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