Growth potential of U-clip interrupted versus polypropylene running suture anastomosis in congenital cardiac surgery: intermediate term results

Although U-clip anastomoses were studied for hemodynamics and patency, their potential for unimpeded growth after congenital cardiovascular surgery has not been investigated yet. In 53 children aged 2.1+/-3.3 years operated on between March 1998 and August 2005 growth of U-clip (U) vs. polypropylene running sutured (P) anastomoses in coarctation repair (Coarc; n=26), bi-directional Glenn (BDG; n=13) and arterial switch operation (ASO; n=14) was retrospectively analysed. Coarc showed 2.39+/-4.33 vs. 3.09+/-2.24 mm of growth during the observation period (21+/-16 vs. 30+/-27 months); no growth (0 vs.16%), restenosis (14 vs. 37%) and reinterventions (14 vs. 11%) were similar (all in U vs. P, P=ns). BDG showed 3.68+/-3.43 vs. 2.50+/-2.55 mm (P=ns) of growth during 15+/-5 vs. 29+/-18 months (P=0.046); no growth (17 vs. 0%), stenosis (0 vs. 14%) and reinterventions (0%) were similar in U vs. P, respectively (P=ns). Main pulmonary artery (MPA) anastomosis in ASO showed 0.28+/-1.73 vs. 1.30+/-3.16 mm of growth during 8+/-14 vs. 28+/-28 months; no growth (60 vs. 14%), stenosis (50 vs. 63%) and reinterventions (0%) were similar (all in U vs. P, P=ns). Anastomotic growth, stenosis and reintervention rates show no difference between interrupted U-clip and polypropylene running sutured technique in Coarc repair, BDG and MPA anastomosis in ASO.

Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency

CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

Compound heterozygous mutations affect protein folding and function in patients with congenital sucrase-isomaltase deficiency

BACKGROUND & AIMS: Congenital sucrase-isomaltase (SI) deficiency is an autosomal-recessive intestinal disorder characterized by a drastic reduction or absence of sucrase and isomaltase activities. Previous studies have indicated that single mutations underlie individual phenotypes of the disease. We investigated whether compound heterozygous mutations, observed in some patients, have a role in disease pathogenesis. METHODS: We introduced mutations into the SI complementary DNA that resulted in the amino acid substitutions V577G and G1073D (heterozygous mutations found in one group of patients) or C1229Y and F1745C (heterozygous mutations found in another group). The mutant genes were expressed transiently, alone or in combination, in COS cells and the effects were assessed at the protein, structural, and subcellular levels. RESULTS: The mutants SI-V577G, SI-G1073D, and SI-F1745C were misfolded and could not exit the endoplasmic reticulum, whereas SI-C1229Y was transported only to the Golgi apparatus. Co-expression of mutants found on each SI allele in patients did not alter the protein's biosynthetic features or improve its enzymatic activity. Importantly, the mutations C1229Y and F1745C, which lie in the sucrase domains of SI, prevented its targeting to the cell's apical membrane but did not affect protein folding or isomaltase activity. CONCLUSIONS: Compound heterozygosity is a novel pathogenic mechanism of congenital SI deficiency. The effects of mutations in the sucrase domain of SIC1229Y and SIF1745C indicate the importance of a direct interaction between isomaltase and sucrose and the role of sucrose as an intermolecular chaperone in the intracellular transport of SI.

A defective SERCA1 protein is responsible for congenital pseudomyotonia in Chianina cattle

Recently, a muscular disorder defined as "congenital pseudomyotonia" was described in Chianina cattle, one of the most important Italian cattle breeds for quality meat and leather. The clinical phenotype of this disease is characterized by an exercise-induced muscle contracture that prevents animals from performing muscular activities. On the basis of clinical symptoms, Chianina pseudomyotonia appeared related to human Brody's disease, a rare inherited disorder of skeletal muscle function that results from a sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1) deficiency caused by a defect in the ATP2A1 gene that encodes SERCA1. SERCA1 is involved in transporting calcium from the cytosol to the lumen of the sarcoplasmic reticulum. Recently, we identified the genetic defect underlying Chianina cattle pseudomyotonia. A missense mutation in exon 6 of the ATP2A1 gene, leading to an R164H substitution in the SERCA1 protein, was found. In this study, we provide biochemical evidence for a selective deficiency in SERCA1 protein levels in sarcoplasmic reticulum membranes from affected muscles, although mRNA levels are unaffected. The reduction of SERCA1 levels accounts for the reduced Ca(2+)-ATPase activity without any significant change in Ca(2+)-dependency. The loss of SERCA1 is not compensated for by the expression of the SERCA2 isoform. We believe that Chianina cattle pseudomyotonia might, therefore, be the true counterpart of human Brody's disease, and that bovine species might be used as a suitable animal model.

