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Role of Cardiac Magnetic Resonancein the Diagnosis and Prognosisof Nonischemic Cardiomyopathy

Amit R. Patel, MD,a Christopher M. Kramer, MDb

JACC: CARDIOVASCULAR IMAGING CME/MOC

CME/MOC Editor: Ragavendra R. Baliga, MD

This article has been selected as this issue’s CME/MOC activity, available

online at http://www.acc.org/jacc-journals-cme by selecting the JACC

Journals CME/MOC tab.

Accreditation and Designation Statement

The American College of Cardiology Foundation (ACCF) is accredited by

the Accreditation Council for Continuing Medical Education (ACCME) to

provide continuing medical education for physicians.

TheACCFdesignates this Journal-basedCME/MOCactivity for amaximum

of 1 AMA PRA Category 1 Credit(s) TM. Physicians should only claim credit

commensurate with the extent of their participation in the activity.

Method of Participation and Receipt of CME/MOC Certificate

To obtain credit for this CME/MOC activity, you must:

1. Be an ACC member or JACC: Cardiovascular Imaging subscriber.

2. Carefully read the CME/MOC-designated article available online and

in this issue of the journal.

3. Answer the post-test questions. At least 2 out of the 3 questions

provided must be answered correctly to obtain CME/MOC credit.

4. Complete a brief evaluation.

From the aDepartment of Medicine and Radiology, University of Chicago, Chi

Radiology and the Cardiovascular Imaging Center, University of Virginia H

received research support from Philips, Astellas, and Myocardial Solution

Health grant NIH U01HL117006-01A1; and is a consultant for Abbott.

Manuscript received April 27, 2017; revised manuscript received August 4, 2

5. Claim your CME/MOC credit and receive your certificate electroni-

cally by following the instructions given at the conclusion of the

activity.

CME/MOC Objective for This Article: After reading this article the

reader should be able to: 1) diagnose the etiology of a nonischemic

cardiomyopathy based on the pattern of late gadolinium enhancement;

2) diagnose the etiology of a nonischemic cardiomyopathy based on

tissue relaxation parameters such as T1, T2, and T2* and synthesize an

appropriate treatment plan; and 3) recognize findings on a cardiac

magnetic resonance exam that are associated with increased risk of

sudden cardiac death.

CME/MOC Editor Disclosure: JACC: Cardiovascular Imaging CME/MOC

Editor Ragavendra R. Baliga, MD, has reported that he has no

relationships to disclose.

Author Disclosures: Dr. Patel has received research support from Philips,

Astellas, and Myocardial Solutions. Dr. Kramer has received National

Institutes of Health grant NIH U01HL117006-01A1; and is a consultant

for Abbott.

Medium of Participation: Print (article only); online (article and quiz).

CME/MOC Term of Approval

Issue Date: October 2017

Expiration Date: September 30, 2018

cago, Illinois; and the bDepartments of Medicine and

ealth System, Charlottesville, Virginia. Dr. Patel has

s. Dr. Kramer has received National Institutes of

017, accepted August 10, 2017.

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Role of Cardiac Magnetic R

esonancein the Diagnosis and Prognosisof Nonischemic Cardiomyopathy Amit R. Patel, MD,a Christopher M. Kramer, MDb

ABSTRACT

Cardiac magnetic resonance (CMR) is a valuable tool for the evaluation of patients with, or at risk for, heart failure and has

a growing impact on diagnosis, clinical management, and decision making. Through its ability to characterize the

myocardium by using multiple different imaging parameters, it provides insight into the etiology of the underlying heart

failure and its prognosis. CMR is widely accepted as the reference standard for quantifying chamber size and ejection

fraction. Additionally, tissue characterization techniques such as late gadolinium enhancement (LGE) and other

quantitative parameters such as T1 mapping, both native and with measurement of extracellular volume fraction;

T2 mapping; and T2* mapping have been validated against histological findings in a wide range of clinical scenarios. In

particular, the pattern of LGE in the myocardium can help determine the underlying etiology of the heart failure. The

presence and extent of LGE determine prognosis in many of the nonischemic cardiomyopathies. The use of CMR should

increase as its utility in characterization and assessment of prognosis in cardiomyopathies is increasingly recognized.

(J Am Coll Cardiol Img 2017;10:1180–93) © 2017 by the American College of Cardiology Foundation.

C ardiac magnetic resonance (CMR) is a valu-able tool for the evaluation of patientswith, or at risk for, heart failure and has a

growing impact on diagnosis, clinical management,and decision making (1,2) (Central Illustration).Through its ability to characterize the myocardiumby using multiple different imaging parameters,CMR provides insight into the etiology of the underly-ing heart failure and its prognosis. CMR is consideredthe reference standard for quantifying chamber sizeand ejection fraction. Additionally, tissue character-ization techniques such as late gadolinium enhance-ment (LGE) and other quantitative parameters suchas T1 mapping with measurement of extracellular vol-ume fraction (ECV), T2 mapping, and T2-star (T2*)mapping have been validated against histologicalfindings in a wide range of clinical scenarios. Inparticular, the pattern of LGE in the myocardiumcan help determine the underlying etiology of theheart failure. Figure 1 shows examples of LGE in aspectrum of patients with nonischemic cardiomyopa-thy. In this review, we examine the role of CMR inthe diagnosis and prognosis of nonischemiccardiomyopathy.

