Journal of Cardiovascular Pharmacology and Therapeutics recent issues

Intracoronary Abciximab Use in Patients Undergoing PCI at a Community Hospital: A Single Operator Experience

Patel, S. S., Rana, H., Mascarenhas, D. A. N. — 2008-05-21

Objective: To evaluate the safety of intracoronary (IC) abciximab during percutaneous coronary intervention (PCI). Background: Adjunctive treatment with glycoprotein IIb/IIIa inhibitors, especially abciximab, during PCI has been shown to improve clinical and procedural outcomes in numerous studies. However, significant bleeding complications exist with its use and this has limited its standard use. Interest has grown in local (IC) use with studies showing safety and long-term effectiveness, especially in patients with high thrombus loads. Methods: A retrospective review of records in a database of patients who had PCI by a single operator at the Easton Hospital. Results: 611 patients received IC abciximab, and there were no complications in 610 (98.3%) patients; only 1 had an allergic reaction. Conclusions: IC abciximab is safe and has a unique role in the catheterization lab and in patients at high risk of bleeding complications who would benefit from its limited use.

Oral Midodrine Is Effective for the Treatment of Hypotension Associated With Carotid Artery Stenting

Sharma, S., Lardizabal, J. A., Bhambi, B. — 2008-05-21

Hypotension is commonly encountered during carotid artery stenting (CAS), mediated by vagal stimulation and suppression of sympathetic outflow. Some patients require treatment with intravenous vasopressors (dopamine, nor-epinephrine, or phenylephrine). The authors describe the successful use of the oral agent midodrine as an alternative to intravenous vasopressors in the treatment of hypotension related to CAS. Of 55 patients who underwent elective CAS, 19 (35%) experienced significant hypotension, and 15 (27%) required vasopressor therapy. Eleven patients received intravenous dopamine infusion in an intensive care setting, whereas 4 received oral midodrine in a regular telemetry unit. All patients eventually recovered and were discharged without any residual cardiovascular or neurological complications. No major side effects were noted with the use of both dopamine and midodrine. Cost of hospitalization was significantly higher in the dopamine group because of the need for ICU admission.

Effects of Nitric Oxide and Noradrenergic Activation in the Posterior Hypothalamus on Arterial Pressure Tolerance to Nitroglycerin in Rats

Guettler, D. L., Ma, S.-X. — 2008-05-21

The effects of nitric oxide (NO) and noradrenergic activation in the posterior hypothalamus on arterial pressure tolerance induced by subcutaneous injection of nitroglycerin (NTG) was investigated in anesthetized Sprague-Dawley rats. Intravenous injections of NTG (3, 10, and 30 µg/kg) and sodium nitroprusside (1, 3, and 10 µg/kg) produced dose-dependant decreases in arterial blood pressure. Tolerance to NTG was produced by subcutaneous administration of 4.0 mg of NTG as 4 separate hourly injections of 1.0 mg each, affecting the dose-dependent response of NTG IV injection. The 4 high-dose NTG pulse injections produced a marked shift in the dose—response curves for arterial pressure depression induced by intravenous injection of the challenge doses of NTG, but did not alter hypotensive responses to sodium nitroprusside. The tolerance responses to arterial pressure depression were enhanced by a bilateral microinjection of NTG (1 nmol) and by diethylamine NONOate (1 nmol), an NO donor, into the posterior hypothalamus. Bilateral microinjection of guanethidine (1.5 nmol), a noradrenergic blocker, into the posterior hypothalamus inhibits NTG tolerance in a period of time within 2 hours. We conclude that exogenous NO and noradrenergic activation in the posterior hypothalamus play an important role in arterial pressure tolerance to systemically administered NTG.

Pharmacoeconomic Concepts in Antiplatelet Therapy: Understanding Cost-Effectiveness Analyses Using Clopidogrel as an Example

Weintraub, W. S. — 2008-05-21

The rising cost of drug therapy has been accompanied by demands from payers for pharmacoeconomic studies to assess the value for money of new treatments.There are 5 types of such analyses: cost analysis (evaluates only costs); cost minimization (compares costs of treatments with identical outcomes); cost-effectiveness (evaluates the cost of treatment in relation to clinical benefit to derive a cost per outcome); cost utility (evaluates cost of treatment in relation to survival adjusted for quality of life,) and cost benefit (evaluates all clinical outcomes, such as prolonged life, in monetary terms). The most commonly used are cost-effectiveness and cost utility. The aim of this article is to provide the nonexpert reader with a basic understanding of these analyses, using pharmacoeconomic evaluations of clopidogrel for acute coronary syndromes as examples. Greater clinician understanding of pharmacoeconomic principles (and pitfalls) will enhance input of the physicians into the decision-making process to maximize the benefit of limited health care resources.

