Published online before print July 21, 2003, doi: 10.1161/01.CIR.0000085568.13915.1E
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;108:512.)
© 2003 American Heart Association, Inc.
Brief Rapid Communications |
Increased Thrombosis After Arterial Injury in Human C-Reactive Protein–Transgenic Mice
From the Harvard–MIT Division of Health Sciences and Technology, Cambridge, Mass (H.D.D., R.V.S., P.S., D.I.S., E.R.E.); Department of Cardiology, Hadassah University Hospital, Jerusalem, Israel (H.D.D.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass (D.I.S., Z.C., E.R.E.); Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham (A.J.S.); and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor (W.P.F., L.P.).
Correspondence to Haim Danenberg, MIT, Bldg 56-322, 77 Massachusetts Ave, Cambridge, MA 02139. E-mail danen{at}mit.edu
Received January 21, 2003; de novo received May 30, 2003; accepted June 16, 2003.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— C-reactive protein (CRP), an acute-phase reactant long considered merely an innocent bystander in the inflammatory process, is now recognized as a powerful predictor of cardiovascular events. Emerging in vitro evidence suggests that CRP may have direct proinflammatory and prothrombotic effects on monocytes and endothelial cells. To determine whether CRP directly modulates vascular cell function in vivo, we subjected wild-type mice, which do not express CRP, and human CRP–transgenic (CRPtg) mice to 2 models of arterial injury.
Methods and Results— Baseline serum CRP levels in CRPtg mice were 18±6 mg/L. CRP levels were undetectable in wild-type mice. Transluminal wire injury led to complete thrombotic occlusion of the femoral artery at 28 days in 75% of CRPtg arteries (6 of 8) compared with 17% (2 of 12) in wild-type mice (P<0.05). In a model of arterial photochemical injury, clot formation time was shortened in CRPtg mice; mean time to occlusion was 33±19 minutes compared with 59±19 minutes in wild-type mice (n=10; P<0.05).
Conclusions— Arterial injury in CRPtg mice results in an expedited and higher rate of thrombotic occlusion. This is the first report of a prothrombotic phenotype directly attributable to the presence of human CRP in vivo. Investigation of the inflammatory-thrombotic axis in CRPtg mice may elucidate the prothrombotic actions of CRP in unstable arterial diseases and may pave the way for novel therapeutic interventions for preventing cardiovascular events.
Key Words: inflammation • risk factors • thrombosis • heart disease
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Inflammation plays a pivotal role in vascular injury and repair. Accordingly, the inflammatory marker C-reactive protein (CRP) has emerged as a powerful predictor for cardiovascular disease, associated with future cardiovascular events in seemingly healthy subjects and with worse prognosis in acute coronary patients.1–3 Long considered an innocent bystander in the atherosclerotic process, new evidence suggests that CRP might have direct proinflammatory effects on cardiovascular cells.4–6 However, direct evidence for a biological contribution of CRP to atherosclerosis in particular and the pathogenesis of cardiovascular disease in general remains elusive.
Mouse CRP circulates only in trace amounts, and its blood level does not change appreciably during inflammation.7 Transgenic mice that express human CRP7,8 might then serve as a model in which to examine the impact of human CRP on vascular repair in vivo. The response to injury of CRP-transgenic (CRPtg) mice was quantitatively and qualitatively different from that of wild-type mice. CRPtg mice experienced much faster and higher rates of complete thrombotic occlusion than their wild-type counterparts. These findings support the notion that the role of CRP in vascular injury and repair is active and direct, and they might explain the association between inflammation and thrombosis in unstable coronary syndromes.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
CRPtg Mice
The C57BL/6 congenic CRPtg mice used in this study have been described previously.7,8 CRPtg mice carry a 31-kb ClaI fragment of human genomic DNA consisting of the CRP gene, 17 kb of 5'-flanking sequence, and 11.3 kb of 3'-flanking sequence.7
Wire Injury Model
Animal care and surgical procedures were in accordance with the guidelines of the Association for Assessment and Accreditation of Laboratory Animal Care and the National Institutes of Health. Male CRPtg mice and age-matched congenic wild-type mice underwent bilateral wire injury of the femoral artery as described previously.9 A longitudinal groin incision exposed the femoral vessels, and under surgical microscopic visualization (Carl Zeiss) the distal portion of the femoral artery was encircled with an 8-0 nylon suture. A vascular clamp was placed proximally at the level of the inguinal ligament, and an angioplasty guidewire (0.010 inch in diameter; Advanced Cardiovascular Systems) was introduced into the arterial lumen through an arteriotomy made just distal to the suture. After release of the clamp, the guidewire was advanced to the level of the aortic bifurcation and pulled back. Guidewire advance and retraction was repeated thrice. The guidewire was then removed and the arteriotomy site ligated. Femoral arteries were harvested for morphometry 28 days after injury, fixed in 4% paraformaldehyde, embedded in paraffin, and cut into 3 segments. Sections (5 µm thick) of each segment were obtained for staining (Verhoeff) or immunohistochemistry. Standard avidin-biotin procedures for smooth muscle cell (SMC) 
-actin (DAKO Co) were used for immunohistochemistry. For morphometric analysis, microscopic images were digitized, and the amounts of media and neointima were quantified using the Adobe Photoshop 5.0 software.
