (1-5 μM) of Cu2+ but was markedly augmented by high concentrations (25 μM) of Cu2+. The increase in the [Ca2+] i response to ATP induced by 25 μM Cu2+ was Mg 2+ dependent and was prevented by verapamil, ciba cron blue, and Zn2+, but not by ryanodine or caffeine pretreatment.

Conclusions: The ATP-induced increase in [Ca2+]i is dependent on the extracellular con centrations of Ca2+ as well as Mg2+ and is antagonized by cibacron blue and Zn2+. On the other hand, Cu2+ produced a biphasic response to the ATP-induced increase in [Ca2+]i in cardiomyocytes.
Effects of Intracellular Calcium Reduction by Dantrolene on Prevention/Treatment of Ischemic Stroke
Authors: Hong Show-Jen , Chiou George C. Y.
Published: November 2007

Background: It has been suggested that cerebral blood vessels and brain cells might depend more on intracellular calcium than extracellular calcium to modulate intracellular free calcium concentrations, [Ca2+]i.

Methods and Results: A potent intracellular calcium antagonist, dantrolene, was used to prevent the ischemic stroke induced in the rat model. It was found that treatment of rats with dantrolene at —1 hour and +1 hour after 60 minutes of ischemic insult prevented by the formation of cortical necrosis 98% and 85%, respectively. Further, the [Ca2+]i of embry onic aorta cells was markedly reduced, and cAMP of the same cultured cells were signifi cantly increased by dantrolene treatment.

Conclusions: These results indicate that ischemic stroke is preventable by dantrolene through reduction of [Ca2+]i and increase of cAMP.
Oxygen Free Radicals and Endotoxic Shock: Effect of Flaxseed
Authors: Pattanaik Uttara , Prasad Kailash
Published: November 2007

Background: Cardiac dysfunction and tissue injury during endotoxemia may be caused by increased levels of oxygen free radicals.

Methods and Results: We therefore investigated the effects of endotoxic shock on cardiac function and contractility, plasma creatine kinase (CK) activity and lactate concentration, oxyradical-producing activity of polymorphonuclear leukocytes (PMNL-CL) and white blood corpuscles, antioxidant reserve (cardiac chemiluminescence [LV-CL]), antioxidant enzyme activity (superoxide dismutase, catalase, glutathione peroxidase), cardiac malondi aldehyde (MDA) concentration, a lipid peroxidation product, and hemodynamics in the absence or prescnce of flaxseed treatment in anesthetized dogs. Flaxseed contains lignans that have antioxidant activities and inhibit platelet-activating factor (PAF). The dogs were assigned to three groups: group I, sham control; group II, endotoxin (ET) treated (5 mg/kg intravenously); group III, ET + flaxseed (2 gm/kg/day orally) for 6 days. ET produced a decrease in cardiac function and contractility and antioxidant enzyme levels, and an increase in cardiac MDA and LV-CL, PMNL-CL, and plasma CK and lactate. Pretreatment with flaxseed attenuated the ET-induced cardiac dysfunction and cellular damage. Protec tion was incomplete for cardiovascular function, plasma CK, and lactate.

Conclusions: These results suggest that oxyradicals and/or PAF may be involved in the deterioration of cardiovascular function and cellular integrity during ET shock and that antioxidant and anti-PAF agents may be effective in the treatment of ET shock.
Effects of Metformin on Collagen Glycation and Diastolic Dysfunction in Diabetic Myocardium
Authors: Jyothirmayi G.N. , Soni B.J. , Masurekar M. , Lyons M. , Regan T.J.
Published: November 2007

Background: Collagen accumulation in the myocardial interstitium of diabetic animals is considered to promote diastolic stiffness through advanced glycosylation. Because in vitro data suggest that metformin can modify glycosylation, this study was undertaken in a canine diabetic model 4 months in duration.

