Assessment of Left Atrial Fibrosis by Late Gadolinium Enhancement Magnetic Resonance Imaging

JACC: CLINICAL ELECTROPHYSIOLOGY

VOL. 3, NO. 8, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 2405-500X/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacep.2017.07.004

STATE-OF-THE-ART REVIEW

Assessment of Left Atrial Fibrosis by Late Gadolinium Enhancement Magnetic Resonance Imaging Methodology and Clinical Implications Johannes Siebermair, MD, MHBA,a,b,c Eugene G. Kholmovski, PHD,a,d Nassir Marrouche, MDa

ABSTRACT Recently, studies using late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) to identify structural changes of atrial tissue have contributed significantly to understanding the pathophysiology and progression of atrial fibrillation (AF). Moreover, imaging of atrial fibrosis using MRI has evolved to be a tool to improve clinical outcome of AF ablation procedures by allowing a patient-specific individualized management approach. LGE-MRI has been shown to predict AF ablation outcome based on pre-procedural imaging to define the extent of atrial fibrosis. The results of the ongoing DECAAF II (Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation) trial might extend ablation strategies from pulmonary vein isolation alone to a substrate-based approach. Furthermore, an improved understanding of the underlying mechanisms of atrial structural remodeling is crucial in order to reduce the occurrence of AF-associated complications (e.g., ischemic stroke and heart failure). This review article provides current methodology of atrial fibrosis imaging using LGE-MRI and delineates actual clinical implications and future directions for this imaging approach. (J Am Coll Cardiol EP 2017;3:791–802) © 2017 by the American College of Cardiology Foundation.

S

ince the introduction of contrast-enhanced

translational approach of those findings aims at

magnetic resonance imaging (MRI) into clinical

increasing success rates and minimizing complica-

practice in 1982 (1) the implications for this

tions like ischemic stroke. The current paper gives in-

technique have proliferated due to technical progress

sights into the established methods of left atrial (LA)

and increasing understanding of cardiac pathophysi-

fibrosis assessment by LGE MRI and points out actual

ology (2,3). The introduction of gadolinium-based

clinical implications and future directions.

contrast agents (GBCAs) in 1984 was a milestone in cardiac imaging (4). Initially intended for assessment

USE OF LGE MRI FOR IMAGING OF

of acute and chronic myocardial infarction (3), late

ATRIAL FIBROSIS

gadolinium enhancement (LGE) MRI has recently emerged as a promising tool to obtain mechanistic in-

Fibrotic myocardial tissue is composed of dis-

sights into structural alterations of the atrial wall (5).

organized myocytes and collagen, and has expan-

In terms of atrial fibrillation (AF) treatment, a

ded extracellular space compared with healthy

From the aComprehensive Arrhythmia and Research Management (CARMA) Center, University of Utah School of Medicine, Salt Lake City, Utah; bDepartment of Medicine I, Klinikum Grosshadern, University of Munich, Munich, Germany; cGerman Cardiovascular Research Center (DZHK), partner site Munich Heart Alliance, Munich, Germany; and the dUCAIR, Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, Utah. Dr. Kholmovski owns stock in and has been a consultant for Marrek Inc. Dr. Marrouche has ownership interest in Marrek, Inc. and Cardiac Designs; has received research funding from Biosense Webster, Medtronic, St. Jude Medical, Boston Scientific; and has received consulting fees from Biotronik, Preventice, Biosense Webster, and Abbott. Dr. Siebermair has reported that he has no relationships relevant to the contents of this paper to disclose. Manuscript received April 29, 2017; revised manuscript received July 7, 2017, accepted July 13, 2017.

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JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 3, NO. 8, 2017 AUGUST 2017:791–802

Methodology and Clinical Implications of Atrial Fibrosis Imaging

ABBREVIATIONS

myocardium (6). LGE-MRI with extracellular

displacement. Thus, the data acquisition for LGE

AND ACRONYMS

gadolinium-based contrast (shortening T1

sequence is only active if the LA displacement is <1.5

relaxation time) is based on a delayed

mm from baseline. In addition, to minimize the effect

contrast wash-in and wash-out in tissue with

of LA motion, imaging data are acquired during the

3D = 3-dimensional AF = atrial fibrillation

increased extracellular space. Due to contrast

diastolic phase of the LA (identified from cine images),

kinetics, the agent diffuses rapidly out of

with data acquisition limited to 15% of the cardiac cy-

ECG = electrocardiogram

capillaries after intravenous administration,

cle. The phase-encoding direction of the LGE scan

GBCA = gadolinium-based

but it is not able to cross into cells with intact

should be left to right to minimize residual respiration

membranes, therefore accumulating in the

artifacts from the chest wall in the LA region. Gener-

IIR = image intensity ratio

extracellular space. In terms of atrial fibrosis,

alized autocalibrating partially parallel acquisitions

IR = inversion-recovery

this leads to contrast accumulation in fibrotic

(GRAPPA) with reduction factor R ¼ 2 in the phase-

LA = left atrial/atrium

areas. As a result, fibrotic tissue has higher

encoding direction is used to speed up scan time. IR

LGE = late-gadolinium-

signal intensity in comparison with healthy

preparation is applied every heartbeat, and fat satu-

enhancement

myocardium in T1-weighted MRI scans. Im-

ration is performed immediately before data acquisi-

LV = left ventricle/ventricular

age contrast between fibrotic and normal

tion. The echo time of the LGE scan is preferably

MRI = magnetic resonance

tissues

using

selected to reduce the signal intensity of partial vol-

magnetization preparation by inversion or

ume fat-tissue voxels and to allow improved delinea-

saturation radiofrequency pulses (7).

