This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fyfe, A. I. Articles by Lusis, A. J. Search for Related Content PubMed PubMed Citation Articles by Fyfe, A. I. Articles by Lusis, A. J. Pubmed/NCBI databases Medline Plus Health Information Coronary Artery Disease

(Circulation. 1997;96:2914-2919.)
© 1997 American Heart Association, Inc.

Articles

Association Between Serum Amyloid A Proteins and Coronary Artery Disease

Evidence From Two Distinct Arteriosclerotic Processes

Alistair I. Fyfe, MD, PhD; L.S. Rothenberg, JD; Frederick C. DeBeer, MD; Rita M. Cantor, PhD; Jerome I. Rotter, MD; ; Aldons J. Lusis, PhD

From the Divisions of Cardiology (A.I.F., A.J.L.) and Medical Genetics (L.S.R.), Department of Medicine, Department of Microbiology and Molecular Genetics (A.J.L.), Molecular Biology Institute, UCLA, Los Angeles, Calif; the University of Kentucky College of Medicine (F.C.D.), Lexington, Ky; and the Division of Medical Genetics (R.M.C., J.I.R.), Departments of Medicine and Pediatrics, Cedars-Sinai Research Institute, Los Angeles, Calif.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Serum amyloid A (SAA) proteins are a family of inflammatory apolipoproteins that may modify high-density lipoprotein structure and function. Elevations of SAA have been reported in unstable coronary syndromes, but the levels and types of SAA protein in humans with spontaneous or transplant-associated coronary artery disease are not known.

Methods and Results SAA levels were analyzed using an ELISA in 76 sera from 36 patients after cardiac transplantation and in 346 other individuals, 85 patients with atherosclerotic coronary disease plus 261 of their relatives. The mean SAA level was 5-fold higher in transplant patients (203±181 µg/mL [23 to 934 µg/mL]) compared with normal subjects without coronary disease (36±16 µg/mL [2.8 to 193 µg/mL], P<.005). The mean SAA level was significantly elevated in patients with transplant coronary disease (206±160 µg/mL, n=23) compared with those without (140±104 µg/mL, n=12, P=.02). Elevated SAA levels were associated with increased mortality after transplantation. On multiple regression analysis, SAA levels were predicted by corticosteroid dose, pretransplant diagnosis of atherosclerotic coronary artery disease, and the presence of transplant coronary disease. SAA levels were elevated in patients with spontaneous atherosclerotic coronary disease (49±31 µg/mL) compared with unaffected relatives (39±36 µg/mL, mean±SD, P=.02). There was no evidence for a genetic contribution to SAA levels. All inducible human SAA protein types were documented by immunoblotting in both spontaneous and transplant coronary disease.

Conclusions Environmentally determined elevations in SAA levels in patients with both spontaneous and transplant coronary artery disease provide further evidence for a potential pathophysiological link between inflammation, lipoprotein metabolism, and the development of atherosclerosis.

Key Words: amyloid • coronary disease • atherosclerosis • transplantation • apolipoproteins • cholesterol

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Serum amyloid A (SAA) proteins comprise acute-phase proteins produced in response to both acute and chronic inflammatory stimuli¹ and whose levels may increase by as much as 1000-fold. The function of these proteins remains unclear, but several lines of evidence suggest they may play a pathophysiological role in atherosclerosis. First, SAA is found as an apolipoprotein on HDL particles and may play a role in acute modification of cholesterol transport during physiological stress. Second, SAAs have been shown to be chemotactic for monocytes.² Third, SAA is present in both mouse³ and human atherosclerotic lesions,⁴ and SAA proteins can be produced by cells of the artery wall.⁴ Fourth, in genetic studies with mice, the induction of SAA expression cosegregates with the development of aortic fatty streak lesions.⁵ The pathophysiological processes that underlie the development of early atherosclerotic lesions have much in common with inflammation (monocyte-endothelial adhesion, transendothelial migration, activation, and production of inflammatory cytokines⁶ ). Furthermore, the transition from chronic stable atherosclerotic CAD into an acute coronary syndrome is associated with an increase in inflammatory activity within the plaque,⁷ reflected in an increase in C-reactive protein and SAA levels.⁸

In mouse models, generalized inflammatory diseases are associated with increased atherosclerosis,⁹ and feeding an atherogenic diet to genetically susceptible mice is associated with induction of inflammatory genes.¹⁰ Patients with systemic lupus erythematosus have a documented increase in CAD.¹¹ There is evidence suggesting a link between inflammation and atherosclerosis in humans with rheumatoid arthritis where the cardiovascular mortality rate was found to be twice that of an age-matched population without rheumatoid arthritis.¹² In another inflammatory coronary arteritis (Kawasaki's disease), SAA levels are elevated.¹³

TxCAD is a diffuse concentric proliferative coronary disease that is immunologically mediated and is the major limiting factor to long-term survival of patients undergoing cardiac transplantation.¹⁴ After kidney transplantation, there is a documented long-term elevation in SAA levels.¹⁵