Photochemical Thrombosis Model
CRPtg and wild-type mice were subjected to arterial injury by photochemical reaction, performed by an operator blinded to the genotype of mouse, as described previously.10 The left common carotid artery was isolated, and a vascular flow probe (Transonic Systems) was applied to monitor blood flow. Rose bengal (Fisher Scientific Co) at a concentration of 10 mg/mL in phosphate-buffered saline was injected into the tail vein to administer a dose of 50 mg/kg. The mid portion of the common carotid artery was then illuminated with a 1.5-mW green light laser (540 nm; Melles Griot Inc) until an occlusive thrombus was formed. The time required to form an occlusive thrombus, defined as absence of blood flow for 3 minutes or more, was recorded.
Measurement of Human CRP Levels
Mice were bled at 24 hours after wire injury. Serum human CRP levels were measured in duplicate by a commercial ELISA kit with a lower detection level of 1 µg/mL (Immuno-Biological Laboratories).
Statistics
Data are expressed as mean±SD. Fisher’s exact test was used to determine statistical significance of dichotomous variables (binary arterial occlusion). Comparisons of occlusion time and histological findings were done using the unpaired 2-tailed Student’s t test. Differences were considered statistically significant at P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Wire Injury Model
Serum CRP levels in CRPtg mice were 18±6 µg/mL and increased to 56±5 µg/mL 24 hours after surgery. Serum CRP levels were undetectable in wild-type mice throughout the experiment (Table). Hemoglobin levels and platelet counts of CRPtg mice were not significantly different from those of wild-type mice (Table). The leukocyte counts of CRPtg mice remained within the normal range but were slightly elevated and statistically significantly different from counts in control animals. The rate of complete arterial occlusion observed after injury was significantly higher in CRPtg mice (75%; 6 of 8 arteries) compared with wild-type mice (17%; 2 of 12 arteries) (P=0.015) (Figure 1A). Occlusive lesions in CRPtg arteries (Figure 1C) were typically less cellular than those of wild-type arteries (Figure 1B). Cell number within the internal elastic lamina (per 10 000 µm2) was 54.6±13 and 33.8±16 in the wild-type and CRPtg arteries, respectively (P=0.01). Neointima/media ratio at 4 weeks in wild-type mice was 1.32±0.69 (n=10) but could not be analyzed in CRPtg mice given their high rate of complete thrombotic occlusion. Immunostaining for
-actin revealed 3-fold lower SMC content in the intraluminal lesions of CRPtg mice (22±19% of intraluminal lesion area; Figure 1E) than in wild-type mice (58±19%; Figure 1D).
|
|
Photochemical Thrombosis Model
To elucidate the effect of CRP on the development of arterial thrombosis in real time, carotid arteries of CRPtg mice and their wild-type littermates were subjected to photochemical injury, and blood flow was monitored. Mean time to occlusive thrombus formation in wild-type mice was 59±19 minutes, compared with 33±19 minutes in CRPtg mice (n=10 per group; P<0.05) (Figure 2). This increase confirms and validates the facilitation of thrombosis in CRPtg mice.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
High serum CRP levels are predictive of acute cardiovascular events in seemingly healthy individuals. However, the pathogenic importance of CRP remains undetermined. The present study describes the first in vivo experiments of vascular injury in CRPtg mice and clearly demonstrates a significantly faster and higher rate of arterial thrombosis in mice producing human CRP. These findings, which were verified here in 2 different injury models, indicate a cause-and-effect relationship for CRP in vascular thrombosis and occlusion.
