bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and Safety of a Metabolic Modulator Drug in Chronic Stable Angina: Review of Evidence from Clinical Trials
Authors: Chaitman Bernard R.
Published: June 2007

A number of newer antianginal agents, including nicorandil, trimetazidine, and ivabradine, have been synthesized in recent years, but ranolazine, a piperazine derivative that partially inhibits fatty acid oxidation and the late INa current in animal models, is of particular interest mechanistically. Earlier clinical trials with immediate-release ranolazine led to the current sustained-release version tested in the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) (n = 193) and Combination Assessment of Ranolazine In Stable Angina (CARISA) trials (n = 823) of patients with chronic angina and severe limitation of exercise capacity (ie, < 5 metabolic equivalents). MARISA was a placebo-controlled, randomized trial that compared ranolazine monotherapy (500 mg, 1000 mg, and 1500 mg, twice daily) to placebo. CARISA was a placebo-controlled trial that randomized patients on background 1-blocker or calcium antagonist therapy to placebo or ranolazine (750 mg or 1000 mg, twice daily). Both studies showed a significant increase in total exercise duration, time to angina onset, and time to 1 mm ST segment depression. The average magnitude of increase in exercise duration over placebo was 29 to 56 seconds at peak and 24 to 46 seconds at trough with the 3 doses tested in MARISA, and 24 to 34 seconds greater than placebo with the 2 doses used in CARISA. The beneficial effect was achieved without clinically important changes in rest or exercise heart rate or blood pressure. Weekly angina attack frequency and nitroglycerin usage were significantly reduced in a dose-dependent manner in the 12-week CARISA trial. Reported adverse effects were similar in MARISA and CARISA and consisted of asthenia, nausea, constipation, and dizziness. Syncope, reported in 8 patients at doses of 1000 mg twice daily or more may be related to attenuation of α-1 receptor activity. The mean QTc interval increased with dose and was less than 10 msec on ranolazine at 1000 mg twice daily. The mortality rates at 1 and 2 years in MARISA and CARISA open-label run-on studies were 2% and less than 5%, acceptable for this high-risk population with limited exercise capacity. In conclusion, clinical trial evidence with ranolazine to date is consistent with its proposed mechanism of action and demonstrates an effective antianginal profile that may benefit patients with severe chronic angina.
Electrophysiologic Properties and Antiarrhythmic Actions of a Novel Antianginal Agent
Authors: Antzelevitch Charles , Belardinelli Luiz , Wu Lin , Fraser Heather , Zygmunt Andrew C. , Burashnikov Alexander , Di Diego José M. , Fish Jeffrey M. , Cordeiro Jonathan M. , Goodrow Robert J. , Scomik Fabiana , Perez Guillermo
Published: June 2007

Ranolazine is a novel antianginal agent capable of producing anti-ischemic effects at plasma concentrations of 2 to 6 μM without a significant reduction of heart rate or blood pressure. This review summarizes the electrophysiologic properties of ranolazine. Ranolazine significantly blocks IKr (IC50 = 12 μM), late INa, late ICa, peak ICa, INa-Ca (IC50 = 5.9, 50, 296, and 91 μM, respectively) and IKs (17% at 30,uM), but causes little or no inhibition of Ito or IKl. In left ventricular tissue and wedge preparations, ranolazine produces a concentration-dependent prolongation of action potential duration (APD) in epicardium, but abbreviation of APD of M cells, leading to either no change or a reduction in transmural dispersion of repolarization (TDR). The result is a modest prolongation of the QT interval. Prolongation of APD and QT by ranolazine is fundamentally different from that of other drugs that block IKr and induce torsade de pointes in that APD prolongation is rate-independent (ie, does not display reverse rate-dependent prolongation of APD) and is not associated with early afterdepolarizations, triggered activity, increased spatial dispersion of repolarization, or polymorphic ventricular tachycardia. Torsade de pointes arrhythmias were not observed spontaneously nor could they be induced with programmed electrical stimulation in the presence of ranolazine at concentrations as high as 100 μM. Indeed, ranolazine was found to possess significant antiarrhythmic activity, acting to suppress the arrhythmogenic effects of other QT-prolonging drugs. Ranolazine produces ion channel effects similar to those observed after chronic exposure to amiodarone (reduced late INa, IKs, IKS, and ICa). Ranolazine's actions to reduce TDR and suppress early afterdepolarization suggest that in addition to its anti-anginal actions, the drug possesses antiarrhythmic activity.
Prophylactic Use of Vancomycin in Adult Cardiology and Cardiac Surgery
Authors: Movahed Mohammad-Reza , Kasravi Babak , Bryan Charles S.
Published: June 2007

The recent appearance of Staphylococcus aureus and Staphylococcus epidermidis strains that have reduced susceptibility to vancomycin, and the spread of vancomycin-resistant enterococci, raise the specter of endovascular infections that will be difficult or impossible to cure with available drugs. We review issues concerning the prophylactic use of vancomycin in adult cardiology and cardiac surgery with special attention to dosing and indications. There is no indication for the routine use of prophylactic vancomycin in pacemaker implantations, cardiac catheterization, and transesophageal echocardiography. In institutions with a high incidence of methicillin-resistant S. aureus and S. epidermidis, vancomycin may be used for antibiotic prophylaxis in place of cephalosporins for pacemaker or defibrillator implantation. The strongest evidence in support of the prophylactic use of vancomycin is during cardiac surgeries, particularly valvular surgeries in institutions with a high prevalence of methicillin-resistant S. aureus and S. epidermidis. When vancomycin is used prior to open heart surgery, the dose should be 15 mg/kg rather than the standard 1 g dose that is often recommended in the literature and used by 85% of institutional pharmacists who responded to our survey. Cardiologists and cardiac surgeons should assume leadership roles in promoting its responsible use.
Hypothesis: Atorvastatin Has Pleiotropic Effects that Translate into Early Clinical Benefits on Cardiovascular Disease
Authors: Novela Cristina , Hennekens Charles H.
Published: June 2007

