bluuebunny/crossref_metadata_2025 huggingface dataset:
Ximelagatran: A New Antithrombotic Option in Atrial Fibrillation
Authors: Dager William E.
Published: March 2006

Treatment strategies in patients with atrial fibrillation typically involve pharmacologic or interventional invasive therapies to suppress the rhythm, control ventricular contraction rates, or prevent thromboembolic complications. Current therapies used for rhythm conversion in atrial fibrillation may have undesirable risks or side effects that limit this approach. Lifelong anticoagulation may be necessary to prevent the formation of thrombus in the left atrial chamber that can travel into the cerebral circulation to cause a stroke. Currently, warfarin is the most commonly prescribed anticoagulant for this purpose. Unfortunately, many patients with atrial fibrillation may not receive warfarin because of the difficulties in dosing and maintaining desirable target goals. The oral direct thrombin inhibitor ximelagatran has several pharmacologic properties that provide a unique and potentially desirable treatment option. Clinical studies have demonstrated that ximelagatran, administered in twice-daily doses of 36 mg, is non-inferior to warfarin for thromboprophylaxis against stroke or systemic embolism in atrial fibrillation. The pharmacology of ximelagatran and clinical trials with its use in atrial fibrillation is reviewed.
Microvascular Alterations After Temporary Coronary Artery Occlusion: The No-Reflow Phenomenon
Authors: Reffemann Thorsten , Kloner Robert A.
Published: March 2006

In experimental models of temporary coronary artery occlusion, tissue perfusion at the microvascular level remains incomplete even after patency of the infarct-related epicardial coronary artery is established, and distinct perfusion defects develop within the risk zone. This no-reflow phenomenon can be regarded as a basic cardiac response to ischemia-reperfusion. Perfusion defects observed in the clinical realm after reperfusion therapy for myocardial infarction may substantially be related to this mechanism in addition to microembolization and activation of platelets, as suggested in several recent studies. A major determinant of the amount of no-reflow seems to be infarct size itself. Reperfusion-related expansion of noreflow zones occurs within the first hours after the reopening of the coronary artery with a parallel reduction of regional myocardial flow, resulting in a potential therapeutic window. With various cardioprotective interventions, a close correlation between the size of the anatomic no-reflow and necrosis is a reproducible feature, which suggests a causal link between both entities of ischemic cardiac damage. Although vasodilating interventions failed to uncouple no-reflow zones from necrosis, the steps in the causal chain between microvascular and myocardial damage remain to be identified. On a long-term basis, tissue perfusion after ischemia-reperfusion remains markedly compromised for at least 4 weeks. Recent morphometric cardiac analyses suggested that the level of tissue perfusion after 4 weeks is a significant predictor of various indices of infarct healing, such as scar thickness, and infarct expansion index. As a consequence, improving tissue perfusion might concomitantly improve the healing process, which may provide the pathoanatomic basis for prognostic implications of no-reflow.
Effect of Nesiritide on Length of Hospital Stay in Patients with Decompensated Heart Failure
Authors: Chang Richard , Elatre Wafaa A. , Heywood J. Thomas
Published: March 2006

We examined the effect of nesiritide, administered as initial therapy, on length of hospital stay (LOS) and renal function through a retrospective analysis of 129 consecutive admissions to the coronary care unit in 98 patients diagnosed with congestive heart failure. Nesiritide was infused during 58 admissions (nesiritide group) while other therapies, not including nesiritide, were used during 71 admissions (non-nesiritide group). Although the nesiritide group showed lower baseline left ventricular ejection fraction and systolic blood pressure, higher serum creatinine, and a longer QRS interval, the LOS of this group was significantly shorter compared to the non-nesiritide group (3.91 ± 1.3 vs 4.77 ± 1.7 days, P = .0023). Both groups were similar with respect to body weight change (negative fluid balance), a slight decrease in blood urea nitrogen, and unchanged serum creatinine. Nesiritide as an initial therapy for treatment of congestive heart failure results in a more rapid hospital discharge without compromising renal function.
C-Reactive Protein Increases Oxygen Radical Generation by Neutrophils
Authors: Prasad Kailash
Published: March 2006

