Multimodality Imaging in Restrictive Cardiomyopathies: An ... · Multimodality Imaging in Restrictive Cardiomyopathies: An EACVI expert consensus document In collaboration with the

Multimodality Imaging in Restrictive

Cardiomyopathies An EACVI expert consensus

document In collaboration with the ldquoWorking

Group on myocardial and pericardial diseasesrdquo

of the European Society of Cardiology

Endorsed by The Indian Academy of

Echocardiography

Gilbert Habib12 Chiara Bucciarelli-Ducci3 Alida LP Caforio4 Nuno Cardim5

Philippe Charron67 Bernard Cosyns8 Aurelie Dehaene9 Genevieve Derumeaux10

Erwan Donal11 Marc R Dweck12 Thor Edvardsen1314 Paola Anna Erba15

Laura Ernande10 Oliver Gaemperli16 Maurizio Galderisi17 Julia Grapsa18

Alexis Jacquier19 Karin Klingel20 Patrizio Lancellotti2122 Danilo Neglia23

Alessia Pepe24 Pasquale Perrone-Filardi17 Steffen E Petersen25 Sven Plein26

Bogdan A Popescu27 Patricia Reant28 L Elif Sade29 Erwan Salaun30

Riemer HJA Slart3132 Christophe Tribouilloy33 and Jose Zamorano34

Reviewers Victoria Delgado Kristina Haugaa (EACVI Scientific Documents

Committee) and G Vijayaraghavan (Indian Academy of Echocardiography)

1Aix- Aix-Marseille Univ URMITE Aix Marseille UniversitemdashUM63 CNRS 7278 IRD 198 INSERM 1095 2Cardiology Department APHM La Timone Hospital Boulevard JeanMoulin 13005 Marseille France 3Bristol Heart Institute National Institute of Health Research (NIHR) Bristol Cardiovascular Biomedical Research Unit (BRU) University ofBristol Bristol UK 4Cardiology Department of Cardiological Thoracic and Vascular Sciences University of Padova Italy 5Multimodality Cardiac Imaging Department SportsCardiology and Cardiomyopathies Centre-Hospital da Luz Lisbon Portugal 6Universite Versailles Saint Quentin INSERM U1018 Hopital Ambroise Pare Boulogne-BillancourtFrance 7Centre de reference pour les maladies cardiaques hereditaires APHP ICAN Hopital de la Pitie Salpetriere Paris France 8CHVZ (Centrum voor Hart en VaatziektenmdashUZ Brussel 9Department of Radiology and Cardiovascular Imaging APHM Hopitaux de la Timone Pole drsquoimagerie Medicale 13005 Marseille France 10Department ofPhysiology INSERM U955 Universite Paris-Est Creteil Henri Mondor Hospital DHU-ATVB AP-HP Creteil France 11CardiologiemdashCHU Rennes amp CIC-IT 1414 amp LTSIINSERM 1099 ndash Universite Rennes-1 12Centre for Cardiovascular Science University of Edinburgh 13Department of Cardiology Center for Cardiological Innovation andInstitute for Surgical Research Oslo University Hospital Oslo Norway 14University of Oslo Oslo Norway 15Regional Center of Nuclear Medicine Department ofTranslational Research and New Technology in Medicine University of Pisa Pisa Italy 16University Heart Center Zurich Interventional Cardiology and Cardiac Imaging 19Zurich 17Department of Advanced Biomedical Sciences Federico II University Naples Italy 18Department of Cardiovascular Sciences Imperial College of London London UK19Department of Radiology and Cardiovascular Imaging APHM Hopitaux de la Timone Pole drsquoimagerie Medicale Aix-Marseille Universite CNRS CRMBM UMR 7339 13385Marseille France 20Department of Molecular Pathology Institute for Pathology and Neuropathology University Hospital Tuebingen Tuebingen Germany 21Departments ofCardiology Heart Valve Clinic University of Liege Hospital GIGA Cardiovascular Sciences CHU Sart Tilman Liege Belgium 22Gruppo Villa Maria Care and Research AntheaHospital Bari Italy 23Cardiovascular Department Fondazione Toscana G Monasterio CNR Institute of Clinical Physiology Scuola Superiore SantrsquoAnna Pisa Italy 24MagneticResonance Imaging Unit Fondazione G Monasterio CNRmdashRegione Toscana Pisa Italy 25Department of Advanced Cardiovascular Imaging William Harvey Research InstituteNational Institute for Health Research Cardiovascular Biomedical Research Unit at Barts London UK 26Division of Biomedical Imaging Multidisciplinary Cardiovascular ResearchCentre Leeds Institute of Cardiovascular and Metabolic Medicine LIGHT Laboratories University of Leeds UK 27University of Medicine and Pharmacy lsquoCarol DavilarsquomdashEuroecolab Institute of Cardiovascular Diseases Bucharest Romania 28CHU de Bordeaux Bordeaux France 29Baskent University Ankara Turkey 30Cardiology DepartmentLa Timone Hospital Marseille France 31Department of Nuclear Medicine and Molecular Imaging University of Groningen University Medical Center Groningen Hanzeplein 1Groningen The Netherlands 32Department of Biomedical Photonic Imaging University of Twente PO Box 217 7500 AEEnschede The Netherlands 33Department of

Corresponding author Tel 00 33 (0)4 91 38 75 88 Fax 00 33 (0)4 91 38 47 64 Email gilberthabib3gmailcom

European Heart Journal - Cardiovascular Imaging (2017) 18 1090ndash1091 POSITION PAPERdoi101093ehjcijex034

nloaded from httpsacadem

icoupcomehjcim

agingarticle-abstract181010903828464 by guest on 13 September 2018

Cardiology University Hospital Amiens Amiens France and INSERM U-1088 Jules Verne University of Picardie Amiens France and 34University Hospital Ramon y CajalCarretera de Colmenar Km 9100 28034 Madrid Spain

Received 9 February 2017 editorial decision 13 February 2017 accepted 14 February 2017 online publish-ahead-of-print 16 May 2017

Restrictive cardiomyopathies (RCMs) are a diverse group of myocardial diseases with a wide range of aetiologies including familial geneticand acquired diseases and ranging from very rare to relatively frequent cardiac disorders In all these diseases imaging techniques play acentral role Advanced imaging techniques provide important novel data on the diagnostic and prognostic assessment of RCMs ThisEACVI consensus document provides comprehensive information for the appropriateness of all non-invasive imaging techniques for thediagnosis prognostic evaluation and management of patients with RCM

Keywords echocardiography bull cardiac magnetic resonance bull computed tomography bull nuclear imaging

bull cardiomyopathies bull restrictive cardiomyopathies

Table of Contents

Introduction 1091Definition and classification of RCM 1091Pathophysiology of RCM and clinical presentation 1091aImaging modalities in RCM 1091a

Echocardiography 1091aCardiovascular magnetic resonance (CMR) 1091bCardiac computed tomography (CT) 1091cNuclear imaging 1091c

Main forms of RCM and value of imaging techniques 1091dApparently idiopathic RCM 1091dCardiac amyloidosis 1091eOther causes of familialgenetic RCM 1091k

Hemochromatosis 1091kFabry cardiomyopathy 1091lGlycogen storage disease 1091nPseudoxanthoma elasticum 1091n

Non familialnon-genetic RCM Inflammatory cardiomyopathieswith a restrictive hemodynamic component 1091n

Cardiac Sarcoidosis 1091nSystemic sclerosis 1091p

Non familialnon genetic RCM Radiation therapy and cancerdrug therapy induced RCM 1091q

Cardiac toxicity of radiation therapy 1091qCancer drug induced RCM 1091r

Endomyocardial RCMs 1091sEndomyocardial fibrosis 1091sHypereosinophilic syndrome 1091sCarcinoid heart disease 1091uDrug-induced endomyocardial fibrosis 1091u

Differential diagnosis between RCM and other cardiacdiseases 1091u

Differential diagnosis between RCM and constrictivepericarditis 1091uDifferential diagnosis or association between RCM and othermyocardial diseases 1091u

Conclusion and future directions 1091w

Introduction

Restrictive cardiomyopathies (RCMs) are a diverse group of myocar-dial diseases with a wide range of aetiologies including familial genetic

and acquired diseases and ranging from very rare to relatively frequentcardiac disorders This diversity is also reflected in the inconsistent clas-sification of RCM across guidelines1ndash3 and even in the term lsquorestrictiversquowhich is a functional characterization unlike the morphological defin-ition of the three other main types of cardiomyopathies ie hyper-trophic arrhythmogenic right ventricular or dilated cardiomyopathies4

Independently of the underlying cause the pathophysiology andclinical presentation the initial phenotypic diagnosis of RCM requiresimaging techniques Many advances have occurred in the last decadein the diagnostic and prognostic assessment of RCM This EACVIconsensus document provides comprehensive information for theappropriateness of all non-invasive imaging techniques for the diagno-sis prognostic evaluation and management of patients with RCM

This article was written in close collaboration between theEuropean Association of Cardiovascular Imaging (EACVI) and theWorking Group (WG) on Myocardial and Pericardial diseases ofthe European Society of Cardiology (ESC) The types of RCM cov-ered in this document are those included in the classification systemproposed by the WG on Myocardial and Pericardial diseases1 as wellas some non-sarcomeric hypertrophic cardiomyopathies (HCMs)with a restrictive physiology that in previous classifications wereincluded in the RCM category eg cardiac amyloidosis (CA)

Definition and classification ofRCM

RCM is the least common type of the cardiomyopathies defined asmyocardial disorders in which the heart muscle is structurally and function-ally abnormal in the absence of coronary artery disease arterial systemichypertension valvular disease or congenital heart disease sufficient tocause the observed myocardial abnormality1

According to the historical World Health Organization (WHO)2

and the updated definition proposed by the ESC WG on Myocardialand Pericardial Diseases in 20081 each cardiomyopathy type isdescribed by its clinical presentation This approach is recommendedfirstly because it is the starting point in everyday clinical practice andsecondly because knowledge of aetiologies is still evolving thus atpresent an aetiological classification would not be conclusive

RCM is defined by restrictive ventricular physiology in thepresence of normal or reduced diastolic volumes with normal or

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near-normal left ventricular (LV) systolic function and normal ornear-normal wall thickness1ndash5 Increased interstitial fibrosis may bepresent RCM constitutes a heterogeneous group of heart musclediseases with various causes (Table 1) that may be classified accordingto very different criteria

According to the main pathophysiological mechanism RCM maybe subclassified into infiltrative or storage diseases (eg amyloidosisand glycogen storage disease) obliterative or endomyocardial dis-eases [eg endomyocardial fibrosis (EMF) related or not tohypereosinophilia]

The WHO classification system was based on the distinction be-tween primary and secondary myocardial disorders2 Primary cardio-myopathies were defined as either not caused by an identifiable agenteg idiopathic or related to a primary myocardial cause Secondary dis-eases were related to systemic disorders affecting the myocardiumwith a pathophysiological process starting outside of eg unspecific tothe myocardium The American Heart Association (AHA) proposed aslightly different classification system in which the term lsquoprimaryrsquo wasused to describe diseases in which the heart is the sole or predomin-antly involved organ whereas lsquosecondaryrsquo is used to describe diseases inwhich myocardial dysfunction is part of a systemic disorder3

However the challenge of distinguishing primary and secondarydisorders is illustrated by the fact that many diseases classified as

primary cardiomyopathies (eg glycogen storage disease mitochon-drial cytopathies) in the AHA classification can be associated withmajor extra-cardiac manifestations Conversely pathology in many ofthe diseases classified as secondary cardiomyopathies can predomin-antly (or exclusively) involve the heart (eg EMF or Fabry disease car-diac variant) In addition the term of primary cardiomyopathy as anidiopathic condition is no longer appropriate in a large group of pa-tients since genetics has identified mutations in various genes such assarcomeric causes Therefore the ESC WG on Myocardial ampPericardial Diseases proposed in 2008 to abandon the distinction be-tween primary and secondary causes1

As an alternative to this classification the ESC Working Group onMyocardial and Pericardial Diseases proposed to subclassify RCMand other cardiomyopathies into (i) familial or genetic causes and (ii)non-familialnon-genetic causes because of the recent and increasingknowledge about genetic causes of cardiomyopathies This is espe-cially illustrated in RCM related to CA that may be acquired (amyloid-osis AL or senile amyloidosis) or genetically determined(transthyretin and other genes mutations) and be included in thenon-sarcomeric HCMs as well as in the RCM1 The latter ESC classifi-cation will be used in this position paper

Pathophysiology of RCM andclinical presentation

Restrictive physiology is characterized by a pattern of LV filling inwhich increased stiffness of the myocardium causes a precipitouslyrise of LV pressure with only small increases in volume On cardiaccatheterization this phenomenon is characterized by a dip-and-plateau contour of early diastolic pressure traces The standardechocardiographic features of lsquorestrictiversquo filling are described inSection Echocardiography

Similarly some patients with a restrictive physiology may have sig-nificantly increased wall thickness such as patients with CA RCMshould be differentiated from constrictive pericarditis (CP)67 (seeSection Main forms of RCM and value of imaging techniques)

Imaging modalities in RCM

EchocardiographyEchocardiography plays a key role for the recognition of RCM Theechocardiographic diagnosis requires to differentiate RCM from CP

RCM are usually characterized by normal or small LV cavity size(lt40 mLm2) with preserved LV ejection fraction bi-atrial enlarge-ment and diastolic dysfunction5

Assessment of LV diastolic function and filling pressures is of utmostvalue in RCM In the recent joint American Society ofEchocardiography (ASE)EACVI recommendations for the evaluationof diastolic function by echocardiography8 the four recommended vari-ables to diagnose LV diastolic dysfunction and their abnormal cut-offvalues are annular ersquo velocity (septal ersquo lt 7 cms lateral ersquo lt 10 cms)average Eersquo ratio gt 14 LA maximum volume index gt 34 mLm2 andpeak TR velocity gt 28 ms (Figure 1) Other valuable parameters toidentify the presence of elevated LV filling pressures are the ratio of pul-monary vein peak systolic to peak diastolic velocity or systolic time

Table 1 Main causes of RCM

Cause Familial

genetic

Non-familial

non-genetic

Apparently Idiopathic

Genetic origin X

Unknown origin X

Amyloidosis

ALprealbumin X

Genetic (eg TTR) X

Senile X

Other infiltrative diseases (such as

Gaucherrsquos disease Hurlerrsquos disease)

Inflammatory cardiomyopathies with a

restrictive haemodynamic

component Sarcoidosis SSc

Storage diseases

Haemochromatosis X

Fabry disease X

Glycogen storage disease X

Pseudoxanthoma elasticum X

Radiation therapy X

Drugs X

Endomyocardial diseases (with or

without hypereosinophilia carcinoid

disease drug induced)

X (rare) X (frequent)

Miscellaneous (radiation drug-induced

eg antracycline toxicity serotonin

methysergide ergotamine mercurial

agents and busulfan)

RCM restrictive cardiomyopathy TTR transthyretin SSc systemic sclerosis

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velocity integral to diastolic time velocity integral lt 1 and the changesin EA ratio with Valsalva manoeuver The restrictive filling is consideredreversible if the change of EA ratio during Valsalva is gt_ 05 and fixed if itis lt 05 (more severe form)

The diagnosis of RCM does not equal the presence of restrictivephysiology Patients with true RCM may present with a Grade I dia-stolic dysfunction and move progressively to Grade II or III diastolicdysfunction with worsening of their disease The advanced stages ofRCM are characterized by typical restrictive physiology with a mitralinflow EA ratio gt 25 DT of E velocity lt 150 ms IVRT lt 50 msdecreased septal and lateral ersquo velocities (3ndash4 cms) Eersquo ratio gt 14 aswell as a markedly increased LA volume index (gt50 mLm2)8 thisadvanced restrictive pattern being associated with the worst progno-sis9 Wall thickness is usually normal

Some specific features may also help differentiate secondary RCMincluding several systemic conditions (diabetic cardiomyopathyscleroderma EMF radiation chemotherapy carcinoid heart diseasemetastatic cancers) from apparently idiopathic RCM (see SectionMain forms of RCM and value of imaging techniques) Ultrasonic tis-sue characterization with integrated backscatter has been used to as-sess myocardial texture but is non-specific1011 Finally two-dimensional deformation imaging is useful for the assessment of LVlongitudinal dysfunction which is frequently impaired in most formsof RCM12 (see Section Main forms of RCM and value of imaging tech-niques) and may help differentiating RCM form CP13

