bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Verapamil and Ibutilide for the Suppression of Immediate Recurrences of Atrial Fibrillation after Transthoracic Cardioversion
Authors: Sticherling Christian , Ozaydin Mehmet , Tada Hiroshi , Oral Hakan , Pelosi Frank , Knight Bradley P. , Strickberger S. Adam , Morady Fred
Published: June 2007

Background: Verapamil and ibutilide blunt the atrial fibrillation-induced shortening of atrial refractoriness that may predispose to an immediate recurrence of atrial fibrillation after cardioversion. This study compared the efficacy of verapamil and ibutilide in preventing an immediate recurrence of atrial fibrillation.

Methods and Results: Transthoracic cardioversion was performed in 223 patients with atrial fibrillation. Atrial fibrillation recurred within 10 minutes after cardioversion on two occasions in 21 patients (9.4%). Twenty of these patients were randomly assigned to receive an infusion of either 0. 15 mg/kg of verapamil at a rate of 2 mg/min (11 patients), or 1 mg of ibutilide over 10 minutes (9 patients). Eight patients (73%) had another episode of immediate recurrence of atrial fibrillation after verapamil, compared to two patients (22%) after ibutilide (P<0.05). Including the results after crossover, immediate recurrence of atrial fibrillation occurred in 8 of 12 patients (67%) who received verapamil, compared to 3 of 16 patients (19%) who received ibutilide (P=0.02). Verapamil and/or ibutilide successfully prevented immediate recurrence of atrial fibrillation in 17 of 20 patients (85%). After 700 days of follow-up, there was no significant difference in the recurrence rate of atrial fibrillation between the patients in whom immediate recurrence of atrial fibrillation was prevented by verapamil and/or ibutilide and the patients who were successfully converted to sinus rhythm and did not have immediate recurrence of atrial fibrillation.

Conclusions: Ibutilide is more effective than verapamil in preventing immediate recurrence of atrial fibrillation. Suppression of immediate recurrence of atrial fibrillation by ibutilide and/or verapamil may allow for long-term maintenance of sinus rhythm postcardioversion as often as in patients who do not experience immediate recurrence of atrial fibrillation.
Metalloproteinase in Myocardial Adaptation and Maladaptation
Authors: Tyagi Suresh C. , Hoit Brian D.
Published: June 2007

Ventricular remodeling is a compensatory response that comprises the processes of apoptosis, muscle cell hypertrophy, and rearrangement of the extracellular matrix fibers connecting the muscles. These processes are associated with transformation of endothelium and/or fibroblasts to myofibroblasts. Neutral matrix metalloproteinases, membrane type matrix metalloproteinases, and disintegrin metalloproteinase play a significant role in these processes. The cell-extracellular matrix connections are important in maintaining and synchronizing muscle function. However, a complete extracellular matrix-cell disconnect leads to a decrease in muscle cell strength, apoptosis, and hypertrophy.
Endothelin in Health and Disease: Endothelin Receptor Antagonists in the Management of Pulmonary Artery Hypertension
Authors: Kim Nick H.S. , Rubin Lewis J.
Published: June 2007

Endothelin (ET) has been identified as playing a fundamental role in many disease processes. Therapeutic efforts at interrupting ET's pathologic effects have focused on endothelin receptor antagonists (ERAs), of which two, bosentan and sitaxsentan, have been evaluated for the treatment of both primary and secondary pulmonary arterial hypertension (PAH). We discuss the multiple actions of ET, its role in various disease states, and the effects of ET receptor stimulation and blockade. Current classification and management of PAH are reviewed, along with the promise of greatly improved treatment generated by recent and ongoing clinical trials using ERAs.
Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Induced by Amiodarone: A Report on Two Cases
Authors: Ikegami Haruhiko , Shiga Tsuyoshi , Tsushima Toshio , Nirei Takashi , Kasanuki Hiroshi
Published: June 2007

Background: Amiodarone is an effective antiarrhythmic agent for life-threatening arrhythmias but has some noncardiac toxicity. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by amiodarone during long-term therapy seems to be rare among adverse effects.

Subjects and Results: We report on two elderly cases that developed hyponatremia caused by SIADH occurring during the initial loading period of amiodarone therapy. Both cases improved within 3 weeks after reduction of the dose, although amiodarone was continued.

Conclusions: Amiodarone-induced SIADH may occur during the initial loading period, and it may be improved by reduction of the dose without discontinuation of the drug.
Torsade de Pointes and Sudden Death Induced by Thiopental and Isoflurane Anesthesia in Dogs with Cardiac Electrical Remodeling
Authors: Zhou Shengmei , Cao Ji-Min , Ohara Toshihiko , KenKnight Bruce H. , Chen Lan S. , Karagueuzian Hrayr S. , Chen Peng-Sheng
Published: June 2007

Background: Many anesthetic agents are known to have cardiac effects. The effects of pentobarbital, thiopental and isoflurane on dogs with electrical remodeling are lacking.

Methods and Results: We studied 12 dogs that underwent two anesthesias. First, anesthesia was induced (N=12) with intravenous thiopental (17 mg/kg) induction followed by isoflurane inhalation (1.5%-3% via endotracheal tube). For electrical remodeling, we created complete atrioventricular block (CAVB) and myocardial infarction (MI). In 6 of the 12 dogs we also infused nerve growth factor (NGF) to the right stellate ganglion. All dogs had an implantable cardioverter-defibrillator (ICD) implanted. A second anesthesia was done 66 ± 20 days later. In 8 of the 12 dogs (6 without NGF), pentobarbital was used as the only anesthetic. In the remaining 4 dogs (all with NGF), 3 received thiopental and 1 received isoflurane.