Determining the etiology of a cardiomyopathy is ofclinical importance because it has implications withregard to the optimal treatment strategy and theprediction of prognosis. Although the MOGE(S)(morphofunctional phenotype, organ[s] involvement,genetic inheritance pattern, etiological annotation

including genetic defect or underlying disease orsubstrate, and the functional status of the disease)classification system may play an important role inthe understanding of the cardiomyopathies in thefuture (3), for the purpose of this review, thenonischemic cardiomyopathies have been dividedinto just 4 groups: dilated, genetic, inflammatory,and infiltrative. The genetic cardiomyopathiesinclude disorders such has hypertrophic cardio-myopathy (HCM), left ventricular noncompaction(LVNC), the muscular dystrophies, and arrhythmo-genic right ventricular dysplasia (ARVD). Theinflammatory and/or autoimmune cardiomyopathiesinclude cardiac sarcoidosis (CS) and conditionsassociated with connective tissue disorders such assystemic lupus erythematosus (SLE), rheumatoidarthritis, and others. The infiltrative cardiomyopa-thies include cardiac amyloidosis (CA), cardiac side-rosis, and Anderson-Fabry disease.

DILATED CARDIOMYOPATHIES

Dilated cardiomyopathy likely represents an end-stage manifestation of multiple nonischemic disor-ders that can damage the myocardium. Despitesignificant treatment advances, a randomizedcontrolled trial that included more than 8,000 pa-tients with heart failure and a left ventricular ejectionfraction (LVEF) <40%, with many patients havingsome form of nonischemic cardiomyopathy, revealed

ABBR EV I A T I ON S

AND ACRONYMS

ARVC = arrhythmogenic right

ventricular cardiomyopathy

CA = cardiac amyloidosis

CMR = cardiac magnetic

resonance

CS = cardiac sarcoidosis

DMD = Duchenne muscular

dystrophy

ECV = extracellular volume

HCM = hypertrophic

cardiomyopathy

ICD = implantable

cardioverter-defibrillator

LGE = late gadolinium

enhancement

LV = left ventricular

LVEF = left ventricular ejection

fraction

LVNC = left ventricular

noncompaction

RV = right ventricular

SCD = sudden cardiac death

SLE = systemic lupus

erythematosus

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that after a median follow-up of just 27months, the mortality rate was nearly 20%despite use of modern therapies (4). Themanagement plan is often determined bypatients’ symptoms, abnormalities on theelectrocardiogram, and LVEF; however, thisis an imperfect approach that does notadequately identify those patients who areunlikely to respond to medical therapy orwho at risk for sudden cardiac death (SCD).There has been growing interest in exploitingthe role of myocardial fibrosis, an integralpathophysiological component of dilatedcardiomyopathy, as a biomarker for guidingpatient management and determining prog-nosis. It is increasingly being understood thatfibrosis can occur in 2 forms that can bedetected by CMR (5): irreversible replace-ment fibrosis, which corresponds to thepresence of LGE; and diffuse interstitialfibrosis, which better corresponds to findingson T1 mapping. Replacement myocardialfibrosis is often present in the midwall of theinterventricular septum and can be identifiedin approximately 30% of individuals withdilated cardiomyopathy using LGE imaging

(6,7), and this feature differentiates it from ischemiccardiomyopathy. The presence of LGE is associatedwith abnormalities in contractility and serves as apotential substrate for re-entrant ventriculararrhythmia (8). The presence of LGE identifies acohort of patients who do not respond as well tooptimal medical therapy (9), a finding independent ofother standard clinical parameters such as QRS com-plex duration and N-terminal pro–B-type natriureticpeptide levels. The burden of LGE is independentlyand inversely associated with the change in LVEF thatoccurs following medical therapy.

On the basis of a prospective longitudinal studyperformed in 472 patients with dilated cardiomyop-athy (10), patients with midwall LGE were signifi-cantly more likely to die (27% vs. 11%) or have asignificant arrhythmic event (30% vs. 7%) whencompared with patients without LGE. The findingswere independent of LVEF. These findings weresubsequently confirmed in a larger, multicenterobservational study (11) that showed that the pres-ence and extent of LGE were predictive of all-causemortality, but it also suggested that abnormalities innative myocardial T1 relaxation times may be evenbetter and independent markers of poor outcomes inthese patients. Although not limited to patients withnonischemic cardiomyopathy, another studyrevealed that patients with an LVEF >30% but who

still had LGE involving more than 5% of their leftventricular (LV) mass were just as likely to die orreceive an implantable-cardioverter defibrillator(ICD) shock for ventricular tachycardia as were pa-tients with an LVEF <30% (12). Conversely, thosepatients with an LVEF <30% who had minimal or noLGE did just as well as those patients with anLVEF >30%.

