Author + information
- Received March 8, 2013
- Revision received May 15, 2013
- Accepted May 22, 2013
- Published online September 17, 2013.
- Shao-Liang Chen, MD∗,†∗ (, )
- Feng-Fu Zhang, MD∗,
- Jing Xu, MD∗,
- Du-Jiang Xie, MD∗,
- Ling Zhou, MD∗,
- Thach Nguyen, MD‡ and
- Gregg W. Stone, MD§
- ∗Cardiological Department, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- †Cardiological Department, Nanjing Heart Center, Nanjing, China
- ‡St. Mary Medical Center, Hobart, Indiana
- §Cardiovascular Research Foundation, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Shao-Liang Chen, Cardiological Department, Nanjing First Hospital, Nanjing Medical University, Nanjing 21006, China.
Objectives This study was designed to test the safety and efficacy of pulmonary artery (PA) denervation (PADN) for patients with idiopathic PA hypertension (IPAH) not responding optimally to medical therapy.
Background Baroreceptors and sympathetic nerve fibers are localized in or near the bifurcation area of the main PA. We previously demonstrated that PADN completely abolished the experimentally elevated PA pressure responses to occlusion of the left interlobar PA.
Methods Of a total of 21 patients with IPAH, 13 patients received the PADN procedure, and the other 8 patients who refused the PADN procedure were assigned to the control group. PADN was performed at the bifurcation of the main PA, and at the ostial right and left PA. Serial echocardiography, right heart catheterization, and a 6-min walk test (6MWT) were performed. The primary endpoints were the change of PA pressure (PAP), tricuspid excursion (Tei) index, and 6MWT at 3 months follow-up.
Results Compared with the control group, at 3 months follow-up, the patients who underwent the PADN procedure showed significant reduction of mean PAP (from 55 ± 5 mm Hg to 36 ± 5 mm Hg, p < 0.01), and significant improvement of the 6MWT (from 324 ± 21 m to 491 ± 38 m, p < 0.006) and of the Tei index (from 0.7 ± 0.04 to 0.50 ± 0.04, p < 0.001).
Conclusions We report for the first time the effect of PADN on functional capacity and hemodynamics in patients with IPAH not responding optimally to medical therapy. Further randomized study is required to confirm the efficacy of PADN.
(First-in-Man Pulmonary Artery Denervation for Treatment of Pulmonary Artery Hypertension [PADN-1] study; chiCTR-ONC-12002085)
Idiopathic pulmonary arterial hypertension (IPAH) is characterized by elevations of mean pulmonary artery (PA) pressure (PAP) and pulmonary vascular resistance (PVR) (1). The pathogenesis of IPAH was believed to be due to an imbalance between locally produced vasodilators and vasoconstrictors (2). Recent studies have demonstrated that vascular wall remodeling also contributes to elevated PVR (3). Up to now, the role of neural reflex in the mediation and development of IPAH has not been specifically investigated. In 1962, Osorio et al. (4) reported the existence of a pulmopulmonary baroreceptor reflex that originates in the large pulmonary branches, with neither the afferent nor the efferent fibers belonging to the vagus nerve. In 1980, these findings were again confirmed by Juratsch et al. (5) and Baylen et al. (6). More recently, our animal study (7) demonstrated that PA denervation (PADN) could completely abolish the increment of PAP induced by balloon occlusion at the interlobar segment but not at the basal trunk. On the basis of such findings, we designed a first-in-man study to test the safety and efficacy of PADN by inducing local injury/destruction to the baroreceptor or sympathetic nervous fibers in patients with IPAH who did not respond optimally to current medical therapy.
Patients with IPAH (defined as a mean PAP ≥25 mm Hg at rest) not responding optimally to current medical therapy (defined as a reduction of <5 mm Hg in the resting mean PAP during medication, or unchanged 6-min walk test (6MWT) defined as increment of 6MW distance <50 m) were eligible for the study. A total of 22 patients were screened. One patient was excluded after a positive adenosine test (defined as a decrease of the mean PAP ≥10 mm Hg to an absolute level of <40 mm Hg (8), measured by right heart catheterization). Eight patients refused to consent and were assigned to the control group. These patients continued to receive the same medical therapy as before enrollment. Thirteen patients were included in the study group.