This article seeks to establish the plasma concentrations of SAA after human cardiac transplantation and determine if an association exists between SAA and the development of TxCAD. A relation between SAA and atherosclerosis would provide evidence for a link between chronic inflammation, adverse changes in lipoprotein metabolism, and atherogenesis. We also measured SAA levels in families who contain probands diagnosed with spontaneous CAD to determine if SAA levels predict this atherosclerotic process.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Cardiac Transplant Patients
Blood was taken from a cohort of cardiac transplant recipients at the time of routine biopsy, after informed consent in a study approved by the UCLA Human Subject Protection Committee. From a pool of 420 samples obtained from 155 patients, a group of 23 patients with documented TxCAD (19 men, 4 women) was matched for date of transplant with a group of 13 patients without TxCAD (9 men, 4 women) to control for time-dependent changes in immunosuppression, other medications, and appearance of TxCAD. There were no significant differences between the groups with regard to age (51±13 years) and mean time from orthotopic cardiac transplantation (TxCAD 492 versus no TxCAD 591 days). Thirteen patients were within the first 6 months, 5 patients were within 1 year, and 18 patients were longer than 1 year from transplantation. In the group with TxCAD, 1 patient developed disease at 160 days, 6 patients developed disease between 6 months and 1 year, and 16 patients developed disease after 1 year. In the group without TxCAD, 4 patients were less than 6 months from transplant, 4 were between 6 months and 1 year, and 5 patients were greater than 1 year from transplant. All patients were on standard triple immunosuppressive therapy (cyclosporine A, azathioprine, and prednisone), with the exception of 6 patients who had been weaned totally from prednisone therapy. Twenty seven patients were primary recipients and 9 patients had undergone retransplantation, 8 for a previous diagnosis of TxCAD. SAA was assayed by individuals blinded to the patient's status, biopsy results, immunosuppressive regimen, and the presence of TxCAD. Rejection was assessed according to the standard ISHLT cellular rejection grades,¹⁶ and the presence of TxCAD was assessed as any coronary artery luminal narrowing noted on routine coronary angiography.

The Cedars-Sinai-UCLA Family Sample
The study sample consisted of 31 multiplex multigenerational white pedigrees ascertained through a proband with documented (surgically or angiographically) CAD identified at Cedars-Sinai Medical Center in Los Angeles.^{17 18} A comprehensive description of the demographics, lipoprotein profiles, and select genotypes on this population has been published elsewhere.^{17 18 19 20} Family inclusion criteria required that at least 1 other blood relative be affected with CAD. A total of 391 individuals from these 31 families agreed to participate in this study, which was approved by the institutional Human Subjects Protection Committee. SAA concentrations were measured in 346 subjects for whom adequate serum was available. The average age was 52±18 years; total cholesterol, 201±41 mg/dL; LDL cholesterol, 123±36 mg/dL; HDL cholesterol, 55±17 mg/dL; triglyceride level, 104±70 mg/dL; apoB, 128±34 mg/dL; apoA-I, 179±39 mg/dL; apoA-II, 35±6 mg/dL; and Lp(a), 18±23 mg/dL.^{18 19 20}

Plasma SAA Assays
Plasma samples were stored at -70°C until the time of batch analysis. Plasma samples were analyzed in duplicate for SAA levels using a sandwich enzyme immunoassay (Biosource International) according to the manufacturer's instructions. The limit of detection of this assay is 5 ng/mL, and the published intra-assay and interassay coefficients of variation were 4.9% and 7.8%, respectively.²¹ In these populations, the intra-assay and interassay coefficient of variation between duplicate samples was 11%.

Plasma Cholesterol and Apolipoprotein Assays
The ability of SAA to modify HDL concentrations and composition by displacing apoA-I and apoA-II was assessed by measuring total plasma cholesterol, HDL cholesterol, and apoA-I and A-II levels in the patient populations as previously reported.^{17 18 19 20}

SAA Isotype Analysis
Density of plasma aliquots was adjusted to 1.21 g/mL with solid KBr. Total lipoproteins were floated in a table-top ultracentrifuge for 8.5 hours at 78 000 rpm at 10°C (TLV 100 rotor, Beckman Instruments). From the top, 800 µL was collected and dialyzed against 150 mmol/L NaCl, 0.1% (wt/vol) EDTA, pH 7.4. Aliquots (200 µg) were lyophilized and electrofocused on ultrathin acrylamide gels containing 20% (vol/vol) ampholines, pH 3 to 10, 40% (vol/vol) ampholines, pH 4 to 6.5, and 40% (vol/vol) ampholines, pH 7 to 9 (Pharmacia LKB Biotechnology) as previously described.²² Acrylamide gels were pressure-blotted and immunoblots were developed with a monospecific rabbit anti-human constitutive SAA or acute-phase SAA.²³

Statistical Analyses
SAA concentrations were compared between the four patient groups (transplant with CAD, transplant without CAD, normal subjects with CAD, and normal subjects without CAD) using ANOVA followed by Duncan's multiple-range test. Linear regression analysis was used to investigate if a relation existed between SAA levels and rejection grade (assumed to be linear within the ISHLT scoring system¹⁷ ) or corticosteroid dose.

