bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carvedilol Mitigates Adverse Effects of Epinephrine During Cardiopulmonary Resuscitation
Authors: Huang Lei , Weil Max Harry , Sun Shijie , Tang Wanchun , Fang Xiangshao 
Published: March 2006

Introduction: Earlier studies have implicated the adverse effects of β- and α1-adrenergic receptors during cardiopulmonary resuscitation (CPR). Because carvedilol is both a nonselective β- and α1-selective adrenergic receptor-blocking agent, we hypothesized that pre-treatment with carvedilol would convert the actions of epinephrine to that of a selective a2-agonist. Methods: Ventricular fibrillation (VF) was induced in Sprague-Dawley rats weighing approximately 500 g. Animals were randomized to 4 groups of 5 animals each: (1) placebo pretreatment and epinephrine treatment, (2) carvedilol pretreatment and placebo treatment, (3) carvedilol pretreatment and epinephrine treatment, and (4) placebo pretreatment and placebo treatment. Carvedilol (50 µg/kg) was injected as a bolus into the right atrium 15 minutes before VF was induced. VF was untreated for 8 minutes, after which CPR (chest compression and mechanical ventilation) was begun. Epinephrine (30 µg/kg) was injected into the right atrium 2 minutes after the start of CPR. Electrical defibrillation was attempted after 14 minutes of VF. Results: All but 2 animals were successfully resuscitated. Approximately equivalent increases in coronary perfusion pressure from 23 ± 1 mm Hg to 30 ± 3 mm Hg were observed after the injection of epinephrine independently of carvedilol pretreatment. Carvedilol pretreatment followed by epinephrine treatment reduced early postresuscitation ventricular ectopy (116 ± 147 vs 834 ± 380, P < .01) and minimized increases in arterial blood lactate at 5 minutes after resuscitation (10.9 ± 2.1 mmol/L vs 17.4 ± 3.5 mmol/L, P < .01). The postresuscitation cardiac index measured 4 hours later was increased (307 ± 43 mL • min-1• kg-1 vs 210 ±6 mL • min-1• kg-1, P <.05). Left ventricular diastolic pressures were decreased (6 ± 1 vs 14 ± 1 mm Hg, P < .05). Animals pretreated with carvedilol survived longer (71 ± 1 vs 45 ± 22 hours, P < .05) and with less postresuscitation neurologic deficit. Conclusion: After β- and α1-adrenergic blockade with carvedilol before inducing cardiac arrest, epinephrine administered during CPR yielded better postresuscitation myocardial and neurologic functions and significantly increased postresuscitation survival.
Acetaminophen and Myocardial Stunning after Transient Ischemia in Rabbit Hearts
Authors: Hale Sharon L. , Kloner Robert A. 
Published: March 2006

Background: Myocardial stunning is a lingering contractile dysfunction that occurs after brief ischemia, even in the absence of necrosis. Recent studies have shown that acetaminophen may have some benefit on the return of left ventricular function after brief global ischemia in an in vitro model. This study was conducted to determine whether treatment with acetaminophen results in enhanced myocardial tolerance to transient ischemia-reperfusion by improving left ventricular function and decreasing stunning in an in vivo model. Methods: Anesthetized, open-chest rabbits were randomized to receive acetaminophen (37 mg/kg, n = 13) or saline (n = 11) 15 minutes before a series of transient coronary artery occlusions followed by reperfusion (three 10-minute periods of ischemia with 5 minutes reperfusion between). Hemodynamics and maximal and minimal values of developed pressure velocity (dP/dt) were measured at baseline, during ischemia, and throughout 2 hours of reperfusion. To assess myocardial stunning, echocardiography was used to determine regional systolic wall thickening fractions and global indices of function such as LV cavity dimensions and ejection fraction. Results: Hemodynamic variables, including left ventricular systolic pressure and positive and negative dP/dt, were similar in both groups throughout the study. Left ventricular enddiastolic pressure was significantly lower in the acetaminophen group during occlusion and early reperfusion. The repeated short periods of ischemia in the free wall of the heart caused myocardial stunning in both groups. During ischemia, contractile function in the free wall was severely reduced, and although it improved during reperfusion, dysfunction persisted in the postischemic free wall after 2 hours of reflow, recovering to less than 52% of preischemic values ( P < .01). The degree of dysfunction was similar in both groups. During ischemia, the end-diastolic left ventricular cavity area increased from 1.14 ± 0.05 cm2 at baseline to 1.33 ±0.08 cm2 ( P < .05) in controls, but had recovered after 2 hours of reflow. The end-diastolic area in acetaminophen-treated hearts increased from 1.13 ± 0.08 cm2at baseline to 1.35 ± 0.08 cm2 during ischemia and also recovered 2 hours later. No significant differences in LV cavity areas were noted between the groups. Acetaminophen had no effect on changes in ejection fraction, which decreased similarly in both groups during ischemia to approximately 75% of baseline values. Although ejection fraction improved, it remained depressed at the end of reflow in both groups. Conclusion: Data from this study show that in a rabbit model of myocardial stunning, acetaminophen has a neutral effect on hemodynamics, recovery of fractional thickening, and on indices of global recovery such as left ventricular cavity dimensions or ejection fraction. Thus in the setting of experimental myocardial stunning, treatment with acetaminophen was safe but not cardioprotective.
Tolvaptan Administration Does Not Affect Steady State Amiodarone Concentrations in Patients With Cardiac Arrhythmias
Authors: Shoaf Susan Elizabeth , Elizari Marcelo Víctor , Wang Zhao , Sekar Kumara , Grinfeld Liliana Rosa , Barbagelata N. Alejandro , Lerman Jorge , Bramer Steven Lee , Trongé Jorge , Orlandi Cesare 
Published: March 2006