Medical treatment before enrollment
Before enrollment, all 21 patients received a diuretic (hydrochlorothiazide at a dose of 12.5 mg to 25 mg, once daily, and/or spironolactone at a dose of 20 mg to 40 mg, once daily) and beraprost (120 mg, 4 times daily) (Table 1), with either sildenafil (20 mg, 3 times a day) or bosentan (120 mg, twice daily) or digoxin (0.125 mg, once daily).
All patients were informed that PADN was only tested previously in an animal study that showed that PADN could abolish the elevated PAP response to occlusion of the left interlobar PA by a balloon inflation (7). According to the study protocol, the risk of medications being withdrawn after the PADN procedure was described to each patient. The patients were also informed that they had the right to withdraw their consent at any time. The study protocol was presented in detail to the institutional review board and was approved by the institutional review board and ethics committee. Written consent was obtained from all patients.
Assessment of N-terminal brain natriuretic peptide level
Blood samples were obtained for N-terminal brain natriuretic peptide (NT-BNP) levels before, immediately after the PADN procedure, and at 24 h, 1 week, 1 month, 2 months, and 3 months following the PADN procedure.
Assessment of functional capacity
Functional capacity (9) was determined by the 6MWT, followed by an assessment of dyspnea using the Borg scale (10). The 6MWT was performed at 1 week, 1 month, 2 months, and 3 months following the PADN procedure. The World Health Organization classification (11) at rest and during exercise was recorded by a physician who was blinded to the study design.
Echocardiography was performed at 1 week, 1 month, 2 months, and 3 months following the procedure. Echocardiographic studies were done using a Vivid 7 ultrasound system with a standard imaging transducer (General Electric Co., Easton Turnpike, Connecticut). All of the echocardiograms were performed and interpreted in the medical university's echocardiographic laboratory. All of the measurements were performed following 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) were acquired and stored. 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 was estimated based on the echocardiographic features of the inferior vena cava and assigned a standard value (13). The RV-to-RA pressure gradient was calculated as 4vt2 using the modified Bernoulli equation, where vt is the velocity of the tricuspid regurgitation jet in m/s. The mean PAP was 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 was calculated as the stroke volume divided by pulse pressure (systolic PAP minus diastolic PAP).
Right heart catheterization
Hemodynamic measurements and blood oxygen pressure/saturation determinations from the RA, RV, and PA were done before and immediately after the PADN procedure. These measurements were repeated at 24 h and 3 months.
A 7-F flow-directed Swan-Ganz catheter (131HF7, Baxter Healthcare Corp., Irvine, California) was inserted into an internal jugular or subclavian vein. Measurements of resting RA pressure, RV pressure, systolic/diastolic/mean PAP, PA occlusive pressure (PAOP), cardiac output (CO) (using the thermodilution method), and mixed venous oxygen saturation were recorded. The PVR [PVR = (mean PAP − PAOP)/CO] and transpulmonary pressure gradient (TPG = mean PAP − PAOP) were then calculated. All of the measurements were recorded at the end of expiration. Five criteria (15–17) were 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 was then measured and used rather than the PAOP. The blood samples from the superior vena cava and PA were obtained for the measurements of oxygen pressure and saturation.