C-reactive protein (CRP) has been suggested to play a role in the pathogenesis of atherosclerosis. Neutrophil respiratory burst and levels of CRP are increased during infection. The increase in the neutrophil respiratory burst may be due to factors that are elevated in infection, such as cytokines, tumor necrosis factor, platelet-activating factor, and CRP. The direct effect of CRP on the release of oxygen radicals by neutrophils is not known. This investigation was made to determine if CRP affects the generation of oxygen radicals by neutrophils and if this effect is blocked by antioxidants. The effect of various concentrations (1 to 200 µg/mL blood) of CRP on the generation of oxygen radicals by neutrophils was measured as luminol-dependent chemiluminescence (chemiluminescent activity) on a luminometer (Auto Lumat LB953, EG & G Berthold, Gaithersburg, MD). The unit of chemiluminescent activity is the relative light unit and was expressed as relative light unit/white blood cell (RLU/WBC). Chemiluminescent activity of blood without CRP was slightly higher than that of buffer with or without CRP. CRP markedly increased the chemiluminescent activity of blood. There was no significant change in the chemiluminescent activity of WBCs with 1 µg/mL of CRP. The chemiluminescent activity increased significantly with higher concentrations of CRP. The percent increases in the chemiluminescent activity with 2, 5, 10, 25, 50, 100 and 200 µg/mL of CRP were 45%, 72%, 50%, 70%, 52%, 67%, and 68% respectively. Antioxidants (superoxide dismutase, catalase, and dimethylthiourea) blocked CRP-induced oxygen radicals by WBCs. These results suggest that CRP increases the generation of oxygen radicals from the WBCs. CRP-induced atherosclerosis may be mediated through generation of oxygen radicals by neutrophils.
Aortic Dissection: A Dreaded Disease with Many Faces
Authors: Kasher John Afshin , El-Bialy Adel , Balingit Peter
Published: March 2006

Aortic dissection is a relatively uncommon but catastrophic illness classically thought to present with acute, sharp, chest pain with radiation to the back. However, aortic dissection can manifest in a number of different ways that include congestive heart failure, inferior myocardial infarction, stroke, focal pulse and neurologic deficits, abdominal pain, or acute renal failure. According to some studies, only about 80% of patients with type A dissection present with severe anterior chest pain, and only about 60% describe their pain as being sharp. Another series reports that treating clinicians fail to initially entertain the diagnosis of aortic dissection in up to 35% of cases. Many patients later found to have aortic dissection are initially suspected to have other conditions such as acute coronary syndrome, pericarditis, pulmonary embolism, or even cholecystitis. In this article we present a case of an unusual presentation of aortic dissection and a review of this condition.
Intravenous Nitroglycerin in the Treatment of Decompensated Heart Failure: Potential Benefits and Limitations
Authors: Elkayam Uri , Bitar Fahed , Akhter Mohammed W. , Khan Salman , Patrus Saber , Derakhshani Mahyar
Published: March 2006

Acute decompensated heart failure (ADHF) is a common cause of hospitalizations. Intravenous nitroglycerin is widely used in the treatment of this condition. The use of this drug is based on its nitric oxide-mediated vasodilatory effect, which can lead to beneficial hemodynamic effects as well as improvement of myocardial ischemia and reduction of mitral regurgitation. However, information regarding the use of nitroglycerin for ADHF is limited to mostly hemodynamic evaluations in small groups of patients without cardiovascular outcome data. A single randomized, placebo controlled study that evaluated commonly used doses of nitroglycerin in patients with ADHF was disappointing and failed to show a significant hemodynamic effect or improvement of symptoms compared with placebo. The potential benefit of nitroglycerin seems to be limited by a decreased vasodilatory response in patients with heart failure, which requires an active titration of the drug and the use of high doses (>120 µg/min). In addition, the initial beneficial hemodynamic effect achieved with the appropriate dose of nitroglycerin is associated with neurohumoral activation and limited by an early development of nitrate tolerance that leads to a marked attenuation of the initial effect. More information obtained in large-scale studies that are appropriately designed to evaluate the effect of variable doses of nitroglycerin on short- and long-term cardiovascular outcome, with and without interventions shown to prevent nitrate tolerance, is needed before intravenous nitroglycerin can be recommended as a standard therapy for ADHF.
β-Adrenergic Blockers in Heart Failure: Review of Mechanisms of Action and Clinical Outcomes
Authors: Satwani Shiyam , Dec G. William , Narula Jagat
Published: March 2006