tion of the LA wall. The inversion time (TI) value for the

BMI = body mass index

contrast agent

imaging

PV = pulmonary vein

is

increased

in

LGE-MRI

RA = right atrial/atrium S/I = superior/inferior TI = inversion time

LA

FIBROSIS

ASSESSMENT:

FROM

LGE-MRI

ACQUISITION TO THE FINAL 3-DIMENSIONAL FIBROSIS MODEL (DECAAF APPROACH). The

DECAAF (Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation) study was a multicenter study conducted at 15 clinical centers. Many of the DECAAF centers have adopted this LA LGE-MRI protocol into clinical practice at their centers. Currently, this protocol can be considered the most widely used MRI protocol for LA fibrosis imaging. A detailed description of the protocol is given in the following text. DECAAF LGE-MRI PROTOCOL. Subjects assigned for

atrial fibrosis imaging undergo 3-dimensional (3D) LGE-MRI along with a contrast-enhanced magnetic resonance angiography and cine imaging in order to define the anatomy of the LA and the pulmonary veins (PVs). MRI studies can be performed on 1.5-T and 3-T MRI scanners using either specialized cardiac coils or conventional body and spine phased-array receiver coils. High-resolution LGE images of the LA are acquired 15 to 30 min after GBCA administration using a 3D inversion-recovery (IR) prepared, respirationnavigated, and electrocardiogram (ECG)-triggered gradient-echo pulse sequence with fat saturation. To reduce respiration effects on imaging quality, the navigator is positioned on the right hemidiaphragm,

LGE-MRI scan is identified using a TI-scout scan. Typical scan time for the LGE-MRI studies is expected not to exceed 8 to 12 min depending on patient rhythm and respiratory pattern. The type of contrast agents and the corresponding dosage used by different clinical centers for LGE-MRI of the left atrium are provided in Table 1. S p e c i fi c s c a n p a r a m e t e r s . The specific scan parameters of the DECAAF MRI protocol for LGE imaging of the left atrium on 1.5-T and 3-T scanners are listed in Table 2. LGE-MRI

CONTRAINDICATIONS. Contraindications

for LGE fibrosis protocol are mainly the same contraindication as for conventional MRI scans: cardiac rhythm devices, severe claustrophobia, and other standard contraindications for MRI at the discretion of the physician, like prosthetic cardiac valves, or paramagnetic material in the brain or in the eyes. Decreased renal function is not necessarily a contraindication. Nevertheless, in order to minimize the risk of nephrogenic systemic sclerosis, a severe complication of GBCA administration (8), patients with an estimated glomerular filtration rate <30 ml/min are excluded from fibrosis imaging. For patients with an estimated glomerular filtration rate between 30 and 60 ml/min, it is up to the treating physician in agreement with the patient to schedule an LGE MRI study.

and data acquisition occurs during the end of the

DECAAF

expiration phase. The navigator acceptance window is

evaluated and processed by 2 expert operators using

FIBROSIS

ASSESSMENT. MRI

usually set to
3 mm. The typical LA motion due to

Corview image processing and analysis software

respiration is predominantly in the superior/inferior

(Marrek, Salt Lake City, Utah). The proprietary soft-

(S/I) direction. This motion has lower amplitude than

ware Corview was designed and developed at the

the corresponding diaphragm motion. From our ob-

University of Utah and allows for the complete pro-

data

are

servations, the typical LA displacement in the S/I di-

cess of LA wall segmentation, fibrosis identification,

rection is about 2 times smaller than the diaphragm S/I

and export of final 3D models.

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JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 3, NO. 8, 2017 AUGUST 2017:791–802

Methodology and Clinical Implications of Atrial Fibrosis Imaging

T A B L E 1 Dosage of Contrast Agents for the DECAAF Protocol

Contrast Agent

radiofrequency pulses has to be adjusted. The LA blood pool is used to find an inhomogeneity correc-

Dose (mmol/kg)

tion map. The adjustment is applied to the LA region

Dotarem

0.2

and adjacent tissue. For fibrosis assessment, an al-

Gadovist

0.1–0.2

gorithm automatically selects intensity thresholds

Magnevist

0.2

Multihance

0.1

Omniscan

0.2

assuming the Gaussian intensity distributions for fibrotic tissue (enhanced voxels) and “normal” myocardium. The threshold is selected based on the

DECAAF ¼ Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation.

estimated mean and SD of “normal” myocardium. The operator validates this threshold by visually inspecting the correspondence between enhanced voxels in LGE-MRI images and algorithm-detected

Following acquisition of high-resolution LGE-MRI

voxels. In the cases of discrepancy, the operator ad-

scans, the endocardial borders of the LA are defined,

justs the threshold to reflect an accurate correspon-

including an extent of the PV sleeves, by manually

dence. Typical intensity threshold values are in the

tracing the PV–LA blood pool in each slice of the LGE-

range of 2 to 4 SDs. The use of the same threshold

MRI volume.