The results of numerous long-term, randomized trials show that statins significantly decrease the risks of myocardial infarction, stroke, and vascular death as well as total mortality. The benefits of statins on cardiovascular disease in patients who are not experiencing acute coronary syndromes generally become apparent only after about 2 years. In contrast, atorvastatin conferred an early clinical benefit in the lipid-lowering arm of the long-term Anglo Scandinavian Cardiac Outcomes Trial as well as early benefit on progression of atherosclerosis in the Reversal of Atherosclerosis with Aggressive Lipid Lowering trial. An unexpected finding at baseline in the prospective Interaction of Atorvastatin and Clopidogrel Study was that patients on atorvastatin had significantly decreased platelet activity compared with either patients on other statins or those taking no statins. Atorvastatin has protective effects against membrane lipid peroxidation at pharmacologic concentrations. These and other considerations contribute to the hypothesis that atorvastatin has pleiotropic effects that translate into early clinical benefits on cardiovascular disease.
Circulating Endothelial Cells in Venous Blood as a Marker of Endothelial Damage in Chronic Venous Insufficiency: Improvement with Venoruton
Authors: Cesarone Maria Rosaria , Belcaro Gianni , Pellegrini Luciano , Ledda Andrea , Vinciguerra Giulia , Ricci Andrea , Gizzi Giuseppe , Ippolito Edmondo , Fano Filiberto , Dugall Mark , Acerbi Giovanni , Cacchio Marisa , Di Renzo Andrea , Hosoi Morio , Stuard Stefano , Corsi Marcello
Published: June 2007

Damage to endothelial cells is common in vascular disorders and in reactions associated with transplantation. An elevated number of circulating endothelial cells indicates the extent of endothelial damage in a variety of disorders. In chronic venous insufficiency (CVI), the number of endothelial cells is abnormally increased, and this can be considered an important indication of endothelial damage. A group of 23 subjects with two levels of CVI (severe and very severe with previous ulcerations) with an increased endothelial cell count (seen by microscopy) was studied and treated for 4 weeks with oral Venoruton (0-[beta-hydroxyethyl]-rutosides) (1 g/day) to evaluate the effects of treatment on the circulating endothelial cells in blood taken from a peripheral leg vein. The controls comprised two groups with comparable age and sex distribution, one of healthy individuals and one of CVI subjects. After 4 weeks, a significant decrease was noted in endothelial cells both in subjects with CVI and in those with very severe CVI with previous ulcerations. This study suggests that endothelial cells may play a significant role in venous disease, being both an indication of severe disease and a further problem in itself. The use of Venoruton appears to decrease the number of circulating endothelial cells. This suggests an important role of this compound in protecting the endothelium and offers new potentially important therapeutic options that are not limited only to venous disease.
Comparison of Pyrroloquinoline Quinone and/or Metoprolol on Myocardial Infarct Size and Mitochondrial Damage in a Rat Model of Ischemia/Reperfusion Injury
Authors: Zhu Bo-qing , Simonis Ursula , Cecchini Gary , Zhou Hui-zhong , Li Luyi , Teerlink John R. , Karliner Joel S.
Published: June 2007

The cardioprotective effectiveness of low-dose pyrroloquinoline quinone (PQQ, 3 mg/kg) was compared with metoprolol, a β1-selective adrenoceptor antagonist. Rats underwent 30 minutes of left anterior descending coronary artery occlusion and 2 hours of reperfusion. Metoprolol and/or PQQ were given at the onset of reperfusion to mimic clinical treatment. Metoprolol and/or PQQ reduced infarct size and protected against ischemia-induced left ventricular dysfunction after 2 hours of reper-fusion. Combined therapy augmented left ventricular developed pressure at the end of reperfusion. Metoprolol or PQQ alone enhanced mitochondrial respiratory ratios in ischemic and nonischemic myocardium. Although the PQQ/metoprolol combination therapy increased respiratory ratio values, the effects were small when compared with PQQ alone. Only PQQ decreased lipid peroxidation. Metoprolol and/or PQQ given at the onset of reperfusion reduce infarct size and improve cardiac function. Combination therapy further reduces infarct size. PQQ is superior to metoprolol in protecting mitochondria from ischemia/reperfusion oxidative damage
Statin-Induced Myopathy: The Two Faces of Janus
Authors: Arora Rohit , Liebo Max , Maldonado Frank
Published: June 2007

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have been shown to be effective at lowering low-density lipoprotein cholesterol and decreasing the risk of coronary heart disease. Although safe and well tolerated by most patients, statins have also been associated with muscle-related adverse events. This article reviews statin-associated myotoxicity to clarify the definitions of muscle-related adverse events and discusses their incidences in major statin trials, case reports, and review articles through January 2006. Milder complaints (ie, myalgia) are reported by approximately 5% to 7% of patients who take statins. More severe myotoxicity, namely rhabdomyolysis, is extremely rare for all statins save cerivastatin, and most recent estimates of its incidence are between 0.44 and 0.54 cases per 10 000 person-years. The mechanism of statin-associated myotoxicity has not been satisfactorily defined and is likely due to multiple factors, including membrane instability, mitochondrial dysfunction, and defects in myocyte duplication
Recording of High V1-V3 Precordial Leads May Be Essential to the Diagnosis of Brugada Syndrome During the Ajmaline Test
Authors: Teijeiro Rodrigo , Garro Hugo A. , Acunzo Rafael S. , Albino Ernesto , Chiale Pablo A.
Published: June 2007

