Balloon pulmonary angioplasty

SUMMARY

Balloon pulmonary angioplasty (BPA) is a promising therapeutic option for patients with chronic thromboembolic pulmonary hypertension who are ineligible for pulmonary endarterectomy. The effect of BPA was first reported in 1988, and a few institutions in Japan, including ours, reported refinements of BPA in 2012. BPA has been gaining acceptance worldwide, and it is recognised as a therapeutic option for inoperable patients with chronic thromboembolic pulmonary hypertension in the latest guidelines. Although the efficacy and safety of BPA appear to be comparable to those of pulmonary endarterectomy, many questions remain to be resolved. We will review recent advances in BPA and changes to strategies, including indication, fundamental technique, complications, bail-out technique, outcomes, and treatment goals. Additionally, we address the limitations and future perspectives of BPA.

INTRODUCTION

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension caused by stenosis or obstruction of the pulmonary arteries, which increases pulmonary vascular resistance due to organised thrombi [11. Lang IM, Madani M. Update on chronic thromboembolic pulmonary hypertension. Circulation. 2014;130:508-18. ]. The only established and potentially curative treatment currently available for CTEPH is pulmonary endarterectomy (PEA) [22. Kim NH, Delcroix M, Jenkins DP, Channick R, Dartevelle P, Jansa P, Lang I, Madani MM, Ogino H, Pengo V, Mayer E. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol. 2013;62:D92-9. ]. PEA reduces pulmonary vascular resistance by resecting all formations of organised thrombi under intermittent total circulatory arrest with deep hypothermia [33. Madani MM, Auger WR, Pretorius V, Sakakibara N, Kerr KM, Kim NH, Fedullo PF, Jamieson SW. Pulmonary endarterectomy: recent changes in a single institution’s experience of more than 2,700 patients. Ann Thorac Surg. 2012;94:97-103; discussion 103. ]. However, not all patients are candidates for PEA.

Balloon pulmonary angioplasty (BPA) was first developed in the field of paediatric cardiology to treat congenital hypoplastic and stenotic pulmonary arteries. Since 1988, BPA has been performed for CTEPH cases that are ineligible for PEA [44. Voorburg JA, Cats VM, Buis B, Bruschke AV. Balloon angioplasty in the treatment of pulmonary hypertension caused by pulmonary embolism. Chest. 1988;94:1249-53. ]. In 2001, Feinstein et al reported the results of BPA in 18 cases of inoperable CTEPH [55. Feinstein JA, Goldhaber SZ, Lock JE, Ferndandes SM, Landzberg MJ. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation. 2001;103:10-3. ]. Although BPA successfully decreased pulmonary artery pressure (PAP), its effects were less pronounced than those obtained by PEA, and the hospital mortality rate was high. Therefore, it was not still widely accepted as a therapeutic option for CTEPH for more than 10 years after the first report of BPA for CTEPH.

