This is the second article by Dr Eleanor Roberts looking at how abnormalities in the heart and circulation may be involved in some of the symptoms of ME/CFS.
Read part 1 here, which provides an introduction to the heart, blood vessels and how they are regulated.
Studies have shown that some people with ME/CFS have a higher resting heart rate (HR) than normal, which suggests that parasympathetic nervous system (PNS) cardiac modulation is decreased while sympathetic nervous system (SNS) modulation is increased. However, a meta-analysis combining results from several studies found a lower maximal HR on exercise in people with ME/CFS, potentially reflecting increased SNS and decreased vagus-nerve HR modulation.
Cardiopulmonary exercise testing (CPET) can be used to measure chronotropic intolerance during exercise and post-exertional malaise (PEM). Chronotropic intolerance is an inability of the heart to increase its rate sufficiently to cope with a rise in activity. One meta-analysis showed that, during CPET, at maximal exertion there was an HR response of 90.0% in healthy controls, compared with 87.9% in people with ME/CFS. During a second CPET, the HR response was 90.6% for healthy controls and 84.3% for people with ME/CFS, indicating a significant decline. This was suggested to reflect a reduction in SNS drive at peak exertion, when it would usually be at its highest.
Supporting this abnormal SNS response to exercise, another study found that people with ME/CFS had a relative hyporeactivity of adrenalin during an exercise test (this is normally raised during activity). There is also evidence in ME/CFS of impaired activation of the heart receptors involved in increasing HR, which has been suggested as the mechanism behind a blunted rise in HR during exercise. This could be due to autoantibody-related damage to these receptors.
Another indication of heart function – maximal oxygen uptake, or VO2 max – has also been found to be lower in people with ME/CFS, related to a greater increase in cardiac output relative to VO2, and lower muscle-cell oxygen uptake compared with healthy controls.
Heart rate variability
Relationships have been found between heart rate variability (HRV) in people with ME/CFS and measures of physical and gastrointestinal health, in particular showing that increased fatigue is associated with less HRV. This may be due to autonomic nervous system (ANS) dysfunction. Analysis of HRV in people with ME/CFS may therefore be useful for predicting fatigue severity and ANS-related symptom exacerbation. However, HRV may differ according to sex: while a study in women with ME/CFS showed a significant relationship between low HRV and scores of fatigue severity and autonomic dysfunction, a similar study in men found increased HR and blood pressure (BP) at rest compared with healthy controls, but no difference in HRV.
‘Exercise’ for people with ME/CFS can also mean carrying out cognitive tasks, and an investigation of this found that, while there were no differences in performance accuracy, people with ME/CFS showed a significant relationship between reduced HRV and lower performance speed, along with significantly slower reaction times, significantly higher resting HR, more sustained HR increase during testing, and longer recovery to resting HR following testing. Similar to the above studies, this investigation indicated that people with ME/CFS who have a higher resting HR may be experiencing SNS hyper-arousal and HRV inflexibility. The authors suggested this is due to “a significant loss of vagal (nerve) modulation” in people with ME/CFS, especially during challenging tasks.
Even during sleep there is evidence that people with ME/CFS have an increased HR but decreased HRV. This may be assigned to findings of higher levels of the neurotransmitter noradrenalin and lower plasma levels of the hormone aldosterone, suggesting “persistent ANS hypervigilance due to SNS dominance.” In another study, while people with ME/CFS reported similar sleep duration compared to healthy controls, PNS activity, measured by HRV, was significantly lower during non-REM and slow-wave sleep. Higher HRV in people with ME/CFS was associated with better ‘refreshment’ from sleep and increased ratings of physical and psychological wellbeing. These factors were not related to the amount of time spent in slow-wave sleep and the authors postulated that “recuperation of energy during sleep is associated with autonomic de-arousal (indicated by parasympathetic predominance) during deep sleep,” or, to put it another way, people with ME/CFS may lack quality rather than quantity of recuperative sleep.
Cardiac, blood volume and blood pressure deficits
In ME/CFS, people may exhibit ‘hypovolaemia,’ or low blood volume, related to low cardiac blood vessel, atrial and ventricular filling, and preload failure, leading to a low stroke volume and low cardiac output at rest. The SNS can be activated when hypovolaemia leads to decreased blood vessel filling and reduced vagal tone with these being found in people with ME/CFS, associated with reduced HRV.
A lower cardiac index in people with ME/CFS may, as found in one study, be associated with deficits in cardiac contractility and total blood volume, including decreases in both red blood cell and plasma volume. This was not found in sedentary controls, suggesting it is not primarily due to deconditioning through lack of being able to exercise. The authors concluded that “blood volume deficit may impact adversely on oxygen delivery and nutrient supply, impair haemodynamic regulation and contribute to the exacerbation of fatigue and other ME symptomatology.”
A previous study by this group found people with ME/CFS had reduced cardiac mass and ‘preload’ end-diastolic volume. Such ‘preload failure’ was proposed to be due to hypovolaemia, microvascular leakage, kidney vasodilation and hyperexcretion and inhibition of kidney tubule sodium reabsorption. Indeed, in people with ME/CFS, another study found increased brain natriuretic protein (BNP) levels, associated with smaller cardiac volumes but not associated with length of disease. The authors proposed that this could be due to higher BNP levels causing higher urine production that depletes plasma/blood volumes.
An examination of BP in people with ME/CFS showed that, compared with healthy controls, overall systolic BP variability (BPV) was significantly reduced along with differences in left ventricular diastolic BP and balance of left ventricular and high frequency (PNS-related) diastolic BP. They also found increased low frequency (SNS-related) HRV and significantly reduced PNS markers. They suggested that lower BP could potentially lead to “reduced perfusion of downstream organs and ME symptoms” and that BPV could also be used as a diagnostic tool, alongside HRV measures.
In many people with ME/CFS, the ANS response when standing is abnormal, including increased HR and decreased HRV. Indeed, many people with ME/CFS are diagnosed with postural orthostatic tachycardia syndrome (POTS), proposed to be due to increased SNS/PNS balance. Hypovolaemia is also postulated to contribute to POTS and orthostatic intolerance in ME/CFS. Of note, orthostatic intolerance is also not related to deconditioning, as found in a large study of people with ME/CFS.
In one study, where blood and plasma volume decreases were found alongside significantly lower stroke index and systolic and diastolic BP compared with controls, the authors proposed this represented “a functional consequence of the reduced cardiac function that may explain the high prevalence of orthostatic intolerance seen in those with ME.”
Echocardiographic examination showed that in people with ME/CFS, reduced cardiac function was associated with a small left ventricle and low cardiac output. The authors discussed how POTS and orthostatic intolerance may be a “physiologic compensatory response to smaller stroke volume on standing”. They postulate that reduced preload on standing leads to impaired cerebral oxygenation and activation of circulatory blood volume regulatory systems.
A review of a tilt-table test also found significantly higher HR in people with ME/CFS, suggesting ANS malfunction. This may be due to more prolonged blood vessel dilation due to the neurotransmitter acetylcholine. Also shown are small differences in heart contractility in people with ME/CFS, especially in response to standing. This has been related to cardiac muscle bioenergetic abnormalities, associated with increased cardiac contractility when standing due to impaired oxidative muscle metabolism.
Blood vessel endothelial cell dysfunction can include alterations in the cells or their function that can lead to reduced vascular tone and response. One study found a correlation between peripheral endothelial dysfunction and ME/CFS severity, which the authors related to immune-associated symptoms such as PEM. Such endothelial dysfunction has been proposed to be due to a reduction in the availability of nitric oxide from endothelial cells. This molecule is involved in vasodilation and tissue blood flow regulation as well as cardiac contractility. One study found people with ME/CFS had significantly reduced large and small vessel endothelial function compared to healthy controls.