Digoxin-quinidine interaction in the neonatal dog.

The effects of quinidine on steady state serum and tissue digoxin concentrations in the neonatal dog were studied. To determine the effects of quinidine on serum digoxin concentrations, two groups of neonates were evaluated: Group I (n = 11) was digitalized with 40 micrograms/kg body weight, intramuscularly, and placed on a 10 micrograms/kg per day maintenance dose; Group II (n = 7) was digitalized with 50 micrograms/kg per day, intraperitoneally, and placed on a 20 micrograms/kg per day maintenance dose. After 10 days of digoxin alone, quinidine was coadministered (30 mg/kg per day, intraperitoneally) for 7 days. Serum digoxin concentrations were measured before quinidine and 1, 3 and 7 days after combined digoxin-quinidine therapy. In Group I, the control serum digoxin concentration was 1.38 +/- 0.32 ng/ml and after 7 days of combined therapy it was unchanged (1.39 +/- 0.31 ng/ml). In Group II, the control serum digoxin concentration measured 2.80 +/- 0.49 ng/ml and after 7 days of combined therapy it, too, was unchanged (3.10 +/- 0.65 ng/ml). The effects of combined digoxin-quinidine administration on tissue digoxin concentrations were studied in two other groups of neonates. Group III (n = 6) was given a low maintenance dose of digoxin (10 micrograms/kg per day, intramuscularly) and a full 7 days of coadministered quinidine; in Group IV (n = 6), digoxin was given at a higher dose (20 micrograms/kg per day, intraperitoneally) and a shorter duration of combined digoxin-quinidine therapy (3 days).(ABSTRACT TRUNCATED AT 250 WORDS)

Maturational changes in ventriculoatrial conduction in the intact canine heart.

This study reports on the changes in ventriculoatrial (VA) conduction that occur with maturation. Programmed atrial and ventricular premature extra-stimulation (coupled to a fixed paced cycle length) and rapid atrial pacing were performed in three groups of dogs: Group I = 8 neonates aged 5 to 14 days, Group II = 9 young dogs aged 6 to 9 weeks and Group III = 10 adult dogs. High right atrial, His bundle and right ventricular electrograms were recorded. There were no differences in the AH intervals at rest. In all but five animals, atrioventricular conduction was limited by the atrial functional refractory period (Group I, 109 +/- 12 ms; Group II, 152 +/- 22 ms; Group III, 167 +/- 19 ms). As expected, with rapid atrial pacing, Wenckebach conduction developed at a shorter cycle length in the younger animals (Group I, 145 +/- 20 ms; Group II, 153 +/- 15 ms; Group III, 200 +/- 25 ms, p less than 0.01). Ventriculoatrial conduction was documented in 87% of Group I puppies and 100% of Group II, but only 40% of Group III dogs. The effective and functional refractory periods of the VA conduction system were significantly shorter in the more immature groups of dogs (effective/functional: Group I, 124 +/- 27/168 +/- 22 ms; Group II, 139 +/- 23/202 +/- 13 ms; Group III, 270 +/- 28/326 +/- 25 ms; p less than 0.01). Relative to the adult dog, the immature heart showed a greater incidence of VA conduction and shorter VA refractory periods. This enhanced VA conduction may be of physiologic importance in the initiation and perpetuation of certain supraventricular arrhythmias.

Postnatal development of the putative neuropeptide-Y-mediated sympathetic--parasympathetic autonomic interaction.