Outcome of ventriculoperitoneal shunt implantation for treatment of congenital internal hydrocephalus in dogs and cats: 36 cases (2001-2009)

OBJECTIVE To examine outcome data for cats and dogs with congenital internal hydrocephalus following treatment via ventriculoperitoneal shunting to determine treatment-associated changes in neurologic signs, the nature and incidence of postoperative complications, and survival time. DESIGN Retrospective multicenter case series. ANIMALS 30 dogs and 6 cats with congenital internal hydrocephalus (confirmed via CT or MRI). PROCEDURES Medical records for dogs and cats with internal hydrocephalus that underwent unilateral ventriculoperitoneal shunt implantation from 2001 through 2009 were evaluated. Data collected included the nature and incidence of postoperative complications, change in clinical signs following surgery, and survival time. To compare pre- and postoperative signs, 2-way frequency tables were analyzed with a 1-sided exact McNemar test. RESULTS 8 of 36 (22%) animals developed postoperative complications, including shunt malfunction, shunt infection, and seizure events. Three dogs underwent shunt revision surgery. Thirteen (36%) animals died as a result of hydrocephalus-related complications or were euthanized. Following shunt implantation, clinical signs resolved in 7 dogs and 2 cats; overall, 26 (72%) animals had an improvement of clinical signs. After 18 months, 20 animals were alive, and the longest follow-up period was 9.5 years. Most deaths and complications occurred in the first 3 months after shunt placement. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that ventriculoperitoneal shunt implantation is a viable option for treatment of dogs or cats with congenital hydrocephalus. Because complications are most likely to develop in the first 3 months after surgery, repeated neurologic and imaging evaluations are warranted during this period.

Operative treatment of congenital hip osteoarthritis with high hip luxation (Crowe type IV)

OBJECTIVE The aim of the therapy is mechanical and functional stabilization of high dislocated hips with dysplasia coxarthrosis using total hip arthroplasty (THA). INDICATIONS Developmental dysplasia of the hip (DDH) in adults, symptomatic dysplasia coxarthrosis, high hip dislocation according to Crowe type III/IV, and symptomatic leg length inequality. CONTRAINDICATIONS Cerebrospinal dysfunction, muscular dystrophy, apparent disturbance of bone metabolism, acute or chronic infections, and immunocompromised patients. SURGICAL TECHNIQUE With the patient in a lateral decubitus position an incision is made between the anterior border of the gluteus maximus muscle and the posterior border of the gluteus medius muscle (Gibson interval). Identification of the sciatic nerve to protect the nerve from traction disorders by visual control. After performing trochanter flip osteotomy, preparation of the true actetabulum if possible. Implantation of the reinforcement ring, preparation of the femur and if necessary for mobilization, resection until the trochanter minor. Test repositioning under control of the sciatic nerve. Finally, refixation of the trochanteric crest. POSTOPERATIVE MANAGEMENT During hospital stay, intensive mobilization of the hip joint using a continuous passive motion machine with maximum flexion of 70°. No active abduction and passive adduction over the body midline. Maximum weight bearing 10-15 kg for 8 weeks, subsequently, first clinical and radiographic follow-up and deep venous thrombosis prophylaxis until full weight bearing. RESULTS From 1995 to 2012, 28 THAs of a Crow type IV high hip-dislocation were performed in our institute. Until now 14 patients have been analyzed during a follow-up of 8 years in 2012. Mid-term results showed an improvement of the postoperative clinical score (Merle d'Aubigné score) in 86 % of patients. Good to excellent results were obtained in 79 % of cases. Long-term results are not yet available. In one case an iatrogenic neuropraxia of the sciatic nerve was observed and after trauma a redislocation of the arthroplasty appeared in another case. In 2 cases an infection of the THA appeared 8 and 15 months after index surgery. No pseudoarthrosis of the trochanter or aseptic loosening was noticed.

STAR splicing mutations cause the severe phenotype of lipoid congenital adrenal hyperplasia: insights from a novel splice mutation and review of reported cases

