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A Pilot Study of Urinary Markers of Endothelial Function & Oxidant
Stress for the Prediction of Cardiovascular Disease Risk with
Antiretroviral therapy
Michael S. Boger1, Ginger Milne2, Husamettin Erdem1, Valerie Mitchell1, David W. Haas1, Jason Morrow2, Todd Hulgan1
Divisions of 1Infectious Diseases and 2Clinical PharmacologyDepartment of Medicine
Vanderbilt University School of Medicine
Introduction
• Potent antiretroviral therapy (ART) dramatically improves morbidity & mortality from HIV infection
• ART may increase cardiovascular disease (CVD) risk Friis-Moller N et al. NEJM 2003; 349: 1993-2003DAD Study Group. NEJM 2007; 356: 1723-35
• Traditional Framingham prediction may underestimate CVD risk in HIV infected patients on ART
Law MG et al. HIV Med 2006; 7: 218-30De Socio GV et al. J Infect 2008; 57: 33-40
Introduction
• Inflammation, oxidant stress, & endothelial dysfunction are central to the pathogenesis of atherosclerosis/CVD Deakin S et al. Atheroscler Thromb Vasc Biol 2007; 27: 1390-5
• HIV-infection &/or ART may influence these factors
• hsCRP correlates with CVD outcomes in the general population; limited data in HIV infection
Pearson TA et al. Circulation 2003; 107: 499-511
• A urinary marker (isoprostane) of oxidant stress correlated with traditional CVD risk factors
Wang B et al. Atherosclerosis 2006; 184: 425-30
Basarici I et al. Coron Artery Dis 2007; 18: 615-20
• Vascular reactivity appears impaired in HIV infectionTorriani F et al. 4th IAS Conference 2007. Abstr WEAB302 Solages A et al. Clin Infect Dis 2006; 42: 1325-32
Introduction
• Eicosanoids are involved in inflammation, endothelial function, & oxidant stress
• Urinary assays for eicosanoids are noninvasive, precise, accurate, & reproducible
Milne GL et al. J Biol Chem 2005; 280: 25178-84
• We suspect that quantifying eicosanoids may help assess cardiovascular risk in this population
Eicosanoids: Inflammation, Endothelial Function, & Oxidant Stress
Membrane Phospholipids
Arachidonic Acid
COX
Prostaglandin-H2
Thromboxanes Prostacyclin Prostaglandins
Isoprostanes
Autoxidation
(Platelets) (Endothelium) (Smooth Muscle)
8-ISO-PGF2α(PGF2α)
11 DTxB2(TxB2)
2,3 DN-6KETO(PGI-M)
PGE-M
Khanapure SP et al. Curr Top Med Chem 2007; 7: 311-40
Vasoconstriction
Platelet aggregation
Oxidative tissue damage
Vasoconstriction
Platelet activation
Chemotaxis
Vasodilation
Inhibits platelet aggregation
Inhibits vascular smooth muscle proliferation
Vasoconstriction
Vascular smooth muscle proliferation
Eicosanoids: Inflammation, Endothelial Function, & Oxidant Stress
Membrane Phospholipids
Arachidonic Acid
COX
Prostaglandin-H2
Thromboxanes Prostacyclin
Isoprostanes
Autoxidation
(Platelets) (Endothelium) (Smooth Muscle)
8-ISO-PGF2α(PGF2α)
11 DTxB2(TxB2)
2,3 DN-6KETO(PGI-M)
PGE-M
Khanapure SP et al. Curr Top Med Chem 2007; 7: 311-40
Prostaglandins
Research Hypotheses & Aim
Hypotheses• ART metabolic effects include increased eicosanoid
production• These biomarkers are coupled with inflammation,
oxidant stress, & endothelial dysfunction
Aim• To correlate novel markers of inflammation, oxidant
stress, & endothelial function with serum lipids & hsCRP in HIV infected patients on ART
Study Population
• HIV infection > 12 mos • On ART including ≥ 2 NRTIs• HIV RNA < 400 copies/mL
• No CAD or DM• No lactic acidosis• No malignancy• No aspirin use• No tobacco use
Methods & Statistical Analyses
• Cross-sectional pilot study of a prospective cohort• Urine eicosanoids quantified by liquid
chromatography/mass spectroscopy• Spearman’s correlation• Wilcoxon rank-sum
Characteristics of Study Subjects(N=33)
