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Interventional and surgical therapeutic strategies for pulmonary arterial hypertension: Beyond palliative treatments

Open ArchivePublished:March 11, 2015DOI:https://doi.org/10.1016/j.jjcc.2015.02.001

      Abstract

      Despite significant advances in pharmacological treatments, pulmonary arterial hypertension remains an incurable disease with an unreasonably high morbidity and mortality. Although specific pharmacotherapies have shifted the survival curves of patients and improved exercise endurance as well as quality of life, it is also true that these pharmacological interventions are not always accessible (particularly in developing countries) and, perhaps most importantly, not all patients respond similarly to these drugs. Furthermore, many patients will continue to deteriorate and will eventually require an additional, non-pharmacological, intervention. In this review we analyze the role of atrial septostomy and Potts anastomosis in the management of patients with pulmonary arterial hypertension, we summarize the current worldwide clinical experience (case reports and case series), and discuss why these interventional/surgical strategies might have a therapeutic role beyond that of a “bridge” to transplantation.

      Keywords

      Introduction

      Idiopathic pulmonary arterial hypertension (IPAH) is characterized by a progressive elevation of pulmonary artery pressure (PAP), right heart dysfunction/failure, and untimely death [
      • D’Alonzo G.E.
      • Barst R.J.
      • Ayres S.M.
      • Bergofsky E.H.
      • Brundage B.H.
      • Detre K.M.
      • Fishman A.P.
      • Goldring R.M.
      • Groves B.M.
      • Kernis J.T.
      • Levy P.S.
      • Pietra G.G.
      • Reid L.M.
      • Reeves J.T.
      • Rich S.
      • et al.
      Survival in patients with primary pulmonary hypertension. Results of a national prospective study.
      ,
      • Sandoval J.
      • Bauerle O.
      • Palomar A.
      • Gomez A.
      • Martínez Guerra M.L.
      • Beltran M.
      • Guerrero M.L.
      Survival in primary pulmonary hypertension; validation of a prognostic equation.
      ]. It has long been recognized that the survival of patients with IPAH (formerly called primary pulmonary hypertension or PPH) clearly depends on the adaptation of the right ventricle (RV) to increased pressure-overload as many studies have demonstrated that the variables assessing right ventricular function (or dysfunction) such as right atrial pressure and cardiac index are the most powerful predictors of mortality [
      • D’Alonzo G.E.
      • Barst R.J.
      • Ayres S.M.
      • Bergofsky E.H.
      • Brundage B.H.
      • Detre K.M.
      • Fishman A.P.
      • Goldring R.M.
      • Groves B.M.
      • Kernis J.T.
      • Levy P.S.
      • Pietra G.G.
      • Reid L.M.
      • Reeves J.T.
      • Rich S.
      • et al.
      Survival in patients with primary pulmonary hypertension. Results of a national prospective study.
      ,
      • Sandoval J.
      • Bauerle O.
      • Palomar A.
      • Gomez A.
      • Martínez Guerra M.L.
      • Beltran M.
      • Guerrero M.L.
      Survival in primary pulmonary hypertension; validation of a prognostic equation.
      ]. Indeed, the classic study by D’Alonzo et al. reporting the results of the first registry of the National Institutes of Health of the USA demonstrated that PPH patients with a cardiac index (CI) lower than 2.0 L min m2, or patients with a mean right atrial pressure (mRAP) higher than 20 mmHg had a dismal prognosis [
      • D’Alonzo G.E.
      • Barst R.J.
      • Ayres S.M.
      • Bergofsky E.H.
      • Brundage B.H.
      • Detre K.M.
      • Fishman A.P.
      • Goldring R.M.
      • Groves B.M.
      • Kernis J.T.
      • Levy P.S.
      • Pietra G.G.
      • Reid L.M.
      • Reeves J.T.
      • Rich S.
      • et al.
      Survival in patients with primary pulmonary hypertension. Results of a national prospective study.
      ]. These findings have been validated by contemporary [
      • Sandoval J.
      • Bauerle O.
      • Palomar A.
      • Gomez A.
      • Martínez Guerra M.L.
      • Beltran M.
      • Guerrero M.L.
      Survival in primary pulmonary hypertension; validation of a prognostic equation.
      ] and modern studies and underscore the importance of understanding RV biomechanics and cellular physiology, in order to design integral treatment strategies for patients with PAH.
      There is no question that the advent of PAH-specific pharmacotherapies has shifted the survival curves of PAH patients. New-generation therapies have been shown to improve exercise endurance, quality of life, and survival [
      • Galiè N.
      • Corris P.A.
      • Frost A.
      • Girgis R.E.
      • Granton J.
      • Jing Z.C.
      • Klepetko W.
      • McGoon M.D.
      • McLaughlin V.V.
      • Preston I.R.
      • Rubin L.J.
      • Sandoval J.
      • Seeger W.
      • Keogh A.
      Updated treatment algorithm of pulmonary arterial hypertension.
      ]. However, it is also true that these pharmacological interventions are not always accessible (particularly in developing countries) and, perhaps most importantly, not all patients respond similarly to these drugs [
      • Galiè N.
      • Corris P.A.
      • Frost A.
      • Girgis R.E.
      • Granton J.
      • Jing Z.C.
      • Klepetko W.
      • McGoon M.D.
      • McLaughlin V.V.
      • Preston I.R.
      • Rubin L.J.
      • Sandoval J.
      • Seeger W.
      • Keogh A.
      Updated treatment algorithm of pulmonary arterial hypertension.
      ,
      • Humbert M.
      • Sitbon O.
      • Chaouat A.
      • Bertocchi M.
      • Habib G.
      • Gressin V.
      • Yaïci A.
      • Weitzenblum E.
      • Cordier J.F.
      • Chabot F.
      • Dromer C.
      • Pison C.
      • Reynaud-Gaubert M.
      • Haloun A.
      • Laurent M.
      • et al.
      Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era.
      ]. In fact, many treated patients will continue to clinically deteriorate and will require interventional and/or surgical alternatives such as atrial septostomy (AS), Potts shunt, and lung transplantation [
      • Galiè N.
      • Corris P.A.
      • Frost A.
      • Girgis R.E.
      • Granton J.
      • Jing Z.C.
      • Klepetko W.
      • McGoon M.D.
      • McLaughlin V.V.
      • Preston I.R.
      • Rubin L.J.
      • Sandoval J.
      • Seeger W.
      • Keogh A.
      Updated treatment algorithm of pulmonary arterial hypertension.
      ,
      • Humbert M.
      • Sitbon O.
      • Chaouat A.
      • Bertocchi M.
      • Habib G.
      • Gressin V.
      • Yaïci A.
      • Weitzenblum E.
      • Cordier J.F.
      • Chabot F.
      • Dromer C.
      • Pison C.
      • Reynaud-Gaubert M.
      • Haloun A.
      • Laurent M.
      • et al.
      Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era.
      ,
      • Klepetko W.
      • Mayer E.
      • Sandoval J.
      • Trulock E.P.
      • Vachiery J.L.
      • Dartevelle P.
      • Pepke-Zaba J.
      • Jamieson S.W.
      • Lang I.
      • Corris P.
      Interventional and surgical modalities of treatment for pulmonary arterial hypertension.
      ,
      • Sandoval J.
      • Gaspar J.
      Atrial septostomy and other interventional procedures.
      ]. In the present review we analyze the role of AS and Potts anastomosis in the management of PAH, we summarize the current worldwide clinical experience, and discuss why these interventional/surgical strategies might have a therapeutic role beyond that of a “bridge” to transplantation.