Methods and Results: Untreated diabetics (group II) and diabetics treated with metformin alone (group III) or with insulin (group IV) were compared in the basal state and during volume infusion. Basal hemoglobin A1c, heart rate, aortic pressure, and ejection fraction were comparable. Left ventricular end-diastolic pressure was significantly increased in the untreated diabetics of group II, associated with a reduced end-diastolic volume. By contrast these parameters in the metformin-treated diabetics of group III were comparable with those in the normals of group I. Similarly in group IV end-diastolic volume was higher than that in group II, but filling pressure, although lower, was not significantly so. Calculation of left ventricular chamber stiffness in the basal state indicated a higher level for group II com pared with controls and the treatment groups. During the systemic infusion of dextran, the untreated diabetics of group II had the largest end-diastolic pressure increase and the smallest rise of end-diastolic volume of the treatment groups, consistent with a signifi cantly greater chamber stiffness. Myocardial collagen concentration was increased in group II with an interstitial distribution on morphological exam. Levels of collagen-linked advanced glycosylation end products isolated from the left ventricle were significantly greater in group II than in group I. Treatment with metformin prevented the increment observed in the untreated diabetic but had no effect on the elevated collagen concentration. Conclusions: Untreated diabetics exhibited increased diastolic chamber stiffness associated with collagen-linked glycation in myocardium compared with control animals. Chronic met formin use prevented the abnormalities of function and composition.
The ETA-Receptor Antagonist LU 135252 Prevents the Progression of Established Pulmonary Hypertension Induced by Monocrotaline in Rats
Authors: Dupuis Jocelyn , Prié Stéphane
Published: November 2007

Background: An imbalance between the nitric oxide (NO) and endothelin systems may contribute to the development of pulmonary hypertension (PH). We evaluated the effect of the specific ETA-receptor antagonist LU 135252 (LU) in rats with established monocrota line (MCT)-induced PH and the involvement of NO in the control of pulmonary vascular tone.

Methods and Results: Two weeks after MCT, rats developed PH with a right ventricular pressure (RVP) of 42.3 ± 8.5 vs 28.2 ± 4.1 mmHg for controls (mean ± SD, P < .05). Daily oral therapy with LU (50 mg/kg) or saline was started 2 weeks post-MCT injection for 20 days. LU increased the survival rate nonsignificantly from 41.7% to 66.7%. The surviving MCT + saline rats showed severe PH (RVP of 82.5 ± 8.9 mmHg) and RV hypertrophy with a right-to-left ventricle + septum weight ratio of 69.6% ± 10.2%, which were improved by LU to 53.5 ± 11.1 mmHg and 53.7% ± 9.9%, respectively (P < .01). In isolated lungs, pul monary vascular compliance was reduced by PH and unaffected by LU therapy. After the NO synthase inhibitor Nω-nitro-L-arginine (10-4mol/L), compliance was further reduced, although much less so, in the LU-treated group (P < .01).

Conclusions: In this model, ETA antagonist therapy has a favorable effect on survival and pulmonary hemodynamics and reduces the dependency on NO for the attenuation of re duced vascular compliance.
Nicotine Increases Spatiotemporal Complexity of Ventricular Fibrillation Wavefront on the Epicardial Border Zone of Healed Canine Infarcts
Authors: Ohara Toshihiko , Yashima Masaaki , Hamzei Ali , Favelyukis Mariya , Park Angela , Kim Young-Hoon , Mandel William J. , Chen Peng-Sheng , Karagueuzian Hrayr S.
Published: November 2007

Background: The influence of a pharmacologic agent on wavefront dynamics during ven tricular fibrillation (VF) in a setting of remodeled and healed myocardial infarction (MI) remains poorly explored. We hypothesized that nicotine, by virtue of its complex direct and indirect cardiovascular effects, increases wavefront complexity during VF. Specifically, we sought to determine whether nicotine increases the number and complexity (approximate entropy) of wavelets during stage II VF in hearts with healed MI.

Methods and Results: The left anterior descending coronary artery was permanently occluded in five mongrel dogs and wavefront dynamics during VF studied 5 to 6 weeks after occlusion in the open-chest anesthetized state. VF was induced by rapid pacing and the acti vation pattern mapped on the surviving epicardial border zone (EBZ) of the left ventricle with a plaque (3.2 x 3.8 cm) having 477 bipolar electrodes 1.6 mm apart. VF was mapped before and 20 minutes after 5 μg/kg/min nicotine infusion. Nicotine with a mean arterial plasma con centration of 127 ± 76 ng/mL (range 57 to 240 ng/mL) significantly ( P < .01) increased the number of wavelets from 3.8 ± 0.4 to 5 ± 0.41. The increased number of wavelets was caused by an increase ( P < .01) in the spontaneous breakup of wavefronts from 4.1 ± 0.9 times/s to 6.9 ± 1.1 times/s. Wavebreak over the EBZ was functional in nature as no breakup occurred dur ing normal sinus rhythm. Approximate entropy, a measure of complexity, significantly ( P < .01) increased after nicotine administration from 0.23 ± 0.02 to 0.28 ± 0.01.

