Reduced HRV (heart rate variability) predicts poor sleep quality in CFS

[ahimsa]

This was posted on the co-cure mailing list recently:

Exp Brain Res. 2010 May 26. [Epub ahead of print]
'Reduced heart rate variability predicts poor sleep quality in a
case-control study of chronic fatigue syndrome.'
Burton AR, Rahman K, Kadota Y, Lloyd A, Vollmer-Conna U.

School of Psychiatry, University of NSW, Sydney, Australia.

http://www.ncbi.nlm.nih.gov/pubmed/20502886

Abstract

Parasympathetic function is important in the induction and maintenance
of sleep. We examined whether nocturnal vagal modulation of heart rate
is related to the poor sleep quality commonly reported in chronic
fatigue syndrome (CFS). Heart rate (HR, as R-R intervals) was
continuously monitored during sleep in 20 patients with CFS and 20
matched control subjects. Questionnaires assessed demographic
information, symptoms, functional impairment, and subjective sleep
quality. CFS was associated with more sleep problems in general and
poorer subjective sleep quality on the study night (all p < 0.003),
and reports of repeated awakening during the night were 7 times more
likely compared to healthy subjects (p = 0.017). Time and
frequency-domain parameters of HR variability during sleep were
significantly lower in patients with CFS (all p < 0.006). Multiple
regression analyses revealed that heart rate variability (HRV)
parameters were the best predictors of subjective sleep measures. This
study identified significant reductions in vagal modulation of heart
rate during sleep in CFS. Low HRV strongly predicted sleep
quality-suggesting a pervasive state of nocturnal sympathetic
hypervigilance in CFS.

I was intrigued by this abstract because frequent awakening (up to 10-12 times a night) is my biggest sleep problem. So I searched for reduced HRV and found this other study from 2007:

http://www.cfids-cab.org/rc/Boneva.pdf

Anyone out there want to explain a bit more about what causes reduced HRV and/or suggested treatments? In the little bit of searching that I've done I've seen it linked to everything from depression to congestive heart failure. So it's a bit difficult for me to understand how to view these studies.

I'm hoping someone with more medical knowledge will be able to shed some light on this study as well as any other sleep problems related to autonomic dysfunction/dysregulation.

Thanks!

 

[Dolphin]

I was intrigued by this abstract because frequent awakening (up to 10-12 times a night) is my biggest sleep problem. So I searched for reduced HRV and found this other study from 2007:

http://www.cfids-cab.org/rc/Boneva.pdf

Sorry to be awkward but just to point out to everyone that the Boneva study (but not the initial study) is an empiric criteria (Reeves, 2005) study. It's the Wichita 2-day study cohort which is not as "diluted" as the Georgian cohort but still 10 (most likely - a maximum of 16 anyway but most likely 10) of the 43 CFS cases satisfied the Fukuda definition.

 

[ahimsa]

Sorry to be awkward ...

Please don't feel awkward on my account - I want to know the details behind these studies. I appreciate the additional information. Thank you!

I hope there are others out there who can comment on the general concept of reduced HRV and what it might mean in Fukuda and/or CCC ME/CFS patients (or even in heart failure patients, elderly, etc.).

 

[Mark]

"a pervasive state of nocturnal sympathetic hypervigilance"

From my own experience I can say with confidence that permanent disruption of sleep (failure of sleep) over a long period of time can cause very many of the symptoms of CFS, possibly even enough on its own to cause symptoms approaching a Fukuda but probably not CCC definition. Fatigue, muscle weakness, aches and pains, loss of short term memory and other cogntive impairnents, vulnerability to infection, problems with digestion, (not to mention anxiety and depression), all of these can (IMO) result solely from "a pervasive state of nocturnal hypervigilance" - ie the body never gets to shut down at night. So I reckon that prolonged sleep disturbance - especially if unrecognised - on its own might get you a diagnosis of CFS, with weak criteria. But the more severe neurological and immune symptoms, such as are those listed in the CCC, are more characteristic of 'ME' than 'CFS' (whatever ME and CFS may be...) and I don't know whether they could result from disturbance of sleep / loss of deep sleep alone.

Anyway this is a roundabout way of saying that patients with Reeves/Oxford style definitions and even some Fukuda patients could be found who fit the criteria purely because of sleep disturbance. So the context for this research might be that one subcluster of the "CFS" wastebasket diagnosis is those who have prolonged sleep disturbance, for whatever reason.

