Published online before print February 19, 2008, doi: 10.1161/CIRCULATIONAHA.107.731398
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(Circulation. 2008;117:1302-1309.)
© 2008 American Heart Association, Inc.
Vascular Medicine |
Microsomal Prostaglandin E Synthase-1 Deletion Suppresses Oxidative Stress and Angiotensin II–Induced Abdominal Aortic Aneurysm Formation
From the Institute for Translational Medicine and Therapeutics, University of Pennsylvania (M.W., W.S., E.R., D.J.R., J.A.L., G.A.F.); and the Wistar Institute (E.L., E.P.), Philadelphia, Pa.
Correspondence to Garret A. FitzGerald, MD, Institute for Translational Medicine and Therapeutics, 153 Johnson Pavilion, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104. E-mail garret{at}spirit.gcrc.upenn.edu
Received August 1, 2007; accepted January 2, 2008.
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Abstract |
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Background— Microsomal prostaglandin (PG) E2 synthase-1 (mPGES-1) catalyzes isomerization of the cyclooxygenase product PGH2 into PGE2. Deletion of mPGES-1 modulates experimentally evoked pain and inflammation and retards atherogenesis. The role of mPGES-1 in abdominal aortic aneurysm is unknown.
Methods and Results— The impact of mPGES-1 deletion on formation of angiotensin II–induced abdominal aortic aneurysm was studied in mice lacking low-density lipoprotein receptor (LDLR–/–). Male mice deficient in both mPGES-1 and LDLR (mPGES-1–/– LDLR–/–) and littermate LDLR–/– mice were initiated on a high-fat diet at 6 months of age, followed 1 week later by continuous infusion of angiotensin II (1 µg/kg per minute) for an additional 4 weeks. Angiotensin II infusion upregulated aortic expression of cyclooxygenase-2 and mPGES-1, increased aortic macrophage recruitment and vascular nitrotyrosine staining (which reflects local oxidative stress), and augmented urinary excretion of the isoprostane 8,12-iso-iPF2
-VI (which reflects lipid peroxidation in vivo) and the major metabolite of PGE2 (PGE-M). Deletion of mPGES-1 decreased both the incidence (87.5% versus 27.3%; P=0.02) and the severity of abdominal aortic aneurysm and depressed the aortic and systemic indices of oxidative stress. Deletion of mPGES-1 also depressed urinary PGE-M, whereas it augmented excretion of PGD2 and PGI2 metabolites, reflecting rediversion of the accumulated PGH2 substrate in the double knockouts.
Conclusions— Deletion of mPGES-1 protects against abdominal aortic aneurysm formation induced by angiotensin II in hyperlipidemic mice, coincident with a reduction in oxidative stress. The potential efficacy of selective inhibition of mPGES-1 in preventing or retarding aneurysm formation warrants further investigation.
Key Words: aneurysm • aorta • drugs • prostaglandins
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Introduction |
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Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by localized connective tissue degradation and smooth muscle cell apoptosis, leading to aortic dilatation and rupture. AAA is estimated to cause
1% of all deaths among men aged 65 to 85 years in developed countries.1 Although associated with common cardiovascular risk factors,1,2 the pathogenesis of AAA is poorly understood. Many cases are undiagnosed until they declare clinically by aneurysm leakage or rupture, and specific treatments that retard aneurysm development or induce its regression remain to be identified. Human aortic aneurysm biopsies stain strongly for cyclooxygenase (COX)-2 ex vivo, and a preliminary study of 15 patients taking nonsteroidal antiinflammatory drugs (NSAIDs) with 63 control subjects suggested that aneurysmal growth might be retarded by such treatment.3 Deletion or selective inhibition of COX-2, but not inhibition of COX-1, decreases AAA formation in hyperlipidemic mice.4,5
Clinical Perspective p 1309
Prostaglandins (PG) are formed by the action of both COX-1 and COX-2. The latter enzyme is more readily induced by inflammatory cytokines and is the dominant source of prostaglandins formed in response to lipopolysaccharide infusion in humans.6 However, placebo-controlled trials have revealed that NSAIDs selective for inhibition of COX-2 confer a cardiovascular hazard.7 Randomized comparisons of these drugs with traditional NSAIDs and epidemiological data are consistent with studies of human pharmacology and rodent biology in attributing this risk largely to suppression of the cardioprotective properties of COX-2–derived prostacyclin (PGI2). This risk is likely to be modulated at the individual level by the patient’s underlying cardiovascular risk, the extent of drug exposure, and concomitant therapies.8
Microsomal prostaglandin E synthase-1 (mPGES-1)9,10 catalyzes the isomerization of PGH2 into PGE2 and is a member of the membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) superfamily; it has been suggested as an alternative antiinflammatory drug target.9 Two other PGE synthases have been identified: mPGES-211 and cytosolic PGES.12,13 However, mPGES-1 is the dominant source of PGE2 biosynthesis, at least in mice.14 mPGES-1 is often coregulated with COX-215 but has been colocalized with both COX isoforms in some settings.12,16 mPGES-1 deletion in mice has been reported to modulate experimentally evoked pain and inflammation to a degree indistinguishable from treatment with traditional NSAIDs.17,18 It has also been implicated in immune-induced pyresis.19 However, in contrast to the effects of inhibition or deletion of COX-2, mice deficient in mPGES-1 exhibit a favorable cardiovascular profile. Deletion of mPGES-1 does not enhance responsiveness to a thrombogenic stimulus in vivo14 and retards atherogenesis in hyperlipidemic mice.20 These properties may reflect rediversion of the mPGES-1 substrate, PGH2, to PGI synthase, as biosynthesis of PGI2 is augmented in these mice.14,20 Such a cardiovascular profile may render selective inhibitors of mPGES-1 a more attractive option than NSAIDs selective for inhibition of COX-2 in the treatment or prevention of inflammatory disorders of the cardiovascular system, such as AAA. In this study, we report that mPGES-1 deletion has a dramatic impact on AAA formation induced by infusion of angiotensin II (Ang II) in hyperlipidemic mice lacking the low-density lipoprotein receptor (LDLR–/–). This may reflect suppression of oxidant stress, concomitant with augmented formation of both PGI2 and PGD2 consequent to mPGES-1 substrate rediversion.
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Methods |
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Knockout Mice and the Ang II Infusion Aneurysm Model
mPGES-1–/– LDLR–/– mice and their littermate controls (LDLR–/–) were generated by intercrossing mPGES-1+/– LDLR–/– mice, as described previously.20 Mice used in these studies had an
75% C57BL/6 and 25% DBA/1lacJ genetic background. The impact of mPGES-1 deletion on AAA development was studied in the Ang II–induced AAA model in LDLR–/– mice. Male mPGES-1–/– LDLR–/– mice and littermate LDLR–/– mice were initiated on a high-fat diet (0.2% cholesterol, 21% saturated fat; formula TD 88137, Harlan Teklad) at 6 months of age, followed 1 week later by continuous infusion of Ang II (Calbiochem, Darmstadt, Germany) at a rate of 1 µg/kg per minute for an additional 4 weeks. The Ang II was administered subcutaneously via Alzet osmotic minipumps (model 2004) as described previously.21 All animals were housed according to guidelines of the Institutional Animal Care and Usage Committee of the University of Pennsylvania, and all experiments were approved by the that committee. Systolic blood pressure was measured in conscious mice throughout the time course of the study with a computerized noninvasive tail-cuff system and calculated as described previously.14
Preparation of Mouse Aortae and Quantification of Aneurysms
Mice were euthanized and perfused with ice-cold PBS. The abdominal aorta was dissected out, immediately put into PBS, and cleaned of adventitial fat. The maximal abdominal aortic diameter was measured with the use of a caliber under a dissection microscope, while the aorta rested in PBS buffer without any physical stretching. A >50% increase in external diameter of the abdominal aorta was used to define the occurrence of an AAA. AAA severity was classified visually as described previously22 and also assessed by the external diameter and the wet weight of the abdominal aorta.