Age in years, median (IQR) 45 (39-51)
Female sex, n (%) 8 (24%)
Non-white race, n (%) 18 (55%)
BMI, median (IQR) 26 (24-27)
hsCRP mg/dL, median (IQR) 2.2 (0.76-5.87)
CD4 cells/mm3, median (IQR) 515 (324-738)
HIV RNA copies/mL, median (range)
Non-HDL mg/dL, median (IQR)
Lipoatrophy, n (%)
50 (50-470)
124 (106-170)
9 (27%)
PI-based ART, n (%)
Intermittent NSAID use
15 (45%)
20 (55%)
Results: Urinary Eicosanoids
Eicosanoid*
(ng/mg cr)
Reference1-4 Study Population
PGF2α 1.60 ± 0.60 2.01 ± 1.40
TxB2 0.37 ± 0.14 0.31 ± 0.17
PGI-M 0.14 ± 0.05 0.13 ± 0.06
PGE-M M: 10.40 ± 1.50
F: 6.00 ± 0.70
M: 13.57 ± 15.37
F: 6.57 ± 5.39Morrow JD et al. J Chromatogr 1993; 612: 179-85
Murphey LJ et al. Anal Biochem 2004; 334: 266-75
Daniel VC et al. J Chromatogr 1994; 653: 117-22
Morales CR et al. Clin Chim Acta 2001; 314: 93-9
* Data are mean ± 1 SD
Results: Gender Differences in Urinary Eicosanoids
PGF2α*(ng/mg cr)
Total (N= 33)
Men (N=25)
Women (N =8)
Overall 1.9 (1.3-2.4) 1.8 (1.3-2.4) 2.0 (1.3-2.3)
PI use
Yes
No
1.4 (0.76-2.3)
2.2 (1.4-2.5)
1.4 (0.73-2.4)
1.9 (1.4-2.4)
1.3 (0.89-1.9)
2.3 (2.1-5.5)
Lipoatrophy
Yes
No
2.3 (1.4-2.5)
1.8 (1.1-2.3)
2.3 (1.4-2.9)
1.6 (0.92-2.3)
1.6 (0.76-2.5)
2.0 (1.6-2.2)
*Data are median (IQR)
No association with age, race, CD4, HIV RNA, NSAID use, BMI
p=0.04p=0.07
Results: Gender Differences in Urinary Eicosanoids
PGI-M*(ng/mg cr)
Total (N= 33)
Men (N=25)
Women (N =8)
Overall 0.12 (0.08-0.16) 0.12 (0.08-0.16) 0.10 (0.07-0.17)
PI use
Yes
No
0.11 (0.07-0.15)
0.12 (0.09-0.17)
0.12 (0.07-0.15)
0.12 (0.09-0.17)
0.07 (0.04-0.24)
0.13 (0.07-0.17)
Lipoatrophy
Yes
No
0.15 (0.12-0.17)
0.11 (0.08-0.14)
0.15 (0.12-0.18)
0.11 (0.08-0.14)
0.11 (0.04-0.17)
0.10 (0.07-0.19)
*Data are median (IQR)
No association with age, race, CD4, HIV RNA, NSAID use, BMI
p=0.07
Results: Correlation of Urinary Eicosanoids & hsCRP
Eicosanoid* Total
(N= 33)
Men
(N=25)
Women
(N =8)
PGF2α 0.36, 0.04 0.33, 0.11 0.29, 0.49
TxB2 0.33, 0.06 0.12, 0.55 0.84, 0.01
PGI-M 0.39, 0.04 0.34, 0.12 0.89, 0.02
PGE-M 0.26, 0.19 0.25, 0.30 0.29, 0.54
*Data are correlation coefficient, p-value
Results: Correlation of Urinary Eicosanoids & Non-HDL Cholesterol
Eicosanoid* Total
(N= 33)
Men
(N=25)
Women
(N =8)
PGF2α 0.02, 0.91 0.03, 0.89 -0.19, 0.65
TxB2 0.38, 0.04 0.50, 0.02 -0.11, 0.80
PGI-M 0.19, 0.33 0.42, 0.06 -0.67, 0.15
PGE-M 0.23, 0.26 0.35, 0.14 -0.14, 0.76
*Data are correlation coefficient, p-value
Summary
• Minimally invasive, reliable methods to predict metabolic problems of ART are needed
• Urinary eicosanoids may be promising markers of CVD health in HIV patients on ART
• These markers of inflammation, oxidant stress & endothelial function correlated with non-HDL cholesterol & hsCRP
• Sex-specific associations of urinary eicosanoids with traditional CVD risk factors were seen
• Larger studies including CVD outcomes are needed to confirm & expand our findings
Acknowledgements
Jason Morrow, MD
Acknowledgements
• Persons with HIV infection who volunteered for this study
• NIH/NCCAM Career Development Award K23 AT002508
• Vanderbilt CTSA grant 1UL1RR024975 (NCRR/NIH)
• Vanderbilt-Meharry CFAR P30 AI54999
• NIH Molecular Basis of Infectious Diseases Training Program T32 AI07474-13
• Vanderbilt University GCRC
• Vanderbilt Human Analytical Isoprostane Core Facility
A Pilot Study of Urinary Markers of Endothelial Function & Oxidant
Stress for the Prediction of Cardiovascular Disease Risk with
Antiretroviral therapy
Michael S. Boger1, Ginger Milne2, Husamettin Erdem1, Valerie Mitchell1, David W. Haas1, Jason Morrow2, Todd Hulgan1
Divisions of 1Infectious Diseases and 2Clinical PharmacologyDepartment of Medicine
Vanderbilt University School of Medicine