Familial polymorphic ventricular arrhythmias: a quarter century of successful medical treatment based on serial exercise-pharmacologic testing.

OBJECTIVES: We sought to determine whether objective tests of antiarrhythmic drug efficacy could produce favorable short- and long-term outcomes in a family with idiopathic malignant ventricular arrhythmias. BACKGROUND: In 1973 a family presented with a history of several generations of syncopal spells and sudden death. Some individuals had nonspecific electrocardiographic (ECG) changes. Their QT intervals were normal at rest and with exercise. Autopsies in two young family members showed no cardiac abnormalities, specifically no evidence of arrhythmogenic right ventricular dysplasia, other cardiomyopathy, myocarditis or gross abnormality of the conduction system. METHODS: Available family members had screening ECGs. Symptomatic members had a battery of tests, including electrophysiologic studies, ambulatory ECGs, audiograms, exercise stress testing, serum catecholamine levels during rest and exercise and isoproterenol infusion. Serial exercise-pharmacologic testing was performed in symptomatic family members until induction of an arrhythmia during exercise required higher work loads or became impossible. RESULTS: Arrhythmias were not induced during electrophysiologic studies. In several family members tested, ventricular premature beats and then rapid polymorphic ventricular arrhythmias occurred whenever the sinus rate exceeded 130 beats/min. Emotional stress, isoproterenol infusion and exercise all elicited similar arrhythmias. Catecholamine levels during exercise were, however, unequivocally normal in two of three family members tested. Beta-blockers appeared to be the most effective pharmacologic agent for prevention of these arrhythmias. The efficacy of treatment has been confirmed during a follow-up of 25 years. CONCLUSIONS: This family appears to have catecholamine hypersensitivity as the basis for their ventricular arrhythmias. Guided therapy using serial exercise-pharmacologic testing provided reliable protection for this familial ventricular arrhythmia during a 25-year follow-up.

Fluorescent in situ hybridisation (FISH) for hemizygous deletion at the elastin locus in patients with isolated supravalvular aortic stenosis.

Both Williams syndrome and isolated supravalvular aortic stenosis (SVAS) are caused by mutations at the elastin locus. Deletion demonstrable by FISH is the hallmark of Williams syndrome, whereas the mutations reported so far in SVAS have been more subtle. FISH positive elastin hemizygosity has not been reported in isolated SVAS. This report records our experience of FISH for elastin deletion in isolated SVAS and specifically reports a patient with non-Williams related SVAS, positive for the elastin deletion by FISH.

Prognostic significance of ventricular arrhythmia after repair of tetralogy of Fallot: a 12-year prospective study.

OBJECTIVE: The aim of this study was to examine the prognostic significance of ventricular arrhythmia on the ambulatory electrocardiogram (ECG) after repair of tetralogy of Fallot. BACKGROUND: Ventricular arrhythmia is common after repair of tetralogy of Fallot and has been proposed as the basis for late sudden death. The prognostic significance of ventricular arrhythmia on ambulatory ECG and the indications for therapy are uncertain. METHODS: We performed a 48-h ambulatory ECG in 86 patients (3 to 45 years old [mean age 14 years]) after repair of tetralogy of Fallot. These patients were then followed up prospectively for 12 years. RESULTS: At initial assessment in 1980, 47 patients (55%) had infrequent uniform ventricular extrasystoles (16 patients) or normal cardiac rhythm (31 patients) Group 1), and 39 patients (45%) had frequent uniform ventricular extrasystoles (> 30/h, 2 patients), complex extrasystole (30 patients) or nonsustained ventricular tachycardia (7 patients) (Group 2). There were no significant clinical or hemodynamic differences between the groups. In addition, nine patients had supraventricular tachyarrhythmia. Antiarrhythmic therapy was prescribed only for the 10 patients who had symptoms attributable to arrhythmia. There were two sudden deaths in Group 1 (4%) and one nonsudden death in Group 2 (2.5%). The absolute difference in mortality between groups was therefore 1.5% (95% confidence limits -6% to +9%), excluding a clinically significant difference in outcome. All but 1 of the 39 patients with complex ventricular arrhythmia are alive and well, including those with elevated (> or = 60 mm Hg) right ventricular pressure. CONCLUSIONS: Nonsustained ventricular arrhythmia on ambulatory ECG does not identify patients at high risk for sudden death after repair of tetralogy of Fallot. There does not appear to be any advantage in potentially dangerous long-term antiarrhythmic therapy for asymptomatic postoperative patients.

