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1.
Pediatr Cardiol ; 23(6): 580-6, 2002.
Article in English | MEDLINE | ID: mdl-12530488

ABSTRACT

A current debate on the surgical management of patients with tetralogy of Fallot (TOF) focuses largely on primary repair vs initial shunt in younger and/or smaller patients. To characterize practice patterns throughout the United States with respect to the choice of initial surgical procedure in patients with TOF, we analyzed data from a multicenter database. This retrospective study focused on 938 patients from 12 institutions who underwent their initial operation during the 10-year period 1986 through 1995. Overall, the percentage of shunts decreased from 35.1% (1986-1990) to 22.0% (1991-1995) (p < 0.0001). The percentage of primary repairs increased accordingly. However, there was marked interinstitutional variability. For the group of patients aged 3 months or less the overall in-hospital mortality was significantly higher than that for older patients for both shunts and repairs. Multiple logistic regression analysis indicated that age, weight, date of surgery, and the interactions between date of surgery and institutional volume and between age and institutional volume were significant predictors of the initial surgical management of TOF. With this model only part of the observed variance could be explained. Other unidentified variables, including "institutional preference," may be significant factors influencing the choice of initial surgical procedure.


Subject(s)
Cardiac Surgical Procedures , Tetralogy of Fallot/surgery , Age Factors , Body Weight , Child, Preschool , Coronary Artery Disease/congenital , Coronary Artery Disease/mortality , Coronary Artery Disease/surgery , Decision Making , Down Syndrome/mortality , Down Syndrome/surgery , Follow-Up Studies , Hospital Mortality , Humans , Infant , Infant Welfare , Infant, Newborn , Predictive Value of Tests , Pulmonary Artery/abnormalities , Pulmonary Artery/surgery , Pulmonary Valve Stenosis/congenital , Pulmonary Valve Stenosis/mortality , Pulmonary Valve Stenosis/surgery , Retrospective Studies , Statistics as Topic , Tetralogy of Fallot/mortality , Time Factors , Treatment Outcome , United States
2.
Pacing Clin Electrophysiol ; 24(9 Pt 1): 1398-402, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11584463

ABSTRACT

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.


Subject(s)
Electrocardiography/drug effects , Heart Atria/drug effects , Heart Block/chemically induced , Sulfonamides/pharmacology , Animals , Animals, Newborn , Cardiac Pacing, Artificial , Dogs , Heart Atria/physiopathology , Heart Block/physiopathology
3.
Pacing Clin Electrophysiol ; 24(5): 816-23, 2001 May.
Article in English | MEDLINE | ID: mdl-11388101

ABSTRACT

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.


Subject(s)
Action Potentials/drug effects , Animals, Newborn/physiology , Anti-Arrhythmia Agents/pharmacology , Atrial Function/drug effects , Heart Rate/drug effects , Phenethylamines/pharmacology , Sulfonamides/pharmacology , Ventricular Function , Analysis of Variance , Animals , Blood Pressure/drug effects , Dogs , Dose-Response Relationship, Drug , Electrophysiology , Heart Ventricles/drug effects , Linear Models
4.
Pediatr Cardiol ; 22(1): 23-8, 2001.
Article in English | MEDLINE | ID: mdl-11123122

ABSTRACT

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.


Subject(s)
Accelerated Idioventricular Rhythm/diagnosis , Heart Defects, Congenital/complications , Accelerated Idioventricular Rhythm/etiology , Discrete Subaortic Stenosis/etiology , Electrocardiography, Ambulatory , Female , Heart Defects, Congenital/surgery , Heart Septal Defects, Ventricular/complications , Heart Ventricles , Humans , Infant, Newborn , Male
5.
Clin Pediatr (Phila) ; 38(1): 13-20, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9924637

ABSTRACT

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.


Subject(s)
Carnitine O-Palmitoyltransferase/deficiency , Abnormalities, Multiple/genetics , Deficiency Diseases/genetics , Deficiency Diseases/mortality , Fatal Outcome , Humans , Infant, Newborn , Male , Phenotype
6.
Am J Hypertens ; 11(2): 196-202, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9524048

ABSTRACT

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.


