Redistribution of pulmonary blood flow as a cause for the progression of pulmonary hypertensionin after chronic thrombo-emboli.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease with
progressive pulmonary vascular damage that develops after an episode of
pulmonary embolisms.
Recent research in an animal shunt model revealed that hyperdynamic flow leads
to an uncontrolled proliferation of endothelial cells in the pulmonary
arterioles and pathologic vasoconstriction. In addition, it was found that the
pulmonary endothelium senses the mechanical stretch and responds by enhancing
collagen tissue in the vessel wall leading to a further remodeling of the
pulmonary arterioles. Furthermore, there is also the clinical observation that
hyperdynamic pulmonary flow in patients with a congenital atrial septal defect
can lead to endothelial dysfunction and arterial remodeling, causing PH. Based
on these findings we hypothesize that in patients with CTEPH, hyperdynamic flow
and increased PAP in the non-obstructed parts of the pulmonary vascular bed
lead to endothelial dysfunction inducing pathologic vasoconstriction and
vascular remodeling, finally inducing progressive increase in PAP.

We aim to investigate whether this damage results from altered
pulmonary blood flow patterns and related increases in shear stress and
vascular remodelling. To test our hypothesis we will make use of novel
techniques to quantify pulmonary perfusion in the lungs during the course of
the disease by magnetic resonance perfusion imaging.

In 30 patients with CTEPH we will quantify the dynamic pulmonary blood
flow using 3-dimensional contrast-enhanced MRI. After 6 months we will repeat
this 3D contrast- enhanced MRI. According to our hypothesis decrease in flow
and an increase in pulmonary vascular resistance in the non-obstructed parts
during follow up relative to changes in flow and resistance in obstructed parts
will be considered as evidence that vascular remodelling takes place in the
non-obstructed vessels.

The MRI causes so far we know from literature no damage to people. Injecting of
the bolus in an armvein is a routine job and will be done by a doctor,
therefore no problem is expected. The contrast liquid gadolineum is not harmful
for patients, unless the patient has a decreased kidney function. In that case
the patient will be excluded.
In PH, independent of cause, increased pulmonary vascular pressure enhances
mechanical stretch which is sensed by the pulmonary endothelium and causes
endothelial injury/dysfunction. To assess whether endothelial dysfunction is
the underlying cause of pulmonary vasoconstriction in CTEPH, the following
markers for endothelial dysfunction will be determined:
- soluble adhesion molecules of the selectin class (soluble platelet selectin
[sP-selectin], soluble endothelium
selectin [sE-selectin], soluble leukocyte selectin
[sL-selectin]) using a commercial quantitative colorimetric ELISA.
- Nitric oxide (NO, potent vasodilator) using a commercial quantitative
colorimetric assay.
- endothelin-1 (potent vasoconstrictor and platelet-aggregation stimulant)
using a commercial radioimmunoassay.
- urinary levels of prostacyclin metabolites (potent vasodilator and
anti-platelet-aggregation).
- urinary levels of thromboxane A2 metabolites (potent vasoconstrictor and
platelet-aggregation).