Conclusions: Nicotine increases the number of wavelets and their complexity during VF by promoting spontaneous wavebreak over the EBZ of healed MI.
Protamine Reversal of Heparin After Cardiopulmonary Bypass Increases Lung Resistance, Not Elastance
Authors: Gilbert Timothy B. , Barnas George M. , Miller David W. , Sequeira Alejandro J.
Published: November 2007

Background: Protamine, an immunologically active, cationic amine, has been suspected of impairing lung mechanics when administered after cardiopulmonary bypass (CPB) to reverse heparin. Whether such adverse changes are an effect of protamine itself, the forma tion of heparin-protamine complexes, the extent of heparin anticoagulation, or its chemical reversal is not known.

Methods and Results: Using a computer-controlled, forced-ventilation method over a vari ety of physiological tidal volume (VT) and frequency ( f) combinations, we prospectively studied 18 adult, elective patients before systemic heparinization and after protamine rever sal to confirm and, possibly, elucidate an etiology for any adverse pulmonary effects. Prot amine and heparin doses, their sum (Σ-dose) and differential (Δ-dose) doses, and activated clotting times were tabulated. In all patients, lung resistance ( RL) and, to a lesser extent, elastance ( EL) increased after CPB, compared with pre-CPB values ( P < .05). However, RL particularly increased after CPB with increases correlated to the Δ-dose, where RL PRE-POST = -0.037 [Δ-dose] - 0.56 f - 0.019VT + 36.1 ( r = .652, P < .05). No other significant correla tions were found among the remaining clinical parameters and changes in either RL or E L, or any chest wall component (all P > .05).

Conclusions: The changes seen in RL after CPB were greatest in those patients receiving the most nearly balanced doses of heparin and protamine, and were not related significantly to the total heparin or protamine doses, or their sum. This suggests that the extent of antico agulation reversal or formation of heparin-protamine complexes, and not protamine itself, are more responsible for changes seen in lung mechanics. The changes seen were limited solely to RL, and not in either EL nor the chest wall mechanical properties.
Concomitant Block of the Rapid (IKr) and Slow (IKs) Components of the Delayed Rectifier Potassium Current is Associated With Additional Drug Effects on Lengthening of Cardiac Repolarization
Authors: Geelen Peter , Drolet Benoit , Lessard Etienne , Gilbert Philippe , O'Hara Gilles E. , Turgeon Jacques
Published: November 2007

Background: The delayed rectifier potassium current, which comprises both a rapid (I Kr) and a slow (IKs) component, is a major outward current involved in repolarization of cardiac myocytes. IKr is the target of most drugs that prolong repolarization, whereas electrophysio logical effects resulting from combined block of IKr and IKs still need to be characterized.

Methods and Results: Studies in isolated, buffer-perfused guinea pig hearts were under taken to compare lengthening of cardiac repolarization under conditions of IKr block alone, I Ks block alone, or combined block of IKr and IKs. In protocol A, isolated perfusion with N-acetylprocainamide (NAPA) (I Kr block), indapamide (IKs block), or combined NAPA/ indapamide was performed at a pacing cycle length of 250 msec. Increases in monophasic action potential duration measured at 90% polarization (MAPD90) from baseline after per fusion with NAPA 100 μmol/L (IC50 for block of IKr) was 19 ± 6 msec (P < .05), after indap amide 100 μmol/L (EC50 for block of IKs) 13 ± 2 msec (P < .05), but 42 ± 5 msec after combined NAPA 100 μmol/L and indapamide 100 μmol/L (P < .05 vs. baseline and isolated administrations), suggesting the possibility of excessive lengthening of cardiac repolariza tion by blocking both IKr and IKs. As well, in protocol B where sequential perfusions with dofetilide (IKr blocker), dofetilide/indapamide, and indapamide in the same hearts were used, combined dofetilide/indapamide infusion showed a greater increase in MAPD90 dur ing all pacing cycles studied (250 to 150 msec).