Sodium channel-blocking agents are routinely used to unveil the Brugada syndrome in patients in whom the typical electrocardiographic pattern is absent or doubtful. In this article, the authors report a patient with syncopal episodes of unknown origin in whom the conventional electrocardiographic result was normal and a negligibly small “saddle back” type repolarization was present in lead V2 recorded 2 intercostal spaces above the conventional site. Intravenous ajmaline (50 mg) did not elicit the type 1 pattern of the Brugada syndrome in the precordial leads obtained at their usual level, but a clear-cut coved-type repolarization was apparent in high right precordial leads. These findings indicate that high precordial leads should be routinely recorded while assessing the ajmaline test in patients suspected of having the Brugada syndrome
Oxidative Stress in Renal Transplant Patients Who Develop Cardiovascular Disease
Authors: El-Ghar Suzan M.G.A. , Qureshi Mabood , Shoker Ahmed , Prasad Kailash
Published: June 2007

Cardiovascular disease limits life expectancy of successful renal transplant patients. Reactive oxygen species have been implicated in the development of atherosclerosis, and high levels could be due to increased production or a decrease in antioxidant reserve. Cardiovascular disease in renal transplant recipients could be due to elevated levels of malondialdehyde (an index of levels of reactive oxygen species) and homocysteine and reduced levels of glutathione. Renal transplant recipients with and without cardiovascular disease were studied along with healthy controls. Serum malondialdehyde, plasma homocysteine, and red blood cell glutathione were measured. The results suggest that levels of serum malondialdehyde and plasma homocysteine were higher in patients with or without cardiovascular disease compared with controls; however, the values were similar in both groups of transplant patients. Glutathione levels in red blood cells were similar in all 3 groups. Renal transplant recipients without cardiovascular disease have high levels of oxidative stress and may develop cardiovascular disease with time.
Ranolazine, an Inhibitor of the Late Sodium Channel Current, Reduces Postischemic Myocardial Dysfunction in the Rabbit
Authors: Hale Sharon L. , Kloner Robert A.
Published: June 2007

Ranolazine is a selective inhibitor of the late sodium current relative to peak sodium channel current, and via this mechanism, it may decrease sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces the frequency of angina attacks, but there is little information on its effects on myocardial stunning after short-term ischemia. The objective of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial stunning after ischemia/reperfusion in rabbits. Myocardial stunning was induced in rabbits by 15 minutes of coronary artery occlusion (CAO) followed by 3 hours reperfusion. Ten minutes before CAO, rabbits were randomly assigned to vehicle (n = 15) or ranolazine (2 mg/kg bolus plus 60 μg/kg/min infusion, IV, n = 15). Myocardial stunning was assessed by LV 2-dimensional echocardiography using, as a marker of severity, ischemic free-wall fractional thickening (FWft; systolic wall thickness – diastolic wall thickness/diastolic wall thickness). Regional ejection fraction (EF) was also assessed. During CAO, FWft was depressed in both groups, indicating an ischemic insult (FWft was reduced from 0.62 ± 0.05 at baseline to 0.10 ± 0.04 in vehicle and from 0.73 ± 0.05 to 0.26 ± 0.07 in ranolazine, P < 0.05, ranolazine vs vehicle). After reperfusion, previously ischemic myocardium remained stunned; however, FWft recovered significantly better in ranolazine (0.51 ± 0.05) than in vehicle (0.35 ± 0.04, P = .027). Baseline EF was 0.65 ± 0.02 in the ranolazine and 0.68 ± 0.02 in vehicle ( P = ns). During CAO, EF was reduced by 36% ± 6% in vehicle versus only 20% ± 6% in ranolazine ( P < .05). At the end of reperfusion, EF remained depressed in both groups, but the reduction in the vehicle group (25% ± 5%) was significantly worse than in ranolazine (9% ± 4%, P = .017). Improvement in function was independent of necrosis (negligible) or differences in hemodynamics (no differences between groups). Ranolazine treatment reduced myocardial stunning following brief ischemia/reperfusion suggesting that inhibiting the late sodium channel current may be a novel approach to treating stunning independent of effects on hemodynamics.
Effect of Atorvastatin on Type 2 Diabetic Dyslipidemia
Authors: Save Vipul , Patil Neela , Moulik Nivedita , Rajadhyaksha Girish
Published: June 2007

