Exercise Capacity in Congenital Heart Disease: The Role of Muscle Metabolism

A decrease in exercise capacity is widely seen in patients suffering from
various congenital heart diseases, including pulmonary arterial hypertension
(PAH), Fontan circulation or tetralogy of Fallot (TOF). Several studies have
shown lower maximal oxygen consumption compared to healthy controls.The lower
exercise capacity seen in these patients has typically been attributed to a
diminished cardiorespiratory function. As a result, scientific research into
exercise intolerance in these patients has focused mainly on the hemodynamic
and cardiorespiratory function * e.g., reduced ventricular function and cardiac
output. Patients with pulmonary arterial hypertension, tetralogy of Fallot or a
Fontan circulation are at risk of developing progressive heart failure over
time, with consequential reduction of cardiac output and peripheral
circulation. Results of recent research has shown that in addition to cardiac
output, peripheral hemodynamic and muscular changes such as atrophy,
morphological, vascular or metabolic changes may contribute to exercise
intolerance in these patients. It is, however, unclear whether these muscular
changes are an adaptation to inactivity, reduced peripheral circulation or
whether these are intrinsic abnormalities associated with the cardiac disease.
Insight in this will help assessing if and which interventions (training,
metabolic suppletion) might be beneficial in optimizing exercise tolerance, and
thus quality of life for these patients. In the proposed study, the focus will
be set at the peripheral factor thought to play an important role in the
reduced exercise tolerance in these groups of patients.
This study will, for the first time, acquire measurements of skeletal muscle
metabolic function in these groups of patients aiming to find significant
differences with healthy controls. Since no such data exist for these groups of
patients this study will be performed using sample sizes of 15 subjects for
each group.

To investigate whether patients with pulmonary arterial hypertension, Fontan
circulation and tetralogy of Fallot have an impaired skeletal muscle energy
metabolism compared to healthy controls.

A cross-sectional case-controlled study using in vivo 31P Magnetic Resonance
Spectroscopy measurements in skeletal muscle during a standardized in-magnet
whole body exercise test.

Risk assessment for all groups:
31P MRS is a save and reliable technique for patients without
contra-indications for undergoing MRI and is widely used in clinical
examination and scientific research to non-invasively obtain in-vivo
measurements of phosphorus concentrations in the human body. The combination of
in-magnet exercise testing and 31P MRS is used successfully in a previously
conducted study by van Brussel et al (2015) using adolescent subjects suffering
from an idiopathic inflammatory myopathy. A study conducted by Werkman et al
(2016) used a similar combination of in-magnet exercise and 31P MRS using
adolescent subjects with cystic fibrosis.
Patients included in the proposed study will have no contra-indications for
performing an exercise test at maximum intensity. During regular follow-up
these patients undergo a cardiopulmonary exercise test (CPET) once every two
years. Nevertheless, these patients are at higher risk when performing a
maximal exercise test compared to healthy subjects. Therefore, patients will
only perform the second exercise test, which is a maximal intra-MRI exercise
test. Also subjects will be screened for any contra-indications before
undergoing a MRI examination.


Burden for patients and controls:
Patients with pulmonary arterial hypertension, Fontan circulation and tetralogy
of Fallot undergo a CPET on a regular basis during their follow-up. Therefore,
this data already exists and a CPET does not have to be repeated for this
study. This is both patient-friendly as well as reducing the risk for
participating patients, since they don*t have to perform a maximal exercise
test. Participating patients need to visit the Neuro Imaging Center just once
for approximately 1 hour. During this visit participants have to perform an
exercise test inside a 3T MRI scanner using a MR-compatible ergometer. Personal
data acquired from the subject*s CPET will be used to recreate work load
increments on the MR-compatible ergometer resulting in exercise intensity at 0
- 100% of VO2max.
Patients with pulmonary arterial hypertension, Fontan circulation and tetralogy
of Fallot are expected to have decreased exercise capacity. According to our
hypothesis, assuming these subjects are expected to have an altered muscular
metabolism, chances are to induce muscle pain temporarily as in untrained
subjects. Since subjects undergo a short maximal exercise test, we expect
muscle pain to be minimised and therefore classify the burden for patients as
minimal. We will monitor these patients accordingly during the study period.

Since healthy subjects have no contra-indications to perform exercise at
maximal intensity we classify the burden for healthy subjects as minimal and
will not monitor these subjects during the study period.