Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 2000;102:2100-2104

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Eisenberg, M. S.
Right arrow Articles by Rabbani, L. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eisenberg, M. S.
Right arrow Articles by Rabbani, L. E.
Related Collections
Right arrow Growth factors/cytokines
Right arrow Transplantation
Right arrow Other etiology
Right arrow Other Vascular biology

(Circulation. 2000;102:2100.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Elevated Levels of Plasma C-Reactive Protein Are Associated With Decreased Graft Survival in Cardiac Transplant Recipients

Marc S. Eisenberg, MD; Hong Jun Chen, MD; Mark K. Warshofsky, MD; Robert R. Sciacca; Hal S. Wasserman, MD; Allan Schwartz, MD; LeRoy E. Rabbani, MD

From the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.

Correspondence to LeRoy E. Rabbani, MD, Division of Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th St, New York, NY 10032. E-mail ler8{at}columbia.edu


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background—Inflammation may be involved in the origin of transplant coronary artery disease. We hypothesized that plasma levels of C-reactive protein (CRP) and interleukin-6 (IL-6), markers for systemic inflammation, would correlate with cardiac transplant graft survival.

Methods and Results—We studied 99 consecutive cardiac transplant recipients who were referred for routine endomyocardial biopsy and/or surveillance coronary angiography. Plasma levels of CRP and IL-6 were measured by their respective ELISAs. Patients were divided into 2 groups: those who died or required retransplantation and those who survived without the need for retransplantation. During the follow-up period of 5.0±2.7 years (range, 0.2 to 15.1 years) after transplant, 20 patients died and 9 required retransplantation. There was no significant difference in age, race, sex, cause of native myopathy, presence of diabetes, or use of aspirin, statins, or calcium channel blockers between the 2 groups. Although IL-6 did not relate to graft failure, CRP level was predictive of allograft failure (P=0.003). The risk of allograft failure increased 36% for every 2-fold increase in CRP level. Moreover, CRP levels also correlated significantly with the frequency of grade 3 rejection (P=0.02). In multivariate analysis, when combined with other significant predictors such as donor age and sex mismatching of the graft, CRP still significantly predicted graft failure (P=0.025) with a 32% increase in the risk of graft failure for every 2-fold increase in CRP level.

Conclusions—These findings suggest that elevated plasma levels of CRP are associated with subsequent allograft failure in cardiac transplant recipients.


Key Words: transplantation • inflammation • proteins • survival


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Recent prospective studies suggest that chronic low-grade inflammation plays an important role in the pathogenesis of cardiovascular disease.1 2 3 4 C-reactive protein (CRP), an established marker for underlying systemic inflammation, is a pentameric protein produced by hepatocytes under the influence of inflammatory cytokines, primarily interleukin-6 (IL-6).5 Elevated plasma levels of CRP have been shown to be predictive of subsequent cardiovascular events among apparently healthy men6 7 8 9 and women,10 as well as among patients with stable and unstable angina11 12 13 14 15 and those with a prior history of myocardial infarction.16 Moreover, the efficacy of established therapeutic interventions, such as the use of aspirin6 and HMG-CoA reductase inhibitors,16 relates directly to baseline levels of CRP. Thus, plasma levels of CRP appear to be useful not only in stratifying the risk of future cardiovascular events but also in selecting which patients may benefit from established forms of therapy.

Transplant coronary artery disease (TCAD) remains the leading cause of death or retransplantation in cardiac transplant recipients surviving >6 months.17 It is characterized by a diffuse, proliferative vasculopathy limited to the allograft coronary arteries and is associated with the development of myocardial infarction, ventricular failure, malignant arrhythmias, and sudden death.18 19 The pathogenesis of graft atherosclerosis is not fully elucidated and is likely multifactorial. However, one hypothesis is that TCAD arises from chronic immune stimulation involving the donor-derived endothelium with vascular and inflammatory cell activation.20 21 22 23 24 25 Because of the high incidence of graft failure, cardiac transplant recipients are subject to routine endomyocardial biopsy and surveillance coronary angiography that are invasive, time consuming, and expensive and are associated with risk. An inflammatory marker that is sensitive for assessing the risk of graft failure in a stable cardiac transplant population may allow the elimination of a large number of invasive procedures and might target a group of patients who are at increased risk for subsequent cardiovascular events.