Conclusions: Combined IKr and IKs block may lead to excessive lengthening of cardiac repo larization. This may predispose patients to proarrhythmia during coadministration of drugs.
Clinical Pharmacology of Carvedilol
Authors: Carlson William , Oberg Kristin
Published: November 2007

Background: There is now a wealth of data supporting the use of beta-blockers in heart failure and the additional pharmacological properties of carvedilol are thought to play an important role in the therapeutic efficacy of carvedilol in this disease.

Methods and Results: Carvedilol is licensed for the treatment of essential hypertension, chronic stable angina, and mild to moderate chronic heart failure. This article provides an up-to-date review of the clinical pharmacology of carvedilol, with particular emphasis on its clinical effects in heart failure.

Conclusion: Carvedilol is a multiple-action neurohormonal antagonist that offers non selective beta-blockade, alpha-1 blockade, antioxidant, anti-ischemic mortality, and anti proliferative properties. In addition to reductions in hospitalization and mortality rates, benefits of carvedilol in heart failure include dramatic improvements in left ventricular function and other parameters of cardiac remodeling.
State-of-the-Art Review : Effectiveness of Anagrelide in the Treatment of Symptomatic Patients with Essential Thrombocythemia
Authors: Laguna María Susana , Kornblihtt Laura I. , Marta Rosana F. , Michiels Jan Jacques , Molinas Felisa C.
Published: November 2007

We prospectively evaluated the effect of anagrel ide on platelet counts and the clinical manifestations of micro vascular circulation disturbances in 17 newly diagnosed pa tients with essential thrombocythemia. Ten patients had symp toms related to thrombocythemia, eight at the time of starting anagrelide treatment. The platelet counts before anagrelide treatment and during maintained remission of essential throm bocythemia by anagrelide were 980 (range, 610-2030) and 378 (range, 212-546) x 109/L, respectively. Spontaneous platelet aggregation was found in 6 patients (35%), which disappeared on remission of essential thrombocythemia in five cases ( P = 0.02). Essential thrombocythemia-related microvascular thrombotic and hemorrhagic symptoms disappeared with the normalization of platelet count in all cases during maintained remission of essential thrombocythemia by long term continu ous anagrelide treatment with a follow-up period of between 2 and 6 years. However, ET-related symptoms reappeared in three patients, coinciding with increased platelet count up to 600 x 109/L caused by anagrelide dose reduction. We conclude that reduction of increased platelet to normal (< 400 x 109/L) in symptomatic patients with essential thrombocythemia through use of maintained anagrelide treatment is associated with the disappearance of spontaneous platelet aggregation and the complete relief of thrombotic and hemorrhagic manifestations.
Thromboembolic Prophylaxis With Danaparoïd (Orgaran®) in a High-Thrombosis-Risk Pregnant Woman With a History of Heparin-Induced Thrombocytopenia (HIT) and Widal' s Disease
Authors: Macchi L. , Sarfati R. , Guicheteau M. , Chamlian V. , Pourrat O. , Gruel Y. , Magnin G. , Brizard A. , Boinot C.
Published: November 2007

There is no consensus concerning thromboembolic prophylaxis in high-risk pregnant women with a previous his tory of heparin-induced thrombocytopenia. An alternative an ticoagulant therapy is danaparoïd, whereas unfractioned and low-molecular-weight heparin therapy is contraindicated. We report a case of successful thrombosis prophylaxis using dan aparoid in a high-thrombosis-risk pregnant woman with a his tory of heparin-induced thrombocytopenia during a previous pregnancy and Widal's disease.
Plasma Fibrinogen Level Is an Important Determinant of Prolonged Euglobulin Clot Lysis Time in Hemodialysis Patients
Authors: Borawski Jacek , Myśliwiec Michal
Published: November 2007

