Coronary artery disease (CAD), or atherosclerosis, is responsible for nearly a third of all American deaths annually. Detection of plaques and differentiation of plaque stage remains a complicating factor for treatment. Classification of plaque before significant blockage or rupture could inform clinical decisions and prevent mortality. Current detection methods are either nonspecific, slow, or require the use of potentially harmful contrast agents. Recent advances in hyperspectral imaging could be used to detect changes in the autofluorescence of arteries associated with vessel remodeling and subsequent plaque formation and could detect and classify existing lesions. Here, we present data comparing spectral image characteristics of a mouse model designed to undergo vessel remodeling.
C57Bl/6 mice underwent ligation of three of four caudal branches of the left common carotid artery (left external carotid, internal carotid, and occipital artery) with the superior thyroid artery left intact under IACUC approved protocol. Vessels were harvested at a variety of timepoints to compare degrees of remodeling, including 4 weeks and 5 months post-surgery. Immediately following harvest, vessels were prepared by longitudinal opening to expose the luminal surface to a 20X objective. A custom inverted microscope (TE-2000, Nikon Instruments) with a Xe arc lamp and thin film tunable filter arrary (Versachrome, Semrock, Inc.) were used to achieve spectral imaging. Excitation scans utilized wavelengths between 340 nm and 550 nm in 5 nm increments. Hyperspectral data were generated and analyzed with custom Matlab scripts and visualized in ENVI. Preliminary data suggest consistent spectral features associated with control and remodeled vessels.
© (2019) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.
more »
« less
Reduced Smooth Muscle Contractile Capacity Facilitates Maladaptive Arterial Remodeling
Abstract Albeit seldom considered explicitly, the vasoactive state of a central artery can contribute to luminal control and thereby affect the in vivo values of flow-induced wall shear stress and pressure-induced intramural stress, which in turn are strong determinants of wall growth and remodeling. Here, we test the hypothesis that diminished vasoactive capacity compromises effective mechano-adaptations of central arteries. Toward this end, we use consistent methods to re-interpret published data on common carotid artery remodeling in a nonpharmacologic mouse model of induced hypertension and a model of connective tissue disorder that results in Marfan syndrome. The mice have identical genetic backgrounds and, in both cases, the data are consistent with the hypothesis considered. In particular, carotid arteries with strong (normal) vasoactive capacity tend to maintain wall thickness and in vivo axial stretch closer to homeostatic, thus resulting in passive circumferential wall stress and energy storage close to normal. We conclude that effective vasoactivity helps to control the biomechanical state in which the cells and matrix turnover, thus helping to delineate mechano-adaptive from maladaptive remodeling. Future analyses of experimental data and computational models of growth and remodeling should account for this strong coupling between smooth muscle contractile capacity and central arterial remodeling.
more »
« less
- Award ID(s):
- 1760906
- NSF-PAR ID:
- 10380578
- Date Published:
- Journal Name:
- Journal of Biomechanical Engineering
- Volume:
- 144
- Issue:
- 4
- ISSN:
- 0148-0731
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
null (Ed.)Mechanical forces are essential for proper growth and remodeling of the primitive pharyngeal arch arteries (PAAs) into the great vessels of the heart. Despite general acknowledgement of a hemodynamic-malformation link, the direct correlation between hemodynamics and PAA morphogenesis remains poorly understood. The elusiveness is largely due to difficulty in performing isolated hemodynamic perturbations and quantifying changes in-vivo. Previous in-vivo arch artery occlusion/ablation experiments either did not isolate the effects of hemodynamics, did not analyze the results in a 3D context or did not consider the effects of varying degrees of occlusion. Here, we overcome these limitations by combining minimally invasive occlusion experiments in the avian embryo with 3D anatomical models of development and in-silico testing of experimental phenomenon. We detail morphological and hemodynamic changes 24 hours post vessel occlusion. 3D anatomical models showed that occlusion geometries had more circular cross-sectional areas and more elongated arches than their control counterparts. Computational fluid dynamics revealed a marked change in wall shear stress-morphology trends. Instantaneous (in-silico) occlusion models provided mechanistic insights into the dynamic vessel adaptation process, predicting pressure-area trends for a number of experimental occlusion arches. We follow the propagation of small defects in a single embryo Hamburger Hamilton (HH) Stage 18 embryo to a more serious defect in an HH29 embryo. Results demonstrate that hemodynamic perturbation of the presumptive aortic arch, through varying degrees of vessel occlusion, overrides natural growth mechanisms and prevents it from becoming the dominant arch of the aorta.more » « less
-
Perivascular adipose tissue (PVAT) is increasingly recognized as an essential layer of the functional vasculature, being responsible for producing vasoactive substances and assisting arterial stress relaxation. Here, we test the hypothesis that PVAT reduces aortic stiffness. Our model was the thoracic aorta of the male Sprague–Dawley rat. Uniaxial mechanical tests for three groups of tissue were performed: aorta with PVAT attached (+PVAT) or removed (−PVAT), and isolated PVAT (PVAT only). The output of the mechanical test is reported in the form of a Cauchy stress-stretch curve. This work presents a novel, physiologically relevant approach to measure mechanical stiffness ex vivo in isolated PVAT. Low-stress stiffness ( E 0 ), high-stress stiffness ( E 1 ), and the stress corresponding to a stretch of 1.2 (σ 1.2 ) were measured as metrics of distensibility. The low-stress stiffness was largest in the −PVAT samples and smallest in PVAT only samples. Both the high-stress stiffness and the stress at 1.2 stretch were significantly higher in −PVAT samples when compared with +PVAT samples. Taken together, these results suggest that −PVAT samples are stiffer (less distensible) both at low stress (not significant) as well as at high stress (significant) when compared with +PVAT samples. These conclusions are supported by the results of the continuum mechanics material model that we also used to interpret the same experimental data. Thus, tissue stiffness is significantly lower when considering PVAT as part of the aortic wall. As such, PVAT should be considered as a target for improving vascular function in diseases with elevated aortic stiffness, including hypertension. NEW & NOTEWORTHY We introduce a novel and physiologically relevant way of measuring perivascular adipose tissue (PVAT) mechanical stiffness which shows that PVAT’s low, yet measurable, stiffness is linearly correlated with the amount of collagen fibers present within the tissue. Including PVAT in the measurement of the aortic wall’s mechanical behavior is important, and it significantly affects the resulting metrics by decreasing aortic stiffness.more » « less