Since 2004, we have been attempting to improve the BPA procedure at our hospital. We had performed BPA on 68 patients by 2011 and reported the efficacy of the procedure in that cohort [66. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748-55. ]. Other Japanese institutions have also reported the efficacy of BPA [77. Kataoka M, Inami T, Hayashida K, Shimura N, Ishiguro H, Abe T, Tamura Y, Ando M, Fukuda K, Yoshino H, Satoh T. Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:756-62. , 88. Sugimura K, Fukumoto Y, Satoh K, Nochioka K, Miura Y, Aoki T, Tatebe S, Miyamichi-Yamamoto S, Shimokawa H. Percutaneous transluminal pulmonary angioplasty markedly improves pulmonary hemodynamics and long-term prognosis in patients with chronic thromboembolic pulmonary hypertension. Circ J. 2012;76:485-8. ]. Interest in BPA spread in Japan, and in recent years it has become popular around the world. Now, BPA has been reported worldwide to improve hemodynamics, symptoms, exercise capacity, and right ventricular function with significantly lower rates of complications compared to its original report [55. Feinstein JA, Goldhaber SZ, Lock JE, Ferndandes SM, Landzberg MJ. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation. 2001;103:10-3. ]. Moreover, the therapeutic effects of BPA seem to be maintained during intermediate follow up period [2828. Ogawa A, Satoh T, Fukuda T, Sugimura K, Fukumoto Y, Emoto N, Yamada N, Yao A, Ando M, Ogino H, Tanabe N, Tsujino I, Hanaoka M, Minatoya K, Ito H, Matsubara H. Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension: Results of a Multicenter Registry. Circ Cardiovasc Qual Outcomes. 2017;10. , 2929. Lang I, Meyer BC, Ogo T, Matsubara H, Kurzyna M, Ghofrani HA, Mayer E, Brenot P. Balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. Eur Respir Rev. 2017;26. ]. Acknowledging this, the latest guidelines for CTEPH state that, although there are some concerns and unanswered questions, BPA has emerged as a treatment for inoperable CTEPH [99. Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46:903-75. , 2828. Ogawa A, Satoh T, Fukuda T, Sugimura K, Fukumoto Y, Emoto N, Yamada N, Yao A, Ando M, Ogino H, Tanabe N, Tsujino I, Hanaoka M, Minatoya K, Ito H, Matsubara H. Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension: Results of a Multicenter Registry. Circ Cardiovasc Qual Outcomes. 2017;10. , 2929. Lang I, Meyer BC, Ogo T, Matsubara H, Kurzyna M, Ghofrani HA, Mayer E, Brenot P. Balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. Eur Respir Rev. 2017;26. ]. We have modified the technique and strategy to make BPA curative for CTEPH. This review highlights recent advances in BPA.

INDICATIONS FOR BALLOON PULMONARY ANGIOPLASTY

Although PEA is the gold standard therapy for CTEPH, the procedure is challenging and technically demanding, with higher mortality than most cardiac surgeries. Patients with proximal pulmonary artery disease are considered to be good candidates for PEA because of the ease of access to lesions and their generally excellent outcomes [1010. Thistlethwaite PA, Mo M, Madani MM, Deutsch R, Blanchard D, Kapelanski DP, Jamieson SW. Operative classification of thromboembolic disease determines outcome after pulmonary endarterectomy. J Thorac Cardiovasc Surg. 2002;124:1203-11. , 1111. Ogino H, Ando M, Matsuda H, Minatoya K, Sasaki H, Nakanishi N, Kyotani S, Imanaka H, Kitamura S. Japanese single-center experience of surgery for chronic thromboembolic pulmonary hypertension. Ann Thoracic Surg. 2006;82:630-6. ]. The outcome of PEA in patients with distal pulmonary artery disease was recently reported to be excellent at some expert centres [33. Madani MM, Auger WR, Pretorius V, Sakakibara N, Kerr KM, Kim NH, Fedullo PF, Jamieson SW. Pulmonary endarterectomy: recent changes in a single institution’s experience of more than 2,700 patients. Ann Thorac Surg. 2012;94:97-103; discussion 103. , 1212. Thistlethwaite PA, Kaneko K, Madani MM, Jamieson SW. Technique and outcomes of pulmonary endarterectomy surgery. Ann Thorac Cardiovasc Surg. 2008;14:274-82. ]. However, generally, the outcomes of PEA are much worse for distal disease than for proximal disease. From 10% to 50% of patients are considered inoperable due to the distal location of organised thrombi being deemed inaccessible [99. Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46:903-75. , 1313. Pepke-Zaba J, Delcroix M, Lang I, Mayer E, Jansa P, Ambroz D, Treacy C, D’Armini AM, Morsolini M, Snijder R, Bresser P, Torbicki A, Kristensen B, Lewczuk J, Simkova I, Barbera JA, de Perrot M, Hoeper MM, Gaine S, Speich R, Gomez-Sanchez MA, Kovacs G, Hamid AM, Jais X, Simonneau G. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation. 2011;124:1973-81. , 1414. Kim NH. Assessment of operability in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc. 2006;3:584-8. ]. Even if the lesions are surgically accessible, not all patients are considered operable. Because PEA is an invasive procedure performed under intermittent total circulatory arrest with deep hypothermia [33. Madani MM, Auger WR, Pretorius V, Sakakibara N, Kerr KM, Kim NH, Fedullo PF, Jamieson SW. Pulmonary endarterectomy: recent changes in a single institution’s experience of more than 2,700 patients. Ann Thorac Surg. 2012;94:97-103; discussion 103. ], patients of advanced age, with comorbidities, and in poor general condition are also considered ineligible for PEA.

