Dictyostelium, a microbial model for brain disease.

BACKGROUND: Most neurodegenerative diseases are associated with mitochondrial dysfunction. In humans, mutations in mitochondrial genes result in a range of phenotypic outcomes which do not correlate well with the underlying genetic cause. Other neurodegenerative diseases are caused by mutations that affect the function and trafficking of lysosomes, endosomes and autophagosomes. Many of the complexities of these human diseases can be avoided by studying them in the simple eukaryotic model Dictyostelium discoideum. SCOPE OF REVIEW: This review describes research using Dictyostelium to study cytopathological pathways underlying a variety of neurodegenerative diseases including mitochondrial, lysosomal and vesicle trafficking disorders. MAJOR CONCLUSIONS: Generalised mitochondrial respiratory deficiencies in Dictyostelium produce a consistent pattern of defective phenotypes that are caused by chronic activation of a cellular energy sensor AMPK (AMP-activated protein kinase) and not ATP deficiency per se. Surprisingly, when individual subunits of Complex I are knocked out, both AMPK-dependent and AMPK-independent, subunit-specific phenotypes are observed. Many nonmitochondrial proteins associated with neurological disorders have homologues in Dictyostelium and are associated with the function and trafficking of lysosomes and endosomes. Conversely, some genes associated with neurodegenerative disorders do not have homologues in Dictyostelium and this provides a unique avenue for studying these mutated proteins in the absence of endogeneous protein. GENERAL SIGNIFICANCE: Using the Dictyostelium model we have gained insights into the sublethal cytopathological pathways whose dysregulation contributes to phenotypic outcomes in neurodegenerative disease. This work is beginning to distinguish correlation, cause and effect in the complex network of cross talk between the various organelles involved. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.

Do advanced glycation end products contribute to food allergy?

Sugars can bind non-enzymatically to proteins, nucleic acids or lipids and form compounds called Advanced Glycation End Products (AGEs). Although AGEs can form in vivo, factors in the Western diet such as high amounts of added sugars, processing methods such as dehydration of proteins, high temperature sterilisation to extend shelf life, and cooking methods such as frying and microwaving (and reheating), can lead to inordinate levels of dietary AGEs. Dietary AGEs (dAGEs) have the capacity to bind to the Receptor for Advanced Glycation End Products (RAGE) which is part of the endogenous threat detection network. There are persuasive epidemiological and biochemical arguments that correlate the rise in food allergy in several Western countries with increases in dAGEs. The increased consumption of dAGEs is enmeshed in current theories of the aetiology of food allergy which will be discussed.

Effect of the right ventricular isolation procedure on ventricular vulnerability to fibrillation.

A certain critical mass of myocardium is believed to be necessary to initiate ventricular fibrillation. The right ventricular isolation procedure, employed clinically to confine ventricular tachyarrhythmias to the right ventricle, decreases the ventricular mass available for fibrillation by isolating the ventricles from each other. The effect of this procedure on ventricular fibrillation thresholds is unknown. Left and right ventricular fibrillation thresholds were measured before and after right ventricular isolation in 10 adult mongrel dogs utilizing a single 5 ms stimulus of increasing current strength applied to the epicardium during the vulnerable period. There were no significant differences in heart rate, aortic blood pressure, left atrial pressure, temperature, arterial blood gases or regional myocardial blood flow between the study periods. In 9 of the 10 dogs, the isolated right ventricle could not sustain ventricular fibrillation despite the utilization of stimulus strengths of up to 80 mA. In the 10th dog, the right ventricular fibrillation threshold increased 150%, from 20 to 50 mA. The left ventricular fibrillation threshold markedly increased in every dog, with an average increase from 23 +/- 2 to 40 +/- 4 mA (p less than 0.0005). To determine whether time, cardiopulmonary bypass or the right ventricular incision could cause similar changes in ventricular fibrillation threshold, five different dogs underwent the entire experimental protocol except for incomplete isolation of the right ventricle. There were no significant changes in ventricular fibrillation thresholds in these dogs. Thus, in the canine model, right ventricular isolation can prevent the occurrence of sustained fibrillation in the isolated right ventricle and can significantly increase the left ventricular fibrillation threshold.

Outcomes of cardiac surgery in patients > or = 80 years: results from the National Cardiovascular Network.

