Newton DJ, Kennedy G, Chan KKF, Lang CC, Belch JJF, Khan F
Vascular and Inflammatory Diseases Research Unit, Institute of Cardiovascular Research, University of Dundee, Dundee, UK
There is accumulating evidence that myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is associated with increased cardiovascular risk. The aim of this study was to assess vascular endothelial function directly in the forearm macro and microcirculations of patients with ME/CFS.
Flow-mediated dilatation was assessed using ultrasound to measure the percentage increase in brachial artery diameter during the hyperaemia following 5 minutes of ischaemia in 30 ME/CFS patients and 27 healthy controls. Post-occlusive reactive hyperaemia was assessed in 9 ME/CFS patients and 9 healthy controls using laser Doppler flowmetry to measure the increase in forearm skin microcirculation after 5 minutes of ischaemia.
Flow-mediated dilatation was significantly lower in the ME/CFS group (median [interquartile range]: 5.99 [3.65] versus 9.24 [3.47]%, p<0.001). Post-occlusive reactive hyperaemia was also significantly lower in ME/CFS patients (area under the response curve: 19.76 [15.46] versus 38.70 [18.14] AU∙min, p=0.012). ME/CFS patients also had significantly higher levels of serum high-sensitivity C-reactive protein (p=0.016) and triglycerides (p=0.034), and lower levels of serum high-density lipoprotein cholesterol (p=0.041).
These findings provide direct evidence of endothelial dysfunction in both the large and small vessels of patients with ME/CFS, which may warrant a large prospective trial of cardiovascular outcomes in the disease.
Comment by ME Research UK
ME/CFS is associated with cardiovascular symptoms including autonomic dysfunction and cardiac dysfunction, and impaired blood pressure regulation. In addition, several research groups have reported raised levels of oxidative stress, low-grade inflammation and increased arterial stiffness. These different evidential strands form a picture of increased cardiovascular risk in people with the illness, something of great potential importance to patients and healthcare services.
One potential site of oxidative injury – cumulative cell damage caused by oxygen “free radicals” – is the vascular endothelium, the thin layer of cells that lines the inner surface of every blood vessel. The vascular endothelium in fact lines the entire circulatory system, from the smallest capillaries to the arteries and all the way to the heart, and has very distinct and unique functions that include the movement of hormones, the maintenance of blood vessel tone, and the recruitment of white blood cells. Damage to the vascular endothelium would be expected to lead to dysfunction of the endothelial cells themselves and a reduced ability of the blood vessels to open to full capacity. Could the vascular endothelium be damaged in ME/CFS patients?
Building on their previous programme of cardiovascular research in adults and children with ME/CFS, including investigations of arterial stiffness, Dr David Newton and colleagues at the Vascular and Inflammatory Diseases Research Unit, University of Dundee decided to investigate both large-vessel and small-vessel endothelial function, both of which are known to be related to cardiovascular risk and outcome. Large-vessel function was measured using flow-mediated dilatation (see below), and small-vessel (microvascular) function was measured by laser Doppler flowmetry of the forearm skin after cuff occlusion of blood flow to the arm.
What is flow-mediated dilatation?
- When blood flow increases through a blood vessel, the vessel dilates (or increases in diameter) – this phenomenon is called flow-mediated dilatation.
- It is the most widely used research technique for assessing the health of the vascular endothelium, the layer of active cells which lines the entire circulatory system and participates in the regulation of blood flow in response to the needs of tissues and organs.
- To measure flow-mediated dilatation, arterial blood flow (usually to a limb) is temporarily stopped and then restarted, causing blood flow to overshoot (reactive hyperaemia) as the vessels dilate. The resultant increase in blood vessel diameter can be measured using an ultrasound probe.
- In patients with dysfunction of the endothelium – seen in cardiovascular diseases and in inflammatory conditions such as systemic lupus – the blood vessels are less able to dilate, and so flow-mediated dilatation is lower than in healthy people.
- Flow-mediated dilatation has become a valuable assessment tool, since a disturbance of endothelial function is now considered to be a key event in the development of atherosclerosis.
Flow-mediated dilatation was significantly lower in the 30 CDC-defined patients than in the 27 age and gender-matched control subjects (median of 5.99 versus 9.24%, respectively, p<0.001). Importantly, after glyceryl trinitrate was given to patients and controls, there was no significant difference between the groups, demonstrating that the impaired flow-mediated dilatation was most likely to be due to endothelial dysfunction and not to some other cause (such as damaged smooth muscle). As regards the small vessels, ME/CFS patients had a significantly lower blood flow response in forearm skin than did control subjects (peak flow 38.33 versus 69.80 arbitrary units, respectively, p=0.002). ME/CFS patients also had significantly higher levels of serum hs-CRP and triglycerides, and lower levels of HDL cholesterol in blood samples – all indicative of increased oxidative stress and cardiovascular risk.
The importance of this investigation was that it was the first ever to measure and demonstrate vascular endothelial dysfunction directly in ME/CFS patients. Since the experiments measured the response of the vascular endothelium to a “shear stress” (i.e., the stopping and starting of blood flow), the reduced vascular responses support the hypothesis that some functions of the endothelium are damaged in ME/CFS patients, both in large vessels and in the small-vessel microcirculation. The authors of the scientific paper say that their findings “
build on previous work reporting indirect markers of endothelial dysfunction, such as increased oxidative stress, inflammation and arterial stiffness”, and that these results taken together with previous evidence “
point to an increased cardiovascular risk in ME/CFS patients”.
This essay is an extract from our article (pdf 1.1 MB) in the Spring 2012 issue of Breakthrough.