Results: During the first anesthesia, none of 12 dogs had cardiac arrhythmia. During the second anesthesia, none of the 8 dogs that received pentobarbital developed ventricular fibrillation (VF). In contrast, all the dogs receiving either thiopental or isoflurane died of VF within 2 to 3 minutes. QT and P-P intervals before VF were 440 ± 36 milliseconds and 298 ± 28 milliseconds, longer and shorter (respectively) than those obtained the day prior to surgery (315 ± 25 milliseconds, P < 0.001; 330 ± 22 milliseconds, P < 0.01, respectively).

Conclusion: Thiopental and isoflurane are not arrhythmogenic in normal dogs and dogs with acute MI and CAVB, but are extremely proarrhythmic in dogs with chronic MI and CAVB. Consistent with the results of in vitro studies, pentobarbital did not induce ventricular arrhythmia in dogs with cardiac electrical remodeling.
Atrial Fibrillation: Epidemiologic Considerations and Rationale for Conversion and Maintenance of Sinus Rhythm
Authors: Singh Bramah N.
Published: June 2007

Atrial fibrillation is now the most common cardiac arrhythmia for which a patient is hospitalized. Clinically, it presents in a form that is paroxysmal, persistent, or permanent and may be symptomatic or asymptomatic, occurring in the setting of either no cardiac disease (“lone atrial fibrillation”) or, most often, in association with an underlying disease. Atrial fibrillation is associated with a 2-fold increase in mortality and, in the United States alone, causes over 75,000 cases of stroke per year. The annual prevalence of stroke is 5% to 7%, but the use of adequate anticoagulation can reduce this to less than 1%. Atrial fibrillation is a disorder of the elderly, with almost equal prevalence in men and women. In the United States, 80% of atrial fibrillation occurs in patients over the age of 65 years, and its prevalence tracks that of heart failure, which may be the cause, as well as the result, of the arrhythmia. Both conditions are increasing in epidemic proportions in the aging population. The most common causes of atrial fibrillation are hypertensive heart disease, coronary artery disease, and heart failure with a miscellany of lesser conditions, with about 10% lacking structural heart disease. Unlike other supraventricular arrhythmias, cure by the use of catheter ablation and surgical techniques has not been a reality except in a relatively small number of cases. However, restoration and maintenance of sinus rhythm remain the initial goal of therapy for most patients. Pharmacologic approaches remain the mainstay of therapy for rate control and anticoagulation as well as for maintenance of sinus rhythm following pharmacological or electrical conversion. The changing epidemiology of atrial fibrillation is highlighted, with the focus on its conversion by the use of newer and novel antifibrillatory agents relative to the mechanisms of the arrhythmia, to restore the stability of sinus rhythm.
Antiarrhythmic Drug Therapy of Atrial Fibrillation: Focus on New Agents
Authors: Dorian Paul
Published: June 2007

The precise mechanisms of clinical effect of antiarrhythmic agents and the ideal “molecular targets” against arrhythmias, in particular atrial fibrillation, are poorly understood. Current antiarrhythmic drug development, particularly for drugs expected to be active against atrial fibrillation, has focused on drugs with multiple ionic mechanisms of action, in particular on those that block multiple potassium channels. Investigation of antiarrhythmic agents is complicated by the diversity of animal-disease models studied, by the potential multiple mechanisms of arrhythmias, and by the incompletely understood relationships between risks and benefits of antiarrhythmic drug therapy. Furthermore, rhythm control strategies in large groups of patients with atrial fibrillation have failed to show substantial clinical benefit. Nevertheless, drugs that block multiple potassium channels and appear to have relatively little organ toxicity, such as tedisamil, may represent an important new avenue in the therapeutic approach to highly symptomatic arrhythmias such as atrial fibrillation.
Heart Failure Complicated by Atrial Fibrillation: Mechanistic, Prognostic, and Therapeutic Implications
Authors: Gronefeld Gerian C. , Hohnloser Stefan H.
Published: June 2007

Atrial fibrillation and congestive heart failure are two distinct clinical entities that are responsible for significant morbidity and mortality in the Western world. Hypertension, coronary artery disease, and nonischemic cardiomyopathy represent the most prevalent underlying pathologies of both diseases, implying a coincidence of both in many patients. The prevalence of atrial fibrillation with a progressive degree of congestive heart failure is increasing, as judged by New York Heart Association functional class. Moreover, the presence of congestive heart failure has been identified as one of the most powerful independent predictors of atrial fibrillation, with a sixfold increase in relative risk of its development. On the other hand, atrial fibrillation can cause or significantly aggravate symptoms of congestive heart failure in previously asymptomatic or well-compensated patients. In some patients, symptomatic dilated cardiomyopathy may develop over time entirely due to atrial fibrillation with rapid ventricular rates. Upon restoration of sinus rhythm, this type of “tachymyopathy” has been shown to be often reversible. Recent investigations of the physiologic and structural changes of the atrial myocardium (“electrical and structural remodeling”) have shown that neurohumoral activation, fibrosis, and apoptosis are demonstrable with both diseases. On the other hand, experimental data suggest that the substrates of atrial fibrillation in congestive heart failure are different from those of pure atrial tachycardia-related forms of atrial fibrillation. This review highlights the clinical and pathophysiologic similarities and differences of atrial fibrillation and congestive heart failure relevant to the understanding, treatment, and prevention of these diseases in the population at risk.
Low Density Lipoproteins Modulate Collagen Metabolism in Fibroblasts
Authors: Joseph Jacob , Ranganathan Subramanian , Mehta Jawahar L.
Published: June 2007

