New mutations in ZFPM2/FOG2 gene in tetralogy of Fallot and double outlet right ventricle.

Conotruncal defects (CTDs) represent 15-20% of all congenital heart defects. Mutations in a number of genes have been associated with CTD in humans and animal models. We investigated the occurrence and the prevalence of GATA4, NKX2.5, ZFPM2/FOG2, GDF1, and ISLET1 gene mutations in a large cohort of individuals with CTD, including tetralogy of Fallot with or without pulmonary atresia (TOF, 178 patients), double outlet right ventricle (DORV, 13 patients), and truncus arteriosus (11 patients). Denaturing high-performance liquid chromatography (DHPLC) analysis followed by bidirectional sequencing disclosed no putative pathogenic mutation in GATA4, ISLET1, and GDF1 genes. Two novel (Ile227Val, Met544Ile) and one previously reported (Glu30Gly) possibly pathogenic missense variants were identified in the ZFPM2/FOG2 gene in 3 sporadic patients of 202 (1.5%) with CTD, including 1 of 178 (0.6%) with TOF and 2 of 13 (15.4%) with DORV. Mutation analysis also detected one known missense change (Arg25Cys) in NKX2.5 gene in two (1.1%) sporadic patients with TOF. These sequence alterations were found to be absent in 500 population-matched controls. In conclusion, the present results (i) indicate and confirm that mutations in the GATA4, GDF1, and ISLET1 genes are not major determinants in the pathogenesis of TOF, (ii) provide supportive evidence of an association between ZFPM2/FOG2 gene and TOF/DORV, and (iii) provide additional examples of the possible contribution of the Arg25Cys change in the NKX2.5 to a small number of TOF cases.

Severe Ebstein's anomaly can benefit from a small ventricular septal defect: two cases.

Ebstein's anomaly is a rare congenital heart defect. Associated lesions are uncommon, and the mortality rates can be as high as 54% during the first month of life. Two cases of severe Ebstein's anomaly with ventricular septal defect are described. It is speculated that this rare association, allowing adequate forward pulmonary blood flow in the neonate, permitted the reported patients to survive the neonatal period, which is the most life-threatening time. The authors propose that the presence of a small ventricular septal defect can be beneficial for such patients, averting the need for surgery during early infancy when the risk is highest.

Coronary artery dimensions may be misclassified as normal in Kawasaki disease.

BACKGROUND: Current American Heart Association guidelines indicate that patients with Kawasaki disease and no coronary artery abnormalities on echocardiography at any stage of illness may be discharged from cardiologic follow-up 1 year after onset of illness. METHODS AND RESULTS: To determine whether coronary artery dimensions in patients with Kawasaki disease whose vessels are classified as "normal" by Japanese Ministry of Health criteria have a distribution similar to expected population norms when adjusting for body surface area, we studied 125 patients during 4 intervals from onset of illness: (1) 10 days or less, (2) 2 weeks (11 to 21 days), (3) 6 weeks (22 days to 3 months), and (4) 1 year (4 months to 1.5 years). Using two-dimensional echocardiography, we measured the internal lumen diameter of the left main, proximal left anterior descending, and proximal right coronary arteries. Mean body surface area-adjusted dimensions of the proximal left anterior descending and right coronary arteries were significantly larger (P < .01) in patients with Kawasaki disease than those in subjects in all periods, except for a marginal difference at 6 weeks for the proximal right coronary artery (P = .02); for the left main coronary artery, this difference achieved statistical significance in the period of 10 days or less, with a trend at 2 weeks (P = .02). Among patients classified as having normal coronary arteries on all echocardiograms by the Japanese Ministry of Health criteria, 27% had at least 1 body surface area-adjusted coronary dimension more than 2 standard deviations above the expected mean. CONCLUSIONS: Coronary artery dilation in Kawasaki disease is thus more prevalent than previously reported, highlighting the need for systematic long-term surveillance of this population.

Partial atrioventricular canal with congestive heart failure in the first year of life: surgical options.

BACKGROUND: An important subgroup of patients with partial atrioventricular canal require an operation in the first year of life because of refractory congestive heart failure. METHODS: From June 1982 to April 1995, of 128 patients with partial atrioventricular canal, 35 patients (27%) underwent surgical treatment at less than 1 year of life. Associated cardiac anomalies were present in 22 patients. Only 7 patients (20%) had Down's syndrome. Five patients with left ventricular hypoplasia underwent aortic coarctectomy (3 patients) or Norwood operation (2 patients). The other 30 patients underwent anatomic repair in 24 cases and aortic coarctectomy in 6. The surgical results of patients submitted for anatomic repair were retrospectively correlated with the echocardiographic mitral valve diameter. RESULTS: There were 7 deaths (29%) after anatomic repair, 2 (22%) after aortic coarctectomy, and 2 (100%) after Norwood operation. Infants with a mitral valve diameter less than 2.5 x 10-2 m/m2 died at repair. In a mean follow-up of 73.5 months there were five secondary mitral valve plasties and three repairs after aortic coarctectomy. CONCLUSIONS: Among patients with partial atrioventricular canal, there is an important subgroup with clinical signs of heart failure in the first year of life. Left-sided obstructive lesions and complex mitral valve anomalies seem to play a fundamental role in the clinical evolution and prognosis of these patients. The echocardiographic mitral valve diameter may be useful for determining the correct surgical indication.