We hypothesized that plasma levels of circulating inflammatory markers relate to the risk of allograft failure among stable cardiac transplant recipients. In particular, we sought to demonstrate that elevated levels of CRP and IL-6 would be associated with decreased allograft survival.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Study Population
Cardiac transplant patients who presented to the cardiac catheterization laboratory for either annual surveillance coronary angiography and endomyocardial biopsy or only endomyocardial biopsy were eligible for enrollment. Patients were recruited between December 1994 and September 1995. Ninety-nine consecutive patients were enrolled. The follow-up period ended on December 1, 1997. The median interval between transplantation and study enrollment was 2 years (range, 5 days to 14 years). Immunosuppressive regimens included cyclosporine, prednisone, and azathioprine, adjusted at the physician’s discretion. Cellular-rejection episodes of biopsy grade 3A or greater were treated with either steroid pulses (oral or intravenous) or cytolytic therapy (OKT3 or antithymocyte globulin). Treatment of cellular-rejection episodes of biopsy grades below 3A depended on individual physicians, patient symptoms, and abnormal hemodynamic values.26 The study was approved by the Columbia-Presbyterian Medical Center Institutional Review Board. All patients gave informed consent before entry into the study.

Plasma Samples and Laboratory Analysis
Blood samples for plasma were collected from a central venous line on the day of recruitment before the patient’s annual surveillance coronary angiography and/or endomyocardial biopsy. Blood was stored on ice in a tube containing sodium citrate until plasma was separated by centrifugation at 2000g for 15 minutes. Plasma samples were frozen at -80°C until their use for inflammatory factor level determination and lipid analysis. For each patient, plasma was thawed and assayed for CRP by an ELISA based on purified protein and polyclonal anti-CRP antibodies (Calbiochem).27 Levels of IL-6 were measured by an ELISA according to the commercial IL-6 ELISA kit from Immunotech. Lipid analysis was performed by conventional enzymatic methods.

Statistical Analysis
Patients were divided into 2 groups for comparison. One group consisted of patients who survived without the need for retransplantation, and the other group consisted of patients who died or required retransplantation by the end of the follow-up period. Data are presented as mean±SD for continuous variables and as frequency for categorical variables. Continuous variables were compared between groups with the use of Student’s t test, except for CRP and IL-6 levels, which were not normally distributed. For these variables, the nonparametric Mann-Whitney test was used to test for the significance of differences between the groups. Categorical variables were compared through {chi}2 analysis. Kaplan-Meier curves were constructed for the frequency of graft failure as a function of time after transplantation. The significance of potential predictors of graft failure was assessed with the log-rank test. Hazard ratios were calculated, and a multivariate proportional-hazards model was used to determine which set of variables best predicted graft survival.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
Baseline Clinical Characteristics
Ninety-nine patients were enrolled in the study. Of the 99 patients, 29 died or required retransplantation (20 patients died, and 9 underwent retransplantation). Table 1Down reveals the characteristics of the patients in both the graft failure and graft survival groups. There was no significant difference in mean age, sex, or use of diabetic medication between the 2 groups. No patient admitted to smoking at the time of the study. The white blood cell count, hematocrit, platelet count, blood urea nitrogen, creatinine, lipid levels, and cytomegalovirus (CMV) status were similar in both groups. The origin of the cardiomyopathy leading to transplantation was similar in each group. There was no difference in the use of aspirin, calcium channel blockers, or statins at the time of enrollment between the 2 groups, as well as no difference in immunosuppressive regimens used. There was no significant difference in the time from transplant between the 2 groups. The mean time to follow-up in the graft survival group (n=70) was 5.2±2.4 years, whereas in the graft failure group (n=29), it was 4.5±3.4 years. Of the baseline clinical variables, only donor age, female donor, and sex mismatch were significantly different between the 2 groups.


View this table:
[in this window]
[in a new window]
  		Table 1. Patient Characteristics

CRP levels were not normally distributed; therefore, the log transform was performed. As demonstrated in Figure 1Down, the levels were significantly higher in the group with graft failure. There was no significant difference in plasma IL-6 levels between the 2 groups.