OBJECTIVE The steroidogenic acute regulatory protein (StAR) transports cholesterol to the mitochondria for steroidogenesis. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH) which is characterized by impaired synthesis of adrenal and gonadal steroids causing adrenal insufficiency, 46,XY disorder of sex development (DSD) and failure of pubertal development. Partial loss of StAR activity may cause adrenal insufficiency only. PATIENT A newborn girl was admitted for mild dehydration, hyponatremia, hyperkalemia and hypoglycaemia and had normal external female genitalia without hyperpigmentation. Plasma cortisol, 17OH-progesterone, DHEA-S, androstendione and aldosterone were low, while ACTH and plasma renin activity were elevated, consistent with the diagnosis of primary adrenal insufficiency. Imaging showed normal adrenals, and cytogenetics revealed a 46,XX karyotype. She was treated with fluids, hydrocortisone and fludrocortisone. DESIGN, METHODS AND RESULTS Genetic studies revealed a novel homozygous STAR mutation in the 3' acceptor splice site of intron 4, c.466-1G>A (IVS4-1G>A). To test whether this mutation would affect splicing, we performed a minigene experiment with a plasmid construct containing wild-type or mutant StAR gDNA of exons-introns 4-6 in COS-1 cells. The splicing was assessed on total RNA using RT-PCR for STAR cDNAs. The mutant STAR minigene skipped exon 5 completely and changed the reading frame. Thus, it is predicted to produce an aberrant and shorter protein (p.V156GfsX19). Computational analysis revealed that this mutant protein lacks wild-type exons 5-7 which are essential for StAR-cholesterol interaction. CONCLUSIONS STAR c.466-1A skips exon 5 and causes a dramatic change in the C-terminal sequence of the protein, which is essential for StAR-cholesterol interaction. This splicing mutation is a loss-of-function mutation explaining the severe phenotype of our patient. Thus far, all reported splicing mutations of STAR cause a severe impairment of protein function and phenotype.

Comparison between pulsed-wave Doppler- and tissue Doppler-derived Tei indices in fetuses with and without congenital heart disease

OBJECTIVES The aim of this study was to compare the right (RV) and left (LV) ventricular Tei indices obtained by pulsed-wave Doppler (PD) and tissue Doppler (TD) methods in fetuses with structurally normal and abnormal hearts. METHODS This was a retrospective cross-sectional study of 147 fetuses that had a fetal echocardiogram and Tei index measured during a 2-year period. The RV and LV Tei indices were measured using both PD and TD methods. The difference between the two methods of Tei index measurement was tested using paired sample t-test, Pearson correlation coefficient was used to examine their relationship, and the agreement between the methods was tested using Bland-Altman analysis. RESULTS A total of 87 fetuses had normal hearts and 60 had a congenital heart defect. Both PD and TD Tei indices were measured successfully from at least one ventricle in 123 cases and from both ventricles in 110 cases. The mean TD Tei index was significantly higher than the mean PD Tei index for both ventricles (P < 0.0001). There was a weak but statistically significant correlation between the PD and TD Tei indices of the right ventricle (r = 0.20, P = 0.029), whereas the PD and TD Tei indices of the left ventricle did not correlate significantly (r = 0.04, P = 0.684). When pairs of Tei indices measured by two different methods (123 pairs for the right ventricle and 111 for the left ventricle) were tested with Bland-Altman analysis, the bias and precision were 0.147 and 0.254, respectively, for the right ventricle, and 0.299 and 0.276, respectively, for the left ventricle. CONCLUSIONS Correlation between Tei indices measured by PD and TD methods is weak and the agreement between individual measurements is poor. Therefore, they should not be used interchangeably in the assessment of fetal cardiac function.

Abnormal lung function in adults with congenital heart disease: prevalence, relation to cardiac anatomy, and association with survival

BACKGROUND: Restrictive lung defects are associated with higher mortality in patients with acquired chronic heart failure. We investigated the prevalence of abnormal lung function, its relation to severity of underlying cardiac defect, its surgical history, and its impact on outcome across the spectrum of adult congenital heart disease. METHODS AND RESULTS: A total of 1188 patients with adult congenital heart disease (age, 33.1+/-13.1 years) undergoing lung function testing between 2000 and 2009 were included. Patients were classified according to the severity of lung dysfunction based on predicted values of forced vital capacity. Lung function was normal in 53% of patients with adult congenital heart disease, mildly impaired in 17%, and moderately to severely impaired in the remainder (30%). Moderate to severe impairment of lung function related to complexity of underlying cardiac defect, enlarged cardiothoracic ratio, previous thoracotomy/ies, body mass index, scoliosis, and diaphragm palsy. Over a median follow-up period of 6.7 years, 106 patients died. Moderate to severe impairment of lung function was an independent predictor of survival in this cohort. Patients with reduced force vital capacity of at least moderate severity had a 1.6-fold increased risk of death compared with patients with normal lung function (P=0.04). CONCLUSIONS: A reduced forced vital capacity is prevalent in patients with adult congenital heart disease; its severity relates to the complexity of the underlying heart defect, surgical history, and scoliosis. Moderate to severe impairment of lung function is an independent predictor of mortality in contemporary patients with adult congenital heart disease.