The Protective Effect of Bergamot Oil Extract on Lecitine-like OxyLDL Receptor-1 Expression in Balloon Injury-related Neointima Formation

2008-05-21

Lectin-like oxyLDL receptor-1 (LOX-1) has recently been suggested to be involved in smooth muscle cell (SMC) proliferation and neointima formation in injured blood vessels. This study evaluates the effect of the nonvolatile fraction (NVF), the antioxidant component of bergamot essential oil (BEO), on LOX-1 expression and free radical generation in a model of rat angioplasty. Common carotid arteries injured by balloon angioplasty were removed after 14 days for histopathological, biochemical, and immunohistochemical studies. Balloon injury led to a significant restenosis with SMC proliferation and neointima formation, accompanied by increased expression of LOX-1 receptor, malondialdehyde and superoxide formation, and nitrotyrosine staining. Pretreatment of rats with BEO-NVF reduced the neointima proliferation together with free radical formation and LOX-1 expression in a dose-dependent manner. These results suggest that natural antioxidants may be relevant in the treatment of vascular disorders in which proliferation of SMCs and oxyLDL-related endothelial cell dysfunction are involved.

Physiologic Properties and Regulation of the Actin Cytoskeleton in Vascular Smooth Muscle

Tang, D. D., Anfinogenova, Y. — 2008-05-21

Vascular smooth muscle tone plays a fundamental role in regulating blood pressure, blood flow, microcirculation, and other cardiovascular functions. The cellular and molecular mechanisms by which vascular smooth muscle contractility is regulated are not completely elucidated. Recent studies show that the actin cytoskeleton in smooth muscle is dynamic, which regulates force development. In this review, evidence for actin polymerization in smooth muscle upon external stimulation is summarized. Protein kinases such as Abelson tyrosine kinase, focal adhesion kinase, Src, and mitogen-activated protein kinase have been documented to coordinate actin polymerization in smooth muscle. Transmembrane integrins have also been reported to link to signaling pathways modulating actin dynamics. The roles of Rho family of the small proteins that bind to guanosine triphosphate (GTP), also known as GTPases, and the actin-regulatory proteins, including Crk-associated substrate, neuronal Wiskott-Aldrich Syndrome protein, the Arp2/3 complex, and profilin, and heat shock proteins in regulating actin assembly are discussed. These new findings promote our understanding on how smooth muscle contraction is regulated at cellular and molecular levels.

Ischemic Postconditioning's Benefit on Reperfusion Ventricular Arrhythmias Is Maintained in the Senescent Heart

Dow, J., Bhandari, A., Kloner, R. A. — 2008-05-21

The purpose of this study is to determine if postconditioning's beneficial effect on ventricular arrhythmias is maintained in elderly hearts. In elderly populations, the cardioprotective effects of ischemic preconditioning are lost. Previously, the authors observed that ischemic postconditioning markedly reduced reperfusion-induced ventricular arrhythmias in adult rats. Whether this benefit is maintained in senescent hearts is unknown. Here, the authors study young adult rats compared with senescent animals. They chose 24-month-old Fischer female rats as these rats are approaching the end of their normal life span. Unlike some studies that suggest that the benefits of preconditioning and postconditioning are lost in the elderly, their data show that antiarrhythmic protection conferred by postconditioning is present in both the young and old rats.

Aspirin Resistance: Biological and Clinical Implications

Tseeng, S., Arora, R. — 2008-02-20

Cardiovascular events are the leading causes of mortality and morbidity in the United States. This development has prompted the rise of aspirin therapy in the prevention of atherothrombotic events. However, not all patients benefit to the same extent from aspirin therapy and many continue experiencing atherothrombotic complications. Researchers have labeled this phenomenon aspirin resistance, and despite drawing much attention from both researchers and lay people the cause remains unknown. Much needs to be clarified and standardized regarding the phenomenon of aspirin resistance, including the prevalence, definition, appropriate measurement methods, mechanisms, and, most important, linking low response to aspirin with worsened clinical outcomes.

The First Year Post-Heart Transplantation: Use of Immunosuppressive Drugs and Early Complications

2008-02-20

A large number of heart transplants are performed annually in different transplant centers in the United States. This is partly because of the improved survival of patients who undergo cardiac transplantation, thus making it a more viable option in the management of end-stage heart failure. The survival benefit after heart transplantation is a result of newer immunosuppressive drug regimens and a better understanding of their effects and interactions. Several studies, mostly involving a small number of patients, describe use and comparison of the many distinct immunosuppressive drugs available to date. Interestingly, many transplant centers perform in-house typical induction treatment regimens because of their own experience and intra-institutional preference. This review summarizes current practices of immunosuppressive drug therapy in the first year post–heart transplant based on the available clinical evidence and discusses future options of heart transplant immunosuppressive drug therapies.

Effect of Selective Serotonin Reuptake Inhibitors on Cardiovascular Morbidity and Mortality

Von Ruden, A. E., Adson, D. E., Kotlyar, M. — 2008-02-20

Depression in patients with coronary artery disease is associated with increased cardiovascular morbidity and mortality. It is not clear, however, if treatment with selective serotonin reuptake inhibitors (SSRIs) decreases the rate of future cardiovascular events. This paper reviews the available literature regarding the effect of SSRI use on cardiovascular outcomes. Thirteen studies addressing this issue were identified. Of these, 5 concluded that SSRI use is associated with decreased cardiovascular morbidity or mortality, 2 concluded that SSRI use was associated with worsened prognosis, and 6 studies found no statistically significant association. Almost all of the published literature examining the effect of SSRIs on cardiovascular outcomes is based on observational studies, thereby precluding definitive conclusions. Randomized controlled studies are clearly needed to definitively address this issue.

Cyclooxygenase-2 Inhibitors and Most Traditional Nonsteroidal Anti-inflammatory Drugs Cause Similar Moderately Increased Risks of Cardiovascular Disease

Hennekens, C. H., Borzak, S. — 2008-02-20

Cyclooxygenase-2 inhibitors relieve pain from inflammatory conditions by decreasing the gastrointestinal side effects from traditional nonsteroidal anti-inflammatory drugs. Basic research provided plausible mechanisms and some observational epidemiological studies, case-control and cohort, indicated that patients prescribed with cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory drugs had increased risks for myocardial infarction and stroke. Because patients prescribed with cyclooxygenase-2 inhibitors were systematically different, uncontrolled and uncontrollable confounding by indication was as large as the observed risks. Thus, epidemiological studies or their meta-analyses could not discern whether, and if so, how much, the risks were real. A comprehensive meta-analysis of randomized trials indicated that cyclooxygenase-2 inhibitors increased the risk of vascular events by 42%, almost exclusively myocardial infarction, as did high-dose regimens of ibuprofen and diclofenac, but not naproxen. Individual clinical judgments and policy decisions should include cardiovascular disease and noncardiovascular disease risks including gastrointestinal side effects and clinical benefits including improved quality of life from less pain and disability.

Differential Effects of Carvedilol and Metoprolol Succinate on Plasma Norepinephrine Release and Peak Exercise Heart Rate in Subjects With Chronic Heart Failure

2008-02-20

Dosing equivalency of carvedilol and metoprolol remains a debate. Degree of β₁-blockade is best assessed by blunting of the exercise-induced heart rate. Accordingly, the authors have investigated dosing equivalency by examining baseline and peak exercise heart rates and norepinephrine levels in subjects with chronic heart failure treated with carvedilol or metoprolol. Thirty-seven subjects treated with carvedilol (32.9 ± 3.5 mg; n = 23) or metoprolol succinate (XL) (96.4 ± 15.9 mg; n = 14) referred for cardiopulmonary exercise testing were studied prospectively. Carvedilol versus metoprolol XL subjects did not differ with respect to baseline heart rate (73 ± 2 vs 70 ± 3 bpm), or baseline plasma norepinephrine levels (597.5 ± 78.3 vs 602.1 ± 69.6 pg/mL), P = NS. However, despite similar peak exercise norepinephrine levels (2735.8 ± 320.1 vs 2403.1 ± 371.6 pg/mL), heart rate at peak exercise was higher in subjects receiving carvedilol (135 ± 4 bpm) than those receiving metoprolol XL (117 ± 6 bpm), P = 0.02. Similar norepinephrine release and more complete β₁-blockade is observed in well-matched subjects with chronic heart failure treated with a mean daily dose of metoprolol XL 96.4 mg compared with carvedilol 32.9 mg.

Coronary Endothelial Dysfunction and Impaired Microcirculation Response to Atrial Natriuretic Peptide in Hyperinsulinemia

2008-02-20

Endothelial dysfunction occurs in hyperinsulinemia (HI). Coronary microcirculation responses to vasoactive agents are examined in 57 patients with angiographically normal coronary arteries. Patients were divided into 2 groups, 37 with normoinsulinemia (NI) and 20 with HI based on results of a 75-g oral glucose tolerance test. Epicardial artery vasoactivity in response to acetylcholine chloride is measured to assess endothelial function. Coronary microcirculation function is evaluated by intracoronary administration of 50 µg of adenosine triphosphate, 1 mg of isosorbide dinitrate, and 0.05 mg/kg of atrial natriuretic peptide. Epicardial artery vasoconstriction in response to 100 µg of acetylcholine is mildly reduced in HI (P = .04). Coronary flow reserve in response to adenosine triphosphate in NI is similar to that in HI. In NI, the resting mean (SD) peak velocity in response to isosorbide dinitrate (40.7 [10.9] cm/s) vs atrial natriuretic peptide (39.6 [10.9] cm/s) is similar. In contrast, the resting mean (SD) peak velocity in response to atrial natriuretic peptide (31.3 [9.3] cm/s) vs isosorbide dinitrate (43.5 [10.0] cm/s) in HI is statistically significantly blunted (P < .001). Atrial natriuretic peptide may have a pathologic effect on coronary microcirculation even in mild endothelial dysfunction among patients with HI.

