The Blood Volume Paradox in Chronic Fatigue Syndrome (ME/CFS) and POTS

Discussion in 'Chronic Fatigue Syndrome (ME/CFS) Research' started by Cort, Jul 29, 2016.

  1. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    Kunihisa Miwa, a Japanese ME/CFS researcher, has been on something of a role. Through no less than five studies he pioneered the small heart findings in chronic fatigue syndrome (ME/CFS). Systrom basically validated Miwa's finding in his large study of people with unexplained exercise intolerance - some of whom had ME/CFS.
    Miwa appears to be something of a lone wolf; his ME/CFS studies were either authored just by him or by one other person. Miwa may not be working with a lot of researchers, but he's certainly up to date; he refers to ME/CFS as ME in this and other papers, and the patients in this study had to meet not the Canadian Consensus Criteria, but the International Consensus Criteria developed in 2011.

    Miwa recognized that the small hearts found in chronic fatigue syndrome (ME/CFS) patients were likely due not to some defect but to reduced blood flows. If the heart, like any other muscle, doesn't work out it won't grow, and the heart needs blood, and lots of it, to work itself into shape.

    In this study (ME/CFS=8, HC=5) people Miwa examined some factors - renin (plasma renin enzymatic activity), aldosterone and antidiuretic hormone (ADH) - that affect blood volume. He also also did an echocardiograph and examined the effects of desmopressin - an ADH replacement - to see if it helped.


    As before Miwa found evidence of a smaller than usual heart (LV end-diastolic diameter) and reduced output (stroke volume index, cardiac index) in the ME/CFS patients. Mean blood pressure was also lower. More importantly, the factors designed to increase blood volume such as renin enzymatic activity (p<.06), aldosterone (p<.02), and ADH (p<.004) were significantly lower or nearly significantly lower (p<.05) in the ME/CFS patients.

    The Low Blood Volume Paradox

    Low blood volume has been a recognized issue in ME/CFS since Streeten and Dr. Bell nailed it way back in the year 2000. In fact the Streeten-Bell study - done on 15 randomly selected ME/CFS patients - may have described postural orthostatic tachycardia syndrome (POTS) before it showed up in the literature. Streeten and Bell found reduced blood pressure, reduced blood volume, increased norepinephrine levels and excessive tachycardia upon standing. (This study appears to precede any studies on POTS. If so, chronic fatigue syndrome may have birthed POTS.)

    Demonstrating another overlap with ME/CFS and POTS Miwa's findings mimic those of a 2005 POTS study (reduced blood volume, aldosterone and plasma renin activity).

    Streeten would go on to show way back in 2001 that blood pooling in the veins as well as low blood volume was preventing sufficient amounts of blood from getting to the heart. Military antishock trousers were reportedly quite effective in reducing the problem.

    (Military antishock trousers are inflated with a pump. They don't seem to have ever be suggested as a viable treatment option but do indicate that blood pooling the veins is very important is very important). The excessive tachycardia, Streeten believed, was an attempt to increase blood flows to the brain.

    Jump forward 15 years and David Systrom shows up with a large study years in the making which shows that unexplained fatigue associated with exercise is characterized by reduced preload (blood flows to the heart), reduced blood volume and blood pooling in the veins; i.e. exactly the same problem Streeten and Miwa found but being applied to a much larger set of patients.

    Systrom suggested that problems with the veins were more important than blood volume but Hurwitz's large study suggested that blood volume was most important factor in the low cardiac output found in ME/CFS. About half the patients in Hursitz's study had low blood volume and they were the sickest.

    The fact that POTS, ME/CFS and some other disorders were included in Systrom's study indicates this problem is present in an array of diseases. Miwa describers the tachycardia in POTS in the same way that Streeten did - as a reaction to the low blood levels reaching the heart. We know now, though, that POTS is more complicated than once thought, and that autoimmune processes targeting the receptors that effect heart rates are involved as well. .

    Low blood volume appears to be common, though, in both ME/CFS and POTS. Ordinarily, low blood volume should trigger the renin-angiotensin-aldosterone system and ADH (vasopressin) to increase it, but in what's called the renin-aldosterone paradox, both these systems appear to poop out in ME/CFS and POTS.

