Authors

Khan F, Spence VA, Kennedy G, Belch JJF

Institution

Vascular Diseases Research Unit, The Institute of Cardiovascular Research, Ninewells Hospital and Medical School, Dundee, UK

Background

Although the aetiology of chronic fatigue syndrome (CFS) is unknown, there have been a number of reports of blood flow abnormalities within the cerebral circulation and systemic blood pressure defects manifesting as orthostatic intolerance. Neither of these phenomena has been explained adequately, but recent reports have linked cerebral hypoperfusion to abnormalities in cholinergic metabolism. Our group has previously reported enhanced skin vasodilatation in response to cumulative doses of transdermally applied acetylcholine (ACh), implying an alteration of peripheral cholinergic function.

Methods and results

To investigate this further, we studied the time course of ACh-induced vasodilatation following a single dose of ACh in 30 patients with CFS and 30 age and gender-matched healthy control subjects. No differences in peak blood flow were seen between patients and controls, but the time taken for the ACh response to recover to baseline was significantly longer in the CFS patients than in control subjects. The time taken to decay to 75% of the peak response in patients and controls was 13.7±11.3 vs. 8.9±3.7 min (p=0.03), respectively, and the time taken to decay to 50% of the peak response was 24.5±18.8 vs 15.1±8.9 min (p=0,03), respectively.

Conclusions

Prolongation of ACh-induced vasodilatation is suggestive of a disturbance to cholinergic pathways, perhaps within the vascular endothelium of patients with CFS, and might be related to some of the unusual vascular symptoms, such as hypotension and orthostatic intolerance, which are characteristic of the condition.

Publication

Clinical Physiology and Functional Imaging, 2003 Sep; 23(5): 282–5
Download full paper (pdf 59 KB)

Non-technical summary

When we stimulate blood vessels with acetylcholine (as described previously) its effects usually fade fairly quickly and blood flow returns to normal. This is because an enzyme called cholinesterase is continually removing acetylcholine from the vessel wall and limiting its activity.

However, in further experiments we found that the blood flow response to acetylcholine in people with ME/CFS, as well as being abnormally high, was also abnormally prolonged (by about 10 minutes). This suggests that in this illness, there is either a reduced amount of cholinesterase available to remove the acetylcholine, or else it is not as effective.

These findings are further evidence of a disturbance to acetylcholine in ME/CFS, and suggest that a cholinesterase abnormality is involved, although this needs to be confirmed by measuring the enzyme directly.

Comment by ME Research UK

In recent years, the use of acetylcholine in the assessment of endothelial function has played a significant part in the study of various pathological conditions, such as hypertension, diabetes, hypercholesterolaemia, and atherosclerosis, all of which are associated with endothelial dysfunction. This research group at the University of Dundee, and others, have successfully pioneered a combination of iontophoretic drug delivery and laser Doppler imaging to measure blood flow responses in the skin in a variety of conditions. The method allows very small amounts of drug to be administered non-invasively to a localized area, and is consequently very safe.

As the authors discuss in this paper, it has been proposed that the symptoms of ME/CFS are, in part, cholinergically mediated (1). Two recent studies using brain spectroscopy have revealed metabolic disturbances with significantly elevated choline levels in various regions of the central nervous system (2, 3). Such metabolic disturbances might be linked to regional reductions in cortical to cerebral perfusion ratios, which are characteristic findings in many CFS patients (4, 5). In addition, abnormalities specific to the cholinergic pathway also exist in the peripheral microcirculation of ME/CFS patients (6). While it is unclear how abnormalities in regional blood flow and choline metabolism in the central nervous system might be linked to the enhanced acetylcholine mediated responses in the peripheral vasculature (7), these previous findings taken together have important implications for vascular integrity in ME/CFS — after all, orthostatic intolerance is a recognised feature of many ME/CFS patients. There are several possible ways in which increased vasodilatation to acetylcholine could be mediated, and this study represents further investigations into the phenomenon.

