Low grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome
Authors
Spence VA, Kennedy G, Belch JJF, Hill A, Khan F
Institution
Vascular and Inflammatory Diseases Research Unit, The Institute of Cardiovascular Research, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, UK
Support
This work was supported by a project grant from ME Research UK.
Introduction
Some of the symptoms reported by people with chronic fatigue syndrome (CFS) are associated with various cardiovascular phenomena. Markers of cardiovascular risk, including inflammation and oxidative stress, have been demonstrated in some CFS patients, but little is known about the relationship of these and prognostic indicators of cardiovascular risk in this patient group.
Methods and results
We sought to investigate the relationship between inflammation and oxidative stress and augmentation index, a measure of arterial stiffness, in 41 well characterised CFS patients and in 30 healthy subjects. The augmentation index, normalised for a heart rate of 75 beats per minute (AIx@75), was significantly greater in CFS patients than in control subjects (22.5±1.7 versus 13.3±2.3%, p=0.002). CFS patients also had significantly increased levels of C-reactive protein (2.58±2.91 versus 1.07±2.16 g/mL, p<0.01) and 8-iso-prostaglandin F 2alpha isoprostanes (470.7±250.9 versus 331.1±97.6 pg/mL, p<0.005). In CFS patients, AIx@75 significantly correlated with log C-reactive protein (r=0.507, p=0.001), isoprostanes (r=0.366, p=0.026), oxidised LDL (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, C-reactive protein, tumour necrosis factor alpha, interleukin-1, oxidised low density lipoprotein, high density lipoprotein cholesterol levels, isoprostanes, age and gender), AIx@75 was independently associated with log C-reactive protein (beta=0.385, p=0.006), age (beta=0.363, p=0.022) and female gender (beta=0.302, p=0.03) in CFS patients.
Discussion
The combination of increased arterial wave reflection, 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.
Publication
Spence VA, Kennedy G, Belch JJF, Hill A, Khan F. Low grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome. Clinical Science 2007; 114: 561–6. Read the abstract
Presentation
An abstract containing early results was presented by ME Research UK Chairman Dr Vance Spence at the 8th International IACFS Conference, Florida, USA, in January 2007. Read the abstract
Comment by ME Research UK
One of the cardinal facts about research work generally is that discoveries follow funding (since without it there is no possibility of starting the exploration!). This is certainly clear from the research group at the Vascular Diseases Research Unit, University of Dundee, which, with funding from ME Research UK, has uncovered a range of potentially important findings in people with ME/CFS, reported in scientific papers from 2003 to 2007. These findings include:
Increased oxidative stress
The researchers found a pattern of significantly increased oxidative stress: increased oxLDL and isoprostanes with decreased HDL and GSH (Kennedy et al 2004). As isoprostanes also act as vasoconstrictors, for ME/CFS patients their presence, accompanied by additional free radicals during exercise, may be responsible for some of the symptoms — such as pain — seen after exercise. These findings have now been confirmed by at least four other research groups worldwide who have also shown excessive free radicals in blood, urine and muscle tissues of ME/CFS patients.
Abnormal acetylcholine metabolism
Acetylcholine is a substance produced by the layer of endothelial cells lining all blood vessels, causing them to open. The group found that vascular responses to acetylcholine are increased compared with matched control subjects (Spence et al 2000, Khan et al 2004a and b). This finding is in contrast with research into a wide variety of cardiovascular diseases — such as diabetes, stroke and high cholesterol — where blood flow responses to acetylcholine are normally blunted.
Increased neutrophil apoptosis
Data from 2005 indicate that ME/CFS patients have detectable abnormalities in a type of white blood cell (called neutrophil) — specifically a larger proportion of dying (apoptotic) cells than in healthy subjects — consistent with an activated inflammatory process which is possibly the consequence of a past or present infection (Kennedy et al 2003 2004a). Accompanying these markers of neutrophil apoptosis, they have found that high-sensitivity C-reactive protein levels, recognised as a marker of the inflammatory process, were also significantly increased.
Presence of signs of physical illness
Importantly, a high proportion of the patients investigated in this unit have had measurable signs of muscle weakness in the arms and/or legs, indicating that clinical signs (rather than self-reported symptoms) can, in fact, be detected in these patients if physicians take care to do a full physical examination (Kennedy et al 2004b). Intriguingly, reports in the older literature (1950s and 1960s) on epidemics of ‘classical’ ME included the presence of clinical signs (e.g., muscle weakness/swelling, sensory nerve changes, observable recurrences of flu-like illness, etc.).