value for all patients is not feasible because the

Next, the endocardial border is morphologically

contrast between normal and fibrotic myocardium in

dilated (by 4 pixel layers, 2.5 mm) and then manually

LGE-MRI of the left atrium depends on multiple fac-

adjusted to create the shell of the epicardial LA sur-

tors: patient heart rate and rhythm during MRI study,

face. In a final step, the endocardial segmentation is

type and dosage of contrast agent, time between

subtracted from the epicardial layer to define the wall

contrast administration and LGE-MRI scan, patient-

segmentation. The mitral valve and extents of the

specific contrast clearance rate, choice of TI value

left ventricle (LV) are manually excluded. The

for LGE scan, strength of the main field of MRI

resulting LA wall segmentation includes the 3D

scanner, patient body mass index (BMI), blood he-

extent of the LA wall and the antral regions of the 4

matocrit, and oxygenation level. For 3D visualization of LA fibrosis, the following

PVs. Before fibrosis assessment, the image intensity

color coding may be used: healthy tissue is depicted

inhomogeneity caused by spatially variable sensi-

as blue, whereas any tissue with LGE is depicted as

tivity profiles of receiver coils and nonuniform

green and yellow. Additionally, a color lookup-table mask

may

be

applied

to

better

differentiate

enhanced and non-enhanced tissue. Patients’ processed images are assigned to 1 of the established 4 T A B L E 2 Technical Specifications for LGE-MRI Image Acquisition

(DECAAF Protocol)

Utah stages, on the basis of LA wall enhancement as a percentage of the total LA wall volume: stage I,

3-T scanner Axial imaging volume with FOV

400  400  110 mm

Sampling matrix

320  320  44

Voxel size

1.25  1.25  2.5 mm (reconstructed to 0.625  0.625  1.25 mm)

TR/TE

3.1/1.4 ms

FA

14

Sampling bandwidth

740 Hz/pixel

defined as <10%, stage II $10 to <20%, stage III $20 to <30%, and stage IV $30%. The process from the LGE-MRI dataset to the final 3D fibrosis map of the LA is illustrated in Figure 1. Quantification of right atrial (RA) fibrosis by LGEMRI can be performed in a similar fashion (9). Of note, the correction of the image intensity inhomogeneity and accurate segmentation of the atrial

1.5-T scanner Axial imaging volume with FOV

360  360  110 mm

wall are more challenging for the RA than for the LA

Sampling matrix

288  288  44

because of the RA’s proximity to receiver coils and a

Voxel size

1.25  1.25  2.5 mm (reconstructed to 0.625  0.625  1.25 mm)

significant trabeculation of the RA free wall.

TR/TE

5.2/2.4 ms

COMPARISON

FA

20

LGE-MRI TO OTHER LABS. MRI techniques used by

Sampling bandwidth

290 Hz/pixel

different clinical centers for the assessment of LA

DECAAF ¼ Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation; FA ¼ flip angle; FOV ¼ field-of-view; LGE ¼ late gadolinium enhancement; MRI ¼ magnetic resonance enhancement; TE ¼ echo time; TR ¼ repetition time.

OF

FIBROSIS

ASSESSMENT

BY

fibrosis and post-ablation scar are similar to those used for the DECAAF study. All groups are using ECGtriggered, respiratory navigated gradient echo pulse sequences with IR preparation and fat saturation.

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Methodology and Clinical Implications of Atrial Fibrosis Imaging

F I G U R E 1 LA Fibrosis Assessment From LGE-MRI

Following acquisition of high-resolution LGE-MRI scans, the endocardial borders of the left atrium (LA) are defined, including an extent of pulmonary vein (PV) sleeves, by manually tracing the PV–LA blood pool in each slice of the LGE-MRI volume. Next, the endocardial border is morphologically dilated (by 4 pixel layers, 2.5 mm) with manual adjustment to create a shell of the epicardial LA surface (step 2). The endocardial segmentation is subtracted from the epicardial layer to define the wall segmentation, with manual exclusion of the mitral valve and extension of the left ventricle. The next step is the quantification of fibrosis based on the relative intensity (signal intensity) of LGE. Finally, a 3-dimensional model of the LA is rendered with the maximum enhancement intensities being projected on the model surface. The following color coding is used: healthy tissue is depicted as blue, whereas any tissue with LGE is depicted as green and yellow. LGE ¼ late gadolinium enhancement; MRI ¼ magnetic resonance imaging.

The pulse sequence is acquired 15 to 30 min after

to segment the LA walls from LGE images. Contrast-

administration of 0.1 to 0.2 mmol/kg GBCA. Typical

enhanced magnetic resonance angiography acquired

scan parameters used by the different centers are

at the same cardiac and respiratory phases as 3D LGE-

presented in Table 3.

