ECHOCARDIOGRAPHY (RM LANG, SECTION EDITOR)

Redefining the Role of Cardiovascular Imaging in Patientswith Pulmonary Arterial Hypertension

Benjamin H. Freed & Amit R. Patel & Roberto M. Lang

Published online: 12 February 2012# Springer Science+Business Media, LLC 2012

Curr Cardiol Rep (2012) 14:366–373DOI 10.1007/s11886-012-0253-2

Abstract While pulmonary arterial hypertension is a dis-ease primarily affecting the pulmonary vasculature, the rightventricle plays an integral part in the disease process.Although widely used, two-dimensional echocardiogra-phy is limited in visualizing the right ventricle and,therefore, assessment of its structure and function hasbeen largely subjective or invasive. Advanced imagingmodalities such as real-time three-dimensional echocar-diography and cardiovascular magnetic resonance overcomemany challenges of two-dimensional echocardiography andhave provided further insight into the pathophysiology ofpulmonary arterial hypertension. Indices of right ventricularfunction obtained from these noninvasive techniques arebeing assessed for their prognostic capabilities as wellas their ability to monitor response to pulmonary arterialhypertension–specific therapies. Future research is needed tocompare the accuracy, reproducibility, and prognostic value ofeach of these parameters to definitively establish the role ofcardiovascular imaging in the management of patients withpulmonary arterial hypertension.

Keywords Right ventricle . Pulmonaryarterialhypertension .

Cardiovascular imaging . Two-dimensional echocardiography.

Real-time three-dimensional echocardiography.

Cardiovascular magnetic resonance . Prognostic parameters .

Clinical end points

Introduction

Pulmonary arterial hypertension (PAH) is an insidious anddebilitating disease with no known cure. Without treatment,the estimated median survival is 2.8 years [1]. PAH encom-passes a group of diseases such as idiopathic PAH, familialPAH, and pulmonary hypertension (PH) associated withdrugs/toxins, connective tissue disease, congenital heart dis-ease, or HIV. All of these diseases are grouped together asPAH or World Health Organization Class I PH, because theyare thought to share a common pathophysiology thatincludes pulmonary arterial endothelial dysfunction, smoothmuscle and endothelial cell proliferation, and pulmonaryarterial vasoconstriction [2].

From a hemodynamic standpoint, remodeling of thepulmonary vasculature leads to increased pulmonaryvascular resistance and pulmonary arterial pressurewhich, in turn, induces right ventricular (RV) hypertrophy,dilation, tricuspid regurgitation, ischemia, and eventual RVdysfunction. From a clinical standpoint, patients with PAHprogressively become more short of breath, fluid overloaded,and unable to perform simple activities of daily living. Whilethis is a disease primarily of the pulmonary vasculature, thecause of death is usually RV failure [3].

Significant advances in our understanding of the patho-physiology of PAH in the last two decades have led tomultiple therapies that have improved quality of life anddecreased mortality. In this decade, 1-year survival rate is

B. H. Freed :A. R. Patel :R. M. LangSection of Cardiology, Department of Medicine,University of Chicago Medical Center,Chicago, IL, USA

A. R. Patele-mail: apatel2@medicine.bsd.uchicago.edu

R. M. Lange-mail: rlang@medicine.bsd.uchicago.edu

B. H. Freed (*)University of Chicago MC 5084,5841 South Maryland Avenue,Chicago, IL 60637, USAe-mail: benjamin.freed@uchospitals.edu

85% versus 68% in the 1980s [4]. Despite this significantimprovement in short-term survival, the long-term prognosisof patients with PAH remains poor [5]. Clinical managementof these patients is driven, in part, by the ability to predictsurvival and monitor response to therapy. Since the responseof the right ventricle to increased afterload is what determinesan individual patient’s symptoms and survival, the ability toimage the right ventricle, assess its structure, and quantify itsfunction is essential for the management of these patients.

To underscore the important role cardiovascular imaginghas in improving the course of this disease, an expert panelfrom the 4th World Symposium on Pulmonary Hypertensionwrote “…techniques that image the RV morphologic andfunctional change in the face of increasing outflow obstructioncan greatly advance our understanding of the disease” and“RV function has potent prognostic abilities, and it isreasonable to consider indexes of RV function as endpoints inpivotal clinical trials” [6].

Despite this, noninvasive imaging has had a limited rolein the management of patients with PAH. For example, in aneffort to better risk stratify these patients, a recentlypublished risk score was developed that included manywell-known hemodynamic and functional independentpredictors of adverse outcomes. The only echocardiographicimaging parameter used in this score was the presence of apericardial effusion [7••]. While known to be a powerfulindependent predictor of mortality in this patient population,it reveals little information on the pathophysiology of the rightventricle [8].

In terms of treatment, the primary end point in most ofthe major randomized placebo-controlled PAH-specifictherapy trials has been and continues to be the 6-minute walktest [9, 10]. Imaging parameters have rarely been used asprimary or secondary end points even though they would

likely provide greater insight into what effects drugs arehaving on the RV structure and function. In addition, as willbe discussed in detail later, imaging modalities such ascardiovascular magnetic resonance (CMR) provide suchexcellent reproducibility of RV measurements that usingCMR-derived parameters in future PAH-specific therapytrials will allow researchers to have to recruit lesspatients to detect a statistically significant change in a shorteramount of time [11•].

To understand the reason noninvasive imaging modalitieshave been relatively underutilized in this patient population,it is important to discuss the strengths and weaknesses oftwo-dimensional (2D) echocardiography (2DE), real-timethree-dimensional (3D) echocardiography (RT3DE), andCMR in terms of their ability to assess the right ventricleand provide parameters to predict adverse outcomes andmonitor response to therapy (Table 1). This article reviewsthe current role of these imaging modalities in the manage-ment of patients with PAH and discusses potentially newnoninvasive markers that may further contribute to ourunderstanding of this disease.

Two-Dimensional Echocardiography

One of the biggest reasons imaging has not had amajor impactin the care of patients with PAH is because the most widelyused imaging modality, 2DE, is quite limited when it comes tovisualizing the right ventricle. Unlike the left ventricle, theright ventricle has a complex crescent shape and its extensivetrabeculations makes it difficult to define the endocardialborder [12]. The retrosternal position of the right ventriclecan limit 2DE windows and the more dilated the right ventricleis, the more difficult it is to visualize the entire RV cavity.

Table 1 Strengths and weaknesses of imaging modalities in the assessment of RV size and function

Imaging modality Strengths Weaknesses

Two-dimensional echocardiography Widely accessible Limited acoustic windows

Least costly modality Load- and angle-dependant parameters

Rapid image acquisition Lack of standardized normal values for parameters

Facilitates diagnosis of PH Limited ability to quantify actual degree of dysfunction

Real-time three-dimensionalechocardiography

Accurate and reproducible RV assessment Limited acoustic windows

Rapid image acquisition Operator-dependent

Not widely available

Requires custom software for post-processing

Cardiovascular magnetic resonance Accurate and reproducible RV assessment Not widely available

Facilitates diagnosis of PH More costly and time consuming

Imaging is independent of patient’s body habitus Can provoke claustrophobia

Patients must lie completely supine

PH pulmonary hypertension, RV right ventricular.

Curr Cardiol Rep (2012) 14:366–373 367

Recognizing these challenges, the American Society ofEchocardiography (ASE) published comprehensive guide-lines in 2010 for the systematic assessment of the rightventricle using, primarily, 2DE [13••]. The document detailsa variety of RV parameters that can be used for the deter-mination of both RV structure and function. While it isoutside the scope of this article to discuss each RV measurein detail, the focus will be to describe a few parameters inthe context of predicting outcomes in patients with PAH andmonitoring response to PAH-specific therapy.

Prognostic Value of 2DE-Derived RV Parameters

Tricuspid annular plane systolic excursion (TAPSE) is anindirect measurement of RV function and is acquired byplacing an M-mode cursor through the tricuspid annulus inthe apical four-chamber view to measure the amount oflongitudinal motion of the annulus at peak systole [13••].Since the right ventricle primarily contracts in the longitu-dinal direction due to an abundance of longitudinal myocar-dial fibers, TAPSE is thought to be fairly accurate inassessing the contractility of the right ventricle. The prog-nostic role of TAPSE was tested in 47 patients with PAHwho were followed for 2 years for the primary end point ofmortality [14]. These authors found that patients with aTAPSE ≥ 18 mm were significantly more likely to survivethan those patients with a TAPSE less than 18 mm. In otherwords, for every 1-mm decrease in TAPSE, the risk of deathincreases by 17%. While TAPSE is easy to obtain, it issignificantly load- and angle-dependent and assumes thatthe displacement of a single segment represents the functionof the entire right ventricle [13••].

Another RV parameter that is described in the ASEdocument is the myocardial performance index, which iscommonly referred to as the Tei index. This measure is aglobal estimate of both RV systolic and diastolic functionand is obtained by calculating the sum of isovolumic con-traction and relaxation time divided by RV ejection time[13••]. It is acquired by using the pulsed Doppler methodor the tissue Doppler method. As a prognostic variable,patients with PAH who had a Tei index less than 0.83 hadsignificantly better survival than patients with a Tei index ≥0.83 [15]. While the Tei index is a powerful independentpredictor of outcomes in patients with PAH and its acquisi-tion is not affected by the complex geometry of the rightventricle, it can be challenging to acquire and unreliable inpatients with irregular heart rates [13••].

2D longitudinal strain, like TAPSE, assesses RV functionin the longitudinal direction by measuring percentagechange in myocardial deformation throughout the cardiaccycle [13••]. 2D longitudinal strain is obtained by using theDoppler or speckle tracking methods. The speckle trackingmethod measures changes in position of myocardial

acoustic markers (speckles) in relation to each otherthroughout the cardiac cycle [16]. The more negative thelongitudinal strain value, the greater the deformation of themyocardial fibers and the better the contractility. In a studyinvolving 80 patients with PAH, patients with an RVlongitudinal strain more negative than −12.5% weresignificantly more likely to survive than patients withan RV longitudinal strain more positive than −12.5%[17•]. In other words, for every 5% worsening in strain,the risk of death increased over threefold. UnlikeTAPSE, 2D longitudinal strain takes the whole rightventricle into account when measuring function but isload-dependent and requires customized software [16].

Utility of 2DE-Derived RV Parameters as ClinicalEnd Points

There are only a few studies evaluating the role of2DE-derived parameters as clinical end points in ran-domized, placebo-controlled PAH-specific therapy trials[8, 18]. In separate trials evaluating the effects of thenonselective endothelin receptor antagonist, bosentan,and the prostacyclin analogue, epoprostenol, treatmentwith these therapies showed improvement in a variety of2DE-derived RV measurements including RV end-systolicarea, curvature of the interventricular septum, and maximumtricuspid regurgitant jet velocity. Unfortunately, many of thesemakers are difficult to reproduce and have yet to be validatedin larger patient-population studies.

2DE is currently the most widely accessible and leastcostly imaging modality. While this imaging modality tech-nique produces independent, prognostic parameters of RVfunction that may serve as clinical end points in PAH-specific therapy trials, it is quite limited in providing a trulyaccurate and reproducible assessment of the right ventricle(Fig. 1). Furthermore, many of the 2DE-derived RVmeasurements are load- and angle-dependent, lack standard-ized normal values, and predominantly provide information asto whether the right ventricle is normal or abnormal ratherthan the actual degree of dysfunction.

Real-Time Three-Dimensional Echocardiography

Fortunately, cardiovascular imaging technology has improvedconsiderably in the last decade creating imaging modalitiesthat overcome many of the challenges of 2DE by providinggreater coverage than 2DE and real-time 3D data sets. RT3DEis one such imaging modality (Fig. 1). Matrix arraytechnology using transthoracic echocardiography (TTE)enables the rapid acquisition of full-volume 3D data ofthe right ventricle allowing more accurate and reproduciblemeasures of RV size and function than 2DE [19].

