A non-invasive exercise test for evaluating sport-related arterial blood flow limitation in the leg: an exploratory study

A professional cyclist covers approximately 25,000 km a year and flexes the hip
8,000,000 times in a year, while leg blood flow is in the range of 10-15 litres
per minute. This poses a substantial hemodynamic load on the iliac artery. As a
result, a proportion of endurance athletes develop a limitation in leg
circulation due to arterial narrowing in this iliac artery. An early *Lancet*
study of the department of Sports Medicine of Máxima Medical Centre (MMC) found
that 20% of professional cyclists were suffering from such a sport-related Flow
Limitation in the Iliac Artery (FLIA) necessitating treatment. The incidence in
recreational cyclists is unknown, but with 849,000 recreational cyclists in the
Netherlands cycling over 3,000 km a year with an impressive 1,000,000 hip
flexions, many of them travel similar distances as a professional cyclist,
incurring similar risks for developing FLIA. If untreated, FLIA may have a
pronounced impact on quality of life. Professional athletes may have to end
their careers prematurely. In a substantial subset of cyclists, abnormalities
may even lead to complete occlusion and/or thrombosis, with severe symptoms in
daily life.

Clinical experience suggests that early detection and treatment leads to better
outcomes. If diagnosed at a late stage, conservative management including
changes in training behaviours and body position, or least-invasive surgical
repair options will no longer suffice. The only options remaining would be to
cease participation in the provocative activities altogether, or to undergo
extensive and risky reconstructive vascular surgery. Understanding the early
pathogenesis in order to improve detection is thus of paramount importance.
Unfortunately, early detection is often missed due to the non-specific
presentation of symptoms and the high level of specialisation required for
clinical evaluation. There is a wide range of differential diagnoses that could
contribute to the non-specific symptoms observed in the early stages of FLIA,
including common musculoskeletal and tendinous injuries, mechanical or
neurogenic pain referred from the low back or SI joint, hip acetabular labral
tear, chronic exertional compartment syndrome, or fibromuscular dysplasia.
Currently available diagnostic evaluations can have low sensitivity for an
athletic population.

There is no single gold-standard evaluation for diagnosing FLIA. The current
consensus suggests that the best single functional test is a provocative
maximal exercise test on a cycle ergometer, followed by measuring blood
pressure at the ankle and brachial arteries (ankle-brachial blood pressure
index; ABI) in a competitive posture. In the rare case that the problem is
unilateral, the sensitivity is 73%. If the problem is bilateral, the
sensitivity is only 43%. Imaging techniques, including echo-Doppler
examination, magnetic resonance angiogram (MRA), and computed tomography (CT)
scan are more sensitive, but they are more expensive, less accessible, and not
part of primary care evaluation, instead being typically reserved for
investigation of more severe or complex presentations, and to guide surgical
repair.

Near-infrared Spectroscopy (NIRS) is an innovative technique that measures
relative oxygenation in the muscle, as the balance of oxygenated and
deoxygenated haemoglobin and myoglobin. Impaired arterial leg circulation, such
as observed in peripheral vascular disease (PVD) has been shown to produce a
drop in oxygen saturation of skeletal muscle tissue relative to workload or
exercise performance, and delays in reoxygenation kinetics after exercise and
ischemic vascular occlusion tests (VOT). Consequently, NIRS may be able to
detect alterations in oxygenation that are associated with the level of
arterial insufficiency. We recently reported proof of concept studies regarding
the potential diagnostic role of both power output and NIRS in patients with
diagnosed sport-related FLIA.

Complaints reported in the early stages of FLIA are powerlessness and pain in
the leg muscles when cycling near maximal exertion, which rapidly disappear
with rest. Traditionally, incremental ramp cycling exercise to maximal exercise
tolerance has been used as a provocative functional test, after which clinical
outcome measures including ABI are tested. As the condition progresses however,
symptoms can occur earlier during exercise at a lower intensity and take longer
to resolve during recovery. Multi-stage exercise protocols are commonly used to
understand metabolic responses related to submaximal exercise intensity.
Therefore, a progressive multi-stage cycling protocol with brief recovery
intervals between work intervals will be introduced. This protocol is designed
to allow for multiple opportunities to evaluate work and recovery responses in
an intensity-dependent manner. Subjective symptoms, performance impairments
(including limitations to cycling power output) and muscle oxygenation kinetic
delays will be evaluated across submaximal workloads including after maximal
intensity.