[Pulmonary valvuloplasty in childhood: the immediate results and long-term follow-up]. / Valvuloplastica polmonare in età pediatrica: risultati immediati e follow-up a lungo termine.

BACKGROUND: Pulmonary balloon valvuloplasty is the treatment of choice of pulmonary valve stenosis, but early results and long-term follow-up in a numerous and homogeneous pediatric population are poorly known. MATERIAL AND METHODS: From April 1984 to April 1994, 202 valvuloplastic procedures were performed in 197 patients (age 52.5 +/- 150 months). Hemodynamic data were analysed according with valvular morphology and patient's age at procedure. During a follow-up period of 50 +/- 38 months, clinical and instrumental data were collected. RESULTS: After pulmonary valvuloplasty RV pressure decreased from 86 +/- 28 to 41 +/- 21 mm Hg (p < 0.001), transvalvular pressure gradient from 67 +/- 27 to 24 +/- 14 mm Hg (p < 0.001) and RV/LV pressure ratio from 1.01 +/- 0.29 to 0.53 +/- 0.19 (p < 0.001). Overall success rate was 95% (187/197 patients). Pulmonary valve dysplasia and/or annulus hypoplasia significantly influenced the efficacy of the procedure and/or the recurrence of valvar stenosis (18.8% vs 2.7%, p < 0.01). During the follow-up period, clinical examination was unremarkable, and transvalvular pressure gradient did not change (23 +/- 9 vs 24 +/- 6 mm Hg at discharge, p = NS). Freedom from restenosis was 98% at 3 years and 96% at 5 and 10 years. CONCLUSIONS: Pulmonary balloon valvuloplasty is a safe, effective and possibly definitive treatment for isolated pulmonary valve stenosis in infants and children. Age at valvuloplasty does not influence the success of the procedure, as opposed to valvular dysplasia and/or annulus hypoplasia that positively relate to the need of surgical valvotomy and/or the recurrence of stenosis during a long-term follow-up. In conclusion, prognosis of the majority of infants and children after a successful valvuloplasty is excellent during a long-term follow-up period.

Echocardiographically guided repair of tetralogy of Fallot.

Although 2-dimensional, Doppler, color flow echocardiography is accepted as a safe diagnostic method to guide the surgical treatment of certain heart defects, cardiac catheterization remains mandatory for patients with tetralogy of Fallot. Based on the excellent diagnostic correlation between echocardiography and angiocardiography, a policy of echo-guided primary repair of uncomplicated, selected cases of tetralogy of Fallot was introduced at Ospedale Bambino Gesù. In the last 5 years, of 139 patients who had surgery for tetralogy of Fallot, 105 underwent primary repair. In 56 patients (53.3%), surgery was guided only by echocardiography (group I). In the remaining 49 patients (46.7%) (group II), unclear imaging of cardiovascular anatomy (n = 23), or echo-suspected associated malformations (n = 26) prompted cardiac catheterization. The 2 groups did not differ in age and weight at surgery. Intraoperative examination did not show diagnostic errors in patients of group I; cardiac catheterization and surgery confirmed the suspected associated anomalies in 16 of 26 patients of group II (38.4% false-positive). Echocardiography showed an overall sensitivity of 100% and specificity of 85% for detection of associated malformations. In conclusion, echocardiography proved to be adequate for selection of patients with uncomplicated forms of tetralogy of Fallot for primary repair.

[The bidirectional cavo-pulmonary anastomosis: a clinico-functional assessment in a medium-term follow-up]. / Anastomosi cavo-polmonare bidirezionale: valutazione clinico-funzionale in un follow-up a medio termine.

BACKGROUND: The bidirectional cavo-pulmonary anastomosis is a useful surgical procedure for patients with complex congenital heart disease characterized by univentricular physiology. This operation significantly increases effective pulmonary blood flow and rarely causes distortion of the main pulmonary arterial branches. The aim of this study was to evaluate the clinical and pathophysiologic consequences of bidirectional cavo-pulmonary anastomosis as well as the effectiveness of this surgical approach as a definitive palliation. METHODS: Clinical, hemodynamic and functional data of 12 patients who had undergone a bidirectional cavo-pulmonary anastomosis were reviewed. Each patient underwent clinical examination, chest x-ray, ambulatory EKG, bidimensional color-Doppler echocardiography, spirometric analysis, lung perfusion scintigraphy, cardiac catheterization and angiography, and stress test. Stress test data were compared to those obtained by a normal population of age-matched children. RESULTS: After a mean follow-up interval of 28 +/- 20 months all patients showed a good clinical condition. Improved oxygenation, exercise tolerance and growth velocity were noted in all patients. Only 34% of patients showed abnormalities of chest x-ray, 29% manifested significant arrhythmias during ambulatory EKG and 20% showed abnormal ventricular function echocardiographically. Spirometry was normal in all patients, while lung perfusion scintigraphy was constantly abnormal with right/left and upper/lower perfusion mismatch. At cardiac catheterization a reduction of end diastolic volume (from 106.9 +/- 50.6 to 67.3 +/- 41.6 ml, p < 0.05) and end systolic volume (from 58.0 +/- 27.9 to 32.5 +/- 33.5 ml, p < 0.05) was noted. The functional evaluation of these patients was highly abnormal due to an impaired response to effort as evidenced by work time (p < 0.0001 vs normal) and stress-induced cardiovascular modifications. CONCLUSIONS: On the basis of these findings, we suggest that: 1) bidirectional cavo-pulmonary anastomosis is useful as an intermediate step towards a Fontan procedure, as it improves the hemodynamic performance of the systemic ventricle; 2) conversely, bidirectional cavo-pulmonary anastomosis should not be considered a form of definitive palliation for complex congenital heart disease because in these patients the response to exercise remains unsatisfactory.