MRI can be used to simplify segmentation of LA

Besides Corview, 2 other tailored software pack-

endocardial surface. Some groups quantify LA fibrosis

ages are in use to assess atrial fibrosis, Itk-SNAP

analyzing

Version 2.2.0 (10) and QMass MR Software Version

segmented LA walls and relying on expert operator

7.2 (Medis Medical Imaging Systems, Leiden, the

decision to select detection thresholds, which typi-

Netherlands) (11).

cally range from 2 to 4 SDs above the mean for normal

signal

intensity

distribution

of

the

The main difference between the centers per-

myocardium (12–15). Other groups use the LA blood

forming assessment of LA fibrosis is how LGE images

pool as a reference to identify enhanced LA wall

are analyzed to quantify LA fibrosis. The majority of

voxels (11,16–20). The image intensity ratio (IIR)

those centers use manual or semimanual approaches

method proposed by Khurram et al. (17) normalizes

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JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 3, NO. 8, 2017 AUGUST 2017:791–802

Methodology and Clinical Implications of Atrial Fibrosis Imaging

the intensity of the LA wall by the mean value of the blood pool intensity. This approach may reduce

T A B L E 3 Detailed Scan Parameters for LGE Fibrosis Assessment

Field Strength

TR/TE/FA

Voxel Size

DECAAF Centers (12,14)

Center

1.5 T

5.2/2.4/20

1.251.252.5

Beth Israel Center, Boston (75)

1.5 T

5.3/2.1/25

1.31.34.0

Bordeaux, France (13)

1.5 T

6.2/2.4/22

1.251.252.5

CARMA Center, Salt Lake City (15)

1.5 T

5.2/2.4/20

1.251.252.5

Johns Hopkins, Baltimore (11,17)

1.5 T

3.8/1.52/10

1.31.32.0

tify pre-existing LGE, and an IIR >1.61 to identify pre-

King’s College, United Kingdom (20)

1.5 T

5.5/3.0/25

1.31.34.0

existing dense LGE, respectively (17,18). By contrast,

DECAAF Centers (12,14)

3T

3.1/1.4/14

1.251.252.5

a group from Barcelona University has proposed the

Barcelona, Spain (19)

3T

2.3/1.4/11

1.251.252.5

use of an IIR <1.2 to identify healthy atrial myocar-

CARMA Center, Salt Lake City (15)

3T

3.1/1.4/14

1.251.252.5

intraoperator and interoperator variability in quantification of LA fibrosis. However, currently, there is no agreement on what IIR value should be used as the threshold for fibrosis identification. A group from Johns Hopkins University used an IIR >0.97 to iden-

dium, IIR between 1.2 and 1.32 for interstitial fibrosis, and IIR >1.32 for dense scarring (21). The discrepancy

Abbreviations as in Table 2.

in IIR thresholds between the groups may be attributed to the fact that these groups have used scanners

fibrotic and normal tissue because T1 relaxation time

with different field strengths, different contrast

of tissue can change significantly due to contrast

agents, and different time intervals between contrast

clearance (24). Scanners with higher field strength

administration and LGE-MRI scans. All these factors

(clinical use up to 3-T, research up to 9.4-T) might

can change the ratio of image intensities of myocar-

achieve better spatial resolution. Second, it remains a

dium and blood pool. Furthermore, this ratio is

challenge to differentiate between transmural and

dependent on the TI value, the heart rate and rhythm

partial thickness of LA fibrosis due to the limited

during MRI acquisition, a patient-specific contrast

spatial resolution of LGE-MRI scans. Another main

clearance rate, the BMI, blood hematocrit, and

issue in atrial MRI is cardiac and respiratory motion.

oxygenation level.

Because data acquisition for LGE-MRI of atrial walls

REPRODUCIBILITY OF LA FIBROSIS ASSESSMENT.

Interobserver variability of LA fibrosis assessment has been studied by a few groups. The Comprehensive Arrhythmia Research and Management (CARMA) center has reported on inter-observer correlation coefficients in a range of 0.79 to 0.97, which demonstrate

high

reproducibility

with

respect

to

segmentation of LA wall and fibrosis quantification (12,15). Other experienced groups reported a correlation coefficient of 0.93 with respect to quantification of LGE, with a reported interobserver agreement of 0.96 (13). Such high correlation coefficients for observer variability are a reflection of experience in acquisition of good quality LGE-MRI data, accurate segmentation of LA wall, and reproducible fibrosis quantification in high-volume centers.

cannot be performed within a single heart cycle, the data acquisition process has to be ECG-triggered. Modern MRI protocols limit the data acquisition interval to <20% of the RR intervals (120 to 200 ms) with adjustment of the acquisition window duration and position depending on heart rate and rhythm. For gating, the QRS complex has to be accurately detected by the scanner to ensure that data are acquired at the same time of cardiac cycle (25). Data acquisition is performed in atrial diastole to minimize motion artifacts and extend data acquisition duration. In contrast to patients with stable RR intervals (sinus rhythm, atrial flutter), imaging of the left atrium in arrhythmia (atrial fibrillation, premature beats) remains a challenge. For such patients, data acquisition should be performed early after the R-wave, and the duration of the data acquisition window should be

CHALLENGES IN IMAGING OF LA FIBROSIS: WHY

shortened to 10% to 12% of the average RR interval.

ARE POOR IMAGES POOR? Several challenges in

To minimize respiratory motion artifacts, a respira-

atrial fibrosis imaging are of major concern. First,

tory gating algorithm is applied. Conventional breath-

atrial walls (2 to 4 mm) are 2- to 3-fold thinner than

hold imaging with long breath-holds (>10 s) is often

ventricular walls (22). Considering a spatial resolution

challenging for patients with cardiopulmonary dis-

of 1.2 to 1.5 mm of LGE-MRI scans, the partial volume

ease and is not feasible for atrial fibrosis imaging,

effect from surrounding tissue bears the risk of

where high spatial resolution in all 3 dimensions is

wrongly characterizing adjacent tissue as LA wall (23).

required.