View larger version (8K):
[in this window]
[in a new window]
  		Figure 1. Semilog graph of distribution of CRP levels in patients with and without graft failure. Levels were significantly higher in group with graft failure (P<0.05).

Predictors of Allograft Failure
Table 2Down shows the results of univariate analysis to identify potential predictors of graft failure. The presence of female donor, sex mismatch, increased donor age, and elevated levels of CRP were all univariate predictors of allograft failure. IL-6 levels did not relate to graft failure. Table 3Down shows the results of the multivariate analysis. In this analysis, donor age (OR, 1.61 per 10-year increase; 95% CI, 1.16 to 2.28; P=0.005), sex mismatch (OR, 3.06; 95% CI, 1.39 to 6.76; P=0.006), and CRP level (OR, 1.32 for every 2-fold increase; 95% CI, 1.04 to 1.69; P=0.025) were independent predictors of allograft failure. Thus, independent of the other univariate predictors of graft failure, CRP level significantly predicted graft failure with a 32% increase in the risk of graft failure for every 2-fold increase in CRP level. Figure 2Down shows the Kaplan-Meier curve depicting the effect of enrollment CRP levels on graft survival with patients dichotomized into those with levels >1.06 mg/L and those with levels <=1.06 mg/L. This cutoff corresponded to the median level of CRP in the study population. Patients with CRP levels >1.06 mg/L had significantly worse graft survival.


View this table:
[in this window]
[in a new window]
  		Table 2. Univariate Predictors of Graft Survival


View this table:
[in this window]
[in a new window]
  		Table 3. Multivariate Predictors of Graft Survival



View larger version (17K):
[in this window]
[in a new window]
  		Figure 2. Kaplan-Meier curve depicting effect of enrollment CRP levels on graft survival with patients dichotomized into those with levels >1.06 mg/L and those with levels <=1.06 mg/L. This cutoff corresponded to median level of CRP in study population. Patients with CRP levels >1.06 mg/L had significantly worse graft survival (P<0.005).

Although CRP levels did not relate to the frequency of either grade 1 or 2 rejections per year, CRP levels did correlate significantly with the frequency of grade 3 rejections per year (correlation coefficient, 0.25; P=0.02). In addition, CRP levels correlated significantly with the donor age (correlation coefficient, 0.30; P=0.004) and recipient age (correlation coefficient, 0.20; P=0.05); however, CRP levels did not correlate with either the donor or recipient sex or the cause of the native myopathy.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
In this study, we demonstrate that elevated plasma levels of CRP are associated with subsequent allograft failure in stable cardiac transplant recipients. Moreover, we found that CRP levels correlated significantly with the frequency of grade 3 rejections per year. This is the first report to demonstrate that plasma levels of a circulating inflammatory marker are correlated with allograft failure among stable cardiac transplant patients.

Inflammation may play an important role in the initiation and progression of native arteriosclerosis1 2 3 4 28 and likely plays an important role in the pathogenesis of graft atherosclerosis,20 21 22 23 24 25 29 which remains the leading cause of death or retransplantation in cardiac transplant recipients surviving >6 months.17 Our finding that elevated plasma levels of CRP are associated with subsequent cardiovascular events among stable cardiac transplant patients extends previous observations about inflammation and cardiovascular risk. It is unclear whether CRP is just a marker for underlying systemic inflammation; thus, elevated levels may reflect enhanced immune or inflammatory activity in these patients. Several prior studies have reported the association between CMV infection and cardiac allograft vasculopathy.30 31 In one study, CMV infection was associated with an overall decreased survival, with only 32% of CMV-positive patients surviving 5 years after transplantation compared with 68% of CMV-negative patients.30 32 However, our study failed to show a significant relationship between CMV status and cardiac graft failure. Other immunological and nonimmunological factors that have been associated with increased risk for TCAD include human leukocyte antigen mismatch,33 34 humoral rejection,35 donor and recipient age,36 37 38 obesity,25 39 and hyperlipidemia.25 31 36 37 39 In this study, CRP levels did correlate significantly with the donor age and recipient age. Thus, CRP may in fact reflect other immunological or inflammatory mechanisms that predispose to increased risk of allograft failure.

