Henry Gelband

Mechanisms of Digitalis Toxicity: Effects of Ouabain on Phase Four of Canine Purkinje Fiber Transmembrane Potentials

Microelectrode technics were used to study effects of ouabain (O), 2×10−7 moles/liter, on phase 4 of Purkinje fiber (PF) transmembrane potentials (TMP). Perfusion for 25-35 min with O caused an increase in phase 4 depolarization which resulted in either increased automaticity or occurrence of low-amplitude potentials (LAP). Increased automaticity was more frequent when PF had been stretched, when [K+]o = 2.5 mmoles/liter, and when O caused a marked decrease in resting membrane potential (RMP). LAP occurred at all [K+]o (2.5, 4.0, and 5.0 mmoles/liter), and were the typical response of unstretched fibers in which RMP had not decreased markedly. The magnitude of the LAP increased at [K+]o = 4.0 mmoles/liter and at faster stimulus rates. Threshold potential (TP) was decreased to a slightly greater extent than RMP. Although LAP did not result in spontaneous action potentials, superimposition of subthreshold depolarizations on LAP resulted in excitation. Whether O-induced increases in phase 4 slope result in automaticity or LAP depends on interrelationships between RMP, TP, and level of membrane potential reached during phase 4. Although hearts developing LAP due to digitalis toxicity may not demonstrate increased automaticity, the presence of phase 4 depolarization in the form of LAP may cause an impairment of conduction which is dependent on cycle length.

Physiology of Canine Intraventricular Conduction and Endocardial Excitation

The sequence of conduction through the intraventricular conducting system and endocardial muscle was studied by microelectrode mapping of large areas of isolated canine ventricular tissue. We found that most of the endocardium of the right ventricular free wall is activated simultaneously whereas the left endocardial muscle is activated in an apex-to-base sequence. Right septal activation is from apex to base, and the left septum is activated first at the junction of the middle and lower thirds of the septum and then as a bidirectional wave front toward the apex and the base. These right-left differences occur because the sites of impulse input into muscle on the right encompass the entire free wall, base of the papillary muscle, and the lowermost septum, and on the left are primarily limited to the lower ventricular cavity, lower septum, and bases of the papillary muscles. These patterns of left ventricular excitation relate to the presence of a functionally continuous ring of conducting tissue formed by a merger of the major divisions of the left bundle branch on the upper left ventricular free wall. The “ring” itself is electrophysiologically isolated from muscle, but connects to a network of subendocardial conducting tissue extending to the apex and having input to muscle only in its lower portions.

Correlation between Effects of Ouabain on the Canine Electrocardiogram and Transmembrane Potentials of Isolated Purkinje Fibers

Isolated canine Purkinje fiber bundles (PF) were perfused with the blood of intact donor dogs to correlate changes induced by ouabain (O) in the PF transmembrane potential (TP) and the donor ECG. O was administered intravenously to the donor, and standard microelectrode technics were used to record the TP. The only significant O effect prior to occurrence of toxic arrhythmias was induction of ST-T wave changes in the ECG and prolongation of action potential duration (APD). Early O toxicity was defined as the onset of junctional or ventricular premature contractions or junctional tachycardia. Simultaneous with early toxicity there were decreases in AP amplitude, resting membrane potential, maximal slope of phase O depolarization, APD, and plateau, and slowing of conduction, which often varied in extent from cycle to cycle. With increased duration of early toxicity or onset of late toxicity (ventricular tachycardia), TP changes were accentuated. Increased automaticity occurred at the time of early toxicity when plasma potassium concentration ([K + ]o) < 4 mEq/liter. In three of seven instances in which [K + ]o > 4.0 mEq/liter, low amplitude potentials were recorded during phase 4. The possible role of these potentials in relation to the generation of toxic arrhythmias is discussed.

Mechanisms of spontaneous alternation between reciprocating tachycardia and atrial flutter-fibrillation in the Wolff-Parkinson-White syndrome.

