This paper lists various factors that could be at the source of the orthostatic intolerance (POTS) found in CFS.
Reduced vascular nitric oxide production
Stewart (11/05) published two studies that suggest increased angiotensin production in low-flow POTS patients could, by increasing production of the superoxide free radical, bind with and therefore remove from the circulation, nitric oxide, an important vasodilator. Reduced levels of NO could cause the impaired blood vessel dilation and reduced blood flows to the skin found in low-flow POTS patients.
Increased levels of circulating vasodilators
Stewart, Khan and Spence and now Shibao propose the orthostatic intolerance found in some CFS patients is not due to ANS abnormalities but to increased levels of vasoactive products.
Vasoactive products are able to alter how the vasculature – the blood vessels – function. As the first two papers on orthostatic tolerance on this website demonstrated POTS patients appear to have disturbed blood vessel functioning (inappropriately increased or decreased vasoconstriction). Several researchers have believed this is likely due to autonomic nervous system dysfunction but these Stewart, Khan and Spence don’t think so.
Stewart noted that many vasoactive substances (endothelial – NO, PG1-2, endothelin, EDHF; metabolites– adenosine, Ca2+, CO2, H+ ions, lactate; autacoids – histamine, bradykinin, 5-HT (serotonin), PAF, prostaglandins; neurogenic inflammatory products – CGRP, substance P) could effect vascular functioning in CFS. Several of the vasodilators produced by the endothelium that lines the blood vessels are under investigation now and they are briefly reviewed below.
Reduced acetylcholinesterase (AChE) and increased acetylcholine-induced vasodilation
As Stewart has been uncovering vasculature dysfunction in low-flow POTS patients, Spence and Khan (Spence et. al. 2000, Khan et. al. 2003) have uncovered a possible counterpart to it in the skin. Acetylcholine -the chief neurotransmitter acting on the cholinergic synapses – dilates the blood vessels in response to various agents that act on the blood vessel endothelium. (Endothelial cells are the flat cells that line the walls of the blood and lymphatic vessels.)
Abnormalities in the skin cholinergic pathways in CFS patients were first noted in 2000 (Spence et. al. 2000) when CFS patients displayed increased skin capillary dilation in response to acetylcholine (but surprisingly enough not to sodium nitroprusside) administered on the skin. A normal reaction to sodium nitroprusside indicated nitric oxide was probably not involved in the microcirculatory abnormalities seen.
The increased capillary dilation indicated that CFS patients exhibited increased blood flows to their skin. Why is this important? One reason is increased skin blood flows could contribute to the blood pooling that occurs in at least some CFS patients.
A follow up study (Khan et. al. 2003) did not find increased peak capillary blood flows but did find that peak blood flows were sustained for much longer in CFS patients than controls. The prolonged skin blood flows suggested that reduced degradation of ACh was occurring in the microvasculature. Acetylcholine is degraded by acetycholinesterase (AChE).
Normal blood flows in response to a vasodilator (MCh) not degraded by AChE indicated that reduced AChE expression in the vascular endothelium appeared to be the cause of the increased skin vasodilation found. By hanging around longer than it should ACh apparently caused increased blood flows to the capillaries and blood pooling.
Interestingly given the prevalence of infectious episodes in CFS the authors noted that AChE inhibition is seen in cells infected with the herpes simplex virus. AChE inhibition can also exist for years after some cells have cleared the lymphyocytic choriomeningitis virus.
Update
In a brief e-mail to the CFS Research chat group Vance Spence reported that after an examination of a wide variety of signaling agents (G-protein receptors, IP3, intracellular Calcium, nitric oxide, GMP, H202, prostanoids, etc. these researchers are ‘fairly certain’ they have narrowed the problem down to one of the them.
A recent publication on the MERGE website indicates the researchers are most interested in endothelian-derived hyperpolarizing factor (EDHF), prostacyclin and, somewhat surprisingly – nitric oxide. Results from this study should be available sometime this year. It’s nice to see some progress made!
Mast cell activation
Shibao et. al. (2005) suggest mast cell activation could produce the hyperadrenergic activation (increased NE production) seen in some POTS patients. Their attention was directed to this area because of ‘flushing’ episodes commonly reported by some POTS patients. ‘Flushing’ episodes are characteristic of a disorder called mast cell activation (MCA) which causes palpitations, light headedness, dizziness in response to stimuli such as exercise or standing.
The symptoms of this disorder, like those of POTS, are strikingly similar to those experienced by CFS patients. The flushing episodes occur when mast cells degranulate (spill the contents of their granules) into the bloodstream. One of those products, histamine, stimulates gastric secretion, constricts the smooth muscles of the bronchii, and vasodilates capillaries and arterioles.
