Multidirectional wall shear stress promotes advanced coronary plaque development: comparing five shear stress metrics

Abstract

Aims: Atherosclerotic plaque development has been associated with wall shear stress (WSS). However, the multidirectionality of blood flow, and thus of WSS, is rarely taken into account. The purpose of this study was to comprehensively compare five metrics that describe (multidirectional) WSS behaviour and assess how WSS multidirectionality affects coronary plaque initiation and progression.

Methods and results: Adult familial hypercholesterolaemic pigs (n = 10) that were fed a high-fat diet, underwent imaging of the three main coronary arteries at three-time points [3 (T1), 9 (T2), and 10-12 (T3) months]. Three-dimensional geometry of the arterial lumen, in combination with local flow velocity measurements, was used to calculate WSS at T1 and T2. For analysis, arteries were divided into 3 mm/45° sectors (n = 3648). Changes in wall thickness and final plaque composition were assessed with near-infrared spectroscopy-intravascular ultrasound, optical coherence tomography imaging, and histology. Both in pigs with advanced and mild disease, the highest plaque progression rate was exclusively found at low time-averaged WSS (TAWSS) or high multidirectional WSS regions at both T1 and T2. However, the eventually largest plaque growth was located in regions with initial low TAWSS or high multidirectional WSS that, over time, became exposed to high TAWSS or low multidirectional WSS at T2. Besides plaque size, also the presence of vulnerable plaque components at the last time point was related to low and multidirectional WSS. Almost all WSS metrics had good predictive values for the development of plaque (47-50%) and advanced fibrous cap atheroma (FCA) development (59-61%).

Conclusion: This study demonstrates that low and multidirectional WSS promote both initiation and progression of coronary atherosclerotic plaques. The high-predictive values of the multidirectional WSS metrics for FCA development indicate their potential as an additional clinical marker for the vulnerable disease.

Keywords: Atherosclerosis; Coronary artery disease; Histopathology; Invasive imaging; Wall shear stress.

Graphical Abstract

Figure 1

Methodology of WSS calculation and analysis, and the relationship between local (multidirectional) WSS levels and the subsequent plaque growth rate in both plaque initiation and progression. (A) IVUS (pink) and computed tomography (white) contours were fused to reconstruct the grey lumen surface. This surface, together with local flow measurements between the side branches (three examples shown), was used as input for computational fluid dynamics (CFD), resulting in local WSS values (yellow = high; blue = low). (B) From the three-dimensional reconstructions, a two-dimensional map of the WSS levels at T₁ and T₂ and of the WT (T₁–T₃) was created. For the analysis, the artery was divided in 3 mm/45° sectors. (C) The mean (±SD) WT at T₁–T₃ in advanced-diseased (AD) (n = 1893 sectors at T₁ and T₂ and n = 1240 sectors at T₃) and mildly-diseased (MD) (n = 1755 sectors) pigs with two representative IVUS frames from T₃ (red contour = lumen; green contour = vessel wall). *P < 0.05 compared to T1, ^#P < 0.05 compared to T₂ (statistics: two-way repeated-measures analysis of variance with Bonferroni post hoc). (D) The effect of low/mid/high levels of the respective WSS metrics on the subsequent plaque growth rate (estimated mean ± SEM) in plaque initiation (T₁–T₂) and plaque progression (T₂–T₃). Important to note: for the AD pigs, the T₂–T₃ data are derived from three (instead of five) pigs (n = 1240 sectors), which means that the analysis of a difference in the relation between T₁–T₂ and T₂–T₃ (^$) could only be performed in these three animals. *P < 0.05 compared to the low tertile; ^#P < 0.05 compared to the mid tertile; ^$P < 0.05 compared to T₁–T₂ in the same tertile (statistics: linear mixed effects model). CFI, cross-flow index; OSI, oscillatory shear index; RRT, relative-residence time; TAWSS, time-averaged WSS; transWSS, transverse WSS.

Figure 2

The long-term effect of sustained or changed levels of (multidirectional) WSS on the plaque growth rate in advanced-diseased (AD) and mildly-diseased (MD) pigs. The plaque growth rate during plaque initiation (T₁–T₂) and plaque progression (T₂–T₃) in regions with either sustained low (L), low turning to high (H), high turning to low, or sustained high WSS between T₁ and T₂. Analysis is depicted for all WSS metrics (TAWSS, OSI, RRT, CFI, and transWSS]. Number of analysed sectors: for AD pigs T₁–T₂: n = 1893 and T₂–T₃: n = 1240; for MD pigs: n = 1755. *P < 0.05 compared to sustained low; ^#P < 0.05 compared to low (T₁)/high (T₂); ^$P < 0.05 compared to high (T₁)/low (T₂) (statistics: linear mixed effects model).

Figure 3

Association between T₁ WSS levels and final plaque composition detected by OCT and NIRS in advanced-diseased (AD) pigs at T_last. (A) OCT and NIRS analysis method on an imaginary two-dimensional map: all NIRS or OCT positive 3 mm/45° sectors were selected. Within these positive regions, the percentage of positive sectors that was preceded by one of the WSS tertiles was quantified. (B) The percentage of NIRS-positive sectors (n = 33) that was preceded by low (black bars), mid (grey bars), or high (white bars) levels of the respective T₁ WSS tertiles (TAWSS, OSI, RRT, CFI, and transWSS). *P < 0.05 for the overall relations (statistics: χ² test). (C) Example images of fibrous, lipid-rich, and fibrous cap atheroma (arrowhead) plaques on OCT. n, number of sectors of ADs presenting with each respective plaque classification at T_last. (D) The percentage of sectors presenting with fibrous or lipid-rich plaque that was preceded by low (black bars), mid (grey bars), or high (white bars) levels of the respective WSS metrics. Fibrous plaques displayed no significant relation (P = ns). *P < 0.05 for the overall relations (statistics: χ² test).

Figure 4

Relation between histological plaque classification and T₁ (multidirectional) WSS levels in the advanced-disease pigs pigs. (A) Histological examples of plaques according to the revised American Heart Association plaque classification. (B) Distribution of the plaque types over regions with preceding low, mid, or high levels of the respective WSS metrics (TAWSS, OSI, RRT, CFI, and transWSS). P-value is for the overall relations (statistics: χ² test).

Figure 5

The effect of T₁ (multidirectional) WSS levels on final histological plaque composition in advanced-diseased pigs. (A–C) The absolute lipid (Oil-red-O staining, red = lipid) (A), macrophage (CD68 staining, brown = macrophages) (B) or necrotic core (Miller staining, purple = collagen) (C) area (example positive staining indicated in yellow) preceded by low, mid, or high levels of one of the five WSS metrics (mean ± SD) (TAWSS, OSI, RRT, CFI, and transWSS). *P < 0.05 vs. low tertile of the respective WSS metric; ^#P < 0.05 vs. mid tertile (statistics: linear mixed effects model).