Plaque vulnerability, defined as the likelihood that a plaque would rupture, is difficult to quantify due to lack of in vivo plaque rupture data. Morphological and stress-based plaque vulnerability indices were introduced as alternatives to obtain quantitative vulnerability assessment. Correlations between these indices and key plaque features were investigated. In vivo intravascular ultrasound (IVUS) data were acquired from 14 patients and IVUS-based 3D fluid-structure interaction (FSI) coronary plaque models with cyclic bending were constructed to obtain plaque wall stress/strain and flow shear stress for analysis. For the 617 slices from the 14 patients, lipid percentage, min cap thickness, critical plaque wall stress (CPWS), strain (CPWSn) and flow shear stress (CFSS) were recorded, and cap index, lipid index and morphological index were assigned to each slice using methods consistent with American Heart Association (AHA) plaque classification schemes. A stress index was introduced based on CPWS. Linear Mixed-Effects (LME) models were used to analyze the correlations between the mechanical and morphological indices and key morphological factors associated with plaque rupture. Our results indicated that for all 617 slices, CPWS correlated with min cap thickness, cap index, morphological index with r = -0. 6414,0. 7852, and 0. 7411 respectively (p<0. 0001). The correlation between CPWS and lipid percentage, lipid index were weaker (r = 0. 2445, r = 0. 2338, p<0. 0001). Stress index correlated with cap index, lipid index, morphological index positively with r = 0. 8185,0. 3067, and 0. 7715, respectively, all with p<0. 0001. For all 617 slices, the stress index has 66. 77% agreement with morphological index. Morphological and stress indices may serve as quantitative plaque vulnerability assessment supported by their strong correlations with morphological features associated with plaque rupture. Differences between the two indices may lead to better plaque assessment schemes when both indices were jointly used with further validations from clinical studies.
Cardiovascular diseases (CVD), especially acute coronary syndromes, are closely associated with atherosclerotic plaque progression and rupture. Accurate assessment of plaque vulnerability is of ultimate importance to CVD research, diagnosis, prevention and proper treatment. Plaque vulnerability is defined as the likelihood that a plaque would rupture. While this vulnerability concept is well accepted, its quantification is extremely difficult due to lack of actual plaque rupture and clinical event data. In this paper, morphological plaque vulnerability index (morphological index) and stress-based plaque vulnerability index (stress index) will be introduced as plaque assessment using morphological and mechanical data. These indices provide computable quantitative plaque vulnerability measures for patient screening purpose using morphological and mechanical data while the absolute vulnerability is not available. Correlations between these indices and key plaque features including cap thickness and necrotic lipid-rich core (referred to as lipid thereafter) will also be investigated. Atherosclerotic plaque progression and rupture are believed to be associated with morphological factors, plaque components, material properties, and mechanical stress/strain conditions, etc. [1–7]. More and more studies have shown that the mechanical forces play an important role in plaque progression and rupture process and should be considered with plaque morphology and compositions together for better plaque vulnerability assessment [1,8–12]. Considerable advances in medical imaging technology have made it possible to construct image-based computational models integrating plaque morphology, components, and mechanical stress/strain conditions and obtain plaque vulnerability assessment based on more complete information [12–13]. Based on in vivo magnetic resonance imaging (MRI) carotid plaque data with actual plaque rupture indicated by ulceration (n = 12,5 with ulceration), Tang et al. reported that mean plaque wall stress (PWS) from all ulcer nodes in ruptured plaques was 86% higher than that from all non-ulcer nodes (123. 