Prior to all genetic analyses, multiple regression analyses were performed on the Cedars-Sinai families to adjust for the significant effects of sex and age on SAA concentrations. Familial correlations were calculated using the FCOR program of the SAGE package²⁴ of genetic epidemiology programs. Individuals in the Cedars families were classed as having CAD, blood relatives of those with CAD, and control subjects without CAD and compared for SAA levels by one-way ANOVA. Since no significant differences were detected between the latter two categories, individuals were then grouped into those with CAD and those without for ANOVA comparing the four groups.

	Results

Top Abstract Introduction Methods Results Discussion References

 
SAA After Cardiac Transplantation
SAA concentrations were analyzed in 76 sera from 36 patients taken at 530±514 (12 to 2379) days after cardiac transplantation. The average SAA concentration (203±181 µg/mL, range 23 to 934 µg/mL, Fig 1), was 5-fold higher than SAA levels taken from 261 normal healthy individuals in the Cedars-Sinai UCLA Family Study (39±36 µg/mL, P<.0001). Four samples from 1 patient with documented small-bowel undifferentiated lymphoma with SAA levels ranging from 320 to 934 µg/mL were excluded from this and further analysis. The intrapatient variation in SAA levels taken 48±40 (range 4 to 165) days apart was 25±12%. There was no correlation between SAA levels and the concurrent acute cellular rejection status of the patient (Fig 2). In the absence of rejection, SAA levels (178±142 µg/mL, n=48) were no different from those obtained at the time of documented rejection (182±145 µg/mL, n=28, P=NS). SAA levels in 23 patients with documented TxCAD were significantly higher than SAA concentrations in the 12 patients without TxCAD (206±160 versus 138±104 µg/mL, P=.02). In the 9 patients who died, SAA levels averaged 291±154 µg/mL compared with 78±52 µg/mL in those still living (P<.002). Eight of the 9 deaths were attributable to TxCAD. SAA levels in the 24 patients with a pretransplant diagnosis of ischemic cardiomyopathy were 196±145 µg/mL and 142±133 µg/mL in those with nonischemic cardiomyopathy (1 valvular, 1 Kawasaki's, 10 idiopathic dilated cardiomyopathy, P=.05). There was no significant difference in SAA levels between patients with their first (n=26) or second (n=9) cardiac transplant. There was no gender effect on SAA levels in the transplant population.

View larger version (17K): [in this window] [in a new window]   Figure 1. Plasma SAA levels in a normal population and their affected relatives (CAD). SAA levels are shown in heart transplant recipients without TxCAD (CTx) and in those with TxCAD (CTx + TxCAD). The number of individuals is included in parentheses. Cardiac transplantation is associated with a 5-fold increase in SAA and a further increase is seen in TxCAD.

View larger version (14K): [in this window] [in a new window]   Figure 2. There is no significant relationship between cardiac acute cellular rejection on endomyocardial biopsy and plasma SAA concentration.

As corticosteroid therapy might be expected to inhibit the production of acute-phase proteins, including SAA, we analyzed the relation between total daily dose of prednisone and SAA serum levels (Fig 3). There is a significant small positive relation between daily corticosteroid dose and SAA levels. There was no relation between SAA levels and total corticosteroid dose exposure. Multiple stepwise regression analysis was undertaken to determine the effects of gender, time from transplant, rejection status, corticosteroid dose, pretransplant diagnosis, and the presence of TxCAD on SAA concentrations. Corticosteroid dose, pretransplant CAD, and TxCAD predicted 7%, 5%, and 3%, respectively, of the variance in SAA levels (P=.01). There was no significant relation between SAA levels and LDL, HDL, apoA-I, apoA-II, or triglyceride levels after cardiac transplantation (data not shown).

View larger version (15K): [in this window] [in a new window]   Figure 3. Relation between daily corticosteroid dose and SAA levels. There is a small positive correlation between SAA levels and corticosteroid dose (r2=.07, P=.02).

To confirm the induction of the acute-phase members of the SAA family in cardiac transplant patients, HDL from the 6 recipients with the highest SAA levels (Fig 4B) was compared with 4 recipients with the lowest SAA levels (Fig 4A) by isoelectric focusing and immunoblot analyses. The minor non–acute-phase constitutive SAAs were detected in similar amounts in both groups (data not shown). The product and posttranslational modification of the SAA₁ gene (pI 6.4 and pI 6.0, respectively) were the major isotypes detected in both groups with the more prominent expression of the SAA₂ gene (pI 7.5 and pI 7.0) in the recipients with higher SAA levels.²⁵ In these patients, total SAA is more than 10-fold increased (Fig 4B) compared with the lower-SAA group (Fig 4A).

View larger version (46K): [in this window] [in a new window]   Figure 4. Isoelectric focusing and immunoblot analyses of 200 µg HDL from patients after cardiac transplantation. Antibody used is monospecific rabbit anti-human acute-phase SAA1 and SAA2. 4A, 4 patients with the lowest SAA levels: lane 1, acute-phase HDL standard heterozygous at the SAA2 locus; lanes 2 to 5, HDL from 4 patients; lane 6, normal HDL standard from a pool of 7 healthy individuals. 4B, 5 patients with the highest SAA levels; lane 1, acute-phase HDL standard heterozygous at the SAA2 locus; lanes 2 to 6, patients with the highest SAA levels.

SAA in Spontaneous CAD
To assess if there is an association between SAA levels and the development of atherosclerotic CAD, we measured levels in 85 patients with documented CAD and 261 family members, taken from the Cedars-Sinai UCLA family study.^{17 18 19 20} SAA concentrations in plasma were significantly higher in patients with CAD than in unaffected family members (49±31 versus 39±36 µg/mL, P=.02). There was a significant gender effect noted in the unaffected population; women (n=152) demonstrated higher SAA levels than men (n=109, 47±39 versus 29±31 µg/mL, P<.001). This effect carried into those affected with CAD; women (n=23, 65±43 µg/mL) had significantly higher SAA levels than men (n=62, 40±25 µg/mL, P<.02). There was no age effect seen in women, but men tended to have increased SAA levels after age 36 (data not shown).

The elevations in SAA in both the transplant and spontaneous CAD population do not rule out a genetic basis for SAA levels that predispose first to the development of spontaneous CAD, requiring transplantation, and then the development of TxCAD. We therefore assessed the relative genetic and environmental contributions to SAA levels in those without CAD. We calculated the correlations in SAA levels of marital pairs, sibling pairs, first-cousin pairs, and parent/offspring pairs (Table). Preliminary analysis shows that SAA levels are more likely to be environmentally rather than genetically determined, as unrelated individuals living in the same environment (maritals) had a higher correlation in SAA levels (r=.55) than related individuals (cousins) living apart (r=.10) or parent/offspring (r=.30).

View this table: [in this window] [in a new window]   Table 1. Familial Correlations in SAA Levels in the Cedars-Sinai CAD Population

There was no relation between SAA and HDL cholesterol levels or apoA-I and A-II levels in the CAD subjects or unaffected control population (data not shown). We also could not demonstrate any significant changes in apoA-I and A-II levels in relation to SAA or to any of the populations studied.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
While SAA proteins show pathophysiological associations consistent with a role in cholesterol metabolism, this series of investigations is the first to show that there is an association between elevations in SAA protein and the development of CAD in humans. It is interesting to note that this association holds for two distinct atherosclerotic processes, one likely due to an inflammatory cascade of events secondary to lipoprotein oxidation²⁶ and the other due to both specific and nonspecific immunity.¹⁴ The rapidity of development of TxCAD compared with spontaneously occurring atherosclerosis¹⁴ makes it interesting to speculate that the magnitude of elevation of SAA is in some way related to the time course of the atherosclerotic process, either as a marker or an element in the pathophysiological pathway. The data from the populations studied do not clearly support either concept. The precise role of SAA protein is unclear; however, it is assumed that any protein whose concentration may increase by as much as 1000-fold in response to injury may be implicated in either a protective response or subsequent repair. It is known that SAA is a protein that associates with HDL particles and in high concentrations may displace constitutive apoA-I²⁷ and A-II.²⁸ This may promote atherogenesis by interfering with the ability of HDL to mediate cholesterol efflux from cells²⁹ or by other mechanisms.³⁰ Lipid oxidation is increased after heart transplantation,³¹ and oxidized lipids are associated with induction of SAA in mice fed an atherogenic diet.^{5 10} It has been shown that SAA-enriched HDL is preferentially targeted to peripheral tissues; macrophages possess a receptor for SAA³² and are principal cellular elements of both spontaneous and transplant atherosclerotic plaques.

It has been previously demonstrated that SAA levels are elevated for at least 1 year after renal transplantation.¹⁵ Elevated SAA levels in our cardiac transplant patients were similar in magnitude to those documented after renal transplantation.¹⁵ Elevated levels persisted for up to 6 years after transplantation, and multiple samples followed over a 1-year period in several of our patients showed a variability of 25%. Since acute cellular rejection is associated with acute inflammation, it was somewhat surprising that the biopsy score of rejection showed no association with the SAA protein concentration. The profile of cytokines released from cardiac allografts after human cardiac transplantation contains cytokines³³ such as interleukin-6, which are able to stimulate SAA production.³⁴

The use of corticosteroids might be expected to inhibit the production of SAA through inhibition of monokine production. In fact, the converse appeared to be true, with increased SAA levels at larger daily doses of corticosteroids. This is consistent with in vitro data that show that prednisone enhances the production of SAA by hepatocytes,³⁴ and SAA mRNA in arterial smooth muscle cell cultures was not produced in the absence of dexamethasone.⁴ Clinically, this is consistent with the reported association between corticosteroid usage and TxCAD³⁵ and preliminary data suggesting that steroid-free immunosuppressive regimens are associated with a decrease in the incidence of TxCAD.^{36 37}

SAA levels were associated with mortality in the cardiac transplant population; recently published data demonstrate the prognostic value of SAA levels in patients with spontaneous atherosclerosis and unstable angina.⁸ In this study,⁸ levels of SAA >30 µg/mL were associated with progression to myocardial infarction, urgent coronary revascularization, and death. SAA levels in that particular study were measured using an automated assay, which may explain differences in baseline normal reported values. The data in unstable angina are consistent with acute or chronic inflammation in unstable coronary syndromes³⁸ and are supported by studies demonstrating lymphocyte³⁹ and monocyte activation,⁴⁰ with expression of class II HLA in atherosclerotic plaques associated with unstable angina.⁷ It is noteworthy that studies in chronic inflammatory disease such as rheumatoid arthritis consistently demonstrate a relation between mortality and increasing indicators of inflammation with cardiovascular disease as the major cause of death.¹²

