A large family characterised by nocturnal sudden death.

BACKGROUND: We recently identified a novel mutation in large family characterised by premature nocturnal sudden death. In the present paper we provide an overview of the findings in this family. METHODS: From 1958 onwards, when the first patient presented, we collected clinical data on as many family members as possible. After identification in 1998 of the underlying genetic disorder (SCN5A, 1795insD), genotyping was performed diagnostically. RESULTS: Since 1905 unexplained sudden death occurred in 26 family members, 17 of whom died during the night. Besides sudden death, symptomatology was rather limited; only six patients reported syncopal attacks. In one of them, a 13-year-old boy, asystolic episodes up to nine seconds were documented. Until now, the mutation has been found in 114 family members (57 males, 57 females). Carriers of the mutant gene exhibited bradycardia-dependent QT-prolongation, intrinsic sinus node dysfunction, generalised conduction abnormalities, a paucity of ventricular ectopy, and the Brugada sign. Cardiomyopathy or other structural abnormalities were not found in any of the carriers. Electrophysiological studies showed that mutant channels were characterised by markedly reduced INa amplitude, a positive shift of voltage-dependence of activation and a substantial negative shift of voltage-dependence of inactivation of INa. From 1978 onwards, a pacemaker for anti-brady pacing was implanted for prevention of sudden death. In patients in whom a prophylactic pacemaker was implanted no unexplained sudden death occurred, whereas 5 sudden deaths occurred in the group of patients who did not receive a pacemaker. CONCLUSION: We have described a large family with a SCN5A-linked disorder (1795insD) with features of LQT3, Brugada syndrome and familial conduction system disease. Anti-brady pacing was successful in preventing sudden death. The mode of death is possibly bradycardic.

Possible bradycardic mode of death and successful pacemaker treatment in a large family with features of long QT syndrome type 3 and Brugada syndrome.

INTRODUCTION: We recently identified a novel mutation of SCN5A (1795insD) in a large family with features of both long QT syndrome type 3 and the Brugada syndrome. The purpose of this study was to detail the clinical features and efficacy of pacemaker therapy in preventing sudden death in this family. METHODS AND RESULTS: The study group consisted of 116 adult family members: 60 carriers (29 males) and 56 noncarriers (28 males) of the mutant gene. Investigations included 24-hour Holter monitoring, ergometry, and electrophysiologic studies. Mean, lowest, and highest heart rate were lower in the carriers, but heart rate variability was comparable. In carriers, disproportional QT prolongation was present during bradycardia. No complex ventricular ectopy was recorded, and there were fewer isolated premature beats (both ventricular and atrial) in carriers. All patients were asymptomatic, except for two individuals who experienced syncope; in one of these patients, asystolic episodes (up to 9 sec) were repeatedly recorded. Prolonged HV intervals were present in 5 of 6 patients. Thirty carriers received a prophylactic backup pacemaker. During median follow-up of 4.5 years (range 0.0 to 22.6), their survival rate was 100%. There were five sudden deaths among the remaining 30 carriers without a pacemaker (P = 0.019). CONCLUSION: This family with a high incidence of nocturnal sudden death is characterized by bradycardia-dependent QT prolongation, intrinsic sinus node dysfunction, and generalized conduction abnormalities. There is a striking absence of complex ventricular ectopy, and pacemaker implantation was effective in preventing sudden death. These findings raise the possibility of a bradycardic rather than tachycardic mode of death.

Metabolic responses to moderate exercise in lambs with aortopulmonary shunts.

