Discussion
vascular dysfunction, preload failure, cardiovascular disease, endothelial dysfunction
CARDIOVASCULAR DISEASE, ENDOTHELIAL DYSFUNCTION, DISEASE, VASCULAR DILATION, SECONDARY, ENDOTHELIAL DYSFUNCTION
The present study is one of the first studies to investigate vascular function in ME/CFS patients, and was a substudy of a multi-center, national, randomized and placebo-controlled trial that investigated the effect of B-cell depletion using the monoclonal antibody rituximab in this poorly understood disease. We found significantly lower endothelial function measured with FMD, and lower microvascular regulation measured with PORH, in patients with ME/CFS compared to healthy control groups. The vascular dilation after administration of glyceryl nitrate in ME/CFS patients was similar to healthy controls, showing that the intrinsic ability to dilate adequately was present. We found no significant correlation between FMD and PORH. There were tendencies towards lower FMD and PORH in patients with moderate to severe ME/CFS symptoms. However, there were no significant correlations between measures of vascular function and disease severity or physical function measures except for a significant correlation between PORH and steps per 24 hours at baseline. Overall, the patients experienced a slight clinical improvement during follow-up in the trial. There was no corresponding improvement in endothelial function measured by FMD, but a significant improvement in PORH from baseline to repeated measurement at 18 months. There was no difference in changes of endothelial function (FMD or PORH) during follow-up between the rituximab and placebo groups.Our findings support our first hypothesis of reduced vascular function in ME/CFS patients, and confirm previous findings [Nevertheless, it is a significant and important finding that our group of ME/CFS patients had such markedly reduced vascular function compared to healthy individuals. The observed endothelial dysfunction argues for a pathomechanistic effect of the vascular system in ME/CFS.The mechanisms for vascular dysfunction in ME/CFS patients are unclear. Endothelial dysfunction, in both large and small vessels, is a well-known risk factor for cardiovascular disease later in life [We recently summarized our hypotheses on possible pathomechanisms in ME/CFS [However, the endothelial dysfunction could also be a secondary phenomenon and therefore not directly associated with disease severity or improvement in patients experiencing symptom fluctuations during follow-up. Another possible mechanism for reduced vascular function could be inactivity. A meta-analysis of the effects of exercise on FMD concluded that exercise training contributed to an increase in FMD [In the present study, there was no clear relation between endothelial dysfunction and severity of disease symptoms, although we observed a tendency towards higher FMD and PORH values in patients with milder symptoms.There was no correlation between microvascular function measured by PORH, and endothelial function of the brachial artery measured by FMD. These methods both measure endothelial-dependent vascular function, but large and small vessels are regulated by somewhat different mechanisms, and studies of both measures have often found a poor or lacking correlation between FMD and PORH [Strengths of the present study: The RituxME study was a high quality study, with a double-blind randomized design, and selection of patients according to well-established and stringent criteria. The patients followed a strict and thorough follow-up regime. Endothelial function was measured using two different and complementary methods, both well documented. Vascular measures in the healthy control groups were similar to other studies of healthy individuals in comparable age groups [Weaknesses of the present study: Our patient sample was limited (39 patients). However, such patient numbers are not uncommon in FMD studies, and are often sufficient to show significant differences between groups [Clinical implications of this study: We think our findings of reduced endothelial function, both micro- and macrovascular, are of clinical importance. FMD and PORH measurements are not regarded as useful diagnostic tools for any patients groups, but are used to evaluate risk on a group level. Our study supports growing evidence that ME/CFS patients have a markedly reduced endothelial function compared to the normal population. This is an important discovery in a field with a scarcity of objective and measurable abnormalities. Our study does not answer the question of why these patients have reduced endothelial function. Reduced endothelial function might be an associated symptom rather than a central mechanism of the disease. However, we suspect that in ME/CFS the endothelial dysfunction is related to an abnormal immune response, and may be a factor in the pathomechanism. Together with reduced venous tone (“preload failure”), and arteriovenous anastomoses [