Evaluating a strategy of PAH therapy pre-treatment in ...
Evaluating a strategy of PAH therapy pre-treatment in patients with atrial septal defects and pulmonary arterial hypertension to permit safe repair (“treat-and-repair”)Andrew Constantine MBBS BA & Konstantinos Dimopoulos MD MSc PhDFrom the Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, UK & the National Heart and Lung Institute, Imperial College London, UK.Correspondance to:Dr Konstantinos DimopoulosAdult Congenital Heart CentreRoyal Brompton and Harefield NHS Foundation TrustSydney Street, London SW3 6NP, UKTel +44 2073 528121E- mail: k.dimopoulos02@Pulmonary arterial hypertension (PAH) associated with congenital heart disease (PAH-CHD) remains a major cause of morbidity and mortality in the growing adult congenital heart disease population. In the face of sustained progress, fewer patients are presenting with severe pulmonary vascular disease (PVD) with reversal of the shunt, cyanosis and multi-organ involvement, characteristic of Eisenmenger syndrome. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jPi52iON","properties":{"formattedCitation":"[1]","plainCitation":"[1]","noteIndex":0},"citationItems":[{"id":411,"uris":[""],"uri":[""],"itemData":{"id":411,"type":"article-journal","title":"Epidemiological changes in Eisenmenger syndrome in the Nordic region in 1977-2012","container-title":"Heart (British Cardiac Society)","page":"1353-1358","volume":"103","issue":"17","source":"PubMed","abstract":"OBJECTIVE: Improved diagnostic tools, timely closure of the shunt and a better understanding of the complexity of Eisenmenger syndrome (ES) have led to improved care and treatment in tertiary centres. These may have decreased the incidence of ES and improved survival of patients with ES, although evidence is still lacking. The aim of this study was to investigate temporal changes in incidence, prevalence and mortality in patients with ES for 35 years in the Nordic region.\nMETHODS: This was a retrospective population-based study including 714 patients with ES. Survival analysis was performed based on all-cause mortality and accounting for immortal time bias.\nRESULTS: The incidence of ES decreased from 2.5/million inhabitants/year in 1977 to 0.2/million inhabitants/year in 2012. Correspondingly, prevalence decreased from 24.6 to 11.9/million inhabitants. The median survival was 38.4 years, with 20-year, 40-year and 60-year survival of 72.5%, 48.4%, and 21.3%, respectively. Complex lesions and Down syndrome were independently associated with worse survival (HR 2.2, p<0.001 and HR 1.8, p<0.001, respectively). Age at death increased from 27.7 years in the period from 1977 to 1992, to 46.3 years from July 2006 to 2012 (p<0.001).\nCONCLUSIONS: The incidence and prevalence of ES in the Nordic region have decreased markedly during the last decades. Furthermore, the median age at death increased throughout the study period, indicating prolonged life expectancy in the ES population. However, increasing age represents decreased incidence, rather than improved survival. Nonetheless, longevity with ES is still shorter than in the background population.","DOI":"10.1136/heartjnl-2016-310979","ISSN":"1468-201X","note":"PMID: 28450553","journalAbbreviation":"Heart","language":"eng","author":[{"family":"Hjortsh?j","given":"Cristel S?rensen"},{"family":"Jensen","given":"Annette Schophuus"},{"family":"S?rensen","given":"Keld"},{"family":"Nagy","given":"Edit"},{"family":"Johansson","given":"Bengt"},{"family":"Kronvall","given":"Thomas"},{"family":"Dellborg","given":"Mikael"},{"family":"Estensen","given":"Mette-Elise"},{"family":"Holmstr?m","given":"Henrik"},{"family":"Turanlahti","given":"Maila"},{"family":"Thilén","given":"Ulf"},{"family":"S?ndergaard","given":"Lars"}],"issued":{"date-parts":[["2017"]]}}}],"schema":""} [1] By contrast, patients with predominant systemic-pulmonary shunts and varying degrees of PAH are more commonly encountered. It is widely accepted that, in the absence of PVD, repair of a significant systemic-pulmonary shunt confers a clear benefit, improving or normalising life expectancy in young patients. The presence of preoperative PAH is, however, associated with atrial tachyarrhythmias, heart failure and mortality in the post-operative period ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"DPtunbGw","properties":{"formattedCitation":"[2]","plainCitation":"[2]","noteIndex":0},"citationItems":[{"id":406,"uris":[""],"uri":[""],"itemData":{"id":406,"type":"article-journal","title":"A Comparison of Surgical and Medical Therapy for Atrial Septal Defect in Adults","container-title":"The New England Journal of Medicine","page":"5","volume":"333","issue":"8","source":"Zotero","abstract":"Background. The surgical closure of an atrial septal defect is frequently recommended for patients over 40 years of age. However, the prognosis for such patients with unrepaired defects is largely unknown, and the outcome for patients operated on after the fourth decade of life has not yet been compared with that for medically treated patients in a controlled follow-up study.","language":"en","author":[{"family":"Konstantinides","given":"Stavros"},{"family":"Geibel","given":"Annette"},{"family":"Olschewski","given":"Manfred"},{"family":"G?rnandt","given":"Lothar"},{"family":"Roskamm","given":"Helmut"},{"family":"Spillner","given":"Gerhard"},{"family":"Just","given":"Hanj?rg"},{"family":"Kasper","given":"Wolfgang"}],"issued":{"date-parts":[["1995"]]}}}],"schema":""} [2]. Moreover, an adverse medium and long-term outcome has been described in patients with PAH after CHD repair, despite successful defect correction.Disease targeted therapies are, nowadays, routinely used in PAH patients, including those with CHD, to reduce pulmonary vascular resistance (PVR), reduce morbidity and improve exercise capacity and quality of life. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Gju2idWr","properties":{"formattedCitation":"[3]","plainCitation":"[3]","noteIndex":0},"citationItems":[{"id":462,"uris":[""],"uri":[""],"itemData":{"id":462,"type":"article-journal","title":"Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension","container-title":"Circulation","page":"20-25","volume":"121","issue":"1","source":"PubMed","abstract":"BACKGROUND: Advanced therapy (AT) for pulmonary arterial hypertension in the context of congenital heart disease (Eisenmenger syndrome) improves pulmonary hemodynamics, functional class, and the 6-minute walk test. We examined the potential effect of AT on survival in this population.\nMETHODS AND RESULTS: Data on all Eisenmenger patients attending our center over the past decade were collected. Survival rates were compared between patients on and off AT with the use of a modified version of the Cox model, which treats AT as a time-varying covariate. Baseline differences were adjusted for the use of propensity scores. A total of 229 patients (aged 34.5 + or - 12.6 years; 35.4% male) were included. The majority had complex anatomy, and 53.7% were in New York Heart Association class > or = III at baseline assessment. Mean resting saturations were 84.3%. Sixty-eight patients (29.7%) either were on AT or had AT initiated during follow-up. During a median follow-up of 4.0 years, 52 patients died, only 2 of them while on AT. Patients on AT were at a significantly lower risk of death, both unadjusted and after adjustment for baseline clinical differences by propensity score regression adjustment (C statistic=0.80; hazard ratio, 0.16; 95% confidence interval, 0.04 to 0.71; P=0.015) and propensity score matching (hazard ratio, 0.10; 95% confidence interval, 0.01 to 0.78; P=0.028).\nCONCLUSIONS: AT for pulmonary arterial hypertension in a contemporary cohort of adults with Eisenmenger syndrome was associated with a lower risk of death. Survival benefits should be considered together with improved hemodynamics and functional class when decisions are made about AT in this population.","DOI":"10.1161/circulationaha.109.883876","ISSN":"1524-4539","note":"PMID: 20026774","journalAbbreviation":"Circulation","language":"eng","author":[{"family":"Dimopoulos","given":"Konstantinos"},{"family":"Inuzuka","given":"Ryo"},{"family":"Goletto","given":"Sara"},{"family":"Giannakoulas","given":"Georgios"},{"family":"Swan","given":"Lorna"},{"family":"Wort","given":"Stephen J."},{"family":"Gatzoulis","given":"Michael A."}],"issued":{"date-parts":[["2010",1,5]]}}}],"schema":""} [3] The success of oral PAH therapies led to a dilemma being posed: ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"DqF8WW3k","properties":{"formattedCitation":"[4]","plainCitation":"[4]","noteIndex":0},"citationItems":[{"id":403,"uris":[""],"uri":[""],"itemData":{"id":403,"type":"article-journal","title":"Evaluating operability in adults with congenital heart disease and the role of pretreatment with targeted pulmonary arterial hypertension therapy","container-title":"International Journal of Cardiology","page":"163-171","volume":"129","issue":"2","source":" (Crossref)","abstract":"Pulmonary arterial hypertension (PAH) associated with congenital heart disease remains a major problem despite advances in cardiac surgery. Recently, advanced therapies for PAH have become available and have been effective in reducing pulmonary vascular resistance and symptoms in patients with near-systemic pulmonary arterial pressures, previously thought to have irreversible pulmonary vascular disease. This has led to a new dilemma, namely could intracardiac communications previously considered inoperable due to severe pulmonary vascular disease become amenable to surgery after successful treatment with advanced therapy? We address, hereby, the potential merits and hazards of a “treat-and-repair” approach using advanced therapies in patients with PAH associated with congenital heart disease.","DOI":"10.1016/j.ijcard.2008.02.004","ISSN":"01675273","language":"en","author":[{"family":"Dimopoulos","given":"Konstantinos"},{"family":"Peset","given":"Ana"},{"family":"Gatzoulis","given":"Michael A."}],"issued":{"date-parts":[["2008",9]]}}}],"schema":""} [4] Can intracardiac communications, previously considered inoperable due to severe PAH, become amenable to surgery after successful treatment with vasodilators? This has come to be known as the “treat-and-repair” approach. Despite great interest by physicians around the world and numerous retrospective case series reported, the short and long-term consequences of the “treat-and-repair” approach remain unclear. Evidence is hard to obtain in CHD, especially in sub-populations such as PAH-CHD. Multicentre registries are invaluable in this setting. In this issue of the International Journal of Cardiology, Bradley et al. present data on “treat-and-repair”, focusing on patients with an atrial septal defect (ASD) and PAH precluding intervention. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"595ouqVv","properties":{"formattedCitation":"[5]","plainCitation":"[5]","noteIndex":0},"citationItems":[{"id":467,"uris":[""],"uri":[""],"itemData":{"id":467,"type":"article-journal","title":"\"Treat-to-close\": Non-repairable ASD-PAH in the adult: Results from the North American ASD-PAH (NAAP) Multicenter Registry","container-title":"International Journal of Cardiology","source":"PubMed","abstract":"BACKGROUND: Adults presenting with an unrepaired atrial septal defect and pulmonary arterial hypertension (ASD-PAH) are typically classified as \"correctable\" or \"non-correctable\". The use of directed PAH medical therapy in non-correctable ASD-PAH leading to favorable closure candidacy, repair status and long-term follow-up is not well studied. We therefore sought to characterize response to PAH targeted therapy in 'non-correctable' ASD-PAH.\nMETHODS AND RESULTS: Nine North American tertiary care centers submitted retrospective data from adults with unrepaired ASD-PAH that did not meet recommendations for repair at initial presentation (1996-2017). Sixty-nine patients (women 51(74%), 40?±?15?years, mean pulmonary artery pressure (mPA) 51?±?13?mm?Hg, pulmonary vascular resistance (PVR) 8.7?±?4.9 Wood units, Qp:Qs 1.6?±?0.4) were enrolled. All patients were prescribed PAH targeted therapy and late shunt repair occurred in 19(28%) (Women 15(29%) vs. Men 4(22%), p?=?0.6). At late follow-up (4.4?