Published online before print July 9, 2007, doi: 10.1161/CIRCULATIONAHA.106.686774
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(Circulation. 2007;116:385-391.)
© 2007 American Heart Association, Inc.
Epidemiology |
Soluble Receptor Activator of Nuclear Factor-
B Ligand and Risk for Cardiovascular Disease
From the Department of Neurology (S.K., J.S., K.S., J.W.), Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine III and Institute for Clinical Immunology (G.S.), University of Erlangen-Nuremberg, Erlangen, Germany; Departments of Laboratory Medicine (P.S., A.M.) and Internal Medicine (P.E., G.E.), Bruneck Hospital, Bruneck, Italy; and Cardiovascular Division (Q.X.), King’s College London, University of London, London, UK.
Correspondence to Stefan Kiechl, Department of Neurology, Innsbruck Medical University, Anichstr 35, A-6020 Innsbruck, Austria. E-mail Stefan.Kiechl{at}i-med.ac.at
Received December 25, 2006; accepted May 18, 2007.
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Abstract |
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Background— Overexpression of receptor activator of nuclear factor-
B ligand (RANKL) is a prominent feature of vulnerable atherosclerotic lesions prone to rupture and was thought to contribute to the transition from a stable to an unstable plaque phenotype in both human and murine atherosclerosis because of its ability to promote matrix degradation, monocyte/macrophage chemotaxis, and vascular calcification. Methods and Results— The Bruneck Study is a prospective, population-based survey of men and women 40 to 79 years of age at the 1990 baseline examination. Levels of soluble RANKL and other variables were assessed in 909 subjects (1990). All cases of cardiovascular disease were carefully recorded between 1990 and 2005. During follow-up, cardiovascular disease (defined as ischemic stroke and transient ischemic attack, myocardial infarction, and vascular death) manifested in 124 of the 909 subjects. Baseline serum level of RANKL emerged as a highly significant predictor of vascular risk (adjusted hazard ratio per 1-unit increase in soluble RANKL, 1.27; 95% confidence interval, 1.16 to 1.40; P<0.001). Predictive significance was independent of that afforded by the classic vascular risk factors, C-reactive protein, osteoprotegerin concentration, and severity of carotid atherosclerosis. Findings were internally consistent and robust in a variety of sensitivity analyses. Notably, soluble RANKL was not associated with carotid or femoral artery atherosclerosis.
Conclusions— Our study lends large-scale epidemiological support to a role for RANKL in cardiovascular disease. In the absence of a significant association between RANKL and atherosclerosis, the idea that RANKL promotes plaque destabilization and rupture is a highly appealing concept.
Key Words: atherosclerosis • cardiovascular diseases • myocardial infarction • osteoprotegerin • RANK ligand • stroke
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Introduction |
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Involvement of immunoinflammation and matrix degeneration in the destabilization of atherosclerotic plaques is widely recognized, but the underlying mechanisms and effector pathways are not fully elucidated. A deeper understanding of these key processes holds great promise for designing new specific plaque-stabilizing therapies. The receptor activator of nuclear factor-
B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system is a novel cytokine network initially discovered to control bone homeostasis and later implicated in atherosclerosis and acute vascular syndromes alike.1 A recent series of intriguing investigations suggested that RANKL is upregulated in vulnerable atherosclerotic lesions prone to rupture and potentially contributes to the transition from a stable to an unstable plaque phenotype in both human and murine atherosclerosis.2 In advanced lesions, RANKL is expressed by activated endothelial cells and T cells harbored within the plaque and is released from mast cells containing large amounts of RANKL in pericellular granula.1–6 RANKL is a member of the tumor necrosis factor superfamily, which, on ligation with its cognate transmembrane receptor RANK, stimulates chemokine release, monocyte/macrophage matrix migration, and matrix metalloproteinase activity; enhances endothelial permeability and angioneogenesis; and is assumed to promote vascular calcification.1,3,6–8 RANKL also exists in circulation as a biologically active molecule, making it suitable for laboratory assessment.6
Clinical Perspective p 391
The present study aims to investigate the potential association between soluble RANKL (sRANKL) and risk for cardiovascular disease (CVD), which commonly originates from plaque disruption and subsequent atherothrombosis. Analyses were carried out on the extensive data pool of the prospective population-based Bruneck Study and focused on the follow-up period between 1990 and 2005.9–16
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Methods |
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Study Subjects and Examination
The Bruneck Study is a prospective, population-based survey of the epidemiology and pathogenesis of atherosclerosis and disorders of the brain and bone.9–16 All subjects are white. At the 1990 baseline evaluation, the study population comprised a sex- and gender-stratified random sample of all inhabitants of Bruneck (125 men, 125 women from each of the fifth through eighth decades of age). A total of 93.6% participated, with blood samples for measurement of sRANKL, OPG, and other parameters available in 909 subjects. Between 1990 and the quinquennial reevaluations in 1995, 2000, and 2005, detailed information about fatal and nonfatal new-onset CVD was carefully collected in all subjects (follow-up, 100%). The study protocol was approved by the appropriate ethics committees, and all study subjects gave their written informed consent. Risk factors were assessed by means of validated standard procedures described previously9–16 and are outlined in the online-only Data Supplement.
