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Arterial Remodeling Correlates Positively with Serological Evidence of Inflammation in Patients with Chronic Stable
Angina Pect
January 2006
The development and even progression of coronary atherosclerotic lesions may occur without compromising the lumen in the early phases due to outward growth of the vessel wall; a concept known as “positive” or “outward” arterial remodeling.1 Remodeling of the arterial wall is an important mechanism in determining luminal narrowing of native atherosclerotic lesions1–4 and restenosis after percutaneous coronary interventions.5–7 Moreover, data have suggested that arterial remodeling may be “negative” or “inward”, even in the early stages of plaque development.3 Recently, an association has been identified between the degree of coronary artery remodeling and unstable coronary syndromes. Two recent studies have shown an association between positive arterial remodeling and both unstable angina pectoris and acute myocardial infarction.8,9
Inflammatory processes, both cellular and humoral, appear central in all stages of atherogenesis, from the nascent atherosclerotic plaque, through to disruption and thrombosis of a complex vulnerable atherosclerotic lesion.10 The adherence and migration of the cellular components of inflammation are mediated by cellular adhesion molecules (CAMs), whereas the selectins appear important in initiating the rolling of leukocytes across the endothelial surface. These “adhesion molecules” are known to be found in increased levels within atherosclerotic lesions compared with the normal arterial wall, and although difficult to estimate, assays exist that allow the estimation of the soluble forms of these molecules. Preliminary data have shown that some of these soluble adhesion molecules may be elevated in patients with clinical atherosclerotic diseases,11 however, there is conflicting evidence to the contrary. Furthermore, some of these molecules, such as high-sensitivity C-reactive protein (hsCRP), intercellular adhesion molecule (sICAM-1), and interleukin-6 (IL-6) have been shown to predict risk of subsequent cardiovascular events, although opinion is conflicting here as well.12
In patients with chronic stable angina pectoris, it is unclear whether arterial remodeling may predict risk of a future acute coronary event. Thus, we sought to prospectively investigate the relationship between a select group of soluble inflammatory markers (hsCRP, sVCAM-1, sICAM-1, and E-selectin) and the degree of arterial remodeling in patients with stable angina pectoris.
Methods
Study population. Patients with known coronary artery disease scheduled for a percutaneous coronary intervention, but with stable symptomatology, were eligible for enrollment. At the time of the procedure, information regarding patient demographics was obtained, including cardiovascular risk factors and current medications. All patients participating were required to give informed consent. Ethics committee approval was provided by the Monash University Human Ethics Committee (Melbourne, Australia).
Intravascular ultrasound imaging. A 2.9 Fr (Ultracross) or 3.2 Fr (Atlantis) mechanical imaging catheter (Boston Scientific Corp., Natick, Massachusetts) with a single element transducer was used. Intracoronary glyceryl trinitrate (100 µg) was given during all IVUS studies before imaging. All IVUS studies were recorded on high-resolution super VHS tapes for offline analysis. Quantitative (cross-sectional) analysis of the IVUS images was performed using a commercially available software program (Tape Measure, Indec Corp., Mountain View, California). Plaque plus media cross-sectional area was used as a surrogate of plaque area, because media thickness cannot be measured accurately at imaging frequencies between 20 and 40 MHz. For each cross-section, vessel wall area, lumen area, plaque area (vessel area minus lumen area), and percent area stenosis (plaque area divided by vessel area x 100) were made. Cross sections with excessive calcification (calcium arc > 90°) were excluded from analysis because of acoustic shadowing of deeper structures precluding measurement of the vessel area. In each coronary artery, a 10–20 mm vessel segment was identified in which the most severe stenosis was included and no side branches were observed.
Three sites were selected for analysis: the lesion site that had the smallest lumen area by IVUS and > 50% area stenosis, and the proximal and distal reference sites that had the largest lumen area and Measurement of soluble inflammatory markers. Blood samples were collected at the time of the IVUS study, and the serum stored at -80ºC until analysis. Serum concentrations of ICAM-1, VCAM-1 and E-selectin were performed by an investigator experienced with enzyme immunoassay, blinded to the patient clinical and IVUS data, using commercially available ELISA assays and standards (R&D Systems, Inc., Minneapolis, Minnesota). Specimens were analyzed for CRP with a highly sensitive particle-enhanced turbidometric immunoassay technique (Dade Behring, Inc., Deerfield, Illinois) by the same blinded investigator.
Statistical analyses. All soluble inflammatory marker levels were analyzed for normality. If normality was not identified, then log-transformed values of these measures were analyzed and utilized as appropriate.
The RI was assessed and analyzed as both a categorical and continuous variable. Defining arterial remodeling as either “positive” or “negative”, using the criteria described previously, comparisons with levels of soluble inflammatory markers was performed, using two-way analysis of variance techniques. The RI was assessed as a continuous variable and comparisons with the various soluble inflammatory markers performed using linear regression analyses, both univariate and with stepwise multivariate correction. All probabilities are two-sided with statistical significance taken as p Demographic data. The information regarding patient characteristics is presented in Table 1.
Arterial remodeling. Of the 31 patients, using the previously defined criteria, 10 patients had positive remodeling (mean RI 1.18 ± 0.03), and 14 had negative remodeling (mean RI 0.83 ± 0.03) at the index site (Figures 1 and 2). The mean RI of all 31 patients was 0.98 ± 0.03. Of note, there were no significant differences between these positive and negative remodeling groups regarding the presence of any cardiovascular risk factors or medications (p = NS).
Soluble markers of inflammation. The distribution of data for levels of soluble inflammatory markers was not normal, and thus log transformation was performed, as the data followed a lognormal distribution.
Categorical analyses of RI with soluble markers of inflammation. By defining arterial remodeling as simply positive or negative, and analyzing this nominal variable with the continuous variables of levels of soluble inflammatory markers, significant differences were identified for E-selectin only. The mean log transformed values for E-selectin in the group with positive versus negative remodeling was 1.80 ± 0.04 versus 1.62 ± 0.05, respectively (p = 0.02). Although not reaching statistical significance, there was a strong trend toward a difference for sICAM-1 in the group with positive versus negative remodeling (2.52 ± 0.03 versus 2.43 ± 0.03, respectively; p = 0.06). There was no significant difference between the two groups for either sVCAM-1 (p = 0.23) or hsCRP (p = 0.81).
Continuous analyses with RI and soluble markers of inflammation. Using the actual values of remodeling index obtained for each patient and performing linear regression analyzes with soluble markers of inflammation, there were significant correlations identified for both sVCAM-1 and sICAM-1. The log sVCAM-1 and RI correlation coefficient was 0.38 (p = 0.04), and the log sICAM-1 and RI correlation coefficient was 0.42 (p = 0.02). The log E-selection and RI correlation coefficient, although weaker at 0.32, showed a trend toward significance (p = 0.08). There was no significant correlation between log hsCRP and RI (p = 0.42).
Using stepwise multivariate analysis, correcting for age, body-mass index, hypertension, diabetes mellitus, total cholesterol level and smoking status, log sVCAM-1 only remained an independent predictor of the RI (p = 0.03), with log sICAM-1 no longer statistically significant (p = 0.10).
Discussion
In this group of patients with stable angina pectoris undergoing percutaneous coronary intervention, we identified a positive relationship between arterial remodeling at the culprit site and systemic markers of inflammation. This may represent a sub-population of patients at greater risk for an adverse outcome from coronary intervention or at greater risk of an acute coronary event in the future.
The association between the degree of coronary artery remodeling and unstable coronary syndromes has been identified in a number of studies. Two recent studies have shown an association between positive arterial remodeling and both unstable angina pectoris and acute myocardial infarction.8,9 However, what is unclear is by what mechanism the positive arterial remodeling leads to unstable syndromes. Cardiovascular risk factors have been suggested as predictive of the degree of arterial remodeling, but with some conflicting results. In one study in patients undergoing percutaneous coronary intervention, there were no plaque characteristics as identified by IVUS that predicted arterial remodeling, nor were any risk factors predictive of negative remodeling apart from smoking, which was associated with negative remodeling.4 However, histopathological studies of arterial remodeling have not found an association between smoking and negative remodeling.3,13 Lipoproteins have been described in relation to arterial remodeling, and HDL level was correlated with positive arterial remodeling in the aforementioned histopathological study. One small IVUS-based study found an association between total cholesterol levels and positive arterial remodeling,14 although this has not been confirmed by the other larger studies. Thus, there is no clear association between any cardiovascular risk factors and the degree of arterial remodeling in the literature, consistent with the lack of association between any risk factors and arterial remodeling found in our study population, although clearly our study was not powered to exclude such an association.
