assessment of myocardial fibrosis with cardiovascular magnetic

STATE-OF-THE-ART PAPER

Assessment of Myocardial FibrosisWith Cardiovascular Magnetic Resonance

Nathan Mewton, MD, PHD,*† Chia Ying Liu, PHD,* Pierre Croisille, MD, PHD,†David Bluemke, MD, PHD,*‡ João A. C. Lima, MD, MBA*

Baltimore and Bethesda, Maryland; and Lyon, France

Diffuse interstitial or replacement myocardial fibrosis is a common feature of a broad variety of cardiomyopathies.Myocardial fibrosis leads to impaired cardiac diastolic and systolic function and is related to adverse cardiovascularevents. Cardiovascular magnetic resonance (CMR) may uniquely characterize the extent of replacement fibrosis andmay have prognostic value in various cardiomyopathies. Myocardial longitudinal relaxation time mapping is anemerging technique that could improve CMR’s diagnostic accuracy, especially for interstitial diffuse myocardial fibro-sis. As such, CMR could be integrated in the monitoring and therapeutic management of a large number of patients.This review summarizes the advantages and limitations of CMR for the assessment of myocardial fibrosis. (J AmColl Cardiol 2011;57:891–903) © 2011 by the American College of Cardiology Foundation

One of the most common histological features of the failingheart is myocardial fibrosis. Replacement fibrosis, oftenpresent in the terminal stages of heart failure, has beenreported in histopathological autopsy studies (1,2). Thepathophysiological mechanisms that lead to this fibrosis arevarious, with some being acute, as in myocardial infarction(3), and others being progressive and potentially reversible,as in hypertensive cardiomyopathy (4). Myocardial fibrosisin animal and patient studies is associated with worseningventricular systolic function, abnormal cardiac remodeling,and increased ventricular stiffness (5–7). In recent clinicalstudies, fibrosis has also been shown to be a major indepen-dent predictive factor of adverse cardiac outcome (8–12).

In therapeutic guidelines for heart failure due to variouscardiomyopathies, there are no specific therapeutic strategiesbased on the tissue composition of the myocardial wall, eitherin the early or more advanced stages of disease. This lack ofspecific treatment might result in inappropriate therapies,which can lead to increased morbidity and additional financialburden to health care services (13). Lack of personalizedtreatment is also secondary to the absence of accurate clinicaltools to precisely phenotype patients with heart disease.

Recent reports have demonstrated the advantages ofusing cardiovascular magnetic resonance (CMR) for thenoninvasive imaging of heart failure patients (14,15). CMRhas been established as the reference imaging method forthe assessment of cardiac anatomy and function by provid-ing highly accurate and reproducible measures of both theleft and right ventricles and also for the assessment ofmyocardial viability (16–18). The field of CMR is rapidlyevolving with continuing technological progress and therecent development of applications that have further en-hanced its capacity to characterize myocardial tissue. In thisreview, we focus on CMR characterization of the differenttypes of myocardial fibrosis and its etiology through lategadolinium enhancement and myocardial longitudinal re-laxation time (T1) mapping.

Myocardial Fibrosis:Pathogenesis and Consequences

Fibrosis pathophysiology. In physiological conditions, thefibrillar collagen network is in intimate contact with all thedifferent cell types of the myocardium and plays a criticalrole in the maintenance of ventricular shape, size, andfunction (Fig. 1).

Myocardial fibrosis, defined by a significant increase inthe collagen volume fraction of myocardial tissue, is alwayspresent in end-stage heart failure (19). The distribution ofmyocardial fibrosis, however, varies according to the under-lying pathology and accounts for discrepancies among dif-ferent pathological reports in which only qualitative asopposed to quantitative measurements were made (19–22).The progressive accumulation of collagen accounts for aspectrum of ventricular dysfunctional processes that com-

From the *Division of Cardiology, Johns Hopkins University, Baltimore, Maryland;†Departement de Radiologie, Hôpital Cardiovasculaire Louis Pradel, Hospices Civilsde Lyon, Lyon, France; and ‡Radiology and Imaging Sciences, National Institutes ofHealth Clinical Center, National Institute of Biomedical Imaging and Bioengineer-ing, Bethesda, Maryland. Dr. Mewton was supported by a post-doctoral researchgrant from the French Federation of Cardiology. This project was also part of aresearch effort funded by a National Institutes of Health grant no. P20HL101397 toDr. Lima. All other authors have reported that they have no relationships to disclose.Deborah Kwan, MD, served as Guest Editor for this paper.

Manuscript received August 3, 2010; revised manuscript received November 8,2010, accepted November 19, 2010.

Journal of the American College of Cardiology Vol. 57, No. 8, 2011© 2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. doi:10.1016/j.jacc.2010.11.013

monly affect diastole first andsubsequently involve systolicperformance (5).Subtypes of myocardial fibrosis.Different types of myocardial fi-brosis have been reported ac-cording to the cardiomyopathicprocess (Fig. 1).