Cardiovascular magnetic resonanceCardiovascular magnetic resonance (CMR) imaging can contributeimportantly to the diagnosis of RCM and the differential diagnosis

from pericardial constriction14 The CMR methods most commonlyused for the assessment of RCM include static (black blood) imagescine and contrast enhanced imaging as well as parametric mapping

Static images are used to delineate cardiac pericardial and vascularmorphology T1 and T2 weighted black blood images are sensitive todifferent tissue characteristics and provide complementary informa-tion T1 weighted images show high signal from fat as may for ex-ample be seen in Fabryrsquos disease while T2 weighted short tauinversion recovery (STIR) images show high signal in myocardial oe-dema for example in acute sarcoidosis

CMR allows accurate volumetric assessment of the heart and canaccurately measure chamber size and function15 Typical cine CMRimages are averaged over several heart beats to maximize image qual-ity and temporal resolution but real-time imaging can also be per-formed to demonstrate the typical septal shift during respiratorymanoeuvers and identify restrictive physiology16 Velocity encodedCMR in standardized imaging planes perpendicular to the atrio-ven-tricular (AV) heart valves is used to demonstrate the typical restrict-ive filling patterns of accentuated early filling and absent or reducedlate filling17

A unique feature of CMR of relevance to the imaging of RCM is tis-sue characterization with late gadolinium enhancement (LGE)Following intravenous administration gadolinium-based contrastagents are retained preferentially in tissues with an expanded extra-cellular space such as fibrosis scar or infiltration Characteristic pat-terns of contrast enhancement can be observed in several of theRCMs contributing to the differential diagnosis of Fabry diseaseamyloidosis EMF and sarcoidosis (Figure 2) In many of these condi-tions the presence of LGE also has important prognostic

Figure 1 ASEmdashEACVI criteria for grading LV diastolic function in patients with depressed LVEF and patients with myocardial disease and normalLVEF after consideration of clinical and other two-dimensional data (from reference 8 with permission)

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relevance18ndash20 Finally parametric mapping methods have increasingapplications in RCM and allow quantitative measurement of tissuecharacteristics T2-weighted CMR is now the method of choice todetect and quantify myocardial iron content in iron deposition car-diomyopathy and to guide appropriate therapy21 A low myocardialT2 value in this context is currently considered the most powerfulmarker of adverse outcome22 More recently T1 mapping has beenused to quantify the extent of myocardial inflammation and fibrosisNative T1 relaxation times as measured with T1 mapping withoutthe need for contrast agent administration are altered in several con-ditions including amyloidosis and may have incremental value overLGE imaging23 The combination of native and post-contrast T1 map-ping allows an estimation of the myocardial extracellular volume(ECV) fraction which in amyloidosis can even show differences insubtypes of the disease24 T1 mapping may also be useful in iron over-load instead of the more established T2 mapping25

Cardiac computed tomographyThe key advantage of computed tomography (CT) is its high-spatialresolution and the anatomical detail it provides However the associ-ated radiation exposure largely limits this modality to static imagingprecluding dynamic analyses of LV haemodynamics filling or relax-ation Nevertheless CT is well suited to identifying the anatomic fea-tures of impaired cardiac filling that characterize RCM These includedilatation of the atria coronary sinus and inferior vena cava and thepresence of pulmonary congestion and pleural effusions These fea-tures are also observed in a range of other conditions and the pre-dominant role of CT with respect to RCM is in the exclusion of thesealternative diagnoses In particular CT is well suited to detecting the

thickening and calcification of the pericardium most commonly asso-ciated with CP26 Similarly CT allows assessment of extra-cardiac in-volvement in systemic conditions such as sarcoidosis (eg pulmonarynodules pulmonary fibrosis and lymphadenopathy) or amyloidosis(eg inhomogeneous hepatomegaly diffuse lung parenchymal in-volvement small kidneys) further aiding in the differential diagnosis

When other imaging modalities are not available CT may be usefulin evaluation of patients with RCM owing to its ability to measure LVwall thickness and mass detect regional wall thickening27 regions ofreplacement fibrosis2728 and measure myocardial ECV fraction byequilibrium contrast-enhanced CT to assess diffuse fibrosis29 Theseadvances may increase the clinical utility of CT in the future clinical as-sessment of patients with RCM particularly when echocardiographyand CMR are non-diagnostic or contraindicated

Nuclear imagingNuclear imaging modalities have a potential clinical role in two formsof RCM amyloidosis and sarcoidosis (see Sections Cardiac amyloid-osis and Non familialnon-genetic RCM inflammatory cardiomyopa-thies with a restrictive haemodynamic component) Nuclear imagingmodalities have the advantage of specific targeted molecular imagingPositron emission tomography (PET) has the technical advantages ofhigh-spatial resolution robust built-in attenuation correction quanti-tative analysis and low-patient radiation exposure whereas singlephoton emission computed tomography (SPECT) has the advantageof a robust cheaper and well-validated camera system

There are increasing data on the role of nuclear tracers withSPECT and more recently with PET for early identification and differ-ential diagnosis of CA particularly transthyretin-related amyloidosis(ATTR)

Radiolabelled SPECT phosphate derivatives initially developed asbone-seeking tracers were noted to localize to amyloid depositsusing [99mTc]-diphosphanate30 In clinical practice the most usedSPECT tracers are 99mTc-DPD mainly in Europe and Asia and99mTc-PYP in the USA Their main advantage is avid uptake byATTR and minimal uptake with the light-chain (AL) amyloidosis sub-type providing one of the best non-invasive ways to differentiatethese subtypes of CA3132

The imaging technique is simple Briefly after administering 740MBq of 99mTc-DPD or [99mTc]-HDP3233 or of 99mTc-PYP34

intravenously a whole-body scan is performed 3 h or 1 h later (anter-ior and posterior projections) If there is active uptake in the heartchest SPECT is performed The analysis is performed by semi-quantitative visual scoring of the cardiac as compared to the bone up-take (scores from 0 to 3) and by computing the ratio after correctionfor background counts of the mean counts in the heart region overthe mean counts in the contralateral chest (HCL ratio)

Other nuclear imaging approaches have been recently proposedfor the diagnosis and prognostic stratification of patients with sus-pected amyloidosis31 PET imaging using new amyloid tracers like the[11C]-labelled Pittsburgh Compound B (PiB) or [18F]-florbetapir ispromising and under early clinical investigation The use of neuronalimaging by [123-I]-MIBG SPECT has been suggested for early recog-nition of cardiac involvement and prognostic stratification of individ-uals with TTR mutation34

The inflammatory nature of cardiac sarcoidosis (CS) renders PETuseful for its diagnosis as [18F]FDG accumulates in inflammatory cells

Figure 2 Seventy-four year-old patient presenting with breath-lessness Cine CMR showed global LV hypertrophy impaired longi-tudinal LV shortening and dilated atria Late gadolinium enhancedCMR in the figure showed diffuse endocardial enhancement consist-ent with infiltrative disease Subsequently the patient was found tohave amyloidosis LV left ventricle RV right ventricle LA leftatrium RA right atrium

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in the heart FDG is preferred in combination with a perfusion tracerto improve specificity due to better matchmismatch pattern recog-nition Unlike in CMR there is no distinct pattern of FDG uptake thatis pathognomonic for CS though focal or focal on diffuse uptake issuggestive of the disorder35 At present [18F]FDG-PET appears to bemore sensitive but less specific than CMR36 and its use seems mostappropriate in patients who have contraindications to CMR incon-clusive findings on CMR or where CMR is not available also to moni-tor response to therapy The development of FDG PETMRtechniques offers the ability to assess LV wall function the pattern ofmyocardial injury and disease activity in a single scan37 (Figure 3)

In summary several imaging techniques are available in the evalu-ation of RCM all of which have both advantages and limitationsTable 2 summarizes the value of different imaging modalities in

various forms of RCM Although non-invasive techniques are suffi-cient in most cases final histologic diagnosis may sometimes be ne-cessary and may be obtained by biopsies specimens from the heart[endomyocardial biopsies (EMB)] or other organs Figure 4 illustratesby histology and immunohistology different disease entities of RCMwhich will be discussed in the following chapters

Main forms of RCM and value ofimaging techniques

Apparently idiopathic RCMApparently idiopathic RCM may be caused by mutations in sarco-meric disease genes and may even coexist with HCM in the same

Figure 3 Patient with acute myocardial sarcoidosis (from reference 37 with permission) Patient (62-year-old male) followed for histologically pro-ven pulmonary sarcoidosis treated by steroids for 10 years presented with symptoms of acute breathlessness Cardiac involvement was suspectedLGE-CMR (A) images showed patchy LGE of the lateral wall Matched FDG-PET (B) and fused FDG-PETMR (C and D) images obtained in short-axisview showed intense uptake in exactly the same territory as the pattern of injury on CMR (maximum standardized uptake value of LGE territoryblood pool uptake ratio = 27) A two-chamber cine CMR (E) sequence showed mild hypokinesis of the lateral wall and mild overall LV systolic im-pairment (LV ejection fraction = 52) Maximum intensity projection FDG-PET (F) cine view confirmed abnormal myocardial uptake without evi-dence of increased activity outside of the heart

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family38ndash40 and may require EMB (to exclude CA) family screeningand genetic investigations Most affected individuals have severe signsand symptoms of heart failure Several studies have reported that66ndash100 die or receive a cardiac transplant within a few years ofdiagnosis

The echocardiographic diagnosis is one of restrictive physiologyand mostly preserved LV ejection fraction Typically idiopathic RCMis characterized by diastolic dysfunction with apparently preservedsystolic function dilated atria and the absence of ventricular hyper-trophy or dilatation (Figure 5 and see Supplementary data onlineVideos S1 and S2) Longitudinal function may be decreased the rightventricle may be involved but there is no lsquopathognomonicrsquo echocar-diographic pattern of apparently idiopathic RCM CMR with LGEmay facilitate the diagnosis of infiltrative myocardial disease and isthus particularly useful for ruling out a particular cause of RCM41

Cardiac amyloidosisCA is one of the most frequent causes of RCM and may be geneticfa-milial (ATTR) or non-genetic non-familial (ALprealbumin senile)

The diagnosis requires awareness expertise and a high level of clin-ical suspicion with integration between clinical electrocardiographicand echocardiographic data The lsquomismatchrsquo between the presenceof LV hypertrophy (LVH) in echocardiography and its absence on theECG (no LVH absolute or relative low-voltage QRS) is suggestive ofCA and is often the first disease lsquored flagrsquo4243 Typical echocardio-graphic findings in CA patients include (Figure 6A) a non-dilated LVwith moderate concentric LVH and a lsquogranular sparklingrsquo appearanceof the myocardial texture valvular thickening (mainly the AV valves)biatrial dilatation right ventricular free wall hypertrophy inter atrialseptum infiltration (loss of physiological echo drop-out) and mild

pericardial effusion44 In the early stages of the disease CA may pre-sent as asymmetrical septal hypertrophy sometimes with LV outflowtract obstruction and can then be wrongly diagnosed as HCM Thepresence of intra-atrial thrombus also seems to be relatively frequentin patients with CA even in sinus rhythm45

Patients often show (Figure 6B) advanced diastolic dysfunction(Grade II or III) and increased LV filling pressures The classical trans-mitral restrictive pattern may only be seen at advanced disease stagesThe typical tissue Doppler imaging (TDI) pattern of CA with low sys-tolic (srsquo) and diastolic (ersquo arsquo) myocardial velocities Of note Eersquo ratiois usually abnormally increased even in the presence of LV abnormalrelaxation pattern (diastolic dysfunction Grade I)46

LV systolic dysfunction is also a common finding in this disease Inearly stages despite preserved LV ejection fraction longitudinal func-tion is abnormal (abnormal long axis systolic velocities (srsquo) and strain)(Figure 7A) as well as myocardial contraction fraction a recentlydescribed systolic parameter47

Two-dimensional speckle-tracing echocardiography (2D-STE) isimportant as many systolic strain parameters (longitudinal circum-ferential radial) are abnormal in CA particularly in the longitudinalaxis typically with prominent involvement of LV basal segments andapical sparing48 (Figure 7B) reflecting the predominant deposition ofamyloid in basal segments The combination of a prominent reduc-tion of longitudinal strain in LV basal segments with increased Eersquoratio suggests CA in early stages49

Multiple echocardiographic parameters have been associated withadverse outcomes in CA including M- mode and two-dimensionaldata (maximal wall thickness LV fractional shortening and LV ejectionfraction right ventricle dilatation) blood pool Doppler data (restrict-ive filling pattern myocardial performance index Tissue Doppler

Table 2 Value of different imaging modalities in various forms of RCM

TTE TDI and strain imaging CMR Nuclear imaging Cardiac CT PET

Apparently idiopathic RCM thornthornthorn thornthorn thornthorn 0 thorn 0

Cardiac amyloidosis thornthornthorn thornthornthorn thornthornthorn thornthornthorn thorn thornOther causes of familialgenetic RCM

Haemochromatosis thornthornthorn thorn thornthornthorn thorn 0 0

Fabry cardiomyopathy thornthorn thornthorn thornthornthorn 0 0 0

Glycogen storage disease thornthorn thornthorn thornthorn thorn 0 0

Pseudoxanthoma elasticum thornthorn thorn thornthorn thorn 0 0

Inflammatory CM with a restrictive component

Cardiac sarcoidosis thorn 0 thornthorn thornthorn thorn thornthornthornSystemic sclerosis thornthorn thornthorn thornthorn thorn 0 0

Radiation therapy and cancer drug therapy induced RCM

Cardiac toxicity of radiation therapy thornthorn thorn thornthorn thorn 0 0

Cancer drug induced RCM thornthornthorn thornthorn thornthorn 0 0 0

Endomyocardial RCMs

Endomyocardial fibrosis thornthornthorn thorn thornthornthorn 0 0 0

Hypereosinophilic syndrome thornthornthorn thorn thornthornthorn 0 0 0

Carcinoid heart disease thornthornthorn 0 thornthorn 0 0 0

Drug-induced endomyocardial fibrosis thornthornthorn 0 thornthorn 0 0 0

Differential diagnosis with CP thornthornthorn thornthorn thornthorn 0 thornthornthorn 0

RCM restrictive cardiomyopathy TDI tissue Doppler imaging CMR cardiovascular magnetic resonance PET positron emission tomography CT computed tomography TTEtransthoracic echocardiography

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derived data (myocardial velocities long axis velocity gradient peaklongitudinal systolic basal antero-septal strain gt -75)50 and 2D-STEparameters [global longitudinal strain (GLS) mid-septum systolic lon-gitudinal strain apical LSlt -145]5152

CMR is often used after CA is suspected by echocardiography toconfirm or refute the diagnosis and in experienced hands representsa powerful tool with important diagnostic and prognostic implica-tions Cine images may demonstrate typical anatomical features like

Figure 4 Imaging of RCM at the cellular level Different disease entities of RCM are visualized by histology and immunohistology Sarcoidosis withtypical granulomas fibrosis (blue tissue) (A Masson trichrome stain) and numerous CD68thornmacrophages and giant cells (B immunohistochemistry)Hypereosinophilic syndrome with myocyte necrosis eosinophilic granulocytes (C Giemsa stain) and CD68thornmacrophages (D immunohistochemis-try) Storage diseases haemochromatosis with iron containing myocytes (E Prussian blue) and fibrosis (F Sirius red) AL-amyloidosis (G AL-amyloidimmunohistochemistry (green) H Kongo red) Glycogenosis with hypertrophic vacuolated myocytes and fibrosis (I Masson trichrome stain) andlarge amounts of glycogen (J PAS stain (red)) (A and B x100 CndashJ x200)

