Magnetic Resonance Imaging for Identifying Patients with...

DOI: 10.1161/CIRCEP.113.000156

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Magnetic Resonance Imaging for Identifying Patients with Cardiac

Sarcoidosis and Preserved or Mildly Reduced Left Ventricular Function at

Risk of Ventricular Arrhythmias

Running title: Crawford et al.; MRI and Outcomes in Cardiac Sarcoidosis

Thomas Crawford, MD1; Gisela Mueller, MD2; Sinan Sarsam, MD3; Hutsaya Prasitdumrong,

MD2; Naiyanet Chaiyen, MD2; Xiaokui Gu, MD, MA1; Joseph Schuller, MD4; Jordana Kron,

MD5; Khaled Nour, MD6; Alan Cheng, MD7; Sang Yong Ji, MD7; Shawn Feinstein, BS5;

Sanjaya Gupta, MD1; Karl Ilg, MD1; Mohamad Sinno, MD1; Saddam Abu-hashish, MD1;

Mouaz AI-Mallah, MD6; William Sauer, MD4; Kenneth Ellenbogen, MD5;

Fred Morady, MD1; Frank Bogun, MD1

1Section of Cardiac Electrophysiology, Division of Cardiovascular Medicine, Department of Internal Medicine, 2Department of Radiology, University of Michigan, Ann Arbor, MI; 3Department of Internal

Medicine, Detroit Medical Center, Detroit, MI; 4Section of Cardiac Electrophysiology, University of Colorado, Denver, CO; 5Department of Cardiac Electrophysiology, Virginia Commonwealth University,

Richmond, VA; 6Division of Cardiology, Henry Ford Hospital, Detroit, MI; 7Section of Cardiac Electrophysiology, Division of Cardiology, Johns Hopkins University, Baltimore, MD

Correspondence:

Thomas Crawford, MD

Cardiovascular Center

The University of Michigan

1500 East Medical Center Drive, SPC 5853

Ann Arbor, MI 48109-5853

Tel: 734-936-6858

Fax: 734-936-7026

E-mail: [email protected]

Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs, [16] Myocardial cardiomyopathy disease, [22] Ablation/ICD/surgery, [30] CT and MRI, [106] Electrophysiology

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DOI: 10.1161/CIRCEP.113.000156

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Abstract:

Background - The purpose of this study was to assess whether delayed enhancement (DE) on

magnetic resonance imaging (MRI) is associated with ventricular tachyarrhythmia (VT/VF) or

death in patients with cardiac sarcoidosis (CS) and left ventricular ejection fraction (LVEF)

>35%.

Methods and Results - 51 patients with CS and LVEF>35% underwent DE-MRI. DE was

assessed by visual scoring and quantified with the full-width at half-maximum method. The

patients were followed for 48.0 20.2 months. 32 of 51 patients (63%) had DE. Forty patients had

no prior history of VT (primary prevention cohort). Among those, 3 patients developed VT and

two patients died. DE was associated with risk of VT/VF or death (p=0.0032 for any DE, and

p<0.0001 for right ventricular DE). The positive predictive values of the presence of any DE,

multifocal DE, and right ventricular DE for death or VT/VF at mean follow-up of 48 months

were 22%, 48%, and 100%, respectively. Among the 11 patients with a history of VT prior to

the MRI, 10 patients had subsequent VTs, one of whom died.

Conclusions - RV DE in patients with CS is associated with a risk of adverse events in patients

with CS and preserved ejection fraction in the absence of a prior history of VT. Patients with DE

and a prior history of VT have a high VT recurrence rate. Patients without DE on MRI have a

very low risk of VT.

Key words: magnetic resonance imaging, sarcoidosis, sarcoid, ventricular tachycardia, death, delayed enhancement, implantable cardioverter-defibrillator

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Cardiac sarcoidosis can present with ventricular arrhythmias and sudden death, even in

asymptomatic patients with normal cardiac function. 1-3 In addition, the progression of cardiac

sarcoidosis can be unpredictable and there are no validated sudden death risk stratification

methods for these patients. For these reasons, implantable cardioverter-defibrillator (ICD)

implantation has been advocated for all patients with cardiac sarcoidosis, regardless of the extent

of myocardial involvement.4

The purpose of this study was to assess whether delayed enhancement (DE) on cardiac

magnetic resonance imaging (MRI) is associated with ventricular tachycardia in patients with

cardiac sarcoidosis and preserved or mildly reduced left ventricular function.

Methods

Multicenter Registry for Cardiac Sarcoidosis

A multicenter registry for the purpose of research collaboration of this rare disease was

established, with the University of Michigan serving as the coordinating center for this study.

This registry was approved by all institutional review boards with data use agreements in place.

Using previously published criteria5, 6, patients who met diagnostic criteria for cardiac

sarcoidosis (CS) were identified. Patients from the University of Michigan, Henry Ford Hospital,

University of Colorado, Johns Hopkins University, and Virginia Commonwealth University were

included. Medical records were reviewed to identify patients who had cardiac MRIs, a left

ventricular (LV) ejection fraction >35%, and at least 6 months of follow-up. Stored electrograms

(EGMs) documenting arrhythmia episodes were reviewed to confirm appropriateness of ICD

therapies (antitachycardia pacing or ICD discharge). Electrocardiograms and stored electrograms

were analyzed and ventricular arrhythmias were classified as monomorphic VT, polymorphic VT,

or ventricular fibrillation (VF). Ventricular arrhythmia in the non-ICD group was defined as

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cardiac arrest, VT lasting at least 30 seconds or requiring defibrillation. VT/VF storm was

3 episodes of VT/VF in a 24-hour period.

