Physiological Stress 15O-H2O Total-body PET/CT protocol

In the department Nuclear Medicine and Molecular Imaging of the UMCG, a
traditional clinical protocol for cardiac quantitative perfusion starts with a
Computed Tomography (CT) transmission scan. Subsequently, the rest image
acquisition using Positron Emission Tomography (PET) is initiated directly
after an injection of 400 MBq of 15O-H2O, lasting in total 5-6 minutes. Then,
10 minutes of delay must be held for 15O-H2O decay before acquisition of the
stress phase. The last consists in the administration of 140 µg /kg/min of
adenosine infusion, followed after 2 minutes by an injection of 400 MBq of
15O-H2O, and finally, the acquisition of stress images by a second PET scan
that lasts 5-6 minutes.
At present, only pharmacological stressors can be used for the stress phase of
a Myocardial Perfusion Imaging (MPI) PET, mainly due to the characteristics of
the radiotracers. Since these radiotracers have a short half-life time, this
does not allow for the performance of physiological stressors outside the
PET/CT camera.

Several physiological stressors have been proposed for the acquisition of
stress images on different modalities of perfusion imaging, including breathing
manoeuvres, increased intrathoracic pressure or Valsalva manoeuvre and bicycle
exercise.

Breathing manoeuvres are based on the O2 and CO2 response. CO2 is a recognized
vasodilator of myocardial blood vessels that leads to changes in myocardial
oxygenation. Several studies have assessed and validated a
breathing-manoeuvres-stress-protocol consisting of hyperventilation for 60
seconds followed by breath-holding for 15 to 60 seconds. It has been reported
that elevated levels of PaCO2 can cause myocardial hyperaemia at the same
extent as adenosine. However, it is important to highlight that all these
results were demonstrated with cardiac magnetic resonance imaging (MRI) and
taking only anatomical and functional parameters into account, while perfusion
parameters were lacking. It must be emphasized that breathing manoeuvres are
safe and well-tolerated with only transient symptoms reported such as headache
and dizziness. Additionally, it is easier to perform, and patients remain in
total self-control. Another advantage is the lower cost, and also that the
stress procedure can be reversed rapidly within 2-3 breaths.

Valsalva manoeuvre consists of a persistent exhalation with a closed glottis
for 20 seconds, with the aim of increasing the intrathoracic pressure to 20-40
mmHg. This manoeuvre triggers an autonomic response in blood pressure, heart
rate and blood flow. In studies performed with MRI to investigate heart and
brain function and perfusion, the Valsalva Manoeuvre has been proposed and
evaluated in comparison with stressors such as acetazolamide injection,
breathing CO2 and breath holding. It has been reported in brain MRI that
performing a Valsalva manoeuvre for 5 seconds produces a similar effect as
breath-holding for 20 seconds.

Regarding exercise as stressor, a cycling ergometer compatible with MRI was
created in the early 2010. This ergometer was developed for cardiac MRI to
study the left ventricular function and structure by avoiding the use of
dobutamine. However, cardiac MRI lacks the quantitative information regarding
Myocardial Blood Flow (MBF) and Coronary Flow Reserve (CFR).

For 15O-H2O PET, there is only one study available that compared bicycle
exercise against adenosine stress. The authors concluded that it seems feasible
to use a supine ergometer as physiological stressor in this imaging modality,
however, the sample size was quite small (i.e. 10 patients) and consisted only
of healthy volunteers, so the consistency of these outcomes in patient groups
still needs to be studied.

The rationale of Total-body PET was already constructed in 2000, whereas the
first pilot studies were performed in 2018. This new technology enables a
longer follow-up time of the radiotracer with less noise and lower radiation
dose. Furthermore, one of the main advantages of this modality within the
research field is that it allows for simultaneous imaging of multiple organs.
Based on this last benefit, the blood flow towards organs which are related to
the heart will also be evaluated (i.e. brain, kidneys and spleen).

