ABC | Volume 114, Nº3, March 2020

Original Article Leocádio et al. Netrin-1 and IL-1 β : prognosis in ACS Arq Bras Cardiol. 2020; 114(3):507-514 Table 5 – Hazard Ratios for high Netrin-1 and IL-1β and all-cause mortality, cardiovascular mortality and fatal or new non-fatal MI in older (>60 years) females All-cause mortality Cardiovascular mortality Fatal or new non-fatal MI HR (95% CI) p HR (95% CI) p HR (95% CI) p Netrin-1 Crude 2.15 (1.17 – 3.93) 0.013 2.31 (1.09 – 4.92) 0.029 2.25 (0.92 – 5.54) 0.075 Adjusted * 2.08 (1.04 – 4.16) 0.038 2.68 (1.06 – 6.74) 0.036 1.82 (0.65 – 5.07) 0.247 IL-1β Crude 1.57 (0.87 – 2.81) 0.127 2.23 (1.05 – 4.75) 0.036 2.27 (0.92 – 5.58) 0.073 Adjusted * 2.03 (1.06 – 3.89) 0.031 3.01 (1.26 – 7.17) 0.013 3.05 (1.12 – 8.32) 0.029 CI: confidence interval. HR: hazard ratio. IL-1β: Interleukin - 1beta. MI: myocardial infarction. * Adjusted for age, type of Acute Coronary Syndrome, diabetes, hypertension and dyslipidemia. These factors lead us to believe that the highest number of unfavorable outcomes, as well as the higher risk of death from all causes and from cardiovascular causes observed in women over 60 years of age with higher Netrin-1 levels are associated with the severity of event and the higher degree of inflammation (as suggested by the high levels of IL-1 β ) which may have contributed to a worse prognosis. Regarding IL-1 β , high levels of this one and other pro‑inflammatory cytokines have already been identified in patients with ACS. 26 Nonetheless, few studies were addressed to the prognostic value of this cytokine. 27,28 In agreement with our results, these studies suggest that higher levels of IL-1 β were seen inpatientswithACSwhounderwent newevents during follow-up. IL-1 β is capable of increasing the expression of molecules that contribute to plaque rupture and thrombus formation, culminating in the occurrence of ACS. 10,29 Thus, higher levels of serum IL-1 β could reflect exacerbated inflammation, favoring the occurrence of cardiovascular complications. Higher IL-1 β levels suggest an exacerbated inflammation that could impair cardiac remodeling. Adverse remodeling after MI is the structural basis for ischemic heart failure. Although adequate amounts of IL-1 β and other inflammatory cytokines are essential in the initial phase of remodeling, the decrease of cytokine levels is needed to promote effective healing. 30 It has been described that elevated levels of IL-1 β up to two months after infarction in patients with STEMI were strongly associated with a worsening of cardiac function after one year of follow-up. 31 Furthermore, cytokine was a strong predictor of left ventricular hypertrophy, which is important in predicting cardiovascular morbidity and mortality. 31 Several factors may help to understand the absence of association with worse prognosis found among men and younger women. Cardiac and vascular tissues are influenced by hormones such as estrogen and testosterone, varying according to sex and age. 32,33 Older women have a larger left ventricle mass than men, due to factors that indicate lower arterial capacity, such as reduced carotid wall thickness. 33 The relationship between inflammatory cytokines and gender has not yet been elucidated, although differences between concentrations are observed in the literature. 32 Studies indicate that IL- β concentration is higher in males. 33,34 Furthermore, cytokine levels are inversely related to age, as seen in our work and literature. 35 The literature does not provide data on sex differences for Netrin-1. Since we did not observe statistical gender differences in the levels of the markers, our hypothesis is that in our female group the levels of these were higher than the normal. This possible increase may be related to the higher frequency of cardiovascular risk factors in this group in the present study, factors that may lead to an increase in levels of inflammatory markers. 36 However, even after adjusting for these factors, high levels of Netrin-1 and IL‑1 β remained associated with worse prognosis, demonstrating that these inflammatory markers are independently associated with worse prognosis, and may be related to the reduction of arterial capacity already observed in older women when compared to men. We point out as limitations of the study its unicentric characteristic and the absence of a control group. Furthermore, we did not collect data from the pre-event period, whichwould allow us to determine the variation in marker concentration after ACS. Conclusions Higher levels of Netrin-1 and IL-1 β are associated with worse prognosis in elderly females with ACS. The mechanism for such association can be related to maintenance of inflammation and adverse cardiac remodeling, propitiating further cardiovascular events. Author contributions Conception and design of the research and Analysis and interpretation of the data: Leocádio P, Goulart A, Santos I, Lotufo P, Bensenor I, Alvarez-Leite, J; Acquisition of data: Leocádio P, Menta P, Dias M, Fraga J, Goulart A, Santos I, Lotufo P, Bensenor I; Statistical analysis: Leocádio P, Goulart A, Santos I; Obtaining financing: Lotufo P, Bensenor I; Writing of the manuscript: Leocádio P, Menta P, Dias M, Fraga J; Critical revision of the manuscript for intellectual content: Goulart A, Santos I, Lotufo P, Bensenor I, Alvarez-Leite, J. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. 512