The euglobulin clot lysis time (ECLT), a traditional measure of plasminogen activation, directly depends on plasma fibrinogen (FBG) level. This fact was neglected in studies concluding that prolonged ECLT in chronic hemodialysis (HD) patients pointed exclusively to impaired fibrinolysis. We studied the relations between ECLT and plasma FBG levels in HD patients in relation to certain hepatic and inflammatory markers. Median ECLT of 320 minutes (range, 150 to 620 minutes) and plasma FBG of 306 mg/dL (range, 171 to 553 mg/dL) were higher in 75 HD patients than in 60 healthy controls (Mann-Whitney p < 0.0001). There were positive associations between these parameters both in the patients (Spear-man p = 0.273, p = 0.018) and the controls (p= 0.672, p < 0.0001). The FBG-corrected ECLT (plasma FBG/ECLT) (in mg/min x dL]) in the patients (0.92 [range, 0.47 to 2.43]) was not different (p = 0.065) from that in the controls (1.08 [0.58 to 1.67]). In the patients, serum alanine aminotransferase inversely correlated with ECLT (p = -0.306, p = 0.008) and FBG (p = -0.310, p = 0.007). whereas serum C-reactive protein was associated positively with these variables (p = 0.383, p = 0.0007: p = 0.477. p <0.0001, respectively). The FBG-corrected ECLT was not related to either marker. In conclusion, increased plasma FBG level, a continuum between liver dysfunction and stimulation by chronic inflammation, is an important determinant of prolonged ECLT in HD patients. The FBG-corrected ECLT value suggests that baseline activation of fibrinolysis is normal in these patients, and that this simple index could be useful in its laboratory assessment.
Comparison of Cyclooxygenase Inhibition with Two Different Doses of Enteric Coated Aspirin in Normal Young and Elderly Subjects and Elderly with Cerebrovascular Disease
Authors: Vial Janet Helen , Narkowicz Christian
Published: November 2007

There is still controversy about the optimum dose and formulation of aspirin for prophylaxis of thrombo-embolic events in patients with cerebrovascular disease. Enteric coated formulations of aspirin have po tential advantages over rapidly absorbed formulations in terms of fewer side effects and more selective platelet cyclooxygenase inhibition. We compared 7-day courses of 100 mg and 650 mg per day enteric coated aspirin in young, healthy subjects and in two groups of elderly sub jects of 70 years and above, one group without vascular disease and the other with cerebrovascular disease. Prior to aspirin treatment, the elderly with cerebrovascular dis ease had higher levels of the urinary thromboxane A2 (TXA2) metabolite 11-dehydro-TXB2; the mean in the el derly ill was 4,064 ± 1,762 pg/mg creatinine (n = 8) com pared to levels of 982 ± 139 pg/mg creatinine (n = 17) in the young, and 1,560 ± 380 pg/mg creatinine (n = 14) in the healthy elderly (p < 0.05 and p < 0.01, respectively). Aspirin (100 mg) inhibited serum TXB2 generation in all groups, with the greatest percentage inhibition occurring in the elderly with cerebrovascular disease. In the ill el derly serum TXB2 was 1.9 ± 0.05% (n = 8) of control compared to 4.2 ± 0.6% (n = 17, p < 0.05) in the young and 9.4 ± 3.5% (n = 14, p < 0.01) in the healthy elderly. All young and diseased elderly subjects achieved greater than 90% inhibition with 100 mg aspirin, but 4 of 14 healthy elderly subjects achieved less than 90% inhibi tion. The 650-mg dose of aspirin produced further inhibi tion in serum TXB2 in the young and healthy elderly sub jects and inhibited serum TXB2 to greater than 90% of control levels in all subjects. The higher dose also pro duced greater reductions in 11-dehydro-TXB2 levels, and these were statistically significant in the young and ill elderly. Urinary-6-keto PGF1α was not significantly de creased at either dose, except in the elderly ill taking 650 mg a day in whom it was reduced to 55 ± 18% of control (n = 8, p < 0.05). Thus enteric coated aspirin at doses of 100 and 650 mg taken daily for 7 days inhibited platelet cyclooxygenase with relative sparing of endothelial cy clooxygenase. The elderly with cerebrovascular disease were more sensitive to the platelet and endothelial cyclo oxygenase inhibition effects of enteric coated aspirin than the healthy elderly and healthy young groups.
An Approach to Factor Assays in Patients with Strong Lupus Anticoagulants
Authors: Armitage John , Ashcraft Joy , Kim Anne , Kaplan Harold S.
Published: November 2007

