David E. Euler

Cardiac dysrhythmias in the conscious dog after surgically induced autonomic imbalance

The ventrolateral cardiac nerve in the dog is a primary branch of the left sympathetics and represents a direct neural link between the central nervous system and the heart. Its electric excitation elicits characteristic shifts in pacemaker and tachydysrhythmias related to its explicit innervation of the inferior atrial, atrioventricular (A-V) junctional and ventricular tissues. Total denervation of the canine heart, sparing the ventrolateral cardiac nerve, produced a long-term model in which only these portions of the heart retained their sympathetic innervation. The trained unanesthetized model dog was subjected to severe exercise in order to determine the effects of elevated levels of sympathetic tone upon these important regions of the conduction system. Reproducible tachydysrhythmias were elicited in all six animals completing the regimen of periodic testing over a period of 136 to 378 days after operation. The abnormal rhythms consisted of shifting cardiac pacemakers and supraventricular A-V junctional and ventricular tachycardias with frequent premature systoles. Comparable abnormalities were not observed in a similarly tested sham-operated animal or in dogs with a totally denervated heart. The exercise-induced dysrhythmias gradually disappeared with time, presumably in relation to autonomic reinnervation of the heart. The characteristic patterns of ventrolateral cardiac nerve and upon its presumed influence upon Purkinje fiber and A-V nodal automaticity and temporal dispersion of refractoriness in myocardial tissues.

Sinus node dysfunction: An overview with emphasis on autonomic and pharmacologic consideration

Sinus node dysfunction is a disorder of impulse generation and impulse conduction. Previous works have emphasized that the dysfunction occurs not only within the sinus node but also within the escape pacemaker. Adrenergic and cholinergic mechanisms, as well as pulsations and pressure within the sinus node artery, play an important role in normal sinus node activity. Although perinodal fibers act as a buffer zone for sinoatrial conduction, their role in man is yet to be clarified. During normal sinus node activity, pacemaker shifts from the sinus node to the crista terminalis have been shown to occur. Following sinus node destruction, similar shifts do occur. Clinical methods of determining sinus node function, such as the sinus node recovery time and sinus atrial conduction time, are useful but have limitations. Dynamic electrocardiographic monitoring provides the best clinical method available for detecting sinus node dysfunction. Digitalis appears to improve the parameters of sinus node function by increasing the automaticity of latent atrial pacemakers. The atrial arrhythmia of sinus node dysfunction appears to be related to the characteristics of latent atrial pacemaker and enhanced cholinergic tone.

Autonomic Neural Control of Cardiac Rhythm: The Role of Autonomic Imbalance in the Genesis of Cardiac Dysrhythmia

Cardiac dysrhythmias result from abnormalities in rate, regularity, or sequence of cardiac activation, and because of direct actions of the autonomic nervous system upon each of these properties, imbalance in this system may play an important role in the genesis of cardiac dysrhythmia. A canine model has been developed in which the extrinsic innervation of the heart is ablated with the exception of the ventrolateral cardiac nerve. This nerve is distributed primarily to the inferior atrial, AV junctional, and ventricular tissues. Following recovery from surgery, the animal is placed on a treadmill and required to perform strenuous exercise. In all of six animals which sustained repeated exercise testing over periods of 4-12 months, dysrhythmias of varying complexities were elicited. None appeared in parallel experiments conducted in control or sham-operated animals. The dysrhythmias consisted of supraventricular, AV junctional, or ventricular tachycardias with occasional premature atrial or ventricular systoles. The dysrhythmias were not influenced by atropine but were generally controlled by propranolol.

Cardioprotective effects of the Aminopeptidase P inhibitor apstatin : Studies on ischemia/reperfusion injury in the isolated rat heart

Aminopeptidase P and angiotensin-converting enzyme (ACE) are responsible for the metabolism of exogenously administered bradykinin in the coronary circulation of the rat. It has been shown that ACE inhibitors decrease cytosolic enzyme release from the ischemic rat heart and reduce reperfusion-induced ventricular arrhythmias by increasing endogenous levels of bradykinin. It was hypothesized that the aminopeptidase P inhibitor apstatin could do the same. In an isolated perfused rat heart preparation subjected to global ischemia and reperfusion, both apstatin and ramiprilat (an ACE inhibitor) significantly decreased creatine kinase (CK) and lactate dehydrogenase (LDH) release. The difference between the postischemia and preischemia levels of released CK was reduced 68% by apstatin and 68% by ramiprilat compared with control. The corresponding reductions in LDH release were 74% for apstatin and 81% for ramiprilat. A combination of the inhibitors was not significantly better than either one alone. Apstatin and ramiprilat also significantly reduced the duration of reperfusion-induced ventricular fibrillation by 69 and 61%, respectively. The antiarrhythmic effect of apstatin was reversed by HOE140, a bradykinin B2-receptor antagonist, suggesting that apstatin is acting by potentiating endogenously formed bradykinin. The results demonstrate that the aminopeptidase P inhibitor apstatin is cardioprotective in this model of cardiac ischemia/ reperfusion injury.