      Atrial septostomy

      Historical development and rationale

      For some time now there has been clinical as well as experimental evidence suggesting that in the setting of PAH an inter-atrial right-to-left shunt may be of benefit. From the clinical point of view, we know that PAH patients with a patent foramen ovale live longer than those without shunting [
      • Rozkovec A.
      • Montanes P.
      • Oakley C.M.
      Factors that influence the outcome of primary pulmonary hypertension.
      ]. We also know that Eisenmenger patients with a comparable degree of pulmonary hypertension live longer and do not develop severe RV dysfunction when compared to patients with PAH [
      • Hopkins W.E.
      The remarkable right ventricle of patients with Eisenmenger syndrome.
      ,
      • Hopkins W.E.
      • Ochoa L.L.
      • Richardson G.W.
      • Trulock E.P.
      Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome.
      ]. Interestingly, Hopkins et al. [
      • Hopkins W.E.
      • Ochoa L.L.
      • Richardson G.W.
      • Trulock E.P.
      Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome.
      ] have shown that despite having similar degrees of pulmonary hypertension, patients with Eisenmenger syndrome have a lower RAP and better CI than patients with PAH, reflecting better RV performance (Fig. 1) [
      • Hopkins W.E.
      • Ochoa L.L.
      • Richardson G.W.
      • Trulock E.P.
      Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome.
      ]. It could be said that the idea behind the creation of a right-to-left shunt at inter-atrial level (AS) in patients with PAH was partly derived from the studies of patients with Eisenmenger syndrome.
      Figure thumbnail gr1
      Fig. 1Despite similar levels of pulmonary artery pressures and pulmonary vascular resistances, patients with Eisenmenger syndrome show lower right atrial pressure and higher cardiac index than those with primary pulmonary hypertension suggesting a better performance of the right heart in Eisenmenger syndrome.
      Adapted from Hopkins et al. [
      • Hopkins W.E.
      • Ochoa L.L.
      • Richardson G.W.
      • Trulock E.P.
      Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome.
      ].
      From the experimental point of view, the first study supporting the role of interatrial shunts was published by Austen et al. over 50 years ago [
      • Austen W.G.
      • Morrow A.G.
      • Berry W.B.
      Experimental studies of the surgical treatment of primary pulmonary hypertension.
      ]. This particular study is extraordinary not only because it was the first to show that an inter-atrial shunt in PPH was beneficial but also because they described most of the knowledge we have about the physiological changes caused by AS. In their original publication they described the results obtained in 20 dogs with chronic RV pressure-overload, a model created in a 3-month period by progressive constriction of the pulmonary artery with a band placed via thoracotomy as the first intervention. Through a second thoracotomy, the heart was exposed and cannulated, connecting the superior vena cava with the left atria, forming a right-to-left shunt. This shunt could be manipulated by clamping. When the shunt was opened there was a significant decrease in RV and in right atrial (RA) pressures along with an increase in cardiac output and systemic pressure. As expected, there was also a decrease in arterial oxygen saturation (SaO2%). All of these changes were reversed when the shunt was closed (Fig. 2A) .
      Figure thumbnail gr2
      Fig. 2Hemodynamic effects of an inter-atrial shunt in an experimental model of right ventricular hypertension. Acute hemodynamic effects at rest with the shunt open and closed (A). Hemodynamic effects of an atrial septal defect (ASD) in dogs during mild (ME) and severe (SE) exercise (B). LV, left ventricular; RA, right atrial; RV, right ventricular; RVEDP, right ventricular end-diastolic pressure.
      Adapted from Austen et al. [
      • Austen W.G.
      • Morrow A.G.
      • Berry W.B.
      Experimental studies of the surgical treatment of primary pulmonary hypertension.
      ].
      A second set of experiments, performed in a separate group of dogs, consisted of the surgical creation of an atrial septal defect through a second operation in 50% of the dogs with the other 50% serving as the control group (sham group). Hemodynamic measurements were performed 10 days after surgery and were performed at rest and during mild and severe exercise as defined by running on a lead for 200 and 400 yards, respectively. These dogs were previously trained to perform the exercises. Fig. 2B, constructed with the data presented by the author, summarizes the results of this experiment. Dogs with an atrial septal defect were able to significantly increase their cardiac output during both mild and severe exercise at the expense of only a modest increase in right ventricular end-diastolic pressure (RVEDP). On the other hand, dogs in the control group not only did not increase cardiac output, but also had a marked increase in RVEDP during mild exercise. A significant number of dogs in the control group did not tolerate severe exercise, and died during or immediately after the test [
      • Austen W.G.
      • Morrow A.G.
      • Berry W.B.
      Experimental studies of the surgical treatment of primary pulmonary hypertension.
      ].
      Austen et al. concluded that “the results of both groups of experiments indicate that the presence of a R-to-L shunt at the atrial level has the beneficial effects of decompressing the hypertensive RV and of augmenting systemic blood flow” [
      • Austen W.G.
      • Morrow A.G.
      • Berry W.B.
      Experimental studies of the surgical treatment of primary pulmonary hypertension.
      ]. This statement made more than 50 years ago has provided the physiological rationale for AS. Austen et al. also suggested that the shunt should be created at interatrial level and even proposed this operation to be seriously considered for the management of severe PPH [
      • Austen W.G.
      • Morrow A.G.
      • Berry W.B.
      Experimental studies of the surgical treatment of primary pulmonary hypertension.
      ]. An operation to create an interatrial shunt never took place in part because William Rashkind (first catheter-balloon in 1966 [
      • Rashkind W.J.
      • Miller W.W.
      Creation of an atrial septal defect without thoracotomy. A palliative approach to complete transposition of the great arteries.
      ]) and Sang C Park (first blade-catheter in 1978 and 1982 [
      • Park S.C.
      • Neches W.H.
      • Zuberbuhler J.R.
      • Lenox C.C.
      • Mathews R.A.
      • Fricker F.J.
      • Zoltun R.A.
      Clinical use of blade atrial septostomy.
      ,
      • Park S.C.
      • Neches W.H.
      • Mullins C.E.
      • Girod D.A.
      • Olley P.M.
      • Falkowski G.
      • Garibjan V.A.
      • Mathews R.A.
      • Fricker F.J.
      • Beerman L.B.
      • Lenox C.C.
      • Zuberbuhler J.R.
      Blade atrial septostomy: collaborative study.
      ]) described the techniques to create an atrial septal defect without the need of a thoracotomy. These interventional procedures were, and are still in use, mainly for the management of several congenital heart diseases.
      With accepted techniques to create an atrial septal defect, the scenario was ready to attempt this procedure in the setting of human PPH and, a year later, in 1983 Rich and Lam were the first to perform it [
      • Rich S.
      • Lam W.
      Atrial septostomy as palliative therapy for refractory primary pulmonary hypertension.
      ]. The patient was a 22-year-old woman with severe PPH, refractory to any type of vasodilator used at the time. She received a Park blade AS that was completed with a Rashkind balloon catheter technique. The patient tolerated the procedure well; however, in the next 24 h she became agitated, and dyspneic. The patient was hypoxemic and acidotic, developed refractory systemic hypotension, and died. The autopsy of this patient showed a 9 mm septostomy and signs of marked RV hypertrophy. The left side of the heart was found markedly dilated and in the lungs there were signs of pulmonary venous congestion, findings that were interpreted as being the result of pulmonary edema due to the sudden increase in preload to the left ventricle. Another possibility to explain the death of the patient was severe refractory hypoxemia, as the SaO2% significantly decreased from 87% to 57% after the procedure.
      Perhaps as the consequence of a first disappointing result, the procedure remained relatively neglected until the report of the first series of patients in 1991 by Nihill et al. [
      • Nihill M.R.
      • O’Laughlin M.P.
      • Mullins C.E.
      Effects of atrial septostomy in patients with terminal cor pulmonale due to pulmonary vascular disease.
      ]. They performed AS in 14 patients with severe PAH. There were two procedure-related deaths in this series, again due to refractory hypoxemia, but they also reported, for the first time, 9 long-term survivors who clinically improved after the procedure. The other important series of AS in patients with PPH was that of Kerstein and colleagues from Columbia University published in 1995 [
      • Kerstein D.
      • Levy P.S.
      • Hsu D.T.
      • Hordof A.J.
      • Gersony W.M.
      • Barst R.J.
      Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension.
      ]. Kerstein et al. studied 15 patients with severe PPH in functional classes III and IV. Again they used the combined procedure of blade-balloon AS (BBAS) in most of the patients. They reported two procedural deaths but also clinical improvement in most of the survivors. They were also the first ones to show that the long-term survival of PAH patients with AS was better than that of historical controls.
      As an attempt to decrease the procedure-related mortality, in 1998, our group [
      • Sandoval J.
      • Gaspar J.
      • Pulido T.
      • Bautista E.
      • Martínez-Guerra M.L.
      • Zeballos M.
      • Palomar A.
      • Gómez A.
      Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment.
      ] adopted the balloon dilation technique [
      • Hausknecht M.J.
      • Sims R.E.
      • Nihill M.R.
      • Cashion W.R.
      Successful palliation of primary pulmonary hypertension by atrial septostomy.
      ,
      • Rothman A.
      • Beltran D.
      • Kriett J.M.
      • Smith C.
      • Wolf P.
      • Jamieson S.W.
      Graded balloon dilation atrial septostomy as a bridge to transplantation in primary pulmonary hypertension.
      ], in a step-by-step manner, without the blade, to create the interatrial shunt. We reported our initial experience in 15 patients with idiopathic PAH, most of them in functional class IV. We had only one procedure-related death and most of our patients had an improvement in functional class, exercise endurance, and predicted 3-year survival. Spontaneous closure of the defect was a frequent finding in our series, so we performed a total of 22 independent procedures in these 15 patients without complications, with only one procedure-related death [
      • Sandoval J.
      • Gaspar J.
      • Pulido T.
      • Bautista E.
      • Martínez-Guerra M.L.
      • Zeballos M.
      • Palomar A.
      • Gómez A.
      Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment.
      ].

      Balloon dilatation atrial septostomy

      The procedure of balloon dilatation AS (BDAS) has been the most employed technique in the past few years and it involves a standard right and left heart catheterization [
      • Sandoval J.
      • Gaspar J.
      Atrial septostomy and other interventional procedures.
      ]. A Brockenbrough needle and a Mullins's dilator are used to perforate the septum, and non-compliant peripheral balloons of different sizes are used to perform the septostomy, in a controlled, “step-by-step” manner (Fig. 3). Three minutes after each dilatation step is performed, we measure and re-assess changes in hemodynamic variables in particular the changes in SaO2% and left ventricular end-diastolic pressure (LVEDP). The final size of the shunt is limited by (1) the drop in SaO2%, which should not be larger than 10% from baseline and (2) by the increase in LVEDP, which should be kept below 18 mmHg [
      • Sandoval J.
      • Gaspar J.
      Atrial septostomy and other interventional procedures.
      ]. When possible, a trans-esophageal echocardiogram should be used to help visualize the precise site of puncture and also to size the interatrial septostomy created (Fig. 4).
      Figure thumbnail gr3
      Fig. 3BDAS technique. Perforation of the inter-atrial septum with the catheter and the Brockenbrough needle at the tip (A and B), a guidewire is passed to the left atrium (C), over the guidewire a dilator (4 mm) is used as a first dilation (D), the septostomy is completed with non-compliant balloons of different size filled with contrast media (E and F).
      From Sandoval et al. [
      • Sandoval J.
      • Gaspar J.
      Atrial septostomy and other interventional procedures.
      ,
      • Sandoval J.
      • Gaspar J.
      • Pulido T.
      • Bautista E.
      • Martínez-Guerra M.L.
      • Zeballos M.
      • Palomar A.
      • Gómez A.
      Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment.
      ].
      Figure thumbnail gr4
      Fig. 4Trans-esophageal echocardiography during atrial septostomy in a patient with pulmonary arterial hypertension allows visualization of the shunt created (arrow) and permits the measurement of the defect. LA, left atrium; LV, left ventriculum; RA, right atrium; RV, right ventriculum.
      From Kurzyna et al. [
      • Kurzyna M.
      • Dabrowsky M.
      • Torbicki A.
      • Burakowski J.
      • Kuca P.
      • Fijałkowska A.
      • Sikora J.
      Atrial septostomy for severe primary pulmonary hypertension. Report of two cases.
      ].