All patients who are ineligible for PEA are considered candidates for BPA, as well as patients with residual or recurrent pulmonary hypertension after PEA. Iodine allergy is a contraindication for BPA, because the use of contrast medium is essential for performing the procedure. Additionally, performing BPA in patients with renal dysfunction must be considered carefully in the light of the risk of progression of renal failure. Because BPA should be performed in a staged fashion over multiple procedures [66. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748-55. ], in our institute, patients required an average of 5.8 sessions.

After selecting patients who are candidates for BPA, lesion type-specific indications for each pulmonary artery must be considered. Figure 1 shows the angiographic classification of lesion morphology [1515. Kawakami T, Ogawa A, Miyaji K, Mizoguchi H, Shimokawahara H, Naito T, Oka T, Yunoki K, Munemasa M, Matsubara H. Novel angiographic classification of each vascular lesion in chronic thromboembolic pulmonary hypertension based on selective angiogram and results of balloon pulmonary angioplasty. Circ Cardiovasc Interv. 2016;9:e003318. ]. We previously reported that the outcomes and complication rate of BPA are highly dependent on lesion characteristics [1515. Kawakami T, Ogawa A, Miyaji K, Mizoguchi H, Shimokawahara H, Naito T, Oka T, Yunoki K, Munemasa M, Matsubara H. Novel angiographic classification of each vascular lesion in chronic thromboembolic pulmonary hypertension based on selective angiogram and results of balloon pulmonary angioplasty. Circ Cardiovasc Interv. 2016;9:e003318. ]. Operators who are inexperienced in BPA can effectively and safely treat ring-like stenosis and web lesions, because generally the outcome is good and the complication rate is low for these lesion types. Importantly, patients should be informed about the risks and benefits of BPA and PEA before undergoing treatment.

THE BPA PROCEDURE

Treatment before BPA

Anticoagulants should be continued during the BPA procedure to maintain a prothrombin time international ratio between 2.0 and 3.0, and heparin can be substituted. Pulmonary hypertension-targeted drugs can be continued if the drugs were prescribed prior to BPA. Since only small reductions in the mean PAP can be expected [1616. Reichenberger F, Voswinckel R, Enke B, Rutsch M, El Fechtali E, Schmehl T, Olschewski H, Schermuly R, Weissmann N, Ghofrani HA, Grimminger F, Mayer E, Seeger W. Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension. Eur Respir J. 2007;30:922-7. , 1717. Jais X, D’Armini AM, Jansa P, Torbicki A, Delcroix M, Ghofrani HA, Hoeper MM, Lang IM, Mayer E, Pepke-Zaba J, Perchenet L, Morganti A, Simonneau G, Rubin LJ; Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension Study Group. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronic Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol. 2008;52:2127-34. , 1818. Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319-29. ], the addition of these drugs to the treatment regimen shortly before BPA should be avoided to save time and money.

General BPA procedure

Before the BPA procedure, oxygen is administered to maintain an oxygen saturation of 98% to 100%, which reduces mean PAP by approximately 10%. The BPA procedure is approached via either the right internal jugular vein or right femoral vein. In most cases, we perform BPA through the right femoral vein because one operator can manipulate both the guiding catheter and guidewire with lower radiation exposure compared to the right jugular vein approach. After inserting a 6-7 Fr long introducer sheath (BRIGHT TIP® Sheath Introducer; Cordis/Johnson & Johnson, New Brunswick, NJ, USA) into the pulmonary artery via a 9 Fr sheath (ArrowFlex; Wayne, PA, USA) using a 0.035-inch wire (Radifocus® Guidewire M; Terumo, Tokyo, Japan), 500-2,000 units of heparin are administered to reach an activated clotting time around 200 seconds, and 500 units of heparin are additionally added every hour. A 6-7 Fr guiding catheter such as the Mach 1 peripheral MP, Mach 1 JR4, Mach 1 JL4, or Mach 1 AL1 catheter (all Boston Scientific, Marlborough, MA, USA) is advanced into the segmental artery [66. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748-55. , 1515. Kawakami T, Ogawa A, Miyaji K, Mizoguchi H, Shimokawahara H, Naito T, Oka T, Yunoki K, Munemasa M, Matsubara H. Novel angiographic classification of each vascular lesion in chronic thromboembolic pulmonary hypertension based on selective angiogram and results of balloon pulmonary angioplasty. Circ Cardiovasc Interv. 2016;9:e003318. , 1919. Ogawa A, Matsubara H. Balloon pulmonary angioplasty: a treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension. Front Cardiovasc Med. 2015;2:4. ]. Table 1 shows the suitable guiding catheter for each segmental pulmonary artery in both lungs. To engage many segmental arteries using only one guiding catheter, the MP type catheter is suitable for the right lobe, and the AL1 type is suitable for the left lobe. After performing selective pulmonary angiography, a 0.014-inch or 0.018-inch guidewire is used to cross the lesion. Then a balloon catheter of an appropriate diameter is selected to dilate the lesion.