Understanding the onset of symptoms and objective signs of flow limitation with
progressive exercise intensity will improve understanding of severity and
progression of this condition. These outcome measures will be compared to
healthy subjects, in order to develop normative values related to healthy
performance, compared to pathological impairment. The use of a common
multi-stage performance assessment protocol will improve the applicability of
using this approach for screening and early detection of FLIA outside of a
specialised vascular clinic.

It has been suggested that altered vascular function and structure may
contribute to the appearance of symptoms in patients in which obvious stenosis
or intraluminal disease is not apparent on imaging. In addition to standard
clinical evaluation of the aortoiliac tract with echo-Doppler ultrasound,
vascular flow velocity will be recorded for later offline analysis of pulse
wave velocity as a measurement of arterial stiffness.

Our main aim for the future is to improve diagnostic testing for FLIA. NIRS and
pedal force measurements are very promising in this respect, since they may be
used in a clinical setting, in a research laboratory, and in the field in a
high-performance setting. However, there is a lack of understanding on the
physiological and pathophysiological behavior of NIRS in response to exercise.
This current exploratory study will give us important information in an
exercise domain.

Primary Objective:
1. To describe muscle oxygenation kinetics with near-infrared spectroscopy
across exercise workloads from submaximal to maximal, during a progressive
multi-stage cycling exercise protocol.
2. To describe differences in intensity-dependent muscle oxygenation kinetics
in patient legs affected with FLIA compared to control subject healthy
unaffected legs.
3. To describe differences in the ratio of cycling power output to
deoxygenation of the primary locomotor muscle in legs affected with FLIA
compared to healthy unaffected legs.

Secondary Objective(s):
1. To investigate and compare measures of arterial stiffness in a population of
trained cyclists with and without FLIA.

Observational exploratory prospective research

n/a

The following applies to healthy athletes:
All tests are non-invasive and do not impose additional burden or risk for
athletes already engaged in regular endurance training. Now no costs are
charged to the athlete (normally ¤ 350 for such a sports medical examination).

Prior to the cycling test, a short physical examination and with additional
brief, non-invasive Doppler ultrasound examination is performed to check
whether the control can cycle unimpeded of vascular problems.
If an abnormality is found that matches a vascular limitation in the subject:
The test subject receives the normal exercise test and extensive free training
advice including reporting.
The sports physician with expertise in the vascular problem decides the nature
of the abnormality in relation to any complaints and recommends whether or not
to take further steps.

If none are found and the subject is cleared to participate in the study:
1. The test subject receives the normal exercise test and extensive free
training advice including reporting of exercise thresholds and maximum
endurance capacity.
2. The subject returns within two weeks for a multi-stage protocol which is
expected to provide additional diagnostic information and build norms. This
multi-stage protocol also provides additional information that the subject can
use for optimal training.

The following followed for the 'healthy' sports 'patient':

All examinations are non-invasive, and the patient receives extra information
about training advice outside normal care (free test with breathing gas
analysis). The patient is also asked to return within two weeks for normal
diagnostic care. Normative values **can be created for this improvement of the
top clinical care of our top clinical care.
Cycling protocol (in short, see full protocol in the appendix):
1. The cycling test is a normal exercise test, in which the cyclists will
gradually cycle to their (expected) maximum within 8-12 minutes. During the
test, muscle oxygenation is measured using NIRS on the major muscle (vastus
lateralis) during cycling. The bicycle contains a system that can measure the
pedal force (PPM). All additional measurements are non-invasive and do not or
hardly hinder cycling. In addition, breathing gas anaylsis will compute the
oxygen uptake and carbon dioxide production. This is a commonly used method
within the hospital for a better understanding of exercise-related complaints
in the field of heart and lung disease. In addition, it is extremely suitable
for determining the cyclist to give extensive and accurate cycling advice. This
can be used by the cyclist to train in a more targeted way to improve their
fitness, so that the subjects also benefit from the studies.
2. The test consists of a progressively increasing block protocol, in which
multiple blocks of intensity are performed by the athletes. The same
measurements as in the first test are performed (oxygen uptake, NIRS and PPM).
This protocol is also used in the literature to provide training advice to
cyclists.

For both:
A brief arterial occlusion test is performed before and after the exercise test
to determine baseline oxygenation in the thighs. This is a commonly used
technique with NIRS that is applied for patients with peripheral vascular
diseases.