0 vs. 66. 3 kPa, p<0. 0001). Mean flow shear stress (FSS) from all ulcer nodes in ruptured plaques was 170% higher than that from all non-ulcer nodes (38. 9 vs. 14. 4 dyn/cm2, p<0. 0001) [12]. Mean critical PWS (CPWS) from the 5 ruptured plaques was 126% higher than that from the 7 non-ruptured ones (247. 3 vs. 108 kPa, p = 0. 0016 using log transformation) [12]. Using finite element analysis to calculate the plaque structural stress (PSS) for 4429 intravascular ultrasound (IVUS) frames from 53 patients, Teng et al. found PSS was higher in non-calcified thin-cap fibroatheroma and in patients with the factors contributing to the acute syndrome such as plaque burden > = 70%, mean lumen area < = 4mm2 [14]. Based on a comparative study of 40 patients with 20 symptomatic and 20 asymptomatic, Li et al. reported that lumen curvature and fibrous cap thickness were the major factors affecting plaque stress distribution. Furthermore lumen curvature in plaques of symptomatic patients was significantly larger compared to that of asymptomatic patients [15]. Based on the simulation results of endothelial shear stress (ESS) in the human coronary of 7 patients, Hetterich et al. claimed plaque prevalence was highest in areas of low ESS (49. 6%) and followed by high ESS quartile (34. 8%) while in parts exposed to intermediate-low and intermediate-high ESS quartiles, few plaques were found (20. 0% and 24. 0%) (p<0. 001) [16]. In a comparison study between 54 asymptomatic and 45 acutely symptomatic patients, Zhu et al. reported that plaque wall stresses at critical vulnerable sites were significantly higher in acutely symptomatic group comparing to the asymptomatic group (median, inter quartile range: 198. 0 kPa (119. 8–359. 0 kPa) vs 138. 4 kPa (83. 8–242. 6 kPa), P = 0. 04) [17]. In another multi-patient study based on in vivo MRI data of carotid plaques, Huang et al. demonstrated that mean PWS at the hemorrhage nodes were higher than that from the non-hemorrhage nodes (75. 6 vs. 68. 1 kPa), and mean FSS at hemorrhage nodes were also higher than that from the non-hemorrhage nodes (15. 0 vs. 11. 5dyn/cm2) [18]. A very noticeable finding for vulnerable plaque research was concerned with microcalcifications [19–23]. Vengrenyuk et al. [19–20], Bluestein et al. [21], Maldonado et al. [22], Cardoso and Weinbaum [2], and Kelly-Arnold et al. [23] demonstrated that plaque cap with micro-calcification inclusions are associated with elevated stress levels and may be related to plaque rupture. For plaque progression studies, in a multi-patient IVUS-based follow-up study (n = 20), Samady et al. divided slices into low, intermediate, and high wall shear stress (WSS) groups and found that low-WSS segments demonstrated greater reduction in vessel (P<0. 001) and lumen area (P<0. 001), and high-WSS segments demonstrated an increase in vessel (P<0. 001) and lumen (P<0. 001) area [24]. In a follow-up study of 506 patients with acute coronary syndrome (ACS) to assess plaque natural history, Stone et al. reported that increase in plaque area was predicted by baseline large plaque burden; decrease in lumen area was independently predicted by baseline large plaque burden and low wall shear stress [25]. In this paper, in vivo intravascular ultrasound (IVUS) data were acquired to construct 3D models with fluid-structure interactions (FSI) and cyclic bending and obtain plaque morphological and mechanical stress/strain data for analysis. Six hundred and seventeen (617) slices were obtained from 14 patients. Based on morphological features available from IVUS Volcano Histology (VH), three morphological characteristic-related indices (lipid index, cap index, and morphological index) were introduced consistent with American Heart Association (AHA) plaque classifications [26]. Flow shear stress (FSS) and plaque wall stress/strain (PWS/PWSn) were collected at the critical sites in each slice to investigate their correlations with the morphological related factors. The Linear mixed-effect (LME) Models were used to analyze the correlation between each of the mechanical condition and each of the indices.