Analyses in Plasma
Blood was drawn from the vena cavae of CO2-euthanized mice, and EDTA (final concentration, 10 mmol/L) was added immediately. Plasma glucose, total cholesterol, and triglyceride levels were measured enzymatically on a Cobas Fara II autoanalyzer (Roche Diagnostic Systems Inc, Nutley, NJ) with reagents from Wako Chemicals (Richmond, Va).
Real-Time Polymerase Chain Reaction Analysis of Gene Expression in Mouse Aorta
TaqMan gene expression assays (Applied Biosystems, Foster City, Calif; catalog No. 4331182) for mPGES1 (Mm00452105_m1), COX-1 (Mm00477214_m1), COX-2 (Mm00478374_m1), and Ang II receptors (AT1A: Mm01957722_s1; AT1B: Mm02620758_s1; AT2: Mm01341373_m1) were performed on an ABI Prism 7900 Sequence Detection System. Results were normalized with 18S rRNA (Hs99999901_s1).
Histological Examination of Vascular Morphology
Suprarenal abdominal aortae were harvested on day 8 of the Ang II infusion. Peroxidase-quenched sections (8 µm) of OCT-embedded abdominal aorta were blocked with 3% BSA (in PBS) containing 20 µg/mL goat IgG (Jackson ImmunoResearch, West Grove, Pa) followed by incubation with primary antibodies: FITC-conjugated mouse anti--smooth muscle actin clone 1A4 (Sigma-Aldrich, St Louis, Mo), biotinylated rat anti-CD11b (BD Biosciences, San Jose, Calif), rabbit anti-nitrotyrosine IgG (Millipore, Billerica, Mass), rabbit anti-mouse mPGES-1 antibody (Santa Cruz Biotechnology, Santa Cruz, Calif), and rabbit anti-mouse COX-1 and COX-2 antibodies (Cayman Chemicals, Ann Arbor, Mich). Sections were then incubated with either biotinylated goat anti-rabbit IgG, mouse anti-FITC IgG (Jackson ImmunoResearch, West Grove, Pa), followed by Vectastain ABC avidin-biotin (Vector Laboratories, Burlingame, Calif) or directly with Vectastain ABC avidin-biotin, and developed with DAB (DAKO, Carpinteria, Calif). All sections were counterstained with Gill’s Formulation No. 1 hematoxylin (Fisher Scientific, Fair Lawn, NJ), and isotype controls were run in parallel, with negligible staining observed in all cases. CD11b, nitrotyrosine, mPGES-1, COX-1, and COX-2 staining was performed on nonfixed OCT-embedded samples, and smooth muscle cell staining was performed on Prefer (Anatech, Battle Creek, Mich) fixed and OCT-embedded samples.
Analysis of Prostanoids
Urine was collected for 24 hours at baseline and 4 weeks after Ang II infusion. Systemic production of PGE2, thromboxane A2 (TxA2), PGI2, and PGD2 was determined by stable isotope dilution, tandem mass spectrometric quantification of their major urinary metabolites23: 9,15-dioxo-11-hydroxy-2,3,4,5-tetranor-prostan-1,20-dioic acid (PGE-M), 2,3-dinor-thromboxane B2 (Tx-M), 2,3-dinor-6-keto PGF1 (PGI-M), and 11,15-dioxo-9-hydroxy-2,3,4,5-tetranor-prostan-1,20-dioic acid (PGD-M), respectively. The nonenzymatic lipid peroxidation product, 8,12-iso-iPF2-VI, was measured as previously published.23 Metabolite levels were corrected for urinary creatinine (Oxford Biomedical Research, Oxford, Mich).
Statistical Analysis
Data are expressed as mean±SEM. Comparisons of multiple groups were performed by ANOVA and a Bonferroni post-ANOVA multiple comparison test when the ANOVA was significant. When only 2 mean values were compared, the 2-tailed Mann-Whitney t test was used. Differences were considered statistically significant at P<0.05.
