Khan – American ME and CFS Society

Effect of intermittent vitamin D3 on vascular function and symptoms in chronic fatigue syndrome–a randomised controlled trial

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.

TRIAL REGISTRATION: www.controlled-trials.com, ISRCTN59927814.

Source: Witham MD, Adams F, McSwiggan S, Kennedy G, Kabir G, Belch JJ, Khan F. Effect of intermittent vitamin D3 on vascular function and symptoms in chronic fatigue syndrome–a randomised controlled trial. Nutr Metab Cardiovasc Dis. 2015 Mar;25(3):287-94. doi: 10.1016/j.numecd.2014.10.007. Epub 2014 Oct 22. https://www.ncbi.nlm.nih.gov/pubmed/25455721

Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome

Abstract:

Some of the symptoms reported by people with CFS (chronic fatigue syndrome) are associated with various cardiovascular phenomena. Markers of cardiovascular risk, including inflammation and oxidative stress, have been demonstrated in some patients with CFS, but little is known about the relationship between these and prognostic indicators of cardiovascular risk in this patient group. In the present study, we investigated the relationship between inflammation and oxidative stress and augmentation index, a measure of arterial stiffness, in 41 well-characterized patients with CFS and in 30 healthy subjects.

AIx@75 (augmentation index normalized for a heart rate of 75 beats/min) was significantly greater in patients with CFS than in control subjects (22.5+/-1.7 compared with 13.3+/-2.3% respectively; P=0.002). Patients with CFS also had significantly increased levels of CRP (C-reactive protein) (2.58+/-2.91 compared with 1.07+/-2.16 mug/ml respectively; P<0.01) and 8-iso-prostaglandin F(2alpha) isoprostanes (470.7+/-250.9 compared with 331.1+/-97.6 pg/ml respectively; P<0.005). In patients with CFS, AIx@75 correlated significantly with logCRP (r=0.507, P=0.001), isoprostanes (r=0.366, P=0.026), oxidized LDL (low-density lipoprotein) (r=0.333, P=0.039) and systolic blood pressure (r=0.371, P=0.017). In a stepwise multiple regression model, including systolic and diastolic blood pressure, body mass index, CRP, tumour necrosis factor-alpha, interleukin-1, oxidized LDL, high-density lipoprotein-cholesterol levels, isoprostanes, age and gender, AIx@75 was independently associated with logCRP (beta=0.385, P=0.006), age (beta=0.363, P=0.022) and female gender (beta=0.302, P=0.03) in patients with CFS.

The combination of increased a, inflammation and oxidative stress may result in an increased risk of future cardiovascular events. Assessment of arterial wave reflection might be useful for determining cardiovascular risk in this patient group.

Source: Spence VA, Kennedy G, Belch JJ, Hill A, Khan F. Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome. Clin Sci (Lond). 2008 Apr;114(8):561-6. https://www.ncbi.nlm.nih.gov/pubmed/18031285

Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome

Abstract:

The aetiology of chronic fatigue syndrome (CFS) remains controversial and a number of hypotheses have been put forward to explain it. Research into the condition is hindered by the considerable heterogeneity seen across patients but several reports have highlighted disturbances to cholinergic mechanisms in terms of central nervous system activity, neuromuscular function and autoantibodies to muscarinic cholinergic receptors. This paper examines an altogether separate function for acetylcholine and that is its role as an important and generalized vasodilator.

Most diseases are accompanied by a blunted response to acetylcholine but the opposite is true for CFS. Such sensitivity is normally associated with physical training so the finding in CFS is anomalous and may well be relevant to vascular symptoms that characterise many patients. There are several mechanisms that might lead to ACh endothelial sensitivity in CFS patients and various experiments have been designed to unravel the enigma. These are reported here.

Source: Spence VA, Khan F, Kennedy G, Abbot NC, Belch JJ. Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids. 2004 Apr;70(4):403-7. http://www.ncbi.nlm.nih.gov/pubmed/15041034

Plasma endothelin-1 levels in chronic fatigue syndrome

Comment on: Increased plasma endothelin-1 levels in fibromyalgia syndrome. [Rheumatology (Oxford). 2003]

SIR, We read with interest the report by Pache et al. [1] showing increased endothelin-1 (ET-1) levels in patients with a diagnosis of fibromyalgia syndrome (FMS) and their conclusion that elevated ET-1 levels might contribute to some of the apparent vascular disturbances that characterize the syndrome. Pache et al. also point to the overlap between the clinical presentation of FMS and other ‘stress-associated disorders including chronic fatigue syndrome (CFS) and depression’. Whether FMS or CFS is stress-induced is a contentious issue in itself, but of equal concern is the view that FMS should be considered to be part of the spectrum of illness under the generic name ‘chronic fatigue syndrome’. Clearly, the symptoms of FMS and CFS have much in common [2, 3] but it has been said that FMS represents an additional burden of suffering among those with CFS [4], those patients meeting the case definitions for both FMS and CFS having a worse course, worse overall health and greater disease impact [2]. Furthermore, while many FMS patients experience fatigue, it has been estimated that only about one-fifth fulfil the specific criteria required for CFS [5]. Clinical similarities apart, there are biological differences between the two; for example, cerebrospinal fluid levels of substance P are elevated in FMS but not in CFS patients [6], and cardiovascular responses to postural challenge are characteristic of many CFS patients but are not apparent in those with FMS [7].

You can read the rest of this comment here: http://rheumatology.oxfordjournals.org/content/43/2/252.long

Source: Kennedy G, Spence V, Khan F, Belch JJ. Plasma endothelin-1 levels in chronic fatigue syndrome. Rheumatology (Oxford). 2004 Feb;43(2):252-3; author reply 253-4. http://rheumatology.oxfordjournals.org/content/43/2/252.long (Full article)

Peripheral cholinergic function in humans with chronic fatigue syndrome, Gulf War syndrome and with illness following organophosphate exposure

Abstract:

In the present study, we have investigated whether the peripheral cholinergic abnormalities that we have reported previously [Spence, Khan and Belch (2000) Am. J. Med. 108, 736-739] in patients with chronic fatigue syndrome (CFS) are also present in those with Gulf War syndrome (GWS) and agricultural workers exposed to organophosphate pesticides, where cholinesterase inhibition is specifically implicated. We also looked at whether these abnormalities might be due to a reduction in the activity of cholinesterase expressed on the vascular endothelium.

We used laser Doppler imaging to measure the forearm skin blood flow responses to iontophoresis of acetylcholine and of methacholine (which is resistant to breakdown by cholinesterase) in patients with CFS, GWS and those with a history of ill health after definite organophosphate exposure, as well as in matched healthy controls.

The response to acetylcholine was significantly higher in patients with CFS than in controls ( P =0.029, repeated-measures ANOVA), but was normal in those with GWS and those exposed to organophosphates. The methacholine response was higher than the acetylcholine response in all patient groups except for those with CFS, where there was no difference between the responses. Although there are many clinical similarities between these three illnesses, our results indicate peripheral cholinergic abnormalities in the vascular endothelium of only patients with CFS, suggesting that this syndrome has a different aetiology, which might involve inhibition of vascular cholinesterase.

Source: Khan F, Kennedy G, Spence VA, Newton DJ, Belch JJ. Peripheral cholinergic function in humans with chronic fatigue syndrome, Gulf War syndrome and with illness following organophosphate exposure. Clin Sci (Lond). 2004 Feb;106(2):183-9. http://www.ncbi.nlm.nih.gov/pubmed/14503920