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REVIEW TOPIC OF THE WEEK

The Diagnosis and Evaluation ofDilated Cardiomyopathy

Alan G. Japp, PHD,a Ankur Gulati, MD,a Stuart A. Cook, MD,a,b,c Martin R. Cowie, MD,a,b Sanjay K. Prasad, MDa,b

ABSTRACT

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Dilated cardiomyopathy (DCM) is best understood as the final common response of myocardium to diverse genetic and

environmental insults. A rigorous work-up can exclude alternative causes of left ventricular (LV) dilation and dysfunction,

identify etiologies that may respond to specific treatments, and guide family screening. A significant proportion of DCM

cases have an underlying genetic or inflammatory basis. Measurement of LV size and ejection fraction remain central to

diagnosis, risk stratification, and treatment, but other aspects of cardiac remodeling inform prognosis and carry thera-

peutic implications. Assessment of myocardial fibrosis predicts both risk of sudden cardiac death and likelihood of LV

functional recovery, and has significant potential to guide patient selection for cardioverter-defibrillator implantation.

Detailed mitral valve assessment is likely to assume increasing importance with the emergence of percutaneous

interventions for functional mitral regurgitation. Detection of pre-clinical DCM could substantially reduce morbidity

and mortality by allowing early instigation of cardioprotective therapy. (J Am Coll Cardiol 2016;67:2996–3010)

© 2016 by the American College of Cardiology Foundation.

D ilated cardiomyopathy (DCM) is defined asleft ventricular (LV) dilation and systolicdysfunction in the absence of coronary

artery disease or abnormal loading conditions propor-tionate to the degree of LV impairment (1). (Only keyreferences are cited in this paper; additional support-ing references for each section can be found in theOnline Appendix). One of the leading causes of heartfailure (HF), DCM predominantly affects youngeradults and is the most frequent indication for cardiactransplantation. The condition is best regarded notas a single disease entity, but rather as a nonspecificphenotype, the final common response of myocar-dium to a number of genetic and environmentalinsults (Table 1). Until recently, the evaluation of

m the aDepartment of Cardiology, Royal Brompton Hospital, London

dicine, National Heart & Lung Institute, Imperial College, London, Unite

nal Heart Centre Singapore, Singapore. This work was supported by the N

medical Research Unit at the Royal Brompton and Harefield NHS Founda

nt support was received from CORDA and the Rosetrees Trust. Prof. Cook

wie serves as a consultant to Medtronic, Boston Scientific, St. Jude Med

yer, Pfizer/Bristol-Myers Squibb, and ResMed; has received research gran

d ResMed; and has received speaker fees from Servier, Novartis, St. Jud

sMed. Dr. Prasad has received honoraria from Schering. All other authors h

the contents of this paper to disclose. Drs. Japp and Gulati contributed e

nuscript received February 16, 2016; revised manuscript received March

DCM has scarcely deviated from the standardapproach to systolic HF. However, advanced imagingtechniques, together with modern genetic, bio-marker, and biopsy analysis, increasingly allow formore rigorous assessment of etiology and cardiacremodeling, as well as earlier disease detection. Inthis review, we examine the role of a more detailedapproach to DCM in contemporary practice and itsemerging potential to guide individualized treatmentstrategies.

PART 1: EVALUATION OF ETIOLOGY

Before diagnosing DCM, it is necessary to excludeconditions with phenotypic overlap. Thereafter,

, United Kingdom; bDepartment of Cardiovascular

d Kingdom; and the cDepartment of Cardiology, Na-

ational Institute for Health Research Cardiovascular

tion Trust and Imperial College London. Additional

has served as a consultant for GlaxoSmithKline. Prof.

ical, Servier, Daiichi-Sankyo, Neurotronik, Novartis,

ts to Imperial College from Bayer, Boston Scientific,

e Medical, Boston Scientific, Medtronic, Bayer, and

ave reported that they have no relationships relevant

qually to this work.

21, 2016, accepted March 21, 2016.

AB BR E V I A T I O N S

AND ACRONYM S

CMR = cardiovascular magnetic

resonance

CRT = cardiac

resynchronization therapy

DCM = dilated cardiomyopathy

EMBx = endomyocardial biopsy

FMR = functional mitral

regurgitation

HF = heart failure

ICD = implantable

cardioverter-defibrillator

LGE = late gadolinium

enhancement

SCD = sudden cardiac death

TTE = transthoracic

echocardiography

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identification of a specific underlying etiology mayallow targeted disease-specific treatment, guide theneed for family screening, or inform prognosis.

EXCLUSION OF OTHER CAUSES. Ischemic cardio-myopathy is conventionally distinguished from DCMby the presence of $75% stenosis in the left mainstem, proximal left anterior descending artery, or 2 ormore epicardial coronary arteries on invasive orcomputed tomography coronary angiography (2). Lategadolinium enhancement (LGE) cardiovascular mag-netic resonance (CMR) provides an alternativeapproach and may identify prior myocardial infarc-tion (subendocardial or transmural LGE) in as manyas 13% of patients with suspected DCM and unob-structed coronary arteries (3). In addition to ischemiccardiomyopathy, DCM must also be distinguishedfrom other nonischemic cardiomyopathies and phys-iological adaptations that may generate similar pat-terns of LV remodeling (Table 2).

ROUTINE ETIOLOGICAL WORK-UP. A suggestedetiological evaluation for patients with DCM is listedin Table 1. Regular alcohol consumption of at least 80g/day for over 5 years has frequently been associatedwith LV dilation and dysfunction (4). Anthracyclinecardiotoxicity is governed principally by total cumu-lative dose and may not become apparent until over10 years after exposure. Although presentationtoward the end of pregnancy or shortly after deliverysuggests peripartum cardiomyopathy, patientsshould still be assessed for alternative causes becausethe hemodynamic stress of pregnancy may unmasklatent myocardial dysfunction. The prevalence ofhuman immunodeficiency virus (HIV)–associatedcardiomyopathy has substantially declined withantiretroviral therapy (5); however, many patients arenot diagnosed with HIV infection until the advancedstages of disease, and HIV testing is therefore advis-able in patients with unexplained DCM.