The ability of LGE burden to risk stratify patientswas independent of LVEF and the presence ofinducible ventricular tachycardia during an electro-physiology study. Interestingly, the presence of >5%myocardial LGE burden was associated with anannualized event rate of death or significantarrhythmia of nearly 20%; whereas the absence ofLGE was associated with only a 3% annualized eventrate. In another study, which prospectively enrolled399 patients with dilated cardiomyopathy who had anLVEF >40%, the presence of a midwall pattern of LGEwas present in 25% of individuals and was associatedwith a 9-fold increase in the risk of SCD or abortedSCD when compared with patients without LGE (13).

The potential role of LGE-CMR for identifying pa-tients with nonischemic cardiomyopathy who are atrisk of SCD is of particular interest given the findingsof a recently published randomized controlled trialsuggesting that ICD insertion guided by LVEF alonemay not be associated with improved survival (14).Similarly, LGE may be helpful for predicting responseto biventricular pacemaker resynchronization ther-apy. In a study of 559 patients with both ischemicand nonischemic cardiomyopathy (15), LGE-guidedbiventricular pacemaker implantation was associ-ated with a significant improvement in identifyingpatients who were most likely to benefit from biven-tricular pacing. Those patients who did not have LGEdid significantly better following resynchronizationtherapy relative to those patients who had LGE andrelative to those who underwent ICD insertionwithout LGE guidance. Regardless of the ability ofLGE to predict which patients may or may notrespond to resynchronization therapy, the presenceof LGE in the septal midwall was an independentpredictor of morbidity and mortality in patients withdilated cardiomyopathy who were undergoingcardiac resynchronization therapy (16).

GENETIC CARDIOMYOPATHIES. Hypertrophiccardiomyopathy. HCM is the most common geneticheart disease because, with the advent of moreadvanced imaging and genetic testing, it is nowidentified in up to 1 in 200 to 300 individuals (17). Amutation in a gene coding for any of the cardiaccontractile proteins can lead to the phenotype of

CENTRAL ILLUSTRATION Evaluation of Nonischemic Cardiomyopathy Using CMR

Patel, A.R. et al. J Am Coll Cardiol Img. 2017;10(10):1180–93.

This chart demonstrates a potential approach for incorporating the use of cardiac magnetic resonance (CMR) as part of the initial evaluation

and follow-up of patients with suspected nonischemic cardiomyopathy. During the initial evaluation a comprehensive CMR examination,

which includes cine CMR, T1-mapping, T2-mapping, T2*-mapping, and very importantly, late gadolinium enhancement (LGE), may be

performed. The multiple variables will need to be integrated by a physician with both clinical and CMR expertise to provide a diagnosis and

improved understanding of patient prognosis. Occasionally, follow-up imaging with CMR may be helpful. In the case of dilated cardio-

myopathy and genetic cardiomyopathy repeat CMR imaging, which includes LGE, may be helpful when a clinical deterioration occurs. In

limited situations, a CMR examination without LGE may be helpful to evaluate for treatment response. However, repeat CMR without LGE

may often be helpful for monitoring treatment response in inflammatory and infiltrative cardiomyopathies. In these cardiomyopathies, a

repeat CMR which includes LGE may occasionally be considered to determine if a new form of myocardial injury has occurred when an

unexpected clinical deterioration has occurred.

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FIGURE 1 Examples of LGE in a Variety of Nonischemic Cardiomyopathies

F

Cardiac Sarcoid Dilated CMP

Myocarditis

Cardiac Amyloid Hypertrophic CMP

RV

A

P

R LF

H

AR

PH

LH

*

*

Pulm HTN

(Top left) A 4-chamber view of patchy distribution of late midwall and epicardial late gadolinium enhancement (LGE) (arrows) in a patient

with cardiac sarcoidosis. (Top right) A 3-chamber view of a midwall stripe pattern of late gadolinium enhancement (arrows) in a patient with

dilated cardiomyopathy. (Middle left) A 4-chamber view of patchy epicardial and midwall late gadolinium enhancement along the lateral wall

(arrows) in a patient with myocarditis. (Middle right) A midventricular short-axis image in a patient with pulmonary hypertension (HTN) with

right ventricular (RV) dilation and hypertrophy (*) along with late gadolinium enhancement in the anterior and inferior right ventricular

insertion points (arrows). (Bottom left) A 3-chamber view of a LGE image in a patient with cardiac amyloid. The left ventricular blood pool is

nulled (*), and there is subtle circumferential subendocardial late gadolinium enhancement throughout the left ventricle. The late

gadolinium enhancement is most pronounced at the base of the left ventricle within hypertrophied myocardium (arrow). (Bottom right)

A midventricular short-axis image in a patient with hypertrophic cardiomyopathy with evidence of asymmetrical septal hypertrophy with

extensive midwall LGE within the hypertrophied myocardium (arrows). CMP ¼ cardiomyopathy.

