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The Essential Role of Imaging in the Evaluationof Patients With Pulmonary Arterial Hypertensionin Association With Congenital Heart Disease

CLASSIFICATION OF PAH-CHDThe heterogeneity of cardiac morphologyand its functional consequences require acustomized classification, including adetailed description of cardiac morphol-ogy, previous surgical and/or catheterintervention/s, and current functional andhemodynamic status of the patient.

LEFT TO RIGHT SHUNTSLeft to right shunts are the most commonsubstrate for PAH-CHD, accounting forapproximately 38% of patients with CHDand pulmonary hypertension (PH) in arecent report from Canada.3 This groupincludes patients with Eisenmenger syn-drome, where the development of PAHoccurs in the presence of a nonrestrictiveleft to right shunt—intracardiac (usuallypost-tricuspid) or extracardiac. In about50%-70% of cases, patients develop irre-versible and progressive pulmonary vas-cular disease in the first few years of life,resulting eventually in reversal of bloodflow through the shunt and cyanosis.4 Ex-amples of these lesions are large ventric-ular septal defects (VSD), patent ductusarteriosus (PDA), complete atrioventricu-lar septal defects (AVSD), truncus arteri-osus, or functionally univentricular heartswithout pulmonary stenosis. In cardiac le-sions with a left to right shunt at thepre-tricuspid level, ie, patients with largeatrial septal defects (ASD) with initialvolume and not pressure overload, the de-velopment of pulmonary vascular diseaseis less frequent and later in life. Only

one-tenth to one-fifth of patients with ahemodynamically important and large in-teratrial communication will eventuallydevelop pulmonary vascular disease,mostly in late adulthood.

FONTAN CIRCULATIONPulmonary arterial hypertension can alsocomplicate other subgroups of CHD, bothin their natural history and after surgicalrepair; such an example of the uniquefeatures of the pulmonary circulation inCHD is represented by the Fontan “circu-lation,” where systemic venous return isdirected to the lungs without an inter-posed ventricular pump (Figure 1). At firstglance, it may appear to be out of line withthe classical definition of PAH (increasedpulmonary vascular resistance [PVR] ofgreater than 3 Wood units per metersquared or MPAP of more than 25 mmHg). However, there is evidence of anabnormal pulmonary vascular bed in thesepatients, as suggested by an abnormal re-sponse to exogenous nitric oxide admin-istration.5 We submit, herewith, that pa-tients with the Fontan circulation shouldbe considered in the PAH-CHD group, aseven a minimal increase in PVR can havea major adverse effect on the pulmonarycirculation and thus cardiac output giventhe absence of a subpulmonary ventricle.Based on these considerations, a more re-fined classification of PAH that coexistswith CHD has been proposed to betteraddress this rather heterogeneous patientgroup that cannot be assumed to be sim-

ilar in terms of pathophysiology and he-modynamics (Table 1).6

ROLE OF IMAGINGMultimodality imaging plays a key role inassessing and managing patients withPAH-CHD. It is important to recognizethe strengths/weaknesses and the comple-mentary nature of different imaging mo-dalities as well as the complex nature ofthe diagnostic questions that need to beaddressed.

In this review, we will focus on theimaging tools commonly employed toevaluate PAH in CHD patients and theirrelative contribution to diagnostic assess-ment, evaluation of the functional and he-modynamic impairment, and longer-termprognostication.

ECHOCARDIOGRAPHYTransthoracic echocardiography (TTE) isthe first-line cardiovascular imaging mo-dality in the assessment of patients withvarious types of PAH because it is easy toapply, relatively inexpensive, and pro-vides accurate information on cardiacanatomy and physiology.

In the setting of PAH-CHD, TTE isparticularly suitable for the real-time in-terrogation of structural abnormalities aswell as hemodynamic disturbances. In themajority of these patients, TTE allows theevaluation of cardiac anatomy (ie, orien-tation and veno-atrial, atrioventricular,and ventriculo-arterial connections), themorphology of cardiac structures, ventric-

Key Words—cardiovascular magnetic resonance, echocardiography, Fontan circulation, myocardial performance index, right ventricular functionCorrespondence: [email protected]: Sonya V. Babu-Narayan is supported by an Intermediate Clinical Research Fellowship from the British Heart Foundation. This project wassupported by the NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. Thisreport is independent research by the National Institute for Health Research Biomedical Research Unit Funding Scheme. The views expressed in thispublication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health.

Pulmonary arterial hypertension (PAH) is a hemodynamic and pathophysio-logic condition defined as an increase in mean pulmonary artery pressure(MPAP) of �25 mm Hg at rest measured at right heart catheterization (RHC).1,2

Patients with PAH associated with congenital heart disease (PAH-CHD) are agrowing population consisting of an anatomically and phenotypically hetero-geneous group, where differences among specific cardiac defects, along withtheir varied clinical course and prognosis, influence treatment choices for theindividual patient.

Giancarlo Scognamiglio, MD, PhD,

Sonya V. Babu-Narayan, MRCP, PhD,

Michael B. Rubens, FRCR,

Michael A. Gatzoulis, MD, PhD, FESC, FACC,

Wei Li, MD, PhD, FESC, FACCRoyal Brompton and Harefield NHS FoundationTrust, London, United Kingdom

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171Advances in Pulmonary Hypertension

ular and valvular function, the presence ofshunt lesions, and hemodynamic assess-ment (eg, severity of valvular regurgita-tion and evaluation of shunts and veloci-ties across obstructive lesions).7

In addition, in the context of PAH-CHD, TTE is especially helpful in provid-ing information on the following aspects:

• Pulmonary artery pressure• Right ventricular (RV) involvement• Prognostication/outcome

Pulmonary Artery PressurePulmonary artery systolic pressure.Pulmonary artery systolic pressure(PASP) can be estimated using tricuspid

regurgitation (TR) velocity (V) by apply-ing the Bernoulli equation [PASP �4V2 � estimated right atrial (RA) pres-sure, where V is the average peak TRvelocity]. In patients with CHD, PASPcan also be calculated using maximum flowvelocity across a VSD or an aortopulmo-nary shunt (PDA, Blalock-Taussig shunt)(PASP � systolic blood pressure – 4V2).8-9

A few aspects must be kept in mind toensure accurate estimates of PASP.

• Although PASP measured by echocar-diography correlates relatively wellwith PASP measured invasively, Bland-Altman analysis in the clinical settingdemonstrates that large (10-20 mm Hg)differences between invasive and non-invasive PASP are common. The mostcommon causes of inaccurate estima-tion of PASP include an incompleteDoppler envelope, resulting in underes-timation of pressure or an overestimateof RA pressure from inferior vena cavadiameter and collapsibility.10

Figure 1: The Fontan operation and its various modifications. (a) ClassicFontan operation. (b) Lateral tunnel with fenestration, (c) extracardiacFontan. f, fenestration; IVC, inferior vena cava; PA, pulmonary artery; RA,right atrium; SVC, superior vena cava. (Reprint from Gatzoulis MA, Webb GD,Daubeney PEF. Diagnosis and Management of Adult Congenital HeartDisease. Oxford, UK: Churchill-Livingstone. 2003; page 85.).

Table 1: Proposed classification of PAH in the setting of congenitally malformed hearts as based on circulatorypathophysiology (modified from 6). Abbreviations: ASD, interatrial communication; AVSD, atrioventricular septaldefect; (i)PAH, (idiopathic) pulmonary arterial hypertension; PVR, pulmonary vascular resistance; PDA, patentarterial duct; POF, patent oval foramen; PVH, pulmonary venous hypertension; VSD, ventricular septal defect

Significantshuntinglesions

iPAH-likelesions

PAH due to pastor present PVH

Eisenmengerphysiology

Fontan-likephysiology

UnilateralPAH

HypoplasticPA system

a) For correctivesurgery, PVR islow andpresents noproblemb) For correctivesurgery, PVRelevated, riskincreased butacceptedc) For correctivesurgery, PVRelevated, risktoo high, notoperable

a) Smallunoperatedlesion (eg, POF,ASD, VSD, PAD)nothemodynamicallyrelated to PAHb) Small residueafter correctivesurgery of ashunting lesion,nothemodynamicallyrelated to PAH

a) After correctivesurgery ofpulmonaryvenous stenosisor aortic/mitralvalvar disease orcoarctation, withnormal wedgepressure and leftventricularfunctionb) PAH due to leftventriculardysfunction withabnormal wedgepressure andincreased PVR

a) ClassicalEisenmengerphysiology: nosubpulmonaryoutflowobstruction;predominantlyright to leftshunting atatrial,ventricular, orarterial level, nointraventricularmixingb) Functionallyuniventricularphysiology: nosub-pulmonaryoutflowobstruction;systemicdesaturation isdue tointraventricularmixing

a) After Fontanoperation withthe right atriumbeing incorporateb) Fontan with alateral orextracardiacconduit, rightatrium excluded,no fenestrationc) Anatomy asaboved) Withfenestration

a) Due to asurgical shuntpreviouslycreated toincreasepulmonaryblood flow,which has ledto significantPAH on thatsideb) Due tocongenitalorigin of onepulmonaryartery or ofmajorcollateralvessels fromthe aorta,causing PAH

a) Aftercorrectivesurgery oftetralogy ofFallot withoutmajoranatomicalobstructionsof thepulmonaryvascularsystem, andPAHb) Aftercorrectivesurgery ofpulmonaryatresiawithout majoranatomicalobstructionsof thepulmonaryvascularsystem, andPAH

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172 Advances in Pulmonary Hypertension

• The right ventricular systolic pressure(RVSP) calculated from TR velocitymay only be taken as the PASP in theabsence of RV outflow obstruction. InCHD, more care should be taken to ex-clude any obstruction along the pulmo-nary pathway, especially after pulmonicvalve surgery or in patients with previoussystemic to pulmonary shunts. In somecases, peripheral or segmental pulmonarystenosis may also be present; this willrequire complementary imaging such ascardiovascular MRI to delineate.

• Velocity measurements are angle de-pendent. Tricuspid regurgitant jetsshould be taken from multiple acousticwindows (apical 4-chamber views, RVinflow, and off axis if necessary) withaccurate transducer angulation in orderto obtain a parallel intercept angle be-tween the ultrasound beam and jet toavoid underestimation. In some cases oftrivial regurgitant jet and suboptimalcontinuous-wave Doppler spectrum, theinjection of contrast agents (agitated sa-line, sonicated albumin, or air-blood-salinemixture) may be required to achieveclear delineation of the jet envelope.11

• Close relationship between PASP andRV cardiac output exists. In cases of“end-stage” PAH, where both advancedRV dysfunction and increased PVRcause a significant reduction in stroke

volume, PASP may appear “pseudonor-malized” as a consequence of the lowdriving pressure generated by the failingRV.12 Underestimation of RV pressuremay also occur with the development ofdiastolic RV dysfunction, characterizedby high RA pressure and a stiff RV.

• Furthermore, in cases of severe TR thepeak velocity may underestimate thetrans-tricuspid pressure gradient be-cause of early equalization of pressurebetween RA and RV, leading to trunca-tion of the Doppler envelope.12

Pulmonary artery mean and end-diastolic pressure. Mean pulmonary ar-tery pressure and pulmonary end-diastolicpressure (PADP) are especially usefulwhen TR velocity cannot be obtained orwhen further information is required.

A jet of pulmonary regurgitation, pres-ent in the majority of patients with PAH-CHD, permits the measurement of theend-diastolic pulmonary pressure usingthe modified Bernoulli equation:[PADP � 4 � (end-diastolic pulmonaryregurgitant velocity)2 � RA pressure].

Similarly, MPAP can be determinedfrom early peak pulmonic regurgitationvelocity using the modified Bernoulliequation and adding the estimated RApressure.13 Mean pulmonary artery pres-sure can also be estimated by using pul-

monary acceleration time (AT) measuredfrom the onset of RV ejection to peakpulmonary flow velocity (Figure 2). Gen-erally, the shorter the AT, the higher thePVR and hence the pulmonary artery pres-sure. A value �105 ms is suggestive ofPH.14 Mean pulmonary artery pressure canalso be derived by regression formulaswhere: MPAP � 79 � (0.45 � AT). Thesame authors also found that in patientswith ATs �120 ms, the formula [MPAP �90 � (0.62 � AT)] performed better.15

In addition to AT, the shape of the flowwave is of interest, as PH is associatedwith a deceleration of flow in mid systole(notching). In the presence of increasedPVR and low arterial compliance, pulsewave reflection has greater magnitude andpropagates more rapidly, arriving at theright ventricular outflow tract (RVOT)during systole.16

In patients with a Fontan circulation, aspreviously discussed, even a minor in-crease in pulmonary artery pressure mayhave significant hemodynamic conse-quences on the Fontan circulation. Con-ventional diagnostic criteria for PAH can-not be applied in this type of circulation.Information about MPAP in this settingcan be derived from mean flow velocityacross a fenestration between the Fontan ortotal cavopulmonary connection pathwayand the atria; when such a fenestration is

Figure 2: (a) Estimation of mean and diastolic pulmonary artery pressure by continuous-wave Doppler signal ofpulmonary regurgitation (PR). Point 1 indicates maximal early diastolic PR velocity, which can be used to calculateMPAP. Point 2 marks end-diastole PR velocity used to calculate end-diastolic pulmonary artery pressure. (b) Measure-ment of pulmonary AT from the pulsed-wave Doppler signal of pulmonary arterial flow.

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present and can be interrogated by echoDoppler [MPAP � 4 V2 � left atrial (LA)mean pressure]. If this value is more than17 mm Hg, it is highly suggestive of PAH.

Comprehensive diagnosis of PAH-CHD should combine Doppler pressuremeasurements with other accompanyingechocardiographic features such as ven-tricular size and systolic function, as it isthe RV that plays the key role in deter-mining clinical presentation and progno-sis in PAH-CHD.

Assessment of RV Morphology andFunctionRight ventricular morphology. Nor-mally the RV is a thin-walled chamber. Inmost forms of PAH, as a result of chronicprogressive pressure loading, progressiveRV remodelling occurs, initially in theform of hypertrophy and later as dilata-tion, along with progressive contractileimpairment and, eventually, RV failure.

Compared to the patients with otherforms of PAH, Eisenmenger syndrome he-modynamics and resulting RV remodellingare distinctly different. In adults with Eisen-menger syndrome with post-tricuspid de-fects and 2 ventricles, the RV often appearsgreatly hypertrophied with no significantdilatation. This unique physiopathologicadaptive model is explained by the preser-vation of a “fetal-like” phenotype withoutloss of RV hypertrophy and the presence ofa ventricular communication, allowing bothventricles to function as a single entity.17

In contrast, adults with PH and a pre-tricuspid shunt (ie, ASD) show greaterLA, RA, and RV dilatation. It can there-fore be postulated that loss of RV hyper-trophy during infancy, lack of a trainingeffect on the RV during childhood, and theabsence of a ventricular communication thatpairs the 2 ventricles functionally likely ex-plain the differing RV response.18

Eccentricity index. In patients withPAH, the high RV pressure may reducethe trans-septal pressure gradient betweenthe 2 ventricles and leads to the frequentlyobserved flattening of the intraventricularseptum (IVS). M-mode analysis, with itshigh temporal resolution, can accuratelyestimate differences in the timing of left-ward IVS shift during the cardiac cycle.Two-dimensional echo permits the quan-

tification of the septal deformation usingthe eccentricity index, measured from aparasternal short axis view at the level ofthe chordae tendineae as the ratio of theleft ventricle (LV) dimension parallel andperpendicular to the IVS respectively. It isusually measured both at end diastole andend systole with a normal value of 1.0,which occurs when the LV cavity main-tains a round and symmetrical configura-tion on short-axis imaging. Mild, moder-ate, and severe septal bowing isrepresented by values of 1.1–1.4, 1.5–1.8,and �1.8.19

LV filling abnormalities. Intraventricu-lar septum deformation also alters LVshape, size, and diastolic filling. Thus, acommon echocardiographic finding inthese patients is blunted early diastolicfilling of the LV, which in this scenario isnot indicative of LA hypertension, butinstead represents a marker of abnormalventriculo-ventricular interaction. In fact,increased RV pressure and prolonged RVsystole cause early diastolic reversal ofthe IVS. As a result, early diastolic trans-mitral filling is reduced and redistributedto late diastole.20

Right ventricular function. Assessmentof RV function is the single most impor-tant aspect of the echocardiographic ex-amination in patients with PAH, becausesymptoms and outcome both depend onthe ability of the RV to adapt to an in-creased pulmonary vascular load.

Right ventricular dysfunction is chal-lenging to quantify on echocardiography.All available acoustic windows and viewsshould be used to provide complementaryinformation and allow for a comprehen-sive assessment. Qualitative assessmentof function based on visual inspection iscommonly used in practice, but is limitedby a significant interobserver variability,which is especially problematic when as-sessing relative changes in RV function inthe same patient.

Tricuspid annular plane systolic excur-sion. Differences in muscle fiber orienta-tion of the RV suggest that longitudinalshortening plays a greater role in RV emp-tying than in the LV. This predominantlylongitudinal contractile pattern of the RVcan be easily obtained.

Tricuspid annular plane systolic excur-sion (TAPSE) is the longitudinal systolicdisplacement of the RV base toward theRV apex and has been shown to correlatestrongly with RV ejection fraction (EF).21

Tricuspid annular plane systolic excursioncan be derived using 2D guided M-mode(Figure 3a), is simple and highly repro-ducible, and has been recommended byAmerican Society of Echocardiography(ASE) guidelines as part of routine echo-cardiographic evaluation.8 Normal valuesvary between 2.3 cm–2.6 cm, with aTAPSE of 2.0 cm likely representing thelowest acceptable normal value. Values inthe range of 1.8 cm–2.0 cm, 1.6 cm–1.8cm, and �1.6 cm are consistent with mild,moderate, and severe RV systolic dys-function.19 A significant limitation ofTAPSE in PAH-CHD is that it is highlyload dependent, such that it may becomepseudonormalized in the presence of sig-nificant ventricular volume loading, suchas with left to right shunting or severeTR.22

Tissue Doppler imaging. Analogous toTAPSE, systolic wave velocity by tissueDoppler imaging (TDI) is a measure oflongitudinal myocardial contraction. Tis-sue Doppler imaging like TAPSE is loaddependent and may become pseudonor-mal under conditions of increased ventric-ular volume loading. Mean value in nor-mal controls is approximately 15 cm/s atthe annulus, with a lower accepted refer-ence limit of normal of 10 cm/s.8

Fractional area change. A more quan-titative approach of assessing RV functionis to measure the RV functional areachange (FAC), [(end-diastolic area – end-systolic area)/end-diastolic area] � 100,which has demonstrated a close correla-tion with RVEF by MRI.23 It is obtainedby tracing areas of the RV at end diastoleand end systole from the apical 4-chamberview beneath the trabeculations. Unfortu-nately, incomplete visualization of the RVcavity, especially when the RV is dilated,as well as difficulties in endocardial def-inition lead to relatively poor reproduc-ibility, thus making it an unreliable toolfor serial assessment.

Myocardial performance index. Themyocardial performance index (MPI),also known as the Tei index, provides a

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global assessment of both RV systolic anddiastolic function. It can be calculated ei-ther from Doppler imaging (apical4-chamber view for the tricuspid inflowpattern and the parasternal short-axisRVOT view for the determination of ejec-tion time) or from TDI (single image fromthe lateral annulus of the tricuspid valve),according to the formula: MPI � (iso-volumic contraction time � isovolumicrelaxation time)/RV ejection time.24

Values greater than 0.40 by pulsed-wave Doppler or greater than 0.55 by tis-sue Doppler signify RV dysfunction.8 Ithas a good reproducibility, does not relyon geometric assumptions, and can be ap-plied even in the presence of a suboptimalacoustic window. On the other hand, it isrelatively load dependent and unreliablewhen RA pressure is elevated. Right ven-tricular ejection time, a component ofMPI, has been shown to increase on tar-geted therapy for PAH.

Total isovolumic time. The total iso-volumic time (t-IVT), which represents thesum of both isovolumic relaxation time(IVRT) and isovolumic contraction time

(IVCT), can be calculated by subtractingfilling time and ejection time from RR in-terval. It can be expressed as seconds perminute when calculated using the followingformula: t-IVT�60 – [(ejection time �heart rate/1000) � (total filling time � heartrate/1000)].

Total isovolumic time is the time dur-ing the cardiac cycle heart neither ejectingnor filling. It is the total wasted time. Inpatients with increased pulmonary arterypressure, reduced pulmonary artery com-pliance will limit RV ejection time andprolonged tricuspid regurgitation durationwill result in shortened filling time.Therefore, t-IVT will be significantlyprolonged, and as a consequence strokevolume and hence cardiac output de-creases.18,25 Total isovolumic time canbe used for monitoring disease progres-sion and assessing prognosis.

Advanced right ventricular imaging.Speckle tracking—strain and strain rateexamine the deformation and rate of de-formation of the myocardial segments.These represent a method of assessing in-

trinsic RV myocardial contractility that isless load dependent, but currently remainoutside the standard echocardiographic pro-tocols due to the lack of normative data andhigh interobeserver variability.26

Real time 3-dimensional echocardi-ography can overcome the limitations of2D echo in the assessment of RV vol-umes and EF. Three-dimensional echo-cardiographic RV volumes are compa-rable to those derived by MRI, althoughlittle data exist for significantly dilated ordysfunctional ventricles.27 Technologies,able to create a 3D model of the RV by apost-processing analysis of anatomical land-marks identified in any 2D view, are cur-rently under investigation in an ongoingstudy in PAH.28

Echocardiographic Predictors ofClinical OutcomeDifferent echocardiographic variableshave been demonstrated to yield prognos-tic information that may guide clinicalmanagement. From the current literature,and according to the European Society ofCardiology (ESC) guidelines, the echo-

Figure 3: (a) TAPSE by M-mode recording. (b) Kaplan-Meier curve for TAPSE. Patients with TAPSE <15 mm hadhigher mortality rates than patients with TAPSE >15 mm. (Reprinted with permission from Moceri P, Dimopoulos K,Liodakis E, et al. Echocardiographic predictors of outcome in Eisenmenger syndrome. Circulation. 2012;126:1461-1468.)

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cardiographic indices most closely asso-ciated with unfavorable outcome, includingRA area index, diastolic eccentricity index,pericardial effusion, MPI, and TAPSE,are all indicators of RV decompensation.

However, prognosis is significantly af-fected by the etiology of PAH. Patientswith Eisenmenger syndrome exhibit a bet-ter prognosis compared with idiopathicPAH and connective tissue disease–associated PAH. Patients may survive de-cades after the initial diagnosis of PAH-CHD, even before the advent of advancedtargeted PAH therapy. As mentioned be-fore, the difference in outcome is thought

to be related to better adaptation of the RVto systemic or high pulmonary arterypressure. In support of this view, we haverecently demonstrated that the longitudi-nal function of the RV is preserved ormildly impaired in the majority of patientswith Eisenmenger syndrome, and thateven though RV dilation was prevalent, itwas less severe than that described in id-iopathic PAH and was not related to ad-verse outcome.29

Right ventricular long axis function(TAPSE). Right ventricular longitudinalcontraction in Eisenmenger patients has

been shown to be an independent prog-nostic factor, both in our cohort, whereeven small reductions in TAPSE were as-sociated with adverse outcome (Figure3b), and in another recent prospectivestudy from Van De Bruaen and colleagueswhere TAPSE �15.9 mm was predictiveof lower event-free survival and higherall-cause mortality.30

Ratio of RV effective systolic to dia-stolic duration. The duration of TR, amarker of impaired adaptation to pressureoverload and of RV failure, is stronglyrelated to outcome. In fact, in these cir-

Figure 4: (a) Measurement of effective RV systolicand diastolic duration on trans-tricuspid Doppler.(b) Measurement of RA area on 2D echocardiogram.(c) Time-dependent receiver operating characteristiccurves at 1.5 years for the echocardiographiccomposite score (TAPSE <15 mm, ratio of RVeffective systolic to diastolic duration >1.5, rightatrial area >25 cm2, RA/LA area ratio >1.5).(Reprinted with permission from Moceri P,Dimopoulos K, Liodakis E, et al. Echocardiographicpredictors of outcome in Eisenmenger syndrome.Circulation. 2012;126:1461-1468.).

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cumstances RV filling time is limited byprolongation of TR in presystole and/orearly diastole, and cardiac output mayconsequently decrease. In order to im-prove the diagnostic power of echo inEisenmenger patients, a ratio of RV ef-fective systolic to diastolic duration canbe calculated (Figure 4a). Durations ofsystole and diastole can be measured fromthe clearest Doppler signal of TR from theapical view. Effective systolic duration ismeasured from the onset to the end of TR.Effective diastolic duration is measuredfrom the end of TR to the onset of thesubsequent TR signal. A ratio �1.5 is anindependent predictor of outcome.29

Right atrial area and ratio of RA to LAarea. Parameters reflecting high centralvenous pressure have also been shown topredict mortality in PAH. Right atrial di-lation is a reflection of long-standing pres-sure overload and ensuing heart failure.Quantitative assessment of RA size is per-formed from the apical 4-chamber view(Figure 4b). Right atrial measurements areobtained at the end of ventricular systole,when chamber size is maximal. Rightatrial area is usually measured, as it hasbeen reported to predict adverse outcomein the setting of PAH. Eisenmenger pa-tients with pre-tricuspid shunts, who arethought to have a worse prognosis com-pared with those with post-tricuspidshunts,31 are expected to have larger atriabecause of the long-standing shunt at theatrial level. Right atrial dilation, beyondbeing a marker of right-sided overloadand possibly stiffness of a hypertrophiedRV, is also a predisposing factor for ar-rhythmias. Mortality risk is significantlyincreased when RA area is �25 cm2 orRA/LA ratio is �1.5.29

All the parameters discussed abovehave their limitations when used in isola-tion. Comprehensive assessment with acombination of multiple parameters pro-vides the most accurate prognostication.

In our cohort, a composite score basedon these strong echocardiographic predic-tors of outcome (TAPSE �15 mm, ratio ofRV effective systolic to diastolic duration�1.5, RA area �25 cm2, and RA/LA arearatio �1.5) identified patients with morethan 3-fold increased risk of death at 1.5

years, with a very high area under the curveon receiver operating curve (Figure 4c).

CHEST RADIOGRAPHY ANDCARDIAC COMPUTEDTOMOGRAPHYA plain chest x-ray provides a record ofcardiac size, which in the CHD populationas a whole carries prognostic signifi-cance.32 The typical changes of PAH onthe chest x-ray are enlargement of thecentral pulmonary arteries with relativepruning of the distal vessels. There mayalso be signs of specific chamber enlarge-ment or other features to suggest a partic-ular underlying defect (Figure 5).

Although disadvantaged by the needfor ionizing radiation and contrast, com-

puted tomography (CT) has an importantpart to play in the investigation of PAH-CHD, as it provides information on car-diac chambers, great arteries, lung vascu-lature, and parenchyma and mediastinalstructures in a single acquisition with highspatial resolution.33 This is particularlythe case when acoustic windows havebeen poor (limiting echocardiography),lung disease is present, or devices such aspacemakers prevent cardiovascular mag-netic resonance (CMR) scanning.