The reduced HRV then...the research is just saying there's a correlation between reduced HRV and sleep quality in this grouping patients...I'm not clear which is more likely to cause the other - or another association suspected...and wonder whether there's any such correlation in other patients with sleep apnea...but it seems their conclusion is that this suggests that "sympathetic hypervigilance" is going on in CFS sleep disturbance.

TH2 hyperstimulation (as result of active XMRV infection or otherwise), and over-reaction to environmental triggers, sounds like it could cause "sympathetic hypervigilance" - sounds a good description of what I've had going on anyway.

 

[IamME]

In addition to what IllSince1989 says, Andrew Lloyd is a fully fledged psychologiser (he was one of the first off the starting block to rubbish XMRV and spread rumours about the WPIs research) -- this is the School of Psychiatry after all. The notion that reduced HRV and sleep dysfunction automatically = nocturnal hypervigilence is stupid and a complete leap of perverse logic. Even if it *was* true, "hypervigilence" would not be important because it's not the cause of ME, unlike a differential diagnosis. Mark, bad insomnia cannot cause all the symptoms/signs of ME. What they're trying to do is make this finding fit a stress hypothethis, an affective disorder or PTSD-like illness which they believe can be magicked away with CBT/GET by using a correlation/causation fallacy. Nothing must get in the way of that message.

http://www.abc.net.au/rn/allinthemind/stories/2007/1945419.htm

What the psychiatrists would call cognitive behavioural therapy. And that basically is a combination of approaches to manage symptoms, say, pain relief for instance [No - it's not actually]; approaches to give people sensible advice about the issue of rest versus exercise in relation to the fatigue syndrome. Managing the sleep/wake cycle if it's gone off the rails, managing mood disorder if it's present, and finally a structured, gradually incrementing graded physical exercise program.

http://www.mja.com.au/public/issues/172_10_150500/lloyd/lloyd.html

In the absence of a clear understanding of the underlying pathophysiology, CFS is best described as an illness rather than a disease.4 Illness is a subjective state of suffering -- physical, psychological and social [...] In disorders associated with broad disturbances of central nervous system function there is commonly an interplay between cultural, personal and biomedical factors. Thus, it is not surprising that cognitive-behavioural approaches have shown benefit in clinical trials [...]

A recent evaluation of patients with chronic fatigue in Hong Kong may provide an important insight for our "Western" medical practice.7 For these patients the notion of having a "medical" versus "psychiatric", or "biomedical" versus "psychosocial", cause of their illness made little sense. Their perception was that, while they were clearly unwell, the potential causes of that suffering could lie across a broad domain of personal, social or medical factors. If Australian patients and their doctors could rediscover this basic concept, and could also accept prolonged fatigue as a legitimate illness experience, there would be no need for the polarisation of aetiological models (and political views) that has become characteristic of medical practice in relation to CFS in the USA and UK. This unnecessary polarisation is intellectually shallow and harmful to patients.

To build an effective therapeutic alliance, doctors should endeavour to maximise non-specific treatment effects [...] The cornerstones of good management include providing information about the illness and its natural history; empirical treatment of disturbances of mood and sleep which commonly co-occur in CFS; and encouraging a rehabilitative approach to the illness, including graded physical activity as well as psychological and social support

I think he used to be more pro-biomedical but has become incresingly obsessed with GET, referring to "fatigue states" and this sort of psychogibberish sophistry.

 

[Sean]

I think he used to be more pro-biomedical but has become incresingly obsessed with GET, referring to "fatigue states" and this sort of psychogibberish sophistry.

Agree with that.

Ian Hickie, an Australian psychiatrist who sometimes works with Lloyd on CFS stuff, is another to watch out for. He has been very influential both within Aust and internationally (works with Reeves, White, Wessely, et al, you get the idea, was co-author on the CDC Fukuda definition, & the Australian Clinical Guidelines, and IIRC he gave us the useless and dangerous SPHERE 'test' for somatising). But he has largely managed to escape serious scrutiny so far.

Do a PubMed search for (Hickie IB) AND (Lloyd AR)

For example:

http://www.ncbi.nlm.nih.gov/pubmed/10901768

 

[anciendaze]

Heart Rate Variability as a measure of cardiac function

There were studies back in the late 1980's which surprised many cardiologists by showing reduced heart rate variability was an indicator of declining cardiac health. This came out of studies on cardiac dynamics using fairly advanced mathematical theories unfamiliar to most cardiologists. Where a natural assumption that variability increased as you approached a breakdown was wrong was in the misunderstanding of adaptability to changing conditions. Reduced variability meant that feedback in response to changing conditions was not taking place. There is plenty of reason to associate poor cardiac health with poor sleep.

