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J Am Coll Cardiol, 2007; 49:23-31, doi:10.1016/j.jacc.2006.03.073
(Published online 12 December 2006). © 2007 by the American College of Cardiology Foundation |
Erasmus Medical Center, Thoraxcenter, Rotterdam, the Netherlands.
Manuscript received December 1, 2005; revised manuscript received February 28, 2006, accepted March 7, 2006.
* Reprint requests and correspondence: Prof. Patrick W. Serruys, Thoraxcenter, Bd-406, Dr Molewaterplein 40, 3015-GD Rotterdam, the Netherlands. (Email: p.w.j.c.serruys{at}erasmusmc.nl).
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Abstract |
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BACKGROUND: Plaque composition, favoring propensity to vulnerability, might be nonuniformly distributed along the vessel, which might explain the greater likelihood for plaque erosion or rupture to occur in the proximal but not in the distal tracts of the coronary artery or in LMS.
METHODS: A total of 72 patients were included prospectively; 48 (32 men; mean age 57 ± 11 years; 25 with stable angina and 23 affected by acute coronary syndromes) underwent a satisfactory nonculprit vessel investigation through spectral analysis of intravascular ultrasound radiofrequency data (IVUS-Virtual Histology, Volcano Corp., Rancho Cordova, California). The region of interest was subsequently divided into LMS and LMS carina, followed by 6 consecutive nonoverlapping 6-mm segments in left anterior descending artery in 34 patients or in circumflex artery in 14 patients.
RESULTS: Necrotic core content (%): 1) was minimal in LMS (median [interquartile range]: 4.6 [2 to 7]), peaked in the first 6-mm coronary segment (11.8 [8 to 16]; p < 0.01), and then progressively decreased distally; 2) was overall greater in patients with acute coronary syndromes (11.4 [5.5 to 19.8]) than stable angina (7.3 [3.2 to 12.9]; p < 0.001); 3) was largely independent from plaque size; and 4) did not correlate to systemic levels of C-reactive protein or lipid profile.
CONCLUSIONS: Plaques located in the LMS carry minimal necrotic content. Thus, they mimic the distal but not the proximal tract of the left coronary artery, where plaque rupture or vessel occlusion occurs more frequently.
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Similarly, 1) angiographic studies in patients with ST-segment elevation myocardial infarction recently have shown that sites of occlusion are clustered within the proximal third of each of the vessels (2,3), and 2) intravascular ultrasound (IVUS) analyses have observed that plaque rupture rarely occurs in the LMS or the distal part of the coronary arteries, whereas it is far more common in the proximal part of the coronary vessels (4), especially in the left anterior descending (LAD) artery (5).
The reasons why vulnerable or ruptured plaques tend to spare the LMS and distal segments of the left coronary vessels remain poorly understood. Plaque composition, favoring propensity to vulnerability (6–8), might also be nonuniformly distributed along the coronary arteries.
We sought to investigate whether the plaques located in the LMS, which are known to be at low probability of rupture, differ in terms of composition from those sited in the proximal tract of LAD or circumflex artery (CFX), where rupture or occlusion occurs more frequently. This may contribute establishing in vivo the role of plaque composition as key determinant of vulnerability in humans. In this context, the role of clinical presentation, length of LMS, lipid profile, and systemic level of C-reactive protein (CRP) also were investigated.
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Methods |
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According to the protocol, not more than one vessel per patient could be evaluated, and the region of interest was subsequently divided into the following coronary segments: LMS and LMS carina, based on anatomical landmarks, followed by 6 consecutive nonoverlapping 6-mm segments, with the first one to be started at the coronary ostium of either the LAD or CFX arteries. The length chosen for those coronary segments located distally to the LMS carina was based on the median length of LMS in the study population.
To ensure that the ostial-proximal part of the LMS was included in the IVUS pullback and to rule out the occurrence of deep intubation by the guiding catheter, the last part of the pullback was filmed and each angiogram carefully inspected before patient inclusion. An analyzable interrogated vessel length of at least 35 mm beyond LMS carina, starting from coronary ostium, was the main selection criterion, once the patient was included in the study. This protocol was approved by the hospital ethics committee and is in accordance with the Declaration of Helsinki. Written informed consent was obtained from every patient.
Intravascular ultrasound-virtual histology (VH) acquisition and analysis. Details regarding the validation of the technique, on explanted human coronary segments, have previously been reported (9). Briefly, IVUS radiofrequency data (IVUS-Virtual Histology, Volcano Corp., Rancho Cordova, California) uses spectral analysis of IVUS radiofrequency data to construct tissue maps that classify plaque into 4 major components. In preliminary in vitro studies, 4 histological plaque components (fibrous, fibro-lipid, necrotic core, and calcium) were correlated with a specific spectrum of the radiofrequency signal (9). These different plaque components were assigned color codes. Calcified, fibrous, fibrolipidic, and necrotic core regions were labeled white, green, greenish-yellow, and red, respectively (10).
IVUS-VH data were acquired after intracoronary administration of nitrates using a continuous pullback (0.5 mm/s) with commercially available mechanical sector scanners (Ultracross 30-MHz catheter, Boston Scientific, Santa Clara, California or Eagle Eye 20-MHz catheter, Volcano Corp.), by a dedicated IVUS-VH console (Volcano Corp.). The IVUS-VH data were stored on a CD-ROM/DVD and sent to the imaging core lab for offline analysis (Cardialysis). IVUS B-mode images were reconstructed from the RF data by customized software and contour detection was performed using cross-sectional views with a semi-automatic contour detection software to provide geometrical and compositional output (IvusLab 3.0 for 30 MHz acquisitions and IvusLab 4.4 for 20-MHz acquisitions, respectively; Volcano Corp.) (10).
The contours of the external elastic membrane (EEM) and the lumen-intima interface enclosed an area that was defined as the coronary plaque plus media area. Plaque burden was calculated as ([EEMarea – Lumenarea/EEMarea] x 100). Plaque eccentricity was defined as minimum plaque thickness divided by maximum plaque thickness. Geometrical and compositional data were obtained for each cross-sectional area (CSA), and an average was calculated for each coronary and for the total coronary tree. RF data were normalized using a technique known as "blind deconvolution," an iterative algorithm that deconvolves the catheter transfer function from the backscatter, thus accounting for catheter-to-catheter variability (11,12).
Biochemical measures. Antecubital venous blood was collected from all patients at entry, left in ice for 45 min, centrifuged at 1,700 g at 4°C for 15 min and serum obtained finally stored at –80°C. High-sensitivity CRP was measured in serum using a commercially available kit (N High Sensitivity CRP, Dade Behring, Marburg, Germany). Plasma concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured in the local laboratory. The Friedewald formula was used to derive low-density lipoprotein (LDL) cholesterol levels.
Statistical analysis. The sample size was calculated on the assumption that plaques located in the most proximal 6-mm segment of the LAD or CFX would display a mean necrotic core content of approximately 10% and a standard deviation of 10%, based on previous findings (13), with a relative necrotic core content of around 5% in plaques located in the LMS. To detect this effect size with 80% power and a type I error (alpha) of 0.05, at least 46 patients were required (model 1). Model 2 also was created to explore whether in patients with LMS length beyond median value (long LMS cohort) plaque composition differs in the proximal compared to the distal tract of the LMS. No formal sample size was calculated for model 2 as it was meant to be a hypothesis generating analysis.
Values are expressed as mean ± SD and median and interquartile range (IQR) whenever appropriate. Because all cross-sectional areas, provided by IVUS analysis, were shown to have a non-normal distribution at Kolmogorov-Smirnov goodness-of-fit test, they were log-transformed before analysis. Similarly, to all percentages relative to stenosis rate and plaque composition an arcsin transformation was applied (14). Assumptions for normality were checked after transformation based on a p value >0.20 at Kolmogorov-Smirnov test and on visual assessment of Q-Q plots of residuals.
Comparisons between the 2 groups were performed with the Student t test. The Fisher exact test was used for categorical variables. Comparisons among coronary segments were accomplished through a general linear mixed model and post-hoc comparisons by Tukey honest significance difference test (15). Spearman’s correlation coefficients were used to detect any association between variables. Probability was significant at a level of <0.05. Statistical analysis was performed using Statistica 6.1 Software (Statsoft Inc., Tulsa, Oklahoma) and R-language (R Foundation, Free Software Foundation, Boston, Massachusetts).
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Results |
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Change in plaque composition along the study vessel. Fibrous tissue was the most prevalent component of plaque composition in each analyzed segment throughout the 2 models, followed by fibrolipidic tissue, necrotic core and calcium (Table 3). No significant change was observed in terms of relative plaque composition throughout the study vessel with respect to fibrous and calcified tissue content. The percentage of fibrolipidic tissue decreased in the second and third 6-mm segment when contrasted to the LMS. When compared to the sixth coronary segment, however, no difference emerged among the vessel tracts in terms of fibrolipidic content at post-hoc analysis.
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6 mm and long LMS >6 mm). These 2 groups did not differ in terms of baseline and procedural characteristics. When each coronary segment was separately analyzed, no difference emerged between the 2 groups for IVUS-derived quantitative vessel analysis. The same held true if all 384 coronary segments were cumulatively considered independently from their anatomical location. Calcium, fibrous, and fibrolipid content did not differ between the 2 groups (data not shown). The pattern of necrotic distribution in relation to LMS length is shown in Figure 3.
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Discussion |
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These findings have been recently confirmed by mapping the distribution of angiographic sites of occlusive or nonocclusive culprit lesions along the coronary arteries in patients with ST-segment elevation ACS (2,3).
The reason why vulnerable plaques show a tendency to cluster in partially predictable hot spots located within the proximal tracts of coronary vessel is largely unknown. Atherosclerotic plaques also cluster within the proximal portions of the 3 major coronaries (17–20). Thus, the risk to undergo rupture may be identical for each coronary plaque independently from its anatomical location, being rupture simply more likely to occur where atherosclerotic plaques are more frequently clustered (21). This may easily explain the nonuniform distribution of ruptured or prone-to-rupture plaques without calling into question the idea that plaque rupture is partially a site-specific phenomenon.
Alternatively, plaques located within the proximal third of each coronary may harbor some specific hallmark of vulnerability which makes them individually more likely to undergo rupture. To gain some insights into this topic of debate, we hypothesized that plaque necrotic core content, which is a well-known determinant of vulnerability (7,8,22), may differ along the coronary vessel, being greater at the spots where plaque rupture is known to be more frequent.
Our main findings can be summarized as follows:
Some preliminary unpublished findings by our group suggest that plaque necrotic core content, as assessed through IVUS-VH, may be the only independent predictor for mechanically deformable regions (high-strain spots) (23) throughout the coronary arteries in humans. Thus, when our findings are put in perspective of current evidence, they support the idea that vulnerability may cluster in necrolipid-rich regions throughout the vessel.
Necrotic core content in the present study was greater in patients with ACS, suggesting again that plaque composition in itself may play a pivotal role in determining vulnerability. Interestingly, it was recently reported that when rupture of coronary plaques occurs in the LMS, the distal half of LMS is more likely to be involved (24). Our findings that the distal LMS tends to harbor a greater necrotic core content compared with proximal half, together with the well-established role of shear stress in bifurcated lesions (25), may contribute to explain the nonuniform distribution of plaque rupture even within the LMS.