Enalapril for severe heart failure in infancy.

Eight infants aged between 4 days and 12 weeks with severe heart failure that was refractory to optimal conventional treatment with diuretics were treated with enalapril. The starting dose was 0.1 mg/kg/day, increasing according to response to 0.12-0.43 mg/kg/day. One infant with severe myocarditis did not tolerate enalapril because of hypotension and later died of intractable heart failure. Six of the remaining patients had congenital systemic to pulmonary shunts and one had a simple aortic coarctation. Two weeks after starting enalapril the clinical features of heart failure had improved in all the infants, the mean (SEM) plasma sodium concentration had increased from 129 (2.4) to 136 (1.1) mmol/l and plasma urea concentration had fallen from 7.0 (0.85) to 2.9 (0.85) mmol/l. These data suggest that enalapril is a potentially useful treatment for severe heart failure in infancy.

Cardiac anomalies in Williams-Beuren syndrome.

We have described some of the cardiological findings in 66 patients with Williams-Beuren syndrome and analysed the two dimensional cross sectional echocardiograms in 61 of them in comparison with normal controls. Supravalvar aortic narrowing was shown in all patients examined echocardiographically and may be a useful diagnostic sign. We documented a 7.8% incidence of systemic hypertension, a 15% clinical and echocardiographic incidence of mitral valve prolapse, and a 11.6% incidence of bicuspid aortic valve.

Bronchial compression by an enlarged left atrium in infants; a cause of hypovascularity of the left lung.

In three infants seen recently at our institution we noted signs of compression of the left main bronchus associated with enlarged left atria. None of our cases demonstrated the more usual signs of hyperinflation which are a hyperlucent lung field, depressed hemidiaphragm and mediastinal shift away from the affected side. In addition, hypoperfusion of the left lung was noted in each case. We believe that bronchial compression due to an enlarged left atrium, with consequent hypoxic vasoconstriction as a clinically significant entity, which is not well described and may be unappreciated in infants in whom the typical signs of hyperinflation are absent.

Mycotic aneurysm of the pulmonary artery. Direct surgical approach with preservation of lung tissue.

A solitary mycotic aneurysm of the right apical lower segmental pulmonary artery developed in an 8 year old child with infective endocarditis, ventricular septal defect and pulmonary hypertension. Surgical treatment was undertaken to prevent rupture and achieved by direct ligation of the feeding vessel and endoaneurysmorrhaphy with preservation of all lung tissue. Successful surgical treatment has been described in eight previous cases of mycotic pulmonary artery aneurysm though in only one adult patient has lung resection been avoided.

Left ventricular outflow tract obstruction due to anomalous mitral valve: successful mitral valve replacement in a four month old infant.

A four month old infant was investigated for heart failure was found to have mitral incompetence and severe subvalvar aortic stenosis. The left ventricular outflow tract obstruction was found to be due to an anatomically anomalous mitral valve. The obstruction could only be relieved by removal of the mitral valve and its replacement with a St Jude's prosthesis. Two years after operation the child is fit and active. There have been no difficulties with anticoagulant treatment.

Natural history of left ventricular function in neonatal Coxsackie myocarditis.

Three neonates are described who had severe congestive cardiac failure following Coxsackie-B virus infection. Overall left ventricular function was depressed and accompanied by regional differences in wall motion. Recovery has been gradual, and after 40 or more months of follow-up, all three infants still have evidence of myocardial damage. This provides further evidence linking myocarditis with dilated cardiomyopathy.

The relationship of myocarditis to dilated cardiomyopathy.

Three patients with congestive cardiomyopathy are reported in whom high neutralizing antibody titres to Coxsackie B viruses were detected. At post-mortem examination, all three had histologically demonstrable chronic inflammation of the myocardium. The hearts of ten patients dying in cardiac failure due to other causes showed no comparable inflammatory infiltration. This provides further evidence that Coxsackie B viral myocarditis is involved in the pathogenesis of some cases of dilated cardiomyopathy. One patient also had pulmonary veno-occlusive disease. This has been reported in association with myocarditis once previously in an infant. A viral aetiology has been postulated. It seems likely in this patient to have also been due to a Coxsackie B virus.