Cardiovascular Disease
Myocardial infarction was deemed confirmed when World Health Organization criteria for definite disease status were met.17 Ischemic stroke and transient ischemic attacks were classified according to the criteria of the National Survey of Stroke.18 Vascular mortality included deaths from ischemic stroke, myocardial infarction, rupture of aortic aneurysms, and sudden cardiac deaths. The diagnosis of symptomatic peripheral artery disease and angina pectoris required a positive response to the Rose questionnaire with the vascular nature of complaints confirmed by standard diagnostic procedures (ankle-brachial pressure index or angiography and exercise ECG or coronary angiography). Revascularization procedures (angioplasty and surgery) were carefully recorded. Ascertainment of events or procedures did not rely on hospital discharge codes or the patient’s self-report but on a careful review of medical records provided by the general practitioners, death certificates, Bruneck Hospital files, and the extensive clinical and laboratory examinations performed as part of the study protocols.9,11,16 Major advantages of the Bruneck Study are that virtually all subjects living in the Bruneck area were referred to the local hospital and that the network existing between the local hospital and the general practitioners allowed retrieval of practically all medical information on persons living in the area. In the primary analysis, the CVD end point comprised all incident cases of ischemic stroke and transient ischemic attack, myocardial infarction, and vascular death. Sensitivity analyses focused on individual diseases and extended composite outcomes categories, also considering new-onset peripheral artery disease, revascularization procedures, and angina pectoris (see the online-only Data Supplement).
Laboratory Methods
Blood samples were drawn in 1990, 1995, and 2000 after an overnight fast and 12 hours of abstinence from smoking9–16 and were immediately frozen. Serum levels of RANKL and OPG in samples taken in 1990 and 1995 were analyzed in 2000 after 5 and 10 years of storage at –70°C (without any thawing-freezing cycle), and serum samples taken in 2000 were shortly frozen and processed with the other samples. High consistency in absolute levels of serum RANKL and OPG in the 3 assessments (1990, 1995, and 2000) indicates long-term stability of these molecules under the storage conditions applied.10,11 OPG was measured with a sandwich enzyme immunoassay (R&D Systems, Minneapolis, Minn).11 The assay detects both monomer and dimeric forms of OPG, including OPG bound to its ligands.19 The detection limit of this assay is 0.14 pmol/L, and intra-assay and interassay variability is <10%. All samples were measured in duplicate and averaged.11 Serum levels of uncomplexed sRANKL were measured with a sandwich-type assay (Biomedica, Vienna, Austria).10 Because of the larger number of sera, components of the sRANKL ELISA kit were purchased as bulk reagents from Biomedica. Signal amplification was used to achieve a lower detection limit of 0.08 pmol/L. All analyses were performed with a single batch of reagents and were done in a blinded fashion by a single technician. The intra-assay and interassay coefficients of variation were 5% and 8%, respectively. Other parameters were assessed with standard procedures.9–16
Assessment of Atherosclerosis
Atherosclerosis was assessed in 1995 and 2000. The ultrasound protocol involved the scanning of the internal (bulbous and distal segments) and common (proximal and distal segments) carotid arteries of either side and of the femoral arteries 40 mm proximal and 10 mm distal to the bifurcation in the superficial and deep branches.9–16 Assessment of the mean maximum common carotid and femoral artery intima-media thickness and of atherosclerosis summing scores, as well as the 2-stage model of atherosclerosis progression, have been detailed previously11–16 and are summarized in the online-only Data Supplement.