Pulmonary vessel injury caused by the guidewire, guiding catheter, balloon dilation, or contrast medium injection at high pressure would play a role in inducing lung injury in BPA [3030. Ejiri K, Ogawa A, Fujii S, Ito H, Matsubara H. Vascular Injury Is a Major Cause of Lung Injury After Balloon Pulmonary Angioplasty in Patients with Chronic Thromboembolic Pulmonary Hypertension. Circ Cardiovasc Interv. 2018;11. ]. Using a guidewire with the smallest possible tip load, stopping the tip of the guidewire within the angiographically visible range of the distal vessels, and injecting the contrast agent gently may all help to reduce the risk of pulmonary vessel injury.

Other complications such as haematoma or bleeding at the puncture site, allergic reaction to contrast agent, and vasovagal reflex are rarely seen.

Lesion dilatation

It is necessary to determine how to dilate the lesion to achieve maximal therapeutic efficacy and reduce the risk of pulmonary vessel injury, which could potentially become lethal. To dilate the lesion, balloon size, vessel size, the number of organised thrombi and patient haemodynamics must be considered. Balloon size is the only one of these factors we can control.

The pathological findings of lesions after BPA suggest that balloon dilatation itself can cause dissection of the tunica media in treated sites, as in a case where the organised thrombi had partially detached from and stretched the thin vessel wall [2020. Kitani M, Ogawa A, Sarashina T, Yamadori I, Matsubara H. Histological changes of pulmonary arteries treated by balloon pulmonary angioplasty in a patient with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2014;7:857-9. ]. We investigated how the lumen enlarges immediately after BPA and revealed that the lumen enlargement is due to an overall expansion induced by the stretching of the arterial wall [3131. Shimokawahara H, Ogawa A, Mizoguchi H, Yagi H, Ikemiyagi H, Matsubara H. Vessel Stretching Is a Cause of Lumen Enlargement Immediately After Balloon Pulmonary Angioplasty: Intravascular Ultrasound Analysis in Patients With Chronic Thromboembolic Pulmonary Hypertension. Circ Cardiovasc Interv. 2018;11. ]. Dilatation using a larger balloon appears to decrease residual stenosis at the lesion site; however, it also increases the probability of damage to the vessel wall in case of overdilatation, which may result in an oozing haemorrhage. In addition, treated vessels can show spontaneous enlargement after BPA [2121. Nagayoshi S, Ogawa A, Matsubara H. Spontaneous enlargement of pulmonary artery after successful balloon pulmonary angioplasty in a patient with chronic thromboembolic pulmonary hypertension. EuroIntervention. 2016;12:e1435. ]. A second dilatation at the enlarged site can be performed in the following BPA session using an optimally sized balloon while minimising the risk of vessel injury, if necessary.

Considering these circumstances, we dilate the lesion sequentially in two sessions. A smaller balloon relative to the actual vessel size is selected for the initial BPA session to reduce the risk of pulmonary vessel injury and restore minimal blood flow to the occluded or stenotic pulmonary vessels. However, using only smaller balloon might reduce the therapeutic efficacy in each procedure. It might be necessary to treat as many segmental pulmonary arteries as possible to maintain the effectiveness of single procedure. At the second session with improved hemodynamics due to the first session, a balloon catheter of 100-120% the size of the reference vessel diameter indicated on the angiogram is selected to optimise the dilatation of the lesion ( Figure 2 ). Systematic procedure checking all the segmental pulmonary arteries and dilating as many lesions as possible within consecutive two sessions might be ideal to improve hemodynamics effectively with minimum risk of complication. The systematic procedure might be also beneficial for the improvement of oxygenation in patients with CTEPH as described later in the paragraph of GOALS FOR BPA.

