Abstract
Normal blood flow is essential for proper heart formation during embryonic development, as abnormal hemodynamic load (blood pressure and shear stress) results in cardiac defects seen in congenital heart disease (CHD). However, the detrimental remodeling processes that relate altered blood flow to cardiac malformation and defects remain unclear. Heart development is a finely orchestrated process with rapid transformations that occur at the tissue, cell, and subcellular levels. Myocardial cells play an essential role in cardiac tissue maturation by aligning in the direction of stretch and increasing the number of contractile units as hemodynamic load increases throughout development. This study elucidates the early effects of altered blood flow on myofibril and mitochondrial configuration in the outflow tract myocardium in vivo. Outflow tract banding was used to increase hemodynamic load in the chicken embryo heart between Hamburger and Hamilton stages 18 and 24 (~24 h during tubular heart stages). 3D focused ion beam scanning electron microscopy analysis determined that increased hemodynamic load induced changes in the developing myocardium, characterized by thicker myofibril bundles that were more disbursed in circumferential orientation, and mitochondria that organized in large clusters around the nucleus. Proteomic mass-spectrometry analysis quantified altered protein composition after banding that is consistent with altered myofibril thin filament assembly and function, and mitochondrial maintenance and organization. Additionally, pathway analysis of the proteomics data identified possible activation of signaling pathways in response to banding, including the renin-angiotensin system (RAS). Imaging and proteomic data combined indicate that myofibril and mitochondrial arrangement in early embryonic stages is a critical developmental process that when disturbed by altered blood flow may contribute to cardiac malformation and defects.
Highlights
The heart is the first functional organ in the embryo, and starts beating by the coordinated interaction of primitive myofibril bundles and energy supplying mitochondria as soon as the early heart tube is formed (Wainrach and Sotelo, 1961)
Immature myofibril organization was characterized by the overall lack of myofibril alignment and instances where more than one fibril radiated from the same z-band center
Control tissue contained an array of mitochondrial shapes ranging from very long and tubular-like to almost spherical, indicating that mitochondrial maturation is in an active fusion/fission maturation phase
Summary
The heart is the first functional organ in the embryo, and starts beating by the coordinated interaction of primitive myofibril bundles and energy supplying mitochondria as soon as the early heart tube is formed (Wainrach and Sotelo, 1961). Throughout normal development, myofibril and mitochondrial cell volume fractions increase, myofibril bundles align to the longitudinal axis of the myocyte (which themselves align in the direction of maximal contraction), and myofibrils together with mitochondria arrange in an orderly pattern (Fischman, 1967; Manasek, 1970; Brook et al, 1983; Rai et al, 2008). These developmental changes take place in order to ensure optimal force transfer and contraction in the heart (Raeker et al, 2014). In late fetal and adult periods, myocardial mitochondria are stacked in orderly rows within a myofibrillar lattice, and contact surrounding ATP consumption sites to aid in contraction (Roberts et al, 1979; Vendelin et al, 2005)
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