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Am J Physiol Heart Circ Physiol 294: H2831-H2837, 2008. First published April 25, 2008; doi:10.1152/ajpheart.91428.2007
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Mild inflammatory activation of mammary arteries in patients with acute coronary syndromes

Chiara Foglieni,1 Francesco Maisano,1 Lorella Dreas,2 Alessio Giazzon,1 Giacomo Ruotolo,1 Elisabetta Ferrero,3 Laura Li Volsi,1 Stefano Coli,1 Gianfranco Sinagra,2 Bartolo Zingone,2 Ottavio Alfieri,1 Anton E. Becker,1 and Attilio Maseri1

1Clinical Cardiovascular Biology Laboratory and Cardiac Surgery Unit, Cardiothoracic and Vascular Department, University Vita-Salute, San Raffaele Scientific Institute, Milano; 2Cardiac Surgery Unit, Ospedali Riuniti, Trieste, Italy; and 3Laboratory of Tumor Immunology and Department of Oncology, San Raffaele Scientific Institute, Milano, Italy

Submitted 10 December 2007 ; accepted in final form 23 April 2008


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
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Acute coronary syndromes (ACS) are characterized by multiple unstable coronary plaques and elevated circulating levels of inflammatory biomarkers. The endothelium of internal mammary arteries (IMA), which are atherosclerosis resistant, is exposed to proinflammatory stimuli as vessels that develop atherosclerosis. Our study investigated the IMA endothelial expression of inflammatory molecules in patients with ACS or chronic stable angina (CSA). IMA demonstrated normal morphology, intact endothelial lining, and strong immunoreactivity for glucose transporter 1. E-selectin expression was observed more frequently in IMA of ACS patiention than CSA patients (ACS 61% vs. CSA 14%, P = 0.01). High fluorescence for major histocompatibility complex (MHC) was significantly more frequent on the luminal endothelium (ACS 66.7% vs. CSA 17.6%, P = 0.001 for class I; and ACS 66.7% vs. CSA 6.2%, P = 0.0003 for class II-DR) and on the vasa vasorum (ACS 92.9% vs. CSA 33.3% and 7.7%, P = 0.0007 and P < 0.0001 for class I and class II-DR, respectively) of ACS patients than CSA patients. ICAM-1, VCAM-1, Toll-like receptor 4, tissue factor, IL-6, inducible nitric oxide synthase, and TNF-{alpha} expression were not significantly different in ACS and CSA. Circulating C-reactive protein [ACS 4.8 (2.6–7.3) mg/l vs. CSA 1.8 (0.6–3.5) mg/l, P = 0.01] and IL-6 [ACS 4.0 (2.6–5.5) pg/ml vs. CSA 1.7 (1.4–4.0) pg/ml, P = 0.02] were higher in ACS than CSA, without a correlation with IMA inflammation. The higher E-selectin, MHC class I and MHC class II-DR on the endothelium and vasa vasorum of IMA from ACS patients suggests a mild, endothelial inflammatory activation in ACS, which can be unrelated to the presence of atherosclerotic coronary lesions. These findings indicated IMA as active vessels in coronary syndromes.

endothelium; E-selectin; major histocompatibility complex class I; major histocompatibility complex class II-DR

CORONARY ARTERY DISEASE (CAD) is characterized by coronary atherosclerosis, and multiple and/or complex coronary plaques frequently prevail in patients with acute coronary syndromes (ACS) (4, 10, 17, 26, 31, 39) than in patients with chronic stable angina (CSA) (29, 36). However, in patients with CAD, the atherosclerotic lesions only rarely and scarcely affect arteries, such as the internal mammary artery (IMA) (30), which is commonly used for coronaroaortic bypass graft (CABG).

Inflammation plays a main role in the pathogenesis of CAD (19), and both atherosclerotic-prone and -resistant vessels of CAD patients are exposed to systemic proinflammatory stimuli, particularly to biomarkers. Among them, C-reactive protein (CRP) and IL-6 are frequently more elevated in ACS patients than in CSA patients (27) and may be associated with recurrent instability (6, 7).

Therefore, one important issue to understand is whether vessels nonsusceptible to atherosclerosis are unresponsive to inflammatory stimulation or respond following a different way. A wide immunogenic repertoire, suggestive of vascular heterogeneity (8, 34, 35), has been described for the endothelium of several vessels, indicating a different phenotype for coronary and internal mammary arteries (IMA). The endothelial cell phenotype (2) can be also influenced by the local environment; in sclerotic arteries, the systemic proinflammatory scenario may induce endothelial upregulation of adhesion molecules (i.e., VCAM-1, ICAM-1, and selectins), tissue factor, and Toll-like receptors (TLR) and an alteration of nitric oxide synthase (NOS) activity (12, 13, 48). The reactivity of arteries not prone to atherosclerosis is still poorly known (35, 49).

Therefore, we undertook a study in patients with ACS or CSA to investigate whether IMA, which are typically atherosclerosis resistant, respond to systemic inflammatory stimuli by exhibiting evidence of vascular endothelial inflammatory markers by comparing patients with ACS, which is typically characterized by elevated circulating inflammatory markers, and patients with CSA, who typically do not exhibit elevated circulating inflammatory markers.


   METHODS
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 METHODS
RESULTS
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Patients. IMA specimens were consecutively collected from 32 patients undergoing coronary bypass surgery (CABG). Fifteen patients had ACS, with five patients in the setting of myocardial infarction and ten patient in the setting of unstable angina. Seventeen patients scheduled for elective CABG because of chronic stable angina with stable symptoms for at least the last 6 mo served as controls. All patients were men except for one woman with chronic stable angina. Nine ACS and six CSA patients had cardiac extracorporeal circulation during the CABG procedure, and seventeen patients were operated with beating hearts. From each patient, the following clinical data were obtained: age (range: 40–85 yr), presence of hypercholesterolemia (total plasma cholesterol concentration >200 mg/dl or ongoing lipid-lowering drug therapy), hypertension (any history of elevated blood pressure requiring antihypertensive therapy or a systolic blood pressure >140 mmHg and/or a diastolic blood pressure >90 mmHg in >2 measurements in hospital), active smoking, and ACS family history. Patients with inflammatory diseases, insulin-dependent diabetes, or previous ACS were excluded. The institutional ethic committee approved the protocol, and all patients gave their informed consent.

Serological measurements. Peripheral blood samples were taken on the day before surgery and processed to obtain multiple microvials of serum and plasma. High-sensitivity CRP (hsCRP) and IL-6 levels were determined using high-sensitivity ELISA assays (from DBC, London, ON, Canada, and R&D Systems, Minneapolis, MN, respectively); HDL, LDL, total cholesterol, triglyceride, and glucose contents were measured by automated routine systems.

Biopsy processing. Immediately after excision, distal left IMA segments exceeding the length required for the graft but at least 1.5 cm long were rinsed in 0.9% saline solution and sequentially cut into 1- to 1.5-mm-thick rings perpendicularly to the vessel length. Perivascular fat was left to preserve the vasa vasorum. Up to three artery rings were embedded in Killik medium in the same mold (BioOptica, Milano, Italy), snap frozen in iso-pentane (Sigma-Aldrich, Milano, Italy) and liquid nitrogen, and then stored at –80°C.

Histology and confocal microscopy. Histology was performed on 4-µm-thick cross sections adhered to poly-L-lysine-coated glass slides. Hematoxylin and eosin or Movat's pentachrome evaluated the absence of vascular damage consequent to the harvesting procedure and of IMA wall remodeling. The presence of adventitial vasa vasorum and infiltrating inflammatory cells was also assessed. An Eclipse55i microscope equipped with a DS-L1 camera (Nikon, Tokyo, Japan) was used by a pathologist that worked blindly. The endothelial presence was confirmed on serial sections by immunofluorescence against the constitutive endothelial markers CD31/PECAM-1 [identified by monoclonal antibody (MAb) anti-CD31/PECAM-1, clone M89D3].

The presence of endothelial inflammatory activation was assessed by confocal microscopy on 10-µm-thick serial sections submitted to the following panel of antibodies: MAb anti-E-selectin (clone P2H3, Chemicon, Temecula, CA), MAb anti-VCAM-1 (clone 1.4c3, Chemicon), MAb anti-major histocompatibility complex (MHC) class I (clone W6/32, DAKO, Carpinteria, CA), MAb anti-MHC class II-DR [clone D1-12, specific for the DR epitope, a kind gift of R. Accolla (1)], polyclonal antibody (PAb) anti-IL-6 (R&D Systems), PAb anti-glucose transporter 1 (GLUT1, DAKO), MAb anti-human tissue factor type I (clone 9.BG.19, US-Biological, Swampscott, MA), PAb anti-TLR4 (Santa Cruz Biotechnology, Santa Cruz, CA), MAb anti-TNF-{alpha} (clone 1E8-G6, Santa Cruz Biotechnology; revealed either by rabbit anti-mouse IgG-Alexa fluor 594 or donkey anti-rabbit IgG-Alexa fluor 488, Molecular Probes, Eugene, OR), and MAb anti-inducible NOX (iNOS)-FITC conjugated (clone 6, BD Bioscience, Franklin Lakes, NJ). Nuclear fragmentation was assessed by 4,6-diaminidino-2-phenylindole (Sigma-Aldrich) stain. Sections were examined within 24 h of immunolabeling by a Leica TCS SP2 AOBS (Leica Microsystems, Wetzlar, Germany) confocal microscope. z-Series were collected from single channels, processed to obtain free projection max images by Leica confocal software, and finally merged by Adobe Photoshop. Sections from one IMA stained for CD31/PECAM-1 were included in every experiment as a positive reference standard for the settings of the confocal microscope. The reproducibility of semiquantitative analysis was assessed on seven IMA specimens by evaluating 2 sections/marker in two different stainings.

The presence and expression intensity of each marker were assessed blindly, and semiquantitative evaluation was applied with a three-grade scoring system (bright, moderate, and weak/absent fluorescence). Scoring was reduced to a two-grade system when opportune (weak/absent vs. bright). The percentage of patients for each grade was calculated and submitted for statistical analysis (22).

Statistics. Based on preliminary results, a two-proportion power analysis was applied, which, for a group size of n = 15, provides a 80% power to detect a difference of 0.5 between the null hypothesis and the alternative using a two-sided {chi}2-test and a significance level of 0.05.

Data are presented as means ± SD. IL-6 and CRP levels had a skewed distribution and were therefore log transformed before being used in statistical analyses; however, in Table 1, we show untransformed medians and corresponding interquartile ranges (IQRs).


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  		Table 1. Baseline clinical characteristics of patients

 
Data were analyzed using JMP 6.0 software (SAS Institute). Continuous data were compared with a Wilcoxon signed-ranks test, whereas categorical variables were compared with a {chi}2-test. Probability values of <0.05 were considered statistically significant.

Multivariate analysis was applied to correlate clinical parameters with categorical variables.


   RESULTS
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DISCUSSION
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Clinical data. The main clinical characteristics of ACS and CSA patients are shown in Table 1; the two groups were comparable for risk factors except for a lower consumption of Ca2+ channel blockers (P = 0.04) in ACS patients than in CSA patients.

Patients with ACS had significantly higher circulating levels of inflammatory markers than those in the CSA group [hsCRP: 4.8 (2.6–7.3) vs 1.8 (0.6–3.5) mg/l, P = 0.01; and IL-6: 4.0 (2.6–5.5) vs 1.7 (1.4–4.0) pg/ml, P = 0.02, medians and IQRs]. Lipid profiles and serum glucose levels were not significantly different in the two groups.

Morphological preservation of vascular biopsies. The collected IMA segments demonstrated a preserved morphology, with no cautery burns or discontinuities in the luminal cell linings. CD31/PECAM-1 showed a uniform luminal immunostaining, confirming that the arterial endothelial lining was intact (Figs. 1a and 2a) in IMA of both groups.


Figure 1
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  		Fig. 1. Expression of inflammatory markers on internal mammary arteries (IMA) by confocal microscope. Images from an acute coronary syndrome (ACS) patient demonstrate endothelial lining integrity by CD31/PECAM-1 and the different endothelial distributions of glucose transporter 1 (GLUT1), E-selectin, inducible nitric oxide synthase (iNOS), and Toll-like receptor 4 (TLR4). A: single-channel free projection max (FPM) view at –60° of perspective. Two serial sections are shown from the same artery doubly stained for CD31/PECAM-1 + iNOS and E-selectin + GLUT1. B: a portion of the IMA endoluminal surface strongly expressing TLR4. Inserts, magnified FPM and z-projections from x and y sides to demonstrate the patchy distribution of TLR4. 4,6-Diaminidino-2-phenylindole (DAPI) nuclear dye is superimposed in all images.

 

Figure 2
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  		Fig. 2. Confocal microscopy of major histocompatibility complex (MHC) class I and class II-DR antigens in IMA and the vasa vasorum (VV) from ACS and chronic stable angina (CSA) patients. Comparisons between representative ACS and CSA patients are shown. A: the CD31/PECAM red signal identifies endothelial cells, showing continuous endothelial lining on IMA. FPM of serial sections labeled for MHC class I or MHC class II-DR (red signal) but not ICAM-1 (green signal) shows a striking difference in endothelial signal intensity between ACS and CSA. B: FPM images of the VV (arrows) showing the typical irregular shape. The red signal indicates the labeling of the endothelial wall of the VV by CD31/PECAM, MHC class I, MHC class II-DR, and ICAM-1, respectively, and shows the difference in expression intensities between ACS and CSA. ICAM-1 was low and comparable in both sections, whereas MHC class I and MHC class II-DR were high in sections from the ACS patient and low in sections from the CSA patient. All sections were counterstained with DAPI (blue signal).

 
No atherosclerotic features, inflammatory infiltrates, or nuclear fragmentation were observed (data not shown). Several adventitial vasa vasorum and perivascular capillaries (Fig. 2b) were present in both groups.

Expression of inflammatory markers. The differences between ACS and CSA patients were limited to E-selectin expression on the IMA luminal endothelium, which was graded as weak/absent versus bright. A bright signal was significantly more frequent on IMA of ACS patients (Fig. 1a) than CSA patients (8 ACS vs. 2 CSA, 61.5% vs 14.3%, P = 0.01, not shown); no significant differences were found on the vasa vasorum. Among E-selectin-positive patients, two ACS patients also expressed TLR4, with a patchy distribution on the luminal endothelium (Fig. 1b). TLR4 was not detected on the vasa vasorum of ACS patients or in CSA specimens (not shown).

ICAM-1, iNOS, GLUT1, VCAM-1, tissue factor, IL-6, and TNF-{alpha} failed to show appreciable differences in expression in IMA sections between the two groups of patients. In particular, GLUT1 (Fig. 1a) was highly expressed, with the presence of typical clusters (15), whereas iNOS (Fig. 1a) and ICAM-1 (Figs. 2, a and b, right) were moderately expressed on the luminal endothelium and vasa vasorum of IMA in both ACS and CSA patients. Conversely, VCAM-1, tissue factor, IL-6, and TNF-{alpha} were undetectable in specimens of ACS or CSA patients (not shown).

Expression of MHC class I and class II-DR antigens. The endothelial luminal surface and vasa vasorum of IMA sections from all patients expressed MHC class I and class II-DR molecules (Fig. 2). The three-grade score (defined as described in METHODS) indicated that a high intensity of the signals was significantly more frequent in ACS patients than in CSA patients (Fig. 3). A bright fluorescence for MHC class I antigen expression was observed on the luminal endothelium in 66.7% of ACS patients but only in 17.6% of CSA patients (10 ACS vs. 3 CSA, P = 0.001; Fig. 3A) and on the vasa vasorum in 92.9% of ACS patients versus 33.3% of CSA patients (13 ACS vs. 5 CSA, P = 0.0007; Fig. 3C).


Figure 3
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  		Fig. 3. MHC class I (A and C) and MHC class II-DR (B and D) showed the difference in activation of IMA from ACS patients compared with CSA patients. The frequency of expression intensities in the two groups of patients is summarized in histograms. Histograms show significantly different patterns of endothelial expression for MHC class I and MHC class II-DR in ACS versus CSA patients ({chi}2-test). A higher frequency of bright signals and a lower frequency of weak fluorescence for both classes of MHC on IMA (A and B) and VV endothelia (C and D) were observed in ACS patients compared with CSA patients.

 
MHC class II-DR was brightly expressed on the luminal endothelium in 66.7% of ACS patients versus 6.2% of CSA patients (10 ACS vs. 1 CSA, P = 0.0003; Fig. 3C) and on the vasa vasorum in 92.9% of ACS patients versus 7.7% of CSA patients (13 ACS vs. 1 CSA, P < 0.0001; Fig. 3B).

No differences were observed between patients in which IMA samples were taken with or without the cardiac extracorporeal circulation. The marker expression was unrelated to risk factors or pharmacological treatment in patients with ACS and CSA.

Circulating levels of CRP and IL-6 were not statically correlated with the expression of E-selectin or MHC class I and class II-DR on the luminal endothelium or vasa vasorum of IMA.


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
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Our study demonstrates a significantly greater prevalence of high expression of E-selectin, MHC class I, and MHC class II-DR molecules on the luminal endothelium of IMA in patients with ACS than in patients with CSA. Moreover, MHC molecules were significantly more expressed on the vasa vasorum of IMA in patients with ACS than in patients with CSA. Such elevated expression was observed in the absence of inflammatory infiltrates in IMA walls, suggesting that in patients with ACS, the systemic inflammatory activation reported in coronary arteries (4, 5, 44) and complex carotid plaques (4, 5, 44) may also involve IMA and their vasa vasorum.

Expression of cell adhesion molecules and circulating biomarkers. The higher values of circulating CRP and IL-6 measured in ACS patients than in CSA patients are consistent with previous findings and suggest the presence of a systemically detectable inflammatory component in ACS (25, 27, 28) and may be influenced by regional vascular responsiveness. Recent studies showed high expression of endothelial NOS, angiotensin-converting enzyme, and endothelin (40) on the luminal endothelium of IMA that might attenuate the proatherogenic effect of CRP in patients with CAD (16, 24). However, the association between circulating levels of CRP and IL-6 and the expression of molecules by endothelial cells has not been adequately investigated so far. Transcription of CRP in the liver is IL-6 dependent (14), and, in turn, the secreted CRP stimulates IL-6 release from the vascular endothelium (46). We hypothesize that this loop occurs in a precise time window and could explain the absence of the IL-6 signal inside endothelial cells in all our IMA specimens. CRP can inhibit endothelial NOS in vitro, inducing a significant increment of ICAM-1 and VCAM-1 but not E-selectin (45). The higher expression of E-selectin on the luminal endothelium of IMA in ACS patients versus CSA patients would be compatible with increased levels of soluble E-selectin, as reported in ACS patients in some studies (18, 32). However, studies on the association between circulating levels of CRP and IL-6 and plasma levels of inflammatory markers and soluble forms of selectins and cell adhesion molecules have given conflicting results in patients with ACS (21). In our study, the levels of CRP and IL-6 displayed a positive statistical trend (not shown) but not a correlation with the endothelial expression of E-selectin, MHC class I, and MHC class II-DR molecules, suggesting a more complex, indirect pattern of activation of the IMA endothelium.

Expression of GLUT1, TLR4, and iNOS: IMA responsiveness. Recent findings have suggested that IMA are not only passive conduits (40). We show here, on IMA collected before surgery and morphologically normal, a strong endothelial expression of GLUT1, which indicates intense glucose transport and metabolism. These findings support and extend the hypothesis that IMA are active vessels. Indeed, GLUT1 signals were similar in both ACS and CSA patients. These observations are in agreement with those on rat small contractile arteries, suggesting that GLUTs cannot account for the severity of vascular disease progression observed between the different vascular beds (15).