      Worldwide clinical experience

      It could be summarized that the clinical deterioration and death of patients with IPAH is partly secondary to a drop in cardiac output and systemic blood flow, as well as congestion, dilation, and failure of the right ventricle. Thus, the presence of an atrial septal defect would, in theory, allow a right-to-left shunt-mediated increase of cardiac output and would help decompress the right ventricle, therefore ameliorating cardiac pump failure [
      • Sandoval J.
      • Rothman A.
      • Pulido T.
      Atrial septostomy for pulmonary hypertension.
      ]. Based on these premises, multiple hospitals around the world have attempted the use of AS for the treatment of PAH. However, since its first report as a treatment for PAH over 30 years ago [
      • Rich S.
      • Lam W.
      Atrial septostomy as palliative therapy for refractory primary pulmonary hypertension.
      ], the precise role of AS in the management of PAH continues to be relatively uncertain, mainly due to the fact that most of the knowledge we have about the procedure comes from small cohorts of patients, case reports, or non-controlled clinical trials. Furthermore, the indication for the procedure and the etiology of pulmonary vascular disease [World Health Organization (WHO) group] has not been the same in the patients reported. Lastly, the advent of new pharmacological treatments of IPAH changed the treatment algorithm [
      • Galiè N.
      • Corris P.A.
      • Frost A.
      • Girgis R.E.
      • Granton J.
      • Jing Z.C.
      • Klepetko W.
      • McGoon M.D.
      • McLaughlin V.V.
      • Preston I.R.
      • Rubin L.J.
      • Sandoval J.
      • Seeger W.
      • Keogh A.
      Updated treatment algorithm of pulmonary arterial hypertension.
      ,
      • Barst R.J.
      Role of atrial septostomy in the treatment of pulmonary vascular disease.
      ] and new clinical trials are needed to reduce any potential confounders when evaluating safety and efficacy of pharmacotherapies. Interestingly, despite all these limitations, the experience with AS has increased in the past few years.
      In the most recent review of the worldwide experience [
      • Sandoval J.
      • Torbicki A.
      Atrial septostomy.
      ], 372 procedures performed in 324 patients were identified; 304 have been reported in case series [
      • Nihill M.R.
      • O’Laughlin M.P.
      • Mullins C.E.
      Effects of atrial septostomy in patients with terminal cor pulmonale due to pulmonary vascular disease.
      ,
      • Kerstein D.
      • Levy P.S.
      • Hsu D.T.
      • Hordof A.J.
      • Gersony W.M.
      • Barst R.J.
      Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension.
      ,
      • Sandoval J.
      • Gaspar J.
      • Pulido T.
      • Bautista E.
      • Martínez-Guerra M.L.
      • Zeballos M.
      • Palomar A.
      • Gómez A.
      Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment.
      ,
      • Sobrino N.
      • Frutos A.
      • Calvo L.
      • Casamayor L.M.
      • Arcas R.
      Palliative interatrial septostomy in severe pulmonary hypertension.
      ,
      • Thanopoulos B.D.
      • Georgakopoulos D.
      • Tsaousis G.S.
      • Simeunovic S.
      Percutaneous balloon dilatation of the atrial septum: immediate and midterm results.
      ,
      • Rich S.
      • Dodin E.
      • McLaughlin V.V.
      Usefulness of atrial septostomy as a treatment for primary pulmonary hypertension and guidelines for its application.
      ,
      • Hayden A.M.
      Balloon atrial septostomy increases cardiac index and may reduce mortality among pulmonary hypertension patients awaiting lung transplantation.
      ,
      • Rothman A.
      • Slansky M.S.
      • Lucas V.W.
      • Kashani I.A.
      • Shaughnessy R.D.
      • Channick R.N.
      • Auger W.R.
      • Fedullo P.F.
      • Smith C.M.
      • Kriett J.M.
      • Jamieson S.W.
      Atrial septostomy as a bridge to lung transplantation in patients with severe pulmonary hypertension.
      ,
      • Kothari S.S.
      • Yusuf A.
      • Juneja R.
      • Yadav R.
      • Naik N.
      Graded balloon atrial septostomy in severe pulmonary hypertension.
      ,
      • Reichenberger F.
      • Pepke-Zaba J.
      • McNeil K.
      • Parameshwar J.
      • Shapiro L.M.
      Atrial septostomy in the treatment of severe pulmonary arterial hypertension.
      ,
      • Kurzyna M.
      • Dabrowsky M.
      • Torbicki A.
      • Burakowski J.
      • Kuca P.
      • Fijałkowska A.
      • Sikora J.
      Atrial septostomy for severe primary pulmonary hypertension. Report of two cases.
      ,
      • Allcock R.J.
      • O'Sullivan J.J.
      • Corris P.A.
      Atrial septostomy for pulmonary hypertension.
      ,
      • Vachiery J.L.
      • Stoupel E.
      • Boonstra A.
      • Naeije R.
      Balloon atrial septostomy for pulmonary hypertension in the prostacyclin era.
      ,
      • Micheletti A.
      • Hislop A.
      • Lammers A.
      • Bonhoeffer P.
      • Derrick G.
      • Rees P.
      • Haworth S.G.
      Role of atrial septostomy in the treatment of children with pulmonary arterial hypertension.
      ,
      • Kurzyna M.
      • Dabrowski M.
      • Bielecki D.
      • Fijalkowska A.
      • Pruszczyk P.
      • Opolski G.
      • Burakowski J.
      • Florczyk M.
      • Tomkowski W.Z.
      • Wawrzynska L.
      • Szturmowicz M.
      • Torbicki A.
      Atrial septostomy in treatment of end-stage right heart failure in patients with pulmonary hypertension.
      ,
      • Ciarka A.
      • Vachiery J.L.
      • Houssiere A.
      • Gujic M.
      • Stoupel E.
      • Velez-Roa S.
      • Naeije R.
      • van de Borne P.
      Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension.
      ,
      • Law M.A.
      • Grifka R.G.
      • Mullins C.E.
      • Nihill M.R.
      Atrial septostomy improves survival in select patients with pulmonary hypertension.
      ,
      • O’Byrne M.L.
      • Berman-Rosenzweig E.S.
      • Barst R.J.
      The effect of atrial septostomy on the concentration of brain-type natriuretic peptide in patients with idiopathic pulmonary arterial hypertension.
      ,
      • Lammers A.E.
      • Derrick G.
      • Haworth S.G.
      • Bonhoeffer P.
      • Yates R.
      Efficacy and long-term patency of fenestrated Amplatzer devices in children.
      ,
      • Troost E.
      • Delcroix M.
      • Gewillig M.
      • Van Deyk K.
      • Budts W.
      A modified technique of stent fenestration of the interatrial septum improves patients with pulmonary hypertension.
      ,
      • Fenstad E.R.
      • Le R.J.
      • McGoon M.D.
      • Reeder G.
      • Hagler D.J.
      • Cabalka A.K.
      • Kane G.C.
      • Frantz R.P.
      Atrial septostomy in patients with pulmonary arterial hypertension.
      ,
      • Sandoval J.
      • Gaspar J.
      • Peña H.
      • Santos L.E.
      • Córdova J.
      • del Valle K.
      • Rodríguez A.
      • Pulido T.
      Effect of atrial septostomy on the survival of patients with severe pulmonary arterial hypertension.
      ,
      • Velázquez Martín M.
      • Albarrán González-Trevilla A.
      • García Tejada J.
      • Ruiz Cano M.J.
      • Montezo Cabezas J.M.
      • García Aranda Domínguez B.
      • Jurado Román A.
      • Escribano Subias P.
      Utilidad de la septostomía auricular como tratamiento paliativo en pacientes con hipertensión pulmonar grave y disfunción ventricular.
      ,
      • Baglini R.
      Atrial septostomy in patients with end-stage pulmonary hypertension. No more needles but wires, energy and close anatomical definition.
      ], and 20 as case reports [
      • Hausknecht M.J.
      • Sims R.E.
      • Nihill M.R.
      • Cashion W.R.
      Successful palliation of primary pulmonary hypertension by atrial septostomy.
      ,
      • Rothman A.
      • Beltran D.
      • Kriett J.M.
      • Smith C.
      • Wolf P.
      • Jamieson S.W.
      Graded balloon dilation atrial septostomy as a bridge to transplantation in primary pulmonary hypertension.
      ,
      • Collins T.J.
      • Moore J.W.
      • Kirby W.C.
      Atrial septostomy for pulmonary hypertension.
      ,
      • Unger P.
      • Stoupel E.
      • Vachiery J.L.
      • De Backer D.
      Atrial septostomy under transesophageal guidance in a patient with primary pulmonary hypertension and absent right superior vena cava.
      ,
      • Fulwani M.
      • Nabar A.
      • Iyer R.
      • Lokhandwala Y.
      Palliative blade-balloon atrial septostomy in primary pulmonary hypertension.
      ,
      • Takigiku K.
      • Shibata T.
      • Yasui K.
      • Iwamoto M.
      Successful blade atrial septostomy in a patient with severe primary pulmonary hypertension—a case report.
      ,
      • Allcock R.J.
      • O'Sullivan J.J.
      • Corris P.A.
      Palliation of systemic sclerosis-associated pulmonary hypertension by atrial septostomy.
      ,
      • Chau E.M.C.
      • Fan K.Y.Y.
      • Chow W.H.
      Combined atrial septostomy and oral sildenafil for severe right ventricular failure due to primary pulmonary hypertension.
      ,
      • Moscussi M.
      • Dairywala I.T.
      • Chetcuti S.
      • Mathew B.
      • Li P.
      • Rubenfire M.
      • Vannan M.A.
      Balloon atrial septostomy in end-stage pulmonary hypertension guided a novel intracardiac echocardiographic transducer.
      ,
      • Wawrzynska L.
      • Remiszewski P.
      • Kurzyna M.
      • Fijałkowska A.
      • Burakowski J.
      • Dabrowski M.
      • Orłowski T.
      • Roszkowski K.
      • Dłutek P.
      • Klepetko W.
      • Torbicki A.
      A case of a patient with idiopathic pulmonary arterial hypertension treated with lung transplantation: a bumpy road to success.
      ,
      • Rogan M.P.
      • Walsh K.P.
      • Gaine S.P.
      Migraine with aura following atrial septostomy for pulmonary arterial hypertension.
      ,
      • Fraisse A.
      • Chetaille P.
      • Amin Z.
      • Rouault F.
      • Humbert M.
      Use of Amplatzer fenestrated atrial septal defect device in a child with familial pulmonary hypertension.
      ,
      • Prieto L.R.
      • Latson L.A.
      • Jennings C.
      Atrial septostomy using a butterfly stent in a patient with severe pulmonary arterial hypertension.
      ,
      • O’Loughlin A.J.
      • Keogh A.
      • Muller D.W.
      Insertion of a fenestrated Amplatzer atrial septostomy device for severe pulmonary hypertension.
      ,
      • Lagioia A.
      • Atamañuk N.
      • Bortman G.
      Tratamiento intervencionista de la hipertensión pulmonar.
      ,
      • Althoff T.F.
      • Knebel F.
      • Panda A.
      • McArdle J.
      • Gliech V.
      • Franke I.
      • Witt C.
      • Baumann G.
      • Borges A.C.
      Long-term follow-up of a fenestrated Amplatzer atrial septal occluder in pulmonary arterial hypertension.
      ,
      • Baglini R.
      • Scardulla C.
      Reduction of a previous atrial septostomy in a patient with end-stage pulmonary hypertension by a manually fenestrated device.
      ,
      • Demerouti E.
      • Manginas A.
      • Rammos S.
      • Athanassopoulos G.
      • Karatasakis G.
      • Pavlides G.
      Postpartum pulmonary arterial hypertension: two cases covering a wide spectrum of presentations.
      ,
      • Kapoor A.
      • Khanna R.
      • Batra A.
      • Kumar S.
      Inoue balloon atrial septostomy in severe persistent pulmonary hypertension following surgical ASD closure.
      ,
      • Roy A.K.
      • Gaine S.P.
      • Walsh K.P.
      Percutaneous atrial septostomy with modified butterfly stent and intracardiac echocardiographic guidance in a patient with syncope and refractory pulmonary arterial hypertension.
      ] (Table 1). AS has largely been performed in young people, mostly women (∼70%), and most of them with IPAH in functional classes III and IV (∼77%). Reports of AS in patients with pulmonary hypertension associated with surgically corrected congenital heart disease (9%), collagen tissue disease (5%), and few cases of distal chronic thromboembolic pulmonary hypertension (3.5%) have also been reported. Most frequently, AS has been performed after failure of maximal medical treatment in a significant number of patients [
      • Sandoval J.
      • Torbicki A.
      Atrial septostomy.
      ] (Table 1), refractory congestive heart failure, recurrent syncope, or both being the most common indications for the procedure.
      Table 1Worldwide experience with atrial septostomy in the management of PAH.
      Adapted from Ref.
      • Sandoval J.
      • Torbicki A.
      Atrial septostomy.
      .
      ReferencenAgeFemaleNYHASyncopeCHFBothProcedures
      Nihill et al.
      • Nihill M.R.
      • O’Laughlin M.P.
      • Mullins C.E.
      Effects of atrial septostomy in patients with terminal cor pulmonale due to pulmonary vascular disease.
      1420.5 ± 12.178.6%3.8 ± 0.456314
      Sobrino et al.
      • Sobrino N.
      • Frutos A.
      • Calvo L.
      • Casamayor L.M.
      • Arcas R.
      Palliative interatrial septostomy in severe pulmonary hypertension.
      336.0 ± 5.033%4.0 ± 033
      Kerstein et al.
