Abstract 15332: A Novel Mouse Model of Left Ventricular Noncompaction: Iroquois Homeobox Genes 3 and 4 Are Required for Ventricular Compaction
Left ventricular noncompaction (LVNC) is a primary congenital cardiomyopathy characterized by prominent trabeculations and intra-trabecular recesses in the ventricular wall. This disease is suggested to be due to a premature arrest in the myocardial compaction process, but its genetic basis and pathologic mechanism remain largely unknown. Here we show that Irx3;Irx4 double knockout (DKO) mouse mutants represent a novel model of LVNC. Irx3 and Irx4 belong to the family of Iroquois homeobox (Irx) genes, encoding transcription factors important for cardiac function. During embryogenesis, Irx3 and Irx4 exhibit overlapping expression in the developing ventricles. While Irx3 is critical for the maturation and functioning of the ventricular conduction system and Irx4 for establishing ventricular identity, mice lacking either Irx3 or Irx4 do not have gross cardiac malformations. Strikingly, we found that Irx3;Irx4DKO mice show postnatal lethality and exhibit thinner ventricular walls as early as E14.5. By P0, noncompacted trabeculations are present in the chambers and by P14, there are abnormal muscular growths that resemble the polypoid pattern of LVNC in humans, characterized by multiple muscular nodes in the left ventricle. Optical projection tomography revealed that, unlike Irx3KO hearts which are morphologically normal, Irx4KO hearts display a subtle increase in trabeculation. Importantly, contrary to normal Irx3-/-;Irx4+/- heart morphology, Irx3+/-;Irx4-/- and Irx3;Irx4DKO hearts have the highest amount of trabeculation, abnormal bridging below the papillary muscles, and disorganised muscle structures. These data suggest that the noncompaction phenotype is due to the loss of Irx3 in an Irx4KO background, and that Irx3 compensates for the loss of Irx4. Furthermore, Irx3;Irx4DKO hearts at P21 exhibited increased expression of heart failure marker genes and increased Bmp10 pathway activation, which has been implicated in LVNC disease development. Taken together, our data indicate Irx3 and Irx4 possess overlapping functions which are essential to myocardial compaction. This novel mouse model will allow further studies on the compaction and myocardial muscle formation process, as well as potential therapeutic targets.
Author Disclosures: W. Liu: None. K. Kim: None. R. Mo: None. Y. Zhou: None. M. van Eede: None. B. Bruneau: None. M. Henkelman: None. C. Hui: None.
- © 2016 by American Heart Association, Inc.