Plaque Rupture in Coronary Atherosclerosis Is Associated With Increased Plaque Structural Stress

Objectives The aim of this study was to identify the determinants of plaque structural stress (PSS) and the relationship between PSS and plaques with rupture. Background Plaque rupture is the most common cause of myocardial infarction, occurring particularly in higher risk lesions such as fibroatheromas. However, prospective intravascular ultrasound–virtual histology studies indicate that <10% higher risk plaques cause clinical events over 3 years, indicating that other factors also determine plaque rupture. Plaque rupture occurs when PSS exceeds its mechanical strength; however, the determinants of PSS and its association with plaques with proven rupture are not known. Methods We analyzed plaque structure and composition in 4,053 virtual histology intravascular ultrasound frames from 32 fibroatheromas with rupture from the intravascular ultrasound–virtual histology in Vulnerable Atherosclerosis study and 32 fibroatheromas without rupture on optical coherence tomography from a stable angina cohort. Mechanical loading in the periluminal region was estimated by calculating maximum principal PSS by finite element analysis. Results PSS increased with increasing lumen area (r = 0.46; p = 0.001), lumen eccentricity (r = 0.32; p = 0.001), and necrotic core ≥10% (r = 0.12; p = 0.001), but reduced when dense calcium was ≥10% (r = −0.12; p = 0.001). Ruptured fibroatheromas showed higher PSS (133 kPa [quartiles 1 to 3: 90 to 191 kPa] vs. 104 kPa [quartiles 1 to 3: 75 to 142 kPa]; p = 0.002) and variation in PSS (55 kPa [quartiles 1 to 3: 37 to 75 kPa] vs. 43 kPa [quartiles 1 to 3: 34 to 59 kPa]; p = 0.002) than nonruptured fibroatheromas, with rupture primarily occurring either proximal or immediately adjacent to the minimal luminal area (87.5% vs. 12.5%; p = 0.001). PSS was higher in segments proximal to the rupture site (143 kPa [quartiles 1 to 3: 101 to 200 kPa] vs. 120 kPa [quartiles 1 to 3: 78 to 180 kPa]; p = 0.001) versus distal segments, associated with increased necrotic core (19.1% [quartiles 1 to 3: 11% to 29%] vs. 14.3% [quartiles 1 to 3: 8% to 23%]; p = 0.001) but reduced fibrous/fibrofatty tissue (63.6% [quartiles 1 to 3: 46% to 78%] vs. 72.7% [quartiles 1 to 3: 54% to 86%]; p = 0.001). PSS >135 kPa was a good predictor of rupture in higher risk regions. Conclusions PSS is determined by plaque composition, plaque architecture, and lumen geometry. PSS and PSS variability are increased in plaques with rupture, particularly at proximal segments. Incorporating PSS into plaque assessment may improve identification of rupture-prone plaques.

R upture of a coronary plaque is the precipitating event in the majority of myocardial infarctions (MI) (1). Postmortem (2) and in vivo intravascular studies (3,4) identify fibroatheromas (FAs), and in particular thin-cap fibroatheromas (TCFAs), as the most common predisposing lesion.
TCFAs are widespread in human coronary artery disease, including asymptomatic individuals and those with stable and unstable syndromes (3). However, the incidence of major adverse cardiovascular events (MACEs) associated with TCFAs identified by intravascular ultrasound-virtual histology (IVUS-VH) is <10% over w3 years of follow-up (3,4), suggesting that factors other than plaque and lumen size or plaque phenotype are important in determining plaque rupture.
Plaque rupture occurs when intraplaque stress exceeds the material strength of the overlying fibrous cap; increased plaque structural stress (PSS) is therefore a potential mechanism that determines rupture of a higher risk lesion. PSS can be calculated through an engineering technique known as finite element analysis (FEA), which approximates a solution to the equations of mechanical equilibrium by considering tissue material properties, plaque geometry, and local hemodynamic forces. Histological and IVUS-VH studies have identified necrotic core size, fibrous cap thickness, and the presence of microcalcification as important determinants of PSS (5)(6)(7). PSS has also been shown to be increased in patients presenting with acute coronary syndromes (ACS) versus stable symptoms (8). However, the determinants of PSS and its relationship to plaques that demonstrate rupture in vivo in human coronary arteries are not known. We sought to identify the parameters that determine PSS and variations in PSS across ruptured and nonruptured FAs identified using IVUS-VH to determine whether plaque stress is increased in plaques that have experienced rupture, and whether incorporating PSS into plaque assessment improves identification of rupture-prone plaques.   Figure 3. Because PSS varies between frames, analysis was also performed after dividing plaques into 2-mm segments and averaging PSS across the IVUS-VH frames composing each segment.
To estimate PSS at the exact site of rupture, the luminal boundary of frames demonstrating rupture was reconfigured with necrotic core present beneath this. PSS derived from these frames was compared with PSS from frames from the control cohort that demonstrated rupture after balloon inflation (Online

