Abstract
Autoimmune diseases are associated with a dramatically increased risk of atherosclerotic cardiovascular disease and its clinical manifestations. The increased risk is consistent with the notion that atherogenesis is modulated by both protective and disease-promoting immune mechanisms. Notably, traditional cardiovascular risk factors such as dyslipidaemia and hypertension alone do not explain the increased risk of cardiovascular disease associated with autoimmune diseases. Several mechanisms have been implicated in mediating the autoimmunity-associated cardiovascular risk, either directly or by modulating the effect of other risk factors in a complex interplay. Aberrant leukocyte function and pro-inflammatory cytokines are central to both disease entities, resulting in vascular dysfunction, impaired resolution of inflammation and promotion of chronic inflammation. Similarly, loss of tolerance to self-antigens and the generation of autoantibodies are key features of autoimmunity but are also implicated in the maladaptive inflammatory response during atherosclerotic cardiovascular disease. Therefore, immunomodulatory therapies are potential efficacious interventions to directly reduce the risk of cardiovascular disease, and biomarkers of autoimmune disease activity could be relevant tools to stratify patients with autoimmunity according to their cardiovascular risk. In this Review, we discuss the pathophysiological aspects of the increased cardiovascular risk associated with autoimmunity and highlight the many open questions that need to be answered to develop novel therapies that specifically address this unmet clinical need.
Key points
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Autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis, are associated with an increased risk of atherosclerotic cardiovascular disease and cardiovascular death.
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Epidemiological data in large cohorts of patients and experimental evidence in preclinical models have clearly established the link between autoimmunity and atherosclerosis.
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Both shared and distinct mechanisms increase the risk of atherosclerosis in patients with systemic lupus erythematosus, rheumatoid arthritis or other connective-tissue autoimmune diseases.
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Endothelial dysfunction, increased cytokine signalling (IL-1β, IL-6 and tumour necrosis factor) and leukocyte activation (monocytes, macrophages and neutrophils), and aberrant T cell and B cell functions are key mechanisms for accelerated atherosclerosis in patients with autoimmune diseases.
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Knowledge about the functional role of classic autoimmune disease-associated autoantibodies in promoting atherosclerosis is limited.
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Anti-inflammatory therapies that are being evaluated for atherosclerotic cardiovascular disease might represent important opportunities for reducing the risk of atherosclerosis particularly in patients with autoimmunity.
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Acknowledgements
C.J.B. was supported by grants from the Vienna Science and Technology Fund (LS18-090), by the Leducq Foundation (Transatlantic Network of Excellence; TNE-20CVD03) and the EU Horizon Europe (TillT; 101080897).
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Glossary
- Clonal haematopoiesis of indeterminate potential
-
(CHIP). A common, age-related condition in which somatic mutations in some genes in haematopoietic progenitor cells result in the clonal expansion of leukocytes. The presence of CHIP is associated with a significantly increased risk of cardiovascular disease.
- Endothelial-to-mesenchymal transition
-
A process in which endothelial cells change their molecular and cellular phenotype to that of mesenchymal cells (such as myofibroblasts and smooth muscle cells). Endothelial-to-mesenchymal transition has been implicated in the development of atherosclerosis.
- Lipoprotein(a)
-
An LDL particle that contains apolipoprotein(a). Lipoprotein(a) is one of the strongest genetically determined risk factors for atherosclerotic cardiovascular disease.
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Porsch, F., Binder, C.J. Autoimmune diseases and atherosclerotic cardiovascular disease. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-024-01045-7
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DOI: https://doi.org/10.1038/s41569-024-01045-7
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