The presence of heart disease has been linked to the onset of impairments in
other major organs (i.e. brain, kidney, spleen), and parallel, primary
dysfunctions in these organs have also been demonstrated to impact the
prognosis regarding cardiovascular health. Regarding brain-heart interactions,
an association between Coronary Artery Disease (CAD) and the incidence of
ischemic stroke and/or ischemic transitory attack has been demonstrated. The
other way around, depression, anxiety and other brain disorders have been
proven to impact the overall prognosis in CAD patients. Furthermore, a link
between CAD and the cognitive domain was found with MRI, evidenced by CAD
patients that had a significantly decreased Cerebral Blood Flow (CBF) relative
to healthy controls. However, further research with more sensible techniques
such as PET/CT is needed to enlighten the possible relation between heart and
brain perfusion.

With respect to kidney-heart interactions, it has been described that elderly
CAD patients have a higher prevalence of reduced renal function when compared
with younger patients (i.e. diminished estimated-Glomerular Filtration Rate).
As a matter of fact, patients with CAD have an increased risk of developing
chronic kidney disease. Furthermore, when the stage of renal insufficiency is
reached in patients with CAD, it increases their risk of major adverse
cardiovascular events.

Finally, regarding heart-spleen interactions, less links have been proposed,
but some interesting associations have been theorized. In a preclinical study,
it was found that the Splenic Blood Flow (SBF) was prioritized in settings of
decreased cardiac output. More recently, SBF was showed to behave similar to
myocardial blood flow (MBF) in patients undergoing Cold Pressor Stress (CPS).
Lastly, splenic switch-off (i.e. visible decrease in splenic signal intensity
during adenosine stress as compared to rest) has been proposed as a tool to
evaluate the success/failure of the adenosine-induced MBF response.

However, the underlying physiological phenomena responsible for these
interactions remain unclear. Moreover, objective evidence regarding the changes
that each of these organs undergo in response to alterations in the other in
terms of perfusion status and organ-blood flow has not been documented.

The primary objective:
Study the feasibility of physiological stressors and their effect in myocardial
perfusion 15O-H2O Total-body PET/CT with stress adenosine as a reference in
healthy volunteers and in CAD patients.

The secondary objectives:
1. Explore the measurement and associated blood flows in the connected organs
brain, kidneys and spleen to the heart.
2. Obtain the information regarding the subjects experience with each of the
proposed physiological stressors. For this, a symptom questionnaire was
developed to be addressed at the end of the protocol.

It is a feasibility study, which will assess the effect of physiological
stressors in myocardial perfusion using 15O-H2O Total-body PET/CT with
conventional adenosine stress as a reference in healthy volunteers and patients
with CAD.

This study will be carried out with the Biograph Vision Quadra scanner in the
UMCG, the Netherlands.

The two non-investigational products used in this protocol (i.e.15O-H2O and
adenosine) are registered products used within indication.
However, the main risk of this protocol is the ionizing radiation. This can
cause cancer which manifests itself after many years or decades. The estimated
associated risk of developing fatal cancer is proportional to the dose and also
to the participant*s age at the time of exposure. The risk for younger people
is higher than for older people and the risk for females is higher than for
males of the same age. The Total Research Protocol Dose (TRPD) quoted for each
cohort are in addition to standard clinical care. According to report 26 of the
Netherlands Commission on Radiation Dosimetry, radiation exposure of this study
is allowed to be in category 2b at most. All participants in this study will
receive a maximum of 200 MBq per IV administration of 15O-H2O, with a total
radiation effective dose of 1.1 mSv for 15 healthy volunteers and 0.88 mSv for
5 CAD patients. The 15 healthy volunteers who will perform the complete
protocol will receive an additional dose of 1.0 mSv from the ultra-low-dose
CTs, whereas the 5 CAD patients who will get 4 scans will receive an additional
dose of 0.8 mSv from the ultra-low-dose CTs, based in Tin Filter technology
which is available and already has been used in our department previously.
Therefore, the total radiation dose of the complete protocol is 2.1 mSv (5
scans). The total radiation dose of the protocol with 4 scans is 1.68 mSv. The
radiation dose for healthy volunteers will be 2.1 mSv meanwhile, the radiation
dose for the CAD patients is 1.68 mSv with this protocol. Since total radiation
exposure in this study is 2.1 mSv, males must be at least 10 years old and
females must be at least 20 years old to fall into category 2b.