Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome.

BACKGROUND: Long-QT (LQT) syndrome is a cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. Both autosomal dominant LQT (Romano-Ward syndrome) and autosomal recessive LQT (Jervell and Lange-Nielsen syndrome, JLNS) have been reported. Heterozygous mutations in 3 potassium channel genes, KVLQT1, KCNE1 (minK), and HERG, and the cardiac sodium channel gene SCN5A cause autosomal dominant LQT. Autosomal recessive LQT, which is associated with deafness, has been found to occur with homozygous mutations in KVLQT1 and KCNE1 in JLNS families in which QTc prolongation was inherited as a dominant trait. METHODS AND RESULTS: An Amish family with clinical evidence of JLNS was analyzed for mutations by use of single-strand conformation polymorphism and DNA sequencing analyses for mutations in all known LQT genes. A novel homozygous 2-bp deletion in the S2 transmembrane segment of KVLQT1 was identified in affected members of this Amish family in which both QTc prolongation and deafness were inherited as recessive traits. This deletion represents a new JLNS-associated mutation in KVLQT1 and has deleterious effects on the KVLQT1 potassium channel, causing a frameshift and the truncation of the KVLQT1 protein. In contrast to previous reports in which LQT was inherited as a clear dominant trait, 2 parents in the JLNS family described here have normal QTc intervals (0.43 and 0.44 seconds, respectively). CONCLUSIONS: A novel homozygous KVLQT1 mutation causes JLNS in an Amish family with deafness that is inherited as an autosomal recessive trait.

Neurodevelopmental outcome of infants with hypoplastic left heart syndrome.

The neurodevelopmental outcome of hypoplastic left heart syndrome in infants remains unclear. All 11 survivors of staged surgical repair of hypoplastic left heart syndrome received standardized neurodevelopmental assessments at one regional children's hospital. Seven children (64%) had major developmental disabilities. Quality-of-life outcomes must be considered when management options for children with hypoplastic left heart syndrome are evaluated.

Association of distal displacement of the left subclavian artery and coarctation of the aorta.

Previously noted but undocumented observation of distal displacement of the left subclavian artery in patients with discrete coarctation of the aorta was verified by an objective two-dimensional echocardiographic method in 28 patients with aortic coarctation and in 43 control subjects. Relative position of brachiocephalic arteries to one another was evaluated by the ratio of the distance between the left common carotid and the left subclavian artery to the distance between the innominate and the left common carotid artery. Large distance between the left common carotid and the left subclavian artery was reflected by high value of the derived ratio. In neonates with aortic coarctation, the ratio was 1.69, SD +/- 0.66, compared to 1.04, SD +/- 0.40 in the control group. In older children this ratio was less discriminatory. We also observed that the left subclavian artery formed an acute angle (less than 90 degrees) with the proximal (upstream) segment of the aortic arch in infants with aortic coarctation. In all control infants, this angle was equal to or greater than 90 degrees. A corresponding necropsy study confirmed the echocardiographic findings. We conclude that distal displacement of the left subclavian artery is associated with coarctation of the aorta. It can be accurately visualized and objectively assessed by the two-dimensional echocardiographic technique proposed.

Cardiac microdialysis in isolated rat hearts: interstitial purine metabolites during ischemia.

Cardiac microdialysis is a recently developed technique that allows intramyocardial interstitial fluid (ISF) to be sampled via the implantation and perfusion of a small, hollow dialysis fiber within the myocardium. The purpose of this paper is to describe initial studies using cardiac microdialysis in the isolated perfused heart. Microdialysis probes, constructed in the laboratory, were implanted in the left ventricular myocardium of isolated perfused rat hearts and perfused at 0.5 microliter/min with Krebs-Henseleit buffer. The effluent dialysate, assayed for adenosine, inosine, hypoxanthine, xanthine, and uric acid, was used as an index of intramyocardial levels of these purine metabolites. All metabolites were elevated initially after implantation, declined rapidly in the first 45 min, and were then stable for the next 90 min. Based on in vitro percent recovery data, baseline dialysate concentrations were extrapolated to yield estimates of intramyocardial ISF (in microM) 0.47 adenosine, 0.85 inosine, 0.29 hypoxanthine, 0.49 xanthine, and 8.6 uric acid. During global zero-flow ischemia (37 degrees C), dialysate levels of all purine metabolites were elevated, with inosine being the predominant compound. Pretreatment of the hearts with 50 microM erythro-9-(2-hydroxy-3-nonyl)adenine, an adenosine deaminase inhibitor, markedly enhanced ISF adenosine accumulation and attenuated the accumulation of inosine, hypoxanthine, and xanthine. The simplicity and versatility of cardiac microdialysis in the isolated perfused heart suggest that this technique may be a valuable adjunct to the many studies performed using this preparation.

The effect of mediastinal irradiation on cardiac function of patients treated during childhood and adolescence for Hodgkin's disease.