      • Kerstein D.
      • Levy P.S.
      • Hsu D.T.
      • Hordof A.J.
      • Gersony W.M.
      • Barst R.J.
      Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension.
      1524.9 ± 11.386.6%3.53 ± 0.527816
      Rich et al.
      • Rich S.
      • Dodin E.
      • McLaughlin V.V.
      Usefulness of atrial septostomy as a treatment for primary pulmonary hypertension and guidelines for its application.
      638.8 ± 7.783.3%3.7 ± 0.566
      Thanopoulos et al.
      • Thanopoulos B.D.
      • Georgakopoulos D.
      • Tsaousis G.S.
      • Simeunovic S.
      Percutaneous balloon dilatation of the atrial septum: immediate and midterm results.
      66.1 ± 2.6NA3 ± 0336
      Hayden
      • Hayden A.M.
      Balloon atrial septostomy increases cardiac index and may reduce mortality among pulmonary hypertension patients awaiting lung transplantation.
      635
      mean value.
      83.3%4.0 ± 0156
      Sandoval et al.
      • Sandoval J.
      • Gaspar J.
      • Pulido T.
      • Bautista E.
      • Martínez-Guerra M.L.
      • Zeballos M.
      • Palomar A.
      • Gómez A.
      Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment.
      1533 ± 987%3.6 ± 0.648322
      Rothman et al.
      • Rothman A.
      • Slansky M.S.
      • Lucas V.W.
      • Kashani I.A.
      • Shaughnessy R.D.
      • Channick R.N.
      • Auger W.R.
      • Fedullo P.F.
      • Smith C.M.
      • Kriett J.M.
      • Jamieson S.W.
      Atrial septostomy as a bridge to lung transplantation in patients with severe pulmonary hypertension.
      1237 ± 1283.3%3.6 ± 0.565113
      Kothari et al.
      • Kothari S.S.
      • Yusuf A.
      • Juneja R.
      • Yadav R.
      • Naik N.
      Graded balloon atrial septostomy in severe pulmonary hypertension.
      1116.2 ± 8.936%3.62 ± 0.6918211
      Reichenberger et al.
      • Reichenberger F.
      • Pepke-Zaba J.
      • McNeil K.
      • Parameshwar J.
      • Shapiro L.M.
      Atrial septostomy in the treatment of severe pulmonary arterial hypertension.
      1735.9 ± 14.270.6%3.7 ± 0.5410320
      Kurzyna et al.
      • Kurzyna M.
      • Dabrowsky M.
      • Torbicki A.
      • Burakowski J.
      • Kuca P.
      • Fijałkowska A.
      • Sikora J.
      Atrial septostomy for severe primary pulmonary hypertension. Report of two cases.
      226.5 ± 6.4100%4.0 ± 022
      Allcock et al.
      • Allcock R.J.
      • O'Sullivan J.J.
      • Corris P.A.
      Atrial septostomy for pulmonary hypertension.
      956.4 ± 22.4100%3.7 ± 0.5912
      Vachiery et al.
      • Vachiery J.L.
      • Stoupel E.
      • Boonstra A.
      • Naeije R.
      Balloon atrial septostomy for pulmonary hypertension in the prostacyclin era.
      16NANA3.6 ± 0.418
      Micheletti et l.
      • Micheletti A.
      • Hislop A.
      • Lammers A.
      • Bonhoeffer P.
      • Derrick G.
      • Rees P.
      • Haworth S.G.
      Role of atrial septostomy in the treatment of children with pulmonary arterial hypertension.
      208.4 ± 5.655%3.5 ± 0.5127122
      Kurzyna et al.
      • Kurzyna M.
      • Dabrowski M.
      • Bielecki D.
      • Fijalkowska A.
      • Pruszczyk P.
      • Opolski G.
      • Burakowski J.
      • Florczyk M.
      • Tomkowski W.Z.
      • Wawrzynska L.
      • Szturmowicz M.
      • Torbicki A.
      Atrial septostomy in treatment of end-stage right heart failure in patients with pulmonary hypertension.
      1133.0 ± 1254.5%3.3 ± 0.51114
      Ciarka et al.
      • Ciarka A.
      • Vachiery J.L.
      • Houssiere A.
      • Gujic M.
      • Stoupel E.
      • Velez-Roa S.
      • Naeije R.
      • van de Borne P.
      Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension.
      1148.0 ± 554.5%3.5 ± 0.518211
      Law et al.
      • Law M.A.
      • Grifka R.G.
      • Mullins C.E.
      • Nihill M.R.
      Atrial septostomy improves survival in select patients with pulmonary hypertension.
      4312.5
      median value.
      81%3–41822346
      O’Byrne et al.
      • O’Byrne M.L.
      • Berman-Rosenzweig E.S.
      • Barst R.J.
      The effect of atrial septostomy on the concentration of brain-type natriuretic peptide in patients with idiopathic pulmonary arterial hypertension.
      529.4 ± 10.560%3–42215
      Lammers et al.
      • Lammers A.E.
      • Derrick G.
      • Haworth S.G.
      • Bonhoeffer P.
      • Yates R.
      Efficacy and long-term patency of fenestrated Amplatzer devices in children.
      78.9 ± 5.457%3.1 ± 0.4347
      Troost et al.
      • Troost E.
      • Delcroix M.
      • Gewillig M.
      • Van Deyk K.
      • Budts W.
      A modified technique of stent fenestration of the interatrial septum improves patients with pulmonary hypertension.
      1548.2 ± 20.580%4.0 ± 01517
      Fenstad et al.
      • Fenstad E.R.
      • Le R.J.
      • McGoon M.D.
      • Reeder G.
      • Hagler D.J.
      • Cabalka A.K.
      • Kane G.C.
      • Frantz R.P.
      Atrial septostomy in patients with pulmonary arterial hypertension.
      840.0 ± 1389%3–4811
      Sandoval et al.
      • Sandoval J.
      • Gaspar J.
      • Peña H.
      • Santos L.E.
      • Córdova J.
      • del Valle K.
      • Rodríguez A.
      • Pulido T.
      Effect of atrial septostomy on the survival of patients with severe pulmonary arterial hypertension.
      3435.0 ± 1085%3.5 ± 0.69141150
      Velázquez Martín et al.
      • Velázquez Martín M.
      • Albarrán González-Trevilla A.
      • García Tejada J.
      • Ruiz Cano M.J.
      • Montezo Cabezas J.M.
      • García Aranda Domínguez B.
      • Jurado Román A.
      • Escribano Subias P.
      Utilidad de la septostomía auricular como tratamiento paliativo en pacientes con hipertensión pulmonar grave y disfunción ventricular.
      7NA71%3–4259
      Baglini
      • Baglini R.
      Atrial septostomy in patients with end-stage pulmonary hypertension. No more needles but wires, energy and close anatomical definition.
      1145.5 ± 1245.5%3.6 ± 0.51111
      Total in series30430.7 years
      mean value.
      201/282 (71.6%)3.9±0.386/288 (29.8%)145/288 (50.3%)57/288 (19.8%)352
      Case reports
      • Hausknecht M.J.
      • Sims R.E.
      • Nihill M.R.
      • Cashion W.R.
      Successful palliation of primary pulmonary hypertension by atrial septostomy.
      ,
      • Rothman A.
      • Beltran D.
      • Kriett J.M.
      • Smith C.
      • Wolf P.
      • Jamieson S.W.
      Graded balloon dilation atrial septostomy as a bridge to transplantation in primary pulmonary hypertension.
      ,
      • Collins T.J.
      • Moore J.W.
      • Kirby W.C.
      Atrial septostomy for pulmonary hypertension.
      ,
      • Unger P.
      • Stoupel E.
      • Vachiery J.L.
      • De Backer D.
      Atrial septostomy under transesophageal guidance in a patient with primary pulmonary hypertension and absent right superior vena cava.
      ,
      • Fulwani M.
      • Nabar A.
      • Iyer R.
      • Lokhandwala Y.
      Palliative blade-balloon atrial septostomy in primary pulmonary hypertension.
      ,
      • Takigiku K.
      • Shibata T.
      • Yasui K.
      • Iwamoto M.
      Successful blade atrial septostomy in a patient with severe primary pulmonary hypertension—a case report.
      ,
      • Allcock R.J.
      • O'Sullivan J.J.
      • Corris P.A.
      Palliation of systemic sclerosis-associated pulmonary hypertension by atrial septostomy.
      ,
      • Chau E.M.C.
      • Fan K.Y.Y.
      • Chow W.H.
      Combined atrial septostomy and oral sildenafil for severe right ventricular failure due to primary pulmonary hypertension.
      ,
      • Moscussi M.
      • Dairywala I.T.
      • Chetcuti S.
      • Mathew B.
      • Li P.
      • Rubenfire M.
      • Vannan M.A.
      Balloon atrial septostomy in end-stage pulmonary hypertension guided a novel intracardiac echocardiographic transducer.
      ,
      • Wawrzynska L.
      • Remiszewski P.
      • Kurzyna M.
      • Fijałkowska A.
      • Burakowski J.
      • Dabrowski M.
      • Orłowski T.
      • Roszkowski K.
      • Dłutek P.
      • Klepetko W.
      • Torbicki A.
      A case of a patient with idiopathic pulmonary arterial hypertension treated with lung transplantation: a bumpy road to success.
      ,
      • Rogan M.P.
      • Walsh K.P.
      • Gaine S.P.
      Migraine with aura following atrial septostomy for pulmonary arterial hypertension.
      ,
      • Fraisse A.
      • Chetaille P.
      • Amin Z.
      • Rouault F.
      • Humbert M.
      Use of Amplatzer fenestrated atrial septal defect device in a child with familial pulmonary hypertension.
      ,
      • Prieto L.R.
      • Latson L.A.
      • Jennings C.
      Atrial septostomy using a butterfly stent in a patient with severe pulmonary arterial hypertension.
      ,
      • O’Loughlin A.J.
      • Keogh A.
      • Muller D.W.
      Insertion of a fenestrated Amplatzer atrial septostomy device for severe pulmonary hypertension.
      ,
      • Lagioia A.
      • Atamañuk N.
      • Bortman G.
      Tratamiento intervencionista de la hipertensión pulmonar.
      ,
      • Althoff T.F.
      • Knebel F.
      • Panda A.
      • McArdle J.
      • Gliech V.
      • Franke I.
      • Witt C.
      • Baumann G.
      • Borges A.C.
      Long-term follow-up of a fenestrated Amplatzer atrial septal occluder in pulmonary arterial hypertension.
      ,
      • Baglini R.
      • Scardulla C.
      Reduction of a previous atrial septostomy in a patient with end-stage pulmonary hypertension by a manually fenestrated device.
      ,
      • Demerouti E.
      • Manginas A.
      • Rammos S.
      • Athanassopoulos G.
      • Karatasakis G.
      • Pavlides G.
      Postpartum pulmonary arterial hypertension: two cases covering a wide spectrum of presentations.
      ,
      • Kapoor A.
      • Khanna R.
      • Batra A.
      • Kumar S.
      Inoue balloon atrial septostomy in severe persistent pulmonary hypertension following surgical ASD closure.
      ,
      • Roy A.K.
      • Gaine S.P.
      • Walsh K.P.
      Percutaneous atrial septostomy with modified butterfly stent and intracardiac echocardiographic guidance in a patient with syncope and refractory pulmonary arterial hypertension.
      2030 ± 13.513 (68.5%)3.9 ± 0.32 (20%)10 (50%)8 (40%)20
      Abbreviations. NYHA: New York Heart Association Functional Class; CHF: Congestive heart failure; NA: not available.
      * mean value.
      ** median value.
      Worldwide, different types of septostomies have been performed (Table 2). Whether it is a BBAS, BDAS (No Park-blade catheter is used), or a combination of both, it appears that BDAS is the procedure of choice. The intervention has been repeated in 48 occasions due to spontaneous closure of the defect. The size of the defect has varied from 8 to 18 mm with mean value of ∼11 mm. Globally, overall 14% of the patients have died from procedure-related complications, 8% deaths were immediate (within 24 h due to refractory hypoxemia) and an additional 6% within one month. However, most importantly, the large majority of patients, that is ∼86%, survived the procedure with a 90% improvement in functional capacity. Approximately 13% of the patients received a lung transplant and in the long-term, 63 late deaths and 179 survivors were reported [
      • Sandoval J.
      • Torbicki A.
      Atrial septostomy.
      ]. Table 3 shows the variables associated with procedure-related mortality. Baseline right atrial pressure (RAP), in particular a RAP higher than 20 mmHg, remains, as shown in previous analyses [
      • Klepetko W.
      • Mayer E.
      • Sandoval J.
      • Trulock E.P.
      • Vachiery J.L.
      • Dartevelle P.
      • Pepke-Zaba J.
      • Jamieson S.W.
      • Lang I.
      • Corris P.
      Interventional and surgical modalities of treatment for pulmonary arterial hypertension.
      ,
      • Sandoval J.
      • Gaspar J.
      Atrial septostomy and other interventional procedures.
      ,
      • Sandoval J.
      • Rothman A.
      • Pulido T.
      Atrial septostomy for pulmonary hypertension.
      ], the most significant risk factor for death during the procedure. Low SaO2% after the procedure, perhaps as a result of an oversized septostomy, is also associated with a higher risk of death.
      Table 2Type of septostomy and outcome in the worldwide experience.
      Adapted from Ref.
      • Sandoval J.
      • Torbicki A.
      Atrial septostomy.
      .
      ReferenceProc.BladeBDASBBASSize mmImmediate death (24 h)Mortality 1-monthLate deathsTotal deathsLTFollow-up months
      Nihill et al.
      • Nihill M.R.
      • O’Laughlin M.P.
      • Mullins C.E.
      Effects of atrial septostomy in patients with terminal cor pulmonale due to pulmonary vascular disease.
      144108–202125131.5 (0–96)
      Sobrino et al.
      • Sobrino N.
      • Frutos A.
      • Calvo L.
      • Casamayor L.M.
      • Arcas R.
      Palliative interatrial septostomy in severe pulmonary hypertension.
      3316 ± 6110–13 Mo
      Kerstein et al.
      • Kerstein D.
      • Levy P.S.
      • Hsu D.T.
      • Hordof A.J.
      • Gersony W.M.
      • Barst R.J.
      Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension.
      164124–1824620–45 Mo