RESULTS
BASELINE PATIENT AND IVUS-VH DEMOGRAPHICS. We analyzed PSS in patients who had spontaneous plaque rupture on GS-IVUS from the VIVA study (n ¼ 25 patients, n ¼ 32 plaques) compared with patients undergoing elective PCI in which plaque rupture was excluded by both GS-IVUS and OCT (n ¼ 32 patients, n ¼ 32 plaques) (Figures 1 and 2 There were no significant differences in plaque classification between the 2 groups, with VH-TCFA being the predominant plaque type accounting for rupture or undergoing PCI for stable angina (91 vs. 75%; p ¼ 0.14) ( Table 2). PB was lower in ruptured plaques (59.5% vs. 63.5%; p ¼ 0.01), but minimal luminal area (MLA) and multiple components of plaque composition (% fibrous/fibrofatty tissue, necrotic core, dense calcium) were similar. Patient demographics and plaque composition for the cohort of patients with only VH-TCFAs also did not differ significantly between the groups (Online Tables 1 and 2).

DETERMINANTS OF PSS IN VH-DEFINED FIBROATHEROMAS.
We used FEA to estimate both the level and location of PSS in both ruptured and nonruptured plaques and the plaque and vessel determinants of PSS. Both luminal area and luminal eccentricity correlated positively with PSS (r ¼ 0.46, p ¼ 0.001; r ¼ 0.32, p ¼ 0.001, respectively), whereas a negative correlation was observed with PB (r ¼ À0.23; p ¼ 0.001) ( Table 3). A positive, albeit weaker, correlation with PSS was also observed when frames with necrotic core $10% were considered (r ¼ 0.12; p ¼ 0.001) ( Table 3), indicating that necrotic core affects PSS only when its contribution exceeds 10%. In contrast, dense calcium $10% and maximum arc of dense calcium demonstrated weak negative correlations with PSS (r ¼ À0.12 and À0.13, respectively; both p ¼ 0.001) ( Table 3), suggesting that calcification may offer a plaque "shielding" effect when present in significant amounts. Fibrous/fibrofatty tissue was associated with PSS only when increasingly confluent, with no correlation seen with % tissue (r ¼ 0.02; p ¼ 0.13) ( Table 3), but a weak negative correlation observed with maximum arc (r ¼ À0.19; p ¼ 0.001). PSS variability during the cardiac cycle was correlated with broadly similar parameters to peak PSS (Online Table 3), although fibrous/fibrofatty tissue (%) was negatively correlated and maximum arc of dense calcium was not correlated.
Our data show that PSS is determined by a number of factors, which differ depending on plaque type and extent of disease. We therefore undertook regression analysis to assess whether individual plaque parameters could predict PSS in    Costopoulos et al. Certain IVUS-VH features have been associated with a higher MACE risk, notably VH-TCFA, PB $70%, and MLA #4 mm 2 , and further increased by combinations of these features (3,4,9). PSS and variation in PSS were significantly higher in ruptured versus nonruptured VH-TCFAs ( Figures 6C and 6D Figures 6E and 6F). We also performed receiver operating characteristic curve analysis to assess the ability of PSS to predict plaque rupture ( Figures 7A to   7C). Inclusion of PSS significantly improved the ability of the combination of VH-FA þ PB $70% to identify plaque rupture ( Figure 7C). An optimal PSS cutoff of 135 kPa was identified for this cohort,     Figure 4F).

DISCUSSION
Plaque rupture is the precipitating event in the majority of MIs, and is thought to occur at sites of plaque weakness (1). PSS is a potential trigger of rupture, with rupture occurring when PSS exceeds     (15,16). In addition, FAs in the proximal segments are particularly at risk (15,17). We find a similar pattern with rupture clustering in the RCA and LAD, and close to the coronary ostia, especially in the LAD (15,17), similar to postmortem studies (17). We also find that proximal or peri-MLA plaque segments are more prone to rupture (10), and are sites expected to have higher PSS because of their larger luminal area, in accordance with Laplace's law (s ¼ Pr/h, where s ¼ circumferential stress, P ¼ intra-arterial pressure, r ¼ vessel radius, and h ¼ vessel wall thickness). Plaque segments proximal to the rupture site also showed higher PSS, and this was associated with significant differences in plaque composition.
More importantly, we demonstrate that both PSS and variation in PSS are higher in ruptured than nonruptured plaques, which was also seen when only VH-  other abbreviation as in Figure 1.
promote cap fatigue (18) However, OCT was not performed in the VIVA study, but was necessary in the unruptured patient population to exclude rupture, thereby ensuring that the nonruptured group truly consisted of intact plaques.

CONCLUSIONS
We demonstrate that IVUS-VH-based PSS is dependent on components of plaque composition and plaque and lumen architecture that are also associated with plaque vulnerability and rupture, thereby indirectly linking PSS to plaque rupture.
More importantly, PSS is higher in plaques with proven rupture, particularly in segments proximal to the rupture site, which have increased necrotic core.
PSS >135 kPa appears to be a good predictor of rupture in higher risk regions. Our results suggest that incorporation of PSS calculations into coronary plaque assessment may improve our ability to identify those plaques that proceed to rupture and clinical events. and is proposed as a mechanism that determines rupture in high-risk regions. Incorporation of PSS into assessment of coronary atherosclerotic plaques may improve our ability to identify those that cause clinical events.