Unlike human CRP, mouse CRP is not an acute-phase reactant, and it is synthesized in only trace amounts.7 However, male CRPtg mice constitutively produce human CRP, with serum levels ranging between 10 and 20 µg/mL7—levels that are comparable to or eclipse those considered to indicate high risk in humans.11 Consequently, CRPtg mice provide an ideal model for studying the biological activities of human CRP in vivo.
The transluminal femoral wire injury model serves as a reliable model for studying the molecular mechanisms involved in the arterial wall response to injury.9,12,13 Complete thrombosis of the artery is normally infrequent, occurring in only 10% to 15% of cases.12 In the present study, the thrombosis rate in wild-type arteries was 17%, and the neointima/media ratio at 4 weeks was 1.32±0.69, similar to results reported previously using wild-type C57BL/6J mice.13 The finding of organized thrombi in 75% of the injured arteries in CRPtg mice indicates an increased thrombotic response to injury mediated by human CRP. The facilitated thrombosis in the rose bengal photochemical thrombosis model further supports this interpretation. The high rate of complete occlusion in the wire injury model and consequent low rate of patent vessels masked neointimal formation in CRPtg mice. Modified experimental protocols that would incorporate antithrombotic and anticoagulant agents are thus warranted to study the effect of human CRP on neointimal formation in the wire injury model.
Large epidemiological studies have correlated CRP levels with an increased risk of cardiovascular events in both healthy and acute cardiac patients. This correlation was much stronger than the association of high CRP and the burden of atherosclerosis or the extent of vascular disease.14 CRP-facilitated thrombotic occlusion fits into this scheme of events; vascular repair is impaired by increased thrombosis, which leads to a higher rate of complications after plaque rupture and vascular trauma. Although only a mediocre marker for atherosclerosis, CRP is a useful marker and an effector in the pathogenesis of cardiovascular events. Thus, it complements lipoprotein analysis in predicting atherosclerosis and its acute event risk.
Why does human CRP evoke rapid and frequent thrombosis? The interplay between inflammation and thrombosis is becoming increasingly well appreciated.15 CRP directly acts as a proinflammatory stimulus inducing expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemotactic protein-1 by human endothelial cells4,5 and interleukin-1ß and tumor necrosis factor- release by monocytes.16 In turn, IL-1ß and TNF- stimulate tissue factor expression from monocytes. Furthermore, CRP was reported to directly increase tissue factor from peripheral blood monocytes17 and endothelial cells.18 Thus, CRP is capable of recruiting and activating monocytes and increasing expression of tissue factor, the key initiator for thrombosis. Recently, CRP was shown to induce plasminogen activator inhibitor-1 expression and activity in human endothelial cells, further supporting CRP association and atherothrombosis.19
The present report is the first to show that CRP is a risk factor and possible causal agent, rather than merely a risk marker, for increased rate of arterial thrombosis in vivo and worsened outcome after controlled vascular injury. These findings might help us understand the recent observation that, whereas lipoproteins predict burden of atherosclerotic disease, CRP may be more strongly associated with risk of acute cardiovascular events. Further research is now warranted to elucidate the inflammatory-thrombotic relationship and the exact role of CRP in thrombotic sequelae and to develop therapeutic strategies to treat patients deemed at high risk because of elevated CRP.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557–1565.
2. Ridker PM. Inflammatory biomarkers, statins, and the risk of stroke: cracking a clinical conundrum. Circulation. 2002; 105: 2583–2585.
3. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836–843.
4. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 2165–2168.
5. Pasceri V, Cheng JS, Willerson JT, et al. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. 2001; 103: 2531–2534.
6. Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation. 2002; 106: 913–919.
