Health Rising blog post: The Blood Volume Paradox in Chronic Fatigue Syndrome (ME/CFS) and POTS by Cort Johnson, 29 July 2016.

Kunihisa Miwa, a Japanese ME/CFS researcher, has been on something of a roll. 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.

The Exercise Intolerance in ME/CFS, POTS and FM Explained?

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 he found in his 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.


The study confirmed… “that the vast majority of the patients with ME had a small heart shadow….and their cardiac function was actually impaired with a low cardiac output.”

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 Hurwitz’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

highly effective at acutely decreasing orthostatic tachycardia and standing tachycardia in patients with POTS, and this was associated with an improvement in symptom burden in these patients. Longer-term studies are needed to assess this therapy.

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 bemore 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.

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