ABC | Volume 111, Nº6, December 2018

Original Article Santos et al OX-LDL and Oral Contraceptives Arq Bras Cardiol. 2018; 111(6):764-770 Table 3 – Correlation analysis between LDL-oxidized (mU/mL) and fasting lipid profile variables (mg/dL) and CRP (mg/dL) Crossings Correlation coefficient (rs) p value* Oxidized LDL and TG 0.32 0.03 Oxidized LDL and CT 0.47 < 0.01 Oxidized LDL and LDL-cholesterol 0.29 0.05 Oxidized LDL and HDL-cholesterol 0.26 0.08 Oxidized LDL and PCR 0.20 0.19 Oxidized LDL: oxidized low-density lipoprotein; TG: triglycerides; TC: total cholesterol; HDL-cholesterol: high-density lipoprotein cholesterol; LDL-cholesterol: low‑density lipoprotein cholesterol; CRP: C-reactive protein; * Spearman's correlation test. Table 4 – Categorical analysis based on the median of oxidized LDL COC p value* No n (%) Yes n (%) Oxidized LDL < 247 15 (71.4%) 6 (28.6%) < 0.01 > 247 6 (28.6%) 15 (71.4%) Oxidized LDL: oxidized low-density lipoprotein; COC: combined oral contraceptive. *Fisher’s exact test. It is also interesting to note that the use of COC has been suggested as an independent factor for plasma CRP elevation in women of reproductive age. This increase appears to be associated with changes in estrogen β receptor function and levels, increased cortisol, increased TNF- α , hypomethylation in the DNA of macrophages, and alterations in hepatic PCR synthesis. It is also worth noting that the current use of COC can independently represent 20 to 32% of the variation of CRP in these women. 33 In addition, it was also shown that one in three women on COC shows CRP > 3 mg/L, which according to the literature can markedly increase the risk of cardiovascular events. 29 In addition, as in our results, research has shown a significant elevation of blood pressure in women on use of COC. 7,34,35 In fact, according to some studies, COC use may be related to mild and moderate arterial hypertension, with increases ranging from 20 to 40 mmHg in SBP and 10 to 20 mmHg in the diastolic pressure. Also, according to the studies, this elevation can be reversed within 3 months after COC descontinuation. 34 Such elevation of blood pressure may occur due to changes in electrolyte concentrations, oxidative stress, insulin resistance, and increased production of renin and hepatic angiotensinogen in these women. 34,35 Therefore, in addition to the fact that oxidized LDL emerges as a non-traditional risk factor for future cardiovascular events in postmenopausal women, 14 and that, in the pathophysiology of atherosclerosis, besides being present in all stages of the atherosclerotic process, it begins to be deposited in the arterial wall of young adults, even before the initial formation of the atheromatous plaque, 36 it is suggested that women taking COC present a greater future cardiovascular risk than women who do not use this group of drugs. Oxidation of LDL-cholesterol is closely related to endothelial dysfunction in a positive feedback process. The endothelial dysfunction associated with the arterial vascular inflammatory process are mainly responsible for the oxidation of LDL cholesterol, which in turn causes endothelial cell toxicity and chemotactic attraction of monocytes/macrophages through feedback of endothelial dysfunction. This mechanism is known as the oxidative theory of atherogenesis. 37,38 The results presented here point to mechanisms that may help elucidate the outcome of a multicenter study that showed that COC use is associated with a 5-fold increased risk of myocardial infarction in Europe and more than 4-fold in non-European countries. It is worth mentioning that this increase is closely linked to COC formulations with estrogen (≥ 50 μg), and the presence of classic risk factors such as smoking, hypertension, dyslipidemia, and obesity. 16,17 Another interesting study showed that women taking COC with ethinyl estradiol dosages between 30 and 40 μg had a risk of arterial thrombosis between 1.3 and 2.3. At lower dosages (20 μg), the risk was 0.9 and 1.7 times, when compared to women who did not use this group of drugs. These results suggest that even at low dosages, COCs may increase the risk of atherothrombosis, a fact that should be taken into consideration during its prescription, especially in women presenting cardiovascular and metabolic disease risk factors. 17,39 Finally, the present study has limitations that need to be discussed. One of them is the non-stratification of COC types. Although being of 3rd generation, COC has different formulations in concentrations of estrogen and progestin, a fact that, in addition to being able to cause different effects on the metabolism, limits the generalization of the results as to the type of hormone present in the formulation of contraceptives. In addition, dietary control was not adequately performed, although we did not select volunteers in control or dietary limitation, and the influence of diet on our results cannot be completely excluded. It is also 768