      Rich et al.
      • Rich S.
      • Dodin E.
      • McLaughlin V.V.
      Usefulness of atrial septostomy as a treatment for primary pulmonary hypertension and guidelines for its application.
      642NA213NA
      Thanopoulos et al.
      • Thanopoulos B.D.
      • Georgakopoulos D.
      • Tsaousis G.S.
      • Simeunovic S.
      Percutaneous balloon dilatation of the atrial septum: immediate and midterm results.
      668.7 ± 1.20022 Mo (4–48)
      Hayden
      • Hayden A.M.
      Balloon atrial septostomy increases cardiac index and may reduce mortality among pulmonary hypertension patients awaiting lung transplantation.
      66NA224NA
      Sandoval et al.
      • Sandoval J.
      • Gaspar J.
      • Pulido T.
      • Bautista E.
      • Martínez-Guerra M.L.
      • Zeballos M.
      • Palomar A.
      • Gómez A.
      Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment.
      222210 ± 3112516 Mo (0–36)
      Rothman et al.
      • Rothman A.
      • Slansky M.S.
      • Lucas V.W.
      • Kashani I.A.
      • Shaughnessy R.D.
      • Channick R.N.
      • Auger W.R.
      • Fedullo P.F.
      • Smith C.M.
      • Kriett J.M.
      • Jamieson S.W.
      Atrial septostomy as a bridge to lung transplantation in patients with severe pulmonary hypertension.
      131310.2 ± 1.3212550–18 Mo
      Kothari et al.
      • Kothari S.S.
      • Yusuf A.
      • Juneja R.
      • Yadav R.
      • Naik N.
      Graded balloon atrial septostomy in severe pulmonary hypertension.
      11114–15211420 Mo (0–60)
      Reichenberger et al.
      • Reichenberger F.
      • Pepke-Zaba J.
      • McNeil K.
      • Parameshwar J.
      • Shapiro L.M.
      Atrial septostomy in the treatment of severe pulmonary arterial hypertension.
      202010.6 ± 1.641550–18 Mo
      Kurzyna et al.
      • Kurzyna M.
      • Dabrowsky M.
      • Torbicki A.
      • Burakowski J.
      • Kuca P.
      • Fijałkowska A.
      • Sikora J.
      Atrial septostomy for severe primary pulmonary hypertension. Report of two cases.
      227 ± 1.410–5 Mo
      Allcock et al.
      • Allcock R.J.
      • O'Sullivan J.J.
      • Corris P.A.
      Atrial septostomy for pulmonary hypertension.
      121215.3 ± 2.802210–30 Mo
      Vachiery et al.
      • Vachiery J.L.
      • Stoupel E.
      • Boonstra A.
      • Naeije R.
      Balloon atrial septostomy for pulmonary hypertension in the prostacyclin era.
      1818NA1113NA
      Micheletti et al.
      • Micheletti A.
      • Hislop A.
      • Lammers A.
      • Bonhoeffer P.
      • Derrick G.
      • Rees P.
      • Haworth S.G.
      Role of atrial septostomy in the treatment of children with pulmonary arterial hypertension.
      2221736.9 ± 2.402222.1 y (1 Mo–6.7 years)
      Kurzyna et al.
      • Kurzyna M.
      • Dabrowski M.
      • Bielecki D.
      • Fijalkowska A.
      • Pruszczyk P.
      • Opolski G.
      • Burakowski J.
      • Florczyk M.
      • Tomkowski W.Z.
      • Wawrzynska L.
      • Szturmowicz M.
      • Torbicki A.
      Atrial septostomy in treatment of end-stage right heart failure in patients with pulmonary hypertension.
      14146.6 ± 1.6016728.1 Mo (0.8–20.2)
      Ciarka et al.
      • Ciarka A.
      • Vachiery J.L.
      • Houssiere A.
      • Gujic M.
      • Stoupel E.
      • Velez-Roa S.
      • Naeije R.
      • van de Borne P.
      Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension.
      111115.2 ± 2.70NA
      Law et al.
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      463051112.2 ± 2.92891931981–2005
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      541NA04–216 days
      Lammers et al.
      • Lammers A.E.
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      • Bonhoeffer P.
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      7711.7 ± 2.2025.7 Mo (18–31)
      Troost et al.
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      17174 (3–5)123640.7 year (0–5.9)
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      1111NA01121243 ± 183 days
      Sandoval et al.
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      50508.5 ± 2.51212258.5 ± 38 Mo
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      99Mean 11044118 Mo (0–67)
      Baglini
      • Baglini R.
      Atrial septostomy in patients with end-stage pulmonary hypertension. No more needles but wires, energy and close anatomical definition.
      1111NA2248.2 ± 3.8 Mo
      Series35240 (11.4%)273 (77.5%)39 (11%)Mean 10.824 (6.8%)17 (4.8%)6210235
      Case reports
      • Hausknecht M.J.
      • Sims R.E.
      • Nihill M.R.
      • Cashion W.R.
      Successful palliation of primary pulmonary hypertension by atrial septostomy.
      ,
      • Rothman A.
      • Beltran D.
      • Kriett J.M.
      • Smith C.
      • Wolf P.
      • Jamieson S.W.
      Graded balloon dilation atrial septostomy as a bridge to transplantation in primary pulmonary hypertension.
      ,
      • Collins T.J.
      • Moore J.W.
      • Kirby W.C.
      Atrial septostomy for pulmonary hypertension.
      ,
      • Unger P.
      • Stoupel E.
      • Vachiery J.L.
      • De Backer D.
      Atrial septostomy under transesophageal guidance in a patient with primary pulmonary hypertension and absent right superior vena cava.
      ,
      • Fulwani M.
      • Nabar A.
      • Iyer R.
      • Lokhandwala Y.
      Palliative blade-balloon atrial septostomy in primary pulmonary hypertension.
      ,
      • Takigiku K.
      • Shibata T.
      • Yasui K.
      • Iwamoto M.
      Successful blade atrial septostomy in a patient with severe primary pulmonary hypertension—a case report.
      ,
      • Allcock R.J.
      • O'Sullivan J.J.
      • Corris P.A.
      Palliation of systemic sclerosis-associated pulmonary hypertension by atrial septostomy.
      ,
      • Chau E.M.C.
      • Fan K.Y.Y.
      • Chow W.H.
      Combined atrial septostomy and oral sildenafil for severe right ventricular failure due to primary pulmonary hypertension.
      ,
      • Moscussi M.
      • Dairywala I.T.
      • Chetcuti S.
      • Mathew B.
      • Li P.
      • Rubenfire M.
      • Vannan M.A.
      Balloon atrial septostomy in end-stage pulmonary hypertension guided a novel intracardiac echocardiographic transducer.
      ,
      • Wawrzynska L.
      • Remiszewski P.
      • Kurzyna M.
      • Fijałkowska A.
      • Burakowski J.
      • Dabrowski M.
      • Orłowski T.
      • Roszkowski K.
      • Dłutek P.
      • Klepetko W.
      • Torbicki A.
      A case of a patient with idiopathic pulmonary arterial hypertension treated with lung transplantation: a bumpy road to success.
      ,
      • Rogan M.P.
      • Walsh K.P.
      • Gaine S.P.
      Migraine with aura following atrial septostomy for pulmonary arterial hypertension.
      ,
      • Fraisse A.
      • Chetaille P.
      • Amin Z.
      • Rouault F.
      • Humbert M.
      Use of Amplatzer fenestrated atrial septal defect device in a child with familial pulmonary hypertension.
      ,
      • Prieto L.R.
      • Latson L.A.
      • Jennings C.
      Atrial septostomy using a butterfly stent in a patient with severe pulmonary arterial hypertension.
      ,
      • O’Loughlin A.J.
      • Keogh A.
      • Muller D.W.
      Insertion of a fenestrated Amplatzer atrial septostomy device for severe pulmonary hypertension.
      ,
      • Lagioia A.
      • Atamañuk N.
      • Bortman G.
      Tratamiento intervencionista de la hipertensión pulmonar.
      ,
      • Althoff T.F.
      • Knebel F.
      • Panda A.
      • McArdle J.
      • Gliech V.
      • Franke I.
      • Witt C.
      • Baumann G.
      • Borges A.C.
      Long-term follow-up of a fenestrated Amplatzer atrial septal occluder in pulmonary arterial hypertension.
      ,
      • Baglini R.
      • Scardulla C.
      Reduction of a previous atrial septostomy in a patient with end-stage pulmonary hypertension by a manually fenestrated device.
      ,
      • Demerouti E.
      • Manginas A.
      • Rammos S.
      • Athanassopoulos G.
      • Karatasakis G.
      • Pavlides G.
      Postpartum pulmonary arterial hypertension: two cases covering a wide spectrum of presentations.
      ,
      • Kapoor A.
      • Khanna R.
      • Batra A.
      • Kumar S.
      Inoue balloon atrial septostomy in severe persistent pulmonary hypertension following surgical ASD closure.
      ,
      • Roy A.K.
      • Gaine S.P.
      • Walsh K.P.
      Percutaneous atrial septostomy with modified butterfly stent and intracardiac echocardiographic guidance in a patient with syncope and refractory pulmonary arterial hypertension.
      201468–18mm3 (15%)2 (10%)1510–60Mo
      Total372402874527/372 (7.2%)19/372 (5.1%)
      Abbreviations. Proc.: procedures; BDAS: balloon dilation atrial septostomy; BBAS: blade-balloon atrial septostomy; LT: lung transplant. Mo: months.
      Table 3Variables associated with immediate mortality after atrial septostomy.
      VariableHazard ratio (95% confidence interval)p-value
      Age (years)1.01 (0.990–1.037)0.263
      NYHA2.82 (1.02–7.81)0.045
      Syncope0.17 (0.04–0.75)0.019
      Right heart failure3.09 (1.24–7.66)0.015
      Type, BDAS1.51 (0.641–3.58)0.343
      Size (mm)0.97 (0.797–1.24)0.973
      Baseline RAP (mmHg)1.13 (1.07–1.19)0.000
      Baseline RAP>20mmHg11.4 (3.75–34.7)0.000
      RAP after (mmHg)1.18 (1.07–1.31)0.001
      Baseline PAP (mmHg)1.03 (1.01–1.05)0.001
      LAP after (mmHg)1.26 (1.07–1.48)0.005
      Baseline SaO2%0.99 (0.88–1.11)0.944
      SaO2% after0.91 (0.87–0.95)0.000
      Delta (decrease) SaO2%1.09 (1.05–1.13)0.000
      Baseline Cardiac Index (L min m2)0.32 (0.12–0.85)0.022
      Cardiac Index after (L min m2)0.46 (0.64–1.32)0.154
      Delta (increase) Cardiac Index (%)1.01 (1.006–1.03)0.003
      Abbreviation. LAP, left atrial pressure.
      Hemodynamically, a modest but significant decrease in RAP (from 14.8 ± 8 mmHg to 11.8 ± 6.3 mmHg; p < 0.001), followed by a similar increase in left atrial pressure (from 5.9 ± 3.3 mmHg to 8.3 mmHg ± 4; p < 0.001) has been reported. Importantly, an increased CI (from 2.0 ± 0.68 L min m2 to 2.61 ± 0.80 L min m2; p < 0.001) and a significant decrease in arterial oxygen saturation (from 93.1 ± 3.9% to 83.0 ± 8.4%; p < 0.001) are usually reported. Pulmonary and systemic pressures do not appear to change. It is important to stress the fact that most of the hemodynamic variables reported have been obtained during resting condition and the hemodynamic status might be different during exercise when the septostomy could be serving as a better “safety valve”. The better function of a septostomy during exercise might explain the improvement in exercise endurance reported in many patient series [
      • Sandoval J.
      • Gaspar J.
      • Pulido T.
      • Bautista E.
      • Martínez-Guerra M.L.
      • Zeballos M.
      • Palomar A.
      • Gómez A.
      Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment.
      ,
      • Allcock R.J.
      • O'Sullivan J.J.
      • Corris P.A.
      Atrial septostomy for pulmonary hypertension.
      ,
      • Vachiery J.L.
      • Stoupel E.
      • Boonstra A.
      • Naeije R.
      Balloon atrial septostomy for pulmonary hypertension in the prostacyclin era.
      ,
      • Troost E.
      • Delcroix M.
      • Gewillig M.
      • Van Deyk K.
      • Budts W.
      A modified technique of stent fenestration of the interatrial septum improves patients with pulmonary hypertension.
      ].
      The hemodynamic effects of an AS also highly depend on the baseline RAP. Table 4 shows how a higher baseline RAP will result in more pronounced hemodynamic effects, especially when RAP > 20 mmHg. However, as mentioned repeatedly in this review, patients with a RAP > 20 mmHg will also have a significantly higher risk of death during the procedure as a result of refractory hypoxemia. Thus, it appears that the best risk/benefit ratio corresponds to the group with a RAP between 10 and 20 mmHg. Nevertheless, the size of the septostomy should be individualized when possible, as it should be noted that even when RAP is lower than 10 mmHg there is a significant increase in CI as well as an improvement in functional class suggesting, perhaps, that performing a septostomy at an early stage during disease could also be of benefit [
      • Sandoval J.
      • Torbicki A.
      Atrial septostomy.
      ].
      Table 4Hemodynamic results and outcome after atrial septostomy according to baseline right atrial pressure.
      VariableBaseline RAP < 10 (N = 27)p-valueBaseline RAP 10–20 (N = 51)p-valueBaseline RAP > 20 (N = 26)p-value
      Age (years)23 ± 1428 ± 1427.5 ± 12
      Syncope (%)65.2%26.2%12%
      RVF (%)26%33.3%64%
      Both (RVF + syncope)8.7%40.5%24%
      BeforeAfterBeforeAfterBeforeAfter
      RAP (mmHg)5.8 ± 1.965.48 ± 3.10.62214.1 ± 3.211.4 ± 3.80.00125.8 ± 4.919.2 ± 4.40.001
      Cardiac Index (L min m2)2.37 ± 0.612.80 ± 0.70.0012.10 ± 0.702.7 ± 0.90.0011.6 ± 0.52.2 ± 0.60.001
      SaO2%93.5 ± 4.187.2 ± 7.40.00192.9 ± 4.182.8 ± 7.40.00192.2 ± 4.578.3 ± 9.70.001
      Mean PAP (mmHg)62.8 ± 1764 ± 19.60.58864.9 ± 16.765.6 ± 16.70.61764.8 ± 2369.9 ± 24.70.185
      Mortality 1-month0/27 (0%)2/51 (4%)11/26 (42.3%)

