Author + information
- Received December 1, 2005
- Revision received February 28, 2006
- Accepted March 7, 2006
- Published online January 2, 2007.
- Marco Valgimigli, MD, PhD,
- Gastón A. Rodriguez-Granillo, MD, PhD1,
- Héctor M. Garcia-Garcia, MD,
- Sophia Vaina, MD, PhD,
- Peter De Jaegere, MD, PhD,
- Pim De Feyter, MD, PhD and
- Patrick W. Serruys, MD, PhD⁎ ()
- ↵⁎Reprint requests and correspondence:
Prof. Patrick W. Serruys, Thoraxcenter, Bd-406, Dr Molewaterplein 40, 3015-GD Rotterdam, the Netherlands.
Objectives We sought to investigate whether plaques located in the left main stem (LMS) differ in terms of necrotic core content from those sited in the proximal tract of the left coronary artery.
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.
The distribution of ruptured or prone-to-rupture plaques is known to be nonuniform throughout the coronary tree (1–5). Pathological studies have suggested the so called “thin-cap atheromas”—necrotic-rich core plaques at high risk for rupture—are infrequent in the left main stem (LMS) and in the distal tracts of the coronary vessels, whereas they group together with ruptured and healed plaques in the proximal segments of the 3 main coronary arteries (1).
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.
Study protocol and patient enrollment
This was a single-center, investigator-driven, observational study aimed at evaluating the distribution of plaque composition along the left coronary artery in consecutive patients referred to our institution for elective or urgent percutaneous coronary intervention in whom the nonculprit, nontreated vessel was judged suitable for a safe IVUS 35-mm pullback or more, based on angiographic (absence of the following: >50% stenotic disease, extensive calcification, severe vessel tortuosity) and clinical (hemodynamic stability) findings.
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] × 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).
Antecubital venous blood was collected from all patients at entry, left in ice for 45 min, centrifuged at 1,700 gat 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.
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 ttest. 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).
From December 11, 2003, to July 27, 2005, 72 patients were prospectively included in the protocol. Twenty-four patients were subsequently excluded from the final analysis because of short (<36 mm) IVUS pullback in 16, uncertainty regarding the true interface lumen-vessel wall based on IVUS grey-scale in 4 and occurrence of angiographically confirmed deep intubation of the guiding catheter during the pullback in 4 patients. Thus, 48 patients (32 men), ages 30 to 75 years (mean age, 57 ± 11 years) constituted the final patient population. Their baseline characteristics are provided in Table 1.
The study vessel was the LMS and the LAD artery in 34 (71%) patients and LMS and CFX in 14 (29%). The overall LMS length was 7.49 ± 4 mm (median [IQR], 6 [4.8 to 9.3]; range, 3.4 to 20) in the SA group versus 7.8 ± 5 mm in the acute coronary syndromes (ACS) group (p = 0.64). Lumen and vessel CSAs decreased significantly, starting from the first 6-mm segment of the coronary artery as compared with LMS (Table 2).Plaque CSA in the LMS was significantly increased only compared with the most distal 6-mm segment. The degree of plaque eccentricity was relatively constant throughout the vessel except in the LMS carina, where it resulted to be higher compared with both the LMS and the coronary segments distal to the first one. Plaque burden did not change along the vessel in model 1, despite a trend being progressively increased from proximal to distal.
Model 2 (Table 2), in which LMS has been stratified into the proximal and distal segment after selection of those patients (n = 24) with long LMS (length >6 mm), mainly confirmed the trends observed along the vessels in model 1.
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.
The necrotic core increased significantly in the first, second, and third 6-mm segment compared with the LMS. When the most distal segment of the study vessel was taken as reference, the necrotic core remained greater in both the first and second 6-mm segment at post-hoc analysis. As shown in Figure 1,the necrotic core was the plaque component with the highest relative change along the vessel. Changes in terms of plaque composition in model 2 are shown in Table 3.
Change in plaque composition according to clinical presentation
No significant change in calcium, fibrous, and fibrolipidic content with respect to clinical presentation (stable vs. unstable) was observed when all 384 coronary segments were pooled together (Fig. 2).Necrotic core (%) was significantly increased in patients with (median [IQR]: 11.4 [5.5 to 19.8]) as compared with those (median [IQR]: 7.3 [3.2 to 12.9]) without ACS (p < 0.001) (Fig. 2). After introducing anatomical location stratified into 8 coronary segments in the model, the increase in necrotic core in patients with ACS was mainly confined to the LMS (6.9 [2.6 to 9.4] vs. 3.5 [1.4 to 6.2] in stable patients; p = 0.02), in the first (14.9 [7.7 to 19.6] vs. 11.5 [4.9 to 17.3] in stable patients; p = 0.03), second (12.2 [5.5 to 16.1] vs. 9.4 [5.1 to 20.6] in stable patients; p = 0.03), and third 6-mm coronary segment (11.4 [5.4 to 15] vs. 8 [3.6 to 14.4] in stable patients; p = 0.04). However, the statistical interaction between necrotic core and the anatomical location of the segments did not reach the significance (p = 0.12).