REACTIVE INTERSTITIAL FIBROSIS.The first type of fibrosis is inter-

stitial reactive fibrosis with a diffuse distribution within theinterstitium, but it can also be more specifically perivascular

(23). This type of fibrosis has a progressive onset andfollows the increase in collagen synthesis by myofibroblastsunder the influence of different stimuli. It has mostly beendescribed in hypertension and diabetes mellitus, where theactivation of the renin-angiotensin aldosterone system,beta-adrenergic system, the excess of reactive oxygen spe-cies, and metabolic disturbances induced by hyperglycemiaare major contributors (23–28) (Fig. 2). But this type offibrosis is also present in the aging heart, in idiopathicdilated cardiomyopathy (2,21), and in left ventricular (LV)pressure-overload and volume-overload states induced bychronic aortic valve regurgitation and stenosis (29,30). It has

Abbreviationsand Acronyms

CMR ! cardiovascularmagnetic resonance

LGE ! late gadoliniumenhancement

LV ! left ventricle

MOLLI ! Modified Look-Locker Inversion Recovery

Figure 1 Etiophysiopathology of Myocardial Fibrosis

Myocardial fibrosis is a complex process that involves each cellular component of the myocardial tissue. The myocardial fibroblast has a central position in this processby increasing the production of collagen and other extracellular matrix components under the influence of various factors (renin-angiotensin system, myocyte apoptosis,pro-inflammatory cytokines, reactive oxygen species).

892 Mewton et al. JACC Vol. 57, No. 8, 2011Cardiovascular Magnetic Resonance and Fibrosis February 22, 2011:891–903

also been reported in the remote noninfarcted myocardiumafter infarction (31).

Interstitial fibrosis is an intermediate marker of diseaseseverity, as has been shown in hypertensive cardiomyopathy,and it precedes irreversible replacement fibrosis (27,32). It isreversible under specific therapy (4,33,34). Therefore, thereis some clinical interest in its assessment for the manage-ment of patients with hypertension, diabetes, primary di-lated cardiomyopathy, and valvular disease.

INFILTRATIVE INTERSTITIAL FIBROSIS. This subtype of fi-brosis is induced by the progressive deposit of insolubleproteins (amyloidosis) or glycosphingolipids (Anderson-Fabry disease) (35,36) in the cardiac interstitium. Althoughthis subject is not the primary focus of this review, theirpathophysiology follows similar patterns, and the earlydetection of cardiac involvement is of critical importance totherapeutic management.

REPLACEMENT FIBROSIS. This replacement or scarring fibro-sis corresponds to the replacement of myocytes after celldamage or necrosis by plexiform fibrosis, mainly type I collagen(37). Replacement fibrosis appears as soon as the myocyteintegrity is affected. It can have a localized distribution (isch-emic cardiomyopathy, myocarditis, hypertrophic cardiomyop-athy, sarcoidosis) or a diffuse distribution (chronic renal insuf-ficiency, toxic cardiomyopathies, miscellaneous inflammatorydisease) according to the underlying etiology (14,15,38).

Interstitial fibrosis and infiltrative fibrosis ultimately leadto replacement fibrosis in the later stages of disease, wherecellular damage and cardiomyocyte necrosis/apoptosisappear (27).

Detection of Myocardial Fibrosis

Endomyocardial Biopsies

Previously, the only methodology available to assess myo-cardial fibrosis was the histopathological assessment of

endomyocardial tissue biopsies or of autopsy pieces. Thismethodology enables qualitative macroscopic assessmentafter Masson Trichrome staining (22) and quantitativeabsolute assessment of the collagen volume fraction in tissuesamples by quantitative morphometry with picrosirius red,which specifically stains fibrillar collagen under polarizedlight (1,21,39). Although this technique offers an absolutequantification of fibrosis in myocardial samples (3), it has 3evident drawbacks: 1) invasive biopsies are required;2) sampling error restricts the accuracy of biopsy in the caseof localized fibrosis (7,40); and 3) fibrotic involvement ofthe whole LV cannot be determined.

