Orthostatic Intolerance in CFS II – Types

The evidence indicates that many CFS patients display symptoms and laboratory findings associated with orthostatic dysfunction. There are several different kinds of orthostatic dysfunction. Stewart (2003a) reports that three abnormal responses to tilt testing have been identified; vasovagal faint, dysautonomia and postural tachycardia syndrome (POTS). The first two occur in CFS but are not common. The orthostatic intolerance that is most commonly occurring in CFS is called postural tachycardia syndrome or POTS.

Vasovagal faint or neurocardiogenic syncope

This is a delayed response (7-20 minutes) to a TILT test that culminates in a fainting episode. Vasovagal faint appears to be the technical name for a ‘fainting spell’. In these patients peripheral vasoconstriction occurs upon standing but slow decreases in vasoconstriction eventually result in a precipitous fall in blood pressure and heart rate and a fainting spell. CFS patients often faint during tilt tests but rarely do so otherwise.

Dysautonomia-induced orthostatic intolerance 

This occurs when peripheral (i.e. outside the CNS) nerve failure or central nerve atrophy results in rapidly reduced blood pressure (systolic and diastolic) during the TILT test. Interestingly transient forms of dysautonomia induced OI can occur during infections or inflammatory episodes.

These patients typically experience other symptoms of dysautonomia such as abnormal papillary activity, gastrointestinal symptoms and sweating episodes. While tests indicate that some CFS patients do exhibit a degree of autonomic instability they are not thought to display this kind of braod sweeping dysautonomia (Stewart 2003a)

Postural Tachycardia Syndrome (POTS) 

While the name is relatively new POTS has been referred in the medical literature for many years. The many synonyms that still exist for POTS (a table lists 13 recent ones!) illustrates how fluid the field of orthostatic research is.



POTS is characterized by rapidly increased heart beat upon standing caused by low blood flows to the heart. The symptoms found in POTS appear to arise from decreased blood flows to the brain, increased cerebrovascular resistance, and (an unexplained) hyperventilation associated with low carbon dioxide levels.

Low blood pressure and high resting heart beat can be persent. Low blood pressure (neurally mediated hypotension (NMH) is not a requirement for POTS. The only overt autonomic abnormality in POTS is increased heart beat upon standing.

Symptoms

POTS symptoms are manifold; they include: dizziness, lightheadedness, shortness of breath upon standing, fatigue, exercise intolerance, frequent urination, headache, flu-like symptoms, tingling and/or numbness in the extremities, poor sleep, abdominal discomfort, irritable bowel syndrome, poor balance and coordination, visual disturbances (floaters), allergies and chemical sensitivities, chest pain, neurocognitive disorders, anxiety, palpitations (sound familiar?).

In contrast to those people who simply experience fainting upon standing people with POTS are often disabled, and unable to attend school or hold a job. POTS effects up to a million Americans.

A window into chronic fatigue syndrome (ME/CFS)? 

While OI has been a subject of interest in CFS since 1995, Rowe (2002) points out that as early as 1940 Maclean and Allen suggested orthostatic tachycardia resulting from impaired venous blood flows to the heart upon standing (i.e. POTS) contributed to diseases (effort syndrome, neuro-circulatory asthenia, irritable heart) now believed to be synonymous with CFS. They recommended two treatments (increased fluid and sodium intake) now commonly prescribed in CFS.

Stewart states the clinical findings for the orthostatic intolerance found in POTS and pediatric CFS patients show great similarity. No other diseases have as great a symptom overlap with CFS as does POTS. One research group believes some people with POTS have misdiagnosed as having CFS.

Almost all CFS patients with OI appear to have POTS and some POTS patients have CFS. Both diseases often occur after an infectious event. As with CFS the great majority of POTS sufferers are female. Stewart suggests from 25-50% of CFS sufferers probably have POTS. He believes POTS could be a milder form of CFS (Stewart 2000)

Some general differences have been noted. Children with POTS usually have less severe symptoms and recover more quickly than those with CFS. In addition while POTS can be debilitating, POTS appears not to be as disabling as CFS. The similarities between the two diseases are undoubtedly more important than their differences. Research into POTS will surely spur insights into CFS and vice-versa.

