Catheter Denervation of Pulmonary Arteries in Treatment of IPAH & SPAH
Catheter Denervation of Pulmonary Arteries in Treatment of IPAH & SPAH
The aim of research proposal is to assess and compare the safety and efficacy of
 radiofrequency denervation of pulmonary arteries on decrease in pulmonary vascular resistance
 and mean pulmonary artery pressure (MPAP) in 20 patients with IPAH (mean pulmonary artery
 pressure >25 mmHg) and in 20 patients with secondary pulmonary hypertension due to pulmonary
 disease or due to left heart disease not responding optimally to medical therapy.
METHODS:

 Patient population. Patients with IPAH and SPAH (defined as a mean PAP >25 mm Hg at rest) not
 responding optimally to current medical therapy (defined as a reduction of <5mmHg in the
 resting mean PAP during medication, or unchanged 6-min walk test (6MWT) defined as increment
 of 6MW distance <50 m) will be eligible for the study. The patients will be informed that
 they have the right to withdraw their informed consent at any time. After signing a
 previously approved institutional written informed consent 20 patients with proven IPAH and
 20 patients with proven SPAH and 20 control patients (10 with IPAH and 10 with SPAH) will be
 randomly assigned to radiofrequency denervation of pulmonary arteries or to sham group.
 Patients of age <18 years, patients with structural heart diseases with left-to right
 shunting and/or with Eisenmenger syndrome will be excluded from the trial. Medical treatment
 before enrollment including a diuretics sildenafil or bosentan or digoxin or any other
 necessary medication will not be discontinued. Blood samples will be obtained for N-terminal
 brain natriuretic peptide (NT-BNP), troponin T, mbCK, CK and other usually accepted
 biological markers of pulmonary hypertension levels before, immediately after the pulmonary
 artery denervation (PADN) procedure, and at 3 and 6 months following the PADN procedure. For
 the assessment of potential anatomical complications at the sight of PADN a multisliced
 computed tomography angiography of pulmonary trunk and pulmonary arteries will be obtained
 before and 6 months after PADN procedure. Assessment of functional capacity (9) will be
 determined by the six-minutes walk test (6MWT), followed by an assessment of dyspnea using
 the Borg scale (10). The 6MWT will be performed at 3 month and 6 months following the PADN
 procedure. The World Health Organization classification (11) at rest and during exercise will
 be recorded by a physician blinded to the study design.

 Echocardiography will be performed at 3 month and 6 months following the procedure.
 Echocardiographic studies will be done using a Vivid 7 ultrasound system with a standard
 imaging transducer (General Electric Co., Easton Turnpike, Connecticut). All of the
 measurements will be performed according the recommendations of the American Society of
 Echocardiography (12). Digital echocardiographic data that contained a minimum of 3
 consecutive beats (or 5 beats in cases of atrial fibrillation) will be acquired and analyzed.
 Right ventricular (RV) systolic pressure is equal to systolic PAP in the absence of pulmonary
 stenosis. Systolic PAP is equal to the sum of the right atrial (RA) pressure and the RV-to-RA
 pressure gradient during systole. RA pressure will be estimated based on the
 echocardiographic features of the inferior vena cava and assigned a standard value (13). The
 RV-to-RA pressure gradient will be calculated as 4vt2 using the modified Bernoulli equation,
 where vt is the velocity of the tricuspid regurgitation jet in m/s. The mean PAP will be
 estimated according to the velocity of the pulmonary regurgitation jet in m/s. The tricuspid
 excursion index (Tei) (14) is defined as (A-B)/B, where A is the time interval between the
 end and the onset of tricuspid annular diastolic velocity, and B is the duration of tricuspid
 annular systolic velocity (or the RV ejection time). PA compliance for patients will be
 calculated as the stroke volume divided by pulse pressure (systolic PAP minus diastolic PAP).
 Hemodynamic measurements and blood oxygen pressure/saturation determinations from the RA, RV,
 and PA will be performed as previously described using right heart catheterization before and
 immediately after the PADN procedure. These measurements will be repeated at 24 h, 3 months
 and 12 months. Measurements of resting RA pressure, RV pressure, systolic/diastolic/mean PAP,
 PA occlusive pressure (PAOP), cardiac output (CO) and mixed venous oxygen saturation will be
 recorded. The pulmonary vascular resistance (PVR) [PVR ¼(mean PAP- PAOP)/CO] and
 transpulmonary pressure gradient (TPG ¼ mean PAP- PAOP) will then be calculated. All of the
 measurements will be recorded at the end of expiration. Five criteria (15-17) will be used to
 evaluate whether a PAOP measurement was valid: 1) the PAOP was less than the diastolic PAP;
 2) the tracing was comparable to the atrial pressure waveform; 3) the fluoroscopic image
 exhibited a stationary catheter following inflation; 4) free flow was present within the
 catheter (flush test); and 5) highly oxygenated blood (capillary) was obtained from the
 distal portion in the occlusion position. If the PAOP measurement was unreliable, the left
 ventricular end-diastolic pressure will then be measured and used rather than the PAOP.