In a previous study we found, after an overnight fast of 18 hours, a lower arterial glucose concentration and a depressed glycogenolysis in lambs with aortopulmonary left-to-right shunts. During exercise, glucose and free fatty acids (FFA) concentrations normally increase. The aim of this study was to investigate whether the shunt lambs could compensate for a depressed glycogenolysis by increasing gluconeogenesis and by increasing levels of blood substrates such as FFA and glycerol during exercise. Therefore, we investigated glucose kinetics, with [U-(13)C]glucose, in five 7-week-old shunt and 7 control lambs of a similar age, at rest and during moderate exercise (treadmill; 50% of VO(2) peak). The glucose production rate and the rate of disappearance of glucose were lower in shunt than in control lambs, both at rest and during exercise. We found no difference in metabolic clearance rate of glucose, glucose recycling, or gluconeogenesis between both groups of lambs. Glycogenolysis was at rest lower in shunt than in control lambs and tended to be lower during exercise. The arterial concentrations of pyruvate, lactate, FFA, and total and free glycerol increased during exercise in both groups of lambs. In conclusion, shunt lambs have lower arterial glucose concentrations than control lambs, both at rest and during moderate exercise. This was due to a lower glucose production rate, in particular a lower glycogenolysis. In addition, the reduced glycogenolysis rate was not offset by an increase in gluconeogenesis nor by an increase in other substrates that can be utilized by working muscles.

A sodium-channel mutation causes isolated cardiac conduction disease.

Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encoding the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening; however, a chief function of the Na+ channel is to initiate cardiac impulse conduction. Here we provide the first functional characterization of an SCN5A mutation that causes a sustained, isolated conduction defect with pathological slowing of the cardiac rhythm. By analysing the SCN5A coding region, we have identified a single mutation in five affected family members; this mutation results in the substitution of cysteine 514 for glycine (G514C) in the channel protein. Biophysical characterization of the mutant channel shows that there are abnormalities in voltage-dependent 'gating' behaviour that can be partially corrected by dexamethasone, consistent with the salutary effects of glucocorticoids on the clinical phenotype. Computational analysis predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN5A mutations.

Cross-stimulation during lead impedance monitoring.

At the age of 4 years, a total cavopulmonary connection was performed in a boy with a complex congenital heart defect. On addition, a DDDR pacemaker was implanted for sick sinus syndrome. Atrial and ventricular leads were epicardially placed at the left atrium and left ventricle. At the age of 10 years, a new epicardial ventricular lead was placed because of malfunction of the existing lead. At the same operation the pulse generator was replaced by a Medtronic Kappa DR 731. After replacement, the boy experienced episodes of phrenic nerve stimulation associated with feelings of discomfort. Holter recordings revealed ventricular stimulation from the atrial stimulus for 2 consecutive beats. This phenomenon repeated exactly every 3 hours and was caused by the automatic lead impedance measurement that used a 5-V, 1-ms stimulus output.

Perinatal changes in myocardial metabolism in lambs.

BACKGROUND: Lactate accounts for a third of myocardial oxygen consumption before and in the first 2 weeks after birth. It is unknown how the remainder of myocardial oxygen is consumed. Glucose is thought to be important before birth, whereas long-chain fatty acids (LC-FA) are the prime substrate for the adult. However, the ability of the myocardium of the newborn to use LC-FA has been doubted. METHODS AND RESULTS: We measured the myocardial metabolism of glucose and LC-FA with [U-(13)C]glucose and [1-(13)C]palmitate in chronically instrumented fetal and newborn lambs. In fetal lambs, myocardial oxidation of glucose was high and that of LC-FA was low. Glucose and LC-FA accounted for 48+/-4% and 2+/-2% of myocardial oxygen consumption, respectively. In newborn lambs, oxidation of glucose decreased, whereas oxidation of LC-FA increased. Glucose and LC-FA accounted for 12+/-3% and 83+/-19% of myocardial oxygen consumption. To test whether near-term fetal lambs could use LC-FA, we increased the supply of LC-FA with a fat infusion. In fetal lambs during fat infusion, the oxidation of LC-FA increased 15-fold. Although the oxidation of LC-FA was still lower than in newborn lambs, the contribution to myocardial oxygen consumption (70+/-13%) was the same as in newborn lambs. CONCLUSIONS: These data show that glucose and lactate account for the majority of myocardial oxygen consumption in fetal lambs, whereas in newborn lambs, LC-FA and lactate account for the majority of myocardial oxygen consumption. Moreover, we showed that the fetal myocardium can use LC-FA as an energy substrate.

Lower arterial glucose concentrations in lambs with aortopulmonary shunts after an 18-hour fast.

Spontaneously occurring hypoglycemia has been described in children with severe acute congestive heart failure. Hypoglycemia may be the result of an increase in glucose utilization in tissues, a decrease in glucose production, or a decrease in the dietary intake of nutrients. To determine whether hypoglycemia may also occur in congenital heart disease with volume overloading, we investigated glucose metabolism during and after an 18-hour fast in nine lambs with an aortopulmonary left-to-right shunt and nine control lambs. Plasma levels of hormones involved in the endocrine control of glucose metabolism were determined. The glucose production rate (rate of appearance [Ra]) was studied using [U-13C]glucose. Gluconeogenesis through the Cori cycle was estimated by measuring glucose 13C recycling. The arterial glucose concentration (3,409 +/- 104 v 4,338 +/- 172 micromol/L, P < .001) and Ra of glucose (16.97 +/- 0.89 v 25.49 +/- 4.28 micromol x min(-1) x kg(-1), P < .05) were lower in shunt versus control lambs. There were no differences in hormone levels between control and shunt lambs. Fractional glucose 13C recycling via the Cori cycle (6.9% +/- 2.8% v 7.1% +/- 2.5%) and gluconeogenesis from pyruvate and lactate (1.24 +/- 0.58 v 1.95 +/- 0.67 micromol x min(-1) x kg(-1)) were similar in both groups of lambs. The sum of glycogenolysis and gluconeogenesis from precursors other than pyruvate and lactate was lower in shunt versus control lambs (15.73 +/- 1.07 v 23.54 +/- 4.27 micromol x min(-1) x kg(-1), P < .05). In conclusion, after an 18-hour fast, the arterial glucose concentration is lower in lambs with aortopulmonary shunts. This lower glucose concentration is associated with a decreased glucose production rate. In shunt lambs, glycogenolysis is decreased, while there is no difference in gluconeogenesis or hormonal control.

Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.

Congenital long QT syndrome (cLQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The most common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG. We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG. Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG. Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS.

Myocardial lactate metabolism in fetal and newborn lambs.

BACKGROUND: Around birth, myocardial substrate supply changes from carbohydrates before birth to primarily fatty acids after birth. Parallel to these changes, the myocardium is expected to switch from the use of primarily lactate before birth to fatty acids thereafter. However, myocardial lactate uptake and oxidation around birth has not been measured in vivo. METHODS AND RESULTS: We measured myocardial lactate uptake, oxidation, and release with infusion of [1-13C]lactate and myocardial flux of fatty acids and glucose in chronically instrumented fetal and newborn (1 to 15 days) lambs. Myocardial lactate oxidation was the same in newborn (81.7+/-14.7 micromol. min-1. 100 g-1, n=11) as in fetal lambs (60.7+/-26.7 micromol. min-1. 100 g-1, n=7). Lactate uptake was also the same in newborn as in fetal lambs. Lactate uptake was higher than lactate flux, indicating lactate release simultaneously with uptake. In the newborn lambs, lactate uptake declined with age. Lactate uptake was strongly related to lactate supply, whereas lactate oxidation was not. The supply of fatty acids or glucose did not interfere with lactate uptake, but the flux of fatty acids was inversely related to lactate oxidation. CONCLUSIONS: We show that lactate is an important energy source for the myocardium before birth as well as in the first 2 weeks after birth in lambs. We also show that there is release of lactate by the myocardium simultaneously with uptake of lactate. Furthermore, we show that lactate oxidation may be attenuated by fatty acids but not by glucose, probably at the level of pyruvate dehydrogenase.

Lactate kinetics at rest and during exercise in lambs with aortopulmonary shunts.

In a previous study [G. C. M. Beaufort-Krol, J. Takens, M. C. Molenkamp, G. B. Smid, J. J. Meuzelaar, W. G. Zijlstra, and J. R. G. Kuipers. Am. J. Physiol. 275 (Heart Circ. Physiol. 44): H1503-H1512, 1998], a lower systemic O2 supply was found in lambs with aortopulmonary left-to-right shunts. To determine whether the lower systemic O2 supply results in increased anaerobic metabolism, we used [1-13C]lactate to investigate lactate kinetics in eight 7-wk-old lambs with shunts and eight control lambs, at rest and during moderate exercise [treadmill; 50% of peak O2 consumption (VO2)]. The mean left-to-right shunt fraction in the shunt lambs was 55 +/- 3% of pulmonary blood flow. Arterial lactate concentrations and the rate of appearance (Ra) and disappearance (Rd) of lactate were similar in shunt and control lambs, both at rest (lactate: 1, 201 +/- 76 vs. 1,214 +/- 151 micromol/l; Ra = Rd: 12.97 +/- 1.71 vs. 12.55 +/- 1.25 micromol. min-1. kg-1) and during a similar relative workload. We found a positive correlation between Ra and systemic blood flow, O2 supply, and VO2 in both groups of lambs. In conclusion, shunt lambs have similar lactate kinetics as do control lambs, both at rest and during moderate exercise at a similar fraction of their peak VO2, despite a lower systemic O2 supply.

