Structural and Functional Microcirculatory Aspects of Patients with (suspected) Connective Tissue Disease and Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is described as a group of disorders
characterized by a progressive increase of the pulmonary vascular resistance
leading to right ventricular failure and premature death. PAH includes
idiopathic PAH (IPAH), familial PAH (FPAH) and PAH secondary to connective
tissue diseases (CTD). Microvascular dysfunction may be a common denominator
linking PAH with CTD. A CTD with a high prevalence of PAH is systemic sclerosis
(SSc), a disorder typically characterized by structural impairment of the
microcirculation as assessed with capillary microscopy in the nailfold, and a
possible impairment of endothelium-(in)dependent microcirculatory function in
the skin as assessed with iontophoresis combined with laser Doppler fluxmetry.
In several PAH centres including our centre, a group of patients with PAH can
be distinguished displaying signs and symptoms suggestive of CTD that lack the
characteristics of any classifiable disease, called undifferentiated connective
tissue disease (UCTD). Whereas most (~80-90%) of the patients with systemic
sclerosis exhibit peripheral structural impairment of microvascular function,
this is only true for a minority (~14%) of patients with UCTD. Presently it is
unknown whether patients with UCTD and PAH are characterized by impaired
peripheral microvascular function. It is also not known whether patients with
UCTD and impaired microvascular function are at increased risk for developing
PAH. This would enable early identification of these patients, which is of
paramount importance given the severe prognosis of CTD-related PAH. This is
especially relevant now that it is recognized that several newly developed
vasoactive agents have effects on vascular remodelling, including prostanoids,
endothelin-1 antagonists, and PDE-5 inhibitors. Another unknown issue is
whether assessment of morphological and functional derangements can be of aid
in differentiating phenotypes of patients with PAH, monitoring microvascular
disease progression and/or treatment response, and predicting prognosis in
these patients.

The proposed project focuses on: a) implementation of an improved, standardized
method for performing quantitative nailfold capillaroscopy to visualize
morphological patterns and evaluate its diagnostic use in patients with
(possible) CTD and suspected PAH and its use in monitoring disease progression
and response to therapy; b) assessment of the relationship between, on the one
hand structural, and on the other functional characteristics of the
microcirculation, and the subtype and severity of PAH; c) investigate whether
newly developed treatments have an effect on skin microcirculation, and if such
an effect correlates with the clinical and/or hemodynamic response to these new
therapies in patients with PAH.

Observational, cross sectional.

Because of its readily accessibility, the skin and nailfold capillaries will be
used to investigate the microcirculation. Noninvasive tools used in this study
to investigate microcirculatory structure and function respectively, are
capillary microscopy of the nailfold, and iontophoresis with acetylcholine (to
assess endothelial dependent vasoactivity) and nitroprusside (to assess
endothelial independent vasoactivity) combined with laser Doppler techniques.

As stated above non-invasive tools will be used:

a) Capillaroscopy:
-no restrictions
-no risk
-investigation will take ~45 minutes

b) Iontophoresis combined with laser Doppler:
-participants have to refrain from eating, smoking and beverages at least 4
hours
-except for local transitory redness of the skin (fading away within
approximately 30 minutes) in some cases, no risks are expected
-investigation will take ~45 minutes