Cardiac Magnetic Resonance Imaging (MRI)

All patients underwent cardiac MR imaging including cine imaging of cardiac morphology and

function, and delayed enhanced imaging (DE-MRI). All studies were performed on 1.5 Tesla

scanners (Signa Excite CV/i; General Electric; Milwaukee, Wisconsin; Magnetom Sonata;

Siemens Medical Solutions; Erlangen, Germany, Philips Health Care, Best, The Netherlands).

Cine imaging was performed in ventricular short- and long-axis planes using a segmented 2D

steady-state-free-precession (SSFP) pulse sequence (repetition time, 2.78 - 4.10 ms; echo time,

1.0 - 1.72 ms; in plane resolution (phase; frequency) 256; 256 – 288; 288); Field - of- view 320

– 440 mm; slice thickness, 5-8 mm). Fifteen minutes after administration of 0.20 mmol/kg of

intravenous gadolinium contrast material {Gadopentetate dimeglumine (Magnevist®; Berlex

Pharmaceuticals); Gadoteridol (Prohance®, Bracco Diagnostics); Gadobenate dimeglumine

(MultiHance®, Bracco Diagnostics)}, DE-MRI was performed using an inversion-recovery

prepared gradient echo sequence (repetition time, 3.82- 6.98 ms; echo time, 1.2- 3.36 ms; in

plane resolution (phase: frequency) 256: 256; Field - of- view 320 - 420 mm; slice thickness, 8

mm) in ventricular short- and long-axis planes at matching cine image slice locations. Inversion

times were chosen individually to null the signal of normal myocardium, using Look-Locker

technique for Philips and Siemens, and test scans for GE magnets. Typical inversion times were

250 - 360 ms.

Data Analysis

All DE-MRI images were analyzed off-line (QMASS 7.2.26, Medis, Leiden, the Netherlands) by

two experienced reviewers (HP, GM) blinded to all clinical data. Differences were resolved by

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consensus. First, endocardial and epicardial borders were manually drawn in the short axis view

(Figure 1). The left ventricle was divided into 17 anatomic segments 7 and the right ventricle

into 12 anatomic segments. 8 The presence or absence of delayed enhancement was determined

for each segment by visual scoring. In addition, we quantified the extent of the left ventricular

scar as percentage of the left ventricular mass, using a semi-automated threshold technique the

“Full-Width-Half-Maximum” method (FWHM) 9 (Figure 2): tissue with a signal intensity above

50% of the maximum signal of the enhanced myocardium was quantified as scar tissue.

Statistical analysis:

The analysis was performed with SPSS v. 19 (IBM, Armonk, New York), SAS 9.2 (SAS

Institute Inc., Cary, NC), and R. Continuous variables were expressed as mean 1 standard

deviation (SD). Student’s t-test was used to compare means. Categorical variables were

compared with the Chi-square test or Fisher’s exact test, as appropriate.

Estimates of the positive predictive value, negative predictive value, sensitivity and

specificity at mean follow-up duration of 48 months were obtained from time-dependent ROC

analysis using Kaplan-Meier estimator. To determine optimal cut-off values for the extent of DE

that separated patients with ventricular arrhythmias from patients without ventricular arrhythmias

during follow-up, sets of sensitivity and 1-specificity at month 48 were generated by varying

number of segments with DE and later by varying percentages of LV mass with DE in a separate

analysis. ROC curves were then constructed using these values, and a cut-off was chosen to be

optimal if it had the shortest Euclidean distance to the reference point (0, 1), which represents

100% sensitivity and 100% specificity. 10-12A P value <0.05 was considered statistically

significant. VT/VF free survival was estimated with Kaplan-Meier analysis. Event-free survival

was compared between groups using logrank test. Hazard ratios were calculated with Cox

ork), SASASASASSSS 999.9 2222 (S(S(S(SASASASAS

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regression. The primary endpoint was VT/VF free survival in patients with no VT/VF prior to

the MRI. The secondary endpoint was VT/VF free survival in all patients (primary and

secondary prevention).

Results

Patient Characteristics

In a cohort of 176 patients with cardiac sarcoidosis, 61 patients had both a cardiac MRI and an

ejection fraction >35%. After excluding 5 patients due to un-interpretable MRIs, 3 patients due

to angiographic evidence of transmural infarction not appreciated before the MRI was performed,

and 2 patients due to insufficient follow-up < 6 months, 51 patients were included in the analysis.

Forty patients underwent MRI before the first known occurrence of ventricular tachycardia (VT)

or ventricular fibrillation (VF) and comprised the primary cohort. Eleven patients underwent

MRI following an episode of documented ventricular tachycardia (secondary cohort). Baseline

characteristics of subjects are described in Table 1. Thirty-one patients underwent ICD

implantation (20/40 patients in the primary and 11/11 patients in the secondary cohort). The

recommendation for ICD implantation was at the discretion of the treating physician after

discussion with the patient. Two patients underwent pacemaker implantation.

All patients had biopsy-proven extra-cardiac sarcoidosis and five patients also had

pathology-proven cardiac sarcoidosis (four by endomyocardial biopsy and one after cardiac

transplantation). Forty-one patients had biopsy-proven pulmonary involvement, 3 had a positive

lymph node biopsy, 3 had a positive biopsy of the central nervous system, 2 had a positive skin

biopsy, and one had a positive liver biopsy. The mean age at diagnosis of extra-cardiac

sarcoidosis was 45 years (range 30-65) and the mean age when cardiac involvement was

diagnosed was 49 years (range 24-72).