The occurrence of flushing episode can easily be monitored by testing for methylhistamine levels in the blood. Interestingly Spence and Khan reported that CFS patients displayed exaggerated responses to histamine relative to controls.
POTS patients experiencing flushing episodes displayed significantly greater NE activity than did healthy controls. In contrast to ‘normal’ POTS patients, these POTS patients exhibited significantly increased levels of methylhistamine after exercise. It is noteworthy that both CFS and POTS patients have trouble exercising.
The authors noted that a peptide (neuropeptide Y (NPY)) released with NE is able to induced mast cell degranulation. Why some POTS patients might be more sensitive to or produce more NPY than others was not discussed.
This presents the scenario of a positive feedback loop consisting of mast cell induced vasodilation that triggers the SNS nerves to release NE and NPY which in turn triggers mast cell to degranulate (via NPY). Because they are located close to the blood vessels and peripheral nerves, mast cells are well positioned to effect SNS activity in the vasculature.
CO2 levels and low blood oxygen
As noted earlier, in 2001 Cheney stated he believed the low blood volume in CFS could be a compensatory reaction to extracellular alkalosis (decreased plasma pH). Cheney suggests cellular dysfunction highlighted by reduced mitochondrial activity and energy production results in intracellular acidosis – a common occurrence in any chronic disease. In the case of CFS he believes intracellular acidosis probably occurs when RNase L dysfunction causes reduced protein synthesis.
Increased plasma adenosine levels
Adenosine is a breakdown product of ATP. Especially during periods of anoxic ischemia ATP catabolism results in high levels of adenosine. (Ischemia refers to low oxygenation of the tissues due to low blood flows.)
When adenosine binds to alpha 1 adrenoreceptors on endothelial cells NE release (and therefore vasoconstriction) is inhibited. Besides depressing brain activity and causing sleepiness, adenosine is an endothelium dependent and independent vasodilator. Increased adenosine levels also result in increased MSNA activity.
CFS patients exhibit increased sleepiness and increased MSNA activity and may exhibit reduced NE spillover (production). Hypoperfusion (low blood flow) in the some brain areas, in the localized sites in the blood vessels (hypercoagulation) and in the muscles may also occur in CFS. CFS patients displayed significantly increased plasma adenosine levels in small 1997 study.
Many CFS and POTS patients report an infectious episode shortly precedes their getting CFS. It is intriguing that ‘autonomic neuropathies’ can follow infectious illnesses. (Autonomic neuropathy is a disease of the autonomic nerves that results in nerve loss.
The autonomic nervous system regulates cardiovascular activity, among other things.) An infection, therefore, could damage nerves in the extremities of POTS and CFS patients causing denervation (nerve loss) and an inability to vasoconstrict the blood vessels.
Several factors including hypersensitive nerves and increased muscle sympathetic nerve activity but normal nerve signal intensity, suggest denervation in the extremities of some POTS patients. Stewart reports high-flow POTS patients, in particular, often experience an infectious event before becoming ill (Stewart 2004). Anecdotal reports suggest, however, – in contrast to CFS patients – that POTS patients with an infectious onset heal more quickly than others do.
Stewart suggests chronically elevated vasoactive cytokines such as IL-1, IL-6 and TNF-a could result in increased vasoreactivity and inflammation in CFS. A recent publication indicated that IL-1 and IL-6 are elevated in the acute phase response to some infectious illnesses that are known to place one at risk for CFS.
Hyde believes the dysfunctions in CFS are the result of a widespread ‘micro-vasculitis (inflammation of the small blood vessels) effecting the immune system, thyroid gland and cardiovascular system.
This inflammation is primarily the result of nervous system viruses that affect not only the CNS but also the capillaries and arteries of the peripheral vasculature. A chronic infection could lead to the production of the vasoactive cytokines described above. A study is currently examining the relationship between cytokine levels and orthostatic intolerance in CFS. (See Ongoing Research below.)
Anecdotal reports indicate POTS sometimes resolves itself during pregnancy (Stewart 2004). During one period of pregnancy the Th1/Th2 cytokine becomes skewed towards Th1 cytokine production – a shift that could possibly help resolve a chronic infection.
Reduced red blood cell mass
Hurwitz is currently engaged in large study examining whether reduced red blood cell (RBC) mass is an important component in CFS. In 1998 Streeten and Bell argued that because reduced RBC mass resulted in less oxygen delivery to the tissues it was analogous to having reduced blood volume. Hurwitz has found that 80% of women and 60% of men have low blood volume.
As well as being responsible for low blood flows to the brain during standing, low blood volume could interfere with proper oxygen and nutrient delivery to the tissues. Low blood volume could also trigger increased SNS activity.