CMR

In the last 10 years, CMR has emerged as a noninvasiveimaging method that allows a comprehensive assessment ofmyocardial anatomy and function with unequaled levels ofaccuracy and reproducibility. The use of gadolinium extracel-lular contrast agents with CMR using late post-gadoliniummyocardial enhancement (LGE) sequences have furtherpushed our ability to accurately and precisely analyze myocar-dial tissue composition, especially myocardial fibrosis content.Physical basis of CMR tissue characterization. T1, T2

RELAXATION TIMES, PROTON DENSITY. In CMR images,the pixel signal intensity is based on the relaxation ofhydrogen nuclei protons in the static magnetic field, oftypically 1.5- or 3.0-T scanners. The relaxation of thehydrogen nucleus proton is specifically characterized by 2distinct magnetic resonance relaxation parameters: 1) the T1or spin-lattice relaxation time, which corresponds to thespecific time decay constant when the proton recoversapproximately 63% of its longitudinal magnetization equi-librium value; and 2) the transverse relaxation time (T2) orspin-spin relaxation time, which corresponds to the specifictime when the proton transverse magnetization drops toapproximately 37% of its original value. Both of those times

Figure 2 Diabetic Cardiomyopathy

Mild myocardial interstitial fibrosis stained in blue with Masson trichrome (white arrows) in a patient with long-duration type 1 diabetes mellitus at autopsy,with (A) perivascular fibrosis and (B) mild fibrosis between myocytes. Reprinted with permission from Konduracka et al. (28).

893JACC Vol. 57, No. 8, 2011 Mewton et al.February 22, 2011:891–903 Cardiovascular Magnetic Resonance and Fibrosis

are measured in milliseconds. Another constitutional pa-rameter that needs to be added to explain the pixel signalintensity is the density of mobile hydrogen atoms within thetissue voxel or proton density.

Both the T1 and T2 relaxation times depend on themolecular environment of the water molecules in the tissueand therefore characterize each tissue very specifically. T1and T2 relaxation times vary significantly from one type oftissue to another, but also within the same tissue dependingon its physiopathological status (inflammation, edema, fi-brosis). The CMR imaging techniques used also result indifferent contrast images. Specific CMR sequences can beused to selectively reveal certain molecular environmentswithin the tissue. Those differences are further enhancedwith the use of gadolinium extracellular magnetic resonancecontrast agents.

GADOLINIUM CMR ENHANCEMENT. Gadolinium contrastagents reduce the T1 relaxation time of adjacent tissue.Thus, the local gadolinium tissue concentration will inducedifferences in signal intensity in the T1-weighted image.Given various specific properties of the tissue, the T1shortening induced by the gadolinium contrast agent gen-erates specific differences in signal intensity. The majortissue parameters that influence the final voxel signal inten-sity in the contrast-enhanced images are local perfusion;extracellular volume of distribution; water exchange ratesamong the vascular; interstitial, and cellular spaces; andwash-in and wash-out kinetics of the contrast agent (41,42).

GADOLINIUM CMR OF MYOCARDIAL FIBROSIS ENHANCED.

The physiological basis of the LGE of myocardial fibrosis isbased on the combination of an increased volume of

distribution for the contrast agent and a prolonged wash-outrelated to the decreased capillary density within the myo-cardial fibrotic tissue (41,43). The increase in gadoliniumconcentration within fibrotic tissue causes T1 shortening,which appears as bright signal intensity in the CMR imagebased on conventional inversion-recovery gradient echosequences. Thus, the discrimination between scarred/fibrotic myocardium and normal myocardium relies oncontrast concentration differences combined with the cho-sen setting of the inversion-recovery sequence parameters.These parameters are set to “null” the normal myocardialsignal that appears dark in the final image relative to thebright signal of the scarred/fibrotic myocardium.

Of note, gadolinium contrast agents are not specificmarkers for myocardial fibrosis. Late gadolinium enhance-ment is caused by modifications of the contrast distributionspace as well as wash-in and wash-out kinetics of the contrastinto interstitial space or extracellular matrix. Therefore, quan-tification of late enhancement (e.g., T1 mapping) explores thevolume of the extracellular matrix. This volume is increased inmyocardial fibrosis but can also be increased in other patho-logical processes, such as inflammation and edema.Measuring myocardial fibrosis with LGE. CLINICAL

APPLICATIONS. The clinical application of myocardialLGE with CMR started with the assessment of experimen-tal acute myocardial infarction followed by measurements inchronic infarct experimental models and patients (44–46).After having shown that the regional differences in signalintensity were correlated to the extent and severity ofmyocardial injury, Kim et al. (47) reported in experimentalstudies that the spatial extent of hyperenhancement was thesame as the spatial extent of the collagenous scar at 8 weeks

Different Prevalence Reports of Myocardial Scarring/Fibrosis of the LV in Various Nonischemic Cardiac Pathologiesas Defined With Qualitative Analysis of LGE Cardiovascular Magnetic ResonanceTable 1 Different Prevalence Reports of Myocardial Scarring/Fibrosis of the LV in Various Nonischemic Cardiac Pathologiesas Defined With Qualitative Analysis of LGE Cardiovascular Magnetic Resonance

Cardiac Disease Category (Ref. #)Total

Patients (n)Prevalence ofFibrosis (%)

Range ofPrevalence (%) LGE Pattern LGE Preferential Location

NIDCM (8,40,50–55) 350 47 9–88 Mid-wall, patchy foci, subendocardialnonsystemized

