Premature cardiovascular disease is a major cause of mortality in patients with systemic lupus erythematosus (SLE) with the risk of myocardial infarction increased up to 50-fold. In the initial funding period we have shown that the prevalence of coronary artery atherosclerosis is increased remarkably in SLE, but the mechanisms remain unclear. Based on our preliminary data we propose that two related mechanisms - pro-atherogenic inflammatory mediators andthe metabolic syndrome - predispose to accelerated atherosclerosis in SLE. In addition to defining the mechanisms for accelerated atherosclerosis it is important to define the effects of drugs used to reduce cardiovascular risk in high-risk patients. Low dose aspirin, by inhibiting thromboxane A2 biosynthesis, has profound antiplatelet effects, but some patients have impaired thromboxane suppression - a phenomenon termed aspirin resistance. An explanation is that aspirin-independent thromboxane synthesis may occur through enhanced COX-2 activity, as would occur in an inflammatory condition such as lupus. However, little is known about the effects of low-dose aspirin in SLE.rThus, we propose to test the following hypotheses: 1) that accelerated coronary artery atherosclerosis in SLE is associated with the metabolic syndrome and increased concentrations of inflammatory mediators; 2) that aspirin insensitive thromboxane biosynthesis is increased in patients with lupus and is mediated by increased COX-2 activity. Continuation of the proposed studies will build on our initial findings and generate important information regarding the inter-relationship between inflammation and atherosclerosis, and suggest strategies for reversing or preventing accelerated atherosclerosis in SLE, and potentially other diseases. Lay Summary: The risk of heart attack is almost 50 times in higher in patients with lupus than healthy people. Our study will find out what causes accelerated atherosclerosis in lupus and why some patients do not respond to aspirin.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065082-07
Application #
7373655
Study Section
Special Emphasis Panel (ZRG1-CICS (01))
Program Officer
Kirby, Ruth
Project Start
1999-09-30
Project End
2011-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
7
Fiscal Year
2008
Total Cost
$335,359
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Solus, Joseph F; Chung, Cecilia P; Oeser, Annette et al. (2015) Genetics of serum concentration of IL-6 and TNFα in systemic lupus erythematosus and rheumatoid arthritis: a candidate gene analysis. Clin Rheumatol 34:1375-82
Bradham, William S; Ormseth, Michelle J; Oeser, Annette et al. (2014) Insulin resistance is associated with increased concentrations of NT-proBNP in rheumatoid arthritis: IL-6 as a potential mediator. Inflammation 37:801-8
Kawai, Vivian K; Avalos, Ingrid; Oeser, Annette et al. (2014) Suboptimal inhibition of platelet cyclooxygenase 1 by aspirin in systemic lupus erythematosus: association with metabolic syndrome. Arthritis Care Res (Hoboken) 66:285-92
Manavathongchai, Siriporn; Bian, Aihua; Rho, Young Hee et al. (2013) Inflammation and hypertension in rheumatoid arthritis. J Rheumatol 40:1806-11
Ormseth, M J; Swift, L L; Fazio, S et al. (2013) Free fatty acids are associated with metabolic syndrome and insulin resistance but not inflammation in systemic lupus erythematosus. Lupus 22:26-33
Lipson, Aliza; Alexopoulos, Nikolaos; Hartlage, Gregory Randell et al. (2012) Epicardial adipose tissue is increased in patients with systemic lupus erythematosus. Atherosclerosis 223:389-93
Lertnawapan, R; Bian, A; Rho, Y H et al. (2012) Cystatin C is associated with inflammation but not atherosclerosis in systemic lupus erythematosus. Lupus 21:279-87
Bradham, William S; Bian, Aihua; Oeser, Annette et al. (2012) High-sensitivity cardiac troponin-I is elevated in patients with rheumatoid arthritis, independent of cardiovascular risk factors and inflammation. PLoS One 7:e38930
Rho, Young Hee; Solus, Joseph; Raggi, Paolo et al. (2011) Macrophage activation and coronary atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Care Res (Hoboken) 63:535-41
Kawai, V K; Solus, J F; Oeser, A et al. (2011) Novel cardiovascular risk prediction models in patients with systemic lupus erythematosus. Lupus 20:1526-34

Showing the most recent 10 out of 40 publications