Background: Tolvaptan, a nonpeptide selective vasopressin receptor (V2) antagonist, is in development for the treatment of congestive heart failure and hyponatremia. Tolvaptan is primarily metabolized via CYP3A4. This study was conducted to determine the extent of the pharmacokinetic interaction between tolvaptan and steady state amiodarone, an antiarrhythmic drug commonly prescribed for patients with congestive heart failure and a known inhibitor of other drugs metabolized by CYP3A4. Methods: This was a multicenter, open-label, 1-arm, 3-period, sequential treatment study conducted in 11 men (10) and women aged 49 to 80 years. They were primarily Caucasian (20) subjects, with a history of cardiac arrhythmias who were otherwise healthy. Subjects were to have been on oral amiodarone maintenance therapy of 200 mg/day for at least 10 months. All subjects took 200 mg amiodarone once daily on each study day; on days 3 and 4, they were also coadministered 30 and 90 mg of tolvaptan, respectively. The plasma concentrations of amiodarone and its metabolite desethylamiodarone were determined for 24 hours postdose on days 2, 3, and 4, tolvaptan concentrations were determined for 24 hours postdose on days 3 and 4. Results: As determined by the ratio of the geometric means and 90% confidence intervals (0.5 to 2.0) for the maximal plasma concentration and the area under the curve during the dosing interval for both amiodarone and desethylamiodarone, tolvaptan coadministration had no effect on either amiodarone and desethylamiodarone disposition, as all the geometric mean ratios (amiodarone + tolvaptan [30 or 90 mg] vs amiodarone alone) were approximately 1. Conclusion: Tolvaptan coadministration does not alter steady-state amiodarone or desethylamiodarone concentrations. Tolvaptan concentrations did not appear to be different from historical controls. The most frequently reported adverse event was polyuria (15 of 21 subjects for amiodarone + 30 mg tolvaptan); an expected outcome due to the known potent aquaretic action of tolvaptan. The combination of amiodarone and tolvaptan was well tolerated.
Carvedilol Improves Myocardial Contractility Compared With Metoprolol in Patients With Chronic Hibernating Myocardium After Revascularization
Authors: Schwarz Ernst R. , Gupta Rajiv , Diep Tu Phuong , Nowak Bernd , Kostin Sawa , Grohmann Beate , Uretsky Barry F. , Schaper Jutta 
Published: March 2006

Background: We tested the hypothesis of whether carvedilol delays morphologic degeneration and improves functional outcome compared with metoprolol tartrate in patients with hibernating myocardium undergoing surgical revascularization. We have previously shown that patients with chronic hibernating myocardium undergo progressive cellular degeneration and fibrosis. Methods: Twenty patients with multivessel coronary artery disease revascularization and hibernating myocardium as assessed by technetium-99m perfusion scintigraphy and fluorine-18-fluorodeoxyglucose positron emission tomography were randomized to receive either carvedilol or metoprolol tartrate for at least 2 months before surgery, and this was continued for 7 months postoperatively. Left ventricular ejection fraction and regional wall motion abnormalities were assessed by left ventriculography at baseline and 7 months postoperatively. Intraoperative transmural needle biopsy samples were obtained for microscopic analysis. Results: Postoperatively, the ejection fraction increased from 31% ± 5% to 44% ± 4% ( P < .005) in the carvedilol group (n = 10), and from 30% ± 6% to 40% ± 6% in the metoprolol tartrate group ( P < .05 vs preoperatively and vs carvedilol). Wall motion abnormalities in the carvedilol group improved from -2.1 ± 0.4 to -0.6 ± 0.5 ( P < .05) and from -2.3 ± 0.5 to -1.6 ± 0.6 in the metoprolol tartrate group ( P < .05 vs preoperatively and vs carvedilol). Microscopic analysis after 72 ± 18 days of either treatment showed mild cardiomyocyte degeneration and moderate-to-severe fibrosis (28% ± 7%) in the carvedilol group compared with moderate cardiomyocyte degeneration and moderate-to-severe fibrosis (33% ± 6%) in the metoprolol tartrate group. Apoptosis, as assessed by the terminal deoxynucleotidyl transferase nick end labeling method, was observed in only 1 patient in each group. Conclusions: Carvedilol treatment of hibernating myocardium results in improved functional recovery after revascularization compared with metoprolol tartrate, and this might partially be related to reduced cardiomyocyte degeneration.
Bivalirudin vs Heparin in Percutaneous Coronary Intervention: A Pooled Analysis
Authors: Ebrahimi Ramin , Lincoff A. Michael , Bittl John A. , Chew Derek , Wolski Kathy , Wadhan Nitin , Toggart Edward J. , Topol Eric J. 
Published: March 2006

Objective: This study evaluates outcomes with bivalirudin vs heparin in various patient subgroups and the overall population during percutaneous coronary interventions (PCI). Background: Recent data suggest that bivalirudin, a reversible direct thrombin inhibitor, provides ischemic protection superior to heparin and comparable to heparin plus glycoprotein (GP) IIb/IIIa inhibitors but with significantly fewer bleeding complications. Whether this advantage persists in different subgroups has not been fully defined. To our knowledge, this is the largest pooled analysis of bivalirudin to date. Methods: Four randomized controlled trials were identified that compared bivalirudin to heparin (with or without GP IIb/IIIa inhibitors) in PCI. The incidence of death, myocardial infarction (MI), revascularization, and major bleeding at 48 hours was compared between these two agents overall and in patients with and without diabetes mellitus, hypertension, renal insufficiency, and advanced age. Results: The trials consisted of 11,638 patients (bivalirudin, 5,861; heparin, 5,777). There were no significant differences in patient characteristics between the two groups. At 48 hours, the incidence of death, MI, revascularization, and major bleeding was significantly reduced in the bivalirudin group (7.8% vs 1.08%, P < .001); individual ischemic end points were significantly reduced for death (0.01% vs 0.02%, P = .049) and revascularization (2.0% vs 2.7%, P = .02), with similar reductions for major bleeding (2.7% vs 5.8%, P < .001). Subgroup analysis was generally consistent with the overall findings. Conclusion: This analysis further supports the superiority of bivalirudin compared with heparin. Bivalirudin provides excellent ischemic protection with a significant reduction of bleeding complications, even in high-risk subgroups.
Intramyocardial Injection of Allogenic Bone Marrow-Derived Mesenchymal Stem Cells Without Immunosuppression Preserves Cardiac Function in a Porcine Model of Myocardial Infarction
Authors: Makkar Raj R. , Price Matthew J. , Lill Michael , Frantzen Malka , Takizawa Kaname , Kleisli Thomas , Zheng Jie , Kar Saibal , McClelan Robert , Miyamota Takeshi , Bick-Forrester Justin , Fishbein Michael C. , Shah Prediman K. , Forrester James S. , Sharifi Behrooz , Chen Peng-Sheng , Qayyum Mohammed 
Published: March 2006

Background: We investigated the efficacy of directly injected allogenic bone marrow-derived mesenchymal stem cells in improving left ventricular function in a porcine model of myocardial infarction. Methods: Left ventricular infarction was created in 16 adult Yorkshire pigs by coil embolization and thrombotic occlusion distal to the second diagonal artery. One month after myocardial infarction was induced, the animals were randomized to either direct injection of allogenic mesenchymal stem cells or sham treatment (culture medium). Allogenic bromodeoxyuridine-labeled mesenchymal stem cells (2 ± 0.1 × 108) were directly injected into the infarct and peri-infarct areas during an open chest procedure. No immunosuppressive therapy was used. The left ventricular function was measured using serial biplane left ventricular angiography at baseline, 30, 60, and 90 days before sacrifice. Mesenchymal stem cells were localized using bromodeoxyuridine, and differentiation of mesenchymal stem cells was assessed by confocal microscopic colocalization of bromodeoxyuridine with immunofluorescent antibodies specific for cardiomyocytes (troponin I and MF-20) and endothelial cells (von Willebrand factor). Results: Mesenchymal stem cells labeled with bromodeoxyuridine engrafted the peri-infarct zone and colocalized with both cardiomyocyte-specific and endothelial cell-specific immunofluorescence. No intramyocardial bromodeoxyuridine was observed in sham-treated animals. At the time of the mesenchymal stem cell injection 30 days after myocardial infarction, the left ventricular ejection fraction (LVEF) was 58% ± 3% in mesenchymal stem cell-treated pigs and 56% ± 2% in sham-treated pigs ( P = NS). LVEF deteriorated progressively thereafter in untreated pigs (8.5% and 10.5% decline at 60 days and 90 days after myocardial infarction, respectively), but was preserved in mesenchymal stem cell-treated pigs (2.1% increase and -2.0% decline at 60 and 90 days post-MI respectively) ( P < .05). Conclusions: Direct intramyocardial injection of mesenchymal stem cells results in successful intramyocardial engraftment and differentiation into cardiomyocytes and endothelial cells and preserves left ventricular function after myocardial infarction in pigs.
Sarcoplasmic Reticulum Adenosine Triphosphatase Overexpression in the L-type Ca2+ Channel Mouse Results in Cardiomyopathy and Ca2+-Induced Arrhythmogenesis
Authors: Rubio Marta , Bodi Ilona , Fuller-Bicer Geraldine A. , Hahn Harvey S. , Periasamy Muthu , Schwartz Arnold 
Published: March 2006

Background: Overexpression of the L-type voltage-dependent calcium channel α1C-subunit (L-VDCC OE) in transgenic mice results in adaptive hypertrophy followed by a maladaptive phase associated with a decrease in sarcoplasmic reticulum adenosine triphosphatase (SERCA)2a expression at 8 to 10 months of age. Overexpressing SERCA to manipulate calcium (Ca2+) cycling and prevent pathologic phenotypes in some models of heart failure has been proven to be a promising genetic strategy.Objective: In this study we investigated whether genetic manipulation that increases Ca2+uptake into the sarcoplasmic reticulum by overexpressing SERCA1a (skeletal muscle specific) into the L-VDCC OE background could restore or further deteriorate Ca2+cycling, contractile dysfunction, and electrical remodeling in the heart failure phenotype.Results: We found that the survival rate of L-VDCC OE/SERCA1a OE double transgenic mice decreased by 50%. L-VDCC OE/SERCA1a OE mice displayed an accelerated phenotype of severe dilation of both ventricles associated with deteriorated left ventricular function. Voltage clamp experiments revealed enhanced increased inward Ca2+current density and decreased the transient outward potassium current. Action potential duration in double transgenic ventricular myocytes was prolonged, and isoproterenol induced early afterdepolarization. These mice demonstrated a high incidence of spontaneous left ventricular arrhythmia. Expression of the proarrhythmic signaling protein Ca2+/calmodulin-dependent kinase II (CaMKII) was increased while connexin43 expression was decreased, defining an important putative mechanism in the electrophysiologic disturbances and mortality.Conclusions: Despite previous reports of improved cardiac function in heart failure models after SERCA intervention, our results advocate the need to elucidate the involvement of augmented Ca2+cycling in arrhythmogenesis.
A Vigilant, Hypoxia-Regulated Heme Oxygenase-1 Gene Vector in the Heart Limits Cardiac Injury After Ischemia-Reperfusion In Vivo
Authors: Tang Yao Liang , Qian Keping , Zhang Y. Clare , Shen Leping , Phillips M. Ian 
Published: March 2006