OBJECTIVE: Intense stellate ganglion stimulation causes a long-lasting inhibition of cardiac vagal responses in adult dogs. This inhibition is thought to result from the release of neuropeptide Y from sympathetic nerve terminals, which, in turn, blocks the release of acetylcholine from parasympathetic neurons. The purpose of this study was to characterize the developmental expression of this autonomic interaction in the dog. METHODS: We studied and compared the effects of 5-min trains of right stellate ganglion stimulation on cardiac chronotropic responses to supramaximal vagal stimulation trains in 10 neonatal dogs, 8 one-month-old puppies, 8 two-month-old puppies and 8 adult dogs. RESULTS: In the adult group, after 5 min of stellate stimulation, inhibition of the vagal chronotropic response was observed in 7 of 8 (87.5%). Inhibition was observed in 100% of the one-month-olds and in 87.5% of the two-month-olds. In contrast, in the neonates, inhibition was observed in only 4 of 10 (40%) (P < 0.05). The maximum percent inhibition of the cardiac vagal response was significantly less in the neonates than in the older puppies (P < 0.001) and adults (P < 0.01), and the summated inhibition also tended to be less in the neonates (P < 0.05 compared to one- and two-month-old puppies). Finally, in 60% of the neonates and 37.5% of all other animals vagal responses after stellate stimulation were facilitated, i.e. at least 20% greater than the pre-stellate stimulation values. CONCLUSION: The putative neuropeptide-Y-mediated, sympathetic-parasympathetic interaction is not fully expressed in the canine neonate. It appears to develop quite rapidly postnatally, being fully expressed by 1 month of age. We hypothesize that this developmental change is likely the result of maturation of sympathetic nervous system function after birth. The facilitation of the vagal chronotropic response, observed in some animals after stellate stimulation, is a new finding, and may represent yet another type of autonomic interaction.

Procainamide elimination kinetics in pediatric patients.

Procainamide kinetics were studied in six children after a single intravenous dose. Two-compartment kinetic analysis of serum concentration-time curves of five children, who received a dose of 5.5 +/- 0.9 mg/kg (mean +/- SD), revealed the following values for kinetic parameters: distribution half-life, 10.3 +/- 3.4 min; elimination half-life, 1.7 +/- 0.1 hr; elimination constant, 1.2 +/- 0.3 hr-1; plasma clearance 19.4 +/- 2.0 ml/min/kg, and steady-state volume of distribution, 2.2 +/- 0.3 l/kg. A sixth patient, who received an accidental overdose of 28 mg/kg, had altered elimination kinetics due to drug-induced hypotension. N-acetylprocainamide (NAPA) was detected in serum samples obtained soon after procainamide dosing and peak concentrations were attained at 1 to 2 hr. NAPA levels were lower than corresponding procainamide concentrations at most sampling periods. The findings of short elimination half-life and rapid plasma clearance of procainamide in children suggest that continuous intravenous infusion may be necessary to maintain therapeutically effective plasma concentrations in these patients.

Normal pulmonary vascular resistance and left ventricular hypertrophy in young infants with bronchopulmonary dysplasia: an echocardiographic and pathologic study.

To evaluate the cardiac anatomy and functional hemodynamics in young infants with chronic lung disease, nine patients, aged 2 to 7 months, with a clinical diagnosis of bronchopulmonary dysplasia (BPD) underwent echocardiographic examination. All infants required supplemental O2 (mean FIO2 35%) to maintain adequate systemic oxygenation (Pao2 greater than 50 mm Hg). None of the infants had evidence of a patent ductus arteriosus at the time of examination. Echocardiographic measurements of left and right ventricular systolic time intervals revealed normal systolic time interval ratios suggesting pulmonary vascular resistances. However, echocardiographic evidence of left ventricular hypertrophy was found in eight of the nine infants, while right ventricular anterior wall thickness and right ventricular diastolic dimensions were not increased. Two infants died; marked left ventricular hypertrophy was noted at the time of postmortem examination while the right ventricular wall thickness was normal. The findings of left ventricular hypertrophy led to a retrospective review of autopsy material of seven patients who died with BPD over the past year. In six of seven cases examined, left ventricular posterior wall thickening was noted (range 7 to 11 mm); while the right ventricular wall thickness was normal (range 2 to 5 mm). These data suggest that (1) as assessed by echocardiography, the pulmonary vascular resistance is not significantly elevated in young infants with BPD, and (2) a hypertrophic left ventricle evolves which may assume importance in the pathogenesis of pulmonary edema in BPD, though the precise etiology remains undetermined.

Dose-dependent electrophysiologic effects of amiodarone in the immature canine heart.

The electrophysiologic effects of incremental doses of intravenous amiodarone were studied in the intact neonatal canine heart and were compared with the responses observed in the adult. Seven neonatal puppies aged 5 to 14 days, and 6 adult dogs were studied. Assessment of sinus and atrioventricular (AV) nodal function and atrial and ventricular refractory periods was performed using standard His bundle recording techniques and programmed extrastimulation before and after doses of 2.5, 5 and 10 mg/kg of intravenous amiodarone. Amiodarone depressed sinus node cycle length, sinus node recovery time and AV nodal conduction in both groups. Atrial and ventricular refractory periods were also prolonged in a dose-dependent fashion in both the neonatal and adult dogs. Although similar responses to amiodarone were observed in both groups, the immature dogs were more sensitive to amiodarone in prolongation of atrial refractory periods and depression of sinus node recovery time. The neonatal group, however, demonstrated more resistance to amiodarone-induced depression of AV nodal conduction. Thus, intravenous amiodarone produces dose-dependent electrophysiologic changes in the neonate similar to those in the adult, although the significant differences in drug sensitivity may be clinically important.

Atrial vulnerability in the immature canine heart.

The induction of repetitive atrial responses during atrial extrastimulation (atrial vulnerability) was studied in 3 groups of dogs. Group I consisted of 19 neonatal puppies (age 3 to 15 days), group II of 10 older puppies (age 5 to 11 weeks) and group III of 10 adult dogs. In all dogs, atrial extrastimulation was performed coupled to a constant paced rhythm that was 85 +/- 7% of the sinus cycle length at rest in group I, 86 +/- 6% in group II and 83 +/- 10% in group III. In all groups, atrial repetitive responses were observed as the atrial functional refractory periods were approached during extrastimulation; however, the number of repetitive atrial responses was greater and the duration of repetitive firing longer in the neonates. In the neonatal group as many as 28 repetitive atrial responses were induced (9.4 +/- 8.2 beats) and the duration of repetitive atrial firing averaged 838 ms (range 120 to 2,425). In contrast, in only 1 of 20 older puppies and adult dogs were more than 2 repetitive atrial beats observed (number of repetitive atrial beats in group II, 1.7 +/- 1; in group III, 1.2 +/- 0.5). Thus, the normal neonatal atrium is more susceptible to intraatrial reentry in response to premature extrastimulation than the more mature canine atrium. This enhanced atrial vulnerability may be related to the shorter atrial refractory periods of the neonate and may be of importance in understanding the genesis of certain dysrhythmias in the human neonate.

Dual atrioventricular nodal pathways: a benign finding in arrhythmia-free children with heart disease.

The incidence and significance of dual atrioventricular (A-V) nodal pathways are described in 78 children with associated congenital or acquired heart disease. None of these patients had clinical or electrocardiographic evidence of arrhythmia. Dual A-V nodal pathways were observed in 35 percent of the preoperative group and in 33 percent of the postoperative group. Despite this substrate for A-V nodal reentry, supraventricular tachycardia was neither induced during electrophysiologic evaluation nor did it develop clinically over a follow-up period of 1 month to 15 years. It is concluded that dual A-V nodal pathways are common and may be a benign finding in arrhythmia-free children with heart disease.

Hemodynamics and intracardiac conduction after operative repair of tetralogy of Fallot.

Electrophysiologic studies were performed in 47 children aged 3 to 18 years, 15 of whom had cardiac arrhythmias 1 to 15 years after repair of tetralogy of Fallot. Six exhibited sinus or atrioventricular nodal dysfunction, 8 had ventricular extrasystoles, and 1 had supraventricular tachycardia. Hemodynamic and electrophysiologic data were obtained at postoperative catheterization. Although electrophysiologic responses were abnormal in a proportion of both the children with and those without arrhythmia, hemodynamic values were similar. Three of 6 children with impaired sinus impulse generation or atrioventricular nodal conduction had a prolonged A-H interval, and in 3 Wenckebach heart block developed at low pacing rates. Ventricular ectopic rhythm was not associated with any particular abnormality of basic intracardiac conduction intervals. Thus, arrhythmias and conduction abnormalities are not consistently related to residual right ventricular hypertension. Abnormalities in electrophysiologic function are common after repair of tetralogy of Fallot in patients with sinus rhythm and may have prognostic implications for these patients.

Left isomerism and complete atrioventricular block: a report of six cases.