To improve spatial resolution, a prolonged acquisi-

Besides these issues, many other factors may affect

tion time may be used, with the limitation of image

image quality and contrast between fibrotic and

artifacts and blurring due to patients’ respiration,

normal myocardium, such as surface coil proximity,

cardiac, and global motion. Further, longer acquisi-

field strength, patient hematocrit, BMI, or dosage of

tion times may result in reduced contrast between

contrast agent (26).

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Methodology and Clinical Implications of Atrial Fibrosis Imaging

T A B L E 4 Available Literature on LGE Fibrosis Imaging

Year

Type of Study

Ablation

Oakes et al. (75)

First Author (Ref. #)

2009

Single center

Yes

Peters et al. (76)

2009

Kuppahally et al. (38)

2010

Single center

Kuppahally et al. (77)

2010

Mahnkopf et al. (37) Akoum et al. (40)

N

Enrollment

Primary Result

LGE MRI is able to assess pre-ablation LA fibrosis

81

12/2006–01/2008

Yes

35

04/2005–05/2007

Yes

68

—

Single center

No

65

06/2006–3/2008

LA wall fibrosis by DE-MRI is inversely related to LA strain and strain rate

2010

Single center

No

333

12/2006–11/2009

The degree of LA structural remodeling as detected using DE-MRI is independent of AF type and associated comorbidities

2011

Single center

Yes

144

11/2006–11/2008

Overall post-ablation LA wall scarring predicts recurrence in moderate fibrosis stages

Daccarett et al. (46)

2011

Multicenter

No

387

McGann et al. (78)

2011

Single center

Yes

37

Recurrence of AF correlates with post-procedural LGE Echocardiographic LA reverse remodeling after catheter is predicted by pre-ablation delayed enhancement of LA by MRI

—

LA fibrosis is associated with a history of stroke

07/2009–01/2010

No-reflow areas in LGE MRI after ablation predict chronic scar formation

Akoum et al. (9)

2012

Single center

No

344

11/2006–11/2009

Significant atrial fibrosis is associated with sinus node dysfunction

Akoum et al. (12)

2013

Single center

No

178

04/2009–09/2010

Atrial fibrosis is associated with LAA thrombi and spontaneous echo contrast

Akkaya et al. (62)

2013

Single center

Yes

384

07/2007/–3/2010

Amount of structural remodeling in AF patients depending on LV systolic dysfunction

Malcolme-Lawes et al. (16)

2013

Multicenter

Yes

50

—

LA scar quantified automatically correlates with colocated endocardial voltage

Bisbal et al. (19)

2014

Single center

No

15

06/2012–03/2013

Harrison et al. (10)

2014

Animal study

Yes

16

—

DE-CMR can identify and localize gaps after PVI

McGann et al. (15)

2014

Single center

Yes

426

12/2006–05/2009

LA remodeling, measured by LGE-MRI, predicts outcome of AF catheter ablation

Marrouche et al. (14)

2014

Multicenter

Yes

329

08/2010–08/2011

Pre-ablation LA fibrosis predicts outcome after catheter ablation of AF (DECAAF trial)

Parmar et al. (79)

2014

Single center

Yes

70

08/2011–12/2012

Electroanatomic mapping overestimates scar assessed by LGE-MRI after AF ablation

Akoum et al. (80)

2015

Multicenter

Yes

177

08/2010–08/2011

LGE-MRI of ablation-induced scarring demonstrates that chronic PV encirclement is rarely achieved

Fukumoto et al. (18)

2015

Single center

Yes

20

04/2010–04/2013

Intensity of LGE can differentiate between ablation-induced and pre-existing atrial scarring

Chrispin et al. (81)

2016

Single center

Yes

9

—

Khurram et al. (82)

2016

Single center

Yes

165

11/2011–12/2013

Chrispin et al. (11)

2017

Single center

No

179

—

Histopathological validation of CMR and endocardial voltage mapping to define acute and chronic atrial ablation injury

AF rotor incidence is not correlated to global or regional extent of atrial LGE LGE >35% predicts early AF recurrence The presence of pre-ablation LA LGE extent was associated with increasing LA volume

AF ¼ atrial fibrillation; CMR ¼ cardiac magnetic resonance; DE ¼ delayed enhancement; LA ¼ left atrial/atrium; LAA ¼ left atrial appendage; LV ¼ left ventricular; PV ¼ pulmonary vein; PVI ¼ pulmonary vein isolation; other abbreviations as in Table 2.