All these results are very exciting (not to say unexpected), though it is important to recognise that these tests are not yet diagnostic markers. However, they show that if scientific effort and funding are directed towards a problem, researchers can uncover, within a proportion of ME/CFS patients, biological anomalies that might well help to explain many of the clinical features associated with the illness, and might also indicate areas for therapeutic treatment.
It is against this background, then, that the latest paper from the University of Dundee must be seen, for it reports four things in ME/CFS patients compared to controls well matched for age, gender distribution, smoking status, height and weight:
- Significantly increased serum high-sensitivity (hs)CRP levels
- Significanly elevated levels of isoprostanes and oxidized LDL
- Significantly increased arterial wave reflection, a composite measure of arterial stiffness and wave reflection
- A significant independent association between increased arterial wave reflection and hsCRP
As a finding alone, (1) would still be interesting. Raised hsCRP levels — reported for the first time in this scientific paper in ME/CFS patients — are known to indicate chronic, low-grade, sub-clinical inflammation; indeed, a prospective epidemiological study (Bassuk et al 2004) covering 30 years have found that a single hsCRP measurement strongly predicted a cardiovascular event, independent of traditional risk factors such age, smoking, hypertension, dyslipidaemia and diabetes. Whether markers of inflammation, including hsCRP, continue to be raised over the longer term in ME/CFS remains to be determined, however; one Australian report suggests that raised levels are not sustained into the chronic phase of illness in ‘post-infective fatigue syndromes’ and so play little or no role in the development of persistent symptoms (Hickie et al 2006).
The central finding — (3) above — was that the parameter of arterial wave reflection, a combined measure of elastic and muscular arterial stiffness and wave, was significantly increased compared with controls. As the authors point out, the “augmentation index” of arterial wave reflection has been shown to be an important determinant of cardiovascular risk and outcome; to be an independent predictor of all-cause mortality in patients with end-stage renal disease; and to be a significant predictor of major adverse cardiovascular events in patients with established coronary artery disease. In this regard, then, this result is no trivial finding. The cause of the increased arterial wave reflection in ME/CFS patients remains unknown, however: lifestyle characteristics such as smoking, obesity and physical fitness also play a role in the development of arterial stiffness (Vlachopoulos et al 2006), but only a small percentage of these patients were smokers, and body weight and BMI were similar in CFS patients and control subjects. Reduced physical conditioning has been associated with increased arterial stiffness (Bruunsgaard 2005), and might be involved to some degree. Interestingly, this is not the first report suggesting increased arterial wave reflection in ME/CFS patients. Van de Putte et al in 2005 reported increased arterial stiffness and hypotension in a cohort of 32 adolescent CFS patients, a finding which could not be explained by changes in arterial wall characteristics or lifestyle. The concatenation of two different reports augments the fascination of the result. The independent relationship — (4) above — between the arterial wave reflection (a marker of stiffness) and hsCRP (a marker of low-level sub-chronic inflammation) indicates an association only, and whether chronic, sub-clinical inflammation is the cause of increased arterial wave reflection in ME/CFS remains to be seen.
So, does this mean that people with ME/CFS in the population are at increased cardiovascular risk, as suggested by the combination of increased arterial wave reflection, inflammation and oxidative stress? The authors point out that very few long term follow-up studies have been carried out in ME/CFS patients and none on the occurrence of other health conditions, so it is not possible to estimate cardiovascular risk in this patient group at present. Nevertheless, given that Lerner et al (1997) has shown repetitively abnormal T-wave oscillations, indicative of cardiomyopathy, in his CFS patients, and that a recent report on mortalities in CFS cited heart failure as a major cause of death at a considerably younger age than would have been expected from the general population (Jason et al 2006), the possibility that overall cardiovasular risk is increased overall cannot be excluded — though neither should it be assumed. The authors are clear, however: in the absence of a long programme of work, including confirmation by other research groups, the results of the study can be hypothesis generating only, and they cannot say at this point whether suppressing inflammation in carefully selected ME/CFS patients would lead to an improvement in arterial stiffness and long-term cardiovascular outcomes.
