Inflammation and cardiovascular disease - Part I: Mechanisms and biomarkers

Abstract

Inflammation is a fundamental driver of atherosclerotic cardiovascular disease (ASCVD), orchestrating immune activation, endothelial dysfunction, and plaque instability. While lipid-lowering therapies can reduce the burden of ASCVD, persistent inflammation remains a critical determinant of residual cardiovascular risk, highlighting the need for deeper investigation into inflammatory pathways. Key mediators, including interleukin-6, high-sensitivity C-reactive protein, and myeloperoxidase, amplify immune cell infiltration, foam cell formation, and extracellular matrix degradation, exacerbating atherosclerotic progression. Beyond these well-established markers, emerging inflammatory biomarkers, such as cluster of differentiation (CD)47, serum and glucocorticoid-regulated kinase 1 (SGK1), P-selectin, and growth differentiation factor 15 (GDF15), provide novel insights into vascular inflammation and immune dysregulation. CD47 modulates macrophage-mediated immune evasion, allowing apoptotic debris to accumulate within plaques, while SGK1 enhances pro-inflammatory signaling and endothelial dysfunction. P-selectin facilitates leukocyte adhesion and platelet aggregation, contributing to plaque destabilization and thrombotic risk. GDF15, a stress-responsive cytokine, is associated with adverse cardiovascular outcomes, linking metabolic dysfunction to chronic inflammation. Likewise, inflammasome activation, particularly through NACHT, LRR, and PYD domains-containing protein 3 and absent in melanoma 2 pathways, triggers cytokine cascades that perpetuate vascular injury, while clonal hematopoiesis of indeterminate potential promotes myeloid-driven inflammation and atherosclerotic acceleration. The expanding role of these biomarkers underscores the complexity of inflammation in ASCVD and highlights their potential for refining cardiovascular risk assessment and elucidating novel mechanisms underlying plaque progression.

Keywords

Cardiovascular disease / Chronic kidney disease / Atherosclerotic cardiovascular disease / Inflammatory biomarkers / Vascular inflammation / Plaque instability and thrombosis

Funding

None.

Conflict of interest

Krishnaswami Vijayraghavan is the Guest Editor for this special issue but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. While, Corina Grancorvitz is an employee of Kiniksa Pharmaceuticals but declared no known competing financial interests or personal relationships that could have influenced the work reported in this paper. Other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

References

[1] Mensah GA, Fuster V, Murray CJL, Global Burden of Cardiovascular Diseases and Risks Collaborators. Global burden of cardiovascular diseases and risks, 1990-2022. J Am Coll Cardiol. 2023; 82(25):2350-2473. doi: 10.1016/j.jacc.2023.11.007

[2] Martin SS, Aday AW, Almarzooq ZI, et al. 2024 heart disease and stroke statistics: A report of US and global data from the American Heart Association. Circulation. 2024; 149(8):e347-e913. doi: 10.1161/CIR.0000000000001209

[3] Lloyd-Jones DM, Allen NB, Anderson CAM, et al. Life’s essential 8: Updating and enhancing the American heart association’s construct of cardiovascular health: A presidential advisory from the American heart association. Circulation. 2022; 146(5):e18-e43. doi: 10.1161/CIR.0000000000001078

[4] Sun J, Li Y, Zhao M, et al. Association of the American heart association’s new “life’s essential 8” with all-cause and cardiovascular disease-specific mortality: Prospective cohort study. BMC Med. 2023; 21(1):116. doi: 10.1186/s12916-023-02824-8

[5] Alfaddagh A, Martin SS, Leucker TM, et al. Inflammation and cardiovascular disease: From mechanisms to therapeutics. Am J Prev Cardiol. 2020; 4:100130. doi: 10.1016/j.ajpc.2020.100130

[6] Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014; 114(12):1852-1866. doi: 10.1161/CIRCRESAHA.114.302721

[7] Dou M, Chen Y, Hu J, Ma D, Xing Y. Recent advancements in CD47 signal transduction pathways involved in vascular diseases. Biomed Res Int. 2020; 2020:4749135. doi: 10.1155/2020/4749135

[8] Yarmohammadi F, Karimi G. Serum and glucocorticoid-regulated kinase 1 (SGK1) as an emerging therapeutic target for cardiac diseases. Pharmacol Res. 2024; 208: 107369. doi: 10.1016/j.phrs.2023.107369

[9] Escopy S, Chaikof EL. Targeting the P-selectin/PSGL-1 pathway: Discovery of disease-modifying therapeutics for disorders of thromboinflammation. Blood Vessels Thromb Hemost. 2024; 1(3):100015. doi: 10.1016/j.bvth.2024.100015

[10] Di Candia AM, Avila DX, Moreira GR, Villacorta H, Maisel AS. Growth differentiation factor-15, a novel systemic biomarker of oxidative stress, inflammation, and cellular aging: Potential role in cardiovascular diseases. Am Heart J Plus. 2021; 9:100046. doi: 10.1016/j.ahjo.2021.100046

[11] Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res. 2019; 124(2):315-327. doi: 10.1161/CIRCRESAHA.118.313591

[12] Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol. 2001; 21:1876-1890. doi: 10.1161/hq1201.100220

[13] Tall AR, Bornfeldt KE. Inflammasomes and atherosclerosis: A mixed picture. Circ Res. 2023; 132(11):1505-1520. doi: 10.1161/CIRCRESAHA.123.321637

[14] Sagulenko V, Thygesen SJ, Sester DP, et al. AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death Differ. 2013;20(9):1149-1160. doi: 10.1038/cdd.2013.37

[15] Cavalli G, Colafrancesco S, Emmi G, et al. Interleukin 1α: A comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases. Autoimmun Rev. 2021;20(2):102763. doi: 10.1016/j.autrev.2021.102763

[16] Ridker PM, Rane M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ Res. 2021;128(11): 1728-1746. doi: 10.1161/CIRCRESAHA.121.319077

[17] Fanola CL, Morrow DA, Cannon CP, et al. Interleukin-6 and the risk of adverse outcomes in patients after an acute coronary syndrome: Observations from the SOLID-TIMI 52 (stabilization of plaque using darapladib-thrombolysis in myocardial infarction 52) trial. J Am Heart Assoc. 2017;6(10):e005637. doi: 10.1161/JAHA.117.005637

[18] Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017; 377(2):111-121. doi: 10.1056/NEJMoa1701719

[19] Khetarpal SA, Qamar A, Bick AG, et al. Clonal hematopoiesis of indeterminate potential reshapes age-related CVD: JACC review topic of the week. J Am Coll Cardiol. 2019; 74(4):578-586. doi: 10.1016/j.jacc.2019.05.045

[20] Tall AR, Fuster JJ. Clonal hematopoiesis in cardiovascular disease and therapeutic implications. Nat Cardiovasc Res. 2022; 1(2):116-124. doi: 10.1038/s44161-021-00015-3