Table 3 summarized the correlation results between the three mechanical factors (CPWS, CPWSn, and CFSS) and 5 morphological factors: min cap thickness, cap index, lipid percentage, lipid index and morphological index. CPWS correlated significantly with each of the five morphological factors. There was a significant correlation between CPWS and the morphological index with correlation coefficient r = 0. 7411, p-value<0. 0001. Cap index (r = 0. 7852) showed a slightly stronger correlation with CPWS than min cap thickness (r = -0. 6414). The correlations showed opposite sign because thinner cap thickness had higher cap index. Lipid percentage and lipid index yielded weaker correlation than CPWS with correlation coefficient r = 0. 2445 and r = 0. 2338, respectively. Fig 4 shows the distribution of the CPWS with respect to cap index, min cap thickness, lipid index and morphological index. Statistically significant correlations were also observed between the CPWSn and 5 morphological factors (min cap thickness, cap index, lipid percentage, lipid index and morphological index) based on results from the 617 slices (see Table 3). Correlation results between CPWSn and min cap thickness, cap index and morphological index are similar to those of CPWS, but much weaker. CPWSn had negative correlation with lipid percentage and lipid index which is different from the results of CPWS. CFSS had significant correlations with lipid percentage and lipid index with r = 0. 1144 and r = 0. 0825, respectively. However, CFSS did not have significant correlations with min cap thickness, cap index, and morphological index. It is natural that min cap thickness and CPWS correlate strongly. However, lipid content does not have similar strong correlation because some lipid core could have very thick cap. CFSS and min cap thickness did not have significant correlation because they do not correspond very well. Individual patient correlations between CPWS and min cap thickness, cap index, lipid percentage, lipid index, morphological index were obtained for each of the 14 plaques and results are summarized in Table 4. For all 14 plaques, CPWS had significant positive correlations with cap index and morphological index, and negative correlation with min cap thickness. On the other hand, correlations between CPWS and lipid percentage, lipid index showed mixed results for the 14 patients. The number of patients showing positive/no significant/negative correlation between CPWS and lipid percentage were 4/10/0 respectively, while only 5 out of 14 patients showed significant positive correlation between CPWS and lipid index and the remaining 9 showed no correlation. Table 5 shows that correlation results of the stress index is similar to those of CPWS. There are significant correlations between stress index and all 5 morphological indices and factors. The correlation coefficient between stress index and cap index is the highest with r = 0. 8185. There is a strong correlation between stress index and morphological index with r = 0. 7715. The correlation coefficients between stress index and min cap thickness, lipid percentage and lipid index were r = -0. 7127,0. 3139,0. 3067 respectively, all with p< 0. 0001. For the 617 slices, each slice was assigned a stress index and 3 morphological related indices: cap index, lipid index and morphological index. Table 6 gives the agreement rates between stress index and cap index, lipid index, and morphological index. The matching rates (two indices have the same value for a slice) between stress index and cap index, lipid index and morphological index were 57. 37%, 25. 93% and 66. 77% respectively. The result demonstrated the stress index has a strong agreement with morphological feature closely related to the plaque vulnerability, and could be used to aid the assessment of plaque vulnerability and plaque rupture.