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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mPGES-1 Deletion Attenuates Ang II–Induced Aortic Aneurysm
Ang II infusion induces formation of aneurysms predominantly of the abdominal aortae in hyperlipidemic mice.21,24 mPGES-1 deletion decreased both the incidence (LDLR–/–: 87.5% versus mPGES-1–/– LDLR–/–: 27.3%) of AAA formation and its severity, as reflected by the maximal diameter and the wet weight of the abdominal aorta (Figure 1A to 1E). Sudden death due to rupture of the abdominal aorta was both delayed and reduced in the mPGES-1–/– LDLR–/– mice (Figure 1F and 1G). Ang II infusion increased blood pressure, but a divergence was not observed between LDLR–/– and mPGES-1–/– LDLR–/– mice throughout the study (Figure 1H). There was no impact of mPGES-1 deletion on fasting plasma total cholesterol, free cholesterol, high-density lipoprotein cholesterol, triglycerides, or glucose in LDLR–/– mice (Table).
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Ang II Upregulates mPGES-1 and Increases Oxidative Stress
Considering the advanced stage of most of the AAAs formed after 4 weeks of Ang II infusion (Figure 1D), we sought evidence for pathogenesis in samples harvested at an earlier time point: day 8 of Ang II treatment. The most striking morphological change at this time was that Ang II caused macrophage recruitment to the adventitia and endothelium; however, this was not affected by deletion of mPGES-1 (Figure 2). CD11b was used in this study as a macrophage marker, although it may also identify granulocytes. The number of CD11b-positive cells (Figure 2B) was not altered by mPGES-1 deletion. Ang II increased aortic expression of both COX-2 and mPGES-1, but not COX-1, as detected by real-time polymerase chain reaction, and deletion of mPGES-1 abolished detection of its transcript, whereas expressions of COX-2 and COX-1 were not altered significantly (Figure 3A). Immunohistochemistry confirmed upregulation of mPGES-1 and COX-2 but not COX-1 in Ang II–treated LDLR–/– mice. mPGES-1 staining was apparent in smooth muscle cells and endothelial cells in Ang II–treated mice (Figure I in the online-only Data Supplement), whereas Ang II–induced COX-2 expression was most striking in endothelial cells in both single and double knockout mice with some staining of adventitial cells in LDLR–/– mice (Figure II in the online-only Data Supplement). mPGES-1 deletion significantly attenuated Ang II–induced indices of both aortic and systemic oxidative stress (Figure 3B and 3C). Peroxynitrite, the product of the reaction of O2– and nitric oxide, reacts with and nitrates tyrosine groups of proteins. Thus, the relative level of immunoreactive nitrotyrosine in a tissue is a widely recognized marker of general oxidative stress. Ang II treatment potently augmented immunoreactive nitrotyrosine in aortic endothelium, adventitia tunica, and tunica media (Figure 3B, top and middle panels), which is indicated by the staining of smooth muscle actin (Figure 3B, bottom panel). This effect on tissue nitrotyrosine was evident even before aneurysm formation was detected. mPGES-1 deletion significantly attenuated this index of aortic oxidative stress. The pro-oxidant effect of Ang II was also reflected by increased urinary 8,12-iso-iPF2-VI, a sensitive index of lipid peroxidation in vivo.25 Deletion of mPGES-1 depressed significantly Ang II–induced augmentation of urinary 8,12-iso-iPF2-VI (Figure 3C).
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Differential Impact of mPGES-1 Deletion on Systemic Prostanoid Generation
Coincident with increased aortic expression of mPGES-1, Ang II infusion augmented systemic biosynthesis of its product, PGE2, as reflected by urinary excretion of its major metabolite, PGE-M. This effect was abolished in mice lacking mPGES-1 (Figure 4A). Ang II increased excretion of metabolites of PGD2, PGI2, and TxA2. mPGES-1 deletion augmented further the production of PGD2 and PGI2, but not of TxA2, at baseline or after Ang II treatment (Figure 4B to 4D).