High levels of low-density lipoprotein are associated with atherosclerosis, and myocardial and arterial remodeling. We postulated that low-density lipoprotein influences collagen synthesis and degradation in fibroblasts as a potential mechanism of tissue remodeling. Incubation of cultured human skin fibroblasts with low-density lipoproteins resulted in a time-dependent and dose-dependent increase in the secretion of matrix metalloproteinase activity measured by gelatin zymography. Western blot analysis showed a concomitant increase in matrix metalloproteinase-1 protein. Northern blot analysis demonstrated an increase in collagen I messenger RNA after treatment with low-density lipoprotein. The matrix metalloproteinase-1 secretory response of fibroblasts to low-density lipoprotein was attenuated by heparin, which inhibits low-density lipoprotein uptake through the low-density lipoprotein-receptor. These observations suggest that low-density lipoprotein has a regulatory effect on collagen metabolism in fibroblasts.
Pharmacologic Reversion of Persistent Atrial Fibrillation with Amiodarone Predicts Long-Term Sinus Rhythm Maintenance
Authors: Galperín Jorge , Elizari Marcelo V. , Chiale Pablo A. , Molina Remberto Torres , Ledesma Raúl , Scapín Angel O. , Blanco Manuel Vázquez , Bonato Ricardo , Lago Manuel ,   Grupo de Estudio de Fibrilación Auricular Con Amiodarona (GEFACA) Investigators
Published: June 2007

Objective: The study analyzed the role of differentvariables that determine long-term sinus rhythm maintenance inpatients with persistent atrial fibrillation who are treated withamiodarone.

Background: It has been recognized that different factors influence long-term sinus rhythm preservation after the conversion of persistent atrial fibrillation. Although the duration of the arrhythmia appears to be the most important factor, consistent information regarding the role of the mode of arrhythmia conversion (pharmacologic or electric) is still lacking.

Methods: One hundred and forty one anticoagulated patients with persistent atrial fibrillation (median duration 8 months, percentiles 25 and 75: 2-24) were treated for 4 weeks with oral amiodarone (600 mg/day). Those in whom the arrhythmia persisted underwent electric cardioversion. After restoration of normal sinus rhythm (either pharmacologic or electric), all patients received a daily dose of amiodarone (200 mg) and were followed for a median of 19 months (percentiles 25 and 75: 8-34 months).

Results: Sixty eight patients (48.22%) regained sinus rhythm during the initial period of amiodarone treatment with 600 mg/day (Group I) and 73 (51.78%) required electric cardioversion (Group II). During the entire follow-up, atrial fibrillation relapsed in 63 patients: 17 (25%) in Group I and 46 (63%) in Group II. Recurrences of the arrhythmia were strikingly less frequent in patients whose atrial fibrillation lasted 12 months or less (33/103, 32.3%) than in those whose atrial fibrillation lasted more than 12 months (30/38, 78.94%). In the multivariate analysis, the mode of reversion (HR, 0.37; CI, 0.21-0.65) and the duration of the arrhythmia (HR, 2.55; CI, 1.54-4.20) were the determinants for long-term sinus rhythm maintenance. Age, sex, left atrium size, left ventricle diameter, and the shortening fraction did not significantly influence the rate of arrhythmia recurrence. Among the 141 patients included in the study, 113 patients were followed for at least 1 year, and cardiac rhythm was assessed at this time. Of these, only 1 of 48 patients (2.1%) in Group I was in atrial fibrillation, in marked contrast with 18 of 65 patients (27.8%) in Group II (RR, 0.075; 95% CI, 0.01-0.54).

Conclusions: In patients with persistent atrial fibrillation, long-term preservation of sinus rhythm under chronic amiodarone treatment may be anticipated when the arrhythmia lasts 12 months or less and/or its reversion is obtained pharmacologically. We may confidently assume that these two factors have a beneficial additive influence on the outcome.
Amiodarone Rescue Therapy for Severe Decompensated Heart Failure Initially Unsuitable for β-Blockers
Authors: Choo Daniel C. , Huiskes Bonnie , Jones Jennifer , Fabbri Sharon , Hawkins Lee Ann , Chatterjee Kanu , De Marco Theresa , Heywood J. Thomas
Published: June 2007

Background: β-Blocker therapy is now standard therapy for patients with stable heart failure; however, fluid-overloaded, New York Heart Association Class IV patients tolerate β-blockers poorly. Amiodarone, a drug with antiadrenergic effects, has been shown to improve survival for patients with heart rates of 90 beats per minute or greater.

Methods: We reviewed 26 patients with severe decompensated heart failure who were started on oral amiodarone for heart rate control. β-Blocker titration was attempted when patients became clinically stable.

Results: The mean age of the patients was 48.5±17.5 years, and 73% were male. Fifteen patients were New York Heart Association Class IV, and 11 were Class III. Of these, 23 (88%) were fluid-overloaded, and 11 (42%) were on inotropic agents when amiodarone was started. The mean ejection fraction was 16.1 ± 6%. The initial dose of amiodarone was 346 ± 120 mg/day. Twenty (77%) patients were successfully started on β-blockers. At follow-up prior to β-blockers, 20 (77%) patients improved by at least one New York Heart Association class. Heart rate decreased from a mean of 98 ± 15 to 78 ± 13 beats per minute (P < .0001). Echocardiograms were available in 12 patients, with ejection fractions increasing from 16.1 ± 8% to 26.8 ± 13% (P= .004).