In a group of 36 consecutive patients with the Wolff- Parkinson-White (WPW) syndrome undergoing electrophysiological studies because of paroxysms of reciprocating tachycardia (RT) and/or atrial flutter-fibrillation (AF), 7 patients (19%) had repeated episodes of spontaneous alternation between RT and AF. Electrophysiological studies demonstrated left-sided anomalous pathways (AP) in all 7 patients. Atrial vulnerability, as evidenced by the occurrence of repetitive atrial responses or a paroxysm of AF following a single atrial premature stimulus, was also noted in all. Invariably, spontaneous conversion of RT to AF (7 patients) was triggered by an atrial premature depolarization which resulted in atrial asynchrony during the atrial vulnerable phase. In contrast, spontaneous conversion of AF to RT (3 of the 7 patients) required the presence or the development of antegrade unidirectional block in the AP prior to the cessation of AF. The demonstration of atrial vulnerability in association with the phenomenon of spontaneous alternation between RT and AF provides further information pertaining to the understanding of the mechanisms of tachyarrhythmias in the WPW syndrome. It is suggested that the occurrence of this electrophysiological phenomenon may be more common than is generally appreciated, and optimal medical treatment should be directed toward controlling both RT and AF in this group of Wolff-Parkinson- White patients.

Electrophysiologic Properties of Isolated Preparations of Human Atrial Myocardium

The electrophysiologic properties of human atrium were studied with intracellular microelectrodes in 22 preparations of human right atrial tissue obtained at the time of corrective open heart surgery. Two types of fibers were identified: the first had electrical characteristics typical of atrial contractile cells and the second those of atrial specialized fibers. Automaticity developed only in the latter type of cell. In 36 impalements of specialized atrial fibers, resting membrane potential was −86 ± 5 mv (mean ±SD), transmembrane action potential amplitude was 102 ± 12 mv, transmembrane action potential overshoot was 16 ± 4 mv. Similar results were obtained in 49 impalements of contractile fibers. Conduction velocity measured 0.28−0.33 m/sec in contractile fibers and 0.41−0.45 m/sec in specialized atrial fibers. Action potential duration of specialized atrial fibers was linearly related to the basic cycle length between 200 and 1000 msec. At cycle lengths greater than 1000 msec the increase in action potential duration was no longer linear. There was a decrease of 58 mv in resting membrane potential of specialized atrial fibers when exposed to a tenfold increase in extracellular [K+]. This decrease occurred in a linear fashion in [K+] above 5 mM. These experiments provide reference values for future studies dealing with electrophysiology of human atrial tissue.

Lung mechanics in congenital heart disease with increased and decreased pulmonary blood flow

Respiratory rate, tidal volume, dynamic lung compliance, functional residual capacity, and pulmonary resistance were measured withim 24 hours of cardiac catheterization in 25 infants, 12 of whom had increased pulmonary blood flow and 13 of whom had decreased PBF. There were no differences in the two groups of patients with respect to VT and FRC. Respiratory rate and pulmonary resistance were higher in infants with increased PBF. Lung compliance was significantly lower in infants with increased PBF (4.9 ml/cm H2O) than in those with decreased PBF (8.9 ml/cm H2O) (P less than 0.01). The decrease in CL in infants with increased PBF significantly correlated with mean pulmonary artery pressure (r = 0.798). No correaltion was found between CL and left atrial pressure or magnitude of the left-to-right shunt. Compliance was normal in patients with increased PBF and normal PAP, suggesting that PAP and not PBF is the primary factor that affects CL in patients with intracardiac left-to-right shunts.

Clinical and electrophysiologic observations in patients with concealed accessory atrioventricular bypass tracts

Abstract In 12 of 46 consecutive patients with paroxysmal supraventricular tachycardia or atrial flutter-fibrillation, without electrocardiographic evidence of ventricular preexcitation, electrophysiologic studies suggested the presence of accessory atrioventricular (A-V) pathways capable only of retrograde conduction (concealed Wolff-Parkinson-White syndrome). The ages of these patients ranged from 29 days to 71 years (mean 39.2 years). Most patients were clinically symptomatic with palpitations, dizziness, weakness or congestive heart failure. One patient had “cardiac dysrhythmia” described by an obstetrician during intrauterine life. Eleven patients manifested A-V reciprocating tachycardia involving the normal pathway for anterograde conduction and the accessory pathway for retrograde conduction. The remaining patient manifested recurrent paroxysms of atrial flutter-fibrillation as a result of rapid ventriculoatrial activation through the accessory pathway during the atrial vulnerable phase. The electrophysiologic observations were analyzed with regard to clinical and electrocardiographic characteristics in these patients. The presence of concealed accessory pathways should be suspected in patients presenting with (1) an “incessant” form of tachycardia, (2) spontaneous onset of A-V reciprocal rhythms or reciprocating tachycardias after acceleration of the sinus rate without antecedent atrial extrasystoles or P-R interval prolongation, (3) slowing of the tachycardia rate consequent to the development of functional bundle branch block, (4) retrograde P waves (negative in leads II, III and aVF) discernible after the QRS complexes, with the R-P interval being shorter than the P-R interval during both A-V reciprocal rhythm and reciprocating tachycardia, and (5) oc-currence of atrial flutter-fibrillation in association with A-V reciprocal rhythms. It is suggested that medical treatment in patients having concealed accessory pathways should be aimed at increasing the refractoriness of either the A-V node or the accessory pathway for reciprocating tachycardia, while increasing the refractoriness of the atrium and the accessory pathway in cases with atrial flutter-fibrillation. Pacemaker therapy and surgical intervention may be indicated in selected patients refractory to antiarrhythmic agents.

