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The first of two of three blogs exploring the renin-angiotensin-aldosterone system in ME/CFS and COVID-19. Warning – this blog is complex…

Back in 1997, they had a couple of important things right – orthostatic intolerance (OI) is basically caused by not getting enough blood to the brain when one stands (or sits). Even back then, researchers knew that problem could be caused in different ways. Blood pooling in the lower body upon standing – probably because of damaged autonomic nerves – was one. Low blood volume (@75% of normal) was another factor making it difficult to get blood to the brain upon standing.

The 1997 paper, “Hypovolemia in Syncope and Orthostatic Intolerance Role of the Renin-Angiotensin System“, brought a big surprise, though. Not only did they find markedly low blood volume – in some cases 1,000 ml low (about the size of a large Coke bottle) – but they found low plasma renin activity as well – and that didn’t make sense.

renin-angiotensin-aldosterone

The renin-angiotensin-aldosterone system that regulates blood volume presents a paradox in ME/CFS and FM.

Renin is the first leg of the renin-angiotensin-aldosterone system (RAAS) that’s designed to deliver optimal blood volume levels. If blood volume is low, renin activity should be high.

First, renin stimulates angiotensin II, which increases blood pressure and stimulates sodium absorption. Angiotensin II then stimulates the production of aldosterone – the main factor – which regulates blood pressure, plasma sodium and potassium levels and blood volume. (Aldosterone secretion can also be stimulated by potassium, adrenocorticotropic hormone (ACTH), and low sodium levels in the blood (hyponatremia).)

Given the “profound” low blood volume found, both renin and aldosterone levels should have been dramatically increased, but the opposite was happening; they were both decreased in postural orthostatic tachycardia syndrome (POTS). With that, the “renin-aldosterone paradox” had been born.

The authors believed that reduced angiotensin levels were probably responsible, but also suggested the damaged autonomic nerves in the kidney could be a factor.

More surprises were in store.

The Ang II Surprise

In a 2006 paper, Stewart and Medow found that low blood volume was not universal at all in POTS. It was decreased in patients they called low-flow POTS, but not in two other subgroups.

Angiotensin enzyme in conjunction with angiotensin. Very high levels of Ang II may be wreaking havoc in POTS and ME/CFS

The big news, though, was that instead of having low Ang II levels, the low blood volume and low-flow POTS patients had dramatically increased Ang II levels (2-3 times normal), as well as low renin levels.

Angiotensin II does more than increase blood volume. At high levels it can have some decidedly negative effects. Ang II ramps up vasoconstriction (narrowing) in the blood vessels by prompting the release of norepinephrine from the sympathetic nerves. It also jacks up oxidative stress levels through the formation of the superoxide radical and ultimately peroxynitrite. Increased peroxynitrite, then, can reduce the levels of nitric oxide – an important vasodilator.

High Ang II levels potentially set the stage for a ramped up fight/flight system, narrowed blood vessels, inflammation and possibly reduced blood flows to the brain. Since Ang II acts like a neurotransmitter in the brain, it could have multiple effects there as well.

Narrowing of the blood vessels (increased vasoconstriction) caused by Ang II could itself cause low blood volume simply by reducing the total volume of the blood the vessels could carry. The body senses the amount of space available in the blood vessels and seeks to provide the correct amount of blood. It might simply be providing the amount of blood needed to fill the reduced blood vessel capacity that was present.

High Ang II levels also appear to be responsible for the defects in the vasodilation in the small blood vessels in the skin, which sometimes cause acrocyanosis (bluish color) in the hands and feet.

There was another twist as well. With all that sympathetic nervous system activity going on, the low blood volume POTS patients should have high blood pressure – instead, they often have the opposite.

ACE-2 Enzyme

Five years later, a deeper dive into the renin-aldosterone paradox produced more answers – and more questions. In “Abnormalities of Angiotensin Regulation in Postural Tachycardia Syndrome“, Vanderbilt researchers suggested they’d found a reason for the high Ang II levels – reduced activity of the angiotensin converting enzyme 2 (ACE-2) that breaks down angiotensin. That was a timely finding as the ACE-2 enzyme had only been discovered seven years earlier.

ACE-2 enzyme

Levels of the ACE-2 enzyme appear to be low in ME/CFS and POTS

The ACE enzymes (ACE and ACE-2) break down angiotensin in different ways. The first ACE enzyme (discovered in 1956) breaks down angiotensin into angiotensin II and angiotensin.