7. Szalai AJ, McCrory MA. Varied biologic functions of C-reactive protein: lessons learned from transgenic mice. Immunol Res. 2002; 26: 279–287.[CrossRef][Medline] [Order article via Infotrieve]
8. Szalai AJ, Briles DE, Volanakis JE. Human C-reactive protein is protective against fatal Streptococcus pneumoniae infection in transgenic mice. J Immunol. 1995; 155: 2557–2563.[Abstract]
9. Reis E, Smyth S, Coller B. Mouse model of transluminal femoral artery injury. In: Simon DI, Rogers C, eds. Contemporary Cardiology: Vascular Disease and Injury: Preclinical Research. Totowa, NJ: Humana Press; 2001: 103–113.
10. Nagashima M, Yin Z-F, Zhao L, et al. Thrombin-activatable fibrinolysis inhibitor (TAFI) deficiency is compatible with murine life. J Clin Invest. 2002; 109: 101–110.[CrossRef][Medline] [Order article via Infotrieve]
11. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973–979.
12. Roque M, Fallon JT, Badimon JJ, et al. Mouse model of femoral artery denudation injury associated with the rapid accumulation of adhesion molecules on the luminal surface and recruitment of neutrophils. Arterioscler Thromb Vasc Biol. 2000; 20: 335–342.
13. Reis ED, Roque M, Dansky H, et al. Sulindac inhibits neointimal formation after arterial injury in wildtype and apolipoprotein E–deficient mice. Proc Natl Acad Sci U S A. 2000; 97: 12764–12769.
14. Folsom A, Pankow J, Tracy R, et al. Association of C-reactive protein with markers of prevalent atherosclerotic disease. Am J Cardiol. 2001; 88: 112–117.[CrossRef][Medline] [Order article via Infotrieve]
15. Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation. 2001; 103: 1718–1720.
16. Ballou S, Lozanski G. Induction of inflammatory cytokine release from cultured human monocytes by C-reactive protein. Cytokine. 1992; 4: 361–368.[CrossRef][Medline] [Order article via Infotrieve]
17. Cermak J, Key N, Bach R, et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood. 1993; 82: 513–520.
18. Napoleone E, Di Santo A, Bastone A, et al. Long pentraxin PTX3 upregulates tissue factor expression in human endothelial cells: a novel link between vascular inflammation and clotting activation. Arterioscler Thromb Vasc Biol. 2002; 22: 782–787.
19. Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation. 2003; 107: 397–403.
This article has been cited by other articles:
 |
|
 |
|
  T. Koike, S. Kitajima, Y. Yu, K. Nishijima, J. Zhang, Y. Ozaki, M. Morimoto, T. Watanabe, S. Bhakdi, Y. Asada, et al. Human C-Reactive Protein Does Not Promote Atherosclerosis in Transgenic Rabbits Circulation, November 24, 2009; 120(21): 2088 - 2094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-W. Park, S.-C. Yun, J.-Y. Lee, W.-J. Kim, S.-J. Kang, S.-W. Lee, Y.-H. Kim, C. W. Lee, J.-J. Kim, S.-W. Park, et al. C-Reactive Protein and the Risk of Stent Thrombosis and Cardiovascular Events After Drug-Eluting Stent Implantation Circulation, November 17, 2009; 120(20): 1987 - 1995. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Liu, W Zhang, X Tian, X Zhang, F Zhang, and X Zeng Prevalence, risk factors and outcome of digital gangrene in 2684 lupus patients Lupus, October 1, 2009; 18(12): 1112 - 1118. [Abstract] [PDF]
|
|
|
|
|
|
G. D. Norata, P. Marchesi, V. K. Pulakazhi Venu, F. Pasqualini, A. Anselmo, F. Moalli, I. Pizzitola, C. Garlanda, A. Mantovani, and A. L. Catapano Deficiency of the Long Pentraxin PTX3 Promotes Vascular Inflammation and Atherosclerosis Circulation, August 25, 2009; 120(8): 699 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Schiele, N. Meneveau, M. F. Seronde, R. Chopard, V. Descotes-Genon, J. Dutheil, J.-P. Bassand, and on behalf on the 'Reseau de Cardiologie de Franche C-reactive protein improves risk prediction in patients with acute coronary syndromes Eur. Heart J., July 4, 2009; (2009) ehp273v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Pons-Estel, L. A. Gonzalez, J. Zhang, P. I. Burgos, J. D. Reveille, L. M. Vila, and G. S. Alarcon Predictors of cardiovascular damage in patients with systemic lupus erythematosus: data from LUMINA (LXVIII), a multiethnic US cohort Rheumatology, July 1, 2009; 48(7): 817 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Devaraj, U. Singh, and I. Jialal The Evolving Role of C-Reactive Protein in Atherothrombosis Clin. Chem., February 1, 2009; 55(2): 229 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M Ridker C-Reactive Protein: Eighty Years from Discovery to Emergence as a Major Risk Marker for Cardiovascular Disease Clin. Chem., February 1, 2009; 55(2): 209 - 215. [Full Text] [PDF]