Comparative effects of antiarrhythmic drugs on the ventricular fibrillation threshold

The purpose of this study was to compare the effects of several different antiarrhythmic drugs on the ventricular fibrillation threshold (VFT). Experiments were performed on open-chest dogs anesthetized with pentobarbital. The VFT was measured on the right ventricle by scanning the vulnerable period with a single 10-ms electrical stimulus. The following antiarrhythmic drugs were each given intravenously to eight different dogs: procainamide (25 mg/kg). lidocaine (2 mg/kg + 70 μg/kg/min), flecainide (3 mg/kg), timolol (0.1 mg/kg), clofilium (1 mg/kg), dl-sotalol (5 mg/kg), and bethanidine (4 mg/kg). The drugs resulted in the following increases in the VFT: procainamide, 33 ± 13%; lidocaine, 21 ± 5%; flecainide, 38 ± 10%; timolol, 19 ± 6%; clofilium, 14 ± 6%; sotalol, 33 ± 10%; and bethanidine, 69 ± 15%. The changes in VFT were all significant (p < 0.01) except for clofilium. Only procainamide and sotalol caused stimulus-induced runs of nonsustained polymorphic ventricular tachycardia that spontaneously reverted to sinus rhythm after 4 s or more. In individual experiments, the occurrence of nonsustained polymorphic tachycardia that resembled ventricular fibrillation could not be correlated with a change in the VFT. In addition, there appeared to be no relationship between a drug-induced increase of the VFT and alterations in the QRS duration, the QT interval, or the ventricular effective refractory period. Bethanidine had the greatest effect on the VFT, in spite of the fact that this drug shortened the ventricular effective refractory period. The results suggest that the ability of an antiarrhythmic drug to alter the VFT cannot be based on the electrophysiologic actions of the drug. Furthermore, the VFT may not provide an accurate index of a drugs antifibrillatory activity.

The use of programmed electrical stimulation to assess the fibrillatory propensity of ionic and nonionic contrast media.

Coronary angiography occasionally results in ventricular fibrillation. To compare the fibrillatory propensity of conventional ionic and nonionic contrast media, we measured QT intervals and performed programmed electrical stimulation during intracoronary injection of Renografin 76 (R76), Hypaque 76 (H76), and iopamidol (IOP) in 16 open chest dogs. In ten dogs the incidence of ventricular fibrillation following induction of a single premature ventricular beat after every fourth atrial paced beat was 19/20 with R76, 8/20 with H76, and 0/20 with IOP (P less than .001). When two premature beats were induced, the incidence of ventricular fibrillation was 20/20 with R76, 19/20 with H76, and 1/20 with IOP (P less than .001). In six additional dogs, the mean prolongation of the QT interval was 170 +/- 20 msec with R76, 105 +/- 14 msec with H76, and 63 +/- 9 msec with IOP (P less than .001). Thus, programmed electrical stimulation readily induces ventricular fibrillation during intracoronary injection of conventional ionic contrast media. The incidence of ventricular fibrillation parallels the amount of QT interval prolongation produced. H76, which lacks EDTA and sodium citrate, is less fibrillatory than R76. However, the nonionic medium IOP appears far less fibrillatory than either R76 or H76.

Effect of Esmolol on the Ventricular Fibrillation Threshold

The effect of esmolol on the ventricular fibrillation threshold (VFT) was determined in 11 open-chest dogs anesthetized with sodium pentobarbital. Since changes in VFT by antiarrhythmic drugs have been shown to depend on the method used to test vulnerability to fibrillation, two methods were studied. The vulnerable period was scanned with a train of pulses (100 Hz, 4 ms, 20 pulses) in nine experiments and a single pulse (10 ms) in eight experiments. Following control measurements, esmolol was administered as an intravenous bolus of 500 micrograms/kg followed by a continuous infusion of 300 micrograms/kg/min. After 15 min of infusion, the adequacy of beta-blockade was tested by the administration of 0.5 micrograms/kg of isoproterenol. Isoproterenol increased the heart rate by only 18 +/- 2 beats/min following esmolol administration which was significantly less than the control response (79 +/- 7 beats/min, p less than 0.01). Although the VFT measured with the single-pulse technique did not change in response to esmolol (14.1 +/- 1.1 mA vs. 14.3 +/- 1.2 mA), the VFT measured with the train-of-pulses technique significantly increased (3.7 +/- 0.5 mA to 14.5 +/- 2.8 mA, p less than 0.01). Twenty minutes after discontinuing esmolol, the VFT measurements were repeated and did not differ from control values with either technique. The increase in heart rate in response to isoproterenol also returned to control values (80 +/- 6 beats/min). The results suggest that the ability of esmolol to raise VFT as measured by the train-of-pulses technique is due to beta-adrenergic blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in blood flow and S-T segment during coronary arterial occlusion in denervated and nondenervated canine hearts