It is notable that women in the CAD population demonstrated higher SAA levels than men, despite the known predisposition of men to the development of coronary atherosclerosis. There is no sex difference in the development of TxCAD.¹⁴

In summary, these data from patients with both spontaneous and transplant atherosclerosis suggest a link between SAA protein and CAD. It is interesting to speculate that the induction of SAA proteins by environmental factors (diet, transplantation) modify the function but not the concentration of HDL cholesterol. As an example, qualitative modifications to HDL lead to a reduction in atherosclerosis in apoA-I transgenic mice,⁴¹ whereas apoA-II transgenic mice demonstrate increased atherosclerosis susceptibility³¹ despite comparable HDL elevations. HDL may not only become ineffective at reverse cholesterol transport but rather augment cholesterol delivery to the artery wall.

The study is limited by the small number of transplant patients studied and the retrospective nature of the analysis. Whether SAA levels will predict the development of TxCAD in a prospective trial will be important to confirm these findings. The larger number of non–transplant patients confirmed the association between SAA and coronary atherosclerosis; these patients were selected through probands with CAD and retrospectively analyzed. We hope the pathophysiological insights provided by this association will stimulate prospective studies in large human populations. The recent report that C-reactive protein levels predict myocardial infarction and ischemic stroke in men provides further evidence for inflammation in cardiovascular disease.⁴²

	Selected Abbreviations and Acronyms

 

apoA-I = apolipoprotein A-I apoA-II = apolipoprotein A-II CAD = coronary artery disease HDL = high-density lipoprotein ISHLT = International Society for Heart and Lung Transplantation LDL = low-density lipoprotein Lp(a) = lipoprotein(a) pI = isoelectric point SAA = serum amyloid A TxCAD = transplant coronary disease

	Acknowledgments

 
This work was supported in part by U.S. PHS grants HL28481, HL30568, and NCRR 1-P41RR03655. It was presented in part at the American Heart Association Scientific Conference on the Molecular Cellular Biology of the Vascular Wall, Boston, Mass, October 1993, and the 10th International Symposium on Atherosclerosis, Montreal, Canada, October 1994. The assistance of the UCLA cardiac transplant program in serum collection is gratefully acknowledged.

	Footnotes

 
Reprint requests to Alistair I. Fyfe, Division of Cardiology, UCLA, 47-123 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095-1679.

Received February 25, 1997; revision received May 22, 1997; accepted June 6, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Malle E, Steinmetz A, Raynes JG. Serum amyloid A (SAA): an acute phase protein and apolipoprotein. Atherosclerosis.. 1993;102:131-146.[Medline] [Order article via Infotrieve]

2. Badolato R, Wang JM, Murphy WJ, Lloyd AR, Michiel DF, Bausserman LL, Kelvin DJ, Oppenheim JJ. Serum amyloid A is a chemoattractant: induction of migration, adhesion, and tissue infiltration of monocytes and polymorphonuclear leukocytes. J Exp Med.. 1994;180:203-209.[Abstract/Free Full Text]

3. Qiao J-H, Xie P-Z, Fishbein MC, Kreuzer J, Drake TA, Demer LL, Lusis AJ. Pathology of atheromatous lesions in inbred and genetically engineered mice: genetic determination of arterial calcification. Arterioscler Thromb.. 1994;14:1480-1497.[Abstract/Free Full Text]

4. Meek RL, Urieli-Shoval S, Benditt EP. Expression of apolipoprotein serum amyloid A mRNA in human atherosclerotic lesions and cultured vascular cells: implications for serum amyloid A. Proc Natl Acad Sci U S A.. 1994;91:3186-3190.[Abstract/Free Full Text]

5. Liao F, Lusis AJ, Berliner JA, Fogelman AM, Kindy M, deBeer MC, deBeer FC. Serum amyloid A protein family: differential induction by oxidized lipids in mouse strains. Arterioscler Thromb.. 1994;14:1475-1479.[Abstract/Free Full Text]

6. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature.. 1993;362:801-809.[Medline] [Order article via Infotrieve]

7. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation.. 1994;89:36-44.[Abstract/Free Full Text]

8. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. 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]

9. Qiao J-H, Castellani LW, Fishbein MC, Lusis AJ. Immune-complex–mediated vasculitis increased coronary artery lipid accumulation in autoimmune-prone MRL mice. Arterioscler Thromb.. 1993;13:932-940.[Abstract/Free Full Text]

10. Liao F, Andalibi A, deBeer FC, Fogelman AM, Lusis AJ. Genetic control of inflammatory gene induction and NFB like transcription factor activation in response to an atherogenic diet in mice. J Clin Invest.. 1993;91:2572-2579.

