Effect of BMPR-2 Gene Mutations on Hemodynamic Response by Iloprost Inhalation in Pulmonary Arterial Hypertension (PILGRIM)

• Major cardiovascular Events (cardiovascular mortality, all cause mortality, hospitalization) [ Time Frame: After 2 years follow-up ] [ Designated as safety issue: No ]
• Six-minutes walking test [ Time Frame: After 3 months active follow-up ] [ Designated as safety issue: No ]
• WHO/NYHA class [ Time Frame: After 3 months active follow-up ] [ Designated as safety issue: No ]
• Echo parameters [ Time Frame: After 3 months active follow-up ] [ Designated as safety issue: No ]
• NT-proBNP [ Time Frame: After 3 months active follow-up ] [ Designated as safety issue: No ]

• Major cardiovascular Events (cardiovascular mortality, all cause mortality, hospitalization) [ Time Frame: After 2 years follow-up ] [ Designated as safety issue: No ]
• Six-minutes walking test [ Time Frame: After 6 months active follow-up ] [ Designated as safety issue: No ]
• WHO/NYHA class [ Time Frame: After 6 months active follow-up ] [ Designated as safety issue: No ]
• Echo parameters [ Time Frame: After 6 months active follow-up ] [ Designated as safety issue: No ]
• NT-proBNP [ Time Frame: After 6 months active follow-up ] [ Designated as safety issue: No ]

In the present study, the investigators want to investigate the prevalence of BMPR-2 gene mutations in the Korean PAH patients (Step-I) and to test that the PAH patients treated with iloprost inhalation solution (Ventavis®) would show hemodynamic response, especially assessed by exercise echocardiography (Step-II).

Pulmonary arterial hypertension (PAH) consists of a group of vascular abnormalities with elevated pulmonary arterial pressure and pulmonary vascular resistance. Idiopathic or familial PAH is progressive over several years and believed to be fatal without treatment. (1-2) The results of the Endothelin Antagonist tRial in mildly symptomatic PAH (EARLY) indicate that early diagnosis and treatment of PAH might improve time to clinical worsening and emphasize that PAH needs to be diagnosed and treated in the early stages. (3) Germline mutations of bone morphogenetic protein receptor (BMPR)-2, a member of the transforming growth factor (TGF)-β superfamily, have been found in familial and sporadic forms of idiopathic PAH,(4-6) and in appetite-suppressant PAH.(7) The BMPR-2 gene, on chromosome 2q33, has 13 exons. Exons 1-3 encode an extracellular domain, exon 4 encodes the transmembrane domain, exons 5-11 a serine/threonine kinase domain, and exons 12 and 13 a very large intracellular C-terminus of unknown function that appears to be unique to BMPR-2. (8) Mutations in familial PAH have been reported in all exons except for 5 and 13. (9) About 10-25% of sporadic cases of idiopathic PAH are thought to have BMPR-2 mutations (10) and rare cases of PAH associated with congenital heart disease, connective tissue disease and drug induced PAH were reported. (11-12) It is likely that genetic predispositions exist based on normal variations in genes that may influence the pulmonary circulation. However, the studies regarding prevalence of BMPR-2 gene mutations in Korean patients have not been performed.

In a previous study, family members of familial PAH patients showed an increased pulmonary artery systolic pressure (PASP) rise during exercise as assessed by echocardiography. (13-14) In other study, relatives of idiopathic/familial PAH patients displayed enhanced frequency of pulmonary hypertensive response during exercise and that this response is associated with mutations in the BMPR-2 gene. (15) These results suggest that asymptomatic gene carriers, in the absence of manifest pulmonary hypertension, might have enhanced PASP during exercise and more risk to develop resting pulmonary hypertension in the future compared with patients without gene mutations. Therefore, the treatment response by variable vasodilators (ex. calcium channel blockers, endothelin antagonist or prostacyclin analogues..) may be different based on the presence of BMPR-2 gene. In the present study, we want to investigate the prevalence of BMPR-2 gene mutations in the Korean PAH patients(Step-I) and to test that the PAH patients treated with iloprost inhalation solution (Ventavis®) would show hemodynamic response, especially assessed by exercise echocardiography (Step-II).