|
|
|
|
|
|
T. B. Grammer, W. Marz, W. Renner, B. O. Bohm, and M. M. Hoffmann C-reactive protein genotypes associated with circulating C-reactive protein but not with angiographic coronary artery disease: the LURIC study Eur. Heart J., January 2, 2009; 30(2): 170 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Molins, E. Pena, G. Vilahur, C. Mendieta, M. Slevin, and L. Badimon C-Reactive Protein Isoforms Differ in Their Effects on Thrombus Growth Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2239 - 2246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wu, M. J. Stevenson, J. M. Brown, E. A. Grunz, T. L. Strawn, and W. P. Fay C-Reactive Protein Enhances Tissue Factor Expression by Vascular Smooth Muscle Cells: Mechanisms and In Vivo Significance Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 698 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M Ridker High-Sensitivity C-Reactive Protein as a Predictor of All-Cause Mortality: Implications for Research and Patient Care Clin. Chem., February 1, 2008; 54(2): 234 - 237. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Xing, F. G. Hage, Y.-F. Chen, M. A. McCrory, W. Feng, G. A. Skibinski, E. Majid-Hassan, S. Oparil, and A. J. Szalai Exaggerated Neointima Formation in Human C-Reactive Protein Transgenic Mice Is IgG Fc Receptor Type I (Fc{gamma}RI)-Dependent Am. J. Pathol., January 1, 2008; 172(1): 22 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. F. Bodary Links Between Adipose Tissue and Thrombosis in the Mouse Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2284 - 2291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Westrick, M. E. Winn, and D. T. Eitzman Murine Models of Vascular Thrombosis Arterioscler Thromb Vasc Biol, October 1, 2007; 27(10): 2079 - 2093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Hage and A. J. Szalai C-Reactive Protein Gene Polymorphisms, C-Reactive Protein Blood Levels, and Cardiovascular Disease Risk J. Am. Coll. Cardiol., September 18, 2007; 50(12): 1115 - 1122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Momin, N. Melikian, S. B. Wheatcroft, D. Grieve, L. C. John, A. El Gamel, M. T. Marrinan, J. B. Desai, C. Driver, R. Sherwood, et al. The association between saphenous vein endothelial function, systemic inflammation, and statin therapy in patients undergoing coronary artery bypass surgery J. Thorac. Cardiovasc. Surg., August 1, 2007; 134(2): 335 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G O'Neill, D. A Isenberg, and A. Rahman Could antibodies to C-reactive protein link inflammation and cardiovascular disease in patients with systemic lupus erythematosus? Ann Rheum Dis, August 1, 2007; 66(8): 989 - 991. [Full Text] [PDF]
|
|
|
|
 |
|
 E. Grad, M. Golomb, I. Mor-Yosef, N. Koroukhov, C. Lotan, E. R. Edelman, and H. D. Danenberg Transgenic expression of human C-reactive protein suppresses endothelial nitric oxide synthase expression and bioactivity after vascular injury Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H489 - H495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Ridker C-Reactive Protein and the Prediction of Cardiovascular Events Among Those at Intermediate Risk: Moving an Inflammatory Hypothesis Toward Consensus J. Am. Coll. Cardiol., May 29, 2007; 49(21): 2129 - 2138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E. Szmitko and S. Verma C-Reactive Protein and Reendothelialization: NO Involvement Circ. Res., May 25, 2007; 100(10): 1405 - 1407. [Full Text] [PDF]
|
|
|
|
|
|
