Details

Autor(en) / Beteiligte

• Chi, Neil C.
• Bussen, Markus
• Brand-Arzamendi, Koroboshka
• Ding, Chunhua
• Olgin, Jeffrey E.
• Shaw, Robin M.
• Martin, Gail R.
• Stainier, Didier Y. R.
• Olson, Eric N.

Titel

Cardiac conduction is required to preserve cardiac chamber morphology

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2010-08, Vol.107 (33), p.14662-14667

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• Electrical cardiac forces have been previously hypothesized to play a significant role in cardiac morphogenesis and remodeling. In response to electrical forces, cultured cardiomyocytes rearrange their cytoskeletal structure and modify their gene expression profile. To translate such in vitro data to the intact heart, we used a collection of zebrafish cardiac mutants and transgenics to investigate whether cardiac conduction could influence in vivo cardiac morphogenesis independent of contractile forces. We show that the cardiac mutant dco s226 develops heart failure and interrupted cardiac morphogenesis following uncoordinated ventricular contraction. Using in vivo optical mapping/calcium imaging, we determined that the dco cardiac phenotype was primarily due to aberrant ventricular conduction. Because cardiac contraction and intracardiac hemodynamic forces can also influence cardiac development, we further analyzed the dco phenotype in noncontractile hearts and observed that disorganized ventricular conduction could affect cardiomyocyte morphology and subsequent heart morphogenesis in the absence of contraction or flow. By positional cloning, we found that dco encodes Gja3/Cx46, a gap junction protein not previously implicated in heart formation or function. Detailed analysis of the mouse Cx46 mutant revealed the presence of cardiac conduction defects frequently associated with human heart failure. Overall, these in vivo studies indicate that cardiac electrical forces are required to preserve cardiac chamber morphology and may act as a key epigenetic factor in cardiac remodeling.