Biomechanical forces and endothelial-to-mesenchymal transition (EndoMT) are known to mediate valvulogenesis. However, the relative contributions of myocardial contractile and hemodynamic shear forces remain poorly understood. We integrated 4-D light-sheet imaging of transgenic zebrafish models with moving-domain computational fluid dynamics to determine effects of changes in contractile forces and fluid wall shear stress (WSS) on ventriculobulbar (VB) valve development. Augmentation of myocardial contractility with isoproterenol increased both WSS and Notch1b activity in the developing outflow tract (OFT) and resulted in VB valve hyperplasia. Increasing WSS in the OFT, achieved by increasing blood viscosity through EPO mRNA injection, also resulted in VB valve hyperplasia. Conversely, decreasing myocardial contractility by Tnnt2a morpholino oligonucleotide (MO) administration, 2,3-butanedione monoxime treatment, or Plcγ1 inhibition completely blocked VB valve formation, which could not be rescued by increasing WSS or activating Notch. Decreasing WSS in the OFT, achieved by slowing heart rate with metoprolol or reducing viscosity with Gata1a MO, did not affect VB valve formation. Immunofluorescent staining with the mesenchymal marker, DM-GRASP, revealed that biomechanical force-mediated Notch1b activity is implicated in EndoMT to modulate valve morphology. Altogether, increases in WSS result in Notch1b- EndoMT-mediated VB valve hyperplasia, whereas decreases in contractility result in reduced Notch1b activity, absence of EndoMT, and VB valve underdevelopment. Thus, we provide developmental mechanotransduction mechanisms underlying Notch1b-mediated EndoMT in the OFT.
Today's Top 5
5. African American Women More Stenting than White Women
4. Food As Medicine
Food as medicine?: individualized diets delivered to home associated with less hospital admissions and lower costs (matching, not randomized)https://t.co/PIneGFk1P8 by @SethABerkowitz and colleagues @UNC editorial @Dmozaffarian @JerryMande @TuftsNutrition @JAMAInternalMed pic.twitter.com/0YxFalC9iC— Eric Topol (@EricTopol) April 22, 2019
3. Is It Time for a Treatment Regimen Review?
Anyone on niacin should have their regimen reviewed. The evidence for its use is old & weak. And non-existent for many current uses. And if you don’t tolerate statins, there're other options. This review nicely shows paucity of evidence. https://t.co/oik6V3Xdek @JAMANetworkOpen pic.twitter.com/XDEWyaMgZs— Harlan Krumholz (@hmkyale) April 19, 2019
2. An Important Heart Failure Position Paper
#HF in Cardiomyopathies: a #ESC_HFA wonderful position paper @escardio— Giuseppe Galati (@GiuseppeGalati_) April 23, 2019
A milestone for differential diagnosis & for approaching #HF in this field
Being cited again by an important paper and in particular by this it’s amazing @ESC_Journals @MarcoMetra https://t.co/5GcoAHNHrK pic.twitter.com/B9bPsExZOk