Association of congenital, diffuse electrical disease in children with normal heart: sick sinus syndrome, intraventricular conduction block, and monomorphic ventricular tachycardia.

INTRODUCTION Rhythm disturbances in children with structurally normal hearts are usually associated with abnormalities in cardiac ion channels. The phenotypic expression of these abnormalities ("channelopathies") includes: long and short QT syndromes, Brugada syndrome, congenital sick sinus syndrome, catecholaminergic polymorphic ventricular tachycardia, Lènegre-Lev disease, and/or different degrees of cardiac conduction disease. METHODS The study group consisted of three male patients with sick sinus syndrome, intraventricular conduction disease, and monomorphic sustained ventricular tachycardia. Clinical data and results of electrocardiography, Holter monitoring, electrophysiology, and echocardiography are described. RESULTS In all patients, the ECG during sinus rhythm showed right bundle branch block and long QT intervals. First-degree AV block was documented in two subjects, and J point elevation in one. A pacemaker was implanted in all cases due to symptomatic bradycardia (sick sinus syndrome). Atrial tachyarryhthmias were observed in two patients. The common characteristic ventricular arrhythmia was a monomorphic sustained ventricular tachycardia, inducible with ventricular stimulation and sensitive to lidocaine. In one patient, radiofrequency catheter ablation was successfully performed. No structural abnormalities were found in echocardiography in the study group. CONCLUSION Common clinical and ECG features suggest a common pathophysiology in this group of patients with congenital severe electrical disease.

SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome.

BACKGROUND Congenital long-QT syndrome (LQTS) is potentially lethal secondary to malignant ventricular arrhythmias and is caused predominantly by mutations in genes that encode cardiac ion channels. Nearly 25% of patients remain without a genetic diagnosis, and genes that encode cardiac channel regulatory proteins represent attractive candidates. Voltage-gated sodium channels have a pore-forming alpha-subunit associated with 1 or more auxiliary beta-subunits. Four different beta-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome. METHODS AND RESULTS We present a case of a 21-month-old Mexican-mestizo female with intermittent 2:1 atrioventricular block and a corrected QT interval of 712 ms. Comprehensive open reading frame/splice mutational analysis of the 9 established LQTS-susceptibility genes proved negative, and complete mutational analysis of the 4 Na(vbeta)-subunits revealed a L179F (C535T) missense mutation in SCN4B that cosegregated properly throughout a 3-generation pedigree and was absent in 800 reference alleles. After this discovery, SCN4B was analyzed in 262 genotype-negative LQTS patients (96% white), but no further mutations were found. L179F was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells that contained the stably expressed SCN5A-encoded sodium channel alpha-subunit (hNa(V)1.5). Compared with the wild-type, L179F-beta4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-beta4) increase in late sodium current consistent with the molecular/electrophysiological phenotype previously shown for LQTS-associated mutations. CONCLUSIONS We provide the seminal report of SCN4B-encoded Na(vbeta)4 as a novel LQT3-susceptibility gene.

Irrigated-tip catheter ablation of intraatrial reentrant tachycardia in patients late after surgery of congenital heart disease.

OBJECTIVES The aim of this study was to evaluate irrigated-tip catheter for ablation of intraatrial reentrant tachycardias late after surgical repair of congenital heart disease. BACKGROUND In congenital heart disease patients, the right atrium can be markedly enlarged with areas of low blood flow. Radiofrequency (RF) lesion creation may be hampered by insufficient electrode cooling at sites with low blood flow. METHODS Thirty-six consecutive patients with intraatrial reentrant tachycardia refractory to antiarrhythmic therapy from two centers were included in the study. Entrainment pacing and electroanatomic mapping (CARTO) were used to delineate reentrant circuits and critical isthmus sites. RF ablation was performed using an irrigated-tip catheter (Navistar Thermocool). RESULTS Fifty-two intraatrial reentrant tachycardia circuits were identified, and 48 were targeted with RF ablation. RF ablation was performed using a mean of 13 +/- 11 irrigated RF applications per tachycardia isthmus with a mean power of 36 +/- 8 W. In a historical control group of congenital heart disease patients managed with conventional catheter ablation, the number of lesions per isthmus was higher (23 +/- 11) and mean power was lower (27 +/- 14 W). Acute success was achieved in 45 intraatrial reentrant tachycardias (94% of targeted tachycardias and 87% of all tachycardias). After a mean follow-up of 17 +/- 7 months, 33 (92%) of 36 patients were free of recurrence. Five patients (14%) developed paroxysmal atrial fibrillation. CONCLUSIONS The combination of modern techniques including electroanatomic mapping and catheter irrigation allows safe and highly effective ablation of intraatrial reentrant tachycardia in patients with surgically repaired congenital heart disease.