-
Introduction: The mechanical stability of an atheroma fibrous cap (FC) is a crucial factor for the risk of heart attack or stroke in asymptomatic vulnerable plaques. Common determinants of plaque vulnerability are the cap thickness and the presence of micro-calcifications (µCalcs). Higher local stresses have been linked to thin caps(<65µm) and, more recently, our lab demonstrated how µCalcs can potentially initiate cap rupture [1-3]. When combined, these two factors can compromise to a greater extent the stability of the plaque. On this basis, we quantitatively analyzed both individual and combined effects of key determinants of plaque rupture using a tissue damage model on idealized atherosclerotic arteries. Our results were then tested against a diseased human coronary sample. Methods: We performed 28 finite element simulations on three-dimensional idealized atherosclerotic arteries and a human coronary sample. The idealized models present 10% lumen narrowing and 1.25 remodeling index (RI)(Fig.1A). The FC thickness values that we considered were of 50, 100, 150 and 200µm. The human coronary presents a RI=1.31, with 31% lumen occlusion and a 140µm-thick cap(Fig.1B). The human model is based on 6.7μm high-resolution microcomputed tomography (HR-μCT) images. The µCalc has a diameter of 15µm and each artery was expanded up to a systolic pressure of 120mmHg. Layer-specific material properties were de-fined by the HGO model coupled with the hyperelastic failure description proposed by Volokh et al. [4] to repli-cate the rupture of the FC. We considered a max. princi-pal stress for rupture of 545kPa[5]. The lipid core and the µCalc were considered as elastic materials (Ecore = 5kPa, νcore = 0.49; EµCalc= 18,000 kPa, νµCalc=0.3). To obtain a detailed analysis of the cap stresses and rupture progres-sion, a sub-modeling approach was implemented using ABAQUS (Dassault Systemes, v.2019) (Fig. 1). Results: We investigated the quantitative effect of cap thickness and µCalc by simulating tissue failure and de-riving a vulnerability index (VI) for each risk factor. The VI coefficient was defined as the peak cap stress (PCS) normalized by the threshold stress for rupture (545kPa). The relationship between the risk factors and VI was de-termined by deriving the Pearson’s correlation coefficient (PCC) followed by one-tailed t-test (SPSS, IBM, v.25). The null hypothesis was rejected if p<0.05. The presence of the µCalc is the factor that manifests the greater impact on cap stability, leading to at least a 2.5-fold increase in VI and tissue rupture regardless of cap thickness (Fig.2A,B). One µCalc in the cap is the first predictor of vulnerability, with PCCµCalc=0.59 and pµCalc=0.001. Our results also confirm the substantial in-fluence of cap thickness, with an exponential increase in stresses as the cap becomes thinner. The 50µm cap is the only phenotype that ruptures without µCalc (Fig2A). The human sample exhibits PCS levels that are close to the idealized case with 150µm cap and it doesn’t rupture in the absence of the µCalc (PCShuman=233kPa, PCSideal= 252kPa). Conversely, the phenotypes with the µCalc showed an increase in VI of about 2.5 and reached rup-ture under the same blood pressure regime. Conclusions: Our results clearly show the multifactorial nature of plaque vulnerability and the significance of micro-calcifications on the cap mechanical stability. The presence of a μCalc strongly amplifies the stresses in the surrounding tissue, and it can provoke tissue failure even in thick caps that would otherwise be classified as stable. Clearly, plaque phenotypes with a thin cap and μCalcs in the tissue represent the most vulnerable condition. Finally, these observations are well validated by the case of the human atherosclerotic segment, which closely compares to its corresponding idealized model. The novel imple-mentation of the tissue damage description and the defi-nition of a vulnerability index allow one to quantitatively analyze the individual and combined contribution of key determinants of cap rupture, which precedes the for-mation of a thrombus and myocardial infarction.more » « less
-
A Mathematical Model of Maladaptive Inward Eutrophic Remodeling of Muscular Arteries in HypertensionAbstract We propose a relatively simple two-dimensional mathematical model for maladaptive inward remodeling of resistive arteries in hypertension in terms of vascular solid mechanics. The main premises are: (i) maladaptive inward remodeling manifests as a reduced increase in the arterial mass compared to the case of adaptive remodeling under equivalent hypertensive pressures and (ii) the pressure-induced circumferential stress in the arterial wall is restored to its basal target value as happens in the case of adaptive remodeling. The rationale for these assumptions is the experimental findings that elevated tone in association with sustained hypertensive pressure down-regulate the normal differentiation of vascular smooth muscle cells from contractile to synthetic phenotype and the data for the calculated hoop stress before and after completion of remodeling. Results from illustrative simulations show that as the hypertensive pressure increases, remodeling causes a nonmonotonic variation of arterial mass, a decrease in inner arterial diameter, and an increase in wall thickness. These findings and the model prediction that inward eutrophic remodeling is preceded by inward hypertrophic remodeling are supported by published observations. Limitations and perspectives for refining the mathematical model are discussed.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1115/1.4052888