The presence of persistent tachyarrhythmia(>100 beats/min) raises suspicion of tachycardia-induced cardiomyopathy. Marked LV recovery fol-lowing effective rate or rhythm control, typicallywithin 4 weeks, confirms the diagnosis. Atrioven-tricular block may indicate an underlying geneticetiology (e.g., lamin A/C mutation or myotonic dys-trophy) or inflammatory disease (e.g., sarcoidosis,giant cell myocarditis, or Lyme disease).

Echocardiography has a limited role in definingDCM etiology. However, prominent inferolateralhypokinesis/akinesis is often observed in musculardystrophy or acutemyocarditis. CMRmay aid etiologicevaluation through detection of myocardial edema(e.g., active myocarditis or sarcoidosis), and

classification of LGE distribution (e.g.,muscular dystrophy, previous myocarditis,sarcoidosis, or Chagas disease). AlongsideCMR, 18F-fluorodeoxyglucose positron emis-sion tomography is emerging as a valuabletool for diagnosing cardiac sarcoidosis andmonitoring disease activity.Inflammatory card iomyopathy and therole of endomyocard ia l b iopsy . The com-bination of myocardial inflammation(myocarditis) and dysfunction is termed in-flammatory cardiomyopathy. In patients withrecent-onset DCM, identification of myocar-ditis has important clinical implications dueto the high potential for LV recovery. Anacute onset of symptoms, “flu-like” pro-drome, or elevated serum troponin/inflam-matory markers may raise suspicion.

Although viruses are the most common trigger inEurope and North America, serology is generally un-helpful, partly because of high background sero-positivity rates. A subset of patients with acutemyocarditis progresses to chronic DCM: amonghistology-confirmed cases, the reported incidence ofDCM varies between 14% and 52% (6).

CMR enables noninvasive detection of myocarditisthrough 3 combined tissue characterization tech-niques (“Lake Louise criteria”) (Figures 1E and 1F) (7).It offers high diagnostic accuracy in acute myocar-ditis, but is less sensitive in chronic inflammatorydisease. Endomyocardial biopsy (EMBx) remains thegold standard investigation, and modern immuno-histochemical methods improve sensitivity comparedwith the traditional histopathological Dallas criteria.Biopsy findings carry clear treatment implications inDCM patients with suspected giant cell myocarditis,eosinophilic myocarditis, or sarcoidosis, and EMBx isindicated in these patient groups (8).

Beyond this, molecular genetic analysis of biopsyspecimens for cardiotropic viruses can delineatewhether chronic inflammation is due to viral persis-tence or autoimmunity to cardiac proteins. Lack ofsuch analysis was an important limitation of earlynegative trials of immunosuppressive therapy inmyocarditis because immunosuppression may beineffective in patients with ongoing viral infection(9). A recent placebo-controlled trial of immuno-suppression in DCM patients with chronic activeinflammation, but undetectable viral genomes,demonstrated dramatic improvements in left ven-tricular ejection fraction (LVEF) and functional class(10). Limited data also suggest potential benefit fromantiviral therapy with interferon-beta in patients withpersistent cardiotropic viruses (11).

TABLE 1 Causes of DCM

Cause Examples Routine Work-Up Selective Work-Up

Idiopathic

Genetic See Table 3 Detailed family historyECG (AV block) [LMNA]*Ferritin and transferrin saturation

[hemochromatosis]*

Clinical screening of first-degree relativesif no other cause for DCM identified.

Consider genetic testing if familialinvolvement, AV block, or raisedferritin/transferrin saturation.

Toxins Alcohol, amphetamines, cocaine, anthracyclines(e.g., doxycycline), trastuzumab, clozapine,chloroquine, carbon monoxide, cobalt,lead, mercury

Detailed history of toxin exposureGGT, LFT, MCV

Urine toxicology screen if high suspicionof cocaine/amphetamine abuse.

Infectious Viral� Adenovirus, Coxsackie A and B,

cytomegalovirus, Epstein-Barr,human herpes virus 6, HIV,parvovirus B19, varicella

Bacterial� Brucellosis, diphtheria, psittacosis,

typhoid feverFungalSpirochetal� Borreliosis (Lyme disease), Leptospirosis

(Weil disease)Protozoal� Chagas disease, schistosomiasis,

toxoplasmosisRickettsial

Troponin HIV serology in all patients with riskfactors and/or unexplained DCM

Trypanosoma Cruzi serology if travelto or residence in Central/South America.

Consider EMBx if suspicion of myocarditis(see “Inflammatory cardiomyopathy andthe role of endomyocardial biopsy,” p. 2997)

Targeted serological testing if suspectedLyme disease or rickettsial infection.

Metabolic/endocrine Electrolyte disturbances� Hypocalcemia, hypophosphatemia, uremiaEndocrine abnormalities� Cushing’s disease, acromegaly hypo/

hyperthyroidism, pheochromocytomaNutritional deficiencies� Carnitine, thiamine, selenium

Urea, creatinine, Na, K, Ca, PO4

Thyroid function testsPlasma glucoseUrinary metanephrines

Targeted endocrine investigations ifsuggestive clinical features.

Trace element/nutritional screen ifsignificantly malnourished.

Inflammatory/infiltrative/autoimmune

Hypersensitivity myocarditisInfiltrative diseases� Hemosiderosis, sarcoidosisVasculitis� Churg-Strauss, Kawasaki disease,

polyarteritis nodosaConnective tissue disorder� Scleroderma� Dermatomyositis� Systemic lupus erythematosus

ESR, CRPECG (AV block), CXR

(hilar lymphadenopathy),and serum ACE [sarcoidosis]*

EMBx if suspicion of sarcoidosis orvasculitis (unless confirmedextracardiac disease and myocardialinvolvement demonstrable on imaging).

Autoantibody screen if raised ESR/CRPor skin/joint/systemic features.

