Orthostatic Intolerance in Chronic Fatigue Syndrome (ME/CFS) IV: A Biomarker? plus Conclusions, Link, etc. (Feb 2004/2007)

A Biomarker for Chronic Fatigue Syndrome (ME/CFS?)

Naschitz and colleagues in Israel noticed in 2000 – to their surprise – that CFS patients had a specific pattern of ‘cardiovascular reactivity’ in response to tilt tests. They used statistical analyses of common measures of autonomic function (heart rate, blood pressure) obtained during tilt table testing to create a ‘hemodynamic instability score’. These scores enabled researchers to differentiate CFS patients from a wide variety of control groups. This study was notable in the large number of control groups tested.

The authors posit that the very complex interactions between the heart and the neuro-endocrine systems that are involved in baroreflex activation give rise to specific disease patterns in certain illnesses.

CFS patients versus

Sensitivity %


All groups



Non-CFS but fatigued






Mediterranean fever






Neurally mediated syncope (fainting)



Healthy controls



Generalized anxiety disorder


Not significant


With the notable (and rather surprising?) exception of the patients with generalized anxiety disorder, this test was remarkably effective. Forty-five percent of patients with the anxiety disorder had similar HIS scores. The authors gave no indication why CFS patients had similar scores to anxiety patients. Since anxiety disorder is linked to over activity of the sympathetic nervous system perhaps this is not a surprising finding.

In another study a specific cutoff point for fractal HRV had a high sensitivity (90%) and specificity (72%) when it was used to discriminate CFS patients from controls. It appears that measures of ANS function during tilt may have a high discriminatory value; i.e. may provide a biomarker and possibly – dare one say it? – afford CFS some legitimacy.

One interesting and very promising side notes of this study was its restriction to patients with mild to moderate CFS. Patients with more severe CFS were unable to complete the 30 minute Tilt table test without fainting. Thus this finding is probably quite robust.


The extent and significance of orthostatic intolerance in CFS is still unclear. With some exceptions we find the same heterogeneity in test results that plagues other research efforts into CFS. The rapidly evolving nature of the field of orthostatic intolerance and the heterogeneous nature of the CFS patient population guarantee a  certain lack of clarity will prevail. In particular, tests of BP and the Valsalva maneuver have differed between groups.

Estimates of orthostatic intolerance (neurally mediated hypotension, POTS, etc.) in CFS patients have ranged from over 90% to less than 20%. The latest research indicates approximately 40% of CFS patients are believed to fulfill the parameters for POTS.

Perhaps the most significant finding regarding OI prevalence in CFS, however, was the increased rate of symptoms for all CFS patients undergoing TILT tests regardless of whether they meet the stated definition of OI (Poole et. al. 2000). As in other fields of CFS research, studies have been plagued by small sizes, different methodologies and parameters and poorly defined CFS and control patient sets.

Some consistencies have, however, emerged. CFS typically display ANS abnormalities when challenged, not at rest. CFS patients also consistently display significantly increased heart rates and significantly decreased heart rate variability.

These findings suggest over activation of the sympathetic nervous system (‘fight or flight’) and under activation of the parasympathetic nervous system (rest and digest) is occurring. A subset of CFS patients appear to have reduced blood volumes. When CFS patients have orthostatic intolerance it is generally in the form of POTS.

The splintering of the POTS patients into three coherent subsets – all of which occur in CFS – further refines (and complicates) our understanding of the orthostatic dysfunction occurring. It is generally agreed POTS occurs when insufficient venous flows of blood to the heart during standing triggers a compensatory response consisting of an increased heart beat.

The proximate causes of the increased blood pooling are varied; they include inadequate peripheral vasoconstriction in the legs possibly caused by denervation; increased local blood blows in the legs caused by increased levels of a local vasodilating agent such as NO or acetylcholine and inadequate vaso and venoconstriction in the abdomen. Symptoms appear to be exacerbated by reduced blood volume in a subset of CFS patients.

The ultimate causes of these dysfunctions are unknown but may include pathogen induced vasodilation of the peripheral blood vessels, endothelial dysfunction, blunted HPA axis activity or others. While deconditioning can cause POTS, no studies indicate deconditioning plays a major role in the orthostatic intolerance seen in CFS.

A most promising development in this field is the possible development of a biomarker created using heart rate and blood pressure changes during a tilt test. This test, which was surprisingly effective in differentiating CFS patients from a variety of control groups, suggested a distinctive pattern of ANS dysfunction occurred in CFS patients.

While orthostatic intolerance does not appear to be primary in CFS, its prevalence in CFS and similar symptoms indicate it is an integral part of it. It is likely the disruptions underlying OI will be found to some extent in most CFS patients whether they meet the standards for OI or not.

Uncovering the source of the OI seen in CFS will undoubtedly contribute greatly to our understanding of the pathophysiology of CFS. Thankfully this is one of the few areas of ‘CFS’ research that has some funding; several projects are underway that should illuminate this most intriguing aspect of CFS in the near future.>

(Produced Fall 2004, brief update 2007)


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