JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO.

25, 2016

2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2016.03.590

REVIEW TOPIC OF THE WEEK

The Diagnosis and Evaluation of

Dilated 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

Dilated cardiomyopathy (DCM) is best understood as the nal 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 specic treatments, and guide family screening. A signicant proportion of DCM
cases have an underlying genetic or inammatory basis. Measurement of LV size and ejection fraction remain central to
diagnosis, risk stratication, and treatment, but other aspects of cardiac remodeling inform prognosis and carry thera-
peutic implications. Assessment of myocardial brosis predicts both risk of sudden cardiac death and likelihood of LV
functional recovery, and has signicant potential to guide patient selection for cardioverter-debrillator 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;67:29963010)
2016 by the American College of Cardiology Foundation.

D ilated cardiomyopathy (DCM) is dened as

left ventricular (LV) dilation and systolic
dysfunction in the absence of coronary
artery disease or abnormal loading conditions propor-
tionate to the degree of LV impairment (1). (Only key
references are cited in this paper; additional support-
ing references for each section can be found in the
Online Appendix). One of the leading causes of heart
failure (HF), DCM predominantly affects younger
adults and is the most frequent indication for cardiac
transplantation. The condition is best regarded not
as a single disease entity, but rather as a nonspecic
phenotype, the nal common response of myocar-
dium to a number of genetic and environmental
insults (Table 1). Until recently, the evaluation of
DCM has scarcely deviated from the standard
approach to systolic HF. However, advanced imaging
techniques, together with modern genetic, bio-
marker, and biopsy analysis, increasingly allow for
more rigorous assessment of etiology and cardiac
remodeling, as well as earlier disease detection. In
this review, we examine the role of a more detailed
approach to DCM in contemporary practice and its
emerging potential to guide individualized treatment
strategies.
PART 1: EVALUATION OF ETIOLOGY
Before diagnosing DCM, it is necessary to exclude
conditions with phenotypic overlap. Thereafter,

Listen to this manuscripts tional Heart Centre Singapore, Singapore. This work was supported by the National Institute for Health Research Cardiovascular
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aDepartment of Cardiology, Royal Brompton Hospital, London, United Kingdom; bDepartment of Cardiovascular
Medicine, National Heart & Lung Institute, Imperial College, London, United Kingdom; and the cDepartment of Cardiology, Na-
Biomedical Research Unit at the Royal Brompton and Hareeld NHS Foundation Trust and Imperial College London. Additional
grant support was received from CORDA and the Rosetrees Trust. Prof. Cook has served as a consultant for GlaxoSmithKline. Prof.
Cowie serves as a consultant to Medtronic, Boston Scientic, St. Jude Medical, Servier, Daiichi-Sankyo, Neurotronik, Novartis,
Bayer, Pzer/Bristol-Myers Squibb, and ResMed; has received research grants to Imperial College from Bayer, Boston Scientic,
and ResMed; and has received speaker fees from Servier, Novartis, St. Jude Medical, Boston Scientic, Medtronic, Bayer, and
ResMed. Dr. Prasad has received honoraria from Schering. All other authors have reported that they have no relationships relevant
to the contents of this paper to disclose. Drs. Japp and Gulati contributed equally to this work.

