Evaluation and testing of the microvascular function in asymptomatic athletes

Regular aerobic exercise has been shown to reduce the risk for fatal and
non-fatal cardiac events and is therefore highly recommended both for healthy
subjects and patients with cardiovascular disease. However, in selected cases,
acute vigorous exercise may also be the trigger for a potential fatal cascade
leading to myocardial infarction or sudden cardiac death (SCD). In order to
reduce the burden of (fatal) cardiac events, the use of pre-participation
screening is recommended for athletes to detect potential causes of (fatal)
cardiac events an early stage. Exercise electrocardiography is particularly
recommended to detect obstructive coronary artery disease (CAD). However, in
many athletes (up to 95%) with an abnormal exercise test result, no obstructive
CAD is found during further diagnostic evaluation such as myocardial perfusion
imaging and/or coronary angiography. As the pathophysiology of an abnormal
exercise test in the absence of obstructive CAD among athletes remain unknown,
uncertainty exists with respect to prognostic implications in these athletes,
and, in addition, it leads to therapeutic dilemma*s. Based on preliminary
(animal) studies, possible explanations may be an inadequate increase in
myocardial capillary density in response to development of training-induced
myocardial hypertrophy or coronary microvascular dysfunction due to remodeling
of intramural coronary arteries. Both mechanisms will eventually result in an
insufficient myocardial blood supply during exercise and may therefore serve as
a trigger for a cascade leading to myocardial infarction or potentially lethal
arrhythmias. More knowledge on the pathophysiological mechanisms in humans will
eventually lead to better diagnostic and therapeutic strategies in this
population.

The main objective of this study is to evaluate whether myocardial ischemia in
the absence of obstructive CAD in athletes is associated with a reduced
myocardial perfusion when compared to control subject with a low a priori risk
of CAD and without the presence of epicardial coronary artery disease. The
secondary objectives are to evaluate whether myocardial ischemia in the absence
of obstructive CAD in athletes is associated with a different levels of the
precursor endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) when
compared with the control subjects

A single-center prospective observational case-control study among asymptomatic
recreational and competitive athletes who underwent pre-participation screening
at the department of Sports Medicine of Máxima Medical Center and/or visited
the department of Cardiology of Máxima Medical Center. Athletes with an
abnormal exercise test and abnormal myocardial perfusion scintigraphy (MPS)
indicating myocardial ischemia within the last five years but without
epicardial coronary artery disease will be selected. These athletes will be
compared with a gender and age-matched historic control group consisting of
individuals with a low a priori risk and without the presence of significant
epicardial CAD who already underwent 82Rb PET / CCTA as part of standard
diagnostic procedure, using a database from the same hospital. All athletes and
control subjects will undergo a blood test. Only athletes will undergo 82Rb PET
and coronary computed tomography angiography (CCTA).

At a population level, the results of this study will lead to a better
understanding of microvascular coronary (dys)function in asymptomatic athletes.
Consequently, this may lead to an increased insight in a potential pathological
substrate in athletes with concordant abnormal results as these athletes could
be prone to suffer cardiac (lethal or non-lethal) events and should be advised
to refrain from vigorous exercise. Also, a better understanding of the
underlying pathophysiological mechanisms will eventually lead to increased
insights in therapeutic and prognostic consequences. In that way, athletes can
be provided with a tailored treatment and advice with respect to continuation
of sports activities. For the individual athlete, the results of this study
will provide a more precise assessment of the extent of myocardial ischemia. In
case of other abnormal findings (e.g. coronary artery disease), the subject
will be referred to their own general practitioner with a recommendation for
referral to a cardiologist. If the subject is currently being treated by a
cardiologist, a direct referral will be initiated and the subject will be
treated according to the current standards. For healthy control subjects, there
is no direct individual benefit. these subjects will only undergo blood tests
at Máxima Medical Center. The risks of a direct venipuncture are hematoma and
bleeding at the site of puncture, in very exceptional cases thrombophlebitis.

Only athletes with documented myocardial ischemia (N = 10) will undergo 82Rb
PET / CCTA and will be exposed to radiation with a total effective radiation
dose of approximately 5.8 * 7.1 mSv. Prior to the 82Rb PET / CCTA, two
intravenous lines will be placed which are both required (1 line for
administration of 82Rubidium and 1 line for administration of Adenosine). Risks
of an intravenous line are minimal and comparable to a normal direct
venipuncture (see above). Rubidium is generator produced potassium analog with
physical half-life of 76 seconds and the administration in humans for the
measurement of myocardial blood flow first occurred in the early 80s. With
increased PET/CT systems, the number of patients grew but it still represents
only a small percentage by comparison with the use of 99mTc-sestamibi. No
adverse effects of administration of Rubidium are known. Adverse effects that
are described during adenosine administration are bradycardia, premature atrial
or ventricular beats, dyspnea, blushing, nausea and vomiting. All side effects
disappear immediately when administration is discontinued. Adenosine has been
used for many years worldwide in pharmacological myocardial stress testing and
has a well-established safety record. It has a minimal effect on heart rate and
blood pressure during continuously perfusion and leads only to a modest
increased oxygen requirement. The department of Nuclear Medicine of the Jeroen
Bosch Hospital is also using Adenosine during 82Rb PET for many years.
Therefore, staff and personnel members are well experienced with the use and
potential side effects of Adenosine infusion. Athletes are continuously
monitored during administration and if serious side effects occur;
administration will be discontinued immediately.

All athletes with documented ischemia will be subjected to an effective
radiation dose of 5.8 * 7.1 mSv. When compared to the 2.6 mSv annual radiation
exposure from natural sources in the Netherlands (36), this is a 2.2 to
2.7-fold increase in radiation exposure. A previous study showed that there is
an increased non-fatal cancer risk of 0.01% per mSv of exposure to radiation
(37), leading to an increased risk of non-fatal cancer of 0.058 * 0.071% in the
participating athletes. In order to avoid a high cumulative dose the use of
radiation should be minimized. In this perspective, other non-invasive
modalities to investigate the microcirculation were considered. Perfusion MRI
is one of these modalities. The main advantage of this procedure is that MRI
does not use ionizing radiation. However, PET is currently the golden standard
for the assessment of microvascular function due to the highly accurate
myocardial blood flow quantification (38). In contrast with 82Rb PET, absolute
measures of rest and stress flow with perfusion MRI did not correlated well.
Also, robust fully-quantitative models have been developed only in experimental
settings. Due to these limitations, visual assessment of the myocardial
perfusion remains clinically the most used analysis tool when cardiac MRI is
used (39). In the present study, the main study parameters are myocardial blood
flow and flow reserve. As accurate quantitative measurements are needed, these
parameters can only be obtained via PET-82Rb in the current clinical practice.

Coronary CT will be used to obtain anatomical imaging of the coronary arteries.
This non-invasive modality can accurately detect and exclude the presence of
epicardial CAD. As epicardial CAD may induce an impaired myocardial blood flow,
it is necessary to rule out its presence. In this way, the calculated
myocardial blood flow and flow reserve via 82Rb PET / CCTA will solely reflect
the microvascular function. The index athletes underwent coronary angiography
(CAG) as part of the diagnostic procedures. However, this CAG is performed
months to years before recruitment for the present study. Therefore, as CAD at
the time of study enrollment cannot be ruled out with certainty, the coronary
anatomy will be evaluated also at the time of study enrollment.
For this purpose, 82Rb PET will be combined with a CCTA scan, which imposes an
additional radiation dose of 3.4 * 4.1 mSv which is lower than the radiation
dose of CAG (5 * 7 mSv).