The pathogenesis of the acute coronary syndromes is frequently related to atherosclerotic plaque disruption and subsequent thrombosis and the composition of the plaque has been well described as a critical determinant of both risk of rupture and subsequent thrombogenicity. In particular a large lipid core and a thin fibrous cap render a lesion susceptible or vulnerable to disruption and thrombosis. Therefore, the association between positive arterial remodeling and unstable coronary syndromes could be related to plaque composition. One study showed that IVUS-identified “soft” plaques were associated with positive arterial remodeling, and “fibrocalcific” plaques with negative arterial remodeling.15 However, in that study, plaques were divided into one of only two groups, either “soft” or “fibrocalcific” on the basis of echogenicity relative to the surrounding adventitia. This simplistic differentiation has limited ability to accurately characterize atherosclerotic lesions. Other IVUS-based studies, however, have corroborated this finding.4 In contrast, a large-scale histopathological study, using the AHA classification of lesion morphology, failed to identify any lesional characteristics that were associated with arterial remodeling.3 However, recent histopathological studies in patients with acute myocardial infarction and sudden death did show a correlation between lipid core size and macrophage-positive areas with positive arterial remodeling.8,16
The “vulnerable” atherosclerotic lesion responsible for the majority of cases of acute coronary syndromes is associated with an increase in inflammatory cells within the plaque, including macrophages and T-cells. The accumulation of lipidic material within macrophages leads to their transformation into foam-cells. Lipid-laden macrophages have been postulated to be responsible for the vulnerability of atherosclerotic lesions via the production of matrix-degrading substances (in particular, the matrix metalloproteinases and heparinases).17 In addition, they play a central role in determining the thrombogenicity of a given atherosclerotic lesion upon disruption, mediated by tissue factor.1,8,19 Humoral, as well as cellular, components of inflammation are elevated within these vulnerable atherosclerotic lesions, and the soluble forms of these factors are measurable within serum. Some of these molecules, such as high-sensitivity C-reactive protein (hsCRP), intercellular adhesion molecule-1 (sICAM-1) and interleukin-6 (IL-6), have been shown to predict risk of subsequent cardiovascular events.20 Both ICAM-1 and VCAM-1 vascular cellular adhesion molecules are expressed by endothelial cells and macrophages and have been identified atop human atheroma.21 Levels of hsCRP have been the most extensively studied to date, and hsCRP has been shown to predict future risk among patients with both stable and unstable coronary syndromes, post-myocardial infarction and post-percutaneous coronary intervention.22 Cardiovascular risk factors are also associated with elevated levels of such soluble inflammatory markers, in particular diabetes and smoking, which have been correlated with hsCRP, E-selectin, sICAM-1, and IL-611.23,24
In patients with chronic stable angina pectoris, it is unclear whether arterial remodeling may predict risk of a future acute coronary event. Furthermore, there have been no studies, to our knowledge, addressing the potential association between soluble markers of inflammation and arterial remodeling. Our study shows that in univariate analyses, both sICAM-1 and sVCAM-1 showed a modest, but statistically significant, correlation with the degree of arterial remodeling, with a trend toward correlating arterial remodeling with E-selectin levels. However, only sVCAM-1 levels remained significantly correlated with arterial remodeling after multivariate analysis.
Interestingly, there was no significant association with hsCRP and arterial remodeling in this study. This lack of association warrants further consideration especially in light of recent data questioning the independent predictive role of hsCRP for future cardiovascular events.25
Our study contains a relatively small sample size, and this may limit our ability to detect a statistically significant association between RI and the levels of the soluble markers of inflammation studied. However, this study was performed with a prospective and consecutive design, and the significant results obtained should form the basis of further investigation with larger numbers, addressing the association between RI and soluble markers of inflammation in both stable and unstable coronary syndromes. We found a larger percentage of patients with negative versus positive arterial remodeling (45% versus 32%) in our study. However, this is consistent with other studies of arterial remodeling in patients with stable angina pectoris. Clearly, further studies in patients with unstable coronary syndromes are required to address the association of soluble markers of inflammation and arterial remodeling.
We have demonstrated a significant positive association between levels of both sVCAM-1 and sICAM-1 with positive arterial remodeling in patients with stable angina pectoris. This suggests that inflammatory processes may play a role in positive arterial remodeling, and implies a potential mechanism whereby positively remodeled atherosclerotic lesions may be prone to disruption and subsequent thrombosis. Further studies addressing these issues are warranted.
Ethics approval. Ethics approval was provided by the Monash University Human Ethics Committee (Melbourne, Australia).
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