Subgrouping Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Linking the Powerhouses of Cells to the Autonomic Nervous System (MITAP)
Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Are Autonomic Phenotypes Necessary to Clear Conflicting Results?
The goal of this study is to investigate whether mitochondrial dysfunction is present in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) by subgrouping them into autonomic phenotypes. The main questions it aims to answer are:
- When patients with ME/CFS are exposed to situations stressing the mitochondria and autonomic nervous system, is the response of their mitochondria and autonomic nervous system dependent on to which autonomic profile the patients belong?
- Is the presence of mitochondrial dysfunction dependent on to which autonomic profile a patient with ME/CFS belongs? Researchers will compare healthy control subjects because very little is known about the link between mitochondria and the autonomic nervous system. It is therefore important that this is also investigated in healthy control subjects to gain a better understanding of which biological changes are normal and which changes may be involved in the symptoms of patients with ME/CFS.
Participants will:
- Undergo an exercise test (to stress the mitochondria) and an orthostatic test (to stress the autonomic nervous system)
- Fill in questionnaires
- Undergo blood collection
Descripción general del estudio
Estado
Intervención / Tratamiento
Descripción detallada
ME/CFS is a debilitating disease with unknown pathophysiology. Mitochondrial dysfunction has been proposed as a potential pathophysiological mechanism because the mitochondria are important for energy metabolism. Moreover, patients with mitochondrial diseases experience similar symptoms as patients with ME/CFS, including fatigue, pain and autonomic symptoms. However, literature reports conflicting results regarding mitochondrial dysfunction in patients with ME/CFS. As ME/CFS patients present with a broad range of symptoms, subgrouping them might provide new insights.
Next to mitochondrial dysfunction, the involvement of the autonomic nervous system (ANS) has been proposed as it can be linked to common symptoms such as autonomic symptoms, post-exertional malaise (PEM) and cognitive impairments. Recently, ME/CFS patients were subgrouped into autonomic phenotypes. The presence of autonomic symptoms in patients with mitochondrial diseases highlights that there is a link between the mitochondria and ANS. Although the nature of this link remains unclear, a recent animal study showed that activation of adrenergic receptors - the binding sites of catecholamines (i.e. messengers of the ANS) - increased the production of reactive oxidative species, which are in turn known to influence autonomic function, damage the mitochondria, and regulate mitochondrial DNA methyltransferase (DNMT) expression. Mitochondrial DNMTs are responsible for mtDNA methylation (mtDNAm), which directly affects mitochondrial gene expression and could thus have a major impact on mitochondrial function. Interestingly, Buyn et al. reported that heart rate variability, an important marker to subgroup patients with ME/CFS into autonomic phenotypes, was associated with mtDNAm in a study investigating air pollution in 48 healthy males.
This raises the question whether mitochondrial dysfunction in patients with ME/CFS depends on to which autonomic phenotype they belong and whether this relation can be explained by mtDNAm, which is influenced by reactive oxygen species production upon adrenergic receptor activation. Consequently, this relation may lead to autonomic phenotype-dependent mitochondrial dysfunction. Hence, this project entails a cross-over study designed to clear the conflicting results regarding mitochondrial dysfunction in patients with ME/CFS by subgrouping them into autonomic phenotypes.
The investigators will perform an experimental cross-over study, in which the autonomic phenotypes will be validated and linked to additional biological information (i.e., mitochondrial (dys)function and mitochondrial DNA methylation). Study participants will visit the hospital twice with two weeks in between the visits. During each visit, autonomic, clinical and biological outcomes will be assessed before and after the experimental procedure, which include a single bout of submaximal exercise (Aerobic Power Index) to create a high-energy demand situation and stress the mitochondria, and an orthostatic test (Active Standing test) to stress the autonomic nervous system (ANS). The order of these experimental procedures is defined by randomly dividing all participants into two groups. Additionally, this project will assess the presence and severity of post-exertional malaise (PEM) 24h and 7 days after the experimental procedure via online assessments allowing the investigators to determine whether autonomic phenotype and mitochondrial function can predict PEM severity.
Tipo de estudio
Inscripción (Estimado)
Fase
- No aplica
Contactos y Ubicaciones
Ubicaciones de estudio
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Jette, Bélgica, 1090
- Universitair Ziekenhuis Brussel - Vrije Universiteit Brussel
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
- Between the ages of 18 and 70
- Speak Dutch
- ME/CFS syndrome (confirmed by a medical diagnosis)
- Healthy individuals wishing to participate must be currently pain-free and healthy (i.e., participants must not be ill during the period of study participation)
Exclusion Criteria:
- Pregnant women or women who were pregnant in the past year
- Persons with a chronic illness such as a rheumatological, endocrine, neurological or psychiatric condition
- Persons with a history of cancer or heart disease
- Persons taking medications that affect the autonomic nervous system such as beta blockers
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Ciencia básica
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación cruzada
- Enmascaramiento: Doble
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
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Experimental: Healthy controls
Study participants will visit the hospital twice with two weeks in between the visits. During each visit, autonomic, clinical and biological outcomes will be assessed before and after the experimental procedure, which include a single bout of submaximal exercise (Aerobic Power Index) to create a high-energy demand situation and stress the mitochondria, and an orthostatic test (Active Standing test) to stress the autonomic nervous system (ANS). The order of these experimental procedures is defined by randomly dividing all participants into two groups. Additionally, this project will assess the presence and severity of post-exertional malaise (PEM) 24h and 7 days after the experimental procedure via online assessments allowing us to determine whether autonomic phenotype and mitochondrial function can predict PEM severity. |
The Aerobic Power Index (API) will be used to create a high-energy demand situation and stress the mitochondria. Briefly, cycling starts at a constant rate of 70 cycles/min and workload of 25 Watt/min, increasing 25 Watt/min until the patient reaches 75% of the age-predicted maximal heart rate.
