The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

The Exercise Response to Pharmacologic Cholinergic Stimulation in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Myalgic encephalomyelitis/Chronic fatigue syndrome (ME/CFS), otherwise known as Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME), is an under-recognized disorder whose cause is not yet understood. Suggested theories behind the pathophysiology of this condition include autoimmune causes, an inciting viral illness, and a dysfunctional autonomic nervous system caused by a small fiber polyneuropathy. Symptoms include fatigue, cognitive impairments, gastrointestinal changes, exertional dyspnea, and post-exertional malaise. The latter two symptoms are caused in part by abnormal cardiopulmonary hemodynamics during exercise thought to be due to a small fiber polyneuropathy. This manifests as low biventricular filling pressures throughout exercise seen in patients undergoing an invasive cardiopulmonary exercise test (iCPET) along with small nerve fiber atrophy seen on skin biopsy. After diagnosis, patients are often treated with pyridostigmine (off-label use of this medication) to enhance cholinergic stimulation of norepinephrine release at the post-ganglionic synapse. This is thought to improve venoconstriction at the site of exercising muscles, leading to improved return of blood to the heart and increasing filling of the heart to more appropriate levels during peak exercise. Retrospective studies have shown that noninvasive measurements of exercise capacity, such as oxygen uptake, end-tidal carbon dioxide, and ventilatory efficiency, improve after treatment with pyridostigmine. To date, there are no studies that assess invasive hemodynamics after pyridostigmine administration. It is estimated that four million people suffer from ME/CFS worldwide, a number that is thought to be a gross underestimate of disease prevalence. However, despite its potential for debilitating symptoms, loss of productivity, and worldwide burden, the pathophysiology behind ME/CFS remains unknown and its treatment unclear. By evaluating the exercise response to cholinergic stimulation, this study will shed further light on the link between the autonomic nervous system and cardiopulmonary hemodynamics, potentially leading to new therapeutic targets.

The hypothesis of our study is that hemodynamic, ventilatory and oxygen exchange variables such biventricular filling pressures and systemic oxygen extraction can be improved by cholinergic stimulation in patients with ME/CFS. The objective of this study is to examine the exercise response to pharmacologic cholinergic stimulation in ME/CFS patients already undergoing a clinically indicated invasive cardiopulmonary exercise test (iCPET). This will be achieved by inhibiting acetylcholinesterase with pyridostigmine, thus increasing acetylcholine levels, downstream levels of norepinephrine, and enhancing vascular regulation. To test our hypothesis, we propose the following specific aims: Define the response of peak oxygen uptake(VO2) to pyridostigmine. Define the gas exchange responses, such as end-tidal carbon dioxide(CO2) and ventilatory efficiency to pyridostigmine. Define the hemodynamic responses, such as right atrial pressures, pulmonary artery pressure, pulmonary capillary wedge pressures, cardiac output, heart rate, stroke volume, pulmonary vascular resistance and systemic vascular resistance to pyridostigmine. Evaluate the response of skeletal muscle oxygen extraction and lactate to pyridostigmine. These determinations will occur during a clinically indicated iCPET, which includes exercising on a stationary cycle with a right heart catheter (RHC) and a radial arterial line in place. To stimulate the cholinergic response, a single dose of an oral acetylcholinesterase inhibitor, pyridostigmine, versus placebo will be given after the iCPET. Recovery cycling will be performed after a rest period of 50 minutes. This will be administered in a randomized, double-blind, placebo-controlled trial.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Chronic Fatigue Syndrome, Myalgic Encephalomyelitis, Exercise Intolerance, Dysautonomia, Low Ventricular Filling Pressures (Preload Failure), Postural Orthostatic Tachycardia Syndrome, Orthostatic Hypotension, Fibromyalgia

Myalgic encephalomyelitis/Chronic fatigue syndrome, Myalgic encephalomyelitis, Chronic fatigue syndrome, Pyridostigmine, Exercise Intolerance, Invasive Cardiopulmonary Exercise Test

Subjects will be assigned randomly to receive either pyridostigmine or placebo, both study participants and investigators will be blinded.

Define the response of oxygen uptake to pyridostigmine expressed both as mL/min and mL/min/kg. The difference in peak oxygen uptake from first iCPET to second iCPET. Research has shown that ME/CFS patients have inability to reproduce results on two consecutive cardiopulmonary exercise tests(CPET). Traditionally this is demonstrated with a two-day CPET protocol, but in this study we investigate the acute effects of pyridostigmine administration on the early stages of post exertional malaise(PEM).

Arterial and mixed-venous blood gases and pH are measured at peak exercise and Qc is calculated using the direct Fick principle Qc=VO2/(Ca-Cv). Change in peak Qc between first and second iCPETs is measured in L/min.

Peak versus rest change in cardiac output expressed in L/min between first and second iCPETs. Cardiac output is determined using the direct Fick principle.

Difference in peak arterial-venous oxygen content difference normalized to hemoglobin (Ca-vO2)/[Hgb] between first and second iCPETs

Difference in perception of fatigue at peak exercise between first and second iCPETs. Used Borg Scale 0 (minimal) to 10 (maximal).

Difference in perceived dyspnea at peak exercise between first and second iCPETs. Used Borg Scale 0 (minimal) to 10 (maximal).

Inclusion Criteria: Meets the Institute of Medicine (IOM) criteria for ME/CFS Completing the clinically indicated invasive cardiopulmonary exercise test (iCPET) Exclusion Criteria: Obesity (BMI > 30 kg/m2) Non-controlled asthma Anemia (Hb < 10 g/dl) Active or treated cancer History of interstitial lung disease (ILD) Chronic obstructive pulmonary disease (COPD) Pulmonary hypertension (PH) Congestive heart failure (CHF) Active arrhythmias Valvular heart disease Coronary artery disease (CAD) Other conditions that could predict a limitation or not completion of the study. Pregnancy Submaximal testing in clinically indicated iCPET Pulmonary mechanical limitation to exercise in clinically indicated iCPET. Pulmonary arterial hypertension in clinically indicated iCPET. Pulmonary venous hypertension in clinically indicated iCPET. Exercise induced pulmonary arterial hypertension in clinically indicated iCPET. Exercise induced pulmonary venous hypertension in clinically indicated iCPET. Persistent hypotension during or after the clinically indicated iCPET. Refractory arrhythmia during or after the clinically indicated level 3 CPET.

Individual participant data that underlie the results reported in this article, after de-identification(text, tables, figures, and appendices) will be available for researchers who provide a methodologically sound proposal to achieve aims in the approved proposal.

Proposals should be directed to jsquires1@bwh.harvard.edu. To gain access, data requestors will need to sign a data access agreement.

Joseph P, Pari R, Miller S, Warren A, Stovall MC, Squires J, Chang CJ, Xiao W, Waxman AB, Systrom DM. Neurovascular Dysregulation and Acute Exercise Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Placebo-Controlled Trial of Pyridostigmine. Chest. 2022 Nov;162(5):1116-1126. doi: 10.1016/j.chest.2022.04.146. Epub 2022 May 6.