Functional sympatholysis in heart failure: role of reactive oxygen species

Heart failure is associated with poor prognosis and high levels of morbidity
and mortality. Despite of improvements in pharmacological therapy, the
prognosis in heart failure patients remains poor. Exercise training
significantly improves symptoms and prognosis in heart failure. However, heart
failure is associated with poor exercise tolerance, characterized with an
imbalance between matching blood supply to oxygen demand. This importantly
limits the benefits of exercise training in subjects with heart failure.
The sympathetic nervous system importantly contributes to successful
redistribution of blood during exercise by causing a strong vasoconstriction in
the inactive areas. Simultaneously, the constriction in the active areas is
attenuated, leading to an increased blood flow to the active muscles. This
process is commonly referred to as functional sympatholysis and contributes to
successful matching of the oxygen supply to demand of blood. Altered functional
sympatholysis may leads to an impaired redistribution of blood during exercise,
consequently contributing to poor exercise tolerance. Whilst previous studies
reported an impaired functional sympatholysis in subjects with cardiovascular
risk (e.g. hypertension), no previous study in humans examined the impact of
heart failure on functional sympatholysis.
Previous data provided evidence that an increased production of reactive oxygen
species contributes to the impaired functional sympatholysis in animals with
heart failure. To study this hypothesis in humans, we will examine whether
dietary nitrate supplementation using beetroot juice (a successful intervention
to lower oxidative stress) can alter functional sympatholysis in humans with
heart failure.

The primary aim of this project is to examine the impact of heart failure on
functional sympatholysis. The second aim of this study is to examine whether
nitrate supplementation can improve the effects of functional sympatholysis in
heart failure.

Cross-over intervention trial

Day 1 (1h)
• Medical screening

Day 2/3 (3h, beetroot juice or placebo ingested 2.5h before the test)
• Determination of MVC
• Venous blood sampling
• 10-minute forearm occlusion, measurement of maximal tissue
desaturation/oxygen consumption
• Resting period of >20 minutes in the supine position
• 5-minute baseline measurement of blood pressure, forearm muscle oxygenation
and brachial artery diameter and red blood cell velocity
• 6-minute period of continuous assessment of blood pressure, forearm muscle
oxygenation and brachial artery diameter and red blood cell velocity + cold
pressor test at minutes 4 and 5.
• Resting period of >20 minutes in the supine position
• 5-minute baseline measurement of blood pressure, forearm muscle oxygenation
and brachial artery diameter and red blood cell velocity
• 6-minute period of continuous assessment of blood pressure, forearm muscle
oxygenation and brachial artery diameter and red blood cell velocity during
handgrip exercise (0.5 Hz, metronome-assisted) at 10% MVC + cold pressor test
at minutes 4 and 5.
• After a resting period of >20 minutes, the above 2 steps are repeated with
handgrip exercise at 20 or 30% MVC. The order of handgrip exercise performance
(10, 20 and 30% MVC) will be randomised between subjects.

For the second aim, we will administer dietary nitrate through beetroot juice.

Performance of handgrip exercise in healthy individuals or in those with heart
failure is not associated with a health risk. Also, our non-invasive techniques
(NIRS, ultrasound) and interventions (cold pressor test, beetroot juice) are
not associated with a health risk.
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