ABC | Volume 114, Nº3, March 2020

Original Article High Serum Netrin-1 and IL-1β in Elderly Females with ACS: Worse Prognosis in 2-years Follow-up Paola Leocádio, 1 Penélope Menta, 1 Melissa Dias, 1 Júlia Fraga, 1 Alessandra Goulart, 2 Itamar Santos, 2, 3 Paulo Lotufo, 2,3 Isabela Bensenor, 2,3 Jacqueline Alvarez-Leite 1 Departamento de Bioquímica e Imunologia - Universidade Federal de Minas Gerais, 1 Belo Horizonte, MG – Brazil Centro de Pesquisa Clínica e Epidemiológica do Hospital Universitário da Universidade de São Paulo, 2 São Paulo, SP – Brazil Departamento de Clínica Médica da Faculdade de Medicina da Universidade de São Paulo, 3 São Paulo, SP – Brazil Mailing Address: Paola Leocádio • Departamento de Bioquímica e Imunologia - Universidade Federal de Minas Gerais - Avenida Antonio Carlos, 6627. Postal Code 31270-901, Pampulha, Belo Horizonte, MG – Brazil E-mail: paolaleocadio@yahoo.com.br Manuscript received January 22, 2019, revised manuscript March 23, 2019, accepted June 03, 2019 DOI: https://doi.org/10.36660/abc.20190035 Abstract Background: Several markers have been evaluated for a potential impact on clinical decisions or mortality prediction in acute coronary syndrome (ACS), including Netrin-1 and IL-1 β that have been associated with cardiovascular disease. Objective: Our study examined the prognostic value of Netrin-1 and IL-1 β in patients with ACS (2-year follow-up). Methods: We evaluate Netrin-1, IL-1 β and other risk factors in the serum sample of 803 patients. Kaplan-Meier curves and Cox regression were used for the analysis of all-cause mortality, cardiovascular mortality, and a combined outcome of fatal myocardial infarction (MI) or new non-fatal MI, considering p-value < 0.05. Results: There were 115 deaths from all causes, 78 deaths due to cardiovascular causes and 67 events in combined outcomes. Netrin-1 levels above the median (>44.8 pg/mL) were associated with a worse prognosis (all-cause mortality and cardiovascular mortality) in elderly females, even after model adjustment (HR: 2.08, p = 0.038 and HR: 2.68, p = 0.036). IL-1 β levels above the median (>13.4 pg/mL) in elderly females were associated with increased risk of all outcomes after adjustment (all-cause mortality - HR: 2.03, p = 0.031; cardiovascular mortality - HR: 3.01, p = 0.013; fatal MI or new non-fatal MI - HR: 3.05, p = 0.029). For males, no associations were observed between Netrin-1 or IL-1 β and outcomes. Conclusion: High serum levels of Netrin-1 and IL-1 β showed significant association with worse prognosis in elderly females. They may be useful as prognostic indicators in ACS. (Arq Bras Cardiol. 2020; 114(3):507-514) Keywords: Acute Coronary Syndrome/physiopathology; Netrin-1; Interleukin-1 beta; Atrial Remodeling; Hypertension; Diabetes Mellitus; Dyslipidemias; Stroke; Aged; Women. Introduction Coronary heart disease (CHD) is the leading cause of death and years of life lost. 1 Responsible for the largest number of deaths in Brazil, CHD has high prevalence and a poor prognosis. 2 Despite the reduction in acute coronary syndrome (ACS) mortality observed in recent decades, 1 it is estimated that near 14% of patients who have had a myocardial infarction (MI) will die of it. 3 The risk of illness and death is 1.5 to 15 times higher for patients who survive the acute stage of MI than for the general population. 3 Of those who have a first MI, approximately 17% of males and 21% of females at ≥ 45 years will have a recurrent MI or fatal CHD within five years. 3 Inflammation is an important factor in the pathophysiology of ACS as well as in the cardiac remodeling after AMI. Several markers have been evaluated for a potential impact on clinical decisions or mortality prediction. 4 Recently, neuronal guidance molecules, especially Netrin-1, have been identified as important modulators of atherosclerosis, although their specific role (protective or deleterious) is still controversial. 5-7 Netrin-1 is a member of a family of proteins structurally similar to laminins, which are structural components of the basal membrane of tissues. 8 The role of Netrin-1 in cardiovascular disease and inflammation is an emerging area of study. 5 Interleukin-1 (IL-1) is one of the major mediators of inflammation-induced coagulation. 9 IL-1 β is capable of inducing the expression of other molecules that favor the recruitment of inflammatory cells to the lesion and tissue injury. 10 A high level of IL-1 has been described in MI. 11,12 Recently, a randomized clinical trial among people who suffered a MI showed that canakinumab, an agent that block IL-1 β reduced the incidence of non-fatal CHD, non-fatal stroke events and cardiovascular death. 13 Despite the importance of these two molecules in ACS, studies evaluating their prognostic value are scarce. Our objective was to evaluate the role of these molecules as predictors of prognosis in a 2-year follow-up. 507