Instead of being just a marker for underlying immune or inflammatory activity, CRP may have a pathogenic role. CRP has been shown to activate complement40 41 42 and to stimulate the production of tissue factor by mononuclear cells.43 Impaired hemostatic function has been shown to be predictive of future cardiovascular events in healthy men44 and patients with known CAD.11 45 46 47 Moreover, impaired fibrinolysis has been demonstrated in heart transplant recipients48 49 and has been correlated with both the presence and severity of TCAD in these patients.50 In fact, the distribution of certain hemostatic factors in endomyocardial biopsy specimens has been shown to be an important predictor of the clinical outcome of cardiac allografts. Patients whose transplanted hearts developed depletion of tissue plasminogen activator in arteriolar smooth muscle had a significantly higher rate of subsequent graft failure.51

Whether CRP serves as a marker for underlying systemic inflammation or in fact has a prothrombotic role, it appears to be useful in assessing the risk of graft failure in a stable cardiac transplant population and thus may be effective in targeting which patients might benefit from therapeutic interventions. Moreover, Kobashigawa et al52 found that after cardiac transplantation, the early use of pravastatin decreases the incidence of cardiac rejection accompanied by hemodynamic compromise, improves 1-year survival, and reduces the development of coronary vasculopathy. This may be due in part to a cholesterol-independent effect of pravastatin on immune or inflammatory function.52 53 It has been shown that the efficacy of pravastatin in survivors of myocardial infarction is greater among those with elevated levels of both CRP and serum amyloid A.16 Furthermore, the use of pravastatin among survivors of myocardial infarction resulted in significant reductions in CRP levels over 5 years of follow-up that were not related to the magnitude of lipid alterations.53 In view of the latter studies, our study suggests not only that plasma levels of CRP may be useful in selecting which cardiac transplant patients may benefit from established forms of therapy but that CRP may actually be a modifiable marker of risk.53

In this study, there was no significant difference in the use of aspirin, statins, or calcium channel blockers at the time of enrollment between the graft failure and graft survival groups. Only 14% of our study population were being treated with statins at the time of study enrollment. The reason is that our recruitment period ended before the publication of the study by Kobashigawa et al52 showing the beneficial effects of pravastatin on outcomes after cardiac transplantation. Also, our study design only looked at the use of these therapies at the time of recruitment and did not take into account the duration of treatment or dosage. Thus, we are unable to address whether graft failure is influenced by these therapies or whether these therapies influence plasma CRP levels. Moreover, the analyses are based on 1 determination of CRP level, and the effect of changes in CRP levels could not be assessed.

Plasma levels of IL-6 did not relate to graft failure in our stable cardiac transplant patients. IL-6 is known to induce the production of CRP by hepatocytes,5 and levels of IL-6 have been shown to be elevated in and predictive of outcome in acute coronary syndromes54 55 Reports of an association between episodes of cardiac transplant rejection and elevated plasma levels of IL-6 have been variable.56 57 58 This variability may be accounted for in part by differences in assay sensitivity and detection limits among the various studies and may explain why our study did not show an association between graft failure and plasma IL-6 levels.

One limitation of our study was that the median interval between transplantation and study enrollment was 2 years (range, 5 days to 14 years). However, there was no significant correlation between the time after surgery and CRP level in patients without graft failure. In addition, 3 of the 99 subjects—2 from the graft failure group and 1 from the graft survival group—had grade 3A rejection at the time of blood sampling. Reanalyzing the data without these 3 subjects made no significant difference in the results.

In summary, we have demonstrated that elevated plasma levels of CRP are associated with subsequent allograft failure in stable cardiac transplant recipients. In addition, we found that CRP levels correlated significantly with the frequency of grade 3 rejections per year. These findings confirm previous observations about inflammation and cardiovascular risk and extend them to the cardiac transplant population.


*    Acknowledgments
 
Dr Rabbani was supported in part by the Sol and Margaret Berger Foundation, Clifton, NJ.