 

[Cort]

I agree that Lloyd appears to have become more behaviorist but be careful about damning a study because of its authors. HRV readings are probably the most consistently abnormal readings in CFS research - which is really saying something.

Lloyd's big research project the Dubbo studies - had nothing at all to do with behavior - it took a straight shot at the immune system to try and explain why people were coming down with CFS after an infection. I'd be cautious of categorizing Lloyd too narrowly - yes he does believe behavioral therapies are helpful but he's also been very interested in immune functioning and pathogens as well as gene expression.

 

[Dolphin]

he's also been very interested in immune functioning and pathogens as well as gene expression.

I'm not convinced he's interesting in finding pathogens and using anti-viral and anti-microbial treatments.

Here's his other recent contribution to the literature - he was the lead author and corresponding author for this letter to Science:

Science 14 May 2010:
Vol. 328. no. 5980, p. 825
DOI: 10.1126/science.1183706
Prev | Table of Contents | Next

Technical Comments
Comment on "Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome"
Andrew Lloyd,1 Peter White,2 Simon Wessely,3 Michael Sharpe,4 Dedra Buchwald5

Lombardi et al. (Reports, 23 October 2009, p. 585) reported a significant association between the human retrovirus XMRV and chronic fatigue syndrome (CFS). However, the cases with CFS and the control subjects in their study are poorly described and unlikely to be representative. Independent replication is a critical first step before accepting the validity of this finding.

1 Centre for Infection and Inflammation Research, University of New South Wales, Sydney, Australia 2052.
2 Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
3 Department of Psychological Medicine, Institute of Psychiatry, Kings College London, UK.
4 School of Molecular and Clinical Medicine, University of Edinburgh, UK.
5 Center for Clinical and Epidemiological Research, University of Washington, Seattle, WA 98101, USA.

* To whom correspondence should be addressed. E-mail: a.lloyd@unsw.edu.au

The finding of a significant association between xenotropic murine leukemia virusrelated virus (XMRV) and the enigmatic clinical illness, chronic fatigue syndrome (CFS), has the potential to revise our understanding of the pathogenesis of this condition and raise serious public health concerns (1). It is unusual to find such a strong association between an infectious agent and a well-defined chronic disease, much less an illness like CFS. As such, critical evaluation of the results is paramount. Experienced CFS researchers will remember the 1991 "discovery" of an HTLV-2like retrovirus in CFS (2), which subsequent studies failed to replicate (36).

For reliable results, clearly defined cases should be compared to a control group similar in all aspects other than the disease. The 101 patients studied in (1) were "patients fulfilling the 1994 CDC Fukuda criteria for chronic fatigue syndrome and the 2003 Canadian Consensus Criteria for chronic fatigue syndrome/myalgic encephalitis (CFS/ME) and presenting with severe disability" [supporting online material for (1)], but the latter requires physical signs precluded in the former. The patients were selected, in part, with immunologic perturbations such as in RNase L pathways, yet there are no biomarkers that have demonstrated reliability in affirming the diagnosis of CFS (7). Lombardi et al. (1) provided no description of demographics, illness duration, pattern of onset, or evaluation for exclusionary medical and psychiatric conditions. Likewise, the characteristics of the controls, and details of collection, handling, and storage of specimens, are not described. It is therefore impossible to critically evaluate the findings.

CFS is likely to arise from complex genes-x-environment risk factors, making a simple causative link between XMRV and CFS unlikely. Even if confirmed, further research will be needed to demonstrate causality. In relation to prostate cancer, with which a comparable association with XMRV was reported (8), negative replication studies are mounting (9). Similarly, three negative replication studies in well-characterized cases of CFS have now been published (1012). This outcome serves as a cogent reminder of the need for independent replication before findings such as this can be accepted.