The reasons why the plaque necrotic core seems to exceed in the proximal as compared with the distal tracts of the coronary vessel or the LMS remain speculative at the present time. Low-oscillatory shear stress is known to induce a loss of the physiological flow-oriented alignment of the endothelial cells, an enhancement of the expression of adhesion molecules, and a weakening of cell junctions, ultimately leading to an increase in permeability to lipids and macrophages (25). The segments located in the first few centimeters of the coronary arteries, because of flow turbulence generated by high-velocity blood impacting against anatomical flow dividers (26), may be more exposed to low-oscillatory shear stress compared with the most proximal (i.e., LMS) or more distal coronary segments, thus possibly explaining our present findings (27). Concomitant quantitative measurement of shear stress and plaque composition along coronary vessels in vivo would be pivotal in corroborating this working hypothesis.
Study limitations. On the basis of previous findings and the well-known role of necrotic core content in determining vulnerability (6–8,22), our investigation was primarily focused on the distribution of necrotic core content along the left coronary artery. To assess relatively minor changes in plaque composition along the longitudinal artery axis, such as that observed for fibrous tissue, a larger, properly powered sample size is clearly needed. In keeping with previous considerations, all other analyses and comparisons performed in the current report should be regarded as exploratory and hypothesis-generating because we cannot rule out the possibility that inflation of type I error due to multiple comparisons may have confounded our results.
In our study, the operators were left free to wire the most suitable vessel for the IVUS pullback, provided it was supplying a major left ventricle territory, which resulted in the predominance of LAD as a region of interest, whereas the CFX artery was mainly investigated in those patients presenting with small or tortuous LAD. The distribution of necrotic core along the vessel did not differ in LAD as compared with CFX. The same held true for other studied plaque components. However, the applied selection process may have biased this comparison. Thus, whether the distribution of plaque composition may differ in relation to the studied vessel remains to be tested. Similarly, to maximize patients’ safety and avoid potential IVUS-related complications, individuals with severe angiographic calcification were excluded. Despite the fact this decision may have clearly contributed to generate some selection bias, the distribution of calcium along the coronary vessel intriguingly mirrored the one observed for the necrotic core. Further studies are needed to investigate the specific role of calcium content in determining plaque vulnerability.
Patients with proximal occlusions have bigger myocardial ischemia and, thus, they are more likely to present to hospital and be referred for angioplasty. Similarly, myocardial infarction with LMS as culprit artery often may result in immediate death. Thus, it may be argued that a selection bias might have artificially increased the prevalence of patients with culprit lesions located in the proximal compared to distal tracts of coronaries or LMS. This is obviously theoretical possible. However, for the following reasons, we believe that this possibility is relatively unlikely:
Summary and conclusions. Plaque composition was found to be not uniformly distributed along the left coronary artery with a progressive increase in necrotic core starting from the proximal half of the LMS to the most proximal segments of the LAD or CFX, followed by a steady decline toward those segments which are more distally located along the vessel. The necrotic core appeared to be increased in patients with ACS, especially in the LMS and in the 3 proximal coronary segments of LAD or CFX, whereas it did not correlate with the CRP or lipid profile. The relatively site-specificity of necrotic core content toward the proximal segment of the left coronary artery is in keeping with the increasing evidence that a clear clustering of ruptured or prone to rupture plaques occurs in humans within this region (2,3,5). Our findings 1) reinforce the notion the plaque composition may be a major determinant for and subsequently a potential target of plaque vulnerability in humans and 2) call for prospective evaluation of the independent role of plaque composition on long-term outcome in patients with established coronary artery disease.
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Footnotes |
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This article has been cited by other articles:
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  A. N. DeMaria, J. J. Bax, O. Ben-Yehuda, P. Clopton, G. K. Feld, G. S. Ginsburg, B. H. Greenberg, J. D. Knoke, W. Y.W. Lew, J. A.C. Lima, et al. Highlights of the year in JACC 2007. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 490 - 512. [Full Text] [PDF]
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