Pooled data from the CARMA center and from

of the left atrium depend on the heart rate and reg-

Cochet et al. (13) reveal that appropriate images for

ularity of heart rhythm. Recent data demonstrate a

quantification of the LA wall can be obtained in 82.7%

significant lower scar visibility in patients with a

to 100% of MRIs. This depends primarily on the heart

tachycardic heart rate (>100 beats/min) (28). In

rhythm (regular vs. irregular) at the time of the MRI

addition, arrhythmia adversely affects image quality

assessment (13–15). In a retrospective analysis of

of LGE-MRI, resulting in LA wall blurring and

DECAAF data, errors of the attending technologist

ghosting artifacts. Therefore, we recommend accu-

were identified as the primary source (62%) of poor

rate rate control or cardioversion before image

quality scans (wrong TI or phase-encoding direction,

acquisition in patients with a tachycardic or irregular

errors in navigator prescription, and partial coverage

heart rate.

of the left atrium). Additionally, 31% of the poor-

In case of hardware issues, the type of scanner has

quality scans were patient-related, and 7% were the

a major impact on the quality of LGE imaging of the

result of hardware issues (27). With respect to

LA. Our analyses of image quality on 1.5- and 3-T

patient-related issues, arrhythmia and irregular res-

scanners revealed poor image quality in 20% of

piratory patterns were causative for poor image

scans acquired by old generations of 1.5-T scanners.

quality at the same rate (each 40%). Both overall

The 3-T or modern 1.5-T scanners with specialized

image quality and fibrosis/scar visibility of LGE-MRI

cardiac coils are preferable for LGE-MRI of LA.

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JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 3, NO. 8, 2017 AUGUST 2017:791–802

With respect to image quality, the DECAAF study

Methodology and Clinical Implications of Atrial Fibrosis Imaging

data suggest a potential regression of structural al-

clearly showed a significant learning curve with the

terations, which is best when AF ablation is per-

number of patients assessed (28). Progress in imaging

formed in early Utah stages (38).

techniques and scanner hardware, as well as better

Those mechanistic insights may provide the hy-

training of MRI technologists, may further improve

pothesis for future cohort and investigational studies

image quality of LGE-MRI of the LA.

assessing progression and reversibility of atrial fibrotic remodeling by interventions.

IMPLICATION OF LA FIBROSIS IMAGING OUTSIDE AND

At the moment, the decision to invasively treat a

INSIDE THE ELECTROPHYSIOLOGY LABORATORY. Atrial

patient for AF is based on symptoms, temporal

fibrosis is a common pathophysiological contributor

behavior of the arrhythmia, age, and comorbidities

to initiation and maintenance of AF. Hence, including

associated with the arrhythmia on presentation

fibrosis imaging into the diagnosis, monitoring,

(34,39). LGE-MRI has been shown to be a powerful

and treatment of AF may be crucial for improvement

predictor for outcome when correcting for other

of outcomes and understanding of disease progres-

confounding factors (14). For patients with higher

sion (29). Table 4 summarizes the available literature

Utah classes (i.e., class III/IV with diffuse and exten-

on LGE-MRI imaging.

sive fibrosis), a conventional, noninvasive approach

The concept of the self-perpetuation of AF (“AF

should be considered because the potential for long-

begets AF”) by structural remodeling is well estab-

term freedom from AF is very low after interven-

lished in animal models (30). Studies in goats have

tional therapy (2,40,41) (Figure 2). In addition,

shown that high-frequency atrial pacing leads to

pre-ablation LGE-MRI can also help in counseling

atrial remodeling with a dedifferentiation of atrial

patients about both expected outcome of catheter

myocytes to a more fetal phenotype (31). In vitro data

ablation and alternative treatment options.

suggest a profound cardiomyocyte–fibroblast interaction regulating myofibroblast function that can

UPSTREAM APPROACHES FOR

result in an increase in atrial interstitial fibrosis (32).

AF TREATMENT

Those fibrotic alterations have been shown to maintain AF and to increase its burden (33).

Therapeutic measures to reduce the risk for AF, such

Clinical outcomes of catheter- and non–catheter-

as blood pressure control, moderate exercise, and

based interventions (34) are still unsatisfactory.

optimization of other comorbidities, have already

Several observations in recent years have led to new

been shown to be effective in certain groups of pa-

mechanistic insights in AF. On the basis of the most

tients (theoretically by reducing the fibrotic burden)

current guidelines of the European Society of Cardi-

(35,42,43). The visualization of an atrial substrate by

ology (35) and a recently published consensus docu-

LGE-MRI offers the chance to determine the effect of

ment (36), the understanding of AF is changing from a

upstream interventions by documentation of pro-

sole rhythm disturbance toward the concept of a

gression or reversal of atrial remodeling. Although

combined rhythm plus atrial cardiomyopathy phe-

not yet conclusively elucidated, fibrosis assessment

nomenon that is well intertwined. The consensus

may also have the potential to further clarify the role

paper characterizes this atrial cardiomyopathy as

of antiarrhythmic effects of nonantiarrhythmic drugs

“any complex of structural, architectural, contractile

in terms of upstream therapy, as already suggested

or electro-physiological changes affecting the atria

for angiotensin-converting enzyme inhibitors (TRACE

with the potential to produce clinically-relevant

[Trandolapril Cardiac Evaluation] study) (44), where

manifestations” (36). Imaging atrial fibrosis using

a direct involvement on a molecular basis is assumed

LGE-MRI may be an option to identify patients at risk

(45). Proper patient selection is mandatory to rein-

for AF before the initiation of the arrhythmia. Cochet

vestigate whether these drugs are beneficial in spe-

et al. (13) demonstrated significant structural changes

cific subgroups, that is, in patients in whom fibrosis is

in atria of non-AF individuals (11.1
4.7% atrial

very likely to develop and contribute to AF, at a point

fibrosis). This extent of fibrosis is consistent with

before fibrosis is too advanced for any further

findings of our center (9%, unpublished data). Data by

rhythm-controlling therapies to be helpful.