A dedicated 7.5-F multiple-function (temperature sensing and ablation) catheter (PADN, patent application in progress) consisted of 2 parts: catheter shaft and handle (Fig. 1A). This catheter had a tapered (to 5-F) circular tip with 10 pre-mounted electrodes (separated from each other by 2 mm) (Fig. 1B). The circular tip had an outer diameter of 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, and 45 mm, respectively. The “connect” cable linked the handle to the “connect” box (Fig. 1C). There were 3 ports (Fig. 1D) on either side of the connect box: “Catheter” was for the connection of the cable and the catheter handle, “RF” was for connecting with all kinds of radiofrequency generators used in the market, and “ECG” was for connecting with electrocardiogram monitoring equipment. On the surface of the “connect” box, there was 1 button marked by numbers 1 to 10 and “OFF” and “NULL.” Numerical buttons indicated the location of each electrode on the circular tip of the catheter. When a whole system was set up (Fig. 1E), turning the numerical button on the connect box to “1” would indicate that the ablation was performed through the first electrode at the catheter tip.
A baseline PA angiography was performed to identify the PA bifurcation level and calculate the PA diameter (Figs. 2A to 2C). An 8-F long sheath was inserted through the femoral vein and advanced to the main PA (MPA) (Fig. 2A). The PADN catheter was advanced along this long sheath (Fig. 2B). After gently withdrawing the sheath and pushing the PADN catheter, the circular tip would be released from the sheath (Fig. 2C). Then, by slightly rotating and pushing the handle in a clockwise direction, the circular tip would be positioned at the ostium of the left PA (Level 1 of ablation, <2 mm distal to orifice, (Fig. 2D). After ablation at this level, counterclockwise rotation and withdrawing the handle would allow the circular tip to slide down to the distal bifurcation area of the MPA (Level 2 of ablation, <2 mm proximal to the bifurcation level) (Fig. 2E). Finally, continuously rotating and pushing the handle was performed until the circular tip jumped into Level 3 of ablation (<2 mm distal to the ostial right PA) (Fig. 2F).
Three criteria were 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 (Fig. 2G) or ease in, withdrawing proximally (Fig. 2H); and 3) angiographic confirmation. Following these confirmations, ablation would begin from the 1st to the 10th electrode at Level 1 and then at Levels 2 and 3. Following the first round of ablation at each level, the catheter tip was gently withdrawn, rotated, and re-advanced to ensure that the entire diameter of the vessel axis was being ablated.
The following ablation parameters were programmed at each level: temperature >50°C, energy = 10 W, and time = 60 s. The procedure would be stopped if the patient complained of intolerable chest pain. The electrocardiogram and hemodynamic pressure were monitored and continuously recorded throughout the procedure. Procedural success was 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 were monitored in the cardiac care unit for at least 24 h after the PADN procedure.
An intravenous bolus of 5,000 U of heparin was given immediately following the insertion of the venous sheath. An additional approximately 2,000 to 3,000 U of heparin was added if the procedural time was greater than 1 h. Following the procedure, oral warfarin was prescribed and adjusted according to the international normalized ratio to be between 1.5 and 2.5 for all patients. If there were contraindications for warfarin, aspirin (100 mg/day) and clopidogrel (75 mg/day) were prescribed indefinitely. Immediately after the PADN procedure, all medications (diuretics, sildenafil, bosentan, beraprost, and digoxin) were discontinued in the study group; the use of supplemental oxygen was left to the physician's discretion.
For patients in the control group, all medications that were previously prescribed before screening were continued. Their doses were adjusted and left to the physician's discretion.
The primary endpoints were improvement of functional capacity by the 6MWT and mean PAP at 3 months. Clinical adverse events (including PA perforation/dissection, acute thrombus formation in the PA, all-cause death, rehospitalization due to PAH, and lung transplantation) served as secondary endpoints and were assessed by an independent event committee.
PAH was defined as a resting mean PAP ≥25 mm Hg. Normal PAOP is between 6 and 12 mm Hg. The normal TPG is ≤12 mm Hg. Pre-capillary PAH was defined as a mean PAP ≥25 mm Hg in association with PAOP ≤15 mm Hg and PVR >3 Woods units. Post-capillary PAH was defined as a mean PAP ≥25 mm Hg in association with PAOP >15 mm Hg and a PVR ≤3 Woods unit (15,16).