Much of this enquiry into the nature of the orthostatic dysfunction found in CFS will focus on findings from studies on POTS patients.

Possible causes

POTS was at first believed to originate in a dysfunctional cardiac response to standing. In the 90’s Streeten turned this idea by its head by arguing that the increased heartbeat was an appropriate response to reduced heart blood flows caused by blood pooling in the extremities. As heart blood volume dropped the heart beat was increased in order to ensure sufficient blood flowed to the brain.. Reduced venous heart flows of blood are now agreed to be the proximate cause of POTS.



The ultimate cause of the reduced cardiac blood flows is unclear; two theories – low blood volume, blood pooling in the extremities – both of which may be correct, have garnered most of the interest. The outcome of increased blood pooling and low blood volume is similar; both result in increased tachycardia (heart beat) that is sometimes followed by low blood pressure or fainting or both on tilt.

Low Blood Volume

In a small study in 1997 Jacob et al. demonstrated that reduced blood volume was associated with low plasma renin and a trend towards low aldosterone levels in about half the patients with OI. In another very small study Streeten and Bell (1998) found CFS patients demonstrated low red blood cell (RBC) mass but not low mean plasma or blood volume levels.

While mean plasma and blood volume were not significantly different from controls the range of readings was very high; a subset of CFS patients clearly did have reduced blood and/or plasma volume. Because the RBC’s carry oxygen to the tissues and organs of the body Streeten and Bell argued that low RBC mass and normal blood volume was analogous to have normal RBC mass and low blood volume. In either case insufficient oxygen was very likely reaching the brain.

Several possible causes for low blood volume in CFS have been proposed:

  • dyfunctional renin-angiotensin-aldosterone system
  • altered sympathetic nervous system (SNS) activity
  • extracellular alkalosis
  • deconditioning

Renin converts angiotension into its active form angiotensin II (see Glossary) which increases blood volume by (a) inducing water retention in the proximal tubule of the kidney and (b) by inducing sodium retention through the activation of aldosterone. Both renin and aldosterone levels were low in Jacob’s study. This was highly unexpected – renin and aldosterone levels are usually increased in patients with low blood volume. Given the patients low blood volume it sounds like even normal renin and aldosterone readings would have probably been considered abnormal in these patients.

Aldosterone secretion can be induced by angtiotensin II, potassium and ACTH. Since electrolyte levels were normal, and ACTH is involved in acute rather than chronic conditions, it appears low angiotensin levels are the source of the trend towards low aldosterone in CFS. Jacob’s speculated that autonomic denervation (reduced nerve supply) of the kidneys could also cause reduced low renin production. It is perhaps notable given the increased symptoms of POTS patients given beta adrenoreceptor antagonists that the authors note that these agents decrease plasma renin levels. Some of the symptoms patients taking these drugs experienced may have been due to further eductions in blood volume due to low renin levels.

Because a chronic state of adrenergic activation (i.e. increased SNS activity) can either cause low blood volume or low blood volume can cause increased SNS activity, it is hard to tell which causes which (Stewart 2003a).

Dr. Cheney believes low blood volume may be due to a compensatory response to extracellular alkalosis (= intracellular acidosis) called ‘contraction alkalosis’. Reduced blood volume results in less tissue perfusion which in turn increases blood pH (alkalosis). Since this scenario suggests increasing blood volume would interfere with this compensatory response it could explain why CFS patients do not respond well to plasma volume enhancers such as fludrocortisone.

There is evidence for increased SNS activity in CFS. Low blood volume can also be induced by deconditioning. In one study 15 days of bed rest resulted in a 15% reduction in plasma volume (Kimberly and Shoemaker 2002).