Subject(s)
Heart Rate , Hypertension/physiopathology , Adolescent , Black People , Humans , Male , Sympathetic Nervous System/physiology , White People
7.
J Auton Nerv Syst ; 64(2-3): 107-14, 1997 Jun 06.
Article in English | MEDLINE | ID: mdl-9203131

ABSTRACT

We investigated the effects of mild hypothermia (34.3 +/- 0.2 degrees C [mean +/- SD]), hyperthermia (40.8 +/- 0.2 degrees C) and hypoxia (PaO2 = 43 +/- 4 mmHg) on the response to heart rate to continuous right vagus nerve stimulation (the 'vagal chronotropic response') in young puppies, aged 5-22 days. Puppies were anesthetized with alpha-chloralose, vagotomized and pre-treated with propranolol (1 mg/kg i.v.) and phentolamine (1 mg/kg, 1-2 mg/kg/h i.v.). Hypoxia (n = 9) did not significantly alter the resting sinus cycle length and did not alter the response of sinus cycle to a 30 s train of 8 Hz right vagal stimulation. Mild hypothermia (n = 8) increased the resting sinus cycle length by 16 +/- 4% and greatly augmented the vagal chronotropic response (from 76 +/- 27% change in the sinus cycle length (normothermia) to 155 +/- 38% (hypothermia)). Both the sinus cycle length and the vagal chronotropic response turned towards pre-hypothermia values with rewarming. Mild hypothermia also increased the negative chronotropic response to 20 micrograms/kg/min i.v. of methacholine (12 +/- 2% change in the sinus cycle length (normothermia) versus 24 +/- 14% (hypothermia)), suggesting that a postsynaptic mechanism is involved in the hypothermia-induced augmentation of the cardiac vagal chronotropic response. In contrast to hypothermia, mild hyperthermia (n = 8) decreased the resting sinus cycle length slightly (-5 +/- 5% change) and significantly attenuated the cardiac vagal chronotropic response (from 88 +/- 28% change in sinus cycle length (normothermia) to 50 +/- 26% (hyperthermia)). These changes were also reversible with the re-establishment of normothermia. This demonstrates that clinically relevant, environmentally-induced changes in body temperature can directly and reversibly modify parasympathetic efferent responses.


Subject(s)
Animals, Newborn/physiology , Autonomic Nervous System/physiology , Environment , Heart Rate/physiology , Temperature , Vagus Nerve/physiology , Animals , Dogs , Female , Fever/physiopathology , Hypothermia/physiopathology , Hypoxia/physiopathology , Male
8.
Cardiovasc Res ; 31 Spec No: E96-103, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8681351

ABSTRACT

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.


Subject(s)
Autonomic Nervous System/growth & development , Heart/innervation , Neuropeptide Y/physiology , Animals , Animals, Newborn , Dogs , Electric Stimulation , Parasympathetic Nervous System/growth & development , Stellate Ganglion/physiology , Sympathetic Nervous System/growth & development , Vagus Nerve/physiology
11.
Am J Med Sci ; 310 Suppl 1: S133-8, 1995 Dec.
Article in English | MEDLINE | ID: mdl-7503117

ABSTRACT

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.


Subject(s)
Heart Diseases/prevention & control , Adult , Child , Health Education , Health Promotion , Humans , Public Health
12.
Circulation ; 91(9): 2400-6, 1995 May 01.
Article in English | MEDLINE | ID: mdl-7729027

ABSTRACT

BACKGROUND: The measurement of left ventricular mass (LVM) is important because individuals with increased LVM are at increased risk for cardiovascular diseases, including myocardial infarction and congestive heart failure. There are limited longitudinal data on the acquisition of LVM in children and young adults and the relative importance of sex, growth, excess body weight, and blood pressure (BP) on change in LVM. METHODS AND RESULTS: The study cohort consisted of a cross section of 160 healthy children and young adults 9 to 22 years of age at first exam in the biracial community of Bogalusa, La. All had stable BP levels recorded over a 2- to 3-year period. Repeated examinations were performed 4 to 5 years apart. At each exam, 6 BPs were obtained with a mercury sphygmomanometer by trained examiners. The mean of the observations was used, with the fourth Korotkoff phase serving as the measure of diastolic BP. Anthropometric data, including height (HT), weight (WT), and triceps skin fold thickness (TSF), were also obtained, and M-mode echocardiograms were performed. Ponderal index (PI = WT/HT3) was used as a measure of weight-for-height. Tracking of HT (r = .68 to .76), WT (r = .73 to .82), PI (r = .77 to .89), TSF (r = .70 to .80), BP (r = .47 to .60), and LVM (r = .40 to .70) was strong in both sexes (P < .0001). LVM indexed for linear growth (LVM/HT2.7) tracked in females (r = .56, P < .0001) but not in males. In univariate cross-sectional analyses, LVM/HT2.7 correlated with WT, PI, and TSF in both sexes (r = .21 to .60, P < .05) and with systolic BP (SBP) in females (r = .23, P < .05). WT was the only independent correlate of LVM/HT2.7 in both sexes in multivariate cross-sectional analysis in a model containing age, SBP, WT, and TSF as independent variables (r2 = .08 to .28, P < .02). In longitudinal univariate analyses, initial measurements of WT, PI, and TSF predicted final LVM/HT2.7 in both sexes (r = .28 to .56, P < .01), and SBP was significant for females (r = .27, P < .05). In multivariate analyses, initial WT was associated with final LVM and LVM/HT2.7 in both sexes (r2 = .27 to .54, P < .01). Finally, baseline LVM correlated with final SBP in both sexes (r = .21 to .27, P < .05), and initial LVM/HT2.7 correlated with final SBP in females (r = .26, P < .05) with a trend for males (r = .17). CONCLUSIONS: These data indicate that linear growth is the major determinant of cardiac growth in children and that excess weight may lead to the acquisition of LVM beyond that expected from normal growth. Increased mass may also precede the development of increased BP. The development of obesity may therefore be a significant, and possibly modifiable, risk factor for developing left ventricular hypertrophy and hypertension, risk factors for cardiovascular morbidity and mortality.


Subject(s)
Heart Ventricles/growth & development , Adolescent , Adult , Blood Pressure , Body Constitution , Body Weight , Child , Cohort Studies , Female , Follow-Up Studies , Heart Diseases/etiology , Heart Ventricles/physiopathology , Humans , Louisiana , Male , Risk Factors
13.
Pediatr Res ; 35(2): 244-9, 1994 Feb.
Article in English | MEDLINE | ID: mdl-8165061

ABSTRACT

We performed intracardiac electrophysiologic studies of the effects of vasoactive intestinal peptide (VIP, 0.125 micrograms/kg/min) on sinus and atrioventricular (AV) nodal function, intracardiac conduction, and myocardial refractoriness in two groups of neonatal dogs (aged 6-16 d). Group I consisted of eight neonates in whom VIP was administered after bilateral vagotomy and beta-blockade with propranolol. Group II consisted of five neonates studied after vagotomy and propranolol, plus total chemical sympathectomy (6-hydroxydopamine). In both groups, VIP resulted in a significant shortening of sinus cycle length. AV nodal conduction time, measured as the AH interval (the time from the onset of the atrial electrogram to the onset of the His bundle electrogram in the His electrode catheter) during atrial pacing, also shortened after VIP. His-Purkinje conduction time and atrial effective refractory periods were unchanged by VIP. In other experiments, the direct chronotropic effect of VIP was evaluated in five isolated neonatal canine hearts using a modified Langendorff technique. In these hearts, the spontaneous cycle length decreased from 403 +/- 88 to 293 +/- 69 ms, or -28 +/- 4% (mean +/- SD), after exposure to 0.1-0.5 nmol of VIP (p < 0.001). In nine other newborns (aged 4-16 days), the effect of selective alpha 1- and alpha 2-adrenergic receptor blockade on the positive chronotropic effect of VIP was evaluated. The effect of VIP on sinus cycle length was not altered by the alpha 1-adrenergic receptor blocker prazosin or by the alpha 2-adrenergic receptor blocker yohimbine.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Heart/drug effects , Heart/physiology , Vasoactive Intestinal Peptide/pharmacology , Vasoactive Intestinal Peptide/physiology , Animals , Animals, Newborn , Atrioventricular Node/drug effects , Atrioventricular Node/physiology , Blood Pressure/drug effects , Blood Pressure/physiology , Dogs , Electrophysiology , Heart Rate/drug effects , Heart Rate/physiology , Prazosin/pharmacology , Receptors, Adrenergic, alpha/drug effects , Receptors, Adrenergic, alpha/physiology , Yohimbine/pharmacology
14.
Pediatr Res ; 35(1): 55-61, 1994 Jan.
Article in English | MEDLINE | ID: mdl-8134200

ABSTRACT

We have previously demonstrated that vagal phase-response curves (PRC), which characterize the effects of critically timed, brief vagal stimuli on sinus node automaticity, exhibit a fundamentally different shape in the canine newborn than in the adult. In this study we analyzed the changes in sinus cycle length in response to critically timed, brief vagal stimuli, delivered to the decentralized cervical right and left vagosympathetic trunks, in two older age groups: 14 1-mo-old puppies (ages 21-36 d), and eight 2-mo-old puppies (ages 56-62 d). Vagal PRC were constructed by plotting the magnitude (percent change) of the vagal chronotropic response as a function of the phase of the cardiac cycle at which the vagus nerve was stimulated. At 1 mo of age adult-type PRC were observed, but in only six of the puppies (43%) and only in response to right vagal stimulation. By 2 mo of age adult-type PRC were observed in seven of eight puppies (88%) in response to right vagal stimulation and in three of eight (38%) in response to left vagal stimulation. Thus, clear developmental changes in the phase dependence of the vagal chronotropic response can be tracked over the first 2 mo of life in the dog.


Subject(s)
Sinoatrial Node/growth & development , Sinoatrial Node/physiology , Vagus Nerve/physiology , Animals , Animals, Newborn , Dogs , Electric Stimulation , Heart Rate/physiology , Parasympathetic Nervous System/growth & development , Parasympathetic Nervous System/physiology , Time Factors
15.
Pediatr Res ; 34(2): 139-43, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8233714

ABSTRACT

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.


Subject(s)
Heart Rate/physiology , Vagus Nerve/physiology , Acetylcholine/metabolism , Animals , Animals, Newborn , Dogs , Electric Stimulation , Phentolamine/pharmacology , Physostigmine/pharmacology , Propranolol/pharmacology , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/metabolism , Sympathectomy, Chemical
17.
Zhongguo Yao Li Xue Bao ; 14(2): 106-9, 1993 Mar.
Article in English | MEDLINE | ID: mdl-8351998

ABSTRACT

In the present study, the responses of neonatal and adult dog hearts to phenylephrine (PE) and phentolamine (PA) were investigated in order to determine the influence of age factors. PA resulted in the slowing of the heart rate, the prolongation of corrected sinus node recovery time, atrial refractory period (ARP), ventricular effective refractory period (VERP), and ventricular functional refractory period (VFRP), and a significant inhibition of conducting tissues in neonatal dogs. In contrast, no such effects were seen in adult dogs. PE had a positive chronotropic effect in neonatal dogs but no such effect in adult dogs. In conclusion, alpha-adrenoceptors played an important excitatory role in the neonatal dog heart.


Subject(s)
Heart/drug effects , Phentolamine/pharmacology , Phenylephrine/pharmacology , Age Factors , Animals , Blood Pressure/drug effects , Dogs , Female , Heart Conduction System/drug effects , Heart Rate/drug effects , Male , Refractory Period, Electrophysiological/drug effects , Stimulation, Chemical
18.
Circulation ; 87(3): 950-62, 1993 Mar.
Article in English | MEDLINE | ID: mdl-8443914

ABSTRACT

BACKGROUND: Previous clinical reports have suggested that cocaine intoxication may produce severe ventricular arrhythmias due to a direct effect on the heart. However, the effects of high plasma levels of cocaine on the electrophysiology of the heart have not been well characterized and remain poorly understood. METHODS AND RESULTS: The purpose of this study was to characterize the electrophysiological effects of high doses of cocaine on the in situ dog heart. In dogs anesthetized with morphine and alpha-chloralose, cocaine (2-11 micrograms/mL) increased both atrial and ventricular refractory periods and produced rate-dependent increases in atrial, atrioventricular, His-Purkinje, and ventricular conduction intervals. The time constant for the onset of cocaine's conduction slowing effect following a reduction in pacing cycle length from 400 to 260 msec was approximately two beats, and the time constant for diastolic recovery from conduction slowing was approximately 200 msec, which are similar to values reported for several class Ib antiarrhythmic drugs. Cocaine produced a rate-dependent increase in QT interval that was greatest at high heart rates yet produced no change in the ST (QT-QRS) interval. This suggests that high plasma levels of cocaine delay repolarization primarily via slowing of conduction. Cocaine's effects on both atrioventricular and intraventricular conduction were significantly larger in autonomically blocked than in autonomically intact animals. CONCLUSIONS: We conclude that high plasma levels of cocaine, similar to those reported in autopsy reports following fatal cocaine overdose in humans, produce significant rate-dependent conduction slowing effects on atrial, atrioventricular, and ventricular conduction in the in situ heart. These rate-dependent effects are intensified following autonomic blockade.