Manuscript received February 16, 2016; revised manuscript received March 21, 2016, accepted March 21, 2016.
JACC VOL. 67, NO. 25, 2016
JUNE 28, 2016:29963010
identication of a specic underlying etiology may
allow targeted disease-specic treatment, guide the
need for family screening, or inform prognosis.
EXCLUSION OF OTHER CAUSES. Ischemic cardio-
myopathy is conventionally distinguished from DCM
by the presence of $75% stenosis in the left main
stem, proximal left anterior descending artery, or 2 or
more epicardial coronary arteries on invasive or
computed tomography coronary angiography (2). Late
gadolinium enhancement (LGE) cardiovascular mag-
netic resonance (CMR) provides an alternative
approach and may identify prior myocardial infarc-
tion (subendocardial or transmural LGE) in as many
as 13% of patients with suspected DCM and unob-
structed coronary arteries (3). In addition to ischemic
cardiomyopathy, DCM must also be distinguished
from other nonischemic cardiomyopathies and phys-
iological adaptations that may generate similar pat-
terns of LV remodeling (Table 2).
ROUTINE ETIOLOGICAL WORK-UP. A suggested
etiological evaluation for patients with DCM is listed
in Table 1. Regular alcohol consumption of at least 80
g/day for over 5 years has frequently been associated
with LV dilation and dysfunction (4). Anthracycline
cardiotoxicity is governed principally by total cumu-
lative dose and may not become apparent until over
10 years after exposure. Although presentation
toward the end of pregnancy or shortly after delivery
suggests peripartum cardiomyopathy, patients
should still be assessed for alternative causes because
the hemodynamic stress of pregnancy may unmask
latent myocardial dysfunction. The prevalence of
human immunodeciency virus (HIV)associated
cardiomyopathy has substantially declined with
antiretroviral therapy (5); however, many patients are
not diagnosed with HIV infection until the advanced
stages 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, typically
within 4 weeks, conrms the diagnosis. Atrioven-
tricular block may indicate an underlying genetic
etiology (e.g., lamin A/C mutation or myotonic dys-
trophy) or inammatory disease (e.g., sarcoidosis,
giant cell myocarditis, or Lyme disease).
Echocardiography has a limited role in dening
DCM etiology. However, prominent inferolateral
hypokinesis/akinesis is often observed in muscular
dystrophy or acute myocarditis. CMR may aid etiologic
evaluation through detection of myocardial edema
(e.g., active myocarditis or sarcoidosis), and
Japp et al. 2997
The Diagnosis and Evaluation of DCM
classication of LGE distribution (e.g., ABBREVIATIONS
muscular dystrophy, previous myocarditis, AND ACRONYMS
sarcoidosis, or Chagas disease). Alongside
18 CMR = cardiovascular magnetic
CMR, F-uorodeoxyglucose positron emis- resonance
sion tomography is emerging as a valuable
CRT = cardiac
tool for diagnosing cardiac sarcoidosis and resynchronization therapy
monitoring disease activity. DCM = dilated cardiomyopathy
Inammatory cardiomyopathy and the EMBx = endomyocardial biopsy
r o l e o f e n d o m y o c a r d i a l b i o p s y . The com-
FMR = functional mitral
bination of myocardial inammation regurgitation
(myocarditis) and dysfunction is termed in- HF = heart failure
ammatory cardiomyopathy. In patients with ICD = implantable
recent-onset DCM, identication of myocar- cardioverter-debrillator
ditis has important clinical implications due LGE = late gadolinium
to the high potential for LV recovery. An enhancement
acute onset of symptoms, u-like pro- SCD = sudden cardiac death
drome, or elevated serum troponin/inam- TTE = transthoracic
echocardiography
matory markers may raise suspicion.
Although viruses are the most common trigger in
Europe and North America, serology is generally un-
helpful, partly because of high background sero-
positivity rates. A subset of patients with acute
myocarditis progresses to chronic DCM: among
histology-conrmed cases, the reported incidence of
DCM varies between 14% and 52% (6).
CMR enables noninvasive detection of myocarditis
through 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 inammatory
disease. Endomyocardial biopsy (EMBx) remains the
gold standard investigation, and modern immuno-
histochemical methods improve sensitivity compared
with the traditional histopathological Dallas criteria.
Biopsy ndings carry clear treatment implications in
DCM patients with suspected giant cell myocarditis,
eosinophilic myocarditis, or sarcoidosis, and EMBx is
indicated in these patient groups (8).
Beyond this, molecular genetic analysis of biopsy
specimens for cardiotropic viruses can delineate
whether chronic inammation is due to viral persis-
tence or autoimmunity to cardiac proteins. Lack of
such analysis was an important limitation of early
negative trials of immunosuppressive therapy in
myocarditis because immunosuppression may be
ineffective in patients with ongoing viral infection
(9). A recent placebo-controlled trial of immuno-
suppression in DCM patients with chronic active
inammation, but undetectable viral genomes,
demonstrated dramatic improvements in left ven-
tricular ejection fraction (LVEF) and functional class
(10). Limited data also suggest potential benet from
antiviral therapy with interferon-beta in patients with
persistent cardiotropic viruses (11).
2998 Japp et al. JACC VOL. 67, NO. 25, 2016

The Diagnosis and Evaluation of DCM JUNE 28, 2016:29963010

T A B L E 1 Causes of DCM

Cause Examples Routine Work-Up Selective Work-Up

Idiopathic
Genetic See Table 3 Detailed family history Clinical screening of rst-degree relatives
ECG (AV block) [LMNA]* if no other cause for DCM identied.
Ferritin and transferrin saturation Consider genetic testing if familial
[hemochromatosis]* involvement, AV block, or raised
ferritin/transferrin saturation.
Toxins Alcohol, amphetamines, cocaine, anthracyclines Detailed history of toxin exposure Urine toxicology screen if high suspicion
(e.g., doxycycline), trastuzumab, clozapine, GGT, LFT, MCV of cocaine/amphetamine abuse.
chloroquine, carbon monoxide, cobalt,
lead, mercury
Infectious Viral Troponin HIV serology in all patients with risk

Adenovirus, Coxsackie A and B, factors and/or unexplained DCM
cytomegalovirus, Epstein-Barr, Trypanosoma Cruzi serology if travel
human herpes virus 6, HIV, to or residence in Central/
parvovirus B19, varicella South America.
Bacterial Consider EMBx if suspicion of myocarditis

Brucellosis, diphtheria, psittacosis, (see Inammatory cardiomyopathy and
typhoid fever the role of endomyocardial biopsy, p. 2997)
Fungal Targeted serological testing if suspected
Spirochetal Lyme disease or rickettsial infection.

