Original ArticleAnti-inflammatory effect of rosuvastatin in patients with HIV infection: An FDG-PET pilot study
Introduction
Patients with human immunodeficiency virus (HIV) have a significantly increased risk of cardiovascular disease (CVD).1 HIV+ individuals are 2-4 times more likely to suffer a myocardial infarction (MI),2,3 and CVD now accounts for 10% of all deaths in this population.1 HIV infection is associated with accelerated progression of atherosclerosis, an association that appears to be independent of traditional CVD risk factors.4
Atherosclerosis is a multi-faceted disease with inflammation playing a central role in atherosclerosis initiation and progression, and the triggering of events such as MI and stroke. HIV infection has been associated with persistently increased systemic inflammation, immune activation and pro-coagulant changes despite effective antiretroviral therapy.5 These effects are thought to drive endothelial dysfunction, monocyte/macrophage activation, and accelerated atherosclerosis, as well as MI and post-MI fibrosis and reduced left ventricular function.6 Monocyte-derived macrophages are a principal mediator of inflammation in atherosclerotic plaques.7,8 Activation of monocyte-derived macrophages infiltrating atherosclerotic plaques appears to occur at early stages in the bone marrow and spleen.9,10
Statins are a widely prescribed lipid-lowering drug-class that reduces cardiovascular morbidity and mortality in both primary and secondary prevention.11 In addition to their lipid-lowering effects, statins may have additional pleiotropic effects, including improvements in endothelial function, stabilization of atherosclerotic plaques, anti-inflammatory, immune-modulatory and anti-thrombotic effects.12 Tissue uptake of 18F-fluorodeoxyglucose (18F-FDG) as measured by 18F-FDG positron emission tomography/computed tomography (PET/CT) scanning is a widely employed and sensitive technique for directly assessing inflammation in arterial walls and other organs such as the spleen and bone marrow. This is because inflammatory cells (mainly macrophages) have higher metabolic activity (i.e. higher rate of glycolysis) than other organ specific cell types (i.e. smooth muscle cells, endothelial cells, fibroblasts, osteoblasts, T-lymphocytes, etc.).13 Given the potential link between inflammation and accelerated atherosclerosis in HIV+ patients, in this study we use 18F-FDG PET/CT to quantify regional haemopoietic activity14 and inflammation as measured by FDG bone marrow, spleen and ascending aorta uptake in HIV+ patients with moderate CVD risk, and also measured markers of monocyte activation in this group. We hypothesized that monocyte markers of inflammation would be elevated in an HIV+ cohort compared to an HIV− cohort. Furthermore, in our HIV+ cohort, we hypothesized that imaging markers of inflammation in the ascending aorta as well as bone marrow and spleen as measured by 18F-FDG PET/CT, as well as markers of systemic inflammation including monocyte activation and markers of monocyte activation would improve in HIV+ patients with moderate CVD risk randomized to therapy with rosuvastatin compared to HIV+ patients randomized to standard of care.
Section snippets
Methods
Participants were enrolled from the Immunodeficiency Clinic at the Ottawa Hospital General Campus, Ottawa, Ontario, Canada. Eligible participants were those with documented serologic evidence of HIV infection; ≥ 40 years of age; receiving standard ART for >2 years with a viral load below the limits of detection while on ART, a current CD4 count >350 cells/μL; and with a baseline Framingham risk score of 10-20%. Nine HIV- controls with no known cardiovascular disease were selected as age matched
Baseline participant characteristics
Thirty-five HIV+ patients were recruited, 86% of whom were men. Average age was 51.5 ± 6.9 years and the average BMI was 25.7 ± 3.8 kg/m2. Participants were well-matched between the treatment groups, with regards to CVD risk factors, with the exception of BMI, which was higher in the patients receiving statin treatment as well as the proportion of male sex, which was higher in the control group. Additionally, groups were matched with regards to age, sex, smoking, Framingham risk, duration of
Discussion
The present pilot study demonstrated that, in a cohort of HIV+ patients with moderate cardiovascular risk and on optimal medical therapy, there were elevated levels of baseline inflammation as measured by monocyte expression, serum inflammatory markers and FDG-PET markers of inflammation in the bone marrow, spleen and ascending aorta. In addition, treatment with low-dose rosuvastatin for 6 months resulted in significantly decreased FDG uptake in the bone marrow, spleen and thoracic aorta in the
Conclusions
In conclusion, the present study observed that monocyte markers of inflammation were elevated in HIV+ patients compared to HIV- controls. Additionally, there was a significant decrease in FDG-PET uptake in the bone marrow, spleen, and thoracic aorta following treatment with rosuvastatin for 6 months in HIV+ patients compared to HIV+ patients receiving usual care. These data suggest wide-range anti-inflammatory effects of rosuvastatin in HIV+ individuals with well-controlled infection on ART,
Acknowledgments
This study was supported by Ontario HIV Treatment Network (OHTN) grant support ($374252). KEB is supported by a CIHR Fellowship Award. RSBB was a Career Investigator supported but the Heart and Stroke Foundation of Ontario, the UOHI Vered Chair of Cardiology and a University of Ottawa Distinguished Chair of Cardiovascular Imaging Research. PM is supported by a Research Chair from the OHTN. GD was supported by a CIHR new investigator salary support award (supported by OHTN) while at UOHI.
Disclosures
EF, JW,
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Paul MacPherson and Girish Dwivedi are co-senior author.