Prevalence in CFS

Research has demonstrated that low blood volume ‘almost certainly’ occurs in a subset of CFS and POTS patients (Stewart 2003a). A trend toward low blood volume is associated with reduced low VO2 max in CFS patients (Farquhar et. al. 2002).

Other studies have shown that increased blood volume is associated with increased endurance in healthy people (Hageberg et.al. 1998). This, of course, suggests reduced blood volume could contribute to the fatigue in CFS. Stewart (2003) argues, however,  that low blood volume cannot account for all the circulatory abnormalities seen in CFS or POTS. In particular low blood volume cannot account for the increased leg blood flows seen in some POTS patients.

Summary

The extent, significance and cause of low blood volume in POTS and CFS patients is unclear.

Blood Pooling

Blood pooling upon standing both CFS and POTS patients display increased blood pooling in the legs (sometimes manifested by swelling) that results in increased losses of blood from the upper body and heart and thus the brain. As mentioned earlier the tachycardia seen in POTS and CFS is believed to be a compensatory mechanism designed to combat the low venous flows of blood into the heart during standing.

The question researchers are trying to answer is where does the blood go and why? Stewart (2003) states that increased blood pooling could be due several factors: This gets quite complicated.

  • An autonomic neuropathy primarily found in the legs could inhibit vasoconstrictive activity. (Autonomic neuropathy refers to reduced numbers of the nerves that control blood flows in the legs.)
  • Similarly a beta receptor hypersensitivity could cause increased blood vessel dilation in the legs. (Beta receptors cause the blood vessels in the legs to dilate allowing more blood flow (i.e. pooling) in the veins.)
  • Altered venoconstriction could result in increased blood flows in the veins.
  • Increased capillary filtration resulting in fluid leakage into the surrounding tissues could cause blood pooling (i.e. ‘leaky’ capillaries.)

Autonomic neuropathy (Warning – Extremely Complicated Section)

The presence of hypersensitive alpha adrenergic nerve receptors on the veins of some POTS patients suggests that autonomic denervation (nerve loss) in the lower body is a cause of blood pooling. Denervated arteries have thinner walls, are smaller and show greater sensitivity to NE. Instead of clustering at the endpoints of muscles denervated nerves tend to flow over them.

Apparently the receptors on the remaining nerves attempt to ‘make up’ for the reduced nerve levels by increasing their sensitivity. Alpha adrenoreceptors cause the arteries to vasoconstrict. The cause of the possible nerve loss is unclear. Infections can cause nerve damage.

Autonomic neuropathies that cause orthostatic intolerance (among other things) rise, for instance, due to reduced immuno-vigilance during the progression of AIDS. Several researchers believe CFS is a disease of reduced immuno-vigilance.

Increased sensitivity to phenylephrine – a vasoconstrictor, and isopreterenol – a vasodilator, and resistance to tyramine – an agent that enhances NE release, suggests noradrenergic neuronal dysfunction. Noradrenergic refers to nerves that release noradrenaline, i.e. norepinephrine (NE). Noradrenergic receptors are activated by NE. Since NE is the principal vasoconstrictor these findings suggest reduced vasoconstriction due to reduced NE release is occurring.

Short term improvements following administration of the alpha adrenoreceptor agonist  (enhancer) Midodrine also suggest impaired noradrenergic functioning (Jacob et. al. 2000). (Midodrine enhances norepinephrine release.) Reduced NE release upon tyramine administration suggests either decreased neuronal NE stores or reduced NE release (Jacob et. al. 1999).

Reduced NE spillover – Reduced NE ‘spillover’ also occurs. After NE is released from the neuron into the synapse much of it is immediately taken up again. Some of it, however, always spills over into the blood. By triggering NE release and then measuring NE blood levels researchers are able to assess NE spillover. To further complicate matters it turns out  that OI patients also display reduced NE clearance (reuptake).