OBJECTIVES: The purpose of this study was to evaluate characteristics and outcomes of patients age > or =80 undergoing cardiac surgery. BACKGROUND: Prior single-institution series have found high mortality rates in octogenarians after cardiac surgery. However, the major preoperative risk factors in this age group have not been identified. In addition, the additive risks in the elderly of valve replacement surgery at the time of bypass are unknown. METHODS: We report in-hospital morbidity and mortality in 67,764 patients (4,743 octogenarians) undergoing cardiac surgery at 22 centers in the National Cardiovascular Network. We examine the predictors of in-hospital mortality in octogenarians compared with those predictors in younger patients. RESULTS: Octogenarians undergoing cardiac surgery had fewer comorbid illnesses but higher disease severity and surgical urgency than younger patients. Octogenarians had significantly higher in-hospital mortality after cardiac surgery than younger patients: coronary artery bypass grafting (CABG) only (8.1% vs. 3.0%), CABG/aortic valve (10.1% vs. 7.9%), CABG/mitral valve (19.6% vs. 12.2%). In addition, they had twice the incidence of postoperative stroke and renal failure. The preoperative clinical factors predicting CABG mortality in the very elderly were quite similar to those for younger patients with age, emergency surgery and prior CABG being the powerful predictors of outcome in both age categories. Of note, elderly patients without significant comorbidity had in-hospital mortality rates of 4.2% after CABG, 7% after CABG with aortic valve replacement (CABG/AVR), and 18.2% after CABG with mitral valve replacement (CABG/MVR). CONCLUSIONS: Risks for octogenarians undergoing cardiac surgery are less than previously reported, especially for CABG only or CABG/AVR. In selected octogenarians without significant comorbidity, mortality approaches that seen in younger patients.

Genetic factors contribute to bleeding after cardiac surgery.

BACKGROUND: Postoperative bleeding remains a common, serious problem for cardiac surgery patients, with striking inter-patient variability poorly explained by clinical, procedural, and biological markers. OBJECTIVE: We tested the hypothesis that genetic polymorphisms of coagulation proteins and platelet glycoproteins are associated with bleeding after cardiac surgery. PATIENTS/METHODS: Seven hundred and eighty patients undergoing aortocoronary surgery with cardiopulmonary bypass were studied. Clinical covariates previously associated with bleeding were recorded and DNA isolated from preoperative blood. Matrix Assisted Laser Desorption/Ionization, Time-Of-Flight (MALDI-TOF) mass spectroscopy or polymerase chain reaction were used for genotype analysis. Multivariable linear regression modeling, including all genetic main effects and two-way gene-gene interactions, related clinical and genetic predictors to bleeding from the thorax and mediastinum. RESULTS: Nineteen candidate polymorphisms were assessed; seven [GPIaIIa-52C>T and 807C>T, GPIb alpha 524C>T, tissue factor-603A>G, prothrombin 20210G>A, tissue factor pathway inhibitor-399C>T, and angiotensin converting enzyme (ACE) deletion/insertion] demonstrate significant association with bleeding (P < 0.01). Adding genetic to clinical predictors results improves the model, doubling overall ability to predict bleeding (P < 0.01). CONCLUSIONS: We identified seven genetic polymorphisms associated with bleeding after cardiac surgery. Genetic factors appear primarily independent of, and explain at least as much variation in bleeding as clinical covariates; combining genetic and clinical factors double our ability to predict bleeding after cardiac surgery. Accounting for genotype may be necessary when stratifying risk of bleeding after cardiac surgery.

Cryosurgery for cardiac arrhythmias: acute and chronic effects on coronary arteries.