Objectives: The effect of a cardiac specific, hypoxia-regulated, human heme oxygenase-1 (hHO-1) vector to provide cardioprotection from ischemia-reperfusion injury was assessed. Background: When myocardial ischemia and reperfusion is asymptomatic, the damaging effects are cumulative and patients miss timely treatment. A gene therapy approach that expresses therapeutic genes only when ischemia is experienced is a desirable strategy. We have developed a cardiac-specific, hypoxia-regulated gene therapy “vigilant vector” system that amplifies cardioprotective gene expression. Methods: Vigilant hHO-1 plasmids, LacZ plasmids, or saline (n = 40 per group) were injected into mouse heart 2 days in advance of ischemia-reperfusion injury. Animals were exposed to 60 minutes of ischemia followed by 24 hours of reperfusion. For that term (24 hours) effects, the protein levels of HO-1, inflammatory responses, apoptosis, and infarct size were determined. For long-term (3 week) effects, the left ventricular remodeling and recovery of cardiac function were assessed. Results: Ischemia-reperfusion resulted in a timely overexpression of HO-1 protein. Infarct size at 24 hours after ischemia-reperfusion was significantly reduced in the HO-1-treated animals compared with the LacZ-treated group or saline-treated group ( P < .001). The reduction of infarct size was accompanied by a decrease in lipid peroxidant activity, inflammatory cell infiltration, and proapoptotic protein level in ischemia-reperfusion-injured myocardium. The long-term study demonstrated that timely, hypoxia-induced HO-1 overexpression is beneficial in conserving cardiac function and attenuating left ventricle remodelling. Conclusions: The vigilant HO-1 vector provides a protective therapy in the heart for reducing cellular damage during ischemia-reperfusion injury and preserving heart function.
Chlorthalidone Improves Endothelial-Mediated Vascular Responses in Hypertension Complicated by Nondiabetic Metabolic Syndrome
Authors: Dell’Omo Giulia , Penno Giuseppe , Del Prato Stefano , Pedrinelli Roberto 
Published: March 2006

Background: The study was conducted to evaluate the vascular effects of chlorthalidone, a distal tubule-acting natriuretic agent, in hypertensive patients with nondiabetic metabolic syndrome, an insulin-resistant condition characterized by endothelial dysfunction and high risk for diabetes mellitus development. Methods: Thirteen untreated hypertensive patients with Adult Treatment Panel-III-defined nondiabetic metabolic syndrome were assigned to 3-month treatment with chlorthalidone. The end-points were baseline and post-treatment evaluation of (1) forearm blood flow (strain-gauge plethysmography) responses to graded intra-arterial acetylcholine infusion to test endothelial-mediated vasomotor function, with sodium nitroprusside as a control for endothelium-independent vasodilatation; (2) minimum forearm vascular resistance, the ratio of mean blood pressure and maximal blood flow in response to 13-minute arterial occlusion, as a hemodynamic correlate of arteriolar structure; and (3) transcapillary albumin escape rate (the 1-hour decay rate of 125I-albumin, 6-8 μC ev) as a measure of systemic capillary permeability. Additional measurements included baseline and posttreatment lipids, fasting, and postload glucose and insulin as well as the homeostasis model assessment, an index of insulin sensitivity. Results: Chlorthalidone reduced blood pressure, augmented acetylcholine-mediated vasodilatation, decreased minimum forearm resistance, and slowed the transcapillary albumin escape rate. Metabolic parameters did not change significantly except for an increase in low-density lipoprotein cholesterol levels. Conclusions: Chlorthalidone improved endothelial function, reversed abnormal arteriolar structure, and slowed albumin permeation in hypertensive patients with nondiabetic metabolic syndrome.
Heparin Therapy Leads to Platelet Activation and Prolongation of PFA-100 Closure Time
Authors: Williams Marlene S. , Ng’alla Ladina S. 
Published: March 2006

Background: Heparin is used in the treatment of venous and arterial thromboembolic events, including unstable angina. Once unfractionated heparin is discontinued during the acute phase of unstable angina, it has been demonstrated that the disease process may be reactivated within hours. It is hypothesized that this reactivation may be a result of direct platelet activation by heparin that can linger even after the drug itself has been stopped. Prior studies have shown that heparin can either increase or decrease platelet activation. More recent studies have also shown conflicting effects of unfractionated heparin on PFA-100 testing. Methods: We studied the in-vitro effects of unfractionated heparin on platelet function and PFA-100 testing. Unfractionated heparin was incubated with whole blood taken from 18 healthy volunteers. Platelet activation and aggregation was assessed with and without the presence of heparin. Results: Platelet aggregation and activation were increased in the presence of heparin. Unfractionated heparin also significantly prolonged collagen/adenosine diphosphate closure time but did not affect collagen/epinephrine closure time. Conclusions: Unfractionated heparin leads to direct platelet activation and increases platelet aggregation in vitro. Unfractionated heparin causes prolongation of the collagen/adenosine diphosphate closure time in PFA-100 testing, possibly as a result of direct binding to von Willebrand factor in solution and interference with von Willebrand factor-glycoprotein Ib binding.