Cardiac Oxidative Stress Is Elevated at the Onset of Dilated Cardiomyopathy in Streptozotocin-Diabetic Rats

Crespo, M. J., Zalacain, J., Dunbar, D. C., Cruz, N., Arocho, L. — 2008-02-20

The association between nitric oxide synthase (eNOS and iNOS) status, oxidative stress, and cardiac function was evaluated in streptozotocin (STZ)-diabetic rats to understand the etiology of diabetic cardiomyopathy. Cardiac function was determined by echocardiography. eNOS and iNOS status and superoxide production were assessed by immunohistochemistry and chemiluminescence, respectively. In STZ-diabetic rats, stroke volume, cardiac output, and left ventricular ejection fraction were significantly lower than in controls (CT, P < .05), whereas left ventricular end-systolic volume was higher. Cardiac NOS activity increased from 161 ± 18 cpm/mg tissue in CT rats to 286 ± 20 cpm/mg tissue (P < .001) in STZ-diabetic rats. Furthermore, superoxide production and cardiac eNOS and iNOS levels were higher in STZ-diabetic rats than in CT rats (P < .05). An increased activation of cardiac eNOS and iNOS is observed concomitantly with decreased cardiac function. Thus, increased oxidative stress in the heart may be implicated in the development of dilated cardiomyopathy in STZ-diabetic rats.

Pretreatment With High-Dose Statin, But Not Low-Dose Statin, Ezetimibe, or the Combination of Low-Dose Statin and Ezetimibe, Limits Infarct Size in the Rat

Birnbaum, Y., Lin, Y., Ye, Y., Merla, R., Perez-Polo, J. R., Uretsky, B. F. — 2008-02-20

Statins reduce infarct size by upregulating nitric oxide synthases and PGI₂ production. In this article, the infarct size-limiting effect of low-dose simvastatin + ezetimibe, ezetimibe, and high-dose statins were compared. Rats received 3-day water, atorvastatin (10 mg/kg/d), simvastatin (10 mg/kg/d), simvastatin (2 mg/kg/d), simvastatin (2 mg/kg/d) + ezetimibe (1 mg/kg/d), or ezetimibe. Rats underwent 30-minute coronary artery occlusion and 4-hour reperfusion. Atorvastatin and simvastatin 10 reduced infarct size, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. Atorvastatin and simvastatin 10 increased nitric oxide synthases activity, whereas simvastatin-2, ezetimibe, and simvastatin-2 + ezetimibe had only a small effect. Atorvastatin and simvastatin 10 significantly increased myocardial 6-ketoprostaglandin F₁ levels, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. High-dose statin is required to decrease infarct size, upregulate myocardial nitric oxide synthases activities, and increase 6-keto prostaglandin F₁ levels. Combination of ezetimibe and low-dose statin is ineffective in modulating myocardial biochemical changes associated with cardioprotection.

Role of Oxidants and Antioxidants in Atherosclerosis: Results of In Vitro and In Vivo Investigations

Siekmeier, R., Steffen, C., Marz, W. — 2008-01-02

Both in vitro and in vivo studies have shown that oxidants are central in the development of atherosclerosis. Consequently, additional studies evaluated the protective effects of various natural and synthetic antioxidants, alone and in combination, with most studies focusing on -tocopherol (vitamin E). Here, we summarize the role of oxidants in the pathomechanism of atherosclerosis. We also discuss epidemiological studies and others focused on the protective effect of vitamin E against atherosclerosis. Other antioxidants are also considered if they were included in studies involving vitamin E. The protective effect of antioxidants on atherosclerotic pathomechanisms has been confirmed in vitro, but only in some animal studies. Various epidemiological and observational studies have produced conflicting results on the protective effect of antioxidants. Most studies of primary or secondary prevention failed to show a protective effect. These conflicting results are biased by a number of factors, including differences between the study groups. Therefore, we describe these studies in detail.

Efficacy and Safety of Bivalirudin Versus Heparins in Reduction of Cardiac Outcomes in Acute Coronary Syndrome and Percutaneous Coronary Interventions

Singh, S., Molnar, J., Arora, R. — 2008-01-02

Recent data suggest that bivalirudin, a reversible direct thrombin inhibitor, may be noninferior to heparins (unfractionated heparin/low molecular weight heparin) in providing protection against cardiovascular events, with significantly fewer bleeding complications. Whether this advantage is consistent has not been fully defined. We evaluated cardiac outcomes with bivalirudin vs the heparins in management of acute coronary syndromes (ACS), including patients undergoing percutaneous coronary interventions (PCI). Formal computer-aided searches of electronic databases (MEDLINE, PubMed, Cochrane Controlled Trials Registry) were performed by scrutiny of the reference lists of trials and review articles, abstracts, meeting proceedings, and the manufacturers of direct thrombin inhibitors. Five randomized controlled trials (BAT, 1995; CACHET, 2002; REPLACE-2, 2003; REPLACE-1, 2004; and ACUITY, 2006) comparing bivalirudin to the heparins in patients with ACS, including patients undergoing PCI, were identified. The meta-analysis consisted of 25 457 patients (bivalirudin, 15 077; heparins, 10 380). The primary safety end point was major bleeding, defined as intracranial, intraocular, or retroperitoneal hemorrhage; clinically overt blood loss leading to a hemoglobin drop exceeding 3 g/dL (or 10% of hematocrit) and transfusion of 2 or more units of whole blood or packed red blood cells. The combined relative risks (RR) across all of the studies and the 95% confidence intervals of death, myocardial infarction (MI), and revascularization (bivalirudin vs heparins) were computed using the Mantel-Haenszel fixed-effect model, whereas the random-effect model was used for major bleeding. A 2-sided error < .05 was considered to be significant. There were no significant differences in patient characteristics between the 2 groups. Compared to the heparins, the risk of death, MI, revascularization, and composite ischemic end points were similar with bivalirudin monotherapy. However, the risk of major bleeding was significantly lower with bivalirudin use (RR = 0.553; 95% CI = 0.402-0.761; P = .001). The present meta-analysis suggests that bivalirudin may be noninferior to the heparins in reducing the composite of ischemic end points. Additionally, compared to the heparins, bivalirudin monotherapy may lower the rate of major bleeding.