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Figure 5 Multimodality imaging findings in three patients with apparently idiopathic RCM (A) (TTE) and (B) (CMR) Impressive dilatation of bothatria predominating on the right cavities contrasting with small LV and RV cavities (Supplementary data online Video S1) (C) More classical form ofidiopathic RCM with normal ventricular systolic function and severe atrial dilatation RA right atrium RV right ventricle LV left ventricle LA leftatrium (Supplementary data online Video S2) (D) Multimodality imaging in a severe RCM Patient in atrial fibrillation and a pace maker for severe AVblock Huge atria that can be seen on the CT (1) the chest X-ray (2) and the Echocardiography (6) There is a severe tricuspid regurgitation (5) and asevere alteration of the longitudinal systolic and diastolic function as shown by the tissue Doppler (5) and the strain data (4) Extensive circumferentialsubendocardial late gadolinium enhancement is observed by CMR (3)

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thickened LV wall biatrial enlargement reduced long-axis shorteningand pleural or pericardial effusion The presence of amyloid proteinin the myocardial interstitium is associated with abnormalgadolinium-chelate contrast kinetics and characteristic patterns ofcontrast distribution LGE images typically show circumferential sub-endocardial contrast enhancement or bilateral septal subendocardialLGE with dark mid-wall (zebra pattern) (Figure 8A)5354 but other pat-terns of enhancement have also been described In atypical casesother differential diagnoses should be considered such as HCM or

Fabryrsquos disease Cardiac involvement can extend to the right ventricleand atrial walls as potentially detected by LGE The extent of myo-cardial LGE correlates with New York Heart Association functionalclass LV wall thickness lower ECG voltage and cardiac biomarkers(troponins brain natriuretic peptide)55 With more advanced diseaseamyloid infiltration may be transmural with corresponding global en-hancement on LGE images which is an independent predictor ofpoorer outcomes over stroke volume and pro-NT brain natriureticpeptide19

Figure 6 (A) Two-dimensional echocardiography in a 52-year-old male with CA AL type associated with plasma cell dyscrasia non-dilated LVwith moderate concentric LVH with lsquogranular sparklingrsquo appearance mitral valve thickening mild to moderate biatrial dilatation inter atrial septum in-filtration (loss of physiological echo drop-out) and mild pericardial effusion RA right atrium RV right ventricle LV left ventricle LA left atrium Aoaorta (B) Diastolic function in the same patient EA1 (PWD transmitral inflow) low-systolic and diastolic myocardial velocities (TDI) Eersquo =25 re-flecting high-LV filling pressures

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Figure 7 (A) Two-dimensional-STE apical longitudinal view in systemic AL amyloidosis severely abnormal longitudinal strain particularly in thebasal and medial LV segments (B) Systemic AL amyloidosis multiple myeloma 2D-STE relative apical sparing typical of CA Note the abnormal GLS(-49)

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Amyloid deposits increase the longitudinal relaxation time (T1)

magnetic property of the heart Thus myocardial non-contrast T1values are longer in CA than in controls a finding with higher sensitiv-ity for detecting early subclinical cardiac involvement than LGE23

ECV estimation from pre- and post-contrast T1 mapping has beenused to quantify interstitial amyloid deposition which appears to bemore extensive in transthyretin amyloidosis (TTR) than in immuno-globulin AL56 The addition of parametric mapping to standard CMRimages is promising to be a powerful and quantitative diagnostic toolthat also allows differential diagnosis from other diseases with similarphenotypic expression

Scintigraphy employs molecular-targeted radiolabelled compoundsto detect systemic and organ-specific amyloid deposits Scintigraphy isa valuable alternative to CMR particularly for patients with ATTRamyloidosis due to its very high sensitivity Scintigraphy may also beused following an inconclusive CMR study or for phenotyping CA(ATTR vs AL) or in the differential diagnosis with sarcomericHCM5758 The [99mTc]-labelled bisphosphonate compounds pyro-phosphate (PYP)58 and 33-diphosphono-12-propanodicarboxylicacid (DPD)59 and hydroxydiphosphonate (HDP)33 (which are rou-tinely used as bone scintigraphy agents) bind through unknown mech-anisms to amyloid protein All have proven very sensitive for detecting

Figure 8 (A) CMR in a 79-year-old patient with CA showing mild septal hypertrophy (16 mm) biatrial enlargement and diffuse patchy uptake ofgadolinium throughout the mid-ventricular and basal segments of the septal anterior and inferior wall with sparing of the apicolateral wall (Notesmall areas of bilateral subendocardial LGE in the septal wall characteristic of CA (arrows) and LGE in the right ventricular free wall and the leftatrium) RA right atrium RV right ventricle LV left ventricle LA left atrium (B) Late-phase planar 99mTc-DPD-scintigraphy (anterior views) in a pa-tient with ATTR amyloidosis (A) and a normal control (B) Note intense cardiac uptake in (A) demonstrating CA Moreover increased soft tissue up-take particularly in the shoulder region and the abdominal wall with obscuring of bone uptake can be observed as a typical pattern of ATTRamyloidosis

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cardiac involvement in ATTR amyloidosis with reported sensitivitiesup to 100 on late phase planar scintigraphy Typical uptake patternsbesides cardiac uptake in ATTR amyloidosis include increased soft tis-sue uptake (mainly muscular uptake in the gluteal shoulder chest andabdominal wall regions) with obscuring of bone uptake (Figure 8B)However in AL amyloidosis cardiac uptake is found in less than half ofpatients and is generally less intense (likely due to the lower concen-tration of calcium-containing products in AL amyloid) Additionally ALpatients have generally no muscular [99mTc]-DPD or [99mTc]-HDPuptake while visceral uptake (liver spleen) may be more common

Even if there are not yet large comparative studies the diagnosticperformance of nuclear imaging for CA is established In general[99mTc]-DPD can differentiate subtypes60 and can be more sensitivethan CMR33 or echocardiography in diagnosing early disease being anindependent prognostic marker61 In a recent study by Bokhariet al58 using 99mTc-PYP while patients with AL had some uptakethe visual score was significantly less than in patients with ATTRallowing the differentiation between ATTR and AL amyloidosis with97 sensitivity and 100 specificity

Hence whole body planar DPD and HDP scintigraphy may help tophenotype CA particularly through differentiating ATTR from ALamyloidosis (or from sarcomeric HCM where no DPD uptake isseen) which often have overlapping imaging features on echocardiog-raphy and CMR but very distinct clinical course and prognosisMoreover a recent comparison of [99mTc]-DPD scintigraphy andLGE showed that despite a general good agreement between bothtechniques LGE may sometimes underestimate cardiac amyloid

burden33 Finally myocardial tracer uptake on scintigraphy is corre-lated with disease severity (measured by circulating troponin and LVwall mass) and has been shown to be a powerful prognostic deter-minant of outcome in ATTR CA3261

Recent investigations found that bone scintigraphy enables thediagnosis of cardiac ATTR amyloidosis to be made reliably withoutthe need for histology in patients who do not have a monoclonalgammapathy62 The algorithm proposed (Figure 9) that cardiac ATTRamyloidosis can be reliably diagnosed in the absence of histology pro-vided an echocardiogram or CMR is suggestive of amyloidosis car-diac uptake is present on scintigraphy and there is absence of adetectable monoclonal gammapathy Histological confirmation andtyping of amyloid should be sought in all cases of suspected CA inwhich these criteria are not met

In summary all these imaging techniques are useful and give add-itional information including echocardiography nuclear techniquesand CMR (Table 3)63 but also EMB and genetic testing to differenti-ate ATTR mutant from wild type Figure 10 illustrates the value ofmultimodality imaging in a patient with CA

Other causes of familialgenetic RCMHaemochromatosis

Iron overload cardiomyopathy (IOC) results from iron accumulationin the myocardium mainly because of genetic disorders of iron me-tabolism (primary haemochromatosis) or multiple transfusions (suchas in thalassaemia or myelodysplastic syndromes)

Figure 9 Diagnostic algorithm for patients with suspected amyloid cardiomyopathy (from reference 62 with permission) AApoA1 apolipoproteinA-I DPD 33-diphosphono-12-propanodicarboxylic acid HDMP hydroxymethylene diphosphonate PYP pyrophosphate

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In the early stages myocardial iron overload (MIO) causes diastolic

LV dysfunction64 If no effective iron chelation is instituted in timethe majority of patients develops LV dilatation and reduced LV ejec-tion fraction (EF) (dilated phenotype)65 In a minority of cases withsevere MIO restrictive LV dysfunction can lead to pulmonary hyper-tension right ventricular dilatation and right-sided heart failure withpreserved LVEF (restrictive phenotype)66

Echocardiography is a useful modality in the follow-up of iron-loaded patients A pseudonormalized pattern of transmitral inflow isfrequently encountered and may be unmasked by tissue Doppler67

LV diastolic dysfunction and reduced EF may both be masked by ananaemia-induced high-cardiac output state in haematologic patientsThere are few data relating diastolic function to outcome inhaemochromatosis68

However due to the lower accuracy in quantifying biventricularsystolic function and the lack of parameters able to predict MIO reli-ably echocardiography is only the second-line imaging method afterCMR6970

The method of choice for assessing IOC is CMR which allowstissue characterization including quantification of MIO The para-magnetic effect of iron-loaded myocardium affects T1 T2 and T2relaxation times which can be used to calculate MIO The best vali-dated method for quantifying MIO is T2 mapping T2 values cor-relate closely with hepatic and myocardial iron content andcorrelate better with LV dilatation and LV dysfunction than serumferritin or liver iron concentration A T2 value of lt 20 ms at 15Tesla typically measured in the interventricular septum is used asa conservative cut-off for segmental and global heart iron overloadand patients with the lowest T2 values have the highest risk of de-veloping arrhythmia and heart failure T2 CMR has revolutionizedIOC management with the death rate in patients with thalassaemiafalling dramatically in countries where T2 CMR has been adoptedIn the assessment of IOC the first cardiac T2 assessment shouldbe performed as early as possible and the effectiveness of iron che-lation71 and reversal of MIO can be reliably guided by follow upscans72 A multislice approach can detect the uneven distributionof MIO allowing early identification of patients at risk of cardiaccomplications73

T2 is dependent on field strength and sensitive to field inhomo-geneity T2 and T1 mapping techniques offer some advantages overT2 and have been compared with standard methods with initialstudies showing close correlation with T2

In patients where the diagnosis is unclear a multiparametric CMRapproach that evaluates cardiac function myocardial fibrosis andoedema may allow further clarification of the underlying mechanismsleading to the LV dysfunction74

In summary cardiac involvement is frequent in haemochromatosisCMR is the main imaging technique for diagnosis and follow-up ofcardiac haemochromatosis allowing both reliable measurement ofLV and RV dimension and function and tissue characterization includ-ing quantification of MIO

Fabry cardiomyopathy

Cardiac involvement is very common and is the most frequent causeof death not only in haemizygote males but also in female heterozy-gote carriers with a-Gal A deficiency with a reduction of life expect-ancy of approximately 20 and 15 years respectively75 The heart maybe the only organ affected in the classic phenotype of Fabry diseaseand this is designated the lsquocardiac variantrsquo76

Cardiovascular manifestations include renovascular and systemichypertension aortic root dilatation mitral prolapse and congestiveheart failure77 Fabry cardiomyopathy mainly consists of progressiveLVH which may cause substantial morbidity and contribute to thereduced life expectancy of affected patients both male andfemale7879

LVH is a hallmark of Fabry cardiomyopathy80 In patient populationswith HCM the prevalence of Fabry disease ranges from 0 to 12 de-pending on the patient selection criteria used but is close to 1 in thelargest series81 LVH is generally symmetrical although asymmetricseptal hypertrophy has been described and the condition can mimicthe phenotypical and clinical features of HCM including obstructiveHCM82 Typically the echocardiogram shows marked increases inwall thickness and ventricular dilatation later in the disease processValve leaflet thickening can be seen and this produces valve impair-ment that usually does not require surgical treatment83

Table 3 Multimodality imaging in the differential diagnosis between HCM and CA (from Cardim et al63)

Imaging data HCM Cardiac amyloidosis

Echo CMR cardiac CT

LVH Severe asymmetric Moderate concentric lsquosparklingrsquo

Left ventricular outflow tract obstruction Frequent Rare (may exist in early stages)

Pericardial effusion Rare Frequent

IAS hypertrophy Rare Frequent

Apical sparing Rare Frequent

LGE RV insertion points intramural Diffuse subendocardial (global or segmental)

T1 mapping Under research Work in progress typical patterns

CNI99mTc-DPD uptake No Yes (TTRmdashsenile and familial

CMR cardiovascular magnetic resonance HCM hypertrophic cardiomyopathy LVH left ventricular hypertrophy LGE late gadolinium enhancement TTR transthyretin

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Echocardiography using TDI can detect the first signs of myocar-

dial damage in a patient with Fabry cardiomyopathy and normal car-diac wall thickness84 Furthermore TDI studies have been shown to

be useful in detecting cardiac involvement in female carriers with nosystemic manifestations of Fabry disease A reduction of TDI veloc-ities may represent the first sign of initial intrinsic myocardial

Figure 10 Multimodality imaging in a patient with familial TTR amyloidosis (A) Two-dimensional echo long-axis view showing LV hypertrophy andpericardial effusion (Supplementary data online Video S3) (B) Apical sparing by two-dimensional strain (Supplementary data online Video S4) (C)Intense cardiac uptake on 99mTc scintigraphy (D) CMR confirming LV hypertrophy and pericardial effusion (Supplementary data online Video S5)RV right ventricle LV left ventricle LA left atrium Per pericardial effusion

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impairment85 These reduced TDI velocities in mutation positiveswithout LVH are consistent with the hypothesis that myocardial dys-function precedes LVH86

CMR with LGE may be useful in the non-invasive recognition ofmyocardial fibrosis in the context of cardiac involvement of Fabrydisease87 The LGE pattern of distribution helps in the differenti-ation between HCM and Fabry cardiomyopathy18 Patients withFabry cardiomyopathy typically present with a pattern character-ized by the involvement of the inferolateral basal or mid-basal seg-ments87 Furthermore the myocardial T2 relaxation time isprolonged in patients with Fabry disease compared with that inHCM patients and its measurement could be complementary tothe LGE technique More recently native T1 mapping was shownto be the most reliable technique to differentiate Fabry cardiomy-opathy from all the other LVH phenocopies by demonstrating alow native T1 value of the affected myocardium (whilst other LGEarea of different disease would display a high native T1 values)18

This important difference is due to the characteristic fatty nature ofthe infiltration in Fabry disease

Finally for most males with Fabry disease the diagnosis can bemade by measuring leucocyte and plasma a-Gal activity while genetictesting is useful in patients with normal levels of enzyme activity18 Afamilial screening should be performed in patients with Fabryrsquos dis-ease (Figure 11)

In summary cardiac involvement is frequent in Fabry disease and isassociated with worse outcome Imaging techniques especially TDIand CMR allow a comprehensive evaluation of cardiac involvementeven before morphological manifestations such as hypertrophydevelop

Glycogen storage disease

Glycogen storage disease is defined as the absence or deficiency ofone of the enzymes responsible for making or breaking down glyco-gen in the body The enzyme deficiency causes either abnormal tissueconcentrations of glycogen or incorrectly or abnormally formedglycogen8889 There are 11 different types of glycogen storage dis-eases causing different forms of heart failure Most well-known areDanon and Pompe diseases809091

Danon cardiomyopathy is progressive and typically manifests ahypertrophic phenotype with preserved LVEF and normal cavity di-mensions early in the course of disease and later progression todilated features in 11ndash12 of men89 HCM is predominant in male pa-tients whereas an equal prevalence of hypertrophic and dilated car-diomyopathy is seen in female patients90

Echocardiography demonstrates increased LV mass and wallthickness although LV systolic function is preserved Taking intoconsideration the possible progress to cardiac failure serial echo-cardiograms with attention to LV thickness and mass are importantin the care of these patients9192 Echocardiography is also thestandard method to evaluate the cardiac response to enzyme re-placement therapy

Typical findings in CMR consist of significantly reduced LV globalfunction and increase of LV end-diastolic and end-systolic volumesPerfusion defects mainly subendocardial are visible in almost all seg-ments on rest first-pass perfusion images They may be obvious in theinfero-septal segments and partly transmural in the lateral and

anterior walls LGE appears to be a rare finding in Pompe disease butwhen present is seen in the subendocardium and in places transmur-ally in the anterior and lateral walls9394

A diagnosis of Danon disease is always confirmed by EMB results99mTc-methoxyisobutylisonitrile myocardial imaging has also been

employed as an imaging diagnostic test for glycogen storage diseaseto detect myocardial damage as a non-invasive method There hasbeen a positive rate of detection of damage with G-MPI of 77895

