Eugene Patterson

Electrical stimulation to identify neural elements on the heart : Their role in atrial fibrillation

Experimental Studies: Anesthetized dogs were subjected to a right then left thoracotomy. Two modes of electrical stimulation were used to activate ganglionated plexi (GP) on the epicardium of the atria: (1) Near the base of each pulmonary vein (PV), trains of high frequency stimuli (HFS) were coupled to each atrial paced beat so as to fall within the refractory period to achieve nerve stimulation without atrial excitation; and (2) Continuous HFS was applied via plaque electrodes sutured to epicardial fat pads (containing a GP) near the right superior (RS) and left superior (LS) PVs. The chest was then closed. An ablation catheter, inserted percutaneously, was positioned fluoroscopically in the right atrium across from the epicardial plaque electrode near the RSPV. Transeptal puncture was used to place an ablation catheter at the LSPV-left atrial junction. HFS applied to each of the epicardial fat pads induced atrial fibrillation (AF) and also caused high grade AV block due to a strong parasympathetic effect on the AV node. Radiofrequency ablation from the right and left atrial endocardium abolished the vagal response to HFS delivered to the plaque electrodes on the fat pads close to the RSPV and LSPV, respectively.Clinical Studies: Sixty (60) patients with paroxysmal or persistent AF underwent PV antrum isolation (27 patients) or PV antrum isolation plus left atrial GP ablation (33 patients). Endocardial HFS at the border of the PV antra near the 4 GPs produced AF and high grade AV block (vagal response) during AF. RFA at these sites abolished the vagal response. Testing in a small number of patients with very short follow-up suggests that adding GP ablation to PV antrum isolation may increase ablation success (absence of AF recurrence) from 70% to 91%.Conclusions: These basic and clinical studies suggest that localized cardiac autonomic ganglia (GPs) may play a critical role in the initiation and maintenance of AF.

Focal Atrial Fibrillation: Experimental Evidence for a Pathophysiologic Role of the Autonomic Nervous System

Focal AF and Autonomic Nerves. Introduction: Focal paroxysmal atrial fibrillation (AF) was shown recently to originate in the pulmonary veins (PVs) and superior vena cava (SVC). In the present study, we describe an animal model in which local high‐frequency electrical stimulation produces focal atrial activation and AF/AT (atrial tachycardia) with electrogram characteristics consistent with clinical reports.

Autonomic Mechanism to Explain Complex Fractionated Atrial Electrograms (CFAE)

Objective: To simulate complex fractionated atrial electrograms (CFAE) during sustained atrial fibrillation (AF) in experimental animals.

Pathophysiologic basis of autonomic ganglionated plexus ablation in patients with atrial fibrillation

The intrinsic cardiac autonomic nervous system (ganglionated plexuses [GP]) plays a significant role in the initiation and maintenance of atrial fibrillation (AF) in both experimental models and AF patients. Left atrial GP, located in epicardial fat pads and the ligament of Marshall, contain afferent neurons from the atrial myocardium and the central autonomic nervous system, efferent neurons (cholinergic and adrenergic neurons), and interconnecting neurons, which allow communication between GP. Stimulation of the GP produces both parasympathetic stimulation (markedly shortens action potential duration) and sympathetic stimulation (increases calcium transient) in the pulmonary vein (PV) myocardium and atrial myocardium. In a canine model, GP stimulation resulted in early afterdepolarizations, and calcium transient triggered firing in the adjacent PV and initiated AF. Fractionated atrial potentials (FAP) were consistently located in the left atrium close to the stimulated GP. Ablation of the stimulated GP eliminated the FAP surrounding the GP. In patients with paroxysmal AF, epicardial and endocardial high-frequency stimulation produced a positive vagal response (transient AV block during AF and hypotension), allowing the identification and localization of five major left atrial GP (superior left GP, inferior left GP, Marshall tract GP, anterior right GP, inferior right GP). High-density electroanatomic maps of the left atrium and PVs obtained during AF showed the FAP are located in four main left atrial areas (left atrial appendage ridge FAP area, superior-left FAP area, inferoposterior FAP area, anterior-right FAP area). All five GP are located within one of the four FAP areas. In 63 patients with paroxysmal AF, GP ablation alone (before PV antrum isolation) significantly decreased the occurrence of PV firing (47/63 patients before ablation vs 9/63 patients after ablation, P <.01). GP ablation also decreased the inducibility of sustained AF (43/63 patients vs 23/63 patients, P <.01) and markedly reduced or eliminated the left atrial FAP areas.

Spontaneous Pulmonary Vein Firing in Man: Relationship to Tachycardia‐Pause Early Afterdepolarizations and Triggered Arrhythmia in Canine Pulmonary Veins In Vitro

Introduction: Rapid firing originating within pulmonary veins (PVs) initiates atrial fibrillation (AF). The following studies were performed to evaluate spontaneous PV firing in patients with AF to distinguish focal versus reentrant mechanisms.