Dose-Dependent Effect of Rosuvastatin Treatment on Urinary Protein Excretion

2008-01-02

Concerns have been raised because of observations of proteinuria associated with rosuvastatin treatment. In this open-label study, a potential dose-dependent effect was investigated of rosuvastatin on urinary protein excretion and renal function parameters in 90 hyperlipidemic patients randomly assigned to rosuvastatin 10 mg/day (n = 45) or 20 mg/day (n = 45). Urinary samples were collected from patients and 40 age- and gender-matched controls to determine electrolyte, uric acid, creatinine, and protein (total, albumin, IgG, and 1-microglobulin) levels at baseline and after 12 weeks. A dose-dependent increase in the excretion of 1-microglobulin (17.6% in rosuvastatin 10 vs 34.9% in rosuvastatin, 20 mg/day; P = .03 for the comparison between groups) was observed. A trend toward an increase in the estimated glomerular filtration rate was noted in only patients receiving 20 mg/day of rosuvastatin. These findings indicate that rosuvastatin treatment increases the urinary excretion of 1-microglobulin urinary excretion in a dose-dependent manner without adversely affecting renal function.

Increased Incidence of In-Stent Thrombosis Related to Cocaine Use: Case Series and Review of Literature

2008-01-02

The purpose of this article was to determine the incidence of in-stent thrombosis (IST) after coronary stent implantation in patients with cocaine abuse. A retrospective review was done of medical records of consecutive patients who underwent coronary stent implantation for obstructive coronary artery disease at a single inner-city institution from January 1997 to October 2006. Patients with temporal cocaine use were identified by positive urine drug screen. IST was confirmed angiographically. Of the 81 patients with active cocaine use that underwent coronary stent implantation, 4 (5%) suffered IST (mean period from stent implantation, 28.5 ± 14 days). All procedures were performed successfully and received intravenous IIb/IIIa antagonist intraprocedurally. All patients were prescribed dual antiplatelet therapy with aspirin and clopidogrel at discharge; however, all 4 patients that suffered from IST continued cocaine abuse were noncompliant with the prescribed dual antiplatelet therapy. Of these 4 patients, 2 presented with ST segment elevation myocardial infarction (50%), whereas 2 presented with non-ST-segment elevation myocardial infarction (50%). One was managed medically. Two received repeat percutaneous coronary intervention, and 1 underwent coronary artery bypass surgery. The patient that underwent surgery died in the postoperative period. The remaining 3 patients survived. Patients with active cocaine abuse who undergo successful coronary stent revascularization have a high (5%) incidence of stent thrombosis. A majority of patients that suffer stent thrombosis continue cocaine abuse and are noncompliant with antiplatelet therapy.

A Study on Regression of Hypercholesterolemic Atherosclerosis in Rabbits by Flax Lignan Complex

Prasad, K. — 2008-01-02

Flax lignan complex (FLC) isolated from flaxseed suppresses the development of hypercholesterolemic atherosclerosis. The objectives of this study were to investigate if FLC produces regression of atherosclerosis and if regression is associated with reductions in serum lipids and oxidative stress. The studies were conducted in 4 groups of rabbits: group I, control diet (2 months); group II, 0.25% cholesterol diet (2 months); group III, 0.25% cholesterol diet (2 months) followed by regular diet (4 months); and group IV, 0.25% cholesterol diet (2 months) followed by regular diet and FLC (4 months). Serum lipids and oxidative stress parameters were measured before and at various intervals thereafter on their respective diets. The aortas were removed at the end of the protocol for assessment of atherosclerotic plaques and oxidative parameters. Atherosclerosis in group II was associated with hyperlipidemia and increased oxidative stress. Atherosclerotic changes were accelerated in group III, and this was associated with reductions in serum lipids and oxidative stress. Atherosclerotic lesions in group IV were similar to group II, but significantly smaller than those in group III, and were associated with reductions in serum lipids and oxidative stress similar to that in group III. These results indicate that FLC does not produce regression but prevents the acceleration of atherosclerosis due to the removal of cholesterol in the diet. These effects of FLC are not associated with reductions in serum lipids and oxidative stress.

