Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in approximately 50% of POTS and fibromyalgia patients.RESEARCH QUESTION: Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN? STUDY DESIGN AND METHODS: We analyzed 1,516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mm Hg, results from 160 patients meeting ME/CFS criteria who had skin biopsy test results were compared with 36 control subjects. Restto-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO 2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO 2 tertiles.RESULTS: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 AE 2 vs 8.3 AE 1.5; P < .0001) and peak VO 2 (80% AE 21% vs 101.4% AE 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% AE 19% vs 99.5% AE 23.8% vs 99.9% AE 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low-and normal-flow participants (0.74% AE 0.1% vs 0.88 AE 0.11 vs 0.86 AE 0.1; P < .0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% were consistent with SFN (epidermal innervation #5.0% of predicted; P < .0001). Denervation severity did not correlate with exertional measures.

Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome–Results From Open-Label Cyclophosphamide Intervention Study

“…The clinical symptoms of ME/CFS suggest inadequate regulation of autonomic functions including blood flow. In a recent study of invasive cardiopulmonary exercise testing in upright position in ME/CFS patients, two types of peripheral neurovascular dysregulation were demonstrated; reduced cardiac output due to impaired venous return with low ventricular filling pressure ("preload failure"), and arterio-venous shunting with impaired peripheral oxygen extraction (53). These physiological changes are plausible contributors to several hallmark symptoms of ME/CFS, such as post-exertional malaise, and are associated with microcirculatory dysregulation, possibly related to small-fiber neuropathy (53).…”

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

“…Exercise studies have indicated that low oxygen uptake by muscle cells, and insufficient metabolic adaptations to incremental exercise, are linked to exertion intolerance in patients with ME/CFS ( 75 – 78 ). Reduced tissue perfusion through dysautonomia and/or inadequate autoregulation of blood flow have been found in persons with unexplained exertion intolerance, possibly via mechanisms of endothelial and microcirculatory dysfunction effects on vascular endothelium ( 66 , 76 , 77 , 79 , 80 ). In summary, we find that the metabolic changes in patients with ME/CFS are compatible with disrupted energetics enforced by tissue hypoxia on exertion.…”

Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

“…Impaired oxygen extraction in muscles during exercise tests has also been demonstrated by noninvasive measurements (13). According to the CPET test results, the circulatory disturbances could not be explained by deconditioning in patients with orthostatic intolerance and reduced cerebral blood flow upon head-up tilt testing (14) nor in patients with exercise intolerance and low biventricular filling pressures or impaired AV oxygen extraction (12). It would, however, be expected that physical deconditioning and other effects of long-lasting disease may contribute to symptom worsening.…”

“…We speculate that these illnesses could be associated with a pattern of autoantibodies occurring after triggers such as systemic infections (21), but not resolving properly over time. In ME/CFS, a persistent functional autoantibody pattern could disturb blood itoring, a subgroup of the patients had reduced right atrial pressure and venous return (preload failure), with reduced cardiac output and reduced peak oxygen uptake on exertion (12). Other ME/CFS patients showed evidence of microcirculatory disturbances with impaired peripheral oxygen extraction, compatible with arteriovenous (AV) shunting and possibly related to neurovascular dysregulation and small fiber neuropathy (12).…”

“…In ME/CFS, a persistent functional autoantibody pattern could disturb blood itoring, a subgroup of the patients had reduced right atrial pressure and venous return (preload failure), with reduced cardiac output and reduced peak oxygen uptake on exertion (12). Other ME/CFS patients showed evidence of microcirculatory disturbances with impaired peripheral oxygen extraction, compatible with arteriovenous (AV) shunting and possibly related to neurovascular dysregulation and small fiber neuropathy (12). Impaired oxygen extraction in muscles during exercise tests has also been demonstrated by noninvasive measurements (13).…”