PRIMARY OBJECTIVE:To determine the contractile strength and the (ultra)structure of single diaphragm muscle fibers of CTEPH patients SECONDARY OBJECTIVES:1. To determine whether diaphragm muscle fiber weakness is part of a generalized muscle…
ID
Source
Brief title
Condition
- Other condition
- Muscle disorders
- Pulmonary vascular disorders
Synonym
Health condition
aandoeningen van de ademhalingsspieren
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main study parameter/endpoint: Contractile force and structure of single
diaphragm muscle fibers
Secondary outcome
Secondary study parameters/endpoints: * Morphological determination of muscle
fiber cross sectional area * Muscle fiber ultrastructure by electronmicrocopy *
Posttranslational modification of contractile proteins * Diaphragm cytokine
profile * Gene expression analysis by Affymetrix
* Comparison of findings from diaphragm muscle to those from the
non-respiratory pectoralils major muscle * Correlation between diaphragm muscle
fiber strength and pulmonary function
Background summary
Pulmonary arterial hypertension (PAH) is defined by an isolated increase in
pulmonary vascular resistance and eventual right ventricular failure. Patients
with PAH are severely limited in their daily-life activities because of
dyspnoea; the sensation of dyspnoea is very uncomfortable and is an important
factor limiting exercise tolerance in these patients. The mechanism underlying
dyspnoea in PAH are incompletely understood. We propose that the pathogenesis
of this disorder is caused largely by weakening of the diaphragm muscle, the
primary inspiratory muscle.
Evidence for our proposition has been provided by recent studies suggesting
that the inspiratory muscles in PAH are (i) weakened, and (ii) subjected to
increased activity. It was shown that inspiratory pressure generation is
significantly impaired in PAH patients. For instance, volitionally assessed
maximal inspiratory mouth pressures and non-volitionally assessed
transdiaphragmatic pressures during bilateral anterior magnetic phrenic nerve
stimulation were markedly lower in PAH patients compared with control subjects.
The notion that the inspiratory muscles are more active in patients with PAH
comes from the observation that patients with PAH hyperventilate during
exercise, at rest, and even during sleep. This continuous and unrelenting
hyperventilation places an increased demand on the inspiratory muscles. Thus,
patients with PAH need to breath more with weaker inspiratory muscles. This
apparent disbalance in the demand placed on the inspiratory muscles on the one
hand and the capacity of the inspiratory muscles to generate pressure on the
other hand is likely to be a major contributor to the sensation of dyspnoea in
PAH.
Recent studies from our group support the notion of diaphragm weakness in PAH.
First, the maximal force generating capacity of intact diaphragm strips was
decreased by ~30% in rats with PAH compared to control rats. Interestingly,
this diaphragm weakness was not part of a generalized muscle weakness, as the
force generating capacity of the extensor digitorum longus muscle was preserved
in PAH rats. Secondly, post-mortem analysis of diaphragm structure in PAH
patients revealed significant muscle fiber atrophy, with no change in
quadriceps muscle. However, it is unclear whether this specific diaphragm fiber
atrophy is found only in end-stage PAH or is also present in ambulatory PAH
patients. Thus, whereas the evidence for diaphragm weakness in animal models is
accumulating, the evidence for its occurrence in patients is lacking. The few
studies directed at testing the presence of diaphragm weakness in PAH patients
indicated that twitch transdiaphragmatic pressure obtained via magnetic
phrenic-nerve stimulation was reduced; however, such reduction of twitch
pressure might very well involve phenomena that reside outside the diaphragm.
In this observational study, we propose to determine conclusively whether
diaphragm weakness occurs in patients with PAH. To this end, studies on
diaphragm muscle biopsies are indispensable: these will allow to study directly
the contractile strength of isolated muscle fibers as well as the muscle fiber
structure and the gene/protein expression profiles. The diaphragm biopsies will
be obtained during pulmonary thrombo endarterectomy (PTE) of chronic
thromboembolic pulmonary hypertension (CTEPH) patients. Thus, these biopsies
will position us uniquely to determine, for the first time, the effect of PAH
on diaphragm fiber contractile performance
Our study may provide rationale for the development of novel therapeutic
strategies aimed to modulate the respiratory frequency to reduce the overload
on the respiratory muscles, and thus also the sensation of dyspnoea in PAH
patients.