      What is the optimal size for septostomy?

      As previously discussed, one of the main objectives of septostomy is to increase systemic blood flow and cardiac output; however, a significant increase in cardiac output after septostomy might not always be beneficial. Fig. 5 shows that there is a negative correlation between the increase in CI and the drop in SaO2% after septostomy, which prompts the question: what is the optimal size for an AS?
      Figure thumbnail gr5
      Fig. 5Correlation between the change in cardiac index (delta CI%) and the change in arterial oxygen saturation (delta SaO2%); r = −0.49; p ≤ 0.001.
      Reproduced from Sandoval et al. [
      • Sandoval J.
      • Torbicki A.
      Atrial septostomy.
      ].
      Indeed, there is not a definitive answer: the size of the septostomy should be individualized. We should aim to increase cardiac output and to decompress the RV but refractory hypoxemia should be avoided. Based on recent experimental data it would appear that increasing cardiac output no more than 20% from baseline would provide the best results and benefits. In a study by Zierer et al. [
      • Zierer A.
      • Melby S.J.
      • Voeller R.K.
      • Moon M.R.
      Interatrial shunt for chronic pulmonary hypertension: differential impact of low-flow vs. high-flow shunting.
      ], the effect of an inter-atrial shunt on right atrial and RV mechanics was addressed. They used a canine model of RV hypertension produced by banding, similar to that used by Austen et al. many years ago [
      • Austen W.G.
      • Morrow A.G.
      • Berry W.B.
      Experimental studies of the surgical treatment of primary pulmonary hypertension.
      ]. Two degrees of shunting were explored: low flow, equivalent to 15% of the total cardiac output, and high flow representing almost 30% of the total output, which was manipulated by controlling venous return. In their results, Zierer et al. demonstrate that the slope of Emax in both chambers, that is, cardiac contractility, did not change at any level of flow but the compliance, in particular the compliance of the right atrium, increased especially at a low flow. Apart from the improved compliance of the right atrium, there was also a significant shift from the reservoir-to-conduit function ratio of the right atrium. They also showed that as a result of the increase in LV preload by the shunt, cardiac output and systemic oxygen delivery were also increased except at high flow where the beneficial effects on systemic oxygen delivery reversed. It could be said that the take-home message from Zierer and collaborators’ work is that, when performing a septostomy, we should try to keep the shunt between 15% and 20% of the baseline cardiac output at the most. Weimar et al., from the same group of investigators, studied the impact of shunt fraction on cardiac output and oxygen delivery using basically the same experimental model of pulmonary hypertension [
      • Weimar T.
      • Watanabe Y.
      • Kazui T.
      • Lee U.S.
      • Montecalvo A.
      • Schuessler R.B.
      • Moon M.R.
      Impact of differential right-to-left shunting on systemic perfusion in pulmonary arterial hypertension.
      ]. They demonstrated that (1) a shunt flow of 11% of the baseline cardiac output increased cardiac function and oxygen delivery and (2) arterial oxygen saturation decreased only when the shunt flow increased above 18%. Altogether, these two studies would suggest that in severe PH, increasing a shunt fraction between 11% and 15% of the baseline cardiac output would be the ideal target for an AS in patients (Fig. 6).
      Figure thumbnail gr6
      Fig. 6Impact of shunt fraction on cardiac output (CO) and oxygen delivery in an experimental model of right ventricular hypertension. In severe right ventricular hypertension, a shunt flow of 11% of the baseline cardiac output increased CO (A) and oxygen delivery (DO2I) (B). Arterial oxygen saturation (SaO2) decreased only when the shunt flow increased above 18%, suggesting that in severe pulmonary hypertension, a shunt of fraction between 11% and 18% of the baseline CO represents the ideal shunt fraction to achieve in our patients.
      Adapted from Weimar et al. [
      • Weimar T.
      • Watanabe Y.
      • Kazui T.
      • Lee U.S.
      • Montecalvo A.
      • Schuessler R.B.
      • Moon M.R.
      Impact of differential right-to-left shunting on systemic perfusion in pulmonary arterial hypertension.
      ].