368 Curr Cardiol Rep (2012) 14:366–373

Accuracy and Reproducibility of RT3DE in Assessmentof the Right Ventricle

Our group previously published a multimodality study com-paring the ability of RT3DE, CMR, and cardiac computedtomography (CCT) to quantitatively assess the right ventricle

[20•]. The study included 28 patients referred for a clinicallyindicated CCT study (5 of whom had PAH). Whilevolumetric analysis of CMR images yielded the mostaccurate RV measurements among the three imagingmodalities, there was a strong correlation between RT3DEand CMR (0.89, 0.87, and 0.87 for end-systolic volume

Fig. 1 a Two-dimensional echocardiography modified apical four-chamber and end-diastolic short-axis view showing dilated RV withinterventricular septal flattening representing right ventricular volumeoverload. M-mode cursor through tricuspid annulus shows a “normal”TAPSE of 22 mm. b Three-dimensional echocardiography post-processing segmental analysis of the RV in the same patient showinginlet (green), outlet (yellow), and apex (pink). Three-dimensionalreconstruction of the RV shows an abnormal RVEF of 39%. c

Cardiovascular magnetic resonance short-axis plane of the right andleft ventricle at end-diastole in the same patient. Endocardial tracing(yellow line) of the RV from base to apex at end-diastole and end-systole show an abnormal RVEF of 41%. Note that apical slices andend-systolic short-axis slices are not pictured. LA—left atrium; LV—left ventricle; RA—right atrium; RV—right ventricle; RVEF—rightventricular ejection fraction; TAPSE—tricuspid annular plane systolicexcursion

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[ESV], end-diastolic volume [EDV], and ejection fraction[EF], respectively), with RT3DE only slightly underes-timating the volumes and EF (9 mL, 14 mL, and 2%for EDV, ESV, and EF, respectively). A recent meta-analysis of multiple studies examining the accuracy ofRV size and function confirms that this underestimationexists but it is not statistically significant. Interestingly,in this study, intra-observer and inter-observer variabilityfor RT3DE was somewhat lower than CMR (~10% vs12%). Although CCT slightly overestimated the volumesand EF, it also provided a highly accurate and repro-ducible analysis of RV volume and function.

The excellent accuracy and reproducibility of RT3DEis not diminished in patients with an abnormal rightventricle. Grapsa et al. [21] showed that, in 60 patientswith PAH who underwent CMR and RT3DE imaging onthe same day, RT3DE RV volume, function, and masscorrelated well with CMR measurements and were highlyreproducible.

It is clear that RT3DE rapidly and efficiently provides anaccurate assessment of the right ventricle that is far superiorto 2DE, but image acquisition is operator-dependent,specialized software is required for post-processing,and, similar to 2DE, the retrosternal position of theright ventricle sometimes limits the ability to achieveadequate TTE imaging windows. These weaknesses arelikely somewhat responsible for why, to the best of ourknowledge, there is no published data regarding theprognostic ability of RV parameters using RT3DE inpatients with PAH or the use of RT3DE-derived RVparameters as end points in clinical trials.

Cardiovascular Magnetic Resonance

CMR is a multiparametric imaging modality that can provideinformation related to several aspects of PAH such as assess-ment of RV size and function, assessment of myocardial tissuecharacteristics, and even assessment of the pulmonary artery“function” itself. Similar to RT3DE, CMR has been shown toprovide accurate and reproducible measurements of RV sizeand function and is, in fact, regarded by many as the referencestandard [22]. Imaging is typically accomplished by acquiring aseries of sequential cines spanning the entire right ventricleusing the steady-state free precession pulse sequence. Breath-hold times are minimized by implementing parallel imaging.The 3D CMR data set allows complete coverage of the RVinflow, RVapex, and RVoutflow regardless of ventricular sizeor shape. The short-axis imaging plane is used most often foranalysis; however, some authors advocate imaging in the axialplane because it potentially provides better measurement repro-ducibility [23]. RV EDVs and ESVs are calculated using themethod of disk by tracing the RV endocardium in each slice

spanning from base to apex at the point of the cardiac cyclewhere the right ventricle has the largest and smallest cavity,respectively (Fig. 1). RV mass is calculated by multiplying themyocardial volume by the specific density of myocardium(1.05 g/cm3) and right ventricular ejection fraction (RVEF) iscalculated by using the standard formula [(RVEDV–RVESV)/RVEDV *100] [24]. More recently, techniques such as lategadolinium enhancement are being used to characterizethe extent of myocardial damage or fibrosis that occursin some of these patients. Other techniques, such asvelocity-encoded imaging, provide insights about thefunction of the pulmonary artery itself via measurements suchas pulmonary artery pulsatility.

Accuracy and Reproducibility of CMR in Assessmentof the Right Ventricle

The reproducibility of RV volumes, EF, and mass usingCMR was recently examined in 60 patients (20 with normalright ventricle, 20 with dilated right ventricle due to an atrialseptal defect, and 20 with dilated right ventricle due toTetralogy of Fallot) [11•]. The inter- and intra-observercomparisons of the right ventricle were excellent for RVvolume, good for RVEF, and fair for RV mass. Most impor-tantly, these authors found that for a randomized controlledtrial with a power of 80% and a P value of 0.05, only 34patients were required to detect a 10-mL change in RV EDV,3% change in RVEF, and a 10-g change in RV mass. Anotherstudy showed that, in 111 patients with PAH who underwentCMR and 6-minute walk test at baseline and 1 yearlater, a 10-mL increase in stroke volume was clinically rele-vant because it correlated with an increase in 6-minute walkdistance by greater than 41 m [25•]. Although somemight argue if a change in 6-minute walk distance by41 m is clinically meaningful, it is clear that the repro-ducibility of CMR is excellent, permitting fewer patientsand shorter follow-up to detect statistical changes inclinical trials.

Prognostic Value of CMR-Derived RV Parameters

There are very few publications regarding the use of CMRas a tool for providing noninvasive predictors of survival inpatients with PAH. In 2007, van Wolferen et al. [26]reported that, in 64 patients with PAH who underwentCMR imaging at baseline and after 1 year, CMR-derivedparameters of RV function such as stroke volume index, RVEDV index, and left ventricular EDV index were all indepen-dent predictors of mortality. RV mass index trended in thatdirection while other authors found that a ventricular massindex (ratio of right and left ventricular end-diastolic mass) of≥ 0.7 predicted significantly worse 1- and 2-year outcomes[27]. Additionally, Gan et al. [28] found that, in 70 patients

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with PAH who underwent CMR imaging at baseline,pulmonary artery pulsatility (relative change in pulmonaryartery lumen area during cardiac cycle) was a strong,independent predictor of adverse outcomes in this patientpopulation.

Several studies have reported that, when using contrast-enhanced CMR in patients with PAH, late gadoliniumenhancement of the RV insertion points strongly corre-lated with multiple indices of RV function [29–33]. Ourgroup found that the presence of late gadolinium en-hancement of the RV insertion points was a marker formore advanced disease and poor prognosis in patientswith PH [34]. We also found that CMR-derived RVEF,much like nuclear-derived RVEF, is an independentnoninvasive imaging predictor of adverse outcomes inthis patient population [35, 36]. Recently, van de Veerdonk etal. [37••] confirmed that, in 110 patients with newlydiagnosed PAH, CMR-derived RVEF measured at base-line was an independent predictor of mortality. In addi-tion, they found that even though pulmonary vascularresistance measured at baseline was also predictive ofmortality, after a year of PAH-targeted therapy, onlychanges in RVEF were associated with survival. Thisfinding suggests that RVEF, as measured by CMR, is aclinically important determinant of prognosis.

Utility of CMR-Derived RV Parameters as ClinicalEnd Points

Regarding the use of CMR-derived parameters for clin-ical end points, Wilkins et al. [38] showed that patientswho were randomized to receive sildenafil, a phospho-diesterase inhibitor, had a significant decrease in RVmass of 8 - 9 g in the first 4 months of treatmentcompared to patients who received bosentan. Whethersildenafil decreased RV mass via direct cardiac effectsor through decreasing RV afterload is not entirely clearbut the continued use of CMR-derived imaging parameters asend points in PAH-specific therapy trials will likely help inanswering these questions.

The inherently 3D nature of CMR makes it much moreconducive to measuring the complex geometry of the rightventricle compared to 2DE. Unlike echocardiography ingeneral, CMR is not limited by good acoustic windowsand can accurately assess the RV geometry regardless ofhow abnormal it is. In addition, although right heart cathe-terization is still the gold standard for diagnosing PH, CMRcan help facilitate the diagnosis by noninvasively locatingand quantifying intra- and extracardiac shunts as well asidentifying chronic thromboembolic disease. Of course,CMR has its own limitations. Unlike echocardiography, itis expensive and not widely available. Data acquisition andpost-processing can be time consuming and the need for

patients to lie flat in the scanner can be somewhat challenging.However, with improved technology, many of the parametersmentioned above can be attained in almost the same amountof time as a standard 2DE.

