The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure
| Status: | Enrolling by invitation |
|---|---|
| Conditions: | Fibromyalgia, Infectious Disease, Neurology, Pulmonary |
| Therapuetic Areas: | Immunology / Infectious Diseases, Neurology, Pulmonary / Respiratory Diseases, Rheumatology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 3/2/2019 |
| Start Date: | March 8, 2019 |
| End Date: | October 15, 2019 |
Chronic fatigue syndrome (CFS), otherwise known as 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 a level 3 CPET 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 CFS/ME 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
CFS/ME 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.
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 a level 3 CPET 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 CFS/ME 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
CFS/ME 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 the investigators' study is that small fiber polyneuropathy is a cause of
low biventricular filling pressures/preload failure of the heart and poor oxygen extraction
in the muscle bed, leading to symptoms of exertional intolerance and post-exertional malaise.
The objective of this study is to examine the exercise response to pharmacologic cholinergic
stimulation in patients already undergoing a clinically indicated level 3 cardiopulmonary
exercise test (CPET). This will be achieved by inhibiting acetylcholinesterase with
pyridostigmine, thus increasing acetylcholine levels, downstream levels of norepinephrine,
and enhanced vascular regulation.
To test our hypothesis, the investigators propose the following specific aims:
1. Define the gas exchange responses, such as oxygen uptake, end-tidal carbon dioxide
(CO2), and ventilatory efficiency to pyridostigmine
2. Define the hemodynamic responses, such as right atrial pressures, pulmonary capillary
wedge pressures and cardiac output to pyridostigmine
3. Evaluate skeletal muscle oxygen extraction to pyridostigmine
These determinations will occur during a clinically indicated level 3 CPET, which includes
exercising on a stationary bicycle 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 level
3 CPET. Recovery cycling will be performed after a rest period of 50 minutes. This will be
administered in a double-blind, randomized control trial.
low biventricular filling pressures/preload failure of the heart and poor oxygen extraction
in the muscle bed, leading to symptoms of exertional intolerance and post-exertional malaise.
The objective of this study is to examine the exercise response to pharmacologic cholinergic
stimulation in patients already undergoing a clinically indicated level 3 cardiopulmonary
exercise test (CPET). This will be achieved by inhibiting acetylcholinesterase with
pyridostigmine, thus increasing acetylcholine levels, downstream levels of norepinephrine,
and enhanced vascular regulation.
To test our hypothesis, the investigators propose the following specific aims:
1. Define the gas exchange responses, such as oxygen uptake, end-tidal carbon dioxide
(CO2), and ventilatory efficiency to pyridostigmine
2. Define the hemodynamic responses, such as right atrial pressures, pulmonary capillary
wedge pressures and cardiac output to pyridostigmine
3. Evaluate skeletal muscle oxygen extraction to pyridostigmine
These determinations will occur during a clinically indicated level 3 CPET, which includes
exercising on a stationary bicycle 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 level
3 CPET. Recovery cycling will be performed after a rest period of 50 minutes. This will be
administered in a double-blind, randomized control trial.
Inclusion Criteria:
- Low filling pressures during a clinically indicated invasive cardiopulmonary exercise
test
Exclusion Criteria:
- Submaximal testing
- Exercise induced pulmonary arterial hypertension
- Exercise induced pulmonary venous hypertension
- Severe hypotension during or after test
- Refractory arrhythmia during or after test
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