Spatial phenotyping of the endocardial endothelium as a function of intracardiac hemodynamic shear stress
Introduction
Endothelial cell (EC) structure and function is strongly influenced by the frictional force of wall shear stress (WSS) at the blood-EC interface. The effects of WSS on EC phenotype are well described to play an important role in blood vessel physiology and pathology. In regions where undisturbed WSS dominates, ECs are healthy. Conversely, ECs in regions of disturbed WSS, characterized by flow separation and transient flow reversals, have a pro-inflammatory, pro-oxidative stress phenotype and represent sites where atherosclerosis preferentially develops (Civelek et al., 2009, Davies et al., 2013).
Endocardial endothelial cells (EECs) line the heart chambers and represent an important barrier between the circulation and underlying myocardium. Studies in rat and pig demonstrate that EECs, which may originate from precursor vascular ECs, differ from mature vascular ECs with regard to morphology, gene and protein expression and labile molecule production (Hendrickx et al., 2004, Mebazaa et al., 1995). EECs are important in regulating cardiac contraction; endocardial denudation results in loss of contractile strength (Brutsaert et al., 1988, Mebazaa et al., 1993, Shen et al., 2013, Smith et al., 1991). This is attributed to the production and release of paracrine signaling agents such as nitric oxide (NO) (Smith et al., 1991). Unlike vascular ECs, the role of hemodynamics in the regulation of EEC biology has not been carefully studied.
Preservation of flow patterns throughout the LV is important to maintain its efficient function (Gharib et al., 2006). For example, diastolic vortex formation prevents the dissipation of blood kinetic energy and therefore reduces the myocardial force required to eject blood during systole (Kilner et al., 2000). Recent advances in cardiac imaging have enabled more detailed descriptions of intracardiac hemodynamics (Rodriguez Muñoz et al., 2012). In particular, the development of four-dimensional (4D) flow MRI enables 3D velocity encoding with ECG-gating, providing accurate spatial and temporal information. This technology has demonstrated that flow patterns within the LV change with age and gender and that blood residence times vary within the LV (Föll et al., 2013, Hendabadi et al., 2013). The influence of spatio-temporal differences of hemodynamics on EEC biology in the LV is poorly understood.
Here we calculated regional LV WSS using 4D flow MRI in humans and pigs to show that WSS varies regionally throughout the left ventricle of both species. We then isolated EECs from sites matched to the regional hemodynamic characteristics in pig LV and profiled gene expression by RNA sequencing to demonstrate significant regional differences of EEC phenotypes.
Section snippets
4D Flow MRI acquisition
Four-dimensional (4D) flow MRI (4D flow MRI) was performed to assess intracardiac hemodynamics in humans and pigs. For human MRI, IRB approval and informed consent were obtained from all 4D flow MRI study participants. The specifics of image acquisition and analysis were as previously described (Markl et al., 2012, Markl et al., 2016 McCormick et al., 2016). Studies were performed on 8 healthy volunteers (mean age: 24±1.8 years; four females and four males, heart rate 63.5±beats per minute, LV
Regional differences in LV wall shear stress and oscillatory shear index
To investigate regional WSS in healthy humans and pigs, we selected three heart regions: base, inferior to the aortic valve on the posterior heart wall, mid-ventricle (midV), inferior to the mitral valve on the free wall, and the apex (Fig. 1A). Following selection of two-dimensional planes, the images were segmented to define the LV lumen and 12 reference points were positioned. Hemodynamic characteristics were calculated as previously described (Stalder et al., 2008, Markl et al., 2012,
Discussion
The endocardial lining of the heart represents a greatly understudied endothelial compartment, particularly with regard to its phenotypic relationship with WSS. Here we report regional WSS and oscillatory (OSI) flow dynamics throughout the human and pig cardiac cycles, and establish corresponding spatial relationships with endocardial endothelial cell gene expression profiles.
Preservation of blood flow patterns within the LV is important in maintaining its function (Gharib et al., 2006). The
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgments
Supported by NIH NRSA Training Grant T32 HL07954 (MEM), AHA Postdoctoral Fellowship16POST29110001 (MEM), AHA Postdoctoral Fellowship13POST14070010 (YJ), NIH, United States R00 HL108157 (WRTW), NIH, United States R01 HL115828 (MM), NIH, United States K25 HL119608 (AJB) and NIH, United States P01 HL06220 (PFD).
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