Acute effects of exercise in heart failure - a pilot study

Aging of the population and prolongation of lives has led to an increase in the
prevalence of chronic diseases such as heart failure. Heart failure (HF) is a
syndrome characterized by a variety of abnormalities, such as a low exercise
tolerance, reduced exercise-induced blood flow and endothelial dysfunction and
autonomic nerve dysfunction characterized by an enhanced sympathetic
activation.14, 17 Despite improvements in pharmacological therapy, HF is a
disease with a high morbidity and mortality and poses a large financial burden
on the society. Exercise training is a promising new therapy for improvement of
symptoms and prognosis in heart failure.1-4 Recent studies have revealed that
high-intensity training results in a larger improvement in physical fitness in
HF patients than traditional moderate-intensity training.1, 5 As the changes in
local and systemic physiological factors represent principle stimuli for
vascular adaptation to exercise training, better insight into these acute
effects of exercise is of special importance.

One of the most important stimuli for vascular adaptation relates to the
exercise-induced increase in shear stress in the active and inactive regions.9
In peripheral conduit arteries, the blood flow pattern varies during one
cardiac cycle. The large antegrade component during systole is followed by a
retrograde component in early diastole.18 Shear stress elicited during exercise
is an important stimulus for vascular adaptations, with antegrade shear being
related to improvement in vascular function whilst the retrograde component is
thought to exert a proatherogenic effect on the endothelium.9, 11 To date, no
previous study compared shear pattern responses to acute moderate and
high-intensity exercise.

Previous studies in healthy volunteers found that leg cycling exercise is
associated with an increased retrograde flow in upper body arteries during the
initial phase of exercise probably owing to sympathetic vasoconstriction.19
This discrepancy at the onset of exercise disappears when continuing exercise,
resulting in an attenuation of the retrograde shear rate when skin temperature
increases during prolonged exercise.10 As HF patients experience an enhanced
sympathetic nerve activity and a disturbed thermoregulation characterized by
attenuated cutaneous vasodilator responses to heating, the reversal of the
retrograde flow during exercise could be delayed.12-14 This different response
can have important implications for the development of effective exercise
training programs for HF patients. To our knowledge, no previous study
performed a comprehensive comparison of the acute responses to exercise between
healthy control and heart failure. Differences in these responses may prevent
heart failure patients to optimally benefit from exercise training.

The primary aim of this project is to investigate acute effects of moderate-
and high-intensity exercise in heart failure patients and their age- and
sex-matched controls on retrograde and antegrade shear in the brachial artery,
expressed in the oscillatory index, using non-invasive echo-Doppler.

Subjects will report to the laboratory on 3 separate days. After performance of
a maximal cycling test on day 1, subjects perform 2 bout of exercise (high and
moderate-intensity). The order of day 2 and 3 will be randomized between
subjects. Six hours prior to day 2 or 3, subjects ingest a telemetric
temperature pill to record core body temperature, whilst also skin temperature
on the lower arm will be examined. After cannulation of the antecubital vein, a
10-minute rest will be implemented. Heart rate (HR), blood pressure (RR), heart
rate variability (HRV) will be registered and a venous blood sample will be
drawn before and at pre-determined time points after the exercise intervention.
During exercise, brachial artery blood flow will be assessed by Duplex
ultrasound. A continuous registration of forearm skin temperature and core body
temperature will be acquired during the whole study protocol. Tests will be
performed at the same time of day and under the same conditions (>24 h no
exercise, >18 h no coffee/tea/chocolate/alcohol/vitamin C). Subjects are
instructed to ingest a meal about 2 hours before testing, which will be kept
similar between both exercise days.

Day 1 (2h)
• Medical screening
• Incremental maximal cycling test

Day 2/3 (2.5h)
• An antecubital vein is cannulated for blood sampling for determination of
troponin
• Start of continuous registration of skin and core body temperature
• Baseline measurement of heart rate, blood pressure and HRV
• Venous blood sampling
• Exercise session with ultrasound measurement of brachial artery blood flow
and continuous registration of heart rate
• Measurement of heart rate, blood pressure and HRV at 0, 30 and 60 minutes
post-exercise
• Venous blood sampling at 0, 30 and 60 minutes post-exercise
• Stop continuous registration of skin and core body temperature 60 minutes
post-exercise

The cannulation of the antecubital vein can induce a haematoma (~5%). However,
this is completely reversible within 2 weeks and will not lead to permanent
damage.

Exercise training is not associated with a health risk. Moreover, exercise
training typically causes a decreased cardiovascular risk, whilst vascular and
cardiac function and structure improve after a period of exercise training.
Also a number a previous studies have demonstrated that the cardiac workload
during high intensity training is not significantly different to the
(traditional) moderate-intensity training and can be safely applied in subjects
with cardiovascular disease or impaired cardiac function.15, 16 Therefore, both
types of exercise are associated with a cardiac load that is typically used
during heart failure/cardiac rehabilitation, whilst it also suggested that it
is not associated with an increased risk for development of health-related
problems. Nonetheless, all exercise sessions will be attended by or supervised
by a trained exercise physiologists and/or physiotherapist and/or physician.
The presence of a physician in the room is dependent on the age and medical
status of the participants.Moreover, subjects will be monitored using a Polar
heart rate monitor continuously during every training session, whilst each
training session will be performed at the hospital. This will ensure that all
exercise training sessions are performed in a well-controlled environment in
the unlikely case that medical assistance is necessary before, during or after
the exercise session.

Also the blood flow measurements with the ultrasound technique and temperature
measurements are not related to any potential risk.

The telemetric temperature pill (CorTempTM) is registered at the Food and Drug
Administration (FDA) for 22 years.31 No negative incidents regarding the
ingestion of the CorTempTM are reported after distribution of 35.000 pills. The
Department of Physiology has extensive experience with core body temperature
measurements using the CorTempTM (>1000 measurements). We have not experienced
any negative consequences in our participants.

At the department of Physiology, we have a long-standing tradition in
performing all previously mentioned tests (maximal cycling test, heart rate
variability measurements, blood flow measurements and temperature monitoring).
All procedures are performed routinely at the Department of Physiology and have
been accepted by the ethics committee in numerous previous applications.
Moreover, there is a long history of performing exercise training studies at
our department.