Since reduced NE clearance should lead to increased NE spillover, this may suggest CFS patients have really, really low NE spillover (?). It is intriguing that CFS patients also appear to display reduced uptake of another neurotransmitter, acetycholine, in the blood vessels of the skin.

Reduced NE spillover suggests one of three scenarios is occurring; poor NE production or storage, impaired NE release, or low blood volume. There is evidence for at least three of these in CFS.

The presence of hypersensitive adrenergic receptors, as noted above, suggest autonomic denervation has occurred. Jacob has suggested that damage to the nerve terminals in the legs could impair the NE reuptake mechanisms and cause reduced NE clearance (Jacob et. al. 1999).

Reduced nerve levels could result in reduced NE spillover, reduced NE production or storage or impaired NE release. Because of the reduced circulation it imposes, hypovolemia could cause the reduced NE spillover. This appears to suggest that in states of low blood volume there may not be enough blood reaching to the nerve terminals to carry away normal amounts of NE?

McGregor et. al. suggest increased tyrosine excretions in CFS patients are the result of increased catabolic activity in CFS. Since tyrosine is the precursor to NE, increased tyrosine excretions could lead to decreased tyrosine availability and reduced NE production (see Chap VII CFS ABA).  All of McGregor’s amino acid findings have recently been called into question, however (Chalmers et. al. 2005). This theory no long appears viable. It appears that reduced spillover is due to both autonomic denervation and low blood volume.

Another conundrum

Interestingly, despite reduced NE release in response to tyramine OI patients also display increased plasma NE levels. How to explain decreased NE secretion and increased NE levels in the blood?

This appears to be due to different types of NE release. Apparently the hyper alpha adrenoreceptor sensitivity but normal B2 adrenoreceptor sensitivity in OI patients suggests nerve damage in the lower extremities has resulted in hypersensitive local nerve terminals while normal humoral norepinephrine production leads to normal B2 receptor activity.

Thus OI patients appear to exhibit reduced local nerve functioning but intact nerve functioning of the nerves served by the circulation. Jacob believes this pattern is consistent either with a functional abnormality of the sympathetic nerves or a disrupted ‘architecture’ of the nerve synapse in OI patients (Jacob et. al. 2000).

Beta receptor hypersensitivity 

Because beta adrenoreceptors dilate the blood vessels B AR hypersensitivity could theoretically result in reduced vasoconstriction and blood pooling. The importance of beta receptors in the skeletal muscles is, however, controversial, and Stewart (2003a) discards this explanation. A 2002 study (Stewart and Weldon) which demonstrated that beta adrenoreceptor blockers (beta blockers) increased the symptomology of POTS patients argued against excessive beta adrenoreceptor activity in POTS.

Altered venoconstriction

Stewart states there is little evidence that venoconstriction (as opposed to arterial vasoconstriction) plays a role in the orthostatic response anywhere in the body but the abdomen. Reduced venoconstriction may play a role in the OI experienced by ‘normal-flow’ POTS patients. (See below)

Increased capillary filtration

Streeten believed reduced heart blood volume occurs when the peripheral arteries fail to constrict enough to prevent bloodfrom pooling in the peripheral veins and capillaries when standing (Streeten and Bell 1998). Since NE is the primary vasoconstrictive agent in the peripheral arteries the reduced NE ‘spillover’ in the peripheral arteries seen in POTS patients buttresses Streeten’s theory of reduced arterial vasoconstriction.

In the last five years Stewart has engaged in a series of studies that indicate a variety of vascular problems in the extremities lead to the excessive blood pooling in POTS (Stewart 2000, Stewart et. al. 2002, Stewart 2003a). These vascular problems appear to be the greatest contributor to the orthostatic dysfunction seen in CFS. Of course it’s never as simple as that…

The (dreaded) subsets

Any discussion of the cause of the blood pooling seen in POTS and CFS patients is complicated by the subsets Stewart has found in a series of studies of adolescent POTS patients. Reading Stewart’s latest paper (2004) is like Yogi Berra said ‘Déjà vu all over again”. Once upon a time POTS (and CFS) appeared like a homogeneous disorder.