Better understanding of the pathophysiology of heart failure has shifted the treatment of heart failure away from enhancing myocardial contractility to a new paradigm that targets the root cause of disease progression by blocking the adverse effects of excessive neurohormonal activation. β-Adrenergic receptor-blockers have emerged as a cornerstone in the management of symptomatic heart failure. This article reviews the normal functioning of the β-adrenergic pathway, the consequences of hyperadrenergism on this crucial signaling pathway, and the mechanisms by which chronic β-blocker therapy reverses these abnormalities. The clinical evidence from controlled trials of the efficacy of β-blockers in treating heart failure is summarized. Finally, the concomitant use of β-blockers and positive inotropic agents in advanced heart failure is discussed.
Lipid-Lowering Therapy in Patients with Peripheral Arterial Disease
Authors: Ebrahimi Ramin , Saleh Jahandar R. , Toggart Edward J. , Hayatdavoudi Baubac , Wolf Christopher J. , Wadhani Nitin N. , Shah Atman P.
Published: March 2006

Peripheral arterial disease (PAD) is a prevalent, chronic, and progressive atherosclerotic disease process involving the conduit vessels of the extremities. Most patients who present with objective signs of PAD are asymptomatic. These patients are at an increased risk of dying from cardiovascular events. Lipid management is the mainstay of risk-factor modification for patients with cardiovascular disease. Some evidence suggests that hypocholesterolemic drugs may halt the progression of atherosclerotic peripheral vascular disease. More recently, treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors have demonstrated improved function in patients with symptomatic peripheral vascular disease. This paper reviews the role of lipid therapy in patients with peripheral arterial disease with focus on functional improvement and symptomatic relief based on the available data.
Smoking Increases Inflammation and Metalloproteinase Expression in Human Carotid Atherosclerotic Plaques
Authors: Kangavari Simon , Matetzky Shlomo , Shah Prediman K. , Yano Juliana , Chyu Kuang-Yuh , Fishbein Michael C. , Cercek Bojan
Published: March 2006

Objectives: To evaluate the effects of cigarette smoking on the composition of human carotid endarterectomy plaques.

Background: Smoking has been recognized as a major risk factor in atherogenesis. It is believed that smoking contributes to the atherosclerotic process and plaque instability in part by increasing the adherence of macrophages to the vessel wall and inducing the release of proteolytic enzymes. However, data are lacking in humans.

Methods: Carotid endarterectomy specimens of 21 smokers and 21 nonsmokers matched for age, gender, and symptoms were immunohistochemically stained with antibodies against CD68 (macrophages [MAC]), macrophage-derived metalloelastase (MMP-12), and tissue inhibitor of metalloproteinase 1 (TIMP-1). Sections were also evaluated for elastin content by van Gieson staining. The stained areas were planimetrically quantified as the percentage of immunopositive tissue area of the total tissue area.

Results: Smoking was associated with increased macrophage immunoreactivity (9.1% ± 7.4% vs 3.4% ± 2.9%; P = .003) as well as increased expression of MMP-12 (13.4% ± 6.7% vs 5.5% ± 3.5%; P = .0004). However, plaques from smokers had decreased TIMP-1 expression (7.7% ± 5.7% vs 13.1% ± 8.5%; P = .04) and decreased elastin content (26.9% ± 14.5% vs 38.9% ± 18.4%; P = .02).