Subject(s)
Autonomic Nervous System/physiology , Cocaine/pharmacology , Heart Rate/physiology , Heart/drug effects , Animals , Arrhythmias, Cardiac/etiology , Bundle of His/physiology , Cardiac Pacing, Artificial , Coronary Circulation , Dogs , Dose-Response Relationship, Drug , Electrophysiology , Female , Heart/physiology , Heart Conduction System/drug effects , Hemodynamics , Male , Osmolar Concentration , Refractory Period, Electrophysiological
19.
J Pharmacol Exp Ther ; 263(2): 608-16, 1992 Nov.
Article in English | MEDLINE | ID: mdl-1331407

ABSTRACT

We evaluated the effects of ethmozine on resting conduction intervals, myocardial refractory periods and His-Purkinje and intraventricular conduction in vivo in 11 neonatal dogs aged 7 to 16 days. Ethmozine produced significant prolongation in resting sinus cycle length (P < .05), in the atrioventricular nodal (P < .001) and His-Purkinje conduction time (P < .01) intervals and in the QRS duration (P < .01). Ventricular, but not atrial refractory periods were significantly prolonged (P < .05). Rate-dependent changes in His-Purkinje and intraventricular conduction were demonstrated after ethmozine by direct pacing of the bundle of His and right ventricular pacing. The development of steady-state conduction delay at a paced cycle length of 200 msec was characterized by a time constant (tau on) of 23.5 beats. The time constant of diastolic recovery (tau off) from rate-dependent conduction delay, determined during His bundle extrastimulation, was 171 msec. Ethmozine was highly proarrhythmic. A total of 7 arrhythmias were induced in 6 out of 12 neonates after administration of ethmozine. We also characterized ethmozine block of cardiac sodium channels in isolated neonatal canine ventricular myocytes using the whole cell variation of the patch clamp technique. Ethmozine (1.3-40 microM) produced a use-dependent block of cardiac Na channels that was dependent upon both drug concentration and pulse duration. Drug binding to inactivated channel states accounted for the observed use-dependent block. The time constant of recovery from use-dependent block ranged between 10 and 30 sec at 16 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Heart Conduction System/drug effects , Moricizine/pharmacology , Myocardium/metabolism , Sodium/metabolism , Animals , Arrhythmias, Cardiac/drug therapy , Blood Pressure , Bundle of His/drug effects , Dogs , Electrophysiology , Heart Ventricles/metabolism , Moricizine/blood , Sodium Channels/drug effects , Time Factors
20.
J Pharmacol Exp Ther ; 262(2): 670-6, 1992 Aug.
Article in English | MEDLINE | ID: mdl-1323658

ABSTRACT

Previous studies have suggested that there are developmental changes in the sodium channel blocking properties of class I antiarrhythmic drugs, yet this hypothesis has not been well tested using measurements of sodium current. In this study we defined the effects of lidocaine on the cardiac sodium current in neonatal (1-2-day old) and adult rat ventricular myocytes using the whole-cell variation of the patch-clamp technique (16 degrees C, [Na]i = 15 mM, [Na]o = 25 mM). Lidocaine (30 microM) produced significantly more tonic block at negative holding potentials (e.g., -140 mV) in neonatal myocytes (23.2 +/- 7.0%, mean +/- S.E.M., n = 9) compared to adult (6.5 +/- 1.1%, n = 12) (P less than .05). The percentage of use-dependent block obtained during trains of 10-msec pulses at a cycle length of 200 msec was also significantly greater in neonatal myocytes (22.5 +/- 5.6%, n = 9) compared to adult myocytes (6.9 +/- 2.2%, n = 7) (P less than .02). Analysis of the kinetics of block development at -20 mV indicated that neonatal cells have a lower dissociation constant for lidocaine interaction with inactivated channels (10.1 +/- 1.3 microM) compared to adult cells (16.5 +/- 1.9 microM)(P less than .02). A marked difference was found for the time constant of recovery from channel block, where neonates recovered from block approximately twice as slowly as adults (e.g., at -140 mV tau = 1.54 +/- 0.28 sec, n = 11 in neonates vs. tau = 0.64 +/- 0.07 sec, n = 13 in adults) (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Heart/drug effects , Lidocaine/pharmacology , Sodium Channels/drug effects , Age Factors , Animals , In Vitro Techniques , Rats
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