To determine the frequency of cardiac dysfunction in patients treated during childhood or adolescence with mediastinal irradiation for Hodgkin's disease (HD), 28 patients underwent cardiac evaluation 19 to 182 months (median, 90 months) after the completion of radiation therapy. No patient had symptoms of cardiac disease. All were normotensive. All patients had a normal cardiothoracic ratio. There were no abnormalities of voltage or rhythm in the ECGs. The left ventricular end diastolic volume was increased in 19.2% of patients, none of whom had evidence of impaired left ventricular function. The left ventricular ejection fraction (LVEF) was increased in 15.3% of patients. No patient had a decreased LVEF. Pericardial thickening was demonstrated on echocardiograms from 12 of 28 patients (42.9%). Thickening was more frequent among those patients observed for 72 or more months (47.1%; eight of 17) than among those with shorter periods of follow-up (36.4%; four of 11). This study demonstrates that cardiac dysfunction is an infrequent sequela of mediastinal irradiation following treatment using an equally weighted, anterior-posterior technique. Longitudinal study of these patients will be necessary to determine the clinical significance and evolution of the occult pericardial thickening that was identified.

Two-dimensional echocardiography in complete transposition of the great arteries.

Sixty three patients with complete transposition of the great arteries (d-TGA) were studied by two dimensional echocardiography in order to assess: great artery relationships; ventriculo-arterial connections; presence and nature of the left ventricular outflow obstruction (LVOTO). From the parasternal short axis view at the great arteries level, four different relationships were imaged: the aorta was anterior and to the right in 35 patients, the two vessels were in a direct anterior-posterior position in 15 or side by side in 3 and the aorta was anterior and to the left in 10. Differently from normals, early pulmonary bifurcation of the artery arising from the left ventricle was imaged in 42 patients (84%) from the apical approach and in 36 (72%) from the subcostal longitudinal view. Left ventricular outflow tract obstruction was diagnosed in 29 patients (46%) and two distinct types of obstruction were differentiated: fixed and dynamic. We conclude that information derived from two-dimensional echocardiography is a valuable tool for the medical management, cardiac catheterization and surgical treatment of infants and children with d-TGA.

Two-dimensional echocardiographic examination of mitral valve abnormalities associated with coarctation of the aorta.

Coarctation of the aorta is frequently associated with left ventricular inflow tract abnormalities that may be difficult to detect even at cardiac catheterization. This study involved patients with coarctation who underwent comprehensive two-dimensional echocardiographic investigations emphasizing visualization of the mitral valve and its apparatus. Of the 56 patients studied, 23 had completely normal study results, while in 33 (59%) results showed abnormalities of the mitral complex. The latter were divided into two groups: those having major mitral abnormalities (n = 12) and those with minor anomalies of the valve and apparatus (n = 21). The first group included patients with a supravalve stenosing ring, congenital mitral stenosis, mitral valve prolapse, and parachute mitral valve. Minor anomalies were classified as abnormalities of the papillary muscles, chordae tendineae, or combinations of both. No mitral malformations were found in a control group of patients. We conclude that two-dimensional echocardiography is a sensitive and accurate noninvasive method for assessing either significant or subtle forms of left ventricular inflow disease in patients with aortic coarctation. Its use is recommended for the acute medical and surgical management of these patients as well as for their long-term follow-up evaluation.

A rare form of isolated interrupted aortic arch: the value of two-dimensional echocardiography in the precatheterization evaluation.

Preoperative evaluation of a 12-year-old girl, previously diagnosed as having a coarctation of the aorta, revealed a rare form of isolated interruption of the aortic arch. Two-dimensional echocardiography played an important role in the delineation of the defect and significantly reduced the need for invasive techniques. It helped to anticipate problems in reaching left-sided structures at cardiac catheterization, saving time and unnecessary trauma. This technique also ruled out associated intracardiac anomalies that were not detailed at cardiac catheterization.

Two-dimensional echocardiographic recognition of the right aortic arch.

A mirror-image right aortic arch (RAA) is frequently associated with congenital heart disease. The chest roentgenogram with or without contrast remains the noninvasive diagnostic method of choice. While 2-dimensional (2-D) echocardiography has been used to elucidate the left aortic arch (LAA), detailed description of the technique for RAA has not been reported. This study was pursued to delineate the 2-D echocardiographic approach to the patient with RAA. Twenty-seven patients in this study had LAA (Group A) and 27 had RAA (Group B). The 2-D echocardiographic examinations concentrated on the standard suprasternal long-axis (SSNL), parasternal long and short axes, and the subcostal abdominal short-axis views. When the SSNL failed to demonstrate LAA, an alternate position for RAA was utilized. The SSNL correctly identified the LAA in all Group A patients, but in Group B it located only the ascending aorta. This simulated an interrupted aortic arch anomaly. Transducer realignment to position 2 confirmed RAA in all Group B patients. In the parasternal axes, the left descending aorta was detected posterior to the atrioventricular groove or the left ventricle in every Group A patient but in no Group B patient. The descending aorta was found to the left of the spine on the abdominal short-axis view in both groups. The 2-D echocardiographic technique proposed for RAA is simple, rapid, and definitive. It should be pursued whenever LAA cannot be demonstrated, especially in children suspected of having a congenital heart defect. Anticipation of RAA can expedite chest and cardiovascular surgery.