In Vitro Effects of Acute Amiodarone and Dronedarone on Epicardial, Endocardial, and M Cells of the Canine Ventricle

Moro, S., Ferreiro, M., Celestino, D., Medei, E., Elizari, M. V., Sicouri, S. — 2008-01-02

Amiodarone (AM) is an antiarrhythmic agent widely used in the treatment of ventricular and supraventricular arrhythmias. Dronedarone (DR) is a new compound with a pharmacological profile similar to that of AM, but iodine free. We previously demonstrated that chronic AM treatment reduces transmural dispersion of repolarization (TDR) in the canine heart. We used standard microelectrode technique to evaluate the effects of acute AM (100 µM) and DR (30 µM) on epicardial (EPI), endocardial (ENDO), and M region tissues obtained from the left ventricular wall of the canine heart. Amiodarone (100 µM, 120 min of exposure) produced little change in the action potential duration of ENDO and EPI tissues, but it shortened the action potential of M cells, especially at slow rates, leading to a decrease in TDR. Similar results were observed with DR. Acute AM (100 µM) and DR (30 µM) eliminated d-sotalol—induced early afterdepolarizations (EADs) and triggered activity in 3 of 3 and 2 of 6 M cell preparations, respectively. The reduction of TDR and the elimination of EAD-induced triggered activity differentiates AM and DR from other class III agents. These effects may explain the efficacy and low arrhythmogenicity of acute AM and suggest a potential safe use of DR as an antiarrhythmic agent.

Homeostatic Role of Toll-like Receptor 4 in the Endothelium and Heart

Harrington, L. S., Belcher, E., Moreno, L., Carrier, M. J., Mitchell, J. A. — 2008-01-02

Toll-like receptor 4 (TLR4) is a pattern recognition receptor for lipopolysaccharide from Gram negative bacteria and thus is integral to the innate immune response in mammals. In addition, TLR4 is associated with atherosclerosis in murine models. The current study shows that blood vessels from TLR4^-/- mice have an intact endothelial layer and comparable expression of nitric oxide synthase 3 protein. However, endothelium-dependent dilation in response to acetylcholine in vessels from TLR4^-/- mice is greatly reduced. By contrast, endothelium-independent smooth muscle dilation in response to sodium nitroprusside in vessels from TLR4^-/- mice remains intact. Furthermore, this study shows that hearts from TLR4^-/- mice display signs of left ventricular dilation. In contrast to results in vessels from TLR4^-/- mice, endothelium-dependent responses to acetylcholine in vessels from TLR2^-/- mice remain intact. These observations illustrate a novel role for TLR4 in the homeostatic control of a functional endothelium and, thereby, cardiovascular health.

Implantable Cardioverter Defibrillator Therapy and the Need for Concomitant Antiarrhythmic Drugs

Singh, S., Murawski, M. M. — 2007-09-17

Implantable cardioverter defibrillators (ICDs) are increasingly used for the prevention of sudden cardiac death in patients with life-threatening ventricular arrhythmias (VAs); however, there is a potential for severe and debilitating anxiety caused by symptoms associated with ICD therapy and anticipation of shocks. Anxiety is a psycho-logic stressor, including physiologic components that may lead to adrenergic excitation triggering new arrhythmias and ICD therapies. This often requires concomitant antiarrhythmic medication to reduce the frequency of shocks and symptomatic arrhythmias treated by anti-tachycardia pacing. Although published studies have documented the efficacy of currently available antiarrhythmics, they have limitations in patients with heart failure, may affect the defibrillation threshold, and/or have been associated with major side-effects. In conclusion, for the patient with an ICD experiencing symptomatic ventricular tachycardia (VTs) episodes or ICD shocks, there is a need for pharmacologic therapy to reduce the incidence of such events without affecting the performance of the ICD or causing major side-effects.

Supernormal Conduction in the Anomalous Bundles of the Wolff-Parkinson-White Syndrome: An Overlooked Electrophysiologic Property With Potential Clinical Implications

2007-09-17

The anterograde refractory period (RP) of the accessory pathway (AP) is the main determinant factor of ventricular rate during atrial fibrillation in the Wolff-Parkinson-White (WPW) syndrome. We describe 3 examples of anterograde supernormal conduction (SNC) and 1 of retrograde SNC in APs. The paradoxical early recovery of propagation due to SNC, well inside a prolonged anterograde RP in the AP, may play a relevant role to determine the rate of ventricular response during atrial fibrillation, eventually leading to extremely fast ventricular rates, syncope, and even ventricular fibrillation in patients with WPW syndrome supposed a priori to be exposed to a low risk of sudden cardiac death. This may require very precise conditions, including an enhanced adrenergic influence on the heart. Retrograde SNC in APs may also participate in the mechanism of paroxysmal supraventricular tachycardias that are not easily induced by programmed cardiac stimulation.