The use of cryosurgery near major coronary arteries for the treatment of supraventricular and ventricular tachyarrhythmias has caused concern over the possible deleterious acute and chronic effects of cryothermia on vessel patency and integrity. The present study was designed to examine both the acute and chronic effects of cryothermia on major coronary vessels in an experimental model that simulates clinical conditions. In the acute phase of the study, 10 dogs underwent direct cryothermic exposure of the left anterior descending (LAD) coronary artery while coronary artery flow and regional myocardial blood flow were calculated. Direct cryothermic exposure of the LAD resulted in total cessation of LAD blood flow 20 +/- 4 seconds after institution of cryothermia. Arterial patency returned 29 +/- 8 seconds after termination of cryothermic exposure. In the second phase of this study, 16 dogs had cryolesions applied directly over the LAD at myocardial temperatures of 37 degrees C and during elective cardioplegic arrest at myocardial temperatures of 6 to 12 degrees C. In addition, cryothermia was applied directly to the coronary sinus in these animals. The animals were allowed to live either 48 hours, 2 weeks, or 6 months after the initial procedure, and the cryolesions and underlying vessels were examined histologically. Although coronary arteriography at 6 months showed all coronary arteries to be patent, microscopic examination revealed coronary intimal hyperplasia to be present in the majority of the coronary arteries at the site of the cryolesion, particularly if the cryolesion had been applied during hypothermic, cardioplegic arrest. Cryothermia had no effect on the coronary sinus. This study provides evidence for cryothermia-induced coronary arterial damage that may produce hemodynamically significant coronary artery stenosis and suggests that caution be exercised when it is necessary to create cryolesions in the vicinity of major coronary arteries.

Functional consequences of the right ventricular isolation procedure.

The right ventricular free wall was surgically isolated from the remainder of the heart in eight dogs to evaluate the functional consequences of this procedure. Each dog was instrumented with ultrasonic dimension transducers in the right and left ventricular free walls, intracavitary micromanometers, and pulmonary artery flow probes. Volume loading and vena caval occlusions were performed to assess diastolic compliance and systolic function. Right ventricular unstressed myocardial segment length increased from 14.2 +/- 0.7 to 15.0 +/- 0.8 mm (p less than 0.5). There was an accompanying significant postoperative loss of right ventricular diastolic compliance (p less than 0.005). Regional right ventricular systolic function and regional left ventricular diastolic compliance and systolic function were preserved after the procedure. Postoperatively, when the right ventricular free wall was not paced and left silent, right ventricular stroke work decreased from 7.0 +/- 0.8 to 2.7 +/- 0.5 gm-m/m2 (p less than 0.05). These data demonstrate that the diastolic compliance of the right ventricular free wall decreases significantly after right ventricular isolation. However, there were no changes in regional right ventricular systolic or regional left ventricular function. The isolated right ventricular free wall contributes significantly to postoperative cardiac performance.

Cryosurgical denervation of the heart: acute and chronic effects.

A newly developed procedure for total cardiac denervation employing cryosurgical techniques is described. Thirty-three dogs underwent cryosurgical cardiac denervation. Twenty-seven survived the procedure and were divided into three groups. Completeness of denervation was evaluated by recording hemodynamic responses to sodium nitroprusside-induced hypotension, phenylephrine-induced hypertension, and direct cardiac autonomic nerve stimulations acutely (group I, n = 11) and 2 weeks after denervation (group II, n = 5). Serial drug infusion studies were performed during an 8-month period in group III animals (n = 11). Myocardial biopsies for catecholamine content were done in groups II and III. Both direct and reflex hemodynamic responses to autonomic neural stimulation were abolished in the acutely denervated hearts. Furthermore, at 2 weeks, direct neural stimulation was without effect, and myocardial catecholamine content was 95% depleted (p less than 0.001). Serial drug infusion studies revealed a changing spectrum of responses, suggesting the onset of reinnervation by 8 months following the procedure. Myocardial catecholamine content was 85% depleted at that time (p less than 0.001). Cryosurgical cardiac denervation is an effective technique offering the advantages of safety, simplicity, and completeness.

Inhaled nitric oxide, right ventricular efficiency, and pulmonary vascular mechanics: selective vasodilation of small pulmonary vessels during hypoxic pulmonary vasoconstriction.

OBJECTIVE: In the setting of acute pulmonary artery hypertension, techniques to reduce right ventricular energy requirements may ameliorate cardiac failure and reduce morbidity and mortality. Inhaled nitric oxide, a selective pulmonary vasodilator, may be effective in the treatment of pulmonary artery hypertension, but its effects on cardiopulmonary interactions are poorly understood. METHODS: We therefore developed a model of hypoxic pulmonary vasoconstriction that mimics the clinical syndrome of acute pulmonary hypertension. Inhaled nitric oxide was administered in concentrations of 20, 40, and 80 ppm. RESULTS: During hypoxic pulmonary vasoconstriction, the administration of nitric oxide resulted in a significant improvement in pulmonary vascular mechanics and a reduction in right ventricular afterload. These improvements were a result of selective vasodilation of small pulmonary vessels and more efficient blood flow through the pulmonary vascular bed (improved transpulmonary vascular efficiency). The right ventricular total power output diminished during the inhalation of nitric oxide, indicating a reduction in right ventricular energy requirements. The net result of nitric oxide administration was an increase in right ventricular efficiency. CONCLUSION: These data suggest that nitric oxide may be beneficial to the failing right ventricle by improving pulmonary vascular mechanics and right ventricular efficiency.