Hyperlipidemia is commonly observed in patients with type 2 diabetes and is an independent risk factor for cardiovascular disease. The authors tested the effect of atorvastatin (10 mg/d) on 110 hyperlipidemic type 2 diabetes patients with low-density lipoprotein cholesterol (LDL-C) levels exceeding 130 mg/d. The primary efficacy end point was the percentage change in LDL-C and high-density lipoprotein cholesterol (HDL-C), and secondary efficacy included the percentage change in apolipoproteins at weeks 6, 12, and 24. The tertiary goal was percentage change in free radical scavenger enzymes and oxidative stress. LDL-C was reduced by 25%, 39.3%, and 49.2%. A similar trend was observed in total cholesterol, triglyceride, non-HDL-C, and apolipoprotein (apo) B-100. HDL-C was raised by 3.2%, 6%, and 8.2%. A similar trend was seen in apo A-1. Copper zinc-superoxide dismutase and glutathione were raised significantly ( P < .001); however, changes in glutathione-S-transferase and glutathione peroxidase activities were nonsignificant. Malondialdehyde was decreased significantly ( P < .001). Atorvastatin improves the lipoprotein profile and oxidative status in patients with type 2 diabetes.
A Review of the Investigational Antiarrhythmic Agent Dronedarone
Authors: Tafreshi Mohammad J. , Rowles Joie
Published: June 2007

Arrhythmias are a major cause of morbidity and mortality, and atrial fibrillation is the most widespread disorder of cardiac rhythm. Amiodarone is an effective antiarrhythmic agent that has been in clinical use for about 20 years. It is effective for multiple types of arrhythmias, including atrial fibrillation, and has a low incidence of cardiac adverse events, including Torsade de Pointes. It has many noncardiac adverse effects that are serious and limit its long-term use. Dronedarone is an investigational antiarrhythmic agent that is designed to have similar cardiac effects to amiodarone but with fewer adverse effects. This review presents some of the animal and human studies that evaluate the effects of dronedarone.
Diminished Global Fibrinolytic Capacity in Patients With Mitral Valve Prolapse Is Associated With Transient Ischemic Attacks
Authors: Atalar Enver , Aqil Tayfun , Aytemir Kudret , Haznedarolu Ibrahim , Ozer Necla , Kiliq Harun , Kuru Gtilcan , Aksdyek Serdar , Ovtinq Kenan , Kes Sirri , Kirazli erafettin , Ozmen Ferhan
Published: June 2007

Although mitral valve prolapse (MVP) has shown to be associated with thromboembolic complications, the cause of thromboembolic events in those patients is still unknown. The purpose of this study was to evaluate the fibrinolytic activity in MVP patients. The study included 35 consecutive patients (25 women, mean age 25 ±11 years) with echocardiografically documented MVP and 25 age- and sex-matched subjects as a control group. Four of MVP patients have a history of transient ischemic attack (TIA). Global fibrinolytic capacity (GFC), a new technique that examines the effectiveness of the entire fibrinolytic system, was measured. Global fibrinolytic capacity was found to be nonsignificantly increased in MVP patients (3.14 ±1.42 μg/mL) compared to those in control subjects (2.36 ±1.33,ug/mL) (p>0.05). However, in four of these MVP patients who had a history of transient ischemic attack, the GFC level was significantly lower than in patients who have no history of transient ischemic attack (1.67 ± 0.6 μg/mL vs 3.27 ±1.46 (jtg/mL, p=0.003). Furthermore, the GFC levels of these four patients were less than those of controls (p=0.04). These results showed that global fibrinolytic activity was similar in MVP patients without a history of TIA and control subjects. However, MVP patients with a history of TIA had significantly decreased global fibrinolytic activity compared to controls and as well as MVP patients without a history of TIA.
Buerger's Disease and Anticardiolipin Antibodies: A Worse Prognosis?
Authors: de Godoy Jose Maria Pereira , Braile Domingo Marcolino , Godoy Moacir Fernandes
Published: June 2007

The case of a 26-year-old male chronic smoker is reported, who had thrombotic incidences on three occasions in both upper and lower limbs over a 10-month period. Laboratory examinations, including hematologic studies and creatinine, cholesterol, and glucose levels, were normal. However, IgG and IgM anticardiolipin antibodies were detected. Duplex ultrasonography confirmed deep venous thrombosis in both lower limbs (two occurrences) and computer tomography depicted an inferior cava vein thrombosis. The patient fulfilled all of Shionoya's criteria for Buerger's disease, thus suggesting an association between anticardiolipin antibodies and this disease.
Hemostatic Abnormalities Following Bone Marrow Transplantation
Authors: Tamaki Shigehisa , Wada Hideo , Ohfuzi Kazuya , Shibata Takeshi , Masuya Masahiro , Kageyama Shinichi , Gabazza Esteban C. , Kawakami Keiki , Tsuji Kohta , Miyanishi Eiki , Minami Nobuyuki , Nobori Tsutomu , Shikut Hiroshi
Published: June 2007

Hemostatic abnormalities in 26 patients following bone marrow transplantation (BMT) were examined. In the event-free survival group, the plasma levels of antithrombin (AT) and protein C (PC) were significantly decreased 1 and 2 weeks after BMT, and the plasma levels of thrombomodulin (TM) and tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPA-PAI-I complex) were significantly increased from 4 weeks to 13 weeks after BMT. Excepting AT, there was no significant difference in hemostatic parameters before BMT among the event-free survival, 6-month survival, and death within 6 months groups. On day 0 following BMT, only plasma AT levels were significantly lower in the 6-month survival group than in the death within 6 months group. From 1 to 3 weeks after BMT, plasma levels of AT or PC were significantly lower in the death within 6 months group than in the 6-month survival group. From 1 to 5 weeks after BMT, the plasma levels of TM and tissue type plasminogen activator-plasminogen activator inhibitor-I complex (tPA-PAI-I complex) were significantly higher in the 6-month survival group than in the death within 6 months group. From 1 to 13 weeks after BMT, the plasma levels of D-dimer or soluble fibrin monomer (SFM) were significantly higher in the death within 6 months group than in the 6-month survival group. There was no remarkable difference in plasma levels of thrombin-antithrombin comlex or plasmin-plasmin inhibitor complex following BMT between these groups of patients. These findings suggest that the decrease in the plasma AT or PC level reflects early occurrence of complications of prognostic significance and that the increase in vascular endothelial cell markers such as plasma levels of TM or tPA-PAI-I complex reflects occurrence of complications during the middle course of BMT. Plasma levels of D-dimer and SFM may be useful markers for predicting complications associated with poor prognosis after BMT.
Difference in Mortality After Hip Fracture is Associated with Postdischarge Prescription of Antithrombotic Prophylaxis: A Case-Control Study
Authors: Grion Anna Maria , Gallo Umberto , Bano Francesca , Ragazzi Michele , Cestrone Adriano , Orsini Arturo , Salomoni Marina , Gaion Rosa Maria , Pengot Vittorio
Published: June 2007