Comparison of longevity, pacing, and sensing characteristics of steroid-eluting epicardial versus conventional endocardial pacing leads in children.

OBJECTIVE: Because of either cardiac anatomy or small size, pacing in children often occurs by means of epicardial leads. The disadvantage of epicardial leads is the shorter longevity of these leads compared with endocardial leads. During short-term follow-up, improved stimulation thresholds were found for the newer steroid-eluting epicardial leads. The longevity of these leads may be better than that of conventional epicardial leads. An improved longevity of epicardial leads may influence the choice to either epicardial or endocardial pacing in children. METHODS: We studied the longevity and the pacing and sensing characteristics of 33 steroid-eluting epicardial pacing leads (group I, 15 atrial, 18 ventricular) implanted between November 1991 and October 1996 in 20 children with a mean age of 7.6 +/- 6.5 years (mean +/- SD), and 29 endocardial pacing leads (group II, 15 atrial, 14 ventricular) implanted during the same period in 21 children with a mean age of 11.7 +/- 4.7 years. RESULTS: The mean follow-up in group I was 2.9 +/- 1.6 years and in group II 3.1 +/- 1.7 years (P =.61). The 2-year survival of the leads in group I was 91% +/- 5% and in group II 86% +/- 7% (P =.97). Lead failure occurred in both groups in 4 leads (P =.85). Chronic stimulation and sensing thresholds were similar. CONCLUSIONS: Steroid-eluting epicardial leads have the same longevity as the conventional endocardial leads. Pacing and sensing thresholds were similar and did not change during follow-up. Therefore steroid-eluting epicardial pacing leads are a good alternative for endocardial leads in small children and in children with congenital heart disease.

Increased myocardial lactate oxidation in lambs with aortopulmonary shunts at rest and during exercise.

Free fatty acids are the major fuels for the myocardium, but during a higher load carbohydrates are preferred. Previously, we demonstrated that myocardial net lactate uptake was higher in lambs with aortopulmonary shunts than in control lambs. To determine whether this was caused by an increased lactate uptake and oxidation or by a decreased lactate release, we studied myocardial lactate and glucose metabolism with 13C-labeled substrates in 36 lambs in a fasting, conscious state. The lambs were assigned to two groups: a resting group consisting of 8 shunt and 9 control lambs, and an exercise group (50% of peak O2 consumption) consisting of 9 shunt and 10 control lambs. Myocardial lactate oxidation was higher in shunt than in control lambs (mean +/- SE, rest: 10.33 +/- 2.61 vs. 0. 17 +/- 0.82, exercise: 38.05 +/- 8.87 vs. 16.89 +/- 4.78 micromol. min-1. 100 g-1; P < 0.05). There was no difference in myocardial lactate release between shunt and control lambs. Oxidation of exogenous glucose, which was approximately zero at rest, increased during exercise in shunt and control lambs. The contribution of glucose and lactate to myocardial oxidative metabolism increased during exercise compared with at rest in both shunt and control lambs. We conclude that myocardial lactate oxidation is higher in shunt than in control lambs, both at rest and during exercise, and that the contribution of carbohydrates in myocardial oxidative metabolism in shunt lambs is higher than in control lambs. Thus it appears that this higher contribution of carbohydrates occurs not only in the case of pressure-overloaded hearts but also in myocardial hypertrophy due to volume overloading.

Determination of organ substrate oxidation in vivo by measurement of 13CO2 concentration in blood.