Other storageinfiltrative diseases (Gaucher disease mucopolysac-charidoses) may be rarely associated with cardiac involvement9697

Pseudoxanthoma elasticum

Pseudoxanthoma elasticum is a rare inherited connective tissue dis-order associated with coronary and peripheral arterial disease andaccelerated atherosclerosis in medium sized arteries98 Cardiac in-volvement may start as a diffuse arteriopathy secondary to elasticfibre dysgenesis involving the small intramural coronary vessels(lsquosmall-vessel diseasersquo) and it may reach the clinical presentation ofcongestive heart failure even thoughmdashquite oftenmdashwith normal epi-cardial vessels99

Echocardiography detects impaired LV systolic and diastolic func-tion100 Other imaging modalitiesmdashas functional testsmdashsuch as per-fusion CMR or nuclear myocardial perfusion imaging may be usefulto demonstrate early coronary involvement andor the direct conse-quences of ultrastructural defects of the elastic tissue of the heartIncreased awareness for silent ischaemia is recommended98101

An important study with arterial stiffness evaluation demonstratesthe early detection of accelerated atherosclerosis and the impair-ment of the elastic properties of the aorta A lower elasticity in largearteries a higher cardiac output and a higher total vascular imped-ance were observed in patients with pseudoxanthoma elasticum withrespect to the control group101

Non-familialnon-genetic RCMinflammatory cardiomyopathies with arestrictive haemodynamic componentCardiac sarcoidosis

Sarcoidosis is a multisystem inflammatory granulomatous disease ofunknown origin CS is frequently isolated102 Its diagnosis is difficultand has benefited from the use of multimodality imaging

Although echocardiography is not the method of choice for thediagnosis of CS it can offer very useful information in some cases103

An unexplained reduced LV ejection fraction lt 40 in a patient witha histological diagnosis of extra-CS is suggestive of CS104

Characteristic echocardiographic changes suggestive of CS are wallthickness gt 13 mm (due to granulomatous expansion) or lt 7 mm(due to fibrosis) aneurysmal dilatation especially at the level of the in-ferior and posterior walls105 regional wall motion abnormalitieswithout any specific coronary distribution interspersed with normo-kinetic segments106

CMR is one of the imaging modalities recommended for the diag-nosis of CS in current guidelines103 and CMR may be more sensitivefor cardiac involvement than currently used clinical criteria107

Myocardial inflammation may be identified by T2 STIR images andearly contrast enhancement while areas of fibrosis are detected byLGE108 (Figure 12) The typical pattern of CS on LGE is patchy focal

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enhancement sparing the endocardial border not following a coron-ary artery distribution109 and involving mainly the basal and lateralLV walls110 Single or often multiple lesions are seen and other moreatypical LGE patterns have also been described Importantly no LGEpattern is pathognomonic for CS Moreover CMR offers prognosticinformation myocardial scar determined by LGE is a predictor forventricular arrhythmia and sudden cardiac death in patients withsarcoidosis111

Nuclear imaging has also an important role in the assessment ofCS Although the major diagnostic criteria for CS include [67Ga]-

citrate scintigraphy its sensitivity for CS is significantly lower than[18F]FDG-PETCT112 For this reason [18F]FDG-PETCT have cur-rently replaced [67Ga]-scintigraphy in the majority of centres beingnowadays the most commonly used imaging test for detecting myo-cardial inflammation Advantages of [18F]FDG-PETCT over [67Ga]includes favourable tracer kinetics lower radiation exposure andbetter quality images113 Active sarcoid lesions present increased[18F]FDG uptake on PETCT imaging due to utilization of glucose asan energy source by inflammatory cell in infiltrates114 However[18F]FDG-PETCT has not been officially adopted in the diagnostic

Figure 11 Familial Fabryrsquos disease in two brothers (A) EKG in a 55-year-old male showing a pattern of apical hypertrophy (B) Apical transthoracicview showing an apical hypertrophy (arrow) (C) CMR finding of predominantly apical hypertrophy (D) Inferolateral late gadolidium enhancement(E) EKG in his young brother showing milder but similar abnormalities (F) Concentric diffuse hypertrophy in the brother RV right ventricle LV leftventricle LA left atrium RA right atrium

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guidelines115 mainly due to the high variability of [18F]FDG uptake inthe normal myocardium that requires adequate patient preparationto prevent errors Strategies for myocardial suppression to maximizethe accuracy of the procedure include prolonged fasting dietarymodifications and a heparin load before imaging116 The imagingprotocol includes preferable gated cardiac [18F]FDG and whole

body images117 A cardiac perfusion scan could be combined to com-pare [18F]FDG-PET and perfusion patterns (Table 4)118

Pitfalls in [18F]FDG PETCT imaging are myocarditis CA infec-tion and myocardial metastases causing focal [18F]FDG uptakeThere are very few circumstances under which [18F]FDG will befalsely negative as in case of corticosteroids treatment or lsquoold non-activersquo sarcoidosis

[18F]FDG-PETCT sensitivity and specificity for CS have been re-ported at 89 and 78 respectively114 Quantitative analysis furtherimproved these figures reaching a sensitivity of 973 and a specificityof 836 for the diagnosis of CS In addition standardized uptake value(SUVmax) on [18F]FDG-PETCT was found the only independentpredictor among clinical and imaging variables for diagnosing CS119

Serial [18F]FDG-PETCT imaging can be utilized to assess the re-sponse to therapies Decrease [18F]FDG uptake in cardiac lesionsfollowing therapy has been reported in case of corticosteroid treat-ment as well as immunosuppressive therapies120121 Figure 13 illus-trates the value of serial [18F]FDG PETCT in a patient with CStreated with high dose corticosteroids

[18F]FDG-PETCT only moderately correlated with CMR mainlydue to the different significance of findings LGE by CMR represents car-diac damage and scarring whereas [18F]FDG uptake represents activeinflammation When CMR and [18F]FDG -PETCT were comparedwith the Japanese Ministry of Health and Welfare guidelines CMR had ahigher specificity with lower sensitivity than nuclear imaging122

In summary [18F]FDG-PETCT and CMR are powerful imagingtechniques for accurate detection and therapy monitoring of CSProtocols for imaging with these modalities are increasingly welldefined however large prospective studies supporting new guidelinesfor CS imaging are warranted

Systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disease characterizedby vascular and fibrotic lesions of skin and internal organs and repre-sents a model of progressive interstitial myocardial fibrosis triggered

Figure 12 Patient with known CS The image shows a late gado-linium enhanced CMR image in the vertical long axis plane Severalfocal areas of myocardial enhancement can be seen (arrows) con-sistent with granulomatous myocardial infiltration

Table 4 Interpretation criteria by combining rest perfusion imaging and FDG findings in suspected cardiac sarcoid-

osis Adapted from Blankstein et al118

Rest perfusion FDG Interpretation

Normal perfusion and metabolism

Normal No uptake Negative for CS

Normal Diffuse Diffuse FDG most likely due to suboptimal patient preparation

Abnormal perfusion or metabolism

Normal Focal Could represent early disease

Defecta No uptake Perfusion defect represents scar from sarcoidosis or other aetiology

Abnormal perfusion and metabolism

Defect Focal in area of perfusion defect Active inflammation with scar in the same location

Defect Focal on diffuse with focal in area of

perfusion defect

Active inflammation with scar in the same location with

either diffuse inflammation or suboptimal preparation

Defect Focal in area of normal perfusion Presence of both scar and inflammation in different segments

of the myocardium

CS cardiac sarcoidosisaEpicardial coronary artery disease should be always ruled out in these patients to avoid misinterpretation due to hibernating myocardium

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by increased endothelin production and also focal hypoperfusion123

Cardiovascular involvement has been shown to be one of the leadingcauses of mortality in SSc and can occur in up to 70 of patients as afinding on autopsy124125 Although the primary myocardial involve-ment remains clinically silent in the majority of patients it can lead tofurther diastolic and systolic LV dysfunction126 which carries a poorprognosis Early diagnosis and accurate staging of myocardial involve-ment are therefore crucial for the management of these patients andfor therapeutic strategies

Conventional echocardiographic assessment of the LVEF hasshown limited sensitivity being able to identify only 5 of patientswith cardiac involvement127 Results of studies using TDI andspeckle-tracking echocardiography suggested that myocardial vel-ocity and strain might be more sensitive than conventional measuresin identifying subtle cardiac dysfunction in asymptomatic patientswith SSc128129

Since myocardial fibrosis is the primary abnormality underlying SSccardiac involvement methods that enable early identification of fibro-sis should be preferred EMB is the gold standard for the detection ofmyocarditis that may be found in SSc patients and might help to de-tect cardiac involvement at an early stage of the disease as inflamma-tion was found in 96 and fibrosis in 100 of all SSc patientsinvestigated130 Importantly prognosis was poor and associated withthe degree of cardiac inflammation and fibrosis revealing an eventrate of 28 within 225 months follow-up130

CMR with LGE imaging has been used to detect myocardial areaswith replacement fibrosis in patients with an advanced stage of

SSc131 However at an early stage of the disease myocardial fibrosisin SSc is usually diffuse and thus undetected by LGE-CMR ECV esti-mation using pre- and post-contrast T1 mapping has been used tovisualize increased collagen content in SSc132 A recent study hasdemonstrated that ECV imaging performed early during SS revealsmyocardial abnormalities consistent with diffuse myocardial fibrosisthat are not apparent on LGE imaging therefore representing anearly marker of disease133 In addition the ECV abnormalities corre-lated with diastolic LV dysfunction which occurred in 45 of the pa-tients134 This study also evaluated the systolic circumferential strainby CMR that was also found decreased but without any correlationwith ECV increase suggesting therefore that LV systolic dysfunctionmay be related not only to myocardial fibrosis but also to other phe-nomena such as myocardial ischaemia

In SSc myocardial ischaemia unrelated to coronary artery diseaseis common with impairment of microcirculation and coronary vaso-spasm135 Therefore stress echocardiography CMR stress perfusionand SPECT have been proposed to evaluate myocardial perfusion inSS patients

Non-familialnon-genetic RCM radiationtherapy and cancer drug therapy inducedRCMCardiac toxicity of radiation therapy

In general the development of radiotherapy-induced RCM suggests aprior high-dose chest irradiation (gt60 Gy) It can also occur at lower

Figure 13 Forty-one year-old male with a total AV block bradycardia and weakness The patient was suspected of CS Echocardiography wasnormal A FDG PETCT was performed after careful patient preparation with a fatty diet and showed heterogeneous spotty high uptake in the leftventricle of the heart (left whole body PET and upper row right short axis PETCT) The patient was treated with high-dose corticosteroids and therepeated FDG PETCT after 3 months shows fully normalization of the myocardium (right whole body FDG PETCT and lower short axis PETCT)

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radiation exposure when anthracycline is used136 RCM occurs as aresult of diffuse myocardial fibrosis On echocardiography theclassical features of RCM are found Although its value in radiation-related myocardial fibrosis is still unclear ECV estimation usingpre- and post-contract T1 mapping by CMR is directly related to col-lagen content137 The presence of decreased mean LV mass end-diastolic dimension and end-diastolic wall thickness together withdilation of both atria and self-reported dyspnoea is suggestive ofRCM in this population138 Cardiac CT has little value in the diagnosisof RCM after radiotherapy except for the detection of any associatedvascular disease There is no proven value of nuclear cardiology inthe detection of RCM after radiation exposure However perfusionscintigraphy imaging can reveal fixed regional perfusion defects whichpossibly indicate direct damage and the presence of local fibrosis139

Cancer drug induced RCM

The typical structural manifestation of cancer drug induced cardiomy-opathy corresponds to a LV eccentric remodelling with dilation of in-ternal cavity and thinning of myocardial walls140 When clinical heartfailure is overt this picture is associated with a significant reduction ofLV ejection fraction In the more advanced stages LV diastolic func-tion can be strongly altered with an abnormal increase of LV fillingpressure This will induce the classic lsquorestrictiversquo physiology with thetypical standard Doppler-derived transmitral pattern EA ratio gt 2or even gt 3 and short E velocity deceleration time (usually lt 150ndash160 msec) The presence of a restrictive pattern in a patient with can-cer drug induced cardiotoxicity has a recognized prognostic valueexactly as this occurs in the general clinical setting8

Currently the restrictive diastolic pattern is detectable in particu-lar in patients undergoing anthracyclines (Cardiotoxicity type 1) itbeing possibly evident not only during treatment (acute cardiotoxic-ity) but alsomdashand more oftenmdashafter the completion (even severalyears after) of cancer therapies140 (Figure 14 see Supplementarydata online Videos S6 and S7) Early cardiotoxicity occurring duringor within 1 year of completion of treatment is the most importantrisk factor for the development of late cardiotoxicity which occursbeyond a year of completion of treatment This is very important toknow in children undergoing anthracyclines therapy In fact they candevelop late cardiotoxicity during adulthood and should be thereforecarefully monitored for years by echocardiography Cumulative aswell as peak anthracycline doses affect adults and children alike

The restrictive physiology of diastolic pattern is instead very rarein patients undergoing trastuzumab therapy and similar drugs(Cardiotoxicity type 2)140 This kind of cardiotoxicity is usually re-versible with cancer therapy interruption However since trastuzu-mab can be sequentially added to anthracyclines a combined effectanthracyclinesthorn trastuzumab on the degree of LV filling pressurescannot be excluded and should therefore be carefully monitored

When a restrictive LV diastolic pattern is detectable in patientsreceiving cancer drugs the echocardiographic exam should be ex-tended to a quantitative evaluation of LV longitudinal function In factwhen high levels of LV filling pressure are evident a reduction of GLSmeasurable by speckle tracking echocardiography is usually observedIf speckle tracking echocardiography is not available pulsed tissueDoppler-derived srsquo velocity of the mitral annulus or even the simple M-mode derived mitral annular plane systolic excursion represent muchmore than simple surrogates of LV longitudinal dysfunction

Figure 14 Twenty-five year-old woman treated for Hodgkin disease in infancy with anthracyclins Chest X ray (1) and echocardiography (2 and 3)show a non-dilated left ventricle with a relatively preserved LV contractility (Supplementary data online Video S6) However mitral flow (4) and pul-monary venous flow (5) show a severely restrictive pattern and tricuspid flow recording (6) reveals pulmonary hypertension Severe longitudinal dys-function is evidenced by two-dimensional strain (Supplementary data online Videos S6 and S7)

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In this cohort of patients CMR can be useful both for the accuratevolumetric assessment with cine imaging but also with the LGE tech-nique for the detection of myocardial fibrosis140 ie the first deter-minant of LV diastolic dysfunction and LV filling pressure increase

Endomyocardial RCMsEndomyocardial fibrosis

EMF is an often-neglected disorder in the tropical and subtropical re-gions of the world which is characterized by the development of aRCM141 and is associated with a high morbidity and mortality142 Asetiologic causes of EMF infections inflammation allergy malnutritionand toxic agents are discussed143 At the histological level EMF ischaracterized by a marked endocardial thickening due to the depos-ition of fibrous tissue (Figure 15)144

An echocardiographic examination of 1063 individuals revealedthat most subjects (55) had a biventricular involvement and 28revealed a right-sided prevalence with mild-moderate structural andfunctional echocardiographic abnormalities145

Regarding the diagnosis of EMF transthoracic echocardiographicchanges can be useful for visualizing structural abnormalities espe-cially in chronic EMF142144 The main echocardiographic features in-clude apical obliteration of the left andor right ventricles reducedvolume of the ventricular cavity endocardial thickening and a restrict-ive pattern (Figure 16 see Supplementary data online Video S8)

EMF may be difficult to differentiate from other cardiomyopathies(Loefflerrsquos endocarditis ChurgndashStrauss syndrome or rheumatoidarthritis tuberculous pericarditis CP or apical HCM)142146ndash148

After initial echocardiographic analysis CMR149 including LGE

imaging should be performed which is now the gold standard forimaging the disease (Figure 17) In a CMR study of 36 patients it wasshown that LGE-CMR can provide detailed information on ventricu-lar morphology including the existence of thrombus or calcificationsand revealing functional information which is useful in the diagnosisand prognosis of EMF through quantification of the typical pattern ofthe endocardial fibrous tissue deposition150 Adjunctive diagnostictools such as EMB can be considered in ambiguous cases151 and canhelp in patient management

Hypereosinophilic syndrome

Eosinophilic EMF is a rare cause of RCM resulting from toxicity of eo-sinophils towards cardiac tissues152 The causes for eosinophilic infil-tration of myocardium are hypersensitivity parasitic infestationsystemic disease myeloproliferative syndrome and idiopathic hyper-eosinophilic syndrome152

Cardiac disease follows three stages with involvement of the endo-cardium the myocardium and the pericardium The first is eosino-philic myocarditis (acute necrotic stage) due to infiltration ofeosinophils and release of the contents of their granules in themyocardium152 There is no relationship between the extent of theinfiltrate and clinical symptoms153 The intermediate phase is thethrombotic stage characterized by mural thrombi along the damagedendocardium (more often in the apex of the left ventricle) The thirdstage is the later fibrotic stage in which the granulation tissue ischanged into hyaline fibrosis The endocardial scar can result in a de-crease of ventricular compliance and in RCM154

Figure 15 Histologic finding in a patient with EMF

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On echocardiography classical findings are progressive endo-myocardial thickening apical obliteration of one or both ventriclesby echogenic material suggestive of fibrosis or thrombus forma-tion posterior mitral leaflet involvement and papillary dysfunctionresulting in mitral regurgitation154155 (Figure 18A) Pericardial ef-fusion can be present as well as the typical RCM pattern of

normal-to-small ventricles with large atria156 Echocardiographycan also be useful for monitoring the effects of specific therapieson the reversal of endomyocardial infiltration in hypereosinophiliccardiomyopathy157

CMR is very useful in EMF both for diagnosis of endocardial in-volvement and for detection of thrombus formation in both

Figure 17 LV EMF in a 58-year-old man presenting with congestive heart failure (A) Cine four chamber view in end-diastolic phase showing athickening of LV apex (black arrow) a reduced volume of the LV cavity and a left atrial enlargement (B) LGE four chambers view showing a markedendocardial thickening with late gadolinium enhancement (black arrow) and an apical thrombus (open arrow)

Figure 16 (A) (TTE) and (B) (CMR) Right ventricular EMF in a 50 year-old woman (Supplementary data online Video S8) The apex of the rightventricle is obliterated (white arrow) with subsequent surgical confirmation RA right atrium RV right ventricle LV left ventricle LA left atrium

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ventricles158ndash161 (Figure 18B) The gold standard is EMB but the highresolution of CMR and transthoracic echocardiography (TTE) is fre-quently sufficient for diagnosis and follow-up3

Carcinoid heart disease

Carcinoid heart disease occurs in 20ndash70 of patients with metastaticcarcinoid tumours and will lead to increased morbidity and mortality inthese patients162 The endocardial fibrosis results in retraction and fix-ation of the heart valves Right-sided valves are mainly affected163 Left-sided valvular pathology occurs in approximately 10 of patients withcarcinoid heart disease and is associated with right-to-left shuntingbronchial carcinoid or poorly controlled carcinoid syndrome164165

The hallmarks of carcinoid heart disease are a combination ofright-sided valvular dysfunction and typical morphological changes ofthe valves like valve leaflet thickening shortening retraction reducedmobility or incomplete coaptation of the tricuspid leaflets166ndash168

CMR has an additive value in carcinoid heart diseases especiallywhen echocardiography is inconclusive and for accurate measure-ments of right ventricular function and assessment of carcinoid pla-ques using LGE168 Figure 19 and Supplementary data online VideosS9 and S10 illustrate the value of multimodality imaging in a patientwith carcinoid heart disease

Drug-induced EMF

Animal data suggest the possibility of drug-induced EMF induced by5-HT2B serotonin receptor agonists such as fenfluramine derivativespergolide cabergolide and methysergid and ergotamine169ndash171 butvery scarce data are currently reported in man Indeed only one caseof RCM is reported after fenfluramine-phentermine exposure172 Inaddition a case of sub-aortic obstruction within the LV outflow tractrelated to drug-induced EMF has been recently reported in a patientexposed to benfluorex an agonist of 5-HT2B serotoninergicreceptors173

Differential diagnosis betweenRCM and other cardiac diseases

Differential diagnosis between RCM andCPDifferential diagnosis between RCM and CP can be a challenge astheir clinical presentation is relatively similar with right heart fail-ure symptoms preserved LV ejection fraction and diastolic dys-function However as the treatment of these two conditions isvery different constriction being potentially curable by surgerymaking the correct diagnosis is critically important The differen-tial diagnosis could be performed particularly using the comple-mentary elements obtained from TTE CMR cardiac CT orcardiac catheterization (Table 5)

Cardiac catheterization was the first method historically used tohelp in the differential diagnosis of RCM and CP but is not alwaysconclusive174175

In both RCM and CP biatrial dilatation venous dilatation as well aspericardial effusion can be observed Several echocardiographic par-ameters have been identified to differentiate myocardial diseasesfrom pericardial constriction10176 In case of RCM some degree of

LV or biventricular hypertrophy or unusual echo texture can benoted (RCM of infiltrative origin) In case of CP pericardial thickening(gt3 mm) or hyperechogenicity of the pericardium can be observedBut one of the main characteristics of CP is the absence of transmis-sion of the intrathoracic pressure variations to the heart which arephysiologically present during the respiratory cycle

Both TTE and real-time cine CMR allow the identification of somekey findings which differentiate the two pathologies septal bulgingoccurring with cavity volume variations and the exaggeratedrespiratory-related LV-RV coupling highlighted by a respiratory septalshift observed in CP and a significant respiratory variation of the dia-stolic flow The respiratory septal shift is defined by a difference in themaximal septal excursion into LV between inspiration and expiration(Supplementary data online Video S11)176 Using CMR this parameterhas a sensitivity of 80 and specificity of 100 to detect CP17

Other echocardiographic findings have been reported to be usefulfor differentiating RCM and CP including TDI (ersquo) E velocity deceler-ation time pulmonary vein flow left atrial volume and Eersquo ratio177

Figure 20 shows an algorithm proposed by the recent ASEEACVIrecommendations for the evaluation of diastolic function by echocar-diography8 comparing CP and RCM The presence of a normal annu-lar ersquo velocity in a patient referred with heart failure diagnosis shouldraise suspicion of pericardial constriction8

LV myocardial velocities178ndash181 and deformation11 measured byboth TTE and CMR182 are reduced at a greater degree in RCM com-pared to CP Both echocardiography and CMR provide concordantdiagnostic information and incremental value for differentiating CPfrom RCM Complementary assessment of structural (pericardialthickening) mechanical (myocardial velocities and strains) and hae-modynamic (respiratory septal shift) by both TTE and CMR increasethe cost-efficacy and confidence for the diagnosis of RCM vs CP

Cardiac CT provides excellent anatomic delineation of the pericar-dium allowing for accurate measurement of pericardial thickness (ab-normal if gt 4mm)183 although a normal pericardial thickness doesnot exclude CP184 Cardiac CT is superior to CMR in detecting peri-cardial calcifications185 Finally multimodality imaging should be per-formed in patients with suspected CP since each imaging modalitypresents with both advantages and limitations (Table 5 Figure 21)

In summary the differentiation between RCM and CP is frequentlydifficult and should take into account both clinical presentation andmultimodality imaging The absence of pericardial thickening doesnot rule out CP Echocardiography CMR and CT provide comple-mentary information and in many patients all three should be per-formed when CP is suspected

Differential diagnosis or associationbetween RCM and other myocardialdiseasesAlthough in its most typical laquo apparently idiopathic raquo form RCM pre-sents without LV hypertrophy in some patients some forms of car-diomyopathy may resemble or be associated with RCM ParticularlyHCM may resemble RCM in some patients The classical HCMphenotype presents with enhanced contractility small cavityreduced indexed stoke volume LVOT obstruction Grade 1 diastolicdysfunction with some fibrosis186187 As the disease progresses

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Figure 18 (A) Multimodality imaging in hypereosinophilic syndrome with cardiac involvement showing severe restriction of the posterior mitralleaflet associated with involvement of the subvalvular apparatus and severe mitral regurgitation by echocardiography (a b) and CMR (C) with worsen-ing in the follow-up (D) From reference 155 with permission RA right atrium RV right ventricle LV left ventricle LA left atrium (B) CMR in a pa-tient with hypereosinophilic syndrome and Loefflerrsquos syndrome Cine image (still frame) (A) demonstrates a dilated left ventricle and moderatepericardial effusion (asterisks) T2-weighted image (B and C) shows subendocardial high-signal intensity suggestive of inflammation (white arrows)and T1-weighted images after contrast administration (DndashF) demonstrate endocardial fibrosis (arrowheads) Of note an RV apical thrombus is evi-dent in the cine image and in the T1-weighted sequences (triangles) (from 159 with permission)

Multimodality imaging in restrictive cardiomyopathies 1091vD

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extensive fibrosis52 reduced systolic function52 diastolic dysfunc-tion188189 marked dilatation of the atria190 relative thinning of theLV walls loss of LVOT obstruction190ndash192 and pulmonary hyperten-sion192 dominate the picture mimicking RCM

Isolated LV non-compaction is a rare form of cardiomyopathy193

which should also be differentiated from RCM but is also sometimesassociated with a restrictive pattern or even a true RCM194 (Figure22 Supplementary data online Video S12)

Conclusion and future directions

RCM represents a heterogeneous group of cardiac diseases with dif-ferent pathophysiological processes clinical presentation treatmentand prognosis The two main objectives of the clinician are to ruleout CP and to find a potentially treatable cause of RCM Imaging

techniques including echocardiography cardiac CT CMR and nu-clear techniques are of utmost value for the diagnostic and prognos-tic assessment of RCM These techniques give additional informationand should frequently be used in combination in the same patient tomaximize diagnostic performance Finally additional investigationssuch as EMB familial screening and genetic studies are frequently ne-cessary in these patients For these reasons patients with suspectedRCM should be referred to specialized centres that can provide mul-timodality imaging and a multidisciplinary team approach

Supplementary data

Supplementary data are available at European Heart JournalmdashCardiovascular Imaging online

Conflict of interest None declared

Figure 19 Carcinoid disease with right heart involvement (A) (TTE) and (C) (CMR) restriction of the movements of the tricuspid leaflets whichare thickened The right ventricle myocardium is also involved (B) Massive tricuspid regurgitation (TTE) (C) CMR showing dilatation of right heartcavities and restricted tricuspid leaflet (arrow) (Supplementary data online Videos S9 and S10) RA right atrium RV right ventricle LV left ventricleLA left atrium

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Figure 20 ASEEACVI algorithm comparing CP and RCM From 8 with permission

Table 5 Multimodality imaging to differentiate RCM from constrictive pericarditis

Constrictive pericarditis RCM

Chest X-ray

Pericardial calcification thornthornthorn rare

Two-dimensional and M-mode echocardiography

Abrupt septal movement (lsquonotchrsquo or lsquobouncersquo) in early diastole thornthornthorn 0

Septal movement toward left ventricle in inspiration thornthornthorn 0

Left atrial enlargement thorn thornthornthornThick pericardium thornthornthorn 0

Pulsed-wave Doppler

Respiratory variation in mitral and tricuspid flow velocity gt25 lt15

Diastolic flow reversal in expiration within the hepatic vein thornthornthorn thornTDI

Mitral medial annulus velocities ersquo gt 8 cms Eersquo lt 15 ersquo lt 8 cms Eersquo gt 15

Deformation imaging

Reduced longitudinal strain 0 thornthornCardiac CTCMR

Thick pericardium (cardiac CT) thornthornthorn 0

Pericardial calcifications (cardiac CT) thornthornthorn 0

Left atrial enlargement (cardiac CTCMR) thorn thornthornthornAbrupt septal movement (lsquonotchrsquo or lsquobouncersquo) in early diastole (CMR) thornthornthorn 0

Septal movement toward left ventricle in inspiration (CMR) thornthornthorn 0

Reduced longitudinal strain (CMR) 0 thornthorn

RCM restrictive cardiomyopathy TDI tissue Doppler imaging CMR cardiovascular magnetic resonance CT computed tomography

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References1 Elliott P Andersson B Arbustini E Bilinska Z Cecchi F Charron P et al

Classification of the cardiomyopathies a position statement from the EuropeanSociety Of Cardiology Working Group on Myocardial and Pericardial DiseasesEur Heart J 200829270ndash6

2 Richardson P McKenna W Bristow M Maisch B Mautner B OrsquoConnell J et alReport of the 1995 World Health OrganizationInternational Society and feder-ation of cardiology task force on the definition and classification of cardiomyo-pathies Circulation 199693841ndash2

3 Maron BJ Towbin JA Thiene G Antzelevitch C Corrado D Arnett D et alContemporary definitions and classification of the cardiomyopathies anAmerican Heart Association Scientific Statement from the Council on Clinical

Figure 21 Multimodality imaging in a patient with CP (A) CMR Cine four chambers view in end-diastolic phase showing a circumferential pericar-dial thickening (black arrows) biatrial dilatation and septal convexity inversion (open arrow) (B) Cardiac CT Axial thoracic CT scan showing a cir-cumferential pericardial thickening (black arrows) CMR in CP illustrating the respiratory septal shift (difference in the maximal septal excursion intoLV between inspiration and expiration) (Supplementary data online Video S11)

Figure 22 LV hypertrabeculation (arrows) in a young patient with severe RCM (Supplementary data online Video S12)

1091y G Habib et alD

ownloaded from

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ber 2018

Cardiology Heart Failure and Transplantation Committee Quality of Care andOutcomes Research and Functional Genomics and Translational BiologyInterdisciplinary Working Groups and Council on Epidemiology andPrevention Circulation 20061131807ndash16

4 Nihoyannopoulos P Dawson D Restritive cardiomyopathies Eur J Echocardiogr20091023ndash33

5 Kushwaha SS Fallon JT Fuster V Restrictive cardiomyopathy N Engl J Med1997336267ndash76

6 Tam JW Shaikh N Sutherland E Echocardiographic assessment of patientswith hypertrophic and restrictive cardiomyopathy imaging and echocardiog-raphy Curr Opin Cardiol 200217470ndash7

7 Hancock EW Differential diagnosis of restrictive cardiomyopathy and constrict-ive pericarditis Heart 200186343ndash9

8 Nagueh SF Smiseth OA Appleton CP Byrd BF 3rd Dokainish H Edvardsen Tet al Recommendations for the evaluation of left ventricular diastolic functionby echocardiography an update from the American Society ofEchocardiography and the European Association of Cardiovascular Imaging EurHeart J Cardiovasc Imaging 2016171321ndash60

9 Klein AL Hatle LK Taliercio CP Oh JK Kyle RA Gertz MA et al Prognosticsignificance of Doppler measures of diastolic function in cardiac amyloidosis ADoppler echocardiography study Circulation 199183808ndash816

10 Hyodo E Hozumi T Takemoto Y Watanabe H Muro T Yamagishi H et alEarly detection of cardiac involvement in patients with sarcoidosis by a non-invasive method with ultrasonic tissue characterisation Heart 2004901275ndash80

11 Bhandari AK Nanda NC Myocardial texture characterization by two-dimensional echocardiography Am J Cardiol 198351817

12 Schiano-Lomoriello V Galderisi M Mele D Esposito R Cerciello G BuonauroA et al Longitudinal strain of left ventricular basal segments and Eersquo ratio differ-entiate primary cardiac amyloidosis at presentation from hypertensive hyper-trophy an automated function imaging study Echocardiography 2016 doi101111echo13278

13 Sengupta PP Krishnamoorthy VK Abhayaratna WP Korinek J Belohlavek MSundt TM 3rd et al Disparate patterns of left ventricular mechanics differentiateconstrictive pericarditis from restrictive cardiomyopathy JACC CardiovascImaging 2008129ndash38

14 Kramer CM Barkhausen J Flamm SD Kim RJ Nagel E Society forCardiovascular Magnetic Resonance Board of Trustees Task Force onStandardized Protocols Standardized cardiovascular magnetic resonance(CMR) protocols 2013 update J Cardiovasc Magn Reson 20131591

15 Bellenger NG Davies LC Francis JM Coats AJ Pennell DJ Reduction in samplesize for studies of remodeling in heart failure by the use of cardiovascular mag-netic resonance J Cardiovasc Magn Reson 20002271ndash8

