Sympathetic paraganglioma in a patient with unrepaired tetralogy of Fallot: a case report and review of the literature.

CONTEXT: Paragangliomas are a type of neuroendocrine tumor that has been reported to be present in patients with cyanotic congenital heart disease. This report documents the first case of a patient with successful resection of a sympathetic paraganglioma in the setting of unrepaired tetralogy of Fallot, the most common cause of cyanotic heart disease, with pulmonary atresia. OBJECTIVE: We present a 33-yr-old woman with hypertensive crises from a paraganglioma who presented for surgical resection. PATIENT AND METHODS: The patient's preoperative workup was consistent with a functioning sympathetic paraganglioma. Preoperative transesophageal echocardiogram displayed normal ventricular function, moderate-severe right ventricular hypertrophy, severe right ventricular hypertension, an overriding aorta, bidirectional shunting, pulmonary atresia, and aortopulmonary collaterals. RESULTS: The patient underwent a successful laparoscopic resection of a functioning 7-cm paraganglioma after careful preoperative preparation and intraoperative monitoring. Pathology returned as a well-defined, partially hemorrhagic mass measuring 7.0 × 4.5 × 4.5 cm adjacent to and compressing the adrenal gland. CONCLUSION: Surgical resection of paraganglioma tumors in rare patients such as this one is appropriate; however, surgery requires meticulous perioperative management with a multidisciplinary approach. Future studies are needed to determine whether there is a link between neuroendocrine tumors and cyanotic congenital heart disease.

Review of ambulatory pulmonary artery catheterization in the management of advanced heart failure.

The use of pulmonary artery catheterization (PAC) has declined secondary to associated complications and lack of demonstrable efficacy in the inpatient setting. Few studies have been published on the use of PAC in nonacute heart failure (HF) patients. The purpose of this study was to review the use of PAC in guiding advanced therapy in nonacute ambulatory HF patients. A retrospective observational study assessing our group's practice pattern with regard to the use of PAC in 515 ambulatory HF patients, outcomes, and adverse events that resulted from its use was performed. A total of 159 ambulatory HF patients were referred for PAC; 7% underwent heart transplant, 6% had ventricular assist device (VAD) placement, 18% underwent inotropic therapy, and 48% had addition of therapy while 14% had subtraction of therapy. Adverse events occurred in 4% of ambulatory PAC. Patients who underwent heart transplant, VAD, or inotropic therapy had significantly elevated pulmonary capillary wedge pressures, mean pulmonary artery pressures, and depressed cardiac index. Patients selected for inotropic therapy also had significantly elevated right atrial pressures and depressed ejection fractions. PAC use safely guided medical therapy in more than half of the nonacute ambulatory patients.

Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development.

BACKGROUND: During mouse development, the precursor cells that give rise to the auditory sensory organ, the organ of Corti, are specified prior to embryonic day 14.5 (E14.5). Subsequently, the sensory domain is patterned precisely into one row of inner and three rows of outer sensory hair cells interdigitated with supporting cells. Both the restriction of the sensory domain and the patterning of the sensory mosaic of the organ of Corti involve Notch-mediated lateral inhibition and cellular rearrangement characteristic of convergent extension. This study explores the expression and function of a putative Notch target gene. RESULTS: We report that a putative Notch target gene, hairy-related basic helix-loop-helix (bHLH) transcriptional factor Hey2, is expressed in the cochlear epithelium prior to terminal differentiation. Its expression is subsequently restricted to supporting cells, overlapping with the expression domains of two known Notch target genes, Hairy and enhancer of split homolog genes Hes1 and Hes5. In combination with the loss of Hes1 or Hes5, genetic inactivation of Hey2 leads to increased numbers of mis-patterned inner or outer hair cells, respectively. Surprisingly, the ectopic hair cells in Hey2 mutants are accompanied by ectopic supporting cells. Furthermore, Hey2-/-;Hes1-/- and Hey2-/-;Hes1+/- mutants show a complete penetrance of early embryonic lethality. CONCLUSION: Our results indicate that Hey2 functions in parallel with Hes1 and Hes5 in patterning the organ of Corti, and interacts genetically with Hes1 for early embryonic development and survival. Our data implicates expansion of the progenitor pool and/or the boundaries of the developing sensory organ to account for patterning defects observed in Hey2 mutants.