The expression of TLR4 in a few specimens coexpressing E-selectin might suggest a possible but infrequent contribution of endothelial interactions with pathogens to IMA reactivity in patients with ACS (3, 11, 20). Moreover, the sporadic TLR4 expression is in agreement with the moderate expression of iNOS, which was comparable between patients with ACS and CSA, as an increase in iNOS should be in contrast with the absence of atherosclerosis in IMA.

Endothelial molecule expression and IMA activation. A wide repertoire of surface molecules has been described in endothelial cells of several human arteries including IMA (8, 9, 16, 23, 34, 35), but the changes in their expression in endothelial cells in coronary syndromes are still largely unknown (40, 41).

Our findings on endothelial adhesion molecules appear in agreement with previous immunohistochemical studies on IMA endothelium from individuals submitted to CABG (35, 41). According to our results, several authors reported high endothelial expression of MHC class I and MHC class II-DR, moderate expression of iNOS (35, 41) and ICAM-1, VCAM-1 and E-selectin (35, 41), and the absence of tissue factor (47); the absence of a CAD patient group with ACS and CSA precluded any further comparison.

The modest differences that we observed in E-selectin and the absence of upregulation of iNOS, ICAM-1 and VCAM-1 (37), together with a lack of immunoreactivity for TNF-{alpha}, might suggest the absence of TNF-{alpha}-dependent stimulation of IMA endothelium in both ACS and CSA.

Conversely, the enhanced expression of MHC class I and MHC class II-DR in IMA and their vasa vasorum in patients with ACS suggests the possibility of an immunomediated mechanism (38, 42).

Reports on IMA rings and endothelial cells isolated from IMA in culture have shown that statins inhibit the transcritption of MHC class II-DR induced by IFN-{gamma} and class II transactivator (CIITA) promoter pIV dependent (16, 24). Our results were not significantly correlated with pharmacological treatment including statins. This could signify an independency from CIITA pIV transcription. Moreover, our observations appear consistent with the high expression of MHC class II-DR on endothelial cells of coronary microvessels in patients with unstable angina (33), as previously reported, and collectively support the hypothesis of a role for MHC antigens in the endothelial inflammatory activation in ACS. The extent of endothelial expression of MHC class I and class II-DR in myocardial microvessels has been correlated with myocardial inflammation and endothelial dysfunction of peripheral arteries in patients without CAD (43). Therefore, our findings could support a role for IMA in the inflammatory-dependent, atherosclerosis-independent response of the vascular endothelium in CAD. We speculate that phenotypical heterogeneity between IMA and atherosclerotic-prone arteries is involved in the different endothelial responsiveness, intended not only as resistance to atherosclerosis but also as contribution to vascular bed activation.

Study limitations. In the present study, a generalization about gender influence and a multivariate analysis appeared not reliable because of the low number of patients, and trends only can be provided by our data.

By confocal microscopy, we studied 12 markers, and a larger amount of tissues would have been required to analyze a sufficiently large number of cells with a similar spatial orientation for a reliable quantitative analysis of fluorescence. Moreover, specifically addressed investigations are required to confirm our speculations and to establish the clinical significance of our findings, i.e., to provide a mechanism clarifying why IMA display mild inflammatory activation and how it affects the occurrence of the inflammatory process leading patients to unstable angina.

Conclusions. Our study proposes that the vascular inflammatory process characterizing unstable patients has to be widespread and involves also IMA, which are known to be protected from atherosclerosis. These findings support the hypothesis that IMA are active vessels, giving further rise to the notion of vascular bed-specific endothelial responsiveness. They contribute to expand the concept of widespread activation of the vascular endothelium in patients with ACS and of widespread inflammation in coronary arteries and challenge the importance of single vulnerable plaques.


   GRANTS
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REFERENCES
 
This work was supported by Italian Ministry of University and Research Grant RBLA05ACJZ_003 and by the Fondazione Internazionale di Ricerca per il Cuore Onlus.


   ACKNOWLEDGMENTS
 
We thank Raffaella Rusconi for the technical assistance with specimen collection.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. Foglieni, CCB Laboratory, Cardiovascular Dept., San Raffaele Scientific Institute, via Olgettina 58, Milano 20132, Italy (e-mail: foglieni.chiara{at}hsr.it)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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