Neuromuscular disease Dystrophinopathies (Duchenne/Becker muscular dystrophy/X-linked DCM)

Limb-girdle muscular dystrophiesFacioscapulohumeral muscular dystrophyEmery-Dreifuss muscular dystrophyFriedreich’s ataxiaMyotonic dystrophy

Creatine kinaseSkeletal muscle weaknessFamily history (X-linked inheritance

pattern†), ECG (“posterolateralinfarction”), echo (posterolateralakinesia/dyskinesia)[dystrophinopathies]*

Gait ataxia [Friedreich’s ataxia]*Myotonia/cataracts [myotonic

dystrophy]*ECG (AV block) [Emery-Dreifuss

type 1/myotonic dystrophy]*

Specialist evaluation � muscle biopsy/electromyography/genetic testingif muscle weakness, elevatedcreatine kinase, or other cardiac/extracardiac markers.

Other Pregnancy

Tachyarrhythmia 12-lead ECG Ambulatory ECG monitoring.

*Specific causes of DCM to which the aforementioned diagnostic tests apply. †X-linked inheritance pattern: principally males affected, no male–male transmission.

ACE ¼ angiotensin-converting enzyme; AV ¼ atrioventricular; CRP ¼ C-reactive protein; CXR ¼ chest x-ray; DCM ¼ dilated cardiomyopathy; ECG ¼ electrocardiogram; Echo ¼ echocardiography;EMBx ¼ endomyocardial biopsy; ESR ¼ erythrocyte sedimentation rate; GGT ¼ gamma-glutamyl transferase; HIV ¼ human immunodeficiency virus; LFT ¼ liver function tests; LMNA ¼ lamin A/C gene;MCV ¼ mean corpuscular volume.

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Myocarditis thus represents an exciting prospectfor mechanism-based therapy in DCM. However,conclusive benefit from EMBx-guided treatment isawaited. A European Society of Cardiology WorkingGroup recently called for broader use of EMBx toimprove the diagnosis of myocarditis (12). When

applied to DCM, their proposed multiparametriccriteria would ultimately lead to EMBx in any symp-tomatic patient with no clear etiology—a distinctdeparture from previous consensus statements (8,13)and international HF guidelines (14,15). For now, arational approach to this conflicting guidance is to

TABLE 2 Differentiation of DCM From Conditions With Phenotypic Overlap

Condition Features Favoring Alternate Diagnosis Comments

Ischemic cardiomyopathy � See “Exclusion of Other Causes,” p. 2997 HF etiology is traditionally dichotomized into ischemic andnonischemic categories on the basis of coronaryangiography.

LGE-CMR tissue characterization provides incrementalinformation, which when combined with angiography,enables a more precise classification of ischemic vs.nonischemic etiology (Online Ref. 1).

Hypertensive heart disease � History of chronic, poorly controlled hypertension� Increased LV wall thickness

Advanced HCM � Long-standing history of HCM� Extensive patchy myocardial fibrosis on LGE-CMR� Increased LV wall thickness

ARVC � Revised ARVC task force criteria (Online Ref. 2)� Disproportionate RV remodeling and dysfunction (Online Ref. 3)� RV regional wall motion abnormalities or localized dyssynchrony

(“accordion sign”) in subtricuspid region (Online Refs. 4,5)� Strong arrhythmic propensity exceeding severity of LV impairment

(Online Ref. 6)� Characteristic LGE patterns (e.g., LGE in RV free wall and/or LV

inferolateral subepicardium [Online Ref. 3] or circumferential LVmidwall LGE extending to right side of septum [Online Ref. 7])

Distinguishing DCM (with adverse RV remodeling) fromthe biventricular or left-dominant forms of ARVCcan be challenging, particularly because bothpresentations may be caused by mutationsin desmosomal protein genes.

Myocardial noncompaction � Deep, perfused intertrabecular recesses evident on color Doppler(Online Ref. 8)

� Trabeculated LV mass >20% total LV mass on CMR (Online Ref. 9)� Proposed alternative CMR criteria (Online Ref. 10)

� Noncompacted myocardial mass >25%/mass index >15 g/m2

� Trabeculation of basal segments 4–6� Ratio of noncompacted to compacted myocardial

thickness >3.0 in 1 or more segments

Prominent trabeculation secondary to LV remodeling iscommon in DCM (Online Ref. 11). Conventional noncompactiondiagnostic criteria (ratio of noncompacted to compactedmyocardial thickness >2.1 at end-systole on echo, and>2.3 at end-diastole on CMR) have been criticized fortheir poor specificity and inability to discriminatebetween “pathological noncompaction” and DCMwith “hypertrabeculation” (Online Refs. 10,12).

Athlete’s heart � No symptoms/signs of heart failure� Normal natriuretic peptide levels� Normal ECG� Normal LV diastolic function (Online Ref. 13)� Normal LV peak systolic strain (Figure 4)� Normal/supranormal contractile reserve� High peak VO2 on cardiopulmonary exercise testing� Reverse remodeling with deconditioning (Online Ref. 14)

Physiological LV dilation has been reported in up to 15%of highly trained athletes (Online Ref. 15).

Among athletes participating in extreme endurance sports,such as cycling, LV dilation may also be associated witha concomitant reduction in resting LVEF (Online Ref. 16),thereby fulfilling diagnostic criteria for DCM.

Cirrhotic cardiomyopathy � Advanced chronic liver disease� QT interval prolongation (>440 ms) (Online Ref. 17)� Normal LVEF at rest, but with latent systolic dysfunction that is

unmasked by physiological, pharmacological, or iatrogenic stress(Online Ref. 17)

Cirrhotic cardiomyopathy is an under-recognized and importantcomplication of cirrhosis from any cause; it should besuspected in patients with liver disease who developcardiac failure or hemodynamic deterioration.

See the Online Appendix for table references.

ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; CMR ¼ cardiovascular magnetic resonance; HCM ¼ hypertrophic cardiomyopathy; HF ¼ heart failure; LGE ¼ late gadolinium enhancement;LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; RV ¼ right ventricular; VO2 ¼ oxygen consumption; other abbreviations as in Table 1.

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consider the incremental value of EMBx on an indi-vidual case basis. Where experimental treatments,such as immunosuppression or antiviral therapy, arenot under consideration, given the current diagnosticyield and procedural risks of EMBx, it would appeardifficult to justify its universal inclusion in the diag-nostic work-up of DCM.GENETIC CAUSES OF DCM. Molecular genetic anal-ysis has uncovered “causal” mutations for DCM inover 60 genes (Table 3). In 2012, truncating mutationsof the titin (TTN) gene were shown to be present in25% of familial or severe transplant DCM cases (16).More recently, TTN truncations were found in w13%of unselected nonfamilial DCM cases, but also in 2%of the general population (17). Although the pro-bability of pathogenicity of a TTN truncation inDCM patients is very high (>95%), population

controls with a TTN truncation invariably exhibit anormal cardiac phenotype, likely due to additionalmodifier gene effects, environmental factors, or lateonset of disease.

In some patients with genetic DCM, a particulargene defect may be suggested by cardiac conductionabnormalities (e.g., LMNA or SCN5A mutations) orelevated serum creatine kinase/muscle weakness(e.g., muscular dystrophy or LMNA mutation). How-ever, most cases have no specific distinguishingphenotypic features. Identification of other affectedfamily members is therefore the most importantpointer to a genetic basis, and all patients should un-dergo a detailed family history covering $3 genera-tions. As the prevalence of familial DCM is significantlyunderestimated by family history alone, screening byelectrocardiography (ECG) and echocardiography is

FIGURE 1 Multifaceted Role of CMR in Dilated Cardiomyopathy

(A and B) Measurement of biventricular volumes and ejection fraction. (C and D) Measurement of left atrial volume by the biplane area-length method.

(E and F) Diagnosis of myocarditis. (E) T2-weighted STIR short-axis image revealing regional edema (arrows). (F) LGE-CMR shows localized myocardial

enhancement corresponding to STIR. (G and H) Detection of midwall replacement fibrosis (arrows) by LGE-CMR. (I and J) Assessment of interstitial fibrosis.

No replacement fibrosis is identified by LGE-CMR (J), but the septal T1 is high (1,043 ms), compared with normal myocardial T1 (968 ms, arrow) (I). (K and L)

Diagnosis of myocardial iron overload. (K) A ROI (green shaded area) is delineated in a short-axis slice acquired at increasing echo times. (L) T2* is estimated

from the ROI signal intensity (SI) plotted against echo time (TE). Ao ¼ aorta; CMR ¼ cardiovascular magnetic resonance; LGE ¼ late gadolinium

enhancement; ROI ¼ region of interest; STIR ¼ short-tau inversion-recovery.

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also recommended for first-degree relatives of pa-tients with apparently idiopathic DCM.

At present, routine genetic testing is only recom-mended in familial disease ($2 affected family

members) (15), where its diagnostic yield is 30% to35%. Currently, the identification of a causal muta-tion carries few implications for prognosis or treat-ment of the index case, and the principal rationale for

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testing is to allow mutation-specific cascadescreening of family members (see Part 4). An excep-tion is LMNA mutations, which are associated withhigh rates of conduction system disease, ventriculararrhythmias, and sudden cardiac death (SCD) andmay consequently lower the threshold for prophy-lactic implantable cardioverter-defibrillator (ICD)implantation (18).

Looking ahead, the correlation of distinctivephenotypic features with rare alleles and elucidationof the molecular pathways responsible could revolu-tionize our approach to treatment, as recentlyexemplified by a study in patients with a variant ofthe SCN5A gene (19). This cohort exhibited a strikingDCM phenotype associated with various arrhythmiasand frequent premature ventricular complexes.Functional characterization of the mutation in vitrorevealed an activating effect on the Nav1.5 sodiumchannel, predicted to cause rate-dependent ventric-ular ectopy. Although patients responded poorly toconventional HF therapy, treatment with sodium-channel blocking drugs produced a dramatic reduc-tion in ectopy and normalization of LV function.

PART 2: ASSESSMENT OF REMODELING

The extent of LV dilation and contractile impairmentin DCM is a major determinant of adverse outcomes,and reversal of these abnormalities, LV reverseremodeling, is a key therapeutic goal. In addition toLV wall thinning and dilation (Figure 2A), adverseremodeling characteristics in DCM include func-tional mitral regurgitation (FMR), myocardial fibrosis(Figures 2B and 2C), dyssynchronous ventricularcontraction, and enlargement of other chambers.Increasingly, detailed characterization of these pa-rameters may also hold value in predicting prognosisand guiding treatment (Central Illustration).

LV SIZE AND SYSTOLIC FUNCTION. Two-dimensional(2D) transthoracic echocardiography (TTE) is the front-line investigation for estimation of LV volumes andLVEF. In contrast to 2D imaging, 3-dimensional (3D)TTE avoids geometric assumptions and offers supe-rior reproducibility, which may have important real-world implications for DCM assessment in relationto eligibility for device/pharmacotherapy and serialmonitoring for cardiotoxicity. Administration ofechocardiography contrast agents improves the accu-racy of 2D/3D volume assessment, particularly whenimage quality is suboptimal.

CMR combines high spatial resolution multiplanarimaging with excellent delineation of the blood-myocardium interface to enable precise quantifica-tion of cardiac chamber volumes (Figures 1A and 1B).

Although CMR is the gold standard for ventricularassessment, its routine use is limited by restrictedavailability, expense, and device incompatibility.

Myocardial deformation imaging techniques (e.g.,speckle-tracking echocardiography-derived strain orCMR myocardial tagging) offer greater sensitivitythan LVEF for identifying subtle abnormalities ofsystolic function, and may assume a role in the earlydetection of disease (see Part 4).