Borreliosis (Lyme disease), Leptospirosis
(Weil disease)
Protozoal

Chagas disease, schistosomiasis,
toxoplasmosis
Rickettsial
Metabolic/endocrine Electrolyte disturbances Urea, creatinine, Na, K, Ca, PO4 Targeted endocrine investigations if

Hypocalcemia, hypophosphatemia, uremia Thyroid function tests suggestive clinical features.
Endocrine abnormalities Plasma glucose Trace element/nutritional screen if

Cushings disease, acromegaly hypo/ Urinary metanephrines signicantly malnourished.
hyperthyroidism, pheochromocytoma
Nutritional deciencies

Carnitine, thiamine, selenium
Inammatory/inltrative/ Hypersensitivity myocarditis ESR, CRP EMBx if suspicion of sarcoidosis or
autoimmune Inltrative diseases ECG (AV block), CXR vasculitis (unless conrmed

Hemosiderosis, sarcoidosis (hilar lymphadenopathy), extracardiac disease and myocardial
Vasculitis and serum ACE [sarcoidosis]* involvement demonstrable on imaging).

Churg-Strauss, Kawasaki disease, Autoantibody screen if raised ESR/CRP
polyarteritis nodosa or skin/joint/systemic features.
Connective tissue disorder

Scleroderma

Dermatomyositis

Systemic lupus erythematosus
Neuromuscular disease Dystrophinopathies (Duchenne/ Creatine kinase Specialist evaluation  muscle biopsy/
Becker muscular dystrophy/X-linked DCM) Skeletal muscle weakness electromyography/genetic testing
Limb-girdle muscular dystrophies Family history (X-linked inheritance if muscle weakness, elevated
Facioscapulohumeral muscular dystrophy pattern), ECG (posterolateral creatine kinase, or other cardiac/
Emery-Dreifuss muscular dystrophy infarction), echo (posterolateral extracardiac markers.
Friedreichs ataxia akinesia/dyskinesia)
Myotonic dystrophy [dystrophinopathies]*
Gait ataxia [Friedreichs ataxia]*
Myotonia/cataracts [myotonic
dystrophy]*
ECG (AV block) [Emery-Dreifuss
type 1/myotonic dystrophy]*
Other Pregnancy
Tachyarrhythmia 12-lead ECG Ambulatory ECG monitoring.

*Specic causes of DCM to which the aforementioned diagnostic tests apply. X-linked inheritance pattern: principally males affected, no malemale transmission.
ACE angiotensin-converting enzyme; AV atrioventricular; CRP C-reactive protein; CXR chest x-ray; DCM dilated cardiomyopathy; ECG electrocardiogram; Echo echocardiography;
EMBx endomyocardial biopsy; ESR erythrocyte sedimentation rate; GGT gamma-glutamyl transferase; HIV human immunodeciency virus; LFT liver function tests; LMNA lamin A/C gene;
MCV mean corpuscular volume.

Myocarditis thus represents an exciting prospect
for mechanism-based therapy in DCM. However,
conclusive benet from EMBx-guided treatment is
awaited. A European Society of Cardiology Working
Group recently called for broader use of EMBx to
improve the diagnosis of myocarditis (12). When
applied to DCM, their proposed multiparametric
criteria would ultimately lead to EMBx in any symp-
tomatic patient with no clear etiologya distinct
departure from previous consensus statements (8,13)
and international HF guidelines (14,15). For now, a
rational approach to this conicting guidance is to
JACC VOL. 67, NO. 25, 2016 Japp et al. 2999
JUNE 28, 2016:29963010 The Diagnosis and Evaluation of DCM

T A B L E 2 Differentiation of DCM From Conditions With Phenotypic Overlap

Condition Features Favoring Alternate Diagnosis Comments

Ischemic cardiomyopathy
Hypertensive heart disease
Advanced HCM
ARVC
Myocardial noncompaction
Athletes heart
Cirrhotic cardiomyopathy

See Exclusion of Other Causes, p. 2997

History of chronic, poorly controlled hypertension

Increased LV wall thickness

Long-standing history of HCM

Extensive patchy myocardial brosis on LGE-CMR

Increased LV wall thickness

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 LV
midwall LGE extending to right side of septum [Online Ref. 7])

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/m 2

Trabeculation of basal segments 46

Ratio of noncompacted to compacted myocardial
thickness >3.0 in 1 or more segments

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 VO 2 on cardiopulmonary exercise testing

Reverse remodeling with deconditioning (Online Ref. 14)

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)
HF etiology is traditionally dichotomized into ischemic and
nonischemic categories on the basis of coronary
angiography.
LGE-CMR tissue characterization provides incremental
information, which when combined with angiography,
enables a more precise classication of ischemic vs.
nonischemic etiology (Online Ref. 1).
Distinguishing DCM (with adverse RV remodeling) from
the biventricular or left-dominant forms of ARVC
can be challenging, particularly because both
presentations may be caused by mutations
in desmosomal protein genes.
Prominent trabeculation secondary to LV remodeling is
common in DCM (Online Ref. 11). Conventional noncompaction
diagnostic criteria (ratio of noncompacted to compacted
myocardial thickness >2.1 at end-systole on echo, and
>2.3 at end-diastole on CMR) have been criticized for
their poor specicity and inability to discriminate
between pathological noncompaction and DCM
with hypertrabeculation (Online Refs. 10,12).
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 with
a concomitant reduction in resting LVEF (Online Ref. 16),
thereby fullling diagnostic criteria for DCM.
Cirrhotic cardiomyopathy is an under-recognized and important
complication of cirrhosis from any cause; it should be
suspected in patients with liver disease who develop
cardiac failure or hemodynamic deterioration.