Conclusions: This study demonstrates that cigarette smoking increases markers of inflammation and tissue destruction in atherosclerotic plaques. This change in plaque composition may at least in part explain the effect of smoking on the instability of human atherosclerotic plaques.
Hyperhomocysteinemic Diabetic Cardiomyopathy: Oxidative Stress, Remodeling, and Endothelial-Myocyte Uncoupling
Authors: Tyagi Suresh C. , Rodriguez Walter , Patel Anuj M. , Roberts Andrew M. , Falcone Jeff C. , Passmore John C. , Fleming John T. , Joshua Irving G.
Published: March 2006

Accumulation of oxidized-matrix (fibrosis) between the endothelium (the endothelial cells embedded among the myocytes) and cardiomyocytes is a hallmark of diabetes mellitus and causes diastolic impairment. In diabetes mellitus, elevated levels of homocysteine activate matrix metalloproteinase and disconnect the endothelium from myocytes. Extracellular matrix functionally links the endothelium to the cardiomyocyte and is important for their synchronization. However, in diabetes mellitus, a disconnection is caused by activated metalloproteinase, with subsequent accumulation of oxidized matrix between the endothelium and myocyte. This contributes to endothelial-myocyte uncoupling and leads to impaired diastolic relaxation of the heart in diabetes mellitus. Elevated levels of homocysteine in diabetes are attributed to impaired homocysteine metabolism by glucose and insulin and decreased renal clearance. Homocysteine induces oxidative stress and is inversely related to the expression of peroxisome proliferators activated receptor (PPAR). Several lines of evidence suggest that ablation of the matrix metalloproteinase (MMP-9) gene ameliorates the endothelial-myocyte uncoupling in diabetes mellitus. Homocysteine competes for, and decreases the PPARγ activity. In diabetes mellitus, endothelial-myocyte uncoupling is associated with matrix metalloproteinase activation and decreased PPARγ activity. The purpose of this review is to discuss the role of endothelial-myocyte uncoupling in diabetes mellitus and increased levels of homocysteine, causing activation of latent metalloproteinases, decreased levels of thioredoxin and peroxiredoxin, and cardiac tissue inhibitor of metalloproteinase (CIMP) in response to antagonizing PPARγ.
Emerging Role of Direct Thrombin Inhibitors in Nonvalvular Atrial Fibrillation: Potential and Peril
Authors: Kim Harold J. , Arora Rohit
Published: March 2006

Ximelagatran, an emerging new direct, oral, fixed-dose thrombin inhibitor may offer an attractive alternate to warfarin for patients with nonvalvular atrial fibrillation. The lack of drug-to-drug interactions and need for coagulation monitoring parameters such as international normalized ratio and a short half-life make therapeutic control and withdrawal in the event of bleeding easier. The side-effect profile, including elevation of liver enzymes, may temper the clinical utility of long-term use ximelagatran.
Trends in the Care of Patients With Acute Myocardial Infarction at a University-Affiliated Veterans Afffairs Medical Center
Authors: Bansal Darpan , Gaddam Venkat , Aude Y. Wady , Bissett Joe , Fahdi Ibrahim , Garza Luis , Joseph Jacob , Molavi Behzad , Pai B. V. , Sinha Anjan , Smith Eugene S. , Mehta J. L.
Published: March 2006

Background: Acute cardiac care of the veterans at Veterans Administration (VA) hospitals has been thought of as poor in quality. We examined the use of life-saving, evidence-based medical therapy in patients admitted with acute myocardial infarction to the University of Arkansas for Medical Sciences-affiliated VA Medical Center in Little Rock and compared the use of this therapy with other hospitals in Arkansas and in the rest of the nation.

Methods: Use of life-saving medical therapy in 117 patients admitted with acute myocardial infarction from January 2002 to December 2002 was compared with the National Registry of Myocardial Infarction database for the identical period.