Six children, aged 12 days to 13 years, with left isomerism and complete atrioventricular (A-V) block are presented. In all six patients the diagnosis of left isomerism was suggested by an interrupted inferior vena cava found during cardiac catheterization and angiocardiography; four patients had complex heart disease consisting of endocardial cushion defect, five had a common atrium, three had pulmonary stenosis, three had patient ductus arteriosus and two had dextrocardia. Further anatomic abnormalities included situs inversus of the viscera (four patients) as well as partial malrotation of the bowel. Of the six patients, four had congenital complete A-V block, whereas the remaining two had A-V conduction disturbances documented during early infancy that progressed to complete A-V block later in life. All six patients required pacemaker implantation and five of the six patients died. This report discusses the clinical presentation of complete AV block and left isomerism and reviews the literature.

Sinus and atrioventricular nodal function: Preoperative and early postoperative assessment in children.

Ninety-three rapid atrial pacing studies were performed in 38 children to compare preoperative and early postoperative function of the sinus and atrioventricular (AV) nodes. The interval between the preoperative and postoperative studies was under 6 months in the majority of patients. Postoperative studies were performed within 48 hours of operation and between 4 and 8 days after operation. Sinus nodal function as measured by sinus nodal recovery time (SNRT) was an unreliable index in determining depression since the number who improved postoperatively (10/55) was nearly equal to the number that worsened (12/55). The majority who had abnormal function postoperatively demonstrated a junctional rather than sinus recovery focus. This finding appears a more definitive and more reproducible indicator of sinus node depression in the postoperative patient. Postoperative AV nodal function was decreased (as measured by the cycle length [CL] at which Wenckebach periodicity occurred) in 15 of 55 studies (27%) of the entire group. There was nearly an equal chance for improvement (24%) in function. This also applied to those patients who had sequential studies. Therefore, this method of assessment for AV nodal function was unreliable, or else the operation did not affect the node significantly. The latter is unlikely in view of late postoperative data. The greatest utility of this test was to determine the capability for AV conduction in certain patients with slow escape rhythms in the absence of surface P waves, and to differentiate complete heart block from AV dissociation when atrial activity was absent. Despite the variability of effects on the sinus and AV nodes in these patients, those who demonstrated depression had a significantly higher incidence of dysrhythmias (80% of patients with sinus nodal depression and 100% of patients with AV nodal depression).

Ethnic (black-white) contrasts in heart rate variability during cardiovascular reactivity testing in male adolescents with high and low blood pressure: the Bogalusa Heart Study.

Heart rate variability (HRV) is used to study autonomic effects on the heart. The time domain PNN50 (percentage of consecutive RR intervals differing by > 50%) measures high frequency in HRV primarily reflecting parasympathetic activity. The ratio of low to high frequency power (LF/HF) measured by fast Fourier analysis is used to measure sympathetic to parasympathetic balance. In adults, increased sympathetic tone has been found in hypertensive individuals. The present study was performed to look for differences in HRV by race and between subjects with high and low blood pressure (BP). Heart rate variability data was analyzed from Holter monitor recordings in 39 healthy male subjects aged 13 to 17 years (50% white). Half were selected with Korotkoff fourth sound (K4) DBP > 85th percentile for height measured twice, 3 to 5 years apart (average 116/75 mm Hg). Half had DBP < 15th percentile for height (average 101/57 mm Hg). Subjects underwent a physical examination including BP, height, and weight before cardiovascular reactivity testing including measurements taken while supine and standing, and during 20% maximal isometric hand grip, Valsalva maneuver, and immersion of the hand in water at 4 degrees C. The LF/HF ratio was significantly higher and the PNN50 was significantly lower in whites compared with ratios for blacks during all CV reactivity tests (all P < .05). There was a trend for higher LF/HF ratio and lower PNN50 in blacks and whites with higher levels of BP, although this did not reach statistical significance. It was concluded that healthy white adolescents exhibit increased sympathetic tone compared with that of blacks during CV reactivity tests. A trend towards sympathetic predominance during reactivity testing was demonstrated in children with higher levels of DBP.

Preventive cardiology and its potential influence on the early natural history of adult heart diseases: the Bogalusa Heart Study and the Heart Smart Program.