Prostaglandin E1 in suspected ductus dependent cardiac malformation.

Fifty two sick neonates with major duct dependent cardiac defects were given short term intravenous infusions of prostaglandin E1 (alprostadil) in doses varying between 0.005 and 0.1 micrograms/kg/minute. The object of the study was to try to achieve an effective but safe regiment that could be instituted as soon as such a diagnosis was suspected. Effective clinical improvement was achieved at each dosage but the incidence of side effects seemed to be dose related, and no serious side effects were noted at a dosage of 0.005 to 0.01 micrograms/kg/minute. It is recommended that a low dosage regimen be started before transfer to a paediatric cardiac centre.

Spontaneous closure of coronary artery fistula.

A coronary artery fistula diagnosed in a 1 year old girl closed spontaneously during childhood. This outcome has been documented in only three previous cases.

Myocarditis in siblings leading to chronic heart failure.

Two brothers, aged 7 and 9, presented 4 years apart with progressive heart failure following a probable viral infection. Electrocardiograms of both showed widespread precordial Q waves. Cardiac catheterization in each case revealed almost equal right atrial, right ventricular and pulmonary artery pressures and poorer contraction of the right than left ventricle. High neutralizing antibody titres to Coxsackie B4 virus were found in the siblings and their mother. Widespread post-myocarditic scarring of both ventricles was found at autopsy on the elder brother. These findings provide further evidence that Coxsackie myocarditis accounts for some cases of dilated cardiomyopathy and suggest that familial factors may be important.

Late sudden death after repair of tetralogy of Fallot: a clinicopathologic study.

Retrospective analysis was performed to determine the likely cause of death in six patients who died suddenly 1-9 years after repair of tetralogy of Fallot. The integrity of the atrioventricular conduction system and myocardium was examined in three hearts at necropsy. Two of three patients who complained of palpitation or syncope had frequent premature ventricular complexes on routine ECGs. All the patients had complete right bundle branch block and one had left-axis deviation after repair. Postoperative cardiac catheterization (four patients) showed no residual ventricular septal defects, but right ventricular pressure was elevated in all. At necropsy, the atrioventricular conduction tissue was related to the margin of perimembranous ventricular septal defect in two patients, but was well posterior in one patient with an infundibular muscular defect. Histologic examination showed that in all cases the atrioventricular node, atrioventricular bundle and left bundle branch were undamaged. There was, however, extensive fibrosis of the right ventricular myocardium in the ventriculotomy site (three patients), septum (one patient) and outflow tract (one patient). These clinical and necropsy findings suggest that ventricular arrhythmia rather than atrioventricular block was responsible for sudden death in these patients after repair of tetralogy of Fallot.

Ischemic injury to the brachial plexus following subclavian flap aortoplasty.

An ischemic brachial plexus lesion developed 6 days postoperatively in an infant undergoing subclavian flap aortoplasty for coarctation. To our knowledge, this complication has never been previously reported. Types of postoperative brachial plexus lesions are discussed. The blood supply to the brachial plexus is described. An ischemic lesion of the plexus should be suspected when brachial palsy follows operations that involve sacrifice of the subclavian artery.

Platelet kinetics in congenital heart disease.

The survival of 111indium labelled platelets has been determined in a series of 47 subjects comprising nine with cyanotic congenital disease (Eisenmenger's syndrome), seven with congenital heart disease associated with left to right shunts, six with primary pulmonary hypertension, six with peripheral vascular disease, 11 with cardiac disorder associated with low cardiac output and eight normal volunteers. Compared with the value in the normals of 9.5 days, mean survival was significantly shortened in those with Eisenmenger's syndrome (8.4 days) and with peripheral vascular disease (8.5 days). It was normal in patients with left to right shunts (9.5 days). Gamma camera imaging in selected patients failed to reveal any abnormal sites of deposition of labelled platelets except in one patient with peripheral vascular disease who had bilateral abnormal activity in his lower limbs and a shortened platelet survival (8.0 days). From theoretical considerations, it was concluded that the reduction in platelet survival in Eisenmenger's syndrome was such that, had it been the result of pulmonary intravascular platelet deposition, abnormal activity should have been visible on chest scanning with the gamma camera. The absence of scintigraphic evidence of abnormal platelet deposition in the lungs of these patients, combined with the linear configuration of their platelet survival curves, suggests that the accelerated platelet destruction is in the reticuloendothelial (RE) system rather than intravascular. Indirect evidence in favour of increased RE destruction of platelets in Eisenmenger's syndrome was the finding of an approximate doubling of intrasplenic platelet transit time, indicating abnormal platelet pooling within the spleen.