This study was undertaken to determine whether a prolongation of pharmaceutical antithrombotic prophylaxis beyond hospitalization for hip fracture is associated with a reduced mortality rate. One hundred seventy-nine cases with hip fracture (patients older than 50 years of age) admitted to local general hospitals in 1999 who received postdischarge prescription of any antithrombotic agent (heparin, oral anticoagulants, antiplatelet drugs) and 179 ageand sex-matched patients with hip fracture who did not were included. Postdischarge mortality was assessed at 90 days. Compared with patients who did not receive postdischarge prescription of antithrombotic agents, those who did had an odds ratio of 0.22 (95% confidence interval 0.08-0.59) for all causes of mortality. This result did not change after excluding nonvascular mortality (odds ratio, 0.17; confidence interval, 0.03-0.73; p=0.011). Patients admitted to the hospital for hip fracture are at high risk of death after discharge if they are not given antithrombotic treatment. To substantiate these data, ad hoc prospective randomized trials are needed.
Osteoblast Growth Inhibition by Unfractionated Heparin and by Low Molecular Weight Heparins: An in-vitro Investigation
Authors: Kock H. J. , Handschin A. E.
Published: June 2007

Osteoporosis is a rare but potentially severe complication under high-dose, long-term unfractionated heparin therapy. Low-molecular-weight heparins (LMWHs) have gained increased importance in antithrombotic therapy over the past decade. Whether this heterogeneous group of drugs carries a comparable risk of osteoporosis in long-term application is unknown. In a standardized in vitro model, the effects of 4 different low-molecular-weight heparins (nadroparin, enoxaparin, dalteparin, certoparin) on osteoblast growth were studied at the same dose (50,μg/mL). As control, the effect of unfractionated heparin (Liquemin) was tested on human osteoblasts in vitro at an equal dose. Human osteoblast cell cultures were incubated with equal doses of the heparins, and cell concentrations were measured after 48 and 96 hours. In addition, a fluorescence assay was performed to detect potential cytotoxic effect of heparins on bone cells. In comparison to control groups of non-incubated cell cultures, LMWHs caused a significant inhibition of osteoblast growth (p<0.05). Therefore, the risk of osteoporosis under long-term therapy with high doses of LMWHs cannot be excluded and should be further evaluated in clinical trials.
Association of Platelet-Derived Microparticles With C-C Chemokines on Vascular Complication in Patients With Acute Myocardial Infarction
Authors: Matsumoto Noriko , Nomura Shosaku , Kamihata Hiroshi , Kimura Yutaka , Iwasaka Toshiji
Published: June 2007

The levels of platelet-derived microparticles (PDMPs), platelet activation markers (P-selectin, CD63, and PAC-1 on activated platelets), and C-C chemokines (monocyte chemotactic peptide [MCP]-1 and regulated on activation normally T-cell expressed and secreted [RANTES] were measured and compared in patients with acute myocardial infarction (AMI) or stable pectoris angina. These substances are thought to participate in the development of complications in patients with AMI. The percentage binding of anti-P-selectin, CD63, and PAC-1 antibody to platelets, and the levels of PDMPs (per 104 platelets) were higher in the patients with AMI than in those with stable pectoris angina (P-selectin, 23.1% 2.1% vs. 10.3% 1.2%, p<0.001; CD63, 24.6% 3.3% vs. 11.2% 3.1%, p<0.01; PAC-1, 14.1% 1.7% vs. 9.3% 2.1%, p<0.05; PDMPs, 613 71 vs. 413 55, p<0.01). There were no differences in platelet levels of GPIIb/IIIa and GPIb between groups. Levels of MCP-1 and RANTES were higher in the patients with AMI than in patients with stable pectoris angina (MCP-1, 430 3 vs. 265 23, p<0.01; RANTES, 175 32 vs. 8829, p<0.001). The effects of percutaneous transluminal coronary angioplasty (PTCA) on the levels of these agents in patients with AMI were studied. Platelet activation markers were significantly decreased in patients with AMI after PTCA. RANTES level was also significantly decreased after treatment, but MCP-1 level was not changed. In addition, this tendency was clearer in STENT patients. These findings suggest that in patients with AMI PTCA, particularly STENT, may prevent the development of complications in which activated platelet and RANTES participate.
Tissue Factor and Thrombomodulin in Hemodialysis Patients: Associations with Endothelial Injury, Liver Disease, and Erythropoietin Therapy
Authors: Borawski Jacek , Naumnik Beata , Mysliwiec Michal
Published: June 2007