References and Notes

1. V. C. Lombardi et al., Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 326, 585 (2009).
2. E. DeFreitas et al., Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc. Natl. Acad. Sci. U.S.A. 88, 2922 (1991).
3. J. W. Gow et al., Search for retrovirus in the chronic fatigue syndrome. J. Clin. Pathol. 45, 1058 (1992).
4. M. Honda et al., Japanese patients with chronic fatigue syndrome are negative for known retrovirus infections. Microbiol. Immunol. 37, 779 (1993).
5. A. S. Khan et al., Assessment of a retrovirus sequence and other possible risk factors for the chronic fatigue syndrome in adults. Ann. Intern. Med. 118, 241 (1993).
6. W. Heneine et al., Lack of evidence for infection with known human and animal retroviruses in patients with chronic fatigue syndrome. Clin. Infect. Dis. 18 (suppl. 1), S121 (1994).
7. M. Lyall, M. Peakman, S. Wessely, A systematic review and critical evaluation of the immunology of chronic fatigue syndrome. J. Psychosom. Res. 55, 79 (2003).
8. R. Schlaberg, D. J. Choe, K. R. Brown, H. M. Thaker, I. R. Singh, XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Proc. Natl. Acad. Sci. U.S.A. 106, 16351 (2009).
9. O. Hohn et al., Lack of evidence for xenotropic murine leukemia virus-related virus(XMRV) in German prostate cancer patients. Retrovirology 6, 92 (2009).
10. O. Erlwein et al., Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS ONE 5, e8519 (2010).
11. H. C. Groom et al., Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology 7, 10 (2010).
12. F. J. M. van Kuppeveld et al., Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. BMJ 340, c1018 (2010).
13. M.S. has been paid by insurers for independent advice on medical claims that might include CFS. He has also been paid by lawyers for independent advice on litigation that might include CFS.


--------------------------------------------------------------------------------
Received for publication 22 October 2009. Accepted for publication 18 April 2010.

 

[gracenote]

From the full text of the article.

Whether reduced HRV during sleep is linked to the common experience of sleep problems and unrefreshing sleep in CFS has not been explored. The objective of this study is to examine this link, hypothesising that diminished HRV during sleep is associated with poorer sleep quality in subjects with CFS. The effects of relevant covariates of sleep quality including levels of current stress, and psychological distress were also considered.

The 30-item perceived stress questionnaire (PSQ) was used to assess current levels of stress (Levenstein etal. 1993) and common symptoms of psychological distress were reported via the Kessler 10 (K10; Kessler etal. 2002). Functional impairment was assessed by The Brief Disability Questionnaire (BDQ; Von KorV etal. 1996). The 34-item Somatic and Psychological Health Report (SPHERE; Hickie etal. 2001) was used to assess a wide range of physical and psychological symptoms.

The low levels of nocturnal HRV found in our study, are suggestive of a pervasive state of sympathetic hypervigilanceone which is consistent with previous reports of hypoactivity in the prefrontal cortex in this population.

This doesn't appear to me to be a study to determine any kind of medical causation of sleep difficulties in CFS. Why would they even choose to use assessments of psychological health in a study such as this? This is more of the same in my opinion.

I think they would have gotten more useful information by comparing CFS with other medical conditions that show low HRV. I found this on Wiki (not up to doing a better search at the moment):

A range of other outcomes/conditions may also be associated with modified (usually lower) HRV, including congestive heart failure, diabetic neuropathy, depression post-cardiac transplant, susceptibility to SIDS and poor survival in premature babies.

 

[Tammie]

Ironically due to really bad sleep of late (worse than the usual, I mean), I am actually awake in the AM (which has not happened in a long time) & as a result am not at all alert (wouldn't hypervigilance make me more alert?!) ....I am, in fact quite foggy, so my logic may be off, but this occurred to me.........

While this study focused on nocturnal HRV, in general reduced heart rate variability does not just mean that the resting heart rate is too high (as would be the case with hypervigilance) but it also measn that the max heart rate may not be as high, either

..... studies have shown that ME/CFS patients cannot get their heart rates up very high during exercise (one of the differences that has been cited by actual good biomedical research that differentiates ME/CFS from depression).....so if you turn this study on its head, using their logic, then it would seem that the inability to raise max heart rate much at all would indicate just the opposite

I have actually recently been paying attention to my own heart rate variabilty, so the timing of this article is kind of interesting......and I noticed that pre-ME/CFS my heart rate could vary (from its lowest immediately upon waking to its highest immediately after exercise) by more than 130 points, and now, when I manage to get any exercise (granted not at the same intensity, and not often, but I do still manage to swim some or do some other exercise on occassion), my heart rate, at best varies less than 30 points from waking to post exertion (not only does that not fit with what would happen if this were depression, but it also does not fit with what would happen if I were just out of shape)....and though my resting heart rate has increased a bit, the reduced variability is for the most part on the other end of the spectrum (ocurring after any exertion)