Effects on the Canine P Wave of Discrete Lesions in the Specialized Atrial Tracts

The role of the specialized atrial tracts in determining the polarity, morphology, and duration of normal and ectopic P waves in the canine heart was studied by producing discrete surgical lesions in selected portions of these tracts. Effects of these lesions were correlated with changes in the polarity, morphology, and duration of the P waves and with conduction time to selected atrial sites when the atria were paced from the sinoatrial (SA) node, the left atrial portion of Bachmanns bundle, the low interatrial septum near the atrioventricular (AV) node, and the posterior-inferior left atrium. A lesion in the anterior internodal tract where it leaves the head of the SA node prolonged conduction time between the SA and AV nodes and significantly increased P wave duration when the atria were paced from the SA node and low interatrial septum sites. A lesion in the branch of the anterior internodal tract running through Bachmanns bundle significantly changed P wave polarity, morphology, and duration when the atria were paced from the SA node, Bachmanns bundle, and low interatrial septum sites. A lesion in the posterior internodal tract failed to change P wave polarity, morphology, or duration. When the atria were paced from the posterior-inferior left atrium, the lesions had no significant effect on P-wave polarity, morphology, or duration. It is concluded that specialized atrial tracts play a functionally important role in the sequence of atrial activation during many normal and ectopic rhythms.

Electrophysiologic consequences of chronic experimentally induced left ventricular pressure overload

Cardiac electrophysiologic alterations were evaluated 1 to 8 months after partial supracoronary aortic constriction in cats. This procedure induced left ventricular systolic hypertension and hypertrophy with marked connective tissue infiltration. In situ, premature ventricular complexes were observed during or after vagal slowing of sinus rate in 8 (26%) of the 31 experimental animals, while an additional 3 of the 31 developed ventricular fibrillation. No arrhythmias were recorded in 31 normal or 7 sham-operated cats. In vitro, 29% of the left ventricular preparations from cats with pressure overload and 5% from control cats showed spontaneous ectopic activity. During stimulation at cycle lengths of 800 to 1,000 ms, multiple site impalements of subendocardial muscle cells within fibrotic regions revealed heterogeneous electrical abnormalities. These included short action potential duration, low amplitude action potentials generated from low resting potentials, split upstrokes and electrically silent areas. Impalements in nonfibrotic areas of the left ventricle showed prolongation of muscle action potential duration. Long-term disturbances in cellular electrophysiologic properties may favor the development of arrhythmias and thereby contribute to sudden cardiac death in left ventricular hypertension and hypertrophy.

Depressed Transmembrane Potentials during Experimentally Induced Ventricular Failure in Cats

Transmembrane potentials and isometric force were recorded in right ventricular muscles from cats with right ventricular failure 3–127 days after chronic partial pulmonary artery obstruction. For the majority of failed muscles (at 36°C, 30 stimuli/min), resting potential, action potential overshoot, action potential maximum rate of rise, isometric active force at optimal length (Po), and dP/dt were decreased compared with the same parameters in normal muscles. Time to peak force and duration of contraction were unaltered. Action potential configuration was changed and action potential duration was lengthened in failed muscles. Epinephrine (10−6M) markedly increased Po and resting potential in severely depolarized failed muscles. These data suggest that electrical depression might exacerbate the contractile deficit in experimental chronic right ventricular failure.