Received April 5, 2000; revision received May 9, 2000; accepted June 8, 2000.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Ross R. The pathogenesis of atherosclerosis: a prospective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
  2. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844–2850.[Free Full Text]
  3. Lagrand WK, Visser CA, Hermens WT, et al. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation. 1999;100:96–102.[Abstract/Free Full Text]
  4. Ridker PM, Haughie P. Prospective studies of C-reactive protein as a risk factor for cardiovascular disease. J Invest Med. 1998;46:391–395.[Medline] [Order article via Infotrieve]
  5. Pepys MB, Baltz ML. Acute phase proteins with specific reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol. 1983;34:141–212.[Medline] [Order article via Infotrieve]
  6. 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.[Abstract/Free Full Text]
  7. Ridker PM, Cushman M, Stampfer MJ, et al. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998;97:425–428.[Abstract/Free Full Text]
  8. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation. 1998;97:2007–2011.[Abstract/Free Full Text]
  9. Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999;99:237–242.[Abstract/Free Full Text]
  10. Ridker PM, Buring JE, Shih J, et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998;98:731–733.[Abstract/Free Full Text]
  11. Thompson SG, Kienast J, Pyke SDM, et al, for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. 1995;332:635–641.[Abstract/Free Full Text]
  12. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med. 1994;331:417–424.[Abstract/Free Full Text]
  13. Haverkate F, Thompson SG, Pyke SDM, et al, for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet. 1997;349:462–466.[Medline] [Order article via Infotrieve]
  14. Rebuzzi A, Quaranta G, Liuzzo G, et al. Incremental prognostic value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris. Am J Cardiol. 1998;82:715–719.[Medline] [Order article via Infotrieve]
  15. Biasucci C, Liuzzo G, Grillo R, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation. 1999;99:855–860.[Abstract/Free Full Text]
  16. Ridker PM, Rifai N, Pfeffer MA, et al, for the Cholesterol and Recurrent Events (CARE) Investigators. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation. 1998;98:839–844.[Abstract/Free Full Text]
  17. Gao S, Schroeder J, Hunt S, et al. Retransplantation for severe accelerated coronary disease in heart transplant recipients. Am J Cardiol. 1988;62:876–881.[Medline] [Order article via Infotrieve]
  18. Hosenpud JD, Shipley GD, Wagner CR. Cardiac allograft vasculopathy: current concepts, recent developments, and future directions. J Heart Lung Transplant. 1992;11:9–23.[Medline] [Order article via Infotrieve]
  19. Ravalli S, Szabolcs M, Albala A, et al. Increased immunoreactive endothelin-1 in human transplant coronary artery disease. Circulation. 1996;94:2096–2102.[Abstract/Free Full Text]
  20. Tilney NL, Whitley WD, Diamond JR, et al. Chronic rejection: an undefined conundrum. Transplantation. 1991;52:389–398.[Medline] [Order article via Infotrieve]
  21. Paul LC, Fellstrom B. Chronic vascular rejection of the heart and the kidney: have rational treatment options emerged? Transplantation. 1992;53:1169–1179.[Medline] [Order article via Infotrieve]
  22. Russell ME, Wallace AF, Hancock WW, et al. Upregulation of cytokines associated with macrophage activation in the Lewis-to-F344 rat transplantation model of chronic cardiac rejection. Transplantation. 1995;59:572–578.[Medline] [Order article via Infotrieve]
  23. Salomon RN, Hughes CCW, Schoen FJ, et al. Human coronary transplantation-associated arteriosclerosis: evidence for a chronic immune reaction to activated graft endothelial cells. Am J Pathol. 1991;138:791–798.[Abstract]
  24. Miller LW. The role of inflammation in the development of allograft coronary disease. Transplant Proc. 1997;29:2583–2584.[Medline] [Order article via Infotrieve]
  25. Richenbacher PR, Kemna MS, Pinto FJ, et al. Coronary artery intimal thickening in the transplanted heart. Transplantation. 1996;61:46–53.[Medline] [Order article via Infotrieve]