Mahnkopf et al. (37) stress the fact that this atrial myopathy/fibrosis may be a precursor for the development of AF by demonstrating that fibrotic atrial

PREDICTING CLINICAL OUTCOME WITH RESPECT TO STROKE AND HEART FAILURE

alterations are already present in the early stages of AF. In order to monitor the effect of invasive ap-

There is increasing evidence for an association of AF,

proaches on structural remodeling, our LGE-MRI

atrial fibrosis, and cardioembolic stroke. Fibrosis

797

798

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JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 3, NO. 8, 2017 AUGUST 2017:791–802

Methodology and Clinical Implications of Atrial Fibrosis Imaging

F I G U R E 2 Management of AF, Guided by Fibrosis Imaging

The flowchart delineates management of patients with atrial fibrillation (AF) by the use of LGE-MRI. With respect to clinical outcome, assessment of temporal fibrosis behavior is a potential parameter to manage patients with AF recurrence after pulmonary vein isolation. Both pre-ablation fibrosis as well as extensive progression of post-ablation fibrosis are associated with low success rates of catheter ablation; those patients should be considered for treatment with a nonablative approach. Abbreviations as in Figure 1.

detected using LGE-MRI has been demonstrated to be

with a rare autosomal recessive disease (atrial dilated

associated with stroke (46). Further data identified

cardiomyopathy) give proof of evidence that the risk

pre-ablation fibrosis burden as a significant risk factor

of stroke might be independently associated with

for the presence of spontaneous echo contrast in

structural fibrotic remodeling in the absence of AF

transesophageal echocardiography (12), adding addi-

(50). Further considerations suggest a potential un-

tional predictive power to already established risk

derlying procoagulative state, mediated by PAR

scores (39,47,48).

signaling, which on the one hand might predispose to

Recent data raise the question of whether there is

thromboembolic events and on the other hand

always a direct causal relationship between stroke

contribute to atrial fibrosis (51). According to these

and AF. The ASSERT (Asymptomatic Atrial Fibrilla-

findings, risk of stroke in AF should be considered a

tion and Stroke Evaluation in Pacemaker Patients and

continuum in which cumulative risk factors have to

the Atrial Fibrillation Reduction Atrial Pacing Trial)

be assessed, and the additional value of fibrosis

showed that stroke events had only a very poor cor-

assessment has to be further investigated in pro-

relation to the time of AF episodes (49), and patients

spective controlled trials (52).

Siebermair et al.

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 3, NO. 8, 2017 AUGUST 2017:791–802

Methodology and Clinical Implications of Atrial Fibrosis Imaging

HEART FAILURE. The association between AF and

might be the preferred option. In case of stable or

heart failure was initially described in 1914 (53).

even regressive fibrotic alterations, another invasive

Today, more than 100 years later, the prevalence of

approach could be considered, including re-isolation

AF in heart failure is estimated to be as high as 13% to

of PVs, connection or homogenization of existing

27% (54). Despite the causal relationship of AF and HF

scar, or performance of additional linear ablations in

being only incompletely understood, AF is suspected

order to reduce risk of macro–re-entrant tachycar-

to be both the cause and consequence of heart failure

dias. Finally, because the requirement of a durable,

(55–57). In most cases, the causal relationship be-

complete PV isolation for long-term AF freedom is

tween congestive heart failure and AF might be

still under discussion, LGE-MRI could help to spe-

driven by ventricular dysfunction that leads to atrial

cifically determine gaps in lesion sets before a redo

fibrosis perpetuating AF (58,59). Wijesurendra et al.

procedure (66). Thus, the MRI data could be used to

(60) demonstrated that depressed LV energetics

successfully guide the repeat procedure.

remain unaltered, independent from restoration of sinus rhythm, suggesting a primary ventricular cause.

FIBROSIS AS AN ABLATION TARGET TO

Atrial fibrosis is considered a key player in the

IMPROVE OUTCOME

development of AF on the basis of heart failure (59,61). Akkaya et al. (62) showed that AF patients

LGE-MRI provides a tool to improve our under-

with heart failure present with a higher degree of

standing of the causal and temporal relationship of

atrial fibrosis on LGE-MRI, further highlighting a

electrical and structural remodeling in the natural

causal relationship between LV dysfunction and atrial

course of AF. Voltage mapping by sampling electrical

structural remodeling leading to AF initiation and

signals from atrial tissue is the gold standard to assess

maintenance. However, human studies on assessing

and stage the extent of atrial fibrosis; this is based

the role of atrial fibrosis in the setting of heart failure

upon the assumption that fibrotic tissue would yield a

are scarce, and further research is warranted.

low voltage signal (67). As early as 1999, Callans et al. (68) described a correlation between electroanatomic

SELECTING APPROPRIATE CANDIDATES FOR

properties and histopathological findings of fibrotic

TREATMENT (RECURRENCE POST-ABLATION)

alterations in porcine animal models. Jadidi et al. (69) and others report a correlation of MRI data and elec-

Because fibrosis reflects the hallmark of structural

trophysiological properties: lower bipolar voltage in

remodeling, assessment of changes of fibrotic alter-

fibrotic areas compared with nonfibrotic tissue.

ations might give new insights into AF treatment

However, the sole consideration of low voltage bears

strategies in case of recurrence after catheter abla-

limitations. For example, slow conduction induced by

tion.

functional

This

is

based

on

echocardiographic

data

alterations,

for

example,

connexin

showing that LA function could improve after surgi-

changes, can mimic low voltage without being related

cal or catheter-based treatment of AF (38,63,64).

to fibrotic remodeling (70).