 

[Dolphin]

I have actually recently been paying attention to my own heart rate variabilty, so the timing of this article is kind of interesting......and I noticed that pre-ME/CFS my heart rate could vary (from its lowest immediately upon waking to its highest immediately after exercise) by more than 130 points, and now, when I manage to get any exercise (granted not at the same intensity, and not often, but I do still manage to swim some or do some other exercise on occassion), my heart rate, at best varies less than 30 points from waking to post exertion (not only does that not fit with what would happen if this were depression, but it also does not fit with what would happen if I were just out of shape)....and though my resting heart rate has increased a bit, the reduced variability is for the most part on the other end of the spectrum (ocurring after any exertion)

Interesting although just in case anyone is confused, Heart Rate Variability, has a specific definition e.g. http://en.wikipedia.org/wiki/Heart_rate_variability

 

[Dolphin]

12 out of the 20 were from the Dubbo study (RRV: N = 7; EBV: N = 4; Coxiella burnetii: N = 1), the other 8 from Dr. Lloyd's practice.

Thought this was interesting:

Heart rate variability can be affected by a number of
mechanisms. For example, it can be directly affected by
levels of activity—it can be increased as a result of exercise
training (Levy et al. 1998; Malfatto et al. 1996). Relating to
this, previous authors have speculated that the reduced
HRV seen in CFS may be a result of cardiovascular deconditioning
(Freeman and Komaroff 1997; De Lorenzo et al.
1998). In the current study, the patients with CFS were
matched for age, BMI and activity, and additionally there
was not substantive between-group diVerence in resting
HR. It is therefore unlikely that cardiac deconditioning was
a determinant of the documented differences in HRV.

 

[Dolphin]

I think they would have gotten more useful information by comparing CFS with other medical conditions that show low HRV. I found this on Wiki (not up to doing a better search at the moment):

A range of other outcomes/conditions may also be associated with modified (usually lower) HRV, including congestive heart failure, diabetic neuropathy, depression post-cardiac transplant, susceptibility to SIDS and poor survival in premature babies.

Sounds good.

After finding that low HRV is the main factor, they then speculate this might caused by hypoactivity in the prefrontal cortex:

Hypoactivity in the prefrontal circuits
and a lack of inhibitory neural processes typically characterise
psychopathological states, including anxiety, depression,
and post-traumatic stress disorder (Thayer and
Friedman 2004, Thayer 2006).

They don't tell us of the "physical" conditions where low HRV is an issue.

I think how they link hypoactivity in the prefrontal cortex to CFS is weak:

There is some evidence that individuals with CFS may
exhibit anatomical and functional alterations in the prefrontal
cortex—as evidenced by lowered cerebral activity in the
dorsolateral and dorsomedial prefrontal cortices during
fatigue provoking tasks (Caseras et al. 2008) and a bilateral
reduction of grey-matter volume in the prefrontal cortex
(Okada et al. 2004; De Lange et al. 2009). However, dissection
of the mechanisms involved in this process need to
be interpreted with caution: it is not known whether the
changes seen in the prefrontal cortex in CFS are a symptom
or a cause of CFS (De Lange et al. 2009). Nevertheless,
since the role of the prefrontal cortex is essential in active
tonic inhibition of sympathoexcitatory threat circuits, such
alterations in the prefrontal cortex seen in CFS subjects
could be expected to lead to a decrease in vagal drive
defaulting to a sympathetically driven system.

They then suggest other forms of dysautonomia seen in CFS could be due to this

We speculate that changes in the prefrontal cortex seen
in CFS may not only contribute to the reduction of tonic
vagal activity as seen in our study, but may also be manifested
in other forms of dysautonomia seen in CFS.

We recently have research which looks at this a bit differently:
"Impaired cardiovascular response to standing in Chronic Fatigue Syndrome"
Full text at: http://www.imet.ie/imet_documents/Impaired CV responses to standing in CFS.pdf

start of discussion section of that paper:

We have demonstrated that the skeletal muscle bioenergetic abnormality recently described in patients with CFS [1] associates with a similar cardiac bioenergetic abnormality. This impairment is associated with an increase in cardiac contractility on standing (i.e. the heart has to work harder for the same degree of physiological stress), the severity of which associates with symptoms on standing in those with CFS.