Importantly, the authors have found that following stimulation of the skin microvessels with acetylcholine, the time taken for blood flow to return to baseline from the peak vasodilator response is significantly increased in ME/CFS patients. This implies that there is a prolongation of the acetylcholine-mediated vasodilator response, supporting previous findings of this group that cumulative doses of acetylcholine elicited significantly higher peak blood flows in ME/CFS patients than in matched controls (6), and suggesting an abnormally slow clearance of acetylcholine from the vascular endothelium. Given that the aetiology of ME/CFS is commonly associated with viral onset and immunological disturbance sometimes linked to persistent viral infection (8, 9), the authors speculate that the findings can be explained by virus-associated under-expression of acetylcholine on endothelial cells (10, 11).

While the significance of these results in relation to the vascular integrity of this patient group remains to be determined, the authors suggest that since one of the characteristic signs of ME/CFS is the development of symptoms when upright, it may be that there is a defect in the regulation of local blood flow, possibly involving the cutaneous circulation (12). Their findings of a prolonged vasodilatation in response to acetylcholine delivered iontophoretically to skin blood vessels suggests that signalling mechanisms acting on the vascular endothelium might well be implicated in the type of postural orthostatic tachycardia syndrome (POTS) associated with ME/CFS patients (12).

As the authors conclude, if increased cutaneous blood flow in response to cumulative doses of acetylcholine is mediated by a prolongation of the response of individual doses in ME/CFS patients, then further study of the actions of acetylcholine as an endothelium-dependent vasodilator is warranted most especially in those ME/CFS patients in whom chronic orthostatic intolerance is a significant symptom.

References

  1. Chaudhuri A, Majeed T, Dinan T, Behan PO. Chronic fatigue syndrome: a disorder of central cholinergic transmission. J Chronic Fatigue Syndrome 1997; 3: 3–16.
  2. Tomoda A, Miike T, Yamada E et al. Chronic fatigue syndrome in childhood. Brain Dev 2000; 22: 60–4.
  3. Puri BK, Counsell SJ, Zaman R, et al. Relative increase in choline in the occipital cortex in chronic fatigue syndrome. Acta Psychiatr Scand 2002; 106: 224–6.
  4. Schwartz RB, Garada BM, Komaroff AL, et al. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. Am J Roentgenol 1994; 162: 935–41.
  5. Costa DC, Tannock C, Brostoff J. Brainstem perfusion is impaired in the chronic fatigue syndrome. Q J Med 1995; 88: 767–73.
  6. Spence VA, Khan F, Belch JJF. Enhanced sensitivity of the peripheral cholinergic vascular response in patients with chronic fatigue syndrome. Am J Med 2000; 108: 736–9.
  7. Bou-Holaigah I, Rowe CP, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. J Am Med Assoc 1995; 274: 961–7.
  8. Tirelli U, Marotta G, Improta S, Pinto A. Immunological abnormalities in patients with chronic fatigue syndrome. Scand J Immunol 1994; 40: 601–8.
  9. Patarca R, Mark T, Fletcher MA, Klimas N. Review: immunology of chronic fatigue syndrome. J Chronic Fatigue Syndrome 2000; 6: 69–107.
  10. Kirkpatrick CJ, Bittinger F, Unger RE, et al. The non-neuronal cholinergic system in the endothelium: evidence and possible pathobiological significance. Jpn J Pharmacol 2001; 85: 24–8.
  11. Oldstone MBA, Holmstoen J, Welsh RM. Alterations of acetylcholine enzymes in neuroblastoma cells persistently infected with lymphocyctic choriomeningitis virus. J Cell Physiol 1997; 91: 459–72.
  12. Stewart JM. Pooling in chronic orthostatic intolerance: arterial vasoconstrictive but not venous compliance defects. Circulation 2002; 105: 2274–81.