Patients receiving maintenance hemodialysis (HD) present with hemostatic abnormalities, which may be aggravated by comorbid conditions, especially liver disease. The factors that influence plasma levels of thrombomodulin (TM), an initiator of the anticoagulant protein C pathway, and those of tissue factor (TF), which triggers the extrinsic coagulation pathway, were assessed. In 63 HD patients, TM and TF levels were higher than those in healthy controls. In bivariate analysis, TF positively correlated with TM, and both were directly associated with the presence of viral hepatitis B or C marker, serum liver enzymes, use of erythropoietin therapy, hemoglobin levels, and duration of HD therapy, and inversely correlated with body mass index. TF was also positively associated with plasma von Willebrand factor (vWF) antigen, and inversely associated with activated partial thromboplastin time. In multivariate analysis, increased vWF, alanine aminotransferase, and use of erythropoietin independently predicted both TF and TM levels. HD patients with vWF and ALT levels lower than middle, and not treated with erythropoietin had normal TF but increased TM concentrations compared with levels in healthy controls. Increased plasma levels of TM and TF in patients on maintenance HD are surrogates of vascular endothelial injury. Liver disease and use of erythropoietin treatment are also important determinants of these markers, and should be considered in further studies.
Protein S Deficiency in Repetitive Superficial Thrombophlebitis
Authors: Godoy José Maria Pereira de , Braile Domingos Marcolino
Published: June 2007

Protein S deficiency is one of the principal congenital thrombophilias reported. The objective of this study was to assess the prevalence of protein S deficiency in patients with repetitive superficial thrombophlebitis. Thirty-six consecutive patients, 28 female and eight male, who presented with repetitive superficial thrombophlebitis (two or more cases); age range, 17 to 58 years, mean, 38.2 years; were evaluated. Coagulometry was used to determine the biologic activity of protein S. In 5.5% of the patients with repetitive superficial thrombophlebitis, protein S deficiency was detected.
Ineffectiveness of Measuring Routine Vital Signs in Adult Inpatients With Deep Venous Thrombosis
Authors: Potti Anil , Panwalkar Amit , Hebert Brian , Sholes Kaley , Jo Lewis Mary , Hanley James
Published: June 2007

The purpose of this study was to evaluate the benefit, if any, of routine monitoring of vital signs on clinical outcomes in hospitalized patients with deep venous thrombosis (DVT). One hundred forty-nine patients with DVT included in this study were categorized into two groups: those that underwent measurement of vital signs every 6 hours or those that had vital signs measured every 8 hours. Vital signs included pulse, blood pressure, respiratory rate, and temperature. Frequency of measurement of vital signs did not alter average length of stay; for patients with every-4-hours measurement, this was 5.16 days and was not statistically significant from patients with every-8-hours measurement, who stayed an average of 4.85 days (p = 0.507). Similarly, more frequent vital sign evaluation did not result in a statistically significant difference in survival, progression of disease, nor did it predict the disposition of the patient. These results suggest that present frequency of measurement of vital signs is not cost or time effective because they do not result in a favorable outcome, length of stay, or disposition. The study further serves to highlight the need for an individualized assessment of vital sign measurement, because this will also lead to a more efficient allocation of hospital resources.
Glanzmann's Thrombasthenia Proposed Optimal Management During Surgery and Delivery
Authors: Bell Julie-Anne , Savidge Geoffrey F.
Published: June 2007

Glanzmann's thrombasthenia (GT) is an autosomal recessive disorder of platelet function. Conventional management is by platelet transfusion, given before invasive interventions. Alloimmunization resulting in platelet refractoriness and an unpredictable response to platelet infusion have provided particular management difficulties in the past. More recently recombinant (r)VIIa (Novoseven) has a valuable role in the treatment of platelet function disorders. Treatment of a patient with GT during two pregnancies and spinal surgery is reported. An algorithm is presented to provide a structured and consistent approach to treatment.
Prevention of Thromboembolism with Low-Molecular-Weight Heparin in Orthopedic Surgery: A 5-Year Experience
Authors: Wenzl M. E. , Hasse W. , Seide K. , Wolter D.
Published: June 2007

A regimen of prophylaxis of thromboembolism with low molecular weight heparin (LMWH) and unfractionated heparin (UFH) in orthopedic surgery is presented. Over a 5-year period, 11,905 patients have been operated in all fields of orthopedic surgery in a big trauma center. In 498 cases, deep vein thrombosis (DVT) was clinically suspected and phlebography was performed: 122 patients had confirmed DVT (rate 0.98%); 59.8% of the DVT were limited to the calf. Nineteen pulmonary embolisms (rate 0.16%) were diagnosed (3 lethal). Heparin-induced thrombocytopenia type II was diagnosed in 12 of 122 patients. Only one of these had received LMWH. The related rates of DVT were highest for tibial head fractures (12.4%), total knee replacement (6.7%), and multiple trauma (6.4%). The extent of DVT was most severe in multiple trauma. The results proved the regimen to be of good clinical use and showed that more attention has to be paid to fractures, especially of the knee; and to patients with multiple injuries.
Venous Thrombosis Among Patients with AIDS
Authors: Majluf-Cruz Abraham , Silva-Estrada Mara , Sánchez-Barboza Rita , Montiel-Manzano Guadalupe , Treviño-Pérez Sandra , Santoscoy-Gómez Mario , de Chávez-Ochoa Adriana Ruiz , la Penña Norma Corona-de , Nieto-Cisneros Leopoldo
Published: June 2007

