In this study we found increased levels of both MDA and CO levels in the CFS group. We can therefore conclude that oxidative stress is present in our group of female CFS patients.
Although there are still many controversies concerning CFS, it is now a well-established condition with several million sufferers. It is likely that physicians avoid making this diagnosis due to the fact that CFS is still a diagnosis per exclusionem and that it has well-known overlapping syndromes. There is also the fact that many CFS patients do not seek medical attention due to their social and/or economic status. Nevertheless, many scientists are investigating the answers to the numerous questions CFS still poses: epidemiology, etiology, pathogenesis and treatment have not been completely defined.
Among the possible mechanisms of pathogenesis, oxidative stress is especially interesting as it can lead to potential therapeutic options and secondary prevention. It appears to play an important role in the development of, and also contributes to, some of the symptoms in CFS [14
The MDA is a product of lipid peroxidation of polyunsaturated fatty acids and it can be found in physiological conditions in lower concentrations. High levels of MDA are indicative of oxidative stress. The MDA is potentially very noxious [22
] and its toxicity can be directed towards cardiovascular stability. Primarily, MDA reacts with apoB fractions of oxidized lipoproteins (LDL), which causes impaired interaction of the modified lipoproteins and macrophages [22
]. This phenomenon is the basis of atherogenicity. Another probable toxic action of MDA involves collagen. Even if the nature of the cross-link has not yet been determined in detail, the inter-molecular cross-linking of collagen through MDA may significantly contribute to the stiffening of cardiovascular tissue [22
]. It is quite possible that the presence of MDA at higher levels may predict the insurgence of vascular pathologies. Polidori and collaborators found higher levels of antioxidants and lower levels of MDA in healthy subjects when compared in a case-control study with congestive heart failure patients [23
]. Plasma from atherosclerotic patients was richer in MDA studied by Tamer et al
]. In two studies reported by Boaz et al
], serum MDA values were markedly higher in hemodialysis patients with cardiovascular complications than in those without such complications.
The second significant finding in the CFS group was raised levels of CO, the product of protein oxidation. As generation of carbonyl derivatives occurs by many different mechanisms, the level of CO groups in proteins is widely used as a marker of oxidative protein damage, often correlating well with the progression of the disease. To date, accumulation of CO has been observed in several human diseases including Alzheimer's, Parkinson's and Huntington's diseases; diabetes; inflammatory bowel disease; adult (or acute) respiratory distress syndrome; chronic renal and lung diseases; sepsis; arthritis; preeclampsia and amyotrophic lateral sclerosis [31
]. The level of oxidized proteins also increases with aging and in age-related diseases [31
], which is why it was important that the two groups studied were matched in terms of age. Protein oxidation products in CFS patients have so far been investigated only by Smirnova and Pall [30
]. This group had similar results to ours but they found even more significantly elevated CO levels (p
< 0.0005) in CFS patients compared to controls.
The third important finding of our study was the unfavorable lipoprotein profiles in the CFS group. We found significantly lower levels of HDL-C and higher levels of TG in the study group. HDL-C is the beneficial form of blood cholesterol which protects the artery wall from atherosclerosis [43
]. Even in individuals whose LDL levels are low, HDL remains a strong independent predictor of coronary artery disease risk [44
]. Besides preventing cholesterol accumulation in cells of the artery wall, HDL-C acts as an anti-inflammatory agent by degrading lipid oxidation products [43
]. In this way, HDL-C acts against products of lipid peroxidation which are potentially atherogenic. We also found higher TG levels in the CFS group of patients. High levels of triglycerides are a well-known factor for atherosclerosis and are included in the Framingham charts that have been widely used by clinicians to quantify an individual's absolute risk for coronary heart disease.
Oxidative stress plays an important role in atherosclerosis. The LDL carries cholesterol from the liver to the circulatory system. It is susceptible to oxidation by reactive oxygen species (ROS), and damage is seen both to the lipid and to the protein moiety [48
]. In an environment where oxidative stress is present and where there are lower levels of antioxidant HDL-C and higher levels of TG, oxidation of LDL might be more pronounced [50
To date, only a few studies have been conducted that have implicated an increased risk of cardiovascular events in CFS patients with no comorbidities. Kennedy et al
. used 8-Iso-prostaglandin F2α
as a lipid peroxidation marker with a potential potent biological activity [19
]. They found significantly elevated levels of F2-isoprostanes and oxidized LDL and decreased HDL in nonobese, normotensive patients. Isoprostane levels were even greater in CFS patients who had additional cardiovascular risk factors. Similarly to our study, they concluded that CFS patients have a lipid profile and oxidant biology that is consistent with cardiovascular risk.
Three years later, the same group observed a relationship between inflammation and oxidative stress and augmentation index, a measure of arterial stiffness [51
]. They have shown that patients with CFS have higher serum CRP levels, elevated levels of isoprostanes and oxLDL, and significantly increased AIx@75, which indicates a significantly increased risk of a future cardiovascular event in these patients.
We also suggest a follow-up of our group of patients which should include an imaging technique in order to assess possible early atherosclerosis.
One limitation of the present study is that we did not measure the levels of oxidized LDL, which is associated with the development of atherosclerosis. A second limitation is the small number of patients. This is mainly due to difficulties in recruiting patients due to the relatively low incidence and prevalence of CFS. Furthermore, we were faced with skepticism about CFS both from the patients and the medical community, which made it difficult to mobilize patients.
In conclusion, in the present study we used two reliable biomarkers of oxidative stress rarely used before with CFS patients. We found signs of lipid and protein oxidative damage, as well as an unfavorable lipid profile in nonobese premenopausal female CFS patients with no comorbidities. We suggest that in this otherwise low risk group there are signs of possible early atherogenesis. This would mean that women who have CFS are at an increased risk for cardiovascular events and are in need of early intervention including antioxidant supplementation and LDL lowering strategies.