Results: Heparin/low-molecular-weight heparin and glycoprotein IIb/IIIa inhibitors were used in 88% and 66% of patients, respectively. Aspirin, β adrenergic-blocking agents, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) were used in 92%, 93%, 62%, and 79% of the patients, respectively. The use of these therapies was better than in similar patients in Arkansas ( P < .001) and the United States as a whole ( P < .01). Calcium-channel blockers were used in 16% of the patients. At a mean follow-up period of 1.5 years, use of β blockers and aspirin had decreased, whereas the use of statins and ACE inhibitors/ARBs was unchanged.

Conclusion: This study shows that patients with acute myocardial infarction admitted to this university-affiliated VA Medical Center receive evidence-based life-saving medical therapy more often than in the rest Arkansas or in the entire United States. More important, patients at this federal institution continue to receive life-saving medical therapy during follow-up. Better use of evidence-based therapy may be related to affiliation of this VA Medical Center with a teaching institution where board certified cardiologists are involved in short- and long-term care of these patients.
Evaluation of Methods for the Measurement of Low-Density Lipoprotein Cholesterol
Authors: Bairaktari Eleni T. , Seferiadis Konstantin I. , Elisaf Moses S.
Published: March 2006

A high concentration of low-density lipoprotein cholesterol (LDL-C) in plasma is one of the strongest risk factors for atherosclerotic cardiovascular disease and mortality. The most common approach to determining LDL-C in the clinical laboratory is the Friedewald calculation. There is an increased interest to improve the accuracy of LDL-C estimated by this equation. The expert panel convened by National Cholesterol Education Program has recommended the development of accurate direct methods to measure LDL-C. Several homogeneous and fully automated methods have been introduced in recent years that show improved precision and accuracy over earlier methods, especially the Friedewald calculation. Each of the atherogenic particles in plasma—very-low, intermediate-, and low-density lipoprotein—as well as lipoprotein (a), contain one molecule of apolipoprotein B (apoB) and thus, plasma total concentration of apoB reflects the number of atherogenic particles. Several studies suggested that the measurement of apoB could improve the prediction of risk of coronary artery disease. Thus, in addition to the newly developed direct assays, alternative calculation procedures have been proposed that also take into consideration total serum apoB concentration for the estimation of LDL-C and the presence of small, dense LDL particles. The new generation of homogenous methods for the measurement of LDL-C and the use of serum apoB concentration for the estimation of LDL-C can contribute to the accurate LDL-C determination.
Administration of Vascular Endothelial Growth Factor Adjunctive to Fetal Cardiomyocyte Transplantation and Improvement of Cardiac Function in the Rat Model
Authors: Schuh Alexander , Breuer Sebastian , Al Dashti Raja , Sulemanjee Nasir , Hanrath Peter , Weber Christian , Uretsky Barry F. , Schwarz Ernst R.
Published: March 2006

Background: The functional impact of cellular transplantation and the potential role of the addition of angiogenic factors for survival of engrafts remain controversial.

Methods: Vascular endothelial growth factor (VEGF) (25 ng/mL) was added to cultured fetal cardiomyocytes labeled with bromodeoxyuridine (BrDU), which was injected into the border zones of myocardial infarction 4 weeks after coronary occlusion in rat hearts. Group 1 (n = 12) received cells plus VEGF protein (100 ng), group 2 (n = 12) received cells without VEGF, group 3 (n = 10) received VEGF without cells, and group 4 (n = 12) received pure culture medium. Cardiac function was then assessed by transthoracic two-dimensional echocardiography and Langendorff perfusion system. In situ hybridization for Y chromosomes of transplanted cells, detection of BrDU-labeled cells, and platelet/endothelial cell adhesion molecule-1 (PECAM-1) staining for endothelial cells was performed.