Therefore, besides the goal of initial proper patient

During the past decade, arbitrary thresholds to

selection, left atrial fibrosis and its progression

define fibrotic areas have been established in clinical

should be considered before and after initial and

practice, a bipolar voltage #0.05 mV has been

repeat ablative therapy (Figure 2). LGE-MRI provides

considered as atrial scar on the basis of baseline

promising results to visualize the temporal behavior

noise in early electroanatomic mapping systems

of atrial fibrosis after ablation by subtracting post-

(10,71). Malcolme-Lawes et al. (16) provide the first

ablation scarring from the total extent of initial

point-by point comparison of fibrosis, assessed by

fibrotic atrial tissue. Interestingly, patients free of AF

LGE-MRI, and colocated endocardial voltage, and

recurrence after catheter ablation showed a signifi-

confirm previous work of Jadidi et al. (69), demon-

cant reduction in LA fibrosis burden in follow-up MRI

strating that increasing levels of LGE correlate with

studies (65). Hypothetically, in the case of extensive

lower voltages. LGE levels of 5 SD above blood pool

post-ablation progression of fibrosis, it might not be

were correlated to 0.38
0.28 mV, indicating that

justified to schedule the patient for another invasive

0.05 mV as an arbitrary threshold might underesti-

procedure unless no other treatment options are

mate the extent of fibrotic areas (16,69). According

available. Currently, various studies are assessing the

to Harrison et al. (10), because ablation-induced

best treatment option in this group of patients. In

scarring reveals a voltage of 0.3 to 0.6 mV, a

general, nonablative management (adequate rate

threshold of #0.05 could significantly underestimate

control either by drugs or atrioventricular node

the extent of ablation injury. This group provides

ablation after permanent pacemaker implantation)

the first histopathological validation of LGE and

799

800

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Methodology and Clinical Implications of Atrial Fibrosis Imaging

endocardial voltage mapping for definition of atrial

DECAAF II trial further investigates this hypothesis

scarring by acute and chronic ablation injury by

and will probably generate additional insights into the

providing signal intensity thresholds for both abla-

role of atrial fibrosis as a potential target for catheter

tion types. According to those studies and our

ablation of AF. This additional information could help

experience, patient-specific cutoff voltage values for

to improve our understanding of the underlying

fibrosis have to be established, and more histopath-

mechanisms driving AF, and could serve as a basis for

ological validation studies for atrial fibrosis are

establishing novel ablation approaches, e.g., ablation

crucial. It has to be validated whether MRI, which

of rotational activity or focal triggers.

offers the option to assess atrial structure in 3D and

In conclusion, atrial fibrosis has to be considered as

not just the endocardial surface as provided by

a potential key factor in the management of AF.

voltage mapping, is able to reliably identify the

Because fibrosis development is a multifactorial pro-

location and transmural extent of fibrotic changes.

cess resulting in complex neurohumoral and cellular

Further, other methods to assess structural changes

interactions (6,73,74), its consideration for AF treat-

have to be investigated, as echo studies could show

ment bears the potential to significantly improve AF

that 3D speckle tracking offers the chance to obtain

understanding and outcomes. Further, MRI as a

information on mechanical and substrate abnormal-

potent noninvasive diagnostic tool allows for follow-

ities (38,72).

up investigations without radiation exposure or risk

Recent data provide increasing evidence that AF

of invasive work-up. Nevertheless, LGE-MRI tech-

might represent more a state of electrical and struc-

niques to assess LA fibrosis require significant

tural remodeling with increased susceptibility to AF

expertise; therefore, further technical improvements

than just the consequence of PV triggers (36,67). This

and more generalized imaging methods have to be

theory is also supported by our data showing that re-

established worldwide. The DECAAF II study will

sidual fibrosis after AF ablation procedure is a strong

probably help to improve the wide adoption of this

predictor of arrhythmia recurrence (41). Nevertheless,

important imaging tool.

available MRI data validating post-ablation PV scarring with repeat EP studies suggest a better clinical

ADDRESS FOR CORRESPONDENCE: Dr. Nassir Mar-

outcome with increasing number of totally isolated

rouche, Comprehensive Arrhythmia Research and

PVs (66). A final conclusion for the data has to be

Management (CARMA) Center, University of Utah,

drawn in order to finally clarify the role of an existing

30 North 1900 East, Room 4A100, Salt Lake City,

causative atrial substrate in AF with a potential for

Utah

therapeutic substrate modification. The ongoing

utah.edu.

84132.

E-mail:

nassir.marrouche@carma.

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KEY WORDS atrial fibrillation, atrial fibrosis, delayed enhancement, LGE-MRI