REMODELING OF OTHER CARDIAC CHAMBERS. Leftatrial (LA) dilation is frequently observed in DCM as aconsequence of diastolic dysfunction, FMR, atrialfibrillation, and LV cavity enlargement. LA volume isthe preferred measure of LA size (Figures 1C and 1D)and predicts adverse outcomes in DCM (20). Adverseright ventricular (RV) remodeling, resulting fromsecondary pulmonary hypertension or primarymyocardial disease, is also common in DCM patients.TTE enables accurate assessment of tricuspid regur-gitation and pulmonary artery systolic pressure, buthas a limited estimation of RV size and function. CMRoffers greater accuracy and reproducibility for mea-surement of RV volumes and ejection fraction(Figures 1A and 1B), and these indexes provide inde-pendent prognostic information in DCM (21,22).

Together, LA and RV remodeling may yield insightinto aspects of DCM not fully reflected in indexes ofLV remodeling. Future research should aim to deter-mine whether changes in these variables over timebetter predict disease trajectory and long-term re-sponses to treatment.

FUNCTIONAL MITRAL REGURGITATION. IncreasingLV size and sphericity causes tethering of the mitralleaflets, which, together with annular dilation, leadsto defective leaflet coaptation and “functional”regurgitation (Figures 3A and 3B). FMR perpetuates LVremodeling and is associated with increasedmorbidity and mortality, independently of LVEF (23).Reduction of FMR severity in DCM patients receivingoptimal medical therapy and/or cardiac resynchroni-zation therapy (CRT) is associated with improvedtransplant-free survival (24,25). Surgical annuloplastycan also reduce FMR and is accompanied by im-provements in LV remodeling and symptoms (26).

With the emergence of percutaneous transcathetermitral valve therapies, such as the edge-to-edgeMitraClip repair system (Abbott Vascular, AbbottPark, Illinois) (Figures 3C to 3F) (27), the importance ofFMR assessment in DCM is likely to increase.Currently, one of the major challenges lies in gradingFMR severity. The 3D echocardiographic color Dopplertechniques (e.g., en face planimetry of vena contractaarea) permit direct and accurate assessment of

TABLE 3 Genes Associated With DCM

Protein Location Gene Protein Protein Function

Sarcomere MYH6 a-myosin heavy chain

Force generation � transmission

MYH7* b-myosin heavy chain

TPM1 a-tropomyosin

ACTC Cardiac actin

TNNT2* Cardiac troponin T

TNNC1 Cardiac troponin C

TNNI3* Cardiac troponin I

MYPN Myopalladin

MYBPC3 Myosin-binding protein C

Cytoskeleton ACTN2 a-actinin 2

Force transmission � structural integrity

CRYAB a-B-crystallin

DTNA a-dystrobrevin

SGCA a-sarcoglycan

SGCB b-sarcoglycan

SGCD d-sarcoglycan

SGCG Y-sarcoglycan

CAV3 Caveolin

LDB3 Cypher/ZASP

SYNM Desmulin

DMD Dystrophin

FHL2 Four-and-a-half LIM protein 2

FKTN Fukutin

FKRP Fukutin-related protein

ILK Integrin-linked kinase

VCL Metavinculin

CSRP3 Muscle LIM protein

NEXN Nexilin

PLEC1 Plectin-1

PDLIM3 PDZ LIM domain protein 3

TTN* Titin

TCAP Titin-cap/telethonin

Desmosomes DES Desmin

Cell–cell adhesion � intracellular signalingDSC2 Desmocollin 2

DSG2 Desmoglein 2

DSP* Desmoplakin

PKP2 Plakophilin 2

Sarcoplasmic reticulum PLN Phospholamban Regulates sarcoendoplasmic reticulumcalcium ATPase pump

RYR2 Ryanodine receptor 2 Calcium-channel component

Nuclear envelope LMNA* Lamin A/CMaintain structural organization and stabilityof nuclear envelope

TMPO Thymopoietin

EMD Emerin

Link nucleus to cytoskeletonLAP2a Lamin-associated polypeptide 2a

SYNE1/2 Nesprin 1/2

Nucleus ANKRD1 Cardiac ankyrin repeat protein

Transcription cofactor

EYA4 Eyes absent 4

FOXD4 Forkhead box D4

HOPX Homeobox only protein

NFKB1 NF-kappa B1

PRDM16 PR domain containing 16

TBX20 T-box 20

ZBTB17 Zinc finger and BTB domain containing protein 17

RBM20 RNA-binding protein 20 RNA-binding protein of spliceosome

Continued on the next page

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TABLE 3 Continued

Protein Location Gene Protein Protein Function

Ion channel SCN5A* Sodium channel, type V Voltage-gated cardiac sodium ion channel

ABCC9 Sulfonylurea receptor 2A Component of ATP-sensitive potassium channel

Mitochondria CPT2 Carnitine palmitoyltransferase 2

Supply and/or regulation of energy metabolism

FRDA Frataxin

DNAJC19 HSP40 homolog, C19

SDHA Succinate dehydrogenase

SOD2 Superoxide dismutase

TAZ/G4.5 Tafazzin

mtDNA Mitochondrial respiratory chain

Extracellular matrix LAMA2 Laminin-a-2Extracellular constituent of basement membraneinvolved in cell adhesion and signaling

LAMA4 Laminin-a-4

Other CTF1 Cardiotrophin 1 Cytokine

PSEN1/2 Presenillin 1/2 Gamma secretase intramembrane protease complex

HFE Hemochromatosis Regulation of iron uptake/metabolism

LAMP2 Lysosome-associated membrane protein 2 Lysosomal transport protein

* and bold indicates most prevalent mutated genes among patients with dilated cardiomyopathy.

ATP ¼ adenosine triphosphate; DCM ¼ dilated cardiomyopathy; mtDNA ¼ mitochondrial deoxyribonucleic acid; RNA ¼ ribonucleic acid.