Results: Echocardiography revealed smaller end-diastolic left ventricular dimensions in transplanted hearts in group 1 (0.83 ± 0.13 cm 4 weeks after coronary occlusion before transplantation and 0.69 ± 0.14 cm 2 months after transplantation, P < .05) and in group 2 (0.88 ± 0.09 cm after coronary occlusion before transplantation and 0.76 ± 0.08 cm 2 months after transplant), and increases in fractional shortening (34.2% ± 8.53% before transplant and 45.3% ± 10.9% after [ P < .05] in group 1; 26.9% ± 6.02% before transplant and 37.15% ± 8.08% after [ P < .005] in group 2), whereas groups 3 and 4 showed a decrease in fractional shortening. Transplanted hearts developed higher pressures at rest (group 1, 96.8 ± 20.8 mm Hg; group 2, 98.6 ± 21.9 mm Hg) compared with controls (group 4, 70.9 ± 25 mm Hg) ( P < .05) and during inotropic stimulation (group 1, 111 ± 19.5 mm Hg and group 2, 113.3 ± 32.6 vs group 4, 80.7 ± 31.6 mm Hg, P < .05). Histologic analysis demonstrated the presence of transplanted cells in border zones of infarcted host myocardium with neovascularization in all transplanted hearts.

Conclusion: Transplantation of fetal cardiomyocytes results in improvement of left ventricular function. The addition of VEGF does not contribute to further improvement of left ventricular function and angiogenesis in the present model.
The Influence of Extracellular Acidosis on the Effect of IKr Blockers
Authors: Lin Congrong , Ke Xiaogang , Cvetanovic Ivana , Ranade Vasant , Somberg John
Published: March 2006

Background: Myocardial infarction causes the acidification of the cellular environment and the resultant acidosis maybe arrhythmogenic. The effect of acidosis on the action of antiar-rhythmic drugs, an important issue in the antiarrhythmic drug therapy after myocardial infarction, remains to be studied.

Methods: To evaluate the effect of acidosis on rectifier potassium current (Ikr) blockers, the human ether-a-go-go-related gene (HERG), which encodes IKr, was expressed in Xenopus laevis oocytes. The two electrodes voltage clamp technique was used and the experiments were performed at room temperature.

Results: Quinidine (10 µM) inhibited HERG tail current by 37% ± 5% at pH7.4. The block decreased to 5% ± 2% with extracellular pH at 6.2. Dofetilide (0.3 µM) inhibited HERG tail current by 34% ± 3% and 1% ± 2% at extracellular pH 7.4 and 6.2, respectively. Azimilide (10 µM) inhibited HERG tail current by 59% ± 3% and 17% ± 3% at extracellular pH 7.4 and 6.2. There were significant differences in the HERG inhibition by quinidine, dofetilide, and azimilide between pH 7.4 and pH 6.2 ( P < .01). The drug concentration blocking 50% of current (IC50) was 5.8 ± 0.3 µM for azimilide, 9.9 ±1.0 µM for quinidine, and 0.5 ± 0.02 µM for dofetilide at pH 7.4. When extracellular pH was decreased from 7.4 to 6.2, the IC50 increased to 95.5 ± 11.3 µM for azimilide, 203.2 ± 15.7 µM for quinidine, and 12.6 ± 1.2 µM for dofetilide. Unlike quinidine, dofetilide, and azimilide, there was no significant difference in the percentage of current block by amiodarone between pH 6.2 and 7.4. For amiodarone, the IC50 was 38.3 ± 8.5 µM at pH 7.4 and 27.3 ± 1.6 µM at pH 6.2.

Conclusion: Our data show that the Ikr blocking effect of azimilide, dofetilide, and quinidine was attenuated at acid pH, whereas this was not the case for amiodarone. These observations may explain the efficacy of amiodarone in reducing arrhythmic death in patients after a myocardial infarction compared with other IKr blockers.
Successful Treatment of Hypotension Associated With Stunned Myocardium with Oral Midodrine Therapy
Authors: Sharma Sanjiv , Bhambi Brijesh
Published: March 2006