      Are there any direct beneficial effects of atrial septostomy on the RV?

      Whereas the main objective of an AS would be increasing cardiac output and systemic blood flow, decompression of the right heart has been postulated. However, whether the RV is actually “decompressed” in patients after AS remains to be investigated. Espínola-Zavaleta et al. [
      • Espínola-Zavaleta N.
      • Vargas-Barrón J.
      • Tazar J.I.
      • Casanova J.M.
      • Keirns C.
      • Cárdenas A.R.
      • Gaspar J.
      • Sandoval J.
      Echocardiographic evaluation of patients with pulmonary hypertension before and after atrial septostomy.
      ] have shown that following AS, not only there is a significant reduction in right atrial but also a reduction in both end-systolic and end-diastolic RV areas between 3 and 6 months after procedure, a finding that would be compatible with the idea of decompression of the RV. Following the same line of thought, a report from O’Byrne et al. has demonstrated a significant decrease in B-type natriuretic peptide (BNP) after septostomy [
      • O’Byrne M.L.
      • Berman-Rosenzweig E.S.
      • Barst R.J.
      The effect of atrial septostomy on the concentration of brain-type natriuretic peptide in patients with idiopathic pulmonary arterial hypertension.
      ], suggesting a reduction in RV wall distention.
      AS may also have other beneficial direct effects on RV function. Ciarka et al. [
      • Ciarka A.
      • Vachiery J.L.
      • Houssiere A.
      • Gujic M.
      • Stoupel E.
      • Velez-Roa S.
      • Naeije R.
      • van de Borne P.
      Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension.
      ] showed a significant decrease in muscle sympathetic nerve activity after the procedure. Sympathetic overdrive exists in PAH and may be one of the mechanisms involved in RV failure and poor prognosis [
      • Bristow M.R.
      • Zisman L.S.
      • Lances B.D.
      • Abraham W.T.
      • Badesch D.B.
      • Groves B.M.
      • Voelkel N.F.
      • Lynch D.M.
      • Quaife R.A.
      The pressure-overloaded right ventricle in pulmonary hypertension.
      ,
      • Velez Roa S.
      • Ciarka A.
      • Najem B.
      • Vachiery J.L.
      • Naeije R.
      • van de Borne P.
      Increased sympathetic nerve activity in pulmonary artery hypertension.
      ]. Perhaps, a decrease in sympathetic overdrive after AS could also reflect decompression of the RV, as the drop in sympathetic activity after AS correlated with a decrease in RAP [
      • Ciarka A.
      • Vachiery J.L.
      • Houssiere A.
      • Gujic M.
      • Stoupel E.
      • Velez-Roa S.
      • Naeije R.
      • van de Borne P.
      Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension.
      ]. Fig. 7 summarizes some of the physiological effects of an AS in the setting of PAH. First, as a result of the right-to-left shunt, there is an increase in left ventricular preload and therefore an increase in cardiac output [
      • Sandoval J.
      • Rothman A.
      • Pulido T.
      Atrial septostomy for pulmonary hypertension.
      ,
      • Diller G.P.
      • Lammers A.E.
      • Haworth S.G.
      • Dimopoulos K.
      • Derrick G.
      • Bonhoeffer P.
      • Gatzoulis M.A.
      • Francis D.P.
      A modeling study of atrial septostomy for pulmonary arterial hypertension, and its effect on the state of tissue oxygenation and systemic blood flow.
      ,
      • Koeken Y.
      • Kuijpers N.H.L.
      • Lumens J.
      • Arts T.
      • Delhass T.
      Atrial septostomy benefits severe pulmonary hypertension patients by increase of left ventricular preload reserve.
      ], and second, there is decompression of the right heart [
      • O’Byrne M.L.
      • Berman-Rosenzweig E.S.
      • Barst R.J.
      The effect of atrial septostomy on the concentration of brain-type natriuretic peptide in patients with idiopathic pulmonary arterial hypertension.
      ,
      • Espínola-Zavaleta N.
      • Vargas-Barrón J.
      • Tazar J.I.
      • Casanova J.M.
      • Keirns C.
      • Cárdenas A.R.
      • Gaspar J.
      • Sandoval J.
      Echocardiographic evaluation of patients with pulmonary hypertension before and after atrial septostomy.
      ] which may decrease RV wall stress and oxygen demand, and a possible improvement in RV performance, which in turn contributes also to the increase in cardiac output.
      Figure thumbnail gr7
      Fig. 7Summary of the potential physiological effects of balloon dilatation atrial septostomy. First, as a result of the right-to-left shunt, there is an increase in left ventricular (LV) preload and therefore an increase in cardiac output. Secondly, there is decompression of the right heart, which decreases right ventricular (RV) wall stress and may in turn improve RV performance and contribute to the increase in cardiac output.
      Reproduced from Sandoval et al. [
      • Sandoval J.
      • Torbicki A.
      Atrial septostomy.
      ].

      Current indications, management, and limitations of atrial septostomy

      The indications for the procedure have not changed since 1998 [
      • Sandoval J.
      • Rothman A.
      • Pulido T.
      Atrial septostomy for pulmonary hypertension.
      ], but have evolved from the time when no other options were available to rescue the patient with severe RV failure after maximal medical therapy. According to the latest WHO guidelines [
      • Galiè N.
      • Corris P.A.
      • Frost A.
      • Girgis R.E.
      • Granton J.
      • Jing Z.C.
      • Klepetko W.
      • McGoon M.D.
      • McLaughlin V.V.
      • Preston I.R.
      • Rubin L.J.
      • Sandoval J.
      • Seeger W.
      • Keogh A.
      Updated treatment algorithm of pulmonary arterial hypertension.
      ], AS should be considered as a palliative procedure or as a bridge in patients deteriorating despite maximal medical therapy. The ideal candidate for AS would be a WHO class III patient, with syncope or severe RV dysfunction despite maximal medical therapy and the recommended procedure would be a step-by-step BDAS.
      Perhaps the biggest limitation of AS is that it should only be performed in centers with established experience in both pulmonary hypertension and AS. As mentioned, before the procedure it will be critical to assure that the patient has an arterial saturation higher than 90% on room air, and optimize cardiac function. During the procedure a careful monitoring of SaO2%, cardiac output, and LVEDP is mandatory and always attempt a step-by-step procedure. After AS, oxygen delivery should be optimized by securing an appropriate hemoglobin level by blood transfusion or with erythropoietin treatment. Long-term anticoagulation will also be necessary.
      As mentioned before, according to the worldwide clinical experience, spontaneous closure of septostomy is not an infrequent outcome presenting several months after the procedure [
      • Sandoval J.
      • Torbicki A.
      Atrial septostomy.
      ]. As an attempt to prevent spontaneous closure, Micheletti and coworkers in England proposed the use of a fenestrated Amplatzer [
      • Micheletti A.
      • Hislop A.
      • Lammers A.
      • Bonhoeffer P.
      • Derrick G.
      • Rees P.
      • Haworth S.G.
      Role of atrial septostomy in the treatment of children with pulmonary arterial hypertension.
      ], an approach that has been followed by others [
      • Fraisse A.
      • Chetaille P.
      • Amin Z.
      • Rouault F.
      • Humbert M.
      Use of Amplatzer fenestrated atrial septal defect device in a child with familial pulmonary hypertension.
      ,
      • O’Loughlin A.J.
      • Keogh A.
      • Muller D.W.
      Insertion of a fenestrated Amplatzer atrial septostomy device for severe pulmonary hypertension.
      ,
      • Althoff T.F.
      • Knebel F.
      • Panda A.
      • McArdle J.
      • Gliech V.
      • Franke I.
      • Witt C.
      • Baumann G.
      • Borges A.C.
      Long-term follow-up of a fenestrated Amplatzer atrial septal occluder in pulmonary arterial hypertension.
      ,
      • Baglini R.
      • Scardulla C.
      Reduction of a previous atrial septostomy in a patient with end-stage pulmonary hypertension by a manually fenestrated device.
      ]. An alternative approach would be to use a butterfly stent as reported by Prieto [
      • Prieto L.R.
      • Latson L.A.
      • Jennings C.
      Atrial septostomy using a butterfly stent in a patient with severe pulmonary arterial hypertension.
      ] and others [
      • Troost E.
      • Delcroix M.
      • Gewillig M.
      • Van Deyk K.
      • Budts W.
      A modified technique of stent fenestration of the interatrial septum improves patients with pulmonary hypertension.
      ,
      • Roy A.K.
      • Gaine S.P.
      • Walsh K.P.
      Percutaneous atrial septostomy with modified butterfly stent and intracardiac echocardiographic guidance in a patient with syncope and refractory pulmonary arterial hypertension.
      ]. However, these approaches have become controversial, as a follow-up publication from the group using Amplatzer reported the occlusion of the device in four out of nine patients despite the use of warfarin or aspirin [
      • Lammers A.E.
      • Derrick G.
      • Haworth S.G.
      • Bonhoeffer P.
      • Yates R.
      Efficacy and long-term patency of fenestrated Amplatzer devices in children.
      ]. What promotes closure of the septostomy in some patients but not others remains inconclusive. We have postulated that the septostomy closes because the perforation was too small or, as a consequence of decompression of the RV, the gradient of pressure between the right and left atria decreases, thus promoting closure as a physiological response. More recently, Guerrero et al. [
      • Guerrero M.
      • Cajigas H.
      • Awdish R.
      • Greebaum A.
      • Khandelwal A.
      • Sandoval J.
      First-in-man experience with cryoplasty during graded balloon atrial septostomy to reduce spontaneous closure in a patient with severe pulmonary arterial hypertension.
      ] reported on the use of cryoplasty to freeze the borders of the septostomy with the same objective: to maintain the septostomy open. However, we do not know whether cryoplasty indeed prolongs the patency of the defect or whether there are any long-term complications.