  26. Itescu S, Tung TCM, Burke EM, et al. An immunological algorithm to predict risk of high-grade rejection in cardiac transplant recipients. Lancet. 1998;352:263–270.[Medline] [Order article via Infotrieve]
  27. Macy EM, Hayes TE, Tracy RP. Variability in the measurement of C-reactive protein in healthy subjects: implications for reference intervals and epidemiologic applications. Clin Chem. 1997;43:52–58.[Abstract/Free Full Text]
  28. Ridker PM, Hennekens CH, Roitman-Johnson B, et al. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet. 1998;351:88–92.[Medline] [Order article via Infotrieve]
  29. Lemstrom KB, Raisanen-Sokolowski AK, Hayry PJ, et al. Triple drug immunosuppression significantly reduces aortic allograft arteriosclerosis in the rat. Arterioscler Thromb Vasc Biol. 1996;16:553–564.[Abstract/Free Full Text]
  30. Grattan M, Moreno-Cabral C, Starnes V, et al. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA. 1989;261:3561–3566.[Abstract]
  31. McDonald K, Rector T, Braulin E, et al. Association of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection. Am J Cardiol. 1989;64:359–362.[Medline] [Order article via Infotrieve]
  32. Kuvin JT, Kimmelstiel CD. Infectious causes of atherosclerosis. Am Heart J. 1999;137:216–226.[Medline] [Order article via Infotrieve]
  33. Uretsky BF, Murali S, Reddy PS, et al. Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation. 1987;76:827–834.[Abstract/Free Full Text]
  34. Olivari MT, Homans DC, Wilson RF, et al. Coronary artery disease in cardiac transplant patients receiving triple-drug immunosuppressive therapy. Circulation. 1989;80(suppl III):III-111–III-115.
  35. Hammond EH, Yowell RL, Price GD, et al. Vascular rejection and its relationship to allograft coronary artery disease. J Heart Lung Transplant. 1992;11:S111. Abstract.[Medline] [Order article via Infotrieve]
  36. Gao SZ, Schroeder JS, Alderman EL, et al. Clinical and laboratory correlates of accelerated coronary artery disease in the cardiac transplant patient. Circulation. 1987;76 (suppl V):V-56–V-61.
  37. Gao SZ, Schroeder JS, Hunt SA, et al. Influence of graft rejection on incidence of accelerated graft coronary artery disease: a new approach to analysis. J Heart Lung Transplant. 1993;12:1029–1035.[Medline] [Order article via Infotrieve]
  38. Sharples LD, Caine N, Mullins P, et al. Risk factor analysis for the major hazards following heart transplantation: rejection, infection, and coronary occlusive disease. Transplantation. 1991;52:244–252.[Medline] [Order article via Infotrieve]
  39. Winters GL, Kendall TJ, Radio SJ, et al. Posttransplant obesity and hyperlipidemia: major predictors of severity of coronary arteriopathy in failed human heart allografts. J Heart Transplant. 1990;9:364–371.[Medline] [Order article via Infotrieve]
  40. Volanakis JE. Complement activation by C-reactive protein complexes. Ann N Y Acad Sci. 1982;389:235–250.[Medline] [Order article via Infotrieve]
  41. Wolbink GJ, Brouwer MC, Buysmann S, et al. CRP-mediated activation of complement in vivo: assessment by measuring circulating complement-C-reactive protein complexes. J Immunol. 1996;157:473–479.[Abstract]
  42. Torzewski J, Torzewski M, Bowyer DE, et al. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol. 1998;18:1386–1392.[Abstract/Free Full Text]
  43. Cermak J, Key NS, Bach RR, et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood. 1993;82:513–520.[Abstract/Free Full Text]
  44. Ridker PM, Vaughan DE, Stampfer MJ, et al. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet. 1993;341:1165–1168.[Medline] [Order article via Infotrieve]
  45. Jansson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease: a 7-year follow-up. Circulation. 1993;88:2030–2034.[Abstract/Free Full Text]
  46. Hamstem A, deFaire U, Walldius G, et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987;2:3–9.[Medline] [Order article via Infotrieve]
  47. Ardissino D, Merlini PA, Gamba G, et al. Thrombin activity and early outcome in unstable angina pectoris. Circulation. 1996;93:1634–1639.[Abstract/Free Full Text]
  48. Hunt BJ, Segal H, Yacoub M. Endothelial cell haemostatic function after heart transplantation. Transplant Proc. 1991;23:1182–1183.[Medline] [Order article via Infotrieve]