    The Renin Aldosterone Paradox

    Miwa doesn't posit a clear answer to the renin-aldosterone paradox but suggests that central nervous system/HPA axis and "structural or functional brain abnormalities" are to blame. The top of the HPA axis chain - the hypothalamus - is part of the limbic system in the lower brain. It links the nervous and endocrine systems together via the pituitary gland. (The hypothalamus also regulates our circadian rhythms (and thus sleep) and the autonomic nervous system.

    ADH (vasopressin) is produced in the hypothalamus and then carried into the blood via the pituitary gland. Aldosterone is produced by the adrenal glands in response to angiotensin II, ACTH, potassium or via messages from the stretch receptors in the heart that blood pressure has fallen.

    Dr. Bateman's Big Picture

    In her talk "the Big Picture and ME/CFS" Dr. Bateman proposed a similar scenario. First, she focused on the Zinn's findings from the Stanford Symposium which suggested that people with ME/CFS were asleep when they were awake, and awake when they were asleep. The Zinn's proposed a "limbic encephalopathy" - a brain disorder concentrated in the lower regions of the brain - was present.

    Dr. Bateman echoed that idea noting that the Japanese had found inflammation in the lower part of the brain, and that a Rhomberg test - an indicator of deep brain issues - is often positive in ME/CFS/FM.
    Then she noted a bevy of hormones including ADH (vasopressin) are produced in the lower part of the brain. With his functional or structural brain abnormalities Miwa appears to be positing that this area is producing the low blood volume, and perhaps the vein problem in ME/CFS.


    Miwa proposes the use of desmopressin, a drug not often associated with ME/CFS. Desmopressin is a synthetic analogue of vasopressin. Vasopressin, which is decreased in both ME/CFS and POTS, increases blood vessel "tone" and blood pressure. Desmopressin doesn't increase blood vessel tone but it does increase blood volume. It’s most frequently used in diabetes insipidus and for night-time bed-wetting.

    The IACFS/ME Primer doesn't mention desmopressin but a 2012 study found that desmopressin significantly reduced the heart rate in POTS patients. The authors of the POTS study found desmopressin effective in the short term, but would not recommend its daily use until further studies had been done. They did say it's been proven safe for children with night-time bedwetting problems.

    One risk of daily use is hyponatremia - low blood sodium concentrations - which might be exacerbated by the large amounts of water some patients drink. The authors concluded that desmopressin is

    That's significantly better than the finding that fludrocortisone - another drug commonly used in orthostatic intolerance - was no better than placebo.

    New Studies

    Researchers have been showing more interest in blood volume enhancement as of late. Medow's study quantifying the effects of saline on ME/CFS should be out this year, and he just got a nice NIH grant to examine the effectiveness of oral rehydration salts in increasing blood volume in ME/CFS.

    Oral rehydration salts (ORS) were developed by the World Health Organization to combat diseases such as cholera. They are cheap, easy to make and surprisingly effective.

    Medow states in the grant that he believes that the ORS may be more effective than IV saline infusions in increasing blood volume and improving blood flows to the brain.

    We've made some progress since Bell and Streeten identified the low blood volume, problems with the veins, and rapid heart rates 15 years ago in ME/CFS. We know that smaller than usual hearts are also present in ME/CFS and POTS and people with idiopathic exercise intolerance (who have not been diagnosed with ME/CFS). Researchers are taking a deeper look at blood volume, and we know that the inflammation in the lower brain may have something to do with it.

    If Dr. Bateman is right further brain studies will highlight this area. We should know in the next year or so.
    Last edited: Aug 4, 2016
    J.G, Justin, Arugula and 5 others like this.
  2. Great article as always, Cort!!!

    I'm does one go about finding out if their heart is small?

    (Other than getting into a serious romantic relationship with them.) :smug: :D:smuggrin:
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  3. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member


    I think you have to have a echocardiogram (echocardiograph?). That's what Miwa used in this study. I believe she found that when during the diastolic phase the diameter of left ventricle was not as large as in the healthy controls - if that makes sense...(lol)
    Last edited: Aug 1, 2016
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  4. susan murphy

    susan murphy Member

    I have had several echocardiograms and they have all been normal. I do have blood pooling in the legs. How does one measure blood volume?
  5. November Girl

    November Girl Active Member

    I wonder if a normally trained technician or physician would even notice the difference that shows up in the echocardiograms. We only see what we know to look for. It would be nice to use the Desmopressin even for a short term basis for times that we need an extra boost.
    I wonder if I could talk my primary doc into prescribing it; or Violetta Renesca, the NP I see at INMI at NOVA (Dr. Klimas' clinic.)
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  6. November Girl