Length of LMS as a predictor of plaque composition along the study vessel
Patients were stratified into 2 groups based on median LMS length (short LMS ≤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.
In a segment-based analysis, necrotic core was largely independent from plaque area (r = 0.17; p = 0.06; R2= 0.09) (Fig. 4).Similarly, we failed to find an association between necrotic core content and CRP levels (r = 0.09, p = 0.8), level of LDL cholesterol (p = 0.11, p = 0.23), or HDL cholesterol (r = −0.2, p = 0.4) at entry. However, there was a significant, although weak, direct correlation between necrotic core and cholesterol/HDL ratio (r = 0.18, p = 0.01; R2= 0.1).
There is increasing evidence that the distribution of ruptured or prone-to-rupture plaques is not uniform along the coronary vessel: they cluster in the proximal tract of the 3 major coronary vessels whereas they tend to spare both the LMS and distal segments of coronary arteries (4,16).
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:
1. The plaque necrotic content was minimal in the LMS, particularly in the most proximal tract, whereas it peaked in the first 6-mm segments after the ostium of the 2 major left coronaries, progressively decreasing toward the more distal segments.
2. The plaque CSA was largely unrelated to necrotic core content throughout the left coronary vessel. This statement is supported by the absence of correlation between necrotic content in plaques and plaque CSA at the segment-based analysis and by the observation that plaque CSA showed a progressive increase in the distal-proximal direction along the vessel whereas plaque necrotic content did not.
3. The necrotic core was greater in patients with clinical instability presenting with ACS compared to those affected by stable atherosclerotic disease.
4. The necrotic core content was not related to systemic inflammatory status, as measured by a well-recognized prognostic marker of inflammation such as CRP nor LDL or HDL alone, whereas it showed a significant although weak correlation to cholesterol/HDL ratio.
5. The length of left main trunk was shown to affect the distribution of necrotic core along the vessel. In patients with long LMS, necrotic core content peaked immediately in the first coronary segment after LMS and rapidly decreased distally. Conversely, the necrotic core content peaked in the second 6-mm segment in patients with short LMS and it resulted to be increased in the 2 most distally analyzed segments compared to the long LMS group.
It is tempting to speculate that the observed clustering of ruptured or prone-to rupture plaques in the proximal segment of each coronary artery is not just a simple reflection of the nonuniform distribution of atherosclerosis along the coronary vessel. The necrotic content of those plaques located in these proximal segments, independent of their size, was greater, both compared with the LMS and with those segments that are more distally located. The plaques located within the proximal segments of the left coronary artery, being relatively richer in necrotic content, may undergo rupture more easily than those located in the LMS or in the distal tracts of the vessel.
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.
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:
1. The necrotic core in our series clustered in the same coronary spots in which previous studies, based on postmortem examination, found a greater prevalence of ruptured or healed plaques.
2. Our results are based on the investigation of the nonculprit vessel. Thus, they are potentially less prone to suffer from clinical selection due to the location of the culprit lesion in the culprit vessel.
3. Although it seems to be exacerbated in patients presenting with clinical instability, the nonuniform distribution of plaque composition along the vessel also has been observed in patients with stable coronary disease, in whom the selection bias due to the importance of the culprit lesion is less obvious, at least for the comparison LMS versus proximal tracts of LAD or CFX.
Thus, based on these considerations, we think that our findings, especially when put in the context of previous evidence (1–5), may help reinforcing the notion that there may be some hot spots along the coronary vessel which are per se more prone to develop vulnerable plaque and as such undergo plaque rupture.
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.
↵1 Dr. Rodriguez-Granillo has received a research grant from Volcano Corp.
- Abbreviations and Acronyms
- acute coronary syndrome
- circumflex artery
- C-reactive protein
- cross-sectional area
- external elastic membrane
- high-density lipoprotein
- interquartile range
- intravascular ultrasound
- left anterior descending artery
- low-density lipoprotein
- left main stem
- virtual histology
- Received December 1, 2005.
- Revision received February 28, 2006.
- Accepted March 7, 2006.
- American College of Cardiology Foundation
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