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The presenting symptoms leading to the screening for and subsequent diagnosis of

cardiac sarcoidosis were palpitations (19), dyspnea (17), syncope (1), cardiac arrest (2), chest

pain (2), and fatigue (1). A seizure occurred in one patient who subsequently was diagnosed with

both cardiac and neuro-sarcoidosis. Nine patients were devoid of any cardiac symptoms at the

time of diagnosis. Thirty patients had functional New York Heart Association (NYHA) class I;

twenty-one patients had a history of congestive heart failure and had a NYHA functional class II

or III. There were no patients with severe heart failure symptoms.

Standard electrocardiography (ECG) revealed complete atrioventricular block in 3

patients, 10 patients with right bundle branch block, 4 patients with left bundle branch block, and

2 with an interventricular conduction block pattern.

Overall, 33 patients were treated with at least one immunosuppressant medication: 24

patients were treated with steroids, 15 patients with methotrexate, 5 with hydrochloroquine, 3

with infliximab, 3 with mycophenolate mofetil, and 1 with cyclophosphamide. Eight patients

were treated with antiarrhythmic medications: 2 patients with amiodarone, 3 with sotalol, 2 with

flecainide, and 1 with dofetilide.

MRI Analysis

Thirty-two of the 51 patients (63%) had DE. 21/40 primary prevention patients had DE on MRI

and all eleven patients in the secondary prevention subgroup had DE (p=0.04). Twenty-four of

31 ICD patients had DE on MRI, while only 8/20 patients who did not undergo ICD implantation

had DE on MRI (p=0.07).

DE was multifocal in 16 patients and unifocal in 16 patients. The delayed-enhanced

tissue involved a mean of 9.3±12.0% of the LV mass (range <1% to 36%). Supplemental Figure

1 shows the distribution of scar burden among the study patients. In 12 patients the burden of DE

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was 1-9%, in 13 patients it was 10-19%, in 3 it was 20-29%, in 2 patients the DE burden was 30-

39%, and in 2 patients it was >40% of the LV mass.

DE was present in a mean of 5.2±5.3 segments in the 17-segment model of the LV, and

in a mean of 1.4±3.2 right ventricular (RV) segments in the 12-segment model of the right

ventricle. DE was found in the septum in 29 patients, in the inferior wall in 25 patients, in the

lateral wall in 24 patients, and in the apex in 2 patients. Thirteen patients had additional RV DE

(RV DE did not occur in any patients without LV DE). Among the 13 patients, the RV base was

involved in 8 patients, the RV mid-portion in 10 patients, and the RV apex in 7 patients. In

patients with RV involvement the LV scar burden was 23.7 16.5 grams (15.0 11.2% LV mass),

and in patients with no RV DE the scar size was 2.7 6.0 grams (7.1 11.5% LV mass), (p<0.01).

Sixteen patients had multifocal left ventricular DE and the scar measured 19.6 15.1 grams

(14.4 10.6% LV mass), and in 16 patients with unifocal DE the scar size was 1.0 0.62 grams

(0.7 2.6% LV mass), (p<0.001).

Delayed Enhancement and Adverse Outcomes:

Primary Prevention Cohort

Among patients with no prior history of VT (primary cohort, n=40), three patients developed

spontaneous VT requiring ICD therapy (antitachycrdia pacing or ICD discharge) during follow-

up, and two patients died. The three VT patients all had DE observed on baseline MRI study

(their LV ejection fractions were 55, 66, and 50%). Of the two patients who died, one patient did

not have DE, and the other did. The cause of death of the patient with DE was a traumatic fall

resulting in massive internal hemorrhage. The cause of death of the patient without DE is

unknown. One patient with DE <1% on MRI developed complete heart block and underwent a

pacemaker implantation 15 months later. None of the patients without DE had VT during follow-

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up.

The presence of any DE (LV or RV) was associated with risk of VT/VF or death

(p=0.0032). The positive and negative predictive values of DE prediction of VT/VF or death at

48 months after MRI were 22% and 100%, respectively.

The presence of right ventricular DE was also associated the combined endpoint of

VT/VF or death (p<0.0001). The sensitivity and specificity of RV DE prediction of VT/VF or

death at 48 months were 67% and 100%, respectively. The positive predictive value and the

negative predictive value of RV DE for the combined endpoint at 48 months were 100% and

97%, respectively. Table 2 shows the sensitivities, specificities, positive and negative predictive

values for VT/VF or death for LV DE, RV DE, any DE, and multifocal DE. Figure 3 shows a

Kaplan-Meier curve for freedom from VT/VF or death in patients with and without RV DE

without a prior history of VT prior to the MRI [primary cohort; P= 0.0032].

Secondary Prevention Cohort

Among patients with a prior history of VT (secondary cohort, n=11), 10 patients had at least one

episode of VT/VF and one of these patients subsequently died from recurrent VT/VF. One

patient in this cohort did not have subsequent VT/VF or atrioventricular block. At 48 months

after the MRI, the sensitivity and specificity for any DE to predict VT/VF or death were 100%

and 0%, respectively, and the positive and negative predictive values were 82% and 0%. The

presence of RV DE had a sensitivity and specificity of 89% and 100% and the positive and

negative predictive values were 100% and 67% for VT/VF prediction, respectively. Table 3

shows patient characteristics in the primary and secondary prevention cohorts.