Septum, RV-LV insertionpoints

HCM (51,56–68) 1,654 69 45–100 Mid-wall, diffuse, heterogeneous Within hypertrophied regions,RV-LV insertion points

Aortic valve disease (65,69,70) 153 46 27–62 Mid-wall, multifocal Very variable, basal septumand inferior walls

Pulmonary sarcoidosis (71–73) 170 28 26–32 Mid-wall, subepicardial, ischemic-like Inferoseptal-, inferolateral-basal

Cardiac amyloidosis (74,75) 54 72.5 69–76 Diffuse subendocardial, patchysubendocardial

Global

Hypertensive cardiomyopathy (65,76) 1,670 39 28–50 Patchy, nonspecific, ischemicpattern

None

Diabetic cardiomyopathy (12) 107 28 NA Nonspecific, ischemic pattern None

Heart transplant (77) 53 51 NA Ischemic pattern, midwall,diffuse, spotted

Inferoseptal

Thalassemia major (78) 115 24 NA Multifocal, epicardial, midwall Inferoseptal, septum

Chagas disease (79) 51 69 NA Subendocardial ischemic-like,subepicardial

Inferolateral, global

Chronic hemodialysis (80) 24 79 NA Ischemic pattern, diffuse,midwall-focal

None

HCM ! hypertrophic cardiomyopathy; LGE ! late gadolinium enhancement; LV ! left ventricle; NA ! not applicable; NIDCM ! nonischemic dilated cardiomyopathy; RV ! right ventricle.


with highly significant correlations. The clinical impact ofLGE extent in patients with chronic ischemic cardiomyop-athy was further demonstrated with the clinical study in 50patients undergoing revascularization showing that the de-gree of improvement in the global mean wall-motion scoreand the ejection fraction was significantly related to thetransmural extent of LGE (46).

During the chronic phase of infarction, when a densefibrotic scar replaces the infarcted myocardium, Mahrholdtet al. (17) showed the accuracy and the clinical reproduc-ibility of delayed enhancement for infarct size determina-tion. Moreover, Ricciardi et al. (48) and Wu et al. (49)showed the higher sensitivity for infarct detection by LGE-CMR as compared with single-photon emission computedtomography, and other studies have confirmed the ability ofCMR to detect microinfarctions.

The number of studies assessing myocardial fibrosis byLGE in other types of cardiomyopathies has dramaticallyincreased in the last 10 years (Table 1) (12,40,50–80).Different patterns of enhancement have been reportedaccording to the underlying etiology, and LGE-CMR hasbecome a first-line noninvasive exam for the etiologicassessment of new-onset myocardial dysfunction (14,15,50).

LGE-CMR also provides prognostic information thatcould be used to define more appropriate therapeutic strat-egies. In ischemic cardiomyopathy, the transmural extent ofLGE is predictive of myocardial wall recovery after revas-cularization, but it is also predictive of adverse LV remod-eling (46,81). At the clinical level, infarct size is an inde-pendent prognostic factor for heart failure, arrhythmicevents, and cardiac mortality (9,11,82). In nonischemicdilated cardiomyopathy, Assomull et al. (8) showed that thepresence of myocardial LGE was associated with a 3-foldincrease of hospitalization for heart failure or cardiac deathand a 5-fold increase of sudden cardiac death or ventriculararrhythmias. In hypertrophic cardiomyopathy, Rubinshteinet al. (56) and Kwon et al. (57) reported that LGE wasstrongly associated with arrhythmia and remained signifi-cantly associated with subsequent sudden cardiac death afteradjustment for other risk factors. In the same way, LGE issignificantly and independently associated with adversecardiac events in patients with cardiac amyloidosis (74) andin patients undergoing aortic valve replacement (83). Re-cently, the additional prognostic value of LGE was dem-onstrated in hypertensive (76) and diabetic (12) patients freeof any cardiac symptoms and with preserved ejection frac-tion. Finally, the clinical significance of LGE also offerspotential targets for new therapeutic strategies designed forthe purpose of personalizing medical management, al-though such paradigm requires further development andtesting. In this regard, there is a crucial need for LGE-CMR assessment standardization in clinical practice (84).

LGE LIMITATIONS. If LGE allows a sensitive and reproduc-ible qualitative assessment of myocardial replacement fibro-sis, it is limited in its accuracy for absolute quantification of

myocardial fibrosis, and the assessment of diffuse fibrosis isrestricted by technical and physiopathological characteris-tics. First, with conventional LGE imaging sequences,signal intensity is expressed on an arbitrary scale that differsfrom one imaging study to another and therefore is unsuit-able for direct signal quantification in cross-sectional orlongitudinal comparisons. The late gadolinium-enhancedmyocardial fibrotic tissue is defined on the basis of thedifference in signal intensity between fibrotic and normalmyocardium, and this difference generates the image con-trast. In addition, LGE is influenced not only by tech-nical parameters set during image acquisition (inversiontime [85], slice thickness, and so on), but also accordingto the intensity threshold that is arbitrarily set duringpost-processing to differentiate normal from fibroticmyocardium (86).

