Spatiotemporal transfer of nitric oxide in patient-specific atherosclerotic carotid artery bifurcations with MRI and computational fluid dynamics modeling

Highlights

• The numerical model was developed to simulated the NO distribution in atherosclerotic carotid artery bifurcations with models constructed from MRI.

• The lipid pool and calcification would increase the space-averaged NO concentration, and the intraplaque hemorrhage would decrease it.

• The blood flow and hemodynamic indicators based on wall shear stress control the luminal NO concentration in atherosclerotic area.

• The pathologically high or low NO concentration could navigate the delivery of NO-related drugs and identify the risk of plaque.

Abstract

Despite great progress in nitric oxide (NO) controlled releasing strategies, the in vivo spatiotemporal NO distribution of arteries is still unclear, which makes it impossible to assess the status of arteries and render NO-based therapies in vivo largely fruitless. Here, we presented personalized computational modelling to calculate the NO distribution on the endothelial surface and in the arterial wall of human atherosclerotic carotid artery bifurcations using models constructed from MRI. The computational results indicated the distribution of NO in the atherosclerotic artery is highly uneven. The volume-weighted average NO concentration (C_V) in regions with lipid plaques (9.76 ± 2.82 nM) was about 22 times higher than that in the plaque-free regions. Regions where also the calcified plaque components and the intraplaque hemorrhages are present would increase and abate the C_V, respectively. The dynamic blood flow during the cycle would directly affect the distribution of NO on the endothelial surface. The luminal NO distribution is closely related to hemodynamic indicators, including wall shear stress (WSS), time averaged wall shear stress (TAWSS), oscillating shear index (OSI) and relative residence time (RRT). In conclusion, atherosclerotic components determine the space-averaged NO concentration in arterial wall and blood flow controls the luminal NO concentration.

Introduction

Nitric oxide (NO) is a key signaling molecule essential for regulating cardiovascular diseases (such as atherosclerosis), and performs protective or harmful effects according to its concentration [1,2]. Too high and too low local concentration of NO can both lead to cardiovascular diseases [3]. Therefore, the significant and therapeutic potential of NO have triggered substantial interest in the precisely controllable NO delivery in recent years [4]. However, the development of novel drugs capable of controlling NO concentration has been largely fruitless and the NO-based therapies in vivo are limited clinically [1]. The main reason is that the spatiotemporal distribution of NO at targeted regions with atherosclerosis is unclear [1,2,4].

The transfer of endogenous NO in atherosclerotic arteries is a complex process, which may be affected by both the hemodynamics in the artery [5,6], and the atherosclerotic components in the plaque. For instance, the endothelial NO synthase (eNOS) has the ability to generate NO in response to WSS [7], and macrophages within the intraplaque lipid-rich core would produce a high level NO by inducible nitric oxide synthase (iNOS) upon inflammatory stimulation [[8], [9], [10]]. Besides, the hemoglobin in the intraplaque hemorrhage and smooth muscle cells would consume NO by various superoxide radicals [[11], [12], [13]]. These complex transport processes are hard to be investigated experimentally and numerical simulations have shown to be a powerful tool [[14], [15], [16], [17]]. However, little quantitative information about NO transport exists concerning atherosclerotic arteries.

It has been well documented that the local biomechanical forces greatly affect the initialization, progression and stability of atherosclerotic plaque [[18], [19], [20]]. For carotid arteries, atherosclerosis is generally developed in the carotid sinus adjacent to the carotid artery bifurcation [21]. The low WSS and high OSI in this site indicates the multidirectional shear stress environment at this site, which would activate multiple pathways and lead to endothelial dysfunction [[22], [23], [24]]. Besides, the helicity-based descriptors would also affect the physiological environment of endothelium [25]. Previous studies have shown the positive relationship between NO concentration and WSS, so the carotid sinus would have low NO concentration [14]. The deficiency of NO could be linked with the atherosclerosis especially in the early stage [26], which has been proved by the experiments with eNOS disrupted ApoE-KO mice [27,28]. Moreover, high wall structure stress of carotid sinus can cause the damage of endothelium [29], which could also lead to the inablility of eNOS. We hypothesized that local NO transfer may reflect the local biomechanical environment on both the arterial endothelium and the arterial wall, and hence be a novel indicator of the status of arteries.

Recent progress in NO-releasing cardiovascular implants and drugs particularly emphasize NO donors and biomaterials, which are expected to ameliorate the temporal production of physiologically relevant NO concentrations [2,[30], [31], [32], [33], [34]]. For example, Nitrate esters, SIN-1, Nitroglycerin, Nicorandil, Inorganic nitrate and other NO donors can increase the NO concentration [35], L-NIL, L-NMA, L-NNA and other NO inhibitors can inhibit the vascular production of NO [36]. There is an urgent need of theoretical guidance on the local distribution of NO concentration in vivo to design clinically relevant implants. In addition, the atherosclerotic compositions are highly related to the pathological status of diseased arteries including plaque formation and rupture [[37], [38], [39], [40], [41]]. Therefore, in this study, we aimed to theoretically elucidate the relationship between the specific spatiotemporal distribution of the NO concentration and the multifarious components of atherosclerotic plaque in the cardiovascular. To achieve the goal, we constructed nine human carotid artery models with different multi-atherosclerotic components based on high resolution MR images (MRI), and conducted numerical simulation of blood flow as well as NO transport-based patient specific flow conditions. The time-averaged and space-averaged NO concentration at the media/adventitia interface, plaque component interface and the lumen/wall interface of carotid arteries as well as hemodynamic indicators based on WSS were calculated and compared.