  49. Hunt BJ, Segal H, Yacoub M. Hemostatic changes in heart transplant recipients and their relationship to accelerated coronary sclerosis. Transplantation. 1993;55:309–315.[Medline] [Order article via Infotrieve]
  50. Warshofsky MK, Wasserman HS, Wang W, et al. Plasma levels of tissue plasminogen activator and plasminogen activator inhibitor-1 are correlated with the presence of transplant coronary artery disease in cardiac transplant recipients. Am J Cardiol. 1997;80:145–149.[Medline] [Order article via Infotrieve]
  51. Labarrere CA, Pitts D, Halbrook H, et al. Tissue plasminogen activator, plasminogen activator inhibitor-1, and fibrin as indexes of clinical course in cardiac allograft recipients: an immunocytochemical study. Circulation. 1994;89:1599–1608.[Abstract/Free Full Text]
  52. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med. 1995;333:621–627.[Abstract/Free Full Text]
  53. Ridker PM, Rifai N, Pfeffer MA, et al, for the Cholesterol and Recurrent Events (CARE) Investigators. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation. 1999;100:230–235.[Abstract/Free Full Text]
  54. Neumann FJ, Ott I, Gawaz M, et al. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation. 1995;92:748–755.[Abstract/Free Full Text]
  55. Manten A, de Winter RJ, Minnema MC, et al. Procoagulant and proinflammatory activity in acute coronary syndromes. Cardiovasc Res. 1998;40:389–395.[Abstract/Free Full Text]
  56. George JF, Kirklin JK, Naftel DC, et al. Serial measurements of interleukin-6, interleukin-8, tumor necrosis factor-{alpha}, and soluble vascular cell adhesion molecule-1 in the peripheral blood plasma of human cardiac allograft recipients. J Heart Lung Transplant. 1997;16:1046–1053.[Medline] [Order article via Infotrieve]
  57. Kimball PM, Radovancevic B, Isom T, et al. The paradox of cytokine monitoring: predictor of immunologic activity as well as immunologic silence following cardiac transplantation. Transplantation. 1996;61:909–915.[Medline] [Order article via Infotrieve]
  58. Abdallah AN, Billes MA, Doutremepuich C, et al. Evaluation of plasma levels of tumour necrosis factor alpha and interleukin-6 as rejection markers in a cohort of 142 heart-grafted patients followed by endomyocardial biopsy. Eur Heart J. 1997;18:1024–1029.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Eur. J. Cardiothorac. Surg.Home page
K. I. Paraskevas
Applications of statins in cardiothoracic surgery: more than just lipid-lowering
Eur. J. Cardiothorac. Surg., March 1, 2008; 33(3): 377 - 390.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
A. Hognestad, K. Endresen, R. Wergeland, O. Stokke, O. Geiran, T. Holm, S. Simonsen, J. K. Kjekshus, and A. K. Andreassen
Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients
J. Am. Coll. Cardiol., August 6, 2003; 42(3): 477 - 482.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
H. O. Ventura and M. R. Mehra
C-Reactive protein and cardiac allograft vasculopathy: is inflammation the critical link?
J. Am. Coll. Cardiol., August 6, 2003; 42(3): 483 - 485.
[Full Text] [PDF]

Home page
 CirculationHome page
M. H. Yen, G. Pilkington, R. C. Starling, N. B. Ratliff, P. M. McCarthy, J. B. Young, G. M. Chisolm, and M. S. Penn
Increased Tissue Factor Expression Predicts Development of Cardiac Allograft Vasculopathy
Circulation, September 10, 2002; 106(11): 1379 - 1383.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
K. BURKHARDT, M. RADESPIEL-TROGER, H. D. RUPPRECHT, M. GOPPELT-STRUEBE, R. RIESS, L. RENDERS, I. A. HAUSER, and U. KUNZENDORF
An Increase in Myeloid-Related Protein Serum Levels Precedes Acute Renal Allograft Rejection
J. Am. Soc. Nephrol., September 1, 2001; 12(9): 1947 - 1957.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Eisenberg, M. S.
Right arrow Articles by Rabbani, L. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eisenberg, M. S.
Right arrow Articles by Rabbani, L. E.
Related Collections
Right arrow Growth factors/cytokines
Right arrow Transplantation
Right arrow Other etiology
Right arrow Other Vascular biology

Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2000 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.