Wnt5a functions in planar cell polarity regulation in mice.

Planar cell polarity (PCP) refers to the polarization of cells within the plane of a cell sheet. A distinctive epithelial PCP in vertebrates is the uniform orientation of stereociliary bundles of the sensory hair cells in the mammalian cochlea. In addition to establishing epithelial PCP, planar polarization is also required for convergent extension (CE); a polarized cellular movement that occurs during neural tube closure and cochlear extension. Studies in Drosophila and vertebrates have revealed a conserved PCP pathway, including Frizzled (Fz) receptors. Here we use the cochlea as a model system to explore the involvement of known ligands of Fz, Wnt morphogens, in PCP regulation. We show that Wnt5a forms a reciprocal expression pattern with a Wnt antagonist, the secreted frizzled-related protein 3 (Sfrp3 or Frzb), along the axis of planar polarization in the cochlear epithelium. We further demonstrate that Wnt5a antagonizes Frzb in regulating cochlear extension and stereociliary bundle orientation in vitro, and that Wnt5a(-/-) animals have a shortened and widened cochlea. Finally, we show that Wnt5a is required for proper subcellular distribution of a PCP protein, Ltap/Vangl2, and that Wnt5a interacts genetically with Ltap/Vangl2 for uniform orientation of stereocilia, cochlear extension, and neural tube closure. Together, these findings demonstrate that Wnt5a functions in PCP regulation in mice.

Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation.

The planar cell polarity (PCP) pathway is conserved throughout evolution, but it mediates distinct developmental processes. In Drosophila, members of the PCP pathway localize in a polarized fashion to specify the cellular polarity within the plane of the epithelium, perpendicular to the apicobasal axis of the cell. In Xenopus and zebrafish, several homologs of the components of the fly PCP pathway control convergent extension. We have shown previously that mammalian PCP homologs regulate both cell polarity and polarized extension in the cochlea in the mouse. Here we show, using mice with null mutations in two mammalian Dishevelled homologs, Dvl1 and Dvl2, that during neurulation a homologous mammalian PCP pathway regulates concomitant lengthening and narrowing of the neural plate, a morphogenetic process defined as convergent extension. Dvl2 genetically interacts with Loop-tail, a point mutation in the mammalian PCP gene Vangl2, during neurulation. By generating Dvl2 BAC (bacterial artificial chromosome) transgenes and introducing different domain deletions and a point mutation identical to the dsh1 allele in fly, we further demonstrated a high degree of conservation between Dvl function in mammalian convergent extension and the PCP pathway in fly. In the neuroepithelium of neurulating embryos, Dvl2 shows DEP domain-dependent membrane localization, a pre-requisite for its involvement in convergent extension. Intriguing, the Loop-tail mutation that disrupts both convergent extension in the neuroepithelium and PCP in the cochlea does not disrupt Dvl2 membrane distribution in the neuroepithelium, in contrast to its drastic effect on Dvl2 localization in the cochlea. These results are discussed in light of recent models on PCP and convergent extension.

Regulation of polarized extension and planar cell polarity in the cochlea by the vertebrate PCP pathway.

The mammalian auditory sensory organ, the organ of Corti, consists of sensory hair cells with uniformly oriented stereocilia on the apical surfaces and has a distinct planar cell polarity (PCP) parallel to the sensory epithelium. It is not certain how this polarity is achieved during differentiation. Here we show that the organ of Corti is formed from a thicker and shorter postmitotic primordium through unidirectional extension, characteristic of cellular intercalation known as convergent extension. Mutations in the PCP pathway interfere with this extension, resulting a shorter and wider cochlea as well as misorientation of stereocilia. Furthermore, parallel to the homologous pathway in Drosophila melanogaster, a mammalian PCP component Dishevelled2 shows PCP-dependent polarized subcellular localization across the organ of Corti. Taken together, these data suggest that there is a conserved molecular mechanism for PCP pathways in invertebrates and vertebrates and indicate that the mammalian PCP pathway might directly couple cellular intercalations to PCP establishment in the cochlea.