See the Online Appendix for table references.

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

consider the incremental value of EMBx on an indi-
vidual case basis. Where experimental treatments,
such as immunosuppression or antiviral therapy, are
not under consideration, given the current diagnostic
yield and procedural risks of EMBx, it would appear
difcult 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 in
over 60 genes (Table 3). In 2012, truncating mutations
of the titin (TTN) gene were shown to be present in
25% 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 in
DCM patients is very high (>95%), population
controls with a TTN truncation invariably exhibit a
normal cardiac phenotype, likely due to additional
modier gene effects, environmental factors, or late
onset of disease.
In some patients with genetic DCM, a particular
gene defect may be suggested by cardiac conduction
abnormalities (e.g., LMNA or SCN5A mutations) or
elevated serum creatine kinase/muscle weakness
(e.g., muscular dystrophy or LMNA mutation). How-
ever, most cases have no specic distinguishing
phenotypic features. Identication of other affected
family members is therefore the most important
pointer 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 signicantly
underestimated by family history alone, screening by
electrocardiography (ECG) and echocardiography is
3000 Japp et al. JACC VOL. 67, NO. 25, 2016

The Diagnosis and Evaluation of DCM JUNE 28, 2016:29963010

F I G U R E 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 brosis (arrows) by LGE-CMR. (I and J) Assessment of interstitial brosis.
No replacement brosis is identied 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 aorta; CMR cardiovascular magnetic resonance; LGE late gadolinium
enhancement; ROI region of interest; STIR short-tau inversion-recovery.

also recommended for rst-degree relatives of pa- members) (15), where its diagnostic yield is 30% to
tients with apparently idiopathic DCM. 35%. Currently, the identication of a causal muta-
At present, routine genetic testing is only recom- tion carries few implications for prognosis or treat-
mended in familial disease ($2 affected family ment of the index case, and the principal rationale for
JACC VOL. 67, NO. 25, 2016
JUNE 28, 2016:29963010
testing is to allow mutation-specic cascade
screening of family members (see Part 4). An excep-
tion is LMNA mutations, which are associated with
high rates of conduction system disease, ventricular
arrhythmias, and sudden cardiac death (SCD) and
may consequently lower the threshold for prophy-
lactic implantable cardioverter-debrillator (ICD)
implantation (18).
Looking ahead, the correlation of distinctive
phenotypic features with rare alleles and elucidation
of the molecular pathways responsible could revolu-
tionize our approach to treatment, as recently
exemplied by a study in patients with a variant of
the SCN5A gene (19). This cohort exhibited a striking
DCM phenotype associated with various arrhythmias
and frequent premature ventricular complexes.
Functional characterization of the mutation in vitro
revealed an activating effect on the Nav1.5 sodium
channel, predicted to cause rate-dependent ventric-
ular ectopy. Although patients responded poorly to
conventional 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 impairment
in DCM is a major determinant of adverse outcomes,
and reversal of these abnormalities, LV reverse
remodeling, is a key therapeutic goal. In addition to
LV wall thinning and dilation (Figure 2A), adverse
remodeling characteristics in DCM include func-
tional mitral regurgitation (FMR), myocardial brosis
(Figures 2B and 2C), dyssynchronous ventricular
contraction, and enlargement of other chambers.
Increasingly, detailed characterization of these pa-
rameters may also hold value in predicting prognosis
and 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 and
LVEF. 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 relation
to eligibility for device/pharmacotherapy and serial
monitoring for cardiotoxicity. Administration of
echocardiography contrast agents improves the accu-
racy of 2D/3D volume assessment, particularly when
image quality is suboptimal.
CMR combines high spatial resolution multiplanar
imaging with excellent delineation of the blood-
myocardium interface to enable precise quantica-
tion of cardiac chamber volumes (Figures 1A and 1B).
Japp et al. 3001
The Diagnosis and Evaluation of DCM
Although CMR is the gold standard for ventricular
assessment, its routine use is limited by restricted
availability, expense, and device incompatibility.
Myocardial deformation imaging techniques (e.g.,
speckle-tracking echocardiography-derived strain or
CMR myocardial tagging) offer greater sensitivity
than LVEF for identifying subtle abnormalities of
systolic function, and may assume a role in the early
detection of disease (see Part 4).
REMODELING OF OTHER CARDIAC CHAMBERS. Left
atrial (LA) dilation is frequently observed in DCM as a
consequence of diastolic dysfunction, FMR, atrial
brillation, and LV cavity enlargement. LA volume is
the preferred measure of LA size (Figures 1C and 1D)
and predicts adverse outcomes in DCM (20). Adverse
right ventricular (RV) remodeling, resulting from
secondary pulmonary hypertension or primary
myocardial disease, is also common in DCM patients.
TTE enables accurate assessment of tricuspid regur-
gitation and pulmonary artery systolic pressure, but
has a limited estimation of RV size and function. CMR
offers 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 insight
into aspects of DCM not fully reected in indexes of
LV remodeling. Future research should aim to deter-
mine whether changes in these variables over time
better predict disease trajectory and long-term re-
sponses to treatment.
FUNCTIONAL MITRAL REGURGITATION. Increasing
LV size and sphericity causes tethering of the mitral
leaets, which, together with annular dilation, leads
to defective leaet coaptation and functional
regurgitation (Figures 3A and 3B). FMR perpetuates LV
remodeling and is associated with increased
morbidity and mortality, independently of LVEF (23).
Reduction of FMR severity in DCM patients receiving
optimal medical therapy and/or cardiac resynchroni-
zation therapy (CRT) is associated with improved
transplant-free survival (24,25). Surgical annuloplasty
can also reduce FMR and is accompanied by im-
provements in LV remodeling and symptoms (26).
With the emergence of percutaneous transcatheter
mitral valve therapies, such as the edge-to-edge
MitraClip repair system (Abbott Vascular, Abbott
Park, Illinois) (Figures 3C to 3F) (27), the importance of
FMR assessment in DCM is likely to increase.
Currently, one of the major challenges lies in grading
FMR severity. The 3D echocardiographic color Doppler
techniques (e.g., en face planimetry of vena contracta
area) permit direct and accurate assessment of
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The Diagnosis and Evaluation of DCM JUNE 28, 2016:29963010