Elective prolongation of atrioventricular conduction by multiple discrete cryolesions: a new technique for the treatment of paroxysmal supraventricular tachycardia.

The present study describes a surgical method for the permanent prolongation of atrioventricular (AV) conduction. In 22 dogs, a series of nine discrete cryolesions were placed along the perimeter of the triangle of Koch while the His bundle electrogram was being monitored continuously. Ten dogs underwent a sham operation to control for the effects of cardiopulmonary bypass and atriotomy on AV conduction. The conduction time through the AV nodal region was significantly (p less than 0.01) prolonged acutely (3 hours postoperatively) and chronically (14 weeks postoperatively) in the animals subjected to cryosurgery. Thus selective cryosurgery in the AV nodal region produces a permanent alteration in AV conduction. This cryosurgical technique may result in ablation of the electrophysiological substrate required for paroxysmal supraventricular tachycardia resulting from AV nodal reentry.

Encircling endocardial ventriculotomy for refractory ischemic ventricular tachycardia. II. Effects on regional myocardial blood flow.

Previous experimental studies of the encircling endocardial ventriculotomy (EEV) have shown a significant alteration of normal local electrical activity within the encompassed region. Although this procedure may result in isolation of ventricular arrhythmias, the data are more suggestive of a less specific effect on regional myocardial blood flow. This study examines the effect of EEV on local myocardial blood flow using the radioactive tracer microsphere technique in 10 dogs. Flows were determined before and after an EEV with the animals on cardiopulmonary bypass at controlled perfusion pressures, temperatures, and heart rates. Blood flow was studied at subepicardial and subendocardial levels inside, outside, and bordering the EEV. Prior to performance of the EEV, subepicardial blood flow in the left ventricular myocardium ranged from 0.81 +/- 0.07 to 0.89 +/- 0.08 ml/gm/min. Subendocardial flows ranged from 0.80 +/- 0.07 to 0.91 +/- 0.09 ml/gm/min. There was no significant difference between any of the flows across each respective layer of myocardium. Following the EEV procedure, blood flow to the subendocardium within the EEV fell to 0.33 +/- 0.07 ml/gm/min, while flow to the subendocardium of the normal regions of the same hearts actually increased to 1.21 +/- 0.23 ml/gm/min. Similar changes occurred at subepicardial levels, with flow at the center of the EEV falling to 0.66 +/- 0.10 ml/gm/min despite a tendency for normal subepicardial flow to increase to 1.78 +/- 0.24 ml/gm/min. Superimposed ischemia to the EEV-encompassed myocardium, created by occlusion of the distal left anterior descending coronary artery (LAD), accentuated this abnormality by demonstrating that the region continues to receive some flow from epicardially based coronary vessels. The data from this study show that the EEV decreased regional blood flow to the encompassed myocardium and suggests that myocardial ischemia may be responsible for ablation of the delicate re-entrant mechanisms that sustain ventricular tachyarrhythmias.

Encircling endocardial ventriculotomy for refractory ischemic ventricular tachycardia. III. Effects on regional left ventricular function.

In order to assess the effects of the encircling endocardial ventriculotomy (EEV) on regional left ventricular function, we cannulated seven adult mongrel dogs for cardiopulmonary bypass. Two pairs of miniature pulse-transit transducers were placed in mid-myocardium of the left ventricle, one pair in a region that would later be encompassed by an EEV and the other pair in a region of remote normal myocardium. Pressure-dimension data were analyzed during vena caval occlusions (after volume loading) both on and off cardiopulmonary bypass and both before and after performance of an EEV. The EEV results in a significant decrease in diastolic compliance of the encompassed myocardium. No significant compliance changes occurred in the control regions of the same hearts. This change in regional diastolic compliance is partially responsible for a loss of systolic excursion within the EEV-encompassed region and may help to explain the severe left ventricular dysfunction that has been observed in some patients following an EEV.

