ABC | Volume 114, Nº2, February 2020

Short Editorial Atherosclerosis, Inflammation, and Genetics – And you Thought it Was Just LDL-cholesterol Luis Henrique Wolff Gowda k Universidade de São Paulo (USP), Faculdade de Medicina do Hospital das Clínicas do Instituto do Coração (Incor), São Paulo, SP – Brazil Short Editorial related to the article: Association between Periodontitis, Genetic Polymorphisms and Presence of Coronary Artery Disease in Southern Brazil Mailing Address: Luis Henrique Wolff Gowdak • Universidade de São Paulo (USP), Faculdade de Medicina do Hospital das Clínicas do Instituto do Coração (Incor). Av. Dr. Eneas de Carvalho Aguiar, 44. Postal Code 05466040, São Paulo, SP – Brazil E-mail: luis.gowdak@incor.usp.br Keywords Atherosclerosis/physiopathology; Inflammation; Coronary Artery Disease/history; Mortality andMorbidity; Polymorphism, Genetic; Risk Factors. DOI: https://doi.org/10.36660/abc.20200038 As the twentieth century unfolded, based on numerous epidemiological observations and intervention trials, cardiovascular risk factors were identified and targeted with the aim of decreasing cardiovascular disease burden worldwide. Along the centuries, changes in human eating patterns, a progressive decrease in physical activity, and a higher prevalence of obesity, all of which are contributing factors to the alarming rates of diabetes, hypertension, and hypercholesterolemia we see in our daily practice, have led us to assume that atherosclerosis-related disorders (myocardial infarction, ischemic cardiomyopathy, stroke, and peripheral artery disease) are an inevitable consequence of the evolutionary process we have to face in present times. However, due to advances in noninvasive imaging of the vascular system, atherosclerotic lesions in the aorta and coronary and carotid arteries happen to be found in mummies from ancient Egypt, 1 whose estimated mean age at the time of death was only 45 years. If the so-called “classical risk factors” were less prevalent in ancient times, different, non-traditional factors must have played a significant role in the development and progression of atherosclerosis. 2 Microbial and parasitic inflammatory burdens that were likely present in ancient cultures inherently lacking modern hygiene and antimicrobials could have evoked a chronic inflammatory status. Given that patients with today’s chronic systemic inflammatory diseases, including human immunodeficiency virus infection, systemic lupus erythematosus, and rheumatoid arthritis experience early- onset atherosclerosis and coronary events, is it possible that the chronic inflammatory load secondary to infection resulted in atherosclerosis in ancient times? Moreover, atherosclerosis is a complex, multifactorial biological process, and, as such, it is also subject to gene-environment interplay; therefore, although the contribution of today’s classical risk factors to the development of atherosclerosis is inquestionable, their role in the appearance of atherosclerotic lesions in the vascular tree involves not only inflammation and activation of the immune system but also genetic factors that facilitate or oppose the formation of lipid accumulation in the arterial wall. Progress in cell and molecular biology has allowed us to refine our understanding of the mechanisms involved in the onset of atherosclerosis. LDL-cholesterol particles play a significant role in the genesis of atherosclerotic plaque in the presence of endothelial dysfunction, an omnipresent feature in individuals with cardiovascular risk factors. 3 Proliferation and migration of smooth muscle cells in response to the release of growth factors and the accumulation of mononuclear phagocytes rich in plasma-derived lipids (foam cells) contribute to the development of atheroma. 4 Further studies revealed that the immune system played a role in atherosclerosis through not only innate (macrophages) but also adaptive (T cell and other lymphocytes) pathways. 5 Cells directly involved in atherosclerosis establish a complex network of cross-talking by the release of cytokines, notably interleukin-1. 6 Once recognized as an inflammatory disease, a highly sensitive assay for the measurement of C-reactive protein (hsCRP) proved to be a marker for patients at high risk for cardiovascular events due to atherosclerosis and a useful tool in selecting patients for aggressive lipid control for risk reduction. In the JUPITER trial, statin therapy in patients with hsCRP values above the median for the population (> 2 mg/L) but with LDL-cholesterol level < 130 mg/dL had a 44% reduction in first-ever cardiovascular events. 7 More recently, the CANTOS trial allocated the anti-interleukin-1 antibody (canakinumab) to patients with stable post-acute coronary syndromes who had hsCRP values > 2 mg/L on statin therapy. 8 Individuals who achieved a reduction of hsCRP to < 2 mg/L in response to anti-inflammatory therapy had a > 30% reduction in cardiovascular and all-cause mortality. 9 It is nowwidely accepted that genetic factors also contribute significantly to the risk of coronary artery disease (CAD), and the heritability of CAD has been estimated to be between 40% and 60%. 10 Using genome-wide association studies (GWAS), common single nucleotide polymorphisms (SNP) present in ≥ 5% of the population across the human genome can be identified, and the allele frequency of each SNP can be compared in cases and controls. The first association of CAD revealed by the GWAS approach was a block containing multiple SNP at 9p21.3 locus. 11 Since then, new SNP have been found to correlate significantly with the presence and extension of atherosclerotic CAD; these SNP are related to different aspects that govern the biology of atherosclerosis including, but not limited to, cell-to-cell interactions, immune response, cholesterol absorption, and lipoprotein(a) levels. 12 The CRP gene +1444C > T variant in the 3’ untranslated region (UTR) influences both basal and stimulated CRP levels. 13 273