Myocardial stunning, a reversible decrease in the contractile function of the myocardium after an ischemic insult, often leads to hypotension that requires therapy with intravenous inotropes. We used the oral agent midodrine to treat hypotension that complicated myocardial stunning after successful revascularization with percutaneous coronary intervention in the setting of myocardial infarction and ischemia. Oral midodrine may offer a useful substitute to intravenous inotropic therapy and can shorten the duration of intensive care unit and hospital stay in this setting.
Pharmacotherapy of Congestive Heart Failure in Elderly Patients
Authors: Burger Peter C. , Rocca Hanspeter Brunner-La
Published: March 2006

With longer life expectancy, as well as better survival rates after myocardial infarction, the population of elderly patients with congestive heart failure steadily increases. Large, randomized, placebo-controlled studies have shown significant beneficial effects for several classes of drugs (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers, aldosterone antagonists) in patients with congestive heart failure. In most of these studies, however, elderly patients were either excluded or represented only a minority of the study population. Therefore, the treatment benefit for the large population of patients aged 65 and older is still not very well documented. In this paper, we critically review the current literature with regard to outcome of heart failure therapy in this particular subpopulation.
Dietary Vitamin E Supplementation Attenuates Hypertension in Dahl Salt-Sensitive Rats
Authors: Vasdev Sudesh , Gill Vicki , Parai Sushil , Gadag Veeresh
Published: March 2006

There is strong evidence that excess dietary salt (NaCl) is a major factor contributing to the development of hypertension. Salt-sensitive humans and rats develop hypertension even on a normal-salt diet. Salt sensitivity is associated with glucose intolerance and insulin resistance in both humans and animal models, including Dahl salt-sensitive (DSS) rats. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes that bind sulfhydryl groups of membrane proteins, altering calcium channels, and increasing cytosolic free calcium ([Ca2+] i) and blood pressure. Vitamin E lowers tissue aldehyde conjugates, cytosolic [Ca2+] i, and blood pressure in spontaneously hypertensive rats and fructose-induced hypertensive Wistar Kyoto rats, models of insulin resistance. This study investigated the effect of a normal-salt diet on tissue aldehyde conjugates, cytosolic [Ca2+] i, and blood pressure in DSS rats and the effect of vitamin E supplementation on blood pressure and associated biochemical changes in these animals. Seven-week-old DSS rats were divided into 3 groups of 6 animals each and treated for 6 weeks with diets as follows: low-salt (0.4% NaCl); normal-salt (0.7% NaCl) and normal salt (0.7% NaCl) plus vitamin E (34 mg/kg feed). At completion, animals in the normal-salt group had significantly elevated systolic blood pressure, cytosolic [Ca2+] i, and tissue aldehyde conjugates compared with the low-salt group. They also showed smooth muscle cell hyperplasia in small arteries and arterioles of the kidney. Dietary vitamin E supplementation significantly attenuated the increase in systolic blood pressure and associated biochemical and histopathologic changes.
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.
Elevated Troponins and the Churg-Strauss Syndrome: A Case Report
Authors: Zaky Joseph , Caraang Chris , Yu Roger , El-Bialy Adel
Published: March 2006

In a patient with persistently elevated troponin levels but normal ischemic work-up, a diagnostic dilemma can ensue. This is the case of a 65-year-old woman whose only cardiac risk factor was age. She presented repeatedly with chest pain, elevated troponins, and consistently elevated eosinophil levels until the fourth admission when she presented with multi-organ abnormalities including asthma and vasculitis that led to the diagnosis of Churg-Strauss syndrome (CSS). Initiation of corticosteroids immediately resolved all of her presenting symptoms; troponin and eosinophil levels quickly normalized. Eosinophilia from CSS can lead to multi-organ damage including the heart. Therefore, one must consider CSS in the differential of eosinophilia as early detection and treatment may be critical in decreasing morbidity and mortality.
Review of Antiplatelet Therapy in Secondary Prevention of Cerebrovascular Events: A Need for Direct Comparisons Between Antiplatelet Agents
Authors: Jamieson Dara G. , Parekh Amit , Ezekowitz Michael D.
Published: March 2006

