Ammendment of protocol: Intravenous iron treatment in iron deficient patients with idiopathic pulmonary arterial hypertension. Title amendment: Skeletal muscle strength in healthy persons and patients with pulmonary hypertension

Patients with pulmonary arterial hypertension (PAH) develop progressive right
heart failure which eventually will lead to death. During the progression of
the disease the physical performance of these patients deteriorates.
Maintaining there exercise capacity is a major goal in PAH treatment. Iron
treatment is known to have a positive effect on physical performance in
patients with left heart failure and iron deficiency. Whether this is also
effective in patients with right heart failure (PAH) and iron deficiency is
until now not investigated.

Amendment: Preliminary results of the iron study (NL33043.029.10) have revealed
that administration of iron improves the exercise capacity of iron deficient
PAH patients. However, no change in maximal force, calcium sensitivity and
passive force was measured in the biopsies of the quadriceps muscle (ex vivo).
With the quadriceps biopsies we are the first to measure muscle strength and
are able to show that although there
might be atrophy of the muscle, the intrinsic properties of the sarcomeres
seems to be intact. The contradiction between exercise capacity and muscle
strength is interesting and requires further investigation. Therefore, we would
like to include healthy age matched controls to further increase our
understanding of the correlation between in vivo exercise capacity and ex vivo
muscle strength.

To evaluate the effects of intravenous iron suppletion in iron deficient PAH
patients.

Amendment: to compare exercise capacity and isolated muscle strength in IPAH
patients and healthy controls

In this study, 30 idiopathic IPAH patients with iron deficiency will be
included. The patients must have stable disease for at least 3 months under
optimal treatment. At baseline 6MWD, maximal and submaximal (75% Wmax)
cardiopulmonary exercise testing (CPET), and a biopsy of the quadriceps muscle
are performed. Also blood iron parameters are measured and hepcidin, IL-6 and
TNF-* levels are determined, a QOL questionnaire has to be filled in, and NYHA
functional class is established. Cardiac function is measured by MRI. Patients
receive iron infusions weekly until iron levels are restored (correction
phase), followed by monthly infusions to maintain iron levels (maintenance
phase). The endpoint is 12 weeks after the iron infusion and all baseline
measurements are repeated.

Amendment: 10 healthy control subjects visit the hospital for maximal and
submaximal CPET, general lab measurements and quadricepsbiopsy

Included patients receive a high dose iron infusion of 1000mg iron in 250 ml
NaCl 0.9%. Before iron infusion, blood samples are drawn to measure iron
parameters. Four weeks after iron administration, iron parameters are measured
in the general practitioners setting. When iron parameters are still under
normal values, a repeat infusion will be given of 500 mg iron (equals 10 ml
Ferinject).

Amendment: not applicable

The patients will be hospitalised two days at the beginning and two days at the
end of the study to perform the exercise and strength tests, six minute walking
distance and for biopsy of the quadriceps muscle. Also NYHA functional class
will be determined and a QOL questionnaire has to be filled in. Patients then
receive a high dose iron infusion (1000mg iron). They will get an intravenous
line in the elbow for iron infusion. This intravenous line gives some small
discomfort for the patients, however this is a very regularly done procedure.
The risks of Ferinject infusion are headache, gastrointestinal complaints
(nausea, vomiting), fever, hypotension, muscular pain, paresthesia, urticaria,
anaphylactic reactions and phlebitis at injection side or discomfort of the
infusion fluid. Around administration, patients are extensively monitored.
We hypothesize that iron deficient IPAH patients will benefit from iron
treatment with improved exercise capacity.

Amendment: The control patients will be in the hospital for one day in this
study to perform the exercise tests, and for biopsy of the quadriceps muscle