Myocardial ischemia, reperfusion and free radical injury

Reperfusion of coronary arteries to limit myocardial ischemic injury and extent of myocardial necrosis is possible by either the use of fibrinolytic therapy, coronary angioplasty or coronary artery bypass surgery. The concept that early reperfusion may salvage jeopardized myocardium is derived from basic experimental studies which purported to demonstrate that the ultimate extent of irreversible myocardial injury could be reduced by reperfusion of the ischemic myocardium within 3 hours from the onset of regional myocardial ischemia. It is firmly established that salvage of ischemic myocardium is dependent on early restoration of blood flow to the myocardium at risk. Despite dependency on reoxygenation for ultimate survival, myocardial tissue that is reperfused and reoxygenated may be subjected to additional injurious insult due to reactive metabolites of oxygen. The cytotoxic species of oxygen are referred to as "oxygen free radicals." Coincident with the influx of inflammatory cells into the reperfused region is an additional loss of otherwise viable myocardial cells. There is strong support for the concept that the polymorphonuclear leukocyte is a contributor to the phenomenon of "reperfusion" or "reoxygenation" injury in the blood perfused heart. This discussion focuses on the role of the neutrophil as a potential contributor to the extension of tissue injury and reviews those interventions, which although in the experimental stage, offer promise of becoming therapeutically important in the future and may help elucidate the mechanisms underlying the potentially deleterious role of the neutrophil in situations involving whole blood reperfusion of the ischemic myocardium.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28563/1/0000365.pd

Sudden coronary death: pharmacological interventions for the prevention of ventricular fibrillation

Sudden coronary death in patients with coronary artery disease remains a major medical problem in most industrialized nations and in most instances is associated with the unexpected development of ventricular fibrillation. Despite the development of new anti-arrhythmic drugs, few, if any, are suitable for long-term prophylactic application and none were developed specifically for the prevention of ventricular fibrillation. This article discusses the importance of the preclinical phase of drug development in an attempt to focus on those electrophysiological mechanisms which superimpore upon a vulnerable myocardium thus leading to the onset of lethal arrhythmias. It is against this background that potentially useful pharmacological interventions must be assessed if specific therapy for the prevention of sudden coronary death is to become a reality.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24972/1/0000399.pd

Rationale of therapy in the patient with acute myocardial infarction and life-threatening arrhythmias: A focus on bretylium

Experimental evidence suggests a number of pathologic and electrophysiologic mechanisms that may help initiate ventricular arrhythmias accompanying myocardial ischemia and infarction. Early and late phase events are associated with reentry or an enhancement of focal mechanisms, or both. These can initiate ventricular tachycardia (VT) or ventricular fibrillation (VF), or both. The presence of distinct mechanisms that may initiate and maintain life-threatening dysrhythmias early in myocardial ischemia suggest different pharmacologic approaches for their prevention or suppression. Another consideration concerns patients subjected to coronary artery angioplasty or thrombolytic therapy and the development of arrhythmias associated with reperfusion of the once ischemic myocardium. The electrophysiologic mechanisms associated with reperfusion arrhythmias are unknown, and little is known about appropriate therapy for each episode of cardiac dysrhythmia.Ventricular extrasystoles or VT usually precedes VF. These premonitory arrhythmias are poor criteria for the institution of antiarrhythmic drug therapy, because VF develops within 1 to 10 minutes after the appearance of the rhythmic disturbances. Some authorities suggest that all patients with acute myocardial infarction should receive prophylactic antiarrhythmic therapy, because warning arrhythmias either do not occur at all or provide insufficient time to intervene pharmacologically.Many of the new class 1 antiarrhythmic agents effectively reduce the frequency of premature ventricular depolarizations, but lack specific antiflbrillatory activity. However, the recent introduction of bretylium into clinical cardiology opens a new approach to preventing life-threatening ventricular dysrhythmias. Along with other members of class III, bretylium exerts different cardiac electrophysiologic effects than do the other 3 classes of drugs. Bretylium has been designated as class III because it increases the action potential duration and prolongs the effective refractory period. The other class III drugs, including amiodarone, sotalol, clofilium and pranolium, experimentally prevent the establishment of a reentry pathway that can initiate VF. Bretylium along with these other class III agents is primarily antifibrillatory rather than antiarrhythmic. Thus, antiarrhythmic agents that reduce the frequency and complexity of premature ventricular depolarizations are not necessarily antifibrillatory. It is necessary to reorient our thinking about how pharmacologic interventions may influence the course of events in patients at risk of developing life-threatening ventricular arrhythmias. Because the lethal event is most often associated with VF, it may be sufficient to have an agent that protects against this electrophysiologic disorder even though it does not completely prevent or suppress other ventricular arrhythmias.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24751/1/0000173.pd