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FIGURE 2 Left Ventricular Noncompaction

LV

LV

RV

Diastolic still frames from cine images of (left) a 2-chamber view and (right) a 4-chamber view are shown. The myocardium is thin, and the

left ventricle (LV) and right ventricle (RV) are heavily trabeculated (arrows).

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HCM. Although echocardiography is typically used forscreening for HCM, CMR is more sensitive for theidentification of more unusual sites of hypertrophyand for apical HCM (18). It is the most accurate way ofmeasuring LV mass, which is important becausehigher LV mass is associated with a worse outcome(19). Similar to echocardiography, CMR can identifysystolic anterior motion of the mitral valve, measurethe LV outflow gradient using velocity encoded im-aging, and assess mitral regurgitation.

In addition, and most importantly, CMR offers theability to identify and quantify myocardial fibrosis.Between one-half and two-thirds of patients withHCM may have LGE with a characteristic pattern ofpatchy involvement, particularly at the right ven-tricular (RV) septal insertion sites and in those wallswith the greatest hypertrophy. Studies have exam-ined the relationship between the presence of LGEand outcome in HCM. One such study of 711 patientsfollowed for a mean of 3.5 years found no relationshipbetween LGE and risk of SCD after adjusting for otherrisk factors (20). However, a recent meta-analysis of 5studies, including the latter study involving 2,993patients with a median follow-up of 3 years, demon-strated that the presence of LGE was associatedwith a 3.4-fold increase in risk for SCD, a 1.8-foldincrease in all-cause mortality, a 2.9-fold increase incardiovascular mortality, and a trend to increasein heart failure death (21).

Given the high prevalence of LGE, its presencealone cannot be used as an indication for ICD insertionbecause the risk of SCD in HCM is <1% per year. Thus,

the extent of LGE may have more discriminatory valuethan its presence. A 4-center study of 1,293 patientsfollowed for 3.3 years showed that LGE $15% of LVmass was associated with a 2-fold increase in SCDevent risk (22). The aforementioned meta-analysisshowed that after adjusting for baseline characteris-tics, the extent of LGE was strongly associated withthe risk of SCD with a hazard ratio of 1.36 per increasein LGE extent of 10% (21).

Evidence is mounting with regard to the diagnosticand prognostic role of interstitial fibrosis in HCM. Onestudy demonstrated mildly elevated native T1 inHCM, highest in segments that subsequentlydemonstrated LGE (23). Native T1 is accurate indiscriminating HCM from hypertensive heart disease(24). A study of HCM and idiopathic dilated cardio-myopathy showed that native T1 performed betterthan ECV at discriminating cardiomyopathies fromnormal (25). ECV is also useful because it is elevatedin phenotypically positive HCM, as well as genotype-positive, phenotype-negative individuals (26). Post-contrast T1 time was shown to be associated withnonsustained ventricular tachycardia in a study of100 patients with HCM, and thus, may be a markerof risk once it has been studied in larger groups ofpatients (27).

In addition to the extent, the location and/orpattern of LGE may be more predictive of adverseoutcome than the presence of LGE alone, and the rolesof native T1 and ECV remain to be fully elucidated.The ongoing National Institutes of Health–fundednatural history study Hypertrophic Cardiomopathy

FIGURE 3 Duchenne Muscular Dystrophy

A short-axis image of the midventricle obtained in a patient

with Duchenne muscular dystrophy shows epicardial late

gadolinium enhancement (LGE) along the lateral wall (white

arrows) and midwall late gadolinium enhancement in the

septum (yellow arrows).

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Registry (Novel Predictors of Prognosis in Hyper-trophic Cardiomyopathy) (NCT01915615), using CMR,genetics, and biomarker evaluation in 2,750 patientswith HCM, is likely to offer further insight intoidentifying risk markers including LGE, native T1,and ECV (28).

LV noncompaction. Left ventricular noncompaction(LVNC) cardiomyopathy is characterized by extensiveLV trabeculations (Figure 2), as well as an increasedrisk of clinical heart failure, thrombosis, and mortal-ity. The accurate diagnosis of LVNC by noninvasiveimaging can be quite difficult because of substantialoverlap between it and conditions such as dilatedcardiomyopathy and even normal LV trabeculation.The role of CMR in the diagnosis of LVNC continues toevolve. Petersen et al. (29) proposed a CMR criterionof a noncompacted-to-compacted myocardium ratioof 2.3:1 and demonstrated a sensitivity of 86% and99% in a study of 177 patients with and withoutcardiac disease. However, when using this criterion,up to 43% of individuals who undergo CMR as part ofscreening studies such as the Multi-Ethnic Study ofAtherosclerosis can meet imaging criteria (30). Simi-larly, another screening study showed that up to14.8% of normal individuals met at least 1 diagnosticcriterion for LVNC (31). Thus, clinical criteria ofsymptomatic heart failure or LV dysfunction on CMRlikely need to be included to improve the specificityof diagnosis.

Jacquier et al. (32) proposed another set of criteriain a study of patients with LVNC compared with pa-tients with DCM, HCM, and control subjects. Theseinvestigators found that a trabeculated LV mass>20% of the LV mass was 94% sensitive and specificfor the diagnosis of LVNC. LGE may be seen in LVNC,but it is infrequent enough that its presence is specificbut not sensitive in making the diagnosis (33). How-ever, its presence may be important for prognosticpurposes. In a study of 113 patients followed for amean of 4 years, LV dilatation, LV dysfunction, andLGE (seen only in 11 patients) were predictive of car-diac events whereas the degree of LV trabeculationwas not (34). More CMR studies of this condition areneeded to establish its role in this condition as thesensitivity is high, but the specificity remainsproblematic.

Muscular dystrophies. Although the muscular dystro-phies are often characterized by skeletal muscledegeneration and progressive weakness, a majorproblem can be the development of dilated cardio-myopathy, which often goes undetected until it is inits advanced stages. Early detection allows for thepotential to introduce therapy that could alter the

natural history. Even though cardiomyopathy is animportant cause of death in Duchenne musculardystrophy (DMD), the majority of patients (w70%) in1 cross-sectional study had an LVEF >55%, whereas20% of patients had an LVEF between 45% and 54%,6% of patients had an LVEF of 35% to 44%, and only3% had an LVEF <35%.

Because of the relative insensitivity of LVEF foridentifying boys with DMD who are at risk for heartfailure, CMR techniques such as myocardial taggingoffer the potential to detect abnormalities in sys-tolic function before a reduction in LVEF or LVdilation occurs (35). Circumferential strain may beabnormal even in patients with DMD who are <10years of age, and it continues to worsen with agingdespite the preservation of LVEF. In patients withLV dysfunction, circumferential strain may beabnormal even in the absence of LGE (36). Thesefindings suggest that abnormalities in strain precedeboth the reduction of LVEF and the development ofmyocardial scar.

In addition to abnormalities in circumferentialstrain, the presence of LGE (Figure 3) may also pre-cede a decrease in LVEF (37). In 1 study (38), 36% ofpatients with DMD had LGE, and the prevalenceincreased with age. Only 30% of patients with LVEF>55% had LGE, whereas 84% of patients withLVEF <55% had LGE. Importantly, 10% of those in-dividuals with LGE died during an average follow-upof 11 months, whereas only 1 patient without LGE

FIGURE 4 Cardiac Amyloidosis

50

100

100

200

250

50

100

150

200Cardiac Amyloid: T1=1175ms Healthy Volunteer: T1=1049ms

2000

1800

1600

1400

1200

1000

Short-axis images of the midventricle encoded with a native myocardial T1 color map generated from a series of images acquired at increasing

repetition times acquired using the Modified Look Locker Image (MOLLI) pulse sequence is shown in (left) a patient with cardiac amyloidosis

and (right) a healthy volunteer. The T1 times shown in this figure are obtained from a region of interest drawn manually in the interventricular

septum. The T1 times can be even higher in patients with more extensive cardiac amyloidosis than the example shown here. The normal

native T1 value on the particular scanner used to acquire these images is <1,050 ms.

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died. The burden of LGE was also associated with anincreased risk of death. The presence of LGE alsoidentifies individuals at risk for progressive LVdysfunction because in patients with LGE, the LVEFdecreased an average of 2.2% annually (39). Figure 3 isan example of LGE in a patient with DMD.Arrhythmogenic right ventricular cardiomyopathy.Arrhythmogenic right ventricular cardiomyopathy(ARVC) is an inherited cardiomyopathy that leads toventricular arrhythmias and often causes SCD inyoung persons. CMR is an important adjunct inmaking the diagnosis of ARVC, primarily because ofits accuracy in assessing RV dilatation and dysfunc-tion (40). Diagnostic findings in this disease includeRV dilatation and global or regional dysfunction,including focal RV systolic bulging or aneurysm asdefined by cine CMR, and are carefully defined tomeet Task Force Criteria that were redefined in 2010(40). The finding of fatty infiltration in the RV freewall is not part of the diagnostic criteria because thisis a nonspecific finding. The newer criteria are morerestrictive than the older 1994 criteria and are morespecific but may be less sensitive (41), although thisissue continues to be debated in published reports. Incertain cases, LGE of the RV free wall can be seen (42),although this can be difficult to identify definitivelybecause of the thin RV wall in this disorder. LVinvolvement in ARVC is increasingly recognized (43).Quantitative functional RV imaging with strain mea-sures by CMR feature tracking may objectify regionalfunctional measures and improve on diagnostic

accuracy for ARVC compared with qualitative analysisof cine images (44). The hallmarks of the diagnosis,however, remain RV dilatation and dysfunction.