T A B L E 3 Genes Associated With DCM

Protein Location Gene Protein Protein Function

Sarcomere MYH6 a-myosin heavy chain

MYH7* b-myosin heavy chain
TPM1 a-tropomyosin
ACTC Cardiac actin
TNNT2* Cardiac troponin T Force generation  transmission
TNNC1 Cardiac troponin C
TNNI3* Cardiac troponin I
MYPN Myopalladin
MYBPC3 Myosin-binding protein C
Cytoskeleton ACTN2 a-actinin 2
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
Force transmission  structural integrity
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
DSC2 Desmocollin 2
DSG2 Desmoglein 2 Cellcell adhesion  intracellular signaling
DSP* Desmoplakin
PKP2 Plakophilin 2
Sarcoplasmic reticulum PLN Phospholamban Regulates sarcoendoplasmic reticulum
calcium ATPase pump
RYR2 Ryanodine receptor 2 Calcium-channel component
Nuclear envelope LMNA* Lamin A/C
TMPO Thymopoietin Maintain structural organization and stability
of nuclear envelope
EMD Emerin
LAP2a Lamin-associated polypeptide 2a Link nucleus to cytoskeleton
SYNE1/2 Nesprin 1/2
Nucleus ANKRD1 Cardiac ankyrin repeat protein
EYA4 Eyes absent 4
FOXD4 Forkhead box D4
HOPX Homeobox only protein
Transcription cofactor
NFKB1 NF-kappa B1
PRDM16 PR domain containing 16
TBX20 T-box 20
ZBTB17 Zinc nger 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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JUNE 28, 2016:29963010 The Diagnosis and Evaluation of DCM

T A B L E 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
FRDA Frataxin
DNAJC19 HSP40 homolog, C19
SDHA Succinate dehydrogenase Supply and/or regulation of energy metabolism
SOD2 Superoxide dismutase
TAZ/G4.5 Tafazzin
mtDNA Mitochondrial respiratory chain
Extracellular matrix LAMA2 Laminin-a-2
Extracellular constituent of basement membrane
LAMA4 Laminin-a-4
involved in cell adhesion and signaling
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 adenosine triphosphate; DCM dilated cardiomyopathy; mtDNA mitochondrial deoxyribonucleic acid; RNA ribonucleic acid.

effective regurgitant orice area, circumventing the
geometric assumptions inherent to 2D assessment. At
present, such measurements are time-consuming and
technically demanding, but with continued evolution
of 3D echocardiographic technology and automated
analysis software, they may gradually supplant 2D
methods. Velocity-encoded CMR offers a useful alter-
native modality for evaluating FMR, especially when
echocardiography is equivocal.
MYOCARDIAL FIBROSIS. Replacement brosisfocal
reparative scarring that follows myocyte injury or
necrosisoccurs 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 for
ventricular re-entrant arrhythmia (29) and is inde-
pendently associated with an increased risk of mor-
tality and HF morbidity in DCM (30,31). Moreover, its
presence and extent in DCM hearts, as assessed by
LGE-CMR, substantially determines the likelihood of
LV reverse remodeling in response to pharmacolog-
ical therapy (32,33) and CRT (34). These observations
conrm an intuitive notion: DCM ventricles that
exhibit replacement of viable myocardium with
reparative scar are less likely to recover than those
without established brosis. In the current era, this
might inform the selection of patients for device
therapy (Part 3). Looking ahead, advances in left
ventricular assist device technology and the early
promise of stem cell therapy (35) could conceivably
establish brosis assessment as a key component of
DCM evaluation, yielding a new LGE-CMRguided
treatment paradigm in which patients with extensive
myocardial scarring and low remodeling potential are
directed towards replacement or regenerative thera-
pies (Central Illustration).
VENTRICULAR DYSSYNCHRONY. In selected DCM
patients with mechanical dyssynchrony, resynchro-
nization of ventricular contraction through biven-
tricular pacing leads to major improvements in LV
remodeling and outcomes. QRS interval prolongation
was the primary criterion for dyssynchrony in the
pivotal clinical trials of CRT, making it a cornerstone
of patient selection, particularly when associated
with left bundle branch block (LBBB) morphology.
More recently, long-term outcome analyses and
meta-analyses of landmark trials have reafrmed the
central role of the surface ECG in guiding patient
selection, demonstrating a clear and consistent
benet from CRT in those with LBBB and QRS interval
duration $150 ms (36,37).
Mechanical dyssynchrony is also detectable by
echocardiographic techniques in up to 50% of
HF patients without QRS interval prolongation.
However, no echocardiographic index of dyssyn-
chrony predicts CRT response beyond established
criteria (38). Furthermore, in patients with QRS
duration <130 ms, but with echocardiographic evi-
dence of dyssynchrony, there is no benet and
possibly excess mortality from CRT (39). It now
seems unlikely that dyssynchrony evaluation by
echocardiography will have any role in patients with
LBBB and QRS interval duration $150 ms or those
with narrow QRS intervals. Further study is war-
ranted to explore its potential to rene selection
3004 Japp et al.
The Diagnosis and Evaluation of DCM
F I G U R E 2 Pathological Appearances of Dilated Cardiomyopathy
(A) Left ventricular cavity dilation (asterisk) with wall thinning. (B) Extensive left ven-
tricular midwall replacement brosis (arrows). (C) Myocyte hypertrophy (black arrow),
myocyte atrophy (blue arrow), nuclear pleomorphism (arrowheads), and increased
interstitial brosis (stained with Picrosirius red); magnication 500.
JACC VOL. 67, NO. 25, 2016
JUNE 28, 2016:29963010
among patients with borderline QRS interval (130 to
150 ms) or non-LBBB pattern.
PART 3: EVALUATION FOR AN ICD
In selected DCM patients, implantation of an ICD
reduces the incidence of SCD and overall mortality
(40). Current guidelines recommend ICD implanta-
tion in patients with DCM who have a reasonable life
expectancy and quality of life and either: 1) a history
of ventricular arrhythmia with hemodynamic com-
promise (secondary prevention); or 2) New York Heart
Association functional class II/III symptoms and
LVEF #35%, despite optimal medical therapy (pri-
mary prevention) (15,18). However, ICDs are moder-
ately expensive, do not improve quality of life, and
entail a signicant risk of morbidity. Thus, evaluation
for ICD requires an individualized assessment of the
potential risks and benets.
PREDICTION OF LV FUNCTIONAL RECOVERY.
Approximately one-third of DCM patients may expe-
rience partial or complete recovery with medical
treatment, which, in turn, is associated with a favor-
able prognosis (41). Patients should therefore receive
at least 3 months of optimal medical therapy prior to
formal evaluation for an ICD (15,18), but LV functional
recovery may continue well beyond this point, lead-
ing to a risk of unnecessary implantation. By
informing the likelihood of reverse remodeling, LGE-
CMR could help to optimize ICD deployment, identi-
fying patients with high remodeling potential who
may warrant lengthier periods of treatment before
ICD decision-making. The same principle extends to
DCM patients with a reversible etiology, such as
alcohol-related, peripartum, or acute inammatory
cardiomyopathy, underscoring the importance of
etiological evaluation. The most obvious drawback of
this approachthe risk of SCD during the deferment
periodcould conceivably be ameliorated by wear-
able cardioverter-debrillators, thereby affording
temporary protection against ventricular arrhyth-
mias, while avoiding the complications of long-term
ICD implantation.
NOVEL RISK PREDICTION TOOLS FOR SCD. The
limitations of current ICD guidelines are well docu-
mented: the majority of patients equipped with an
ICD do not receive an appropriate therapy, whereas
most cases of SCD occur among patients who do not
satisfy implantation criteria. The incorporation of
novel risk stratication tools for SCD to improve
evaluation for ICD is therefore appealing, but pre-
sents major challenges in practice.
In a recent meta-analysis of SCD risk stratication
techniques in DCM, several LV remodeling and
JACC VOL. 67, NO. 25, 2016 Japp et al. 3005
JUNE 28, 2016:29963010 The Diagnosis and Evaluation of DCM

C ENTR AL I LL U STRA T I O N Potential for Detailed DCM Assessment to Guide Therapy

Stage of left Latent Established Advanced

ventricular (LV)
remodeling
Early LV phenotype LV volume Severely LV volume
(e.g. strain, and LVEF and LVEF
LV enlargement,
Limited or no Extensive
LV
diffuse fibrosis)
replacement fibrosis replacement fibrosis
Wall thinning
+/or +/
+/ Right ventricular
Pathogenic gene mutation Functional mitral regurgitation remodeling
Altered biomarkers LV dyssynchrony
Active myocarditis Refractory to conventional therapies

Treatment Retard remodeling: Reverse remodeling: Regenerate: Replace:

strategies Neurohormonal blockade Stem cell Cardiac
Neurohormonal blockade
therapy transplant
(Consider ICD based on Molecular / gene therapy Cardiac resynchronization
established and novel Bridge to Destination
Imaging & biomarker surveillance Mitral valve interventions
risk factors for sudden recovery LV therapy LV
cardiac death, for all Molecular / gene therapy assist device assist device
three stages)
Immunosuppressive / antiviral treatment

Japp, A.G. et al. J Am Coll Cardiol. 2016;67(25):29963010.

(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 brosis, 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 dilated
cardiomyopathy; ICD implantable cardioverter-debrillator; LV left ventricular; LVAD left ventricular assist device; LVEF left ventricular ejection fraction;
SCD sudden cardiac death.

electrophysiological variables were associated with
an increased risk of arrhythmic outcomes. With the
exception of fragmented QRS complexes (odds ratio:
6.73), none of the variables individually provided
more than modest predictive power (odds ratio: w2
to 4) (42). Nonetheless, integration of these variables
into a composite SCD risk score (Central Illustration)
might yield more clinically meaningful risk strati-
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 (29,31,4345). We
previously showed that myocardial brosis identied
by LGE-CMR is an independent predictor of SCD risk
and all-cause mortality, providing prognostic infor-
mation that is incremental to LVEF (31). These nd-
ings have since been corroborated by a meta-analysis
incorporating 1,488 DCM patients (46). In DCM pa-
tients undergoing guideline-directed ICD implanta-
tion for primary prevention, the presence of LGE is
associated with a hazard ratio of 10 to 15 for subse-
quent SCD or appropriate ICD therapy
Conversely, the absence of midwall LGE identies a
population of DCM patients at low risk of SCD, even
when LVEF is #35%. The combination of LGE-CMR
with biomarker analysis may offer even greater
discriminatory power, identifying an ultra-low risk
of arrhythmic outcomes (e.g., 1% to 3%/year) among
DCM patients who meet current criteria for ICD
implantation (45).
PART 4: DETECTION OF THE
PRE-DCM PHENOTYPE
Strategies to detect pre-symptomatic DCM have a
clear rationale, because early treatment can retard
adverse remodeling, prevent HF symptoms, and
increase life expectancy. Moreover, the established
DCM phenotype may be preceded by more subtle
manifestations 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).
(43). FAMILIAL SCREENING FOR DCM. Clinical screening
with ECG and echocardiography should be offered to
3006 Japp et al. JACC VOL. 67, NO. 25, 2016

The Diagnosis and Evaluation of DCM JUNE 28, 2016:29963010

F I G U R E 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, leaet 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 leaets. (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 orice appearance in diastole.
AMVL anterior mitral valve leaet; LA left atrium; LV left ventricle; PMVL posterior mitral valve leaet.
JACC VOL. 67, NO. 25, 2016 Japp et al. 3007
JUNE 28, 2016:29963010 The Diagnosis and Evaluation of DCM

F I G U R E 4 Differentiation of Athletes 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%).

rst-degree relatives of DCM patients who lack a clear late-onset disease (47,48). Identication of a patho-
underlying etiology. As DCM exhibits age-dependent genic gene mutation rationalizes screening by allow-
penetrance, repeated screening is advocated (e.g., ing mutation-specic cascade testing of family
every 2 to 5 years until 50 to 60 years of age) to detect members. Relatives without the mutation can be
3008 Japp et al. JACC VOL. 67, NO. 25, 2016