Statistical Analysis
All calculations were performed with the SPSS 12.0 (SPSS Inc, Chicago, Ill) and BMDP (BMDP Statistical Software Inc, Los Angeles, Calif) software packages. Continuous variables are presented as mean±SD and dichotomous variables as percentages. Person-years of follow-up for each participant were accrued from the 1990 baseline until diagnosis of CVD, death, or October 1, 2005, whichever came first. The primary analysis focused on the composite CVD end point (ischemic stroke/transient ischemic attack, myocardial infarction, and vascular death). Subjects who suffered an outcome event were censored with respect to subsequent follow-up; ie, only the first event was considered in the analysis. Cox proportional-hazards models were used to assess whether baseline sRANKL was an independent risk predictor for incident CVD.20 Because of a lack of generally accepted cutoffs for defining the pathological range of sRANKL, we decided to analyze RANKL as a continuous variable. Several models were run. The first one included age, gender, previous CVD, and baseline sRANKL level; the second, composed of a forward stepwise selection procedure, also included variables for hypertension, cigarette smoking, C-reactive protein, lipoprotein(a), fasting glucose, OPG, and the severity of baseline atherosclerosis in the carotid arteries. Analyses were repeated and confirmed after exclusion of subjects who had experienced CVD before the study baseline. In separate models, sRANKL, OPG, and all other variables were entered as time-dependent covariate (with a quinquennial update). Given the moderately skewed distribution of sRANKL, analyses were repeated after loge transformation of sRANKL. Because these analyses yielded very similar results, we present only data from the primary approach for ease of presentation and interpretation. Proportional-hazards assumptions were confirmed for sRANKL and OPG by testing each variable with an interaction for time (Cox models with time-dependent covariates).20 Differential associations in subgroups were analyzed by inclusion of appropriate interaction terms. Associations between sRANK and the various measures of atherosclerosis were tested by means of linear and logistic regression models. Multiple regression analyses were adjusted for fixed sets of covariates assessed in previous analyses of the vascular risk profiles of the Bruneck Study population.15,16 All reported probability values are 2 sided.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Data on the distribution of sRANKL in the general community and on intraindividual variations in serum concentrations over time were published previously (mean±SD, 1.16±0.93 pmol/L; range, 0.10 to 17.0 pmol/L).10 Levels of RANKL did not correlate with age, gender, serum creatinine and vascular risk factors.10,21 In the 15-year follow-up period, 124 individuals experienced a myocardial infarction, ischemic stroke, transient ischemic attack, or vascular death (primary outcome), corresponding to an incidence rate of 10.7 per 1000 person-years. Population characteristics according to CVD status and the multivariable CVD risk profile are depicted in Tables 1 and 2
. sRANKL emerged as a highly significant and independent risk predictor for CVD. A large number of sensitivity analyses further substantiated our findings. First, results were virtually unchanged when controlling the analysis for standard cardiovascular drugs and hormone replacement therapy and for the presence and severity of heart failure (New York Heart Association scale)1,22,23 (Table 3). Second, when the outcome category was extended to account for revascularization procedures, new-onset peripheral artery disease and de novo angina (extended composite end points) results were similar. Details are depicted in Table 4, as are associations between sRANKL and individual disease categories. Third, after exclusion of subjects with preexisting CVD, findings closely matched those of the original analysis (Table 3). Accordingly, the predictive significance of sRANKL for CVD risk was nearly identical in subjects with and without previous CVD (P=0.750 for interaction). Fourth, the association between sRANKL and CVD risk was internally consistent. No evidence was present of a differential association in men and women or in patients with and without heart insufficiency (P=0.747 and 0.216 for interaction) and no effect measure modification for the associations of sRANKL and OPG with CVD risk (P=0.252 for interaction). Fifth, consideration of changes in variable levels over time (Cox models with multiple time-dependent covariates) confirmed the results on the basis of baseline levels (Table 3). To further elaborate the scale of relationship, hazard ratios were computed for tertile groups of sRANKL. Results, depicted in the Figure, indicate a dose-response relation with continuous increase in risk across tertile groups.
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Addition of OPG and/or sRANKL to an equation including all other multivariable risk predictors resulted in a modest increase in the area under the receiver-operating characteristic curve (by 0.003 for the addition of OPG, by 0.010 for the addition of sRANKL, and by 0.015 for the addition of both variables) but in a significant improvement in the likelihood function (likelihood ratio statistic, P=0.048, P<0.001, and P<0.001). Probability values derived from the Hosmer-Lemeshow calibration statistic (comparing observed and predicted risk using decile categories of predicted probabilities) amounted to 0.154 for the multivariable model not including OPG and sRANKL and to 0.206, 0.771, and 0.939 for models also considering OPG, sRANKL, or both.
