Endothelial dysfunction in ME/CFS – and cytochrome CYP2C9

Endothelial dysfunction in ME/CFS

Vascular endothelial dysfunction has been measured directly in ME/CFS patients. This information is from: International Journal of Cardiology, 2012 Feb 9; 154(3):335–6

ME Research UK has described the study here: Large and small artery endothelial dysfunction in chronic fatigue syndrome :

• Flow‐mediated dilatation was assessed using ultrasound to measure the percentage increase in brachial artery diameter during the hyperaemia following 5 minutes of ischaemia in 30 ME/CFS patients and 27 healthy controls. 
• In addition, post‐occlusive reactive hyperaemia was assessed in 9 ME/CFS patients and 9 healthy controls using laser Doppler flowmetry to measure the increase in forearm skin microcirculation after 5 minutes of ischaemia.
• Flow‐mediated dilatation was significantly lower in the ME/CFS group than in the control group.
• Post‐occlusive reactive hyperaemia in the forearm microcirculation was also significantly lower in ME/CFS patients.

(Read more about the measurement technique: Measurement of endothelial function by brachial artery flow-mediated vasodilation and Post occlusive reactive hyperemia (PORH))


This study is indeed interesting, because endothelial dysfunction in ME/CFS patients is also mentioned in this presentation from Øystein Fluge from Haukeland University Hospital: B-lymphocyte depletion with Rituximab induction and maintenance in ME/CFS. A multicenter, randomised, double-blinded and placebo-controlled study.

Wikipedia about Endothelial dysfunction:

• In human vascular diseases, endothelial dysfunction is a systemic pathological state of the endothelium (the inner lining of blood vessels) and can be broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium.
• Endothelial dysfunction can result from and/or contribute to several disease processes, as occurs in hypertension,hypercholesterolaemia, diabetes, septic shock, Behcet's disease, and it can also result from environmental factors, such as from smoking tobacco products and exposure to air pollution
• Nitric Oxide (NO) reduction is considered the hallmark of endothelial dysfunction. A key and quantifiable feature of endothelial dysfunction is the inability of arteries and arterioles to dilate fully in response to an appropriate stimulus that stimulates release of vasodilators from the endothelium like NO. Endothelial dysfunction is commonly associated with decreased NO bioavailability, which is due to impaired NO production by the endothelium and/or increased inactivation of NO by reactive oxygen species.

Cytochrome P450 2C9

The human body is designed with redundancy - when a function fails, then another function will support or take over.

In this study an inhibition of nitric oxide synthase (NOS) occurs and nitric oxide production is compromised, then a CYP-dependent vasodilator mechanism is been observed :

Cytochrome P450 2C9 plays an important role in the regulation of exercise-induced skeletal muscle blood flow and oxygen uptake in humans

(So if vasodilation is somehow impaired in ME/CFS patient, I hypothesize that the use of Cytochrome P450 2C9 (CYP 2C9) could be a useful redundancy???)

But “too much vasodilation” can be damaging, if it is after lack of oxygen in the tissue – like reperfusion injury in myocardial infarction (heart attack).

Wikipedia about reperfusion injury:

• Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function.

This article, Fundamentals of Reperfusion Injury for the Clinical Cardiologist, informs “Decreasing reperfusion injury via modulation of nitric oxide bioavailability is an active area of research.“

You could get the thought that the other redundancy system might also be a target of modulation. And this is in fact the case:

Inhibition of cardiac cytochrome P450: a new approach to cardiac ischaemia and reperfusion damage:

“Inhibition of CYP2C9 is a promising approach for the treatment of myocardial infarction, and should be further developed.”

CYP2C9 is drug-metabolizing cytochrome, and the inhibition in this study was done be giving the antibiotic chloramphenicol.

There are different genetic types of CYP2C9, and people with certain types of CYP2C9 is poor drug metabolizers. This article Cytochrome P450 2C9-CYP2C9 gives the information that, the haplotypes CYP2C9*2 and CYP2C9*3 have decreased metabolism for some drugs.

But what happens in the endothelial cells in people with CYP2C9*2 and CYP2C9*3 ?

From this article, CYP2C9*2 and CYP2C9*3 Alleles Confer a Lower Risk for Myocardial Infarction, we get the information:

• Both the CYP2C9*2 and theCYP2C9*3 allele lead to decreased enzyme activity.
• Endothelial cells synthesize and release endothelium-derived hyperpolarizing factor (EDHF), which causes hyperpolarization of underlying vascular smooth muscle cells via activation of Ca2+-activated K+ channels.
• Decreased concentrations of CYP2C attenuate EDHF-mediated vascular response in porcine coronary artery endothelial cells.
• The researchers hypothesized that reduced CYP2C9 activity attributable to genetic alterations may modulate vascular function and influence the risk of vascular disease.
• But, in the present study, a protective effect was observed. This was surprising because one would have expected carriers of CYP2C9 mutant alleles to exhibit reduced CYP2C9 metabolic capacity, leading to decreased endothelial EDHF synthesis and an increased risk for Myocardial Infarction. However, CYP enzymes also contribute to oxidative stress through the formation of oxygen radicals in the vasculature.

Endothelial dysfunction in ME/CFS - and cytochrome CYP2C9

Let us take this knowledge a little further in a hypothesis.

If ME/CFS patients have endothelial dysfunction and reduced decreased NO bioavailability, - do they need to borrow a little redundancy from a ”strong” CYP2C9?

But what if ME/CFS patients have decreased CYP2C9 enzyme activity?

Both the CYP2C9*2 and theCYP2C9*3 allele lead to decreased enzyme activity.

ME/CFS patients is known to have low tolerance for drugs, and some patients also have the co-morbidity Mutiple Chemical Sensitivity (MCS). Do CYP2C9*2 and the CYP2C9*3 occur more frequently in ME/CFS/MCS?

This study, Xenobiotic Sensor- and Metabolism-Related Gene Variants in Environmental Sensitivity-Related Illnesses: A Survey on the Italian Population, compared the frequency of gene polymorphisms of selected cytochrome P450 (CYP) metabolizing enzymes in the three cohorts of 156 diagnosed MCS, 94 suspected MCS, and 80 FM/FCS patients:

• The researchers found significantly higher frequency of polymorphisms CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2D6*4 and CYP2D6*41 in patients compared with controls. 
• Moreover, the compound heterozygosity for CYP2C9*2 and *3 variants was useful to discriminate between either MCS or FM/CFS versus suspected MCS.

…we need more research in this area!

And I need more pieces to the puzzle...

If ME/CFS patients have endothelial dysfunction and reduced decreased NO bioavailability,  Why do patients not have hypertension?

And if  NO bioavailability and if  EDHF endothelium-dependent relaxation both are compromised in ME/CFS patients - do they get hypertension?

Most ME/CFS patients I know have normotension or hypotension. And where do POTS fit in? Is it the blood-regulation there has gone wrong, and not the "tension"?

Can someone help me to an answer?

Wikipedia on EDHF and hypertension: In mice lacking both eNOS and COX-1, EDHF-mediated response appeared to compensate the absence of endothelial NO in females but not in males. In female mice, the deletion of eNOS and COX-1 did not affect mean arterial blood pressure, while males become hypertensive. In accordance with this study, EDHF has been suggested to be more important in female arteries to confer endothelium-dependent dilatation, while NO played a predominant role in arteries from males.

Is the answer in the caveolae?

Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation

Is the answer an auoimmune reaction against the caveolae?

Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome