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Image-guided left ventricular lead placement in cardiac resynchronization therapy: focused on image fusion methodsPremysl Hajek 1 *, Iva Safarikova 1, 2, Jan Baxa 3

1 Ceske Budejovice Hospital, Department of Cardiology, Ceske Budejovice, Czech Republic2 University of South Bohemia in Ceske Budejovice, Faculty of Health and Social Sciences, Budejovice, Czech Republic3 Charles University in Prague, University Hospital and Faculty of Medicine in Pilsen, Department of Imaging Methods, Pilsen, Czech Republic

AbstractCardiac resynchronization therapy is an effective and widely accessible treatment for patients with advanced, drug-refractory heart failure. It has been shown to reverse maladaptive ventricular remodeling, increase exercise capacity, and lower hospitalization and mortality rates. However, there still exists a considerable proportion of patients who do not respond favorably to the therapy. Tailored left ventricular (LV) lead positioning instead of empiric implantation is thought to have the greatest potential to increase response rates. In our paper, we focus on the rationale for guided LV lead implantation and provide a review of the non-invasive imaging modalities applicable for navigation during LV lead implantation, with special attention to the latest achievements in the field of multimodality imaging and image fusion techniques. Current limitations and future perspectives of the concept are discussed as well.

Keywords: Cardiac resynchronization; Coronary sinus; Guided implantation; Image fusion; Mechanical activation; Multimodality imaging; Myocardial scar; Non-responder

Highlights:• Despiteitsgeneralefficacy,cardiacresynchronizationtherapyfailsin30–50%ofpatients.• Tailoredleftventricularleadimplantationisconsideredthemostpromisingmeasuretotakefulladvantageofthetherapy.• Conventionalimagingprovideslimitedinformation;onlymultimodalityimagingandimage-fusionprovideeffectiveguidance.• Withalternativeapproachestoresynchronization,thereisanurgentneedforcomprehensiveimaginginclinicalpractice.

Abbreviations:2D,two-dimensional;2Y,2-yearfollow-up;3D,three-dimensional;3D-RTE,three-dimensionalrealtimeechocardiography; 6M,6-monthfollow-up;AHR,acutehemodynamicresponse;AV,anteriorveinsoftheleftventricle;CMR,cardiacmagneticresonance;CRT,cardiacresynchronizationtherapy;CS,coronarysinus;CT,computedtomography;CX,circumflexartery;EDV,end-diastolicvolume;EF,ejectionfraction;ESV,end-systolicvolume;HF,heartfailure;ICM,ischemiccardiomyopathy;LA,leftatrium;LAD,leftanteriordescendingartery;LAO,leftanterioroblique;LBBB,leftbundlebranchblock;LEAA,latestelectricallyactivatedarea(s); LGE,lategadoliniumenhancement;LMAS,latestmechanicallyactivatedsegment(s);LV,leftventricle/ventricular;LVESV,leftventricularend-systolicvolume;MDCT,multi-detectorcomputedtomography;MPI,myocardialperfusionimaging;MRI,magneticresonanceimaging;PET,positronemissiontomography;RA,rightatrium;RAO,rightanterioroblique;RCT,randomized,controlledtrial;RV,rightventricle/ventricular;SDI,systolicdyssynchronyusingendocardialtrackingofCMRcineimagesinshortandlongaxis;SPECT,singlephotonemissioncomputedtomography;SQUEEZ,StretchQuantifierofEndocardialEngravedZones;SSFP,steadystatefreeprecision;STE,speckletrackingechocardiography;TEE,transesophagealechocardiography

* Author for correspondence:PremyslHajek,CeskeBudejoviceHospital,DepartmentofCardiology,B.Nemcove585/54, 37001CeskeBudejovice,CzechRepublic;e-mail:premek.hajek@email.czhttp://doi.org/10.32725/jab.2019.019Submitted:2019-08-18•Accepted:2019-10-30•Prepublishedonline:2019-11-13JApplBiomed17/4:199–208•EISSN1214-0287•ISSN1214-021X©2019TheAuthors.PublishedbyUniversityofSouthBohemiainČeskéBudějovice,FacultyofHealthandSocialSciences. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense.

Reviewarticle

Introduction

Since the first resynchronization device became commercially availableintheUnitedStatesin2001,cardiacresynchroniza-tion therapy (CRT) has evolved into an effective andwidelyaccessible treatment option for patients with drug-refractory heart failure (HF) (Abraham et al., 2002). Despite advances

in technology and implantation techniques, there still exists a substantial proportion of patients who do not respond fa-vorably to the therapy in terms of functional improvement or reversal of maladaptive remodeling, with the latter being emphasized as the only reliable surrogate metric for assess-ing clinical outcomes (Groenning et al., 2000).The reportedrates of these non-responders vary depending on the criteria usedbutareestimatedtobe30–50%(AuricchioandPrinzen,

J Appl BiomedDOI:10.32725/jab.2019.019

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2011).Strategiesforachievinghigherresponseratesfocusonseveral issues: candidate selection, optimal device program-ming, and appropriate left ventricular (LV) lead positioning. Among these, improving the latter is perceived as having the greatestpotentialbenefits(Daubertetal.,2017).

 Fig. 1.ComprehensiveimaginginCRTimplantation.Eachcirclerepresentsanindividualtaskforthepreoperativeimaging,withapplicablemodalitieslisted.Inthecentre,therearemethodsthatprovidemultiplepiecesofinformationfromasinglestudy:CTandCMR,albeitthelatterprovidesonlylowqualitydelineationoftheCStributaries.X-MRIisanexampleoftechnologythatenablesfusionofaCMR-derived3Dmodelwithfluoroscopyvenograms.ThefusionofvenogramswithMPI-derivedmodelsisalsoclinicallyapplicable.Distinctivecombinationsofmodalitiesevaluatedinclinicaltrials are as well mentioned (multimodality imaging).

In this paper, we provide a review of multimodality imag-ing and image fusion techniques applicable for implantation navigation(Fig.1).

Current approach to CRT-delivery and rationale for guided implantation

Limitations to empiric left ventricular lead implantationTheprerequisite for the restorationof energetically efficientcontraction is compensation for altered electrical wave prop-agationthroughtheventricles.Thiscanbeeffectuatedbysi-multaneous stimulation of the right ventricle (RV) and thelatestelectricallyactivatedarea(LEAA)oftheLV(Abrahametal.,2002).Findings fromearlyhemodynamic studiesaswellas randomized, controlled trials suggest that the lateral and posterolateral aspects of the mid-ventricular or basal portions of the LV, supposedly harboring the LEAAs, are optimal forLVpacing(Brignoleetal.,2013;Butteretal.,2001;Dekkeretal.,2004;Kutyifaetal.,2013;Singhetal.,2011).Withmoredata available, however, it has become obvious that this guide-lines-endorsedapproachdoesnotworkforallCRTrecipients(Dekkeretal.,2004).

Major determinants for the effective resynchronizationTheoverallmyocardialscarburdenaswellashighscardensitycorrelates inversely with LV functional improvement and are predictiveofworseoutcomes(AdelsteinandSaba,2007;Adel-steinetal.,2011;Ypenburgetal.,2007a).Thismayresultfromthe paucity of contraction-capable tissue but is mainly caused by impaired electrical wave front propagation (Lambiase et al., 2004).ScardistributionwithrespecttoLVleadpositionisalsoofconsiderable importance(Chaliletal.,2007).Bynon-con-tact endocardial mapping, areas with low amplitude signals and low conduction velocities were identified (Ypenburg etal.,2007b).Pacingatthesesitesthatcorrespondedtoscarred

myocardiumandactuallyrepresentedLEAAs,wasassociatedwithQRSprolongationand it failedtorestoresynchronicityunless the LV stimulus preceded theRV stimulation by 30– 40ms(Bleekeretal.,2006;Ypenburgetal.,2007b).

In a study of 559patients, Leyva et al. (2011) used lategadolinium enhancement cardiacmagnetic resonance (LGE-CMR) in209 to guideLV leadplacement away fromfibrotictissue. Compared with patients paced at viable myocardium, patients in whom the LV lead was placed over scarred tissue had thehighest riskof cardiovasculardeath (HR=6.34), aswell as the composite endpoint of all-cause death or hospital-izationformajorcardiacevents(HR=4.74).Inthenon-scarpaced group, a scar tissue burden of less than the cut off value of10%waspredictiveofbetterclinicaloutcomes.Inaddition,fibrosis of the segments adjacent to the target segment may alsointerferewithafavorableresponse(Adelsteinetal.,2011;Beckeretal.,2011).

Since it is not feasible, in routine practice, to determine electrical wavefront propagation and LEAAs non-invasively,the mechanical activation sequence, traced by echocardiog-raphy-based methods, CMR, or myocardial perfusion imag-ing (MPI), serves as a surrogate for the electrical potential spread. Available evidence is derived mainly from two rand-omized, controlled trials – TARGET and STARTER (Khan etal., 2012; Saba et al., 2013) – that used 2-dimensional (2D)speckletrackingechocardiography(STE)radialstrainanalysisto guide LV lead implantation towards the late mechanically activated segment (LMAS). In theTARGET trial, the guidedimplantation was associated with a reduction of LV end-sys-tolicvolume(LVESV)by>15%in70%ofpatients,whereasinthestandard-implantationgroup,itwasseeninonly55%of

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cases.Thisimpliesthatabout7patientshavetoundergoguid-edimplantationtogainoneadditionalresponder(Khanetal.,2012). IntheSTARTERtrial (Sabaetal.,2013),patientsas-signed to guided implantation experienced less clinical events (combined endpoint of all-cause death and HF-related hos-pitalization)by26%atthe2-yearfollow-up.Thiswasdrivenmainlybyareductioninthehospitalizationrate(HR=0.48, p = 0.049). None of the trials showed a benefit for guided LV lead implantation relative to mortality.

MPI by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) representsan accessible alternative to echocardiography-based approach-es. The tracer (thallium-201 or technetium-99m in SPECT,18-fluorodeoxyglucoseinPET)count-variationtemporalanal-ysis produces time-activity curves for each sample volume, permitting a phase-polar map of mechanical activation to be constructed (Phase Analysis Technique)(Chenetal.,2008).

Besides the myocardial viability and activation pattern, suitable coronary venous anatomy is an essential precondition for successful guided (as well as non-guided) LV lead delivery.

Thenumber and trajectories of coronary veins are acknowl-edgedtobehighlyvariable,withanaverageof2–5potentiallysuitable coronary sinus (CS) first-order tributaries, i.e., those of acceptable diameter, subtending the posterolateral aspects ofLV,mostoften recognizedby theauthors–Fig.2 (Chris- tiaensetal.,2008;Jongbloedetal.,2005;Spenceretal.,2014;VandeVeireetal.,2006).Therearealsostudiesdemonstratingthat more than one suitable vein is present in less than half of thepatientsundergoingCRTimplantation(Khanetal.,2009),and in almost one-third, no suitable vein is found that sub-tends theempiricallyoptimal regions (Spencer et al., 2014).Withoutpreoperativeimaging,theactualnumberandcourseof the vessels remain unknown to the implanter until the CS is cannulated and a contrast venogram is obtained, which pre-cludes an optimal strategy being determined prior to the pro-cedure. A comprehensive evaluation of the coronary venous system with computed tomography (CT) would help to assess the patient’s suitability for transvenous implantation and pre-dict technical difficulties that might arise from unfavorableanatomy(Fig.2).

 

Fig. 2. 3Dreconstructionofthecoronaryvenoussystem.Posterolateral(a) and superior (anterolateral aspect of the left ventricle) (b)views.Thefirsttributary of the coronary sinus (CS) is the posterior interventricular vein (PIV, or middle cardiac vein), running in the posterior interventricular groove. In this example, the posterior veins of the left ventricle (PVLV) are represented by a couple of subtle tributaries, not suitable for lead deployment. Note the acute angulation (on the lateral view (c) which may preclude successful deployment of the lead into the left lateral vein (LLV) that subtends the empiricallyoptimalposterolateralaspectoftheLV.Thegreatcardiacvein(GCV)continuesastheanteriorinterventricularvein(AIV)intheanteriorinterventricular groove.

a b c

Comprehensive imaging to facilitate optimal site selection during CRTIt is obvious that a combination of imaging modalities is need-ed for effective and unrestricted guidance. Generally, three dis-tinct concepts of comprehensive imaging have been proposed and evaluated: multimodality imaging, methods deriving all the relevant information from single imaging study (one-stop shops),andreal-timeimagefusion(Fig.1).

Multimodality imagingMultimodality imaging refers to the complementary use of mostly echocardiography-based methods to define the LMAS, plus one or more other imaging modalities to provide informa-tionontissueviabilityand/orcoronaryvenousanatomy.Thepreoperatively obtained data can be put together to determine the target position, which is usually displayed on a polar plot map.The implantation itself is, however, performedusing astandard,plainfluoroscopiccontrol,withthepolarplotmapserving as only indirect navigation tool.

Inanobservationalstudyof100consecutivepatients(Ber-tinietal.,2016),STE longitudinal strainwasused todefinethemostdelayedsegmentandLGE-CMRtoavoidfibrosis.At6months,78%ofpatientsfromtheguidedgroupreverse-re-

modeled, compared to 56% in the standard-implantationgroupand54%vs.32%ofthepatientswereclassifiedassu-per-responders(LVESVreduction≥30%).Ofnote,quadripolarleadswereusedmoreoftenintheguidedgroup(64%vs.10%).

In a randomized, controlled trial, Sommer et al. (2016)evaluated the superiority of guidance towards the LMAS sep-aratefromscar,asdefinedbySTEradialstrainandSPECT,re-spectively.Thiswassupplementedbya3DCTreconstructionof the coronary venous system (n=89).Notably,inthecontrolgroup (n =93),the“routine”CRTimplantationwasguidedbyleftventricularelectricaldelay (QLV).Asaresult, thedistri-bution of concordant and adjacent LV leads was comparable betweengroups(99%vs.98%)aswellasQLVvalues.Therateofnon-response,mainlyintermsoffailuretoimproveNYHAclassortoincreasethesix-minutewalkdistance,was26%intheguidedgroupcomparedto42%inthecontrolgroup(ORfornon-response=2.29;p=0.02).Nodifferencewasobservedregarding the combined end-point of all-cause death and HF-hospitalizationorreverseremodeling.

One-stop imaging shops for CRT-guidanceThemost promising alternative tomultimodality imaging iscardiacCT.NuclearimagingandCMRarealsocapableofpro-

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viding multiple pieces of information from a single imaging study, albeit the visualization of CS branches is of lower quali-ty(Maetal.,2012;Zhouetal.,2014).

Conventional viability assessment using cardiac CT relies onasimilarpremiseasCMR,i.e.,thealtereddistributionofprimarily extracellular, interstitial contrast agent with com-parable kinetics (iodine as well as gadolinium). However, apart from being highly susceptible to inadequate contrast agent dosing, late-enhancement imaging fails to reliably de-lineate chronic scarring. In this context, evaluation of rela-tive hypoperfusion on the first-pass contrast scan and local wall thickness <6mmhas been shown (Behar et al., 2017a;Mendozaetal.,2010)tobemoresensitive.CurrentCTscansenable the analysis of regional wall deformation by tracing endocardial-surface features (trabeculae), depicted inversely as a  surface of contrast-enhanced 3D blood cast. Followingimage acquisition, an endocardial-surface mesh consisting of multipletriangularpatchesisgenerated.Displacementofthevertices in each of the patches is tracked over the cardiac cycle, which allows changes in the surface area to be calculated and expressedusing ametric called SQUEEZ (StretchQuantifierof Endocardial Engraved Zones) (Pourmorteza et al., 2012).RegionaltimedelaytopeakSQUEEZE-derivedstrainforeachsegment is measured to define the LMAS with a temporal res-olution of 70–100 ms. (For comparison, echocardiographyandCMRprovideresolution20msand35–50ms,respective-ly.)The tissue is consideredviable if theSQUEEZamplitude>10%. Deploying the LV lead into the vein subtending theCT-derivedtarget in18patientswhoweresubjectstoaCRTupgradewith an existing pacing system resulted in anAHRrateof92%(a 10%increaseincontractility(LVdP/dtmax)). In 70%of cases, theCT-SQUEEZtarget correspondedwith thesiteofthebestachievableAHRofalleligiblevenoustargets.At6months,clinicalimprovementwasseenmoreoften(90%vs.

60%) inpatientspacedatCT-SQUEEZtargets (Pourmortezaetal.,2012).

Image fusion techniquesSimplevisualcorrespondencewasusedinthelandmarkTAR-GETandSTARTERtrials(andthemajorityofothers,includingthe discussed multimodality imaging studies) to match the bi-planefluoroscopicviewwiththerespectiveechocardiogra-phic projection.This approach inevitably leads to inaccuratealignment of the coronary veins with the myocardial surface (Fig. 3).AsdemonstratedinastudywithCT,theoverallagree-mentwiththeleadpositionclassification,onthebasisoffluo-roscopy,wasonly35%forLVleadsandonly22%forRVleads(Sommeretal.,2014).InterobserveragreementonLVandRVlead positions was poor, and the situation may be even wor-se in patients with extensively remodeled and rotated hearts (Singhetal.,2005).Partlyduetotheseconstraints,target-leadconcordance was achieved in only a limited number of patients intheprincipaltrials(64%and30%forTARGETandSTAR-TER,respectively,asanexample)(Khanetal.,2012;Sabaetal.,2013).Onthecontrary,co-registrationofthe3Dechocar-diography-derived endocardial shell, containing information onwallmotion,with the3D reconstructionof the coronaryvenogram, obtained through high-speed rotation angiography in37subjects toCRT implant, the concordance rateof97%wasachieved(Döringetal.,2013;Tournouxetal.,2007).

A precursor of real-time image integration is represented byasimultaneousprojectionofaLGE-CMRderived interac-tive3D,color-coded,surface-renderednavigationalmodelandthematchedfluoroscopicview(Laksmanetal.,2014).Analyz-ing the data according to a pre-specified algorithm, the soft-ware provided information about the suitability of individual segments forbothRVandLV leaddeployment: theRV leadwas placed toward the apex (or away from scar), with the tar-

 

Fig. 3. Anexampleillustratingtheimprecisionof2Dvisualizationof3Dstructures.Coronaryvenousreconstructionwithcommonleftventricularsegmentclassificationandcorresponding2Dfluoroscopicviews.

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get for the LV lead being determined by assessing (1) the low-est local scar burden, (2) the greatest mechanical delay, and (3)  the distance from the RV lead.With this approach, the LV lead was successfully delivered to the prescribed or immedi-atelyadjacentsegmentin97%ofcases(30of31patients).Re-verseremodelingcriteria (LVESVreduction≥15%)weremetin74%ofpatients,while58%metthesuper-responsecriteria(LVESVreduction>30%)(Laksmanetal.,2014).

The feasibility of fusing a 2D fluoroscopic viewwith 3DCMR-deriveddataregardingcardiacanatomy(i.e.,myocardialsurface segmentation, scar distribution, and transmurality), and coronary venous anatomy along with information on the LMASwastestedinacohortof21subjects(Maetal.,2012).Whereasamodelofallfourchamberswascreatedautomati-cally, reconstruction of the CS required manual segmentation. The cine steady-state free precision (SSFP) sequences wereperformed for motion analysis on the basis of regional volume changes, and delayed-enhancement imaging for automated scardelineation.The3DroadmapwasmanuallyregisteredtoliveX-raydatausingmultipleviewsofacatheterloopedintherightatriumandaleadintheRVasregistrationfeatures,en-suringcorrectspatialorientation.Thealignmentoftheoverlaywas maintained automatically throughout the procedure. Nev-ertheless,guidancebasedonthe3Dimageprojectedasa2Dmono-plainX-rayviewdoesnotallowtheactualpositionoftheLV lead to be easily appreciated. To overcome the constraints inherenttoplain2Dvisualizationofa3Dstructure,thesoft-waretransformsthe3Droadmap intoaclassic2Dbull’seyeplot, depicting all the information critical for comprehensive navigation, including the principal tributaries of the CS and theactualleadposition.However,theCMR-derivedvisualiza-tion of the distal CS branches was of lower quality, particularly in the presence of atrial fibrillation or ectopic beats. Provided the image quality was satisfactory; a contrast venogram was notrequiredforimplantation(Maetal.,2012).

The effectiveness of themethod on invasivelymeasuredAHR and LV reverse remodeling was assessed by Shetty etal.(2013).Leadswereimplantedintargetsegmentsin15of20patients.Comparedtoanacuteresponserateof50%withempiricnavigation,CMR-based guidancewasnot associatedwitha significant increase in theacute response rate (60%).However,inonly2ofthe8patientswhofailedtoacutelyre-

sponddespitebeingpacedattheCMR-target,anypositionre-lated to better hemodynamic response existed. Of the patients whoshowed>15%LVESVreductionatthe6-monthfollow-up(60%),92%werepacedinthetargetsegment,whilethiswasthecase inonly50%ofnon-responders.Conversely,50%ofthe non-responders did not experience reverse remodeling de-spitebeingpacedinthepreferredsegment.Interestingly,AHRdid not necessarily predict reverse-remodeling at 6 months, sinceitwasachievedinonly71%ofacuteresponders.

The need for further work-flow optimization resulted inthedevelopmentoftheX-MRIfacilitythatincorporatesMRIscanner and a biplane angiography suite, connected to a ded-icatedworkstation(Beharetal.,2017b).Thekeyfeaturerep-resents an integrated software platform designed for rapid processing of comprehensive CMR data that is displayed asa 3Dmodelonabiplanefluoroscopy screen.Thewholepro-cessofanalyzingthedataandcreatingthe3Dmodelisfullyautomated, with an opportunity for the clinician to adjust the results after each step (anatomical segmentation, scar distri-bution, transmurality and burden, mechanical activation, and LMAS identification; CS anatomy is not part of the reconstruc-tion), and, more importantly, the process is completed while thepatientisbeingtransferredfromtheMRItotheelectro-physiology laboratory and is being prepared for implantation (Fig. 4).The3Dmodelisunfoldedintoacolor-coded16-seg-ment model bull’s-eye plot and the target segment selected by thephysician(Fig. 5).OncetheCSiscannulated,theepicardialand endocardial shells are fused with the occlusive coronary venogram(Fig.6).

Whereas in the preceding settings theCMRneeds to beperformed days or even weeks before the implantation owing to lengthy computational processing, the capacity of the cur-rent system permits the implantation to immediately follow image acquisition. Nevertheless, even with this cutting-edge technology,only71%oftheleadsweredeployedoverthetar-getsegments.Therestofthemwerepositionedatoradjacentto scarred tissue due to a lack of viable CS tributaries. It is noteworthy in this context that the detailed scar visualization allowed for the poles of multipolar leads to be directed away fromfibrosis.TheresultwasameandecreaseinQRSlengthof25ms(significant),but,beingafeasibilitystudy,itlacksanyoutcomeevaluation(Beharetal.,2017b).

Fig. 4. X-MRIimagingworkflow.Thefirststepinvolvestheautomatedsegmentationandmanualadjustmentoftheepicardialandendocardialslicestogeneratea3-dimensional(3D)mesh.Endocardialwallmotionistrackedoverthecardiaccycletogeneratevolumevs.timecurvesforthe16segments.Followingregistrationofthecinetolategadoliniumenhancementsequences,areasofmyocardialfibrosisareidentified,andbothscaranddyssynchronydataarereviewedandtargetsselected.The3Dshellisthenregisteredtothex-ray(XR)oncethepatientisonthecatheterlaboratorytableusingfiducialmarkers,whichshowupwhite(fromtheCMRsequences)andgraywithacentraldarkdot(leadball-bearing)onthex-ray.Verticalandhorizontaltranslationusingbiplanefluoroscopyisused,inadditiontorotationaboutthex,y,andzaxestolineupthemarkersasdemonstratedontherighthandpanel.Followingthisprocess,theCMR-derived3DmodelisregisteredtotheXRsystemandeveryfluoroscopiccinedemonstratestheepicardialandendocardial shell overlaid in the correct orientation.ReproducedwithpermissionfromElsevierduetotheCreativeCommonLicense(Beharetal.,2017b).

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Fig. 5. ProcessingoftheMRIdataset.ThisdisplayscreenisseenfollowingtheprocessingoftheCMRdatasetandismimickedonthelargescreeninthe catheter laboratory. Total scar burden calculated as a mean of all myocardial segments. (Top middle) Scar distribution denoted in gray upon an American Heart Association 16-segment model. (Top right)Scarburden(%scarpermyocardialsegmentvolume),displayedin5%ranges. (Bottom right)Scartransmuralitydemonstratingthemeantransmuralityfromendocardiumtoepicardium.Thosesegments>50%transmuralmyocardial fibrosis are also denoted in red. (Bottom left) Mechanical activation curves for the 16 segments, corresponding to the colors shown in themiddlepanels.Endocardialtrackingoftheleftventricleprovidesabsolutechangesinthevolumepersegment(ml,yaxis)overthecardiaccycle.Becausetheseareabsolutevolumechanges,theapicalsegmentsarealwaysatthebottombecausetheyhaveasmallerstartandendvolume.Whentheuser hovers over a segment in the top middle panel, the associated volume time curve appears in bold; in this case, the target posterolateral segment is shown. (Bottom middle)Targetselectionpanel.Uponreviewingthescarlocation,burden,transmurality,andmechanicalactivationcurves,targetsegments are chosen (seen here in white; basal anterior, mid-posterolateral).ReproducedwithpermissionfromElsevierduetotheCreativeCommonLicense(Beharetal.,2017b).

Fig. 6. CMR-DerivedImageOverlayWithTargetSegmentSelection. (Top left) Anteroposterior venogram with overlay ofCMR-derivedepicardial/endocardialshellwith16-segmentAmerican Heart Association model showing an anterior interventricularvein.The3DCMR-derivedshellhasthesame colors as displayed in the guidance platform as shown inSupplementalFigures1a2.Inferoseptal,anteroseptal,and anterior segments are colored in yellow, green, and blue, respectively. (Top right) left anterior oblique (LAO) 20venogramwithautomatedrotationandalignmentofthe16-segment model with the x-ray. Inferolateral veins are demonstrated. (Bottom left)LAO40projection.Positioningof a quadripolar left ventricular lead into a preselected target segment (green). (Bottom right)LAO40projection,alternateviewwithCMR-derivedscardistribution(red).Attempted positioning and pacing using left ventricular poles out of regions of scar.ReproducedwithpermissionfromElsevierduetotheCreativeCommonLicense(Beharetal.,2017b).

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Theconsiderableoverlayaccuracyofa3Depicardialsur-faceonaSPECTMPIwith3Dvenousanatomy,reconstructedfrom dual-view fluoroscopy venograms, was demonstratedbyZhouetal.(2014).Followingmanualidentificationofthemajor coronary veins on dual-view fluoroscopy venograms,vesselbifurcationsservedasfiducialmarkersfora3Drecon-

struction of the venous tree and interventricular grooves on a 3DSPECTimageaslandmarksforpropersurface-veinalign-ment(Fig.7).Theoveralldistance-basedmismatcherrorbe-tweenthefluoroscopicandcontrast-enhancedCTvenogramsregistered on SPECT imageswas 4.6 ± 3.6mm (range 0 to16.9 mm).

Fig. 7.SPECT-VeinNavigationToolKit.Majorleftventricular(LV)veinsweredrawnonfluoroscopicvenograms,reconstructedtoa3Dstructure,andfusedwithaSPECTLVepicardialsurface.Themidpartoftheanteriorvein(blue line) was aligned with the optimal segment (white).ReproducedandadaptedwithpermissionfromElsevier(Zhouetal.,2014).

Ludwig et al. (2015) recently presented technique thatmergesSPECT-deriveddataregardingviabilityandactivationtiming with CT images to create a comprehensive 3D sur-face-rendered model. Anatomically discrete regions of the cor-onary venous system were used as a fiducial system: by match-ing theMDCT venogram with a virtual venogram obtainedthrough continuous recording of the mapping catheter´s spa-tiallocation,anaccurateregistrationoftheSPECT-MDCTfu-sionimageisensured.MDCTalsoreliablydepictsthecourseofleftphrenicnerveovertheepicardialsurface.Themethodwasfound to be feasible, with acceptable procedural times.

Applicability of advanced imaging techniques in a clinical practiceThe concept of guided CRT implantation sounds appealingparticularly in specific subgroups of patients with ICM and/oraborderlinesurfaceECG(QRS130–150ms,anon-specif-ic ventricular conduction disturbance). Studies so far have consistently demonstrated the beneficial effect on functional, hemodynamic, and echocardiographic parameters when indi-vidual tasks, i.e., pacing an LMAS that is free from fibrosis, are accomplished.Fewrandomizedtrialshaveprovidedevidenceon favorable clinical outcomes. Table 1 summarizes the results of principal trials in terms of navigation success rates and clinical outcomes in comparison with control groups. None-theless, when the analyses are performed according to the in-tention-to-treat principle, the results suddenly lose their once impressiveshine.Reasonsforthismaybeasfollows:(1)10to15%ofpatientsconsideredforCRTarenoteligiblefortheim-aging study due to contrast agent allergy, renal disease, claus-

trophobia,etc.,(2)inanother10%ofpatients,unsatisfactoryimage quality prevents any advanced analysis, and, above all, (3) the preferred or neighboring segments are reached in only about two-thirds of patients, mainly due to lack of suitable venous tributary or because of technical constraints (i.e., lead instability, inadequate pacing threshold, phrenic nerve stimu-lation, etc.).

Apart from higher costs, other issues also come together to keep the concept from being adopted into clinical practice:• Thevastmajorityoftheadvancedmodalitiesutilizepur-

pose-built facilities and software platforms installed on workstations specially developed to investigational purposes. As such, they are currently not commercially available.

• Data post-processing and evaluation require speciallytrained clinicians, equipped with skills and expertise great-ly exceeding routine practice standards.

• Reproducibility of findings derived from these imagingstudies is limited by a substantial inter-individual vari-ability unless the data are analyzed in a fully automated process; notably, these are the most accessible modalities (e.g., echocardiography-based) that are particularly prone to misinterpretation.

• Data acquisition, synthesis, and interpretation arehuge-ly time-consumingprocesses.Therefore, for themajorityof centers outside of research institutions, it would not be feasible to perform the pre-implantation studies on a rou-tine. Broadening the spectrum of cardiac conditions sub-mitted to imaging may, however, offer a possible solution: CMRiscurrentlyacornerstoneintheevaluationalgorithm

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for severe myocardial dysfunction, so are cardiac CT and MPI for the non-invasive diagnosis of coronary artery dis-ease in selected patients. Adjustments of current protocols canyieldthedesiredinformation.Remarkably,acoronaryvenogram can be easily obtained at the venous phase of coronary angiography without the need of additional con-trast medium, and with only a slight increase in radiation exposure!

• Evenwhensuccessfullyadoptedintopractice,image-guid-edCRT implantationwould inevitably give rise tomanyimportant questions, e.g.: What should be the strategyoncenosuitablecoronaryveinisdetected?Whatshouldbethe acceptable distance from the target segment and when should the patient be assigned to epicardial surgery, which permitssite-selectiveLVpacing?Whatscarburdenthresh-old (and other fibrosis characteristics) should be therapy exclusion criteria for patients otherwise eligible according to the current clinical practice guidelines?

Conclusion and future perspectives

Non-invasive, image-facilitated navigation for guided LV lead placement inCRThas been shown to be a clinically feasibleapproach to take full advantage of the method’s potential. It is logistic and workup issues rather than a paucity of evidence, or technical constraints that actually impedes the concept from being implemented into routine practice. Although the data are not invariably convincing, there are specific populations that may particularly profit from tailored implantation: these are patients with ICM, non-specific conduction impairment, a history of previously failed implantation, or those who ini-tiallyfailedtorespond.Fromtheclinicalstandpoint,itmustfinally be acknowledged that alternative methods of stimula-tion, such as multipoint or multisite pacing, LV endocardial pacing, either conventional or leadless (wireless), may be able to compensate for suboptimal LV lead placement. At the same time, these techniques will allow for virtually unrestricted lead positioning – an advantage that can only be fully exploitedthrough tailored implantation.

Conflict of interestsNo relationships with industry and other entities are declared. Theauthorshavenoconflictofinteresttobedeclared.Nofi-nancial support was received.

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