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Ang II–induced AAA formation in mice is mediated by its receptors.22 Deletion of mPGES-1 did not apparently affect the aortic expression of any of the angiotensin receptors: AT1A, AT1B, or AT2 (Figure III in the online-only Data Supplement). An 60% reduction in aortic activity of matrix metalloproteinase 2 (MMP-2) was associated with mPGES-1 deficiency in the Ang II–treated mice (Figure IV in the online-only Data Supplement). Activity of aortic MMP-9 was much lower than that of MMP-2 in the same zymography study, and comparative analysis of the impact of mPGES-1 deletion on MMP-9 versus MMP-2 activity was unsuccessful.
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Discussion |
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Studies in mice and humans have implicated COX-2 and its products in the pathogenesis of aortic aneurysm. Because this is a common but probably underdiagnosed and potentially fatal condition, the possibility of a chemopreventative strategy has considerable appeal. However, the appreciation that NSAIDs selective for COX-2 (which include several of the older traditional NSAIDs) themselves confer a cardiovascular hazard7 limits their utility in a population often characterized by diffuse atherosclerotic disease, a condition associated with AAA.26 Recently, mPGES-1 has emerged as a potentially attractive alternative drug target to COX-2. Although other sources of formation of PGE2 have been identified11–13 and prostanoids other than PGE2, such as PGI2,27,28 can mediate pain and inflammation, mPGES-1 deletion has been as effective as traditional NSAIDs in alleviating some paradigms of pain and inflammation in mice.17,18
In the present study, we report that mPGES-1 deletion has a marked impact on the development and extent of Ang II–induced AAA formation in mice. It is unclear to what extent this commonly used model29 simulates the human condition. However, there is increased expression of COX-2 both in the lesions of this model and in human aneurysmal tissue,3 and there is some preliminary evidence that prostaglandins might contribute to lesion progression in humans.3 Patients presenting with aortic aneurysm are often characterized by extensive atherosclerotic disease. Because placebo-controlled trials7 have shown that NSAIDs selective for inhibition of COX-2 confer a cardiovascular hazard, they are not an attractive therapeutic option despite data in mice and humans implicating COX-2 in the pathogenesis of AAA.
Initial studies in mice raise the possibility that selective inhibitors of mPGES-1 may have a more favorable cardiovascular profile than COX-2 inhibitors. We have reported previously that mPGES-1 deletion, unlike deletion or inhibition of COX-2 or deletion of the PGI2 receptor, does not enhance the response to a thrombogenic stimulus in vivo.14 Furthermore, unlike inhibition and deletion of COX-2, which have been reported to variably influence atherogenesis,30 mPGES-1 deletion markedly retards lesion progression in LDLR–/– mice.20 Finally, we and others have reported that mPGES-1 deletion failed to elevate blood pressure, even in mice on a high-salt diet.14,31 However, Jia et al32 have reported a hypertensive response to mPGES-1 deletion. Potential explanations for these divergent results include differences in genetic background, a more intense salt-loading regimen, and the use of wild-type but not littermate controls. mPGES-1 deletion did not augment the hypertensive response to Ang II in hyperlipidemic mice in the present study. Although the extent to which these early observations extend to treating humans with selective mPGES-1 inhibitors remains to be established, they raise the prospect of an attractive approach to limiting inflammatory diseases in patients with established cardiovascular disease. Selective inhibitors of mPGES-1 are under development. Experiments with knockout mice suggest that they may be less likely to confer cardiovascular hazard than NSAIDs selective for inhibition of COX-2, perhaps because of substrate rediversion to cardioprotective prostanoids.