Similar features of cardiac physiologyassociated with PAH described previouslycan also be identified using cardiac CT.Communications between chambers canbe visualized and the direction of shuntinferred by the direction of contrast (Fig-

Figure 5: Chest x-ray of a patient with ASD and PH. The main pulmonaryartery (long arrow) and its main branches are enlarged, and the peripheralpulmonary vessels by comparison are “pruned.” The heart is enlarged andthe shape suggests right heart enlargement. The aortic knuckle (shortarrow) is small—a feature typical of ASD.

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ure 6a). Although excellent at providinganatomical detail, it is generally not themodality of choice for providing func-tional data. If necessary, biventricularfunction can be assessed, though this ne-cessitates greater radiation exposure tocapture information throughout the car-diac cycle.

The CT pulmonary angiogram is thetest of choice to assess the proximal anddistal pulmonary arteries noninvasively.In doing so, pulmonary artery dilatationcan be identified as well as the presence ofthrombus, which may form in situ due tosluggish blood flow in an inflamed pul-monary vascular bed rather than beingembolic in origin (Figures 6b and c).

High-resolution CT scanning providesvaluable information on lung paren-chyma, which can be abnormal in patientswith CHD because of bronchiectasis orhypoplasia. It may also detect parenchy-mal changes due to PAH, for example,ground glass changes, nodular opacities,and serpiginous intrapulmonary vessels.In those with chronic thromboembolicPH, it may also identify within the lungtissue hemorrhage, infarction, or a mosaicpattern (due to heterogeneous lung perfu-sion). High-resolution CT has a vital rolein identifying patients with pulmonaryveno-occlusive disease, where advancedtherapies might be harmful. The key fea-tures of this rare entity on CT are inter-

lobular septal thickening, ground glassshadowing, and adenopathy.

When contrast is enhanced, this tech-nique is particularly adept in the assess-ment of extracardiac features, particularlynative or surgically fashioned systemic topulmonary shunts. Collateral vessels arereadily identified. These include dilatedbronchial arteries (a feature commonlyseen in PAH) or bypassing vessels incases of pulmonary venous occlusion.

An analytic technique called fractalanalysis has been studied to determinewhether the degree of branching withinthe pulmonary arteries of children andyoung adults with PAH, half of whom hadCHD, could be used as a noninvasive

Figure 6: Computed tomography pulmonary angiograph of patient with AVSD and PAH. (a) The common AV valve andatrial and ventricular components of the AVSD are seen, the right atrium is dilated, and there is RV hypertrophy. (b)The main pulmonary artery is dilated and larger in cross-section than the ascending aorta. (b and c) Extensivethrombus is present in the branch pulmonary arteries (arrows).

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Figure 7: Representative examples of segmented pulmonary artery masks, and below them the derived skeletonizedrepresentations for patients with mild, moderate, and severe PH. (Reprinted with permission from Moledina S, deBruyn A, Schievano S, et al. Fractal branching quantifies vascular changes and predicts survival in pulmonaryhypertension: A proof of principle study. Heart. 2011;97:1245-1249.).

Figure 8: (A) Cardiovascular magnetic resonance still systolic frame from balanced steady-state free precession cineimage demonstrating a large PDA (asterisk) measuring 13 mm diameter. The pulmonary artery is severely dilatedwith maximum diastolic diameter 50 mm. The RV is severely hypertrophied. (B) A corresponding in-plane phasevelocity map is shown, and blood flow is demonstrated to be predominantly from the main pulmonary artery to theaorta in systole.

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measure of PH (Figure 7).34 This indexcompared well with conventional markersof disease severity such as functionalclass, 6-minute walk test distance, andindexed PVR, and predicted death amongthe cohort [HR 5.6 (95% CI 1.2 to 25; P �0.027)].

CARDIOVASCULAR MAGNETICRESONANCECardiovascular magnetic resonance hasthe major advantage of being able to im-

age in any plane with high spatial andtemporal resolution without requiring ion-izing radiation. As repeated examinationsbecome common, the latter characteristicis particularly beneficial for patients withPAH-CHD.

In order to optimize image quality,breath holding is required. This may beproblematic for some patients with PAH-CHD. In addition, pacemakers/devicescurrently represent a contraindication toroutine CMR.

CMR acquisition and subsequent anal-ysis of a stack of contiguous cine imagecovering the whole heart from base toapex provides the gold standard assess-ments of right and left ventricular size andfunction,35 especially so for heavily tra-beculated RVs. However, analysis re-mains operator dependent.