Presently, there is no clear consensus on the intensitythreshold settings to use for clinical assessment of myocar-dial fibrosis. Various methods have been reported to definelate enhanced myocardium, with significantly different re-sults (86–89). This is one of the factors explaining thevariability in the frequency of myocardial fibrosis found byLGE in various cardiomyopathies from different studies(Table 1). This questions the reliability and reproducibilityof LGE for myocardial fibrosis quantification in a clinicalsetting.

Another concern with the use of myocardial LGE hasemerged with its increasing use to define the myocardial“gray zone” in clinical studies. The “gray zone” has beenarbitrarily defined on late enhancement CMR images asmyocardium with intermediate signal intensity enhancementbetween normal and scarred/fibrotic myocardium (90). Thisarea reflects tissue heterogeneity within the infarct peripheryand has been shown to strongly correlate with ventriculararrhythmia inducibility and post-myocardial infarction mortal-ity in ischemic cardiomyopathy (90,91). The use of this “grayzone” in ischemic cardiomyopathy and other types of cardio-myopathies further expands the assessment and the quantifi-cation of hyperenhanced myocardium for purposes that gobeyond pure quantification of myocardial fibrosis.

Finally, although LGE-CMR is the most accuratemethod to measure myocardial replacement fibrosis, itssensitivity is limited for the assessment of diffuse interstitialfibrosis. In LGE-CMR, image contrast relies on the differ-ence in signal intensity between fibrotic and “normal”myocardium, and such differences may not exist if theprocess is diffuse.Measuring myocardial fibrosis with T1 mapping.T1 MAPPING BASICS. The recent technical improvements inacquisition sequences now enable us to perform myocardialT1 mapping with high spatial resolution by using 1.5-Tmagnetic resonance imaging scanners within a single breathhold (92). Compared with LGE images, T1-mapping CMRtechniques allow us to eliminate the influences of window-ing and variations in signal enhancement by directly mea-


Figure 3 T1 Map Construction and T1 Recovery Graph After Contrast Administration

(A) T1 map after 15 min of gadolinium administration in an inferior infarct case. This is the Modified Look-Locker Inversion Recovery Sequence that uses 17 heart-beatsto reconstruct 11 images with different inversion times during mid-diastole. It is necessary to combine all images to generate the final T1 map. For that, it is necessaryto apply algorithms to define the best fitting curve over the 11 acquired initial voxels linking for the same location. Those fitting algorithm are very sensitive to motionand image quality/artifacts. The result is a T1 map imaging where the T1 time for the global or segmented left ventricle can be assessed. (B) Graph showing the recov-ery of absolute myocardial T1 value in a healthy heart (short axis, mid-ventricle) at different time points before and after contrast administration (0, 2, 4, 6, 8, 10, 15,and 20 min). T1 values are expressed as mean " SD. The global and regional mean T1 values will vary significantly with the time of assessment. The SD of T1 value ismore significant before contrast administration. Reprinted with permission from Messroghli et al. (93).


suring the underlying T1 relaxation times. Therefore, itallows signal quantification (in milliseconds) on a standard-ized scale of each myocardial voxel to characterize myocar-dial tissue.

T1 MAPPING METHODOLOGY. A T1 map of the myocar-dium is a parametric reconstructed image, where each pixel’sintensity directly corresponds to the T1 relaxation time ofthe corresponding myocardial voxel. Signal recovery fromeach myocardial voxel is sampled with multiple measure-ments after a specific preparation pulse sequence, and theassociated T1 relaxation time is calculated from thesemeasurements by the combination of all acquisitions. T1maps can be obtained any time before or after gadoliniumcontrast administration. The pre-contrast T1 map is abaseline reference. The post-contrast T1 maps are assessedat different time points after contrast administration andcould be used to obtain the curve of myocardial T1 recoveryreflecting the contrast agent wash-out (Fig. 3) (93).

Different CMR acquisition sequences have been used toobtain myocardial T1 maps (6,75,92,94,95). This is anessential point to consider before performing myocardial T1maps, because it directly influences the accuracy and repro-ducibility of the final T1 measurements. This should also beconsidered when comparing results between different stud-ies. Different T1 mapping strategies will have varyingsensitivities to motion artifacts, heart rate, and intrinsic T1value ranges (94).

The most assessed T1 mapping sequence has been de-scribed by Messroghli et al. (92,94,96,97) and is theModified Look-Locker Inversion-recovery (MOLLI) se-quence. MOLLI provides high-resolution T1 maps ofhuman myocardium in native and post-contrast situationswithin a single breath hold.

This sequence has been thoroughly described, optimized,and tested in phantom studies, on healthy volunteers, andischemic cardiomyopathy patients. Although it is sensitive to

heart rate extreme values and tends to slightly underestimatethe true heart T1 value, the method allows a rapid and highlyreproducible T1 map of the heart with high levels of intra andinter-observer agreement (93). However, in the only report onthe clinical validation of T1 mapping against histology for theassessment of myocardial fibrosis, Iles et al. (6) used a differenttype of sequence (VAST [Variable Sampling of the k-space inTime] inversion-recovery prepared 2D fast gradient echosequence with variable sampling of k-space). This sequence,which is very similar to the MOLLI sequence, has been lesswell validated in the literature.

T1 maps can be obtained at different slice levels, with anaverage acquisition time of 15 to 20 s (1 breath hold) for 1T1 map (93). Figure 4 demonstrates T1 maps at themid-ventricle level.

THE ADVANTAGES OF T1 MAPPING. T1 mapping enablesdirect myocardial signal quantification (in milliseconds) on astandardized scale. This allows a better characterization ofmyocardial tissue composition on a global or regional level.Myocardial areas of delayed enhancement can be measuredin terms of their spatial extent, but also in terms of themagnitude of their signal intensity: The composition ofeach myocardial slice can be analyzed as a T1 distributionhistogram, which gives a more accurate description of themyocardial tissue composition (Fig. 5). One hypothesiswould be to use this T1 distribution (mean T1 peak value,distribution scatter) to identify specific myocardial patternssuch as myocardial diffuse fibrosis, specific myopathies, orthe peri-infarction or “gray zone.”

The pre-contrast mean T1 value of normal myocardium isof 977 " 63 ms, and the post-contrast values between 10and 15 min of normal myocardium have been reported to beapproximately 483 " 20 ms (93) at 1.5-T. Pre-contrast T1values of myocardial fibrosis (infarct scar) are significantlylonger than those of normal myocardium (1,060 " 61 ms vs.

Figure 4 T1 Maps of the Myocardium at the Mid-Ventricular Short-Axis Level in a Healthy Volunteer

(A) Pre-contrast, (B) post-gadolinium contrast (0.15 mmol/kg) at 12 min, and (C) at 25 min acquired with the MOLLI sequence.The mean T1 value for the left ventricle (LV) can be obtained at each time after tracing the endocardial and epicardial countours of the LV (A).


987 " 34 ms), although the range of pre-contrast T1 valuedistribution overlaps with that of fibrotic myocardium (97).

Post-contrast T1 values of scarred myocardium (replace-ment fibrosis) are significantly shorter than those of normalmyocardium due to the retention of gadolinium contrast infibrotic tissue. Messroghli et al. (97) reported T1 values ofapproximately 390 " 20 ms in chronic infarct scar com-pared with 483 " 23 ms in normal myocardium for T1 mapsobtained between 10 and 15 min after contrast administra-tion at 0.15 mmol/kg.

The accuracy of post-contrast T1 mapping to assessmyocardial interstitial and replacement fibrosis has hadlimited validation. In a study of 9 patients after cardiactransplantation, T1 time at 15 min after gadolinium admin-istration showed an inverse correlation with myocardialcollagen content.

Even if there is overlap between T1 values for interstitialand replacement fibrosis, T1 mapping can accurately differ-entiate both interstitial and replacement fibrosis from nor-mal myocardium (98). In an in vitro magnetic resonancestudy of selected human myocardium samples, Kehr et al.

(98) showed that post-contrast T1 values for both diffuseand replacement fibrosis were significantly different from T1values for normal myocardium. Although there was nosignificant difference between the respective diffuse fibrosisand replacement fibrosis T1 values, there was a significantcorrelation between T1 value and myocardial collagen con-tent. However, the real clinical benefit of T1 mappingremains to be shown. When applied with rigorous method-ology, T1 mapping could be the ideal tool to assess andquantify diffuse myocardial fibrosis. It could also improvethe accuracy of delayed enhancement and myocardial scarcharacterization.

REPORTED CLINICAL APPLICATIONS OF T1 MAPPING.

There are very few studies published using T1 mapping in theclinical setting. They are reported in Table 2 (6,75,96,98,99).