We also examined the relation between sRANKL level and atherosclerosis assessed during the 1995 examination. Intima-media thickness and the loge-transformed atherosclerosis score emerged as unrelated to sRANKL in both the carotid (adjusted regression coefficients for a 1-unit increase in sRANKL, 3.0; 95% confidence interval [CI], –6.8 to 12.8; P=0.483; and –0.013; 95% CI, –0.099 to 0.073; P=0.770) and femoral (1.0; 95% CI, –8.8 to 10.8; P=0.871; and –0.041; 95% CI, –0.16 to 0.07; P=0.489) arteries. Comparisons of subjects with (55.2%) and without (44.8%) carotid atherosclerosis or with (43.2%) and without (56.8%) femoral atherosclerosis again showed sRANKL to be similar in both groups (odds ratios for a 1-unit increase in sRANKL, 1.00; 95% CI, 0.90 to 1.11; P=0.976; and odds ratio, 0.98; 95% CI, 0.88 to 1.10; P=0.773). When we focus on atherosclerosis progression between 1995 and 2000, a total of 40.0% and 21.0% of study subjects experienced early atherogenesis or stenotic transformation of preexisting plaques (advanced atherogenesis), respectively. The odds ratios of early and advanced atherogenesis amounted to 1.00 (95% CI, 0.90 to 1.10) and 0.76 (95% CI, 0.54 to 1.07). Again, the relations fell short of statistical significance. Finally, the proportions of individuals who experienced early and advanced atherogenesis during follow-up according to tertile groups for sRANKL were as follows: 40.9%, 37.2%, and 41.7% and 22.7%, 22.0%, and 18.4% (P for trend=0.849 and 0.427).
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Discussion |
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In recent years, a number of experimental studies have yielded intriguing preliminary evidence for a role of RANKL in plaque destabilization and acute vascular syndromes.1–4,6–8 Functionally, RANKL was shown to enhance chemokine (monocyte chemotactic protein-1) release from peripheral blood mononuclear cells and matrix metalloproteinase activity in vascular smooth muscle cells.1–4,6,8 Monocyte/macrophage matrix migration and matrix degeneration are key processes in the final chain of events causing plaque disruption. In addition, RANKL is assumed to stimulate osteogenic differentiation and calcification of vascular smooth muscle cells.1,3,6 Focal calcium deposits in the intimal and medial layers are capable of amplifying wall shear stresses and attenuating plaque stability.24 Upregulation of RANKL is triggered by proinflammatory cytokines like interleukin-1
, tumor necrosis factor-, and interleukin-6 and may be viewed as part of the immunoinflammatory milieu seen in advanced plaques.1,4,6 Cellular sources of and targets for the paracrine action of RANKL in the vasculature are activated endothelial cells, T cells, mast cells, and osteoblasts on the one hand and macrophages and dendritic cells on the other.1–4,6 RANKL is (almost) absent in normal vasculature but shows strong immunostaining in advanced atherosclerosis, especially plaques with a vulnerable phenotype and thrombus material obtained from ruptured coronary lesions.1,2 The rapidly growing knowledge about the regulation of RANKL expression and the pleiotropic effects of RANKL on plaque inflammation, mineralization, and matrix integrity contrasts with the considerable paucity of epidemiological (in vivo) data currently restricted to a few stimulating, albeit small, investigations. In 12 patients with unstable angina hallmarked by vulnerable coronary lesions, RANKL mRNA levels in T cells and expression of its receptor RANK on monocytes were significantly higher than in healthy control subjects or in patients with stable angina.2 Two studies have suggested an inverse association between levels of sRANKL and symptomatic coronary artery disease, but these evaluations are limited by small sample size,25 cross-sectional design,21,25 and presentation of preliminary data.21 Our study is the first to provide large-scale epidemiological support for a role of RANKL in vascular disease. As the main finding, baseline levels of sRANKL significantly predicted the risk for CVD over a 15-year follow-up period. Predictive significance was independent of gender, traditional and novel risk factors, previous CVD, and heart failure (Table 3). It was highest for acute vascular syndromes like myocardial infarction and ischemic stroke and less pronounced or even absent for de novo stable angina and intermittent claudication usually arising from stable vessel stenosis (Table 4). Of particular note and in line with these findings, the sRANKL association did not extend to the presence, severity, and progression of femoral or carotid artery atherosclerosis. For some ultrasound measures, even nonsignificant inverse association trends emerged. Taken together, these findings rule out the possibility that elevated CVD risk among subjects with high sRANKL is mediated by an enhanced burden of atherosclerosis and, vice versa, nicely support the alternative concept that RANKL contributes to the destabilization of existent plaques.