Otros nombres:
The ANS will be stressed via an Active Standing (AS) test, an ecological valid orthostatic test. Subjects will start in a supine position followed by standing up within five seconds, these instructions will be explained to the subjects prior to the start of the AS test. After standing up, the subjects need to maintain an upright posture quietly for seven minutes, afterwards the patients will be returned to the supine position.
Otros nombres:
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Experimental: ME/CFS patients
Study participants will visit the hospital twice with two weeks in between the visits. During each visit, autonomic, clinical and biological outcomes will be assessed before and after the experimental procedure, which include a single bout of submaximal exercise (Aerobic Power Index) to create a high-energy demand situation and stress the mitochondria, and an orthostatic test (Active Standing test) to stress the autonomic nervous system (ANS). The order of these experimental procedures is defined by randomly dividing all participants into two groups. Additionally, this project will assess the presence and severity of post-exertional malaise (PEM) 24h and 7 days after the experimental procedure via online assessments allowing us to determine whether autonomic phenotype and mitochondrial function can predict PEM severity. |
The Aerobic Power Index (API) will be used to create a high-energy demand situation and stress the mitochondria. Briefly, cycling starts at a constant rate of 70 cycles/min and workload of 25 Watt/min, increasing 25 Watt/min until the patient reaches 75% of the age-predicted maximal heart rate.
Otros nombres:
The ANS will be stressed via an Active Standing (AS) test, an ecological valid orthostatic test. Subjects will start in a supine position followed by standing up within five seconds, these instructions will be explained to the subjects prior to the start of the AS test. After standing up, the subjects need to maintain an upright posture quietly for seven minutes, afterwards the patients will be returned to the supine position.
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Mitochondrial function will be investigated in patients with ME/CFS compaired to healthy controls at baseline and after a physical exercise test.
Periodo de tiempo: Blood collection immediatly before procedure and after
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The primary objective is to examine the difference in mitochondrial function between 75 ME/CFS patients and 30 healthy controls. Mitochondrial function will be determined in isolated peripheral blood mononuclear cells (PBMCs). Following the manufacturer's instructions, the Seahorse XF Cell Mito Stress Test Kit (Agilent) will be used to determine the oxygen consumption rate (OCR). |
Blood collection immediatly before procedure and after
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Autonomic nervous system (ANS) function will be explored in patients with ME/CFS and healthy controls at baseline and after an orthostatic test.
Periodo de tiempo: During intervention (approximately 45 mins) in hospital
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The investigators will explore autonomc nervous system (ANS) function, enabling clinical stratification of 75 patients with ME/CFS. During the othostatic test or active standing test, the ANS will be monitored with the SOMNOTouch NIBP device, providing a non-invasive continuous blood pressure monitoring. |
During intervention (approximately 45 mins) in hospital
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Autonomic nervous system (ANS) function will be explored in patients with ME/CFS and healthy controls at baseline and after an orthostatic test.
Periodo de tiempo: During intervention (approximately 45 mins) in hospital
|
The investigators will explore autonomc nervous system (ANS) function, enabling clinical stratification of 75 patients with ME/CFS. During the othostatic test or active standing test, the ANS will be monitored with the SOMNOTouch NIBP device, providing a non-invasive continuous heart rate monitoring. |
During intervention (approximately 45 mins) in hospital
|
|
Autonomic nervous system (ANS) function will be explored in patients with ME/CFS and healthy controls at baseline and after an orthostatic test.
Periodo de tiempo: During intervention (approximately 45 mins) in hospital
|
The investigators will explore autonomc nervous system (ANS) function, enabling clinical stratification of 75 patients with ME/CFS. During the othostatic test or active standing test, the ANS will be monitored with the SOMNOTouch NIBP device, providing a non-invasive continuous arterial stiffness measurement. |
During intervention (approximately 45 mins) in hospital
|
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Prediction of severity of post-exertional malaise in patients with ME/CFS.
Periodo de tiempo: 24hours after both study visits
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Prediction of the severity of early- (24h) post-exertional malaise (PEM) in 75 patients with ME/CFS via online assessments including the Chronic Fatigue Syndrome Symptom List. |
24hours after both study visits
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Prediction of severity of post-exertional malaise in patients with ME/CFS.
Periodo de tiempo: 7 days after both study visits
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Prediction of the severity of late-onset (7 days) PEM in 75 patients with ME/CFS via online assessments including the Quality of Life Scale (quality of life, health and other areas of life, min score = not at all, max score=absolutely), Fatigue Severity Scale (min score 0=strongly disagree, max score 6=strongly agree), International Physical Activity Questionnaire and Chronic Fatigue Syndrome Symptom List. |
7 days after both study visits
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Colaboradores e Investigadores
Patrocinador
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades Neuroinflamatorias
- Enfermedades musculoesqueléticas
- Enfermedades del Sistema Nervioso
- Enfermedades Musculares
- Procesos Patológicos
- Encefalomielitis
- Enfermedades Neuromusculares
- Enfermedad crónica
- Atributos de la enfermedad
- Condiciones Patológicas, Signos y Síntomas
- Síndrome de Fatiga Crónica
- Técnicas de investigación
- Técnicas y procedimientos de diagnóstico
- Diagnóstico
- Técnicas de diagnóstico, sistema respiratorio
- Técnicas de diagnóstico, cardiovascular
- Pruebas de funciones cardíacas
- Pruebas de funciones respiratorias
- Ergometría
- Prueba de ejercicio
Otros números de identificación del estudio
- EC-2023-391
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Información sobre medicamentos y dispositivos, documentos del estudio
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