Qualitative MRI Data and Ventricular Arrhythmia in All Patients

Fourteen of 51 patients (29%) had VT (VT cycle length: 342±91 ms) or VF. All 14 of these

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patients with VT/VF had DE involving the left ventricle in 10.9±3.6 segments. Among them, 14

had septal, 12 had inferior, and 12 had lateral involvement. No specific anatomical location of

DE in the LV was associated with VT/VF. Multifocal DE was present in 11/14 patients with CS

and VT, as compared to 5/37 patients with CS without VT (p-value <0.001). Ten of 14 patients

with VT/VF had RV involvement (5.1±4.2 RV affected segments), only 3 of the 37 patients

without VT/VF had RV involvement (p<0.001).

Qualitative MRI Data and Adverse Events in All Patients

Table 4 indicates qualitative and quantitative measurements of DE with the predictive statistics

for combined adverse events (VT/VF or death) at mean follow-up time of 48 months. The

presence of DE had a positive predictive value of 48% for future adverse events. The PPV was

increased to 70% in the presence of multifocal DE involving the left ventricle and in the presence

of RV involvement the PPV further increased to 100%.

Quantitative MRI Data and Adverse Events in All Patients

All patients with 9 involved segments had VT by 48 months after MRI; only 1 patient in whom

< 9 segments were involved had VT. In this patient 5 segments were involved with DE. Table 5

shows MRI characteristics of patients with and without incident VT. By time dependent ROC

analysis, at 48 months, DE involving >=9 segments on the combined left and right ventricular

segmental analysis resulted in 92% sensitivity and 88% specificity for differentiating patients

with VT/VF from those without VT/VF (area under the curve, 0.90). DE exceeding 6% of the

LV mass was associated with 75% sensitivity and a specificity of 82% for identifying patients

with VT/VF (AUC, 0.79).

LV and RV Function and Volumes

The mean LV ejection fraction was 0.53 0.10 in the primary prevention cohort and 0.46 0.09 in

th the ppredictive ststttatatatatisi

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f DE had a positive predictive value of 48% for future adverse events. The PPV

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ith 9 i l d t h d VT b 48 th ft MRI l 1 ti t i

f DEDEDEDE hhhhadadadad aaa ppososossiiiti ive predictive value of 484848% %% for future aaadvererererses events. The PPV

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the secondary prevention cohort (p=0.04). The LV ejection fraction was similar in patients with

DE and patients without DE (0.52±0.10 versus 0.52±0.09, p=0.93). The mean LV end-diastolic

volume was 172 mL and tended to be larger in patients with DE compared to patients without

DE (194±45 vs. 143±73; p=0.11).

The mean RV ejection fraction was 0.46±0.13 in patients with DE and 0.45±0.07 in

patients without DE (p=0.7). The LV ejection fraction tended to be lower in patients with VT

than patients without VT (48.7±10.1 vs. 53.4±9.4, p=0.3). Patients with VT also had a lower RV

EF than those without VT (39.8±12.9 vs. 46.9±9.8, p=0.217).

Follow-up post MRI

The 51 patients were followed for 48.0 20.2 months after the DE-MRI. Thirty-one patients

underwent ICD implantation (20 patients for primary and 11 patients for secondary prevention).

Two patients underwent pacemaker implantation.

Thirteen patients sustained at least one episode of ventricular tachycardia (cycle length

342±91 ms) or ventricular fibrillation following the MRI. The mean length of follow-up after

ICD implantation was 31 months (range 6-80). Appropriate ICD therapy occurred in 13/32

patients with DE on MRI. In these 13 patients, the number of appropriate ICD therapies ranged

from 1 to 81 (mean 13.4±23.4) during the follow-

episode of VT/VF storm (median 4, mean 13). Monomorphic VT occurred in 12 out of 13

patients. Two patients had at least one episode of polymorphic VT or VF. In one patient, all five

episodes of arrhythmia were polymorphic VT. None of the patients who did not undergo ICD

implantation experienced syncope during follow-up. There were no ventricular high rate

episodes in the two patients with pacemakers.

Immunosuppressive medication was used in all 13 of patients with VT post MRI, but

i s

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irteen patients sustained at least one episode of ventricular tachycardia (cycle len

) i l fib ill i f ll i h MRI Th l h f f ll f

ientntntnts s ss wewwew rererere fffollololowed for 48.0 20.2 monthhhhsss aaafter the DEEE-MRRRRII.I Thirty-one patients

ICICICICDDDD implantaatiion (220 pppaaatientts ffoforr prrimmmarry and dd 11111111 pppatttieeents foor sseece ondadadad ryy ppreveveventr

nts undndnderwent pacemaker iiimplantattttioion.

irteen pppatients ss sustained at least one epipp sode of ventricuulllal r taaaccchycyy ardia (c(( ycycycyclelele len

) i l fib ill i f ll i h MRI Th l h f f ll f


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only in 28/38 patients with no VT (p=0.048). None of the patients without DE had documented

ventricular tachycardia during follow-up.

Discussion

Main Findings

Patients with cardiac sarcoidosis are at risk for VT / VF despite normal or near normal left

ventricular ejection fraction. RV multifocal delayed enhancement is associated with a combined

endpoint of VT/VF or death. However, the presence of a low scar burden determined by DE was

not associated with adverse outcomes. In particular, lack of DE was associated with a low risk of

VT. These findings may help to improve risk stratification in patients with cardiac sarcoidosis.

Risk Stratification of Patients with Cardiac Sarcoidosis

The diagnosis of cardiac sarcoidosis is a class IIa indication for ICD implantation according to

expert consensus as part of the ACC/AHA/HRS guidelines for prevention of sudden cardiac

death.13 In a multicenter study of patients with primary and secondary prevention ICDs most

patients receiving appropriate therapies had an LVEF >35%.14 However, ICD implantation is

associated with life-long device related morbidity and may not be required in most patients. In

addition, the criteria for the diagnosis of cardiac sarcoidosis remain controversial.7, 15 Therefore,

because the presence of DE is associated with VT even in the setting of preserved left ventricular

function, cardiac MRI may be a useful tool for ICD patient selection.

