T1 mapping and exercise 31P-MR spectroscopy for cardiomyopathy phenotyping

This research protocol aims to explore two novel magnetic resonance imaging
(MRI) techniques to visualize cardiac muscle properties and function that
cannot be characterized properly with commercially available pulse sequences.
MRI is the gold standard imaging modality for patients with dysfunction of the
cardiac muscle, called cardiomyopathy. In many patients, the exact cause of
cardiomyopathy cannot be diagnosed because current imaging modalities have
important limitations. One of these limitations is the fact that mild and
diffuse myocardial fibrosis cannot be visualized, even though this is an
important hallmark of cardiomyopathy. A second limitation is the fact that
myocardial energy metabolism cannot be quantified noninvasively during
physiological exercise. Potential solutions for these limitations are a novel
MRI technique called T1 mapping, and an 31P MR spectroscopy protocol (31P-MRS)
to visualize myocardial high-energy phosphate metabolism during physiological
exercise using an MRI compatible ergometer, respectively.
Patients who have a clinical indication for a standard 30 min
cardiomyopathy MRI protocol will be asked to participate in this research
protocol, which will take an additional 30 min. The MRI data acquisition
procedures will be similar to standard MRI procedures and all safety
precautions will be in place. The exercise protocol consists of baseline MR
spectroscopy at rest and during exercise. During the exercise protocol a
stepwise increase in heart rate will be achieved until 85% of the predicted
value for age and sex. The exercise test consists of cycling on the
MR-compatible ergometer, while lying in the MRI scanner. The ergometer has been
tested and validated with healthy volunteers in the MRI environment. The MRI
protocol will consist of scout acquisitions and a reference scan for the
positioning of the patient (5 min), T1 mapping (5 min), a routine clinical
cardiomyopathy protocol including late gadolinium enhancement (25 min), and the
exercise protocol (25 min). The total MRI procedure will be completed within 60
minutes. The research protocol does not require any additional contrast
administration.
We expect to detect differences in T1 times, as well as in
exercise-induced kinetic changes in high-energy phosphate dynamics during
exercise between healthy volunteers and several groups of cardiomyopathy
patients.
During the past decennium it has become clear that miRNAs hold great
promise as a new class of biomarkers. By adding the identification of
miRNA-signatures to this study protocol these signatures can be related to the
different stages of cardiomyopathies which will be identified bij the new MRI
techniques.

The main objective of this study is to explore two novel MRI techniques to
characterize myocardial properties that are expected to be useful for the
diagnosis of various forms of cardiomyopathy. Furthermore, we will explore
whether different stages of cardiomyopathies which are to be identified by the
new MRI techniques, exhibit different miRNA signatures.

We will employ a novel MRI sequence called T1 mapping to quantify the extent of
diffuse myocardial fibrosis, and a 31P-MRS protocol to visualize myocardial
high-energy phosphate metabolism during physiological exercise using an MRI
compatible ergometer. These two objectives are feasible in a 30 min research
protocol that can be added to a standard clinical 30 min cardiomyopathy
protocol that is clinically indicated in a range of patients with suspected or
proven myocardial dysfunction. Also, MiRNA-profiling will be performed in these
patients. This research protocol will be used in healthy volunteers and in a
range of patients with cardiomyopathy.

For all patients undergoing MRI, the research protocol consists of a
noninvasive imaging protocol. For the majority of patients from categories a-d,
the research protocol will be a 30 min extension of the clinically indicated
MRI for which they were referred by their treating cardiologist. In addition,
one blood sample will be taken to measure hematocrit, a parameter required to
calculate extracellular matrix volume based on the T1 mapping results; this
blood sample will be taken from the canula that is required for contrast
administration during the routine MRI protocol. In some categories with low
inclusion rates, patients will be asked to undergo an MRI which was not
requested by their treating cardiologist. However, it should be noted that in
these patient categories, the additional MRI does provide valuable information
about cardiac function (volumes, ejection fraction, fibrosis) which may benefit
the patient*s clinical follow-up. Patients from category c1 have a clinical
indication for MRI before CRT device implantation. The research protocol will
encompass a 30 min extension of the MRI protocol. In addition, it will include
a standardized follow-up to document response to CRT. An outpatient clinic
visit and echocardiography at baseline and at 1 year follow-up are routine
clinical practice, but the research protocol will include two SF36
questionnaires and two 6 minute walking distance tests (one each at baseline
and 1 year follow-up).
When patients wish to stop the scanning procedure and get out of the
scanner they can press a *panic button*, which is standard procedure for every
MRI. This *panic button* can also be used during the exercise protocol.
Patients are also able to talk to the researchers in the control room at any
time during the experiment. Potential hazards from high energy radiofrequency
or gradient pulses are not any higher than in the manufacturer*s sequences. MRI
does not require ionizing radiation, and gadolinium contrast is well tolerated
with only very rare cases of gadolinium allergy reported in the literature.