Continuous variables are expressed as mean ± SD. The normality test for all of the continuous variables was performed using Kolmogorov-Smirnov and Shapiro-Wilk tests. Differences in continuous variables between different time points in the PADN group or between the PADN and control groups were analyzed using paired-sample Student t tests or Wilcoxon rank sum tests, as appropriate. The categorical variables were compared using the Fisher exact test. Statistical significance was defined as a 2-sided p value < 0.05. All of the analyses were performed using the statistics program SPSS version 16.0 (SPSS Institute, Chicago, Illinois).
Between March and May 2012, a total of 21 patients with PAH not responding optimally to current medical treatment were included (Table 1).
All patients presented with dyspnea and fatigue. Patients in the PADN group had more frequent chest pain (77%), compared with 50% in the control group (p = 0.033). The average time interval between the onset of symptom to diagnosis was 3.5 years. All patients did not respond optimally to current medical treatment after an average of 3.3 years combination of therapy using at least 2 drugs.
Baseline echocardiographic variables were comparable between the 2 groups (Table 2). After 3 months treatment, there were no significant differences in echocardiographic measurements in the control group.
PADN procedure was associated with significant reduction of the systolic PAP and mean PAP through the 3 months follow-up. The size of the pericardial effusion (thickness of the fluid layer) was reduced from 3.5 ± 0.8 mm at baseline to 2.7 ± 0.5 mm (p < 0.001) immediately following the PADN procedure. This metric was decreased to 0.7 ± 0.4 mm at the 3-month follow-up (p < 0.001). Importantly, the RV Tei index was significantly improved from 0.7 ± 0.04 at baseline to 0.5 ± 0.04 (p < 0.001) at 3 months.
Right heart catheterization
At baseline, there were no differences in hemodynamic measurements between the PADN and control groups (Table 3). Procedural success was achieved in 12 (92.3%) patients. Procedural failure (a reduction of 6 mm Hg in the mean PAP) was recorded in 1 patient. This patient developed intolerable chest pain induced by the PADN procedure after ablation of the ostial left PA branch. The procedure was stopped for this patient.
Immediately following the PADN procedure, the systolic PAP and mean PAP significantly decreased from a baseline of 86 ± 8 mm Hg to 72 ± 5 mm Hg (p < 0.01) and from 55 ± 5 mm Hg to 39 ± 7 mm Hg (p < 0.01), respectively. These reductions were maintained through 3 months follow-up. Following the reduction of PAP, CO increased significantly (from 2.0 ± 0.2 l/min · m2 to 2.8 ± 0.3 l/min · m2, p < 0.001), leading to the significant reduction of TPG and PVR and significant increment of venous O2 saturations in PA.
In the PADN group, PA compliance increased significantly from 0.20 ± 0.04 ml/mm Hg at baseline to 0.38 ± 0.06 ml/mm Hg at 3 months (p < 0.001), and this remained unchanged in the control group.
Assessment of functional capacity
In the PADN group, the baseline NT-BNP was 2,005 ± 442 pg/ml, which was significantly reduced to 822 ± 201 (p = 0.003) at 3 months following the procedure (Table 4). After 1 week, the 6MW distance increased significantly from a baseline of 324 ± 21 m to 459 ± 42 m (p = 0.009) at 1 month, 487 ± 47 m (p = 0.004) at 2 months, and 491 ± 38 m (p = 0.004) at 3 months. This improvement was associated with significant improvements in the World Health Organization class and BORG score. There was no improvement in either 6MW distance or functional classes in the control group.
In the PADN group, all medications were discontinued except for the oral anticoagulant (with 1 patient also on diuretics). Three patients (23%) needed supplemental oxygen as required before the procedure. No PA perforation/dissection/aneurysm or acute thrombus formation in the PA for the PADN group was observed. There were no patients requiring lung transplantation in either group. By contrast, rehospitalization was required in 5 patients (62.5%) in the control group, and none in the PADN group (p < 0.001).
