Initial deployment of the cardiogenic gene regulatory network in the basal chordate, Ciona intestinalis.

The complex, partially redundant gene regulatory architecture underlying vertebrate heart formation has been difficult to characterize. Here, we dissect the primary cardiac gene regulatory network in the invertebrate chordate, Ciona intestinalis. The Ciona heart progenitor lineage is first specified by Fibroblast Growth Factor/Map Kinase (FGF/MapK) activation of the transcription factor Ets1/2 (Ets). Through microarray analysis of sorted heart progenitor cells, we identified the complete set of primary genes upregulated by FGF/Ets shortly after heart progenitor emergence. Combinatorial sequence analysis of these co-regulated genes generated a hypothetical regulatory code consisting of Ets binding sites associated with a specific co-motif, ATTA. Through extensive reporter analysis, we confirmed the functional importance of the ATTA co-motif in primary heart progenitor gene regulation. We then used the Ets/ATTA combination motif to successfully predict a number of additional heart progenitor gene regulatory elements, including an intronic element driving expression of the core conserved cardiac transcription factor, GATAa. This work significantly advances our understanding of the Ciona heart gene network. Furthermore, this work has begun to elucidate the precise regulatory architecture underlying the conserved, primary role of FGF/Ets in chordate heart lineage specification.

A single GATA factor plays discrete, lineage specific roles in ascidian heart development.

GATA family transcription factors are core components of the vertebrate heart gene network. GATA factors also contribute to heart formation indirectly through regulation of endoderm morphogenesis. However, the precise impact of GATA factors on vertebrate cardiogenesis is masked by functional redundancy within multiple lineages. Early heart specification in the invertebrate chordate Ciona intestinalis is similar to that of vertebrates but only one GATA factor, Ci-GATAa, is expressed in the heart progenitor cells and adjacent endoderm. Here we delineate precise, tissue specific contributions of GATAa to heart formation. Targeted repression of GATAa activity in the heart progenitors perturbs their transcriptional identity. Targeted repression of endodermal GATAa function disrupts endoderm morphogenesis. Subsequently, the bilateral heart progenitors fail to fuse at the ventral midline. The resulting phenotype is strikingly similar to cardia bifida, as observed in vertebrate embryos when endoderm morphogenesis is disturbed. These findings indicate that GATAa recapitulates cell-autonomous and non-cell-autonomous roles performed by multiple, redundant GATA factors in vertebrate cardiogenesis.

Pericardial effusion as a complication of chronic graft versus host disease.

A 24-year-old man with previous matched unrelated donor allogenic bone marrow transplant for aplastic anaemia and chronic graft versus host disease on steroid taper presented with progressively worsening anasarca. CT revealed large pericardial effusion, while echocardiogram was concerning for early tamponade physiology. He underwent emergent pericardiocentesis with pericardial drain placement. Extensive rheumatological and infectious work-up was unrevealing with patient's presentation attributed to pericardial graft versus host disease. This highlights the need of physicians to be aware of pericardial serositis as a complication of graft versus host disease due to its life-threatening complications, which require immediate intervention.

Marantic endocarditis: incidental infarcts leading to diagnosis of pancreatic cancer.

Non-bacterial thrombotic endocarditis (NBTE) is a well-described phenomenon associated with malignancies due to hypercoaguable state. In the setting of pancreatic cancer, NBTE is more commonly diagnosed postmortem. We describe a case of a man who was diagnosed with pancreatic carcinoma after incidental finding of NBTE. Imaging incidentally revealed multiple strokes, bilateral renal and splenic infarcts, while subsequent workup for cardioembolic source demonstrated a 1.1×0.7 cm mitral valve vegetation. As multiple blood cultures were sterile and patient lacked clinical signs of infection, an underlying malignancy was suspected. CT abdomen demonstrated a dilated pancreatic duct, MRI showed a 2.8×2.2 cm pancreatic head mass. Endoscopic biopsy of the mass revealed pancreatic adenocarcinoma. Other than NBTE, there were no other clinical or laboratory findings to clearly suggest pancreatic cancer. Thus, incidental discovery of this mitral valve vegetation led to the diagnosis of pancreatic malignancy.