Using both cine imaging and in-planeflow mapping, intracardiac shunts can beeasily identified and quantified. By compar-ing the ratio of flow through the pulmonary

Figure 9: Typical flow patterns in the RVOT at different cardiac phases for a patient with manifest PH (A, D, and G), apatient with latent PH (B, E, and H), and a normal subject (C, F, and I). PA indicates main pulmonary artery; PV,pulmonary valve; and RV, right ventricle. At maximum outflow (A through C), flow profiles were distributedhomogenously across the cross sections of the main pulmonary artery in the manifest PH group (A), the latent PHgroup (B), and the normal group (C). In later systole (D through F), a vortex was formed in the manifest PH group(D). No such vortex could be found in the latent PH group (E) or the normal group (F). After pulmonary valve closure(G through I), the vortex in the PH group persisted for some time. In all cases, continuous diastolic blood flowupward along the anterior wall of the main pulmonary artery could be observed. (Reprinted with permission fromReiter G, Reiter U, Kovacs G, et al. Magnetic resonance-derived 3-dimensional blood flow patterns in the mainpulmonary artery as a marker of pulmonary hypertension and a measure of elevated mean pulmonary arterialpressure. Circ Cardiovasc Imaging. 2008;1:23-30.).

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artery to that in the aorta using flow map-ping, Qp:QS can be determined and aorticflow mapping can be used to determine car-diac output. Tricuspid and pulmonary regur-gitation can be assessed with cine imaging,through-plane and in-plane flow.

With the addition of contrast enhancedmagnetic resonance angiography, extra-cardiac shunts (Figures 8a and b) as wellas the pulmonary vasculature can be de-lineated.36 Septal motion can be qualita-tively noted on cine imaging just as inechocardiography.

Late gadolinium enhancement for myo-cardial tissue characterization has been ap-plied to PAH and typically demonstratesareas of enhancement at the RV-LV inser-tion points. Histological data, however, sup-port the concept that the myocardial disar-ray at these sites is a normal feature ofinsertion-region anatomy exaggerated inPH by the hypertrophy of the RV.37

Significant efforts have been given overto noninvasively assessing pulmonarypressures using CMR with indices such asRV mass,38 septal deviation,39 pulmonaryartery stiffness,40 and more recently4-dimensional flow patterns41 (Figure 9).Of the longer established measures, nonehas emerged as a reliable measure in pa-tients with PAH.42 Moreover, none havebeen routinely tested in a CHD populationwhere the presence of pre-existing RVhypertrophy, septal defects, shunts, andarterial abnormalities may confoundmany of these parameters.

In the setting of a hybrid CMR inter-ventional lab, PVR derived from the Fickmethod has been shown to be inaccuratein conditions of high pulmonary bloodflow or increased oxygen concentration.With promising results, the same tech-nique has been used to show that PVR canbe determined noninvasively in a smallcohort with mainly atrial and ventricularseptal defects. A pulmonary flow of 6.05l/min/m2 or a Qp/QS ratio �2.5/1 had aspecificity of 100% for predicting PVR of�3.5 Wood units/m2 on receiver-operatorcharacteristic analysis.43

CMR Assessment of Treatment andPrognosisThe main measure used in clinical prac-tice and as a trial endpoint in PAH is the

6-minute walk test. However, this hasfaced considerable criticism given its lim-itations and failure to demonstrate a rela-tionship with clinical endpoints. This hasspurred investigation into alternative sur-rogates, one of which has been RV massas assessed by CMR.44 This measure,when employed after medical and surgicaltherapies, has been shown to reflect im-provements in indices of remodelling.45

Cardiovascular magnetic resonance hasalso been used to prognosticate in patientswith PAH. Right ventricular dilatation46

and impaired systolic RV function47 as wellas increased degrees of pulmonary arterystiffness are predictors of a poor outcome inPAH. Unfortunately, data specific to PAH-CHD have yet to be published.

CMR in Eisenmenger SyndromeCardiovascular magnetic resonance inEisenmenger syndrome occasionally cor-rectly defines the precise nature and func-tional significance of the underlyingCHD. In surgically palliated patients,CMR can be used to assess the presenceand patency of surgical shunts. It is alsouseful for assessment of other relevantextracardiac features such as PDA or aor-topulmonary collaterals. The central pul-monary arteries should be imaged forpresence of aneurysmal dilatation, poorexpansibility, sluggish flow, and in siturather than thromboembolic pulmonaryarterial thrombus.48

CONCLUSIONIn summary, multimodality imaging playsa major role in assessing patients withPAH-CHD in terms of anatomy, physiol-ogy, presence, extent and progression ofPAH, and RV function. Different imagingmodalities come with strengths and weak-nesses, and physicians and imaging spe-cialists should be aware of their comple-mentary and prognostic role, as to providethe optimal therapy and outcomes for thepatient with PAH-CHD.

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