Trace Element, Immune and Opioid Biomarkers of Unstable Angina, Increased Atherogenicity and Insulin Resistance: Results of Machine Learning

Abstract

Background: Aberrations in endothelial cells, immune and oxidative pathways are associated with atherosclerosis (ATS) and unstable angina (UA). The role of trace elements, minerals, and the endogenous opioid system (EOS) in UA are less well established. Methods: We measured lipid, insulin resistance (IR), and immune, trace element (copper and zinc), mineral (magnesium, calcium), EOS (β-endorphin and mu-opioid receptor (MOR)) and antioxidant (vitamin D3) biomarkers in patients with ATS (n=60) and UA (n=60) and healthy controls (n=58). Results: ATS patients showed increased atherogenic and IR indices, IL-6, IL-10, β-endorphin, copper and magnesium, and lower zinc than healthy controls. Logistic regression showed that UA was significantly discriminated from ATS without UA with an accuracy of 85.5% using calcium, IL-10, β-endorphin, MOR, triglycerides, IR (all positively), and copper and vitamin D3 (inversely). Neural networks showed that UA was discriminated from ATS without UA with an area under the ROC curve of 0.942 using MOR, β-endorphin, calcium, insulin resistance, vitamin D3 and copper as input variables. We found that 50.0% of the variance in IR was explained by the regression on copper, IL-10, IL-6 (all positively), and zinc (inversely), while 32.9% of the variance in the atherogenic index of plasma was explained by copper, IL-10 (both positively), and magnesium (inversely). Conclusion: UA is not only mediated by insulin resistance, atherogenicity, and immune disorders, but also by aberrations in the endogenous opioid system and trace elements as well as lowered antioxidant levels. Copper appears to play a key role in IR and atherogenicity.

Intersections between copper, β-arrestin-1, calcium, FBXW7, CD17, insulin resistance and atherogenicity mediate depression and anxiety due to type 2 diabetes mellitus: a nomothetic network approach

“…Nevertheless, comorbid depressive ratings in unstable angina were not only associated with atherogenicity, insulin resistance, lowered zinc but also with increased IL-6 and calcium levels [122].…”

“…The latter may, however, be explained by specific effects of calcium mineralization of arteries and calcification of plaques in unstable angina [122].…”

A pathway phenotype linking metabolic, immune, oxidative, and opioid pathways with comorbid depression, atherosclerosis, and unstable angina

“…5,6 Recently, we found that ATS may be discriminated from normal controls by using a combination of different biomarkers in machine learning models, namely an increased HOMA-IR index, IL-6, IL-10 (a negative immune regulatory cytokine), β-endorphin, copper and magnesium, and lower zinc. 24 Moreover, ATS with UA was significantly discriminated from ATS without UA by increased levels of triglycerides (TG), IR, IL-10, β-endorphin, and mu-opioid receptors (MOR), and lowered vitamin D3, another antioxidant. 24 In this respect, it is interesting to note that increased IL-10 may play a protective role in ATS and in major depression.…”

“…24 Moreover, ATS with UA was significantly discriminated from ATS without UA by increased levels of triglycerides (TG), IR, IL-10, β-endorphin, and mu-opioid receptors (MOR), and lowered vitamin D3, another antioxidant. 24 In this respect, it is interesting to note that increased IL-10 may play a protective role in ATS and in major depression. 25,26 Indeed, IL-10 is a major component of the compensatory immune regulatory system (CIRS), which attenuates the IRS in chronic immune disorders including ATS and major depression.…”

“…[30][31][32] These endogenous opioid system (EOS) peptides have immune-regulatory effects and, therefore, increased levels may exert CIRS functions in both CVD/ATS and major depression. 24,30 Finally, a recent meta-analysis showed that elevated copper levels are associated with major depression and are involved in the pathophysiology of that illness. 33 Nevertheless, no studies have examined whether UA is accompanied by depressive symptoms and whether their association may be explained by shared pathways including increased atherogenicity (as assessed with AIP and Castelli risk 1 indices) and IR (as assessed with an increased HOMA-IR index), IRS (elevated IL-6) and CIRS (elevated IL-10) activation, lowered levels of antioxidants such as zinc and vitamin D, aberrations in the EOS as indicated by increased β-endorphin and MOR levels, and increases in copper.…”