ACE-2 has been referred to as the “protective arm of the renin-angiotensin system“. It breaks down angiotensin to angiotensin (1-9) and angiotensin II into angiotensin (1-7). Basically, it protects against high Ang II levels being present. Plus, in contrast to Ang II, ACE-2’s end product, angiotensin (1-7), opens up the blood vessels (i.e. is a vasodilator). The low levels of Ang (1-7) found in this study suggested that ACE-2 enzyme activity was low.

Note that ACE-2 also cleaves or breaks up other peptides including bradykinin.

The authors suggested two reasons ACE-2 levels appeared to be low: (1) high Ang II levels; or (2) negative feedback from the low blood volume. (Low blood volume should prompt a reduction in ACE-2 – increasing Ang II – and then aldosterone – the main blood volume enhancer.)

Another Ang II Problem Crops Up – Impaired Baroreflex Sensitivity

The Vanderbilt researchers didn’t waste any time. The very next year, in Altered Systemic Hemodynamic & Baroreflex Response to Angiotensin II in Postural Tachycardia Syndrome, they investigated the impact of high Ang II levels in POTS patients.

They infused Ang II into POTS patients and healthy controls. As suspected ,the healthy controls responded to the increased Ang II with increased blood pressure: the POTS patients, however, did not.

That suggested that Ang II receptors lining the smooth muscles of the blood vessels were simply not responding well in POTS and that the desensitization hypothesis might be correct.

Interestingly, the study found that Ang II was, on the other hand, doing its job of retaining sodium. That indicated that problems with sodium retention were not causing the low blood volume seen in many POTS patients.

Then they found another possible high Ang II-related problem – a balky baroreflex sensitivity response. The baroreflex response refers to the rapid changes seen in heart beat intervals when blood pressure changes. The heart should, in a matter of seconds, alter its beat in response to any changes in blood pressure. The diminished baroreflex sensitivity seen in the POTS patients was strongly correlated with increased Ang II levels. Since the baroreflex response impacts the heart rate, the researchers proposed that high Ang II levels likely contributed to the excessively high heart rate seen in POTS during resting and standing.

The findings suggested that the Ang II levels were having various effects: blood pressure was not being regulated normally, and the heart rate appeared to be affected. Sodium retention, though, was fine.

The cause of the ACE-2 inhibition – the putative cause of the high Ang II levels – was unclear. The authors speculated that genetic mutations might play a role, but then introduced a strange possibility: they might not be measuring Ang II at all; but might be measuring Ang 3 or 4. Perhaps Ang II levels were normal, but Ang III or IV levels were increased.

In 2018, the same Oklahoma team that uncovered the presence of adrenergic and muscarinic autoantibodies in POTS found autoantibodies to ang II receptors in a small study. They believe these antibodies stimulate Ang II receptor activity and thus increase Ang II levels.

The Gist

  • The renin-angiotensin-aldosterone system regulates blood volume in the body.
  • People with ME/CFS and/or postural orthostatic tachycardia syndrome (POTS) tend to have low blood volume.
  • When low blood volume is present, the activity of the renin-angiotensin-aldosterone system should be increased. In what has been termed the renin-aldosterone paradox – renin and aldosterone levels are decreased in ME/CFS and POTS.
  • Low levels of some forms of angiotensin suggest that levels of the ACE-2 enzyme – which has been called the protective arm of the RAA system –  are decreased. The ACE-2 enzyme breaks down Ang II and other peptides including bradykinin (see next blog)
  • High levels of Ang II can increase sympathetic nervous system activity, produce systemic vasoconstriction (narrowed blood vessels), increase the heart rate, inflammation and oxidative stress.
  • Miwa believes the low aldosterone levels may  be caused by a balky HPA axis in ME/CFS.  At the end of the day, though, the cause of the renin-aldosterone paradox and the low blood volume in ME/CFS/POTS is unclear.
  • The SARS-CoV-2 coronavirus enters the body through receptors for the ACE-2 enzyme. Recent research suggests that many, if not all of the coronavirus’s effects, could derive from its disruption of the renin-aldosterone-angiotensin system and its failure to properly regulate a substance called bradykinin
  • Two years ago, Wirth and Scheibenbogen proposed that bradykinin plays a major role in ME/CFS. The next blog will explore whether a similar bradykinin storm is present in COVID-19 and ME/CFS.