A recent study by Mehta et al. 16 evaluated electrophysiologic testing for risk

stratification in patients with asymptomatic cardiac sarcoidosis. In that study, the majority of

patients with inducible VT had a reduced left ventricular ejection fraction and therefore the

patient population at risk was different than in the present study. The incremental value of

electrophysiologic testing compared to left ventricular ejection fraction is unclear and is not

yy

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findings may help to improve risk stratification in patients with cardiac sarcoido

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sensus as part of the ACC/AHA/HRS guidelines for prevention of sudden cardia

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osiiisss ofofofof cacacacardrdrdrdiaiaiaiacc cc saaaarcrcrcrcoiiiidoddd sisisiissss isisis aaaa clalaaassssss IIIIIII aaaa inininndididicacacacatititit ononon forororor IIIICDCDCDCD iiimpmpmpmplaaantntntntatatatatioioioon acacaccocococ rrdrdr ininining

senssssususus aaas ss papapartrtrt oooof ff f thththt ee e ACACACC/C/C//AHAHAHAHA/A/A/A HRHRHRRSSSS guuuuidididelelelelinininesesess fffforoor pppprerereevevevev ntntntioioioon n nn ofofof ssssudududdedededen n n cacacacardrrr ia

n aa mulu tit ceecentnttere sstututt dydydd oof ff f papatititit ene tsttts wwitititith h hh prp imimii ara y y ana dd d d sesecoconddnddara y y prp evevene tititiiono ICDC ssyy moo by guest on June 21, 2018http://circep.ahajournals.org/

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evaluated in the present study. The present study indicates that DE-MRI might help to improve

risk stratification of patients with the clinical diagnosis of CS who have preserved or mildly

reduced left ventricular function. In our study, the severity of heart failure did not predict

ventricular arrhythmia, although the sample size is too small to draw definitive conclusions.

Late gadolinium Enhancement in Patients with Cardiac Sarcoidosis

Granulomatous infiltration of the myocardium leads to post-inflammatory scarring, and similar

to post-infarction patients, reentry may be facilitated. Both inflammation and scarring can be

identified by MRI. 17, 18 In the 2006 revision of the Japanese Ministry of Health criteria for

cardiac sarcoidosis, DE-MRI was included as a diagnostic imaging technique.19 Patel et al. 7

showed that MRI identified cardiac involvement in 21 out of 81 patients with extra-cardiac

sarcoidosis. In the latter study, the rate of major adverse events (death, defibrillator shock, or

pacemaker requirement) was 9-fold higher in DE-MRI–positive patients than in DE-MRI–

negative patients. The majority of these patients however had an ejection fraction of <35% and

therefore these patients already met criteria for ICD implantation based on prior guidelines15.

Since patients with an ejection fraction <35% were excluded from the present study, the patient

population substantially differs from the patients described by Patel, et al. Unlike in the study by

Patel, et al, patients with and without prior VT were included in this study. Since the MRI

findings were predictive for future adverse events in both patient groups, they were considered

together. Combining both groups is further justified since a large report indicates that secondary

prevention patients with CS have a similar prevalence of VA compared to primary prevention

patients with CS. 20

In contradistinction to the study by Patel, et al, the mere presence of DE was not

associated with adverse outcomes. The positive predictive value of any DE in the present study

of Health criteria fffforororo

chniqquue.e 19191919 PaPaPP tetet ll etetetet aaaall.

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a

hese patients alread met criteria for ICD implantation based on prior g idelines

at MRMRMRMRI I idididdenenentifififieeed cardiac involvement in nn 21221 out of 81 ppppatieeentntntn s with extra-cardiac

s. Innn the latter sttudyyy, theee rrrate oofff mammajorr aaadvverrse evevvvenenenenttst (d(d(deathh, deeeefififibrilllalal ttot rr sshoccckkk,

requuuuiriririremmemementttt)))) was 999 ff-fold ddd hihihih ghgher iiinnn n DEDEDEDE-MRMRMRMRIIII–II popopopositititit vvvve pppatatata ieiii ttnts– thahah nnnn inininin DDDDE-EE MRMRMRMRIIII–

atients. ThThThe mamamaajojojo iiritytyty of ff thhhese papp tiiientts however hhhhaddd an ejejejejectititionooo ffffracttiioi n of fff <3<3<3<35%

hh titi tts llr dd tet itit iia ff IICDCD ii lla tnt tatiio bba dd iio idid leliin


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14

for VT/VF was only 22%, but the predictive value of the MRI increased to about 48% in the

presence of multifocal delayed enhancement. Multifocal delayed enhancement is seen in patients

with larger amounts of scar tissue and therefore it is not surprising that patients with VT more

often had DE involving multiple left and right ventricular segments. A cut-off value of >=9

involved segments separated patients with and without future VTs suggesting that a threshold

effect may be present. Right ventricular involvement appears to be particularly important for

arrhythmogenesis; it was predictive of adverse events in primary prevention patients and for the

group as a whole. The positive predictive value for future adverse events (VT/VF or death) was

100% in the presence of right ventricular involvement. Schuller et al 20 reported that right

ventricular dysfunction in particular was associated with appropriate ICD therapy.

Limitations

This was a retrospective analysis in a small number of patients with CS that were drawn from a

multicenter registry. Limitations inherent to registry patients apply to this study. Arrhythmic

events were more frequent in the secondary prevention group than in the primary prevention

group. ROC cut-off values were determined from both patient groups to distinguish patients with

ventricular arrhythmias from patients without ventricular arrhythmias. It is unclear whether the

MRI data from both secondary and primary prevention populations can be extrapolated to

primary prevention patients.

