Betablocker Therapy in Pulmonary Arterial Hypertension

Idiopathic Pulmonary Arterial Hypertension (iPAH) is a rare disease in young
humans with an estimated incidence of 10 per million per year. PAH is
characterized by progressive pulmonary vascular remodeling and the associated
increased right ventricular (RV) afterload eventually leads to right heart
failure and premature death. Even with maximal treatment, prognosis remains
poor: 5 year survival is about 50%. Currently available medical treatments aim
to reduce RV afterload by dilating small pulmonary arteries, thereby *
secondarily* improving RV function. Recognition of the key role of RV function
in patient survival has not yet resulted in a treatment to directly improve RV
function.
Preclinical and clinical left heart failure studies have shown detrimental
effects of a chronically increased adrenergic activity on left ventricular (LV)
function. This is the fundamental basis for beta adrenergic receptor (AR)
blockade in current left heart failure management. Beta-AR blockade attenuates
maladaptive LV remodeling and reduces mortality by about 30%. Absence of major
effects of beta-AR blockers on the pulmonary vasculature and fear of
side-effects have prevented their use in PAH patients until now.
We conducted two independent pre-clinical studies to assess the effects of
chronic beta-AR blocker treatment in experimental animal models of
PAH-associated RV failure. The two studies showed that Bisoprolol and
Carvedilol reverse maladaptive RV remodeling and improve RV function and animal
survival. Strengthened by these results we propose a proof-of-concept clinical
study, assessing the safety and efficacy of beta-blocker treatment in 30 stable
human iPAH patients.

The main question of this study is: *Is selective beta-blocker treatment safe
and effective in reducing sympathetic overdrive, thereby improving RV function
and remodeling in patients with iPAH?*.
In addition to the determination of RVEF, we will explore how beta-blocker
therapy affects sympathetic overdrive, remodeling of the RV, single beat
elastance, exercise capacity and mechanical efficiency.

This study is a randomized, placebo controlled, double blind cross over study.

After obtaining informed consent, these 30 iPAH patients will be randomized to
either Bisoprolol- or placebo-treatment in a double-blinded fashion. A
cross-over trial design will be used to increase the power of the study and to
assess long-term effects of Bisoprolol-treatment and -withdrawal. The
medication will be given in an escalating dose regimen (as described in the
*farmacotherapeutisch kompas*, www.fk.cvz.nl) and treatment will be monitored
along the guidelines of the American Heart Association.

Safety monitoring will include two- and later on four-weekly visits to the
outpatient clinic, with physical examination and measurements of body weight,
blood pressure, ECG evaluation and 6MWD.
Time points 1, 3 and 5 (6 months periods): this includes a complete assessment
of the patient
* Clinical assessment: physical examination, NYHA class, ECG, routine lab
including NT-proBNP and urine tests for proteinuria.
* Imaging of right ventricular function: the primary measure of this study will
be right ventricular ejection fraction measured by means of MRI. Additional MRI
and echocardiographic measurements will be performed.
* Right Heart Catheterization (performed under local anesthesia): Measurements
of pressures in the pulmonary artery, right ventricle and right atrium, while
patients are breathing room air and at end-expiration.
* Exercise capacity by means of a maximal incremental cycle testing
(CardioPulmonary Exercise Test) to measure maximal work load, VO2 max,
anaerobic threshold, heart rate response, oxygen pulse and ventilatory
efficiency. And by means of 6 minute walking distance.
* Heart Rate Variability (HRV)
* Nuclear scanning: a comprised PET protocol will be performed to measure
11C-acetaat, oxygen-15-labeled water (H215O) and ¹¹C-HED uptake in the right
ventricle.
Every 2 weeks the patients will be seen on the outpatient clinic for physical
examination, laboratory tests and a questionnaire.

PAH is characterized by progressive pulmonary vascular remodeling and the
associated increased right ventricular (RV) afterload eventually leads to right
heart failure and premature death. Even with maximal treatment, prognosis
remains poor: 5 year survival is about 50%.
Radiation limits is * 18,3 mSv during the whole study. This is a small
exceeding of the allowed limit of 10mSv/year. Because the risks of exceeding
radiation limits are a long term risk, we believe that the poor prognosis of
patients with iPAH and the relevance of the study question justify these
PET-scans.
The most common adverse reaction reported by patients who have used Bisoprolol
is (orthostatic) hypotension and mild ankle edema. Other possible side-effects
are bradycardia and any degree heart block. Although Bisoprolol has a very
favorable safety profile, side-effects may occur and frequent communication
between the patients and study investigators/coordinators will likely be
necessary.