[Anomalous insertion of the mitral valve. A rare form of subaortic obstruction in children]. / Anomala inserzione della mitrale. Una rara forma di ostruzione sottoaortica nell'infanzia.

Among different anatomical causes of subaortic obstruction, anomalous attachment of the mitral valve on ventricular septum is one of the rarest. We report our experience with 4 such cases of subaortic obstruction. Their age at first observation ranged between 1 and 6 months. All patients had viscero-atrial situs solitus, levocardia and normal atrio-ventricular and ventriculo-arterial connections. None had associated cardiac septal defects. Cases with atrio-ventricular canal were excluded. All patients showed a systolic ejection murmur and electrocardiographic features of left ventricular hypertrophy; 3 presented congestive heart failure in the first 3 months of life. Diagnosis was made by 2D-echocardiography and cardiac catheterization in 3 patients and intraoperatively in 1. Only in the last 2 patients, correct diagnosis was made at the initial 2D-echocardiographic examination. Due to left ventricular hypertrophy, in the first 2 patients hypertrophic obstructive cardiomyopathy was originally suspected. One patient died intraoperatively during attempted transaortic resection of subaortic obstruction. Other 2 patients underwent left ventricle-aortic conduit implantation. Of these 2 patients, 1 died 3 months later for sepsis and the other was reoperated upon 3 years later for mitral valve replacement and conduit take-down, with good clinical result. The fourth patient is waiting for surgical intervention. Subaortic obstruction due to anomalous attachment of the mitral valve on ventricular septum may present with early congestive heart failure; the best diagnostic tool is 2D-echocardiography. Left ventricle-aortic conduit may represent a surgical alternative to transaortic resection.

Ductus arteriosus in pulmonary atresia with and without ventricular septal defect. Anatomic and functional differences.

The pulmonary circulation is dependent on the ductus arteriosus in all patients with pulmonary atresia and intact ventricular septum and in some with pulmonary atresia and ventricular septal defect (tetralogy of Fallot type). To assess the time of ductal closure in these two patient categories, we compared the ages at first operation in 58 patients with pulmonary atresia and intact ventricular septum and 32 with pulmonary atresia and septal defect. The age distribution differed significantly between the groups. Whereas 90% of the children with intact ventricular septum required surgery in the first week of life, 50% of those with ventricular septal defect underwent surgery after the first month and 25% after the third month. The previously described and now confirmed anatomic differences of ductus arteriosus or different levels of endogenous prostaglandins may explain persistent patency of the ductus in pulmonary atresia with ventricular septal defect. The phenomenon may have important clinical implications regarding the timing and choice of surgical procedure.

[Rib notchings in Cooley's anemia]. / Incisure costali nella anemia di Cooley.

In 3 cases of Cooley's anemia rib notchings were found. In the first case the clinical pattern did not allow to exclude postductal type of aortic coarctation and thus was performed a venous digital aortography (SVC) showing the integrity of the aortic arch and the absence of intercostal arterial collateral circulation. Only two previous descriptions of rib notchings in thalassemia were found in literature, and the authors shortly describe the 3 observed cases and suggest some possible pathogenetic interpretations either of rib notchings in thalassemia or of the relatively late appearance (adolescence) of rib notchings.

Fully automated ambulatory blood pressure in the diagnosis and therapy of hypertension.

Technical characteristics of a fully automatic apparatus for ambulatory semicontinuous blood pressure monitoring are described. Initially, we ascertained the reliability and the fidelity in the reproduction of studied events (blood pressure, heart rate, ECG). Good results were obtained, even in comparison with other methods (blood pressure semiautomatic or invasive monitoring). We then studied the results of the research on 200 hypertensive subjects. The easy applicability of this method allowed us to demonstrate blood pressure variability over a 24-h patient period. We now can evaluate the factors contributing to blood pressure variability and the alterations contributing to the meaning of circadian rhythm. We are now able to comment on the prevalent incidence of organic or neurogenic components in single hypertensive states, the possible coexistence of asymptomatic coronary heart disease, and on the choice and efficacy of hypotensive drugs.