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Coupling of atherosclerosis progression and bone disturbances in inflammatory rheumatic diseases
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Cardiovascular diseases (CV) and osteoporosis (OP) are among the most prevalent health problems, significantly contributing to increased morbidity and mortality of the population. The incidence of these conditions increases with age and they frequently coexist in the same patient. Epidemiological studies have demonstrated that patients with CV diseases have an increased risk for osteoporotic fractures and that patients with low bone mass have an increased risk for CV events. The inflammatory process has been implicated in the pathogenesis of both diseases, particularly in patients with immune-mediated rheumatic diseases like Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE).
In this work we hypothesize that bone and vascular disturbances share common pathophysiological mechanisms and that a connection between the progression of both conditions exists. Therefore, the aim of this thesis was to understand the interaction between vessels and bones in the context of inflammatory rheumatic diseases through the study of the effect of inflammation on tissues.
In the first part of this study we evaluated how, in chronic inflammatory rheumatic diseases, namely RA and SLE, the vessels are disturbed, leading to vascular alterations and CV disease. For that we have assessed the early vascular alterations observed in these patients without previous CV events, through the determination of serum levels of vascular biomarkers and the study of endothelial function. We have then assessed the incidence of CV events in the RA cohort after 5 years and identified the contribution of traditional CV disease risk factors and RA-related parameters to CV events. We found that RA and SLE show distinct patterns of early vascular changes, more pronounced in SLE patients, and that the inflammatory activity was central to the increased endothelial activation biomarkers and to endothelial dysfunction. Additionally, patients with RA have a much higher incidence of CV events than the incidence reported for the general Portuguese population, for which the inflammatory and endothelial activation markers contribute significantly.
In the SLE cohort, we evaluated how bone metabolism biomarkers, specifically OPG (osteoprotegerin) and RANKL (receptor activator of nuclear factor-ƙB ligand), are affected by the disease. We have found that these patients have an increased sRANKL/OPG ratio, due to reduced OPG levels. Also, both OPG and sRANKL levels were associated with SLE specific antibodies, but not with corticosteroids therapy, suggesting that the increased osteoclastic stimuli are driven by SLE disease mechanisms.
Finally, we intended to comprehend the role of inflammation as common contributor to the interplay between bones and vessels. For that we have first used a mouse model of atherosclerosis (ApoE-/-) and evaluated bones and vessels disturbances and verified their association with inflammatory markers. Our results suggest that inflammation is not the principal driver for atherosclerosis progression and bone disturbances in this animal model, but that altered lipid transport and high-fat diet, associated with mice aging, may play a more significative role.
Secondly, using bone and vessel samples from organ donors and atheroma plaques from endarterectomized patients with advanced atherosclerosis, we have evaluated the role of inflammation in the relationship between bone changes and vascular pathology. Our results suggest that the relationship between the changes observed in bones and vessels in the context of atherosclerotic disease and osteoporosis, may rely on the intrinsic connection between the tissues involved, independently of the progression of both diseases.
Overall, our results suggest that the connection between atherosclerosis and osteoporosis rely on an intrinsic connection between the tissues and that the contribution of the risk factors for the diseases progression, including inflammation, affect more pronouncedly patients with immune-mediated rheumatic diseases.
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Palavras-chave
Atherosclerosis Osteoporosis Inflammation Immune-mediated Systemic Diseases Cardiovascular Diseases Teses de doutoramento - 2019