In a placebo controlled, double blinded study Hurwitz is examining the efficacy of Procrit, a drug which stimulates the bone marrow to produce RBC’s, in raising blood volume and ameliorating symptoms in CFS. Most interestingly he is also examining an immune system hormone or substance that he believes is hampering RBC production in CFS patients. So he is tying together immune system activity and orthostatic intolerance. Exciting stuff! See Ongoing Research below.
Update
Dr. Hurwitz did find reduced blood volume was present in most CFS patients and that Procrit did increase their red blood cell volumes to normal but that it had no effect on their disease. This is not the first study to find that simply increasing blood volume does not aid CFS patients.
Still low blood volume is present in CFS and Dr. Hurwitz is now engaged in attempting to find its source. He believes increased levels of pro-inflammatory cytokines are the cause (2/07) As of 2012, however, Hurwitz had not reported any findings.
Norepinephrine transporter (NET) deficiency
NET’ is a Na/Cl dependent transporter that is responsible for clearing from 50-90% of the NE released from the synaptic cleft and transporting it back into the neuron. (The synaptic cleft is simply the opening between the pre-synaptic and post-synaptic nerve terminals. It is what neurotransmitters fill during nerve activity. How intriguing that the clearance of two neurotransmitters (acetylcholine, norepinephrine) appears to reduced in CFS patients.)
The reduced NE clearance POTS patients exhibit makes NET deficiency an intriguing idea. There are also indications that less NE than normal is taken up by neurons in CFS patients. Researchers recently discovered a genetic polymorphism that codes for reduced NET activity.
Humans heterozygous for the NET polymorphism display a volatile supine heart rate (HR), orthostatic tachycardia, decreased NE clearance and reduced tyramine responsiveness. CFS patients have similar findings. Experimentally induced decreased NET activity in rats results in chronically elevated levels of NE, increased heart rate and mean arterial blood pressure.
CFS patients also display increased NE levels. Rats with reduced NET appear to have reduced sympathetic outflows and reduced LF power. CFS patients appear to display increased LF activity (Carson et. al 2002).
CFS patients display several laboratory findings (including reduced NE clearance) similar to those found in people with a NET polymorphism that reduces NET activity. Neither the frequency of the NET polymorphism in CFS patients or the general populations, however, has been assessed.
Ehlers-Danlos Syndrome
Rowe found a significant subset of CFS patients fulfilled the parameters of Ehlers-Danlos Syndrome, a connective tissue disorder characterized by joint hypermobility (Rowe et. al. 1999). Shoemaker states a large percentage of his CFS patient population also fulfill the parameters for Ehlers-Danlos Syndrome (see the Shoemaker talk at the 2004 AACFS conference).
One’s degree of joint hypermobility is assessed by doing a series of tests that produce a ‘Beighton Score’
One point is assessed if you are able to
- Pull back the fifth finger of either hand beyond 90 degrees (possible 2 points)..
- Touch either thumb to the underside of the forearm
- Hyperextend either knee beyond 190 degrees
- Hyperextend either elbow 190 degrees
- Put both palms flat on the floor without bending your knees while bent at the waist.
The maximum point total is 9. A small study found CFS patients had an average Beighton score of 6.3 compared to 0.5 for controls (Pocinko 2004).
In the summer 2004 edition of the CAA’s CFIDS chronicle, Dr. Alan Pocinki, a physician who has been treating CFS patients since 1987, noted the high incidence of joint hypermobililty in his CFIDS patients, and indicated how it contribute to the pathophysiology of CFS (Pocinki 2004).
He posited that increased tissue elasticity in the blood vessels could cause balloon-like veins that collect blood causing blood pooling. This could lead to orthostatic intolerance, cold hands and feet and low to normal to low blood pressure. Increased catecholamine production due to poor vascular tone could cause the ‘tired but wired’ feeling so common in CFS (What an apt term!) as well as the unrefreshing sleep. These same overly elastic blood vessels could predispose individuals to migraines, hemorrhoids and varicose veins.
Other connections to CFS possibly occur. The joint pain typical in CFS (no swelling or redness) could result when hypermobile joints strain the tissues around them. Increased elasticity of the gastrointestinal and genitourinary tracts could be the source of the irritable bowel syndrome and frequent urination that often occurs in CFS patients.
Increased pulmonary elasticity could account for the ‘breathless’ feeling CFS patients sometimes get. Finally Pocinki notes both anxiety and sleep problems are common in individuals with joint hypermobility.
More information about Ehlers-Danlos syndrome can be found via the Ehlers-Danlos National Foundation.
Low tyrosine levels
All catecholamines (NE, epinephrine) are ultimately derived from tyrosine. First dopamine and then NE and E are formed out of tyrosine. Tyrosine is made available for transformation after it is transported by a sodium carrier into a noradrenergic ‘ending’ (nerve). Increased tyrosine excretion in CFS patients has been suggested to disrupt catecholamine production and proper SNS functioning in CFS patients.