Not all patients underwent ICD implantation. It is possible that the VF/VF occurrences in

those patients are underestimated, since these arrhythmias can terminate spontaneously.

Since all patients with VT/VF underwent ICD implantation, serial MRIs could not be

performed, and therefore we cannot comment on dynamic changes of the areas of DE over time.

Likewise, patients without ICDs did not undergo serial MRIs, which may have shown changes

nts (V( T/VF or deeatatatath)h)hh

0 repporortettedddd thththth tatatt rrigiggghthththt

n

o

r registry. Limitations inherent to registry patients apply to this study. Arrhythm

e more freq ent in the secondar pre ention gro p than in the primar pre entio

dyyysfsffsfunununu ctctcttioioioonn ininin particular was associatedddd wwith appropriiate ICICICICD therapy.

nssss

retrososoospeepepective anallllysisiii in aaa a ssmsmall ll nunununumbbmbmber offf f paaatitititienenentsststs witittithhh h CSCSCS thtt atttt wwwwere drdd awn ffffro

r regigigistryyy. LiLiLimimimimita iitions inii hheh rentt to regigigistryyy pppattiiie tnts apppplplply y y y to ttthihhih s st dduddy.yy ArArArArrhrhrhhytytyty hm

ff tt iin tthhe dda tntiio thth ii thth iim titi


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15

over time. Due to difficulty with nulling of the RV, it is possible that involvement of the right

ventricle may have been underestimated. In the presence of DE, Patel et al 7 reported a twofold

increase of sensitivity for CS compared to the Japanese Health and Welfare criteria. Not all

patients meeting criteria for CS based on published criteria had DE. Inclusion in this study was

based on the up-dated diagnostic criteria from 2006, 6 which may explain why significant

myocardial scarring determined by the presence of DE was not observed in every patient

diagnosed with CS. Because the MRIs were performed at various stages of the work-up for the

diagnosis of cardiac sarcoidosis, there may be bias related to the timing of the test. Given the

limited timeframe of follow up, patients with lesser degree of DE might have had events

occurring late and not captured within the study period.

Misclassification bias is also a potential limitation of this study. However, if patients with

artifact were included, then this misclassification of myocardial scarring would bias our results

towards no relationship between the presence of DE and subsequent VT/VF.

Conclusions

Patients with cardiac sarcoidosis can have VT/VF despite a normal or near normal left

ventricular ejection fraction. The presence of DE, especially multifocal or in the right ventricle,

is predictive of adverse events in patients with CS and preserved left ventricular function. Lack

of DE is associated with a low risk of VT/VF. Further investigation is needed to determine the

value of DE-MRI for sudden death risk stratification with the use of other testing in patients with

cardiac sarcoidosis.

Funding Sources: Work supported with the generosity of The University of Michigan Cardiovascular Center Inaugural Grant and Boston Scientific Corporation

g g of the test. Givenenenen tth

ht haaveve hhhh ddadad eeveventntttssss

sclassification bias is also a potential limitation of this study. However, if patient

re included, then this misclassification of myocardial scarring would bias our res

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ateeee aaaandndndnd nnnnototot capapappttut red within the study peeeririririodo .

scccclaaaassification bbiasss is alsososo a ppooteneenttial liiimitaatioooonn n ofofoff ttthisss ssstuddy.. HHHHoowevvererere , iif pattttieeent

re inclcclcludududud dded, ththththen ttthihihhis miscccclalalalassificatatatatioiioionn offf myoyocacacacardrdrddiaiaiaal scscsccararriiing wououououldldldld biai s our res

o rellllatiiionshihihip pp bebbb twt een thhhe prpp esence off f DEDEDED anddd s bbubbsequqq eneee t VTVTVTT V/VVVF.FF


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Conflict of Interest Disclosures: None

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Stevevevevenenenensososon n n n LWLWLWW,,, , Sweeney MO, Americannn CCCoollege of Caaardr iooololology F, American Hean n TaTaTaask Forceccece oooon nnn PrrPracacactititiiceccc GGGG,, HeHeHeH ararart tt RhRhRhytyy hmm S. 20200201212121 aacccccccf/f/f/f ahahaha/a/a/a hrs fofofofocucucuc sess d d d upupupupdadadaatet edddd iiiinto the acccf//ahaaa/hhhrs 22200000 8 8 gguidiidelinneees foror deveveviciciceee-e bbasesesed thherapppyy y of ccccarararddiaac rhyhyhythieees:ss AAA repporororort ofof theee aameeeririricacc n coccc lllleege eee ooof carardiolololo oggogyy y founununndattioon/a/a/a/ammmem riiiicacacac n hhearrrt

n taskskkk fffforrororcce on practiititice guiuiuiuidedededellines s ananana d ddd ththththe hhhearrrttt hrhrhrhytytytythmhmhmh ssssociiietttty. CiCiCiC rrrrculatttiiion.e283-3-3--3535352.2.2

H, Hiroe, M,M,MM, IIIIwawawawai,iii, KKKK... GuGuGuGuidiiddelelellinininine fofofofor r rr dididdiagagagagnonononosisiisis s ofofofof ccccararara dididiacacacc ssssararararcocococoididididososososisissis:: StStStStuduuu y reporm didi ThTh JJ MMii ii t ff HH llthh dd WW lflf 19199393 2:233 2424


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, Sauer W, Schuller J, Bogun F, Crawford T, Sarsam S, Rosenfeld L, Mitiku TY,M