Substrate oxidation by various organs in animals as well as in humans is usually studied by experiments in which radioactively labeled substrates are used and the production of 14CO2 is measured. In vivo, substrate oxidation by an organ has, up to now, not been determined by means of stable isotopes. Problems in the determination of the concentration of 13CO2 in blood may have impeded the use of 13C-labeled substrates. For the determination of 13CO2 concentration in blood a direct method for the determination of total CO2 concentration in blood was combined with the determination of the isotope ratio (13C/12C) of CO2 by isotope ratio mass spectrometry. The intra-assay relative standard deviation of the CO2 concentration (mean: 19.26 mmol l-1; n = 7) was 0.8%. The inter-assay relative standard deviation of the CO2 concentration in solutions of a weighed amount of Na2CO3 determined over a 5 year period was 0.64% (mean: 21.99 mmol l-1; n = 22). The intra-assay relative standard deviation of 13C in CO2 was 0.03% (mean 13C/12C: 0.0111557; n = 5). From the 13CO2 concentration in arterial and venous blood, substrate oxidation by various organs can be calculated. As an illustration, the determination of myocardial glucose oxidation in lambs, both at rest and during exercise, is described.

The right auricle tunnel as intercaval tunnel in total cavopulmonary connection may prevent atrial flutter.

OBJECTIVE: Total cavopulmonary connection (TCPC) is a routine operation for palliation of children with cardiac anomalies in whom biventricular repair is impossible. The original technique consists of the creation of a semi-prosthetic intercaval tunnel. A substantial proportion of these patients develop atrial flutter. We developed a technique for creating an intercaval tunnel that uses the tissue of the right auricle as intercaval tunnel. This technique avoids suture lines in the neighbourhood of the blood supply of the sinus node and leaves the terminal crest free. Since atrial flutter frequently occurs after Mustard and Senning operations in which suture lines are similar as for creating the lateral tunnel in TCPC we postulated that our technique for creating the intercaval tunnel without prosthetic material might prevent atrial flutter. METHODS: All the children that qualified for a TCPC were included. Whenever possible our operative technique was applied. In the other cases a semi-prosthetic conduit was used for creating the intercaval tunnel. Of 47 consecutive patients 30 (64%) had a tunnel of right auricle tissue, 12 (26%) had a tunnel of prosthetic material. Five patients did not need an intercaval tunnel and were omitted in this study. Only surviving patients were included in this study. Patients that needed more atrial surgery then necessary for TCPC were also omitted. Postoperative ECG's and Holter monitorings were studied. RESULTS: Overall mortality was 7 of 47 patients (14.9% 70% CL 9.4-22.2%). There was no mortality due to rhythm disturbances. Atrial flutter occurred in 3 of 31 included patients (9.7, 70% CL 4.3-18.5%). In the right auricle group 1 of 22 patients (4.5, 70% CL 0.6-14.6%) had atrial flutter compared to 2 of 9 patients (22.2, 70% CL 7.5-45.0%) in the prosthesis group (P=0.13). CONCLUSION: The use of the right auricular technique for creating the intercaval tunnel TCPC is applicable in the majority of patients qualifying for a TCPC. Mortality and morbidity are equal comparing the two techniques. However, markedly less atrial flutter occurs in the group where the right auricle was used as intercaval tunnel. Therefore, we recommend the use of our technique for total cavopulmonary connection.

Sotalol for atrial tachycardias after surgery for congenital heart disease.