16 Cosyns B Plein S Nihoyanopoulos P Smiseth O Achenbach S Andrade MJet al European Association of Cardiovascular Imaging (EACVI) EuropeanSociety of Cardiology Working Group (ESC WG) on Myocardial andPericardial diseases European Association of Cardiovascular Imaging (EACVI)position paper multimodality imaging in pericardial disease Eur Heart JCardiovasc Imaging 20151612ndash31

17 Francone M Dymarkowski S Kalantzi M Rademakers FE Bogaert J Assessmentof ventricular coupling with real-time cine MRI and its value to differentiateconstrictive pericarditis from restrictive cardiomyopathy Eur Radiol200616944ndash51

18 Sado DM White SK Piechnik SK Banypersad SM Treibel T Captur G et alIdentification and assessment of Anderson-Fabry disease by cardiovascular mag-netic resonance noncontrast myocardial T1 mapping Circ Cardiovasc Imaging20136392ndash8

19 Fontana M Pica S Reant P Abdel-Gadir A Treibel TA Banypersad SM et alPrognostic value of late gadolinium enhancement cardiovascular magnetic res-onance in cardiac amyloidosis Circulation 20151321570ndash9

20 Schelbert EB Piehler KM Zareba KM Moon JC Ugander M Messroghli DRet al Myocardial fibrosis quantified by extracellular volume is associated withsubsequent hospitalization for heart failure death or both across the spectrumof ejection fraction and heart failure stage J Am Heart Assoc 2015412

21 Anderson LJ Holden S Davis B Prescott E Charrier CC Bunce NH et alCardiovascular T2-star (T2) magnetic resonance for the early diagnosis ofmyocardial iron overload Eur Heart J 2001222171ndash9

22 Modell B Khan M Darlison M Westwood MA Ingram D Pennell DJ Improvedsurvival of thalassaemia major in the UK and relation to T2 cardiovascularmagnetic resonance J Cardiovasc Magn Reson 20081042

23 Karamitsos TD Piechnik SK Banypersad SM Fontana M Ntusi NB Ferreira VMet al Noncontrast T1 mapping for the diagnosis of cardiac amyloidosis JACCCardiovasc Imaging 20136488ndash97

24 Banypersad SM Sado DM Flett AS Gibbs SD Pinney JH Maestrini V et alQuantification of myocardial extracellular volume fraction in systemic AL amyl-oidosis an equilibrium contrast cardiovascular magnetic resonance study CircCardiovasc Imaging 2013634ndash9

25 Alam MH Auger D McGill LA Smith GC He T Izgi C et al Comparison of 3T and 15 T for T2 magnetic resonance of tissue iron J Cardiovasc Magn Reson20161840

26 Yared K Baggish AL Picard MH Hoffmann U Hung J Multimodality imaging ofpericardial diseases JACC Cardiovascular imaging 20103650ndash60

27 Zhao L Ma X Feuchtner GM Zhang C Fan Z Quantification of myocardialdelayed enhancement and wall thickness in hypertrophic cardiomyopathy mul-tidetector computed tomography versus magnetic resonance imaging Europeanjournal of radiology 2014831778ndash85

28 Hamilton-Craig C Seltmann M Ropers D Achenbach S Myocardial viability bydual-energy delayed enhancement computed tomography JACC Cardiovascularimaging 20114207ndash8

29 Bandula S Banypersad SM Sado D Flett AS Punwani S Taylor SA et alMeasurement of tissue interstitial volume in healthy patients and those withamyloidosis with equilibrium contrast-enhanced mr imaging Radiology2013268858ndash64

30 Kula RW Engel WK Line BR Scanning for soft-tissue amyloid Lancet1977192ndash3

31 Aljaroudi WA Desai MY Tang WH Phelan D Cerqueira MD Jaber WA Roleof imaging in the diagnosis and management of patients with cardiac amyloid-osis state of the art review and focus on emerging nuclear techniques J NuclCardiol 201421271ndash83

32 Glaudemans AW van Rheenen RW van den Berg MP Noordzij W Koole MBlokzijl H et al Bone scintigraphy with (99m)technetium-hydroxymethylenediphosphonate allows early diagnosis of cardiac involvement in patients withtransthyretin-derived systemic amyloidosis Amyloid 20142135ndash44

33 Minutoli F Di Bella G Mazzeo A Donato R Russo M Scribano E et alComparison between (99m)Tc-diphosphonate imaging and MRI with late gadolin-ium enhancement in evaluating cardiac involvement in patients with transthyretinfamilial amyloid polyneuropathy AJR Am J Roentgenol 2013200W256ndash65

34 Coutinho MC Cortez-Dias N Cantinho G Conceic~ao I Oliveira A Bordalo eSa A et al Reduced myocardial 123-iodine metaiodobenzylguanidine uptake aprognostic marker in familial amyloid polyneuropathy Circ Cardiovasc Imaging20136627ndash36

35 Youssef G Beanlands RSB Birnie DH Nery PB Cardiac sarcoidosis applica-tions of imaging in diagnosis and directing treatment Heart2011972078ndash87

36 Ohira H Tsujino I Ishimaru S Oyama N Takei T Tsukamoto E et alMyocardial imaging with 18F-fluoro-2-deoxyglucose positron emission tomog-raphy and magnetic resonance imaging in sarcoidosis Eur J Nucl Med MolImaging 200835933ndash41

37 Apgral R Dweck MR Trivieri MG Robson PM Karakatsanis N Mani V et alClinical Utility of Combined FDG-PETMR to Assess Myocardial Disease JACCCardiovasc Imaging 2016 Jun 29 piiS1936-878X(16)30259ndash5 doi 101016jjcmg201602029 [Epub ahead of print]

38 Mogensen J Arbustini E Restrictive cardiomyopathy Curr Opin Cardiol200924214ndash20

39 Arbustini E Morbini P Grasso M Fasani R Verga L Bellini O et al Restrictivecardiomyopathy atrioventricular block and mild to subclinical myopathy in pa-tients with desmin-immunoreactive material deposits J Am Coll Cardiol199831645ndash53

40 Arbustini E Buonanno C Trevi G Pennelli N Ferrans VJ Thiene G Cardiacultrastructure in primary restrictive cardiomyopathy Chest 198384236ndash8

41 Cannavale A Ordovas KG Rame EJ Higgins CB Hypertrophic cardiomyopathy withrestrictive phenotype and myocardial crypts J Thorac Imaging 201025W121ndash3

42 Rapezzi C Lorenzini M Longhi S Milandri A Gagliardi C Bartolomei I et alCardiac amyloidosis the great pretender Heart Fail Rev 201520117ndash24

43 Rapezzi C Arbustini E Caforio AL et al Diagnostic work-up in cardiomyopa-thies bridging the gap between clinical phenotypes and final diagnosis A pos-ition statement from the ESC Working Group on Myocardial and PericardialDiseases Eur Heart J 2013341448ndash58

44 Koyama J Ikeda S Ikeda U Echocardiographic assessment of the cardiac amy-loidoses Circ J 201579721ndash34

45 Feng D Edwards WD Oh JK Chandrasekaran K Grogan M Martinez MWet al Intracardiac thrombosis and embolism in patients with cardiac amyloidosisCirculation 20071162420ndash6

46 Innelli P Galderisi M Catalano L Martorelli MC Olibet M Pardo M et alDetection of increased left ventricular filling pressure by pulsed tissue Dopplerin cardiac amyloidosis J Cardiovasc Med 20067742ndash7

47 Tendler A Helmke S Teruya S Alvarez J Maurer MS The myocardial contrac-tion fraction is superior to ejection fraction in predicting survival in patientswith AL cardiac amyloidosis Amyloid 20152261ndash6

48 Phelan D Collier P Thavendiranathan P Popovic ZB Hanna M Plana JC et alRelative apical sparing of longitudinal strain using two-dimensional speckle-trackingechocardiography is both sensitive and specific for the diagnosis of cardiac amyl-oidosis Heart 2012981442ndash8

Multimodality imaging in restrictive cardiomyopathies 1091zD

ownloaded from

httpsacademicoupcom

ber 2018

49 Schiano-Lomoriello V Galderisi M Mele D Esposito R Cerciello G Buonauro

A et al Longitudinal strain of left ventricular basal segments and Eersquo ratio differ-entiate primary cardiac amyloidosis at presentation from hypertensive hyper-trophy an automated function imaging study Echocardiography2016331335ndash43

50 Bellavia D Pellikka PA Al-Zahrani GB Abraham TP Dispenzieri A Miyazaki Cet al Independent predictors of survival in primary systemic (Al) amyloidosisincluding cardiac biomarkers and left ventricular strain imaging an observationalcohort study J Am Soc Echocardiogr 201023643ndash52

51 Ternacle J Bodez D Guellich A Audureau E Rappeneau S Lim P et al Causesand consequences of longitudinal LV dysfunction assessed by 2D strain echo-cardiography in cardiac amyloidosis JACC Cardiovasc Imaging 20169126ndash38

52 Quarta CC Solomon SD Uraizee I Kruger J Longhi S Ferlito M et al LeftVentricular structure and function in TTR-related versus AL cardiac amyloid-osis Circulation 20141291840ndash9

53 Maceira AM Joshi J Prasad SK Moon JC Perugini E Harding I et alCardiovascular magnetic resonance in cardiac amyloidosis Circulation2005111186ndash93

54 Vogelsberg H Mahrholdt H Deluigi CC Yilmaz A Kispert EM Greulich S et alCardiovascular magnetic resonance in clinically suspected cardiac amyloidosisnoninvasive imaging compared to endomyocardial biopsy J Am Coll Cardiol2008511022ndash30

55 Syed IS Glockner JF Feng D Araoz PA Martinez MW Edwards WD et alRole of cardiac magnetic resonance imaging in the detection of cardiac amyloid-osis JACC Cardiovasc Imaging 20103155ndash64

56 Fontana M Banypersad SM Treibel TA Abdel-Gadir A Maestrini V Lane Tet al Differential myocyte responses in patients with cardiac transthyretin amyl-oidosis and light-chain amyloidosis a cardiac MR imaging study Radiology2015277388ndash97

57 Di Bella G Pizzino F Minutoli F Zito C Donato R Dattilo G et al The mosaicof the cardiac amyloidosis diagnosis role of imaging in subtypes and stages ofthe disease Eur Heart J Cardiovasc Imaging 2014151307ndash15

58 Bokhari S Castano A Pozniakoff T Deslisle S Latif F Maurer MS (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosisfrom the transthyretin-related familial and senile cardiac amyloidoses CircCardiovasc Imaging 20136195ndash201

59 Hutt DF Quigley AM Page J Hall ML Burniston M Gopaul D et al Utility andlimitations of 33-diphosphono-12-propanodicarboxylic acid scintigraphy in sys-temic amyloidosis Eur Heart J Cardiovasc Imaging 2014151289ndash98

60 Perugini E Guidalotti PL Salvi F Cooke RM Pettinato C Riva L et alNoninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-33-diphos-phono-12-propanodicarboxylic acid scintigraphy J Am Coll Cardiol2005461076ndash84

61 Rapezzi C Quarta CC Guidalotti PL Pettinato C Fanti S Leone O et al Role of(99m)Tc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis JACC Cardiovasc Imaging 20114659ndash70

62 Gillmore JD Maurer MS Falk RH Merlini G Damy T Dispenzieri A et alNonbiopsy diagnosis of cardiac transthyretin amyloidosis Circulation20161332404ndash12

63 Cardim N Galderisi M Edvardsen T Plein S Popescu BA DrsquoAndrea A et alRole of multimodality cardiac imaging in the management of patients withhypertrophic cardiomyopathy an expert consensus of the EuropeanAssociation of Cardiovascular Imaging Endorsed by the Saudi HeartAssociation Eur Heart J Cardiovasc Imaging 201516280

64 Bosi G Crepaz R Gamberini MR Fortini M Scarcia S Bonsante E et al Leftventricular remodelling and systolic and diastolic function in young adults withbeta thalassaemia major a Doppler echocardiographic assessment and correl-ation with haematological data Heart 200389762ndash6

65 Leon MB Borer JS Bacharach SL Green MV Benz EJ Jr Griffith P et alDetection of early cardiac dysfunction in patients with severe beta-thalassemiaand chronic iron overload N Engl J Med 19793011143ndash8

66 Kremastinos DT Farmakis D Aessopos A Hahalis G Hamodraka E Tsiapras Det al Beta-thalassemia cardiomyopathy history present considerations and fu-ture perspectives Circ Heart Fail 20103451ndash8

67 Cogliandro T Derchi G Mancuso L Mayer MC Pannone B Pepe A et alSociety for the Study of Thalassemia and Hemoglobinopathies (SoSTE)Guideline recommendations for heart complications in thalassemia majorJ Cardiovasc Med 20089515ndash25

68 Efthimiadis GK Hassapopoulou HP Tsikaderis DD Karvounis HI GiannakoulasGA Parharidis GE et al Survival in thalassaemia major patients Circ J2006701037ndash42

69 Giakoumis A Berdoukas V Gotsis E Aessopos A Comparison of echocardio-graphic (US) volumetry with cardiac magnetic resonance imaging in transfusiondependent thalassemia major Cardiovasc Ultrasound 2007524

70 Pennell DJ Udelson JE Arai AE Bozkurt B Cohen AR Galanello R et al AmericanHeart Association Committee on Heart Failure and Transplantation of the Council

on Clinical Cardiology and Council on Cardiovascular Radiology and ImagingCardiovascular function and treatment in b-thalassemia major a consensus state-ment from the American Heart Association Circulation 2013128281ndash308

71 Pepe A Meloni A Capra M Cianciulli P Prossomariti L Malaventura C et alDeferasirox deferiprone and desferrioxamine treatment in thalassemia majorpatients cardiac iron and function comparison determined by quantitative mag-netic resonance imaging Haematologica 20119641ndash7

72 Meloni A Positano V Ruffo GB Spasiano A DrsquoAscola D Peluso A et alImprovement of heart iron with preserved patterns of iron store by CMR-guided chelation therapy European Heart J Cardiovasc Imaging 201516325ndash34

73 Casale M Meloni A Filosa A Cuccia L Caruso V Palazzi G et alMultiparametric cardiac magnetic resonance survey in children with thalassemiamajor a multicenter study Circ Cardiovasc Imaging 20158e003230

74 Pepe A Positano V Capra M Maggio A Pinto CL Spasiano A et al Myocardialscarring by delayed enhancement cardiovascular magnetic resonance in thalas-saemia major Heart 2009951688ndash93

75 Linhart A Kampmann C Zamorano JL Sunder-Plassmann G Beck M Mehta Aet al European FOS Investigators Cardiac manifestations of Anderson-Fabrydisease results from the international Fabry outcome survey Eur Heart J2007281228ndash35

76 MacDermot KD Holmes A Miners AH Natural history of Fabry disease inaffected males and obligate carrier females J Inherit Metab Dis200124(Suppl 2)13ndash4

77 Gambarin FI Disabella E Narula J Diegoli M Grasso M Serio A et al When shouldcardiologists suspect Anderson-Fabry disease Am J Cardiol 20101061492ndash9

78 West M Nicholls K Mehta A Clarke JT Steiner R Beck M et al Agalsidase alphaand kidney dysfunction in Fabry disease J Am Soc Nephrol 2009201132ndash9

79 Perrot A Osterziel KJ Beck M Dietz R Kampmann C Fabry disease focus oncardiac manifestations and molecular mechanisms Herz 200227699ndash702

80 Nagueh SF Anderson-Fabry disease and other lysosomal storage disordersCirculation 20141301081ndash90

81 Weidemann F Linhart A Monserrat L Strotmann J Cardiac challenges in pa-tients with Fabry disease Int J Cardiol 20101413ndash10

82 Hoigne P Attenhofer Jost CH Duru F Oechslin EN Seifert B Widmer U et alSimple criteria for differentiation of Fabry disease from amyloid heart diseaseand other causes of left ventricular hypertrophy Int J Cardiol 2006111413ndash22

83 Feriozzi S Schwarting A Sunder-Plassmann G West M Cybulla MInternational Fabry Outcome Survey Investigators Agalsidase alpha slows thedecline in renal function in patients with Fabry disease Am J Nephrol200929353ndash61

84 Pieroni M Chimenti C Russo A Russo MA Maseri A Frustaci A TissueDoppler imaging in Fabry disease Curr Opin Cardiol 200419452ndash7

85 Toro R Perez-Isla L Doxastaquis G Barba MA Gallego AR Pintos G et alClinical usefulness of tissue Doppler imaging in predicting preclinical Fabry car-diomyopathy Int J Cardiol 200913238ndash44

86 Zamorano J Serra V Perez de Isla L Feltes G Calli A Barbado FJ et alUsefulness of tissue Doppler on early detection of cardiac disease in Fabry pa-tients and potential role of enzyme replacement therapy (ERT) for avoidingprogression of disease Eur J Echocardiogr 201112671ndash7

87 De Cobelli F Esposito A Belloni E Pieroni M Perseghin G Chimenti C et alDelayed-enhanced cardiac MRI for differentiation of Fabryrsquos disease fromsymmetric hypertrophic cardiomyopathy AJR Am J Roentgenol 2009192W97-102

88 Boucek D Jirikowic J Taylor M Natural history of Danon disease Genet Med201113563ndash8

89 Maron BJ Roberts WC Arad M Haas TS Spirito P Wright GB et al Clinicaloutcome and phenotypic expression in LAMP2 cardiomyopathy JAMA20093011253ndash9

90 Drsquosouza RS Levandowski C Slavov D Graw SL Allen LA Adler E et al Danondisease clinical features evaluation and management Circ Heart Fail20147843ndash9

91 Gussenhoven WJ Busch HF Kleijer WJ de Villeneuve VH Echocardiographicfeatures in the cardiac type of glycogen storage disease II Eur Heart J1983441ndash3

92 Rees A Elbl F Minhas K Solinger R Echocardiographic evidence of outflowtract obstruction in Pompersquos disease (glycogen storage disease of the heart)Am J Cardiol 1976371103ndash6

93 Barker PC Pasquali SK Darty S Ing RJ Li JS Kim RJ et al Use of cardiac mag-netic resonance imaging to evaluate cardiac structure function and fibrosis inchildren with infantile Pompe disease on enzyme replacement therapy MolGenet Metab 2010101332ndash7

94 Nucifora G Miani D Piccoli G Proclemer A Cardiac magnetic resonance imag-ing in Danon disease Cardiology 201212127ndash30

95 Wei LG Gao JQ Liu XM Huang JM Li XZ A study of glycogen storage diseasewith 99Tcm-MIBI gated myocardial perfusion imaging Ir J Med Sci2013182615ndash20

1091aa G Habib et alD

ownloaded from

httpsacademicoupcom

ber 2018

96 Lo Iudice F Barbato A Muscariello R Di Nardo C de Stefano F Sibilio M et al

Left ventricular diastolic dysfunction in type I Gaucher Disease An EchoDoppler Study Echocardiography 201532890ndash5

97 Braunlin E Wang R Cardiac issues in adults with mucopolysaccharidoses cur-rent knowledge and emerging needs Heart 20161021257ndash62

98 Przybojewski JZ Maritz F Tiedt FA van der Walt JJ Pseudoxanthoma elasticumwith cardiac involvement A case report and review of the literature S Afr MedJ 198159268ndash75

99 Campens L Vanakker OM Trachet B Segers P Leroy BP De Zaeytijd J et alCharacterization of cardiovascular involvement in pseudoxanthoma elasticumfamilies Arterioscler Thromb Vasc Biol 2013332646ndash52

100 Nguyen LD Terbah M Daudon P Martin L Left ventricular systolic and dia-stolic function by echocardiogram in pseudoxanthoma elasticum Am J Cardiol2006971535ndash7

101 Saban-Ruiz J Fabregate Fuente R Sanchez-Largo Uceda E Fabregate Fuente MPseudoxanthoma elasticum case report with arterial stiffness evaluated by a re-search cardiovascular profiling system Eur J Dermatol 201020785ndash7

102 Kandolin R Lehtonen J Airaksinen J Vihinen T Miettinen H Ylitalo K et alCardiac sarcoidosis epidemiology characteristics and outcome over 25 yearsin a nationwide study Circulation 2015131624ndash32

103 Birnie DH Sauer WH Bogun F Cooper JM Culver DA Duvernoy CS et alHRS expert consensus statement on the diagnosis and management of arrhyth-mias associated with cardiac sarcoidosis Heart Rhythm 2014111305ndash23

104 Judson MA Costabel U Drent M Wells A Maier L Koth L et al OrganAssessment Instrument Investigators TW The WASOG Sarcoidosis OrganAssessment Instrument An update of a previous clinical tool Sarcoidosis VascDiffuse Lung Dis 20143119ndash27

105 Chiu CZ Nakatani S Yamagishi M Miyatake K Cheng JJ EchocardiographicManifestations in Patients with Cardiac Sarcoidosis J Med Ultrasound200210135ndash40

106 Hourigan LA Burstow DJ Pohlner P Clarke BE Donnelly JE Transesophagealechocardiographic abnormalities in a case of cardiac sarcoidosis J Am SocEchocardiogr 200114399ndash402

107 Patel MR Cawley PJ Heitner JF Klem I Parker MA Jaroudi WA Detection ofmyocardial damage in patients with sarcoidosis Circulation 20091201969ndash77

108 Hundley WG Bluemke DA Finn JP Flamm SD Fogel MA Friedrich MG et alACCFACRAHANASCISCMR 2010 expert consensus document on cardio-vascular magnetic resonance a report of the American College of CardiologyFoundation Task Force on Expert Consensus Documents J Am Coll Cardiol2010552614ndash62

109 Schulz-Menger J Wassmuth R Abdel-Aty H Siegel I Franke A Dietz RFriedrich M G Patterns of myocardial inflammation and scarring in sarcoidosisas assessed by cardiovascular magnetic resonance Heart 200692399ndash400

110 Seward JB Casaclang-Verzosa G Infiltrative cardiovascular diseases cardiomyo-pathies that look alike J Am Coll Cardiol 2010551769ndash79

111 Lancefield T Voskoboinik A Taylor AJ Nadel J Late gadolinium enhancementidentified with cardiac magnetic resonance imaging in sarcoidosis patients isassociated with long-term ventricular arrhythmia and sudden cardiac death EurHeart J Cardiovasc Imaging 201516634ndash41

112 Okumura W Iwasaki T Toyama T Iso T Arai M Oriuchi N et al Usefulness offasting 18F-FDG PET in identification of cardiac sarcoidosis J Nucl Med2004451989ndash98

113 Keijsers RG Grutters JC Thomeer M Du Bois RM Van Buul MM Lavalaye FJet al Imaging the inflammatory activity of sarcoidosis sensitivity and inter obser-ver agreement of (67)Ga imaging and (18)F-FDG PET Q J Nucl Med Mol Imaging20115566ndash71

114 Ishimaru S Tsujino I Takei T Tsukamoto E Sakaue S Kamigaki M et al Focaluptake on 18F-fluoro-2-deoxyglucose positron emission tomography images in-dicates cardiac involvement of sarcoidosis Eur Heart J 2005261538ndash43

115 Youssef G Leung E Mylonas I Nery P Williams K Wisenberg G et al The useof 18F-FDG PET in the diagnosis of cardiac sarcoidosis a systematic review andmetaanalysis including the Ontario experience J Nucl Med 201253241ndash8

116 Tang R Wang JT Wang L Le K Huang Y Hickey AJ et al Impact of patientpreparation on the diagnostic performance of 18F-FDG PET in cardiac sarcoid-osis a systematic review and meta-analysis Clin Nucl Med 201641e327-39

117 Skali H Schulman AR Dorbala S (18)F-FDG PETCT for the assessment ofmyocardial sarcoidosis Curr Cardiol Rep 201315352

118 Blankstein R Osborne M Naya M Waller A Kim CK Murthy VL et al Cardiacpositron emission tomography enhances prognostic assessments of patientswith suspected cardiac sarcoid J Am Coll Cardiol 201463329ndash36

119 Yokoyama R Miyagawa M Okayama H Inoue T Miki H Ogimoto A et alQuantitative analysis of myocardial 18F-fluorodeoxyglucose uptake by PETCTfor detection of cardiac sarcoidosis Int J Cardiol 2015195180ndash7

120 Yamagishi H Shirai N Takagi M Yoshiyama M Akioka K Takeuchi K et alIdentification of cardiac sarcoidosis with (13) N-NH(3)[18F]FDG PET J NuclMed 2003441030ndash6

121 Osborne MT1 Hulten EA Singh A Waller AH Bittencourt MS Stewart GCet al Reduction in 18F-fluorodeoxyglucose uptake on serial cardiac positronemission tomography is associated with improved left ventricular ejection frac-tion in patients with cardiac sarcoidosis J Nucl Cardiol 201421166ndash74

122 Ohira H Birnie DH Pena E Bernick J Mc Ardle B Leung E et al Comparisonof (18)F-fluorodeoxyglucose positron emission tomography (FDG PET) andcardiac magnetic resonance (CMR) in corticosteroid-naive patients with con-duction system disease due to cardiac sarcoidosis Eur J Nucl Med Mol Imaging201643259ndash69

123 Leask A The role of endothelin-1 signaling in the fibrosis observed in systemicsclerosis Pharmacol Res 201163502ndash3

124 Tyndall AJ Bannert B Vonk M Airo P Cozzi F Carreira PE et al Causes andrisk factors for death in systemic sclerosis a study from the EULARScleroderma Trials and Research (EUSTAR) database Ann Rheum Dis2010691809ndash15

125 Follansbee WP Miller TR Cirtoss EI Orie JE Bernstein RL Kiernan JM et al Acontrolled clinicopathologic study of myocardial fibrosis in systemic sclerosis(scleroderma) J Rheumatol 199017656ndash62

126 Meune C Avouac J Wahbi K Cabanes L Wipff J Mouthon L et al Cardiac in-volvement in systemic sclerosis assessed by tissue-doppler echocardiographyduring routine care a controlled study of 100 consecutive patients ArthritisRheum 2008581803ndash9

127 Allanore Y Meune C Vonk MC Airo P Hachulla E Caramaschi P et alPrevalence and factors associated with left ventricular dysfunction in theEULAR Scleroderma Trial and Research group (EUSTAR) database of patientswith systemic sclerosis Ann Rheum Dis 201069218ndash21

128 DrsquoAndrea A Stisi S Bellissimo S Vigorito F Scotto di Uccio F Tozzi N et alEarly impairment of myocardial function in systemic sclerosis non-invasive as-sessment by Doppler myocardial and strain rate imaging Eur J Echocardiogr20056407ndash18

129 Yiu KH Schouffoer AA Marsan NA Ninaber MK Stolk J Vlieland TV et al Leftventricular dysfunction assessed by speckle-tracking strain analysis in patientswith systemic sclerosis Arthritis Rheum 2011633969ndash78

130 Mueller KA Mueller II Eppler D Zuern CS Seizer P Kramer U et al Clinicaland histopathological features of patients with systemic sclerosis undergoingendomyocardial biopsy PLoS One 201510e0126707

131 Hachulla AL Launay D Gaxotte V deGroote P Lamblin N Devos P et alCardiac magnetic resonance imaging in systemic sclerosis a cross-sectional ob-servational study of 52 patients Ann Rheum Dis 2009681878ndash84

132 Ugander M Oki AJ Hsu LY Kellman P Greiser A Aletras AH et alExtracellular volume imaging by magnetic resonance imaging provides insightsinto overt and sub-clinical myocardial pathology Eur Heart J 2012331268ndash78

133 Barison A Gargani L De Marchi D Aquaro GD Guiducci S Picano E et alEarly myocardial and skeletal muscle interstitial remodelling in systemic scler-osis insights from extracellular volume quantification using cardiovascular mag-netic resonance Eur Heart J Cardiovasc Imaging 20151674ndash80

134 Thuny F Lovric D Schnell F Bergerot C Ernande L Cottin V et alQuantification of myocardial extracellular volume fraction with cardiac MRimaging for early detection of left ventricle involvement in systemic sclerosisRadiology 2014271373ndash80

135 Follansbee WP Curtiss EI Medsger TA Jr Steen VD Uretsky BF Owens GRet al Physiologic abnormalities of cardiac function in progressive systemic scler-osis with diffuse scleroderma N Engl J Med 1984310142ndash8

136 Lancellotti P Nkomo VT Badano LP Bergler-Klein J Bogaert J Davin L et alExpert consensus for multi-modality imaging evaluation of cardiovascular com-plications of radiotherapy in adults a report from the European Association ofCardiovascular Imaging and the American Society of Echocardiography EurHeart J Cardiovasc Imaging 201314721ndash40

137 Messroghli D Nordmeyer S Dietrich T Dirsch O Kaschina E Savvatis K et alAssessment of diffuse myocardial fibrosis in rats using small-animal Look-Lockerinversion recovery T1 mapping Circ Cardiovasc Imaging 20114636ndash40

138 Constine L Schwartz R Savage D King V Muhs A Cardiac function perfusionand morbidity in irradiated long-term survivors of Hodgkinrsquos disease Int J RadiatOncol Biol Phys 199739897ndash906

139 Marks L Yu X Prosnitz R Zhou SM Hardenbergh P Blazing M et al The inci-dence and functional consequences of RT-associated cardiac perfusion defectsInt J Radiat Oncol Biol Phys 200563214ndash23

140 Plana JC Galderisi M Barac A Ewer MS Ky B Scherrer-Crosbie M et al Expertconsensus for multimodality imaging evaluation of adult patients during andafter cancer therapy a report from the American Society of Echocardiographyand the European Association of Cardiovascular Imaging Eur Heart J CardiovascImaging 2014151063ndash93

141 Dato I How to recognize endomyocardial fibrosis J Cardiovasc Med201516547ndash51

142 Mocumbi AO Endomyocardial fibrosis A form of endemic restrictive cardio-myopathy Glob Cardiol Sci Pract 2012201211

Multimodality imaging in restrictive cardiomyopathies 1091abD

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ber 2018

143 Bukhman G Ziegler J Parry E Endomyocardial fibrosis still a mystery after 60

years PLoS Negl Trop Dis 20082e97144 Mocumbi AO Carrilho C Sarathchandra P Ferreira MB Yacoub M Burke M

Echocardiography accurately assesses the pathological abnormalities of chronicendomyocardial fibrosis Int J Cardiovasc Imaging 201127955ndash64

145 Mocumbi AO Ferreira MB Sidi D Yacoub MH A population study of endo-myocardial fibrosis in a rural area of Mozambique N Engl J Med 200835943ndash9

146 Kharabish A Haroun D Cardiac MRI findings of endomyocardial fibrosis(Loefflerrsquos endocarditis) in a patient with rheumatoid arthritis J Saudi HeartAssoc 201527127ndash31

147 Schneeweis C Berger A Kelle S Fleck E Gebker R Endomyocardial fibrosisin patients with confirmed Churg_Strauss syndrome Rheumatology 20145384

148 Maia CP Gali LG Schmidt A de Almeida Filho OC Santos MK et al A chal-lenging differential diagnosis distinguishing between endomyocardial fibrosisand apical hypertrophic cardiomyopathy Echocardiography 2016331080ndash4

149 Cury R Abbara S Sandoval LJ Houser S Brady T and Palacios IF Visualizationof endomyocardial fibrosis by delayed-enhancement magnetic resonanceImaging Circulation 2005111e115ndash7

150 Salemi VMC Rochitte CE Shiozaki AA Andrade JM Parga JR de Avila LF et alLate gadolinium enhancement magnetic resonance imaging in the diagnosis andprognosis of endomyocardial fibrosis patients Circ Cardiovasc Imaging20114304ndash11

151 Roper D Hillier SD Burstow DJ Platts D Non-tropical endomyocardial fi-brosis associated with sarcoidosis Eur Heart J Cardiovasc Imaging 201415472

152 Seguela PE Iriart X Acar P Montaudon M Roudaut R Thambo JB Eosinophiliccardiac disease molecular clinical and imaging aspects Arch Cardiovass Dis2015108258ndash68

153 Al Ali AM Straatman LP Allard MF Ignaszewski AP Eosinophilic myocarditiscase series and review of literature Can J Cardiol 2006221233ndash7

154 Ommen SR Seward JB Tajik AJ Clinical and echocardiographic features ofhypereosinophilic syndromes Am J Cardiol 20001110ndash3

155 Simonnet B Jacquier A Salaun E Hubert S Habib G Cardiac involvement inhypereosinophilic syndrome role of multimodality imaging Eur Heart JCardiovasc Imaging 201516228

156 Acquatella H Schiller NB Puigbo JJ Gomez-Mancebo JR Suarez C AcquatellaG Value of two-dimensional echocardiography in endomyocardial disease withand without eosinophilia A clinical and pathologic study Circulation1983671219ndash26

157 Rotoli B Catalano L Galderisi M Luciano L Pollio G Guerriero A et al Rapidreversion of Loefflerrsquos endocarditis by imatinib in early stage clonal hypereosi-nophilic syndrome Leuk Lymphoma 2004452503ndash7

158 Puvaneswary M Joshua F Ratnarajah S Idiopathic hypereosinophilic syndromemagnetic resonance imaging findings in endomyocardial fibrosis Australas Radiol200145524ndash7

159 Porto AG McAlindon E Hamilton M Manghat N Bucciarelli-Ducci CDiagnosing cardiac involvement in the hypereosinophilic syndrome by cardiacmagnetic resonance Am J Cardiol 2013112135ndash6

160 Pillar N Halkin A Aviram G Hypereosinophilic syndrome with cardiac involve-ment early diagnosis by cardiac magnetic resonance imaging Can J Cardiol2012515e11ndash3

161 ten Oever J Theunissen LJ Tick LW Verbunt RJCardiac involvement in hyper-eosinophilic syndrome Neth J Med 201169240

162 Haugaa KH Bergestuen DS Sahakyan LG Skulstad H Aakhus S Thiis-EvensenE et al Evaluation of right ventricular dysfunction by myocardial strain echocar-diography in patients with intestinal carcinoid disease J Am Soc Echocardiogr201124644ndash50

163 Modlin IM Shapiro MD Kidd M Carcinoid tumors and fibrosis an associationwith no explanation Am J Gastroenterol 2004992466ndash78

164 Connolly HM Pellikka PA Carcinoid heart disease Curr Cardiol Rep2006896ndash101

165 Pellikka PA Tajik AJ Khandheria BK Seward JB Callahan JA Pitot HC et alCarcinoid heart disease Clinical and echocardiographic spectrum in 74 patientsCirculation 1993871188ndash96

166 Urheim S Edvardsen T Torp H Angelsen B Smiseth OA Myocardial strain byDoppler echocardiography Validation of a new method to quantify regionalmyocardial function Circulation 20001021158ndash64

167 Zahid W Bergestuen D Haugaa KH Ueland T Thiis-Evensen E Aukrust Pet al Myocardial function by two-dimensional speckle tracking echocardiog-raphy and activin A may predict mortality in patients with carcinoid intestinaldisease Cardiology 201513281ndash90

168 Moerman VM Dewilde D Hermans K Carcinoid heart disease typical findingson echocardiography and cardiac magnetic resonance Acta Cardiol201267245ndash8

169 Nebigil CG Etienne N Messaddeq N Maroteaux L Serotonin is a novel sur-vival factor of cardiomyocytes mitochondria as a target of 5-ht2b receptor sig-naling FASEB J 2003171373ndash5

170 Hutcheson JD Setola V Roth BL Merryman WD Serotonin receptors andheart valve diseasendashit was meant 2b Pharmacol Ther 2011132146ndash57

171 Fielden MR Hassani M Uppal H Day-Lollini P Button D Martin RS et alMechanism of subendocardial cell proliferation in the rat and relevance forunderstanding drug-induced valvular heart disease in humans Exp Toxicol Pathol201062607ndash13

172 Fowles RE Cloward TV Yowell RL Endocardial fibrosis associated with fenflur-amine-phentermine N Engl J Med 19983381316

173 Szymanski C Marechaux S Bruneval P Andrejak M de Montpreville VT Belli Eet al Sub obstruction of left outflow tract secondary to benfluorex-inducedendocardial fibrosis IJC Heart Vasculature 2015967ndash9

174 Vaitkus PT Kussmaul WG Constrictive pericarditis versus restrictive cardiomy-opathy a reappraisal and update of diagnostic criteria Am Heart J19911221431ndash41

175 Shabetai R Pathophysiology and differential diagnosis of restrictive cardiomyop-athy Cardiovasc Clin 198819123ndash32

176 Kusunose K Dahiya A Popovic ZB Motoki H Alraies MC Zurick AO et alBiventricular mechanics in constrictive pericarditis comparison with restrictivecardiomyopathy and impact of pericardiectomy Circ Cardiovasc Imaging20136399ndash406

177 Welch TD Ling LH Espinosa RE Anavekar NS Wiste HJ Lahr BD et alEchocardiographic diagnosis of constrictive pericarditis Mayo clinic criteria CircCardiovasc Imaging 20147526ndash34

178 Ha JW Ommen SR Tajik AJ Barnes ME Ammash NM Gertz MA et alDifferentiation of constrictive pericarditis from restrictive cardiomyopathy usingmitral annular velocity by tissue Doppler echocardiography Am J Cardiol200494316ndash9

179 Ha JW Oh JK Ommen SR Ling LH Tajik AJ Diagnostic value of mitral annularvelocity for constrictive pericarditis in the absence of respiratory variation inmitral inflow velocity J Am Soc Echocardiogr 2002151468ndash71

180 Sengupta PP Mohan JC Mehta V Arora R Pandian NG Khandheria BKAccuracy and pitfalls of early diastolic motion of the mitral annulus for diagnos-ing constrictive pericarditis by tissue Doppler imaging Am J Cardiol200493886ndash90

181 Rajagopalan N Garcia MJ Rodriguez L Murray RD Apperson-Hansen CStugaard M et al Comparison of new Doppler echocardiographic methods todifferentiate constrictive pericardial heart disease and restrictive cardiomyop-athy Am J Cardiol 20018786ndash94

182 Amaki M Savino J Ain DL Sanz J Pedrizzetti G Kulkarni H et al Diagnosticconcordance of echocardiography and cardiac magnetic resonance-based tissuetracking for differentiating constrictive pericarditis from restrictive cardiomyop-athy Circ Cardiovasc Imaging 20147819ndash27

183 Adler Y Charron P Imazio M Badano L Baron-Esquivias G Bogaert J et al2015 ESC Guidelines for the diagnosis and management of pericardial diseasesThe Task Force for the Diagnosis and Management of Pericardial Diseases ofthe European Society of Cardiology (ESC)Endorsed by The EuropeanAssociation for Cardio-Thoracic Surgery (EACTS) Eur Heart J2015362921ndash64

184 Talreja DR Edwards WD Danielson GK Schaff HV Tajik AJ Tazelaar HDet al Constrictive pericarditis in 26 patients with histologically normal pericar-dial thickness Circulation 20031081852ndash7

185 Yared K Baggish AL Picard MH Hoffmann U Hung J Multimodality imaging ofpericardial diseases JACC Cardiovasc Imaging 20103650ndash60

186 Elliott PM Anastasakis A Borger MA Borggrefe M Cecchi F Charron P et al2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomy-opathy the Task Force for the Diagnosis and Management of HypertrophicCardiomyopathy of the European Society of Cardiology Eur Heart J2014352733ndash92

187 Olivotto I Maron BJ Appelbaum E Harrigan CJ Salton C Gibson CM et alSpectrum and clinical significance of systolic function and myocardial fibrosis as-sessed by cardiovascular magnetic resonance in hypertrophic cardiomyopathyAm J Cardiol 2010106261ndash7

188 Biagini E Spirito P Rocchi G Ferlito M Rosmini S Lai F et al Prognostic impli-cations of the Doppler restrictive filling pattern in hypertrophic cardiomyop-athy Am J Cardiol1041727ndash31

189 Melacini P Basso C Angelini A Calore C Bobbo F Tokajuk B et alClinicopathological profiles of progressive heart failure in hypertrophic cardio-myopathy Eur Heart J 2010312111ndash23

190 Nistri S Olivotto I Betocchi S Losi MA Valsecchi G Pinamonti B et alPrognostic significance of left atrial size in patients with hypertrophic cardiomy-opathy (from the Italian Registry for Hypertrophic Cardiomyopathy) Am JCardiol 200698960ndash5

1091ac G Habib et alD

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191 Maron BJ Spirito P Implications of left ventricular remodeling in hypertrophiccardiomyopathyAm J Cardiol 1998811339ndash448

192 Olivotto I Cecchi F Poggesi C Yacoub MH Patterns of disease progression inhypertrophic cardiomyopathy an individualized approach to clinical staging CircHeart Fail 20125535ndash46

193 Habib G Charron P Eicher JC Giorgi R Donal E Laperche T et al WorkingGroups lsquoHeart Failure and Cardiomyopathiesrsquo and lsquoEchocardiographyrsquo of the

French Society of Cardiology Isolated left ventricular non-compaction in adultsclinical and echocardiographic features in 105 patients Results from a Frenchregistry Eur J Heart Fail 201113177ndash85

194 Rapezzi C Leone O Ferlito M Biagini E Coccolo F Arpesella G Isolated ven-tricular non-compaction with restrictive cardiomyopathy Eur Heart J2006271927

Multimodality imaging in restrictive cardiomyopathies 1091adD

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Cardiology University Hospital Amiens Amiens France and INSERM U-1088 Jules Verne University of Picardie Amiens France and 34University Hospital Ramon y CajalCarretera de Colmenar Km 9100 28034 Madrid Spain

Received 9 February 2017 editorial decision 13 February 2017 accepted 14 February 2017 online publish-ahead-of-print 16 May 2017

Restrictive cardiomyopathies (RCMs) are a diverse group of myocardial diseases with a wide range of aetiologies including familial geneticand acquired diseases and ranging from very rare to relatively frequent cardiac disorders In all these diseases imaging techniques play acentral role Advanced imaging techniques provide important novel data on the diagnostic and prognostic assessment of RCMs ThisEACVI consensus document provides comprehensive information for the appropriateness of all non-invasive imaging techniques for thediagnosis prognostic evaluation and management of patients with RCM

Keywords echocardiography bull cardiac magnetic resonance bull computed tomography bull nuclear imaging

bull cardiomyopathies bull restrictive cardiomyopathies

Table of Contents

Introduction 1091Definition and classification of RCM 1091Pathophysiology of RCM and clinical presentation 1091aImaging modalities in RCM 1091a

Echocardiography 1091aCardiovascular magnetic resonance (CMR) 1091bCardiac computed tomography (CT) 1091cNuclear imaging 1091c

Main forms of RCM and value of imaging techniques 1091dApparently idiopathic RCM 1091dCardiac amyloidosis 1091eOther causes of familialgenetic RCM 1091k

Hemochromatosis 1091kFabry cardiomyopathy 1091lGlycogen storage disease 1091nPseudoxanthoma elasticum 1091n

Non familialnon-genetic RCM Inflammatory cardiomyopathieswith a restrictive hemodynamic component 1091n

Cardiac Sarcoidosis 1091nSystemic sclerosis 1091p

Non familialnon genetic RCM Radiation therapy and cancerdrug therapy induced RCM 1091q

Cardiac toxicity of radiation therapy 1091qCancer drug induced RCM 1091r

Endomyocardial RCMs 1091sEndomyocardial fibrosis 1091sHypereosinophilic syndrome 1091sCarcinoid heart disease 1091uDrug-induced endomyocardial fibrosis 1091u

Differential diagnosis between RCM and other cardiacdiseases 1091u

Differential diagnosis between RCM and constrictivepericarditis 1091uDifferential diagnosis or association between RCM and othermyocardial diseases 1091u

Conclusion and future directions 1091w

Introduction

Restrictive cardiomyopathies (RCMs) are a diverse group of myocar-dial diseases with a wide range of aetiologies including familial genetic

and acquired diseases and ranging from very rare to relatively frequentcardiac disorders This diversity is also reflected in the inconsistent clas-sification of RCM across guidelines1ndash3 and even in the term lsquorestrictiversquowhich is a functional characterization unlike the morphological defin-ition of the three other main types of cardiomyopathies ie hyper-trophic arrhythmogenic right ventricular or dilated cardiomyopathies4

Independently of the underlying cause the pathophysiology andclinical presentation the initial phenotypic diagnosis of RCM requiresimaging techniques Many advances have occurred in the last decadein the diagnostic and prognostic assessment of RCM This EACVIconsensus document provides comprehensive information for theappropriateness of all non-invasive imaging techniques for the diagno-sis prognostic evaluation and management of patients with RCM

This article was written in close collaboration between theEuropean Association of Cardiovascular Imaging (EACVI) and theWorking Group (WG) on Myocardial and Pericardial diseases ofthe European Society of Cardiology (ESC) The types of RCM cov-ered in this document are those included in the classification systemproposed by the WG on Myocardial and Pericardial diseases1 as wellas some non-sarcomeric hypertrophic cardiomyopathies (HCMs)with a restrictive physiology that in previous classifications wereincluded in the RCM category eg cardiac amyloidosis (CA)

Definition and classification ofRCM

RCM is the least common type of the cardiomyopathies defined asmyocardial disorders in which the heart muscle is structurally and function-ally abnormal in the absence of coronary artery disease arterial systemichypertension valvular disease or congenital heart disease sufficient tocause the observed myocardial abnormality1

According to the historical World Health Organization (WHO)2

and the updated definition proposed by the ESC WG on Myocardialand Pericardial Diseases in 20081 each cardiomyopathy type isdescribed by its clinical presentation This approach is recommendedfirstly because it is the starting point in everyday clinical practice andsecondly because knowledge of aetiologies is still evolving thus atpresent an aetiological classification would not be conclusive

RCM is defined by restrictive ventricular physiology in thepresence of normal or reduced diastolic volumes with normal or

Multimodality imaging in restrictive cardiomyopathies 1091D

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Cause Familial

genetic

Non-familial

non-genetic

Genetic origin X

Unknown origin X

Amyloidosis

ALprealbumin X

Genetic (eg TTR) X

Senile X

Storage diseases

Haemochromatosis X

Fabry disease X

Radiation therapy X

Drugs X

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Endomyocardial RCMs

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Echo CMR cardiac CT

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Systemic sclerosis

perfusion defect

of the myocardium

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Drug-induced EMF

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Supplementary data

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Chest X-ray

Pulsed-wave Doppler

Deformation imaging

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Cause Familial

genetic

Non-familial

non-genetic

Genetic origin X

Unknown origin X

Amyloidosis

ALprealbumin X

Genetic (eg TTR) X

Senile X

Storage diseases

Haemochromatosis X

Fabry disease X

Radiation therapy X

Drugs X

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Endomyocardial RCMs

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Echo CMR cardiac CT

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Systemic sclerosis

perfusion defect

of the myocardium

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Drug-induced EMF

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Supplementary data

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Chest X-ray

Pulsed-wave Doppler

Deformation imaging

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ber 2018

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Endomyocardial RCMs

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

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httpsacademicoupcom

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ownloaded from

httpsacademicoupcom

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Echo CMR cardiac CT

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ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

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Drug-induced EMF

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

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httpsacademicoupcom

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httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Endomyocardial RCMs

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httpsacademicoupcom

ber 2018

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ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

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httpsacademicoupcom

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Echo CMR cardiac CT

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ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

Endomyocardial RCMs

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

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ownloaded from

httpsacademicoupcom

ber 2018

Echo CMR cardiac CT

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

Endomyocardial RCMs

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

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httpsacademicoupcom

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ownloaded from

httpsacademicoupcom

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Echo CMR cardiac CT

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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Echo CMR cardiac CT

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Echo CMR cardiac CT

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Echo CMR cardiac CT

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Echo CMR cardiac CT

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Echo CMR cardiac CT

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

Echo CMR cardiac CT

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

Echo CMR cardiac CT

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

Systemic sclerosis

perfusion defect

of the myocardium

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

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httpsacademicoupcom

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

jex034-TF3

jex034-TF4

jex034-TF5

jex034-TF6

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Drug-induced EMF

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

Supplementary data

ownloaded from

httpsacademicoupcom

ber 2018

Chest X-ray

Pulsed-wave Doppler

Deformation imaging

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

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httpsacademicoupcom

ber 2018

ownloaded from

httpsacademicoupcom

ber 2018

jex034-TF1

jex034-TF2

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