Micro- and macrovasculair adaptations in patients with peripheral arterial disease during supervised exercise therapy: a MRI study

PAOD is an highly prevalent condition in the age group above 50 years and
significantly affects patients
physical activities, well-being, and places a large financial burden on the
health care system. Remarkably little
is known about the mechanisms of human adaptation to peripheral ischemia.
The most important goals in the treatment of claudication is to improve the
patient*s functional status. Multiple
prospective studies showed a benefit of exercise therapy in patients with PAOD,
with the greatest
improvements under supervised exercise therapy. Unfortunately, still a large
variability among treated
patients exists in terms of walking improvement and quality of life. Key to
identify which patients will rehabilitate
is to (i) identify the underlying working mechanisms of rehabilitation and (ii)
study the relationship between the
adaptive mechanism and functional improvement, both preferably at an early
stage of treatment.
Out of the numerously suggested adaptive mechanisms, ranging from vascular,
blood rheologic,
biomechanical, to metabolic adaptation, we focus on vascular adaptive
mechanisms in response to exercise
rehabilitation. With invasive experiments in animal models, it has been
demonstrated that vascular
adaptations play an important role in the recovery from peripheral arterial
occlusions. For exercise treatment
collateral artery formation, as a response to exercise elevated vessel wall
shear stress, is generally thought to
significantly contribute to the rehabilitation. Although intensive exercise
training very likely increases growth of
(latent) pre-existing arterioles it remains unclear whether this explains the
degree of rehabilitation. In depth
research studies in human PAOD patients on the potential vascular mechanisms
underlying rehabilitation are
limited, have not been able to separate macro- from microvascular adaptations,
and have provided conflicting
results up to now. Moreover, the formation of collaterals could thus far not be
visualized and its specific role
not determined. Previous research focussed on Doppler flow measurements or
plethysmography, which
both cannot detect effects from collateral of microcirculatory adaptations.
It is only recently that non-invasive Magnetic Resonance Imaging (MRI) has
evolved that far that both macroas
well as microvascular adaptations can be imaged and quantified. Macrovascular
adaptations may involve
the macrovascular flow (e.g. vasodilation or stenosis progression), and the
formation of collateral arteries,
which can be assessed by contrast-enhanced MR Angiography and Cine
Phase-Contrast MR
Angiography. Microvascular adaptations could involve changes of muscle tissue
perfusion (e.g.
vasodilative capacity of microvessels), redistribution of perfusion, and/or
changes of microvascular oxygen
delivery, which can be assessed by contrast-enhanced MRI combined with
pharmacokinetic modelling
and dynamic blood-oxygen-level-dependent (BOLD) imaging of reactive hyperemia.

Given that previous studies demonstrated the feasibility of the required MRI
techniques, we propose to study
the macro- and microvascular adaptations in PAOD patients undergoing supervised
exercise therapy. It is
expected to provide valuable insights into the contribution of each vascular
mechanism to the rehabilitation and
to identify which vascular mechanism fails or is insufficient for a successful
rehabilitation. Improvement of future
treatment requires the identification of relevant adaptive mechanisms. With
this we will provide early noninvasive
MRI readout tools to diagnose and monitor the potential rehabilitation during
any form of therapy for
PAOD that affects the peripheral vasculature.

New patients with intermittent claudication (Fontaine stage II) will be
followed for 6 months after
they started a supervised treadmill exercise program. Patient examinations
comprise MRI, ankle-brachial
pressure index (ABPI), walking performance, and quality of life at 3
time-points: referral and 3 and 6 months
during the treatment

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