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effective regurgitant orifice area, circumventing thegeometric assumptions inherent to 2D assessment. Atpresent, such measurements are time-consuming andtechnically demanding, but with continued evolutionof 3D echocardiographic technology and automatedanalysis software, they may gradually supplant 2Dmethods. Velocity-encoded CMR offers a useful alter-native modality for evaluating FMR, especially whenechocardiography is equivocal.

MYOCARDIAL FIBROSIS. Replacement fibrosis—focal“reparative” scarring that follows myocyte injury ornecrosis—occurs in approximately one-third of pa-tients with advanced DCM (28), typically in the mid-wall (Figure 2B), and is detectable by LGE-CMR(Figures 1G and 1H) (3). It provides a substrate forventricular re-entrant arrhythmia (29) and is inde-pendently associated with an increased risk of mor-tality and HF morbidity in DCM (30,31). Moreover, itspresence and extent in DCM hearts, as assessed byLGE-CMR, substantially determines the likelihood ofLV reverse remodeling in response to pharmacolog-ical therapy (32,33) and CRT (34). These observationsconfirm an intuitive notion: DCM ventricles thatexhibit replacement of viable myocardium withreparative scar are less likely to recover than thosewithout established fibrosis. In the current era, thismight inform the selection of patients for devicetherapy (Part 3). Looking ahead, advances in leftventricular assist device technology and the earlypromise of stem cell therapy (35) could conceivablyestablish fibrosis assessment as a key component ofDCM evaluation, yielding a new LGE-CMR–guided

treatment paradigm in which patients with extensivemyocardial scarring and low remodeling potential aredirected towards replacement or regenerative thera-pies (Central Illustration).VENTRICULAR DYSSYNCHRONY. In selected DCMpatients with mechanical dyssynchrony, resynchro-nization of ventricular contraction through biven-tricular pacing leads to major improvements in LVremodeling and outcomes. QRS interval prolongationwas the primary criterion for dyssynchrony in thepivotal clinical trials of CRT, making it a cornerstoneof patient selection, particularly when associatedwith left bundle branch block (LBBB) morphology.More recently, long-term outcome analyses andmeta-analyses of landmark trials have reaffirmed thecentral role of the surface ECG in guiding patientselection, demonstrating a clear and consistentbenefit from CRT in those with LBBB and QRS intervalduration $150 ms (36,37).

Mechanical dyssynchrony is also detectable byechocardiographic techniques in up to 50% ofHF patients without QRS interval prolongation.However, no echocardiographic index of dyssyn-chrony predicts CRT response beyond establishedcriteria (38). Furthermore, in patients with QRSduration <130 ms, but with echocardiographic evi-dence of dyssynchrony, there is no benefit andpossibly excess mortality from CRT (39). It nowseems unlikely that dyssynchrony evaluation byechocardiography will have any role in patients withLBBB and QRS interval duration $150 ms or thosewith narrow QRS intervals. Further study is war-ranted to explore its potential to refine selection

FIGURE 2 Pathological Appearances of Dilated Cardiomyopathy

(A) Left ventricular cavity dilation (asterisk) with wall thinning. (B) Extensive left ven-

tricular midwall replacement fibrosis (arrows). (C) Myocyte hypertrophy (black arrow),

myocyte atrophy (blue arrow), nuclear pleomorphism (arrowheads), and increased

interstitial fibrosis (stained with Picrosirius red); magnification �500.

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among patients with borderline QRS interval (130 to150 ms) or non-LBBB pattern.

PART 3: EVALUATION FOR AN ICD

In selected DCM patients, implantation of an ICDreduces the incidence of SCD and overall mortality(40). Current guidelines recommend ICD implanta-tion in patients with DCM who have a reasonable lifeexpectancy and quality of life and either: 1) a historyof ventricular arrhythmia with hemodynamic com-promise (secondary prevention); or 2) New York HeartAssociation functional class II/III symptoms andLVEF #35%, despite optimal medical therapy (pri-mary prevention) (15,18). However, ICDs are moder-ately expensive, do not improve quality of life, andentail a significant risk of morbidity. Thus, evaluationfor ICD requires an individualized assessment of thepotential risks and benefits.

PREDICTION OF LV FUNCTIONAL RECOVERY.

Approximately one-third of DCM patients may expe-rience partial or complete recovery with medicaltreatment, which, in turn, is associated with a favor-able prognosis (41). Patients should therefore receiveat least 3 months of optimal medical therapy prior toformal evaluation for an ICD (15,18), but LV functionalrecovery may continue well beyond this point, lead-ing to a risk of unnecessary implantation. Byinforming the likelihood of reverse remodeling, LGE-CMR could help to optimize ICD deployment, identi-fying patients with high remodeling potential whomay warrant lengthier periods of treatment beforeICD decision-making. The same principle extends toDCM patients with a “reversible” etiology, such asalcohol-related, peripartum, or acute inflammatorycardiomyopathy, underscoring the importance ofetiological evaluation. The most obvious drawback ofthis approach—the risk of SCD during the defermentperiod—could conceivably be ameliorated by wear-able cardioverter-defibrillators, thereby affordingtemporary protection against ventricular arrhyth-mias, while avoiding the complications of long-termICD implantation.

NOVEL RISK PREDICTION TOOLS FOR SCD. Thelimitations of current ICD guidelines are well docu-mented: the majority of patients equipped with anICD do not receive an appropriate therapy, whereasmost cases of SCD occur among patients who do notsatisfy implantation criteria. The incorporation ofnovel risk stratification tools for SCD to improveevaluation for ICD is therefore appealing, but pre-sents major challenges in practice.

