Long-term results of the subclavian flap repair for coarctation of the aorta in infants.

BACKGROUND: Coarctation is a congenital narrowing of the aorta that often requires repair during infancy. The subclavian flap aortoplasty was once widely favored for its avoidance of a circumferential suture line and low incidence of recoarctation. The aim of this study is to report the long-term results of the subclavian flap repair for coarctation of the aorta in infants. METHODS: Our operative database was queried for infants with coarctation who underwent subclavian flap aortoplasty from 1966 to 1991. Medical records were reviewed for patient characteristics and outcomes. Survivors were identified for additional phone interview. RESULTS: Fifty-five patients met the inclusion criteria. There were 7 early deaths (in hospital), 11 late deaths, 5 patients lost to follow-up, and 32 known long-term survivors with a mean follow-up of 22.0 years (range 2.4-34.9). Hospital mortality was not associated with patient characteristics but was associated with earlier year of surgery (P = .015). A trend toward decreased overall survival was seen in patients with coarctation with associated cardiac defects (P = .072). Reintervention for recoarctation was required in 3 (6.6%) patients and was not related to the patient characteristics. There were no apparent complications related to subclavian artery sacrifice. CONCLUSIONS: Subclavian flap aortoplasty provides excellent long-term results for the repair of coarctation in infants. The incidence of recoarctation requiring reintervention is low and compares favorably with other techniques. Compromise of growth or function of the left arm was not appreciated. The subclavian flap technique remains a viable surgical option for the repair of coarctation in infants.

Cardiac resynchronization therapy: evaluation of ventricular dysynchrony and patient selection / Terapia de resincronización cardiaca: evaluación de la disincronía ventricular y selección de pacientes

Cardiac resynchronization therapy (CRT) is an established treatment modality for systolic heart failure. Aimed to produce simultaneous biventricular stimulation and correct the lack of ventricular synchrony in selected patients with congestive heart failure, CRT has shown to improve mortality and reduce hospital admissions when compared to medical treatment. At present, the indication criteria for the implantation of a CRT device include an ejection fraction of less than 35%, heart failure symptoms consistent with NYHA functional class III-IV and a QRS complex duration equal or longer than 120 milliseconds. It has been reported that 30% of patients who meet those criteria still may not derive clinical benefit from CRT. Due to the existing diversity of imaging modalities and resources for their process and analysis, a great expectation in terms of more accurate diagnosis of ventricular dyssynchrony has been raised. Reliable identification of dyssynchrony could allow us to better predict the favorable response of an individual patient to CRT and therefore offer this procedure to those individuals most likely to benefit. We review the available techniques for the study of ventricular dyssynchrony for CRT patient selection and the results of its application in clinical trials. Despite tremendous progress in the imaging technology available for the assessment and diagnosis of ventricular dyssynchrony, an ideal method has not been identified and the duration of the QRS complex in the surface ECG remains the accepted criteria of dyssynchrony in the selection of patients for CRT.

La terapia de resincronización cardiaca es una modalidad de tratamiento bien establecida para la insuficiencia sistólica cardiaca. Dirigida a producir una estimulación biventricular simultánea y a corregir la falta de sincronía ventricular en pacientes seleccionados con insuficiencia cardiaca congestiva, la terapia de resincronización cardiaca ha mostrado ser capaz de mejorar los índices de mortalidad y reducir las admisiones hospitalarias cuando se compara con el tratamiento médico. Actualmente, los criterios para la implantación de un dispositivo de terapia de resincronización cardiaca incluyen una fracción de eyección menor a 35%, síntomas de insuficiencia cardiaca consistentes con la clase funcional NYHA III-IV, y una duración del complejo QRS igual o mayor de 120 milisegundos. Se ha reportado que 30% de los pacientes que cumplen con estos criterios pueden inclusive no obtener beneficio clínico de la terapia de resincronización cardiaca. Debido a la diversidad existente de los estudios de imagenología y de los recursos para su proceso y análisis, ha surgido una gran expectativa en términos de un diagnóstico más exacto de la asincronía ventricular. La identificación confiable de la asincronía nos podría permitir predecir mejor la respuesta favorable de un paciente en particular a la terapia de resincronización cardiaca y así ofrecer este procedimiento a aquellos pacientes con mayores probabilidades de beneficiarse de dicha terapia. Hacemos una revisión de las técnicas disponibles para el estudio de la asincronía ventricular para la selección de pacientes para esta terapia y los resultados de su aplicación en pruebas clínicas. A pesar de los grandes progresos alcanzados en la tecnología de imágenes disponibles para la evaluación y diagnóstico de la asincronía ventricular, no se ha identificado un método ideal y la duración del complejo QRS en el ECG de superficie sigue siendo el criterio aceptado de asincronía en la selección de pacientes para terapia de resincronización cardiaca.