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Chronic Fatigue Syndrome (ME/CFS)

The renin-aldosterone paradox had not gone unnoticed in chronic fatigue syndrome (ME/CFS) – which also features low blood volume. In 2014, Miwa found normal plasma renin, but lower aldosterone levels in ME/CFS, and declared that a similar renin-aldosterone paradox was present in ME/CFS.

In 2016, Miwa found low plasma renin activity, low aldosterone and low antidiuretic hormone. This time, Miwa linked the low renin-aldosterone activity to impaired brain functioning – specifically, reduced HPA (hypothalamus-pituitary-adrenal) activity. Aldosterone is produced by the adrenal glands.

Pointing to other HPA axis problems in ME/CFS (low cortisol, insufficient responses to corticotropin-releasing hormone and adrenocorticotropic hormone challenge tests), Miwa asserted that a blunted HPA axis was likely responsible.

In doing so, Miwa showed a way to link high Ang II levels to blood vessel vasoconstriction and inflammation, and low aldosterone levels. As high Ang II levels were jacking up the fight/flight system – clamping down on the blood vessels and producing inflammation – they were failing to promote aldosterone release from the adrenal glands because of a balky HPA axis.

(Miwa also found that providing desmopressin, an antidiuretic which reduces the amount of water excreted in the urine, eliminated orthostatic intolerance during a standing test, and improved stroke volume (amount of blood pumped by the heart), and significantly improved daily living scores in 5/10 patients with low “urinary osmotic pressures” in the study.)

Treatments for the Impaired Renin-Angiotensin-Aldosterone System seen in ME/CFS and POTS.

Treatments help some and not others, and can come with side effects. Remarkably few studies have been done given how often some of the drugs are used in POTS. Possible treatments include:

  • Fludrocortisone (Florinef) – an aldosterone enhancer that increases sodium and water retention – Find out more here.
  • Desmopression (DDAVP, Stimate) – a synthetic analog of arginine vasopressin that increases intravascular volume.
  • Erythropoietin – a hormone that increases blood volume.
  • Saline Infusions  – increases blood volume – find out more here.
  • Oral rehydration solution (WHO formula) – increases blood volume – find out how here.

At this point, much remains unclear.

It’s clear the renin-angiotensin-aldosterone system (RAAS) that regulates blood volume is messed up in ME/CFS and POTS, and is likely causing the low blood volume there.

Low, instead of high, plasma renin and aldosterone levels in the face of the low blood volume found has led researchers to term this situation “the renin-aldosterone” paradox in POTS and ME/CFS.

Two studies suggest that the activity of the ACE-2 enzyme is reduced (but it’s possible that Ang II levels are not being accurately assessed.) It’s not clear why ACE-2 activity is reduced, but genetic issues or low blood volume could account for it.

The low aldosterone levels remain the biggest mystery – and the biggest problem – since aldosterone is the main blood volume enhancer in the body. Given the low blood volume and high Ang II levels found in ME/CFS/POTS, aldosterone levels should be sky-high but are low. Miwa believes that a blunted HPA axis (aldosterone is produced by the adrenal glands) could account for the low aldosterone levels, but the cause is still unclear.

The high Ang II levels could be contributing to/causing the increased sympathetic nervous system (fight/flight) activity, narrowed blood vessels, the low blood volume, and inflammation.

Drugs and other treatments can help some people with the renin-aldosterone paradox, but can come with side effects.

*Please note that other kinds of POTS exist which do not produce low blood volume or problems with RAA system.

Conclusion

Renin-aldosterone-paradox

The renin-aldosterone paradox in ME/CFS and POTS has confused researchers for years

Why the focus now on the agonizingly complex renin-angiotensin-aldosterone system in ME/CFS and POTS? A system that has unresolved problems and no answers?

This is a setup blog to prepare for the next blog or two. Those blogs will cover an intriguing possible connection that’s shown up between ME/CFS and COVID-19 which features the same renin-angiotensin-aldosterone system this blog focused on.

A lot of thought is now being aimed at RAA system, and in particular, a “messenger” called bradykinin. Bradykinin, to my knowledge, has never been thought to be a major player in ME/CFS – that is, until 2018, when Wirth and Scheibenbogen pegged it as a possible major player in ME/CFS. Could COVID-19 already be informing us about what’s happening in ME/CFS and POTS? Time will tell.

Coming up next: The Bradykinin Storm in COVID-19 and Chronic Fatigue Syndrome (ME/CFS) (??)

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