Singh JP, Danik S, Markowitz SM, Almquist AK, Krahn AD, Wolfe LG, Feinsn

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Jr Jacobs AK Adams CD Antman EM Anderson JL H nt SA Halperin JL

, Saaaaueueueuerrr W,W,W,W SSchhhuuuller J, Bogun F, Crawfordrdrdrd TT, Sarsam S,,,, Roooseseses nfeld L, Mitiku TY,M, MMMMehta D, GrGrGreeeee nssnspopoponnn n AJAJAJ,,, OrOOrO tmmmanaa MMM,,, Deeluurgggioiooio DDDDB,B, VVVValalaladadadriririr R, ,, NaNaNaNarararar simhmhmhhananan CCC,

SiSiSiSinnngn h JP, Daniik SSS, Marararkkokk wiwiwitttzt SMM, AAAlmmququistttt AKAKAKK, KKrKraaahn ADA ,,, WWoW lffffe eee LGLG, Feeeinnnsn KAKAKA. Efficacacacacyy aanddd ssafetetety y y of iiimpmpmpm laaanttababable caardididid aaac ddddeefibbbrrrir llattorrs fofofofor treaeaeae tmtmt eent ofofof

arrhhhhytytyythmhmhmhmiias inii p ttatiiients wiwiwiwithhthth cardidididiaaaca sarcoidididdosssisisisis. EuEuEuE ropappp ce. 20222 13333;1;1;11555:3444477-7 35353535444.

DP, CCaC mm AAAJJJ, BBBBorggggggreffef MMMM, BuBBB xton AE,EEE CCChahhh ititman B,BBB FFFFromememeer MMM,M GGGGregogogorarararatotootos GMoss AJ, MyMyMyMyererere bubububurgrgrgrg RRRJ,J,J, PPPPrirriiororori iii SGSGSGSG,, , QuQuQuQuininninononononeseseses MMMMA,A,AA, RRRRodododennenn DDDDM,MM,M, SSSSililili kakakka MMMMJ,J,JJ, Tracy C

JJr JJ bob AKAK AdAd CDCD AAnttm EEMM AA dnd JLJL HH tnt SSAA HH lal iri JLJL


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Table 1: Patient Demographics

Characteristic No DE DE P value

Number of patients (N) 19 32

Age (years) 53.3±10.9 49.8±9.9 0.24

Sex (%Male) 15 17 0.08

RaceAfrican AmericanCaucasianHispanic Unknown

8812

161510

0.590.741.00.13

Length of follow-up (months) 53.8±16.9 44.0±21.4 0.10

MRI Parameters:LV EFLV end-diastolic volume (mL) RV EFLV Mass (g)DE (% of LVM)

0.52±0.09 143±73

0.45±0.07 98.6±28.5

0

0.52±0.10 194±45

0.46±0.13 124.5±32.9 14.5±12.1

0.930.110.700.01

<0.0001

HF Class:NYHA functional class INYHA functional class IINYHA functional class IIINYHA functional class IV

10720

201110

0.480.860.54NS

Anti-arrhythmic medication 2 6 0.69

Steroids 12 12 0.08

Non-Steroid Immunosuppressants 8 15 0.74

Atrial Fibrillation 3 3 0.66

Diabetes Mellitus 3 3 0.66

Chronic Kidney Disease 3 6 0.78

COPD 4 2 0.17

Hypertension 10 14 0.54

Dyslipidemia 5 8 0.92Abbreviations: LV – left ventricle, EF – ejection fraction, g – gram, m – meter, LVM – left ventricular mass, , mL – milliliter, DE – delayed enhancement HF – heart failure, NYHA – New York Heart Association, COPD - Chronic Obstructive Pulmonary Disease

2222111.1.4444 000.0.10101010

Fd

Fa

%

0 52±0 09 0 52±0 10 0 93

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Fddd-dd-diiaii stolic vvvolololumuumu e ee (m(m(mL)L)LL)

Fassss (g(g(gg)))

% of LLLLVMVMVM)))

0.52±0±0±0.00.09 1414143±±733

0...45±00.007 98989898.6.6.66±2±2±28.8.8.555

0000

0.52±000±0.1. 0 1919191 4±4±4±45444

000.446±±0..133312224.44.4 5±5±5±5 323232.9999 14141414.5..5±1±1±12.2.2.2 1111

0.930.0.0.111110.7070700.0.0.01010101

<0<0<0.0.0000000 1

AA ffununctctioionanalll l clclllasasss III 1010110 20202020 0.0.4848 by guest on June 21, 2018http://circep.ahajournals.org/

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Table 2: Sensitivity, specificity, positive and negative predictive values of delayed enhancement

for the combined endpoint of VT/VF, death in the primary cohort (n=40) at mean follow-up of

48 months.

