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 incidence of SCD, the use of pre-participation screening is
recommended for athletes to detect potential causes of SCD at 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. The etiology and
prognostic implications of an abnormal exercise test in the absence of
obstructive CAD among athletes remains unknown. 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.

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 athletes with a normal exercise test. The
secondary objectives are to evaluate different levels of the precursor
endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) between the
two groups.

A single-center observational case-control study among asymptomatic
recreational and competitive athletes that 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 will be selected.
When sufficient athletes with abnormal test results are included, athletes with
normal test results will be matched for age, BMI and type of sport (1:1 ratio).
All included athletes will undergo a PET-CT and blood will be collected.

All athletes will undergo blood tests at Máxima Medical Center. Blood samples
with a total of 4 tubes (13 mL of blood) will be collected to evaluate routine
laboratory investigations (C-reactive protein, leucocyte count, kidney
function, glucose and lipid profile) and the plasma levels of eNOS and ET-1.
The risks of a direct venipuncture are hematoma and bleeding at the site of
puncture, in very exceptional cases thrombophlebitis.

All athletes 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). Adverse effects that are described during
adenosine administration are bradycardia, premature atrial or ventricular
beats, dyspnea, blushing, nausea and vomiting. All side effects disappear when
administration is discontinued. Athletes are continuously monitored during
administration and if serious side effects occur; administration will be
discontinued immediately.

All participating athletes 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, 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, 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. 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. 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).

Although there is no major benefit for individual study participants, the
results of this study may lead to a better understanding of microvascular
coronary (dys)function in asymptomatic athletes on a population level, and
consequently, to an increased insight whether athletes with positive exercise
test result are prone to suffer cardiac (lethal) events and should be advised
to refrain from competitive sports. In case of 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 under treatment of a cardiologist, a direct referral will be
initiated and the subject will be treated according to the current standards.