 The blood samples from the superior vena cava and PA will be obtained for the measurements of
 oxygen pressure and saturation. PADN procedure. A baseline PA angiography will be performed
 to identify the PA bifurcation level and calculate the PA diameter. An 8-F long sheath will
 be inserted through the femoral vein and advanced to the main PA (MPA). The PADN catheter
 will be advanced along this long sheath. After gently withdrawing the sheath and pushing the
 PADN catheter, the tip will be released from the sheath. Then, by slightly rotating and
 pushing the handle the tip will be positioned first at the ostium of the left PA (Level 1 of
 ablation, <2 mm distal to orifice. After ablation at this level, the catheter tip will be
 positioned at the ostium of right PA (Level 2 of ablation, <2mm proximal to the bifurcation
 level). Finally, denervation of main pulmonary artery will be done by pulling the denervation
 catheter back into Level 3 of ablation (<2 mm proximal to both ostia of right and left PA-s)
 into main pulmonary artery.Three criteria will be used to ensure that the electrodes were
 tightly in contact with the endovascular surface: 1) strong manual resistance when rotating
 the handle; 2) inability to advance distally or ease in, withdrawing proximally 3)
 angiographic confirmation and 4) actual electrode contact pressure (gm) readings provided by
 RF denervation system used. The procedure will be stopped if the patient complained of
 intolerable chest pain. The electrocardiogram and hemodynamic pressure will be monitored and
 continuously recorded throughout the procedure. Procedural success will be defined as a
 reduction in the mean PAP >10 mm Hg (as measured by the Swan-Ganz catheter), and there were
 no complications. The patients will be monitored in the intensive cardiac care unit for at
 least 24 h after the PADN procedure. Commercially available and approved radiofrequency
 technology for pulmonary vein isolation will be utilized for new clinical indication.

 Peri-procedural medications. An intravenous bolus of 5,000 U of unfractionated heparin will
 be given immediately following the insertion of the venous sheath. An additional
 approximately 2,000 to 3,000 U of heparin will be added if the procedural time exceeds 1 h.
 Following the procedure, oral warfarin will be prescribed and adjusted according to the
 international normalized ratio to be between 2 and 2.5 for all patients. If there would be
 contraindications for warfarin, aspirin (100 mg/day) and clopidogrel (75 mg/day) will be
 prescribed indefinitely. Immediately after the PADN procedure, all medications (diuretics,
 sildenafil, bosentan, beraprost, digoxin etc.) will be discontinued for 24h.

 Endpoints. The primary endpoints will be decrease in mean PAP and pulmonary vascular
 resistance at 3 and 6 months and improvement of functional capacity by the 6MWT. Clinical
 adverse events (including PA perforation/dissection, acute thrombus formation in the PA,
 all-cause death, rehospitalization due to PAH, and lung transplantation) will be secondary
 endpoints and will be assessed by an independent event committee. Statistical analysis.
 Continuous variables will be expressed as mean + SD. Differences in continuous variables
 between different time points in the PADN group will be analyzed using paired-sample Student
 t tests or Wilcoxon signed- rank sum tests, as appropriate nonparametric statistical methods.
 Each patient in the trial will serve as his/her own control before and after PADN and sham
 group patients as a control group of overall efficacy of the procedure. The categorical
 variables will be compared using the Fisher exact test. Statistical significance will be
 defined as a 2-sided p value < 0.05. All of the analyses will be performed using WinStat
 statistical software package for Microsoft Excel, version 2009.
Inclusion Criteria:

 -  Patients with IPAH and SPAH (defined as a mean PAP >25 mm Hg at rest) not responding
 optimally to current medical therapy (defined as a reduction of <5mmHg in the resting
 mean PAP during medication, or unchanged 6-min walk test (6MWT) defined as increment
 of 6MW distance <50 m) will be eligible for the study.

 Exclusion Criteria:

 - Patients of age <18 years, patients with structural heart diseases with left-to right
 shunting and/or with Eisenmenger syndrome will be excluded from the trial.