Although the origin was a mystery at least it was a single mystery. Ongoing research, however, has indicated the presence of not one or two and but now three distinct subsets of POTS patients; two of which have opposite laboratory findings (!). This is obviously quite complicated. Stewart states all three subsets are found in CFS. The subsets consist of

  • Hi-flow POTS patients – have high blood flows, low arterial resistance (vasoconstriction) and normal to decreased peripheral venous pressure in the extremities.
  • Low-flow POTS patients – have low blood flows, increased arterial resistance and increased peripheral venous pressure in the extremities (and probably low blood volume).
  • Normal flow POTS – have normal blood flows and arterial resistance but disrupted arterial and/or venoconstriction in the abdomen.

Hi-flow POTS

These patients display reduced peripheral arteriole vasoconstriction (a relative peripheral vasodilation) in combination with increased microvasculature (capillary) filtration. Thus reduced blood vessel vasoconstriction results in increased peripheral blood flows and increased blood volume in the capillaries.

The increased capillary filtration does not, interestingly, appear to be effected by posture – the vasoconstrictive defects present in these patients are present all the time – they are simply accentuated by standing. These patients are designated ‘hi-flow’ because they exhibit higher than normal flows of blood in their lower extremities.

These patients also display decreased releases of the catecholamine (norepinephrine) responsible for constricting the arteries. The current theory regarding these patients posits they have a ‘long axon’ neuropathy that interferes with NE production in the lower extremities (Stewart 2004). (A neuropathy is a disease of the nerves.)

These patients appear to have very positive responses to alpha adrenergic receptor enhancers. (Alpha adrenoreceptors cause the smooth muscles of blood vessels to vasoconstrict.) The authors do not speculate what may be causing this ‘disease’ but do note that many things, including infection, can cause neuropathies. Stewart (2004) reports that hi-flow POTS patients often experience infectious events just prior to getting POTS.

Low-flow POTS

Low flow POTS patients are the most difficult to explain. They exhibit defective local blood flow regulation, increased peripheral resistance (vasoconstriction), decreased vein area and probably reduced blood volume of some degree (Stewart and Montgomery 2004).

Thus low-flow POTS patients have reduced levels of blood to start with plus increased resistance to blood flow in their legs (and in contrast to hi-flow POTS their arms) and decreased vein capacity to boot. In contrast to hi-flow POTS patients who have increased blood flows in their microvasculature, low-flow POTS patients appear to have reduced microvasculature blood flows.

The reduced peripheral vein capacity seen suggests that either a ‘venous remodeling’ or a persistent vasoconstriction has taken place. In spite of their reduced peripheral blood flows, low flow POTS patients still exhibit reduced heart blood flows during standing.

Stewart suggests their reduced vein capacity (remodeling) could be due to reduced blood volume.  A layman like myself could see low blood volume resulting in increased vasoconstriction (to maintain blood pressure) and reduced heart blood flows but Stewart does not believe low blood volume is responsible for the vascular abnormalities in these patients.

Stewart believes the main problem in these patients is not due to damaged nerves due but to a dysfunction in the small blood vessels in the legs. Some evidence suggests that these local receptors are responsible for as much as 45% of the orthostatic response.

Poor Muscle Pump Activity 

As if low-flow POTS patients didn’t have enough problems, a recent study (Stewart et. al. 2004) found that they exhibit abnormalities in muscle pump activity as well. The ‘muscle pump’- a major part of the orthostatic response – consists of a series of very small involuntary muscle contractions that propel blood upwards during standing.

Since skeletal muscle integrity is dependent upon proper flows of blood and low-flow POTS patients display low peripheral flows of blood Stewart examined low-flow POTS patients to determine if they displayed reduced muscle mass and therefore muscle pump activity (Stewart et. al. 2004).