Conduction defects, ventricular arrhythmias, and late death after surgical closure of ventricular septal defect.

One hundred and eighty-seven patients who had surgical closure of a ventricular septal defect between 1958 and 1975 were followed for up to 21 years. there were 17 late sudden deaths of which eight occurred in completely fit patients while nine were already under medical care. In an attempt to elucidate possible risk factors and reoperative and serial postoperative electrocardiograms of all patients were studied. Fifty-one unselected healthy follow-up patients agreed to 24 hour ambulatory monitoring. Progressive exercise testing (Bruce protocol) was carried out on 31 of them and an additional seven patients. There was a significant correlation between recorded ventricular arrhythmias and conduction defects, particularly progressive conduction defects. Transient complete heart block carried a bad prognosis and grade 3-4b ventricular arrhythmias were a major risk factor and recorded in 10 of the 17 patients who died. Long-term postoperative electrocardiographic follow-up is recommended and 24 hour ambulatory monitoring and exercise testing complement the findings of the resting electrocardiogram. The long-term treatment of survivors found to have ventricular arrhythmias must be considered.

Fetal cardiac arrhythmia: antepartum diagnosis of a case of congenital atrial flutter.

A case of antepartum atrial tachyarrhythmia was detected in the 36th week of pregnancy. Cardiotocograph recordings done twice daily enabled close surveillance of the fetal condition after oxytoxin challenge testing had failed to show evidence of hypoxia. After a diagnosis of fetal cardiac arrhythmia had been made, elective caesarean section in the 40th week of pregnancy resulted in delivery of an infant in atrial flutter and cardiac failure. Both these problems were soon resolved by cardioversion and subsequent treatment with digoxin. Cardiac catheterisation showed no underlying cardiac abnormality. Increasing use of antenatal cardiotocography may show that intrauterine tachyarrhythmias are more common than had generally been believed.

Detection of late arrhythmia and conduction disturbance after correction of tetralogy of Fallot.

The electrocardiographic conduction disturbances were evaluated retrospectively, in relation to prognosis, in 196 patients who underwent correction of tetralogy of Fallot. The follow-up was one to 20 years (mean 10). After surgery complete right bundle-branch block occurred in 187 patients (95%), right bundle-branch block and left axis deviation in 17 patients (9%), and progressive conduction defects, either left axis deviation or right bundle-branch block, developed during follow-up in 21 patients (11%). Nine patients (4.6%) died suddenly and two patients developed complete heart block late after the operation. Though late sudden death or complete heart block occurred in 19 per cent of patients with progressive conduction defects as opposed to 4 per cent of the group with stable conduction defects, the difference was not significant. Twenty-four hour ambulatory electrocardiographic monitoring was performed in 74 patients; 41 per cent had significant (Lown grade 2, 3, or 4) ventricular arrhythmias. The incidence of ventricular arrhythmia in the group with progressive conduction defects (80%) was significantly higher than in the group with stable conduction defects (30%). As occult arrhythmia may be the cause of sudden death, it is important to identify these patients.

Hypoplastic and fibrotic sinus node associated with intractable tachycardia in a neonate.

A case of fetal and neonatal persistent atrial tachycardia is described in a child with complete transposition of the great arteries. At autopsy, serial sections of the conducting tissue showed that the sinus node was hypoplastic and markedly fibrotic. The sinus node consisted of a small area of cells clustered around the nodal artery. Although the underlying mechanism of neonatal persistent tachycardia is unclear, it is possible that the hypoplasia and fibrosis of the sinus node was the substrate in the present case. This mechanism should be considered in any newborn infant in whom sinus rhythm cannot be established.