Train hard is smart for the heart; an exercise study on clinical outcome and mechanisms in heart failure patients

In Western countries, heart failure (HF) is a major cause of death. Despite
current advances in the pharmacological management of HF, the prevalence is
rapidly increasing and the prognosis remains poor. Physical fitness is the
single best predictor of both cardiac and all-cause deaths among patients with
cardiovascular disease and outperforms ejection fraction as a prognostic index
(for survival) in HF. Despite the overwhelming evidence to promote physical
activity, little is known regarding the type of exercise that yields optimal
beneficial effects in HF. Some studies in healthy subjects or those with
cardiovascular risk suggest greater fitness and cardiovascular adaptations
after high intensity exercise than with *traditional* moderate exercise. The
rationale is that high intensity exercise (i.e. short bouts of exercise at ~90%
of the maximal heart rate) allows patients to complete work at higher
workload/intensity, but for a short period of time, inducing beneficial
peripheral adaptations in vessels and muscles, without overloading the heart. A
sound comparison between the effects of *traditional* moderate versus high
intensity exercise training in HF patients has never been examined.
Peripheral factors, such as endothelial dysfunction and increased vascular
tone, are fundamental to the pathogenesis of HF. These peripheral vascular
changes can be explained through changes in dilator (i.e. nitric oxide) and
constricting (i.e. endothelin-1) pathways. However, the mechanisms responsible
for the exercise-related improvement are not fully understood. Reversing the
peripheral vascular changes most likely contributes to the positive effects of
exercise in heart failure. While evidence supports a role for nitric oxide to
partly explain the beneficial effects of *traditional* exercise, no previous
study examined the impact of high intensity exercise on nitric oxide in HF.
Moreover, the impact of exercise on the vasoconstrictor endothelin-1 in HF
patients has never been studied. This is of special interest, as I recently
demonstrated a detrimental role of endothelin-1 in explaining the increased
vascular tone during physical inactivity and aging.

The overall aim of this project is to compare acute and chronic effects of
moderate versus high intensity exercise training in HF patients. Specifically,
we will:
1. Compare the effects of *traditional* moderate intensity versus novel high
intensity exercise training in heart failure patients (NYHA-class II/III). To
this end, physical fitness, clinical outcome and cardiovascular function will
be examined before and after 12-week of exercise training.
2. Examine the impact of moderate as well as high intensity exercise training
in heart failure patients (NYHA-class II/III) on the NO-pathway and ET-pathway.
Therefore, I will examine the nitric oxide-mediated endothelial function and
endothelin-1-mediated vascular tone before and after the 12-week interventions.

Randomised intervention study

1. moderate-intensity training (traditional training) for 12 weeks (3 times per
week)
2. high-intensity training for 12 weeks (3 times per week)
3. control

The brachial catheterisation can induce a haematoma (~5%). However, this is
completely reversible within 2 weeks and will not lead to permanent damage.
Subjects will be informed regarding this potential risk associated with the
invasive procedure of the test.

The pharmaceutical drugs are all accepted for human use and will be infused in
the forearm only (not in systemic doses), leading to a localised effect only.
In addition, all substances will be removed by the body within minutes to hours
(dependent on the substance). Moreover, >4,000 studies have previously used one
or more of these substances to examine the local effects of endothelin and
nitric oxide in the arms or legs of healthy humans as well as various patient
groups (including heart failure). To the best of our knowledge, none of these
previous studies reported the presence of (serious) adverse events.

Blood will be taken for later analysis. This will be taken from the canula that
will be inserted into the brachial artery for the invasive test. Therefore, the
number of invasive procedures will be minised to 2.

Exercise training is not assciated 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. Some studies have even demonstrated
that the beneficial effects of exercise on remodelling of the heart are
superior during high-intensity training compared with traditional
moderate-intensity training in subjects with heart failure. Therefor, both
types of exercise are not associated with an increased risk for development of
healt-related problems.