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 ∼50% of POTS and fibromyalgia patients.

Research Question

Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?

Study Design and Methods

We analyzed 1516 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 mmHg, results from 160 patients meeting ME/CFS criteria who had skin-biopsy test results were compared to 36 controls. Rest-to-peak changes in cardiac output (Qc) were compared to 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±2 vs. 8.3±1.5; P<0.0001) and peak VO 2 (80%±21 vs. 101.4%±17; P<0.0001) than controls. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4±19% vs. 99.5±23.8% vs. 99.9±19.5% predicted; P<0.01). In contrast, systemic oxygen extraction was impaired in high-flow versus low and normal-flow participants (0.74±0.1% vs. 0.88±0.11 vs. 0.86±0.1; P<0.0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% was consistent with SFN (epidermal innervation ≤5.0% of predicted; P < 0.0001). Denervation severity did not correlate with exertional measures.

Interpretation

These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance–depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.

Abbreviation:

Ca-vO2/[Hb] ( Arterial–mixed venous oxygen content difference/hemoglobin concentration), iCPET ( Invasive cardiopulmonary exercise test), NAM ( National Academy of Medicine, formerly the Institute of Medicine), ME/CFS ( Myalgic encephalomyelitis/chronic fatigue syndrome), MM ( Mitochondrial myopathy), mPAP ( Mean pulmonary artery pressure), PAWP ( Pulmonary arterial wedge pressure), PLF ( Preload failure), POTS ( Postural orthostatic tachycardia syndrome), PVR ( Pulmonary vascular resistance), RAP ( Right atrial pressure), Qc ( Cardiac output), SFN ( Small fiber neuropathy), VO2 ( Oxygen uptake), vPO2 ( Venous oxygen tension)

Source: Phillip Joseph, MD, Carlo Arevalo, MD, Rudolf K.F. Oliveira, MD, PhD, Donna Felsenstein, MD, Anne Louise Oaklander, MD, PhD, David M. Systrom, MD. Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. February 09, 2021. DOI:https://doi.org/10.1016/j.chest.2021.01.082 https://journal.chestnet.org/article/S0012-3692(21)00256-7/fulltext

Cardiac dysfunction and orthostatic intolerance in patients with myalgic encephalomyelitis and a small left ventricle

Abstract:

The etiology of chronic fatigue syndrome (CFS) is unknown. Myalgic encephalomyelitis (ME) has been recently postulated to be the cause of CFS. Orthostatic intolerance (OI) has been known as an important symptom in predicting quality of life in CFS patients. Cardiac function may be impaired in patients with ME.

The presence or absence of OI was determined both symptomatically and by using a 10-min stand-up test in 40 ME patients. Left ventricular (LV) dimensions and function were determined echocardiographically in the ME patients compared to 40 control subjects.

OI was noted in 35 (97%) of the 36 ME patients who could stand up quickly. The mean values for the cardiothoracic ratio, systemic systolic and diastolic pressures, LV end-diastolic diameter (EDD), LV end-systolic diameter, stroke volume index, cardiac index and LV mass index were all significantly smaller in the ME group than in the controls. Both a small LVEDD (<40 mm, 45 vs. 3%) and a low cardiac index (<2 l/ min/mm2, 53 vs. 8%) were significantly more common in the ME group than in the controls. Both heart rate and LV ejection fraction were similar between the groups.

In conclusion, a small LV size with a low cardiac output was common in ME patients, in whom OI was extremely common. Cardiac dysfunction with a small heart appears to be related to the symptoms of ME.

 

Source: Miwa K. Cardiac dysfunction and orthostatic intolerance in patients with myalgic encephalomyelitis and a small left ventricle. Heart Vessels. 2015 Jul;30(4):484-9. doi: 10.1007/s00380-014-0510-y. Epub 2014 Apr 16. https://www.ncbi.nlm.nih.gov/pubmed/24736946

 

Physiological responses to incremental exercise in patients with chronic fatigue syndrome

Abstract:

PURPOSE: The purpose of this investigation was to characterize the physiological response profiles of patients with chronic fatigue syndrome (CFS), to an incremental exercise test, performed to the limit of tolerance.

METHODS: Fifteen patients (12 women and three men) who fulfilled the case definition for chronic fatigue syndrome, and 15 healthy, sedentary, age- and sex-matched controls, performed an incremental progressive all-out treadmill test (cardiopulmonary exercise test).

RESULTS: As a group, the CFS patients demonstrated significantly lower cardiovascular as well as ventilatory values at peak exercise, compared with the control group. At similar relative submaximal exercise levels (% peak VO(2)), the CFS patients portrayed response patterns (trending phenomenon) characterized, in most parameters, by similar intercepts, but either lower (VCO(2), HR, O(2pulse), V(E), V(T), PETCO(2)) or higher (B(f), V(E)/VCO(2)) trending kinetics in the CFS compared with the control group. It was found that the primary exercise-related physiological difference between the CFS and the control group was their significantly lower heart rate at any equal relative and at maximal work level. Assuming maximal effort by all (indicated by RER, PETCO(2), and subjective exhaustion), these results could indicate either cardiac or peripheral insufficiency embedded in the pathology of CFS patients.

CONCLUSION: We conclude that indexes from cardiopulmonary exercise testing may be used as objective discriminatory indicators for evaluation of patients complaining of chronic fatigue syndrome.

 

Source: Inbar O, Dlin R, Rotstein A, Whipp BJ. Physiological responses to incremental exercise in patients with chronic fatigue syndrome. Med Sci Sports Exerc. 2001 Sep;33(9):1463-70. http://www.ncbi.nlm.nih.gov/pubmed/11528333