Liquid ventilation improves pulmonary function and cardiac output in a neonatal swine model of cardiopulmonary bypass.

OBJECTIVE: Neonatal and infant cardiopulmonary bypass results in multiorgan system dysfunction. Organ protective strategies have traditionally been directed at the myocardium and brain while neglecting the sometimes severe injury to the lungs. We hypothesized that liquid ventilation would improve pulmonary function and cardiac output in neonates after cardiopulmonary bypass. METHODS: Twenty neonatal swine were randomized to receive cardiopulmonary bypass with or without liquid ventilation. In the liquid-ventilated group, a single dose of perflubron was administered before bypass. The control group was conventionally ventilated. Each animal was placed on nonpulsatile, hypothermic bypass. Low-flow cardiopulmonary bypass was performed for 60 minutes. The flow rate was returned to 125 ml/kg per minute, and after warming to 37 degrees C, the animals were removed from bypass. Hemodynamic and ventilatory data were obtained after bypass to assess the effects of liquid ventilation. RESULTS: Without liquid ventilation, cardiopulmonary bypass resulted in a significant decrease in cardiac output, oxygen delivery, and static pulmonary compliance compared with prebypass values. Input pulmonary resistance and characteristic impedance increased in these control animals. At 30, 60, and 90 minutes after bypass, the animals receiving liquid ventilation showed significantly increased cardiac output and static compliance and significantly decreased input pulmonary resistance and characteristic impedance compared with control animals not receiving liquid ventilation. CONCLUSIONS: Liquid ventilation improved pulmonary function after neonatal cardiopulmonary bypass while increasing cardiac output. The morbidity associated with cardiopulmonary bypass may be significantly reduced if the adverse pulmonary sequelae of bypass can be diminished. Liquid ventilation may become an important technique to protect the lungs from the deleterious effects of cardiopulmonary bypass.

Intraoperative perfusion contrast echocardiography. Initial experience during coronary artery bypass grafting.

Intraoperative evaluation of the effectiveness of myocardial revascularization has been limited by an inability to assess regional myocardial perfusion. Microbubbles of sonicated diatrizoate sodium and diatrizoate meglumine (Renografin) have been an effective echocardiographic contrast agent and have been employed clinically during cardiac catheterization. This recent development in contrast-enhanced two-dimensional echocardiography permits real-time imaging of transmural myocardial blood flow but has not been evaluated in the operating room. This study represents the initial surgical application of this directed technique and was designed to evaluate the safety and efficacy of intraoperative perfusion contrast echocardiography in assessing the results of coronary artery bypass grafting. Twenty men with significant coronary artery disease ranging in age from 49 to 73 years were studied. Direct contrast agent injection into completed saphenous vein bypass grafts caused the myocardium supplied by each graft to be well delineated and provided a tomographic view of contrast distribution. The enhanced region was well correlated with the size and distribution of the native vessel. Rapid contrast washout (less than 20 seconds) indicated satisfactory regional perfusion. Contrast echocardiography prolonged the operation less than 10 minutes and did not result in any perioperative complications.

Cryosurgical modification of retrograde atrioventricular conduction. Implications for the surgical treatment of atrioventricular nodal reentry tachycardia.

Paroxysmal supraventricular tachycardia resulting from atrioventricular nodal reentry is a common arrhythmia that usually responds to medical therapy. When atrioventricular nodal reentry tachycardia is refractory to medical therapy, cryoablation or endocardial catheter ablation of the His bundle has been employed to protect the ventricles from the tachycardia. However, these techniques necessitate implantation of a permanent ventricular pacemaker. A cryosurgical procedure that ablates the anatomic-electrophysiologic substrate for atrioventricular nodal reentry tachycardia while preserving antegrade atrioventricular conduction has been described. The purpose of the present study was to determine the effects of this procedure on retrograde atrioventricular conduction and on the ventricular echo phenomenon in particular. Thirty adult mongrel dogs underwent either the cryosurgical procedure (n = 20) or a sham operation (n = 10). The animals were studied either immediately postoperatively (acute cryosurgery group and control group, n = 10 for each group) or 14 weeks postoperatively (chronic cryosurgery group, n = 10). Decremental ventricular pacing and programmed premature ventricular pacing protocols were used to determine the retrograde atrioventricular nodal conduction time, Wenckebach point, atrioventricular nodal refractory periods, and ventricular echo reflection time. No electrophysiologic alterations were noted in the sham-operated group. In the acute cryosurgery group, the retrograde Wenckebach point, atrioventricular nodal conduction time, functional refractory period of the atrioventricular node, effective refractory period of the atrioventricular node, and ventricular echo reflection time were all significantly prolonged. In the chronic cryosurgery group, no significant change in ventriculoatrial conduction was noted, but the ventricular echo phenomenon was eliminated in all but one animal. These data further document that this cryosurgical procedure is capable of ablating the anatomic-electrophysiologic substrate necessary for atrioventricular nodal reentry tachycardia while preserving atrioventricular conduction.