Cardiac Arrhythmia and Injury Induced in Rats by Burst and Pulsed Mode Ultrasound With a Gas Body Contrast Agent

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135652/1/jum200928111519.pd

EFFECT OF INFARCT SIZE LIMITATION BY PROPRANOLOL ON VENTRICULAR ARRHYTHMIAS AFTER MYOCARDIAL INFARCTION

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75625/1/j.1749-6632.1982.tb55220.x.pd

BMY21190, A Potent Inhibitor of cAMP Phosphodiesterase

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72811/1/j.1527-3466.1994.tb00291.x.pd

Bretylium: A prototype for future development of antidysrhythmic agents

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25154/1/0000590.pd

Electrophysiologic and antiarrhythmic actions of nadolol: Acute ischemia in the presence of previous myocardial infarction

The actions of the [beta]-adrenergic receptor antagonist, d,l-nadolol, were examined in anesthetized dogs subjected to circumflex coronary artery ligation in the presence of previous anterior myocardial infarction. With circumflex ligation, control dogs (N = 18) developed premature ventricular boats and ventricular tachycardia, followed by ventricular fibrillation (N = 16, 89%). Immediate arrhythmias (2 to 5 minutes) were accompanied by activation delays and continuous diastolic electrical activity in acutely ischemic epicardial tissue. Delayed arrhythmias (6 to 12 minutes) were accompanied by delayed activation and continuous diastolic electrical activity in acutely ischemic mid-myocardium. Nadolol (8 mg/kg, intravenously) (N = 10) reduced ventricular arrhythmias during both phases of arrhythmia development and increased survival (70%, p = 0.001 vs control). Nadolol failed to alter activation in acutely ischemic epicardium, but prevented beat-to-beat changes in epicardial and mid-myocardial activation. Atrial pacing of nadolol-treated animals at heart rates comparable with those of the control group reversed the beneficial effects of nadolol on the development of ventricular arrhythmias and ventricular fibrillation (70%; p = 0.07 vs nadolol; p = 0.21 vs control, respectively). The beneficial effects of nadolol could not be attributed to reduced epicardial delays, but were associated with the suppression of beat-to-beat conduction abnormalities that preceded ventricular fibrillation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27090/1/0000081.pd

Cardioprotective effects of amlodipine in the ischemic-reperfused heart

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27711/1/0000098.pd

Reperfusion injury after myocardial infarction: The role of free radicals and the inflammatory response

Development of thrombolytic therapy as a treatment for myocardial infarction has focused attention on the events that occur upon reperfusion of ischemic myocardial tissue. Although it is well documented that salvage of the ischemic myocardium is dependent upon timely reperfusion, it is likely that the very events critical for survival may, in fact, lead to further tissue injury. A widely recognized source of reperfusion injury is the generation of oxygen-derived free radicals. These reactive oxygen species, which are formed within the first moments of reperfusion, are known to be cytotoxic to surrounding cells. In addition, strong support exists for the involvement of the inflammatory system in mediating tissue damage upon reperfusion. Coincident with the recruitment of neutrophils and activation of the complement system is an increase in the loss of viable cells. Although a number of mechanisms are likely to be involved in reperfusion injury, this discussion focuses on the roles that oxygen-derived free radicals and the inflammatory system play in mediating reperfusion injury.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30553/1/0000186.pd