R. Schwartz, S. Osborne-Lawrence, L. Hahner, L. L. Gibson, A. K. Gormley, W. Vongpatanasin, W. Zhu, R. A. Word, D. Seetharam, S. Black, et al. C-Reactive Protein Downregulates Endothelial NO Synthase and Attenuates Reendothelialization In Vivo in Mice Circ. Res., May 25, 2007; 100(10): 1452 - 1459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Palmerini, A. Marzocchi, C. Marrozzini, L. B. Reggiani, C. Savini, G. Marinelli, R. Di Bartolomeo, and A. Branzi Preoperative C-reactive protein levels predict 9-month mortality after coronary artery bypass grafting surgery for the treatment of left main coronary artery stenosis Eur. J. Cardiothorac. Surg., April 1, 2007; 31(4): 685 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-Y. Chong and G. Y.H. Lip Viewpoint: The prothrombotic state in heart failure: A maladaptive inflammatory response? Eur J Heart Fail, February 1, 2007; 9(2): 124 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Lange, C. S. Carlson, L. A. Hindorff, E. M. Lange, J. Walston, J. P. Durda, M. Cushman, J. C. Bis, D. Zeng, D. Lin, et al. Association of Polymorphisms in the CRP Gene With Circulating C-Reactive Protein Levels and Cardiovascular Events JAMA, December 13, 2006; 296(22): 2703 - 2711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Libby and P. M. Ridker Inflammation and Atherothrombosis: From Population Biology and Bench Research to Clinical Practice J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A33 - A46. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Paffen and M. P.M. deMaat C-reactive protein in atherosclerosis: A causal factor? Cardiovasc Res, July 1, 2006; 71(1): 30 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hemelaar, P. Kenemans, C.G. Schalkwijk, D.D.M. Braat, and M.J. van der Mooren No increase in C-reactive protein levels during intranasal compared to oral hormone therapy in healthy post-menopausal women Hum. Reprod., June 1, 2006; 21(6): 1635 - 1642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, I. Jialal, B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, and I. Jialal The Verdict Is Still Out Circulation, May 2, 2006; 113(17): 2128 - 2151. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Montaner, I. Fernandez-Cadenas, C. A. Molina, M. Ribo, R. Huertas, A. Rosell, A. Penalba, L. Ortega, P. Chacon, and J. Alvarez-Sabin Poststroke C-Reactive Protein Is a Powerful Prognostic Tool Among Candidates for Thrombolysis Stroke, May 1, 2006; 37(5): 1205 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, J. T. Willerson, and P. M. Ridker C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C19 - C31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Jialal, S. Devaraj, and U. Singh C-Reactive Protein and the Vascular Endothelium: Implications for Plaque Instability J. Am. Coll. Cardiol., April 4, 2006; 47(7): 1379 - 1381. [Full Text] [PDF]
|
|
|
|
|
|
C. Mineo, A. K. Gormley, I. S. Yuhanna, S. Osborne-Lawrence, L. L. Gibson, L. Hahner, R. V. Shohet, S. Black, J. E. Salmon, D. Samols, et al. Fc{gamma}RIIB Mediates C-Reactive Protein Inhibition of Endothelial NO Synthase Circ. Res., November 25, 2005; 97(11): 1124 - 1131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Palmerini, A. Marzocchi, C. Marrozzini, P. Ortolani, F. Saia, L. Bacchi-Reggiani, S. Virzi, S. Gianstefani, and A. Branzi Preprocedural Levels of C-Reactive Protein and Leukocyte Counts Predict 9-Month Mortality After Coronary Angioplasty for the Treatment of Unprotected Left Main Coronary Artery Stenosis Circulation, October 11, 2005; 112(15): 2332 - 2338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Torzewski C-Reactive Protein and Atherogenesis: New Insights from Established Animal Models Am. J. Pathol., October 1, 2005; 167(4): 923 - 925. [Full Text] [PDF]
|
|
|
|
|
|
A. Pandolfi C-reactive protein: A potential new molecular link between inflammation, thrombosis and vascular cell proliferation? Cardiovasc Res, October 1, 2005; 68(1): 3 - 4. [Full Text] [PDF]
|
|
|
|
|
|