The interplay between RANKL and its naturally occurring decoy receptor OPG deserves further consideration. Under normal circumstances, OPG binds competitively to RANKL and neutralizes its effects like activation of nuclear factor-B and adaptor protein-1 transcription factor complexes.1,3,6 In 2 recent studies, however, high concentrations of OPG were reported to enhance smooth muscle cell apoptosis, matrix metalloproteinase-2 and -9 release, and monocyte chemotaxis,2,26 even though relevance of these findings to the in vivo situation is not yet proven. Particularly high levels of OPG have been observed in endarterectomy specimens from patients with symptomatic carotid stenosis, ie, recently disrupted plaques.27 In our study, high RANKL and high OPG emerged as independent and positive predictors of CVD risk. Both variables were weakly and inversely correlated with each other (r=–0.135), and no effect measure modification existed of the relation between sRANKL and CVD risk by OPG level. A positive association between OPG and CVD risk was consistently demonstrated in a number of previous studies and may be explained by the proposed ability of serum OPG to reflect the overall activity of the RANKL/RANK/OPG system.1,10,28–30
Strengths of our study include its representative nature for the general community (nearly complete participation and follow-up); the high degree of accuracy in assessing CVD end points and atherosclerosis; extensive clinical and laboratory characterization of study subjects, ensuring the best possible control for confounding conditions; and the availability of repeated measurements of sRANKL and all other parameters, allowing us to account for changes in variable levels over time (supplementary analysis; Table 3). Several limitations also warrant attention. First, only part of the sRANKL measured in serum is actually of vascular origin, and little is known about the clearance of sRANKL. It is currently unknown how good sRANKL is as a surrogate for RANKL concentrations in the vasculature. Any major deviation, however, can be expected to weaken evident relations rather than to create spurious ones. Second, our study on its own does not allow us to settle the causality of the association between sRANKL and CVD risk. Theoretically, elevated sRANKL among subjects at high vascular risk could be an epiphenomenon of plaque inflammation.
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Conclusions |
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The present study lends strong epidemiological support to a role of RANKL in CVD. Unlike most classic risk factors, RANKL apparently does not promote atherosclerosis, but intriguing preliminary evidence suggests that RANKL is engaged in plaque destabilization and rupture. If this concept gains confirmation in future experimental and epidemiological research, it may well lead to the development of novel therapeutic strategies (antagonism of RANKL in patients with acute vascular syndromes or vulnerable plaques). Specific blockage of RANKL by a monoclonal antibody called denosumab has proven efficacy to increase bone mass in postmenopausal women and is currently being tested to stop bone loss in postmenopausal osteoporosis, bone metastasis, and rheumatoid arthritis in phase II and III trials.31
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Acknowledgments |
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Sources of Funding
The present study was supported by a grant from the Austrian National Bank (Project 8715), the Pustertaler Verein zur Prävention von Herz- und Hirngefässerkrankungen and the START Prize of the Austrian Ministry of Science, Austria, and British Heart Foundation, UK.
Disclosures
None.
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CLINICAL PERSPECTIVE
Therapeutic strategies currently used in vascular medicine focus primarily on decelerating atherosclerosis, preventing atheroma-associated thrombus formation or reopening stenosed/occluded vessels. Drug therapy able to rapidly stabilize vulnerable plaques is not yet available, even though statins may enhance the stability of atherosclerotic lesions long term. Our understanding of the molecular mechanisms rendering plaques susceptible to rupture and mediating the fissuring event is still incomplete. Recently, overexpression of receptor activator of nuclear factor-B ligand (RANKL), a tumor necrosis factor family member, was shown to be a prominent feature of unstable atheroma, and it was suggested that it played a role in the transition from stable to vulnerable plaque phenotype because of its ability to promote monocyte/macrophage chemotaxis and matrix degradation. Data from the Bruneck Study lend large-scale epidemiological support to this concept and demonstrate a significant association between soluble RANKL level and cardiovascular disease risk. The findings are clinically relevant in light of the current testing of specific blockage of RANKL as a means of stopping bone loss in osteoporosis, bone metastasis, and rheumatoid arthritis, and RANKL may well become a routine aspect of the care of patients with these diseases in near future. Our data help dispel concerns about the vascular safety of this therapy. Although now speculative, RANKL antagonism also may qualify as a novel plaque-stabilizing therapy for patients with acute vascular syndromes. The next steps are to thoroughly replicate key findings in independent studies, to elaborate the effects of RANKL in advanced atherosclerosis, and to test RANKL antagonism in appropriate animal models.
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Footnotes |
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The online-only Data Supplement, consisting Methods, is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.106.686774/DC1.
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