The role of inflammation in the pathogenesis of cardiovascular morbidity in patients with acromegaly

Acromegaly is caused by an excess of growth hormone (GH), which stimulates the
secretion of insulin-like growth factor-1 (IGF-1). Patients are characterized
by a long-term increase in cardiovascular (CV) morbidity. The pathogenesis of
these complications is not completely elucidated. Recent studies link CV
diseases to inflammatory processes and it is suggested that CV morbidity in
acromegaly might be due to effects of IGF-1 and/or GH on the immune system.
However, the inflammatory profile of acromegaly patients is largely unknown and
results of previous studies are conflicting.
We hypothesize that prolonged exposure to GH and IGF-1, induces activation of
innate immune responses, which might contribute to the long-term CV morbidity
in acromegaly.

Primary Objective: To examine comprehensively the role of inflammation in the
pathogenesis of CV complications in acromegaly. This will be done by exploring
the inflammatory and metabolic profiles of patients with acromegaly and
correlating these profiles with clinical parameters of atherosclerosis and CV
risk factors;

Secondary Objectives:
To investigate the role of GH/IGF-1 exposure on epigenetic reprogramming of the
monocytes in patients with acromegaly.
To investigate in vivo vascular imaging parameters as measure of vascular
inflammation and the presence of atherosclerotic disease.
To investigate inflammatory markers and metabolic characteristics in muscle in
order to elucidate the molecular and metabolic mechanisms governing this
process.
To investigate the contribution of genetic factors to CV morbidity in patients
with acromegaly by performing whole genome association studies.
To investigate the correlation between the gut and mouth microbiome and the CV
morbidity in patients with acromegaly.

investigator initiated, single-center explorative cross-sectional and partly
prospective study at the Radboudumc Nijmegen.

All patients (N=160) and controls (N=80) will undergo venapunction; they will
provide stool, urine (in some cases) and perform an oral swab themselves. Of
these 160 patients, a selected group of patients (N=60), including patients
with active acromegaly and patients with controlled acromegaly (either
surgically cured or biochemically controlled by use of medication), and 30
controls will also undergo non-invasive vascular ultrasound measurements. The
untreated patients from the previous selected group will be included in a
prospective sub-study. In this prospective part of the study, the newly
diagnosed patients with (active) acromegaly will also undergo muscle biopsies
(N=20). The described procedures are associated with no (cross sectional part)
or minor risks (prospective part) and represent a low burden to subjects.
Temporary (4 weeks) cessation of statin therapy is not expected to be harmful
to the participants. There are no direct benefits for the patients
participating in the study. However on the large scale, future patients with
acromegaly might benefit from the knowledge accumulated in this study,
particularly if the study identifies inflammatory pathways that could be
targeted in these patients in addition to treatment that reduces GH/IGF-1
production.