Beghetti, Maurice

Schulze-Neick, Ingram

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Cardiol Young 2008; 18: 22–25r Cambridge University PressISSN 1047-9511doi: 10.1017/S1047951107001850First published online 15 January 2008Editorial CommentClassifying pulmonary hypertension in the setting of thecongenitally malformed heart – cleaning up a dog’s dinnerIngram Schulze-Neick,1 Maurice Beghetti21National UK Service for Pulmonary Hypertension in Children, Cardiac Unit, Great Ormond Street Hospital,London, United Kingdom; 2Pediatric Cardiogy Unit, De´partement de l’enfant et de l’adolescent, UniversityHospital of Geneva, SwitzerlandGOOD CLASSIFICATIONS OF DISEASES IN HUMANShave contributed greatly to medical progressby improving communication, allowing com-parisons, and supporting large scale epidemiologicand therapeutic studies. Well known examples are theclassification of malignant tumours, the Diagnosticand Statistical Manual of mental diseases, or thefunctional classification of exercise tolerance in heartdisease prepared by the New York Heart Association,not to mention large works such as the classificationof diseases by the World Health Organisation, ofwhich the classification of pulmonary hypertension asa rare, so-called orphan, disease is part.The advent of targeted specific treatment forpulmonary hypertension in the new millenniummade it obvious that a new scheme was needed forthe classification of aetiologically different formsso as to reflect their therapeutic accessibility. Therevised classification proposed by groups meeting inEvian in 1998,1 and Venice in 2003,2 achieved thisaim successfully, with many clinical studies basedon, and a number of therapeutic substances licensedaccording to, the new classification.How was this done? The crucial achievement ofthe classification has been the fact that a numberof diseases are grouped together as ‘‘pulmonary arterialhypertension’’, unifying those forms where thepulmonary vascular disease process takes place inthe arterial side of the pulmonary arterial tree and,in most cases, responds to the modern options fortreatment provided by agents such as prostanoids,antagonists of endothelin receptors, and inhibitor ofthe phosphodiesterase Type V. The new classifica-tion also implied similar severity and prognosis inthe respective groups of patients, and was usedavidly in almost all major therapeutic trials. Forexample, the idiopathic variant, the old ‘‘primary’’pulmonary hypertension, and the form associated withcongenital cardiac disease, previously considered a‘‘secondary’’ variant, are probably quite differentdiseases, despite similarities in features such as thehistological aspects. Patients from both of thesesubgroups, nonetheless, profited from this classifi-cation in becoming officially treatable as soonas new substances were licensed for ‘‘pulmonaryarterial hypertension’’.The success of this general classification is incontrast, however, with the still incoherent sub-classification of pulmonary arterial hypertensionseen in the setting of congenitally malformedhearts, which lacks insight despite notable attemptsat improvement,3 thus prompting the justified andnecessary initiative by van Albada and Berger4 toimprove the nosology. This is not at all an academicexercise, but a very necessary task in view of theincreasing numbers of grown-up patients withcongenitally malformed hearts and pulmonaryarterial hypertension, who will come to outnumberby far those patients with more ‘‘classical’’ variantsof the disease.5 The difficulties with restructuringthe classification, however, soon become apparent.Any modification should be simple enough to allowgrouping of sufficient numbers of patients to showefficacy of therapies, but also to satisfy theircomplicated anatomy and physiology.Van Albada and Berger4 must be commended fortheir clear analysis of the problems with the currentCorrespondence to: Ingram Schulze-Neick, National UK Service for PulmonaryHypertension in Children, Cardiac Unit, Great Ormond Street Hospital,London WC1N 3JH, United Kingdom. Tel: 144 (0)207 405 9200 ext 1005/1007/6707; Fax: 144 (0)207 905 2321; E-mail: neicki@gosh.nhs.ukhttps:/www.cambridge.org/core/terms. https://doi.org/10.1017/S1047951107001850Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 30 May 2017 at 18:03:08, subject to the Cambridge Core terms of use, available atclassification (See Table 1) by introducing a muchneeded view, which is the recognition of thehaemodynamic burden to the lung. Being led by thisvariable, they recognise several risk factors fordeveloping pulmonary arterial hypertension, rephrasedby us as:> Pre- or post-tricuspid location of the shunt, inother words with or without additional stress ofpressure on the pulmonary arterial system> Increased flow of blood to the lungs> Non-restrictive nature of shunting, either in theabsence of surgery, or because of a residual lesiondespite surgery> The timing of surgical correction> The presence of intra- and extracardiac abnorm-alities> Individual susceptibility and genetic factors,such as trisomy 21.The classification proposed by van Albada andBerger4 is certainly useful, and represents a much-needed step in the right direction. This is because itfollows one important rule. Classifications are mostuseful if they are unidimensional, in other wordsorganised along one easily recognisable variable toform the index, such as age, size, gender, or severity.The more this variable correlates with others, themore does the classification itself assume predictivepower. A well-known and successful classification ofthis type is the one proposed by the New York HeartAssociation for classification of exercise tolerance.If other variables are introduced to see what else theclassification could do, however, in this case toimprove understanding of prognosis and therapeuticdecisions, as well as to help in the adequate designand interpretation of clinical research, then thisintroduces the same potential caveats from whichthe previous classifications have suffered, namely amultidimensional approach which immediately con-fuses the situation. The reason for this is because thepatients not only have pulmonary arterial hyperten-sion. First and foremost they have congenitallymalformed hearts.Neither anatomy alone, nor the haemodynamicrisk factors, clearly predict the clinical course andprognosis of pulmonary arterial hypertension asseen in the setting of the congenitally malformedheart. These features vary markedly, depending oninstitution and doctor providing treatment, aswell as the patient him or herself. It is necessary totake all these aspects into account when decid-ing optimal therapeutic strategies. Treatment ofthe congenital malformation itself, by surgicallynormalising or ameliorating circulation and myo-cardial loading conditions, by corrective or palliativesurgery, or even by abstinence from surgery, createsa range of different physiologies. Indeed, theseare the issues which interfere with the presentlyexisting systems for classification. This is becausethe different cardiovascular physiologies that resultfrom corrected or uncorrected malformations maydominate the clinical state and fate of the patientand the response to therapy to a more importantdegree than the concomitant pulmonary arterialhypertension alone.What are these special physiologies? This isexactly the issue addressed by van Albada andBerger,4 which, if we may take it a few steps further,leads to the following view: first, there is the groupof patients that simply needs surgery as opposedto those patients who do not yet have the typicalphysiology of the Eisenmenger patient, but maystill be operable if their pulmonary vascularresistance was minimally lower. This subgroup isactually very important, since the pulmonaryvascular disease may progress despite successfulsurgery. Then, second, there are those patients withhaemodynamics similar to idiopathic pulmonaryhypertension, namely those with insignificant shunt-ing who have not undergone operative correction,Table 1. Existing and suggested classifications of systemic-to-pulmonary shunts associated with pulmonary arterial hypertension(rearranged to allow comparison).Item/Author WHO (2003) Galie` (2006) van Albada & Berger (2007)1. type simple, combined, complex pre-tricuspid, post-tricuspid,combined, complexpre-tricuspid, post-tricuspid2. dimensions small, large restrictive, non-restrictive,small, largerestrictive, non-restrictive3. direction of shunt — left, right, bidirectional