Conclusions: Amiodarone may be an effective rescue therapy for patients with decompensated heart failure and serve as a bridge to subsequent β-blocker therapy.
Upregulation of Angiotensin II Type 2 Receptor and Limitation of Myocardial Stunning by Angiotensin II Type 1 Receptor Blockers during Reperfused Myocardial Infarction in the Rat
Authors: Jugdutt Bodh I. , Menon Vijayan
Published: June 2007

Background: We have previously shown that angiotensin II type 1 receptor blockers induce cardioprotection and upregulate angiotensin II type 2 receptor during in vivo postischemicreperfusion in dogs. Whether angiotensin II type 1 receptor blockers upregulate angiotensin II type 2 receptors in rats is controversial, and whether surmountable and insurmountable angiotensin II type 1 receptor blockers exert similar protective effects during reperfused myocardial infarction is not known.

Methods: We assessed the effects of the surmountable angiotensin receptor blocker valsartan, and the insurmountable angiotensin receptor blocker irbesartan, on hemodynamics and left ventricular systolic and diastolic function (echocardiography/Doppler) in vivo and infarct size (triphenyl tetrazolium chloride method), and regional angiotensin II type 1 receptor and angiotensin II type 2 receptor expression (immunoblots) ex vivo, after anterior reperfused myocardial infarction in rats. The rats were randomized to four groups: intravenous valsartan (10 mg/kg, n = 8), irbesartan (10 mg/kg, n = 8), or saline vehicle (controls, n = 14) over 30 minutes before reperfused myocardial infarction, and sham (n = 8). Angiotensin II type 1 receptor blockade was assessed by the inhibition of angiotensin II pressor responses.

Results: Compared with the control group, both angiotensin receptor blockers significantly decreased infarct size, limited the increase in left atrial pressure, improved positive left ventricular dP/dtm,x and dP/dtm,,, improved left ventricular ejection fraction and diastolic function, and limited infarct expansion after reperfused myocardial infarction. Both angiotensin receptor blockers increased angiotensin II type 2 receptor protein in the postischemic-reperfused zone, with no change in angiotensin II type 1 receptor protein. There were no changes in the sham group.

Conclusion: The overall results indicate that the angiotensin receptor blockers valsartan and irbesartan both induce cardioprotection, limit myocardial stunning, and upregulate angiotensin II type 2 receptor protein expression after reperfused myocardial infarction in the rat. Patients who are already receiving angiotensin receptor blockers and develop acute coronary syndromes might benefit from these cardioprotective effects during reperfusion therapy.
Effect of Angiotensin II lype 2 Receptor Blockade on Activation of Mitogen-Activated Protein Kinases after Ischemia-Reperfusion in Isolated Working Rat Hearts
Authors: Kumar Dinender , Menon Vijayan , Ford William R. , Clanachan Alexander S. , Jugdutt Bodh I.
Published: June 2007

Background: The stress-responsive mitogen-activated protein kinases (MAPKs) (p38-MAPK, c-Jun NH2-terminal kinase [JNK-1 and JNK-2], and extracellular signal regulated kinases [ERK-1 and ERK-2]) might be involved in angiotensin II (AIJ)-induced ischemiareperfusion injury. Cardioprotection induced by All type 1 (AT1) and type 2 (AT2) receptor blockade during ischemia-reperfusion is associated with protein kinase Cc (PKCe), nitric oxide, and cyclic guanosine monophosphate (cGMP) signaling. Our aim was to assess the effect of selective AT, and AT2receptor blockade with losartan and PD123,319, respectively, on MAPK expression after ischemia-reperfusion in isolated working rat hearts.

Methods: Groups of six hearts were subjected to global ischemia (30 minutes) followed by reperfusion (30 minutes) and exposed to no drug/no ischemia-reperfusion (control), ischemia-reperfusionlno drug, and ischemia-reperfusion with losartan (1 MM), or PD123,319 (0.3,uM) and additional groups. AT,/AT2receptor expression, MAPKs, PKCE, and cGMP, and changes in mechanical function were measured. Western blotting was done on left ventricular tissue for AT,/AT2, p38/phosphorylated-p38 (p-p38), phosphorylated (p)-JNK-1/-2, phosphorylated (p)-ERK-1/-2, and PKCe proteins; Northern blots for AT,/AT2mRNA; and enzyme immunoassay for cGMP.

Results: Compared with controls, ischemia-reperfusion induced significant left ventricular dysfunction, decreased AT2protein and mRNA, increased p-p38 and p-JNK-1/-2, did not change p-ERK-1/-2 or PKCe, and decreased cGMP. PD123,319 improved left ventricular recovery after ischemia-reperfusion, increased AT2protein and mRNA, mildly increased p-p38, normalized p-JNK-1, did not change p-ERK-1/-2, and increased PKCe and cGMP. Losartan did not change p-p38, increased p-JNK-1, and did not change pERK- 1/-2, PKCe, or cGMP.

Conclusions: The overall results suggest that the activation of p38-MAPK and JNK might be linked to All signaling and play a significant role in acute ischemia-reperfusion injury as well as in the cardioprotective effect of AT2receptor blockade.
Ventricular Fibrillation Resulting from Acute Right Ventricular Infarction from Isolated Occlusion of a Right Ventricular Branch Artery
Authors: Chang Kirk Y. , Ebrahimi Ramin , Bersohn Malcolm M.
Published: June 2007

Malignant ventricular arrhythmias can result from isolated right ventricular infarction, and reports of this phenomenon in the literature are rare. We present a case of a 46-year-old man with acute onset of chest pain angiographically confirmed to be a result of isolated occlusion of a right ventricular branch artery. He developed ventricular fibrillation within 5 hours of symptom onset. This case highlights the point that despite its benign clinical appearance and preserved left ventricular function, necrosis of right ventricular tissue can have life-threatening consequences.
Left Ventricular Performance During Acute Rate Control in Atrial Fibrillation: The Importance of Heart Rate and Agent Used
Authors: Pinter Arnold , Dorian Paul , Paquette Miney , Ng Alvina , Burns Mark , Spanu Ileana , Freeman Michael , Korley Victoria , Newman David
Published: June 2007

Background: The relation between heart rate and left ventricular function during rate control in atrial fibrillation is incompletely understood.

