Authors

Witham MD, Adams F, McSwiggan S, Kennedy G, Kabir G, Belch JJF, Khan F

Institution

Medical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK

Publication

Nutrition, Metabolism & Cardiovascular Diseases, 2015 Mar; 25(3): 287-94

Funding

Funded by ME Research UK, grant number MERUK/2009/2. We acknowledge the financial support of NHS Research Scotland through NHS Tayside in facilitating this research.

Abstract

Background and aims

Low 25-hydroxyvitamin D levels are common in patients with chronic fatigue syndrome; such patients also manifest impaired vascular health. We tested whether high-dose intermittent oral vitamin D therapy improved markers of vascular health and fatigue in patients with chronic fatigue syndrome.

Methods and results

Parallel-group, double-blind, randomised placebo-controlled trial. Patients with chronic fatigue syndrome according to the Fukuda (1994) and Canadian (2003) criteria were randomised to receive 100,000 units oral vitamin D3 or matching placebo every 2 months for 6 months. The primary outcome was arterial stiffness measured using carotid-femoral pulse wave velocity at 6 months. Secondary outcomes included flow-mediated dilatation of the brachial artery, blood pressure, cholesterol, insulin resistance, markers of inflammation and oxidative stress, and the Piper Fatigue scale. As many as 50 participants were randomised; mean age 49 (SD 13) years, mean baseline pulse wave velocity 7.8 m/s (SD 2.3), mean baseline office blood pressure 128/78 (18/12) mmHg and mean baseline 25-hydroxyvitamin D level 46 (18) nmol/L. 25-hydroxyvitamin D levels increased by 22 nmol/L at 6 months in the treatment group relative to placebo. There was no effect of treatment on pulse wave velocity at 6 months (adjusted treatment effect 0.0 m/s; 95% CI -0.6 to 0.6; p = 0.93). No improvement was seen in other vascular and metabolic outcomes, or in the Piper Fatigue scale at 6 months (adjusted treatment effect 0.2 points; 95% CI -0.8 to 1.2; p = 0.73).

Conclusion

High-dose oral vitamin D3 did not improve markers of vascular health or fatigue in patients with chronic fatigue syndrome.

Highlights

  • We randomised 50 patients with CFS/ME to receive six months of intermittent high-dose vitamin D or placebo.
  • Vitamin D did not improve pulse-wave velocity or flow-mediated dilatation of the brachial artery compared to placebo.
  • Vitamin D did not improve markers of oxidative stress or inflammation compared to placebo.
  • Vitamin D did not improve symptoms of fatigue compared to placebo.

Comment by ME Research UK

Low levels of circulating vitamin D in the blood are associated with increased blood pressure and poorer vascular health, and they are known to increase the risk of future cardiovascular threats, such as heart attack and stroke. For this reason, several large trials are now underway across the world to explore the effects of vitamin D supplementation – which involves giving high-dose vitamin D by mouth to increase levels in the body. A variety of diseases are being studied, including the disease osteomalacia which involves softening of the bones and which (like ME/CFS) comes with fatigue, muscle pain and problems with skeletal muscle.

In 2009, a study by London-based researchers found vitamin D levels to be considerably lower in ME/CFS patients than in healthy people. Also, investigations funded by ME Research UK at the University of Dundee had discovered an association between lower vitamin D levels and arterial stiffness (see overview), dysfunction of the endothelium which lines blood vessels (full text), and inflammation. These results suggested that low vitamin D might well be contributing to the burden of illness of ME/CFS patients, and were the reason why ME Research UK decided to fund a prospective randomized trial. The idea was to determine whether vitamin D supplementation could reverse the impairments in vascular health and alleviate some of the symptoms of the illness.

In the trial, 50 ME/CFS patients, diagnosed according to the Fukuda (1994) and Canadian (2003) criteria, were divided into two groups: one half received 100,000 units of vitamin D3 by mouth while the other half received an indistinguishable placebo. Doses were given every 2 months for 6 months. As the researchers were particularly interested in the effect on vascular function, the main outcome measure was arterial stiffness, measured using a technique called ‘pulse waveform analysis’ (see below), which previous research had shown to be worse in ME/CFS patients than in healthy people. Other measurements included blood pressure, cholesterol, and markers of inflammation, as well as fatigue and other symptoms.

After 6 months, high-dose oral vitamin D3 levels in the blood had increased significantly (by 22 nmol/L) in the treatment group compared with the placebo group. However, the increase in vitamin D levels had no effect on arterial stiffness levels at 6 months, and no improvement was seen in other vascular and metabolic outcomes or in fatigue or other symptoms.

The lack of effect of supplementary vitamin D on vascular or inflammatory markers in ME/CFS patients contrasts with its positive effects in other diseases. In type 2 diabetes mellitus patients, for example, vitamin D (at the same dose as the ME/CFS patients in Dundee) improved endothelial function and blood pressure, while in stroke patients improvements in endothelial function have been observed after supplementation.

The reasons for these negative results are unclear. Could low vitamin D levels be a result of ME/CFS itself – in which case, supplying more would not necessarily reverse the vascular dysfunction. Or might larger or more frequent dosing be needed in order to produce a clinically relevant effect in this specific group of patients? This last possibility is in the researchers’ minds, and they are deciding on the next experimental steps. As principal investigator Dr Khan says, “Given the increased arterial stiffness we’d previously found in our ME/CFS patients, it was certainly worth investigating whether it could be reversed by vitamin D supplementation, which is a cheap and very convenient therapy. Our thanks go to the patients in Tayside who took part, some of whom had travelled long distances. We are grateful to them all.”

Pulse wave analysis

When you place your fingers on your wrist, you can feel your pulse; that is, the regular increase in pressure as each pulse of blood travels down the radial artery. This pulse can also be detected by a pressure sensor applied to the wrist, and this is the technique used by Dr Khan and his colleagues to determine arterial stiffness.

The sensor produces a continuous recording of the fluctuations in pressure caused by each pulse wave (see Figure below), and their shape is analysed to determine how stiff the artery is. The pulse pressure wave is composed of a wave generated by the ejection of blood from the heart and a reflected wave from the periphery. As arteries get stiffer, the velocity of both waves increases, causing the reflected wave to arrive earlier in the aorta and augment the size of the pulse. The measured ‘augmentation index’ is therefore related to blood vessel stiffness.

pulse wave