INFLAMMATORY CARDIOMYOPATHIES

SARCOIDOSIS. Sarcoidosis is a multiorgan, inflam-matory disorder characterized by noncaseating gran-ulomatous infiltration. Clinical manifestations ofcardiac involvement can range from none to SCD oradvanced heart failure requiring heart trans-plantation. Although only 5% of patients withsarcoidosis have clinical manifestations of CS, 25%have evidence of cardiac involvement at autopsy (45),and the primary presentation of CS can be SCD.Because CS is a patchy disorder and often involvesonly small amounts of myocardium without causingobvious abnormalities in LV function, commonly usedtests such as the electrocardiogram, ambulatorymonitoring, signal-averaged electrocardiography,echocardiography, myocardial perfusion imaging, andelectrophysiology testing do not reliably detect it (46).Even endomyocardial biopsy has a poor sensitivitybecause of myocardial sampling errors related to thepatchy pattern of sarcoid infiltration (47).

CMR is becoming the preferred imaging modalityfor detecting CS, and a consensus document pub-lished by the Heart Rhythm Society suggested thatpatients with sarcoidosis undergo CMR if an abnor-mality on an initial screening test is noted (48).Several groups have shown that CMR can readily

FIGURE 5 Cardiac Siderosis

H

FA P

RL

H

FA P

RL

H

FA P

RL

H

FA P

RL

H

FA P

RL

HA P

L

T2* Myocardium = 12ms

TE 2.6 ms

Ec 1 (TE 2.6 ms)

TE 4.9 ms

Ec 2 (TE 4.9 ms)

TE 7.2 ms

Ec 3 (TE 7.2 ms)

TE 9.5 ms

Ec 4 (TE 9.5 ms) Ec 5 (TE 11.8 ms)

TE 11.8 ms

Ec 6 (TE 14.1 ms)

TE 14.1 ms

A series of left ventricular short-axis images acquired using a single breath-hold T2* pulse sequence in a patient with sickle cell anemia. A series of images are acquired

at increasing echo times (TE). The signal intensity in the myocardium decreases as the echo time increases (arrows). The rate of decay is used to calculate the T2*

relaxation time, which is reduced in this patient and indicates the presence of significant myocardial iron overload.

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identify individuals with CS because of its ability toidentify small areas of myocardial involvement usingLGE (49,50). Nearly 20% of individuals with extrac-ardiac sarcoidosis have cardiac involvement on thebasis of CMR findings, even when LVEF is preserved(51). The true diagnostic performance of CMR in thedetection of CS is unknown because there is noacceptable reference standard. Instead, the use ofCMR in the setting of sarcoidosis is currently mostoften discussed in terms of its ability to risk stratifypatients and to affect their treatment plan. Thedetection of CS using CMR has been shown to identifypatients at risk for cardiac death more accurately thanthe more commonly used diagnostic criteria pub-lished by the Japanese Ministry of Health and Welfare(52). The presence of LGE is associated with anincreased risk of death or significant ventriculararrhythmia even in patients with preserved LVEF,and the risk of adverse outcomes is modulated by theburden of myocardial damage and the presence of RV

dysfunction (53). A recent meta-analysis (54) of 11studies evaluating the role of CMR in patients withsarcoidosis revealed that the presence of LGE had anodds ratio of 7.4 for identifying patients at risk for acomposite endpoint that included all-cause mortalityand ventricular arrhythmogenic events. Furthermore,the absence of LGE is associated with a low risk ofmajor cardiovascular events even when the LVEF isseverely impaired (55). In addition to ventricular ar-rhythmias, patients with CS with LGE also have anincreased burden of atrial fibrillation and atrialflutter (56).

Although the presence of LGE is a powerful pre-dictor of risk in patients with sarcoidosis, it may notidentify patients who have earlier stages of CS beforethe development of myocardial scar or overt inflam-mation. Abnormalities in myocardial T2 times mayprecede the development of LGE (57); however, morestudies are needed to understand the clinical impactof this finding.

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SLE AND OTHER CONNECTIVE TISSUE DISORDERS. SLEis associated with a full range of cardiovascularcomplications, including accelerated coronary dis-ease and its associated complications such asmyocardial infarction, microvascular disease,myocarditis, vasculitis (58), pericarditis, pulmonaryhypertension, conduction disease, and valvularheart disease. Although these complications of SLEare well known, they are often clinically silent andrequire advanced imaging technologies such asCMR to detect them (59). In 1 study comparing theutility of echocardiography and CMR in patientswith SLE, 45% of all patients with SLE and a priorhistory of cardiovascular complications hadevidence of LGE on CMR, yet only 33% of thoseindividuals with LGE on CMR were identified byechocardiography (60).

The mechanism of accelerated coronary arterydisease in patients with SLE is not thought tobe secondary to traditional risk factors. Varma et al.(61) used a novel, post-contrast, high-resolutionT1-weighted inversion recovery pulse sequence toevaluate the pattern and burden of coronary wallcontrast enhancement in SLE patients. Whencompared with patients with coronary artery disease,patients with SLE had a diffuse pattern of coronarywall contrast enhancement, whereas patients withcoronary artery disease had a patchy pattern ofenhancement, despite similar total enhancementburden (61). These findings suggest that SLE isassociated with diffuse rather than focal coronaryinflammation. In the same study, it was noted thatpatients with SLE had global perfusion defectsduring hyperemia consistent with microvasculardisease, rather than the regional perfusion defectsmore consistent with obstructive epicardial coronaryartery disease. In another study that included20 patients with SLE and typical and atypicalchest pain without evidence of epicardial coronarydisease who underwent adenosine CMR, 44% hadvisible perfusion defects (62). When comparedwith control subjects, patients with SLE also hada significant reduction in myocardial perfusionreserve.

CMR can also detect lupus myocarditis (63). CMRwas recently used to evaluate 32 patients with SLEand new-onset heart failure; 15% had evidence ofacute myocarditis, 31% had evidence of transmuralmyocardial infarction, 28% had diffuse sub-endocardial scar suggestive of vasculitis, and 15% hadLV dysfunction without evidence of inflammation orfibrosis. The burden of CMR abnormalities wascorrelated with lupus activity and duration. Inanother study (64), 37% of patients with SLE had

evidence of LGE that was typically small and mostoften found in the interventricular septum. Onlythose patients with a larger burden of LGE had evi-dence of functional abnormalities such as a decreasedE/A ratio on echocardiography or reduced exercisetolerance. The presence of LGE has also been associ-ated with heart block (65).

Interest is growing in quantifying the burden ofmyocarditis in SLE to guide treatment response (66).Initial approaches used T2-weighted and pre- andpost-contrast T1-weighted images to calculate a T2

ratio as a marker of increased myocardial edema andearly global relative contrast enhancement ratio as amarker of increased capillary leak indicative ofmyocardial inflammation (67). By using such mea-surements, it was evident that when compared withcontrol subjects or individuals with inactive SLE,patients with active SLE had a higher T2 ratio andearly global enhancement ratio. Although promising,these types of measurements are limited by imagingartifacts and the absence of an absolute quantitativeparameter. Other investigators have advocated fortechniques capable of measuring actual T2 and T1

relaxation times to identify lupus myocarditis and tomonitor treatment response (68). In 1 study (69), pa-tients with active SLE had increased myocardial T2

times, a finding suggesting the presence of myocar-dial edema or inflammation when compared withpatients with inactive SLE and control subjects.Furthermore, the T2 relaxation time improved withrepeat imaging following clinical improvement. Otherinvestigators have shown similar findings with theuse of T1 mapping and ECV techniques (70). AlthoughCMR identifies myocardial involvement in SLE, thereare no published studies examining the prognosticvalue of CMR or whether following treatmentresponse using CMR is associated with improvedoutcomes in these patients.

CMR plays a similar role in other systemic inflam-matory disorders such as rheumatoid arthritis, large-and medium-vessel vasculitides such as Takayasuarteritis, giant cell arteritis, polyarteritis nodosa, andKawasaki disease; small-vessel vasculitides such asmicroscopic polyangiitis; and necrotizing vasculitidesincluding Wegener disease and Churg-Strauss syn-drome. As a group, these vasculitides can be associ-ated with aneurysm, dissection, and narrowing ofarteries and tissue-level complications such asmyocardial ischemia and infarction. Like SLE, thesedisorders can also be associated with the develop-ment of myocarditis, and, as described earlier, CMR iswell suited to evaluate the full range of potentialcardiovascular complications that occur in thesepatients.

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INFILTRATIVE CARDIOMYOPATHIES

CARDIAC AMYLOIDOSIS. CA is a rare infiltrativedisorder in which abnormally folded proteins aredeposited within the myocardium. There are 2 majorsubtypes that must be distinguished from each other:light chain (AL) amyloidosis and transthyretin (ATTR)amyloidosis. AL amyloidosis is a plasma cell dyscrasiathat is often treated with chemotherapy or stem celltransplantation, whereas ATTR amyloidosis resultsfrom the production of an abnormally folded trans-thyretin (i.e., prealbumin) in the liver, and targetedtreatments are in development. AL amyloidosis israre and accounts for only a small percentage of pa-tients with CA. Conversely, the genetic mutationsresponsible for ATTR are present in 3.0% to 3.5% ofAmericans of African descent; however, the pene-trance of the mutation is not known, and the diseaseis almost certainly underdiagnosed. The annualmortality rate of both types of CA is relatively high,especially for AL amyloidosis. Given the developmentof new treatment strategies, there is a need to di-agnose the disease during its earlier stages.