Abstract Myocardial blood flow and S-T segment measurements were made before and during occlusion of the left anterior descending coronary artery in chronically denervated and sham-denervated canine hearts. At similar heart rates, blood pressures and levels of work, left ventricular endocardial and epicardial blood flow values, as measured by radiolabeled microspheres, were significantly lower in denervated hearts than in shamdenervated control hearts. These results suggest that long-term cardiac denervation lowers metabolic demands of the left ventricle as reflected by decreased blood flow to the denervated left ventricle. Under the same conditions, blood flow measured in the right ventricle of denervated and sham-denervated hearts did not show any significant differences. Thus, it is possible that under normal circumstances the neural input to the right ventricle may be less than that to the left ventricle and may play a lesser role in controlling right ventricular tissue metabolic demands. During occlusion of the left anterior descending coronary artery, local epicardial and endocardial S-T segment elevation, measured by epicardial plaque and endocardial plunge electrodes, was less in denervated hearts than in sham-denervated hearts in areas of severely reduced blood flow (30 ml/min per 100 g or less). Also during occlusion the denervated hearts exhibited fewer arrhythmias than did the sham-denervated control hearts. The lower local S-T segment elevation found in the denervated hearts was not due to marked differences in blood flow between the areas sampled in the denervated and sham-denervated hearts. This decreased incidence of arrhythmia combined with less evidence of altered electrical activity suggests that denervation affords protection during coronary occlusion.

The effects of elevated intracranial pressure on the canine electrocardiogram

Striking electrocardiographic abnormalities have been noted in some patients with central nervous system injury. To study the relationship between the electrocardiogram and intracranial pressure, intracranial pressure was elevated in 14 open chest pentobarbital-anesthetized dogs. The right vagus was stimulated to produce sinus slowing and the right atrium was paced at a constant cycle length fast enough to prevent arrhythmias and maintain heart rate constant (750 msec in 11 dogs and 600 msec in three dogs). In nine dogs, intracranial pressure was sequentially elevated to 100, 150, and 200 mmHg. Systolic arterial blood pressure consistently rose to exceed intracranial pressure (P less than 0.005). At a pressure of 150 and 200 mmHg, mean QT intervals shortened significantly in recorded leads II, X, Y, and Z from 0.01). T wave changes were also noted that consisted of increasing positivity in leads II, X, and Y and increasing negativity in lead Z. To delinate the role of the sympathetic nervous system, an additional five dogs were subjected to an intracranial pressure of 200 mmHg before and after bilateral stellate ganglionectomy and timolol (0.1 mg/kg IV). Elimination of sympathetic influences did not significantly alter the electrocardiographic effects of elevated intracranial pressure. Thus, intracranial hypertension results in significant QT shortening and T wave changes that are not entirely mediated by the sympathetic nervous system.

Adrenergic influences on ischemic and reperfusion arrhythmias in a canine model with diminished collateral blood flow

To examine the role of adrenergic influences on genesis of ischemic and reperfusion arrhythmias, the left anterior descending coronary artery (LAD) was cannulated and perfused by a shunt from the left carotid artery in 38 open-chest pentobarbital-anesthetized dogs. Ischemia was produced by shunt occlusion and retrograde diversion of collateral flow from the LAD. The diverted blood was collected and returned to the animal by intravenous (i.v.) injection. The shunt was opened and the ischemic myocardium reperfused after 30 min of ischemia. Microsphere injections in six dogs during shunt occlusion and retrograde bleeding showed that blood flow to the ischemic zone was <1.5% of normal zone flow. The remaining 32 dogs were randomized into four treatment groups. Dogs (n = 8) were treated before shunt occlusion with either saline, nadolol (1 mg/kg), prazosin (0.2 mg/kg), or bilateral stellate transection. As compared with saline treatment, nadolol and stellate transection significantly reduced heart rate (HR), and prazosin significantly reduced mean arterial blood pressure (MAP) (p < 0.05). However, none of the antiadrenergic interventions significantly reduced the number or frequency of ectopic beats during either the la or lb phases of ischemia. None of the 32 dogs developed ventricular fibrillation (VF) during ischemia, but all dogs fibrillated within 30 s of reperfusion. The size of the ischemic zone ranged from 21 to 38% of the left ventricle, and there were no differences among the four treatment groups. The results suggest that when ischemia is severe, the adrenergic nervous system does not play a significant role in genesis of ischemic-induced ectopy or reperfusion-induced VF.