Thrombosis has been considered an uncommon complication in patients with AIDS. In a 42-month period, 28 adult male homosexuals with AIDS experienced 34 thrombotic events. All but three received HAART regimen, two a successful round of double nucleoside analog therapy, and one patient received no treatment. Median age of group was 38.5 years (range, 24 to 56 years). Median time from HIV infection to thrombosis was 40.5 months (range, 3 to 108 months). No patient had previous thrombosis, family history of thrombosis, or prothrombotic conditions. There were 31 deep vein thromboses, two pulmonary thromboembolisms, and one renal vein thrombosis. Six patients had two thrombotic events. The rate of thrombosis during the 42-month study period was 1.52% (cumulative incidence = 0.30%/year), while the rate of thrombosis in 600 patients before the era of protease inhibitor therapy was 0.33% (cumulative incidence approximately 0.055%/year) (p < 0.001). Due to high incidence of thrombotic recurrences and hemorrhagic complications while using oral anticoagulants, acetylsalicylic acid was initiated; no thrombotic episodes were recorded while using this drug. Protein C and protein S deficiency were found in nine and two patients, respectively. Two patients had lupus anticoagulant and two activated protein C resistance (APCR) without FV Leiden mutation (APCR test was negative after initial screening). Fifteen patients had no thrombophilic abnormalities. These data suggest that protease inhibitors could be a risk factor for venous thrombosis not due to thrombophilic abnormalities but likely related to abnormalities in platelets or endothelium.
Anti-beta2-Glycoprotein I Antibody and Hypertension in Cerebral Ischemia
Authors: Chen Wei Hsi
Published: June 2007

Hypertension is known as a cause of endothelial cell damage and it activates humoral immunity. Therefore, it may modulate the anti-beta2-glycoprotein I antibody (aβGPI) to commit for thrombosis. To elucidate the relation between aβGPI and hypertension in cerebral ischemia, the blood aβGPI level was examined in healthy subjects, hypertensive subjects, and patients with cerebral ischemia with and without hypertension, respectively. The results showed that the blood aβGPI level increased in cerebral ischemia patients with hypertension rather than hypertensive subjects, and patients without hypertension rather than healthy individuals. However, the blood aβGPI level showed no difference between healthy individuals and hypertensive subjects, nor cerebral ischemia patients with and without hypertension. The serum globulin level did not change among them. Therefore, aβGPI displays a vital role for cerebral ischemia in both hypertensive and normotensive subjects. An activation of humoral immunity involving aβGPI warrants further investigation in cerebral ischemia.
A Large Deletion due to a New Mutation (Intron 13/Exon 23) in a Sporadic Case of Severe Hemophilia A
Authors: Lombardi Anna Maria , Cabrio Laura , Zanon Ezio , Sartori Maria Teresa , Navaglia Filippo , Plebani Mario , Girolami Antonio
Published: June 2007

A case of sporadic hemophilia A in a young child was investigated from a molecular biology point of view. The propositus is a 4-year-old severe hemophiliac who was first seen when he was 2 years old. At that time, easy bruising and hematomas were noted because of accidental falls while toddling. The coagulation study showeda prolonged partial thromboplastin time and a factor VIII level of 1.3% of normal. Molecular biologic analysis showed a large deletion involving intron 13 up to exon 23. In the inversion study, the propositus exhibited only a 10 kb band, and this result suggests that intron 22 was deleted while his mother shows a normal pattern. To further examine the length of the deletion, a long polymerase chain reaction by means of primers amplifying the region from exon 13 to 23. In the index patient, an approximate 13-kb product was obtained, whereas no product was obtained from his mother. The mother investigated by means of polymorphism was shown not to be a carrier.
Long-term Behavior of Endothelial and Coagulation Markers in Eisenmenger Syndrome
Authors: Caramuru Lúcia H. , Lopes Antonio Augusto , Maeda Nair Y. , Aiello Vera D. , Filho Cyrillo Cavalheiro
Published: June 2007

The long-term behavior of endothelial markers was studied in patients with Eisenmenger syndrome who were subjected to conventional therapy (no vasodilators) and observed for 18 months. Biochemical markers were analyzed comparatively in patients with class II or III symptoms (group 1, n=10) and patients with class IV symptoms (group 2, n=7). Plasma von Willebrand factor antigen (vWF: Ag), thrombomodulin, tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1), and D-dimer were determined by immunoenzymatic assay at baseline, and at 6, 12, and 18 months. At baseline, the main clinical difference between groups was a decreased peripheral oxygen saturation in group 2 versus group 1 (77±5% and 86±4%, respectively, p=0.001). Basal vWF: Ag and t-PA were increased and thrombomodulin was decreased in both groups in comparison with controls (p<0.0001), while D-dimer was increased in group 2 only (p=0.0003). In response to treatment, there was a decrease in vWF: Ag in both groups (19% and 23%, respectively in groups 1 and 2, at 18 months vs. baseline, p<0.0001) and t-PA in group 1 (38% vs. baseline, p=0.0485). Plasma vWF: Ag tended to be higher in group 2 in comparison with group 1 during the whole follow-up. Levels of PAI-1 greater than 38.4 ng/mL (upper 90% limit for normals) and D-dimer greater than 500 ng/mL were detected in individual patients (both groups) during the follow-up period. Thrombomodulin remained decreased in both groups. Thus, severity of symptoms in the Eisenmenger syndrome appears to correlate with low oxygen saturation and higher vWF: Ag levels. Improvement of endothelial dysfunction may occur in response to treatment, although increased risk for thrombosis persists, in view of residual abnormalities.
Fibrinogen Seoul (FGG Ala341Asp): A Novel Mutation Associated With Hypodysfibrinogenemia
Authors: Song Kyung Soon , Park Noh Jin , Choi Jong Rak , Doh Hyun Joo , Chung Kwang Hoe
Published: June 2007