All patients had chest pain during the PADN procedure, with 1 patient having intolerable pain for whom the PADN procedure was not completed. There were 2 deaths during the 3-month follow-up. One patient died from septic shock 87 days following the PADN procedure. This 42-year-old lady with IPAH was first treated with bosentan for 3 months. Bosentan was stopped because of severe liver damage, then diuretics and sildenafil were prescribed for 2.2 years. This patient went for the PADN procedure and after the procedure, the mean PAP was reduced from 59 mm Hg at baseline to 23 mm Hg at 2 months follow-up. Her 6MWT increased from 134 m before, to 245 m post-PADN procedure. At 87 days after the PADN procedure, this patient developed fever and severe fatigue. Her white blood cells increased to 2.2 × 109/l. During 8-h treatment at the local hospital, a total of 2,000 ml of saline was infused, without an increase in blood pressure (systolic blood pressure was between 70 and 78 mm Hg). Immediately after being transferred to our hospital, the blood lactate level was 24.6 mmol/l, and the patient was completely cyanotic. The mean PAP by right heart catheterization was stable between 25 and 28 mm Hg. The patient died after 4 h of treatment. Another patient from the control group died from RV failure at 72 days.
We report for the first time, to our knowledge, the safety and benefit of PADN in the treatment of IPAH. The major finding is that PADN is safe and associated with significant hemodynamic improvements, resulting in a significant increase in functional capacity.
Up to the present time, the treatment for IPAH has been directed at restoring the balance between vasodilation (e.g., prostacyclin, nitric oxide, and vasoactive intestinal peptide) and vasoconstriction (e.g., thromboxane A2, endothelin, and serotonin), growth inhibitors, mitogenic factors, and antithrombotic and prothrombotic factors (1,2). Recently, several classes of drugs have been developed. These medications have been reported to be associated with mild-to-moderate improvements in clinical symptoms, functional capacity, hemodynamics, and clinical outcomes (18–21), suggesting that diverse pathological pathways contribute to the progression of PAH and that more effective therapy is needed. However, the severe side effects are the more common reasons limiting the use of these medications.
Mechanisms of PADN
Anatomic and pathological studies have revealed marked hypertrophy of the muscular layer of the PA in patients with PAH, suggesting active vasoconstriction (1,2,22). Moreover, baroreceptor structures have been described in the PA (4,5), but the controversies regarding the types of the afferent and efferent fibers have existed for a long time (4,5,23). Circulating catecholamine levels in PAH have been reported to be either increased (24,25) or to remain within normal limits (26,27). This discrepancy may be related to the fact that pressure overload–induced failing RV in PAH subjects via local mechanisms (28). This postulation was verified by Velez-Roa et al. (29), who reported increased sympathetic nerve traffic in advanced PAH, a finding that was further confirmed by Wensel et al. (30). Furthermore, Juratsch et al. (5) reported that the significantly increased PAP and PVR induced by balloon distension of the MPA were completely abolished by surgical denervation of the bifurcation of the MPA and chemical sympathectomy using 6-hydroxydopamine (a known mediator of adrenergic nerves). These results suggested that the efferent limb of this reflex is predominantly mediated via the adrenergic nervous system.
Before our present study in humans, the dynamic change of PA hemodynamic measurements was investigated in our animal laboratory (7). The results showed that during occlusion of left interlobar PA, PAP and PVR gradually increased and reached peak values after 5 min, and that this pressure response was completely abolished after PADN at the MPA bifurcation level rather than at sites 5 mm distal to the ostial. In this animal study, we also found that it was somewhat difficult to keep the tip of the conventional ablation catheter in tight and constant contact with the PA wall because of the movement of the PA with inspiration and expiration. So we designed a dedicated PADN catheter with a circular tip and appropriate diameter in order to improve the stability and the constant contact with the PA wall. With better and more reliable equipment, we performed this first-in-man study. The results showed that PADN performance at the bifurcation area of the MPA was associated with significant reduction of PAP and PVR, and significant improvement of 6MWT. This finding might raise concerns about the conventional pathogenesis of PAH, and might suggest the effectiveness of PADN for IPAH patients with unsatisfactory clinical response to medication, a similar new understanding on the effect of renal denervation for treatment of refractory hypertension (31).