Methods: Twenty-four patients (age 67 ± 11 years) with symptomatic recent onset rapid atrial fibrillation and rapid ventricular rate (> 110 bpm) were randomly assigned to receive either intravenous digoxin (13 mcg/kg) or intravenous diltiazem (0.25 mg/kg bolus plus a maintenance infusion). A portable radionuclide detector was used to collect validated measures of relative left ventricular volumes, along with heart rate data, every 15 seconds for 6 hours.

Results: Heart rate decreased significantly at 15 minutes and 180 minutes in the diltiazem group (from 133 ± 18 bpm to 111 ± 26 bpm [P < .01] to 94 ± 24 bpm [P < .001]) but not in the digoxin group (from 129 ± 18 bpm to 126 ± 17 bpm [P = NS] to 118 ± 15 bpm [P = NS]). Left ventricular ejection fraction improved in both groups to a similar extent (from 39 ± 10% to 50 ± 8%, [P < .05] after diltiazem, and from 38 ± 8% to 52 ± 11% [P < .05] after digoxin at baseline vs 180 minutes, respectively). The ejection fraction vs heart rate slope was steeper in the digoxin group than in the diltiazem group (-0.34 ± 0.18 vs -0.16 ± 0.17, P = .048) indicating a more pronounced improvement in ejection fraction per unit decrease in heart rate.

Conclusion: In patients with acute atrial fibrillation, digoxin led to similar improvements in ejection fraction compared to diltiazem despite a slower and less potent heart rate slowing.
Current Medical Management of Chronic Stable Angina
Authors: Thadani Udho
Published: June 2007

Severe atherosclerotic narrowing of one or more coronary arteries is responsible for myocardial ischemia and angina pectoris in most patients with stable angina. The coronary arteries of patients with stable angina also contain many more non-obstructive plaques, which are prone to rupture resulting in acute coronary syndrome (unstable angina, myocardial infarction, sudden ischemic death). Therefore, the medical management must use strategies which not only relieve symptoms and prolong angina free walking but also reduce the incidence of adverse clinical outcomes. Whether any of the approved antianginal drugs, nitrates, betablockers, and calcium channel blockers reduce the incidence of adverse clinical outcomes in patients with stable angina has not been studied to date. Published data shows that percutaneous coronary revascularization procedures and coronary bypass surgery are effective in relieving angina but these procedures do not reduce mortality or the incidence of myocardial infarction compared to anti-anginal drug therapy. From the available data, an initial trial of medical treatment with anti-anginal drugs and strategies to reduce adverse clinical outcomes (smoking cessation, daily aspirin, treatment of dyslipidemias and hypertension) is indicated in most patients with stable angina pectoris. The initial choice of drug will depend on the presence or absence of comorbid conditions. Patients who do not respond to medical therapy or do not wish to take anti-anginal drugs and whose life style is limited because of anginal symptoms should be offered percutaneous revascularization procedures with or without stent placement or coronary bypass surgery. New drug -coated stents hold promise but long-term data and large-scale trials assessing the continued long-term improvement in symptoms and reduction of adverse outcomes is needed before offering such devices to all patients with stable angina. Newer medical therapies such as metabolic modulators and sinus rate lowering drugs also hold promise but need further evaluation. Patients who have refractory angina despite optimal medical therapy and are not candidates for revascularization procedures may be candidates for some new techniques of enhanced exterual Counterpulsation, Spinal Cord Stimulation, sympathectomy or direct transmyocardial revascularization. The usefulness of these techniques, however, needs to be confirmed in large randomized trials.
Myocardial Energy Metabolism During Ischemia and the Mechanisms of Metabolic Therapies
Authors: Stanley William C.
Published: June 2007

The primary effect of ischemia is reduced aerobic adenosine triphosphate (ATP) formation in mitochondria. This triggers accelerated glycolysis and reduced cell pH, Ca2+ accumulation, K+ efflux, adenosine formation, and the clinical signs of ischemia: chest pain and a shift in the ST segment. Traditional therapies for angina are aimed at either decreasing the need for ATP by suppressing heart rate, blood pressure, and cardiac contractility, or at increasing oxygen delivery to the mitochondria, or both. An additional approach to treating angina is to suppress myocardial fatty acid oxidation, increase pyruvate oxidation, and reduce anaerobic glycolysis. High fatty acid levels result in oxygen wasting and inhibit the oxidation of pyruvate in the mitochondria. In experimental models, the partial inhibition of myocardial fatty acid oxidation with agents such as oxfenicine, ranolazine, and trimetazidine stimulates glucose oxidation and reduces lactate production during ischemia. Clinical studies demonstrate that this approach is as effective as traditional hemodynamic therapies at improving exercise tolerance and reducing the frequency of angina. Moreover, because these agents do not suppress heart rate, blood pressure, or contractility, they are effective as add-on therapy to Ca2+-channel and β-adrenergic receptor antagonists.
Antiarrhythmic and Proarrhythmic Properties of QT-Prolonging Antianginal Drugs
Authors: Singh Bramah N. , Wadhani Nitin
Published: June 2007