In a recent meta-analysis of SCD risk stratificationtechniques in DCM, several LV remodeling and

CENTRAL ILLUSTRATION Potential for Detailed DCM Assessment to Guide Therapy

LV

Retard remodeling:• Neurohormonal blockade• Molecular / gene therapy• Imaging & biomarker surveillance

Stage of left ventricular (LV) remodeling

Treatmentstrategies

(Consider ICD based on established and novel risk factors for sudden cardiac death, for all three stages)

Regenerate:• Stem cell

therapy• ‘Bridge to

recovery’ LVassist device

Replace:• Cardiac

transplant• ‘Destination

therapy’ LVassist device

Reverse remodeling:• Neurohormonal blockade• Cardiac resynchronization• Mitral valve interventions• Molecular / gene therapy• Immunosuppressive / antiviral treatment

+/–• Functional mitral regurgitation• LV dyssynchrony• Active myocarditis • Refractory to conventional therapies

+/or• Pathogenic gene mutation• Altered biomarkers

LV volumeand LVEF

Limited or noreplacement fibrosis

Severely LV volumeand LVEF

Extensivereplacement fibrosis

Wall thinning

+/– Right ventricular remodeling

Early LV phenotype(e.g. strain,LV enlargement,diffuse fibrosis)

Established Advanced Latent

Japp, A.G. et al. J Am Coll Cardiol. 2016;67(25):2996–3010.

(Left) Detection of latent DCM through enhanced screening and surveillance of at-risk subjects may permit targeted treatment measures to arrest the myopathic process

and prevent remodeling. (Middle) For patients with an established DCM phenotype, a combination of pharmacological, genetic, device, and mechanical strategies may

be deployed to promote reverse remodeling. (Right) In advanced disease, particularly with widespread myocardial fibrosis, emerging regenerative treatments, such as

cell-based therapies or intensive mechanical unloading, may offer an alternative to transplantation or long-term LVAD. Novel risk prediction tools integrating multiple

prognostic variables may allow individualized SCD risk assessment for patients at all stages of remodeling to guide optimal use of ICD implantation. DCM ¼ dilated

cardiomyopathy; ICD ¼ implantable cardioverter-defibrillator; LV ¼ left ventricular; LVAD ¼ left ventricular assist device; LVEF ¼ left ventricular ejection fraction;

SCD ¼ sudden cardiac death.

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electrophysiological variables were associated withan increased risk of arrhythmic outcomes. With theexception of fragmented QRS complexes (odds ratio:6.73), none of the variables individually providedmore than modest predictive power (odds ratio: w2to 4) (42). Nonetheless, integration of these variablesinto a composite SCD risk score (Central Illustration)might yield more clinically meaningful risk stratifi-cation and warrants further prospective assessment.Notably, this meta-analysis did not include LGE-CMR,which has been shown to predict arrhythmic out-comes in DCM in multiple studies (29,31,43–45). Wepreviously showed that myocardial fibrosis identifiedby LGE-CMR is an independent predictor of SCD riskand all-cause mortality, providing prognostic infor-mation that is incremental to LVEF (31). These find-ings have since been corroborated by a meta-analysisincorporating 1,488 DCM patients (46). In DCM pa-tients undergoing guideline-directed ICD implanta-tion for primary prevention, the presence of LGE isassociated with a hazard ratio of 10 to 15 for subse-quent SCD or appropriate ICD therapy (43).Conversely, the absence of midwall LGE identifies a

population of DCM patients at low risk of SCD, evenwhen LVEF is #35%. The combination of LGE-CMRwith biomarker analysis may offer even greaterdiscriminatory power, identifying an “ultra-low” riskof arrhythmic outcomes (e.g., 1% to 3%/year) amongDCM patients who meet current criteria for ICDimplantation (45).

PART 4: DETECTION OF THE

PRE-DCM PHENOTYPE

Strategies to detect pre-symptomatic DCM have aclear rationale, because early treatment can retardadverse remodeling, prevent HF symptoms, andincrease life expectancy. Moreover, the establishedDCM phenotype may be preceded by more subtlemanifestations of myocardial injury, dysfunction,or remodeling. Improved detection of latent disease,if paired with effective interventions, could sub-stantially reduce the clinical burden of DCM(Central Illustration).

FAMILIAL SCREENING FOR DCM. Clinical screeningwith ECG and echocardiography should be offered to

FIGURE 3 Echocardiographic Assessment of Functional Mitral Regurgitation and Guidance of Percutaneous Mitral Interventions

(A and B) Transthoracic echocardiography appearances of functional mitral regurgitation with annular dilation, leaflet tenting, and central

regurgitation. (C and D) Real-time transesophageal echocardiography guidance of mitral clip implantation. (C) 3-dimensional imaging shows

the clip (black arrow) in the LA aligned with the AMVL (a) and PMVL (b). (D) After crossing the valve, 2-dimensional imaging guides retraction

of the clip arms (white arrows) and grasping of the leaflets. (E and F) 3-dimensional transesophageal echocardiography en-face views of

the mitral valve in diastole (E) and systole (F) following mitral clip deployment. Note the typical double orifice appearance in diastole.

AMVL ¼ anterior mitral valve leaflet; LA ¼ left atrium; LV ¼ left ventricle; PMVL ¼ posterior mitral valve leaflet.

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FIGURE 4 Differentiation of Athlete’s Heart From Early DCM by Myocardial Deformation Imaging

Two-dimensional speckle tracking-derived longitudinal strain curves from 6 myocardial segments on standard 4-chamber view. (A) An

endurance cyclist with a left ventricular (LV) end-diastolic diameter of 62 mm and mildly impaired LV ejection fraction exhibiting normal

longitudinal strain (mean global strain of �17%). (B) A patient with idiopathic dilated cardiomyopathy (DCM) with mild LV enlargement

(LV end-diastolic diameter 59 mm) and borderline LV ejection fraction exhibiting reduced longitudinal strain (mean global strain of �7%).

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first-degree relatives of DCM patients who lack a clearunderlying etiology. As DCM exhibits age-dependentpenetrance, repeated screening is advocated (e.g.,every 2 to 5 years until 50 to 60 years of age) to detect

late-onset disease (47,48). Identification of a patho-genic gene mutation rationalizes screening by allow-ing mutation-specific cascade testing of familymembers. Relatives without the mutation can be

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discharged, whereas mutation carriers merit morefrequent clinical surveillance (e.g., every 1 to 3 years)(47,48).