Patients experiencing stroke or transient ischemic attack (TIA) are at high risk for recurrent (secondary) strokes, which comprise 29% of all strokes in the United States. Current recommendations for prevention of secondary stroke from the American College of Chest Physicians (ACCP) call for the broad use of platelet antiaggregation (antiplatelet) agents for patients with a history of noncardioembolic stroke or TIA. Five agents—aspirin, ticlopidine, clopidogrel, extended-release dipyridamole (ER-DP), and triflusal—have demonstrated efficacy in large-scale clinical studies in the prevention of recurrent vascular events and/or stroke in patients with a history of stroke. The results of the following studies are reviewed and compared: the Swedish Aspirin Low-Dose Trial (SALT), the United Kingdom Transient Ischaemic Attack (UK-TIA) Aspirin Trial, Dutch Transient Ischemic Attack (Dutch TIA) study (aspirin), the Canadian American Ticlopidine Study (CATS), the Ticlopidine Aspirin Stroke Study (TASS), the African American Antiplatelet Stroke Prevention Study (AAASPS) (ticlopidine), the Clopidogrel versus Aspirin in Patients at Risk of Recurrent Ischemic Events (CAPRIE) trial, the Management of Atherothrombosis With Clopidogrel in High-Risk Patients study (MATCH) (clopidogrel), the second European Stroke Prevention Study (ESPS2) (aspirin plus ER-DP), and the Triflusal versus Aspirin in Cerebral Infarction Prevention (TACIP) study. In comparative monotherapy studies of patients with previous stroke, ticlopidine demonstrates statistically significant improved efficacy over aspirin, and clopidogrel demonstrates nonsignificant slight improvement over aspirin for the prevention of ischemic cardiac and cerebrovascular events; however, the adverse event profile of ticlopidine (including rash, diarrhea, and neutropenia) will probably limit its long-term use. Among combination approaches, only aspirin plus ERDP has demonstrated statistically significant, clinically meaningful additive benefit over monotherapy with each agent. Clopidogrel plus aspirin did not significantly improve preventive efficacy and increased the risk of serious side effects, including life-threatening bleeding episodes. The 15,500-patient PRoFESS (the Prevention Regimen for Effectively Avoiding Second Strokes) study, with results expected in 2008, will directly compare aspirin plus ER-DP with clopidogrel monotherapy for the prevention of recurrent stroke and should provide statistically robust estimates of comparative efficacy for the development of improved recommendations.
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.
Effectiveness of Oral Magnesium in a Patient With Ventricular Tachycardia Due to Hypomagnesemia
Authors: Tsuji Atsutoshi , Araki Kiyoshi , Maeyama Katsuhiro , Hashimoto Keitaro
Published: March 2006

A 12-year-old girl with occasional symptoms of chest discomfort was diagnosed with ventricular tachycardia on cardiac evaluation. No evidence of organic heart disease was apparent, but a laboratory evaluation revealed hypomagnesemia. Ventricular tachycardia disappeared after treatment with 200 mg/day of oral magnesium hydroxide, and no further chest discomfort was reported. In addition to routine cardiac evaluation for arrhythmia, serum magnesium levels should be checked in patients with suspected idiopathic benign ventricular tachycardia. Treatment with oral magnesium is a physiologic therapy and should be considered for patients with ventricular tachycardia due to hypomagnesemia.
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.
Metabolic Modulators for Chronic Cardiac Ischemia
Authors: Parang Pirouz , Singh Bramah , Arora Rohit
Published: March 2006

Many patients with ischemic heart disease continue to experience anginal symptoms despite revascularization and treatment with antianginal medications. The effectiveness of current anti-ischemic medications is limited by their hemodynamic side effects, such as hypotension and bradycardia, which result in compromised organ perfusion. In this article, we review five novel agents (ranolazine, trimetazidine, L-carnitine, ribose, and dichloroacetate) under investigation for treatment of ischemic heart disease that work by enhancing the efficiency of the myocardium, rather than decreasing its work. This new paradigm promises to eliminate these side effects.