The effects of cardioplegic potassium concentration and myocardial temperature on electrical activity in the heart during elective cardioplegic arrest.

A major objective of cardioplegic arrest for protection of the heart during cardiac operations is total electromechanical quiescence. Recent studies from our laboratory in which we used multiple bipolar intracardiac and unipolar intramural electrodes have detected the presence of electrical activity in the lower atrial septum, the atrioventricular node-His bundle complex, and in ventricular myocardium during elective cardioplegic arrest that cannot be detected on the limb-lead electrocardiogram. Moreover, this low-amplitude electrical activity is not associated with visible mechanical activity of the heart and occurs at ventricular septal temperatures previously thought to be adequate for myocardial protection. The present study was designed to determine the effect of cardioplegic solution potassium concentration and myocardial temperature on the occurrence and duration of low-amplitude electrical activity during elective cardioplegic arrest. Fifty adult mongrel dogs were subjected to two consecutive 20 minute periods of cardioplegic arrest. The animals were divided into six groups, depending upon the cardioplegic solution potassium concentration they received and on whether or not topical cooling techniques were employed. The probability of occurrence of low-amplitude electrical activity during the arrest interval was significantly decreased by application of topical hypothermic techniques and reinfusion of hyperkalemic, as compared to normokalemic, cardioplegic solution. These effects of hyperkalemic cardioplegic solution and myocardial hypothermia acted synergistically, but independently, to decrease the likelihood of low-amplitude electrical activity occurring during the period of cardioplegic arrest. Nevertheless, low-amplitude electrical activity did occur in all groups after each cardioplegic solution administration and was not detected by routine monitoring techniques. This suggests that low-amplitude electrical activity may represent a fundamental type of metabolic activity that can be recorded from the heart during arrest and may be responsible for the temporary depression in ventricular function that frequently follows a period of elective cardioplegic arrest.

In acute lung injury, inhaled nitric oxide improves ventilation-perfusion matching, pulmonary vascular mechanics, and transpulmonary vascular efficiency.

Acute respiratory distress syndrome continues to be associated with significant morbidity and mortality related to ventilation-perfusion mismatch, pulmonary hypertension, and right ventricular failure. It has been suggested that inhaled nitric oxide, which is a selective pulmonary vasodilator, may be effective in the treatment of acute respiratory distress syndrome; however, the effects of nitric oxide on cardiopulmonary interactions are poorly understood. We therefore developed a model of acute lung injury that mimics the clinical syndrome of acute respiratory distress syndrome. In our model, inhaled nitric oxide significantly reduced pulmonary artery pressure, pulmonary vascular resistance, and pulmonary vascular impedance. In addition, inhaled nitric oxide improved transpulmonary vascular efficiency and ventilation-perfusion matching, which resulted in increased arterial oxygen tension. Although arterial oxygen tension increased, oxygen delivery did not improve significantly. These data suggest that by improving ventilation-perfusion matching and arterial oxygen tension while lowering pulmonary vascular resistance and impedance, nitric oxide may be beneficial in patients with acute respiratory distress syndrome. However, additional measures to enhance cardiac performance may be required.

Long-term survival benefits of coronary artery bypass grafting and percutaneous transluminal angioplasty in patients with coronary artery disease.

