The use of antiplatelet agents in cardiac disease.

In this clinical review, the authors focus on the process of platelet activation and thrombosis in acute and chronic coronary syndromes. New antithrombotic therapies have emerged for various cardiovascular diseases, based on the evolving concept of vascular injury and platelets and the knowledge of the pathophysiology of the underlying disease states. An understanding of these mechanisms is crucial to therapeutic decision making with antiplatelet regimens, which are also discussed in detail.

Management of mobile right atrial thrombi: a therapeutic dilemma.

BACKGROUND: Mobile right atrial thrombus is an uncommon finding on two-dimensional (2D) echocardiography. Therapeutic alternatives include systemic heparinization, systemic or local thrombolysis, and surgical removal. We report our clinical experience in six patients over a 3-year period (6000 echocardiograms) at a tertiary care referral center. METHODS: There were four men and two women with a mean age of 63 years (range: 47 to 73 years). Indications for echocardiography consisted of progressive dyspnea and chest pain in five patients and syncope with chest pain in one patient. RESULTS: All were observed to have a mobile thrombus in the right atrium. Ventilation perfusion (V/Q) scanning confirmed V/Q mismatch in all patients. Subsequent echocardiography (minutes to 1 day later) in three patients demonstrated absence of the thrombus suggesting pulmonary embolization. One patient died during transesophageal echocardiography (TEE) and autopsy confirmed a large pulmonary embolization in the main pulmonary artery. Treatment consisted of heparinization in 3 patients, systemic thrombolysis in 1 patient, and surgical removal of the thrombus in 1 patient. At surgery, a long serpiginous thrombus was seen in the right atrium, tethered to a fenestrated eustachian valve. There were 3 deaths: 1 patient treated with heparin; 1 patient treated with thrombolysis; and 1 during TEE. Two of the three patients treated with heparin and one patient undergoing surgical removal survived hospitalization. CONCLUSIONS: Mobile thrombus in the right atrium is an unusual echocardiographic finding. It portends a poor prognosis with death due to pulmonary embolism.

Circadian variation in sudden cardiac death: effects of age, sex, and initial cardiac rhythm.

STUDY OBJECTIVE: Previous studies based on data obtained from vital statistics records have demonstrated circadian variation in the occurrence of sudden cardiac death. The purpose of this study was to examine the effects of age, sex, and initial cardiac rhythm on circadian variability in sudden cardiac death. METHODS: This study employed a retrospective analysis of the records of adult patients with witnessed cardiac arrest who underwent resuscitation in an urban paramedic system during a 5-year period. RESULTS: The records of 2,250 consecutive patients with witnessed cardiac arrest were reviewed. Spectral analysis was used to decompose the data into frequency components. A circadian variation in the occurrence of sudden cardiac death was demonstrated, with a low occurrence rate between midnight and 6 AM and a 2.4-fold increase between the rate at 6 AM and the rate at noon. The same circadian pattern was noted among both men and women, among both patients aged 18 to 70 and those older than 70 years, and among patients with various initial cardiac arrest rhythms (ventricular tachycardia or fibrillation, asystole, and electromechanical dissociation). However, the outcome of resuscitation in these patients (ie, the rate of successful resuscitation and the rate of survival) did not demonstrate circadian variation. CONCLUSION: Witnessed out-of-hospital sudden cardiac death demonstrated circadian variation, and this variability was observed regardless of the patient's age, sex, or initial cardiac arrest rhythm. The outcome of resuscitation did not show circadian variability. These results suggest a common pathophysiologic mechanism leading to sudden cardiac death.

Subpectoral implantation of ICD generators: long-term follow-up.

A nonthoracotomy surgical approach using an endocardial electrode and combined implantation of a subcutaneous patch and the implantable cardioverter defibrillator (ICD) generator in a subpectoral pocket has been described. We report the long-term follow-up results in patients undergoing implantation using this approach. The patient population consisted of 28 patients (22 men and 6 women) with a mean age of 59 +/- 12 years. The underlying heart disease consisted of coronary artery disease in 20 patients and dilated cardiomyopathy in 8 patients. Sustained ventricular tachycardia was the mode of presentation in 16 patients and sudden cardiac death in 12 patients. The mean left ventricular ejection fraction was 31% +/- 6%. The lead system consisted of an 8 French bipolar passive fixation rate sensing lead positioned at the right ventricular apex, an 11 French spring coil electrode positioned at the superior vena cava-right atrial junction (surface area 700 mm2), and submuscular placement of a large patch (surface area 28 cm2) on the anterolateral chest wall near the cardiac apex via a submammary incision. A defibrillation threshold of < or = 15 joules (J) was required for implantation. This criterion was not satisfied in five patients; thus, a limited thoracotomy was performed via the submammary incision, and the large patch was placed epicardially. The mean R wave amplitude was 12 +/- 3 mV, the mean pacing threshold was 1.0 +/- 0.5 V at 0.5 msec, and the mean defibrillation threshold was 12.6 +/- 3 J. ICD generators implanted were the Ventak-P in 17, PCD-7217 in 5, and the Cadence V-100 in 6 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypersensitivity reaction associated with acute hepatic dysfunction following a single intravenous dose of procainamide.