Noninvasive Markers for the Future

The application of advanced imaging technology to patientswith PAH has allowed further mechanistic insights into thepathophysiology of this disease. New noninvasive markersare being identified that clearly discriminate patients withdisease versus patients without disease and even allow thedifferentiation between different severities of the disease.Several of these markers are mentioned below. The prognosticcapabilities and the use of these parameters as clinical endpoints have yet to be tested.

Although abnormal interventricular septal motion is awell-known sign of increased pulmonary artery pressureand predicts poor outcomes in patients with PH, it isnot used to quantify the severity of disease. Usingdynamic 3D analysis of septal curvature from CMR,our group was able to show that the curvature valueprogressively decreased with the severity of PH, discriminat-ing patients with no PH and mild PH from patients withmoderate to severe PH [39]. This curvature value correlatedvery well with invasive measurements of PH and had bettercorrelation than when we applied the same method using 2Dimaging.

Another marker exploits the right ventricle and pulmonaryvasculature relationship. Normally the right ventricle ejectsblood into a highly distensible and low impedance pulmonarycirculation. In PH, pulmonary vessel remodeling leads toincreased vessel stiffness that elevates RV pulsatileworkload and decreases RV contractility [40]. Sanz etal. [41] reported that, although patients with exercise-induced PH have normal pulmonary pressures at rest,CMR-derived measurements of pulmonary artery stiff-ness are significantly decreased compared to patientswithout PH. This suggests that indices of pulmonaryartery stiffness might be used to detect PH before overtchanges in pulmonary pressures.

Much like 2D longitudinal strain using speckle-trackingtechniques, CMR is also able to measure RV longitudinalstrain using strain-encoded imaging. Shehata et al. [42]showed that, using a pulse sequence that is able torapidly quantify RV longitudinal strain in a single heartbeat, patients with PH have significantly reduced peaksystolic longitudinal strain in the basal, mid, and apicalregions of the right ventricle compared to patientswithout PH.

RV perfusion and metabolism using noninvasive imagingtechniques have also been studied as potential markers of

Curr Cardiol Rep (2012) 14:366–373 371

disease in patients with PH. In one study, RV perfusionwas assessed using adenosine-stress CMR. The RVmyocardial perfusion reserve was significantly decreasedin patients with PAH versus patients without PAH [43].In another study, RV perfusion and metabolism wasassessed using positron emission tomography in 16patients with PAH [44]. Using 13N-NH3 for perfusionimaging and 18F-FDG for metabolic imaging, theauthors found that myocardial blood flow was reducedand myocardial glucose uptake was significantly increased inpatients with PAH.

Conclusions

The right ventricle plays a central role in the patho-physiology of PAH. The inability to accurately measureRV size and function by 2DE has made it particularlydifficult to use these parameters as predictors of adverseoutcomes or end points in PAH-specific therapy trials.In its place, clinical trials often utilize parameters suchas the 6-minute walk test, which is effort-dependent,and becoming a less valuable surrogate [45], and rightheart catheterization, which is still the gold standard butan invasive procedure.

The identification of RV parameters that are nonin-vasive, accurate, reproducible, easy to obtain, assessprognosis, and monitor response to therapy are essentialfor comprehensive risk stratification and for providingclues as to how PAH-specific drugs are affecting theheart. Advanced imaging modalities such as RT3DE andCMR allow the visualization of the right ventricle inways that have dramatically improved our understandingof a variety of cardiovascular diseases and have thepotential to provide many of these sorely neededparameters.

There are still many limitations to the use of RT3DEand CMR, and multimodality studies comparing thereproducibility and prognostic power of a variety ofright heart parameters from 2DE, RT3DE, and CMRare necessary. A direct comparison of these parametersis needed in an effort to streamline studies and providephysicians with the best noninvasive test for thispatient population. Either way, the role of cardiovascu-lar imaging in assessing RV structure and function israpidly evolving and its inclusion in the management ofPAH will undoubtedly help in improving outcomes inthese patients.

Disclosure Conflicts of interest: B.H. Freed: none; A.R. Patel:has received grant support from Astellas; and has receivedspeaking fees from the Medical Education Speakers Network (MESN);R.M. Lang: none.

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