Spence VA, Kennedy G, Belch JJF, Hill A, Khan F
Vascular and Inflammatory Diseases Research Unit, The Institute of Cardiovascular Research, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, UK
This work was supported by a project grant from ME Research UK.
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.
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.
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.
The work was also presented as a poster at the Scottish Society for Experimental Medicine in 2007.
Comment by ME Research UK
An essential characteristic of the blood vessels that deliver blood throughout the body is the flexibility of their walls. This affects how each pulse of blood from the heart is transmitted through the cardiovascular system from the larger to the smaller arteries, and ultimately to the capillaries and back to the heart. Normal, healthy arteries have reasonably flexible (elastic) walls which allow the heart to eject blood into the blood vessels easily and smoothly. If the arteries become stiff, the heart has to work harder and, ultimately, blood pressure becomes higher. A certain amount of stiffening occurs normally with age, but diseases such as atherosclerosis can worsen this. Stiff arteries have been linked to kidney problems and heart disease, and may also contribute to the orthostatic hypotension (dizziness on standing) experienced by some ME/CFS patients. Furthermore, increased arterial stiffness has also been reported in children with ME/CFS.
With funding from ME Research UK, researchers at the Vascular and Inflammatory Diseases Research Unit, University of Dundee, have uncovered a range of potentially important cardiovascular findings in ME/CFS patients, including increased oxidative stress (these toxic molecules can, amongst other things, damage blood vessels), abnormal metabolism of acetylcholine (an important neurotransmitter and dilator of blood vessels), and increased early death of white blood cells (which may indicate active inflammation). All this has provided accumulating evidence of a compromised cardiovascular system in patients with ME/CFS, and of the potential importance of inflammation in this disease process.
Increased arterial stiffness has previously been associated with inflammation and the risk of cardiovascular problems in other patient groups, but little is known about these relationships in ME/CFS. Accordingly, Dr Faisel Khan in Dundee decided to investigate the presence of arterial stiffness in adult patients with ME/CFS, as well as its relationship with markers of inflammation.
With a grant from ME Research UK, 41 ME/CFS patients attended the blood flow laboratory at the University of Dundee, as well as 30 healthy, age-matched volunteers. Blood samples were obtained from which to measure a number of chemical markers of inflammation and oxidative stress. These included C-reactive protein which increases dramatically in inflammation, as well as isoprostanes and oxidised low-density lipoprotein which are sensitive markers of oxidative stress. Arterial stiffness was measured using a technique called a pulse waveform analysis system, producing a parameter called the augmentation index (see below). Dr Khan found that patients with ME/CFS had significantly stiffer arteries than healthy, age-matched control subjects; their average augmentation index was 22.5%, compared with 13.3% for controls. Patients also had higher levels of C-reactive protein (2.58 versus 1.07 µg/mL) and isoprostanes (470.7 versus 331.1 pg/mL) than controls, indicating significant inflammation and oxidative stress. Furthermore, the extent of arterial stiffness was significantly correlated with C-reactive protein, isoprostanes, oxidised low-density lipoprotein and blood pressure levels, suggesting a relationship between arterial stiffness, and inflammation and oxidation.
The cause of increased arterial stiffness in ME/CFS is still unknown. While lifestyle characteristics such as smoking, obesity and physical fitness also play a role in its development, the patients in this study were no different to the than control subjects in this regard. In addition, reduced physical conditioning has been associated with increased arterial stiffness, and might be involved to some degree, however, The relationship with inflammatory markers found in the current study suggests that long-term inflammation may be a potential cause of arterial stiffness in ME/CFS: but Dr Khan is careful to emphasise that this is an association only and that the current his results do not prove cause and effect.
Do these results mean that people with ME/CFS are at an increased risk of developing cardiovascular problems such as heart disease? In the paper, Dr Khan points 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 such as cardiovascular disease. It is therefore not possible to estimate cardiovascular risk in this patient group at present. However, his work does raise the possibility that suppressing inflammation in carefully selected patients may lead to an improvement in arterial stiffness and a reduction in long-term cardiovascular problems, something already achieved in patients with rheumatoid arthritis. However, further research is needed before this can be answered definitively.
Pulse wave analysis
When you place your fingers on your wrist just below the thumb, you can feel your pulse; that is, the regular increase in pressure as each pulse of blood travels down the radial artery from the heart into your hand. 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, and computer software analyses their shape to determine how flexible the artery is. Stiff arteries cause a certain amount of wave reflection which increases, or augments, the size of the pulse. The augmentation index calculated by the software is therefore related to blood vessel stiffness.
The pulse pressure wave from the heart is composed of a forward-travelling wave from the heart generated by left ventricular ejection and a backward-arriving reflected wave from the periphery. As arterial stiffness increases, transmission velocity of both the forward and reflected waves increases and this causes the reflected wave to arrive earlier in the central aorta and to increase (augment) pressure in late systole. Augmentation of the pressure wave is, therefore, a manifestation of early wave reflection and is the boost of pressure from the first systolic shoulder to the systolic pressure peak. This can be expressed in absolute terms (augmented pressure [AP]) or as a percentage of pulse pressure (augmentation index [AIx]).
This article is from the spring 2008 issue of ME Research UK’s Breakthrough magazine.