thiourea and Death--Sudden--Cardiac

Sudden cardiac death resulting from ventricular tachyarrhythmias remains the leading cause of death in industrially developed countries, accounting for between 300,000 and 500,000 deaths each year in the United States. Yet, despite the enormity of this problem, the development of safe and effective anti-arrhythmic agents remains elusive. The identification of effective anti-arrhythmic agents is critically dependent upon the use of appropriate animal models of human disease. During the last 25 years, a canine model of sudden cardiac death has proven to be useful in both the identification of factors contributing to ventricular fibrillation (VF) and the evaluation of potential anti-arrhythmic therapies. The present review provides a detailed retrospective analysis of the data obtained with this model. Briefly, VF was reliably and reproducibly induced by the combination of acute myocardial ischemia at site distant from a previous myocardial infarction during submaximal exercise (to activate the autonomic nervous system). This exercise plus ischemia test identified 2 stable populations of dogs: those that development malignant arrhythmias (susceptible, n=303) and those that rarely developed even single premature ventricular activation (resistant, n=209). The susceptible animals exhibited an elevated sympathetic activation (due to an enhanced beta2-adrenoceptor responsiveness) and a subnormal parasympathetic regulation. Several interventions have proven to be particularly effective in preventing VF in the susceptible dogs; including calcium channel antagonists, left stellate ganglion disruption, ATP-sensitive potassium channel antagonists, beta-adrenoceptor antagonists, and non-pharmacological interventions (endurance exercise training and dietary omega-3 fatty acids).

Topics: Animals; Anti-Arrhythmia Agents; Autonomic Nervous System; Blood Pressure; Calcium; Death, Sudden, Cardiac; Disease Models, Animal; Dogs; Electrocardiography; Exercise; Fish Oils; Heart; Heart Rate; Humans; Sulfonamides; Thiourea; Ventricular Fibrillation

There is increasing evidence for a fatal interaction of myocardial ischemia, ventricular arrhythmias and sudden cardiac death in some patients with coronary artery disease. Evidence comes from autopsy studies, from the evaluation of patients who survived an episode of sudden cardiac death, from follow-up data of these patients either treated or not by revascularization therapy and/or an implantable cardioverter-defibrillator and indicate that reducing the individual ischemic burden will be beneficial to reduce the incidence of sudden cardiac death. Studies in patients with stable and especially with unstable angina using Holter monitoring could demonstrate that there is a close and causal relationship between myocardial ischemia inducing or aggravating life-threatening ventricular arrhythmias and sudden cardiac death particularly in patients with unstable and postinfarction status. This review summarizes some of our clinical knowledge on this topic and indicates that preventive strategies for myocardial ischemia are the antiarrhythmic treatment of choice in patients with severe coronary artery disease and patients with evidence or at risk for ischemic proarrhythmia.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Autopsy; Blood Coagulation; Coronary Disease; Death, Sudden, Cardiac; Defibrillators, Implantable; Electrocardiography; Humans; Ligation; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Myocardial Revascularization; Potassium Channel Blockers; Risk; Risk Factors; Sulfonamides; Tachycardia, Ventricular; Thiourea; Time Factors

ATP-sensitive potassium (K(ATP)) channels are activated during myocardial ischemia. The ensuing potassium efflux leads to a shortening of the action potential duration and depolarization of the membrane by accumulation of extracellular potassium favoring the development of reentrant arrhythmias, including ventricular fibrillation. The sulfonylthiourea HMR 1883 was designed as a cardioselective blocker of myocardial K(ATP) channels for the prevention of arrhythmic sudden death in patients with ischemic heart disease. We investigated the effect of HMR 1883 on sudden cardiac arrhythmic death and electrocardiography (ECG) changes induced by 20 min of left anterior descending coronary artery occlusion in pentobarbital-anesthetized pigs. HMR 1883 (3 mg/kg i.v.) protected pigs from arrhythmic death (91% survival rate versus 33% in control animals; n = 12; p<.05). Ischemic areas were of a similar size. The compound had no effect on hemodynamics and ECG, including Q-T interval, under baseline conditions and no effect on hemodynamics during occlusion. In control animals, left anterior descending coronary artery occlusion lead to a prompt and significant depression of the S-T segment (-0.35 mV) and a prolongation of the Q-J time (+46 ms), the former reflecting heterogeneity in the plateau phase of the action potentials and the latter reflecting irregular impulse propagation and delayed ventricular activation. Both ischemic ECG changes were significantly attenuated by HMR 1883 (S-T segment, -0.14 mV; Q-J time, +15 ms), indicating the importance of K(ATP) channels in the genesis of these changes. In conclusion, the K(ATP) channel blocker HMR 1883, which had no effect on hemodynamics and ECG under baseline conditions, reduced the extent of ischemic ECG changes and sudden death due to ventricular fibrillation during coronary occlusion.

Topics: Anesthesia; Animals; Arrhythmias, Cardiac; Coronary Disease; Death, Sudden, Cardiac; Electrocardiography; Hemodynamics; Myocardial Ischemia; Potassium; Sulfonamides; Swine; Thiourea