Ventricular Tachyarrhythmias Related to Early Afterdepolarizations and Triggered Firing: Relationship to QT Interval Prolongation and Potential Therapeutic Role for Calcium Channel Blocking Agents

The ventricular tachyarrhythmias associated with the long QT syndromes have remained enigmatic because of the striking heterogeneity in the events precipitating the arrhythmia (intense sympathetic stimulation vs drug administration or electrolyte abnormalities which prolong repolarization). The absence of comprehensive diagnostic criteria and rational therapy stems from a poor understanding of the mechanistic bases for these arrhythmias. The purpose of this report is to demonstrate the use of current tool s (pacing, monophasic action potential recordings and drugs) to explore new characteristics of these arrhythmias in patients which might be compared to those observed in experimental models. Although limited in scope, recent experimental observations suggest that arrhythmias with many of these characteristics might result from triggered firing associated with early afterdepolarizations (Brachmann , et al., 1983; Da-

Antiarrhythmic and antifibrillatory actions of the levo- and dextrorotatory isomers of sotalol.

The electrocardiographic responses to programmed ventricular stimulation and acute posterolateral myocardial ischemia were studied in conscious dogs treated with the resolved optical isomers of sotalol. Studies were conducted 3-7 days after anterior myocardial infarction to determine the relative contributions of beta-adrenergic receptor blockade and direct Class III electrophysiologic actions in the antiarrhythmic and antifibrillatory actions of the isomers. With cumulative i.v. administration of up to 8 mg/kg, both the beta-blocking levorotatory isomer and the dextrorotatory isomer suppressed the induction of ventricular tachyarrhythmias by programmed stimulation in at least 50% of dogs tested. Both isomers produced equivalent 15-20% increases in normal zone ventricular refractoriness, thereby preventing propagation of programmed ventricular extrastimuli of sufficient prematurity to elicit tachyarrhythmias. The levorotatory isomer of sotalol prolonged the PR interval; the administration of the dextrorotatory isomer increased QTc and, in several dogs, was associated with the development of ventricular ectopy. The prior administration of 8 mg/kg of either optical isomer of sotalol prevented the immediate spontaneous development of ventricular fibrillation in response to ischemia at a distance from the previous site of infarction. These results suggest that alterations in ventricular refractoriness may underlie the antiarrhythmic and antifibrillatory actions of the optical isomers of sotalol and of racemic sotalol.

Early myocardial dysfunction in streptozotocin-induced diabetic mice: a study using in vivo magnetic resonance imaging (MRI)

BackgroundDiabetes is associated with a cardiomyopathy that is independent of coronary artery disease or hypertension. In the present study we used in vivo magnetic resonance imaging (MRI) and echocardiographic techniques to examine and characterize early changes in myocardial function in a mouse model of type 1 diabetes.MethodsDiabetes was induced in 8-week old C57BL/6 mice with two intraperitoneal injections of streptozotocin. The blood glucose levels were maintained at 19–25 mmol/l using intermittent low dosages of long acting insulin glargine. MRI and echocardiography were performed at 4 weeks of diabetes (age of 12 weeks) in diabetic mice and age-matched controls.ResultsAfter 4 weeks of hyperglycemia one marker of mitochondrial function, NADH oxidase activity, was decreased to 50% of control animals. MRI studies of diabetic mice at 4 weeks demonstrated significant deficits in myocardial morphology and functionality including: a decreased left ventricular (LV) wall thickness, an increased LV end-systolic diameter and volume, a diminished LV ejection fraction and cardiac output, a decreased LV circumferential shortening, and decreased LV peak ejection and filling rates. M-mode echocardiographic and Doppler flow studies of diabetic mice at 4 weeks showed a decreased wall thickening and increased E/A ratio, supporting both systolic and diastolic dysfunction.ConclusionOur study demonstrates that MRI interrogation can identify the onset of diabetic cardiomyopathy in mice with its impaired functional capacity and altered morphology. The MRI technique will lend itself to repetitive study of early changes in cardiac function in small animal models of diabetic cardiomyopathy.

Chapter 59 – Electrophysiologic Characteristics of Atrioventricular Nodal Reentrant Tachycardia: Implications for the Reentrant Circuits

Atrioventricular nodal reentrant tachycardia (AVNRT), the most common form of paroxysmal supraventricular tachycardia, 1 is a fascinating complex of arrhythmias. AVNRT was originally proposed to result from reentry totally confined within the compact atrioventricular (AV) node. 2 3 However, the typical form of AVNRT (slow/fast) is now thought to involve the AV node, a component of atrial myocardium, and at least two atrionodal connections. 4 5 6 7 8 9 10 11 12 13 14 15 16 Much of the current understanding about the components of the reentrant circuit has evolved from the development of ablation procedures, in which one of the atrionodal connections, remote from the compact AV node, is destroyed, eliminating AVNRT without producing AV block. 4 5 6 7 8 9 10 11 12 16 17 18

Accelerated thrombolysis and reperfusion in a canine model of myocardial infarction by liposomal encapsulation of streptokinase

The aim of thrombolytic therapy for acute myocardial infarction with plasminogen activators such as streptokinase is to lyse the coronary thrombus and reestablish blood flow as quickly as possible so that heart tissue loss is minimized and mortality rates are improved. Streptokinase has been encapsulated in large unilamellar phospholipid vesicles and tested in an animal model of acute myocardial infarction. The time required to restore vessel patency has been reduced more than 50% when compared with findings for free streptokinase. The total dosage of streptokinase required was lower, and smaller remnant thrombi were observed with the encapsulated agent. Results from this initial unoptimized study may have significant implications for further reduction in mortality from heart attacks by therapy with plasminogen activators.