Different institutions have utilised various imaging techniques to determine balloon size, including intravascular ultrasound [66. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748-55. , 2222. Kopec G, Waligora M, Stepniewski J, Zmudka K, Podolec P, Matsubara H. In vivo characterization of changes in composition of organized thrombus in patient with chronic thromboembolic pulmonary hypertension treated with balloon pulmonary angioplasty. Int J Cardiol. 2015;186:279-81. ], optical coherence tomography [2323. Inohara T, Kawakami T, Kataoka M, Yamamoto M, Kimura M, Kanazawa H, Yuasa S, Hayashida K, Maekawa Y, Fukuda K. Lesion morphological classification by OCT to predict therapeutic efficacy after balloon pulmonary angioplasty in CTEPH. Int J Cardiol. 2015;197:23-5. ], and pressure wire [2424. Roik M, Wretowski D, Labyk A, Kostrubiec M, Irzyk K, Dzikowska-Diduch O, Lichodziejewska B, Ciurzynski M, Kurnicka K, Golebiowski M, Pruszczyk P. Refined balloon pulmonary angioplasty driven by combined assessment of intra-arterial anatomy and physiology--multimodal approach to treated lesions in patients with non-operable distal chronic thromboembolic pulmonary hypertension--technique, safety and efficacy of 50 consecutive angioplasties. Int J Cardiol. 2016;203:228-35. ]. Each of these imaging techniques may have advantages over angiography, but all of them also have disadvantages, such as the cost, time, and effort necessary to use them. Furthermore, they may increase the risk of complication because of their procedural complexity.

Management after BPA

All patients should undergo chest radiography immediately after BPA. If there are no complications, special procedures are unnecessary after BPA. Patients can be discharged on the next day after BPA.

Patients with haemosputum during BPA should undergo lung physical therapy and be administered an expectorant drug. We do not need to monitor the haemodynamics continually except for the saturation in completely stable patients. Treatment with supplemental oxygen is needed for hypoxic patients. Anticoagulants should be continued after BPA to maintain a prothrombin time international ratio between 2.0 and 3.0.