T1 MAPPING LIMITATIONS. To date, all of the publishedclinical studies using T1 mapping have been realized onsmall groups of selected patients, with different types of T1acquisition sequences. Although the use of T1 mapping formyocardial fibrosis assessment appears to be promising

Figure 5 Comparison of Late Gadolinium Enhanced Studies With CorrespondingT1 Maps and T1 Values Distribution Histograms in Different Cardiomyopathies

(A) Chronic inferior myocardial infarction; (B) cardiac amyloidosis; (C) nonischemic dilated cardiomyopathy. In each example, the short-axis late gadolinium images showimages with different patterns of enhancement, transmural localized in the case of a myocardial infarction scar (A1), sub-endocardial diffuse in the case of cardiac amy-loidosis (B1), or sub-epicardial and heterogeneous in the case of dilated cardiomyopathy (C1). In the middle panel are the corresponding T1 maps (A2, B2, B3)obtained after MOLLI acquisitions. From those T1 maps, a mean left-ventricular (LV) T1 value can be obtained. This information can also be processed more preciselythrough the analysis of the distribution histogram of the LV T1 values. Very distinct patterns of distributions can be seen on those examples, but this has to be shown infurther larger clinical studies. This might also be a new way to assess and quantify myocardial fibrosis.


when combined with LGE imaging, its accuracy is sensitiveto many confounding factors. Those factors are as follows:

1. The physical properties of gadolinium contrast agents(dose, concentration, relaxivity, rate of injection, andwater exchange rate) significantly affect the final myo-cardial voxel T1 value.

2. The time delay of the T1 mapping measurement aftergadolinium administration also significantly affects theresulting T1 values. Because the T1 value exponentiallyincreases with the wash-out of gadolinium contrast fromthe myocardium, the time of T1 mapping acquisition willhave a significant influence on the final myocardial voxelT1 value (93). Therefore, in clinical studies, when per-forming T1 mapping acquisition, the acquisition timeafter contrast administration should be carefully moni-tored and reported. Solutions to this problem mayinclude normalization to noncardiac tissue (e.g., muscle,blood) or characterization of the time as a T1 curve.

3. The types of T1 mapping acquisition sequence that willaffect the sensitivity to motion artifacts (arrhythmia),heart rate, and T1 extreme values (92,94). Recently,

various acquisition protocols with shorter acquisitiontimes have been reported with good levels of accuracy(100,101).

4. The gadolinium myocardial wash-out rate, which mainlydepends on each patient’s individual glomerular filtrationrate, should be carefully accounted for when performingT1 mapping. Although the influence of renal dysfunctionon myocardial T1 mapping remains incompletely under-stood, Maceira et al. (75) proposed a correction model ofmyocardial T1 value by blood T1 value in their study ofcardiac amyloid patients that significantly improved T1mapping sensitivity.

5. The presence of LGE areas will have to be accounted forin order to assess the true T1 value of nonaffectedmyocardial areas. Those areas have been shown tosignificantly influence global myocardial slice mean T1value and therefore interfere with the diagnosis of diffuseinterstitial fibrosis (6).

6. The hematocrit level will affect the partition coefficientof the gadolinium contrast agent to be considered for theclinical use of T1 mapping.

Clinical Studies Using T1 MappingTable 2 Clinical Studies Using T1 Mapping

First Author (Ref. #) Cardiac Disease CategoryPatient Sample Size

(n) T1 Mapping Method Results

Messroghli et al. (96) Acute myocardial infarction 8 NA ! T1 pre-contrast value of the infarctedmyocardium was significantly prolonged(#18 " 7%) compared with noninfarctednormal myocardium.

! T1 10-min post-contrast value of theinfarct was significantly reduced(–27 " 4%) compared with normalmyocardium.

Messroghli et al. (98) Chronic myocardial infarction 24 MOLLI ! T1 pre-contrast value of the infarctedmyocardium was significantly prolongedcompared with noninfarcted normalmyocardium (1,060 " 61 ms vs.987 " 34 ms).

! T1 post-contrast value of the infarct wassignificantly reduced compared withnormal myocardium.

! Difference between baseline and post-contrast T1s significantly more pronouncedin the acute than in the chronic studies atall time points.

Sparrow et al. (99) Chronic aortic regurgitation 8 MOLLI ! No significant difference in slice averagedmyocardial T1 pre- and post-contrastvalues in the patient group compared withcontrols.

Maceira et al. (75) Cardiac amyloidosis 22 NA ! Subendocardial T1 post-contrast value at 4min was significantly shorter in amyloidpatients than in controls (427 " 73 ms vs.579 " 75 ms).

Iles et al. (6) Chronic heart failure 25 VAST ! T1 15-min post-contrast values correlatedsignificantly with collagen volume fractionon myocardial biopsies (R ! –0.7).

! T1 15-min post-contrast values weresignificantly shorter in heart failurepatients than controls (383 " 17 ms vs.564 " 23 ms) even after exclusion of LGEareas.

LGE ! late gadolinium enhancement; MOLLI ! Modified Look-Locker Inversion Recovery; NA ! not applicable; VAST ! inversion recovery gradient echo sequence with Variable Sampling of the k-spacein Time.


7. Even if myocardial T1 values have been shown to be thesame between basal, mid-cavity, and apical sections ofthe LV in healthy volunteers, it is unknown whether allsections are affected equally by diffuse interstitial fibrosis.For practical reasons, T1 maps in patients are performedat a single-section level of the LV (usually mid-ventricle). Therefore, this sampling limitation mightaffect the final T1 values in a myocardium in which thefibrosis process is not homogenous.