Not only did low-flow POTS patients exhibit reduced muscle pump activity but that they also had decreased muscle mass and venous capacity. The authors speculated low-flow POTS patients could be immersed in vicious circle (reduced muscle pump activity = reduced blood flow = reduced muscle mass = reduced muscle pump activity, etc.) leading to progressively lower  and lower muscle pump activity.

Since neither sedentary people nor those with congestive heart failure nor other types of POTS patients display decreased muscle pump activity, it does not appear to be the result of deconditioning.

Local blood vessel dysfunction 

While the phenomena of local vasoconstriction is a rich field of study, just how blood vessel walls initiate vasoconstriction in response to increased pressure is unknown. As noted earlier local blood vessels respond to the increased blood pressure caused by blood pooling by constricting.

This vasoconstriction stops blood from pooling in the capillaries and veins. It appears that in low blood flow POTS patients these blood vessels are too constricted. This, of course, inhibits blood flow to the veins (venous remodeling), reduced muscle mass and muscle pump activity.

The abnormalities in calf blood flow seen in low-flow POTS patients appear to originate in defects in themyogenic response or the venoarteriolar response. The myogenic response occurs when the smooth muscles constrict the arteries in response to increased blood pressure.

Calcium channel activity is believed to play a key role in the myogenic response. The venoarteriolar response is believed to occur when increased blood volume in the small veins triggers stretch receptors to constrict the arterioles upstream of that vein. As blood begins to pool in the veins and enlarge them the stretch receptors activate causing the arterioles at the head of the veins to constrict.

A large number of local vasoactive agents could effect local blood flow regulation. They include

  • endothelial vasoactive products – NO, PG1-2, endothelin, EDHF
  • metabolites – adenosine, Ca2+, CO2, H+ ions, lactate
  • autacoids – histamine, bradykinin, 5-HT (serotonin), PAF, prostaglandins
  • local neurogenic mechanisms such as the axon reflex
  • neurogenic inflammation – CGRP, substance P

Endothelial agents with vasodilatory properties such as nitric oxide, histamine and acetylcholine appear to be responsible for the venoarteriolar response. These two responses have been held to be distinct but a recent report indicates that NO, a venoarteriolar agent, is able to modify the myogenic response by altering the sensitivity of the Ca receptors on smooth muscles.

These patients often display acrocyanosis – mottled looking blue and pink skin in the lower extremities – and the skin is generally cool to the touch. These are both due to reduced peripheral flows of blood. They also often exhibit pallor.

Summary:

Overactive local myogenic or venoarteriolar responses and/or low blood volume in the low-flow POTS patients appear to cause either increased vasoconstriction in the periphery and/or a venous remodeling that results in reduced vein area in the lower extremities.

Disrupted local blood flows could be due to impaired calcium channel functioning (myogenic) or improper endothelial cell functioning. While increased peripheral vasoconstriction is accompanied by reduced blood volume, low blood volume is unlikely to account for all the abnormalities found in low-flow POTS patients.

Normal-flow POTS patients 

These patients display normal peripheral blood flows but impaired vasoconstriction and blood pooling in the abdominal (splanchnic) area. Whether the impaired vasoconstriction is due to reduced veno or arteriole constriction is unknown. Either a partial dysautonomia (i.e. limited to the abdomen) or a local regulatory dysfunction is likely responsible.

Summary

These studies suggest several subsets of POTS exist in CFS. Depending on which subset is involved, the central factors appear to be nerve damage (long-axon neuropathy – hi-flow POTS); local blood flow constrictions due to a disruption in the small blood vessels (low-flow POTS), low blood volume (low-flow POTS) and impaired vasoconstriction in the abdominal area (normal-flow POTS).

At this point, therefore, both nervous system and vascular components to the orthostatic dysfunctions found in CFS patients. Aside from infection in hi-flow POTS patients there is little speculation as to the ultimate cause of these disruption.

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