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Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Assessment of atherosclerosis in chronic granulomatous disease
Christopher T Sibley1, Tyra Estwick1, Anna Zavodni1
1From the Department of Radiology and Imaging Sciences, National Institutes of Health Clinical Center (C.T.S., A.Z., A.C.K., E.B.T., D.A.B.), Laboratory of Host Defenses (T.E., P.B.S., A.K.R.S., H.L.M., K.A.Z., J.I.G.), Biostatistics Research Branch (C.-Y.H.), and Laboratory of Clinical Infectious Diseases (S.M.H.), National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute (A.T.R.), National Institutes of Health, Bethesda, MD.
Insights
Patients with chronic granulomatous disease (CGD) have less carotid artery atherosclerosis despite cardiovascular risk factors. This suggests NADPH oxidase may play a role in atherosclerosis development.
Area of Science:
- Cardiovascular Research
- Immunology
- Medical Imaging
Background:
- Chronic granulomatous disease (CGD) involves immunodeficiency due to NADPH oxidase defects, potentially reducing oxidative stress.
- This study investigates the impact of CGD on atherosclerosis development.
Purpose of the Study:
- To assess cardiovascular risk factors, inflammation, and subclinical atherosclerosis in CGD patients versus controls.
- To explore the relationship between CGD, risk factors, and atherosclerosis burden.
Main Methods:
- Prospective assessment of 41 CGD patients and 25 controls.
- Utilized MRI and CT to quantify atherosclerosis in carotid and coronary arteries.
- Analyzed traditional risk factors, inflammatory markers (hs-CRP, oxLDL, HDL), and neutrophil activation.
Main Results:
- CGD patients showed higher hypertension, hs-CRP, oxLDL, and lower HDL than controls.
- Despite risk factors, CGD patients had 22% less carotid artery wall volume (P<0.001).
- Carotid artery findings were consistent across CGD subtypes and independent of risk factors; coronary calcification was similar.
Conclusions:
- Reduced carotid atherosclerosis in CGD patients, despite risk factors, questions NADPH oxidase's role in clinically significant atherosclerosis.
- Further high-resolution studies are needed to explore NADPH oxidase inhibition's therapeutic potential in cardiovascular disease.
Background:
Patients with chronic granulomatous disease (CGD) experience immunodeficiency because of defects in the phagocyte NADPH oxidase and the concomitant reduction in reactive oxygen intermediates. This may result in a reduction in atherosclerotic injury.
Methods And Results:
We prospectively assessed the prevalence of cardiovascular risk factors, biomarkers of inflammation and neutrophil activation, and the presence of magnetic resonance imaging and computed tomography quantified subclinical atherosclerosis in the carotid and coronary arteries of 41 patients with CGD and 25 healthy controls in the same age range. Univariable and multivariable associations among risk factors, inflammatory markers, and atherosclerosis burden were assessed. Patients with CGD had significant elevations in traditional risk factors and inflammatory markers compared with control subjects, including hypertension, high-sensitivity C-reactive protein, oxidized low-density lipoprotein, and low high-density lipoprotein. Despite this, patients with CGD had a 22% lower internal carotid artery wall volume compared with control subjects (361.3±76.4 mm(3) versus 463.5±104.7 mm(3); P<0.001). This difference was comparable in p47(phox)- and gp91(phox)-deficient subtypes of CGD and independent of risk factors in multivariate regression analysis. In contrast, the prevalence of coronary arterial calcification was similar between patients with CGD and control subjects (14.6%, CGD; 6.3%, controls; P=0.39).
Conclusions:
The observation by magnetic resonance imaging and computerized tomography of reduced carotid but not coronary artery atherosclerosis in patients with CGD despite the high prevalence of traditional risk factors raises questions about the role of NADPH oxidase in the pathogenesis of clinically significant atherosclerosis. Additional high-resolution studies in multiple vascular beds are required to address the therapeutic potential of NADPH oxidase inhibition in cardiovascular diseases.
Clinical Trial Registration Url:
http://www.clinicaltrials.gov. Unique identifier: NCT01063309.
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