Limitations of predictive genetic testing, particu-larly for relatives found to carry a pathogenic muta-tion, include the attendant psychological burden, theinability to predict time and severity of disease onset,and the lack of available therapies to avert diseasedevelopment. Such issues highlight the critical role ofgenetic counseling in facilitating informed decisionsregarding testing and supporting patients followingresults.

DETECTING LATENT DISEASE: THE PRE-DCM

PHENOTYPE. Left ventricular enlargement (LVE)without systolic dysfunction represents a well-defined precursor of inherited DCM. Among asymp-tomatic relatives of patients with idiopathic orfamilial DCM screened by echocardiography, <5%meet criteria for DCM, but 15% to 25% exhibit LVE, ofwhich 10% to 20% progress to overt DCM within5 years (49,50).

Myocardial deformation imaging (Figure 4) mayprovide phenotypic markers of latent DCM earlierthan LVE. Among relatives of patients with DCMcaused by a sarcomeric gene mutation, mutationcarriers exhibited substantially reduced strain andstrain rate compared with noncarriers, despite allhaving normal LV size and LVEF (51). In patientsreceiving potentially cardiotoxic cancer therapy, re-ductions in global longitudinal strain $10% consis-tently precede and predict the development of overtLV dysfunction (52). Subclinical detection in thesepatients is crucial because timely intervention (e.g.,change in chemotherapy regimen) may preventdisease progression, whereas systolic dysfunction isoften irreversible once LVEF declines.

LGE-CMR can detect myocardial replacementfibrosis prior to overt LV remodeling in patients withlaminopathy or Becker’s muscular dystrophy (53,54).However, the assessment of diffuse interstitialfibrosis (Figure 2C) by emerging T1 mapping methods(Figures 1I and 1J) may allow differentiation ofdiseased from healthy myocardium, even in theabsence of LGE (55), and holds considerable promisefor early DCM diagnosis (56). In a study of LMNAmutation carriers, myocardial extracellular volumefraction, assessed by T1 mapping, was significantlyhigher in mutation carriers than in healthy controlsubjects, even in carriers who lacked any otherclinical or LGE-CMR evidence of DCM phenotypicexpression (57).

One further CMR tissue characterization tech-nique, T2*, exemplifies the potential of early disease

detection to prevent DCM, specifically in transfusion-dependent patients (e.g., with beta-thalassemiamajor) at risk of cardiac iron overload. T2* CMRpermits accurate noninvasive monitoring of cardiaciron (Figures 1K and 1L), enabling optimization of ironchelation therapy and reversal of myocardial ironloading before the onset of LV dysfunction and HF.The introduction of T2* monitoring for thalassemiapatients has contributed to a 70% decline in U.K.mortality from cardiac iron overload since 2000.

Serum protein biomarkers can deliver insights intomultiple facets of cardiac remodeling, includingmyocyte death, extracellular matrix remodeling,ventricular stretch, and oxidative stress, and maytherefore play an adjunctive role in uncovering latentdisease. For example, high-sensitivity cardiac tropo-nin assays provide a potential avenue for the detec-tion of low-grade, subclinical myocardial injury.Among cancer patients receiving cardiotoxic chemo-therapy, elevations in serum troponin strongly pre-dict subsequent LV dysfunction (58). In the longerterm, the application of proteomics to DCM offers theprospect of characterizing the molecular and cellularpathways that underpin disease progression (59).Ultimately, this could shift disease detection to theearliest stages of development, while simultaneouslyuncovering new targets for molecular therapies.

Major work on several fronts is now requiredto establish the clinical utility of subclinical DCMdetection strategies. A clinical trial is ongoing todetermine whether strain surveillance in patientsreceiving cardiotoxic chemotherapy reduces theincidence of overt LV dysfunction compared withLVEF surveillance (SUCCOUR [Strain sUrveillanceduring Chemotherapy for improving CardiovascularOutcomes]; ACTRN12614000341628). In familial DCM,LVE represents a promising entry point for random-ized clinical trials to establish whether early neuro-hormonal blockade prevents disease developmentamong at-risk relatives. At present, the potential forstrain imaging, T1 mapping, or serum biomarkers toact as early markers of phenotypic expression ininherited DCM remains at the conceptual stage. Thecurrent priority should be to confirm their abilityto predict disease development and ascertain theoptimal cutoff values for this.

CONCLUSIONS

DCM constitutes a broad cardiac phenotype that canarise from a multitude of myocardial insults. Rigorousetiological evaluation may allow for specific treatmenttargeted to the underlying cause. Molecular genetictesting and EMBx reveal the culprit trigger in many

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otherwise unexplained cases, although tailored treat-ment strategies for genetic abnormalities or myocar-ditis remain investigative at present. Detailedcharacterization of remodeling, particularlywith CMR,may help to further inform etiology and prognosis, aswell as guide major treatment decisions. Novel imag-ing techniques and serum biomarkers offer thepotential for earlier disease detection, with theopportunity to delay or possibly arrest disease pro-gression. Further work is now required to determinewhether these approaches to DCM evaluation can leadto meaningful improvements in patient outcomes.ACKNOWLEDGMENTS The authors are grateful toDrs. Mary Sheppard and Jan Lukas Robertus, RoyalBrompton Hospital, London, for the histological

images and analysis; Dr. Dan Sado, King’s CollegeHospital, London, for the T1 color map images andanalysis; and Dr. David Oxborough, Liverpool JohnMoores University, Liverpool, for the strain imagesand analysis. In addition, the authors thank Dr. RaviAssomull, Ealing Hospital, London, and Dr. TevfikIsmail, Royal Brompton Hospital, London, for pro-viding a critical review of the manuscript prior tosubmission.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Ankur Gulati, Cardiovascular Magnetic ResonanceUnit, Royal Brompton Hospital, Sydney Street,London SW3 6NP, United Kingdom. E-mail: ankur0@hotmail.com.

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KEY WORDS imaging, implantablecardioverter-defibrillator, remodeling

APPENDIX For a list of supplementalreferences, please see the online version ofthis article.