Differential regulation of p53 function by the N-terminal ΔNp53 and Δ113p53 isoforms in zebrafish embryos.

BACKGROUND: The p53 protein family coordinates stress responses of cells and organisms. Alternative promoter usage and/or splicing of p53 mRNA gives rise to at least nine mammalian p53 proteins with distinct N- and C-termini which are differentially expressed in normal and malignant cells. The human N-terminal p53 variants contain either the full-length (FL), or a truncated (ΔN/Δ40) or no transactivation domain (Δ133) altogether. The functional consequences of coexpression of the different p53 isoforms are poorly defined. Here we investigated functional aspects of the zebrafish ΔNp53 ortholog in the context of FLp53 and the zebrafish Δ133p53 ortholog (Δ113p53) coexpressed in the developing embryo. RESULTS: We cloned the zebrafish ΔNp53 isoform and determined that ionizing radiation increased expression of steady-state ΔNp53 and Δ113p53 mRNA levels in zebrafish embryos. Ectopic ΔNp53 expression by mRNA injection caused hypoplasia and malformation of the head, eyes and somites, yet partially counteracted lethal effects caused by concomitant expression of FLp53. FLp53 expression was required for developmental aberrations caused by ΔNp53 and for ΔNp53-dependent expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A, p21, Cip1, WAF1). Knockdown of p21 expression markedly reduced the severity of developmental malformations associated with ΔNp53 overexpression. By contrast, forced Δ113p53 expression had little effect on ΔNp53-dependent embryonal phenotypes. These functional attributes were shared between zebrafish and human ΔNp53 orthologs ectopically expressed in zebrafish embryos. All 3 zebrafish isoforms could be coimmunoprecipitated with each other after transfection into Saos2 cells. CONCLUSIONS: Both alternative N-terminal p53 isoforms were expressed in developing zebrafish in response to cell stress and antagonized lethal effects of FLp53 to different degrees. However, in contrast to Δ113p53, forced ΔNp53 expression itself led to developmental defects which depended, in part, on p21 transactivation. In contrast to FLp53, the developmental abnormalities caused by ΔNp53 were not counteracted by concomitant expression of Δ113p53.

Quantitative assessment of pulmonary insufficiency by Doppler echocardiography in patients with adult congenital heart disease.

We determined the utility of continuous wave (CW) Doppler for quantification of pulmonary insufficiency (PI) confirmed by pulmonary angiography in patients with postoperative adult congenital heart disease. A total of 41 patients with PI were divided into two groups on the basis of PI severity by pulmonary angiography: group A (n = 27) with severe PI and group B (n = 14) with mild or moderate PI. Nine patients in group A had pulmonic valve replacement and reverted to mild PI after surgery. Their pre- and postoperative data were compared. All underwent a two-dimensional/Doppler study with interrogation of the PI jet for jet width by color Doppler and peak flow velocity, deceleration time (DT), pressure half-time (PHT), diastolic period (DP), and PI flow time (FT) by CW Doppler. The no-flow time (NFT), NFT/FT ratio, and NFT/DP fraction were calculated. Group A had a larger right ventricle (4.1 +/- 0.9 vs. 3.5 +/- 0.6 cm, P = .033), higher PI peak velocity (2.1 +/- 0.5 vs. 1.7 +/- 0.5 m/s, P = .04), shorter DT (261 +/- 61 vs. 317 +/- 83 ms, P = .018) and PHT (76 +/- 29 vs. 132 +/- 53, P < .0001), longer NFT (146 +/- 66 vs. 40 +/- 42 ms, P < .0001), and higher ratios of NFT/FT (46% +/- 27% vs. 13% +/- 14%, P < .0001) and NFT/DP (29% +/- 13% vs. 10% +/- 9%, P < .0001). The PHT and DT lengthened, and the NFT shortened in patients who underwent pulmonic valve replacement (all P < .05). By binary logistic regression, NFT and PHT were the best predictors for severe PI. An NFT of 80 ms had 84% sensitivity and 93% specificity, and a PHT of 100 ms had 93% sensitivity and 93% specificity for identifying angiographically severe PI. CW Doppler accurately distinguishes severe from lesser degrees of PI in patients with postoperative adult congenital heart disease.

Antisense inhibition of cyclin D1 expression is equivalent to flavopiridol for radiosensitization of zebrafish embryos.