Comparison with drug therapy
More than 25 randomized control trials with >3,200 patients with PAH (IPAH, associated PAH, chronic thromboembolic pulmonary hypertension, and others) have been performed to test the effects of a variety of drugs (32). The average improvement of functional capacity as assessed using the 6MWT was 35.61 m, with a range of −10 to +108 m. This increase appeared to be an improvement of approximately 10.8%, which was significantly lower than the 29% (absolute increase of 101 m) observed in our study. Hemodynamic parameters were also investigated in randomized control trials with drugs. The weighted mean reduction in the mean PAP was −2.86 mm Hg, with a range of −1.00 to −9.30 mm Hg. The weighted mean reduction in the PVR was −520 dyne · s · cm−5. These values are significantly different from the −13 mm Hg and −822 dyne · s · cm−5 improvements that were observed following PADN. On the other hand, current medications had several limitations for treatment of PAH, such as high cost, severe side effects, complex intravenous or subcutaneous injection setup, and unpredictable long-term effects. One special finding of our study was that all medications (sildenafil or bosentan) were discontinued safely for all patients except for 1 who continued to receive a diuretic after PADN. This might imply that there is a “pure” effect of PADN itself on improvements in cardiac function, hemodynamic measurements, and functional capacity. Of course, the toxic effect of medications prescribed before the enrollment could not be excluded.
NT-BNP, the precursor of BNP, may be a more sensitive measure of RV strain than BNP (32). NT-BNP levels <1,400 pg/ml (33,34) indicate the worse stage at which the PAH patients were, as in our study, unresponsive to medications. The results from the current study suggested that local sympathetic nerve activity modulates PAH, and (PADN) by inducing local injury or damage of this reflex arc localizing in the bifurcation area of the MPA was associated with significant reduction of PAP and PVR, which led to improvement of cardiac function and functional capacity. On the other hand, although there are no PA perforation in this report, the danger and the possibility of aneurysm formation should be kept in mind. Thus, a learning curve is critical in order to maintain the safety of the PADN procedure. Furthermore, taking hemodynamics and functional capacity into consideration, the benefit of the PADN procedure for IPAH patients seems to become stable after 3 months follow-up. Extended follow-up was required to assess long-term improvement. Similar to all kinds of catheter-based procedures, the PADN is possible to be repeat performed. Finally, the improvement of PA compliance might indicate the possibility of a change of pathological features in distal PA segments, 1 of the main lesions in IPAH patients (35).
Given the small numbers, possible bias in patient selection and the fact that this is not a placebo-controlled double-blind study, the discussion should be further moderated to indicate that much more study is required before this therapy can even be considered for treating PAH. Although the results are promising and intriguing, only carefully designed trials with controls and appropriate blinding must be done in a much larger cohort and at multiple centers before definitive conclusions about efficacy can be determined.
We report the effect of PADN on hemodynamics and functional capacity in patients with PAH. Future studies are needed in a randomized, multicenter setting with a larger patient population, to confirm these preliminary findings.
The authors thank Ms. Tian Xu and Ms. Rong Wang for their help in data-collection. They also very much appreciate the help of Ms. Cindy Chen and her superb secretarial work.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Dr. Shao-Liang Chen is a Fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine of Jaingsu Province, China.
- Abbreviations and Acronyms
- 6-min walk test
- cardiac output
- idiopathic pulmonary arterial hypertension
- main pulmonary artery
- N-terminal brain natriuretic peptide
- pulmonary artery
- pulmonary artery denervation
- pulmonary artery hypertension
- pulmonary artery occlusive pressure
- pulmonary artery pressure
- pulmonary vascular resistance
- right atrium/atrial
- right ventricle/ventricular
- tricuspid excursion index
- transpulmonary pressure gradient
- Received March 8, 2013.
- Revision received May 15, 2013.
- Accepted May 22, 2013.
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