Observations from pediatric epidemiology studies over the past 20 years document that atherosclerosis and essential hypertension begin in childhood. Evidence of coronary artery disease and hypertensive cardiovascular renal disease is found and relates strongly to clinical cardiovascular risk factors. Obesity, especially central obesity, and hyperinsulinemia are commonly found, and these cluster with other risk factors. Lifestyles, such as poor eating behavior and tobacco usage, also begin early and influence cardiovascular risk. The implication from these pediatric observations is that intervention should begin early to prevent unhealthy lifestyles and encourage adoption of healthy behaviors. Where adult heart diseases pervade the major part of the United States population and other industrialized cultures, various epidemiologic strategies of prevention are needed. A high-risk, clinical approach can be applied to individuals with heart disease or to individuals with underlying risk factors and their families. Primary and secondary prevention are both important and should be implemented by primary care physicians. A population approach is also needed because of the widespread occurrence of heart disease. A public health approach to prevention can occur through health education and health promotion programs. Physicians should play a role in encouraging prevention for the general population. The future direction of Preventive Cardiology for our nation rests on educating children to adopt and maintain healthy lifestyles. The Bogalusa Heart Study has made a major contribution in providing the background information for that direction.

Fatal carnitine palmitoyltransferase II deficiency in a newborn: new phenotypic features.

We describe the term male infant of asymptomatic, healthy nonconsanguineous parents presenting on the first day of life with nonketotic hypoglycemia, seizures, hepatomegaly, cardiomegaly with biventricular hypertrophy, and ventricular arrhythmias. Cranial ultrasound revealed cystic dysplasia with several foci of hyperechogenicity within the right basal ganglia. Free carnitine was markedly decreased in the urine and plasma with a pronounced elevation of plasma long-chain acylcarnitines. Fibroblast carnitine palmitoyltransferase II activity was reduced to 26% and 38% in the father and mother, respectively. The infant expired on day 5 of life from malignant ventricular tachy-arrhythmias. Diffuse lipid accumulation was evident at autopsy, including in the liver, heart, kidney, adrenal cortex, skeletal muscle, and lungs. This new case of infantile CPT-II deficiency illustrates the severity of the early onset form of CPT-II deficiency.

Accelerated ventricular rhythm in children: a review and report of a case with congenital heart disease.

We report a child with accelerated ventricular rhythm (AVR) and congenital heart disease. Three children with congenital heart defect associated with AVR were previously reported, but in each AVR occurred only postoperatively. Because our patient's 24-hour electrocardiograph recording showed AVR rates, and differences between sinus and AVR rates, exceeding published childhood limits, we reviewed the topic. On the basis of our review, we suggest guidelines for diagnosing AVR and differentiating it from ventricular tachycardia.

Modulation of electrophysiological properties of neonatal canine heart by tonic parasympathetic stimulation.

The effects of tonic right and left vagal stimulation (RVS and LVS) on electrophysiological properties of the immature myocardium and specialized conduction system were evaluated in 11 neonatal canines pretreated with propranolol (1 mg/kg iv). Electrophysiological studies were performed by recording intracardiac electrograms from multiple endocardial catheters during programmed electrical stimulation. Assessments were made of sinus node function, intra-atrial, atrioventricular (AV) nodal and His-Purkinje conduction, and atrial and ventricular refractoriness in the control state and during RVS and LVS at 4-12 Hz. Vagal stimulation prolonged the sinus cycle length; RVS produced a 38% increase and LVS a 25% increase at 8 Hz (P less than 0.01). There were no changes in the intra-atrial or His-Purkinje conduction times. Comparable increases occurred during RVS and LVS in the paced cycle length resulting in AV nodal Wenckebach, the AV nodal conduction time at a paced cycle length of 340 ms, and the effective and functional refractory periods of the AV node, suggesting symmetrical influences of the right and left vagus on neonatal AV nodal function. Right atrial effective and functional refractory periods shortened significantly during vagal stimulation (ERP, 36% RVS and 23% LVS; FRP, 27% RVS and 15% LVS), and in 5 of 11 neonates, a sustained regular atrial tachyarrhythmia was induced during atrial extra-stimulation. Small yet significant increases were observed in the right ventricular ERP and FRP during vagal stimulation. This study provides information regarding the functional integrity of the parasympathetic nervous system and its potential role as a modulator of the electrophysiological properties of the newborn heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Ibutilide induced intraatrial Wenckebach periodicity in the neonatal canine heart.