PURPOSE: Flavopiridol, a small molecule pan-cyclin inhibitor, has been shown to enhance the radiation response of tumor cells both in vitro and in vivo. The clinical utility of flavopiridol, however, is limited by toxicity, previously attributed to pleiotropic inhibitory effects on several targets affecting multiple signal transduction pathways. Here we used zebrafish embryos to investigate radiosensitizing effects of flavopiridol in normal tissues. METHODS AND MATERIALS: Zebrafish embryos at the 1- to 4-cell stage were treated with 500 nM flavopiridol or injected with 0.5 pmol antisense hydroxylprolyl-phosphono nucleic acid oligomers to reduce cyclin D1 expression, then subjected to ionizing radiation (IR) or no radiation. RESULTS: Flavopiridol-treated embryos demonstrated a twofold increase in mortality after exposure to 40 Gy by 96 hpf and developed distinct radiation-induced defects in midline development (designated as the "curly up" phenotype) at higher rates when compared with embryos receiving IR only. Cyclin D1-deficient embryos had virtually identical IR sensitivity profiles when compared with embryos treated with flavopiridol. This was particularly evident for the IR-induced curly up phenotype, which was greatly exacerbated by both flavopriridol and cyclin D1 downregulation. CONCLUSIONS: Treatment of zebrafish embryos with flavopiridol enhanced radiation sensitivity of zebrafish embryos to a degree that was very similar to that associated with downregulation of cyclin D1 expression. These results are consistent with the hypothesis that inhibition of cyclin D1 is sufficient to account for the radiosensitizing action of flavopiridol in the zebrafish embryo vertebrate model.

Coordinate control of cell cycle regulatory genes in zebrafish development tested by cyclin D1 knockdown with morpholino phosphorodiamidates and hydroxyprolyl-phosphono peptide nucleic acids.

During early zebrafish (Danio rerio) development zygotic transcription does not begin until the mid-blastula transition (MBT) 3 h after fertilization. MBT demarcates transition from synchronous short cell cycles of S and M phases exclusively to full cycles encompassing G1 and G2 phases. Transcriptional profiling and RT-PCR analyses during these phases enabled us to determine that this shift corresponds to decreased transcript levels of S/M phase cell cycle control genes (e.g. ccna2, ccnb1, ccnb2 and ccne) and increased transcript levels of ccnd1, encoding cyclin D1, and orthologs of p21 (p21-like) and retinoblastoma (Rb-like 1). To investigate the regulation of this process further, the translation of ccnd1 mRNA, a G1/S checkpoint control element, was impaired by microinjection of ccnd1-specific morpholino phosphorodiamidate (MO) 20mer or hydroxyprolyl-phosphono peptide nucleic acid (HypNA-pPNA) 16mer antisense oligonucleotides. The resulting downregulation of cyclin D1 protein resulted in microophthalmia and microcephaly, but not lethality. The phenotypes were not seen with 3-mismatch MO 20mers or 1-mismatch HypNA-pPNA 16mers, and were rescued by an exogenous ccnd1 mRNA construct with five mismatches. Collectively, these results indicate that transcription of key molecular determinants of asynchronous cell cycle control in zebrafish embryos commences at MBT and that the reduction of cyclin D1 expression compromises zebrafish eye and head development.

Loss of heparan N-sulfotransferase in diabetic liver: role of angiotensin II.

The basis for accelerated atherosclerosis in diabetes is unclear. Diabetes is associated with loss of heparan sulfate (HS) from the liver, which may impede lipoprotein clearance and thereby worsen atherosclerosis. To study hepatic HS loss in diabetes, we examined regulation of HS N-deacetylase/N-sulfotransferase-1 (NDST), a key enzyme in hepatic HS biosynthesis. Hepatic NDST mRNA, protein, and enzymatic activity were suppressed by >50% 2 weeks after induction of type 1 diabetes in rats. Treatment of diabetic rats with enalapril, an ACE inhibitor, had no effect on hyperglycemia or hepatic NDST mRNA levels, yet increased hepatic NDST protein and enzymatic activity. Similar results were obtained in diabetic animals treated with losartan, which blocks the type 1 receptor for angiotensin II (AngII). Consistent with these findings, diabetic livers exhibited increased ACE expression, and addition of AngII to cultured hepatoma cells reduced NDST activity and protein. We conclude that diabetes substantially suppresses hepatic NDST mRNA, protein, and enzymatic activity. AngII contributes to suppression of NDST protein and enzymatic activity, whereas mRNA suppression occurs independently. Suppression of hepatic NDST may contribute to diabetic dyslipidemia, and stimulation of NDST activity by AngII inhibitors may provide cardiovascular protection.

An unexpected surgical complication of ventricular assist device implantation identified by transesophageal echocardiography: a case report.

Ventricular assist devices are used for circulatory support for patients with cardiogenic shock and refractory heart failure. Although early and late complications of left ventricular assist devices have been reported, we report a rare surgical complication of a left ventricular assist device implantation. This unexpected surgical complication was accurately identified by transesophageal echocardiography.