left, right, bidirectional4. state of surgical repair non, partial, complete non, partial, complete non, surgical shunt, pulmonaryartery banding, complete5. associated cardiac anomalies — — pulmonary arterial stenosis,pulmonary venous stenosis,left ventricular dysfunction6. associated extracardiac anomalies absent/present absent/present absent/presentSchulze-Neick and Beghetti: Classifying pulmonary hypertension in the setting of the congenitally malformed heart 23https:/www.cambridge.org/core/terms. https://doi.org/10.1017/S1047951107001850Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 30 May 2017 at 18:03:08, subject to the Cambridge Core terms of use, available ator those who have undergone repair but still haveinsignificant residual defects. There is then a thirdgroup of patients in whom the arterial side of thepulmonary vascular tree has developed additionalactive disease as a reaction to pulmonary venoushypertension which existed either in the past (eg.,obstructive lesions on the left side of the heart whichwith successful repair) or which is an ongoingproblem (eg., left myocardial disease with increasedenddiastolic pressures). The Eisenmenger physiologymakes up a fourth entity with its own importantpathophysiological considerations. Those with theFontan circulation then represent a fifth subset, withvery fragile and specific physiology. In these patients,as with those in the other groups, the increase inpulmonary vascular resistance leads ultimately tofailure of the circulation. Making up a sixth group,there are those with the unusual forms of congenitalmalformations that produce unilateral pulmonaryarterial hypertension, mainly because of the surgicalshunts, systemic-to-pulmonary collateral arteries,abnormalities of the right or left pulmonary arteries.A final seventh group is constituted by those withincreased pulmonary vascular resistance due togeneral hypoplasia of the pulmonary vascular bed,in whom pulmonary vasodilating therapy may beexplored in the absence of any other therapeuticoptions. To make things more complicated, allgroups come combined not only with their ownpast or ongoing risk of developing pulmonary arterialhypertension, but also with the risk of failure of thesubpulmonary ventricle to sustain this afterload.Thus classifying these groups according to theirunderlying physiology (Table 2) shows their commonelements determining clinical course and thepotential for discussions regarding possibilities oftreatment.The current body of evidence as condensed by vanAlbada and Berger4 regarding the specific treatment ofpatients with the Eisenmenger syndrome underlinesthe fact that this new pathophysiologically orientedconcept for classification of pulmonary arterialhypertension as seen in the setting of the congenitallymalformed heart, shown here with its entire spectrum,is already implicitly used in a fruitful way. Thissuggested classification, at first glance, may appear tobe out of line with the classifications proposed inEvian and Venice, as the group with the Fontan-likecirculations does not represent patients with pulmon-ary hypertension according to the classical andhaemodynamically simple definition of an increasedpulmonary vascular resistance of greater than 3 Woodunits per meter squared, or a mean pulmonary arterialpressure of more than 25 millimetres of mercury.When examined more closely, however, it becomesapparent that this group unequivocally needs to be Table2.Newproposedclassificationofpulmonaryarterialhypertensioninthesettingofcongenitallymalformedheartsasbasedoncirculatorypathophysiology.SignificantshuntinglesionsiPAH-likephysiologyPAHduetopastorpresentPVHEisenmengerphysiologyFontan-likephysiologyUnilateralPAHHypoplasticPASystema)forcorrectivesurgery,PVRislowandpresentsnoproblema)smallunoperatedlesion(eg.,POF,ASD,VSD,PAD)nothaemo-dynamicallyrelatedtoPAHb)smallresiduaeaftercorrectivesurgeryofashuntinglesion,nothaemodynamicallyrelatedtoPAHa)aftercorrectivesurgeryofpulmonaryvenousstenosisoraortic/mitralvalvardiseaseorcoarctation,withnormalwedgepressureandleftventricularfunctionb)PAHduetoleftventriculardysfunctionwithabnormalwedgepressureandincreasedPVRa)classicalEisenmengerphysiology:nosub-pulmonaryoutflowobstruction;predominantlyright-to-leftshuntingatatrial,ventricularorarteriallevel,nointraventricularmixingb)functionallyuniventri-cularphysiology:nosub-pulmonaryoutflowobstruction;systemicdesaturationisduetointraventricularmixinga)afterFontan-operationwiththerightatriumbeingincorporateda)duetoasurgicalshuntpreviouslycreatedtoincreasepulmonarybloodflowwhichhasledtosignificantPAHonthatsideb)duetocongenitaloriginofonepulmonaryarteryorofmajorcollateralvesselsfromtheaorta,causingPAHa)aftercorrectivesurgeryoftetralogyofFallotwithoutmajoranatomicalobstructionsofthepulmonaryvascularsystem,andPAHb)aftercorrectivesurgeryofpulmonaryatresiawithoutmajoranatomicalobstructionsofthepulmonaryvascularsystem,andPAHb)forcorrectivesurgery,PVRelevated,riskincreasedbutacceptedc)forcorrectivesurgery,PVRelevated,risktoohigh,notoperableb)Fontanwithalateralorextracardiacconduit,rightatriumexcluded,nofenestrationc)anatomyasaboveunderb),withfenestrationAbbreviations:ASD,interatrialcommunication;(i)PAH,(idiopathic)pulmonaryarterialhypertension;PVR,pulmonaryvascularresistance;PAsystem,pulmonaryvascularsystem;PAD,persistentlypatentarterialduct;POF,patentovalforamen;PVH,pulmonaryvenoushypertension;VSD,ventricularseptaldefect.24 Cardiology in the Young February 2008https:/www.cambridge.org/core/terms. https://doi.org/10.1017/S1047951107001850Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 30 May 2017 at 18:03:08, subject to the Cambridge Core terms of use, available atpart of this classification, as even a minimal increase inpulmonary vascular resistance causes an important,clinically relevant, problem which is very analogousphysiologically with that of patients with classicalsevere pulmonary arterial hypertension and whichresults in similar consequences, both in symptoms andmost likely necessary medical therapy.It is clear that, in all classifications, there is andmust be an element of simplification, which alsoimplies a specific bias and some weaknesses. Aclassification, nonetheless, is an instrument withwhich to work. Thus, it needs to stand the test oftime. If successful, it may prove a very useful tool forresearch, clinical use and ultimately the benefit ofpatients. Eventually, it will find its place in officialrecommendations, such as guidelines for treatment.Modifications such as those proposed by van Albadaand Berger4 are an important and necessary part ofthis comprehensive process of classification. The nextWorld Congress on Pulmonary Hypertension, to beheld in the United States of America in 2008, willdevelop still another subclassification of pulmonaryarterial hypertension as seen in the setting of thecongenitally malformed heart, and will aim toimprove further the assessment and treatment ofthese complicated patients. Hopefully those preparingthe next modification will take note both of thesuggestion of van Albada and Berger,4 and our owncomments.References1. Rich S. Executive summary from the World Symposiumon Primary Pulmonary Hypertension. World Symposium onPrimary Pulmonary Hypertension. Evian, France, 1998.2. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification ofpulmonary hypertension. J Am Coll Cardiol 2004; 43: 5S–12S.3. Galie` N. Classification of patients with congenital systemic-to-pulmonary shunts associated with pulmonary arterial hyper-tension: current status and future directions. In: Beghetti M,Barst R, Naeije R, Rubin L (eds). Pulmonary Arterial Hyperten-sion Related to Congenital Heart Disease. Urban & Fischer,Mu¨nchen Jena, 2006, pp. 11–16.4. van Albada MI, Berger RMF. Pulmonary arterial hypertension incongenital cardiac disease – the need for refinement of the Evian-Venice classification. Cardiol Young 2008; 18. This issue.5. Schulze-Neick I. Pulmonary hypertension in congenital heartdisease. Deutsche Medizinische Wochenschrift (1946) 2006; 131:S322–S324.Schulze-Neick and Beghetti: Classifying pulmonary hypertension in the setting of the congenitally malformed heart 25https:/www.cambridge.org/core/terms. https://doi.org/10.1017/S1047951107001850Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 30 May 2017 at 18:03:08, subject to the Cambridge Core terms of use, available at

Classifying pulmonary hypertension in the setting of the congenitally malformed heart - cleaning up a dog's dinner

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