Tissue ACE Inhibitors for Secondary Prevention of Cardiovascular Disease in Patients With Preserved Left Ventricular Function: A Pooled Meta-analysis of Randomized Placebo-controlled Trials

Saha, S. A., Molnar, J., Arora, R. R. — 2007-09-17

Objective. A pooled meta-analysis of published, randomized placebo-controlled clinical trials to evaluate the role of tissue angiotensin-converting enzyme (ACE) inhibitors in secondary prevention of cardiovascular disease in patients with preserved left ventricular function. Sources. Peer-reviewed journals listed in Index Medicus/MEDLINE, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews. Study selection . Randomized placebo-controlled clinical trials of at least 12 months' duration, in patients with a prior cardiovascular event or at high risk for cardiovascular events, were analyzed. Data synthesis and analysis. A total of 31 555 patients (136 882 patient-years) from 4 trials were selected for the meta-analysis. Relative risk estimations were made using data pooled from these trials, and statistical significance was determined using the 2 test. The number of patients needed to treat was also calculated for each outcome. Results. Tissue ACE inhibitors significantly reduced the risk of all-cause mortality, cardiovascular mortality, acute myocardial infarction, and stroke (P < .001 for each). The need for invasive coronary revascularization was reduced (P = .03), as was the risk of hospitalization for congestive heart failure (P = .001). The occurrence of new-onset diabetes was also significantly reduced (P < .001), but the risk of hospitalization for angina was not significantly affected (P = .677). Treating about 100 patients for about 4.5 years would prevent 1 death, 1 non-fatal myocardial infarction, 1 cardiovascular death, or 1 invasive coronary revascularization. Conclusions. Tissue ACE inhibitors have demonstrated benefit when used for secondary prevention of cardiovascular disease in patients with preserved left ventricular function in randomized placebo-controlled clinical trials.

Greater Inhibition of Platelet Aggregation and Reduced Response Variability With Prasugrel Versus Clopidogrel: An Integrated Analysis

2007-09-17

Multiple studies report response variability to a 300-mg clopidogrel loading dose (LD). Pooled platelet aggregometry data compared responses (change in maximal platelet aggregation [MPA] or inhibition of platelet aggregation [IPA]) to clopidogrel 300-mg (n = 131) or prasugrel 60-mg (n = 109) LDs. Poor responder rates were determined using empiric criteria (IPA < 10% and MPA < 10% for 20 µM and 5 µM adenosine diphosphate [ADP]) and Bayesian model-based criteria (IPA < 20% and MPA < 15% for 20 µM ADP; IPA < 25% and MPA < 20% for 5 µM ADP). Prasugrel achieved greater MPA and IPA from 2 to 24 hours post-LD (P < .001). For 20 µM ADP, poor responder rates for clopidogrel ranged from 17% to 43%; no prasugrel poor responders were observed. Regardless of the criterion, prasugrel 60 mg achieved greater IPA and fewer poor responders than the clopidogrel 300-mg LD.

Cardiovascular and Endothelial Effects of Fish Oil Supplementation in Healthy Volunteers

2007-09-17

Consumption of fish oil (FO) is associated with reduced adverse cardiovascular events. In a randomized, blinded, placebo-controlled trial, 26 subjects (17 men and 9 women; mean age [± SD] 31 ± 3.7 years) received 1 g FO capsule (n = 14) or placebo (1 g of corn oil, n = 12) for 14 days. At day 0 and day 14, heart rate (HR), blood pressure, endothelium-dependent brachial artery flow-mediated vasodilation (EDV), and endothelium-independent nitroglycerin-mediated vasodilation (EIDV) were assessed with ultrasound. FO supplementation resulted in a significant increase in EDV (20.4% ± 13.2% vs 9.9% ± 5.4%; P = .036) and EIDV (32.6% ± 16.8% vs 18.0% ± 14.9%; P = .043). Resting HR decreased by a mean of 5.9 ± 9.4 bpm (FO) compared with placebo (mean increase of 0.73 ± 4.8 bpm [P = .05]). FO supplementation in healthy subjects is associated with improved endothelial function and decreased resting HR.

Improvement of Cardiac Function Persists Long Term With Medical Therapy for Left Ventricular Systolic Dysfunction

Chen, D., Chang, R., Umakanthan, B., Stoletniy, L. N., Heywood, J. T. — 2007-09-17

In certain patients with left ventricular (LV) systolic dysfunction, improvements in cardiac function are seen after initiation of medical therapy; however, the long-term stability of ventricular function in such patients is not well described. We retrospectively analyzed 171 patients who had a baseline ejection fraction of 45% or less, a follow-up echocardiogram at 2 to 12 months after initiation of medical therapy, and a final echocardiogram. We found that 48.5% of the patients demonstrated initial improvements in LV function after initiation of medical therapy, and the improvements appear to be sustained (88% of patients) at 44 ± 21 months follow-up. A nonischemic etiology and younger age were the only independent predictors of change of LV ejection fraction of 10 or more at a mean 8.4 ± 3.4 months after optimal medical therapy. Our study revealed a trend toward improved long-term survival in individuals with an early improvement in LV ejection fraction with medical therapy, especially in those with sustained improvement.

Conversion of Atrial Fibrillation to Sinus Rhythm During Treatment With Intravenous Esmolol or Diltiazem: A Prospective, Randomized Comparison

2007-09-17

Prior studies have suggested that intravenous diltiazem reduces the probability of spontaneous conversion of atrial fibrillation (AF) to sinus rhythm in the electrophysiology laboratory and in patients with postoperative AF. Whether diltiazem exerts the same effect in patients presenting to the emergency department (ED) with spontaneous AF is unclear. Fifty patients presenting to the ED with new-onset or paroxysmal AF and a rapid ventricular rate (>100 beats per minute) were randomly assigned to receive intravenous diltiazem or esmolol during the first 24 hours of presentation. Conversion to sinus rhythm occurred in 10 patients (42%) in the diltiazem group compared with 10 patients (39%) in the esmolol group (P = 1.0). Diltiazem does not decrease the likelihood of spontaneous conversion of AF to sinus rhythm in the ED setting.