The Diagnosis and Evaluation of DCM JUNE 28, 2016:29963010

discharged, whereas mutation carriers merit more detection to prevent DCM, specically in transfusion-
frequent clinical surveillance (e.g., every 1 to 3 years) dependent patients (e.g., with beta-thalassemia
(47,48). major) at risk of cardiac iron overload. T2* CMR
Limitations of predictive genetic testing, particu- permits accurate noninvasive monitoring of cardiac
larly for relatives found to carry a pathogenic muta- iron (Figures 1K and 1L), enabling optimization of iron
tion, include the attendant psychological burden, the chelation therapy and reversal of myocardial iron
inability to predict time and severity of disease onset, loading before the onset of LV dysfunction and HF.
and the lack of available therapies to avert disease The introduction of T2* monitoring for thalassemia
development. Such issues highlight the critical role of patients has contributed to a 70% decline in U.K.
genetic counseling in facilitating informed decisions mortality from cardiac iron overload since 2000.
regarding testing and supporting patients following Serum protein biomarkers can deliver insights into
results. multiple facets of cardiac remodeling, including
myocyte death, extracellular matrix remodeling,
DETECTING LATENT DISEASE: THE PRE-DCM
ventricular stretch, and oxidative stress, and may
PHENOTYPE. Left ventricular enlargement (LVE)
therefore play an adjunctive role in uncovering latent
without systolic dysfunction represents a well-
disease. For example, high-sensitivity cardiac tropo-
dened precursor of inherited DCM. Among asymp-
nin assays provide a potential avenue for the detec-
tomatic relatives of patients with idiopathic or
tion of low-grade, subclinical myocardial injury.
familial DCM screened by echocardiography, <5%
Among cancer patients receiving cardiotoxic chemo-
meet criteria for DCM, but 15% to 25% exhibit LVE, of
therapy, elevations in serum troponin strongly pre-
which 10% to 20% progress to overt DCM within
dict subsequent LV dysfunction (58). In the longer
5 years (49,50).
term, the application of proteomics to DCM offers the
Myocardial deformation imaging (Figure 4) may
prospect of characterizing the molecular and cellular
provide phenotypic markers of latent DCM earlier
pathways that underpin disease progression (59).
than LVE. Among relatives of patients with DCM
Ultimately, this could shift disease detection to the
caused by a sarcomeric gene mutation, mutation
earliest stages of development, while simultaneously
carriers exhibited substantially reduced strain and
uncovering new targets for molecular therapies.
strain rate compared with noncarriers, despite all
Major work on several fronts is now required
having normal LV size and LVEF (51). In patients
to establish the clinical utility of subclinical DCM
receiving potentially cardiotoxic cancer therapy, re-
detection strategies. A clinical trial is ongoing to
ductions in global longitudinal strain $10% consis-
determine whether strain surveillance in patients
tently precede and predict the development of overt
receiving cardiotoxic chemotherapy reduces the
LV dysfunction (52). Subclinical detection in these
incidence of overt LV dysfunction compared with
patients is crucial because timely intervention (e.g.,
LVEF surveillance (SUCCOUR [Strain sUrveillance
change in chemotherapy regimen) may prevent
during Chemotherapy for improving Cardiovascular
disease progression, whereas systolic dysfunction is
Outcomes]; ACTRN12614000341628). In familial DCM,
often irreversible once LVEF declines.
LVE represents a promising entry point for random-
LGE-CMR can detect myocardial replacement
ized clinical trials to establish whether early neuro-
brosis prior to overt LV remodeling in patients with
hormonal blockade prevents disease development
laminopathy or Beckers muscular dystrophy (53,54).
among at-risk relatives. At present, the potential for
However, the assessment of diffuse interstitial
strain imaging, T 1 mapping, or serum biomarkers to
brosis (Figure 2C) by emerging T 1 mapping methods
act as early markers of phenotypic expression in
(Figures 1I and 1J) may allow differentiation of
inherited DCM remains at the conceptual stage. The
diseased from healthy myocardium, even in the
current priority should be to conrm their ability
absence of LGE (55), and holds considerable promise
to predict disease development and ascertain the
for early DCM diagnosis (56). In a study of LMNA
optimal cutoff values for this.
mutation carriers, myocardial extracellular volume
fraction, assessed by T 1 mapping, was signicantly CONCLUSIONS
higher in mutation carriers than in healthy control
subjects, even in carriers who lacked any other DCM constitutes a broad cardiac phenotype that can
clinical or LGE-CMR evidence of DCM phenotypic arise from a multitude of myocardial insults. Rigorous
expression (57). etiological evaluation may allow for specic treatment
One further CMR tissue characterization tech- targeted to the underlying cause. Molecular genetic
nique, T2*, exemplies the potential of early disease testing and EMBx reveal the culprit trigger in many
JACC VOL. 67, NO. 25, 2016 Japp et al. 3009
JUNE 28, 2016:29963010 The Diagnosis and Evaluation of DCM

otherwise unexplained cases, although tailored treat-
ment strategies for genetic abnormalities or myocar-
ditis remain investigative at
characterization of remodeling, particularly with CMR,
may help to further inform etiology and prognosis, as
well as guide major treatment decisions. Novel imag-
ing techniques and serum biomarkers offer the
potential for earlier disease detection, with the
opportunity to delay or possibly arrest disease pro-
gression. Further work is now required to determine
whether these approaches to DCM evaluation can lead
to meaningful improvements in patient outcomes.
ACKNOWLEDGMENTS The authors are grateful to
Drs. Mary Sheppard and Jan Lukas Robertus, Royal
Brompton Hospital, London, for the histological
images and analysis; Dr. Dan Sado, Kings College
Hospital, London, for the T 1 color map images and
present. Detailed analysis; and Dr. David Oxborough, Liverpool John
Moores University, Liverpool, for the strain images
and analysis. In addition, the authors thank Dr. Ravi
Assomull, Ealing Hospital, London, and Dr. Tevk
Ismail, Royal Brompton Hospital, London, for pro-
viding a critical review of the manuscript prior to
submission.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Ankur Gulati, Cardiovascular Magnetic Resonance
Unit, Royal Brompton Hospital, Sydney Street,
London SW3 6NP, United Kingdom. E-mail: ankur0@
hotmail.com.

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KEY WORDS imaging, implantable
cardioverter-debrillator, remodeling
A PPE NDI X For a list of supplemental
references, please see the online version of
this article.