Quantification of plaque vulnerability by its strict definition based on in vivo data is not currently realistic due to its statistical nature and lack of available in vivo data for plaque rupture and rupture-related clinical events. The morphological and stress-based plaque vulnerability indices introduced in this paper provided a possible approach for quantitative plaque vulnerability assessment using features known to be closely associated with plaque rupture. These indices may get closer to serve as appropriate approximations to plaque vulnerability as more plaque rupture and clinical event data are investigated and continued research adds more supporting evidence for the use of those alternative indices. Currently, histology is serving as the gold standard for plaque vulnerability assessment. It has been well established that cap thickness and lipid size are closely related to plaque vulnerability. Our stress index was introduced trying to have best match with the morphological index. The stress index had a 66. 77% agreement rate with morphological index. It should be emphasized that the disagreement between stress index and morphological index may lead to better plaque assessment strategies when both indices were used together to supplement each other. Large lipid core gives a higher morphological index. However, if its cap is thick, the slice may have a lower stress index. Large curvature causes higher CPWS which leads to a high stress index, which the morphological index may be low due to cap thickness and lipid size features. Further investigations are needed to investigate the differences of the two indices and seek for potential improvement on plaque assessment techniques and patient screening tools. It is clear that CPWS and min cap thickness have strong correlations. However, CFSS did not have significant correlations with min cap thickness and cap index. CFSS showed weak positive correlation with lipid percentage and lipid index. This may be related the fact the higher CFSS values are associated to lumen narrowing, thicker vessel wall and larger lipid core. In general, CFSS is only one value for a slice and FSS from entire vessel should be used for further investigations [8]. Several factors such as cap thickness and lumen surface inflammation are known to be related to plaque vulnerability and quantitative measurements of those features will bring improvement to our index accuracies. Among several modalities, Optical Coherence Tomography (OCT) may help advance our ability to diagnose vulnerable from non-vulnerable plaques to enhance future risk prediction and effective treatment for patients. OCT uses light rather than ultrasound; has a resolution of 15–20 microns and therefore can measure fibrous cap thickness; can classify plaque as fatty, fibrotic, calcific, or thrombotic; and can detect thin-cap fibroatheromas and plaque erosions in patients presenting with an acute coronary syndrome. The major limitations of OCT are penetration so that overall plaque burden cannot be measured and the inability to image through blood or penetrate red thrombus. We are currently working on techniques combining IVUS with OCT to obtain good overall plaque 3D geometry with better cap thickness quantifications. Some other limitations of this study include: a) Patient-specific and tissue-specific material properties were not available for our study. We are currently investigate other approaches to measure patient-specific material properties in vivo; b) Currently, IVUS resolution is at 100–150 microns, mostly depending on the transducer frequency, which is not enough to clearly identify the thin caps with thickness under 100 micron. Optical coherence tomography can be used jointly with IVUS procedures and can provide spatial resolution of 10–20 microns. These combined approaches are also under investigation; c) While patient-specific angiography was used to extract vessel curvature variations in cardiac cycle for our cyclic bending, only angiography from one view angle was used. 3D curvature re-constructed from multiple angiography images with different (preferably orthogonal) view angles should be used in our future models [24]; d) Because IVUS data does not contain the adventitial layer of the vessel, our model also did not include that, as this is done in the current literature. It is arguable if simply adding a layer without actual data support would give us a better model. The adventitial layer should have considerable effect on stress/strain calculations. So our results should be understood with that simplification; e) Microcalcifications were not included in the current morphological index due to limitations of imaging; f) Interaction between the heart and vessel were not considered in this model. A model coupling heart motion and coronary bending would be designed when required data become available.
Cardiovascular diseases are closely related to atherosclerotic plaque progression and rupture. Early detection of vulnerable plaques and prediction of potential plaque rupture and related clinical events are of vital importance. Plaque vulnerability, defined as the likelihood that a plaque would rupture, is difficult to measure due to lack of in vivo plaque rupture data. Morphological and stress-based plaque vulnerability indices were introduced in this paper as alternatives to obtain quantitative vulnerability assessment with potential improvement of patient screening tools. In vivo intravascular ultrasound data were acquired from patients and computational coronary plaque models were constructed to obtain data for analysis and index assignments. For the 617 slices from the 14 patients, morphological and stress indices were assigned to each slice using methods consistent with American Heart Association plaque classification schemes. Correlation analyses were performed for all the morphological and mechanical factors considered. The stress index has 66. 77% agreement with morphological index. Morphological and stress indices may serve as quantitative plaque vulnerability assessment supported by their strong correlations with morphological features associated with plaque rupture. Differences between the two indices may lead to better plaque assessment schemes when the complementary indices were jointly used with further validations from clinical studies.
Morphological and Stress Vulnerability Indices for Human Coronary Plaques and Their Correlations with Cap Thickness and Lipid Percent: An IVUS-Based Fluid-Structure Interaction Multi-patient Study