11. Tsakraklides VG, Blieden IC, Edwards JE. Coronary atherosclerosis and myocardial infarction associated with systemic lupus erythematosus. Am Heart J.. 1974;87:637-641.[Medline] [Order article via Infotrieve]

12. Wolf F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, Spitz PW, Haga M, Kleinheksel SM, Cathey MA. The mortality of rheumatoid arthritis. Arthritis Rheum.. 1994;37:481-494.[Medline] [Order article via Infotrieve]

13. Gidding S, Cabana V, Getz G, Rowley A. Serum amyloid A, HDL cholesterol, and apolipoprotein A1 in Kawasaki disease. Circulation. 1993;88(suppl II):11-12. Abstract.

14. Fyfe AI. Transplant atherosclerosis: the clinical syndrome, pathogenesis and possible role as a model of spontaneous atherosclerosis. Can J Cardiol.. 1992;8:509-519.[Medline] [Order article via Infotrieve]

15. Ogata F, Kohoda Y, Suzuki M, Hirasawa Y. High levels of serum amyloid A persist for a long time after kidney transplantation. Nephron.. 1990;55:216-217.[Medline] [Order article via Infotrieve]

16. Billingham ME, Cary NRB, Hammond ME, Kemnitz J, Marboe C, McAllister HA, Snovar DC, Winters GL, Zerbe A. A working formula for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. J Heart Transplant.. 1990;9:587-592.[Medline] [Order article via Infotrieve]

17. Bu X-D, Warden CH, Xia Y-R, DeMeester C, Puppione DL, Teruya S, Lokensgard B, Daneshmand S, Brown J, Gray RJ, Rotter JI, Lusis AJ. Linkage analysis of the genetic determinants of high density lipoprotein concentration and composition: evidence for involvement of the apolipoprotein A-II and cholesterol ester transfer protein loci. Hum Genet.. 1994;93:639-648.[Medline] [Order article via Infotrieve]

18. Rotter JI, Bu X, Cantor RM, Warden CH, Brown J, Gray RJ, Blanche PJ, Krauss RM, Lusis AJ. Multilocus genetic determinants of LDL particle size in coronary artery disease families. Am J Hum Genet.. 1996;58:585-594.[Medline] [Order article via Infotrieve]

19. DeMeester CA, Bu X, Gray RJ, Lusis AJ, Rotter JI. Genetic variation in lipoprotein(a) levels in families enriched for coronary artery disease is determined almost entirely by the apolipoprotein(a) gene locus. Am J Hum Genet.. 1995;56:287-293.[Medline] [Order article via Infotrieve]

20. Warden CH, Daluiski A, Bu X, Purcell-Huynh DA, DeMeester C, Shieh B-H, Puppione DL, Gray RM, Reaven GM, Chen Y-DI, Rotter JI, Lusis AJ. Evidence of linkage of the apolipoprotein AII locus to plasma apolipoprotein AII and free fatty acid levels in both mice and humans. Proc Natl Acad Sci U S A.. 1993;90:10886-10890.[Abstract/Free Full Text]

21. McDonald TL, Weber A, Smith JW. A monoclonal antibody sandwich immunoassay for serum amyloid A (SAA) protein. J Immunol Methods.. 1991;144:149-155.[Medline] [Order article via Infotrieve]

22. DeBeer MC, Beach CM, Shedlofsky SI, deBeer FC. Identification of a novel serum amyloid A protein (SAA) in BALB/c mice. Biochem J.. 1991;180:45-49.

23. Whitehead AD, deBeer MC, Steel DM, Ritz M, Lelias JM, Lane WS, deBeer FC. Identification of novel members of the serum amyloid A protein (SAA) superfamily as constitutive apolipoproteins of high density lipoprotein. J Biol Chem.. 1992;295:677-687.

24. S.A.G.E. Statistical analyses for genetic epidemiology; computer program package available from the Department of Biometry and Genetics, LSU Medical Center. Release 2.2, New Orleans, La; 1994.

25. Strachan AF, Brandt WF, Woo P, van der Westhuyzen DR, Coetzee CA, deBeer MC, Shepard EG, deBeer FC. Evidence that the six major isoforms of human serum amyloid A protein are coded for by three genes at two genetic loci. J Biol Chem.. 1989;264:18368-18373.[Abstract/Free Full Text]

26. Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, Watson AD, Lusis AJ. Atherosclerosis: basic mechanisms: oxidation, inflammation, and genetics. Circulation.. 1995;91:2488-2496.[Abstract/Free Full Text]

27. Coetzee GA, Strachan AF, van der Westhuyzen DR, Hoppe HC, Jeenah MS, deBeer FC. Serum amyloid A-containing human high density lipoprotein 3: density, size and apolipoprotein composition. J Biol Chem.. 1986;261:9644-9651.[Abstract/Free Full Text]

28. Kumon Y, Suehiro T, Ikeda Y, Yoshida K, Hashimoto K, Ohno F. Influence of serum amyloid A protein on high-density lipoprotein in chronic inflammatory disease. Clin Biochem.. 1993;26:505-511.[Medline] [Order article via Infotrieve]

29. McKnight GL, Reasoner J, Gilbert T, Sundquist KO, Hokland B, McKernan PA, Champagne J, Johnson CJ, Bailey MC, Holly R, O'Hara PJ, Oram JF. Cloning and expression of a cellular high density lipoprotein-binding protein that is up-regulated by cholesterol loading of cells. J Biol Chem.. 1992;267:12131-12141.[Abstract/Free Full Text]