Aneurysmal lesions in both humans and mice exhibit the hallmarks of inflammation, and the attendant oxidant stress has been implicated in the pathogenesis of the disease.33–35 In the present study, we show that infusion of Ang II results in early recruitment of macrophages and extensive evidence of oxidative stress in the vasculature, as reflected by medial staining for nitrotyrosine, especially proximal to the endothelium and the adventitia. Deletion of mPGES-1 has a marked impact on such staining as well as on a systemic index of oxidant stress25: urinary excretion of the most abundant F2 isoprostane, 8,12-iso-iPF2–VI. Although macrophage recruitment was unaltered by mPGES-1 deletion, the impact on oxidant stress may have reflected an alteration in their production of prostaglandins. Thus, concomitant with suppression of PGE2, biosynthesis of both PGI2 and PGD2 is augmented in mice lacking mPGES-1. Both PGI236 and PGD237 have been implicated previously in restraining oxidant stress via their induction of antioxidant enzymes. Although Ang II increased formation of TxA2, which has pro-oxidant properties,38 TxA2, unlike PGI2 and PGD2, was not increased further consequent to mPGES-1 deletion during AAA formation.
Prostaglandin intermediates that accumulate after inhibition or deletion of synthases downstream of the COXs may be shuttled between cells to form transcellular products of functional importance. An example is the diversion of platelet PGH2 substrate to endothelial PGI2 synthase,39 which contributed to the functional effects of thromboxane synthase inhibitors.40 Evidence for substrate rediversion within cells after mPGES-1 deletion has been shown previously.41 The predominant products of rediversion vary according to cell type; thus, PGI2 is by far the most abundant product in vascular smooth muscle cells, whereas both TxA2 and PGI2 may result from mPGES-1 deletion in macrophages.41 Rediversion of substrate to endothelial PGI2 might also be relevant given the upregulation of COX-2 in both endothelial cells and smooth muscle cells by Ang II infusion in the present studies. Measurement of urinary metabolites reflects alterations in systemic biosynthesis of prostanoids and does not permit direct assignation of cellular origin to a particular product. PGD2 is a product of macrophage COXs, and this may account for its augmented formation in the present study. However, if so, it is surprising that thromboxane biosynthesis is not altered. A more intriguing possibility is that it derives from mast cells. PGD2 is the predominant COX product in mast cells,42 and mast cells have previously been implicated in atherosclerotic plaque destabilization.43 Future studies will address the origin and the functional relevance of increased formation of PGD2 in the attenuation of AAA consequent to mPGES-1 deletion.
MMPs are thought to be involved in AAA pathogenesis.44–46 Deletion of mPGES-1 impaired aortic MMP-2 activity (Figure IV in the online-only Data Supplement). This may be due to a direct effect of mPGES-1–derived PGE2 and/or the suppressed vascular oxidative stress consequent to mPGES-1 deletion. Previous work has demonstrated that PGE2 may regulate MMP-2 expression47,48 and that suppression of oxidative stress was associated with attenuated MMP-2 activity in Ang II–infused ApoE–/– mice,33 a model distinct from but similar to the one used in this study. It is presently unclear whether the reduction in activity of MMP-2 and perhaps other proteases derives from suppression of PGE2 or substrate rediversion to other products of COX, such as PGI2 and PGD2.
In the present study, we provide evidence that deletion of mPGES-1 retards AAA formation and severity. This suggests the potential utility of mPGES-1 inhibitors in a condition presently not amenable to chemoprevention. Given that mPGES-1 deletion has a concomitant beneficial impact on atherogenesis,20 mPGES-1 inhibition may have particular value in the treatment of inflammatory syndromes in patients with established cardiovascular disease.
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Acknowledgments |
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Technical support was kindly provided by Irene Crichton, Helen Zou, and Wenxuan Li.
Sources of Funding
This study was supported by National Institutes of Health grants HL-083799 and HL-62250 and an American Heart Association Scientist Development Grant to Dr Wang (0735397N). Dr FitzGerald is the McNeil Professor in Translational Medicine and Therapeutics.
Disclosures
Dr FitzGerald has served as a consultant to AstraZeneca, Biolipox, Daiichi, the Genome Institute of the Novartis Foundation, Lilly, Novartis, and Merck. The other authors report no conflicts.
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The online-only Data Supplement, which contains Figures I through IV, is available with this article at http://circ.ahajournals.org/cgi/content/ full/CIRCULATIONAHA.107.731398/DC1.
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