During its advanced stages, CA is often suggestedon echocardiography by the presence of severe LVhypertrophy with preserved systolic function, dilatedatria, and restrictive physiology. CMR is emerging as avaluable tool for the detection of CA. In addition tothe classical abnormalities seen during echocardiog-raphy, circumferential subendocardial LGE mostpronounced at the base and middle of the ventricle ispresent in 80% of patients with CA, and many of theother 20% of patients have alternative patterns ofLGE. Diffuse subendocardial LGE has a specificity ofnearly 95% for the diagnosis of CA (71,72). The inter-pretation of LGE images can often be difficult becauseof the diffuse nature of LGE and because the nullingtime of the LV cavity can often be significantlyaltered. Typically, on inversion recovery imaging, theLV cavity has a significantly shorter inversion timethan the normal myocardium. However, in CA, the LVcavity and myocardium often have very similarinversion times, and occasionally the inversion timeof the myocardium is shorter than that of the LVcavity. These characteristic alterations in inversiontime can be readily recognized on inversion timescouts acquired after the administration ofgadolinium-based contrast agents and have a veryhigh sensitivity for the diagnosis of CA (73). The dif-ference in inversion time between the LV cavity andthe myocardium is also an important prognosticmarker because it provides insight into the burden ofCA (74). Similarly, the transmurality of the LGE is

another important and independent marker ofpatients’ prognosis (75), given that the presence oftransmural LGE is associated with a >5-fold increasein mortality compared with patients with CA butwithout LGE.

Because it is challenging to quantify the burden ofLGE in patients with CA, there is significant interestthe use of quantitative ECV measurements. ECV issignificantly elevated in patients with CA and isinversely correlated with the QRS complex voltageand other commonly used biomarkers for CA (76).Similarly, because many patients with amyloidosishave renal disease and gadolinium-based contrastagents cannot be used, there has been significant in-terest in the utility of native T1-mapping techniquesto diagnose CA (Figure 4). Native T1 times have beenshown to be significantly elevated in patients with CAand correlated with other relevant biomarkers (77,78).Both native T1 mapping and ECV have also beenshown to predict prognosis in these patients (79).

CARDIAC SIDEROSIS. Cardiac siderosis or myocardialiron overload is rare but can occur in conditionssuch as thalassemia or hemochromatosis. Withouttreatment, it is associated with significant risk of deathand heart failure (80). CMR is particularly well suitedto detect iron overload quantitatively by takingadvantage of the effect of iron deposits on theT2* relaxation time of surrounding protons in themyocardium (Figure 5). The T2* relaxation time line-arly falls with increasing iron load (81). The reductionof T2* relaxation time in the presence of myocardialiron overload is only modestly associated with LVEFand is not associated with abnormalities of diastolicfunction. Patients with cardiac siderosis who havesevere reductions in T2* relaxation time (<10 ms) areat risk for ventricular tachycardia despite havinga normal LVEF and diastolic function (82,83).A T2* relaxation time of<20 ms has been proposed as acutoff value for diagnosing cardiac siderosis, whereasa value of<10ms is associated with poor prognosis andrequires initiation of iron chelation therapy (84).T2* relaxation times can be serially monitored inpatients who are receiving iron chelation therapywhenever the T2* relaxation time drops below acertain threshold. The therapy is continued until theT2* relaxation times rise above another threshold.Such a strategy has resulted in a significant decrease incardiac morbidity and mortality in patients with thal-assemia who require frequent blood transfusions (80).

ANDERSON-FABRY DISEASE. This X-linked lyso-somal storage disease is characterized by defi-ciency of a-galactosidase A. Early CMR studies of

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Anderson-Fabry disease showed LGE related to theextent of LV hypertrophy, typically located inthe basal inferolateral wall and in the midwall orsubepicardium (85). T1 mapping in Anderson-Fabrydisease demonstrates characteristically reducednative T1 in patients with phenotypic LV hypertro-phy compared with other hypertrophic diseases(86,87), which generally have an elevated T1.Patients with Anderson-Fabry disease also demon-strate an intermediate reduction in native T1 beforethe onset of hypertrophy (88). CMR has been usedto follow regression of LV hypertrophy with enzymereplacement therapy in this disorder (89).

CONCLUSIONS

Although a discussion of all the available data relatedto the utility of CMR in nonischemic cardiomyopathy

is beyond the scope of this review, we have selectedrepresentative disease states to demonstrate thevalue of this imaging modality. Its ability to charac-terize the myocardium using techniques such as LGE,T1 mapping with ECV measurements, T2 mapping,and T2* imaging provides important insights into theunderlying etiology of cardiomyopathy. It addition-ally can be used to help risk stratify patients, guidepatient management plan, and evaluate treatmentresponse. CMR should be routinely used in the work-up of patients with nonischemic cardiomyopathy.

ADDRESS FOR CORRESPONDENCE: Dr. ChristopherM. Kramer, Departments of Medicine and Radiology,University of Virginia Health System, 1215 Lee Street,Box 800170, Charlottesville, Virginia 22908. E-mail:ckramer@virginia.edu.

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KEY WORDS amyloidosis, cardiomyopathy,cardiovascular magnetic resonance, heartfailure, hypertrophic cardiomyopathy,sarcoidosis

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