In recent years there has been a major reorientation of drug therapy for cardiac arrhythmias, its changing role, and above all, a radical change in the class of arrhythmia drugs because of their impact on mortality. The decline in the use of sodium-channel blockers has led to an expanding use of β-blockers and simple or complex class III agents for controlling cardiac arrhythmias. Success with these agents in the context of their side effects has spurred the development of compounds with simpler ion-channel blocking properties that have less complex adverse reactions. The resulting so-called pure class III agents, such as dofetilide or ibutilide, were found to have antifibrillatory effects in atrial fibrillation and flutter and in ventricular tachyarrhythmias. Such agents are effective and have diversity, but they have come into therapeutics with a price: the sometimes-fatal torsades de pointes. The drug amiodarone, a complex compound that was synthesized as an antianginal agent, has been an exception in this regard. Its therapeutic use is associated with a negligibly low incidence of torsades de pointes, even though the drug produces significant bradycardia and QT lengthening to 500 to 700 msec. Recent electrophysiologic studies suggest that this paradox is likely due to the differential block of ion channels in endocardium, epicardium, midmyocardial (M) cells, and Purkinje fibers in the ventricular myocardium. There is also clinical evidence suggesting that amiodarone reduces the “torsadogenic” effects of pure class III agents. Ranolazine was also synthesized for the development of antianginal properties that stem from a partial inhibition of fatty acid oxidation; it too has been found to have electrophysioloigic properties. These are somewhat similar to those of amiodarone on ion channels in endocardium, epicardium, M cells, and Purkinje fibers in the ventricular myocardium, but the drug does not prolong the QT interval to the same extent as amiodarone does. Thus, the drug produces modest increases in repolarization as judged by its effects on the action potential duration (APD) without the potential for the development of torsades de pointes. By virtue of its suppressant action on early afterdepolarizations and triggered activity in Purkinje fibers and M cells, the drug appears to have a powerful potential for reducing the torsadogenic proclivity of conventional class III antiarrhythmic compounds. The rationale for the therapeutic niche for amiodarone, and especially in the case of ranolazine, in the prevention of drug-induced torsades de pointes is discussed.
Dual Roles of 5-Hydroxytryptamine in Ischemia-Reperfusion Injury in Isolated Rat Hearts
Authors: Takano Shizuko , Hoshino Yuji , Li Libing , Matsuoka Isao , Ono Tomoyuki , Kimura Junko
Published: June 2007

Background: 5-Hydroxytryptamine (5-HT) has been shown to be involved in exacerbating cardiac ischemia-reperfusion injury; however, the role of 5-HT in the injury has yet to be established. This study demonstrates that 5-HT has dual roles in ischemia-reperfusion injury.

Methods and Results: The role of 5-HT in cardiac ischemia-reperfusion injury was examined in isolated rat hearts perfused with oxygenated Krebs-Henseleit solution. A 30-minute global ischemia and 30-minute reperfusion exacerbated functional cardiac parameters such as left ventricular end-diastolic pressure, coronary flow, heart rate, and total lactate dehydrogenase release. The 5-HT2A receptor antagonist sarpogrelate (0.3-1.0 μM) improved cardiac function during ischemia-reperfusion. High-performance liquid chromatography analysis revealed an elevation in the level of 5-HT in the coronary effluent immediately after ischemia, suggesting that 5-HT is released from the ischemic heart and that sarpogrelate protects the heart from ischemia-reperfusion injury by blocking 5-HT2A receptors. However, 5-HT (0.3-1.0,μM) applied exogenously unexpectedly improved the cardiac mechanical parameters during ischemia-reperfusion, increased coronary flow, and increased the level of NO in the effluent, which was inhibited by L-NG-nitro-arginine methyl ester, a NO synthase blocker.

Conclusions: Present results suggest dual roles of 5-HT in ischemia-reperfusion injury. During ischemia, 5HT is released endogenously, constricts coronary smooth muscles via 5-HT2A receptors, and aggravates cardiac function. In contrast, 5-HT applied exogenously affects predominantly non-5HT2A receptors on the endothelium and induces coronary vasodilatation via endothelial NO production, which is protective against ischemia-reperfusion injury.
Drug and Drug-Device Therapy in Heart Failure Patients in the Post-COMET and SCD-HeFT Era
Authors: Reiffel James A.
Published: June 2007

Reduced left ventricular ejection fraction and heart failure are the most important risk factors for sudden cardiac death. Recent trials have contributed to the knowledge base of critical therapies for the treatment of left ventricular systolic dysfunction and heart failure as it relates to arrhythmic and sudden cardiac death. Both pharmacologic and device therapies can reduce sudden cardiac death. The trials discussed in this paper have identified the pharmacologic and device interventions that are likely to improve the length and quality of life of the patient with left ventricular dysfunction and reduce the risk of sudden cardiac death. The mortality and anti-arrhythmic effects of angiotensin-converting enzyme inhibitors and β-blockers have been confirmed in large-scale controlled clinical heart failure trials. Recent trials have evaluated which agents are most effective and which patients will derive the most benefit from device therapy in terms of the reduction in the risk of sudden cardiac death and in the amelioration of heart failure. The recent data from the Carvedilol or Metoprolol European Trial (COMET) and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) are discussed as the latest in the series of landmark studies that have shaped the current approaches to treating patients with heart failure and that have altered the heart failure treatment paradigm.
A Review of Carvedilol Arrhythmia Data in Clinical Trials
Authors: Kowey Peter R.
Published: June 2007