Dysfibrinogenemia is a coagulation disorder caused by a variety of structural abnormalities in the fibrinogen molecule that result in fibrinogen function. The molecular basis of hypodysfibrinogenemia was investigated in a 66-year-old woman with peripheral artery obstructive disease and in her family members. Plasma level of functional fibrinogen determined using the Clauss method was lower (75 mg/dL; normal, 140–460 mg/dL) than that measured with immunologic nephelometric assay (137 mg/dL; normal, 180–400 mg/dL). Similar results were also observed in two family members through two generations. DNA was extracted from whole blood, and the coding regions and intron/exon boundaries of gamma chain gene (FGG) were amplified. A novel (Fibrinogen Seoul) heterozygous FGG mutation (GCT->GAT, Ala341Asp) was identified in all three affected family members. Thrombin-catalyzed polymerization was found to be defective on the analysis of purified fibinogen from the propositus. Molecular modeling also showed a conformational change of fibrinogen structure.
Modulatory Effects of Escherichia coli Capsular–Derived Sulfaminoheparosans and Heparins on Tissue Factor–Mediated Activation of Platelets: Flow Cytometric Analysis
Authors: Maddineni Jyothi , Jeske Walter P. , Baltasar Francis , Cornelli Umberto , Manoni Marco , Hoppensteadt Debra A. , Fareed Jawed
Published: June 2007

Sulfaminoheparosans (alternatively known as bioheparins) represent sulfated derivatives obtained from the K5 capsular polysaccharide of Escherichia coli. Previous studies have shown that these agents are structurally comparable to heparins and capable of exerting anticoagulant and antiprotease effects like heparins. Furthermore they are also able to release tissue factor pathway inhibitor (TFPI). Tissue factor (TF) plays a vital role in the pathogenesis of thrombotic and cardiovascular disorders. Anticoagulants such as heparins and bioheparins inhibit this thrombogenic mediator and thereby downregulate the activation of prothrombin and factor X. This study was carried out to determine the effects of several bioheparin fractions and heparins on TF-mediated platelet activation and their direct effect on platelets using human whole blood flow cytometry. Four different sulfaminoheparosan fractions with mean molecular weights of 20, 9, 7, and 6 kDa were tested for their inhibitory effects on platelet activation at two different concentrations (100 and 10 µg/mL). Unfractionated heparin and a low-molecular-weight heparin, tinzaparin, were also tested under the same experimental conditions for comparative modulatory responses. Fresh whole blood from healthy female and male volunteers (n = 5) was mixed with each of these agents and incubated with TF (diluted thromboplastin C) to activate platelets. Platelets were labeled with the antibodies CD61 FITC (GP IIIa) and CD62 PE (P-selectin). The data were analyzed in terms of percent platelet aggregation and platelet P-selectin expression. At 100 µg/mL, all of these agents strongly and significantly inhibited (approximately 40%) the platelet activation induced by TF in comparison to saline control. The inhibitory effects of each of these agents were slightly weaker (approximately 24% inhibition) at 10 µg/mL. The inhibitory effects of these agents on P-selectin expression correspond to their effects on platelet aggregation. At 100 µg/mL all the agents produced greater than 80% inhibition of P-selectin expression whereas at 10 µg/mL, the inhibition is greater than 70% except for bio-20 kDa, which produced less than 50% of inhibition. No molecular weight dependence was observed with bioheparin fractions in terms of inhibitory effects on platelet aggregation or P-selectin expression. None of the bioheparins and heparins exhibited any direct effects on platelets. These observations suggest that both the bioheparins and heparins are capable of inhibiting TF-mediated activation of platelets. Thus the therapeutic effects of bioheparins in the TF-mediated pathogenesis of platelet activation may be similar to those of heparins.
Stromelysin-1 5A/6A and eNOS T-786C Polymorphisms, MTHFR C677T and A1298C Mutations, and Cigarette-Cannabis Smoking: A Pilot, Hypothesis-Generating Study of Gene-Environment Pathophysiological Associations With Buerger’s Disease
Authors: Glueck Charles J. , Haque Mofiz , Winarska Magdalena , Dharashivkar Swapna , Fontaine Robert N. , Zhu Binghua , Wang Ping
Published: June 2007

Buerger’s disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American), compared to 21 age-gender-race matched healthy controls, 5A/6A stromelysin- 1 homozygosity was present in 7 of 21 (33%) BD cases versus 5 of 21 (24%) controls (risk ratio 1.4; 95% confidence interval [CI] 0.5-3.7), and eNOS T-786C homozygosity was present in 3 of 21 (14%) BD cases versus 1 of 21 (5%) controls (risk ratio 3.0; 95% CI 0.3-26.6). C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity was present in 7 of 21 cases (33%) versus 11 of 21 controls (52%) (risk ratio 0.6; 95% CI 0.3-1.3). In 18 patients who stopped and 3 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, superficial phlebitis, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In 15 patients, to increase vasodilatory NO via endothelial NO synthase, l-arginine (15 g/day) was given, along with folic acid (5 mg), vitamin B6 (100 mg), and B12 (2000 mg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months receiving l-arginine-folic acid, 11 of 15 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo/heterozygous for stromelysin-1 5A/6A and eNOS T-786C mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by l-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts.