Published online before print May 6, 2004, doi: 10.1161/01.RES.0000130944.49657.b8
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© 2004 American Heart Association, Inc.
Clinical Research |
Cardiac Angiotensin II Participates in Coronary Microvessel Inflammation of Unstable Angina and Strengthens the Immunomediated Component
From the Clinica Medica Generale e Cardiologia (G.G.N., M.B., P.A.M., I.C., M.C., M.L.P., M.B., G.F.L.), University of Florence, Italy; and Institute of Thoracic and Cardiovascular Surgery (T.T., M.C.), University of Siena, Italy.
Correspondence to Dr Gian Gastone Neri Serneri, Clinica Medica Generale e Cardiologia, University of Florence, Viale Morgagni 85, 50134 Florence, Italy. E-mail gg.neriserneri{at}dfc.unifi.it
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Abstract |
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Angiotensin (Ang) II is now recognized to be a mediator of a wide variety of inflammatory processes. This study investigated renin-angiotensin system (RAS) components and a number of inflammatory mediators in left ventricular biopsies from 2-vessel disease unstable angina (UA) (n=43) and stable angina (SA) (n=15) patients undergoing coronary bypass surgery. Biopsy samples from 6 patients undergoing valve replacement for mitral stenosis served as controls. UA patients were randomly assigned to angiotensin-converting enzyme (ACE)-inhibitor (ramipril), AT1 antagonist (valsartan), or placebo and treated during the 5 days preceding coronary bypass surgery, performed from 6 to 9 days after coronary angiography. During coronary angiography coronary blood flow was measured and samples were obtained from aorta and coronary sinus for determination of Ang I and Ang II gradients. The hearts of UA patients produced Ang II in a greater amount than in SA patients (P<0.01). UA biopsy samples showed numerous DR+ cells, identified as lymphocytes, macrophages, and endothelial cells. Reverse-transcriptase polymerase chain reaction showed overexpression of AGTN, ACE, and AT1-R genes, as well as upregulation of TNF-
, IL-6, IFN-
, and iNOS genes (P<0.01), with no differences between nonischemic and potentially ischemic areas. AGTN, ACE, and cytokine genes were mainly localized on endothelial cells. Ramipril and valsartan markedly decreased the expression levels of TNF-, IL-6, and iNOS, and, to a lesser extent, of IFN- genes, but did not affect the number of DR+ cells, with no significant difference between the 2 treatments. These results show that locally generated Ang II amplifies the immunomediated inflammatory process of coronary microvessels occurring in unstable angina.
Key Words: angiotensin II • unstable angina • myocardial inflammation
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Introduction |
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Unstable angina (UA) classes IIB and IIIB of Braunwald classification1 are an acute manifestation thought to be caused by recent inflammatory activation within coronary atherosclerotic plaque, often resulting in the plaque erosion or rupture with consequent nonocclusive thrombus development.2 Unstable or vulnerable plaques are characterized by increased accumulation of inflammatory cells, particularly macrophages and T-lymphocytes, and by a large lipid core and a thin fibrous cap.3 A high number of inflammatory cells express DR molecules and IL-2 receptors,4,5 thus indicating that antigen presentation, as well as an immunological reaction, occurred.6 However, the concept that UA is only an intraplaque event is strongly restrictive because recent studies have shown that >1 coronary plaque is activated in acute coronary syndromes.7 Moreover, we showed that also coronary microvessels are involved in UA by an acute inflammatory process with cellular and molecular characteristics of an immunomediated reaction.8 The complex pathophysiology of UA is also suggested by the link that seems to exist between renin-angiotensin system (RAS) and atherosclerosis.9 Several immunohistochemical and biochemical studies have shown a marked accumulation of angiotensin-converting enzyme (ACE), angiotensin (Ang) II, angiotensin type 1 receptor (AT1-R), and the co-expression of Ang II and IL-6 in human atherosclerotic plaques of patients with acute coronary syndromes.10–13 In a recent study,14 we demonstrated that cardiac RAS is activated in UA, but not in patients with stable angina (SA), resulting in an increased Ang II formation. Experimental studies in transgenic rats have shown that an exaggerated Ang II cardiac production can induce coronary vasculopathy.15 These findings are potentially relevant for the pathophysiology of UA, because there is growing evidence that local RAS has important modulatory activity in the atherogenic process9 and is provided with significant proinflammatory actions.16,17
Therefore, we planned this study to investigate whether locally generated Ang II induces myocardial inflammation and, if so, to also investigate the cellular and molecular features of this inflammatory reaction.
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Materials and Methods |
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Please note that additional information is included in the online data supplement available at http://circres.ahajournals.org.
Study Population
We examined 43 patients with UA in classes IIB (n=18) and IIIB (n=25) and 15 patients with SA in Canadian classes II (n=4) and III (n=11). Patients with UA and SA were considered for inclusion in the study if they had a 2-vessel disease, 1 of which had to be the left anterior descendent (LAD) artery, and if they had been scheduled for a coronary artery bypass graft because the condition was unsuitable for percutaneous transluminal angioplasty. The distribution of coronary vessel disease and baseline clinical characteristics of the study population are reported in Table I of the online data supplement (see http://circres.ahajournals.org). Diagnosis of UA and SA and risk evaluation of UA patients followed the American College of Cardiology/American Heart Association Guidelines.18,19 High-risk patients and patients with recent (ie, within the preceding 3 months) myocardial infarction were not accepted for the study. We considered eligible for the study only patients who had had the onset of UA <5 days before admission and who experienced at 
2 episodes of angina at rest or 1 episode lasting >20 minutes, associated with transient ischemic ST segment changes and troponin T levels <0.1 (troponin T-negative). All UA patients received aspirin (100 mg/d) and nitrates. In addition to this therapy, 18 patients were treated with beta-blockers, 27 with heparin, and 13 received calcium-antagonists. Anginal episodes were recorded until to surgery. Patients with SA were using aspirin (100 mg/d) and nitrates. Patients with conduction disturbances or heart failure or patients treated with ACE inhibitors in the 2 weeks preceding the hospital admission were also excluded from the study, as were patients who at admission had myocardial ischemia associated with pulmonary edema, hypotension, or threatening arrhythmias. Eligible patients were enrolled in the study after coronary angiography that was performed from 48 to 96 hours after admission. We also assessed severity of coronary lesions and presence and grade of coronary collateral circulation. Patients who at admission had had recent infectious diseases, known or suspected neoplasia, and erythrocyte sedimentation rate >20 mm/h were not considered eligible for the study. UA patients were randomly assigned to ramipril (5 mg/d, n=14), valsartan (80 mg/d, n=14), or placebo (n=15) groups. The patients were treated during the 5 days preceding the scheduled coronary artery bypass graft, which was performed from 6 to 9 days after coronary angiography. None of the patient showed a decrease in systolic or diastolic arterial blood pressure 5 mm Hg during the 5 days of drug administration. The protocol of this study complies with the principles of the Helsinki declaration and was approved by the Ethical Committee of our Institution. All patients gave informed consent to participate and to have blood samples and biopsy specimens taken for the study.
Experimental Procedures
During coronary angiography, we measured coronary blood flow with the thermodilution technique (mean of 3 measurements)20 and drew blood samples from aorta and coronary sinus for the determination of cardiac oxygen extraction and for the measurement of aorta–coronary sinus Ang I and II gradients.14 Ten patients who underwent coronary angiography for atypical chest pain and did not show significant lesions served as the control group for the measurement of Ang I and II aorta–coronary sinus gradients. In UA patients, we performed a transmural biopsy (10x0.5 mm) through a biopsy needle (MN1416; diameter 2.1 mm; BIP Gembh) from the antero-lateral wall of the left ventricle close to the apex in the distribution territory of the LAD artery (potentially ischemic area) immediately after sternotomy and before inducing cardioplegia. In the 12 UA patients with LAD and coronary right artery (CRA) disease, a second biopsy was performed in the free left ventricle wall in an area that was supplied by obtuse marginal branches and was normally perfused at 211Thallium scintigraphy (nonischemic area). The surgeon did not take the biopsy specimens if the area selected for biopsies appeared as a site of an old infarction. Cardiac specimens were also obtained from the antero-lateral wall of the left ventricle of 6 patients with mitral stenosis who were undergoing surgical valve replacement (control hearts [CHs]). Handling of biopsy specimens for reverse-transcriptase polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemical studies were performed as previously described21 (see http://www.circresahajournals.org).
Measurement of Cardiac Ang II Formation
Cardiac Ang I and II formation was measured by means of aorta–coronary sinus concentration gradient indexed by coronary blood flow, following the procedure detailed in an earlier article.14 Plasma concentrations of both angiotensins were determined by radioimmunoassay after C18 Sep-Pak cartridge extraction and high-performance liquid chromatography separation.14,21
Immunohistochemical Detection of Inflammatory Cells and Morphometric Analysis
The presence and identification of activated inflammatory cells in the myocardium were determined by immunohistochemical analysis using human monoclonal antibodies for major histocompatibility class II molecules (human leukocyte antigen [HLA]-DR), CD68+ macrophages, CD3+ T-lymphocytes, and CD31+, and von Willebrand+ endothelial cells on serial sections. We used double staining for investigating colocalization of DR and ACE proteins with von Willebrand-positive cells using a commercial kit (Vectastain, Elite, ABC Kit; Vector Laboratories). We tested the presence of neutrophils by immunostaining for elastase.8 The number of DR-positive (DR+) inflammatory (lymphocytes and macrophages) and endothelial cells was expressed as cells/mm2.8
RT-PCR Quantification of mRNAs for RAS Components, Chymase, Cytokines, MCP-1, and iNOS
RT-PCR was used to evaluate gene expression of renin, angiotensinogen (AGTN), ACE, AT1-R, AT2-R, chymase, inducible nitric oxide (iNOS), IL-1ß, tumor necrosis factor (TNF)-, IL-6, interferon (IFN)-, and monocyte chemoattractant protein (MCP)-1. RT-PCR was performed as previously reported8 by means of specific primers, and gene levels were expressed as ratios to the constitutively expressed gene for glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Characteristics of primers and operative conditions for RT-PCR are reported in the online section.
In Situ Hybridization Studies of mRNAs for AGTN, ACE, Cytokines and iNOS
The in situ hybridization procedure was performed with specific cDNA photobiotin-labeled probes8,14,21 on adjacent serial sections (see http://www.circresahajournals.org).
Immunohistochemical Analysis for Cytokine and iNOS Proteins
The endothelial source of cytokine proteins were assayed by double-staining immunohistochemical analysis using primary monoclonal antibodies against human TNF-, IL-6, IFN-, and iNOS, and second primary monoclonal antibody against human von Willebrand according to the recommendations provided by the supplier (Vectastain, Elite, ABC Kit; Vector Laboratories).
Statistical Analysis
Data are expressed as means±SD. Comparisons between groups were made with Student t test for paired and unpaired data. We used 1-way ANOVA followed by Tukey multiple-range comparison test, as appropriate, to examine the differences among the 3 groups. Relationships between cardiac Ang II formation and severity of angiographic coronary lesions were tested by linear regression analysis. We used BMDP statistical software (BMDP Statistical Software Inc) for all calculations.
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Results |
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Clinical Course
No patients had heart failure, myocardial infarction, or died before, during, or after the surgical procedure. Sixteen of 43 UA and 3 of 15 SA patients experienced anginal episodes during the interval between their enrollment and surgery; none of these episodes lasted >5 to 6 minutes. Only 3 patients experienced angina in the 2 days preceding surgery. After the randomization codex was opened, 2 of these patients turned out to be using placebo and the other 1 was using an ACE inhibitor. Collateral blood flow was angiographically demonstrable in 14 of 43 UA patients, and in 8 supplied the area of ventricular wall from which biopsy specimens were taken.
Cardiac Angiotensin Formation
Baseline concentrations of Ang I and II and PRA in peripheral venous blood of UA patients did not differ from values of SA patients or controls. By contrast, cardiac Ang II formation was higher (P<0.01) in UA than in SA patients or controls (6.9±4.8 pg/mL versus 0.7±0.6 pg/mL and –0.1±0.3 p/mL, respectively) (data are shown in Table III of the online data supplement available at http://circres.ahajournals.org.) No correlation was found between cardiac Ang II formation and severity of angiographic coronary lesions (r=0.23, NS).
Expression Levels of Cardiac RAS Components
RT-PCR revealed that AGTN, ACE, AT1-R, AT2-R, and chymase genes were expressed in all myocardial ventricular specimens from anginal patients who were using the placebo and from CH (Figure 1). mRNA for renin was not detected. The expression levels of AGTN, ACE, and AT1-R genes in UA biopsy samples were significantly higher (P<0.01 for all genes) than in those from SA or CH. There were not significant differences between nonischemic and potentially ischemic areas in the patients with LAD and CRA disease (Figure 1). AT2-R and chymase gene expression did not differ among anginal patients and controls (Figure 1).
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Negative and positive controls for in situ hybridization studies showed that the signal was specific for mRNA and that the mRNA in the biopsy samples was intact. AGTN and ACE genes were expressed only in trace amounts in myocardial biopsy samples from SA and CH, whereas they were overexpressed in the biopsy samples from UA patients and were detected almost exclusively in microvessel endothelial cells (Figure 1).
Coronary Microvessel Inflammation and Ang II Blockade
Numerous cells that expressed HLA-DR molecules, were observed in UA biopsy samples, but were very rare in SA biopsy samples, and no DR+ cells were found in CH (Figure 2). The majority of DR+ cells was represented by endothelial cells because they were positively immunostained by both von Willebrand and CD31+ antibodies (Figure 2). The remaining DR+ cells were identified as macrophages and lymphocytes and were detected in the myocardial interstitium, but not in the lumen of microvessels. In SA hearts, lymphocytes and macrophages minimally contributed to DR positivity and their number was significantly lower than in UA hearts (Figure 2). In UA hearts, the number of DR+ cells did not differ between nonischemic and potentially ischemic areas (Figure 2). Double immunostaining showed that DR and ACE proteins colocalized on von Willebrand–positive cells (ie, endothelial cells) (Figure 3). No elastase-positive cell was detected.
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RT-PCR revealed that expression of mRNAs for cytokines and iNOS was negligible or absent in CH. In SA biopsy specimens, only TNF- and iNOS genes were clearly expressed at a higher level than in CH (P<0.05 and P<0.01, respectively) (Figure 4). Conversely, in myocardial biopsy specimens from UA patients TNF-, IL-6, IFN-, and iNOS genes were overexpressed from 1.6-fold for TNF- (P<0.001) to 7.1-fold for IL-6 (P<0.001) when compared with SA hearts (P<0.001). IL-1ß and MCP-1 genes were barely expressed in both SA and UA hearts (Figure 4). In patients with LAD and CRA disease, expression levels of mRNA for cytokines and iNOS did not differ between nonischemic and potentially ischemic areas (Figure 4).
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In situ hybridization studies revealed that in SA biopsy specimens, signals for TNF- and iNOS appeared only in trace amounts on endothelial cells, and signals for IFN- and IL-6 were undetectable. By contrast, in UA biopsy samples, genes for cytokines and iNOS were overexpressed and almost exclusively localized in the endothelium of microvessels (online Figure I, see http://www.circresahajournals.org). Cardiomyocytes did not express mRNAs either for cytokines or for iNOS (online Figure I). Double staining showed that immunoreactivity for TNF-, IL-6, IFN-, and iNOS proteins colocalized with von Willebrand-positive cells (Figure 5). No signal was detected on cardiomyocytes (Figure 5). The cellular localization of the genes for the various cytokines and iNOS did not differ between nonischemic and potentially ischemic areas. We did not find any immunoreactivity for cytokine and iNOS proteins in CH, and only weak signals for TNF- and iNOS proteins were found in SA biopsy specimens.
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Ramipril or valsartan treatment significantly reduced the mRNA expression levels of cytokines and iNOS in comparison with biopsy specimens from UA patients using placebo without differences between the 2 treatments (Figure 6). The decrease in the expression levels of TNF- and IL-6 was 91±7% and 89±5%, respectively, and that of iNOS was 78±5%, whereas IFN- gene expression decreased, 53±5%, significantly less than those of the other genes (P<0.01). Conversely, the blockade of Ang II activity did not significantly change either the total number of DR+ cells or the number of the endothelial and inflammatory cells (Figure 7). The effect of Ang II blockade slightly, but not significantly, modified mRNA expression levels of RAS components and was similar in potentially ischemic and in nonischemic areas (data not shown).
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Discussion |
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Cardiac RAS Activation and Myocardial Ischemia
The present results provide additional evidence 14 that cardiac Ang II formation is increased in UA patients and suggest that locally generated Ang II plays a role in coronary microvessel inflammation. This statement is supported by the presence of inflammatory cells (T lymphocytes and macrophages) and endothelial cells expressing DR molecules, and by the upregulation of mRNAs for iNOS and various inflammatory cytokines (TNF-
, IL-6, IFN-). The expression of HLA-DR molecules on the inflammatory and endothelial cells as well as the overexpression of IFN- genes provide evidence of an immunomediated reaction, 22 thus confirming our previous study. 8The possibility that both cardiac RAS activation and coronary microvessel inflammation may be a reaction to myocardial necrosis, 23 surgery, 24 or ischemia should be considered. Myocardial necrosis or surgery may be reasonably excluded as causes of RAS activation and microvessel inflammation because the enrolled UA patients were troponin-negative, and myocardial biopsies were performed before extracorporeal circulation. The lack of differences in the cytokine levels and in the number and types of DR+ cells between the nonischemic and potentially ischemic areas in the UA patients with LAD and CRA disease without lesions of left circumflex (LCX) artery makes it highly unlikely that the RAS activation and coronary microvessel inflammation are consequence of myocardial ischemia. Acute myocardial ischemia can induce an inflammatory reaction according to the classic scheme of ischemia reperfusion injury. In this condition, neutrophils are principally involved, but the absence of elastase in our biopsy specimens is against this hypothesis. Likewise, various histological and molecular features differentiate the coronary microvascular inflammation found in UA patients from the late phase of ischemic preconditioning and hibernating myocardium. In the late phase of ischemic preconditioning, IL-1ß and TNF- genes are coexpressed and iNOS is selectively upregulated in the myocytes, 25,26 but not in small vessels and fibroblasts as, instead, we found. Hibernating myocardium is associated with degeneration of cardiomyocytes, loss of contractile material, fibrosis, and MCP-1 gene overexpression.27,28 By contrast, all these findings were not observed in UA coronary microvessel inflammation.
Ang II–Dependent Inflammation
ACE inhibitor (ramipril) or AT1-R antagonist (valsartan) treatment markedly reduced (from 70% to 90%) the expression levels of TNF-, IL-6, and iNOS genes in comparison with placebo. Although RT-PCR allows only a semiquantitative assay, the marked decrease in gene expression overcomes the limits of the method and substantiates the differences between active treatment and placebo. The insignificant differences between the 2 drugs in the cytokine reduction exclude a nonspecific effect. The incomplete reversion of cytokine and iNOS levels after Ang II blockade does not speak against the notion that Ang II plays a role in the microvessel inflammation. This partial effect may result from a variety of causes, including a nonoptimum dosage and duration of ramipril or valsartan administration, the impossibility to fully inhibit cardiac RAS, and the possible contribution of AT2 receptors in inflammatory signal transduction mechanism.29 Thus, the notable and ready attenuation of the expression levels of cytokine and iNOS genes corroborate the hypothesis that the increased cardiac Ang II generation plays a major role in the Ang II-associated inflammatory process. It is, however, to be emphasized that in the present study, ramipril or valsartan was used as a tool for investigating the contribution of Ang II to the UA microvessel inflammation and not for a clinical assessment of UA treatment for which large-scale clinical trials are required.
In this study, we did not investigate the mechanisms by which Ang II induces the expression of the inflammatory genes in UA myocardium. Specifically addressed studies are needed because Ang II can elicit cellular inflammatory responses through a variety of signal transduction mechanisms, such as nuclear factor (NF)-
B and activating protein (AP)-1.30 Moreover, Ang II may induce cellular responses through other molecular pathways, such as free radical generation, particularly through NAD(P)H complex,31,32 that mediates the activation of Akt/protein kinase B32 and JAK-STAT signaling.33 The inhibitory effect of ramipril and valsartan on the expression of TNF-, IL-6, and iNOS genes indirectly suggests an Ang II-dependent NF-B activation, because these genes and iNOS are controlled by this system. The lack of MCP-1 gene activation suggests that AP-1 and Rho were not activated because MCP-1 expression is mediated by these signal transduction systems.30,34 However, no certain conclusion can be drawn because the timing and the duration of MCP-1 activation are not well-defined.
Immunomediated Inflammatory Component
The Ang II-dependent inflammation was associated with an immunomediated inflammatory component demonstrated by the expression of HLA-DR molecules on T cells, macrophages, and endothelial cells, as well as by the overexpression of IFN- gene and protein, which reflects a recent immunological reaction.22 ACE inhibition and AT1-R blockade caused a marked decrease in the expression levels of TNF-, IL-6, and iNOS genes, whereas they did not affect the number of inflammatory cells and decreased the expression levels of the IFN- gene significantly less than the other cytokines (–53±5% versus 
–84±9%, P<0.01). These data suggest a major effect of Ang II to stimulate expression of some, but not all, cytokines by endothelial cells rather than to influence activated (ie, DR+) inflammatory cells. However, these findings do not exclude the fact that Ang II can affect T-cell activity, because these cells are provided with AT1 receptors,35,36 and Ang II increases the number of IFN-–secreting cells37 and stimulates the production of IFN- and IL-2.30 The decrease in the IFN- gene expression after ramipril or valsartan administration was milder than that of the other cytokines and is consistent with the minor effect of Ang II on the immunomediated component than on the nonspecific inflammatory component.
The overexpression of IFN- gene on the microvascular endothelial cells reflects the immunological activation of the endothelium, which is followed by endothelial ACE activation, because there is evidence that IFN- induces the transcription of ACE gene and upregulates its enzymatic activity in the endothelial cells.38 It is noteworthy that the enhanced Ang II formation in UA patients is essentially caused by a selective increase in ACE activity.14This mechanism appears to be different from that responsible for the enhanced Ang II generation in heart failure, which is mainly supported by an increased cardiac Ang I formation, related to the elevated plasma renin activity.21
Microvessel Inflammation and Unstable Angina
The clinical significance of this study remains to be established. The locally increased Ang II formation does not seem to directly contribute to myocardial ischemia with its vasoconstrictor activity, because coronary vascular resistance was not augmented and Ang II appears to be generated downstream the resistance arterioles.14 However, it is worth stressing that we investigated our patients from 9 to 18 days after the onset of anginal attacks. Therefore, it cannot be ruled out that the inflammatory process of coronary microvessels, which is presumably more intense at the onset of angina, can hamper coronary flow at the capillary level, and so may contribute to myocardial ischemia. Only additional specifically addressed studies could clarify this issue. Likewise, the potential clinical meaning of the inhibition of Ang II activity remains to be investigated. The present study has a pathophysiological significance because it extends current knowledge of UA by demonstrating that the inflammatory process that supports UA is not confined into the culprit plaques, but is widespread in the coronary vascular bed. This fact challenges the concept of a single vulnerable plaque as the pathological basis of UA. Our results are consistent with recent angiographic,39 angioscopic,40 and intracoronary ultrasound7,41 investigations that, in patients with myocardial infarction or UA, have shown the simultaneous presence of numerous eroded and thrombosed plaques, diffused on the coronary arteries, even if only 1 plaque may be the culprit plaque.41 Our research, together with these studies, suggests that the pathomorphological substrate underlying the majority of acute coronary syndromes is not a fissuration or rupture of individual plaque, but rather an acute widespread inflammatory process of the coronary vascular bed, in the context of which 1 or more atherosclerotic plaques may easily break. Both the activated plaques and coronary microvessel inflammation show similar cellular and molecular characteristics, including the upregulation of local RAS,10–12 the high number of DR+ lymphocytes and macrophages, and the endothelial activation.4,5 This points to common mechanism(s) underlying both conditions. The high number of DR+ cells, the upregulation of IFN- gene and the overexpression of IL-2 receptor on plaque lymphocytes5 suggest that immunological factors may have a role in triggering UA.
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Acknowledgments |
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The financial support of the Ministero dell’Università e della Ricerca Scientifica e Tecnologica, Rome, Italy (Grant 9906108278) is gratefully acknowledged.
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Footnotes |
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Received October 17, 2003; revision received April 22, 2004; accepted April 26, 2004.
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References |
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1. Braunwald E. Unstable angina: an etiologic approach to management. Circulation. 1998; 98: 2219–2222.
2. Libby P. Inflammation in atherosclerosis. Nature. 2002; 420: 868–874.[CrossRef][Medline] [Order article via Infotrieve]
3. Lee RT, Libby P. The unstable atheroma. Arterioscler Thromb Vasc Biol. 1997; 17: 1859–1867.
4. Arbustini E, De Servi S, Bramucci E, Porcu E, Costante AM, Grasso M, Diegoli M, Fasani R, Morbini P, Angoli L, Boscarini M, Repetto S, Danzi G, Niccoli L, Campolo L, Lucreziotti S, Specchia G. Comparison of coronary lesions obtained by directional coronary atherectomy in unstable angina, stable angina, and restenosis after either atherectomy or angioplasty. Am J Cardiol. 1995; 75: 675–682.[CrossRef][Medline] [Order article via Infotrieve]
5. van der Wal AC, Piek JJ, de Boer OJ, Koch KT, Teeling P, van der Loos CM, Becker AE. Recent activation of the plaque immune response in coronary lesions underlying acute coronary syndromes. Heart. 1998; 80: 14–18.