30. Warden CH, Hedrick CC, Qiao J-H, Castellani LW, Lusis AJ. Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science.. 1993;261:469.[Abstract/Free Full Text]

31. Chancerelle Y, Lorgeril M, Viret R, Chiron B, Dureau G, Renaud S, Kerfonou J-F. Increased lipid peroxidation in cyclosporine-treated heart transplant recipients. Am J Cardiol.. 1991;68:813-816.[Medline] [Order article via Infotrieve]

32. Kisilevsky R, Subrahmanyan L. Serum amyloid A changes high density lipoprotein's cellular affinity: a clue to serum amyloid A's principal function. Lab Invest.. 1992;66:778-785.[Medline] [Order article via Infotrieve]

33. Fyfe AI, Daly PA, Galligan L, Pirc L, Feindel CM, Cardella CJ. Coronary sinus sampling of cytokines after cardiac transplantation: evidence for macrophage activation and interleukin 4 production within the graft. J Am Coll Cardiol.. 1993;21:171-176.[Abstract]

34. Smith JW, McDonald TL. Production of serum amyloid A and C-reactive protein by HepG2 cells stimulated with combinations of cytokines or monocyte conditioned media: the effects of prednisone. Clin Exp Immunol.. 1992;90:783-789.

35. Valantine H, Pinto FJ, St. Goar F, Alderman EL, Popp RL. Intracoronary ultrasound imaging in heart transplant recipients: the Stanford experience. J Heart Lung Transplant.. 1992;11:S60-S64.[Medline] [Order article via Infotrieve]

36. Kobashigawa JA, Gleeson MP, Stevenson LW, Kawata N, Moriguchi JD, Hamilton MH, Hage A, Drinkwater DC, Laks H. Late steroid weaning in cardiac transplant patients is not associated with an increase in transplant coronary artery disease. J Heart Lung Transplant.. 1994;13:S48. Abstract.

37. Radley-Smith RC, Yacoub M. Long term results of pediatric heart transplantation. J Heart Lung Transplant.. 1992;11:S277-S281.[Medline] [Order article via Infotrieve]

38. Koachi R, Takebayashi S, Hiroki T, Nobuyoshi M. Significance of adventitial inflammation of the coronary artery in patients with unstable angina: results at autopsy. Circulation.. 1985;71:709-716.[Abstract/Free Full Text]

39. Sernini GG, Abbate R, Gori AM, Attanasio M, Martini F, Giusti B, Dabizzi P, Poggesi L, Modesti PA, Francesco T, Rostagno C, Boddi M, Gensini F. Transient lymphocyte activation is responsible for the instability of angina. Circulation.. 1992;86:790-797.[Abstract/Free Full Text]

40. Mazzone A, De Servi S, Ricevuti G, Mazzucchelli I, Fossati G, Pasotti D, Bramucci E, Angoli L, Marsico F, Specchia G, Notario A. Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease. Circulation.. 1993;88:358-363.[Abstract/Free Full Text]

41. Rubin EM, Krauss RM, Spangler EA, Verstuyft JG, Clift R. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature.. 1991;353:265-267.[Medline] [Order article via Infotrieve]

42. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin and the risk of cardiovascular disease in apparently healthy men. N Engl J Med.. 1997;336:973-979.[Abstract/Free Full Text]

This article has been cited by other articles:

				R. L. He, J. Zhou, C. Z. Hanson, J. Chen, N. Cheng, and R. D. Ye Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2 Blood, January 8, 2009; 113(2): 429 - 437. [Abstract] [Full Text] [PDF]

				H. Y. Lee, S. D. Kim, J. W. Shim, S. Y. Lee, H. Lee, K.-H. Cho, J. Yun, and Y.-S. Bae Serum Amyloid A Induces CCL2 Production via Formyl Peptide Receptor-Like 1-Mediated Signaling in Human Monocytes J. Immunol., September 15, 2008; 181(6): 4332 - 4339. [Abstract] [Full Text] [PDF]

				N. Cheng, R. He, J. Tian, P. P. Ye, and R. D. Ye Cutting Edge: TLR2 Is a Functional Receptor for Acute-Phase Serum Amyloid A J. Immunol., July 1, 2008; 181(1): 22 - 26. [Abstract] [Full Text] [PDF]

				T Lappalainen, M Kolehmainen, U Schwab, L Pulkkinen, D E Laaksonen, R Rauramaa, M Uusitupa, and H Gylling Serum concentrations and expressions of serum amyloid A and leptin in adipose tissue are interrelated: the Genobin Study Eur. J. Endocrinol., March 1, 2008; 158(3): 333 - 341. [Abstract] [Full Text] [PDF]

				S. Bozinovski, A. Hutchinson, M. Thompson, L. MacGregor, J. Black, E. Giannakis, A.-S. Karlsson, R. Silvestrini, D. Smallwood, R. Vlahos, et al. Serum Amyloid A Is a Biomarker of Acute Exacerbations of Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., February 1, 2008; 177(3): 269 - 278. [Abstract] [Full Text] [PDF]