Complications of BPA and BPA-related pulmonary injury

The in-hospital death rate of BPA has been reported in the range of 0-10.0% ( Table 2 ) [55. Feinstein JA, Goldhaber SZ, Lock JE, Ferndandes SM, Landzberg MJ. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation. 2001;103:10-3. , 66. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748-55. , 2424. Roik M, Wretowski D, Labyk A, Kostrubiec M, Irzyk K, Dzikowska-Diduch O, Lichodziejewska B, Ciurzynski M, Kurnicka K, Golebiowski M, Pruszczyk P. Refined balloon pulmonary angioplasty driven by combined assessment of intra-arterial anatomy and physiology--multimodal approach to treated lesions in patients with non-operable distal chronic thromboembolic pulmonary hypertension--technique, safety and efficacy of 50 consecutive angioplasties. Int J Cardiol. 2016;203:228-35. , 2525. Andreassen AK, Ragnarsson A, Gude E, Geiran O, Andersen R. Balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension. Heart. 2013;99:1415-20. ]. The cause of death in all patients was reported to be deterioration of right heart failure after BPA. However, it is not known whether the deaths were directly related to the BPA procedure. The most frequent and characteristic complication of BPA is lung injury. The incidence of lung injury caused by BPA has been reported in the range of 9.6-51.9% [55. Feinstein JA, Goldhaber SZ, Lock JE, Ferndandes SM, Landzberg MJ. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation. 2001;103:10-3. , 66. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748-55. , 77. Kataoka M, Inami T, Hayashida K, Shimura N, Ishiguro H, Abe T, Tamura Y, Ando M, Fukuda K, Yoshino H, Satoh T. Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:756-62. , 88. Sugimura K, Fukumoto Y, Satoh K, Nochioka K, Miura Y, Aoki T, Tatebe S, Miyamichi-Yamamoto S, Shimokawa H. Percutaneous transluminal pulmonary angioplasty markedly improves pulmonary hemodynamics and long-term prognosis in patients with chronic thromboembolic pulmonary hypertension. Circ J. 2012;76:485-8. , 2424. Roik M, Wretowski D, Labyk A, Kostrubiec M, Irzyk K, Dzikowska-Diduch O, Lichodziejewska B, Ciurzynski M, Kurnicka K, Golebiowski M, Pruszczyk P. Refined balloon pulmonary angioplasty driven by combined assessment of intra-arterial anatomy and physiology--multimodal approach to treated lesions in patients with non-operable distal chronic thromboembolic pulmonary hypertension--technique, safety and efficacy of 50 consecutive angioplasties. Int J Cardiol. 2016;203:228-35. , 2525. Andreassen AK, Ragnarsson A, Gude E, Geiran O, Andersen R. Balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension. Heart. 2013;99:1415-20. ]. However, there is no established definition for BPA-related lung injury, and therefore the incidence of BPA-related lung injury differs across institutes. Previously, reperfusion itself was believed to be the cause of reperfusion lung injury; thus, it appeared unavoidable. However, the incidence of lung injury after BPA decreased with operators’ experience [66. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748-55. ]. We defined BPA-related lung injury as being characterised by newly developed chest radiographic opacity that corresponds to treated segments, along with worsening oxygen saturation [1515. Kawakami T, Ogawa A, Miyaji K, Mizoguchi H, Shimokawahara H, Naito T, Oka T, Yunoki K, Munemasa M, Matsubara H. Novel angiographic classification of each vascular lesion in chronic thromboembolic pulmonary hypertension based on selective angiogram and results of balloon pulmonary angioplasty. Circ Cardiovasc Interv. 2016;9:e003318. ]. Approximately 80% of lung injuries resulted from vessel injury, and approximately 70% of these vessel injuries were caused by the guidewire, including vessel perforation particularly in subtotally or totally occluded vessels. The complication rate also varies across lesion types [1515. Kawakami T, Ogawa A, Miyaji K, Mizoguchi H, Shimokawahara H, Naito T, Oka T, Yunoki K, Munemasa M, Matsubara H. Novel angiographic classification of each vascular lesion in chronic thromboembolic pulmonary hypertension based on selective angiogram and results of balloon pulmonary angioplasty. Circ Cardiovasc Interv. 2016;9:e003318. ].

Bail-out technique for pulmonary vessel injury during BPA

Even with maximum effort to avoid complications of BPA, it is impossible to eliminate their occurrence. If BPA-related pulmonary vessel injury has occurred, the following conditions occur concomitantly: coughing (not necessarily accompanied by bloody sputum), an increase in heart rate and PAP, and a decrease in oxygen saturation. These conditions might negatively impact on each other, causing the patient to fall into a vicious cycle of clinical deterioration. It is necessary to stop bleeding immediately, before these conditions progressively worsen. The use of appropriate devices to maintain oxygenation and administration of sedative drugs to relieve patient discomfort associated with coughing bloody sputum should be undertaken immediately. Bleeding can be stopped in many cases by neutralising the heparin and blocking the proximal site of the lesion for 10-15 minutes with a balloon catheter. When bleeding cannot be stopped by these procedures, an embolic agent should be injected into the vessel. Since injected gelatine will disappear and occluded vessels recanalise spontaneously within one month, we consider gelatine to be the most effective and appropriate embolic agent for treating BPA-related vessel injury. In case of pulmonary artery rupture after BPA, a covered stent can be used to stop bleeding [2626. Ejiri K, Ogawa A, Matsubara H. Bail-out technique for pulmonary artery rupture with a covered stent in balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. JACC Cardiovasc Interv. 2015;8:752-3. ].

OUTCOMES OF BPA

Figure 3 shows a representative case. The patient’s mean PAP decreased from 49 mmHg to 19 mmHg after four sessions of BPA. The patient’s symptoms were completely relieved without using a pulmonary hypertension-targeted drug or home oxygen therapy. Dramatic improvement of lung perfusion is recognised on both global pulmonary angiography and lung perfusion scintigraphy ( Figure 3 ).