The purpose of this study was to evaluate long-term survival benefits of bypass surgery and angioplasty versus medical therapy in 9263 patients at Duke University Medical Center between 1984 and 1990 with coronary artery disease confirmed by cardiac catheterization to involve one, two, or three vessels. Clinical data were prospectively entered into an established cardiovascular database, and annual follow-up was 97% complete for a mean interval of 5.3 years and a maximal interval of 10 years. Outcomes were analyzed with the Coronary Artery Surgery Study "method A" to define patient groups treated by medicine (n = 2449), angioplasty (n = 2924), or bypass surgery (n = 3890). Differences among treatment groups in baseline characteristics were adjusted by Cox proportional hazard models. The anatomic severity of coronary artery stenosis best defined survival benefit from bypass surgery and angioplasty versus medical treatment. One or both interventional treatments provided better long-term survival than did medical treatment for all levels of disease severity. All patients with single-vessel disease, except those with at least 95% proximal left anterior descending stenosis, benefited from angioplasty versus bypass. All patients with three-vessel disease and those two-vessel patients with > or = 95% proximal left anterior descending stenosis benefited from bypass surgery versus angioplasty. All other patients with two-vessel disease and those with > or = 95% proximal left anterior descending stenosis only had similar survival with either interventional treatment. The absolute survival benefit was greatest for patients with severe three-vessel disease treated with bypass surgery.

Encircling endocardial ventriculotomy for refractory ischemic ventricular tachycardia. I. Electrophysiological effects.

The direct endocardial surgical techniques introduced for the treatment of refractory ischemic ventricular tachyarrhythmias have resulted in decreased surgical mortality rates and increased success rates in comparison to previous indirect techniques. Since the mechanism of action of one of these new techniques, the encircling endocardial ventriculotomy (EEV), is unknown, the present study was designed to clarify the electrophysiological effects of this procedure. Epicardial and intramural electrophysiology was studied in 18 dogs before and after undergoing an EEV. In the absence of induced myocardial ischemia, the procedure caused an epicardial conduction delay of 23 +/- 3 msec (p less than 0.0001) across the boundaries of the incision. When the EEV enriched acutely ischemic myocardium, it was capable in certain instances of isolating spontaneous ventricular electrical activity to the myocardium encompassed by the incision and thereby protecting the remainder of the heart from the arrhythmia. The EEV resulted in total ablation of all (2 Mv/msec) electrical activity at 20 of 48 (42%) subendocardial electrode sites and at 12 of 44 (27%) subepicardial sites monitored within the encompassed myocardium. These data suggest that although the EEV may be capable of isolating ischemic ventricular tachyarrhythmias to the encompassed myocardium, it most commonly ablates the anatomic-electrophysiological substrate necessary for the genesis and perpetuation of these arrhythmias.

The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation.

Computerized mapping of atrial fibrillation was performed in animals and man. To study atrial fibrillation in a systematic manner, we developed a clinically relevant experimental model of atrial fibrillation. Chronic mitral regurgitation was created surgically in 25 dogs without opening the pericardium. After several months of chronic mitral regurgitation, the atria became enlarged and sustained atrial fibrillation could be induced by standard programmed electrical stimulation techniques. Computerized isochronous activation maps of the atria were recorded during atrial fibrillation from 208 bipolar electrodes simultaneously. In a parallel study, human atrial fibrillation was mapped with a separate 160-channel intraoperative mapping system in patients with paroxysmal atrial fibrillation who were undergoing surgical correction of the Wolff-Parkinson-White syndrome. The canine activation sequence maps demonstrated a spectrum of rhythm abnormalities ranging from simple atrial flutter to complex atrial fibrillation. They also showed that macroreentrant circuits within the atrial myocardium were responsible for the entire spectrum of arrhythmias. Atrial reentry was also documented during human atrial fibrillation. All patients had nonuniform conduction around regions of bidirectional block in both atria resulting in multiple discrete wave fronts. In addition, six patients had a single reentrant circuit in the right atrium in which bidirectional block of the activation wave front occurred along the sulcus terminals between the venae cavae. The left atrium in all patients demonstrated multiple wave fronts and conduction block, but left atrial reentry could not be detected. Both the experimental study and the clinical study demonstrated that multiple wave fronts, nonuniform conduction, bidirectional block, and large (macroreentrant) reentrant circuits occur during atrial fibrillation. The presence of macroreentrant circuits and the absence of either microreentrant circuits or evidence of atrial automaticity suggests that atrial fibrillation should be amenable to surgical ablation.