β-Blockers are currently being evaluated more intensively to define their role in clinical use as antiarrhythmic agents. β-Adrenergic blockade has been studied in relation to atrial fibrillation, ventricular arrhythmias, and sudden death; however, it is apparent from a number of studies that not all β-blockers are equally effective. Randomized clinical trial data, both in heart failure and post-myocardial infarction (MI) patients, have shown differences in mortality benefits in addition to a variable effect on arrhythmias and sudden death. Carvedilol, a third-generation β-blocker with proven clinical benefit in the management of heart failure and post-MI patients, has properties that may make it an effective antiarrhythmic agent. This paper reviews the current clinical arrhythmia data available for carvedilol from large-scale clinical trials and small studies. The trial evidence demonstrates that carvedilol therapy can be an effective adjunctive rate-control therapy in patients with atrial fibrillation, prevent mortality in patients with heart failure or post-MI with left ventricular dysfunction, with or without atrial fibrillation, and reduce its onset and the incidence of ventricular arrhythmia and sudden death.
Combined Treatment With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers: A Review of the Current Evidence
Authors: Tsouli Sofia G. , Liberopoulos Evagelos N. , Kiortsis Dimitrios N. , Mikhailidis Dimitri P. , Elisaf Moses S.
Published: June 2007

Several studies have shown that angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are useful in the treatment of hypertension, cardiovascular disease, chronic heart failure, and some types of nephropathy. In this context, dual renin-angiotensin system blockade with both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may be more effective than treatment with each agent alone. Many clinical trials have demonstrated the beneficial effect of this combined treatment on proteinuria, hypertension, heart failure, and cardiovascular events. Moreover, these studies demonstrated that dual renin-angiotensin system blockade is generally safe and well tolerated. Long-term studies are under way to confirm these effects and also investigate the effectiveness of dual reninangiotensin system blockade on cerebrovascular disease and prevention of type 2 diabetes mellitus. These studies are expected to define the optimal use of combination treatment in everyday clinical practice. This review considers the most important clinical trials that evaluated the effect of dual renin-angiotensin system blockade on blood pressure, heart failure, and renal function.
Effect of Levosimendan and Milrinone on Regional Myocardial Ischemia/Reperfusion-Induced Arrhythmias in Dogs
Authors: Papp Julius Gy. , Pollesello Piero , Varró András F. , Végh Ágnes S.
Published: June 2007

Phosphodiesterase inhibitors as inodilators in heart failure are associated with promotion of arrhythmias. Calcium sensitizers have been proposed for the treatment of severe decompensated heart failure. The effect of levosimendan, a calcium sensitizer, and milrinone, a phosphodiesterase inhibitor, on ventricular arrhythmias was compared in a model of acute regional myocardial ischemia and reperfusion. The left anterior descending coronary artery in dogs was occluded for 25 minutes, followed by reperfusion. The 2 drugs were administered in a hemodynamically equieffective dose (0.1 μmol/kg) 10 minutes before coronary occlusion. Levosimendan, but not milrinone, significantly attenuated the pronounced increase in the number of ventricular premature beats (-63%), tachycardia (-50%), fibrillation (-70%), and inhomogeneity of ventricular electrical activation. Levosimendan significantly improved the overall survival rate. Levosimendan has a more beneficial profile than milrinone regarding the development of ventricular arrhythmias during and after regional myocardial ischemia
The Effect of Apolipoprotein E Polymorphism on the Response to Lipid-Lowering Treatment With Atorvastatin or Fenofibrate
Authors: Christidis Dimitrios S. , Liberopoulos Evangelos N. , Kakafika Anna I. , Miltiadous George A. , Cariolou Marios , Ganotakis Emmanuel S. , Mikhailidis Dimitri P. , Elisaf Moses S.
Published: June 2007

Although the effect of apolipoprotein E gene polymorphism on the response to treatment with statins has been studied, the results are conflicting. Moreover, little is known about the possible effect of apolipoprotein E alleles on the response to treatment with fibrates. The purpose of this study was to evaluate the effect of apolipoprotein E polymorphism on lipid-lowering response to treatment with atorvastatin and fenofibrate in patients with different types of dyslipidemia. The study population included 136 patients with heterozygous familial hypercholesterolemia (type IIA dyslipidemia) treated with atorvastatin (20 mg/day) and 136 patients with either primary hypertriglyceridemia (type IV dyslipidemia) or mixed hyperlipidemia (type IIB dyslipidemia) treated with micronized fenofibrate (200 mg/day). Overall, no significant associations were detected between apolipoprotein E genotype and response to treatment with atorvastatin. In patients treated with fenofibrate, significant associations were noted between apolipoprotein E genotype and changes in apolipoprotein B, apolipoprotein E and triglyceride levels. Specifically, in apolipoprotein E2, apolipoprotein E3, and apolipoprotein E4 individuals, apolipoprotein B reductions were 22%, 17%, and 8%, respectively ( P = .003); apolipoprotein E reductions were 45%, 20%, and 15%, respectively ( P = .006); whereas triglyceride reductions reached 53%, 36%, and 33%, respectively ( P = .033). In conclusion, apolipoprotein E genotype had no significant effect on the response to treatment with atorvastatin in patients with heterozygous familial hypercholesterolemia, but in patients with primary hypertriglyceridemia or mixed hyperlipidemia, there was a clear association between apolipoprotein E genotype and response to treatment with fenofibrate.
Effect of Barnidipine on Blood Pressure and Serum Metabolic Parameters in Patients With Essential Hypertension: A Pilot Study
Authors: Spirou Athanasia , Rizos Evangelos , Liberopoulos Evangelos N. , Kolaitis Nikolaos , Achimastos Apostolos , Tselepis Alexandros D. , Elisaf Moses
Published: June 2007