      Impact on long-term survival: effects of atrial septostomy combined with pharmacotherapies

      Based on the review of the worldwide collective experience, AS stands as an additional strategy for the treatment of severe RV failure from PAH. It improves hemodynamic variables that correlate with clinical improvement and survival. In the majority of patients, the procedure has been performed in an advanced stage of disease with a significantly higher risk of death, yet, in spite of the severity of disease in these patients, the procedure frequently leads to a clinical and hemodynamic improvement. Unfortunately, the exact impact of septostomy on the survival of the patients with PAH is difficult to assess, as there are no controlled long-term studies (something that it is also true for most of the current pharmacological interventions). However, the survival rates for patients with a long-term follow-up in different case series appear to be better when compared with either historical controls or predicted survival [
      • Kerstein D.
      • Levy P.S.
      • Hsu D.T.
      • Hordof A.J.
      • Gersony W.M.
      • Barst R.J.
      Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension.
      ,
      • Sandoval J.
      • Gaspar J.
      • Pulido T.
      • Bautista E.
      • Martínez-Guerra M.L.
      • Zeballos M.
      • Palomar A.
      • Gómez A.
      Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment.
      ,
      • Law M.A.
      • Grifka R.G.
      • Mullins C.E.
      • Nihill M.R.
      Atrial septostomy improves survival in select patients with pulmonary hypertension.
      ,
      • Troost E.
      • Delcroix M.
      • Gewillig M.
      • Van Deyk K.
      • Budts W.
      A modified technique of stent fenestration of the interatrial septum improves patients with pulmonary hypertension.
      ]. In addition, the worldwide clinical experience suggests that the procedure-related mortality is decreasing, perhaps as a consequence of recommendations made during the PAH world symposium in 1998 [
      • Sandoval J.
      • Rothman A.
      • Pulido T.
      Atrial septostomy for pulmonary hypertension.
      ]. Unfortunately, as it is the case for PAH-specific pharmacotherapies, there is a significant drop of cumulative survival in time, reflecting the palliative nature of the procedure. In other words, AS does not cure or reverse PAH and the beneficial effects of the procedure wear off with time.
      Another aspect that remains incompletely studied is the effect of AS not only as a bridge, but also as an adjuvant to pharmacotherapy. In a recent study, we have reported the long-term effects of concomitant specific pharmacological treatment after the septostomy in 11 out of 34 patients treated in our institution [
      • Sandoval J.
      • Gaspar J.
      • Peña H.
      • Santos L.E.
      • Córdova J.
      • del Valle K.
      • Rodríguez A.
      • Pulido T.
      Effect of atrial septostomy on the survival of patients with severe pulmonary arterial hypertension.
      ]. It is important to underscore that, different from most of the previous reports in the world literature, the septostomy in these patients was performed at an earlier stage and before the use of medical treatment. In our study, we demonstrate that the survival of the group with septostomy plus concomitant pharmacological treatment was significantly better than that of the group with septostomy alone (median survival: 83 vs. 53 months; log-rank 6.52; p < 0.01) suggesting a potential benefit from combining therapeutic strategies.

      Potts anastomosis

      This intervention, initially described many years ago for the management of several forms of congenital heart disease, consists of the anastomosis of the left pulmonary artery with the aorta [
      • Potts W.J.
      • Smith S.
      • Gibson S.
      Anastomosis of the aorta to a pulmonary artery; certain types in congenital heart disease.
      ]. Potts anastomosis has been recently revived for the management of PAH as a surgical alternative to AS based on a similar physiological rationale: to increase systemic output and to decompress the RV. Perhaps the main difference is that the right-to-left shunt occurs at the post-tricuspid level, similar to what is observed in patients with Eisenmenger Syndrome due to a patent ductus arteriosus [
      • Blanc J.
      • Vouhé P.
      • Bonnet D.
      Potts shunt in patients with pulmonary hypertension.
      ,
      • Baruteau A.E.
      • Serraf A.
      • Lévy M.
      • Bonnet D.
      • Jais X.
      • Vouhé P.
      • Simonneau G.
      • Belli E.
      • Humbert M.
      Potts shunt in children with idiopathic pulmonary arterial hypertension: long-term results.
      ]. Theoretically, the main advantage of a Potts anastomosis over an AS is that it creates a permanent post-cardiac right-to-left shunt that does not lead to arterial oxygen desaturation in the upper part of the body, including the brain and the coronary circulation.
      Blanc et al. [
      • Blanc J.
      • Vouhé P.
      • Bonnet D.
      Potts shunt in patients with pulmonary hypertension.
      ] have described the use of this procedure in two boys with supra-systemic pulmonary hypertension after an arterial switch for transposition of the great arteries with significant post-operative improvement. In a subsequent communication from the same group of investigators, Baruteau et al. [
      • Baruteau A.E.
      • Serraf A.
      • Lévy M.
      • Bonnet D.
      • Jais X.
      • Vouhé P.
      • Simonneau G.
      • Belli E.
      • Humbert M.
      Potts shunt in children with idiopathic pulmonary arterial hypertension: long-term results.
      ] described the use of this intervention in eight children with supra-systemic PH with functional class IV despite maximal medical treatment. The procedure was performed via a left thoracotomy without cardio-pulmonary bypass and the size of the shunt was ∼9 mm. Two patients who had interrupted medical treatment died within two weeks after the procedure due to a hypertensive crisis, but six children survived and remained with a good functional class. Six-minute walking distance improved in all survivors and the serum levels of BNP decreased almost to normal values.
      Although creating a post-tricuspid shunt would be intuitive based on data from Eisenmenger patients, it remains to be investigated whether a post-tricuspid defect will prove to be superior to an AS. Furthermore, to date, surgically created Potts anastomoses have only been performed in children; however, adults with severe RV failure might have a different post-operative prognosis and higher peri-operative mortality. To by-pass the potential risks associated with surgery, an innovative technique to create a transcatheter Potts shunt (TPS) has been recently described by Esch et al. [
      • Esch J.J.
      • Shah P.B.
      • Cockrill B.A.
      • Farber H.W.
      • Landzberg M.J.
      • Mehra M.R.
      • Mullen M.P.
      • Opotowsky A.R.
      • Waxman A.B.
      • Lock J.E.
      • Marshall A.C.
      Transcatheter Potts shunt creation in patients with severe pulmonary arterial hypertension: initial clinical experience.
      ]. In this report, four patients with severe PAH underwent TPS under general anesthesia. Vascular perforation was guided by fluoroscopy and the shunt was created via placement of a stent between the vessels. Although considered technically successful in three cases, one patient died during the procedure as a result of uncontrolled hemothorax and one more died a few days later as result of ventilation-associated pneumonia. The two survivors, however, had a significant symptomatic improvement and no late complications after 4 and 10 months of follow-up were reported.
      Baruteau and coworkers have recently published a compendium of their experience with both surgical anastomosis and TPS in the management of PAH [
      • Baruteau A.E.
      • Emre Belli E.
      • Boudjemline Y.
      • Laux D.
      • Lévy M.
      • Simonneau G.
      • Carotti A.
      • Humbert M.
      • Bonnet D.
      Palliative Potts shunt for the treatment of children with drug-refractory pulmonary arterial hypertension: updated data from the first 24 patients.
      ]. Their pooled data on 24 children (1.5–17 years) who underwent a Potts shunt, 19 surgical, and 5 transcatheter, for drug-refractory PAH, show severe postoperative complications occurring only in 6 patients (25.0% from the surgical group) including 3 early deaths (12.5%) due to low cardiac output. After a median follow-up of 2.1 years (range, 3 months to 14.3 years) functional class dramatically improved in the 21 survivors (WHO-functional class I or II), mean 6-min walk distance improved, none of the patients had experienced syncope, and none had any reports of worsening of RV failure. The BNP/NT-proBNP levels normalized in all patients. The authors concluded that palliative Potts shunt prolonged survival and dramatically and consistently improved functional class in children with severe, drug-refractory PAH.
      All together, it would appear that Potts anastomosis would be an innovative approach for management of PAH and an alternative to AS. However, more experience and refinement of the technique are required to reduce the risk of the procedures and to establish TPS as a therapeutic modality for advanced PAH. Computed tomography of the thorax prior to the procedure could help select the ideal candidates for surgery as has been proposed by Guo et al. [
      • Guo K.
      • Langleben D.
      • Afilalo J.
      • Shimony A.
      • Leask R.
      • Marelli A.
      • Martucci G.
      • Therrien J.
      Anatomical considerations for the development of a new transcatheter aortopulmonary shunt device in patients with severe pulmonary arterial hypertension.
      ] who described two types of relationships between left lower pulmonary artery and descending aorta: in Type 1, the distance between the vessels is minimal and in type 2 the distance is greater, thus increasing the risk of bleeding. Theoretically, Type 1 patients make the better candidates for surgical anastomosis.

      Non-invasive creation of an atrial septal defect

      In the future, we anticipate seeing attempts to create a septostomy noninvasively by means of histotripsy, which is an ultrasonic technique that produces nonthermal, mechanical tissue fractionation through the use of high-intensity ultrasound pulses [
      • Xu Z.
      • Owens G.
      • Gordon D.
      • Cain C.
      • Ludomirsky A.
      Noninvasive creation of an atrial septal defect by histotripsy in a canine model.
      ,
      • Takey Y.
      • Muratore R.
      • Kalisz A.
      • Okajima K.
      • Fujimoto K.
      • Hasegawa T.
      • Arai K.
      • Rekhtman Y.
      • Berry G.
      • Di Tullio M.R.
      • Homma S.
      In vitro atrial septal ablation using high-intensity focused ultrasound.
      ]. In a pilot study, Xu et al. applied this technique to create an atrial septal defect in an open chest model in dogs [
      • Xu Z.
      • Owens G.
      • Gordon D.
      • Cain C.
      • Ludomirsky A.
      Noninvasive creation of an atrial septal defect by histotripsy in a canine model.
      ]. With this treatment they were able to produce a right-to-left interatrial shunt in 9 of the 10 dogs, without significant damage to the surrounding tissues. Takey et al. have also been developing this approach in alternative animal models with similar satisfactory results [
      • Takey Y.
      • Muratore R.
      • Kalisz A.
      • Okajima K.
      • Fujimoto K.
      • Hasegawa T.
      • Arai K.
      • Rekhtman Y.
      • Berry G.
      • Di Tullio M.R.
      • Homma S.
      In vitro atrial septal ablation using high-intensity focused ultrasound.
      ]. However, human trials are warranted.

      Conclusions and future directions

      Despite significant advances in pharmacological treatments, PAH remains incurable. Interventional and surgical interventions have been categorized as palliative treatments for PAH; however, if we consider that (1) a palliative treatment is by definition a “therapy that relieves or alleviates the problem but does not treat the underlying cause” and (2) no current pharmacological treatment has been shown to reverse or even prevent the progression of vascular remodeling in patients with PAH (as it has been elegantly shown by Stacher, Tuder and collaborators [
      • Stacher E.
      • Graham B.B.
      • Hunt J.M.
      • Gandjeva A.
      • Groshong S.D.
      • McLaughlin V.V.
      • Jessup M.
      • Grizzle W.E.
      • Aldred M.A.
      • Cool C.D.
      • Tuder R.M.
      Modern age pathology of pulmonary arterial hypertension.
      ]), one could ask which PAH-specific drug is not a palliative treatment? It is true that the safety and efficiency of any interventional/surgical therapy remain to be evaluated in a controlled fashion, but the fact that these strategies improve hemodynamics, quality of life, and prolong survival in a high-risk population of PAH patients should not be overlooked. Unfortunately, an adequately controlled study evaluating safety and efficiency of any interventional therapy has been limited by the relative success of PAH-specific treatments in recent years and mainly by the lack of training/expertise worldwide. However, as we observe the long-term evolution of patients treated after the “new medications era” and wait for the anticipated release of new targeted therapies into the drug pipeline, we should consider additional strategies in an attempt to provide a more integral support for the failing RV. Indeed, the potential benefit of combining interventional strategies such as septostomy with a pharmacological treatment certainly deserves more attention in the future. We strongly suggest that either surgical or interventional strategies should be available in PAH-referral centers. It remains a possibility that we are indeed taking too long to perform any non-pharmacological strategy, and the optimal timing to use them will have to be investigated in the coming years.

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