Spatiotemporal transfer of nitric oxide in patient-specific atherosclerotic carotid artery bifurcations with MRI and computational fluid dynamics modeling
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.
Section snippets
Magnetic resonance images acquisition and analysis
Nine patients with atherosclerotic plaque in carotid arterial bifurcation received MRI examination. Clinical data was obtained and reviewed by our institutional review board with the local ethics procedure. All the patients approved informed consent. The basic information for the selected nine patients in this study is list in Supplementary Table 1.
Multi-weighted MRI technology, including T1-weighted (T1W), T2-weighted (T2W) and time-of-fight (TOF) sequences, was performed on each patient
The NO distribution is highly nonuniform in the atherosclerotic carotid arteries
Fig. 2 shows the time-averaged NO distribution (CNO) of three representative atherosclerotic carotid arteries at the media/adventitia interface, plaque component interface and the lumen/wall interface (endothelial surface) (the other results are in Supplementary data). It is clear that for all the three kinds of atherosclerotic carotid arteries the distribution of CNO in the arteries is uneven with high concentration around lipid in the media/adventitia interface. The maximum concentration of
Discussion
The spatiotemporal concentration distribution of NO at the diseased regions is closely related to clinical therapeutics and diagnosis of atherosclerosis. Here, we constructed nine human carotid artery bifurcation models with different atherosclerotic components based on high resolution MRI images, and simulated the hemodynamic environments and NO transport numerically using patient specific flow conditions. Our results indicated that the time-averaged NO (CNO) is unevenly distributed with
Conclusion
Combining patient-specific medical images and computational fluid mechanics, we presented personalized computational modelling to calculate the NO distribution on the endothelial surface and in the arterial wall of atherosclerotic carotid artery bifurcations. The computational results indicated that the dynamic blood flow during the cycle would directly affect the distribution of NO on the endothelial surface. However, the atherosclerotic components, especially the intraplaque lipid and
Sources of funding
This work was supported by the National Natural Science Research Foundation of China Grants-in-Aid (grant nos. 11827803, 31570947, 11772036, 31971244, 11421202 and 61533016), and the 111 Project (B13003).
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
None.
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These authors contributed equally to this work.