• Step I: BMPR-2 gene analysis
  BMPR-2 gene analysis on 100 IPAH or heritable PAH Patients
  Intervention: Drug: Iloprost
• Active Comparator: Step-II: Iloprost and Exercise Echo
  Illoprost inhalation for 3 months & Check-up before and after treatment; WHO functional classification Assessment of exercise capacity (6M walk test) Cardiopulmonary exercise echocardiography NT-proBNP
  Intervention: Drug: Iloprost

Inclusion Criteria:

1. The patients aged from 20 to 80 years
2. Newly diagnosed WHO category I PAH patients: Patients who meet the following criteria within 3 months obtained by right heart catheterization (mean PAP of more than 25 mm Hg at rest and mean pulmonary arterial wedge pressure (PCWP) or left ventricular end-diastolic pressure of 15 mm Hg or less) or echocardiography (peak PAP of more than 40mmHg and mean PAP more than 30mmHg).
3. Previously diagnosed PAH patients who refractory to conventional treatment except iloprost inhalation solution (Ventavis): Patients meet the echo criteria (peak PAP of more than 40mmHg and mean PAP more than 30mmHg) who have been treated with PAH medications except iloprost inhalation solution (Ventavis) after diagnosed as WHO Group 1 PAH based on prior RHC data (above criteria) but refractory to them.
4. The patients who are able to undergo low intensity exercise test (low dose bicycle or walking)

Exclusion Criteria:

1. The patients with other left heart disease (category II in WHO classification of pulmonary hypertension); ex. Congestive HF, cardiomyopathy, significant valvular heart disease, significant arrhythmia, suspicious elevated PCWP.

2. The patients with category III,IV and V in WHO classification of pulmonary hypertension:

   • Pulmonary hypertension with lung disease and/or hypoxemia
   • Chronic obstructive pulmonary disease
   • Interstitial lung disease
   • Sleep disorder breathing
   • Alveolar hyperventilation disorders
   • Chronic exposure to high altitude
   • Developmental abnormalities
   • Pulmonary hypertension due to chronic thrombotic and/or embolic disease
   • Thromboembolic obstruction of the proximal pulmonary arteries
   • Thromboembolic obstruction of the distal pulmonary arteries
   • Non-thrombotic pulmonary embolism (e.g. tumor or parasitic)
   • Miscellaneous disorders affecting the pulmonary vasculature
   • Patients with contraindication to Ventavis;(Hypersensitive to Ventavis, High risk of bleeding, which can be increased by use of Ventavis (e.g. active peptic ulcer, trauma, intracranial hemorrhage)
   • Severe coronary disease
   • Unstable angina
   • History of Acute myocardial infarction within 6 months
   • Uncompensated heart failure not under close medical monitoring
   • Severe arrhythmia
   • Suspected pulmonary congestion
   • Cerebrovascular disease within 3 months (e.g. transient ischemic attack, stoke)
   • Pulmonary hypertension due to venous occlusive disease, valvular defect with dysfunction of cardiac muscle, which is independent of pulmonary hypertension)
   • Pregnancy
   • Women with high probability of pregnancy
   • Breast feeding
   • Renal failure (creatinine clearance: less than 30mL/min)
3. The patients concurrently using other pulmonary vasodilator (ex. Inhaled NO, endothelin antagonists) except PDE5 inhibitor
4. The patients with poor echo window which is unavailable to accept the echo data
5. The patients who cannot do any exercise
6. The patients who changes medication administered during ventavis treatment
7. The patients with allergic reaction to ventavis
8. The patients with other systemic disease (ex. Leukemia, MM, Sickle cell anemia, significant liver disease)

• Seoul National University Hospital
• Seoul National University Bundang Hospital
• The Catholic University of Korea
• Bayer