Sensitivity SpecificityPositive

Predictive Value

Negative Predictive

Value

AUC(c-statistic)

Any DE 100% 69% 22% 100% 84%

RV DE 67% 100% 100% 97% 83%

LV DE 100% 69% 22% 100% 84%

Multifocal LV DE 67% 94% 48% 97% 80%

Abbreviations: DE – delayed enhancement, RV – right ventricle, LV – left ventricle, VT/VF – ventricular tachycardia/ventricular fibrillation

Table 3: Characteristics of patients from the primary and secondary prevention cohorts

Primary Prevention

N=40

Secondary Prevention

N=11P value

Age (years) 53 10.2 46 9.4 0.04

LV EF (%) 53.6 9.4 46.3 9.1 0.69

RV EF (%) 46.9 9.8 37.1 13.3 0.11

LV mass (g) 111.0 34.2 122.3 31.0 0.34

LV scar tissue (%) 5.63 8.8 21.6 13.3 0.003

Number of LV segments with DE 3.5 4.2 11.7 3.3 0.001

Number of RV segments with DE 0.7 2.4 4.0 4.4 0.033

Abbreviations as above

100% 84844%%

97979797%%%% 80808080%%%%

n nv

C

ns: DDDDEEEE –– dededed lall yeeed ddd enhancement, RV – right vvventn ricle, LV – left vvventricle, VT/VF – venvennenntrrrriici ular fibibibbrrillation

ChChCharacttte iiristststiiics ffof ppp ttatiiie ttntss frffromm ttthehehe pppriirimaryyy andndnd sssece onndaddaryryry pppreve ttntioioion cohhho ttrts


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Table 4: Quantitative and qualitative assessment of DE-MRI predicting adverse outcomes (VT/VF or death) in patients with CS

(primary and secondary prevention patients) at mean follow-up of 48 months

Sensitivity Specificity Positive Predictive Value

Negative Predictive Value

AUC(c-statistic)

Any DE 100% 65% 48% 100% 82%

LV DE 100% 65% 48% 100% 82%

Multifocal LV DE 83% 88% 70% 94% 86%

RV DE 83% 100% 100% 95% 92%

DE Involvement >=9 segments 92% 88% 72% 97% 90%

>=6% of LV DE 75% 82% 58% 91% 79%


88838 % 101010100%0%0%0% 101100%%%0%

9292922%%% 88888888%%%% 72727272%%%%

7575%% 82828282%%%% 5858588%%%%


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Table 5: Characteristics of patients with and without incident VT, controlling for prior history of

VT.

No VT/VF(N = 38)

VT/VF(N = 13) Hazard Ratio P-value

Age 53.2±10.1 44.8±8.8 1.0 (0.9 – 1.0) 0.29

NYHA Class I 23 7 1.0 (0.3 – 3.2) 0.94

NYHA Class II 9 6 2.1 (0.7 – 6.5) 0.20

NYHA Class III 6 0 0 (0 – N/A) 1.0

NYHA Class IV 0 0 N/A N/A

MRI LV EF (%) 53.1±9.4 49.2±10.5 1.0 (0.9 – 1.1) 0.80

MRI RV EF (%) 46.6±9.9 40.3±13.5 1.0 (0.9 – 1.1) 0.91

LV mass (g) 109.3±34.6 124.5±28.7 1.0 (1.0 – 1.0) 0.17

DE (% of LVM) 5.9±9.6 18.5±13.2 1.0 (1.0 – 1.1) 0.28

Number of Segments with DE (left and right ventricles) 3.6±5.0 15.6±6.3 1.1 (1.0 – 1.2) 0.0043


0 (0 N/A) 1

N/N/N/N/AAAA NNNN

0L

F (%) 53 1±9 4 49 2±10 5 1 0 (0 9 1 1) 0

E 0

g 0

f Segments with DE

F (%(%(%(%)))) 53.1±9.4 494949.2±10.5 1.1.1.0 0 (0.9 – 1.1) 0

EFFFF (((%( ) 46666 66.66±999.9 4040.3333±±1± 333.555 111.1 00 (0000.99.9 – 111.1. ) ) 0

g) 1010101 999.9 33±34343434.6666 1212124.444 5±5±5±5±28282828 77.77 1.111 00 00 (1 00.00 –––– 1111.0000) )) 000

LVMMMM)))) 5.55 9±±±±9.99 66 6 181818 5.55±1±1±113.33 2 22 1.111 0 00 (1(1(11 0.000 – 1111.1111) ))) 0

fff SeSegmgmenentsts wwititithhh DEDE


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Figures Legends:

Figure 1: Stack of manually drawn endocardial and epicardial borders in the left ventricular

short axis and automated identification of delayed enhancement in a patient with incessant VT.

Figure 2: Polar view of automated analysis displaying the extent of DE (in percent) in the same

patient illustrated in Figure 1.

Figure 3: Freedom from VT/VF/death in patients with and without RV DE and no history of

VT/VF prior to the MRI (primary cohort) [n=40]. In this group three patients had VT/VF and

two patients died. [P=0.0032]

V DEEEE aandnddd nnoo hihihihiststororororyyyy oddd

o n

t

or totototo ttttheheheh MMMMRIRI (p(p(p( rimary cohort) [n=40]. IIInn n tht is group thhrer e papapap tients had VT/VF an

tssss ddddied. [P=0.000032]]]


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William Sauer, Kenneth Ellenbogen, Fred Morady and Frank BogunFeinstein, Sanjaya Gupta, Karl Ilg, Mohamad Sinno, Saddam Abu-Hashish, Mouaz Al-Mallah,Xiaokui Gu, Joseph Schuller, Jordana Kron, Khaled Nour, Alan Cheng, Sang Yong Ji, Shawn Thomas Crawford, Gisela Mueller, Sinan Sarsam, Hutsaya Prasitdumrong, Naiyanet Chaiyen,

or Mildly Reduced Left Ventricular Function at Risk of Ventricular ArrhythmiasMagnetic Resonance Imaging for Identifying Patients with Cardiac Sarcoidosis and Preserved

Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2014 American Heart Association, Inc. All rights reserved.

Dallas, TX 75231is published by the American Heart Association, 7272 Greenville Avenue,Circulation: Arrhythmia and Electrophysiology

published online September 29, 2014;Circ Arrhythm Electrophysiol.

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Supplemental Material Supplemental Figure 1: Bar graph showing distribution of scar burden in the patient cohort.

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