In nine anesthetized canine neonates, the high right atrium was paced at progressively shorter cycle lengths while recording high right atrial electrograms and left atrial appendage monophasic action potentials before and after the administration of the new Class III agent, ibutilide. Prior to ibutilide administration, 1:1 conduction was maintained from the high right atrium to the left atrial appendage at all paced cycle lengths, down to 160 ms. Following ibutilide, a pattern of intraatrial conduction was observed in two of nine neonates at a cycle length of 160 ms that was consistent with the development of intraatrial Wenckebach periodicity. This represents one of the only demonstrations of drug induced intraatrial Wenckebach periodicity in vivo and suggests that this rarely reported form of atrial conduction block might play a role in ibutilide's clinical efficacy against atrial arrhythmias.

Comparison of the rate dependent effects of dofetilide and ibutilide in the newborn heart.

This study compared the rate dependent changes in atrial and ventricular monophasic action potential duration in the newborn canine heart in response to two Class III antiarrhythmic agents: dofetilide, a pure Ikr blocker, and ibutilide, a Na+ channel opener. Newborn dogs were anesthetized with pentobarbital, vagotomized, and given propranolol to eliminate autonomic responses. A 4 Fr electrical catheter was placed in the right atrium for pacing. Monophasic action potential durations (APDs) at 90% repolarization (APD90) were recorded from the epicardial surface of the left ventricle and atrium with Ag-AgCl2 suction electrodes. APD90 was measured as cardiac cycle length was shortened by pacing, in the control condition and following two doses of dofetilide (n = 8) or ibutilide (n = 9). Slopes of the APD90 versus decreasing paced cycle length (PCL) relationships were then compared. Large dose dependent increases in atrial and ventricular APD90 were observed after dofetilide and ibutilide. In the neonatal atrium, there were no changes in the APD90 versus PCL relationship with either drug, indicating no rate dependency of drug effect. In contrast, in the ventricle, a steeper APD90 versus PCL slope was noted after dofetilide and ibutilide, indicating a significant loss of drug effect at faster heart rates (i.e., reverse rate dependency). In spite of probable different cellular mechanisms of action, the rate dependent characteristics of dofetilide and ibutilide are identical in the neonatal heart. There is no evidence of (reverse) rate dependency in the atrium, predicting that both agents would be effective at rapid atrial tachycardia rates. For both, however, marked reverse rate dependency is observed in the neonatal ventricle.

Time-dependent changes in the chronotropic response to vagal stimulation in the newborn canine.

We characterized changes in the vagal chronotropic response during 3-min trains of vagal stimulation at 3, 5, and 8 Hz in anesthetized, chemically sympathectomized (6-hydroxydopamine) newborn canines (< 15 d of age). In response to vagal stimulation, the sinus cycle length gradually increased (within 30 s) to a maximum value that was dependent upon the stimulation frequency (p < 0.001). The chronotropic response then attenuated over the remainder of the vagal train. However, unlike in adult dogs, the degree of attenuation of the vagal chronotropic response (fade) was also highly dependent upon the frequency of vagal stimulation in the range 3-8 Hz (p < 0.002). We then compared the maximum change in sinus cycle length and fade in a group of neonates while stimulating the vagus at 3 Hz before and after the administration of physostigmine (0.2 mg/kg i.v.). Physostigmine resulted in a significant increase not only in the maximum percent change in sinus cycle length but in the magnitude of attenuation of the vagal response as well. Therefore, unlike the adult, in the newborn the magnitude of both the vagal response and fade are dependent upon concentrations of acetylcholine released in response to modest levels of vagal stimulation (< or = 8 Hz). This may be the result of differences between the newborn and the adult in the prestreceptor mechanisms of fade or in the susceptibility of the muscarinic receptor to desensitization by the neurotransmitter acetylcholine.