    November Girl Active Member

    And thanks for the usual great article. I haven't nearly digested it yet.
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  7. Issie

    Issie Well-Known Member

  8. Issie

    Issie Well-Known Member

    Back before POTS was acknowledged as a "real" physiological disorder and not a psychological disorder or caused by deconditioning a doc made the mistake of using the terminology of saying POTS people had the "Grinch Syndrome" or a small heart. He said we had a small heart due to deconditioning. We were up in arms. So mad that he would dismiss what we knew was way more than being deconditioned. We were deconditioned but is was an effect, not a cause. Many of us had our hearts checked to see if in fact we had "small" hearts. Most of us didn't. But many of us had dyastolic dysfunction. Some of us also had leaky mitral valves.

    Could this be the same case, An effect rather than a cause?

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  9. Issie

    Issie Well-Known Member

    As for the question of checking blood volume and blood flows. Mayo Clinic in AZ does this too. They lay you on a table with pressure cuffs at your ankles and thighs. They measure the pressure and size of your legs while lying before any exercise. Then they tilt you up and measure them again - both pressure and size. And then you walk really fast on a treadmill and they measure again. They can tell by the measurements and pressures what your blood is doing in your legs. There is one doc there that is one of his many specialties. I was positive for blood pooling. There is another test that some docs do that is more invasive to check for blood volume. This one seemed to work fine and gave us the info we needed.

    And yes, as Cort said, an echocardiogram is how they look at the heart. They can also do a nuclear stress test and look at the heart before and after exercise. (Yes, I've done that too. Thank goodness for good insurance. Wish I still had that one.)

    Last edited: Jul 30, 2016
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  10. haystacks

    haystacks New Member

    I've been trying an alternative version using less table salt, and stevia instead of sugar, as I have ME/CFS and blood pressure right at the lower end of the normal scale. And always thirsty to boot. But I'm going to now try the 'proper' ORS. I've avoided it to date because of the sugar content, but I guess the glucose is a vital part. My question is, IF it helps at all, how long is it safe to take it for, and have any studies suggested that raising blood volume via taking ORS then prompts the body to do it for itself?
    HurricaneTexas likes this.
  11. Yes, it does make sense. Thank you :)
  12. November Girl

    November Girl Active Member

    The last echo I had was nearly 20 years ago. It showed "mild left ventricular cardiomyopathy." I'd almost forgotten that.
  13. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

  14. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    I have heard that and it makes sense. Why would they look for it? They probably don't even conceive that it's happening. Systrom after all, presented a whole hypothesis for patients with exercise intolerance. I don't know but I wonder if its on most doctors radar screens ???

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  15. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    Yes! The idea is that it's an effect of the problems with preload - not a cause of anything. The heart itself is's a bit smaller (lol) but not because of deconditioning. Systrom destroyed that hypothesis with his more invasive testing which showed that people with idiopathic exercise intolerance and smaller hearts had opposite findings to people who are deconditioned!

    I love it when that happens...:wacky:

  16. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    So Issie - what did you end up doing for the blood pooling?

    And yes - thanks goodness for good insurance ;)
  17. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    The left ventricle is the one that Miwa has focused on in all his studies I believe.
  18. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    My guess is that you have to take it continuously. I have not heard that the body learns how to do that. I haven't heard of side effects from the ORS but then again it's usually taken for short periods of time.
    haystacks likes this.
  19. voner

    voner Active Member

    hey Cort,

    Thanks for the article!! You thinkin' of getting some nice new trousers? Could be a trend setter.
  20. Issie

    Issie Well-Known Member

    I got some medical thigh high compression hose. I faithfully wore them for about 3 years. I also got some compression socks from Dr Leonards catalog that were just as good as the more expensive hose. Those were just knee highs. I found that they helped but made my neuropathy worse and I had more issues with my higher blood pressure - I'm HyperPOTS. I also figured out an abdominal binder worked well or better for me. (I like a neoprene one that I found in the sport section at Ross. About $8.00.) That also helped my ribs and back stay in place better because of EDS and helped my naseau. I still wear the knee high socks when I will be on my feet alot, riding or just having a really POTsie day. I fidget alot and keep my legs and feet moving and circulating my blood. And I found treating MCAS helped everything.

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