P. Cirillo, P. Golino, P. Calabro, G. Cali, M. Ragni, S. De Rosa, G. Cimmino, M. Pacileo, R. De Palma, L. Forte, et al. C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation Cardiovasc Res, October 1, 2005; 68(1): 47 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Wang, S. Oparil, Y.-F. Chen, M. A. McCrory, G. A. Skibinski, W. Feng, and A. J. Szalai Estrogen Treatment Abrogates Neointima Formation in Human C-Reactive Protein Transgenic Mice Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2094 - 2099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Singh, S. Devaraj, and I. Jialal C-Reactive Protein Decreases Tissue Plasminogen Activator Activity in Human Aortic Endothelial Cells: Evidence that C-Reactive Protein Is a Procoagulant Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2216 - 2221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nakakuki, M. Ito, H. Iwasaki, Y. Kureishi, R. Okamoto, N. Moriki, M. Kongo, S. Kato, N. Yamada, N. Isaka, et al. Rho/Rho-Kinase Pathway Contributes to C-Reactive Protein-Induced Plasminogen Activator Inhibitor-1 Expression in Endothelial Cells Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2088 - 2093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. T.H. Yeh A New Perspective on the Biology of C-Reactive Protein Circ. Res., September 30, 2005; 97(7): 609 - 611. [Full Text] [PDF]
|
|
|
|
|
|
E. Shagdarsuren, M. Wellner, J.-H. Braesen, J.-K. Park, A. Fiebeler, N. Henke, R. Dechend, P. Gratze, F. C. Luft, and D. N. Muller Complement Activation in Angiotensin II-Induced Organ Damage Circ. Res., September 30, 2005; 97(7): 716 - 724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. B. Schwedler, K. Amann, K. Wernicke, A. Krebs, M. Nauck, C. Wanner, L. A. Potempa, and J. Galle Native C-Reactive Protein Increases Whereas Modified C-Reactive Protein Reduces Atherosclerosis in Apolipoprotein E-Knockout Mice Circulation, August 16, 2005; 112(7): 1016 - 1023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Trion, M.P.M. de Maat, J.W. Jukema, A. van der Laarse, M.C. Maas, E.H. Offerman, L.M. Havekes, A.J. Szalai, H.M.G. Princen, and J.J. Emeis No Effect of C-Reactive Protein on Early Atherosclerosis Development in Apolipoprotein E*3-Leiden/Human C-Reactive Protein Transgenic Mice Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1635 - 1640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Inoue, T. Kato, T. Uchida, M. Sakuma, A. Nakajima, M. Shibazaki, Y. Imoto, M. Saito, S. Hashimoto, Y. Hikichi, et al. Local Release of C-Reactive Protein From Vulnerable Plaque or Coronary Arterial Wall Injured by Stenting J. Am. Coll. Cardiol., July 19, 2005; 46(2): 239 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Szalai, G. S. Alarcon, J. Calvo-Alen, S. M. A. Toloza, M. A. McCrory, J. C. Edberg, G. McGwin Jr, H. M. Bastian, B. J. Fessler, L. M. Vila, et al. Systemic lupus erythematosus in a multiethnic US Cohort (LUMINA). XXX: association between C-reactive protein (CRP) gene polymorphisms and vascular events Rheumatology, July 1, 2005; 44(7): 864 - 868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Hirschfield, J. R. Gallimore, M. C. Kahan, W. L. Hutchinson, C. A. Sabin, G. M. Benson, A. P. Dhillon, G. A. Tennent, and M. B. Pepys Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice PNAS, June 7, 2005; 102(23): 8309 - 8314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tanaka, K. Shimada, T. Sano, M. Namba, T. Sakamoto, Y. Nishida, T. Kawarabayashi, D. Fukuda, and J. Yoshikawa Multiple Plaque Rupture and C-Reactive Protein in Acute Myocardial Infarction J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1594 - 1599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Bisoendial, J. J.P. Kastelein, J. H.M. Levels, J. J. Zwaginga, B. van den Bogaard, P. H. Reitsma, J. C.M. Meijers, D. Hartman, M. Levi, and E. S.G. Stroes Activation of Inflammation and Coagulation After Infusion of C-Reactive Protein in Humans Circ. Res., April 15, 2005; 96(7): 714 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Boekholdt, T. T. Keller, N. J. Wareham, R. Luben, S. A. Bingham, N. E. Day, M. S. Sandhu, J. W. Jukema, J. J.P. Kastelein, C. E. Hack, et al. Serum Levels of Type II Secretory Phospholipase A2 and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women: The EPIC-Norfolk Prospective Population Study Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 839 - 846. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. J. Kullo and C. M. Ballantyne Conditional Risk Factors for Atherosclerosis Mayo Clin. Proc., February 1, 2005; 80(2): 219 - 230. [Abstract] [PDF]
|
|
|
|
 |
|
 M. A. Crowther Pathogenesis of Atherosclerosis Hematology, January 1, 2005; 2005(1): 436 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Biasucci CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Clinical Use of Inflammatory Markers in Patients With Cardiovascular Diseases: A Background Paper Circulation, December 21, 2004; 110(25): e560 - e567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R. Moreno and V. Fuster The year in atherothrombosis J. Am. Coll. Cardiol., December 7, 2004; 44(11): 2099 - 2110. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Black, I. Kushner, and D. Samols C-reactive Protein J. Biol. Chem., November 19, 2004; 279(47): 48487 - 48490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Tunon, L. M. Blanco-Colio, J. L. Martin-Ventura, and J. Egido Intensive treatment with statins and the progression of cardiovascular diseases: the beginning of a new era? Nephrol. Dial. Transplant., November 1, 2004; 19(11): 2696 - 2699. [Full Text] [PDF]
|
|
|
|
|
|
T. Khreiss, L. Jozsef, L. A. Potempa, and J. G. Filep Opposing Effects of C-Reactive Protein Isoforms on Shear-Induced Neutrophil-Platelet Adhesion and Neutrophil Aggregation in Whole Blood Circulation, October 26, 2004; 110(17): 2713 - 2720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Toutouzas, A. Colombo, and C. Stefanadis Inflammation and restenosis after percutaneous coronary interventions Eur. Heart J., October 1, 2004; 25(19): 1679 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Melamed, A. Shirom, S. Toker, S. Berliner, and I. Shapira Association of Fear of Terror With Low-Grade Inflammation Among Apparently Healthy Employed Adults Psychosom Med, July 1, 2004; 66(4): 484 - 491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Jialal, S. Devaraj, and S. K. Venugopal C-Reactive Protein: Risk Marker or Mediator in Atherothrombosis? Hypertension, July 1, 2004; 44(1): 6 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M Ridker, N. J. Brown, D. E. Vaughan, D. G. Harrison, and J. L. Mehta Established and Emerging Plasma Biomarkers in the Prediction of First Atherothrombotic Events Circulation, June 29, 2004; 109(25_suppl_1): IV-6 - IV-19. [Full Text] [PDF]
|
|
|
|
|
|
S. Verma, P. E. Szmitko, and E. T.H. Yeh C-Reactive Protein: Structure Affects Function Circulation, April 27, 2004; 109(16): 1914 - 1917. [Full Text] [PDF]
|
|
|
|
|
|
P. M Ridker and N. Cook Clinical Usefulness of Very High and Very Low Levels of C-Reactive Protein Across the Full Range of Framingham Risk Scores Circulation, April 27, 2004; 109(16): 1955 - 1959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Paul, K. W.S. Ko, L. Li, V. Yechoor, M. A. McCrory, A. J. Szalai, and L. Chan C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, February 10, 2004; 109(5): 647 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Goldschmidt-Clermont and E. D. Peterson On the Memory of a Chronic Illness Sci. Aging Knowl. Environ., November 12, 2003; 2003(45): re8 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M Ridker and on behalf of the JUPITER Study Group Rosuvastatin in the Primary Prevention of Cardiovascular Disease Among Patients With Low Levels of Low-Density Lipoprotein Cholesterol and Elevated High-Sensitivity C-Reactive Protein: Rationale and Design of the JUPITER Trial* Circulation, November 11, 2003; 108(19): 2292 - 2297. [Full Text] [PDF]
|
|
|
|
|
|
S. K. Venugopal, S. Devaraj, and I. Jialal C-Reactive Protein Decreases Prostacyclin Release From Human Aortic Endothelial Cells Circulation, October 7, 2003; 108(14): 1676 - 1678. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||