T1 mapping is a very sensitive technique that needs to beperformed in rigorous conditions in order to enhance itsaccuracy for fibrosis assessment and allow cross-sectionalcomparisons (102). Although the post-contrast T1 value ofmyocardial fibrosis is significantly different from that ofnormal myocardium, myocardial T1 distribution can besignificantly scattered, and this might limit its sensitivity fordisease states with less severe fibrosis.

T1 mapping is still an emerging technique. Before it canbe used for clinical applications, a more standardized histo-logically validated technique needs to be identified andassessed in clinical studies on various and larger groups ofpatients and in multicenter settings.Equilibrium contrast CMR. Recently Flett et al. (103)reported a new CMR method to assess diffuse myocardialfibrosis: equilibrium contrast CMR. This was implementedto improve myocardial T1 mapping by excluding confound-ing factors such as heart rate, body composition, and renalclearance variability. It is based on 3 elements: 1) a bolus ofgadolinium followed by continuous infusion to achieveblood/myocardium equilibrium; 2) a measurement of theblood volume of distribution (1-hematocrit); and 3) a pre-and post-equilibrium T1 measurement by CMR. Thismethod allows a precise calculation of the gadoliniummyocardial volume distribution that reflects diffuse myocar-dial fibrosis.

In a selected population of pre-surgical aortic stenosis andhypertrophic cardiomyopathy patients undergoing myec-tomy, Flett et al. (103) validated this method against fibrosisquantification by histology on selective surgical biopsies.They showed that equilibrium contrast CMR correlatedstrongly with biopsy histological fibrosis. These data arepreliminary and, as for T1 mapping, have to be confirmed inlarger and different cardiomyopathy populations. Also, thismethod imposes a more complex image acquisition protocolthat questions its clinical applicability at the time whenCMR availability is still a major limitation in comparisonwith other cardiac imaging techniques.

Other Methods to Explore Myocardial Fibrosis

This review focuses on CMR as the most promisingaccessible and accurate noninvasive imaging tool to assessmyocardial fibrosis in a routine clinical practice. Othernoninvasive methods have been used to characterize myo-cardial fibrosis (perfusable tissue index with positron emis-sion tomography, procollagen-derived pro-peptides and

matrix metalloproteinases as serum fibrosis biomarkers,single-photon emission computed tomography imagingwith specific radiolabeled agents) or its functional conse-quences (tissue Doppler echocardiography, CMR tissuetagging) and have been reported in the literature (104) butdo not constitute the focus of this review. The cross-sectional combination of different imaging modalities mightincrease the diagnostic accuracy for myocardial fibrosis, butthis still needs to be established.

Future Perspective

CMR has recently been proposed as a comprehensive tool inthe clinical arena for the diagnosis and management ofpatients with heart failure (14). LGE-CMR, after showingits prognostic power to predict myocardial recovery inischemic cardiomyopathy, has also shown its diagnosticaccuracy for myocardial replacement fibrosis assessment indifferent types of cardiomyopathies. LGE presence has apowerful independent clinical prognostic value not only inischemic cardiomyopathy (9,11,81,82), but also in all othertypes of cardiomyopathies (8,69,74,105). This knowledge isnow being converted in efficient methods to monitor ther-apeutic applications through new studies designed to im-prove our therapeutic options.

The emergence of T1 mapping further improves ourknowledge and the clinical assessment of myocardial diffusefibrosis and further refines the information provided byLGE-CMR. It might help us to better stratify much largerand lower cardiovascular risk patient populations (diabetics,hypertensive), detecting subclinical myocardial changes be-fore the onset of diastolic and systolic dysfunction. For themoment, clinical data are scarce, and the clinical value ofthis technique remains to be shown, specifically in largergroups of patients and in prospective studies. T1 mappingusing standardized imaging protocols combined with LGEwill be of great help for a more precise myocardial tissuecharacterization. This combination of tissular informationmight help the clinician to better understand and diagnosesooner the underlying cardiomyopathic process. This infor-mation will also help to improve therapeutic strategies andenable a more direct monitoring of their effect, thus im-proving clinical outcomes (4,32).

AcknowledgmentThe authors thank M. Viallon for her advice and assistancein writing the manuscript.

Reprint requests and correspondence: Dr. João A. C. Lima,Johns Hopkins University, Division of Cardiology, Department ofMedicine, 600 North Wolfe Street/Blalock 524, Baltimore, Mary-land 21287-0409. E-mail: [email protected].

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Key Words: cardiac magnetic resonance y late gadolinium enhancementy myocardial fibrosis y T1 mapping.


assessment of myocardial fibrosis with cardiovascular magnetic

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