±?2.9?years) 6-minute walk test distance (6MWTD) was significantly better in the group that underwent repair (486?±?89?m vs. 375?±?139?m, p?<?0.05). Transthoracic echo showed significant improvement in right ventricular (RV) function (severe dysfunction in repaired 8(40%) vs. unrepaired groups 35(69%), p?<?0.05). Divergent survival curves suggest that with larger studies and more follow-up, differences in survival between repaired and unrepaired groups may be important. (repaired: 17(94%) vs. unrepaired: 32(81%), p?=?0.18).\nCONCLUSIONS: This is the first and largest multicenter study evaluating the \"treat-to-close\" approach in non-correctable ASD-PAH. Our new data supports further study of this strategy in patients who have reversibility of PAH in response to targeted therapy. We demonstrate that in the carefully selected patient with non-correctable ASD-PAH, successful shunt repair is possible if post-therapy PVR is ≤6.5 Wood units. Patients who underwent repair had improved RV function following PAH targeted therapy. Divergent survival curves suggest that with further study, defect repair may affect medium-term to late survival.","DOI":"10.1016/j.ijcard.2019.03.056","ISSN":"1874-1754","note":"PMID: 31031077","title-short":"Treat-to-close","journalAbbreviation":"Int. J. Cardiol.","language":"eng","author":[{"family":"Bradley","given":"Elisa A."},{"family":"Ammash","given":"Naser"},{"family":"Martinez","given":"Sara C."},{"family":"Chin","given":"Kelly"},{"family":"Hebson","given":"Camden"},{"family":"Singh","given":"Harsimran S."},{"family":"Aboulhosn","given":"Jamil"},{"family":"Grewal","given":"Jasmine"},{"family":"Billadello","given":"Joseph"},{"family":"Chakinala","given":"Murali M."},{"family":"Daniels","given":"Curt J."},{"family":"Zaidi","given":"Ali N."}],"issued":{"date-parts":[["2019",4,17]]}}}],"schema":""} [5] In one of the largest cohorts of its kind, the investigators collected data on 69 adult patients from 9 North American centres, presenting over a 22-year period. Following PAH therapy, 19 patients underwent CHD repair, with an improvement in 6-minute walk test distance and echocardiographic parameters compared to those managed medically. After an average 7.2 years from repair, there was no significant survival difference between the two groups. This study is a welcome initiative and provides some insight into the subject of “treat-and-repair”, but like most registries, it leaves many questions unanswered. In the absence of randomisation or statistical adjustment (e.g. propensity score matching) to account for selection bias, differences between groups receiving intervention versus medical management are difficult to interpret. Indeed, deciding to repair the defect in a patient with clear evidence of PVD remains a complex decision. International PH and CHD guidelines provide haemodynamic cut-offs for deciding operability, based on limited evidence and expert consensus, but allow for a large “grey area” of uncertainty (Figure 1). The recommended cut-offs have also changed over the years and differ between contemporary guidelines. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1srLT9Sh","properties":{"formattedCitation":"[6\\uc0\\u8211{}8]","plainCitation":"[6–8]","noteIndex":0},"citationItems":[{"id":469,"uris":[""],"uri":[""],"itemData":{"id":469,"type":"article-journal","title":"ESC Guidelines for the management of grown-up congenital heart disease (new version 2010)","container-title":"European Heart Journal","page":"2915-2957","volume":"31","issue":"23","source":"PubMed","DOI":"10.1093/eurheartj/ehq249","ISSN":"1522-9645","note":"PMID: 20801927","journalAbbreviation":"Eur. Heart J.","language":"eng","author":[{"family":"Baumgartner","given":"Helmut"},{"family":"Bonhoeffer","given":"Philipp"},{"family":"De Groot","given":"Natasja M. S."},{"family":"Haan","given":"Fokko","non-dropping-particle":"de"},{"family":"Deanfield","given":"John Erik"},{"family":"Galie","given":"Nazzareno"},{"family":"Gatzoulis","given":"Michael A."},{"family":"Gohlke-Baerwolf","given":"Christa"},{"family":"Kaemmerer","given":"Harald"},{"family":"Kilner","given":"Philip"},{"family":"Meijboom","given":"Folkert"},{"family":"Mulder","given":"Barbara J. M."},{"family":"Oechslin","given":"Erwin"},{"family":"Oliver","given":"Jose M."},{"family":"Serraf","given":"Alain"},{"family":"Szatmari","given":"Andras"},{"family":"Thaulow","given":"Erik"},{"family":"Vouhe","given":"Pascal R."},{"family":"Walma","given":"Edmond"},{"literal":"Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of Cardiology (ESC)"},{"literal":"Association for European Paediatric Cardiology (AEPC)"},{"literal":"ESC Committee for Practice Guidelines (CPG)"}],"issued":{"date-parts":[["2010",12]]}}},{"id":4,"uris":[""],"uri":[""],"itemData":{"id":4,"type":"article-journal","title":"2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)","container-title":"European Heart Journal","page":"67-119","volume":"37","issue":"1","source":"PubMed","DOI":"10.1093/eurheartj/ehv317","ISSN":"1522-9645","note":"PMID: 26320113","title-short":"2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension","journalAbbreviation":"Eur. Heart J.","language":"eng","author":[{"family":"Galiè","given":"Nazzareno"},{"family":"Humbert","given":"Marc"},{"family":"Vachiery","given":"Jean-Luc"},{"family":"Gibbs","given":"Simon"},{"family":"Lang","given":"Irene"},{"family":"Torbicki","given":"Adam"},{"family":"Simonneau","given":"Gérald"},{"family":"Peacock","given":"Andrew"},{"family":"Vonk Noordegraaf","given":"Anton"},{"family":"Beghetti","given":"Maurice"},{"family":"Ghofrani","given":"Ardeschir"},{"family":"Gomez Sanchez","given":"Miguel Angel"},{"family":"Hansmann","given":"Georg"},{"family":"Klepetko","given":"Walter"},{"family":"Lancellotti","given":"Patrizio"},{"family":"Matucci","given":"Marco"},{"family":"McDonagh","given":"Theresa"},{"family":"Pierard","given":"Luc A."},{"family":"Trindade","given":"Pedro T."},{"family":"Zompatori","given":"Maurizio"},{"family":"Hoeper","given":"Marius"},{"literal":"ESC Scientific Document Group"}],"issued":{"date-parts":[["2016",1,1]]}}},{"id":242,"uris":[""],"uri":[""],"itemData":{"id":242,"type":"article-journal","title":"2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines","container-title":"Journal of the American College of Cardiology","page":"25255","source":"","DOI":"10.1016/j.jacc.2018.08.1029","ISSN":"0735-1097, 1558-3597","title-short":"2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease","language":"en","author":[{"family":"Stout","given":"Karen K."},{"family":"Daniels","given":"Curt J."},{"family":"Aboulhosn","given":"Jamil A."},{"family":"Bozkurt","given":"Biykem"},{"family":"Broberg","given":"Craig S."},{"family":"Colman","given":"Jack M."},{"family":"Crumb","given":"Stephen R."},{"family":"Dearani","given":"Joseph A."},{"family":"Fuller","given":"Stephanie"},{"family":"Gurvitz","given":"Michelle"},{"family":"Khairy","given":"Paul"},{"family":"Landzberg","given":"Michael J."},{"family":"Saidi","given":"Arwa"},{"family":"Valente","given":"Anne Marie"},{"family":"Hare","given":"George F. Van"}],"issued":{"date-parts":[["2018",8,16]]}}}],"schema":""} [6–8] For “treat-and-repair” to enter clinical practice, we need selection criteria to identify patients in whom this strategy is likely to be safe and effective. It is generally accepted that cyanotic patients at the extreme end of the spectrum of PAH-CHD (Eisenmenger syndrome, Figure 1), should not be offered repair, as they are likely to have irreversible PVD. Similarly, patients with PAH in the presence of a small (coincidental) defect should not be repaired, as the defect may act as a relief valve for the pressure-loaded right ventricle rather than being the cause of PAH. There remains a large population of patients with larger defects and raised PVR, in whom the decision to repair is influenced by haemodynamics (Figure 1). The population described by Bradley et al. had a wide range of pulmonary vascular resistances, from near-normal to over 15WU, in both the “treat-and-repair” and medical management groups. Patients who underwent repair had a greater average drop in PVR after PAH therapy compared to the unrepaired group. However, approximately half of the subsequently repaired patients had a PVR after PAH therapy above the cut-off of 4.6WU (equivalent to a PVRindexed 8WU*m2), which would preclude closure according to current international guidelines, while many more remained within the “grey zone” (PVR>2.3WU, PVRindexed>4WU*m2). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5vBTWwbV","properties":{"formattedCitation":"[7]","plainCitation":"[7]","noteIndex":0},"citationItems":[{"id":4,"uris":[""],"uri":[""],"itemData":{"id":4,"type":"article-journal","title":"2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)","container-title":"European Heart Journal","page":"67-119","volume":"37","issue":"1","source":"PubMed","DOI":"10.1093/eurheartj/ehv317","ISSN":"1522-9645","note":"PMID: 26320113","title-short":"2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension","journalAbbreviation":"Eur. Heart J.","language":"eng","author":[{"family":"Galiè","given":"Nazzareno"},{"family":"Humbert","given":"Marc"},{"family":"Vachiery","given":"Jean-Luc"},{"family":"Gibbs","given":"Simon"},{"family":"Lang","given":"Irene"},{"family":"Torbicki","given":"Adam"},{"family":"Simonneau","given":"Gérald"},{"family":"Peacock","given":"Andrew"},{"family":"Vonk Noordegraaf","given":"Anton"},{"family":"Beghetti","given":"Maurice"},{"family":"Ghofrani","given":"Ardeschir"},{"family":"Gomez Sanchez","given":"Miguel Angel"},{"family":"Hansmann","given":"Georg"},{"family":"Klepetko","given":"Walter"},{"family":"Lancellotti","given":"Patrizio"},{"family":"Matucci","given":"Marco"},{"family":"McDonagh","given":"Theresa"},{"family":"Pierard","given":"Luc A."},{"family":"Trindade","given":"Pedro T."},{"family":"Zompatori","given":"Maurizio"},{"family":"Hoeper","given":"Marius"},{"literal":"ESC Scientific Document Group"}],"issued":{"date-parts":[["2016",1,1]]}}}],"schema":""} [7] Moreover, 30% of the cohort that underwent repair were receiving intravenous prostanoid therapy, indicating the presence of severe PVD in many patients. It is, therefore, not surprising that the vast majority of patients needed to stay on PAH therapy after repair. The concept of “safe repair” of a defect in PAH-CHD patients eludes us. With advances in intervention and surgery, combined with expert perioperative care, many PAH-CHD patients may survive to hospital discharge. The difficulty in drawing conclusions from the “treat-to-repair” literature to date is, in part, due to the fact that mechanisms behind PVD in patients with pre-tricuspid shunts, such as ASDs, are incompletely understood. Compared to PAH associated with post-tricuspid shunts, PAH associated with pre-tricuspid shunts occurs later in life and is rare. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"wA4Knyec","properties":{"formattedCitation":"[9]","plainCitation":"[9]","noteIndex":0},"citationItems":[{"id":407,"uris":[""],"uri":[""],"itemData":{"id":407,"type":"article-journal","title":"Physiological differences between various types of Eisenmenger syndrome and relation to outcome","container-title":"International Journal of Cardiology","page":"455-460","volume":"179","source":" (Crossref)","abstract":"Background: Eisenmenger syndrome (ES) is the most advanced form of pulmonary arterial hypertension (PAH) related to congenital heart disease. Several studies have suggested that the presence and location of the shunt de?nes the natural history of these patients by in?uencing right ventricular adaptation to PAH. We aimed to echocardiographically assess differences in cardiac physiology and outcome between various types of ES.\nMethods and results: In this longitudinal cohort study, 191 patients with ES and non-complex congenital heart disease were recruited, 36 with pre-tricuspid and 155 with post-tricuspid shunts. Patients with pre-tricuspid shunts were older, had higher BNP concentrations and lower exercise tolerance compared to patients with post-tricuspid shunts. Right ventricular (RV) function was impaired in patients with atrial septal defects, with larger right ventricles, impaired systolic function and adaptation. The left ventricular eccentricity index was signi?cantly higher in pre-tricuspid defects. Within post-tricuspid shunts, patients with atrio-ventricular septal defects had better right ventricular function compared to ventricular septal defects, while in those with a patent ductus arteriosus this was worse. There was a trend towards lower mortality in patients with post versus pretricuspid shunts, which was signi?cant for patients above the age of 48 years.\nConclusion: The presence of a post-tricuspid shunt appears to carry physiological and possibly prognostic bene?ts in ES compared to patients with pre-tricuspid shunts. This should be borne in mind when management decisions and advanced therapies are considered.","DOI":"10.1016/j.ijcard.2014.11.100","ISSN":"01675273","language":"en","author":[{"family":"Moceri","given":"Pamela"},{"family":"Kempny","given":"Aleksander"},{"family":"Liodakis","given":"Emmanouil"},{"family":"Alonso Gonzales","given":"Rafael"},{"family":"Germanakis","given":"Ioannis"},{"family":"Diller","given":"Gerhard-Paul"},{"family":"Swan","given":"Lorna"},{"family":"Marino","given":"Philip S."},{"family":"Wort","given":"Stephen J."},{"family":"Babu-Narayan","given":"Sonya V."},{"family":"Ferrari","given":"Emile"},{"family":"Gatzoulis","given":"Michael A."},{"family":"Li","given":"Wei"},{"family":"Dimopoulos","given":"Konstantinos"}],"issued":{"date-parts":[["2015",1]]}}}],"schema":""} [9] Increased pulmonary blood flow is thought to be a necessary, but not sufficient component for the development of PAH. The process also requires a genetic predisposition or additional contributory factors that allow the activation of a cascade of mediators and result in vasoconstriction and vascular remodelling. Patients with sizable ASDs typically present with right ventricular dilatation. If PVD develops, however, the RV is subjected to an additional (pressure) load, which may result in RV hypertrophy, further dilatation, progressive dysfunction and reduction in the shunt. In these patients, closing the defect will abolish the volume load and may lead to a decrease in RV size, but will not abolish the pressure load and long-term impact of PVD on prognosis. In conclusion, despite reassuring signals in the short-to-medium-term, the long-term consequences of a “treat-and-repair” strategy are yet to be proven in patients with PAH and systemic-pulmonary shunts. At present, the decision to follow a “treat-and-repair” approach should be made on an individual basis after comprehensive, multidisciplinary evaluation in a specialist PAH-CHD centre with appropriate patient consent, explaining the significant uncertainty behind this approach. For now, the old adage holds: “I can close it” does not mean “I should close it”. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8hcDHbx9","properties":{"formattedCitation":"[10]","plainCitation":"[10]","noteIndex":0},"citationItems":[{"id":377,"uris":[""],"uri":[""],"itemData":{"id":377,"type":"article-journal","title":"Pulmonary hypertension related to congenital heart disease: a call for action","container-title":"European Heart Journal","page":"691-700","volume":"35","issue":"11","source":" (Crossref)","DOI":"10.1093/eurheartj/eht437","ISSN":"0195-668X, 1522-9645","title-short":"Pulmonary hypertension related to congenital heart disease","language":"en","author":[{"family":"Dimopoulos","given":"K."},{"family":"Wort","given":"S. J."},{"family":"Gatzoulis","given":"M. A."}],"issued":{"date-parts":[["2014",3,1]]}}}],"schema":""} [10] Figure 1Figure 1 legendAlgorithm describing the diagnostic pathway for the 4 types of pulmonary arterial hypertension in congenital heart disease (PAH-CHD). Initially, clinical and anatomical variables are used to separate groups 1, 3 and 4 PAH-CHD. For patients with ongoing left-right shunts, pulmonary vascular resistance is then used to differentiate into those who do not have pulmonary arterial hypertension and those with group 2 PAH-CHD. According to the international guidelines, there is a significant area of uncertainty (yellow box). This is where a “treat-and-repair” strategy may be considered. Abbreviations: ASD = atrial septal defect; CHD = congenital heart disease; L-R = left-to-right heart; PAH = pulmonary arterial hypertension; PAH-CHD = pulmonary arterial hypertension in congenital heart disease; PVR(i) = pulmonary vascular resistance (indexed); R-L = right-to-left heart; RHC = right heart catheterization; TR = tricuspid regurgitation. Conflict of interestDr. Constantine has received a personal educational grant from Actelion Pharmaceuticals (a Janssen Pharmaceutical company). Dr. Dimopoulos has received nonfinancial support from Actelion Pharmaceuticals; and has been a consultant to and received grants and personal fees from Actelion Pharmaceuticals, Pfizer, GlaxoSmithKline, and Bayer/MSD. References ADDIN ZOTERO_BIBL {"uncited":[],"omitted":[],"custom":[]} CSL_BIBLIOGRAPHY [1]C.S. Hjortsh?j, A.S. Jensen, K. S?rensen, E. Nagy, B. Johansson, T. Kronvall, M. Dellborg, M.-E. Estensen, H. Holmstr?m, M. Turanlahti, U. Thilén, L. S?ndergaard, Epidemiological changes in Eisenmenger syndrome in the Nordic region in 1977-2012, Heart Br. Card. Soc. 103 (2017) 1353–1358. doi:10.1136/heartjnl-2016-310979.[2]S. Konstantinides, A. Geibel, M. Olschewski, L. G?rnandt, H. Roskamm, G. Spillner, H. Just, W. Kasper, A Comparison of Surgical and Medical Therapy for Atrial Septal Defect in Adults, N. Engl. J. Med. 333 (1995) 5.[3]K. Dimopoulos, R. Inuzuka, S. Goletto, G. Giannakoulas, L. Swan, S.J. Wort, M.A. Gatzoulis, Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension, Circulation. 121 (2010) 20–25. doi:10.1161/circulationaha.109.883876.[4]K. Dimopoulos, A. Peset, M.A. Gatzoulis, Evaluating operability in adults with congenital heart disease and the role of pretreatment with targeted pulmonary arterial hypertension therapy, Int. J. Cardiol. 129 (2008) 163–171. doi:10.1016/j.ijcard.2008.02.004.[5]E.A. Bradley, N. Ammash, S.C. Martinez, K. Chin, C. Hebson, H.S. Singh, J. Aboulhosn, J. Grewal, J. Billadello, M.M. Chakinala, C.J. Daniels, A.N. Zaidi, “Treat-to-close”: Non-repairable ASD-PAH in the adult: Results from the North American ASD-PAH (NAAP) Multicenter Registry, Int. J. Cardiol. (2019). doi:10.1016/j.ijcard.2019.03.056.[6]H. Baumgartner, P. Bonhoeffer, N.M.S. De Groot, F. de Haan, J.E. Deanfield, N. Galie, M.A. Gatzoulis, C. Gohlke-Baerwolf, H. Kaemmerer, P. Kilner, F. Meijboom, B.J.M. Mulder, E. Oechslin, J.M. Oliver, A. Serraf, A. Szatmari, E. Thaulow, P.R. Vouhe, E. Walma, Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of Cardiology (ESC), Association for European Paediatric Cardiology (AEPC), ESC Committee for Practice Guidelines (CPG), ESC Guidelines for the management of grown-up congenital heart disease (new version 2010), Eur. Heart J. 31 (2010) 2915–2957. doi:10.1093/eurheartj/ehq249.[7]N. Galiè, M. Humbert, J.-L. Vachiery, S. Gibbs, I. Lang, A. Torbicki, G. Simonneau, A. Peacock, A. Vonk Noordegraaf, M. Beghetti, A. Ghofrani, M.A. Gomez Sanchez, G. Hansmann, W. Klepetko, P. Lancellotti, M. Matucci, T. McDonagh, L.A. Pierard, P.T. Trindade, M. Zompatori, M. Hoeper, ESC Scientific Document Group, 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT), Eur. Heart J. 37 (2016) 67–119. doi:10.1093/eurheartj/ehv317.[8]K.K. Stout, C.J. Daniels, J.A. Aboulhosn, B. Bozkurt, C.S. Broberg, J.M. Colman, S.R. Crumb, J.A. Dearani, S. Fuller, M. Gurvitz, P. Khairy, M.J. Landzberg, A. Saidi, A.M. Valente, G.F.V. Hare, 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, J. Am. Coll. Cardiol. (2018) 25255. doi:10.1016/j.jacc.2018.08.1029.[9]P. Moceri, A. Kempny, E. Liodakis, R. Alonso Gonzales, I. Germanakis, G.-P. Diller, L. Swan, P.S. Marino, S.J. Wort, S.V. Babu-Narayan, E. Ferrari, M.A. Gatzoulis, W. Li, K. Dimopoulos, Physiological differences between various types of Eisenmenger syndrome and relation to outcome, Int. J. Cardiol. 179 (2015) 455–460. doi:10.1016/j.ijcard.2014.11.100.[10]K. Dimopoulos, S.J. Wort, M.A. Gatzoulis, Pulmonary hypertension related to congenital heart disease: a call for action, Eur. Heart J. 35 (2014) 691–700. doi:10.1093/eurheartj/eht437. ................
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