This increased tyrosine excretion in CFS patients is believed to be the result of increased proteolysis (protein degradation) relative to protein synthesis. Increased proteolysis occurs in response to injury, infection, etc. During this process the body destroys cells in order to provide the amino acids needed to build the cells needed to combat the trauma, infection, etc.
Increased elastase activity
Monocytes secrete elastase in order to dissolve elastin, the protein that gives connective tissues such as blood vessels, tendons and ligaments their elasticity. Once elastin is dissolved monocytes can make their way through the connective tissues to the scene of injury or trauma.
Despite its role in maintaining arterial elasticity elastase as been only poorly studied with regarding to diseases of increased arterial stiffness such as arteriosclerosis. Recent studies, however, indicate elastase may play a role in the development of aneuryisms.
Increased serum elastase levels were just recently associated with increased arterial stiffness in adolescents with CFS. Dr. De Meirleir has found increased elastase levels in CFS and elastase is, of course, one of two enzymes associated with the increased RNase L fragmentation.
Could increased elastase levels effect cardiovascular functioning in CFS? We now have evidence from multiple sources that that cardiovascular functioning is impaired in CFS; the CDC’s allostatic stress studies, MERGE’s findings of increased cardiovascular risk factors and Dr. Cheney’s findings of increased diastolic dysfunction. It appears that elastase upregulation could effect both the orthostatic intolerance and the cardiovascular problems found in CFS.
Deconditioning
Because deconditioning can cause OI it must be accounted for. Deconditioning can rather quickly lead to reduced elevated heart rate, reduced blood volume, reduced baroreceptor responsiveness, reduced total peripheral resistance and increased venous pooling and muscle sympathetic nerve activity (Pawelczyk et. al. 2001).
(A subset of CFS and POTS patients have reduced blood volume, increased venous pooling and increased MSNA. Most have elevated heart rates.)
Interestingly, in deconditioning while resting MSNA is usually increased, MSNA in response to orthostasis is reduced. MSNA levels have been reported to increased, decreased or normal after deconditioning.
Neither a hypoadrenergic state (low NE), nor baroreflex dysfunction, nor a defect in the vascular smooth muscle can account for the orthostatic intolerance seen after deconditioning (Pawelczyk et. al. 2001). Pawelczyk posits that a smaller heart and a greater increase in sympathetic nervous system activity could lead to low blood volume and a hyperadrenergic state after prolonged bed rest.
Many CFS patients appear to display increased sympathetic nervous system activity (increased NE) and low blood volume. Whether CFS patients have reduced heart size is unknown to me. Increased NE levels in CFS patients, however, appear to be caused not by increased NE production but by decreased NE clearance. Indeed NE spillover is reduced in CFS. Reduced NE clearance has not to my knowledge been addressed in deconditioning.
Some POTS and CFS patients display increased peripheral resistance (low-flow POTS) and low blood volume. These patients appear to most closely fit the profile of deconditioning induced orthostatic intolerance. Stewart, however, discounts the idea that deconditioning contributes to the orthostatic intolerance seen in this group (Stewart et. al. 2004).
High-flow POTS patients do not appear to exhibit low blood volume or increased peripheral resistance. Instead they have normal blood volume and decreased peripheral resistance. They do not appear to fit a profile of deconditioning.
It is unfortunate given the prominence given deconditioning in the pathophysiology of CFS by some that physical activity rates are rarely quantified in studies. Using subsets of mostly bed bound (deconditioned) vs. ‘active’ mostly non-bed bound (non-deconditioned) CFS patients in studies could be most helpful.
Using an epidemiological study to quantify activity levels across the CFS population would be most illuminating. Just on a personal note – since I am not deconditioned –deconditioning cannot account for the orthostatic abnormalities I have encountered.
Some work on this issue has been done. One study that measured physical rates found that deconditioning could’ve accounted for some portion of the ANS abnormalities found. Two studies that attempted to control.for the effects of deconditioning in CFS by using sedentary control groups found that deconditioning did not appear to play a significant role in the ANS abnormalities seen.
Other causes of POTS
While baroreceptor functioning in OI has been well studied and the venoarteriolar and myogenic responses are being studied, and metabolic responses advanced, there has been little discussion of the vestibular-otolith (inner ear) system. As I remember Lauren Hillenbrandt, the author of Seabiscuit, suffered from an extreme inner-ear disruption that left her virtually immobile for many years. Just to illustrate the high degree of heterogeneity found in CFS she also had a terrible reaction to sodium (!) – the very substance many doctors advise CFS patients to load up to increase blood volume.