Intermittent Outpatient Nesiritide Infusion Reduces Hospital Admissions in Patients With Advanced Heart Failure

Schwarz, E. R., Najam, S., Akel, R., Sulimanjee, N., Bionat, S., Rosanio, S. — 2007-09-17

Recombinant B-type natriuretic peptide (BNP) is a therapeutic modality in patients with decompensated congestive heart failure. Retrospectively tested are the effects of intermittent outpatient nesiritide infusion on symptoms, hospital readmission rates, endogenous BNP, and renal function in patients with advanced heart failure. Twenty-four patients in heart failure in New York Heart Association (NYHA) classes III-IV received a 6- to 8-hour intermittent nesiritide outpatient infusion (0.01 mcg/kg/min continuously intravenously) once weekly for a total duration of 3 months in addition to standard medical therapy. Data were analyzed retrospectively to compare hospital readmission rates, endogenous BNP levels, blood urea nitrogen, and creatinine levels 1 year before and up to 12 months after starting treatment. All patients tolerated nesiritide infusions well with no significant adverse events. At the end of the observation period, NYHA classes had improved 1 class in 16 patients and 2 classes in 4 patients and remained unchanged in 4 patients. There was a significant reduction in hospital readmissions within 1 year with nesiritide treatment compared with the year before (0.94 ± 0.8 vs 3.6 ± 2.2, P < .005). No significant changes were seen regarding endogenous BNP levels (1002 ± 870 vs 1092 ± 978 pg/mL, P = .95), blood urea nitrogen levels (45 ± 28 vs 45 ± 26 mg/dL, P = .96), and a tendency of slightly elevated creatinine levels that did not differ significantly compared with prior levels (1.76 ± 0.85 vs 1.1 ± 0.56 mg/dL, P = .5). Intermittent outpatient nesiritide treatment resulted in improved symptoms and reduced hospital readmission rates without a significant decline in renal function in patients with advanced heart failure but did not alter endogenous BNP levels.

Erythropoietin Induces Excessive Neointima Formation: A Study in a Rat Carotid Artery Model of Vascular Injury

Reddy, M. K., Vasir, J. K., Hegde, G. V., Joshi, S. S., Labhasetwar, V. — 2007-09-17

A therapeutic strategy that would mitigate the events leading to hyperplasia and facilitate re-endothelialization of an injured artery after balloon angioplasty could be effective for a long-term patency of the artery. It is hypothesized that erythropoietin (EPO), which has both anti-inflammatory and antiapoptotic properties, will prevent hyperplasia, and its ability to proliferate and mobilize endothelial progenitor cells will re-endothelialize the injured artery. To test this hypothesis, EPO (5000 IU/kg) in solution was injected intraperitoneally 6 hours before vascular injury and then on every alternate day for a week or as a single dose (5000 IU/kg) in a sustained release gel formulation 1 week before the vascular injury. Morphometric analysis revealed nearly continuous re-endothelialization of the injured artery in EPO solution-treated animals (90% vs less than 20% in saline control); however, the treatment also caused excessive neointima formation (intima/media ratio, 2.10 ± 0.09 vs 1.60 ± 0.02 saline control, n = 5, P < .001). The EPO gel also induced similar excessive neointima formation. Immunohistochemical analysis of the injured arteries from the animals treated with EPO solution demonstrated a significant angiogenic response in adventitia and media, thus explaining the formation of excessive neointima. Although the results are in contrast to expectation, they explain a greater degree of stenosis seen in hemodialysis access fistulas in patients who are on EPO therapy for anemic condition. The results also caution the use of EPO, particularly in patients who are at a risk of vascular injury or are suffering from an atherosclerotic condition.

Acute In Vitro Effects of Dronedarone, an Iodine-Free Derivative, and Amiodarone, on the Rabbit Sinoatrial Node Automaticity: A Comparative Study

Celestino, D., Medei, E., Moro, S., Elizari, M. V., Sicouri, S. — 2007-09-17

Amiodarone is a potent antiarrhythmic drug commonly used in the treatment of supraventricular and ventricular arrhythmias. Dronedarone is a recently developed iodine-free compound (Sanofi Recherche), structurally related to amiodarone. Amiodarone and dronedarone have shown similar long-term effects on sinoatrial node automaticity in vivo and in vitro in the rabbit heart. In the present study, we used a microelectrode technique to compare the acute in vitro electrophysiologic effects of amiodarone (100 µM) and dronedarone (100 µM) on the rabbit sinus node. Like amiodarone, dronedarone induces a marked reduction in sinus node automaticity, evidenced by decreases in spontaneous beating rate, action potential amplitude, and slope of phase 4 depolarization. Isoproterenol dose-dependently increases sinus node automaticity in the presence of either amiodarone or dronedarone. The data suggest that dronedarone may be a useful antiarrhythmic alternative to amiodarone in the treatment of supraventricular arrhythmias.