6. Lando PA, Olsson C, Kalland T, Newton D, Koto M, Dahlsen M. Regulation of superantigen-induced T cell activation in the absence and in the presence of MHC class II. J Immunol. 1996; 157: 2857–2863.[Abstract]
7. Spagnoli LG, Bonanno E, Mauriello A, Palmieri G, Partenzi A, Sangiorgi G, Crea F. Multicentric inflammation in epicardial coronary arteries of patients dying of acute myocardial infarction. J Am Coll Cardiol. 2002; 40: 1579–1588.
8. Neri Serneri GG, Boddi M, Modesti PA, Cecioni I, Coppo M, Papa ML, Toscano T, Marullo A, Chiavarelli M. Immunomediated and ischemia-independent inflammation of coronary microvessels in unstable angina. Circ Res. 2003; 92: 1359–1366.
9. Brasier AR, Recinos A 3rd, Eledrisi MS. Vascular inflammation and the renin-angiotensin system. Arterioscler Thromb Vasc Biol. 2002; 22: 1257–1266.
10. Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ. Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation. 1996; 94: 2756–2767.
11. Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M, Nussberger J, Harringer W, Drexler H. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation. 2000; 101: 1372–1378.
12. Hoshida S, Kato J, Nishino M, Egami Y, Takeda T, Kawabata M, Tanouchi J, Yamada Y, Kamada T. Increased angiotensin-converting enzyme activity in coronary artery specimens from patients with acute coronary syndrome. Circulation. 2001; 103: 630–633.
13. Fukuhara M, Geary RL, Diz DI, Gallagher PE, Wilson JA, Glazier SS, Dean RH, Ferrario CM. Angiotensin-converting enzyme expression in human carotid artery atherosclerosis. Hypertension. 2000; 35: 353–359.
14. Neri Serneri GG, Boddi M, Poggesi L, Simonetti I, Coppo M, Papa ML, Lisi GF, Maccherini M, Becherini R, Boncompagni A, Toscano T, Modesti PA. Activation of cardiac renin-angiotensin system in unstable angina. J Am Coll Cardiol. 2001; 38: 49–55.
15. Muller DN, Mervaala EM, Dechend R, Fiebeler A, Park JK, Schmidt F, Theuer J, Breu V, Mackman N, Luther T, Schneider W, Gulba D, Ganten D, Haller H, Luft FC. Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy. Am J Pathol. 2000; 157: 111–122.
16. Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med. 2002; 8: 1249–1256.[CrossRef][Medline] [Order article via Infotrieve]
17. Luft FC. Workshop: mechanisms and cardiovascular damage in hypertension. Hypertension. 2001; 37: 594–598.
18. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Kereiakes D, Alpert JS, Eagle KA, Faxon DP, Fuster V, Gardner TJ, Gregoratos G. Russell RO, Smith SC Jr. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: executive summary and recommendations. Circulation. 2000; 102: 1193–1209.
19. Gibbons RJ, Chatterjee K, Daley J, Douglas J, Fihn SD, Gardin JM, Grunwald MA, Levy D, Lytle BW, O’Rourke RA, Schafer WP, Williams SV, Ritchie JL, Gibbons RJ, Cheitlin MD, Eagle KA, Gardner TJ, Garson A Jr, Russell RO, Ryan TJ, Smith SC Jr. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation. 1999; 99: 2829–2848.
20. Neri Serneri GG, Boddi M, Arata L, Rostagno C, Dabizzi P, Coppo M, Bini M, Lazzerini S, Dagianti A, Gensini GF. Silent ischemia in unstable angina is related to an altered cardiac norepinephrine handling. Circulation. 1993; 87: 1928–1937.
21. Neri Serneri GG, Boddi M, Cecioni I, Vanni S, Coppo M, Papa ML, Bandinelli B, Bertolozzi I, Polidori G, Toscano T, Maccherini M, Modesti PA. Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular function. Circ Res. 2001; 88: 961–968.
22. Delves PJ, Roitt IM. Advances in immunology, II: the immune system. N Engl J Med. 2000; 343: 108–117.
23. Cusack MR, Marber MS, Lambiase PD, Bucknall CA, Redwood SR. Systemic inflammation in unstable angina is the result of myocardial necrosis. J Am Coll Cardiol. 2002; 39: 1917–1923.
24. Valen G, Paulsson G, Vaage J. Induction of inflammatory mediators during reperfusion of the human heart. Ann Thorac Surg. 2001; 71: 226–232.
25. Bolli R. The late phase of preconditioning. Circ Res. 2000; 87: 972–983.
26. Wang YP, Sato C, Mizoguchi K, Yamashita Y, Oe M, Maeta H. Lipopolysaccharide triggers late preconditioning against myocardial infarction via inducible nitric oxide synthase. Cardiovasc Res. 2002; 56: 33–42.
27. Elsasser A, Schlepper M, Klovekorn WP, Cai WJ, Zimmermann R, Muller KD, Strasser R, Kostin S, Gagel C, Munkel B, Schaper W, Schaper J. Hibernating myocardium: an incomplete adaptation to ischemia. Circulation. 1997; 96: 2920–2931.
28. Frangogiannis NG, Shimoni S, Chang SM, Ren G, Shan K, Aggeli C, Reardon MJ, Letsou GV, Espada R, Ramchandani M, Entman ML, Zoghbi WA. Evidence for an active inflammatory process in the hibernating human myocardium. Am J Pathol. 2002; 160: 1425–1433.
29. Ruiz-Ortega M, Lorenzo O, Ruperez M, Konig S, Wittig B, Egido J. Angiotensin II activates nuclear transcription factor kappaB through AT(1) and AT(2) in vascular smooth muscle cells: molecular mechanisms. Circ Res. 2000; 86: 1266–1272.
30. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol. 2003; 35: 881–900.[CrossRef][Medline] [Order article via Infotrieve]
31. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000; 86: 494–501.
32. Ushio-Fukai M, Alexander RW, Akers M, Yin Q, Fujio Y, Walsh K, Griendling KK. Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells. J Biol Chem. 1999; 274: 22699–22704.
33. Schieffer B, Luchtefeld M, Braun S, Hilfiker A, Hilfiker-Kleiner D, Drexler H. Role of NAD(P)H oxidase in angiotensin II-induced JAK/STAT signaling and cytokine induction. Circ Res. 2000; 87: 1195–1201.
34. Funakoshi Y, Ichiki T, Shimokawa H, Egashira K, Takeda K, Kaibuchi K, Takeya M, Yoshimura T, Takeshita A. Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. Hypertension. 2001; 38: 100–104.
35. Nataraj C, Oliverio MI, Mannon RB, Mannon PJ, Audoly LP, Amuchastegui CS, Ruiz P, Smithies O, Coffman TM. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J Clin Invest. 1999; 104: 1693–1701.[Medline] [Order article via Infotrieve]
36. Tsutsumi K, Stromberg C, Saavedra JM. Characterization of angiotensin II receptor subtypes in the rat spleen. Peptides. 1992; 13: 291–296.[CrossRef][Medline] [Order article via Infotrieve]
37. Shao J, Nangaku M, Miyata T, Inagi R, Yamada K, Kurokawa K, Fujita T. Imbalance of T-cell subsets in angiotensin II-infused hypertensive rats with kidney injury. Hypertension. 2003; 42: 31–38.
38. Villard E, Alonso A, Agrapart M, Challah M, Soubrier F. Induction of angiotensin I-converting enzyme transcription by a protein kinase C-dependent mechanism in human endothelial cells. J Biol Chem. 1998; 273: 25191–25197.
39. Goldstein 2000 Goldstein JA, Demetriou D, Grines GL, Pica M, Shollkfeb M, O’Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000; 343: 915–922.
40. Asakura 2001 Asakura M, Ueda Y, Yamaguchi O, Adachi T, Hirayama A, Hori M, Kodama K. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol. 2001; 37: 1284–1288.
41. Rionfold 2002 Rioufol G, Finet G, Ginon I, Andre-Fouet X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF, Tabib A. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002; 106: 804–888.
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