Higb-titer lupus anticoqgulants (LACs) may present technical and diagnostic dffficulties in the evaluation of patients with specific factor deficiencies or inhibitors. These potent LACS, although infrequently encountered, may be very confusing because they do not generate the characteristic pattern of rising factor levels with increasing sample dilutions. In addition, they may prevent assessment of individual factor defects by lowering activities below detectable or evaluable levels (<1%). To help resolve these problems, our taboratory has developed an approach that incorporates a variation of the platelet neutralization procedure (PNP), wherein we add phospholipid (PL) to adsorb the LAC in each of the dilutions of the individual factor assays. Using factor VIII for the prototypic studies, we characterized three basic result patterns that might arise, depending on the amount of factor activity recovered. As observed in patients exhibiting two of these patterns, an appreciable increase in activity agrees with the neutralization of a LAC and provides evidence against a coexistent severe deficiency of that factor and presumptive evidence against a coexistent, strong specific factor inhibitor. Key .Words: Lupus anticoagulants-Factor assays-Factor inhibitors.
The Platelet Aggregation Score and Its Correlation to β- Thromboglobulin and Platelet Factor 4 Levels
Authors: Kaplan Svetlana , Kaplan Alexander , Marcoe Karen F. , Gey Gerge O. , Schiller Harvey , Roby Paul V. , Fisher Llod D. , El-Massry Sherif , Sauvage Lester R.
Published: November 2007

We describe a new method of interpreting platelet aggregometry results and its correlation to platelet secretory protein levels. We studied 123 healthy male volunteers, 37-85 years of age. The aggregation response to 2.5 μM ADP was measured in a standardized platelet suspension (SPS) prepared from platelet-rich plasma. Turbidimetic measurements included amplitude of the primary aggregation wave (Amp1), maximum aggregation amplitude (Amax), and area under the aggregation curve (Sagg). A platelet aggregation (PA) score was calculated as ( Amp1 /Amax) ·Sagg ·(whole-blood platelet count/SPS platelet count). β-Thromboglobulin (β-TG)and . platelet factor 4 (PF4) levels were measured by radioimmunoassay. The PA score correlated significantly (p < 0.0001) with β-TG ( r = 0.86) and PF4 ( r = 0.87). It was concluded that the PA score correlates closely with individual subjects' propensities to platelet activation, as reflected by plasma β-TG and PF4 levels. Key Words: Platelets-Platelet aggregometry-Platelet secretory proteins.
Asymptomatic Carotid Stenosis and Risk of Stroke: A Natural History Study
Authors: Nicolaides A.N. , Thomas D.
Published: November 2007

In patients with asymptomatic carotid stenosis >70% diameter, the annual incidence of ipsilateral stroke is 3-4%. Multicentre randomised studies such as the asymptomatic carotid atherosclerosis study (ACAS) in the U.S.A. and the ACST in Europe aim to answer the question whether carotid endarterectomy can reduce the incidence of stroke in such patients. If the surgical risk is too close to benefit or if a high proportion of patients not at risk of stroke are entered into the ACAS or ACST studies, the latter may fail to demonstrate the benefit of carotid endarterectomy (CE). The need to identify a high risk stroke group (ipsilateral stroke >7% per annum) with randomisation of this group to a subsequent study will then become apparent. If the ACAS and ACST studies indicate that the risk of stroke is reduced by 50% (i.e., from 4 to 2%), it has been calculated that the cost of preventing one stroke will be 1.2 million US dollars because of the large number of operations required. It will still be necessary to identify a high-risk group or, better, a low-risk group in order to spare many patients unnecessary operation. A multicentre, natural history study has been set up under the auspices of the International Union of Angiology and monitored from St Mary's Hospital Medical School in London with over 50 centres taking part. Patients with asymptomatic carotid stenosis 50-70% and 70-90% are entered in a ratio of 1 to 2, a number of noninvasive tests are performed, and the patients are followed for 5 years. The tests performed are (a) Grading the degree of internal carotid stenosis using duplex scanning; (b) grading the opposite side; (c) plaque characterisation; (d) presence of ultrasonic ulceration; (e) plaque thickness (mm); (f) cerebral reactivity to CO2 using velocity of internal carotid artery and (optional) middle cerebral artery ; (g) CT brain scan for the presence of silent infarction ; (h) intima-media thickness of the common carotid; and (i) identification of conventional risk factors: hypertension, hypercholeterolaemia, smoking, family history, diabetes. The key end points are stroke (including fatal stroke) and ipsilateral stroke. Patients who die from cardiovascular death other than stroke or noncardiovascular death and patients who develop hemispheric transient ischaemic attacks followed by CE are considered to have reached an exit end point. Because this is a natural history study, the clinician in charge of all patients is free to treat them in any way considered appropriate. Patients in the Medical Limb of the ACST study may be entered into the Natural History (ACSRS) study.