Study objective
PRIMARY OBJECTIVE:To determine the contractile strength and the
(ultra)structure of single diaphragm muscle fibers of CTEPH patients
SECONDARY OBJECTIVES:1. To determine whether diaphragm muscle fiber weakness is
part of a generalized muscle weakness, or rather is specific to the diaphragm
muscle.2. To determine whether diaphragm muscle fiber strength correlates with
pulmonary function
Note, that if these studies indicate diaphragm muscle fiber weakness in CTEPH
patients, novel therapeutic strategies aimed to reduce the respiratory
frequency, e.g. *-blockers, can be studied.
Study design
STUDY DESIGN * Prospective, observational study. * The study will be performed
in the AMC in Amsterdam.
STUDY PERIOD * The study will end when the required population size for the
CTEPH patients is reached. FLOW CHART CTEPH patients * Designated pulmonology
physicians at AMC and VUMC will identify eligible CTEPH patients who are
planned for a pulmonary thrombo endarterectomy (PTE) (~15 per year). * In case
the patient agrees with the biopsy procedure, the informed consent form is
signed. * Surgery: during PTE, the surgeon obtains a small biopsy (~50 mg) from
the diaphragm muscle at the end of the PTE procedure at the mid-costal region
of the diaphragm. Moreover, a small biopsy from the pectoralis major muscle
will be obtained; this muscle will be readily accessible due to the already
existing incision through the sternum (note that the pectoralis major biopsy
will allow to compare the findings obtained from the diaphragm to those from a
non-respiratory muscle). The surgical procedure will be attended by the
coordinating investigator or by a trained co-investigator for adequate storage
of tissue and for subsequent transportation to the Laboratory for Physiology at
VUmc. * The majority of the experiments on the biopsies will be performed at
the Laboratory for Physiology at VUmc.
Study burden and risks
The diaphragm (and pectoralis major) biopsy is very small (~50mg) and will
induce only very little and reversible damage. Previous studies performed by
the principal investigator (CAC Ottenheijm) at the Radboud University Nijmegen
Medical Centre (dept. of Pulmonary diseases) using diaphragm biopsies obtained
by comparable procedures as described here, were completed without any adverse
events(~200 biopsies). Furthermore, an evaluation of the pain experienced after
surgery by patients from whom a diaphragm biopsy was obtained (n=30) revealed
that these patients did not observe more pain than patients (n=40) from whom no
biopsy was obtained. The principal investigator (CAC Ottenheijm) was involved
in this evaluation, which was performed at the Radboud University Nijmegen
Medical Centre (dept of Pulmonary Diseases) in 2001. Thus, we are confident
that the risk for the patients are negligible and that the burden can be
considered minimal (patients are already scheduled for, and the biopsy
collection will not significantly delay the duration of, the surgery; the
average duration required for biopsy collection by the surgeon is one minute).
Importantly, the knowledge obtained by experiments on these valuable biopsies
will provide extremely precious insights into the role of diaphragm weakness in
pulmonary hypertension. This knowledge can subsequently be used for novel
treatment strategies to prevent diaphragm muscle weakness in pulmonary
hypertension patients.
The proposed research can be regarded group-related, as the participation of
subjects belonging to the group in question is indispensable. These patients
have CTEPH for years and the pulmonary function can be tested profoundly; such
research is technically and financially not feasible in laboratory animals.
De Boelelaan 1117
1081 HV Amsterdam
NL
De Boelelaan 1117
1081 HV Amsterdam
NL
Listed location countries
Age
Inclusion criteria
- Patients with chronic thromboembolic pulmonary hypertension scheduled for a pulmonary thrombo endarterectomy.
- Age: > 18 years
- Gender: Both male and female
- all ethnic backgrounds
Exclusion criteria
- COPD (GOLD stage II-IV) and CHF (NYHA class III-IV)
- Neuromuscular disease
- chronic use of corticosteroids (defined as >7.5 mg/day for at least 3 months)
- >10% weight loss within last 6 months
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
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CCMO | NL35733.018.11 |