				R. He, L. W. Shepard, J. Chen, Z. K. Pan, and R. D. Ye Serum Amyloid A Is an Endogenous Ligand That Differentially Induces IL-12 and IL-23 J. Immunol., September 15, 2006; 177(6): 4072 - 4079. [Abstract] [Full Text] [PDF]

				A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]

				M. Jernas, J. Palming, K. Sjoholm, E. Jennische, P.-A. Svensson, B. G. Gabrielsson, M. Levin, A. Sjogren, M. Rudemo, T. C. Lystig, et al. Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression FASEB J, July 1, 2006; 20(9): 1540 - 1542. [Abstract] [Full Text] [PDF]

				K. W.J. Lee, J. S. Hill, K. R. Walley, and J. J. Frohlich Relative value of multiple plasma biomarkers as risk factors for coronary artery disease and death in an angiography cohort. Can. Med. Assoc. J., February 14, 2006; 174(4): 461 - 466. [Abstract] [Full Text] [PDF]

				K. Sjoholm, J. Palming, L. E. Olofsson, A. Gummesson, P.-A. Svensson, T. C. Lystig, E. Jennische, J. Brandberg, J. S. Torgerson, B. Carlsson, et al. A Microarray Search for Genes Predominantly Expressed in Human Omental Adipocytes: Adipose Tissue as a Major Production Site of Serum Amyloid A J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2233 - 2239. [Abstract] [Full Text] [PDF]

				R. P. Schleimer Glucocorticoids Suppress Inflammation but Spare Innate Immune Responses in Airway Epithelium Proceedings of the ATS, November 1, 2004; 1(3): 222 - 230. [Abstract] [Full Text] [PDF]

				Q. Sha, A. Q. Truong-Tran, J. R. Plitt, L. A. Beck, and R. P. Schleimer Activation of Airway Epithelial Cells by Toll-Like Receptor Agonists Am. J. Respir. Cell Mol. Biol., September 1, 2004; 31(3): 358 - 364. [Abstract] [Full Text] [PDF]

				P Jousilahti, V Salomaa, V Rasi, E Vahtera, and T Palosuo Association of markers of systemic inflammation, C reactive protein, serum amyloid A, and fibrinogen, with socioeconomic status J Epidemiol Community Health, September 1, 2003; 57(9): 730 - 733. [Abstract] [Full Text] [PDF]

				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]

				R. He, H. Sang, and R. D. Ye Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R Blood, February 15, 2003; 101(4): 1572 - 1581. [Abstract] [Full Text] [PDF]

				K. Walder, L. Kantham, J. S. McMillan, J. Trevaskis, L. Kerr, A. de Silva, T. Sunderland, N. Godde, Y. Gao, N. Bishara, et al. Tanis: A Link Between Type 2 Diabetes and Inflammation? Diabetes, June 1, 2002; 51(6): 1859 - 1866. [Abstract] [Full Text] [PDF]

				M Gunn, J C Stephens, J R Thompson, B J Rathbone, and N J Samani Significant association of cagA positive Helicobacter pylori strains with risk of premature myocardial infarction Heart, September 1, 2000; 84(3): 267 - 271. [Abstract] [Full Text] [PDF]

				G. Sesmilo, B. M.K. Biller, J. Llevadot, D. Hayden, G. Hanson, N. Rifai, and A. Klibanski Effects of Growth Hormone Administration on Inflammatory and Other Cardiovascular Risk Markers in Men with Growth Hormone Deficiency: A Randomized, Controlled Clinical Trial Ann Intern Med, July 18, 2000; 133(2): 111 - 122. [Abstract] [Full Text] [PDF]

				W. Shi, M. E. Haberland, M.-L. Jien, D. M. Shih, and A. J. Lusis Endothelial Responses to Oxidized Lipoproteins Determine Genetic Susceptibility to Atherosclerosis in Mice Circulation, July 4, 2000; 102(1): 75 - 81. [Abstract] [Full Text] [PDF]

				M. Erren, H. Reinecke, R. Junker, M. Fobker, H. Schulte, J. O. Schurek, J. Kropf, S. Kerber, G. Breithardt, G. Assmann, et al. Systemic Inflammatory Parameters in Patients With Atherosclerosis of the Coronary and Peripheral Arteries Arterioscler. Thromb. Vasc. Biol., October 1, 1999; 19(10): 2355 - 2363. [Abstract] [Full Text] [PDF]

				B. Lindelow, C.-H. Bergh, C. Lamm, B. Andersson, and F. Waagstein Graft coronary artery disease is strongly related to the aetiology of heart failure and cellular rejections Eur. Heart J., September 2, 1999; 20(18): 1326 - 1334. [Abstract] [PDF]

				P. M. Ridker Inflammation, Infection, and Cardiovascular Risk : How Good Is the Clinical Evidence? Circulation, May 5, 1998; 97(17): 1671 - 1674. [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fyfe, A. I. Articles by Lusis, A. J. Search for Related Content PubMed PubMed Citation Articles by Fyfe, A. I. Articles by Lusis, A. J. Pubmed/NCBI databases Medline Plus Health Information Coronary Artery Disease