Atrial tachycardias, in particular atrial flutter after surgery for congenital heart disease, is associated with a high mortality. Treatment with various antiarrhythmic drugs and/or antitachycardia pacemakers is not very successful. Sotalol, a Class III drug, has shown to be a promising drug in adults with atrial tachycardias. However, the experience with sotalol in children after surgery for congenital heart disease is limited. Therefore, we describe our results here. Between December 1990 and February 1997, 26 children with atrial tachycardias, most of them with atrial flutter or fibrillation (n = 20), after surgery for congenital heart disease were treated with sotalol orally. The age of the children at the start of treatment was 7.5 +/- 5.8 years (mean +/- SD). The time interval between surgery and the start of atrial tachycardia ranged from 1 day to 14.3 years (3.8 +/- 3.8 years). Conversion to sinus rhythm was achieved in 16 out of 22 hemodynamically stable children with a dosage of 4.0 +/- 1.6 mg/kg per day. The six children without sinus rhythm on sotalol and four hemodynamically unstable patients were treated prophylactically with sotalol after DC cardioversion for their tachycardias. Two children complained of mild transient fatigue. Heart rate decreased during therapy (95 +/- 33 vs 81 +/- 21 beats/min; P = 0.01). QTc-intervals did not change. Proarrhythmias such as torsades de pointes were not encountered. Two children with a preexistent sick sinus syndrome showed aggravation of bradycardia and needed pacemaker implantation. The percentage of children with a recurrence-free interval of 1 and 2 years was 96% and 81%, respectively, for all atrial tachycardias, and 92% and 66% for atrial flutter. The recurrences of atrial tachycardias during the follow-up period, which ranged from 0.1-6.1 years (2.5 +/- 1.8 years) could be treated with only an increase of the dosage of sotalol in all but one patient. We conclude that sotalol is an effective drug for the treatment and prevention of atrial tachycardia in children after surgery for congenital heart disease.

Effectiveness of sotalol for atrial flutter in children after surgery for congenital heart disease.

This study describes the efficacy of oral sotalol in the treatment and prevention of atrial flutter in children after surgery for congenital heart disease. In 11 of 13 children (85%), conversion to sinus rhythm was achieved, and in 8 of 11 within 24 hours.

Quantification of the beta-adrenoceptor ligand S-1'-[18F]fluorocarazolol in plasma of humans, rats and sheep.

Myocardial and pulmonary beta-adrenoceptors can be imaged with 2-(S)-(-)-(9H-carbazol-4-yl-oxy)-3-[1-(fluoromethyl)ethyl]amino-2- propanol (S-1'-[18F]fluorocarazolol, I). Quantification of unmodified fluorocarazolol in plasma is necessary for analysis of PET images in terms of receptor densities. We have determined I and its radioactive metabolites in rat, sheep and human plasma, using (1) solid-phase extraction (C18) followed by reversed-phase HPLC and (2) direct injection of untreated plasma samples on an internal-surface reversed-phase (ISRP) column. The two methods were in good agreement. Unmodified I decreased from over 99% initially to less than 5%, 5-10% and 20% at 60 min post-injection in rats, sheep and human volunteers, respectively. Protein binding in sheep and human plasma was determined by ultrafiltration. The fraction of total plasma radioactivity bound to protein and the fraction representing unmodified radioligand were linearly correlated, suggesting that fluorocarazolol was more than 70% protein-bound, whereas its metabolites showed negligible protein binding. Direct injection of plasma on an ISRP column seems a convenient method for quantification of lipophilic radioligands such as fluorocarazolol.

Late cardiotoxicity after treatment for a malignant bone tumor.

Cardiac function was assessed in long-term survivors of malignant bone tumors who were treated according to Rosen's T5 or T10 protocol, both including doxorubicin. Thirty-one patients, age 10-45 years (median age 17.8 years) were evaluated 2.3-14.1 years (median 8.9 years) following completion of treatment. Cumulative doses of doxorubicin were 225-550 mg/m2 (median dose 360). The evaluation consisted of a history, physical examination, electrocardiogram (ECG), signal averaged ECG, 24-hour ambulatory ECG, echocardiography and radionuclide angiography. Eighteen of 31 (58%) patients showed cardiac toxicity, defined as having one or more of the following abnormalities: late potentials, complex ventricular arrhythmias, left ventricular dilation, decreased shortening fraction, or decreased ejection fraction. The incidence of cardiac abnormalities increased with length of follow-up (P< or = .05). No correlation could be demonstrated between cumulative dose of doxorubicin and cardiac status, except for heart rate variability. When adjusted to body surface area, the left ventricular posterior wall thickness (LVPW index) was decreased in all patients. The incidence of doxorubicin-induced cardiotoxicity is high and increases with follow-up, irrespective of cumulative dose. Life-long cardiac follow-up in these patients is warranted. The results of our study suggest that heart rate variability and LVPW index could be sensitive indicators for cardiotoxicity.