Studies on the effectiveness of BPA from various institutes have reported a reduction of mean PAP ( Table 2 ) [55. Feinstein JA, Goldhaber SZ, Lock JE, Ferndandes SM, Landzberg MJ. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation. 2001;103:10-3. , 66. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748-55. , 2424. Roik M, Wretowski D, Labyk A, Kostrubiec M, Irzyk K, Dzikowska-Diduch O, Lichodziejewska B, Ciurzynski M, Kurnicka K, Golebiowski M, Pruszczyk P. Refined balloon pulmonary angioplasty driven by combined assessment of intra-arterial anatomy and physiology--multimodal approach to treated lesions in patients with non-operable distal chronic thromboembolic pulmonary hypertension--technique, safety and efficacy of 50 consecutive angioplasties. Int J Cardiol. 2016;203:228-35. , 2525. Andreassen AK, Ragnarsson A, Gude E, Geiran O, Andersen R. Balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension. Heart. 2013;99:1415-20. ]. In our institute, 2,283 BPA procedures were performed from November 2004 to January 2019 on 397 patients with CTEPH who were deemed ineligible for PEA. We have achieved an average reduction in mean PAP of 20.5 mmHg with an average of 5.48 BPA procedures per patient. The reduction in mean PAP after PEA was reported to be 19.5 mmHg [33. Madani MM, Auger WR, Pretorius V, Sakakibara N, Kerr KM, Kim NH, Fedullo PF, Jamieson SW. Pulmonary endarterectomy: recent changes in a single institution’s experience of more than 2,700 patients. Ann Thorac Surg. 2012;94:97-103; discussion 103. ]. Therefore, the efficacy of BPA appears comparable with that of PEA.

GOALS FOR BPA

The number of target segments and procedures should be determined based on the treatment goal at each facility. With PEA, all organised thrombi can be resected in bilateral lungs (including distal areas) to cure CTEPH. BPA cannot become an alternative treatment for CTEPH unless its efficacy and safety are equal or superior to those of PEA. It is insufficient to dilate a subset of the pulmonary vessels with the purpose of decreasing only PAP. Previously, the treatment goal of BPA in our institute was to decrease the patient’s mean PAP to less than 30 mmHg. The outcome of BPA in our institute is improving because of our learning curve. As shown in Table 2, not all institutes achieve a reduction of mean PAP below 30 mmHg. The number of targeted segments has been reported to correlate directly with the decrease in PAP [66. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012;5:748-55. ]. Therefore, we attempted to treat as many lesions as possible without causing complications. Currently, the treatment goal of BPA in our institute is to cure the disorder, that is, to achieve a mean PAP less than 25 mmHg and percutaneous oxygen saturation greater than 95% without pulmonary hypertension-targeted drugs or oxygen therapy. The main mechanism of hypoxaemia in patients with CTEPH is thought to be the consequence of a ventilation-perfusion abnormality [2727. Kapitan KS, Buchbinder M, Wagner PD, Moser KM. Mechanisms of hypoxemia in chronic thromboembolic pulmonary hypertension. Am Rev Respir Dis. 1989;139:1149-54. ]. The only option to improve oxygenation is to eliminate all the perfusion defects on perfusion scintigraphy. To achieve this goal, we should strive to treat all affected pulmonary vessels. At our institute, we treat all segmental pulmonary arteries in both lungs ( Figure 4 ) and all types of lesion including tortuous and total occlusion-type lesions.

CONCLUSIONS

The efficacy and safety of BPA have improved dramatically in recent years. Further advances in therapeutic efficacy with minimum risk of complications could make BPA an alternative treatment option for patients with CTEPH who are ineligible for PEA.

PERSONAL PERSPECTIVE - HIROMI MATSUBARA

Similar to PEA, the greatest challenge of BPA is operator training. Since CTEPH is a rare disease, it is difficult but necessary to accumulate a sufficient number of patients at BPA centres so that operators can build experience in the procedure. To overcome this problem, it would be helpful to control the number of BPA centres. In addition, long-term survival and efficacy of BPA need to be clarified. Improvements to BPA-specific devices are also required for the universalization of BPA.