Diagnosis of pericardial cyst in a young child by computed tomography of the thorax.

Computed tomography can be very useful in the assessment of mediastinal masses in children. In this case, it provided for the specific diagnosis of a pericardial cyst in a young child, obviating the need for invasive evaluation or surgery.

Rapid elimination of quinidine in pediatric patients.

The oral absorption and elimination of quinidine in pediatric patients was studied. Single oral doses of quinidine sulfate were administered to 13 patients ranging in age from 4 to 22 years of age. Serum quinidine concentration reached a peak within 30 minutes to two hours after drug administration. The serum half-life of quinidine varied from 2.5 to 6.7 hours and was, on the average, shorter than the reported estimates for adult volunteers and cardiac patients (means ranging from 4.9 to 7.3 hours). Hence more frequent dosing or the use of slow-release preparations may be necessary in some pediatric patients in order to avoid excessive fluctuation in serum drug concentrations over a dosage interval. The oral dose clearance of quinidine (ie, oral dose divided by the area under the serum concentration time curve) varied over a threefold range, from 0.151 to 0.570 liter/hr/kg, and was found to correlate inversely with age (r = .80). In comparison with mean clearance estimates that have been reported for normal adult volunteers (0.293 +/- 0.078 liter/hr/kg), children less than 12 years of age (0.461 +/- 0.117 liter/hr/kg) were found to have significantly higher clearances, whereas no difference was observed between older children (0.287 +/- 0.101 liter/hr/kg) and adults. Inasmuch as the average steady-state serum drug concentration for a given daily maintenance dose is directly related to clearance rate, children less than 12 years of age may require a higher dosage of quinidine on a per kilogram of body weight basis. Proper selection of quinidine dosage, careful adjustment of dosage according to age, and regular monitoring of drug response and serum drug concentration are essential steps to a rational management of quinidine therapy in children.

Closed transventricular pulmonary valvotomy in infants.

In an effort to reassess the efficacy of closed transventricular valvotomy in infants with severe pulmonary stenosis, we reviewed 24 consecutive patients who underwent closed transventricular valvotomy. The age range was 1 day to 11 months (median 53 days), with 10 patients under 1 month and 21 under 6 months of age. The weight range was 2.6 to 9.4 kg (median 4.1 kg). The long-term results were assessed by comparing the postoperative to the preoperative clinical and hemodynamic data. The 20 survivors were followed up for 3 to 133 months (median 54 months). All were asymptomatic upon the last follow-up visit, and their electrocardiograms and chest x-ray films were normal or improved. In 12 patients who had cardiac catheterization 7 to 85 months (median 50 months) after operation, the range for the right ventricular-to-left ventricular, or systemic arterial, peak systolic pressure ratio (RV:LV) was 0.97 to 1.7 preoperatively (mean 1.31) and 0.22 to 0.94 postoperatively (mean 0.42) (p less than 0.001). In order to assess the significance of the RV size for the surgical survival, we measured the preoperative RV end-diastolic volume (RVEDV) in 17 patients. Twelve patients had a normal or enlarged RV and all survived the operation, whereas two of the five patients with an RVEDV more than 2 SD below the normal mean (RVEDV less than 23 ml/m2) died postoperatively (p = 0.075). We conclude that closed transventricular valvotomy can be done successfully in infants with severe pulmonary stenosis and an RV which is not small. The risk of cardiopulmonary bypass is avoided and good long-term results can be obtained. We also present evidence that a small RV (RVEDV less than 23 ml/m2) is a potentially important predictor of the surgical risk.

Two-dimensional echocardiographic recognition and surgical management of aortopulmonary septal defect in the premature infant.

An aorticopulmonary septal defect (APSD) results from failure of proper conotruncal separation. The hemodynamic consequences of this lesion closely resemble that of other large left-to-right shunt defects, especially a patent ductus arteriosus (PDA). Failure to differentiate these 2 abnormalities has not infrequently led to an inappropriate surgical approach in pursuit of the far more common PDA. This report describes the two-dimensional echocardiographic (2-DE) recognition of an APSD in 2 premature infants. Survival of these delicate neonates indicates that successful surgery can be performed even in small infants. A thorough 2-DE examination for an APSD is recommended for any infant before proceeding to surgery for a suspected PDA, especially when cardiac catheterization has not been performed.

Two-dimensional echocardiographic recognition of coronary artery disease in Kawasaki disease. A case report.

Two-dimensional echocardiography (2-DE) was used to demonstrate bilateral coronary artery disease in a 2-month-old child presenting with a mucocutaneous lymph node disease. The classic clinical and laboratory signs of this illness, now known as Kawasaki disease, were reviewed. Identification of the high risk patient prone to developing pericarditis and coronary perivasculitis with subsequent congestive heart failure or myocardial damage is essential for lowering morbidity and mortality rate. The 2-DE successfully demonstrated a large right coronary aneurysm and a markedly abnormal left coronary artery. The 2-DE should be used in every patient suspected of having Kawasaki disease not only to determine coronary artery involvement but also to guide medical management.