The effect of barnidipine, a calcium channel blocker, on metabolic parameters is not well known. The authors conducted the present pilot study to evaluate the possible effects of barnidipine on parameters involved in atherogenesis, oxidative stress, and clotting activity. This open-label intervention study included 40 adult patients with essential hypertension who received barnidipine 10 mg once daily. Barnidipine significantly reduced systolic and diastolic blood pressure as well as isoprostane levels, which represent a reliable marker of oxidative stress. In contrast, barnidipine had a neutral effect on lipid profile and apolipoprotein levels, did not influence glucose homeostasis, had no effect on renal function, and did not cause any changes in electrolyte levels. Moreover, barnidipine did not affect either the clotting/fibrinolytic status (evaluated by measurement of fibrinogen, total plasminogen activator inhibitor, tissue plasminogen activator, and a2 antiplasmin) or the enzymatic activity of the inflammatory/anti-inflammatory mediators lipoprotein-associated phospholipase A2 and paraoxonase 1, respectively. Barnidipine should be mainly considered as an antihypertensive agent with neutral effects on most of the studied metabolic parameters in hypertensive patients. Any antioxidant effect of barnidipine needs further investigation.
Evolving Perspectives on Clopidogrel in the Treatment of Ischemic Stroke
Authors: Gorelick Philip , Sechenova Oksana , Hennekens Charles H.
Published: June 2007

Antiplatelet therapy is indicated for the treatment of ischemic stroke or transient ischemic attack (TIA). Aspirin reduces subsequent occlusive vascular events, including recurrent stroke, by about 25%. In such patients, clopidogrel has been evaluated in an effort to further reduce risk. In the Management of Atherothrombosis with Clopidogrel in High-risk Patients trial, the combination of clopidogrel plus aspirin was compared with clopidogrel alone, and the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial tested the addition of clopidogrel to aspirin. Combination therapy with aspirin plus clopidogrel provided no significant incremental benefit compared with aspirin or clopidogrel alone. In addition, combination therapy increased the risk of serious bleeding. On the basis of the current totality of evidence for long-term treatment of survivors of ischemic stroke or TIA, clopidogrel is an effective alternative for patients who are intolerant to aspirin.
Short-Term Intra-Arterial Infusion of Monocyte Chemoattractant Protein-1 Results in Sustained Collateral Artery Growth
Authors: Seidler Randolph W. , Lenter Martin C. , Guth Brian D. , Doods Henri
Published: June 2007

Monocyte chemoattractant protein-1 (MCP-1) is a stimulator of collateral artery growth and has been shown to increase collateral artery conductance in rabbits and pigs. The minimal infusion duration and the minimally effective dose of MCP-1 are currently unknown, as is the sustainability of the therapeutic effect over a longer observation period than tested before. MCP-1 was infused intra-arterially in pigs after unilateral femoral artery occlusion in different doses and infusion durations between 2 hours and 2 weeks. Two weeks after ligation, arterial conductance under maximal vasodilatation was measured. The long-term efficacy was investigated in 2 additional groups of animals after 6 weeks. Infusion with 2 µg/min of MCP-1 for 6 hours was sufficient to double arterial conductance, and arterial conductance after 6 weeks was still significantly increased.
Assessing the Quality of the Dyadic Relationship in First-Time Parents: Development of a New Instrument
Authors: Ahlborg Tone , Persson Lars-Olof , Hallberg Lillemor R.-M.
Published: June 2007

The purpose of this research was to psychometrically evaluate the Dyadic Adjustment Scale (DAS), modified for use with new, first-time parents by extending the items of communication, sensuality, and sexuality. A total of 820 Swedish respondents, 6 months after the birth of their first child, participated in the study. Psychometric evaluation was conducted with factor analysis. The obtained factor structure was tested with multitrait analysis program. Thirty-three itemswere found to fit into a five-factor solution, explaining 50% of the total variance. Descriptive data revealed thatmost new parentswere satisfied with their intimate relationship in general, but dissatisfied with their sexual lives. Themodified DAS, now called the Quality of Dyadic Relationship Instrument includes 33 items and seems to be a useful, updated measurement for assessing quality of the intimate relationship in new first-time parents.
Tentative Guidelines and Practical Suggestions to Avoid Venous Thromboembolism During Oral Contraceptive Therapy
Authors: Girolami A. , Spiezia L. , Girolami B. , Vianello F.
Published: June 2007

Oral contraceptive therapy (OCT) is widely used in the world. It is usually safe and effective but side effects are occasionally seen. Venous thromboembolism is one of the most feared side effects. To avoid this complication adequate guidelines are needed. These have to take into account family history, personal history, and suitable laboratory investigations. The presence of an idiopathic venous thrombosis in the family or in the personal history is of paramount importance. However it is often difficult to ascertain whether a venous thrombosis is idiopathic or not. Even when there is doubt, a coagulation study should be carried out. An adequate coagulation study in this case should include at least an evaluation of antithrombin, protein C, and protein S. A search for homozygosity of factor V Leiden appears advisable. These defects represent absolute contraindications to the use of OCT. Relative contraindications may be represented by other minor coagulation disorders such as heterozygous factor V Leiden, fibrinolysis defects, and a G-to-A 20210 prothrombin abnormality. Other noncoagulation-related conditions such as hypertension, liver damage, and obesity may represent absolute or relative contraindications to the use of OCT.