Rare cases of hepatotoxicity have been attributed to the antiarrhythmic agent procainamide. We here describe the case of a patient who had a hypersensitivity reaction to procainamide with fever, chills, arthralgia, abdominal pain and acute elevations of serum aminotransferase activities and bilirubin concentration. The reaction occurred after the patient had received a large intravenous dose during cardiac electrophysiological testing. This case should alert physicians to potential hepatotoxic reactions to procainamide, particularly with the increasing popularity of cardiac electrophysiological testing, during which this drug is commonly used.

Determinants of pace-terminable ventricular tachycardia: implications for implantable antitachycardia devices.

The next generation of implantable antitachycardia devices incorporate antitachycardia pacing for the treatment of ventricular tachycardia. To evaluate the potential determinants of pace terminability, we analyzed 62 episodes of induced monomorphic ventricular tachycardia. We found that the tachycardia cycle length and cycle length variability are the major determinants of pace terminability. These findings should be considered in the designing of ventricular tachycardia detection and termination algorithms.

The porcine model for the understanding of thrombogenesis and atherogenesis.

The hypothesis originated by Carl Rokitansky a century ago that thrombosis contributes substantially to atherosclerosis has been rekindled by accumulating experimental and clinical evidence. On the basis of our experience with the experimental porcine model, several important biologic determinants of thrombosis have been identified. The degree of vascular injury seems to be the primary determinant of the thrombotic response. In addition, hemodynamic shear stress and the presence of the von Willebrand factor have important roles in the process of thrombosis. Although there is little evidence that thrombosis is a factor in the initiation of spontaneous, or naturally occurring, atherosclerosis, substantial evidence suggests that thrombosis has an essential role in the progression of spontaneous atherosclerosis and also in the early pathogenic process of the syndromes of accelerated atherosclerosis-namely, heart transplant atherosclerosis, vein graft disease, and coronary restenosis after angioplasty. Advances in the understanding of vascular injury and of the interactions of blood cells with the vascular wall have allowed development of new experimental antithrombotic strategies and subsequent clinical applications in the prevention of these vascular diseases.

Importance of experimental models for the development of clinical trials on thromboatherosclerosis.

Experimental models of vascular injury have enhanced our understanding of the pathophysiological process leading to vascular obstruction in both spontaneous and accelerated atherosclerosis. Based on experimental findings, we present and discuss a pathological classification of vascular injury or damage and its role in the pathogenesis of various vascular diseases. In addition, these animal models have provided insights into the roles of platelets and lipid metabolism in the evolution and progression of atherosclerosis and have suggested potential therapeutic applications. Thus, based on studies in the pig models, antiplatelet agents have been shown for the first time to have a beneficial effect in preventing the formation and progression of coronary atherosclerotic lesions in humans. Similarly, our findings in high density lipoprotein plasma fractions regarding inhibition and even reversal of the process of atherosclerosis in a hypercholesterolemic rabbit model have added new insights to an explosive field of lipoprotein research and provided new avenues of therapeutic strategies. our in vivo and ex vivo pig models of an extracorporeal perfusion chamber mimicking the various coronary conditions have aided in the understanding of the pathophysiology of the acute coronary syndromes and intensified our search for the ideal antithrombotic regimen in these high-risk patients. Finally, a carotid pig model of balloon angioplasty, a dog model of saphenous vein grafting, and a pig model of heart transplantation not only have provided insights into the pathophysiological process of accelerated atherosclerosis but also are allowing development of new antithrombotic and antiproliferative approaches for the prevention of these accelerated vascular diseases. In summary, we are entering an exciting era in vascular research. Significant advances in our understanding of vascular injury or damage as well as the interactions of blood cells and lipids with the vascular wall have allowed us to formulate new experimental strategies with subsequent clinical application in the prevention and progression of these vascular diseases.

The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty.

Coronary angioplasty has become a successful and widely used treatment for patients with coronary artery disease since its first clinical application in 1977. The primary success rate has improved despite the increase in procedure and case complexity. However, acute reocclusion and late restenosis, which constitute the most important problems after successful angioplasty, continue to occur in about 5% and 35% of patients within 3 to 6 months, respectively. Angioscopic and pathologic observations have suggested that a multifactorial pathophysiologic process accounts for acute reocclusion, involving marked thrombosis, intimal dissection, medial and subintimal hemorrhage, vascular recoil and vasocontriction. In contrast, chronic restenosis involves the development of fibrocellular intimal hyperplasia within a milieu created by vascular injury, platelet activation, thrombin generation and the release of mitogens. Although current pharmacologic approaches, which involve antithrombotic and anticoagulant therapy, have been largely ineffective in eliminating acute reocclusion and chronic restenosis, recent advances in the research in thrombosis, platelet receptors and smooth muscle growth regulation have allowed new therapeutic options to be tested in the experimental setting, with subsequent potential clinical applications in patients.

Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation.

Vascular injury represents a critical initiating event in the pathogenesis of various vascular diseases, including atherosclerosis. This review discusses 1) the current understanding and a new pathologic classification of vascular injury; 2) the resultant cellular pathophysiologic responses, specifically, lipid accumulation, platelet aggregation, thrombus formation and smooth muscle cell proliferation; 3) the role of vascular injury in the pathogenesis of spontaneous and accelerated atherosclerosis; and 4) emerging therapeutic approaches in preventing these vascular diseases. The process of type I vascular injury (nondenuding functional injury) followed by lipid accumulation, monocyte and platelet adhesion, smooth muscle cell proliferation and resultant plaque formation represents the prevalent view of the early stages of spontaneous atherogenesis. The syndromes of accelerated atherosclerosis (namely, heart transplant atherosclerosis, coronary vein graft disease and restenosis after percutaneous transluminal coronary angioplasty) appear to share etiologic mechanisms with spontaneous atherosclerosis by means of the "response to injury" hypothesis. However, type II and type III vascular injury (denuding endothelial and intimal injury with or without medial damage) followed by thrombus and its organization by smooth muscle cell proliferation and subsequent fibrosis appear to be responsible for the vascular process. This accelerated and premature occlusive process accounts for significant morbidity and mortality in patients with these conditions. Better understanding of the nature of vascular injury and its pathophysiologic responses in these clinical situations may aid in developing therapeutic strategies for preventing these vascular diseases.

Depletion of myocardial high energy phosphates by induction of ventricular fibrillation prior to cardioplegic arrest.

The effects of a short period of ventricular fibrillation on myocardial high energy phosphates were assessed in two groups of rats. Group 1 underwent hypothermic crystalloid cardioplegia infusion and aortic cross-clamping. In Group 2, cardioplegia and cross-clamping were preceded by ten seconds of induced ventricular fibrillation. In rat hearts that had undergone ventricular fibrillation, adenosine triphosphate levels averaged only 70% (p less than .0001) and creatine phosphate levels averaged only 60% (p less than .0005) of levels measured following standard cardioplegic arrest without ventricular fibrillation. These findings are of potential importance in both routine cardiac surgical procedures and in organ procurement.

Exploration of the atherosclerotic plaque.

During the past 3 decades we have achieved a better understanding of the atherosclerotic process. It has been described as a series of changes in the intima of arteries consisting of the focal accumulation of lipids, complex carbohydrates, blood and blood products, fibrous tissues, and calcium that are also associated with changes in the media. The process begins with a vascular injury that is complicated by the deposition of cholesterol esters and cholesterol. It is followed by the accumulation of lipid ladened monocytes as well as the initiation of immune mechanisms. The proliferation of smooth muscle cells into the lesion assures its permanence by the synthesis of fibrous tissue. Platelet aggregation, thrombosis and hemorrhage are all key components of plaque progression, that ultimately are associated with vascular occlusion and focal vascular spasm. Calcium plays an important role in the development of hard, ulcerated lesions. Atherosclerotic risk factors are believed to accelerate the progression of atherosclerotic plaques and the control of these risk factors may retard their proliferation and progression.

Preservation of myocardial high energy phosphates during cardioplegic arrest with nifedipine.

Nifedipine used both as an additive to cardioplegia solution (CPS) and as pretreatment prior to arrest was studied in a rat model to determine its effect upon ischemic ventricular electromechanical work during arrest and upon high energy phosphate levels. Fifty-one normothermic rats were studied in vivo with infusion of hypothermic (4 degrees C) CPS into the cross-clamped aortic root according to one of the following eight protocols: Group 1, baseline beating hearts; Group 2, CPS containing 15 mEq potassium chloride/liter (KCl/liter); Group 3, CPS containing 30 mEq KCl/liter; Group 4, CPS containing 15 mEq KCl/liter combined with stimulation of the vagus nerve; Groups 5 and 6, CPS with 15 mEq KCl/liter and containing 250 or 500 micrograms of nifedipine per liter; Groups 7 and 8, pretreatment with 100 or 200 micrograms nifedipine/kg given as an intravenous bolus 15 min prior to infusion of CPS with 15 mEq KCl/liter. Time to arrest, number of ischemic ventricular contractions after aortic cross clamping, and ATP and creatine phosphate (CP) levels were recorded. All nifedipine groups arrested more quickly and with fewer ventricular contractions and had ATP and CP levels higher than those of Group 2 (P less than 0.05). There were no differences between the nifedipine groups and Group 3 except that Group 8 (200 micrograms/kg pretreatment) resulted in higher levels of CP than Groups 3, 5, and 6 (P less than 0.05 for all groups). When all groups were combined, time to arrest correlated negatively with ATP (r = -0.863, P less than 0.01) and CP (r = -0.824, P less than 0.01) levels.(ABSTRACT TRUNCATED AT 250 WORDS)